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Copper(I)-mediated intramolecular conjugate additions : total synthesis of (+/-)-1-desoxyhypnophilin… Skupinska, Krystyna A. 2000

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C O P P E R ( I ) - M E D I A T E D I N T R A M O L E C U L A R C O N J U G A T E A D D I T I O N S . T O T A L S Y N T H E S E S O F ( ± ) - l - D E S O X Y H Y P N O P H I L I N A N D (±)-6 ,7-EPOXY-4(15)-HIRSUTEN-5-OL by K R Y S T Y N A A . S K U P I N S K A B.Sc. (Hons.), University of Calgary, 1995 A T H E S I S S U B M I T T E D I N P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F D O C T O R O F P H I L O S O P H Y in T H E F A C U L T Y O F G R A D U A T E S T U D I E S (Department of Chemistry) We accept this thesis as confonriing to the required standard ^ T H E U N I V E R S I T Y O F B R I T I S H C O L U M B I A July, 2000 © Krystyna A . Skupinska, 2000 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it 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 shall not be allowed without my written permission. Department of The University of British Colum Vancouver, Canada Date DE-6 (2/88) ABSTRACT The use of Cu(I)-mediated intramolecular conjugate addition reactions of alkenyltrimethylstannane functions to a,(3-unsaturated ketones to afford novel, functionalized tricyclic ketones 88-91, and 94 was investigated. Vinylogous esters of general structure 71 were prepared by alkylation of the vinylogous esters 76 (m=2) or 82 (m=l) with the allylic bromide 73 and Mel (for 71 where Rx=Me). Compounds 71 were readily transformed via either reduction or Grignard addition, followed by hydrolysis and dehydration of the resultant products, into enones of general structure 70. Treatment of compounds 70 with CuCN in DMSO provided tricyclic ketones 88-91 and 94. The analogous Cu(I)-mediated cyclization of aryltrimethylstannanes was also studied. Upon treatment with CuCN in DMSO, enones 112, 114, and 116 underwent cyclization to provide functionalized, tricyclic ketones 117-119, containing an aromatic ring. Further synthetic transformations involving olefinic ketones 88-91 and 54 were investigated. The oxidative cleavage of the tetrasubstituted double bond of 88-91 and 54 provided triones 142-146. Similar transformation of the olefinic ketals prepared from 88-90 and 54 generated the ketal diones 135, 136, 137 and 141, respectively. Interestingly, treatment of the triones 142, 143 and 144 with a catalytic amount of p-toluenesulfonic acid in refluxing TFfF afforded products of the aldol condensation reaction (149, 148 and 147, respectively). Under similar reaction conditions triketone 146 generated compound 151. The Cu(I)-mediated intramolecular conjugate addition reaction of alkenyltrimethylstannane functions to enones was used in a key step of the total syntheses of the triquinane natural products, (±)-l-deoxyhypnophilin 61 and the related alcohol (±)-62. Vinylogous ester 175 was obtained by alkylation of 82 with the allylic bromide 176. Compound 59 was prepared by treatment of the vinylogous ester 175 with methylmagnesium bromide, followed by treatment of the resultant material with p-toluenesulfonic acid. Conversion of 59 into the tricyclic ketone 60 was accomplished by treatment of the former substance with CuCN in DMSO in a sealed reaction vessel. The ketone function of 60 was reduced to the a alcohol, which was used in the hydroxy-directed hydrogenation of the alkenic function to form the alcohol 196. The alcohol i i function of 196 was oxidized to provide ketone 174. Compound 174 was converted to the enone 197. Introduction of the a methylidene function gave the dienone 198. Monoepoxidation of the internal olefrnic function of 198 afforded the natural product (±)-1-desoxyhypnophilin (61). Subsequent reduction of the ketone function of (±)-61 provided (±)-62. O O 71 (m=1 or 2, R 1 =H or Me) O 88 (m=2, R 1 , R 2=H) 70 (m=1 or 2, 89 (m=2, R 1 =Me, R 2=H) R 1 , R 2=H or Me) 90 (m=2, R 1 , R 2=Me) 91 (m=1, R 1 , R 2=H) 94 (m=1, R 1 =H, R 2=Me) O R 112 (m=2, R 1 , R 2=H) 117 114 (m=2, R 1 , R 2=Me) 118 116 (m=1, R 1 , R 2=H) 119 142 (m=2, n=1, R1 , R 2=H) 143 (m=2, n=1, R 1=Me, R 2=H) 144 (m=2, n=1, R 1 , R 2=Me) 145 (m=1,n=1, R 1 , R 2=H) 146 (m=2, n=2, R 1 =H, R 2=Me) 135 (m=2, n=1, R 1 , R 2=H) 136 (m=2, n=1, R 1=Me, R 2=H) 137 (m=2, n=1, R 1 , R 2=Me) 141 (m=2, n=2, R 1 =H, R 2=Me) O 175 196 i i i TABLE OF CONTENTS ABSTRACT TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES LIST OF ABBREVIATIONS ACKNOWLEDGMENTS I. INTRODUCTION 1 1.1 General introduction 1 1.2 Background: intramolecular conjugate additions of nonstabilized carbanions 4 1.3 Background: copper(l)-mediated intramolecular conjugate additions of alkenylstannane functions 8 1.4 Proposals 15 II. RESULTS AND DISCUSSION 20 2.1 Copper(I) cyanide- mediated intramolecular conjugate additions of alkenyltrimethylstannanes to a, ^-unsaturated ketones 20 2.1.1 Preparation of cyclization precursors 20 2.1.2 Copper(I) cyanide-mediated cyclizations 27 2.2 Copper(I) cyanide-mediated intramolecular conjugate additions of aryltrimethylstannanes to enones. 38 2.2.1 Preparation of cyclization precursors 38 2.2.2 Copper(I) cyanide-mediated cyclizations 44 2.3 Preparation of functionalized, ds-fused bicyclo[6.3.0]undecanes, bicyclo[6.4.0]dodecanes, and bicyclo[7.4.0]tridecanes 46 2.3.1 Introductory remarks 46 2.3.2 Preparation of ketals 49 2.3.3 Oxidative cleavage of the tetrasubstituted double bond 51 i i iv v i i ix x xiv iv 2.4. A l d o l condensation reaction of triones 142 to 146 57 2.5 Total synthesis of (±)- l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) 63 2.5.1 Triquinane natural products: background 63 2.5.2 Isolation of (-)-l-desoxyhypnophilin (61) and (+)-6 J-epoxy-4(15)-nirsuten-5-ol (62) 69 2.5.3 Retro synthetic plan for the synthesis of (±)- l -desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) 70 2.5.4 Synthesis of (±)- l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) 72 III. SUMMARY AND CONCLUSIONS 102 3.1 CuCN-mediated intramolecular conjugate additions of alkenyltrimethylstannanes to enones 102 3.2 CuCN-mediated intramolecular conjugate additions of aryltrimethylstannanes to enones 104 3.3 Preparation of novel carbocyclic structures derived from the products of CuCN-mediated conjugate addition reaction of alkenyltrimethylstannanes to enones 105 3.4 Application of CuCN-mediated intramolecular conjugate addition of allcenyltrimethylstannes to enones in the total synthesis of (±)- l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) 108 3.5 General 111 IV. EXPERIMENTAL SECTION 112 4.1 General 112 4.1.1 Data acquisition and presentation 112 4.1.2 Solvents and reagents 115 4.2 Copper cyanide-mediated intramolecular conjugate additions of alkenyltrimethylstannanes and aryltrimethylstannanes to enones. 117 4.2.1 Preparation of the alkenyltrimethylstannane precursors 117 4.2.2 Preparation of the aryltrimethylstannane precursors 128 4.2.3 CuCN-mediated cyclizations 140 v 4.3 Oxidative cleavage of tricyclic ketals and ketones to form functionalized ds-fused bicyclo[6.3.0]undecane, bicyclo[6.4.0]dodecanes and bicyclo[7.4.0]tridecanes 151 4.3.1 Preparation of ketals from ketones 151 4.3.2 Preparation of ketal diones via oxidative cleavage 156 4.3.3 Preparation of triketones via oxidative cleavage 162 4.4. Aldo 1 condensations 168 4.5. Synthesis of (±)-l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol(62) 176 APPENDIX 206 REFERENCES 209 v i LIST OF TABLES Table 1. Copper(I) cyanide-mediated intramolecular conjugate additions of enones 78, 80, 81 and 86. 27 Table 2. Copper(I) cyanide-mediated conjugate additions of enone 87. 32 Table 3. Copper(I) cyanide-mediated conjugate additions of enone 87 in a sealed . ampoule. 35 Table 4. Copper(I) cyanide-mediated conjugate additions of aryltrimethylstannanes 112,114, and 116. 44 Table 5. Ruthenium tetroxide-catalyzed cleavage of the alkenes 132-134, 88-91 and 54. 55 Table 6. CuCN-mediated cyclization of 59. 78 Table 7. Comparison of 1 H N M R data for synthetic (±)- l-desoxyhypnophil l in 61 with those reported for natural (-)-l-desoxyhypnophilin (400 M H z , CDC1 3 ) . 96 Table 8. Comparison of 1 3 C N M R data for synthetic (±)- l-desoxyhypnophil l in 61 (100.6 M H z , CDCI3) with those reported for natural (-)-l-desoxyhypnophilin (75.5 M H z , CDCI3). 97 Table 9. Comparison of *H N M R data for synthetic ( IS* 25*, 45* 55* 6R*, 85*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.02'6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-ol (400 M H z , CDCI3). 99 Table 10. Comparison of 1 3 C N M R data for synthetic (15* 25* 45* 55* 6R*, 85*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.0 2' 6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) (100.6 M H z , CDCI3) with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-ol (75.5 M H z , CDC1 3 ) 100 Table 11. X H N M R (400 M H z , CDC1 3 ) data for the dione alcohol 147: C O S Y Experiment 169 Table 12. 1 3 C (125.8 M H z , CDC1 3 ) and J H N M R (500 M H z ) data for the dione alcohol 147: H M Q C and H M B C Experiments 170 vn Table 13. Selected 1 3 C (125.8 M H z , CDC1 3 ) and *H N M R (500 M H z ) data for the dione 151: H M Q C and H M B C Experiments 174 Table 14. lR N M R (400 M H z , CDC1 3 ) data for the alcohol 196: C O S Y Experiment. 190 Table 15. *H N M R (400 M H z , CDC1 3 ) data for the ketone 174: C O S Y Experiment. 192 Table 16. 1 3 C (125.8 M H z , CDC1 3 ) and lU N M R (500 M H z ) data for the ketone 174: H M Q C Experiment 193 Table 17. ' H N M R (400 M H z , CDC1 3 ) data for the enone 197: C O S Y Experiment. 196 Table 18. Comparison of C N M R data for synthetic (±)- l-desoxyhypnophil l in 61 (100.6 M H z , CDCI3) with those reported for natural (-)-l-desoxyhypnophilin Table 19. Comparison of *H N M R data for synthetic (±)- l-desoxyhypnophil l in 61 with those reported for natural (-)-l-desoxyhypnophilin (400 M H z , CDC1 3 ) . 201 Table 20. Comparison of 1 3 C N M R data for synthetic (IS* 2S* 4S*, 5S*, 6R*, 8S*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.0 2 , 6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) (100.6 M H z , CDCI3) with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-ol (75.5 M H z , CDC1 3 ) 204 Table 21. Comparison of *H N M R data for synthetic (IS* 2S* 45* 55* 6R*, 8S*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.0 2 , 6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-ol (400 M H z , CDCI3). 205 (75.5 M H z , CDCI3). 200 v i i i LIST OF FIGURES Figure 1. X-ray crystal structure of 147. 58 Figure 2. X-ray crystal structure of 148. 59 Figure 3. Reduction from the a face of 60 is needed to form the cis-anti-cis triquinane. 80 Figure 4. Expected reduction of 94 to the alcohol and hydroxy directing effect in olefin hydrogenation. 83 Figure 5. X-ray crystal structure of 196. 87 Figure 6. *H N M R spectrum of synthetic (±)-l-desoxyhypnophil l in (61) (400 M H z , CDC1 3 ) . 98 Figure 7. : H N M R spectrum of synthetic (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) (400 M H z , CDCI3). 101 ix LIST OF ABBREVIATIONS a - below the plane of a ring or 1,2-relative position A c - acetyl anal. - analysis A P T - attached proton test A r - aryl atm - atmosphere (3 - above the plane of a ring or 1,3-relative position B n - benzyl b.p. - boiling point br - broad B u - butyl B z - benzoyl °C - degrees Celsius calcd - calculated cat. - catalytic cm - centimetre C O D - cyclooctadiene C O S Y - ( 1 H- 1 H) - homonuclear correlation spectroscopy Cp - cyclopentadienyl C-x - carbon number x C y - cyclohexyl d - doublet 8 - chemical shift in parts per mil l ion from tetramethylsilane D B U - l,8-diazabicyclo[5.4.0]undec-7-ene D D Q - 2,3-dichloro-5,6-dicyano-l,4-benzoquinone D I B A L - H - diisobutylaluminum hydride D M F - N , N-dimethylfonnamide D M G - directed metalation group x D M S - dimethyl sulfide D M S O - dimethyl sulfoxide D o M - directed orthometalation E + - electrophile Ed . , Eds. - editor, editors e.g. - exempli gratia (for example) eq - equation equiv. - equivalent(s) Et - ethyl E t 2 0 - diethyl ether = ether g - gram Y - 1,4-relative position gem - geminal G L C - gas-liquid chromatography h - hour(s) F f M B C - heteronuclear multiple bond coherence FIMDS - 1,1,1,3,3,3-hexamethyldisilazane F f M P A - hexamethylphosphoramide F I M Q C - heteronuclear multiple quantum coherence hv - light H R M S - high resolution mass spectrometry H-x - hydrogen number x H z - hertz i - iso IR - infrared J - coupling constant in hertz nJsn-H - n bond coupling for tin and proton nuclei (in K H M D S - potassium 1,1,1,3,3,3-hexamethyldisilazide L - ligand L D A - lithium diisopropylamide L H M D S - lithium 1,1,1,3,3,3-hexamethyldisilazide L T M P - lithium 2,2,6,6-tetramethylpiperidide m - multiplet m - meta m - C P B A - meta-chloroperbenzoic acid M e - methyl M I C - minimal inhibitory concentration min - minute(s) mg - milligram(s) m L - millilitre(s) pg - microgram(s) p L - microlitre(s) irimol - millimole(s) m p . - melting point M S - mass spectrometry n - normal N M R - nuclear magnetic resonance N O E - nuclear Overhauser effect P - page p - para P C C - pyridinium chlorochromate p H - - log 1 0 [H + ] Ph - phenyl PP - pages ppm - parts per milhon Pr - propyl pyr - pyridine q - quartet rt - room temperature s - singlet t - triplet t - tertiary x i i T B A F - tetrabutylarrrrnonium fluoride T B S - te^butyldimethylsilyl T f - trifluoromethanesulfonyl, triflyl T H F - tetrahydrofuran T L C - thin layer chromatography ™ - trade mark T M S - trimethylsilyl T M E D A - A^A^,A^;A^'-tetramethylethylenediamine p-Ts - ^ara-toluenesulfonyl, tosyl p-TsOH - /wa-toluenesulfonic acid -ve - negative v/v - volume-to-volume ratio • - coordination complex ± - racemic x i i i ACKNOWLEDGMENTS First of all, I would like to thank my supervisor Dr. Edward Piers for giving me the opportunity to learn and practice the skills of organic synthesis in his research group. His guidance and patience throughout my studies and especially during writing of this manuscript are greatly appreciated. Thanks to all, past and present, members of the Piers research group for sharing of ideas, chemicals and experiences. I would like to acknowledge the assistance of the technical staff ( N M R lab, X-ray, M S lab and Microanalysis lab) in the Department of Chemistry. The financial assistance from the National Science and Engineering Research Council of Canada, the Alberta Heritage Scholarship Foundation and U B C is gratefully acknowledged. Dr. A l Kaller and Dave Vocadlo were kind to proof-read parts of my thesis. I would like to thank my friends who in many ways contributed to my fmishing this work (especially Dave, Alex , James, L i z , Bianca, Gay, Ipi, Matt, and Pat). I am forever indebted to Ipi Yuyitung for the loan of her computer to write this thesis (as well as her computer desk, chair, microwave, vacuum cleaner and dishes) and to Matt Netherton for his help with the photolysis reaction and computer-related problems. Many thanks to Dave Vocadlo for his words of encouragement, time spent on proof-reading sections of my thesis and for making the year 2000 a very special one. I would like to dedicate this thesis to my parents, who never gave up hope that one day I w i l l graduate...or did they? Dla mamy i taty...ha, a wyscie mysleli , ze nigdy tych studiow nie skoncze! Od dzis prosze sie do mnie zwracac per Dr. Skupinska. Nawet ladnie to brzmi, prawda? xiv I. INTRODUCTION 1.1 General introduction Synthetic organic chemistry is a sub-discipline of chemistry which deals with the construction of carbon based molecules. Since the serendipitous preparation of urea, the first synthetic organic substance, from ammonium isocynate by Wohler in 1828, 1 synthetic organic chemistry has grown and continues to grow in complexity as chemists strive to improve transformations and create increasingly more intricate structures. It is generally accepted that synthetic organic chemists engage in two areas of academic research. Development of new methods of bond construction, improvement of the efficiency and selectivity of existing reactions, and the study of their hmitations and extensions are the main goals of methodological studies. l a the process, many novel compounds are prepared in order to assess the scope of the reaction studied. While the structure of these products is of secondary interest to the method of preparation, the diversity of compounds may serve to illustrate the generality and applicability of the method. It is usually hoped that besides shedding light on the effectiveness of the transformation, the reaction w i l l be added to the array of methods available to organic chemists and w i l l prove useful in a total synthesis, a second area of research conducted by synthetic organic chemists. The goal of any total synthesis is the preparation of a compound, often a naturally occurring substance, via a series of synthetic steps. The choice of the target can be dictated by various motives. Sometimes the compound is known to possess biological activity of interest but is only available in small amounts from natural sources. Another rationale behind a total synthesis may be the desire to unambiguously assign the structure of the isolated compound, since, usually, every transformation used in the synthetic sequence w i l l have a predictable outcome. While the above two reasons are often used in justifying the efforts towards a synthetic target, it is also possible to conduct total synthesis solely for the intellectual and practical exercise resulting from the challenge presented by the target chosen. Whatever the reason, the total synthesis becomes a testing ground for the synthetic methods developed in 1 methodological studies, often proving to be one of its hardest examples. The total synthesis is additionally tied to methodological studies by the fact that, frequently, it requires an improvement in methodology or a development of a new process to accomplish the transformation. Hence, both the methodological studies and total synthesis, although they have different goals, in many instances become connected. The field of synthetic organic chemistry is a rigorous, logical as well as highly creative science. Methodological studies, by necessity, involve a systematic approach to a problem centering on the design of test systems and the consideration of various factors affecting reactivity (e.g. amount of catalyst used, choice of solvents or reaction temperatures). The first challenge facing an organic synthetic chemist engaged in the total synthesis involves the planning of a rational synthetic scheme. Retro synthetic analysis, first developed in 1960s and described by 1991 Nobel laureate E.J . Corey, 2 is a strategy for converting a target molecule into simpler structures via a series of transforms. A transform is an operation that simplifies the molecular complexity (breaking of bonds) or changes functional groups present and is a reverse of a synthetic reaction. This rigorous and logical approach allows the simplification of a complex target molecule into structures that are easily accessible and/or commercially available. However, in spite of a thorough analysis prior to embarking on a total synthesis project, many problems may be encountered along the way, necessitating modifications and refinements in the original plan. The unexpected twists and complications become part of the challenge and learning process, deepening the current knowledge of synthesis and molecular systems. The advancements made in organic chemistry, both in synthetic methods and total synthesis,3"7 would not be possible without concurrent developments in other fields. The development of chromatographic techniques allows for the rapid purification of organic compounds, as well as separation and isolation of complex mixtures of compounds. Structure deteraiination has been greatly facilitated by spectroscopic techniques such as mass spectrometry (MS), nuclear magnetic resonance ( N M R ) spectroscopy, infrared (IR) spectroscopy and X-ray crystallographic diffraction methods. Computers have made possible theoretical modeling of systems, including energy calculations and predictions of molecular conformations, as well as facile manipulation of data. Computational 2 chemistry has recently combined the use of computer technology with that of organic and bioorganic chemistry in the application to the structure-based drug design. A newly developed branch of synthetic chemistry is the area of combinatorial chemistry, where large libraries of compounds can be synthesized, identified and tested for biological activity due to increased automation and emergence of "robotic synthesis". While profiting from these and other advances, organic synthetic chemistry has also had an enormous impact on other fields of science and technology. Materials science and engineering have seen the advent of polymers and their extensive use in many diverse areas from electronics to contact lenses. Synthesis of drugs and their analogues have also affected the fields of pharmaceutical and medical sciences and the pharmaceutical industry. The preparation of organic molecules has allowed the probing of functions of numerous biological systems broadening the knowledge in the areas of biochemistry, molecular biology and pharmacology. As we enter the 21st century, the field of organic chemistry, especially synthesis, is far from becoming stale and outdated. It remains in the center of technological advancement, and promises to remain an interesting and stimulating field of research. 3 1.2 Background: Intramolecular conjugate additions of nonstabilized carbanions Conjugate addition reactions involving the addition of nucleophiles to activated carbon-carbon n bonds, have long been known to organic chemists as powerful synthetic processes for the construction of carbon-carbon bonds. 8 The oldest and most widely used version of this type of reaction involves the conjugate addition of stabilized carbanions (e.g. malonate anion, ketone enolates) to Michael acceptors.9 The discovery of organocopper(I) reagents have initiated the use of nonstabilized carbanionic functions (organometallic reagents such as alkyllithiums, organozincates, organocopper) in conjugate additions 1 0 - 1 1 and in recent years the intermolecular version of this reaction has been used extensively. The development of the intramolecular conjugate additions has also been pursued as a method of ring construction. However, even though the intramolecular conjugate addition of stabilized carbanionic centers has been widely u s e d , 1 2 - 1 5 the corresponding addition of nonstabilized carbanions is still relatively scarce. The difficulty of forming highly reactive nonstabilized nucleophilic species in the presence of an activated-7t system is the main limitation of this reaction. The examples reported in the literature of the intramolecular conjugate additions encompass mainly the organometallic mediated Michael addition of primary alkyl functions, while the addition of unsaturated (alkenyl) functions remains largely unexplored. Among successful applications of intramolecular conjugate additions is the method of Wender and E c k 1 6 involving the use of organobis(cuprates) for spiroannulation (eq 1). In this transformation, the bifunctional reagent adds to the (3-chloro enone 1, generating a nonstabilized primary alkyl organocopper intermediate 2, which undergoes intramolecular conjugate addition to the enone function forming the spiro product 3. O L i (CH 2 ) 4 Li O L iCuSPh O (1) 4 Wender and White 1 7 also reported the preparation and use of aryl- and alkenyl-alkyl bifunctional organocopper reagents such as 5 and 7 (eq 2 and 3). The yields of the spiro products 6 and 8 were lower (39% and 66% respectively) than with the primary alkyl bis(cuprate) employed in the previous study. It should be noted, that although in case of reagent 7 (eq 3) the order of the addition of the reagent functionalities (alkenylcuprate versus alkylcuprate function) is uncertain, formation of product 6 (eq 2) indicates that an aryl function undergoes intramolecular conjugate addition, albeit in a low yield. O PhSCu CuSPh Li , THF , -20 °C 39% PhSCu PhSCu Li , T H F , -20 °C 66% (2) (3) Cooke and coworkers have developed the hthium-halogen exchange-initiated intramolecular conjugate addition reaction to unsaturated esters. Both the addition of primary a lkyl 1 8 and alkenyl 1 9 functions to Michael acceptors were investigated in separate studies (eq 4 and 5). In each of these reactions, an organohthium species, generated by treatment of the iodide (9 or 11) with n-butyllithium at low temperature, adds to a Michael acceptor. In each case, the enolate species formed from the 1,4 addition is quenched by a proton source and produces the cyclized product (10 or 12) in very good yield. C O O B u 1 1 ) " - B u L i , T H F , - 1 0 0 ° C 2) EtOH C O O B u (4) 82% 10 5 C O R 1) n-BuLi, THF, -78 °C 2) H 2 0 11 R = - C ( P P h 3 ) C 0 2 E t 87% C O R (5) A similar approach was applied by Lee and Fuchs 2 0 in the synthesis of ris-fused bicyclic ethers. Treatment of the alkenyl bromide precursor 13 with 1.1 equivalents of t-butyllithium produced the cyclized product 14 (7:1 ratio of diastereomers) via the intramolecular 1,4-addition of the alkenyllithium species to an activated double bond (eq 6). 7:1 13 14 Kocovsky and S rog l 2 1 have recently reported an example of a formation of a four-membered ring by intramolecular conjugate addition of an organocopper(I) species, generated from an organomercury compound 15, to an unsaturated ester moiety (eq 7). BrHg Me 2 CuL i E t 2 0 , -78 °C 75% (7) 15 C 0 2 E t C 0 2 E t 16 Danheiser et al. 2 2 investigated the application of the organozinc compounds in achieving intramolecular conjugate addition with nonstabilized carbanion derivatives (eq 8 and 9). The primary iodide function of compounds 17 and 19, for example, upon treatment with 1.1 to 4.0 equivalents of zinc dust, is thought to generate an organozinc iodide species, which undergoes 1,4 addition to the Michael acceptor. Both five- and six-membered rings can be formed using this method. 6 The mechanistic studies indicate that an organozinc iodide species, formed by oxidative addition of zinc metal to the iodide, cyclizes to form a zinc enolate which is quenched in a work-up step to generate the product. 7 1.3 Background: Copper(I)-mediated intramolecular conjugate additions of alkenylstannane functions One of the focuses of research in our laboratories in recent years has been copper(I) salt-mediated intramolecular conjugate additions of alkenylstannane functions to Micheal acceptors. This direction of research was initiated by the discovery by T. W o n g 2 3 ' 2 4 that treatment of a substrate such as 21 (eq 10) with copper(I) chloride affords an intramolecular cross-coupling of the alkenyltrimethylstannane and alkenyl halide functions in an efficient and stereo specific manner (eq 10). This transformation, although resembling the well known Stille coupl ing, 2 5 " 2 9 proceeds without a Pd(0) catalyst and, in some cases, is faster and cleaner than the corresponding Stille process. 2 3 f n M e 3 | CuCI (2.2 equiv) DMF, 62 °C, 3 min C 0 2 E t 1 80% 21 22 Further experiments 2 4 have demonstated that at least two equivalents of copper(I) chloride are required for the coupling to proceed expediently and efficiently. Wi th one equivalent, the reaction did not go to completion, while 1.5 equivalents produced good yields, but in many cases extended reaction times were required. Mechanistic studies have indicated that the coupling process is initiated by the transmetalation between the alkenylstannane function and the copper(I) salt, generating an intermediate alkenylcopper(I) species and trimethylstannyl chloride (eq 11). While transmetalation of alkenic stannanes by organocopper reagents to form organocuprates had been reported, 3 0 a process of transmetalation with an inorganic copper(I) salt had not been previously observed. S n M e 3 Cu 1 F w ^ L . . R ^ ^ L , ^ Me 3 SnCI (11) y ^ T 7 + 23 24 8 Convincing evidence for this mechanistic proposal was presented in a study by Liebeskind and coworkers,31 who monitored by U 9 S n N M R spectroscopy the reaction of an alkenyltributylstannane and phenyltributylstannane with 1 equivalent of copper(I) iodide in a polar, aprotic solvent (NMP, DMF). The consumption of the alkenylstannane was observed with the formation of tributylstannyl iodide in the process. It was proposed that the second product of the reaction is likely to be the alkenylcopper(I) species. Further investigation by Liebeskind and Al l red 3 2 into the copper(I) salt-mediated cross-coupling of organostannanes with organic iodides showed that the addition of a tributylstannyl halide hindered the progress of the reaction indicating that the transmetalation of the stannane function by copper halide is a reversible process. This observation explains the need for the use of 2 equivalents of CuCl in Wong's work in order to drive the coupling process to completion. A report by Tanaka et al.33 described the use of copper(I) chloride promoted intermolecular conjugate addition of alkenylstannane compounds to allenecarboxylates as part of the synthesis of cephalosporins (eq 12). 26 These observations provided the impetus for the study, in our laboratories, of copper(I)-mediated intramolecular conjugate additions of alkenyltrimethylstannane functions to Michael acceptors. The bulk of the work to date has concentrated on the conjugate additions of alkenyltrimethylstannane functions to a,(3-unsaturated ketones and a,P-alkynic esters. 9 Recent investigations by McEachern and Burns 3 4" 3 6 into the copper(I)-mediated intramolecular Michael additions of alkenyltrimethylstannanes to a,(3-unsaturated ketones demonstrated that treatment of substrates 27-30 with 2.5 equivalents of copper(L) chloride in dry D M F at room temperature resulted in the formation of the cw-fused bicyclo[4.3.0]nonenone derivatives 31-34. The process was rapid and efficient with substrates 27 and 28. However, sterically more bulky groups at the [3-position of the enone (substrates 29 and 30) resulted in a lower yields of the cyclized products (33 and 34) and formation of substantial amounts of uncyclized chloro- and protio-destannylated by-products (i.e. 29 and 30 where the Me 3Sn- group was replaced by - C l or -H) . 3 5 2 7 R = H 31 96% 28 R = Me 32 82% 29 R = Et 33 48% 30 R = /-Pr 34 15% The use of 2.5 equivalents of CuCl was required for the conversion of 27 into 31 to proceed to completion in a minimum amount of time. With 1.0 equivalent of copper(I) chloride, the conversion was sluggish (18 h), while the use of a catalytic amount of CuCl (0.1 equivalents) required 48 h and temperature of 60 °C for the reaction to reach completion. Further investigations showed that treatment of substrates 28-30 with 2.5 equivalents of CuCN in DMSO at 60 °C produced results superior to those derived from the use of CuCl. Although, the CuCN-mediated reactions generally require longer reaction times and elevated temperatures to reach completion within a reasonable time periods, substantially better yields (compared to the CuCl-mediated reactions) were obtained with substrates containing more bulky R groups (R = Et, t-Pr, 29 and 30) (eq 14).3 5 10 2 7 R = H 31 94% 28 R = Me 3 2 9 2 % 29 R = Et 3 3 9 1 % 30 R = APr 3 4 7 3 % A possible mechanistic pathway has been proposed for the copper(I) chloride-mediated intramolecular conjugate additions (Scheme 1) and it is believed that a similar mechanism occurs when CuCN is used in place of CuCI. 3 5 The initial step is proposed to be a reversible transmetalation between the alkenyltrimethylstannane ruction of 35 and copper(I) chloride that generates trimethylstannyl chloride and the alkenylcopper(I) intermediate 36. The alkenylcopper(I) function of the intermediate 36 then adds in a 1,4 fashion to the a,(3-unsaturated ketone moiety to generate the copper(I) enolate 37, which, upon work-up, forms the cyclized product 38. The intermediate alkenylcopper(I) species 36 may also react with a proton source ("H+") prior to cyclization, thus generating the protiodestannylated, uncyclized product 39. The predominant pathway would be determined by the relative rates of the two processes. 