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Lithium-iodine exchange initiated intramolecular additions : application of a novel annulation protocol… Harrison, Christian L. 2004

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LITHIUM-IODINE EXCHANGE INITIATED INTRAMOLECULAR ADDITIONS: APPLICATION OF A NOVEL ANNULATION PROTOCOL TO THE TOTAL SYNTHESIS OF (±)-MANGICOL F. by Cristian L. Harrison B. Sc. (with honours), Concordia University, 1996 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) W e accept this thesis as conforming to the required s tandard THE UNIVERSITY OF BRITISH COLUMBIA Spring 2004 © Cristian L. Harrison i 11 Abstract This dissertation is divided into two sections: methodological work and application of one of the developed methods to the total synthesis of the racemic version of naturally occurring mangicol F . In the first section, the possibility of effecting intramolecular conjugate addition reactions initiated by lithium-iodine exchanges was explored. The required substrates for the initial study were cyclic a,p-unsaturated ketones (Michael acceptors) bearing alkenyl iodide functionalized sidechains. The preparation of such substrates began with the facile hydriodination of acetylenic esters, supplying alkyl Z-iodoalkenoates such as 66, which were subsequently converted (in two steps) into their corresponding allylic bromides. Alkylation of cyclic vinylogous esters such as 45 with allylic bromides 44 afforded compounds such as 46 which were converted into the required enone substrates, 47. Stereoselective intramolecular conjugate additions of the anions of these substrates, generated by lithium-iodine exchange reactions, were cleanly effected at -78 °C in the presence of the additives T M S C 1 and H M P A , furnishing czs-fused bicyclic ketones of general structure 48 in very good yields. In addition, this methodology was extended to the formation of tricyclic ketones (ie. 59 and 61) via the use of cyclic alkenyl iodides (58) and aryl iodides (60), respectively. The substrates required for the second methodology project were the vinylogous ester intermediates (46). Intramolecular addition of alkenyl anions, generated by lithium-iodine exchange, to the carbonyl function of the vinylogous esters furnished, after an acid-promoted hydrolysis-dehydration protocol, bicyclic dienones of general structure 50 in excellent yields. This methodology was extended to the formation of tricyclic compounds such as aryl enone (172) and furyl enone (177) via the use of aryl iodide (143) and furyl iodide (162) substrates, respectively. Ill To commence the work described in the second part of this dissertation, the second method described above was employed to prepare approximately 30 g of bicyclic dienone 164. This latter material was the starting material for the total synthesis of the tetracyclic sesterterpene diol, (±)-mangicol F (52). Stereoselective hydrogenation of 164 with Lindlar 's catalyst supplied enone 198. The third ring in the tetracyclic core of (±)-mangicol F was installed via an annulation sequence that involved the stereoselective conjugate addition of cuprate 208 to the enone function of 198. After conversion of the tributylgermanium function in 210 to the iodide in 211, a palladium-catalyzed coupling between the alkenyl iodide and the enolate anion of the ketone was effected to complete the annulation sequence, by producing enone 212. Stereoselective hydrogenation of the alkene function in tricyclic enone 212 followed by IBX-promoted dehydrogenation of the resulting ketone furnished enone 239. The fourth ring in the core of (±)-mangicol F was installed via an annulation protocol that began with the conjugate addition of organocopper species 249 to enone 239, furnishing 240. Base-promoted ring closure followed by stereoselective methylation of the resulting tetracyclic ketone afforded compound 236. Dehydration of the alcohol resulting from the reduction of the carbonyl function in 236 furnished diene 194. The final quaternary chirality centre in the core of (±)-mangicol F was introduced via a chemoselective cyclopropanation reaction, using ethyl diazoacetate. After conversion of the ester function in 291 into its corresponding aldehyde, selective cleavage of the cyclopropyl C - C bond distal to the spiro-junction was achieved via hydrogenolysis, supplying 193. Addition of the alkenyllithium 347 to aldehyde 193 afforded a diastereomeric mixture of alcohols 348 and 349. Reaction of the hydroxyl function of 348 with acetic anhydride and ketohydroxylation of the alkene function on the sidechain of the resulting acetate supplied the mono-acetate of mangicol F. Hydrolysis of the acetate function afforded (±)-mangicol F (52). The total synthesis of mangicol F was effected in 21 steps and in 0.94% overall yield from known materials. Further, iv due to X-ray crystallographical data obtained at a late stage of the synthesis, the relative configuration at the hydroxyl bearing carbon chirality centre in the sidechain was assigned, information that had not been determined in the original isolation report due to lack of material. V Table of Contents Abstract i i Table of Contents v List of Tables v i i List of Figures v i i i List of General Procedures x List of Abbreviations and Acronyms x i Acknowledgments xiv 1. Introduction 1 1.1 General 1 1.2 Background 4 1.3 Proposals 9 2. Lithium-Iodine Exchange Initiated Intramolecular Addition Reactions 16 2.1 Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition Reactions of Alkenyl and Aryl Anion Functions 16 2.1.1 Introductory Remarks 16 2.1.2 Preparation of Substrates 18 2.1.3 Designing and Tailoring the L i - I Exchange Initiated Intramolecular Conjugate Additions 27 2.1.4 Testing the scope of the reaction 32 2.1.5 Formation of Tricyclic Ketones 35 2.2 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Addition Reactions 42 2.2.1 Substrate Preparation 42 2.2.2 Lithium-Iodine Exchange Promoted 1,2-Addition Reactions 44 3. The Total Synthesis of (±)-Mangicol F 50 3.1 Isolation and Structure Determination 50 3.2 Biogenesis of the Mangicols 52 3.3 Retrosvnthetic Analysis 54 3.4 The Total Synthesis of (±)-Mangicol F 59 3.4.1 Preparation of the Tetracyclic Core of Mangicol F 59 vi 3.4.2 Establishing the final quaternary carbon chirality centre and installing the double bond into the six-membered ring 85 3.4.2.1 Initial studies on the installation of the double bond into the six-membered ring 85 3.4.2.2 Nitrile alkylation approaches to the establishment of the final chirality centre in the core 91 3.4.2.3 Cyclopropanation approaches to the establishment of the final chirality centre in the core 108 3.4.2.3.1 Identification of the products of cyclopropanation 108 3.4.2.3.2 Results from the Various Attempts to Open Aldehyde 297 112 3A2.3 .3 Attempts at Introduction of the Quaternary Centre via a Cyclopropylmalonate 116 3.4.2.4 Summary of the Attempts to Introduce the Final Quaternary Chirality Centre into the Tetracyclic Core of Mangicol F 120 3.4.3 Elaboration of the Sidechain-the Total Synthesis of Mangicol F 121 3.4.3.1 Model Studies 121 3.4.3.2 Application of the Model Work to the Total Synthesis of Mangicol F and 17-ep/-Mangicol F 128 3.4.4 Summary of the Total Synthesis of Mangicol F 136 4 . Experimental 141 4.1 General 141 4.1.1 Data Acquisition, Presentation and Experimental Techniques 141 4.1.2 Reagents and Solvents 144 4.2 Lithium-Iodine Exchange Initiated Intramolecular Addition Reactions 145 4.2.1 Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition Reactions 146 4.2.2 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Addition Reactions 214 4.3 The Total Synthesis of Mangicol F 236 Endnotes and References 307 Appendix 1: ' H - N M R and 1 3 C - N M R Spectra of Those Compounds Related to the Total Synthesis of Mangicol F Lacking Microanalysis 315 Appendix 2: X-ray Crystallography Experimental Data 325 vi i List of Tables Table 1 Results of Optimization Studies for the L i - I Exchange Initiated Intramolecular Conjugate Addition 30 Table 2 The Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition of Alkenyl Anion Functions to Differently Substituted Cycl ic Enones 33 Table 3 The Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition to Differently Sized Cycl ic Enones 34 Table 4 Lithium-Iodine Exchange Promoted Cyclization of Cycloalkenyl Anions 41 Table 5 Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition of A r y l Anions 41 Table 6 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Additions: Substituent Effects 46 Table 7 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Additions: Effects of Ring Size 46 Table 8 Lithium-Iodine Exchange Initiated 1,2-Addition of A r y l Anion Functions 47 Table 9 Lithium-Iodine Exchange Initiated 1,2-Addition of Furyl Anion Functions 48 Table 10 Catalyst studies in the hydrogenation of dienone 164 62 Table 11 Study of the Pd(0) catalyzed intramolecular coupling of alkenyl iodides with ketone enolates employing various commercially available base systems 68 Table 12 Study of the deprotonation of ketone 235 with different bases 77 Table 13 Results from the elimination experiments on nitriles 273 and 275 100 Table 14 Attempts at the hydrolysis of the methyl enol ether mixture 290 106 Table 15 Results from the addition of alkenyl anion 334 to aldehyde 328 123 Table 16 Comparison of the ' H - N M R spectral data of synthetically prepared (±)-mangicol F (52) with those reported for natural mangicol F 134 Table 17 Comparison of the I 3 C - N M R spectra of synthetically prepared mangicol F (52) and the authentic sample 135 vi i i List of Figures Figure 1 Selected compounds synthesized in the early stages of modern synthetic ^ chemistry Figure 2 Longifolene, synthesized by E . J. Corey in 1961 2 Figure 3 The CP-molecules 3 Figure 4 Representative examples of bifunctional reagents bearing trialkyltin and trialkylgermanium moieties 5 Figure 5 Selected members of the mangicol family 15 Figure 6 Compounds 54 and 56 21 Figure 7 Conceivable transition states for the cyclization process 28 Figure 8 Isolated members of the neomangicol family 50 Figure 9 Isolated members of the mangicol family 51 Figure 10 Biogenetic synthesis of geranylfarnesyl diphosphate from 1 3 C-label led acetic acid 52 Figure 11 Proposed biosynthesis of the mangicol core 53 Figure 12 Retrosynthetic analysis of mangicol F - elaboration of the sidechain 55 Figure 13 Retrosynthetic analysis of mangicol F - installation of the 4 t h ring 56 Figure 14 Retrosynthetic analysis of mangicol F - preparation of the spirotricyclic subunit 57 Figure 15 Comparison of analogous examples from the two methodological studies described in Chapter 2 60 Figure 16 Proposed mechanism of Pd(0)-catalyzed coupling of alkenyl iodide with ketone enolate 67 Figure 17 Three-dimensional representation of the most stable conformation of enone 212 69 Figure 18 O R T E P diagram representing the crystal structure of dinitrobenzoate ester 216 71 Figure 19 Explanation for mixed products in the Michael addition of cuprate 227 to enone 239 81 Figure 20 Preparation of cuprate 227 from tributylstannane 243 81 Figure 21 The goal of the initial studies on ketone 236 86 Figure 22 The proposed alkenyl triflate approach 86 Figure 23 O R T E P diagram representing the crystal structure of ester 265 93 Figure 24 Predicted facial selectivity of the alkylation of the anion of nitrile 271 97 ix Figure 25 O R T E P diagram representing the crystal structure of ester 274 99 Figure 26 Comparison of the 0 - C - C - ( H - 1 2 ) dihedral angles of alcohols 252 and 273 102 Figure 27 Proposed method for the preparation of aldehyde 193 from nitrile 276 104 Figure 28 Summary of the nitrile anion alkylation approaches to aldehyde 193 107 Figure 29 Proposed preparation of aldehyde 193 via cyclopropanation 108 Figure 30 The two bond cleavages necessary to eventually prepare aldehyde 193 from 321 118 Figure 31 Comparison of the three most fruitful approaches to aldehyde 193 from alcohol 252 121 Figure 32 The proposed preparation of mangicol F and its C-17 epimer from aldehyde 193 128 Figure 33 O R T E P diagram representing the crystal structure of ester 350 131 List of General Procedures X General Procedure 1 General Procedure 2 General Procedure 3 General Procedure 4 General Procedure 5 General Procedure 6 General Procedure 7 General Procedure 8 Hydriodination of Acetylenic Esters 146 D I B A L H Reduction of a,|3-Unsaturated Esters to their Corresponding Al ly l i c Alcohols 146 Conversion of A l l y l i c Alcohols into their Corresponding Al ly l i c Bromides 147 a'-Alkylation of 3-Isobutoxycyclohex-2-en-l-ones with A l k y l , A l l y l i c and Benzylic Halides 155 Reduction of 3-Isobutoxycyclohex-2-en-l-ones and Hydrolysis-Dehydration of the Resultant Products 164 1,2-Addition of Grignard Reagents to 3-Isobutoxycyclohex-2-en-l-ones and Hydrolysis-Dehydration of the Resultant Products 171 r-BuLi-initiated Intramolecular Conjugate Addition of Alkenyl and A r y l Functions to a,(3-Unsaturated Ketones 180 £-BuLi-initiated Intramolecular 1,2-Addition of Alkenyl and A r y l Functions to Vinylogous Esters; Hydrolysis-Dehydration of the Resulting 3° Alcohol 219 List of Abbreviations 8 Chemical shift in parts per mil l ion from M e 4 S i A c Acetyl , Acetic aq. Aqueous B n Benzyl br Broad B u Butyl B u L i Butyllithium C O S Y Correlation spectroscopy c-Pr Cyclopropyl d Doublet D C I Desorption chemical ionization D E P T Distortionless enhancement by polarization transfer D I B A L H Diisobutylaluminum hydride D M A P 4-(A^N-Dimethylamino)pyridine D M E 1,2-Dimethoxyethane D M F N,Af-Dimethyl formamide D M P U Af,Af'-Dimethylproylene urea D M S Dimethyl sulfide D M S O Dimethyl sulfoxide EI Electron ionization equiv Equivalents ESI Electrospray ionization E t 2 0 Diethyl ether G C Gas chromatography H M B C Heteronuclear multiple bond correlation H M P A Hexamethylphosphoramide H M Q C lH-Detected heteronuclear multiple quantum coherence H P L C High pressure liquid chromatography H R F A B M S High resolution fast atom bombardment mass spectrometry H R M S High resolution mass spectrometry I B X Iodoxybenzoic acid IR Infrared K D A "Potassium A?,A^-diisopropylamide" L A H Lithium aluminum hydride L D A Li thium Af, N-diisopropylamide m Multiplet m - C P B A meta-Chloroperbenzoic acid M e Methyl M e L i Methyllithium M M 2 Molecular mechanics level 2 mp Melt ing point M S Mass spectrometry N M O N-methylmorpholine-Af-oxide N M R Nuclear magnetic resonance nOe Nuclear Overhauser enhancement N O E S Y Nuclear Overhauser enhancement spectroscopy O R T E P Oak Ridge thermal ellipsoid plot Ph Phenyl q Quartet it Room temperature s Singlet t Triplet T B A F Tetra-n-butylarnmonium fluoride T B A I Tetra-n-butylammonium iodide T B S terr-Butyldimethylsilyl T E S Triethylsilyl T f Trifluoromethanesulfonyl T H F Tetrahydrofuran T L C Thin layer chromatography T M E D A N,N,N' ,N'-Tetramethylethylenediamine TMSC1 Trimethylsilyl chloride T P A P Tetra-n-propylammonium perruthenate Ts Tosyl, Toluenesulfonyl U B C University of British Columbia U V Ultraviolet xiv Acknowledgments First and foremost, I would like to extend my sincerest gratitude to my research supervisor, Professor Edward Piers. Your intellectual guidance, mentorship and assistance in the preparation of this manuscript have played an invaluable role in my learning experience as a graduate student in your research group. Your support, both moral and financial, throughout the successes, hardships and failures of this work has been greatly appreciated. Further financial support throughout the course of my career as a graduate student from F C A R (Fonds pour la Formation de Chercheurs et l 'A ide a la Recherche) in the form of a graduate student scholarship and from the Department of Chemistry at the University of British Columbia in the form of Teaching Assistantships was valued immeasurably. For intellectual conversations with regards to chemistry in general, and for providing the type of environment only possible amongst a close-knit group of graduate students and postdoctoral fellows, I would like to thank members of the Piers research group, both past and present. Particularly gratifying has been the time spent, both within and outside the laboratory environment, with the following exceptional individuals: Dr. Stephen Lau, Dr. Arturo Orellana, Dr. Denise Andersen, Dr. Sebastien Caille, Dr. Shawn Walker and Dr . Urmi la Deo Jangra. Finally, for the incredible aid provided by carrying through synthetic material and tying up several loose ends, I am indebted to Diana Wallhorn. Much of the spectral and analytical work was carried out by the various facilities available at the Department of Chemistry: the N M R Facility, the Mass Spectrometry Centre, the Microanalytical Laboratory and the Crystallography Facility. Thanks in particular for helpful discussions to Marietta Austria, Liane Darge, Dr . Nick Burlinson, Peter Borda and Dr. Brian Patrick. Thanks also to the guys at the mechanical and electrical shops, in particular, Ron for keeping my vacuum pump in prime condition. XV To the two people who tirelessly proofread this manuscript, Dr. Stephen Lau and Diana Wallhorn, words cannot describe my gratitude for your patience, time and hard work. I would be amiss i f I failed to acknowledge those who have enriched my life outside of the laboratory during my six and a half year sojourn at the University of British Columbia. Diana Wallhorn, my sweetheart, best friend and soulmate. Throughout the good times, hard times, stress and rewards all associated with being a graduate student, you have shared your support, experience and love with me. I am extremely thankful for everything you have done for me and taught me about life. I love you. To Patricia Goodwin, my mother, and to Keith Harrison, my father, I am greatly thankful for everything that you have taught me and shared with me, in your own ways, about growing up and what it means to be a decent and courteous human being. To Matt Harrison, my brother, with whom I grew up, I would particularly like to extend my gratitude for stimulating conversations that have helped me keep the progress towards my Ph. D . and the work involved with that process in perspective at all times. Thanks for always being better than me at video games. I would like to offer a final word of thanks to all of my friends from Montreal (a place that w i l l always be home to me) and to those I have made here in Vancouver, through chemistry and playing ultimate, for support and for not making fun of me too much for still being a student. In particular, I would like to thank Steve Lau, who helped me develop my guitar playing skills, a medium through which I was able to relax and have fun. xvi To Patricia Goodwin, Mom. "Maistryefull merveylous and Archimastrye Is the Tincture of holy Alkimy; A wonderful Science, secrete Philosophie, A singular grace and gifte ofth'Almightie: Which never was found by labour of Mann, But it by Teaching, or by Revalacion begann." omas Norton, The Ordinall of Alchemy, c. 1477) 1 1. Introduction 1.1 General Chemical synthesis is concerned with the discovery of new methods for chemical transformations and with the total synthesis of structurally interesting and/or useful natural products and non-naturally occurring target compounds. Elegantly stated by Nicolaou, 1 in a concise review of chemical synthesis, "...the harvest of chemical synthesis touches upon our lives in myriad ways: medicines, high-tech materials for computers, communication and transportation equipment, nutritional products, vitamins, cosmetics, plastics, clothing, and tools for biology and physics." With such a diverse range of applications, it is probably not too surprising that this field of research still thrives in the information age, when others have been rendered obsolete by the efficiency of modern technology. Figure 1: Selected compounds synthesized in the early stages of modern synthetic chemistry. HOOC haemin COOH equilenin strychnine The art of chemical synthesis has been around since the early 19 t h century. However, beginning in the 1920's, and continuing through the 1960's, chemists witnessed the appearance of many of the fundamental reactions and reagents that would soon define synthetic chemistry. The discovery of reagents such as V . Grignard's alkylmagnesium halides provided the basis for the development of anionic chemistry. Reactions such as the 4+2 cycloaddition developed by O. Diels and K . Alder laid the groundwork for the construction of carbocycles. Natural product synthesis pioneers such as H . Fischer (haemin, 1929), 2 W . Bachmann (equilenin, 1939) 3 and R. Chapter 1 2 B . Woodward (strychnine, 1954) 4 were among the first to construct some of the more complex naturally occurring polycyclic frameworks of the time (see Figure 1), often employing what, by today's standards, would be considered sequences of simple and straightforward reactions. It was not until 1961, however, that E . J. Corey, 5 in his total synthesis of the natural product longifolene (see Figure 2), would introduce his systematic approach to retrosynthetic analysis, a doctrine that would eventually earn him the Nobel Prize for Chemistry (1990). This idea revolutionized the way many chemists perceived and approached natural product synthesis, and some have even spoken of it as the concept that turned natural product synthesis from an art into a science. Figure 2: Longifolene, synthesized by E . J. Corey in 1961. longifolene As in many other fields of science and engineering, technological advancements in the latter half of the 20 t h century have provided the means for vast discoveries in the field of chemical synthesis. Most notable to the synthetic chemist was the invention of nuclear magnetic resonance spectrometers. A s the magnetic field capabilities of these instruments have expanded, and as the development of pulse programs to respond to specific needs has advanced, more and more structural information about newly discovered or prepared compounds quickly became available to the synthetic chemist. This technology has certainly removed much of the guesswork in chemical synthesis. A s a result of these technological advancements, structurally complex natural products have yielded to total synthesis significantly more frequently than in the past. Furthermore, the development of new methods of chemical transformation as tools for natural product synthesis, and improvements made upon older methods, have furnished a means to this end. The C P -Chapter 1 3 molecules (Figure 3), two compounds first isolated by Pfizer in 1995, are testament to this fact. Despite the technology available at the time, it was not until 1997 6 that chemists were able to completely elucidate the structures of the CP-molecules, CP-263,114 and CP-225,917. Visual inspection of the structures of these compounds reveals unequivocally the challenge that lay before synthetic chemists: an extremely compact polycyclic core exhibiting a bridgehead olefin, flourished with a multitude of functional groups. Within two years, a team of six chemists at the Scripps Research Institute, under the direction of K . C. Nicolaou, were able to completely synthesize both of the CP-partners. 7 Their synthesis included the development of new cascade cyclization reactions and the tweaking of an intramolecular Diels-Alder reaction so that the cycloaddition would furnish only a single isomer of the core, elegantly displaying the intertwining of total synthesis and synthetic methodology. 8 Figure 3: The CP-molecules. The fact remains, however, that syntheses of such complex molecules, while graceful, are often long and convoluted. This particular synthesis of the CP-molecules was no exception. Forty synthetic steps were required to synthesize milligrams of CP-263,114 from many grams of starting materials. Since many natural products, such as the CP-molecules, contain carbocyclic frameworks, it seems reasonable, then, to believe that the development of newer and simpler methods for the construction of polycyclic scaffolds is an area of chemical synthesis in which significant explorations may still usefully be carried out. O O 0 : CP-263,114 CP-225,917 Chapter 1 , 4 1.2 Background For the purpose of effecting annulation sequences in chemical synthesis, bifunctional conjunctive reagents have emerged as powerful tools. Bifunctional reagents possess two reactive sites, each of which may be characterized as either donor (d) or acceptor (a) sites.9 Conjunctive reagents have been defined by Trost 1 0 as "...those reagents which are simple building blocks that are incorporated in whole or in part into a more complex system...". In general, bifunctional reagents contain all the carbons required to form the new ring. They do, however, become more complicated, often bearing extra atoms for a specific purpose or functional groups for providing a "handle" for further reactivity once the annulation is complete. Scheme 1 A n example of such a reagent1 1 (1) is shown in the preparation of bicyclic enone 2 (Scheme 1). The bifunctional Grignard reagent (1) serves as a propan-l-ol d ,a -synthon (3); the acetal function masks an aldehyde, the acceptor site that w i l l be deployed later in the annulation sequence. A simple cyclic enone (4) serves as the corresponding donor-acceptor partner for 1. The Grignard reagent undergoes a conjugate addition reaction, in the presence of catalytic copper(I) bromide-dimethyl sulfide complex, to the cyclic enone to afford the intermediate keto acetal 5. A c i d hydrolysis of the acetal then reveals the aldehyde, which undergoes an intramolecular aldol condensation-dehydration sequence to afford bicyclic enone, Chapter 1 5 2. Depending on the need, keto acetal 5 may be isolated for further manipulation prior to the ring closure. Otherwise, acid may simply be added to the conjugate addition reaction mixture, initiating the ring closure. In this example the bifunctional reagent contained the remaining three carbons required to form the cyclopentene ring. In addition, it employed an aldehyde function as an aldol precursor to generate, upon ring closure, an enone, the alkene portion of which is contained within the five-membered ring. As such, the newly formed ring is susceptible to further reactions. In recent years, our laboratory has been significantly involved with the preparation and study of bifunctional conjunctive reagents bearing trialkylstannyl- and trialkylgermylalkenyl functions. Judicious choice of the group 14 element (Sn or Ge) in conjunction with an appropriate second functional group can provide a range of bifunctional reagents to serve a diverse variety of roles in annulation sequences. Three such bifunctional reagents (6, 7 and 8) are illustrated in Figure 4. Associated with each bifunctional reagent is an example, though not necessarily the sole example, of a synthon to which the reagent may function as the synthetic precursor. The remainder of this section wi l l serve to discuss each reagent in Figure 4 in its utility as the synthetic precursor to its depicted synthon. Figure 4: Representative examples of bifunctional reagents bearing trialkyltin and trialkylgermanium moieties. 6 7 8 1 "3 The bifunctional reagent 6 (R = Me) has been effectively employed in an annulation sequence requiring a copper(I)-tin transmetallation to promote an intramolecular conjugate Chapter 1 6 1 3 addition. This reagent (6) serves as the synthetic equivalent of a but-2-ene a ,d -synthon (Figure 4). The order of deployment of the donor and acceptor sites is not negotiable with this reagent due to the inherent reactivity of the allylic bromide moiety. A s such, the acceptor site is deployed first, and the donor site is deployed at a later stage in the sequence, as illustrated in Scheme 2. A l l y l i c bromide 6 reacts with the lithium enolate of vinylogous ester 9 to furnish compound 10. D I B A L H reduction of the ketone function of vinylogous ester 10, followed by acid-promoted hydrolysis and dehydration of the resultant product cleanly affords enone 11, a suitable substrate for intramolecular conjugate addition reactions. Treatment of the alkenyl stannane (11) with copper(I) chloride in dry D M F promotes a transmetallation reaction, and the resulting alkenyl copper species undergoes an intramolecular addition reaction to afford the bicyclic ketone, 12. This annulation sequence works cleanly with a variety of differently substituted and functionalized 5- and 6-membered vinylogous esters. 1 4 Bifunctional reagent 7 (Figure 4, R = Me) is another trialkylstannylalkene that has been prepared and studied in our laboratory. It is similar to 6 in the fact that the donor site is still on the internal carbon; it serves as the synthetic equivalent of a but-l-ene d 2,a 4-synthon. However, it Chapter 1 7 differs from compound 6 in that the donor site may be deployed first and the terminal acceptor site later. Transmetallation of the trimethylstannyl group of compound 7 (R = Me) with MeLi at low temperatures affords reagent 13 (Scheme 3). While kept cold, this reagent undergoes neither a cyclization to form methylidenecyclopropane, nor a nucleophilic substitution with another molecule of 13. However, when unsaturated hydrazides such as 14 are added to the reaction mixture, a conjugate addition reaction is observed. When the reaction mixture is warmed up, an intramolecular substitution occurs between the formed hydrazide cc-anion (15) and the terminal alkyl chloride, affording functionalized cyclopentane 16.15 L i 14 Scheme 3 The use of reagents such as 7 as synthetic equivalents of but-l-ene a2d4-synthons was met with limited success. The chloride could be replaced with an iodide, but the lithium-iodine exchange reaction of the resulting alkyl iodide proved to be problematic in the presence of the trialkyltin moiety, presumably due to the relatively weak carbon-tin bond. The bond dissociation energy of the carbon-tin bond in Me4Sn has been determined16 to be 65 kcal/mol. However, the bond dissociation energy of the carbon-germanium bond in Me4Ge is 76 kcal/mol. As such, it was reasoned that the replacement of the trialkyltin group with a trialkylgermanium group to form bifunctional reagents such as 8, might display greater stability of the carbon-metal bond in the face of a lithium-iodine exchange reaction, but still provide a means of deploying the desired alkenyl acceptor site later in the annulation sequence. This turned out to be true, and from the Chapter 1 8 alkyllithium formed by the reaction of 8 (R = M e , Figure 4) with B u L i , it was possible to prepare the organocuprate species 17 (Scheme 4). Reagent 17 cleanly underwent in situ conjugate addition reactions with cyclic enones such as 4 . 1 7 In the presence of iodine, the resulting alkenylgermane (18) undergoes iododegermylation to afford alkenyl iodide 19. A palladium-catalyzed intramolecular coupling between the alkenyl iodide and the enolate of the ketone completes the annulation sequence, furnishing bicyclic enone 20. While initially, the olefin occupies an external position, it is impossible to prevent it from migrating into conjugation with the ketone under the reaction conditions. This annulation sequence has been effectively employed to prepare a variety of bicyclic enones 1 7 ' 1 8 as well as tricyclic enones. 1 8 O Me3Ge GeMe3 O I 2 , C H 2 C 1 2 18 Cu(CN)Li 17 1. 2 B u L i , T H F , -78 °C 2. CuCN, -45 °C 19 Pd(PPh 3) 4 f-BuOK f-BuOH-THF GeMe3 Scheme 4 20 The utility of the annulation sequence depicted in Scheme 4 has been evidenced by its employment in the total synthesis of the tetraquinane diterpenoid crinipellin B , 21 . 1 9 In this particular case, the bifunctional reagent 17 was utilized to establish the third ring in the angular triquinane portion of the tetracyclic core (Scheme 5). To that end, bicyclic enone 22 was treated with 17 to afford the ds-fused bicyclic ketone 23. Iododegermylation of the alkenylgermanium Chapter 1 9 moiety cleanly afforded alkenyl iodide 24, which was now ready to undergo the final step of the annulation sequence. Thus, the palladium(O) catalyzed intramolecular coupling between the alkenyl iodide and the enolate of the cyclopentanone system furnished the angular triquinane 25 . 1 9 The presence of the methyl group at the newly formed angular position prevents the external olefin from migrating into conjugation with the ketone. HO Scheme 5 ^ 1.3 Proposals Intramolecular conjugate addition is a long-standing method for the formation of carbocyclic structures in organic synthesis. Considerable effort has been made to develop methods of generating suitable organometallic nucleophiles in the presence of activated Michael acceptors, due to a number of problems that are associated with this type of reaction. Often, mixtures of products derived from both intramolecular 1,2- and 1,4-addition are observed. In other cases, the organometallic species required for the intramolecular conjugate addition can never be prepared because alkyllithium reagents being used to prepare them add to the Michael Chapter 1 10 acceptor portion of the molecules first. One technique that has proven to be valuable in this area is the generation of the organometallic species via a copper(I)-tin transmetallation (see Scheme 2). Another is the generation of the organometallic species via a lithium-iodine exchange reaction. BuLi 26 27 Scheme 6 Studies 2 0 have shown that the lithium-iodine exchange with butyllithium or t-butyllithium often occurs more rapidly than the reaction of the alkyllithium reagent with a carbonyl function also present in the molecule (Scheme 6). When an alkenyl iodide such as 26 is treated with B u L i in an appropriate solvent, the corresponding alkenyllithium species is rapidly generated, which then undergoes an intramolecular 1,2-addition, furnishing a bicyclic compound bearing an angular hydroxyl group (27) in good yield. -COOf-Bu COOf-Bu BuLi 28 30 BuLi 29 Scheme 7 Several examples of intramolecular conjugate additions initiated by lithium-iodine exchange have appeared in the literature in recent years. The first examples of this type of Chapter 1 11 annulation protocol seem to have been disclosed by Cooke and coworkers, in 1984. This publication described a procedure for the lithium-iodine exchange initiated intramolecular conjugate additions of primary alkyl and alkenyl carbanions to cc,p-unsaturated esters and ketones (see Scheme 7). Thus, when iodides such as 28 and 29 are treated with an alkyllithium reagent, cyclic compounds 30 and 31 are obtained, respectively, in very good yields. Another example reported by Cooke and coworkers 2 2 involves the lithium-iodine exchange initiated intramolecular conjugate addition of alkyl anions to ct,p-alkynic esters. In this case (Scheme 8), the allenoate species resulting from the intramolecular conjugate addition of the anion formed from 32 is trapped with T M S C l to supply the cyclic product 33. This annulation protocol has been successfully employed in the formation of four-, five- and six-membered carbocyclic compounds. 2 1 ' 2 2 ' 2 3 TMS^ / C O O f - B u COOf-Bu B u L i T M S C l 32 33 Scheme 8 Another remarkable example of a lithium-iodine exchange initiated intramolecular conjugate addition reaction was published by Comins 2 4 in 1996 (Scheme 9). In this work, aryl and alkenyl iodides were treated with butyllithium, and the resulting anions cyclized onto dihydropyridone Michael acceptors. The stereochemical outcome of this reaction is determined by the presence of an alkyl or an aryl group that is situated at the 6-position of the dihydropyridone ring. The formed anion approaches the Michael acceptor unit from the face opposite to the C-6 group. Thus, aryl iodide 34 is treated with B u L i to provide, after cyclization, tricyclic tetrahydropyridone 35. In the case of the alkenyl iodide, 36, the resulting enolate anion is trapped with Comins ' reagent (37) to furnish the alkenyl triflate, 38. The synthetic utility of Chapter 1 12 this protocol was borne out by its employment in the total synthesis of the alkaloid indolizidine 209D (39). O PrT N I BuLi 35 1. r-BuLi 2. CI N N(Tf) 2 37 Scheme 9 indolizidine 209D (39) In 1994, our laboratory published a convenient method for the preparation of alkyl Z-3-iodoalk-2-enoates such as 41 from acetylenic esters such as 40 (see Scheme 10).25 Reduction of select examples of these Z-3-iodoalk-2-enoates (e.g. 41), followed by conversion of the resulting alcohols (e.g. 42) to allylic bromides using P h 3 P * B r 2 and imidazole, neatly furnished bifunctional reagents such as 43. Bifunctional reagents of this type have proven useful as 1 3 synthetic precursors to propene d ,a -synthons, and in the Comins case, in particular, have been deemed useful as annulation precursors in a sequence involving an intramolecular conjugate addition. Chapter 1 H-13 -COOEt NaT HOAc H COOEt D I B A L H 40 41 P h 3 P ' B r 2 , imidazole d a Scheme 10 It is proposed (see Scheme 11) that these reagents (of general structure 44) could be employed as bifunctional reagents to generate carbo-bicyclic ketones via intramolecular conjugate addition reactions. A variety of vinylogous esters (45) may be alkylated with a series of bifunctional reagents (44) to generate vinylogous esters such as 46, bearing an alkenyl iodide function. Presuming these vinylogous esters can be converted to the corresponding enones (of general structure 47), they might then be used to carry out intramolecular conjugate addition reactions, leading to the preparation of a series of carbo-bicyclic ketones, of general structure 48. 1. L D A 2. I 44 45 1. D I B A L H or R 3 M g B r * 2. H + R L i Scheme 11 Chapter ,1 14 Prior research in our group has involved carrying out such cyclizations by implementing a copper-tin transmetallation reaction on alkenylstannane precursors to generate the appropriate anionic intermediate. This methodology, while versatile in its range of products, has been limited to conjugate addition reactions due to the fact that the anionic intermediate is an organocopper species. Thus, the vinylogous ester must be converted into the corresponding enone prior to the transmetallation. Interestingly, this transformation may be effected by reduction with D D 3 A L H , or by 1,2-addition with alkyl- or alkenyl Grignard reagents, or alkyllithium reagents, generating, upon acid-promoted dehydration and hydrolysis of the resulting allylic alcohol, a variety of 0-substituted enones. On the other hand, it seems reasonable to assume that an alkenyllithium species generated by lithium-iodine exchange of the alkenyl iodide (of general structure 46), should undergo an intramolecular 1,2-addition reaction with the ketone function of the vinylogous ester moiety (as in Scheme 12). Since the intermediate bis-allylic tertiary alcohol (49) would likely be very unstable, it would presumably have to be immediately treated with an acid to promote a dehydration and hydrolysis sequence, furnishing bicyclic dienones such as 50. Scheme 12 Bicycl ic moieties that could be easily derived from the products of the two proposed reactions above exist in many natural products. Of particular interest is the structurally unique series of sesterterpene polyols known as the mangicols (e.g. 51-53, Figure 5). A bicyclic system comprised of a czs-fused hexahydroindane system exists buried within the tetracyclic core of all of the mangicols. It was reasoned, based upon the locations of the various functional groups of the products from the two proposed reactions above, that the remaining two five-membered rings Chapter 1 15 could be established by a variety of hypothetical means. Thus, if the two methodological proposals above were to prove successful, then it is proposed that they be employed in the total synthesis of some of the members of the mangicol family. Figure 5: Selected members of the mangicol family. R 51 mangicol E: R = O H 53 mangicol G 52 mangicol F: R = H 16 2. Lithium-Iodine Exchange Initiated Intramolecular Addition Reactions 2.1 Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition Reactions of Alkenyl and Aryl Anion Functions 2.1.1 Introductory Remarks To explore the possibil i ty of carrying out intramolecular conjugate addition reactions initiated by lithium-iodine exchange, an array of suitable Michael acceptor substrates bearing alkenyl iodide functions needed to be prepared. The goal of the intramolecular conjugate addition experiments that would follow was to demonstrate that this reaction could be employed to generate a variety of different types of products, such as those shown in Schemes 13-17. O The simplest modification that was to be made to the core substrate was to add different alkyl groups at various positions (see Scheme 13). Particularly accessible, via known chemistry, are enones substituted at the p- and y-positions. Furthermore, it should be possible to prepare these enones with different substituents at the end of the sidechain containing the alkenyl iodide moiety. Illustrated in Scheme 11 (Chapter 1) is the general structure (47) of the desired enones 1 2 3 required for the preparation of bicyclic ketones such as 48, where R , R and R are all alkyl substituents. A second modification to the core structure of the enone substrates would be to introduce strained cycloalkyl moieties. This is desired to demonstrate that strained ring-bearing bicyclic Chapter 2 17 ketones such as 55 can be prepared from enones such as 54 (Scheme 14). It can be envisioned that such systems are amenable to numerous further reactions. A s natural product targets are very rarely as simple as the bicyclic products being prepared in this study, the compatibility of "handles" for further reactivity at various sites with the reaction conditions is of considerable importance to such a methodological study. Scheme 14 A more direct method to achieve the goal described in the previous paragraph is to install protected functional groups into the substrates. To this end, benzyl-protected alcohols such as 56 are desired to demonstrate that bicyclic ketones such as 57 are available via this methodology (Scheme 15). 56 57 Scheme 15 A s mentioned earlier, many natural products are particularly complex in structure, and often contain more than two rings. While the previously mentioned modifications to the substrates may lead indirectly to such structures, it would be of particular use i f this methodology could be applied to the direct preparation of tricyclic ketones such as 59 (Scheme 16). Chapter 2 58 Scheme 16 In addition to the types of polycyclic structures such as 59, there exist numerous polcyclic natural products whose structures contain indane subunits. Thus, it would also be of particular interest to demonstrate that, as illustrated in Scheme 17,. substituted enones such as 60 might be employed for the preparation of tricyclic compounds containing an aromatic ring, as in 60 61 Scheme 17 2.1.2 Preparation of Substrates For the purpose of testing a lithium-iodine exchange initiated intramolecular conjugate addition reaction, several different types of substrates, described in the previous section, were desired. It would be most convenient if a general method for their preparation were available. For this reason, the method of alkylation of vinylogous esters developed by Stork and Danheiser27 followed by conversion of the resulting alkylated product into an enone seemed a reasonable approach. Chapter 2 19 Stork and Danheiser reported that vinylogous ester 9 (Scheme 18) can be selectively deprotonated at the a'-position by L D A in dry T H F at -78 °C. This bears advantage over more conventional enones which, i f hindered at the a'-position, may often experience deprotonation at the y-position. The resulting enolate anion (of the vinylogous ester) can then be alkylated by the addition of an electrophile followed by the slow warming of the reaction mixture to room temperature. The authors presumed that aggregation of the lithium enolates prevented alkylation at -78 °C. Reduction of the resulting alkylated vinylogous ester (62) with L A H followed by acid promoted dehydration and hydrolysis of the resulting allylic alkoxide (63) affords the y-allyl enone, 64. Scheme 18 6 4 Since Stork and Danheiser demonstrated that allylic bromides are suitable for the a'-alkylation of vinylogous esters (Scheme 18), it seemed that differently substituted bifunctional Chapter 2 20 reagents, displaying allylic bromide and iodoalkene functions, and of general structure 44, would be appropriate for the initial experiments in the preparation of the substrates. A s mentioned in Chapter 1 (see Scheme 10), a convenient method for the preparation of Z-iodoalkenoates from acetylenic esters had been developed in our laboratory. 2 5 The key feature to the success of this reaction seems to be the use of a relatively small amount of the solvent, acetic acid. Conversion of ester 66 to bromide 68 (Scheme 19) has been previously reported, 2 0 1 3 and it was assumed that the same two-step transformation would translate to all of the bifunctional reagents required for this study. The first acetylenic ester employed in the preparation of the bifunctional reagents was commercially available ethyl but-2-ynoate, 65. Subjection of this reactant to the action of N a l (Scheme 19) in acetic acid for 1.5 h at 110 °C provided ethyl Z-3-iodobut-2-enoate, 66, as reported by Piers and coworkers. On large scale, this material was treated, without purification with D I B A L H . The resulting allylic alcohol (67) was converted into bromide 68 by reaction with Pri3P<*Br2 in the presence of stoichiometric imidazole . 2 0 b When carried out on a scale large enough to produce 35 g of bromide 68, the overall yield for this three-step sequence is 60%. -COOEt Nal acetic acid 65 66 1. D I B A L H , E t 2 0 ) COOEt 2. N H 3 , aq. NH 4 C1 pH ~8 67 P h 3 P ' B r 2 , imidazole, C H 2 C 1 2 Scheme 19 68 In order to install strained rings and masked functional groups into the vinylogous ester sidechains (e.g. compounds 54 and 56 from the previous section), these attributes needed to be Chapter 2 21 present in the bifunctional reagents. Thus, two more bifunctional reagents were required. Since the acetylenic ester precursors to these bifunctional reagents were not commercially available, their preparation was required. Figure 6: Compounds 54 and 56. O In the first case, it was desired to demonstrate bicyclic ketone products appended with strained-ring moieties could be formed via this methodology. To this end, a cyclopropane ring at the terminus of the bifunctional reagent was chosen as an appropriate system. Generation of the acetylenic ester precursor (71, Scheme 20)28 for this process was carried out by the method of Corey and Fuchs. 2 9 Commercially available cyclopropanecarboxaldehyde (69) was treated with Pri3P=CBr2 to generate dibromoolefin 70. This reagent was subsequently allowed to react with 2 equivalents of M e L i followed by methyl chloroformate to furnish acetylenic ester 71. The yields obtained for this two step process were similar to those reported. 2 8 Br A 69 P h 3 P = C B r 2 Br H C H 2 C 1 2 A 70 1. M e L i (2 equiv.) THF ) 2. CICOOMe C O O M e 71 Scheme 20 The final acetylenic ester to be prepared was designed to illustrate, i f successful, that the lithium-iodine exchange initiated intramolecular conjugate addition protocol could be employed to generate bicyclic structures bearing a masked hydroxyl function at an external position. After considering a number of common hydroxyl protecting groups, the benzyl ether was chosen Chapter 2 22 because it seemed the least l ikely to be cleaved either in the hydriodination step (hot acetic acid) or under the conditions of the lithium-iodine exchange reaction (as might occur with some of the silyl protecting groups). Acetylenic ester 74 (Scheme 21) is a previously reported compound. 3 0 However, the authors described its preparation from ethylene glycol via a lengthy route, including a Corey-Fuchs acetylenation of benzyloxyethanal. It was felt that compound 74 could be prepared by a simpler method from commercially available propargyl alcohol (72). Protection of the hydroxyl function as the benzyl ether via a standard method provided acetylene 73. This substance was treated with B u L i followed by methyl chloroformate, affording acetylenic ester 74. M 1. NaH, THF M 1. BuLi , THF X O O M e 2. BnBr B n O ^ / S ^ - 2. CICOOMe B n C X 92% 7 3 100% ? 4 Scheme 21 The next test was to determine i f the two prepared acetylenic esters (71 and 74) would respond predictably to the standard hydro-iodination conditions. First, the y-cyclopropyl acetylenic ester 71 was heated with N a l in acetic acid at 110 °C for 1.5 h (Scheme 22). The result was clean addition of H I across the triple bond to afford Z-iodoalkenoate 75, without any observable opening of the cyclopropane ring. Gratifyingly, under identical conditions, Z -iodoalkenoate 76 was generated from y-benzyloxy acetylenic ester 74 without any noted cleavage of the benzyl protecting group. With esters 75 and 76 in hand, it remained for them to be converted into their corresponding allylic bromides. Thus, both esters 75 and 76 were reduced with two equivalents of D I B A L H to afford alcohols 77 and 78, respectively. In turn, each of these alcohols was treated with Pli3P<*Br2 and imidazole, neatly furnishing bromides 79 and 80, respectively. Chapter 2 23 Nal l . D I B A L H , E t 2 0 R ZZ I C O O M e X O O M e acetic acid R' 2. N H 3 , aq. NH 4 C1 pH ~8 R OH 71: R = c-Pr 74: R = B n O C H 2 75: R = c-Pr : 82% 76: R = B n O C H 2 : 84% 77: R = c-Pr : 92% 78: R = B n O C H 2 : 92% P h 3 P ' B r 2 , imidazole, C H 2 C 1 2 Bn = C H 2 I R Br Scheme 22 79: R = c-Pr : 96% 80: R = B n O C H 2 : 86% Following the method described by Stork and Danheiser, the lithium enolate of 9 (Scheme 23) was generated by addition of the vinylogous ester to a cold solution of L D A in dry T H F . Addition of allylic bromide 68 to the reaction mixture followed by slow warming of the resulting deep red mixture to room temperature (~4 h) afforded the desired vinylogous ester (81) in 91% yield. It was at this stage, however, that a technical issue with the substrate preparation was discovered. While it is possible to further alkylate vinylogous esters bearing sidechains with a vinyltin group (such as 10), this turns out not to be the case for alkenyl iodides such as 81. Subjecting vinyl iodide 81 to the action of L D A resulted primarily in dehydro-iodination to form alkyne 83. This was evidenced by the presence of a 3-proton broad singlet situated at 8 -1.6 in the ! H - N M R spectrum of the product. None of the desired alkylated product (82) was observed. Chapter 2 24 1. LDA, THF -78 °C » 2. 68, THF -78 °C -> rt 1. LDA, THF -78 °C 2. Mel, THF -78 °C -> rt Scheme 23 This problem, however, is easily circumvented by adding the alkenyl iodide bearing sidechain subsequently to any other substituents that were desired at the a'-position of the vinylogous ester. For this reason, two other alkylated vinylogous esters were prepared (Scheme 24) via the Stork-Danheiser method:27 first, the previously reported31 oc'-methyl vinylogous ester (84) and second, the ct'-benzyl vinylogous ester (85). Each of these vinylogous esters was then alkylated with allylic bromide 68, to afford vinylogous esters 82 and 86, respectively. In order for the alkylation of the two cc'-substituted vinylogous esters to be successful, dry FfMPA (2 equiv.) was added to the reaction mixture prior to the addition of the allylic bromide (68). 1. LDA, THF -78 °C 2. Mel, THF or BnBr, THF -78 °C -> rt 1. LDA, HMPA, THF, -78 °C » 2. 68, THF -78 °C -> rt 84: R = Me: 91% 85: R = Bn : 76% 82: R = Me : 35% 86: R = Bn : 79% Scheme 24 Chapter 2 25 Having established a convenient and general method for the preparation of vinylogous esters bearing iodoalkenyl-functionalized sidechains, the remaining two allylic bromides could now be employed in the preparation of the remainder of the desired vinylogous ester precursors. Thus, treatment of vinylogous ester 9 with L D A in cold (-78 °C) T H F (Scheme 25) followed by the addition of allylic bromide 79 afforded vinylogous ester 87 in 82% yield. Likewise, the alkylation of vinylogous esters 9 and 84 (with the aid of H M P A in the case of 84) with allylic bromide 80 smoothly afforded vinylogous esters 88 and 89, respectively. Scheme 25 Conversion of the vinylogous esters into the enones required for the conjugate addition studies could be effected in one of two manners. The first, as previously mentioned, is by D E B A L H reduction of the ketone function of the vinylogous ester followed by acid-promoted hydrolysis and dehydration of the resulting allylic alcohol. The second method, useful for generating P-substituted enones, is by 1,2-addition of a Grignard reagent to the ketone function of the vinylogous ester, again followed by acid-promoted hydrolysis and dehydration, to furnish a more complex or functionally more diverse compound. Under the first set of conditions, as Chapter 2 26 illustrated in Scheme 26, vinylogous esters 81, 82, and 86-89 were all cleanly reduced with D I B A L H . After work-up with NH3-NH4CI (pH ~8 solution), the residual material, in each case, was treated with 1 equivalent of p - T s O H in Et^O, furnishing enones 90-92, 54, 56, and 93, respectively. 