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Carbocycle construction in terpenoid synthesis : subtitle the total synthesis of (±)-sarcodonin G and… Gilbert, Michael W. 2002

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CARBOCYCLE CONSTRUCTION IN TERPENOID SYNTHESIS. THE TOTAL SYNTHESES OF (±)-SARCODONIN G AND (±)-1-EPI-9-NORPRESILPHIPERFOLAN-9-ONE. by MICHAEL W. GILBERT B.Sc, University of Ottawa, 1995 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 2002 © Michael W. Gilbert, 2002 UBC Rare Books and Special Collections - Thesis Authorisation Form Page 1 of 1 In presenting this thesis in part ia l fulfilment of the requirements for an advanced degree at the University of Br i t i sh Columbia, I agree that the Library shall make i t freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shal l not be allowed without my written permission. The University of Br i t i sh Columbian Vancouver, Canada http://www.library.ubc.ca/spcoll/thesauth.html 6/11/2002 11 ABSTRACT Carbocycle construction represents a significant challenge in synthetic studies geared towards terpenoid natural products. A step-wise annulation approach to the construction of the diterpenoid framework of the cyathanes (54) was investigated, ultimately leading to the first reported total synthesis of (±)-sarcodonin G (36). The sesquiterpenoid carbon skeleton of the presilphiperfolanes (270) was assembled via a tandem cyclization strategy, affording the known ketone, (±)-l-epi-9-norpresilphiperfolan-9-one (306). The construction of the cyathane 5-6-7 fused tricyclic framework commenced with 3-methyl-2-cyclohexen-l-one 38, representing the B-ring. The annulation sequences for A and C-rings utilized the bifunctional reagents 39 and 44, respectively. With the help of these reagents, the 5-6-6 fused tricycle 155 was quickly assembled from 38. Intermediate 155 was further elaborated, including a key Sml2-mediated ring expansion, to afford the 5-6-7 fused tricycle 159, which displays the complete cyathane framework. The target structure, (±)-sarcodonin G (36), was obtained in several steps from 159. In addition, an advanced intermediate in the synthesis of 36 was transformed into substance 269, a likely synthetic precursor of the corresponding keto triol natural product, (±)-cyathin A 4 (37). Assembly of the presilphiperfolane 5-5-6 fused tricyclic carbon skeleton 270 was approached via a tandem cyclization strategy involving free-radical reactions. The key intermediates of this synthetic study, xanthates 367, were readily prepared from enone 49 in several steps. BusSnH-mediated free-radical reaction of 367 yielded a mixture of I l l cyclization products, alkenes 368, whose frameworks include the carbon skeleton of the natural product presilphiperfolan-9-ol (53). Alkenes 368 were subjected to oxidative cleavage conditions, affording the known ketone (±)-l-epi-9-norpresilphiperfolan-9-one (306). 368 53 iv T A B L E O F C O N T E N T S A B S T R A C T ii T A B L E O F C O N T E N T S i v L I S T O F T A B L E S vi L I S T O F F I G U R E S ix L I S T O F A B B R E V I A T I O N S x A C K N O W L E D G E M E N T S xiii I. I N T R O D U C T I O N 1 1.1. General 1 1.2. Proposal 10 II. R E S U L T S A N D D I S C U S S I O N 14 2.1. Studies Towards Cyathane Diterpenoid Synthesis 14 2.1.1. Background 14 2.1.1.1. Cyathane History and Biogenesis 14 2.1.1.2. Hydrocarbon Cyathanes 17 2.1.1.3. Oxidized Cyathanes 17 2.1.1.4. Biological Activity of the Cyathanes 24 2.1.2. Previous Studies in Cyathane Synthesis 26 2.1.2.1. Total Syntheses of Cyathanes 26 2.1.2.2. Approaches to the Cyathanes 32 2.1.3. Total Synthesis of (±)-Sarcodonin G 42 2.1.3.1. Retrosynthetic Analysis 42 2.1.3.2. Preparation of 5-6-6 Fused Tricycle 151 43 2.1.3.2.1. Preparation of Bifunctional Reagent 44 44 2.1.3.2.2. Preparation of c/s-Fused Bicyclic Dimethylhydrazone 102 55 2.1.3.2.3. Preparation of Ketone 187 58 2.1.3.2.4. Preparation of Alcohol 151 60 2.1.3.3. Preparation of Ketone 112 66 2.1.3.4. Preparation of Iodides 160 76 2.1.3.5. Preparation of Keto Ester 159 83 2.1.3.6. Preparation of Keto Aldehyde 240 88 2.1.3.7. Preparation of (±)-Sarcodonin G (36) 98 2.1.4. Studies Towards the Synthesis of (± ) -Cya th in A 4 103 2.1.4.1. Retrosynthetic Analysis 103 2.1.4.2. Preparation of Keto Alcohol 254 105 2.1.4.3. Attempted Preparation of Diol 231 110 2.2. Studies Towards Presilphiperfolane Sesquiterpenoid Synthesis 122 2.2.1. Background: Presilphiperfolane Isolation, Biogenesis and Biological Activity 122 2.2.2. Previous Syntheses 126 2.2.3. Studies Towards the Synthesis of (±)-Presi lphiperfolan-9-ol 129 2.2.3.1. Retrosynthetic Analysis 130 2.2.3.2. Preparation of Ketone 315 132 2.2.3.3. Preparation of Aldehyde 314 135 2.2.3.4. Preparation of the Tandem Cyclization Precursors, Xanthates 50 138 2.2.3.5. Tandem Free-radical Cyclization 140 III. C O N C L U S I O N S 155 IV. E X P E R I M E N T A L 162 4.1. General 162 4.1.1. Data Acquisition and Presentation 162 4.1.2. Solvents and Reagents 164 4.2. Total Synthesis of (±)-Sarcodonin G 167 4.3. Synthetic Studies Towards (± ) -Cyath in A 4 219 4.4. Total Synthesis of (±) - l -Epi -9-presi lphiperfo ian-9-one 232 V . R E F E R E N C E S A N D F O O T N O T E S 249 vi L I S T O F T A B L E S Table 1. Addition of Germylcopper(I) Reagents (167-170) to Ethyl 2-Butynoate (171) 47 Table 2. Isomerization of C-3 Substituted Cycloheptenones 251 and 252 96 Table 3. Comparison of IR and MS Spectral Data for Synthetic (±)-Sarcodonin G (36) with those Reported for Natural (-)-Sarcodonin G (36) 99 Table 4. Comparison of ! H NMR Data for Synthetic (±)-Sarcodonin G (36) (CDC13,400 MHz)with those Reported for Natural (-)-Sarcodonin G (36) (CDC13,250 MHz) 100 Table 5. Comparison of 1 3 C NMR Data for Synthetic (±)-Sarcodonin G (36) (CDCI3,100.6 MHz) with those Reported for Natural (-)-Sarcodonin G (36) (CDCI3,62.5 MHz) 101 Table 6. J H NMR Data for Synthetic (±)-Triol 268 (CDCl3,400MHz) 116 Table 7. Comparison of the ! H NMR (CDCI3,400 MHz) Data for Ketone 306 with those Reported for (±)-1 -Epi-9-norpresilphiperfolan-9-one (306) 151 Table 8. Comparison of the 1 3 C NMR (CDCI3,100.6 MHz) Data for Ketone 306 and those Reported for (±)-1 -Epi-9-norpresilphiperfolan-9-one (306) 152 Table 9. *H NMR (CDC13,400 MHz) Data for Ethyl (Z)-3-Tri-methylgermyl-2-pentenoate (165): NOED Experiment 169 Table 10. 1 3 C NMR (CDC13,100.6 MHz) and *H NMR (CDC13, 400 MHz) Data for Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (165): HMQC Experiment 170 Table 11. ! H NMR (CDCI3,400 MHz) Data for Ethyl (£)-3-Tri-methylgermyl-2-pentenoate (174): NOED Experiment 172 V l l Table 12. I 3 C NMR (CDC13,100.6 MHz) and *H NMR (CDC13, 400 MHz) Data for Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (174): HMQC Experiment 173 Table 13. 'H NMR (CDCI3,400 MHz) Data for Ethyl (£)-3-Tri-methylgermyl-3-pentenoate (164): NOED Experiment 175 Table 14. *H NMR (CDC13,400 MHz) Data for Keto Ester 159: NOED Experiment 206 Table 15. 1 3 C NMR (CDCI3,100.6 MHz) and ! H NMR (CDCI3, 400 MHz) Data for Keto Ester 159: HMQC Experiment 207 Table 16. 1 3 C NMR (CDCI3,100.6 MHz) and *H NMR (CDCI3, 400 MHz) Data for Ketone 240: HMQC Experiment 214 Table 17. Comparison of lU NMR Data for Synthetic (l/?*,6/?*,9/?*)-3-[(5*)-2-Hydroxy-l-methylethyl]-6,9-dimethyl-10-oxo-tricyclo[7.5.0.02'6]tetradeca-2,12-diene-12-carboxaldehyde [(±)-Sarcodonin G] (36) (CDC13,400 MHz) with those Reported for Natural (-)-Sarcodonin G (36) (CDCl3,250MHz) 217 Table 18. Comparison of 1 3 C NMR Data for Synthetic (l/?*,6/?*,9/?*)-3-[(S*)-2-Hydroxy-l-methylethyl]-6,9-dimethyl-10-oxo-tricyclo[7.5.0.02'6]tetradeca-2,12-diene-12-carboxaldehyde [(±)-Sarcodonin G] (36) (CDC13,400 MHz) with those Reported for Natural (-)-Sarcodonin G (36) (CDCI3,62.5 MHz) 218 Table 19. ! H NMR (CDCI3,400 MHz) Data for Diester 269: NOED Experiment 228 Table 20. 1 3 C NMR (CDCI3,100.6 MHz) and 'H NMR (CDCI3, 400 MHz) Data for Diester 269: HMQC Experiment 230 Table 21. 1 3 C NMR (CDC13,100.6 MHz) and lU NMR (CDC13, 400 MHz) Data for l-(l-Methyl-cyclopent-2-enyl)-propan-2-one (315): HMQC Experiment 234 Table 22. 1 3 C NMR (CDCI3,100.6 MHz) and : H NMR (CDC13, 400 MHz) Data for the 1:1 Mixture of 2-Methyl-3-(1 -methyl-cyclopent-2-enyl)-propionaldehydes (333): HMQC Experiment 237 viii Table 23. 1 3 C NMR (CDCI3,100.6 MHz) and ] H NMR (CDC13, 400 MHz) Data for 2,2-Dimethyl-3-(l-methyl-cyclopent-2-enyl)-propionaldehyde (314): HMQC Experiment 239 Table 24. 1 3 C NMR (CDCI3,100.6 MHz) and *H NMR (CDC13, 400 MHz) Data for a 1:1 Mixture of 2,2-Dimethyl-l-(l-methyl-cyclopent-2-enyl)-7-phenyl-hept-6-yn-3-ol (366): HMQC Experiment 242 Table 25. Comparison of the 'H NMR (CDCI3,400 MHz) Data for (lR*,4R*,7S*,8R*)-4,6,6-Trimethyltricyclo-[5.3.1.0411]undecan-9-one (306) with those Reported for (±)-l-Epi-9-norpresilphiperfolan-9-one (306) 247 Table 26. Comparison of the 1 3 C NMR (CDCI3,100.6 MHz) Data for (lR*,4R*,7S*,8R*)-4,6,6-Trimethyltricyclo-[5.3.1.04'H]undecan-9-one (306) and those Reported for (±)-1 -Epi-9-norpresilphiperfolan-9-one (306)....: 248 LIST OF FIGURES FIGURE 1. ! H NMR Spectrum for Synthetic (±)-Sarcodonin G (36) (CDC13,400 MHz) X LIST OF ABBREVIATIONS a - below the plane of the ring or 1,2 relative position Ac - acetyl AIBN - azobisisobutyronitrile anal. - analysis APT - attached proton test ax - axial P - above the plane of a ring or 1,3-relative position 9-BBN - 9-borabicyclo[3.3.0]nonane Bn - benzyl bp - boiling point br - broad Bu - butyl Bz - benzoyl calcd - calculated cm - centimeter COSY - (1H-1H)-homonulcear correlation spectroscopy 18-cr-6 - 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) CSA - camphorsulfonic acid C-x - carbon number x d - doublet 5 - chemical shift in parts per million from tetramethylsilane A - heat DBN - l,5-diazabicyclo[4.3.0]non-5-ene DBU - l,8-diazabicylco[5.4.0]undec-7-ene DDQ - 2,3-dichloro-5,6-dicyano-l,4-benzoquinone DEAD - diethyl azodicarboxylate DIBALH - diisobutylaluminum hydride DIEA - diisopropylethylamine DMAP - 4-dimethylaminopyridine DMSO - dimethyl sulfoxide DNA - deoxyribonucleic acid E - entgegen (configuration) ed. - edition ED., Eds. - editor, editiors ED50 - effective dose epi - epimeric eq - equatorial equiv. - equivalent(s) Et - ethyl g - gram glc - gas-liquid chromatography h - hour(s) HMBC - ('H-^C) heteronuclear multiple bond coherence HMPA - hexamethylphosphoramide xi HMQC (1H-1 3C) heteronuclear multiple quantum coherence HPLC high performance liquid chromatography HRMS high resolution mass spectroscopy H-x hydrogen number x Hz hertz i iso IC 5 0 inhibitory concentration (for 50% of a biological sample) i-PrDMS wo-propyldimethylsilyl IR infrared J coupling constant in hertz KDA potassium diisopropylamide KHMDS potassium 1,1,1,3,3,3,-hexamefhyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LiHMDS lithium 1,1,1,3,3,3-hexamethyldisilazide m multiplet m meta M molar mCPBA meta-chloroperoxybenzoic acid Me methyl mg milligram(s) microgram(s) MHz megahertz min minute(s) mL milliliter(s) uL microliter(s) mm millimeter(s) um micrometer(s) mmol millimole(s) mol. molecular mp melting point Ms methanesulfonyl n normal NBS N-bromosuccinimide NIS AModosuccinimide NMR nuclear magnetic resonance NOE nuclear Overhauser enhancement P page P para PCC pyridinium chlorochromate pH -logio[H+] Ph phenyl PMB para-methoxybenzyl PNB para-nitrobenzoyl PP pyrophosphate ppm parts per million PPTS - pyridinium p-toluenesulfonate Pr - propyl pyr - pyridine q - quartet R - rectus (configuration) s - singlet S - sinister (configuration) sec - secondary t - triplet t - tertiary TBAF - tetrabutylammonium fluoride TBDPS - tert-butyldiphenylsilyl TBS - terr-butlydimethylsilyl tert - tertiary Tf - trifluoromethanesulfonyl TFA - trifluoroacetic acid THF - tetrahydrofuran tic - thin layer chromatography TMS - trimethylsilyl TPAP - tertrapropylammonium perruthenate Ts - para-toluenesulfonyl uv - ultraviolet -ve - negative v/v - volume to volume ratio w/v - weight to volume ratio • - coordination or complex ± - racemic ACKNOWLEDGMENTS xm Firstly, I would like to thank Dr. Edward Piers, my supervisor and mentor, for continued guidance throughout my stay at UBC. For giving me the opportunity to join his research group and for teaching me the science of organic synthesis, I am forever grateful. Many thanks to the members of Piers research group, past and present, for creating an atmosphere of cooperative learning. I am especially appreciative of the advice, friendly competition and many heated debates provided by Robert Britton from Day 1 of our graduate studies. I would also like to thank Arturo Orellana for the countless hours spent proofreading this manuscript. The assistance of the technical staff (NMR, MS and Microanalysis labs) in the Department of Chemistry at UBC is gratefully acknowledged. I would like to extend a special thank-you to Mrs. L. Darge and Mrs. M. Austria of the NMR lab for their ongoing help and advice. I will always treasure the friends I made in Vancouver, especially the Brew-Club members, Rob B., Art, Rob G., Carl, Mark, Todd and Roger, who made my stay in B.C. an unforgettable one. This thesis is dedicated to my parents, whose support and encouragement continuously fuel my ambitions. Finally, I wish to thank Sara for being her wonderful self and making everything worthwhile. 1 I. INTRODUCTION 1.1. General As we enter the 21 s t century, synthetic organic chemistry is at center stage of scientific and technological discovery. Since its conception nearly two centuries ago, this discipline of chemistry has played in increasingly important role in biological and medicinal research. As an example, the ability to synthesize organic compounds represents the foundation of pharmaceutical drug-discovery programs, which have lead to numerous biomedical breakthroughs. The evolution of synthetic chemistry has been possible, in large, because of technological advances in the fields of chemical separation and identification. With a growing library of proven synthetic methods and an upward number of commercially available reagents, synthetic chemistry allows for increasingly short and efficient preparations of target structures. There are numerous motives that might entice a chemist in choosing to synthesize a target structure from commercially available materials, a study known as total synthesis. The target structures are often naturally occurring compounds or families of structurally related compounds that have limited availability from natural sources. In some cases, these natural compounds have demonstrated potentially important biological activity and total synthesis can provide additional quantities of material for further biological and chemical evaluation. Total synthesis also provides a testing ground for novel methods of bond construction. The limitations of a novel reaction developed in simple models systems are often revealed in complex total syntheses. To be sure, total synthesis represents an exciting yet challenging study through which one can learn the many facets of chemistry. 2 Terpenoid natural products, which have attracted significant attention from synthetic chemists, display a seemingly unlimited complexity with regard to construction of carbon skeleta, the backbones of the structures. Biosynthetically evolving from 5-carbon building blocks (C5) generally represented by isoprene (1), terpenoids are classified as either mono-(Cio), sesqui-(Cis), di-(C2o), sester-(C2s) or triterpenoids (C30) . Through isotope-labeling experiments and NMR studies on the resulting metabolites, chemists have uncovered many of nature's strategies for the transformation of simple chains of isoprene units into complex carbocyclic terpenoids. These biosynthetic pathways often involve a combination of enzyme-catalyzed cyclizations, rearrangements and alkyl shifts. The elaborate architecture displayed in structure 2, representing the carbon skeleta of the recently discovered salvadione triterpenoids,1 nicely illustrates the complexity of carbocycle construction in terpenoid chemistry. Several of the different tactics employed by synthetic chemists in terpenoid construction, including biomimetic, tandem and step-wise annulation approaches, shall be outlined. 1 2 3 A biomimetic synthetic strategy is one in which the key reactions are based on the proposed biogenesis of the target structure. For example, according to the Stork-Eschenmoser hypothesis,2'3 certain polyunsaturated molecules with trans C=C double bonds should cyclize in a stereospecific manner to furnish polycyclic systems with trans,anti,trans stereochemistry at the ring fusions. Recently, Demuth and coworkers reported4 a biomimetic cascade cyclization of a polyalkene, which led to a total synthesis of (±)-stypoldione (6) (Scheme 1). A photo-induced electron transfer (PET) reaction triggered cyclization of polyalkene 3, yielding a mixture of trans-anti-trans 6-6-6 fused tricyclic substances 5. The natural product, (±)-stypoldione (6), was ultimately obtained in 11 steps from 5. 5 Reagents: hv, poly(oxy-l,2-ethanediyloxycarbonyl-l,4-phenylenecarbonyl), 1,4-dicyano-2,3,5,6-tetramethylbenzene, biphenyl, MeCN, H 2 0. Scheme 1 4 Many types of reactions, including pericyclic, radical, cationic and anionic processes, have been incorporated in cascade or tandem sequences for the construction of carbocycles.5 For instance, a radical-based tandem cyclization was employed in the synthesis of triquinane silphiperfolene (11), as reported by Curran and coworkers (Scheme 2).6 The key intermediate of the study, bromide 8, was prepared in several steps from enone 7. Treatment of 8 with BusSnH and AIBN gave tricycle 10 via the radical intermediate 9. Transformation of 10 into the target structure 11 was accomplished in few steps. 11 Scheme 2 5 Although the combination of several bond-forming steps in one tandem sequence certainly appeals, the difficult task of controlling the selectivity in each step must also be considered. As an example, Curran and coworkers reported7 unexpected stereoselectivity difficulties in their investigation of a tandem cyclization approach to (±)-crinipellin A (12) (Scheme 3). In a model study directed towards the synthesis of the B-C-D ring system of 12, BusSnH-mediated tandem free radical cyclization of iodide 13 afforded a 1:5 mixture of 15 and 16. Although this remarkable reaction showed the desired cis geometry at both ring fusions, the tandem approach was not carried through to the target structure 12, because the major isomer (16) displayed the isopropyl appendage in the unnatural p-configuration. Scheme 3 6 An attractive approach to the construction of carbocycles involves the use of bifunctional reagents in stepwise annulation sequences.8 An annulation sequence is a ring-forming process in which two molecular fragments are united with the formation of two new bonds.9 The reactive sites leading to the newly formed bonds can be described as either acceptor (a) or donor (d) sites.10 Upon analysis of the potential reactive sites of a substrate, one may envisage the annulation synthon that displays the desired corresponding acceptor or donor reactive sites. This relationship is illustrated in the reported11 synthesis of the Wieland-Miescher ketone12 20 via the well-known Robinson 13 annulation (Scheme 4). Under base-mediated conditions, diketone 17 undergoes a Michael addition with methyl vinyl ketone (18) to give adduct 19. Treatment of 19 with pyrrolidine results in an intramolecular aldol condensation, yielding the Wieland-Miescher ketone (20). Therefore, methyl vinyl ketone (18), the synthetic equivalent of the 2-butanone a4,d]-synthon 22, represents an excellent annulation reagent for diketone 17, corresponding to donor-acceptor synthon 21. 21 22 Scheme 4 7 Recently, one of the areas of study in the Piers group has been the development of novel bifunctional reagents and their application in annulation sequences. For example, the first total synthesis of (±)-crinipellin B (23)14'15 employed novel bifunctional reagents in the annulation sequences leading to the A- and B-rings, as outlined in Schemes 5 and 6. 23 The bifunctional reagent 24, which is readily transformed into cuprate 25, the synthetic equivalent of the 1-butene a2,d4-synthon 26, was employed in the preparation of the B-ring (Scheme 5). The synthesis commenced with 2-methyl-2-cyclopentenone (27), which was transformed in several steps into the 5,5-fused bicyclic compound 28, representing the C-D ring system. The annulation sequence began with a conjugate addition of a cuprate 25 to enone 28, affording adduct 29. Treatment of 29 with iodine provided the corresponding alkenyl iodide. Slow addition of ?-BuOK/?-BuOH to solution of this alkenyl iodide and (Pli3P)4Pd in TFfF resulted in the triquinane product 30. 8 Reagents: a) r-BuLi, THF; CuCN; b) 25, TMSBr, THF; NH4CI, N H 4 O H , H 2 0; c) I2, CH2C12; d) (Ph3P)4Pd, r-BuOK, r-BuOH-THF. Scheme 5 The annulation sequence leading to the A-ring employed bifunctional reagent 31, the synthetic equivalent of the 1-propene a ,d -synthon 32 (scheme 6). The conversion of triquinane 30 into ketone 33 was accomplished in a few steps. Alkylation of the enolate derived from 33 with reagent 31 yielded adduct 34, as the major product. Treatment of 34 with butyllithium resulted in a cyclization, affording the tetracyclic alcohol 35. The target structure, (±)-crinipellin B (23), was ultimately obtained from 35 in 10 steps. Reagents: a) LDA, THF; 3 1 ; b) BuLi, THF; NaHC03, H 2 0. Scheme 6 10 1.2. Proposal In the first part of the research program described in this thesis, it was planned to employ a sequential annulation strategy to the assembly of 5-6-7 fused ring systems. It was anticipated that the carbon framework of the structurally-related diterpenoids, sarcodonin G (36) and cyathin A 4 (37),16'17 would be accessible from commercially available 3-methyl-2-cyclohexen-l-one (38), which would ultimately serve as the B-ring of these two natural products (Scheme 7). Scheme 7 The annulation sequence leading to construction of the C-ring was anticipated to involve bifunctional reagent 39, representing the 1-pentene a ,d -synthon 40 (Scheme 8). The preparation of the 6-6 fused bicycles 41, utilizing enone 38 and reagent 39, was 18 previously reported by our group. The 6-membered C-ring in 41 was thought to be a suitable precursor to the 7-membered C-rings illustrated in partial structures 42 and 43, representing sarcodonin G (36) and cyathin A 4 (37), respectively. 11 B d 38 42 HO HO Scheme 8 The A-ring construction was anticipated to result from an annulation sequence employing the (Z)-2-pentene a5,d3-synthon 45, which translates to bifunctional reagent 44 (Scheme 9). A representation of the sequence, starting with partial structure 46, is illustrated. The annulation sequence, which includes a methylation step, was anticipated to give alcohol 47. Partial structure 48, representing the A- and B-rings of both target compounds 42 and 43, was expected to be available from 47 via a Still-Mitra rearrangement protocol 19 12 1—1 \ — G e M e 3 > 44 . 45 46 47 HO 48 Scheme 9 The second part of the research study described herein revolves around the possible use of a proposed tandem cyclization strategy, envisaged for the construction of 90 the 5-5-6 fused framework of (±)-presilphiperfolan-9-ol (53) (Scheme 10). It was hoped that the key cyclization precursors, intermediates 50, would be available in a few steps from enone 49, which would become the C-ring of target 53. Tandem formation of the A-and B-rings was anticipated to involve a radical-mediated cyclization of 50 via the intermediate 51. The P-isomer of the proposed cyclization products 52, which display a 5-5-6 fused ring system, is a known precursor of (±)-presilphiperfolan-9-ol (53). 13 Scheme 10 14 II. RESULTS AND DISCUSSION 2.1. Studies Towards Cyathane Diterpenoid Synthesis 2.1.1. Background 2.1.1.1. Cyathane History and Biogenesis The history of the cyathane family of diterpenoids begins in 1966 with Brodie's 21 discovery of the bird's nest fungus Cyathus helenae in the Canadian Rockies. In a chance observation, cultures of C. helenae were shown22 to inhibit the growth of bacteria. Starting in the early 1970s, Ayer and co-workers characterized numerous biologically active cyathane components from several Cyathus fungi. To date, over forty different cyathanes have been isolated and characterized. Using bioassay guided fractionation methods, Ayer and coworkers isolated several C20 compounds from the cyathin extracts. Each of these novel diterpenoids was named cyathin and was classified according to its molecular formula. The cyathin name includes a letter that denotes the degree of unsaturation (A for 30 hydrogens, B for 28 hydrogens and C for 26 hydrogens) and a subscript number that indicates the number of oxygen atoms. A trivial numbering scheme was assigned to the novel 5-6-7 fused tricyclic core (54) of the cyathanes. 17 1*5 54 15 In 1979, Ayer and coworkers reported their investigations into cyathane biogenesis through labeling experiments.24 Since the biosynthetic pathway was presumed to involve acetate incorporation into geranylgeranyl pyrophosphate, [l,2-13C2]-labeled acetate (55) was fed to Cyathus earlei and the labeling pattern of the resulting 11-0-acetylcyathatriol product (56) was determined by 1 3 C NMR analysis (eq 1). 56 Recently, Sassa and coworkers reported a study of the fungal diterpene cyclase, cyathadiene synthase. Treatment of a cell-free extract of Hericum erinaceum with deuterated all-trans-geranylgeranyl diphosphate (57) for 2 h at 30 °C provided the deuterated cyatha-3,12-diene 58 in 30% yield (eq 2). Both Ayer's and Sassa's results (vide supra) support the biosynthetic pathway postulated24 by Ayer in 1979 (Scheme 11). 16 The first steps of the postulated biosynthetic pathway involve tandem cationic ring closures of all-trans-geranylgeranyl diphosphate (59) to form the hydroazulene-like cation (61), which undergoes a Wagner-Meerwein migration to provide a 6-7 fused bicyclic intermediate (62). Cyclization of the isopropylidene moiety onto the bicyclic core of 62 provides the 5-6-7 fused tricyclic cation 63, which displays the cyathin skeletal core. 17 2.1.1.2. Hydrocarbon Cyathanes Several cyathadiene hydrocarbons, postulated25 progenitors of the oxygenated cyathanes, have recently been isolated. In 1993, Cassidy reported the isolation of cyatha-12,18-diene (64) from a non-polar fraction of Higginsia sp extract. In 2001, Sassa and coworkers isolated25 cyatha-3(18),12-diene (65) and cyatha-3,12-diene (66) from the erinacine-producing basodiomycete Hericium erinaceum. 64 65 66 The isolation of hydrocarbons 64-66 suggests that intermediate 63 in Ayer's proposed pathway {vide supra) can follow different sequences of elimination and/or hydride shifts prior to oxidation.25 2.1.1.3. Oxygenated Cyathanes Nature's elaboration of the cyathane core includes, primarily, oxidation at allylic positions. Oxygenation on the three cyathin rings as well as on the methyl and isopropyl appendages has been noted. Certain oxygenation patterns introduce, from a synthetic viewpoint, considerable structural complexity to the cyathin structures. The diverse oxygenation patterns of several structurally elucidated cyathanes are discussed below. 18 The most common sites of oxygenation on the cyathin core are the carbons of the C-ring and its methyl appendage, C-15. Cyathin A 3 (67) , the first cyathane to yield to structural elucidation,27 exhibits oxygen functions at C - l l , 14 and 15. 67 In their study of Cyathus helenae extracts, Ayer and coworkers reported several cyathanes that display an oxidation pattern similar to that of cyathin A 3 . The structures of allocyathin B3 (68) , cyathin B3 (69) , and cyathin C 3 (70) were elucidated through chemical correlations with cyathin A 3 (67) . 27,28 68 69 Extracts of the tropical species of bird's nest fungus Cyathus earlei yielded several acetylated cyathin-type compounds as well as three new cyathanes: allocyathin B2 (71) , cyathin B 2 (72) and cyathatriol ( 7 3 ) . 2 9 19 . O H ;HO 71 72 •** J O H H O C H 2 O H 7 3 In 1985, Cassidy and co-workers isolated30 cyathanes 74-76 from the extracts of the marine sponge Higginsia sp. The structure of cyathane 74, which includes oxygen functions at C-10, 13 and 15, was verified by X-ray crystallographic analysis. H 2 O H H 2OAc 74 75 76 The erinacines, which are glycosylated cyathanes, were isolated from the mycelia of the fungus Herimicium erinaceum.31'34 The xylose moiety of erinacine A (77) was 31 cleaved using a P-glucosidase and the resulting aglycone product was identified as allocyathin B 2(71) (eq 3). 29 20 78 A number of cyathanes exhibit extensive oxygenation on the A-, B- and/or C-rings. The structure17 of neoallocyathin A 4 (79), which displays an epoxide function in the A ring, was confirmed through chemical correlations with cyathin A 3 (67) (eq 4). 