11 38 39 Scheme 1 Several experiments were carried out to support this mechanistic proposal. 3 5 First, the amount of trialkylstannyl chloride produced in the cyclization reaction was quantified. Since M e 3 S n C l reacts rapidly with water, a substrate containing a B u 3 S n function (40, eq 15) was studied. In this case, 0.96 equivalents of n -Bu 3 SnCl was isolated, supporting the prediction that 1 equivalent of trialkylstannyl chloride should be produced per equivalent of the starting material consumed (eq 15). 12 Moreover, it was determined that the addition of «-Bu 3SnCl to the reaction mixture prior to the CuCl, inhibits the conjugate addition. This observation is in agreement with the results of previous experiments reported by Liebeskind. 3 1 Another aspect of the proposed mechanism is that a proton source is necessary for the formation of the protiodestannylated compound 39 (see Scheme 1). It was suggested that even though D M F and DMSO were dried prior to use,3 7 the extreme hygroscopicity of these solvents makes it possible that small amounts of moisture could be present. The cyclization reaction was repeated with substrates 27 and 28 in the presence of water (10:1 DMF-H 2 0) . The yield of product 31 was not greatly affected; however, cyclized product 32 was obtained in only 17% yield and was accompanied by a large amount (63%) of protiodestannylated material.35 2.5 equiv CuCl D M F - H 2 0 , rt 92% 2.5 equiv CuCl D M F - H 2 0 , rt 1 7 % 32 It was suggested that the intramolecular conjugate addition step with hindered substrates is relatively slow, allowing the protonation of the intermediate alkenylcopper(I) species by water to occur in preference. Up to this point, most of the work involving the intramolecular copper (I)-mediated conjugate additions to enones had been limited to substrates in which the enone was incorporated into a 6-membered ring. The only exceptions involved the 13 preparation of the bicyclo[3.3.0]oct-6-en-3-ones 43 and 44 by P. A. Burns, as shown in eq 18. 3 4 O o 2.5 equiv CuCI DMF, rt R (18) S n M e 3 41 R = H 42 R = Me 43 76% 44 77% The methodology was also extended to include intramolecular copper(I) chloride-mediated conjugate additions of alkenyltrimethylstannane and aryltrimethylstannane function to the triple bonds of oc,R-alkynic esters.38-39 To date, various functionalized cyclobutane derivatives (e.g. 45 —> 46, eq 16) were prepared via this method in good to excellent yields. 2.5 equiv CuCI (19) 45 46 14 1.4 Proposals The development of the intramolecular copper(I)-mediated conjugate addition methodology opened doors to many extensions, which could allow a facile preparation of fused, functionalized carbocycles. This has already been demonstrated by the synthesis of tricyclic compounds (e'g. 49, Scheme 2) by base-promoted intramolecular alkylations of substrates (e.g. 48) that had been produced by the intramolecular copper(I)-mediated conjugate additions of allcenyltrimethylstannane functions to enone Michael acceptors (e.g. 47)40 47 48 49 Scheme 2 Variations in the structure of the group containing the alkenylstannane function, as well as changes in the size of the ring containing the enone function, would theoretically allow the preparation of a variety of functionalized compounds with interesting carbon skeletons. In particular, it was envisaged that precursors such as 50 would generate, upon treatment with a copper(I) salt, tricyclic compounds of general structure 51. The tetrasubstituted double bond of compounds 51 could then serve as a handle in further synthetic transformations. For instance, oxidative cleavage of the alkene would generate functionalized bicycles 52 in which a relatively small ring (5- or 6-membered, m = 1 or 2) is fused to a medium sized ring (8- or 9-membered, n = 1 or 2) (Scheme 3). 15 o 0 0 Scheme 3 Preparation of such ring systems is of interest because many natural products contain as part of their structure medium-sized rings (especially 8-membered) 4 1 fused to 5- or 6-membered carbon rings. Many synthetic efforts have in the past been directed towards the synthesis of such ring systems. 4 2 It has been shown by preliminary studies by D . J. Wal lace 4 3 that tricyclic systems of general structure 51 can be prepared in good yields. Attempts were made to oxidatively cleave the double bond of compound 55 with the use of osmium tetroxide to form the functionalized bicyclo[7.4.0]dodecane compound 56 (Scheme 4). However, use of this reagent proved to be problematic since the oxidative cleavage was successful only when a stoichiometric amount of OSCM was used. Furthermore, the reaction gave poor results when attempted directly on the olefrnic ketone 53 and it was found necessary to convert the carbonyl function into a ketal (53 —> 55) prior to oxidation (Scheme 4). It was also found that efforts to effect cleavage of more substituted substrates (e.g. 54 or the corresponding ketal) failed as well. 53 R = H 55 56 54 R = Me Scheme 4 Tricyclic ketones of general structure 58, containing an aromatic ring, could theoretically be prepared via copper(I)-mediated intramolecular conjugate additions of 16 substrates such as 57 (eq 20), transformations analogous to that depicted in Scheme 3. The cyclization precursors of general structure 57 would contain an ao'/trimethylstannane function, which in theory could also be functionalized (various R groups), thus providing a route to more elaborate carbon frameworks. A short investigation of this process was going to be attempted as an extension of the Cu(I)-mediated cyclization method. 9 O In addition to explorations into extensions to the conjugate addition method (Scheme 3, eq 20), it was proposed to apply the methodology to a total synthesis of a natural product. The target molecules chosen, (±)- l -desoxyhypnophil in 61 and the corresponding alcohol ( ± ) - 6 2 , 4 4 have a linear triquinane skeleton similar to compound 51 (Scheme 3, m, n = 1). 0 OH " 2 _ b o HiJ \ HlnJ \ <-)-61 M - 6 2 The key step of the synthesis was envisaged to be a copper(I)-mediated intramolecular conjugate addition reaction involving the key intermediate 59, as shown in 17 Scheme 5.* The resultant product 60 was envisaged to be a suitable precursor for the synthesis of (±)- 61 and (±)- 62. O O O OH Me 3StT 59 60 (±)-61 (±)-62 Scheme 5 (-)-l-Desoxyhypnophilin (61) and its corresponding alcohol (+)-62 are new fungal metabolites isolated from Lentinus crinitus widespread in Eastern Africa. 4 4 They belong to a class of sesquiterpenoids with a hirsutane skeleton 63. 4 5 The hirsutane class of compounds possess a triquinane, tricyclo[6.3.0.02'6]undecane, framework with the cis-anti-cis fusion. Members of this family include hirsutene 64, hypnophilin 65, hirsutic acid-C 66, complicatic acid 67 and coriolin 68. * The numbering system normally employed for hirsutane sesquiterpenoids is used in naming of compounds 61 and 62 in the text of the thesis. The experimental section of this thesis contains IUPAC names of both 61 and 62 as well as IUPAC names of all of the synthetic intermediates. It should be noted that throughout this thesis the structures of the synthetic racemic compounds 61 and 62 are drawn as the enantiomers of the isolated compounds (-)-61 and (+)-62. This was done in order to keep the representation of the Cu(I)-mediated cyclization products (such as 60, see Scheme 5) in agreement with the convention established in the methodology part of this work. 18 The hirsutane-type sesquiterpenoids have attracted and continue to attract the interest of synthetic chemists due to their biological activities and extensive functionalization. Over the years, special interest has been directed towards the synthesis of the highly oxygenated substances coriolin (68)45-46 and hypnophilin (65).45 Especially in the 1980s and 1990s, the hirsutanes have been a testing ground for new cyclopentane annulation methods. Discussion of these syntheses is beyond the scope of this thesis, and the reader is directed to a recent review on the polyquinane synthesis 4 5 for more information. Selected approaches are briefly outlined in the discussion section of this thesis. 19 II. RESULTS AND DISCUSSION 2.1 Copper(I) cyanide-mediated intramolecluar conjugate additions of alkenyltrimethylstannanes to a,P-unsaturated ketones. 2.1.1 Preparation of the cyclization precursors In order to investigate the use of the Cu(I)-mediated intramolecular conjugate additions in the synthesis of tricyclic ketones of general structure 69, it was necessary to prepare 4-substituted cyclopent-2-en-l-ones 70 (m = 1) and cyclohex-2-en-l-ones 70 (m = 2). A possible route to the synthesis of the required cyclohexenone and cyclopentenone systems was envisaged to involve an adaptation of the method developed by S t o r k 4 7 ' 4 8 for the synthesis of 4-alkylcyclohex-2-en-l-ones (Scheme 6). Enones of general structure 70 could be obtained from the vinylogous esters 71 by treatment of the latter compounds with D I B A L - H or Grignard reagents (R 2 MgBr) and subsequent treatment of the resultant products with aqueous acid. The vinylogous esters 71 should be attainable by sequential alkylations of 72 with the allylic bromide 73 and an alkyl halide (R*X). The five-membered ring allylic bromide 73 has been previously prepared in our laboratories from the allylic alcohol 74, which in turn is accessible from the commercially available (3-keto ester 75.3 9-4 9.5 0 20 75 74 73 Scheme 6 Since previous work in this area in our laboratories had shown that Stork's method is viable to prepare 4-substituted cyclohex-2-en-l-ones, it was decided to first synthesize the substituted cyclohex-2-en-l-ones 70, where m = 2 and R 1 and R 2 were either H or Me. Alkylation of the enol ether 76 5 1 was accomplished by treatment of a cold solution of 76 in THF with L D A , followed by the addition of the bromide 73 (see Scheme 7). The solution was allowed to warm to room temperature and, after aqueous work-up and flash chromatography of the crude product on silica gel, the vinylogous ester 77 was obtained in 85% yield. The structure of the alkylated product 77 was confirmed by spectroscopic methods. The J H N M R spectrum displayed a 6-proton doublet at 8 0.94 (/ = 6.5 Hz), characteristic of the methyl groups of the isobutyl unit. A one-proton singlet at 8 5.30 was indicative of the alkenyl proton of the vinylogous ester moiety. The characteristic 9-proton singlet at 8 0.10 confirmed the presence of the Me 3 Sn group. This signal was accompanied by small satellite doublets with an average coupling constant of 53 Hz (VSII-H), which result from the two bond coupling of the methyl protons to N M R active u 7 S n and 1 1 9 S n isotopes.52 The 1 3 C N M R spectrum of 77 showed the Me 3 Sn carbon signal at 8 -9.2. Resonances at 8 102.3, 138.3, 151.1 and 177.1 can be assigned to alkenyl carbons and a ketone carbonyl signal was present at 8 200.8. The *H N M R and 1 3 C N M R spectra also contained all other expected signals. The IR spectrum of compound 77 exhibited an absorption band at 1659 cm"1, characteristic of 21 the carbonyl stretching frequency of a six-membered ring enone, and at 1610 cm" 1, which typically results from an alkene stretching absorption. Finally, the high resolution mass spectral determination confirmed the molecular mass of the vinylogous ester 77. Conversion of compound 77 into the enone 78 was achieved by treatment of the former substance with D I B A L - H , followed by acid-catalyzed hydrolysis and dehydration O - T s O H , H 2 0 , E t 2 0 ) of the resulting alcohol (Scheme 7 ) . 4 7 ' 4 8 . 5 3 Work-up and purification of the resulting crude o i l by flash chromatography on silica gel afforded the desired enone 78 in 86% yield. Spectroscopic data confrrmed the structure of the product. The two signals for the alkenyl protons of the enone function appeared at 8 5.96 for the a proton and at 8 6.78 for the (3 proton and showed mutual coupling of 10.0 Hz . The 1 3 C N M R spectrum showed the resonance at 8 199.8, typical of the carbonyl resonance of a six-membered ring enone. Four alkenic carbon signals were also visible, two of which had negative phase in the A P T experiment (8 129.0 and 8 154.4) and therefore could be assigned to the a and P carbons of the enone 78, respectively. 22 85 % 7 7 78 1) LDA, THF, -78 °C -» 0 °C 2) H M P A 3) Mel , 0 ° C - > rt 81 Scheme 7 Methylation of the vinylogous ester 77 by sequential treatment with L D A and methyl iodide in the presence of H M P A , gave compound 79 in 88% yield. The additional 3-proton singlet in the *H N M R spectrum of 79 at 5 1.06 confirmed the incorporation of the methyl group. Subjection of this material to reduction by D I B A L - H , followed by treatment of the resultant alcohol with aqueous acid (p-TsOH), afforded the enone 80 in 88% yield. In the *H N M R spectrum of 80, two signals for the alkenyl protons of the enone function appeared at 8 5.84 for the a proton and at 5 6.78 for the (3 proton and showed mutual coupling of 10.0 Hz. The 1 3 C N M R spectrum showed the carbonyl resonance at 5 199.5. Four alkenic carbon signals were also visible, two of 23 which had negative phase in the APT experiment (8 127.1 and 8 159.7, CH) and therefore could be assigned to the a and (3 carbons of the enone, respectively. Alternatively, treatment of the vinylogous ester 79 with MeMgBr, followed by acid-catalyzed dehydration-hydrolysis of the resultant tertiary alcohol with p-TsOH resulted in the formation of the enone 81 in 89% yield. The *H N M R spectrum of 81 showed, in addition to the 9-proton singlet for the methyls of the Me 3 Sn group at 8 0.14, two other 3-proton singlets at 8 1.17 and 1.94 attributed to the methyl groups at the (3 and Y positions. The 1 3 C N M R spectrum displayed a resonance at 8 199.2 characteristic of a cyclohexenone carbonyl. Two alkenic carbon signals of the enone function were visible at 8 127.2 (CH) and 168.8 (C). Suitable reaction conditions for the formation of the enolate anion of the vinylogous ester 82 have been reported3 6-5 4 for the preparation of the 4-substituted cyclopentenone derivative 84 (eq 21). The vinylogous ester 82 was treated with L D A in THF in the presence of H M P A at -78 °C for 20 min, and the solution was then warmed briefly to 0 °C. The allylic bromide 83 was added at -78 °C and the solution was warmed to room temperature to afford, after work-up and purification of the crude product, the alkylated product 84 in 40% yield. It was noted that, in the absence of H M P A , the reaction proceeded poorly and if the enolate solution was not warmed to 0 °C prior to the addition of the electrophile, the yield decreased substantially. When the above conditions were employed for the alkylation of 82 with the allylic bromide 73, the yield of the alkylated product 85 was only ~ 20% (Scheme 8). Several optimization experiments revealed that the best yield was obtained when the 24 vinylogous ester 82 was treated with L D A in T H F at -78 °C for 30 min and then the mixture was then allowed to warm to 0 °C for 15 min. Over the 15 min of warming, the solution slowly turned from pale yellow to dark orange in colour. The reaction mixture was subsequently recooled to -78 °C, and H M P A and a solution of the bromide 73 in T H F were added sequentially. The solution was then warmed to 0 °C. Under these reaction conditions, the isolated yield of the alkylated compound 85, after work-up and purification, was 77%. The structure of 85 was confirmed by spectroscopic methods. The *H N M R spectrum showed the presence of the M e 3 S n moiety, evident by the 9-proton singlet at 8 0.09. The spectrum also displayed a 6-proton doublet at 8 0.96, due to the methyl groups of the isobutyl ( ( C H ^ - C H - C H ? ) , as well as a doublet at 8 3.70 due to methylene protons adjacent to the oxygen (-OCH2-CH). 87 Scheme 8 Subjection of compound 85 to reduction by D I B A L - H , followed by acid-catalyzed hydrolysis and dehydration of the resultant product, afforded the enone 86 in 78% yield (Scheme 8). The IR spectrum of compound 86 exhibited a carbonyl stretching band at 1717 cm"1 and an alkene stretch at 1612 cm"1, characteristic of a five-membered ring enone moiety. In the J H N M R spectum of 86 the two signals for the alkenyl protons 25 of the enone function appeared at 8 6.12 for the a proton and at 8 7.56 for the p proton and showed mutual coupling of 6.0 Hz . The 1 3 C N M R spectrum showed the carbonyl carbon resonance at 8 209.6. Four alkenic carbon signals were also visible, two of which had negative phase in the A P T experiment (8 133.6 and 8 168.2), and therefore could be assigned to a and (3 carbons of the enone, respectively. Reaction of the vinylogous ester 85 with M e M g B r , followed by treatment of the acquired product with p - T s O H , converted compound 85 into the enone 87 in 76% yield. The successful incorporation of the methyl group was confirmed by the *H N M R spectrum, which displayed a 3-proton singlet at 8 2.09. In addition only a single 1-proton signal at 8 5.87 attributed to the alkenyl proton was observed. A l l other spectroscopic data were also consistent with the assigned structure. The molecular mass was confirmed by high resolution mass spectral analysis on the molecular ion. 26 2.1.2 Copper(I) cyanide-mediated cyclizations The enones 78, 80, and 81 underwent rapid and efficient conversion to the corresponding m-tricyclo[6.4.0.02'6]dodec-2(6)-en-ll-ones 88-90 (eq 22, Table 1, entries 1-3) upon treatment with 2.5 equivalents of copper(I) cyanide in D M S O at 60 °C at a substrate concentration of 0.05 M . Slightly longer times were necessary for the reaction to reach completion when a methyl group was present at the (3 position of the enone function of the starting material (substrate 81; compare entries 1-3, Table 1). • 78,80,81,86 88-91 Table 1. Copper(I) cyanide-mediated intramolecular conjugate additions of enones 78, 80, 81 and 86 (eq 22)a Entry Substrate m R 1 R 2 Equiv CuCN Time (h) Product Yield (%) 1 78 2 H H 2.5 4 88 94 2 80 2 Me H 2.5 4 89 91 3 81 2 Me Me 2.5 6 90 87 4 86 1 H H 5.0 17 91 80b "All reactions were carried out at 60 °C using commercial CuCN. b~6% of uncyclized, protiodestannylated material was also isolated (MS, XH NMR). Ketones 88-90 were obtained in excellent yields (87-94%) after aqueous workup and purification of the crude products by flash chromatography on silica gel, followed by Kugelrohr distillation of the resultant oils under reduced pressure (0.1-0.2 torr). Evidence for the formation of compounds 88, 89 and 90 was provided by the IR and N M R spectra of these materials. For instance, the IR spectrum of the tricyclic compound 90 exhibited a carbonyl stretching absorption at 1715 cm"1, typical of a cyclohexanone 27 carbonyl function. The ^ N M R spectrum of 90 showed two 3-proton singlets at 5 0.98 and 1.15 due to the angular methyl groups, as well as two multiplets in the aliphatic region between 8 1.76 and 2.39, corresponding to a total of 14 protons, in agreement with the assigned structure. In the 1 3 C N M R spectrum, a signal for the carbonyl carbon was seen at 8 214.0, while the two alkene carbon signals appeared at 8 141.9 and 151.2. Additionally, the molecular mass was corifirmed by high resolution mass spectroscopic analysis on the molecular ion. The cis fusion of the formed ring system was not proven spectroscopically on the tricyclic compounds, but was assigned by analogy to previous work . 3 4 The structures of compounds 88 and 8943 were confirmed in a similar manner. Intramolecular cyclization of the enone 86 (Table 1, entry 4) required the use of 5.0 equivalents of C u C N and an increase of the reaction time to 17 h for the conversion to proceed in 80% yield. When 2.5 equivalents of C u C N were used, the reaction was sluggish and only a 55% yield of the cyclized product 91 was obtained after a reaction time of 17 h. The major side product N M R and M S analysis) was the protiodestannylated, uncyclized material 92 (see Scheme 9). The increased difficulty of the cyclization onto a preexisting five-membered ring enone, as opposed to the six-membered ring enone, is most likely.due to the fact that 91, a linearly fused triquinane, is considerably more strained than the tricycles 88-90. Consequently, the transition state leading to 91 would be expected to be higher in energy than those producing 88-90. The need for the use of 5.0 equivalents of C u C N in the reaction of 86 may be explained by invoking the proposed reaction pathway (Scheme 9). The additional C u C N shifts the initial equilibrium of the tin-copper transmetalation step and generates more of the alkenylcopper(I) species 93. This, in turn, facilitates the ring closure step and thus increases the yield of 91. In addition, C u C N , a weak Lewis ac id , 3 5 may facilitate the conjugate addition reaction by coordinating with the ketone functionality and activating the enone function towards Michael addition. The use of excess of C u C N salt would be expected to assist in this process. 28 o o o o ,SnMe 3 CuCN .Cu H H 86 93 91 92 Scheme 9 The intramolecular conjugate addition reaction of the enone 87 was of particular interest in this study. Compound 87 was chosen as a model system for the planned total synthesis of the triquinane natural product, (±)- l-desoxyhypnophil in (61) (Scheme 10). The only difference between the structure of 94 (model compound) and 59 (intermediate for the synthesis of 61) is the presence of a gem-dimethyl group on the alkenylstannane ring of 59. The method developed for the intramolecular conjugate addition of the model system 87 was thus related to the planned key step of the synthesis (59 —> 61, Scheme 10) and, therefore, the primary objective of these initial studies was to achieve the most efficient conversion of 87 into 94. A s was already noted, the cyclization onto a pre-existing five-membered ring enone presented some challenges in the case of substrate 86. In addition, the steric and electronic effects due to the presence of the methyl group at the (3 position of the enone were expected to have a deleterious effect on the intramolecular conjugate addition of the enone 87. 29 Scheme 10 Treatment of the enone 87 with 2.5 equivalents of CuCN at 0.05 M concentration of the substrate in DMSO at 60 °C resulted in a very slow reaction as determined by the G L C analyses of aliquots of the reaction mixture (see Table 2 below, entry 1). After 18 h, the crude reaction mixture contained the starting material 87 (-62%), the priotiodestannylated material 95 (-28%), and a small amount of the desired cyclized product 94 (-10%). After work-up and separation of the mixture by flash column chromatography on silica gel, the cyclized product 94 was obtained in approximately 5% yield. In addition, the destannylated material 95 was isolated in 21% yield and 50% of the starting material 87 remaining unreacted. The structures of the products were confirmed by spectroscopic methods. The IR spectrum of the tricyclic compound 94 exhibited a carbonyl stretching band at 1742 cm"1, typical of a five-membered ring ketone. Evidence for the formation of 94 was further provided by the lH N M R spectrum, which showed a 3-proton singlet at 5 1.19 due to the methyl group, as well as the expected signals in the aliphatic region (8 1.88-2.85) corresponding to the remaining 13 protons. In the 1 3 C N M R spectrum the carbonyl carbon resonance was visible at 8 219.9, while two alkene carbon signals appeared at 8 143.3 and 151.1. Additionally, the molecular mass of compound 94 was corrfirmed by high resolution mass spectroscopic analysis on the molecular ion (FIRMS calcd for 30 C12H16O: 176.1201; found: 176.1197). The structure of the protiodestannylated material 95 was confirmed similarly. The IR carbonyl stretching absorption appeared at 1713 cm"1, typical of a cyelopentenone functionality. The lH N M R spectrum of 95 indicated the presence of two alkenic protons, with resonances at 8 5.38 and 5.88. The latter signal was a triplet with a coupling constant of 1.0 Hz, and therefore could be assigned to the proton resulting from protiodestannylation. The 1 3 C N M R resonance of the carbonyl and the alkene conjugated with the carbonyl function remained essentially unchanged in comparison to the starting material 87, and appeared at 8 208.9, and at 8 130.8 and 8 181.3 respectively. Two other alkenic carbon signals were also visible at 8 126.2 and 141.7. The high resolution mass spectrum of 95 indicated the molecular mass in agreement with that calculated for C 1 2 H 1 6 0 (calcd: 176.1201; found: 176.1206). Various reaction conditions were investigated for the conversion of 87 into 94 (eq 23). The results are summarized in Table 2. The numbers reported in Table 2 do not refer to the isolated yields, but rather to the relative ratios of 87, 94 and 95 in the crude reaction mixture, as determined by the G L C analyses. 31 87 94 95 Table 2. Copper(I) cyanide mediated conjugate additions of enone 87. Entry Equiv Temp. Time Ratio in crude reaction mixture ( G L C ) C u C N ( ° Q (h) 87 94 95 1 2.5 60 18 62 10 28 2 5 60 18 39 16 45 3 10 60 18 12 10 78 4 10 90 3 32 39 29 18 0 39 61 5 20 90 3 14 46 40 18 0 46 54 6 40 90 3 1 46 53 18 0 44 56 a A n aliquot of the reaction mixture was withdrawn via a capillary and was subjected to a mini work-up (saturated NH4CI pH 8, Et 2 0). Small amount of the organic phase was injected onto a G L C column. A n increase in the amount of C u C N from 2.5 to 5 to 10 equivalents (Table 2, entries 1-3) resulted in the increased consumption of the starting material 87 over a period of 18 h (62% versus 39% versus 12% of 87 remaining), with a concomitant increase in the formation of the protiodestannylated material 95 (28% versus 45% versus 78%). Surprisingly, the formation of the cyclized product 94 (-10-16%) was not significantly affected by the increase in the amount of C u C N employed. When the proposed reaction pathway for the conversion of 87 into 94 and 95 is considered (Scheme 11), it seems plausible that the additional C u C N would affect the transmetalation equilibrium. Thus, more of the stannane 87 would be converted to the alkenylcopper(I) intermediate 96. However, under the reaction conditions used here the yield of the 32 cyclized material 94 remains essentially unchanged, suggesting that rather than undergoing the conjugate addition reaction, the majority of the alkenylcopper(I) species 96 reacts with a proton source to generate 95. The protonation of 96 to form 95 may occur as a result of moisture in the reaction mixture or upon work-up with aqueous NH4CI-NH3. 95 94 Scheme 11 Increasing the temperature of the reaction mixture from 60 °C to 90 °C affected the rate and yield of the conversion of the starting material 87 into the cyclized product 94. When 10 equivalents of CuCN were used, all of 87 was consumed at 90 °C after 18 h (Table 2, entry 4) and the amount of the cyclized product 94 was significantly greater (39%), compared to the reaction performed at 60 °C (10% of 94 after 18 h, entry 3). Clearly, an increase in temperature causes an increase in the rate of cyclization and hence facilitates formation of the tricyclic product 94. The amount of the cyclized product 94 formed was not significantly affected by further increase in the amount of copper(I) cyanide from 10 to 20 to 40 equivalents (-39-46%, entries 4-6). In addition, once all of the stannane 87 was essentially consumed 33 (entry 6) after 3 h, the extension of the reaction time to 18 h did not cause further increase in the yield of the cyclized product 94 (-44-46%). The presumed protonation of the alkenylcopper(I) species 96 to generate 95 would prevent further increase in the amount of the cyclized product 94. Previous work 3 5 has indicated that in cases where the cyclization is particularly difficult due to steric and/or electronic effects, protiodestannylation is the predominant reaction. Several alternative sources of the proton have been discussed.35 However, as yet this issue remains unresolved. It was postulated35 that, most likely, the protiodestannylated material results from the reaction of the alkenylcopper(I) intermediate with water that is either present in the reaction mixture (wet solvent) or seeps through the septum during the reaction. DMSO is notorious for being an extremely hygroscopic solvent, and it is very difficult (if not impossible) to obtain this solvent in anhydrous form Hence the possibility of trace amounts of water being present in the solvent, despite drying 3 7 and storing of the solvent under inert atmosphere over molecular sieves, is a valid concern. It was suggested35 that even though the reactions were performed under an inert atmosphere of argon, which was passed over K O H pellets and Drierite™, the atmosphere, too, could potentially contain traces of water. In the present work, according to the above argument, an approximate amount of water that would be needed to destannylate 50% of the starting material 87 would require a concentration of 0.05% H 2 0 in DMSO (v/v). That is, for 0.3 mmol of 87 in 6 ml of DMSO, 0.15 mmol or approximately 3 ul of H 2 0 would result in 50% destannylation. In a search for reaction conditions under which the amount of protiodestannylated product would be decreased, some reactions were performed in a sealed ampoule with a large excess (-50 equivalents) of CuCN in DMSO at 60 °C. 3 5 Thus, in a fashion analogous to that used in previous work, several reactions with substrate 87 were carried out in a "sealed-vessel" in an effort to exclude a possible external "influx" of moisture (Table 3). 