81: R 1 = H ; R 2 = Me 90: R 1 = H ; R 2 = Me : 100% 82: R 1 = Me; R 2 = Me 91: R 1 = Me; R 2 = Me : 89% 86: R 1 = Bn; R 2 = Me 92: R 1 = Bn; R 2 = Me : 81% 87: R 1 = H ; R 2 = c-Pr 54: R 1 = H ; R 2 = c-Pr : 98% 88: R 1 = H ; R 2 = C H 2 O B n 56: R 1 = H; R 2 = C H 2 O B n : 78% 89: R 1 = Me; R 2 = C H 2 O B n 93: R 1 = Me; R 2 = C H 2 O B n : 70% Scheme 26 V i a the second method, the addition of M e M g B r to vinylogous esters 81 and 88 afforded, after acid-promoted dehydration and hydrolysis of the resulting tertiary allylic alkoxides, (3-methyl enones 94 and 95, respectively (Scheme 27). Scheme 27 Modification of the ring size of the vinylogous ester was proposed as a final structural variation for this portion of the study of the lithium-iodine exchange initiated intramolecular Chapter 2 27 conjugate additions of alkenyl anion functions. The results from this set of experiments would determine the synthetic use of this reaction in the formation of bicyclic products that bear more ring strain than the originally discussed bicyclo[4.3.0]nonanones. For this purpose, four other enones were prepared in a manner identical with that just described. 96:n = l ; R 1 = H 99: n = 1; R 1 = H : 97% 102: n = 1; R 1 = H; R 2 = H : 70% 97:n = 3 ; R 1 = H 100: n = 3; R 1 = H : 87% 103: n = 3; R 1 = H ; R 2 = H : 82% 98:n = 3 ;R 1 = Me 101: n = 3; R 1 = Me : 92% 104: n = 3; R 1 = Me; R 2 = H : 35% 105: n = 3; R 1 = H ; R 2 = Me : 75% Scheme 28 Scheme 28 shows the preparation of the final enones for use in this portion of the study. Five-membered vinylogous ester 96 was alkylated with allylic bromide 68 to provide compound 99, which was then reduced with D D 3 A L H , affording, upon acid-promoted hydrolysis and dehydration (p-TsOH, Et20), enone 102. Likewise, seven-membered vinylogous esters 97 and 98 were alkylated with compound 68, affording compounds 100 and 101, respectively, which were in turn, reduced with D I B A L H . Treatment of the resulting allylic alcohols with p - T s O H in E t i O afforded seven-membered ring enones 103 and 104, respectively. Enone 105 was obtained by treatment of 100 with M e M g B r in Et20 followed by aqueous HC1 work-up. 2.1.3 Designing and Tailoring the L i - I Exchange Initiated Intramolecular Conjugate Additions. Work carried out previously in our laboratory 1 3 had demonstrated that cyclizations of alkenylcopper species analogous to some of those being employed in this study generated cis-fused bicyclic ring systems. Examination of molecular models suggests that transition state 106a (Figure 7), which would lead to the formation of a cw-fused bicyclic ring system, adopts a Chapter 2 28 conformation such that the alkenyl anion-bearing sidechain occupies a pseudo-axial position on the six-membered ring. In this conformation, the approach of the alkenyllithium function to the P-position of the enone appears to be unobstructed by other elements of the molecule. B y contrast, the conformation depicted in transition state 106b would be necessary for the formation of a trans-fused bicyclic ring system. It is clear from the diagram representing this transition state that there are two factors that could hinder the formation of frans-fused bicyclic systems. The first is angle strain; there is a large distance between the alkenyl anion and the P-position of the enone, impeding any reaction between these two sites. Second, there is steric interference toward the approach of the alkenyl anion to the P-position of the enone from this angle due to the enone's y-substituent (in this case, H). Consequently, it is presumed, that the lithium-iodine exchange initiated intramolecular conjugate addition reaction would also generate as-fused bicyclic ring systems. Figure 7: Conceivable transition states for the cyclization process. t t 106a: favoured 106b: disfavoured In theory, treating alkenyl iodides such as those prepared in Section 2.1.2 with either B u L i or / - B u L i should rapidly generate the corresponding alkenyllithium function required for the intramolecular conjugate addition process, without reaction of the alkyllithium reagent with the carbonyl group. 2 0 A t first, it was sought to determine if, in fact, this was the case with alkenyl iodides in the presence of vinylogous ester moieties. Logically, in such a scenario, one must begin with the simplest possible substrate, and subject it to the most rudimentary of reaction conditions. To that effect, alkenyl iodide 90 was chosen as the test substrate. It bears no Chapter 2 * 29 substituents on the enone ring to hinder the reaction, nor does it display any functional groups other than those required for the proposed reaction. Scheme 29 Since lithium-iodine exchanges are normally quite effective when carried out at cold temperatures and in ethereal solvents, these conditions were chosen for the test reactions. Thus, a cold (-78 °C) well-stirred solution of alkenyl iodide 90 in dry T H F was treated with a solution of B u L i (2 equivalents) in hexanes (Scheme 29). The reaction mixture was allowed to warm slowly to room temperature after which it was subjected to standard aqueous work-up. Purification by flash column chromatography afforded the bicyclic ketone 107 in a meagre 31% yield. The identity of this compound was confirmed by the matching of its ^ - N M R spectral data 1 ^ with those previously reported. However, several other products were obtained from this reaction. One of these seemed to be the product of lithium-iodine exchange and protonation, where no ring closure was observed. In another case, the ! H - N M R spectrum displayed several new alkyl signals, including a three-proton triplet, likely indicating the addition of B u L i to the carbonyl function. These results were perceived as positive indications that the desired reaction was in fact taking place, and that optimization of the reaction conditions by elimination of the undesired side-reactions could afford improved yields of the desired bicyclic ketone, 107. With this type of reaction, there are a number of remedies that may be employed to coax the reaction to furnish higher yields of clean product. For example, i f the reaction is considered merely as a conjugate addition reaction, then one such remedy is the addition of a Lewis acid to 32 the reaction mixture. Lewis acids coordinate with carbonyl oxygen atoms and in the case of Chapter 2 30 a,P-unsaturated ketones, this coordination results in the activation of the P-carbon towards nucleophilic addition. Under these conditions, the alkenyl anion formed by lithium-iodine exchange would be expected to cyclize faster, thus reducing formation of any uncyclized material. When the reaction is considered from an anionic standpoint, a possible solution would be the addition of an agent such as H M P A to the reaction mixture. H M P A is often thought of as a deaggregating agent, 3 3 ' 3 4 acting to break apart clusters of anions, and thus to expose the anionic function to a more facile reaction with electrophiles. Another source of the problem may be at the level of the lithium-iodine exchange reaction. In many cases, the employment of f -BuLi over B u L i has more efficiently provided clean lithium-iodine exchange products. Furthermore, t-B u L i would be less inclined to add to the relatively hindered carbonyl group than the originally employed B u L i . With these weapons in our arsenal, a study aimed at optimizing the conditions of this reaction was embarked upon. Table 1: Results of Optimization Studies for the L i - I Exchange Initiated Intramolecular Conjugate Addition. O 0 1. RLi, THF conditions3 • 2. H 2 0 91 9 107 RLi (2.2 equiv.) HMPA (equiv.) TMSC1 (equiv.) Yield of 107 (%)b R = B u 0 0 31 R = B u 2.5 0 52 R = r-Bu 2.5 0 65 R = B u 2.5 4 90 R = r-Bu 2.5 4 87 conditions: A solution of 90 in dry THF was cooled to -78 °C (-0.1 M). Any additives were then introduced into the reaction mixture via a syringe, and the resulting mixture was stirred for 5 min. To the mixture was added, rapidly via a syringe, a solution of the alkyllithium reagent (BuLi: 1.6 M in hexanes; f-BuLi: 1.7 M in pentane). The reaction mixture was allowed to warm to room temperature over 15 min, then ¥i of the volume of the reaction mixture of water was added, isolated yield of 107 after chromatography. Chapter 2 31 To our gratification, the results, summarized in Table 1, illustrated that these standard rectifications were in fact, of particular aid to the clean production of bicyclic ketone 107. A t first H M P A was added to the reaction mixture. Under reaction conditions identical with those mentioned above, bicyclic ketone 107 was isolated in 52% yield, an improvement of 21% over the reaction without any additives. When 7-BuLi was employed in place of B u L i , again in the presence of H M P A , a reasonable improvement in the yield of 107 (65%) was once again observed. The activating agent chosen for this study was T M S C l due to reports in the literature of the beneficial effects of this reagent on the conjugate addition of Gilman reagents and higher order organocuprates in T H F . 3 6 It is postulated that the presence of T M S C l promotes a multicentre interaction between the oxygen of the enone, the Si and the CI from T M S C l , and the lithium from the cuprate. 3 7 Although these studies were carried out specifically on organocuprates, it was reasoned that similar effects would be observed with alkenyllithium intermediates. In the event, T M S C l was found to have a positive influence on the outcome of the reaction, when combined with H M P A . The last two examples in Table 1 demonstrate its effect; yields of 90% and 87% of ketone 107 are obtained with alkyllithium reagents B u L i and r -BuLi , respectively. Monitoring the reaction progress by T L C reveals the presence of a non-polar product after the addition of the alkyllithium reagent. Upon addition of water, however, the product that gave rise to this spot on T L C no longer seemed to be present. It is presumed that the compound in question is the silyl enol ether of ketone 107, but that the excess T M S C l generates aqueous HC1 in water, resulting in the hydrolysis of this intermediate to the ketone. Careful work-up under basic conditions (aq. NaHCOs) afforded small amounts of a compound displaying signals in its ' H - N M R spectrum consistent with those expected for the bicyclic compound containing a si lyl enol ether function. Chapter 2 32 Although, in the final two examples, it is observed that B u L i affords a slightly higher yield of 107 than ?-BuLi, it should be noted that without T M S C 1 , there is a significant difference in yields in favour of the latter alkyllithium reagent. Furthermore, in select examples discussed later, r -BuLi was found to generate the bicyclic ketone products more cleanly, and in substantially better yields than B u L i . Hence, for all other examples in this study, f -BuLi was the alkyllithium reagent of choice for the lithium-iodine exchange. In recent years, D M P U has emerged as a reagent that bears similarities to H M P A in terms of its enhancement of reactions such as conjugate additions and ct-deprotonations of ketones. 3 8 It is considered to be less toxic and less carcinogenic than H M P A and was obviously considered as an alternative to H M P A in the intramolecular conjugate addition reaction. Unfortunately, though, when put to trial, the presence of D M P U failed to produce results similar to those obtained in the presence of H M P A . In fact, the results obtained when employing either 2.5 or 10 equivalents of D M P U were similar to those obtained when no H M P A or D M P U was added. Thus, D M P U was abandoned as the deaggregating agent for this reaction. 2.1.4 Testing the scope of the reaction. Having established a set of reaction conditions for the lithium-iodine exchange initiated intramolecular conjugate addition that reproducibly afforded good yields of bicyclic ketone 107 from alkenyl iodide 90, it became time to test these conditions on the remainder of the substrates (54, 56, 90-95 and 102-105). Each of these substrates was submitted, in turn, to the reaction conditions devised in Section 2.1.3, and the results from these experiments are summarized in Table 2 and in Table 3, below. Chapter 2 33 Table 2: The Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition of Alkenyl Anion Functions to Differently Substituted Cycl ic Enones. O 1. H M P A , T M S C l THF, -78 °C 2. 2 / -BuLi, -78 °C -> it 3 . H 2 0 Substrate R 1 R 2 R 3 Product Yield (%)a 90 H M e H 107 87 b 91 M e M e H 108 85 b 92 B n M e H 109 81 54 H c-Pr H 55 96 56 H C H 2 O B n H 57 78 93 M e C H 2 O B n H 110 83 94 H M e M e 111 72 b 95 M e C H 2 O B n M e 112 83 "Isolated Yields. H-NMR spectra of compounds 107, 108, and 111 match those of the identical compounds reported in ref. 13. Demonstrated in Table 2 are the results from the cyclization of alkenyl anions generated by lithium-iodine exchange onto a variety of differently substituted six-membered Michael acceptors, furnishing bicyclic ketones 55, 57, and 107-112. In general, the yields for this reaction with the different substrates are very good. Two effects were of concern in this set of experiments: the effect of substitution at the y-position of the enone, and that of substitution at the P-position. Substitution at the y-position was expected to improve the yields of the reaction by implicating a buttressing effect, and forcing the alkenyl anion closer to the Michael acceptor. With very little room for improvement on the initial system, though, it is not surprising that there is very little effect, i f any, that arises from the substitution of the y-proton (R 1 ) on the enone with other substituents. There is no notable difference in yield between the cyclizations of compounds 90, 91 and 92. Comparison of the Chapter 2 34 cyclizations of two of the benzyloxy-substituted alkenyl iodides 56 and 93 reveals only a slight improvement in yield (from 78% to 83%) due to the presence of the methyl group. On the other hand, the presence of a substituent at the P-position of the enone was expected to hinder the reaction, for steric reasons. This certainly seems to be the case when the cyclization of 90 is compared with that of 94. A s noted, there is a reduction in yield from 87% to 72%. Overall, yields for cyclizations of benzyloxy-substituted enones 56, 93 and 95 were particularly gratifying, as the resulting bicyclic ketones (57, 110 and 112, respectively) each display three functional groups as 'handles' for further reactivity: a carbonyl group, an olefin, and a protected hydroxyl function. Another important aspect of the formation of bicyclic ketones from monocyclic precursors is the possibility of generating bicyclic structures with differently sized rings. With this goal in mind, substrates 102-105 were subjected to reaction conditions identical with those optimized for the cyclization of compound 90. Reducing the ring size of the Michael acceptor from six carbons to five results in a reduction in yields, but not one that is dramatic. Table 3: The Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addition to Differently Sized Cycl ic Enones. O 1. H M P A , TMSC1 THF, -78 °C 2. 2 f-BuLi, -78 °C -> rt 3 . H 2 0 Substrate n R 1 R 2 Product Yield (%)a 102 1 H H 113 78 b 90 2 H H 107 87 103 3 - H H 114 83 c 104 3 M e H 115 78 c 105 3 H M e 116 51 c Isolated Yields. H-NMR spectra of compound 113 matches that of the identical compound reported in ref. 13. cCyclization of all seven-membered enones afforded inseparable mixtures of cis- and frans-fused bicyclic ketones in approximately 1:1 ratios. Chapter 2 35 More interesting were the results obtained during attempts to translate this methodology to seven-membered Michael acceptors. As mentioned in the footnote to Table 3, subjecting alkenyl iodide 103 to the cyclization conditions furnishes an inseparable mixture of cis- and trans-fused bicyclic ketones. This is evidenced by ' H - N M R spectroscopy of the mixture obtained from the cyclization of compound 103. Most notable is the presence of two signals corresponding to the allylic methyl groups (~8 1.7) and two signals corresponding to the alkenyl protons, appearing near 8 5.4. Examination of molecular models reveals that, in spite of the fact that three of the carbons within the ring are sp -hybridized and in conjugation with each other, there is significantly greater flexibility in the seven-membered enone than in the six-membered enone. This augmentation in flexibility allows the alkenyl anion-bearing sidechain to comfortably reach either face of the enone system, thus generating the two diastereomers. The same ratio of the two diastereomers was observed when a methyl group was placed at the P-position of the enone (i.e. 104 -> 115). Surprisingly, however, no notable biasing toward the e f -fused system was observed when a methyl substituent was located at the y-position (i.e. 105 -> 116). 2.1.5 Formation of Tricyclic Ketones. The success of the lithium-iodine exchange initiated intramolecular conjugate addition prompted us to investigate the possibility of generating tricyclic ketones from cycloalkenyl iodides and aromatic iodides. Conceptually, this series of substrates could be prepared, as outlined in Section 2.1.2, by the Stork-Danheiser alkylation followed by reduction of the vinylogous ester and hydrolysis-dehydration of the resulting alcohol. What materialized as a greater hurdle was that there are currently no general methods for the preparation of the desired Chapter 2 36 set of allyl and benzyl bromides for the alkylation process. Thus, a variety of methods needed to be developed or researched from the literature for preparation of the required bromides. To date, there are seemingly no convenient methods for the preparation of cycloalkenyl iodides from readily available starting materials. However, a significant amount of work has been carried out in our laboratories with cycloalkenylstannanes.14b'39 Since alkenylstannanes can be converted into alkenyl iodides, it was decided that alkenylstannanes would be appropriate precursors. O. / C 0 O R L N a H ( M n ( C F 3 S 0 2 ) 0 C O O R M e 3 S n C O O R • V=/ Me 3Sn(PhS)CuLi V V 2 . ( C F 3 S 0 2 ) 2 0 ^J>)n (j>)n 117: n= l ; R = Me 118: n = 2; R = Et 119: n= l ; R = Me 120: n = 2; R = Et 121:n = l ; R = Me 122: n = 2; R = Et Me 3 Sn, -Br Ph 3 P«Br 2 , imidazole M e 3 S n n 125: n = 1 126: n = 2 Scheme 30 123: n = 1 124: n = 2 The two desired cyclic allyl bromides 125 and 126 were prepared by a four-step process, as demonstrated in Scheme 30. Thus, conversion of the (3-keto esters 117 and 118 into alkenyl triflates 119 and 120, respectively, was effected with NaH and trifluoromethanesulfonic anhydride. Displacement, either by direct substitution or conjugate addition-elimination, of the triflate functions with the trimethyltin moiety was accomplished with lithium phenylthio(trimethylstannyl)cuprate, affording 3-trimethylstannylalkenoates 121 and 122. The ester functions of 121 and 122 were reduced by the action of DIBALH, affording alcohols 123 and 124, respectively. Finally, conversion of each of the resulting alcohols into the corresponding bromides (125 and 126) was achieved with triphenylphosphine dibromide. The Chapter 2 14b,39 preparations of stannanes 125 and 126 proceeded with yields comparable to those reported. There is ample literature precedence for the iododestannylation of cyclic alkenylstannanes.4 0 Consequently, it was presumed that at some stage after the alkylation of vinylogous esters with bromides 125 and 126, it would be possible to convert the resulting alkenylstannanes into their corresponding alkenyl iodides. Four aryl iodides were also envisioned for this study, and each had to be prepared individually. The first, 2-bromomethyliodobenzene (128), a previously reported compound, 4 1 was prepared by the reaction of commercially available alcohol 127 with triphenylphosphine dibromide (Scheme 31). Ph 3 P-Br 2 , imidazole 127 C H 2 C 1 2 89% Scheme 31 128 The second aryl iodide was prepared from known arene 129.42 Fol lowing the procedure outlined by Stara et al.,42 lithium-bromine exchange of compound 129 followed by treatment with iodine furnished alcohol 130, which was subsequently converted into bromide 131 (Scheme 32). I 1. 2 BuLi , THF -78 °C 2. h 66% OMe 130 Scheme 32 Ph 3 P«Br 2 , imidazole > C H 2 C 1 2 78% The remaining two aryl iodides were prepared from commercially available alcohols. Directed orzTio-metallation of 3-methoxybenzyl alcohol 132, followed by treatment with iodine afforded predominantly iodoarene 133,43 due to the combined directing effects of both directing groups (Scheme 33). Directed orzTio-metallation4 4 of 1-naphthalenemethanol (135) followed by Chapter 2 38 iodine treatment afforded 2-iodo-l-naphthalenemethanol (136). The alcohols 133 and 136 were efficiently converted into bromides 134 and 137, respectively. 135 42% 136 78% 137 Scheme 33 Vinylogous esters 138 and 139 have been reported prior to this work, along with enone 141 . 1 4 b They were prepared as outlined in Scheme 34, by the Stork-Danheiser method involving vinylogous ester alkylation. Compound 139 was reduced with D D 3 A L H , and the resulting alcohol was hydrolysed and dehydrated by the action of p - T s O H , furnishing enone 141. It was presumed that stannanes 138 and 141 could be converted into the corresponding iodides (140 and 142, respectively) by treatment with iodine. Thus, iododestannylation of stannane 138 provided 140 in 84% yield. D I B A L H reduction of 140 followed by acid-promoted hydrolysis and dehydration of the resulting allylic alcohol neatly supplied enone 58. Iodide 142 was quantitatively furnished by iododestannylation of alkenylstannane 141. Chapter 2 39 142: 100% 141: 79% 58: 75% Scheme 34 Stork-Danheiser alkylation of vinylogous ester 9 with bromides 128, 131, 134 and 137 neatly afforded vinylogous esters 143-146, respectively (Scheme 35), which, upon reduction with D I B A L H and acid-promoted hydrolysis and dehydration of the resulting alcohols, furnished enones 60 and 147-149. Chapter 2 40 143: 100% 144: 95% 145: 80% 146: 61% 1 1. D I B A L H | 2.p-TsOH 60:82% 147:90% 148:85% 149:76% Scheme 35 The results of the lithium-iodine exchange promoted cyclization of the two cycloalkenyl iodides 137 and 139 are summarized in Table 4. In each of these cases, the yields are comparable with those obtained from their acyclic brethren (see Section 2.1.3). The ring size of the cycloalkenyl iodide portion of the substrate seems to bear no effect on the outcome of this reaction. Chapter 2 41 Table 4: Lithium-Iodine Exchange Promoted Cyclization of Cycloalkenyl Anions. Substrate n Product Yield (%)a 58 1 59 9 1 b 142 2 150 88 b "Isolated Yields. H-NMR spectra of compounds 59 and 150 matched those of the identical compounds reported in ref. 14b In Table 5 is summarized the results of the lithium-iodine exchange initiated cyclizations of the aryllithium species generated from enones 60, 147 and 148. The cyclization of the substrate bearing the unsubstituted aryl iodide (60) was highly successful, supplying tricyclic ketone in 93% yield. The addition of methoxy-substituents to the aryl rings (i.e. compounds 147 and 148) led to no significant loss of yield in comparison to that obtained from the cyclization of compound 60. Table 5: Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addit ion of A r y l Anions. O Substrate R 1 R 2 Product Yield (%)a 60 H H 61 93 147 O M e H 151 80 148 H O M e 152 90 "Isolated Yields. Chapter 2 42 The final example in this series of experiments is the generation of tetracycle 153 from enone 149, illustrated in Scheme 36. While slightly lower than the yields obtained with the other three aryl iodides, the 75% yield obtained from this reaction is still very good. In conclusion, the lithium-iodine exchange initiated intramolecular conjugate addition of alkenyl anion functions to cyclic Michael acceptors is a successful method for the generation of bicyclic and tricyclic ketones. The procedure is general, requiring no modifications for individual substrates, and yields are typically in the mid- to high 80% range. Furthermore, the methodology can be extended to the lithium-iodine initiated cyclization of aryl anion functions onto cyclic Michael acceptors. Yields in these cases are consistent and comparable with those derived from the alkenyl iodide examples. The results from this series of experiments have been published in the literature. 4 5 2.2 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Addition Reactions. 2.2.1 Substrate Preparation Introduced in Section 1.3 was the concept that the lithium-iodine exchange reaction could initiate an intramolecular 1,2-addition reaction onto the ketone function of vinylogous esters. Conveniently, a number of the types of vinylogous esters required for this study were prepared as intermediates in the substrate preparation for the method studied in Section 2.1. One Chapter 2 43 other class of substrate was prepared as an extension to the aryl iodide portion of the study: furyl iodides. Furyl iodides were chosen substrates for this reaction due to the emergence of a recent report from Keay's research group, 4 6 which described a novel method for the preparation of 4-substituted 3-furanmethanols. Since conversions of benzylic alcohols into their corresponding benzylic bromides have already been described in the previous section, it was presumed that 3-furanmethanols, exhibiting structures similar to benzylic alcohols, would undergo the same transformation without difficulty. To that end, two 4-iodo-3-furanmethanol substrates were prepared following the method described by Keay et al. as illustrated in Scheme 37. The hydroxyl function of 3-furanmethanol (154) is protected as the TBS-ether (155). Subjection of the TBS-ether to the action of B u L i promotes a [1,4]0->C silyl migration, affording furanmethanol 156. Directed orr/io-metallation, followed by treatment with iodine in D M E furnishes 4-iodo-3-furanmethanol 157. A portion of furanmethanol 157 was treated with T B A F to cleanly provide compound 158. Both alcohols 157 and 158 were allowed to react with Ph 3 P«Br 2 , affording iodofuryl bromides 159 (92%) and 160 (64%), respectively. O H TBSC1 imidazole O T B S BuLi , H M P A - T H F H D M F -78 °C -> rt T B S 154 155 156 1. BuLi , D M E -78 °C -> rt 2. L i C l 3.1 2 159: R = TBS : 92% 160: R = H : 64% Scheme 37 Chapter 2 44 Stork-Danheiser alkylation of vinylogous ester 9 with both bromides 159 and 160 (Scheme 38) supplied furyl-substituted vinylogous esters 161 (84%)and 162 (79%), respectively. 2.2.2 Lithium-Iodine Exchange Promoted 1,2-Addition Reactions. Initially, it was sought to determine the success of this reaction under the simplest of conditions. Thus, as in Section 2.1.2, the simplest substrate (81) was chosen, and was treated with f -BuLi in cold (-78 °C) T H F , as illustrated in Scheme 39. Analysis by T L C of the reaction mixture revealed the presence of two new compounds: one as a spot near the solvent front, and one as a highly UV-active spot, slightly below (more polar than) the spot corresponding to the starting material. No starting material remained in the reaction mixture. It was presumed that the least polar spot was related in some way to the expected tertiary bis-allylic alcohol intermediate (163), and that the UV-active material was likely to be the desired dienone, 164. However, the mildly acidic nature of T L C grade silica gel may promote some hydrolysis of the intermediate on the T L C plate, so no further accurate conclusions could be drawn from this result. Therefore, it was decided that the hydrolysis reaction should be driven to completion via a mildly acidic work-up. After the reaction mixture was warmed to room temperature, it was stirred in the presence of 1 M aqueous HC1 for 30 minutes. T L C analysis at this stage revealed the presence of only a single compound: the same U V active material that was observed prior to work-up. Delightfully, after purification by silica gel chromatography, the desired dienone 164 was FT X T 161: R = TBS : 84% 162: R = H : 79% 9 Scheme 38 Chapter 2 45 obtained in 93% yield. The identity of this material was primarily determined by ' H - N M R and infrared spectroscopy. The ' H - N M R spectrum of compound 164 revealed two distinct signals in the olefinic region, the first at 8 5.8 (a doublet with a small 2.4 H z coupling constant) and the second at 8 6.3 (a doublet of doublets). These two signals correspond well with the expected signals for the a - and 8-protons of a conjugated dienone system. Since 8-protons of conjugated dienones experience electronic effects similar to P-protons of enone systems, this data was consistent with the proposed structure of dienone 164. The infrared spectrum of compound 164 displayed a carbonyl stretch at 1655 cm" 1, corresponding well with a conjugated ketone. Data from 1 3 C - N M R spectroscopy, H R M S and microanalysis were also consistent with the proposed structure of compound 164. Scheme 39 The success of this reaction catalyzed a rapid study on the cyclization of other alkenyl iodide substrates that had already been prepared. The results of this study are summarized in Table 6 and in Table 7. 81 163 164 Chapter 2 46 Table 6: Lithium-Iodine Exchange Initiated Intramolecular 1,2-Additions: Substituent Effects. or 1.2f-BuLi ,THF -78 °C -> rt 2. 1 M aq. HC1 Substrate R 1 R 2 Product Yield (%)a 81 H M e 164 93 82 M e M e 165 77 87 H c-Pr 166 96 88 H C H 2 O B n 167 56 89 M e C H 2 O B n 168 81 Isolated yields. The results from Table 6 demonstrate the effects, i f any, that substituent modification has on the outcome of the lithium-iodine exchange initiated cyclization of vinylogous esters. It is most interesting to observe that these cyclizations are useful for the generation of products such as 167 and 168, which bear benzyl-protected hydroxyl functions. Table 7: Lithium-Iodine Exchange Initiated Intramolecular 1,2-Additions: Effects of Ring Size. 1. 2 r-BuLi, THF - 7 8 ° C - > r t 2. 1 M aq. HC1 Substrate n R Product Yield (%)a 99 0 H 169 90 81 1 H 164 93 100 2 H 170 91 101 2 M e 171 82 Isolated yields. A s with the intramolecular conjugate additions studied in Section 2.1, it was deemed that modifying the vinylogous ester ring size would prove to be a useful extension to the present Chapter 2 47 study. Thus, results from the cyclizations of 5-membered (93), 6-membered (73) and 7-membered (94 and 95) vinylogous esters have been compared in Table 7. With a range of yields between 82% and 91%, there seems to be no notable effect of the size of the vinylogous ester on the outcome of this reaction. It is interesting to note that generation of bicyclo[5.3.0]decane systems was more successful in this case than with the conjugate addition reactions described in Section 2.1.3. While it is not certain whether one or both of the cis- and trans-fused diastereomers are initially formed, it seems unlikely that either one would be problematic in the dehydration-hydrolysis sequence. Extension of this study to the lithium-iodine exchange promoted intramolecular 1,2-additions of aryl and furyl anion functions completed the devised set of experiments. The results from these reactions are illustrated in Table 8, in Scheme 40, and in Table 9. Table 8 demonstrates the results from the cyclizations of aryl iodide substrates 143-145. Once again, very high yields of clean products (17247-174) are obtained from these reactions. Furthermore, treatment of naphthyl iodide 146 (Scheme 40) with f -BuLi followed by acidic work-up affords tetracycle 17548 in 87% yield. Table 8: Lithium-Iodine Exchange Initiated 1,2-Addition of A r y l Anion Functions. Substrate R 1 R 2 Product Yield (%)a 143 H H 172 92 144 M e O H 173 97 145 H M e O 174 95 "Isolated yields. Chapter 2 48 The final two aromatic examples employed for this study were furyl iodides 161 and 162. As demonstrated in Table 9, treatment of these substrates with j - B u L i followed by aqueous acidic work-up furnishes tricycles 176 and 177 in 89% and 90% yields, respectively. These yields are comparable to the yields obtained from the cyclizations of the other aryl iodides. Furthermore, there seem to be no i l l effects due to the presence of the bulky si lyl group on the furan ring. Table 9: Lithium-Iodine Exchange Initiated 1,2-Addition of Furyl Anion Functions. Substrate R Product Yield (%)a 161 T B S 176 89 162 H 177 90 'Isolated yields. In conclusion, the rapid lithium-iodine exchange reaction has proven to be a valuable initiator of intramolecular addition reactions for the formation of compounds containing carbo-bicyclic and tricyclic moieties. In two distinctly different reactions, the lithium-iodine exchange has been employed to initiate a cyclization: the first via intramolecular conjugate addition to a cyclic Michael acceptor, the second via intramolecular 1,2-addition to the carbonyl portion of a Chapter 2 49 cyclic vinylogous ester. In both cases, a single set of reaction conditions was all that was required to carry out the desired transformations on a variety of differently substituted and functionalized compounds. Due to the abundance of naturally occurring compounds that exhibit, either isolated or as substructures, bicyclic moieties similar to those presented thus far, these two reactions wi l l l ikely prove beneficial additions to the arsenal of reactions available to the synthetic chemist. 50 3. The Total Synthesis of (±)-Mangicol F 3.1 Isolation and Structure Determination. In 1998, Fen ica l 4 9 et al. reported the isolation of the marine fungus Fusarium sp. strain CNC-477 from a driftwood sample collected in the Bahamas Islands. The fungal isolate was cultured in a seawater-based medium, and the mycelium were separated by filtration and extracted. Due to Fenical's interest in the isolation and identification of potential anti-cancer agents, the extracts were subjected to bioassay-guided (against human colon cancer cell line HCT-116) fractionation, including C-18 flash chromatography, Sephadex LH-20 chromatography and reversed-phase C-18 H P L C . From these extracts were isolated two structurally novel rearranged sesterterpene polyols, neomangicols A and B (178 and 179, Figure 8). From a separate cultivation experiment was isolated neomangicol C (180). Neomangicols A and B were found to possess significant in vitro cytotoxicity toward the HCT-116 human cancer cell line. Neomangicol C was found to be inactive in all bioassays that were performed. Figure 8: Isolated members of the neomangicol family. 178 neomangicol A: R = CI 180 neomangicol C 179 neomangicol B: R = Br From the same mycelium extracts that produced neomangicols A and B , were isolated a second family of closely related compounds, mangicols A - G (Figure 9).50 The members of this family of sesterterpene polyols were purified by the protocol described above. Similar in Chapter 3 51 structure to the neomangicols, several of the mangicols also display cytotoxic activity against human tumor cell lines. Furthermore, mangicols A and B (181 and 182) showed significant anti-inflammatory activity in the PMA-induced (phorbol myristate acetate) mouse ear edema assay. Figure 9: Isolated members of the mangicol family. Structure determinations of both the neomangicols and the mangicols were carried out largely by advanced N M R techniques, including D E P T , C O S Y , N O E S Y , F f M B C and H M Q C experiments and by H R F A B M S . Mangicol A (181) is the only member of the family in which the configurations of all chirality centres (C-17, C-18 and C-19) have been determined. No stereochemical assignment was given to C-17 in mangicols D (184) and F (52), to C-17 and C-19 in mangicol E (51) or to C-17, C-18 and C-19 in mangicols B (182), C (183) and G (53). In cases such as this, it is often left up to the synthetic chemist to synthesize the various possible diastereomers and to match the spectral data of the correct diastereomer with that of the natural product. From a structural perspective, the members of the mangicol family are of interest to synthetic chemists for a variety of reasons. The mangicols possess tetracyclic cores that are hitherto undescribed in the literature. In particular, the spirotricyclic subunit of the core is of synthetic interest. Furthermore, a number of provoking stereochemical challenges to the synthetic chemist are present within the core of the molecule. The core structures of mangicol C , 181 mangicol A : R 1 = OH; R 2 = H 182 mangicol B: R 1 = H ; R 2 = O H 183 mangicol C: R 1 = R 2 = H 184 mangicol D: R 1 = OH; R 2 = H 51 mangicol E: R 1 = H ; R 2 = O H 52 mangicol F: R 1 = R 2 = H 53 mangicol G Chapter 3 52 mangicol F and mangicol G , for example, possess seven carbon chirality centres, three of which are quaternary while five are contiguous. The spirotricyclic nature of the eastern portion of the molecule serves to rigidify the molecule, significantly hindering conformational freedom within the core. Furthermore, three methyl groups are present on the p-face of the molecule, arranged such that the entire molecule resembles a three-pronged "plug". For the purposes of chemical reactivity, access to sites located within the cavernous interior of this structure wi l l be highly restricted. The challenges that would be presented to the synthetic chemist in the total syntheses of these compounds make the mangicols significantly worthwhile targets. 3.2 Biogenesis of the Mangicols. One manner in which the biosynthesis of terpenes may be determined is through 1 3 C labelling experiments. A s illustrated in Figure 10, terpenes are generally derived from the head-to-tail junctions of individual isoprene units, which in turn are generated within a l iving 13 organism from units of acetate and acetic acid. Thus, i f the organism is fed only C labelled sodium acetate, then the incorporation of 1 3 C into the organism's metabolites may provide some insight into the mechanism by which the metabolites have been constructed. Figure 10: Biogenetic synthesis of geranylfarnesyl diphosphate from C-labelled acetic acid. Sesterterpene (geranylfarnesyl diphosphate, 186) The Fenical group carried out two separate feeding experiments on the fungal organism in a seawater-based medium, 5 0 the first containing sodium [l- 1 3C]acetate and the second, sodium O isoprene diphosphate (185) O P P Chapter 3 53 [l,2- 1 3C]acetate. The 1 3C-enriched mangicols were then isolated from the mycelium extracts as described in Section 3.1, and studied by ' H - N M R spectroscopy. Results from the sodium [1,2-13C]acetate feeding experiment led theFenical group to believe that the mangicol cores were 13 likely to have been synthesized from a single 25-carbon unit, due to uniform incorporation of C throughout all 25 carbons. A series of more complicated studies on the results from both experiments has allowed Fenical to propose the biosynthetic route to the mangicol cores which is described in Figure 11. Figure 11: Proposed biosynthesis of the mangicol core. 1. 1,2-hydride transfer 2. H + abstr. 192 Formation of the eleven-membered ring in structure 187 (Figure 11) is likely to occur from appropriately folded geranylfarnesyl diphosphate in a manner similar to the cyclization leading to the humulene skeleton. This process has been observed in the biosynthesis of other Chapter 3 54 natural products. 5 1 Two subsequent 1,2-alkyl shifts (187 -> 188 -> 189) lead to the formation of the occidental five-membered ring of the mangicol core. Two simple cation-induced ring closures then account for the formation of the remainder of the tetracyclic core and two 1,2-hydride transfers complete the formation of 192, a substructure present in all members of the mangicol family. 3.3 Retrosynthetic Analysis. Initial examination of the structures of the members of the mangicol family (see Figure 9, Section 3.1) of natural products reveals that there are three different hydrindane systems within the core of each of the molecules, all of which revolve around the same six-membered ring. This was a key factor in the decision to attempt the total synthesis of members of this family. Both methodology projects described in Chapter 2 focussed on the preparation of different hydrindane systems, and thus, it seemed reasonable that a number of possible synthetic approaches to members of the mangicol family were available via these methods. Upon examination of the chirality centres within the structures of the mangicol molecules, particularly those located on the sidechains, mangicol F quickly becomes obvious as the appropriate target for the initial racemic total synthesis. There is only one chirality centre located on the sidechain of mangicol F , and its stereochemistry is as yet undetermined. Therefore, the total synthesis of mangicol F would serve as a basis for the synthesis of the other mangicols, as well as an appendix to the characterization of these structurally interesting compounds. Studying the structure of mangicol F reveals that a number of different combinations of oxidative functional group manipulations could possibly lead to the preparation of the highly oxygenated sidechain from an appropriate hydrocarbon precursor. With this reasoning in mind, disconnection of the C-17-C-18 bond would yield aldehyde 193 (see Figure 12), which was Chapter 3 55 presumed to be an appropriate starting material for the extension of the sidechain. Aldehyde 193 was reasoned to be available from hydrocarbon 194, which bears an exocyclic olefin in the appropriate position on the western five-membered ring. Within the Piers laboratory, a number of different methods have been employed to generate quaternary chirality centres for the purpose of sidechain extension and elaboration from exocyclic olefins. Since a variety of methods might be devised for the preparation of mangicol F from 194, this compound is considered to be the target intermediate from the perspective of the core synthesis. The focus of the retrosynthetic analysis from this point on is therefore the rapid and efficient preparation of tetracyclic diene 194. Figure 12: Retrosynthetic analysis of mangicol F - elaboration of the sidechain. Two critical features of the tetracyclic core must be addressed at this stage: the stereochemistry of the quaternary ring junction carbon, C-10, in the tetracyclic diene, 194, and the double bond located within the six-membered ring. The installation of these two features was thought to be possible from ketone 195 (see Figure 13). Several methods are available for the removal of an oxygen atom from a molecule to leave behind a double bond. Two methods for this process are particularly appealing. In the first, conversion of the ketone into its vinyl triflate followed by hydrogenolysis would afford the appropriate olefin. In the second, reduction of the ketone to its corresponding alcohol followed by dehydration would accomplish the same task. Establishing the desired stereochemistry at the bridgehead carbon, C-10 was not expected to be problematic. Should the establishment of this centre be the final result of an annulation sequence, Chapter 3 56 then formation of the c/s-fused system would be expected. In general, this is the case with most annulation sequences. Furthermore, the presence of a substituent at C-10 would eliminate the possibility of equilibration via the enolate of the ketone. Figure 13: Retrosynthetic analysis of mangicol F - installation of the 4 ring. 52 mangicol F Retrosynthetic "conversion" of tetracyclic ketone 195 into tricyclic enone 196 (Figure 13) was presumed to be possible via a methylidenecyclopentane annulation transform, involving a bifunctional reagent of general structure 7. In the forward sense, this type of annulation sequence involves the conjugate addition of the cuprate derived from the stannane functional group, followed by the cyclization of the enolate of the ketone onto the remaining alkyl chloride in the sidechain, as described in Scheme 3 (Chapter 1). A possible impediment to this procedure might occur due to the nature of the R-substituent in 196. It is known that methyl groups have a deleterious effect on conjugate additions of organocuprates when located at the a-position of the Michael acceptors. 5 2 Should this be a factor in the conjugate addition of the cuprate derived from stannane 7 to enone 196, then the methyl group could conceivably be replaced with an electron-withdrawing substituent, such as an ester group. A s described earlier, the ester could be converted into a methyl group at a later stage in the synthesis. Due to hindrance from the Chapter 3 57 southern five-membered ring in tricyclic enone 196, the conjugate addition reaction was expected to occur from the a-face of the enone. Figure 14: Retrosynthetic analysis of mangicol F - preparation of the spirotricyclic subunit. 0 O O FUGe-+ 197 198 \ J l H 1. / ' H \ _ ) ^ O H A OH 5 2 mangicol F 164 The next stages of the retrosynthetic pathway (Figure 14) involve a series of retrosynthetic functional group manipulation and alkylation transforms to convert enone 196 into 197. In the forward direction, this transformation is likely to be realized with three sequential synthetic protocols. The first step would be the stereoselective hydrogenation of the alkene function in compound 197, rendering a product with the desired stereochemistry at C-4. In the second synthetic step of the transformation of compound 197 into 196, the "R"-group wi l l be installed, either by alkylation or acylation of the regioselectively formed enolate of the ketone starting material. Once the product of the alkylation (or acylation) is established, dehydrogenation of the cyclic ketone to its corresponding enone (compound 196) should be possible via one of several methods available for carrying out this synthetic transformation. Establishing the eastern five-membered ring should be possible through an annulation sequence such as that illustrated in Scheme 4 (Chapter 1). In this case, Michael acceptor 198 Chapter 3 58 could presumably be treated with the organocuprate reagent derived from a bifunctional reagent of general structure 8 (Figure 14), affording the c/s-fused hydrindane system. Completion of the annulation sequence should afford compound 197. Finally, compound 198 (Figure 14) was presumed to be available from bicyclic dienone 164, prepared via the methodological work described in Chapter 2, through a stereo- and chemoselective hydrogenation process. Chapter 3 59 3.4 The Total Synthesis of (±)-Mangicol F. 3.4.1 Preparation of the Tetracyclic Core of Mangicol F. A s briefly discussed in Section 3.3, it was vital that a rapid and efficient method be discovered for the preparation of the tetracyclic core of the various members of the mangicol family. Since many of the mangicols differ only in the degree of oxidation of the sidechain, it was hoped that the bulk of the work would be applied to the sidechain elaborations, once the common core compound had been established. The general idea was to apply as many simple reactions as possible that were amenable to scale-up to the synthesis of the tetracyclic core. Two methodology projects were described in Chapter 2, both leading to the preparation of hydrindane systems that could be of use to the synthesis of mangicol F . A comparison of the two reactions forming the bicyclic systems (107 and 164) that could most likely be used as key starting materials in the total synthesis of mangicol F is made in Figure 15, below. The first decision to make was which of these two reactions would be the most appropriate as the first key step in the synthesis. It was immediately evident that the preparation of the bicyclic dienones (such as 164) bore significant advantages over that of the ds-fused bicyclic ketones (such as 107). One major advantage was apparent in the reaction conditions themselves. In order to prepare the bicyclic ketone 107 on a large scale, excessive quantities of the two additives (TMSC1 and H M P A ) were required. First, both of these reagents require distillation prior to use, a practice not particularly desirable with a large amount of H M P A , due to its documented Chapter 3 60 toxicity and carcinogenicity. Furthermore, the unfavourable attributes associated with H M P A require its appropriate disposal after use, the cost and danger of which are again, not particularly appealing. A second advantage is conspicuous in the dienone products (e.g., 164), themselves. The ct,P-unsaturation of these ketones (absent in 107) provides a suitable handle for a variety of annulation sequences, any number of which could be utilized for the installation of the eastern five-membered ring of the core. Figure 15: Comparison of analogous examples from the two methodological studies described in Chapter 2. Having established the nature of the first key step of the synthesis, it was imperative to determine the amenability of the cyclization process to large scale. In the studies discussed in Chapter 2, most examples were carried out on approximately 150 mg (-0.3 rnmol) of starting material. The reaction was cautiously scaled up on an incremental basis, until 30 g of the starting alkenyl iodide 81 was submitted to the action of r -BuLi in cold (-78 °C) T H F . The cyclization reaction, on this scale, reproducibly furnished -10 g (83%) of the desired bicyclic dienone 164 (see Scheme 39). The reaction was not scaled up any further than this due to the lack of appropriate glassware and apparatus for large-scale, cold-temperature chemistry. This scale was also chosen for its convenience; the reaction was performed by inserting a wide-bore cannula into a fresh bottle of f -BuLi and transferring the entire contents of the bottle into the reaction mixture as rapidly as possible. For the initial purposes of this synthesis, the scaled-up reaction was carried out in parallel three times, and the combined crude material was purified by column chromatography. Chapter 3 61 Many reactions occur from the convex face of cw-fused bicyclic systems. In spite of the fact that one of the two angular carbons of dienone 164 is sp 2-hybridized, it was still presumed that its concave face would be less available for reactivity than its convex face. Furthermore, it was suspected that the y,8-double bond would be more prone to reduction than the a,p-double bond due to the fact that it is further away from, and thus, less affected by the electron-withdrawing nature of the carbonyl group (i.e. the former double bond is expected to be the more electron-rich of the two). With this in mind, a simple and straightforward hydrogenation reaction (1 atm) using 10% Pd on activated charcoal was attempted on dienone 164 in M e O H (Scheme 41). 164 198 199 Scheme 41 The initial results from the hydrogenation of dienone 164 with 10% Pd on activated charcoal were promising. Two new spots were observed by T L C after 15 min, one UV-active, the other non-UV-active, and no starting material remained. ' H - N M R spectroscopic analysis of the fractions pertaining to the two spots revealed that they each contained a single compound. The presence of a 3-proton doublet at 8 -0.9 in each spectrum indicated that each compound had resulted from the stereoselective reduction of the y,8-olefin. The structure of 198 was confirmed by comparison of its spectral data (IR, ' H - N M R , 1 3 C - N M R and HREEVIS) with that reported by Kakiuchi et al. In the latter work, compound 198 was prepared as the minor compound in a reaction that produced a mixture of the two C-9 epimers of enone 198. Compound 199, lacking any olefinic protons or UV-activity, was tentatively identified as the over-reduced product illustrated in Scheme 41, and was not characterized further. Chapter 3 62 It was postulated that the over-reduction of dienone 164 might have occurred via migration of the double bond in enone 198 out of conjugation followed by reduction of the resulting non-conjugated olefin. Platinum, ruthenium and iridium are often considered, in that order, as lower in reactivity than palladium in terms of their abilities to isomerize double bonds. 5 4 Thus, a quick set of experiments was devised to determine i f any of these other heterogeneous catalysts would be more useful for this reaction than 10% Pd on activated charcoal. Under reaction conditions similar to those described above, 5% Pt on alumina and iridium black were tested and the results are summarized in Table 10. Table 10: Catalyst studies in the hydrogenation of dienone 164. O O H 2 , catalyst »-solvent, 1 atm + 198 200 Catalyst Solvent Yield of 198 (%)a Yield of 200 (%)a 5% Pt on alumina M e O H 72 22 5% Pt on alumina E t O A c 64 16 5% Pt on alumina Benzene 60 30 Iridium black M e O H 32 b 68 b "Isolated yields. These numbers represent a ratio determined by H-NMR spectroscopy of the crude material, noting that there was no remaining starting material. The hydrogenation of dienone 164 in the presence of either platinum or iridium resulted in the formation of a new compound, 200, along with the desired enone 198. The structure of compound 200 was tentatively identified as the non-conjugated enone based on data from its ! H -N M R data. Noteworthy were the presence of a 3-proton broad singlet near 5 1.7, indicative of an allylic methyl group, and the absence of any signal in the olefinic region. Interestingly, the formation of the isomerized material seems to increase as the reactivity of the catalyst in favour of isomerization decreases. Furthermore, of the three solvents chosen for the hydrogenation of 164 in the presence of 5% Pt on alumina, methanol has been described as the most likely to Chapter 3 63 promote isomerization. 