21 Oxygenation on both the A- and C-rings was noted in cyafrins A 4 (80) and B 4 (81), which were isolated36 from the extracts of Cyathus africanas, a fungus collected in Tanzania. HO H 2 OH H 2 O H 80 81 82 83 22 A novel group of cyathanes, named scabronines, were isolated38"40 from the fruiting bodies of the mushroom Sarcodon scabrosus. As in all scabronines, scabronines A (84), B (85) and C (86) display an acid function at the C-9 angular carbon. C 0 2 H C 0 2 H C 0 2 H Few members of the cyathane family display an oxygenation pattern that excludes the C-ring. Cyanthiwigins A (87) and C (88), which display oxygenation on the A- and/or B-rings, were isolated by Green and coworkers from the extracts of Apipolasis reiswigi.41 87 88 Oxygenation of the isopropyl group attached to C-3 is a rare feature in the cyathane family. In 1978, Ayer and coworkers reported17 the isolation of cyathins A 4 (37) and C 5 (89), which display oxygenation of the C-3 isopropyl group 4 2 23 37 89 Onychiol B (90), isolated from the rhizome of the fern Onchium japonicum, displays oxygenation on the B- and C-rings and on the isopropenyl group attached at A -3. 90 In 1989, Shibata and coworkers reported16 the isolation of eight novel cyathane-type diterpenoids from the fruiting bodies of Sarcodon scabrosus: sarcodonins A-H. Of these eight sarcodonins, only A (91) and G (36), which display oxygenation on the isopropyl moiety, yielded to structural elucidation. The absolute stereochemistry of sarcodonin G (36) was determined by X-ray crystallographic analysis of its p-bromobenzoate derivative. 24 HO P 91 36 2.1.1.4. Biological Activity of the Cyathanes Members of the cyathane family have been shown to exhibit diverse biological activities. The cyathin complexes of the Cyathus fungi C. helenae, C. earli and C. striatus exhibit ' ' pronounced antibacterial and antifungal activities. The cyathanes isolated from Myrmekioderma styx exhibit37 moderate cytotoxic activity against the P388 leukemia cell line and the A549 human lung tumor cell line, with ICso's as low as 5.6 and 4.0 ug/mL, respectively. The cyanthiwigin cyathanes exhibit41 cytotoxic activity against P388 leukemia cells, with ICso's as low as 2.5 ug/mL. The straitin cyathane-xylosides were shown to have leishmanicidal activity.44 Saito and coworkers recently reported45 that certain erinacines31"34'46 behave as potent kappa opioid receptor agonists. Activation of membrane-bound opioid receptors (J I , 8 and K), which are located throughout the nervous system 4 7 can induce various physiological effects including antinociception and neurotransmitter release.48 Morphine, an opioid drug used in the clinical management of pain, acts on the LI receptor and causes untoward side effects such as tolerance, dependence and respiratory depression. Stein and coworkers have reported49 that activation of the K receptor induces hyperalgesia in a 25 rat model of inflammation. It is postulated that the application of erinacines as selective K receptor agonists may produce the desired antinociceptive activity without the adverse side effects observed with LI receptor agonists. Certain members of the erinacine31"33 and scabronine38"40'50 cyathanes exhibit the ability to stimulate the biosynthesis of nerve growth factor (NGF) in vitro. NGFs play an important role in the early development of the embryonic central nervous system as well as in the phenotypic maintenance and cell regulation of neurons in adults. The role of NGFs in a novel mode of treatment for neurodegenerative disorders is currently under investigation.51 However, the inability52 of NGFs to penetrate the blood brain barrier (BBB) has limited their clinical application to the direct infusion into the cerebral spinal 53 fluid.-" The inconvenience of this medical implementation initiated a search for low-molecular-weight NGF inducers, such as the erinacines and scabronines, which can penetrate the BBB. 26 2.1.2. Previous Studies in Cyathane Synthesis The diverse biological activities and structural novelty displayed by the cyathanes have made them attractive targets for total synthesis.54 From a synthetic viewpoint, the diverse oxygenation patterns, the anti 1,4 angular methyls and the 5-6-7 fused tricyclic core represent significant challenges. As an illustration of the diverse approaches to the construction of the cyathane framework, the outlines of the studies described in this section focus primarily on key ring-forming steps. 2.1.2.1. Total Syntheses of Cyathanes Although the first structural elucidation of a cyathane appeared in the literature in the early 1970s, the first account of a cyathane total synthesis, reported by Snider and coworkers,55'56 was not published until 1996. Their synthetic sequence leading to (±)-allocyathin B 2 (71) and (+)-erinacine A (77) relied on an intramolecular carbonyl ene reaction as a key step (Scheme 12). The synthesis commenced with the known 5-6 fused bicyclic ketone 92, which was converted to aldehyde 93 in four steps. TMS-accelerated copper(I)-catalyzed conjugate addition of isopentenylmagnesium bromide to 93 provided a mixture of epimeric aldehydes 94. Methylation of 94 afforded aldehyde 95. Treatment of 95 with Me2AlCl resulted in an intramolecular carbonyl ene reaction, furnishing alcohol 96, which displayed the complete cyathane skeleton. This material was transformed into (l)-allocyathin B2 (71) in ten chemical operations. Glycosylation of racemic 71 with 2,3,4-tri-O-acetyl-a-D-xylopyranosyl bromide provided a 1:1 mixture of 27 (+)-erinacine A triacetate and its diastereomer. Deacetylation of the former with potassium carbonate in methanol afforded (+)-erinacine A (77). Reagents: a) H2C=C(CH3)CH2CH2MgBr, CuBrDMS, TMSC1, HMP A; b) r-BuOK, Mel; c) Me2AlCl; d) 2,3,4-tri-(9-acetyl-a-D-xylopyranosyl bromide, Hg(CN)2, HgCl2; e) K 2 C0 3 , MeOH. Scheme 12 In 1998, Tori and coworkers reported the second total synthesis of (!)-allocyathin B 2 (71), which involved three key aldol condensation reactions (Scheme 13). Dione 97, precursor for the firstaldol condensation, was prepared in five steps from 3-28 methyl-2-cyclohexen-l-one (38). Intramolecular condensation of 97 provided the fused hydrindenone system 98, which was transformed into compound 99 in four chemical operations. Base-mediated intramolecular cyclization of 99, followed by dehydration of the resultant tertiary alcohol using S O C I 2 , furnished the a,P-unsaturated lactone 100. Conversion of 100 to dialdehyde 101 was accomplished in five steps. Aldol condensation of 101, with concomitant acetate hydrolysis, provided (±)-allocyathin B 2 (71). 101 71 Reagents: a) 5% aq. KOH, MeOH, b) LiHMDS; c) SOCl 2, pyr; d) KOH, MeOH. Scheme 13 29 Taking advantage of an advanced intermediate in a synthetic study of verrucosane natural products,58 Piers and Boulet developed a synthesis59 of (!)-cyatha-12,18-diene (64) (Scheme 14). The sequence commenced with the known bicyclic enone 102, which was transformed into dione 103 in six steps. Base-mediated intramolecular aldol condensation of 103 afforded tricyclic enone 104. Metal-ammonia reduction of 104 provided ketone 105, which displayed the requisite trans stereochemistry at the ring fusion. The branching point in a divergent synthetic plan, compound 105 was also employed in the total syntheses of several verrucosane natural products.58 Lewis-acid catalyzed homologation of 105, followed by decarboxylation of the resultant [3-keto ester, provided the 5-6-7 fused tricyclic ketone 106. Final conversion of 106 to (!)-cyafha-12,18-diene (64) was accomplished in two steps. 105 106 64 Reagents: a) NaOMe, b) Li, NH 3 , r-BuOH; solid NH4CI; c) BFyOEt, N 2CHC0 2Et; DMSO, NaCl, Scheme 14 30 Recently, Ward and coworkers completed the total synthesis of allocyathin B 3 (68), a synthetic endeavor that began while Ward was a student in Ayer's group.60"62 The first part of the synthesis, reported by Ayer and coworkers,60 relied on two key cycloaddition reactions (Scheme 15). Diels-Alder reaction between benzoquinone 107 and dienes 108, gave the ds-fused bicycle 109. Photochemical [2+2] cycloaddition of 109 with allene, followed hydrolysis of the silyl enol ether function, afforded tricycle 110 as the major isomer. Epoxidation of the exocyclic double bond, followed by 1,2 reduction of the enone, furnished a mixture of epoxides 111. Treatment of 111 with benzenethiol and potassium hydroxide caused a sequence of reactions, commencing with a nucleophilic ring-opening of the epoxide to give intermediate 112. Fragmentation of 112, followed by intramolecular aldol condensation of the resultant triketone 113, ultimately provided tricycle 114. 31 O + T M S O OTMS 107 110 108 d,e OTMS b,c 111 PhS 112 113 114 Reagents: a) xylene, b) allene, hv; c) Rexyn 101 acidic ion exchange resin; d) m-CPBA; e) 9-BBN; f) PhSH, 5% aq. KOH, Scheme 15 Transformation of Ayer's advanced intermediate 114 (vide supra) to (±)-allocyathin B 3 (68) was completed by Ward and coworkers.61'62 Conversion of 114 to keto aldehyde 115 required ten chemical operations (Scheme 16). Acid-promoted aldol cyclization of 115 proceeded with a concomitant intramolecular benzoyl transfer. The 32 resultant hemiketal was methylated, providing 5-6-7 fused tricycle 116. The task of affixing an isopropyl moiety at C-3 (cyathane numbering) of 116 was accomplished in eight steps, affording intermediate 117. (±) Allocyathin B 3 (68) was obtained from 117 in three steps. 114 115 116 Reagents: a) p-TsOH; b) Mel, Ag 2 0. Scheme 16 2.1.2.2. Approaches to the Cyathanes In addition to the total synthesis publications, there have been numerous reports that describe novel methods of constructing the cyathane skeletal core. In 1994, Dahnke and Paquette reported63 a synthetic approach to the cyathane core via an anionic oxy-Cope rearrangement. An inverse demand Diels-Alder reaction between tropone (118) and 33 2-mefhylidene-l,3-dithiolane (119) provided bicyclo[3.2.2]nonane 120 (Scheme 17). Several steps, which included a resolution of enantiomers, afforded the levorotatory enantiomer of ketone 121 from intermediate 120. Treatment of (-)-121 with the enantiopure organolithium reagent 122 provided the rearrangement precursor 123. Oxyanion accelerated Cope rearrangement of 123 furnished the 5-6-7 fused tricycle 124. Compound 124 was transformed into ketone 125 in six steps, which included a methylation at C-9 from the P-face. Unfortunately, the requisite installation of a methyl group at C-6, which must occur from the a-face, proved difficult and this synthetic approach to cyathanes was ultimately abandoned. 122 123 Reagents: a) Et3N, -*; b) 122; c) KH, 18-cr-6, Scheme 17 34 In 1999, Wright and coworkers disclosed a novel approach to the cyathane core that relied on sequential oxidative coupling and [4+3] cycloaddition steps.64 The sequence began with a TMSCl-accelerated copper(I)-catalyzed addition of the Grignard reagent derived from bromide 126 to 3-methyl-2-cyclopenten-l-one (Scheme 18). Exposure of the resultant adduct 127 to a carbon anode promoted an oxidative coupling reaction, yielding the tricyclic product 128. Ketone 128 was converted to its cyclic ketal derivative 129. Treatment of 129 with oxyallyl cation 130, which was generated in-situ from trichloroacetone, resulted in a [4+3] cycloaddition. The cycloaddition products 131 were dechlorinated with a zinc-copper couple to afford compound 132, which displayed a 5-6-7 fused carbon skeleton present in cyathanes. 126 127 128 129 Reagents: a) Mg; Cul, TMSC1; 3-methyl-2-cyclopenten-l-one; b) carbon anode, LiOC^, 2,6-lutidine; c) p-TsOH, HO(CH2)2OH, CH(OEt)3; d) 1,1,3-trichloroacetone, NaOCH2CF3; e) Zn-Cu couple, NH4CI. Scheme 18 35 Magnus and Shen reported65 a synthetic approach to the cyathane core that relied on a key [5+2] annulation reaction (Scheme 19). The sequence commenced with diethyl adipate (133), which was converted to the mixture of ketones 134. Transformation of 134 to alcohol 135 was accomplished in four steps. Irradiation of 135 in the presence of 0 2 resulted in an oxidative rearrangement, affording the unstable pyranone 136. Treatment of 136 with TFA generated the corresponding pyrylium ylide 137, which underwent an intramolecular [5+2] cycloaddition to give the 5-6-7 fused tricycle 138. Reagents: a) O2, rose bengal, hv; DMS; b) TFA. Scheme 19 36 Takeda and coworkers reported a rapid assembly of the cyathane tricyclic core via a Brook rearrangement-mediated [3+4] annulation (Scheme 20).66 Dienone 139, precursor of the key annulation, was obtained in two chemical operations from the known enone 91, which was also employed in Snider's cyathane studies (see Scheme 12, vide supra). Addition of the enolate of 139 to a solution of the acryloylsilane 140 resulted in a [3+4] annulation via intermediates 141 and 142. 1,2-Adduct 141 underwent a Brook rearrangement to afford the divinylcyclopropane intermediate 142. A homo-Cope rearrangement of 142 afforded compound 143, which displayed the 5-6-7 fused tricyclic cyathane ring system. 143 Reagents: a) LDA, 140. Scheme 20 37 In 2001, Wender and coworkers reported an asymmetric approach to the cyathane core via a transition metal-catalyzed [5+2] cycloaddition.67 (,S)-(-)-Limonene (144) was converted to keto aldehyde 145 in two steps (Scheme 21). An intramolecular aldol condensation of 145 provided enal 146. Transformation of 146 to 147 required ten chemical operations. Treatment of 147 with [Rh(CO)2Cl]2 caused the key intramolecular [5+2] cycloaddition. The proposed pathway of this cycloaddition involved an initial complexation of the alkyne and vinylcyclopropane moieties of 147 with the Rh-catalyst. Upon oxidative addition, this complex provided intermediate 148. Strain-driven cleavage of the cyclopropane ring in 148 led to intermediate 149. Reductive elimination of 149 provided the cycloaddition product 150, which displays the cyathane 5-6-7 fused tricyclic ring-system. 38 Scheme 21 39 In a synthetic study directed towards (±)-sarcodonin G (36), Piers and Cook prepared the 5-6-6 fused tricycle 151 via sequential ring closure and Still-Mitra [2,3] sigmatropic rearrangement reactions.68'69 The synthesis of 151 commenced with an alkylation of the anion derived from trans-fused bicyclic dimethylhydrazone 152 with iodide 44, affording adduct 153 (Scheme 22). Conversion of 153 to keto alkenyl iodide 154 was accomplished in four steps. A stereoselective BuLi-mediated anionic cyclization of 154 yielded the 5-6-6 fused tricyclic carbinol 155. Conversion of 155 to the corresponding (tributylstannyl)methyl ether derivative 156, followed by BuLi-mediated transmetallation, provided carbanion intermediate 157. A [2,3]-sigmatropic rearrangement of 157 afforded alcohol 151, which displayed the desired C-3,4 double bond and possessed the correct relative configuration of the stereogenic center at C-l8 (cyathane numbering). Reagents: a) KDA, HMPA; 44; b) BuLi; c) KH, 18-cr-6; Bu3SnCH2I d) BuLi. Scheme 22 41 The work described in this thesis involves synthetic studies directed towards the diterpenoids sarcodonin G (36) and cyathin A 4 (37). Both compounds display the cyathane 5-6-7 fused ring system with identical relative configurations at the ring-fusion centers. In addition, both compounds are among the few cyathanes that display a hydroxyl function on the isopropyl side chain at C-3 (see Section 2.1.1.3., vide supra). The structural differences between sarcodonin G (36) and cyathin A 4 (37) are restricted to the C-ring and its one-carbon appendage. Although both compounds display a ketone function at C-10, sarcodonin G (36) displays an aldehyde function at C-15 whereas cyathin A 4 (37) displays hydroxyl functions at C - l l and C-15. In addition, sarcodonin G (36) displays a C - l 1,12 double bond as opposed to the C-12,13 double bond exhibited by cyathin A 4 (37). These similarities and differences of structures 36 and 37 lend themselves to a centralized and divergent synthetic approach that addresses the oxygenation and unsaturation pattern of the C-ring in the later stages of the syntheses.* * In the text of this thesis, Ayer's cyathane numbering system is used in most descriptions of cyathane-type natural products and a systematic IUPAC-based numbering system is used to describe the synthetic intermediates and the final products. The experimental section of this thesis contains IUPAC names for the synthetic intermediates and the final products. 42 2.1.3. Total Synthesis of (l)-Sarcodonin G 2.1.3.1. Retrosynthetic Analysis Our proposed synthetic plan for the construction of the cyathane natural product sarcodonin G (36) is outlined in Scheme 23. The target compound 36 can presumably be derived from keto aldehyde 158 via a selenenylation/oxidation/elimination sequence to introduce a double bond in the seven-membered ring, followed by a cleavage of the PMB ether to generate the alcohol function. Reduction of keto ester 159, followed by Dess-Martin oxidation of the resultant diol, should provide the corresponding keto aldehyde 158. In theory, the 5-6-7 fused tricyclic keto ester 159 can be obtained from the 5-6-6 fused tricycle 160 via a radical-based ring-expansion reaction. A sequence of ethoxy carbonylation and iodomethylation steps should provide the ring-expansion precursor 160 from ketone 161. Ketone 161 should be available from alcohol 160 through a protection of the hydroxyl function as a PMB ether and an oxidative cleavage of the exocyclic double bond. On the basis of previous work in our laboratories (see Section 2.1.2.2 , vide supra),6S'69 alcohol 160 was expected to be accessible from the bicyclic dimethylhydrazone 161 and the bifunctional reagent 44 via keto alkenyl iodide 154. Conversion of 154 to 151 would involve sequential BuLi-mediated cyclization and Still— IVlitra. [2,3]-sigmatropic rearrangement reactions. 43 152 Scheme 23 2.1.3.2. Preparation of 5-6-6 Fused Tricycle 101 As described in Section 2.1.2.2 (Scheme 22, vide supra), previous work in our laboratories by K. L. Cook provided a synthetic route to the 5-6-6 fused tricyclic alcohol 151 from the bifunctional reagent 44 and trans-fused bicyclic dimethylhydrazone 152 (eq 5).69 Since our study involved transformation of the advanced intermediate 151 into the 44 target compound sarcodonin G (vide supra), we embarked on a large-scale preparation of 151 and investigated several possible improvements to the previous synthesis. 2.1.3.2.1. Preparation of Bifunctional Reagent 44 In Cook's study, the synthesis of iodide 44 (Scheme 24) commenced with the known alcohol 162, which was readily obtained in three steps from commercially available materials.70 Transmetallation of 162 with MeLi, followed by addition of Me3GeBr, provided the corresponding germane 163. Treatment of 163 with Ph3P-I.2 and Et3N furnished 44 in high yield. (5) 152 M e 3 S n ^ ^ O H M e 3 G e ^ ^ O H M e 3 G e ^ ^ 1) M e L i , T H F , - 7 8 ° C P h 3 P - l 2 ) E t 3 N 2) M e 3 G e B r C H 2 C I 2 , rt 162 163 (79 %) 4 4 (95%) Scheme 24 45 An alternative synthesis of 44, which would circumvent the tin-germanium exchange step (vide supra), is outlined in Scheme 25. Presumably, alcohol 163, a known precursor to iodide 44, could be obtained from a reduction of ester 164. On the basis of previous studies by our group, it was thought that a stereospecific deconjugation of the ethyl (Z)-2-pentenoate 165 would provide ethyl (£)-3-pentenoate 164. Compound 165 should to be available from ethyl 2-pentynoate (166) via a germylcuprate conjugate addition reaction also developed in our laboratories. Me 3 Ge^^ Me 3 Ge^^ OH 44 163 164 \ > 165 166 Scheme 25 46 The first step of our proposed synthesis of 44 involved the preparation of ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) from the commercially available ethyl 2-pentynoate (166) (eq 6). \ C 0 2 E t 166 M e 3 G e (6) The preparation of ethyl 3-trimethylgermyl-2-butenoates via conjugate addition of (trimethylgermyl)copper(I) reagents 167-170 to ethyl 2-butynoates has recently been reported71 by Piers and Lemieux. M e 3 G e C u M e 2 S Me 3 GeCu(CN)Li 167 168 (Me 3 Ge) 2 CuLi Me 3 Ge(Me)Cu(CN)Li 2 169 170 Treatment of alkynic ester 171 with germylcopper(I) reagents 167-170 was shown to afford the E- and Z-alkenylgermane isomers, 172 and 173 (Table 1). Conjugate addition of reagents 167 and 168 to alkynic ester 171 afforded the Zs-isomer 172 in high yields (entries 1-2, Table 1). A mixture of 172 and its geometric isomer 173 were obtained employing cuprate reagent 169 (entry 3, Table 1). Of particular interest to our study, conjugate addition of 170 favored formation of the Z-isomer 173 over the E-isomer 172 in a 3.9:1 ratio (entry 4, Table 1). 47 Table 1. Addition of Germylcopper(I) Reagents (167-170) to Ethyl 2-Butynoate (171). C -0 2 Et 1) reagent, T H F , -78 °C • 2) A c O H ; aq N H 4 C I - N H 3 \ ^ G e M e 3 J + E t 0 2 C ^ \ . G e M e 3 X X 0 2 E t 171 172 173 Entry Reagent 172:173 Ratio Yield (%) 1 Me3GeCuMe2S 167 >99:1 81 2 Me3GeCu(CN)Li 168 >99:1 90 3 (Me3Ge)2CuLi 169 1.7:1 90 4 Me3Ge(Me)Cu(CN)Li2 170 1:3.9 86 On the basis of the stereoselectivity displayed by the reaction summarized in entry 4 (Table 1), the conjugate addition of germylcuprate reagent Me3Ge(Me)Cu(CN)Li2 (170) was applied to the preparation of ethyl (Z)-3-trimethylgermyl-2-pentenoate (165). Ethyl 2-pentynoate (166) was added to a cold (-78 °C) solution of 170, and the resultant mixture was treated with AcOH (eq 7). Upon aqueous work-up and purification of the resulting material by flash chromatography, ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) and the corresponding E-isomer, 174, were obtained in 71% and 20% yields, respectively. \ 1) Me3Ge(Me)Cu(CN)Li2(170) THF, -78 °C M e 3 G e ^ C 0 2 E t 166 2) AcOH Et0 2 CT 165 (71%) 174 (20%) (7) Et 48 The structure of 1 6 5 was confirmed by spectrometric analysis. The JR spectrum of 1 6 5 exhibited an ester carbonyl stretch at 1718 cm - 1. The 'H NMR spectrum of 1 6 5 displayed singlets at 8 0.29 (9H) and 6.21 (1H) attributed to the Me3Ge- moiety and the olefinic proton, respectively. The 1 3 C NMR resonances for the olefin carbons and the ester carbonyl carbon were observed at 8 126.6 and 166.8, and at 8 171.4, respectively. 165 'pi NMR NOED experiments were performed to establish the geometry of the alkene function in 165 . Thus, irradiation at 8 2.30, a quartet attributed to the allylic methylene protons (H-4), caused enhancement of the signals at 8 6.21 and at 8 0.29, assigned to the olefinic proton (H-2) and the Me3Ge- protons, respectively. When the signal at 8 0.29 (Me3Ge-) was irradiated, enhancement of the quartet at 8 2.30 (H-4) was observed. Irradiation of the signal at 8 6.21 (H-2) also caused the quartet at 8 2.30 (H-4) to be enhanced. These experiments, along with the spectral data presented above are consistent with the structural assignment for ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) . Spectrometric analysis of the E'-isomer 1 7 4 supported its assigned structure. The ester carbonyl stretch of 1 7 4 was observed at 1718 cm - 1 in its IR spectrum. The *H NMR 49 signals for the Me3Ge- moiety and olefinic proton in 174 were displayed at 8 0.23 and 5.89, respectively. The 1 3 C NMR spectrum of 174 displayed resonances at 8 124.5 and 164.9, and at 8 171.3, representing the olefin and carbonyl carbons, respectively. The geometry of the alkene function in 174 was established by ] H NMR NOED experiments. Irradiation at 8 2.73, a quartet attributed to the allylic methylene protons (H-4), caused enhancement of the singlet at 8 0.23, assigned to the protons of the MesGe- group. Irradiation of the olefinic proton (H-2) signal at 8 5.89 caused enhancement of the singlet at 8 0.23 (Me3Ge-). When the signal at 8 0.29 (Me3Ge-) was irradiated, the signals at 8 2.73 (H-4) and 5.89 (H-2) were enhanced. These experiments confirm the E configuration of the alkene function in 174. The formation of 165 and 174 can be rationalized by the possible pathway71 depicted in Scheme 26. A reversible cis addition of cuprate 170 to ethyl 2-pentynoate (166) provides the alkenyl copper immediate 175. Although direct protonation of 175 would produce the ^-isomer 174 (path a), it appears that the majority of 175 isomerizes to the allenoate species 176 (path b). Protonation of allenoate 176 would occur predominantly from the side opposite to of the bulky Me3Ge- moiety (path c), providing 174 50 primarily the Z-isomer 165. Protonation of allenoate 176 from the same side as the Me3Ge- moiety (path d) would provide Zs-isomer 174. Scheme 26 With the ethyl (Z)-2-pentenoate 165 in hand, the next step involved a stereospecific deconjugation to provide ethyl (£)-3-pentenoate 164 (eq 8). Me3Ge> Et0 2 CT Me-aGe EtO-C (8) 165 164 51 70 In 1990, Piers and Gavai reported a study on the stereospecific deconjugations of ethyl 3-trimethylstannyl-2-pentenoates. For example, addition of (Z)-2-pentenoate 177 to a solution of LDA, followed by an inverse addition of the resultant enolate to a solution of AcOH, provided (£)-3-alkenoate 178 (eq 9). In a similar fashion, (E)-2-alkenoate 179 was transformed, completely stereoselectively, into the corresponding (Z)-3-alkenoate 180 (eq 10). y i) LDA, THF, HMPA, -78 °C; 0 °C; -78 °C M e 3 S n r_iu2o 2) AcOH, Et20,-99 °C B 0 2 C 177 178 (87%) M o I 1) LDA, THF, HMPA, 0 M e 3 S n ^ .78 °C; 0 °C; -78 °C M e 3 S " (9) (10) >2Et 2) AcOH, Et20, -99 °C X 0 2 E t 179 180 (82%) It was expected that the application of this deconjugation reaction (vide supra) to ethyl (Z)-3-trimethylgermyl-2-pentenoate 165 would provide the corresponding ethyl (E)-3-pentenoate 164. Thus, a solution of 165 in THF was added to a solution of LDA and HMPA in THF (eq 11). Subsequent inverse addition of the resultant enolate solution to a cold (-98 °C) solution of AcOH in Et 20 provided, upon work-up, a 91% yield of the desired ethyl (£)-3-pentenoate 164. 52 M e 3 G e E t 0 2 C 2) A c O H , E t 2 0 , -99 °C 1) L D A , T H F , H M P A , -78 °C; 0 °C; -78 °C M e 3 G e E t 0 2 i (11) 165 164 (91%) Standard spectroscopic methods were used to confirm the structure of trimethylgermyl alkenoate 164. A carbonyl absorption at 1737 cm - 1 in the IR spectrum of 164 was characteristic of an aliphatic ester. The ! H NMR spectrum of 164 displayed a singlet (2H) at 8 3.16, attributed to the allylic methylene a to the ester function. The signals corresponding to the alkenyl methyl and proton moieties were observed at 8 1.69 (doublet, J = 6.7 Hz) and 8 5.87 (quartet, J = 6.7 Hz), respectively. The 1 3 C NMR spectrum displayed resonances at 8 135.5 and 135.7, assigned to the olefinic carbons. The 1 3 C signal for the ester carbonyl carbon was observed at 8 171.8. 164 The geometry of the alkene function in 164 was confirmed by ! H NMR NOED experiments. Irradiation at 8 1.69, attributed to the methyl protons (H-5), caused enhancement of resonances at 8 5.87 and 3.16, assigned to the olefinic proton (H-4) and 53 methylene protons (H-2), respectively. When the olefinic proton (H-4) signal at 8 5.87 was irradiated, the signals at 8 1.15 (Me3Ge-) and 1.69 (H-5) were enhanced. These experiments, along with the spectral data presented above are consistent with the structural assignment for ethyl (£)-3-trimethylgermyl-3-pentenoate (164). The stereoselective formation of 164 from 165 may be qualitatively rationalized70 as shown in Scheme 27. The relative transition states for the kinetically controlled deprotonation of two ground state conformations, 165a and 165b, leading to the respective extended enolates 181 and 182, were considered. The transition state leading to the extended enolate 182 would be highly destabilized by the developing A 1 ' 2 strain (between CH3 -5 and the Me3Ge-group). On the other hand, the transition state leading to the extended enolate 181 would be destabilized by the relatively smaller steric repulsions due to A 1 ' 2 strain (H-4 and Me3Ge-) and A 1 ' 3 strain (CH3-5 and H-2). In addition, if the transition state leading to the extended enolate 181 contains some allylic anion-type character it may experience stabilization from the fact that the 181 contains a cis alkyl group.72 Strong evidence provided by experimental and theoretical studies suggests that allylic anions systems containing cis alkyl groups are more stable than those possessing trans alkyl moieties.73 Hence, for this reason and for steric reasons, the deprotonation step would be expected to favor the formation of the allylic anion 181, which affords the £-alkenoate 164, upon protonation. 