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Evaluation of methods to generate substituted tetrahydroxanthone ring systems : DMAP promoted cycloisomerizations Castillo Contreras, Emmanuel Benigno 2015

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Evaluation of Methods to Generate Substituted Tetrahydroxanthone RingSystems: DMAP Promoted CycloisomerizationsbyEmmanuel Benigno Castillo ContrerasB. Sc., Universidad Auto´noma del Estado de Me´xico, 2007a thesis submitted in partial fulfillmentof the requirements for the degree ofDoctor of Philosophyinthe faculty of graduate and postdoctoral studies(Chemistry)The University of British Columbia(Vancouver)January 2015c© Emmanuel Benigno Castillo Contreras, 2015AbstractThis dissertation presents investigations on the synthesis of polyoxygenated tetrahydroxanthone ring systems.Chapter 1 provides a brief overview of the family of naturally occurring compounds called xanthones. Theclassification, isolation, biological properties and the synthetic approaches to this family of compounds isincluded. Because the work of this dissertation was inspired by the tetrahydroxanthone unit embedded insimaomicin α (1.1), a detailed review of the synthetic methods available to access tetrahydroxanthone unitsis presented.Chapter 2 describes eight synthetic approaches that were investigated to construct substituted tetrahy-droxanthones. A stereospecific intramolecular [3+2] dipolar cycloaddition of nitrile oxides resulted in thesynthesis of novel fused tetracyclic isoxazolines, tetracyclic isoxazoles, and aminotetrahydroxanthones. Anintramolecular hydroacylation promoted by N-heterocyclic carbenes produced substituted tetrahydroxan-thones and hexahydroxanthones.Chapter 3 describes the successful synthesis of polyoxygenated tetrahydroxanthones through a 4-dimethyl-aminopyridine-promoted cycloisomerization of o-alkynoylphenol derivatives. It is proposed that the cycloi-somerization is initiated by the 1,4-addition of DMAP, followed by either a Morita-Baylis-Hillman-typealdol reaction, or deprotonation of the phenol. However, the actual mechanism remains unknown. Thecycloisomerization of o-alkynoylphenol derivatives was useful in the synthesis of 1,4,5-trioxygenated or 1,5-dioxygenated tetrahydroxanthones with variable substituents at position 7. The diastereoselectivity of thereaction modestly favoured the trans-isomer.iiPrefaceA portion of the research reported in Chapter 2 was published in 2014: Emmanuel B. Castillo-Contreras,Alexander M. Stahl and Gregory R. Dake. “Annulated Isoxazoles via [3 + 2] Cycloaddition of AlkenylBromides and Oximoyl Chlorides and Ag(I) Promoted Elimination.” J. Org. Chem. 2014, 79, 7250–7255.Professor Gregory Dake wrote the manuscript. I wrote the experimental section of the paper and I wroteChapter 2 in its entirety. I performed all of the synthesis and almost all of the characterization. Compound2.149a was crystallized by undergraduate research student Alexander Stahl. UBC Professional Officer BrianO. Patrick performed X-Ray crystallographic analyses.A portion of the research reported in Chapter 3 was published in 2014: Emmanuel B. Castillo-Contrerasand Gregory R. Dake. “DMAP Promoted Tandem Addition Reactions Forming Substituted Tetrahydroxan-thones.” Org. Lett. 2014, 16, 1642–1645. Professor Gregory Dake wrote the manuscript. I wrote all theexperimental section of the paper and I wrote Chapter 3 in its entirety. I performed all of the synthesis andcharacterization. UBC PhD Candidate Spencer Serin performed X-Ray crystallographic analyses.iiiTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiiList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xList of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviiList of Abbreviations and Symbols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xviiiAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxivDedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvi1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 General Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Xanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2.1 Xanthone Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2.2 Classification of Xanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3 Fully Aromatic Xanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.3.1 Synthetic Approaches to Fully Aromatic Xanthones . . . . . . . . . . . . . . . . . . 71.4 Partially Saturated Xanthones: Dihydroxanthones and Hexahydroxanthones . . . . . . . . . 91.4.1 Synthetic Approaches to Dihydroxanthones and Hexahydroxanthones . . . . . . . . 101.5 Partially Saturated Xanthones: Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . 11ivTable of Contents1.5.1 Polycyclic Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131.5.1.1 Simaomicin α: Isolation and Characterization . . . . . . . . . . . . . . . 141.5.1.2 Simaomicin α: Biological Properties . . . . . . . . . . . . . . . . . . . . 161.5.1.3 Analysis of the partially saturated Ring of Polycyclic Tetrahydroxanthones 171.6 Synthetic Approaches to Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . . . . 181.6.1 Total Synthesis of ent-Simaomicin α . . . . . . . . . . . . . . . . . . . . . . . . . 181.6.2 [4+2] Cycloaddition of 2-Styrylchromenones . . . . . . . . . . . . . . . . . . . . . 211.6.3 Addition of Cyclic Enamines to Salicylaldehydes . . . . . . . . . . . . . . . . . . . 231.6.4 Lithium Enolate Addition to Acetylsalicyl Chloride . . . . . . . . . . . . . . . . . . 241.6.5 Oxidative Rearrangement of Spirochromanones . . . . . . . . . . . . . . . . . . . . 251.6.6 Fries Rearrangement Followed by Nucleophilic Aromatic Substitution . . . . . . . . 261.6.7 [4+2] Cycloaddition of Chromenones and Dienes . . . . . . . . . . . . . . . . . . . 261.6.8 Conjugate Addition/Aldol Cascade Sequence . . . . . . . . . . . . . . . . . . . . . 281.6.9 Intramolecular Dieckmann Condensation of Chromanones . . . . . . . . . . . . . . 301.6.10 Vinylogous Addition of Siloxyfurans to Benzopyryliums . . . . . . . . . . . . . . . 311.6.11 Sequential Palladium-Catalyzed C–O, C–C Bond Formation . . . . . . . . . . . . . 321.6.12 Tetrahydroxanthone Construction Within Total Syntheses . . . . . . . . . . . . . . . 331.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinonesand Tetracyclic Isoxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362.1 Synthesis of Isoquinolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372.2 Efforts Towards Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402.2.1 Oxa-Michael/Claisen Cascade Sequence . . . . . . . . . . . . . . . . . . . . . . . . 412.2.2 2,6-Dibromobenzoquinone Route . . . . . . . . . . . . . . . . . . . . . . . . . . . 452.2.3 Intermolecular Nitrile Oxide [3+2] Dipolar Cycloaddition . . . . . . . . . . . . . . 492.2.3.1 Preparation of Nitrile Oxide Precursors: Synthesis of Oximoyl Chlorides . 502.2.3.2 Synthesis of Dipolarophiles for [3+2] Dipolar Cycloadditions . . . . . . . 542.2.3.3 [3+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . 552.2.3.4 Reductive Cleavage of the N–O Bond of Isoxazolines and Isoxazoles . . . 622.2.3.5 Attempts to Form the Pyran ring of Tetrahydroxanthones: IntramolecularBuchwald-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 64vTable of Contents2.2.3.6 Attempts to Form the Pyran Ring of Tetrahydroxanthones: Keto/PhenolCondensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662.2.4 Intramolecular Nitrile Oxide [3+2] Dipolar Cycloaddition . . . . . . . . . . . . . . 682.2.4.1 Synthesis of Bromocyclohexenyl Phenyl Ethers . . . . . . . . . . . . . . . 692.2.4.2 [3+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . 712.2.4.3 Synthesis of Tetracyclic Isoxazoles and Aminotetrahydroxanthones . . . . 732.2.5 Intramolecular [3+2] Cycloaddition of N-Benzyl Nitrones . . . . . . . . . . . . . . 752.2.6 Miscellaneous Attempts for the Synthesis of Tetrahydroxanthones . . . . . . . . . . 772.2.6.1 [4+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . 772.2.6.2 Nozaki-Hiyama-Kishi-type Attempts . . . . . . . . . . . . . . . . . . . . 782.2.6.3 Intramolecular Nucleophilic Addition of Vinyl Bromides Using Palladium(0) 782.2.6.4 Intramolecular N-Heterocyclic Carbene Catalysis . . . . . . . . . . . . . 802.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842.4 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852.4.1 General Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852.4.2 Synthesis of Isoquinolinone 2.13b and Derivatives . . . . . . . . . . . . . . . . . . 862.4.3 Synthesis of Xanthone 2.56 and Derivatives . . . . . . . . . . . . . . . . . . . . . . 902.4.4 Intermolecular [3+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . 962.4.4.1 Synthesis of Benzaldehydes 2.81 and 2.187 . . . . . . . . . . . . . . . . . 962.4.4.2 Synthesis of Oximoyl Chlorides . . . . . . . . . . . . . . . . . . . . . . . 982.4.4.3 Preparation of Dipolarophiles . . . . . . . . . . . . . . . . . . . . . . . . 1002.4.4.4 Intermolecular [3+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . 1032.4.4.5 Attempts to Convert Isoxazolines and Isoxazoles into TetrahydroxanthoneDerivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082.4.5 Intramolecular [3+2] Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . 1102.4.5.1 Synthesis of Bromocyclohexenyl Phenyl Ethers . . . . . . . . . . . . . . . 1112.4.5.2 Synthesis of 2-((2-Bromocyclohex-2-en-1-yl)oxy)benzaldehyde Oximes . 1142.4.5.3 Synthesis of Bromoisoxazolines . . . . . . . . . . . . . . . . . . . . . . . 1182.4.5.4 Synthesis of Isoxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212.4.5.5 Synthesis of Vinylogousamides . . . . . . . . . . . . . . . . . . . . . . . 1252.4.6 Intramolecular [3+2] Cycloaddition of N-Benzyl Nitrones . . . . . . . . . . . . . . 1262.4.7 Miscellaneous Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127viTable of Contents3 Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations 1313.1 Reported Cycloisomerizations of Phenolic Nucleophiles to Ynones . . . . . . . . . . . . . . 1333.1.1 Synthesis of Chromenones Using Basic or Acidic Conditions . . . . . . . . . . . . . 1333.1.2 Synthesis of Chromenones Using Electrophiles or Nucleophiles . . . . . . . . . . . 1363.1.3 Synthesis of Chromenones Using Metal Catalysis . . . . . . . . . . . . . . . . . . . 1383.2 Synthesis of o-Alkynoylphenol Derivatives 3.65a and 3.65b . . . . . . . . . . . . . . . . . 1413.3 Synthesis of o-Alkynoylphenol Derivatives 3.75a, 3.75b, and 3.75c . . . . . . . . . . . . . . 1443.4 Synthesis of Polyoxygenated Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . . 1473.4.1 Cycloisomerization of Methoxymethyl Ethers 3.65a and 3.75a . . . . . . . . . . . . 1473.4.2 Cycloisomerization of o-Alkynoylphenol Derivative 3.66a . . . . . . . . . . . . . . 1493.4.3 Synthesis of Tetrahydroxanthone Derivatives 3.89 . . . . . . . . . . . . . . . . . . . 1523.5 Reaction Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1583.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1623.7 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1633.7.1 General Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1633.7.2 Synthesis of o-Vanillin Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 1633.7.3 Synthesis of Ynones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643.7.3.1 Synthesis of Ynones 3.62 . . . . . . . . . . . . . . . . . . . . . . . . . . 1663.7.3.2 Synthesis of Ynones 3.66 . . . . . . . . . . . . . . . . . . . . . . . . . . 1703.7.3.3 Synthesis of Ynone 3.79 . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833.7.4 Synthesis of Tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873.7.5 NMR Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1934 Conclusions and Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954.1 Chapter 2: Conclusions and Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . 1964.2 Chapter 3: Conclusions and Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204Appendix A Selected Spectra for Chapter 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Appendix B Selected Spectra for Chapter 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Appendix C X-ray Crystallographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339viiList of TablesTable 1.1 Biological activity of simaomicin α against bacteria and fungi . . . . . . . . . . . . . 16Table 1.2 In vitro antimalarial activity against Plasmodium falciparum strains K1 and FCR3 ofsimaomicin α and other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Table 2.1 Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldolcondensation of methyl salicylate and 2.25 . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Table 2.2 Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldolcondensation of methyl salicylate and 2.30 . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Table 2.3 Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldolcondensation of salicylaldehyde and cyclohexenone derivatives 2.37 . . . . . . . . . . . . . 44Table 2.4 Attempted coupling of 2.49 with methyl 2.50 . . . . . . . . . . . . . . . . . . . . . . 46Table 2.5 Condensation of methyl salicylate and 2,6-dibromobenzoquinone . . . . . . . . . . . 47Table 2.6 Synthesis of selected oximoyl chlorides . . . . . . . . . . . . . . . . . . . . . . . . . 53Table 2.7 Evaluation of conditions for the cleavage of the N–O bond of isoxazoline 2.117 . . . . 63Table 2.8 Attempted ketone/aromatic bromide coupling of isoxazoline 2.117 . . . . . . . . . . 65Table 2.9 Attempted conditions to cyclize isoxazoline 2.128 into 2.129 . . . . . . . . . . . . . 67Table 2.10 Activation of 2.95a towards second-order nucleophilic substitution (SN2) . . . . . . . 70Table 2.11 Alkylation of o-vanillin using allylic bromocyclohexene electrophiles . . . . . . . . . 70Table 2.12 Evaluation of dehydrobromination conditions for bromoisoxazoline 2.147a . . . . . . 72Table 2.13 Synthesis of fused tetracyclic isoxazoles 2.149 . . . . . . . . . . . . . . . . . . . . . 74Table 2.14 Evaluation of conditions for the intramolecular nucleophilic addition of alkenyl bro-mide 2.144b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Table 2.15 Evaluation of bases for the intramolecular nucleophilic addition of alkenyl halidesusing palladium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80viiiList of TablesTable 2.16 Synthesis of hexahydroxanthones and tetrahydroxanthones via N-heterocyclic car-bene (NHC) catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Table 3.1 Intramolecular cycloisomerization of o-alkynoylphenols promoted by nucleophiles . . 137Table 3.2 4-dimethylaminopyridine (DMAP)-Promoted cycloisomerization of o-alkynoylphenolderivatives: solvent effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Table 3.3 Screening of reagents for the cycloisomerization of 3.75a into tetrahydroxanthones3.84a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Table 3.4 Cycloisomerization of o-alkynoylphenol derivative 3.66a using inorganic bases . . . . 150Table 3.5 Cycloisomerization of o-alkynoylphenol derivative 3.66a into tetrahydroxanthones3.84a and chromenone 3.85a using organic bases and nucleophiles . . . . . . . . . . . . . . 151Table C.1 X-ray crystallographic data for compounds 2.103a, 2.149a, and 2.153b . . . . . . . . 339Table C.2 X-ray crystallographic data for compounds 2.103a, 2.149a, and 2.153b . . . . . . . . 341ixList of FiguresFigure 1.1 Simaomicin α, a type II polyketide . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Figure 1.2 Xanthone skeleton and numbering . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Figure 1.3 Xanthone biosynthetic pathway in plants . . . . . . . . . . . . . . . . . . . . . . . . 3Figure 1.4 Fungi: biosynthetic pathway of xanthones . . . . . . . . . . . . . . . . . . . . . . . 4Figure 1.5 Degree of hydrogenation of xanthones . . . . . . . . . . . . . . . . . . . . . . . . . 5Figure 1.6 Examples of di, tetra and hexahydroxanthones . . . . . . . . . . . . . . . . . . . . . 5Figure 1.7 Representative fully aromatic simple xanthones . . . . . . . . . . . . . . . . . . . . 6Figure 1.8 Representative polycyclic fully aromatic xanthones . . . . . . . . . . . . . . . . . . 7Figure 1.9 Representative dihydroxanthones and hexahydroxanthones . . . . . . . . . . . . . . 9Figure 1.10 Representative monomeric tetrahydroxanthones . . . . . . . . . . . . . . . . . . . . 12Figure 1.11 The tetrahydroxanthones: Representative dimeric tetrahydroxanthones . . . . . . . . 12Figure 1.12 The tetrahydroxanthones: Representative polycyclic tetrahydroxanthones . . . . . . 13Figure 1.13 The simaomicins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Figure 1.14 ORTEP figure of simaomicin α, taken from Lee et al . . . . . . . . . . . . . . . . . 15Figure 1.15 Analysis of the partially saturated ring of naturally-occurring tetrahydroxanthones . . 18Figure 2.1 Structure of simaomicin α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Figure 2.2 Aldol functionality embedded in the structure of tetrahydroxanthone 2.3 . . . . . . . 50Figure 2.3 Dipolarophiles selected for treatment with nitrile oxides . . . . . . . . . . . . . . . 54Figure 2.4 Solid state molecular structure of compound 2.103a, ellipsoids at 30% . . . . . . . . 57Figure 2.5 Comparison of the 13C NMR spectra of reported isoxazoles with 2.107 . . . . . . . 59Figure 2.6 Regiochemistry of the [3+2] cycloaddition of nitrile oxides and substituted dipo-larophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Figure 2.7 Attempted [3+2] dipolar cycloaddition between nitrile oxide precursor 2.88 and 2.118 62xList of FiguresFigure 2.8 Solid state molecular structure of isoxazole 2.149a, ellipsoids at 30% . . . . . . . . 72Figure 3.1 a) Literature approaches for the synthesis of tetrahydroxanthones. b) Our approachto tetrahydroxanthones to build the E and F rings in the same reaction vessel . . . . . . . . . 132Figure 3.2 Intramolecular addition of phenolic nucleophiles to alkynes, 5-exo-dig vs 6-endo-digmode of cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Figure 3.3 Characteristic 1HNMRsignals of tetrahydroxanthones 3.84a-t and 3.84a-c and chromenone3.85a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Figure 3.4 Solid state molecular structure of compound 3.89b. Ellipsoids at 30% probability . . 154Figure 3.5 Assignment of the trans and cis structure of compounds 3.89a-t and 3.89a-c by com-parison with the 1H NMR signals of compounds 3.89b-t and 3.89b-c . . . . . . . . . . . . . 155Figure 3.6 Solid state molecular structure of compound 3.89c . . . . . . . . . . . . . . . . . . 156Figure 3.7 Solid state molecular structure of compounds 3.89b-t and 3.89c . . . . . . . . . . . 163Figure 4.1 Solid state molecular structure of compound 3.89b-t . . . . . . . . . . . . . . . . . 201Figure C.1 Compound 2.103a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340Figure C.2 Compound 2.149a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340Figure C.3 Compound 2.153b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340Figure C.4 Compound 3.89b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Figure C.5 Compound 3.89c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342xiList of SchemesScheme 1.1 The Grover, Shah and Shah method to synthesize xanthones . . . . . . . . . . . . . 8Scheme 1.2 Classical methods to xanthones: via biaryl and via benzophenone . . . . . . . . . . 8Scheme 1.3 Tatsuda’s total synthesis of nidulalin A . . . . . . . . . . . . . . . . . . . . . . . . 10Scheme 1.4 Synthesis of hexahydroxanthones using BCl3 . . . . . . . . . . . . . . . . . . . . . 11Scheme 1.5 Merchant’s synthesis of hexahydroxanthones . . . . . . . . . . . . . . . . . . . . . 11Scheme 1.6 Biosynthetic route of simaomicin α . . . . . . . . . . . . . . . . . . . . . . . . . . 15Scheme 1.7 En route to ent-simaomicin α: Constructing the tetrahydroxanthone framework . . 19Scheme 1.8 Ready’s construction of the tetrahydroxanthone core . . . . . . . . . . . . . . . . . 19Scheme 1.9 En route to ent-simaomicin α: Joining together the AB and DEF fractions . . . . . 20Scheme 1.10 Ready’s total synthesis of simaomicin α . . . . . . . . . . . . . . . . . . . . . . . 21Scheme 1.11 [4+2] Cycloaddition of 2-styrylchromenones . . . . . . . . . . . . . . . . . . . . . 22Scheme 1.12 [4+2] Cycloaddition of 2-styrylchromenones and enamines . . . . . . . . . . . . . 22Scheme 1.13 [4+2] Cycloaddition of 3-styrylchromenones and conjugated aldehydes . . . . . . . 23Scheme 1.14 Addition of cyclic enamines to salicylaldehydes . . . . . . . . . . . . . . . . . . . 23Scheme 1.15 Addition of cyclic enamines to acetylsalicyl chloride . . . . . . . . . . . . . . . . . 24Scheme 1.16 Lithium enolate addition to acetylsalicyl chloride . . . . . . . . . . . . . . . . . . 24Scheme 1.17 Oxidative rearrangement of spirochromanones . . . . . . . . . . . . . . . . . . . . 25Scheme 1.18 Fries rearrangement followed by nucleophilic aromatic substitution . . . . . . . . . 26Scheme 1.19 Resonance forms of γ-pyrone derivatives . . . . . . . . . . . . . . . . . . . . . . . 26Scheme 1.20 [4+2] cycloaddition of electron deficient chromenones . . . . . . . . . . . . . . . . 27Scheme 1.21 Enantioselective [4+2] cycloaddition of electron deficient chromenones . . . . . . . 27Scheme 1.22 [4+2] cycloaddition of chromenones: proposed transition state . . . . . . . . . . . 28Scheme 1.23 Condensation of cyclohexenone and salicylaldehyde . . . . . . . . . . . . . . . . . 28Scheme 1.24 Condensation of cyclohexenone and salicylaldehyde: Proposed mechanistic pathways 29xiiList of SchemesScheme 1.25 Condensation of cyclohexenone and salicylaldehyde: Effect of substituents . . . . . 30Scheme 1.26 Condensation of cyclohexenone and salicyl N-tosylamine . . . . . . . . . . . . . . 30Scheme 1.27 Dieckmann condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Scheme 1.28 Vinylogous addition of siloxyfurans to benzopyryliums . . . . . . . . . . . . . . . 32Scheme 1.29 Tandem Buchwald-Hartwig-type/Suzuki-Miyaura method . . . . . . . . . . . . . . 33Scheme 1.30 Nicolaou’s total synthesis of blennolide C . . . . . . . . . . . . . . . . . . . . . . 33Scheme 1.31 Porco’s total synthesis of kibdelone C . . . . . . . . . . . . . . . . . . . . . . . . . 34Scheme 1.32 Construction of the tetrahydroxanthone core . . . . . . . . . . . . . . . . . . . . . 35Scheme 2.1 One retrosynthetic analysis of simaomicin α . . . . . . . . . . . . . . . . . . . . . 37Scheme 2.2 Retrosynthetic analysis of isoquinolinone 2.2 . . . . . . . . . . . . . . . . . . . . . 38Scheme 2.3 Attempt to synthesize the AB rings of simaomicin α . . . . . . . . . . . . . . . . 38Scheme 2.4 Synthesis of the AB rings of simaomicin α . . . . . . . . . . . . . . . . . . . . . 39Scheme 2.5 Synthesis of 4-formyl-2,5-dimethoxybenzoic acid (2.15) . . . . . . . . . . . . . . . 39Scheme 2.6 Synthesis of 4-formylbenzamide 2.16 . . . . . . . . . . . . . . . . . . . . . . . . . 39Scheme 2.7 Construction of epoxide 2.18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Scheme 2.8 Proposed routes for the synthesis of tetrahydroxanthones . . . . . . . . . . . . . . . 40Scheme 2.9 (a) Synthesis of tetrahydroxanthones performed by Bra¨se and co-workers. (b) Pro-posed synthesis of the tetrahydroxanthone core via an oxa-Michael/aldol cascade sequence . 41Scheme 2.10 Synthesis of 3-hydroxycyclohex-1-ene-1-carbonitrile (2.25) . . . . . . . . . . . . . 42Scheme 2.11 Synthesis of 3-(phenylsulfonyl)cyclohex-2-en-1-ol (2.30) . . . . . . . . . . . . . . 43Scheme 2.12 Attempt to condense sulfonyl methoxycyclohexene 2.35 with ethyl salicylate . . . . 44Scheme 2.13 Attempt to make 1-oxotetrahydroxanthone . . . . . . . . . . . . . . . . . . . . . . 45Scheme 2.14 Resonance forms of compounds 1.161 and 2.37a . . . . . . . . . . . . . . . . . . . 45Scheme 2.15 (a) Kelly synthesis of xanthones. (b) Proposed route to tetrahydroxanthones . . . . 46Scheme 2.16 Reaction mechanism of the addition of salicylate to 2,6-dibromobenzoquinone . . . 48Scheme 2.17 Synthesis of 3-Bromo-1,4-dihydroxyxanthone . . . . . . . . . . . . . . . . . . . . 48Scheme 2.18 Failed attempt to couple DEF rings and epoxide 2.18 . . . . . . . . . . . . . . . . 49Scheme 2.19 (a) Reported sequence for the synthesis of β-hydroxy ketones using nitrile oxides.(b) Proposed synthesis of tetrahydroxanthones using [3+2] dipolar cycloaddition . . . . . . . 50Scheme 2.20 Formal oxidation of aldoximes to obtain nitrile oxides . . . . . . . . . . . . . . . . 51Scheme 2.21 Nitrile oxide precursors: Synthesis of oximoyl chlorides . . . . . . . . . . . . . . . 51Scheme 2.22 Mechanistic rationale for the formation of oximoyl chlorides . . . . . . . . . . . . . 52xiiiList of SchemesScheme 2.23 Synthesis of 6-bromo-2,5-dimethoxybenzaldehyde . . . . . . . . . . . . . . . . . . 52Scheme 2.24 Synthesis of dipolarophiles following literature procedures . . . . . . . . . . . . . 55Scheme 2.25 Attempt to synthesize isoxazoline 2.100 . . . . . . . . . . . . . . . . . . . . . . . 55Scheme 2.26 Attempted [3+2] dipolar cycloaddition between nitrile oxide precursor 2.85 and 2-bromo-2-cyclohexen-1-ol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Scheme 2.27 [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.84 and bicyclo alkene2.92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Scheme 2.28 [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.85 and bicyclo alkene2.92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Scheme 2.29 [3+2] Dipolar cycloaddition of nitrile oxide precursor 2.85 and 2-bromo-2-cyclohexen-1-one . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Scheme 2.30 [3+2] Dipolar cycloaddition reactions of nitrile oxide precursor 2.86 and cyclo-hexenone derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Scheme 2.31 [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.87 and cyclohexenone 60Scheme 2.32 [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.88 and alkene 2.92 . 61Scheme 2.33 [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.88 and cyclohexenonederivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Scheme 2.34 Attempted isoxazoline reactive cleavage using iron and ammonium chloride . . . . 62Scheme 2.35 (a) Intramolecular Buchwald-Hartwig-type/Suzuki-Miyaura coupling (b) Proposedroute for the synthesis of tetrahydroxanthones via intramolecular Buchwald-type cyclizationfollowed by reductive isoxazoline cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Scheme 2.36 (a) Synthesis of tetrahydroxanthenes by Ramachary and co-workers. (b) Proposedsynthesis of tetracyclic isoxazoline 2.129 under acidic conditions . . . . . . . . . . . . . . . 66Scheme 2.37 The synthesis of 2.132 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Scheme 2.38 Proposed route for the synthesis of tetrahydroxanthones via intramolecular [3+2]dipolar cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Scheme 2.39 Intramolecular [3+2] cycloaddition of nitrile oxides: Synthesis of isoxazoline 2.147a 71Scheme 2.40 Reaction mechanism for the formation of 2.150a . . . . . . . . . . . . . . . . . . . 72Scheme 2.41 Reductive cleavage of isoxazole 2.149a . . . . . . . . . . . . . . . . . . . . . . . . 73Scheme 2.42 Synthesis of vinylogous amide 2.153b and its solid state molecular structure. Ellip-soids at 30% probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74Scheme 2.43 Attempted cleavage of the N–O bond of isoxazoline 2.147b . . . . . . . . . . . . . 75xivList of SchemesScheme 2.44 (a) Synthesis of hexahydroxanthone 2.158. (b) Proposed route for the synthesis of1-hydroxy tetrahydroxanthones via [3+2] cycloaddition of nitrones. . . . . . . . . . . . . . . 75Scheme 2.45 Proposed mechanism for the oxidation of N-alkylated isoxazolidines using m-CPBA 76Scheme 2.46 Synthesis of bromo isoxazolidine 2.164 . . . . . . . . . . . . . . . . . . . . . . . . 76Scheme 2.47 Oxidation of N-alkylated isoxazolidines with m-CPBA . . . . . . . . . . . . . . . 77Scheme 2.48 (a) Synthesis of tetrahydroxanthones 1.154a and 1.154b. (b) Proposed synthesis ofthe tetrahydroxanthone core utilizing a [4+2] cycloaddition between chromenones and dienes 77Scheme 2.49 Proposed route for the synthesis of 1-hydroxytetrahydroxanthones via intramolecu-lar nucleophilic addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Scheme 2.50 (a)Nucleophilic addition of aryl bromides using palladium as catalyst. (b) Proposedsynthesis of tetrahydroxanthonol 2.169b using palladium as catalyst . . . . . . . . . . . . . 79Scheme 2.51 (a) Synthesis of chromanones using NHC. (b) Proposed synthesis of hexahydrox-anthones or tetrahydroxanthones using NHC . . . . . . . . . . . . . . . . . . . . . . . . . . 81Scheme 2.52 Synthesis of NHC catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Scheme 2.53 Proposed mechanism for the synthesis of tetrahydroxanthone 2.176b viaNHCcatal-ysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Scheme 2.54 Proposed conversion of tetrahydroxanthone 2.176b into 2.3 . . . . . . . . . . . . . 84Scheme 2.55 Attempts to construct the tetrahydroxanthone core . . . . . . . . . . . . . . . . . . 85Scheme 2.56 Proposed optimization for the synthesis of tetrahydroxanthones using NHC catalysis 85Scheme 3.1 Cycloaddition of o-alkynoylphenol derivatives can sometimes produce a mixture of6-endo-dig and 5-exo-dig products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Scheme 3.2 Synthesis of chromenones from o-alkynoylphenol derivatives using either para-toluenesulfonic acid or potassium carbonate . . . . . . . . . . . . . . . . . . . . . . . . . . 134Scheme 3.3 Possible modes of cyclization of ynone 3.21. Indanone 3.23 was not observed . . . 134Scheme 3.4 Synthesis of chromenones from o-alkynoylphenol derivatives using NaOMe . . . . 135Scheme 3.5 Chromenone synthesis: Cycloisomerization of o-alkynoylphenol derivatives usingTfOH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135Scheme 3.6 Chromenone synthesis via oxa-Michael addition using iodine(I) chloride . . . . . . 136Scheme 3.7 Reaction mechanism for the synthesis of iodochromenone 3.30 . . . . . . . . . . . 136Scheme 3.8 Addition of ICl across the alkyne of ynones with electron rich substituents attach tothe alkyne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137xvList of SchemesScheme 3.9 Gold(I)-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenol (3.35) ando-alkynoylphenol 3.17. 5-Exo-dig vs 6-endo-dig cyclizations . . . . . . . . . . . . . . . . . 139Scheme 3.10 Cycloisomerization of o-alkynoylphenol derivatives using (triphenylphosphine)gold(I)chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139Scheme 3.11 Gold(I)-catalyzed cycloisomerization of ynones with different alkyl ethers . . . . . 139Scheme 3.12 Palladium(II)-catalyzed cycloisomerization of o-alkynoylphenol derivatives . . . . 140Scheme 3.13 (a) Reported routes to synthesize chromenones from phenoxyynones. (b) Proposedroutes to synthesize tetrahydroxanthones from o-alkynoylphenol derivatives . . . . . . . . . 141Scheme 3.14 A retrosynthetic analysis for the synthesis of o-alkynoylphenol derivatives 3.56 . . . 141Scheme 3.15 Synthesis of 5-bromo o-vanillin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142Scheme 3.16 Attempt to synthesize o-alkynoylphenol derivative 3.62a . . . . . . . . . . . . . . 142Scheme 3.17 Synthesis of o-alkynoylphenol derivatives 3.62a and 3.62b . . . . . . . . . . . . . 143Scheme 3.18 A retrosynthetic analysis of o-alkynoylphenol derivative 3.66a . . . . . . . . . . . 144Scheme 3.19 Synthesis of o-alkynoylphenol derivatives 3.66a, 3.66b, and 3.66c . . . . . . . . . 145Scheme 3.20 Synthesis of ynone 3.79, the arrows indicate heteronuclear multiple-bond correla-tion spectroscopy (HMBC) correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146Scheme 3.21 Mechanistic rationale for the conversion of 3.73b into 3.73d via benzyne . . . . . . 146Scheme 3.22 Attempt to synthesize o-alkynoylphenol derivative 3.66d . . . . . . . . . . . . . . 147Scheme 3.23 Proposed cycloisomerization of compound 3.65a promoted by Lewis acids . . . . . 147Scheme 3.24 Synthesis of 3,5-dinitrobenzoates 3.89a-t and 3.89a-c . . . . . . . . . . . . . . . . 153Scheme 3.25 Synthesis of tetrahydroxanthone derivatives 3.89b-t and 3.89b-c, and chromenone3.85b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Scheme 3.26 Methanolysis of tetrahydroxanthone ester 3.89a-t . . . . . . . . . . . . . . . . . . 155Scheme 3.27 Synthesis of tetrahydroxanthone 3,5-dinitrobenzoates 3.89c-t and 3.89c-c, and chromenone3.85c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Scheme 3.28 Intramolecular tandem cycloisomerization of o-alkynoylphenol derivative 2.166a . 157Scheme 3.29 Intramolecular tandem cycloisomerization of ω-oxo o-alkynoylphenol derivative2.166b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Scheme 3.30 Possible chromenone as intermediate in the synthesis of tetrahydroxanthones . . . . 157Scheme 3.31 Treatment of chromenones with DMAP does not lead to tetrahydroxanthones . . . . 158Scheme 3.32 Proposed mechanistic pathways for the synthesis of tetrahydroxanthone 2.166a andchromenone 3.83a using DMAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159xviList of SchemesScheme 3.33 Representative examples of Morita-Baylis-Hillman (MBH) products using ynonesand ynoates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Scheme 3.34 DMAP-promoted Morita-Baylis-Hillman between allenolate 3.113 and isatin 3.112 160Scheme 3.35 Proposed chair transition state for the formation of trans and cis tetrahydroxan-thone derivatives 3.89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Scheme 3.36 Attempt to support the Morita-Baylis-Hillman/oxa-Michael mechanism over theoxa-Michael/aldol mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162Scheme 3.37 Synthesis of tetrahydroxanthones via DMAP-promoted intramolecular tandem cy-cloisomerization of o-alkynoylphenol derivatives . . . . . . . . . . . . . . . . . . . . . . . 162Scheme 4.1 Proposed retrosynthetic analysis of simaomicin α . . . . . . . . . . . . . . . . . . 196Scheme 4.2 Synthesis of the AB rings of simaomicin α . . . . . . . . . . . . . . . . . . . . . 196Scheme 4.3 Attempted strategies to construct the tetrahydroxanthone core . . . . . . . . . . . . 197Scheme 4.4 Synthesis of tetracyclic bromoisoxazolines 2.147 and isoxazoles 2.149 and theirreductive cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197Scheme 4.5 Synthesis of tetrahydroxanthone 2.176b using NHC catalysis . . . . . . . . . . . . 198Scheme 4.6 Variables that can be explored for the optimization of the synthesis of tetrahydrox-anthones through NHC-promoted intramolecular hydroacylation . . . . . . . . . . . . . . . 199Scheme 4.7 Proposed conversion of tetrahydroxanthone 2.176b into tetrahydroxanthone 2.166a 199Scheme 4.8 The cycloaddition of o-alkynoylphenol derivatives generates two six-membered rings,one C–O bond, one C–C bond, and one stereogenic centre . . . . . . . . . . . . . . . . . . 200Scheme 4.9 Proposed reaction mechanism for the cycloaddition of o-alkynoylphenol derivative3.62a using DMAP as a nucleophile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Scheme 4.10 Proposed formal synthesis of simaomicin α . . . . . . . . . . . . . . . . . . . . . 202Scheme 4.11 The DMAP-promoted cycloisomerization of o-alkynoylphenol derivatives may beused for the synthesis of campestroside and puniceaside B . . . . . . . . . . . . . . . . . . 203xviiList of Abbreviations and Symbolsδ chemical shift1D one-dimensional2D two-dimensionalatm atmosphereBOM benzyloxymethylbr broadca. circaCAN ceric ammonium nitratecat catalyticconcd concentratedCOSY correlated spectroscopym-CPBA meta-chloroperoxybenzoic acidCSA camphorsulfonic acidd day or days or doublet (in NMR)DA Diels-AlderDABCO 1,4-diazabicyclo[2.2.2]octaneDAIB (diacetoxy) iodobenzenexviiiList of Abbreviations and Symbolsdba dibenzylideneacetoneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCC N,N ′-dicyclohexylcarbodiimideDCE dichloroethaneDCM dichloromethanedd doublet of doubletsDEA N,N-diethylacetamidedec decompositionDIAD diisopropyl azodicarboxylateDMF dimethylformamideDMAP 4-dimethylaminopyridineDMP Dess-Martin periodinaneDMSO dimethylsulfoxidedppb 1,4-bis(diphenylphosphino)butanedppe 1,2-bis(diphenylphosphino)ethanedppf 1,1’-bis(diphenylphosphino)ferrocenedppm 1,1-bis(diphenylphosphino)methanedppp 1,3-bis(diphenylphosphino)propanedr diastereomeric ratiodt doublet of tripletsE1 first-order eliminationE2 second-order eliminationEAS electrophilic aromatic substitutionxixList of Abbreviations and Symbolsee enantiomeric excessESI electrospray ionizationequiv molar equivalentsEWG electron withdrawing groupFMO frontier molecular orbitalGSS Grover, Shah and ShahHMBC heteronuclear multiple-quantum correlation spectroscopyHOMO highest occupied molecular orbitalHTIB [hydroxy(tosyloxy)] iodobenzeneHMBC heteronuclear multiple-bond correlation spectroscopyHRMS high resolution mass spectrometryHSQC heteronuclear single-quantum correlation spectroscopyHz HertzIBX 2-iodoxybenzoic acidIC50 half maximal inhibitory concentrationIEDDA inverse electron-demand Diels-AlderIUPAC International Union of Pure and Applied ChemistryJ coupling constantKHMDS potassium bis(trimethylsilyl)amideLC liquid chromatographyLCT liquid chromatography tandemLDA lithium diisopropylamideLG leaving groupxxList of Abbreviations and SymbolsLHMDS lithium bis(trimethylsilyl)amideLRMS low resolution mass spectrometryLUMO lowest unoccupied molecular orbitalm multipletMBH Morita-Baylis-HillmanMIC minimum inhibitory concentrationmmHg millimetres of mercuryMOM methoxymethylMOMCl methoxymethyl chloridemp melting pointMS mass spectrometryMs2O methanesulfonyl anhydrideMsCl methanesulfonyl chlorideMTM methylthiomethylMTMCl methylthiomethyl chlorideNAS nucleophilic aromatic substitutionNCS N-chlorosuccinimideNGDI neglected global diseases initiativeNHC N-heterocyclic carbeneNHK Nozaki-Hiyama-KishiN-MeImid N-methylimidazoleNMR nuclear magnetic resonanceNR no reactionxxiList of Abbreviations and SymbolsORTEP Oak Ridge thermal ellipsoid plot programPCC pyridinium chlorochromatepdt productpKa negative base-10 logarithm of the acid dissociation constantPMB p-methoxybenzyl or 4-methoxybenzylPPA polyphosphoric acidppm parts per million or mg/mLpsi pounds per square inchq quartetRa • Ni Raney nickelrr regioisomeric ratiort room temperatures singletSN2 second-order nucleophilic substitutiont tripletTBAI tetrabutylammonium iodideTBAF tetrabutylammonium fluorideTBS tert-butyldimethylsilylTBSCl tert-butyl(chloro)dimethylsilanetd triplet of doubletsTMEDA tetramethylethylenediamineTEMPO (2,2,6,6-tetramethyl-piperidin-1-yl)oxylTFA trifluoroacetic acidxxiiList of Abbreviations and SymbolsTfOH trifluoromethanesulfonic acidTHF tetrahydrofuranTIPS triisopropylsilylTLC thin layer chromatographyTMS trimethylsilylTOF time of flightTS transition statep-TsCl para-toluenesulfonyl chloridep-TsOH para-toluenesulfonic acidTTN thallium(III) nitrateUV ultra violetVMH Vilsmeier-Haackw/w weight over weightxs excessxxiiiAcknowledgmentsFirst, I would like to thank my research supervisor, Professor Gregory R. Dake, for letting me become amember of his research group, for his patience, support, and guidance throughout my entire doctoral studies.I am particularly thankful for his time spent proofreading this dissertation and for helping me shape it into areadable document.I would like to thank Professor Glenn M. Sammis for accepting the challenge of proofreading this dis-sertation, for sitting next to me and going through it paragraph for paragraph. Any errors that remain, eitherscientific in nature or grammatical, are my own.I also want to thank past members of the Dake lab: Kristle, Jenn, Jenny, Julien and Andreas for sharingtheir knowledge with me and for making the time spent in the lab memorable, I learnt so much from youguys. Jenny and Julien, I am thankful that we became good friends and I really appreciate you guys keepingin touch. And, what would be of me without the present members of the Dake group: Andrew, Benny,Spenny and Chris? You guys make my days bright, no matter what it looks like outside the window, I amreally glad you guys came into my life. Professor Loosley, thank you for the silly times; Spenny, you are mycrystal man! Also, I would like to give a big thank you to all the undergraduate and summer students that Ihad the pleasure to work with, special thanks go to Doris, Alex and Arran, you guys made me more patientand taught me how to confer knowledge.A big thank you to the staff of the NMR lab, mass spec lab, X-ray lab, mec shop, IT services and chemstores, you are the invisible hands who made it possible for me to finish this dissertation. Special thanks to:Maria Ezova for her help while running 2D NMR and NOE experiments; John Elis for making sure all thechemicals were promptly delivered and for getting us sometimes free chemicals; Marshal for running all thehigh res mass spec; Ken Love for keeping our pumps up and running.I once read somewhere that our friends are the family that we chose to live with, and I am really convincedthat this is true. I am very thankful that I had the opportunity to meet a lot of very good friends within thechemistry department and out of it. These people became my new family in a place where I knew nobody,xxivAcknowledgmentswhere I felt like a scared mouse not knowing what to do or where to go, but thanks to these human beings, Ifelt like I was at home.To my friends: Danielle Covelli, my dearest foola, you really don’t know what it meant to me to have asurprise cake on my first birthday not at home. I was pretty sure my first birthday in Vancouver would be likeHarry Potter’s 11th birthday, with a cake drawn on the sand, singing “happy birthday” to myself. I will alwaysremember the good times we spent together dancing to“just dance” and getting happy. And thank you verymuch for that night at triple O’s on Broadway, it meant a lot to me to know that I had your support. Niushita,you are my very special CM! You really don’t know how much I admire you, you are a role model for me.Thank you for caring and for listening when I needed to talk, you’ll always have a place in my heart and a bedto crash in at my parents’s place whenever you happen to wander around Me´xico. La Claire! You’ll alwaysbe man che´ri, thank you for all the hugs and all the bites you let me give you :D I was starving!A la banda latı´nida: A Ale y Taquito, que aunque no estuvieron presentes, desde lejos me mandabantodo su apoyo sin importar que hubiera entre nosotros casi cuatro mil kilo´metros de distancia, porque deser un cuarteto con su octeto de electrones completo, pasamos a ser los pies del tripie´, que mientras nosmantengamos juntos, nunca nos dejaremos caer. Carmelita, hsieh hsieh por compartir aventuras conmigo, ypor pasarme tus recetas para hacer pasteles; tambie´n te tengo que agradecer que te hayas animado a hablarme,porque gracias a ello nacio´ un lazo muy fuerte entre los dos, eres como mi de familia. Jannu, aunque tu´ yyo somos como el agua y el aceite, que pude, podría y, en su defecto, pudiera parecer que no se mezclan, sı´hacen emulsiones duraderas. Gracias por hacerme no olvidar de do´nde vengo y a quie´n me debo. A los Jayos(Jayito y Pacheco, pues), gracias por los buenos momentos y las fiestas. Oh y gracias Jayito por decirme quehuelo como a duty free de aeropuerto, mejor piropo que e´se, no existe. Montse, que´ te puedo decir manta?Si empiezo, la lista no termina, ası´ que lo resumire´ en: gracias por tu apoyo incondicional, por estar en lasbuenas y en las mejores, por escucharme y soportarme, por ser mi roommate y por lavar los trastes y porser como mi segunda hermana. Mi Palomita! muchas gracias por compartir parte de tu vida conmigo, portu sencillez y por tu alegrı´a, tenemos que irnos a Parı´s a castigar las tarjetas de cre´dito ja ja ja! Rodrigo,gracias por escucharme y por los cafe´s y sobre todo por aguantar mis relatos con lujo de detalle ;) y tambie´npor ayudarme a texer en LATEX cuando me atoraba.And last, but not least, I would really like to thank my friends from the Health initiative for Men: Billy,Ely, William, Nathan and also to Charles, you guys are the brothers I never had and even better than that.Thank you for all the dinners, board game nights, for all the fun times I’ve spent with you, and also for sharingyour life stories with me. A huge hug to each of you.xxva mi familia, porque no serı´a nada sin sus ensen˜anzasa Chichito y Reyna, porque han dado la vida y el alma para que yo pueda alcanzar mis suen˜os,tengan la certeza que les estoy eternamente agradecidoa mi Askomikota por haber sido mi primer maestra en la vida y por todo tu apoyo y carin˜o,porque me has amado desde que nacı´, sin importar que´xxviChapter 1Introduction1.1 General IntroductionThe work presented in this dissertation was inspired by simaomicin α (1.1, Figure 2.1), a naturally occurringtype II polyketide that exhibits remarkable activity against two cell lines of Plasmodium falciparum, a proto-zoan parasite that causes malaria in humans. It was found that simaomicin αwas more active against malariathan artemether, artemisinin and chloroquine, which currently are the main drugs used for the treatment ofthis disease.1 Simaomicin α is a polycyclic tetrahydroxanthone with a fused heptacyclic core that incorpo-rates two ring systems: a dioxygenated isoquinolinone, the AB ring system, and a tetraoxygenated tetrahy-droxanthone, the DEF ring system. The partially saturated ring of the tetrahydroxanthone moiety presentsa trans-1,4-dihydroxylated pattern, which is observed in many naturally occurring polycyclic tetrahydroxan-thones (see Section 1.5.1.3, Figure 1.15 page 18).2ONOOOHOMeOOHOHOHOSimaomicin αABC D E FGH1.1Figure 1.1. Simaomicin α, a type II polyketide.The polycyclic tetrahydroxanthones are a subgroup of the xanthone family, which presents a fully aro-matic ring system that resembles the DEF portion of simaomicin α. Although synthetic approaches to accessthe tetrahydroxanthone core have been reported (Section 1.6), there is no general route that can allow the syn-1Introductionthesis of the 1,4-dihydroxylated species. This dissertation outlines my efforts to develop a reliable approachto this type of tetrahydroxanthones that may be used for the synthesis of a variety of naturally occurringtetrahydroxanthones and derivatives with a simpler chemical architecture.In the following sections the xanthone family, its classification, isolation, biosynthesis, biological proper-ties and a few synthetic approaches to the xanthone unit will be discussed. Dihydroxanthones, hexahydroxan-thones and the few available methods to access these units will also be mentioned. Tetrahydroxanthones willbe discussed with a strong emphasis on polycyclic tetrahydroxanthone simaomicin α. The isolation, biosyn-thesis, and biological properties of this natural compound will be presented in detail. The total synthesisof ent-1.1, which was performed by Ready and co-workers in late 2013, will be outlined.3 The syntheticapproaches to construct the tetrahydroxanthone core will also be disclosed in detail in this chapter.1.2 XanthonesXanthones are highly oxygenated secondary metabolites derived from plants, fungi, lichens and bacteria.4–10The first isolated members of this family were yellow compounds, and were given the name “xanthones”(9H-xanthen-9-ones) from the Greek “xanthos”, which means yellow.11 Biogenetically, the xanthone nu-cleus can derive from polyacetate or shikimic acid units. According to its biosynthetic origin, carbon atomscorresponding to the acetate-derived ring are numbered 1-4, while the carbon atoms corresponding to theshikimate-derived ring are numbered 5-8 (Figure 1.2). A detailed description of the biosynthesis of xan-thones will be discussed in Section 1.2.1. Although the numbering of these compounds is not consistent inthe literature, IUPAC recommendations for the parent compound (1.2), Figure 1.2) will be followed in thisdissertation.OO148576239a4a8a10a910xanthoneA COHHOHOOOHshikimic acidOOOOpolyacetateB1.21.3 1.4Figure 1.2. Xanthone skeleton and numbering.2Introduction1.2.1 Xanthone BiosynthesisThe biosynthesis of xanthones has been of great interest for the scientific community and has been thoroughlystudied for the past 45 years. In 1961 there was still much speculation regarding the biosynthetic pathwaysthat gave rise to the xanthone core.11 From the oxygenation pattern observed in the xanthones, it was inferredthat the C ring may be of “polyacetic acid” origin.9,11 However, experimental data helped determine that, inplants, the A ring is derived from the shikimate route, while the C ring was constructed from the acetate-malonate polyketide route (see Figure 1.2).12–15The biosynthesis of xanthones in plants begins with shikimic acid (1.3),16 which is then converted intophenylalanine (1.5). Phenylalanine is transformed into 3-hydroxybenzoic acid with the elimination of a 2-carbon unit (1.6). Subsequent condensation with three acetate units yields tetraketone 1.7. Cyclization of theside chain, followed by aromatization renders compound 1.8. Oxidative phenolic coupling of 1.8 can generatetwo different xanthones: 1.9 and 1.10 (Figure 1.3). Radio labelling experiments performed on Gentianalutea supported this route; the plant was fed with 14C-labelled phenylalanine or 14C-labelled acetate and itwas shown that the A ring derived from phenylalanine, while the B ring derived from acetate.17,18OHHOHOOOHshikimic acid phenylalanineNH2OHO3-hydroxybenzoic acidOHOHOOHOOOO3 x OROO OHHO OHO OHHO OHOHOOHxanthoneO OHO OHxanthoneO OHOHOHHO1.3 1.5 1.61.71.81.81.91.10Figure 1.3. Xanthone biosynthetic pathway in plants.12–153IntroductionUnlike plants, fungi-derived xanthones arise exclusively from a single chain polyketide species. Conden-sation of eight acetate units produce polyketide 1.12, which, upon a subsequent cyclization and decarboxy-lation of the tail, forms anthroquinone 1.13. Oxidative cleavage of the B ring affords benzophenone 1.14.The synthesis of 1.15 is dependent on the producing organism. The benzophenone can undergo a directcyclization to form xanthone 1.15 or it can form tetrahydroxanthone 1.16. Tetrahydroxanthone 1.16 can thenform xanthone 1.15 after a sequence of oxidation, decarboxylation, and dehydration.9OOR8 x OHO O O OOO O OC16 polyketideacetate equivOH O OHanthroquinoneOOH O OHHOCO2HbenzophenoneOH O OHOxanthoneOH O OHOCO2HOHtetrahydroxanthone1.11 1.12 1.131.141.151.16Figure 1.4. Fungi: biosynthetic pathway of xanthones.9Studies towards the biosynthesis of phenolic natural compound xanthoquinodins using 13C-labelled ac-etate experiments supported this theory.19,20 As early as 1953,20 it had been proposed that many phenolicnatural compounds utilized a head-to-tail linkage of acetate units.1.2.2 Classification of XanthonesIn 1961 there were only 18 naturally occurring xanthones known. After half a century, this number hasincreased by two orders of magnitude and now includes over 2000 members. The xanthones have beenclassified according to their chemical structure, based on the degree of saturations present in the A or Crings, on their type of substituents, and their degree of oxygenation of the nucleus.According to the degree of saturation of the core, these compounds have been classified as fully aromatic,di, tetra, and hexahydroxanthones (Figure 1.5).9 These can be present as monomers, dimers, heterodimersor polycyclic structures. With respect to the types of substituents attached to their core, xanthones have been4Introductionclassified in six main groups: simple xanthones, xanthone glycosides, prenylated xanthones, xanthonolig-noids, bis-xanthones and miscellaneous xanthones. These can be further classified depending on to the de-gree of oxygenation exhibited in the nucleus as non, mono, di, tri, tetra, penta, and hexaoxygenated species.21OOOOOOdihydroxanthonesOOtetrahydroxanthonesOOhexahydroxanthoneOO148576239a4a8a10a910A CBxanthone1.21.171.181.191.201.21Figure 1.5. Degree of hydrogenation of xanthones.The terms dihydroxanthones, tetrahydroxanthones and hexahydroxanthones are not consistently used inthe literature. For example, Jørgensen22 refers to 1.23 as a tetrahydroxanthone while Hsung23 names it adihydroxanthone. Bra¨se24 considers diversonol (1.24) a tetrahydroxanthone and not a hexahydroxanthone.For this dissertation, the terms dihydroxanthone, tetrahydroxanthone, and hexahydroxanthone will be usedas follows: a dihydroxanthone will be a tricyclic structure bearing the xanthone core that is missing oneunsaturation in the C ring (1.22), a tetrahydroxanthone will contain only one double bond in the partiallysaturated ring (1.23), and a hexahydroxanthone will exhibit ring C fully saturated (1.24), as exemplified inFigure 1.6.OOH O OHOHOHdiversonola hexahydroxanthoneOOH OHOHCNa tetrahydroxanthoneFOOH OH2NOC OHa dihydroxanthone1.22 1.23 1.24Figure 1.6. Examples of di, tetra and hexahydroxanthones.5Introduction1.3 Fully Aromatic XanthonesThe first isolated members of the xanthone family were fully aromatic species.9 Representative fully aromaticsimple xanthones include tetraoxygenated xanthone 1.25,14 C-glycoside xanthone mangiferin (1.26),25 mis-cellaneous xanthone 1.27,26 prenylated xanthone ugaxanthone (1.28), xanthonolignoid cadensin D (1.29)and bis-xanthone jacarelhyperol A (1.30)27 (Figure 1.7).OOHOHOOMeOMea tetra-oxygenated xanthoneOOHOHOOHOHmangiferina C-glycoside xanthoneOHOOHOHOHOOHOOHOMeClOOHOOHOHOHOOHO OOH OHO OHOMeOMeOMeOOOOHOHOOOOHOHOHOHOHjacarelhyperol Aa bis-xanthonecadensin Da xanthonolignoidugaxanthonea prenylated xanthonea miscellaneous xanthone1.25 1.26 1.271.28 1.29 1.30Figure 1.7. Representative fully aromatic simple xanthones.Polycyclic fully aromatic xanthones are polyketides that exhibit a highly oxygenated angular hexacyclicor heptacyclic core. The core of the polycyclic xanthones is made up of two units: a polyoxygenated fullyaromatic xanthone and typically a cyclic amide, which is rare in aromatic polyketides (Figure 1.8).28 Most ofthe polycyclic xanthones exhibit antibacterial,29,30 antibiotic31,32 and cytotoxic activity.33–35 It has also beenfound that they are active against Gram-positive bacteria,10 including methicillin-resistant Staphylococcusaureus and vancomycin-resistant Enterococcus faecalis.36A key feature of the polycyclic xanthones is the high degree of oxygenation of the xanthone unit, hav-ing dihydroxylated species (acremoxanthone A 1.31 and B 1.32,29 and xanthofulvin 1.3935), trihydroxy-lated species (lysolipin I 1.33,32 vinixanthone 1.38,33 and xantholipin 1.3634), and tetrahydroxylated species(cervinomycins A1 1.34 and A2 1.35,30 and FD-594 1.3731).6IntroductionOOHOOMeO OH OOHOHAcOacremaxanthone AOOHOOMeO OH OOOHAcOacremaxanthone BOHOOOOOMeOMeNOOHOcervinomycin A1OOHOHOOMeOMeNOOHOcervinomycin A2OOHOMeOOHOOHOFD-594OHOHHOlysolipin IOOHOOClNOHOMeOO OMeMeOHOOOHOOClHNOOxantholipinOMeOOOHHOOOHvinixanthoneHOHOOHOOOHOHOHOOOxanthofulvinHOHOOHOOHOOHHOOHOO1.31 1.32 1.331.34 1.35 1.361.37 1.38 1.39Figure 1.8. Representative polycyclic fully aromatic xanthones.1.3.1 Synthetic Approaches to Fully Aromatic XanthonesAlthough naturally occurring fully aromatic xanthones exhibit a broad range of biological properties,29–36the availability of these compounds is limited by the amount that can be isolated from their natural source. Togain access to larger quantities of these compounds for further biological studies, the development of routesto access the xanthone core was desired. The fully aromatic xanthones are the most widespread type of xan-thones in nature and many efforts for the synthesis of the xanthone core have been developed. Several reviewson the fully aromatic xanthones, including their synthetic approaches have been published.8–10,15,37–39One of the earliest methods to synthesize the xanthone core was the distillation of a mixture made up ofa phenol, an ortho-hydroxybenzoic acid, and acetic anhydride.40 However, the harsh conditions employed,low yield, and substantial formation of byproducts, considerably limited the use of this route. Differentmethods to access xanthones were developed based on that approach. Among these, three methods were7Introductionpredominantly used and are referred to as traditional methods for the synthesis of xanthones: a) the Grover,Shah and Shah (GSS) synthesis, b) the synthesis via benzophenone, and c) the