5 4 Once again, the results shown in Table 10 illustrate a reversal in this trend. Scheme 42 Compound 200 was subjected to dilute aqueous HC1 in T H F . Regrettably, ' H - N M R analysis of the crude product (displaying a single UV-active spot by T L C ) revealed it to be composed of both C-9 epimers of enone 198. Having discerned that non-conjugated enone 200 was of little value to this synthesis, it was reasoned that perhaps employing a less active palladium based catalyst could control the over-reduction of 164. A t this time, a report by Biichi and Wiies t 5 5 was discovered that described the selective hydrogenation of the y,8-olefin of damascenone (201, Scheme 42). Lindlar 's catalyst was found to promote the quantitative formation of compound 202 from damascenone, while all other catalysts employed afforded unidentified mixtures of products. This prompted an attempt to hydrogenate dienone 164 in the presence of Lindlar 's catalyst. Gratifyingly, the sole product of this reaction carried out under 1 atm of H2, was the desired enone, 198, which was obtained in 96% yield. Installation of the third ring was presumed to be possible via the annulation sequence devised by Piers and Marais, employing a tri alkyl germanium-bearing bifunctional reagent such as compounds 206 or 207 (Scheme 43). Thus, initially addressed was the preparation of such reagents. In 1995, Piers and Lemieux reported 5 6 a convenient method for the preparation of 2-trimethylgermylalk-l-enes such as 204 from 1-trimethylsilylalk-l-ynes such as 203, using Chapter 3 64 trimethylgermane and hydrogen hexachloroplatinate hexahydrate (Scheme 43). While the preparation of these trimethylgermanium species is high yielding, it suffers the disadvantage that trimethylgermane has a boiling point that is below room temperature. It must be stored in the freezer, but is more commonly prepared immediately prior to use via reduction of trimethylgermanium bromide. The product is collected by distillation from the reaction mixture and transferred directly into a cold solution of the 1-trimethylsilylalk-l-yne and the H2PtCl6 '6H 2 0 catalyst in CH2CI2 via a syringe that has been cooled in dry ice. Thus, it was sought to determine i f the same reaction could be effected with commercially available tributylgermane, which has a considerably higher boiling point than trimethylgermane. R 3 Ge O H 1. Me 3 GeH or Bu 3 GeH, \ H 2 PtCl 6 «6H 2 0, C H 2 C 1 2 ^ ^ ^ O H M e 3 S i ^ ' . . . 2.^-TsOH 204: R = Me : 63% M i 205 : R = Bu : 60% P h 3 P , I 2 imidazole, C H 2 C 1 2 RoGe 206: R = M e : 77% Scheme 43 207:R = B u : 7 8 % Upon treatment of compound 203 with tributylgermane in the presence of H2PtCl6 -6H 20, results comparable with those reported by Piers and Lemieux for the trimethylgermane addition were obtained (Scheme 43). 2-Tributylgermylalk-l-ene 205 was obtained in 60% yield. The transformation of alcohol 204 into iodide 206 has been described previously 5 7 and this procedure was found to be equally effective when alcohol 205 was employed as the starting material. Furthermore, preparation of cyanocuprate 17 (Scheme 44) has been effected numerous times, and the cuprate itself has been shown to effectively add to cyclic enones in the presence of T M S C l . 1 7 - 1 9 In some cases, 1 7 ' 1 9 cyanocuprate 17 (Scheme 44) has even been successfully added Chapter 3 65 to bicyclic enones in which, analogously to compound 198, the P-carbon of the enone is an angular carbon. The products of these reactions are exclusively cis-fused bicyclic products, a trend that translates generally to other cuprates. 5 8 ' 5 9 ' 6 0 Thus, the addition of cuprate 17 to enone 198 was attempted under conditions similar to those reported by Piers and Marais , 1 7 with the replacement of T M S C 1 by BF3-Et20 (Scheme 44). Concomitantly, the addition of cuprate 208, derived from lithium-iodine exchange of alkyl iodide 207 followed by the addition of solid C u C N , was attempted. Both reactions were found to proceed smoothly, affording the desired e f -fused bicylic ketones 209 and 210 in very good yields. 198 209: R = Me : 83% 211: 92% from 209 210: R = Bu : 79% 92% from 210 Scheme 44 The iododegermylation 6 1 of other alkenyltrimethylgermanes 1 7 - 1 9 employed in this type of methylenecyclopentannulation sequence has been successfully carried out. Thus, as expected, treatment of solutions of either trimethylgermane 209 or tributylgermane 210 in dichloromethane with solid iodine afforded the desired alkenyl iodide 211 in very high yields (Scheme 44). Subjection (Scheme 45) of alkenyl iodide 211 to conditions similar to those 1 7 - 1 9 illustrated in Scheme 4 and in Scheme 5 (Chapter 1), afforded the desired enone (212) in 70% yield. Another product, displaying two broad singlets in the olefinic region of its ^ - N M R spectrum, characteristic of an exocyclic double bond, was produced in 11% yield. In order to determine i f this by-product was merely the non-conjugated enone related to compound 212, the former material was isolated and was treated with f -BuOK in f -BuOH. However, it was not Chapter 3 66 found to equilibrate to a mixture of itself and enone 212. Thus, the possibility that this compound was an equilibrium partner with 212, but bearing an exocyclic olefin (i.e. the mechanistic precursor to enone 212) was excluded. Considering that it seemed unlikely that the by-product of this reaction arose from the predicted cyclization onto C-2 of compound 211, attention was given to the possibility that it may have evolved from a similar cyclization onto C-4, affording ketone 213. Precedent by Piers 18 and Oballa revealed that in certain circumstances, cyclization may occur with either of the two possible enolates generated under thermodynamic conditions (see Figure 16 for the mechanism). In the event, Pd(0) inserts oxidatively into the carbon-iodine bond of 214, for example, affording presumed intermediate 215. Treatment of this system with a base, under equilibrating conditions, affords an equilibrium mixture of enolates 216 and 217. Nucleophilic addition of the enolate 217 to the electrophilic Pd centre afford tricyclic species 219, which undergoes reductive elimination to furnish the desired product, 221. However, enolate 216 also undergoes cyclization with the palladium centre, generating intermediate 218. Upon reductive elimination, bridged tricyclic product 221 is obtained. The report by Piers and Obal la 1 8 described that variation of the substitution pattern around the bicyclic system coaxes the reaction in favour of forming either the six-membered palladacycle intermediate (leading to the formation of the five-membered ring) or the eight-membered palladacycle (furnishing the bridged compound). O f particular interest was that substitution of the proton on C-6 with a methyl group resulted, in all examples, in almost complete formation of the bridged product. 211 Scheme 45 212:70 % 213: 11% Chapter 3 67 Figure 16: Proposed mechanism of Pd(0)-catalyzed coupling of alkenyl iodide with ketone enolate. L H 220: 33% H 221: 41% Once the new carbon-carbon bond has been formed, the reaction is irreversible. Furthermore, the geometry of the bridged system in compound 220 precludes the migration of the double bond into conjugation with the ketone since this would form a bridgehead olefin that violates Bredt's rule. Thus, based on this mechanism operating analogously in the Pd(0)-catalyzed intramolecular coupling of ketone 211, and on the afore-mentioned acquired ' H - N M R data, the structural identity of the by-product was confirmed to be that of the bridged tricyclic ketone, 213 (Scheme 45). The cyclization of compound 211 was carried out a number of additional times with similar results. One observation was of particular interest. Initially, a stock solution of z-BuOK in Chapter 3 68 f -BuOH had been prepared and stored in an Aldr ich Sure-Seal® amber bottle. With time, the overall yields of this reaction improved slightly, and the ratio of 212 to bridged isomer 213 became increasingly satisfactory. However, upon preparation of a fresh batch of the base solution, the yield and ratio of product 212 to by-product 213, were noted to have regressed to values similar to those initially obtained. While the best yield and ratio of products from this reaction is reasonably good (and is reported in Scheme 45), it did not seem to be scientifically sound to require the base solution to "age" prior to use. Thus, a quick study was carried out on a series of bases to determine i f there was a system available that would provide reliable results while employing a freshly prepared base solution. The results from this study are presented in Table 11. Table 11: Study of the Pd(0) catalyzed intramolecular coupling of alkenyl iodides with ketone enolates employing various commercially available base systems. Entry3 Base Alcohol Overall Yield (%)b Ratio of 212:213c 1 f -BuOK f-BuOH 81 7:1 2 r-BuONa f -BuOH 78 10:1 3 r -BuOLi r -BuOH 68 1:0 4 N a O M e M e O H 89 1:0 aAll reactions were carried out by stirring the substrate with Pd(PPh3)4 for 10 minutes, followed by slow addition (1.5-3 h) of a solution of the base in a 10% mixture of the alcohol in THF. bCombined yields of isolated products. cRatio of isolated yields. The results summarized in Table 11 demonstrate that there is a noticeable trend of improving ratios of 212 to 213 as the counter ion in the tert-butoxide series is altered. There is, however, a reduction in the yields of the desired product, which also follows this trend. O f greater interest is the substitution of the tert-butoxide bases with sodium methoxide. In this case, Chapter 3 69 the yield of 212 was significantly greater than those noted in the te?t-butoxide series, and none of the undesired isomer 213 was observed. These results were highly reproducible. However, it should be noted that the addition of the base solution to the reaction mixture in a dropwise manner, over a period of 3 h, is critical to the success of this reaction. The final step in the preparation of the tricyclic portion of the core of mangicol F is to reduce the enone olefinic bond stereoselectively, such that the methyl group occupies the P-orientation on the newly formed chirality centre. Examination of molecular models reveals that, in order to avoid most steric interactions, while maintaining a planar enone system, the six-membered ring of 212 must adopt a boat-like conformation. A representation of this conformation is depicted in Figure 17. For the sake of simplicity, the six-membered ring here is represented as an exact boat, although in reality, slight deviation from this conformation is more likely to be appropriate. Thus, the five-membered ring projecting upwards in Figure 17 represents the southern ring in the tricylic system. The eastern ring projects outwards from the plane of the page. From the projection illustrated in Figure 17, it can be observed that the methyl group in the southern ring projects slightly outward from the page, sterically obscuring the P-face of the enone olefinic bond. Figure 17: Three-dimensional representation of the most stable conformation of enone 212. Due to the planar requirement of the conjugated enone, the conformation of compound 212 represented in Figure 17 is relatively rigid. In this conformation, it is apparent that the De-face of the olefin is the only face that is open to reaction, particularly i f that reaction were to occur via use of a bulky catalyst, or more specifically, a sterically demanding heterogeneous O 212 O Chapter 3 70 catalyst. A s such, initial attempts at the reduction of this olefin involved a standard hydrogenation with 10% Pd on activated charcoal as the catalyst. Delightfully, only one product was obtained from this reaction, in quantitative yield, and was eventually shown to be ketone 214, displaying the desired stereochemistry at the newly formed chirality centre, C-4 (see Scheme 46). None of the signals in the ' H - N M R spectrum of compound 214 were sufficiently isolated to allow for selective irradiation (i.e. nOe difference experiments). However, the configurations of both C-4 and C-5 of this material were determined via X-ray crystallography of a derivatized version of compound 214. These results are described shortly hereafter. 0 0 H 2 (1 atm), 10% Pd/C MeOH 100% Scheme 46 Interestingly, the relative configuration at C-5 is that shown in 214, despite the mechanistic requirement for syn-addition of the elements of H 2 across the double bond when employing heterogeneous catalysts. 6 3 Examination of molecular models revealed that the trans-fused epimer of 214 is highly strained due to the presence of the southern five-membered ring. It was also interesting to note that treatment of 214 with r - B u O K in f -BuOH resulted in the complete recovery of compound 214. It is likely that, under the hydrogenation conditions, enolization of the ketone occurs to allow for epimerization of C-5. However, a discussion of the source promoting such an epimerization is unnecessary, since later in the synthesis, the chirality of this centre was to be eliminated due to rehybridization of the carbon centre to an sp -carbon. With the tricyclic portion of the core in hand, it was necessary to determine the stereochemical outcome of those reactions that had produced carbon chirality centres. While nOe experiments seemed attractive, the strained geometry of the five-membered rings prevented definitive data on these systems from being acquired. Thus, X-ray crystal structures were Chapter 3 71 required as evidence. Ketone 214 is a colourless o i l , and as such, had to be altered in order to acquire crystal structure data. Stereoselective reduction (Scheme 47) of the ketone to the a-alcohol 215 followed by esterification of the latter substance with 3,5-dinitrobenzoyl chloride afforded dinitrobenzoate 216 as a solid compound which was recrystallized from methanol. O 214 215 216 Scheme 47 Results from the X-ray diffraction data (see the O R T E P diagram in Figure 18) confirmed the structural identity of ester 216, and as such, the relative configurations of carbons 1, 2, 5, 9 and 10 in compound 214 were firmly established. Figure 18: O R T E P diagram representing the crystal structure of dinitrobenzoate ester 216. Completion of the tetracyclic core of the mangicols would require two key transformations. The first, installation of the fourth and final ring in the mangicol core, would employ a methylenecyclopentane annulation method that was developed by Piers and Karunaratne 1 5 and is illustrated in Scheme 3 (Chapter 1). The second key conversion would Chapter 3 72 involve installation of the angular methyl group. As discussed in Section 3.3 (retrosynthetic analysis), it was decided that the latter procedure should be performed first. This decision was made in order to avoid possible site-selective complications with the alkylation at a later stage in the synthesis. In the event, treatment (Scheme 48, below) of ketone 214 with L D A in cold (-78 °C) T H F , followed by the addition of iodomethane afforded ketone 217 as a mixture of epimers in 75% overall yield. 214 217 218 PhSeCl CH 2 C1 2 v EtOH, reflux Scheme 48 Conceptually, the insertion of the double bond required for the annulation sequence was to be effected following a standard selenoxide elimination method. 6 4 Thus, treatment of the epimeric mixture of ketones (217) in T H F with L D A followed by T M S C l furnished a single compound in 96% yield (Scheme 48). This compound was identified by ' H - N M R spectroscopy as compound 218 due to the presence of a three-proton singlet near 8 1.6, and a nine-proton singlet near 8 0.2. Treatment of a solution of the silyl enol ether (218) in CH2CI2 with solid P h S e C l 6 5 afforded a mixture of phenyl selenides (219). Oxidation of this mixture to its corresponding mixture of selenoxides was accomplished with m - C P B A . 6 6 The resulting Chapter 3 73 selenoxides, in the presence of diisopropylamine, immediately underwent elimination reactions to afford an inseparable mixture of the desired enone 220 and its exocyclic olefin isomer, 221, in 88% overall yield. Subjection of this mixture to the action of RhCl3-3H20 in refluxing ethanol 6 7 afforded the desired endocyclic olefin isomer, 220, in 46% yield. 1. MeLi , THF Me 3 SnSnMe 3 • Me 3SnCu«SMe 2 2. C u B r ^ M e 2 1 222 222 Me 3Sri M e 3 S n . / H THF, MeOH ^ ^ ^ X D H + H ^ OH 223 7 8 ° C - > r t 2 2 4 2 2 5 Ph 3P, CC1 4 reflux t M e 3 S n 226 Scheme 49 With enone 220 in hand, attention was turned to the installation of the fourth ring. This was presumed to be possible via an annulation sequence such as that described in Figure 4 (Chapter 1) employing alkenylstannane 226 (Scheme 49). The preparation of such alkenylstannanes can be routinely carried out via a method developed by Piers and Chong. 6 8 Thus, hexamethylditin was treated with methyllithium followed by C u B r S M e 2 to generate the trimethylstannylcopper-dimethyl sulfide reagent, 222 (Scheme 49). Upon stannylcupration of alkyne 223 with reagent 222, followed by protonation of the resulting alkenylcopper species, the desired trimethylstannane, 224, is obtained along with a lesser amount of isomer 225. Isolation of trimethylstannane 224 from the mixture followed by its treatment with Ph 3 P in CCI4 6 9 furnishes the bifunctional reagent, 226. Chapter 3 74 Me3Siji 1. MeLi , THF, -78 °C Cu(CN)Li CI 2. CuCN CI O O 227, BF 3«OEt 2, THF C l X — -220 O 228 Scheme 50 229 Enone 220 was treated with the cuprate (227) prepared from stannane 226, as shown in Scheme 50. Disappointingly, however, the expected product, ketone 228, was not observed in the reaction mixture. Only the starting enone was recovered. In order to determine i f the issue was merely steric in nature, enone 220 was also treated with a simpler but analogous Gilman reagent, (H2C=CH)2CuLi. Once again, only the starting material was recovered from the reaction mixture. It appeared that the combined effects of the steric interference from the southern ring of the tricyclic enone, and the inductive interference from the a-methyl group 5 2 , briefly touched upon in Section 3.3, significantly hampered the progress of this reaction. A different approach was therefore required to achieve the installation of the final ring in the core. It was decided to attempt the required annulation by enhancing the reactivity of the enone acceptor. To that end, ketone 214 in cold (-78 °C) T H F - H M P A was treated with L D A 70 followed by ethyl cyanoformate, based on the protocol devised by Mander and Sethi, to afford P-keto ester 230 in 70% yield (Scheme 51). Following the method reported by Christoffers and 71 Mann, P-keto ester 230 was converted into a-ethoxycarbonyl-a,p-unsaturated ketone 232 via the mixture of selenides, 231, in 78% overall yield. Chapter 3 75 O O o 1. L D A , THF -78 °C PhSe E t O O C 1. NaH, THF, B 0 0 C 0 ° C 2. NCCOOEt, H M P A 70% 2. PhSeCl 214 230 231 H 2 0 2 , H 2 0 C H 2 C 1 2 78% | from 230 Q .. . E t O O C Scheme 51 232 Treatment of the activated Michael acceptor 232 with cuprate 227 in T H F (Scheme 52) afforded a single compound. Structurally, this compound was identified, by ^ - N M R spectroscopy, as P-keto ester 233. Installation of the desired sidechain was evidenced by the presence of a two-proton triplet at 8 -3.6, and of two one-proton broad singlets near 8 4.9. For steric reasons, ketone 233 was expected to display the desired configuration at the newly formed chirality centre. Treatment of compound 233 with K H in refluxing T H F afforded compound 234 as a single compound. Spectroscopic studies of compound 234 involving nOe experiments revealed that the addition of the cuprate had occurred from the ct-face of the enone. First, H-6 and H-12 were identified by homonuclear C O S Y experiments. Positive nOe enhancements were observed at H-6 when H-12 was irradiated (and vice versa), indicating that they must reside on the same side of the six-membered ring as each other. Furthermore, a weak positive enhancement of the 3-proton triplet (ester C H 3 ) was observed upon selective irradiation of either H-6 or H-12, indicating that the newly formed five-membered ring was as-fused to the six-membered ring. Chapter 3 76 O O O EtOOC. 227, BF 3 .OE t 2 THF, -78 °C CI 232 233 234: small scale, R = COOEt 50% from 232 235: large scale, Cu(CN)L i CI Scheme 52 R = H : 73% from 232 Unfortunately, when the cyclization step (Scheme 52) was scaled up, the only compound obtained from the reaction mixture differed from compound 234 significantly in terms of its 1 H -N M R and 1 3 C - N M R data. The ' H - N M R spectrum of the product displayed no signals Furthermore, only 18 signals (21 carbons are present in 234), of which only one was in the 13 carbonyl region, were observed by C - N M R spectroscopy. Thus, compound 235 was tentatively identified as the product of decarboethoxylation of compound 234. It is presumed that the 79 decarboethoxylation process occurred via a method similar to that reported by Krapcho et al., due to the formation of KC1 under the reaction conditions. CS Chem 3 D ® molecular dynamics calculations aided the determination that the as-fused product (235) is more stable than the trans-fused product by approximately 1.3 kcal/mol. Hence, the product of decarboethoxylation (235) was presumed to possess a a's-fusion between the six-membered ring and the newly formed five-membered ring. Having discovered that cuprate additions to a-methyl enone 220 are not a viable approach to this synthesis, and that the potassium hydride-promoted cyclization of compound 233 did not reliably furnish synthetically useful amounts of P-keto ester 234, it was clear that an obstacle in the synthesis had been reached. However, coincidentally, the opportunity to attempt an alternative approach had been presented by the acquisition of an experimentally useful corresponding to either the methyl or the methylene portion of the ethoxycarbonyl group. Chapter 3 77 amount of compound 235. Thus, it was decided to subject compound 235 to the action of a bulky base under kinetically controlled conditions to determine the chemoselectivity, i f any, of deprotonation. Three different bases were incorporated into this study: L D A , L iNEt2, and the L D A - r - B u O K 7 3 system (referred to hereafter as K D A ) . L D A is the typical amide base chosen to deprotonate ketones. L iNEt2 was chosen for this study since it should have a pKb similar to that of L D A , but is less bulky. K D A is generally referred to as a stronger base than L D A , often successfully removing a proton from a carbon in reaction where L D A had failed. The results from this study are presented in Table 12. Table 12: Study of the deprotonation of ketone 235 with different bases. O . O H _" 1. base, additive THF, -78 °C 2. M e l 235 236 Entry Base Additive Yield of 236 (%)a 1 L D A None -2 L i N E t 2 H M P A 81 3 K D A None 98 Isolated yields. The results described in Table 12 illustrate that the chemoselective deprotonation of compound 235 is achievable. Furthermore, upon the addition of iodomethane to the resulting enolate solution, only a single product was observed by both T L C and ' H - N M R spectroscopy of the purified material. This compound was identified structurally as compound 236 by its ! H -N M R spectrum. In particular, the presence of a 3-proton singlet near 8 1.1 was indicative of a successful methylation. The stereochemical configuration of C-10 was identified by nOe difference spectroscopy. Selective irradition of H-12 displayed enhancements of the signals corresponding to the three methyl groups and to H-6 (H-6 and H-12 were identified by Chapter 3 78 comparison of the chemical shifts and coupling constants with those observed for the same protons in ester 234, which were identified by ^ - C O S Y experiments). K D A was determined to be the most effective base for carrying out the conversion of 235 into 236, since in most cases, it furnished the desired product with good conversion, and in yields higher than those obtained with L iNEt2. Li thium diethylamide, while effective and more easily prepared than K D A , often afforded inseparable mixtures of compounds 235 and 236. In such cases, resubmission of the mixture to the reaction conditions was sufficient to complete the conversion. 214 1. L D A , THF -78 °C 2. NCCOOEt, H M P A 70% EtOOC PhS 1. NaH, THF, E t 0 0 C 0 ° C 2. PhSeCl 230 H 2 0 2 , H 2 0 C H 2 C 1 2 78% from 230 1. K D A , THF -78 °C 2. M e l EtOOC 235: large scale, 233 R = H : 73% from 232 -236: R = Me (98%) 227, BF 3«OEt 2 THF, -78 °C EtOOC Scheme 53 The preparation of tetracyclic ketone 236 from tricyclic ketone 214 seemed particularly long and convoluted. A s summarized in Scheme 53, the process involved six synthetic steps, which include the seemingly redundant addition of the ester function to ketone 214. For this reason, it was decided to modify the approach to tetracyclic ketone 236, such that it did not include the addition and subsequent removal of the ethoxycarbonyl group. Chapter 3 79 The first stage in this approach was the preparation of the required enone. While the selenoxide elimination sequences described above are reliable, a novel and synthetically appealing method has emerged, 7 4 stemming from Nicolaou's work on the CP-molecules. 8 o-Iodoxybenzoic acid ( IBX) is the first intermediate in the preparation of the Dess-Martin periodinane, and is easily synthesized from o-iodobenzoic acid and o x o n e ® . 7 5 In Nicolaou's work, I B X has been demonstrated to act effectively in the single-step preparation of cyclic enones from their corresponding ketones (e.g., Scheme 54). In particular, I B X seems to have been most effective in the preparation of unsubstituted cyclic enones, such as in the transformation of ketone 237 into enone 238. .0 IBX (1.5 equiv.) toluene-DMSO 70 °C, 24 h 84% 237 238 Scheme 54 It was decided that the above-mentioned reaction bore a certain amount of promise for this work, and thus, was attempted on a small scale (Scheme 55) on tricyclic ketone 214. O . O IBX (2.5 equiv.) toluene-DMSO 214 110 °C, 12 h 84% Scheme 55 239 While a number of minor difficulties did present themselves throughout the course of the initial experiment, it was found to be generally successful. A t the temperatures prescribed in the Nicolaou report 7 4 the reaction did not seem to proceed at all . Upon slowly raising the temperature to 110 °C, a faint UV-active spot was observed by T L C after 1 h, at the same Rf as the starting material. In order to discern the completion of the reaction, aliquots of the reaction mixture were removed on a regular basis, and, after work-up with aqueous N a H C 0 3 , were Chapter 3 80 injected through a GC column. Upon optimization of these reaction conditions, it was found that, at 110 °C, this reaction required 12 h to achieve completion, affording enone 239 in a single step, in 84% yield. Without a methyl substituent at the a-position of the enone, it was expected that the cuprate addition to Michael acceptor 239 would prove to be more successful than the analogous conjugate addition to enone 220 (see Scheme 50). Thus, under conditions identical with those described in Scheme 50, enone 239 was treated with cuprate 227 in the presence of BF3-OEt2. The initial results of this experiment are illustrated in Scheme 56. While cuprate 227 did in fact add conjugately to enone 239, this process was accompanied by significant conjugate addition of a methyl group to the starting enone, resulting, ultimately, in a disastrous loss of material. Scheme 56 This competitive conjugate addition of a methyl group during the conjugate addition of 77 alkenyl cuprates such as 227 has been previously observed. This competition has been reasonably attributed to the reactions summarized in Figure 19. Treatment of trimethylstannane 226 with MeLi presumably results in the establishment of an equilibrium, which, as demonstrated, proves deleterious to the outcome of this reaction. Addition of the copper source to the reaction mixture results in the formation of two separate cuprate species: the desired 78 cuprate 227 and methyl cyanocuprate, 242. In general, the accepted order of ligand transfer from different lower-order organocuprate species to enones favours alkenyl ligands over alkyl Chapter 3 81 ligands. Therefore, it was somewhat surprising to find that appreciable amounts of ketone 241 were formed in this reaction. Figure 19: Explanation for mixed products in the Michael addition of cuprate 227 to enone 239. O M e 3 S n 226 CI + M e L i Li 13 CI + Me 4 Sn CuCN CuCN MeCu(CN)Li 242 + Cu(CN)Li CI y 239 227 240 In order to circumvent this problem, Piers and Roberge 7 7 suggested that, as illustrated in Figure 20, the reaction of tributylstannane 243 with B u L i might bias the equilibrium towards the desired alkenyllithium species (13) and thus prevent the formation of butyl cyanocuprate upon addition of C u C N . This did in fact turn out to be the case, and in a number of examples, tributylstannane 243 has been demonstrated to be superior to trimethylstannane 226 in the formation of cuprate 227. Furthermore, the tributylstannane bears the advantage of being significantly less volatile than its trimethyl analogue, making it considerably easier to handle. Figure 20: Preparation of cuprate 227 from tributylstannane 243. Bu 3Siji Li J ^ + BuLi ^ = w X I ^ ^ "CI 243 13 CuCN r Cu(CN)Li CI + Bu 4 Sn 227 The preparation of tributylstannane 243 was carried out via a protocol identical with that used to prepare trimethylstannane 226. Stannylcupration 6 8 (Scheme 57) of alkyne 245 with Chapter 3 82 Bu 3 SnCu-SMe2 (244, formed by the treatment of hexabutylditin with B u L i followed by C u B r S M e 2 ) followed by in situ protonation, furnished a mixture of stannanes 246 and 247, with the former substance being the major product. After compound 246 was isolated from the mixture by chromatography, it was subjected to the action of P h 3 P in C C I 4 , 6 9 cleanly furnishing tributylstannane 243. 1. BuLi , THF Bu 3 SnSnBu 3 *• Bu 3SnCu«SMe 2 2. CuBr«SMe2 2 244 2 4 4 Bu3Srp B u 3 S n ^ H THF, MeOH ^ ^ - ^ ^ O H + ^ ^ ^ 245 - 7 8 ° C - > r t 246:67% 247:13% Ph 3P, CCI4 reflux 1 B u 3 S n 243: 99% Scheme 57 It had been observed previously (Scheme 56), that the combined yield of cuprate addition products derived from the attempted addition of cyanocuprate 227 to enone 239 totalled less than 50%. Work by Lipshutz et al. has demonstrated that, in certain circumstances, homocuprates formed from C u B r S M e 2 (Scheme 58) furnish products of conjugate addition in more reliable yields than the corresponding cyanocuprates. Therefore, it was decided initially to attempt the desired conjugate addition with homocuprate 248, derived from stannane 243. Somewhat embarrassingly, an error was made in the setup of this experiment, leading to the "accidental" formation of the organocopper reagent 249. As demonstrated in Scheme 58, this error arose from simply adding too much of the copper(I) bromide-dimethyl sulfide complex. Thus, the solution of tributylstannane 243 was treated sequentially with 1 equivalent of B u L i in cold (-78 °C) T H F and 1 equivalent of solid C u B r S M e 2 . Chapter 3 83 B u 3 S n 1. BuLi (1 equiv) 243 CI 2. CuBr«SMe2 (0.5 equiv) CuLi 'SMe? 248 1. BuLi (1 equiv) 2. CuBr«SMe2 (1 equiv) Cu«SMe2 CI 249 Scheme 58 Tributylstannane 243 was treated with B u L i in cold (-78 °C) T H F followed by the addition of 1 equivalent of solid C u B r S M e 2 to the reaction mixture. This generated, in situ, organocopper species 249 (Scheme 58). Addition of BF3-OEt 2 to the mixture (Scheme 59) followed by a solution of enone 239 in T H F rapidly produced a brown mixture. Gratifyingly, but somewhat surprisingly, T L C analysis of this mixture revealed that no starting material remained after 15 min. After work-up with aqueous NH3-NH4CI (pH ~8), followed by chromatography, ketone 240 was cleanly furnished in 93% yield. The infrared spectrum of compound 240 displayed an intense peak at 1703 cm" 1, indicative of the ketone carbonyl function. Evidence that the reaction had been successful also came from ' H - N M R spectroscopy, which showed that the spectrum of the product possessed two one-proton signals in the olefinic region (8 4.85 and 4.92) and a two-proton signal at 8 3.6, corresponding to the two protons on the carbon bearing the chlorine atom. 1 .249 ,BF 3 OEt 2 T H F , - 7 8 ° C ^ 2. N H 3 - N H 4 C I , H 2 0 H 240: 93% Scheme 59 Completion of the annulation sequence (Scheme 60) was effected by treating ketone 240 with r - B u O K in T H F - f - B u O H to afford a mixture of compound 235 and its a-epimer, 250, in 93% overall yield, with a ratio of 4.5:1 in favour of the ds-isomer, 235. These configurational Chapter 3 84 assignments were based on the assumption that, since these two products are formed under equilibrating conditions, then their ratio should lie in favour of the thermodynamically more stable product. B y molecular modelling calculations, compound 235 had been previously determined to be the more stable product, by a margin of approximately 1.3 kcal/mol. Chromatographic separation of the two epimers was possible and treatment of the Trans-fused isomer, 250, with r -BuOK in T H F - r - B u O K refurnished the 4:1 mixture of the two epimers. However, separation of the epimers was not necessary, since subjection of the mixture to K D A in T H F , followed by treatment of the resulting enolate with M e l , afforded a single product, the required methylated ketone 236, in 89% yield. /-BuOK THF-r-BuOH 93% 240 1. K D A , THF, -78 °C 2. Mel Scheme 60 2 3 6 : 8 9 % The goal of the initial stages of this synthesis was to discover a rapid and effective method for the generation of a common tetracyclic intermediate from which the completion of the synthesis could be carried out in a number of different manners. This goal was achieved upon generation of tetracyclic ketone 236. The preparation was carried out in a highly convergent manner, in which three four-carbon units are sequentially added to a six-membered core ring that stems from dihydroresorcinol. The methodological work that was described in Section 2.2 was Chapter 3 85 effectively employed to generate a synthetically useful amount of dienone 164. From bicyclic dienone 164, tetracyclic ketone 236 was obtained in 9 steps and in 40% overall yield (Scheme 61). The key features of the synthesis of this advanced tetracyclic intermediate from 164 are the uses of two well-developed bifunctional reagents to install two four-carbon units via highly efficient annulation sequences. 3.4.2 Establishing the final quaternary carbon chirality centre and installing the double bond into the six-membered ring. 3.4.2.1 Initial studies on the installation of the double bond into the six-membered ring. A t this stage, a number of different routes are available to convert tetracyclic ketone 236 into a precursor suitable for the elaboration of the sidechain at C-7. Two key conversions were required to achieve this goal. In the first stage (Figure 21), the carbonyl function must be used as a handle for the installation of the carbon-carbon double bond into the six-membered ring (e.g. 236 —» 194). The second conversion wi l l involve the stereoselective introduction of the final quaternary centre in the western five-membered ring, using the exocyclic olefin as a handle. Chapter 3 86 Figure 21: The goal of the initial studies on ketone 236. 52 : mangicol F Trapping of the enolate of ketone 235 (Figure 22), formed under basic conditions, with a reagent such as PhN(Tf) 2 was expected to furnish alkenyl triflate 251. A t this stage, various palladium- 8 0 and nickel-based 8 1 catalytic reductive systems might possibly serve to cleave the triflate group, thus rendering diene 194. Dissatisfyingly, no reaction was observed upon the treatment of ketone 236 with a number of bases (including K D A and L i N E t 2 - f - B u O K ) followed by the addition of a triflating agent to the reaction mixture. Figure 22: The proposed alkenyl triflate approach. 236 251 194 At this point, attention was turned to a more conventional method for the formation of olefins: dehydration of alcohols via syn-elimination. For syn-elimination it was imperative that the P-alcohol (252, Scheme 62) could be prepared in a stereoselective manner. The a-face of the carbonyl function was considered, upon examination of molecular models, to be the least hindered of the two faces, due to crowding of the P-face provided by the three methyl groups. After screening of several different carbonyl reductants, including NaBFL, and L-Selectride®, D I B A L H was determined to be the most appropriate agent for this reaction. Treatment of ketone 236 with D I B A L H in E t 2 0 furnished a -3:1 mixture of alcohols 252 and 253 in near quantitative Chapter 3 87 yield. Distinction between the two compounds was made possible by comparison of their 1 H -N M R spectra. The most notable difference between the two spectra lay in the coupling constants of the carbinol protons ( H - l l ) arising from the adjacent angular protons (H-12). It was expected that when the two protons bore a zrans-relationship, the coupling constants would be greater than when they were located on the same side of the six-membered ring. The H - l l - H - 1 2 coupling constant observed in the ' H - N M R spectrum of compound 252 was 12 H z , while that observed for compound 253 was 4 H z . This identification was deemed satisfactory at this time; however, more definitive identification of compound 252 was made possible by X-ray crystallographic data obtained at a later stage in the synthesis. 1. D I B A L H , E t 2 0 0 ° C 2. N H 3 - N H 4 C I , H 2 0 ( P H ~8) 2 5 2 TPAP, N M O , C H 2 C 1 2 + -3:1 2 5 3 Scheme 62 Oxidation of the ct-alcohol (253) via the method developed by Ley et al. followed by reduction of the crude ketone (236) furnished a second 3:1 mixture of alcohols 252 and 253. On preparative scale, after two cycles, the desired (3-alcohol (252) was obtained in 94% overall yield. With alcohol 252 in hand, the next step was to locate a suitable reagent for the dehydration process. Arbitrarily, the first two reagents chosen from several reagents available for the dehydration of alcohols were the Burgess reagent8 3 (254) and the Mart in sulfurane 8 4 (255). These reagents were appealing due to their commercial availability, the Burgess reagent in particular due to its documented mode of action regarding syn-eliminations of cyclic alcohols. Chapter 3 88 © © E t 3 N S 0 2 N C O O M e 254 ! (Burgess reagent) benzene, reflux + 6 other products from the rearrangement of the core. 252 194: major Scheme 63 In refluxing benzene, P-alcohol 252 was allowed to react with the Burgess reagent (254, Scheme 63). After 3 h, only a single spot was observed by T L C analysis of the reaction mixture. This spot appeared very close to the solvent front, even when plain petroleum ether was employed as the developing solvent. This is consistent with the fact that the expected product from this reaction, diene 194, would contain not a single heteroatom, and thus, display similar polarity to simple hydrocarbons. ' H - N M R spectral analysis of the material isolated by flash chromatography revealed three signals in the olefinic region, consistent with the structure of diene 194. However, the ^ - N M R spectrum of this material also revealed it to be impure. Several signals, all smaller than the three mentioned above, were observed in the olefinic region of the spectrum. It seemed that a significant amount of rearrangement of the tetracyclic core was occurring during the reaction. Analysis of the material by G C - M S revealed that all compounds present in the mixture, possessed a molecular mass identical with that of diene 194. OH 252 Ph 2 S(OR F ) 2 255 -^(Martin sulfurane) CDC1 3 , rt R F = PhC(CF 3 ) 2 194: major Scheme 64 + minor impurities stemming from the rearrangement of the core. Of In spite of reportedly operating via carbocationic intermediates, the Martin sulfurane bore an advantage over the Burgess reagent in that dehydrations with the Martin sulfurane occur very rapidly (often within seconds) at low temperature. Therefore, P-alcohol 252 was treated with the Martin sulfurane (255) in pentane at room temperature (Scheme 64). T L C analysis of Chapter 3 89 the reaction mixture revealed, after 5 min, that none of the starting alcohol remained. ' H - N M R spectral analysis of the purified material revealed that the product was in fact, cleaner than that obtained via reaction of 252 with the Burgess reagent (i.e. fewer signals were observed in the olefinic region and the ratio of the signals corresponding to the desired product to those of the major impurity had significantly improved). However, due to the fact that the isomers could not be separated from each other, it was felt that this transformation still required further study. SMe 252 1. NaH, imidazole THF, reflux 2 . C S 2 * 3. M e l 100% 1,2-dichlorobenzene *> reflux 256 Scheme 65 257 observed on larger scales Two frequently employed methods for alcohol dehydration still seemed attractive: the two step xanthate thermolysis method (Chugaev elimination), 8 6 and a single step method employing l, l ' - thiocarbonyldiimidazole. 8 7 Xanthate 256 was prepared from (3-alcohol 252 in quantitative yield via deprotonation of the hydroxyl group followed by sequential treatment of the resulting alkoxide with distilled C S 2 and iodomethane (Scheme 65). Thermolysis of xanthate 256 was effected in refluxing 1,2-dichlorobenzene, exclusively affording diene (194) in -80% yield. The high boiling point of 1,2-dichlorobenzene (-180 °C), combined with the lack of polarity in the diene made separation of the two materials particularly cumbersome. Xanthate 256 was resistant to thermolytic reaction in lower boiling solvents such as o-xylene (bp -140 °C). Furthermore, upon an attempt to scale this reaction up, migration of the exocyclic double Chapter 3 90 bond to the endocyclic position (i.e. diene 253) was observed. Tentative identification of the structure of 253 was assigned based on the two new signals observed in its " H - N M R spectrum: a 3-proton singlet near 8 1.6 and a 1-proton broad singlet at 85.2. Due to the uncontrolled formation of this by-product, the xanthate pyrolysis approach was abandoned. The fourth and final method employed in the endeavour to dehydrate (3-alcohol 252 was the single-step method using 1,1 '-thiocarbonydiimidazole (258). 8 7 This reagent is analogous to the xanthate elimination method in that a similar thiocarbamate intermediate (259, Scheme 66) is formed in situ, which then undergoes thermolysis to furnish the diene. Of the three single-step methods for effecting this transformation examined so far, reagent 258 was advantageous in that it furnished the best ratio of the desired diene to rearranged by-products. Unlike the xanthate (256), the thiocarbamate intermediate underwent elimination in refluxing o-xylene, allowing for a considerably simpler purification. Moreover, the experimental details were considerably less complicated than those required for the Chugaev elimination. Thus, for experimental purposes, in particular once the reaction was scaled up, reagent 258 was deemed to be the reagent of choice for the installation of the endocyclic double bond. OH S, 258, D M A P O o-xylene, reflux S 252 N' 259 194: 77% Scheme 66 Chapter 3 91 3.4.2.2 Nitrile alkylation approaches to the establishment of the final chirality centre in the core. A useful protocol for the introduction of a quaternary carbon chirality centres into ring systems is to convert an exocyclic double bond into its corresponding cycloalkanenitrile and then to alkylate the anion of the nitrile. This method was initially chosen to stereoselectively establish the necessary quaternary centre in the western five-membered ring of the core structure of mangicol F . The following portion of the thesis is therefore divided into two parts: the synthetic approach to the nitrile and the alkylation of the anion of the nitrile. O H . . . O T E S TESC1, D M A P , imidazole^ T H F - D M F , 70 °C 100% Scheme 67 252 260 It was decided that the initial approach to this necessary conversion would begin with alcohol 252 as the starting material. Consequently, the hydroxyl function of this compound required protection. Chosen for this task was the triethylsilyl (TES) protecting group, due to its stability relative to that of the T M S group. 8 8 Initial attempts to install the T E S group, showed that the steric encumbrance in the vicinity of the hydroxyl group in alcohol 252 was itself an interesting challenge. Standard 8 8 treatment of the alcohol with TESC1, D M A P and imidazole in D M F at 55 °C furnished absolutely none of the desired silyl ether. However, further experimentation revealed that when a mixture of alcohol 252, TESC1, D M A P and imidazole in a 1:1 mixture of T H F - D M F was heated to 70 °C for 18 h (Scheme 67), the T E S ether, 260, was obtained in quantitative yield. O T E S O T E S 260 1. BH3«THF, THF 0 ° C 2. NaOH, H 2 0 2 H 2 0 76% OTES 261 Scheme 68 Dess-Martin periodinane CH 2 C1 2 95% O H C 262 Chapter 3 92 Generation of aldehyde 262 from 260 (Scheme 68) was presumed to be possible via a on standard hydroboration procedure followed by oxidation of the resultant primary alcohol to the corresponding aldehyde. Thus, treatment of compound 260 with a B H 3 - T H F complex in cold (0 °C) T H F (Scheme 68) and oxidation of the intermediate with H 2 0 2 - N a O H furnished an inseparable mixture (-3:1) of alcohols 261 in 76% overall yield. The mixture of alcohols was oxidized with the Dess-Mart in periodinane, 9 0 affording, in 95% yield, an inseparable epimeric mixture of aldehydes 262. Characteristic of aldehyde functions was the presence of two doublets at 8 9.6 and 8 9.8 in the ' H - N M R spectrum of the mixture. Scheme 69 For purposes of characterization, it was desired to separate the diastereomeric mixture of aldehydes 262. Unfortunately, separation of these isomers by standard chromatographic methods proved ineffective. Therefore, the aldehyde mixture was treated with f -BuOK in ? - B u O H - T H F (Scheme 69). Under these conditions, equilibration of the two aldehydes furnished a single aldehyde that corresponded to the less abundant of the two aldehydes present in the original mixture. This compound was assigned the structure shown in formula 263, due to the fact that there is clearly significantly greater steric hindrance within the concave face of the western Chapter 3 93 hydrindane subunit than on the convex face. A small amount of aldehyde 263 was reduced with D E B A L H to furnish, for characterization purposes, alcohol 264. A t this stage, it was clear that a crystal structure would serve to corroborate the expected c/s-fused nature of the western hydrindane subunit of the core. For this reason, alcohol 264 was converted into the p-nitrobenzoate ester, 265, a process that occurred in 82% yield. Gratifyingly, ester 265 was obtained as a solid compound and was recrystallized from heptane. The O R T E P diagram representing the crystal structure of 265 is illustrated in Figure 23. Figure 23: O R T E P diagram representing the crystal structure of ester 265. From the O R T E P diagram illustrated in Figure 23, it is clear that the methyl group on C -10 and the proton on C-6 share a ds-relationship with each other and are located on the same side of the boat-shaped six-membered ring as the southern five-membered ring. This evidence confirms that, as predicted, the annulation sequence employed to introduce the western five-membered ring occurred on the a-face of the tricyclic precursor. It also confirms that the methylation reaction employed to install the methyl group at C-10 occurred with the desired stereoselectivity. A final piece of information gathered from the O R T E P diagram, albeit indirectly, is that the hydroboration of compound 260 occurs, again as expected, predominantly from the P-face of the exocyclic alkene. C27 C30 04 C16 Chapter 3 94 With aldehyde 263 in hand, it was now possible to continue with the establishment of the final quaternary centre in the core of mangicol F . In order to do so, the next required transformation was conversion of the aldehyde function into its corresponding nitrile. While methods such as that reported by Sampath Kumar et al.91 can effect a one-pot conversion of aldehydes into nitriles, a milder method was desired to effect this transformation, due to the presence of the si lyl ether function in the molecule. A report by Cl ive and Hisaindee 9 2 described a particularly mild, but more importantly, only mildly acidic (acetic acid) method for converting carbonyl functions into their corresponding oximes, the first of two steps commonly employed in the preparation of nitriles from aldehydes. In this work, the carbonyl compound (266) was treated with H 2 N O H H C I in the presence of N a O A c in water, affording oxime mixture 267 (Scheme 70). Q H O ^ H 2 N O H . H C l , H 2 0 NaOAc 79% Scheme 70 267 Modification of this procedure was required due to the lack of solubility of aldehyde 263 in water and, thus, the reaction mixture was set up as follows. Hydroxylamine hydrochloride was stirred for five minutes in water with 1 equivalent of N a O A c , thus liberating the hydroxylamine. This solution was then added to a solution of aldehyde 263 in T H F . Within a half-hour, the conversion was complete, furnishing a mixture of Z - and Zs-aldoximes 268 and 269 (respectively) in 90% overall yield (Scheme 71). O H C O T E S O T E S 263 H 2NOH«HCl, H 2 0 • NaOAc, THF H Q 90% 1.5:1 ratio Scheme 71 Chapter 3 95 Not surprisingly, the spectra of the two oximes displayed a number of similarities. The presence of the aldoxime functions in each compound was determined by the ' H - N M R spectra of the two compounds. Each spectrum displayed a doublet near 8 7 (HC=N) and a broad singlet, also near 8 7, arising from the hydroxyl proton. The configurations of the aldoximes were assigned based on a comparison of the two ' H - N M R spectra. The two most identifiable protons in each spectrum were the aldoxime (HC=N) proton and the "oc"-proton, H-7. The Z-aldoxime, 268, was presumed to be the compound in which the presence of the hydroxyl portion of the oxime function affected the chemical shift of H-7. The E-aldoxime, 269, was presumed to be the compound in which the presence of the hydroxyl group affected the chemical shift of the aldoxime (HC=N) proton. The hydroxyl group was presumed to have a deshielding effect on the proton closest to i t . 9 3 A s predicted, these effects were observed in the ' H - N M R spectra of the two aldoximes. The aldoxime proton in the Z-aldoxime, 268, appeared at 8 6.6, while that of the E-aldoxime, 269, appeared further downfield, at 8 7.4, due to the effect of the hydroxyl group. Similarly, H-7 of the Zs-aldoxime, 269, was located at 8 2.4 (akin to the location of H-7 in aldehyde 263), while H-7 of the Z-aldoxime, 268, experiencing the effect of the hydroxyl group, was located at 8 3.1. In the second step of the conversion of aldehydes to nitriles, the aldoxime is dehydrated to afford the desired nitrile. While a large number of different methods exist to carry out this conversion, 9 4 a convenient mild method has been developed by Palomo et al.,95 employing a S O C I 2 - D M F complex. Reportedly, the combination of SOCI2 and D M F furnishes the dehydrating agent 270 (Scheme 72). Experimentally, the preparation of dehydrating agent 270 from D M F and SOCI2 was carried out in an addition funnel, using benzene as the solvent. The cloudy mixture was allowed to stand for 15 min, during which time, a pale yellow oi l separated out at the bottom of the funnel. This oi l was added dropwise to a mixture of the aldoximes and Chapter 3 96 pyridine in benzene. After the reaction mixture had been heated for 1 h at reflux, the reaction was complete. Overall, the nitrile 271 was obtained in 69% yield from the mixture of oximes. The configuration of nitrile 271 was presumed to be the same as that of its aldehyde precursor, 263. Primary evidence that the product obtained from the reaction was nitrile 271 was obtained from the infrared spectrum of the product, which displayed a weak band at 2235 cm" 1. The most convincing signal displayed in the ^ - N M R spectrum of compound 271 was a signal with three different /-values, located at 5 2.3, which was presumed to be the nitrile a-proton. Scheme 72 With nitrile 271 in hand, the next required step of the synthesis involved stereoselective alkylation of this material. Prediction of the stereochemical outcome of the alkylation reaction was based on the steric surroundings of the anion of nitrile 271 (Figure 24). For the purpose of clarity, only the western hydrindane subunit of the anion of nitrile 271 is depicted in Figure 24. Furthermore, the six-membered ring in the diagram is portrayed as a boat, when it is more likely to adopt a conformation slightly twisted from the boat conformer. The anion of 271 is illustrated as one resonance hybrid structure, implying bond geometry at the a-carbon similar to that of an sp 2-hybridized carbon (i.e. trigonal planar with bond angles of approximately 120°). Chapter 3 Figure 24: Predicted facial selectivity of the alkylation of the anion of nitrile 271. 