54 M e 3 G e H Q EtO ^ • " C H 3 7 H 165b M e 3 G e H MM LDA LDA Me3Ge X ,CH 3 EtO I N AcOH M e 3 G e C H 3 Q >=< > H EtO 182 M e 3 G e % H - Q M t AcOH )H 3 5 183 M e 3 G e H 165a 181 Scheme 27 164 The final steps in the synthesis of bifunctional reagent 44 from ester 164 were straightforward (Scheme 28). DIBALH reduction of ester 164 provided alcohol 163 in 88% yield. As demonstrated by Cook (see Scheme 24 earlier), addition of 163 and E13N to a solution of Pli3P-l2 in CH2CI2 provided the corresponding iodide 44 in high yield. All spectral data derived from compounds 163 and 44 were identical to those reported' by Cook. 69 M e 3 G e Et0 2C 164 DIBALH M e 3 G p ^ \ B 2 0 , -78 °C to rt 163 (88%) Ph3P-l2, Et3N M e 3 G e ^ C H 2 C I 2 , rt 44 ( 9 5 % ) Scheme 28 55 2.1.3.2.2. Preparation of cw-Fused Bicyclic Dimethylhydrazone 102 With the desired electrophile 44 in hand, preparation of the trans-fused bicyclic dimethylhydrazone 152 from the ketones 41 was investigated (eq 12). 41 152 The known bicyclic ketones 41 were prepared following a 3-step procedure I o developed in our laboratories. Commercially available 5-chloro-l-pentyne (184) was added to a solution of Me3SnCuDMS complex, providing, upon work-up, the bifunctional reagent 39 (Scheme 29). A copper-catalyzed conjugate addition of the Grignard reagent derived from 39 to 3-methyl-2-cyclohexen-l-one (38) afforded the cyclic keto chloride 185. KH-mediated cyclization of the keto chloride 185, followed by an ethoxide-mediated epimerization reaction, yielded a 78:22 mixture of the trans- and cis- fused bicyclic ketones 41. 56 184 185 (91 %) M e 3 S n C u D M S M e 3 S n T H F , -78 °C CI 1) MeL i , T H F , -78 °C; M g B r E t 2 0 2) C u B r - D M S , B F 3 - E t 2 0 , 38 39 (68%) 1) K H , T H F , reflux 2) E t O H 41 (82%, 78:22 trans/cis ratio) Scheme 29 As described in Cook's study,69 the conversion of ketones 41 into the corresponding hydrazone derivatives was accomplished by treatment of a benzene solution of the former with dimethylhydrazine and a catalytic amount of CSA (eq 13). The resultant mixture was refluxed for 72 h with azeotropic removal of water. Upon solvent removal and purification of the resultant material by flash chromatography, the cis- and trans-fused bicyclic dimethylhydrazones, 186 and 152, were obtained in 39% and 43% yields, respectively. 41 186 (39%) 152 (43%) 57 In the previous study, the Trans-fused isomer 152 was carried through to the next step but the undesired c/s-fused isomer 186 was abandoned. For our large-scale synthesis, a method of recycling the large quantities of the c/s-fused 186 was sought. Although 186 did not appear to isomerize under standard base-mediated conditions (NaOMe/MeOH or f-BuOK/f-BuOH), acid-mediated isomerization conditions (CSA, benzene) yielded significant amounts of the desired trans-fused isomer 152 (eq 14). Thus, a catalytic amount of CSA was added to a benzene solution of the 186 and the resultant mixture was refluxed for 48 h. Upon work-up and purification of the resulting material by flash chromatography, 186 and 152 were obtained in nearly a 1:1 ratio. The cis-fused isomer 186 was recycled twice through the epimerization step, yielding additional 152 for a total overall yield of 71% from the mixture of ketones 41. Me2NN' PhH, reflux C S A Me2NN' (14) 186 152 1:1 ratio of 186:152 58 2.1.3.2.3. Preparation of Ketone 187 With building blocks 152 and 44 in hand, the synthetic sequence leading to ketone 187 was investigated (eq 15). Cook's preparation of 187 from 152 and 44 is outlined in Scheme 30. Deprotonation of the trans-fused hydrazone 152 with KDA, followed by addition of HMPA and iodide 44 to the resulting enolate solution, afforded adduct 153 after work-up. The crude 153 was taken up in a buffered aqueous THF mixture and the latter was treated with sodium periodate. The resultant mixture was heated to 40 °C and stirred for 72 h, affording ketone 188 in 46% yield. Isomerization of 188 was accomplished by treatment of this material with r-BuOK/f-BuOH, thus providing a 69% yield of isomer 187. The overall yield from 152 to 187 was 32% and the reaction times for the last two steps totaled 90 h. 59 Scheme 30 The optimized experimental procedures employed for our large-scale conversion of 152 to 187 are outlined in Scheme 31. Alkylation of the potassium enolate derived from 152 with iodide 44 was accomplished in the presence of DMPU, a less-toxic alternative to carcinogenic HMPA. The crude hydrazone 153 was subjected to hydrolysis with NaOAc/AcOH in aqueous THF, affording a mixture of isomeric ketones 189 in 69% yield from 152. A 3 h isomerization of 189 in NaOMe/MeOH afforded a 66% yield of ketone 187 and 22% of three other diastereomers. The mixture of undesired ketone isomers was resubmitted to the same isomerization reaction to yield an additional quantity of 187 for a total overall yield of 82% from 189. In comparison with the previous synthesis (vide supra), the total overall yield from 152 to 187 had been 60 increased from 32% to 57% and the total reaction times of the latter two steps had decreased from 90 h to 24 h. All spectral data derived from 187 were identical with those of the corresponding data reported69 by Cook. Scheme 31 2.1.3.2.4. Preparation of Alcohol 151 With ketone 187 in hand, the sequence of reactions leading from this substance to alcohol 151 was investigated (eq 16). 61 In 1996, Piers and Cook reported an annulation method that relied on sequential BuLi-mediated ring closure and Still-Mitra [2,3]-sigmatropic rearrangement19 reactions. For example, methylation of 190, followed by iododegermylation, gave keto alkenyl iodide 191 (Scheme 32). Treatment of 191 with BuLi resulted in an anionic ring closure, affording the cw-fused alcohol 192. Conversion of 192 to its tributylstannylmethyl ether derivative, followed by a Still-Mitra [2,3]-sigmatropic rearrangement, provided alcohol 193. Reagents: a) r-BuOK, THF, HMPA; Mel; b) I2, CH2C12; c) BuLi, THF; d) KH, 18-cr-6; Bu3SnCH2I; BuLi. Scheme 32 This novel annulation sequence (vide supra) was successfully applied to the conversion of 187 to 151, as reported in Cook's previous study. The experimental procedures developed69 by Cook were also employed in our large-scale preparation of 151 (Scheme 33). Methylation of 187 furnished 194 in 85% yield. The reaction involving iododegermylation of 194 with NIS in CH2C12 was stopped after 1 h, affording the corresponding alkenyl iodide 154 in 91% yield. In Cook's study, the NIS-mediated 62 iododegermylation process was stopped after 15 min, affording 154 in only 69% yield. A BuLi-mediated anionic ring-closure of keto alkenyl iodide 154 provided alcohol 155 in 86% yield. Treatment of 156, the tributylstannylmethyl ether derivative of alcohol 155, with BuLi resulted in the required [2,3]-sigmatropic rearrangement, affording alcohol 151 in 88% yield from 155. All spectral data derived from the 194, 154, 155 and 151 were identical with those reported69 by Cook. Scheme 33 63 Many stereochemical aspects of the sequence of transformations leading from 187 to 151 have been discussed elsewhere.68'69 However, several key features noted69 by Cook that support the assigned relative configurations of intermediates 194,155 and 151, are certainly worth outlining. The successful stereoselective axial methylation of 187 was confirmed by *H NMR NOED experiments performed on compound 194. In the ! H NMR spectrum of 194, the newly introduced methyl group (Mea) and the angular proton (Ha) gave rise to signals at 8 1.17 and 2.44, respectively. In NOED experiments, irradiations at 8 1.17 and 2.24 resulted in a mutual enhancement of these two resonances, thus establishing the cis relationship between the newly introduced methyl moiety (Mea) and the angular proton (Ha). Me3Ge' 194 The BuLi-mediated cyclization of iodide 154 was completely stereoselective, affording the ds-fused tricycle 155, exclusively (Scheme 34). The cis configuration of the ring-fusion of 155 was not unambiguously determined. However, on the basis of previously reported studies and molecular modeling, the presence of the angular methyl Mea in 195, the intermediate derived from 154, was expected to result in the exclusive 64 formation of a ds-fused cyclization product 197. The molecular conformation of the transition state necessary for the cyclization of the alkenyllithium intermediate 195 leading to as-fused alcohol 197 (path a) would appear to be considerably less strained than that leading to the corresponding trans-fused alcohol 196 (path b). The molecular conformation of the transition state leading to the trans-fused alcohol 196 would likely experience significant angle strain in the forming five membered ring in addition to the steric strain involving gauche interaction between the angular methyl Mea and the incoming alkenyllithium moiety. 155 197 196 Scheme 34 The stereospecific nature of the Still-Mitra [2,3]-rearrangement, which provided alcohol 151 from tributylstannylmethyl ether 156, has been well established (Scheme 35).1 9 7 4 Transmetallation of tributylstannylmethyl ether 156 with BuLi afforded the 65 carbanion intermediate 157. The rearrangement process would take place in a suprafacial manner, affording alkoxide 198. Thus, the relative configuration of alcohol 151, obtained upon aqueous work-up of 198 could be assigned with confidence. Scheme 35 66 2.1.3.3. Preparation of Ketone 112 Having completed a large-scale preparation of alcohol 151, which represents the most advanced intermediate in Cook's study,69 the preparation of ketone 161 was investigated (eq 17). The first step was envisaged to be the protection of the hydroxyl moiety in 151 by converting this material into the corresponding p-methoxybenzyl ether 199 (eq 18). The p-methoxybenzyl (PMB) protecting group was chosen for its resistance to acidic and basic conditions. When required, the PMB group can be readily removed under mild neutral conditions with DDQ at room temperature.75 Thus, the alkoxide derivative of alcohol 151, which was generated via a deprotonation of 151 by KH in THF, was treated with p-methoxybenzyl chloride and a catalytic amount of Bu4N+T. The Bu4N+T caused a Finkelstein-type in situ conversion of the PMBC1 into the more reactive electrophile, p-methoxybenzyl iodide. Standard work-up and purification of the resultant material by flash chromatography provided the p-methoxybenzyl ether 199 in 91% yield. 67 HO' 1) K H , T H F , rt 2) PMBCI, Bu 4NI P M B O (18) 151 199 (91%) The successful formation of ether 199 was supported by *H NMR spectroscopic analysis of the product. The lH NMR spectrum of 199 displayed a 3-proton singlet at 8 3.78, representing the methoxy moiety of the PMB protecting group. In addition, two doublets were observed at 8 6.86 (2H, J = 8.9 Hz) and 8 7.23 (2H, J = 8.9 Hz), representing the aromatic protons of the para-substituted benzyl group. With the ether diene 199 in hand, the next task was the chemoselective oxidative cleavage of the C-10(19) exocyclic double bond to form ketone 161 (eq 19). However, it was found (vide infra) that this chemoselective oxidation was difficult to achieve owing to the small difference in reactivity between the C-10(19) exocyclic double bond and the C-2 endocyclic double bond. P M B O P M B O O (19) 199 161 68 Ozonolysis was the first method investigated to achieve the required chemoselective oxidative cleavage. Following a standard ozonolysis procedure, a gaseous flow of ozone in 0 2 was passed through a cold solution of diene 199 in MeOH/CH2Cl2 for 10 min, at which point the solution turned light blue, indicating the presence of excess ozone in the mixture (eq 20). Reductive work-up with dimethyl sulfide was followed by removal of the volatiles under reduced pressure. Purification of the resultant material by flash chromatography provided a major product, which was tentatively assigned structure 200. 199 200 The assigned structure of compound 200 was supported by spectrometric analysis. A molecular mass peak at 412 in the mass spectrum of 200 confirmed its C26H36O4 chemical formula. The *H NMR spectrum of 200 displayed 3-proton singlets at 8 1.24 and 0.86, attributed to the H-17 and H-18 angular methyl protons, respectively. Previously, the *H NMR signal for the corresponding H-17 and H-18 angular methyl protons in diene 200 had been noted at 8 1.01 and 0.92, respectively. The apparent deshielding of the H-17 angular methyl protons in 200 relative to those of 199 was attributed to the newly introduced P-face epoxide function at C-2,3 in 200. This rationale 69 for the proposed structure of 200 was based on an analogous argument by Ayer and coworkers (vide infra). A similar (3-face selective epoxidation was noted by Ayer and coworkers in their reported structural elucidation studies on neoallocyathin A 4 (79) involving spectroscopic 17 correlations with a derivative of cyathin A 3 (67) (see Section 2.1.1.3., vide supra). Compound 201, a diacetyl derivative of cyathin A 3 (67), was treated with m-CPBA to afford the P-epoxide 202 (Scheme 36). Treatment of a methanol solution of 202 with potassium carbonate gave neoallocyathin A 4 (79), which was spectroscopically identical with the corresponding natural product. 201 Scheme 36 202 70 The rationale used to assign the structure of 200 in our study (vide supra) was based on the following evidence presented by Ayer and coworkers. The ! H NMR signal attributed to the H-17 angular methyl protons of 202 was noted at 8 1.28. The J H NMR signal for the corresponding H-17 methyl protons in 201 had previously been noted at 8 1.07. The downfield shift of the H-17 signal for 202 relative to that of the H-17 signal for 201 was attributed to significant deshielding by the newly introduced C-2,3 P-epoxide in 202. Although the epoxidation of 201 upon treatment with m-CPBA, as reported by Ayer and coworkers, was certainly expected, the epoxidation of 200 by ozonolysis, as noted in our study (vide supra), was not anticipated. A brief review of the literature provided some insight into this undesired ozonolysis side-reaction. The proposed mechanism for the ozonolysis reaction of non-hindered olefins (path a) involves three steps (Scheme 37).76 The first step is an electrophilic cycloaddition of ozone to the alkene (see 203 —• 204, Scheme 37). Cleavage of the resultant ozonide 204 provides carbonyl 205 and carbonyl oxide zwitterion 206, which recombine to afford the cyclic ozonide 207. Reductive work-up of 207 with dimethyl sulfide provides two carbonyl compounds, 208. On the other hand, it has been shown that some hindered alkenes appear to be too sterically encumbered to allow for an electrophilic cycloaddition with ozone.77 Alternatively, upon treatment with ozone, a hindered alkene (203) may form the peroxyepoxide intermediate 209 (path b). Loss of one molecule of dioxygen from 209 78 provides epoxide 210. 71 In our study, the observed formation of a P-face epoxide upon ozonolysis of 199, represented by partial structure 211, may be rationalized with the help of Scheme 38. Only partial structures are illustrated because the state of the alkene at C-10, which is ultimately cleaved in this step, is not known at the time of the epoxidation. On the basis of molecular models, an approach by ozone to the a-face of C-2 double-bond in 211 (path a) would experience more steric interference, including 1,3-diaxial interaction with Me-18, than would the corresponding P-face approach (path b). Loss of dioxygen by the resulting peroxyepoxide 212 would afford intermediate 213, displaying a P-configuration of the epoxide moiety. 72 M e R M e 213 Scheme 38 212 In an attempt to prevent epoxide formation, the ozonolysis was repeated in the presence of Sudan Red 7B,7 9 a dye that allows detection of low ozone concentrations. Despite careful observation and short reaction times, the epoxidation could not be prevented and the desired reaction could not be accomplished. Therefore, the ozonolysis approach to preparing 161 from 199 was abandoned and alternative methods for the chemoselective oxidative cleavage were investigated. Certain transition metal-based oxidants have been shown to effect the cleavage of C-C double bonds via the pathway illustrated in Scheme 39.80 Treatment of an alkene (203) with ruthenium tetroxide or osmium tetroxide generates intermediate 214 via a stereospecific sv/z-addition. Vicinal diol 215, derived from 214, can be oxidatively 73 cleaved by treatment with a periodate reagent. The proposed mechanism of this transformation involves cleavage of the cyclic adduct 216 to afford carbonyl compounds 208. v ° 203 M = Ru or Os O O HO OH u /u   n V r" J i R R 214 NaO O H O ^ ^ O H O ^ ^ O N a l 0 4 V\_7 * " p w i " " ' ^ 1""" 'R R R 216 R R 215 O x 2 R ' ^R A : 208 Scheme 39 Ruthenium tetroxide is a toxic, volatile oxidant that is generally prepared by in situ oxidation of Ru0 2 by a stoichiometric amount of periodate. The periodate reagent therefore serves the dual purpose of re-oxidizing the catalyst and cleaving the diol intermediate. Thus, in the presence of two equivalents of periodate and a catalytic amount of ruthenium dioxide, an olefin can undergo complete oxidative cleavage. Using modified conditions described by Sharpless and coworkers,81 a solution of the diene 199 in a 1:1:1.5 mixture of acetonitrile, carbon tetrachloride and water was treated with a catalytic amount of ruthenium dioxide and two equivalents of sodium periodate (eq 21). 74 Work-up and purification of the resultant material by flash chromatography provided one major product and 50% of recovered starting material (199). On the basis of spectroscopic analysis, the major product was tentatively assigned structure 217, derived from the oxidative cleavage of both double bonds in diene 199. A molecular mass peak at 428 in the mass spectrum of 217 confirmed its C26H36O5 chemical formula. The *H NMR spectrum of 217 displayed signals at 5 1.15 and 2.65, attributed to H-17 and H - l , respectively. The corresponding 'H NMR signals for the H-17 and H - l in diene 199 were previously noted at 8 1.01 and 1.99, respectively. The downfield shifts noted for the signals of the H-17 and H - l of 217 relative to those of diene 199 may be partially attributed to deshielding by the newly introduced carbonyl at C-2 in 217. (30%) Considering the lack of chemoselectivity displayed by ruthenium tetroxide, the less reactive osmium tetroxide oxidant was investigated. Like ruthenium tetroxide, osmium tetroxide is a toxic, volatile oxidant and is generally used in catalytic amounts with in-situ re-oxidation. Gratifyingly, treatment of diene 199 with a catalytic amount of osmium tetroxide and several equivalents of sodium periodate afforded the desired ketone 161 as the main product. However, the reaction was quite sluggish and, despite long reaction times (12-24 h) and increased reaction temperatures (from 20 °C to 50 °C), 75 the yields were disappointingly low (30-40%). Addition of sodium bicarbonate and replacement of the sodium periodate co-oxidant with potassium periodate slightly improved the observed yields.56 The optimal reaction conditions involved the addition of potassium periodate and sodium bicarbonate to a solution of diene 199 in 5:1 r-BuOH-H2O (eq 22). A catalytic amount of osmium tetroxide was added and the resultant brown mixture was stirred for 72 h. Standard work-up and purification of the resultant material by flash chromatography provided the ketone 161 in 65% yield. 199 161 (65%) Spectroscopic analysis of product 161 confirmed that the required chemoselective oxidative cleavage of the exocyclic double bond in 199 had been achieved. The IR spectrum of the ketone 161 showed a sharp absorption band at 1703 cm - 1, characteristic 1 "\ of an aliphatic ketone function. The C NMR spectrum of ketone 161 displayed a carbonyl carbon signal at 8 216.3. Olefinic 1 3 C NMR resonances were observed at 8 137.7 and 138.2, confirming the integrity of the C-2 double bond in 161. 76 2.1.3.4. Preparation of Iodides 160 With ketone 161 in hand, the preparation of iodides 160 via sequential ethoxy carbonylation and halomethylation steps was investigated (eq 23). In 1983, Mander and coworkers reported an efficient method for effecting the alkoxycarbonylation of ketones with high C-selectivity (Scheme 40).82 Their method was based on the reaction of lithium enolates with alkyl cyanoformate reagents. For example, deprotonation of 2-methylcyclohexanone 218 with LDA generated the corresponding lithium enolate 219, which, when treated with methyl cyanoformate in the presence of HMPA, afforded the p-keto ester 220. O OLi O O N ^ C ^ O M e (86%) Scheme 40 77 The alkoxycarbonylation of ketone 161 following Mander's procedure was attempted several times with either LDA or LiHMDS as the base and either methyl or ethyl cyanoformate as the acylating reagent (eq 24). To our disappointment, the desired keto ester 221 was not produced and nearly quantitative recovery of starting material was noted in most attempts. R = Et or Me To determine whether or not the generation of the enolate of 161 had occurred, the ketone was again treated with base (LDA or LiHMDS) and the resulting solutions were treated with TMSC1. However, the corresponding enol silyl ether was not detected and, in each case, starting material was completely recovered. A rationale for the apparent difficulty in generating the requisite ketone enolate of 161 was based on steric 83 and stereoelectronic effects (Scheme 41). In accordance with Corey's proposal, the axial proton H a in 222, a partial structure representing ketone 161, should be more readily abstracted than H b , the equatorial proton, for stereoelectronic reasons. However, on the basis of possible steric interaction between the incoming base and the angular methyl group (Mea), the transition state energy for the deprotonation of 222 with a bulky base (LDA or LiHMDS) leading to enolate 223 was expected to be relatively high. 78 B u l k y b a s e Scheme 41 In 1990, Weiler and coworkers reported an efficient method of generating P-keto esters, which employed the relatively small bases NaH and K H . 8 4 For example, a solution of ketone 224 and dimethyl carbonate in THF was refluxed in the presence of several equivalents of sodium hydride and 0.1 equivalent of potassium hydride (eq 25). Upon work-up, the desired P-keto ester 225 was obtained in 87% yield. o o o N a H , K H , C O ( O M e ) 2 > ( ^ J < Q U Q ( 2 G ) T H F , re f lux 224 225 (87%) A diethyl carbonate version of Weiler's procedure84 was applied to our synthesis. A mixture of ketone 161 and diethyl carbonate in THF was refluxed with sodium hydride and a catalytic amount of potassium hydride (eq 26). Upon work-up and purification of the resultant material by flash chromatography, product 226 was obtained in 74 % yield as a 1:1 tautomeric mixture of enol ester 226a and keto ester 226b. 79 P M B O H ' H ' C 0 2 E t & N a H , K H ( E t O ) 2 C O 226a + (26) T H F , ref lux P M B O 161 H 0 2 E t P M B O 226b ( 7 4 % , 1:1 mix tu re) The structures of 226a and 226b were confirmed by spectroscopic methods. The JR spectrum of the mixture of tautomers 226 displayed an absorption at 1649 cm - 1, attributed to the ester carbonyl stretch of the enol ester 226b. In addition, absorptions at 1709 and 1743 cm - 1, derived from the ketone and ester carbonyls of the keto ester 226a, were also observed. The ! H NMR spectrum of the mixture of tautomers 226 displayed overlapping triplets (3H) at 8 1.29 and overlapping quartets (2H) at 8 4.19, attributed to the methyl and methylene protons of the ethoxyl moieties. A doublet of doublets (1H, J = 5.5, 13.5 Hz) at 8 3.68 was assigned to the H - l l proton of the a-keto ester tautomer 226a. The larger of the two coupling constants, 13.5 Hz, was attributed to the trans diaxial relationship between H - l 1 and the P-face H-12 proton. A singlet (1H) at 8 12.4 was attributed to the hydroxyl proton of the enol ester tautomer 226b. The assigned 1:1 ratio of 226a and 226b was supported by an observed 1:1 integral ratio for the signals at 8 3.68 and 12.4, attributed to H - l l in 226a and the hydroxyl proton in 226b, 80 respectively. The 1 3 C NMR resonances of the alkenic enol carbons in 226b appeared at 8 170.6 (C-10) and 94.8 (C-ll), respectively. The ester carbonyl carbons in 226a and 226b were displayed at 8 178.2and 173.5, respectively. The next transformation, an iodomethylation reaction, was to be carried out on the mixture of tautomers, 226a and 226b, to give iodides 160 (eq 27). 226b A literature search revealed a protocol by Clark and Miller for the selective C -alkylation of P-dicarbonyl compounds through the intermediacy of tetrabutylammonium o r fluoride salt complexes (Scheme 42). Treatment of a mixture of 227a and 227b with tetrabutylammonium fluoride (TBAF) in THF afforded the monosolvate 228. On the basis of several NMR studies on 228, the authors ruled out a proton transfer to the fluoride anion. They proposed that hydrogen-bonding between the fluoride anion and the 81 enolic hydroxyl proton results in a derealization of the charge on the fluoride ion into the enol 7t-system. This derealization appears to reduce the amount of enolic double bond character and increase the carbanion character at C - 3 . Treatment of 228 with iodomethane resulted in a highly C-selective alkylation, affording 229 in nearly quantitative yield. O O A A 227a TBAF Bu 4 N© + F 6 e ,H O H O T H F 0 0 5 ^ 227b 228 Mel, CHCI 3 , rt O O 229 (95%) Scheme 42 It was hoped that the high degree of C-selectivity noted in the aforementioned alkylation of a TBAF monosolvate with iodomethane could be reproduced in our study with diiodomethane as the electrophile. Thus, a solution of a 1:1 mixture of enol ester and keto ester tautomers 226 in TFfF was treated with a solution TBAF in THF. The 82 resultant solution of the corresponding monosolvate was treated with ten equivalents of diiodomethane, providing a 3:1 mixture of the epimeric iodides 160 after work-up (eq 28). 226b The structures of the epimeric iodides 160 were confirmed by spectroscopic methods. The JR spectrum of the mixture of iodides 160 exhibited the ketone and ester carbonyl stretching bands at 1708 and 1735 cm - 1, respectively. The X H NMR spectrum of the mixture of iodides 160 displayed overlapping multiplets (2H) between 8 4.36-4.45 attributed to the protons of the iodomethyl moieties. The assigned 3:1 ratio of the 160 isomers was supported by a 3:1 integral ratio of two X H NMR signals observed at 8 2.67 and 8 2.77, representing the angular ring-fusion protons (H-l) of the major and minor isomers, respectively. Since the mixture of isomers 160 was to be employed in the ensuing ring-expansion reaction, the respective relative configurations of the major and 83 minor isomers were not determined. The 1 3 C NMR spectrum of 160 displayed resonances at 8 169.3 and 210, assigned to the major isomer's ester and ketone carbonyl carbons, respectively. The 1 3 C NMR resonances for the ester and ketone carbonyl carbons of the minor isomer were observed at 8 168.4 and 208.6, respectively. 2.1.3.5. Preparation of Keto Ester 159 The next step in the synthesis of sarcodonin G involved a ring expansion of the a-halomethyl P-keto esters 160 to form the homologated y-keto ester 159 (eq 29). P M B O C 0 2 E t P M B O (29) OoEt 160 159 Concurrent studies by the research group of Dowd and that of Beckwith resulted in the discovery of a novel radical-mediated ring expansion of a-halomethyl P-keto esters. Dowd and coworkers reported studies on the Bu3SnH-mediated ring expansion of a-bromomethyl P-keto esters to the corresponding y-ketoester. ' As an example, treatment of bromide 230 with Bu3SnH and a catalytic amount of AIBN in refluxing benzene afforded y-keto ester 231 in a good yield (eq 30). Beckwith and coworkers reported an analogous ring expansion of iodide 232, affording y-keto ester 231, also in good yield (eq 30).88 84 O / X X } 2 E t B u 3 S n H , A I B N 230 (X = Br) 232 (X = I) P h H , re f lux (30 ) OoEt 231 7 3 % 231 7 6 % To our disappointment, attempts to effect BusSnH-mediated ring expansion reactions of iodides 1 6 0 , following Dowd's procedure,87 resulted in complex mixtures of unidentified products, (eq 31). Despite variations in the concentration of the iodides and addition time of the reagents, the desired ring-expansion product was not detected. P M B O ' C 0 2 E t A I B N , B u 3 S n H • P h H , re f lux c o m p l e x m ix tu re (31 ) 160 Recently, Hasegawa and coworkers reported an analogous SimVmediated ring-o n expansion reaction to produce homologated y-keto esters. For example, treatment of aromatic a-bromomethyl P-keto ester 233 with 2 equiv of SmJ.2 provided the ring-expansion product 234 (eq 32). However, addition of SmJ.2 to a solution of the aliphatic 85 a-bromomethyl p-keto ester 230, a substrate used in Dowd's study (vide supra)?7 provided the ring-expansion product 231 in relatively modest yield (eq 33). rt 230 231 ( 4 4 % ) The proposed mechanism of the SiruVmediated ring expansion of a-bromomethyl P-keto ester 230, which is similar to that proposed for the analogous BusSnH-mediated reactions, is depicted in Scheme 43. The first step involves single electron transfer from Sml2 to 230, providing the carbon radical 235. Attack of the resultant primary radical on to the ketone carbonyl function yields a cyclopropyloxy radical intermediate 236. Fragmentation of 236, which involves cleavage of the ring fusion bond, provides the seven-membered carbocycle 237. The resonance-stabilized radical 237 undergoes a one-electron transfer from a second equivalent of Sml2, to yield the samarium enolate 239. In the presence of methanol or water, the samarium enolate is protonated to generate y-keto ester 231. 