synthesis using biaryl ethers.5The GSS synthesis, developed in 1955, is a one-pot procedure that uses a salicylic acid (1.40) and anelectron rich phenol (1.41)41 that in the presence of fused zinc chloride and phosphoryl trichloride at 60 to70 ◦C afford xanthone 1.43 (no yield was reported). This method proceeds through a Friedel-Crafts acylationto afford a benzophenone (1.42) that, depending on the reactivity of the phenol species, can cyclize to yieldthe desired xanthone (Scheme 1.1). The GSS method is limited to the coupling of highly activated phenols(typically floroglucinol) with salicylic acid derivatives.42OHOOHHO+OHHOOHZnCl2POCl3OHOOHOHOHOHOHOOHOHO1.40 1.41 1.42 1.43Scheme 1.1. The Grover, Shah and Shah method to synthesize xanthones.41Procedures that do not require the use of highly activated phenols may give rise to a variety of substitutedfully aromatic xanthones. In the synthesis via benzophenone intermediates (Scheme 1.2), a phenol (1.45) istreated with a carboxylic acid derivative (1.44) to generate a benzophenone (1.47) through a Friedel-Craftsacylation reaction at the ortho position. The benzophenone cyclization can proceed through an intramolec-ular nucleophilic aromatic substitution mechanism43,44 (when X = OH or OMe) or through an oxidativecoupling45 (when X = H) to afford the desired xanthone (1.48).The synthesis through biaryl ether intermediates starts with theUllman condensation of an ortho-halogen-ated benzoic acid (or benzoic ester) (1.44) and the sodium salt of a phenol (1.45) to provide a biaryl ether(1.46). Once formed, the biaryl ether undergoes an electrophilic acylation to form the desired xanthone(1.48).46YX + HOOOHXORRR ROR RYR ROY = CO2H       COCl       CNX = OH       OMe       HY = CO2H       CO2MeX = F       Cl       BrUllmann Friedel-Crafts1.44 1.451.46 1.471.48Scheme 1.2. Classical methods to xanthones: via biaryl and via benzophenone.43–468IntroductionNew approaches to make the xanthone core have been developed and some are modifications of theclassical methods mentioned above.47–57 With the development of new methods, xanthones can now besynthesized from xanthenes,58 thioxanthonedioxides,59 benzoquinones,60 via benzyne,61,62 through Diels-Alder reactions of chromenones,63 from extended poly-β-ketides,64,65 and by condensation of salicylates and2,6-diiodobenzoquinone.661.4 Partially Saturated Xanthones: Dihydroxanthones andHexahydroxanthonesPartially saturated xanthones are derivatives that have one, two or three unsaturations in the partially satu-rated ring, giving rise to dihydro, tetrahydro and hexahydroxanthones, respectively. Dihydroxanthones, firstisolated in 1936, are scarce in the xanthone family and consist mostly of monomeric species. The monomericdihydroxanthones include F390 B and C,67 globosuxanthone A68 (1.50), GS-169 and nidulalin A70 (1.54).Only three dimeric dihydroxanthones are known: phomalevones A and B (homodimers)71 and lysolipin X(1.51) (heterodimer).32OOOH OHOHMeO2Cglobosuxanthone AOOOHnidulalin AOHMeO2COOapplanatin AOHOHO HOHOOOH HOHOHOHmonodictysin AOOOH HOHOHmonodictysin Blysolipin XOOHOOClNOHOMeOO OMeMeOHO OH1.49 1.50 1.511.52 1.53 1.54Figure 1.9. Representative dihydroxanthones and hexahydroxanthones.Hexahydroxanthones, first isolated in 1932,72 are the least common members of the xanthone family.The absence of polycyclic hexahydroxanthones in the literature is remarkable and only three dimeric hexahy-droxanthones are known. Applanatin A73 (1.49), diversonol74 (1.24), ergoflavin (also known as ergochromeCC),72 ergochrome DD, ergochrome CD,75 isocochlioquinone,76 and monodictysins A (1.52), B (1.53),and C77 are examples of hexahydroxanthones. Figure 1.9 shows some representative dihydroxanthones andhexahydroxanthones.9IntroductionAlthough scarce among the literature, dihydroxanthones and hexahydroxanthones have gained attentionfrom the synthetic community because of their complex structural architecture and their useful biologicalproperties, including antibiotic, antifungal,71,76 and cytotoxic activity.67–69,77,781.4.1 Synthetic Approaches to Dihydroxanthones and HexahydroxanthonesDespite the variety of biological activities exhibited by dihydroxanthones and hexahydroxanthones, very littlework has been done to develop synthetic methods for the construction of these compounds. Currently thereare nomethodologies available for the synthesis of dihydroxanthones, and there are only a couple of examplesfor the synthesis of hexahydroxanthones.In 2009, Tatsuda and co-workers reported the total synthesis of dihydroxanthone nidulalin A (1.54,Scheme 1.3).79 The nine-step linear route to access racemic 1.54 began with disubstituted dimethyl phthalate1.55, which was transformed into benzophenone 1.56 in 90% over three steps. Formation of the pyrone ringwas achieved through an oxidative cyclization using lead(IV) acetate to afford dihydroxanthone 1.57 in 39%yield. Further manipulation including three reductions, hydrolysis, protection and oxidation afforded racemic1.54 in 17% over five steps. Resolution of the racemic mixture was performed using (-)-camphanic acid toobtain enantiomerically pure (-)-nidulalin A (1.54) and enantiomerically pure (+)-nidulalin A (ent-1.54) in80% and 76% yield, respectively.OMOMMeO2CMeO2COMeOHMeO2COMeOOHOHOOMeOOOHMeO2CPb(OAc)4NaOAcCH3NO2, rt39%OOMeOOOHMeO2C OHOOOHMeO2C(±)-Nidulalin A(±)-90%over 3 steps17%over 5 steps1.55 1.561.571.571.54Scheme 1.3. Tatsuda’s total synthesis of nidulalin A.79While developing a methodology to obtain benzophenones, Whalley and co-workers devised a routeto access substituted hexahydroxanthones (Scheme 1.4). Whalley’s synthesis of hexahydroxanthones beganwith the addition of 2,6-dimethoxyphenyllithium (1.58) to anhydride 1.59 to afford phenone 1.60 in 47%yield. The phenone, upon treatment with trichloroborane, afforded hexahydroxanthone 1.61 in 66% yield.10IntroductionOOCO2MeOO OOOH CO2MeOHHHOOOOHHOOLi+1) THF2) CH2N247%BCl366%1.58 1.59 1.60 1.61Scheme 1.4. Synthesis of hexahydroxanthones using BCl3.80In 1995, Merchant and co-workers reported a synthesis of hexahydroxanthones from a phenol and acyclohexenyl carboxylic acid (Scheme 1.5). Treatment of 1.62 with carboxylic acid 1.63 in the presenceof polyphosphoric acid (PPA) in dichloromethane (DCM) afforded hexahydroxanthone 1.66 in 67% yield.The authors discovered that polyphosphoric acid promoted the formation of ester 1.64, which underwent asubsequent Fries rearrangement to produce ortho-acylated phenol 1.65. The phenol, in turn, underwent anintramolecular oxa-Michael addition to produce the desired hexahydroxanthone 1.66.81OH +OHOPPADCM OOO O 100 ºC 67%OHO1.62 1.63 1.64 1.65 1.66Scheme 1.5. Merchant’s synthesis of hexahydroxanthones.811.5 Partially Saturated Xanthones: TetrahydroxanthonesTetrahydroxanthones are secondary metabolites that occur in fungi, plants, ferns, lichens and bacteria (1.19and 1.20 in Figure 1.5, page 5). These are the most widespread class of naturally-occurring partially satu-rated xanthones and exist as monomers, dimers and polycyclic structures. To date, over a hundred differenttetrahydroxanthones have been isolated.82Monomeric tetrahydroxanthones are typically polyhydroxylated compounds and include the blennolidesA-C,83 campestroside,84 3,4-dihydroglobosuxanthone A,85 α and β-diversonolic esters,86 EQ-7,69 garci-mangosxanthone C,87 globosuxanthone B,68 GS-4 (also known as 1,9a-dihydronidulalin A),88 microdipla-solol,89 penexanthone B,90 tetrahydroswertianolin,91 wightianone,92 zeyloxanthone93 and a recently iso-lated94 unnamed tetrahydroxanthone. Figure 1.10 shows a selection of representative monomeric tetrahy-droxanthones.The dimeric tetrahydroxanthones are polyhydroxylated compounds that can be found as homodimers, un-symmetrical dimers or heterodimers. These include ascherxanthone A,95 beticolins,96–101 dicerandrols,10211IntroductionOOOHOzeyloxanthoneOOOH OHMeO2C OHα-diversonolic esterOOOHMeO2C OHEQ-7HOOOHOHCO2MeHOOMeglobosuxanthone BOOOHOHcampestrosideOOOHMeOOHgarcimangosxanthone COHHOOOHOOHOHOH 148576239a4a8a10a91014239a4aCB1.67 1.68 1.691.70 1.71 1.72Figure 1.10. The tetrahydroxanthones: Selected monomeric tetrahydroxanthones.ergochromes,72,103–110 eumitrins,111–113 hirtusneanoside,114 neosartorin,115 penexanthones,90 phomoxan-thones,116 and rigulotrocins.117 Figure 1.11 shows a selection of representative dimeric tetrahydroxanthones.OOOOOClOHOHCO2MeHOHHOOHbeticolin 0OOOH OHOHMeO2COO OHOHHO CO2Mesecalonic acid C (ergochrome AB)OOAcOHOCO2MeOHOO OHOHMeO2Ceumitrin A2HOOHOOHO OHOOOH OHHO OOOdicerandrol AOO OHOHOAcAcOHOOOHOOAcOAcphomoxanthone BOOOH OHHO CO2MeHO OHOO OHCO2Merugulotrosin A1.73 1.74 1.751.76 1.77 1.78Figure 1.11. The tetrahydroxanthones: Representative dimeric tetrahydroxanthones.12Introduction1.5.1 Polycyclic TetrahydroxanthonesPolycyclic tetrahydroxanthones are the most studied partially saturated xanthones, perhaps due to their com-plex chemical architecture and the outstanding biological activities they exhibit. Bra¨se refers to polycyclicxanthone derivatives as “privileged structures” because of their ability to bind on different classes of recep-tors, which makes them biologically active against a broad range of diseases.9The polycyclic tetrahydroxanthones are polyketides with a highly oxygenated angular hexacyclic framethat typically incorporates an isoquinolinone ring system, which is rare in the polyketide family. Examples ofpolycyclic tetrahydroxanthones include the albofungins,118,119 actinoplanones,120 kigamicins,121,122 kibde-lones,123 isokibdelones,124 Sch 42137,125 Sch 54445126 and Sch 56036.127 Figure 1.12 show representativeexamples of polycyclic tetrahydroxanthones.OOHOHOONOHOHONH2HalbofunginO OOHClHNOOHOHNO OOMeOMeOactinoplanone EOOONOOHOMeOHOHOHOHSch 42137OClNOOHOOHOMeONH2OHSch 54445HHOHONOOH OHOHOOHSch 56036HHOMeONOOOHOOOHOOOHOHO OHkigamicin AH ONOHOHOHOOHOMeOOOClkibdelone ANOOCl OOOOMeOHOOHOHHisokibdelone AOOH OHO CO2MeNOHOOparnafungin A11.79 1.80 1.811.82 1.83 1.841.85 1.86 1.87Figure 1.12. The tetrahydroxanthones: Representative polycyclic tetrahydroxanthones.13IntroductionThis dissertation aims on the development of a methodology to access highly oxygenated tetrahydrox-anthones that may be useful for the synthesis of tetrahydroxanthone-containing natural product derivativeslike the ones exhibited in Figure 1.12. More specifically, the investigation presented in Chapters 2 and 3 wasfocused on a methodology to access the tetrahydroxanthone fragment embedded in simaomicin α. The fol-lowing section will discuss the isolation, biosynthesis and biological properties of simaomicin α. The totalsynthesis of ent-sima will be discussed in detail in Section 1.6.1.1.5.1.1 Simaomicin α: Isolation and CharacterizationIn 1985, Lee and co-workers isolated a culture named LL-D42067 from a soil sample collected in San Simao,Brazil. Microscopic evaluation of this culture showed it belonged to the genus Actinomadura and its phos-pholipid pattern was typical of Actinomadura madurae, but it was a new subspecies called simaoensis. Fer-mentation of the culture rendered two compounds originally named LL-D42067α and LL-D42067β.128,129In 1990, Maiese and co-workers130 reported the structure elucidation of simaomicin α and simaomicinβ (1.1 and 1.88, respectively),130 despite the compounds had previously been isolated and were known asLL-D42067α and LL-D42067β, respectively. It was found that 1.1 and 1.88 were structurally related totetrahydroxanthones albofungin (1.79) and actinoplanone A (1.89).ONOOOHOMeOOHOHOHOsimaomicin αABC D E FGH ONOOOHOMeOOHOHOHOHsimaomicin βABC D E FGH1234561110157829916171213141819282726 252423222120albofunginABCDE F GOOHOHOONOHOHONH2HO OOHClHNH2OOHOHNO OOMeOMeOABCDE F Gactinoplanone A1.1 1.88 1.79 1.89Figure 1.13. The simaomicins.The structure of the simaomicins was elucidated from their 13C NMR, UV spectra and their degrees ofunsaturation, concluding that the simaomicins were polycyclic tetrahydroxanthones. A striking feature in the1H NMR of the simaomicins was the presence of only one signal in the aromatic region. X-ray crystallog-raphy confirmed the structure of simaomicin α (1.1), showing that it was a heptacyclic type II polyketidethat contained an isoquinolinone ring (AB system) connected to a tetrahydroxanthone unit (DEF system)and it featured a methylenedioxy ring that was in line with the tetrahydroxanthone unit and not with the iso-quinolinone (Figure 1.13). The partially saturated ring (ring F) exhibited a 1,4-dihydroxylated pattern in atrans configuration. The relative configuration could be established from the X-ray analysis as shown in the14IntroductionORTEP (Figure 1.14, taken directly from the original publication). However, the absolute configuration wasnot determined. It was found that simaomicin β was the N-demethylated version of simaomicin α.2Figure 1.14. ORTEP figure of simaomicin α, taken from Lee et al.2It was speculated that the carbon skeleton of simaomicin α may not be derived from the folding of asingle polyketide chain. Two hypotheses for the construction of the tetrahydroxanthone were proposed: thecondensation of two independent subunits or the oxidative cleavage of a carbonylic unit derived from a singlepolyketide chain, followed by loss of a CO unit (most likely through decarboxylation), and ring closure.An isotope labelling experiment was performed, feeding Actinomadura madurae sp. simaoensis with13C-labelled acetate, and it was found that the whole carbon skeleton was derived from acetate (Scheme 1.6).Therefore, it was concluded that simaomicin α derived from the folding of a single polyketide chain. Itappeared that the E ring was formed after oxidative cleavage of the carbonyl in the quinone precursor, followedby loss of CO2, and back cyclization by attack of the incipient phenol towards ring F.131= CH3COOHHNOHOHOHOOOONOHOMeOHOO OHOO HOH**Simaomicin αCO2D E FABC = CH3 frommethionine*1.90 1.911.1Scheme 1.6. Biosynthetic route of simaomicin α.13115Introduction1.5.1.2 Simaomicin α: Biological PropertiesSimaomicin α was tested against bacteria and fungi and was found to be extremely potent against Gram-positive bacteria, but inactive against Gram-negative bacteria and fungi (Table 1.1 shows the minimum in-hibitory concentration (MIC) exhibited by simaomicin α against bacteria and fungi). When tested against avariety of chicken coccidia, simaomicin α showed remarkable activity against all important commercialchicken coccidia at a concentration of 1.00 ppm, which made simaomicin α the most potent naturally-occurring anticoccidial agent reported.130Table 1.1. Biological activity of simaomicin α against bacteria and fungi.130Test organism MIC(µg/mL)Staphylococcus aureus ≤ 0.06Staphylococcus epidermidis ≤ 0.06Streptococcus faecalis ≤ 0.06Streptococcus (Enterococcus sp.) ≤ 0.06Streptococcus mutans ≤ 0.06Streptococcus sanguis ≤ 0.06Micrococcus luteus ≤ 0.06Bacillus cereus ≤ 0.06Candida albicans 256Saccharomyces cerevisiae 32Escherichia coli 512Klebsiella pneumoniae 512Morganella morganii 512Acinetobacter calcoaceticus 512It is known that human T-cell leukemia-derived Jurkat cells are defective at the G1 checkpoint132 andthat bleomycin (a DNA-damaging agent) arrests the cell cycle at the G2 phase. Tomoda and co-workers133tested simaomicin α (1.1, Figure 1.13) against Jurkat cells and found the compound itself was innocuous tothe cell cycle in concentrations up to 6.0 nM. However, when bleomycin-treated Jurkat cells were exposedto 1.1 in concentrations < 0.6 nM, the cell cycle checkpoint G2 was disrupted, suggesting that simaomicinα sensitized cancer cells to anti-cancer compounds. Further studies by the Tomoda group allowed to findthat simaomicin α arrested the cell cycle of Jurkat cells at G1 phase, and subsequently induced apoptoticcell death, potentially making simaomicin α an effective agent against several solid tumours that exhibited amultidrug resistance phenotype.134While testing a library of compounds for antimalarial activity (Table 1.2), Otoguro and co-workers testedsimaomicin α against two streams of Plasmodium falciparum: K1 (a drug-resistant strain) and FCR3 (a drug-16Introductionsensitive strain). Gratifyingly, simaomicin α exhibited the most potent activity against both malaria strainsfrom the four compounds tested and it was also considerably more potent that the most commonly-used drugsagainst malaria (Table 1.2 shows the half maximal inhibitory concentration (IC50) for some commonly useddrugs against malaria and some test compounds).1 It was found that simaomicin α was 4.6 times more activeagainst FCR3 (a drug-sensitive strain) than against K1 (a drug-resistant strain). The authors proposed thatthe decreased activity towards a drug-resistant strain may be due to the presence of an isoquinolinone moietyin its structure.1Table 1.2. In vitro antimalarial activity against Plasmodium falciparum strains K1 and FCR3 of simaomicinα and other compounds.1Compound IC50 (ng/mL)K1 strain FCR3 strainArtemethera 2.3 0.7Artemisinina 6.8 5.1Chloroquinea 184 15.0Hedamycin 230 170Simaomicin α 0.045 0.0097Triacsin C 6.0 8.0Triacsin D 770 560a Commonly-used antimalarial drug1.5.1.3 Analysis of the partially saturated Ring of Polycyclic TetrahydroxanthonesThe secondary metabolites tetrahydroxanthones are an important family of naturally-occurring compoundsbecause they exhibit a broad spectrum of biological properties19,95,135–138 and can be found as monomeric,homodimeric, heterodimeric and polycyclic species. Due to their biosynthetic route, most of these com-pounds have polyhydroxylated structures.131Figure 1.15 shows the tetrahydroxanthone unit embedded in different naturally-occurring polycyclic tetrahy-droxanthones. These compounds exhibit a di or trioxygenated pattern in the partially saturated ring. In thecase of albofungins (1.93), campestroside (1.79), puniceasides (1.98) and Sch 54445 (1.99) the partiallysaturated ring has two hydroxyl groups in positions 1 and 4 in a cis configuration, while the simaomicins(1.100) present the hydroxyl groups in a trans configuration. For the kigamicins (1.97) and actinoplanones(1.92), the partially saturated ring has three hydroxyl groups in positions 1, 3 and 4. Isokibdelones (1.95)and kibdelones (1.96) present a 1,2,4-trihydroxylated partially saturated ring. A common feature of thesestructures is the presence of hydroxyl groups at positions 1 and 4 of the tetrahydroxanthone unit in either acis or trans relative configuration.17IntroductionOOOHOHcampestrosideOOOHHOpuniceasidesHOOROOHOHOROHalbofunginOOOHOHOROMeOMeOactinoplanonesOOOHOROHOMeSch 54445HHOOHOHOHOOHOMekibdelonesOOROHOROHOHOkigamicinsOOHOHOHOOHOMeisokibdelonesOOHOHOMeOHsimaomicinsOAOROHB C A B C A B CA B CA B CA B CA B C A B C A B C1.92 1.93 1.941.95 1.96 1.971.98 1.99 1.100Figure 1.15. Analysis of the partially saturated ring of naturally-occurring tetrahydroxanthones.1.6 Synthetic Approaches to TetrahydroxanthonesDespite the interest of the synthetic organic community on tetrahydroxanthones, syntheses of partially satu-rated xanthones have been less common in the literature. This might be because the partially saturated ringis more challenging to synthesize than fully aromatic xanthones. For this reason, novel and reliable methodsto access partially saturated xanthones –and in particular tetrahydroxanthones– are desired.1.6.1 Total Synthesis of ent-Simaomicin αIn mid 2013, Ready and co-workers reported the total synthesis of ent-simaomicin α (ent-1.1).3 The syn-thesis of the unnatural compound (established by the opposite of the optical rotation value) unequivocallydemonstrated the absolute configuration of simaomicin α (1.1). The synthesis of enantiomeric simaomicinα began with enzymatically resolved (R)-6-hydroxycyclohex-2-en-1-one (1.101), which would become theF ring of simaomicin α. The preformed F ring 1.101 already had a hydroxyl group in what would becomeposition C-25. Further manipulation of hydroxyenone 1.101 afforded iodocyclohexenol 1.102, which wasused to bring together rings D and F of the tetrahydroxanthone unit. Iodo-lithium exchange on 1.102 wasfollowed by treatment with salicylaldehyde derivative 1.104 (ring D) to render diol 1.105 (Scheme 1.7).Diol 1.105 was then oxidized using DMP to yield ene-dione 1.106, which was not stable under the pu-rification conditions used. Cleavage of the MOM group was achieved using HClO4 and the incipient phenol18IntroductionOOH1) BnBr, Ag2O2) I2, cat DMAP3) NaBH4, CeCl3    67%, 3 stepsOHI OBn(d.r. 4:1)OBn 1) Me2AlCl, (CH2O)n2) MOMCl, NaOH3) PCC/Al2O3    77%, 3 stepsOBnCHOOMeBr OHOMeBr OMOMOBnOMeBr OOMeOH OHOBnMeLi,BuLi78%F22 252621D192820D192820 F22 2526211.101 1.1021.103 1.1041.105Scheme 1.7. En route to ent-simaomicin α: Constructing the tetrahydroxanthone framework.3immediately underwent cyclization on carbonyl C-26 to yield hemiketal tetrahydroxanthone 1.107. Underthe acidic conditions, the hydroxyl at C-26 was substituted through an SN2′ attack of water at C-22 to yielda mixture of cis and trans tetrahydroxanthones 1.108 in a 1:1 diastereomeric ratio (Scheme 1.8).1) DMP2) HClO4    42 ºC73%2 stepsd.r 1:1OBnOMeBr OOMeOH OHOBnD F22 2526OBnOMeBr OO OHOBnD E F26 2522OBnOMeBr OOOBnD E F262522OHH2OOBnOMeBr OOMeO OOBnD F2225261.1051.106 1.1071.108Scheme 1.8. En route to ent-simaomicin α: Ready’s construction of the tetrahydroxanthone core.3The configuration at C-22 was set in a two-step sequence: treatment of the diastereomeric mixture oftetrahydroxanthones 1.108 with Dess-Martin periodinane (DMP) was followed by Noyori asymmetric trans-fer hydrogenation.139 The free hydroxyl was then protected as a benzyloxymethyl (BOM) ether to affordtrans-tetrahydroxanthone 1.110 in 10-20:1 diastereomeric ratio (trans:cis). Further allylation, dihydroxyla-tion and oxidative cleavage yielded aldehyde 1.111.The isoquinolinone unit (AB system) was synthesized in four steps starting from 4-bromo-2,5-dimethoxy-benzoic acid, which was treated with oxalyl chloride to obtain the respective acid chloride. Addition of N-methylalaninol under basic conditions to the acid chloride afforded an amide alcohol that was oxidized using19Introduction(2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) to yield aldehyde 1.112. Treatment of aldehyde 1.112with boron trichloride and para-toluenesulfonic acid (p-TsOH) served two purposes. It selectively demethy-lated the position ortho to the amide, and activated the aldehyde towards an intramolecular electrophilicaromatic substitution (EAS). Subsequent dehydration formed the A ring of the isoquinolinone unit. Thephenol at C-13 was then protected as a triisopropylsilyl (TIPS) ether to yield bromoisoquinolinone 1.113(Scheme 1.9).Lithium-bromine exchange was performed on 1.113. Nucleophilic addition of the lithium carbanionto aldehyde 1.111 proved to be challenging since the aldehyde in 1.111 conferred acidity to the adjacentmethylene hydrogens (C-15). After optimization of the reaction conditions, the method first used by Knochelusing LaCl3•2LiCl, was satisfactory for this transformation, yielding 1.114 as a 1:1 mixture of epimers(Scheme 1.9).OBnOMeBr OO OHOBnOBnOMeBr OO OBOM1) DMP2)    HCO2H•Et3N3) BOMCl    65% 3 steps OBnD E F2522NHRuTsNPhPh ClOMeOMeBrNOO1) BCl3, TsOH, ∆2) TIPSOTf    54%, 4 stepsOTIPSOMeBrNO1) PdII (cat), X-Phos    (Allyl)SnBu3, 80 ºC2) OsO4, NMO3) NaIO4/SiO2    97%, 3 steps OBnOMeOO OBOMOBnHO1) BuLi,LaCl3•2LiCl76%OBnOMeOO OBOMOBnHONOTIPSMeOOA B124 53 1161314 12ABD E F123456111015 2916171213141819282726 2524232221202522D E FD E FB1.1081.1091.1091.1101.1111.112 1.1131.114Scheme 1.9. En route to ent-simaomicin α: Joining together the AB and DEF fractions.3The configuration at C-10 was set using the same Noyori asymmetric transfer hydrogenation catalyst(1.109) as for C-22, yielding diastereomerically enriched 1.114a in a 16:1 ratio. The G ring was constructedby deprotecting the phenol at C-13 using TBAF first and then deprotecting the phenol at C-6 through anoxidation/reduction sequence. Treatment of the 1,3-diol with chloroiodomethane in the presence of cesium20Introductioncarbonate, successfully afforded the methylenedioxy ring in compound 1.115. Formation of the C ring wasaccomplished by subjecting tetrahydroxanthone 1.115 to palladium(II) acetate, in what the authors called a“dehydrogenative coupling”, yielding the polycyclic tetrahydroxanthone 1.116. Treatment of the latter withboron trichloride afforded ent-simaomicin α (ent-1.1) as shown in Scheme 1.10.1) DMP2)     HCO2H•Et3N    92%, 2 steps    d.r. 13:1OBnOMeOO OBOMOBnHONOTIPSMeOO 1) Bu4NF2) CAN,    Na2S2O43) CH2ICl    Cs2CO3    65%, 3 stepsOBnOMeOO OBOMOBnONOHOOD E FABPd(OAc)2, 92 ºC61%BCl3, DCM-78 ºC88%(-)-(ent)-simaomicin αHNHRuTsNPhPh Cl10 1026 252226 2522OBnOMeOO OBOMOBnONOHOOABC D E FG 1026 2522HOHOMeOO OHOHONOHOOHABC D E FG 1026 2522ent-1.1141.1091.1091.114a 1.1151.1161.1Scheme 1.10. Ready’s total synthesis of simaomicin α.3The absolute configuration of natural simaomicin α was obtained by comparison of its spectroscopicalproperties with the synthetic compound, which were identical except for the sign of the optical rotation.Therefore, the absolute configuration of (+)-simaomicin α was assigned as (10S,22S,25S).1.6.2 [4+2] Cycloaddition of 2-StyrylchromenonesThe first synthesis of tetrahydroxanthones was accomplished by Scho¨berg and co-workers in 1954 when theauthors were studying Diels-Alder (DA) reactions of 2-styrylchromenones as dienes with suitable dienophiles(Scheme 1.11). When non-activated 2-styrylchromone 1.117a was treated with maleic anhydride (1.118), thedesired tetrahydroxanthone (1.119a) was obtained in moderate yield. It was unexpected that electron richstyrylchromenones (1.117b-1.117d) gave the desired tetrahydroxanthones (1.119b-1.119d) in lower yields.Despite the high temperature of the reaction (ca. 140 ◦C), the double bond in the partially saturated ring didnot move into conjugation with the carbonyl group (between carbon atoms 4a and 9a) of the tetrahydroxan-thone.14021IntroductionO ArORR'+ OOO O ArORR'OOOxylenesca. 140 ºCR = H,        R' = H,        Ar = PhR = H,        R' = H,        Ar = C6H4-OMe-pR = OCH3, R' = H,        Ar = PhR = OCH3, R' = OCH3, Ar = PhR = H,        R' = H,        Ar = Ph,                  47%R = H,        R' = H,        Ar = C6H4-OMe-p, 32%R = OCH3, R' = H,        Ar = Ph                   22%R = OCH3, R' = OCH3, Ar = Ph                   30%HHreplacements1.117a1.117b1.117c1.117d1.1181.119a1.119b1.119c1.119dScheme 1.11. Synthesis of tetrahydroxanthones: [4+2] Cycloaddition of 2-styryl-chromenones.140In 1992, Letcher and co-workers performed a modified version of the method used by Scho¨nberg. Thetreatment of 2-styrylchromenones (such as 1.120) with cyclic pyrrolidine enamines (such as 1.121) in re-fluxing ethanol afforded fused tetracyclic tetrahydroxanthones (like 1.122, Scheme 1.12).141,142 The inverseelectron-demand Diels-Alder (IEDDA) reaction proceeded in moderate yields (50-60%). Even though thiscyclization proceeded at a temperature lower than that used by Scho¨nberg,140 the double bond in the partiallysaturated ring was not in the position expected after a Diels-Alder reaction (between C-4 and C-4a). Instead,it had moved into conjugation with the carbonyl group between carbon atoms C-9a and C-4a. The authorsproposed a 1,3-hydrogen shift, but made no comments on why this had happened under the reaction condi-tions. The reaction can also be performed using acyclic pyrrolidine enamines to yield dihydroxanthones.143OOPhN+OOPhHHEtOH, ∆50%9a4a 41.120 1.121 1.122Scheme 1.12. Synthesis of tetrahydroxanthones: [4+2] Cycloaddition of 2-styrylchromenones andenamines.141,142In 2012, Chen and co-workers reported an elegant enantioselective inverse electron-demand Diels-Alderreaction to form tetrahydroxanthones. The C-ring of the synthesized tetrahydroxanthone was a bicyclo[2.2.2]-oct-2-ene (1.126, as shown in Scheme 1.13).The reaction utilized organocatalyst diphenylprolinol silyl ether 1.125, anα,β-unsaturated aldehyde as thedienophile (1.124) and a 2-vinylchromenone as the diene (1.123). The reaction proceeded through tetrahy-droxanthone 1.128, which is the DA adduct between 1.123 and the less hindered alkene of 1.127. Under thebasic conditions of the reaction, enolate 1.129 underwent an intramolecular aldol reaction to yield unexpected“cage” tetrahydroxanthone 1.126 in 89% yield and 94% enantiomeric excess.144 Although this method set22IntroductionOO+OOCO2EtNH OTESPhPhOHOHCO2EtOOCHOCO2EtH OOCHOCO2EtHdioxanert, 24 h89% yield94% eeNTESO PhPhH1.123 1.1241.1251.1251.1261.1271.128 1.129Scheme 1.13. Synthesis of tetrahydroxanthones: [4+2] Cycloaddition of 3-styrylchromenones and con-jugated aldehydes.144four stereogenic centres in a Diels-Alder/aldol cascade sequence (two of which were quaternary centres),it only rendered tetrahydroxanthones where the C ring is a bicyclo[2.2.2]-oct-2-ene with the double bondbetween carbon atoms C-1 and C-2, which is not observed in naturally-occurring tetrahydroxanthones.1.6.3 Addition of Cyclic Enamines to SalicylaldehydesIn 1965, Leo A. Paquette145 developed a method for the synthesis of tetrahydroxanthones using enaminesand aldehydes (Scheme 1.14). Treatment of salicylaldehyde (1.130) with morpholinocyclohexene (1.131)yielded hexahydroxanthonol 1.133 through initial nucleophilic attack of the enamine to the aldehyde, fol-lowed by cyclization from the the phenol to the in situ-formed imminium ion. Sarett oxidation of the ben-zylic alcohol rendered a ketone where the α hydrogen was acidic and prone to deprotonation. Under thebasic conditions of the reaction mixture, elimination of morpholine yielded tetrahydroxanthone 1.20 in 55%yield.146 Although able to form the tetrahydroxanthone unit, the reaction conditions employed are harsh,and the use of oxidizing agent chromium(VI) oxide limits the applicability of this method to the synthesis ofunsubstituted tetrahydroxanthones.OHONO+ O NOOHCrO3pyridine55% OO121212O NOOHHPhHrt1.130 1.131 1.132 1.133 1.20Scheme 1.14. Synthesis of tetrahydroxanthones: Addition of cyclic enamines to salicylaldehydes.145Related to the synthesis of tetrahydroxanthones explored by Paquette, Miyano and co-workers built thetetrahydroxanthone unit by using salicylic acid and N,N ′-dicyclohexylcarbodiimide (DCC), which was used23Introductionto activate the carboxylic acid towards nucleophilic attack. The reactive intermediate was then treated with1.131 to yield tetrahydroxanthone 1.20 in one step. This transformation avoids the use of toxic chromium(VI),although the reaction also produced several byproducts and the yield was only 2%.147In 1966, during their studies towards the synthesis of dehydrorotenone, Matsui and co-workers148 treatedacetylsalicylchloride (1.134) with enone 1.131 to produce phenone 1.135 (Scheme 1.15). The phenone thenunderwent an intramolecular oxa-Michael addition (initiated by the phenolic oxygen) to form tetrahydroxan-thone enolate 1.136. The enolate then eliminated morpholine to yield tetrahydroxanthone 1.20 in 65% yield.ClOONO+ O NOOO NOOOOEt3NCHCl365%OO1.134 1.131 1.135 1.136 1.20Scheme 1.15. Synthesis of tetrahydroxanthones: Addition of cyclic enamines to acetylsalicyl chlo-ride.1471.6.4 Lithium Enolate Addition to Acetylsalicyl ChlorideIn 1987, Watanabe and co-workers published amethod to synthesize tetrahydroxanthones using the trimethylsi-lyl enol ether of cyclohexenone (1.137). A lithium enolate was generated in situ, and it was immediatelyreacted with acetylsalicyl chloride (1.134) to generate 1,3-diketone 1.138. Hydrolysis of the acetate underacidic conditions generated a phenol that spontaneously condensed with the 1,3-diketone to produce tetrahy-droxanthone 1.20 in 90% yield149 (Scheme 1.16). Sotiropoulos and co-workers performed a similar reac-tion using camphor instead of cyclohexenone, and obtained the corresponding tetrahydroxanthone in 61%yield.150ClOOOTMS+ OOOOOOHCl90%PhLiO1.134 1.137 1.138 1.20Scheme 1.16. Synthesis of tetrahydroxanthones: Lithium enolate addition to acetylsalicyl chloride.14924IntroductionThe use of strong bases to generate the lithium enolate in situ combined with the strong acidic conditionsto form the pyrane ring of the tetrahydroxanthones, limits the use of this methodology to the synthesis ofunsubstituted tetrahydroxanthones. It is expected that any hydroxyl groups present in the partially saturatedring would undergo dehydration under the acidic conditions, yielding a fully aromatic xanthone as the finalproduct.1.6.5 Oxidative Rearrangement of SpirochromanonesAn elegant method to access tetrahydroxanthones was described by Kapil and co-workers in 1991. Theirstrategy was a thallium(III) nitrate (TTN)-promoted oxidative 1,2-ring expansion of 2-spirochromanones(such as 1.139). Tetrahydroxanthones were obtained in almost quantitative yields. The authors noted thataddition of acids, such as BF3 • Et2O, p-TsOH, and HClO4, reduced both the amount of TTN needed (from2.3 to 1.2 molar equivalents (equiv)) and the reaction time (from 2.5 to 0.5 h).151It is known that TTN is used to convert saturated ketones into α,β-unsaturated ketones.152 In the case ofspirochromanones, enol 1.141 attacks electrophilic thallium(III) to yield organothallium compound 1.142.Because the latter lacks β-hydrogen atoms to undergo β-hydride elimination, the oxygen atom in the chro-manone can assist in the 1,2-migration of an alkyl group to expand the spirocycle and thus form oxo-nium tetrahydroxanthone intermediate 1.143. The oxonium intermediate promptly rearranges to form 7-chlorotetrahydroxanthone 1.140 as shown in Scheme 1.17.151,153OOnTl(NO3)3HClO496% OOnCl ClOOHnClTl ONO2ONO2O2NOOOnCl TlONO2ONO2OOnCl H1.139 1.1401.141 1.142 1.143Scheme 1.17. Synthesis of tetrahydroxanthones: Oxidative rearrangement of spirochromanones.151Kumar and co-workers developed a new route that avoided using highly toxic thallium(III) nitrate. Theauthors used hypervalent iodine reagent [hydroxy(tosyloxy)] iodobenzene (HTIB) instead, but the yield wasinferior (80%).154 Although the use of highly toxic thallium(III) compounds can be avoided by the use ofhypervalent iodine, there have been no studies on the use of polyhydroxylated spirocycles to obtain naturally-25Introductionoccurring tetrahydroxanthones such as those shown in Figure 1.15. Also, it is unknown if the 1,2-alkylmigration proceeds with any sort of regioselectivity.1.6.6 Fries Rearrangement Followed by Nucleophilic Aromatic SubstitutionIn 1997, Hepworth and co-workers reported the synthesis of 3,3-dimethyl-1-oxotetrahydroxanthone (1.146)through a three step sequence. Fluorobenzoate 1.144 was obtained from the condensation of 2-fluorobenzoylchloride and dimedone in the presence of DBU. When fluorobenzoate 1.144 was treated with aluminumchloride in refluxing DCE, a Fries-type rearrangement took place to yield fluorobenzophenone 1.145. Afteran attempt to recrystallize 1.145 from refluxing ethanol, the benzophenone underwent a nucleophilic aromaticsubstitution to yield oxotetrahydroxanthone 1.146 in 82% yield over two steps (Scheme 1.18).155 The last stepcan also take place if a different halogen (bromine or chlorine) is present in the aromatic ring.OOOFO OFO OOOHAlCl3DCEEtOH∆82%1.144 1.145 1.146Scheme 1.18. Synthesis of tetrahydroxanthones: Fries rearrangement followed by NAS.1551.6.7 [4+2] Cycloaddition of Chromenones and DienesIn the early studies of chromenones as dienophiles for Diels-Alder reactions, Scho¨nberg and co-workers140suggested that γ-pyrone derivatives (1.147) would not be suitable towards [4+2] cycloaddition. The authorshypothesized that the neutral form of the γ-pyrone (1.147) would be in resonance with the zwitterionic form1.148, rendering the double bond unavailable for Diels-Alder cycloadditions (Scheme 1.19).OOOO1.147 1.148Scheme 1.19. Resonance forms of γ-pyrone derivatives.It was observed that the γ-pyrone ring can be activated towards [4+2] cycloaddition if an electron with-drawing group (EWG) was placed at the C-3 position of the chromenone, rendering the double bond highlyelectron deficient and readily available towards [4+2] cycloaddition. Hsung and co-workers synthesized3-cyano-6-fluorochromanone (1.152) through a three-step sequence.2326IntroductionFluorohydroxyacetophenone 1.149 was subjected to Vilsmeier-Haack conditions to produce oxofluo-rochromenone 1.150. Treatment of the oxofluorochromenone with methoxylamine hydrochloride yieldedO-methyloxime 1.151, which, under acidic conditions, furnished 3-cyano-6-fluorochromanone (1.152) in37% over three steps. The [4+2] cycloaddition was carried out by mixing 1.152 with 1-methoxybutadiene,to obtain the desired tetrahydroxanthones 1.154a and 1.154b in good yield in an 8:1 ratio, respectively(Scheme 1.20).23OOHFOOHOFPOCl3DMF68% OOHNFOMeOOCNFp-TsOH,∆57%OMe+PhH300 ºC81%dr 8 : 1endo : exoOOFendoCNHOMeOOF CNHOMeexo+H2NOMe•HCl95%1.149 1.150 1.1511.1521.1531.154a 1.154bScheme 1.20. Synthesis of tetrahydroxanthones: [4+2] cycloaddition of electron deficientchromenones.23In 2012, Jørgensen and co-workers reported a stereoselective [4+2] cycloaddition between 3-cyanochromen-one 1.155 and α,β,γ,δ-unsaturated aldehyde 1.156 in the presence of proline-derivative catalyst 1.157. Whenthe aforementioned reagents were combined in chloroform with eight equivalents of N,N-diethylacetamide(DEA) for two days, cyanotetrahydroxanthones 1.158a and 1.158b were obtained in high yield, excellent di-astereomeric ratio (dr>20 : 1, exo to endo, respectively) and good enantiomeric excess (90% ee) (Scheme 1.21).22The authors studied the effect of the substituents of the chromenone and found that, under the same reactionconditions, aldehydes and esters performed very poorly compared with the nitrile group.OOCNOOH OOH+Oexo endo+N NO OOONH NHNH •TFACHCl3, DEA60 ºC, 48 h, 91%dr >20 : 1, exo : endo90% eeHH H1.155 1.1561.1571.158a 1.158bScheme 1.21. Synthesis of tetrahydroxanthones: Enantioselective [4+2] cycloaddition of electron defi-cient chromenones.2227IntroductionWhen the ratio of the diastereomeric mixture of products (>20:1, exo to endo, respectively) was com-pared with the results obtained by Hsung and co-workers (8:1, endo to exo, respectively),23 a complete switchin stereoselectivity was observed. The stereospecificity of the reaction, although not studied in great detailby the authors,22 was explained by the ability of the asymmetric organocatalyst to form hydrogen bonds withthe electron rich nitrogen atom in the nitrile group. The authors proposed transition state 1.159 to explainthe absolute configuration of the observed product (Scheme 1.22).OO CNOOHNHNNR1 OOR1HONβα αβ1.159 1.160Scheme 1.22. [4+2] cycloaddition of chromenones: proposed transition state.22The Diels-Alder reaction of electron deficient chromenones with electron rich dienes is a good methodto synthesize tetrahydroxanthones that exhibit the double bond in the partially saturated ring between carbonatoms C-2 and C-3. Within the naturally-occurring polycyclic tetrahydroxanthones, Sch 54445 (Figure 1.15)is the only compound that shows this type of tetrahydroxanthone core.1.6.8 Conjugate Addition/Aldol Cascade SequenceIn 2004, Bra¨se and Lesch reported the synthesis of tetrahydroxanthones using salicylaldehyde (1.130) and2-cyclohexenone (1.161). The reaction was carried out in water with a substoichiometric amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) (50 mol%). After two days of sonication at room temperature (rt),tetrahydroxanthone 1.162 was obtained in 83% yield (Scheme 1.23).156HOOH OODABCOH2Oultrasound83%O+1.130 1.161 1.162Scheme 1.23. Synthesis of tetrahydroxanthones: Condensation of cyclohexenone and salicylalde-hyde.156The authors proposed two possible reaction mechanisms to explain the condensation of salicylaldehydeand 2-cyclohexenone. Because DABCO is widely used as a promoter for Morita-Baylis-Hillman (MBH) re-actions,157 the authors suggested that DABCO initiated a MBH reaction between cyclohexenone and salicy-laldehyde to yield cyclohexenone derivative 1.164, which underwent an intramolecular oxa-Michael addition28Introductionof phenol, followed by elimination of water to yield tetrahydroxanthone 1.162. Salicylaldehyde is a vinylo-gous carboxylic acid with a pKa value of 8.2,158 while protonated DABCO has a pKa value of 8.79,159 thusan alternative mechanism involved an acid-base reaction to produce a phenoxide that may undergo an anionicoxa-Michael addition to cyclohexenone, followed by aldol condensation to yield tetrahydroxanthone 1.162(Scheme 1.24).HOOOOO+NNHONN OHOOHOOOOOOHMBH reactionOxa-Michael- Oxa-Michael- H2OAldol-H2O1.1301.130 1.1611.1631.1631.1641.1331.162Scheme 1.24. Condensation of cyclohexenone and salicylaldehyde: Proposed mechanistic path-ways.156Further studies were carried out to investigate the effect of different substituents on both the salicylalde-hyde and the 2-cyclohexenone. In general, substituted salicylaldehydes were worse substrates than unsub-stituted salicylaldehyde itself, whether the substituent was an electron withdrawing group or an electrondonating group. Also, when 3 and 4-substituted 2-cyclohexen-1-ones were used, fully aromatic xanthones(1.169) and xanthenes (1.170, no carbonyl group between the two aromatic rings) were obtained as majorproducts. The authors attributed the aromatization to the increased acidity of the hydrogen at carbon C-4 ofthe 4-substituted cyclohexenone (1.166).Since 4-substituted cyclohexenones were unstable toward basic conditions, optimization of the reactionconditions lead to the conclusion that bases weaker than DABCO were ideal for the formation of the desiredtetrahydroxanthones (1.167), and at the same time abated the amount of byproducts 1.169 and 1.170. Theauthors tested imidazole, tri-n-butylphosphine, 4-dimethylaminopyridine (DMAP), and N-methylimidazole(N-MeImid) and found the latter to be the most effective base. Interestingly, DMAP furnished the desiredproducts in low yields, but produced no byproducts. Regarding the substituents on 2-cyclohexenones, nosubstituents at position 3 were tolerated. Only small, non-electronwithdrawing substituents (such as R =Me, 1.166a, R = OH, 1.166b, and R = CH2OH, 1.166c) were tolerated at position 4, although yields werecompromised (1.167a - 65%, 1.167b - 32% and 1.167c - 63%, Scheme 1.25).16029IntroductionHOOH OON-MeImiddioxane/H2OultrasoundO+MeOR R+OMeO MeOR1R: R1 = O: R1 = H, H1.165 1.166 1.167 1.1691.170Scheme 1.25. Condensation of cyclohexenone and salicylaldehyde: Effect of substituents.160Similarly, Shi and co-workers161 condensed salicylN-tosylimine (1.171) and 2-cyclohexen-1-one (1.161),Scheme 1.26. Although Bra¨se and co-workers had used DABCO to promote the condensation of salicylalde-hyde and cyclohexenone, the attempt to condense 1.171 with 1.161 gave no products under the reactionconditions used (room temperature and tetrahydrofuran (THF) as solvent). Other bases used to attemptthe condensation included 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), DMAP and inorganic bases such asK2CO3, KOtBu and KOH, but no condensation products were obtained. However, the reaction proceededto form tosylaminohexahydroxanthone 1.172 in 70% when dimethylphenylphosphine (25 mol%) was used.Treatment of 1.172 with DBU (25 mol%) afforded tetrahydroxanthone (1.162) in 80% over two steps.HNTsOH OOPPhMe2MS 4 ÅTHFO+TsHN HH OODBU80%over2 steps1.171 1.161 1.172 1.162Scheme 1.26. Synthesis of tetrahydroxanthones: Condensation of cyclohexenone and salicyl N-tosylamine.161The condensation of salicylaldehyde or salicylaldehyde imines with 2-cyclohexen-1-one is a promis-ing method to access tetrahydroxanthones related to the hemisecalonic acids. Bra¨se and co-workers haveused this method to make polysubstituted tetrahydroxanthones by manipulation of the products derived fromcondensation of salicylaldehydes and 2-cyclohexenones.162 Use of enantiomerically pure 4,5-disubstituted-2-cyclohexenones results in enantiomerically pure substituted tetrahydroxanthones.163 Bra¨se and co-workershave also made dimeric tetrahydroxanthones following this method.164 The total synthesis of blennolide Cwas reported in 2008 using this approach.241.6.9 Intramolecular Dieckmann Condensation of ChromanonesIn 2008, Tietze and co-workers reported a stereoselective synthesis of tetrahydroxanthones (Scheme 1.27).The synthesis began with orcinol (1.173), which was transformed to isopentenylorcinol 1.174 in six steps.30IntroductionIsopentenylorcinol was then transformed into chromane 1.176 through a palladium-mediated tandemWacker-Heck process using chiral ligand (S,S)-Bn-BOXAX (1.175) in moderate yield and enantiomeric excess (ee).Chromane 1.176 was then transformed into chromanone 1.177 via catalytic reduction of the α,β-unsaturatedester using hydrogen over palladium. The chromane thus formed was oxidized with manganese(III) ac-etate/tert-butyl hydroperoxide to yield 1.177. The chromanone was then subjected to Dieckmann con-densation conditions. The use of standard bases for this transformation, such as lithium diisopropylamide(LDA), lithium bis(trimethylsilyl)amide (LHMDS) and potassium bis(trimethylsilyl)amide (KHMDS) gavelow yields. Gratifyingly, the tetrahydroxanthone 1.178 could be obtained in moderate yield (63%) usingTiCl4/Et3N at 0 ◦C.165 Tietze and co-workers recently used this methodology to synthesize ent-BlennolideA.166OOMe OOMeOTiCl4, NEt3DCM, 0 ºC63% OOMe O OHOHOHOMeOHNOBnNOBnOMeO OOMeOMeO6 steps55% yield88% ee2 steps1.173 1.1741.1751.1761.1761.177 1.178Scheme 1.27. Synthesis of tetrahydroxanthones: Dieckmann condensation.1651.6.10 Vinylogous Addition of Siloxyfurans to BenzopyryliumsIn 2011 Porco and co-workers reported the synthesis of racemic Blennolides B and C (also known as hemise-calonic acids B and E, respectively). The strategy to construct the tetrahydroxanthone core was a vinylogousnucleophilic addition of 2-siloxyfurans to 2-carboxymethylchromenones (Scheme 1.28). When chromenone1.179 was treated with diisopropylsilyl ditriflate in the presence of 2,6-lutidine, intermediate silylene ben-zopyrylium 1.180 was obtained. The intermediate benzopyrylium 1.180 was immediately treated with 2-trimethylsiloxyfuran (1.181) in the presence of triethylamine trihydrofluoride. The in situ-formed vinylo-gous enolate then attacked the carbonyl of the oxonium intermediate, furnishing 2-butenolidechromanone1.182. Reduction of the double bond of the butenolide to make 2-butyrolactonechromanone (1.183) wasaccomplished with nickel boride, made in situ from NiCl2/NaBH4.31IntroductionOOCO2Me2,6-LutidineOHOOCO2MeO SiiPr iPrOTfTfO SiiPr iPrOTfOOOHMeO2C OOO OTMSOOOHMeO2COHOHE = CO2MeHNaHTHF67%Et3N•3HF93%OOOHMeO2C OOHNiCl2•6H2ONaBH4THF/H2O86%1.179 1.1801.1811.1821.1831.184Scheme 1.28. Synthesis of tetrahydroxanthones: Vinylogous addition of siloxyfurans to benzopyryli-ums.167The ensemble of the tetrahydroxanthone was accomplished through a Dieckmann condensation, justlike the last step in the Tietze’s synthesis of tetrahydroxanthones,165,166 and was carried out by subjecting2-butyrolactonechromanone to basic conditions. Treatment of 1.183 with sodium methoxide in methanolresulted in the opening of the lactone, but the use of sodium hydride in anhydrous THF successfully providedtetrahydroxanthone 1.184 in 67% yield.168 The Porco group reported the total synthesis of secalonic acidsA (ergochrome AA) and B (ergochrome BB) using this methodology in early 2014.167 This synthesis oftetrahydroxanthones was specifically designed for the synthesis of secalonic acid derivatives, thus it couldnot be applied towards the synthesis of polycyclic tetrahydroxanthones.1.6.11 Sequential Palladium-Catalyzed C–O, C–C Bond FormationIn 2011, Shipman and co-workers reported a method for the synthesis of 7-arylated tetrahydroxanthones.Synthesis of the tetrahydroxanthone unit started with cyclohexenone (1.185) and 2,3-dibromobenzoyl chlo-ride (1.186) to build 2,5-dibromobenzoyl-2-cyclohexenone (1.187). The tetrahydroxanthone ring was con-structed through a palladium-catalyzed C–O bond formation, which was followed by Suzuki-Miyaura crosscoupling with phenylboronic acid PhB(OH)2 to install the aryl substituent in position 7 in a two-step one-potreaction (Scheme 1.29).The sequential palladium-catalyzed C–O, C–C bond formation was used to synthesize a library of tetrahy-droxanthones with different substituents at position 7. However, no examples with substituents in the par-tially saturated ring of the tetrahydroxanthone moiety were shown.170 In a second publication by the Ship-32IntroductionBrBrOOH OOPd2(dba)3PhB(OH)2Xphos, Cs2CO3dioxane, 101 ºC78%BrBrOO 1) LDA, THF-78 ºC2)Cl1.185 1.186 1.187 1.188Scheme 1.29. Synthesis of tetrahydroxanthones: Tandem Buchwald-Hartwig-type/Suzuki-Miyauramethod.169man group in 2013, 3-hydroxytetrahydroxanthone was synthesized using the ethyl vinylogous ester of 1,3-cyclohexanedione.169 This method has potential for the synthesis of tetrahydroxanthones; however, the syn-thesis of polyhydroxylated tetrahydroxanthones is limited to the availability of substituted cyclohexenonesand their stability, as they are prone to aromatize.1.6.12 Tetrahydroxanthone Construction Within Total SynthesesAlthough several total syntheses of naturally occurring polycyclic tetrahydroxanthones have been reported,these require a custom synthesis of the tetrahydroxanthone core that depends on the target molecule. In 2008,Nicolau and co-workers reported the total synthesis of tetrahydroxanthone blennolide C (1.194, Scheme 1.30).171OCO2MeOTBS1) Br2, Et3N2) NaBH4,CeCl386%OHCO2MeOTBSBr1a) MeLi, tBuLib)        .2) IBX41%OTBSOO OAllylCO2MeOHOO OHOHCO2Me1) Py•HF2) Pd(PPh3)4    nBu3SnHOHHOO OHCO2MeOOAllyl18%over2 stepsO CNAllylO OAllyl1.189 1.1901.1911.1911.1921.1931.194Scheme 1.30. Synthesis of tetrahydroxanthones: Nicolaou’s total synthesis of blennolide C.171Cyclohexenol 1.190 was synthesized from cyclohexenone 1.189 in 86% yield over two steps. Lithium-bromine exchange of 1.189 was followed by addition of acyl cyanide 1.191. Oxidation of the intermediate us-ing IBX furnished benzoylcyclohexenone 1.192 in 41% over two steps. Removal of the tert-butyldimethylsilyl(TBS) group, followed by deprotection of the phenol functionalities using Pd(PPh3)4 and Bu3SnH yielded in-33Introductiontermediate 1.193, which underwent an intramolecular oxa-Michael addition to yield blennolide C (1.194) in18% over two steps. The removal of the TBS group was required as it presumably prevented the oxa-Michaeladdition.171 This approach can be seen as a hybrid of the methods used by Watanabe149 and Bra¨se.156,160For the total synthesis of kibdelone C (1.200, Scheme 1.31), Porco and co-workers constructed the 1,2,4-trihydroxylated tetrahydroxanthone core in a two-step sequence.172 The ABCD ring system of kibdelone C(1.195) was treated with 1.196 under basic conditions. Intermolecular oxa-Michael addition to β-iodo-α,β-unsaturated ester 1.196 (ring F) took place and, after elimination of iodide, 1.197 was obtained in 44% yield.Even though compound 1.197 was subjected to acidic conditions, it failed to undergo electrophilic aromaticacylation. The ester of the F ring was then hydrolyzed under basic conditions and the putative carboxylicacid was then treated with cyanuric chloride (1.198) and pyridine. The intermediate acyl chloride was veryreactive and it immediately cyclized to form the E ring of kibdelone C (compound 1.199).ONOHOHOHOOHOMeOHHOOnPrClkibdelone C22ABC D E F6168 914OHNOHOMeOHMeOOnPrClABC D61622MeO2COOOHF8 914+K3PO4DMSO50 ºC44%ONOHOMeOHMeOOnPrClABC D61622 MeO2COOOHF8914IONOHOMeOHMeOOnPrClABC D61622OOOHF8 914ON NN ClClCl1) LiOH2)39% over2 stepsE1.195 1.1961.1971.1971.1981.199 1.200Scheme 1.31. Synthesis of tetrahydroxanthones: Porco’s total synthesis of kibdelone C.172The synthesis was finished by hydrolysis of the acetonide and demethylation of the ether in ring B throughceric ammonium nitrate (CAN) oxidation followed by reduction with sodium thiosulfate.172 The synthesis ofthe tetrahydroxanthone unit in Porco’s total synthesis of kibdelone C is complimentary to the route Nicolauand co-workers used to construct the tetrahydroxanthone unit in their total synthesis of blennolide C.171 Toconstruct the pyrane ring of the tetrahydroxanthone moiety, Porco and co-workers first installed the phenylether bond and finished the ring construction by an intramolecular acylation.Ready and co-workers also reported the total synthesis of kibdelone C in 2011173 (Scheme 1.32). Theirapproach to the tetrahydroxanthone unit required the synthesis of substituted 2-iodo-2-cyclohexen-1-ol 1.20134Introduction(ring F). Lithium-iodine exchange of 1.201 was performed using methillithium/tert-butyllithium and thelithiated anion was added to pentasubstituted bromobenzaldehyde 1.202 to yield cyclohexenyl benzyl alcohol1.203 in 80%. To form the E ring of the tetrahydroxanthone, both allylic alcohols were oxidized using DMP.Cleavage of MOM and TBS protecting groups provided oxonium intermediate 1.204. The hydroxyl groupof the hemiacetal underwent an intramolecular conjugated addition to the oxonium ion to form acetonide1.205. The configuration at C-1 was set by the configuration of the alcohol at C-2, since the formation of theacetonide occurred from the same face of the tricyclic system.173 A similar approach to the construction of thetetrahydroxanthone core was used in the total synthesis of ent-simaomicin α3 (Scheme 1.8 and Scheme 1.9,Section 1.6.1)OHI OTBSOBnCHOOMeBr OMOMOBnOMeBr OOMeOH OHOTBSMeLi, tBuLiTHF, -78 ºC80% yield1:1 drD D FOBnOMeBr OO1) DMP2) HClO4    acetoneOHD E FOTBSF+OTBSOHO OBnOMeBr OOOHOD E FO124a9a4a9a12124a9a 66% yield1.2011.2021.2031.2031.204 1.205Scheme 1.32. Total synthesis of kibdelone C: Construction of the tetrahydroxanthone core.1731.7 SummarySeveral synthetic approaches to synthesize the tetrahydroxanthone unit have been published in the literature.However, there is not a general method that could enable the synthesis of tetrahydroxanthones with the hy-droxylation pattern exhibited in most naturally occurring polycyclic tetrahydroxanthones. This dissertationpresents the synthetic approaches that I undertook towards the synthesis of polyoxygenated tetrahydroxan-thones, particularly those resembling the tetrahydroxanthone core of simaomicin α.35Chapter 2Attempts to Access the AB and DEF Ringsof Simaomicin α: Synthesis ofIsoquinolinones and Tetracyclic IsoxazolesThe neglected global diseases initiative (NGDI)174 at the University of British Columbia (UBC) aims to find asolution for 20 global diseases including malaria. Malaria, which is one of the top three deadliest diseases forhumans, is caused by parasitic protozoan Plasmodium falciparum and it mostly affects developing countriesin tropical and subtropical regions. One of the main concerns in the 21st century is the development ofresistance of P. falciparum against malarial drugs.175 Simaomicin α (1.1, Figure 2.1) has been found tobe more active against malaria than the current drugs used for the treatment of this disease (see Table 1.2,Section 1.5.1.2). Therefore, the synthesis of simaomicin α, or structurally related compounds, are of greatimportance from a medicinal chemistry approach.ONOOOHOMeOOHOHOHOSimaomicin αHABC D E FG1.1Figure 2.1. Structure of simaomicin α.36Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesSimaomicin α (1.1) consists of two main structural frameworks: an isoquinolinone, rings A and B, and ahighly oxygenated tetrahydroxanthone, rings D, E and F. A disconnection strategy to access simaomicin α ispresented in Scheme 2.1. It was envisioned that formation of the C ring would be performed as the last stepthrough an oxidative coupling of the isoquinolinone and tetrahydroxanthone units present in compound 2.1.In turn, compound 2.1 could be elaborated through the coupling of tetrahydroxanthone 2.3 and isoquinolinone2.2 via lithium-bromine exchange, followed by a nucleophilic attack of the incipient carbanion to the leasthindered carbon atom of the epoxide.ONOPGPGOO O OPGOPGOOPGOPGBr+(+)-Simaomicin αAB D E FONOOOHOMeOOHOHOHOHABC D E FGONOOOHOMeOOHOHOHOHABD E FG1.1 2.1 2.2 2.3Scheme 2.1. One retrosynthetic analysis of simaomicin α.This retrosynthetic analysis of simaomicin α lead to two simpler structures: isoquinolinone 2.2 andtetrahydroxanthone 2.3. A concise approach to isoquinolinones will be discussed in the first part of this chap-ter. It will be followed by exploratory routes to attempt the construction of the tetrahydroxanthone species,which resulted in the synthesis of a xanthone and several fused tetracyclic isoxazoles, isoxazolines and isox-azolidines. An approach to simple tetrahydroxanthones will also be presented. The successful synthesis ofthe polyoxygenated tetrahydroxanthone core will be presented in chapter 3.2.1 Synthesis of IsoquinolinonesThis section will describe an approach to isoquinolines related to the isoquinolinone unit present in simaomicinα (Figure 2.1). For this study, isoquinolinone 2.2 was selected as the target molecule. Based on the func-tional groups present in 2.2, it was foreseen that the epoxide would be the most reactive group, and therefore,it would be installed at a late stage (Scheme 2.2). The epoxide could be constructed from aldehyde 2.4through a Johnson-Corey-Chaykovsky reaction.176 In turn, the isoquinolinone ring in 2.4 could be formedby an intramolecular electrophilic aromatic substitution of γ-oxobenzamide 2.5, to generate the A ring ofthe isoquinolinone. Benzamide 2.5 may be synthesized from N-methylamine 2.6 and benzoic acid 2.7 vianucleophilic acyl substitution.37Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesA BNO OPGOPG OA BNO OPGOPGH BNO OPGOPGHO OOBNHO OPGOPGHOOHO+Oepoxidation EAS amideformation2.2 2.4 2.5 2.6 2.7Scheme 2.2. Retrosynthetic analysis of isoquinolinone 2.2.Amodel study for the synthesis of isoquinolinones was performed, as shown in Scheme 2.3. 