97 H O T E S H o C K D A THF (partial representation) HaCf 8" I proposed transition state for the methylation of the anion of nitrile 271 From the representation of the anion of nitrile 271 shown in Figure 24, it can clearly be seen that the approach of the electrophile from the top face of the nitrile anion suffers impedence from the axial methyl group on C-10, situated 2 carbons away from the reaction centre. On the other hand, there is very little such hindrance from the bottom face of the nitrile. In the event, treatment of nitrile 271 with K D A in cold (-78 °C) T H F (Scheme 73) followed by the addition of neat iodomethane to the reaction mixture furnished, after chromatogaphy, a single nitrile, 272, in 92% yield. Initial confirmation that the alkylation of the anion of nitrile 271 had been successful was obtained via spectroscopic analyses of the product. First, a new three-proton singlet was now present in the aliphatic region of the ' H - N M R spectrum of 272. Furthermore, G C - M S analysis of the product, 272, revealed not only that the compound was homogeneous (i.e. a single diastereomer), but also that the parent fragment had a mass that was 14 amu greater than that of the starting material, 271. O T E S O T E S 1. K D A , THF, -78 °C 2. Me l 271 92% Scheme 73 N C 272 It remained to determine i f the alkylation had occurred from the predicted face of the anion of nitrile 272 (as shown in Figure 24). Unfortunately, there were no usefully isolated signals present in the ' H - N M R spectrum of nitrile 272 to provide a clear window for selective Chapter 3 98 irradiation for the purposes of obtaining nOe results. Therefore, in order to determine the stereochemical outcome of the alkylation reaction, it was decided to endeavour to grow crystals of a derivative of compound 272 for X-ray analysis. Since compound 272 itself exists as a colourless o i l , the silyl ether function was cleaved by treatment of 272 with T B A F in T H F (Scheme 74). The resulting alcohol, 273 (again, a colourless oil), obtained in 80% yield, was esterified with p-nitrobenzoyl chloride and D M A P in D M F , furnishing solid ester 274 in 62% yield. This material was recrystallized from methanol. O Scheme 74 Gratifyingly, the results from the X-ray analysis of crystals of 274, illustrated in Figure 25, demonstrated that the alkylation of the anion of nitrile 271 had occurred from the desired face. It is clear from the O R T E P diagram in Figure 25 that the newly installed methyl group on C-7 is located on the side of the five-membered ring opposite to that of the methyl group on C -10, the structural feature of nitrile 271 presumed to be responsible for the stereoselectivity of the alkylation reaction. Chapter 3 99 Figure 25: O R T E P diagram representing the crystal structure of ester 274. 04 A t this point, small-scale experiments were carried out on alcohol 273, in an attempt to determine the conditions required for its dehydration. While most of the methods described earlier (Section 3.4.2.1) were applied directly to the alcohol, the Chugaev elimination required derivatization of the alcohol as its corresponding xanthate. Therefore (Scheme 75), alcohol 273 was treated with N a H and imidazole in refluxing T H F . The resulting alkoxide was then treated with C S 2 followed by iodomethane to furnish xanthate 275 in 69% yield. Scheme The results from the elimination experiments are described in Table 13. Disappointingly, none of the methods previously described were particularly effective in carrying out the desired Chapter 3 100 reaction. The Martin sulfurane, even in refluxing CCI4 was completely unreactive towards alcohol 273. l ,l '-Thiocarbonyldiimidazole did display some activity towards the alcohol, but furnished a mixture of at least four products. The major product was isolated from the reaction mixture and was tentatively identified as the desired nitrile, 276, due to the presence of a new signal in the olefinic region of its ' H - N M R spectrum. It is also noteworthy that 1,2-dichlorobenzene was employed as the solvent for this reaction, as no reaction was observed in refluxing oxylene. Finally, the Chugaev elimination of xanthate 275 furnished two different compounds in a 1:1 ratio. Table 13: Results from the elimination experiments on nitriles 273 and 275. 273 (R = H) or 276 275 (R = C(=S)SMe Nitrile Conditions Results 273 Martin sulfurane3 N o reaction. 273 Thiocarbonyldiimidazole, D M A P b Multiple products observed 275 1,2-dichlorobenzene Two products obtained "This reaction was carried out in refluxing CC1 4. This reaction was carried out in refluxing 1,2-dichlorobenzene. cThe Chugaev elimination was carried out at reflux. While one of the products from the Chugaev elimination was identified as the desired nitrile 276, the other bore characteristics that were similar to those of the starting material, by ' H -N M R spectroscopy. The single-proton doublet corresponding to the "carbinol" proton was still present, although it exhibited a smaller coupling and was further downfield. Furthermore, the S-methyl group signal was also still present in the spectrum. This compound was identified as dithiocarbonate 277 (Scheme 76), the product of a rearrangement that is known to occur in competition with Chugaev eliminations. 9 6 The smaller coupling constant observed in the ' H -N M R spectrum (signal due to Ff-11, 277) corroborates this presumption due to the inversion of Chapter 3 101 configuration expected with this rearrangement. While methods are available to carry out the conversion of dithiocarbonates to alcohols, they require multiple steps and, often, hazardous 97 reagents. 275 276 277 Scheme 76 It was curious that the dehydration of alcohol 252 was particularly facile, whereas considerably greater difficulties were observed with the dehydration of alcohol 273. For this reason, M M 2 molecular dynamics calculations (CS Chem3D Pro software) were applied to the two alcohols. The results demonstrated that there was merely a two-degree difference in the dihedral angles highlighted in Figure 26. Therefore, it was felt that the lack of reactivity associated with compound 273 towards elimination was due to the mechanism of syn-elimination. The main requirement for effective syra-elimination to occur is that the leaving group and the proton involved in the elimination be able to adopt a conformation such that the two groups are as near to co-planarity with each other as possible. Examination of molecular models reveals that as the conformations of the two molecules are changed such that the hydroxyl group and H-12 approach co-planarity, the western five-membered ring moves to a position such that it is perpendicular to the "plane" of the six-membered ring. In this conformation, the methyl group on C-7 (compound 273) and the proton on C-5 are very close to each other in space. Therefore, the intermediates related to compound 273 experienced a greater difficulty in achieving the conformation required for facile syn-elimination than those related to compound 252. Such was not the case with compound 252, which bears an sp2-centre at C-7. Chapter 3 Figure 26: Comparison of the 0 - C - C - ( H - 1 2 ) dihedral angles of alcohols 252 and 273. OH . OH 102 252 dihedral angle: -63° NC i 273 dihedral angle: -61° Since the dehydration of alcohol 273 proved problematic, it was decided to attempt the nitrile anion alkylation approach starting with diene 194. Therefore, a small-scale hydroboration was attempted on diene 194. As illustrated in Scheme 77, hydroboration with B H 3 T H F in T H F , was limited to the exocyclic double bond. The mixture of alcohols 278 was obtained, after basic oxidative work-up, in 70% yield over two steps (i.e. from alcohol 252). OH Chugaev elimination 1. BH3.THF, THF, 0 ° C 2. NaOH, H 2 0 2 H 2 0 194 Scheme 77 HO' 278: 70% from 252 5:1 ratio The following sequence of reactions was carried out via protocols similar to the sequence previously described, and thus, wi l l not be covered in great detail. Furthermore, the reactions were carried out in rapid succession and on small scale, and thus, complete characterization of the intermediates was not effected. Identification of the intermediates was ascertained by comparison of the ' H - N M R spectra with those of the analogous compounds described previously. For this reason, descriptions of the preparation of compounds 278-281 does not appear in the experimental section of this thesis. Chapter 3 103 Scheme 78 Illustrated in Scheme 78 is the reaction sequence employed to prepare nitrile 276 from alcohol 278. The mixture of alcohols, 278, was oxidized to aldehyde mixture 279 via the method described by Ley et a/. , 8 2 employing T P A P and N M O in the presence of 3 A molecular sieves. The resulting mixture of aldehydes was converted into nitrile mixture 280, via the one-step procedure developed by Sampath Kumar et al.,91 in 87% yield. The mixture of nitriles proved to be more resistant to the alkylation conditions than did nitrile 271; therefore, H M P A was added to the reaction mixture prior to the addition of the iodomethane. Interestingly, some of the selectivity observed in the alkylation of the anion of nitrile 271 was lost in the alkylation of the anion of the nitrile mixture 280, and a 3:1 mixture of alkylated products was obtained, in favour of the desired nitrile 276. While there were problems associated with each of the two described procedures involving nitrile anion alkylations, it was still important to discover a method for the conversion of nitrile 276 into aldehyde 193 (see Figure 27). The proposed method for accomplishing this task was via the conversion of the nitrile functional group into its corresponding aldehyde (282), followed by one-carbon homologation of the resulting aldehyde. Chapter 3 Figure 27: Proposed method for the preparation of aldehyde 193 from nitrile 276. 104 reduction OHC homologation 276 282 CHO A very common and simple method for the conversion of nitriles into aldehydes is via the use of D I B A L H . 9 8 While stronger aluminum based reducing agents such as L i A l F L are known to reduce nitriles directly to their corresponding amines, D I B A L H is effective at the partial reduction of nitriles to their corresponding aldimines. These aldimines are isolable, but this method has found greater synthetic use when combined with a mildly acidic work-up, thus hydrolyzing the resulting aldimines to their corresponding aldehydes. Therefore, nitrile 276 was treated with D I B A L H (Scheme 79) followed by a mi ld acidic work-up involving aqueous citric ac id , 9 9 supplying aldehyde 282 in 53% yield. A further 30% of nitrile 276 was recovered from the reaction mixture. Thus, the yield based on recovered starting material is 76%. 1. D I B A L H , D M E 276 2. aq. citric acid 53% Scheme 79 OHC 282 Aldehyde homologation is a well-established procedure, and many methods have been developed to accommodate a variety of structurally different aldehyde substrates. Of particular interest was the procedure developed by Magnus and R o y , 1 0 0 employing commercially available methoxymethyltrimethylsilane, 283. Different methods are available for the work-up of this reaction, some of which furnish the desired aldehydes directly upon work-up. For example (Scheme 80) when cyclohexane carbaldehyde (285) is treated with reagent 284 (prepared by the reaction of 283 with sec-BuLi), (3-hydroxyalkylsilane mixture 286 is obtained. Treatment of 286 Chapter 3 105 with 90% formic acid furnishes homologated aldehyde, 287. However, upon exposure of 286 to K H in refluxing T H F , methyl enol ether 288 may be isolated instead. sec-Buhi, THF Me 3 Sk OMe CHO M e 3 S i C H 2 O C H 3 283 284, THF -30 °C OH 285 -30 °C 80% SiMe* Li 284 90% H C O O H OMe CHO 286 76% 287 K H , THF reflux 95% OMe 288 Scheme 80 Aldehyde 282 was treated with reagent 284 in T H F at - 30 °C (Scheme 81), generating p-hydroxysilane mixture 289. This mixture of silanes was isolated, then a small portion was treated with 90% formic acid. Surprisingly, no reaction was observed by T L C . Treatment of the same silane mixture (289) with K H in refluxing T H F furnished methyl enol ether mixture, 290. OHC MeO 282 Me 3Si 90% HCOOH X CHO 193 290 Scheme 81 Interestingly, mild acid (acetic acid) treatment of the enol ether mixture (290) did not succeed in the hydrolysis of the enol ethers. However, it was important to devise a strategy for Chapter 3 106 the hydrolysis of the enol ether i f the nitrile anion alkylation approach were to remain a viable option to the synthesis of mangicol F. The two principal options were to increase the strength of the acid being used to effect the hydrolysis, or to attempt a method reported by Kosarych and Cohen , 1 0 1 which involves the use of the T M S C l - N a l system. Both of these approaches were attempted, and the results are summarized in Table 14. Table 14: Attempts at the hydrolysis of the methyl enol ether mixture 290. 285 CHO 193 Entry Conditions Result 1 3 M Aqueous HC1 in T H F , reflux No reaction 2 Concentrated H C 1 0 4 in T H F , rt Minor amount of product observed 3 T M S C 1 , N a l , M e C N Decomposition of material The results displayed in Table 14 show that these attempts to hydrolyze methyl enol ether mixture 290 to its corresponding aldehyde, 193 were very inefficient processes. However, since aldehyde 193 was still presumed to be the most useful precursor for the sidechain extension to mangicol F , the small amount that was obtained from the perchloric acid-promoted hydrolysis (entry 2, Table 14) was purified by chromatography and a clean ! H - N M R spectrum was obtained of the material. The product of the hydrolysis was identified as aldehyde 193 by the various aspects of its ^ - N M R spectrum. In particular, a doublet of doublets (7 = 3.8, 2.5 Hz) located at 8 9.8 revealed the presence of an aldehyde proton. The two cc-protons had different chemical shifts, and were each displayed as doublets of doublets. The higher field a-proton (8 2.4) exhibited geminal coupling (7 = 14.4 Hz) and coupling to the aldehyde proton (7 = 2.5 Hz) . The lower field a-proton (8 2.5) also exhibited geminal coupling (7 = 14.4 Hz) and coupling to Chapter 3 107 the aldehyde proton (7 = 3.8 Hz) . Furthermore, the usual doublet at 8 5.4, corresponding to the single olefinic proton accompanied its allylic partner, a multiplet between 8 2.4 and 2.5. Figure 28: Summary of the nitrile anion alkylation approaches to aldehyde 193. 194 276 In summary, two approaches to aldehyde 193 from alcohol 252 were attempted employing a nitrile anion alkylation as the key transformation. The main difference between the two approaches is that in the first approach (Route A , Figure 28) the nitrile anion alkylation procedure was attempted prior to the elimination step, while in the second approach (Route B , Figure 28), the two steps were reversed. The second approach (Route B) bore two significant advantages over the first (Route A ) . The dehydration of the system at the beginning of the sequence precluded the necessity for the T E S protecting group, thus eliminating the protection and deprotection steps from the overall synthesis. Furthermore, the absence of the protecting group allowed for the single-step conversion of aldehyde 279 into nitrile 280, resulting in an overall increase in yield for the transformation and the elimination of a third synthetic step from Chapter 3 108 the sequence. However, the poor yield and loss of selectivity in the key nitrile anion alkylation step prompted an investigation into other approaches to the generation of the final quaternary centre from the exocyclic olefin. 3.4.2.3 Cyclopropanation approaches to the establishment of the final chirality centre in the core. In addition to the nitrile anion alkylation approaches described in the previous section, introduction of the final quaternary carbon chirality centre to the core of mangicol F was thought to be achievable via a stereoselective cyclopropanation reaction (see Figure 29). For example, the cyclopropyl ring of a substance such as ester 291 could presumably be reductively cleaved and the resultant product, i f it possessed the correct configuration, could then be converted into aldehyde 193. Examination of molecular models of diene 194, reveals that the P-face of the exocyclic alkene function is sterically less encumbered than the a-face. Thus, it was presumed that a stereoselective cyclopropanation from the P-face of this double bond would be possible. Figure 29: Proposed preparation of aldehyde 193 via cyclopropanation. 3.4.2.3.1 Identification of the products of cyclopropanation. It seemed most convenient to attempt the initial cyclopropanation studies with commercially available ethyl diazoacetate and a rhodium catalyst. 1 0 2 The product of this reaction was expected to be cyclopropyl ester 291 (see Figure 29). Thus, a solution of diene 194 and commercially available rhodium(II) acetate dimer in D M E was treated over a period of 3 h, with the aid of a syringe pump, with a solution of ethyl diazoacetate in D M E (Scheme 83). Although, Chapter 3 109 under these conditions, cyclopropanation of the exocyclic alkene function occurred in high yield, it was disappointing to observe that the reaction was not stereoselective. In fact, all four possible isomers (291-294) were generated. Three of these were each produced in 30% yield, while the fourth isomer was formed in a yield of about 5%. It was at least gratifying to note that, based on the presence of four olefinic signals in the ' H - N M R spectrum of the crude mixture, the cyclopropanation of diene 194 had occurred exclusively at the exocyclic double bond, and that the endocyclic olefin had remained intact. H 1. Rh 2 (OAc) 4 , D M E • 2. Ethyl diazoacetate D M E COOEt 291 : 30% V H mixture A COOEt 292 : 5% J 194 EtOOC" X H 293 : 30% V Scheme 82 mixture B EtOOC The four cyclopropanation products were separable into two mixtures of two esters each. Unfortunately, it was not possible at this stage to determine with accuracy, which of the diastereomers were present in each mixture. However, via reasonable deductions, based on molecular modelling and on results obtained from the following experiments, configurational assignments were given to esters 291-294 as shown in Scheme 82. The remainder of this section wi l l endeavour to justify the assignments given above. Three of the four diastereomers 291-294 were generated in identical yields (30% each), and the fourth was produced in only 5% yield. It was concluded that ester 292 was the minor Chapter 3 110 ester. Examination of a molecular model of diene 194 indicated that the transition state leading to the formation of 292 would be sterically hindered by elements of the southern five-membered ring, particularly, the "down" proton located on C-5. It also appeared that the transition states leading the formation of the remaining three isomers (ie. 291, 293 and 294) would not experience such hindrance. A s such, these three isomers were expected to be formed in similar yields. Assignment of the relative configurations of the remaining three diastereomers was based on the results from the following experiments, ester mixture A 296 298 299 Scheme 83 The two mixtures were each carried through reduction-oxidation procedures, followed by ring opening of the resulting aldehydes, as shown in Schemes 83 and 84. In the first case, mixture A (Scheme 83), consisting of esters 291 and 292, was reduced with D I B A L H , and the resulting chromatographically inseparable mixture of alcohols (295 and 296) was oxidized to the corresponding mixture of aldehydes (297 and 298), which were separable by chromatography on silica gel. Hydrogenolysis of aldehyde 297 (described in detail in the following section) Chapter 3 111 furnished aldehyde 193, a known compound that was previously synthesized and characterized in ths work. On the other hand, hydrogenolysis of aldehyde 298 provided a compound exhibiting a ! H - N M R spectrum similar to that of aldehyde 193. This substance was presumed to be aldehyde 299. ester mixture B (293 + 294) 1. D I B A L H , E t 2 0 0 ° C 2. N H 3 - N H 4 C I „ H 2 0(pH~8) OH 301 303 299 Scheme 84 From ester mixture B , obtained from the cyclopropanation of diene 194 (Scheme 82) was obtained, via D I B A L H reduction, the chromatographically inseparable mixture of alcohols 300 and 301. This mixture was oxidized with T P A P and N M O , but unfortunately, this time the mixture of aldehydes (302 and 303) was inseparable by chromatography. Hydrogenolysis of the mixture supplied the inseparable mixture of aldehydes 193 and 299. From the results obtained in the experiments described above, the following conclusions were made with regards to the mixtures of esters obtained from the cyclopropanation of diene 194, (Scheme 82). First, because only one of the two esters in mixture 1 (ester 292) led to the incorrect ring-opened aldehyde, 299, then ester 294 (the other ester that would ultimately lead to aldehyde 299) must be in mixture 2. Second, since the components of mixture 2 were inseparable Chapter 3 112 at any stage in the following steps, they were presumed to be esters 293 and 294. In these two compounds, the ester functions are located in the position farthest from the bulk of the tetracyclic core, and thus, the two substances were expected to exhibit similar dipole moments. 3.4.2.3.2 Results from Various Attempts to Open Aldehyde 297. OHC H 297 In the previous section describing the identification of esters 291-294, it was mentioned that the opening of the cyclopropane ring of aldehyde 297 was accomplished via hydrogenolysis. However, this was not the first method employed to open this cyclopropane ring. This section wi l l describe the events that led to the discovery of the optimal procedure employed to open cyclopropyl aldehyde 297. Two reports 1 0 3 ' 1 0 4 were initially chosen from the literature, describing protocols for the selective ring opening of cyclopropyl aldehydes. A method devised by Huang and Forsyth 1 0 3 effected the regioselective ring opening of a-cyclopropyl aldehydes such as 304 with a T M S C 1 - T B A I mixture in methylene chloride to produce aldehydes such as 305 (Scheme 85). This procedure 1 0 4 was developed as an alternative to a dissolving metal reduction of similar compounds (such as 306, Scheme 86), reported earlier by the same authors. CHO 304 C H 2 C 1 2 86% Scheme 85 305 Chapter 3 113 OHC1 K L i , N H 3 64% OHC 306 Scheme 86 307 With aldehyde 297 in hand, it was possible to attempt the opening of the cyclopropane ring via the above-mentioned procedures. Thus, aldehyde 297 was treated, as described by Huang and Forsyth, with a mixture of T M S C l and T B A I in CH2CI2 (Scheme 87). Interestingly, the ! H - N M R spectrum of the single product that was isolated from the reaction mixture displayed signals that were inconsistent with the expected structure of aldehyde 308. The product did, in fact, display a one proton signal in the aldehyde region, split into a doublet of doublets. In other words, the aldehyde function was on a carbon that possessed two protons. Moreover, there were two olefinic signals in the ' H - N M R spectrum of the product: the first corresponding to the endocyclic olefin in the six-membered ring, the second matching, in shape and in chemical shift, the signal that was observed in compound 257. Thus, the product resulting from the T M S C l - T B A I - p r o m o t e d ring opening of aldehyde 297 was idendified as aldehyde 309. In addition to the spectroscopic evidence, the initial report by Huang and Forsyth describes aldehyde 310 (Scheme 87), as a by-product of the ring opening procedure. It is presumed that Lewis acid-promoted opening of the cyclopropane ring via elimination gives rise to compound 309. H £HO T M S C l T B A I C H 2 C 1 2 X I 308 297 310 309 257 Scheme 87 Chapter 3 114 Lithium in liquid ammonia has also been found to promote the ring opening of cyclopropyl aldehydes (eg. Scheme 86).104 Therefore, aldehyde 297 was subjected to dissolving metal reduction conditions (Scheme 88), employing lithium metal in liquid ammonia. Once again, however, the desired product was not obtained. Instead, the single product obtained after chromatography, was identified as aldehyde 311, based the similarities between its ^ - N M R spectrum and that of aldehyde 309. The only notable difference between the two spectra was the lack of the olefinic proton signal from the cyclopentene ring in the spectrum of 311. It is thought that aldehyde 311 via the ring opening of the radical anion intermediate 312a to form intermediate 312b. Although a single isomer of 306 was obtained, no stereochemical assignment of the newly formed carbon chirality centre was ascertained. 1. L i , N H 3 , THF, -78 °C 2. EtOH Scheme 88 Another reaction often employed in the ring opening of cyclopropanes is hydrogenolysis. Numerous reports demonstrate that a-cyclopropyl ketones, such as 313, undergo cyclopropane hydrogenolysis exclusively at the bond proximal to the ketone, furnishing 314 (Scheme 89).105 Therefore, it was expected that aldehyde 297 would experience hydrogenolysis at the bond distal to the spiro ring junction. Chapter 3 115 O H 2 , 10% Pd/C O 313 314 EtOH Scheme 89 Subjection of a solution of aldehyde 297 in methanol to H2 in the presence of 10% Pd on activated charcoal (Scheme 90) furnished a mixture of five compounds. One of these compounds was recovered starting material, 297. The second displayed a ^ - N M R spectrum identical with that of the previously prepared aldehyde, 193. The third, a strikingly non-polar compound, was tentatively identified as dimethyl acetal 315, based on the presence of two methyl singlets at 8 3.3 in its ' H - N M R spectrum. Treatment of this material with dilute aqueous HC1 in T H F quantitatively regenerated aldehyde 297. The remaining material, more polar than the starting material, as observed by T L C analysis, was a mixture of two alcohols, as indicated by the presence of signals characteristic of carbinol protons between 8 3.3 and 3.7 in the ' H - N M R sepctrum of the mixture. One of these alcohols produced a ' H - N M R spectrum that matched that previously observed for alcohol 295. The remaining alcohol was identified as alcohol 316 due to the fact that oxidation of the mixture of alcohols furnished aldehydes 297 and 193, respectively. Later, alcohol 316 was obtained as a pure compound and was further characterized. OHC H x CH 2 OH 295 H 2 (1 atm) 10% P d / C MeOH H >—OMe MeO 315 316 Scheme 90 Since one of the by-products (dimethyl acetal 315) of this reaction is probably produced because of the presence of traces of acid in the reaction mixture, it seemed reasonable that the Chapter 3 116 addition of a base to the mixture, prior to the reaction, would suppress its formation. Under the conditions shown in Scheme 91, aldehyde 297 was converted into a mixture of aldehyde 193 and alcohol 316 in 91% overall yield. Nearly quantitatively, alcohol 316 was converted into aldehyde 193 by the action of T P A P . 8 2 H 2 (1 atm) 1 0 % P d / C K 2 C 0 3 , H 2 0 MeOH OHC Scheme 91 316: 40% TPAP, N M O , 3 A mol. sieves, C H 2 C 1 2 (quantitative) 3A2 .3 .3 Attempts at Introduction of the Quaternary Centre via a Cyclopropvlmalonate. It was shown (vide supra) that aldehyde 193 may be prepared from diene 194 via a protocol involving cyclopropanation and hydrogenolysis as its key steps. However, the poor stereoselectivity of the cyclopropanation reaction resulted ultimately in loss of half of the material because of appreciable production of an unusable diastereomer. For this reason, a brief search for a more stereoselective method of cyclopropanation was embarked upon. It was felt that this goal would be acheivable i f a bulkier diazo compound was employed to carry out the cyclopropanation reaction. To that end, dimethyl diazomalonate (315) was prepared as described in Scheme 92. Chapter 3 U7 0 0 0 0 V NaN 3 , EtOH ^ V ^ C l • N 3 + NaCl acetone 317 318 318,Et„N M e O O G .COOMe M e O O a .COOMe ' 3 » y C H 3 C N N 2 319 320 Scheme 92 A modification of the procedure described by McElwee-White and Dougherty 1 0 6 was employed to prepare p-toluenesulfonyl (tosyl) azide (318) from tosyl chloride (317) and sodium azide. Reagent 318 was then employed in the triethylamine-promoted diazotization of dimethyl malonate (319), as described by Regi tz , 1 0 7 to cleanly furnish dimethyl diazomalonate, 320. 1. Rh 2 (OAc) 4 , D M E ^ 2. 320, D M E O M e O O C 321 Scheme 93 A solution of diene 194 and R l i2 ( O A c )4 in D M E was treated, dropwise over a period of three hours, with a solution of dimethyl diazomalonate, 320, in D M E (Scheme 93). After purification of the resulting crude material by flash chromatography, a single compound, cyclopropylmalonate 321, was obtained. ' H - N M R spectroscopy of this compound revealed the presence of two methyl groups as 3-proton singlets at 8 3.70 and 8 3.73. Furthermore, in a nOe difference experiment, simultaneous irradiation of the signals due to these two methyl groups promoted a weak nOe enhancement of the methyl singlet at 8 1.08, indicating that the cyclopropanation had occurred from the P-face of the exocylclic alkene function. Chapter 3 118 Figure 30: The two bond cleavages necessary to eventually prepare aldehyde 193 from 321. MeOOC. MeOOC 321 CHO 193 Starting with cyclopropyl malonate 321, there were two possible approaches to aldehyde 193, differing only in the order in which the reactions would be carried out (see Figure 30). In the first approach one of the ester functions would be removed via a decarbomethoxylation, such 108 as that described by Krapcho et al., and then the cyclopropane ring would be opened. In the second approach, the two sequences would be reversed. .COOMe T ^ T COOH C JX KCN, DMF r >>< \ ^ COOMe \ ^ COOH Scheme 94 While a number of authors 1 0 9 have reported that the decarbomethoxylation of cyclopropylmalonates is a feasible procedure, Krapcho et al?2 have divulged that the treatment of cyclopropylmalonate 322 with K C N in D M F (Scheme 94) results in the exclusive formation of the dicarboxylic acid, 323. With conflicting reports in the literature, it became somewhat more difficult to predict the outcome of the reaction and no choice remained but to actually attempt the decarbomethoxylation on malonate 321. Along with the Krapcho decarbomethoxylation reaction, two other reactions were also attempted with cyclopropylmalonate 321: a dissolving metal reduction and a hydrogenolysis. The results from these three reactions are summarized in Scheme 95, below. The Krapcho decarbomethoxylation of cyclopropyl malonate, 321 ( N a C N in wet D M S O ) did not furnish a product that displayed the expected ' H - N M R spectrum of the desired product. The major product displayed a single 3-proton singlet in the methyl ester region of the ' H - N M R spectrum, indicating that overall, decarbomethoxylation had occurred. However, the ester Chapter 3 119 function was attached to a methylene group (two a-protons), indicating that the cyclopropane ring had been opened. Moreover, two olefinic proton signals were displayed in the ! H - N M R spectrum of the product, the first corresponding to the endocyclic olefin in the six-membered ring, the second matching, in shape and in chemical shift, the analogous olefinic proton signal that had been observed in the spectrum of compound 257. Thus, the product resulting from the Krapcho decarbomethoxylation protocol was identified as ester 324. MeOOC. MeOOC NaCN, H 2 0 DMSO, 100 °C MeOOC H 1 / / H \ / 257 ^Ca, N H 3 THF, -78 °C H 2 , 10% Pd/C MeOH, 800 psi MeOOC. MeOOC Scheme 95 Dissolving metal reduction of compound 321 (Scheme 95), employing a method described by Ireland et al.uo also met with disappointment. The only product isolated from the reaction was malonate 325. The structure of compound 325 was identified based on the similarities between its X H - N M R spectrum and the spectrum of compound 311, the product of the dissolving metal reduction of cyclopropyl aldehyde 297 (Scheme 88),. Finally, attempts to effect hydrogenolysis of malonate 321 were also unsuccessful. Vigorously stirring a mixture of malonate 321 and 10% Pd on activated charcoal in M e O H , under a hydrogen atmosphere at ambient pressure, resulted in the complete recovery of starting Chapter 3 120 material. Upon stirring the mixture for two days, in a hydrogenator pressurized to 800 psi, a product was obtained that displayed a ' H - N M R spectrum that was almost identical with that of malonate 321, except that the olefin signal (from the double bond in the six-membered ring) was no longer present. A s illustrated in Scheme 95, this product was identified as cyclopropyl malonate 326. 3.4.2.4 Summary of the Attempts to Introduce the Final Quaternary Chirality Centre into the Tetracyclic Core of Mangicol F . In summary, four different approches were investigated to effect the preparation of aldehyde 193 from alcohol 252. Only two of these approaches actually furnished the desired aldehyde (193). Three of these approaches, however, demonstrated some applicability to the synthesis of mangicol F , and each displayed obvious advantages and disadvantages. In the nitrile anion alkylation approach (Section 3.4.2.2), methylated nitrile 273 is obtained from alcohol 252 in eight steps, and in 33% overall yield (see route A , Figure 31). Difficulties with the dehydration protocol caused the abandonment of this approach, with three steps remaining to obtain aldehyde 193. A second nitrile anion alkylation approach was attempted (route B) , in which the dehydration step was carried out prior to the installation of the nitrile functional group. In this case, alcohol 252 was converted into aldehyde 282 in 6 steps and in 15% overall yield. Unfortunately, only a small amount of aldehyde 193 was obtained upon homologation of aldehyde 282. Furthermore, the stereoselectivity of the key nitrile anion alkylation step had been reduced in comparison to that achieved in the previous approach. Chapter 3 121 Figure 31: Comparison of the three most fruitful approaches to aldehyde 193 from alcohol 252. CHO 193 Finally, alcohol 252 was converted into aldehyde 193 (route C) in five steps and in 15% overall yield via the cyclopropanation-cyclopropane hydrogenolysis route. In spite of the fact that the yield of usable material from the key cyclopropanation reaction was only 30%, this approach was determined to be the best of the three, as it is two steps shorter than the second nitrile anion alkylation approach, and it has a better overall yield. 3.4.3 Elaboration of the Sidechain-the Total Synthesis of Mangicol F . 3.4.3.1 Model Studies The goal of this brief study was to simulate the elaboration of the sidechain of mangicol F by constructing it onto a structurally simple substrate. Due to its commercial availability, 2-cyclohexylethanol (327) was chosen as a convenient precursor to the system desired for the model study. This substance was oxidized by the action of T P A P 8 2 and N M O (Scheme 96), Chapter 3 122 furnishing a useful quantity of 2-cyclohexylethanal (328). The objective of this study was to convert aldehyde 328 into the a,a'-dihydroxy ketone 329. TPAP, N M O »> "OH 3 A mol. sieves C H 2 C 1 2 H .OH ^O 327 328 OH 329 V ^ O H A OH 52 (mangicol F) Scheme 96 l-Bromo-2-methylpropene (330) has often been employed as the synthetic equivalent of the 2-methylpropene d 1-synthon (331). For this reason, and due to its commercial availability, reagent 330 was chosen as the precursor to the alkenyl Grignard reagent, 332.111 Thus, 1-bromo-2-methylpropene was converted into 332 by reaction with magnesium turnings in the presence of a catalytic amount of iodine (Scheme 97). Reaction of this intermediate with aldehyde 328 furnished a mixture of compounds, from which was isolated, in 35% yield, the desired alcohol, 333. Br Mg, cat. I 2 * THF, reflux MgBr 328, THF^ -78 °C 330 332 333 : 35% 3 3 1 Scheme 97 Although the primary objective of this model study was simply to demonstrate that a,ct'-dihydroxy ketone 329 could be prepared, optimization of the steps such that reasonable yields Chapter 3 123 would be obtained was also required. Thus, other methods of generating alkenyl anions from bromide 330 were investigated. The results derived from this investigation are summarized in Table 15. Table 15: Results from the addition of alkenyl anion 334 to aldehyde 328. Br conditions M 1.328, THF, -78 °C 2 . H 2 0 ' 330 334 Entry Conditions Results (Yield of 333)a 1 M g turnings, cat. I2, T H F , reflux 35% 2 1. M g turnings, cat. I2, T H F , reflux 2. C e C l 3 , T H F , -78 °C 55% 3 r -BuLi , T H F , -78 °C 55% 4 1. f -BuLi , T H F , -78 °C 2. C e C l 3 , T H F , -78 °C b Isolated yields. Complex mixture of products obtained, with none of 333 observed. A s demonstrated by the results in Table 15, the cerium(III) chloride-mediated Grignard addition and the addition of the alkenyl lithium reagent (334, M = L i ) 1 1 2 to aldehyde 328 both proceeded in identical yields. These reactions were found to be more efficient than that using the Grignard reagent, 332. When the organocerium variant of 334 ( M = C e C k ) was prepared via the corresponding organolithium species, 1 1 3 a complex mixture of products was obtained upon the addition of aldehyde 328 to the reaction mixture. As such, it was decided that the most appropriate method for the preparation of 333 was via the use of the alkenyllithium reagent. Since the following steps were to be oxidative in nature, a s i lyl group was chosen to protect the secondary hydroxyl function. The protected oc-hydroxy ketone that would be obtained after the following few steps could then be deprotected with fluoride under neutral conditions. The treatment of allylic alcohol 333 with TBSC1 in the presence of D M A P and E t 3 N furnished the T B S ether 335 in excellent yield (Scheme 98). Chapter 3 124 333 TBSC1, E t 3 N , D M A P D M F 88% Scheme 98 O T B S 335 The subsequent steps in the preparation of the desired a,a'-dihydroxy ketone would involve the oxidation of the olefinic function in compound 335. O f interest in this matter was an article published by Paquette et a / . 1 1 4 dealing with the total synthesis of (+)-taxusin. In this work, conversion of substance 336 into ketone 338 was carried out via two steps, as shown in Scheme 99. In the first step, dihydroxylation of 336 provided compound 337. This substance was further oxidized with T P A P and N M O , to supply a-hydroxy ketone 338. TBSO s Os0 4 , pyr.; NaHSC-3 73% T B S O v O M O M 337 O M O M TPAP, N M O C H 2 C 1 2 86% T B S O ' O M O M Scheme 99 Since the procedure described by Paquette et al. (shown in Scheme 99) required the use of stoichiometric O s 0 4 in the first step, two alternative approaches to this reaction were employed (Scheme 100) for the dihydroxylation of 335. In the first, a catalytic amount of O s 0 4 was used in the presence of a co-oxidant, trimethylamine-N-oxide dihydrate, as described by Chapter 3 125 P o l i . 1 1 5 In this case, two products were isolated after chromatography: the dihydroxylated material, 339, as a mixture of diastereomers, and the over-oxidized material, ketone 340. 1 H -N M R spectral identification of compounds 339 and 340 was made based on the upfield shift of the methyl singlets from 81.8 (for compound 335) to between 81.2 and 81.4 and on the presence of the appropriate number of "carbinol" protons. Over-oxidation is a common side-reaction in homogeneous dihydroxylations" 6 (i.e. when the co-oxidant is in the same solution phase as the osmium tetroxide). OTBS Os0 4 , Me 3 NO«2H 2 0 C H 2 C 1 2 * 335 OH 339 : 52% 340: 41% K 2 0 s 0 4 , K 3 Fe(CN) 6 , K 2 C 0 3 , M e S 0 2 N H 2 , f-BuOH, H 2 0 OTBS H X TPAP, N M O , C H 2 C 1 2 OH 3 3 9 : 5 5 % Scheme 100 In the second approach (Scheme 100), dihydroxylation of compound 335 with the dihydrate of potassium osmate, in the presence of a co-oxidant, potassium ferricyanide, as described by Sharpless et al.,ni was attempted. Under the biphasic ( f - B u O H - H 2 0 ) conditions illustrated in Scheme 100, TBS-protected allylic alcohol 335 was dihydroxylated, furnishing, after chromatography, a diastereomeric mixture of alcohols (339) in 55% yield. In this case, 36% of the starting material was recovered from the reaction mixture. At this stage, the oxidation of compound 339 was attempted. A s shown in Scheme 100, treatment of the diastereomeric mixture of alcohols 339 with T P A P and N M O 8 2 did not produce Chapter 3 126 compound 340. Instead, a complex mixture of products was obtained from the reaction mixture, as observed by T L C analyses. It has been reported 1 1 8 that treatment of alkenes with KMnC>4 and acetic acid in wet acetone furnishes cc-hydroxy ketones. Selectivity in this reaction can be obtained when, as in compound 335 (Scheme 101), one of the two olefinic carbons bears two substituents. It seemed reasonable that compound 335 could be converted directly into compound 340 under these conditions. In the event, treatment of TBS-protected allylic alcohol 335 with K M n C u and acetic acid in wet acetone resulted in the exclusive formation of compound 340, in 46% yield (Scheme 101). Starting material (34%) was also recovered from the reaction mixture. In order to complete this comparative study, compound 340 was treated with T B A F in T H F , supplying a,a '-dihydroxy ketone 329 in 85% yield. The ! H - N M R spectrum revealed that the proton signals for the side chain region of compound 329 were a reasonable match with those reported for the analogous protons in mangicol F . 5 0 335 340 329 Scheme 101 A report by Katzenellenbogen et a / . 1 1 9 described the chemoselective dihydroxylation of the cyclopentenoid double bond in tetracyclic enone 341 with K M n C u (Scheme 102), thus demonstrating that acetyl functions were also stable in the presence of KM11O4. O f particular interest in this report, however, was the hydrolysis of the acetate function in the product, 342. In this case, the acetate group was hydrolyzed with K2CO3 in wet T H F - M e O H , with no adverse effect on the formed oc-hydroxy ketone moiety in compound 343. For this reason, it was presumed that a similar sequence of reactions could be carried out on the model system employed in this work. Chapter 3 127 QAc Q OR K M n 0 4 acetone-water 85% O m H 2 0 , 84% K 2 C 0 3 , THF, M e O H f - 3 4 2 : R _ A c 2 JJ. .... L *-343 :R = H Scheme 102 A s illustrated in Scheme 103, allylic alcohol 333 was converted to its acetate by reaction with acetic anhydride and triethylamine in the presence of D M A P . Subjection of the acquired allylic acetate, 344, to the action of K M n 0 4 and acetic acid in wet acetone furnished the highly oxygenated material 345 in a meagre yield of 35%. Since the reaction had appeared to be complete by T L C analysis, it was presumed that some of the acetate function had been hydrolyzed during work-up or chromatography. Hydrolysis of the acetate function with K2CO3 in wet T H F - M e O H cleanly furnished compound 329. The ' H - N M R spectra of compounds 344 and 345 were very similar to those of compounds 335 and 340, respectively, with the acetyl C H 3 (8 2.1) taking the place of the TBS-signals. A c 2 0 , E t 3 N, D M A P T H F - M e O H - H 2 0 81% OAc K M n 0 4 , HOAc acetone-water 35% 344 OAc K 2 C 0 3 , H 2 0 THF-MeOH 100% Scheme 103 Chapter 3 128 3.4.3.2 Application of the Model Work to the Total Synthesis of Mangicol F and \l-epi-Mangicol F . The model work described in the previous section demonstrated the possibility of elaborating the sidechain portion of mangicol F from an aldehyde via two different approaches. Based on the simplicity of the reactions involved in the model studies, it was reasonable to assume that these methods could be applied to the synthesis of mangicol F . The only difference between the model system and the actual system is that, in the latter case, addition of the alkenyl lithium species to the aldehyde would furnish two diastereomers. It was hoped that these two diastereomers would be separable, as they would then lead to the formation of mangicol F and its C-17 epimer (see Figure 32). In the original report describing the isolation and characterization of the mangicols, 5 0 no stereochemical assignment was given to C-17 in mangicol F . The synthesis of mangicol F and its C-17 diastereomer would hopefully lead to the identification of the relative configuration at C-17. Figure 32: The proposed preparation of mangicol F and its C-17 epimer from aldehyde 193. O OH 52 : mangicol F and its C-17 epimer O f the successful reactions carried out in the model studies, only one posed any particular problems: the initial addition of the alkenyllithium reagent to the aldehyde (55% yield). Piers and 120 Oballa have reported that the use of the corresponding alkenyl iodide as the starting material in the addition of the same alkenyllithium species to ketones is much more efficient than when the reaction is carried out starting with the alkenyl bromide (330). The preparation of l-iodo-2-Chapter 3 129 methylpropene (346) from commercially available l-bromo-2-methylpropene (330) has been described by Inokawa et a/ . , 1 2 1 and is illustrated in Scheme 104. KI, N iBr 2 , Zn Br 330 D M F - H M P A 60 °C 93% Scheme 104 346 Alkenyl iodide 346 was converted into its corresponding alkenyllithium reagent (347) by its reaction with 2 equivalents of ?-BuLi in diethyl ether (see Scheme 105). Addition of an ethereal solution of aldehyde 193 to the reaction mixture resulted in the complete consumption of the aldehyde, as observed by T L C monitoring of the reaction mixture. Two new compounds, displaying similar polarity by T L C were observed. After a chromatographic separation (three columns were required to completely separate the two materials), the two products of the addition were identified as the desired alcohols, 348 and 349. r-BuLi (2 equiv.) E t 2 0 , -78 °C 346 347, E t 2 0 , -78 °C CHO 193 348 : 41% Scheme 105 349 : 33% The IR spectrum of each of the two compounds displayed an intense broad band above 3300 cm' 1 . Further, the ' H - N M R spectrum of each of the two compounds distinctly displayed the newly appended allylic alcohol moieties. The alkenyl proton gave rise to a signal located near 6 5.3. The allylic carbinol proton was represented by a distinct multiplet near 8 4.5. Finally, the two new allylic methyl groups appeared as broad singlets near 81.7. Each of these identifiable Chapter 3 130 signals bore good correlation to the analogous signals observed in the H - N M R spectrum of the model compound, 333. The relative configurations of the hydroxyl-bearing carbons in compounds 348 and 349 were not determined at this stage. However, in the following steps, X-ray crystallographical data were obtained pertaining to one of the derivatives of alcohol 348, unequivocally establishing the relative configuration of C-18. Based on these data, the relative configuration of both alcohols 348 and 349, as well as the relative configurations of all subsequent intermediates could be assigned. Initially, experiments began with the T B S ether of 348, which was chosen arbitrarily out of the two diastereomers (348 and 349). Unfortunately, this approach was halted due to the lack of reactivity of the substrate in the permanganate oxidation step. Therefore, all further experiments were carried out on the acetate derivatives of alcohols 348 and 349. A s illustrated in Scheme 106, treatment of allylic alcohol 348 with acetic anhydride and triethylamine in the presence of D M A P afforded acetate 350 in 81% yield. Gratifyingly, ester 350 was isolated as a solid and could be recrystallized from heptane. The O R T E P diagram of this material, generated from data obtained by X-ray crystallography and depicted in Figure 33, represents the crystal structure of ester 350. While all other stereochemical issues in the synthesis to date had been resolved, they are well summarized in this O R T E P diagram. Most importantly, though, was that the configurational assignment with respect to C-18 could now be made. A c 2 0 , E t 3 N , D M A P Scheme 106 D M F 81% Chapter 3 131 Figure 33: O R T E P diagram representing the crystal structure of ester 350. C24 C9 A o C13 C25 C14 A s can be seen from Figure 33, the configuration at C-18 in ester 350, for the enantiomer drawn, is S. The results from these crystallographic data also show, in hindsight, that the configurations of the hydroxyl-bearing carbons in compounds 348 and 349 (Scheme 105) are as shown. None of the subsequent reactions in the synthesis are expected to invert the configuration With the expectation of completing the total synthesis of mangicol F or of its C-17 epimer, ester 350 was subjected to the ketohydroxylation-deprotection sequence that was developed for the model system and described in the previous section. Thus, stirring a mixture of acetate 350, K M n 0 4 and acetic acid in wet acetone for 18 h furnished ketone 351 in 52% yield (Scheme 107). Even after this length of reaction time, 42% of the starting material was recovered. Finally, quantitative hydrolysis of the acetate function of compound 351 was achieved by reaction of this substance with potassium carbonate in a T r T F - M e O H - F b O solvent system. This procedure produced a,cc'-dihydroxy ketone, 352. at C-18. Chapter 3 132 AcO K M n 0 4 , HOAc • acetone-water 52% A c 0 , 350 K 2 C 0 3 , H 2 0 T H F - M e O H 100% / O H / \ OH 329 Scheme 107 Comparison of the ' H - N M R and 1 3 C - N M R spectral data of compound 352 with those of reported for mangicol F (52) by Fenical et al.50 revealed that, while very similar, the two compounds were not identical. Therefore, compound 352 was tentatively identified as ll-epi-mangicol F . 1 2 2 From the final three steps in the preparation of 17-epr-mangicol F (352) it can be seen that the reactions studied in the model work translate well to a system that is very close in structure to that of mangicol F . The same three reactions were carried, out again, this time starting with alcohol 349 (Scheme 108). Treatment of compound 349 with acetic anhydride furnished the required acetate 353 in 84% yield. Subjection of 353 to the ketohydroxylation conditions devised for compound 350 afforded acetate 354 in 57% yield, while leaving 34% of the starting material intact. Finally, hydrolysis of the acetate function by treatment of 354 with potassium carbonate in wet T H F — M e O H quantitatively supplied the a,a'-dihydroxyketone. Comparison (Table 16 and Table 17, vide infra) of the ! H - N M R and 1 3 C - N M R spectra of the latter material with those Chapter 3 133 reported for the originally isolated mangicol F (52) 5 0 showed that these two materials were identical. The synthetic material, however, was obtained as a racemate. 349 A c 2 0 , E t 3 N D M A P , D M F 84% A c Ov \ = 353 \ 1 - 1 / HO*' 52 : mangicol F K M n 0 4 , HO Ac acetone-water 57% K 2 C 0 3 , H 2 0 T H F - M e O H 100% AcO Scheme 108 Chapter 3 134 Table 16: Comparison of the ' H - N M R spectral data of synthetically prepared (±)-mangicol F (52) with those reported 5 0 for natural mangicol F . 52: mangicol F Assignment3 Reported Datab for Mangicol F 5 0 Data for Synthetic (±)-Mangicol F b 1 1.47 (m) 1.37-1.57 (Part of the 7 H m) 2 1.70 (ddd, 7=9 .5 , 7.6, 2.6 Hz) 1.69 (ddd, 7 = 9.4, 7.1, 2.4 Hz) 3a 1.87 (dddd, 7 = 12.6, 8.6, 8.6, 7.2 Hz) 1.73-20.8 (Part of the 6 H m) 3b 1.54 (m) 1.37-1.57 (Part of the 7 H m) 4a 1.99 (dddd, 7 = 12.6, 8.4, 8.4, 4.2 Hz) 1.73-20.8 (Part of the 6 H m) 4b 1.45 (m) 1.37-1.57 (Part of the 7 H m) 5 1.79 (dq, 7 =7.5, 2.3 Hz) 1.73-20.8 (Part of the 6 H m) 7a 1.74 (m) 1.73-20.8 (Part of the 6 H m) 7b 1.23 (m) 1.15-1.28 (Part of the 2 H m) 8a 1.84 (m) 1.73-20.8 (Part of the 6 H m) 8b 1.22 (m) 1.15-1.28 (Part of the 2 H m) 9 2.51 (m) 2.46-2.55 (m) 11 5.44 (d, 7 = 1.6 Hz) 5.44 (d ,7= 1.7 Hz) 13a 1.51 (m) 1.37-1.57 (Part of the 7 H m) 13b 1.42 (m) 1.37-1.57 (Part of the 7 H m) 14a 2.01 (m) 1.73-20.8 (Part of the 6 H m) 14b 1.43 (m) 1.37-1.57 (Part of the 7 H m) 16a 2.11 (d ,7= 14.0 Hz) 2.12 (dd, 7 = 14.1, 1.7 Hz) 16b 1.49 (m) 1.37-1.57 (Part of the 7 H m) 17a 4.88 (ddd,7 = 9.0, 7.5, 1.5 Hz) 4.88 (ddd, 7 = 9.1, 7.6, 1.7 Hz) 17b 3.81 (d, 7 = 7.5 H z , OH) 3.82 (d, 7 =7.6 H z , OH) 19 4.63 (s, OH) 4.67 (s, O H ) 20 1.38 (s) 1.38 (s) 21 1.34 (s) 1.34 (s) 22 1.04 (s) 1.04 (s) 23 0.85 (d ,7= 7.4 Hz) 0.85 (d, 7 =7.3 Hz) 24 1.09 (d, 7 = 7.2 Hz) 1.09 (d, 7 = 7.1 Hz) 25 1.13 (s) 1.13 (s) aAssignments made by the authors of the isolation report. Both samples were recorded at similar concentrations in acetone-d6 (referenced to 5 2.05). The 'H-NMR spectrum of natural mangicol F was recorded at 600 MHz, while the 'H-NMR spectrum of synthetic (±)-mangicol F was recorded at 400 MHz. Chapter 3 135 Table 17: Comparison of the C - N M R spectra of synthetically prepared mangicol F (52) and the authentic sample. 