34 87 94 95 Table 3. Copper(I) cyanide-mediated conjugate additions of enone 87 in a sealed ampoule. Entry Equiv. Temp. Ratio in crude reaction mixture ( G L C ) C u C N ( ° Q 87 94 95 1 10 60 77 12 10 2 10 90 42 42 16 3 20 90 13 57 30 4 40 90 0 67 29 5 50 90 0 83 11 " A l l reactions were performed in a flame-dried Kimble™, glass ampoule sealed with an oxygen torch. The reaction vessels were heated in an oil bath at 90 °C for 18 h. A comparison of entry 1 (Table 3) with entry 3 (Table 2), and entry 2 (Table 3) with entry 4 (Table 2), employing the same amount of C u C N (10 equivalents) and temperature (60 or 90 °C), revealed that the amount of the cyclized product 95 was essentially unchanged (-10% at 60 °C and -40% at 90 °C) regardless of whether the reaction was performed in a septa sealed flask or in a sealed ampoule. However, when the reaction was carried out in a sealed ampoule, relatively large amounts (77% at 60 °C and 42% at 90 °C, Table 3, entries 1 and 2) of the alkenylstannane 87 remained unreacted after 18 h. In contrast, when the reaction was performed in a non-sealed flask after 18 h, 12% of 87 at 60 °C and 0% of 87 at 90 °C remained in the crude reaction mixture (Table 2, entries 3 and 4). This observation suggests that when the reaction is not performed under sealed conditions, there is a driving force present which pushes the transmetalation equilibrium (87 + C u C N - M e 3 S n C N + 96) (Scheme 11) towards the formation of the alkenylcopper(I) species 96. Apparently, this phenomenon does not occur when the 35 reaction is carried out in a sealed reaction vessel. A possible explanation, invoking the argument discussed previously, could be that there is, in fact, a way for moisture to seep into the reaction mixture that is not sealed in an ampoule. The alkenylcopper(I) intermediate 96 could react with H 2 0 , thus shifting the transmetalation equilibrium (87 —> 96). Water originating from wet DMSO may contribute to the protiodestannylation, but is not the only factor in this process. If this were the case, the same amount of protiodestannylated product would be expected to form under both sealed and non-sealed reaction conditions. Another potential source of proton, which was not investigated, but cannot be discounted, is the presence of -OH groups on the surface of the glass reaction vessels. The contact surface area of the DMSO solution in the glass reaction flask or the sealed ampoule was not controlled and the glassware was not silated prior to use. The addition of a large excess of CuCN resulted in a significant increase in the amount of the cyclized product 94 formed (Table 3, entries 4 and 5). The use of 50 equivalents of CuCN in DMSO (90 °C) in a sealed glass ampoule gave the highest amount of the desired cyclized material 94 (entry 5). The isolated yield of 94, however, was somewhat lower than that expected on the basis of the G L C analyses. Thus, in a number of experiment carried out under conditions as summarized in entry 5, Table 3, the isolated yields of 94 were in the range of 50-59% after work-up and column chromatography of the crude material on silica gel. The protiodestannylated material 95 was obtained in yields of 10-14%. Some polar, unidentified material was not eluted from the silica columns. The goal of this study was to find conditions for the transformation of 87 into 94 that would provide a good yield of the product. These conditions would be applied subsequently in a key step of the projected total synthesis of (±)-l-desoxyhypnophilin (61). Even though the use of a large excess of CuCN in D M S O was necessary, the yield of the cyclized product 94, although not excellent, was acceptable. It should be noted that several reactions were attempted in which CuCl was used in the place of CuCN, but these proved to be highly unsatisfactory. For example, when 50 equivalents of CuCl in a sealed ampoule were used, -66% of the material produced was the protiodestannylated 36 product 95, while only - 6 % of the cyclized material 94 was formed. Several other unidentified products (possibly chloro-destannylated material or the product of a oxidative coupling reaction) were also produced. 37 2.2 Copper(I) cyanide-mediated intramolecular conjugate additions of aryltrimethylstannanes to enones 2.2.1 Preparation of cyclization precursors To test the viability of the CuCN-mediated cyclizations of arylstannanes and to complement the studies carried out by J. G. K. Yee 5 5 on the intramolecular conjugate additions of aryltrimethylstannanes to a,j5-alkynic ester functions, it was of interest to study the analogous conjugate additions of aryltrimethylstannanes to a,(3-unsaturated ketones. It was envisaged that tricyclic ketones of general structure 58 could be obtained by CuCN-mediated intramolecular conjugate additions involving substrates such as 57 (see the retro synthetic scheme in Scheme 12). Enones of general structure 57 could be obtained from the vinylogous esters 98, by treatment of the latter materials with DIBAL-H or Grignard reagents (R 2MgBr), and subsequent dehydration-hydrolysis of the resulting alcohols with aqueous acid. The vinylogous esters 98 should be attainable by sequential alkylations of 72 with the aryl bromides 99 and alkyl halides (R^X). The required bromides 99 could be obtained by bromination of the corresponding alcohols 100. The trimethylstannyl group could be introduced via directed orthometalation56 of the commercially available alcohols 101. 38 Scheme 12 Generally, the directed orthometalation (DoM) reaction involves the deprotonation of an aromatic compound (general structure 102) at the site ortho to the directed metalation group (DMG). The base employed is normally an alkyllithium, R L i . The ort/zo-hthium species 104 formed can then be treated with an electrophile (E +) yielding a 1,2-disubstituted aromatic product 105 (Scheme 13). 5 6 The use of a coordinating solvent (e.g. THF) and the addition of a bidentate ligand (L) such as N, N, A^N'-tetramethylethyldiamine (TMEDA) to the reaction mixture increases the basicity of the alkyllithium reagent by breaking down the alkyllithium aggregates and forming monomers and dimers in solution.5 6 Although the C H 2 0 " is a weak directed metalation group, it has shown promising synthetic utility. 5 7 39 The first step in the preparation of 2-trimethylstannylbenzyl bromide was a directed orthometalation reaction 5 6 of benzyl alcohol (106). Benzyl alcohol (106) was treated with 2 equivalents of n - B u L i in T M E D A and E t 2 0 , and the resulting dianionic species was allowed to react with trimethylstannyl chloride (eq 24). The spectral properties of the derived product 107 were in agreement with those previously reported. 5 7 1) n-BuLi, T M E D A / O H -78 °C -> rt, E t 2 0 „ „ [ M e 3 S n ^ ^ ( 2 4 ) 2) Me 3 SnCI (I J 64% 106 107 2-Trimethylstannylbenzyl alcohol 107 was converted to the bromide 108 using a standard bromination procedure (eq 25) . 5 0 Thus, alcohol 107 was treated with bromotriphenylphosphonium bromide (formed from bromine and triphenylphosphfne in situ)5S'59 in the presence of imidazole to afford, in 94% yield, 2-trimethylstannylbenzyl bromide (108). The X H N M R spectrum of 108 displayed a 9-proton singlet at 5 0.39 with a small satellite doublet ( 2 / S „ . H = 54.0 Hz) due to the M e 3 S n group. The benzylic protons ( -CH 2 Br) appeared as a singlet at 8 4.51, and four aromatic proton signals were visible at 8 7.24 (1H), 7.30 (1H) and 7.38-7.54 (2H). / O H Rr f B r 2 / P P h 3 r M e 3 S n N J ^ imidazole ^ M ^ S n ^ ^ i . (25) C H 2 C I 2 94% 107 108 4-Methyl-2-trimethylstannylbenzyl alcohol* (109) was converted to the bromide 110 in 81% yield in a similar manner (eq 26). The structure of 110 was confirmed on the basis of spectral evidence in a fashion analogous to that employed in the case of 108. This compound was prepared by J. G . K . Yee. 40 M e 3 S n 109 B r 2 / P P h 3 imidazole M e 3 S n CHgClg 81% (26) 110 Alkylat ion of the vinylogous ester 76 with the alkylating agent 108 proceeded in excellent yield (97%) (Scheme 14). The successful incorporation of the benzylic moiety was confirmed by spectroscopic analysis of the product 111. Four aromatic proton signals were visible in the *H N M R spectrum of 111 at 8 6.92-7.22 (2H), 7.22-7.30 (1H) and 7.42-7.48 (1H). A 9-proton singlet due to the M e 3 S n group appeared at 8 0.31. The two 3-proton doublets for the methyl groups of the isobutyl unit appeared at 8 0.97 and 0.98. The alkenic proton of the enone functionality was visible at 8 5.34. cr 76 1) L D A THF -78 °C -> 0 °C-> rt 2) 108 or 110, -78 °C - » r t 1) DIBAL-H or MeMgBr 2) p-TsOH, H 2 0 - E t 2 0 M e 3 S n 1 1 1 R 1 = H 97% 1 1 3 R 1 = Me 96% Scheme 14 M e 3 S n 112 R 1 , R 2 = H 82% 114 R 1 , R 2 =Me 86% The vinylogous ester 111 was converted into the enone 112 in 82% overall yield by reduction of the ketone function with D I B A L - H and acid-catalyzed dehydration-hydrolysis of the resultant alkenyl-ether alcohol (Scheme 14). In the *H N M R spectrum of 112 the alkenic proton signals of the enone function appeared at 8 5.98 and 6.78 and displayed a mutual coupling of 10.0 Hz . Alkylat ion of the vinylogous ester 76 with the bromide 110 provided compound 113 in 96% yield. 1,2-Addition of the methylmagnesium bromide to the ketone function of 113, followed by acid-catalyzed dehydration-hydrolysis of the resultant alcohol, provided the enone 114 (86%) (Scheme 14). The X H N M R spectrum of the enone 114 41 showed one alkenic signal at 8 5.87, two 3-proton methyl singlets at 8 1.88 and 2.31, as well as three aromatic proton signals at 8 7.07-7.12 (2 H) and 7.12-7.32 (1H). The vinylogous ester 115 was also readily prepared via an alkylation reaction (Scheme 15). Thus, treatment of 82 with L D A in T H F , followed by the sequential addition of H M P A and the bromide 108 gave, upon work-up and purification of the crude material on silica gel, the compound 115 in 68% yield. The *H N M R spectral signals of compound 115 could be assigned to particular protons based on their chemical shifts and coupling constants. Thus, the methyl groups of the isobutyl unit appeared as a 6-proton doublet at 8 0.96 ( / = 6.5 Hz) , with the methylene doublet (-OCH2-) at 8 3.72 ( / = 6.5 Hz) and a methine (-CH-) multiplet at 8 1.97-2.09. The M e 3 S n singlet appeared at 8 0.30. There were four aromatic signals visible at 8 7.13-7.25 (3H) and 7.38-7.45 (1H). The methylene protons a to the enol ether function are diastereotopic and appeared as doublet of doublets (dd) at 8 2.30 and 2.57. The geminal coupling for these protons was 18.0 Hz , while additional coupling to the methine (CH) signal at 8 2.75-2.83 exhibited coupling constants of 2.0 and 7.0 Hz , respectively. The benzylic methylene protons (Ar-CH?-) are also diastereotopic and appeared at 8 2.47 and 3.35. The geminal coupling constant was 14.0 H z , while the vicinal couplings to the adjacent methine proton at 8 2.75-2.83 showed coupling constants of 11.5 and 4.0 Hz , respectively. Scheme 15 Reduction of ketone 115 with D I B A L - H , followed by treatment of the acquired alcohol with aqueous acid, gave the enone 116 in 62% yield. The *H N M R spectrum of the enone 116 showed the methyl signal of M e 3 S n group as a singlet at 8 0.29, with a 42 satellite doublet (average coupling constant of 53 H z ( 2/S„-H))- There were 4 aromatic proton signals visible at 8 7.18-7.23 (m, 2H), 7.23-7.33 (m, 1H) and 7.45 (br d, 1H). The alkenic proton a to the carbonyl of the enone appeared at 8 6.19 as a doublet with coupling ( / = 5.5 Hz) to the P proton at 8 7.57. The latter signal showed additional coupling (J = 2.0 Hz) to the methine (-CH-) (8 3.18-3.27, m, 1H). The methylene signals a to the C = 0 appeared at 8 2.09 and 2.52 and showed gerninal coupling ( / =19.0 Hz) , as well as additional coupling ( / = 2.0 and 6.5 H z respectively) to the adjacent methine proton (-CH-) (8 3.18-3.27, m, 1H). The two diastereotopic benzylic protons at 8 2.77 and 2.84 displayed a gerninal coupling constant of 14.0 Hz , and both additionally coupled to the methine proton at 8 3.18-3.27 ( / = 8.0 H z for both). Other spectral data ( 1 3 C N M R , IR, H R M S ) were also found to be in agreement with the assigned structure. 43 2.2.2 Copper(I) cyanide-mediated cyclizations of aryltrimethvlstarrnanes to enones Upon treatment with 2.5 equivalents of copper(I) cyanide in D M S O at 60 °C, the stannanes 112, 114 and 116 underwent intramolecular conjugate addition reactions in good to excellent yields (eq 27; Table 4). 112 m = 2 , R 1 , R 2 = H 117 114 m = 2 , R 1 , R 2 =Me 118 116 m = 1 , R 1 , R 2 = H 119 Table 4. Copper(I) cyanide-mediated conjugate additions of aryltrimethylstannanes 112, 114, and 116." Entry Substrate Time (h) Product Yie ld (%) 1 112 2 117 87 2 114 29 118 66 b 3 a A i i 116 2 119 b A , . . 75 "All reactions were carried out using 2.5 equivalents of CuCN. b A small amount of protiodestannylated material was also obtained (XH NMR, MS). The CuCN-mediated cyclization of enone 112 proceeded (Table 4, entry 1) rapidly and efficiently to give the cyclized product 117 in 87% yield. The IR spectrum o f the cyclized ketone 117 exhibited a ketone carbonyl stretching absorption at 1720 cm" 1. In the N M R spectrum a 4-proton multiplet in the aromatic region (5 7.11-7.22) was visible, as well as signals due to the 10 aliphatic protons (8 1.70-3.64). In the 1 3 C N M R spectrum the carbonyl carbon resonance appeared at 8 212.5, and the aromatic carbon signals resonated at 8 123.7, 124.9, 126.7, 127.0 (all C H , -ve phase in the A P T ) and at 8 142.2 and 145.0 (both C). 44 The conjugate addition of the substrate containing a methyl group in the (3 position of the enone, 114, proceeded quite slowly (Table 4, entry 2). After a reaction time of 2 h, a substantial amount (approximately 60%) of starting material 114 was present in the reaction mixture as determined by the G L C analysis. The progress of the reaction was monitored for 29 h. Upon work-up and purification of the crude material by flash column chromatography, the cyclized product 118 was obtained in 66% yield. A small amount of protiodestannylated material was also isolated ( G L C - M S , X H N M R ) . This material was not fully characterized, but the 1 H N M R spectrum showed four aromatic proton signals (5 7.00-7.11) and an alkenic proton at 8 5.87. The X H N M R spectrum of the cyclized product 118 displayed two 3-proton methyl singlets at 8 1.28 and 2.29. Three aromatic signals were also visible at 8 6.88 (1H), 6.96 (1H) and 7.08 (1H). Other signals appeared between 8 1.82 and 3.17. The 1 3 C N M R spectrum of compound 118 showed a carbonyl resonance at 8 212.2, and a total of six aromatic carbon signals at 8 122.7, 124.6, 127.8 (all C H , -ve phase in A P T ) and 136.5, 137.9 and 150.4 (all C). The intramolecular conjugate addition reaction involving the substrate 116 (entry 3) took place in a short amount of time and produced a very good yield of compound 119 (75%). In this experiment, 2.5 equivalents of C u C N were used. The spectral data for cis-6, 7-benzobicyclo[3.3.0]octan-3-one have been reported previously in the literature 6 0 and compound 119 displayed identical spectral data. These examples of the intramolecular conjugate additions of aryltrimethylstannane functions to a,(3-unsaturated ketones demonstrate that they proceed in a manner analogous to the additions of the alkenyltrimethylstannanes. Cyclizations involving both six- and five-membered ring enones were investigated. 45 2.3. Preparation of functionalized, cis-fused bicyclo[6.3.0]undecanes, bicyclo[6.4.0]dodecanes, and bicyclo[7.4.0]tridecanes 2.3.1 Introductory remarks In recent years, there has been a profusion of synthetic efforts directed towards the construction of carbocyclic systems in which small (usually 5 - or 6- membered) rings are fused to medium-sized rings. Particularly, synthetic approaches to systems containing eight-membered carbocycles 4 1 - 6 1 have been explored intensively. This interest has been stimulated by the discovery of cyclooctanoid fragments in many, structurally diverse terpenoid natural products such as precapnelladiene (120), 7,8-epoxy-4-basement-6-one (121) and variecolin (122), to name just a few. Precapnelladiene (120) 7,8-Epoxy-4-basement-6-one (121) Variecolin (122) While over 100 natural products containing an eight-membered ring are now known, nine-membered ring terpenes are not as common. Very recently, a synthetic approach to the functionalized cyclononane-containing substance, jatrophatrione (123), an unusual antileukemic diterpene, has been reported. 6 2 ' 6 3 Reports on the isolation of several new xenicane-type 6 4 diterpenes (e.g florlide H (124)), possessing substituted cyclononane ring systems, have also been published. 6 5 4 6 Jatrophatrione (123) Florlide H (124) Efforts towards the assembly of cyclooctanoid systems have provided a wide array of synthetic strategies,4 1 which include the direct formation of the eight-membered rings via cycloaddition reactions, sigmatropic rearrangements, cyclizations, and coupling processes, as well as indirect formation via ring expansions, fragmentations, rearrangements and oxidative/reductive protocols. Since discussion of these methods is beyond the scope of this thesis, the reader is referred to an excellent recent review by Mehta and Singh that summarizes methods that have been used for the construction of cyclooctanoid systems and that discusses the application of these methods to the synthesis of natural products. 4 1 Oxidative cleavage of the tetrasubstituted double bond of bicyclo[3.3.0]oct-l(5)-ene or bicyclo[4.2.0]oct-l(6)-ene moieties has been previously employed in the synthesis of 8-membered rings. A n early example of this method by Mehta and coworkers, 6 6 applies the ruthenium tetroxide promoted oxidative cleavage of a double bond of the triquinane 125 to provide the bicyclic dione 126, an intermediate in the total synthesis of (±)-precapnelladiene (120) (Scheme 16). 6 7 H R u 0 2 , N a l 0 4 C C I 4 , M e C N , H 2 0 80% 125 126 (±)-Precapnelladiene (120) Scheme 16 47 Another example of generating 8-membered rings by oxidative cleavage of a double bond involves the formation of 128 from 127 as reported by Little and coworkers. 6 8 This transformation, achieved with ozone, played a key role in the synthesis of taxol analogues (eq 28). Galatsis demonstrated the use of the same method 6 9 in the preparation of functionalized 1,4-cyclooctadione ring systems. For example, the substrate 129, contairiing a tetrasubstituted double bond as part of a 6-4 ring system, was converted efficiently into 130 (eq 29). Remarkably, in the latter report, the alkene function of ketone 129a or ketal 129b (shown below) could not be cleanly cleaved by ozone and both compounds had to be converted to 129 in order for the reaction to succeed. Additionally, the configuration of the - O T B S group also had a significant bearing on the yield of the oxidative cleavage. The yield of the cyclooctadione resulting from the treatment of 129c with ozone was found to be 57%, considerably lower than the yield obtained with the use of substrate 129. 48 129a 129b 129c These observations indicate that, although the method may be generally effective, structural intricacies of the starting material in the proximity of the olefinic bond affect the success of its ozonolysis. 2.3.2 Preparation of ketals Preliminary w o r k 4 3 (see Section 1.4 ear her) into the oxidative cleavage of the tetrasubstituted alkenic function of the ketone 53 with OsCU showed that this reaction was unsuccessful. On the other hand, sequential treatment of the corresponding ketal 55 with OSO4 and NaHS03, followed by reaction of the resultant diol with N a l Q i , gave the ketal dione 56 in 67% yield (Scheme 17). 53 55 56 Scheme 17 49 For this reason, attempts to effect oxiditive cleavage of the olefinic ketals prepared from 88-90 and 54* were investigated first (eq 30). In any case, masking the ketone functions of compounds 88-90 and 54 prior to oxidative cleavage would provide a useful way of differentiating synthetically between the newly generated carbonyl functions and one present in the precursors. Solutions of the ketones 88-90 and 54 in benzene containing 2,2-dimethy 1-1,3-propanediol and a catalytic amount of p-toluenesulfonic acid were refluxed with azeotropic removal of water (eq 30). The crude products, upon purification by column chromatography on silica gel, followed by a bulb-to-bulb distillation of the acquired liquids, afforded the ketal olefins 131-134 in very good to excellent yields (78-90%). O H OH p-TsOH, C 6 H 6 reflux (30) 88 m = 2, n = 1, R 1 f R 2 = H 89 m = 2, n = 1, = Me, R 2 = H 90 m = 2, n = 1, R 1 ( R 2 = M e 54 m = 2, n = 2, R 1 = H, R 2 = Me 131 82% 132 78% 133 83% 134 90% Spectral data provided evidence for the successful formation of the desired ketals 131-134. The IR spectrum of 131 showed a strong absorption due to the C - O - C of the ketal function at 1105 cm" 1. Compounds 132,133 and 134 showed analogous IR bands at 1113, 1115, and 1113 cm" 1, respectively. The lH N M R spectrum of 131 showed signals characteristic of the 2,2-dimethylpropylene ketal function - two 3-proton singlets at 8 0.93 and 0.94 due to the methyl groups and a 4-proton multiplet at 8 3.40-3.51 due to the methylene protons. The corresponding signals of 132 were visible at 8 0.93 (3H), 0.94 (3H), and at 8 3.41-3.53 (4H). The ^ N M R spectrum of ketal 133 showed four 3-proton singlets at 8 0.84, 0.88, 0.96 and 0.99, as well as four distinct signals for each of the methylene protons of the ketal at 8 3.35, 3.41, 3.48 and 3.51. Each of these signals * Compound 54 was prepared by D . J. Wallace. 50 displayed a geminal coupling of 11.0 Hz . The ketal 134 showed three 3-proton singlets at 8 0.90, 1.00 and 1.05 due to the methyl groups, as well as a 2-proton multiplet at 8 3.35-3.43 and two doublets ( / = 16.0 Hz) at 8 3.49 (1H) and 3.52 (1H), due to the four methylene protons of the ketal unit. In addition, 1 3 C N M R spectra and H R M S of ketals 131-134 were in agreement with the assigned structures. 2.3.3 Oxidative cleavage of the tetrasubstituted double bond The ozonolysis reaction is generally a very useful transformation, and thus is widely taught in introductory organic chemistry courses. In a typical procedure, a solution of the ketal 131 in cold methanol was treated with ozone until the reaction mixture turned pale blue in colour, indicating that the presence of excess of ozone in the mixture. Reductive work-up with dimethyl sulfide, removal of volatiles and purification of the crude compound by flash column chromatography on silica gel provided the ketal dione 135 as a colourless solid in quantitative yield (eq 31). The structure of the product 135 was confirmed using spectroscopic techniques. The 1 3 C N M R spectrum provided convincing evidence for the oxidative cleavage, since two carbon signals, characteristic of carbonyl carbon resonances, were visible at 8 211.6 and 212.3. The strong absorption at 1694 cm' 1 in the IR spectrum of 135 additionally confrrmed the formation of the carbonyl groups. The *H N M R spectrum displayed signals that could be assigned to the 2,2-dimethylpropylene ketal group: two 3 proton 51 singlets of the methyls at 8 0.84 and 0.96, as well as four distinct 1-proton signals at 8 3.34, 3.40, 3.42 and 3.60 due to the methylene protons. Each pair of methylene protons is diastereotopic and showed a gerninal coupling constant of 11.5 Hz . In addition, the high resolution mass measurement on the peak corresponding to the molecular ion confirmed the molecular mass of 135. In spite of the initial successful ozonolysis of the double bond of the ketal 131, much lower yields were obtained from the substrates 132 and 133. When compound 132 was treated with ozone, the corresponding ketal dione 136 was isolated in only 63% yield. The yield decreased to 37% in the case of substrate 133. In this reaction, the process yielded a complex mixture of unidentified compounds, as indicated by T L C analyses. Only compound 137 was isolated. A possible explanation for the poor yields obtained from ozonolysis of compounds 132 and 133 can be suggested. The generally accepted mechanism of ozonolysis, proposed by R. Criegee, involves a three-step pathway (Scheme 18) . 7 0 In the first step, an electrophilic 1,3-dipolar cycloaddition of ozone to the carbon-carbon double bond forms a primary ozonide 138. The primary ozonide decomposes into a carbonyl compound and zwitterionic carbonyl oxide. In the third step, the two species recombine to give an ozonide 139. 52 139 Scheme 18 In a reductive work-up step, the ozonide 139 is reduced by, for example, dimethyl sulfide, to generate two carbonyl functions and dimethyl sulfoxide as a by-product. However, it has been suggested 7 1 that when an olefin is sterically hindered, the structure of the primary ozonide is different from 138 and is more likely to be a peroxyepoxide 140. R A R R R 140 The peroxyepoxide species 140, upon decomposition, may form epoxides as the reaction products as well as other products of partial cleavage. 7 1- 72 Such products have been known to form from hindered alkenes. 7 2 The alkene function of 133 is sterically more hindered than that of 131, due to the fact that R 1 and R 2 are both methyl groups. Hence, it could be expected that other products would be formed during the ozonolysis and/or reductive work-up step. In the case of compound 132 (R 1 = Me) the double bond is also somewhat more hindered than that present in 131, and therefore, a lower yield of product 136 might be anticipated. Since the oxidative cleavage of tricyclic substrates such as 132 and 133 by ozone was not generally applicable other methods were explored. The choice of ruthenium tetroxide as an oxidizing agent was suggested by work of Mehta (vide supra, Scheme 16). 6 6 Ruthenium tetroxide is a more powerful oxidant than osmium tetroxide and, in 53 addition, is also known to cleave carbon-carbon double bonds that are resistant to ozonolysis. 7 3 Ruthenium tetroxide is a toxic, highly volatile (b.p. 40 °C) yellow compound, which tends to explode in the solid state. 7 4 For these reasons, the reagent is usually used in catalytic amounts and is prepared by in situ oxidation of R u 0 2 or RuCi3 by a stoichiometric oxidant such as sodium periodate. The reaction is typically done in a heterogenous solvent system of water and carbon tetrachloride. R u 0 2 is a black solid that is insoluble in water and most other solvents and, as a result, remains at the interface of the two-phase system When the R u 0 2 comes in contact with the oxidant (e.g. NaI0 4 ) that is dissolved in the water, it is oxidized to RuCv Ru04 is only moderately soluble in water, but is very soluble in carbon tetrachloride and therefore dissolves in the organic layer of the two-phase solvent sys tem 7 3 A modification of this procedure by Sharpless and coworkers 7 5 includes the addition of acetonitrile as a co-solvent, which presumably prevents the loss of activity of the ruthenium catalyst in cases where carboxylic acids are present or generated. This method is now a generally accepted procedure for ruthenium tetroxide catalyzed oxidative cleavage of alkenes. The Sharpless protocol was used to effect the oxidative cleavage of the olefinic ketals 132-134 and the olefinic ketones 88-91 and 54. Treatment of each of these substrates with a catalytic amount of R u 0 2 and 4.2 equivalents of NaI04 in a 1:1:1.5 (v/v) mixture of acetonitrile, carbon tetrachloride and water at room temperature, resulted, in each case, in the cleavage of the tetrasubstituted alkenic function in very good to excellent yields (79-95%) (eq 33, Table 5). The reactions were fast and were typically completed ( T L C analysis) in 15 to 30 minutes at room temperature. 54 R u 0 2 x H 2 0 (2.2-2.4 mol %) 4.2 equiv N a l 0 4 M e C N - C C I 4 - H 2 0 (1:1:1.5v/v) 1 15-30 min, rt (33) K = 6 6 Table 5. Ruthenium tetroxide catalyzed cleavage of the alkenes 132-134, 88-91 and 54. Entry Substrate X m n R R Product Y ie ld (%) 1 132 K 2 1 M e H 136 95 2 133 K 2 1 M e M e 137 83 3 134 K 2 2 H M e 141 81 4 88 0 2 1 H H 142 95 5 89 0 2 1 M e H 143 94 6 90 0 2 1 M e M e 144 91 7 91 0 1 1 H H 145 79 8 54 0 2 2 H M e 146 87 The evidence for the successful formation of compounds 136, 137, 141-146 was provided by spectroscopic analyses. The 1 3 C N M R spectrum of the ketal dione 136 showed two carbonyl carbon resonances at 8 212.0 and 212.5. The ketal diones 137 and 141 displayed analogous carbon signals at 8 211.7 and 215.1 for 137 and at 8 215.1 and 217.2 for 141. In the IR spectrum of 136, the C - O - C stretching frequency due to the ketal function appeared at 1103 cm" 1, while the carbonyl streching band appeared at 1685 cm"1. The corresponding absorptions for 137 were visible at 1107 and 1688 cm" 1, and for 141 at 1104 and 1693 cm" 1. The structures of the triketones 142-146 were similarly confirmed by spectral data. The 1 3 C N M R spectrum of compound 142 displayed three carbonyl carbon signals at 8 208.5, 211.2 and 211.8. The corresponding carbonyl signals were visible at 8 207.5, 210.6 and 214.3 for 143, at 8 207.5, 210.9, and 215.9 for 144, 8 211.5, 213.3 and 214.3 55 for 145, and at 8 210.9, 212.9 and 216.3 for 146. In the IR spectrum of the triketone 142 a wide carbonyl band was present at 1693 cm"1. The triketones 143 and 144 displayed similar absorptions at 1698 cm" 1. The trione 145 displayed two distinct carbonyl stretching bands in the IR spectrum at 1762 cm"1 and at 1697 cm" 1, characteristic of the carbonyl of a five-membered ring and a larger (6-8 C H 2 units) ring respectively. 7 6 The trione 146 also displayed two carbonyl absorption bands at 1705 and 1697 cm" 1. Clearly, the Ru04-catalyzed oxidation method provided an efficient and rapid method for the oxidative cleavage of the alkenic function of the substrates listed in Table 5. Functionalized, ds-fused bicyclo[6.3.0]undecane, bicyclo[6.4.0]dodecane and bicyclo[7.4.0]tridecane systems were prepared via this method from the corresponding tricyclic olefinic precursors 132-134, 88-91 and 54. 56 2.4. Aldol condensation reactions of the triones 142-146. Further synthetic manipulations using the novel bicyclic triketones 142-146 were envisaged. In particular, a possibility of generating structurally more complex products via acid-catalyzed aldol condensations of these substrates was pursued. When each of the compounds 144 and 143 was treated with a catalytic amount of /7-toluenesulfonic acid in refluxing T H F , the corresponding aldol condensation products 147 and 148 were obtained in isolated yields of 97% and 94%, respectively (eq 34). The IR spectra of the products 147 and 148 showed strong, broad absorptions at 3406 cm"1 and 3382 cm" 1, respectively, indicating the presence of a hydroxyl group. The carbonyl stretching absorption was visible at 1701 cm"1 for 147 and at 1716 cm"1 for 148. In addition, for each of these products, only two carbonyl signals were visible in the 1 3 C N M R spectrum at 8 211.1 and 214.6 for the 147 and at 8 209.9 and 210.7 for 148. The 1 3 C N M R spectra also displayed a carbon signal at 8 79.3 for 147 and at 8 82.6 for 148, again suggesting the presence of a hydroxyl group. These observations indicated the formation of aldol condensation products when substrates 144 and 143 were treated with acid. Analyses of molecular models of various possible aldol condensation products derived from 144 and 143, each involving the closing of a five-membered ring, indicated that structures 147 and 148, respectively, would show the least amount of strain, and 57 should be thermodynamically favoured. X-ray crystallographic studies confirmed that the aldol condensation between C-12 and C-6 of 144 and 143 occurred, and that the products formed were, in fact, 147 and 148 (Figure 1 and 2). The assignments of the *!! N M R and 1 3 C N M R signals of the product 147 were accomplished using two dimensional N M R techniques: correlation spectroscopy ( C O S Y ) , " C ^ H one bond and long range correlation experiments ( H M Q C and H M B C ) . The results of these experiments are summarized in the experimental section of this thesis. Figure 1. X-ray crystal structure of 147 (50% probability thermal ellipsoids are shown for the non-hydrogen atoms). X-ray crystallographic analyses were performed by S. J. Rettig (deceased October 27, 1998) of the U B C X-ray Crystal Structure Laboratory. 