2,5-Dimethox-ybenzal (2.8) was oxidized to 2,5-dimethoxybenzoic acid (2.9) using potassium permanganate.177 The car-boxylic acid was then transformed first to its acid chloride in situ using thionyl chloride, and then it wastreated with aminoacetaldehyde dimethylacetal (2.10a) to yield amide 2.11a in 85% yield.178 For the con-struction of the A ring of the isoquinolinone, amide 2.11a was treated with boron trifluoride diethyl etheratein dichloromethane at 0 ◦C.179 However, only the hydrolysis of the dimethyl acetal was observed, obtainingaldehyde 2.12a in 95% yield. As it can be observed, the nitrogen atom in 2.12a lacked the methyl group thatis present in the desired isoquinolinone 2.2.OMeOMeHOO1) SOCl2, ∆2) Et3N, DMAPNHH OMeOMeOMeOMeNOHMeOOMe, 85%BF3•Et2ODCM, 0 ºC95%OMeOMeNOHOB B BHOMeOMeHOBKMnO4, 80 ºC88%2.8 2.92.10a2.11a 2.12aScheme 2.3. Attempt to synthesize the AB rings of simaomicin α.Two routes to obtain N-methylated amide 2.11b were followed: 1) Amide 2.11a was treated with sodiumhydride and methyl iodide in THF/toluene, to obtain amide 2.11b in 65% yield,180 and 2) Carboxylic acid2.9 was converted to its acyl chloride in situ and N-methylaminoacetaldehyde dimethylacetal (2.10b) wasadded to the reaction mixture to afford amide 2.11b in 86% yield. Treatment of amide 2.11b with borontrifluoride diethyl etherate at room temperature resulted in the exclusive deprotection of the dimethyl acetal.When amide 2.11b was treated with a strong Brønsted acid, concentrated H2SO4 at 60 ◦C, isoquinolinone2.13b was obtained in 65% yield .Although isoquinolinone 2.13b was very similar to the AB ring system in simaomicin α, the desiredisoquinolinone (2.2) required a formyl group in position 6 of the aromatic ring. It was planned that 4-formyl-2,5-dimethoxybenzoic acid (2.15) would give access to 2.2. The synthesis of 2.15 was carried out follow-ing literature procedures (Scheme 2.5).181 Protection of the aldehyde functionality of 2.8 as the dimethylacetal was achieved using trimethyl orthoformate under acidic conditions. Directed ortho metalation of38Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOMeOMeHOO1) SOCl2, ∆2) Et3N, DMAPNHOMeOMeOMeOMeNOMeOOMeBF3•Et2ODCM, 0 ºC99%OMeOMeNOOOMeOMeNOB BBBAH2SO460 ºC65%H86%2.92.10b2.11b2.12b2.13bScheme 2.4. Synthesis of the AB rings of simaomicin α.dimethylacetal 2.14 was achieved with tBuLi in the presence of tetramethylethylenediamine (TMEDA), fol-lowed by treatment with anhydrous carbon dioxide. Quenching with hydrochloric acid yielded 4-formyl-2,5-dimethoxybenzoic acid (2.15) in 66% yield over three steps.OMeOMeOHHC(OMe)3,pTsOHMeOH, ∆quan OMeOMeOMeOMea) sBuLi, TMEDATHFb) CO2, HCl66% OMeOMeOHHOO2.8 2.14 2.15Scheme 2.5. Synthesis of 4-formyl-2,5-dimethoxybenzoic acid (2.15).181Carboxylic acid 2.15 was utilized towards the synthesis of isoquinolinone 2.2. Treatment of 2.15 withoxalyl chloride and catalytic dimethylformamide (DMF) yielded the corresponding acyl chloride. The useof thionyl chloride resulted in low yield and a significant amount of byproducts. Slow addition of N-methylaminoacetaldehyde dimethylacetal (2.10b) to the acid chloride afforded amide 2.16 in 84% yield.Attempts to form the A ring of isoquinolinone 2.17 were unsuccessful, and only decomposition of the start-ing material was observed (Scheme 2.6).OMeOMeHOOHOa) (COCl)2b) Et3N, DMAP          84%NHOOOMeOMeNOHOOMeMeOOMeOMeNOHOXH2SO460ºC2.15 2.10b 2.16 2.17Scheme 2.6. Synthesis of 4-formylbenzamide 2.16.39Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesIt was inferred that the aldehyde of 2.16 was decomposing under the strong acidic reaction conditionsbecause the 1H NMR of the crude reaction did not show any signals above 9 ppm. To circumvent the de-composition of the aldehyde, closure of the ring A was postponed until a later stage in the synthesis. Thefocus changed to the conversion of the aldehyde into an epoxide. Compound 2.16 was subjected to Johnson-Corey-Chaykovsky conditions182,183 providing epoxide 2.18 in 96% yield (Scheme 2.7). With epoxide 2.18readily available, a tetrahydroxanthone was required to assemble the DEF and AB fractions, as shown inScheme 2.1.OMeOMeNOHOOMeMeOMe3SiI, NaHDMSO96%OMeOMeNOOMeMeOO2.16 2.18Scheme 2.7. Construction of epoxide 2.18.2.2 Efforts Towards TetrahydroxanthonesOO OPGOPGOPGOPGBrD E FOHOD OR FOW D FOOOBrBr ROOHO++D F+ON OYOOD EOO X WOPGPGO+OHDOOPGOHA BE DCFScheme 2.8. Proposed routes for the synthesis of tetrahydroxanthones.Several routes to synthesize the tetrahydroxanthone DEF fragment of simaomicin α were envisioned,these included the oxa-Michael addition of a phenol or enol to an α,β-unsaturated cyclohexenone derivativefollowed by a Dieckmann condensation (routes A and B, Scheme 2.8). Cycloaddition reactions were also40Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesconsidered, either a [3+2] cycloaddition of nitrile oxides across alkenes (route C), or the [4+2] cycloaddi-tion of electron deficient chromenones and electron rich 1,3-dienes (route D). It was also envisioned that thetetrahydroxanthone core could be obtained through intramolecular cyclizations of substituted salicylaldehy-des (route E) or via tandem intramolecular Baylis-Hillman/oxa-Michael addition of a phenol to a tetheredynone (route F).In the following sections, the attempts to synthesize the tetrahydroxanthone core using routes A-E willbe discussed. The synthesis of tetrahydroxanthones using route F will be detailed in Chapter 3.2.2.1 Oxa-Michael/Claisen Cascade SequenceThe oxa-Michael/Claisen cascade sequence used by Bra¨se and co-workers156 was of particular interest forthe synthesis of DEF ring of simaomicin α because it brings the together preformed D and F rings ofthe tetrahydroxanthone and makes the E ring in one step.160 However, the condensation of salicylalde-hyde (1.130) and 2-cyclohexen-1-one (1.161) yields a tetrahydroxanthone in which the carbonyl group ison carbon atom C-1 and the double bond of the partially saturated ring is situated between carbon atomsC-9 and C-9a (1.162, Scheme 2.9a). This configuration of the tetrahydroxanthone moiety is not present insimaomicin α (1.1, Scheme 2.1) nor in any other important polycyclic tetrahydroxanthones (Figure 1.15,Section 1.5.1.3).120–127,130,184–186It was envisioned that the DEF system of simaomicin α (2.3) may be constructed in a similar cascadereaction using a salicylic ester (2.19) instead of salicylaldehyde, and a cyclohexene derivative like 2.20 insteadof cyclohexenone (Scheme 2.9b). It was proposed that a cyclohexene ring with a nitrile group (W = CN)would facilitate the cascade oxa-Michael/Claisen condensation due to its small size.HOOH OODABCOH2Oultrasound83%O+XOOH O+OWD E FD FOPGOPGOPGOPGBrOPGOPGOPGOPGBr(a)(b)9 9a4a9a4aD E FD F119ReportedProposedW = electron withdrawing group1.130 1.161 1.1622.19 2.20 2.21Scheme 2.9. (a) Synthesis of tetrahydroxanthones performed by Bra¨se and co-workers.156 (b) Proposedsynthesis of the tetrahydroxanthone core via an oxa-Michael/Claisen cascade sequence.41Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesThe oxa-Michael/Claisen cascade sequence was attempted using cyclohexenol 2.25 as the Michael ac-ceptor. The synthesis of 2.25 began with the treatment of 3-bromocyclohexene (2.22) with potassium cyanidein DMF to afford cyclohexenyl nitrile 2.23 in 34% (Scheme 2.10).187,188 Epoxidation of the alkene and treat-ment with LDA afforded the desired cyclohexenol in 18% yield over three steps . The spectral data of 2.25agreed with that reported in the literature, showing two characteristic 1H NMR signals as broad singlets at δ4.33 and 6.60 ppm.189Br KCN18-C-6DCM, rt34%CN m-CPBADCM, rt64%CNOLDA, THF-78 ºC84%CNHO2.22 2.23 2.24 2.25Scheme 2.10. Synthesis of 3-hydroxycyclohex-1-ene-1-carbonitrile (2.25).187,188To attempt the oxa-Michael/Claisen condensation, cyclohexenol 2.25 was treated with methyl salicylate(2.26) and DABCO in water. No reaction was observed after 24 h of sonication (Table 2.1, entry 1). Thereaction was then attempted using similar conditions to those used by Co´rdova and co-workers (entry 2),190but only starting material was recovered. When triethylamine was added to the reaction mixture, no reactionwas observed either (entry 3). It was speculated that the condensation of methyl salicylate with 2.25 wasunsuccessful due to the weak electron-withdrawing effect of the nitrile group.Table 2.1. Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldol conden-sation of methyl salicylate and 2.25.OOMeOH+NCOHadditivesolventOOOHCND D FEF2.26 2.25 2.27entry additive equiv solvent T (◦C) % yield1 DABCO 1.0 H2O rta NR2 PhCO2H190 0.2 PhCH3 rt NR3 PhCO2H, Et3N190 0.2, 1.1 PhCH3 rt NRThe reactions were performed at a 0.1 M concentration for 24 h, using 1.1 equivof 2.26. a Reaction carried out in a sonicator, concentration 2 M.The use of a stronger electron withdrawing group was explored (W = sulfone). The synthesis of 3-(Phenylsulfonyl)cyclohex-2-en-1-ol (2.30) was performed similarly to the synthesis of 2.25 (Scheme 2.10).Bromocyclohexene 2.22 was treated with thiophenol in the presence of sodium hydride to obtain sulfide2.28. Epoxidation of the olefin was achieved using meta-chloroperoxybenzoic acid (m-CPBA) and the sulfide42Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoleswas oxidized to the corresponding sulfone. Epoxide 2.29 was then treated with DBU to afford the desiredcyclohexenol 2.30 in 74% yield over three steps (Scheme 2.11). The identity of the product was confirmedby comparison of the nuclear magnetic resonance (NMR) data with the values reported in the literature.191Br PhSH,NaHTHFquanSPh m-CPBADCM, rtquanSO2PhODBU,THF74%SO2PhHO2.22 2.28 2.29 2.30Scheme 2.11. Synthesis of 3-(phenylsulfonyl)cyclohex-2-en-1-ol (2.30).191Cyclohexenol 2.30 was treated with methyl salicylate in water in the presence of DABCO (Table 2.2,entry 1).156 However, only starting material was recovered, which may be due to its poor solubility in water.The solvent was changed to methanol to increase the solubility of the substrates, but no reaction was observed(entry 2). WhenDBUwas used as the promoter, the reaction was equally ineffective (entry 3). It was expectedthat inorganic bases would deprotonate the phenol, forming an anionic phenoxide that may undergo an anionicoxa-Michael addition. Mild (pKa = 10) and strong (pKa = 18 and 40) inorganic bases were tested (entries 6to 7), but these promoters did not produce the desired product.Table 2.2. Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldol conden-sation of methyl salicylate and 2.30.OOMeOH+PhO2SOHadditivesolventOOOHSO2PhD D FEFOHODF+OSO2Ph2.26 2.30 2.33 2.32entry additive equiv solvent T (◦C) % yield1 DABCO 1.0 H2O rta NR2 DABCO 1.1 CH3OH rta NR3 DBU 1.1 PhCH3 115 NR4 Et3N 1.1 THF rt 10 (2.32)5 Et3N 1.1 THF 80 27 (2.32)6 K2CO3 1.1 THF rt – 60 NR7 NaH 1.5 THF rt NR8 NaOCH3 2.2 CH3OH rt NRThe reactions were performed at a 0.1M concentration for 24 h, using 1.1 equiv of 2.26.a The reaction was performed in the sonicator, concentration 2 M.It was observed that treatment of the reaction mixture with triethylamine resulted in transesterificationproduct 2.32, although it was a low-yielding process (entries 4 and 5). To avoid transesterification, com-pound 2.35, the methyl ether of cyclohexenol 2.30, was prepared using sodium hydride and methyl iodide43Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesin THF. Compound 2.35 was treated with ethyl salicylate in the presence of sodium hydride. The reactionwas attempted in THF at room temperature or in dimethylsulfoxide (DMSO) at 40 ◦C but no reaction wasobserved in either case (Scheme 2.12).OOOMeSO2PhXO OEtOH+PhO2SOMeNaHTHForDMSOD D FEF2.34 2.35 2.36Scheme 2.12. Attempt to condense sulfonyl methoxycyclohexene 2.35 with ethyl salicylate.The condensation of cyclohexenol derivatives had been attempted using ethyl salicylate (2.34) as theD ring precursor, but the desired tetrahydroxanthone had not been obtained; either starting material wasrecovered, or transesterification had occurred. Salicylaldehyde (1.130) was then used as the precursor forthe D ring. The initial reaction published by Bra¨se156 was reproduced and tetrahydroxanthone 1.162 wasobtained in 65% yield (Table 2.3, entry 1). However, no reaction was observed when 2-bromo-2-cyclohexen-1-one (2.37a, X = Br) was used as theMichael acceptor (entry 2). The reaction was attempted using inorganicbases, but only the decomposition of 2-bromo-2-cyclohexen-1-one 2.37a was observed (entries 3 and 4).Table 2.3. Studies towards the synthesis of tetrahydroxanthones: Oxa-Michael addition/aldol conden-sation of salicylaldehyde and cyclohexenone derivatives 2.37.HOOH OOO+ XXOHbasesolventD D FEF+OOD FE1.130 2.37 2.38 1.162entry X base equiv solvent % yield1 H DABCO 0.5 H2Oa 65b2 Br DABCO 0.5 H2Oa NR3 Br K2CO3 1.5 THF dec4 Br NaH 1.0 THF decThe reactions were performed at rt for 24 h at a 0.1 M concentration using 1.1equiv of 1.130. a The reaction was performed in the sonicator.Furthermore, treatment of 2-cyclohexenone (1.161, X = H) with methyl salicylate (2.26) in the presenceof 0.5 equiv of DABCO in water under sonication resulted in recovered starting material (Scheme 2.13).156The reaction between methyl salicylate (2.26) and 2-cyclohexenone (1.161) may have failed because methylsalicylate possessed an extra oxygen atom attached to the carbonyl group, which rendered the carbonyl po-sition less electrophilic. Additionally, the methoxy group in methyl salicylate is bulkier than the hydrogen44Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesatom in salicylaldehyde, which may have prevented the carbonyl from getting in proximity with the enolateproduct of the oxa-Michael addition.OOOD FEXOMeOOH O+ DABCOwatersonicationD F2.26 1.161 2.39Scheme 2.13. Attempt to make 1-oxotetrahydroxanthone.The proposed reaction mechanism between salicylaldehyde and cyclohexenone involves an oxa-Michaeladdition followed by an aldol condensation to form aldol 2.45 (Scheme 2.14a).160 However, for the caseof 2-bromo-2-cyclohexen-1-one, the bromine atom can behave as an electron withdrawing group throughinductive effect. Alternatively, the bromine atom can also act as an electron donating group through reso-nance effect, delocalizing one of its lone pairs with the olefin of the α,β-unsaturated ketone, rendering the βcarbon atom more electron rich, therefore less likely to undergo nucleophilic attack from the phenolate ion(Scheme 2.14b).O OHOOOOOBrOBrOHOOOOO Br(a)(b)OHOO1.161 2.40 2.41 2.422.37a 2.43 2.41 2.442.45Scheme 2.14. Resonance forms of compounds 1.161 and 2.37a.Attempts tomake the tetrahydroxanthone unit either by condensation ofmethyl salicylate with 2-cyclohex-enol derivatives (Table 2.1 and Table 2.2), or condensation of salicylaldehyde and 2-bromo-2-cyclohexen-1-one (Table 2.3) were unsuccessful. A different approach to the tetrahydroxanthone fragment was attempted.2.2.2 2,6-Dibromobenzoquinone RouteIn the Kelly synthesis of cervinomycins A1 and A2,192 the authors built the xanthone ring using a condensa-tion between 2,6-diiodobenzoquinone (2.46) and benzoate 2.47 (Scheme 2.15a). The substitution proceededthrough an addition/elimination mechanism. Reduction of the quinone, followed by treatment with acid,afforded the xanthone unit in an overall 47% yield. Analogously, it was envisioned that the treatment of45Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles2,6-dibromobenzoquinone (2.49) with an anion derived from methyl 2,6-dioxocyclohexane-1-carboxylate(2.50) may generate tetrahydroxanthone 2.51, which could be further converted into the desired tetrahydrox-anthone 2.3 (Scheme 2.15b).OO OPGOPGOPGBrHOO OOOBr BrMeO D E FD F+OPGOOOPGOPGIHOOOOI IMeO D E FD F+OMeOMe1) KF, DMF, 75 ºC2) Na2SO4, rt3) concd H2SO4    20 - 60 ºC            47%(a)(b)OOOPGOPGBrD E FOOMeOMereportedproposed2.46 2.47 2.482.49 2.50 2.51 2.3Scheme 2.15. (a) Kelly synthesis of xanthones.192 (b) Proposed route to tetrahydroxanthones.2,6-Dibromobenzoquinone (2.49) was prepared from phenol following literature procedures.193,194 Thiscompound (2.49) was chosen over 2,6-diiodobenzoquinone because the brominated species is easily syn-thesized in the laboratory195 and is less sterically hindered.196 Methyl 2,6-dioxocyclohexane-1-carboxylate(2.50) was prepared from 1,3-cyclohexanedione, according to literature procedures.197 Attempts to coupledibromoquinone and 2.50 under a variety of conditions were unsuccessful (Table 2.4).Table 2.4. Attempted coupling of 2.49 with methyl 2.50.OBr BrOBasesolventOBr OO+HOOMeOO OOD F D FE2.502.49 2.51entry base equiv solvent T (◦C) t (h) % yield1 NaH 1.1 THF rt 2 deca2 NaH 1.1 THF 40 14 deca3 NaH 1.1 THF 60 2 deca4 NaH 1.0 DMSO rt 0.1 deca5 NaH 2.0 CH3CN rt 1 deca6 K2CO3 1.0 CH3CN rt 24 deca7 Cs2CO3 1.0 CH3CN rt 24 deca8 LDA 1.1 THF -78 ◦C 0.5 decaThe reactions were performed at a 0.1 M concentration using 1 equiv of 2.50and 2.49 each. a Compound 2.50 had decomposed (observed by TLC).46Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesSince compound 2.50 could not be recovered, it was speculated that 2.50, or the anion derived thereof,was unstable under basic conditions. Although the reaction of 2,6-dibromobenzoquinone (2.49) with 2,6-dioxocyclohexane-1-carboxylate (2.50) only resulted in the decomposition of the latter, it was believed thatthe use of 2,6-dibromobenzoquinone (2.49) may result in a concise and short approach for the synthesis oftetrahydroxanthones. Attention was focused on the coupling of 2.49 and methyl salicylate (2.26), althoughthis would result in the formation of a xanthone and not a tetrahydroxanthone.The coupling of 2.49 and 2.26 was attempted using potassium fluoride in DMF at 75 ◦C, which are theoriginal conditions reported by Kelly and co-workers.192 However, these conditions only led to the decom-position of 2.49 (Table 2.5, entries 1 and 2). Potassium and cesium carbonate in DMF were ineffective aswell (entries 3, 4, and 8). Ullman-type coupling was attempted, but it was also unsuccessful (entries 5 and6). When the reaction was carried out using potassium carbonate in DMSO at 60 ◦C (entry 8), the couplingof two molecules of methyl salicylate and one molecule of dibromobenzoquinone was observed, affordingcompound 2.53 in 20% yield.Table 2.5. Condensation of methyl salicylate and 2,6-dibromobenzoquinone.OBr BrOBasesolventOBr OO+HOMeOOOMeOD F D FOO OOOMeOOMeO+2.49 2.26 2.52 2.53entry base equiv solvent T (◦C) time (h) % yield1 KF 1.1 DMF 90 4 dec2 KF 3.0 DMF 0–80a 2 dec3 K2CO3 1.5 DMF rt 16 NR4 Cs2CO3 1.2 DMF 80 4 NR5 CuBr 1.0 DMF rt–110a 2 dec6 CuBr/TMEDA 1.0 CH3CN rt–80a 2 dec7 K2CO3 1.0 CH3CN rt 16 NR8 K2CO3 1.0 DMSO 60 16 20 (2.53)9 NaOCH3 1.5 CH3OH rt 2 NR10 tBu Li 1.1 THF -78–80a 2 dec11 NaH 1.5 THF rt 2 NR12 NaH 1.2 DMF rt 16 dec13 NaH 1.2 PhCH3 80 2 dec14 NaH 1.1 DMSOb 60 16 62The reactions were performed at a 0.1 M concentration using 1 equiv of 2.49 and 2.26. a Reactions waremonitored by TLC every two hours. If there was no change, the temperature would be increased by 20 ◦C.b The reaction was performed at a 0.066 M concentration.47Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesFurther investigation focused on obtaining a controlled mono addition ofmethyl salicylate to dibromoben-zoquinone. The best result was found when sodium hydride was used in DMSO at 60 ◦C (Table 2.5, entry14). It was found that a very slow addition (over 30 min) of deprotonated salicylate to dibromobenzoquinoneresulted in the mono addition, otherwise a rapid addition of the deprotonated salicylate resulted in the addi-tion of two equivalents of salicylate.The mode of substitution in the addition of 2.26a to dibromobenzoquinone 2.49 could be either ipso,on the same carbon atom bearing the bromine atom, or cine, on the carbon atom adjacent to the bromineatom.198 The substitution pattern of the product was determined by 1H NMR spectroscopy to be ipso, whichwas confirmed by the coupling constant (J) values of the hydrogen atoms present in the quinone (J = 2.3 and2.8 Hz).66 The proposed reaction mechanism is outlined in Scheme 2.16. Oxa-Michael addition of salicylateanion (2.26a) to either ipso carbon of dibromobenzoquinone 2.49 generates enolate intermediate 2.54, whichthen loses a bromide ion to regenerate the benzoquinone.OBr BrOO OBrOOBr OBr OODOMeOO OMe O OMeD F D FF2.49 2.26a 2.54 2.52Scheme 2.16. Reaction mechanism of the addition of salicylate to 2,6-dibromobenzoquinone.The conversion of bromosalicyl benzoquinone 2.52 into 3-bromo-1,4-dihydroxyxanthone (2.56) was ac-complished through a two-step sequence (Scheme 2.17). Reduction of 2.52 to hydroquinone 2.55 usingsodium dithionate was followed by intramolecular Friedel-Crafts acylation under acidic conditions, to yieldthe desired xanthone in 82% yield over two steps. The identity of the xanthone was corroborated by thedisappearance of the signal characteristic of the hydrogen para to the bromine atom at chemical shift 6.46ppm in the 1H NMR spectrum.OOBr OOMeONa2S2O4EtOAc90%OHOHBr OOMeOH2SO460 ºC92%OHOHBr OO2.52 2.55 2.56Scheme 2.17. Synthesis of 3-Bromo-1,4-dihydroxyxanthone.The coupling of epoxide 2.18 with bromoxanthone 2.56 was attempted. A metal-bromine exchangefollowed by attack of the carbanion (generated in situ) to the least substituted carbon of epoxide 2.18 had48Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesbeen proposed for the coupling of the AB and DEF units (see Scheme 2.1, page 37). To ensure that thexanthone would be compatible with the reaction conditions, the two hydroxyl groups in xanthone 2.56 werefirst protected as benzyl ethers using sodium hydride in THF, affording 2.57 in 90% yield.Unfortunately, the coupling of epoxide 2.18 with 2.57 was unsuccessful. Metal-bromine exchange on2.57 using either isopropylmagnesium bromide or sec-butyllithium in THF at -78 ◦C did not take place Itwas observed that the organometallic reagent had added to the carbonyl carbon of the xanthone before metal-bromine exchange could occur. It was also observed that the epoxide decomposed under the strong basicconditions of the reaction mixture (Scheme 2.18).OOOBnOBnBr+ XOMeOMeNOOMeMeOOConditionsOMeOMeNOOOOBnOBnOHOO2.18 2.57 2.58Scheme 2.18. Failed attempt to couple DEF rings and epoxide 2.18.Although the syntheses of substituted xanthones 2.56 and 2.57 were successful, attempts to couple xan-thone 2.57 with epoxide 2.18 resulted in addition of the organometallic to the carbonyl carbon of the tetrahy-droxanthone and further decomposition of the epoxide occurred. Tetrahydroxanthones analogous to 2.3wererequired for the coupling with epoxide 2.18, thus attention was focused on the development of a route to ac-cess polyoxygenated tetrahydroxanthones. The following two sections will discuss the attempts to make thetetrahydroxanthone core using nitrile oxides and cyclohexene derivatives.2.2.3 Intermolecular Nitrile Oxide [3+2] Dipolar CycloadditionThe structure of tetrahydroxanthone 2.3 features a β-hydroxy ketone –an aldol– as outlined in Figure 2.2.The classical method to obtain β-hydroxy ketones, the aldol reaction, involves the formation of a new C–Cbond by the coupling between aldehydes or ketones in the presence of acids or bases.199 The aldol reactioncould either use the same carbonylic compound (an aldol dimerization) or different carbonylic species (acrossed aldol reaction).199,200 The β-hydroxy ketone present in compound 2.3 can be seen as the product ofa cross aldol reaction. When both carbonylic species bear α hydrogen atoms, cross aldol reactions tend toproduce aldol dimerization products.A concise method for the synthesis of β-hydroxy ketones that would result from a cross aldol reactionis the reductive cleavage of isoxazolines followed by hydrolysis (Scheme 2.19a).201–206 Isoxazolines can besynthesized from two readily available functional groups: a nitrile oxide and an alkene using a [3+2] dipolar49Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOOD E FOPGOPGBrOPGOPGα β2.3Figure 2.2. Aldol functionality embedded in the structure of tetrahydroxanthone 2.3.cycloaddition.207,208 This method presents the advantage of forming both a C–C bond and a C–O bond inthe positions required for the β hydroxy ketone in a concerted step.209 It was envisioned that 1-hydroxytetrahydroxanthones could be prepared using the [3+2] dipolar cycloaddition of nitrile oxides across alkenesfollowed by reductive cleavage of the N–O bond (Scheme 2.19b).N +ON HOOO a) reductivecleavageb) hydrolysisreported (a)(b)NClOH R1 N O R1R2R2 OO OHR1reductive cleavagecoupling ofR and R2 to form ether bond+ D E FD F DFOPGRMeOOPGOPGOMeRMeO36512412 3 456254613363636proposed2.59 2.60 2.61 2.622.63 2.64 2.65 2.66Scheme 2.19. (a) Reported sequence for the synthesis of β-hydroxy ketones using nitrile oxides.207,208(b) Proposed synthesis of tetrahydroxanthones using [3+2] dipolar cycloaddition.The proposed sequence involves an intermolecular cycloaddition between an aromatic nitrile oxide anda functionalized cyclohexene (2.64, the dipolarophile) to yield isoxazoline 2.65. The selection of the sub-stituent groups in both the oximoyl chloride (R) and the functionalized cyclohexene (R1 and R2) has to becarefully chosen because these groups would be used for the construction of the pyranone ring of the tetrahy-droxanthone moiety.2.2.3.1 Preparation of Nitrile Oxide Precursors: Synthesis of Oximoyl ChloridesNitrile oxides are reactive species that are prone to undergo dimerization and, in some cases, hydrolysis.210The majority of these compounds are not able to withstand storage, thus, it is preferred to prepare nitrileoxides in situ.211 The majority of the methods to access the nitrile oxide group require oxidation of ketoximesand aldoximes or dehydration of nitro compounds.212–214 Aldoximes have been widely used to generate nitrile50Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesoxides in situ due to their easy availability.215,216 The overall transformation from aldoximes to nitrile oxidesis a formal oxidation where two hydrogen atoms have been removed (Scheme 2.20).R HN OH NOR[O]2.67 2.68Scheme 2.20. Formal oxidation of aldoximes to obtain nitrile oxides.Aldoximes are readily synthesized by treatment of aldehydes with hydroxylamine.217 They can be ox-idized to nitrile oxides using either chlorine gas,212 ceric ammonium nitrate,218 sodium hypochlorite,201[hydroxy(tosyloxy)] iodobenzene,219 or (diacetoxy) iodobenzene.220 A stepwise generation of the nitrile ox-ides from aldoximes is to first form the oximoyl chloride, which upon treatment with a base renders the nitrileoxide in situ.The synthesis of oximoyl chlorides is usually a two-step process. The aldehyde is treated with aqueous hy-droxylamine at reflux temperature to obtain an aldoxime. The aldoxime is treated with N-chlorosuccinimide(NCS),216 or chloramine-T,214 and a catalytic amount of pyridine to afford the oximoyl chloride.217 Thesetransformations are generally high yielding and do not require the use of inert atmosphere or dry solvents.The formation of the oximoyl chloride is supported by the absence of a characteristic signal, the C–H bondof the oxime at δ 8.25 ppm.ROH RNHOHRNClOH Et3N NORNCSpyridineCHCl340 ºCH2NOHH2O∆2.69 2.70 2.71 2.68Scheme 2.21. Nitrile oxide precursors: Synthesis of oximoyl chlorides.217The speculated mechanism for the oxidation of the aldoxime to the oximoyl chloride is depicted inScheme 2.22. Analogous to an enol functional group, the oxime carbon atom acts as a nucleophile to re-act with the electrophilic chlorine source. It is proposed that oxonium species 2.73 is formed during thecourse of the reaction; a blue/green color typically observed during this transformation may be due to thisintermediate.210,212,216 The anion of succinimide (2.74) then abstracts the hydrogen atom from the geminalchloro nitroso carbon to furnish oximoyl chloride 2.85.51Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesR HN ONClOOHR HN OClHNOOR ClN O HHNOO+PSfrag2.72 2.77 2.73 2.74 2.75 2.76Scheme 2.22. Mechanistic rationale for the formation of oximoyl chlorides.For the synthesis of simple tetrahydroxanthone analogues that resembled simaomicin α, it was requiredto use nitrile oxide precursors with a highly oxygenated pattern, specifically at positions C-3 and C-6. Also,an appropriate substituent at position C-2 was required to allow for the synthesis of the pyranone ring ofthe tetrahydroxanthone moiety (see Scheme 2.19b). Commercially available benzaldehydes salicylaldehyde,4-methoxybenzaldehyde (p-anisaldehyde), and ortho-vanillin were selected due to their oxygenation pat-tern. For the synthesis of oximoyl chlorides with a higher oxygenation pattern (2.88, 2.89, 2.90, and 2.91,Table 2.6), 2,5-dimethoxybenzaldehyde was elaborated into 2-bromo-3,6-dimethoxybenzal-dehyde (2.81)and 2-hydroxy-3,6-dimethoxybenzaldehyde (not shown).Aldehyde 2.81was prepared following literature procedures.221 Protection of 2,5-dimethoxybenzaldehyde(2.78) using 2,2-dimethylpropane-1,2-diol was followed by directed ortho lithiation using n-butyllithium andthe incipient anion was quenched with 1,2-dibromotetrachloroethane to produce bromide 2.80. Aromatic ac-etal 2.80 was then treated with concentrated hydrochloric acid to furnish bromobenzaldehyde 2.81 in 60%yield over three steps.OHOHBrOMeOMeOMeOMeOH OHOMeOMeToluene, ∆97%OO OMeOMeOOBrconcd HCl99%n-BuLi, -20 ºChexanes, PhHBrCl2CCCl2BrTHF62%2.78 2.79 2.80 2.81Scheme 2.23. Synthesis of 6-bromo-2,5-dimethoxybenzaldehyde.221Several oximoyl chlorides were synthesized (the results are shown in Table 2.6). The nitrile oxide pre-cursor derived from benzaldehyde (2.84) was made to try simple reactions and understand the behaviourof the [3+2] dipolar cycloaddition (Scheme 2.27). Oxidation of the oxime derived from salicylaldehyde217resulted in chlorinated oximoyl chloride 2.85. The reaction conditions were optimized and it was found thattwo equivalents of NCS afforded 2.85 in 90% yield. The introduction of a chlorine atom at position C-5 ofthe aromatic ring had not been foreseen; however, it did not affect the ability of the compound to undergo52Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles[3+2] dipolar cycloadditions. Furthermore, it could be used as a potential handle to attach other substituents,increasing the complexity of the molecule.Oximes derived from p-anisaldehyde, o-vanillin and 2.81 furnished desired oximoyl chlorides 2.86, 2.87,and 2.88 in excellent yields. However, when the oxime of o-vanillin was subjected to standard conditions forthe synthesis of oximoyl chlorides217 (1.1 equiv of NCS and a catalytic amount of pyridine in chloroform),a mixture of several unidentified compounds was obtained. The formation of side products was averted byusing 20 mol% of pyridine. The formation of oximoyl chloride 2.88 proceeded smoothly. Although it was anelectron rich species with two electron donating groups (methoxy groups), no chlorination of the aromaticring was observed. The oximoyl chloride was stable even when left standing on the bench-top at roomtemperature for several days. Unlike 2.88, the synthesis of other highly oxygenated oximoyl chlorides 2.89,2.90 and 2.91 could not be achieved. Either chlorination occurred exclusively on the aromatic ring or theoximoyl chloride decomposed immediately. It seemed that the presence of highly electron donating groups(like methoxy) in the presence of a hydroxyl ortho to the oxime, rendered these compounds very unstable.Table 2.6. Synthesis of selected oximoyl chlorides.NHOHCHCl3, 40 ºCNO OCl+NRNClOHR2.82 2.77 2.83NClOH66%NClOH90%OHClNClOH97%ONClOH98%OHONClOH96%BrOONClOHNOT OBTAINEDOHNClOHNOT OBTAINEDOHONClOHNOT OBTAINEDBrOHOHO OOCl2.84 2.85 2.86 2.87 2.882.89 2.90 2.91The reactions were performed using 1.1 equiv of NCS (2.77), except for compound 2.85 (2.0 equiv wereused). Pyridine was used in a catalytic amount, except for compound 2.87 (20 mol% was used).53Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles2.2.3.2 Synthesis of Dipolarophiles for [3+2] Dipolar CycloadditionsIt had been envisioned that the dipolarophile component of the [3+2] cycloaddition would be a cyclohexenederivative, which would become the F ring of the desired tetrahydroxanthone (see Scheme 2.19b). Thiscyclohexene derivative had to fulfill one condition: there must be a hydroxyl or a carbonyl group at position C-1 (allylic position) that would be used for the closing of the pyranone ring (ring E) of the tetrahydroxanthone.Several cyclohexene derivatives were selected as potential dipolarophiles for the coupling with nitrileoxide precursors. Cyclohexenone (1.161) was considered because it was expected that the carbonyl groupwould enable the ring closure for the formation of the pyranone ring. Other cyclohexenone derivatives werealso contemplated (Figure 2.3).R1R2F256431OAcOAcOAcBrOBrOCO2Et OHBrO OOH2.64 2.92 2.93 1.161 2.37a 2.95a 2.95b 2.95Figure 2.3. Dipolarophiles selected for treatment with nitrile oxides.From the dipolarophiles selected, only cyclohexenone was commercially available and the rest were syn-thesized (Scheme 2.24). Bicyclo 2.92 was made from furan and ethyl acrylate following literature proce-dures.222 The reaction yielded both diastereomers and their identity was confirmed by comparing the 1HNMR data with the reported values, observing peaks at chemical shift (δ) 4.20 (q, J = 7.1 Hz, 2H) and 2.18(dt, J = 11.6, 4.3 Hz, 1H).223 trans-2-Cyclohexene-1,4-diol diacetate (2.93, Scheme 2.24a) was synthesizedfrom 1,3-cyclohexadiene using catalytic palladium(II) acetate, following a modification of literature proce-dures.224 The NMR data of 2.93 matched the literature values, a broad singlet (br s) at δ 5.89 ppm for thealkene hydrogens and a multiplet at δ 5.32 ppm for the base of the acetates.All brominated cyclohexenes were synthesized from cyclohexenone (Scheme 2.24c). Bromination usingelemental bromine inDCM, followed by treatment with triethylamine produced 2-bromo-2-cyclohexen-1-one(2.37a) in 93% yield. Luche reduction afforded 2-bromocyclohex-2-en-1-ol (2.95a) in 97% yield. Synthesisof acetate 2.95b was achieved in 98% by treatment of the allylic alcohol with acetic anhydride in the presenceof pyridine.A dipolarophile that would allow for the F ring of the tetrahydroxanthone to have a 1,4-dihydroxylationpattern must contain a hydroxyl substituent in position C-6. It was envisioned that 6-hydroxy2-cyclohexen-1-one (2.95) would serve this purpose. Compound 2.95 was synthesized in 16% from cyclohexenone usingRubottom oxidation conditions (Scheme 2.24d).22554Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesPd(OAc)2LiClAcOH48%OAcOAcO OEtO ZnCl2OCO2EtOBr2, DCMEt3N93%OBrNaBH4CeCl3•7H2OMeOH97%OHBrAc2OpyridineDCM98%OAcBr(a) (b)(c)O LDATHFTMSClOTMS m-CPBAHCl16%O(d)OH35%2.96 2.93 2.97 2.98 2.921.161 2.37a 2.95a 2.95b1.161 2.99 2.95Scheme 2.24. Synthesis of dipolarophiles following literature procedures.225–227Not all oximoyl chlorides were synthesized at the same time, instead, as they were obtained, they wereused to attempt [3+2] dipolar cycloaddition reactions with different dipolarophiles. Similarly, not all dipo-larophiles were available to attempt the [3+2] dipolar cycloaddition, some reactions were run parallel in timeto each other, while others were run in different time frames.2.2.3.3 [3+2] Dipolar CycloadditionsThe [3+2] dipolar cycloadditions were studied starting with oximoyl chloride 2.85. Treatment of 2.85 with2.93 in the presence of triethylamine at room temperature in DMF resulted in the decomposition of the nitrileoxide and the diacetate 2.93 was recovered in 92%. When triethylamine was added to the solution of 2.85and 2.93, the reaction mixture went from orange to green and it eventually turned dark red, which suggestedthat the nitrile oxide species had been formed in situ (Scheme 2.25a).NClOHOHClXOAc Et3NDMF, rt N OOHClOAcOAcAcO(a)2.85 2.93 2.100Scheme 2.25. Attempt to synthesize isoxazoline 2.100.Failure of coupling between oximoyl chloride 2.85 and 1,4-diacetoxy-cyclohex-2-ene 2.93 may be due tosteric hindrance of the latter. Nitrile oxide precursor 2.85 was treated with racemic 2-bromo-2-cyclohexenylacetate (2.95b, R = OAc) in the presence of triethylamine at room temperature; however no cycloadduct55Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesproduct was observed (Scheme 2.26). The lack of reactivity may have been due to the steric bulk of theacetate group itself, so the cycloaddition was attempted using 2-bromo-2-cyclohexen-1-ol (2.95a, R = H)in the presence of triethylamine at room temperature. Unfortunately no cycloadduct product was observed(Scheme 2.26a). A less bulky nitrile oxide precursor, with no ortho-substituents, was used to attempt the[3+2] cycloaddition with 2.95b. Oximoyl chloride 2.86 was treated with 2-bromo-2-cyclohexenyl acetate(2.95b) but no cycloaddition product was isolated and only decomposition of the nitrile oxide precursor wasobserved (Scheme 2.26b).NClOHOHClORBrEt3NDMF, rtNRN OOHClORX+(b)(a)NClOHOAcBrEt3NDMF, rtNRN O OAcX+O O2.85 2.94 2.1012.86 2.95b 2.102Scheme 2.26. Attempted [3+2] dipolar cycloaddition between nitrile oxide precursor 2.85 and 2-bromo-2-cyclohexen-1-ol.The lack of reactivity towards [3+2] dipolar cycloadditions between the incipient nitrile oxide and allylicalcohol derivatives may be due to the pseudoaxial position that the allylic substituent in the dipolarophileadopts in the half chair conformation. The use of allylic cyclohexenol derivatives was stopped. Reactionsemploying different dipolarophiles were tested in parallel.Nitrile oxide precursor 2.84was treated with racemic bicyclo alkene 2.92 in the presence of triethylaminein DMF and only two different compounds were obtained in 76% yield. The [3+2] dipolar cycloaddition ofnitrile oxides with this type of dipolarophiles had precedent in the literature. Benzaldehyde-derived nitrileoxides underwent [3+2] dipolar cycloadditions when treated with norbornene derivatives. The authors notedthat only regioisomeric exo adducts had been formed.203,228,229Although the [3+2] cycloaddition between nitrile oxide precursor 2.84 and dienophile 2.92 could haveproduced up to four different compounds (Scheme 2.27), the 1H NMR of the crude reaction showed that themixture consisted of two products in a 1.4:1 ratio. Flash chromatography over silica gel allowed for the twoproducts to be separated. However, a combination of one-dimensional and two-dimensional NMR data wasnot sufficient to discern between the two structures, although both compounds showed characteristic NMR56Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolessignals. The major regioisomer was crystallized and was analyzed through X-ray crystallography and an OakRidge thermal ellipsoid plot program (ORTEP) was obtained (Figure 2.4), corresponding to exo regioisomer2.103a, which exhibited 1H NMR signals for hydrogen atoms H4, H7, and H7a convoluted into a multipletfrom δ 4.73 to 4.87 ppm. The signals for the same hydrogen atoms (H4, H7, and H7a) for the minor exoregioisomer 2.103b are three well resolved doublets at δ 4.93 ppm (d, J 8.0 Hz), 4.98 ppm (d, J 6.0 Hz), and4.74 ppm (d, J 5.2 Hz), respectively.C6C7C3C4C9C5C8C17C19C20C11C12C13C14C15 C16N2O21O1O10O18OONOO2.103aFigure 2.4. Solid state molecular structure of compound 2.103a, ellipsoids at 30%.The two products from the [3+2] cycloaddition between 2.84 and 2.92 were identified as the regioisomersproducts of the exo cycloaddition (2.103a and 2.103b).228 No endo product was detected by NMR.NClOH+Et3NDMF76%OCO2Et OONexoOONexoCO2EtCO2EtOONendoNOT OBSERVEDH7H4H7H4H7aH3aH7aH3a H4H7H7aH3a+ +δ = 4.73 - 4.87 δ = 4.98δ = 4.93δ = 4.74OONendoNOT OBSERVEDH4H7H7aH3a+CO2EtCO2Et2.84 2.92 2.103a 2.103b 2.104a 2.104bScheme 2.27. [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.84 and bicyclo alkene 2.92.When nitrile oxide precursor 2.85 was treated with bicycle 2.92, two [3+2] cycloadducts were obtainedin 57% yield (Scheme 2.28). It was observed by 1H NMR that the crude reaction mixture consisted exclu-sively of the regioisomeric exo adducts (2.105) in 1.4:1 ratio (2.105a:2.105b) and no endo [3+2] cycloadductproducts were observed by 1H NMR. Assignment of the structure of regioisomers 2.105a and 2.105b wasdone by comparing the NMR data with that of compounds 2.103a and 2.103b, respectively. Characteristic1H NMR signals for compound 2.105a are those assigned to hydrogen atoms H4, H7, and H7a, which appearas a multiplet from δ 4.87 to 4.96 ppm. In contrast, the signals for hydrogen atoms (H4, H7, and H7a) forregioisomer 2.105b are three doublets at δ 4.97 ppm (d, J 8.1 Hz), 5.01 ppm (d, J 6.0 Hz), and 4.84 ppm (d,J 3.9 Hz), respectively. Similar results were observed when the diastereomer of bicycle 2.92 was used. An57Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesinseparable mixture of exo regioisomers was obtained in 72% yield in a 1.9:1 ratio. No endo regioisomerswere observed by NMR.NClOH+ Et3NDMF57%OCO2Et OON+OHClOHClOONOHClexoexoH7aH3aH7aH3aH7H4 H4H7CO2EtCO2Et2.85 2.92 2.105a 2.105bScheme 2.28. [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.85 and bicyclo alkene 2.92.The [3+2] dipolar cycloaddition of nitrile oxide precursor 2.85with 2-bromo-2-cyclohexen-1-one (2.37a)yielded isoxazole 2.107 in 42% yield. The expected isoxazoline 2.106, which is the immediate product ofthe [3+2] cycloaddition, was not observed. Presumably, isoxazoline 2.106 is formed, but it readily loses oneequivalent of hydrogen bromide to yield aromatic isoxazole 2.107 (Scheme 2.29). Only the regioisomericisoxazole that has the keto group at position C-7 (2.107) was obtained and no regioisomer with the carbonylgroup at C-4 (not shown) was observed.NClOH+Et3NDMFOBrOHClNOHClO O NOHClO OHBrαα7a1233a4 567-HBr42%2.85 2.37a 2.106 2.107Scheme 2.29. [3+2] Dipolar cycloaddition of nitrile oxide precursor 2.85 and 2-bromo-2-cyclohexen-1-one.Comparison of the 1H NMR data obtained with literature values of similar isoxazoles was inconclu-sive.230–235 Fortunately, 13C NMR data allowed for the establishment of 2.107 as the structure for the prod-uct. The 13C NMR spectrum of the compound obtained was compared with the 13C NMR data of isoxazoles2.109 and 2.108, which had been reported in the literature (Figure 2.5).234,235 The 13C NMR spectrum of2.107 showed peaks at δ 159.8 and 186.6 ppm, which corresponded to the isoxazole with the carbonyl groupat C-7.The regiochemistry of the [3+2] cycloaddition of nitrile oxides is dependent on both electronic and stericeffects.209 Due to the nature of the nitrile oxide, it is expected that the oxygen atom would attack the mostelectron deficient carbon of the dipolarophile. For 2-bromo-2-cyclohexen-1-one, the product shows the oxy-gen atom of the nitrile oxide attached to the α-carbon of the ketone. This regioselectivity had been observed58Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNOHClO O7a1233a4 567N O O7a1233a4 567N O 7a1233a4 567O159.8 ppm 186.6 ppm 181.3 ppm 191.2 ppm160.9ppm186.3 ppm2.107 2.108 2.109Figure 2.5. Comparison of the 13C NMR spectra of reported isoxazoles with 2.107.by Simpson and co-workers who suggested that it might be due to the ‘presumed steric influence’ of thebromine atom.230However, the bromine atom might also have an electronic effect on the dipolar cycloaddition. Elec-tronegative atoms that have lone pairs increase the energy level of the frontier molecular orbital (FMO) ofdipolarophiles, increasing the coefficient of the highest occupied molecular orbital (HOMO) of the β carbonatom,236 compared with the HOMOof cyclohexenone. This results in reversal of the regiochemistry of the cy-cloaddition where the HOMO of the dipolarophile attacks the lowest unoccupied molecular orbital (LUMO)of the dipole and not viceversa (Figure 2.6).237N OArN OArN OArBrOBrOOOLUMOHOMOLUMOHOMOLUMOHOMOONOBrH ArNOHH ArO2.110 2.111Figure 2.6. Regiochemistry of the [3+2] cycloaddition of nitrile oxides and substituted dipo-larophiles.237Dipolar cycloadditions between nitrile oxide precursor 2.86 and cyclohexenones 1.161 and 2.37a werealso studied. Treatment of 2.86 with 2-bromo-2-cyclohexen-1-one (2.37a) yielded the desired isoxazolederivative 2.112 in almost quantitative yield (Scheme 2.30a). However, the reaction with 2-cyclohexenone(1.161) yielded an inseparable mixture of isoxazolines 2.113a and 2.113b in 59% yield in a regioisomericratio (rr) 2.3:1, respectively (Scheme 2.30b).The NMRdata showed that both regioisomers were bicyclic structures with a cis ring junction (both com-pounds exhibited a coupling constant value of 9.6 Hz, which is characteristic of cis-hexahydrobenzofuranonesystems,209,230,238,239 compared with J = 10.5 Hz for the trans system).240 The major regioisomer (2.113a)was identified by its characteristic chemical shift of hydrogen atoms Ha and Hb at δ 4.09 ppm and 4.9059Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNClOH+Et3N, DMFrt, 98%O N OMeO MeOBrONClOH+Et3N, DMFrt, 59%rr: 1.1:1O N OMeO MeOON OMeO O+(a)(b)HaHbHaHb δ = 4.48δ = 4.90δ = 2.51δ = 4.092.86 2.37a 2.1122.86 1.161 2.113a 2.113bScheme 2.30. [3+2] Dipolar cycloaddition reactions of nitrile oxide precursor 2.86 and cyclohexenonederivatives.ppm, respectively, while the minor regioisomer (2.113b) exhibited characteristic chemical shifts for hydro-gen atoms Ha and Hb at δ 4.48 ppm and 2.51 ppm, respectively.This result was inconsistent with the work reported by Simpson and co-workers,230 who had observedonly one regioisomer for the [3+2] cycloaddition between nitrile oxides and 2-cyclohexenone. In their re-search, the authors used 2,6-dichlorobenzonitrile oxide. The regioselectivity observed by Simpson and co-workers may also be attributed to steric effects arisen from the chlorine atoms flanking the nitrile oxide, andnot exclusively from electronic effects.241 In the reaction shown in Scheme 2.30b, the nitrile oxide (generatedin situ from oximoyl chloride 2.86) does not present any steric encumbrance and, therefore, the regioselec-tivity was compromised.Nitrile oxide precursor 2.87, derived from o-vanillin, was reacted with 2-cyclohexen-1-one. Only oneregioisomer was observed, although the yield wasmoderate (43%). The product was identified as isoxazoline2.114 from its 1H NMR data, observing a doublet of triplets at δ 4.78 ppm with a coupling constant of J =8.40 Hz for hydrogen Ha and a doublet (d) at δ 4.11 ppm with a coupling constant of J = 8.75 Hz for hydrogenHb.NClOHOMeOEt3NDMF, rt43%NOMeOOOHHO+HbHa2.87 1.161 2.114Scheme 2.31. [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.87 and cyclohexenone.The reaction between nitrile oxide precursor 2.88 and bicyclo alkene 2.92 afforded isoxazolines 2.115aand 2.115b in 71% yield as a mixture of regioisomers in a 1:1.34 ratio, respectively. The 1H NMR data from60Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoleseach regioisomer was compared with the data for compounds 2.103a and 2.103b. The minor regioisomer(2.115a) showed characteristic NMR signals for hydrogen atoms H4 and H7 at δ 4.82–4.86 ppm, as onemultiplet, and hydrogen atom H7a at δ 4.61 ppm (d, J 5.6 Hz). In contrast, the major regioisomer (2.115b)showed the signals for hydrogen atoms (H4, H7, and H7a) as three sharp doublets at δ 4.96 ppm (d, J 8.0 Hz),5.01 ppm (d, J 6.0 Hz), and 4.67 ppm (d, J 4.8 Hz), respectively. No endo product was observed by NMR.NClOH+Et3NDMF71%14:1OCO2Et OON+BrOMeMeOOMeMeOBrexoOONOMeMeOBrexoCO2EtCO2EtH7aH3aH7H4 H4H3aH7a H72.88 2.92 2.115a 2.115bScheme 2.32. [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.88 and alkene 2.92.The reaction between nitrile oxide precursor 2.88 and 2-bromo-2-cyclohexen-1-one produced isoxazole2.116 in 55% yield (Scheme 2.33a). The product showed characteristic 13C NMR signals at δ 186.6 ppm and159.9 ppm. When 2-cyclohexenone was used as the dipolarophile, isoxazoline 2.117 was obtained in 78%yield (Scheme 2.33b). Only one regioisomer was observed by 1H NMR, which showed peaks at δ 5.22 ppmas a multiplet and δ 4.35 ppm as a doublet (J = 10.8 Hz). These signals were characteristic for regioisomer2.117 (see Scheme 2.30b).209NClOH+Et3NDMF78%OOMeMeONBrOBr OMeOOMeHbHa(a)(b)NClOH+Et3NDMF55%OBrOMeMeONOMeMeOO OBr Br2.88 2.37a 2.1162.88 1.161 2.117Scheme 2.33. [3+2] Dipolar cycloaddition between nitrile oxide precursor 2.88 and cyclohexenonederivatives.Nevertheless, when nitrile oxide precursor 2.88 was treated with racemic 6-hydroxy-2-cyclo-hexenone(2.95), no cycloadduct was observed. It is unclear how the free hydroxyl group in the cyclohexenone preventsthe [3+2] dipolar cycloaddition of nitrile oxides across across the double bond.61Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNBrOOMeOOMeOHHbHaXN ClOH+ Et3NDMFOOMeMeOBrOH2.88 2.95 2.118Figure 2.7. Attempted [3+2] dipolar cycloaddition between nitrile oxide precursor 2.88 and 2.118.2.2.3.4 Reductive Cleavage of the N–O Bond of Isoxazolines and IsoxazolesIsoxazolines and isoxazoles can be converted into aldols or 1,3-diketone compounds by reductive cleavageof their N–O bond. Since the mid 1950’s, a few methods to cleave the N–O bond of isoxazolines have beenreported in the literature.201–208,242The isoxazoline reductive cleavage was first attempted on tricyclic isoxazolines 2.103a and 2.103b fol-lowing the procedure described by Chen and co-workers,243 which used iron(0) and ammonium chloride inethanol/water (Scheme 2.34). The reaction was monitored by thin layer chromatography, but no reaction wasobserved after two days. The reaction was then carried out using iron powder instead of iron turnings, butthis had no effect in the reaction outcome. Also, the reaction was attempted at 100 ◦C, but no cleavage ofthe N–O bond was observed. Cleavage of the N–O bond of isoxazoline 2.105b was attempted, unfortunately,this reaction was not successful.OON HHor orxCO2EtFe0, NH4ClEtOH, H2O80 ºCOO H OHCO2Et2.103a 2.103b 2.119a 2.119bScheme 2.34. Attempted isoxazoline reactive cleavage using iron and ammonium chloride.243Isoxazoline 2.117 presented a highly oxygenated aromatic ring, that was similar to tetrahydroxanthone 2.3.The cleavage of this isoxazoline was investigated in more detail, the results are summarized in Table 2.7. Theuse of iron(0)/ammonium chloride205,243 was not considered due to the previous unsuccessful attempts. Cat-alytic hydrogenation using 10% w/w Pd/C was explored (Table 2.7 entry 1),242 however, no aldol productwas observed. Instead, desbromo isoxazoline 2.121 was obtained in almost quantitative yield. The identityof the product was confirmed from the 1HNMR spectra. A signal for the hydrogen atom ortho to the isoxazo-line ring appeared as a doublet at δ 7.19 ppm and showed a characteristic coupling constant of 3.0 Hz, whichcorresponded to a meta coupling. Furthermore, the hydrogen para to the isoxazoline appeared as a doubletof doublets with characteristic J values of 3.0 and 9.0, which indicated the presence of hydrogen atoms at its62Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesortho and meta positions. Reductive cleavage of the isoxazolidine was attempted using platinum(IV) oxideas the catalyst (Table 2.7 entry 2); however only desbromo compound 2.121 was obtained in 33% yield.The most widely used method in the literature to obtain β-hydroxyketones from isoxazolines is the re-ductive hydrogenation using Raney nickel (Ra • Ni) as the catalyst under acidic conditions.207,208 However,treatment of 2.117 with Ra •Ni (entry 3) did not afford the desired aldol product and instead yielded des-bromo compound 2.121 exclusively in 70% yield. The N–O cleavage was attempted in a hydrogenator at 50psi of hydrogen (3.4 atmospheres, entry 4), but desbromo isoxazoline 2.121 was formed exclusively in 80%yield.In the attempts to cleave the N–O bond of isoxazoline species 2.117, hydrogenation conditions onlyresulted in the reduction of the the C–Br bond of the aromatic ring, hence other methods that did not usehydrogen were tested (Table 2.7 entries 5, 6, and 7). Molybdenum hexacarbonyl,244 samarium (II) iodide,202and nickel particles generated in situ243 were studied. Unfortunately, none of these conditions rendered anyproduct and only starting material was recovered.Table 2.7. Evaluation of conditions for the cleavage of the N–O bond of isoxazoline 2.117.ConditionsN OOMeBrOMeOO OHOMeOMeON OOMeHOMeO2.117 2.120 2.121entry additive equiv solvent H2 pressure T (◦C) time (h) 2.121 % yield†1242 Pd/C (10%) 0.1 MeOH 1 atm rt 1.5 982245 PtO2 0.2 EtOH 1 atm rt 72 333246 Ra •Nia cat EtOH/H2Ob 1 atm 80 6 704 Ra •Nia cat EtOH/H2Ob 3.4 atm rt 72 805244 Mo(CO)6 2.0 CH3CN/H2Oc NA 80 18 NR6202 SmI2 4.0 THF NA rt 1.2 NR7243 NiCl2/NaBH4 xs/1.6 DMF/THFd NA rt 0.1 NRThe reactions were performed at a 0.05 M concentration using a balloon filled with hydrogen (except where not applica-ble). † Compound 2.120 was not observed. a The reaction was carried out using boric acid (9 equiv) as an additive.b In a 5:1 ratio, respectively c In a 15:1 ratio, respectively d In a 2:1 ratio, respectively. The reaction was carried outat a 0.06 M concentration. DMF was used as a saturated solution of NiCl2.The failure to open the isoxazoline using Raney nickel is not completely understood. Reading throughthe literature it was found that most groups used Raney nickel grade W-2 from ‘Alpha chemicals’.207 Unfor-tunately, Raney nickel W-2 was not available from any of our providers. A different type of Raney nickelwas purchased from ‘Aldrich’, but the cleavage of the N–O bond was unsuccessful.63Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles2.2.3.5 Attempts to Form the Pyran ring of Tetrahydroxanthones: Intramolecular Buchwald-TypeReactionsThe reduction of the C–Br bond was undesirable because in our approach, we had planned to use the bromineatom for the formation of the pyranone ring of tetrahydroxanthone 2.3 (Scheme 2.19, page 50). If the isoxa-zoline cleavage conditions were reducing this valuable group, a change in the sequence of the synthetic stepswould avoid the reduction of the C–Br bond. Thus it was decided to install the ether bond first and, oncethe tetracyclic compound had been formed, the cleavage of the isoxazoline would afford the tetrahydroxan-thone core.NOMeBrOOOMeON OOMe OMeOMeOOMe O OHBuchwaldtypeReductivecleavageBrBrO O OOPd2(dba)3PhB(OH)2Xphos, Cs2CO3dioxane, 101 ºC78%(a)(b)reportedproposed1.187 1.1882.117 2.122 2.123Scheme 2.35. (a) Intramolecular Buchwald-Hartwig-type/Suzuki-Miyaura coupling169 (b) Proposedroute for the synthesis of tetrahydroxanthones via intramolecular Buchwald-type cycliza-tion followed by reductive isoxazoline cleavage.Very few methods to carry out an intramolecular enolate/aryl bromide coupling were known in the lit-erature. One of these involved treatment of the substrate with LDA247 or sodamide in tert-butanol.248 As itwas described in Section 1.6.11, Shipman and co-workers had developed a method for the synthesis of sim-ple tetrahydroxanthones using an intramolecular C–O bond formation between an enolate and an aromatichalide.170 Previous to that publication, any other methods that dealt with the coupling of in situ-generatedenolates and aromatic bromides had been used for the synthesis