52 : mangicol F Assignment3 Reported Datab for Mangicol F 5 0 Data for Synthetic (±)-Mangicol F b 1 58.0 57.7 2 47.8 47.6 3 33.0 32.8 4 33.5 33.3 5 42.5 42.3 6 57.5 57.3 7 45.0 44.8 8 31.9 31.8 9 38.4 38.2 10 145.2 145.2 11 131.3 131.1 12 45.6 45.4 13 40.3 40.1 14 38.8 38.7 15 46.9 46.8 16 49.6 49.5 17 73.1 73.0 18 217.7 217.7 19 77.6 77.6 20 28.2 28.1 21 28.6 28.5 22 24.8 24.6 23 22.5 22.3 24 22.0 21.9 25 30.6 30.4 "Assignments made by the authors of the isolation report. Both samples were recorded at similar concentrations in acetone-d6 (referenced to 5 29.9). The 1 3C-NMR spectra of natural mangicol F and of synthetic (±)-mangicol F were recorded at 100 MHz. Chapter 3 136 3.4.4 Summary of the Total Synthesis of Mangicol F . The total synthesis of mangicol F began with a product from the methodology project described in Section 2.2. The key feature to this methodology that defined its ultimate use in the synthesis was its ability to rapidly generate more than 30 g of bicyclic dienone 164 in high yield. Schemes 109a and 109b illustrate the summary of the total synthesis of mangicol F at the end of this section (see pages 139 and 140). A chemo- and stereoselective hydrogenation with Lindlar 's catalyst of dienone 164 afforded bicyclic enone 198 in 96% yield. Enone 198 was an appropriate partner for the four-carbon bifunctional reagent 17 in a Piers' laboratory developed annulation sequence. Thus, treatment of enone 198 with cyanocuprate 17 furnished as-fused bicyclic ketone 209 in 83% yield. Iododegermylation followed by an intramolecular P d catalyzed coupling between the alkenyl iodide and the enolate of the ketone of the resulting iodide 211 cleanly completes the annulation sequence, generating tricyclic enone 212. Installation of the final ring in the core of mangicol F was effected by employment of a second annulation sequence previously developed in the Piers laboratory. In preparation for this annulation sequence, a reduction-oxidation protocol was applied to enone 212. Stereoselective catalytic hydrogenation followed by the IBX-promoted oxidation of the resulting ketone furnished enone 239. Treatment of enone 239 with bifunctional organocopper reagent 249 afforded ketone 240 in 93% yield. Completion of the annulation sequence was accomplished by the reaction of the ketone 240 with f -BuOK in f -BuOH. Prior to the establishment of the single oxygenated sidechain of mangicol F , two remaining issues with the core required resolution: the installation of the methyl substituent on C-10 and the reduction of the carbonyl group into an endocyclic olefin. Installation of the methyl group was effected by the high-yielding (98%) alkylation of the enolate of ketone 235 (generated by the reaction of 235 with K D A ) . Stereoselective reduction of ketone 236 with D I B A L H Chapter 3 137 provided, in 94% yield, alcohol 252, which, upon heating with l,l '-thiocarbonyldiimidazole (258), efficiently afforded diene 194. In preparation for the elaboration of the sidechain, the final quaternary centre in the core needed to be established. This was accomplished via a cyclopropanation reaction followed by a cyclopropane ring opening. Thus, the rhodium(II) catalyzed cyclopropanation of diene 194 was effected with ethyl diazoacetate, affording a-cyclopropyl ester 291 in approximately 30% yield, the first of only two reactions in this synthesis with an actual, isolated yield under 75%. Reduction of the ester function with D I B A L H followed by oxidation of the resulting alcohol with T P A P and N M O furnished a-cyclopropyl aldehyde 297 in 80% yield over the two steps. Palladium-promoted hydrogenolysis of the cyclopropane ring supplied a mixture of aldehyde 193 and alcohol 316 in 91% combined yield. Alcohol 316 was quantitatively converted into aldehyde 193 by the action of T P A P and N M O . Elaboration of the sidechain of mangicol F was effected in four steps, including a protection-deprotection sequence. Thus, the reaction of aldehyde 193 with alkenyllithium species (347), generated by the reaction of l-iodo-2-methylpropene with two equivalents of t-B u L i , afforded the diastereomeric mixture of alcohols 348 and 349. A l l y l i c alcohol 349 was acetylated and then ketohydroxylated by the action of K M n 0 4 , furnishing compound 354 in 48% yield (for the two steps). Finally, quantitative base-promoted hydrolysis of the acetate protecting group completed the total synthesis of mangicol F , 52. Incidentally, allylic alcohol 348 was transformed, by the same three synthetic steps, into 17-epz-mangicol F , with a similar overall yield. In the manner described above, racemic mangicol F was synthesized from vinylogous ester 9 in 21 steps, and in 0.94% overall yield. The key highlights to this total synthesis include the use of three different bifunctional reagents in separate annulation sequences to rapidly and highly stereoselectively prepare the tetracyclic core of the natural product and the use of a Chapter 3 138 cyclopropanation-cyclopropane ring opening protocol to establish the final quaternary chirality centre within the core. Furthermore, this approach to the synthesis permitted the preparation of mangicol F and its C-17 epimer. X-ray crystallographic data obtained at a late stage in the synthesis allowed for the unambiguous assignment of the configuration at the carbinol carbon, a feature of the natural product that had not been determined in the original characterization, due to lack of material. Chapter 3 139 2 f-BuLi THF 89% H 2 , Lindlar's cat MeOH 96% GeMe 3 198 C u - S M e 2 249 BF 3 -OEt 2 THF 93% 240 1. H 2 , 10% Pd/C MeOH, 100% « • — — - — — — — • — 2. IBX, toluene DMSO, 84% 239 ?-BuOK ?-BuOH 93% 212 1. Pd(PPh 3) 4 > THF 2. NaOMe/ MeOH 89% H > I 2 , CH 2C1 21 209 : R = GeMe 3 & L ^ 2 1 1 : R = I 1. D I B A L H , E t 2 0 94% 235 N^NXN^>N \=i \=J 258 236 Rh 2 (OAc) 4 ^ HC(N 2 )COOEt x D M E , 30%^ 2. 258, o-xylene 77% CHO 297 1. D I B A L H , E t 2 0 2. TPAP, N M O C H 2 C 1 2 80% (2 steps) H COOEt 291 Scheme 109a Chapter 3 140 Scheme 109b 141 4. Experimental 4.1 General. 4.1.1 Data Acquisition, Presentation and Experimental Techniques. Melt ing points were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures refer to the air-bath temperatures of Kugelrohr (bulb-to bulb) distillations. Unless otherwise noted (i.e. due to high volatility of certain compounds) all products were submitted to a pressure of 0.1-0.3 Torr (vacuum pump) for at least 0.5 h prior to weighing for yield determination, in order to remove traces of solvent from chromatography and/or moisture from the samples. Infrared (IR) spectra were recorded by employing one of two techniques of sample preparation. In the case of liquid samples, the dried materials were analyzed as thin films between two N a C l plates. When the samples were solid, the spectra were recorded as potassium bromide pellets. Without exception, all spectra were recorded employing a Perkin-Elmer 1710 FT-IR with internal calibration. Proton nuclear magnetic resonance ( ' H - N M R ) spectra were recorded on Bruker models WH-400 (400 M H z ) , A V - 4 0 0 (400 M H z ) and A V - 3 0 0 (300 M H z ) spectrometers. The samples were prepared by dissolution into deuteriochloroform (CDCI3) or acetone-d6 (C3D6O), as indicated. Deuteriochloroform was stored over flame-activated 3 A molecular sieves, and was filtered through oven-dried basic alumina prior to use. Signal positions (8 values) are given in parts per mil l ion (ppm) from tetramethylsilane (8 0.0) and were measured relative to the signals for chloroform (8 7.24) or acetone (8 2.05). Coupling constants (7 values) are reported in Hertz (Hz). In more complex cases, coupling constants were assigned in accordance with the methods outlined by Hoye, et al.123 The spectral data are presented in the following format: chemical shift (ppm), multiplicity, number of protons, coupling constants, and assignments (when known). The Chapter 4 142 abbreviations employed for multiplicity are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Carbon nuclear magnetic resonance ( 1 3 C - N M R ) spectra and the attached proton test experiments (APT) were recorded on Bruker models A V - 3 0 0 (75 M H z ) or A V - 4 0 0 (100 M H z ) spectrometers. The solvents employed in the sample preparation were deuteriochloroform, deuteriobenzene or deuterioacetone, as indicated. Chemical shifts are reported in ppm from tetramethylsilane (5 0.0), and were measured relative to the signals for chloroform (8 77.0) or acetone (8 29.9). Where indicated, the D E P T experiments were used to differentiate the methyl and methine signals (negative phase) from methylene and quaternary carbon signals (positive phase). The spectral data are presented as follows: chemical shift (ppm), D E P T assignment (+ve or -ve). In some cases, structural assigments (proton and/or carbon) were supported by homonuclear correlation spectroscopy ( C O S Y ) experiments, lD-nOe (nuclear Overhauser enhancement) difference experiments, ( ! H , 1 3 C ) heteronuclear multiple quantum coherence ( H M Q C ) experiments and by heteronuclear multiple bond correlation ( H M B C ) experiments, which were carried out on Bruker models A V - 3 0 0 and A V - 4 0 0 spectrometers. L o w - and high-resolution electron ionization (EI) mass spectra were recorded on a Kratos M S 50 mass spectrometer. Desorption chemical ionization (DCI) mass spectra were recorded on a Kratos M S 80 or on a Kratos Concept II H Q mass spectrometer. Electrospray ionization (ESI) mass spectra were recorded on a Micromass L C T mass spectrometer. A l l mass spectrometry experiments were carried out by the U B C Mass Spectrometry Centre. For some compounds (particularly those containing R.3Ge or R^Si moities), the high resolution mass spectrometry mass determinations were made based on the ( M - R ) + peak. A l l samples submitted for H R M S were found to be homogeneous by G C - M S , G C and/or T L C analysis. Chapter 4 143 The progress of most reactions was monitored by T L C analysis of aliquots extracted directly from the reaction mixtures. These analyses were carried out on commercially available, aluminum-backed silica gel 60 F254 plates (E. Merck, type 5554, thickness 0.2 mm). Initial visualization (when possible) was accomplished by using U V light (254 nm). Further visualization was then carried out by heating the T L C plates after staining with one or more of the following stains: (1) ammonium molybdate (5% w/v) and cerium(IV) sulfate (0.1% w/v) in 10% aqueous sulfuric acid, (2) vanillin (6% w/v) in a 9:1 mixture of EtOH-4% (v/v) aqueous sulfuric acid, (3) K M n 0 4 (1.5% w/v) and K 2 C 0 3 (6.5% w/v) in 0.1% aqueous NaOH. Flash chromatography was performed with 230-400 mesh silica gel purchased from Silicycle, using the technique descibed by Still et al.nA Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been thoroughly flame dried. The Teflon® cannulae and stainless steel needles employed for the handling of anhydrous solvents and reagents were oven-dried for at least 12 h, cooled in a desiccator and flushed with dry argon prior to use. Plastic syringes used for the handling of anhydrous solvents and reagents were flushed with dry argon prior to use. The accurate handling of small quantities of solvents and liquid reagents was performed using a set of Hamilton Gastight® (10-1000 uL) syringes which were vacuum-dried (0.1-0.3 Torr) for one hour, stored in a desiccator and flushed with dry argon prior to use. Unless otherwise noted, removal of solvent or concentration under reduced pressure refers to solvent removal by rotary evaporator employing a water aspirator (-25 Torr) and a 40-50 °C water bath. Cold temperatures were maintained by using one of the following baths: 0 °C, ice/water; -20 to -30 °C, dry ice/aqueous CaCl; -45 °C, dry ice/acetonitrile; -78 °C, dry ice/acetone; -98 °C, liquid N2/toluene. Chapter 4 144 4.1.2 Reagents and Solvents. Argon gas, purchased from Praxair, used for reactions carried out in an inert atmosphere, was dried by bubbling it through concentrated sulfuric acid followed by passing through a drying tube filled with Drierite® and potassium hydroxide pellets. A l l of the following solvents were distilled under an atmosphere of dry argon. T H F and diethyl ether were distilled from sodium benzophenone ketyl. Acetonitrile, benzene, dichloromethane, ethylene glycol dimethyl ether ( D M E ) and methanol (when distilled) were distilled from calcium hydride. The following reagents and solvents were distilled from calcium hydride under an atmosphere of dry argon: boron trifluoride-diethyl etherate (BF3-OEt2), carbon disulfide, N,N-diethylamine, A^^-diisopropylamine, A^W-dimethylpropylene urea ( D M P U ) , hexamethylphosphoric triamide ( H M P A ) , and triethylamine. A^,A^-Dimethylformamide ( D M F ) was dried, by allowing it to stand for three sequential 24 hour periods over freshly flame-activated 3 A molecular sieves. When not used immediately, the above-mentioned reagents and o solvents were stored over flame-activated 3 A molecular sieves, under an atmosphere of dry argon, in sealed Aldr ich Sure-Seal® amber bottles. Chlorotrimethylsilane ( T M S C l ) and chlorotriethylsilane (TESC1) were distilled from calcium hydride under an atmosphere of dry argon, and were used immediately upon distillation. Solutions of methyllithium (1.3 M in diethyl ether, Acros Organics), butyllithium (1.6 M in hexanes, Acros Organics), ^-butyllithium (1.7 M in pentane, Aldr ich Chemical Co.) were standardized by titration against diphenylacetic a c i d 1 2 5 (MeLi) or Af-benzylbenzamide 1 2 6 (BuLi , f-BuLi) in T H F . Diisobutylaluminum hydride ( D I B A L H ) was purchased from Acros Organics as a solution (1.0 M ) in hexanes and was used without standardization. Chapter 4 145 Iodomethane and deuteriochloroform were filtered through a short column of oven-dried (-140 °C, for at least 12 h) basic alumina (Brockman activity 1) which had been cooled in a desiccator prior to filtration, prior to use. Potassium hydride was obtained as a 35% suspension in mineral o i l and sodium hydride was purchased as a 60% suspension in mineral oi l . Both reagents were acquired from the Aldrich Chemical Co . When indicated, the mineral oi l was removed from these suspensions by three sequential washings (followed by decantation of the solvent) with H P L C grade pentane under a flowing atmosphere of dry argon. Li thium diisopropylamide ( L D A ) was prepared by adding a solution of butyllithium (1.6 M in hexanes, 1 equivalent) to a solution of dry diisopropylamine (1.1 equivalents) in dry T H F at -78 °C, and then allowing the pale yellow mixture to stir for 10 min. A l l other reagents and solvents were commercially available and were used without further purification. Petroleum (pet.) ether refers to light pet. ether, a hydrocarbon mixture with a boiling point range of -30 -60 °C. Chapter 4 146 4.2 Lithium-Iodine Exchange Initiated Intramolecular Addition Reactions. 4.2.1 Lithium-Iodine Exchange Initiated Intramolecular Conjugate Addit ion Reactions-General Procedure 1: Hydriodination of Acetylenic Esters. 2 5 Nal, HO Ac j R - ^ C 0 0 R UO°C ' R , / A C 0 0 R * A stirred solution of the acetylenic ester (1 equiv.), N a l (1.5 equiv.) in acetic acid (~6 equiv.) was heated to 110 °C for 1-1.5 h. The warm reaction mixture was poured into water ( -3-4 times the volume of acetic acid). The oily brown residue was extracted three into E t 2 0 (three x one quarter of the volume of water). The ethereal extracts were washed portionwise with a saturated aqueous solution of N a H C 0 3 until such time as the further addition of the N a H C 0 3 solution failed to produce effervescence. The ethereal solution was washed (brine, 1 x the volume of ether), dried (MgS04) and concentrated under reduced pressure. The residual brown oil was purified by flash chromatography. General Procedure 2: D I B A L H Reduction of a.p-Unsaturated Esters to their Corresponding A l l y l i c Alcohols. { 1. D I B A L H , Et 2 O,0°C COOR 2 R i / ^ / ° ^ n 2. N H 3 - N H 4 C I , H 2 0 To a cold (0 °C) stirred solution of the cc,P-unsaturated ester (1 equiv.) in dry E t 2 0 (-10 m L per mmol of cc,p-unsaturated ester) was added, via a syringe, a solution of D I B A L H in hexanes (1.0 M , 2.5-3 equiv.). The reaction mixture was stirred for 0.5-1 h, then was treated with an aqueous solution of N H 3 - N H 4 C I (pH - 8 , 250 u L per mmol of D I B A L H ) and allowed to warm to room temperature. After 1 h, anhyd. M g S 0 4 (-1 g per 5 mmol of D I B A L H ) was added to the milky white mixture. The mixture was stirred for an additional hour, then was filtered Chapter 4 147 through a pad of Celite®. The remaining solid material was washed with Et20 (3 x the volume of the solvent in the reaction mixture). The combined filtrate and washes were concentrated under reduced pressure and the residual oi l was purified by flash chromatography. General Procedure 3: Conversion of A l l y l i c Alcohols into their Corresponding A l l y l i c Pri3P»Br2 was prepared by the dropwise addition of bromine (1.5 equiv.) to a cold (0 °C) stirred solution of Ph3P (1.5 equiv.) and imidazole (3 equiv.) in dry CH2CI2 (-10 m L per mmol of allylic alcohol). The resultant mixture was stirred for 30 min. To the mixture was added, via a cannula, a solution of the allylic alcohol (1 equiv.) in dry CH2CI2 (-1 m L per mmol of allylic alcohol). After 30 min, Florisil® (-2 g per 5 mmol of the allylic alcohol) was added to the reaction mixture followed by pentane (volume equal to that of the reaction mixture). The resultant mixture was concentrated under reduced pressure (rotary evaporator bath set at room temperature). The residual material was suspended in pentane (2 x the volume of the reaction mixture) and was stirred vigorously. The mixture was concentrated under reduced pressure, as before, and the residual material was once again suspended in pentane (2 x the volume of the reaction mixture). The mixture was filtered through a pad of Celite® on top of a pad of silica gel (-10-20 g each per mmol of allylic alcohol). The remaining solid material was washed with pentane (-10 x the volume of the reaction mixture). The combined filtrate and washes were concentrated under reduced pressure. In general, the allylic bromides were used immediately, and without purification, in alkylation reactions, but for characterization purposes, some were purifiable by column chromatography. Bromides. 26 Chapter 4 148 Preparation of Ethyl (Z)-3-Iodobut-2-enoate (66). C O O E t N a l , H O A c 65 110°C • 5 ^ / C O O E t 66 Following General Procedure 1, commercially available ethyl but-2-ynoate (65) was converted into compound 66 with the following quantities of reagents and solvents: ester 65 (50 g, 450 mmol), N a l (101 g, 675 mmol), acetic acid (160 mL, 2700 mmol). ^ - N M R spectroscopy of the residual brown oi l displayed no signals that did not match those reported by Piers and W o n g , 2 5 and was thus, not purified due to the large scale upon which this reaction was being carried out. Preparation of (Z)-3-Iodobut-2-en-l-ol (67). In a 5 L round bottom flask fitted with a mechanical stirrer, and following General Procedure 2, ester 66 was converted into allylic alcohol 67 with the following quantities of reagents and solvents: ester 66 (crude, 107 g, -450 mmol), D I B A L H (1.0 M solution in Et20, 900 mmol), CH2CI2 (used for large scale, 2 L ) . Flash chromatography (200 g of silica gel, 4:1 - » 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 69 g (77%, 2 steps) of the title compound, a colorless o i l . ' H - N M R data matched those previously reported. 2 0 1 5 66 67 Chapter 4 149 Preparation of (Z)-4-Bromo-2-iodobut-2-ene (68). OH Ph^P'B^, imidazole CH 2 C1 2 , 0°C I Br 67 68 Following General Procedure 3, allylic alcohol 67 was converted into allylic bromide 68 with the following quantities of reagents and solvents: alcohol 67 (35 g, 177 mmol), Ph3P (56 g, 212 mmol), imidazole (18 g, 265 mmol), B r 2 (10.8 m L , 212 mmol), C H 2 C 1 2 (900 mL) . Removal of the solvent by rotary evaporation (room temperature water bath) afforded 35 g of the crude title compound as a pink oi l . The crude oi l displayed a clean ^ - N M R spectrum matching that previously reported 2 0 1 5 and was used in the subsequent alkylation step without further purification. Preparation of Methyl ("Z)-3-Cyclopropyl-3-iodopropenoate. Following General Procedure 1, acetylenic ester 71 was converted into a,f3-unsaturated ester 75 with the following quantities of reagents: ester 71 (1.17 g, 9.42 mmol), N a l (2.1 g, 14.1 mmol) and acetic acid (6 m L , 94 mmol). The crude ester was carried through to the next step, but a small amount was purified by flash chromatography for characterization purposes, yielding a colorless liquid. 71 Nal, HO Ac 110 °C IR 3009, 2950, 1728, 1605, 1434, 1292, 1223, 1171, 1143, 1021 cm" 1. ' H - N M R 8 0.80-0.90 (m, 4 H , cyclopropyl methylenes), 1.67-1.74 (m, 1H, cyclopropyl methine), 3.72 (s, 3H , O C H 3 ) , 6.40 (2, 1H, HC=C, J = 0.7 Hz) . Chapter 4 1 5 0 13, C - N M R 8 10.5, 26.1, 51.5, 122.0, 127.0, 164.9. H R M S for C 7 H 9 O 2 I ( M + ) 251.9647, found 261.9651. Anal . Calcd for C 7 H 9 0 2 I : C , 33.36; H , 3.60. Found: C , 33.66; H , 3.63. Preparation of (Z)-3-Cyclopropyl-3-iodoprop-2-en-l-ol. X O O E t 1. D I B A L H , E t 2 0 , 0°C 2. N H 3 - N H 4 C I , H 2 0 O H Following General Procedure 2, ester 75 was converted into allylic alcohol 77 with the following quantities of reagents and solvents: crude ester 66 (1.95 g, -7.3 mmol), D I B A L H (1.0 M solution in E t 2 0 , 19.0 mmol), dry E t 2 0 (75 mL) . Flash chromatography (150 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 1.6 g (78% over two steps) of the title compound as a colorless o i l . IR 3305, 3006, 2867, 1635, 1422, 1358, 1195, 1148, 1024 cm" 1. ] H - N M R 8 0.66-0.69 (m, 2H, cyclopropyl methylene), 0.71-0.77 (m, 2H, cyclopropyl methylene), 1.44 (t, 1H, O H , J = 5.9 Hz), 1.61-1.68 (m, 1H, cyclopropyl methine), 4.19 (dd, 2H , C H 2 0 , J = 5.9, 5.9 Hz) , 5.89 (td, 1H, HC=CI, J = 5.9, 1.2 Hz) . 1 3 C - N M R 8 8.9, 24.4, 67.1, 113.6, 131.8. Chapter 4 H R M S for C 6 H 9 O I ( M + ) 223.9698, found 223.9703. 151 Anal . Calcd for C 6 H 9 O I : C , 32.17; H , 4.05. Found: C, 32.16; H , 3.95. Preparation of (Z)-3-Bromo-l-cyclopropyl-l-iodoprop-l-ene (79). " O H Ph 3P»Br 2, imidazole CH 2 C1 2 , 0°C Br Following General Procedure 3, allylic alcohol 77 was converted into allylic bromide 79 with the following quantities of reagents and solvents: alcohol 77 (1.5 g, 6.7 mmol), Ph 3 P«Br 2 (10.7 mmol), imidazole (910 mg, 13.4 mmol) and dry CH2CI2 (60 mL) . Filtration of the acquired crude mixture through silica gel and removal of the solvent by rotary evaporation afforded the title compound, pure enough for characterization, in approximately 77% yield. However, the poor stability of this compound precluded the possibility for combustion analysis, and required its immediate use in the alkylation step. The colorless l iquid (that quickly became pink on standing at rt) exhibited IR 3006, 2961, 1617, 1431, 1360, 1278, 1201, 1178, 1050, 1025 cm" 1. • H - N M R 5 0.69-0.79 (m, 4 H , cyclopropyl methylenes), 1.61-1.67 (m, 1H, cyclopropyl methine), 4.03 (d, 2H , C H 2 B r , J = 7.9 Hz) , 5.98 (t, 1H, J = 7.9 Hz) . 1 3 C - N M R 5 9.2, 24.3, 35.8, 119.6, 128.6. H R M S for C 6 H 8 7 9 B r I ( M + ) 285.8854, found 285.8853. Chapter 4 152 Preparation of Methyl (Z)-4-Benzyloxy-3-iodobut-2-enoate (76). -COOEt Nal, HOAc BnO 110 °C B n < - ) 74 Following General Procedure 1, acetylenic ester 7 4 3 0 was converted into cc,p-unsaturated ester 76 with the following quantities of reagents: ester 74 (10.3 g, 50.4 mmol), N a l (11.3 g, 75.6 mmol) and acetic acid (30 mL, 504 mmol). The crude ester was carried through to the next step, but a small amount was purified by flash chromatography for characterization purposes, yielding a colorless liquid. IR 3030, 2949, 2864, 1734, 1636, 1497, 1435, 1360, 1291, 1171, 1110, 1054 cm" 1. ! H - N M R 8 4.25 (d, 2H, O C H 2 , J = 1.7 Hz) , 4.56 (s, 3H, O C H 3 ) , 6.82 (t, 1H, HC=C, J =1.1 Hz), 7.30-7.36 (m, 5H); 1 3 C - N M R 8 51.7, 72.6, 79.0, 116.3, 123.5, 127.7, 128.0, 128.5, 137.1, 164.8. H R M S for C12H14O3I (DCI, M+H+) 332.9988, found 332.9988. Anal . Calcd for C 1 2 H 1 3 0 3 l : C , 43.40; H , 3.94. Found: C, 43.51; H , 4.05. Chapter 4 153 Preparation of (Z)-4-Benzyloxv-3-iodobut-2-en-l-ol (78). I 1. D I B A L H , E t 2 0 , 0°C B n O ^ ^ J ^ / C O O E t 2. N H 3 - N H 4 C I , H 2 0 76 Following General Procedure 2, ester 76 was converted into alcohol 78 with the following quantities of reagents and solvents: crude ester 76 (16.5 g), D I B A L H (1.0 M solution in Et20, 125 mmol), Et20 (250 mL) . Flash chromatography (200 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 6.2 g (41% over two steps) of the title compound as a colorless o i l . TR 3368, 3030, 2857, 1650, 1497, 1455, 1358, 1274, 1212, 1093, 1028 cm" 1. X H - N M R 6 1.50-1.60 (br. s, 1H, OH) , 4.17 (s, 2H), 4.27 (br. s, 2H), 4.51 (s, 2H), 6.24-6.27 (m, 1H, HC=CI), 7.25-7.35 (m, 5H). 1 3 C - N M R 5 66.6, 71.9, 77.5, 104.5, 127.9, 127.9, 128.5, 135.9, 137.5. H R M S for C „ H 1 3 0 2 I ( M + ) 303.9960, found 303.9965. Anal . Calcd for C11H13O2I: C , 43.44; H , 4.31. Found: C , 43.72; H , 4.26. Chapter 4 154 Preparation of (Z)-l-Benzyloxy-4-bromo-2-iodobut-2-ene (80). Ph 3P*Br 2, imidazole BnO. CH 2 C1 2 , 0°C B n O OH Br 78 80 Following General Procedure 3, alcohol 78 was converted into bromide 80 with the following quantities of reagents and solvents: alcohol (6.2 g, 20.4 mmol), P h 3 P » B r 2 (32.6 mmol), imidazole (2.8 g, 40.8 mmol) and dry CH2CI2 (150 mL) . Flash chromatography (60 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 4.2 g (56%) of the title compound, a colorless o i l . IR 3030, 2859, 1637, 1496, 1455, 1355, 1274, 1205, 1104, 1046, 1028 cm ' 1 . 1 H - N M R 5 4.05 (d, 2H , C H 2 B r , / = 7.7 Hz) , 4.20 (d, 1H, = C I C H 2 0 , J = 0.8 Hz) , 4.51 (s, 2H, P h C H 2 0 ) , 6.25 (tt, 1H, HC=CI, J = 7.7, 0.8 Hz) , 7.28-7.35 (m, 5H). 1 3 C - N M R 5 .34.0, 71.9, 77.3, 110.2, 127.9, 127.9, 128.5, 131.9, 137.3. H R M S for C 7 H 1 2 0 7 9 B r I ( M + ) 365.9116, found 365.9118. Anal . Calcd for C 7 H 1 2 0 B r I : C , 36.00; H , 3.30. Found: C , 36.03; H , 3.35. Chapter 4 155 General Procedure 4: a'-AIkylation of 3-Isobutoxvcvclohex-2-en-l-ones with A l k y l , A l l y l i c and Benzylic halides. 2 7 To a cold (-78 °C), stirred solution of L D A (1.05-1.1 equiv, see Section 4.1.2) in dry T H F (10-15 m L per mmol) was added, dropwise via a cannula, a solution of the vinylogous ester (1.1-1.2 equiv) in dry T H F (~5 m L per mmol of vinylogous ester). In those examples requiring H M P A (2-3 equiv) or D M P U (5-10 equiv) as an additive, it was added, dropwise via a syringe, at this time. The mixture was warmed to room temperature and stirred for a period of 1 h (during which time it turned either a deep yellow or brick red), and then was cooled back to -78 °C. To the resulting solution was added, dropwise via a cannula, the electrophile (1 equiv) either neat or as a solution in dry T H F (~5 m L per mmol of electrophile). The mixture was stirred for 1 h, was warmed slowly to room temperature, and then was stirred for an additional hour. Aqueous N H 3 -N H 4 C I (pH ~8, about one-half the total reaction mixture volume) was added and stirring was continued for 15 min. The phases were separated and the aqueous phase was extracted three times with Et20. The combined organic extracts were washed (brine), dried (MgS04), and concentrated under reduced pressure. Flash chromatography (50-100 g of silica gel per g of crude product), followed by removal (vacuum pump) of traces of solvent from the acquired material, afforded the desired product. 2. R 2 X , THF, -78 °C -> rt 1. L D A , THF, -78 °C -> rt Chapter 4 156 Preparation of 6-Benzyl-3-isobutoxycyclohex-2-en-l-one (85). O' 1. L D A , THF, -78 ° C - > r t 2. Benzyl bromide, THF, -78 °C -> rt 9 85 Following General Procedure 4, vinylogous ester 9 and benzyl bromide were converted into compound 85 with the following quantities of reagents and solvents: L D A (5.4 mmol), vinylogous ester 9 (1.0 g, 5.9 mmol), benzyl bromide (770 uL , 6.5 mmol) and dry T H F (50 mL). Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired crystals afforded 1.17 g (76%) of the title compound as a colourless crystalline solid that exhibited mp 49-50 °C. IR 3065, 2937, 1645, 1604, 1496, 1455, 1385, 1245, 1201, 995, cm" 1. * H - N M R 8 0.95 (d, 3H, ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz) , 0.95 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz), 1.54-1.64 (m, 1H), 1.86-1.93 (m, 1H), 1.97-2.03 (m, 1H), 2.34-2.52 (m, 4H), 3.36 (dd, 1H, J = 13.2, 3.2 Hz) , 3.56-3.58 (m, 2H, O C H 2 ) , 5.34 (s, 1H, =CHC=0) , 7.16-7.30 (m, 5H). 1 3 C - N M R 5 19.0, 25.5, 27.7, 28.1, 35.6, 47.0, 74.7, 102.2, 126.0, 128.3, 129.2, 140.2; 177.2, 200.3. H R M S for C17H22O2 (M+) 258.1620, found 258.1620. Anal . Calcd. for C17H22O2: C , 79.03; H , 8.58. Found: C , 79.24; H , 8.36. Chapter 4 157 Preparation of 6-((Z)-3-Iodobut-2-en-l-yl)-3-isobutoxycyclohex-2-en-l-one (81). O' 1. L D A , THF, -78 °C -> rt 2. 68, THF, -78 °C -> rt 9 81 Following General Procedure 4, vinylogous ester 9 and allylic bromide 68 were converted into compound 81 with the following quantities of reagents and solvents: L D A (42.2 mmol), vinylogous ester 9 (8.4 g, 50.0 mmol), bromide 68 (10.0 g, 38.3 mmol) and dry T H F (400 mL) . Flash chromatography (300 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired solid afforded 12.1 g (91%) of the title compound, a colourless o i l . IR 2959, 1657, 1606, 1195 cm" 1. 1 H - N M R 5 0.95 (d, 6 H , ( C H 3 ) 2 C H J = 6.7 Hz) , 1.70-1.78 (m, 1H), 1.97-2.06 (m, 2H), 2.23-2.33 (m, 2H), 2.43 (dd, 1H, J = 7.0, 5.2 Hz) , 2.48 (d, 3H , = C I C H 3 , J = 1.3 Hz) , 2.54-2.59 (m, 1H), 3.56 (m, 2H), 5.30 (s, 1H, =CHC=0) , 5.44 (m, 1H). 1 3 C - N M R 6 19.0, 26.1, 27.6, 28.2, 33.6, 36.8, 44.6, 63.6, 74.7, 102.1, 133.2, 177.2, 200.1. H R M S for C i 4 H 2 i 0 2 I ( M + ) 348.0586, found 348.0585. Anal . Calcd for C 1 4 H 2 1 0 2 I : C , 48.27; H , 6.08. Found: C , 48.42; H , 6.08. Chapter 4 158 Preparation of 6-((Z)-3-Iodobut-2-en-l-vl)-3-isobutoxy-6-methylcyclohex-2-en-l-one (82). Following General Procedure 4, vinylogous ester 84 and allylic bromide 68 were converted into compound 82 with the following quantities of reagents and solvents: L D A (2.2 mmol), vinylogous ester 84 (447 mg, 2.4 mmol), dry H M P A (835 uL , 4.8 mmol), bromide 68 (631 mg, 2.44 mmol) and dry T H F (30 mL) . Flash chromatography (50 g of silica gel, 4:1 ->• 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired solid afforded 290 mg (35%) of the title compound as a colourless crystalline solid that exhibited mp 55-56 °C. IR 2968, 1650, 1610, 1461, 1385, 1246, 1203, 1062 cm" 1. ! H - N M R 8 0.95 (d, 6H , ( C H 3 ) 2 C H , J = 6.7 Hz) , 1.11 (s, 3H, C H 3 ) , 1.69-1.75 (m, 1H), 1.87-1.94 (m, 1H), 1.96-2.03 (m, 1H), 2.21-2.27 (m, 1H), 2.40-2.48 (m, 6H), 3.56 (d, 2H , O C H 2 , J = 6.5 Hz) , 5.23 (s, 1H, =CHC=0) , 5.34 (m, 1H, C H 3 C I = C H C H 2 ) . 1 3 C - N M R 8 19.0, 22.6, 26.0, 27.7, 32.1, 33.8, 43.8, 44.3, 74.7, 101.3, 103.4, 131.6, 176.1, 203.1. H R M S for C,5H2 3 0 2 I ( M + ) 362.0743, found 362.0744. Anal . Calcd for C15H23O2I: C , 49.73; H , 6.40. Found C, 49.70; H , 6.34. Chapter 4 159 Preparation of 6-Benzyl -6-((Z)-3-iodobut-2-en-l-yl)-3-isobutoxycyclohex-2-en-l-one (86). Following General Procedure 4, vinylogous ester 85 and allylic bromide 68 were converted into compound 86 with the following quantities of reagents and solvents: L D A (0.9 mmol), vinylogous ester 85 (250 mg, 1.0 mmol), dry H M P A (348 p L , 2.0 mmol), bromide 68 (275 mg, 1.1 mmol) and dry T H F (15 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 270 mg (79%) of the title compound, a colourless o i l . IR 3027, 2958, 1651, 1610, 1495, 1451, 1385, 1198, 1020 cm" 1. 1 H - N M R 8 0.94 (d, 6H , ( C H 3 ) 2 C H , J = 6.7 Hz) , 1.76-1.80 (m, 2H), 1.95-2.02 (m, 1H), 2.21 (dd, 1H, J = 14.0, 6.9 Hz) , 2.34-2.48 (m, 6H), 2.68 (d, 1H, J = 13.6 Hz) , 3.08 (d, 1H, J = 13.6 Hz) , 3.54-3.56 (m, 2H, O C H 2 ) , 5.29 (s, 1H, =CHC=0), 5.39-5.42 (m, 1H, C H 3 C I = C H C H 2 ) , 7.10-7.25 (m, 5H, aromatic). 1 3 C - N M R 8 19.0, 25.9, 27.6, 28.8, 33.8, 41.4, 42.8, 48.1, 74.7, 102.1, 103.8, 126.3, 128.0, 130.6, 131.3, 137.4, 176.2, 201.8. H R M S for C 2 1 H 2 7 0 2 I ( M + ) 438.1056, found 438.1055. Chapter 4 Anal . Calcd for C21H27O2I: C , 57.54; H , 6.21. Found C , 57.80; H , 6.32. 160 Preparation of 6-((Z)-3-Cyclopropyl-3-iodoprop-2-en-l-yl)-3-isobutoxycyclohex-2-en-l-one (87). Following General Procedure 4, vinylogous ester 9 and allylic bromide 79 were converted compound 87 with the following quantities of reagents and solvents: L D A (5.7 mmol), vinylogous ester 9 (1.1 g, 6.3 mmol), bromide 79 (1.5 g, 5.2 mmol) and dry TFfF (50 mL) . Flash chromatography (60 g of silica gel, 4:1 - » 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 1.6 g (82%) of the title compound as a colourless o i l . TR 2958, 1657, 1606, 1471, 1384, 1367, 1194, 992 cm" 1. • H - N M R 8 0.62-0.72 (m, 4 H , cyclopropyl C H 2 ) , 0.95 (d, 3H, ( C H 3 ) C H ( C H 3 ) , J =6.7 Hz) , 0.95 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz) , 1.60-1.80 (m, 2H), 1.97-2.05 (m, 2H), 2.26-2.36 (m, 2H), 2.43 (m, 2H), 2.55-2.62 (m, 1H), 3.53-3.60 (m, 2H, O C H 2 ) , 5.30 (s, 1H, =CHC=0) , 5.59 (td, 1H, C H 3 C I = C H C H 2 , J = 6.8, 1.2 Hz) . 1 3 C - N M R 8 9.2, 19.3, 24.9, 26.4, 27.9, 28.5, 36.8, 45.0, 75.0, 102.5, 114.3, 131.5, 177.5, 200.4. Chapter 4 161 H R M S for C16H23O2I ( M + ) 374.0743, found 374.0746. Anal . Calcd for C i 6 H 2 3 0 2 I : C , 51.35; H , 6.19. Found: C, 51.67; H , 6.27. Preparation of 6-(( ,Z)-4-Benzyloxy-3-iodobut-2-en-l-yn-3-isobutoxycyclohex-2-en-l-one (88). Following general procedure 4, vinylogous ester 9 and allylic bromide 80 were converted into compound 88 with the following quantities of reagents and solvents: L D A (3.0 mmol), vinylogous ester 9 (548 mg, 3.3 mmol), bromide 80 (1.0 g, 2.7 mmol) and dry T H F (40 mL) . Flash chromatography (60 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 1.1 g (81%) of the title compound, a colourless o i l . IR 3030, 2960, 1651, 1605, 1470, 1454, 1384, 1367, 1195, 1112 cm" 1. ! H - N M R 5 0.95 (d, 6 H , ( C H 2 ) 2 C H , J = 6.7 Hz), 1.70-1.80 (m, 1H), 1.95-2.07 (m, 2H), 2.31-2.46 (m, 4H), 2.63-2.71 (m, 1H), 3.53-3.60 (m, 2H), 4.17 (br. s, 2H), 4.47 (s, 2H), 5.31 (br. s, 1H, =CHC=0) , 5.96 (t, 1H, = C H C H 2 , 7 = 7.2 Hz) , 7.25-7.34 (m, 5H). 1 3 C - N M R 5 19.0, 26.3, 27.6, 28.3, 36.1, 44.5, 71.4, 74.7, 77.9, 102.2, 106.3, 127.7, 127.9, 128.3, 136.0, 137.7, 177.2, 199.7. Chapter 4 162 H R M S for C21H27O3I ( M + ) 454.1005, found 454.0998. Anal . Calcd for C21H27O3I: C , 55.52; H , 5.99. Found: C , 55.52; H , 6.12. Preparation of 6-((Z)-4-Benzyloxy-3-iodobut-2-en-l-yl)-3-isobutoxy-6-methylcyclohex-2-en-l-one (89). Following general procedure 4, vinylogous ester 84 and allylic bromide 80 were converted into compound 89 with the following quantities of reagents and solvents: L D A (11.4 mmol), vinylogous ester 84 (2.3 g, 12.6 mmol), bromide 80 (2.1 g, 5.7 mmol), dry D M P U (3 mL, 25 mmol) and dry T H F (1 L ) . Flash chromatography (250 g of silica gel, 9:1 toluene-E tOAc) followed by removal of traces of solvent from the acquired liquid afforded 2.1 g (78%) of the title compound, a colourless oi l . IR 3030, 3960, 1651, 1610, 1456, 1368, 1241, 1196, 1101, 1031 cm" 1. 1 H - N M R 5 0.95 (d, 6 H , ( C H ? > C H , J = 6.6 Hz) , 1.14 (s, 3H , C H 3 ) , 1.75 (ddd, 1H, J = 13.7, 5.8, 5.8 Hz) , 1.91 (ddd, 1H, J = 13.7, 7.0, 7.0 Hz) , 1.96-2.04 (m, 1H), 2.38 (dd, 1H, J = 14.6, 7.4 Hz) , 2.43-2.46 (m, 2H), 2.53 (dd, 1H, J = 14.6, 6.5 Hz) , 3.57 (d, 2H , J = 6.5 Hz) , 4.16 (d, 2H, Chapter 4 163 = C I C H 2 0 , J = 0.7 Hz) , 4.46 (s, 2H), 5.25 (s, 1H, =CHC=0) , 5.86 (dd, 1H, =CH, J = 7.4, 6.5 Hz) , 7.23-7.34 (m, 5H). 1 3 C - N M R 5 19.0, 22.6, 25.9, 27.6, 32.1, 43.5, 43.7, 71.3, 74.7, 78.0, 101.2, 107.3, 127.7, 127.9, 128.3, 134.4, 137.6, 176.1, 202.8. H R M S for C22H29O3I ( M + ) 468.1162, found 468.1153. Anal . Calcd for C22H29O3I: C , 56.42; H , 6.24. Found: C, 56.64; H , 6.28. Chapter 4 164 General Procedure 5: Reduction of 3-isobutoxvcvclohex-2-en-l-ones and dehydration-hydrolysis of the resultant products. I I 1. DIBALH, Et 20,0 °C X To a cold (0 °C), stirred solution of the vinylogous ester (1 equiv) in dry Et20 (7-10 m L per mmol of vinylogous ester) was added, dropwise via a syringe, a solution of D I B A L H (1.0 M in hexanes, 1.5 equiv). The mixture was stirred for 30 min and then was treated with aqueous NH3-NH4CI (pH ~8, ~250 u L per mmol of D I B A L H ) . The biphasic mixture was warmed to room temperature and stirred for 1 h, becoming a thick white slurry. The mixture was treated with anhydrous M g S 0 4 (50 - 100 mg per mmol of D I B A L H ) , was stirred for 1 h, and then was filtered through a pad of Celite®. The remaining solid material was washed with Et20 (3 x the volume of the reaction mixture). The combined filtrate and washes were concentrated under reduced pressure and the remaining oil was dissolved in dry Et20 (10 m L per mmol of starting vinylogous ester). The solution was treated with H2O (~5 equiv) and T s O H » H 2 0 (0.05-0.1 equiv). The mixture was stirred for 1 h. Aqueous NH3-NH4CI (pH ~8, about one-half the total reaction mixture volume) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted three times with Et20. The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. Flash chromatography (50-100 g of silica gel per g of crude product), followed by removal (vacuum pump) of traces of solvent from the acquired material, afforded the desired enone. R 2. N H 3 - N H 4 C I , H 2 0 (pH 8), rt 3. /7-TsOH, H 2 0, Et 20, rt Chapter 4 165 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)cyclohex-2-en-l-one (90). 2. NH3-NH4CI, H 2 0 (pH 8), rt 3. p-TsOH, H 2 0 , E t 2 0 , rt 1. D I B A L H , E t 2 O , 0 ° C O 90 Following general procedure 5, vinylogous ester 81 was converted into enone 90 with the following quantities of reagents and solvents: vinylogous ester 81 (1.5 g, 4.3 mmol), D I B A L H (12.9 mmol), dry E t 2 0 (reduction, 100 mL); p - T s O H « H 2 0 (41 mg, 0.22 mmol), and dry E t 2 0 (hydrolysis-dehydration, 50 mL) . Flash chromatography (60 g of silica gel, 1:1 pet. ether-Et 20) followed by removal of traces of solvent from the acquired liquid afforded 1.2 g (100%) of the title compound, a colourless o i l . IR2947, 1679, 1615 c m 1 . • H - N M R 8 1.70-1.80 (m, 1H), 2.09 (dqd, 1H, J = 9.8, 4.8, 1.4 Hz) , 2.25-2.40 (m, 3H), 2.48-2.59 (m, 2H), 2.52 (dd, 3H ,=CICH 3 , / = 3.0, 1.2 Hz) , 5.45 (tq, 1H, HC=CI , / = 6.9, 1.2 Hz) , 5.98 (ddd, 1H, =CHC=0 , 7 = 10.1, 2.5, 0.6 Hz), 6.82 (ddd, 1H, H C = C H C = 0 , J= 10.1, 2.6, 1.4 Hz) . 1 3 C - N M R 8 28.3, 33.6, 35.6, 36.8, 41.1, 103.8, 129.4, 131.9, 153.6, 199.4. H R M S for C 1 0 H 1 3 O I ( M + ) 276.0011, found 276.0007. Anal . Calcd for C 1 0 H 1 3 O I : C, 43.48; H , 4.75. Found: C , 43.78; H , 4.84. Chapter 4 166 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)-4-rnethylcyclohex-2-en-l-one (91). O' 1. D I B A L H , E t 2 0 , 0 °C 2. NH3-NH4CI, H 2 0 (pH 8), rt 3. p-TsOH, H 2 0 , E t 2 0 , it 82 91 < Following general procedure 5, vinylogous ester 82 was converted into enone 91 with the following quantities of reagents and solvents: vinylogous ester 82 (290 mg, 0.8 mmol), D I B A L H (1.4 mmol), dry E t 2 0 (reduction, 10 mL) ; p - T s O H « H 2 0 (8 mg, 0.04 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et 20) followed by removal of traces of solvent from the acquired liquid afforded 207 mg (89%) of the title compound, a colourless o i l . IR 2957, 1681, 1427, 1390, 1374, 1264, 1224, 1115, 1065 cm" 1. } H - N M R 8 1.17 (s, 3H , C H 3 ) , 1.74-1.81 (m, 1H), 1.93-2.01 (m, 1H), 2.26-2.28 (m, 2H), 2.44-2.48 (m, 2H), 2.52-2.53 (m, 3H, =CICH 3 ) , 5.39 (tq, 1H, HC=CI , J = 7.0, 1.5 Hz) , 5.88 (d, 1H, =CHC=0 , J = 10.1 Hz) , 6.65 (d, 1H, H C = C H C = 0 , J= 10.1 Hz) . 1 3 C - N M R 6 25.1, 33.6, 33.9, 34.2, 36.4, 47.5, 104.6, 127.9, 130.3, 158.0, 199.3. H R M S for C n H i s O I ( M + ) 290.0168, found 290.0167. Anal . Calcd for C u H , 5 O I : C, 45.54; H , 5.21. Found: C , 45.81; H , 5.21. Chapter 4 167 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)-4-benzylcyclohex-2-en-l-one (92). o 1. D I B A L H , E t 2 0 , 0 ° C 2. NH3-NH4CI, H 2 0 (pH 8), rt 3. p-TsOH, H 2 Q , E t 2 0 , rt Following general procedure 5, vinylogous ester 86 was converted into enone 92 with the following quantities of reagents and solvents: vinylogous ester 86 (1.56 g, 4.0 mmol), D I B A L H (8.0 mmol), dry E t 2 0 (reduction, 40 mL); p - T s O H « H 2 0 (38 mg, 0.20 mmol), and dry E t 2 0 (hydrolysis-dehydration, 40 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et 20) followed by removal of traces of solvent from the acquired liquid afforded 1.19 g (81%) of the title compound, a colourless o i l . IR 3027, 2916, 1682, 1603, 1496, 1455, 1388, 1226, 1168, 1074, 1003 cm" 1. ' H - N M R 5 1.89-1.94 (m, 2H), 2.29-2.41 (m, 4H), 2.52 (d, 3H , C H 3 , J = 1.3 Hz) , 2.80 (d, 1H, C H 2 P h , J = 13.7 Hz) , 2.86 (d, 1H, C H 2 P h , J = 13.7 Hz) , 5.41 (tq, 1H, HC=CI , J = 7.1, 1.3 Hz) , 5.96 (d, 1H, C H C = 0 , J = 10.3 Hz) , 6.65 (d, 1H, H C = C H C = 0 , J = 10.3 Hz) , 7.12-7.28 (m, 5H). 1 3 C - N M R 5 31.0, 33.9, 34.0, 40.3, 44.6, 45.6, 104.9, 126.8, 128.2, 129.0, 130.2, 130.4, 136.5, 156.6, 199.0. H R M S for C 1 7 H 1 9 O I ( M + ) 366.0481, found 366.0476. Anal . Calcd for C i 7 H 1 9 O I : C, 55.75; H , 5.23. Found: C , 56.02; H , 5.26. Chapter 4 168 Preparation of 4-((Z)-3-Cyclopropyl-3-iodoprop-2-en-l-yl)cyclohex-2-en-l-one (54): Following general procedure 5, vinylogous ester 87 was converted into enone 54 with the following quantities of reagents and solvents: vinylogous ester 87 (800 mg, 2.1 mmol), D I B A L H (3.2. mmol), dry E t 2 0 (reduction, 25 mL); / ? -TsOH«H 2 0 (21 mg, 0.11 mmol), and dry E t 2 0 (hydrolysis-dehydration, 20 mL). Flash chromatography (50 g of silica gel, 4:1 -> 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 632 mg (98%) of the title compound, a colourless o i l . IR 3006, 2941, 1679, 1450, 1389, 1252, 1210, 1024 cm" 1. 1 H - N M R 8 0.63-0.77 (m, 4 H , cyclopropyl), 1.62-1.80 (m, 2H), 2.07-2.11 (m, 1H), 2.28-2.39 (m, 3H), 2.47-2.57 (m, 2H), 5.61 (td, 1H, HC=CI , J = 7.7, 1.1 Hz) , 5.98 (dd, 1H, H C C = 0 , J = 10.1, 2.4 Hz) , 6.81 (ddd, 1H, H C = C H C = 0 , / = 10.1,2.5, 1.3 Hz) . 1 3 C - N M R 8 9.0, 24.6, 28.4, 35.8, 36.9, 40.8, 115.4, 129.5, 129.7, 153.5, 199.3. H R M S for C i 2 H 1 5 O I ( M + ) 302.0168, found 302.0167. Anal . Calcd for C 1 2 H i 5 O I : C, 47.70; H , 5.00. Found: C , 48.00; H , 5.23. Chapter 4 169 Preparation of 4-((Z)-4-Benzyloxv-3-iodobut-2-en-l-yl)cyclohex-2-en-l-one (56): Following general procedure 5, vinylogous ester 88 was converted into enone 56 with the following quantities of reagents and solvents: vinylogous ester 88 (610 mg, 1.34 mmol), D I B A L H (2.0 mmol), dry E t 2 0 (reduction, 15 mL) ; p - T s O H » H 2 0 (13 mg, 0.07 mmol), and dry E t 2 0 (hydrolysis-dehydration, 15 mL). Flash chromatography (50 g of silica gel, 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 401 mg (78%) of the title compound, a colourless o i l . JR 3030, 2859, 1682, 1497, 1454, 1389, 1355, 1252, 1210, 1109 cm" 1. ] H - N M R 5 1.72-1.81 (m, 1H), 2.10 (dddd, 1H, p'-methylene, J = 13.3, 10.0, 4.8, 1.2 Hz) , 2 .31-2.43 (m, 3H), 2.52 (ddd, 1H, a'-methylene, J = 16.8, 4.8, 4.8 Hz) , 2.57-2.63 (m, 1H, y -methine), 4.19 (d, 2H , = C I C H 2 0 , J= 1.0 Hz) , 4.51 (s, 2H , O C H 2 P h ) , 5.95-6.01 (m, 2H, HC=CI and H C C = 0 ) , 6.81 (ddd, 1H, H C = C H C = 0 , / = 10.2, 2.6, 1.4 Hz) , 7.26-7.35 (m, 5H). 1 3 C - N M R 5 28.5, 35.7, 36.9, 40.4, 71.9, 77.9, 107.4, 127.9, 127.9, 128.5, 129.8, 133.7, 137.6, 153.2, 199.3. H R M S for C i 7 H i 9 0 2 I ( M + ) 382.0430, found 382.0426. Chapter 4 Anal . Calcd for C i 7 H i 9 0 2 I : C , 53.42; H , 5.01. Found: C , 53.65; H , 5.12. 170 Preparation of 4-((Z)-4-Benzyloxy-3-iodobut-2-en-l-yl)-4-methylcyclohex-2-en-l-one (93). Following general procedure 5, vinylogous ester 89 was converted into enone 93 with the following quantities of reagents and solvents: vinylogous ester 89 (300 mg, 0.64 mmol), D I B A L H (0.96 mmol), dry E t 2 0 (reduction, 10 mL); p - T s O H « H 2 0 (6 mg, 0.03 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 178 mg (70%) of the title compound, a colourless o i l . IR 3028, 2928, 1680, 1497, 1455, 1390, 1358, 1223, 1100 cm" 1. • H - N M R 5 1.20 (s, 3H , C H 3 ) , 1.76-1.83 (m, 1H, p'-methylene), 1.94-2.01 (m, 1H, P ' -methylene), 2.37-2.39 (m, 2H), 2.45-2.49 (m, 2H), 4.19 (d, 2 H , C I C H 2 0 , J = 1.1 Hz) , 4.50 (s, 2H, O C H 2 P h ) , 5.88-5.93 (m, 2H, HC=CI and H C C = 0 ) , 6.66 (d, 1H, H C = C H C = 0 , J = 10.1 Hz) , 7.27-7.34 (m, 5H). 1 3 C - N M R 8 25.1, 33.7, 34.1, 36.4, 46.6, 71.7, 77.9, 108.1, 127.8, 127.8, 128.0, 128.4, 132.1, 137.5, 157.5, 198.9. Chapter 4 171 Anal . Calcd for C 1 8 H 2 i 0 2 I : C , 54.56; H , 5.34. Found: C, 54.69; H , 5.47. General Procedure 6: 1,2-Addition of Grignard reagents to 3-isobutoxycyclohex-2-en-l-ones and hydrolysis-dehydration of the resultant products. To a cold (0 °C), stirred solution of the vinylogous ester (1 equiv) in dry TF£F (-10 m L per mmol of vinylogous ester) was added, dropwise via a syringe, a solution of the Grignard reagent (2-2.5 M in Et20, 2 equiv) The resulting mixture was stirred for 1.5 h. To the reaction mixture was added, sequentially, H2O (-5 equiv) and 10% aqueous H C l (-10 drops per mmol of vinylogous ester). After the mixture had been stirred for 30 min, it was treated with equal volumes (one-half of the total reaction mixture volume each) of aqueous NH3-NH4CI (pH -8) and Et20. The phases were separated and the aqueous phase was extracted three times with E t 2 0 . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. Flash chromatography (50-100 g of silica gel per g of crude product), followed by removal (vacuum pump) of traces of solvent from the acquired material, afforded the desired enone. Chapter 4 172 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)-3-methylcyclohex-2-en-l-one (94). O' o 1. MeMgBr, THF, 0 °C 2. H 2 0 ; 10% aq. HC1 81 94 Following general procedure 6, vinylogous ester 81 was converted into enone 94 with the following quantities of reagents and solvents: vinylogous ester 81 (200 mg, 0.57 mmol), M e M g B r (2.5 M solution in E t 2 0 , 460 p L , 1.15 mmol), dry T H F (6 mL) . Flash chromatography (8 g of silica gel, 4:1 —» 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 151 mg (91%) of the title compound, a colourless o i l . IR 2944, 1669, 1626, 1436, 1379, 1293, 1250, 1201, 1095, 1046 cm" 1. 1 H - N M R 5 1.81-1.89 (m, 1H, p'-methylene), 1.98 (d, 3H , C H 3 = C H , J = 0.7 Hz) , 1.98-2.07 (m, 1H, p'-methylene), 2.25-2.32 (m, 2H), 2.35-2.54 (m, 3H), 2.52 (d, 3 H , C = C I C H 3 , J = 1.2 Hz) , 5.43 (tq, 1H, HC=CI , J= 6.1, 1.2 Hz) , 5.86 (s, 1H, =CHC=0) . 1 3 C - N M R 5 22.9, 26.4, 33.6, 34.1, 38.1, 38.9, 103.6, 127.3, 132.4, 164.2, 199.2. H R M S for C n H 1 5 O I ( M + ) 290.0168, found 290.0171. Anal . Calcd for C n H i 5 O I : C, 45.54; H , 5.21. Found: C, 45.82; H , 5.32. Chapter 4 173 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)-3-methylcycIohex-2-en-l-one (95). O' o 1. MeMgBr, THF, 0 °C 2. H 2 0 ; 10% aq. HC1 89 OBn 95 OBn Following general procedure 6, vinylogous ester 89 was converted into enone 95 with the following quantities of reagents and solvents: vinylogous ester 84 (500 mg, 1.07 mmol), M e M g B r (2.5 M solution in E t 2 0 , 1.6 mmol), dry T H F (20 mL) . Flash chromatography (30 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 373 mg (85%) of the title compound, a colourless o i l . IR 3029, 2973, 2862, 1670, 1617, 1497, 1455, 1381, 1332, 1271, 1277, 1114, 1028 cm" 1. 1 H - N M R 5 1.21 (s, 3H, C H 3 C ) , 1.75 (ddd, 1H, J = 13.7, 7.1, 5.5 H z , H-5), 1.91 (d, 3H, J = 1.3 Hz , C H 3 C = C H ) , 1.97 (ddd, 1H, 13.7, 8.8, 5.5 Hz , H-5'), 2.34-2.49 (m, 4H), 4.17 (d, 2H , J = 1.0 Hz , O C H 2 C I C = C ) , 4.49 (s, 2H , O C H 2 P h ) , 5.81-5.85 (m, 2H), 7.26-7.36 (m, 5H). 1 3 C - N M R 8 20.0, 20.1, 24.2, 24.3, 34.1, 34.2, 38.8, 44.6, 71.7, 77.9, 107.9, 127.7 (2 carbons), 127.9, 132.5 (2 carbons), 137.4, 166.7, 198.6. H R M S for C 1 9 H 2 4 0 2 I (DCI, M + H1") 411.0821, found 411.0821. Anal . Calcd for C i 9 H 2 3 0 2 I : C , 55.62; H , 5.65. Found: C , 55.88; H , 5.72. Chapter 4 174 Preparation of 5-((Z)-3-Iodobut-2-en-l-yl)-3-isobutoxycyclopent-2-en-l-one (99). rr 1. L D A , THF, -78 °C ->• rt 2. 68, THF, -78 °C -> rt O -I 99 96 Following General Procedure 4, vinylogous ester 96 and allylic bromide 68 were converted into compound 99 with the following quantities of reagents and solvents: L D A (4.2 mmol), vinylogous ester (770 mg, 5.0 mmol), (Z)-l-bromo-3-iodobut-2-ene (1.0 g, 3.8 mmol) and dry T H F (30 mL) . Flash chromatography (50 g of silica gel, 4:1 —» 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 1.3 g (97%) of the title compound, a colourless o i l . JR 2961, 1695, 1595, 1470, 1427, 1351, 1234, 1174, 995 cm" 1. ' H - N M R 5 0.96 (d, 6H , ( C H 3 ) 2 C H , J = 6.7 Hz) , 2.01-2.08 (m, 1H), 2.28-2.35 (m, 2H), 2.47-2.58 (m, 5H), 2.68 (ddd, 1H, J = 17.5, 7.2, 0.8 H z ) , 3.67-3.75 (m, 2H), 5.21 (s, 1H, =CHC=0), 5.36-5.39 (m, 1H, C H 3 C I = C H C H 2 ) . 1 3 C - N M R 5 10.1, 27.8, 33.6, 33.9, 37.9, 44.0, 77.9, 103.1, 103.8, 131.9, 189.2, 206.8. H R M S for C i 3 H 1 9 0 2 I ( M + ) 334.0430, found 334.0429. Anal . Calcd for C i 3 H i 9 0 2 I : C , 46.72; H , 5.73. Found: C , 46.84; H , 5.77. Chapter 4 175 Preparation of 3-Isobutoxycyclohept-2-en-l-one (97). O •o /-BuOH, /?-TsOH, benzene, reflux Dean-Stark trap To a solution of commercially available 1,3-cycloheptanedione (2.6 g, 20.6 mmol) in 40 m L of dry benzene was added isobutanol (3.1 m L , 330 mmol) and p-toluenesulfonic acid (59 mg, 0.3 mmol). The reaction vessel was fitted with a Dean-Stark trap and the mixture was heated at reflux for 14 h. The reaction mixture was concentrated under reduced pressure. Kugelrohr distillation of the residual material afforded a pale yellow oi l , shown by ' H - N M R spectroscopy to contain minor impurities. Flash chromatography (150 g of silica gel, 1:1 pet. ether-Et 20) followed by removal of traces of solvent from the acquired oi l afforded 2.8 g (74%) of the title compound as a colourless o i l . IR 2958, 2872, 1650, 1607, 1471, 1383, 1368, 1238, 1191, 1175, 1003 cm" 1. 1 H - N M R 6 0.68 (d, 6 H , J = 6.8 Hz , ( C H 3 ) 2 C H ) , 1.68-1.80 (m, 4H), 1.88-1.95 (m, 1H, ( C H 3 ) 2 C H ) , 2.48-2.51 (m, 4H), 3.41 (d, 2H , J = 6.5 Hz , O C H 2 ) , 5.28 (s, 1H, =CHC=0) . 1 3 C - N M R 5 18.9 (2 carbons), 21.2, 23.4, 27.6, 32.8, 41.5, 74.6, 105.6, 176.2, 202.0. H R M S for C n H 1 8 0 2 ( M + ) 182.1307, found 182.1308. Anal . Calcd for C n H i 8 0 2 : C , 72.49; H , 9.95. Found: C , 72.32; H , 9.99. Chapter 4 176 Preparation of 3-Isobutoxy-7-methylcyclohept-2-en-l-one (98): Following General Procedure 4, vinylogous ester 97 and iodomethane were converted into compound 98 with the following quantities of reagents and solvents: L D A (4 mmol), vinylogous ester 97 (800 mg, 4.4 mmol), iodomethane (275 p L , 4.4 mmol) and dry T H F (40 mL). Flash chromatography (50 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired oi l afforded 612 mg (78%) of the title compound as a colourless o i l . IR2934, 1720, 1698, 1459, 1378, 1210 cm" 1. ! H - N M R 6 0.94 (d, 6 H , J = 6.7 H z , ( C H 3 ) 2 C H ) , 1.10 (d, 3H , J = 6.6 H z , C H 3 ) , 1.42-1.62 (m, 1H), 1.66-2.02 (m, 4H), 2.39-2.45 (m, 1H), 2.60-2.72 (m, 2H), 3.42-3.51 (m, 2H, C H 2 0 ) , 5.36 (br.s, 1H, =CHC=0) . 1 3 C - N M R 5 16.7, 19.1 (2 carbons), 23.4, 27.7, 30.8, 33.1, 43.8, 74.6, 105.8, 176.3, 203.6. H R M S for C i 2 H 2 o 0 2 ( M + ) 196.1463, found 196.1464. Anal . Calcd for C i 2 H 2 0 O 2 : C , 73.43; H , 10.27. Found: C , 73.07; H , 10.32. Chapter 4 177 Preparation of 7-((Z)-3-Iodobut-3-en-l-yl)-3-isobutoxycyclohept-2-en-l-one (100). Following General Procedure 4, vinylogous ester 97 and allylic bromide 68 were converted into compound 100 with the following quantities of reagents and solvents: L D A (4.7 mmol), vinylogous ester (924 mg, 5.1 mmol), (Z)-l-bromo-3-iodobut-2-ene (1.1 g, 4.2 mmol) and dry T H F (50 mL) . Flash chromatography (60 g of silica gel, 4:1 pet. ether-Et 20) followed by removal of traces of solvent from the acquired liquid afforded 1.3 g (87%) of the title compound, a colourless crystalline solid that exhibited mp 53-54 °C. IR 2951, 2872, 1637, 1611, 1471, 1383, 1368, 1240, 1192, 1148, 1008 cm" 1. 1 H - N M R 5 0.93 (d, 3H , J = 6.7 Hz , CH3CHCH3), 0.93 (d, 3H , J = 6.7 H z , CH3CHCH3), 1.46-1.52 (m, 1H), 1.65-1.71 (m, 1H), 1.84-1.20 (m, 3H), 2.14-2.20 (m, 1H), 2.40-2.45 (m, 1H), 2.45 (br.s, 3H, =CCH 3 ) , 2.49-2.71 (m, 3H), 3.41-3.51 (m, 2H), 5.34 (s, 1H), 5.44-5.48 (m, 1H). 