58 Figure 2. X-ray crystal structure of 148 (50% probability thermal ellipsoids are shown for the non-hydrogen atoms). The presence of the methyl groups in the R 1 and R 2 positions of 144 and 143 seems to influence the thermodynamically controlled equilibrium of the reaction. Treatment of the triketone 142, where R 1 and R 2 are both H , with a catalytic amount of p-T s O H in refluxing T H F , resulted in formation of approximately 1:1 mixture of the triketone 142 and the aldol product 149 (eq 35). After 3 days of refluxing conditions, no further change in the ratio of the starting material and product was observed. 59 o H . 0 p-TsOH, THF reflux (35) 142 149 The aldol product 149 was isolated as a white solid in 46% yield, and its structure was determined by comparison of its spectral data to those of compounds 147 and 148. The IR spectrum of 149 showed a broad absorption band at 3436 cm"1 as well as absorption arising from the carbonyl stretching at 1698 cm" 1. The 1 3 C N M R spectrum displayed two carbonyl carbon signals at 8 210.2 and 213.5 as well as a signal at 8 82.0, due to a carbon bonded to a hydroxyl group. The ! H N M R spectrum displayed al l signals corresponding to the expected number of protons. In addition, the H R M S measurement on the molecular ion confirmed the molecular mass of 149. The recovered starting material 142 was isolated in 52% yield. The spectral properties ( X H N M R , 1 3 C N M R ) and the melting point (mp. 128-130 °C) of recovered 142 were compared to those of the original material 142 (mp. 129-131 °C). The comparison demonstrated that isomerization of the tertiary centre a to the C=0 , which could potentially generate a 6-8 ring system with a trans fusion, did not occur. A n analogous acid-catalyzed aldol condensation reaction was not observed when the triketone 145 was treated with />-TsOH in refluxing T H F . The unreacted starting material 145 was isolated from the reaction mixture in quantitative yield (eq 36). A n aldol condensation of the 5-8 membered ring system analogous to that observed for the 6-8 ring systems (vide supra) would generate the tricyclic ring system 150. Compound 150 would undoubtedly be more strained than 149, the aldol product derived from 142, which possesses a 6-8 carbon framework. 60 145 1 5 0 A n acid-catalyzed aldol reaction was also performed on the triketone 146, which possesses a 6-9 bicyclic fused ring system Thus, treatment of this material withp-TsOH in refuxing T H F provided a single product in 79% yield. However, in contrast to the products 147-149, the IR spectrum of this product did not show the hydroxyl stretching absorption, but displayed absorption bands at 1713 and 1664 cm" 1, the latter suggesting the presence of an alkene function. In addition, the 1 3 C N M R spectrum showed two signals at 8 136.4 and 168.1, consistent with the presence of an alkene function, and two carbonyl carbon signals at 8 209.5 and 195.8. This data, along with mass spectral data, indicated that the aldol condensation had been followed by elimination of water to form an a,(3-unsaturated ketone (eq 37). 146 151 152 The two possible products 151 and 152, both resulting from the formation of a 6-5 system from the nine-membered ring, could be formed by condensation between carbons 6 and 2 in 146 (151) or carbons 3 and 7 (152). Since the product obtained was a viscous oi l , X-ray crystallography could not be used directly to deterrnine its structure. To distinguish between the two possible products, an H M B C (heteronuclear multiple bond correlation) experiment was performed in conjunction with an H M Q C (heteronuclear multiple quantum coherence) experiment. It was expected that only compound 152 61 would show a long range (two and three bond) correlation ( H M B C ) between the carbon of the C-2 carbonyl and the protons of the methyl group (Me-14). On the other hand, compound 151 would show a correlation between a carbon of the alkenic function (i.e. C-2) and the methyl group (Me-14). In fact, the multiple bond correlation between the alkene signal at 8 168.1 (C-2) and the methyl group protons (8 1.26) (H-14) was observed. Such a correlation would be impossible in the case of 152. Therefore, the identity of the aldol product as 151 had been established. In summary, it was shown in this brief study that intramolecular aldol condensations involving substances 142-144 and 146 readily produce products that possess novel carbon skeletons. Thus, the substances 142-144, upon treatment with p-T s O H in T H F provided the functionalized tricyclo[5.5.0.02'9]dodecanes 147-149. On the other hand, the triketone 146, when treated under similar conditions, generated the functionalized tricyclo[7.4.0.02'6]tridecane 151. 62 2.5 Total synthesis of (±)-l-desoxyhypnophilin (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) 2.5.1 Triquinane Natural Products: Background Among the most popular synthetic targets in the 1980s and 1990s were the polyquinane natural products. During the 1970s and 1980s many members of this general class of compounds, including sesqui- (C15), di- (C20) and sester- (C25) terpenoids, were isolated from various terrestrial and marine organisms. Indeed, reports regarding the structure elucidation of novel polyquinane natural products isolated from previously unexplored sources continue to appear periodically in the literature. 7 7 - 7 9 The wide interest devoted to this class of natural products has been in part due to their potent biological activity; many members have been found to possess antitumor, antibacterial, or antiviral properties.45 The numerous reported syntheses of polyquinane natural products, fueled by the interest in their unique structures, provided a testing ground for new cyclopentane annulation methodologies.4 5'8 0 In our laboratories, exploration of the use of bifunctional reagents in 5-membered ring annulations culminated in the synthesis of the linear triquinane (±)-9(12)-capnellane (153),81 as well as the first synthesis of a tetraquinane natural product, (±)-crinipellin B (154).82 One of the most prevalent polyquinane synthetic targets has been the sesquiterpene coriolin (68), a metabolite of Coriolus consors with interesting antibiotic and antitumor properties.83 This highly oxygenated hirsutane-type compound was the objective of over 20 different total and formal syntheses since 1980, with the most recent 63 approaches having been reported in 1999 . 8 4 ' 8 5 A related substance, hypnophilin (65), 8 6 isolated from Pleurotellus hypnophilus, has also been a popular target. Hypnophilin (65) displays activity toward gram-positive and gram-negative bacteria, fungi, yeast and cancer cel ls . 8 7 coriolin hypnophilin 1-desoxyhypnophilin 68 65 61 A s an illustration of the various synthetic innovations in the assembly of the triquinane framework, some approaches to their formation are worth outlining. Since numerous methods have been developed, those discussed in this section w i l l involve the synthesis of hypnophilin (65), which is particularly relevant due to its structural similarity to the chosen target compound of this study, 1-desoxyhypnophilin (61). The key step in the first reported total synthesis of (+)-hypnophilin by Little and coworkers 8 7 was the construction of the triquinane framework of 162 via an intramolecular 1,3-diyl trapping reaction (Scheme 19). The precursor for this reaction was prepared from the furanone 155. The primary alcohol group of this compound was first protected as a benzyl ether. This protection step was followed by reduction of the lactone function to provide a diastereomeric mixture of lactols. Conversion of the lactol moiety into the corresponding methyl acetal, followed by removal of the benzyl protecting group, afforded 156. Swem oxidation of the alcohol 156 provided an aldehyde which was treated under previously developed conditions 8 8 with cyclopentadiene to form the fulvene 157. A Diels-Alder reaction of 157 and dimethylazodicarboxylate provided the dicarbamate 158. The internal double bond of 158 was selectively hydrogenated with diimide and the acetal function was converted to the lactol 159 by treatment with acetic acid. The dicarbamate 159 was saponified and the resulting hydrazine was oxidized with potassium ferric cyanide to provide the diazene 160. Reaction of the masked aldehyde with methylenetriphenylphosphorane provided compound 161. The diazene 161 was 64 converted via a 1,3-diyl trapping reaction to the triquinane 162 in excellent yield (90%). The diradical intermediate of this reaction was generated by photolysis of the diazaene 161 at low temperature. Four other minor products were obtained in the 1,3-diyl trapping reaction. However, when the reaction temperature was maintained at -60 °C the ratio of the major compound 162 to the combined minor products was 30:1. Having formed the triquinane skeleton, elaboration of this advanced intermediate 162 into the final product 65 required only a few steps. Thus, treatment of 162 with meto-chloroperoxybenzoic acid (m-CPBA) , followed by heating the resultant epoxide with L D A led to the formation of diol 163. The primary alcohol function was protected as a benzoate ester and oxidation of the free allylic alcohol using P C C afforded the enone 164. The angular methyl group was installed by the treatment of 164 with a cuprate reagent. The benzoyl protecting group was then removed to yield 165. The ketone 165 was treated with a bulky base, hthium tetramethylpiperidide, to afford a mixture of the si lyl enol ethers in a ration of 6:1. The mixture of the enol ethers was subjected to the Saegusa 8 9 conditions to introduce the enone function of 166. The yield of the desired product was quite low (30%), although, based on the recovered ketone 165, it was reported to be 93%. The a methylidene was formed in a three-step procedure. Compound 165 was treated with L D A and the resultant enolate was reacted with formaldehyde gas to generate a mixture of diastereomeric alcohols. Treatment of this mixture with tosyl chloride and a subsequent ehmination reaction promoted by l,5-diazabicyclo[5.4.0]undec-5-ene (DBU) afforded the dienone 167. Monoepoxidation of the strained internal olefin gave (±)-hypnophilin (65) in 50% isolated yield along with some recovered starting material (30%). 65 Reagents: a) C 6 H 5 C H 2 B r , A g 2 0 ; 76%; b) DIBAL-H; 97 %; c) MeOH, H + ; d) H 2 , PdOH; 94 %; e) (COCI) 2, DMSO, Et 3 N; f) A c O H , pyrrolidine, cyclopentadiene; 55 %; g) MeOOC-N=N-COOMe; 90 %; h) KOOC-N=N-COOK, AcOH; 96 %; i) aq. A c O H , heat; 95 %; j) KOH; K 3 Fe(CN) 6 ; 86 %; k) C H 2 = P P h 3 ; 67 %; I) hv, -60 °C; 90 %; m) m-CPBA; LDA, heat; 54 %; n) BzCI; 85%; o) P C C ; 89 %; p) Me 2 Cu(CN)Li 2 , B F 3 E t 2 0 ; 93 %; r) KOH; 99 %; s) LTMP, TMSCI; Et 3 N; Pd(AcO) 2 , MeCN; 31 %; t) LDA; C H 2 0 ; 85 %; u) p-TsCI, pyr;DBU; 80 %; v) H 2 0 2 , N a 2 C 0 3 ; 50 %. Scheme 19 66 A more concise approach to (±)-hypnophilin (65), involving an application of the tandem samarium diiodide-mediated radical cyclization, was developed by Curran and coworkers (Scheme 20). 9 0 Lactone 168 was treated with the cuprate reagent derived from l-bromo-3-[(^butyldimethylsilyl)oxy]-2,2-dimethylpropane. Reduction of the resultant carboxylic acid function with Hthium aluminum hydride generated the alcohol 169. Oxidation of this alcohol, followed by the addition of hthium trimethylsilylacetylide to the resultant aldehyde provided 170. Oxidation of the secondary alcohol of 170 gave the ketone which was converted to the corresponding ketal 171. At this stage the key samarium diiode-mediated tandem radical cyclization was performed. Treatment of 171 with SmJ.2 in the presence of H M P A generated the triquinane framework in one step. Hydrolysis of the ketal function of the cyclized product resulted in the formation of 172 in 58% yield over the two steps. The dienone 167 was formed by treatment of 172 with excess L D A and TBSC1 in THF/DMPU followed by the addition of DDQ in 2,6-lutidine. Compound 167 was treated with H 2 0 2 to generate the final product (±)-hypnophilin (65) in 53% yield in a protocol similar to that used by Little. 8 7 Scheme 20 67 The syntheses of (±)-hypnophilin ((±)-65) outlined above, which represent just two of the numerous approaches to triquinane natural products,45-80 provided a proving ground for novel synthetic methods (i.e. a 1,3-diyl trapping reaction and a samarium dhodide tandem radical cyclization approach). The most recent approaches tend to focus on the concise formation of the triquinane skeleton91"93 of both natural and non-natural compounds and continue to provide illustration of the synthetic power of novel methods. 68 2.5.2 Isolation of (-)-l-desoxyhvpnophilin (61) and (+)-6J-epoxy-4(15)-hirsuten-5-ol (62) (-)-l-Desoxyhypnophilin (61) and (+)-6,7-epoxy-4(15)-hirsuten-5-ol (62),* previously unknown substances, were isolated in 1994 from Lentinus crinitus, a fungus collected in Ethiopia from dead w o o d . 4 4 These two metabolites were isolated along with the known (-)-hypnophilin (65) and the corresponding diol (173). The antimicrobial activity of the new compounds 61 and 62 against several test organisms was determined by a serial dilution assay and the minimal inhibitory concentration (MIC) was reported. Compound 61 contains an a-methylidenecyclopentanone moiety, a functional group that is often associated with strong antibiotic activity in natural products. Therefore, it is not surprising that alcohol 62 showed reduced antimicrobial activity in comparison to (-)-l-desoxyhypnophilin (61). For instance, the M I C of compound 61 against Bacillus cereus was 2-5 ug/mL and against Staphylococcus aureus 10-25 ug/mL while the reported M I C of the alcohol 62, in both cases, was greater than 100 u g / m L . 4 4 The numbering system normally employed for hirsutane sesquiterpenoids is used in naming of compounds 61 and 62 in the text of the discussion. The experimental section of this thesis contains I U P A C names of both 61 and 62 as well as I U P A C names of al l of the synthetic intermediates. It should be noted that throughout this thesis the structures of the synthetic racemic compounds 61 and 62 are drawn as the enantiomers of the isolated compounds (-)-61 and (+)-62. This was done in order to keep the representation of the Cu(I)-mediated cyclization products (such as 60, see Scheme 21 on the next page) in agreement with the convention established in the methodology part of this work. 69 2.5.3 Retro synthetic plan for the synthesis of (±)-l-desoxyhvpnophiliri (61) and (±)-6J-epoxy-4(15)-hirsuten-5-ol (62) The proposed synthetic plan for the construction of the natural products (±)-61 and (±)-62 involved formation of the triquinane skeleton by use of the CuCN mediated conjugate addition method (Scheme 21) discussed in greater depth earlier (see Section 2.1.2). Scheme 21 It is clear that the synthesis of the natural product (±)-62 from (±)-l-desoxyhypnophilin 61 would involve a one step reduction process (Scheme 22) analogous to that reported for the synthesis of hirsutic acid C . 9 4 It was anticipated that the epoxide and a methylidene functionalities present in 61 could be introduced into the tricyclic ketone 174. Based on literature precedence in the synthesis of hypnophilin,8 7 the introduction of the exocyclic methylene unit was planned to precede the epoxidation step. In theory, though, the steps could be reversed in the protocol employed in the synthesis of crinipellin B . 8 2 It was conceived that the triquinane skeleton of 174 could be readily generated from the tricyclic compound 60 by stereoselective reduction of the tetrasubstituted double bond. It was envisaged that access to the ketone 60 could be gained via the CuCN-mediated cyclization of the intermediate 59. Presumably, the enone 59 could be prepared by treatment of the vinylogous ester 175 with methylmagnesium bromide, followed by acid hydrolysis of the resultant product. It was anticipated that 175 could be generated by alkylation of the vinylogous ester 82 with the bromide 176 via a procedure analogous to the method developed earlier (Section 2.1.1). Preparation of the bromide 176 from the ester 177 was expected to proceed without complications.50 70 Preparation of the alkenylstannane 177 from the the known p-keto ester 17895 was also predicted to be facile. 2.5.4 Synthesis of (±)- l-desoxyhypnophil in ((±)-61) 2.5.4.1 Preparation of the bromide 176 Synthesis of the required methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate (178) was accomplished by following a literature procedure (Scheme 23). 9 5> 9 6 Scheme 23 Thus, treatment of commercially available dfmedone (179) with triethylamine and p-toluenesulfonyl azide provided, after work-up and successive recrystallizations from ethanol at -25 °C, 2-diazodimedone (180) as yellowish needles in 63% y i e ld . 9 6 The appearance of the product, its melting point, as well as the IR and 1 H N M R spectroscopic data were in full agreement with the reported values. 9 6 - 9 7 The X H N M R spectrum of the product displayed a 6-proton singlet at 8 1.10 due to the gem-dimethyl group and a 4-proton singlet at 8 2.43 due to the methylene protons. The IR spectrum showed a band at 2146 cm" 1, characteristic of a diazo stretching frequency. 2-Diazodimedone (180) was transformed into the (3-keto ester (178) by a photolytic Wol f f rearrangement followed by trapping of the resultant ketene intermediate with methanol. A solution of 2-diazodimedone in T H F and methanol was irradiated until the reaction was complete as judged by T L C analysis. Removal of the solvent, followed by distillation of the resulting material, provided compound 178 as a clear o i l in 89% yield. The preparation of 178 was conveniently carried out on a large scale, since the purifications of both compounds 180 and 178 required no tedious chromatographic separations. Since the published *H N M R spectral data for 178 were recorded on a 60 M H z instrument, 9 5 updated spectral data is provided in the experimental section of this thesis. The X H N M R spectrum displayed two 3-proton singlets at 8 1.04 and 8 1.21 for 72 the gem-dimethyl group and a 3-proton singlet for the methyl ester at 8 3.72. The methine (CH) signal appeared as a doublet of doublets at 8 3.37, which exhibited coupling to the two adjacent diastereotopic methylene protons with coupling constants of 9.0 and 11.0 Hz . The corresponding methylene proton signals appeared at 8 2.12 (1H, dd, / = 9.0 and 13.0 Hz) and as part of the signal at 8 2.17-2.20. The latter signal was overlapping with a broad 2-proton singlet (8 2.19) due to the methylene protons adjacent to the ketone. The next step in the synthesis of (±)- l-desoxyhypnophil in was the conversion of the (3-keto ester 178 into the bromide 176. The preparation of a similar bromide (73) was previously accomplished in the methodological part of this work and an analogous procedure was followed for the preparation of 176 (Scheme 24). Scheme 24 A cool (0 °C) solution of the (3-keto ester 178 in T H F was treated with potassium hydride and the resulting enolate was triflated on oxygen by addition of solid N-phenyltrifluoromethanesulfonimide (PhNTf 2) to the reaction mixture. Upon completion of the reaction E t 2 0 was added to dilute the mixture and the solids were removed by filtration of the mixture through a silica/Celite plug. Concentration of the filtrate and purification of the crude material by chromatography on silica gel afforded the triflate 73 181 in 85% yield. The structure of the product 181 was confirmed by spectroscopic methods. The *H N M R spectrum displayed a 6-proton singlet due to the gem-dimethyl group at 8 1.15. The methyl ester signal was visible at 8 3.76. The signals for the two pairs of methylene protons appeared as triplets at 8 2.47 (2H) and 8 2.54 (2H) and exhibited small mutual coupling with a coupling constant of 2.5 Hz . The successful incorporation of the triflate function was confirmed by the 1 3 C N M R spectrum, which showed a quartet due to the - C F 3 group at 8 118.3 ( / C - F = 319 Hz) . The triflate 181 was converted to the stannane 177 by use of the cyanocuprate reagent M e 3 S n ( C N ) C u L i . 9 8 The cuprate was generated by the addition of 1 equivalent of M e L i to hexamethylditin in T H F at -48 °C, followed by the addition of 1 equivalent of solid copper cyanide (Scheme 25). THF M e 3 S n - S n M e 3 + MeLi ** Me 3 Sn-L i + M e 4 S n J C u C N , THF Me 3 Sn(CN)CuLi Scheme 25 Phenylthiocopper(I) has also been used in place of C u C N ; however commercial CuSPh often provided unreliable yields of the stannane 177. The use of commercially available C u C N in the preparation of the cuprate reagent gave consistently high (> 90%) yields of 177. The successful conversion of the triflate 181 into the stannane 177 was confirmed by both *H and 1 3 C N M R spectroscopy. The *H N M R spectrum of 177 displayed a 9-proton singlet with a satellite peaks ( 2 /s n -H = 55.0 Hz) at 8 0.14, characteristic of the M e 3 S n moiety. A 6-proton singlet due to the gem-dimethyl group was also visible at 8 1.06. The methyl ester singlet appeared at 8 3.69. The signals for the two pairs of methylene protons were displayed at 8 2.40 (2H) and 8 2.45 (2H). In the 1 3 C N M R spectrum a peak at 8 -8.6 corLfrrmed the presence of the M e 3 S n group and the spectrum showed the expected number of carbon signals. 74 A solution of the ester 177 in T H F was treated with 2.5 equivalents of D I B A L - H . After work-up and purification of the crude material by column chromatography on silica gel, the alcohol 182 was obtained as a colourless o i l in quantitative yield. The IR spectrum of the product 182 showed a broad absorption band at 3343 cm"'due to the hydroxyl group. The *H N M R spectrum showed a 9-proton singlet at 8 0.11 due to the M e 3 S n group. A broad - O H signal at 8 1.30 and a 2-proton doublet at 8 4.12 due to the hydroxymethyl group were also visible. The alcohol 182 was converted to the corresponding bromide using triphenylphosphine and bromine in the presence of imidazole. When the reaction was complete, pentane was added to the reaction mixture. The mixture was then filtered through a cake of silica gel/Celite in order to remove a majority of the precipitated triphenylphosphine oxide. It was found that the yields of the bromide 176 improved by about 10% if the residue left in the flask following the filtration was treated with aqueous sodium bicarbonate solution (10%). The aqueous mixture was extracted with pentane and the pentane solution was filtered as above. Concentration of the combined filtrates provided bromide 176 in 93% yield. Spectroscopic data confirmed the conversion of the alcohol 182 into the primary bromide 176. Thus, the *H N M R spectrum showed a 9-proton signal at 8 0.18 attributed to the M e 3 S n moiety, a 6-proton singlet at 8 1.06, two 2-proton signals at 8 2.25 and 8 2.32 as well as a 2-proton singlet at 8 4.02 due to the bromomethyl group. The high resolution mass spectral analysis on the ( M + - C H 3 ) fragment confirmed its molecular mass ( H R M S calcd for C i 0 H 1 8 1 2 0 S n 7 9 B r : 336.9614; found: 336.9620). 75 2.5.4.2 Synthesis of the cyclization precursor (59) With the bromide 176 in hand, the preparation of the cyclization precursor, the enone 59, could be accomplished. A procedure very similar to that employed previously (see Section 2.1.1) for the alkylation of 3-isobutoxycyclopent-2-en-l-one (82) was adopted (Scheme 26). Scheme 26 A solution of the vinylogous ester 82 in T H F was treated with L D A at -78 °C. This mixture was warmed for 15 min to 0 °C, after which time the clear solution became orange in colour. Once the solution had been recooled to -78 °C, H M P A and a solution of the bromide 176 in T H F were added. After aqueous work-up and purification of the crude material by column chromatography on silica gel and bulb-to-bulb distillation (220-230 °C at 0.6 torr), the alkylated product 175 was obtained in 71% yield as a viscous o i l which solidified upon standing (mp. 35-36 °C). The structure of 175 was confirmed by the usual spectroscopic methods. The *H N M R spectrum of 175 showed the presence of the M e 3 S n moiety, as evidenced by the 9-proton singlet at 8 0.08. The gem-dimethyl group appeared as two 3-proton singlets at 8 1.00 and 8 1.02. The spectrum also displayed a 6-proton doublet at 8 0.96, due to the methyl groups of the isobutyl unit ( ( C H ^ - C H - C H ? - ) , as well as a doublet at 8 3.70 due to the methylene protons adjacent to the oxygen ( -OCTL-CH-) . The signal due to the alkenyl proton of the vinylogous ester moiety was visible at 8 5.18. The remaining protons were displayed as multiplets between 8 2.02-2.31 (7H) and 8 2.56-2.62 (3H). The 1 3 C N M R spectrum of 76 175 showed the expected number of carbon signals. In addition, the high resolution mass spectral analysis on the peak corresponding to the molecular ion provided confirmation of the molecular mass of 175 (HRMS calcd for CzoH^CV^Sn: 426.1581; found 426.1575). Reaction of the vinylogous ester 175 with MeMgBr, followed by treatment of the acquired material with /7-TsOH in wet Et 2 0, converted compound 175 into the enone 59. Standard work-up, purification of the crude product by column chromatography, and bulb-to-bulb distillation of the acquired liquid under reduced pressure (125-130 °C at 1.5 torr) gave 59 in 79% yield. This viscous oil solidified upon standing (mp. 31-32 °C). The successful incorporation of the methyl group was confirmed by the *H N M R spectrum, which displayed an additional 3-proton singlet at 8 2.09. The remaining two methyl groups were visible at 8 1.02 and 5 1.05. In addition, a 1-proton singlet at 8 5.87, attributed to the alkenyl proton, was observed. A l l other spectroscopic data were also consistent with the assigned structure. The molecular mass was confirmed by high resolution mass spectral analysis on the (M + -CH 3 ) peak (HRMS calcd for Ci6H 2 5O 1 2 0 Sn: 353.0927; found: 353.0931). 2.5.4.3 CuCN-mediated intramolecular conjugate addition to generate the triquinane 60 The conditions that gave the highest yield of the cyclized product 94 from the model system 87, involved the use of 50 equivalents of CuCN in D M S O in a sealed ampoule with the concentration of substrate 87 at 0.05 M (see Section 2.1.2 and eq 38 below). 50-59% 10-14% 94 95 77 These reaction conditions, when applied to the cyclization of 59 (eq 39, Table 6, entry 1) provided yields of the cyclized product 60 (57%) and protiodestannylated, uncyclized material 183 (14%) similar to those of 94 and 95 obtained with 87. However, the use of such a large excess of C u C N was thought to be impractical in the synthesis of large amounts of the required intermediate 60. In order to optimize the reaction conditions, several reactions were attempted in which both the amount of C u C N and the volume of D M S O were decreased concomitantly. In this manner, the concentration of C u C N was maintained at 2.7 M for all o f the reactions, while the concentration of the stannane 59 was varied (Table 6). 59 60 183 Table 6. CuCN-mediated cyclization of 59 with various amounts of C u C N in D M S O (maintained at 2.7 M ) . Entry Equiv of C u C N (at 2.7 M ) Concentration of 59 (M) Y ie ld of 60 (%) Yie ld of 183 (%) 1 50 0.05 57 14 2 25 0.10 52 15 3 17 0.15 59 11 4 10 0.27 59 14 5 5 0.5 45 14 a 6 2.5 1 33 10 b Approximately 6% of 59 was isolated. "Approximately 20% of 59 was isolated. 78 i Decreasing the amount of C u C N from 50 to 10 equivalents (Table 6, entries 1-4) resulted in essentially unchanged yields of the cyclized product 60 and the protiodestannylated product 183. Further decreases in the amount of C u C N to 5 and 2.5 equivalents resulted in a decrease in the yield of the cyclized product 60 and incomplete consumption of the stananne 59. When 5 equivalents of C u C N were used, 45% of the cyclized material 60 was accompanied by about 6% of the unreacted starting material 59 (entry 5). Considerably worse results were obtained when 2.5 equivalents of C u C N were used (entry 6). The optimal reaction conditions involved the use of 10 equivalents of C u C N (Table 6, entry 4) with the concentration of the starting material 59 at 0.27 M . These reaction conditions were used to prepare sufficient quantities of the cyclized tricyclic ketone 60 for the total synthesis of (±)-l-desoxyhypnophil in. The structures of both compounds 60 and 183 were confirmed by spectroscopic methods. The IR spectrum of the tricyclic compound 60 exhibited a carbonyl stretching band at 1746 cm" 1, characteristic of an isolated cyclopentyl ketone. Further evidence for the formation of 60 was provided by the X H N M R spectrum, which showed three 3-proton singlets at 8 1.05, 1.08 and 1.15 due to the methyl groups. In addition, the expected number of signals in the aliphatic region (8 1.79-2.79), corresponding to the remaining 11 protons, was observed. In the 1 3 C N M R spectrum the carbonyl carbon resonance was visible at 8 219.7, while the two alkene carbon signals appeared at 8 141.0 and 149.0. Additionally, the molecular mass of compound 60 was confirmed by high resolution mass spectroscopic analysis on the molecular ion (FIRMS calcd for C14H20O: 204.1514; found: 204.1519). The structure of the protiodestannylated material 183 was confirmed in a similar manner. The IR carbonyl stretching frequency appeared at 1714 cm" 1, typical of a conjugated cyclopentenone functionality. The X H N M R spectrum of 183 indicated the presence of two alkenic protons, with resonances at 8 5.21 and 8 5.82. The latter signal was a triplet with a coupling constant of 1.5 Hz , and therefore could be assigned to the (3-proton, a result of protiodestannylation. The 1 3 C N M R resonances of the carbonyl and the alkene function conjugated with the carbonyl function appeared at 8 208.7, and at 8 130.7 (CH) and 8 181.2 respectively. Two other alkenic carbon signals were also visible at 8 124.9 (CH) and 140.2. The high resolution mass spectrum of 183 indicated 79 the molecular mass in agreement with that calculated for C14H20O (calcd: 204.1514; found: 204.1517). 2.5.4.4 Reduction of the double bond to form the cis-anti-cis triquinane 174. With the tricyclic ketone 60 in hand, the reduction of the tetrasubstituted double bond to form the cis-anti-cis fused triquinane skeleton of 1-desoxyhypnophilin (61) was the next task (eq 40). Conformational analysis of compound 60 indicates that hydrogenation of the double bond might not be stereoselective for production of the desired cis-anti-cis product. The the A -B ds-fused ring system could result in steric hindrance to the a face of the molecule. On the other hand, the presence of the angular methyl group could provide some steric hindrance to the (3 face of the compound (Figure 3). C H 3 Figure 3. Reduction from the a face of 60 is needed to form the cis-anti-cis triquinane. However, since the linear cis-anti-cis triquinane would be expected to be thermodynamically more stable than the corresponding cis-syn-cis triquinane, the initial plan involved a dissolving metal reduction of the olefin with the ketone functionality 80 protected. It seemed plausible that such a reduction protocol would favour the thermodynamically more stable product. The reduction of unactivated alkenes using a solution of sodium metal in H M P A in the presence of r-butanol has been reported to give nearly thermodynamic product distributions (when more than one product could be formed). Such a distribution arises through equilibration of the organosodium or carbanionic intermediates." This method was successfully appl ied" to the reduction of the tetrasubstituted double bond of a 9(10)-octalin system 184 (eq 41). A mixture of trans and cw-fused decalin 185 was obtained in a 30:1 ratio. 