86 O / II / Br XDoEt 230 S m l 2 ^\__co 2 235 O E t Et Et 237 238 236 Sml ; MeOH C 0 2 E t 239 231 Scheme 43 o n Hasegawa's Sml2-mediated ring-expansion protocol was applied to the mixture of iodides 160. A solution of the 3:1 mixture of epimeric iodides 160 in THF was treated with Sml2 (eq 34). Aqueous acidic work-up and purification of the resultant material by flash chromatography afforded the ring-expansion product, y-keto ester 159, as a single isomer in 71% yield. P M B O ° 1 ) S m l 2 , THF, rt C 0 2 E t 2) H + , H 2 0 P M B O (34) 160 159 (71%) 87 Evidence for the successful ring expansion of 160 was obtained by analysis of the *H and 1 3 C NMR spectra derived of the y-keto ester 159. The ] H NMR spectrum of 159 displayed a doublet of doublets (1H, J = 9.5 and 14 Hz) at 5 3.05 attributed to H-llp. The *H signals for H - l l a and H-12 were attributed to overlapping signals, observed between 5 2.77-2.84. The 1 3 C NMR spectrum of 159 exhibited resonances at 5 39.3 and 38.7, assigned to C - l l and C-12, respectively. HMQC correlations were noted between the H -11 and H-12 signals and the corresponding C - l l and C-12 signals. The 1 3 C NMR spectrum of 159 also displayed resonances at 5 174.5 and 215.0, representing the ester and ketone carbonyl carbons, respectively. H 159 The proposed P-orientation of the ethoxycarbonyl moiety in 159 was supported by *H NMR NOED experiments on 159. Irradiation at 8 2.65, a multiplet (1H) attributed the angular proton H - l , caused enhancement of a singlet at 5 1.06 assigned to H-18 and the doublet of doublets at 6 3.05 (J = 9.5, 14.4 Hz) assigned to H-llp. The larger (14.5 Hz) of the coupling constants for the doublet of doublets at 8 3.05 was attributed to the geminal coupling between H-llp and H - l l a whereas the smaller coupling (9.5 Hz) was 88 attributed to the coupling between H-llp and H-12. The magnitude of the latter coupling suggests that H-llp and H-12 have a trans diaxial-type relationship, which supports the proposed equatorial orientation of the ethoxycarbonyl group in 159. Although the configuration at C-12 in 159 was clearly established, the reasons for the stereoselective a-face protonation, exclusively affording intermediate 159, were not evident to us. 2.1.3.6. Preparation of Keto Aldehyde 240 With the ring-expansion step completed, the transformation of keto ester 159 into keto aldehyde 240 was investigated (eq 35). 159 240 The first step of this transformation was envisioned to be conversion of keto ester 159 to the corresponding keto aldehyde 158 (Scheme 44). Following a standard procedure, a solution of keto ester 159 in Et20 was treated with several equivalents of DIBALH. A suitable work-up procedure provided the mixture of diols 241. The crude 89 diols 241 were taken up in CH2CI2 and treated with Dess-Martin's periodinane reagent.90 After standard work-up and purification of the resultant material by flash chromatography, a 1:1 mixture of epimeric keto aldehydes 158 was obtained in 86% yield. Since the ratio of epimers varied with the duration of the work-up procedure, the C-12 epimerization of the highly enolizable aldehydes 158 presumably occurred during the aqueous NaHCC>3 wash. 158 (86%) Scheme 44 Evidence for the structure, and a measure of the ratio of the epimeric keto aldehydes 158, was obtained by standard spectroscopic methods. The IR spectrum of the mixture of keto aldehydes 158 exhibited ketone and aldehyde carbonyl stretching bands at 1726 and 1697 cm - 1, respectively. The 'H NMR spectrum of 158 displayed a pair of doublets at 8 9.60 and 9.63, attributed to the aldehydic proton signals. A 1:1 integral 90 ratio was observed for these aldehydic proton signals, indicating a 1:1 mixture of aldehydes. The 1 3 C NMR spectrum displayed resonances at 8 201.0 and 201.5, representing the aldehydic carbonyl carbons. The 1 3 C NMR resonances of the ketonic carbonyl carbons appeared at 8 214.9 and 215.8. The next step in the synthesis of sarcodonin G involved the introduction of a double bond in the seven-membered ring at C-12 in 158 to give 240 (eq 36). 158 240 Williams and coworkers have reported a mild method of preparing a,P-unsaturated aldehydes from the corresponding aldehydes via enamine derivatives.91 For example, conversion of aldehyde 242 to the corresponding enamine 243 was accomplished by heating a mixture of 242 and piperidine in benzene with removal of water with 3A molecular sieves (Scheme 45). Treatment of the enamine derivative 243 with phenylselenenyl chloride provided the intermediate 244, which afforded the corresponding a-phenylselenoaldehyde 245 after aqueous work-up. A periodate oxidation of 245 generated the corresponding selenoxide intermediate, which underwent a .yyn-elimination reaction to give the desired a,P-unsaturated aldehyde 246. 91 Scheme 45 It was hoped that William's mild oxidation protocol (vide supra) could be successfully applied to the mixture of aldehydes 158. On the basis of previous studies by Clinton and coworkers,92 the enamine formation step was expected to be chemoselective for the aldehyde function over that involving the ketone function in 158. Thus, aldehydes 158 were converted into the corresponding piperidine enamines 247 by treatment of the former with 5 equivalents of piperidine in refluxing benzene over 3A molecular sieves (Scheme 46). After removal of the solvent and excess piperidine, the resultant crude material was analyzed by ! H NMR spectroscopy, which confirmed the successful formation of enamines 247. The NMR spectrum of 247 displayed two singlets at 8 5.32 and 5.43, representing the olefinic enamine protons (H-20). Overlapping multiplets displayed between 8 1.4-1.6 and between 8 2.5-2.7 were attributed to the methylene protons of the piperidine rings. The crude enamines 247 were taken up in 92 THF and the solution was treated with freshly recrystallized phenylselenenyl chloride. After aqueous work-up, the resultant solution was concentrated and the a-phenylselenoaldehyde 248 was analyzed by ] H NMR spectroscopy. The *H NMR spectrum of crude 248 displayed an aldehydic proton signal at 8 9.19. Several multiplets between 8 7.2 and 7.7 were also observed, attributed to the aromatic protons of a phenylselenide moiety. The relative configuration at C-12 was not determined. 248 Scheme 46 The crude a-phenylselenoaldehyde 248 was taken up MeOH and the solution was treated with solid KIO4 and aqueous K H C O 3 (eq 37). Aqueous work-up and purification of the resultant material by flash chromatography afforded two isomeric a,p-unsaturated aldehydes, 249 and 240, in 75% and 2 % yields, respectively 93 (2%) The structure of 249 was confirmed by spectrometric analysis. The JR spectrum of 249 exhibited a broad band at 1697 cm - 1, representing the carbonyl stretches of the conjugated ketone and aldehyde functions. The ! H NMR spectrum of 249 displayed a 1-proton singlet at 8 9.56 (1H), attributed to the aldehydic H-20 proton. The ! H NMR signal for the olefinic C - l l proton in 249 was observed a singlet at 8 6.63 (1H). The lack of H-H coupling displayed by this olefinic signal supported the proposed C - l 1 position 13 of the double bond in 249. The , J C NMR resonances of the two alkene functions in 249 appeared at 8 136.9, 139.6, 144.2 and 146.1. The 1 3 C NMR resonances of the aldehydic (C-20) and ketonic (C-10) carbonyl carbons appeared at 8 194.7 and 209.6, respectively 94 The structure of the minor product, aldehyde 240, was also confirmed by spectrometric analysis. The ketone and aldehyde functions in 240 were represented by carbonyl stretches in IR spectrum at 1704 and 1688 cm - 1, respectively. The ketone stretch at 1704 cm - 1 is characteristic of an aliphatic ketone, supporting the C-12 position of the double bond in 240. The 'H NMR signals for H-13 and H-20 for 240 were observed as a multiplet at 5 6.63-6.68 and a singlet at 8 9.33, respectively. The multiplicity of the olefinic H-13 signal, attributed to coupling with the adjacent H-14 protons, supports the C-12 positioning of the double bond. The 'H NMR signals for the geminal H - l l protons were observed as a pair of doublets (7 = 14 Hz) at 8 3.46 and 3.72. The 1 3 C NMR resonances of the two alkene functions in 240 appeared at 8 135.7, 137.0, 137.9 and 153.7. The 1 3 C NMR resonances at 8 192.3 and 210.6 were attributed to the aldehydic and ketonic carbonyl carbons, respectively. The ratio of the two products 249 and 240 derived from the selenoxide elimination reaction can be rationalized by comparison of the relative acidities of the H -11 and H-13 protons of selenoxide 250 (eq 38). The H - l l protons in 250, which are a to a carbonyl group, are much more acidic than the H-13 protons since the former experience favorable overlap of the C-H sigma bonds with the 7i-bonds of the adjacent carbonyl function. Thus, the irreversible svn-elimination of the selenoxide moiety should favor the removal of the more acidic proton, H - l l , affording primarily a,P-unsaturated ketone 249. 95 250 249 Since the C-ring alkene function in the target structure, sarcodonin G, is positioned at C-12, the next task at hand involved an isomerization of 249, which displays a C - l l double bond, to afford 240, which displays the requisite C-12 double bond (eq 39). 249 240 In 1984, Mease and Hirsch reported a study on the syntheses and base-catalyzed isomerizations of medium-ring cycloalkenones.93 The effect of C-3 substituents on the base-catalyzed equilibration ratio of carbocycles 251 and 252 was investigated (Table 2). In the unsubstituted case, the product composition of the thermodynamically controlled isomerization of 251 or 252 significantly favored the 2-cycloheptenone isomer 251 (entry 96 1, Table 2). On the other hand, the isomerization of compounds with electron-withdrawing substituents at C-3 favored the 3-cycloheptenone isomer 252 (entries 2-4, Table 2). The authors' explanation for the substituent effect was based on the premise that the 3-cycloheptenone isomers 252 were more effectively conjugated with less conformational demands on the ring system than the corresponding 2-cycloheptenone isomers 251. Table 2. Isomerization of C-3 Substituted Cycloheptenones 251 and 252. 0 0 JL D B N , P h C H 3 ) reflux JL Ox — Ox 251 252 Entry Substituent (X) Composition % of 251 Composition % of 252 1 H 76.8 23.2 .2 C0 2 CH 3 16.8 83.2 3 CN 15.1 84.9 4 C O C H 3 20.7 79.3 The authors also suggested that the double bonds in the 2-cycloheptenone isomers 251 with electron-withdrawing substituents experience destabilization due to similar electronic interactions at both ends of the double bond (entries 2-4, Table 2). As an example, the contributing resonances structures available to 2-cycloheptenone 251 with an electron-withdrawing acyl substituent (entry 4, Table 2) place positives charges at opposite ends of the double bond (Scheme 47). 97 oe o o 251 (entry 4, Table 2) Scheme 47 On the basis of findings by Mease and Hirsch (vide supra), it was expected that 249 could be isomerized under thermodynamically controlled equilibrating conditions to 240. Thus, a benzene solution of 249 containing 2 equivalent of DBN was refluxed for 12 h (eq 40). After removal of solvent and purification of the resultant material by flash chromatography, the desired isomer 240 was isolated in nearly quantitative yield (96%). 249 240 (96%) 98 2.1.3.7. Preparation of (±)-Sarcodonin G (36) The preparation of (±)-sarcodonin G (36) from 240 involved removal of the PMB protecting group (eq 41). Following optimized conditions reported by Oikawa,75 a solution of keto aldehyde 240 in aqueous CH2CI2 was treated with DDQ. After a standard work-up procedure and purification of the resultant material by flash chromatography, (±)-sarcodonin G (36) was isolated in 92% yield.94 The synthetic (±)-sarcodonin G (36) exhibited spectral data in full accordance with those reported16 for the isolated natural product, (-)-sarcodonin G . 9 5 The IR, MS, 'H NMR and 1 3 C NMR spectra of the synthetic material and isolated material are compared in Tables 3, 4 and 5. The ! H NMR spectrum derived from synthetic (±)-sarcodonin G (36) is displayed in Fig. 1. 99 Table 3. Comparison of IR and MS Spectral Data for Synthetic (±)-Sarcodonin G (36) with those Reported16 for Natural (-)-Sarcodonin G (36). Data Synthetic (±)-Sarcodonin G (36) Natural (-)-Sarcodonin G (36) IRa (cm"1) 3445 3400 1703 1705 1640 1640 1450 1450 1376 1380 MS b (m/z) 316.2038 (DCI+) 316(EIMS) a The IR spectra were recorded using KBr pellets. b Exact mass calcd for C 2oH 2 80: 316.2039. 100 Table 4. Comparison of ! H NMR Data for Synthetic (±)-Sarcodonin G (36) (CDC13,400 MHz) with those Reported16 for Natural (-)-Sarcodonin G (36) (CDC13,250 MHz). 18 17 '1 20 CHO 36 s h o w i n g l U P A C - b a s e d n u m b e r i n g 18, "H 8 \ 7 I 6 1 4 \ do 13) \ 1 1 1 2 / M9 15CHO 36 s h o w i n g c y a t h a n e n u m b e r i n g 'HNMR (CDCI3,400 MHz) Signals Displayed" by Synthetic (±)-Sarcodonin G (36) 5 ppm (Multiplicity, J (Hz)) ! H Assignment11 H-x Reported ! H NMR (CDCI3,250 MHz) Signals Displayed by Natural (-)-Sarcodonin G (36) 8 ppm (Multiplicity, / (Hz)) Cyathane Numbering0 0.97 (d, 6.9) H-17 0.96 (d, 7.3) H-20 1.03 (s) H-19 1.01 (s) H-16 1.14 (s) H - l 8 1.12 (s) H-17 1.24-1.30 (m) 1.24 (dt, 3.9, 13.2) 1.46 (s) part of m at 1.59 1.49-1.55 (m) part of m at 1.59 1.58-1.70 (m) part of m at 1.59 1.95 (dt, 5, 13.4) 1.94 (dt, 5.3, 13.3) 2.21-2.40 (m) 2.31 (m) 2.69-2.80 (m) 2.74 (m) 2.98-3.08 (m) H-15 3.02 (sextet, 7.3) H - l 8 3.10-3.20 (m) 3.16 (dd, 13.4,6.4) 3.36 (brd, 12.6) 3.34 (d, 12) 3.41-3.51 (m) 3.42 (d, 13.9), 3.45 (d, 7.3) 3.71-3.75 (m) 3.72 (brd, 13.6) 6.70-6.73 (m) H-13 6.71 (m) H - l l 9.35 (s) H-20 9.31(s) H-15 a The difference between observed and reported 5 is likely due to different CDCI3 reference assignments. b Systematic IUPAC-based numbering system. c Ayer's cyathane numbering system. 3 101 Table 5. Comparison of 1 3 C NMR Data for Synthetic (±)-Sarcodonin G (36) (CDC13, 100.6 MHz) with those Reported16 MHz). 18 for Natural (-)-Sarcodonin G (36) (CDC13, 62.5 20 CHO 36 showing lUPAC-based numbering 1 5 C H O 36 showing cyathane numbering 1 3 C NMR (CDC13,100.6 MHz) Signals Displayed by Synthetic (±)-Sarcodonin G (36) 13 C Assignment3 C-x Reported 1 3 C NMR (CDCI3, 62.5 MHz) Signals Displayed by Natural (-)-Sarcodonin G (36) Cyathane Numberingb 8 ppm 8 ppm 12.7 C-19 12.7 C-16 15.6 C-17 15.6 C-20 24.8 C-19 24.8 C-17 28.6 28.6 32.1 32.1 32.7 32.7 34.1 34.1 35.2 35.2 35.5 35.5 37.7 37.7 39.7 39.5 49.8 49.8 55.3 55.3 65.8 C-16 65.8 C-19 135.9 (two signals 135.8,135.9 superimposed) 141.3 141.2 153.2 C - l 3 153.5 C - l l 192.2 C-20 192.4 C-15 210.3 C-10 210.6 C-14 Systematic IUPAC-based numbering system. b Ayer's cyathane numbering system. 3 102 103 2.1.4. Studies Towards the Synthesis of (±)-Cyathin A 4 After the completion of total synthesis of (±)-sarcodonin G (36), the synthesis of the structurally related cyathane diterpenoid (±)-cyathin A 4 (37)17 was attempted. Our synthetic approach to sarcodonin G (36), which addressed the construction of oxygenation and unsaturation pattern of the C-ring in the later stages of the route, was expected to provide an advanced branching point from which cyathin A 4 (37) could be derived. 2.1.4.1. Retrosynthetic Analysis Our proposed synthetic plan for the construction of cyathin A 4 (37) is outlined in Scheme 48. The target structure 37 should be available from compound 253 via ring opening of the epoxide function to give the corresponding allylic alcohol and cleavage of the PMB ether to generate the hydroxyl function. A chemo- and stereoselective epoxidation of C-12 double bond in 254 should provide epoxide 253. Finally, compound 104 253 should be available via a chemoselective reduction of aldehyde 240, an advanced intermediate available from our previously described total synthesis of sarcodonin G (see Section 2.1.3. vide supra). 254 240 Scheme 48 105 2.1.4.2. Preparation of Keto Alcohol 254 The first step in our proposed synthesis of cyathin A 4 involved a chemoselective reductive transformation of keto aldehyde 240 to give keto alcohol 254 (eq 42). This chemoselective reduction proved difficult to achieve owing to a small difference in reactivity between the aldehyde and ketone carbonyl functions (vide infra). 240 254 Both steric and stereoelectronic effects are important factors that may contribute to the relative reactivity of saturated and unsaturated carbonyl functions towards a hydride source (reducing agent).96 For steric reasons, carbonyls with one alkyl substituent (aldehydes) should be more readily reduced than those with two alkyl substituents (ketones). The steric bulk of a ketone's two alkyl substituents significantly restricts the approach of the nucleophile to the carbonyl and increases the energy of the transition state leading from a trigonal intermediate to the tetrahedral product. For stereoelectronic reasons, the carbonyl function of an a,P-unsaturated aldehyde or ketone function is significantly less electrophilic than that of the corresponding substance lacking the alkene function. The decreased electrophilicity of the former may be partially attributed to a 106 decrease in carbonyl double-bond character as illustrated by contributing resonance structures 255 (Scheme 49). 255 Scheme 49 On balance, the relative transition state energies involved in the reduction of the ketone function and unsaturated aldehyde function of compound 240 might be expected to be energetically similar, since the former is disfavored for steric reasons whereas the later is disfavored for stereoelectronic reasons. Diisobutylaluminum hydride (DIBALH) was the first reducing agent investigated for the chemoselective reduction of 240. Treatment of a cold (-78 °C) Et 20 solution of keto aldehyde 240 with one equivalent of DIBALH simply resulted in the complete recovery of starting material. Consequently, the DIBALH reduction of 240 was repeated in Et 20 at 0 °C, which provided a 46% yield of keto alcohol 254 and diol 256 in a 1:4 ratio, along with 40% recovered starting material (eq 43). The three compounds were easily separated by silica gel flash chromatography. 107 256 (46%, 1:4 ratio of 254:256) Evidence for the successful chemoselective reduction of keto aldehyde 240 to provide keto alcohol 254 was obtained by spectroscopic methods. The IR spectrum of 254 exhibited a broad signal at 3435 cm - 1, attributed to the OH stretching vibration. An absorption band observed at 1701 cm - 1 in the IR spectrum of 254 was characteristic of a saturated ketone. The ] H NMR spectrum of 254 displayed a multiplet (2H) between 5 3.95^ 1.08 assigned to the H-20 methylene protons. The 1 3 C NMR spectrum of 254 displayed resonances at 8 68.8 and 211.3, attributed to the C-20 methylene and the C-10 ketone carbons, respectively. 108 The structure of diol product 2 5 6 was also confirmed by spectroscopic analysis. The IR spectrum of 2 5 6 displayed a broad absorption at 3368 cm"1, representing the OH stretch. The ! H NMR signal for H-10 proton in 2 5 6 was observed at 8 3.42. A multiplet between 8 3.92-3.99 in the ! H NMR spectrum was assigned to the H-20 protons. The 13 C NMR resonance for the C-10 carbon in 2 5 6 was displayed at 8 75.3. The relative configuration of the C-10 hydroxyl moiety was confirmed by ! H NMR NOED experiments on 256 . Irradiation of the H-10 signal, displayed at 8 3.42 in the *H NMR of 256 , caused enhancement of a singlet at 8 0.89, attributed to the H-19 methyl protons. A reciprocal enhancement of the H-10 signal was observed upon irradiation of the H-19 signal. These results support the P-configuration of the C-10 hydroxyl moiety in 256 . On the basis of the low chemoselectivity displayed by the DIBALH reduction of 240 , an alternative reduction method was investigated. The Meerwein-Ponndorf-Verley (MPV) reduction with aluminum isopropoxide has been shown to reduce unsaturated 07 aldehydes to the corresponding allylic alcohols. The proposed mechanistic pathway of O S the aluminum isopropoxide MPV reduction is outlined in Scheme 50. Treatment of an aldehyde (257) with aluminum isopropoxide generates the cyclic coordination complex H Q 256 109 258, which undergoes intramolecular hydride transfer to afford the mixed alkoxide 259 and one equivalent of acetone. Hydrolysis of the mixed alkoxide 259 under acidic or basic conditions affords the corresponding alcohol 260. / - P r O (±L „ a c e t o n e H M e FT 257 258 / - P r O P ( H + nr HfY 9 H H H / - P r O H + or H O " i i i i in i | - j 259 260 Scheme 50 It was hoped that an aluminum isopropoxide-mediated MPV reduction of keto aldehyde 240 would be chemoselective for the aldehyde function. A solution of the keto aldehyde 240 in a 1:1 mixture of benzene and /-proponal was treated with one equivalent of aluminum isopropoxide and the resultant mixture was heated to reflux. Work-up and purification of the resultant material by flash chromatography provided a 1:2 ratio of keto alcohol 254 and diol 256 as well as 40% recovered starting material. Gratifyingly, an MPV reduction of 240 performed in 100% /-propanol at 60 °C afforded an 87% yield of 254 and 256 with an improved ratio of 1.5:1 in favor of the desired keto alcohol 254 (Scheme 51). The undesired diol 256 was subsequently oxidized with Dess-Martin periodinane reagent90 in 86% yield and the resultant keto aldehyde 240 recycled through 110 the MPV reduction. After one cycle, the desired alcohol 254 was obtained in 70% yield from keto aldehyde 240. CH 2 CI 2 , rt (86%) (87%, 1.5:1 ratio of 254:256) Scheme 51 2.1.4.3. Attempted Preparation of Diol 261 With the keto alcohol 254 in hand, the preparation of diol 261 via the epoxide intermediate 253 was investigated (Scheme 52). The first transformation would require an epoxidation method that was (a) chemoselective for the C-12 double bond over the C -I l l 2 double bond in 254, and (b) stereoselective for the a-face of the C-12 double bond. It was anticipated that the hydroxymethyl appendage at C-12, through coordination with a suitable reagent, might help chemoselectively direct the C-12 alkene epoxidation. Based on molecular models, an approach to the a-face of the C-12 alkene appeared slightly less sterically hindered. Thus, it was hoped that an epoxidation of 254 would favour formation of the a-epoxide 253. The next step would involve a ring opening of the epoxide function via a base-mediated deprotonation a to the C-10 ketone function, with subsequent P-elimination of the epoxide oxygen anion. Work-up should then afford diol 261. 254 253 261 Scheme 52 An epoxidation similar to that required for our synthesis (vide supra) was previously noted by Snider and co-workers in their synthetic studies directed towards the diterpenoid allocyathin B 2 (see Section 2.1.2.1., vide supra).56 Their account of several abandoned synthetic routes included the selective epoxidation of intermediate 262 (Scheme 53). Treatment of 262 with r-BuOOH and a catalytic amount of VO(acac)2 112 resulted in a hydroxyl-directed epoxidation of the C-ring double bond, providing a mixture of epoxides 263. This material, which was too acid-sensitive for purification by silica gel chromatography, was treated with TBDMSC1 to afford the corresponding silyl ether epoxides 264 and 265 in a 3:1 ratio. Evidently, the epoxidation step (262 to 263) was threefold stereoselective for the a-face of the C-ring double bond in 262. 264 (3:1 ratio) 265 Scheme 53 It was hoped that a VO(acac)2/f-BuOOH hydroxyl-directed epoxidation of our intermediate 254 would display both the chemo- (ring C double bond vs ring A double bond) and stereoselectivity (a- vs P-face) reported by Snider and coworkers (vide supra). Thus, a cool (0 °C) solution of alkene 254 and r-BuOOH in CH2CI2 was treated with a catalytic amount of VO(acac)2 (Scheme 54)." The resultant mixture was stirred for 2 h at 113 0 ° C . Work-up, followed by attempted purification of a portion of the resultant material by flash chromatography on silica gel, led to product decomposition. lH N M R spectral analysis of the remaining crude material revealed the presence of only one major product, which was subsequently shown to possess structure 264, the product of a a-face epoxidation of 254. Successful reaction of the C - 1 2 alkene in 264 was supported by of the ' H N M R spectroscopic analysis of the product 266. The ' H N M R spectrum derived from the latter did not display signals in the olefinic region (8 5-7). Further evidence supporting the epoxidation was obtained upon analysis of the H - 2 0 methylene signal, observed as a multiplet between 8 4 .8^1 .9 in the * H N M R spectrum of 266. The corresponding signal for the H - 2 0 protons in the lH N M R spectrum of the starting material 254 had been noted at 8 3 . 9 - 4 . 1 . The downfield shift of the signal for the H - 2 0 protons in 266, relative to that for the H - 2 0 protons in 254, was attributed to the newly introduced epoxide function in 266. Evidence supporting the assigned p-configuration of the epoxide in 266 was later obtained through chemical transformations and spectroscopic correlations (vide infra). Without further purification, a benzene solution of crude 266 was treated with D B N , resulting in a ring opening of the epoxide function. Upon solvent removal under reduced pressure and purification of the resulting material by flash chromatography, the allylic alcohol 267 was obtained in 6 5 % yield from 254. 114 267 (65% from 203) Scheme 54 The constitutional structure of 267 was supported by spectroscopic analysis. The IR spectrum of 267 exhibited a broad absorption at 3402 cm - 1 and a carbonyl stretch at 1665 cm - 1, attributed to the hydroxyl and ketone functions, respectively. The ! H NMR spectrum of 267 displayed a singlet (1H) at 8 5.96, representing the H - l l olefinic proton. The 1 3 C NMR resonance for the C-10 ketone carbon in 267 was observed at 8 210.1. ! H NMR NOED experiments preformed on 267, in hopes of confirming the relative configuration of the C-l3 hydroxyl moiety, were not conclusive. Nevertheless, on the basis of spectroscopic analysis of a derivative of 267 (vide infra), the C-l3 hydroxyl moiety was assigned a p-configuration. The PMB protecting group in 267 was removed by treatment of a solution of this material in aqueous CH2C12 with DDQ. Standard work-up and purification of the resultant material by flash chromatography provided triol 268, the C-13 epimer of the target structure, cyathin A 4 (eq 44). 115 The successful removal of the PMB group in 267 was supported by ! H NMR analysis of the product, triol 268. The lack of signals in the aromatic region of the ! H NMR spectrum of 268 showed that the PMB group was no longer present. The signals in the ! H NMR spectrum derived from triol 268 (Table 6) and those reported16 for its C-l3 epimer, cyathin A 4 (37), were compared. The notable differences in the chemical shifts of corresponding protons in 268 and 37 were attributed to the C-l3 epimeric relationship of the two substances. R e p o r t e d 1 H N M R (CDCI 3 , 100 M H z ) S i g n a l s 8 (Mul t ip l ic i ty , J (Hz ) ) : 5.98 (m) 4.40 (m) 4.21 (m) 3.38 (d,6) 0.93 (s) 0.96 (s) 116 Table 6. 'H NMR Data for Synthetic (±)-Triol 268 (CDC13,400 MHz). 18 \ J HJmf/^  ujd»<<H J ) i i H O H O \ H O ^ 2 0 268 *H assignment3 H-x 'HNMR (CDCl3,400MHz) Signals Displayed by Triol 268 8 (Multiplicity, J (Hz)) H-17 0.96 (d, 6.7) H-19 1.04 (s) H - l 8 1.12 (s) 1.43-1.51 (m) 1.53-1.69 (m) 1.81 (dt, 4.9, 13.4) 1.97-2.07 (m) 2.19-2.37 (m) 2.63-2.70 (m) 3.07-3.15 (m) H-16 3.25-3.31 (m) 3.37-3.52 (m) H-20 4.24-4.42 (m) H-13 4.55-4.59 (m) H - l l 6.00 (s) a Systematic IUPAC-based numbering system. Evidently, epoxidation of 254 proceeded with high P-face stereoselectivity to give epoxide 266, which ultimately afforded 267 (Scheme 55). However, the main contributing factors responsible for this undesired selectivity are not fully understood. With only limited amounts of intermediate 254 available, the search for an a-face stereoselective epoxidation method to afford 261 from 254 (path a) via an a-epoxide was not pursued. As an alternative, the preparation of 261 was approached via a Mitsunobu100 117 inversion of the C-13 hydroxyl group in 267 (path b). To minimize the steps required for this transformation, the primary hydroxyl function at C-20 was not protected from the Mitsunobu reaction. 20 261 267 Scheme 55 Following optimized procedures developed by Martin and Dodge,101 a solution of the diol 267 in benzene was treated with PhsP and p-nitrobenzoic acid. Diethyl azodicarboxylate (DEAD) was slowly added and the mixture was stirred for 18 h at room temperature. The solvent was removed and the resulting material was purified by flash chromatography to give the desired diester 269 in 70% yield. 