1 3 C - N M R 5 19.1 (2 carbons), 23.6, 27.8, 28.6, 33.0, 33.6, 38.2, 48.8, 74.8, 102.1, 105.9, 134.0, 176.7, 201.9. H R M S for C i 5 H 2 4 0 2 I (DCI, M + H 4 ) 363.0821, found 363.0822. Anal . Calcd for C15H23O2I: C , 49.74; H , 6.40. Found: C, 50.03; H , 6.43. Chapter 4 178 Preparation of 7-((Z)-3-Iodobut-3-en-l-yl)-3-isobutoxy-7-methylcyclohept-2-en-l-one (101). Following General Procedure 4, vinylogous ester 98 and allylic bromide 68 were converted into compound 101 with the following quantities of reagents and solvents: L D A (2.9 mmol), vinylogous ester (600 mg, 3.1 mmol), D M P U (1.4 m L , 12 mmol), (Z)-l-bromo-3-iodobut-2-ene (613 mg, 2.4 mmol) and dry TF£F (40 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 815 mg (92%) of the title compound, a colourless o i l . IR 2932, 1719, 1695, 1610, 1458, 1426, 1378, 1196, 1066 cm" 1. ! H - N M R 6 0.94 (d, 6H , J = 6.7 H z , C H 3 C H ) , 1.16 (s, 3H , C H 3 C ) , 1.62-1.66 (m, 1H), 1.74-1.83 (m, 3H), 1.93-2.00 (m, 1H), 2.30 (ddd, 1H, J = 14.6, 7.1, 1.1 H z , H4), 2.39-2.48 (m, 3H), 2.48 (s, 3H , =CICH 3 ) , 3.44-3.51 (m, 2H, C H 2 0 ) , 5.30 (s, 1H, =CHC=0) , 5.32 (ddq, 1H, J= 6.8, 6.8, 1 . 4 H z , H C = C I C H 3 ) . 1 3 C - N M R 8 19.1 (2 carbons), 20.1, 25.5, 27.8, 33.9, 35.6, 35.8, 47.6, 51.6, 74.3, 103.1, 104.6, 131.7, 171.4, 206.0. H R M S for C 1 6 H 2 6 0 2 I (DCI, M+H+) 377.0978, found 377.0976. Anal . Calcd for C i 6 H 2 5 0 2 I : C , 51.07; H , 6.70. Found: C, 51.30; H , 6.82. Chapter 4 179 Preparation of 4-((Z)-3-Iodobut-2-en-l-yl)cyclopent-2-en-l-one (102). rr o 1. D I B A L H , E t 2 0 , 0 °C O -I 99 2. NH3-NH4CI, H 2 0 (pH 8), rt 3. p-TsOH, H 2 0 , E t 2 0 , rt Following general procedure 5, vinylogous ester 99 was converted into enone 102 with the following quantities of reagents and solvents: vinylogous ester 99 (500 mg, 1.5 mmol), D I B A L H (2.0 mmol), dry E t 2 0 (reduction, 15 mL) ; p - T s O H « H 2 0 (15 mg, 0.08 mmol), and dry E t 2 0 (hydrolysis-dehydration, 15 mL). Flash chromatography (50 g of silica gel, 4:1 —>• 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 272 mg (70%) of the title compound, a colourless oi l . IR 2913, 1713, 1587, 1427, 1407, 1348, 1289, 1183, 1087, 1034 cm" 1. ! H - N M R 5 2.05 (dd, 1H, a'-methylene, J = 18.8, 2.3 Hz) , 2.25-2.40 (m, 2H, = C H C H 2 ) , 2.50 (d, 3H, C H 3 , J= 1.4 Hz) , 2.50 (dd, 1H, a'-methylene), 3.03-3.09 (m, 1H, y-methine), 5.40 (tq, 1H, HC=CI, J = 6.9, 1.4 Hz) , 6.17 (dd, 1H, H C C = 0 , J = 5.7, 2.0 Hz) , 7.60 (dd, 1H, H C = C H C = 0 , J = 5.7, 2.5 Hz) . 1 3 C - N M R 8 33.7, 40.2, 40.5, 40.9, 104.0, 131.3, 134.5, 167.1, 209.3. H R M S for C9H11OI ( M + ) 261.9855, found 261.9856. Anal . Calcd for C 9 H n O I : C , 41.25; H , 4.23. Found: C , 41.19; H , 4.30. Chapter 4 180 General Procedure 7: f-BuLi-initiated intramolecular conjugate addition of alkenyl and aryl functions to a,[3-unsaturated ketones. A solution of the enone-iodide (1 equiv), dry H M P A (2.5 equiv) and freshly distilled TMS-C1 (4 equiv) in dry T H F (-15 m L per mmol of substrate) was stirred at room temperature for 5 min and then was cooled to -78 °C. A solution of ?-BuLi (1.4—1.7 M in pentane, 2.2 equiv) was added rapidly to the reaction mixture via a syringe. The resulting mixture was stirred for 5 min and then was warmed to room temperature. The mixture was treated with water (-3 m L per mmol of substrate) and was stirred for 1 h, allowing the produced silyl enol ether to be competely hydrolyzed (monitored by T L C ) . The phases were separated and the aqueous phase was extracted three times with EtaO. The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. Flash chromatography (50-100 g of silica gel per g of crude product), followed by removal (vacuum pump) of traces of solvent from the acquired material, afforded the desired cyclized ketone. R 2 . H 2 0 1. T M S C l (4 equiv), T H F - H M P A ; r-BuLi (2.2 equiv), -78 °C -> rt O Chapter 4 181 Preparation of (IS*. 6S*)-9-Methylbicvclor4.3.01non-8-en-3-one (107). O 1. T M S C l , T H F - H M P A ; f-BuLi, -78 °C -> rt 2 . H 2 0 •I =< 90 Following general procedure 7, enone 90 was converted into bicyclic ketone 107 with the following quantities of reagents and solvents: enone 90 (100 mg, 0.36 mmol), r -BuLi (1.7 M solution in pentane, 0.84 mmol), dry H M P A (146 p L , 0.84 mmol), T M S C l (203 uL , 1.60 mmol) and dry T H F (5 mL) . Flash chromatography (6 g of silica gel, 4:1 pet. e ther -Et20) followed by removal of traces of solvent from the acquired liquid afforded 47 mg (87%) of the title compound, a colourless o i l . The ' H - N M R spectrum of ketone 107 matched that previously reported. 1 3 Preparation of (IR*. 65*)-6.9-Dimethylbicvclof4.3.01non-8-en-3-one (107). Following general procedure 7, enone 91 was converted into bicyclic ketone 108 with the following quantities of reagents and solvents: enone 91 (104 mg, 0.36 mmol), r -BuLi (1.7 M solution in pentane, 0.90), dry H M P A (156 uL, 0.90), T M S C l (183 p L , 1.4 mmol) and dry T H F (5 mL) . Flash chromatography (7 g of silica gel, 4:1 pet. e ther -Et20) followed by removal of traces of solvent from the acquired liquid afforded 46 mg (85%) of the title compound, a colourless o i l . The ' H - N M R spectrum of ketone 108 matched that previously reported. 1 3 Chapter 4 182 Preparation of (IR*, 6S*V6-Benzvl-9-methvlbicvclo r4.3.01non-8-en-3-one (109). O 2 . H 2 0 1. TMSCl , T H F - H M P A ; r-BuLi, -78 °C -> rt 109 O Following general procedure 7, enone 92 was converted into bicyclic ketone 109 with the following quantities of reagents and solvents: enone 92 (100 mg, 0.27 mmol), r -BuLi (1.7 M solution in pentane, 0.66 mmol), dry H M P A (118 uL, 0.68 mmol), T M S C l (138 pX, 1.1 mmol) and dry T H F (5 mL) . Flash chromatography (7 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 53 mg (81%) of the title compound, a colourless o i l . IR 3028, 1715, 1603, 1496, 1455, 1203, 1077, 1031 cm" 1. ! H - N M R 6 1.58-1.67 (m, 4 H , incl . C H 3 ) , 1.92 (ddd, 1H, J = 14.0, 10.4, 4.6 Hz) , 2.06-2.17 (m, 2H), 2.21-2.42 (m, 3H), 2.53-2.59 (m, 1H), 2.77-2.81 (m, 3H), 5.27-5.31 (m, 1H, HC=C), 7.18-7.30 (m, 5H). 1 3 C - N M R 5 14.7, 32.2, 35.8, 40.2, 43.8, 44.4, 47.6, 52.3, 124.2, 126.3, 128.0, 130.3, 138.4, 140.5,213.7. H R M S for C i 7 H 2 0 O ( M + ) 240.1514, found 240.1514. Anal . Calcd for C 1 7 H 2 0 O : C , 84.96; H , 8.39. Found: C, 84.88; H , 8.42. Chapter 4 183 Preparation of (IS*. 6S '*)-9-' Cyclopropylbicyclor4.3.01non-8-en-3-one (55). O 1. TMSCl , T H F - H M P A ; J-BuLi, -78 °C -> rt 2 . H 2 0 O 55 Following general procedure 7, enone 54 was converted into bicyclic ketone 55 with the following quantities of reagents and solvents: enone 54 (100 mg, 0.34 mmol), r -BuLi (1.7 M solution in pentane, 1.01 mmol), dry H M P A (146 pX, 0.84 mmoi), T M S C l (174 uL , 1.35 mmol) and dry T H F (5 mL) . Flash chromatography (5 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 55 mg (96%) of the title compound, a colourless o i l . IR 2928, 1718, 460, 1020 cm" 1. ! H - N M R 5 0.31-0.39 (m, 2H, cyclopropyl methylene), 0.54-0.70 (m, 2H, cyclopropyl methylene), 1.07-1.11 (m, 1H, cyclopropyl methine), 1.66-1.75 (m, 1H), 1.94-2.08 (m, 2H), 2.13-2.32 (m, 2H), 2.43 (dd, 1H, J= 15.1, 8.5 Hz) , 2.56-2.63 (m, 3H), 3.00-3.08 (m, 1H), 5.15-5.16 (m, 1 H , H C = C ) . 1 3 C - N M R (100 M H z ) 5 5.2, 7.1, 9.6, 27.4, 34.9, 37.5, 38.2, 41.6, 45.8, 120.6, 147.9, 214.0. H R M S for C i 2 H 1 6 0 ( M + ) 176.1201, found 176.1201. Anal . Calcd for C 1 2 H 1 6 0 : C , 81.77; H , 9.15. Found: C, 81.65; H , 9.26. Chapter 4 184 Preparation of (IS*. 6S*)-9-Benzyloxymethylbicyclo r4.3.0]non-8-en-3-one (57). O 56 •OBn 2 . H 2 0 1. TMSCl , T H F - H M P A ; f-BuLi, -78 °C -» it O 57 OBn Following general procedure 7, enone 56 was converted into bicyclic ketone 57 with the following quantities of reagents and solvents: enone 56 (150 mg, 0.39 mmol), f -BuLi (1.7 M solution in pentane, 0.90 mmol), dry F f M P A (171 p L , 0.98 mmol), T M S C l (199 uL , 1.57 mmol) and dry T H F (15 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 78 mg (78%) of the title compound, a colourless o i l . IR 2849, 1715, 1496, 1455, 1355, 1093 cm" 1. • H - N M R 5 1.70-1.77 (m, 1H), 1.96-2.03 (m, 1H), 2.10-2.22 (m, 2H), 2.26-2.36 (m, 2H), 2.56 (dd, 1H, J = 15.0, 6.2 Hz) , 2.62-2.74 (m, 2H), 3.11-3.20 (m, 1H), 3 .95^ .02 (m, 2H, C H 2 0 ) , 4.42-4.50 (m, 2H, C H 2 0 ) , 5.66 (s, 1H, HC=C), 7.25-7.35 (m, 5H). 1 3 C - N M R 5 27.3, 34.7, 37.5, 38.6, 41.0, 43.1, 67.2, 72.5, 127.6, 127.7, 127.8, 128.4, 138.2, 142.4, 213.5. H R M S for C i 7 H 2 0 O 2 ( M + ) 256.1463, found 256.1463. Anal . Calcd for C i 7 H 2 0 O 2 : C , 79.65; H , 7.86. Found: C, 79.41; H , 7.82. Chapter 4 185 Preparation of (1/?*, 65*)-9-Benzyloxymethyl-6-methylbicyclo[4.3.01non-8-en-3-one (110). O Following general procedure 7, enone 93 was converted into bicyclic ketone 110 with the following quantities of reagents and solvents: enone 93 (110 mg, 0.28 mmol), f -BuLi (1.7 M solution in pentane, 0.61 mmol), dry H M P A (121 uL , 0.69 mmol), T M S C l (141 pX, 1.10 mmol) and dry T H F (6 mL) . Flash chromatography (15 g of silica gel, 4:1 pet. ether-EtOAc) followed by removal of traces of solvent from the acquired liquid afforded 63 mg (83%) of the title compound, a colourless o i l . IR 3031, 2861, 1717, 1497, 1456, 1362, 1212, 1073, 1028 cm" 1. ' H - N M R 8 1.20 (s, 3H , C H 3 ) , 1.79-1.82 (m, 2H), 2.14-2.26 (m, 2H), 2.28-2.37 (m, 3H), 2.56 (dd, 1H, J = 15.3, 6.2 Hz) , 2.66-2.72 (m, 1H), 3.96 (s, 2H , C H 2 0 ) , 4 .42^ .50 (m, 2H, C H 2 0 ) , 5.61 (s, 1H, HC=C) , 7.24-7.33 (m, 5H). 1 3 C - N M R 8 29.3, 34.7, 36.1, 39.5, 40.7, 46.7, 50.9, 67.3, 72.4, 127.3, 127.6, 127.7, 128.4, 138.2, 141.8,213.6. H R M S for C 1 8 H 2 2 0 2 ( M + ) 270.1620, found 270.1619. Chapter 4 Anal . Calcd for C i 8 H 2 2 0 2 : C , 79.96; H , 8.20. Found: C, 79.94; H , 8.24. 186 Preparation of (IS*. 6S*M,9-Dimethvlbicvclor4.3.01non-8-en-3-one ( I I P . Fol lowing general procedure 7, enone 90 was converted into bicyclic ketone 107 with the following quantities of reagents and solvents: enone 90 (101 mg, 0.35 mmol), 7-BuLi (1.7 M solution in pentane, 0.87 mmol), dry H M P A (151 uL, 0.87 mmol), T M S C l (176 uL , 1.39 mmol) and dry T H F (5 mL) . Flash chromatography (9 g of silica gel, 4:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 41 mg (72%) of the title compound, a colourless o i l . The ' H - N M R spectrum of ketone 111 matched that previously reported for compound 111. 1 3 Chapter 4 187 Preparation of (IR*, 65*)-9-Benzyloxymethyl-l,6-dimethylbicyclo[43.01non-8-en-3-one (112). O 1. TMSCl , T H F - H M P A ; f-BuLi, -78 °C -> rt 2. H 2 0 S\ II , OBn 95 Following general procedure 7, enone 95 was converted into bicyclic ketone 112 with the following quantities of reagents and solvents: enone 95 (500 mg, 1.22 mmol), f -BuLi (1.7 M solution in pentane, 2.68 mmol), dry H M P A (530 p L , 3.05 mmol), T M S C l (619 p L , 4.87 mmol) and dry T H F (15 mL) . Flash chromatography (15 g of silica gel, 1:1 pet. e ther -Et20) followed by removal of traces of solvent from the acquired liquid afforded 286 mg (83%) of the title compound, a colourless o i l . IR 2928, 1717, 1454, 1071 cm" 1. 1 H - N M R 5 1.03 (s, 3H), 1.11 (s, 3H), 1.73 (ddd, 1H, / = 14.0, 7.4, 6.4 H z , H-5), 1.91 (ddd, 1H, J = 14.0, 7.6, 5.7 H z , H-5'), 2.23-2.33 (m, 5H), 2.44 (d, 1H, J = 14.6 H z , H-2'), 3.95-3.97 (m, 2H), 4.47 (s, 2H), 5.65 (br. s, 1H), 7.25-7.36 (m, 5H). 1 3 C - N M R 5 22.8, 23.2, 36.6, 37.1, 43.6, 45.1, 48.6, 52.6, 66.9, 72.5, 126.7, 127.6, 127.7 (2 carbons), 128.4 (2 carbons), 138.3, 146.3, 212.8. H R M S for C19H24O2 ( M + ) 284.1776, found 284.1782. Anal . Calcd for Cl9H2402: C , 80.24; H , 8.51. Found: C, 80.44; H , 8.54. Chapter 4 188 Preparation of (IS*. 5S*)-6-Methvlbicvclor3.3.01oct-6-en-3-one (113). Following general procedure 7, enone 102 was converted into bicyclic ketone 113 with the following quantities of reagents and solvents: enone 102 (101 mg, 0.39 mmol), f -BuLi (1.7 M solution in pentane, 0.85 mmol), dry H M P A (148 p L , 0.85 mmol), T M S C l (196 p L , 1.54 mmol) and dry T H F (5 mL) . Flash chromatography (8 g of silica gel, 4:1 pet. e the r -Et20) followed by removal of traces of solvent from the acquired liquid afforded 41 mg (78%) of the title compound, a colourless o i l . The ^ - N M R spectrum of ketone 113 matched that previously 13 reported. Chapter 4 189 Preparation of 2-Iodo-5-methoxybenzyl Bromide (131): OH Ph 3P*Br 2, imidazole CH 2 C1 2 , 0°C Br OMe OMe 131 130 Following General Procedure 3, alcohol 130 was converted into bromide 131 with the following quantities of reagents and solvents: alcohol 130 (377 mg, 1.43 mmol), P h 3 P * B r 2 (2.3 mmol), imidazole (197 mg, 2.9 mmol) and dry C H 2 C 1 2 (20 mL) . Flash chromatography (10 g of silica gel, 4:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired solid afforded 367 mg (78%) of the title compound, a colourless crystalline solid that exhibited mp 119-120 °C. IR 1595, 1562, 1474, 1408, 1297, 1281, 1249, 1210, 1165, 1140, 1046, 1006 cm" 1. ' H - N M R 6 3.78 (s, 3H , O C H 3 ) , 4.52 (s, 2H, C H 2 B r ) , 6.58 (dd, 1H, H4, J = 8.7, 3.0 Hz) , 7.02 (d, 1H, H 6 , J = 3.0 Hz) , 7.68 (d, 1H, H 3 , J = 8.7 Hz) . 1 3 C - N M R 8 38.7, 55.4, 88.3, 116.2, 116.4, 140.5, 141.0, 160.2. Anal . Calcd for C 8 H 8 O B r I : C , 29.39; H , 2.47; Br , 24.44; I, 38.81. Found: C , 29.67; H , 2.43; Br , 24.33; I, 38.65. Chapter 4 190 Preparation of 2-Iodo-3-methoxybenzyl Alcohol (133). OH 1. BuLi , hexanes-Et 20, 0 °C -> rt 2- h OH OMe OMe 132 133 To a cold (0 °C) stirred solution of commercially available alcohol 132 (2.0 g, 14.5 mmol) in 4:1 H P L C grade hexane-dry Et20 (100 mL) was added, slowly via a syringe, B u L i (1.6 M solution in hexane, 32 mmol). 10 m L of dry Et20 was added to partially solubilize the formed thick precipitate and the mixture was stirred at room temperature for 3.5 h, becoming light brown. The reaction mixture was treated with a solution of resublimed iodine (4 g, 15 mmol) in dry Et20 (25 mL) and stirred for a further 15 min. To the mixture was added 15 m L of aqueous N H 3 - N H 4 C I (pH ~8). The aqueous phase was extracted with E t 2 0 ( 3 x 5 mL). The combined organic extracts were dried (MgSCv) and concentrated. Flash chromatography (60 g of silica gel, 2:1 —» 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired solid afforded 2.1 g (54%) of the title compound, a colourless crystalline solid that exhibited mp 88-89 °C. IR 3253, 2836, 1586, 1568, 1470, 1435, 1357, 1289, 1273, 1046, 1011 cm" 1. • H - N M R 8 2.00-2.03 (m, 1H, OH) , 3.88 (s, 3H, O C H 3 ) , 4.70 (d, 2 H , C H 2 O H , J = 6.4 Hz) , 6.75 (d, 1H, J = 8.2 Hz) , 7.07 (d, 1H, J = 8.2 Hz) , 7.29 (dd, 1H, H 5 , J = 8.2, 8.2 Hz) . 1 3 C - N M R 8 56.5, 69.7, 89.4, 110.1, 120.9, 129.4, 144.5, 157.9. Anal . Calcd for C 8 H 9 0 2 I : C , 36.39; H , 3.44. Found: C, 36.67; H , 3.37. Chapter 4 191 Preparation of 2-Iodo-3-methoxybenzyl Bromide (134). OH Ph3P*Br2, imidazole C H 2 C 1 2 , 0°C Br OMe OMe 133 134 Following General Procedure 3, alcohol 133 was converted into bromide 134 with the following quantities of reagents and solvents: alcohol 133 (1.0 g, 3.8 mmol), Ph 3 P»Br 2 (6.1 mmol), imidazole (518 mg, 7.6 mmol) and dry CH2CI2 (40 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired solid afforded 790 mg (64%) of the title compound, a colourless crystalline solid that exhibited mp 85-87 °C. IR 2965, 1567, 1465, 1423, 1300, 1270, 1205, 1059, 1015 cm" 1. 1 H - N M R 8 3.87 (s, 3 H , O C H 3 ) , 4.65 (s, 2H, C H 2 B r ) , 6.71 (dd, 1H, J = 8.2, 1.1 Hz) , 7.09 (dd, 1H, 7=8.2 , 1.1 Hz) , 7.26 (dd, 1H, H 5 , J= 8.2, 8.2 Hz) . 1 3 C - N M R 8 39.4, 56.6, 92.6, 110.6, 122.8, 129.5, 142.0, 158.6. H R M S for C 8 H 9 0 7 9 B r I (DCI, M + l T ) 326.8881, found 326.8880. Anal . Calcd for C 8 H 8 O B r I : C , 29.39; H , 2.47; Br , 24.44; I, 38.81. Found: C , 29.67; H , 2.41; Br , 24.25; I, 38.68. Chapter 4 192 Preparation of 2-Iodo-l-naphthalenemethanol (136). -OH -OH 1. BuLi , T M E D A - E t 2 0 , 0 °C -> rt 135 136 To a cold (-78 °C) stirred solution of B u L i (32 mmol) in dry E t 2 0 was added T M E D A (4.8 mL, 32 mmol) followed (10 mins later) by a solution of commercially available 1-naphthalenemethanol (135, 2 g, 12.6 mmol) in dry E t 2 0 (50 mL) . The pale green mixture was warmed to room temperature, becoming deep blue, and was stirred for 4 h. The reaction mixture was treated with a solution of resublimed iodine (3.5 g, 13.8 mmol) in dry E t 2 0 (50 mL) , becoming colourless. To the mixture was added 75 m L of saturated aqueous Na 2S 2C>3. The aqueous phase was extracted with E t 2 0 (3 x 25 mL) . The combined organic extracts were washed (brine), dried (MgSCU) and concentrated in vacuo. Flash chromatography (250 g of silica gel, 4:1 -> 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired solid afforded 1.5 g (42%) of the title compound, a colourless crystalline solid that exhibited mp 137— 138 °C. IR 3256, 1582,1504, 1421,1181, 1057, 1006 cm" 1. ! H - N M R 5 1.86 (t, 1H, O H , J = 6.4 Hz) , 5.29 (d, 2H , C H 2 O H ) , 7.48-7.58 (m, 3H), 7.81 (d, 1H, J = 8.7 Hz) , 7.86 (d, 1H, J = 8.7 Hz) , 8.25 (d, 1H, / = 8.4 Hz) . 1 3 C - N M R 5 67.2, 99.7, 124.4, 126.4, 127.4, 128.5, 130.2, 132.6, 133.5, 136.0, 138.4. Chapter 4 193 Preparation of l-Bromornethyl-2-iodonaphthalene (137). -OH Br Ph 3 P , Br 2 , imidazole CH 2 C1 2 , 0°C 136 137 Following General Procedure 3, alcohol 136 was converted into bromide 137 with the following quantities of reagents and solvents: alcohol 136 (1.4 g, 4.9 mmol), PhsP»Br2 (7.9 mmol), imidazole (670 mg, 9.8 mmol) and dry CH2CI2 (50 mL) . Flash chromatography (20 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired solid afforded 1.3 g (78%) of the title compound, a colourless crystalline solid that exhibited mp 9 7 -98 °C. IR 1578, 1505, 1437, 1202, 1121, 1044 cm" 1. 1 H - N M R 5 5.13 (s, 2H , C H 2 B r ) , 7.47-7.63 (m, 3H), 7.80-7.86 (m, 2H), 8.1 (d, 1H, J= 8.5 Hz) . 1 3 C - N M R 5 36.5, 100.5, 124.1, 126.6, 127.6, 128.8, 130.5, 131.7, 133.4, 135.7, 136.2. H R M S for C n H 8 7 9 B r I (DCI, M + ) 345.8854, found 345.8855. H R M S for C n H 8 8 1 B r I (DCI, M + ) 347.8834, found 347.8835. Anal . Calcd for C n H g B r l : C , 38.08; H , 2.32. Found: C , 38.25; H , 2.31. Chapter 4 194 Preparation of 6-(2-Iodocyclopent-l-enylmethyl)-3-isobutoxycyclohex-2-en-l-one (140). 138 140 To a stirred solution of alkenylstannane 138 1 4 b (872 mg, 2.11 mmol) in dry C H 2 C 1 2 (50 mL) at room temperature was added, dropwise via a syringe, a solution of iodine in dry CH2CI2 (1 g of I2 in 60 m L of CH2CI2). The solution was added until a persistent purple colour was observed (-40 m L of the iodine solution was required). The resulting mixture was stirred for 10 min and then was treated with 15 m L of saturated aqueous Na2S2C>3. The phases were separated and the aqueous phase was extracted with Et20 (3 x 10 mL) . The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. Flash chromatography (60 g of silica gel, 4:1 pet. ether-Et20) of the residual oi l followed by removal of traces of solvent from the acquired solid afforded 734 mg (93%) of the title compound, a colourless waxy solid that exhibited mp 68-69 °C. IR 2932, 1647, 1606, 1452, 1385, 1316, 1246, 1197, 1039 cm* 1. ^ - N M R 5 0.93 (d, 6H , J = 6.7 Hz , ( C H 3 ) 2 C H ) , 1.62 (dddd, 1H, J = 13.6, 9.3, 9.3, 4.9 Hz), 1.81-2.04 (m, 4H), 2.12-2.22 (m, 1H), 2.24-2.40 (m, 4H), 2.49 (ddd, 1H, J= 17.7, 5.3, 5.3 Hz), 2.57-2.68 (m, 3H), 3.52-3.59 (m, 2H), 5.30 (s, 1H). Chapter 4 195 1 3 C - N M R 5 19.0 (2 carbons), 23.4, 25.5, 27.7, 27.9, 33.1, 33.7, 43.4, 44.2, 74.7, 93.5, 102.1, 146.0, 177.3, 200.2. H R M S for C 1 6 H 2 3 0 2 I ( M + ) 374.0743, found 374.0741. Anal . Calcd for C i 6 H 2 3 0 2 I : C , 51.21; H , 6.45. Found: C, 51.49; H , 6.39. Preparation of 4-(2-Iodocyclopent-l-enylmethyI)cvclohex-2-en-l-one (58). Following general procedure 5, vinylogous ester 140 was converted into enone 58 with the following quantities of reagents and solvents: vinylogous ester 140 (500 mg, 1.33 mmol), D I B A L H (2.0 mmol), dry E t 2 0 (reduction, 10 mL); / ? -TsOH«H 2 0 (13 mg, 0.07 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 300 mg (75%) of the title compound, a colourless oi l . IR 2922, 2847, 1680, 1440, 1388, 1251, 1210, 1126 cm" 1. 196 Chapter 4 1 H - N M R 8 1.72 (dddd, 1H, J = 13.4, 13.4, 9.2, 4.4 Hz) , 1.91-2.06 (m, 3H), 2.25-2.38 (m, 5H), 2.53 (ddd, 1H, J = 16.8, 4.9, 4.9 Hz) , 2.58-2.70 (m, 3H), 5.98 (dd, 1H, J = 10.1, 2.0 Hz) , 6.76-6.79 (m, 1H). 1 3 C - N M R 8 23.5, 28.4, 34.1, 34.6, 36.8, 37.7, 44.2, 94.5, 129.4, 144.8, 153.7, 199.5. H R M S for C 1 2 H 1 5 O I ( M + ) 302.0168, found 302.0170. Anal . Calcd for C 1 2 H i 5 O I : C, 47.70; H , 5.00. Found: C , 47.48; H , 4.92. Preparation of 4-(2-Iodocyclohex-l-enylmethyl)cyclohex-2-en-l-one (58). To a stirred solution of alkenylstannane 141 D (390 mg, 1.10 mmol) in dry C H 2 C 1 2 (20 mL) at room temperature was added, dropwise via a syringe, a solution of iodine in dry C H 2 C 1 2 (1 g of I 2 in 60 m L of C H 2 C 1 2 ) . The solution was added until a persistent purple colour was observed (-15 m L of the iodine solution was required). The resulting mixture was stirred for 15 min and then was treated with 6 m L of saturated aqueous Na 2 S 2 C>3. The phases were separated and the aqueous phase was extracted with E t 2 0 ( 3 x 5 mL) . The combined organic extracts were dried (MgSCU) and concentrated under reduced pressure. Flash chromatography (40 g of silica Chapter 4 197 gel, 4:1 pet. ether-Et20) of the residual oil followed by removal of traces of solvent from the acquired solid afforded 370 mg (100%) of the title compound, a colourless o i l . IR 2932, 1679, 1541, 1508, 1447, 1388, 1328, 1251, 1209, 1181, 1138, 1065 cm" 1. 1 H - N M R 5 1.54-1.80 (m, 5H), 1.98-2.07 (m, 1H), 2.13-2.19 (m, 2H), 2.25-2.42 (m, 3H), 2.52 (ddd, 1H, J = 16.8, 4.9, 4.9 Hz) , 2.61-2.72 (m, 3H), 5.96 (dd, 1H, J = 10.1, 2.2 Hz) , 6.78-6.83 (m, 1H). 1 3 C - N M R 6 22.7, 25.7, 28.3, 31.4, 34.5, 36.8, 42.0, 47.0, 101.0, 129.2, 138.5, 153.7, 199.5. H R M S for C i 3 H 1 7 O I ( M + ) 316.0324, found 316.0324. Anal . Calcd for C i 3 H 1 7 O I : C , 49.38; H , 5.42. Found: C, 49.65; H , 5.42. Chapter 4 198 Preparation of 6-(2-Iodobenzyl)-3-isobutoxycyclohex-2-en-l-one (143): 2. 128, THF, -78 °C -> rt 1. L D A , THF, -78 °C -> rt 9 88 Following general procedure 4, vinylogous ester 9 and commercially available 2-iodobenzyl bromide (128) were converted into compound 88 with the following quantities of reagents and solvents: L D A (10.8 mmol), vinylogous ester 9 (2.0 g, 12 mmol), bromide 128 (3.9 g, 13 mmol) and dry TF£F (100 mL) . Flash chromatography (100 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 4.4 g (100%) of the title compound, a colourless o i l . IR 3050, 2932, 1651, 1607, 1562, 1471, 1385, 1195, 1011 cm" 1. ' H - N M R 5 0.93 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz) , 0.94 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz), 1.62-1.73 (m, 1H), 1.82-1.90 (m, 1H), 1.94-2.04 (m, 1H), 2.35-2.39 (m, 2H), 2.50-2.62 (m, 2H), 3.50-3.60 (m, 3H), 5.34 (s, 1H, =CHC=0) , 6.83-6.90 (m, 1H), 7.15-7.25 (m, 2H), 7.79 (d, 1H, J =7.9 Hz) . 1 3 C - N M R 8 19.0, 25.9, 27.7, 28.5, 40.15, 45.8, 74.8, 100.9, 102.2, 127.9, 128.1, 130.6, 139.6, 143.0, 177.0, 199.6. H R M S for C 1 7 H 2 i 0 2 I ( M + ) 384.0586, found 384.0589. Chapter 4 Anal . Calcd for C 1 7 H 2 i 0 2 I : C , 53.14; H , 5.51. Found: C, 53.25; H , 5.55. 199 Preparation of 6-(2-Iodo-5-methoxybenzyl)-3-isobutoxycyclohex-2-en-l-one (144). 9 2.131, THF, -78 °C -> rt 1. L D A , THF, -78 ° C - > r t MeO 144 Following General Procedure 4, vinylogous ester 9 and bromide 131 were converted into compound 144 with the following quantities of reagents and solvents: L D A 1.4 mmol), vinylogous ester 9 (247 mg, 1.5 mmol), bromide 131 (400 mg, 1.2 mmol) and dry T H F (20 mL) . Flash chromatography (50 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 481 mg (95%) of the title compound, a colourless o i l . IR2958, 1652, 1606, 1568, 1469, 1384, 1288, 1238, 1195, 1046 cm" 1. ! H - N M R 5 0.95 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz) , 0.95 (d, 3 H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz), 1.65-1.74 (m, 1H), 1.87-2.04 (m, 2H), 2.37-2.41 (m, 2H), 2.54-2.61 (m, 2H), 3.43-3.62 (m, 3H), 3,75 (s, 3H , C H 3 0 ) , 5.35 (s, 1H, =CHC=0) , 6.50 (dd, 1H, J = 8.7, 3.0 Hz) , 6.78 (d, 1H, / = 3.0 Hz) , 7.66 (d, 1H, / = 8.7 Hz) . 1 3 C - N M R 8 19.0, 25.9, 27.7, 28.6, 40.2, 45.9, 55.3, 74.8, 89.5, 102.2, 114.0, 116.6, 140.0, 144.1, 159.8, 177.2, 199.7. Chapter 4 200 H R M S for C18H23O3 ( M + minus I) 287.1647, found 287.1648. Anal . Calcd for C 1 8 H 2 30 3 I : C , 52.19; H , 5.60. Found: C, 52.50; H , 5.53. Preparation of 6-(2-Iodo-3-methoxybenzyl)-3-isobutoxycyclohex-2-en-l-one (145) Following General Procedure 4, vinylogous ester 9 and bromide 134 were converted into compound 145 with the following quantities of reagents and solvents: L D A (2.6 mmol), vinylogous ester 9 (476 mg, 2.8 mmol), bromide 134 (770 mg, 2.4 mmol) and dry T H F (30 mL) . Flash chromatography (50 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 932 mg (80%) of the title compound, a colourless oi l . IR3053, 2957, 1646, 1605,1564,1464, 1258, 1202,1074 cm" 1. 1 H - N M R 8 0.94 (d, 3H, ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz), 0.95 (d, 3H , ( C H 3 ) C H ( C H 3 ) , J = 6.7 Hz), 1.63-1.73 (m, 1H), 1.83-1.90 (m, 1H), 1.95-2.03 (m, 1H), 2.34-2.43 (m, 2H), 2.57-2.71 (m, 2H), 3.53-3.62 (m, 3H), 3.86 (s, 3H , O C H 3 ) , 5.35 (br. s, 1H, =CHC=0) , 6.65 (dd, 1H, aromatic, Chapter 4 201 J = 8.1, 1.1 Hz) , 6.82 (dd, 1H, aromatic, J = 8.1, 1.1 Hz) , 7.18 (dd, 1H, aromatic, J = 8.1, 8.1 1 3 C - N M R 8 19.0, 25.9, 27.7, 28.6, 40.5, 45.6, 56.4, 74.8, 102.2, 108.5, 123.2, 128.7, 145.0, 158.2, 177.1, 199.8. H R M S for C i 8 H 2 4 0 3 I (DCI, M+IT") 415.0770, found 415.0764. Anal . Calcd for C i 8 H 2 3 0 3 I : C , 52.19; H , 5.60. Found: C , 52.37; H , 5.68. Following general procedure 4, vinylogous ester 9 and bromide 137 were converted into compound 146 with the following quantities of reagents and solvents: L D A (3.8 mmol), vinylogous ester 9 (700 mg, 4.2 mmol), bromide 137 (1.2 g, 3.5 mmol) and dry T H F (50 mL) . Flash chromatography (50 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 1.1 g (61%) of the title compound, a colourless crystalline solid that exhibited mp 95-97 °C. Hz) . Preparation of 6-(2-Iodo-l-naphthalenemethyl)-3-isobutoxycyclohex-2-en-l-one (146). 9 146 Chapter 4 IR 2962, 166, 1605, 1382, 1240, 1193 c m 1 . 202 1 H - N M R 8 0.94 (d, 3H, ( C H 3 ) C H ( C H 3 ) , J = 6.6 Hz) , 0.95 (d, 3H, ( C H 3 ) C H ( C H 3 ) , J = 6.6 Hz) , 1.75-1.82 (m, 1H), 1.90-2.05 (m, 2H), 2.21-2.31 (m, 1H), 2.39 (dt, 1H, J= 17.5, 4.5 Hz) , 2.66-2.72 (m, 1H), 3.21 (dd, 1H, J = 14.4, 10.8 Hz) , 3.55-3.63 (m, 2H), 4.22 (dd, 1H, J = 14.4, 2.9 Hz), 5.41 (s, 1H, =CHC=0) , 7.39 (d, 1H, J = 8.7 Hz) , 7.47-7.49 (m, 2H), 7.78-7.80 (m, 1H), 7.86 (d, 1 H , 7 = 8.7 Hz) , 8.08-8.11 (m, 1H). 1 3 C - N M R 8 19.0, 26.3, 27.7, 28.9, 36.7, 46.8, 74.8, 100.6, 102.2, 124.7, 126.1, 126.9, 128.3, 128.7, 132.4, 133.5, 136.4, 139.8, 177.5, 199.6. H R M S for C 2 i H 2 4 0 2 I (DCI, M+H+) 435.0821, found 435.0821. Anal . Calcd for C 2 1 H 2 3 0 2 I : C , 58.07; H , 5.34. Found: C, 58.22; H , 5.26. Chapter 4 203 Preparation of 4-(2-Iodobenzyl)cyclohex-2-en-l-one (60). O' o 1, D I B A L H , E t 2 O , 0 ° C 2. N H 3 - N H 4 C I , H 2 0 (pH 8), rt 3. p-TsOH, H 2 0 , E t 2 0 , rt 143 60 Following general procedure 5, vinylogous ester 143 was converted into enone 60 with the following quantities of reagents and solvents: vinylogous ester 143 (190 mg, 0.49 mmol), D I B A L H (0.89 mmol), dry E t 2 0 (reduction, 5 mL) ; / ? -TsOH«H 2 0 (5 mg, 0.03 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL). Flash chromatography (35 g of silica gel, 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 127 mg (82%) of the title compound, a colourless crystalline solid that exhibited mp 84-85 °C. IR 2952, 1672, 1559, 1467, 1416. 1389, 1251, 1213, 1176, 1137, 1008 cm" 1. ' H - N M R 5 1.73-1.81 (m, 1H, p'-methylene), 2.03-2.09 (m, 1H, P'-methylene), 2.30-2.39 (m, 1H), 2.30-2.39 (m, 1H), 2.51 (ddd, 1H, a'-methylene, / = 16.8, 4.7, 4.7 Hz) , 2.77-2.90 (m, 3H), 5.98 (d, 1H, H C C = 0 , J = 10.2 Hz) , 6.82 (d, 1H, H C = C H C = 0 , J = 10.2 Hz) , 6.92 (dd, 1H, J = 7.4, 7.4 Hz) , 7.17 (d, 1H, J = 7.4 Hz), 7.28 (dd, 1H, J = 7.4 Hz) , 7.84 (d, 1H, J = 7.4 Hz) . 1 3 C - N M R 5 28.4, 36.4, 36.8, 45.1, 100.9, 128.3, 128.4, 129.4, 130.5, 139.9, 141.5, 153.1, 199.4. H R M S for C 1 3 H i 3 O I ( M + ) 312.0011, found 312.0011. Chapter 4 Anal . Calcd for C , 3 H 1 3 O I : C , 50.02; H , 4.20. Found: C, 50.06; H , 4.19. 204 Preparation of 4-(2-Iodo-5-methoxybenzyl)cyclohex-2-en-l-one (147). a o 1. D I B A L H , E t 2 0 , 0 °C 2. NH3-NH4CI , H 2 0 (pH 8), rt 3. p-TsOH, H 2 0 , E t 2 0 , rt MeO 144 MeO 1 4 7 Following general procedure 5, vinylogous ester 144 was converted into enone 147 with the following quantities of reagents and solvents: vinylogous ester 144 (440 mg, 1.06 mmol), D I B A L H (1.59 mmol), dry E t 2 0 (reduction, 10 mL); p - T s O H » H 2 0 (10 mg, 0.05 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL). Flash chromatography (50 g of silica gel, 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired liquid afforded 326 mg (90%) of the title compound, a colourless oi l . IR 3000, 2937, 1682, 1590, 1568, 1472, 1391, 1290, 1239, 1164, 1138, 1045, 1006 c m 1 . ' H - N M R 5 1.73-1.82 (m, 1H, p'-methylene), 2.05-2.10 (m, 1H, p'-methylene), 2.35 (ddd, 1H, a'-methylene, J = 16.8, 12.2, 4.9 Hz) , 2.52 (ddd, 1H, a'-methylene, J = 16.8, 4.9, 4.9 Hz), 2.74-2.87 (m, 3H), 3.77 (s, 3H, O C H 3 ) , 5.99 (dd, 1H, H C C = 0 , J = 10.2, 1.2 Hz) , 6.54 (dd, 1H, aromatic H4, J = 8.7, 3.0 Hz) , 6.75 (d, 1H, aromatic He, J = 3.0 Hz) , 6.83 (d, 1H, H C = C H C = 0 , J = 10.2 Hz) , 7.70 (d, 1H, aromatic H 3 , J = 8.7 Hz) . Chapter 4 205 1 3 C - N M R 5 28.4, 36.3, 36.7, 45.0, 55.3, 89.2, 114.0, 116.7, 129.3, 140.1, 142.4, 153.0, 159.8, 199.2. H R M S for C i 4 H 1 5 0 2 I ( M + ) 342.0117, found 342.0115. Anal . Calcd for C i 4 H i 5 0 2 I : C , 49.14; H , 4.42. Found: C , 49.41; H , 4.40. Preparation of 4-(2-Iodo-3-methoxybenzyl)cyclohex-2-en-l-one (148). Following general procedure 5, vinylogous ester 145 was converted into enone 148 with the following quantities of reagents and solvents: vinylogous ester 145 (700 mg, 1.69 mmol), D I B A L H (2.53 mmol), dry E t 2 0 (reduction, 20 mL); p - T s O H « H 2 0 (16 mg, 0.08 mmol), and dry E t 2 0 (hydrolysis-dehydration, 20 mL). Flash chromatography (50 g of silica gel, 1:1 pet. ether-E t 2 0 ) followed by removal of traces of solvent from the acquired solid afforded 487 mg (85%) of the title compound, a colourless crystalline solid that exhibited mp 67-69 °C. IR 3006, 2936, 1670, 1588, 1568, 1466, 1428, 1292, 1268, 1210, 1184, 1073, 1032, 1010 cm" 1. Chapter 4 206 ' H - N M R 5 1.73-1.82 (m, 1H, P '-methylene), 2.03-2.10 (m, 1H, p'-methylene), 2.34 (ddd, 1H, cc'-methylene, J= 17.0, 122, 4.8 Hz) , 2.51 (ddd, 1H, a'-methylene, J = 17.0, 4.8, 4.8 Hz) , 2.83-3.00 (m, 3H), 3.88 (s, 3H, O C H 3 ) , 5.98 (dd, 1H, H C C = 0 , J = 10.2, 1.6 Hz) , 6.69 (dd, 1H, H C = C H C = 0 , J= 10.2, 1.1 Hz) , 6.80-6.86 (m, 2H), 7.23 (dd, 1H, J = 7.9, 7.9 Hz) . 1 3 C - N M R 8 28.5, 36.3, 36.8, 45.4, 56.5, 93.2, 109.0, 123.0, 128.9, 129.2, 143.5, 153.4, 158.4, 199.6. H R M S for C i 4 H 1 5 0 2 I ( M + ) 342.0117, found 342.0114. Anal . Calcd for C i 4 H i 5 0 2 I : C , 49.14; H , 4.42. Found: C , 49.32; H , 4.30. Preparation of 4-(2-Iodo-l-naphthalenemethyl)cvclohex-2-en-l-one (149). Following general procedure 5, vinylogous ester 146 was converted into enone 149 with the following quantities of reagents and solvents: vinylogous ester 146 (450 mg, 1.04 mmol), D I B A L H (1.60 mmol), dry E t 2 0 (reduction, 10 mL); / ? -TsOH»H 2 0 (10 mg, 0.05 mmol), and dry E t 2 0 (hydrolysis-dehydration, 10 mL). Flash chromatography (50 g of silica gel, 1:1 pet. ether-Chapter 4 207 Et20) followed by removal of traces of solvent from the acquired liquid afforded 287 mg (76%) of the title compound, a colourless oi l . IR 3053, 2950, 1680, 1580, 1504, 1457, 1390, 1251, 1213, 1108 cm" 1. 1 H - N M R 5 1.93-2.03 (m, 1H, P'-methylene), 2.07-2.14 (m, 1H, p'-methylene), 2.34 (ddd, 1H, a'-methylene, J = 17.1, 12.4, 5.0 Hz) , 2.58 (ddd, 1H, a'-methylene, J = 17.1, 4.7, 4.7 Hz) , 2.96-3.03 (m, 1H, y-methine), 3.39-3.51 (m, 2H), 5.98 (dd, 1H, H C C = 0 , / = 10.1, 2.1 Hz) , 6.77-6.81 (m, 1H, H C = C H C = 0 ) , 7.44 (d, 1H, J = 8.6 Hz), 7.49-7.55 (m, 2H), 7.81-7.84 (m, 1H), 7.90 (d, 1H, J = 8.7 Hz) , 7.98-8.00 (m, 1H). 1 3 C - N M R 5 29.0, 37.1, 37.1, 41.3, 101.0, 124.2, 126.3, 127.1, 128.8, 129.0, 129.2, 132.5, 133.5, 136.4, 138.0, 153.1, 199.4. H R M S for C i 7 H 1 5 O I ( M + ) 362.0168, found 362.0166. Anal . Calcd for C , 7 H 1 5 O I : C , 56.22; H , 4.44. Found: C , 56.04; H , 4.40. Chapter 4 208 Preparation of (1R*, 8S*YTricvclo r6.4.0.0 2 ' 61dodec-2(6Ven-ll-one (59). O 1. T M S C l , T H F - H M P A ; f-BuLi, -78 °C rt 2 . H 2 0 Following general procedure 7, enone 58 was converted into tricyclic ketone 59 with the following quantities of reagents and solvents: enone 58 (100 mg, 0.33 mmol), f -BuLi (1.7 M solution in pentane, 0.99 mmol), dry H M P A (172 uL , 0.99 mmol), T M S C l (168 uL , 1.32 mmol) and dry T H F (5 mL) . Flash chromatography (5 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 53 mg (91%) of the title compound, a colourless o i l . The ^ - N M R spectrum of ketone 59 matched that previously reported. Preparation of (25*. 7S*YTricvclor7.4.0.0 2 ' 71tridec-l(9)-en-4-one (150). O 1. TMSCl , T H F - H M P A ; f-BuLi, -78 °C -> rt 2 . H 2 0 142 Following general procedure 7, enone 142 was converted into tricyclic ketone 150 with the following quantities of reagents and solvents: enone 142 (100 mg, 0.32 mmol), f -BuLi (1.7 M solution in pentane, 0.70 mmol), dry H M P A (138 uL, 0.79 mmol), T M S C l (160 uL , 1.27 mmol) and dry T H F (5 mL) . Flash chromatography (8 g of silica gel, 4:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 53 mg (88%) of the title Chapter 4 209 compound, a colourless o i l . The ' H - N M R spectrum of ketone 150 matched that previously reported. Preparation of (25*. 75*VTricvclor7.4.0 2 ' 7ltridec-U9),10.12-trien-4-one (61). O 1. T M S C l , T H F - H M P A ; f-BuLi, -78 °C -> rt 2 . H 2 0 O 60 61 Following general procedure 7, enone 60 was converted into tricyclic ketone 61 with the following quantities of reagents and solvents: enone 60 (96 mg, 0.31 mmol), r -BuLi (1.7 M solution in pentane, 0.64 mmol), dry H M P A (133 p L , 0.77 mmol), T M S C l (156 p L , 1.22 mmol) and dry T H F (5 mL) . Flash chromatography (5 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 53 mg (93%) of the title compound, a colourless o i l . IR 3020, 2931, 1713, 1480, 1458, 1330, 1257, 1214 cm" 1. 1 H - N M R 5 1.70-1.81 (m, 1H, H i ) , 1.97-2.09 (m, 1H, H i ) , 2.23-2.30 (m, 2H), 2.62 (dd, 1H, J = 7.5, 15.0 Hz) , 2.70-2.82 (m, 3H), 3.16-3.27 (m, 1H), 3.64 (ddd, 1H, J = 7.5, 7.5, 7.5 Hz) , 7.11-7.22 (m, 4H). 1 3 C - N M R 6 27.6, 36.8, 38.4, 38.4, 42.5, 43.8, 123.7, 124.9, 126.7, 127.0, 142.2, 145.0, 212.5. Chapter 4 HRMS for C i 3 H 1 4 0 (M + ) 186.1045, found 186.1048. 210 Anal. Calcd for C 1 3 H 1 4 0 : C, 83.83; H , 7.58. Found: C, 83.53; H , 7.60. Preparation of (2S*. 71S*)-ll-Methoxytricvclor7.4.027ltridec-l('9)J0J2-trien-4-one (151). O 1. TMSCl , T H F - H M P A ; ?-BuLi, -78 °C -> rt 2. H 2 0 OMe 151 Following general procedure 7, enone 147 was converted into tricyclic ketone 151 with the following quantities of reagents and solvents: enone 147 (100 mg, 0.29 mmol), r-BuLi (1.7 M solution in pentane, 0.64 mmol), dry H M P A (127 uL, 0.73 mmol), T M S C l (176 uL, 1.17 mmol) and dry THF (5 mL). Flash chromatography (7 g of silica gel, 4:1 —» 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 50 mg (80%) of the title compound, a colourless oil. IR2921, 1708, 1614, 1583, 1488, 1424, 1329, 1237, 1144, 1097, 1031 cm' 1. ^ - N M R 8 1.71-1.80 (m, 1H, H 2 ) , 2.00-2.07 (m, 1H, H 2 ) , 2.24-2.27 (m, 2H), 2.57 (ddd, 1H, J = 15.3, 7.6 Hz), 2.67-2.82 (m, 3H), 3.19 (dd, 1H, J = 15.3, 8.1 Hz), 3.54-3.59 (m, 1H, H^), 3.76 (s, 3H, OCH 3 ) , 6.70-6.74 (m, 2H), 7.03 (d, 1H, H 5 , 7 = 8.2 Hz). Chapter 4 2 1 1 13, C - N M R 5 27.6, 37.1, 38.2, 38.6, 42.8, 42.9, 55.3, 110.3, 112.5, 124.2, 137.1, 143.7, 159.2, 212.5. H R M S for C i 4 H 1 6 0 2 ( M + ) 216.1150, found 216.1150. Anal . Calcd for C i 4 H 1 6 0 2 : C , 77.75; H , 7.46. Found: C, 77.53; H , 7.39. Preparation of (25*. 75*)-13-Methoxvtricvclor7.4.0 2 ' 7ltridec-l('9').10J2-trien-4-one ( 1 5 2 ) . O 1. T M S C l , T H F - H M P A ; t-BuU, -78 °C -> rt H OMe 2 . H 2 0 152 Following general procedure 7, enone 1 4 8 was converted into tricyclic ketone 1 5 2 with the following quantities of reagents and solvents: enone 1 4 8 (100 mg, 0.29 mmol), r -BuLi (1.7 M solution in pentane, 0.64 mmol), dry H M P A (127 p L , 0.73 mmol), T M S C l (176 p L , 1.17 mmol) and dry T H F (5 mL) . Flash chromatography (9 g of silica gel, 4:1 —> 1:1 pet. ether-Et.20) followed by removal of traces of solvent from the acquired liquid afforded 58 mg (90%) of the title compound, a colourless crystalline solid that exhibited mp 72-73 °C. IR 2975, 2940, 1713, 1588, 1480, 1427, 1287, 1259, 1221, 1092, 1070 cm" 1. ' H - N M R 5 1.79-1.89 (m, 1H), 2.10-2.29 (m, 2H), 2.37 (ddd, 1H, J = 17.6, 6.1, 4.7 Hz), 2.47 (dd, 1H, J = 15.5, 10.7 Hz) , 2.742.90 (m, 3H), 3.18-3.24 (m, 1H, H 9 a ) , 3.60-3.70 (m, 1H, Ufa), Chapter 4 212 3.77 (s, 3H , C H 3 0 ) , 6.65 (d, 1H, J = 7.9 Hz) , 6.80 (d, 1H, J = 7.9 Hz) , 7.14 (dd, 1H, H 7 , J = 7.9, 7.9 Hz) . 13 C - N M R 8 27.1, 3.1, 37.8, 38.9, 41.2, 41.4, 54.9, 108.1, 116.9, 128.5, 132.8, 144.1, 156.4, 213.6. H R M S for C ,4H,60 2 ( M + ) 216.1150, found 216.1151. Anal . Calcd for C i 4 H i 6 0 2 : C , 77.75; H , 7.46. Found: C, 77.74; H , 7.46. Preparation of ( U S * . 16S*VTetracvclor8.7.0.0 2 70 n'1 6lheptadeca-l('2).3.5.7( ,8).9-pentaen-13-one (153). O 1. T M S C l , T H F - H M P A ; r-BuLi, -78 °C -> rt 2 . H 2 0 149 153 Following general procedure 7, enone 149 was converted into tetracyclic ketone 153 with the following quantities of reagents and solvents: enone 149 (90 mg, 0.25 mmol), r -BuLi (1.7 M solution in pentane, 0.66 mmol), dry H M P A (120 uL , 0.69 mmol), T M S C l (140 uL , 1.10 mmol) and dry T H F (5 mL) . Flash chromatography (5 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired solid afforded 44 mg (75%) of the title compound, a colourless crystalline solid that exhibited mp 103-104 °C. Chapter 4 213 IR 2931, 1707, 1426, 1342, 1202, 1125 cm" 1. ' H - N M R 5 1.82-1.92 (m, 1H, H 1 5 ) , 2.13-2.20 (m, 1H, H 1 5 ) , 2.29-2.35 (m, 2H), 2.64 (dd, 1H, / = 15.3, 6.5 Hz) , 2.85 (dd, 1H, J = 15.3, 6.5 Hz) , 2.95-3.04 (m, 1H), 3.10 (dd, 1H, J = 16.4, 4.3 Hz) , 3.58 (dd, 1H, / = 16.4, 8.5 Hz) , 3.79-3.85 (m, 1H), 7.29 (d, 1H, J = 8.4 Hz) , 7.42-7.52 (m, 2H), 7.71 (d, 1H, J = 8.4 Hz) , 7.77 (d, 1H, J = 8.3 Hz) , 7.84 (d, 1H, 7=8.1 Hz) . 1 3 C - N M R 8 27.7, 36.0, 37.2, 38.0, 42.9, 44.0, 122.0, 124.3, 125.3, 126.2, 127.7, 128.5, 130.3, 133.0, 137.7, 141.9,212.6. H R M S for C i 7 H i 6 0 ( M + ) 236.1201, found 236.1199. Anal . Calcd for C 1 7 H 1 6 0 : C , 86.41; H , 6.82. Found: C, 86.32; H , 6.89. Chapter 4 214 4.2.2 Lithium-Iodine Exchange Initiated Intramolecular 1,2-Addition Reactions-Preparation of 3-Bromomethyl-2-(fe^butyldimethylsilyl)-4-iodofuran (159). I TBS O H Pr^P'Br^ imidazole CH 2 C1 2 , 0°C TBS Br 157 159 Following General Procedure 3 alcohol 157 was converted into bromide 159 with the following quantities of reagents and solvents: alcohol 157 (1.1 g, 3.3 mmol), Pri3P«Br2 (5.3 mmol), imidazole (450 mg, 6.6 mmol) and dry CH2CI2 (30 mL) . Filtration of the acquired crude mixture through silica gel and removal of the solvent by rotary evaporation afforded the title compound, pure enough for characterization, in approximately 92% yield. However, the poor stability of this compound precluded the possibility for combustion analysis, and required its immediate use in the alkylation step. IR 2953, 2929, 2884, 2857, 1549, 1471, 1436, 1363, 1253, 1209, 1092 cm" 1. ^ - N M R 5 0.32 (s, 6H), 0.91 (s, 9H), 4.35 (s, 2H), 7.59 (s, 1H). 1 3 C - N M R 8 -6.1, 17.4, 25.3, 26.3, 69.9, 134.2, 145.0, 158.6. H R M S for C n H i 8 0 7 9 B r I S i ( M + ) 399.9355, found 399.9355. H R M S for C n H 1 8 0 8 1 B r I S i ( M + ) 401.9335, found 401.9337. Chapter 4 215 Preparation of 4-Bromomethyl-3-iodofuran (160). -TBS -OH Ph 3P*Br 2, imidazole CH 2C1 2, 0°C T B S Br 158 160 Following General Procedure 3 alcohol 158 was converted into bromide 160 with the following quantities of reagents and solvents: alcohol 158 (954 mg, 4.3 mmol), P h 3 P » B r 2 (6.8 mmol), imidazole (586 mg, 8.6 mmol) and dry C H 2 C 1 2 (50 mL) . Flash chromatography (20 g of afforded 786 mg (64%) of the title compound, a colourless o i l . IR3143 , 1573, 1433, 1211, 1144, 1047,880 cm" 1. ' H - N M R 5 4.27 (s, 2 H , C H 2 B r ) , 7.42 (d, 1H, 7 = 1.7 Hz) , 7.49 (d, 1H, J = 1.7 Hz) . 1 3 C - N M R 5 23.4, 68.6, 124.6, 141.8, 146.6. H R M S for C 5 H40 7 9 BrI ( M + ) 285.8490, found 285.8487. H R M S for C 5 H40 8 1 BrI ( M + ) 287.8470, found 287.8470. The poor stability of this compound precluded the possibility for combustion analysis. silica gel, 1:1 pet. ether-Et 2Q) followed by removal of traces of solvent from the acquired liquid Chapter 4 216 Preparation of 6-(2-(rg^Butyldimethylsilyl)-4-iodofuran-3-ylmethyl)-3-isobutoxycyclohex-2-en-l-one (161). Following general procedure 4, vinylogous ester 9 and bromide 159 were converted into compound 161 with the following quantities of reagents and solvents: L D A (3.4 mmol), vinylogous ester 9 (680 mg, 4.0 mmol), bromide 159 (1.2 g, 2.9 mmol) and dry T H F (35 mL) . Flash chromatography (50 g of silica gel, 9:1 -> 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 1.2 g (84%) of the title compound, a colourless o i l . IR 3132, 2955, 2857, 1657, 1610, 1471, 1384, 1367, 1251, 1194, 1092 cm" 1. • H - N M R 5 0.23 (s, 3H , C H 3 S i ) , 0.24 (s, 3H, C H 3 S i ) , 0.87 (br. s, 9 H , (CH 3 ) 3 Si ) , 0.95 (d, 3H, J = 6.7 H z , ( C H 3 ) 2 C H ) , 0.96 (d, 3H, J = 6.7 H z , ( C H 3 ) 2 C H ) , 1.60-1.70 (m, 1H), 1.86-1.92 (m, 1H), 1.95-2.05 (m, 1H), 2.29 (dd, 1H, J = 14.7, 11.1 Hz , furanylmethyl C H 2 ) , 2.37-2.40 (m, 2H), 2.52-2.60 (m, 1H), 3.31 (dd, 1H, J= 14.7, 3.9 H z , furanylmethyl C H 2 ) , 3.54-3.61 (m, 2H), 5.34 (s, 1H, C=CHC=0) , 7.57 (s, 1H). 1 3 C - N M R 8 -5.5, -5.2, 17.7, 19.1 (2 carbons), 23.3, 26.3, 26.5 (3 carbons), 27.7, 29.1, 46.1, 70.8, 74.8, 102.2, 135.3, 149.5, 155.7, 177.2, 199.6. Chapter 4 217 H R M S for C2 iH 3 30 3 IS i (DCI, M+H+) 489.1322, found 489.1320. Anal . Calcd for C 2 i H 3 3 0 3 I S i : C , 51.64; H , 6.81. Found: C, 52.00; H , 7.01. Preparation of 6-(4-Iodofuran-3-vlmethyl)-3-isobutoxycyclohex-2-en-l-one (162). 9 162 Following general procedure 4, vinylogous ester 9 and bromide 160 were converted into compound 162 with the following quantities of reagents and solvents: L D A (3.1 mmol), vinylogous ester 9 (607 mg, 3.6 mmol), bromide 160 (740 mg, 2.6 mmol) and dry T H F (30 mL) . Flash chromatography (50 g of silica gel, 4:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 758 mg (79%) of the title compound, a colourless o i l . IR 3140, 2958, 2873, 1655, 1606, 1470, 1384, 1368, 1242, 1195, 1045 cm" 1. ! H - N M R 5 0.94 (d, 3 H , J = 6.7 Hz , ( C H 3 ) 2 C H ) , 0.95 (d, 3H , / = 6.7 H z , ( C H 3 ) 2 C H ) , 1.58-1.68 (m, 1H, ( C H 3 ) 2 C H ) , 1.97-2.05 (m, 2H), 2.36-2.49 (m, 4H), 2.95-3.01 (m, 1H), 3.53-3.60 (m, 2H, C H 2 Q ) , 5.33 (s, 1H, C=CHC=0) , 7,20 (br.s, 1H), 7.37 (d, 1H, J= 1.5 Hz) . Chapter 4 218 1 3 C - N M R 8 19.0 (2 carbons), 25.0, 25.9, 27.7, 28.5, 45.1, 70.8, 74.8, 102.3, 124.9, 140.5, 145.4, 177.2, 199.7. H R M S for C12H20O3I (DCI, M + H + ) 375.0457, found 375.0457. Anal . Calcd for C i 5 H 1 9 0 3 I : C , 48.14; H , 5.12. Found: C , 47.99; H , 5.23. Chapter 4 219 General Procedure 8: r-BuLi-initiated intramolecular 1,2-addition of alkenyl and aryl functions to vinylogous esters; hydrolysis-dehydration of the resulting 3° alcohol. To a cold (-78 °C) stirred solution of the vinylogous ester-iodide (1 equiv) in dry T H F (-15 m L per mmol of substrate) was added, rapidly via a syringe, r -BuLi (1.4-1.7 M solution in pentane, 2.2 equiv). The resulting yellow solution was stirred for 5 min, then was warmed to room temperature. The reaction mixture was treated with water (-1 m L per mmol of substrate) followed by 10% aq. HC1 (-5 drops per mmol of substrate) and was stirred for 30 min, allowing the dehydration-hydrolysis of the 3° alcohol to reach completion (monitored by T L C ) . The mixture was diluted with E t 2 0 (one half the volume of T H F ) and the phases were separated. The aqueous phase was extracted three times with E t 2 0 . The combined organic extracts were dried ( M g S 0 4 ) and concentrated. Flash chromatography (50-100 g of silica gel per g of crude product), followed by removal (vacuum pump) of traces of solvent from the acquired material, afforded the desired cyclized dienone. R 2. H 2 0 ; 10% aq. HC1 1. t-BuU (2.2 equiv), THF, -78 °C -» rt Chapter 4 220 Preparation of 9-Methvlbicvclo r4.3.01nona-l(2),8-dien-3-one (164). o l . f - B u L i , THF, -78 ° C - > r t 2. H 2 0 ; 10% aq. HC1 81 164 Following general procedure 8, vinylogous ester 81 was converted into bicyclic dienone 164 with the following quantities of reagents and solvents: vinylogous ester 81 (2.5 g, 7.2 mmol), r -BuLi (1.7 M solution in pentane, 17.2 mmol) and dry T H F (50 mL) . Flash chromatography (100 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 976 mg (92%) of the title compound, a colourless oi l . IR 2912, 1655, 1610 cm" 1. • H - N M R 5 1.65-1.76 (m, 1H), 1.75-1.80 (m, 3H, C H 3 ) , 2.09-2.39 (m, 3H), 2.50-2.60 (m, 1H), 2.67-2.75 (m, 1H), 2.87-2.98 (m, 1H), 5.76 (br. s, 1H), 6.27 (br. s, 1H). 1 3 C - N M R 5 12.0, 29.3, 37.5, 38.1, 41.3, 115.5, 139.7, 143.9, 174.8, 200.0. H R M S for C 1 0 H i 2 O ( M + ) 148.0888, found 148.0886. Anal . Calcd for C i 0 H 1 2 O : C, 81.03; H , 8.17. Found: C, 80.99; H , 8.19. Chapter 4 221 Large Scale Preparation of 164. A solution of vinylogous ester 81 in 500 m L of dry T H F was cooled to -78 °C. A freshly purchased Aldr ich Sure-Seal® bottle of f -BuLi (1.7 M solution in pentane) was connected to the reaction vessel via a wide-bore cannula. The entire content of the bottle (100 m L , 170 mmol) was transferred as rapidly as possible into the stirred reaction mixture. The reaction vessel, now containing a yellow heterogeneous mixture, was removed from the cold bath. The mixture was stirred for 30 min, during which time, it became an orange solution. To the reaction mixture was added 150 m L of saturated aqueous NH4CI followed by 50 m L of 10% aqueous HC1. The resulting mixture was stirred at room temperature for 10 min. The aqueous phase was extracted with Et20 (2 x 100 mL). The combined organic extracts were washed (saturated aqueous NaHCCh, 150 mL; brine, 150 mL) , dried (MgS04, 10 g) and concentrated under reduced pressure. The above procedure was repeated on the same scale. Flash chromatography (400 g of silica gel, 4:1 -> 1:1 pet. ether-Et20) of the combined crude oils afforded, after concentration and removal of traces of solvent, 23 g (93%) of dienone 164. Chapter 4 222 Preparation of 6,9-Dimethylbicyclo r4.3.01nona-l(2),8-dien-3-one (165). O' 1. f-BuLi, THF, -78 °C -> rt 2. H 2 0 ; 10% aq. H C l 82 165 Following general procedure 8, vinylogous ester 82 was converted into bicyclic dienone 165 with the following quantities of reagents and solvents: vinylogous ester 82 (100 mg, 0.28 mmol), / - B u L i (1.7 M solution in pentane, 0.69 mmol) and dry TF£F (5 mL) . Flash chromatography (7 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 35 mg (77%) of the title compound, a colourless o i l . IR 2928, 1656, 1610, 1450, 1348, 1317, 1283, 1189, 1031, 1005 cm" 1. ' H - N M R 5 1.21 (s, 3H , C H 3 C ) , 1.82 (d, 3H , C H 3 C = C H ) , 1.91 (ddd, 1H, J 13.0, 13.0, 5.6 Hz) , 2.03 (ddd, 1H, J= 13.0, 5.6, 1.9 Hz) , 2.27-2.34 (m, 2H), 2.35-2.45 (m, 1H), 2.53 (ddd, 1H, J = 18.4, 13.0, 5.6 Hz) , 5.75 (s, 1H, C=CH-C=0) , 6.20 (br. s, 1H, C = C H - C H 2 ) . 1 3 C - N M R 5 12.1, 26.4, 34.1, 34.5, 42.5, 47.0, 115.4, 138.5, 141.8, 178.3, 199.4. H R M S for C u H m O ( M + ) 162.1045, found 162.1043. Chapter 4 223 Preparation of 9-Cyclopropylbicyclo"4.3.01non-l(2),8-dien-3-one (166). O' o 2. H 2 0 ; 10% aq. HC1 1. r-BuLi, THF, -78 ° C - > r t Jj 166 Following general procedure 8, vinylogous ester 87 was converted into bicyclic dienone 166 with the following quantities of reagents and solvents: vinylogous ester 87 (100 mg, 0.27 mmol), r -BuLi (1.7 M solution in pentane, 0.73 mmol) and dry TFfF (4 mL) . Flash chromatography (8 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 53 mg (96%) of the title compound, a colourless o i l . IR 3005, 2925, 2853, 1657, 1607, 1454, 1353, 1316, 1292, 1241, 1193, 1050 cm" 1. ' H - N M R 8 0.40-0.56 (m, 2H, cyclopropyl methylene), 0.72-0.82 (m, 2H, cyclopropyl methylene), 1.35-1.39 (m. 1H), 1.67-1.78 (m, 1H), 2.08-2.14 (m, 1H), 2.20-2.26 (m, 1H), 2.35 (ddd, 1H, J = 17.3, 13.8, 4.9 Hz) , 2.51-2.56 (m, 1H), 2.65 (dddd, 1H, J = 17.8, 7.1, 2.8, 1.4 Hz) , 2.89-2.96 (m, 1H), 6.01 (d, 1H, J= 2.1 Hz) , 6.08 (br.s, 1H). 1 3 C - N M R 8 5.4, 7.0, 7.2, 29.3, 37.1, 38.2, 41.7, 115.8, 139.5, 146.3, 174.2, 199.9. H R M S for C 1 2 H 1 4 0 ( M + ) 174.1045, found 174.1047. Anal . Calcd for C i 2 H 1 4 0 : C , 83.20; H , 7.56. Found: C, 82.99; H , 7.56. Chapter 4 Preparation of 9-Benzyloxymethylbicyclor4.3.01non-l(2),8-en-3-one (167) Following general procedure 8, vinylogous ester 88 was converted into bicyclic dienone 167 with the following quantities of reagents and solvents: vinylogous ester 88 (150 mg, 0.33 mmol), r -BuLi (1.7 M solution in pentane, 0.73 mmol) and dry T H F (15 mL) . Flash chromatography (10 g of silica gel, 1:1-0:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 47 mg (56%) of the title compound, a colourless o i l . IR 3032, 2928, 2858, 1654, 1610, 1496, 1454, 1316, 1243, 1188, 1099 cm" 1. ] H - N M R 8 1.69-1.80 (m, 1H), 2.19-2.28 (m, 2H), 2.34 (ddd, 1H, J = 17.2, 13.8, 4.9 Hz), 2.50-2.57 (m, 1H), 2.70-2.78 (m, 1H), 2.95-3.00 (m, 1H), 4.19 (br.s, 2H), 4.54 (s, 2H), 5.86 (br.s, 1H, =CHC=0) , 6.59 (s, 1H, 8-vinyl), 7.26-7.36 (m, 5H). 1 3 C - N M R 8 29.1, 37.5, 38.1, 41.6, 65.2, 72.9, 116.4, 127.7 (3 carbons), 128.4 (2 carbons), 137.6, 140.9, 145.5, 171.6, 199.6. H R M S for C n H 1 8 0 2 ( M + ) 254.1307, found 254.1316. Anal . C a l c d f o r C i 7 H 1 8 0 2 : C , 80.28; H , 7.13. Found: C, 80.29; H , 7.13. Chapter 4 225 Preparation of 9-Benzyloxymethyl-6-methylbicyclo r4.3.01non-l(2),8-en-3-one (168). Following general procedure 8, vinylogous ester 89 was converted into bicyclic dienone 168 with the following quantities of reagents and solvents: vinylogous ester 89 (108 mg, 0.23 mmol), ?-BuLi (1.7 M solution in pentane, 0.51 mmol) and dry T H F (12 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 50 mg (81%) of the title compound, a colourless o i l . JR 3032, 2925, 2859, 1654, 1614, 1454, 1372, 1316, 1284, 1240, 1221, 1195, 1099 cm" 1. • H - N M R 8 1.24 (s, 3H , C H 3 ) , 1.94 (ddd, 1H, J = 13.3, 12.9, 5.4 Hz) , 2.04 (ddd, 1H, / = 12.9, 5.6, 1.9 Hz) , 2.38-2.44 (m, 3H), 2.54 (ddd, 1H, J = 18.3, 13.3, 5.6 Hz) , 4.19 (s, 2H), 4.53 (s, 2H), 5.82 (s, 1H, H-5), 6.50 (br.s, 1H, H-8), 7.24-7.36 (m, 5H). 1 3 C - N M R 8 26.2, 34.1, 34.2, 42.9, 46.9, 65.3, 72.8, 116.2, 127.7 (2 carbons), 127.8, 128.4 (2 carbons), 137.7, 139.7, 143.3, 175.1, 199.1. H R M S for C i 8 H 2 i 0 2 (DCI, M+H+) 269.1452, found 269.1546. Anal . Calcd for C, 8H2o0 2: C , 80.56; H , 7.51. Found: C , 80.30; H , 7.64. 89 168 t>Bn Chapter 4 226 Preparation of 8-Methvlbicvclo"3.3.01octa-U2),7-dien-3-one (169). rr o 1. f-BuLi, THF, -78 °C -> it O -I 2. H 2 0 ; 10% aq. HC1 99 169 Following general procedure 8, vinylogous ester 99 was converted into bicyclic dienone 169 with the following quantities of reagents and solvents: vinylogous ester 99 (122 mg, 0.37 mmol), t-BuLi (1.7 M solution in pentane, 0.80 mmol) and dry T H F (5 mL) . Flash chromatography (5 g of silica gel, 1:1 pet. ether-EtaO) followed by removal of traces of solvent from the acquired liquid afforded 44 mg (90%) of the title compound, a colourless o i l . IR 2941, 2916, 2845, 1689, 1609, 1594, 1442, 1233, 1183, 1148 cm" 1. 1 H - N M R 5 1.93-1.95 (m, 3H, C H 3 ) , 2.17-2.24 (m, 1H, H-4), 2.29 (dd, 1H, J= 17.1, 4.9 Hz , H -6), 2.61 (dd, 1H, J= 17.1, 6.4 H z , H-6), 2.64-2.71 (m, 1H, H-4), 3.32-3.38 (m, 1H, H-5), 5.72 (d, 1H, / = 2.3 H z , H-8), 6.19 (br.s, 1H, H-3). 1 3 C - N M R 8 13.0, 36.8, 42.7, 46.8, 116.4, 137.5, 143.7, 190.6, 210.2. H R M S for C 9 H 1 0 O ( M + ) 134.0732, found 134.0737. Anal . Calcd for C 9 H 1 0 O : C , 80.56; H , 7.51. Found: C, 80.42; H , 7.47. Chapter 4 227 Preparation of 10-Methvlbicvclor5.3.01deca-l(2),9-dien-3-one (170). O' o l . ? - B u L i , T H F , - 7 8 °C -> rt 2. H 2 0 ; 10% aq. H C l 100 170 Following general procedure 8, vinylogous ester 100 was converted into bicyclic dienone 170 with the following quantities of reagents and solvents: vinylogous ester 100 (101 mg, 0.28 mmol), r -BuLi (1.7 M solution in pentane, 0.69 mmol) and dry T H F (4 mL) . Flash chromatography (5 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 40 mg (88%) of the title compound, a colourless o i l . IR 3036, 2934, 2863, 1651, 1605, 1443, 1352, 1263, 1179 cm" 1. ' H - N M R 5 1.50 (dddd, 1H, J = 13.4, 12.2, 8.7, 6.7 Hz) , 1.68-1.78 (m, 1H), 1.78-1.79 (m, 3H, =CCH 3 ) , 1.88-1.97 (m, 1H), 2.09 (dddd, 1H, J = 13.4, 8.6, 5.4, 5.4 Hz) , 2.13-2.20 (m, 1H), 2.51-2.58 (m, 1H), 2.66 (ddd, 1H, J = 14.6, 12.2, 4.2 Hz) , 2.77-2.84 (m, 1H), 3.15-3.22 (m, 1H), 5.90 (s, 1H), 6.22 (br.s, 1H). 