of benzofurans.249,250The ketone/aromatic bromide intramolecular coupling of 2.117was then attempted as shown in Table 2.8.When the isoxazoline was treated with LDA, at -78 ◦C (entry 1), no reaction was observed after two hours.The reaction mixture was slowly warmed to room temperature and, after 2 hours, the starting material haddecomposed. The reaction conditions used by Shipman and co-workers170 (entry 2) afforded compounds2.124 and 2.125; however, the desired isoxazoline 2.122 was not obtained.Willis and co-workers studied the effect of different bases on the synthesis of benzofurans and found thatbis(trimethylsilyl)amide was superior to cesium carbonate.249 KHMDSwas used as the base for the screening64Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesof different palladium sources (entries 3 to 5) and different ligands (entries 6 to 12). The reaction conditionstested resulted in the decomposition of the starting material for all the trials, which may have been attributedto KHMDS. A blank was run subjecting the starting material to the reaction conditions in the sole presenceof KHMDS. It was observed that the starting material was partly decomposed after eight hours and it wascompletely decomposed after 20 hours of reaction time.Table 2.8. Attempted ketone/aromatic bromide coupling of isoxazoline 2.117.NOMeBrOOOMeON OOMe OMeconditionsOMeOOMeOMeBrN OOMe+ +ONH22.117 2.122 2.124 2.125entry base ligand Pd source solvent T (◦C) time (h) 2.124/2.125% yield†1247 LDA – – THF -78 2 dec2170 CsCO3 dppb Pd2(dba)3 dioxane 110 8 21/103249 KHMDS dppb Pd2(dba)3 dioxane 110 8 dec4 KHMDS dppb Pd(PPh3)4 dioxane 110 8 dec5 KHMDS dppb Pd(OAc)2 dioxane 110 8 dec6 KHMDS dppm Pd(OAc)2 dioxane 110 8 dec7 KHMDS dppe Pd(OAc)2 dioxane 110 8 dec8 KHMDS dppp Pd(OAc)2 dioxane 110 8 dec9 KHMDS dppf Pd(OAc)2 dioxane 110 8 dec10 KHMDS iPr3P Pd(OAc)2 dioxane 110 8 dec11 KHMDS nBu3P Pd(OAc)2 dioxane 110 8 dec12 KHMDS Cy3P Pd(OAc)2 dioxane 110 8 dec13 KHMDS – – dioxane 110 20 dec† Compound 2.122 was not observed. The reactions were performed at a 0.1 M concentration in an ar-gon atmosphere.The unexpected compounds that were isolated in entry 2 corresponded to structures 2.124 and 2.125,which were obtained in 21% and 10% yield, respectively. Vinylogous imide 2.124 showed 1H NMR signalsthat corresponded to a symmetric cyclohexene-1,3-dione, a triplet that integrated for four hydrogen atomsand appeared at δ 2.43 ppm and a quintet that integrated for two hydrogen atoms was observed at δ 1.92 ppm,and the aromatic signals showed a third hydrogen atom as a doublet at δ 6.63 ppm with a coupling constant of2.8 Hz, indicating the presence of another hydrogen atom at the meta position. The absence of the bromineatom was corroborated by mass spectrometry (MS).Isoxazole 2.125 was identified through one-dimensional (1D) and two-dimensional (2D) NMR analysis.The 1H NMR spectrum showed a triplet of doublets (td) at δ 2.64 ppm and a triplet (t) at δ 3.03 ppm, which65Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolescorresponded to two CH2 units of the cyclohexadiene ring. The characteristic hydrogen atoms correspondingto the isoxazoline (δ 5.22 and 4.35 ppm) were absent, instead two doublet of triplets at δ 5.95 and 5.66 ppmwere observed. The aromatic region showed only two hydrogen signals with a coupling constant of 9.1Hz, which accounted for two hydrogen atoms ortho to each other. The connectivity was assigned fromthe correlated spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC) andheteronuclear multiple-bond correlation spectroscopy (HMBC) spectra, which were consistent with structure2.116. Mass spectrometry showed molecular ion at 336.2 and 338.2 (m/z) in a 1:1 ratio, indicating thepresence of a bromine atom.Despite the transformations reported in the literature,170,249,250 the intramolecular Buchwald-type cy-clization for compound 2.117 was not successful. In retrospect, other catalysts, such as like copper(I), shouldhave been studied. Beifuss and co-workers published in 2012 a paper concerning the copper (I)-catalyzedintramolecular O-arylation of aryl bromides with 1,3-diketones.2512.2.3.6 Attempts to Form the Pyran Ring of Tetrahydroxanthones: Keto/Phenol CondensationA different method to form the pyrone ring was envisioned. If the aromatic ring of the isoxazolidine specieswere to have a hydroxyl group instead of a bromine atom (2.128), the formation of the pyranone ring of thetetrahydroxanthone would be initiated by the phenol, forming first a hemiketal, followed by condensation ofwater (Scheme 2.36b). A similar transformation was used by Ramachary and co-workers for the synthesisof tetrahydroxanthenes (2.127, Scheme 2.36a).252NOMeOOOacidOMeON OHO Op-TsOHDCM45 ºCOHO O(a)(b)reportedproposed2.126 2.1272.128 2.129Scheme 2.36. (a) Synthesis of tetrahydroxanthenes by Ramachary and co-workers.252 (b) Proposedsynthesis of tetracyclic isoxazoline 2.129 under acidic conditions.The attempts for the intramolecular cyclization of isoxazolidine 2.128 are presented inTable 2.9. Thereaction conditions used by Ramachary and co-workers (entry 1) did not yield the desired product, evenwhen a more polar solvent was used (entry 2). When the solvent used was toluene and the temperature was66Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles80 ◦C (entry 3), the starting material remained unchanged. Use of strong Brønsted acids did not force for thereaction to take place (entries 5 and 6) and when concentrated sulphuric acid was used, the starting materialwas burnt into charcoal.Table 2.9. Attempted conditions to cyclize isoxazoline 2.128 into 2.129.NOMeOOOconditionsOMeON OHN O+OHMeOOO2.128 2.129 2.130entry acid additive solvent T (◦C) 2.130(% yield)†1 p-TsOH – DCM 45 NR2 p-TsOH – DMSO 45 NR3a p-TsOH – PhHb 80 NR4 p-TsOH (CH2OH)2 PhHb 80 605 HClc – AcOH rt NR6 H2SO4d – – 60 dec† The reactions were performed at a 0.1 M concentration using 20 mol% load ofacid (unless otherwise specified). a The reaction was run using 1 equiv of acid.b A Dean-Stark trap was used. c The reaction was run using 5 mol% of acid.d H2SO4 was used as solvent.The cyclization of 2.128 was attempted using catalytic para-toluenesulfonic acid and ethylene glycol asan additive. Unfortunately, the reaction proceeded to form ketal 2.130 in 60% yield. It was expected thatthe diol would add to the carbonyl carbon to produce a hemiketal, which, upon loss of water, would form anO-alkyl oxonium species. It was expected that the highly electrophilic O-alkyl oxonium ion would facilitatethe intramolecular cyclization.It is possible that the isoxazoline ring rendered the carbonyl carbon far away from the phenol functionality,thus, for the cyclization to take place, isoxazoline 2.128 would have to adopt a very strained conformationduring the transition state to attack the π* bond of the carbonyl carbon, therefore compound 2.128 failed tocyclize into 2.129.From the results obtained in Sections 2.2.3.5 and 2.2.3.6, it seemed that the formation of the ether bondto construct the pyranone ring of the tetrahydroxanthone was more challenging than anticipated. A way tosolve this challenge was to rearrange the sequence of steps, installing the ether bond first, and performedan intramolecular [3+2] cycloaddition cycloaddition, followed by cleavage of the isoxazoline N–O bondto afford 1-hydroxy tetrahydroxanthones. The following section will describe the attempts to synthesize67Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles1-hydroxy tetrahydroxanthones through intramolecular [3+2] cycloadditions of nitrile oxides generated insitu.2.2.4 Intramolecular Nitrile Oxide [3+2] Dipolar CycloadditionIntramolecular [3+2] cycloaddition reactions using nitrile oxides have been known since the early 1980s.253,254In 1999, Narasaka and co-workers reported the intramolecular cycloaddition of the nitrile oxide derived from2-(cyclohex-2-en-1-yloxy)benzaldehyde oxime (2.131) using CAN (Scheme 2.37) to produce isoxazoline2.132.218 Also, in 2000 Yao and co-workers reported the synthesis of 2.132 using HTIB as the oxidizingagent.219N OHON OOCANorHTIB2.131 2.132Scheme 2.37. The synthesis of 2.132.An intramolecular [3+2] dipolar cycloaddition route was then developed, as outlined in Scheme 2.38.Salicylaldehyde derivatives (2.133) would be O-alkylated with an allylic cyclohexenyl derivative (2.134),thus installing the ether bond of the pyrone ring of tetrahydroxanthone at the earliest stage. O-Cyclohexenylaldehyde 2.135 would then be converted into oxime 2.136, which would be oxidized to the oximoyl chlorideusing NCS and, upon treatment of the latter with a base, nitrile oxide 2.137 would be formed in situ. It wasexpected that, once formed, the nitrile oxide would undergo a diastereoselective intramolecular [3+2] dipolarcycloaddition across the tethered cyclohexene ring to obtain tetracyclic isoxazoline 2.138. Formation of thedihydropyran ring required for the tetrahydroxanthones and installation of an oxygen atom in the C-1 positionof the tetrahydroxanthone would be done in one step. The last two steps of the proposed sequence to elaborate2.138 into the desired 1-hydroxytetrahydroxanthone 2.140 could be reversed, installing the remaining doublebond of the pyranone ring first and then cleaving the isoxazoline ring or vice versa.To install the unsaturation of the pyranone two options were considered after the intramolecular [3+2]dipolar cycloaddition: an oxidation (if X were a hydrogen atom) or a β-dehydrohalogenation (if X were ahalogen). To avoid over oxidation of the cyclohexene ring, it was considered that β-dehydrobrominationwould be a more viable option. The proposed route was tested using 2-bromocyclohex-2-en-1-ol (2.95a) andsalicylaldehyde (1.130) as the coupling partners.68Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOOa) NCS, Pyb) Et3NN OOHHN OOH2Raney•NiOO OHXNOOHOOHbaseXHONH2OHOX X XN Obaseor heatRR R RRRR2.1332.1342.135 2.136 2.1372.1382.1392.140Scheme 2.38. Proposed route for the synthesis of tetrahydroxanthones via intramolecular [3+2] dipolarcycloaddition.2.2.4.1 Synthesis of Bromocyclohexenyl Phenyl EthersFor the synthesis of bromocyclohexenyl phenyl ethers, bromocyclohexenol (2.95a) had to be converted intoelectrophilic species 2.141. It was planned to convert alcohol 2.95a into tosylate 2.141a, mesylate 2.141band bromide 2.141c (Table 2.10).Tosylate 2.141awas synthesized from bromo cyclohexenol 2.95a, whichwas treated with para-toluenesulfonylchloride (p-TsCl), triethylamine and a catalytic amount of DMAP in DCM at -78 ◦C, forming 2.141a in 58%yield (Table 2.10, entry 1). Treatment of 2.95a with mesyl chloride,255 triethylamine and catalytic DMAPdid not result in the formation of mesylate 2.141b, instead, 1-bromo-6-chlorocyclohex-1-ene (2.141d) wasisolated in 87% yield (entry 2). The conversion of 2.95a into allylic bromide 2.141c was performed usingaqueous concentrated hydrobromic acid in 90% yield (entry 3).The synthesis of cyclohexenyl phenyl ethers was attempted using o-vanillin (2.143) and different allylicbromocyclohexene electrophiles. Mitsunobu conditions resulted in compound 2.145 (Table 2.11, entry 4),which had been observed when treating salicylaldehyde derivatives with azadicarboxylates.256 When 2.141dwas used as the electrophile (entry 2), the desired phenyl ether was obtained in 8% yield. Changing theleaving group for bromide had a significant improvement, obtaining 2.144b in almost quantitative yield (entry3).The synthesis of ether 2.144b was also performed generating the methanesulfonate of alcohol 2.95a insitu following a procedure reported by Willis and co-workers (entries 6 and 5).257 The methanesulfonate was69Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesTable 2.10. Activation of 2.95a towards SN2.BrOHBrLGconditions2.95a 2.141entry electrophile base additive solvent T (◦C) pdt (% yield)† LG1 p-TsCl Et3N DMAP DCM -78–rt 2.141a (58) OTs2 MsCl Et3N DMAP DCM -78 2.141d (87) Cl3 HBra NA NA H2O rt 2.141c (90) Br† The reactions were performed at a 0.5 M concentration using 1.5 equiv of electrophile, 2.0 equivof Et3N, and 2 mol% of DMAP, where indicated. a The reaction was run using 4 equiv of HBr.formed using methanesulfonyl anhydride (entry 5) and triethylamine in DCM at 0 ◦C. A premixed solutionof o-vanillin and DBU was added to the methanesulfonate formed in situ. After warming up first to roomtemperature and then to 40 ◦C, the desired ether was obtained in 98% yield. However, when more accessiblemethanesulfonyl chloride (MsCl) was used instead of methanesulfonyl anhydride (entry 6), the yield of thereaction dropped to 62%.Table 2.11. Alkylation of o-vanillin using allylic bromocyclohexene electrophiles.HOOH YBr+OOBrconditionsO OOO+ NHN OOO O2.143 2.141 2.144b 2.145entry Y base additive solvent T (◦C) 2.144b (% yield)1 OTs Cs2CO3 – DMF † 60 332 Cl Cs2CO3 – DMF † 60 83 Br Cs2CO3 – DMF † 60 974 OH PPh3 DIAD THF 0–rt NA‡5257 OH DBU Ms2O/Et3N DCM 0–40 98*6 OH DBU MsCl/Et3N DCM 0–40 62*† The reactions were performed at a 0.33 M concentration using 1.5 equiv of 2.143 and CsCO3each. ‡ The Mitsunobu reaction was carried out at a 0.20 M concentration using 1.5 equivof 2.143, 1.5 equiv of PPh3 and 1.8 equiv of DIAD. The product isolated was 2.145. 256* The reaction was run at a 0.06 M concentration using 3.0 equiv of 2.143 and 1.5 equiv ofeach DBU, Ms2O and Et3N.70Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesIt was observed that the use of either the allylic bromide or the procedure reported by Willis rendered thedesired phenyl ether in almost the same yield. Either method may be used to install a 2-bromo-2-cyclohexenylalkyl group on the oxygen atom of salicylaldehyde derivatives.2.2.4.2 [3+2] Dipolar CycloadditionsAldehyde 2.144a was synthesized in 72% yield using methanesulfonic anhydride and triethylamine in DCM.Conversion of 2.144a to oxime 2.146a was achieved using aqueous hydroxylamine at 100 ◦C in 98% yield.The oxime was elaborated into its oximoyl chloride using NCS; however, isolation of the oximoyl chloridewas not required, as the nitrile oxide was generated in situ by addition of 1.0 equiv of triethylamine. Theintramolecular [3+2] dipolar cycloaddition then took place and isoxazoline 2.147a was obtained in 63% yieldover 2 steps (Scheme 2.39).OONH2OHH2O, reflux98%a) NCS, Pyb) Et3N63%N OOHHBrBr NOBrOH2.144a 2.146a 2.147aScheme 2.39. Intramolecular [3+2] cycloaddition of nitrile oxides: Synthesis of isoxazoline 2.147a.With isoxazoline 2.147a readily available, the dehydrobromination was evaluated next (Table 2.12). Us-ing this sequence, the last step for the synthesis of 1-hydroxytetrahydroxanthones would be the isoxazolinering cleavage. Mild organic bases did not promote the β-dehydrobromination (entries 1 and 2). Use ofstronger bases was not effective either (entries 3–5); however, when potassium tert-butoxide was used, tracesof a dehydrobromination product were observed by 1H NMR.The reaction conditions used in entries 1–5 were typical for a second-order elimination (E2) mechanism,nevertheless, the dehydrobromination can also proceed through a first-order elimination (E1) mechanism.Therefore, bromide 2.147a was treated with silver(I) trifluoromethanesulfonate in DCM and a new productwas obtained in 21% yield (entry 6). The structure of the isolated compound was assigned from analysis ofits 1H NMR spectrum, and it corresponded to isoxazole 2.150a. A reaction mechanism that could explainthe formation of 2.150a is outlined in Scheme 2.40.Abstraction of a bromide ion by silver(I) formed isoxazoline cation 2.151, which is stabilized by reso-nance. The carbocation then formed isoxazole 2.149a through an E1 mechanism. The acidic conditions,resulting from the presence of trifluoromethanesulfonate as the silver counterion, generated protonated isox-azole 2.149a, which, after a second E1, furnished isoxazole 2.150a.71Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesTable 2.12. Evaluation of dehydrobromination conditions for bromoisoxazoline 2.147a.conditionsN OON OOHHBrN OO+14a9a14a9a14a9aN OOH+14a9a2.147a 2.148a 2.149a 2.150aentry additive equiv solvent T (◦C) 2.149a (% yield) †1 DABCO 1.0 THF• rt NR2 C6H5N 1.0 THF• rt NR3 NaOCH3 10 CH3OH 60 dec4 KOtBu 1.3 DMSO 80 traces5 LDA 1.5 THF rt NR6 AgOTf 1.1 DCM rt –‡7 Ag2CO3 1.1 DMF rt NR8 Ag2CO3 1.6 DMSO 80 78† The reactions were performed at a 0.05 M concentration for 16 h, undress otherwise specified.• The reaction was run at a 0.2 M concentration. ‡ The isolated product 2.150a was obtainedin 21% yield.ON O HH ON O HHON OHH HAg+- AgBr OHN OBrON O2.147a 2.151 2.149a 2.152 2.150aScheme 2.40. Reaction mechanism for the formation of 2.150a.To avoid the ring opening of the pyran ring, a salt of silver(I) that had a basic counterion to act as a protonscavenger, was required. Silver(I) carbonate in DMF was used at room temperature, but no reaction wasobserved (entry 7). When the reaction was performed in DMSO at 80 ◦C, isoxazole 2.149a was obtained in78% yield (entry 8). The structure of compound 2.149a was confirmed by X-ray crystallography (Figure 2.8).Unfortunately, the dehydrobromination proceeded to form the double bond between carbon atoms C-9a andC-1, instead of C-9a and C-4a.ON O2.149aFigure 2.8. Solid state molecular structure of isoxazole 2.149a, ellipsoids at 30%.72Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesAlthough the desired tetracyclic isoxazoline 2.148a was not obtained, the reductive N–O bond cleavagewas attempted on isoxazole 2.149a using catalytic Raney nickel in methanol at atmospheric pressure of hy-drogen gas. A new product was obtained, the structure of whichwas assigned by 1HNMRand 13CNMRdata.Comparing the 1H NMR spectrum of the product with the one from the tetracyclic isoxazole 2.149a it couldbe observed that the six signals for the three methylene hydrogens of the saturated six-membered ring weremerged into three multiplets at δ 2.23–2.48 ppm (m, 3H), 1.89–1.97 (m, 2H) and 1.70–1.50 (m, 1H). Themethine signal for the hydrogen atom at position C-4a had shifted upfield from 5.09 ppm to 4.77 ppm and thetwo hydrogen atoms attached to nitrogen appeared at 5.86 and 10.25 ppm as two broad singlets. Most im-portantly, the 13C NMR spectra showed the appearance of a carbonyl carbon at δ 196.3 ppm (Scheme 2.41).From the NMR data it was concluded that the desired tetrahydroxanthone had not been obtained, and thereductive cleavage of isoxazole 2.149a had produced vinylogous amide 2.153a.N OORaney-NiH2, MeOHquantitative ONH2 O35% (in 5 steps)H H5.09 ppm 4.77 ppm196.3 ppm2.149a 2.153aScheme 2.41. Reductive cleavage of isoxazole 2.149a.2.2.4.3 Synthesis of Tetracyclic Isoxazoles and AminotetrahydroxanthonesAs seen in Table 2.12, attempts to synthesize the tetrahydroxanthone core resulted in the synthesis of isoxa-zole 2.149a. A variety of substituted isoxazoles 2.149 were synthesized to demonstrate the versatility of thistransformation. Commercially available salicylaldehydes were O-alkylated using trimethylsulfonyl anhy-dride and triethylamine in DCM to yield aldehydes 2.144, which were treated with aqueous hydroxylamineto yield oximes 2.146. The oximes were transformed into nitrile oxide precursors using NCS. Treatmentof the oximoyl chlorides (formed in situ) with triethylamine generated nitrile oxide species that underwentintramolecular [3+2] dipolar cycloaddition across the bromoalkene, furnishing bromoisoxazolines 2.147.Isoxazoles 2.149 were obtained by treatment of bromoisoxazolines 2.147 with silver carbonate in DMSO at80 ◦C. Table 2.13 shows the tetracyclic isoxazoles that were synthesized. A structure search in SciFinder R©showed that these fused tetracyclic isoxazoles had not been reported in the literature.The reductive cleavage of the N–O bond of isoxazole 2.149b was attempted using Raney nickel; however,vinylogous amide 2.153b was obtained. X-ray crystallography confirmed the structure of vinylogous amide2.153b as observed in Scheme 2.4273Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesTable 2.13. Synthesis of fused tetracyclic isoxazoles 2.149.OONH2OHH2O, refluxa) NCS, Pyb) Et3NN OOHHBrBr NOBrOHAg2CO3DMSO80 ºCN OO HR R R R2.144 2.146 2.147 2.149ON OON OON OON OOMeO2NON O66% (in 4 steps)14% (in 4 steps) 11% (in 4 steps) 9 % (in 4 steps25% (in 4 steps)BrMeO2.149b 2.149c2.149d 2.149e 2.149fN OORaney•NiH2, MeOHquantitative ONH2 O60% (in 5 steps)H H5.16 ppm 4.79 ppmOMe OMe2.149b 2.153bScheme 2.42. Synthesis of vinylogous amide 2.153b and its solid state molecular structure. Ellipsoidsat 30% probability.Since the last two steps of the proposed sequence for the synthesis of tetrahydroxanthones could beinterchanged (Scheme 2.38, page 69), the cleavage of the N–O bond of bromoisoxazolines 2.147 could beperformed before the installation of the double bond of the pyranone ring. Unfortunately, attempts to breakthe N–O bond of bromo isoxazoline 2.147b using Raney nickel resulted in the reduction of the C–Br bond toyield isoxazoline 2.154 in 92% yield. The structure of the isoxazoline was confirmed by 1H NMR, showinga characteristic peak at δ 3.85 ppm (t, J = 7.7 Hz, 1H), which corresponded to the C–H of the isoxazolinering.219 Isoxazoline 2.154was subjected to reductive N–O cleavage conditions, but no reaction was observed,even when the hydrogenation was performed at 3.4 atm (50 psi).Although the intramolecular [3+2] cycloaddition of nitrile oxides across tethered bromo cyclohexenes didnot yield the desired 1-hydroxytetrahydroxanthones, it resulted in an efficient route to access fused tetracyclicisoxazoles. Reductive cleavage of these compounds resulted in the generation of vinylogous amides 2.153.74Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesN OOHBrHH2Raney-NiMethanol92%N OOHHHOMe OMe2.147b 2.154bScheme 2.43. Attempted cleavage of the N–O bond of isoxazoline 2.147b.2.2.5 Intramolecular [3+2] Cycloaddition of N-Benzyl NitronesIn 1996, Broggini and co-workers reported the conversion of isoxazolidines into 1,3-aminoalcohols.258 In2001 the authors reported the conversion of isoxazolidines into α-hydroxymethyl lactones synthesizing 1-hydroxyhexahydroxanthone (2.158) as outlined in Scheme 2.44a.259OOPhNHOH•HClMeNaHCO3, Al2O3PhH, ∆59% ON OMePhHHHHm-CPBATHF/H2O (9:1)∆52%OOHHOHOOON OMePhHHBrHOOOHBrRRR(a)(b)2.1552.1562.1562.157 2.1582.144 2.159 2.140Scheme 2.44. (a) Synthesis of hexahydroxanthone 2.158.259 (b) Proposed route for the synthesis of1-hydroxy tetrahydroxanthones via [3+2] cycloaddition of nitrones..It was envisioned that the use of vinylic bromide 2.144would result in 9a-bromo-1-hydroxyhexahydroxan-thones 2.159 and that the bromine atom at position C-9a could be used to install the desired double bondbetween carbon atoms C-4a and C-9a. Further oxidative cleavage of the isoxazolidine would afford 1-hydroxytetrahydroxanthones 2.140.Although Broggini and co-workers did not discuss a reaction mechanism on how the oxidation of theisoxazolidine occurred, previous groups who had worked on the oxidation of N-alkylated isoxazolines260,261had proposed a mechanism for this transformation (Scheme 2.45). After the nitrogen atom was converted toN-oxide 2.161 by m-CPBA, a hydrogen atom α to the positively charged nitrogen atom was deprotonated,forming an imminium ion and cleaving the N–O bond of the isoxazolidine ring. Hydrolysis of hydroxynitrone 2.162 resulted in the formation of β-hydroxyketone 2.163.75Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesN OR1R3R2PhN OR1R3R2Phm-CPBAOHN OHR1 R3R2Ph OprotontransferOHR1 R3R2hydrolysis O2.160 2.161 2.162 2.163Scheme 2.45. Proposed mechanism for the oxidation of N-alkylated isoxazolidines usingm-CPBA.260,261Aldehyde 2.144bwas treated with (S)-N-(1-phenylethyl)hydroxylammonium oxalate using sodium bicar-bonate and neutral aluminum oxide.259 The reaction resulted in an inseparable mixture of two diastereomers,in 58% yield. Appearance of signals at δ 1.52 ppm (d, J = 6.39 Hz, 3H) and at δ 4.72 ppm (s, 1H) supportedthe formation of the desired products.PhNHOHOOOMeBrOOHOOHNaHCO3Al2O358%NOOMeOPhBrH• HH NOOMeOPhBrHHH+2.144b 2.164a 2.164bScheme 2.46. Synthesis of bromo isoxazolidine 2.144b.259When isoxazolidine 2.164 was treated with m-CPBA (70% by weight) in a mixture THF/water (9:1),259the reaction failed to produce the desired product. When the solvent was changed to DCM, a mixture ofcompounds was observed. However, when the reaction was carried out using recrystallized m-CPBA (99% byweight) in DCM, the intermediate nitrone 2.165 was observed by NMR. Hydrolysis of 2.165 using catalyticpara-toluenesulfonic acid in THF/water (9:1) at reflux temperature resulted in a large number of products, outof which tetrahydroxanthone 2.166a was identified in 1% yield. The identity of tetrahydroxanthone 2.166awas confirmed by an independent synthesis (see Section 3.4.3, Scheme 3.28, page 157).The synthesis of tetrahydroxanthone 2.166a produced several byproducts and proceeded in very lowyield. The use of other peroxybenzoic acids (2-nitroperoxybenzoic acid, 4-nitroperoxybenzoic acid, and2,4-dinitroperoxybenzoic acid) was envisioned; however, the compounds were not available for purchaseand their synthesis posed a high risk of explosion. Other routes that had been considered for the synthesis oftetrahydroxanthones were explored.76Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNOOMeOPhBrH1) m-CPBADCMOOMeOHNOOMeOHOOPhBrHHH H2) THF/H2O∆, 1%2.164 2.165 2.166aScheme 2.47. Oxidation of N-alkylated isoxazolidines with m-CPBA.260,2612.2.6 Miscellaneous Attempts for the Synthesis of Tetrahydroxanthones2.2.6.1 [4+2] Dipolar CycloadditionsA different type of cycloadditions that was attempted for the synthesis of tetrahydroxanthones was the [4+2]cycloaddition of electron rich 1,3-dienes and electron deficient chromenones. In 1999, Hsung and co-workersreported the synthesis of substituted 9a-carbonitriletetrahydroxanthones 1.154a and 1.154b (Scheme 2.48a).23Since β-dehydrocyanation is not a straightforward process to produce alkenes,262–264 it was decided to usean electron withdrawing group that could undergo β-elimination more easily. A functional group that maybe suitable for this purpose was the sulfone.It was envisioned that tetrahydroxanthone 2.3 could be synthesized through a [4+2] cycloaddition be-tween an electron deficient chromenone such as 2.167, where the EWG (W) would be SO2Ph, and an electronrich, highly oxygenated 1,3-diene such as 2.168. The required geometry of the diene was important becausethe relationship of the two oxygens of ring F had to be anti.OOCNFOMe Tol300 ºC81%dr 8 : 1endo : exoOOFendoCNHOMeOOF CNHOMeexo+OO OPGOPGOPGOPGBrOWOOPGOPGBr PGOOPG+ D E FD E(a)(b)OO OPGOPGOPGOPGBrD E FD E D E D EF F2323239a4a239a4a2314141423141414W+reportedproposed1.152 1.153 1.154a1.154b2.167 2.168 2.169 2.3Scheme 2.48. (a) Synthesis of tetrahydroxanthones 1.154a and 1.154b.23 (b) Proposed synthesis ofthe tetrahydroxanthone core utilizing a [4+2] cycloaddition between chromenones anddienes.77Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesThe proposed reaction was attempted with a simpler chromenone that had no substituents in the aromaticring and the EWG was phenyl sulphone.265 Several electron rich dienes were used as coupling partners,however, no cycloadduct was obtained. The dienes included (1Z,3E)-1,4-bis(benzyloxy)buta-1,3-diene, fu-ran, cyclopentadiene, 1,3-cyclohexadiene and Rawal’s diene.266 Different solvents were screened at temper-atures of 100 ◦C and higher and Lewis acids (EtAlCl2,267 AlCl3 and ZnBr2 268) was also added, but thereaction failed to produce any cycloadduct. In retrospect, a chromenone with a nitrile substituent as the elec-tron withdrawing group should have been used. In 2012, Jørgensen and co-workers published a paper wheredifferent electron withdrawing groups for the [4+2] cycloadditions of chromenones were tried and found thatthe nitrile was a much better electron withdrawing group.222.2.6.2 Nozaki-Hiyama-Kishi-type AttemptsIt was envisioned that the alkenyl bromide of 2.144b could be transformed into a nucleophile to attack theelectrophilic aldehyde, yielding a tetrahydroxanthonol, which could be further elaborated into a tetrahydrox-anthone (Scheme 2.49).OROORXOHORO OH2.155 2.45 2.140Scheme 2.49. Proposed route for the synthesis of 1-hydroxytetrahydroxanthones via intramolecular nu-cleophilic addition.Attempt to convert the alkenyl bromide into an organozinc compound to then undergo intramolecularnucleophilic cyclization resulted in no reaction (Table 2.14, entry 1). It was then attempted to make theGrignard of BrCyenSalCHOb in situ using of magnesium(0);269 however, several unidentified byproductswere obtained and no tetrahydroxanthonol was observed (entry 2). Nozaki-Hiyama-Kishi conditions werealso attempted (entries 3 and 4), however, even after 10 days of reaction time, only starting material wasobserved. Lithium-bromine exchange was attempted using tBuLi at -78 ◦C, but it only led to starting materialdecomposition.2.2.6.3 Intramolecular Nucleophilic Addition of Vinyl Bromides Using Palladium(0)Yamamoto and co-workers had reported the synthesis of anthracenone 2.171 via intramolecular nucleophilicaddition of aryl bromides to ketones using palladium(0) as a catalyst (Scheme 2.50a).271 It was envisioned78Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesTable 2.14. Evaluation of conditions for the intramolecular nucleophilic addition of alkenyl bromide2.144b.OconditionsOOOHOMe OMeBr2.144b 2.169bentry additives solvent T (◦C) t (h) Product†1 Zn THF 66 72 NR2269 Mg THF 66 16 dec3270 CrCl2/NiCl2 DMF rt 240 NR4 CrCl2/NiCl2 DMSO/THF ‡ rt 240 NR5 tBu Li THF -78 1 dec† The reactions were performed at a 0.1 M concentration using 3 molar equiva-lents of additive. No desired product was observed.‡ The reaction was carried out under sonication.that alkenyl bromide 2.144b would react analogously to aryl halides and would undergo an intramolecularnucleophilic addition to the aldehyde present in the molecule (Scheme 2.50b).BrO PhO Pd(OAc)2, KOAcPCy3, 1-hexanolOHO PhOOBrOMeOHOOMe(a)(b)ReportedProposed2.170 2.1712.144b 2.169bScheme 2.50. (a) Nucleophilic addition of aryl bromides using palladium as catalyst.271 (b) Proposedsynthesis of tetrahydroxanthonol 2.169b using palladium as catalyst.Compound 2.144b was treated with catalytic palladium acetate in the presence of cesium carbonate,tricyclohexylphosphine and ethanol. After stirring for 48 hours at 60 ◦C, o-vanillin was obtained in 56%yield (Table 2.15, entry 1). o-Vanillin was obtained after ionization of bromo cyclohexene 2.144b, whichwas initiated by palladium(0) in a Tsuji-Trost-type mechanism.272 When potassium acetate was used as thebase, the same C–O bond cleavage was observed (entry 2).79Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesAs C–I bonds are more reactive than C–Br bonds towards oxidative addition of palladium(0),273 theiodinated version of 2.172 was synthesized from 2-cyclohexen-1-one, following literature procedures.274When the iodinated species was subjected to the reaction conditions used by Yamamoto and co-workers(entries 3 to 5), only o-vanillin could be recovered from the reaction mixture. It was observed that underthe reaction conditions used, the Tsuji-Trost allyl palladium cation formation was favoured over the oxidativeinsertion of palladium between either the C–Br or C–I bonds.Despite the attempts to activate the C–halogen bond towards nucleophilic addition to the aldehyde, thisreaction failed, either undergoing decomposition when using magnesium or tert-butyllithium or cleaving theC–O bond between o-vanillin and the cyclohexene moiety.2.2.6.4 Intramolecular N-Heterocyclic Carbene CatalysisIn 2009, Glorious and co-workers reported the synthesis of chromanones from allyl substituted salicylaldehy-des via intramolecular hydroacylation of unactivated alkenes usingN-heterocyclic carbene (NHC) (Scheme 2.51a).275The authors performed an exhaustive screening of catalysts and found that 2.174 was the ideal NHC requiredfor their transformation. It was then envisioned that this methodology could be extended to the synthesis ofhexahydroxanthones and tetrahydroxanthones if the salicylaldehyde had a cyclohexenyl derivative substituentinstead of an allyl group (Scheme 2.51b).Table 2.15. Evaluation of bases for the intramolecular nucleophilic addition of alkenyl halides usingpalladium.OOXOMePd(OAc)2, basePCy3, alcoholDMFOHOOMeOOHOMeH+2.172 2.169b 2.143entry X base alcohol T (◦C) t (h) 2.143 (% yield)†1 Br Cs2CO3 EtOH 60 48 562 Br KOAc EtOH rt 16 303 I Na2CO3 – 100 1 424 I Na2CO3 1-hexanol 100 1 285 I KOAc 1-hexanol 100 1 30The reactions were performed at a 0.1 M concentration in DMF using 5 mol% ofPd(OAc)2, 10 mol% of Cy3P, 2 equiv of base and 5 equiv of alcohol where applica-ble. † No desired product was obtained. The reactions were monitored by thin layerchromatography (TLC) and o-vanillin was observed as the only product after 30 min.leaving the reactions at 100 ◦C for longer periods of time resulted in decompositionproducts of both the alkenyl iodide and o-vanillin.80Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOMeOOOMeOODBU, dioxane120 ºC, 1 h85%OMeOOXOMeOON SClO4(a)(b)reportedproposed2.1732.1742.1742.1752.172 2.176Scheme 2.51. (a) Synthesis of chromanones using NHC.275 (b) Proposed synthesis of hexahydroxan-thones or tetrahydroxanthones using NHC.The NHC precursor 2.174 was synthesized to explore the intramolecular hydroacylation of 2.172 forthe synthesis of hexahydroxanthones or tetrahydroxanthones. The synthesis of 2.174 was accomplishedfollowing the procedure reported by Glorius and co-workers (Scheme 2.52).276 Mesitylamine (2.177) wastreated with carbon disulfide in the presence of sodium hydroxide forming carbamodithionate in situ, whichwas treated with 2-bromocycloheptan-1-one. Addition of concentrated hydrochloric acid furnished thiazo-lethione 2.178 over three steps. The exocyclic sulfur atom was extruded as SO2 through oxidation withhydrogen peroxide in acetic acid, obtaining the NHC precursor as the acetate salt. Anion exchange was per-formed by treating the crude reaction with sodium perchlorate in methanol at 0 ◦C obtaining NHC catalyst2.174 in 80% over five steps. The obtained solid was identified by comparison of the 1H NMR data with theone reported in the literature, observing a peak at δ 9.52 (s, 1H), which corresponded to the C–H of the thia-zole ring. No acetate anion was detected by 1H NMR, 13C NMR, nor by low resolution mass spectrometry.NH2 1) NaOH, CS2    DMSO2) 2-Bromocycloheptanone3) HCl, EtOH N SS1) H2O2AcOH2) NaClO480% overfive stepsN SClO42.177 2.178 2.174Scheme 2.52. Synthesis of NHC catalyst.27681Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesIt had been envisioned that for the NHC catalysis, the use of a cyclohexenyl with no other substituents(2.172, X = H) would yield hexahydroxanthone 2.176a. It was also proposed that the use of an alkene halide(2.172, X = Br or I) would result in tetrahydroxanthone 2.176b (Table 2.16).Table 2.16. Synthesis of hexahydroxanthones and tetrahydroxanthones via NHC catalysis.OMeOOXOMeOOconditionsOMeOOor2.1722.1742.176a 2.176bentry X base solvent T (◦C) product (% yield)1 H K2CO3 THF 70 NR2 Br K2CO3 THF 70 NR3 I K2CO3 THF 70 NR4 H DBU dioxane 120 2.176a (20)5 Br DBU dioxane 120 2.176b (22)6 I DBU dioxane 120 2.176b (23)7 H DBU dioxane 180† 2.176a (21)8 Br DBU dioxane 180† 2.176b (43)‡9 I DBU dioxane 180† 2.176b (19)The reactions were performed at a 0.5 M concentration using 20 mol% ofNHC catalyst 2.174 and 40 mol% of base and were stored for 1 h.† The reaction was heated up in a microwave reactor. ‡ The catalyst loadwas 43 mol%.The intramolecular hydroacylation was performed on cyclohexenyl o-vanillin derivatives 2.172 (X = H,Br, and I) using potassium carbonate as the base and THF as the solvent at 70 ◦C. Despite the generation ofthe carbene species in situ, which was indicated by the change in colour of the reaction mixture after the basehad been added, no hydroacylation product was observed (entries 1 to 3). Treatment of 2.172 (X = H) withDBU in 1,4-dioxane at 120 ◦C afforded hexahydroxanthone 2.176a in 20% yield. Treatment of either 2.172(X = Br or I) proceeded to form tetrahydroxanthone 2.176b also in low yield (22% and 23%, respectively).The identity of compounds 2.176a and 2.176b was established by comparison of the 1H NMR data withanalogous compounds that did not possess the methoxy group in the aromatic ring.277,278 Compound 2.176ashowed a characteristic signal for the hydrogen at position C-4a at δ 4.12 ppm (dt, J = 4.2 and 11.1 Hz).Compound 2.176b showed two characteristic signals the hydrogen at position C-4a appeared at δ 5.44 ppm(d, J = 9.9 Hz) and the vinylic hydrogen at position C-1 appeared at δ 6.30 ppm (dt, J = 3.9 and 9.9 Hz). Itwas then proposed that an increase in the temperature of the reaction would favour the formation of products,82Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesso the reactions were repeated at 180 ◦C using a microwave reactor (entries 7 to 9). However, the products(2.176a and 2.176b) were obtained in low yield as well (21 and 19%, respectively).It was observed that the yield for the NHC-catalyzed hydroacylation corresponded to the catalyst loading(entries 4-9). It was speculated that the presence of halogens prevented the NHC species from continuingthe catalytic cycle. However, for entries 4 and 7, there was no halogen present that could interfere with thecatalyst, yet the yield also corresponded to the catalyst loading.The mechanistic rationale for the synthesis of 2.176a is based on the mechanistic pathway proposed byGlorius and co-workers (Scheme 2.54).275 The NHC precursor 2.174 is deprotonated by DBU to generatethe active carbene species 2.179, which undergoes nucleophilic addition to aldehyde 2.172a (X = H) to affordzwitterion 1.132, which after proton transfer renders compound 2.180.OOOMeN SS NOOMeONSOMeO HHOS NO HOMeOOOOMeHHDBUHpT2.1742.1792.172a1.1322.1802.1812.176aScheme 2.53. Proposed mechanism for the synthesis of tetrahydroxanthone 2.176b via NHC catalysis.Ring closure of the pyrone ring occurs through an alder-ene-type mechanism initiated by the enaminespecies, generating imminium ion 2.181. In the last step, the oxygen atom of the benzylic alkoxide forms thecarbonyl of tetrahydroxanthone 2.176a and regenerates the carbene to continue the catalytic cycle.To increase the yield of the transformation, two solutions were proposed: to utilize a stoichiometricamount of the NHC precursor or to use a sulfone instead of a halogen as the substituent for the cyclohexenering. The preliminary results using a sulfone as the electron-withdrawing substituent, indicated that the reac-tion proceeded to form tetrahydroxanthone 2.176b in 30% yield, which was slightly higher than the catalyst83Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesload (20 mol%). This transformation required extensive optimization and it was considered that tetrahydrox-anthone 2.176b would need to be further elaborated into the desired tetrahydroxanthone 2.3 through severalsteps.OMeOOOMeOOOOMeOOOHOPGOOOPGOPGOPGBr2.176b 2.182 2.166a 2.3Scheme 2.54. Proposed conversion of tetrahydroxanthone 2.176b into 2.3.The intramolecular NHC-catalyzed hydroacylation reaction was being carried out at the same time as theintramolecular Baylis-Hillman/oxa-Michael addition cascade using ynones tethered to phenols (see Chapter 3).The tandem Baylis-Hillman/oxa-Michael reaction sequence gave promising results, therefore, the NHC-catalyzed hydroacylation was set aside.Although low yields were obtained for this transformation, the intramolecular hydroacylation of tetheredalkenes is an unexplored way of making tetrahydroxanthones. In retrospect, different electron withdrawinggroups should have been tested in positions C-2 and C-3 of the cyclohexenyl, since they may lead to dif-ferent tetrahydroxanthones. When compared with the synthesis of chromanones reported by Glorius andco-workers,275 the use of electron withdrawing groups on the alkene of the cyclohexene for the synthesis oftetrahydroxanthones should be a factor that would require milder reaction conditions.2.3 ConclusionThe synthesis of isoquinolinone 2.13b (Section 2.1, Scheme 2.4), analogous to the AB ring system of simao-micin α (2.2, Scheme 2.1), was achieved in 56% yield over three steps starting with commercially available2,5-dimethoxy-benzoic acid (Scheme 2.4). Although the synthesis of formyl isoquinoline 2.17 (Scheme 2.6)was attempted using the same sequence, the cyclization of the A ring was unsuccessful. This may be due tothe instability of the aldehyde moiety under the strong acidic conditions (Scheme 2.6).Several routes to synthesize the tetrahydroxanthone DEF fragment of simaomicin α were attempted,including oxa-Michael addition/Dieckman condensations, inter and intramolecular [3+2] cycloadditions be-tween nitrile oxides and vinylic bromides, [4+2] cycloaddition between electron rich 1,3-dienes and electrondeficient chromenones, and intramolecular Nozaki-Hiyama-Kishi-type transformation (Scheme 2.55). Un-fortunately, these attempts failed to generate the tetrahydroxanthone core.84Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOO OPGOPGD E FOHOD OMe FOW+D F+ON OYOOD EOO X WORRO+ODN OHXOHOD OMe FW+OHF X XXXXXScheme 2.55. Attempts to construct the tetrahydroxanthone core.The intramolecular [3+2] dipolar cycloaddition of nitrile oxides across alkenes resulted in the synthesisof highly substituted tetracyclic isoxazoles (Table 2.13), which could be further converted in tricyclic vinylo-gous amides. Examples with electron donating and electron withdrawing group were studied (Scheme 2.42).Both tetracyclic isoxazoles and vinylogous amides were structures that had not been reported in the literature.The intramolecular hydroacylation of aldehydes across alkenes using N-heterocyclic carbene (NHC) al-lowed for the synthesis of hexahydroxanthone 2.176a and tetrahydroxanthone 2.176a, albeit the yields corre-sponded to the load of NHC (Table 2.16). This method is an elegant approach to either hexahydroxanthonesor tetrahydroxanthones; however, further optimization is required. Future work could include the screeningof different substituents to activate the alkene, either in position C-2 or C-3 and the use of different NHCcatalysts (Scheme 4.5).OMeOOOMeOOXYNHCScheme 2.56. Proposed optimization for the synthesis of tetrahydroxanthones using NHC catalysis.2.4 Experimental Section2.4.1 General ExperimentalAll reactions sensitive to air or moisture were carried out in flame-dried glassware under an atmosphere ofnitrogen. Tetrahydrofuran was distilled from sodium benzophenone ketyl prior to use. Dichloromethane,85Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesdiisopropylamine and triethylamine were distilled from calcium hydride and degassed by sparging with ar-gon prior to use. Toluene was distilled from sodium and degassed by sparging with argon prior to use.All commercial reagents or materials were used without further purification unless otherwise noted. Thinlayer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates.Triethylamine-washed silica gel was stirred with a 1% solution of triethylamine in hexanes before packing.Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectrawere recorded in deuterochloroform unless otherwise noted. Chemical shifts are recorded in parts per mil-lion (ppm) and are referenced to the centerline of deuterochloroform (δ 7.27 ppm 1H NMR; δ 77.0 ppm 13CNMR). Data was recorded as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quar-tet, m = multiplet, br = broad signal). Coupling constants (J values) are given in Hertz (Hz). Low resolutionelectrospray ionization (ESI) mass spectra were recorded on a Bruker Esquire-LC ion trap mass spectrom-eter equipped with an electrospray ionization source. High resolution ESI mass spectra were recorded on aWaters/Micromass liquid chromatography tandem (LCT) time of flight (TOF) mass spectrometer equippedwith an electrospray ionization source. X-ray crystallography measurements were made on either a BrukerAPEX DUO diffractometer with cross-coupled multilayer optics Cu-Kα radiation or on a Bruker X8 APEXII diffractometer with graphite monochromated Mo-Kα radiation.2.4.2 Synthesis of Isoquinolinone 2.13b and DerivativesOMeOMeHOO1) SOCl2, ∆2) Et3N, DMAPNHH OMeOMeOMeOMeNOHMeOOMe, 85%2.9 2.10a 2.11aN-(2,2-dimethoxyethyl)-2,5-dimethoxybenzamide (2.11a). Thionyl chloride (16.5 mL, 226.2 mmol, 8equiv) was added to 2,5-dimethoxybenzoic acid (2.9) (5.00 g, 27.5 mmol, 1 equiv). The reaction mixturewas heated up to reflux temperature for 3 h. The excess thionyl chloride was removed by rotary evaporationin vacuo. The reaction mixture was dissolved in 75 mL of DCM and was cooled to 0 ◦C. A solution of2,2-dimethoxyethan-1-amine (2.10a) (4.6 mL, 41.8 mmol, 1.5 equiv), triethylamine (5.8 mL, 41.6 mmol,1.5 equiv), and DMAP (0.18 g, 1.5 mmol, 5 mol%) in 75 mL of DCM was added in one portion throughcannula. The reaction mixture was stirred at 0 ◦C for 2 h. Aqueous hydrochloric acid (0.5 M, 200 mL) wasadded. The aqueous layer was extracted with 80 mL of diethyl ether (twice). Drying of he organic layer86Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesover sodium sulfate followed by concentration by rotary evaporation in vacuo produced 6.30 g (85 % yield)of an orange oil. The compound was synthesized following a modification of a literature procedure.178 IR(neat):3384, 2942, 2835, 1644, 1608, 1282, 1214, 1128 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.13 (br s,1H), 7.63 (d, J = 3.1 Hz, 1H), 6.87 (dd, J = 3.2, 9.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.4 Hz,1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.50 (t, J = 5.6 Hz, 2H), 3.32 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 165.1,153.7, 151.8, 121.7, 119.1, 115.5, 113.0, 102.6, 56.4, 55.6, 54.2, 41.3. LRMS (ESI+): 292.4 (M+Na)+.HRMS (ESI+) Calculated for C13H19NO5Na (M+Na)+: 292.1161, found: 292.1153.OMeOMeHOO 1) SOCl2, ∆2) Et3N, DMAPNHOMeOMeOMeOMeNOMeOOMe86%2.9 2.10b 2.11bN-(2,2-dimethoxyethyl)-2,5-dimethoxy-N-methylbenzamide (2.11b). The reaction was performed us-ing 5.04 g of 2,5-dimethoxybenzoic acid (2.9, 27.7 mmol, 1 equiv), 16.2 mL of thionyl chloride (222.1 mmol,8 equiv), 5.8 mL of 2,2-dimethoxy-N-methylethan-1-amine (2.10b, 41.6 mmol, 1.5 equiv), 5.8 mL of tri-ethylamine (41.6 mmol, 1.5 equiv) and 0.18 g of DMAP (1.4 mmol, 5 mol%). After removal of the solventin vacuo, 6.73 g (86% yield) of the title compound was isolated as an orange oil. The compound was usedwithout further purification. 1H NMR (300 MHz, CDCl3) δ 6.78 (d, J = 4.4 Hz, 2H), 6.71 (t, J = 3.5 Hz,1H), 4.60 (t, J = 5.4 Hz, 0.7H), 4.24 (t, J = 5.3 Hz, 0.3H), 3.70 (s, 3H), 3.68 (m, 3H), 3.53 (br s, 1H), 3.38(s, 3H), 3.16 (s, 2H), 3.07 (s, 1H), 2.82 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 169.4, 169.2, 153.7, 149.2,149.0, 127.0, 126.7, 115.3, 113.5, 113.1, 112.4, 103.9, 103.1, 56.1, 56.0, 55.7, 54.8, 54.4, 53.5, 49.6, 37.9,34.1.OMeOMeNOHMeOOMeBF3•Et2ODCM, 0 ºC95%OMeOMeNOHOH2.11a 2.12a2,5-Dimethoxy-N-(2-oxoethyl)benzamide (2.12a). To a solution of 2.11a (1.36 g, 5.1 mmol, 1 equiv)in 25 mL of DCM at 0 ◦C, boron trifluoride diethyl etherate (1.4 mL, 11.0 mmol, 2.2 equiv) was added inone portion. The reaction mixture was stirred for 2.5 h. A white precipitate was formed. The solid wasremoved by vacuum filtration and the reaction mixture was quenched with 100 mL of aqueous hydrochloricacid (1% w/v). The aqueous solution was extracted with DCM (3 x 50 mL). Drying over sodium sulfate and87Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesconcentration in vacuo produced 1.07 g (95% yield) of an orange oil. 1H NMR (400 MHz, CDCl3) δ 9.36(s, 1H), 8.46 (s, 1H), 7.36 (d, J = 3.1 Hz, 1H), 6.66 (dd, J = 3.1, 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 3.99(d, J = 4.8 Hz, 2H), 3.57 (s, 3H), 3.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.8, 165.3, 153.5, 152.0,120.8, 119.0, 115.6, 112.9, 56.2, 56.2, 50.6.OMeOMeNOMeOOMeOMeOMeNOH2SO460 ºC65%2.10b 2.13b5,8-Dimethoxy-2-methylisoquinolin-1(2H)-one (2.13b). A mixture of amide 2.10b (0.92 g, 3.9 mmol,1 equiv) and concentrated sulphuric acid (10 mL, 184 mmol, 47 equiv) was stirred at 60 ◦C for 6 h. Thereaction mixture was quenched with 50 mL of aqueous sodium hydroxide (20 % w/v). The aqueous phasewas extracted with DCM (3 x 50 mL). Drying over sodium sulfate and concentration in vacuo produced 0.53g (65 % yield) of a thick red oil. IR (neat): 3068, 1655, 1245, 1073 cm-1. 1H NMR (300 MHz, CDCl3)δ 6.58 (d, J = 7.5 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 8.9 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H),3.43 (s, 3H), 3.33 (s, 3H), 3.02 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 159.6, 153.1, 146.7, 131.7, 129.6,115.2, 110.9, 107.2, 98.3, 55.4, 54.7, 36.0. LRMS (ESI+): 242.4 (M+Na)+. HRMS (ESI+) Calculated forC12H14NO3 (M+H)+: 220.0974, found: 220.0971.OMeOMeOHHC(OMe)3,pTsOHMeOH, ∆quan OMeOMeOMeOMea) sBuLi, TMEDATHFb) CO2, HCl66% OMeOMeOHHOO2.8 2.14 2.154-Formyl-2,5-dimethoxybenzoic acid (2.15). To a solution of 2,5-dimethoxybenzaldehyde (2.8) (8.49g, 50.0 mmol, 1 equiv) and trimethylorthoformate (9.4 mL, 85.9 mmol, 1.7 equiv) in 210 mL of methanoland 70 mL of chloroform, para-toluenesulfonic acid monohydrate (0.36 g, 1.9 mmol, 3 mol%) was added.The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with solid potassiumcarbonate. Vacuum filtration and removal of the solvent in vacuo afforded an ivory-looking solid, which wassuspended in 500 mL of chloroform. The suspension was washed with 250 mL of water. Drying over sodiumsulfate and concentration by rotary evaporation in vacuo produced 10.66 g (100% yield) of dimethylacetal2.14 as a light yellow oil. This material was used in the next reaction without further purification.To a solution of dimethylacetal 2.14 (10.66 g, 50.2 mmol, 1 equiv) and tetramethylethylenediamine (11.5mL, 75.9 mmol, 1.5 equiv) in 250 mL of THF at -78 ◦C, 1.3 M sec-butyllithium (58.0 mL, 75.4 mmol, 1.588Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesequiv) was added dropwise over a period of 30 min. The reaction mixture turned orange after stirring for 1 h.Dry carbon dioxide gas was bubbled through the solution through a cannula for a period of time of 10 min.The orange suspension was allowed to warm to rt. The reaction mixture was quenched with 100 mL of water.The reaction mixture was washed with diethyl ether (2 x 120 mL). The aqueous layer was acidified and abright yellow precipitate was formed. Filtration and drying under high vacuum produced 6.96 g (66%) of thetitle compound as a bright yellow solid, mp 194–196 ◦C (lit. 196–197 ◦C). 1H NMR (300 MHz, DMSO) δ10.34 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H). 2.15 has been previously prepared, see:Freskos, Morrow, and Swenton 181 for further detail.OMeOMeHOOHOa) (COCl)2b) Et3N, DMAPNHOOOMeOMeNOHOOMeMeO2.15 2.10b 2.16N-(2,2-dimethoxyethyl)-4-formyl-2,5-dimethoxy-N-methylbenzamide (2.16). To a solution of 2.15(1.02 g, 4.9 mmol, 1 equiv) in 25 mL of DCM, oxalyl chloride (0.90 mL, 10.3 mmol, 2 equiv) was added inone portion, followed by one drop of DMF. The reaction mixture was stirred at rt for 4 h. The excess oxalylchloride was removed by rotary evaporation in vacuo. The crude reaction was dissolved in 25 mL of DCMand it was cannula-transferred to a solution of 2.10b (0.70 mL, 5.0 mmol, 1 equiv), triethylamine (0.70 mL,5.0 mmol, 1 equiv) and DMAP (0.62 g, 5.0 mmol, 1 equiv) in 25 mL of DCM. The reaction mixture wasstirred at rt for 16 h. The reaction mixture was successively washed with 50 mL of water (once) and 50 mLbrine (once). Drying over sodium sulfate, concentration by rotary evaporation in vacuo produced a red solidthat after purification using chromatography over silica gel yielded 1.27 g (84%) of the title compound as alight yellow oil. The compound was synthesized following a modification of a literature procedure.182 1HNMR (300 MHz, CDCl3) δ 10.28 (s, 2H), 10.27 (s, 2H), 7.21 (s, 3H), 6.83 (s, 1H), 6.79 (s, 2H), 4.53 (t, J= 5.4 Hz, 2H), 4.23 (t, J = 5.1 Hz, 1H), 3.76 (d, J = 3.4 Hz, 8H), 3.70 (s, 8H), 3.32 (s, 9H), 3.14 (d, J = 5.8Hz, 6H), 2.77 (s, 5H). 13CNMR (75 MHz, CDCl3) δ 188.6, 168.1, 168.0, 156.4, 156.3, 149.0, 148.8, 133.4,133.1, 125.0, 124.9, 112.4, 111.6, 109.3, 103.3, 102.8, 56.1, 56.0, 56.0, 55.9, 54.9, 54.6, 54.3, 52.3, 49.4,37.5, 33.8. LRMS (ESI+): 312 (M+H)+. HRMS (ESI+) Calculated for C15H22NO6 (M+H)+: 312.1447,found: 312.145189Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOMeOMeNOHOOMeMeOMe3SiI, NaHDMSO96%OMeOMeNOOMeMeOO2.16 2.18N-(2,2-dimethoxyethyl)-2,5-dimethoxy-N-methyl-4-(oxiran-2-yl)benzamide (2.18). A solution of 2.16(0.35 g, 1.1 mmol, 1 equiv) in 1 mL of DMSO was cannula-transferred to a suspension of trimethylsulfo-nium iodide (0.74 g, 3.54 mmol, 3 equiv) and 95% sodium hydride (92.8 mg, 3.67 mmol, 3 equiv) in 3 mLof DMSO. The reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with 6 mL ofwater and it was extracted with ethyl acetate (3 x 8 mL). The combined organic extracts were washed withbrine (2 x 6 mL). Drying over sodium sulfate, concentration by rotary evaporation in vacuo produced 0.35g (96% yield) of the title compound as an orange oil. The compound was used without further purification.1H NMR (400 MHz, CDCl3) δ 6.58 (d, J = 8.6 Hz, 1H), 6.52 (s, 1H), 4.45 (t, J = 5.4 Hz, 0.65H), 4.13 (t, J= 5.2 Hz, 0.35H), 3.95 (t, J = 3.1 Hz, 1H), 3.60 (d, J = 4.4 Hz, 3H), 3.56 (d, J = 2.6 Hz, 3H), 3.24 (s, 3H),3.04 (d, J = 1.6 Hz, 3H), 2.91 (s, 3H), 2.69 (s, 3H), 2.42 (dt, J = 2.3, 9.0 Hz, 1H). 13C NMR (101 MHz,CDCl3) δ 168.9, 168.8, 151.8, 149.1, 148.8, 127.8, 127.7, 125.4, 125.2, 110.3, 109.8, 107.7, 103.3, 102.7,55.7, 55.6, 54.1, 54.0, 52.1, 50.4, 50.4, 49.2, 47.6, 40.5, 37.4, 33.6. LRMS (ESI+): 348.4 (M+Na)+. HRMS(ESI+) Calculated for C16H24NO6 (M+H)+: 326.1604, found: 326.1610.2.4.3 Synthesis of Xanthone 2.56 and DerivativesBr KCN18-C-6DCM, rt34%CN m-CPBADCM, rt64%CNOLDA, THF-78 ºC84%CNHO2.22 2.23 2.24 2.253-hydroxycyclohex-1-ene-1-carbonitrile (2.25). A solution of 3-bromocyclohex-1-ene (2.22) (2.0 mL,15.6 mmol, 1 equiv), potassium cyanide (3.05 g, 45.5 mmol, 2.9 equiv) and 18-crown-6 (76.7 mg, 0.3 mmol,1.4 mol%) in 16 mL of DCM was stirred at rt for 4 d. The excess potassium cyanide and potassium bromidewere removed by vacuum filtration. Concentration by rotary evaporation in vacuo produced an orange oil thatafter purification using chromatography over silica gel yielded 0.58 g (34%) of cyclohex-2-ene-1-carbonitrile(2.23) as a yellow, volatile oil. This compound was synthesized following the procedure reported by Brouil-lette and co-workers.188To a solution of 2.23 (0.58 g, 5.4 mmol, 1 equiv) in 48 mL of DCM, m-CPBA (1.81 g, 8.1 mmol, 1.5equiv) was added in one portion. The reaction mixture was stirred at rt for 16 h. The reaction mixture was90Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesquenched with saturated aqueous sodium bisulfite solution at 0 ◦C. The reaction mixture was diluted with100 mL of DCM. The organic phase was washed with water (3 x 200 mL). Drying over sodium sulfate andconcentration by rotary evaporation in vacuo produced an orange oil that after purification using chromatog-raphy over silica gel yielded 420.2 mg (64%) of 2.24 as a mixture of diastereomers.A freshly made solution of LDA (6.88 mmol, 2 equiv) in 7 mL of THF was cannula-transferred to asolution of 2.24 (420.2 mg, 3.41 mmol, 1 equiv) in 7 mL of THF at -78 ◦C. The reaction mixture was stirredfor 5 min. It was then quenched with 0.8 mL of acetic acid (14.0 mmol, 4 equiv). The reaction mixture wasdiluted with 36 mL of ethyl acetate. Filtration and concentration by rotary evaporation in vacuo producedan orange oil that after purification using chromatography over silica gel yielded 0.35 g (84%) of the titlecompound as a slightly yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.45 (s, 1H), 4.14 (s, 1H), 3.73 (br s, 1H),2.09 (m, 2H), 1.76 (m, 2H), 1.49 (m, 2H). Compound 2.25 had been previously synthesized, see: Fleming,Wang, and Steward 187 for further detail.Br PhSH,NaHTHFquanSPh m-CPBADCM, rtquanSO2PhODBU,THF74%SO2PhHO2.22 2.28 2.29 2.303-(Phenylsulfonyl)cyclohex-2-en-1-ol (2.30). To a suspension of thiophenol (3.7 mL, 35.0 mmol, 1equiv) and sodium hydride (1.67 g, 41.86 mmol, 1.2 equiv) in 170mL of THF, 3-bromocyclohex-1-ene (2.22)(4.0 mL, 34.8 mmol, 1 equiv) was added in one portion. The reaction mixture was stirred at rt for 24 h. Thereaction mixture was quenched with 100 mL of saturated aqueous ammonium chloride solution. The aqueouslayer was extracted with diethyl ether (3 x 100 mL). The combined organic fractions were washed with brine(2 x 100 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced 6.62 g(100% yield) of 2.28 as a slightly yellow oil. The compound was used without further purification.To a suspension of 2.28 (6.62 g, 34.8 mmol, 1 equiv) in 50 mL of DCM, a suspension of m-CPBA in200 mL of DCM was added through an addition funnel. The reaction mixture was diluted with 50 mL ofDCM and it was stirred at rt for 16 h. The reaction mixture was quenched with 100 mL saturated aqueoussodium bisulfite solution followed by 250mL of saturated aqueous sodium bicarbonate solution. The reactionmixture was diluted with 100 mL of DCM. The organic phase was separated and the aqueous phase wasextracted with DCM (2 x 100 mL). The combined organic fractions were washed successively with 25% v/vhydrochloric acid (2 x 50 mL) and water (100 mL). Drying over sodium sulfate and concentration by rotaryevaporation in vacuo produced 8.28 g (100% yield) of 2.29 as a turbid oil. The compound was used withoutfurther purification.91Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesA solution of 2.29 (8.28 g, 34.8 mmol, 1 equiv) and DBU (0.54 mL, 3.53 mmol, 0.1 equiv) in 130 mLof THF was stirred at rt for 16 h. The reaction mixture was quenched with 200 mL of saturated aqueousammonium chloride. The aqueous phase was extracted with DCM (3 x 100 mL). The combined organicfractions were washed with brine (once). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a brown oil that after purification using chromatography over silica gel yielded 6.13 g(74%) of the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H),7.59 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 6.95 (s, 1H), 4.35 (s, 1H), 3.19 (s, 1H), 2.11 (s, 2H), 1.81(m, J = 5.0 Hz, 2H), 1.52 (m, J = 5.8 Hz, 2H). Compound 2.29 had been previously synthesized, see Trost,Seoane, Mignani, and Acemoglu 279 for further detail.OOMeOH+PhO2SOHadditivesolventOHOOSO2Ph2.26 2.30 2.323-(Phenylsulfonyl)cyclohex-2-en-1-yl 2-hydroxybenzoate (2.32). To a solution of 2.30 (0.49 g, 2.1mmol, 1 equiv) in 25 mL of THF, triethylamine (0.32 mL, 2.3 mmol, 1.1 equiv) and methyl salicylate (2.26)(0.30 mL, 2.3 mmol, 1.1 equiv) were added. The reaction mixture was stirred at 60 ◦C for 24 h. The solventwas removed by rotary evaporation in vacuo. Purification using flash column chromatography over silica gelyielded 0.20 g (27%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.63 (s,1H), 7.90 (d, J = 7.3 Hz, 2H), 7.81 (dd, J = 8.0, 1.4 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz,2H), 7.50-7.46 (m, 1H), 7.04 (br s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 (t, J = 7.3 Hz, 1H), 5.70 (br s, 1H),2.42-2.30 (m, 1H), 2.27-2.15 (m, 1H), 1.96-1.57 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 162.1, 145.5,138.6, 136.3, 133.9, 133.8, 130.2, 129.5, 128.6, 119.4, 117.9, 112.2, 68.5, 31.8, 27.3, 23.1, 22.8, 19.2, 14.4.BrBrBrOHH5IO6CH3CN, H2O60 ºC, 61%OOBrBr2.183 2.492,6-Dibromocyclohexa-2,5-diene-1,4-dione (2.49). To a suspension of 2,4,6-tribromophenol (15.30 g,46.2 mmol, 1 equiv) in 600 mL of acetonitrile was added a solution of periodic acid (26.76 g, 116.2 mmol,2.5 equiv) in 150 mL of water. The reaction mixture was stirred at 60 ◦C for 16 h. The reaction mixturewas cool to rt and it was extracted with diethyl ether (3 x 200 mL). The combined organic fractions werewashed with water (2 x 100 mL). Drying over sodium sulfate and concentration by rotary evaporation in92Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesvacuo produced a yellow solid. The product was crystallized from ethyl alcohol to yield 7.44 g (61%) of thetitle compound as golden flakes, mp 104–107 ◦C (lit. 130 ◦C). The compound was synthesized followinga procedure reported by Omura.194 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H). Compound 2.49 had beenpreviously synthesized, see Omura 194 for further detail.OOCl OMeOEt3Na) DCM, rt, 20 hb) Et3N, KCN, CH3CN+ +OOOMeO2.184 2.50Methyl 2,6-dioxocyclohexane-1-carboxylate (2.50). To a solution of cyclohexane-1,3-dione (2.184)(1.16 g, 10.0 mmol, 1equiv) in 20 mL of DCM, triethylamine (3.0 mL, 21.6 mmol, 2 equiv) was added.The reaction mixture was stirred at rt for five minutes and methyl chloroformate (0.78 mL, 10.0 mmol,1 equiv) was added dropwise through syringe. The reaction mixture turned from orange to yellow. Thereaction mixture was stirred at rt for 6 h. The solvent was removed by rotary evaporation in vacuo. Thecrude reaction was suspended in 30 mL of acetonitrile and triethylamine (3.0 mL, 21.6 mmol, 2 equiv) andpotassium cyanide (57.2 mg, 0.9 mmol, 8.5 mol%) were added. The reaction mixture was stored at rt for 16h. The solvent was removed by rotary evaporation in vacuo and the remaining solid was dissolved in 100 mLof DCM. The organic layer was washed with 1M hydrochloric acid (2 x 100 mL). Drying over sodium sulfateand concentration by rotary evaporation in vacuo produced 0.92 g (54% yield) of the title compound as anorange oil. 1H NMR (300 MHz, CDCl3) δ 3.43 (s, 3H), 2.13-2.11 (m, 4H), 1.93-1.89 (m, 1H), 1.57-1.53(m, 2H). Compound 2.50 had been previously synthesized, see Hansen, Kamounah, and Ullah 197 for furtherdetail.OBr BrONaH, DMSO60 ºC, 62%OBr OO+HOMeOOOMeO2.49 2.26 2.52Methyl 2-((5-bromo-3,6-dioxocyclohexa-1,4-dien-1-yl)oxy)benzoate(2.52). A suspension of methyl-salicylate (2.26) (0.30 mL, 2.3 mmol, 1equiv) and sodium hydride (68.0 mg, 2.69 mmol, 1 equiv) in 25 mLof DMSO was added dropwise( with the aid of a syringe pump) to a solution of 2.49 (0.60 g, 2.3 mmol, 1equiv) in 5 mL of DMSO. The reaction mixture was stirred at 60 ◦C for 16 h. It was quenched with 50 mLof saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ether (3 x 50 mL).The organic fractions were washed with brine (2 x 50 mL). Drying over sodium sulfate and concentration93Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesby rotary evaporation in vacuo produced a red oil that after purification using chromatography over silicagel yielded 0.48 g (62%) of a yellow solid, melting point (mp) 135–137 ◦C. IR (neat): 3014, 2998, 1726,1586, 1216 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.02 (dd, J = 1.7, 7.8 Hz, 1H), 7.62 (dt, J = 1.7, 11.8 Hz,1H), 7.37 (dt, J = 1.0, 7.7 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 0.8, 8.1 Hz, 1H), 5.53 (d, J =2.3 Hz, 1H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 184.7, 174.0, 164.0, 158.5, 152.0, 138.3, 134.7,134.5, 132.8, 127.2, 123.2, 122.9, 110.8, 52.5. LRMS (ESI+): 361.0 (M+Na)+. HRMS (ESI+) Calculatedfor C14H1079BrO5 (M+H)+: 336.9725, found: 336.9719.OBr BrOK2CO3DMSO20%+     2HOMeOOOO OOOMeOOMeO2.49 2.26 2.53Dimethyl 2,2′-((2,5-dioxocyclohexa-3,6-diene-1,3-diyl)bis(oxy))dibenzoate (2.53). To a suspensionof methyl salicylate (2.26) (0.27 mL, 2.1 mmol, 1 equiv) and potassium carbonate (0.27 g, 2.0 mmol, 1equiv) in 5 mL of DMSO, was cannula-transferred a solution of 2.49 (0.54 g, 2.0 mmol, 1 equiv) in 5 mlof DMSO. The orange solution immediately turned green/black. The reaction mixture was stored at 60◦C for 16 h. Concentration by rotary evaporation in vacuo produced an orange oil that after purificationusing chromatography over silica gel yielded 163.3 mg (20%) of the title compound as a thick yellow oil.1H NMR (300 MHz, CDCl3) δ 8.08 (dd, J = 1.6, 7.8 Hz, 1H), 7.65 (dt, J = 1.7, 11.8 Hz, 1H), 7.39 (dt, J =1.2, 11.4 Hz, 1H), 7.21 (dd, J = 1.3, 8.1 Hz, 1H), 5.47 (s, 1H), 3.87 (s, 3H). 13C NMR (75 MHz, CDCl3)δ 186.9, 175.6, 164.4, 157.9, 152.4, 134.7, 133.0, 127.1, 123.5, 123.2, 110.6, 52.6. LRMS (ESI+): 409.2(M+H)+.OOBr OOMeONa2S2O4EtOAc90%OHOHBr OOMeO2.52 2.55Methyl 2-(3-bromo-2,5-dihydroxyphenoxy)benzoate (2.55). To a solution of 2.52 (2.27 g, 6.74 mmol,1 equiv) in 120 mL of ethyl acetate, a solution of sodium dithionate (5.24 g, 27.1 mmol, 4 equiv) in 25 mLof water was added in one portion. The reaction mixture was stirred vigorously at rt for 16 h. The aqueouslayer was extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed successivelywith 50 mL of 3 M hydrochloric acid and 50 mL of brine. Drying over sodium sulfate and concentration94Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesby rotary evaporation in vacuo produced 2.06 g (90% yield) of the title compound as a pale pink solid, mp164–166 ◦C. IR (neat): 3242, 2948, 1690, 1444, 1434, 1206 cm-1. 1H NMR (300 MHz, Acetone) δ 7.80(s, 1H), 7.70 (s, 1H), 7.38 (dd, J = 1.7, 7.8 Hz, 1H), 7.07 (dt, J = 1.8, 11.7 Hz, 1H), 6.73 (dt, J = 0.9, 11.3Hz, 1H), 6.63 (dd, J = 0.6, 8.3 Hz, 1H), 6.39 (d, J = 2.8 Hz, 1H), 6.06 (d, J = 2.8 Hz, 1H), 3.41 (s, 3H).13C NMR (75 MHz, CDCl3) δ 166.2, 155.5, 149.6, 144.2, 139.0, 133.2, 130.8, 123.0, 121.5, 118.5, 114.7,109.5, 107.1, 51.6. LRMS (ESI+): 341.1 (M+H)+. HRMS (ESI+) Calculated for C14H1079BrO5 (M+H)+:336.9712, found: 336.9703.OHOHBr OOMeOH2SO460 ºC92%OHOHBr OO2.55 2.563-Bromo-1,4-dihydroxy-9H-xanthen-9-one (2.56). A mixture of 2.56 (4.27 g, 12.2 mmol, 1 equiv) andconcentrated sulphuric acid (14.5 mL, 261.3 mmol, 21.5 equiv) was stirred at 60 ◦C for 16 h. The reactionmixture was cooled to rt and it was poured to 450 mL of a mixture of ice and water. The red oily liquid turnedinto a yellow suspension. Vacuum filtration produced 3.42 g (92% yield) of the title compound as a yellowsolid. IR (neat): 3236, 2924, 1646, 1272 cm-1. 1H NMR (400 MHz, Acetone) δ 11.92 (br s, 1H), 9.90 (s,1H), 8.18 (dd, J = 1.6, 8.0 Hz, 1H), 7.93 (dd, J = 1.6, 7.0 Hz, 1H), 7.91 (dd, J = 1.6, 7.2 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.50 (dt, J = 0.9, 7.6 Hz, 1H), 6.94 (s, 1H). 13C NMR (101 MHz, Acetone) δ 181.7, 155.6,152.9, 144.8, 136.3, 135.6, 125.4, 124.7, 120.0, 119.2, 118.2, 112.5, 108.2. LRMS (ESI+): 309.0 (M+H)+.HRMS (ESI+) Calculated for C13H879BrO4 (M+H)+: 306.9606, found: 306.9599. Compound was reportedafter this work was done, see Kraus, and Liu 280 for further detail.OHOHBr OO OBnOBnBr OOCs2CO3BnBrCH3CN90%2.56 2.571,4-Bis(benzyloxy)-3-bromo-9H-xanthen-9-one (2.57). To a suspension of 2.56 (1.59 g, 5.2 mmol, 1equiv) and cesium carbonate (3.80 g, 11.53 mmol, 2.2 equiv) in 50 mL of acetonitrile, benzyl bromide (1.4mL, 11.65 mmol, 2.2 equiv) was added dropwise through syringe. The reaction mixture was stirred at rtfor three days. The solids were removed by vacuum filtration. Concentration by rotary evaporation in vacuoproduced 2.36 g (90%) of a light yellow solid. IR (neat): 3034, 2936, 1659, 1566, 1256 cm-1. 1HNMR (30095Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesMHz, CDCl3) δ 8.32 (d, J = 6.7 Hz, 1H), 7.72–7.60 (m, 5H), 7.48–7.43 (m, 8H), 7.05 (s, 1H), 5.26 (s, 2H),5.17 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 176.7, 155.4, 148.9, 136.2, 134.7, 128.9, 128.7, 128.1, 127.0,124.7, 124.2, 117.7, 111.1, 76.2, 71.5. LRMS (ESI+): 509.3/511.3 (M+Na)+. HRMS (ESI+) Calculatedfor C27H19O4Na79Br: 509.0364, found: 509.0364.2.4.4 Intermolecular [3+2] Dipolar Cycloadditions2.4.4.1 Synthesis of Benzaldehydes 2.81 and 2.187OHOHBrOMeOMeOMeOMeOH OHOMeOMeToluene, ∆97%OO OMeOMeOOBrconcd HCl99%n-BuLi, -20 ºChexanes, PhHBrCl2CCCl2BrTHF62%2.78 2.79 2.80 2.812-Bromo-3,6-dimethoxybenzaldehyde (2.81). A solution of 2,5-dimethoxybenzaldehyde (2.78) (8.50g, 50.1mmol, 1 equiv), 2,2-dimethylpropane-1,3-diol (25.0 g, 240.0 mmol, 4.75 equiv) and para-toluenesulfonicacid monohydrate (2.46 g, 12.7 mmol, 0.2 equiv) in 500 mL of benzene was heated to reflux temperature for16 h, using a Dean Stark trap. The reaction mixture was cooled to rt and it was diluted with 300 mL of DCM.The organic phase was washed with water (4 x 100 mL) until the pH of the washings was neutral. Dryingover sodium sulfate and concentration by rotary evaporation in vacuo produced 12.27 g (97%) of 2.79 as anorange oil. This compound was synthesized following literature procedures.281To a solution of 2.79 (1.04 g, 4.38 mmol, 1 equiv) in 28 mL of hexanes and 9 mL of hexanes, 1.6 M n-butyllithium (4.1 mL, 6.48 mmol, 1.5 equiv) was slowly added at -25 ◦C. The reaction mixture was stored atthis temperature for 16 h. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.96 g, 8.83 mmol, 2 equiv)in 10 mL of THF was added in one portion. The reaction mixture was stirred for 1 h at rt. The solvent wasremoved by rotary evaporation in vacuo and the concentrate was dissolved in 100 mL of ethyl acetate. Theblue organic solution was washed with water (2 x 50 mL). Drying over sodium sulfate and concentrationby rotary evaporation in vacuo produced a light yellow solid that after purification using chromatographyover silica gel yielded 0.89 g (62%) of 2.80 as a white solid, mp 108–111. This compound was synthesizedfollowing literature procedures.282A solution of 2.80 (0.65 g, 2.0 mmol, 1 equiv) in 12 mL of THF was treated with 10 mL of concentrated(concd) hydrochloric acid (116.5 mmol, 60 equiv). The reaction mixture was stirred at rt for 30 min. Thereaction mixture was extracted with diethyl ether (3 x 50 mL). Drying over sodium sulfate and concentration96Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesby rotary evaporation in vacuo produced 0.48 g (99%) of the title compound as a light yellow solid, mp 96–98◦C (lit. 97-98 ◦C). 1H NMR (300 MHz, CDCl3) δ 10.45 (s, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.98 (d, J = 9.1Hz, 1H), 6.91 (s, 1H), 3.93 (s, 3H), 3.92 (s,3H). Compound 2.81 had been previously synthesized, see Li,Lobkovsky, and Porco 221 for further detail.OH OHOMeOMeOMeOMeOHOMeOMem-CPBADCM, rt90%OOMeOMen-BuLi, DMFTHFHCl, rt56%DHP, H2SO4DCM, rt83%OHO2.78 2.185 2.186 2.1872-Hydroxy-3,6-dimethoxybenzaldehyde (2.187). To a solution of m-CPBA (27.28 g, 110.6 mmol, 1.1equiv) in 150mLofDCMwas added dropwise, through an addition funnel, a solution of 2,5-dimethoxybenzal-dehyde (2.78) (17.01 g, 100.3 mmol, 1 equiv) in 50 mL of DCM at 0 ◦C. The reaction mixture was stirredfor 16 h, letting it warm to rt. It was successively washed with saturated aqueous sodium bicarbonate (3 x80 mL) and 80 mL of saturated aqueous sodium dithionate. Drying over sodium sulfate and concentrationby rotary evaporation in vacuo produced a red solid, which was dissolved in 100 mL of methanol. To themethanolic solution was added 50 mL of 20% w/v sodium hydroxide. The reaction mixture was stirred at rtfor 1 h. It was quenched with 6 M hydrochloric acid until the pH was 1. The aqueous layer was extracted withDCM (3 x 100 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produceda dark oil that after purification using kugelrohr distillation (80 ◦C at 0.45 mmHg) yielded 13.90 g (90%) of2.185 as a yellow solid.To a solution of 2.185 (4.73 g, 30.7 mmol, 1 equiv) in 13.5 mL of 3,4-dihydropyran (152.8 mmol, 5equiv) was added a catalytic amount of concentrated sulphuric acid. The colourless solution immediatelyturned black and hot. It was stirred at rt for 1 h. The reaction mixture was diluted with 200 mL of DCMand was washed with 10% w/v sodium hydroxide (3 x 50 mL) and filtration through Celite was needed tobreak the emulsion formed. The organic fractions were washed with 50 mL of brine (once). Drying oversodium sulfate and concentration by rotary evaporation in vacuo produced red oil that after purification usingkugelrohr distillation yielded 6.05 g (83%) of 2.186 as a colourless oil.To a solution of 2.186 (6.05 g, 25.4 mmol, 1 equiv) in 250 mL of THF, 1.43 M n-butyllithium (20 mL,28.6 mmol, 1.1 equiv) was slowly added through a syringe at 0 ◦C. The reaction mixture was stirred for2.5 at rt. The reaction mixture was cooled to -78 ◦C and DMF (8.0 mL, 103.3 mmol, 4 equiv) was addedin one portion. The reaction mixture was stirred for 2 h, letting it slowly warm to rt. The reaction mixturewas quenched with 25 mL of 6 M hydrochloric acid. The organic layer was separated. Drying over sodium97Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolessulfate and concentration by rotary evaporation in vacuo produced green oil that after purification usingchromatography over silica gel yielded 2.61 g (56%) of the title compound as a bright yellow solid. 1HNMR (400 MHz, CDCl3) δ 12.17 (d, J = 0.6 Hz, 1H), 10.30 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H),6.26 (d, J = 8.7 Hz, 1H), 3.83 (s, 7H). Compound 2.187 had been previously synthesized, see Horvath, andChan 283 for further detail.2.4.4.2 Synthesis of Oximoyl ChloridesNHOHCHCl3, 40 ºCNO OCl+NRNClOHR2.82 2.77 2.83Sample Procedure for the Preparation of Oximoyl Chloride (Z)-N-Hydroxybenzimidoyl Chloride(2.84)NHOHCHCl3, 40 ºC66%NO OCl+N NClOH2.188 2.77 2.84(Z)-N-Hydroxybenzimidoyl Chloride (2.84). To a solution of 2.188 (6.17 g, 50.0 mmol, 1 equiv) in 180mL of chloroform was added pyridine (2 drops) followed by the slow addition of NCS (6.82 g, 50.1 mmol,1 equiv). The reaction mixture was stirred at 40 ◦C for 24 h. Concentration by rotary evaporation in vacuoproduced a brown solid that after purification using chromatography over silica gel yielded 5.14 g (66%) ofthe title compound as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 9.54 (s, 1H), 7.88-7.84 (m, 2H),7.48-7.37 (m, 4H). The compound 2.84 had been previously synthesized, see Dubrovskiy, and Larock 217 forfurther detail.NHOHCHCl3, 40 ºC90%NO OCl+N NClOHOH OHCl2.189 2.77 2.85(Z)-N,2-dihydroxy-5-methylbenzimidoyl chloride (2.85). The reaction was performed using 14.63 gof 2.189 (101.2 mmol, 1 equiv), 28.20 g of NCS (207.0 mmol, 2 equiv) and two drops of pyridine in 36098Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesmL of chloroform. Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced19.18 g (90% yield) of the title compound as a light pink solid, mp 120–124 ◦C (dec). 1H NMR (400 MHz,DMSO-d6) δ 12.52 (s, 1H), 10.40-10.33 (br s, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.8, 2.7 Hz, 1H),6.98 (d, J = 8.8 Hz, 1H). 13CNMR (101 MHz, DMSO-d6) δ 154.7, 133.8, 131.1, 128.8, 122.6, 120.7, 118.3.LRMS (ESI-): 168.2 (M-H2Cl)-. HRMS (ESI-)Calculated for C7H335ClNO2 (M-H2Cl)-: 167.9852, found:167.9856.NHOHCHCl3, 40 ºC97%NO OCl+N NClOHMeO MeO2.191 2.77 2.86(Z)-N-hydroxy-4-methoxybenzimidoyl chloride (2.86). The reaction was performed using 9.78 g of2.191 (64.7 mmol, 1 equiv), 8.88 g of NCS (65.1 mmol, 1 equiv) and four drops of pyridine in 240 mL ofchloroform. Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced 11.63g (97% yield) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.26-9.24 (br s,1H), 7.76 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 3.82 (s, 4H). Compound 2.86 had been previouslysynthesized, see Castellano, Kuck, Viviano, Yoo, Lo´pez-Vallejo, Conti, Tamborini, Pinto, Medina-Franco,and Sbardella 284 for further detail.NHOHCHCl3, 40 ºC97%NO OCl+N NClOHOMeOH OHOMe2.193 2.77 2.87(Z)-N,2-dihydroxy-3-methoxybenzimidoyl chloride (2.87). The reaction was performed using 5.03 gof 2.193 (30.1 mmol, 1 equiv), 4.59 g of NCS (33.7 mmol, 1.1 equiv) and 0.49 mL of pyridine (6.06 mmol,0.2 equiv) in 60 mL of chloroform. Drying over sodium sulfate and concentration by rotary evaporation invacuo produced 9.95 g (98% yield) of the title compound as a beige solid. IR (neat): 3290, 2944, 1462, 1254,990 cm-1. 1HNMR (400 MHz, CDCl3) δ 8.80 (br s, 1H), 7.43 (dd, J = 8.1, 1.6 Hz, 1H), 6.99 (dd, J = 8.1, 1.6Hz, 1H), 6.93 (t, J = 8.1 Hz, 1H), 3.93 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 148.4, 146.6, 121.1, 119.4,117.8, 116.4, 114.1, 56.5. LRMS (ESI+): 200.2 (M-H)-. HRMS (ESI+) Calculated for C8H8NO3Na35Cl:224.0090, found: 224.0093.99Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNHOHCHCl3, 40 ºC97%NO OCl+N NClOHOMeBr BrOMeOMe OMe2.195 2.77 2.88(Z)-2-Bromo-N-hydroxy-3,6-dimethoxybenzimidoyl chloride (2.88). The reaction was performed us-ing 1.23 g of 2.195 (4.8 mmol, 1 equiv), 0.66 g of NCS (4.9 mmol, 1 equiv) and one drop of pyridine in 50mL of chloroform. Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced1.40 g (96% yield) of the title compound as a yellow foam. IR (neat): 3222, 1678, 1492, 1218, 984 cm-1.1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 6.96 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 9.1 Hz, 1H), 3.87 (s,3H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 152.8, 150.6, 135.2, 125.6, 114.4, 114.3, 111.0, 57.2,56.8. LRMS (ESI+): 296.2 (M+H)+. HRMS (ESI+) Calculated for C9H1079Br35ClNO3: 293.9533, found:293.9529.2.4.4.3 Preparation of DipolarophilesO OEtOOCO2EtZnCl235%2.97 2.98 2.92Ethyl trans-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (2.92). To a suspension of zinc iodide (1.79g, 5.6 mmol, 10 mol%) in methyl acrylate (2.98) (5.5 mL, 50.3 mmol, 1 equiv), furan (2.97) (22.0 mL, 302.5mmol, 6 equiv) was added. The reaction mixture was stirred at 40 ◦C for 24 h. The reaction mixture was coolto rt and it was filtered through a plug of silica gel. Concentration by rotary evaporation in vacuo produced alight yellow oil that after purification using chromatography over silica gel yielded 1.58 g (18%) of the titlecompound as a light yellow oil plus 1.40 g (16%) of the endo adduct (not shown) as a light yellow oil in anoverall 35% yield. 1H NMR (400 MHz, CDCl3) δ 6.41-6.36 (m, 2H), 5.20 (s, 1H), 5.09-5.08 (m, 1H), 4.20(q, J = 7.1 Hz, 2H), 2.43 (dd, J = 8.5, 3.9 Hz, 1H), 2.18 (dt, J = 11.6, 4.3 Hz, 1H), 1.56 (dd, J = 11.6, 8.5 Hz,2H), 1.29 (t, J = 7.1 Hz, 3H). Compound 2.92 had been previously synthesized, see Fraile, Garcı´a, Massam,Mayoral, and Pires 222 for further detail.trans-Cyclohex-2-ene-1,4-diyl diacetate (2.93). To a solution of lithium hydroxide (0.26 g, 10.8 mmol,1.05 equiv) and lithium chloride (0.12 g, 2.7 mmol, 0.2 equiv) in 16 mL of acetic acid, palladium (II) acetate100Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesPd(OAc)2LiClAcOH48%OAcOAc2.96 2.93(0.12 g, 0.51 mmol, 5 mol%), benzoquinone (0.38 g, 3.46 mmol, 0.3 equiv) and manganese (IV) oxide (1.08g, 12.37 mmol, 1.2 equiv) were added. The reaction mixture was diluted with 32 mL of n-pentane andcyclohexa-1,3-diene (2.96) (1.0 mL, 10.2 mmol, 1 equiv) was added. The reaction mixture was stirred for16 h at rt and it was filtered through a silica gel plug. The solid was rinsed with hexanes (3 x 20 mL) andethyl acetate (3 x 30 mL). To the filtrate was added 30 mL of brine. It was extracted with a 1:1 mixtureof diethyl ether/hexanes (3 x 20 mL). The combined organic fractions were successively washed with brine(3 x 30 mL), water (3 x 10 mL) and 2 M sodium hydroxide (4 x 10 mL). Drying over sodium sulfate andconcentration by rotary evaporation in vacuo produced 0.97 g (48% yield) of the title compound as a yellowoil. 1H NMR (300 MHz, CDCl3) δ 5.55 (d, J = 0.8 Hz, 1H), 4.96 (br s, 1H), 1.78 (dd, J = 8.6, 3.0 Hz, 1H),1.70 (s, 3H), 1.36 (ddd, J = 10.4, 4.4, 2.0 Hz, 1H). Compound 2.93 had been previously synthesized, seeBaeckvall, Bystroem, and Nordberg 224 for further detail.O Br2DCMEt3N93%OBrNaBH4CeCl3•7H2OMeOH97%OHBrAc2OpyridineDCM98%OAcBr1.161 2.37a 2.95a 2.95b2-bromo-2-cyclohexen-1-one (2.37a). To a solution of cyclohex-2-en-1-one (1.161) (10.0 mL, 100.2mmol, 1 equiv) in 100 mL of DCM, a solution of bromine (5.7 mL, 110.1 mmol, 1.1 equiv) in 50 mL of DCMwas added dropwise through an addition funnel at 0 ◦C. The reaction mixture was stirred for 3 h, reaching rt.A solution of triethylamine (21.0 mL, 150.7 mmol, 1.5 equiv) in 50 mL of DCMwas added dropwise throughthe addition funnel at 0 ◦C. The reaction mixture was stirred for 2.5 h. The pink suspension was successivelywashed with 100 mL of 3 M hydrochloric acid (twice), saturated sodium bicarbonate solution (once) andbrine (once). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced 16.32g (93% yield) of the title compound as a light orange solid. 1H NMR (300 MHz, CDCl3) δ 7.28 (t, J = 4.5Hz, 1H), 2.48-2.43 (m, 2H), 2.32 (td, J = 5.9, 4.5 Hz, 2H), 1.91 (dt, J = 13.0, 6.3 Hz, 2H). Compound 2.37ahad been previously synthesized, see Ponaras, and Zaim 285 for further detail.2-Bromocyclohex-2-en-1-ol (2.95a). To a solution of 2.37a (15.01 g, 85.7 mmol, 1 equiv) and cerium(III) chloride heptahydrate (32.26 g, 85.7 mmol, 1 equiv) in 215 mL of methanol, sodium borohydride (3.30g, 85.9 mmol, 1 equiv) was added in small portions. The reaction mixture was stirred at rt for 2 h. It was101Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesquenched with 100 mL of water. The reaction mixture was extracted with diethyl ether (4 x 100 mL) andthe combined organic fractions were washed with brine. Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced 14.67 g (97% yield) of of the title compound as a slightly yellow oil.1H NMR (300 MHz, CDCl3) δ 6.20 (t, J = 4.1 Hz, 1H), 4.23-4.18 (m, 1H), 2.32 (d, J = 4.3 Hz, 1H), 2.20-2.03 (m, 2H), 1.96-1.88 (m, 2H), 1.81-1.57 (m, 2H). Compound 2.95a had been previously synthesized, seeCarren˜o, Urbano, and Di Vitta 227 for further detail.2-Bromocyclohex-2-en-1-yl acetate (2.95b). A solution of 2.95a (0.72 g, 4.0 mmol, 1 equiv), aceticanhydride (0.86 mL, 9.0 mmol, 2.2 equiv), pyridine (0.36 mL, 4.5 mmol, 1.1 equiv) and 2 chips of damp!(damp!) in 10 mL of DCM was stirred at rt for 16 h. The reaction mixture was diluted with 100 mL of DCMand it waswashed with 1.5M hydrochloric acid (3 x 50 mL). Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced 0.88 g (100% yield) of the title compound as a clear oil. 1HNMR (300MHz, CDCl3) δ 6.34 (dd, J = 4.8, 3.4 Hz, 1H), 5.40 (t, J = 4.2 Hz, 1H), 2.09 (s, 3H), 2.07-2.00 (m, 2H), 1.91(dt, J = 8.1, 4.1 Hz, 2H), 1.70-1.62 (m, 2H). Compound 2.95b had been previously synthesized, see Noheda,Garcı´a, Pozuelo, and Herrado´n 226 for further detail.O LDATHFTMSClOTMS m-CPBAHCl16%OOH1.161 2.99 2.956-Hydroxy2-cyclohexen-1-one (2.95). A solution of 1.161 (9.7 mL, 100.2 mmol, 1 equiv) in 30 mL ofTHF was cannula-transferred to a chilled solution of freshly prepared LDA (120 mmol, 1.2 equiv) in 150 mLof THF at -78 ◦C. The reaction mixture was stirred for 1 h. Chlorotrimethylsilane (19.2 mL, 150.2 mmol,1.5 equiv) was added through syringe. The reaction mixture was stirred for 2 h. Concentration by rotaryevaporation in vacuo produced a white solid that was diluted with n-pentane. The precipitate was removedby vacuum filtration. Purification by kugelrohr distillation (60 ◦C at 0.5 mmHg) yielded 15.94 g (95%) of2.99 as a colourless oil.To a suspension of meta-chloroperoxybenzoic acid (25.94 g, 105.2 mmol, 1.1 equiv) in 600 mL of hex-anes at -78 ◦Cwas added a solution of 2.95 (15.94 g, 94.7 mmol, 1 equiv) in 50 mL of hexanes. The reactionmixture was stirred for 16 h. The solid was removed by vacuum filtration. Concentration by rotary evapora-tion in vacuo produced 3.74 g of an oil, which was dissolved in 1.3 L of DCM. To this solution, triethylaminetrihydrofluoride (10.2 mL, 61.3 mmol, 3 equiv) was added in one portion. The reaction mixture was stirredat rt for 16 h. The reaction mixture was successively washed with 200 mL of saturated sodium bicarbonatesolution (once), 1.5 M hydrochloric acid (once) and saturated sodium bicarbonate solution (once). Drying102Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesover sodium sulfate and concentration by rotary evaporation in vacuo produced an orange oil that after pu-rification using kugelrohr distillation (70 ◦C at 0.5 mmHg) yielded 1.69 g (16%) of the title compound as acolourless oil. 1H NMR (400 MHz, CDCl3) δ 7.00 (dddd, J = 9.8, 4.9, 3.3, 1.6 Hz, 1H), 6.10-6.06 (m, 1H),4.18 (dd, J = 13.7, 5.6 Hz, 1H), 3.57-3.48 (br s, 1H), 2.54-2.49 (m, 2H), 2.41-2.34 (m, 1H), 1.91-1.81 (m,1H). Compound 2.95 had been previously synthesized, see Rubottom, and Gruber 225 for further detail.2.4.4.4 Intermolecular [3+2] Dipolar CycloadditionsNClOHEt3N, solvent40 ºC+RNRRR2.196 2.197 2.198Sample Procedure for the [3+2] Dipolar Cycloadditions, Synthesis of Ethyl 3-Phenyl-3a,4,5,6,7,7a-hexahydro-4,7-epoxybenzo[d]isoxazole-5-carboxylate (2.103a) and Ethyl 3-Phenyl-3a,4,5,6,7,7a-hexa-hydro-4,7-epoxybenzo[d]isoxazole-6-carboxylate (2.103b).NClOH+Et3NDMF76%OCO2Et OONexoOONexoCO2EtHHHHHHHH+CO2Et2.84 2.92 2.103a 2.103bTo a solution of nitrile oxide precursor 2.84 (0.34 g, 2.2 mmol, 1 equiv) and dienophile 2.92 (0.37 g, 2.2mmol, 1 equiv) in 20 mL of DMF as solvent, triethylamine (0.31 mL, 2.2 mmol, 1 equiv) was added at rt. Thereaction mixture was stirred for 2 h. The reaction mixture was diluted with 100 mL of ethyl acetate and it waswashed with water (3 x 50 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuoproduced a light brown oil that after purification using chromatography over silica gel yielded 0.47 g (76%)of the mixture of regioisomers as a white solid. 1H NMRof the crude of the reaction showed a 1.24:1 ratio2.103b:2.103a, respectively. The first and last test tubes of the chromatography contained pure regioisomerthat were used to the identification of the compounds. Data for regioisomer 2.103a (exo): IR (neat): 2982,1786, 1724, 1198, 1012 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.71 (td, J = 3.9, 1.7 Hz, 2H), 7.47-7.41 (m,3H), 4.90-4.86 (m, 3H), 4.36 (dq, J = 10.8, 7.2 Hz, 1H), 4.26 (dq, J = 10.8, 7.1 Hz, 1H), 4.04 (d, J = 8.2Hz, 1H), 3.11 (dt, J = 11.3, 5.5 Hz, 1H), 2.14-2.06 (m, 1H), 1.88 (dd, J = 13.0, 5.2 Hz, 1H), 1.40 (t, J = 7.1Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.9, 155.0, 130.3, 129.1, 128.8, 127.0, 86.7, 83.9, 78.9, 61.6,103Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles55.2, 46.1, 27.6, 14.6. LRMS (ESI+): 310.3 (M+Na)+. HRMS (ESI+) Calculated for C16H18NO4 (M+H)+:288.1236, found: 288.1234. See Appendix C for solid state molecular structure.Data for regioisomer 2.103b (endo): IR (neat): 2980, 1788, 1724, 1194, 1010 cm-1. 1H NMR (400MHz, CDCl3) δ 7.71-7.68 (m, 2H), 7.42 (t, J = 3.2 Hz, 3H), 4.96 (dd, J = 16.6, 7.1 Hz, 2H), 4.74 (d, J =5.0 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.97 (d, J = 8.2 Hz, 1H), 3.11 (dt, J = 11.1, 5.5 Hz, 1H), 2.08 (dtd,J = 21.5, 11.3, 5.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.6, 155.5, 130.4,129.1, 128.7, 127.0, 84.3, 83.0, 79.8, 61.7, 58.8, 43.9, 31.9, 14.4. LRMS (ESI+): 310.4 (M+Na)+. HRMS(ESI+) Calculated for C16H18NO4 (M+H)+: 288.1236, found: 288.1231.NClOH+ Et3NDMF57%OCO2Et OON+OHClOHClOONOHClexoexoHHHHHH HHCO2EtCO2Et2.85 2.92 2.105a 2.105bEthyl 3-(5-chloro-2-hydroxyphenyl)-3a,4,5,6,7,7a-hexahydro-4,7-epoxy-benzo [d]isoxazole-5-carbox-ylate (2.105a) and ethyl 3-(5-chloro-2-hydroxy-phenyl)-3a,4,5,6,7,7a-hexahydro-4,7-epoxybenzo[d]isox-azole-6-carboxylate (2.105b). The reaction was performed using 0.88 g of 2.85 (4.3 mmol, 1.1 equiv), 0.64g of 2.92 (3.81 g, 1 equiv) and 0.60 mL of triethylamine (4.3 mmol, 1.1 equiv) in 40 mL of DMF. Afterpurification 0.44 g, (34% yield) of 2.105a and 0.29 g (26% yield) of 2.105b was obtained as off-white solids.Data for regioisomer 2.105a (exo): IR (neat): 3122, 2974, 1896, 1716, 1590, 1200 cm-1. 1H NMR (400MHz, CDCl3) δ 9.66 (s, 1H), 7.29 (dd, J = 8.8, 2.4 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 8.8 Hz,1H), 4.95 (d, J = 5.3 Hz, 1H), 4.89 (t, J = 7.2 Hz, 2H), 4.40 (dq, J = 10.8, 7.2 Hz, 1H), 4.30 (dq, J = 10.8,7.2 Hz, 1H), 4.00 (d, J = 8.1 Hz, 1H), 3.17 (dt, J = 11.3, 5.5 Hz, 1H), 2.13 (ddd, J = 12.9, 11.8, 6.2 Hz,1H), 1.93 (dd, J = 13.1, 5.2 Hz, 1H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.5, 156.5,155.9, 131.6, 127.0, 124.4, 119.0, 114.5, 85.8, 83.7, 79.0, 61.9, 55.3, 46.2, 27.3, 14.6. LRMS (ESI+): 338.2(M+H)+. HRMS (ESI+) Calculated for C15H1735ClNO5 (M+H)+: 338.0795, found: 338.0800.Data for regioisomer 2.105b (endo): IR (neat): 3162, 2994, 1886, 1714, 1594, 1200 cm-1. 1HNMR (400MHz, CDCl3) δ 9.72 (s, 1H), 7.30 (dd, J = 8.5, 2.6 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H),5.00 (dd, J = 17.7, 7.0 Hz, 2H), 4.85 (d, J = 4.3 Hz, 1H), 4.28-4.23 (m, 2H), 4.01 (d, J = 8.1 Hz, 1H), 3.17(dt, J = 10.7, 5.5 Hz, 1H), 2.21-2.11 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13CNMR (101 MHz, CDCl3) δ 171.4,156.5, 156.3, 131.7, 127.0, 124.4, 119.1, 114.5, 83.6, 82.9, 80.0, 61.8, 58.8, 43.7, 32.1, 14.4. LRMS (ESI+):338.2 (M+H)+. HRMS (ESI+) Calculated for C15H1735ClNO5 (M+H)+: 338.0795, found: 338.0801.104Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNClOH+Et3NDMF42%OBrOHClNOHClO O2.85 2.37a 2.1073-(5-Chloro-2-hydroxyphenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (2.107). The reaction was per-formed using 1.29 g of 2.85 (7.5 mmol, 1.15 equiv), 1.15 g of 2.37a (6.6 mmol, 1 equiv) and 1.1 mL oftriethylamine (7.6 mmol, 1.15 equiv) in 15 mL of DMF. After purification 0.72 g (42% yield) of the titlecompound as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.33 (br s, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.28(dd, J = 8.9, 2.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.06 (t, J = 6.0 Hz, 2H), 2.73 (dd, J = 7.4, 5.7 Hz, 2H),2.33 (quintet, J = 6.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 186.6, 159.8, 159.1, 155.1, 131.8, 127.8,127.1, 124.7, 119.3, 114.4, 38.4, 24.0, 22.2. LRMS (ESI+): 264.3 (M+H)+. HRMS (ESI+) Calculated forC13H1135ClNO3 (M+H)+: 264.0427, found: 264.0425.NClOH+Et3N, DMFrt, 98%O N OMeO MeOBrO2.86 2.37a 2.1123-(4-Methoxyphenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (2.112). The reaction was performedusing 1.86 g of 2.86 (10.0 mmol, 1 equiv), 1.75 g of 2.37a (10.0 mmol, 1 equiv) and 3.0 mL of triethylamine(21.5 mmol, 2.1 equiv) in 30 mL of DMF. After purification 2.40 g (98% yield) of the title compound as anorange oil. IR (neat): 2964, 1690, 1400, 1244 cm-1. 1HNMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.8 Hz, 2H),7.02 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.96 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 6.5 Hz, 2H), 2.31-2.23 (m, 2H).13C NMR (101 MHz, CDCl3) δ 161.4, 160.7, 151.5, 129.7, 129.1, 128.1, 120.7, 114.7, 55.6, 38.7, 24.5,21.8. LRMS (ESI+): 266.4 (M+Na)+. HRMS (ESI+) Calculated for C14H13NO3Na (M+Na)+: 266.0793,found: 266.0792.NClOH+Et3N, DMFrt, 59%rr: 1.1:1O N OMeO MeOON OMeO O+HHHH2.86 1.161 2.113a 2.113b3-(4-Methoxyphenyl)-5,6,7,7a-tetrahydrobenzo[d]isoxazol-4(3aH)-one (2.113a) and 3-(4-methoxy-phenyl)-3a,5,6,7a-tetrahydrobenzo[d]isoxazol-7(4H)-one (2.113b). The reaction was performed using1.86 g of 2.86 (10.0 mmol, 1 equiv) as the nitrile oxide precursor, 0.99 mL of 1.161 (10.0 mmol, 1 equiv) as105Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesthe dipolarophile and 1.4 mL of triethylamine (10.0 mmol, 1 equiv) in 30 mL of DMF. After purification 1.46g (60% yield) of the title compounds in a 3:4 ratio (by NMR)2.113b:2.113a, respectively was obtained as acolourless oil. Data for the major regioisomer (2.113a): IR (neat): 3014, 2930, 1716, 1606, 1252, 1020 cm-1.1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H), 4.91-4.88 (m, 1H), 4.10(d, J = 9.3 Hz, 1H), 3.68 (s, 3H), 2.26 (dd, J = 9.6, 5.8 Hz, 2H), 2.12-2.05 (m, 1H), 1.85 (dt, J = 14.5, 3.3 Hz,1H), 1.80-1.74 (m, J = 3.3 Hz, 2H). 13CNMR (101 MHz, CDCl3) δ 206.1, 160.9, 156.1, 128.8, 121.8, 113.7,82.6, 59.0, 55.0, 39.5, 25.8, 18.8. LRMS (ESI+): 246.4 (M+H)+. HRMS (ESI+) Calculated for C14H16NO3(M+H)+: 246.1130, found: 246.1136. Data for the minor regioisomer (2.113b): IR (neat): 3014, 2930, 1716,1606, 1252, 1020 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H),4.49 (d, J = 9.6 Hz, 1H), 3.71 (s, 3H), 2.52 (dt, J = 17.4, 6.1 Hz, 1H), 2.31-2.30 (m, 1H), 1.85 (dt, J =14.5, 3.3 Hz, 2H), 1.72-1.64 (m, 1H), 1.59-1.47 (m, J = 7.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 205.5,161.1, 159.4, 128.6, 119.9, 114.2, 83.5, 55.1, 50.1, 37.3, 24.4, 20.0. LRMS (ESI+): 246.4 (M+H)+. HRMS(ESI+) Calculated for C14H16NO3 (M+H)+: 246.1130, found: 246.1136.NClOHOMeOEt3NDMF, rt43%NOMeOOOHHO+HH2.87 1.161 2.1143-(2-Hydroxy-3-methoxyphenyl)-5,6,7,7a-tetrahydrobenzo[d]isoxazol-4(3aH)-one (2.114). The re-action was performed using 1.21 g of 2.87 (6.0 mmol, 1 equiv) as the nitrile oxide precursor, 1.3 mL of 1.161(12.4 mmol, 2 equiv) as the dipolarophile and 0.84 mL of triethylamine (6.0 mmol, 1 equiv) in 30 mL ofDMF. After purification 0.67 g (43% yield) of the title compound as an orange oil. IR (neat): 3234, 2942,1708, 1688, 1248 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.66 (s, 1H), 6.82-6.77 (m, 2H), 6.73-6.66 (m, 1H),4.80 (d, J = 8.5 Hz, 1H), 4.14 (d, J = 8.8 Hz, 1H), 3.72 (s, 3H), 2.27 (br s, 2H), 2.13-2.10 (m, 1H), 1.89-1.84 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 205.4, 159.7, 147.7, 146.6, 121.5, 118.9, 114.3, 113.3, 82.3,58.2, 55.7, 39.6, 24.5, 19.3. LRMS (ESI+): 284.4 (M+Na)+. HRMS (ESI+) Calculated for C14H15NO4Na:284.0899, found: 284.0899.106Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNClOH+Et3NDMF71%14:1OCO2Et OON+BrOMeMeOOMeMeOBrexoOONOMeMeOBrexoCO2EtCO2EtHHHH HHH H2.88 2.92 2.115a 2.115bEthyl 3-(2-bromo-3,6-dimethoxyphenyl)-3a,4,5,6,7,7a-hexahydro-4,7-epoxybenzo[d]isoxazole-5-car-boxylate (2.115a) and ethyl 3-(2-bromo-3,6-dimethoxyphenyl)-3a,4,5,6,7,7a-hexahydro-4,7-epoxybenzo[d]isoxazole-6-carboxylate (2.115b). The reaction was performed using 0.29 g of 2.88 (1.0 mmol, 1 equiv),0.16 g of 2.92 (1.0 mmol, 1 equiv) and 0.14 mL of triethylamine (1.0 mmol, 1 equiv) in 10 mL of DMF.After purification 0.19 g (44% yield) of 2.115a and 0.12 g (27% yield) of 2.115b was obtained as off-whitesolids. 1H NMRof the crude reaction showed a 1.4:1 ratio 2.115b:2.115a, respectively. Data for regioisomer2.115a (exo): IR (neat): 2954, 1724, 1466, 1258, 1036 cm-1. 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J =9.1 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 4.85 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 5.9 Hz, 1H), 4.61 (d, J = 5.3 Hz,1H), 4.14-3.95 (m, 2H), 3.93 (d, J = 8.3 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 2.92 (dt, J = 11.1, 5.5 Hz, 1H),2.00-1.92 (m, 1H), 1.79 (dd, J = 13.0, 5.2 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)δ 171.5, 153.0, 152.6, 150.6, 121.0, 114.0, 113.5, 110.6, 86.2, 83.3, 78.1, 61.0, 57.8, 56.9, 56.5, 45.6, 27.9,14.2. LRMS (ESI+): 448.3/450.3 (M+Na)+. HRMS (ESI+) Calculated for C18H20NO6Na79Br: 448.0372,found: 448.0375.Data for regioisomer 2.115b (endo): IR (neat): 2958, 1728, 1484, 1264, 1066 cm-1. 1H NMR (400MHz, CDCl3) δ 6.95 (d, J = 9.1 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 5.03 (d, J = 6.0 Hz, 1H), 4.96 (d, J= 8.2 Hz, 1H), 4.66 (d, J = 4.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.91 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H),3.81 (s, 3H), 3.10 (dt, J = 10.9, 5.5 Hz, 1H), 2.00-1.89 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101MHz, CDCl3) δ 171.7, 153.7, 152.9, 151.0, 121.51, 114.6, 113.7, 110.7, 84.1, 82.6, 79.2, 61.8, 61.6, 57.2,56.8, 44.1, 31.6, 14.5. LRMS (ESI+): 450 (M+Na)+. HRMS (ESI+) Calculated for C18H20NO6Na79Br:448.0372, found: 448.0373.NClOH+Et3NDMF55%OBrOMeMeONOMeMeOO OBr Br2.88 2.37a 2.1163-(2-Bromo-3,6-dimethoxyphenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (2.116). The reaction wasperformed using 1.03 g of 2.88 (3.5 mmol, 1 equiv), 0.77 g of 2.37a (4.4 mmol, 1.2 equiv) and 0.62 mL of107Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolestriethylamine (4.4 mmol, 1.2 equiv) in 10 mL of DMF. After purification 0.67 g (55% yield) of the title com-pound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 9.1 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H),3.90 (s, 3H), 3.74 (s, 3H), 2.69 (t, J = 6.5 Hz, 2H), 2.58-2.55 (m, 2H), 2.24-2.17 (m, 2H). 13C NMR (101MHz, CDCl3) δ 186.5, 160.4, 159.1, 152.8, 150.9, 131.2, 120.0, 114.7, 114.3, 111.1, 57.2, 56.8, 39.1, 24.3,20.6. LRMS (ESI+): 354.2 (M+H)+. HRMS (ESI+) Calculated for C15H1579brNO4 (M+H)+: 352.0184,found: 352.0175.NClOH+Et3NDMF78%OOMeMeONBrOBr OMeOOMeHH2.88 1.161 2.1173-(2-Bromo-3,6-dimethoxyphenyl)-5,6,7,7a-tetrahydrobenzo[d]isoxazol-4(3aH)-one (2.117). The re-action was performed using 7.39 g of 2.88 (25.1 mmol, 1 equiv) as the nitrile oxide precursor, 5.0 mL of1.161 (50.9 mmol, 2 equiv) as the dipolarophile and 3.5 mL of triethylamine (25.1 mmol, 1 equiv) in 50 mLof DMF. After purification 6.97 g (78% yield) of the title compound as light yellow solid. IR (neat): 2936,1706, 1480, 1266, 1020 cm-1. 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 9.1 Hz, 1H), 6.82 (d, J = 9.1Hz, 1H), 5.21 (dt, J = 10.4, 5.0 Hz, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 2.53 (dt, J =17.8, 5.6 Hz, 1H), 2.27 (ddd, J = 16.8, 10.1, 5.9 Hz, 1H), 2.21-2.11 (m, 2H), 1.96-1.89 (m, J = 3.5 Hz, 1H),1.80-1.72 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 204.0, 153.0, 152.5, 150.9, 120.8, 114.5, 114.0, 110.9,81.5, 62.2, 57.3, 56.8, 39.7, 27.9, 17.7. LRMS (ESI+): 354.2/356.2 (M+H)+. HRMS (ESI+) Calculated forC15h1779BrNO4 (M+H)+: 354.0341, found: 354.0344.2.4.4.5 Attempts to Convert Isoxazolines and Isoxazoles into Tetrahydroxanthone DerivativesRaney•NiEtOH/H2O80%N OOMeBrOMeON OOMeHOMeO2.117 2.1213-(2,5-Dimethoxyphenyl)-5,6,7,7a-tetrahydrobenzo[d]isoxazol-4(3aH)-one (2.121). To a suspensionof 2.117 (0.42 g, 1.2 mmol, a equiv) and boric acid (0.68 g, 11.0 mmol, 9 equiv) in 20mL of ethanol and 4 mLof water, 87.1 mg of Raney•nickel (catalytic amount) was added. The system was evacuated and was filledwith hydrogen gas at 50 psi. The reaction mixture was stirred at rt for three days. The solids were removed byvacuum filtration over a Celite pad and the solids were rinsed with 50 mL of DCM. The orange filtrate was108Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoleswashed with water (3 x 50 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuoproduced an orange oil that after purification using chromatography over silica gel yielded 0.34 g (80%) ofthe title compound as a light yellow oil. IR (neat): 2914, 1712, 1492, 1224, 1054 cm-1. 1HNMR (300 MHz,CDCl3) δ 7.19 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 9.0, 3.1 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 5.09 (dtd, J = 9.7,3.7, 1.2 Hz, 1H), 4.60 (d, J = 9.8 Hz, 1H), 3.79 (s, J = 0.8 Hz, 3H), 3.79 (s, 3H), 2.46-2.19 (m, 3H), 2.16-1.85(m, 3H). 13C NMR (75 MHz, CDCl3) δ 205.8, 153.7, 152.0, 117.7, 114.9, 114.1, 113.0, 113.0, 82.6, 60.7,56.2, 55.9, 40.1, 26.6, 19.1. LRMS (ESI+): 298.4 (M+Na)+. HRMS (ESI+) Calculated for C15H17NO4Na:298.1055, 298.1056.NOMeBrOOOMePd2(dba)3, dppbCs2CO3, dioxane110 ºC OMeOOMeOMeBrN OOMe+ONH22.117 2.124 2.1252-(Amino(2,5-dimethoxyphenyl)methylene)cyclohexane-1,3-dione (2.124) and 3-(2-bromo-3,6-dime-thoxyphenyl)-6,7-dihydrobenzo[d]isoxazole (2.125). A solution of 2.117 (0.28 g, 0.8 mmol, 1 equiv), ce-sium carbonate (0.61 g, 1.8 mmol, 2.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (18.7 mg, .02 mmol,2.5 mol%) and 1,4-bis(diphenylphosphino)butane (21.8 mg, .05 mmol, 6 mol%) in 2.5 mL of dioxane wasstirred at 110 ◦C for 16 h. The reaction mixture was cooled to rt and it was filtered through a Celite pad. Thesolid was rinsed with ethyl acetate. Drying over sodium sulfate and concentration by rotary evaporation invacuo produced a red oil that after purification using chromatography over silica gel yielded 44.3 mg (21%)of 2.124 as a colourless oil and 25.4 mg (10%) of 2.125 as a colourless oil.Data for compound 2.124: IR (neat): 3205, 2938, 1632, 1568, 1226 cm-1. 1H NMR (400 MHz, CDCl3)δ 6.87 (dd, J = 9.0, 2.9 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.63 (d, J = 2.9 Hz, 1H), 6.48 (br s, 1H), 3.73 (s,3H), 3.71 (s, 3H), 2.44 (t, J = 6.3 Hz, 3H), 1.95-1.88 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.2, 153.6,149.8, 128.6, 114.9, 113.8, 112.4, 109.6, 56.5, 55.9, 39.0, 19.5. LRMS (ESI+): 276.3 (M+H)+. HRMS(ESI+) Calculated for C15H18NO4: 276.1236, found: 276.1229.Data for compound 2.125: 2940, 1624, 1472, 1262, 1034, 998 cm-1. 1H NMR (400 MHz, CDCl3) δ6.98 (d, J = 9.1 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 5.94 (dt, J = 9.6, 2.0 Hz, 1H), 5.67 (dt, J = 9.6, 4.2 Hz,1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.03 (t, J = 9.5 Hz, 2H), 2.62 (tdd, J = 9.5, 4.1, 2.0 Hz, 2H). 13C NMR (101MHz, CDCl3) δ 168.7, 155.6, 153.0, 150.8, 123.7, 121.2, 117.9, 115.0, 113.6, 111.0, 57.2, 56.9, 24.1, 21.3.LRMS (ESI+): 358.3/360.3 (M+Na)+. HRMS (ESI+) Calculated for C15H14NO3Na79Br: 358.0055, found:358.0057.109Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesNOMeOOOOHCH2CH2OHPhH, 80 ºC60%HN OOHMeOOO2.128 2.1302-Methoxy-6-(3a,6,7,7a-tetrahydro-5H-spiro[benzo[d]isoxazole-4,2’-[1,3]dioxolan]-3-yl)phenol (2.130).A solution of 2.128 (0.34 g, 1.3 mmol, 1 equiv), ethylene glycol (0.74 mL, 13.3 mmol, 10 equiv) and para-toluenesulfonic acid monohydrate (72.7 mg, 0.4 mmol, 0.3 equiv) in 13 mL of benzene was heated up toreflux temperature for 16 h using a Dean Stark trap. The reaction mixture was cooled to rt and it was dilutedwith 50 mL of ethyl acetate. The organic phase was washed with water (3 x 20 mL) and brine (20 mL).Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced an orange oil thatafter purification using chromatography over silica gel yielded 0.24 g (60%) of the title compound as a lightyellow oil. 1H NMR (300 MHz, CDCl3) δ 10.25 (s, 1H), 7.16 (dd, J = 7.9, 1.3 Hz, 1H), 6.78 (dd, J = 8.2,1.3 Hz, 1H), 6.71 (t, J = 7.9 Hz, 1H), 4.43-4.41 (m, 1H), 3.75 (s, 3H), 3.64-3.55 (m, 3H), 3.34-3.24 (m, 2H),2.14 (d, J = 12.7 Hz, 1H), 1.73-1.51 (m, 4H), 1.36-1.26 (m, J = 4.1 Hz, 1H). 13C NMR (75 MHz, CDCl3)δ 162.5, 147.8, 147.2, 122.0, 118.5, 114.6, 113.0, 107.0, 80.9, 65.2, 63.5, 55.8, 53.1, 33.6, 23.7, 17.5.2.4.5 Intramolecular [3+2] Dipolar CycloadditionsHOOH HOBr+ DIAD, PPh3THF, 0 ºC60%OOONHN OOO O2.143 2.95a 2.145Isopropyl (E)-2-(2-((isopropoxycarbonyl)oxy)-3-methoxybenzylidene)hydrazine-1-carboxylate (2.145).To a solution of o-vanillin (2.143) (1.11 g, 6.1 mmol, 1 equiv), 2-bromocyclohex-2-en-1-ol (2.95a) (1.14 g,6.4 mmol, 1.05 equiv) and triphenylphosphine (1.70 g, 6.5 mmol, 1.05 equiv) in 3.0 mL of THF, diisopropy-lazodicarboxylate (1.4 mL, 6.8 mmol, 1.1 equiv) was added dropwise and the reaction mixture was sonicatedat rt for 2 h. The reaction mixture was diluted with 20 mL of hexanes. Concentration by rotary evaporationin vacuo produced a light yellow gel that after purification using chromatography over silica gel yielded 1.29g (60%) of the title compound as a yellow oil. IR (neat): 3208, 3056, 1754, 1694, 1548, 1260 cm-1. 1HNMR (300 MHz, DMSO-d6) δ 10.66 (br s, 1H), 8.13 (br s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 8.0Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.00-4.83 (m, J = 5.8 Hz, 2H), 3.77 (s, 3H), 1.30 (d, J = 6.2 Hz, 6H),1.24 (d, J = 6.0 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 152.9, 151.2, 150.5, 138.0, 127.2, 125.6, 117.0,110Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles112.1, 77.2, 72.5, 67.9, 67.8, 55.2, 21.3, 20.8. LRMS (ESI+): 361.4 (M+Na)+. HRMS (ESI+) Calculatedfor C16H22N2O6Na: 361.1376, found: 361.1371.2.4.5.1 Synthesis of Bromocyclohexenyl Phenyl EthersOOBrOHO BrHOHR +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt RH2.133 2.95a 2.144Sample Procedure for the Preparation of 2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehydes 2.1442-((2-Bromocyclohex-2-en-1-yl)oxy)benzaldehyde (2.144a). Triethylamine (1.96 g, 15.2 mmol, 1.5equiv) was added to a solution of 2-bromo-2-cyclohexen-1-ol (1.77 g, 10.0 mmol, 1 equiv) in 50 mL ofmethylene dichloride at 0 ◦C. A solution of methanesulfonic anhydride (2.72 g, 15.2 mmol, 1.5 equiv) in 50mL of methylene dichloride was added dropwise over 30 min. The reaction mixture was stirred at 0 ◦C for30 min, then warmed to rt for 1 h. A solution of salicylaldehyde (3.78 g, 30.3 mmol, 3 equiv) and DBU(4.68 g, 30.2 mmol, 3 equiv) in 50 mL of methylene dichloride was then slowly added dropwise over 30min. The reaction mixture was stirred at rt for 1 h then heated to reflux for 16 h. After it was cooled to rt,the reaction mixture was poured into a separatory funnel and was washed successively with aqueous 2 Mhydrochloric acid (twice), aqueous 2 M sodium hydroxide (twice) and water (twice). Drying over sodiumsulfate, concentration by rotary evaporation in vacuo produced a yellowy thick oil that after purification usingchromatography over silica gel (hexanes:ethyl acetate 9:1 to 4:1) yielded 2.0 g (72%) of the title compoundas a white solid, mp 78–79 ◦C.OOBrOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt72%H1.130 2.95a 2.144aThe reaction was performed using 1.77 g (10.0 mmol, 1 equiv) of 2-bromo-2-cyclohexenol, 2.72 g (15.2mmol, 1.5 equiv) of methanesulfonic anhydride, 1.96 g (15.1 mmol, 1.5 equiv) of triethylamine, 3.78 g (30.3mmol, 3 equiv) of salicylaldehyde and 4.68 g (30.2 mmol, 3 equiv) of DBU. After purification, 2.01 g (72%yield) of the title compound was isolated as a white solid, mp 78–79 ◦C. IR (neat): 2932, 1682, 1596,1229, 653 cm-1. 1H NMR (300 MHz, CDCl3) δ 10.56 (s, 1H), 7.85 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 (td, J =7.9, 1.4 Hz, 1H), 7.11-7.03 (m, 2H), 6.42 (dd, J = 4.7, 3.1 Hz, 1H), 4.89 (s, 1H), 2.30-2.07 (m, 3H), 2.00-1.90 (m, 1H), 1.84-1.68 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 190.2, 161.0, 135.9, 135.5, 128.4, 126.4,111Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles121.6, 120.2, 114.9, 77.65, 29.6, 27.8, 17.1. LRMS (ESI+): 305.2 (M+Na)+. HRMS (ESI+) Calculated forC13H13O2Na79Br (M+Na)+: 302.9997, found: 302.9990.OOOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt98%H BrOO2.143 2.95a 2.144b2-((2-Bromocyclohex-2-en-1-yl)oxy)-3-methoxybenzaldehyde (2.144b). The reaction was performedusing 3.64 g (20.6 mmol, 1 equiv) of 2-bromo-2-cyclohexenol, 5.59 g (31.1 mmol, 1.5 equiv) of methane-sulfonic anhydride, 3.19 g (31.6 mmol, 1.5 equiv) of triethylamine, 9.54 g (62.1 mmol, 3 equiv) of o-vanillinand 9.57 g (61.6 mmol, 3 equiv) of DBU. After purification, 6.40 g (98% yield) of the title compound wasisolated as an off-white solid, mp 64–65 ◦C. IR (neat): 2950, 1687, 1243, 572 cm-1. 1H NMR (300 MHz,CDCl3) δ 10.49 (s, 1H), 7.37 (dd, J = 7.2, 2.1 Hz, 1H), 7.09-7.00 (m, 2H), 6.29 (dd, J = 4.6, 3.0 Hz, 1H), 4.88(s, 1H), 3.82 (s, 3H), 2.21-2.14 (m, 2H), 2.04 (d, J = 8.1 Hz, 1H), 1.80 (dd, J = 15.3, 7.3 Hz, 2H), 1.64-1.61(m, 1H). 13C NMR (75 MHz, CDCl3) δ 190.7, 152.3, 150.7, 135.1, 130.3, 123.7, 120.7, 118.8, 117.9, 79.6,55.9, 30.1, 27.8, 16.5. LRMS (ESI+): 333.3 (M+Na)+. HRMS (ESI+) Calculated for C14H15O3Na79Br:333.0102, found: 333.0099.OOOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt7%H BrBrBr2.133c 2.95a 2.144c5-Bromo-2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde (2.144c). The reaction was performed us-ing 1.77 g (10.0mmol, 1equiv) of 2-bromo-2-cyclohexenol, 2.81 g (15.8 mmol, 1.5 equiv) of methanesulfonicanhydride, 1.60 g (15.8 mmol, 1.5 equiv) of triethylamine, 3.29 g (16.4 mmol, 1.6 equiv) of 5-bromo-2-hydroxybenzaldehyde and 2.55 g (16.4 mmol, 1.6 equiv) of DBU. After purification, 0.25 g (7% yield) ofthe title product was obtained as a light yellow solid, mp 117 ◦C. IR (neat): 2938, 1678, 1598, 1252, 618cm-1. 1H NMR (300 MHz, CDCl3) δ 10.39 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.55 (dd, J = 8.9, 2.5 Hz, 1H),6.97 (d, J = 8.9 Hz, 1H), 6.35 (dd, J = 4.5, 3.3 Hz, 1H), 4.80 (s, 1H), 2.24-2.00 (m, 6H), 1.98-1.87 (m, 2H),1.71 (dd, J = 15.6, 4.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 188.5, 159.8, 138.2,135.6, 130.8, 127.5, 119.6, 116.8, 114.2, 77.9, 30.9, 29.5, 27.6, 16.9. LRMS (ESI-): 359.1 (M-H)-. HRMS(ESI+) Calculated for C13H12O2Na79Br2: 380.9102, found: 380.9103.112Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOOOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt40%H BrOO2.133d 2.95a 2.144d2-((2-Bromocyclohex-2-en-1-yl)oxy)-4-methoxybenzaldehyde (2.144d). The reaction was performedusing 1.81 g (10.2 mmol, 1 equiv) of 2-bromo-2-cyclohexenol, 2.81 g (15.8 mmol, 1.5 equiv) of methanesul-fonic anhydride, 1.60 g (15.8 mmol, 1.5 equiv) of triethylamine, 2.40 g (15.5 mmol, 1.5 equiv) of 2-hydroxy-4-methoxybenzaldehyde and 2.44 g (15.7 mmol, 1.5 equiv) of DBU. After purification, 1.26 g (40% yield)of the title compound was obtained as a light yellow oil. IR (neat): 2939, 1675, 1596, 1254, 620 cm-1. 1HNMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 6.62-6.56 (m, 2H), 6.43 (dd, J = 5.1,3.1 Hz, 1H), 4.87-4.85 (m, 1H), 3.88 (s, 3H), 2.25-2.14 (m, 3H), 1.98-1.90 (m, 1H), 1.79-1.72 (m, 2H). 13CNMR (75 MHz, CDCl3) δ 188.8, 166.1, 162.7, 135.6, 130.4, 120.6, 120.1, 107.1, 100.9, 77.65, 55.9, 29.6,27.8, 17.1. LRMS (ESI+): 333.3 (M+Na)+. HRMS (ESI+) Calculated for C14H15O3Na79Br: 333.0102,found: 333.0107.OOOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt30%H BrO2NO2N2.133e 2.95a 2.144e2-((2-Bromocyclohex-2-en-1-yl)oxy)-5-nitrobenzaldehyde (2.144e). The reaction was performed us-ing 1.78 g (10.0 mmol, 1 equiv) of 2-bromo-2-cyclohexenol, 2.76 g (15.5 mmol, 1.5 equiv) of methanesul-fonic anhydride, 1.52 g (15.1 mmol, 1.5 equiv) of triethylamine, 3.58 g (21.2 mmol, 2.1 equiv) of 2-hydroxy-5-nitrobenzaldehyde and 3.36 g (21.6 mmol, 2.1 equiv) of DBU. After purification, 0.98 g (30% yield) of thetitle compound was obtained as a white powder, mp 114–117 ◦C. IR (neat): 3118, 2953, 1683, 1587, 1342,1268, 667 cm-1. 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.72 (d, J = 2.9 Hz, 1H), 8.42 (dd, J = 9.2,2.9 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 6.49 (dd, J = 5.0, 3.2 Hz, 1H), 5.06 (t, J = 3.6 Hz, 1H), 2.37-2.16 (m,3H), 2.15-2.02 (m, 1H), 1.82-178 (m, 2H). 13CNMR (75 MHz, CDCl3) δ 187.9, 173.9, 142.0, 136.6, 130.6,125.9, 124.9, 118.7, 114.5, 78.3, 29.6, 27.7, 17.1. LRMS (ESI-): 324.2 (M-H)-. HRMS (ESI+) Calculatedfor C13H11O4N79Br: 323.9871, found: 323.9878.2-((2-Bromocyclohex-2-en-1-yl)oxy)-1-naphthaldehyde (2.144f). The reaction was performed using1.81 g (10.2 mmol, 1 equiv) of 2-bromo-2-cyclohexenol, 2.80 g (15.8 mmol, 1.5 equiv) of methanesulfonicanhydride, 1.60 g (15.8 mmol, 1.5 equiv) of triethylamine, 5.40 g (30.7 mmol, 3 equiv) of 2-hydroxy-1-113Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOOOHO BrHOH +a) Ms2O, Et3N, 0 ºCb) DBU, DCM, rt72%H Br2.133f 2.95a 2.144fnaphthaldehyde and 4.78 g (30.8 mmol, 3 equiv) of DBU. After purification, 2.44 g (72% yield) of the titlecompound was obtained as an off-white solid, mp 88–90 ◦C. IR (neat): 3084, 2952, 1234, 649 cm-1. 1HNMR (300 MHz, CDCl3) δ 10.97 (s, 1H), 9.31 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.77 (d, J =8.0 Hz, 1H), 7.65-7.60 (m, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 6.42 (dd, J = 4.9, 3.1Hz, 1H), 4.99 (s, 1H), 2.29-2.05 (m, 3H), 1.99-1.68 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 192.6, 163.1,137.5, 135.6, 131.6, 129.8, 129.1, 128.3, 125.22, 125.10, 119.9, 118.8, 115.7, 78.6, 29.9, 27.7, 16.9. LRMS(ESI+): 355.3 (M+Na)+. HRMS (ESI+) Calculated for C17H16O279Br: 331.0334, found: 331.0337.2.4.5.2 Synthesis of 2-((2-Bromocyclohex-2-en-1-yl)oxy)benzaldehyde OximesOONH2OHH2O, refluxBr NOBrOHR R2.144 2.146Sample Procedure for the Preparation of 2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde oximes2.146Synthesis of 2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde oxime (2.146a). A solution of hydrox-ylamine (0.75 mL, 12.2 mmol, 50% in water, 1.4 equiv) was added to a cloudy solution of aldehyde 2.144a(2.01 g, 7.17 mmol, 1 equiv) in 70 mL of water at 100 ◦C. The reaction mixture was stirred for 16 h. Thereaction mixture was cooled to rt and was extracted three times with ethyl acetate. The combined organicextracts were washed with brine twice and dried over sodium sulfate. The dried extracts were filtered andconcentrated using rotary evaporation in vacuo to produce a yellowy thick oil that after purification usingchromatography over silica gel (hexanes:ethyl acetate 8:2 to 7:3) yielded 2.1 g (98%) of the title compoundas a white solid, mp 119–121 ◦C.114Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOONH2OHH2O, reflux98%Br NOBrOH2.144a 2.146a2-((2-Bromocyclohex-2-en-1-yl)oxy)benzaldehyde oxime (2.146a). The reaction was performed using2.01 g (7.17 mmol, 1 equiv) of aldehyde 2.144a and 0.75 mL (12.2 mmol, 1.4 equiv) of hydroxylamine. Afterpurification, 2.12 g (98% yield) of the title compound was obtained as a white powder, mp 119–121 ◦C. IR(neat): 3272, 2931, 1599, 1451, 1233, 642 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.28 (br s,1H), 7.78 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 8.5, 7.3, 1.7 Hz, 1H), 7.04-6.97 (m, 2H), 6.40 (dd, J = 5.1,3.1 Hz, 1H), 4.81 (d, J = 3.7 Hz, 1H), 2.32-2.05 (m, 3H), 1.93-1.65 (m, 3H). 