118 P M B O H JO° P h 3P> DEAD HO 20 p-nitrobenzoic acid P h H , rt P N B O P N B (45) 267 269 (70%) The assigned structure of diester 269 was supported by standard spectrometric analysis. The IR spectrum of 269 exhibited absorptions at 1729 and 1688 cm - 1, representing the ester and ketone carbonyl stretches, respectively. Sharp absorptions were also observed at 1530 and 1270 cm - 1, characteristic of aromatic nitro groups. The ] H NMR spectrum of 269 displayed doublets at 5 8.06 (2H, J = 8.2 Hz) and 5 8.16 (2H, J = 8.6 Hz) and a multiplet (4H) between 8 8.20-8.29, attributed to the aromatic protons of the para-substituted nitrobenzoate esters. A multiplet (1H) observed between 5 5.70-5.78 in the ! H NMR spectrum of 269 was attributed to the allylic proton on C-13. Unfortunately, the C44H44N2O11 molecular formula of 269 could not be confirmed by mass spectroscopic analysis. Although the mass spectra of 269 were obtained by DCI+ with isobutene and NH3 and by LSMIS with thioglycerol and CHCI3 matrix, a parent ion representing a structure with C44H44N2O11 molecular formula was not detected. The inability to detect the requisite parent molecular ion for 269 was attributed to the labile nature of the p-nitrobenzoate ester moieties under ionization conditions. 119 The assigned relative configuration of the p-nitrobenzoyl moiety at C-l3 in 269 was supported by ] H NMR NOE difference experiments. Irradiation of the signal at 8 2.95 in the 'H NMR of 269, a broad doublet attributed to the angular proton H - l , caused enhancement of a singlet at 8 1.08 and a multiplet between 8 5.70-5.78, assigned to H-18 and H-13, respectively. Irradiation of the H-18 and H-13 signals both caused enhancement of the H - l signal. These results support the assigned a relative configuration of the p-nitrobenzoyl moiety at C-l3 in 269. 120 The target structure, cyathin A 4 (37), was expected to be available from 269 via saponification of the two PNB esters in 269 and subsequent removal of the PMB group (Scheme 56). 37 Scheme 56 With only limited amounts of substance 269 in hand, the first step, a saponification reaction, was attempted. To our disappointment, treatment of a MeOH solution of diester 269 with K2CO3 afforded, upon work-up, a complex mixture of unidentified products (eq 46). The saponification step was also attempted with N a 2 C 0 3 in MeOH but these conditions also led to a complex mixture of products. 121 c o m p l e x (46) m i x t u r e s 269 Unfortunately, limitations in available advanced materials prevented further investigations into the preparation of diol 261. On the basis of time restraints, a scale-up preparation of these advanced intermediates was not pursued and our synthetic study geared towards the natural product cyathin A 4 (37) was abandoned. 122 2.2. Studies Towards Presilphiperfolane Sesquiterpenoid Synthesis 2.2.1. Background: Presilphiperfolane Isolation, Biogenesis and Biological Activity The presilphiperfolane family of sesquiterpenoids share the common carbon skeleton 270, which displays an unusual tricyclo[5.3.1.04'n]undecane framework. The IUPAC-based numbering and presilphiperfolane natural product numbering schemes are illustrated in 270 and 271, respectively.* In 1981, Bohlmann and coworkers reported the first structural elucidation of a member of the presilphiperfolane family, presilphiperfoan-8-ol (272), from the California coastal succulent Eriophyllum staechadifolium.102 In 1996, the research group of Weyerstahl and that of Marco concurrently reported the isolation of presilphiperfolan-9-ol (53) from Artemisia laciniata and from Artemisia 9ft 1 (YK chamaemelifolia, respectively. ' * In the text of this thesis, the presilphiperfolane numbering system 271 is used in most descriptions of presilphiperfolane-related natural products and the IUPAC-based numbering system 270 is used to describe the synthetic intermediates. The experimental section of this thesis contains IUPAC names for the synthetic intermediates. 123 Bohlmann and coworkers have proposed a biogenetic pathway for the formation of presilphiperfolane natural products from (£,,£')-farnesyl diphosphate (273) (Schemes 57 and 58).104 Sequential cationic cyclizations of salt 274 provide the caryophyllen-8-yl cation 276 via 11-membered macrocycle intermediate 275 (Scheme 57). Cyclobutylcarbinyl ring expansion of 276 generates a cyclopentyl cation with a bridging (£)-3-hexenyl chain, 277. Cationic cyclization of 277 affords the tricyclo[5.3.1.04'n]undecyl cation 278, which displays the presilphiperfolane skeleton. 277 278 Scheme 57 124 The natural product presilphiperfolan-9-ol (53) presumably arises directly from cation 278 via an oxygenation step (Scheme 58). On the other hand, a 1,3-hydride shift in 278 generates cation 279 (path a), the precursor for presilphiperfolan-8-ol (2). The biogenetic pathway leading to the presilphiperfolanes is common to several structurally related families of sesquiterpenes, including the silphiperfolanes, the silphinanes and the camaroonanes.102'104,105 The proposed biogenetic pathways to these families share the advanced intermediate 279. 1,2-Alkyl shifts involving cation 279 gives the cameroonane (280) (path b) or silphinane (281) (path c) skeletons. A 1,2-methyl shift in the cameroonane cation 280 affords the silphiperfolane skeleton (282) (path d). 282 Scheme 58 125 Although several members of the presilphiperfolane and related families of sesquiterpenoids exhibit pleasant odiferous qualities, only a select few display pharmaceutically applicable biological activities. As an example, two sesquiterpenoids isolated from Botrytis cinerea, botrydial (283) and dihydoxybotrydial (284), demonstrate phytotoxic and antibiotic properties.106 283 284 Studies107"109 by Hanson and coworkers on the metabolites 283 and 284 support the biosynthetic pathway proposed by Bohlmann and coworkers (vide supra). The fungus Botrytis cinerea was fed [1-13C]- and [2-13C]-acetate as well as [4,5-13C2]-mevalonate, and the labeling patterns of the resulting metabolites were investigated. The pattern of incorporation of three isoprene units, highlighted in 285, into the carbon framework of 286 was rationalized via a sequence of cationic cyclizations in agreement with those proposed by Bohlmann (eq 47). Coates and coworkers have also reported several studies on the presilphiperfolanes biogenesis. 1 1 0 - 1 1 3 126 2.2.2. Previous Syntheses In 2000, Coates and coworkers reported114 the first total synthesis of (±)-cameroonan- 7-ol105 (293) from the known115'116 bicyclic enone 287. The key step in this synthesis involved an intramolecular alkylation reaction (Scheme 59). Enone 287 was subjected to a Sakurai reaction117 with (Z)-2-buten-l-yltrimethylsilane and TiCU, affording a 2:1 mixture of epimers 288. A photochemical free radical hydrobromination of this mixture yielded the corresponding bromides 289. Base-mediated cyclization of these bromides afforded two cyclic ketones, 290 and 291. The desired isomer, ketone 291, was reduced with LiAlFLt, yielding the target structure (±)-cameroonan-7-ol 293 and its epimer, 292, in a 1.4:1 ratio. Reagents: a) (Z)-2-buten-l-yltrimethylsilane, TiCl 4; b) HBr, hu; c) ?-BuOK; d) LiAlELt. Scheme 59 127 In 1996, Weyerstahl and coworkers reported the first total synthesis of (±)-presilphiperfolan-9-ol (53) (Schemes 60 and 61). The 16-step synthesis of (±)-53 commenced with the conversion of the pentenoic acid 294 to the corresponding acid chloride, which was subsequently treated with AICI3 to afford the cyclopentenone 295 (Scheme 60). Copper(I)-catalyzed conjugate addition of the Grignard reagent derived from 2-(2-bromoethyl)-l,3-dioxane to enone 295 provided ketone 296 in good yield. Acid hydrolysis of 296, followed by an aldol cyclization of the resultant keto aldehyde, gave a mixture of hydroxy ketones 297. Jones oxidation of this mixture provided diketone 298, which was transformed to hydroxy ketone 299 in three steps. Conversion of 299 to the corresponding mesylates, followed by a DBU-mediated elimination reaction, gave enone 300. TiCl4-mediated Sakurai conjugate allylation of enone 300 with allyltrimethylsilane provided ketone 301. 294 295 296 297 298 299 300 301 Reagents: a) (COCl)2; AICI3; b) 2-[(l,3)-dioxan-2-yl]-l-ethylmagnesium bromide, Cui, TMEDA, TMSC1; c) acetone, HC1; d) Cr0 3, H 2S0 4 , H 2 0; e) (CH2OH)2, HC(OMe)3, TsOH; f) L J A I H 4 ; g) dil. HC1; h) MsCl, Et3N; DBU; i) allyltrimethylsilane, TiCl 4 . Scheme 60 128 The final synthetic steps leading to (±)-presilphiperfolan-9-ol (53) are illustrated in Scheme 61. Benzoyl peroxide-mediated addition of HBr to enone 301 afforded bromide 302. The Wittig salt derived from bromide 302 was treated with base, resulting in a cyclization that gave the tricyclic alkene 303. A stereoselective a-epoxidation of 303, followed by a ZnBr2-mediated rearrangement of the resultant epoxide 304, afforded norpresilphiperfolan-9-one 305 and its epimer 306. Treatment of 305 with Lombardo's reagent (CH2Br2/Zn/TiCl4) provided the corresponding alkene 307, which was oxidized with mCPBA to give epoxides 308 and 309 in a 3:2 ratio. LiAlEL, reduction of epoxide 308 yielded the target structure, (±)-presilphiperfolan-9-ol (53). 301 302 303 + 309 a - e p o x i d e Reagents: a) HBr, Bz202;b) Ph3P; NaHMDS; c) mCPBA; d) ZnBr2; e) Zn, CH 2Br 2, TiCl 4; f) mCPBA; g) LiAia.. Scheme 61 129 2.2.3. Studies Towards a Formal Synthesis of (±)-Presilphiperfolan-9-ol Our synthetic studies directed towards the formal synthesis of (±)-118 presilphiperfolan-9-ol (53) relied on a proposed radical-mediated tandem cyclization sequence in the construction of the tricyclo[5.3.1.0411]undecane carbon framework (vide infra). Our proposed tandem cyclization sequence commences with the secondary radical 51. The first reaction is a 5-exo cyclization of the 5-hexenyl-type radical 51, which was anticipated to result in the cw-fused 5-5 bicyclic radical 310 (Scheme 62). The 6-heptynyl-type radical 310 was expected to cyclize in a 6-exo fashion, generating the ef-fused bridge in 311. A more detailed analysis of the proposed transition states for the tandem cyclizations and the expected relative configurations for the ring-fusion centers will follow. =^ OH 53 51 310 311 Scheme 62 130 2.2.3.1. Retrosynthetic Analysis Our retrosynthetic plan for the formal synthesis of (±)-presilphiperfolan-9ol (53) is outlined in Scheme 63. The target compound 53 is readily available from the P-isomer of 9ft alkenes 52, as reported by Weyerstahl and coworkers (see Section 2.2.2., vide supra). Treatment of xanthates 50 with Bu3SnH and AIBN should provide the corresponding secondary alkyl radical, the first intermediate in our proposed radical-mediated tandem cyclization leading to alkenes 52 (vide supra). The cyclization precursors, xanthates 50, should be readily derived from alcohols 312. 1,2-Addition of the alkyllithium species derived from the known119 iodide 313 to aldehyde 314 was not expected to be stereoselective and should afford a mixture of alcohols 312. A sequence of chain homologation and a-methylation steps should provide aldehyde 314 from ketone 315. Finally, ketone 315 should be available from enone 49 via a sequence of steps that 19ft include a Carroll [3,3] rearrangement. 53 52 50 Scheme 63 132 2.2.3.2. Preparation of Ketone 315 The first synthetic sequence in our study involved the preparation of ketone 315 from 3-methyl-2-cyclopenten-l-one (49) (eq 48). 49 315 A racemic mixture of the known121"125 alcohol 316 was prepared from commercially available enone 49 by selective 1,2-reduction with CeCl3 and NaBHU (eq 49).126 Alcohol 316, obtained in 81% yield upon purification by flash chromatography, was analyzed by standard spectrometric methods. All spectral data derived from 316 were identical to those reported in the literature.125 CeCI 3 ,NaBH 4 MeOH, -78 °C to 0 °C (49) 49 316 (81%) In 1984, Wilson and coworkers reported127 a dianionic version of the well-known Carroll rearrangement120 of allylic P-keto esters. A THF solution of allylic P-keto ester 133 317 and its tautomer 318 was treated with two equivalents of LDA (Scheme 64). The resultant solution of dianion 319 was heated to 65 °C, generating, after a suitable work-up procedure, the [3,3] rearrangement product, P-keto acid 321. Heating a solution of 321 in CCI4 resulted in a decarboxylation, affording alkenone 322. 320 321 322 Scheme 64 Wilson and coworkers also developed127 an efficient preparation of the allylic P-keto ester 317 from the corresponding allylic alcohol 323 (eq 50). Treatment of a cold (-20 °C) solution of 323 in Et20 with diketene (324), followed by the addition of a catalytic amount of DMAP, provided the corresponding allylic P-keto ester 317 in good yield. The active acylating reagent, compound 325, is formed in-situ by reaction of DMAP and diketene (324), followed by protonation. 134 + )H 323 324 D M A P E t 2 0 , -20 °C ^ N M e 2 o 0 325 The sequence developed by Wilson and coworkers for the preparation of allylic esters and their subsequent Carroll rearrangement was applied to alcohol 316 (Scheme 65). An ethereal solution of 316 and diketene (324) was treated with a catalytic amount of DMAP and the resultant allylic ester 326 was subsequently treated 2.5 equiv. of LDA. Dianion 327 underwent a [3,3] sigmatropic rearrangement to dianion 328, providing keto acid 329 after work-up. A solution of the crude keto acid 329 in CCI4 was refluxed, affording the desired ketone 315. 324 + OH D M A P 2.5 e q u i v . L D A E t 2 0 , -20°C * ^ \ / -78°C to rt 326 327 316 h e a t CCL ^ O 328 329 Scheme 65 315 (77% f r o m 316) 135 The structure of ketone 315 was supported by standard spectrometric analysis. The JR spectrum of 315 displayed a sharp absorption at 1718 cm - 1, characteristic of an aliphatic ketone. The *H NMR spectrum of 315 exhibited a 3-proton singlet at 5 2.11 and a 2-proton singlet at 8 2.49, attributed to the H-3 and H - l , respectively. The J H NMR spectrum of 315 also exhibited overlapping multiplets between 8 5.61-5.68, attributed to the olefinic protons. The 1 3 C NMR resonances for the carbonyl and olefinic carbons of 315 were observed at 8 208.3 and at 8 129.1 and 139.0, respectively. 2.2.3.3. Preparation of Aldehyde 314 With ketone 315 in hand, the preparation of 314 via a sequence of chain-homologation and methylation steps was investigated (eq 51). 315 314 The first transformation of this sequence was attempted with the modified Wittig 128 reagent 331, which was prepared by treatment of a cold (0 °C) solution of 330 in THF with LDA (eq52). 136 C I © e P h 3 P v X>Me LDA © P h g P ^ O M e (52) 0 331 THF, O °C 330 A cold (0 °C) solution of 331 was treated with ketone 315, was stirred for 1 h at 0 °C and then was allowed to warm to room temperature (Scheme 66). After aqueous work-up, the resultant crude mixture of enol ethers 332 was subjected to hydrolysis conditions (TFA in refluxing aqueous CHCI3), affording a 1:1 mixture of aldehydes 333, in 72% yield. P 331 332 C H O reflux 333 (72%) Scheme 66 137 Evidence for the successful carbonyl homologation of ketone 315 was obtained by spectroscopic analysis of aldehydes 333. The IR spectrum of 333 displayed an absorption at 1735 cm - 1, characteristic of aldehydic carbonyls. The ! H NMR spectral signals of the aldehydic protons in 333 were observed as doublets at 8 9.51 (J = 2.9 Hz) and 9.53 (J = 2.7 Hz). Resonances at 8 205.2 and 205.3 in the 1 3 C NMR spectrum of 333 were attributed to the aldehydic carbons. The 1 3 C NMR resonances for the C-2' and C-3' olefinic carbons in 333 were observed at 8 139.2 and 139.5 and at 8 129.4 and 129.9, respectively. With aldehydes 333 in hand, the preparation of the corresponding a,a-dimethyl aldehyde 314 was straightforward (eq 53). Aldehydes 333 were added to a THF solution of potassium hydride and the resultant enolate solution was treated with methyl iodide at 129 0 °C. Work-up and purification of the resulting material by flash chromatography provided the desired aldehyde 314 in 90% yield. The successful a-methylation of 333 was supported by ! H NMR spectroscopic analysis of the product 314. The *H NMR spectrum derived from 314 exhibited 3-proton singlets at 8 1.01 and 1.04 attributed to the H-4 and H-5 methyl protons. The *H NMR spectral resonance for the aldehydic proton in 333 was observed as a 1-proton singlet at 8 9.44. 138 2.2.3.4. Preparation of the Tandem Cyclization Precursors, Xanthates 50 Xanthates 50, the tandem cyclization precursors, were readily prepared in three steps from aldehyde 314 (vide infra) (eq 54). Following a protocol developed by Negishi and coworkers, a cold (-78 °C) Et 20 solution of the known119 iodide 313 was treated with 2.5 equiv. of r-BuLi and the resulting mixture was warmed to 0 °C, generating the corresponding alkyllithium species (eq 55). Upon cooling to -78 °C, the solution of the alkyllithium was treated with aldehyde 314, affording, after a work-up step, a 1:1 mixture of alcohols 312. 312 314 (76%, 1:1 ratio) The 1:1 mixture alcohols 312, inseparable by silica gel flash chromatography, was analyzed by NMR spectroscopy. The lH NMR spectrum of 312 displayed overlapping 1-139 proton multiplets between 8 3.3-3.45, attributed to H-3. The C-3 carbons gave rise to resonances at 8 78.4 and 79.2 in the 1 3 C NMR spectrum of 312. The preparation of xanthates 50 from alcohols 312 was straightforward. A solution of alcohols 312 in THF was added to a THF solution of NaH and the resultant mixture was treated with imidazole and carbon disulfide (eq 56). The resultant solution of dithiocarboxylate anions was treated with methyl iodide, affording the corresponding xanthates. The TMS function on the alkyne moiety was removed by treatment a THF-MeOH solution of the latter material with TBAF, affording the desilylation products 50. The structures of 50 were confirmed by 'H NMR spectroscopic analysis. The ] H NMR spectrum of xanthates 50 displayed two 3-proton singlets at 8 2.55 and 2.57, representing the methyls in the xanthates moieties. The H-3 protons in xanthates 50 were observed as overlapping multiplets between 8 5.79-5.85, characteristic of secondary xanthates. — T M S 1) N a H , i m i d a z o l e , C S 2 , T H F , ref lux; M e l (81%) (56) 2) T B A F , T H F - M e O H , rt (90%) 312 50 140 2.2.3.5. Tandem Free-radical Cyclization With xanthates 50 in hand, attention was turned to the proposed tandem radical-mediated cyclization (eq 57). The xanthate functional group has traditionally served as convenient derivative for the Barton-McCombie deoxygenation of alcohols (Scheme 67). In 1975, Barton and 131 McCombie reported that xanthates (335), readily derived from the corresponding alcohols (334), generate the reduced products (336) via BusSnH-mediated processes that proceed by way of radical intermediates. (57) 50 52 ROH RH 334 335 336 Scheme 67 141 The proposed mechanistic pathway131'132 for the Barton-McCombie radical-mediated reduction of xanthates is illustrated in Scheme 68. The stannyl radical, which displays a high affinity for sulfur, attacks the thiocarbonyl group in xanthate 335, generating radical adduct 337. A (3-scission of the carbon-oxygen bond in 337 provides the alkyl radical 339 and the co-product 338, which is unstable with respect to elimination of carbon oxysufide 340. Abstraction by the alkyl radical 339 of a hydrogen atom from BusSnH generates the desired alkane 336 and regenerates the stannyl radical, which results in propagation of the chain reaction. 336 Scheme 68 142 The radical intermediate obtained from treatment of xanthate-type derivatives with Bu3SnH/AIBN have also been used for reactions other than direct reduction by hydrogen atom abstraction.133'134 For example, in 1990, Rawal and coworkers reported135 the preparation of carbocyclic systems from xanthates via radical-induced epoxide fragmentation (Scheme 69). Xanthate 342 was converted to the corresponding radical 343, which fragmented to the oxy-radical 344. Intramolecular hydrogen abstraction converted 344 into the radical 345. A 5-exo cyclization of the 5-hexenyl radical 345 generated a mixture of the ds-fused bicyclic intermediates 346, which yielded 347 upon hydrogen atom abstraction. S 342 343 344 O H O H O H 345 346 347 Scheme 69 The proposed tandem reactions of the radical intermediate 51, obtained by the Barton-McCombie-type reaction of xanthates 50, are outlined in Scheme 70. In 143 accordance with guidelines136 developed for the stereochemical predictions of radical-mediated cyclizations, a 5-exo cyclization of the 5-hexenyl-type radical in 51 was anticipated to form the ds-fused 5-5 bicyclic intermediate 310. The second reaction, a 6-exo-type cyclization of the 6-heptynyl-type radical in 310, was expected to result in a six-membered ring, as displayed in 311. Finally, hydrogen abstraction by 311 would afford the tricycles 52. Scheme 70 The first cyclization reaction in the proposed sequence (vide supra) is analogous to that of a tandem sequence developed by Curran and coworkers for the total synthesis of (±)-hirsutene (351) (Scheme 71).137 Thus, treatment of iodide 348 with Bu3SnH and AIBN generated the corresponding 5-hexenyl-type radical 349, which underwent a 5-exo 144 cyclization to give the cw-fused 5-5 bicyclic intermediate 350. A 5-exo cyclization of the 5-hexynyl-type radical 350, followed by hydrogen abstraction, afforded (±)-hirsutene (351). 348 Bu 3 SnH, AIBN PhH, reflux 349 Scheme 71 Predictions and rationalizations of stereoselectivity in 5-exo hexenyl cyclization are generally based on the Beckwith-Houk transition state model.138"141 In brief, the Beckwith-Houk model involves a combination of the proposed transition structure for bimolecular radical additions to alkenes and the principles of conformational analysis, which support the postulated chair- and boat-like transition state structures, 352 and 353, for the cyclization of acyclic substrates. 145 352 353 Radical cyclizations resulting in the formation of a 5-5- or smaller fused ring-systems favour chair-like transition-structures and usually form cis- rather than trans-136 fused products. The first step of our proposed tandem sequence, represented by the cyclization of 354 to 356 in Scheme 72, was anticipated to involve a transition state resembling 355 in which Ri = H and R 2 = tethered acetylene or vice versa. $ 354 355 Scheme 72 356 Upon treatment with Bu3SnH/AIBN, the mixture of xanthates 50 was expected to form the secondary radical intermediate 51 (Scheme 73). On the basis of molecular modeling and conformational analysis, the preferred transition state for the cyclization of 51 was expected to resemble structures 51a or 51b, leading to the diastereomeric intermediates, 310 and 357, respectively. The main difference between 51a and 51b is the orientation of the substituents on the radical-bearing carbon. In 51a, the smaller substituent (hydrogen) is positioned over the cyclopentenyl ring. Conversely, in 51b, the larger substituent lies over the ring. On the basis of the possible steric interactions between the larger substituent and the ring-protons in 51b, the transition state for the 146 cyclization of 51 was anticipated to favour a geometry resembling 51a, leading to radical 310. Scheme 73 For the second step of the proposed tandem sequence, a 6-exo cyclization of 6-heptynyl radical 310, the transition structures leading from 310a and 310b to give intermediates 358 and 359, respectively, were considered (Scheme 74). Conformational analysis and molecular modeling studies of these transition structures suggested that a 147 mixture of isomers, favouring 360 via 359, might be obtained. The most notable difference between the two proposed transition structures was the closer structural proximity of the tethered acetylene to the radical center afforded by the transition structure leading from 310b to 359 compared to that afforded by the transition structure leading from 310a to 358. 307 360 Scheme 74 In the event, slow syringe-addition of BusSnH and a catalytic amount of AIBN to a refluxing solution of xanthates 50 in benzene afforded neither tandem cyclization product 307 nor 360 (eq 58). Upon removal of the solvent, a mixture of tin-containing products, representing less than 5% mass balance with respect to xanthates 50, was 148 obtained. Presumably, the products were volatile and consequently, under the work-up conditions, were lost to the atmosphere. O C S 2 M e B u 3 S n H , A I B N P h H , re f lux c o m p l e x m ix tu re (58) 50 The literature pertaining to radical chemistry was reviewed for possible methods of improving our cyclization reaction. Specifically, alterations to our cyclization substrate that might reduce product loss by evaporation were sought. In 1984, Clive and coworkers reported142 that the radical cyclization of phenylacetylene 361 provided the corresponding cyclic product 362 in a yield higher than that obtained from the corresponding cyclization of the non-phenyl derivative 363 to 364 (eq 59). It was expected that phenyl derivatives of our acetylenic substrates would provide less volatile products upon cyclization. Thus, the phenyl-substituted substrates were (59) 361 R = P h 362 R = P h (79%) 363 R = H 364 R = H (24%) 149 prepared following the procedures described earlier for xanthates 50. The known143 iodide 365 was treated with 2.1 equiv. of f-BuLi and the resultant solution of the required alkyllithium species was treated with aldehyde 314 (eq 60). The alcohol adducts 366, obtained in 78% yield, were then transformed into the corresponding xanthates 367. Xanthates 367 were purified by flash chromatography on silica gel and analyzed by standard spectroscopic methods. The 'H NMR spectrum of 367 displayed multiplets between 5 7.20-7.42, representing the aromatic protons of the phenyl ring. Overlapping doublets at 8 5.91 in the *H NMR of 367 were attributed to H-3, the proton on the carbon bearing the xanthate moiety. 314 With xanthates 367 in hand, the proposed tandem cyclization reaction to generate the presilphiperfolane skeleton was further investigated. Treatment of a benzene solution of xanthates 367 with BusSnH and AIBN (slow syringe addition over 18 h) provided a mixture of non-polar compounds, which were inseparable by silica gel flash chromatography (Scheme 75). On the basis of spectroscopic analysis (vide infra), the two 150 main components of this mixture were tentatively assigned structures 368. The 'H NMR spectrum of the mixture displayed two overlapping signals at 8 6.35, attributed to respective olefinic protons in 368. The 1 3 C NMR spectrum of the mixture displayed four olefinic signals between 8 125 and 126, representing the carbons of the double bonds in 368. The known ketone 306, reported as l-epi-9-norpresilphiperfolan-9-one,20 was readily obtained from the mixture of cyclization products 368 upon subjection of the latter to an oxidative cleavage protocol developed81 by Sharpless and coworkers. Treatment of a solution of 368 in MeCN-CCl 4 -H 2 0 with NaI04 and RuCl3 afforded ketone 306, obtained in 40% overall yield from 367. The assigned structure of ketone 306 was supported by comparison of its derived spectral data with those previously reported by Weyerstahl and coworkers for l-epi-9-norpresilphiperfolan-9-one. Comparisons of the ! H and 1 3 C NMR data are included in Tables 7 and 8, respectively. = — P h P h O C S 2 M e B u 3 S n H , A I B N P h H , re f lux 16 h 368 rt 306 ( 4 0 % f r o m 367) Scheme 75 151 Table 7. Comparison of selected (assigned) ! H NMR (CDCI3, 400 MHz) Data for Ketone 306 with those Reported20 for (±)-l-Epi-9-norpresilphiperfolan-9-one (306). 14 12 306 s h o w i n g l U P A C - b a s e d 306 s h o w i n g p r e s i l p h i p e r f o l a n e n u m b e r i n g n u m b e r i n g Assignment H-x (306) ' H N M R 8 ppm (Multiplicity, / (Hz)) Presilphiper-folane Numbering H-x Literature ! H NMR Assignments 8 ppm (Multiplicity, J (Hz)) H - l 1.40 (ddd, 4, 12.5, 13) H-7 1.39 (ddd, 4, 12.5, 13) H - l l 2.19 (dd, 7, 12.5) H-8 2.18 (dd, 7,12.5) H-12 0.88 (s) or 1.01 (s) H-13 0.88 (s) or 1.01 (s) H-13 0.88 (s) or 1.01 (s) H-14 0.88 (s) or 1.01 (s) H-14 1.07 (s) H-12 1.07 (s) 152 Table 8. Comparison of the 1 3 C NMR (CDCI3, 100.6 MHz) Data for Ketone 306 and those Reported2 for (±)-l-Epi-9-norpresilphiperfolan-9-one (306). 