184 1 8 5 trans 91 % cis 3% It was hoped that the application of this method to the reduction of the olefinic bond of 60 would provide the thermodynamically more stable cis-anti-cis triquinane. The transformation was first attempted on a model system that had been prepared during the course of methodological studies. The ketone 94 and its derivatives were used in these preliminary investigations. 94 Several attempts to reduce the olefinic function of the model compound 186, with sodium-HMPA-£-butanol resulted in the recovery of some of the starting material 186 and the formation of two reduction products 187 ( G L C - M S ) in a ratio of ~2:1 (eq 42). These products could not be separated by flash column chromatography on silica gel. 81 This lack of stereoselectivity was disappointing and the difficulties associated with separation of the products caused this approach to be abandoned and other alternatives to be explored. A previous report 1 0 0 had indicated that the presence of a hydroxymethyl group (-CH 2 OH) (e.g. 188, eq 43) afforded some degree of stereochemical control in heterogenous catalytic hydrogenations performed in non-polar solvents. For example, hydrogenation of compound 188 over a catalytic amount of palladium on carbon generated a mixture of products 189a and 189b. When the reaction was performed in ethanol the ratio of 189a to 189b was 94:6. However, when the hydrogenation was carried out in hexanes, a 39:61 ratio of 189a to 189b was obtained. 189a 189b in EtOH 94 6 in hexanes 39 61 Presumably, this effect arises from "anchoring" of the hydroxyl group of the molecule to the surface of the catalyst. It is believed that this property, termed haptophilicity, affects the stereochemical outcome of the hydrogenation process. When the reaction is carried out in ethanol, the solvent elhninates this "anchoring" effect. 82 On the basis of conformational analysis of a molecular model (Dreiding) of compound 94, it was expected that reduction of the carbonyl group would take place stereo selectively from the less hindered (3 face of the molecule. It was hoped that the a alcohol, thus generated, could then be used to induce stereoselectivity in the catalytic hydrogenation of the olefin from the desired a face (Figure 4). 94 Figure 4. Expected reduction of 94 to the alcohol and hydroxy directing effect in olefin hydrogenation. Treatment of the model system 94 with L1AIH4 provided a 6:1 mixture (by G L C analysis) of alcohols 190a and 190b, which were inseparable by chromatography on silica gel (eq 44). 94 190a 190b -6:1 (GLC) It was hoped that by employing a bulky hydride reducing reagent the stereoselectivity of the reaction could be improved. Thus, the ketone function of 94 was reduced using lithium tri-fe^butoxyaluminohydride to provide a single alcohol in excellent yield (>95%) corresponding to the major compound obtained in reduction with LiAlFL; (eq 45). The relative configuration of the alcohol was expected to be as shown in structural formula 190a (eq 45) based on conformational analysis of a Dreiding molecular model of the starting material 94. However, the configuration of the hydroxyl group could not be unambiguously assigned on the basis of NOE experiments. The stereochemistry of 94 83 was later assigned based on the X-ray crystallographic studies employing substrate 196 (vide infra), an intermediate in the synthesis of 1-desoxyhypnophilin (61). O O H Li(f-BuO)3AIH (45) 94 190a single isomer Hydrogenation of 190a over palladium on carbon in hexanes provided a mixture of two products 191 that were found to be inseparable by column chromatography (eq 46). The ratio of the products was determined by G L C analysis to be 4:6. Since the two products could not be successfully separated, the identity of the major and minor products was not determined. Thus, for the purpose of the total synthesis of (±)-l-desoxyhyphophilin, the hydroxy-directed heterogenous hydrogenation conditions attempted here were il l suited for the generation of the cis-anti-cis triquinane. The directing effect in hydrogenations, especially with a hydroxyl moiety, have also been explored in hydrogenation with homogenous catalysts.1 0 1 The most effective catalysts used in these hydrogenations include Wilkinson's rhodium catalyst 192, 1 0 2 the cationic rhodium complex 193 (Brown catalyst)1 0 3 and iridium complex 194 (Crabtree catalyst)1 0 4. It has been found that the polar hydroxyl group coordinates to the metal centre of the catalyst, thereby directing the addition of hydrogen to the proximal face of the olefinic function. 1 0 1 ' 1 0 5 84 Rh(PPh) 3 CI 192 P h 2 | P — R h — ^ P P h , 193 PFe P F f i I ( C y ) 3 P J \ " 8 194 Hydrogenation of the alcohol 190a using the Crabtree catalyst (194) resulted in the formation of a single product 191a in very good isolated yield (-75%) (eq 47). This was a very encouraging result, as the product was expected to have the required stereochemistry (proved in later X-ray crystallographic studies (vide infra)). OH OH H2- 1 a t m [ lr(COD)(PCy 3)(py)] +PF 6-CH2CI2 ~ 75% 190a (47) 1 diastereomer 191a Having accomplished the highly stereoselective reduction of the model alkene 190a to (presumably) yield the product with a cis-anti-cis configuration, this approach was applied to the synthesis of the natural product 1-desoxyhypnophin. Thus, a solution of ketone 60 in T H F at 0 °C was treated with lithium tri-te^butoxyaluminohydride to provide, after work-up and purification of the crude material by column chromatography and bulb-to-bulb distillation under reduced pressure (98-100 °C at 0.4 torr), the alcohol 195 in 87% yield (Scheme 27). The IR spectrum of this compound showed a hydroxyl stretching absorption at 3290 cm"1. A broad 1-proton multiplet at 8 4.18 in the *H N M R spectrum was attributed to the carbinol proton. The relative configuration at the carbinol centre was not deterrnined at this stage, but was revealed after the following step of the synthesis. Hydrogenation of 195 under 1 atm of dry hydrogen gas in the presence of the Crabtree catalyst 194,104 followed by removal of the catalyst and purification of the crude material, provided the alcohol 196 in 95% yield. 85 Scheme 27 The alcohol 196 proved to be a crystalline solid and recrystallization of a small amount of the material from hexanes afforded a sample suitable for X-ray crystallographic analysis.* This analysis established unequivocally the relative configuration of the hydroxyl group and confirmed the expected formation of the cis-anti-cis triquinane skeleton of both 196 and the earlier model system 191a. The assignment of the ' H N M R signals of 196 was accomplished by the analysis of the C O S Y spectrum, summarized in the experimental section. * X-ray crystallographic analysis was performed by S. J. Rettig (deceased October 27, 1998) of the U B C X-ray Crystal Structure Laboratory. 86 Figure 5. X-ray crystal structure of 196 (50% probability thermal ellipsoids are shown for the non-hydrogen atoms). The alcohol 196 was treated with pyridinium chlorochromate (PCC) to afford, after work-up, purification of the crude material by column chromatography on silica gel, and bulb-to-bulb distillation under reduced pressure (99-102 °C at 0.4 torr), the ketone 174 in 92% yield (Scheme 27). The presence of the ketone function was confirmed by the presence of a carbonyl stretching absorption band at 1746 cm"1 in the IR spectrum of 174, as well as a carbonyl carbon signal in the 1 3 C N M R spectrum at 8 220.6. 87 2.5.4.5 Completion of the syntheses of(±)-l-desoxyhypnophilin and (±)-6,7-epoxy-4(15)-hirsuten-5-ol The next task in the synthesis of 1-desoxyhypnophilin was the introduction of a carbon-carbon double bond to form the enone 197. Many methods for accomplishing this type of transformation have been reported in the literature.1 0 6'1 0 7 The Saegusa protocol89 for the formation of the enone function was adopted owing to its successful application in the preparation of a structurally related compound in the synthesis of hypnophilin (65) by Little. 8 7 The first step in this method is the generation of a silyl enol ether. In the case of ketone 174, it was expected that the generation of the silyl enol ether would be chemoselective and would favour the formation of 197a over 197b (Scheme 28) due to the presence of the angular methyl group. Treatment of this mixture with palladium diacetate89 was expected to generate the enone 197 directly from 197a. The starting material 174 would be recovered from 197b after work-up and separation from the enone 197 by chromatography on silica gel. 197 Scheme 28 88 Treatment of a cold (-78 °C) solution of the ketone 174 in T H F with hthium tetramethylpiperide 8 7 in the presence of chlorotrimethylsilane, followed by the addition of triethylarnine (Scheme 29) provided a mixture of the si lyl enol ethers 197a and 197b. Since trimethylsilyl ethers are known to be acid and water labile, the work-up step had to be carried out quickly to rnmimize hydrolysis. The crude material was placed under reduced pressure (vacuum pump) to remove traces of solvent and remaining amines. The *H N M R spectrum of the crude material showed two olefinic signals at 8 4.48 (broad unresolved d, / = 2.0 Hz) and 4.45 (s). Based on their appearance, the former signal can be assigned to the olefinic proton of 197a, while the latter can be attributed to 197b. The ratio of 197a to 197b in the mixture was determined to be 3:2 by the integration of the two olefinic signals. 197 Scheme 29 The poor chemoselectivity of the formation of the si lyl enol ethers was disappointing. L i t t l e 8 7 reported that sequential treatment of substrate 165 with hthium tetramethylpiperidide and trimethylsilyl chloride afforded the enol ethers 166a and 166b in a 6:1 ratio (Scheme 30). On the other hand, when L D A was used as the base 166a and 166b were obtained in a ratio of 3:2. In our work with the ketone 174, the use of L D A 89 provided a 1:1 ratio of the two silyl ethers 197a and 197b. A s was noted above, use of L T M P as the base gave 197a and 197b in a 3:2 ratio. Clearly, for reasons that are not evident, the chemoselectivities reported by Little for the conversion 165 —» 166a + 166b were consistently higher than those observed in our studies with substrate 174. 166b A: LDA, THF , -78 °C; TMSCI 166a:166b 3:2 B: LTMP, THF, TMSCI, -78 °C; NE t 3 166a:166b 6:1 Scheme 30 The si lyl enol ethers 197a and 197b were dissolved in a 2:1 mixture of acetonitrile and methylene chloride (Scheme 29 above). The use of CH2CI2 as a co-solvent was necessary, because the mixture of 197a and 197b was only sparingly soluble in acetonitrile. Palladium acetate was added to this solution and the reaction mixture was stirred at room temperature for 12 h. After work-up and separation of the acquired materials by flash column chromatography on silica gel, the enone 197 was obtained in 52% isolated yield, along with 35% of the recovered ketone 174. Thus, the yield based on recovered starting material was 87%. Evidence for the successful formation of the enone 197 was obtained by analysis of the 1 H and l 3 C N M R spectra. In the 1 3 C N M R spectrum the carbonyl carbon signal appeared at 8 210.8, while the two olefinic carbons gave rise to signals at 8 122.0 (-ve 90 A P T , C H ) and 8 195.8. The signal due to the olefinic proton was visible at 8 5.65 in the *H N M R spectrum Other *H N M R signals have been assigned based on the C O S Y spectrum of 197 and are reported in the experimental section. It was decided to install the a methylidene function prior to the introduction of the epoxide oxygen (Scheme 31). There are several examples reported in the literature where, in systems related in structure to 198, the epoxidation of the more strained, internal alkene function proceeds at a faster rate than epoxidation of the exocyclic o l e f i n . 8 7 ' 9 0 197 198 61 Scheme 31 Several methods for the introduction of the a methylidene function have been reported in the literature and some of these have been applied to the synthesis of biologically active compounds containing a methylidene ketone or lactone u n i t s . 1 0 8 ' 1 0 9 One of the approaches involves the generation of an enolate anion and its subsequent reaction with Eschenmoser's salt (dimethyl(methylene)ammonium iod ide ) 1 1 0 (Scheme 32). Typically, the resulting Mannich intermediate 200 is converted to an ammonium salt 201. Base promoted elimination of the ammonium salt generates the methylidene compound 202 (Scheme 3 2 ) . 1 0 9 ' 1 1 1 91 . 0 1) LDA O Mel H 2 2) CH 2=N +(CH 3) 2r n C Y 199 N(CH3)2 200 O % ^ Y ^N+(CH3)3r 201 Y = alkyl, alkoxy HCO, Scheme 32 R CH2 202 A solution (-78 °C) of the enone 197 was treated with L D A , followed by the addition of the Eschenmoser salt as a suspension in THF (Scheme 33). The crude amine 198a was obtained upon aqueous work-up of the reaction mixture. The successful formation of the amine was supported by the *H N M R spectrum of the crude product, which displayed a signal at 5 5.60 ppm (broad signal) consistent with the presence of a methylene group attached to a tertiary nitrogen atom A small amount of the elimination product 198 was also present in the crude material. The crude 198a was dissolved in methanol and treated with methyl iodide. Further treatment of the resultant crude material with aqueous sodium bicarbonate in CH 2Ci2 afforded, after work-up and purification of the crude product by chromatography on silica gel, the dienone 198 in 30% yield. It was thought that the low yield and poor mass balance in this reaction was a result from incomplete ehmination of the quaternary ammonium salt 198b and its possible loss during aqueous work-up or chromatography. Several attempts to improve the yield of this reaction were made, but unfortunately they proved to be unsuccessful. Therefore, another method to generate 198 more efficiently was investigated. 92 198 198b 30 % Scheme 33 The dienone 198 was prepared in good yield from 197 by a three-step procedure (Scheme 34) . 8 7 A cold (-78 °C) solution of the enone 197 in T H F was treated with L D A . Formaldehyde gas that had been passed through a short column of drying reagent, was bubbled through the resulting solution. After work-up and chromatography of the crude material on silica gel, a mixture of diastereomeric alcohols (198c) (ratio -1:5) was obtained in 73% yield. The mixture of the alcohols 198c was treated with p-toluenesulfonyl chloride and pyridine in CH 2 Ci2 and the mixture was stirred for 4 days. 8 7 The resultant to sylate mixture was treated with D B U to promote the elimination of the elements of /?-toluenesulfonic acid. The dienone 198 was obtained in 76% yield upon work-up and column chromatography of the crude product on silica gel. Spectral data provided information to support the formation of the dienone 198. The *H N M R spectrum displayed three olefinic proton signals at 8 5.11, 5.85 and 5.86 consistent with the structure of 198. In addition, the high resolution mass spectral analysis on the 93 molecular ion was in agreement with that expected for C15H20O (calc. 216.1514; found 216.1518). 198c Scheme 34 The final step in the total synthesis of (±)- l -desoxyhypnophil in was the monoepoxidation of the more strained, internal olefinic function (Scheme 3 5 ) . 8 7 - 1 1 2 It was necessary to closely monitored the reaction by T L C in order to prevent the formation of the bis-epoxide product. Thus, treatment of solution of the dienone 198 in cold (0 °C) T H F and water with hydrogen peroxide provided, after work-up and chromatography of the crude material on iatrobeads, (±)-l-desoxyhypnophil in (61) in 56% isolated yield. A small amount of unreacted dienone 198 was also isolated. The synthetic (±)- l-desoxyhypnophil in exhibited spectral data in full accordance with those reported for the isolated natural product, (-)-l-desoxyhypnophilin. 4 4 Comparison of the *H N M R and 1 3 C N M R spectra for the synthetic material with that of the isolated natural product is presented in Tables 7 and 8. Additionally, the *H N M R spectrum of (±)-61 is presented in Figure 6. Scheme 35 94 (±)- l -Desoxyhypnophil in was converted to the alcohol 62 by reduction of the ketone function with sodium borohydride in ethanol at 0 ° C . 9 4 After aqueous work-up and chromatography of the crude material on iatrobeads, the alcohol 62 was obtained in 68% yield. Signals presumed to arise from the presence of trace amounts of the other epimer of the alcohol were visible in the *H N M R spectrum of the crude mixture. This compound was not isolated by chromatography due to the small scale of the reaction. The spectral data derived from 62 agreed well with those reported for the isolated natural product and are presented in the Tables 9 and 10 below. The 'H N M R spectrum of (±)-62 is shown in Figure 7. 95 Table 7. Comparison of *H N M R data for synthetic (±)- l-desoxyhypnophil l in 61 with those reported for natural (-)-l-desoxyhypnophilin 4 4 (400 M H z , CDC1 3 ) . O Q *H assignment 8,a multiplicity, Hirsutane Lit . *H assignments H-x / ( H z ) numbering of H 8, multiplicity, 7 (Hz) H - l 2.37 ddd H-2 2.40 dt 7=9.0 , 9.0, 11.5 7 = 12,9 H-5 3.41 s H-6 3.44 s H-7 1.97 d H-8 2.00 d 7 = 9 . 0 7 = 9 H-8 2.65-2.75 m H-9 2.73 ddtd 7 = 8 , 12, 9, 12 H-9 1.77 ddd H-10 1.80 ddd 7 = 1.5, 8.0, 12.0 7 = 1, 8, 12 H-9' 1.14m H-10' 1.17 dd 7 = 12, 12 H - l l part of 1.43-1.58 m H - l 1.54 dd 7 = 9 , 13 H - l l ' part of 1.43-1.58 m H - l ' 1.48 ddd 7 = 1,9, 13 H-12 0.90 s H-12 0.92 s H-13 1.10 s H-13 1.12 s H-14 1.14s H-14 1.16s H-15 5.24 s H-15' 5.27 s H-15' 6.03 s H-15 6.05 s "The difference between observed and reported 8 of -0.03 ppm is likely due to the CDC13 reference.(8 7.24 in this work) 96 Table 8. Comparison of C N M R data for synthetic (±)- l-desoxyhypnophil l in 61 (100.6 M H z , CDC1 3 ) with those reported for natural (-)-1-desoxyhypnophilin 4 4 (75.5 M H z , CDCI3). 1 3 C assignments C-x 8 (ppm) observed Hirsutane numbering C-x Li t . 1 3 C signals and DEPT-135 data3 C - l 49.9 C-2 49.8 + C-2 46.5 C-3 46.5 0 C-3 153.4 C-4 153.4 0 C-4 198.1 C-5 198.1 0 C-5 61.1 C-6 61.1 + C-6 76.6 C-7 76.6 0 C-7 30.1 C-8 30.1 -C-8 39.2 C-9 39.2 + C-9 49.5 C-10 49.5 -C-10 42.5 C - l l 42.5 0 C - l l 40.1 C - l 40.1 -C-12 17.5 C-12 17.5 + C-13 28.9 C-13 28.9 + C-14 27.3 C-14 27.3 + C-15 119.9 C-15 119.9 -Amplitude of signals in DEPT-135 spectrum (CH3 or CH = +, C H 2 = -, C = 0) Table 9. Comparison of *H N M R data for synthetic (IS*, 2S*, 4S*, 5S*, 6R*, 8S*)-5,6-epoxy-3-methylidene-2J0J0-trimethyltricyclo[6.3.0.0 2 ' 6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol (62)] with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-o l 4 4 (400 M H z , CDCI3). O H O H isolated (+)-62 showing hirsutane numbering *H assignment 8, multiplicity, 7 (Hz) Hirsutane numbering of H Li t . *H assignments 8, multiplicity, 7 (Hz) H - l 2.27 dt 7 = 11.0, 9.0 H-2 2.27 dt 7 = 11,9 H-4 4.59 dddd 7=2.0, 2.0, 2.0, 11.0 H-5 4.59 dddd 7 = 2 , 2, 2, 10.8 H-5 3.45 d 7 = 2 . 0 H-6 3.45 d 7 = 5 a H-7 1.84 d 7 = 8.5 H-8 1.84 d 7 = 8.5 H-8 2.55-2.70 m H-9 2.65 ddtd 7=7 .5 , 11, 8.5, 11 H-9 1.06-1.14 m H-10' 1.10 dd 7 = 11, 12 H-9' 1.72 dd 7=7.5 , 12.0 H-10 1.72 dd 7=7 .5 , 12.0 H - l l 1.41 d 7=9 .0 H - l 1.42 d 7 = 9 H-12 0.89 s H-12 0.89 s H-13 1.07 s H-13 1.07 s H-14 1.01 s H-14 1.01 s H-15 4.96 d 7=2 .0 H-15' 4.96 d 7 = 2 H-15' 5.23 d 7 = 2 . 0 H-15 5.23 d 7 = 2 O H 1.63 d 7 = 11.0 O H not reported This coupling constant is a mistake since the corresponding coupling to H-4 is reported to have a coupling constant of 2 Hz. 99 Table 10. Comparison of liC N M R data for synthetic (IS*, 2S*, 4S*, 5S*, 6R* 8S*)-5.6- epoxy-3-methylidene-2,10J0-trrmethyltricyclo[6.3.0.0 2 , 6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol (62)] (100.6 M H z , CDC1 3 ) with those reported for natural (+)-6.7- epoxy-4(15)-hirsuten-5-ol 4 4 (75.5 M H z , CDC1 3 ) O H OH numbering C assignments 8 (ppm) Hirsutane 1 3 C signals and C-x observed numbering DEPT-135 data3 C-x C - l 48.7 C-2 48.7 + C-2 48.7 C-3 48.7 0 C-3 159.3 C-4 159.3 0 C-4 74.2 C-5 74.2 + C-5 63.6 C-6 63.6 + C-6 75.4 C-7 75.4 0 C-7 30.3 C-8 30.3 -C-8 39.1 C-9 39.1 + C-9 49.6 C-10 49.6 -C-10 42.4 C - l l 42.4 0 C - l l 39.8 C - l 39.8 -C-12 17.1 C-12 17.1 + C-13 28.9 C-13 28.9 + C-14 27.4 C-14 27.4 + C-15 111.3 C-15 111.3 -a Amplitude of signals in DEPT-135 spectrum (CH3 or CH = +, CH 2 = -, C = 0) 100 III. CONCLUSIONS 3.1 CuCN-mediated intramolecular conjugate additions of alkenyltrimethylstannanes to enones The Cu(I)-mediated intramolecular conjugate addition reaction of alkenyltrimethylstannane functions to enones was applied to the synthesis of functionalized tricyclic ketones 88-91 and 94 (eq 48). O C u C N , D M S O S n M e 3 78 m = 2, R 1 , R 2 = H 80 m = 2, R 1 = Me, R 2 = H 81 m = 2, R 1 , R 2 = Me 86 m= 1, R 1 , R 2 = H 87 m = 1, R 1 = H, R 2 = Me 88 94% 89 9 1 % 90 87% 91 80% 94 59% (48) Compounds 78, 80, and 81, which contain a 6-membered enone (m = 2), underwent rapid and efficient conversion to the corresponding m-tricyclo[6.4.0.0 2 , 6]dodec-2(6)-en-ll-ones 88-90. These conversions employed 2.5 equivalents of copper(I) cyanide in D M S O at 60 °C with the substrate concentration of 0.05 M . The intramolecular 1,4-addition onto the /jve-membered ring enone (m = 1) of compound 86 proved to be more difficult and required the use of 5.0 equivalents of C u C N in D M S O at 60 °C. Additional difficulties arose during attempts to effect the intramolecular cyclization of 87, which in addition to the 5-membered ring (m = 1) also contained a methyl group in the (3 position of the enone. The major product of the reaction under typical conditions was the uncyclized, protiodestannylated material 95 (see eq 49). The conditions for this reaction were modified such that 87 was reliably converted to the tricyclic ketone 94 in yields ranging from 50-59% (eq 49). In this case, the protocol required a large excess (-50 equivalents) of C u C N in D M S O at 90 °C in a sealed reaction vessel. 102 The method developed in this study allowed the preparation of tricyclic ketones 88-90, 94 in good to excellent yields. A n extension to this work may be envisaged (eq 50) in which the cyclization precursors of general structure 203 contain larger rings (m, n > 2) resulting in the generation of a large variety of tricycles 204 (eq 50). To date, only the closure of a five membered ring (x = 1) was investigated. In theory, however, it may be possible to effect the closure of a six-membered ring (x = 2, eq 50), thereby, opening doors for the preparation of additional carbon-based structures via the CuCN-mediated intramolecular conjugate addition of alkenyltrimethylstannane functions to a,(3-unsaturated ketones. 203 204 One of the applications of this method is the rapid assembly of the linear triquinane carbon skeletons. In the later part of this thesis, the use of the CuCN-mediated intramolecular conjugate addition reaction was demonstrated in the key step of a total synthesis of the triquinane natural products, (±)- l -desoxyhypnopmlin (61) and the corresponding alcohol (±)-62. 103 3.2 CuCN-mediated intramolecular conjugate additions of aryltrimethylstannanes to enones AA^/trimethylstannane functions were also demonstrated to undergo analogous CuCN-mediated intramolecular conjugate additions to a, B-unsaturated ketones. This study work showed that substrates 112, 114 and 116undergo cyclizations to generate ketones containing an aromatic ring (117-119) in good to excellent yields (66-87%) (eq 51). 112 m = 2, R 1 , R 2 = H 117 87% 114 m = 2, R 1 , R 2 =Me 118 66% 116 m = 1 , R 1 , R 2 = H 119 7 5 % These examples indicate that the Cu(I)-mediated intramolecular conjugate addition reaction is a viable method of preparation for tricyclic ketones such as 117-119. A n obvious extension of this work is the use of the method in the synthesis of compounds containing various substituents on the aromatic ring. 104 3.3 Preparation of novel carbocyclic structures derived from the products of CuCN-mediated conjugate addition reaction of alkenyltrimethylstannanes to enones The tetrasubstituted double bond contained in the triketones 88-91 and 54 prepared via Cu(I)-mediated intramolecular conjugate additions proved useful as a handle for further synthetic manipulations. In particular, its use in the preparation of medium sized ring systems (8- or 9-membered) fused to 5- or 6-membered rings was explored. O 88-91, 54 Ruthenium tetroxide catalyzed oxidative cleavage of the alkenic function of 132-134, 88-91 and 54 cleanly and efficiently, provided functionalized, cis-fused bicyclo[6.3.0]undecane (145), bicyclo[6.4.0]dodecane (136-144) and bicyclo[7.4.0]tridecane systems (146) in excellent yields (79-94%) (eq 52). 105 ( \)m •R R u 0 2 - x H 2 0 (2.2-2.4 mol %) 4.2 equiv N a l 0 4 M e C N - C C I 4 - H 2 0 (1:1:1.5v/v) 15-30 min, rt 88 X = O, m = 2, n = 1, R 1 , R 2 = H 89 X = O, m = 2, n = 1, R 1 = Me, R 2 = H 90 X = O, m = 2, n = 1, R 1 = Me, R 2 = Me 91 X = 0 , m = 1,n = 1 , R 1 , R 2 = H 54 X = O, m = 2, n = 2, R 1 = H, R 2 = Me 132 X = K, m = 2, n = 1, R 1 = Me, R 2 = H 133 X = K, m = 2, n = 1, R 1 = Me, R 2 = Me 134 X = K, m = 2, n = 2, R 1 = H, R 2 = Me (52) 142 143 144 145 146 136 137 141 The bicyclic carbon skeleton of triketones 142-146 and the presence of multiple ketone functionalities prompted investigations into the acid-catalyzed intramolecular aldol condesations of these substances. It was found that compounds 144 and 143 upon treatment with p - T s O H in refluxing T H F provided products 147 and 148, respectively, in excellent yields. In an analogous manner, product 149 was obtained from 142, albeit in a lower yield (eq 53). 1 4 4 R 1 , R 2 = Me 147 97% 1 4 3 R 1 = Me, R 2 = H 148 94% 1 4 2 R 1 , R 2 = H 149 46% The interesting feature of this reaction from the synthetic point of view is the generation of products 147-149 which possess highly functionalized tricyclo[5.5.0.0 2' 9]dodecane skeleton. This complex carbon framework was easily generated from the corresponding bicyclic triketones. 106 This process, however, was not general in the application to the synthesis of tricycles related to 147-149 from substrates containing 6-9 (146) or 5-8 (145) ring systems. Treatment of 145 with /?-TsOH in refluxing T H F did not generate a new product and only the starting material was isolated. O On the other hand, intramolecular aldol condensation within the nine-membered ring of substrate 146, followed by elimination of water, provided product 151 in a very good yield. 146 107 3.4 Application of CuCN-mediated intramolecular conjugate addition of alkenyltrimethylstannes to enones in the total synthesis of (±)-l-desoxyhypnophilin (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) The total synthesis of a natural product is often an ultimate test for a developed synthetic method (see Section 1.1). The usefulness of the Cu(I)-mediated intramolecular conjugate addition of alkenyltrimethylstannane functions to a , B-unsaturated ketones was demonstrated in the key step of the first total synthesis of (±)- l -deoxyhypnophil in 61 and the related alcohol 62,44 both of which are linear triquinane natural products. The preparation of the bromide 176 was accomplished in 41% overall yield via six highly efficient steps, starting from commercially available dimedone 179. A summary of synthesis is outlined in Scheme 36. Reagents: a) p -TsN 3 , E t 3 N , 0 ° rt, E t 2 0 , 63%; b) hv, MeOH, THF, 89%; c) KH , THF, 0 °C; PhNTf 2 , 0 °C -» rt, 85%; d) Me 3 Sn(CN)CuLi ,THF, -48 °C -> rt, 92%; e) DIBAL-H.THF, -78 °C -» 0 °C, 100%; f) P P h 3 - Br 2 , imidazole, C H 2 C I 2 , 0 °C, 93% Scheme 36 The bromide 176 was used in the alkylation of the vinyligous ester 82 to provide 175 (Scheme 37). This intermediate was transformed into the enone 59 by sequential treatment with M e M g B r and p -TsOH. The enone 59 was used in the key transformation involving the construction of the middle (B) ring of the triquinane skeleton via the 108 CuCN-mediated intramolecular conjugate addition of the alkenyltrimethylstannane function (ring C) to the enone (ring A ) . The reaction conditions developed in the methodology studies were further optimized to provide the tricyclic ketone 60 in 59% yield. The conditions employed involved the use of 10 equivalents of C u C N in D M S O at 90 °C in a sealed ampoule with the concentration of the substrate 59 of 0.27 M . Reduction of the tetrasubstituted alkenic function to generate a cis-anti-cis triquinane skeleton was accomplished via a three-step procedure: Reduction of the carbonyl function of 60 with a bulky hydride reagent provided 195 in excellent yield. Application of a hydroxyl-directed hydrogenation, with the use of the Crabtree catalyst, 1 0 4 provided alcohol 196. The ketone 174 was obtained by oxidation of 196 with P C C , while the enone 197 was formed from 174 by Seagusa method. 8 9 Introduction of the a methylidene unit provided the dienone 198. Subsequent epoxidation of the more strained, internal alkene function provided (±)- l-desoxyhypnophil in (61). Finally, reduction of the ketone function generated the alcohol 62. The syntheses of (±)- l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-birstunen-5-ol (62) were relatively concise and efficient in comparison with other approaches used in the preparation of a structurally related substance (±)-hypnophilin (65) (see Section 2.5.1). The overall yield of (±)- l -desoxyhypnophil in (61) over 17 steps was - 2 % . (±)-6,7-Epoxy-4(15)-hirsuten-5-ol (62) was prepared in -1 .4% overall yield in 18 steps. A summary of the synthesis is outlined in Scheme 37. This synthesis demonstrated that the use of Cu(I)-mediated cyclization in the construction of the triquinane framework is an efficient route for the preparation of natural products (±) - l -desoxyhypnophilin (61) and (±)-6,7-epoxy-4(15)-hirstunen-5-ol (62). 