1 3 C - N M R 5 12.7, 19.9, 31.1, 39.5, 41.3, 41.6, 120.0, 140.4, 142.7, 170.2, 203.8. H R M S for C n H u O ( M + ) 162.1045, found 162.1044. Anal . Calcd for C „ H 1 4 0 : C , 81.44; H , 8.70. Found: C, 81.30; H , 8.80. Chapter 4 228 Preparation of T.lO-DimethylbicvclorS.B.Oldeca-iaig-dien-B-one (171). O" o 1. r-BuLi, THF, -78 ° C - > r t 2. H 2 0 ; 10% aq. HC1 101 171 Following general procedure 8, vinylogous ester 101 was converted into bicyclic dienone 171 with the following quantities of reagents and solvents: vinylogous ester 101 (109 mg, 0.29 mmol), f -BuLi (1.7 M solution in pentane, 0.72 mmol) and dry T H F (4 mL) . Flash chromatography (7 g of silica gel, 4:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 46 mg (90%) of the title compound, a colourless o i l . IR 2917, 2845, 1651, 1614, 1448, 1291, 1262, 1210, 1184 cm" 1. ' H - N M R 5 1.19 (s, 3H, C H 3 ) , 1.74-1.76 (m, 3H, =CCH 3 ) , 1.79-1.93 (m, 3H), 1.95-2.12 (m, 1H), 2.22-2.29 (m, 1H), 2.34-2.43 (m, 1H), 2.55 (ddd, 1H, J = 15.1, 11.0, 4.5 H z , H-4), 2.71 (ddd, 1H, J = 15.1, 6.2, 3.5 H z m H-4), 5.76 (s, 1H, H-6), 6.06 (br.s, 1H, H-9). 1 3 C - N M R 8 13.0, 21.1, 29.9, 38.0, 45.2, 47.3, 49.2, 119.2, 138.8, 139.8, 169.5, 205.1. H R M S for C , 2 H 1 6 0 ( M + ) 176.1201, found 176.1201. Anal . Calcd for C i 2 H 1 6 0 : C , 81.77; H , 9.15. Found: C, 81.82; H , 9.23. Chapter 4 229 Preparation of Tricvclo~7.4.0 2 , 7~rtdec-l(9).2(3U0,12-tetraen-4-one (172). O' o l . f - B u L i , T H F , -78 ° C - > r t 2. H 2 0 ; 10% aq. HC1 88 172 Following general procedure 8, vinylogous ester 88 was converted into tricyclic compound 172 with the following quantities of reagents and solvents: vinylogous ester 88 (107 mg, 0.28 mmol), f -BuLi (1.7 M solution in pentane, 0.64 mmol) and dry T H F (5 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 47 mg (92%) of the title compound, a colourless crystalline solid that exhibited mp 101-102 °C. IR 3040, 2928, 1646, 1463, 1350, 1316, 1244, 1194 cm" 1. 1 H - N M R 6 1.83-1.93 (m, 1H, H I ) , 2.34-2.49 (m, 2H), 2.58-2.64 (m, 1H), 2.72 (dd, 1H, / = 15.6, 6.3 H z , H9), 3.15-3.23 (m, 1H, H9a), 3.25 (dd, 1H, J= 15.6, 8.1 Hz , H9), 6.31 (d, 1H, J = 2.3 Hz , H4), 7.28 (dd, 1H, J = 7.3, 7.3 Hz) , 7.33-7.40 (m, 2H), 7.57 (d, 1H, J = 7.5 Hz) . 1 3 C - N M R 8 29.3, 37.1, 38.2, 42.0, 117.3, 122.8, 125.5, 127.3, 131.7, 138.2, 148.4, 169.1, 199.7. H R M S for C , 3 H i 2 0 ( M + ) 184.0888, found 184.0889. Anal . Calcd for C i 3 H 1 2 0 : C , 84.75; H , 6.56. Found: C , 85.00; H , 6.54. Chapter 4 230 Preparation of ll-Methoxvtricvclor7.4.0 2- 71tridec-l('9),2( ,3),10J2-tetraen-4-one (173). Following general procedure 8, vinylogous ester 144 was converted into tricyclic compound 173 with the following quantities of reagents and solvents: vinylogous ester 144 (100 mg, 0.24 mmol), f -BuLi (1.7 M solution in pentane, 0.56 mmol) and dry T H F (4 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 50 mg (97%) of the title compound, a colourless crystalline solid that exhibited mp 155-156 °C. IR2931 , 2836, 1642, 1601, 1489, 1310, 1288, 1269, 1247, 1192, 1100, 1024 cm" 1. ' H - N M R 8 1.80-1.91 (m, 1H, H I ) , 2.31-2.47 (m, 2H), 2.55-2.62 (m, 1H), 2.68 (dd, 1H, J = 15.5, 5.9 Hz , H9), 3.14-3.24 (m, 2H), 3.83 (s, 3H , C H 3 0 ) , 6.20 (d, 1H, J = 1.5 Hz , H4), 6.83-6.84 (m, 2H), 7.49 (d, 1H, J= 9.2 Hz). 1 3 C - N M R 8 29.3, 37.2, 38.0, 42.3, 55.5, 109.8, 114.5, 115.5, 124.1, 130.9, 150.9, 163.1, 168.8, 199.4. H R M S for C14H14O2 ( M + ) 214.0994, found 214.0996. Chapter 4 231 Anal . Calcd for C 1 4 H 1 4 0 2 : C , 78.48; H , 6.59. Found: C, 78.68; H , 6.54. Preparation of 13-Methoxvtricvclor7.4.02'7ltridec-U9').2('3').10.12-tetraen-4-one (174). Following general procedure 8, vinylogous ester 145 was converted into tricyclic compound 174 with the following quantities of reagents and solvents: vinylogous ester 145 (100 mg, 0.24 mmol), r -BuLi (1.7 M solution in pentane, 0.60 mmol) and dry T H F (5 mL) . Flash chromatography (8 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired liquid afforded 49 mg (95%) of the title compound, a colourless crystalline solid that exhibited mp 72-73 °C. IR 3070, 2931, 2844, 1651, 1618, 1582, 1484, 1283, 1272, 1195, 1076 cm' 1 ; 1 H - N M R 8 1.81-1.92 (m, 1H), 2.30-2.36 (m, 1H), 2.43 (ddd, 1H, J = 17.1, 13.9, 4.9 Hz) , 2.55-2.61 (m, 1H), 2.69 (dd, 1H, J= 15.4, 6.2 Hz) , 3.09-3.19 (m, 1H), 3.21 (dd, 1H, J = 15.4, 8.1 Hz) , 3.88 (s, 3H , O C H 3 ) , 6.71 (d, 1H, / = 2.3 Hz , =CHC=0) , 6.74 (d, 1H, / = 7.9 Hz) , 6.91 (d, 1H, J = 7.9 Hz) , 7.32 (dd, 1H, J = 7.9, 7.9 H z , H7). 145 174 Chapter 4 232 1 3 C - N M R 5 29.3, 37.2, 37.9, 41.8, 55.2, 108.7, 117.4, 120.8, 126.4, 132.8, 150.5, 158.3, 167.0, 200.5. H R M S for C i 4 H 1 4 0 2 ( M + ) 214.0994, found 214.0995. Anal . Calcd for C i 4 H 1 4 0 2 : C , 78.48; H , 6.59. Found: C , 78.40; H , 6.69. Preparation of Tetracvclor8.7.0.0 2 ' 70.' 1 ' 1 61heptadeca-l(2),3,5J('8'),9,lia2 s)-hexaen-13-one: Following general procedure 8, vinylogous ester 146 was converted into tetracyclic compound 175 with the following quantities of reagents and solvents: vinylogous ester 146 (120 mg, 0.28 mmol), f -BuLi (1.7 M solution in pentane, 0.66 mmol) and dry T H F (5 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et 2 0) followed by removal of traces of solvent from the acquired liquid afforded 56 mg (87%) of the title compound, a colourless crystalline solid that exhibited mp 103-104 °C. IR (solution in CHC1 3 ) 3061, 2938, 1645, 1616, 1384, 1319, 1288, 1244, 1196 cm" 1. Chapter 4 233 1 H - N M R 5 1.91-2.02 (m, 1H), 2.44-2.55 (m, 2H), 2.63-2.68 (m, 1H), 2.96 (dd, J = 16.5, 5.8 Hz , H-17), 3.30-3.37 (m, 1H), 3.68 (dd, 1H, J = 16.5, 7.9 Hz , H-17), 6.36 (d, 1H, J= 2.5 Hz , H -12), 7.55-7.57, (m, 2H), 7.60 (d, 1H, J = 8.5 Hz) , 7.77 (d, 1H, J = 8.5 Hz) , 7.87-7.90 (m, 2H). 1 3 C - N M R (400 M H z , benzene-d6, referenced to 128 ppm) 5 29.3, 35.2, 38.6, 41.7, 117.6, 119.9, 125.1, 126.8, 127.4, 128.5, 129.0, 130.7, 135.4, 136.0, 146.8, 168.1, 197.2. H R M S for C i 7 H 1 4 0 ( M + ) 234.1045, found . Anal . Calcd for C 1 7 H i 4 0 : C , 87.15; H , 6.02. Found: C , ; H , . Preparation of 5-(fe^Butyldimethylsilyl)-4-oxatricyclor6.4.0 1 , 81trideca-l(12),2(3),5-trien-ll-one (1761 Following general procedure 8, vinylogous ester 161 was converted into tricyclic compound 176 with the following quantities of reagents and solvents: vinylogous ester 161 (112 mg, 0.23 mmol), f -BuLi (1.7 M solution in pentane, 0.50 mmol), and dry T H F (5 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent 234 Chapter 4 from the acquired solid afforded 59 mg (89%) of the title compound, a colourless crystalline solid that exhibited mp 53-54 °C. JR 3084, 2955, 2929, 2854, 1658, 1640, 1593, 1364, 1240, 1200, 1105 cm" 1. J H - N M R 8 0.20 (s, 6H , (CH 3 ) 2 Si ) , 0.88 (s, 9H , ( C H 3 ) 3 C S i ) , 1.90 (m, 1H, H7), 2.23-2.29 (m, 1H), 2.33-2.47 (m, 2H), 2.51-2.55 (m, 1H), 3.03 (dd, 1H, 15.6, 7.6 H z , H8), 3.37-3.44 (m, 1H), 6.08 (d, 1H, J = 2.2 Hz , C=CHC=0) , 7.76 (s, 1H, H3). 1 3 C - N M R 8 -6.5 (2 carbons), 17.3, 26.2 (3 carbons), 29.4, 29.7, 37.7, 48.7, 119.3, 130.1, 140.3, 144.1, 150.9, 159.8, 199.3. H R M S for C i 7 H 2 4 0 2 S i (DCI, M+H+) 289.1624, found 289.1630. Anal . Calcd for C i 7 H 2 4 0 2 S i : C , 70.79; H , 8.39. Found: C , 70.85; H , 8.49. Chapter 4 235 Preparation of 4-Oxatricvclor6.4.Q 1 ' 8ltrideca-iq2),2(3),5-trien-ll-one (177). O" o 1. f-BuLi, THF, -78 ° C - > r t 2. H 2 0; 10% aq. H C l G 162 177 Following general procedure 8, vinylogous ester 162 was converted into tricyclic compound 177 with the following quantities of reagents and solvents: vinylogous ester 162 (113 mg, 0.30 mmol), r -BuLi (1.7 M solution in pentane, 0.66 mmol), and dry T H F (5 mL) . Flash chromatography (10 g of silica gel, 1:1 pet. ether-Et20) followed by removal of traces of solvent from the acquired solid afforded 47 mg (90%) of the title compound, a colourless crystalline solid that exhibited mp 88-89 °C. IR3112, 2932, 2865, 1656, 1641, 1540, 1368, 1292, 1195, 1097, 1009 cm" 1. * H - N M R 5 1.88-1.99 (m, 1H, H7), 2.26-2.32 (m, 1H), 2.35-2.46 (m, 2H), 2.54-2.59 (m, 1H), 3.03 (dd, 1H, J = 15.6, 8.3 Hz , H8), 3.39-3.47 (m, 1H), 6.12 (d, 1H, J = 2.4 H z , C=CHC=0) , 7.19 (br.s, 1H, H3), 7.58 (br.s, 1H, H I ) . 1 3 C - N M R 8 28.4, 29.4, 37.7, 48.7, 119.7, 130.3, 132.1, 134.7, 136.1, 159.4, 199.3. H R M S for C n H i o 0 2 ( M + ) 174.0681, found 174.0680. Anal . Calcd for C n H , o 0 2 : C , 75.84; H , 5.79. Found: C , 75.68; H , 5.81. Chapter 4 4.3 The Tota l Synthesis of Mang ico l F, 236 Preparation of 3-(Tributylgermyl)but-3-en-l-ol (205). -OH 1. Bu 3 GeH, H2PtCl<5.6H20, CH 2 C1 2 , 0 °C -> rt Bu 3Ge -OH T M S 2. p-TsOH, CH 2 C1 2 , 40 °C 203 205 To a stirred solution of commercially available 4-(trimethylsilyl)but-3-yn-l-ol (203) (19 g, 134 mmol) in 110 m L of dry CH2CI2 at room temperature was added solid hydrogen hexachloroplatinate hexahydrate (695 mg, 1.34 mmol). The mixture was stirred until all solid material had dissolved, then was cooled to 0 °C. To the brown solution was added, over 5 min via a syringe, neat tributylgermane (48 m L , 187 mmol). The reaction mixture was stirred for 0.5 h, was warmed to room temperature and was stirred for a further 15 h. The resulting dark brown suspension was filtered through a pad of silica gel (50 g). The collected solid material was washed with CH2CI2 (5 x 100 mL) . The combined filtrate and washes were concentrated under reduced pressure to a volume of approximately 200 mL. The reaction vessel was fitted with an air condenser. To the reaction mixture was added solid p - T s O H (25 g, 134 mmol), the mixture immediately coming to reflux. The reaction vessel was heated in a 40 °C bath for 2.5 h. To the cooled mixture was slowly added 225 m L of saturated aqueous NaHCOs . The aqueous phase was extracted with Et^O (2 x 100 mL) . The reaction described above was repeated using identical quantities of reagents and solvents. The combined organic extracts from both reactions were dried (MgSC^) and were concentrated under reduced pressure. The resulting crude brown oi l was purified by flash chromatography (1 kg of silica gel, 9:1 -> 4:1 - » 1:1 pet. ether-Et20). Concentration of the appropriate fractions afforded 52.4 g (60%) of the title compound as a light brown oi l . Chapter 4 237 IR 3336, 3046, 2958, 2926, 2856, 1463, 1377, 1174, 1082, 1047 cm" 1. • H - N M R (300 M H z ) 5 0.76-0.83 (m, 6H, C H 2 G e ) , 0.83-0.89 (m, 9 H , C H 3 ) , 1.27-1.33 (m, 12H, CH3CH2CH2), 1.42 (br. s, 1H, OH) , 2.42 (t, 2H, / = 6.5 H z , = C C H 2 ) , 3.60-3.65 (m, 2H, C H 2 O H ) , 5.28 (d, 1H, J = 2.6 Hz) , 5.64 (m, 1H). 1 3 C - N M R 5 12.4, 13.7, 26.5, 27.3, 40.8, 61.1, 125.6, 148.4. The more polar isomer of the product expected from this reaction was not isolated. Chapter 4 238 Preparation of 4-Iodo-2-(tributylgermyl)but-l-ene (207). B u 3 G e -OH Ph3P, I 2, imidazole B u 3 G e CH2C12 205 207 To a stirred solution of triphenylphosphine (79 g, 300 mmol) and imidazole (28 g, 416 mmol) in 600 m L of dry CH2CI2 at room temperature was added, in small portions over 15 min, solid iodine (76 g, 300 mmol). The resulting yellow mixture was stirred for 15 min. To the mixture was added, via a syringe over 10 min, neat alcohol 205 (73 g, 231 mmol). The reaction mixture was stirred for 4 h, then was poured into 300 m L of saturated aqueous NaHCOs. The aqueous phase was extracted with E t 2 0 (2 x 150 mL). The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. The resulting crude oi l was purified by flash chromatography (650 g of silica gel, 19:1 pet. ether-Et20) to afford 75 g (76 %) of the title compound as a colourless o i l . IR 3047, 2958, 2926, 2856, 1463, 1377, 1253, 1166, 1083 cm" 1. 1 H - N M R 5 0.76-0.81 (m, 6H, C H 2 G e ) , 0.83-0.90 (m, 9 H , C H 3 ) , 1.27-1.33 (m, 12H, CH3CH2CH2), 2.69 (m, 2H, =CCH 2 ) , 3.17 (t, 2H, J = 8.2 H z , C H 2 I ) , 5.25 (dt, 1H, J = 2.1, 1.0 H z , =CH), 5.59 (dt, 1H, 7 = 2.1, 1.4 H z , =CH). 1 3 C - N M R 8 4.2, 12.4, 13.7, 26.5, 27.3, 41.9, 124.4, 150.7. H R M S for C i 2 H 2 4 7 2 G e I (DCI, M+JT") 367.0144, found 367.0147. H R M S for C , 2 H 2 4 7 4 G e I (DCI, M+H+) 369.0135, found 369.0133. Chapter 4 239 Preparation of Li thium (3-(Trimethylgermyl)but-3-en-l-yl)cyanocuprate (17). M e 3 G e . / \ ^ l 1. f-BuLi, Et 2 Q, -78 °C M e a G e ^ / ^ / C u l C N J L i ^ 2. CuCN, -78 °C -> -20 °C To a cold (-78 °C) stirred solution of r -BuLi (1.7 M solution in pentane, 2 mmol) in 10 m L of dry Et20 was added, via a cannula, a solution of iodide 206 (300 mg, 1.0 mmol) in 3 m L of dry EtaO, by allowing the solution to run slowly down the inside of the cold flask. The resulting colourless solution was stirred for 10 min, then was treated, in a single portion, with solid copper(I) cyanide (90 mg, 1.0 mmol). The reaction vessel was transferred into a -20 °C bath and the mixture was stirred until it became homogeneous. The reaction mixture was immediately cooled back to -78 °C. This solution of the cuprate reagent must be used immediately. Preparation of Li thium (3-(Tributylgermyl)but-3-en-l-yl)cyanocuprate (208). B u 3 G e . ^ ^ / l 1 .2 r -BuLi ,Et 2 0, -78 0 C B u 3 G e . ^ ^ C u ( C N ) L i 2. CuCN, -78 °C -> -20 °C 207 208 To a cold (-78 °C) stirred solution of f -BuLi (1.7 M solution in pentane, 27 mL, 46 mmol) in 200 m L of dry E t 2 0 was added, via a cannula, a solution of iodide 207 (9.8 g, 23 mmol) in 20 m L of dry Et20, by allowing the solution to run slowly down the inside of the cold flask. The resulting colourless solution was stirred for 10 min, then was treated, in a single portion, with solid copper (I) cyanide (2.1 g, 23 mmol). The reaction vessel was transferred into a - 20 °C bath and the mixture was stirred until a brown colour began to appear. The reaction Chapter 4 240 mixture was immediately cooled back to -78 °C. This solution of the cuprate reagent must be used immediately. Preparation of (65*. 95*)-9-Methvlbicvclo r4.3.01non-l-en-3-one (198). H 2 , Lindlar's cat., MeOH O 164 198 To a solution of dienone 164 (2.5 g, 16.5 mmol) in 150 m L of H P L C grade M e O H at room temperature was added Lindlar 's catalyst (880 mg, 0.41 mmol of Pd). The reaction mixture was stirred vigorously under a H 2 atmosphere (balloon, ~1 atm) for 4 hours. To the reaction mixture was added 150 m L of E t 2 0 . The entire mixture was filtered through Celite (20 g). The collected solid material was washed with E t 2 0 (2 x 50 mL) . The combined filtrate and washings were concentrated under reduced pressure. The resulting colourless oi l was purified by flash chromatography (75 g of silica gel, 1:1 pet. ether-Et 2 0). Concentration of the appropriate fractions afforded 2.3 g (90%) of the title compound as a fragrant colourless o i l . JR 2958, 2868, 1671, 1458, 1417, 1357, 1319, 1242, 1187 cm" 1. 1 H - N M R 6 1.09 (d, 3H, / = 7.1 Hz , C H 3 ) , 1.28-1.38 (m, 1H, H-7), 1.40-1.48 (m, 1H, H-8), 1.59 (dddd, 1H, J = 14.2, 12.5, 12.5, 4.5 Hz , H-5(3), 1.92-2.05 (m, 2H, H-7' and H-8'), 2.19 (dddd, 1H, J = 12.5, 4.8, 4.8, 2.4 H z , H-5a), 2.28 (ddd, 1H, J = 17.1, 14.2, 4.8 H z , H-4p), 2.42 (ddd, 1H, 7 = 17.1, 4.5, 2.4 Hz , H-4a), 2.58-2.66 (m, 1H, H-6), 2.70-2.79 (m, 1H, H-9), 5.81 (s, 1H, H-2). Chapter 4 241 1 3 C - N M R 5 18.5 (-ve), 29.7 (+ve), 30.0 (+ve), 32.3 (+ve), 37.4 (+ve), 37.8 (-ve), 42.4 (-ve), 120.7 (-ve), 180.1 (+ve), 200.5 (+ve). H R M S for C i o H 1 4 0 ( M + ) 150.1045, found 150.1047. Anal . Calcd for C i 0 H 1 4 O : C, 79.96; H , 9.39. Found: C, 79.66; H , 9.58. Table 18: ' H - N M R (400 M H z , CDC1 3 ) data for dienone 198: C O S Y and N O E experiments. O Assignment" ' H - N M R (400 M H z ) 5 (mult., 7 (Hz)) C O S Y Correlations N O E Correlations H-2 5.81 (s, 1H) None H - 4 a 2.42 (ddd, 7 = 17.1,4.5,2.4 Hz) H-4p, H-5a , H-5p H-4(3 2.28 (ddd, J= 17.1, 14.2, 4.8 Hz) H-4a , H-5a , H-5p H - 5 a 2.19 (dddd, J = 12.5, 4.8, 4.8, 2.4 Hz) H-4a , H-4p, H-5p H-5p 1.59 (dddd, J = 14.2, 12.5, 12.5, 4.5 Hz) H-4a , H-4p, H - 5 a H-6(a) 2.58-2.66 (m) H-5a , H-5p, H-7, H-7 ' H-7 1.28-1.38 (m) H-6, H-7 ' , H-8, H-8 ' H-7 ' part of the m at 1.92-2.05 H-6, H-7, H-8, H-8 ' H-8 1.40-1.48 (m) H-7, H-7 ' , H-8 ' , H9 H-8 ' part of the m at 1.92-2.05 H-7, H-7 ' , H-8, H9 H-9(a) 2.70-2.79 (m) H-8, H-8' , H-10 C H 3 (on C-9) 1.09 (d, 7 = 7.1 Hz) H-9 H-2, H-8, H-5p aThe use of the prime descriptor (eg. H-7') in this table designates the proton of a geminal pair that is the furthest downfield of the two. The descriptor a refers to a proton that is below the plane of the page, with respect to the figure shown above, and the descriptor p refers to a proton that is above the plane of the page. Chapter 4 242 Preparation of (IS*, 6S*, 9S*)-9-Methvl-l-(3-(trimethvlgermvnbut-3-en-l-vnbicyclo-r4.3.01nonan-3-one (209). To a cold (-78 °C) stirred solution of cyanocuprate 17 (4 mmol) in 40 m L of dry Et20 was added, via a syringe, neat boron trifluoride-diethyl etherate (756 uL , 6 mmol) followed, via a cannula, by a solution of enone 198 (304 mg, 2.0 mmol) in 10 m L of dry EtaO. The deep orange mixture was stirred for 1.5 h and then was removed from the cold bath for 5 min. To the mixture was added, rapidly, 10 m L of 3 M aqueous H C l in 50 m L of T H F and then 50 m L of water. The resulting mixture was stirred for 20 min and then was treated with 50 m L of aqueous NH3-NH4CI (pH 8). The deep blue aqueous phase was extracted with Et20 (3 x 25 mL) . The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. The residual oi l was purified by flash chromatography (50 g of silica gel, 4:1 pet. ether-Et20). Concentration of the appropriate fractions afforded 544 mg (83%) of the title compound as a colourless o i l . O O 198 209 IR 3045, 2957, 1713, 1456, 1429, 1379, 1308, 1235, 1117, 1050 c m 1 . ^ - N M R 8 0.17 (s, 9H), 0.80 (d, 3H , J = 6.6 Hz) , 1.22-1.41 (m, 3H), 1.63-2.17 (m, 11H), 2.20 (d, 1H, J = 13.9 Hz) , 2.40 (ddd, 1H, J = 15.5, 10.2, 6.9 Hz) , 5.12-5.13 (m, 1H), 5.45-5.47 (m, 1H). Chapter 4 243 1 3 C - N M R 5 -1.8 (3 carbons), 13.8, 25.8, 26.9, 30.7, 31.0, 36.5, 36.8, 41.0, 41.2, 44.0, 49.6, 121.8, 153.9,213.6. Preparation of (15*. 65*. 95*)-9-Methvl-l-( ,3-('tributvlgermvl)but-3-en-l-vl)bicvclo-r4.3.01nonan-3-one (210). To a cold (-78 °C) stirred solution of cyanocuprate 208 (23 mmol) in 220 m L of dry Et20 was added, via a syringe, neat boron trifluoride-diethyl etherate (5 m L , 40 mmol) followed, via a cannula, by a solution of enone 198 (2.0 g, 13.3 mmol) in 20 m L of dry Et^O. Upon addition of the enone on this scale, a thick brown precipitate formed that prevented further agitation with a magnetic stirrer. The reaction mixture was allowed to stand for 1 h, then was removed from the cold bath for 10 min. To the mixture was added 15 m L of 3 M aqueous HC1 followed by 50 m L of H2O. The precipitate dissolved and the resulting mixture was stirred for 20 min and then was treated with 75 m L of aqueous N H 3 - N H 4 C I (pH 8). The deep blue aqueous phase was extracted with Et20 (3 x 50 mL). The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. The remaining crude brown oi l was purified by flash chromatography (150 g of silica gel, 9:1 pet. ether-Et20). Concentration of the appropriate fractions afforded 4.7 g (79%) of the title compound as a colourless o i l . 198 210 IR 2926, 1714, 1463, 1378, 1233, 1082 cm" 1. Chapter 4 244 ' H - N M R (300 M H z ) 5 0.72-0.78 (m, 6H, C H 2 G e ) , 0.80 (d, 3H , J = 4.1 Hz , C H 3 C H ) , 0.82-0.89 (m, 9H , C H 3 C H 2 ) , 1.24-1.42 (m, 15H), 1.64-2.06 (m, 10H), 2.10 (dddd, 1H, J = 15.7, 5.1, 5.1, 1.6 Hz) , 2.18 (d, 1H, / = 13.9 Hz , H-2), 2.41 (ddd, 1H, J = 15.7, 10.4, 7.0 Hz) , 5.10 (d, 1H, J = 2.3 Hz , =CH), 5.51-5.52 (m, 1H, =CH). 1 3 C - N M R 8 12.5, 13.7 (6 carbons), 25.8, 26.5 (6 carbons), 27.0, 27.3, 30.7, 31.1, 36.5, 41.0, 41.2, 44.1,49.6, 122.7, 151.8,213.5. H R M S for C 2 2 H 3 9 0 7 2 G e ( M + m i n u s C4H9) 391.2222, found 391.2225. H R M S for C 2 2 H 3 9 0 7 4 G e (M + minus C 4 H 9 ) 393.2213, found 393.2216. Chapter 4 245 Preparation of (15*. 65*. 95*)4-('3-Iodobut-3-en-l-vn-9-methvlbicvclor4.3.01nonan-3-one (2111 209 211 To a stirred solution of ketone 209 (1.2 g, 3.8 mmol) in 25 m L of dry CH2CI2 at room temperature was added, via a syringe, a solution of iodine (1.2 g, 4.6 mmol) in 25 m L of dry CH2CI2. The resultant deep purple reaction mixture was stirred for 3 h at room temperature, then was treated with 10% aqueous Na2S204 (100 mL). The aqueous phase was extracted with Et20 (2 x 50 mL) . The combined organic extracts were dried (MgS04) and were concentrated under reduced pressure. The crude o i l was purified by flash chromatography (100 g of silica gel, 4:1 pet. ether-Et20) and the appropriate fractions were concentrated to afford 1.2 g (92%) of the title compound as a colourless oi l . IR 2948, 1713, 1619, 1456, 1430, 1340, 1308, 1275, 1234, 1142, 1113 cm" 1. ' H - N M R 5 0.81 (d, 3H, J= 6.4 Hz , C H 3 ) , 1.30-1.42 (m, 1H), 1.42-1.58 (m, 2H), 1.65-1.97 (m, 8H), 2.14 (dddd, 1H, J = 12.1, 5.0, 5.0, 1.7 Hz) , 2.22 (d, 1H, J = 14.0 Hz) , 2.24-2.46 (m, 3H), 5.63 (d, 1H, J= 1.5 Hz) , 5.97-5.98 (m, 1H). , J C - N M R 5 13.7 (-ve), 25.8 (+ve), 26.8 (+ve), 30.5 (+ve), 36.3 (+ve), 36.5 (+ve), 39.9 (+ve), 41.1 (-ve), 41.3 (-ve), 44.0 (+ve), 49.3 (+ve), 111.8 (+ve), 125.4 (+ve), 213.3 (+ve). Chapter 4 246 H R M S for Q4H22OI (DCI, M+H+) 333.0715, found 333.0715. Anal . Calcd for C 1 4 H 2 i O I : C , 50.62; H , 6.37. Found: C , 51.00; H , 6.42. Preparation of (IS*, 65*, 95 l*)-l-(3-Iodobut-3-en-l-yl)-9-methylbicyclor4.3.01nonan-3-one £2111 To a solution of ketone 210 (19.1 g, 42.5 mmol) in 400 m L of dry C H 2 C 1 2 at room temperature was added, portionwise with vigorous stirring, solid iodine (15.1 g, 60 mmol). The reaction mixture was stirred for 15 h at room temperature, then was treated with 10% aqueous Na2S20 4 (300 mL). The aqueous phase was extracted with Et20 (2 x 150 mL) . This procedure was repeated on a second batch of the starting material (210), using the same quantities of reagents and solvents. The combined organic extracts from both reactions were dried (MgS0 4 ) and were concentrated under reduced pressure. The crude o i l was purified by flash chromatography (1 kg of silica gel, 19:1 —» 4:1 —» 1:1 pet. ether-Et20). The appropriate fractions were concentrated to afford 26.0 g (92%) of the title compound as a colourless oi l that exhibited spectral properties identical with those of the product obtained from the iododegermylation of the corresponding trimethylgermane 209 (see previous experimental procedure). 210 211 Chapter 4 247 Preparation of (15*. 95*. 125*)-4.12-Dimethvltricvclor7.3.0.0 1 , 51dodec-4-en-6-one (212). To a solution of sodium methoxide (983 mg, 18 mmol) in 6 m L of H P L C grade M e O H was added 90 m L of dry T H F . The turbid mixture was drawn into a syringe which was connected to a syringe pump. To a solution of ketone 211 (4.3 g, 13 mmol) in 130 m L of dry T H F was added tetrakistriphenylphosphinepalladium(O) (2.3 g, 2.0 mmol). The resulting yellow solution was stirred for 10 min. The N a O M e / M e O H - T H F mixture was added to the reaction mixture, at room temperature, over a period of 3 h. To the brown reaction mixture was added 50 m L of aqueous HC1 (3 M ) , 250 m L of brine and 250 m L of Et20. The aqueous phase was extracted with Et20 (3 x 50 mL) . The combined organic extracts were dried ( M g S O ^ and were concentrated under reduced pressure. The remaining brown oi l was purified by flash chromatography (250 g of silica gel, 9:1 pet. ether-Et20) and concentration of the appropriate fractions afforded 2.3 g (88%) of the title compound as a colourless oi l . IR 2938, 2871, 1681, 1620 ,1456, 1433, 1374, 1334, 1242, 1188, 1163 cm" 1. ' H - N M R 5 0.71 (d, 3H, J = 7.2 Hz , C H 3 ) , 1.18-1.26 (m, 1H), 1.49-1.57 (m, 1H), 1.63-1.92 (m, 6H), 1.93-2.02 (m, 1H), 2.05 (br. s, 3H , =CCH 3 ) , 2.05-2.15 (m, 2H), 2.15-2.22 (m, 1H), 2.32 (ddd, 1H, J= 17.8, 12.3, 5.1 Hz) , 2.41-2.52 (m, 1H). 211 212 Chapter 4 248 1 3 C - N M R 6 16.2 (-ve), 17.3 (-ve), 25.1 (+ve), 29.6 (+ve), 33.9 (+ve), 36.7 (+ve), 37.6 (+ve), 43.5 (+ve), 44.0 (-ve), 45.4 (-ve), 60.5 (+ve), 137.6 (+ve), 153.1 (+ve), 202.6 (+ve). H R M S for C 1 4 H 2 0 O ( M + ) 204.1514, found 204.1515. Preparation of (IS*, 45*. 5/?*, 95*. 125*)-4,12-Dimethvltricvclor7.3.0.0 1 ' 5ldodecan-6-one (214). 212 To dry 10% palladium on activated carbon (131 mg, 0.12 mmol of Pd) under an inert (argon) atmosphere was carefully added a solution of enone 212 (315 mg, 1.5 mmol) in 15 m L of H P L C grade M e O H . The argon atmosphere in the reaction vessel was replaced with a hydrogen atmosphere and the mixture was stirred vigorously at room temperature for 30 min, under positive hydrogen pressure (hydrogenation apparatus, ~1 atm). To the reaction mixture was added 20 m L of E t 2 0 . The mixture was filtered through a pad of Celi te®. The collected solid material was washed with E t 2 0 (3 x 20 mL) . The combined filtrate and washes were concentrated under reduced pressure. Flash chromatography (25 g of silica gel, 4:1 pet. ether-Et 2 0) of the remaining colourless oil afforded, after concentration of the appropriate fractions, 293 mg (92%) of the title compound as a colourless oi l . This reaction was scaled up to 4 g of starting material, with only a 5% reduction in yield. IR 2946, 2872, 1696, 1458, 1378, 1330, 1240, 1146 cm" 1. Chapter 4 249 ! H - N M R (300 M H z ) 8 0.89 (d, 3H, J = 6.8 Hz) , 0.98 (d, 3H , J = 6.3 Hz) , 1.01-1.11 (m, 1H), 1.14-1.22 (m, 1H), 1.28-1.40 (m, 1H), 1.60-1.95 (m, 8H), 1,97 (d, 1H, J = 9.9 Hz , H-5), 1.99-2.15 (m, 2H), 2.25-2.42 (m, 2H). 1 3 C - N M R 8 15.1, 18.9, 24.0, 26.3, 32.3, 33.7, 35.0, 39.4, 40.4, 44.2, 45.7, 59.1, 60.0, 216.1. H R M S for C i 4 H 2 2 0 ( M + ) 206.1671, found 206.1673. Anal . Calcd for C , 4 H 2 2 0 : C , 81.50; H , 10.75. Found: C , 81.63; H , 10.82. Chapter 4 250 Preparation of (15*. 2S*. 55*. 85*. 9R*. 105*V2.10-Dimethyl-8-(3.5-dinitrobenzoyl)oxv-tricvclor7.3.0.01' s1dodecane (216). 1. L-Selectride®, E t 2 0 , -78 °C; NaOH, H 2 0 2 , H 2 0 » 2. 3,5-dinitrobenzoyl chloride, D M A P , C H 2 C 1 2 OoN 214 216 To a cold (-78 °C) stirred solution of ketone 214 (15 mg, 0.07 mmol) in 2 m L of dry E t 2 0 was added, dropwise via a syringe a solution of L-Selectride® in T H F (1M, 0.11 mmol). The reaction mixture was stirred for 1 h and then was warmed to room temperature. To the mixture was added 1 m L of 3 M aqueous N a O H and 1 m L of 30% H2O2. The resulting suspension was stirred for 12 h and then was treated with 2 m L of brine. The aqueous phase was extracted with Et20 ( 3 x 2 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. The residual oi l was dissolved in 2 m L of CH2CI2. The solution was treated with 3,5-dinitrobenzoylchloride (25 mg, 0.11 mmol) and D M A P (14 mg, 0.11 mmol) and then was stirred for 45 min. The reaction mixture was treated with 2 m L of saturated aqueous N a H C 0 3 and was stirred for 15 min. The phases were separated and the aqueous phase was extracted with E t 2 0 (3 x 2 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. Flash chromatography (25 g of silica gel, 4:1 pet. ether-Et20) of the remaining colourless oi l afforded, after concentration of the appropriate fractions, 8 mg (27% over two steps) of the title compound, a colourless crystalline solid. The product was recrystallized from M e O H , furnishing colourless crystals that exhibited mp 116-117 °C. Chapter 4 251 Preparation of Ethyl (IS*. 25*. 5S*. 9R*. lO^^ . lO-Dime thv l -S -oxo t r i cyc lo^J .O .O^I -dodec 6-ene-7-carboxylate (232). O 1. L D A , THF, -78 °C -> rt 2. NCCOOEt, H M P A , THF -78 °C -> rt 214 1. NaH, THF, 0 °C 2. PhSeCl 3. N a H C 0 3 , H 2 0 E t 2 0 , pet. ether EtO To a cold (-78 °C) stirred solution of L D A (0.83 mmol) in dry T H F (8 mL) was added, dropwise via a cannula, a solution of ketone 214 in 2 m L of dry T H F . The reaction mixture was warmed to room temperature for 45 min and then was cooled back to -78 °C. The resulting solution was treated, via a syringe, with neat H M P A (180 p.L, 1.0 mmol) and then, via a syringe, with neat ethyl cyanoformate (82 uL, 0.83 mmol). The resulting solution was allowed to warm slowly to room temperature and then was stirred for 12 h. To the reaction mixture was added 10 m L of aqueous NH3-NH4CI (pH ~8) and 5 m L of Et20. The aqueous phase was extracted with Et20 ( 3 x 5 mL) . The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. The ' H - N M R spectrum of the crude material revealed it to possess the expected signals for the product. Noteworthy were signals for the two methyl groups (3H doublets near 8 1.0), the ethoxycarbonyl group (3 H triplet at 5 1.3 and multiplet at 8 4.2) and a signal corresponding to the enol proton, located at 8 9.2. Chapter 4 252 N a H (60% w/w suspension in mineral o i l , 30 mg, 0.72 mmol) was washed free of the mineral oi l as described in Section 4.1.2 and then was suspended in 3 m L of dry T H F . The suspension was cooled to 0 °C and was treated, dropwise via a cannula, with a solution of crude 230 in 2 m L of dry T H F . The resulting mixture was stirred for 10 min, at which time, no further evolution of H 2 gas was observed, and then was treated, in one portion, with solid PhSeCl . The resulting mixture was stirred for 5 min and then was poured into a separatory funnel containing 5 m L of saturated aqueous NaHCC>3, 5 m L of E t 2 0 and 5 m L of pet. ether. The mixture was swirled carefully and the aqueous phase was drained off. The organic phase was concentrated under reduced pressure and the residual oil was dissolved in 5 m L of dry C H 2 C 1 2 . To the resulting solution was added, dropwise via a syringe, 30% H 2 0 2 (109 p L , 0.96 mmol). The reaction mixture was stirred for 10 min and then was treated with 3 m L of 10% aqueous Na2CC>3. The aqueous phase was extracted with with E t 2 0 ( 3 x 3 mL) . The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. Flash chromatography (8 g of silica gel, 1:1 pet. ether-Et 2 0) of the remaining oi l afforded, after concentration of the appropriate fractions, 101 mg (55% over three steps) of the title compound, a pale yellow oi l . tolMR 8 0.86 (d, 3H,J = 1.2 Hx) , 1.06 (d, 3H, J = 6.5 Hz) , 1.13-1.24 (m, 1H), 1.29 (t, 3 H , / = 7.1 Hz) , 1.28-1.36 (m, 1H), 1.59-1.67 (m, 2H), 1.69-1.80 (m, 2H), 1.86-1.96 (m, 2H), 2.00-2.16 (m, 2H), 2.20 (d, 1H, J = 10.0 Hz) , 2.66 (ddd, 1H, J = 9.2, 3.9, 3.9 Hz) , 4.23 (q, 2H, J = 7.1 Hz) , 7.37 (d, 1H, J = 3.9 Hz). Chapter 4 ' ' 253 Preparation of Ethyl (IS*. 25*. 55*. 6R*. 10R*. 12R*. 135*)-2,13-Dimethvl-7-methvlidene-ll-oxotetracvclori0.3.0.0 1 , 5.0 6 1 01pentadecane-10-carboxvlate (234). 232 234 To a cold (-78 °C) stirred solution of alkenylstannane 226 (112 mg, 0.44 mmol) in dry T H F (3 mL) was added, dropwise via a syringe, a solution of M e L i in Et20 (1.3 M , 0.44 mmol). The resulting green solution was stirred at this temperature for 5 min and then was treated, in one portion, with solid C u C N (39 mg, 0.44 mmol). The reaction vessel was removed from the cold bath and the reaction mixture was stirred vigorously until all the C u C N had dissolved. At this time, the reaction vessel was returned to the cold bath (-78 °C). To the reaction mixture was added, dropwise via a syringe, neat BF3«OEt2 (56 uL, 0.44 mmol). The reaction mixture became deep yellow and was stirred for 10 min. To the cyanocuprate (227) solution was added, dropwise via a cannula, a solution of compound 232 in 1.5 m L of dry T H F . The resulting mixture was stirred for 30 min and then was warmed to room temperature. To the mixture was added 5 m L of aqueous NH3-NH4CI (pH ~8). The biphasic mixture was stirred vigorously, open to the atmosphere, for 30 min, during which time, the aqueous phase became deep blue. The aqueous phase was extracted with with Et20 ( 3 x 3 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. Dry potassium hydride (9 mg, 0.22 mmol) was weighed out in a glove box and suspended in dry T H F (1.5 mL) . To the suspension was added, dropwise via a cannula, a solution of the residual crude oi l (vide supra) in dry T H F (1.5 mL) . The resulting mixture was heated at reflux for 1 h. To the reaction mixture was added aqueous N H 3 - N H 4 C I (pH ~8, 3 mL) . The aqueous phase was extracted with with Et20 ( 3 x 3 mL) . The combined organic extracts were dried Chapter 4 254 (MgS04) and concentrated under reduced pressure. Flash chromatography (4 g of silica gel, 9:1 pet. ether-Et20) of the residual oil afforded, after concentration of the appropriate fractions, 8 mg (34% over two steps) of the title compound, a colourless o i l . 1 H - N M R 6 1.01 (d, 3H , 7 = 7.0 Hz) , 1.06-1.14 (m, 1H), 1.10 (d, 3H , 7 = 7.2 Hz) , 1.20 (t, 3H, 7 = 7.1 Hz) , 1.22-1.32 (m 2H), 1.47 (dddd, 1H, 7 = 13.1, 8.1, 8.1, 5.5 Hz) , 1.53-1.60 (m, 1H), 1.68 (ddd, 1H, 7 = 15.5, 13.3, 8.3 Hz) , 1.77-1.92 (m, 3H), 2.01 (dddd, 1H, 7 = 13.0, 8.1, 8.1, 5.1 Hz), 2.13-2.22 (m, 1H), 2.27-2.35 (m, 3H), 2.67 (d, 1H, 7 = 4.5 Hz) , 2.76-2.86 (m, 1 H) , 3.15 (d, 1H, 7 = 12.7 Hz) , 4.05-4.20 (m, 2H), 4.84 (br.s, 2H). 1 3 C - N M R 5 14.0, 20.7, 20.8, 27.4, 29.8, 30.0, 31.6, 32.3, 32.5, 42.2, 44.1, 47.2, 55.5, 57.2, 60.7, 61.4, 65.6, 108.1, 152.2, 172.0, 210.5. Chapter 4 255 Table 19: 'H-nrnr (400 M H z , CDC1 3 ) data for enone 234: C O S Y and N O E experiments. 234 Assignment" "H-nmr (400 M H z ) C O S Y N O E 5 (mult., 7 (Hz)) Correlations Correlations H-2 Part of the 3 H m at 5 1.77-1.92 H-16 H-5 Part of the 2 H m at 8 1.22-1.32 H-6 H-6 3.15 (d, 7 = 12.7 Hz) H-5, H-17 H-12, H-16, H-20 (weak) H-8 2.13-2.22 (m) H-8' , H-17 H-8 ' Part of the 3 H m at 8 2.27-2.35 H-8 ,H-17 H-12 2.67 (d, 7 = 4.5 Hz) H-13 H-6, H-16, H-21, H-20 (weak) H-13 2.76-2.86 (m) H-12, H-14, H-21 H-14 Part of the 1H m at 8 1.06-1.14 H-13 H-16 1.10 (d, 7 = 7.2 Hz) H-2 H-17 4.84 (br.s) H-6, H-8, H-8 ' H-19 4.05-4.20 (m) H-20 H-20 1.20 (t, 7 = 7.1 Hz) H-19 H-21 1.01 (d, 7 = 7.0 Hz) H-13 aThe use of the prime descriptor (eg. H-7') in this table designates the proton of a geminal pair that is the furthest downfield of the two. Chapter 4 256 Preparation of (15*. 25*. 55*. 9R*. 105*)-2J0-Dimethvltricvclor7.3.0.0 1 , 5ldodec-6-en-8-one (239). To a solution of ketone 214 (3.5 g, 17 mmol) in 60 m L of 2:1 to luene-DMSO was added I B X (12 g, 43 mmol). The reaction vessel was fitted with a reflux condenser and the white heterogeneous mixture was stirred at 105 °C for 10 h. The reaction progress was monitored by G C . The mixture was cooled to room temperature and then was treated with 60 m L of saturated aqueous N a H C 0 3 . The resultant mixture was stirred for 15 min. The aqueous phase was extracted with E t 2 0 (3 x 20 mL) . A thick white precipitate that floated on the aqueous phase always remained in the separatory funnel after each extraction. This solid white material was washed with 10 m L of E t 2 0 . The combined organic extracts and washes were dried (MgS04) and concentrated under reduced pressure. The remaining yellow oi l was purified by flash chromatography (200 g of silica gel, 9:1 pet. ether-Et 2 0) to afford, after concentration of the appropriate fractions, 2.9 g (84%) of the title compound as a colourless o i l . JR 2953, 2871, 1672,1457, 1391, 1262, 1138 cm" 1. ' H - N M R 8 0.80 (d, 3H , J = 1.1 Hz) , 1.02 (d, 3H, J = 6.3 Hz) , 1.15 (dddd, 1H, J = 12.3, 9.3, 7.2, 7.2 Hz) , 1.29 (dddd, 1H, / = 10.5, 6.6, 6.6, 4.0 Hz) , 1.49-1.60 (m, 2H), 1.68-1.75 (m, 2H), 1.77 -1.84 (m, 1H), 1.87-1.99 (m, 2H), 2.01-2.09 (m, 2H), 2.51 (ddd, 1H, / = 8.7, 5.7, 3.1 Hz), 5.82 (dd, 1H, J= 10.2, 2.5 Hz) , 6.55 (dd, 1H, J= 10.2, 3.1 Hz) . IBX, Toluene-DMSO, 105 °C 214 239 Chapter 4 257 1 3 C - N M R 5 17.6 (-ve), 20.0 (-ve), 29.7 (+ve), 32.0 (+ve), 32.7 (+ve), 40.5 (-ve), 41.8 (+ve), 43.5 (-ve), 43.9 (-ve), 57.6 (+ve), 59.8 (-ve), 126.6 (-ve), 152.9 (-ve), 202.8 (+ve). H R M S for C 1 4 H 2 0 O ( M + ) 204.1514, found 204.1517. Anal . Calcd for C i 4 H 2 0 O : C , 82.30; H , 9.87. Found: C, 82.41; H , 9.91. Preparation of 4-Chlorobut-l-en-2-ylcopper(I)-Dimethyl Sulfide (249). S n B u 3 1. BuLi , THF, -78 °C Ci>SMe 2 CI 2. C u B r ' D M S , -78 °C -> -45 °C CI Tributylstannane 243 (1.2 g, 3.1 mmol) was filtered through a plug of oven-dried basic alumina. The remaining solid material was washed with two 1 m L portions of T H F . To a cold ( -78 °C) stirred solution of the combined filtrate and washes in 15 m L of dry T H F was added, via a syringe, a solution of B u L i (1.6 M solution in hexanes, 2 m L , 3.1 mmol) by allowing the B u L i solution to run down the inside of the cold flask. The resulting pale yellow solution was stirred for 10 min, and then was treated, in one portion, with copper bromide-dimethyl sulfide (640 mg, 3.1 mmol). The heterogeneous mixture was stirred at -78 °C for 30 min and then was warmed to -45 °C for 5 min, during which time it became a deep red solution. The red solution was promptly cooled back to -78 °C. This solution of organocopper reagent must be used immediately. Chapter 4 258 Preparation of (IS*. 4S*. 55*. 8R*. 95*. 125*)-8-(4-Chlorobut-l-en-2-yl)-4.12-dimethvltricvclo-r7.3.0.0'-51dodecan-6-one (240) O Cu«SMe 2 CI 1. (249) , BF 3 *OEt 2 , THF, -78 °C 2. aqueous H C l 239 To a cold (-78 °C), freshly prepared solution of organocopper reagent 249 (3.1 mmol) in 15 m L of dry TF£F was added, dropwise via a syringe, neat B F 3 « O E t 2 (525 uL, 4.1 mmol) followed, slowly via a cannula, by a solution of enone 239 (423 mg, 2.1 mmol) in 5 m L of dry T H F . The reaction mixture was stirred at -78 °C for 1 h and then was removed from the cold bath for 5 min. To the mixture was added 2 m L of 3 M aqueous H C l followed immediately by 25 m L of aqueous N H 3 - N H 4 C I (pH 8). The resulting mixture was stirred, open to air, for 30 min, allowing the aqueous phase to become deep blue. The aqueous phase was extracted with E t 2 0 (3 x 10 mL) . The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. The remaining oi l was purified by flash chromatography (50 g of silica gel, 9:1 pet. ether-Et 2 0). Concentration of the appropriate fractions afforded 568 mg (93%) of the title compound as a colourless o i l . IR 3080, 2949, 2872, 1703, 1641, 1454, 1379, 1256, 1180 cm" 1. ' H - N M R 5 0.93 (d, 3H , J = 7.2 Hz) , 1.01 (d, 3H, J = 6.8 Hz) , 1.23 (dddd, 1H, J = 12.7, 8.5, 8.5, 8.5 Hz) , 1.29-1.37 (m, 1H), 1.44-1.56 (m, 2H), 1.61 (ddd, 1H, J= 12.7, 8.2, 4.4 Hz) , 1.68-1.75 (m, 1H), 1.81-1.95 (m, 4H), 2.18-2.23 (m, 2H), 2.30-2.45 (m, 5H), 3.58 (t, 2H , J = 7.4 Hz , CH 2 C1) , 4.85 (s, 1H, =CH), 4.92 (s, 1H, =CH). 259 Chapter 4 1 3 C - N M R 8 19.9 (-ve), 20.3 (-ve), 27.1 (+ve), 31.9 (+ve), 33.4 (+ve), 35.5 (+ve), 38.1 (-ve), 42.6 (+ve), 43.4 (+ve), 43.6 (-ve), 44.8 (+ve), 47.8 (-ve), 48.8 (-ve), 59.9 (+ve), 61.6 (-ve), 112.7 (+ve), 146.7 (+ve), 213.9 (+ve). H R M S for C 1 8 H 2 7 0 3 5 C 1 ( M + ) 294.1750, found 294.1746. H R M S for C 1 8 H 2 7 0 3 7 C 1 ( M + ) 296.1721, found 296.1714. Anal . Calcd for C i 8 H 2 7 O C l : C , 73.32; H , 9.23. Found: C, 73.16; H , 9.53. Preparation of (IS*. 25*. 55*. 65*. IPS*. 12/?*, 135*)-2,13-Dimethvl-7-methvlidenetetracvclo-r i0.3.0.0 1 5 .0 6 1 0 lpentadecan-l l -one (235) and (IS*. 25*. 55*. 65*. 10/?*. 12/?*. 135*V2.13-Dimethvl-7-methvlidenetetracvclori0.3.0.0 1 ' 5.0 6 1 0lpentadecan-ll-one (250). 240 235 250 To a solution of compound 240 (568 mg, 1.93 mmol) in 15 m L of dry T H F and 1.5 m L of terr-butanol at room temperature was added solid potassium tert-butoxide (324 mg, 2.9 mmol). The pale yellow solution was stirred for 0.5 h. To the mixture was added 15 m L of E t 2 0 and 15 m L of aqueous N H 3 - N H 4 C I (pH 8 solution). After 10 min of stirring, the aqueous phase was extracted with E t 2 0 (3 x 10 mL) . The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. Flash chromatography (40 g of silica gel, 19:1 pet.ether-Et 20) of the remaining oi l afforded the two title compounds. Chapter 4 260 The first compound (235) to be eluted from the column (379 mg, 76%), a colourless crystalline solid, exhibited mp 45-46 °C: IR2948, 2901, 2875, 1692, 1648, 1453, 1379, 1328, 1179, 1154 cm" 1. ' H - N M R 8 1.01 (d, 3H , J = 7.0 Hz) , 1.04-1.17 (m, 1H), 1.08 (d, 3 H , / = 7.3 Hz) , 1.33 (ddd, 1H, J= 11.0, 7.0, 3.3 Hz) , 1.42-1.58 (m, 2H), 1.69-1.91 (m, 6H), 1.95-2.09 (m, 2H), 2.14-2.21 (m, 1H), 2.26-2.32 (m, 1H), 2.33 (d, 1H, J = 4.8 Hz) , 2.74-2.86 (m, 3 H) , 4.81 (br. s, 2H). 1 3 C - N M R 5 20.7 (-ve), 20.9 (-ve), 25.3 (+ve), 27.7 (+ve), 31.1 (+ve), 31.8 (-ve), 32.2 (+ve), 32.6 (+ve), 42.1 (-ve), 43.8 (+ve), 47.6 (-ve), 50.7 (-ve), 50.9 (-ve), 58.2 (-ve), 61.0 (+ve), 106.5 (+ve), 154.8 (+ve), 215.6 (+ve). H R M S for C i 8 H 2 6 0 ( M + ) 258.1984, found 258.1983. O 235 Anal . Calcd for C 1 8 H 2 6 0 : C , 83.67; H , 10.14. Found: C,.83.52; H , 10.18. Chapter 4 261 The second compound (250) to be eluted from the column (85 mg, 17%), a colourless o i l , exhibited: IR 2951, 2872, 1706, 1656, 1457, 1379, 1232, 1201 cm" 1. 1 H - N M R (300 M H z ) 5 0.85 (d, 3H, J = 7.3 Hz) , 1.01 (d, 3H , J = 6.5 Hz) , 1.23 (ddd, 1H, / = 12.1, 8.2, 8.2, 8.2 Hz) , 1.39-1.49 (m, 1H), 1.60-1.76 (m, 5H), 1.78-1.94 (m, 3H), 1.96-2.05 (m, 2H), 2.07-2.18 (m, 2H), 2.20-2.32 (m, 1H), 2.23 (d, 1H, J = 9.0 Hz) , 2.34-2.42 (m, 1H), 2.50 (ddd, 1H, J = 13.6, 10.4, 7.1 Hz) , 4.73-4.76 (m, 1H), 4.82-4.85 (m, 1H). 1 3 C - N M R 8 18.1 (-ve), 19.8 (-ve), 21.5 (+ve), 28.9 (+ve), 30.3 (+ve), 32.7 (+ve), 34.9 (+ve), 41.4 (-ve), 45.6 (-ve), 45.8 (+ve), 49.9 (-ve), 51.1 (-ve), 57.5 (-ve), 63.9 (+ve), 64.4 (-ve), 104.6 (+ve), 154.4 (+ve), 214.3 (+ve). H R M S for C i 8 H 2 6 0 ( M + ) 258.1984, found 258.1983. O 250 Anal . Calcd for C i 8 H 2 6 0 : C , 83.67; H , 10.14. Found: C, 83.49; H , 10.30. Chapter 4 262 Preparation of (IS*, 2S*. 55*. 6R*, 105*. 12R*. 13S*)-7-Methvlidene-2,10J3-trimethvltetracvclori0.3.0.0 1 , 5.0 6 , 1 01pentadecan-ll-one (236). 250 Potassium ferr-butoxide (44 mg, 0.39 mmol) was weighed out in a glove box into the reaction vessel. The vessel (10 m L round-bottomed flask) was connected to a vacuum pump and placed under reduced pressure for 1 h. The potassium rerr-butoxide was then suspended in 3 m L of dry T H F . Dry diisopropylamine (55 pL , 0.39 mmol) was added to the mixture, which was then cooled to -78 °C. To the mixture was added, via a syringe, a solution of n -BuLi (1.6 M solution in hexanes, 244 uL, 0.39 mmol), by allowing the n - B u L i solution to run down the inside of the cold flask. The resulting pale yellow solution was stirred for 0.5 h. To the cold (-78 °C) stirred K D A solution was added, via a cannula, a solution of ketone 250 (27 mg, 0.10 mmol) in 1 m L of dry T H F , by allowing the solution to run down the inside of the cold flask. The reaction mixture was stirred for 2.5 h, then was treated, via a syringe, with neat iodomethane (freshly filtered through oven-dried basic alumina, 36 uL, 0.58 mmol). The resulting solution was stirred for 5 min and then was removed from the cold bath for 5 min, during which time it became milky. To the reaction mixture was added 5 ml of aqueous N H 3 -NH4CI (pH 8 solution) and 5 m L of Et20. The aqueous phase was extracted with Et20 ( 3 x 5 mL). The combined organic extracts were dried (MgSCu) and were concentrated under reduced pressure. Purification of the remaining oil by flash chromatography (10 g of silica get, 19:1 pet. ether-Et20) afforded 29 mg (100%) of the title compound as a colourless o i l . IR 3071, 2948, 2869, 1705, 1653, 1453, 1376, 1312, 1283, 1171, 1043 cm" 1. Chapter 4 263 1 H - N M R (300 M H z ) 6 1.02 (d, 3H, J = 7.2 Hz) , 1.02-1.12 (m, 5H), 1.08 (s, 3H , C H 3 C ) , 1.34 (ddd, 1H, J = 11.9, 7.3, 4.1 Hz) , 1.43 (ddd, 1H, J = 11.7, 7.3, 7.3, 4.2 Hz) , 1.52-1.59 (m, 1H), 1.61-2.02 (m, 7H), 2.22-2.36 (m, 3H), 2.46 (d, 1H, J = 3.6 Hz) , 2.80-2.88 (m, 1H), 4.86-4.90 (m, 2H , =CH 2 ) . Selective irradiation of H-12 (doublet at 8 2.46) provided a spectrum that revealed nOe correlations to each of the three methyl groups, as well as a weak correlation to H-6. 236 1 3 C - N M R 5 20.4 (-ve), 21.1 (-ve), 25.3 (-ve), 27.4 (+ve), 28.6 (+ve), 30.7 (-ve), 32.4 (+ve), 32.6 (2 carbons, -i-ve), 41.9 (-ve), 43.8 (+ve), 47.0 (-ve), 53.9 (+ve), 55.8 (-ve), 58.4 (-ve), 60.1 (+ve), 108.4 (-ve), 153.3 (+ve), 219.3 (+ve). H R M S for C i 9 H 2 8 0 ( M + ) 272.2140, found 272.2139. Anal . Calcd for C 1 9 H 2 8 0 : C , 83.77; H , 10.36. Found: C, 84.00; H , 10.330. Chapter 4 264 Preparation of (IS*, 2S*, 5S*. 6R*. IPS*. 12R*. 135*)-7-Methylidene-2.10.13-trimethvl tetracvclo[10.3.0.0'' 5.0 6 ' ' 0lpentadecan-l 1-one (236). 235 236 Potassium terf-butoxide (1.9 g, 16.7 mmol) was weighed out in a glove box, was placed under high vacuum for 1 h, and then was suspended in 70 m L of dry T H F . Dry diisopropylamine (2.3 m L , 16.7 mmol) was added, via a syringe, to the mixture, which was then cooled to -78 °C. To the mixture was added, via a syringe, a solution of n -BuLi (1.6 M solution in hexanes, 10.4 m L , 16.7 mmol), by allowing the n - B u L i solution to run down the inside of the cold flask. The resulting pale yellow solution was stirred for 0.5 h. To the cold (-78 °C) stirred K D A solution was added, via a cannula, a solution of ketone 235 (2.9 g, 11.1 mmol) in 10 m L of dry T H F , by allowing the solution to run down the inside of the cold flask. The reaction mixture was stirred for 2.5 h, then was treated, via a syringe, with neat iodomethane (the iodomethane was filtered neat through a plug of oven-dried basic alumina, 2.1 m L , 0.58 mmol). The resulting solution was stirred for 5 min then was removed from the cold bath for 5 min, becoming milky. To the reaction mixture was added 50 ml of aqueous NH3-NH4CI (pH 8 solution) and 50 m L of Et20. The aqueous phase was extracted with E t i O (3 x 25 mL). The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. Purification of the remaining oi l by flash chromatography (100 g of silica get, 19:1 pet. ether-Et20) afforded 2.9 g (94%) of the title compound as a colourless oi l that exhibited spectroscopic data identical with those of the product of the previous reaction (236). Chapter 4 265 Preparation of (15*. 25*. 55*. 6/?*. 105*. 115*. 12/?*. 135*)-7-Methylidene-2,10,13-trimethyltetracvclori0.3.0.0 1 , s.0 6 , 1 < >1pentadecan-ll-ol (252) and (15*. 25*. 55*. 6/?*. IPS*. 11/?*. 12/?*. 135*)-7-Methvlidene-2.10.13-trimethvltetracvclori0.3.0.0 1 5.0 6 ' 1 0l-pentadecan-ll-ol (2531 To a cold (-45 °C) stirred solution of tetracyclic ketone 236 (505 mg, 1.85 mmol) in 15 m L of dry E t 2 0 was added, via a syringe, a solution of D I B A L H (1 M solution in hexanes, 2.4 mL, 2.4 mmol), by allowing the D I B A L H solution to run down the inside of the cold flask. The resulting colourless solution was allowed to warm to 0 °C over 30 min, then was treated with aqueous N H 3 - N H 4 C I (pH 8 solution, 600 p L (250 p L per mmol of D I B A L H ) ) . The resulting mixture was stirred at room temperature for 30 min, during which time it became milky, and then was treated with 1 g of anhydrous MgS04 . The mixture was stirred for an additional 1 h and then was filtered through a pad of Celite®. The collected solid material was washed with E t 2 0 ( 4 x 1 5 mL). The combined filtrate and washes were concentrated under reduced pressure. The remaining oil was purified by flash chromatography (50 g of silica gel, 9:1 —» 4:1 pet. ether-Et 2 0) to afford the title compounds. The first compound (253) to be eluted from the column (134 mg, 26%), a colourless o i l , exhibited: IR 3503, 3069, 2947, 2868, 1656, 1455, 1376, 1263, 1219, 1124, 1095, 1067, 1041 cm" 1. Chapter 4 266 ! H - N M R 8 0.93 (d, 3H, J= 7.3 Hz) , 0.97 (s, 3H, C H 3 C ) , 1.01-1.11 (m, 1H), 1.06 (d, 3H, J = 6.9 Hz), 1.21-1.34 (m, 2H), 1.38-1.45 (m, 2H), 1.52 (ddd, 1H, / = 11.6, 6.2, 2.1 Hz) , 1,60-1.80 (m, 7H), 1.96 (dddd, 1H, J= 11.6, 8.3, 8.3, 3.2 Hz) , 2.08-2.21 (m, 3H), 2.35-2.43 (m, 1H), 3.56 (dd, 1H, J = 4.4, 3.6 H z , H - l l ) , 4.69 (s, 1H, =CH), 4.78 (s, 1H, =CH). 1 3 C - N M R 8 21.3 (-ve), 21.8 (-ve), 28.3 (-ve), 28.5 (+ve), 32.7 (+ve), 32.8 (+ve), 33.0 (+ve), 35.6 (+ve), 36.3 (-ve), 44.1 (-ve), 45.3 (+ve), 45.9 (+ve), 47.6 (-ve), 48.0 (-ve), 54.4 (-ve), 55.5 (+ve), 78.0 (-ve), 105.8 (+ve), 156.5 (+ve). H R M S for C19H30O ( M + ) 274.2297, found 274.2301. Anal . Calcdfor C19H30O: C , 83.15; H , 11.02. Found: C, 83.18; H , 11.19. The second compound (252) to be eluted from the column (373 mg, 73%), a colourless crystalline solid, exhibited mp 63-64 °C. IR 3350, 3072, 2947, 2868, 1658, 1450, 1399, 1376, 1236, 1149, 1127, 1096, 1031 cm" 1. J H - N M R (300 M H z ) 8 0.93 (s, 3H , C H 3 C ) , 0.96 (d, 3H, J = 7.3 Hz) , 1.02-1.12 (m, 1H), 1.09 (d, 3H, J= 6.9 Hz) , 1.22-1.38 (m, 3H), 1.43-1.62 (m, 5H), 1.64-1.83 (m, 5H), 1.90-2.00 (m, 2H), 2.15-2.25 (m, 1H, H-8), 2.30-2.41 (m, 1H, H-8), 3.32 (dd, 1H, J = 11.7, 6.4 H z , H - l l ) , 4.69 (s, 1H, =CH), 4.81 (s, 1H, =CH). Chapter 4 267 1 3 C - N M R 5 21.6 (-ve), 21.7 (-ve), 22.0 (-ve), 28.2 (+ve), 31.6 (+ve), 32.7 (+ve), 33.4 (+ve), 39.1 (-ve), 39.1 (+ve), 43.1 (-ve), 44.4 (+ve), 45.8 (+ve), 46.9 (-ve), 48.5 (-ve), 56.6 (-ve), 57.9 (+ve), 81.1 (-ve), 106.7 (+ve), 155.3 (+ve). H R M S for C 1 9 H 3 o O ( M + ) 274.2297, found 274.2298. Anal . Calcd for C 1 9 H 3 0 O : C , 83.15; H , 11.02. Found: C, 83.45; H , 10.80. Chapter 4 268 Oxidation-reduction procedure for the conversion of a-alcohol 253 into a mixture of (3-alcohol 252 and a-alcohol 253. 1. TPAP, N M O , CH 2 C1 2 3 A mol. sieves 2. D I B A L H , E t 2 0 -45 °C -> 0 °C 2 5 3 2 5 2 2 5 3 Crushed 3 A molecular sieves (flame-dried in vacuo, 0.5 g) were added to a solution of a-alcohol 253 (191 mg, 0.70 mmol) and Af-methylmorpholine-N-oxide (122 mg, 1.0 mmol) in 10 mL of dry CH2CI2. The mixture was stirred at room temperature for 10 min and then was treated, in a single portion, with solid tetrapropylammonium perrhuthenate (24 mg, 0.07 mmol). The reaction mixture was stirred for 15 min and then was filtered through a short pad of flash silica gel (~ 5 g). The collected solid material was washed with 4:1 pet. ether-Et20 (4 x 15 mL). The combined filtrate and washes were concentrated under reduced pressure. The remaining crude oil exhibited ^ - N M R spectral data identical with those of ketone 236. This material was reduced with D I B A L H under conditions identical with those described previously, affording, after silica gel chromatography of the crude material, 30 mg of the a-alcohol 253 and 113 mg (58% over the oxidation-reduction process) of the crystalline (3-alcohol 252. The combined yield of P-alcohol 252 after two cycles was 486 mg (94%). Chapter 4 269 Preparation of (IS*, 25*. 5S*. 6R*. IPS*. US*. 12/?*, 135*)-7-Methvlidene-ll-triethvlsiIvloxv-2,10J3-trimethvltetracvclori0.3.0.0'' 5.0 6 ' 1 Qlpentadecane (260). To a solution of alcohol 252 (434 mg, 1.58 mmol) in 8 m L of dry T H F was added TESC1 (440 pL , 2.62 mmol) and D M A P (320 mg, 2.62 mmol). The resulting mixture was heated at reflux for 6 h. The reaction mixture was treated with 3 m L of D M F and was stirred for 18 h. The mixture was cooled to room temperature and then was treated with 15 m L of a saturated brine solution and 25 m L of Et20. The aqueous phase was extracted with E t 2 0 (2 x 10 mL). The combined ethereal extracts were dried (MgSC>4) and concentrated under reduced pressure. The remaining yellow oil was purified by flash column chromatography (50 g of silica gel, 19:1 pet. ether-Et20) to afford, after concentration of the appropriate fractions, 613 mg (100%) of the title compound as a colourless o i l . IR 3071, 2951, 2874, 1652, 1454, 1415, 1376, 1239, 1131, 1096, 1074, 1008 cm' 1 . 1 H - N M R 6 0.63 (q, 6H , J = 8.0 Hz) , 0.89 (s, 3H), 0.96 (d, 3H , / = 7.7 Hz) , 0.97 (t, 9H , J = 8.0 Hz) , 1.04 (d, 3H , J = 6.4 Hz) , 1.23-1.34 (m, 2H), 1.42 (ddd, 1H, J = 12.8, 6.7, 1.4 Hz), I. 48-1.80 (m, 10H), 1.83-1.97 (m, 2H), 2.18-2.27 (m, 1H), 2.32-2.39 (m, 1H), 3.42 (d, 1H, 7 = I I . 5 Hz) , 4.71 (br. s, 1H), 4.83 (br. s, 1H). 1 3 C - N M R 8 5.7 (3 carbons), 7.2 (3 carbons), 21.5, 22.0 (2 carbons), 27.8, 31.2, 32.8, 33.2, 38.0, 39.4, 42.8, 43.7, 46.3, 47.0, 48.9, 56.9, 57.9, 82.8, 107.1, 155.1. Chapter 4 270 H R M S for CasHwOSi ( M + ) 388.3161, found 388.3157. Preparation of (IS*. 25*. 55*, 6R*. 75*. 105*, 115*, 12/?