14 12 306 s h o w i n g I U P A C - b a s e d 306 s h o w i n g p r e s i l p h i p e r f o l a n e n u m b e r i n g n u m b e r i n g Assignment C-x (306) 1 3 CNMR 8 ppm (Multiplicity, J (Hz)) Presilphiperfolane Numbering C-x (306) Literature 1 3 C NMR Assignments 8 ppm (Multiplicity, J (Hz)) C - l 50.9 C-7 50.9 C-2 40.6 C-6 40.6 C-3 58.0 C-5 58.0 C-A 47.5 C-4 47.5 C-5 41.9 C-3 41.9 C-6 28.2 C-2 28.2 C-7 52.7 C - l 52.6 C-8 216.2 C-9 216.2 C-9 38.3 C-10 38.3 C-10 21.8 C - l l 21.8 C - l l 59.1 C-8 59.1 C-12 22.7 C-13 22.7 C - l 3 28.9 or 29.0 C-14 29.0 C-14 28.9 or 29.0 C-12 29.0 153 The transformation of ketone 3 0 6 into the target structure (±)-presilphiperfolan-9-ol (53) was briefly investigated (eq 61). ( 61 ) 306 53 The prospect of transforming ketone 3 0 6 into its C - l epimer 3 0 5 , an advanced intermediate in Weyerstahl and coworkers' total synthesis of presilphiperfolan-9-ol (53) , was considered. In the study by Weyerstahl and coworkers (see Section 2.2.2 vide supra), ketones 3 0 5 and 3 0 6 were obtained upon treatment of a benzene solution of epoxide 3 0 4 with ZnBr2 (Scheme 76). If the reaction was stopped after 40 min, ketone 3 0 5 was obtained exclusively. However, prolonged reaction times (70 min) resulted in the formation of 3 0 5 and 3 0 6 in a 3:1 ratio. The same isomers, 3 0 5 and 3 0 6 , were obtained in a 1:7 ratio upon equilibration of 3 0 5 with 0.9 equiv. of NaHMDS. 154 N a H M D S , T H F ; H 2 0 53 Scheme 76 Although the desired isomer 305 was less favoured under thermodynamically controlled epimerizing conditions (vide supra), ketone 306 was nevertheless subjected to base-mediated isomerization conditions (0.9 equiv. LDA /THF, r-BuOK/r-BuOH or NaOMe/MeOH) in hopes of obtaining a minor portion of 305. Disappointingly, in each case, 306 was completely recovered. On the basis of time-restraints, our proposed formal synthesis of presilphiperfolan-9-ol (53) via direct conversion of ketone 305 to ketone 306 was abandoned. Although an alternate method of preparing the target structure 53 from ketone 306 likely exists, a more concise approach to the presilphiperfolane core, displaying all the correct ring-fusion configurations, was desired. Thus, further investigation into the possibility of effectively controlling the stereoselectivity of the tandem cyclization reaction are necessary. 155 III. CONCLUSIONS The work described in the first part of this thesis illustrates a successful application of annulation sequences developed in our laboratories to the construction of the 5-6-7 fused ring system of the cyathanes. The synthetic studies commenced with 3-methyl-2-cyclohexen-l-one (38), which eventually became the B-ring of the cyathane carbon skeleton (Scheme 77). An annulation sequence with bifunctional reagent alkenylstannane 39 was employed in the construction of the C-ring. In turn, the A-ring annulation was achieved with alkenylgermane 44. As a result of the step-wise annulation strategy used in this synthesis, several advanced functionalized intermediates, which display the complete cyathane 5-6-7 fused tricyclic framework 54, were made readily available. 54 Scheme 77 156 A summary of the cyathane synthetic studies, including key intermediate structures, is outlined in Schemes 78 and 79. The synthesis commenced with a coppers-catalyzed conjugate addition of the Grignard reagent derived from 39 to enone 38, affording adduct 185 (Scheme 78). Base-mediated cyclization of 185 gave the known 18 bicyclic enones 41, which represent the B-C ring system of the cyathane core. The subsequent A-ring annulation sequence employed bifunctional reagent 44 in the transformation of 41 to ketone 187, which ultimately afforded the tricyclic alcohol 155. Subjection of 155 to the Still-Mitra protocol yielded carbinol 151. 6 9 With the A-ring and its hydroxyl isopropyl appendage in place, attention was turned to elaboration of the C-ring. Substance 151 was converted to iodides 160, which were subjected to a SmL.-mediated ring expansion reaction. The resulting product, keto ester 159, displayed the complete 5-6-7 fused cyathane framework. 157 160 159 Reagents: a) MeLi, THF, -78 °C; MgBrEt 20; CuBrDMS, BF 3-Et 20, 38; b) KH, THF, reflux; EtOH; c) Me 2NNH 2, CSA, PhH, reflux; d) KDA, DMPU, THF, -78 °C; 44; e) AcOH, NaOAc, THF, H 2 0, 75 °C; f) KOMe, MeOH, 65 °C; g) Et 2NLi, THF, -78 °C; 0 °C; Mel; h) NIS, CH2C12, 0 °C; i) BuLi, THF, -78 °C; j) KH, 18-cr-6, THF, rt; Bu3SnCH2I; BuLi, -78 °C; k) KH, THF, rt; PMBC1, Bu4NI; 1) Os04, KI0 4, f-BuOH, NaHC03, H 2 0, rt; m) KH, NaH, (EtO)2CO, THF, 65 °C; aq. HCI; n) TBAF, THF; CH 2I 2; o) Sml2, THF, rt. Scheme 78 158 Efforts to transform the advanced intermediate 159 into natural product target structures are summarized in Scheme 79. Keto aldehyde 240 was obtained from 159 in five steps. Removal of the PMB protecting group in 240 represented the final step in the first reported94 total synthesis of (±)-sarcodonin G (36).16 Synthetic studies towards a second cyathane target, (±)-cyathin A 4 (37),17 afforded the advanced intermediate 269 in four steps from 240. On the basis of limited amounts of advanced materials, the final deprotection steps involved in the conversion of 269 to the target structure, (±)-cyathin A 4 (37), were not completed. HO 36 37 Reagents: a) DIBALH, Et 20; b) Dess-Martin periodinane, CH2CI2; c) piperidine, 3A mol. sieves, PhH, reflux; PhSeCl, THF, -78 °C; H 20; d) KI0 4, THF, MeOH, H 2 0, rt; 3) DBN, PhH, reflux; f) DDQ, CH2C12-H20; g) Al(/-PrO)3, /-PrOH, 60 °C; h) VO(acac)2, t-BuOOH, CH2C12, 0 °C; i) DBN, PhH, reflux; j) PPh3, p-nitrobenzoic acid, DEAD, PhH. Scheme 79 159 As illustrated by this concise 22-step total synthesis of (±)-sarcodonin G (36) from the known ketones 41, our step-wise annulation strategy provides an efficient approach to the cyathane carbon skeleton. In addition, the specific sequence of transformations and the high stereoselectivity of the reactions allowed for excellent control of the relative configuration of all stereogenic centers. Indeed, the anti configuration of the 1,4 angular methyl groups, which was a problematic issue in several previously reported approaches to the cyathanes (see section 2.1.2., vide supra), was well established at an early point in the synthesis. The hydroxyl isopropyl side chain at C-3, which displays an S configuration at C-18, represents a rare structural complexity with regards to cyathane synthetic studies that had yet to be challenged. In our synthesis, the task of fashioning this side chain was successfully accomplished with complete stereoselectivity via a sequence of steps, culminating with a Still-Mitra rearrangement19 reaction of the cz's-fused cyclization product 155. Of note, the use of a Sm -^mediated ring-expansion reaction to prepare a 5-6-7 tricycle from a 5-6-6 tricycle, was the first reported application of this free-radical reaction, developed by Hasegawa and coworkers,89 in natural product synthesis. The difficulties encountered in our attempt to prepare (±)-cyathin A 4 (37) from advanced intermediate 240 illustrate the synthetic complexity associated with elaboration of highly functionalized ring-systems. While the selective reduction of the aldehyde function at C-20 over the ketone function at C-10 in 240 was eventually accomplished, the subsequent introduction of an a-face hydroxyl moiety at C-l3 represented a serious challenge. In our studies, an intermediate with a P-face hydroxyl moiety at C-l3 was obtained and, following a Mitsunobu-type inversion protocol, this substance was 160 transformed into compound 269, which displays the desired configuration at C-13. Although 269 should provide access to the target structure, ± -37 upon removal of the PMB and PNB moieties, further investigations into a more direct method of introducing the a-face C-13 hydroxyl moiety are warranted. In the second part of this thesis, a tandem radical cyclization was proposed for the assembly of 5-5-6 fused carbocycles. The synthetic study commenced with the commercially available 3-methyl-2-cyclopenten-l-one (49), which was converted to ketone 315 in several steps, including a Carroll [3,3] rearrangement reaction (Scheme 80). Subsequent transformation of ketone 315 into aldehyde 314 proved straightforward. A Negishi-type reaction of lithio species 369 with aldehyde 314 afforded a mixture of alcohols, which was converted into the corresponding mixture of xanthates 367. Bu3SnH-mediated tandem cyclization of xanthates 367 yielded a mixture of alkenes 368, which display the 5-5-6 fused tricyclic ring system of the presilphiperfolane framework. Subjection of 368 to oxidative cleavage conditions afforded the known20 ketone (±)-l-epi-9-norpresilphiperfolan-9-one (306). A formal synthesis of the target structure, (±)-presilphiperfolan-9-ol (53), from cyclization products 368 via ketone 306 was not realized. To obtain 53, the unnatural configuration at C-l , exhibited in 368 and 306, needed to be corrected. Although a substance with the desired relative configuration at C-l might eventually be obtained in several steps from 306, an alternate strategy that would reverse the undesired stereoselectivity in the second of the tandem cyclizations, which afforded 368, would be ideal. The inherently difficult nature of either of these tasks represents a drawback of our' tandem reaction strategy to presilphiperfolane natural product synthesis. Nevertheless, in 161 the course of this synthetic study, a concise approach to 5-5-6 fused tricyclic ring systems was developed, illustrating the power of tandem free radical cyclizations in carbocycle construction. Reagents: a) NaBFLt, CeCl3, MeOH; b) diketene, DMAP, Et 20, -20 °C; LDA, -78 °C to rt; CC14, reflux; c) Ph3P(OMe)CHLi; THF; 0 °C to rt; TFA, H20-CHC13, reflux; d) 369, Et 20, -78 °C; e) NaH, imidazole, CS 2, THF, reflux; Mel, rt; f) AIBN, Bu3SnH, PhH, reflux; g) RuCl3, NaI04, MeCN-CCl 4-H 20. Scheme 80 162 IV. EXPERIMENTAL 4.1. General 4.1.1. Data Acquisition and Presentation Proton nuclear magnetic resonance ( !H NMR) spectra were recorded on Bruker models WH-400 (400 MHz), AM-400 (400 MHz), AV-300 (300 MHz), AV-400 (400 MHz) or AMX-500 (500 MHz) spectrometers using deuteriochloroform (CDCI3) as a solvent. Signal positions (8) are given in parts per million (ppm) from tetramethylsilane and were measured relative to that of chloroform (CHCI3) (8 7.24 ppm). The multiplicity, number of protons and coupling constants are indicated in parentheses following the chemical shift. In some cases, when mixtures of compounds are present, ratios of integration are given. The abbreviations used in describing multiplicity are: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet, br-broad. Coupling constants (J values) are given in Hertz (Hz). 13 Carbon nuclear magnetic resonance ( C NMR) spectra were obtained on Bruker models AV-300 (75.5 Hz), AM-400 (100.6 MHz), AV-400 (100.6 MHz), and AMX-500 (125.8 MHz) spectrometers or a Varian model XL-300 (75.5 MHz) spectrometer using CDCI3 as the solvent. Signal positions (8) are given in parts per million (ppm) from tetramethylsilane and were measured relative to the signal of CDCI3 (8 77.0 ppm). In some cases, the proton and carbon assignments were supported by two-dimensional (1H, 13 C)-heteronuclear multiple quantum coherence experiments (HMQC) which were carried out on the Bruker AV-400 and AMX-500 spectrometers. 163 Infrared (IR) spectra were recorded on a Perkin-Elmer model 1710 Fourier transform spectrophotometer with internal calibration on liquid films (sodium chloride plates) or solid pellets (infrared grade potassium bromide). Only selected characteristic absorptions are listed for each compound. Low and high resolution mass spectra were recorded on a Kratos Concept II HQ or on a Kratos MS 80 mass spectrometer by the UBC MS laboratory. High resolution mass spectra were measured using electron impact ionization (EI) or desorption chemical ionization (DCI) using CH4 or NH3. (M+) and (M-Me)+ ions were detected and analyzed by EI. (M+NH4)+, (M+H)+ and (M+) ions were detected and analyzed by DCI. Unless otherwise noted, the molecular ion (M+) masses are given. Elemental analysis were performed on a Carlo Erba CHN model 1106 or on a Fisons EA model 1108 elemental analyzer by the Microanalytical Laboratory at UBC. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been oven-dried (-140 °C) and/or flame dried. Glass syringes, stainless steel needles and Teflon® cannulae used to handle anhydrous solvents and reagents were oven-dried (-140 °C), cooled in a dessicator and flushed with argon prior to use. Plastic syringes were flushed with argon prior to use. Microsyringes were stored in a dessicator and were flushed with argon prior to use. Cold temperatures were maintained using the following baths: 0 °C, ice-water; -10 °C and -20 °C, aqueous calcium chloride-dry ice (17 g, 27 g of CaCl2/100 mL of H 2 0 respectively); -78 °C, acetone-dry ice; -98 °C, methanol-dry ice. 164 Thin layer chromatography (TLC) was performed using commercial aluminum backed silica gel 60 F 254 plates (E. Merck, type 5554, thickness 0.2 mm). Visualization of the chromatograms was accomplished using ultraviolet light (254 nm) followed by heating of the TLC plate after staining with one of the following solutions: (a) vanillin in a sulfuric acid-ethanol mixture (6% vanillin w/v, 4% sulfuric acid v/v, 10% water v/v in EtOH), (b) phosphomolybdic acid in ethanol (20% phosphomolybdic acid w/v, Aldrich), (c) anisaldehyde in a sulfuric acid-ethanol mixture (5% anisaldehyde v/v and 5% sulfuric acid v/v in EtOH). Flash column chromatography was performed using 230 -^00 mesh silica gel (E, Merck, Silica Gel 60 or Silicycle, Silica Gel). Gas liquid chromatography (GLC) was performed on Hewlett-Packard models 5880A or 5890 capillary gas chromatographs, both equipped with flame ionization detectors and fused silica columns. The former instrument contained a 25 m x 0.21 mm column, while the latter chromatograph utilized a 25 m x 0.20 mm column. Both were coated with HP-5 (crosslinked 5% phenylmethyl silicone). 4.1.2. Solvents and Reagents All solvents and reagents were purified, dried and/or distilled using standard procedures. Diethyl ether (Et20) and tetrahydrofuran (THF) were distilled from sodium/benzophenone, while benzene (CeHe) and dichloromethane (CH2CI2) were distilled from calcium hydride, all under an atmosphere of dry argon. Magnesium was added to methanol and, after the mixture had been refluxed, the methanol was distilled from the resulting solution of magnesium methoxide. Solvents were distilled immediately prior to use. 165 Diisopropylamine, diethylamine, triethylamine, hexamethylphosphoramide (HMPA) and dimethyltetrahydropyrimidinone (DMPU) were distilled from calcium hydride. The reagents were stored in Sure Seal™ (Aldrich Chemical Co. Inc.) bottles over 3 A molecular sieves under an atmosphere of argon. Before use, methyl iodide and deuteriochloroform (CDCI3) were passed through a short column of basic alumina activity I, which had been over-dried (-140 °C), and then cooled in a dessicator prior to use. Petroleum ether refers to a mixture of hydrocarbons with a boiling range of 35-60 °C. Solutions of diisobutylaluminum hydride (DIBALH) in hexanes and t-butyllithium (r-BuLi) in pentane were purchased from Aldrich Chemical Co. Inc. Solutions of methyllithium (MeLi) in diethyl ether and n-butyllithium (n-BuLi) in hexanes were obtained from Aldrich Chemical Co. Inc. and Acros, and were standardized using diphenylacetic acid as a primary standard using the procedure of Kofron and Baclawski.144 Potassium hydride (KH) was obtained as a 35% suspension in mineral oil and sodium hydride (NaH) as a 60% dispersion in mineral oil from Aldrich Chemical Co. Inc., and were rinsed free of oil with solvent under a stream of argon prior to use. Iodine was sublimed and was stored no longer than three months. Aqueous ammonium chloride-ammonia (NH4CI-NH3) (pH 8) was prepared by the addition of -50 mL of concentrated aqueous ammonia (28-30%) to 950 mL of a saturated aqueous ammonium chloride (NH4CI) solution. 166 Lithium diisopropylamide (LDA) was prepared by the addition of a solution of n-butyllithium in hexanes to a solution of diisopropylamine (1.1 equiv.) in dry tetrahydrofuran at -78 °C. The resulting solution was warmed to 0 °C, stirred for 15 min, and cooled back to -78 °C prior to use. Argon was dried by bubbling it through concentrated sulfuric acid (H2SO4) and then passing it through a drying tube packed with potassium hydroxide (KOH) and Drierite®. 4.2. Total Synthesis of the Cyathane Diterpenoid (±) -Sarcodonin G 167 Preparation of Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (165) M e 3 G e v M e 3 G e . E t 0 2 C 165 C 0 2 E t 174 To stirred cold (-10 °C) dry THF (50 mL) was added cold (0 °C) Me3GeH (14.1 g, 0.119 mol) via a cannula. A solution of r-BuLi (1.7 M in pentane, 87.5 mL, 0.149 mol) was added via a syringe over 5 min. The resulting yellow solution was stirred at -10 °C for 5 min to afford a colourless solution. A solution of MeLi (1.4 M in Et20, 106.0 mL, 0.149 mol) was added and the resulting mixture was transferred via a cannula to a cold (-78 °C) stirred suspension of CuCN (13.3 g, 0.149 mol) in dry THF (20 mL). The resulting suspension was stirred a -78 °C for 1 h to afford a colourless solution. A solution of ethyl 2-pentynoate (10.0 g, 0.079 mol) in THF (5 mL) was added via a cannula and the reaction mixture was stirred at -78 °C for 45 min. AcOH (12.4 g, 0.206 mol) was added via a syringe. The resulting heterogeneous mixture was stirred for 5 min and then poured into stirred aqueous NH4CI-NH3 (pH 8, 500 mL). Et 20 (500 mL) was added and the mixture was opened to the atmosphere and then stirred vigorously until the aqueous layer was deep blue. The layers were separated and the aqueous layer was extracted with Et 20 (2 x 200 mL). The combined organic extracts were washed with H 2 0 (2 x 200 mL) and 168 brine (2 x 200 mL), dried over anhydrous MgS04, and concentrated under reduced pressure. The crude oil was subjected to flash chromatography (600 g of silica gel, 40:1 petroleum ether-Et20) to afford two fractions, which were concentrated under reduced pressure. The first fraction to be eluted afforded 13.7 g (71%) of ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) as a colourless oil. The second fraction afforded 3.91 g (20%) of ethyl (£)-3-trimethylgermyl-2-pentenoate (174) as a colourless oil. Ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) exhibited the following spectral data: IR (neat): 2968, 1718, 1607 cm - 1. ! H NMR (CDC13, 400 MHz) 5: 0.29 (s, 9H), 0.99 (t, 3H, J = 7.3 Hz), 1.24 (t, 3H, J = 7.0 Hz), 2.30 (q, 2H, J = 7.3 Hz), 4.12 (q, 2H, J = 7.0 Hz), 6.21 (s, 1H). 1 3 C NMR (CDCI3, 100.6 MHz) 5: -0.4, 13.5, 14.2, 31.9, 59.9, 126.6, 166.8, 171.4. Exact mass calcd for C 1 0 H 2 iO 2 7 4 G e (M+H)+: 247.0753. Found: 247.0762. Anal, calcd for C 1 0 H 2 0 O 2 Ge : C 49.05, H 8.23. Found: C 48.84, H 8.10. Table 9. lH NMR (CDCI3,400 MHz) Data for Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (165): NOED Experiment. Assignments H-x ' H N M R 8 ppm (Multiplicity, J (Hz)) Observed NOEs H-2 a 6.21 (s) H-4, H-5 H-4 a 2.30 (q, 7.3) H-5, H-2, -GeMe3 H-5 0.99 (t, 7.3) H - l ' a 4.12 (q, 7.0) H-2' H-2' 1.24 (t,7.0) -GeMe 3 a 0.29 (s) H-4 "Irradiation of this signal generated the corresponding NOEs in the right hand column 170 Table 10. 1 3 C NMR (CDC13,100.6 MHz) and ! H NMR (CDC13,400 MHz) Data for Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (165): HMQC Experiment. 2'v V Me3Ge. o 165 Assignments C-x 1 3 CNMR 5 ppm APT HMQC 'H NMR Correlations (5 ppm) C - l 166.8 or 171.4 C or CH 2 C-2 126.6 CH or CH 3 H-2 (6.21) C-3 166.8 or 171.4 C or CH 2 C-4 31.9 C or C H 2 H-4 (2.30) C-5 13.5 CH or C H 3 H-5 (0.99) c-r 59.9 C or C H 2 H-l'(4.12) C-2' 14.2 CH or C H 3 H-2' (1.24) -GeMe3 -0.4 CH or C H 3 -GeMe3 (0.29) 171 Ethyl (Zr)-3-trimethylgermyl-2-pentenoate (174) exhibited the following spectral data: IR (neat): 2975, 1718, 1608 cm"1. *H NMR (CDC13, 400 MHz) 5: 0.23 (s, 9H), 1.00 (t, 3H, J = 7.5 Hz), 1.24 (t, 3H, J = 7.2 Hz), 2.73 (q, 2H, J = 7.5 Hz), 4.11 (q, 2H, J = 7.2 Hz), 5.89 (s, 1H). 1 3 C NMR (CDCI3, 100.6 MHz) 5: -2.1, 13.8, 14.2, 25.4, 59.5, 124.5, 164.9, 171.3. Exact mass calcd for C,0H2iO 2 7 4Ge (M+H)+: 247.0753. Found: 247.0758. C 0 2 E t 174 Table 11. 'H NMR (CDCI3,400 MHz) Data for Ethyl (£)-3-Trimefhylgermyl-2-pentenoate (174): NOED Experiment. 174 Assignments H-x 'H NMR 8 ppm (Multiplicity, J (Hz)) Observed NOEs H-2 a 5.89 (s) -GeMe3 tt-A" 2.73 (q, 7.5) H-5, -GeMe3 H-5 1.00 (t, 7.5) H - l , a 4.11 (q, 7.2) H-2' H-2' 1.24 (t, 7.2) -GeMe3 Q 0.23 (s) H-2, H-4, H-5 a Irradiation of this signal generated the corresponding NOEs in the right hand column 173 Table 12. 1 3 C NMR (CDC13,100.6 MHz) and lH NMR (CDC13,400 MHz) Data for Ethyl (Z)-3-Trimethylgermyl-2-pentenoate (174): HMQC Experiment. O 174 Assignments C-x 1 3 CNMR 8 ppm APT HMQC ! H NMR Correlations (5 ppm) C - l 164.9 or 171.3 C or CH 2 C-2 124.5 CH or CH 3 H-2 (5.89) C-3 164.9 or 171.3 C or CH 2 C-4 25.4 C or C H 2 H-4 (2.73) C-5 13.8 CH or C H 3 H-5 (1.00) c - r 59.5 C o r C H 2 H-l'(4.11) C-2' 14.2 CH or C H 3 H-2' (1.24) -GeMe3 -2.1 CH or C H 3 -GeMe3 (0.23) 174 Preparation of Ethyl (Zs)-3-Trimethylgermyl-3-pentenoate (164) Et0 2C 164 To a cold (-78 °C), stirred solution of L D A (130 mmol) in dry T H F (500 mL) was added HMPA (23.3 g, 130 mmol). The mixture was stirred for 30 min and a solution of ethyl (Z)-3-trimethylgermyl-2-pentenoate (165) (13.0 g, 53.1 mmol) in dry T H F (50 mL) was added via a cannula. The resulting mixture was stirred for 30 min at -78 °C, warmed to 0 °C for 1 h and then recooled to -78 °C for 15 min. The mixture was transferred, via a cannula, to a cold (-98 °C) stirred solution of acetic acid (31.9 g, 0.531 mol) in dry E12O (500 mL) . The mixture was allowed to warm to room temperature and saturated aqueous N a H C 0 3 (500 mL) was added. The layers were separated and the aqueous layer was extracted with Et20 (3 x 500 mL) . The combined organic extracts were washed with brine (300 mL) and dried over anhydrous MgSCv The solvent was removed under reduced pressure and the resulting material was purified by flash chromatography (500 g of silica gel, 20:1 petroleum ether-Et 20) to yield 11.8 g (91%) of ethyl (£)-3-trimethylgermyl-3-pentenoate (164) as a colourless o i l . IR (neat): 2976, 1737, 1626 cm - 1. 175 ! H NMR (CDCI3, 400 MHz) 8: 1.15 (s, 9H), 1.21 (t, 3H, J = 7.2 Hz), 1.69 (d, 3H, / = 6.7 Hz), 3.16 (s, 2H), 4.07 (q, 2H, J = 7.2 Hz), 5.87 (q, 1H, J = 6.7 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: -2.0, 14.1, 14.4, 35.3, 60.4, 135.5, 135.7, 171.8. Exact mass calcd for Ci 0 H 2 iO 2 7 4 Ge (M+H)+: 247.0753. Found: 247.0764. Anal, calcd for Ci 0H 2 0O 2GeI: C 49.05, H 8.23. Found: C 49.15, H 8.23. Table 13. *H NMR (CDC13,400 MHz) Data for Ethyl (£)-3-Trimefhylgermyl-3-pentenoate (164): NOED Experiment. .0. V O 164 .Assignments H-x 'HNMR 8 ppm (Multiplicity, J (Hz)) Observed NOEs H-2 a 3.16 (s) H-5, -GeMe3 H-4 a 5.87 (q, 6.7) H-5, -GeMe3 H-5 a 1.69 (d, 6.7) H-2, H-4 H - l ' 4.07 (q, 7.2) H-2' 1.21 (t, 7.2) -GeMe 3 a 1.15 (s) H-2, H-4 a Irradiation of this signal generated the corresponding NOEs in the right hand column 176 Preparation of (i?)-3-Trimethylgermyl-3-penten-l-ol (163) OH 163 To a cold (-78 °C), stirred solution of ethyl (£)-3-trimethylgermyl-3-pentenoate (164) (8.0 g, 32.7 mmol) in dry Et 20 (300 mL) was added a solution of DIBALH (1.0 M in hexanes, 82.5 mL, 82.5 mmol). The resulting mixture was stirred at -78 °C for 1 h, warmed to 0 °C and then stirred for an additional h. Aqueous N H 4 C I - N H 3 (pH 8, 8 mL) was added, and the resulting white slurry was warmed to room temperature and was then stirred for 1 h. Solid anhydrous MgSCv (2.0 g) was added and the mixture was stirred for 1 h. The slurry was filtered through a column of Florisil® (50 g) and the column was washed with Et 20 (3 x 200 mL). The solvent of the combined eluates was removed under reduced pressure and the resulting material was purified by flash chromatography (400 g of silica gel, 8:1 pentane-Et20) to give 5.85 g (88%) of (F)-trimethylgermyl-3-penten-l-ol (163) as a colourless oil. IR (neat): 3331, 1622, 1235, 1043, 824, 754, 597, 570 cm - 1. ! H NMR (CDCI3, 400 MHz) 8: 0.17 (s, 9H), 1.28 (t, 1H, 7= 6.0 Hz), 1.72 (d, 3H, J= 6.6 Hz), 2.51 (t, 2H, J = 7.0 Hz), 3.58 (td, 2H, J = 7.0, 6.0 Hz), 5.88 (q, 1H, J = 6.6 Hz). 177 C NMR (CDCI3, 75.2 MHz) 5: -1.7, 14.4, 33.4, 61.7, 135.1, 138.9. Exact mass calcd for C 7 H, 5 7 4 GeO (M+-Me): 189.0335. Found: 189.0336. Anal, calcd for C8Hi8GeO: C 47.38, H 8.95. Found: C 47.57, H 9.12. Preparation of (Z?)-5-Iodo-3-trimethylgermyI-2-pentene (44) 44 I2 (6.20 g, 24.4 mmol) was added to a solution of Ph3P (6.41 g, 24.4 mmol) in dry CH2C12 (200 mL) and the mixture was stirred for 20 min. (ZT)-3-Trimethylgermyl-3-penten-l-ol (163) (4.13 g, 20.4 mmol) and dry Et3N (3.4 mL, 24 mmol) were added as a solution in dry CH2C12 (20 mL) and the resulting mixture was stirred for 18 h. Most of the solvent was removed under reduced pressure and the residual material was diluted with pentane (100 mL). The mixture was filtered through a sintered glass funnel (8 cm diameter) containing Florisil® (10 cm deep) on top of a thin layer of Celite®. The column was flushed with pentane (600 mL). The solvent of the combined eluates was removed under 178 reduced pressure. The residual material was purified by distillation (48-54 °C / 0.3 Torr) to give 6.02 g (95%) of (£)-5-iodo-3-trimethylgermyl-2-pentene (44) as a colourless oil. IR (neat): 1619, 1236, 1168, 823, 756, 597, 567 cm - 1. 'H NMR (CDC13, 400 MHz) 5: 0.18 (s, 9H), 1.67 (d, 3H, J = 6.7 Hz), 2.78 (t, 2H, J = 8.5 Hz), 3.02 (t, 2H, J = 8.5 Hz), 5.82 (q, 1H, J = 6.7 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: -1.8, 3.9, 14.4, 35.2, 134.5, 142.2. Exact mass calcd for C 7H 1 4 7 4GeI (M+-Me): 298.9352. Found: 298.9359. Anal, calcd for C8H1 7GeI: C 30.73, H 5.48. Found: C 30.86, H 5.74. 179 Preparation of (15*,6/f*)-6-Methyl-7-methylidenebicyclo[4.4.0]decan-2-one Dimeth-ylhydrazoiie (152) 1,1-Dimethylhydrazine (7.50 g, 123 mmol) was added to a stirred solution of the bicyclic ketone 41 1 8 (3.5:1 mixture of the trans- and as-fused isomers, 10.9 g, 61.6 mmol) in dry benzene (300 mL). A catalytic amount of 10-camphorsulfonic acid (1.1 g, 4.7 mmol) was added and the mixture was refluxed for 72 h employing a Dean-Stark trap. The excess 1,1-dimethylhydrazine and most of the solvent were removed by distillation under Ar (90 °C). The remaining material was diluted with Et 20 (100 mL) and saturated aqueous NaHCC«3 (100 mL) was added. The resulting layers were separated and the aqueous layer was extracted with Et 20 (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO,*, concentrated under reduced pressure and purified by flash chromatography (600 g of silica gel, 5:1 pentane-Et20) to yield 5.82 g (42.9%) of the trans-fused bicyclic hydrazone 152 and 5.32 g (39.2%) of the cw-fused bicyclic hydrazone 186 as colourless oils. 180 Isomerization of (l/?*,6/?*)-6-Methyl-7-methylidenebicyclo[4.4.0]decan-2-one Dimethylhydrazone (186) 1,1-Dimethylhydrazine (3.0 g, 50 mmol) was added to a stirred solution of the ds-fused bicyclic hydrazone 186 (5.32 g, 24.1 mmol) in dry benzene (100 mL). A catalytic amount of 10-camphorsulfonic acid (50 mg, 0.2 mmol) was added and the mixture was refluxed for 48 h employing a Dean-Stark trap. The excess 1,1-dimethylhydrazine and most of the solvent were removed by distillation under Ar (90 °C). The remaining material was diluted with Et20 (100 mL) and saturated aqueous NaHC03 (100 mL) was added. The resulting layers were separated and the aqueous layer was extracted with Et20 (3 x 100 mL). The combined organic layers were dried over anhydrous MgSCU, concentrated under reduced pressure and purified by flash chromatography (300 g of silica gel, 5:1 pentane-Et20) to yield 2.55 g (48.3%) of the trans-fused bicyclic hydrazone 152 and 2.45 g (46.3%) of the ds-fused hydrazone 186. The ds-fused bicyclic hydrazone 186 was recycled twice though the epimerization step to yield a total of 9.61 g (71%) of the trans-fused bicyclic hydrazone 152 from 10.9 g of the mixture of ketones 41 (vide supra). The trans-fused bicyclic hydrazone 152 exhibited the following spectral data: IR (neat): 1638, 1446, 1373, 1022, 965, 894 cm - 1. 181 ! H NMR (CDCI3, 400 MHz) 5: 0.88 (s, 3H), 1.22-1.26 (m, 1H), 1.54-1.79 (m, 6H), 1.79-1.89 (m, 2H), 1.95 (dd, 1H, / = 11.7, 3.7 Hz), 2.09-2.16 (m, 1H), 2.25-2.35 (m, 1H), 2.4 (s, 6H), 3.26-3.32 (m, 1H), 4.63^ 1.68 (m, 2H). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 18.1, 22.1, 23.1, 27.4, 28.5, 32.6, 36.5, 43.1, 47.8, 52.5 (two signals superimposed), 105.3, 157.1, 169.5. Exact mass calcd for C14H24N2: 220.1940. Found: 220.1940. Anal, calcd for C1 4H24N2: C 76.31, H 10.98, N 12.71. Found: C 76.16, H 10.86, N 12.72. The ds-fused bicyclic hydrazone 186 exists as a mixture of isomers with respect to the configuration of the imine double bond. The mixture of ds-fused bicyclic hydrazone 186 isomers exhibited the following spectral data: IR (neat): 1635, 1446, 1374, 1021, 967, 892 cm - 1. major minor 182 ! H NMR (CDCI3, 400 MHz) 5: 1.06 (minor) and 1.08 (major) (s, s, 3H total), 1.2-2.5 (m, 12H), 2.36 (minor) and 2.41 (major) (s, s, 6H total), 3.07-3.17 (major) and 3.19-3.26 (minor) (m, m, 1H total), 4.66-4.73 (m, 2H). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 21.6, 22.7, 23.4, 23.7, 27.2, 27.3, 27.4, 28.7, 31.1, 31.5, 31.7, 32.8, 40.7, 41.0, 45.5, 47.4, 47.7 (two signals superimposed), 52.8 (two signals superimposed), 107.2, 155.1, 155.4, 172.0, 174.4 (three signals are not accounted for). Exact mass calcd for C14H24N2: 220.1940. Found: 220.1935. 183 Preparation of (15*,3i?*,<Ji?*)-6-Methyl-7-methylidene-3-[(3£:)-3-tr imethylgerniyl-3-pentenyl]bicyclo[4.4.0]decan-2-one (188) 188 To a stirred solution of f-BuOK (5.00 g, 44.6 mmol) in dry THF (150 mL) was added dry i-Pr2NH (4.52 g, 44.6 mmol). The mixture was cooled to -78 °C. A solution of BuLi (1.6 M in hexanes, 27.9 mL, 44.6 mmol) was added and the mixture was stirred for 30 min. The trans-fused hydrazone 152 (4.93 g, 22.3 mmol) was added as a solution in dry THF (10 mL) and the mixture was stirred at -78 °C for 1 h. Dry DMPU (5.72 g, 44.6 mmol) and a solution of freshly distilled (£)-5-iodo-3-trimethylgermyl-2-pentene (44) (10.5 g, 33.5 mmol) in dry THF (10 mL) were sequentially added and the mixture was stirred at -78 °C for 1.5 h. Aqueous NH4CI-NH3 (pH 8, 200 mL) was added and the mixture was allowed to warm to room temperature. Et 20 (200 mL) was added and the 184 resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 200 mL), and the combined organic layers were washed with brine (200 mL). The solvent was removed under reduced pressure and the resulting crude hydrazone 153 was taken up in THF (30 mL). H 2 0 (7 mL) and solid NaOAc33H20 (13.8 g, 0.101 mol) were added and the mixture was stirred for 5 min. AcOH (43.0 g, 0.716 mol) was added and the mixture was heated to 75 °C for 18 h. The mixture was cooled to room temperature and saturated aqueous NaHC03 (60 mL) was added. Solid NaHC03 was added until the solution was alkaline to litmus paper. Et 20 (150 mL) was added to the mixture and the resulting layers were separated. The aqueous layer was extracted with Et 20 (3 x 150 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous MgSOt. The solvent was removed under reduced pressure and the resulting material was purified by flash chromatography (600 g of silica gel, 40:1 pentane-Et20) to afford 5.60 g (69.0%) of a mixture of ketones 189, of which ketone 188 was the major isomer. For characterization, pure ketone 188 was obtained by flash chromatography (50:1 pentane-Et20) of a small amount of the mixture of ketones 189. Ketone 188 exhibited the following spectral data: JR (neat): 1709, 1639, 1628, 1448, 1376, 1234, 952 cm - 1. 185 ] H NMR (CDCI3, 400 MHz) 5: 0.13 (s, 9H), 0.91 (s, 3H), 1.18-1.30 (m, 1H), 1.43-1.56 (m, 1H), 1.56-1.69 (m, includes 3-proton doublet at 5 1.62, J = 6.6 Hz, 7H total), 1.82-1.89 (m, 2H), 1.91-2.00 m, 1H), 2.01-2.08 (m, 2H), 2.10-2.40 (m, 5H), 4.65-4.72 (m, 2H), 5.67 (q, 1H, J =6.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: -1.7, 13.9, 18.8, 20.9, 26.6 (two signals superimposed), 28.2, 31.4, 32.0, 32.2, 44.9, 50.0, 54.1, 105.8, 132.2, 142.4, 155.7, 215.3. Exact mass calcd for C 2oH 3 4 7 4GeO: 364.1822. Found: 364.1818. Anal, calcd for Czo^GeO: C 66.16, H 9.44. Found C 66.35, H 9.55. 186 Preparation of ( lS* ,3S* , (J / f * ) -6 -Methy l -7 -methy l idene-3 - [ (3£ ) -3 - t r imethy lgermyl -3 -To a stirred solution of NaOMe (7.83 g, 145 mmol) in dry MeOH (300 mL) was added a solution of the mixture of ketones 189 (17.4 g, 48.0 mmol) in dry MeOH (100 mL). The mixture was heated to 65 °C for 3 h and then cooled to room temperature. H 2 0 (300 mL) and Et 20 (500 mL) were added, and the layers were separated. The aqueous layer was extracted with Et 20 (3 x 300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the resulting material was purified by flash chromatography (1 kg of silica gel, 40:1 pentane-Et20) to yield 11.5 g (66.2%) of ketone 187 as well as 3.9 g (22.4%) of a mixture of three other diastereomers. This mixture of isomers was resubmitted to the same isomerization reaction to yield an additional 2.71 g of 187 for a total overall yield of 14.21 g (82%). pentenyl]bicyclo[4.4.0]decan-2-one (187) 187 IR (neat): 1713, 1638, 1623, 1447, 1376, 1234, 1098, 940, 895, 823, 754 cm - 1. 187 ! H NMR (CDCI3, 400 MHz) 8: 0.15 (s, 9H), 0.86 (s, 3H), 1.05-1.17 (m, 1H), 1.17-1.31 (m, 2H), 1.53-1.69 (m, includes 3-proton doublet at 5 1.66, J = 6.6 Hz, 5H total), 1.74-1.89 (m, 3H), 1.90-2.00 (m, 1H), 2.10-2.32 (m, 7H), 4.69 (m, 2H), 5.68 (q, 1H, J = 6.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 5: -1.7, 14.0, 18.9, 21.0, 26.6, 27.7, 29.0, 30.0, 32.2, 36.0, 45.4, 49.7, 58.3, 105.6, 131.9, 143.3, 155.8, 212.7. Exact mass calcd for Ci 9H 3i 7 4GeO (M+-Me): 349.1587. Found: 349.1590. Anal, calcd for C20H34GeO: C 66.66, H 9.44. Found: C 66.25, H 9.38. 188 Preparation of (15*,3S*,<J /?*)-3,6-Dimethyl-7-methylidene-3-[(3£:)-3-triniethylger-myl-3-pentenyl]bicyclo[4.4.0]decan-2-one (194) To a cold (-78 °C), stirred solution of dry Et2NH (4.35 g, 59.5 mmol) in dry THF (100 mL) was added a solution of BuLi (1.6 M in hexanes, 30.2 mL, 48.3 mmol). The mixture was warmed to 0 °C for 30 min and cooled to -78 °C. A solution of ketone 187 (13.5 g, 37.2 mmol) in dry THF (20 mL) was added and the resulting mixture was warmed to 0 °C and stirred for 1 h. Mel (107 g, 750 mmol) was added and the mixture was warmed to room temperature. The mixture was stirred for 1.5 h and aqueous NH4CI-NH3 (pH 8, 100 mL) was added. The resulting layers were separated and the aqueous layer was extracted with Et 20 (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous MgSCv. The solvent was removed under reduced pressure and the resulting crude material was purified by flash chromatography (500 g of silica gel, 50:1 pentane-Et20) to give 11.86 g (84.7%) of ketone 194 as a colourless oil. 194 JR (neat): 1704, 1637, 1623, 1457, 1379, 1234, 1118, 896, 824, 754, 597, 569 cm'1. 189 'H NMR (CDCI3, 400 MHz) 8: 0.17 (s, 9H), 0.86 (s, 3H), 1.17 (s, 3H), 1.18-1.31 (m, 1H), 1.31-1.48 (m, 2H), 1.48-1.61 (m, 1H), 1.63-1.79 (m, includes 3-proton doublet at 8 1.70, J= 6.6 Hz, 6H total), 1.83-1.96 (m, 2H), 2.04-2.33 (m, 5H), 2.44 (dd, 1H, J= 11.9, 3.5 Hz), 4.68^.74 (m, 2H), 5.67 (q, 1H, J= 6.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: -1.7, 14.0, 18.7, 21.2, 24.1 (two signals superimposed), 26.7, 32.1, 32.2, 33.4, 38.0, 44.6, 46.8, 53.7, 105.7, 131.6, 143.5, 155.9, 215.6. Exact mass calcd for C 2 iH 3 6 7 4GeO: 378.1978. Found: 378.1986. Anal, calcd for C 2iH 3 6GeO: C 66.89, H 9.62. Found: C 66.63, H 9.69. 190 Preparation of ( lS*,35*,<Ji?*)-3-[(3£') -3- Iodb-3-pentenyl]-3,6-diniethyl-7-niethyl i -denebicyclo[4.4.0]decan-2-one (154) 154 To a cold (0 °C), stirred solution of ketone 194 (11.4 g, 30.5 mmol) in dry CH2C12 (250 mL) was added solid AModosuccinimide (8.24 g, 36.6 mmol) in one portion and the mixture was stirred for 1 h. This solution was then poured into a cold (0 °C) mixture of aqueous Na 2S 20 3 (1.0 M, 100 mL) and saturated aqueous NaHC0 3 (100 mL). The biphasic mixture was stirred for 0.5 h and the layers were separated. The aqueous layer was extracted with Et 20 (3 x 15 mL) and the combined organic layers were dried over anhydrous MgSC»4. After removal of the solvent under reduced pressure, the remaining crude material was purified by flash chromatography (500 g of silica gel, 40:1 pentane-Et20) to give 10.55 g (91%) of the iodide 154 as a colourless oil. IR (neat): 1703, 1637, 1448, 1380, 895 cm - 1. lH NMR (CDC13, 400 MHz) 8: 0.85 (s, 3H), 1.17 (s, 3H), 1.17-1.30 (m, 1H), 1.48-1.76 (m, includes 3-proton doublet at 8 1.67, J = 7.0 Hz, 9H total), 1.81-1.91 (m, 2 H), 2.04-191 2.17 (m, 2H), 2.21-2.32 (m, 1H), 2.35-2.51 (m, 3H), 4.67^ 1.73 (m, 2H), 6.18 (q, 1H, J = 7.0 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 16.2, 18.7, 21.2, 24.1, 26.6, 32.0, 32.1, 33.6, 33.8, 37.6, 44.8, 46.4, 53.7, 103.0, 105.8, 135.5, 155.7, 215.5. Exact mass calcd for Ci 8H 2 7IO: 386.1107. Found: 386.1101. Anal, calcd for Ci 8H 2 7IO: C 55.96, H 7.04. Found: C 56.09, H 7.01. 192 Preparation of (15* ,2/?* ,3£' ,6S*,9/?*) -3-Ethyl idene-6,9-dimethyl-10-methyl idene-tricyclo[7.4.0.0 2 , 6]tridecan-2-ol (155) To a cold (-78 °C), stirred solution of iodide 154 (10.4 g, 26.9 mmol) in dry THF (200 mL) was added a solution of BuLi (1.6 M in hexanes, 25.3 mL, 40.4 mmol) via syringe. After the mixture had been stirred for 40 min, H 2 0 (100 mL) and Et 20 (100 mL) were added. The biphasic mixture was allowed to warm to room temperature over 0.5 h and the layers were separated. The aqueous layer was extracted with the Et 20 (3 x 100 mL) and the combined organic layers were washed with brine (100 mL) and dried over anhydrous MgSC>4. The solvent was removed under reduced pressure and the resulting crude oil was purified by flash chromatography (500 g of silica gel, 20:1 pentane-Et20) to give 5.99 g (86%) of the alcohol 155 as a colourless oil. IR (neat): 3478, 1660, 1635, 1448, 1375, 1034, 1000, 986, 949, 909, 891, 864, 819 cm - 1. ! H NMR (CDCI3, 400 MHz) 8: 0.92 (s, 3H), 1.01 (s, 3H), 1.17 (s, 1H, exchanges with D20), 1.15-1.31 (m, 2H), 1.31-1.42 (m, 2H), 1.52-1.78 (m, 4H), 1.59 (d, 3H, J = 6.7 155 193 Hz), 1.81-1.95 (m, 2H), 2.07-2.18 (m, 2H), 2.27-2.40 (m, 3H), 4.56^ 1.58 (m, 2H), 5.88 (q, 1H, J =6.7 Hz). 1 3 C NMR (CDC13, 75.2 MHz) 8: 15.2, 19.3, 19.8, 22.6, 26.0, 29.3, 30.7, 32.4, 33.4, 36.4, 41.1, 47.0, 50.4, 81.5, 104.3, 121.5, 149.7, 158.9. Exact mass calcd for Ci 8 H 2 8 0: 260.2140. Found: 260.2144. 194 Preparation of (15*,6S*,9i?*)-3-[(5*)-2-Hydroxy-l-methylethyl]-6,9-dimethyl-10-methylidenetricyclo[7.4.0.0 2' 6]tridec-2-ene (151) To a stirred suspension of KH (3.98 g, 34.7 mmol) in dry THF (80 mL) was added a solution of alcohol 155 (4.52 g, 17.4 mmol) in dry THF (40 mL). The mixture was stirred for 1 h and a solution of 18-cr-6 ether (9.17 g, 34.7 mmol) in THF (40 mL) was added. After the mixture had been stirred 0.5 h, a solution of Bu3SnCH2I (18.71 g, 43.4 mmol) in THF (40 mL) was added via a cannula. The resulting thick white slurry was stirred for 1 h at room temperature and then was cooled to -78 °C. A solution of BuLi (1.6 M in hexanes, 48.8 mL, 78.1 mmol) was added, and the mixture was allowed to warm to room temperature over 30 min. H 2 0 (120 mL) and Et 20 (120 mL) were added, and the resulting layers were separated. The aqueous layer was extracted with Et 20 (3 x 120 mL), and the combined organic layers were dried over anhydrous MgSC^. The solvent was removed under reduced pressure, and the residual material was purified by flash chromatography (200 g of silica gel, 7:1 pentane-Et20) to yield 4.10 g (86%) of the alcohol 151 as a colourless oil. 195 IR (neat): 3388, 1633, 1455, 1373, 1032, 894, 788 cm - 1. ! H NMR (CDCI3, 400 MHz) 5: 0.92 (s, 3H), 0.96 (d, 3H, / = 6.8 Hz), 1.03 (s, 3H), 1.16-1.31 (m, 2H), 1.48-1.59 (m, 4H), 1.59-1.68 (m, 1H), 1.75-1.91 (m, 3H), 1.91-1.99 (m, 1H), 2.10-2.36 (m, 5H), 3.18-3.29 (m, 1H), 3.38-3.45 (m, 2H), 4.64^ 1.68 (m, 2H). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 16.1, 18.4, 24.7, 27.8, 28.5, 28.6, 33.1, 34.0, 34.8, 37.1, 38.8, 42.1, 46.6, 49.3, 66.0, 105.6, 134.5, 144.0, 157.6. Exact mass calcd for Ci 9 H 3 0 O: 274.2297. Found: 274.2289. Anal, calcd for Ci 9 H 3 0 O: C 83.15 H 11.02. Found: C 82.76 H 11.33. 196 Preparation of (lS*,6S*,9/?*)-3-[(S*)-2-(4-Methoxyphenyl)methoxy-l-methyIethyI]-6,9-dimethyl-10-methyIidenetricycIo[7.4.0.02'6]tridec-2-ene (199) To a stirred suspension of KH (354 mg, 8.81 mmol) in dry THF (40 mL) was added a solution of alcohol 151 (1.72 g, 6.28 mmol) in dry THF (40 mL) via a cannula. After the mixture had been stirred for 1 h, 4-methoxybenzyl chloride (1.38 g, 8.81 mmol) and solid BU4NI (465 mg, 1.26 mmol) were sequentially added. The mixture was stirred overnight at room temperature. H2O (60 mL) and Et20 (60 mL) were added and the resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 50 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous MgSC^. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (50 g of silica gel, 25:1 pentane-Et20) to yield 2.25 g (91%) of ether 199 as a colourless oil. PMBO 199 IR (neat): 2933, 2857, 1631, 1613, 1513, 1247 cm - 1. 197 ! H NMR (CDCI3, 400 MHz) 5: 0.92 (s, 3H), 1.00 (d, 3H, J= 6.4 Hz), 1.01 (s, 3H), 1.41-1.68 (m, 6H), 1.75-1.92 (m, 3H), 1.95-2.03 (m, 1H), 2.12-2.40 (m, 5H), 3.22-3.40 (m, 3H), 3.78 (s, 3H), 4.38-4.46 (m, 2H), 4.62-4.70 (m, 2H), 6.86 (d, 2H, J = 8.9 Hz), 7.23 (d, 2H,/=8.9Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 17.1, 18.5, 24.0, 27.2, 28.6, 29.4, 32.5, 33.2, 34.2, 37.5, 39.3, 41.9, 46.7, 48.8, 55.2, 72.5, 74.2, 105.3, 113.7 (two signals superimposed), 129.0 (two signals superimposed), 131.0, 136.0, 140.1, 157.9, 159.1. Exact mass calcd for C27H39O2 (M+H)+: 395.2950. Found: 395.2952. Anal, calcd for C27H38O2: C 82.12, H 9.71. Found C 82.12, H 9.74. 198 Preparation of (l^*,6/?*,9/?*)-3-[(S*)-2-(4-Methoxyphenyl)methoxy-l-methylethyl]-6,9-dimethyltricyclo[7.4.0.02'6]tridec-2-en-10-one (161) To a stirred solution of alkene 199 (2.10 g, 5.32 mmol) in 5:1 r-BuOH-H20 (120 mL) at room temperature were added KI0 4 (7.34 g, 31.9 mmol) and NaHC0 3 (4.47 g, 53.2 mmol). A catalytic amount of Os0 4 (25 mg, 0.01 mmol) was added and the resulting brown mixture was stirred for 72 h. Et20 (100 mL) and FLO (100 mL) were added and the resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 100 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (100 g of silica gel, 20:1 toluene-Et20) to yield 1.37 g (64.9%) of ketone 161 as a colourless oil. 0 P M B O 161 IR (neat): 2938, 2860, 1703, 1613, 1514, 1248 cm"1. 'H NMR (CDC13, 400 MHz) 8: 0.99 (s, 3H), 1.02 (d, 3H, J = 7.3 Hz), 1.03 (s, 3H), 1.35-1.66 (m, 5H), 1.76 (dt, 1H, J = 4.3, 14.3 Hz), 1.96-2.30 (m, 7H), 2.42-2.49 (m, 1H), 2.60 199 (dt, 1H, J = 6.1, 14.3 Hz), 3.20-3.35 (m, 3H), 3.78 (s, 3H), 4.35-4.45 (m, 2H), 6.84 (d, 2H, J = 8.9 Hz), 7.20 (d, 2H, J = 8.9 Hz). 1 3 C NMR (CDC13, 75.2 MHz) 5: 17.1, 17.2, 23.9, 25.8, 26.7, 29.4, 29.9, 32.6, 36.6, 37.8, 39.1, 46.7, 48.5, 50.9, 55.5, 72.6, 74.0, 113.7 (two signals superimposed), 129.0 (two signals superimposed), 130.8, 137.7, 138.2, 159.1, 216.3. Exact mass calcd for C26H40O3N (M+NILf: 414.3008. Found 414.2997. Anal, calcd for C26H36O3: C 78.75, H 9.15. Found C 78.63, H 9.19. 200 Preparation of a 1:1 Mixture of (l/f*,6i?*,9/?*,115*)-3-[(5*)-2-(4-Methoxyphenyl)-methoxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.4.0.0 2 ' 6]trideca-2-ene-ll-car-boxylic Ac id Ethyl Ester (226a) and (l/f*,6i?*,9/?*)-3-[(5*)-2-(4-Methoxyphenyl)-methoxy-l-methylethyl]-6,9-dimethyl-10-hydroxytricyclo[7.4.0.0 2 , 6]trideca-2,10-di-ene-l l -carboxylic A c i d Ethyl Ester (226b) 226a 226b To a stirred suspension of NaH (132 mg, 5.50 mmol) in dry THF (40 mL) was added a solution of ketone 161 (725 mg, 1.83 mmol) in dry THF (10 mL). (EtO)2CO (425 mg, 3.6 mmol) was added via syringe and the mixture was heated to reflux for 20 min. A catalytic amount of KH (5 mg, 0.13 mmol) was added and the mixture was refluxed for a further 18 h. The solution was cooled to room temperature and dilute aqueous HC1 (0.5 M, 30 mL) was added. Et20 (50 mL) was added and the resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 50 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous MgSCU. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (25 g of silica gel, 10:1 pentane-Et20) to yield 625 mg (74%) of a mixture of keto ester 226a and enol ester 226b as a colourless oil. 201 IR (neat): 2937, 2859, 1743, 1709, 1649, 1613, 1514, 1245 cm - 1. A solution of 1:1 mixture of keto ester 226a and enol ester 226b in CDCI3 exhibited the following NMR data: 'H NMR (CDCI3, 400 MHz) 5: 0.95-1.1 (m), 1.23-1.32 (m), 1.35-1.96 (m), 2.00-2.40 (m), 2.52 (bd, 7= 12 Hz), 3.13-3.36 (m), 3.68 (dd, J= 5.5, 13.5 Hz), 3.78 (s), 4.12^ 1.26 (m), 4.35-4.45 (m), 6.82-6.88 (m), 7.18-7.25 (m), 12.4 (s). 1 3 C NMR ( C D C I 3 , 75.2 MHz) 8: 14.2, 14.3, 16.8, 16.9, 17.1, 18.0, 22.6, 23.3, 23.8, 24.1, 24.7, 29.2, 29.4, 29.5, 29.8, 31.7, 32.3, 32.7, 36.4, 37.0, 39.1, 39.3, 41.5, 43.1, 46.8, 48.3, 48.4, 51.2, 53.1, 55.2, 60.2, 60.9, 72.5, 72.6, 73.8, 74.0, 94.8, 113.7 (four signals superimposed), 128.9 (four signals superimposed), 131.0 (two signals superimposed), 136.3, 137.6, 138.3, 139.2, 159.1, 170.6, 173.5, 178.2 (three signals not accounted for). Exact mass calcd for C29H41O5 (M+H)+: 469.2954. Found: 469.2950. Anal, calcd for C Z Q H K A : C 74.33, H 8.60. Found: C 74.19, H 8.60. 202 Preparation of a 3:1 Mixture of (l/?*,6/?*,9/f*)-ll-(Iodomethyl)-3-[(5*)-2-(4-methoxy-phenyl)methoxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.4.0.02'6]-tridec-2-ene-ll-carboxyIic Acid Ethyl Esters (160) To a stirred solution of a mixture of keto ester 226a and enol ester 226b (139 mg, 0.297 mmol) in dry THF (40 mL) was added a solution of TBAF (1.0 M in THF, 0.6 ml, 0.6 mmol). The mixture was stirred for 1 h and neat C H 2 I 2 (800 mg, 3.0 mmol) was added. After the mixture had been stirred for an additional 1 h, Et20 (30 mL) and saturated aqueous NaHCCh (30 mL) were added. The resulting layers were separated and the aqueous layer was washed with Et 20 (3 x 30 mL). The combined organic layers were dried over anhydrous MgSCv, concentrated and purified by flash chromatography (5 g of silica gel, 5:1 petroleum ether-Et20) to yield 141 mg (78.0%) of a 3:1 mixture of diasteriomeric iodides 160 as a colourless oil. PMBO 160 The relative configurations of the isomers were not determined. The 3:1 mixture of diasteriomeric iodides 160 exhibited the following spectral data: 203 IR (neat): 2937, 2859, 1735, 1708, 1614, 1514 cm"1. ! H NMR (CDC13, 400 MHz) (signals assigned to major isomer) 6: 0.94 (s, 3H), 0.98 (s, 3H), 0.99 (d, 3H, J = 5.5 Hz), 1.27 (t, 3H, J= 7.0 Hz), 1.35-2.55 (m, 12H), 2.67 (br d, 1H, J = 12.8 Hz), 3.13-3.35 (m, 3H), 3.52 (m, 2H), 3.79 (s, 3H), 4.20 (dq, 2H, 7= 2.1, 7.0 Hz), 4.36-4.45 (m, 2H), 6.86 (d, 2H, J = 8.6 Hz), 7.22 (d, 2H, / = 8.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) (signals assigned to major isomer) 5: 9.5, 14.0, 17.0, 17.1, 20.7, 23.6, 29.4, 29.8, 32.0, 32.6, 36.1, 39.2, 40.3, 48.1, 49.6, 55.2, 57.9, 62.0, 72.5, 73.8, 113.6 (two signals superimposed), 129.0 (two signals superimposed), 130.8, 137.8, 137.9, 159.0, 169.3, 210. Exact mass calcd for fragment C22H32O4I (M-MeOPhCH2)+: 487.1346. Found: 487.1337 Exact mass calcd for fragment C 8 H 9 0 (MeOPhCH2+): 121.0653. Found: 121.0654 204 Preparation of (li?*,6i?*,9i?*,12S*)-3-[(5*)-2-(4-Methoxyphenyl)methoxy-l-methyI-ethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.0 2 , 6]tetradec-2-ene-12-carboxylic Ac id Ethyl Ester (159) To a stirred solution of a 3:1 mixture of iodides 160 (161 mg, 0.265 mmol) in dry THF (30 mL) was added a solution of SmL: (0.1 M in THF, 7.9 mL, 0.79 mmol). The resulting mixture was stirred for 1 h at room temperature. Dilute aqueous HC1 (0.5 M, 40 mL) and Et 20 (40 mL) were added and the resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 40 mL) and the combined organic layers were washed with brine (40 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (5 g of silica gel, 40:1 petroleum ether-Et20) to yield 91 mg (71%) of keto ester 159 as a colourless oil. JR (neat): 2933, 2859, 1733, 1698, 1514, 1248 cm - 1. 205 *H NMR (CDCI3, 400 MHz) 5: 0.97 (d, 3H, /= 6.8 Hz), 1.00 (s, 3H), 1.07 (s, 3H), 1.18-1.23 (m, 1H), 1.24 (t, 3H, J = 7.1 Hz), 1.40-1.72 (m, 5H), 1.81 (dt, 1H, J = 5.2, 13.3 Hz), 1.85-2.30 (m, 5H), 2.65 (br d, 1H, J = 11.2 Hz), 2.77-2.84 (m, 2H), 3.05 (dd, 1H, J = 9.5, 14.4 Hz), 3.10-3.20 (m, 1H), 3.23-3.34 (m, 2H), 3.78 (s, 3H), 4.08-4.15 (m, 2H), 4.36-4.44 (m, 2H), 6.85 (d, 2H, J = 8.6 Hz), 7.21 (d, 2H, J = 8.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 14.1, 14.6, 16.6, 24.2, 26.6, 29.2, 29.9, 33.0, 33.1, 36.0, 38.3, 38.7, 39.3, 43.3, 49.0, 53.6, 55.2 60.8, 72.5, 73.8, 113.7 (two signals superimposed), 128.9 (two signals superimposed), 130.8, 136.6, 139.4, 159.0, 174.5, 215.0. Exact mass calcd for C30H43O5 (M+H)+: 483.3110. Found: 483.3114. Anal, calcd for C30H42O5: C 74.66, H 8.77. Found: C 74.77, H 8.99. 206 Table 14. *H NMR (CDC13,400 MHz) Data for Keto Ester 159: NOED Experiment. 118 Assignments ' H N M R Observed NOEs H-x 5 ppm (Multiplicity, J (Hz)) H - l f l 2.65 (brd, 11.2) H-18 ,H-ll(p) H-4 part of mat 1.85-2.30, part of mat 1.40-1.72 H-5 part of mat 1.40-1.72 H-7 part of mat 1.40-1.72, H-8 1.81 (dt, 5.2, 13.3), 1.18-1.23 (m) H - l 1(a) part of m at 2.77-2.84 H - l 1(B) 3.05 (dd, 9.5,14.4) H-12 part of mat 2.77-2.84 H-13 part of mat 1.85-2.30 H-14 part of mat 1.85-2.30 H-15 3.10-3.20 (m) H-16 3.23-3.34 (m) H-17 0.97 (d, 6.8) H-18a 1.07 (s) H - l H-19 a 1.00 (s) H - l 1(a) H - l ' 4.08-4.15 (m) H-3', H-7' 7.21 (d, 8.6) H-4', H-6' 6.85 (d, 8.6) H-8' 3.78 (s) H - l " 4.36^.44 (m) H-2" 1.24 (t, 7.1) a Irradiation of this signal generated the corresponding NOEs in the right hand column 207 Table 15. 1 3 C NMR (CDCI3,100.6 MHz) and lU NMR (CDCI3,400 MHz) Data for Keto Ester 159: HMQC Experiment. Assignments C-x W C N M R 5 ppm Observed HMQC Correlations (5 ppm) C - l 43.3 H - l (2.65) C-2 139.4 C-3 136.6 C-4 29.2 H-4 (part of m at 1.40-1.72, part of mat 1.85-2.30) C-5 38.3 H-5 (part of m at 1.40-1.72) C-6 49.0 C-7 36.0 H-7(part of m at 1.40-1.72) C-8 33.1 H-8 (1.81, part of m at 1.18-1.23) C-9 53.6 C-10 215.0 C - l l 39.3 H - l 1 (part of m at 2.77-2.84, 3.05) C-12 38.7 H-12 (part of m at 2.77-2.84) C-13 29.9 H-13 (part of m at 1.85-2.30) C-14 26.6 H-14 (part of m at 1.85-2.30) C-15 33.0 H-15 (3.10-3.20) C-16 73.8 H-16 (3.24-3.34) C-17 16.6 H-17 (0.97) C - l 8 24.2 H - l 8 (1.07) C-19 14.6 H-19 (1.00) C-20 174.5 c - r 60.8 H- l ' (4.08-4.15) C-2' 130.8 C-3', C-7' 128.9 H-3', H-7' (7.21) C-4', C-6' 113.7 H-4', H-6' (6.85) C-5' 159.0 C-8' 55.2 H-8' (3.78) C- l" 72.5 H- l" (4.36^1.44) C-2" 14.1 H-2" (1.24) 208 Preparation of a 1:1 Mixture of (l/?*,6/?*,9/?*)-3-[(S*)-2-(4-MethoxyphenyI)-methoxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.02'6]tetra-dec-2-ene-12-carboxaldehydes (158) 158 To a cold (0 °C) stirred solution of keto ester 159 (181 mg, 0.374 mmol) in dry Et 20 (20 mL) was added a solution of DIBALH (1.0 M in hexanes, 1.8 mL, 1.80 mmol) and the resulting mixture was stirred for 1 h. After this time, the mixture was warmed to room temperature and was stirred for an additional 1 h. Saturated aqueous NH4CI-NH3 (pH 8, 180 uL) was added and the mixture was stirred for 1 h. Anhydrous MgSC"4 (100 g) was added and the mixture was stirred for 1 h. EtOH (2 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through a sintered glass funnel (4 cm diameter) containing Florisil® (4 cm depth) on top of a thin layer of Celite®. The column was washed with 20:1 EtOH-Et20 (50 mL). The solvent of the combined eluates was removed under reduced pressure to give a crude mixture of the diols. The crude mixture of diols was taken up in dry CH2C12 (5 mL) and the solution was added to a solution of Dess-Martin's periodinane reagent (510 mg, 1.2 mmol) in dry CH2C12 (30 mL). After the mixture had been stirred for 1 h, saturated aqueous NaHC03 (100 mL) and saturated aqueous Na2S203 (100 mL) were added. The biphasic mixture 209 was stirred for 1 h and the layers were then separated. The aqueous portion was extracted with Et20 (3 x 10 mL) and the combined organic layers were dried over anhydrous MgSC>4. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (10 g of silica gel, 2:1 petroleum ether-Et20) to give 141 mg (86%) of a 1:1 mixture of epimeric keto aldehydes 158 as a colourless oil. The 1:1 mixture of epimeric keto aldehydes 158 exhibited the following spectral data: JR (neat): 2932, 2857, 1726, 1697, 1514, 1248, 1089 cm - 1. ! H NMR (CDCI3, 400 MHz) 5: 0.96 and 0.99 (s, s, ratio 1:1, 3H), 0.96-1.00 (m, 3H), 1.08 and 1.10 (s, s, ratio 1:1, 3H), 1.14-1.24 (m, 2H), 1.42-1.92 (m, 6H), 2.05-2.46 (m, 5H), 2.53-2.79 (m, 2H), 2.88-3.15 (m, 2H), 3.23-3.35 (m, 2H), 3.78 (s, 3H), 4.35^.44 (m, 2H), 6.82-6.87 (m, 2H), 7.18-7.23 (m, 2H), 9.60 and 9.63 (s, s, ratio 1:1, 1H). 1 3 C NMR (CDCI3, 75.2 MHz) 6: 14.0, 14.3, 16.3, 16.7, 24.1, 24.4, 25.9, 26.7, 27.4, 29.0, 29.1, 29.2, 32.7, 33.0, 33.1, 35.7, 35.8, 36.0, 37.5, 43.0, 43.1, 45.1, 48.9, 49.2, 49.3, 53.4, 54.5, 55.2, 72.5, 73.7, 73.8, 113.6 (two signals superimposed), 113.7 (two signals superimposed), 128.8 (two signals superimposed), 128.9 (two signals superimposed), 130.7, 130.8, 135.9, 137.0, 138.7, 139.7, 159.0, 201.0, 201.5, 214.9, 215.8 (six signals not accounted for). Exact mass calcd for C28H42O4N (M+NRO*: 456.3114. Found: 456.3122. Anal, calcd for C28H38O4: C 76.68, H 8.73. Found: C 77.00, H 8.81. 210 Preparation of (l/?*,6/?*,9/f*)-3-[(S*)-2-(4-Methoxyphenyl)methoxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.0 2 , 6]tetradeca-2,ll-diene-12-carboxaldehyde (249) 249 240 To a stirred solution of a 1:1 mixture of keto aldehydes 158 (106 mg, 0.242 mmol) in dry benzene (12 mL) over 3 A mol sieves was added piperidine (103 mg, 1.21 mmol). The mixture was heated to reflux for 3 h and cooled to room temperature. The solvent and excess piperidine were removed under reduced pressure and the remaining material was taken up in dry THF (12 mL). The mixture was cooled to -78 °C and solid PhSeCl (232 mg, 1.21 mmol) was added. After the mixture had been stirred for 5 min, Et20 (15 mL) and H 20 (15 mL) were added. The biphasic mixture was warmed to room temperature and stirred for 3 h. The phases were separated and the aqueous phase was extracted with Et20 (3 x 10 mL). The combined organic layers were concentrated and taken up in MeOH (10 mL). Saturated aqueous KHC0 3 (2 mL) and solid KI0 4 (557 mg, 2.42 mmol) were sequentially added, and the mixture was stirred for 20 min. Et20 (20 mL) and H2O (20 mL) were added, and the resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 20 mL). The combined organic layers were washed with brine 211 (20 mL) and dried over anhydrous MgSCv The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (5 g of silica gel, 4:1 petroleum ether-Et20) to yield 79.5 mg (75.2%) of the a,P-unsaturated ketone 249 and 2.4 mg (2.3%) of the p,y-unsaturated ketone 240 as colourless oils a,P-Unsaturated ketone 249 exhibited the following spectral data: JR (neat): 2932, 2152, 1697, 1514, 1248 cm"1. ] H NMR (CDC13, 400 MHz) 8: 0.99 (d, 3H, J = 6.7 Hz), 1.03 (s, 3H), 1.10 (s, 3H), 1.22-1.64 (m, 5H), 1.83-1.97 (m, 2H), 2.23-2.43 (m, 4H), 2.59 (dt, 1H, J= 18.6, 4.3 Hz), 2.67 (br d, 1H, J = 9.7 Hz), 3.02-3.13 (m, 1H), 3.24-3.36 (m, 2H), 3.80 (s, 3H), 4.34-4.45 (m, 2H), 6.63 (m), 6.86 (d, 2H, / = 8.6 Hz), 7.21 (d, 2H, J = 8.6 Hz), 9.56 (s, 1H). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 15.9, 16.5, 24.2, 25.2, 26.6, 29.2, 33.1, 33.2, 35.5, 37.6, 43.0, 49.4, 55.0, 55.3, 72.6, 73.7, 113.7 (two signals superimposed), 128.9 (two signals superimposed), 130.7, 136.9, 139.6, 144.2, 146.1, 159.1, 194.7, 209.6. Exact mass calcd for C28H40O4N (M+NHO*: 454.29575. Found: 454.29515 212 Preparation of (l/?*,6/f*,9/?*)-3-[(S*)-2-(4-Methoxyphenyl)methoxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.02'6]tetradeca-2,12-diene-12-carboxaIdehyde (240) 240 To a stirred solution of ketone 249 (51.6 mg, 0.118 mmol) in dry benzene (5 mL) was added DBN (29.3 mg, 0.236 mmol). The mixture was heated to reflux for 12 h and cooled to room temperature. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (2 g of silica gel, 3:1 petroleum ether-Et20) to yield 49 mg (95.8%) of ketone 240 as a colourless oil. IR (neat): 2931, 2854, 1704, 1688, 1513, 1248 cm - 1. *H NMR (CDC13, 500 MHz) 8: 0.99 (d, 3H, J = 6.7 Hz), 1.02 (s, 3H), 1.13 (s, 3H), 1.20-1.30 (m, 1H), 1.50-1.70 (m, 4H), 1.94 (dt, 1H, J = 5.3, 13.1 Hz), 2.15-2.25 (m, 2H), 2.66-2.75 (m, 1H), 3.05-3.10 (m, 1H), 3.14 (dd, 1H, J = 6.4, 19.8 Hz), 3.25-3.35 (m, 3H), 3.46 (d, 1H, J = 14.0 Hz), 3.72 (br d, 1H, J = 14.0 Hz), 3.78 (s, 3H), 4.35^1.46 (m, 2H), 6.63-6.68 (m, 1H), 6.85 (d, 2H, /= 8.6 Hz), 7.20 (d, 2H, J= 8.6 Hz), 9.33 (s, 1H). 213 1 3 C NMR (CDCI3, 75.2 MHz) 5: 12.8, 16.4, 24.2, 29.1, 31.7, 32.9, 33.3, 34.1, 35.9, 38.1, 39.6, 49.4, 55.0, 55.3, 72.7, 73.6, 113.7 (two signals superimposed), 128.9 (two signals superimposed), 130.7, 135.7, 137.0, 137.9, 153.7, 159.2, 192.3, 210.6. Exact mass calcd for C28H40O4N (M+NKUf: 454.29575. Found: 454.29541. Anal, calcd for C28H3604: C 77.03, H 8.31. Found: C 77.03, H 8.36. 214 Table 16. 1 3 C NMR (CDCI3,100.6 MHz) and lK NMR (CDC13,400 MHz) Data for Ketone 240: HMQC Experiment. 18 Assignments 1 3 CNMR Observed HMQC Correlations C-x 8 ppm (8 ppm) C - l 39.6 H - l (part of m at 3.25-3.35) C-2 135.7 C-3 137.0 C ^ 29.1 H-4 (2.15-2.25) C-5 35.9 H - l (part of mat 1.50-1.70) C-6 49.4 C-7 38.1 H-7 (part of m at 1.50-1.70) C-8 32.9 H-8 (1.94, 1.20-1.30) C-9 55.0 C-10 210.6 C - l l 34.1 H - l l (3.46,3.72) C-12 137.9 C-13 153.7 H-13 (6.63-6.68) C-14 31.7 H-14 (2.65-2.75,3.14) C-15 33.3 H-15 (3.05-3.10) C-16 73.6 H-16 (part of m at 3.25-3.35) C-17 16.4 H-17 (0.99) C - l 8 24.2 H-18 (1.13) C-19 12.8 H-19 (1.02) C-20 192.3 H-20 (9.33) C-l* 72.7 H - l ' (4.35-4.46) C-2' 130.7 C-3', C-7' 128.9 H-3', H-7' (7.20) C-4', C-6' 113.7 H-4', H-6' (6.85) C-5' 159.2 C-8' . 