109 Reagents: g) LDA, THF, -78 °C -> 0 °C; HMPA, 176, -78 °C -> 0 °C, 71%; h) MeMgBr, THF, 0 °C -» r t , p- TsOH (cat ) ,Et 2 0-H 2 0, 79%; i) C u C N , DMSO, 90 °C, sealed ampoule, 59%; j) Li(f-BuO) 3AIH, THF, 0 °C, 87%; k) H 2 , 1 atm, [ lr(COD)(PCy 3)(py)] +PF 6", C H 2 C I 2 ) 95%; I) P C C , Celite, C H 2 C I 2 , rt, 92%, m) L iTMP, TMSCI.THF, 0 °C; E t 3 N , -78 °C -> rt, n) Pd(OAc) 2 , M e C N - C H 2 C I 2 (2:1), rt, 52% from 174, o) LDA, THF, -78 °C; H C H O , -30 °C, 73%, p) TsCI, pyr, C H 2 C I 2 ; DBU, 76%, r) H 2 0 2 , N a H C 0 3 , T H F , H 2 0 , 0 °C, 56%; s) N a B H 4 , EtOH, 0 °C, 68%. Scheme 37 110 3.5 General The work described in this thesis combines two areas of academic research typically carried out by a synthetic organic chemist: methodological studies and the total synthesis of a natural product (see Section 1.1). Extensions to a new Cu(I)-mediated intramolecular conjugate addition method and its application to the synthesis of novel carbocyclic compounds were the major goals of this study. The methodology proved useful in the preparation of structurally diverse carbocyclic substances, some of which could potentially find use as lead compounds in pharmaceutical research or as intermediates in the synthesis of other natural and non-natural products. The applicability of the Cu(I)-based method was demonstrated in work leading to to the assembly of a triquinane skeleton of the intermediate 60 in the total synthesis of (±)- l-desoxyhypnophil in (61) and (±)-6,7-epoxy-4(15)-hirstunen-5-ol (62) (see previous page). It was found that the conditions previously employed in cyclizations of systems related in structure to that of 60 had to be adjusted in order to effect the transformation (59 —» 60) effectively. Thus, this total synthesis provided an impetus for further development and increased of the scope of the CuCN-mediated intramolecular conjugate addition reaction of alkenyltrimethylstannanes to a,(3-unsaturated ketone functions. I l l IV. EXPERIMENTAL SECTION 4.1 General 4.1.1 Data Acquisition and Presentation Proton nuclear magnetic resonance ( X H N M R ) spectra were recorded on a Bruker model WH-400 (400 M H z ) or A M X - 5 0 0 (500 M H z ) spectrometers using deuteriochloroform (CDCI3) as the solvent. Signal positions (5) are given in parts per milhon (ppm) from tetramethylsilane and were measured relative to that of chloroform (8 7.24). The multiplicity, number of protons, coupling constants and assignments (where possible) are indicated in parentheses following the chemical shift. The abbreviations used in describing multiplicity are: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet, br-broad. When a hydrogen was observed to be coupled with the same coupling constants to two, three, four or five other hydrogens which are chemically and magnetically nonequivalent, the designation dd, ddd, dddd and ddddd is used, instead of t, q, quintet or sextet. Coupling constants ( / values) are given in Hertz (Hz) and are reported to the nearest 0.5 Hz . The tin-proton coupling constants (Jsn-n) are reported as an average of the 1 1 7 S n and 1 1 9 S n values. In some cases, the proton assignments were supported by two-dimensional ( 'H- 'H) homonuclear correlation spectroscopy ( C O S Y ) , which was carried out using the WH-400 spectrometer. In the *H N M R spectra, H-x and H-x' have been used to designate hydrogens on the same carbon, with H-x ' being the hydrogen at lower field. Carbon nuclear magnetic resonance ( 1 3 C N M R ) spectra were obtained on a Bruker models A C - 2 0 0 E (50.3 M H z ) , A M - 4 0 0 (100.6 M H z ) and A M X - 5 0 0 (125.8 M H z ) spectrometers or a Varian model X L - 3 0 0 (75.5 M H z ) spectrometer using deuteriochloroform (CDC1 3) as the solvent. Signal positions are given in parts per milhon (ppm) from tetramethylsilane and were measured relative to the signal of 112 deuteriochloroform (8 77.0). Attached proton tests (APTs), used to differentiate methyl and methine (negative phase signals) from methylene and quaternary carbons (positive phase signals), were recorded on the Varian X L - 3 0 0 spectrometer. Where A P T data is given, signals with negative phases are indicated in brackets (-ve) following the 1 3 C N M R chemical shift. In some cases, the proton and carbon assignments were supported by two-dimensional ( 1 H , 1 3C)-heteronuclear multiple quantum coherence experiments ( H M Q C ) and heteronuclear multiple bond correlation ( H M B C ) experiments, which were carried out on the Bruker A M X - 5 0 0 spectrometer. 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. L o w and high resolution mass spectra were recorded on a Kratos Concept II H Q or on a Kratos M S 80 mass spectrometer by the U B C M S laboratory. The molecular ion ( M + ) masses are given unless otherwise noted. For some compounds containing the trimethylstannyl (Me 3 Sn) group, the high resolution mass spectrometry molecular mass determinations were based on the ( M + - M e ) peak. Unless otherwise noted, all high resolution mass spectra were measured using electron impact ionization (EI). A l l compounds subjected to high resolution mass measurements were homogeneous by G L C and/or T L C analyses. Elemental analyses were performed on a Carlo Erba C H N model 1106 or on a Fisons E A model 1108 elemental analyzer by the Micro analytical Laboratory at U B C . X-ray crystallographic analyses were performed on a R i g a k u / A D S C C C D area detector with graphite monochromated Mo-Koc radiation by the U B C X-ray Crystallography Laboratory. 113 Melting points (mp.) were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures, which refer to air bath temperatures of the bulb-to bulb (Kugelrorh) distillations, are uncorrected. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been flame- or oven-dried (-140 °C). Glass syringes, stainless steel needles, and Teflon® cannulae for handling anhydrous solvents and reagents were oven dried, 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, -30 °C, -48 °C, aqueous calcium chloride-dry ice (17 g, 35 g, 47 g of CaCl 2 /100 m l of H 2 0 respectively); -78 °C, acetone-dry ice. 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) and/or iodine (iodine which has been preabsorbed onto unbound silica gel), followed by heating of the T L C 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 E tOH) , (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 230-400 mesh silica gel (E. Merck, Silica Ge l 60). Gas liquid chromatography ( G L C ) 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 m m column, while the latter chromatograph utilized a 25 m X 0.20 m m column. Both were coated wi thHP-5 (crosslinked 5% phenylmethyl silicone). 114 Concentration, evaporation or removal of the solvent under reduced pressure refers to solvent removal using a Buchi rotary evaporator at -15 torr (water aspirator). j 4.1.2 Solvents and reagents A l l solvents and reagents were purified, dried and/or distilled using standard procedures. 1 1 3 Diethyl ether (Et 2 0) and tetrahydrofuran (THF) were distilled from sodium/benzophenone, while benzene (CeH 6 ), dichloromethane (CH2CI2), acetonitrile and pyridine 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. Dhsopropylamine, triethylamine and hexamethylphosphoroamide ( H M P A ) were distilled from calcium hydride. Dimethyl sulfoxide ( D M S O ) was dried sequentially over activated 3 A molecular sieves. 3 7 These 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 were passed through a short column of basic alumina activity I, which had been dried in an oven (-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. Copper(I) cyanide, palladium acetate, /Moluenesulfonyl chloride were purchased from Aldr ich Chemical Co. Inc, and were used without further purification. Hexamethylditin was obtained from Organometallics Inc., was stored under an atmosphere of argon in a glove box, and was used without prior purification. Solutions of dhsobutylaluminum hydride ( D I B A L - H ) in hexanes and methylmagnesium bromide in diethyl ether were purchased from Aldr ich Chemical Co. Inc. Solutions of methyllithium in diethyl ether and n-butyllithium in hexanes were obtained from Aldr ich Chemical Co . Inc and Acros, and were standardized using 115 diphenylacetic acid as a primary standard using the procedure of Kofron and B a c l a w s k i . 1 1 4 Potassium hydride was obtained as a 35 weight% suspension in mineral o i l and sodium hydride as a 60% dispersion in mineral o i l from Aldr ich Chemical Co. Inc., and were rinsed free of o i l with solvent under a stream of argon prior to use. A l l other reagents were commercially available and were used with further purification. Aqueous ammonium cWoride-ammonia (NH4CI-NH3) (pH 8) was prepared by the addition of -50 m L of concentrated aqueous ammonia (28-30%) to 950 m L of a saturated aqueous ammonium chloride solution. Li th ium diisopropylamide ( L D A ) was prepared by the addition of a solution of n-butyllitbium in hexanes to a solution of dnsopropylamine (1.1 equivalent) in dry T H F at -78 °C. The resulting solution was warmed to 0 °C, and stirred for 15 min, and cooled back to -78 °C prior to use. 116 4.2 Copper cyanide mediated intramolecular conjugate additions of alkenyltrimethylstannanes and aryltrimethylstannanes to enones 4.2.1 Preparation of the alkenyltrimethylstannane precursors Preparation of6-[(2-trimethylstannylcyclopent-l-en-l-yl)methylJ-3-isobutoxycyclohex-2-en-l-one (77)43 To a cold (-78 °C), stirred solution of L D A (23.0 mmol) in dry T H F (110 mL) was added a solution of 3-isobutoxycyclohex-2-en-l-one (76) 4 7 (3.87g, 23.0 mmol) in dry T H F (60 mL). The solution was warmed to 0 °C and was stirred for 30 min and then at room temperature for 1.5 h. The mixture was subsequently cooled to -78 °C and a solution of the bromide 73 5 0 (4.96 g, 15.3 mmol) in dry T H F (40 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. Water (100 mL) was added and the mixture was extracted with E t 2 0 (3 x 100 mL) . The combined organic extracts were washed with H 2 0 (100 mL) , brine (100 mL) , dried ( M g S O ^ , and concentrated under reduced pressure. The crude material was purified by flash column chromatography (400 g of silica gel, 1:4 Et 20-petroleum ether) to yield 5.37 g (85%) of alkylated product 77 as a viscous colourless o i l which solidified upon standing (mp. 39-40 °C). 76 73 77 IR (film): 1659, 1610 cm" 1. 117 *H N M R (400 M H z , CDC1 3 ) 5: 0.10 (s, 9H , -S rMe j , 2 / S „ - H = 53.0 H z , 0.94 (d, 6H , / = 6.5 Hz , -(C&Oa), 1.48-1.54 (m, 1H), 1.70-2.40 (m, 13H), 2.74-2.75 (m, 1 H ) , 3.56 (d, 2 H , / = 6.5 H z , - O C H 2 - C H ) , 5.30 (s, 1H, =CH). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -9.2 (-ve), 19.1 (2C, -ve), 24.3, 26.0, 27.7 (-ve), 28.4, 33.1, 35.8, 39.4, 43.6 (-ve), 74.7, 102.3 (-ve), 138.3, 151.1, 177.1, 200.8. H R M S calcd for C i 9 H 3 2 O 2 1 2 0 S n : 412.1424; found: 412.1419. Anal , calcd for C i 9 H 3 2 0 2 S n : C 55.50, H 7.84; found: C 55.24, H 7.98. Preparation of 4-[(2-trimethylstannylcyclopent-l-en-l-yl)methyl]cyclohex-2-en-l-one (78)43 To a cool (0 °C), stirred solution of the ketone 77 (1.47 g, 3.57 mmol) in dry C H 2 C 1 2 (40 mL) was added a solution of D I B A L - H (4.70 mL, 1.0 M solution in hexanes, 4.70 mmol) via a plastic syringe. The mixture was stirred at 0 °C for 2 h, after which time a saturated aqueous solution of Rochelle's salt (40 mL) was added. The resulting mixture was warmed to room temperature and stirred, open to air, for 30 min. The layers 77 78 118 were separated and the aqueous layer was extracted with E t 2 0 (3 x 40 mL). The combined organic extracts were washed with H2O (100 mL) , brine (100 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The resulting crude material was dissolved in E t 2 0 (40 mL) containing ~6 drops of H 2 0 and the mixture was treated with a catalytic amount of /?-toluenesulfonic acid (-50 mg). The reaction mixture, open to air, was stirred for 1 h at room temperature. It was diluted with H 2 0 (40 mL) and the layers were separated. The aqueous layer was extracted with E t 2 0 (2 x 40 mL) and the combined organic extracts were washed with brine (40 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The crude oi l was purified by flash column chromatography (70 g of silica gel, 1:4 Et 20-petroleum ether) to provide 1.03 g (86%) of the enone 78 as a colourless oil . IR (neat): 1680, 1614, 1387, 768 c m 1 . J H N M R (400 M H z , CDC1 3 ) 8: 0.11 (s, 9H , -SnMe^. 2 / S N - H = 53.0 Hz) , 1.50-1.62 (m, 1H), 1.78-1.90 (m, 2H), 2.00-2.10 (m, 1H), 2.20-2.61 (m, 9H), 5.96 (dd, 1H, / = 2.0, 10.0 Hz) , 6.78 (ddd, 1H, / = 1.5, 2.0, 10.0 Hz). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -9.2 (-ve), 24.4, 29.1, 34.8 (-ve), 36.1, 37.1, 38.4, 39.5, 129.0 (-ve), 139.6, 149.8, 154.4 (-ve), 199.8. H R M S calcd for C i 5 H 2 4 O 1 2 0 S n : 340.0849; found: 340.0847. Anal , calcd for C 1 5 H 2 4 O S n : C 53.14, H 7.13; found: C 53.36, H 6.98. 119 Preparation of 6-methyl-6-[(2-trimethylstannylcyclopent-l-en-l-yl)methyl ]-3-isobutoxycyclohex-2-en-l-one (79)43 11 79 To a cold (-78 °C), stirred solution of L D A (3.10 mmol) in dry T H F (20 mL) was added a solution of the ketone 77 (1.16 g, 2.81 mmol) in dry T H F (10 mL) . The mixture was warmed to 0 °C and stirred for 1 h. H M P A (0.98 m L , 5.62 mmol) was added and the reaction mixture was stirred for an additional 1 h. The mixture was then cooled to -78 °C and an excess of freshly distilled methyl iodide (-2.6 mL, 42 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. Water (30 mL) was added and the resulting mixture was extracted with E t 2 0 (3 x 30 mL). The combined organic extracts were washed with H 2 0 (2 x 30 mL) , aqueous CuSCU (10%, 30 mL) , brine (100 mL) , dried (MgSC^), and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100 g of silica gel, 1:4 E t 2 0 -petroleum ether) to yield 1.05 g (88%) of alkylated product 79 as a colourless o i l , which solidified upon standing (mp. 39-41 °C). IR (neat): 1652, 1611, 1375, 1200,770 cm"1. X H N M R (400 M H z , CDC1 3 ) 8: 0.12 (s, 9H , -SnMe 3 . 2JSn.H = 53.0 Hz) , 0.94 (d, 6H, / = 6.5 Hz , -(CH3)2), 1.06 (s, 3H, -CH3), 1.51-1.60 (m, 1H), 1.70-1.88 (m, 3H), 1.95-2.12 (m, 2H), 2.13-2.24 (m, 2H), 2.30-2.40 (m, 3H), 2.41-2.51 (m, 1H), 2.80 (br d, 1H, / = 14.0 Hz), 3.55 (d, 2H , / = 6.5 Hz , - O C H 2 - C H ) , 5.24 (s, 1H, =CH). 120 1 3 C N M R (75.5 M H z , CDC1 3 ) 5: -9.1 (-ve), 19.1 (2C, -ve), 24.1 (-ve), 24.8, 26.0, 27.7 (-ve), 31.6, 37.5, 39.0, 41.2, 43.1, 74.6, 101.4 (-ve), 139.9, 150.6, 175.7, 203.3. H R M S calcd for C 2 oH340 2 1 2 0 Sn: 426.1581; found: 426.1584. Anal , calcd for C 2 0 H 3 4 O 2 S n : C 56.50, H 8.06; found: C 56.87, H 7.87. Preparation of 4-methyl-4-[2-trimethylstannylcyclopent-l-en-l-yl)methylJ-cyclohex-2-en-l-one (80)43 SnMe 3 79 ; ;55s^SnMe3 80 To a cool (0 °C), stirred solution of the ketone 79 (1.16 g, 2.74 mmol) in dry C H 2 C 1 2 (35 mL) was added a solution of D I B A L - H (4.10 m L , 1.0 M solution in hexanes, 4.10 mmol) via a plastic syringe. The mixture was stirred at 0 °C for 2 h, after which time a saturated aqueous solution of Rochelle's salt (35 mL) was added. The resulting mixture was warmed to room temperature and stirred, open to air, for 30 rnin. The layers were separated and the aqueous layer was extracted with E t 2 0 (3 x 50 mL). The combined organic extracts were washed with H 2 0 (100 mL) , brine (100 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The resulting crude material was dissolved in E t 2 0 (35 mL) containing ~6 drops of H 2 0 and the mixture was treated with a catalytic amount of /^-toluenesulfonic acid (-50 mg). The solution, open to air, was stirred for 1 h at room temperature. The reaction mixture was diluted with H 2 0 (40 mL) and the layers were separated. The aqueous layer was extracted with E t 2 0 (2 x 40 mL) 121 and the combined organic extracts were washed with brine (40 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. Purification of the resulting crude o i l by flash column chromatography (70 g of silica gel, 1:4 Et 20-petroleum ether) and subsequent bulb-to-bulb distillation (178-182 °C/0.2 torr) of the acquired liquid provided 849 mg (88%) of the enone 80 as a colourless oil . IR (neat): 1684, 1606, 1389, 1222, 768 c m 1 . *H N M R (400 M H z , CDC1 3 ) 8: 0.13 (s, 9H , -SnMe. . 2 / s „ . H = 53.0 Hz) , 1.13 (s, 3H , -CH3), 1.65-1.74 (m, 1H), 1.74-1.85 (m, 2H), 1.93-2.03 (m, 1H), 2.17-2.53 (m, 8H), 5.84 (d, 1H, / = 10.0 Hz) , 6.78 (d, 1H, / = 10.0 Hz). 1 3 C N M R (75.5 M H z , CDCI3) 8: -9.0 (-ve), 25.0, 25.9 (-ve), 34.0, 34.2, 36.3, 38.3, 39.2, 45.5, 127.1 (-ve), 141.6, 149.5, 159.7 (-ve), 199.5. H R M S calcd for C i 6 H 2 6 O 1 2 0 S n : 354.1006; found: 354.0997. Anal, calcd for C i 6 H 2 6 O S n : C 54.43, H 7.42; found: C 54.65, H 7.52. Preparation of 3,4-dimethyl-4f(2-trimethylstannylcyclopent-l-en-l-yl)methyl]cyclohex-2-en-l-one (81) 122 To a cool (0 °C), stirred solution of the ketone 79 (1.11 g, 2.60 mmol) in dry T H F (30 mL) was added a solution of M e M g B r (2.60 mL, 3.0 M solution in E t 2 0 , 7.80 mmol) via a syringe. The mixture was warmed to room temperature and was stirred for 17 hours. Water (30 mL) was added slowly and the resulting mixture was extracted with E t 2 0 (3 x 30 mL). The combined organic extracts were washed with brine (100 mL) , dried (MgSC^) , and concentrated under reduced pressure. The resulting crude material was dissolved in E t 2 0 (30 mL) containing ~6 drops of H 2 0 and the mixture was treated with a catalytic amount of /?-toluenesulfonic acid (-50 mg). The reaction mixture, open to air, was stirred for 2 h at room temperature. It was diluted with H 2 0 (30 mL) and the layers were separated. The aqueous layer was extracted with E t 2 0 (2 x 30 mL) and the combined organic extracts were washed with brine (100 mL) , dried (MgSCU), and concentrated under reduced pressure. The crude oi l was purified by flash column chromatography (50 g of silica gel, 1:4 Et 20-petroleum ether) to provide 854 mg (89%) of the enone 81 as a viscous colourless oi l , which solidified upon standing (mp. 44-46 °C). IR (neat): 1669, 1606, 1184, 769 c m 1 . Tf N M R (400 M H z , CDC1 3 ) 5: 0.14 (s, 9H , -SnMes, 2 / s „ . H = 53.0 Hz) , 1.17 (s, 3H , -CH3), 1.60-1.70 (m, 1H), 1.72-1.83 (m, 2H), 1.94 (s, 3H, -CH3), 1.94-2.02 (m, 1H), 2.20-2.54 (m, 8H), 5.79 (s, 1H, =CH). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -9.0 (-ve), 20.6 (-ve), 24.9, 25.8 (-ve), 34.3, 34.3, 37.2, 38.9, 39.0, 42.6, 127.2 (-ve), 141.5,149.7, 168.8, 199.2. H R M S calcd for C i 7 H 2 8 O 1 2 0 S n : 368.1162; found: 368.1169. Anal, calcd for C 1 7 H 2 8 O S n : C 55.62, H 7.69; found: C 55.86, H 7.65. 123 Preparation of 5-[(2-trimethylstannylcyclopent-l-en-l-yl)methylJ-3-isobutoxycyclopent-2-en-l-one (85) To a cold (-78 °C), stirred solution of L D A (7.48 mmol) in dry T H F (38 mL) was added a solution of 3-isobutoxycyclopent-2-en-l-one (82) 1 1 5 (1.15 g, 7.48 mmol) in dry T H F (38 mL). The mixture was stirred at -78 °C for 30 min and then was warmed to 0 °C for 15 min. It was subsequently cooled back to -78 °C and H M P A (1.75 m L , 9.98 mmol) was added, followed by a solution of the bromide 73 (1.63 g, 4.99 mmol) in dry T H F (10 mL). The reaction mixture was warmed to 0 °C and stirred for 1 h. Water (50 mL) was added and the mixture was extracted with E t 2 0 (3 x 50 mL) . The combined organic extracts were washed with H 2 0 (2 x 50 mL) , aqueous CUSO4 (10%, 50 mL) , brine (100 mL) , dried (MgSC^), and concentrated under reduced pressure. The crude material was purified by flash column chromatography (77 g of silica gel, 2:3 Et 2 0-petroleum ether) to yield 1.53 g (77%) of alkylated product 85 as a colourless oil . IR: 1697, 1600, 1470, 1351, 1173,996 c m 1 . ln N M R (400 M H z , CDC1 3 ) 5: 0.09 (s, 9H , -SnMej, 2 / S n . H = 53.5 Hz) , 0.96 (d, 6H, / = 6.5 Hz , -CH(CH3)2), 1.72-1.85 (br m, 2H), 2.00-2.15 (m, 2H), 2.19-2.33 (m, 3H), 2.35-2.43 (m, 2H), 2.53-2.65 (m, 2H), 2.70 (br d, 1H, / = 14.5 Hz) , 3.70 (d, 2 H , / = 6.5 Hz , - O C H z C H ) , 5.18 (s, 1H, =CH). 82 73 85 124 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -9.4 (-ve), 18.9 (2C, -ve), 24.3, 27.8 (-ve), 33.8, 35.2, 35.8, 39.3, 43.8 (-ve), 77.9, 103.2 (-ve), 138.7, 150.9, 189.0, 207.8. H R M S calcd for C 1 8 H 3 o 0 2 1 2 0 S i r . 398.1268; found: 398.1262. Anal, calcd for C i 8 H 3 o 0 2 S n : C 54.44, H 7.61; found: C 54.70, H 7.55. Preparation of 4-[(2-trimethylstannylcyclopent-l-en-l-yl)methyl]cyclopent-2-en-l-one (86) To a cool (0 °C), stirred solution of the ketone 85 (1.44 g, 3.63 mmol) in dry C H 2 C 1 2 (35 mL) was added a solution of D I B A L - H (4.35 mL, 1.0 M solution in hexanes, 4.35 mmol) via a plastic syringe. The mixture was stirred at 0 °C for 2 hours, after which time a saturated aqueous solution of Rochelle's salt (35 mL) was added. The resulting mixture was warmed to room temperature and stirred, open to air, for 30 min. The layers were separated and the aqueous layer was extracted with C H 2 C 1 2 (3 x 35 mL) . The combined organic extracts were washed with brine (100 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The resulting crude material was dissolved in E t 2 0 (35 mL) containing ~6 drops of H 2 0 and the mixture was treated with a catalytic amount of p-toluenesulfonic acid (-50 mg). The solution, open to air, was stirred for 1 h at room temperature. The mixture was then diluted with H 2 0 (35 mL) and the layers were separated. The aqueous layer was extracted with E t 2 0 (2 x 35 mL) and the combined 125 organic extracts were washed with brine (35 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. Purification of the resulting crude oi l by flash column chromatography (50 g of silica gel, 1:4 Et 2 0-petroleum ether) and subsequent bulb-to-bulb distillation (170-175 °C/0.5 torr) of the acquired material provided 0.922 g (78%) of the enone 86 as a colourless oi l . IR(neat): 1718, 1612, 1184, 771 c m 1 . *H N M R (400 M H z , CDC13) 8: 0.09 (s, 9H, -SnMej, 2 / S n . H = 53.5 Hz) , 1.78-1.90 (m, 2H), 1.98 (dd, 1H, / = 2.0, 19.0 Hz), 2.21-2.43 (m, 6H), 2.46 (dd, 1H, / = 6.5, 19.0 Hz) , 3.05-3.12 (m, 1H), 6.12 (dd, 1H, / = 2.0, 6.0 Hz), 7.56 (dd, 1H, / = 2.0, 6.0 Hz) . 1 3 C N M R (75.5 M H z , CDC13) 8: -9.3 (-ve), 24.4, 36.2, 38.5, 39.3, 40.1 (-ve), 40.6, 133.6 (-ve), 139.2, 150.1, 168.2 (-ve), 209.6. H R M S calcd for C i 4 H 2 2 O 1 2 0 S n : 326.0693; found: 326.0700. Anal , calcd for C i 4 H 2 2 O S n : C 51.73, H 6.82; found: C 51.65, H 7.00. Preparation of 4-[(2-trimethylstannylcyclopent-l-en-l-yl)methyl]-3-methylcyclop en-l-one (87) 126 To a cool (0 °C), stirred solution of the ketone 85 (1.38 g, 3.47 mmol) in dry THF (35 mL) was added a solution of MeMgBr (4.62 mL, 3.0 M solution in Et 2 0, 13.9 mmol) via a syringe. The solution was warmed to room temperature and was stirred for 17 h. Water (35 mL) was added slowly and the resulting mixture was extracted with Et 2 0 (3 x 35 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSCU), and concentrated under reduced pressure. The resulting crude material was dissolved in Et 2 0 (35 mL) containing -6 drops of H 2 0 and the mixture was treated with a catalytic amount of ^-toluenesulfonic acid (-50 mg). The reaction mixture, open to air, was stirred for 4 h at room temperature. The mixture was diluted with H 2 0 (35 mL) and the layers were separated. The aqueous layer was extracted with Et 2 0 (2 x 35 mL) and the combined organic extracts were washed with brine (100 mL), dried (MgS0 4), and concentrated under reduced pressure. Purification of the crude oil by flash column chromatography (106 g of silica gel, 2:3 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (172-180 °C/0.2 toir) of the acquired material provided 888 mg (76%) of the enone 87 as a colourless oil. IR (neat): 1695, 1610, 1446, 766 cm 1 . *H NMR (400 MHz, CDC13) 8: 0.10 (s, 9H, -SnMes, 2 / s „ . H = 53.5 Hz), 1.82 (tt, 2H, / = 7.5, 7.5 Hz), 2.01-2.13 (rn, 2H; s, 3H, -CH3, (8 2.09)), 2.25-2.33 (m, 2H), 2.33-2.45 (m, 3H), 2.60 (br dd, lH, /=5 .0 , 13.5 Hz), 2.91 (brm, 1H), 5.87 (t, l H , / = 1.5 Hz). 1 3 C NMR (75.5 MHz, CDC13) 8: -9.3 (-ve), 17.5, 24.3 (-ve), 36.0, 37.0, 39.3, 41.2, 43.0 (-ve), 130.6 (-ve), 139.3, 150.5, 181.4, 208.6. HRMS calcd for C i 5 H 2 4 O 1 2 0 S n : 340.0849; found: 340.0843. Anal, calcd for Ci 5 H 2 4 OSn: C 53.14, H 7.13; found: C 53.22, H 7.26. 127 4.2.2 Preparation of the aryltrimethylstannane precursors Preparation of 2-trimethylstannylbenzyl alcohol (107) 106 SnMe To a cold (-78 °C), stirred solution of T M E D A (7.39 mL, 50.0 mml) in dry Et 2 0 (200 mL) was added n-BuLi (30.1 mL, 1.60 M in hexanes, 48.2 mmol) via a syringe and stirring was continued for 5 min. Commercially available benzyl alcohol (2.11 mL, 20.4 mmol) was added neat via a syringe and the mixture was warmed to room temperature. After 3 h, the solution turned a dark red colour. The mixture was cooled to -78 °C and trimethyltin chloride (6.00 g, 30.2 mmol) was added in one solid portion. The reaction mixture was warmed to room temperature and stirred for 2 h. Water (200 mL) was added and the mixture was extracted with Et 2 0 (3 x 200 mL). The combined organic extracts were washed with H 2 0 (200 mL), brine (200 mL), dried (MgS0 4), and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (200 g of silica gel, 1:4 Et20-petroleum ether) to yield 3.50 g (64%) of the alcohol 107 as a colourless oil. This oil exhibited spectral properties ('H NMR) identical with those previously reported.57 128 Preparation of 2-trimethylstannylbenzyl bromide (108) To a cool (0 °C), stirred solution of triphenylphosphine (8.48 g, 32.3 mmol) in dry CH 2 C1 2 (130 mL) was added bromine (-1.7 mL) via a syringe, until a yellow colour persisted. A small amount of PPh 3 (-50 mg) was added until the colour disappeared. The mixture was stirred at 0 °C for 15 min, during which time a white precipitate formed. Solid imidazole (2.37 g, 34.8 mmol) was added and the white precipitate disappeared. The mixture was stirred for 15 min before addition of a solution of the alcohol 107 (3.50 g, 12.9 mmol) in dry CH 2 C1 2 (20 mL). The reaction mixture was stirred for 30 min. Most of the solvent was removed under reduced pressure until the volume remaining was approximately 30 mL. Pentane (200 mL) was added. The mixture (containing a precipitate) was filtered through a cake of silica gel (-50 g) and Celite® (-50 g) and the cake was eluted with pentane. To the residue left in the flask was added aqueous NaHC03 (10%, 100 mL) and the aqueous layer was extracted with pentane (2 x 100 mL). The combined organic extracts were filtered through the same cake of silica gel and Celite® (vide supra) and the cake was eluted with -1 L of pentane. Concentration of the combined filtrate under reduced pressure afforded 4.05 g (94%) of the bromide 108 as a colourless oil. IR (neat): 1471, 1220, 764, 609, 529 cm 1 . X H N M R (400 MHz, CDC13) 5: 0.39 (s, 9H, -SnMej, 2 / S n . H = 54.0 Hz), 4.51 (s, 2H, / = 6.0 Hz, -CHiBr), 7.24 (dt, 1H, J = 1.5, 7.5 Hz), 7.30 (dt, 1H, / = 1.5, 7.5 Hz), 7.38-7.54 (m, 2H). 129 1 3 C NMR.(50.3 M H z , CDC1 3 ) 5: -7.8, 36.9, 127.8, 129.0, 129.9, 136.8, 143.5, 144.5. H R M S calcd for C 9 H 1 2 7 9 B r 1 2 0 S n ( M + - M e ) : 318.9144; found: 318.9144. Anal , calcd for C 1 0 H 1 5 B r S n : C 35.98, H 4.53; found: C 36.28, H 4.49. Preparation of4-methyl-2-trimethylstannylbenzyl bromide (110) 109 110 To a cool (0 °C), stirred solution of triphenylphosphine (5.06 g, 19.3 mmol) in dry C H 2 C 1 2 (70 mL) was added bromine (~1 mL) via a syringe, until a yellow colour persisted. A small amount of P P h 3 (-50 mg) was added until the colour disappeared. The mixture was stirred at 0 °C for 15 min, during which time a white precipitate formed. Solid imidazole (1.40 g, 20.8 mmol) was added and the white precipitate disappeared. The mixture was stirred for 15 min before addition of a solution of the alcohol 109* (2.20 g, 7.72 mmol) in dry C H 2 Q 2 (10 mL) . The reaction mixture was stirred for 30 min. Most of the solvent was removed under reduced pressure until the volume remaining was approximately 15 m L . Pentane (100 mL) was added. The mixture (containing a precipitate) was filtered through a cake of silica gel (-20 g) and Celite® (-20 g) and the cake was eluted with pentane. Concentration of the combined filtrate under reduced pressure afforded 2.19 g (81%) of the bromide 110 as a colourless oil . IR (neat): 1594, 1443, 1480, 1210 cm"1. * This compound was prepared by J. G. K . Yee. 130 *H N M R (400 M H z , CDC1 3 ) 8: 0.32 (s, 9H , -SnMe. . 2 / S n . H = 50.0 Hz) , 2.31 (s, 3H , -CH3), 4.50 (s, 2 H , -CHjBr ) , 7.05-7.10 (m, 1H), 7.20-7.45 (m, 2H). 1 3 C N M R (50.3 M H z , CDC1 3 ) 8: -7.9, 21.2, 37.0, 128.9, 129.7 (2C), 137.5, 141.5, 143.2. H R M S calcd for C 1 0 H 1 4 7 9 B r 1 2 0 S n ( M + - M e ) : 322.9301; found: 322.9301. Anal , calcd for C u H 1 7 B r S n : C 37.98, H 4.93; found: C 38.13, H 4.89. Preparation of6-(2-trimethylstannylbenzyl)-3-isobutoxycyclohex-2-en-l-one (111) To a cold (-78 °C), stirred solution of L D A (3.03 mmol) in dry T H F (20 mL) was added a solution of 3-isobutoxycyclohex-2-en-l-one (76) (509 mg, 3.03 mmol) in dry T H F (20 mL). The solution was warmed to 0 °C and stirred for 30 min and then at room temperature for 1.5 h. The mixture was subsequently cooled to -78 °C and a solution of the bromide 108 (506 mg, 1.514 mmol) in dry T H F (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. Water (40 mL) was added and the mixture was extracted with E t 2 0 (3 x 40 mL). The combined organic extracts were washed with H 2 0 (40 mL) , brine (40 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g of silica gel, 1:4 Et 20-petroleum ether) to yield 618 mg (97%) of alkylated product 111 as a viscous colourless oil . 131 IR (neat): 1651, 1615, 1384, 1240, 992, 770 cm"1. A H NMR (400 MHz, CDC13) 5: 0.31 (s, 9H, -SnMej, 2 / S n . H = 53.0 Hz), 0.97 (d, 3H, J = 6.5 Hz), 0.98 (d, 3H, / = 6.5 Hz), 1.53-1.66 (m, 1H), 1.88-1.93 (m, 1H), 1.93-2.04 (m, 1H), 2.30-2.45 (m, 3H), 3.50-3.60 (m, 4H), 5.34 (s, 1H, =CH), 6.92-7.22 (m, 2H), 7.22-7.30 (rn, 1H), 7.42-7.48 (m, 1H). 1 3 C NMR (50.3 MHz, CDC13) 5: -7.2, 19.1 (2C), 26.0, 27.7, 28.6, 38.3, 47.2, 74.8, 102.2, 125.6, 128.4, 129.0, 136.5, 142.5, 146.9, 177.0, 199.8. HRMS calcd for C 2 oH 3 0 0 2 1 2 0 Sn: 422.1268; found: 422.1271. Anal, calcd for C 2 0 H 3 o0 2 Sn: C 57.04, H 7.18; found: C 56.89, H 7.09. Preparation of4-(2-trimethylstannylbenzyl)cyclohex-2-en-l-one (112) S n M e 3 SnMe<= 111 112 To a cool (0 °C), stirred solution of the ketone 111 (278 mg, 0.659 mmol) in dry CH 2 C1 2 (15 mL) was added a solution of DIBAL-H (0.99 mL, 1.0 M solution in hexanes, 0.99 mmol) via a plastic syringe. The mixture was stirred at 0 °C for 2 h, after which time a saturated aqueous solution of Rochelle's salt (15 mL) was added. The resulting 132 mixture was warmed to room temperature and stirred, open to air, for 30 min. The layers were separated and the aqueous layer was extracted with E t 2 0 (3 x 15 mL) . The combined organic extracts were washed with H 2 0 (15 mL) , brine (15 mL) , dried (MgSC^), and concentrated under reduced pressure. The resulting crude material was dissolved in E t 2 0 (15 mL) containing ~3 drops of H 2 0 and the mixture was treated with a catalytic amount of /?-toluenesulfonic acid (-10 mg). The reaction mixture, open to air, was stirred for 2 h at room temperature. It was diluted with H 2 0 (15 mL) and the layers were separated. The aqueous layer was extracted with E t 2 0 (2 x 15 mL) and the combined organic extracts were washed with brine (15mL), dried (MgSC^) , and concentrated under reduced pressure. The crude oi l was purified by flash column chromatography (20 g of silica gel, 1:4 Et 20-petroleum ether) to afford 189 mg (82%) of the enone 112 as a colourless oil . IR (neat): 1682, 1250, 773 c m 1 . X H N M R (400 M H z , CDC1 3 ) 8: 0.31 (s, 9H , -SnMe 3 . 2 /sn-H= 53.0 Hz) , 1.69-1.80 (m, 1H), 2.04-2.14 (m, 1H), 2.33 (ddd, 1H, / = 5.0, 12.5, 17.0 Hz) , 2.51 (ddd, 1H, / = 5.0, 5.0, 17.0 Hz) , 2.65-2.74 (m, 1H), 2.74-2.82 (m, 2H), 5.98 (dd, 1H, / = 2.0, 10.0 Hz , =CH), 6.78 (d, 1H, / = 10.0 H z , =CH), 7.16-7.32 (m, 3H), 7.42-7.48 (m, 1H). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -7.8 (-ve), 29.0, 36.9, 38.2 (-ve), 43.6, 126.1 (-ve), 128.7 (-ve), 128.8 (-ve), 129.3 (-ve), 136.7 (-ve), 142.5, 145.4, 153.4 (-ve), 199.5. H R M S calcd for C i 5 H 1 9 O 1 2 0 S n ( M + - M e ) : 335.0458; found: 335.0457. Anal , calcd for C i 6 H 2 2 O S n : C 55.06, H 6.35; found: C 55.22, H 6.42. 