13C NMR (75 MHz, CDCl3) δ156.5, 146.9, 135.2, 131.4, 126.7, 122.5, 121.8, 120.7, 114.7, 77.4, 29.5, 27.9, 17.0. LRMS (ESI+): 320.3(M+Na)+. HRMS (ESI+) Calculated for C13H15NO279Br: 296.0286, found: 296.0282.OONH2OHH2O, reflux94%Br NOBrOHO O2.144b 2.146b2-((2-Bromocyclohex-2-en-1-yl)oxy)-3-methoxybenzaldehyde oxime (2.146b). The reaction was per-formed using 3.88 g (12.5 mmol, 1 equiv) of aldehyde 2.144b and 1.10 mL (17.8 mmol, 1.4 equiv) of hy-droxylamine. After purification, 3.79 g (94% yield) of the title compound was obtained as light yellow thickoil, which solidified upon standing, mp 159–164 ◦C (decomposed). IR (neat): 3284, 2937, 1475, 1438, 1266cm-1. 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.93(d, J = 8.1 Hz, 1H), 6.36 (dd, J = 4.8, 2.9 Hz, 1H), 4.83 (s, 1H), 3.86 (s, 3H), 2.30-2.22 (s, 1H), 2.18-2.09(m, 3H), 1.96-1.83 (m, 1H), 1.68-1.25 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 152.7, 147.3, 145.9, 135.2,126.9, 124.2, 121.3 118.1, 113.9, 79.3, 56.0, 29.9, 28.1, 16.8. LRMS (ESI+): 350.3 (M+Na)+. HRMS(ESI+) Calculated for C14H17NO379Br: 326.0392, found: 326.0396.115Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOONH2OHH2O, reflux73%Br NOBrOHBr Br2.144c 2.146c5-Bromo-2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde oxime (2.146c). The reaction was per-formed using 0.25 g (0.70 mmol, 1 equiv) of aldehyde 2.144c and 0.09 mL (1.5 mmol, 2 equiv) of hydrox-ylamine. After purification, 0.19 g (73% yield) of the title compound was obtained as a light yellow thickoil, which solidified upon standing, mp 105–110 ◦C (decomposed). IR (neat): 3280, 2951, 1481, 1268, 663,634 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.09 (br s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.8, 2.3 Hz,1H), 6.89 (d, J = 8.9 Hz, 1H), 6.36 (dd, J = 4.9, 3.1 Hz, 1H), 4.72 (s, 1H), 2.27-2.09 (m, 3H), 1.90-1.61 (m,3H). 13C NMR (75 MHz, CDCl3) δ 155.4, 145.5, 135.4, 133.7, 129.2, 124.4, 120.1, 116.4, 114.2, 77.81,60.8, 29.4, 27.7, 16.9. LRMS (ESI+): 398.1 (M+Na)+. HRMS (ESI+) Calculated for C13H14NO279Br2:373.9391, found: 373.9389.OONH2OHH2O, reflux52%Br NOBrOHO O2.144d 2.146d2-((2-Bromocyclohex-2-en-1-yl)oxy)-4-methoxybenzaldehyde oxime (2.146d). The reaction was per-formed using 0.57 g (1.8 mmol, 1 equiv) of aldehyde 2.144d and 0.23 mL (3.8 mmol, 2.1 equiv) of hydrox-ylamine. After purification, 0.31 g (52% yield) of the title compound was obtained as a light yellow oil,which solidified upon standing, mp 97–115 ◦C (decomposed). IR (neat): 3240, 2933, 1608, 1265 cm-1. 1HNMR (300 MHz, CDCl3) δ 9.55 (br s, 1H), 8.55 (s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 6.56-6.54 (m, 2H), 6.36(dd, J = 5.1, 3.0 Hz, 1H), 4.76 (s, 1H), 3.80 (s, 3H), 2.22-2.15 (m, 1H), 2.14-2.01 (m, 2H), 1.90-1.70 (m,2H), 1.68-1.60 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 162.4, 157.6, 146.4, 135.2, 127.6, 120.4, 115.2,106.8, 101.2, 77.3, 55.6, 29.3, 27.7, 16.9. LRMS (ESI+): 328.2 (M+H)+. HRMS (ESI+) Calculated forC14H17NO379Br: 326.0392, found: 326.0389.116Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOONH2OHH2O, reflux74%Br NOBrOHO2N O2N2.144e 2.146e2-((2-Bromocyclohex-2-en-1-yl)oxy)-5-nitrobenzaldehyde oxime (2.146e). The reaction was performedusing 0.96 g (2.9 mmol, 1 equiv) of aldehyde 2.144e and 0.36 mL (5.9 mmol, 1.9 equiv) of hydroxylamine.After purification, 0.74 g (74% yield) of the title compound was obtained as a light yellow oil, which solid-ified upon standing, mp 134.5–141 ◦C (decomposed). IR (neat): 3413, 2929, 1511, 1339, 1269, 674 cm-1.1H NMR (300 MHz, CDCl3) δ 8.67 (d, J = 2.9 Hz, 1H), 8.54 (s, 1H), 8.24 (dd, J = 9.2, 2.9 Hz, 1H), 7.07 (d,J = 9.4 Hz, 1H), 6.45 (dd, J = 5.1, 3.1 Hz, 1H), 4.96 (m, 1H), 2.29 (m, 4.6 Hz, 1H), 2.21-2.07 (m, 2H), 2.05-1.93 (m, 1H), 1.83-1.70 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.7, 145.0, 141.9, 136.2, 126.6, 122.90,122.84, 119.2, 113.4, 77.8, 29.5, 27.7, 17.0. LRMS (ESI-): 339.2 (M-H)-. HRMS (ESI+) Calculated forC13H13N2O4Na79Br: 362.9956, found: 362.9962.OONH2OHH2O, reflux50%Br NOBrOH2.144f 2.146f2-((2-Bromocyclohex-2-en-1-yl)oxy)-1-naphthaldehyde oxime (2.146f). The reaction was performedusing 2.44 g (7.4 mmol, 1 equiv) of aldehyde 2.144f and 0.72 mL (11.1 mmol, 1.5 equiv) of hydroxylamine.After purification, 1.26 g (50% yield) as a light yellow thick oil. IR (neat): 3312, 2935, 1588, 1509, 1234,637 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.93 (s, 1H), 8.86 (dd, J = 8.7, 0.9 Hz, 1H), 7.87 (d,J = 9.0 Hz, 1H), 7.82 (dt, J = 8.0, 0.6 Hz, 1H), 7.58 (ddd, J = 8.6, 6.9, 1.5 Hz, 1H), 7.44 (ddd, J = 8.1, 6.9,1.2 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.41 (dd, J = 5.1, 3.0 Hz, 1H), 4.90 (d, J = 3.5 Hz, 1H), 2.23-2.20 (m,1H), 2.15-2.08 (m, 2H), 1.90-1.82 (m, 2H), 1.70-1.66 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 155.8, 148.0,135.3, 132.1, 131.7, 129.8, 128.4, 128.0, 125.8, 124.7, 120.6, 116.39, 116.32, 78.8, 29.7, 27.8, 16.9. LRMS(ESI+): 348.3 (M+H)+. HRMS (ESI+) Calculated for C17H17NO279Br: 346.0443, found: 346.0446.117Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles2.4.5.3 Synthesis of Bromoisoxazolinesa) NCS, Pyb) Et3NN OOHHBrNOBrOHR R2.146 2.147Sample Procedure for the Preparation of Bromo Isoxazolines 2.147Pyridine (0.14 mL, 1.7 mmol, 0.2 equiv) was added to a solution of oxime 2.146a (2.48 g, 8.4 mmol, 1equiv) in 85 mL of chloroform. The reaction mixture was heated to 40 ◦C. NCS (1.28 g, 9.4 mmol, 1.1 equiv)was added in small portions over a period of 30 min. The reaction mixture was further stirred at 40 ◦C for 3h. Triethylamine (1.2 mL, 8.6 mmol, 1 equiv) was added, converting the yellow-orange solution into a darkred fuming one. The reaction mixture was stirred at 40 ◦C for 2 h. The reaction mixture was diluted with100 mL of methylene dichloride. The organic layer was successively washed with aqueous 1 M hydrochloricacid (once), water (twice) and dried over sodium sulfate. Concentration using rotary evaporation in vacuoyielded an orange solid that after purification using chromatography over silica gel (hexanes:ethyl acetate 8:2to 7:3) yielded 1.54 g (63%) of the title product as a white solid, mp 170–173 ◦C.ON O HHBrONBrHOHa) NCS, Py, CHCl3b) Et3N, 40 ºC63%2.146a 2.147a2a1-Bromo-2a,2a1,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole (2.147a). The reaction was performedusing 2.48 g (8.4 mmol, 1 equiv) of oxime 2.146a, 0.14 mL of pyridine (1.7 mmol, 0.2 equiv), 1.28 g (9.4mmol, 1.1 equiv) of NCS, and 1.2 mL (8.6 mmol, 1 equiv) of triethylamine. After purification, 1.54 g (63%yield) of the title compound was obtained as an off white powder, mp 170–173 ◦C. IR (neat): 2933, 1611,1462, 1209, 665 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.41 (ddd, J = 8.3,7.4, 1.6 Hz, 1H), 7.08-7.02 (m, 2H), 5.13 (t, J = 8.5 Hz, 1H), 4.90 (dd, J = 11.6, 6.0 Hz, 1H), 2.28-2.20 (m,1H), 2.14-2.05 (m, 1H), 1.70-1.65 (m, 1H), 1.39-1.20 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 152.3, 151.5,133.4, 125.9, 122.3, 118.4, 110.5, 89.6, 81.6, 67.1, 30.6, 29.0, 16.9; LRMS (ESI+): 294.3 (M+H)+. HRMS(ESI+) Calculated for C13H13NO279Br: 294.0130, found: 294.0135.118Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON O HHBrON HOHa) NCS, Py, CHCl3b) Et3N, 40 ºC89%BrO O2.146b 2.147b2a1-Bromo-7-methoxy-2a,2a1 ,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole (2.147b). The reactionwas performed using 4.56 g (14.0 mmol, 1 equiv) of oxime 2.146b, 0.22 mL of pyridine (2.7 mmol, 0.2equiv), 2.10 g (15.4 mmol, 1.1 equiv) of NCS, and 2.0 mL (14.0 mmol, 1 equiv) of triethylamine. Afterpurification, 4.04 g (89% yield) of the title compound was obtained as a white solid, mp 170–172 ◦C. IR(neat): 2941, 1572, 1489, 1211, 626 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.41 (dd, J = 5.6, 3.7 Hz, 1H),6.95-6.93 (m, 2H), 5.08 (t, J = 8.3 Hz, 1H), 4.97 (dd, J = 11.3, 5.9 Hz, 1H), 3.81 (s, 4H), 2.20-2.07 (m, 2H),1.60 (dd, J = 7.1, 3.7 Hz, 1H), 1.36-1.09 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 151.2, 149.1, 141.8, 121.8,117.0, 114.3, 110.8, 89.6, 81.7, 77.7, 77.2, 76.8, 66.7, 56.1, 30.3, 28.7, 16.6. LRMS (ESI+): 326.3 (M+H)+.HRMS (ESI+) Calculated for C14H15NO379Br, 324.0235, found: 324.0238.ON O HHBrON HOHa) NCS, Py, CHCl3b) Et3N, 40 ºC72%Br BrBr2.146c 2.147c2a1,9-Dibromo-2a,2a1,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole (2.147c). The reaction was per-formed using 0.19 g (0.5 mmol, 1 equiv) of oxime 2.146c, 0.01 mL of pyridine (0.1 mmol, 0.2 equiv), 0.08g (0.6 mmol, 1.2 equiv) of NCS, and 0.07 mL (0.5 mmol, 1 equiv) of triethylamine. After purification, 0.14g (72% yield) of the title compound was obtained as a foamy clear thick oil. IR (neat): 2952, 1459, 1440,1213, 728, 680 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.9, 2.5 Hz,1H), 6.93 (d, J = 8.9 Hz, 1H), 5.15 (d, J = 8.8 Hz, 1H), 4.90-4.86 (m, 1H), 2.28-2.19 (m, 1H), 2.13-2.04 (m,1H), 1.68-165 (m, 1H), 1.37-1.14 (m, 4H). 13CNMR (75 MHz, CDCl3) δ 151.2, 150.5, 136.1, 128.2, 120.3,114.5, 112.2, 89.9, 81.8, 66.2, 30.5, 28.9, 16.7. LRMS (ESI+): 374.0 (M+H)+. HRMS (ESI+) Calculatedfor C13H12NO279Br2: 371.9235, found: 371.9233.119Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON O HHBrON HOHa) NCS, Py, CHCl3b) Et3N, 40 ºC49%BrOO2.146d 2.147d2a1-Bromo-8-methoxy-2a,2a1 ,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole (2.147d). The reactionwas performed using 0.31 g (1.0 mmol, 1 equiv) of oxime 2.146d, 0.02 mL of pyridine (0.2 mmol, 0.2 equiv),0.15 g (1.1 mmol, 1.1 equiv) of NCS, and 0.14 mL (1.0 mmol, 1 equiv) of triethylamine. After purification,0.15 g (49% yield) of the title compound was obtained as a thick clear oil, which solidified upon standing,mp 131–135.5 ◦C. IR (neat): 2942, 1614, 1591, 1437, 1197, 634 cm-1. 1H NMR (300 MHz, CDCl3) δ7.75 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 8.8, 2.5 Hz, 1H), 6.51 (s, 1H), 5.09-5.03 (m, 1H), 4.86 (dd, J = 11.4,5.9 Hz, 1H), 3.80 (s, 3H), 2.22-2.14 (m, 1H), 2.10-2.02 (m, 1H), 1.68-1.63 (m, 1H), 1.40-1.18 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 163.9, 153.9, 130.1, 127.5, 127.0, 122.0, 110.5, 103.0, 102.0, 89.0, 81.8, 55.6,30.4, 29.0, 17.0. LRMS (ESI+): 326.2 (M+H)+. HRMS (ESI+) Calculated for C14H15NO379Br: 324.0235,found: 324.0241.ON O HHBrON HOHa) NCS, Py, CHCl3b) Et3N, 40 ºC76%Br O2NO2N2.146e 2.147e2a1-Bromo-9-nitro-2a,2a1 ,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole (2.147e). The reaction wasperformed using 0.74 g (2.2 mmol, 1 equiv) of oxime 2.146e, 0.04 mL of pyridine (0.4 mmol, 0.2 equiv),0.33 g (2.4 mmol, 1.1 equiv) of NCS, and 0.3 mL (2.2 mmol, 1 equiv) of triethylamine. After purification,0.56 g (76% yield) of the title compound was obtained as a white powder, mp 166–167.5 ◦C. IR (neat): 3107,2944, 1617, 1460, 1338, 1229, 685 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J = 2.8 Hz, 1H), 8.28 (dd,J = 9.2, 2.8 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 5.22 (t, J = 8.5 Hz, 1H), 5.07-5.01 (m, 1H), 2.35-2.26 (m,1H), 2.23-2.16 (m, 1H), 1.78-1.71 (m, 1H), 1.35-1.20 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 156.7, 150.1,134.9, 128.1, 122.4, 119.3, 110.9, 90.5, 82.8, 64.9, 30.6, 29.4, 16.6. LRMS (ESI+): 341.1 (M+H)+. HRMS(ESI+) Calculated for C13H12N2O479Br: 338.9980, found: 338.9977.120Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON O HHBrON HOHa) NCS, Py, CHCl3b) Et3N, 40 ºC76%Br2.146f 2.147f2a1-Bromo-2a,2a1,3,4,5,5a-hexahydrobenzo[7,8]xantheno[9,1-cd]isoxazole (2.147f). The reactionwas performed using 0.37 g (1.1 mmol, equiv) of oxime 2.146f , 0.02 mL of pyridine (0.2 mmol, 0.2 equiv),0.16 g (1.2 mmol, 1 equiv) of NCS, and 0.15 mL (1.1 mmol, 1 equiv) of triethylamine. After purification,0.27 g (73% yield) of the title compound was obtained as a very thick yellow oil. IR (neat): 3058, 2951, 1620,1442, 1226, 726 cm-1. 1HNMR (300 MHz, CDCl3) δ 9.13 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.80(dt, J = 8.0, 0.6 Hz, 1H), 7.65 (td, J = 7.8, 1.5 Hz, 1H), 7.49-7.44 (m, 1H), 7.19 (d, J = 9.0 Hz, 1H), 5.15-5.10(m, 1H), 4.99 (dd, J = 11.7, 5.9 Hz, 1H), 2.29-2.21 (m, 1H), 2.15-2.06 (m, 1H), 1.68-1.62 (m, 1H), 1.50-1.23(m, 3H). 13C NMR (75 MHz, CDCl3) δ 152.8, 152.3, 134.5, 130.8, 129.6, 128.89, 128.70, 127.0, 125.1,118.9, 103.7, 88.3, 81.4, 68.7, 30.5, 28.7, 16.6. LRMS (ESI+): 346.2 (M+H)+. HRMS (ESI+) Calculatedfor C17H15NO279Br: 344.0286, found: 344.0291.2.4.5.4 Synthesis of IsoxazolesON OON O HHBrRAg2CO3DMSO, 80 ºC R2.147 2.149Sample Procedure for the Preparation Synthesis of tetrahydroxantheno[9,1-cd]isoxazoles (2.149).To a solution of bromoisoxazoline 2.147a (0.30 g, 1.0 mmol, 1 equiv) in 10 mL of dimethyl sulfoxide(5 ml/mmol) at 100 ◦C, silver carbonate (0.32 g, 1.1 mmol, 1.1 equiv) was added. The reaction mixturewas stirred at 100 ◦C for 16 h. The reaction mixture was cooled to rt and was filtered through Celiteő.The filter cake was washed with water. The solution was extracted with ethyl acetate (three times). Thecombined organic extracts were washed with brine twice, dried over sodium sulfate and concentrated usingrotary evaporation in vacuo to yield a brown solid that after purification using chromatography over silicagel (hexanes:ethyl acetate 4:1 to 7:3) yielded 0.17 g (78%) of the title compound as a white solid, mp 94.5◦C.121Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON OON O HHBr Ag2CO3DMSO, 80 ºC78%2.147a 2.149a3,4,5,5a-Tetrahydroxantheno[9,1-cd]isoxazole (2.149a). The reaction was performed using 0.30 g (1.1mmol, 1 equiv) of bromoisoxazoline 2.147a and 0.32 g (1.1 mmol, 1 equiv) of silver carbonate. After purifi-cation, 0.17 g (78% yield) of the title compound was obtained as a white solid, mp 94.5 ◦C. IR (neat): 2943,1685, 1498, 1200 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.6, 1.4 Hz, 1H), 7.33 (td, J = 7.8, 1.3Hz, 1H), 7.04 (dd, J = 14.2, 7.8 Hz, 2H), 5.11-5.07 (m, 1H), 2.81 (ddt, J = 17.8, 6.4, 1.8 Hz, 1H), 2.69 (dddd,J = 17.5, 11.1, 6.2, 2.3 Hz, 1H), 2.49-2.43 (m, 1H), 2.26-2.22 (m, 1H), 1.87 (ddddd, J = 17.0, 14.1, 11.2, 6.0,2.9 Hz, 1H), 1.68-1.59 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 166.2, 156.1, 153.2, 132.1, 125.0, 122.4,118.6, 115.7, 113.1, 70.0, 29.3, 22.4, 20.7. LRMS (ESI+): 214.4 (M+H)+. HRMS (ESI+) Calculated forC13H12NO2: 214.0868, found: 214.0876. See C for solid state molecular structure.ON OON O HHBr Ag2CO3DMSO, 80 ºC79%O O2.147b 2.149b7-Methoxy-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole (2.149b). The reaction was performed us-ing 1.63 g (5.0 mmol, 1 equiv) of bromoisoxazoline 2.147b and 1.55 g (5.6 mmol, 1.1 equiv) of silvercarbonate. After purification, 0.97 g (79% yield) of the title compound was obtained as a white powder, mp142–143 ◦C. IR (neat): 2961, 1684, 1575, 1263 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 7.5, 1.8Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.98 (dd, J = 8.2, 1.7 Hz, 1H), 5.19-5.14 (m, 1H), 3.91 (s, 3H), 2.85 (ddt,J = 17.7, 6.3, 1.7 Hz, 1H), 2.72 (dddd, J = 17.5, 11.1, 6.2, 2.6 Hz, 1H), 2.60 (dddd, J = 12.1, 5.8, 3.7, 2.4Hz, 1H), 2.32-2.24 (m, 1H), 1.90 (tddd, J = 14.0, 11.0, 6.3, 2.8 Hz, 1H), 1.72 (dddd, J = 14.1, 12.2, 9.5, 2.8Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 166.3, 149.5, 145.3, 122.1, 116.7, 116.2, 114.2, 112.9, 70.3, 56.1,29.3, 22.3, 20.6. LRMS (ESI+): 244.5 (M+H)+. HRMS (ESI+) Calculated for C14H14NO3: 244.0974,found: 244.0977.122Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON OON O HHBr Ag2CO3DMSO, 80 ºC69%Br Br2.147c 2.149c8-Bromo-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole (2.149c). The reaction was performed using0.14 g (0.4 mmol, 1 equiv) of bromoisoxazoline 2.147c and 0.21 g (0.8 mmol, 2 equiv) of silver carbonate.After purification, 0.073 g (69% yield) of the title compound was obtained as a white powder, mp 124–125◦C. IR (neat): 3060, 2937, 1684, 1496, 1202 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 2.4 Hz,1H), 7.40 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.08 (ddt, J = 9.7, 5.6, 2.2 Hz, 1H), 2.83(ddt, J = 17.8, 6.4, 1.7 Hz, 1H), 2.69 (dddd, J = 17.5, 11.0, 6.1, 2.5 Hz, 1H), 2.50-2.42 (m, 1H), 2.31-2.21(m, 1H), 1.96-1.80 (m, 1H), 1.62 (dddd, J = 14.0, 12.2, 9.5, 2.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ166.7, 155.1, 152.4, 134.8, 127.6, 120.4, 117.4, 114.6, 112.8, 70.4, 29.3, 22.5, 20.7. LRMS (ESI+): 294.2(M+H)+. HRMS (ESI+) Calculated for C13H11NO279Br: 291.9973, found: 291.9960.ON OON O HHBr Ag2CO3DMSO, 80 ºC77%O O2.147d 2.149d8-Methoxy-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole (2.149d). The reaction was performed us-ing 0.15 g (0.5mmol, 1 equiv) of bromoisoxazoline 2.147d and 0.26 g (1.0 mmol, 2 equiv) of silver carbonate.After purification, 0.087 g (77% yield) of the title compound was obtained as a white powder, mp 151.5–155.0 ◦C. IR (neat): 2935, 1687, 1616, 1254 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz,1H), 6.62 (dd, J = 8.5, 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 5.11-5.04 (m, 1H), 3.80 (s, 3H), 2.80 (ddt, J =17.7, 6.4, 1.6 Hz, 1H), 2.67 (dddd, J = 17.4, 11.0, 6.1, 2.4 Hz, 1H), 2.45 (dddd, J = 12.0, 5.7, 3.6, 2.4 Hz,1H), 2.27-2.22 (m, 1H), 1.95-1.79 (m, 1H), 1.70-1.57 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 165.8, 162.9,157.6, 130.1, 126.0, 122.1, 109.1, 108.4, 103.6, 77.2, 70.4, 55.5, 29.3, 22.4, 20.8. LRMS (ESI+): 244.4(M+H)+. HRMS (ESI+) Calculated for C14H14NO3: 244.0974, found: 244.0978.123Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesON OON O HHBr Ag2CO3DMSO, 80 ºC65%O2N O2N2.147e 2.149e9-Nitro-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole (2.149e). The reaction was performed using0.35 g (1.0 mmol, 1 equiv) of bromoisoxazoline 2.147e and 0.58 g (2.1 mmol, 2.1 equiv) of silver carbonate.After purification, 0.17 g (65% yield) of the title compound was obtained as a white powder, mp 195–196◦C. IR (neat): 2968, 1684, 1619, 1499, 1265 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 2.8 Hz, 1H),8.09 (dd, J = 9.1, 2.8 Hz, 1H), 7.03 (d, J = 9.1 Hz, 1H), 5.16 (ddt, J = 9.7, 5.5, 2.1 Hz, 1H), 2.79 (ddt, J= 18.0, 6.5, 1.6 Hz, 1H), 2.64 (dddd, J = 17.6, 11.0, 6.3, 2.4 Hz, 1H), 2.42 (tdd, J = 7.9, 4.2, 2.0 Hz, 1H),2.27-2.17 (m, 1H), 1.84 (ddd, J = 10.7, 6.4, 2.8 Hz, 1H), 1.57 (dddd, J = 13.9, 12.2, 9.6, 2.8 Hz, 1H). 13CNMR (75 MHz, CDCl3) δ 167.5, 160.7, 151.4, 142.0, 127.0, 120.6, 119.1, 116.46, 116.44, 116.40, 115.5,112.0, 71.3, 28.9, 22.1, 20.3. LRMS (ESI+): 259.3 (M+H)+. HRMS (ESI+) Calculated for C13H11N2O4:259.0719, found: 259.0723.ON OON O HHBr Ag2CO3DMSO, 80 ºC34%2.147f 2.149f3,4,5,5a-Tetrahydrobenzo[7,8]xantheno[9,1-cd]isoxazole (2.149f). The reaction was performed using0.27 g (0.8 mmol, 1 equiv) of bromoisoxazoline 2.147f and 0.44 g (1.6 mmol, 2 equiv) of silver carbonate.After purification, 0.069 g (34% yield) of the title compound was obtained as a white powder, mp 186–187◦C. IR (neat): 2940, 1617, 1592, 1526, 1209 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.82 (dd, J = 8.4, 0.6Hz, 1H), 7.79 (dd, J = 8.5, 3.8 Hz, 2H), 7.63 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.44 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.18 (d, J = 9.0 Hz, 1H), 5.19-5.13 (m, 1H), 2.83 (ddt, J = 17.6, 6.3, 1.7 Hz, 1H), 2.70 (dddd, J = 17.3,10.8, 6.1, 2.5 Hz, 1H), 2.49 (dddd, J = 11.7, 5.7, 3.7, 2.1 Hz, 1H), 2.29-2.20 (m, 1H), 1.85 (tddd, J = 14.0,10.5, 6.3, 2.4 Hz, 1H), 1.70 (dddd, J = 14.1, 11.7, 9.3, 2.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 165.0,155.4, 153.7, 132.5, 130.3, 129.6, 128.20, 128.18, 126.5, 124.9, 119.3, 113.1, 109.8, 70.3, 29.3, 22.3, 20.7.LRMS (ESI+): 264.4 (M+H)+. HRMS (ESI+) Calculated for C17H14NO2: 264.1025, found: 264.1024.124Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesOHN OON O HHBrAgOTfDCM, rt21%2.147a 2.150a2-(6,7-dihydrobenzo[d]isoxazol-3-yl)phenol (2.150a). To a solution of bromoisoxazoline 2.147a (0.15g, 0.51 mmol, 1 equiv) in 10 mL of DCM, silver trifluoromethanesulfonate (0.15 g, 0.6 mmol, 1.1 equiv)was added and the reaction mixture was stirred at rt for 16 h. Concentration by rotary evaporation in vacuoproduced a brown oil that after purification using chromatography over silica gel yielded 22.5 mg (21%) ofthe title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H),7.35 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 9.7 Hz, 1H), 5.88(dt, J = 9.2, 4.4 Hz, 1H), 3.00 (t, J = 9.3 Hz, 2H), 2.65-2.58 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 156.8,131.6, 128.5, 125.4, 120.0, 118.6, 117.9, 23.7, 21.3.2.4.5.5 Synthesis of VinylogousamidesN OORaney•NiH2, MeOHquantitative ONH2 OH HR R2.149 2.153Sample Procedure for the Preparation of 9-amino-2,3,4,4a-tetrahydro-1H-xanthen-1-ones (2.153).N OORaney•NiH2, MeOHquantitative ONH2 OH H2.149a 2.153a9-Amino-2,3,4,4a-tetrahydro-1H-xanthen-1-one (2.153a). The reaction was performed using 0.12 g(0.6 mmol) of isoxazole 2.149a and 30 mg of Raney nickel. After purification, 0.12 g (99% yield) of thetitle compound was obtained as a yellow powder, mp 163.5–165.5 ◦C. IR (neat): 3304, 3154, 2942, 1614,1598 cm-1. 1H NMR (400 MHz, CDCl3) δ 10.25 (br s, 1H), 7.45 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (td, J =7.8, 1.2 Hz, 1H), 6.95 (td, J = 7.6, 1.0 Hz, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H), 5.86 (br s, 1H), 4.77 (dd, J =9.5, 5.8 Hz, 1H), 2.35-2.25 (m, 3H), 1.92-1.79 (m, 2H), 1.64-1.53 (m, 1H). 13C NMR (101 MHz, CDCl3)δ 196.2, 157.9, 152.1, 132.8, 123.5, 121.6, 119.3, 117.4, 100.1, 75.3, 37.8, 29.8, 18.6. MS (ESI+) (m/z):216.3 (M+H)+. HRMS (ESI+) Calculated for C13H14NO2: 216.1025, found: 216.1021.125Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesN OORaney•NiH2, MeOHquantitative ONH2 OH HOMe OMe2.149b 2.153b9-Amino-5-methoxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (2.153b). The reaction was performedusing 0.09 g (0.4 mmol) of isoxazole 2.149b and 25 mg of Raney nickel. After purification, 0.09 g (99%yield) of the title compound was obtained as a light yellow thick oil. IR (neat): 3401, 3233, 2944, 1610,1572, 1465 cm-1. 1H NMR (400 MHz, CDCl3) δ 10.28 (br s, 1H), 7.05 (t, J = 4.6 Hz, 1H), 6.92 (d, J =4.5 Hz, 2H), 5.76 (br s, 1H), 4.79 (dd, J = 9.3, 5.9 Hz, 1H), 3.82 (s, 3H), 2.35 (dd, J = 10.6, 5.3 Hz, 3H),1.95 (ddd, J = 24.0, 11.2, 3.1 Hz, 2H), 1.66-1.55 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 196.3, 152.3,148.8, 147.6, 121.3, 120.0, 115.0, 114.5, 99.9, 75.8, 56.1, 37.8, 29.8, 18.6. LRMS (ESI+): 268.4 (M+Na)+.HRMS (ESI+) Calculated for C14H16NO3: 246.1130, found: 246.1126.2.4.6 Intramolecular [3+2] Cycloaddition of N-Benzyl NitronesPhNHOHOOOMeBrOOHOOHNaHCO3Al2O327%NOOMeOPhBrH• HH2.144b 2.164a(2aR,2a1R,5aS,10bS)-2a1-bromo-7-methoxy-1-((S)-1-phenylethyl)-1,2a,2a1 ,3,4,5,5a,10b-octahydro-xantheno[9,1-cd]isoxazole (2.164a) and (2aS,2a1S,5aR,10bR)-2a1-bromo-7-methoxy-1-((S)-1-phenylethyl)-1,2a,2a1,3,4,5,5a,10b-octahydroxantheno[9,1-cd]isoxazole (2.164b). A suspension of 2.144b (2.23 g, 7.2mmol, 1 equiv), (S)-N-(1-phenylethyl)hydroxylammon-ium oxalate (1.81 g, 8.0 mmol, 1.1 equiv) sodiumbicarbonate (0.93 g, 11.1 mmol, 1.4 equiv) and 2 g of neutral alumina in 140 mL of toluene was heated upto reflux temperature and was stirred for 16 h. The reaction mixture was filtered. Concentration by rotaryevaporation in vacuo produced a green thick oil that after purification using chromatography over silica gelyielded 0.95 g (31%) of a mixture of diastereomers plus 0.84 g (27%) of 2.164b as a thick colourless oil.A second that after purification using chromatography over silica gel yielded 0.42 g (14%) of 2.164a as acolourless oil.Data for diastereomer 2.164a: IR (neat): 2940, 1712, 1590, 1488, 1266 cm-1. 1H NMR (400 MHz,CDCl3) δ 7.43 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.1 Hz, 1H), 6.99 (t, J = 7.9 Hz,126Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazoles1H), 6.87 (d, J = 7.6 Hz, 1H), 5.03 (s, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.35 (br s, 1H), 3.88 (s, 3H), 2.30-2.25(m, 1H), 2.22-2.14 (m, J = 4.1 Hz, 1H), 2.07-1.88 (m, 3H), 1.59 (d, J = 6.5 Hz, 4H). 13C NMR (101 MHz,CDCl3) δ 148.8, 145.9, 142.8, 128.3, 127.3, 127.2, 122.1, 121.7, 111.6, 82.3, 80.1, 71.5, 66.8, 62.6, 56.0,25.1, 22.6, 14.2. LRMS (ESI+): 430.2/432.2 (M+H)+. HRMS (ESI+) Calculated for C22H25NO379Br:430.1018, found: 430.1033.Data for diastereomer 2.164b: IR (neat): 2944, 178, 1580, 1474, 1252 cm-1. 1H NMR (400 MHz,CDCl3) δ 7.47 (dd, J = 8.0, 1.5 Hz, 2H), 7.44-7.37 (m, 3H), 6.72 (d, J = 2.1 Hz, 1H), 6.71 (s, 1H), 5.82-5.77(m, 1H), 4.99-4.96 (m, 1H), 4.72 (s, 1H), 4.64 (q, J = 6.4 Hz, 1H), 4.22 (td, J = 2.6, 1.9 Hz, 1H), 3.81 (s, 3H),2.28-2.13 (m, 2H), 2.11-2.02 (m, 3H), 1.69-1.59 (m, 1H), 1.52 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz,CDCl3) δ 148.7, 145.6, 142.2, 128.3, 126.4, 122.2, 121.5, 111.5, 82.3, 80.0, 72.4, 66.1, 64.2, 56.2, 25.4,23.1, 21.5, 14.4. LRMS (ESI+): 430.2/432.2 (M+H)+. HRMS (ESI+) Calculated for C22H25NO379Br:430.1018, found: 430.1015.2.4.7 Miscellaneous SynthesisHOOH HOI+OOIMs2O, Et3NDCM, 40 ºC77%O O2.143 2.199 2.172a2-((2-Iodocyclohex-2-en-1-yl)oxy)-3-methoxybenzaldehyde (2.172a). The reaction was performed us-ing 1.60 g (7.1 mmol, 1 equiv) of 2-iodocyclohex-2-en-1-ol (2.199), 1.98 g (11.0 mmol, 1.5 equiv) ofmethanesulfonic anhydride, 1.5 mL (10.8 mmol, 1.5 equiv) of triethylamine, 3.32 g (21.6 mmol, 3 equiv)of o-vanillin and 3.3 mL (21.6 mmol, 3 equiv) of DBU. After purification, 1.97 g (77% yield) of the titlecompound was obtained as an off-white solid. IR (neat): 2928, 1684, 1672, 1478, 1248 cm-1. 1HNMR (300MHz, CDCl3) δ 10.45 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.04-6.96 (m, 2H), 6.55 (s, 1H), 4.88 (s, 1H), 3.77(s, 3H), 2.13-2.01 (m, 3H), 1.74-1.66 (m, 2H), 1.57 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ 190.3, 152.1,149.9, 143.3, 130.1, 123.5, 118.5, 117.7, 94.9, 80.7, 55.7, 29.6, 29.3, 16.3. LRMS (ESI+): 381.3 (M+Na)+.HRMS (ESI+) Calculated for C14H15O3NaI: 380.9964, found: 380.9960.127Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesHOOH HO+OOMs2O, Et3NDCM, 40 ºC87%O O2.143 1.190 2.172b2-((cyclohex-2-en-1-yl)oxy)-3-methoxybenzaldehyde (2.172b). The reaction was performed using 2.04g (20.8 mmol, 1 equiv) cyclohex-2-en-1-ol (1.190), 5.38 g (30.9 mmol, 1.5 equiv) of methanesulfonic anhy-dride, 4.3 mL (30.9 mmol, 1.5 equiv) of triethylamine, 9.59 g (62.4 mmol, 3 equiv) of o-vanillin and 9.4 mL(61.6 mmol, 3 equiv) of DBU. After purification, 4,20 g (87% yield) of the title compound was obtained as ayellow oil. 1H NMR (300 MHz, CDCl3) δ 10.41 (s, 1H), 7.37 (dd, J = 7.3, 2.0 Hz, 1H), 7.11-7.02 (m, 2H),5.92 (dt, J = 9.8, 3.3 Hz, 1H), 5.79-5.76 (m, 1H), 4.78 (br s, 1H), 3.84 (s, 3H), 2.12-2.06 (m, 1H), 1.98-1.88(m, 2H), 1.86-1.74 (m, 2H), 1.64-1.54 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 191.4, 153.6, 151.1, 133.1,131.1, 126.6, 124.1, 119.1, 118.3, 76.5, 56.4, 29.1, 25.5, 19.1. LRMS (ESI+): 255.4 (M+Na)+. HRMS(ESI+) Calculated for C14H16O3Na: 255.0997, found: 255.0992.NH2 1) NaOH, CS2    DMSO2) 2-Bromocycloheptanone3) HCl, EtOH N SS1) H2O2AcOH2) NaClO480% overfive stepsN SClO42.177 2.178 2.1743-Mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium perchlorate (2.174). A solution of 2,4,6-trimethylamine (5.7 mL, 40.6 mmol, 1.4 equiv) and sodium hydroxide (1.64 g, 41.0 mmol, 1.4 equiv) in 20mL of DMSO was stirred at 0 ◦C for 1 h. To the dark suspension, 2-bromocycloheptanone (5.50 g, 28.5mmol, 1 equiv) was added. The reaction mixture turned into a white slurry upon cooling. It was stirred at rtfor 2 days. The reaction mixture was quenched with 50 mL of water. The suspension formed was heated to100 ◦C, it was then cooled to rt and the solid was removed by vacuum filtration. The solid was suspended in50 mL of ethanol and 2.5 mL of concentrated hydrochloric acid was added. The reaction mixture was heatedup to reflux temperature for 1.5 h. The reaction mixture was cooled to rt and 50 mL of water was added,forming a yellow paste. The yellow paste was then dissolved in 90 mL of glacial acetic acid and 30% v/vhydrogen peroxide (8.3 mL, 80.0 mml, 2.8 equiv) was added. The reaction mixture was stirred at rt for 16 h.The solvent was removed by rotary evaporation in vacuo to produced a white solid. The solid was dissolvedin 15 mL of methanol and a solution of sodium perchlorate monohydrate (12.39 g, 87.3 mmol, 2.9 mmol)in 75 mL of methanol/water 2:1. The reaction mixture was stirred at rt for 16 and a white precipitate was128Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesformed. The product was filtered by vacuum filtration and drying under high vacuum yielded 8.56 g (80%)of the title compound as a white solid over 5 steps. 1HNMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 7.04 (s, 2H),3.12 (t, J = 5.3 Hz, 2H), 2.54 (t, J = 5.6 Hz, 2H), 2.34 (s, 3H), 1.93 (s, 8H), 1.88-1.84 (m, 2H), 1.62 (dd, J= 6.4, 3.5 Hz, 2H). Compound 2.174 had been previously synthesized, see Lebeuf, Hirano, and Glorius 276for further detail.OMeOOOMeOODBU, dioxane120 ºC, 1 h20%N SClO4HH2.172b2.1742.176a5-Methoxy-1,2,3,4,4a,9a-hexahydro-9H-xanthen-9-one (2.176a). A solution of 2.172b (0.23 g, 1.0mmol, 1 equiv), N-heterocyclic carbene precursor 2.174 (81.3 mg, 0.2 mmol, 20 mol%) and DBU (0.07 mL,0.5 mmol, 0.5 equiv) in 4 mL of dioxane under argon atmosphere was stirred at 120 ◦C for 1h. Concentrationby rotary evaporation in vacuo produced a dark thick oil that after purification using chromatography oversilica gel yielded 47 mg (20%) of the title compound as a light yellow oil. IR (neat): 2936, 2860, 1686,1582, 1486, 1256 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.48 (ddd, J = 7.9, 1.6, 0.5 Hz, 1H), 7.04 (dd, J =7.9, 1.4 Hz, 1H), 6.94 (td, J = 7.9, 0.4 Hz, 1H), 4.13 (ddd, J = 12.6, 11.1, 4.5 Hz, 1H), 3.90 (s, 3H), 2.55-2.35 (m, 3H), 1.93-1.71 (m, 3H), 1.37-1.20 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 194.3, 151.6, 148.8,121.7, 120.7, 118.5, 116.5, 81.3, 56.4, 49.6, 32.6, 24.8, 24.0, 23.9. LRMS (ESI+): 233.4 (M+H)+. HRMS(ESI+) Calculated for C14H17O3: 233.1178, found: 233.1174.OMeOOOMeOODBU, dioxane120 ºC, 1 h20%N SClO4Br2.144b2.1742.176b5-methoxy-2,3,4,4a-tetrahydro-9H-xanthen-9-one (2.176b). A solution of 2.144b (0.32 g, 1.0 mmol,1 equiv), N-heterocyclic carbene precursor 2.174 (0.13 g, 0.4 mmol, 40 mol%) and DBU (0.12 mL, 0.8mmol, 0.8 equiv) in 4 mL of dioxane under argon atmosphere was stirred at 120 ◦C for 1h. Concentration byrotary evaporation in vacuo produced a dark thick oil that after purification using chromatography over silica129Attempts to Access the AB and DEF Rings of Simaomicin α: Synthesis of Isoquinolinones and TetracyclicIsoxazolesgel yielded 0.10 g (43%) of the title compound as a light yellow oil. IR (neat): 2942, 1690, 1584, 1478, 1248cm-1. 1H NMR (300 MHz, CDCl3) δ 7.49 (dd, J = 7.8, 1.7 Hz, 1H), 7.09-7.06 (m, 1H), 6.98 (dd, J = 8.0,1.6 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 4.93 (ddd, J = 8.3, 5.4, 2.6 Hz, 1H), 3.82 (s, 3H), 2.37-2.22 (m, 3H),1.99 (tdd, J = 12.4, 8.9, 3.4 Hz, 1H), 1.89-1.81 (m, 1H), 1.70-1.58 (m, 1H). 13C NMR (75 MHz, CDCl3) δ181.9, 151.6, 148.8, 139.5, 133.8, 122.8, 121.1, 119.0, 116.6, 75.9, 56.2, 28.7, 25.8, 19.5. LRMS (ESI+):231.4 (M+H)+. HRMS (ESI+) Calculated for C14H14O3: 230.0943, found: 230.0948.130Chapter 3Synthesis of Tetrahydroxanthones:4-Dimethylaminopyridine-PromotedCycloisomerizationsThe synthesis of tetrahydroxanthones could be carried out in different ways. It has been observed thatsome literature approaches start with a chromenone derivative possessing two of the three-membered ringspresent in the desired tetrahydroxanthone (exemplified by rings D and E in 3.1), and build the partially hy-drogenated ring of the tetrahydroxanthone unit (ring F of the tetrahydroxanthone) through a cycloadditionreaction (route a).22,23,141,142 Complimentary, some other approaches to the tetrahydroxanthone unit startwith a carbonyl functionality attached to an aromatic ring (exemplified by ring D in 3.2) and construct thepyranone ring (ring E of the tetrahydroxanthone) through coupling with a cyclohexenone derivative (ex-emplified by ring F in 3.3), which constitutes the partially saturated ring of the tetrahydroxanthone (routeb).145,147,149,155,156,161,169 As outlined in Figure 3.1a, the approaches towards the synthesis of tetrahydroxan-thones that have been reported in the literature involve the formation of one of the three six-membered ringspresent in the tetrahydroxanthone unit. In contrast, our approach considers a compound exemplified by 3.4,where it is proposed that both rings E and F of the tetrahydroxanthone unit would be constructed in the samereaction vessel through a tandem cycloisomerization reaction (Figure 3.1b). Importantly, the addition acrossthe alkyne, followed by C–O and C–C bond formation, has to be regioselective.131Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOOOO OR2OOOOO OR2O OHOR2+OOOOHOR2(a)(b)D E FD E D FD E F D E FDR R RR R RR1 R1 R1δ+δ-δ-δ+routearoutebTetrahydroxanthoneTetrahydroxanthone-t Tetrahydroxanthone-c3.1 3.2 3.33.4Figure 3.1. a) Literature approaches for the synthesis of tetrahydroxanthones. b) Our approach totetrahydroxanthones to build the E and F rings in the same reaction vessel.The intramolecular addition of phenolic nucleophiles to alkynes is well established in the literature.286–290Themode of cycloaddition can be either 5-exo-dig to produce benzofuran derivatives, or 6-endo-dig to affordbenzopyran derivatives. Examples of both types of cycloisomerization are presented in Figure 3.2.The synthesis of chromenones and flavones, 2-arylchromenones, has been demonstrated through in-tramolecular oxa-Michael addition of o-propioloylphenol derivatives. Occasionally, the cycloisomerizationproduces mixtures of chromenones, 6-endo-dig product, and aurones, 5-exo-dig product (Scheme 3.1).291OHOPhPPh3 (10 mol%)DMF, rtOOPh42 58OOPh:+3.17 3.18 3.19Scheme 3.1. Cycloaddition of o-alkynoylphenol derivatives can sometimes produce a mixture of 6-endo-dig and 5-exo-dig products.In general, the cycloisomerization of phenols to ynones has been achieved using three types of promoters:acid/base promoters, nucleophilic/electrophilic promoters, and catalytic metal promoters. The three generalapproaches for the synthesis of chromenones through intramolecular cyclization of phenolic nucleophiles toynones will be described in detail in the following section.132Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsPhNHTsPh+OHZnCl2 (10 mol%)TMSCl (50 mol%)DCE, 70 ºC, 45% OHPhPh OPhPhOTBSOHNBoca) BF3•Et2O (5 mol%)CH3CN, rtb) TBAF, rt to reflux74%TMS+ O NBocOHNOOHAgNO3, CH3CN110 ºC44%ONOHO5-exo-dig cyclizationBrOHPhPh[Cp*RuClL*]2 5 mol%NH4BF4 10 mol%DCE, 60 ºC52%BrOPhPhOPhOPiv L*(AuCl)2 5 mol%AgSbF6 10 mol%CH3CN, rt74%, 97% ee OOPiv6-endo-dig cyclization123 4 5123 4 5123 4 5123 4 5 61234 56Ph3.5 3.6 3.7 3.83.9 3.103.11 3.123.13 3.143.15 3.16Figure 3.2. Intramolecular addition of phenolic nucleophiles to alkynes, 5-exo-dig vs 6-endo-dig modeof cyclization.286–2903.1 Reported Cycloisomerizations of Phenolic Nucleophiles to Ynones3.1.1 Synthesis of Chromenones Using Basic or Acidic ConditionsMiranda and co-workers reported a synthesis of chromenones via intramolecular oxa-Michael addition ofphenols to conjugated ynones in the presence of para-toluenesulfonic acid or potassium carbonate (Scheme 3.2).133Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsButynoate 3.20 was transformed into o-alkynoylphenol derivative 3.21 through a photo Fries rearrangement.The cycloisomerization of 3.21 was performed using either para-toluenesulfonic acid in dichloromethane orpotassium carbonate in acetone to produce chromenone 3.22 in quantitative yield.292MeOO Ohν, hexanesrt52%MeOOHO p-TsOH, DCMorK2CO3, acetonequantitativeMeOOO3.20 3.21 3.22Scheme 3.2. Synthesis of chromenones from o-alkynoylphenol derivatives using either para-toluenesulfonic acid or potassium carbonate.292The authors expressed that one of their main concerns was the potential for formation of a benzofuranonederivative through a 5-exo-dig mode of cyclization (Scheme 3.3). The intramolecular oxa-Michael additionappeared to proceed through the 6-endo-dig mode of cyclization exclusively, which the authors rationalizedwas favoured by the ynone function.MeOOHOMeOOOMeOnot observedOO5-exo-dig6-endo-dig123 45 63.213.233.22Scheme 3.3. Possible modes of cyclization of ynone 3.21. Indanone 3.23 was not observed.In 1990, Muckensturm and co-workers reported a synthesis of chromenones from substituted o-alkynoyl-phenol derivative 3.25 and sodium methoxide (Scheme 3.4). Compound 3.25 was prepared from 2-hydroxy-5-methoxybenzaldehyde (3.24). Protection with methylthiomethyl chloride (MTMCl) was followed by theaddition of the lithium anion of 1-hexyne. Oxidation of the putative propargyl alcohol to the ynone specieswas followed by deprotection of the methylthiomethyl (MTM) group to afford compound 3.25 in 65% yieldover four steps. o-Alkynoylphenol derivative 3.25 was cycloisomerized using catalytic sodium methoxide inanhydrous methanol to form chromenone 3.26. The 6-endo-dig cycloisomerization proceeded smoothly in75% yield and it was observed that no 5-exo-dig cycloisomerization product had been formed (Scheme 3.4).293The authors did not report investigation of the effect of milder or stronger bases in catalytic or stoichiometricamounts.134Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOHOnBuMeO NaOMeMeOH75% OOMeOnBuOHOMeO H1) MTMCl2) nBuCCLi, THF3) PDC, DCM4) HgCl2, CH3CN            65%3.24 3.25 3.26Scheme 3.4. Synthesis of chromenones from o-alkynoylphenol derivatives using sodium methoxide.293In 2011, Doi and co-workers studied the effect of different Brønsted acids in the cycloisomerization ofo-alkynoylphenol derivative 3.17 to form flavone 3.18 (Scheme 3.5). Weak acids such as formic acid (pKa =3.77) or acetic acid (pKa = 4.76) did not promote the cycloisomerization. Somewhat stronger acids such astrifluoroacetic acid (TFA) (pKa = 0.23), camphorsulfonic acid (CSA) (pKa = 1.20), and p-TsOH (pKa = -2.80)were similarly ineffective. However, when strongly acidic bis(trifluoromethane)sulfonimide (Tf2NH) (pKa= -11.9 in DCE) was used, the 6-endo-dig product was obtained in 5% yield after 24 h. Trifluoromethanesul-fonic acid (TfOH) (pKa = -12.0) was highly effective as the cycloisomerization produced chromenone 3.18in 80% yield after 10 h of reaction time. No 5-exo-dig product was observed by 1H NMR.291OHOPh40 ºC, DCE 12 h90%OOPhTfOH, DCErt, 24 h41% OHOPhOTfTfOH, DCE, 40 ºC, 10 h80%3.173.273.18Scheme 3.5. Chromenone synthesis: Cycloisomerization of o-alkynoylphenol derivatives usingTfOH.291When o-alkynoylphenol derivative 3.17 was treated with stoichiometric trifluoromethanesulfonic acid(TfOH) at room temperature for 24 h, vinyl triflate 3.27 (41% yield) and chromenone 3.18 (23% yield) wereisolated. Triflate 3.27 was then heated to 40 ◦C for 10 h to produce chromenone 3.18 in 90% yield. The au-thors postulated that vinyl triflate 3.27 was formed via 1,4-addition of trifluoromethanesulfonic acid (TfOH)through “coordination with the carbonyl group”, and that the cycloisomerization produced chromenone 3.18exclusively due to the formation of the vinyl triflate 3.27 intermediate.291135Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations3.1.2 Synthesis of Chromenones Using Electrophiles or NucleophilesIn 2006, Larock and co-workers reported a synthesis of chromenones using o-alkynoylanisole derivative3.29. The o-alkynoylanisole derivative was prepared from 2-methoxybenzaldehyde (3.28) in two steps inquantitative yield. The cycloisomerization of 3.29 was performed using 1.5 equiv of iodine(I) chloride inDCM at either -78 ◦C or room temperature to yield 3-iodo chromenone 3.30 in 96% yield (Scheme 3.6).294OMeOPhICl (1.5 equiv)DCM, 96%OOPhOMeOPhLiH1)2) MnO2, CHCl3     quantitativeI3.28 3.29 3.30Scheme 3.6. Chromenone synthesis via oxa-Michael addition using iodine(I) chloride.294The authors proposed that the cyclization proceeded through the formation of vinyliodonium intermediate3.31, whichwas attacked by the oxygen atom of themethyl phenyl ether forming methyl oxonium species 3.32.The demethylation of 3.32, required to obtain iodochromenone 3.30, occurred through the attack of chlorideion from ICl (Scheme 3.7). The presence of the iodine atom was used to further elaborate the chromenone atposition C-3 with subsequent palladium-catalyzed processes. This method was useful to obtain either sulfuror nitrogen-containing heterocycles as well.OMeOPh OOPhIIClOMeOPhIOClOIPhMeCl3.28 3.31 3.32 3.30Scheme 3.7. Reaction mechanism for the synthesis of iodochromenone 3.30.294Of the 30 examples presented by Larock and co-workers, seven substrates did not have an aromatic ringdirectly attached to the triple bond. From these, three contained a cyclohexenyl group as the substituent,and the remaining four featured aliphatic substituents. When the aliphatic substituent was methoxymethyl(3.33), the cyclization failed, and addition of iodine(I) chloride across the triple bond was observed instead(Scheme 3.8).294 This transformation is therefore limited to substrates with bulky or aromatic substituentsattached to the alkyne. For the synthesis of the tetrahydroxanthone moiety embedded in simaomicin α, it isrequired to have a protected hydroxyl group adjacent to the triple bond. Thus, it is unlikely that this methodwould be useful for the synthesis of 1,4-dioxygenated tetrahydroxanthones.136Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOMeOICl (1.5 equiv)DCM, 90%OOMeClIOMeOMe3.33 3.34Scheme 3.8. Addition of ICl across the alkyne of ynones with electron rich substituents attach to thealkyne.294In 2011, Doi and co-workers reported the synthesis of flavones from o-propynoylphenol derivatives us-ing nucleophiles known to promote Morita-Baylis-Hillman processes (Table 3.1).295 DABCO produced amixture of 6-endo-dig (flavone 3.18) and 5-exo-dig products (aurone 3.19) in a 93:7 ratio, where flavone3.18 was obtained in 72% yield (entry 1). Tributylphosphine and triphenylphosphine were worse promotersthan DABCO as the yield of flavone 3.18 was 31% and 19%, respectively (entries 2 and 3). However, whentributylphosphine was used, the regioselectivity of the cycloisomerization was reversed favouring the 5-exo-dig product (24:76 ratio, 3.18:3.19). Tricyclohexylphosphine was a slightly better promoter than DABCO,rendering the regioisomeric mixture in 94:6 ratio, producing flavone 3.18 in 89% yield (entry 4). DMAPwas the best promoter tested as its use resulted in formation of the 6-endo-dig cyclization product 3.18 in96% yield (entry 5).295Table 3.1. Intramolecular cycloisomerization of o-alkynoylphenols promoted by nucleophiles.295OHOPhconditionsOOPh OOPh+3.17 3.18 3.19entry nucleophile t (h) ratio 3.18:3.19a 3.18 yield (%) b1 DABCO 3 93:7 722 Ph3P 3 42:58 313 nBu3P 3 24:76 194 Cy3P 3 94:6 895 DMAP 1.5 >99:1 96The reactions were performed using 10 mol% of the nucleophile in DMF atroom temperature.a The ratio of 3.18 and 3.19 was determined on the basis of 1H NMR of thecrude products. b Isolated yieldDifferent solvents were screened for the DMAP-catalyzed cycloisomerization using optimized condi-tions. Polar aprotic solvents such as DMF, DMSO, and acetonitrile (entries 1–3), favoured the formationof the 6-endo-dig cyclization product in good yield >75% and excellent ratios (>94:6). Solvents such as137Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsTHF, 1,4-dioxane, and dichloroethane (DCE) (entries 4–6) also favoured the 6-endo-dig cyclization productin good yield >84% and excellent ratios (>92:8), but the cycloisomerizations required a longer reaction time(16 to 24 h). Although toluene still favoured the formation of the 6-endo-dig cyclization product, a significantamount of 5-exo-dig cyclization product was observed (entires 7).Table 3.2. DMAP-promoted cycloisomerization of o-alkynoylphenol derivatives: solvent effect.295OHOPhDMAP (10 mol%)solvent, 30 ºCOOPh OOPh+3.17 3.18 3.19entry solvent t (h) ratio 3.18:3.19a % yield of 3.18b1 DMF 3 >99:1 962 DMSO 3 98:2 933 CH3CN 3 94:6 754 THF 16 92:8 845 1,4-dioxane 24 93:7 876 (CH2Cl)2 16 98:2 917 PhH 22 90:10 81a The ratio was determined based on the 1H NMR of the crude mixture.b Isolated yield.3.1.3 Synthesis of Chromenones Using Metal CatalysisThe metal-catalyzed cycloisomerization of o-alkynoylphenol derivatives into chromenones has also beeninvestigated. In 2008, Pale and co-workers developed a methodology for the synthesis of aurones from 2-(1-hydroxyprop-2-ynyl)phenols such as 3.35. The authors found that treatment of 3.35 with gold(I) chloride(1 mol%) and potassium carbonate (1 mol%) afforded auronol 3.36 (5-exo-dig cyclization product) in 86%yield (Scheme 3.9). In this instance, the 6-endo-dig cyclization product was not observed.However, when o-alkynoylphenol derivative 3.17 was treated with 10 mol% of each gold catalyst andbase, no 5-exo-dig cyclization product was produced and only traces of the 6-endo-dig cyclization productwere detected by 1HNMR.When the cycloisomerization was repeated in the absence of potassium carbonate,chromenone 3.18 was obtained exclusively, albeit in 38% yield.Gouault and co-workers reported a different synthesis of substituted chromenones using gold(I) catalysis.The authors used either allyl or benzyl ether o-alkynoylphenol derivatives to perform the 6-endo-dig cycliza-tion. After screening different additives, the authors found that the optimal conditions to perform the cy-cloisomerization were (triphenylphosphine)gold(I) chloride (10 mol%)/silver hexafluoroantimonate(V) (10138Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOHOPhAuCl (10 mol%)CH3CN, rt, 24 h38% OOPhOHOHPhAuCl (1 mol%)K2CO3 (1 mol%)CH3CN, rt, 30 h86% OOHPhOHOPh OOPhAuCl (10 mol%)K2CO3 (10 mol%)CH3CN, rt, 24 htraces3.35 3.363.173.173.183.18Scheme 3.9. Gold(I)-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenol (3.35) and o-alkynoylphenol 3.17. 5-Exo-dig vs 6-endo-dig cyclizations.296mol%) in DCE at 50 ◦C. A remarkable feature of this transformation was the transfer of the alkyl group fromthe oxygen of the aryl ether to the carbon at position C-3 in the product (Scheme 3.10).297OBnOnPrPPh3AuCl (10 mol%)AgSbF6 (10 mol%)DCE, 50 ºC, 0.5 h45% OOnPrBnOMe OMe3.37 3.38Scheme 3.10. Cycloisomerization of o-alkynoylphenol derivatives using (triphenylphosphine)gold(I)chloride.297Although the transformation presented by Gouault and co-workers involved the migration of the sub-stituent from the oxygen atom to a carbon atom, the group transfer was limited to allyl, benzyl or 4-chlorobenzylethers. If the cycloisomerization conditions were used on an ethyl ether derivative, the cycloisomerizationwas completely inhibited. However, if the PMB ether derivative was used, the 6-endo-dig cyclization didoccur, but the migration of PMB was not observed and instead a hydrogen atom was present at position C-3in the product (Scheme 3.11). No experiments were performed with unprotected phenols and no commenton the reactivity of these species was made.OOnPrEtOMeXOEtO nPr PPh3AuCl (10 mol%)AgSbF6 (10 mol%)DCE, 50 ºC, 0.5 hOMeOPMBOnPrPPh3AuCl (10 mol%)AgSbF6 (10 mol%)DCE, 50 ºC, 0.5 h27% OOnPrHOMe OMe3.393.39 3.403.40Scheme 3.11. Gold(I)-catalyzed cycloisomerization of ynones with different alkyl ethers.297139Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsWhile developing amethodology to access substituted 2,3-dihydro-4H-pyran-4-ones using palladium(II),Gouverneur and co-workers synthesized chromenone 3.45 in 50% yield. The process, as described by theauthors, involved an intramolecular Wacker addition of the phenol to the alkyne, forming palladium interme-diate 3.44. The palladium intermediate reacted with ethyl acrylate in a Heck process to produce disubstitutedchromenone 3.45 (Scheme 3.12).298 No other chromenones were synthesized using this approach.OHO (MeCN)2PdCl2Cu(OAc)2•H2OPPh3, LiBrDME, O2, 65 ºC50% OOPdLnXCO2EtOOCO2Et3.43 3.44 3.45Scheme 3.12. Palladium(I)-catalyzed cycloisomerization of o-alkynoylphenol derivatives.298Based on precedents for the synthesis of chromenones, it was proposed that 1-hydroxyl substitutedtetrahydroxanthones may be synthesized through the cycloisomerization of o-alkynoylphenol derivativessuch as 3.48 (Scheme 3.13). A main feature of our approach is the construction of the E and F rings, form-ing a C–O bond, a C–C bond and stereogenic centre in the same reaction vessel. It was considered that thehydroxyl group at position C-1 of the tetrahydroxanthone could be obtained from the attack of a putativecarbanion to an aldehyde functionality. Three pathways to perform the cycloisomerization were considered:metal-mediated, base-induced and nucleophile-induced processes.Carbophilic metal-ligand species, perhaps palladium(II), gold(I), rhodium(I) or related metals, could acti-vate the alkyne for nucleophilic addition to yield complex 3.49. The activated species 3.49 may then undergoa formal oxymetallation to obtain intermediate chromenone 3.50. In principle, the C–M bond could add tothe aldehyde function to produce tetrahydroxanthone 3.55. The efficiency of the addition to the carbonylspecies would strongly depend on the character of the C–M bond.299–302 Alternatively, treatment of ynone3.48 (R = H) with a base would generate phenoxide species 3.51, which could undergo an intramolecularanionic oxa-Michael addition to yield chromenone carbanion 3.52 that could react with the aldehyde func-tionality to obtain the desired tetrahydroxanthone upon work up. It was also considered that treatment of3.48 with a nucleophile could, in principle, furnish Morita-Baylis-Hillman-type adduct (3.53), which wouldbe activated for an oxa-Michael addition of the phenol species to yield enolate 3.54. Elimination of thenucleophile, initiated by the enolate, should furnish the desired tetrahydroxanthone 3.55.140Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOHOacidic or basic conditions,metal catalysis,nucleophiles OOR R (a)(b)knownsyntheses of chromenonesproposedroutes to synthesizetetrahydroxanthonesOOORMn+OOOMn+OPG OPGRMn+OHOO OPGOOOOOOPG OPGOOOHOR1BaseR = HOOOOOOROPGONu NuNu:OPGRRD E FD EDDD EDD F D E F3.46 3.473.483.49 3.503.51 3.523.53 3.543.55Scheme 3.13. (a) Reported routes to synthesize chromenones from phenoxyynones. (b) Proposedroutes to synthesize tetrahydroxanthones from o-alkynoylphenol derivatives.3.2 Synthesis of o-Alkynoylphenol Derivatives 3.65a and 3.65bo-Alkynoylphenol derivatives were required to attempt the cycloisomerization to obtain the desired tetrahy-droxanthones. It was envisioned that o-alkynoylphenol derivatives such as 3.56 could be obtained from thedouble oxidation of compound 3.57, which may be obtained by the addition of the dianion of 5-hexyn-1-olto a salicylaldehyde derivative (3.58, Scheme 3.14).O OOHHOH OHOHO OHOHH +R R R3.56 3.57 3.58 3.59Scheme 3.14. A retrosynthetic analysis for the synthesis of o-alkynoylphenol derivatives 3.56.141Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationso-Vanillin was chosen as the precursor for the D ring of the tetrahydroxanthone due to its oxygenationpattern. A halogen substituent in the aromatic ring of the reaction substrate is a versatile synthetic tool sincecross-coupling can be used for further functionalization. o-Vanillin (2.143) was brominated in 93% yieldfollowing literature procedures (3.60).303HOOHOBrHOOHOBr2, KBrAcOH, H2Ort, 93%2.143 3.60Scheme 3.15. Synthesis of 5-bromo o-vanillin.303The dianion derived from 5-hexyn-1-ol, prepared in situ, was added to an equimolar mixture of o-vanillin(2.143) and n-butyllithium to obtain compound 3.61 in 30% yield. A variety of oxidation methods (Swern,pyridinium chlorochromate, and manganese(IV) oxide296) failed to produce o-alkynoylphenol derivative3.62a.O OOHOHXOHOHOHOOOHO5-hexyn-1-ol,BuLiTHF30%conditionsH2.143 3.61a 3.62aScheme 3.16. Attempt to synthesize o-alkynoylphenol derivative 3.62a.Protection of the phenol function in o-vanillin and 5-bromo o-vanillin should enable the synthesis of o-propynoylphenol derivatives 3.62a and 3.62b (Scheme 3.17). o-Vanillin wasmixed with potassium carbonatein DMF at room temperature for several hours and methoxymethyl chloride was then added over 30minutes togenerate 3.63a in 97% yield. Rapid addition of methoxymethyl chloride (MOMCl) produced a methyl ether.Addition of the dianion of 5-hexyn-1-ol, generated in situ, to methoxymethyl (MOM) ether 3.63a produceddiol 3.64a in 96% yield. The structure of the diol was confirmed from its 1HNMR spectrum, showing a tripletat δ 5.79 ppm (J = 1.9 Hz), which was assigned to the C–H at position C-1 and the peaks for the four CH2hydrogen atoms of the alkyl chain at δ 3.63 (t, J = 6.1 Hz, 2 H), 2.31 (dt, J = 2.0, 6.8 Hz, 2 H) and 1.72–1.56(m, 4 H) ppm. Diol 3.64a was oxidized using Swern conditions to produce dicarbonylic compound 3.65a in77% yield. The identity of the dicarbonylic compound was corroborated by its 13C NMR spectrum, whichshowed characteristic signals at δ 201.2 ppm and δ 177.1 ppm for each of the carbonylic carbon atoms. The142Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsMOM protecting group was removed using para-toluenesulfonic acid in DCM at room temperature to formo-alkynoylphenol derivative 3.62a in 42% yield. The 1H NMR spectrum of 3.62a exhibited a distinctivesinglet at δ 11.91 ppm, which disappeared by treatment with D2O.OH OHOO OOOO R; R=H, X=HO OOO OO OOHO5-hexyn-1-olBuLiTHF-78 C to rtO OOO OCOCl2DMSOEt3NDCM-78 ºC to rtp-TsOHDCMrtX X XXXMOMCl, K2CO3DMF, rt; R=MOM, X=H, 97%; R=H, X=Br; R=MOM, X=Br, 95%, 96%, 97%, 77%, 60%, 42%, 72%H2.1433.603.63a3.63b3.64a3.64b3.65a3.65a3.65b3.65b3.62a3.62bScheme 3.17. Synthesis of o-alkynoylphenol derivatives 3.62a and 3.62b.Substrate 3.62b was constructed in a similar manner from 5-bromo o-vanillin (3.60, Scheme 3.17). Theprotection of 3.60 as itsMOMether was achieved using potassium carbonate andMOMCl. The incorporationof the MOM group was confirmed by 1H NMR analysis; the signal corresponding to the CH2 of the acetalappeared at δ 5.21 ppm as a sharp singlet, while the signal corresponding to the methyl ether appeared at δ3.63 ppm as a sharp singlet. Addition of the dianion of 5-hexyn-1-ol to 3.63b produced diol 3.64b in 97%yield. Characteristic signals at δ 5.73 ppm, assigned to the C–H at the benzylic position, and δ 3.67-3.60(m, 2H), 2.31 (dt, J = 2.0, 6.8 Hz, 2H), and 1.72-1.56 (m, 4 H) ppm, assigned to the four CH2 of the alkylchain confirmed the identity of 3.64b. Oxidation of the diol using Swern conditions afforded ynone 3.65bin 60% yield. The oxidation product was identified by a singlet at δ 9.76 ppm in the 1H NMR spectrumand two signals at δ 201.1 and 175.8 ppm in its 13C NMR spectrum, corresponding to the carbonylic carbonatoms. Catalytic p-TsOH in DCM at room temperature cleaved the MOM ether to produce o-alkynoylphenolderivative 3.62b in 72% yield. A characteristic sharp singlet in the 1H NMR spectrum of 3.62b at δ 11.82ppm that exchanged with D2O allowed for the identification of the product.143Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations3.3 Synthesis of o-Alkynoylphenol Derivatives 3.75a, 3.75b, and 3.75cSubstrates that incorporated protected hydroxyl functionalities into the F ring of the tetrahydroxanthone werehighly desirable. A convergent disconnection strategy to o-alkynoylphenol derivative 3.66 is presented inScheme 3.18. It uses alkyne 3.68 and aldehyde 3.69 as the two main building blocks to construct 3.66. Akey element of this strategy is the projected oxidation of the two hydroxyl functional groups in 3.67 to producepotentially sensitive aldehyde and conjugated ynone 3.66.OOHO OPG4O OHOPG1O OPG4OHOPG2OPG1OOOPG3OOPG1OHOHOH1 234 5673.66 3.673.683.693.633.70Scheme 3.18. A retrosynthetic analysis of o-alkynoylphenol derivative 3.66a.The synthesis of o-alkynoylphenol derivatives 3.66a, 3.66b, and 3.66c was accomplished starting withthe methoxymethyl ethers of o-vanillin 3.63a and bromo o-vanillin 3.63b (Scheme 3.19). The addition ofsodium acetylide to 3.63awas followed by alcohol protection using tert-butyl(chloro)dimethylsilane (TBSCl)to obtain 3.71a in 59% yield. Spectral evidence for the incorporation of the alkyne included a signal at δ 2.49ppm (d, J = 2.1 Hz, 1 H), while the evidence for the incorporation of the TBS group included the signals atδ 0.95 (s, 9 H), 0.20 (s, 3 H), and 0.12 (s, 3 H) ppm.The terminal alkyne of 3.71a was deprotonated using LDA in THF at -78 ◦C, this carbanion was added to4-tert-butyldimethylsiloxybutanal (3.72) to form compound 3.73a in 86% yield. The identity of the productwas supported by its 1H NMR spectrum (s, 5.91 ppm), corresponding to the C–H at position C-1. Thesignal corresponding to the C–H at position C-4 was observed as a broad singlet at δ 4.37 ppm. The threeCH2 of the alkyl portion appeared