55.3 H-8' (3.78) 215 Preparation of (l/?*,6/f*,9i?*)-3-[(S*)-2-Hydroxy-l-methylethyl]-6,9-diniethyl-10-oxotricyclo[7.5.0.0 ' ]tetradeca-2,12-diene-12-carbaldehyde [ (±) -Sarcodonin G] (36) To a stirred solution of ketone 240 (6.2 mg, 0.014 mmol) in a biphasic mixture of 20:1 CH 2 C1 2 -H 2 0 (5.25 mL) was added DDQ (4.8 mg, 0.021 mmol). The mixture was stirred at room temperature for 0.5 h and H2O (5 mL) was added. The layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSC^. The solvent was removed under reduced pressure and the residual material was purified by flash chromatography (1 g of silica gel, 1:1 petroleum ether-Et20) to yield 4.1 mg (92%) of (±)-sarcodonin G (36) as an amorphous solid. IR (KBr): 3445, 1703, 1640, 1450, 1376 cm - 1. 'H NMR (CDCI3, 400 MHz) 5: 0.97 (d, 3H, J = 6.9 Hz), 1.03 (s, 3H), 1.14 (s, 3H), 1.24-1.30 (m, 1H), 1.46 (s, 1H), 1.49-1.55 (m, 1H), 1.58-1.70 (m, 2H), 1.95 (dt, 1H, J = 5.0, 216 13.4 Hz), 2.21-2.40 (m, 3H), 2.69-2.80 (m, 1H), 2.98-3.08 (m, 1H), 3.10-3.20 (m, 1H), 3.36 (br d, 1H, J = 12.6 Hz), 3.41-3.51 (m, 3H), 3.71-3.75 (m, 1H), 6.70-6.73 (m, 1H), 9.35 (s, 1H). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 12.7, 15.6, 24.8, 28.6, 32.1, 32.7, 34.1, 35.2, 35.5, 37.7, 39.7, 49.8, 55.3, 65.8, 135.9 (two signals superimposed), 141.3, 153.2, 192.2, 210.3. Exact mass calcd for C 2oH 2 80: 316.2039. Found: 316.2038. 217 Table 17. Comparison of *H NMR Data for Synthetic (l/?*,6fl*,9fl*)-3-[(S*)-2-Hydroxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.0 ' ]tetradeca-2,12-diene-12-carbox-aldehyde [(±)-Sarcodonin G] (36) (CDC13, 400 MHz) with those Reported Natural (-)-Sarcodonin G (36) (CDC13,250 MHz). 16 for 20 C H O 36 s h o w i n g I U P A C - b a s e d n u m b e r i n g 15 C H O 36 s h o w i n g I U P A C - b a s e d n u m b e r i n g lH NMR (CDCI3,400 MHz) Signals Displayed0 by Synthetic (±)-Sarcodonin G (36) ! H Assignment H-x Reported *H NMR (CDC13, 250 MHz) Signals Displayed by Natural (-)-Sarcodonin G (36) Cyathane Numbering 0 ppm (Multiplicity, J (Hz)) 8 ppm (Multiplicity, J (Hz)) 0.97 (d, 6.9) H-17 0.96 (d, 7.3) H-20 1.03 (s) H-19 1.01 (s) H-16 1.14 (s) H-18 1.12 (s) H-17 1.24-1.30 (m) 1.24 (dt, 3.9, 13.2) 1.46 (s) part of m at 1.59 1.49-1.55 (m) part of m at 1.59 1.58-1.70 (m) part of m at 1.59 1.95 (dt, 5, 13.4) 1.94 (dt,5.3, 13.3) 2.21-2.40 (m) 2.31 (m) 2.69-2.80 (m) 2.74 (m) 2.98-3.08 (m) H-15 3.02 (sextet, 7.3) H-18 3.10-3.20 (m) 3.16 (dd, 13.4, 6.4) 3.36 (brd, 12.6) 3.34 (d, 12) 3.41-3.51 (m) 3.42 (d, 13.9), 3.45 (d, 7.3) 3.71-3.75 (m) 3.72 (br d, 13.6)) 6.70-6.73 (m) H-13 6.71 (m) H - l l 9.35 (s) H-20 9.31 H-15 a The difference between observed and reported 8 is likely due to the CDC13 reference. 218 Table 18. Comparison of 1 3 C NMR Data for Synthetic (l/?*,6/J*,9/?*)-3-[(5*)-2-Hydroxy-l-methylethyl]-6,9-dimethyl-10-oxotricyclo[7.5.0.02'6]tetradeca-2,12-diene-12-carboxaldehyde [(±)-Sarcodonin G] (36) (CDC13, 400 MHz) with those Reported16 for Natural (-)-Sarcodonin G (36) (CDC13,62.5 MHz). 1 8 1 7 36 showing lUPAC -based 3 6 s h o w i n g lUPAC -based numbering numbering 1 3 CNMR (CDC13,100.6 MHz) Signals Displayed by Synthetic (±)-Sarcodonin G (36) 13C assignment C-x Reported liC NMR (CDC13, 62.5 MHz) Signals Displayed by Natural (-)-Sarcodonin G (36) Cyathane Numbering 5 ppm 8 ppm 12.7 C-19 12.7 C-16 15.6 C-15 15.6 C-20 24.8 C - l 8 24.8 C-17 28.6 28.6 32.1 32.1 32.7 32.7 34.1 34.1 35.2 35.2 35.5 35.5 37.7 37.7 39.7 39.5 49.8 49.8 55.3 55.3 65.8 C-16 65.8 C-19 135.9 (two signals superimposed) 135.8, 135.9 141.3 141.2 153.2 C-13 153.5 C - l l 192.2 C-20 192.4 C-15 210.3 C-10 210.6 C-14 219 4.3. Synthetic Studies Directed Towards Cyathane Diterpenoid (± ) -Cya th in A 4 Preparation of (l/?*,6/?*,9/f*)-12-Hydroxymethyl-3-[(lS*)-2-(4-methoxyphenyI)-meth-oxy-l-methylethyl]-6,9-dimethyItricyclo[7.5.0.0 2' 6]tetradeca-2,12-dien-10-one (254) 254 256 To a stirred solution of keto aldehyde 240 (200 mg, 0.458 mmol) in /-PrOH (10 mL) was added (i-PrO)3Al (140 mg, 0.687 mmol). The mixture was heated to 60 °C for 8 h and cooled to room temperature. Et20 (10 mL) and aqueous NH4CI-NH3 (pH 8, 0.1 mL) were added and the resulting slurry was stirred for 18 h. MgSCu (100 mg) was added and the mixture was stirred for 1 h. The slurry was filtered through a column of Florisil® (1 g) and the column was washed with a mixture of 1:1 Et20-EtOH (10 mL). The solvent of the eluate was removed under reduced pressure and the resulting material was purified by flash chromatography (5 g of silica gel, 9:1 Et20-petroleum ether) to give 110 mg (55%) of keto alcohol 254 and 65 mg (32%) of diol 256 as colourless oils. 220 The diol 256 (65 mg, 0.147 mmol) was taken up in dry CH2CI2 (2 mL) and the solution was added to a solution of Dess-Martin's periodinane reagent (250 mg, 0.6 mmol) in dry CH2CI2 (15 mL). After the mixture had been stirred for 1 h, saturated aqueous NaHCC>3 (50 mL) and saturated aqueous Na2S203 (50 mL) were added. The biphasic mixture was stirred for 1 h and the layers were separated. The aqueous portion was extracted with Et20 (3x5 mL) and the combined organic layers were dried over anhydrous MgSC>4. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (5 g of silica gel, 3:1 petroleum ether-Et20) to give 55 mg (86%) of keto aldehyde 240 as a colourless oil. Keto aldehyde 240 was resubmitted to the reduction reaction to yield an additional 31 mg of keto alcohol 254 for a total overall yield of 141 mg (70%). Keto alcohol 254 exhibited the following spectral data: JR (neat): 3436, 2932, 2855,1702,1613,1513 cm"1. ! H NMR (CDCI3, 400 MHz) 8: 0.99 (d, 3H, J = 6.7 Hz), 1.03 (s, 3H), 1.12 (s, 3H), 1.45-1.65 (m, 6H), 1.91 (dt, 1H, J = 5.0, 12.8 Hz), 2.10-2.35 (m, 2H), 2.45-2.53 (m, 1H), 2.68-2.82 (m, 2H), 3.06-3.15 (m, 1H), 3.21-3.36 (m, 3H), 3.79 (s, 3H), 3.92 (br d, 1H, J = 12.8 Hz), 3.95^.08 (m, 2H), 4.32^.49 (m, 2H), 5.60-5.69 (m, 1H), 6.85 (d, 2H, J = 8.6 Hz), 7.21 (d, 2H, J = 8.6 Hz). 221 1 3 C NMR (CDCI3, 75.2 MHz) 5: 12.9, 16.5, 24.3, 29.2, 30.0, 32.8, 33.0, 36.1, 38.2, 39.3, 40.3, 49.3, 54.6, 55.3, 68.8, 72.5, 73.8, 113.7 (two signals superimposed), 126.6, 128.8 (two signals superimposed), 130.8, 131.7, 136.5, 138.5, 159.0, 211.3. Exact mass calcd for C28H39O4 (M+H)+: 439.28482. Found: 439.28435. Diol 256 exhibited the following spectral data: IR (neat): 3368, 2931, 2860, 1613, 1514 cm - 1. } H NMR (CDCI3, 400 MHz) 5: 0.89 (s, 3H), 0.99 (d, 3H, J = 6.8 Hz), 1.05 (s, 3H), 1.32-1.58 (m, 8H), 1.72-1.90 (m, 2H), 2.02-2.16 (m, 2H), 2.21-2.64 (m, 3H), 3.03-3.13 (m, 1H), 3.24-3.38 (m, 2H), 3.43 (d, 1H, J= 8.1 Hz), 3.79 (s, 3H), 3.92-3.99 (m, 2H), 4.38-4.47 (m, 2H), 5.85 (d, 1H, J = 7.0 Hz), 6.85 (d, 2H, J = 8.7 Hz), 7.21 (d, 2H, J = 8.7 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 5: 16.3, 17.1, 24.5, 28.2, 29.1, 30.3, 31.8, 33.1, 35.8, 37.6, 39.0, 45.2, 49.8, 55.2, 68.4, 72.4, 74.0, 75.3, 113.7 (two signals superimposed), 128.9 (two signals superimposed), 130.0, 130.9, 134.5, 137.6, 142.0, 159.0. Exact mass calcd for C28H44O4N (M+NH0+: 458.32703. Found: 458.32817. 222 Preparation of (l/f*,6^*,9/?*,13S*)-13-Hydroxy-12-hydroxymethyI-3-[(S*)-2-(4-methoxyphenyl)methoxy-l-methyIethyl]-6,9-dimethyltricyclo[7.5.0.02'6]tetradeca-2,ll-dien-10-one (267) 266 267 To a cool (0 °C), stirred solution of keto alcohol 256 (110 mg, 0.250 mmol) in dry CH2CI2 (6 mL) was added r-BuC^H (70% in water, 51 uL, 0.375 mmol) via syringe. VO(acac)2 (7 mg, 0.026 mmol) was added and the mixture was stirred for 2 h. The solution was poured into a cold (0 °C) mixture of aqueous Na2S203 (1.0 M, 3 mL) and saturated aqueous NaHCC>3 (3 mL) and the mixture was stirred for 0.5 h. The resulting layers were separated and the aqueous layer was extracted with CH2C1 2 (3x5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous MgSC>4. The solvent was removed under reduced pressure and the residual material, crude keto epoxide 266, was taken up in dry benzene (10 mL). DBN (62 mg, 0.50 mmol) was added and the mixture was heated to reflux for 6 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude oil was 223 purified by flash chromatography (5 g of silica gel, 50:1 Et20-petroleum ether) to yield 74 mg (65%) of keto diol 267 as a colourless oil. IR (neat): 3402, 2932, 1665, 1514 cm - 1. *H NMR (CDC13, 400 MHz) 8: 0.98 (d, 3H, J = 6.8 Hz), 1.03 (s, 3H), 1.09 (s, 3H), 1.20-1.32 (m, 1H), 1.42-1.67 (m, 5H), 1.78 (dt, 1H, J = 4.9, 13.0 Hz), 1.98-2.09 (m, 1H), 2.13-2.34 (m, 3H), 2.42-2.57 (m, 1H), 3.09-3.20 (m, 2H), 3.32 (d, 2H, J = 7.9 Hz), 3.79 (s, 3H), 4.16^ 1.45 (m, 5H), 5.96 (s, 1H), 6.86 (d, 2H, J = 8.6 Hz), 7.21 (d, 2H, J = 8.6 Hz). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 14.8, 16.5, 24.1, 39.0, 33.0, 33.9, 34.6, 36.0, 36.9, 38.1, 49.4, 55.1, 65.7, 65.8, 70.5, 72.8, 73.9, 113.8 (2 signals superimposed), 124.9, 129.3 (2 signals superimposed), 130.4, 135.6, 140.3, 150.4, 159.3, 210.1. Exact mass calcd for C 28H 3 80 5: 454.27191. Found: 454.27163. 224 Preparation of (li?*,6/?*,9/f*,13S*)-13-Hydroxy-12-hydroxyniethyl-3-[(S*)-2-hydroxy-l-methylethyl]-6,9-dimethyltricyclo[7.5.0.0 2 ' 6]tetradeca-2,ll-dien-10-one (268) 268 To a stirred solution of keto diol 267 (11 mg, 0.024 mmol) in a biphasic mixture of 20:1 C H 2 C 1 2 - H 2 0 (10.5 mL) was added DDQ (11 mg, 0.048 mmol). The mixture was stirred at room temperature for 1 h and H2O (10 mL) was added. The layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSC>4. The solvent was removed under reduced pressure and the residual material purified by flash chromatography (1 g of silica gel, 10:1 Et20-MeOH) to yield 5.4 mg (64%) df keto triol 268 as an amorphous solid. IR: not obtained 225 *H NMR (CDCI3, 400 MHz) 5: 0.96 (d, 3H, J = 6.7 Hz), 1.04 (s, 3H), 1.12 (s, 3H), 1.20-1.34 (m, 2H), 1.43-1.51 (m, 1H), 1.53-1.69 (m, 4H), 1.81 (dt, 1H, J = 4.9, 13.4 Hz), 1.97-2.07 (m, 1H), 2.19-2.37 (m, 2H), 2.63-2.70 (m, 1H), 3.07-3.15 (m, 1H), 3.25-3.31 (m, 1H), 3.37-3.52 (m, 3H), 4.24-4.42 (m, 2H), 4.55-4.59 (m, 1H), 6.00 (s, 1H). 1 3 C NMR: not obtained Exact mass calcd for C20H30O4: 334.21442. Found: 334.21369. 226 Preparation of (l/?*,6/?*,9/f*,13/?*)-3-[(S*)-2-(4-Methoxyphenyl)methoxy-l-methyl-ethyl]-6,9-dimethyl-13-(4-nitro-benzoyl)oxy-12-(4-nitro-benzoyl)oxymethyltricyclo-[7.5.0.0 2 , 6]tetradeca-2,ll-dien-10-one (269) O P N B 269 To a stirred solution of keto diol 267 (20 mg, 0.044 mmol) in dry benzene (2 mL) were added PPh3 (57 mg, 0.217 mmol) and p-nitrobenzoic acid (33 mg, 0.193 mmol). Neat DEAD (38 mg, 0.217 mmol) was added via syringe and the mixture was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (1 g of silica gel, 1:1 Et20-petroleum ether) to give 23 mg (70%) of the keto diester 269 as an amorphous solid. IR (neat): 2920, 2850, 1729, 1688, 1608, 1529 cm"1. ! H NMR (CDC13, 400 MHz) 5: 0.98 (d, 3H, J = 6.7 Hz), 1.08 (s, 3H), 1.21 (s, 3H), 1.34-1.80 (m, 6H), 2.16-2.38 (m, 3H), 2.81-2.87 (m, 1H), 2.93-2.98 (m, 1H), 3.03-3.10 (m, 1H), 3.22-3.35 (m, 2H), 3.75 (s, 3H), 4.31-4.38 (m, 2H), 5.02 (s, 2H), 5.70-5.78 (m, 227 1H), 6.31 (s, 1H), 6.77 (d, 2H, J = 8.6 Hz), 7.12 (d, 2H, J = 8.6 Hz), 8.06 (d, 2H, J = 8.2 Hz), 8.16 (d, 2H, J= 8.6 Hz), 8.20-8.29 (m, 4H). 1 3 C NMR (CDC13, 75.2 MHz) 5: 14.5, 16.7, 24.0, 29.5, 31.9, 33.4, 34.7, 36.2, 38.2, 39.2, 49.3, 54.1, 55.2, 66.0, 72.6, 73.2, 73.9, 113.7, 123.6, 123.7, 128.7, 128.9, 130.7, 130.8, 130.9, 134.7, 134.8, 137.3, 138.0, 141.7, 150.8 (2 signals superimposed), 159.1, 163.8, 164.0, 208.6. Exact mass calcd for C 4 2 H 4 4 N 2 O 1 1 : 752.2945. Parent ion was not detected. Melting point: amorphous material displayed a broad melting point range: 40-60 °C. 228 Table 19. lH NMR (CDCI3,400 MHz) Data for Diester 269: NOED Experiment. 18 N0 2 269 Assignments H-x 'HNMR 5 ppm (Multiplicity, J (Hz)) Observed NOEs H - l a 2.93-2.98 (m) H-13, H-18 H-4 part of mat 2.16-2.38 H-5 part of mat 1.34-1.80 H-7 part of mat 1.34-1.80 H-8 part of mat 1.34-1.80 H - l l f l 6.31 (s) H-20 H-13a 5.70-5.78 (m) H - l , H-l4(p), H-20 H-14(a) part of mat 2.16-2.38 H-14(p)a 2.81-2.87 (m) H-l4(a), H - l , H-15 H-15fl 3.30-3.10 (m) H-14, H-16, H-17 H-16a 3.22-3.35 (m) H-15, H-17 H-17a 0.98 (d, 6.7) H-15, H-16 H-18a 1.08 (s) H - l 229 H-19 1.21 (s) H-20° 5.02 (s) H - l l H - l ' 4.31^ 1.38 H-3', H-7' 7.12 (d, 8.6) H-4', H-6' 6.77 (d, 8.6) H-8' 3.75 (s) H-3", H-7" 8.06 (d, 8.2) or 8.16 (d, 8.6) H-4", H-6" part of m at 8.20-8.29 H-3"', H-7'" 8.06 (d, 8.2) or 8.16 (d, 8.6) H-4'", H-6'" part of mat 8.20-8.29 a Irradiation of this signal generated the corresponding NOEs in the right hand column 230 Table 20. 1 3 C NMR (CDCI3,100.6 MHz) and 'H NMR (CDC13,400 MHz) Data for Diester 269: HMQC Experiment. 18 N0 2 269 Assignments C-x 1 3 CNMR 8 ppm Observed HMQC Correlations (5 ppm) C - l 39.2 H - l (2.93-2.98) C-2 138.0 C-3 137.3 C-4 29.5 H-4 (part of m at 2.16-2.38) C-5 36.2 H-5 (part of m at 1.34-1.80) C-6 49.3 C-7 38.2 H-7 (part of m at 1.34-1.80) C-8 34.7 H-8 (part of mat 1.34-1.80) C-9 54.1 C-10 208.6 C - l l 128.9 H - l l (6.31) C-12 141.7 C-13 73.2 H-13 (5.70-5.78) 231 C-14 31.9 H-14 (2.81-2.87, part of m at 2.16-2.38) C-15 33.4 H-15 (3.30-3.10) C-16 73.9 H-16 (3.22-3.35) C-17 16.7 H-17 (0.98) C - l 8 24.0 H-18 (1.08) C-19 14.5 H-19 (1.21) C-20 66.0 H-20 (5.02) c - r 72.6 H - l ' (4.31-4.38) C-2' 130.7 C-3', C-7' 128.7 H-3', H-7' (7.12) C-4', C-6' 113.7 H-4', H-6' (6.77) C-5' 159.1 C-8' 55.2 H-8' (3.75) C- l" 163.8 orl64.0 C-2" 134.7 or 134.8 C-3", C-7" 130.8 or 130.9 H-3", H-7" (8.06 or 8.16) C-4", C-6" 123.6 or 123.7 H-4", H-6" (part of m at 8.20-8.29) C-5" 150.8 C-l'" 163.8 orl64.0 C-2'" . 134.7 or 134.8 C-3'", C-7'" 130.8 or 130.9 H-3'", H-7'" (8.06 or 8.16) C-4"', C-6'" 123.6 or 123.7 H-4'", H-6'" (part of m at 8.20-8.29) C-5'" 150.8 232 4.4. Synthetic Studies Directed Towards the (±)-Presi lphiperfolan-9-ol Preparation of l-(l-Methyl-cyclopent-2-enyl)-propan-2-one (315) HO' 316 315 To a cold (-20 °C), stirred solution of (±)-3-methylcyclopent-2-en-l-ol (316) (16.51 g, 0.168 mol) in dry Et 20 (250 mL) was added a solution of diketene (16.99 g, 0.202 mol) in dry Et 20 (25 mL) via cannula. A catalytic amount of DMAP (204 mg, 1.68 mmol) was added and the resulting yellow mixture was stirred for 1 h. The mixture was warmed to room temperature, stirred for 18 h and cooled to -78 °C. A cold (-78 °C) solution of LDA (0.73 M in THF, 575 mL, 0.420 mmol) was added over 15 min via cannula and the resulting mixture was stirred for 1 h. The mixture was warmed to 0 °C for 30 min and then to room temperature for 5 h. The mixture was extracted with aqueous NaOH (2N, 3 x 150 mL). The combined aqueous extracts were acidified by dropwise addition of concentrated HCI and back-extracted with Et 20 (3 x 300 mL). The combined ethereal extracts were washed with brine (100 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the remaining material was taken up CCI4 (50 mL). The mixture was heated to reflux for 12 h and cooled to room temperature. Most of the solvent was removed under reduced pressure and the residual 233 material was purified by flash chromatography (150 g of silica gel, 10:1 pentane-Et20) to give 17.8 g (77%) of the ketone 3 1 5 as a clear colourless oil. JR (neat): 3050, 2952, 1718, 1452, 1358 cm"1. 'HNMR (CDCI3, 400 MHz) 5: 1.12 (s, 3H), 1.63-1.74 (m, 1H), 1.78-1.87 (m, 1H), 2.11 (s, 3H), 2.26-2.37 (m, 2H), 2.49 (s, 2H), 5.61-5.68 (m, 2H). 1 3 C NMR (CDCI3, 75.2 MHz) 6: 26.2, 31.2, 31.7, 37.2, 47.2, 54.0, 129.1, 139.0, 208.3. Exact mass calcd for C9H14O: 138.10446. Found: 138.10502. 234 Table 21. 1 3 C NMR (CDCI3,100.6 MHz) and 'H NMR (CDC13,400 MHz) Data for 1-(1-Methyl-cyclopent-2-enyl)-propan-2-one (315): HMQC Experiment. 5' 6' 3 4' 315 Assignments C-x 1 3 CNMR 8 ppm HMQC ! H NMR Correlations (5 ppm) C - l 54.0 H - l (2.49) C-2 208.3 C-3 31.7 H-3 (2.11) c - r 47.2 C-2' 139.0 H-2' (part of m at 5.61-5.68) C-3' 129.1 H-3' (part of m at 5.61-5.68) C-4' 31.2 H-4' (2.26-2.37) C-5' 37.2 H-5'(1.63-1.74, 1.78-1.87) C-6' 26.2 H-6'(1.12) 235 Preparation of a 1:1 Mixture of 2-MethyI-3-(l-methyl-cyclopent-2-enyl)-propion-aldehydes (333) H OMe O 332 333 To a cool (0 °C), stirred solution of (methoxymethyl)triphenylphosphonium chloride (84.3 g, 0.246 mol) in dry THF (1 L) was added a cold (-78 °C) solution of LDA (0.33 M in THF, 943 mL, 0.312 mol) via cannula. The resulting purple solution was stirred for 1 h. A cool (0 °C) solution of ketone 315 (17.0 g, 0.123 mol) in dry THF (100 mL) was added via cannula and the mixture was stirred for 1 h. The mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NaHC03 (300 mL) was added and resulting layers were separated. The aqueous layer was extracted with Et20 (3 x 300 mL). Most of the solvent of the combined organic layers was removed under reduced pressure and the residual material, a crude mixture of enol ethers 332, was taken up in CHC13 (200 mL). TFA (10 mL) and H 2 0 (10 mL) were added and the resulting mixture was heated to reflux for 18 h. The solution was cooled to room temperature and H 2 0 (200ml) was added. The resulting layers were separated and the organic layer was washed with aqueous NaOH (2N, 2 x 100 mL). The organic layer was then washed with brine (200 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (500 g of silica 236 gel, 2:1 petroleum ether-CHiCb) to yield a 13.4 g (72%) of a 1:1 mixture of epimeric aldehydes 333 as clear colourless oils. The 1:1 mixture of epimeric aldehydes 333 exhibited the following spectral data: JR (neat): 2952, 1735, 1457 cm"1. J H NMR (CDC13, 400 MHz) 5: 1.02 and 1.03 (s, s, ratio 1:1, 3H), 1.04 and 1.05 (d, J = 7.1 Hz, d, /= 7.1 Hz, ratio 1:1, 3H), 1.25 and 1.32 (dd, / = 4.8, 14.2 Hz, dd, 7= 3.9, 14.3 Hz, ratio 1:1, 1H), 1.53-1.72 (m, 2H), 1.87-1.99 (m, 1H), 2.22-2.41 (m, 3H), 5.37-5.44 (m, 1H), 5.56-5.63 (m, 1H), 9.51 and 9.53 (d, J= 2.9 Hz, d, J= 2.7 Hz, ratio 1:1, 1H). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 15.9, 16.2, 27.1, 27.6, 31.7, 31.9, 36.8, 37.0, 42.2, 42.9, 43.6, 43.7, 48.4 (two signals superimposed), 129.4, 129.9, 139.2, 139.5, 205.2, 205.3. Exact mass calcd for C 1 0 H 1 6 O: 152.12012. Found: 152.12068. 237 Table 22. 1 3 C NMR (CDC13,100.6 MHz) and ! H NMR (CDC13,400 MHz) Data for the 1:1 Mixture of 2-Methyl-3-(l-methyl-cyclopent-2-enyl)-propionaldehydes (333): HMQC Experiment. 333 Assignment C-x 1 3 C NMR a 8 ppm HMQC ! H NMR Correlations" 8 ppm (Multiplicity, J (Hz)) C - l 205.2, 205.3 H - l (9.51,9.53) C-2 31.7,31.9 H-2 (part of m at 2.22-2.41) C-3 36.8, 37.0 H-3 (1.53-1.72) C ^ 15.9, 16.2 H-4 (1.04, 1.05) c - r 48.4 C-2' 139.2, 139.5 H-2' (5.37-5.44) C-3' 129.4, 129.9 H-3' (5.56-5.63) C-4' 43.6, 43.7 H-4' (part of m at 2.22-2.41) C-5' 42.2, 42.9 H-5'(1.25, 1.32, 1.87-1.99) C-6' 27.1, 27.6 H-6' (1.02, 1.03) a The respective signals of both isomers of 333 are noted. 238 Preparation of 2,2-Dimethyl-3-(l-methyl-cyclopent-2-enyl)-propionaldehyde (314) O 314 To a stirred suspension of KH (3.81 g, 0.095 mol) in dry THF (500 mL) was added a solution of a 1:1 mixture of epimeric aldehydes 333 (13.0 g, 0.086 mol) in dry THF (50 mL). The resulting yellow mixture was stirred at room temperature for 1 h and cooled to 0 °C. Neat Mel (13.5 g, 0.095 mol) was added and the mixture was stirred for 1 h. The resulting slurry was slowly poured into a stirred mixture of 1:1 Et20-H20 (0.5 L). The resulting layers were separated and the aqueous layer was extracted with Et20 (3 x 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous MgSC^. The solvent was removed under reduced pressure and the crude oil was purified by flash chromatography (300 g of silica gel, 15:1 pentane-Et20) to yield 12.8 g (90%) of aldehyde 314 as a clear colourless oil. IR (neat): 3050, 2956, 1727, 1456 cm - 1. 'H NMR (CDC13, 400 MHz) 8: 0.93 (s, 3H), 1.01 (s, 3H), 1.04 (s, 3H), 1.50-1.83 (m, 4H), 2.20-2.30 (m, 2H), 5.45-5.49 (m, 2H), 5.53-5.58 (m, 1H), 9.44 (s, 1H). 239 1 3 C NMR (CDCI3, 75.2 MHz) 8: 22.9, 23.7, 27.7, 31.3, 39.1, 46.6, 48.4, 49.3, 128.9, 140.4, 206.6. Exact mass calcd for CnH, 80: 166.13577. Found 166.13591. Table 23. 1 3 C NMR (CDC13,100.6 MHz) and ! H NMR (CDC13,400 MHz) Data for 2,2-Dimethyl-3-(l-methyl-cyclopent-2-enyl)-propionaldehyde (314): HMQC Experiment. 4' 3' II o 314 Assignment C-x 1 3 CNMR 8 ppm HMQC ! H NMR Correlations 8 ppm (Multiplicity, J (Hz)) C - l 206.6 H - l (9.44) C-2 46.6 C-3 49.3 H-3 (part of m at 1.50-1.83) C-4 22.9 H-4 (1.04) C-5 23.7 H-5 (1.01) c - r 48.4 C-2' 140.4 H-2' (5.45-5.49) C-3' 128.9 H-3' (5.53-5.58) C^T 31.3 H-4' (2.20-2.30) C-5' 39.1 H-5' (part of m at 1.50-1.83) C-6' 27.7 H-6' (0.93) 240 Preparation of a 1:1 Mixture of 2,2-DimethyI-l-(l-methyl-cyclopent-2-enyI)-7-phenyI-hept-6-yn-3-ols (366) P h P h OH 369 366 To a cold (-78 °C), stirred solution of iodide 369 8 1 (1.71 g, 6.69 mmol) in dry Et 20 (40 mL) was added a solution of f-BuLi (1.7 M in pentane, 8.26 mL, 14.05 mmol) via syringe over 2 minutes. The mixture was stirred for 1 h, warmed to 0 °C for 15 min and then recooled to -78 °C for 30 min. A solution of aldehyde 314 (1.0 g, 6.02 mmol) in dry Et 20 (10 mL) was added via cannula and the mixture was stirred for 30 min. H 2 0 (25 mL) was added and the mixture was warmed to room temperature. The resulting layers were separated and the aqueous layer was extracted with Et 20 (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the residual material was purified by flash chromatography (40 g of silica gel, 5:1 petroleum ether-Et20) to give 1.40 g (78%) of a 1:1 mixture of alcohols 366 as a clear colourless oil. The 1:1 mixture of alcohols 366 exhibited the following spectral data: IR (neat): 3500, 3030, 2952, 2230, 1490 cm - 1. 241 'H NMR (CDCI3, 400 MHz) 5: 0.96 and 0.98 (s, s, ratio 1:1, 3H), 0.99 (s, 3H), 1.11 and 1.12 (s, s, ratio 1:1, 3H), 1.32-1.89 (m, 7H), 2.27-2.35 (m, 2H), 2.46-2.65 (m, 2H), 3.42-3.51 (m, 1H), 5.51-5.59 (m, 1H), 5.60-5.72 (m, 1H), 7.22-7.29 (m, 3H), 7.35-7.39 (m, 2H). 1 3 C NMR (CDCI3, 75.2 MHz) 8: 17.1 (two signals superimposed), 24.6, 24.7, 24.8 (two signals superimposed), 28.9, 29.0, 30.2, 30.3, 31.2, 31.4, 38.9 (two signals superimposed), 39.5, 40.3, 48.1 (two signals superimposed), 48.7, 48.9, 78.6, 79.3, 81.1 (two signals superimposed), 90.0, 90.1, 123.8, 123.9, 127.6, 128.2, 128.3 (four signals superimposed), 131.5 (two signals superimposed), 141.3, 141.7. Exact mass calcd for C 2 iH 2 8 0: 296.21402. Found 296.21390. 242 Table 24. 1 3 C NMR (CDCI3,100.6 MHz) and ! H NMR (CDC13,400 MHz) Data for a 1:1 Mixture of 2,2-Dimethyl-l-(l-methyl-cyclopent-2-enyl)-7-phenyl-hept-6-yn-3-ol (366): HMQC Experiment. 5" Q't^^n 4" 366 Assignment C-x 1 3 CNMR° 8 ppm HMQC 'H NMR Correlations a 8 ppm (Multiplicity, J (Hz)) C - l 48.1 H - l (part of mat 1.32-1.89) C-2 38.9 C-3 78.6, 79.3 H-3 (3.42-3.51) C-4 30.2, 30.3 H-4 (part of m at 1.32-1.89) C-5 17.1 H-5 (2.46-2.65) C-6 90.0, 90.1 C-7 81.0 C-8 24.6, 24.7 H-8 (0.96, 0.98) C-9 24.8 H-9 (0.99) c - r 39.5, 40.3 C-2' 141.3, 141.7 H-2' (5.60-5.72) C-3' 127.6, 128.2 H-3' (5.51-5.59) C-A' 31.2,31.4 H-4' (2.27-2.35) C-5' 48.7, 48.9 H-5' (part of m at 1.32-1.89) C-6' 28.9, 29.0 H-6'(1.11, 1.12) C- l" 123.8, 123.9 C-2", C-6" 131.5 H-2", H-6" (7.35-7.39) C-3", C-5" 128.3 H-3", H-5" (part of m at 7.22-7.29) C^l" 128.3 H-4" (part of m at 7.22-7.29) a The respective signals for both isomers of the 1:1 mixture of 366 were noted. 243 Preparation of a 1:1 Mixture of Dithiocarbonic Ac id 0-{l-[ l , l -Dimethyl-cylopent-2-enyl]-5-phenyl-pent-4-ynyl} Ester S-Methyl Esters (367) To a stirred suspension of NaH (49 mg, 2.04 mmol) in dry THF (40 mL) was added a solution of a 1:1 mixture of alcohols 366 (291 mg, 1.021 mmol) in dry THF (1 mL). Carbon disulfide (233 mg, 3.06 mmol) was added via syringe followed by a catalytic amount of imidazole (3.5 mg, 0.05 mmol). The mixture was heated to reflux for 3 h and then cooled to room temperature. Mel (724 mg, 5.11 mmol) was added and the mixture was stirred for 30 min. H2O (20 mL) and Et20 (20 mL) were added and the biphasic mixture was stirred for 10 min. The resulting layers were separated and the aqueous layer was extracted with Et20 (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous MgSCv The solvent was removed under reduced pressure and the residual material was purified by flash chromatography (20 g of silica gel, 20:1 petroleum efher-Et20) to give 332 mg (84%) of a 1:1 mixture of xanthates 367 as a clear red oil. 244 The 1:1 mixture of xanthates 367 exhibited the following spectral data: IR (neat): 3050, 2221, 1715, 1598, 1490, 1230, 1050 cm - 1. *H NMR (CDC13, 300 MHz) 8: 1.02 (s, 3H), 1.05 (s, 3H), 1.11 and 1.12 (s, s, ratio 1:1, 3H), 1.45-1.69 (m, 3H), 1.94-2.15 (m, 3H), 2.24-2.36 (m, 2H), 2.37-2.46 (m, 2H), 2.54 (s, 3H), 5.52-5.58 (m, 1H), 5.61-5.68 (m, 1H), 5.91 (br d, J= 10 Hz, 1H), 7.20-7.30 (m, 3H), 7.32-7.42 (m, 2H). , 3 C NMR (CDCI3, 75.2 MHz) 8: 16.8, 18.9, 24.7, 24.8, 25.1, 28.7, 28.2, 29.7, 31.3, 39.5, 40.1, 48.6, 48.7, 48.9, 80.9, 89.5, 90.4, 123.8, 127.6, 128.0, 128.2, 131.6, 141.2, 141.3. Most of the 1 3 C signals of the respective xanthate isomers 367 were superimposed on each other. Exact mass calcd for C23H31OS2 (M+H)+: 387.18163. Found 387.18155. Anal, calcd for C23H30OS2: C 71.45, H 7.81. Found: C 71.38, H 7.81. 245 To a stirred, refluxing solution of a 1:1 mixture of xanthates 367 (100 mg, 0.258 mmol) in dry, degassed benzene (3 mL) were added solutions of Bu3SnH (0.31 M in benzene, 1 mL, 0.31 mmol) and A I B N (0.061 M in benzene, 1 mL, 0.061 mmol) via syringes on a double barrel syringe pump over 16 hrs. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residual material, a mixture of olefins 368 (ratio not determined), was taken up in a 1:1:1.5 mixture of M e C N - C C L j -H 2 0 (3.5 mL) . N a I 0 4 (150 mg, 0.69 mmol) and a catalytic amount of R u C l 3 (2 mg, 0.01 mmol) were added and the resulting black mixture was stirred at room temperature for 2 h. CH2CI2 (2 mL) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with CH2CI2 (3x2 mL) . The combined organic layers were washed with brine (2 mL) and dried over anhydrous MgS04 . Most of the solvent was removed under reduced pressure and the residual material was diluted 246 with Et20 (5 mL). The mixture was filtered through a short column of Celite® and the column was flushed with Et20 (5 mL). The solvent of the combined eluates was removed under reduced pressure and the crude oil was purified by flash chromatography (1 g of silica gel, 9:1 petroleum ether-Et20) to give 21.3 mg (40%) of the ketone 306 as a clear colourless oil. Ketone 306 exhibited the following spectral data: IR(neat): 2950, 1719 cm"1. 'H NMR (CDC13, 400 MHz) 8: 0.88 (s, 3H), 1.01 (s, 3H), 1.07 (s, 3H), 1.40 (ddd, 1H, J = 4, 12.5, 13 Hz), 1.45-1.69 (m, 5H), 1.72-1.84 (m, 1H), 1.95-2.05 (m, 2H), 2.19 (dd, 1H, J= 7, 12.5 Hz), 2.25-2.53 (m, 2H), 2.71-2.86 (m, 1H). 1 3 C NMR (CDCI3, 100.6 MHz) 8: 21.8, 22.7, 28.2, 28.9, 29.0, 38.3, 40.6, 41.9, 47.5, 50.9, 52.7, 58.0, 59.1, 216.2 Exact mass calcd for Ci 4 H 2 2 0: 206.16707. Found 206.16727. 247 Table 25. Comparison of the ! H NMR (CDCI3,400 MHz) Data for (1R*,4R*,7S*,8R*)-4,6,6-Trimethyltricyclo[5.3.1.04'n]undecan-9-one (306) with those Reported20 for (±)-l-Epi-9-norpresilphiperfolan-9-one (306). 14 12 306 s h o w i n g l U P A C - b a s e d 306 s h o w i n g p r e s i l p h i p e r f o l a n e n u m b e r i n g . n u m b e r i n g Assignment H-x (306) ' H N M R 8 ppm (Multiplicity, J (Hz)) Presilphiper-folane Numbering H-x (306) Literature ! H NMR Assignments 8 ppm (Multiplicity, J (Hz)) H - l 1.40 (ddd, 4, 12.5, 13) H -7 1.39 (ddd, 4, 12.5, 13) H-3 part of mat 1.45-1.69 H-5 1.58 and 1.68 (AB, 13) H -5 part of mat 1.45-1.69 H-3 1.52 (m) and 1.65 (m) H-6 1.95-2.05 (m) H-2 2.01 (m) H-7 2.71-2.86 (m) H - l 2.81 (ddd, 9, 8, 7) H -9 2.25-2.53 (m) H-10 2.31 and 2.47 (AB, 16) H-10 part of m at 1.45-1.69 and 1.72-1.84 (m) H - l l 1.55 (m)and 1.78 (m) H - l l 2.19 (dd, 7, 12.5) H-8 2.18 (dd, 7.12.5) H -12 0.88 (s) or 1.01 (s) H-13 0.88 (s) or 1.01 (s) H-13 0.88 (s) or 1.01 (s) H-14 0.88 (s)or 1.01 (s) H-14 1.07 (s) H-12 1.07 (s) 248 Table 26. Comparison of the 1 3 C NMR (CDCI3,100.6 MHz) Data for (1R*,4R*,7S*,8R*)-4,6,6-Trimethyltricyclo[5.3.1.0411]undecan-9-one (306) and those Reported20 for (±)-l-Epi-9-norpresilphiperfolan-9-one (306). 14 i i 306 s h o w i n g I U P A C - b a s e d 306 s h o w i n g p r e s i l p h i p e r f o l a n e n u m b e r i n g n u m b e r i n g Assignment C-x (306) 1 3 CNMR 8 ppm (Multiplicity, J (Hz)) Presilphiperfolane Numbering C-x (306) Literature 1 3 C NMR Assignments 8 ppm (Multiplicity, J (Hz)) C - l 50.9 C-7 50.9 C-2 40.6 C-6 40.6 C-3 58.0 C-5 58.0 C-4 47.5 C-4 47.5 C-5 41.9 C-3 41.9 C-6 28.2 C-2 28.2 C-7 52.7 C - l 52.6 C-8 216.2 C-9 216.2 C-9 38.3 C-10 38.3 C-10 21.8, C - l l 21.8 C - l l 59.1 C-8 59.1 C-12 22.7 C - l 3 22.7 C - l 3 28.9 or 29.0 C-14 29.0 C-14 28.9 or 29.0 C-12 29.0 REFERENCES AND FOOTNOTES 249 (1) Ahmad, V. U.; Zahid, M.; Ali, M. S.; Ali, Z.; Jassbi, A. R.; Abbas, M.; Clardy, J.; Lobkovsky, E.; Tareen, R. B.; Iqbal, M. Z. J. Org. Chem. 1999, 64, 8465. 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