133 Preparation of 6-(4-methyl-2-trimethylstannylbenzyl)-3-isobutoxycyclohex-2-en-l-one (113) To a cold (-78 °C), stirred solution of L D A (2.75 mmol) in dry T H F (20 mL) was added a solution of 3-isobutoxycyclohex-2-en-l-one (76) (463 mg, 2.75 mmol) in dry T H F (20 mL). The solution was warmed to 0 °C and stirrred for 30 min and then at room temperature for 1.5 h. The mixture was subsequently cooled to -78 °C and a solution of the bromide 110 (479 mg, 1.38 mmol) in dry T H F (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. Water (40 mL) was added and the mixture was extracted with E t 2 0 (3 x 40 mL). The combined organic extracts were washed with H 2 0 (40 mL) , brine (40 mL) , dried ( M g S 0 4 ) , and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g of silica gel, 1:4 Et 20-petroleum ether) to yield 572 mg (96%) of alkylated product 113 as a viscous colourless oil . ER (neat): 1664, 1615, 1467, 1183, 991, 761 c m 1 . *H N M R (400 M H z , CDC1 3 ) 8: 0.29 (s, 9H , -SnMes, 2 / S „ - H = 53.0 Hz) , 0.97 (d, 3H, / = 6.5 Hz), 0.98 (d, 3H, / = 6.5 Hz), 1.55-1.66 (m, 1H), 1.88-1.96 (m, 1H), 1.96-2.05 (m, 1H), 2.30 (s, 3H, -CH3), 2.30-2.43 (m, 3H), 3.45-3.65 (m, 4H), 5.34 (s, 1H, =CH), 7.00-7.15 (m, 2H), 7.22-7.30 (m, 1H). 134 ViC NMR (75.5 MHz, CDC13) 5: -7.9(-ve), 19.0 (2C, -ve), 20.9 (-ve), 25.9, 27.7 (-ve), 28.5, 37.7, 47.2 (-ve), 74.7, 102.2 (-ve), 128.8 (-ve), 129.1 (-ve), 134.8, 137.2 (-ve), 142.3, 143.7, 177.0, 199.9. HRMS calcd for C 2iH32O 2 1 2 0Sn: 436.1424; found: 436.1419. Anal, calcd for C 2 iH 3 2 0 2 Sn: C 57.96, H 7.41; found: C 57.81, H 7.54. Preparation of3-methyl-4-(4-methyl-2-trimethylstannylbenzyl)cyclohex-2-en-l-one (114) S n M e 3 S n M e 3 113 114 To a cool (0 °C), stirred solution of the ketone 113 (236 mg, 0.541 mmol) in dry THF (25 mL) was added a solution of MeMgBr (0.72 mL, 3.0 M solution in Et 2 0, 2.2 mmol) via a syringe. The mixture was warmed to room temperature and was stirred for 17 hours. Water (25 mL) was added slowly and the resulting mixture was extracted with Et 2 0 (3 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSCU), and concentrated under reduced pressure. The resulting crude material was dissolved in Et 2 0 (25 mL) containing ~5 drops of H 2 0 and the mixture was treated with a catalytic amount of ^-toluenesulfonic acid (-10 mg). The reaction mixture, open to air, was stirred for 4 h at room temperature. It was diluted with H 2 0 (25 mL) and the layers were separated. The aqueous layer was extracted with Et 2 0 (2 x 25 mL) and the combined organic extracts were washed with H 2 0 (25 mL), brine (25 mL), dried 135 (MgSCU), and concentrated under reduced pressure. The crude o i l was purified by flash column chromatography (40 g of silica gel, 1:4 Et 20-petroleum ether) to provide 175 mg (86%) of the enone 114 as a viscous, colourless oil . IR (neat): 1670, 1623, 1478, 1377, 1250, 769 c m 1 . lU N M R (400 M H z , CDC1 3 ) 8: 0.31 (s, 9H , -SnMfr,. 2 / S n - H = 52.5 Hz) , 1.70-1.81 (m, 1H), 1.81-2.00 (m, 1H; s, 3H , -CH3, (8 1.88)), 2.20-2.38 (m, 1H; s, 3H , - C H , , (8 2.31)), 2.45 (ddd, 1H, / = 4.5, 11.0, 16.0 Hz), 2.55-2.68 (m, 2H), 3.08 (dd, 1H, / = 4.5, 13.0 Hz) , 5.87 (s, 1H, =CH), 7.07-7.12 (m, 2H), 7.12-7.32 (m, 1H). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: -7.7 (-ve), 21.0 (-ve), 23.6 (-ve), 26.8, 34.0, 39.9, 40.9 (-ve), 127.2 (-ve), 128.5 (-ve), 129.4 (-ve), 135.3, 137.4 (-ve), 141.9, 142.7, 165.3, 199.2. H R M S calcd for C i 8 H 2 6 O 1 2 0 S n : 378.1006; found: 378.0994. Anal , calcd for C i 8 H 2 6 O S n : C 57.33, H 6.95; found: C 57.54, H 6.96. Preparation of5-(2-trimethylstannylbenzyl)-3-isobutoxycyclopent-2-en-l-one (115) 82 108 115 136 To a cold (-78 °C), stirred solution of L D A (2.64 mmol) in dry T H F (20 mL) was added a solution of 3-isobutoxycyclopent-2-en-l-one (82) (408 mg, 2.64 mmol) in dry T H F (20 mL). The mixture was stirred at -78 °C for 30 min and at 0 °C for 15 min. It was subsequently cooled back to -78 °C and H M P A (0.466 mL, 2.64 mmol) was added, followed by a solution of the bromide 108 (441 mg, 1.32 mmol) in dry T H F (10 mL). The reaction mixture was warmed to 0 °C and stirred for 1 h. Water (50 mL) was added and the mixture was extracted with E t 2 0 (3 x 50 mL). The combined organic extracts were washed with H 2 0 (2 x 50 mL) , brine (50 mL) , dried (MgSCU), and concentrated under reduced pressure. The crude material was purified by flash column chromatography (30 g of silica gel, 2:3 Et 20-petroleum ether) to yield 367 mg (68%) of alkylated product 115 as a colourless oil . IR: 1696, 1594, 1470, 1351, 1173, 995 c m 1 . *H N M R (400 M H z , CDC1 3 ) 8: 0.30 (s, 9H , -SnMe. , 2 / S n . H = 53.0 Hz) , 0.96 (d, 6H, / = 6.5 Hz , -CH(CH3)2), 1.97-2.09 (m, 1H, - C H 2 C H ( C H 3 ) 2 ) , 2.30 (dd, 1H, / = 2.0, 18.0 Hz) , 2.47 (dd, 1H, 7=11.5 , 14.0 Hz) , 2.57 (dd, 1H, / = 7.0, 18.0 Hz) , 2.75-2.83 (m, 1H), 3.35 (dd, 1H, / = 4.0, 14.0 Hz) , 3.72 (d, 2 H , / = 6.5 Hz , - O C H z C H ) , 5.25 (s, 1H, =CH), 7.13-7.25 (m, 3H), 7.38-7.45 (m, 1H). 1 3 C N M R (50.3 M H z , CDC1 3 ) 8: -8.1, 18.9 (2C), 27.3, 34.3, 40.0, 46.6, 78.0, 103.6, 125.8, 127.9, 128.7, 136.3, 142.5, 146.3, 189.0, 206.8. H R M S calcd for C i 9 H 2 8 O 2 1 2 0 S n : 408.1111; found: 408.1104. Anal , calcd for C 1 9 H 2 8 0 2 S n : C 56.05, H 6.93; found: C 56.19, H 7.00. 137 Preparation of4-(2-trimethylstannylbenzyl)-cyclopent-2-en-l-one (116) M e 3 S n M e 3 S n — f V O 115 116 To a cool (0 °C), stirred solution of the ketone 115 (335 mg, 0.823 mmol) in dry CH 2 C1 2 (20 mL) was added a solution of DIBAL-H (1.24 mL, 1.0 M solution in hexanes, 1.24 mmol) via a plastic syringe. The mixture was stirred at 0 °C for 2 h, after which time a saturated aqueous solution of Rochelle's salt (20 mL) was added. The resultant mixture was warmed to room temperature and stirred, open to air, for 30 min. The layers were separated and the aqueous layer was extracted with Et 2 0 (3 x 20 mL). The combined organic extracts were washed with H 2 0 (20 mL), brine (20 mL), dried (MgS0 4), and concentrated under reduced pressure. The resulting crude material was dissolved in Et 2 0 (20 mL) containing ~3 drops of H 2 0 and the mixture was treated with a catalytic amount of p-toluenesulfonic acid (-10 mg). The reaction mixture, open to air, was stirred for 2 h at room temperature. It was diluted with H 2 0 (20 mL) and the layers were separated. The aqueous layer was extracted with Et 2 0 (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgS0 4), and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (16 g of silica gel, 2:3 Et20-petroleum ether) to afford 172 mg (62%) of the enone 116 as a colourless oil. IR (neat): 1718, 1182, 770 cm"1. J H NMR (400 MHz, CDC13) 5: 0.29 (s, 9H, -SnMes, 2 7 S „ . H = 53.0 Hz), 2.09 (dd, 1H, / = 2.0, 19.0 Hz, one of -CHCHz-QO)), 2.52 (dd, 1H, J = 6.5, 19.0 Hz, one of 138 -CHCH 2-C(0)), 2.77 (dd, 1H, J= 8.0, 14.0 Hz, one of Ar-CH^CH-), 2.84 (dd, 1H, / = 8.0, 14.0 Hz, one of Ar-CH^-CH-), 3.18-3.27 (rn, 1H, -CH-), 6.19 (d, 1H, / = 5.5 Hz, =CH), 7.18-7.23 (m, 2H), 7.23-7.33 (m, 1H), 7.45 (br d, 1H, / = 8.0 Hz), 7.57 (dd, 1H, /=2.0, 5.5 Hz, =CH). 1 3 C NMR (75.5 MHz, CDC13) S: -7.9 (-ve), 40.9, 43.1 (-ve), 43.7, 126.1 (-ve), 128.4 (-ve), 128.8 (-ve), 134.1(-ve), 136.7 (-ve), 142.3, 145.5, 167.3 (-ve), 209.1. HRMS calcd for C 1 4 H 1 7 O 1 2 0 S n (M+-Me): 321.0301; found: 321.0303. Anal, calcd for C 1 5 H 2 0 OSn: C 53.78, H 6.02; found: C 54.13, H 6.11. 139 4.2.3 CuCN mediated cyclizations General Procedure 1. Copper(I) cyanide mediated cyclizations A solution of the appropriate enone (1 equiv) in dry DMSO (-20 mL/mmol of the enone) was transferred via a cannula to a flask containing CuCN (2.5 equiv) under an atmosphere of argon. The stirred mixture was heated at 60 °C for 3-6 h and then was allowed to cool to room temperature. Saturated aqueous NH4CI-NH3 (pH 8, -20 mL/mmol of the enone) and Et 2 0 (-20 mL/mmol of the enone) were added and the resulting mixture was stirred, open to air, until the aqueous layer became deep blue (-30 min). The layers were separated and the aqueous layer was extracted with Et 2 0 (2 x -20 mL/mmol of the enone). The combined organic extracts were washed with H 2 0 (2 x -20 mL/mmol of the enone), brine (-20 mL/mmol of the enone), were dried (MgS04), and concentrated under reduced pressure. Purification of the crude material was achieved by flash column chromatography on silica gel. Preparation ofcis-tricyclo[6.4.0.&"6]dodec-2(6)-en-ll-one (88j O 78 Following general procedure 1, a mixture of the enone 78 (950 mg, 2.80 mmol) and CuCN (627 mg, 7.00 mmol) in dry DMSO (55 mL) was heated at 60 °C for 4 h. Purification of the crude material by flash column chromatography (50 g of silica gel, 1:4 140 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (76-80 °C/0.1 torr) of the acquired material provided 464 mg (94%) of the ketone 88 as a colourless oil. IR (neat): 1717, 1419 cm'1. ! H NMR (400 MHz, CDC13) 5: 1.70-1.82 (m, 1H), 1.90-2.30 (m, 11H), 2.45-2.59 (m, 2H), 2.88-3.01 (m, 2H). 1 3 C NMR (75.5 MHz, CDC13) 5: 27.1, 27.4, 27.6, 29.1, 35.9, 37.0, 39.4 (-ve), 40.2 (-ve), 41.3, 144.9, 147.3,214.2 HRMS calcd for Ci 2H 1 60:176.1201; found: 176.1198. Anal, calcd for C i 2 H 1 6 0 : C 81.77, H 9.15; found: C 81.65, H 9.23. Preparation of cis-8-methyltricyclo[6.4.0.02,6]dodec-2(6)-en-ll-one (89) O Following general procedure 1, a mixture of the enone 80 (789 mg, 2.23 mmol) and CuCN (512 mg, 5.72 mmol) in dry DMSO (45 mL) was heated at 60 °C for 4 h. Purification of the crude material by flash column chromatography (40 g of silica gel, 1:4 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (102-110°C/0.1 torr) of the acquired material provided 364 mg (85%) of the ketone 89 as a colourless oil. 80 89 141 IR (neat): 1717, 1446 cm-1. J H N M R (400 MHz, CDC13) 8: 1.23 (s, 3H, -CH3), 1.76-1.83 (m, 2H), 1.97-2.30 (m, 11H), 2.48-2.59 (m,2H). 1 3 C N M R (75.5 MHz, CDC13) 8: 27.3, 27.5, 29.4, 30.0 (-ve), 35.1, 35.9, 41.1, 44.3, 45.8, 47.9 (-ve), 144.0, 146.6, 214.3. HRMS calcd for Ci 3H 1 80:190.1358; found: 190.1355. Anal, calcd for C 1 3 H 1 8 0 : C 82.06, H 9.53; found: C 81.90, H 9.49. Preparation ofcis-1,8-dimethyltricyclo[6.4.0.02,1']dodec-2(6)-en-ll-one (90) O 81 90 Following general procedure 1, a mixture of the enone 81 (482 mg, 1.31 mmol) and CuCN (294 mg, 3.28 mmol) in dry DMSO (26 mL) was heated at 60 °C for 6 h. Purification of the crude material by flash column chromatography (18 g of silica gel, 1:4 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (118-120 °C/0.2 torr) of the acquired material provided 240 mg (88%) of the ketone 90 as a colourless viscous oil, which solidified upon standing (mp. 27-29 °C). 142 IR(neat): 1715, 1446 cm"1. lH N M R (400 MHz, CDC13) 8: 0.98 (s, 3H, -CH3), 1.15 (s, 3H, -CH3), 1.76-1.81 (m, 2H), 1.97-2.39 (m, 12H). 1 3 C N M R (75.5 MHz, CDC13) 8: 22.7 (-ve), 25.2 (-ve), 25.6, 27.0, 29.4, 36.3, 37.2, 44.1, 47.4, 48.1, 48.7, 141.9, 151.2, 214.0. HRMS calcd for C 1 4 H 2 0 O : 204.1514; found: 204.1510. Anal, calcd for C i 4 H 2 0 O : C 82.30, H 9.87; found: C 82.46, H 9.85. Preparation ofcis-tricyclo[6.3.0.(?'6]undec-l(8)-en-4-one (91) O Me 3 Sn 86 91 To a stirred solution of the enone 86 (164 mg, 0.505 mmol) in dry D M S O (9.3 ml), under an atmosphere of argon, was added CuCN (227 mg, 2.53 mmol). The reaction mixture was heated at 60 °C for 17 h. Saturated aqueous NEI4CI-NH3 solution (pH 8,10 mL) and E t 2 0 (10 mL) were added and the mixture was stirred, open to air, until the aqueous layer turned deep blue. The layers were separated and the aqueous layer was extracted with E t 2 0 (2 x 10 mL). The combined organic extracts were washed with H 2 0 (2 x 10 mL), brine (10 mL), were • dried (MgS0 4), and concentrated under reduced pressure. 143 Purification of the crude material by flash column chromatography (31 g of silica gel, 1:4 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (84-88 °C/0.3 torr) of the acquired material provided 65 mg (80%) of the ketone 91 as a colourless oil. IR(neat): 1740, 1402, 1255, 1160 cm 1 . J H NMR (400 MHz, CDC13) 5: 2.10-2.23 (m, 9H), 2.10 (ddd, 1H, / = 1.5, 9.5, 19.0 Hz), 2.46-2.60 (rn, 2H), 3.14-3.28 (m, 2H). 1 3 C NMR (75.5 MHz, CDCI3) 8: 27.5, 28.0, 29.4, 37.0, 40.6, 42.6 (-ve), 43.1 (-ve), 45.5, 145.4, 147.4, 220.5. HRMS calcd for C n H 1 4 0 : 162.1045; found: 162.1042. Anal, calcd for C u H 1 4 0 : C 81.44, H 8.70; found: C 81.32, H 8.85. 144 Preparation of cis-2-methyltricyclo[6.3.0.02,1Dundee-1(8)-en-4-one (94) Me 3 Sn H O 87 94 95 To a flame dried, 20 mL glass, sealable ampoule equipped with a magnetic stir bar, under an atmosphere of argon, was added the enone 87 (335 g, 0.986 mmol), dry DMSO (17 mL), and solid CuCN (4.35 g, 48.6 mmol). The ampoule was flushed with a stream of argon gas and sealed using a natural gas-oxygen torch The mixture was heated to 90 °C using an oil bath and was stirred at this temperature for 17 h. The ampoule was opened and the brown reaction mixture was poured into an aqueous solution of NH4CI-N H 3 (pH 8, 50 mL) and the resulting mixture was diluted with E t 2 0 (50 mL). The mixture was stirred vigorously, open to air, until the aqueous phase became blue. The mixture, which contained a purple precipitate that remained insoluble at the interface of the two layers, was filtered through a sintered glass funnel. The solid in the funnel was rinsed with a solution of aqueous NH4CI-NH3 (pH 8, -50 mL) and E t 2 0 (-50 mL). The phases of the combined filtrate were separated and the aqueous layer was extracted with E t 2 0 (2 x 50 mL). The combined organic extracts were washed with H 2 0 (100 mL), brine (50 mL), dried (MgS0 4 ), and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (28 g of silica gel, 1:4 Et20-petroleum ether) to yield 96 mg (55%) of the ketone 94 along with 24 mg (14%) of protiodestannylated material 95, both as colourless oils. Characterization data for cw-2-methyltricyclo[6.3.0.02'6]undec-l(8)-en-4-one (94): IR (neat): 1742, 1401, 1160 cm 1 . 145 X H NMR (400 MHz, CDC13) 8: 1.19 (s, 3H, -CH3), 1.88 (br d, 1H, / = 16.0 Hz), 1.95-2.23 (m, 8H), 2.35 (dd, 1H, / = 1.5, 19.0 Hz), 2.53-2.61 (m, 1H), 2.65 (ddd, 1 H , / = 1.5, 10.0, 19.0 Hz), 2.75-2.85 (m, 1H). 1 3 C NMR (100.6 MHz, CDC13) 8: 25.2, 25.7, 27.8, 29.6, 36.0, 46.7, 48.2, 49.2, 50.8 (-ve), 143.3, 151.1, 219.9. HRMS calcd for d 2H 1 60:176.1201; found: 176.1197. Anal, calcd for C i 2 H i 6 0 : C 81.77, H 9.15; found: C 81.65, H 9.13. Characterization data for the protiodestannylated material 95: IR (neat): 1713, 1615, 1444, 1182 cm 1 . J H NMR (400 MHz, CDC13) 8: 1.84 (tt, 2H, / = 7.5, 7.5 Hz), 1.98 (dd, 1H, / = 10.5, 14.0 Hz), 2.09 (s, 3H, -CH3), 2.13-2.32 (m, 5H), 2.45-2.55 (m, 2H), 2.91 (br m, 1H), 5.38 (s, 1H, =CHC=0), 5.88 (t, 1H, / = 1.0 Hz, =CH-CH 2-). 1 3 C NMR (75.5 MHz, CDC13) 8: 17.4, 23.5, 32.4, 34.6, 35.2, 42.0, 42.9, 126.2, 130.8, 141.7,181.3,208.9. HRMS calcd for C i 2 H i 6 0 : 176.1201; found: 176.1206. 146 Preparation ofcis-1, 2, 4, 4a, 9, 9a-hexahydro-3H.-fluorene-3-one (117) Following general procedure 1, a mixture of the enone 112 (78 mg, 0.22 mmol) and CuCN (50 mg, 0.56 mmol) in dry DMSO (4 mL) was heated at 60 °C for 2 h. The crude material was purified by flash column chromatography (4 g of silica gel, 1:4 Et 2 0-petroleum ether) to provide 36 mg (87%) of the ketone 117 as a colourless oil. IR (neat): 1720, 1457, 1257, 745 cm - 1. *H NMR (400 MHz, CDC13) 8: 1.70-1.81 (m, 1H), 1.97-2.09 (rn, 1H), 2.23-2.30 (m, 2H), 2.62 (dd, 1H, 7= 7.5, 15.0 Hz), 2.70-2.82 (m, 3H), 3.16-3.27 (m, 1H), 3.64 (ddd, 1H, / = 7.5, 7.5, 7.5 Hz), 7.11-7.22 (m, 4H). 1 3 C NMR (75.5 MHz, CDC13) 8: 27.6, 36.8 (-ve), 38.4, 38.4, 42.5, 43.8 (-ve), 123.7 (-ve), 124.9 (-ve), 126.7 (-ve), 127.0 (-ve), 142.2, 145.0, 212.5. HRMS calcd for Ci 3H 1 40:186.1045; found: 186.1048. Anal, calcd for C 1 3 H 1 4 0 : C 83.83, H 7.58; found: C 83.65, H 7.35. 147 Preparation ofcis-4a, 6-dimethyl-l, 2, 4, 4a, 9, 9a-hexahydro-3B.-fluorene-3-one (118) O Following general procedure 1, a mixture of the enone 114 (80 mg, 0.21 mmol) in dry DMSO (4 mL) and CuCN (47 mg, 0.53 mmol) was heated at 60 °C for 29 h. The progress of the reaction was monitored by G L C analysis. The crude material was purified by flash column chromatography (4 g of silica gel, 1:4 Et20-petroleum ether) to provide 30 mg (66%) of the ketone 118 as a colourless oil, as well as 5 mg of protiodestannylated material that was not fully characterized. The 1!! NMR spectrum of the latter material showed the presence of 4 aromatic protons (8 7.00-7.11, m) and an alkenic proton (8 5.87, s, 1H), as well as lack of the -SnMe3 group. IR (neat): 1714, 1452, 1229, 810 cm'1. T i NMR (400 MHz, CDC13) 8: 1.28 (s, 3H, -CHs), 1.82-1.92 (m, 1H), 2.02-2.13 (m, 1H), 2.20-2.36 (m, 3H; s, 3H, -Of , , (8 2.29)), 2.42 (dd, 1H, / = 1.0, 14.5 Hz), 2.60 (d, 1H, / = 14.5 Hz), 2.75 (dd, 1H, / = 6.0, 16.0 Hz), 3.17 (dd, 1H, / = 8.0, 16.0 Hz), 6.88 (s, 1H), 6.96 (d, 1H, / = 7.5 Hz), 7.08 (d, 1H, / = 7.5 Hz). 1 3 C NMR (75.5 MHz, CDC13) 8: 21.3 (-ve), 27.3, 28.2 (-ve), 36.1, 37.3, 45.1 (-ve), 49.3, 50.5, 122.7 (-ve), 124.6 (-ve), 127.8 (-ve), 136.5, 137.9, 150.4, 212.2. HRMS calcd for C 1 5H 1 80:214.1358; found: 214.1363. 114 118 148 Anal, calcd for C i 5 H 1 8 0 : C 84.06, H 8.46; found: C 84.21, H 8.41. Preparation ofcis-6, 7-benzobicyclo[3.3.0]octan-3-one (119) O M e 3 S n H O 116 119 Following general procedure 1, a mixture of the enone 116 (101 mg, 0.30 mmol) and CuCN (65 mg, 0.72 mmol) in dry DMSO (6 mL) was heated at 60 °C for 2 h. The crude material was purified by flash column chromatography (10 g of silica gel, 1:4 Et 2 0-petroleum ether) to provide 39 mg (75%) of the ketone 119 as a colourless oil. This compound has been reported in the literature.60 IR (neat): 1738, 1399, 1154, 750 cm"1. *H N M R (400 MHz, CDC13) 8: 1.95 (dd, 1H, / = 8.0, 19.0 Hz), 2.46-2.60 (m, 2H), 2.69 (ddd, 1H, / = 1.5, 9.0, 19.0 Hz), 2.80 (d, 1H, / = 16.0 Hz), 3.11-3.30 (m, 2H), 3.83-3.92 (m, 1H), 7.14-7.24 (m, 4H). 1 3 C N M R (75.5 MHz, CDC13) 8: 38.4, 39.4 (-ve), 43.5, 43.8, 46.0 (-ve), 124.6 (-ve), 125.4 (-ve), 127.0 (-ve), 127.2 (-ve), 142.3, 144.9, 219.3. HRMS calcd for C i 2 H i 2 0 : 172.0888; found: 172.0889. 149 Anal, calcd for C i 2 H 1 2 0 : C 83.69, H 7.02; found: C 83.90, H 6.97. 150 4.3 Oxidative cleavage of tricyclic ketals and ketones to form functionalized cis-fused bicyclo[6.3.0]nndecane, bicyclo[6.4.0]dodecanes and bicyclo[7.4.0]tridecanes 4.3.1 Preparation of ketals from ketones. General Procedure 2. Conversion of ketones into ketals. To a solution of the appropriate tricyclic ketone (1 equiv) in dry benzene (0.1 M solution) was added 2,2-dimethyl-l,3-propanediol (2.5 equiv) and a catalytic amount of /?-toluenesulfonic acid. The mixture was heated at reflux under an atmosphere of argon with the use of a Dean-Stark trap for 17 h and then was cooled to room temperature. Water (-10 mL/mmol of ketone) was added and the mixture was extracted with Et 2 0 (3 x -10 mL/mmol of ketone). The combined organic extracts were washed with H 2 0 (-10 mL/mmol of ketone) and brine (-30 mL/mmol of ketone), were dried (MgS04) and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel. Preparation of cis-5', 5'-dimethylspiro[(tricyclo[6.4.0.&'6]dodec-2(6)-ene)-ll, 2'-(P, 3'-dioxane)] (131) 88 131 151 Following general procedure 2, the ketal 131 was prepared by heating at reflux a solution of the ketone 88 (175 mg, 0.991 mmol), 2,2-dimethyl-l,3-propanediol (258 mg, 2.48 mmol) and a catalytic amount of j>-toluenesulfonic acid (-10 mg) in benzene (10 mL). Purification of the crude material by flash column chromatography (20 g of silica gel, 1:50 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (85-90 °C/0.1 torr) of the acquired material provided 212 mg (82%) of the ketal 131 as a colourless oil. IR (neat): 1362, 1105, 1018 cm 4 . *H NMR (400 MHz, CDC13) 5: 0.93 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.15-1.23 (m, 1H), 1.50-1.78 (m, 3H), 1.82-1.97 (m, 2H), 2.01-2.20 (m, 8H), 2.44-2.53 (m, 1H), 2.54-2.65 (m, 1H), 3.40-3.51 (m, 4H, -CHb-O-). 1 3 C NMR (75.5 MHz, CDC13) 5: 22.7 (2C, -ve), 24.8, 27.6, 27.8, 29.6, 29.6, 30.1, 33.6, 33.7, 38.6 (-ve), 42.2 (-ve), 70.1, 70.1, 98.4, 144.0, 149.7. HRMS calcd for C i 7 H 2 6 0 2 : 262.1933; found: 262.1928. Anal, calcd for d 7 H 2 6 0 2 : C 77.82., H 9.99; found: C 78.02, H 9.96. Preparation ofcis-5', 5'-dimethylspiro[(8-methyltricyclo[6.4.0.02,6]dodec-2(6)-ene)-11, 2'-(P, 3'-dioxane)] (132) 89 132 152 Following general procedure 2, the ketal 132 was prepared by heating at reflux a solution of the ketone 89 (307 mg, 1.60 mmol), 2,2-dimethyl-l,3-propanediol (419 mg, 4.03 mmol) and a catalytic amount of /?-toluenesulfonic acid (-15 mg) in benzene (16 mL). Purification of the crude material by flash column chromatography (40 g of silica gel, 1:50 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (112-118 °C/0.1 torr) of the acquired material provided 347 mg (78%) of the ketal 132 as a colourless oil. IR (neat): 1360, 1113, 987 cm 1 . : H NMR (400 MHz, CDC13) 5: 0.93 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.06 (s, 3H, -CH3), 1.38-1.49 (m, 2H), 1.57-1.73 (m, 2H), 1.75-1.85 (m, 2H), 1.99-2.22 (m, 9H), 3.41-3.53 (m, 4H, -CH2-0-). 1 3 C NMR (75.5 MHz, CDC13) 5: 22.6 (-ve), 22.7 (-ve), 27.5, 28.2, 28.6 (-ve), 29.3, 29.8, 30.2, 32.7, 33.6, 42.4, 46.1, 46.3 (-ve), 70.2, 70.2, 98.3, 142.2, 148.8. HRMS calcd for C i 8 H 2 8 0 2 : 276.2089; found: 276.2083. Anal, calcd for C 1 8 H 2 8 0 2 : C 78.21, H 10.21; found: C 78.01, H 10.19. 153 Preparation of cis-5', 5'-dimethylspiro[(l, 8-dimethyltricyclo[6.4.0.(?,6]dodec-2(6)-ene)-11, 2'-(l',3'-dioxane)] (133) 90 133 Following general procedure 2, the ketal 133 was prepared by heating at reflux a solution of the ketone 90 (422 mg, 2.06 mmol), 2,2-dimethyl-l,3-propanediol (540 mg, 5.16 mmol) and a catalytic amount of /7-toluenesulfonic acid (-20 mg) in benzene (20 mL). Purification of the crude material by flash column chromatography (45 g of silica gel, 1:50 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (139-145 °C/0.1 torr) of the acquired material provided 495 mg (83%) of the ketal 133 as a colourless oil. IR (neat): 1356, 1115, 987 cm 1 . X H N M R (400 MHz, CDC13) 5: 0.84 (s, 3H, -CH3), 0.88 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 0.99 (s, 3H, -CH3), 1.28-1.35 (m, 1H), 1.49 (d, 1H, / = 15.0 Hz), 1.52-1.60 (m, 1H), 1.67-1.75 (m, 1H), 1.78-1.98 (m, 4H), 2.00-2.20 (m, 6H), 3.35 (dd, 1H, / = 1.0, 11.0 Hz, one of-CH2-O-), 3.41 (d, 1H, / = 1.0, 11.0 Hz, one of-CH2-O-), 3.48 (d, 1H, / = 11.0 Hz, one of-CH2-O-), 3.51 (d, 1H, J= 11.0 Hz, one of-CH2-O-). 1 3 C N M R (75.5 MHz, CDC13) 5: 21.9 (-ve), 22.5 (-ve), 22.6 (-ve), 22.6 (-ve), 26.6, 27.2, 30.0 (2C), 30.2, 33.6, 38.0, 42.3, 46.0, 48.3, 70.1, 70.3, 98.0, 139.5, 153.4. HRMS calcd for Q9H30O2: 290.2246; found: 290.2244. Anal, calcd for Q9H30O2: C 78.57, H 10.41; found: C 78.64, H 10.54. 154 Preparation of cis-5', 5'-dimethylspiro[(l-methyltricyclo[7.4.0.02,7]tridec-2(7)-ene)-12,2'-(r,3'-dioxane)](134) Following general procedure 2, the ketal 134 was prepared by heating at reflux a solution of the ketone 5443 (225 mg, 1.10 mmol), 2,2-dimethyl-l,3-propanediol (286 mg, 2.75 mmol) and a catalytic amount of p-toluenesulfonic acid (-10 mg) in benzene (11 mL). Purification of the crude material by flash column chromatography (20 g of silica gel, 1:19 Et20-petroleum ether) and subsequent bulb-to-bulb distillation of the acquired material (105-110 °C/0.1 torr) provided 288 mg (90%) of the ketal 134 as a colourless oil. IR (neat): 1363, 1113, 988 cm 1 . lR N M R (400 MHz, CDC13) 5: 0.80-0.90 (m, 1H), 0.90 (s, 3H, -CH3), 1.00 (s, 3H, -CH3), 1.05 (s, 3H, -CH3), 1.30 (d, 1H, / = 14.0 Hz), 1.44-1.95 (m, 13H), 1.95-2.15 (m, 2H), 3.35-3.43 (m, 2H, -CH2-O-), 3.49 (d, 1H, / = 16.0 Hz, one of-CH2-O-), 3.52 (d, 1H, / = 16.0 Hz, oneof-CH2-0-). 1 3 C N M R (75.5 MHz, CDC13) 8: 21.7, 22.6 (-ve), 22.8 (-ve), 22.9, 23.1, 23.2, 24.6 (-ve), 25.9, 30.1, 30.2, 37.6, 38.6, 43.7 (-ve), 47.4, 69.9, 70.0, 98.1, 131.1, 143.2. HRMS calcd for C19H30O2: 290.2246; found: 290.2243. 54 134 155 Anal, calcd for C 1 9 H 3 o0 2 : C 78.57, H 10.41; found: C 78.59, H 10.37. 4.3.2 Preparation of ketal diones via oxidative cleavage Preparation of cis-5', 5'-dimethylspiro[(bicyclo[6.4.0]dodecane-2, 6-dione)-ll, 2'-(V, 3'-dioxane)] (135) Into a cold (-78 °C), stirred solution of the ketal 131 (88.5 mg, 0.337 mmol) in methanol (6 mL) was passed ozone in a stream of oxygen gas for approximately 10 min. The reaction mixture turned a pale blue colour, indicating the presence of excess ozone in the mixture. An excess of dimethyl sulfide (~1 mL) was added. The reaction flask innlet was covered with a septum, and the reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the remaining crude solid was purified by flash column chromatography (8 g of silica gel, Et 20) to provide 100.0 mg (100%) of the ketal dione 135 as a colourless solid (mp. 162-163 °C). 3 131 135 fR(KBr): 1694, 1448, 1170, 1094 cm 1 . 156 lK NMR (400 MHz, CDC13) 8: 0.84 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 1.32-1.47 (m, 2H), 1.58 (dm, 1H, / for d = 13.0 Hz), 1.89-2.06 (m, 4H), 2.12 (dd, 1H, / = 2.5, 15.0 Hz), 2.20-2.28 (m, 2H), 2.44 (ddd, 1H, / = 2.5, 2.5, 15.0 Hz), 2.62-2.86 (rn, 4H), 3.21 (br d, 1H, / = 13.0 Hz, -CH-C(O)), 3.34 (dd, 1H, / = 1.0, 11.5 Hz, one of -CH2-O-), 3.40 (d, 1H, J= 11.5 Hz, one of-CH2-O-), 3.42 (dd, 1H, / = 1.0, 11.5 Hz, one of-CH2-O-), 3.60 (d, 1H, / = 11.5 Hz, one of -CH2-O-). 1 3 C NMR (75.5 MHz, CDC13) 8: 22.4 (-ve), 22.8 (-ve), 25.3, 25.4, 28.6 (-ve), 28.7, 28.8, 30.1, 39.5, 39.9, 45.6, 51.2 (-ve), 69.8, 69.9, 97.4, 211.6, 212.3. HRMS calcd for C i 7 H 2 6 0 4 : 294.1831; found: 294.1830. Anal, calcd for C 1 7 H 2 6 0 4 : C 69.34, H 8.92; found: C 69.32, H 8.77. Preparation ofcis-5', 5'-dimethylspiro[(8-methylbicyclo[6.4.0]dodecane-2, 6-dione)-11, 2'-(P, 3'-dioxane)] (136) To a heterogeneous mixture of the ketal alkene 132 (91.0 mg, 0.329 mmol) in C H 3 C N (1.5 mL), CCL, (1.5 mL) and water (2.3 mL) was added sodium periodate (296 mg, 1.38 mmol) and a catalytic amount of R u 0 2 x H 2 0 (1.2 mg, 0.0077 mmol based on x = 1). The mixture, open to the atmosphere, was stirred vigorously for 15 rriin at room temperature. 132 136 157 Water (10 mL) was added and the mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were washed with H 2 0 (10 mL), dried (MgS0 4), and concentrated under reduced pressure. The residual material was filtered through a Pasteur pipette containing flash silica gel and the pipette was eluted with Et 2 0. The eluate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (5 g of silica gel, Et 20) to afford 96.3 mg (95%) of the ketal dione 136 as a colourless solid (mp. 148-151 °C). IR (KBr): 1685, 1455,1373, 1103 cm"1. J H NMR (400 MHz, CDC13) 8: 0.90 (s, 3H, -CH3), 0.99 (s, 3H, -CH3), 1.04 (s, 3H, -CH3), 1.36 (ddd, 1H, / = 3.5, 3.5, 13.0 Hz), 1.43-1.64 (m, 2H), 1.75 (d, 1H, / = 12.0 Hz, H-7), 1.91-2.01 (m, 1H), 2.14-2.25 (m, 3H), 2.25-2.40 (m, 3H), 2.44 (dd, 1H, J= 3.5, 14.0 Hz), 2.53 (dd, 1H, J = 9.0, 12.5 Hz), 2.86 (ddd, 1H, / = 3.5, 7.0, 13.0 Hz), 3.35-3.45 (m, 3H, one of -CH 2-C(0) and -CH2-O-), 3.48 (dd, 1H, / = 1.0, 11.5 Hz, one of -CH2-O-), 3.59 (d, 1H, / = 11.5 Hz, one of-CH 2-0-). 1 3 C NMR (75.5 MHz, CDC13) 5: 22.5 (-ve), 22.7 (-ve), 23.0, 27.0 (-ve), 27.2, 30.2, 32.6, 37.2, 40.1, 41.4, 44.4, 46.1, 55.3 (-ve), 69.9, 70.3, 96.9, 212.0, 212.5. HRMS calcd for C i 8 H 2 8 0 4 : 308.1988; found: 308.1981. Anal, calcd for C 1 8 H 2 8 0 4 : C 70.10, H 9.15; found: C 70.09, H 9.10. 158 Preparation of cis-5', 5'-dimethylspiro[(l, 8-dimethylbicyclo[6.4.0]dodecane-2, 6-dione)-ll,2'-(r, 3'-dioxane)J (137) 133 137 To a heterogeneous mixture of the ketal alkene 133 (101.9 mg, 0.3508 mmol) in C H 3 C N (1.6 mL), CCU (1.6 mL) and water (2.4 mL) was added sodium periodate (312.5 mg, 1.462 mmol) and a catalytic amount of R u 0 2 x H 2 0 (1.5 mg, 0.0097 mmol based on x = 1). The mixture, open to the atmosphere, was stirred vigorously for 15 min at room temperature. Water (10 mL) was added and the mixture was extracted with CH 2 C1 2 (3 x 10 mL). The combined organic extracts were washed with H 2 0 (10 mL), dried (MgSCU), and concentrated under reduced pressure. The residual material was filtered through a Pasteur pipette containing flash silica gel and the pipette was eluted with E t 2 0 . The eluate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (5 g of silica gel, Et 2 0) to afford 94.1 mg (83%) of the ketal dione 137 as a colourless solid (mp. 161-163 °C). IR(KBr): 1688, 1471,1375, 1203, 1107 cm 1 . *H N M R (400 MHz, CDC13) 8: 0.93 (s, 3H, -CH3), 0.98 (s, 3H, -CH3), 1.04 (s, 3H, -CH3), 1.17-1.20 (m, 1H; s, 3H, -CH3, (8 1.19)), 1.57 (ddd, 1H, / = 4.0, 4.0, 14.0 Hz), 1.70 (d, 1H, / = 12.0 Hz), 1.84 (ddd, 1H, / = 4.0, 4.0, 14.0 Hz), 2.01-2.12 (m, 2H), 2.18-2.28 (m, 1H), 2.28-2.46 (m, 5H), 3.01-3.07 (m, 1H), 3.40-3.46 (m, 3H), 3.51 (d, 1H, / = 11.5 Hz), 3.57 (d, l H , / = 11.5 Hz). 159 1 3 C NMR (75.5 MHz, CDC13) 5: 20.4 (-ve), 22.6 (-ve), 22.7 (-ve, 2C), 22.8, 29.0, 30.1, 36.5, 36.6, 39.7, 39.9, 43.7,47.3, 53.0, 69.9, 70.3, 97.3, 211.7,215.1. HRMS calcd for C19H30O4: 322.2144; found: 322.2140. Anal, calcd for C 1 9 H 3 o0 4 : C 70.77, H 9.38; found: C 70.93, H 9.42. Preparation ofcis-5', 5'-dimethylspiro[(l-methylbicyclo[7.4.0]tridecane-2,7-dione)-12, 2'-(!', i'-dioxane)] (141) To a heterogeneous mixture of the ketal-alkene 134 (70.0 mg, 0.241 mmol) in C H 3 C N (1.2 mL), CCI4 (1.2 mL) and water (1.8 mL) was added sodium periodate (216 mg, 1.01 mmol) and a catalytic amount of R u 0 2 x H 2 0 (0.9 mg, 0.0058 mmol based on x = 1). The mixture, open to the atmosphere, was stirred vigorously for 1 h at room temperature. Water (10 mL) was added and the mixture was extracted with CH 2 C1 2 (3 x 10 mL). The combined organic extracts were washed with H 2 0 (10 mL), dried (MgSC^), and concentrated under reduced pressure. The residual material was filtered through a Pasteur pipette containing flash silica gel and the pipette was eluted with Et 2 0. The eluate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (5 g of silica gel, 1:1 Et20-petroleum ether) to afford 62.6 mg (81%) of the ketal dione 141 as a colourless solid (mp. 159-160 °C). 134 141 160 IR(KBr): 1693, 1441, 1104 cm' 1. : H N M R (400 MHz, CDC13) 8: 0.82 (s, 3H, -CH3), 1.00 (s, 3H, -CH 3 ) , 1.20-1.25 (m, 1H; s, 3H, - C H 3 , (5 1.22)), 1.40-1.55 (m, 1H), 1.58 (dm, 1H, / fo r d = 14.0 Hz), 1.69 (d, 1H, / = 15.0 Hz), 1.76-1.85 (m, 3H), 1.95 (dm, 1H, / for d = 14.0 Hz), 2.11-2.28 (m, 4H), 2.28-2.42 (m, 3H), 2.44-2.52 (m, 1H), 2.60 (dd, 1H, / = 8.0, 14.0 Hz), 3.34 (dd, 1H, / = 2.0, 11.5 Hz, one of-CH2-O), 3.40 (dd, 1H, / = 2.0, 11.5 Hz, one of-CH2-O), 3.47 (d, 1H, / = 11.5 Hz, one of -CH 2 -0) , 3.69 (d, 1H, / = 11.5 Hz, one of -CH2-O). 1 3 C N M R (75.5 MHz, CDC13) 8: 21.9 (-ve), 22.0, 22.4 (-ve), 22.9 (-ve), 24.6, 27.2, 30.0, 30.9, 33.8, 40.9 (-ve), 43.5, 43.8, 51.9, 69.9 (2C), 70.0, 97.7, 215.1, 217.2. HRMS calcd for C19H30O4: 322.2144; found: 322.2139. Anal, calcd for Q9H30O4: C 70.77, H 9.38; found: C 70.88, H 9.38. 161 4.3.3 Preparation of triketones via oxidative cleavage General Procedure 3: Ruthenium tetroxide catalyzed oxidation75 of alkenes to form diones To a heterogeneous mixture of the appropriate alkene (1 equiv) in acetonitrile, carbon tetrachloride and water (in 1:1:1.5 v/v ratio) was added sodium periodate (-4.2 equiv) and a catalytic amount of ruthenium dioxide x-hydrate (-2-3 mol%, based on ruthenium dioxide monohydrate, x = 1). The mixture, open to the atmosphere, was stirred vigorously for 15 min at room temperature. Water (10 mL) was added and the mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were washed with H 2 0 (10 mL), dried (MgS0 4), and concentrated under reduced pressure. The residual material was filtered through a Pasteur pipette containing flash silica gel and the pipette was eluted with a 1:1 mixture of CH^Ck-Et^O. The combined eluate was concentrated under reduced pressure and the crude material was purified by flash column chromatography on silica gel. Preparation of cis-bicyclo[6.4.0]dodecane-2,6,l 1-trione (142) O 88 142 162 Following general procedure 3, the alkene 88 was converted into the trione 142 with the following amounts of solvents and reagents: alkene 88 (176.5 mg, 1.001 mmol), NaI04 (898 mg, 4.20 mmol), R u 0 2 x H 2 0 (3.7 mg, 0.024 mmol based on x = 1), C H 3 C N (5 mL), CCI4 (5 mL) and H 2 0 (7.5 mL). The crude solid was purified by flash column chromatography (15 g of silica gel, 1:1 CH 2 C1 2 -Et 2 0) to afford, upon removal of solvent, 197.5 mg (95%) of the trione 142 as a colourless solid (mp. 129-131 °C). IR (KBr): 1693, 1466, 1341, 1159 cm' 1. T i N M R (400 MHz, CDC13) 5: 1.85-2.22 (m, 4H), 2.24-2.49 (m, 6H), 2.50-2.62 (m, 2H), 2.68-2.78 (m, 2H), 2.90-2.99 (m, 1H), 3.25 (ddd, 1H, / = 4.5, 4.5, 7.0 Hz, CH-C(O)-). 