*, 135*)-7-Formvl-ll-triethylsilvloxv-2.10.13-trimethvltetracvclori0.3.0.0 1 5.0 6 1 0lpentadecane (263). OTES . l . B % T H F , T H F , 0°C; OTES NaOH, H 2 0 2 , H 2 0 2. Dess-Martin periodinane, CH 2 C1 2 , reflux 3. f-BuOK, f-BuOH-THF, rt O H C 263 To a cold (0 °C), stirred solution of compound 260 (1.39 g, 3.6 mmol) in 30 m L of dry T H F was added, via a syringe, a solution of borane-THF complex (1 M , 3.2 mmol) in T H F . The reaction mixture was stirred for 1 h and then was treated slowly with 3.1 m L of aqueous N a O H (3 M ) followed by 3 m L of 30% H 2 O 2 . The resulting milky mixture was stirred for 12 h and then was treated with 15 m L of brine and 15 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 (2 x 10 mL). The combined organic extracts were dried (MgS04) and were concentrated under reduced pressure. The resulting crude oi l was purified by flash chromatography (100 g of silica gel, 4:1 pet. e the r -Et20) to afford 1.3 g (76 %) of a mixture of alcohols as a colourless oi l . The mixture of alcohols was dissolved in 30 m L of dry C H 2 C I 2 and was treated with 1.9 g (4.6 mmol) of Dess-Martin periodinane. The resulting suspension was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and was filtered through a pad (-15 g) of Celite®. The remaining solid material was washed with Et20 (3 x 50 mL) . The combined filtrate and washes were concentrated under reduced pressure. The resulting crude oi l was purified by Chapter 4 271 flash chromatography (50 g of silica gel, 9:1 - » 4:1 pet. ether-Et 2 0) to afford 880 mg (71 %) of a mixture of aldehydes as a colourless oi l . The resulting mixture of aldehydes was dissolved in dry T H F . The solution was treated with distilled M e O H (0.5 mL) and solid N a O M e (weighed out in a glove box, 60 mg, 1.1 mmol). The reaction mixture was stirred for 15 min, and then was treated with 20 m L of brine and 20 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 (2 x 10 mL) . The combined organic extracts were dried (MgS04) and were concentrated under reduced pressure. The resulting crude oi l was purified by flash chromatography (25 g of silica gel, 9:1 pet. ether-Et 2 0) to afford 782 mg (89 %) of the title compound as a colourless oi l . IR 2951, 2875, 1725, 1456, 1415, 1377, 1239, 1137, 1098, 1009 cm" 1. 1 H - N M R 8 0.62 (q, 6H , J = 8.1 Hz), 0.88 (s, 3H), 0.95 (d, 3H, J = 7.8 Hz) , 0.96 (t, 9H , J = 9.8 Hz) , 1.03 (d, 3H , / = 6.9 Hz) , 1.17-2.02 (m, 17H), 2.36-2.43 (m, 1H), 3.40 (d, 1H, J = 11.6 Hz) , 9.58 (d, 1H, 7 = 3.1 Hz) . 1 3 C - N M R 8 5.7 (3 carbons), 7.2 (3 carbons), 21.0, 21.6, 22.0, 25.7, 28.1, 32.4, 33.3, 38.3, 40.7, 42.7, 44.1, 49.0, 50.0, 50.4, 51.0, 57.9, 60.1, 82.7, 203.7. H R M S for C 2 3 H 3 9 0 2 S i ( M - C 2 H 5 ) + 375.2719, found 375.2723. Chapter 4 272 Preparation of (IS*. 25*. 55*. 6R*. 75*. 105*. 115*. 12R*. 135* s)-7-Hvdroxvmethvl-ll-triethvlsilvloxv-2.10.13-trimethvltetracvclori0.3.0.0 1 ' 5.0 6 1 01pentadecane (264). To a stirred solution of aldehyde 263 (27 mg, 0.07 mmol) in 1 m L of dry E t 2 0 was added, via a syringe, a solution of D I B A L H (1 M , 0.1 mmol) in hexanes. The reaction mixture was stirred for 0.5 h and then was treated with an aqueous solution of NH3-NH4CI (pH ~8, 25 pL) . The resulting white mixture was stirred for 0.5 h, was treated with M g S C u (0.2 g) and was stirred for another 1 h. The reaction mixture was filtered through a pad of Celite®. The residual solid material was washed with E t 2 0 ( 3 x 5 mL) . The combined filtrate and washes were concentrated under reduced pressure. The remaining crude o i l was purified by flash chromatography (5 g of silica gel, 4:1 pet. ether-Et 2 0) to afford 20 mg (74 %) of the title compound as a colourless o i l . IR 3304, 2952, 2873, 1456, 1376, 1239, 1133, 1086, 1014 cm" 1. ' H - N M R 8 0.62 (q, 6H , J = 8.0 Hz) , 0.92 (d, 3H , J = 6.9 Hz) , 0.95 (t, 9 H , J = 8.0 Hz) , 0.96 (s, 3H), 1.00 (d, 3 H , J= 6.9 Hz) , 1.17-1.45 (m, 7H), 1.49-1.77 (m, 9H), 1.79-1.94 (m, 2H), 2.15-2.26 (m, 1H), 3.27 (d, 1H, J = 11.5 Hz), 3.39 (dd, 1H, J = 9.0, 9.0 Hz) , 3.74 (dd, 1H, J= 9.0, 3.1 Hz) . 1 3 C - N M R 8 5.8 (3 carbons), 7.2 (3 carbons), 20.3, 22.6, 23.3, 27.4, 31.0, 32.7, 33.1, 37.8, 39.7, 42.4, 43.2, 44.6, 45.8, 47.2, 49.1, 55.0, 58.0, 63.5, 82.1. v Chapter 4 273 H R M S for C 2 5 H 4 6 0 2 S i N a (ESI, M + Na + ) 429.3165, found 429.3155. Anal . Calcd for C 2 5 H 4 6 0 2 S i : C , 73.83; H , 11.40. Found: C, 73.57; H , 11.47. Preparation of (IS*. 25*. 55*, 6/?*, 75*, 105*, 115*, 12/?*, 135*)-7-(Z-Hvdroxvimino)-methyl-ll-triethvlsilvloxv^.lO.lS-trimethvltetracvcloriO.S.O.O^^O^^lpentadecane (268) and (15*. 25*. 55*. 6R*. 75*. 105*. 115*. 12R*. 135*)-7-(£-Hvdroxvimino)-methvl- l l - t r iethvlsi lvloxv-2.10.13-trimethvltetracvclori0.3.0.0 1 ' 5.0 6 1 01pentadecane (269). A solution of N H 2 O H » H C l (320 mg, 4.6 mmol) and N a O A c (371 mg, 4.6 mmol) in 3 m L of water was stirred for 5 min and then was added, at room temperature, via a syringe, to a stirred solution of aldehyde 263 (745 mg, 1.8 mmol) in 20 m L of dry T H F . The resulting mixture was stirred for 20 min and then was treated with 20 m L of brine and 20 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 ( 3 x 5 mL) . The combined organic extracts were dried (MgSCU) and were concentrated under reduced pressure. The resulting crude oi l was purified by flash chromatography (50 g of silica gel, 4:1 pet. ether-Et 2 0). Chapter 4 274 The first compound to elute from the column (269, 403 mg, 52%), a colourless crystalline solid, exhibited mp 133-136 °C. IR 3284, 2953, 2873, 1457, 1416, 1376, 1240, 1140, 1104, 1081, 1012 cm" 1. ' H - N M R 5 0.62 (q, 6H , J = 8.1 Hz) , 0.90 (s, 3H), 0.93 (d, 3H , J = 8.2 Hz) , 0.96 (t, 9H , J = 8.1 Hz) , 1.02 (d, 3H , J= 6.8 Hz) , 1.14-1.31 (m, 3H), 1.35-1.76 (m, 14H), 1.80-1.97 (m, 3H), 2.35 (dddd, 1H, J= 10.2, 7.5, 7.5, 5.7 Hz) , 3.38 (d, 1H, J= 11.4 Hz) , 6.99 (br. s, 1H), 7.36 (d, 1H, J = 7.5 Hz) . 1 3 C - N M R 5 5.7 (3 carbons), 7.2 (3 carbons), 21.5, 21.6, 22.1, 27.8, 29.7, 32.5, 33.3, 38.3, 40.7, 42.7, 44.1, 47.7, 48.1, 49.0, 50.6, 54.0, 58.1, 82.8, 156.8. H R M S for C 2 5H46N0 2 Si (ESI, M + H+) 420.3298, found 420.3304. Anal . Calcd for C 2 5 H 4 5 N 0 2 S i : C , 71.54; H , 10.81; N , 3.34. Found: C , 71.48; H , 10.81; N , 3.40. 275 Chapter 4 The second compound to elute from the column (268, 291 mg, 38%), a colourless crystalline solid, exhibited mp 113-116 °C. IR 3195, 2951, 2875, 1457, 1417, 1376, 1339, 1239, 1139, 1084, 1008 cm ' 1 . ' H - N M R 5 0.62 (q, 6H , 7 = 8.0 Hz) , 0.93-0.98 (m, 15H), 1.03 (d, 3H , 7 = 6.8 Hz) , 1.20-1.35 (m, 3H), 1.39-1.52 (m, 5H), 1.55-1.74 (m, 6H), 1.81-1.98 (m, 3H), 3.01-3.09 (m, 1H), 3.40 (d, 1H, 7=11.4 Hz) , 6.63 (d, 1H, 7 = 7.8 Hz) , 7.83 (br. s, 1H). 1 3 C - N M R 5 5.7 (3 carbons), 7.2 (3 carbons), 21.7, 21.9, 22.0, 28.0, 29.0, 32.7, 33.3, 38.5, 41.1, 42.8, 43.3, 44.3, 47.5, 49.0, 50.6, 55.6, 58.0, 82.7, 157.4. H R M S for C 2 5H46N0 2 Si (ESI, M + H1") 420.3298, found 420.3299. Anal . Calcd for C 2 5 H 4 5 N 0 2 S i : C , 71.54; H , 10.81; N , 3.34. Found: C , 71.14; H , 10.86; N , 3.42. Chapter 4 276 Preparation of (IS*, 25*. 55*. 6R*. 75*. 105*. 115*. 12/?*, 135*)-7-Cvano-ll-triethylsilvloxv-2,10,13-trimethvltetracvclori0.3.0.0 1 ' 5.0 6 1 0lpentadecane. HO 268 + 269 271 In an addition funnel flushed with dry argon, a solution of dry D M F (360 p L , 4.7 mmol) in 1.5 m L of dry benzene was added thionyl chloride (339 p L , 4.7 mmol) that had been filtered neat through basic AI2O3. The resulting suspension was swirled gently to allow mixing and then was allowed to stand for 10 min, during which time, a pale yellow oi l separated out at the bottom of the addition funnel. To a solution of the least polar of the two aldoximes (269, 390 mg, 0.93 mmol) and pyridine (751 p L , 9.3 mmol) in 15 m L of dry benzene was added, dropwise via the addition funnel, the pale yellow oi l described above. Care was taken not to add any of the supernatant liquid to the reaction mixture. A thick brown oi l immediately began to form around the sides of the reaction vessel. The mixture was heated at reflux for 1 h. To the cooled reaction mixture was added 15 m L of saturated N a H C 0 3 solution, 15 m L of brine, and 30 m L of E t 2 0 . The aqueous phase was extracted with Et20 (3 x 10 mL) . The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (50 g of silica gel, 9:1 pet. ether-Et^O) to afford 302 mg (87%) of the title compound, a colourless crystalline solid that exhibited mp 84-85 °C. IR 2952, 2873, 2235, 1457, 1415, 1377, 1240, 115, 1083, 1009 cm" 1. Chapter 4 277 ! H - N M R 8 0.60 (q, 6 H , J = 7.9 Hz) , 0.94 (d, 3H, J = 5.8 Hz) , 0.95 (t, 9 H , J = 7.9 Hz) , 1.00 (s, 3H), 1.01-1.07 (m, 1H), 1.02 (d, 3H , / = 6.8 Hz) , 1.24 (ddd, 1H, J = 11.9, 11.9, 5.7 Hz) , 1.31-1.47 (m, 2H), 1.50-1.60 (m, 2H), 1.63-2.09 (m, 11H), 2.28 (ddd, 1H, J = 10.3, 7.4, 6.2 Hz) , 3.33 (d, 1 H , 7 = 11.4 Hz) . 1 3 C - N M R 5 5.7 (3 carbons), 7.2 (3 carbons), 21.4, 21.7, 22.0, 28.3, 29.8, 32.4, 33.2, 35.2, 38.3, 40.6, 42.7, 44.1, 47.4, 48.9, 50.5, 56.0, 57.8, 82.0, 123.7. H R M S for C 2 5 H44NOSi (ESI, M + H1") 402.3192, found 402.3204. Anal . Calcd for C 2 5H4 3 NOSi : C , 74.75; H , 10.79; N , 3.49. Found: C , 74.67; H , 10.95; N , 3.83. The same reaction was carried out on the more polar of the two aldoximes (268), furnishing the title compound in 51% yield. Further, the reaction was effected on a 3:4 mixture of the two aldoximes (268 and 269, respectively), affording the title compound in 69% yield. Chapter 4 278 Preparation of (15*. 25*. 55*. 65*. 75*. 105*. 115*. 12/?*. 135*)-7-Cvano-2,7,10,13-tetramemvl-ll-triemvlsilvloxvtetracvclori0.3.0.0 1 , 5 .0 6 , 1^pentadecane (272). Potassium tert-butoxide (77 mg, 0.69 mmol) was weighed out in a glove box into a round bottom flask. The vessel was evacuated (vacuum pump) for 18 h. The dried f -BuOK was suspended in 5 m L of dry T H F and then treated with dry diisopropylamine (97 p L , 0.69 mmol). The resulting mixture was cooled to -78 °C and was treated, slowly via a syringe, with a B u L i solution (1.6 M in hexanes, 0.69 mmol), by allowing the B u L i solution to run down the inside of the cold flask. The resulting yellow K D A solution was stirred for 0.5 h. To the cold (-78 °C) stirred K D A solution was added, slowly via a syringe, a solution of nitrile 271 (111 mg, 0.28 mmol) in 0.5 m L of dry T H F , by allowing the solution to run down the inside of the cold flask. The resulting mixture was stirred for 1 h and then was treated, via a syringe, with a solution of iodomethane (72 uL , 1.2 mmol) in 0.5 m L of dry T H F , by allowing the solution to run down the inside of the cold flask. The yellow solution was allowed to warm slowly to room temperature, during which time it became a milky white mixture. The mixture was treated with 5 m L of aqueous NH3-NH4CI (pH ~8) and 5 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 ( 3 x 5 mL) . The combined organic extracts were dried (MgSCU) and were concentrated under reduced pressure. The resulting crude oi l was purified by flash chromatography (10 g of silica gel, 19:1 pet. ether-Et 2 0) to afford 106 mg (92%) of the title compound, a colourless o i l . IR 2952, 2875, 2231, 1456, 1380, 1238, 1140, 1100, 1082, 1006 cm ' 1 . Chapter 4 279 ' H - N M R 8 0.60 (q, 6H , / = 8.1 Hz) , 0.95 (d, 3H , J = 7.3 Hz) , 0.96 (t, 9 H , J = 8.1 Hz) , 1.02 (d, 3H, J = 6.7 Hz) , 1.03-1.10 (m, 1H), 1.06 (s, 3H), 1.20-1.03 (m, 1H), 1.25 (s, 3H), 1.33-1.87 (m, 12H), 1.90-2.03 (m, 2H), 2.18 (ddd, 1H, J = 12.6, 12.6, 6.1 Hz) , 3.26 (d, 1H, / = 11.4 Hz) . 1 3 C - N M R 8 5.8 (3 carbons, +ve), 7.2 (3 carbons, -ve) , 20.9 (-ve), 21.2 (-ve), 22.2 (-ve), 22.7 ( -ve), 29.8 (+ve), 32.6 (+ve), 33.2 (+ve), 38.4 (+ve), 38.5 (-ve), 39.2 (+ve), 39.2(+ve), 43.1 (-ve), 44.4 (-ve), 45.3 (+ve), 47.7 (+ve), 48.9 (-ve), 57.8 (+ve), 59.5 (-ve), 82.2 (-ve), 127.2 (+ve). H R M S for C 2 6 H46NOSi (ESI, M + IT") 416.3349, found 416.3356. Anal . Calcd for C 2 6 H 4 5 N O S i : C , 75.12; H , 10.91; N , 3.37. Found: C , 75.20; H , 10.91; N , 4.14. Preparation of (15*. 25*. 55*. 65*. 75*. 105*. 115*. 12/?*. 135*V7-Cvano-l l-hvdroxy-2.7.10.13-tetramethvltetracvclori0.3.0.0 1' 5.0 6' 1 0lpentadecane (273). 272 273 To a room temperature solution of nitrile 272 (106 mg, 0.25 mmol) in dry T H F (5 mL) was added, via a syringe, a solution of T B A F (1 M , 0.34 mmol) in T H F . The resulting mixture was stirred for 0.5 h and then was treated with 5 m L of saturated N a H C 0 3 and 10 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 ( 3 x 5 mL) . The combined organic extracts were dried (MgSCu) and were concentrated under reduced pressure. The resulting crude material was Chapter 4 280 purified by flash chromatography (10 g of silica gel, 4:1 pet. ether-Et20) to afford 55 mg (72%) of the title compound, a colourless crystalline solid exhibiting mp 101-102 °C. IR 3488, 2947, 2871, 2242, 1455, 1380, 1267, 1136, 1055, 1036, 1000 cm" 1. ^ - N M R 8 0.96 (d, 3H , J = 7.4 Hz) , 1.01-1.10 (m, 1H), 1.07 (s, 3H), 1.09 (d, 3H , J = 7.7 Hz) , 1.23-1.33 (m, 2H), 1.27 (s, 3H), 1.39 (dddd, 1H, J= 13.3, 7.6, 7.6, 4.6 Hz) , 1.52-1.68 (m, 5H), I. 69-1.85 (m, 5H), 1.88-2.03 (m, 3H), 2.17 (ddd, 1H, J= 12.2, 12.2, 6.1 Hz) , 3.17 (dd, 1H, / = I I . 6, 5.8 Hz) . 1 3 C - N M R 8 21.0 (-ve), 21.0 (-ve), 22.1 (2 carbons, -ve) , 29.9 (+ve), 32.5 (+ve), 33.4 (+ve), 38.4 (+ve), 38.5 (+ve), 39.3 (-ve), 39.9 (+ve), 43.2 (-ve), 44.6 (-ve), 45.6 (+ve), 46.9 (+ve), 48.5 (-ve), 58.0 (+ve), 59.4 (-ve), 81.4 (-ve), 127.1 (+ve). H R M S for C 2 0 H 3 i N O ( M + ) 301.2406, found 301.2400. Anal . Calcd for C 2 0 H 3 i N O : C, 79.68; H , 10.36; N , 4.65. Found: C , 79.78; H , 10.51; N , 4.70. Chapter 4 281 Preparation of (IS*. 25*. 55*. 65*. 75*. 105*. 115*. 12ft*. 135*)-7-Cvano-ll-(p-nitrobenzovloxv)-2.7.10.13-tetramethvltetracvclori0.3.0.0 1 ' 5.0 6 ' 1 0lpentadecane (274). <-o-< p-nitrobenzoyl chloride D M A P , THF, rt 273 To a room temperature stirred solution of alcohol 273 (14 mg, 0.05 mmol) in 2 m L of dry T H F was added p-nitrobenzoyl chloride (100 mg, 0.54 mmol) and D M A P (56 mg, 0.46 mmol). The resulting mixture was stirred for 10 min and then was treated with 2 m L of aqueous NH3-NH4CI (pH ~8) and 2 m L of E t 2 0 . The aqueous phase was extracted with E t 2 0 ( 3 x 5 mL). The combined organic extracts were dried ( M g S 0 4 ) and were concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (5 g of silica gel, 9:1 pet. ether-Et 2 0) to afford 13 mg (62%) of the title compound, a colourless crystalline solid exhibiting mp 194-195 °C. Chapter 4 282 Preparation of (15*. 25*. 55*. 6/?*, 10/?*, 135*)-7-Methvlidene-2,10,13-trimethvltetracvclori0.3.0.0 1 5 .0 6 1 0lpentadec-l 1-ene (194). (Im)2C=S, D M A P , o-xylene reflux 252 194 To a stirred solution of P-alcohol 252 (440 mg, 1.6 mmol) in (343 mg, 2.8 mmol). The resulting orange solution was heated at reflux for 21 h. The dark brown mixture was cooled to room temperature and was concentrated to a volume of ~1 m L by rotary evaporation. The remaining viscous liquid was transferred onto a silica gel column. Flash chromatography (30 g of silica gel, pet. ether), followed by concentration of the appropriate fractions, afforded 284 mg (69%) of a colourless oi l that consisted of a mixture of the title compound and an impurity (-9%). This impurity presumably arose from cationic rearrangement of the core structure of the starting material. Increasing the polarity of the chromatography solvent to 4:1 pet. ether-Et 2 0 allowed the recovery of 80 mg (18%) of the starting alcohol. The major component of the product mixture, compound 194, exhibited: IR 2952, 2896, 2868, 1651, 1451, 1377 c m 1 . • H - N M R 5 0.83 (d, 3H , J = 7.3 Hz) , 0.98 (s, 3H), 1.09 (d, 3H , J = 7.1 Hz) , 1.09-1.19 (m, 1H), 1.35-1.92 (m, 11H), 2.09 (dddd, 1H, 7 = 12.9, 9.1, 9.1, 1.9 Hz) , 2.22-2.53 (m, 3H), 4.85 (br. s, 1H), 4.89 (br. s, 1H), 5.45 (d, 1H, J= 1.7 Hz) . 1 3 C - N M R 8 21.5, 23.0, 27.0, 27.3, 29.4, 31.1, 32.2, 37.6, 38.8, 40.4, 42.9, 44.4, 48.7, 53.1, 56.3, 107.8, 128.9, 144.4, 156.0. Chapter 4 283 H R M S for C 1 9 H 2 8 ( M + ) 256.2191, found 256.2194. Preparation of Dimethyl Spiro"aft*Vcvclopropane-l,7'-(l'S*. 2'S*. 5'5*, 6'S*. 107?*, 13'5*)-2M0M3-trimethvtetracvclori0.3.0.0 1 ' ' 5 ' .0 6 ' 1 Q ' lpentadec-ll -enel-2-dicarboxvlate (321). 194 321 To a warm (60 °C) stirred solution of diene 194 (36 mg, 0.14 mmol) and rhodium(II) acetate dimer (6 mg, 0.014 mmol) in 0.5 m L of dry D M E was added, over 3 h, via a syringe with the aid of a syringe pump, a solution of dimethyl diazomalonate (111 mg, 0.7 mmol) in 2 m L of dry D M E . The resulting green solution was stirred at 60 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The residual oil was purified by flash chromatography (5 g of silica gel, 9:1 pet. ether-Et20) to afford 16 mg (29%) of the title compound, a colourless o i l . Starting material (25 mg, 70%) was also recovered from the column. 1 H - N M R 8 0.74 (d, 3H , / = 7.3 Hz), 1.06 (d, 3H, / = 7.2 Hz) , 1.08 (s, 3H), 1.08-1.29 (m, 3H), 1.34-1.87 (m, 12 H) , 1.93-2.08 (m, 2H), 2.43-2.55 (m, 1H), 3.70 (s, 3H), 3.74 (s, 3H), 5.36 (d, 1 H , 7 = 1.5 Hz) . Chapter 4 284 Selective irradiation of the spectral region encompassing the two signals at 53.70 and 3.74 resulted in a weak nOe enhancement of the 3 H singlet at 8 1.08. MeOOC 321 1 3 C - N M R 8 21.3, 21.6, 21.9, 29.1, 29.4, 30.8, 31.3, 32.5, 37.5, 39.5, 39.9, 43.1, 44.8, 47.2, 48.1, 49.2, 52.3, 52.4, 56.8, 129.4, 143.8, 169.3, 169.7. Preparation of a mixture of Ethyl Spiror(lff*. 2ft*Vcvclopropane-1.7 ,-(TS*. TS*. 5'S*. 6'S*. 107?*. 13'5*)-2\10\13 ,4rimethvtetracvcloll0.3.0.0 1 ' ' 5 ' .0 6 ' 1 0 ' lpentadec-ll'-enel-2-carboxvlate (291) and its 3 Possible Diastereomers at C - l and C-2 (292-294). To a stirred blue-green solution of diene 194 (377 mg, 1.5 mmol) and Rh 2 (OAc)4 (13 mg, 0.03 mmol) in 5 m L of dry D M E was added, over 3.5 h at room temperature, via a syringe and with the aid of a syringe pump, a solution of ethyl diazoacetate (2.3 m L , 22 mmol) in 10 m L of dry D M E . The resulting green solution was stirred overnight (-15 h). The reaction mixture was concentrated under reduced (water aspirator) pressure by rotary evaporation, and the residual Chapter 4 285 green oi l was subjected to preliminary silica gel chromatography (50 g of silica gel, 9:1 pet. ether-Et20). The fractions containing the 4 diastereomers were combined and concentrated. The remaining colourless oi l was then subjected to silica gel chromatography two more times (50 g of silica gel each, 19:1 pet. ether-Et20) to afford two fractions (colourless oils), each consisting of a mixture of two compounds. The yield of the first mixture to be eluted from the column was 164 mg (33%) and the yield of the second mixture to be eluted from the column was 191 mg (38%). Further separation of the diastereomers is achieved at a later stage in the synthesis. 20 mg (5%) of starting material was also recovered from the column. The ! H - N M R spectrum of the first mixture of esters to elute from the column revealed it to be a 9:1 mixture of two compounds (by integration) and displayed, amongst others, the following signals, characteristic of the desired products: ' H - N M R 8 0.74 (d, 3H , J = 7.3 Hz) , 0.95 (dd, 1H, J = 7.9, 4.8 Hz) , 1.02 (s, 3H), 1.06 (d, 3H, J = 7.1 Hz) , 1.23 (t, 3H, J = 7.1 Hz) , 2.43-2.56 (m, 1H), 4.02-4.17 (m, 2H), 5.35 (d, 1H, J = 1.4 Hz) . The most abundant component of the mixture displayed the following signals by 1 3 C -N M R spectroscopy: , 3 C - N M R 8 14.4, 15.3, 21.7, 21.9, 28.4, 29.1, 30.0, 30.9, 32.5, 35.5, 37.6, 39.9, 40.0 (2 carbons), 43.1, 45.1, 47.2, 49.3, 56.7, 60.2, 129.5, 144.1, 173.1. H R M S (of the mixture) for C23H34O2 ( M + ) 342.2559, found 342.2557. ^ - N M R spectroscopy of the second mixture of products to elute from the column revealed it to be a 1:1 mixture of compounds, displaying signals similar to those noted for the first mixture of compounds, above. Chapter 4 286 Preparation of Spiro"(l/?*. 2S*)-cyclopropane-1.7'-(l'S*. 2'S*. 5'5*. 6'S*. 107?*, 13'S*)-2 M 0 M 3 -Mmethvtetracyclori0.3.0.0 1 , , s '.0 6 ' , 1 01pentadec-11 -enel-2-carbaldehvde (297) and its Diastereomer (298). 297 298 To a cold (0 °C) stirred solution of the diastereomeric ester mixture consisting of esters 291 and 292 (163 mg, 0.48 mmol) in 5 m L of dry Et20 was added, via a syringe, a solution of D I B A L H (1.0 M in hexanes, 1.5 mL, 1.5 mmol). The resulting colourless solution was stirred for 1 h, then was treated with NH3-NH4CI (pH ~8, 375 pL) and was stirred at room temperature for 1 h further. To the white mixture was added 0.5 g of anhydrous M g S 0 4 and stirring was maintained for 0.5 h. The resulting mixture was filtered through a pad of Celi te® (-10 g). The collected solid material was washed with Et20 (3 x 20 mL) . The combined filtrate and washes were concentrated under reduced pressure (water aspirator). The residual colourless oi l (IR 3631 cm"1) was dissolved in 5 m L of dry CH2CI2 and was transferred into a reaction vessel containing 0.5 g of flame-activated 3 A mol. sieves. To the mixture was added N M O (84 mg, 0.71 mmol). After 15 min of stirring, the pale yellow solution was treated, in one portion, with T P A P (9 mg, 0.02 mmol). The resulting black mixture was stirred for 0.5 h, then was concentrated under reduced (water aspirator) pressure. The residual oi l was subjected twice to silica gel chromatography (10 g of silica gel, 19:1 pet. ether-Et20) to Chapter 4 287 afford two compounds: the major aldehyde (297) (99 mg, 70 %) and the minor aldehyde (298) (26 mg, 18%). The major compound to elute from the column (aldehyde 297) exhibited: IR 2951, 2868, 1702, 1455, 1397, 1377, 1173, 1064, 1031 cm" 1. 1 H - N M R 5 0.72 (d, 3H, J = 7.4 Hz) , 1.04 (s, 3H), 1.05 (d, 3H , J = 7.2 Hz) , 1.05-1.23 (m, 4H), 1.38 (dddd, 1H, J = 12.8, 8.2, 8.2, 4.4 Hz), 1.46 (d, 1H, J = 11.2 Hz) , 1.48-1.64 (m, 3H), 1.69-1.90 (m, 7H), 2.03 (dddd, 1H, J= 13.0, 8.9, 8.9, 4.4 Hz) , 2.08 (ddd, 1H, J= 13.4, 9.3, 9.3 Hz) , 2.43-2.52 (m, 1H), 5.35 (d, 1H, J= 1.5 Hz) , 9.40 (d, 1H, 7 = 4.7 Hz) . 1 3 C - N M R 8 16.4 (-ve), 21.7 (+ve), 21.9 (+ve), 29.5 (-ve), 30.0 (+ve), 30.8 (-ve), 32.5 (-ve), 35.5 (-ve), 37.3 (+ve), 37.5 (+ve), 39.7 (-ve), 40.0 (+ve), 43.1 (2 carbons (-ve)), 45.7 (-ve), 47.5 (+ve), 49.1 (+ve), 56.5 (-ve), 129.2 (-ve), 144.1 (+ve), 201.4 (-ve). H R M S for C 2 i H 3 0 O ( M + ) 298.2297, found 298.2295. Anal . Calcd for C21H30O: C , 84.51; H , 10.13. Found: C , 84.22; H , 10.13. Chapter 4 288 Preparation of (15*. 25*. 55*. 6/?*, 7R*. 10i?*, 135*)-7-Formylmethvl-2.7,10,13-tetramethvltetracvcloriOJ.O.O'^.O^^Ipentadec-ll-ene (193) and (15*. 25*. 55*. 6/?*. 7i?*. 10/?*. 135*)-7-Hvdroxvmethvl-2.7.10.13-tetramethvltetracvclori0.3.0.0 1 ' 5.0 6 1 0lpentadec-ll-ene (3161 297 193 316 A 25 m L R B flask was charged with aldehyde 297 (72 mg, 0.24 mmol), anhydrous K2CO3 (30 mg, 0.22 mmol), 5 drops of water and a magnetic stir bar. The resulting suspension was dissolved in 5 m L of absolute E t O H , then, under inert atmosphere (Ar) was treated with 18 mg of 5% Pd on activated charcoal (0.008 mmol of Pd). To the reaction vessel was connected a balloon filled with H 2 gas, and the black mixture was stirred vigorously for 1 h. T L C analysis revealed that no reaction had occurred, so the H 2 atmosphere was replaced with A r gas, and another 18 mg (0.008 mmol) of 5% Pd/C was added to the mixture. Under H 2 atmosphere the reaction mixture was stirred vigorously for a further hour. To the reaction mixture was added 20 m L of 9:1 pet. e ther-Et 2 0 and the resulting mixture was filtered through a pad (~5 g) of Celite®. The collected solid material was washed with E t 2 0 (3 x 25 mL) . The combined filtrate and washes were concentrated under reduced pressure (water aspirator). Flash chromatography of the residual oi l afforded two compounds: the ring-opened aldehyde (43 mg, 51%) and its corresponding alcohol (from over-reduction, 34 mg, 40%). The aldehyde 193, a colourless o i l , exhibited: IR 2936, 2727, 1718, 1455, 1379, 1322, 1288, 1187, 1116, 1061, 1032 cm" 1. Chapter 4 289 * H - N M R 8 0.80 (d, 3H, J = 7.3 Hz) , 0.97 (s, 3H), 1.07 (d, 3H , J = 7.1 Hz) , 1.11 (s, 3H), 1.13-1.25 (m, 1H), 1.31-1.42 (m, 3H), 1.44-1.65 (m, 4H), 1.67-2.02 (m, 5H), 2.37 (dd, 1H, J = 14.4, 2.5 Hz) , 2.42-2.52 (m, 1H), 2.53 (dd, 1H, J = 14.4, 3.8 Hz) , 5.39 (d, 1H, J = 1.7 Hz) , 9.82 (dd, 1H ,7=3 .8 , 2.5 Hz) . 1 3 C - N M R 8 21.4 (-ve), 21.5 (-ve), 23.6 (-ve), 30.6 (-ve), 31.1 (+ve), 32.7 (+ve), 32.8 (+ve), 37.4 (-ve), 38.6 (+ve), 39.7 (+ve), 41.8 (-ve), 44.0 (+ve), 44.2 (+ve), 44.6 (+ve), 46.2 (-ve), 56.1 (+ve), 58.0 (-ve), 58.4 (+ve), 129.7 (-ve), 144.9 (+ve), 203.7 (-ve). H R M S for C21H32O ( M + ) 300.2453, found 300.2450. Anal . Calcd for C 2 i H 3 2 0 : C , 83.94; H , 10.73. Found: C, 83.59; H , 10.69. The alcohol 316, a colourless o i l , exhibited: TR 3326, 2942, 2868, 1455, 1377, 1116, 1052, 1017 cm" 1. ! H - N M R 8 0.80 (d, 3H , J = 7.3 Hz) , 0.82 (s, 3H), 1.06 (d, 3H , J = 7.2 Hz) , 1.07 (s, 3H), 1.12-1.23 (m, 3H), 1.27 (d, 1H, J= 8.9 Hz) , 1.32-1.50 (m, 6H), 1.60-1.87 (m, 7H), 1.94 (dddd, 1H, J = 12.3, 8.5, 8.5, 3.9 Hz) , 2.41-2.50 (m, 1H), 3.65-3.76 (m, 2H), 5.38 (d, 1H, J = 1.6 Hz). U C - N M R 8 21.5, 21.7, 22.9, 30.4, 31.1, 32.6, 33.9, 37.4, 38.8, 39.8, 41.8, 44.1, 44.2, 44.4, 46.4, 48.5, 56.2, 57.7, 60.6, 130.0, 144.5. Chapter 4 H R M S for C21H34O ( M + ) 302.2610, found 302.2611. 290 Preparation of Cyclohexylethanal (328). - O H TPAP, N M O , 3 A mol. sieves CH 2 C1 2 , rt C H O 327 328 A solution of commercially available 2-cyclohexylethanol (327, 2 m L , 14 mmol) and N M O (2 g, 18 mmol) in 70 m L of dry CH2CI2 was stirred over 0.5 g of flame-activated 3 A molecular sieves for 10 min. To the reaction mixture was added, in one portion, solid T P A P (75 mg, 0.2 mmol). The reaction mixture was stirred for 1 h and then was filtered through a pad (-10 g) of silica gel. The remaining solid material was washed with CH2CI2 (3 x 15 mL). The combined filtrate and washes were concentrated under reduced pressure (room temperature rotary evaporator bath). Residual solvent was removed under a stream of dry argon. The aldehyde was used in subsequent experiments without purification due to its volatility. The ! H -N M R spectrum of the crude material revealed it to be greater than 90% pure, and to exhibit the expected signals for the product, including a doublet of doublets at 8 2.3 and a triplet at 8 9.7. Chapter 4 291 Preparation of (2-hydroxy-4-methylpent-3-en-l-yl)cyclohexane (333). To a cold (-78 °C) stirred solution of commercially available l-bromo-2-methylpropene (102 p L , 1 mmol) in dry T H F (10 mL) was added, via a syringe, a solution of ?-BuLi in pentane (1.7 M , 1.95 mmol). The resulting pale yellow solution was stirred for 0.5 h, during which time, it slowly became colourless. To the mixture was added, dropwise via a syringe, neat aldehyde 328 (126 mg, 1 mmol). The reaction vessel was removed from the cold bath for 5 min and then the reaction mixture was poured into 10 m L of saturated aqueous N a H C 0 3 . Et20 (10 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with Et20 ( 3 x 5 mL) . The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (5 g of silica gel, 4:1 pet. ether-Et^O) to afford 96 mg (55%) of the title compound, a colourless o i l . IR 3344, 2922, 2852, 1676, 1448, 1376, 1044 cm" 1. ^ - N M R 8 0.82-1.02 (m, 2H), 1.05-1.38 (m, 6H), 1.45 (ddd, 1H, J= 12.9, 7.3, 5.8 Hz) , 1.57-1.76 (m, 5H), 1.65 (d, 3H, J = 1.1 Hz), 1.69 (d, 3H, J = 1.1 Hz) , 4.42 (dd, 1H, J = 14.5, 7.9 Hz), 5.12 (m, 1H). 1 3 C - N M R 8 18.1, 25.7, 26.2, 26.3, 26.6, 33.3, 33.9, 34.1, 45.5, 66.3, 128.7, 134.5. Chapter 4 292 Preparation of (2-rg^Butyldimethylsilyloxy-4-methyl-pent-3-en-l-yl)cyclohexane (335). To a room temperature solution of allylic alcohol 333 (171 mg, 0.94 mmol) in 8 m L of H P L C grade D M F was added triethylamine (197 uL, 1.4 mmol), D M A P (138 mg, 1.1 mmol) and TBSC1 (222 mg, 1.6 mmol). The resulting mixture was stirred for 18 h and then was treated with saturated aqueous N a H C 0 3 (10 mL) and Et20 (10 mL) . The aqueous phase was extracted with Et20 (3 x 10 mL) . The combined organic extracts were dried ( M g S 0 4 ) and were concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (7 g of silica gel, pet. ether) to afford 246 mg (88%) of the title compound, a colourless oi l . ! H - N M R 8 -0.02 (s, 3H), 0.01 (s, 3H), 0.82-0.97 (m, 2H), 0.85 (s, 9H), 1.06-1.22 (m, 4H), 1.32-1.45 (m, 2H), 1.59 (br. s, 3H), 1.59-1.75 (m, 5H), 1.66 (br. s, 3H), 4.40 (ddd, 1H, J = 7.9, 7.9, 5.5 Hz) , 5.04-5.09 (m, 1H). O H 333 TBSC1, E t 3 N , D M A P , D M F , rt O T B S 335 1 3 C - N M R 8 -4.8 (-ve), -4.1 (-ve), 18.1 (-ve), 18.2 (+ve), 25.6 (-ve), 25.9 (3 carbons, -ve) , 26.3 (+ve), 26.5 (+ve), 26.7 (+ve), 33.2 (+ve), 33.8 (-ve), 34.1 (+ve), 46.3 (+ve), 67.4 (-ve), 130.1 (-ve), 130.4 (+ve). Chapter 4 293 Preparation of (2-fer^Butyldimethylsilyloxy-4-hydroxy-4-methyl-3 (340). O || OH K M n 0 4 , HOAc, H 2 0 , acetone, rt 0 T B S OTBS 335 340 Potassium permanganate (650 mg, 4.1 mmol) was dissolved in 4 m L of H 2 0 . To the solution was added 8 drops of acetic acid and 4 m L of acetone. The resulting purple solution was added, via a syringe, to a solution of TBS-ether 335 in 4 m L of acetone at room temperature. The reaction mixture was stirred for 24 h and then was treated with 11 m L of saturated aqueous Na 2 S03 . The mixture was stirred for 10 min and then the acetone was removed by rotary evaporation. The remaining brown aqueous mixture was extracted with E t O A c (3 x 10 mL). The combined organic extracts were dried (MgSC^) and concentrated under reduced pressure. The residual oi l was purified by flash chromatography (10 g of silica gel, 9:1 E t 2 0-pe t . ether) to afford 134 mg (50%) of the title compound, a colourless oi l . IR 3475, 2928, 2855, 1718, 1471, 1449, 1362, 1255, 1158, 1117, 1006 cm" 1. 1 H - N M R 8 0.06 (s, 3H), 0.07 (s, 3H), 0.83-0.87 (m, 2H), 0.90 (s, 9H), 1.06-1.26 (m, 3H), 1.29-1.41 (m, 1H), 1.34 (s, 3H), 1.39 (s, 3H), 1.53-1.75 (m, 7H), 4.06 (s, 1H), 4.47 (dd, 1H, J = 7.3, 7.3 Hz) . 1 3 C - N M R 8 -4.8 (-ve), -4.6 (-ve), 18.1 (+ve), 25.8 (3 carbons, -ve) , 26.1 (+ve), 26.2 (+ve), 26.4 (+ve), 27.5 (-ve), 28.7 (-ve), 33.1 (+ve), 33.6 (-ve), 33.6 (+ve), 42.3 (+ve), 76.3 (-ve), 78.0 (+ve), 214.3 (+ve). Chapter 4 294 Preparation of (2,4-dihydroxy-4-methyl-3-oxopent-l-yl)cyclohexane (329). O T B S TBAF, THF, rt To a room temperature stirred solution of silyl ether 340 (30 mg, 0.09 mmol) in 2 m L of dry T H F was added, via a syringe, a solution of T B A F in T H F (1 M , 0.12 mmol). The reaction mixture was stirred for 0.5 h and then was treated with 3 m L of aqueous N H 3 - N H 4 C I (pH ~8) and 3 m L of E t 2 0 . The aqueous phase was extracted with Et20 (3 x 10 mL) . The combined organic extracts were dried ( M g S 0 4 ) and concentrated under reduced pressure. The residual oi l was purified by flash chromatography (5 g of silica gel, 1:1 Et20-pet. ether) to afford 17 mg (85%) of the title compound, a colourless o i l . IR 3418, 2921, 2852, 1710, 1448, 1372, 1266, 1189, 1097, 1044 cm" 1. ! H - N M R 8 0.81-0.99 (m, 2H), 1.03-1.31 (m, 4H), 1.36 (s, 3H), 1.38 (s, 3H), 1.52-1.72 (m, 6H), 1.82-1.92 (m, 1H), 3.01 (br. s, 1H), 3.13 (br. s, 1H), 4.51-4.53 (m, 1H). 1 3 C - N M R 8 25.9 (+ve), 26.3 (+ve), 26.4 (+ve), 27.5 (-ve), 27.6 (-ve), 31.9 (+ve), 34.0 (-ve), 34.3 (+ve), 42.0 (+ve), 71.4 (-ve), 76.9 (+ve), 216.9 (+ve). Chapter 4 295 Preparation of (15*. 25*. 55*. 6ft*. IR*. 10ft*. 135*, 185*)-7-(2-Hydroxy-4-methvlpent-3-en-l-vn-2.7.10.13-tetramethvltetracvclori0.3.0.0'' 5.0 6 ' 1 0lpentadec-ll-ene (348) and (15*. 25*. 55*. 6ft*. IR*. 10ft*. 135*. 18ft* s)-7-(2-Hvdroxv-4-methvlpent-3-en-l-vl)-2.7.10.13-tetramethyltetracvclori0.3.0.0 1 , 5.0 6 ' 1 01pentadec-l 1-ene (349). To a cold (-78 °C) stirred solution of ?-BuLi (1.7 M solution in pentane, 252 pL , 0.43 mmol) in dry Et20 (0.5 mL) was added, via a syringe, a solution of 2-methyliodopropene (39 mg, 0.21 mmol, freshly filtered through oven-dried basic AI2O3) in 1 m L of dry Et20, by allowing the 2-methyliodopropene solution to run slowly down the inside of the cold reaction vessel. The resulting colourless solution was stirred for 15 min. To the cold (-78 °C) stirred alkenyllithium solution was added, via a syringe, a solution of aldehyde 193 (43 mg, 0.14 mmol) in 1.5 m L of dry Et20, by allowing the aldehyde solution to run slowly down the inside of the cold reaction vessel. The colourless solution was stirred for 5 min, then the reaction vessel was removed from the cold bath. To the solution was immediately added 3 m L of saturated aqueous NaHCC<3. After 5 min of stirring, the phases were separated and the aqueous phase was extracted with Et20 ( 3 x 1 mL). The combined ethereal extracts were dried (MgSC^) and were concentrated under reduced pressure (water aspirator). Flash column chromatography (10 g of silica gel, 19:1—>9:1 pet. ether) afforded two compounds, each as colourless oils, with yields of 21 mg (41%) of the least polar compound, and 17 mg (33%) of the more polar compound. The first compound (348) to elute from the column exhibited the following data. Chapter 4 296 IR 3368, 2937, 3868, 1673, 1454, 1376, 1274, 1059 c m 1 . ! H - N M R 8 0.80 (d, 3H , J = 7.3 Hz) , 0.84 (s, 3H), 1.03 (d, 3H , J = 7.1 Hz) , 1.08 (s, 3H), 1.10-1.95 (m, 18H), 1.68 (d, 3H , J = 1.2 Hz) , 1.69 (d, 3 H , J = 1.1 Hz) , 2.42-2.52 (m, 1H), 4.51 (ddd, 1H, 7=8 .2 , 7.5, 5.0 Hz) , 5.18-5.24 (m, 1H), 5.39 (d, 1 H , 7 = 1.7 Hz) . 1 3 C - N M R 8 18.1 (-ve), 21.5 (2 carbons, -ve) , 22.6 (-ve), 25.7 (-ve), 30.7 (-ve), 31.1 (+ve), 32.9 (+ve), 33.0 (+ve), 37.4 (-ve), 39.3 (+ve), 40.2 (+ve), 42.0 (-ve), 43.6 (+ve), 44.3 (+ve), 45.2 (+ve), 46.3 (-ve), 52.9 (+ve), 56.1 (+ve), 58.8 (-ve), 66.8 (-ve), 129.9 (-ve), 130.3 (-ve), 133.5 (+ve), 144.5 (+ve). H R M S for C 2 5 H4oO ( M + ) 356.3079, found 356.3074. The second compound (349) to elute from the column exhibited the following data. IR 3351, 2936, 2868, 1675, 1455, 1377, 1320, 1188, 1041 cm" 1. ! H - N M R 8 0.79 (d, 3H , J = 7.2 Hz) , 0.86 (s, 3H), 1.06 (d, 3H , J = 6.0 Hz) , 1.07 (s, 3H), 1.10-1.97 (m, 18H), 1.69 (br. s, 6H), 2.40-2.53 (m, 1H), 4.50 (dddd, 1H, J = 9.2, 6.1, 6.1, 3.3 Hz) , 5.19-5.25 (m, 1H), 5.38 (d, 1H, / = 1.7 Hz) . Chapter 4 297 1 3 C - N M R 5 18.1 (-ve), 21.5 (2 carbons, -ve) , 23.2 (-ve), 25.8 (-ve), 30.7 (-ve), 31.1 (+ve), 33.0 (2 carbons, +ve), 37.5(-ve), 38.5 (+ve), 40.1 (+ve), 42.0 (-ve), 43.6 (+ve), 44.2 (+ve), 45.2 (+ve), 46.2 (-ve), 52.9 (+ve), 56.1 (+ve), 58.3 (-ve), 66.8 (-ve), 129.8 (-ve), 130.2 (-ve), 133.6 (+ve), 144.6 (+ve). H R M S for ( M + ) 356.3079, found 356.3077. Preparation of (15*. 25*. 55*. 6ft*. 7ft*. 10ft*. 135*. 185*)-7-(2-Acetoxv-4-methylpent-3-en-l-vlV2.7.10.13-tetramethvltetracvclori0.3.0.0 1 5.0 6 ' 1 01pentadec-ll-ene (350). To a solution of alcohol 348 (21 mg, 0.060 mmol) in 2 m L of D M F was added solid D M A P (9 mg, 0.074 mmol), then, via syringes, E t 3 N (16 pL , 0.12 mmol) followed by A c 2 0 (11 pL , 0.12 mmol). The resulting mixture was stirred for 1.5 h, then was treated with 3 m L of saturated aqueous N a H C 0 3 and 8 m L of E t 2 0 . The phases were separated and the aqueous phase was extracted with E t 2 0 ( 3 x 3 mL). The combined organic extracts were dried (MgSCU) and were concentrated under reduced pressure. The remaining yellow oi l was purified by flash column chromatography (6 g of silica gel, 9:1 pet. ether-Et 2 0) to afford, after concentration of the appropriate fractions, 19 mg (81%) of the title compound as a colourless crystalline solid. Recrystallization from heptane furnished a substance exhibiting mp 80-82 °C, and appropriate for X-ray crystallography. 348 350 Chapter 4 298 IR 2947, 2868, 173, 1454, 1371, 1245, 1104, 1016 cm" 1. 1 H - N M R 5 0.80 (d, 3H , J = 7.5 Hz) , 0.82 (s, 3H), 1.06 (d, 3H , J = 8.0 Hz) , 1.08 (s, 3H), 1.12-1.52 (m, 9H), 1.54-1.97 (m, 8H), 1.68 (br. s, 3H), 1.73 (br. s, 3H), 1.98 (s, 3H), 2.41-2.53 (m, 1H), 5.10 (d, 1H, J = 9.0 Hz) , 5.38 (s, 1H), 5.65 (ddd, 1H, J = 9.0, 9.0, 4.3 Hz) . 1 3 C - N M R 6 18.4 (-ve), 21.4 (2 carbons, -ve) , 21.7 (-ve), 22.4 (-ve), 25.7 (-ve), 30.8 (-ve), 31.1 (+ve), 33.0 (2 carbons, +ve), 37.4 (-ve), 38.4 (+ve), 40.2 (+ve), 42.0 (-ve), 43.5 (+ve), 44.3 (+ve), 45.2 (+ve), 46.2 (-ve), 50.0 (+ve), 56.1 (+ve), 59.0 (-ve), 69.8 (-ve), 125.5 (-ve), 130.2 (-ve), 135.4 (+ve), 144.5 (+ve), 170.3 (+ve). H R M S for C27H42O2 ( M + ) 398.3185, found 398.3187. Anal . Calcd for C27H42O2: C , 81.35; H , 10.62. Found: C, 80.97; H , 10.95. Preparation of (15*. 25*. 55*. 6ft*. 7ft*. 10ft*. 135*. 18 1S*)-7-(2-Acetoxv-4-hvdroxv-4-methvl-S-oxopent-l-vD^J.lO.n-tetramethvltetracvcloriOJ.O.O^^O^'^pentadec-ll-ene (351). O OH 351 350 Chapter 4 299 To a solution of compound 350 (6 mg, 0.02 mmol) in 0.5 m L of H P L C grade acetone and 25 p L of H 2 0 was added 25 p L of acetic acid and 6 mg (0.038 mmol) of K M n 0 4 . The resulting purple solution was stirred for 18 h, during which time, a brown precipitate slowly formed. To the reaction mixture was added 1 m L of saturated aqueous Na2SC<3. The water-acetone mixture was extracted with E t 2 0 ( 3 x 2 mL). The combined organic extracts were dried (MgSC^) and were concentrated under reduced pressure. Purification by flash column chromatography (-0.5 g of silica gel, 1:1 pet. ether-Et 2 0) afforded 3.4 mg (52%) of the title compound as a colourless oil and 2.5 mg (42%) of recovered starting material. IR 3467, 2944, 2868, 1745, 1719, 1458, 1376, 1253, 1194, 1026 cm" 1. • H - N M R 8 0.80 (d, 3H , J = 7.2 Hz) , 0.90 (s, 3H), 1.06 (d, 3 H , J = 5.6 Hz) , 1.07 (s, 3H), 1.13-1.25 (m, 3H), 1.28-1.50 (m, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.56-1.98 (m, 9H), 2.09 (s, 3H), 2.41-2.53 (m, 1H), 2.74 (s, 3H), 5.39 (d, 1H, J = 1.6 Hz) , 5.70 (dd, 1H, J = 10.3, 1.3 Hz) . 1 3 C - N M R 8 20.8 (-ve), 21.4 (-ve), 21.5 (-ve), 22.5 (-ve), 27.7 (-ve), 27.8 (-ve), 30.5 (-ve), 31.1 (+ve), 32.8 (+ve), 32.9 (+ve), 37.4 (-ve), 38.8 (+ve), 40.0 (+ve), 41.9 (-ve), 43.6 (+ve), 44.3 (2 carbons, +ve), 45.5 (+ve), 46.3 (-ve), 56.1 (+ve), 58.0 (-ve), 72.3 (-ve), 129.9 (-ve), 144.6 (+ve), 170.8 (+ve), 211.9 (+ve). Based on the proximity of the carbinol signal to the solvent signal (for compound 354), this signal (expectedly +ve) is presumed to be hidden underneath the solvent signal. H R M S for C 2 7 H 4 2 0 4 ( M + ) 430.3083, found 430.3085. Chapter 4 300 Preparation of (±)-17-gpz'-Mangicol F (352). O OH 351 K 2 C 0 3 , THF, MeOH, H 2 0 352 To a solution of acetate 351 (3.4 mg, 0.008 mmol) in 250 u L of dry T H F , 250 u L of H P L C grade M e O H and 25 p L of H 2 0 was added anhydrous K 2 C 0 3 (1.3 mg, 0.009 mmol). The resulting mixture was stirred for 2 h. To the mixture was added 1.5 m L of saturated aqueous N a H C 0 3 and 3 m L of E t 2 0 . The phases were separated and the aqueous phase was extracted with E t 2 0 ( 2 x 1 mL) . The combined organic extracts were dried (MgS04) and were concentrated under reduced pressure (water aspirator). The residual colourless oi l was purified by flash column chromatography (-0.5 g of silica gel, 4:1—»1:1 pet. ether-Et 2 0) to afford 3.0 mg (100%) of the title compound as a colourless oi l . ! H - N M R (acetone-d6) 6 0.84 (d, 3H , J = 7.3 Hz) , 0.96 (s, 3H), 1.08 (d, 3 H , J = 7.1 Hz) , 1.10 (s, 3H), 1.14-1.30 (m, 5H), 1.32 (s, 3H), 1.35 (s, 3H), 1.40-1.58 (m, 6H), 1.67-1.97 (m, 3H), 2.21-2.25 (m, 1H), 2.47-2.58 (m, 2H), 2.83 (s, 1H), 2.85 (d, 1H, J = 13.1 Hz) , 4.86 (m, 1H), 5.44 (d, 1 H , 7 = 1.4 Hz) . H R M S for Q5H40O3 ( M + ) 388.2978, found 388.2975. Chapter 4 301 Preparation of (IS*. 25*. 55*. 6/?*, IR*. 10/?*, 13^*,185*)-7-(2-Acetoxv-4-methvlpent-3-en-l-vn^J.lO.B-tetramethvltetracvcloriO^.O.O^lO^^lpentadec-ll-ene (353). To a solution of allylic alcohol 349 (17 mg, 0.048 mmol) in 2 m L of D M F was added solid D M A P (9 mg, 0.074 mmol) and then, via syringes, E t 3 N (20 uL , 0.21 mmol) and A c 2 0 (30 uL, 0.22 mmol). The resulting mixture was stirred for 1,5 h, then was treated with 3 m L of saturated aqueous N a H C 0 3 and 8 m L of E t 2 0 . The phases were separated and the aqueous phase was extracted with E t 2 0 ( 3 x 3 mL). The combined organic extracts were dried (MgSCu) and were concentrated under reduced pressure. The remaining yellow oi l was purified by flash column chromatography (6 g of silica gel, 9:1 pet. ether-Et 2 0) to afford, after concentration of the appropriate fractions, 16 mg (84%) of the title compound as a colourless oi l . IR 2941, 2867, 1734, 1455, 1376, 1241, 1016 cm" 1. ! H - N M R 5 0.79 (d, 3H , J = 7.5 Hz) , 0.80 (s, 3H), 1.06 (d, 3H , J = 6.9 Hz) , 1.07 (s, 3H), 1.10-1.26 (m, 3H), 1.51-1.95 (m, 14H), 1.69 (br. s, 3H), 1.74 (br.s, 3H), 1.98 (s, 3H), 2.41-2.53 (m, 1H), 5.07-5.12 (m, 1H), 5.38 (br. s, 1H), 5.60 (ddd, 1H, J= 9.5, 6.3, 6.3 Hz) . 349 353 1 3 C - N M R 5 18.5 (-ve), 21.3 (-ve), 21.4 (-ve), 21.6 (-ve), 22.6 (-ve), 25.8 (-ve), 30.9 (-ve), 31.1 (+ve), 33.0 (+ve), 33.1 (+ve), 37.4 (-ve), 38.4 (+ve), 40.1 (+ve), 42.0 (-ve), 43.5 (+ve), Chapter 4 302 44.3 (+ve), 45.3 (+ve), 46.0 (-ve), 49.8 (+ve), 56.0 (+ve), 58.8 (-ve), 70.2 (-ve), 125.5(-ve), 130.2 (-ve), 135.8 (+ve), 144.6 (+ve), 170.3 (+vej. FTRMS for C27H42O2 ( M + ) 398.3185, found 398.3187. Preparation of (15*. 25*. 55*. 6ft*. 7ft*. 10/?*. 135*. 185*)-7-(2-Acetoxv-4-hvdroxv-4-methyl-S-oxopent-l-vD^J.lO.lS-tetramethvltetracvcloriO.S.O.O'^.O^^lpentadec-ll-ene (354). To a solution of compound 353 (8 mg, 0.02 mmol) in 0.5 m L of FJPLC grade acetone and 25 p L of H2O was added 25 p L of acetic acid and 10 mg (0.06 mmol) of K M n C v The resulting purple solution was stirred for 18 h, during which time, a brown precipitate slowly formed. To the reaction mixture was added 1 m L of saturated aqueous Na2SC>3. The water-acetone mixture was extracted with Et20 ( 3 x 2 mL). The combined organic extracts were dried (MgSCU) and were concentrated under reduced pressure. Purification by flash column chromatography (-0.5 g of silica gel, 1:1 pet. ether-Et20) afforded 4.9 mg (57%) of the title compound as a colourless oi l and 2.7 mg (34%) of recovered starting material. 353 O OH 354 IR 3483, 2941, 2868, 1745, 1718, 1457, 1375, 1257, 1195, 1027 cm" 1. Chapter 4 303 ' H - N M R 5 0.80 (d, 3H , J = 7.2 Hz), 0.89 (s, 3H), 1.06 (d, 3H , J = 7.7 Hz) , 1.08 (s, 3H), 1.09-1.55 (m, 8H), 1.42 (s, 3H), 1.44 (s, 3H), 1.58-2.02 (m, 9H), 2.08 (s, 3H), 2.41-2.54 (m, 1H), 2.72 (br.s, 1H), 5.38 (d, 1H, J = 1.3 Hz) , 5.66-5.99 (m, 1H). 1 J C - N M R 5 20.8 (-ve), 21.5 (-ve), 21.7 (-ve), 23.2 (-ve), 27.9 (2 carbons, -ve) , 30.4 (-ve), 31.1 (+ve), 32.6 (+ve), 32.8 (+ve), 37.4 (-ve), 38.3 (+ve), 39.5 (+ve), 41.7 (-ve), 44.1 (+ve), 44.4 (+ve), 44.6 (+ve), 46.0 (+ve), 46.4 (-ve), 56.2 (+ve), 58.2 (-ve), 72.9(-ve), 77.6 (+ve), 129.9 (-ve), 144.7 (+ve), 170.9 (+ve), 211.9 (+ve). H R M S for C27H42O4 ( M + ) 430.3083, found 430.3086. Chapter 4 304 Preparation of (±)-Mangicol F (52). To a solution of acetate 354 (4.9 mg, 0.011 mmol) in 250 JJL of dry T H F , 250 u L of H P L C grade M e O H and 25 u L of H 2 0 was added anhydrous K 2 C 0 3 (3 mg, 0.02 mmol). The resulting mixture was stirred for 2 h. To the mixture was added 1.5 m L of saturated aqueous N a H C 0 3 and 3 m L of E t 2 0 . The phases were separated and the aqueous phase was extracted with E t 2 0 ( 2 x 1 mL) . The combined organic extracts were dried (MgS04) and were concentrated under reduced pressure (water aspirator). The residual colourless o i l was purified by flash column chromatography (-0.5 g of silica gel, 4:1—»1:1 pet. ether-Et 2 0) to afford 4.4 mg (100%) of the title compound as a colourless oi l . H R M S for C 2 5 H 4 o 0 3 ( M + ) 388.2978, found 388.2979. Chapter 4 305 Table 20: Comparison of the ' H - N M R spectral data of synthetically prepared (±)-mangicol F (52) with those reported 5 0 for natural mangicol F. 52 : mangicol F Assignment3 Reported Data" for Mangicol F 5 0 Data for Synthetic (+)-Mangicol F b 1 1.47 (m) 1.37-1.57 (Part of the 7 H m) 2 1.70 (ddd, 7=9.5 , 7.6, 2.6 Hz) 1.69 (ddd, 7 = 9.4, 7.1, 2.4 Hz) 3a 1.87 (dddd, 7 = 12.6, 8.6, 8.6, 7.2 Hz) 1.73-20.8 (Part of the 6 H m) 3b 1.54 (m) 1.37-1.57 (Part of the 7 H m) 4a 1.99 (dddd, 7 = 12.6, 8.4, 8.4, 4.2 Hz) 1.73-20.8 (Part of the 6 H m) 4b 1.45 (m) 1.37-1.57 (Part of the 7 H m) 5 1.79 (dq, 7=7 .5 , 2.3 Hz) 1.73-20.8 (Part of the 6 H m) 7a 1.74 (m) 1.73-20.8 (Part of the 6 H m) 7b 1.23 (m) 1.15-1.28 (Part of the 2 H m) 8a 1.84 (m) 1.73-20.8 (Part of the 6 H m) 8b 1.22 (m) 1.15-1.28 (Part of the 2 H m) 9 2.51 (m) 2.46-2.55 (m) 11 5.44 (d, 7 = 1.6 Hz) 5.44 (d, 7 = 1.7 Hz) 13a 1.51 (m) 1.37-1.57 (Part of the 7 H m) 13b 1.42 (m) 1.37-1.57 (Part of the 7 H m) 14a 2.01 (m) 1.73-20.8 (Part of the 6 H m) 14b 1.43 (m) 1.37-1.57 (Part of the 7 H m) 16a 2.11 (d, 7 = 14.0 Hz) 2.12 (dd, 7 = 14.1, 1.7 Hz) 16b 1.49 (m) 1.37-1.57 (Part of the 7 H m) 17a 4.88 (ddd, 7 = 9.0,7.5, 1.5 Hz) 4.88 (ddd, 7 = 9.1, 7.6, 1.7 Hz) 17b 3.81 (d, 7 =7.5 H z , OH) 3.82 (d, 7 =7.6 H z , O H ) 19 4.63 (s, OH) 4.67 (s, OH) 20 1.38 (s) 1.38 (s) 21 1.34 (s) 1.34 (s) 22 1.04 (s) 1.04 (s) 23 0.85 (d ,7= 7.4 Hz) 0.85 (d, 7 = 7.3 Hz) 24 1.09 (d, 7 =7.2 Hz) 1.09 (d,7 = 7.1 Hz) 25 1.13 (s) 1.13 (s) Assignments made by the authors of the isolation report. Both samples were recorded at similar concentrations in acetone-d6 (referenced to 8 2.05). The 'H-NMR spectrum of natural mangicol F was recorded at 600 MHz, while the 'H-NMR spectrum of synthetic (±)-mangicol F was recorded at 400 MHz. Chapter 4 306 1"% Table 21: Comparison of the C - N M R spectra of synthetically prepared mangicol F (52) and the authentic sample. 52: mangicol F Assignment3 Reported Datab for Mangicol F 5 0 Data for Synthetic (i)-Mangicol F b 1 58.0 57.7 2 47.8 47.6 3 33.0 32.8 4 33.5 33.3 5 42.5 42.3 6 57.5 57.3 7 45.0 44.8 8 31.9 31.8 9 38.4 38.2 10 145.2 145.2 11 131.3 131.1 12 45.6 45.4 13 40.3 40.1 14 38.8 38.7 15 46.9 46.8 16 49.6 49.5 17 73.1 73.0 18 217.7 217.7 19 77.6 77.6 20 28.2 28.1 21 28.6 28.5 22 24.8 24.6 23 22.5 22.3 24 22.0 21.9 25 30.6 30.4 "Assignments made by the authors of the isolation report. Both samples were recorded at similar concentrations in acetone-d6 (referenced to 8 29.9). The 1 3C-NMR spectra of natural mangicol F and of synthetic (±)-mangicol F were recorded at 100 MHz. 307 Endnotes and References 1. Nicolaou, K . C ; Vourloumis, D . ; Winssinger, N . ; Baran, P. S. Angew. Chem. Int. Ed. 2000,59,44. 2. Fischer, H . ; Zeile, K . Justus Liebigs Ann. Chem. 1929, 468, 98. 3. Bachmann, W . E . ; Cole, W. ; Wilds, A . L . J. Am. Chem. Soc. 1939, 61, 974. 4. Woodward, R. B . ; Cava, M . P.; Oll is , W . D . ; Hunger, A . ; Daeniker, H . U . ; Schenker, K . J. Am. Chem. Soc. 1954, 76, 4749. 5. (a) Corey, E . J.; Ohno, M . ; Vatakencherry, P. A . ; Mitra, R. B . J. Am. Chem. Soc. 1961, 83, 1251. (b) Corey, E . J. ; Ohno, M . ; Mitra, R. B . ; Vatakencherry, P. A . / . Am. Chem. Soc. 1964, 86, 478. 6. Dabrah, T. T.; Kaneko, T.; Massefski, Jr., W. ; Whipple, E . B . J. Am. Chem. Soc. 1997, 119, 1594. 7. (a) Nicolaou, K . C ; Baran, P. S.; Zhong, Y . - L . ; Choi , H.-S. ; Yoon , W . H . ; He, Y . ; Fong, K . C . Angew. Chem. Int. Ed. 1999, 38, 1669. (b) Nicolaou, K . C ; Baran, P. S.; Zhong, Y . - L . ; Fong, K . C ; He, Y . ; Yoon , W . H ; Choi , H.-S. Angew. Chem. Int. Ed. 1999, 38, 1676. 8. For a review on Nicolaou's synthesis of the CP-molecules and the flurry of methodological work derived therefrom, please see: Nicolaou, K . C ; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 2678. 9. The donor and acceptor terminology, as it applies to synthons, was first introduced by Dieter Seebach in his review article on methods of reactivity umpolung: Seebach, D . Angew. Chem. Int. Ed. 1979,18, 239. 10. Trost, B . M . Acc. Chem. Res. 1978,11, 453. 11. Ba l , S. A . ; Marfat, A . ; Helquist, P. J. Org. Chem. 1982, 47, 5045. 12. A synthon is a structural unit within a molecule, which is related to possible synthetic operations. Corey, E . J.; Cheng, X . - M . in The Logic of Chemical Synthesis; John Wiley and Sons, Inc.: New York, 1989. 13. Piers, E . ; McEachern, E . J.; Burns, P. A . J. Org. Chem. 1995, 60, 2322. 14. For interesting examples of the use of related reagents to prepare tricyclic ketones, see: (a) Piers, E . ; McEachern, E . J. Synlett, 1996, 1087. (b) Piers, E . ; Skupinska, K . A . ; Wallace, D . J. Synlett, 1999, 1867. Endnotes and References 308 15. Piers, E . ; Karunaratne, V . J. Org. Chem. 1983, 48, 111 A. 16. Jackson, R. A . J. Organomet. Chem. 1979,166, 17. 17. Piers, E . ; Marais, P. C. J. Org. Chem. 1990, 55, 3454. 18. Piers, E . ; Oballa, R. Tetrahedron Lett. 1995, 36, 5857. 19. (a) Piers, E . ; Renaud, J. J. Org. Chem. 1993, 58, 11. (b) Piers, E . ; Renaud, J.; Rettig, S. J. Synthesis 1998, 590. 20. (a) Piers, E . ; Marais, P. C . Tetrahedron Lett. 1988, 29, 4053. (b) Piers, E . ; Cook, K . L . ; Rogers, C. Tetrahedron Lett. 1994, 35, 8573. 21. (a) Cooke, M . P. J. Org. Chem. 1984, 49, 1144. (b) Cooke, M . P.; Widener, R. K . J. Org. Chem. 1987, 52, 1381. 22. (a) Cooke, M . P. J. Org. Chem. 1993, 58, 6833. (b) Cooke, M . P.; Gopal, D . J. Org. Chem. 1994, 59, 260. 23. Cooke, M . P.; Huang, J.-J. Synlett 1997, 535. 24. Comins, D . L . ; Zhang, Y . - M . J. Am. Chem. Soc. 1996,118, 12248. 25. Piers, E . ; Wong, T.; Coish, P. D . ; Rogers, C . Can. J. Chem., 1994, 72, 1816. 26. (a) Wiley, G . A . ; Rein, B . M . ; Hershkowitz, R. L . Tetrahedron Lett. 1964, 2509. (b) Wiley, G . A . ; Hershkowitz, R. L. ;Rein, B . M . ; Chung, B . C. / . Org. Chem. 1964, 86, 964. 27. Stork, G . ; Danheiser, R. L . J. Org. Chem. 1973, 38, 1775. 28. Acetylenic ester 71 is a known compound: Piers, E . ; Chong, J. M . ; Morton, H . E . Tetrahedron 1989, 45, 363. 29. Corey, E . J.; Fuchs, P. L . Tetrahedron Lett. 1972, 3769. 30. Sauer, D . R.; Schneller, S. W. ; Gabrielsen, B . Carbohydr. Res. 1964, 86, 964. 31. Piers, E . ; Grierson, J. R.; Lau, C. K . ; Nagakura, I. Can. J. Chem. 1982, 60, 210. 32. (a) Snider, B . B . ; Rodini , D . J.; van Straten, J. J. Am. Chem. Soc. 1980,102, 5872. (b) Yamamoto, Y . ; Yamamoto, S.; Yatagai, H . ; Ishihara, Y . ; Maruyama, K . J. Org. Chem. 1982,47, 119. (c) For a review on Lewis acid-mediated conjugate additions, please see: Yamamoto, Y . Angew. Chem. Int. Ed. 1986, 25, 947. (d) For an interesting example of asymmetric Lewis acid-mediated conjugate additions, please see: Wang, Y . ; Gladysz, J. A . / . Org. Chem. 1995, 60, 903. Endnotes and References 309 33. (a) Reich, H . J. ; Green, D . P.; Phillips, N . H . J. Am. Chem. Soc. 1989, 111, 3444. (b) Reich, H . J. ; Green, D . P. J. Am. Chem. Soc. 1989, 111, 8729. (c) Reich, H . J.; Borst, J. P. J. Am. Chem. Soc. 1991,113, 1835. 34. Of interest here is that work carried out by Col lum and coworkers has shown over the years that H M P A does not always deaggregate anions, and that care must be taken when attempting to generalize the role of H M P A in organic chemistry. For N M R evidence that H M P A does not deaggregate dimers of L D A or L i T M P in T H F or f-BuOMe, please see: Floyd, E . R.; Gilchrist, J. H . ; Harrison, A . T.; Fuller, D . J.; Col lum, D . B . J. Am. Chem. Soc. 1991,113, 5751. 35. (a) Corey, E . J.; Beames, D . J. J. Am. Chem. Soc. 1972, 94, 7210. (b) Seebach, D . ; Neumann, H . Chem. Ber. 1974,107, 847. (c) Bailey, W . F.; Punzalan, E . R. J. Org. Chem. 1990, 55, 5404. 36. (a) Nakamura, E . ; Matsuzawa, S.; Horiguchi, Y . ; Kuwajima. I. Tetrahedron Lett. 1986, 27,4029. (b) Linderman, R. J.; Godfrey, A . ; Home, K . Tetrahedron 1989, 45, 495. (c) Matsuzawa, S.; Horiguchi, Y . ; Nakamura, E . ; Kuwajima. I. Tetrahedron 1989, 45, 349. (d) Bergdahl, M . ; Lindstedt, E . - L . ; Nilsson, M . ; Olsson, T. Tetrahedron 1989,45, 535. 37. Lipshutz, H . ; Dimock, S. H . ; James, B . J. Am. Chem. Soc. 1993,115, 9283. 38. (a) Mukhopadhyay, T.; Seebach, D . Helv. Chim. Acta 1982, 65, 385. (b) Seebach, D . Chem. Br. 1985, 21, 632. 39. (a) Piers, E . ; Tse, H . L . A . Can. J. Chem. 1993, 71, 983. (b) Piers, E . ; Romero, M . A . J. Am. Chem. Soc. 1996,118, 1215. 40. (a) Su, Z . ; Paquette, L . A . / . Org. Chem. 1995, 60, 764. 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Please note that the change in numbering (i.e. 17-e/?z-mangicol F) was made to reflect the numbering system used in the isolation report, which is not in agreement with I U P A C rules for nomenclature of organic compounds. 123. (a) Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. J. Org. Chem. 1994, 59, 4096. (b) Hoye, T. R.; Zhao, H . J. Org. Chem. 2002, 67, 4014. 124. St i l l , W . C ; Kahn, M . ; Mitra, A . J. Org. Chem. 1978,43, 2923. 125. Kofron, W . G . ; Baclawski, L . M . J. Org. Chem. 1976, 41, 1879. 126. Burchat, A . F. ; Chong, J. M . ; Nielsen, N . J. Organomet. Chem. 1997, 542, 281. 315 Appendix 1: 1 H - N M R and 1 3 C - N M R Spectra of Those Compounds Related to the Total Synthesis of Mangicol F Lacking Microanalysis. Integra! X x ipuaddy Appendix 2: X-ray Crystallography Experimental Data. Table 22: X-ray Crystallography Experimental Data Compound # 216 265 274 350 Empirical Formula C 2 1 H 2 6 N 2 0 6 C 3 2 H 4 9 N 0 5 S i C 2 7H 3 4N 2 04 C 2 7 H 4 2 0 2 Formula Weight 402.45 555.81 450.58 398.61 Crystal Colour, Habit Clear, platelet Colourless, needle Clear, platelet Colourless, chip Crystal Dimensions 0.30x0.15 x 0.03 mm 0.12 x 0.07 x 0.03 mm 0.50 x 0.25 x 0.10 mm 0.20 x 0.10 x 0.10 mm Crystal System Monoclinic Triclinic Triclinic Monoclinic Lattice Type C-Centered Primitive Primitive Triclinic Lattice Parameters s A A" • - 'if. . iX . 1 :; A'-". a 32.927(4) A 7.446(2) A 7.6487(3) A 8.700(1) A b 10.610(1) A 12.379(3) A 8.1041(4) A 10.448(2) A c 11.794(1) A 17.485(4) A 19.5906(8) A 13.264(2) A a 71.69(2) ° 79 .581(9 )° 95.84(1) ° P 105.857(6) 0 83.94(1)° 81 .098(9)° 91 .66(1 )° y 86 .34(1)° 85 .81(1)° 92.64(1) ° V 3963.6(8) A 3 1520.7(7) A 3 1178.7(1) A 3 1197.4(3) A 3 Space Group C 2 / c (#15) P i (#2) Pi(#2) Pi(#2) Z Value 8 2 2 2 Dcalc 1.349 g/cm 3 1.214 g/cm 3 1.269 g/cm 3 1.106 g/cm 3 Fooo 1712.00 604.00 484.00 440.00 p.(MoKa) 0.99 cm"1 1.17 cm"1 0.85 cm" 1 0.67 cm"1 Diffractometer Rigaku/ A D S C C C D Rigaku/ A D S C C C D Rigaku/ A D S C C C D Bruker X 8 A P E X 

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