at δ 3.68-3.60 (m, 2 H) and 1.80-1.54 (m,4H). Standard protection anddeprotection sequences, benzylation and tetrabutylammonium fluoride (TBAF)-induced silyl cleavage, gavediol 3.67a that could be readily oxidized using Swern conditions to produce dicarbonylic compound 3.75ain 70% yield over three steps (Scheme 3.19). This compound required triethylamine-washed silica gel forpurification. The structure of the desired ynone 3.75a was supported by its NMR analysis. A characteristicsignal at δ 9.76 ppm was observed in the 1H NMR spectrum, while the 13C NMR spectrum showed signals144Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsat δ 201.2 and 176.7 ppm for each of the carbonyl carbon atoms. Only one methine (C–H) signal at δ 4.41ppm (triplet J = 6.1 Hz) was observed in the 1H NMR spectrum and it was assigned to the hydrogen atomat C-4. Deprotection of the MOM group was performed using para-toluenesulfonic acid in DCM to obtaino-alkynoylphenol derivative 3.66a in 94% yield. The phenol exhibited a sharp singlet at δ 11.81 ppm thatexchanged with D2O.OTBSHOOOOTBSOOOOTBSOHHOOMOMOa) NaCCHb) TBSClTHFOTBSO+LDA, THF-78 ºC to rtOTBSOOOOTBSNaH, BnBrTHFOHOOOOHOBnTBAF4Å MSTHFOOOOOOBn(COCl)2DMSOEt3N, DCM-78 ºC to rtX X X, X=H, X=Br, X=H, 59%, X=Br, 52%, X=H, 86%, X=Br, 54%, X=H, 99%, X=Br, 92%, X=H, 99%, X=Br, 83%, X=CCH, 82%, X=H, 70%, X=Br, 34%, X=CCH, 64%X XXOOHOOOBnp-TsOH•H2ODCM, rt, X=H, 94%, X=Br, 76%, X=CCH, 73%XOBn, X=CCTMS, 87%TMSCuI, (Ph3P)4PdiPr2NH1 234 5673.63a3.63b3.71a3.71b3.72 3.73a3.73b3.733.74a3.74b3.74c3.67a3.67b3.67c3.75a3.75b3.75c3.753.66a3.66b3.66cScheme 3.19. Synthesis of o-alkynoylphenol derivatives 3.66a, 3.66b, and 3.66c.o-Alkynoylphenol derivatives 3.66b and 3.66c were constructed in a similar manner from 3.63b. Thesynthesis of o-alkynoylphenol derivative 3.74c started from triprotected triol 3.74b. Sonogashira cross-coupling between 3.74b and trimethylsilylacetylene using catalytic tetrakistriphenylphosphinepalladium(0)and copper(I) iodide in diisopropylamine afforded 3.74c in 87% yield. Spectral evidence for the coupling oftrimethylsilylacetylene included a signal corresponding to the trimethylsilyl (TMS) group at δ 0.29 ppm inits 1H NMR spectrum and two signals at δ 105.3 and 93.3 in its 13C NMR spectrum.The use of a tert-butyldimethylsilyl ether to protect the propargyl alcohol rather than a trimethylsilylether was critical as silicon ether migration readily occurred during the benzylation process when the smallersilicon protecting group was used (Scheme 3.20). The structure of compound 3.79 was obtained from its 1HNMR spectrum, which showed that the signals for the two methylene hydrogen atoms (positions α and β to145Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsthe aldehyde) appeared as two triplets. A combination of COSY and HMBC techniques showed that bothmethylene signals at δ 2.95 and 2.82 ppm were coupled to each other and also exhibited correlation to thetwo carbonyl carbon atom signals (Scheme 3.20).OTMSOOOOTBSOHOBnOOOOTBSOTMSNaH, BnBrTHF, 90%OBnOOOOHOHTBAF, MSTHF, 98%OBnOOOOHOHOBnOOOOO(COCl)2, DMSOEt3N, DCM-78 ºC, 88%H H1 43.76 3.773.783.783.79Scheme 3.20. Synthesis of ynone 3.79, the arrows indicate HMBC correlations.Amine 3.73d was obtained as a byproduct in 9% yield from the synthesis of compound 3.73b. The iden-tity of the compound was established by analysis of its 1H NMR spectrum, which showed the characteristicsignals for an N,N-diisopropyl aniline at δ 1.15 and 3.68 ppm. It is believed that propargyl alcohol 3.73dwas produced by nucleophilic aromatic substitution of the aromatic bromide through an elimination additionmechanism (Scheme 3.21).OTBSOOOBrNOTBSOOONHOTBSOOONHOTBSO OOTBSOHOTBS3.73b 3.80 3.73dScheme 3.21. Mechanistic rationale for the conversion of 3.73b into 3.73d via benzyne.Propargyl alcohol 3.73d was manipulated as shown previously for 3.73a, 3.73b, and 3.73c. Protectionas the benzyl ether was achieved using sodium hydride, obtaining 3.74d in 69% yield. Deprotection of thetert-butyldimethylsilyl groups was performed in 94% yield using TBAF. The oxidation of diol 3.67d wasperformed using Swern conditions and 3.75d was obtained in 74% yield. However, when the MOM groupwas deprotected using catalytic para-toluenesulfonic acid in DCM at room temperature, o-alkynoylphenolderivative 3.66d could not be obtained (Scheme 3.22).146Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsXOTBSOOOOBnOTBSNOHOOOOBnOHNOOOOOBnONOHOOOOBnOHNNaH, THF69%TBAFTHF94%COCl2DMSOEt3N74%p-TsOHDCMOTBSOOOOTBSOHNOOHO OBnON3.73d 3.74d3.67d3.67d3.75d 3.66dScheme 3.22. Attempt to synthesize o-alkynoylphenol derivative 3.66d.3.4 Synthesis of Polyoxygenated Tetrahydroxanthones3.4.1 Cycloisomerization of Methoxymethyl Ethers 3.65a and 3.75aWe were interested in the cycloisomerization of MOM ethers 3.65a and 3.75a using either Lewis, Brønstedor carbophilic π acids. It was considered that coordination of a Lewis acid with the lone pairs of the oxygenatom of the ynone functionality would activate the latter towards nucleophilic addition, thereby inducing acycloisomerization (Scheme 3.23).O OOROO OOOLewisAcidRLA, R=MOM, R=HTiCl4, 50%or(+)-CSA, 90%δ+ δ- OOOorOOOOHOOOORLAδ+δ-OR3.65a3.62a3.81a 3.82a 2.166a 3.83aScheme 3.23. Proposed cycloisomerization of compound 3.65a promoted by Lewis acids.Treatment of 3.65a with 1.1 equiv of titanium(IV) chloride generated o-alkynoylphenol derivative 3.62aas the only product in 50% yield (cleavage of the MOM group). When Brønsted acid (+)-CSA (15 mol%)was used, 3.62a was obtained in 90% yield. A consideration for our strategy to construct the tetrahydrox-anthone core through 6-endo-dig cyclization of phenol derivatives to ynones involved the activation of thealkyne of MOM ether 3.75a using a carbophilic metal. It was further considered that the C–M bond could147Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsbe used to undergo addition to the aldehyde functionality and thus obtain a tetrahydroxanthone. Precedentfor the 6-endo-dig cyclization of phenol derivatives to ynones include the use of gold(I)296,297 and palla-dium(II)298 catalysts. Attempts to convert ynone 3.75a into tetrahydroxanthones 3.84a were studied usinggold/silver, nickel, and copper catalysts (Table 3.3).Table 3.3. Screening of reagents for the cycloisomerization of 3.75a into tetrahydroxanthones 3.84a.OOOOOO OBnO OHOBnconditionsOOHO OBnOorOorOOOOHOBn-c-tMet3.75a 3.66a3.84a 3.84aentry promoter (equiv) additives (equiv) T ◦C time (h) solvent 3.66a(% yield)a1 PPh3AuCl (0.1) AgSbF6 (0.2) 50 16 DCE NR2 AuCl (0.1) AgSbF6 (0.2)/Cy3P (0.3) rt 16 DCE 803 AuCl3 (0.1) AgSbF6 (0.2)/Cy3P (0.3) rt 16 DCE 704 AuCl (0.1) AgSbF6 (0.2)/Ph3P (0.3) 50 16 DCE 785 AuCl3 (0.1) AgSbF6 (0.2)/Ph3P (0.3) 50 16 DCE dec6 AgSbF6 (0.1) – rt 72 CH3CN NR7 Pd(CH3CN)Cl2 (0.1) – 50 16 CH3CN dec8 (o-Tol)2PdCl2 (0.1) – 50 16 CH3CN dec9 Pd(dppf)Cl2•DCM (0.1) – 50 16 CH3CN dec10 Ni(COD)2 (0.1) – 50 16 CH3CN dec11 (Ph3P)2NiBr2 (0.1) – 50 16 CH3CN 5012 CuI (0.6) – 50 16 CH3CN NR13 ICl (1.0) – 40 16 CH3CN dec14 (+)-CSA (0.4) – rt 16 DCM 9015 p-TsOH (0.4) – rt 16 DCM 94The reactions were run at a 0.1 M concentration. a Isolated yields.Ynone 3.75a was treated with (triphenylphosphine)gold(I) chloride (10 mol%) and silver hexafluoroan-timonate(V) (20 mol%) in DCM (entry 1).297 Under these conditions, cleavage of the MOM group was ob-served after 5 min. Stirring the reaction mixture for 16 h at 50 ◦C produced no further change. Other catalysts(Au(I)/Ag(I) and Au(III)/Ag(I)) with different phosphine ligands were also studied (entries 2–5). Cleavageof the MOM group took place within 0.5 h of reaction time in all cases. o-Alkynoylphenol derivative 3.66adecomposed when gold(III) chloride/silver hexafluoroantimonate and triphenylphosphine was used (entry5). A blank was run using only silver hexafluoroantimonate, however, even after 72 h of reaction time, thestarting material remained unchanged (entry 6).148Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsThe use of different metal catalysts including palladium(II) (entries 7–9), Ni(0) (entry 10) or Ni(II)species (entry 11) resulted in the decomposition of the starting material. o-Alkynoylphenol derivative 3.66awas not observed by TLC at any point during these attempts. Use of copper(I) iodide left the starting mate-rial unchanged (entry 12). When bis(triphenylphosphine)nickel(II) bromide was used,298 o-alkynoylphenolderivative 3.66a was obtained in 50% yield, but the tetrahydroxanthone was not observed (entry 11).It appeared that metal catalysts were ineffective for the conversion of ynone 3.75a into tetrahydroxan-thones 3.84a. Attention was turned to the use of electrophilic species. Iodine monochloride, which had beenused by Larock and co-workers for the synthesis of chromenones,294 resulted in the decomposition of thestarting material (entry 13). No addition of I–Cl across the triple bond was observed either. Use of (+)-camphorsulfonic acid291,292 was ineffective for the synthesis of the tetrahydroxanthone as the only productobserved was o-alkynoylphenol derivative 3.66a in 90% yield (entry 14).From the results presented in Table 3.3, it was concluded that metal and acid treatment of ynone 3.75awas not effective in the production of tetrahydroxanthones. Instead, it resulted in o-alkynoylphenol derivative3.66a in moderate to good yield. A more effective way to cleave the MOM group of ynone 3.75a wastreatment with catalytic para-toluenesulfonic acid in DCM to produce o-alkynoylphenol derivative 3.66a in94% yield (Scheme 3.19, page 145).3.4.2 Cycloisomerization of o-Alkynoylphenol Derivative 3.66aAttention was then turned to the use of bases to promote the conversion of o-alkynoylphenol derivative 3.66ainto tetrahydroxanthones 3.84a. Table 3.4 summarizes the attempts to cycloisomerize 3.66a using inorganicbases. Potassium and cesium carbonate failed to promote the cycloisomerization of 3.66a (entries 1 and 2).Stronger bases such as sodium and potassium hydride, and lithium diisopropylamide were disastrous as thestarting material decomposed after 5 min of reaction time (entries 5–6).Attention was now focused on the conversion of o-alkynoylphenol derivative 3.66a into tetrahydroxan-thones 3.84a and chromenone 3.85a using organic bases and nucleophilic catalysts. A nucleophilic base thatcould increase the conversion of 3.66a and the formation of tetrahydroxanthones 3.84a was desired. DBUgave the first indication of a cycloisomerization process as it was believed that diastereomeric tetrahydrox-anthones 3.84a and chromenone 3.85a were present in the reaction crude, although in a relative low ratio of3.84a to 3.85a (entries 1 and 2). Although both modes of cyclization were considered for the cycloisomer-ization of o-alkynoylphenol derivative 3.66a, which may generate up to six different compounds, only threeproducts were observed in the 1H NMR of the reaction crude. Triethylamine, pyridine and 2,6-lutidine gaveunsatisfactory results as the cycloisomerization proceeded with both a low conversion of o-alkynoylphenol149Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsTable 3.4. Cycloisomerization of o-alkynoylphenol derivative 3.66a using inorganic bases.OOOOOO OBnO OHOBnconditionsOOOor orOOOOHOBn-c-tOOBnH3.66a 3.85a3.84a 3.84aentry base equiv solvent time (h) % yield1 K2CO3 1.2 DMF 144 NR2 Cs2CO3 1.2 DMF 24 trace3 NaH 1.2 THF 0.1 dec4 KH 1.2 THF 0.1 dec5 NaH 7.0 THF 0.1 dec6 LDA 1.05 THF 0.1 decThe reactions were run at rt at a 0.1 M concentration.derivative 3.66a and a low ratio of tetrahydroxanthones 3.84a to chromenone 3.85a (entries 3–5). DABCOappeared as a better promoter for the cycloisomerization as it favoured the conversion of 3.66a and the for-mation of tetrahydroxanthones 3.84a over chromenone 3.85a (entry 6). Phosphine derivatives performedmoderately with average conversions of 3.66a (ca. 50%), but generally with a low ratio of tetrahydroxan-thones 3.84a to chromenone 3.85a (entries 10–14).It was found that quinuclidine and DMAP were the best promoters for the cycloisomerization (entries7–9). Although the use of quinuclidine resulted in the highest conversion of 3.66a (98%), the ratio of tetrahy-droxanthones 3.84a to chromenone 3.85a was moderate at best (entry 7). The highest ratio of tetrahydroxan-thones to chromenone was obtained when 30 mol% of DMAP was used and the reaction proceeded in 95%conversion of 3.66a. When the amount of DMAP was lowered to 10 mol%, similar results were obtained(entry 8).It is known that the intramolecular cycloaddition of phenols to alkynes can proceed through either a6-endo-dig or 5-exo-dig mode (see Figure 3.2, page 133); however, the intramolecular addition of phenolsto ynones is well documented to proceed through a 6-endo-dig mode as shown in Section 3.1. When thecycloisomerization of 3.66a was performed using DMAP, three products were obtained in 51% isolatedyield in a 2.3:1.8:1 ratio after purification using chromatography over silica gel.The characteristic 1H NMR signals for the minor compound (Rf = 0.475) included a triplet at δ 9.77 (J =1.2 Hz), a singlet at δ 6.51 ppm, and a doublet of doublets at δ 4.38 ppm (J = 4.6, 7.7 Hz). The signal at δ 9.77ppm was indicative of an aldehyde functionality, while the signal at δ 6.51 ppm corresponded to a vinylic150Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsTable 3.5. Cycloisomerization of o-alkynoylphenol derivative 3.66a into tetrahydroxanthones 3.84aand chromenone 3.85a using organic bases and nucleophiles.304–311OOBnHOOHOMe6-endo-dig5-exo-digOO OHOBnOMeOO OHOBnOMe+OMeOO HOBnO OMeOO HOBnO+-t -c-t -cconditionsOO OOBnOMe+OMeOO OBnO+1 234 56712 34 5671 23 4 5673.66a3.84a3.84a 3.85a3.86a3.86a 3.87aentry promoter mol % time (h) % conversiona ratio 3.84a:3.85ab1 DBU 40 2 47 1.4:1.02 DBU 100 2 48 2.4:1.03 Et3N 30 0.5 14 1.9:1.04 pyridine 30 0.5 55 1.0:1.05 2,6-lutidine 30 0.5 15 2.4:1.06 DABCO 30 0.5 76 3.6:1.07 quinuclidine 30 0.5 98 3.3:1.08 DMAP 10 0.5 96 7.3:1.09 DMAP 30 0.5 95 7.9:1.010 Ph3P 30 0.5 49 1.0:1.011 (4−OCH3C6H4)3P 30 0.5 50 2.9:1.012 Cy3P 30 0.5 70 1.0:1.013 (iPr)3P 30 0.5 47 1.8:1.014 (NEt2)3P 30 0.5 47 1.8:1.0The reactions were carried out in DCM at rt at a 0.05 M concentration using a stock solution of 3.66a and 1,4-dimethoxybenzene as an internal standard. a Established by integration of the signal at δ 4.47 ppm of 3.66a andthe internal standard in the 1H NMR spectrum of the reaction crude.b Established by integration of signals at δ 4.49 and 4.43 ppm of diastereomers 3.84a and signal at δ 4.38 ppm of3.85a in the 1H NMR spectrum of the reaction crude.hydrogen. The multiplicity of the vinylic signal strongly suggested that the structure of the minor compoundcorresponded to chromenone 3.85a, since the vinylic hydrogen of benzofuranone 3.87a was expected to bea doublet due to coupling with the hydrogen atom at position C-4 (see Table 3.5).312–314 Therefore, it wasdeduced that the cycloisomerization of 3.66a had proceeded through a 6-endo-dig mode.The other two compounds obtained after the cycloisomerization (Rf = 0.48) were identified as diastere-omeric tetrahydroxanthones 3.84a. Themajor component of the two diastereomers showed two characteristictriplet signals in its 1H NMR spectrum at δ 5.06 ppm (J = 4.6 Hz) for H1 and δ 4.49 ppm (J = 5.5 Hz) for151Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsH4. Based on the constant coupling values for hydrogen atoms H1 and H4,315,316 the major diastereomer wasassigned as the trans tetrahydroxanthone 3.84a-t. The minor diastereomer showed two characteristic signalsin its 1H NMR spectrum at δ 5.01 ppm (dd, J = 5.8, 7.9 Hz) for H1 and at δ 4.40 ppm (t, J = 4.4 Hz) for H4and it was assigned as the cis tetrahydroxanthone 3.84a-c as depicted in Figure 3.3.OOOOHOBnOOOOHOBnH4H1 H1H45.06 (t, J = 4.6 Hz)4.49 (t, J = 5.5 Hz)5.01 (dd, J = 5.8, 7.9 Hz)4.43 (t, J = 4.4 Hz)OOOOOBnH44.38 (dd, J = 4.6, 7.7 Hz)6.51(s) 9.77 (t, J = 1.2Hz)-t -c3.84a3.84a 3.85aFigure 3.3. Characteristic 1H NMR signals of tetrahydroxanthones 3.84a-t and 3.84a-c andchromenone 3.85a.From the 1H NMR studies shown in Table 3.5, it was empirically established that 30 mol% of DMAP inDCM at room temperature were the best conditions for the conversion of o-alkynoylphenol derivative 3.66ainto tetrahydroxanthones 3.84a. Also, the use of 30 mol% DMAP was more convenient than 10 mol% dueto the small scale of the reactions.3.4.3 Synthesis of Tetrahydroxanthone Derivatives 3.89Although the 1H NMR data of tetrahydroxanthones 3.84a strongly suggested that the major diastereomerwas the trans-tetrahydroxanthone, further evidence was required to unequivocally assign the cis/trans con-figuration of each diastereomer. Unfortunately, crystals of tetrahydroxanthones 3.84a could not be obtainedfor X-ray spectroscopy analysis. To establish the relative configuration of the diastereomeric tetrahydrox-anthones 3.84a, the free alcohol functionality was derivatized using 3,5-dinitrobenzoyl chloride (3.88).317A sample of 3.66a was treated with DMAP (30 mol%) and, after the o-alkynoylphenol derivative had beenconsumed, 3,5-dinitrobenzoyl chloride (3.88) was added to the reaction crude followed by triethylamine.Tetrahydroxanthone derivatives 3.89a-t and 3.89a-c were obtained in 46% and 19% yield in a 2.4:1 ratio,respectively plus 10% yield of chromenone 3.85a (Scheme 3.24).Both diastereomeric esters were separated using chromatography over silica gel; however, no crystalscould be obtained for their X-ray crystallography analysis. The major diastereomer presented two character-istic triplets in its 1H NMR spectrum at δ 6.53 ppm (J = 3.1 Hz) and at δ 4.57 ppm (J = 3.1 Hz). The minordiastereomer also exhibited two triplet signals in its 1H NMR spectrum at δ 6.47 ppm (J = 4.1 Hz) and at δ152Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOOOOOHO OBnO OOBnONO2NO2OOOOOBnONO2NO21) DMAP (30 mol%)    DCM, rt, 30 min2) Et3N,            75%O NO2NO2Cl+(±) (±)-t -c1414OOOOOBn+3.66a 3.88 3.89a3.89a 3.85aScheme 3.24. Synthesis of 3,5-dinitrobenzoates 3.89a-t and 3.89a-c.4.56 ppm (J = 7.3 Hz). Both set of signals were assigned to the hydrogen atoms in position C-1 and C-4 ofthe tetrahydroxanthone, respectivelyThe cycloisomerization of o-alkynoylphenol derivative 3.66b was performed using DMAP. After thestarting material was consumed, a 1H NMR spectrum of the crude mixture was obtained and signals at δ4.46 (t, J = 5.34 Hz), 4.41 (t, J = 4.67 Hz), and 4.37 (dd, J = 7.75, 4.40 Hz) were observed. Comparisonwith the 1H NMR spectra of compounds 3.84a-t, 3.84a-c, and 3.85a suggested that the 1H NMR signalscorresponded to compounds 3.84b-t, 3.84b-c, and 3.85b, respectively (Scheme 3.25).OOO OBnOOOOHOBnOOHO OBnOBr BrBrOOOOOBnBrDMAP (35 mol%)DCM, rt+ +(±) (±)-t -cOOOOOBnONO2NO2 OOOOOBnONO2NO2BrBr +(±) (±)-t -cOHEt3N,rt53% over 2 stepsH4 H44.46 (t, J = 5.34) 4.41 (t, J = 4.67) 4.37 (dd, J = 7.75, 4.40)H4ClOC6H4(NO2)2 (            )14143.66b 3.84b3.84b3.89b3.89b3.85b3.88Scheme 3.25. Synthesis of tetrahydroxanthone derivatives 3.89b-t and 3.89b-c, and chromenone 3.85b.Unfortunately, any attempts to separate the mixture of diastereomers 3.84b were unsuccessful. To sep-arate the mixture of diastereomers, the alcohol functionality was derivatized using 3.88. The synthesis oftetrahydroxanthone derivatives 3.89b-t and 3.89b, and chromenone 3.85b was achieved by treating ynone153Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations3.66b with DMAP (35 mol%) in DCM at room temperature. The crude reaction was treated with 3,5-dinitrobenzoyl chloride (3.88) and triethylamine to obtain trans-tetrahydroxanthone 3.89b-t (27% yield),cis-tetrahydroxanthone 3.89b-c (12% yield) in a 2.3:1 ratio, and chromenone 3.85b (14% yield) in 53%overall yield over two steps (Scheme 3.25).The diastereomeric tetrahydroxanthone esters exhibited characteristic methine (C–H) signals for the hy-drogen atoms at positions C–1 and C–4 of the tetrahydroxanthone. Signals at δ 6.50 (t, J = 2.7 Hz) and 4.55(t, J = 2.7 Hz) for the major diastereomer and signals at δ 6.46 (t, J = 4.1 Hz) and 4.55 (t, J = 7.2 Hz) for theminor diastereomer.The major diastereomer crystallized after purification and the compound was analyzed by X-ray crystal-lography. The solid state molecular structure, depicted in Figure 3.4, showed that the structure of the majordiastereomer corresponded to tetrahydroxanthone derivative 3.89b-t. The solid state molecular structure un-equivocally established the trans-configuration of the major diastereomer, and it further confirmed that theDMAP-promoted cycloisomerization of o-alkynoylphenol derivatives proceeded through a 6-endo-dig modeof cyclization.OOO BrO OONO2NO2HH(±) -t3.89bFigure 3.4. Solid state molecular structure of compound 3.89b. Ellipsoids at 30% probability.The major diastereomer, trans-tetrahydroxanthone derivative 3.89b-t, exhibited a set of signals in its1H NMR spectrum at δ 6.50 (t, J = 2.7 Hz) and 4.55 (t, J = 2.7 Hz). Therefore, it was inferred that thecompound with the set of signals at δ 6.46 (t, J = 4.1 Hz) and 4.55 (t, J = 7.2 Hz) corresponded to thecis-tetrahydroxanthone derivative 3.89b-c.The 1H NMR spectrum of trans diastereomer 3.89b-t was compared with the 1H NMR spectra obtainedfor compounds 3.89a-t and 3.89a-c (Figure 3.5, page 155). The characteristic 1H NMR signals for the trans-tetrahydroxanthone derivative 3.89a-t were assigned as δ 6.53 (t, J = 3.1 Hz) and 4.57 (t, J = 3.1 Hz) and forthe cis-tetrahydroxanthone were assigned as δ 6.47 (t, J = 4.1 Hz) and 4.56 (t, J = 7.3 Hz).154Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOOOOOBnONO2NO2OOOOOBnONO2NO2OOOOOBnONO2NO2BrOOOOOBnONO2NO2BrH1 H1H1 H1H4H4H4H46.53 (t, J = 3.1 Hz)4.57 (t, J = 3.1 Hz)6.47 (t, J = 4.1 Hz)4.56 (t, J = 7.3 Hz)6.50 (t, J = 2.7 Hz)4.55 (t, J = 2.7 Hz)6.46 (t, J = 4.1 Hz)4.55 (t, J = 7.2 Hz)(±) -c(±) -t(±) -t (±) -c3.89b3.89b3.89a3.89aFigure 3.5. Assignment of the trans and cis structure of compounds 3.89a-t and 3.89a-c by comparisonwith the 1H NMR signals of compounds 3.89b-t and 3.89b-c.The identity of tetrahydroxanthone 3.84a-t was confirmed by cleavage of the dinitrobenzoyl group oftrans tetrahydroxanthone derivative 3.89a-t using potassium carbonate and methanol. After methanolysis,a 1H NMR spectrum of the reaction crude was obtained, observing a triplet at δ 5.06 (J = 4.6 Hz), whichcorresponded to the C–H at position C-1 of compound 3.84a-t.K2CO3, MeOHrt, 2 hOOOOHOBnH1H44.49 (t, J = 5.5 Hz)(±) -t5.06 (t, J = 4.6 Hz)OOOOOBnONO2NO2H1H46.53 (t, J = 3.1 Hz)4.57 (t, J = 3.1 Hz)(±) -t3.89a 3.84aScheme 3.26. Methanolysis of tetrahydroxanthone ester 3.89a-t.Tetrahydroxanthone derivatives 3.89c-t and 3.89c-c, and chromenone 3.85c were synthesized by treat-ment of ynone 3.66c with DMAP (30 mol%) in DCM at room temperature (Scheme 3.27). Derivatization ofthe alcohol functionality was performed on the reaction crude without further purification. Tetrahydroxan-thones 3.89c-t, 3.89c-c were obtained in 41% and 18% in a 2.4:1 ratio, respectively, and chromenone 3.85cwas obtained in 14% yield (Scheme 3.27).155Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOOOOOBnONO2NO2 OOOOOBnONO2NO2 OOOOOBnOOHO OBnO1) DMAP2) Et3N73%+ +2.9 1.3 1.0: :-c-t3.66c 3.89c3.89c 3.85c3.88Scheme 3.27. Synthesis of tetrahydroxanthone 3,5-dinitrobenzoates 3.89c-t and 3.89c-c, andchromenone 3.85c.The major diastereomer was also crystallized and analyzed by X-ray crystallography. The solid statemolecular structure confirmed that the major diastereomer was trans-tetrahydroxanthone 3.89c-t. This com-pound exhibited 1H NMR signals at δ 6.51 (br, s) and 4.91 (br, s) ppm (Figure 3.6). Therefore, the minordiastereomer, which exhibited 1H NMR signals at δ 6.47 (t, J = 4.1 Hz) and 4.56 (t, J = 6.5 Hz), was assignedas the cis-tetrahydroxanthone derivative 3.89c-c.OOOOOO2NO2NO-t3.89cFigure 3.6. Solid state molecular structure of compound 3.89c.The DMAP-promoted cycloisomerization of o-alkynoylphenol derivatives 3.62a and 3.62b was alsostudied. o-Alkynoylphenol derivative 3.62a was treated with catalytic DMAP (30 mol%) in DCM at rt.After 30 min of reaction time, the 1HNMR spectrum of the crude mixture showed an 8:1 ratio of tetrahydrox-anthone 2.166a to chromenone 3.83a, respectively. After purification, tetrahydroxanthone 2.166a was ob-tained in 73% yield and chromenone 3.83a was obtained in 9% yield in an overall 82% yield (Scheme 3.28).Tetrahydroxanthone 2.166a was identified by its characteristic 1H NMR signal at δ 5.05 ppm (t, J = 5.5 Hz),which was assigned to the C–H at position C-1. Chromenone 3.83a showed two characteristic 1H NMR sig-nals, a triplet at δ 9.77 ppm (J = 1.2 Hz) and a singlet at δ 6.17 ppm.o-Alkynoylphenol derivative 3.62b was treated with DMAP (30 mol%) in DCM at room temperature.After 30 min of reaction time, the 1H NMR spectrum showed a 2.4:1 ratio of tetrahydroxanthone 2.166b to156Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsO OOHOOO OHODMAP30 mol%DCM, rt, 0.5 h82%OO OO+8 1:3.62a 2.166a 3.83aScheme 3.28. Intramolecular tandem cycloisomerization of o-alkynoylphenol derivative 2.166a.chromenone 3.83b, respectively. Purification afforded tetrahydroxanthone 2.166b (43% yield) and chromenone3.83b (15% yield). Tetrahydroxanthone 2.166b showed a characteristic signal in its 1H NMR spectrum as atriplet at δ 5.04 ppm (J = 5.3 Hz), which was assigned to the C–H at position C-1, while chromenone 3.83bshowed two characteristic singlets in its 1H NMR spectrum at δ 9.81 and 6.19 ppm.OO OHOBrO OOHOBr DMAP30 mol%DCM, rt 0.5 h43%OO OOBr+2.4 1.0:3.62b 2.166b 3.83bScheme 3.29. Intramolecular tandem cycloisomerization of ω-oxo o-alkynoylphenol derivative 2.166b.It was observed that chromenones 3.85 and 3.83were obtained as minor components of the cycloadditionof o-alkynoylphenol derivatives. It was hypothesized that the chromenone may be an intermediate in theformation of tetrahydroxanthones as shown in Scheme 3.30.OOHORYODMAPDCMOOOROYOOOROHY3.90 3.91 3.92Scheme 3.30. Possible chromenone as intermediate in the synthesis of tetrahydroxanthones.Chromenone 3.85a was treated with DMAP (30 mol%) in DCM at room temperature and the reactionmixture was monitored by 1H NMR. Although the reaction mixture was stirred for 14 days, the 1H NMR ofthe reaction crude did not show any indication that tetrahydroxanthones 3.84a were formed (Scheme 3.31).This experiment strongly suggested that the formation of the chromenone was a dead end for the cycloiso-157Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsmerization of o-alkynoylphenol derivatives, because, once formed, the chromenones could not be convertedinto the desired tetrahydroxanthones.OOOOHOBnXDMAPDCMOOOOOBn3.85a 3.84aScheme 3.31. Treatment of chromenones with DMAP does not lead to tetrahydroxanthones.3.5 Reaction MechanismThe X-ray crystallographic data of compounds 3.89b-t and 3.89c-t (Section 3.4.3, Figure 3.4 and Figure 3.6)unequivocally established that the conversion of o-alkynoylphenol derivatives into tetrahydroxanthones pro-ceeded through a 6-endo-dig mode of cyclization.Two mechanistic pathways for the cycloisomerization of o-alkynoylphenol derivatives into tetrahydrox-anthones were proposed. For instance, if DMAP behaved as a Brønsted base, the formation of tetrahy-droxanthone 2.166a could have proceeded through an anionic oxa-Michael/aldol tandem cycloisomerization(Scheme 3.32a). DMAP (pKBH+ = 9.2) may initially deprotonate the phenol functionality of 3.62a to formphenoxide 3.93a, which undergoes an oxa-Michael addition to the conjugated ynone to produce chromenoneanion 3.94a. Anion 3.94a can then perform a nucleophilic attack to the aldehyde to produce tetrahydroxan-thone alkoxide 3.95a that will produce tetrahydroxanthone 2.166a upon work up. Alternatively, chromenoneanion 3.94a can also be protonated, thus forming chromenone 3.83a instead.It was also considered that DMAPmay behave as a nucleophilic species and that it can potentially undergoa 1,4-conjugated addition to o-alkynoylphenol derivative 3.62a to form zwitterion 3.96a, which can thenattack the carbonyl carbon of the aldehyde function to generate alkoxide 3.97a in a formal Morita-Baylis-Hillman reaction. After proton exchange, alkoxide 3.97a can generate phenoxide intermediate 3.98a, wherethe negatively charged oxygen of the phenoxide can act as a nucleophile an undergo an anionic oxa-Michaeladdition to the enone in 3.98a, to form enolate 3.99a. After elimination of the nucleophile, initiated by theenolate species 3.99a, the desired tetrahydroxanthone 2.166a is formed (Scheme 3.32b).Alternatively, zwitterion 3.96a can deprotonate the phenol functionality either intra or intermolecularlyto produce phenoxide enone 3.100a that can then undergo an anionic oxa-Michael addition to form eno-late 3.101a. The enolate species can follow two paths: either elimination of the nucleophile to producechromenone 3.83a, or an aldol reaction with the aldehyde functionality to produce tricyclic species 3.102a.158Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsIntermediate 3.102a can eliminate the nucleophile with aid of one of the lone pairs of the oxygen atomfrom the pyrone ring to produce oxonium species 3.103a. Subsequent elimination of the proton alpha to thecarbonyl functionality, followed by proton transfer, produces the desired tetrahydroxanthone 2.166a.OOOOHOOOOOOOO HOOOOOOOoxaMichaelaldolOHHprotontransferOOOOHOOHOOO1,4-additionOOO NOHH oxaMichaelOOO NOOOOONHOOOOHaldoleliminationOOOOHNOOOOHoxaMichaeldeprotonation(a)OOHOONNNO NNOONNDMAPHNprotontransferNNNN NNaldolprotontransfer(b)3.62a3.62a3.93a 3.94a3.95a2.166a2.166a2.166a3.83a3.83a3.96a3.97a 3.98a 3.99a3.100a 3.101a3.102a 3.103aScheme 3.32. Proposed mechanistic pathways for the synthesis of tetrahydroxanthone 2.166a andchromenone 3.83a using DMAP.Literature precedent show that ynones and ynoates have been demonstrated to undergo Morita-Baylis-Hillman-type reactions (Scheme 3.33).318–321 These processes generally use a Lewis acid (MoBI3,318 TiCl4,319and MgI2 321) to activate the carbonyl of the aldehyde towards nucleophilic attack. Different MBH nucle-ophiles have been used: tributyltin hydride in the case of ynone 3.104,318 iodide, from tetrabutylammoniumiodide (TBAI), for eneynone 3.106,319 and iodide, frommagnesium iodide, in the case of ynoate 3.108321 andynoate 3.110.172,320 It has also been reported that DMAP promotes the synthesis of Morita-Baylis-Hillman-type products using nitroalkenes,322–324 acrylates,304 and cyclohexenone310 as the conjugated species.159Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOPhMoBI3 (3 mol%)Bu3SnH (1.2 equiv)THF, CO, 60 ºC, 6h40%OPhH+ PhOH OPhOH OTiCl4 (1.3 equiv)TBAI (1.3 equiv)DCM, -78 ºC, 2h82%OOHOPhHCO2MeMgI2, DCM0 ºC, 1h90%+ PhOH OOMeIHIMeOOOBnOBnOHMgI2, DCM-20 ºC, 24h78%OBnOBnOIMeOO3.104 3.105 3.106 3.1073.108 3.109 3.110 3.111Scheme 3.33. Representative examples of MBH products using ynones and ynoates.172,318,319,321Another example that uses DMAP to promote Morita-Baylis-Hillman reactions is the reaction betweenisatins and α-substituted allenolates (Scheme 3.34).325 The proposed reaction mechanism involved a 1,4-conjugate addition of DMAP to allenolate 3.113 to produced zwitterion 3.115, which was in resonance with3.116. The anion of 3.116 then attacked the carbonyl group of the isatin (3.112) obtaining alkoxide 3.117.After proton transfer, intermediate 3.118 was obtained and subsequent elimination of DMAP resulted inMorita-Baylis-Hillman-type product 3.114.NBnOOCO2EtPh DMAP (20 mol%)THF, rt, 3h,93%, dr 2:1+NBnOHOCO2EtPhNCO2EtPhNNBnOOCO2EtPhNBnOHOCO2EtPhNNDMAPNNNNNNCO2EtPh3.1123.1123.1133.113 3.1143.1143.1153.1163.1173.118Scheme 3.34. DMAP-promoted Morita-Baylis-Hillman between allenolate 3.113 and isatin 3.112.325160Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsAlthough two main mechanistic pathways for the transformation of o-alkynoylphenol derivatives intotetrahydroxanthones were proposed, the anionic oxa-Michael/aldol tandem sequence (Scheme 3.32a) was notsupported by the results obtained when treating 3.66a with different inorganic bases. Only nucleophilic basespromoted the synthesis of tetrahydroxanthones (Section 3.4.2, Table 3.4), which suggested that 1,4-additionof DMAP to the ynone in o-alkynoylphenol derivatives may be the activating step. Whether zwitterions 3.96initiate a MBH-type aldol reaction, to generate alkoxides 3.97, or deprotonation of the phenol functionalityto induce 6-endo-dig cyclization is unclear.The treatment of o-alkynoylphenol derivatives 3.66 followed by derivatization of the free phenol re-sulted in diastereomeric tetrahydroxanthone esters 3.89 in a ca. 2.4:1 ratio trans:cis, respectively. Two con-formers were proposed for the generation of the trans and cis diastereomers; however, there are no stericor electronic factors that could greatly favour the trans-conformer 3.119-t over the cis-conformer 3.119-c(Scheme 3.35). A chair-like transition state for the aldol reaction was proposed. For the formation of thetrans-tetrahydroxanthone, the oxygen atom of the aldehyde occupies an equatorial position (3.120-t), whilein the formation of the cis-tetrahydroxanthone the oxygen atom of the aldehyde is placed in an axial position(3.120-c). It is perhaps the difference in energy between the axial-like and the equatorial-like transition statesthat determines the ratio of trans- vs cis-tetrahydroxanthones.HONArONOBnHOHNArONOBnH-t-cHONArONOBnHOHNArONOBnH-t-cHONArONOBnHOHNArONOBnH-t-c3.1193.1193.1203.1203.1213.121Scheme 3.35. Proposed chair transition state for the formation of trans and cis tetrahydroxan-thone derivatives 3.89.A substrate that could only form the F ring of the tetrahydroxanthone was subjected to cycloisomer-ization conditions. O-Benzylated ynone 3.122a was prepared and was treated with DMAP (30 mol%) indideuteromethylene chloride at room temperature. The reaction mixture turned deep red, which may be161Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsindicative of a highly conjugated species. Unfortunately, 1H NMR analysis of the crude mixture did not pro-vide clear signals to support the formation of intermediate 3.123a, which would have supported the DMAP-promoted MBH mechanism (Scheme 3.36).HOOOBnODMAP (30 mol%)CDCl3, rtred?OOBnOONN3.122a 3.123aScheme 3.36. Attempt to support the Morita-Baylis-Hillman/oxa-Michael mechanism over the oxa-Michael/aldol mechanism.3.6 ConclusionThe DMAP-promoted intramolecular tandem cycloisomerization of o-alkynoylphenol derivatives was ef-fective in the synthesis of polyoxygenated tetrahydroxanthones (Scheme 3.37). The cycloisomerization pro-ceeded through a 6-endo-dig mode of cyclization and featured the formation of two six-membered rings, oneC–O bond, one C–C bond, and one stereogenic centre in the same reaction vessel. The cycloisomerization ofo-alkynoylphenol derivatives 3.66 produced a mixture of trans and cis tetrahydroxanthones in ca. 2.4:1 ratio,plus a chromenone as a minor byproduct, while the cycloisomerization of o-alkynoylphenol derivatives 3.62produced racemic tetrahydroxanthones plus chromenone as a minor byproduct.OBnHOOOHORa) DMAPDCMrt, 0.25 hb)           .EtN353 to 75%OOOROR1OBnOOOROR1OBnOOOROOBn+ +HOOOHOR DMAPDCMrt, 0.25 h43 to 82%OOOROHOOORO+-t -cONO2NO2R1 =3.66 3.893.89 3.853.883.62 2.166 3.83Scheme 3.37. Synthesis of tetrahydroxanthones via DMAP-promoted intramolecular tandem cycloiso-merization of o-alkynoylphenol derivatives.162Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsThe structure of the synthesized tetrahydroxanthones was confirmed by X-ray crystallographic analysesof crystallized esters 3.89b-t and 3.89c-t, confirming the trans configuration of the major diastereomers andthe formation of the 6-endo-dig cyclization products (Figure 3.7).Figure 3.7. Solid state molecular structure of compounds 3.89b-t and 3.89c.Previous reports on the use of DMAP to promote the synthesis of Morita-Baylis-Hillman-type productsusing allenolates,325 ynones,318,319 and ynoates,321 as well as the cycloaddition of o-alkynoylphenol deriva-tives to produce chromenones,295 suggest that the cycloisomerization of o-alkynoylphenol derivatives to formtetrahydroxanthones may be initiated by the 1,4-conjugate addition of DMAP to the ynone to form zwitterion3.96a (see Scheme 3.32b, page 159). The zwitterion can then initiate a Morita-Baylis-Hillman-type aldol at-tack to the aldehyde or it can undergo a proton transfer followed by an anionic 6-endo-dig oxa-Michaeladdition. However, the reaction mechanism is not well established.3.7 Experimental Section3.7.1 General ExperimentalSee Section 2.4.1.3.7.2 Synthesis of o-Vanillin DerivativesHOOHOHOOHOBr, KBr, AcOHH2O, 100 ºC93%Br2.143 3.60163Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations5-Bromo-2-hydroxy-3-methoxybenzaldehyde (3.60). To a solution of o-vanillin (2.143) (15.40 g, 100.2mmol, 1.0 equiv) and potassium bromide (24.10 g, 200.5 mmol, 2 equiv) in 80 mL of glacial acetic acid and44 mL of water at 100 ◦C, bromine (5.5 mL, 105.2 mmol, 1.05 equiv) was slowly added through a syringein a period of 15 min. The reaction mixture was stirred for 1.5 h. It was cooled to rt. Concentration byrotary evaporation in vacuo produced a red solid that was suspended in 100 mL of water. The suspensionwas stirred at 0 ◦C for 30 min and it was filtered under vacuum. Drying in vacuo yielded 21.69 g (93%) of thetitle compound as a red solid. 1HNMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 9.84 (s, 1H), 7.29 (d, J = 2.2 Hz,1H), 7.15 (d, J = 2.1 Hz, 1H), 3.90 (s, 3H). Compound 3.60 had been previously synthesized, see Jacks, Bel-mont, Briggs, Horne, Kanter, Karrick, Krikke, McCabe, Mustakis, Nanninga, Risedorph, Seamans, Skeean,Winkle, and Zennie 303 for further detail.3.7.3 Synthesis of YnonesOH OHOHOOOHOhex-5-yn-1-olBuLiTHF30%2.143 3.61a1-(2-hydroxy-3-methoxyphenyl)hept-2-yne-1,7-diol (3.61a). To a solution of o-vanillin (2.143) (2.31g, 15.03 mmol, 1.5 equiv) in 70 mL of THF, 1.37 M nBu Li (11.0 mL, 15.1 mmol, 1.5 equiv) was slowlyadded at -78 ◦C over a period of 15 min with the aid of a syringe pump. The reaction mixture was stirredfor 20 min. A solution of 5-hexynol (1.00 g, 10.2 mmol, 1.0 equiv) and 1.37 M nBu Li (15.6 mL, 21.4mmol, 2.1.0 equiv) in 30 mL of THF that had been been stirred for 1 h at 0 ◦C was cannula-transferred to theyellow suspension of 2.143 and nBu Li. The reaction mixture was stirred at reflux temperature for 16 h. Thereaction mixture was cooled to rt. The reaction mixture was quenched with 100 mL of saturated ammoniumchloride solution and 10 mL of 1 M hydrochloric acid. The aqueous phase was extracted with diethyl ether(3 x 50 mL). The combined organic fractions were washed with brine (2 x 80 mL). Drying over sodiumsulfate and concentration by rotary evaporation in vacuo produced an orange oil that after purification usingchromatography over silica gel yielded 0.77 g (30%) of the title compound as a colourless oil. IR (neat): 3392,2938, 2228, 1596, 1480, 1270 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.11 (s, 1H), 7.03 (dd, J = 6.9, 2.3 Hz,1H), 6.78-6.70 (m, 2H), 5.66 (br s, 1H), 4.44 (br s, 1H), 3.73 (s, 3H), 3.50 (t, J = 6.1 Hz, 2H), 3.30 (br s,1H), 2.17 (td, J = 6.7, 1.7 Hz, 2H), 1.60-1.42 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 147.0, 143.4, 126.9,164Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations119.6, 119.4, 110.9, 86.6, 79.6, 61.8, 60.9, 56.0, 31.4, 24.7, 18.5. LRMS (ESI+): 273.4 (M+H)+. HRMS(ESI+) Calculated for C14H18O4Na: 273.1103, found: 273.1105.HOOO OHOOHOMOMCl, K2CO3DMF, rt97%2.143 3.63a5-Bromo-3-methoxy-2-(methoxymethoxy)benzaldehyde (3.63a). A suspension of o-vanillin (2.143)(15.43 g, 100.2 mmol) and potassium carbonate (15.26 g, 110.3 mmol, 1.0 equiv) in 500 mL of anhydrousDMF was stirred overnight at rt. Chloromethyl methyl ether (8.6 mL, 113.2 mmol, 1.1.0 equiv) was thenadded and the green suspension became red. The reaction mixture was stirred for 30 min at rt. The solventwas removed in vacuo. The remaining solid was suspended in aqueous potassium hydroxide (200 mL, 2.0M) and the bright yellow solution was extracted with DCM (4 x 50 mL). The combined organic extracts werewashed with aqueous potassium hydroxide (1 x 50 mL, 2.0 M) and water (1 x 100 mL). Drying over sodiumsulfate and concentration by rotary evaporation in vacuo produced 19.1 g (97% yield) of an ivory solid. 1HNMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.34 (dd, J = 6.2, 3.2 Hz, 1H), 7.07-7.06 (m, 2H), 5.15 (s, 2H),3.79 (s, 3H), 3.48 (s, 3H). Compound 3.63a had been previously synthesized, see Yamaguchi, Tsuchida,Miyazawa, and Hirai 326 for further detail.HOOO OBrHOOHOBr K2CO3MOMCl95%3.60 3.63b5-Bromo-3-methoxy-2-(methoxymethoxy)benzaldehyde (3.63b). A suspension of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.60) (21.7 g, 93.7 mmol, 1.0 equiv) and potassium carbonate (14.5 g, 105.0 mmol,1.1.0 equiv) in 500 mL of acdmf was stirred overnight at rt. Chloromethyl methyl ether (10.5 mL, 138.2mmol, 1.5 equiv) was then added and the green suspension became red. The reaction mixture was stirred for30 min. The solvent was removed in vacuo. The remaining solid was suspended in aqueous potassium hy-droxide (200 mL, 2.0 M) and the bright yellow solution was extracted with DCM (4 x 50 mL). The combinedorganic extracts were washed with 2 M aqueous potassium hydroxide (1 x 50 mL) and water (1 x 100 mL).Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced 24.4 g (95% yield)of an ivory solid. mp: 61-63 ◦C. IR (neat): 3082, 1687, 1577, 1259, 1069, 926, 842 cm-1. 1H NMR (300165Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsMHz, CDCl3) δ 10.38 (s, 1 H), 7.55 (d, J = 2.3 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 5.21 (s, 2 H), 3.89 (s,3 H), 3.55 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ 189.1, 153.5, 148.7, 131.4, 122.0, 121.0, 117.6, 99.6,58.2, 56.6. LRMS (ESI+): 297/299 (M+Na)+. HRMS (ESI+) Calculated for C10H11O4Na79Br (M+Na)+:296.9738, found: 296.9734.3.7.3.1 Synthesis of Ynones 3.62OH OHOO OOOO O5-HexynolBuLiTHF96%3.63a 3.64a1-(3-Methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol (3.64a). n-Butyllithium (3.6M in hex-anes) (3.50 mL, 10.7 mmol, 2 equiv) was added to a solution of 5-hexynol (0.58 mL, 5.0 mmol, 1.0 equiv) in25 mL of THF at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 30 min. The reaction mixture wasadded dropwise to a solution of 3.63a (1.21 g, 6.2 mmol, 1.2 equiv) in 25 mL of THF at -78 ◦C. The reactionmixture was stirred at -78 ◦C for 2 h. Saturated aqueous ammonium chloride solution (50 mL) was added.The organic and aqueous portions were separated. The aqueous portion was extracted with diethyl ether (3x 25 mL). The combined organic extracts were washed with brine (50 mL). Drying over sodium sulfate andconcentration by rotary evaporation in vacuo produced an orange oil that after purification using chromatog-raphy over silica gel yielded 1.42 g (96%) of the title compound as a slightly yellow oil. IR (neat): 3376,2938, 2228, 2162 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 1.5, 8.0 Hz, 1 H), 7.10 (t, J = 8.0 Hz,1 H), 6.89 (dd, J = 1.5, 8.0 Hz, 1 H), 5.79 (t, J = 1.9 Hz, 1 H), 5.14 (d, J = 6.1 Hz, 1 H), 5.07 (d, J = 6.1 Hz,1 H), 3.81 (s, 3 H), 3.63 (t, J = 6.1 Hz, 2 H), 3.58 (s, 3 H), 2.31 (dt, J = 2.0, 6.8 Hz, 2 H), 1.86 (br. s., 1 H),1.72 - 1.56 (m, 4 H). 13C NMR (101 MHz, CDCl3) δ 152.0, 143.9, 136.0, 125.0, 120.1, 112.6, 99.4, 86.8,79.75, 62.4, 60.2, 57.8, 56.0, 32.0, 25.0, 18.8. LRMS (ESI+): 317 (M+Na)+. HRMS (ESI+) Calculated forC16H22O5Na (M+Na)+: 317.1365, found: 317.1364.166Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOH OHOO OBrOOO OBr 5-hexyn-1-olBuLiTHF97%3.63b 3.64b1-(5-Bromo-3-methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol (3.64b). n-Butyllithium (2.6M in hexanes) (4.10 mL, 10.6 mmol, 2 equiv) was added to a solution of 5-hexynol (0.58 mL, 5.0 mmol,1.0 equiv) in 25 mL of THF at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 30 min. The reactionmixture was added dropwise to a solution of benzaldehyde 3.63b (2.04 g, 6.1 mmol, 1.2 equiv) in 25 mL ofTHF at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 2 h. Saturated aqueous ammonium chloridesolution (50 mL) was added. The organic and aqueous portions were separated. The aqueous portion wasextracted with diethyl ether (3 x 25 mL). The combined organic extracts were washed with brine (2 x 25mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced an orange oilthat after purification using chromatography over silica gel yielded 1.82 g (97%) of the title compound asa thick, orange oil. IR (neat): 3370, 2940, 2232, 1578, 1480, 1158, 1070, 1000, 850 cm-1. 1H NMR (400MHz, CDCl3) δ 7.41 (d, J = 2.4 Hz, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 5.73 (s, 1 H), 5.11 (d, J = 6.1 Hz, 1 H),5.03 (d, J = 6.1 Hz, 1 H), 3.81 (s, 3 H), 3.77 (br. s., 1 H), 3.67 - 3.60 (m, 2 H), 3.56 (s, 3 H), 2.31 (dt, J =2.0, 6.8 Hz, 2 H), 1.72 - 1.56 (m, 4 H) 13C NMR (101 MHz, CDCl3) δ 152.7, 142.9, 137.5, 123.1, 117.3,115.8, 99.3, 87.4, 79.2, 62.3, 59.5, 57.9, 56.3, 31.9, 24.9, 18.8. LRMS (ESI+): 395/397 (M+Na)+. HRMS(ESI+) Calculated for C16H21O5Na79Br (M+Na)+: 395.0470, found: 395.0465.OH OHOO OO OOO OCOCl2DMSOEt3NDCM77%3.64a 3.65a7-(3-Methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.65a). Anhydrous DMSO (0.86 mL,12.1 mmol, 2.5 equiv) was added to a clear solution of oxalyl chloride (0.54 mL, 6.2 mmol, 1.25 equiv)in 16 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 20 min. A slightly yellowsolution of diol 3.64a (1.83 g, 4.9 mmol, 1.0 equiv) in 12.5 mL of DCM at -78 ◦C was then added tothe in situ-formed Swern reagent. The reaction mixture was stirred at -78 ◦C for 40 min. Triethylamine(3.40 mL, 24.4 mmol, 5.0 equiv) was then added. The reaction mixture was stirred at -78 ◦C for 30 min.The cold bath was then removed and the reaction mixture was stirred at rt for 35 min. The reaction was167Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsstopped with water (20 mL). The organic and aqueous portions were separated. The aqueous portion wasextracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (20mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced an orange oilthat after purification using chromatography over silica gel yielded 0.40 g (63%) of the title compound as ayellow oil. IR (neat): 2940, 2210, 1720, 1596, 1234 cm-1. 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1 H),7.37 (dd, J = 2.6, 6.9 Hz, 1 H), 7.08 - 6.95 (m, 2 H), 5.03 (s, 2 H), 3.76 (s, 3 H), 3.46 (s, 3 H), 2.54 (dt, J= 0.9, 7.2 Hz, 2 H), 2.42 (t, J = 7.0 Hz, 2 H), 1.83 (quin, J = 7.1 Hz, 2 H). 13C NMR (75 MHz, CDCl3) δ201.2, 177.1, 153.0, 145.5, 132.6, 124.0, 122.8, 116.8, 99.4, 94.1, 82.1, 57.4, 56.0, 42.3, 20.0, 18.3. LRMS(ESI-): 289 (M-H)-. HRMS (ESI-) Calculated for C16H17O5 (M-H)-: 289.1076, found: 289.1071.OH OHOO OBrO OOO OBrCOCl2DMSOEt3NDCM60%3.64b 3.65b7-(5-Bromo-3-methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.65b). Anhydrous DMSO(2.90 mL, 48.8 mmol, 9.9 equiv) was added to a clear solution of oxalyl chloride (1.80 mL, 20.5 mmol,4.2 equiv) in 12.5 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 20 min and wasthen added to a slightly yellow solution of diol 3.64b (1.83 g, 4.9 mmol, 1.0 equiv) in 12.5 mL of DCMat -78 ◦C. The reaction mixture was stirred at -78 ◦C for 1 h. Triethylamine (8.50 mL, 61.0 mmol, 12.4equiv) was then added. The cold bath was then removed and the reaction mixture was stirred at rt for 30min. Concentration by rotary evaporation in vacuo produced a solid that was suspended in water (50 mL).The aqueous suspension was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts werewashed with water (2 x 25 mL) and brine (1 x 25 mL). Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced an orange oil that after purification using chromatography over silicagel yielded 1.10 g (60%) of the title compound as a slightly yellow oil. IR (neat): 2940, 2208, 1722, 1650,1248, 850 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.76 (s, 1 H), 7.52 (d, J = 2.3 Hz, 1 H), 7.15 (d, J = 2.3 Hz,1 H), 5.07 (s, 2 H), 3.83 (s, 3 H), 3.50 (s, 3 H), 2.62 (t, J = 7.1 Hz, 2 H), 2.51 (t, J = 6.9 Hz, 2 H), 1.91 (quin,J = 7.0 Hz, 2 H) 13CNMR (75 MHz, CDCl3) δ 201.1, 175.8, 154.0, 145.0, 133.9, 125.2, 119.8, 116.5, 99.7,95.3, 82.0, 57.8, 56.5, 42.5, 20.1, 18.6. LRMS (ESI+): 391/393 (M+Na)+. HRMS (ESI+) Calculated forC16H17O5Na79Br (M+Na)+: 391.0157, found: 391.0161.168Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsO OOO OO OOHOp-TsOHDCM42%3.65a 3.62a7-(2-Hydroxy-3-methoxyphenyl)-7-oxohept-5-ynal (3.62a). para-Toluenesulfonic acid monohydrated(78.0 mg, 0.40 mmol, 20 mol%) was added to a solution of 3.65a (0.58 g, 2.0 mmol, 1.0 equiv) in 20 mL ofregular DCM. The reaction mixture was stirred at rt for 1 h. Saturated aqueous sodium bicarbonate solution(20 mL)was added. The organic and aqueous portions were separated. The aqueous phase was extracted withDCM (2 x 20 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo producedan orange oil that after purification using chromatography over silica gel yielded 0.21 g (42%) of the titlecompound as a fluorescent, bright yellow oil. IR (neat): 2939, 2210, 1720, 1598, 1254 cm-11H NMR (400MHz, CDCl3) δ 11.91 (s, 1 H), 9.81 (s, 1 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.06 (d, J = 8.1 Hz, 1 H), 6.86 (t,J = 8.1 Hz, 1 H), 3.88 (s, 3 H), 2.66 (t, J = 7.0 Hz, 2 H), 2.59 (t, J = 7.0 Hz, 2 H), 1.99 (quin, J = 7.0 Hz,2 H). 13C NMR (101 MHz, CDCl3) δ 201.0, 182.6, 153.3, 148.7, 124.2, 120.7, 118.8, 117.9, 98.2, 79.4,56.4, 42.6, 20.2, 18.7 LRMS (ESI+): 269 (M+Na)+. HRMS (ESI+) Calculated for C14H14O4Na (M+Na)+:269.0790, found: 269.0786.O OOO OBrO OOHOBrp-TsOHDCM72%3.65b 3.62b7-(5-Bromo-2-hydroxy-3-methoxyphenyl)-7-oxohept-5-ynal (3.62b). para-Toluenesulfonic acid mono-hydrated (0.12 g, 0.6 mmol, 21 mol%) was added to a solution of 3.65b (1.10 g, 3.0 mmol, 1.0 equiv) in 30mL of DCM. The reaction mixture was stirred at rt for 1 h. Saturated aqueous sodium bicarbonate solution(50 mL) was added. The organic and aqueous portions were separated. The aqueous phase was extractedwith DCM (2 x 25 mL). The combined organic extracts were dried over sodium sulfate then magnesiumsulfate. Concentration by rotary evaporation in vacuo produced an orange oil that after purification usingchromatography over silica gel yielded 0.69 g (72%) of the title compound as a fluorescent, bright yellowoil. IR (neat): 3434, 2940, 2212, 1722, 1596, 1458, 1250, 864 cm-11H NMR (300 MHz, CDCl3) δ 11.82(s, 1 H), 9.76 (s, 1 H), 7.55 (d, J = 2.3 Hz, 1 H), 7.04 (d, J = 1.8 Hz, 1 H), 3.81 (s, 3 H), 2.60 (td, J = 7.1,18.0 Hz, 4 H), 2.05 - 1.84 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 200.8, 181.3, 152.3, 149.5, 125.6, 121.1,169Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations120.4, 110.2, 99.4, 78.9, 56.4, 42.4, 20.0, 18.6 LRMS (ESI-): 323/325 (M-H)-. HRMS (ESI+) Calculatedfor C14H13O4Na79Br (M+Na)+: 346.9895, found: 346.9896.3.7.3.2 Synthesis of Ynones 3.66OHOOOHOOO OOTBSOOONaTHFTBSCl59%3.63a 3.125a 3.71atert-butyl((1-(3-methoxy-2-(methoxymethoxy)phenyl)prop-2-yn-1-yl)oxy)dimethylsilane (3.71a). Aslurry of sodium acetylide (16.4% w/w in toluene) (4.80 mL, 15.2 mmol, 1.5 equiv) was added to 3-methoxy-2-(methoxymethoxy)benzaldehyde (3.63a) (1.97 g, 10.0 mmol, 1.0 equiv) in 50 mL of THF. After 12 h, asolution of (50% w/w solution in toluene) t-butylchlorodimethylsilane (5.90 mL, 17.0 mmol, 1.7 equiv) wasadded to the red suspension. The reaction mixture turned yellow. Water (50 mL) was added. The organicand aqueous portions were separated. The aqueous portion was extracted with diethyl ether (3 x 25 mL).The combined organic extracts were washed with brine (2 x 50 mL). Drying over sodium sulfate and concen-tration by rotary evaporation in vacuo produced a red oil that after purification using chromatography oversilica gel yielded 1.98 g (59%) of the title compound as a white solid, mp 60-61 ◦C. IR (neat): 3310, 3285,2929, 2115, 1260, 1057, 835 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.30 (dd, J = 1.4, 8.0 Hz, 1 H), 7.12 (t,J = 8.0 Hz, 1 H), 6.87 (dd, J = 1.4, 8.0 Hz, 1 H), 5.93 (d, J = 2.1 Hz, 1 H), 5.19-5.13 (m, 2 H), 3.83 (s, 3H), 3.63 (s, 3 H), 2.49 (d, J = 2.1 Hz, 1 H), 0.95 (s, 9 H), 0.20 (s, 3 H), 0.12 (s, 3 H). 13C NMR (75 MHz,CDCl3) δ 151.6, 142.1, 136.0, 124.4, 119.0, 111.6, 98.9, 85.0, 72.4, 59.1, 57.4, 55.6, 25.7, 18.1, -4.9, -5.1.LRMS (ESI+): 359 (M+Na)+. HRMS (ESI+) Calculated for C18H28O4NaSi (M+Na)+: 359.1655, found:359.1656.OHOOOHOOO OOTBSOOOTMP3NaTHFBrBr BrTBSCl52% H3.63b 3.71b((1-(5-Bromo-3-methoxy-2-(methoxymethoxy)phenyl)prop-2-yn-1-yl)oxy)(tert-butyl)dimethylsilane(3.71b). A slurry of sodium acetylide (16.4% w/v in toluene) (24.0 mL, 70.6 mmol, 1.4 equiv) was addedto 3.63b (13.8 g, 50.0 mmol, 1.0 equiv) in 250 mL of THF. After 2 h, a solution of (50% in toluene) tert-170Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsbutylchlorodimethylsilane (30.0 mL, 86.6 mmol, 1.7 equiv) was added to the red suspension. The reactionmixture changed color to yellow and water (250 mL) was added. The organic and aqueous portions wereseparated. The aqueous portion was extracted with diethyl ether (3 x 100 mL). The combined organic extractswere washed with brine (2 x 100 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a red oil that after purification using chromatography over silica gel yielded 10.8 g (52%)of the title compound as a slightly yellow solid. mp: 81-82 ◦C. IR (neat): 3293, 2954, 2116, 1579, 1471,1060, 834 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 5.84(d, J = 2.4 Hz, 1 H), 5.12 (s, 2 H), 3.82 (s, 3 H), 3.59 (s, 3 H), 2.50 (d, J = 2.4 Hz, 1 H), 0.93 (s, 9 H), 0.19(s, 3 H), 0.12 (s, 3 H). 13C NMR (101 MHz, CDCl3) δ 152.6, 141.6, 137.7, 122.3, 117.1, 115.3, 99.1, 84.6,73.1, 59.1, 57.8, 56.2, 25.9, 18.4, -4.6, -4.9 LRMS (ESI+): 437/439 (M+Na)+. HRMS (ESI+) Calculatedfor C18H27O4Na79BrSi (M+Na)+: 437.0760, found: 437.0761.OTBSHOOOOTBSOOOOTBSOHOTBSO+ LDATHF, -78 ºC86%3.71a 3.72 3.73a1-(3-Methoxy-2-(methoxymethoxy)phenyl)-1,7-bis(tert-butylsiloxy)hept-2-yn-4-ol (3.73a). n-Butyl-lithium (2.4 M in hexanes) (6.0 mL, 14.4 mmol, 1.3 equiv) was added dropwise to a solution of diisopropy-lamine (2.0 mL, 14.2 mmol, 1.3 equiv) in 55 mL of THF at -78 ◦C. The reaction mixture was stirred for1 h at -78 ◦C and a solution of 3.71a (3.70 g, 11 mmol, 1.0 equiv) in 55 mL of THF was added dropwise.The turbid red reaction mixture was stirred at -78 ◦C for 1 h and was then slowly warmed to rt. The re-action mixture was then stirred at rt for 4 h. The dark green reaction mixture was cooled to -78 ◦C and4-((tert-butyldimethylsilyl)oxy)-butanal (3.72) (3.35 g, 16.6 mmol, 1.5 equiv) in 20 mL of THF was added.The cloudy orange suspension was warmed to rt and stirred for 2 h. Saturated aqueous ammonium chloridesolution (90 mL)-water (10 mL) was added. The organic and aqueous portions were separated. The aque-ous portion was extracted with diethyl ether (3 x 50 mL). The combined organic extracts were washed withbrine (2 x 80 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo producedan orange oil that after purification using chromatography over silica gel yielded 5.07 g (86%) of the titlecompound as a clear yellow oil. IR (neat): 3414, 2954, 1252, 1052, 833 cm-1. 1H NMR (300 MHz, CDCl3)δ 7.24 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.91 (s, 1 H), 5.14 (dd, J =0.9, 5.1 Hz, 1 H), 5.09 (d, J = 5.1 Hz, 1 H), 4.37 (br. s., 1 H), 3.80 (s, 3 H), 3.68 - 3.60 (m, 2 H), 3.59 (s, 3H), 3.21 (br. s., 1 H), 1.80 - 1.54 (m, 4 H), 0.91 (s, 9 H), 0.88 (d, J = 1.4 Hz, 9 H), 0.16 (s, 3 H), 0.09 (s, 3171Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsH), 0.043 (s, 3 H), 0.040 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ 151.6, 142.1, 136.3, 124.3, 119.2, 119.1,111.4, 98.8, 85.6, 85.5, 85.3, 62.9, 61.9, 59.3, 57.4, 55.6, 34.6, 28.3, 25.8, 25.7, 18.1, -4.7, -5.1, -5.51, -5.54.LRMS (ESI+): 561 (M+Na)+. HRMS (ESI+) Calculated for C28H50O6NaSi2 (M+Na)+: 561.3044, found:561.3051.OTBSHOOOOTBSOOOOTBSOHOTBSO+ LDATHF, -78 ºC54%Br Br3.71b 3.72 3.73b1-(5-Bromo-3-methoxy-2-(methoxymethoxy)phenyl)-1,7-bis(tert-butylsiloxy)hept-2-yn-4-ol (3.73b).n-Butyllithium (2.6M in hexanes) (12.5 mL, 32.5 mmol, 1.2 equiv) was added dropwise to a solution of diiso-propylamine (4.60 mL, 32.7 mmol, 1.3 equiv) in 100 mL of THF at -78 ◦C. The reaction mixture was stirredat -78 ◦C for 1 h. It was then added to a solution of 3.71b (10.8 g, 26.0 mmol, 1.0 equiv) in 160 mL of THF.The reaction mixture was stirred at -78 ◦C for 80 min. A solution of 4-((tert-butyldimethylsilyl)oxy)butanal(3.72) (6.58 g, 32.5 mmol, 1.3 equiv) in 24 mL of THF was then added to the reaction mixture. The darkred solution became an orange suspension. The reaction mixture was stirred at -78 ◦C for 1 h. Saturatedaqueous ammonium chloride solution (250 mL) and water (20 mL) was added. The organic and aqueousportions were separated. The aqueous portion was extracted with ethyl acetate (3 x 100 mL). The combinedorganic extracts were washed with brine (3 x 100 mL). Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced a red oil that after purification using chromatography over silica gelyielded 8.61 g (54%) of the title compound as a clear yellow oil. IR (neat): 3414, 2953, 1579, 1463, 1254,1052, 833, 775 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.34 (m, 1 H), 6.95 (d, J = 2.1 Hz, 1 H), 5.84(s, 1 H), 5.13 - 5.06 (m, 2 H), 3.82 (s, 3 H), 3.64 (d, J = 4.9 Hz, 2 H), 3.59 (d, J = 1.2 Hz, 3 H), 3.01 (t, J =6.4 Hz, 1 H), 1.76 (dd, J = 1.8, 5.2 Hz, 4 H), 0.91 (s, 9 H), 0.89 (d, J = 2.4 Hz, 9 H), 0.17 (s, 3 H), 0.10 (s,3 H), 0.06 - 0.03 (m, 6 H). 13C NMR (101 MHz, CDCl3) δ 152.7, 141.6, 138.2, 122.5, 122.4, 117.0, 115.2,99.1, 85.9, 85.3, 63.2, 62.3, 59.3, 57.8, 56.3, 35.2, 28.6, 26.1, 26.0, 18.5, 18.5, -4.4, -4.8, -5.19, -5.22 LRMS(ESI+): 617/619 (M+H)+. HRMS (ESI+) Calculated for C28H49O6NaSi279Br (M+Na)+: 639.2149, found:639.2144.172Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOTBSHOOOOTBSOOOOTBSOHOTBSO+ LDATHF, -78 ºC9%Br N3.71b 3.72 3.73d5-(5-(Diisopropylamino)-3-methoxy-2-(methoxymethoxy)phenyl)-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-3,13-disilapentadec-6-yn-8-ol (3.73d). n-Butyllithium (2.6 M in hexanes) (12.5 mL, 32.5 mmol,1.2 equiv) was added dropwise to a solution of diisopropylamine (4.60 mL, 32.7 mmol, 1.3 equiv) in 100mL of THF at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 1 h. It was then added to a solutionof 3.71b (10.8 g, 26.0 mmol, 1.0 equiv) in 160 mL of THF. The reaction mixture was stirred at -78 ◦C for80 min. A solution of 4-((tert-butyldimethylsilyl)oxy)butanal (3.72) (6.58 g, 32.5 mmol, 1.3 equiv) in 24mL of THF was then added to the reaction mixture. The dark red solution became an orange suspension.The reaction mixture was stirred at -78 ◦C for 1 h. Saturated aqueous ammonium chloride solution (250mL) and water (20 mL) was added. The organic and aqueous portions were separated. The aqueous portionwas extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (3 x100 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced a red oilthat after purification using chromatography over silica gel yielded 1.47 g (9%) of the title compound as aclear yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.83 (d, J = 1.5 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.86 (s,1H), 5.10-5.04 (m, 2H), 4.43-4.38 (m, 1H), 3.80 (s, 3H), 3.73-3.63 (m, 4H), 3.61 (s, 3H), 2.76 (br s, 1H),1.77-1.73 (m, 2H), 1.67 (dt, J = 11.3, 5.7 Hz, 2H), 1.17 (s, 6H), 1.14 (s, 6H), 0.91 (s, 9H), 0.89 (s, 9H), 0.16(s, 3H), 0.09 (s, 3H), 0.05 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 151.6, 144.8, 135.8, 112.1, 111.9, 106.9,106.8, 99.3, 86.4, 85.2, 63.2, 62.4, 59.8, 57.6, 56.0, 48.2, 35.0, 28.7, 26.1, 26.0, 21.7, 21.6, 18.5, 18.5, -4.4,-4.7, -5.2. LRMS (ESI+): 638.6 (M+H)+. HRMS (ESI+)Calculated for C34H64NO6Si2 (M+H)+: 638.4272,found: 638.4268.OTBSOOOOBnOTBSOTBSOOOOHOTBSNaH, BnBrTHF99%3.73a 3.74a4-(Benzyloxy)-1-(3-methoxy-2-(methoxymethoxy)phenyl)-1,7-bis(tert-butyldimethylsiloxy) hept-2-yne (3.74a). A suspension of hexanes-washed sodium hydride (0.32 g, 8.00 mmol, 2 equiv) in 20 mL ofanhydrous DMF was added to a solution of 3.73a (2.10 g, 3.90 mmol, 1.0 equiv) and benzyl bromide (0.94173Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsmL, 7.9 mmol, 2 equiv) in 20 mL of anhydrous DMF. The light yellow solution immediately turned intoan orange suspension. The reaction mixture was stirred at rt for 5h. It was then stopped by the addition ofsaturated aqueous ammonium chloride solution (25 mL) and water (25 mL). The resulting solution was thenextracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL)and brine (1 x 50 mL).DnC a thick orange oil that after purification using chromatography over silica gelyielded 2.45 g (99%) of the title compound as a slightly yellow oil. IR (neat): 3031, 2929, 2856, 1462, 1256,1052, 834 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.44 - 7.31 (m, 6 H), 7.19 (t, J = 7.9 Hz, 1 H), 6.94 (d, J =8.3 Hz, 1 H), 6.08 (s, 1 H), 5.28 - 5.20 (m, 2 H), 4.83 (dd, J = 1.6, 11.8 Hz, 1 H), 4.53 (dd, J = 1.6, 11.8 Hz,1 H), 4.22 (t, J = 6.4 Hz, 1 H), 3.92 (s, 3 H), 3.69 (s, 3 H), 3.6738 - 3.65 (m, 2 H), 1.96 - 1.82 (m, 2 H), 1.82 -1.64 (m, 2 H), 1.03 (s, 9 H), 0.97 (d, J = 1.6 Hz, 9 H), 0.29 (s, 3 H), 0.22 (s, 3 H), 0.12 (s, 3 H), 0.11 (s, 3 H).13C NMR (101 MHz, CDCl3) δ 151.9, 142.5, 142.5, 138.31, 138.29, 136.74, 136.72, 128.4, 128.2, 127.7,124.6, 119.7, 119.6, 111.7, 99.2, 87.64, 87.59, 83.64, 83.59, 70.47, 70.45, 68.8, 62.9, 59.6, 57.7, 55.9, 32.3,28.8, 26.1, 26.0, 18.46, 18.44, -4.4, -4.7, -5.2. LRMS (ESI+): 651 (M+Na)+. HRMS (ESI+) Calculated forC35H56O6NaSi2 (M+Na)+: 651.3513, found: 651.3515.OTBSOOOOBnOTBSOTBSOOOOHOTBSNaH, BnBrTHF92%Br Br3.73b 3.74b4-(Benzyloxy)-1-(5-bromo-3-methoxy-2-(methoxymethoxy)phenyl)-1,7-bis(tert-butyldimethylsiloxy)hept-2-yne (3.74b). A suspension of hexanes-washed sodium hydride (1.18 g, 29.5 mmol, 2.3 equiv) in 30mL of anhydrous DMF was added to a solution of 3.73b (7.93 g, 12.8 mmol, 1.0 equiv) and benzyl bromide(3.1 mL, 26.0 mmol, 2 equiv) in 100 mL of anhydrous DMF. The light yellow solution immediately turnedinto an orange suspension. The reaction mixture was stirred at rt for 5h. Saturated aqueous ammonium chlo-ride solution (100 mL) and water (10 mL) was added. The resulting solution was then extracted with ethylacetate (3 x 100 mL). The combined organic extracts were washed with water and brine (2 x 100 mL each).Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced a thick, orange oilthat after purification using chromatography over silica gel yielded 8.33 g (92%) of the title compound as aslightly yellow oil. IR (neat): 2953, 2856, 1463, 1254, 1053, 833, 774 cm-1. 1H NMR (400 MHz, CDCl3)δ 7.46 (t, J = 2.4 Hz, 1 H), 7.37 - 7.32 (m, 5 H), 7.00 (dd, J = 1.4, 2.4 Hz, 1 H), 5.94 (d, J = 1.4 Hz, 1 H),5.14 (s, 2 H), 4.77 (d, J = 11.6 Hz, 1 H), 4.48 (dd, J = 1.7, 11.6 Hz, 1 H), 4.16 (t, J = 6.5 Hz, 1 H), 3.85(d, J = 1.0 Hz, 3 H), 3.66 - 3.62 (m, 2 H), 3.61 (s, 3 H), 1.88 - 1.76 (m, 2 H), 1.76 - 1.63 (m, 2 H), 0.97 (d,174Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsJ = 1.0 Hz, 9 H), 0.91 (d, J = 1.7 Hz, 9 H), 0.23 (d, J = 1.7 Hz, 3 H), 0.16 (s, 3 H), 0.06 (s, 3 H), 0.05 (s,3 H). 13C NMR (101 MHz, CDCl3) δ 152.7, 141.70, 141.66, 138.22, 138.19, 128.6, 128.5, 128.3, 127.9,127.7, 122.58, 122.56, 117.0, 115.2, 99.1, 86.90, 86.87, 84.14, 84.09, 70.58, 70.54, 68.72, 68.69, 62.9, 59.3,57.8, 56.2, 32.3, 28.8, 26.1, 26.0, 18.5, 18.4, -4.4, -4.7, -5.1 LRMS (ESI+): 729/731 (M+Na)+. HRMS(ESI+) Calculated for C35H55O6NaSi279Br (M+Na)+: 729.2618, found: 729.2622.OTBSOOOOBnOTBSTMSOTBSOOOOBnOTBSBrTMSCuI(Ph3P)4PdiPr2NH87%3.74b 3.74c4-(Benzyloxy)-1-(3-methoxy-2-(methoxymethoxy)-5-((trimethylsilyl)ethynyl)phenyl)-1,7-bis(tert-bu-tyldimethylsiloxy)hept-2-yne (3.74c). Ethynyltrimethylsilane (0.28 mL, 1.98 mmol, 2 equiv) was added toa suspension of 3.74b (0.71g, 1.00 mmol, 1.0 equiv), copper (I) iodide (12.3 mg, 0.064 mmol, 6.4 mol%) andtetrakistriphenylphosphine palladium (0) (36.0 mg, 0.031 mmol, 3.1 mol%) in 10 mL of diisopropylamine.The reaction mixture was stirred at 60 ◦C for 48 h. Even though there was still some unreacted startingmaterial, the reaction mixture was stopped by addition of saturated aqueous sodium bicarbonate solution (10mL). The newly formed solution was extracted with diethyl ether (3 x 10 mL). The combined organic extractswere washed with brine (2 x 10 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a thick, black oil that after purification using chromatography over silica gel yielded 0.68g (87%) of the title compound as a light brown oil. IR (neat): 2956, 2858, 2158, 1580, 1464, 1250, 1056,776, 732 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 2.0 Hz, 1 H), 7.36 - 7.26 (m, 5 H), 6.98 (t, J =1.5 Hz, 1 H), 5.95 (s, 1 H), 5.19 - 5.15 (m, 2 H), 4.77 (dd, J = 3.2, 11.7 Hz, 1 H), 4.48 (dd, J = 3.2, 11.7Hz, 1 H), 4.19 - 4.12 (m, 1 H), 3.87 (s, 3 H), 3.66 - 3.62 (m, 2 H), 3.61 (s, 3 H), 1.89 - 1.75 (m, 2 H), 1.75 -1.61 (m, 2 H), 0.97 (d, J = 1.2 Hz, 9 H), 0.91 (d, J = 2.4 Hz, 9 H), 0.29 (s, 9 H), 0.24 - 0.20 (m, 3 H), 0.16(s, 3 H), 0.06 (d, J = 3.0 Hz, 6 H) 13C NMR (101 MHz, CDCl3) δ 151.5, 143.2, 138.2, 136.7, 128.5, 128.3,128.3, 127.7, 124.1, 119.2, 115.1, 105.3, 99.2, 99.2, 93.3, 87.2, 87.2, 83.8, 70.5, 68.7, 62.9, 59.4, 57.8, 56.1,32.4, 28.8, 26.1, 26.0, 18.5, 0.2, -4.4, -4.7, -5.1. LRMS (ESI+): 747 (M+Na)+. HRMS (ESI+) Calculatedfor C40H64O6NaSi3 (M+Na)+: 747.3908, found: 747.3913.175Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOTBSOOOOBnOTBSNNaH, THF69%OTBSOOOOTBSOHN3.73d 3.74d3-(8-(Benzyloxy)-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-3,13-disilapentadec-6-yn-5-yl)-N,N-di-isopropyl-5-methoxy-4-(methoxymethoxy)aniline (3.74d). A suspension of hexanes-washed sodium hy-dride (0.23 g, 5.7 mmol, 2.0 equiv) in 20 mL of anhydrous DMF was added to a solution of 3.73d (1.65 g,2.6 mmol, 1.0 equiv) and benzyl bromide (0.62 mL, 5.2 mmol, 2.0 equiv) in 5 mL of anhydrous DMF. Thelight yellow solution immediately turned into an orange suspension. The reaction mixture was stirred at rtfor 1 h. The reaction mixture was quenched with water (50 mL). The resulting solution was then extractedwith ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine (2 x 50 mLeach). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced a yellow oilthat after purification using chromatography over silica gel yielded 1.29 g (69%) of the title compound as aslightly yellow oil. IR (neat): 2956, 2856, 1606, 1464, 1056 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.37-7.31(m, 5H), 6.98 (t, J = 1.1 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.15 (s, 2H), 4.81 (d,J = 11.6 Hz, 1H), 4.51 (dd, J = 11.6, 3.6 Hz, 1H), 4.19 (t, J = 5.9 Hz, 1H), 3.87 (s, 3H), 3.75 (ddd, J =13.2, 6.6, 2.3 Hz, 2H), 3.67 (s, 3H), 3.72-3.64 (m, 2H), 1.90-1.82 (m, 2H), 1.77-1.69 (m, 2H), 1.34 (s, 6H),1.22 (d, J = 2.1 Hz, 6H), 1.20 (d, J = 2.1 Hz, 6H), 1.00 (s, 9H), 0.95 (s, 9H), 0.26 (s, 3H), 0.18 (s, 3H),0.09 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 151.6, 144.8, 138.3, 138.3, 136.2, 135.9, 135.9, 128.4, 128.2,127.6, 112.8, 112.6, 107.4, 107.3, 99.3, 88.0, 87.9, 83.2, 70.4, 68.7, 62.9, 59.7, 57.5, 55.9, 48.2, 32.4, 28.8,26.0, 21.7, 21.5, 18.4, 14.4, -4.4, -4.6, -5.2. LRMS (ESI+): 728.7 (M+H)+. HRMS (ESI+) Calculated forC41H70NO6Si2 (M+H)+: 728.4742, found: 728.4740.OTBSOOOOBnOTBS OHOOOOBnOHTBAFTHF99%3.74a 3.67a4-(Benzyloxy)-1-(3-methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol (3.67a). A clear solu-tion of 3.74a (8.17 g, 13.0 mmol, 1.0 equiv) in 130 mL of THF at rt was treated with a 1.0 M solution oftetrabutylammonium fluoride (30.0 mL, 30.0 mmol, 2.3 equiv). The solution immediately turned yellowand was stirred at rt for 2.5 h. Concentration by rotary evaporation in vacuo produced a red oil that after176Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationspurification using chromatography over silica gel yielded 5.17 g (99%) of the title compound as a slightlyyellow oil. IR (neat): 3392, 2938, 1587, 1480, 1263, 1058, 958 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.41 -7.26 (m, 6 H), 7.13 (t, J = 7.9 Hz, 1 H), 6.93 (dd, J = 1.2, 8.2 Hz, 1 H), 5.88 (t, J = 1.8 Hz, 1 H), 5.17 (dd,J = 1.2, 6.1 Hz, 1 H), 5.11 (dd, J = 0.8, 5.9 Hz, 1 H), 4.85 (dd, J = 5.3, 11.7 Hz, 1 H), 4.53 (dd, J = 3.0,11.6 Hz, 1 H), 4.31 - 4.23 (m, 1 H), 3.86 (s, 3 H), 3.64 (t, J = 6.2 Hz, 2 H), 3.60 (s, 3 H), 2.69 (br. s., 1 H),1.96 - 1.86 (m, 2 H), 1.84 - 1.72 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 151.8, 143.5, 137.7, 135.3, 135.2,128.3, 128.1, 128.0, 127.6, 124.8, 119.8, 112.5, 99.1, 85.9, 84.5, 84.5, 70.5, 68.6, 62.0, 59.5, 57.6, 55.8,32.1, 28.4. LRMS (ESI+): 423 (M+Na)+. HRMS (ESI+) Calculated for C23H28O6Na (M+Na)+: 423.1784,found: 423.1795.OTBSOOOOBnOTBS OHOOOOBnOHTBAFTHF83%Br Br3.74b 3.67b4-(Benzyloxy)-1-(5-bromo-3-methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol (3.67b). A so-lution of 3.74b (8.78 g, 12.4 mmol, 1.0 equiv) in 130 mL of THF at rt was treated with a 1.0 M solution oftetrabutylammonium fluoride (27.0 mL, 27.0 mmol, 2.2 equiv. The solution immediately turned yellow andwas stirred at rt for 1.25 h. Concentration by rotary evaporation in vacuo produced an orange oil that afterpurification using chromatography over silica gel yielded 4.91 g (83%) of the title compound as a slightlyyellow oil. IR (neat): 3380, 2939, 1578, 1480, 1285, 1058, 954 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.47(d, J = 1.5 Hz, 1 H), 7.38 - 7.24 (m, 6 H), 7.02 (d, J = 2.1 Hz, 1 H), 5.84 (br. s., 1 H), 5.12 (dd, J = 1.2,5.8 Hz, 1 H), 5.07 (d, J = 6.1 Hz, 1 H), 4.80 (dd, J = 2.1, 11.6 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.34(d, J = 4.3 Hz, 1 H), 4.27 - 4.19 (m, 1 H), 3.80 (s, 3 H), 3.63 - 3.58 (m, 2 H), 3.57 (s, 3 H), 2.89 (br. s., 1H), 1.92 - 1.80 (m, 2 H), 1.74 (quin, J = 6.5 Hz, 2 H). 13C NMR (101 MHz, CDCl3) δ 152.7, 142.7, 137.6,136.92, 136.88, 128.4, 128.1, 127.7, 122.8, 117.1, 115.8, 99.1, 85.42, 85.36, 85.03, 84.98, 70.68, 70.67,68.58, 68.56, 65.8, 62.1, 59.01, 59.00, 57.7, 56.1, 32.1, 28.40, 28.39. LRMS (ESI+): 501/503 (M+Na)+.HRMS (ESI+) Calculated for C23H27O6Na79Br (M+Na)+: 501.0889, found: 501.0899.177Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOTBSOOOOBnOTBSTMS OHOOOOBnOHTBAFTHF82%3.74c 3.67c4-(Benzyloxy)-1-(5-ethynyl-3-methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol (3.67c). Aclear solution of 3.74c (0.40 g, 0.54 mmol, 1.0 equiv) in 10 mL of THF (10 mL) at rt was treated with a1.0 M solution of TBAF (1.80 mL, 1.80 mmol, 3.3 equiv). The solution immediately turned orange and wasstirred at rt for 2 h. One drop of aqueous 3 M HCl was added. Concentration by rotary evaporation in vacuoproduced an orange oil that after purification using chromatography over silica gel yielded 187.0 mg (82%)of the title compound as an orange oil. IR (neat): 2980, 2946, 2600, 2496, 1476, 1398, 1172, 1036 cm-1. 1HNMR (300 MHz, CDCl3) δ 7.49 (s, 1 H), 7.39 - 7.23 (m, 6 H), 7.02 (s, 1 H), 5.84 (br. s., 1 H), 5.17 (d, J =5.7 Hz, 1 H), 5.10 (d, J = 5.7 Hz, 1 H), 4.82 (d, J = 11.6 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.24 (t, J =5.4 Hz, 1 H), 4.15 (br. s., 1 H), 3.82 (s, 3 H), 3.65 - 3.59 (m, 2 H), 3.58 (d, J = 1.4 Hz, 3 H), 3.09 (s, 1 H),2.67 (br. s., 1 H), 1.95 - 1.82 (m, 2 H), 1.82 - 1.68 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 151.7, 144.4,137.7, 135.5, 135.5, 128.4, 128.2, 127.8, 124.3, 118.5, 115.9, 99.3, 85.5, 85.4, 85.0, 85.0, 83.2, 77.1, 70.8,68.6, 68.6, 62.2, 59.4, 59.4, 57.8, 56.0, 32.2, 28.5. MS (ESI+): 447 (M+Na)+. HRMS (ESI+) Calculatedfor C25H28O6Na (M+Na)+: 447.1784, found: 447.1787.OTBSOOOOBnOTBSNOHOOOOBnOHNTBAFTHF94%3.74d 3.67d4-(Benzyloxy)-1-(5-(diisopropylamino)-3-methoxy-2-(methoxymethoxy)phenyl)hept-2-yne-1,7-diol(3.67d). A clear solution of 3.74d (1.29 g, 1.8 mmol, 1.0 equiv) in 20 mL of THF at rt was treated with a 1.0M solution of tetrabutylammonium fluoride (4.0 mL, 4.0 mmol, 2.2 equiv. The solution immediately turnedyellow and was stirred at rt for 1.5 h. Concentration by rotary evaporation in vacuo produced an orange oilthat after purification using chromatography over silica gel yielded 0.83 g (94%) of the title compound as aslightly yellow oil. IR (neat): 3390, 2966, 1606, 1488, 1060 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.36-7.28(m, 5H), 6.87 (t, J = 2.2 Hz, 1H), 6.51 (dd, J = 4.1, 2.8 Hz, 1H), 5.84 (d, J = 3.7 Hz, 1H), 5.11 (d, J = 6.0 Hz,1H), 5.04 (d, J = 6.0 Hz, 1H), 4.86 (dd, J = 11.7, 3.6 Hz, 1H), 4.53 (dd, J = 11.7, 3.1 Hz, 1H), 4.31-4.26 (m,178Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations1H), 3.89 (t, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.75-3.61 (m, 4H), 3.59 (s, 3H), 1.92 (qd, J = 6.8, 3.3 Hz, 2H),1.83-1.74 (m, 2H), 1.23 (dd, J = 14.6, 7.5 Hz, 2H), 1.18 (s, 6H), 1.16 (s, 6H). 13C NMR (75 MHz, CDCl3)δ 151.8, 145.5, 145.3, 138.0, 137.4, 134.7, 128.5, 128.2, 127.9, 112.3, 111.8, 106.6, 106.3, 99.7, 86.0, 84.9,84.8, 70.9, 68.9, 68.8, 66.0, 62.6, 62.5, 60.7, 57.8, 56.1, 48.2, 48.2, 32.5, 28.9, 21.7, 21.5, 21.4, 15.5. LRMS(ESI+): 500.4 (M+H)+. HRMS (ESI+) Calculated for C29H42NO6 (M+H)+: 500.3012, found: 500.3008.OHOOOOBnOH OOOOOBnOCOCl2DMSOEt3NDCM70%3.67a 3.75a4-(Benzyloxy)-7-(3-methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.75a). Anhydrous DMSO(1.50 mL, 21.1 mmol, 8.4 equiv) was added to a clear solution of oxalyl chloride (0.88 mL, 10.0 mmol, 4equiv) in 30 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 15 min and a slightlyyellow solution of diol 3.67a (1.00 g, 2.5 mmol, 1.0 equiv) in 6 mL of DCM at -78 ◦C was then added in oneportion. The reaction mixture was further stirred at -78 ◦C for 1.5 h. Triethylamine (4.2 mL, 30.1 mmol, 12equiv) was then added. The reaction mixture was stirred at -78 ◦C for 2 h, letting it slowly warm to rt. Itwas then stopped by the addition of water (50 mL). The organic and aqueous portions were separated. Theaqueous portion was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washedwith water and brine (1 x 50 mL each). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a red oil that after purification using chromatography over silica gel yielded 0.69 g (70%)of the title compound as a slightly yellow oil. IR (neat): 2936, 2213, 1721, 1650, 1578, 1262, 1073, 935cm-1. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1 H), 7.49 (dd, J = 2.4, 7.2 Hz, 1 H), 7.38 - 7.26 (m, 5 H), 7.19- 7.11 (m, 2 H), 5.18 (dd, J = 5.8, 5.8 Hz, 2 H), 4.84 (d, J = 11.6 Hz, 1 H), 4.54 (d, J = 11.6 Hz, 1 H), 4.41(t, J = 6.1 Hz, 1 H), 3.87 (s, 3 H), 3.57 (s, 3 H), 2.77 - 2.60 (m, 2 H), 2.24 - 2.13 (m, 2 H). 13C NMR (101MHz, CDCl3) δ 201.2, 176.7, 153.3, 146.1, 137.2, 132.5, 128.6, 128.15, 128.09, 124.3, 123.1, 117.4, 99.7,90.9, 86.1, 71.4, 67.5, 57.8, 56.3, 39.6, 27.8. LRMS (ESI+): 419 (M+Na)+. HRMS (ESI+) Calculated forC23H24O6Na (M+Na)+: 419.1471, found: 419.1475.179Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOHOOOOBnOH OOOOOBnOCOCl2DMSOEt3NDCM34%Br Br3.67b 3.75b4-(Benzyloxy)-7-(5-bromo-3-methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.75b). An-hydrous DMSO (4.30 mL, 60.5 mmol, 8.1.0 equiv) was added to a clear solution of oxalyl chloride (2.70mL, 30.8 mmol, 4.1.0 equiv) in 36 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 20min and was then added to a slightly yellow solution of diol 3.67b (3.57 g, 7.5 mmol, 1.0 equiv) in 36 mL ofDCM at -78 ◦C. The reaction mixture was further stirred at -78 ◦C for 1.25 h. Triethylamine (12.5 mL, 89.7mmol, 12.0 equiv) was then added. The cold bath was removed and the reaction mixture was stirred at rtfor 30 min. Concentration by rotary evaporation in vacuo produced yielded a solid that was then suspendedin water (100 mL). The aqueous suspension was extracted with ethyl acetate (3 x 50 mL). The combinedorganic extracts were washed with water (2 x 50 mL) and brine (1 x 50 mL). Drying over sodium sulfate andconcentration by rotary evaporation in vacuo produced a red oil that after purification using chromatographyover silica gel yielded 1.20 g (34%) of the title compound as a slightly yellow oil. IR (neat): 2936, 2212,1721, 1654m, 1459, 1251, 1052, 928 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.78 (s, 1 H), 7.61 (d, J = 2.3Hz, 1 H), 7.39 - 7.28 (m, 5 H), 7.22 (d, J = 2.3 Hz, 1 H), 5.14 (s, 2 H), 4.84 (d, J = 11.4 Hz, 1 H), 4.54 (d,J = 11.6 Hz, 1 H), 4.41 (t, J = 6.2 Hz, 1 H), 3.88 (s, 3 H), 3.55 (s, 3 H), 2.75 - 2.65 (m, 2 H), 2.20 (q, J =7.0 Hz, 2 H). 13C NMR (75 MHz, CDCl3) δ 201.2, 175.3, 154.1, 145.4, 137.1, 133.6, 128.7, 128.3, 128.2,125.3, 120.3, 116.7, 99.8, 92.0, 85.7, 71.5, 67.5, 58.0, 56.6, 39.6, 27.8. LRMS (ESI+): 497/499 (M+Na)+.HRMS (ESI+) Calculated for C23H23O6Na79Br (M+Na)+: 497.0576, found: 497.0583.OOOOOBnOOHOOOOBnOHCOCl2DMSOEt3N64%3.67c 3.75c4-(Benzyloxy)-7-(5-ethynyl-3-methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.75c). An-hydrous DMSO (0.25 mL, 3.5 mmol, 8 equiv) was added to a clear solution of oxalyl chloride (0.16 mL, 1.8mmol, 4.1.0 equiv) in 5 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 15 min andwas then added to a slightly yellow solution of diol 3.67c (0.19 g, 0.4 mmol, 1.0 equiv) in 3 mL of DCMat -78 ◦C. The reaction mixture was stirred at -78 ◦C for 45 min. Triethylamine (0.74 mL, 5.3 mmol, 12.0180Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsequiv) was then added. The reaction mixture was stirred at -78 ◦C for 1 h letting it slowly warm to -70 ◦C.The cold bath was then removed and the reaction mixture was stirred at rt for 30 min. Concentration byrotary evaporation in vacuo produced a solid that was treated with water (20 mL). The aqueous suspensionwas extracted with DCM (3 x 10 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a red oil that after purification using chromatography over silica gel yielded 0.12 g (64%)of the title compound as a slightly yellow oil. IR (neat): 3286, 2940, 2210, 1722, 1654, 1464, 1328, 1254,1028, 932 cm-1. 1H NMR (300 MHz, CDCl3) δ 9.75 (d, J = 1.1 Hz, 1 H), 7.65 (t, J = 1.6 Hz, 1 H), 7.40 -7.25 (m, 5 H), 7.22 - 7.16 (m, 1 H), 5.20 - 5.14 (m, 2 H), 4.88 - 4.79 (m, 1 H), 4.57 - 4.49 (m, 1 H), 4.45 -4.36 (m, 1 H), 3.86 (d, J = 1.1 Hz, 3 H), 3.54 (d, J = 1.4 Hz, 3 H), 3.13 (d, J = 1.1 Hz, 1 H), 2.73 - 2.63 (m,2 H), 2.24 - 2.13 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 201.1, 175.7, 153.0, 146.6, 137.0, 132.3, 128.5,128.2, 128.1, 127.0, 120.0, 118.1, 99.7, 91.6, 85.7, 82.2, 78.0, 71.4, 67.5, 57.9, 56.3, 39.5, 27.7. LRMS(ESI+): 443 (M+Na)+. HRMS (ESI+) Calculated for C25H24O6Na (M+Na)+: 443.1471, found: 443.1469.OOOOOBnONOHOOOOBnOHNCOCl2DMSOEt3N74%3.67d 3.75d4-(Benzyloxy)-7-(5-(diisopropylamino)-3-methoxy-2-(methoxymethoxy)phenyl)-7-oxohept-5-ynal (3.75d).Anhydrous DMSO (0.95 mL, 13.4 mmol, 8.0 equiv) was added to a clear solution of oxalyl chloride (0.59mL, 6.7 mmol, 4.0 equiv) in 8 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 20 minand was then added to a slightly yellow solution of diol 3.67d (0.83 g, 1.7 mmol, 1.0 equiv) in 8 mL of DCMat -78 ◦C. The reaction mixture was further stirred at -78 ◦C for 1 h. Triethylamine (2.8 mL, 20.1 mmol,12.0 equiv) was then added. The cold bath was removed and the reaction mixture was stirred at rt for 30 min.Concentration by rotary evaporation in vacuo produced yielded a solid that was then suspended in water (50mL). The aqueous suspension was extracted with ethyl acetate (3 x 20 mL). The combined organic extractswere washed with brine (1 x 25 mL). Drying over sodium sulfate and concentration by rotary evaporation invacuo produced a red oil that after purification using chromatography over silica gel yielded 0.61 g (74%) ofthe title compound as a slightly yellow oil. 1HNMR (400 MHz, CDCl3) δ 9.78 (t, J = 1.8 Hz, 1H), 7.38-7.29(m, 5H), 6.86 (s, 1H), 6.10 (s, 1H), 5.47 (t, J = 6.1 Hz, 1H), 5.11-5.08 (m, 2H), 4.64 (d, J = 11.2 Hz, 1H),4.32 (d, J = 11.2 Hz, 1H), 3.83 (s, 3H), 3.51 (dd, J = 13.0, 6.6 Hz, 2H), 3.48 (s, 3H), 2.75-2.65 (m, 1H),2.63-2.55 (m, 1H), 2.21-2.12 (m, 2H), 1.07 (s, 6H), 1.05 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 202.4,181Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations187.5, 170.4, 150.7, 142.0, 139.9, 137.6, 137.1, 128.4, 127.9, 124.0, 118.3, 115.1, 99.3, 78.2, 72.2, 57.6,56.1, 50.1, 40.8, 29.4, 21.3, 21.3, 14.5.OOOOOBnO OOHO OBnOp-TsOHDCM94%3.75a 3.66a4-(Benzyloxy)-7-(2-hydroxy-3-methoxyphenyl)-7-oxohept-5-ynal (3.75a). para-Toluenesulfonic acidmonohydrated (65 mg, 0.3 mmol, 13 mol%) was added to a solution of 3.75a (1.00 g, 2.5 mmol, 1.0 equiv) in25mL of regular DCM. The reaction mixture was stirred at rt for 16 h. Saturated aqueous sodium bicarbonatesolution (50 mL) was added. The organic and aqueous portions were separated. The aqueous portion wasextracted with DCM (3 x 25 mL). DnC an orange oil that after purification using chromatography over silicagel yielded 0.84 g (94%) of the title compound as a fluorescent, bright yellow oil. IR (neat): 2938, 2219,1721, 1598, 1453, 1252, 1085, 736 cm-1. 1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1 H), 9.79 (s, 1 H), 7.55(dd, J = 1.4, 8.2 Hz, 1 H), 7.42 - 7.28 (m, 5 H), 7.11 (d, J = 7.5 Hz, 1 H), 6.90 (t, J = 8.0 Hz, 1 H), 4.85 (d,J = 11.9 Hz, 1 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.46 (t, J = 6.1 Hz, 1 H), 3.91 (s, 3 H), 2.77 - 2.67 (m, 2 H),2.29 - 2.17 (m, 2 H). 13C NMR (101 MHz, CDCl3) δ 201.0, 181.9, 153.4, 148.8, 136.9, 128.7, 128.3, 128.2,124.0, 120.6, 119.1, 118.2, 94.9, 82.9, 71.7, 67.5, 56.4, 39.5, 27.8. LRMS (ESI+): 375 (M+Na)+. HRMS(ESI+) Calculated for C21H20O5Na (M+Na)+: 375.1208, found: 375.1202.OOOOOBnO OOHO OBnOp-TsOHDCM76%Br Br3.75b 3.66b4-(Benzyloxy)-7-(5-bromo-2-hydroxy-3-methoxyphenyl)-7-oxohept-5-ynal (3.66b). para-Toluenesul-fonic acid monohydrated (20.9 mg, 0.10 mmol, 18 mol%) was added to a solution of 3.75b (0.28 g, 0.6 mmol,1.0 equiv) in 10 mL of DCM. The reaction mixture was stirred at rt for 2 h. Saturated aqueous sodium bicar-bonate solution (25 mL) was added. The organic and aqueous portions were separated. The aqueous portionwas extracted with DCM (3 x 10 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced an orange oil that after purification using chromatography over silica gel yielded 0.18 g(76%) of the title compound as a fluorescent, bright yellow oil. IR (neat): 3086, 2937, 2213, 1721, 1599,1456, 1438, 1251, 1052 cm-1. 1H NMR (300 MHz, CDCl3) δ 11.78 (s, 1 H), 9.80 (s, 1 H), 7.69 (d, J = 2.1182Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsHz, 1 H), 7.44 - 7.30 (m, 5 H), 7.17 (d, J = 2.1 Hz, 1 H), 4.86 (d, J = 11.6 Hz, 1 H), 4.58 (d, J = 11.4 Hz, 1 H),4.48 (t, J = 6.3 Hz, 1 H), 3.92 (s, 3 H), 2.78 - 2.67 (m, 2 H), 2.25 (q, J = 6.9 Hz, 2 H). 13C NMR (75 MHz,CDCl3) δ 200.9, 180.9, 152.7, 149.9, 136.8, 128.8, 128.5, 128.4, 125.7, 121.2, 121.0, 110.7, 96.1, 82.5,72.0, 67.5, 56.7, 39.6, 27.8. LRMS (ESI+): 431/433 (M+H)+. HRMS (ESI+) Calculated for C21H20O579Br(M+H)+: 431.0494, found: 431.0501.OOOOOBnO OOHO OBnOp-TsOHDCM73%3.75c 3.66c4-(Benzyloxy)-7-(5-ethynyl-2-hydroxy-3-methoxyphenyl)-7-oxohept-5-ynal (3.66c). para-Toluenesul-fonic acid monohydrated (11.5 mg, 0.061 mmol, 22 mol%) was added to a solution of 2c (0.12 g, 0.28 mmol,1.0 equiv) in 5 mL of regular DCM. The reaction mixture was stirred at rt for 1 h. Saturated aqueous sodiumbicarbonate solution (20 mL) was added. The organic and aqueous portions were separated. The aque-ous portion was extracted with DCM (3 x 10 mL). Drying over sodium sulfate and concentration by rotaryevaporation in vacuo produced a thick, brown oil that after purification using chromatography over silica gelyielded 76.0 mg (73%) of the title compound as a fluorescent, bright yellow oil. IR (neat): 3282, 2942, 2215,1720, 1650, 1604, 1580, 1444, 1282, 1136, 1064 cm-1. 1H NMR (400 MHz, CDCl3) δ 12.00 (d, J = 1.8 Hz,1 H), 9.83 (s, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.53 - 7.29 (m, 5 H), 7.20 (br. s., 1 H), 4.90 (dd, J = 2.0, 11.4Hz, 1 H), 4.61 (dd, J = 1.8, 11.6 Hz, 1 H), 4.58 - 4.42 (m, 1 H), 3.94 (d, J = 2.1 Hz, 3 H), 3.11 (d, J = 2.4Hz, 1 H), 2.91 - 2.61 (m, 2 H), 2.37 - 2.21 (m, 2 H). 13C NMR (101 MHz, CDCl3) δ 200.9, 181.3, 154.0,148.7, 136.8, 128.7, 128.3, 128.1, 120.5, 120.1, 113.0, 95.9, 82.5, 76.7, 71.9, 67.5, 56.4, 39.5, 27.7 LRMS(ESI+): 399 (M+Na)+. HRMS (ESI+) Calculated for C23H21O5 (M+H)+: 377.1389, found: 377.1389.3.7.3.3 Synthesis of Ynone 3.79OTMSHOOOHOOO Oa) NaCCHb) TMSClTHF, 90%TMP33.126((1-(3-Methoxy-2-(methoxymethoxy)phenyl)prop-2-yn-1-yl)oxy)trimethylsilane (3.126). A slurry ofsodium acetylide (16.4% w/w in toluene) (9.5 mL, 30.1 mmol, 1.5 equiv) was added to a solution of 2.143183Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations(3.92 g, 20.0 mmol, 1.0 equiv) in 100 mL of THF over a period of 25 min with the aid of a syringe pump.After stirring at rt for 16 h, a solution of chlorotrimethylsilane (4.5 mL, 34.5 mmol, 1.7 equiv) was addedto the orange suspension. The reaction mixture turned yellow and was further stirred at rt for 1h. Water (50mL) was added. The organic and aqueous portions were separated. The aqueous portion was extracted withdiethyl ether (2 x 50 mL). The combined organic fractions were washed with brine (2 x 50 mL). Drying oversodium sulfate and concentration by rotary evaporation in vacuo produced a red oil that after purificationusing chromatography over silica gel yielded 5.29 g (90% yield) of the title compound as a clear oil. IR(neat): 3286, 2940, 2114, 1578, 1474, 1228, 1022 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 7.9,1.4 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.2, 1.5 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 5.16 (dd, J= 7.2, 5.6 Hz, 2H), 3.82 (s, 3H), 3.61 (s, 3H), 2.53 (d, J = 2.2 Hz, 1H), 0.19 (s, 9H). 13C NMR (101 MHz,CDCl3) δ 151.9, 142.5, 135.7, 124.7, 119.6, 112.0, 99.1, 84.9, 73.1, 58.9, 57.6, 55.8, 0.2. LRMS (ESI+):317.3 (M+Na)+. HRMS (ESI+) Calculated for C15H22O4NaSi: 317.1185, found: 317.1187.OTMSHOOOOTMSOOOOTBSOHOTBSO+ LDATHF, -78 ºC50%3.126 3.72 3.764-(3-Methoxy-2-(methoxymethoxy)phenyl)-2,2,12,12,13,13-hexamethyl-3,11-dioxa-2,12-disilatetra-dec-5-yn-7-ol (3.76). n-Butyllithium (1.58 M in hexanes) (1.20 mL, 1.9 mmol, 1.1.0 equiv) was added drop-wise to a solution of diisopropylamine (0.26 mL, 1.8 mmol, 1.1.0 equiv) in 12 mL of THF at -78 ◦C. Thereaction mixture was stirred for 1 h at -78 ◦C and a solution of 3.126 (3.70 g, 11 mmol, 1.0 equiv) in 6 mLof THF was added dropwise. The yellow reaction mixture was stirred at -78 ◦C for 40 min. To the darkgreen reaction mixture, a solution of 4-((tert-butyldimethylsilyl)oxy)-butanal (3.72) (0.37 g, 1.8 mmol, 1.1.0equiv) in 4 mL of THF was added. The cloudy orange suspension was warmed to rt and stirred for 15 min.Saturated aqueous ammonium chloride solution (50 mL) was added. The organic and aqueous portions wereseparated. The aqueous portion was extracted with diethyl ether (3 x 25 mL). The combined organic fractionswere washed with brine (2 x 25 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced an orange oil that after purification using chromatography over silica gel yielded 0.41 g(50%) of the title compound as a clear yellow oil. IR (neat): 3352, 2938, 2028, 1588, 1480, 1264 cm-1. 1HNMR (300 MHz, CDCl3) δ 7.27 (dt, J = 7.8, 1.3 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.90 (dd, J = 8.2, 1.2 Hz,1H), 5.83 (d, J = 3.3 Hz, 1H), 5.15 (d, J = 5.9 Hz, 1H), 5.08 (d, J = 5.9 Hz, 1H), 4.48 (t, J = 6.2 Hz, 1H),3.84 (s, 3H), 3.64 (t, J = 6.1 Hz, 2H), 3.58 (s, 4H), 1.77 (q, J = 6.8 Hz, 2H), 1.71-1.61 (m, 2H), 0.89 (s, 9H),184Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations0.16 (s, 9H), 0.04 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 152.0, 144.0, 135.5, 125.0, 120.3, 112.7, 99.4,87.8, 83.4, 63.0, 62.8, 60.2, 57.8, 56.1, 35.2, 28.8, 26.1, 18.5, 0.3, -5.1. LRMS (ESI+): 519.4 (M+Na)+.HRMS (ESI+) Calculated for C25H44O6NaSi2: 519.2574, found: 519.2576.OTMSOOOOTBSOHOBnOOOOTBSOTMSNaH, BnBrTHF, 90%3.76 3.774-(3-(Benzyloxy)-3-(3-methoxy-2-(methoxymethoxy)phenyl)prop-1-yn-1-yl)-2,2,9,9,10,10-hexamethyl-3,8-dioxa-2,9-disilaundecane (3.77). A suspension of hexanes-washed sodium hydride (31.3 mg, 0.8 mmol,1.2 equiv) in 6 mL of THF was added to a solution of 3.76 (0.31 g, 0.6 mmol, 1.0 equiv) in 6 mL of THF.The white suspension was stirred at rt for 30 min. To the reaction mixture tetrabutylammonium iodide (0.56g, 1.5 mmol, 2.4 equiv) was added followed by benzyl chloride (0.18 mL, 1.6 mmol, 2.4 equiv). The reactionmixture was stirred at 40 ◦C for 16h. It was then stopped by the addition of saturated aqueous ammoniumchloride solution (10 mL). The aqueous phase was extracted with diethyl ether (3 x 6 mL). The combinedorganic fractions were washed with brine (1 x 10 mL). Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced a thick orange oil that after purification using chromatography oversilica gel yielded 79.5 mg (22%) of the title compound as a slightly yellow oil. IR (neat): 2954, 1482, 1252,1058 cm-1. 1HNMR (300 MHz, CDCl3) δ 7.45-7.29 (m, 6H), 7.16 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 8.1, 1.1Hz, 1H), 5.75 (d, J = 1.3 Hz, 1H), 5.13-5.07 (m, 2H), 4.81 (dd, J = 11.6, 1.9 Hz, 1H), 4.68 (d, J = 11.6 Hz,1H), 4.53 (t, J = 6.2 Hz, 1H), 3.89 (s, 3H), 3.69 (ddd, J = 9.0, 6.1, 2.9 Hz, 2H), 3.48 (s, 3H), 1.87-1.79 (m,2H), 1.77-1.68 (m, 2H), 0.95 (s, 9H), 0.21 (d, J = 2.4 Hz, 9H), 0.11 (d, J = 1.6 Hz, 6H). 13C NMR (75 MHz,CDCl3) δ 152.2, 143.6, 138.1, 133.3, 128.4, 128.4, 127.8, 124.6, 121.0, 112.6, 99.2, 82.5, 70.5, 65.2, 63.0,62.9, 57.6, 56.0, 35.4, 28.9, 26.2, 18.5, 0.4, -5.1. LRMS (ESI+): 609.5 (M+Na)+. HRMS (ESI+)Calculatedfor C32H50O6NaSi2: 609.3044, found: 609.3043.OBnOOOOTBSOTMSOBnOOOOHOHTBAF, MSTHF, 98%3.77 3.787-(Benzyloxy)-7-(3-methoxy-2-(methoxymethoxy)phenyl)hept-5-yne-1,4-diol (3.78). A clear solu-tion of 3.77 (79.5 mg, 0.1 mmol, 1.0 equiv) in 10 mL of THF at rt was treated with a 1.0 M solution of185Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationstetrabutylammonium fluoride (0.3 mL, 0.3 mmol, 2.2 equiv). The reaction mixture was stirred at rt for 5 h.The clear solution was then filtered through a silica/Celite plug and the filter cake was thoroughly rinsed withethyl acetate. Concentration by rotary evaporation in vacuo produced 55 mg (100% yield) of the title com-pound as a yellow oil. The compound was used without further purification. 1H NMR (400 MHz, CDCl3) δ7.42-7.30 (m, 6H), 7.15 (t, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.2, 1.4 Hz, 1H), 5.69 (d, J = 1.4 Hz, 1H), 5.11 (d, J= 5.6 Hz, 1H), 5.08 (dd, J = 5.6, 1.3 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.50-4.48(m, 1H), 3.86 (s, 3H), 3.68-3.57 (m, 2H), 3.47 (d, J = 0.8 Hz, 3H), 1.86-1.80 (m, 2H), 1.78-1.65 (m, 2H).13C NMR (101 MHz, CDCl3) δ 152.2, 143.5, 137.8, 133.3, 128.5, 128.3, 127.9, 124.9, 120.4, 112.5, 99.2,88.0, 83.1, 70.5, 65.2, 62.5, 62.0, 57.7, 56.0, 34.9, 34.9, 28.5.OBnOOOOHOHOBnOOOOO(COCl)2, DMSOEt3N, DCM-78 ºC, 88%3.78 3.797-(Benzyloxy)-7-(3-methoxy-2-(methoxymethoxy)phenyl)-4-oxohept-5-ynal (3.79). Anhydrous dime-thylsulfoxide (0.07 mL, 1.0 mmol, 6 equiv) was added to a clear solution of oxalyl chloride (0.04 mL, 0.5mmol, 3 equiv) in 8 mL of DCM at -78 ◦C. The reaction mixture was stirred at -78 ◦C for 20 min and aslightly yellow solution of diol 3.78 (54.0 mg, 0.1 mmol, 1equiv) in 2 mL of DCM at -78 ◦C was then addedin one portion. The reaction mixture was further stirred at -78 ◦C for 40 min. Triethylamine (0.17 mL, 1.2mmol, 9 equiv) was then added. The reaction mixture was stirred at -78 ◦C for 1 h, letting it slowly warm tort. It was then stopped by the addition of water (10 mL). The organic and aqueous portions were separated.The aqueous portion was extracted with DCM (3 x 5 mL). The combined organic extracts were washed withbrine (1 x 10 mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced ared oil that after purification using chromatography over silica gel yielded 47 mg (88%) of the title compoundas a thick red oil. 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.43-7.28 (m, 6H), 7.17 (t, J = 8.0 Hz, 1H),6.96 (dd, J = 8.2, 1.4 Hz, 1H), 5.83 (s, 1H), 5.11 (dd, J = 8.4, 5.6 Hz, 2H), 4.78 (d, J = 11.7 Hz, 1H), 4.67 (d,J = 11.7 Hz, 1H), 3.88 (s, 3H), 3.45 (s, 3H), 2.95 (t, J = 6.2 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H). 13CNMR (101MHz, CDCl3) δ 199.6, 184.9, 152.2, 143.7, 137.3, 131.5, 128.6, 128.4, 128.1, 125.0, 120.5, 113.1, 99.3,90.8, 84.7, 71.2, 65.0, 57.7, 56.1, 37.8, 37.3. LRMS (ESI+): 419.3 (M+Na)+. HRMS (ESI+) Calculated forC23H24O6Na: 419.1471, found: 419.1467.186Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsOOOOOHO OBnO OHOBnOOOOHOBnOOOOOBnDMAP42 mol%DCM51%+ +1.01.82.3 : :-c-t3.66a 3.84a 3.84a 3.85a3.7.4 Synthesis of Tetrahydroxanthones4-(Benzyloxy)-1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-9H-xanthen-9-one (3.84a and ovanTHXsb) and4-(benzyloxy)-4-(8-methoxy-4-oxo-4H-chromen-2-yl)butanal (3.85a). A solution of 3.66a (51.3 mg, 0.14mmol, 1.0 equiv) in 2 mL of DCM was transferred to a flask containing DMAP (7.4 mg, 0.06 mmol, 0.4equiv). The yellow solution immediately turned dark red. The reaction mixture was stirred at rt for 30min. Concentration by rotary evaporation in vacuo produced a brown oil that after purification using chro-matography over silica gel yielded 12.0 mg (23%) of the trans tetrahydroxanthone 3.84a as an amorphousslightly yellow solid, mp 107-110 ◦C, plus 9.0 mg (18%) of the cis tetrahydroxanthone 3.84b as an amor-phous slightly yellow solid, mp 110-112 ◦C, plus 5.0 mg (10%) of chromenone 3.85a as a colourless oil inan overall 51% yield.Data for tetrahydroxanthone 3.84a-t (trans): IR (neat): 3336, 2940, 1718, 1624, 1582, 1275, 1062 cm-1.1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 1.4, 8.2 Hz, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.42 - 7.29 (m, 5H), 7.20 (dd, J = 1.4, 7.9 Hz, 1 H), 5.06 (t, J = 4.6 Hz, 1 H), 4.92 (dd, J = 11.6, 31.4 Hz, 1 H), 4.49 (t, J =5.5 Hz, 1 H), 4.03 (s, 3 H), 2.31 - 2.18 (m, 2 H), 2.04 - 1.95 (m, 1 H), 1.90 - 1.81 (m, 1 H). 13C NMR (101MHz, CDCl3) δ 179.5, 163.3, 149.1, 146.9, 138.1, 128.7, 128.3, 128.1, 125.1, 124.7, 121.0, 116.5, 114.7,72.9, 72.1, 63.5, 56.6, 25.9, 25.2. LRMS (ESI+): 375 (M+Na)+. HRMS (ESI+) Calculated for C21H21O5(M+H)+: 353.1389, found: 353.1382.Data for tetrahydroxanthone 3.84a-c (cis): IR (neat): 3443, 2923, 1719, 1638, 1578, 1272, 1053 cm-1.1HNMR (300 MHz, CDCl3) δ 7.75 (dd, J = 1.4, 8.2 Hz, 1 H), 7.51 (d, J = 7.5 Hz, 2 H), 7.42 - 7.31 (m, 4 H),7.20 (dd, J = 1.4, 7.9 Hz, 1 H), 5.01 (dd, J = 5.8, 7.9 Hz, 1 H), 4.91 (dd, J = 8.9, 11.9 Hz, 2 H), 4.43 (t, J = 4.4Hz, 1 H), 4.03 (s, 3 H), 2.28 - 2.18 (m, 1 H), 2.18 - 2.00 (m, 3 H), 1.91 - 1.81 (m, 1 H). 13CNMR (101 MHz,CDCl3) δ 179.9, 163.1, 149.1, 146.8, 138.2, 128.7, 128.6, 128.3, 128.0, 125.1, 124.5, 121.5, 116.5, 114.7,72.6, 71.9, 65.2, 56.6, 25.7, 25.6. LRMS (ESI+): 375 (M+Na)+. HRMS (ESI+) Calculated for C21H20O5Na(M+Na)+: 375.1208, found: 375.1207.Data for chromenone 3.85a: IR (neat): 4354, 1722, 1650, 1582, 1274 cm-1. 1HNMR (400MHz, CDCl3)δ 9.77 (t, J = 1.2 Hz, 1 H), 7.77 (dd, J = 1.4, 8.2 Hz, 1 H), 7.42 - 7.29 (m, 6 H), 7.18 (dd, J = 1.4, 8.2 Hz,187Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations1 H), 6.51 (s, 1 H), 4.70 (d, J = 11.6 Hz, 1 H), 4.46 (d, J = 11.6 Hz, 1 H), 4.38 (dd, J = 4.6, 7.7 Hz, 1 H),3.99 (s, 3 H), 2.63 (dt, J = 1.0, 7.2 Hz, 1 H), 2.36 - 2.14 (m, 3 H), 2.09 - 1.93 (m, 1 H), 1.93 - 1.79 (m, 1 H).13C NMR (101 MHz, CDCl3) δ 201.4, 178.3, 167.5, 149.1, 147.0, 137.1, 128.8, 128.4, 128.3, 125.2, 116.8,114.7, 114.7, 109.3, 72.3, 63.5, 56.5, 39.6, 27.1. LRMS (ESI+): 375 (M+Na)+. HRMS (ESI+) Calculatedfor C21H21O5Na (M+Na)+: 375.1208, found: 375.1209.OOOOOHO OBnO OOBnONO2NO2OOOOOBnONO2NO21) DMAP (30 mol%)    DCM, rt, 30 min2) Et3N,            65%O NO2NO2Cl+(±) (±)-t -c3.66a 3.88 3.89a3.89a4-(Benzyloxy)-5-methoxy-9-oxo-2,3,4,9-tetrahydro-1H-xanthen-1-yl 3,5-dinitrobenzoates 3.89a-t and3.89a-c. A solution of 3.66a (53.8 mg, 0.15 mmol, 1.0 equiv) and DMAP (5.8 mg, 0.05 mmol, 30 mol%) in2 mL of DCM was stirred at rt for 30 min. The solvent was removed in vacuo. 3,5-dinitrobenzoyl chloride(42.0 mg, 0.17 mmol, 1.1 equiv) was loaded. The crude reaction mixture was then dissolved in 3 mL of DCMunder nitrogen atmosphere. Triethylamine (0.03 mL, 0.21 mmol, 1.4 equiv) was then added. The reactionmixture was stirred at rt for 2 h. Saturated aqueous ammonium chloride solution (2 mL) was added. Theorganic and aqueous portions were separated. The aqueous portion was then extracted with DCM (3 x 1mL). Drying over sodium sulfate and concentration by rotary evaporation in vacuo produced a red/black oilthat after purification using chromatography over silica gel yielded 37.0 mg (46%) of the trans benzoylatedtetrahydroxanthone 3.89a-t as an amorphous slightly yellow solid, mp 150.0-151.5 ◦C, plus 15.2 mg (19%)of the cis benzoylated tetrahydroxanthone 3.89a-c as an amorphous slightly yellow solid, mp 174.5-175.0◦C, in an overall 65% yield.Data for tetrahydroxanthone 3.89a-t: IR (neat): 3100, 2936, 1727, 1650, 1541, 1342, 1270, 719 cm-1.1H NMR (600 MHz, CDCl3) δ 9.16 (t, J = 2.3 Hz, 1 H), 9.07 (d, J = 2.6 Hz, 2 H), 7.68 (dd, J = 1.3, 7.9Hz, 1 H), 7.50 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.38 - 7.30 (m, 2 H), 7.23 (dd, J = 1.3, 7.9Hz, 1 H), 6.53 (t, J = 3.1 Hz, 1 H), 4.92 (s, 2 H), 4.57 (t, J = 3.1 Hz, 1 H), 4.06 (s, 3 H), 2.48 - 2.34 (m, 1H), 2.27 - 2.13 (m, 3 H). 13C NMR (151 MHz, CDCl3) δ 176.8, 164.9, 161.9, 149.2, 148.7, 146.6, 137.7,134.3, 129.7, 128.7, 128.3, 128.2, 125.4, 124.9, 122.4, 116.7, 116.4, 115.0, 72.8, 70.8, 66.9, 56.6, 24.3, 23.4LRMS (ESI+): 569 (M+Na)+. HRMS (ESI+) Calculated for C28H22N2O10Na (M+Na)+: 569.1172, found:569.1172.188Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsData for tetrahydroxanthone 3.89a-c: IR (neat): 3100, 2925, 1727, 1646, 1541, 1342, 1271, 718 cm-1.1H NMR (400 MHz, CDCl3) δ 9.13 (t, J = 2.4 Hz, 1 H), 9.08 (d, J = 2.4 Hz, 2 H), 7.66 (dd, J = 1.4, 8.2Hz, 1 H), 7.55 (d, J = 6.8 Hz, 2 H), 7.40 (t, J = 6.8 Hz, 1 H), 7.37 - 7.29 (m, 3 H), 7.22 (dd, J = 1.0,8.2 Hz, 1 H), 6.47 (t, J = 4.1 Hz, 1 H), 5.14 (d, J = 11.6, 1 H), 4.97 (d, J = 11.6, 1 H), 4.56 (t, J = 7.3Hz, 1 H), 4.05 (s, 3 H), 2.38 - 2.28 (m, 1 H), 2.27 - 2.16 (m, 2 H), 2.12 - 2.00 (m, 1 H). 13C NMR (101MHz, CDCl3) δ 176.5, 166.5, 162.1, 149.1, 148.7, 146.5, 137.8, 134.2, 129.7, 128.7, 128.4, 128.3, 125.4,124.6, 122.4, 116.7, 116.6, 115.0, 73.7, 72.6, 67.2, 56.6, 25.5, 25.3. LRMS (ESI+): 569 (M+Na)+. HRMS(ESI+) Calculated for C28H22N2O10Na (M+Na)+: 569.1172, found: 569.1182.OOOOOBnONO2NO2 OOOOOBnONO2NO2OOHO OBnOBr BrBrOOOOOBnBra) DMAP (35 mol%)DCM, rtb) Et3N,53%+ +(+) (+)-t -c3.66b 3.89b3.89b 3.85b3.884-(benzyloxy)-7-bromo-5-methoxy-9-oxo-2,3,4,9-tetrahydro-1H-xanthen-1-yl 3,5-dinitrobenzoate (3.89b-t and 3.89b-c) and 4-(benzyloxy)-4-(6-bromo-8-methoxy-4-oxo-4H- chromen-2-yl)butanal (3.85b). Asolution of 3.66b (46.9 mg, 0.10 mmol, 1.0 equiv) and 1,3,5-trimethoxy benzene (6.1 mg, 0.036 mmol, 36mol%) as internal standard in 2 mL of DCM, was treated with DMAP (4.4 mg, 0.035 mmol, 35 mol%).The reaction mixture was stirred at rt for 30 min. The solvent was removed in vacuo and NMR of the crudeshowed 63% yield of the mixed trans and cis tetrahydroxanthones, plus chromenone in a 3:1:1.1 ratio, re-spectively. To the crude reaction mixture, 3,5-dinitrobenzoyl chloride (31.2 mg, 0.13 mmol, 1.3 equiv) wasloaded. The crude reaction mixture was dissolved in 2 mL of DCM. Triethylamine (0.02 mL, 0.14 mmol, 1.4equiv) was then added. The reaction mixture was stirred at rt for 2 h. Saturated aqueous sodium bicarbonatesolution (10 mL) was added. The organic and aqueous portions were separated. The aqueous portion wasthen extracted with DCM (3 x 10 mL). Drying over sodium sulfate and concentration by rotary evaporationin vacuo produced a red/black oil that after purification using chromatography over silica gel yielded 18.3mg (27%) of the trans benzoylated tetrahydroxanthone 3.89b-t as an amorphous slightly yellow solid, mp175.0-177.0 ◦C, plus 8.2 mg (12%) of the cis benzoylated tetrahydroxanthone 3.89b-c as an amorphous yel-lowish solid, mp 147.0-154.0 ◦C, and 6.6 mg (14%) of the chromenone 3.85b as a thick yellow oil in anoverall 53% yield.Data for tetrahydroxanthone 3.89b-t: IR (neat): 3100, 2937, 1728, 1650, 1542, 1344, 1230, 1162, 729cm-1. 1H NMR (400 MHz, CDCl3) δ 9.17 (t, J = 2.0 Hz, 1 H), 9.07 (d, J = 2.0 Hz, 2 H), 7.80 (d, J = 2.0 Hz,1 H), 7.47 (d, J = 6.8 Hz, 2 H), 7.44 - 7.31 (m, 3 H), 7.30 (d, J = 2.0 Hz, 1 H), 6.50 (t, J = 2.7 Hz, 1 H), 4.90189Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizations(s, 2 H), 4.55 (t, J = 2.7 Hz, 1 H), 4.05 (s, 3 H), 2.47 - 2.32 (m, 1 H), 2.26 - 2.08 (m, 3 H). 13C NMR (101MHz, CDCl3) δ 175.4, 165.1, 161.9, 150.0, 148.8, 145.7, 137.6, 134.2, 129.7, 128.7, 128.3, 125.7, 122.5,119.3, 118.8, 118.4, 116.8, 72.9, 70.8, 66.7, 57.0, 24.2, 23.4. LRMS (ESI+): 647/649 (M+Na)+. HRMS(ESI+) Calculated for C28H21N2O10Na79Br (M+Na)+: 647.0277, found: 647.0292.Data for tetrahydroxanthone 3.89b-c: IR (neat): 3089, 2943, 1726, 1639, 1541, 1341, 1269, 719 cm-1.1H NMR (600 MHz, CDCl3) δ 9.19 (t, J = 2.0 Hz, 1 H), 9.10 (d, J = 2.0 Hz, 2 H), 7.81 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2 H), 7.45 - 7.33 (m, 3 H), 7.31 (d, J = 2.0 Hz, 1 H), 6.46 (t, J = 4.1 Hz, 1 H), 5.12(d, J = 11.6 Hz, 1 H), 4.97 (d, J = 11.6 Hz, 1 H), 4.78 - 4.70 (m, 1 H), 4.55 (t, J = 7.2 Hz, 1 H), 4.06 (s, 3H), 2.40 - 2.29 (m, 1 H), 2.28 - 2.17 (m, 2 H), 2.14 - 2.03 (m, 1 H). 13C NMR (101 MHz, CDCl3) δ 175.2,162.1, 149.9, 148.7, 145.7, 137.7, 134.1, 129.8, 128.7, 128.4, 125.4, 122.5, 119.2, 118.8, 118.3, 117.1, 77.6,77.2, 76.9, 73.8, 72.6, 67.1, 57.0, 25.4, 25.3. LRMS (ESI+): 647/649 (M+Na)+. HRMS (ESI+) Calculatedfor C28H21N2O10Na79Br (M+Na)+: 647.0277, found: 647.0283.Data for chromenone 3.85b: IR (neat): 3086, 2940, 1721, 1652, 1576 cm-1. 1HNMR (400MHz, CDCl3)δ 9.76 (s, 1 H), 7.90 (d, J = 2.0 Hz, 1 H), 7.41 - 7.29 (m, 5 H), 7.25 (d, J = 2.0 Hz, 1 H), 6.50 (s, 1 H), 4.69(d, J = 11.9 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.35 (dd, J = 4.4, 7.5 Hz, 1 H), 4.00 - 3.95 (m, 3 H), 2.63(dt, J = 1.0, 7.2 Hz, 1 H), 2.32 - 2.13 (m, 2 H). 13C NMR (101 MHz, CDCl3) δ 201.2, 176.8, 167.8, 149.9,137.0, 128.8, 128.5, 128.3, 126.1, 119.3, 118.6, 118.0, 109.4, 76.7, 72.3, 56.8, 39.5, 27.0. LRMS (ESI+):431/433 (M+H)+. HRMS (ESI+) Calculated for C21H19O5Na79Br (M+Na)+: 453.0314, found: 453.0318.OOOOOBnONO2NO2 OOOOOBnONO2NO2 OOOOOBnOOHO OBnO1) DMAP2) Et3N73%+ +2.9 1.3 1.0: :-c-t3.66c 3.89c3.89c 3.85c3.884-(Benzyloxy)-7-ethynyl-5-methoxy-9-oxo-2,3,4,9-tetrahydro-1H-xanthen-1-yl 3,5-dinitrobenzoate(3.89c-t and 3.89c-c) and 4-(benzyloxy)-4-(6-ethynyl-8-methoxy-4-oxo-4H- chromen-2-yl)butanal (3.85c.)A solution of 3.66c (76.0 mg, 0.2 mmol, 1.0 equiv) in 2 mL of DCM was treated with a solution of DMAP(7.5 mg, 0.06 mmol, 30 mol%) in 3 mL of DCM. The reaction mixture was stirred at rt for 16 h. Con-centration by rotary evaporation in vacuo produced a brown oil that was filtered through a silica gel pad.DMAP (7.5 mg, 0.06 mmol, 30 mol%) and 3,5-dinitrobenzoyl chloride (63.8 mg, 0.3 mmol, 1.4 equiv) wereloaded. The crude reaction mixture was dissolved in 5 mL of DCM under argon atmosphere. Triethylamine(0.04 mL, 0.3 mmol, 1.5 equiv) was then added. The reaction mixture was stirred at rt for 12 h. Saturated190Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsaqueous sodium bicarbonate solution (20 mL) was added. The organic and aqueous portions were separated.The aqueous phase was extracted with DCM (2 x 10 mL). Drying over sodium sulfate and concentration byrotary evaporation in vacuo produced a red oil that after purification using chromatography over silica gelyielded 46.5 mg (41%) of the trans benzoylated tetrahydroxanthone 3.89c-t as a slightly yellow solid, mp161-162 ◦C, plus 20.4 mg (18%) of benzoylated tetrahydroxanthone 3.89c-c as an amorphous yellow solid,mp 175-176 ◦C, plus 10.4 mg (14%) of chromenone 3.85c as a yellow oil in an overall 73% yield.Data for tetrahydroxanthone 3.89c-t: IR (neat): 2340, 3098, 2922, 2162, 1730, 1640, 1542, 1344, 1276,914, 730 cm-1. 1H NMR (600 MHz, CDCl3) δ 9.18 (t, J = 2.0 Hz, 1 H), 9.08 (d, J = 2.0 Hz, 2 H), 7.82 (d,J = 1.5 Hz, 1 H), 7.49 (d, J = 6.7 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.38 - 7.30 (m, 2 H), 7.27 (d, J = 2.0Hz, 1 H), 6.51 (br. s., 1 H), 4.91 (s, 2 H), 4.56 (br. s., 1 H), 4.06 (s, 3 H), 3.13 (s, 1 H), 2.46 - 2.35 (m, 1H), 2.27 - 2.12 (m, 3 H). 13C NMR (151 MHz, CDCl3) δ 175.9, 161.9, 148.7, 134.2, 129.8, 128.7, 128.3,128.3, 124.7, 122.5, 121.1, 119.5, 117.8, 82.4, 78.5, 72.9, 70.8, 66.7, 56.7, 24.2, 23.4 LRMS (ESI+): 593(M+Na)+. HRMS (ESI+) Calculated for C30H22N2O10Na (M+Na)+: 593.1172, found: 593.1160.Data for tetrahydroxanthone 3.89c-c: IR (neat): 3286, 3100, 2964, 2300, 1730, 1652, 1582, 1544, 1346,1280 cm-1. 1H NMR (400 MHz, CDCl3) δ 9.20 (t, J = 2.4 Hz, 1 H), 9.11 (d, J = 2.0 Hz, 2 H), 7.83 (d, J =1.7 Hz, 1 H), 7.55 (d, J = 6.8 Hz, 2 H), 7.42 (t, J = 7.2 Hz, 2 H), 7.36 (t, J = 7.2 Hz, 2 H), 7.28 (d, J = 2.0Hz, 1 H), 6.47 (t, J = 4.1 Hz, 1 H), 5.13 (d, J = 11.3 Hz, 1 H), 4.98 (d, J = 11.6 Hz, 1 H), 4.56 (t, J = 6.5Hz, 1 H), 4.06 (s, 3 H), 3.13 (s, 1 H), 2.37 - 2.30 (m, 1 H), 2.26 - 2.16 (m, 3 H), 2.07 (d, J = 6.1 Hz, 1 H).13C NMR (151 MHz, CDCl3) δ 175.7, 166.6, 162.2, 149.0, 148.8, 146.8, 137.7, 134.2, 129.8, 128.8, 128.5,128.4, 124.5, 122.5, 121.1, 119.6, 117.8, 117.1, 82.4, 78.5, 73.8, 72.5, 67.2, 56.8, 25.4, 25.4. LRMS (ESI+):593 (M+Na)+. HRMS (ESI+) Calculated for C30H22N2O10Na (M+Na)+: 593.1172, found: 593.1166.Data for chromenone 3.85c: IR (neat): 2938, 2254, 1722, 1652, 1580, 1136 cm-1. 1H NMR (400 MHz,CDCl3) δ 9.76 (s, 1 H), 7.91 (d, J = 1.7 Hz, 1 H), 7.40 - 7.29 (m, 5 H), 7.3 (d, J = 1.7 Hz, 1 H), 6.54 -6.47 (m, 1 H), 4.69 (d, J = 11.9 Hz, 1 H), 4.46 (d, J = 11.6 Hz, 1 H), 4.36 (dd, J = 4.4, 7.5 Hz, 1 H),3.98 (s, 3 H), 3.14 (s, 1 H), 2.63 (t, J = 7.0 Hz, 2 H), 2.33 - 2.13 (m, 2 H). 13C NMR (151 MHz, CDCl3)δ 201.3, 177.4, 167.7, 149.0, 149.0, 147.2, 137.0, 128.8, 128.7, 128.5, 128.5, 128.4, 128.3, 128.2, 125.1,121.1, 117.5, 117.4, 109.5, 101.7, 93.5, 78.3, 76.9, 76.7, 72.3, 56.6, 39.5, 29.3, 27.0. LRMS (ESI+): 399(M+Na)+. HRMS (ESI+) Calculated for C23H21O5 (M+Na)+: 377.1389, found: 377.1396.1-Hydroxy-5-methoxy-1,2,3,4,4a,9a-hexahydro-9H-xanthen-9-one (2.166a) and 4-(8-methoxy-4- oxo-4H-chromen-2-yl)butanal (ChromenoneCHOa). DMAP (20.6 mg, 0.16 mmol, 36 mol%) was added to aflask containing a solution of 7b (109.8 mg, 0.44 mmol 1.0 equiv) and 1,3,5-trimethoxybenzene (25.2 mg,0.14 mmol, 32 mol%) as internal standard in 2 mL of DCM. The reaction mixture was stirred at rt for 60191Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted CycloisomerizationsO OOHOOO OHODMAP30 mol%DCM, rt, 0.5 h82%OO OO+8 1:3.62a 2.166a 3.83amin. Concentration by rotary evaporation in vacuo produced an orange solid. NMR of the crude showed90% conversion and an 8:1 ratio of 2.166a:3.83a. The product was filtered through a silica gel pad to afford80.2 mg (73%) of the title compound as a white powder plus 9.9 mg (9%) of the chromenone 3.83a as aslightly yellow oil in an overall 82% yield.Data for tetrahydroxanthone 2.166a: IR (neat):3334, 2936, 1618, 1576, 1274 cm-1. 1HNMR (300 MHz,CDCl3) δ 7.73 (dd, J = 1.4, 8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.15 (dd, J = 1.6, 8.0 Hz, 1 H), 5.05 (t,J = 5.5 Hz, 1 H), 4.21 (br. s., 1 H), 3.98 (s, 3 H), 2.89 - 2.62 (m, 2 H), 2.15 - 1.93 (m, 2 H), 1.93 - 1.72 (m,2 H). 13C NMR (101 MHz, CDCl3) δ 179.0, 166.0, 148.7, 146.6, 124.8, 124.6, 120.4, 116.5, 114.4, 64.1,56.5, 29.8, 28.7, 18.3. LRMS (ESI+): 269 (M+Na)+. HRMS (ESI+) Calculated for C14H15O4 (M+H)+:247.0970, found: 247.0966. mp:132-133 ◦C.Data for chromenone 3.83a: IR (neat):2942, 1721, 1644, 1580, 1274 cm-1. 1HNMR (400 MHz, CDCl3)δ 9.77 (t, J = 1.2 Hz, 1 H), 7.68 (dd, J = 1.5, 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.28 - 7.21 (m, 1 H), 7.11 (dd, J= 1.4, 8.2 Hz, 1 H), 6.17 (s, 1 H), 3.93 (s, 3 H), 2.69 (t, J = 7.5 Hz, 1 H), 2.57 (dt, J = 1.0, 7.2 Hz, 1 H),2.11 - 2.00 (m, 2 H). 13C NMR (101 MHz, CDCl3) δ 201.3, 178.5, 168.9, 168.3, 148.8, 147.0, 124.9, 124.8,116.6, 114.5, 114.4, 110.3, 56.4, 42.8, 33.5, 19.4. LRMS (ESI+): 269 (M+Na)+. HRMS (ESI+) Calculatedfor C14H15O4 (M+H)+: 247.0970, found: 247.0962.OO OHOBrO OOHOBr DMAP30 mol%DCM, rt 0.5 h43%OO OOBr+2.4 1.0:3.62b 2.166b 3.83b7-bromo-1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-9H-xanthen-9-one (2.166b) and 4-(6-bromo-8-me-thoxy-4-oxo-4H-chromen-2-yl)butanal (3.83b). A solution of DMAP (45.4 mg, 0.36 mmol, 32 mol%)in 11 mL of DCM was transferred to a flask containing 3.62b (0.37 g, 1.14 mmol, 1.0 equiv). The reactionmixture was stirred at rt for 30 min. Concentration by rotary evaporation in vacuo produced an orange solid.The man product was crystallized from DCM to obtain 0.16 g (43%) of the title compound as an amorphous192Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationswhite solid mp 164-165 ◦C. Purification of the filtrate using chromatography over silica gel yielded 55.5 mg(15%) of the chromenone.NMR study: A solution of 3.62b (98.5 mg, 0.30 mmol, 1.0 equiv) and 1,3,5-trimethoxybenzene, asinternal standard (17.5 mg, 0.10 mmol, 33 mol%) in freshly distilled DCM (2 mL) was added to a vialcontaining DMAP (11.9 mg, 0.09 mmol, 30 mol%). The reaction mixture was stirred at rt for 30 min.Concentration by rotary evaporation in vacuo produced an orange solid. NMR of the crude showed 89%conversion and a ratio 2.4:1 of 2.166b:3.83b.Data for tetrahydroxanthone 2.166b: IR (neat):3328, 2946, 1616, 1570, 1266, 844 cm-1. 1H NMR (300MHz, CDCl3) δ 7.86 (d, J = 2.3 Hz, 1 H), 7.20 (d, J = 2.3 Hz, 0 H), 5.04 (t, J = 5.3 Hz, 1 H), 4.06 (br.s., 1 H), 3.98 (s, 3 H), 2.87 - 2.61 (m, 2 H), 2.14 - 1.94 (m, 2 H), 1.94 - 1.75 (m, 2 H). 13C NMR (101MHz, CDCl3) δ 177.6, 166.3, 149.5, 145.7, 125.4, 120.8, 119.1, 118.1, 117.8, 77.7, 76.8, 63.9, 56.8, 29.7,28.7, 18.2. LRMS (ESI+): 347/349 (M+Na)+. HRMS (ESI+) Calculated for C14H13O4Na79Br (M+Na)+:346.9895, found: 346.9899.Data for chromenone 3.83b: IR (neat):3184, 2942, 1722, 1644, 1574, 1258, 846 cm-1. 1H NMR (400MHz, CDCl3) δ 9.81 (s, 1 H), 7.84 (d, J = 2.1 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 6.19 (s, 1 H), 3.96 (s, 4H), 2.71 (t, J = 7.6 Hz, 2 H), 2.60 (dt, J = 0.8, 7.1 Hz, 2 H), 2.09 (quin, J = 7.3 Hz, 1 H). 13C NMR (101MHz, CDCl3) δ 201.1, 176.9, 168.5, 149.7, 146.1, 125.7, 119.2, 118.2, 117.8, 110.5, 56.8, 42.8, 33.5, 19.4.LRMS (ESI+): 347/349 (M+Na)+. HRMS (ESI+) Calculated for C14H14O479Br (M+H)+: 325.0075, found:325.0076.3.7.5 NMR ExperimentsOOOOOHO OBnO OHOBnOOOOHOBnOOOOOBnDMAP42 mol%DCM51%+ +1.01.82.3 : :-c-t3.66a 3.84a 3.84a 3.85aA stock solution containing ynone 3.66a (0.05 M, 1 equiv.) and 1,3,5-trimethoxybenzene as internalstandard (0.0115 M, 0.23 equiv.) in DCM was prepared. The stock solution (2 mL) was injected to a vialcontaining the appropriate nucleophile/base (as indicated in Table 3.5) and the reaction mixture was stirredat rt. The solvent was removed in vacuo and an NMR of the reaction crude was obtained. The NMR spectrawere processed and the internal standard signal (singlet at δ 6.09 ppm) was integrated and was calibrated to193Synthesis of Tetrahydroxanthones: 4-Dimethylaminopyridine-Promoted Cycloisomerizationsthe same value as the one obtained for the stock solution. The ratios of the trans and cis tetrahydroxanthones3.84a and 3.84b, and the chromenone 3.85a were obtained by integrating the characteristic signals at δ 5.06ppm (t) for 3.84a, δ 5.01 ppm (dd) for 3.84b and δ 6.51 ppm (singlet (s)) for 3.85a.194Chapter 4Conclusions and Future WorkSimaomicin α is a naturally occurring type II polyketide that exhibits remarkable activity against two celllines of protozoan parasite Plasmodium falciparum that causes malaria in humans. The introduction to thisthesis is a mini review of the naturally occurring tetrahydroxanthones with particular interest on polycyclictetrahydroxanthones related to simaomicin α (1.1). From a medicinal chemistry approach, it was our interestto synthesize simple molecules with a similar chemical architecture as simaomicin α.Wewere particularly interested in theDEF ring system of simaomicin α, which is a 1,4,5,9-tetraoxygenatedtetrahydroxanthone. Hence, an exhaustive survey on the reported methods to access tetrahydroxanthones waspresented. Although several reports on the synthesis of the tetrahydroxanthone moiety have been published,these are either very general methods for the synthesis of unsubstituted tetrahydroxanthones, or they are tai-lored synthesis for the construction of a particular naturally occurring compound. Therefore, research on amethod for the synthesis of highly oxygenated tetrahydroxanthones that could potentially allow the synthesisof simaomicin α or related polycyclic tetrahydroxanthones was desired.195Conclusions and Future Work4.1 C