1 3 C N M R (75.5 MHz, CDC13) 8: 23.1, 29.5, 32.4 (-ve), 38.1, 39.4, 42.3, 42.8, 44.6, 50.9 (-ve), 208.5,211.2,211.8. HRMS calcd for C i 2 H i 6 0 3 : 208.1099; found: 208.1102. Anal, calcd for C 1 2 H 1 6 0 3 : C 69.21, H 7.74; found: C 69.19, H 7.76. Preparation of cis-8-methylbicyclo[6.4.0Jdodecane-2,6,11-trione (143) O 89 143 163 Following general procedure 3, the alkene 89 was converted into the trione 143 with the following amounts of solvents and reagents: alkene 89 (144.8 mg, 0.7609 mmol), NaI04 (683 mg, 3.20 mmol), R u 0 2 x H 2 0 (2.8 mg, 0.018 mmol based on x = 1), C H 3 C N (3.5 mL), CCI4 (3.5 mL) and H 2 0 (5.3 mL). The crude solid was purified by flash column chromatography (14 g of silica gel, 1:1 CH 2 C1 2 -Et 2 0) to afford, upon removal of solvent, 159.6 mg (94%) of the trione 143 as a colourless solid (mp. 118-119 °C). IR (KBr): 1698, 1369, 1252, 1150 cm"1. *H N M R (400 MHz, CDC13) 5: 1.37 (s, 3H,-CH3), 1.52 (ddt, 1H, / = 13.5, 6.0, 2.0 Hz), 2.05-2.16 (m, 3H), 2.24-2.60 (m, 10 H), 3.18 (br d, 1H, / = 8.0 Hz). 1 3 C N M R (75.5 MHz, CDC13) 8: 20.9, 25.3 (-ve), 32.8, 36.2, 36.6, 39.0, 45.1, 45.8, 51.2, 52.8 (-ve), 207.5, 210.6,214.3. HRMS calcd for C 1 3 H i 8 0 3 : 222.1256; found: 222.1259. Anal, calcd for C i 3 H i 8 0 3 : C 70.24, H 8.16; found: C 70.10, H 8.06. Preparation of cis-1,8-dimethylbicyclo[6.4.0]dodecane-2,6,l 1-trione (144) O Following general procedure 3, the alkene 90 was converted into the trione 144 with the following amounts of solvents and reagents: alkene 90 (63.8 mg, 0.312 mmol), NaI0 4 90 144 164 (280 mg, 1.31 mmol), R u 0 2 x H 2 0 (1.4 mg, 0.018 mmol based on x = 1), C H 3 C N (1..5 mL), C C L (1.5 mL) and H 2 0 (2.3 mL). The crude solid was purified by flash column chromatography (4.5 g of silica gel, 1:1 CH 2C1 2-Et 20) to afford, upon removal of solvent, 67.5 mg (91%) of the trione 144 as a colourless solid (mp. 154-156 °C). IR (KBr): 1698, 1321, 1143 cm 1 . ! H NMR (400 MHz, CDC13) 5: 1.23 (s, 3H, -CH3), 1.44 (s, 3H, -CH3), 1.62 (ddd, 1H, / = 3.0, 6.0, 14.5 Hz), 1.95-2.20 (m, 4H), 2.20-2.47 (m, 6H), 2.48-2.58 (m, 1H), 2.98-3.06 (m, 2H). 1 3 C NMR (75.5 MHz, CDC13) 8: 20.8 (-ve), 23.3, 23.9 (-ve), 33.6,36.8, 39.4, 40.3, 45.0, 48.5, 48.8, 56.1, 207.5, 210.9, 215.9. HRMS calcd for C 1 4 H 2 0 O 3 : 236.1413; found: 236.1415. Anal, calcd for C 1 4 H 2 0 O 3 : C 71.16, H 8.53; found: C 70.95, H 8.47. Preparation ofcis-bicyclo[6.3.0]undecane-2,6,10-trione (145) O O 91 145 Following general procedure 3, the alkene 91 was converted into the trione 145 with the following amounts of solvents and reagents: alkene 91 (25.1 mg, 0.155 mmol), NaI0 4 165 (139 mg, 0.650 mmol), R u 0 2 x H 2 0 (0.5 mg, 0.003 mmol based on x = 1), C H 3 C N (0.7 mL), CCLj (0.7 mL) and H 2 0 (1 mL). The crude solid was purified by flash column chromatography (4 g of silica gel, 1:1 CH 2C1 2-Et 20) to afford, upon removal of solvent, 23.7 mg (79%) of the trione 145 as a colourless solid (mp. 132-133 °C). IR (KBr): 1762, 1697, 1444, 1326, 1158 cm 1 . lH NMR (400 MHz, CDC13) 5: 2.11-2.26 (m, 4H), 2.35-2.59 (m, 6H), 2.59-2.75 (m, 2H), 3.02-3.13 (m, 1H), 3.48-3.56 (m, 1H). 1 3 C NMR (100.6 MHz, CDC13) 8: 22.9, 37.1 (-ve), 40.1, 42.3, 43.7, 43.7, 43.9, 49.0 (-ve), 211.5,213.3,214.3. HRMS calcd for C n H i 4 0 3 : 194.0943; found: 194.0946. Anal, calcd for C n H 1 4 0 3 : C 68.02, H 7.27; found: C 67.98, H 7.10. Preparation ofcis-l-methylbicyclo[7.4.0]tridecane-2,7,12-trione (146) Following general procedure 3, the alkene 54 4 3 was converted into the trione 146 with the following amounts of solvents and reagents: alkene 54 (79.3 mg, 0.388 mmol), NaI0 4 O 54 146 166 (348 mg, 1.63 mmol), R u 0 2 x H 2 0 (1.5 mg, 0.0097 mmol based on x = 1), C H 3 C N (1.9 mL), CCU (1.9 mL) and H 2 0 (2.9 mL). The crude solid was purified by flash column chromatography (6 g of silica gel, 1:1 CH 2C1 2-Et 20) to afford, upon removal of solvent, 80.1 mg (87%) of the trione 1 4 6 as a colourless solid (mp. 136-138 °C). IR (KBr): 1705, 1697, 1418, 1332, 1162, 1030 cm"1. : H NMR (400 MHz, CDC13) 8: 1.13 (s, 3H, CH3), 1.52-1.61 (m, 1H), 1.82-1.91 (m, 2H), 1.98-2.30 (m, 9H), 2.38-2.55 (m, 3H), 2.83 (dd, 1H, / = 8.5, 13.5 Hz), 2.90 (d, 1H, / = 15.0 Hz). 1 3 C NMR (75.5 MHz, CDC13) 8: 21.8, 22.8 (-ve), 25.2, 30.5, 34.6, 36.8, 40.3 (-ve), 43.3, 44.4, 45.0, 55.3, 210.9, 212.9, 216.3. HRMS calcd for C i 4 H 2 0 O 3 : 236.1413; found: 236.1421. Anal, calcd for C i 4 H 2 0 O 3 : C 71.16, H 8.53; found: C 71.09, H 8.55. 167 4.4. Aldol Condensations Preparation of 2,9-dimethyltricyclo[5.5.0.&'9]dodecane-3,12-dion-l-ol (147) O A OH 144 147 To a solution of the triketone 144 (12.2 mg, 0.052 mmol) in dry THF (2 mL) was added a catalytic amount of /?-toluenesulfonic acid (-0.5 mg). The mixture was stirred under reflux for 17 h and then was allowed to cool to room temperature. Water (10 mL) was added and the mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were dried (MgS04) and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (1 g of silica gel, 1:1 Et 2 0-EtOAc) to afford 11.8 mg (97%) of the dione alcohol 147 as a white solid. A small amount of the solid was recrystallized from Et 2 0 (mp. 132-133 °C) and the acquired material was subjected to X-ray crystallographic analysis (see Appendix). IR (KBr): 3406, 1701, 1234, 1035 cm 1 . J H NMR (400 MHz, CDC13) 8: 0.92 (s, 3H, -CH3), 1.01 (s, 3H, -CH,), 1.54-1.67 (m, 2H, H-5, H-10), 1.70-1.80 (br signal, 1H, -OH), 1.82-2.00 (m, 6H, H-5', H-6, H-6', H-8, H-8', H-10'), 2.29-2.39 (m, 2H, H-4, H-l l ) , 2.60-2.70 (m, 1H, H-4'), 2.90 (ddd, 1H, / = 10.5, 10.5, 18.0 Hz, H-ll'), 2.95 (s, 1H, H-l). 168 1 3 C NMR (75.5 MHz, CDC13) 5: 17.3 (-ve), 20.7, 22.7 (-ve), 34.8, 35.7, 41.7, 42.6, 45.8, 47.7, 59.5, 70.7 (-ve), 79.3, 211.1, 214.6. HRMS calcd for Ci 4 H 2 o0 3 : 236.1413; found: 236.1415. Anal, calcd for C14H20O3: C 71.16, H 8.53; found: C 70.78, H 8.60. Table 11. *H NMR (400 MHz, CDC13) data for the dione alcohol 147: COSY Experiment. 147 Assignment H-x ' H N M R 8 (multiplicity, / (Hz)) COSY Correlations3 H - l 2.95 (s) H-4 part of mat 2.29-2.39 H-4", H-5 H-4' 2.60-2.70 (m) H-4, H-5 H-5 part of mat 1.54-1.67 H-5', H-6, H-6', H-8, H-8', H-10' part of mat 1.82-2.00 H-10 part of mat 1.54-1.67 H - l l , H - l l ' H - l l part of mat 2.29-2.39 H-10, H - l l ' H-1T 2.90 (ddd,/= 10.5, 10.5, 18.0) H-10 ,H- l l OH 1.70-1.80 (br signal) Me-13, Me-14 0.92, 1.01 Only those correlations which can be assigned unambiguously are reported. 169 Table 12. 1 3 C (125.8 MHz, CDC13) and *H N M R (500 MHz) data for the dione alcohol 147: H M Q C and H M B C Experiments ^ Me13,, 14 O I Me OH 147 Assignment 1 3 C APT H M Q C H M B C C-x N M R *H N M R Correlations J H N M R Correlations 8 ppm (8 ppm) (8 ppm)a C-13 17.3 C H or CH 3 Me-13 (0.92) C-5 20.7 C or CH 2 H-5 (part of mat 1.54-1.67), H-5' (-1.9 ppm) (part of mat 1.82-2.00) C-14 22.7 C H or CH 3 Me-14(1.01) C-10 34.8 C or CH 2 H-10 (part of mat 1.54-1.67), H-10' (-1.85 ppm) (part of mat 1.82-2.00) C - l l 35.7 C or CH 2 H-11 (part of m at 2.29-2.39), H-11' (2.90) C-4 41.7 C or CH 2 H-4 (part of mat 2.29-2.39), H-4' (2.60-2.70) C-6 42.6 C or CH 2 H-6, H-6' (part of m at 1.82-2.00) C-9 45.8 C or C H 2 C-8 47.7 C or CH 2 H-8, H-8' (part of mat 1.82-2.00) Me-14(1.01) C-2 59.5 C or C H 2 C - l 70.7 CH or C H 3 H - l (2.95) Me-13 (0.92) C-7 79.3 C or C H 2 C-12 211.1 C or C H 2 H - l (2.95), H-11 (part of mat 2.29-2.39), H - l 1'(2.90) C-3 214.6 C or C H 2 Me-13 (0.92), H - l (2.95), H-4 (part o fm at 2.29-2.39), H-4' (2.60-2.70) 'Only relevant correlations are reported 170 Preparation of 9-methyltricyclo[5.5.0.02,9]dodecane-3,12-dion-l-ol (148) O 143 148 To a solution of the triketone 143 (31.4 mg, 0.141 mmol) in dry THF (5 mL) was added a catalytic amount of /)-toluenesulfonic acid (-0.5 mg). The mixture was stirred under reflux for 48 h and then was allowed to cool to room temperature. Water (10 mL) was added and the mixture was extracted with CH 2 C1 2 (3 x 10 mL). The combined organic extracts were dried (MgS0 4) and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (3 g of silica gel, 1:1 Et 2 0-EtOAc) to afford 29.4 mg (94%) of the dione alcohol 148 as a white solid. A small amount of the solid was recrystallized from Et 2 0 (mp. 142-143 °C) and the acquired material was submitted for X-ray crystallographic analysis (see Appendix). IR(KBr): 3382, 1716, 1690, 1207, 1061 cm 1 . *H NMR (400 MHz, CDC13) 5: 1.11 (s, 3H, -CH3), 1.55-2.50 (m, 9H), 2.35 (s, 1H), 2.37-2.56 (m, 3H), 2.86 (ddd, 1H, / = 9.5, 12.0, 17.5 Hz), 2.95 (s, 1H). 1 3 C NMR (75.5 MHz, CDC13) 5: 19.5, 23.6(-ve), 36.2, 41.0, 42.7, 43.5, 45.5, 46.2, 62.6 (-ve), 65.7(-ve), 82.6, 209.9, 210.7. HRMS calcd for C i 3 H 1 8 0 3 : 222.1256; found: 222.1253. Anal, calcd for C 1 3 H 1 8 0 3 : C 70.24, H 8.16; found: C 70.15, H 8.02. 171 Preparation of tricyclolS.S.O.O2,9]dodecane-3,12-dion-l-ol (149) O To a solution of the triketone 142 (36.8 mg, 0.177 mmol) in dry THF (5 mL) was added a catalytic amount of p-toluenesulfonic acid (-0.5 mg). The mixture was stirred under reflux for 3 days until no further progress was observed by T L C analysis. The reaction mixture was allowed to cool to room temperature. Water (10 mL) was added and the mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were dried (MgSQ*) and the solvent was removed under reduced pressure. The resulting crude material was purified by flash column chromatography (3 g of silica gel, 1:1 Et 2 0-EtOAc) to afford 17.0 mg (46%) of the dione alcohol 149 as a white solid (mp. 124-126 °C). A significant amount of starting material (19.3 mg (52%)), which displayed properties (mp. 128-130 °C; *H, 1 3 C NMR) identical with those of 142, was also isolated. IR (KBr): 3436, 1698, 1244, 1201, 1147, 1061 cm'1. 'H NMR (400 MHz, CDC13) 5: 1.50-1.65 (m, 1H), 1.70 (d, 1H, / = 15.0 Hz), 1.82-2.06 (m, 5H), 2.18 (dd, 1H, / = 7.5, 15.0 Hz), 2.22 (br signal, 1H), 2.31-2.44 (m, 2H), 2.46 (s, 1H), 2.62 (ddd, 1H, / = 2.5, 13.0, 13.0 Hz), 2.71-2.74 (m, 1H), 2.81 (ddd, 1H, / = 9.5, 12.0, 17.5 Hz), 3.00 (s, 1H). 1 3 C NMR (75.5 MHz, CDC13) 5: 21.5, 31.5, 35.7, 37.9, 41.7 (2C, one -ve), 42.9, 58.9 (-ve), 65.1(-ve), 82.0, 210.2, 213.5. 172 HRMS calcd for C i 2 H 1 6 0 3 : 208.1099; found: 208.1108. Anal, calcd for C i 2 H 1 6 0 3 : C 69.21, H 7.74; found: C 69.15, H 7.70. Preparation ofcis-l-methyltricyclo[7.4.0.02,6]tridec-2(6)-ene-7,12-dione (151) 146 To a solution of the triketone 146 (17.2 mg, 0.0728 mmol) in dry THF (2.5 mL) was under reflux for 22 h and then was allowed to cool to room temperature. Water (10 mL) added a catalytic amount of p-toluenesulfonic acid (-0.5 mg). The mixture was stirred was added and the mixture was extracted with CH 2 C1 2 (3 x 10 mL). The combined organic extracts were dried (MgSC^) and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (5 g of silica gel, 7:3 Et20-petroleum ether) to afford 13.6 mg (79%) of compound 151 as a colourless oil, as well as 2 mg of unreacted starting material. IR(film): 1713, 1664, 1387, 1240 cm 1 . *H NMR (400 MHz, CDC13) 5: 1.26 (s, 3H, -CHj), 1.75-1.89 (m, 3H, H-4, H-4', H-10), 2.02-2.10 (m, 1H, H-10'), 2.26-2.38 (m, 4H, H-9, H-13, H - l l , H-ll') , 2.45-2.59 (m, 6H, H-8, H-5, H-5', H-3, H-3', H-13'), 2.66 (dd, 1H, / = 4.5, 17.0 Hz, H-8'). 173 1 3 C NMR (75.5 MHz, CDC13) 6: 21.5, 26.1(-ve), 28.7, 29.4, 33.3, 39.0, 40.4, 41.3, 42.5 (-ve), 49.5, 136.4, 168.1, 195.8,209.5. HRMS calcd for C i 4 H 1 8 0 2 : 218.1307; found: 218.1313. Table 13. Selected 1 3 C (125.8 MHz, CDC13) and lH NMR (500 MHz) data for the dione 151: H M Q C and H M B C Experiments O 151 Assignment 13C APT H M Q C H M B C C-x NMR *H NMR Correlations *H NMR Correlations3 8 ppm (8 ppm) (8 ppm) C-4 21.5 C or CH 2 H-4, H-4' (part of m at 1.75-1.89) C-14 26.1 C H or CH 3 Me-14(1.26) C-10 28.8 C or CH 2 H-10 (part of mat 1.75-1.89), H-10' (2.02-2.10) H-8' (2.66) C-3 or C-5 29.4 C or CH 2 H-3,H-3* or H-5, H-5' (part ofm at 2.45-2.59) H-4, H-4' (part of m at 1.75-1.89) C-5 or C-3 33.3 C or CH 2 H-3, H-3' or H-5, H-5' (part of mat 2.45-2.59) H-4, H-4' (part of m at 1.75-1.89) C - l l 39.0 C or CH 2 H - l l , H - l T (part ofm at 2.26-2.38) H-10 (part ofm at 1.75-1.89), H-10' (2.02-2.10) C-8 40.4 C or CH 2 H-8 (part ofm at 2.45-2.59) H-8' (2.66) H-10 (part ofm at 1.75-1.89), H-10' (2.02-2.10) C-9 41.4 CH or C H 3 H-9 (part of mat 2.26-2.38) Me-14(1.26), H-10 (part of mat 1.75-1.89), H-8' (2.66) 174 C - l 42.5 C or C H 2 Me-14 (1.26), H-10 (part of mat 1.75-1.89), H-10' (2.02-2.10), H-8' (2.66) C-13 49.5 C or C H 2 H-13 (part of mat 2.26-2.38), H-13' (part of mat 2.45-2.59) Me-14 (1.26) C-6 136.4 C or C H 2 H-4, H-4' (part of mat 1.75-1.89) C-2 168.1 C or C H 2 Me-14 (1.26), H-4, H-4' (part of mat 1.75-1.89) C-7 195.8 C or C H 2 H-8' (2.66) C-12 209.5 C or C H 2 H-10 (part of mat 1.75-1.89), H-10' (2.02-2.10) Only those correlations which can be assigned unambiguously are reported. 175 4.5. Synthesis of (±)-l-desoxyhypnophilin (61) and (±)-6,7-epoxy-4(15)-hirsuten-5-ol (62) Preparation of2-diazo-5,5-dimethyl-l,3-cyclohexanedione (180)95-96 180 To a cool (0 °C), stirred suspension of dimedone (19.0 g, 0.136 mol) and j9-toluenesulfonyl azide (26.8 g, 0.136 mol) (prepared from /7-toluenesulfonyl chloride and sodium azide) in dry Et 2 0 (500 mL) was added triethylarnine (37.9 mL, 0.272 mol). The mixture was stirred for 10 min at 0 °C and was warmed to room temperature for 45 min. Aqueous NaHC03 (10%, 250 mL) was added and the layers were separated. The aqueous phase was extracted with Et 2 0 (3 x 250 mL) and the combined organic extracts were washed with H 2 0 (2 x 500 mL), brine (500 mL), dried (MgSC^), and concentrated under reduced pressure. The resulting crude material was recrystallized three times from ethanol at -25 °C (freezer) to provide 14.2 g (63%) of slightly yellow needle-like crystals. Diazodimedone (180) displayed melting point, IR and *H NMR properties as reported in the literature96 (mp. 106-108 °C, lit. mp. 106-108 °C). IR (KBr): 2146, 1636, 1309 cm"1. X H NMR (400 MHz, CDC13) 5: 1.10 (s, 6H, 2 x CH3), 2.43 (s, 4H, 2 x CHz) 176 Preparation of methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate (178)95> N2 O 180 178 Following the literature procedure, a 1 L , three-necked, pyrex vessel equipped with a stirring bar, a 450 W mercury lamp (water cooled, pyrex filter) in the center, and a gas outlet, was charged with diazodimedone (180) (12.1 g, 73.0 mmol), dry THF (800 mL) and dry MeOH (20 mL). The mixture was purged with nitrogen gas and was irradiated. The progress of the reaction was monitored by TLC. After 3 hours, the solvent was removed under reduced pressure and the residual material was purified by bulb-to-bulb distillation (92-100 °C/1.0 torr) to yield 10.95 g (89%) of the B-keto ester 178 as a colourless oil. This material (178) displayed IR and *H N M R similar to those reported previously in the literature.95 The updated spectral data is presented below. IR(neat): 1756, 1729, 1650, 1437, 1311, 1120, 1043 cm 1 . lH N M R (400 MHz, CDC13) 5: 1.04 (s, 3H, -CH3), 1.21 (s, 3H, -CH3), 2.12 (dd, 1H, / = 9.0, 13.0 Hz, one of -CH2-CH), 2.17-2.20 (m + s (5 2.19), 3H, C-CH2-C(0) + one of -CH2-CH), 3.37 (dd, 1H, / = 9.0, 11.0 Hz, -CH 2 -CH), 3.72 (s, 3H, -COzCHj). 1 3 C N M R (50.3 MHz, CDC13) 5: 27.6, 28.9, 34.5, 40.7, 52.5, 53.0, 54.2, 169.9, 203.1. 177 Preparation of methyl 4,4-dimethyl-2-trifluoromethanesulfonyloxycyclopent-l-enecarboxylate (181) O CF 3 SO ; C02Me 178 181 To a cool (0 °C), stirred suspension of K H (2.73 g of 35 wt% dispersion in mineral oil, washed twice with dry THF (20 mL) and dried under vacuum, 23.8 mmol) in dry THF (150 mL), was added a solution of methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate (178) (3.36 g, 19.8 mmol) in dry THF (50 mL). The mixture was stirred for 30 min. Solid 7Y-phenyltrMuoromethanesulfonimide (8.50 g, 23.8 mmol) was added and the reaction mixture was stirred for 30 min at 0 °C and at room temperature for 90 min. The reaction mixture was diluted with E t 2 0 (200 mL) and filtered through a cake of silica gel (-40 g) and Celite® (-40 g). The cake was eluted thoroughly with E t 2 0 and the combined filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (200 g of silica gel, 1:9 Et20-petroleum ether) to afford, after concentration of appropriate fractions, 5.99 g (85%) of the triflate 181 as a colourless oil. IR (neat): 1729, 1671, 1429, 1347, 1213, 1142 cm 1 . *H N M R (400 MHz, CDC13) 8: 1.15 (s, 6H, 2 x -CH3), 2.47 (t, 2H, J = 2.5 Hz), 2.54 (t, 2H, / = 2.5 Hz), 3.76 (s, 3H, -C0 2 CH3). 1 3 C N M R (75.5 MHz, CDC13) 8: 29.3 (-ve, 2C), 35.2, 43.8, 47.1, 51.8 (-ve), 118.3 (q, / = 319 Hz, -CF 3 ) , 121.8, 151.9, 162.7. HRMS calcd for C i 0 H 1 3 O 5 S F 3 : 302.0436; found: 302.0436. 178 Anal, calcd for d o H ^ C ^ : C 39.73, H 4.34; found: C 39.67, H 4.28. Preparation of methyl 4,4-dimethyl-2-trimethylstannylcyclopent-l-enecarboxylate (177) To a cold (-48 °C), stirred solution of hexamethylditin (7.28 g, 22.2 mmol) in dry THF (200 mL) was added MeLi (1.60 M solution in Et 2 0, 14 mL, 22.2 mmol). The mixture was stirred for 30 min. Solid CuCN (1.99 g, 22.2 mmol) was added and the mixture was stirred for 30 min. A solution of the triflate 181 (4.96 g, 16.4 mmol) in dry THF (20 mL) was added dropwise and the mixture was stirred at -48 °C for 1 h and at 0 °C for 1 h. Aqueous NH4CI-NH3 (pH 8, 150 mL) was added, the mixture was opened to air, and then was stirred vigorously until the aqueous layer turned deep blue. The layers were separated and the aqueous layer was extracted with Et 2 0 (3 x 200 mL). The combined organic extracts were washed with H 2 0 (2 x 200 mL), brine (200 mL), dried (MgSCIO, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (200 g of silica gel, 1:99 then 1:19 Et20-petroleum ether) to yield 4.79 g (92%) of the stannane 177 as a colourless oil. IR(neat): 1704, 1671, 1591, 1314, 1245 cm 1 . lH NMR (400 MHz, CDC13) 5: 0.14 (s, 9H, -SnMe.. 2 / S n . H = 55.0 Hz), 1.06 (s, 6H, 2 x -CH3), 2.40 (m, 2H), 2.45 (m, 2H), 3.69 (s, 3H, -COzCHj). 1 3 C NMR (50.3 MHz, CDC13) 8: -8.6, 29.5 (2C), 39.7, 48.3, 51.2, 55.9, 142.0, 165.8, 166.7. 179 HRMS calcd for C n H 1 9 0 2 2 0 Sn (M +-Me): 303.0407; found: 303.0406. Anal, calcd for C i 2 H 2 2 0 2 S n : C 45.46, H 6.99; found: C 45.61, H 7.18. Preparation of(4,4-dimethyl-2-trimethylstannylcyclopent-l-en-l-yl)methanol (182) To a cold (-78 °C), stirred solution of the ester 177 (4.53 g, 14.3 mmol) in dry THF (100 mL) was added D I B A L - H (1.0 M solution in hexanes, 36 mL, 36 mmol) via a syringe. The reaction mixture was stirred for 1 h at -78 °C and was warmed to 0 °C for 1 h. The mixture was treated with aqueous NH4CI-NH3 (pH 8, 10 mL) and then was stirred for 30 min until a white, gelatinous precipitate formed. MgSCU (1 g) was added to the mixture and stirring was continued for 45 min. The mixture was diluted with E t 2 0 (100 mL) and filtered through a cake of silica gel (-20 g) and Celite® (-20 g). The cake was eluted with E t 2 0 (-1 L). The combined filtrate was concentrated under reduced pressure and the resulting material was purified by flash column chromatography (100 g of silica gel, 1:4 Et20-petroleum ether) to yield 4.13 g (100%) of the alcohol 182 as a colourless oil. IR (neat): 3343, 1619, 1363, 769 cm 1 . *H N M R (400 MHz, CDC13) 5: 0.11 (s, 9H, -SnMes, 2 / S n - H = 54.0 Hz), 1.05 (s, 6H, 2 x -CH3), 1.30 (br s, 1H), 2.24 (br signal, 4H), 4.12 (d, 2H, / = 5.5 Hz). 1 3 C N M R (75.5 MHz, CDC13) 8: -8.9, 29.7 (2C), 39.2, 49.9, 54.7, 63.5, 138.8, 150.7. 177 182 180 HRMS calcd for C i 0 H 1 9 O 1 2 0 S n (M +-Me): 275.0458; found: 275.0460. Anal, calcd for Q i H ^ O S n : C 45.71, H 7.67; found: C 45.81, H 7.84. Preparation of l-bromomethyl-4,4-dimethyl-2-trimethylstannylcyclopentene (176) To a cool (0 °C), stirred solution of triphenylphosphine (8.94 g, 34.1 mmol) in dry CH 2 C1 2 (140 mL) was added bromine (-1.8 mL) via a syringe, until a yellow colour persisted. A small amount of PPh 3 (-50 mg) was added until the solution became clear. The mixture was stirred at 0 °C for 15 min, during which time a white precipitate formed. Solid imidazole (2.50 g, 36.7 mmol) was added and the white precipitate disappeared. The mixture was stirred for 15 min before addition of a solution of the alcohol 182 (3.94 g, 13.6 mmol) in dry CH 2 C1 2 (20 mL). The reaction mixure was stirred for 30 min. Most of the solvent was removed under reduced pressure until the volume remaining was approximately 30 mL. Pentane (200 mL) was added. The mixture (containing a precipitate) was filtered through a cake of silica gel (-50 g) and Celite® (-50 g). To the residue left in the flask was added aqueous NaHC03 (10%, 100 mL) and the aqueous layer was extracted with pentane (2 x 100 mL). The combined organic extracts were filtered through the same cake of silica gel and Celite® (vide supra) and the cake was eluted with -1 L of pentane. Concentration of the combined filtrate under reduced pressure afforded 4.46 g (93%) of the bromide 176, as a colourless liquid. This compound proved to be volatile and a successful elemental analysis was not obtained. 182 176 IR (neat): 1465, 1364, 1200, 771 cm"1. 181 *H NMR (400 MHz, CDC13) 5: 0.18 (s, 9H, -SnMe,. 2 / S „ - H = 54.0 Hz), 1.06 (s, 6H, -2 x -CH3), 2.25 (s, 2H), 2.32 (s, 2H), 4.02 (s, 2H, -CHaBr). 1 3 C NMR (75.5 MHz, CDCI3) 8: -9.6 (-ve), 29.4 (-ve, 2C), 34.1, 39.7, 50.1, 55.2 (-ve), 145.7, 147.8. HRMS calcd for C 1 0 H 1 8 1 2 0 S n 7 9 B r (M+-Me): 336.9614; found: 336.9620. Preparation of 5f(4,4-dimethyl-2-trimethylstannylcyclopent-l-en-l-yl)methyl]-3-isobutoxycyclopent-2-en-l-one (175) To a cold (-78 °C), stirred solution of L D A (18.4 mmol) in dry T H F (100 mL) was added a solution of 3-isobutoxycyclopent-2-en-l-one (82) 1 1 5 (2.84 g, 18.4 mmol) in dry THF (100 mL). The mixture was stirred at -78 °C for 30 rnin and at 0 °C for 15 min. It was subsequently cooled back to -78 °C and HMPA (2.54 mL, 14.6 mmol) was added, followed by a solution of the bromide 176 (4.32 g, 12.3 mmol) in dry T H F (20 mL). The reaction mixture was warmed to 0 °C and stirred for 1 h. Water (200 mL) was added and the mixture was extracted with Et 2 0 (3 x 200 mL). The combined organic extracts were washed with H 2 0 (2 x 100 mL), aqueous CuS0 4 (10%, 100 mL), brine (200 mL), dried 82 176 175 182 (MgS0 4), and concentrated under reduced pressure. The crude material was purified by flash column chromatography (300 g of silica gel, 1:1 Et20-petroleum ether) to yield 3.97 g (76%) of alkylated product 175. Bulb-to-bulb distillation (220-230 °C/0.6 ton) of this material gave 3.70 g (71%) of colourless viscous oil which solidified upon standing (mp. 35-36 °C). IR (KBr): 1688, 1592, 1352, 997 cm"1. *H NMR (400 MHz, CDC13) 8: 0.08 (s, 9H, -SnMe3. 2JSn_H = 53.0 Hz), 0.96 (d, 6H, / = 7.0 Hz, -CH(CH3)2), 1.00 (s, 3H, -CH 3), 1.02 (s, 3H, -CH 3 ) , 2.02-2.31 (m, 7 H), 2.56-2.62 (m, 3H), 3.70 (d, 2H, / = 6.5 Hz, -OCH 2 CH), 5.18 (s, 1H, =CH). 1 3 C NMR (75.5 MHz, CDC13) 8: -9.4 (-ve), 18.9 (-ve, 2C), 27.8 (-ve), 29.4 (-ve), 29.7 (-ve), 33.6, 35.3, 39.4, 43.6 (-ve), 50.9, 54.3, 77.4, 103.3, 138.0, 149.8, 189.0, 207.9. HRMS calcd for C 2 0 H 3 4 O 2 1 2 0 S n : 426.1581; found: 426.1575. Anal, calcd for C 2 0 H 3 4 O 2 S n : C 56.50, H 8.06; found: C 56.67, H 7.94. Preparation of 4-[(4,4-dimethyl-2-trimethylstannylcyclopent-l-en-l-yl)methyl]-3-methylcyclopent-2-en-l-one (59) Me 3 Sn 175 59 183 To a cool (0 °C), stirred solution of the ketone 175 (3.31 g, 7.79 mmol) in dry THF (100 mL) was added a solution of MeMgBr (10.4 mL, 3.0 M solution in Et 2 0, 31 mmol). The mixture was warmed to room temperature and was stirred for 4 hours. Water (100 mL) was added slowly and the resultant mixture was diluted with Et 2 0 (100 mL). The layers were separated and the aqueous layer was extracted with Et 2 0 (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSC^), and concentrated under reduced pressure. The resulting crude material was dissolved in Et 2 0 (100 mL) containing -10 drops of H 2 0 and the mixture was treated with a catalytic amount of /?-toluenesulfonic acid (-100 mg). The reaction mixture, open to air, was stirred for 4 h at room temperature. It was diluted with H 2 0 (100 mL) and the layers were separated. The aqueous layer was extracted with Et 2 0 (100 mL) and the combined organic extracts were washed with brine (100 mL), dried (MgS&O, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (150 g of silica gel, 1:4 Et20-petroleum ether) and subsequent bulb-to-bulb distillation (125-130 °C/1.5 torr) to provide 2.25 g (79%) of a viscous oil which solidified upon standing (mp. 31-32 °C). IR (KBr): 1687, 1620, 1441, 1308, 766 cm"1. J H NMR (400 MHz, CDC13) 5: 0.09 (s, 9H, -SnMej, 2 / S n . H = 53.5 Hz), 1.02 (s, 3H, -CH3), 1.05 (s, 3H, -CH3), 1.97 (dd, 1H, / = 10.5, 13.5 Hz), 2.09 (s, 3H, C=C(CH3)-), 2.12-2.17 (m, 3H), 2.17-2.25 (m, 2H), 2.41 (dd, 1H, / = 6.5, 19.0 Hz), 2.56 (m, 1H), 2.88 (br m, 1H), 5.87 (s, 1H, =CH). 1 3 C NMR (75.5 MHz, CDC13) 8: -9.3 (-ve), 17.5 (-ve), 29.5 (-ve), 29.7 (-ve), 37.2, 39.4, 41.1, 43.0 (-ve), 51.3, 54.3, 130.7 (-ve), 138.6, 149.4, 181.3, 208.6. HRMS calcd for C i 6 H 2 5 O 1 2 0 S n (M+-Me): 353.0927; found: 353.0931. Anal, calcd for C n H 2 8 O S n : C 55.62, H 7.69; found: C 55.84, H 7.72. 184 Preparation of(2S* 6R*)-2J0J0-trimethyltricyclo[6.3.0.02-6]undec-l(8)-en-4-one (60) To a flame dried, 20 mL glass, sealable ampoule equipped with a magnetic stir bar, under an atmosphere of argon, was added the enone 59 (1.75 g, 4.78 mmol), dry DMSO (18 mL), and solid CuCN (4.28 g, 47.8 mmol). The ampoule was flushed with a stream of argon gas and sealed using a natural gas-oxygen torch. The mixture was heated to 90 °C using an oil bath. After about 15 min, all of the CuCN dissolved to form a homogenous, slightly yellow, clear, viscous solution. The mixture was stirred for 17 hours at 90 °C. The ampoule was opened and the brown reaction mixture was poured into an aqueous solution of NH4CI-NH3 (pH 8, 100 mL) and the resultant mixture was diluted with Et 2 0 (100 mL). The mixture was stirred vigorously open to air until the aqueous phase became blue. The mixture, which contained a purple precipitate that remained insoluble at the interface of the two layers, was filtered through a sintered glass funnel. The solid in the funnel was rinsed with aqueous NH4CI-NH3 (pH 8, -50 mL) and Et 2 0 (-50 mL). The phases of the combined filtrate were separated and the aqueous layer was extracted with Et 2 0 (2 x 100 mL). The combined organic extracts were washed with H 2 0 (300 mL), brine (2 x 300 mL), dried (MgS04), and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (100 g of silica gel, 1:4 Et20-petroleum ether) to yield 580 mg (59%) of the ketone 60 along with 137 mg (14%) of protiodestannylated material 183, both as colourless oils. 185 Characterization data for (2S*, 6i?*)-2,10,10-trimethyltricyclo[6.3.0.0 2' 6]undec-l(8)-en-4-one (60): IR(neat): 1746, 1402, 1363, 1164 c m 1 . lH N M R (400 M H z , CDC1 3 ) 8: 1.05 (s, 3H , -CH3), 1.08 (s, 3H , -CH3), 1.15 ( s ,3H, -CH3), 1.79-2.00 (m, 5H), 2.05 (m, 2H), 2.29 (dd, 1H, / = 1.5, 18.5 Hz) , 2.50-2.59 (m, 1H), 2.63 (ddd, 1H, / = 1.5, 10.0, 18.5 Hz), 2.70-2.79 (m, 1H). 1 3 C N M R (75.5 M H z , CDCI3) 8: 25.1 (-ve), 30.4 (-ve), 30.5 (-ve), 36.4, 41.4, 44.3, 45.2, 46.6, 48.1, 49.4, 50.0 (-ve), 141.0, 149.0, 219.7. H R M S calcd for C 1 4 H 2 0 O : 204.1514; found: 204.1519. Anal , calcd for C i 4 H 2 0 O : C 82.30, H 9.87; found: C 82.36, H 9.87. Characterization data for the protiodestannylated material 183: IR (neat): 1714, 1620, 1437, 1186 cm"1. lH N M R (400 M H z , CDC1 3 ) 8: 0.98 (s, 3H , -CH3), 1.00 (s, 3H , -CH3), 1.88 (dd, 1H, / = 11.0, 14.5 Hz) , 1.92-2.11 (m, 5 H ; s, 3H, -CH3, (8 2.05)), 2.37-2.47 (m, 2H), 2.81-2.89 (br m, 1H), 5.21 (br s, 1H), 5.82 (t, 1H, / = 1.5 Hz). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: 17.3 (-ve), 29.7 (-ve), 29.8 (-ve), 34.8, 38.5, 41.7, 42.7 (-ve), 47.4, 50.1, 124.9 (-ve), 130.7 (-ve), 140.2, 181.2, 208.7. H R M S calcd for C i 4 H 2 0 0 : 2 0 4 . 1 5 1 4 ; found: 204.1517. 186 Preparation of(2S* 4S* 6R*)-2MlO-trimethyltricyclo[63.0.&fi]undec-l(8)-en-4-ol (195) 60 195 To a cool (0 °C), stirred solution of the ketone 60 (322 mg, 1.57 mmol) in dry THF (30 mL) was added a solution of Li(f-BuO) 3AlH in THF (2.36 mL, 1.0 M , 2.36 mmol) via a syringe. The mixture was stirred at 0 °C for 1 h. A saturated aqueous solution of Rochelle's salt (30 mL) was added, and the mixture was diluted with E t 2 0 (30 mL) and then was stirred open to air for 30 min. The layers were separated and the aqueous phase was extracted with E t 2 0 (2 x 30 mL). The combined organic extracts were washed with H 2 0 (30 mL), brine (30 mL), dried (MgSCv) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (20 g of silica gel, 1:4 Et20-petroleum ether) and by bulb-to-bulb distillation (98-100 °C/0.4 torr) to provide 282 mg (87%) of the alcohol 195 as a colourless viscous oil, which solidified upon standing (mp. 44-46 °C). IR (KBr): 3290, 1463, 1445, 1360, 1343, 1065 cm"1. *H N M R (400 MHz, CDC13) 8: 1.05 (s, 3H, -CH3), 1.08 (s, 3H, -CH3), 1.10 (s, 3H, -CH,), 1.48-1.59 (m, 2H), 1.69 (ddd, 1H, / = 1.5, 4.5, 13.0 Hz), 1.84 (br s, 1H), 1.88-2.00 (m, 5H), 2.18-2.26 (m, 1H), 2.45-2.55 (m, 2H), 4.18 (br m, 1H, -CH(OH)). 187 UC NMR (75.5 MHz, CDC13) 8: 25.9 (-ve), 30.6 (-ve), 30.7 (-ve), 37.3, 41.7, 44.2, 44.9, 45.3, 45.5, 52.3, 52.4 (-ve), 75.6 (-ve), 140.0, 151.8. HRMS calcd for Ci 4H 2 20:206.1671; found: 206.1677. Anal, calcd for C 1 4 H 2 2 0 : C 81.50, H 10.75; found: C 81.78, H 10.89. Preparation of (IS* 2S* 4S* 6R* 8R*y2,10,10-trimethyltricyclo[63.0.626]undecan-4-ol (196) OH OH 195 196 To a solution of the alcohol 195 (276 mg, 1.34 mmol) in dry CH 2 C1 2 (13 mL) at room temperature was added (l,5-cyclooctadiene)(pyridme)(tricyclohexylphosplime)iridium(I) hexafluorophosphate (Crabtree catalyst)104 (115 mg, 0.142 mmol). The reaction flask was evacuated and refilled three times with hydrogen gas. The reaction mixture was stirred for 17 h under an atmosphere of hydrogen (1 atm). The solvent was removed under reduced pressure and Et 2 0 (15 mL) was added to the residual solid. The mixture was stirred for 1 h. The mixture was filtered through a cake of silica gel (~5 g) and Celite® (~5 g) and the collected material was washed with Et 2 0 (-100 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (20 g of silica gel, 2:3 Et20-petroleum ether) to afford 264 mg (95%) of the alcohol 196 as a white solid (mp. 67-69 °C). A small amount of the solid 188 was recrystallized from hexanes and the acquired material (mp. 69-71 °C) was subjected to X-ray crystallographic analysis (see Appendix). IR (KBr): 3246, 1461, 1074 cm 1 . J H NMR (400 MHz, CDC13) 5: 0.88 (s, 3H, -CH3), 0.91 (s, 3H, -CH3), 1.02 (s, 3H, -CH3), 1.09 (dd, 1H, / = 6.5, 13.0 Hz, H-9), 1.14-1.25 (m, 1H, H- l l ) , 1.25-1.40 (m, 2H, H-5, H-ll'), 1.42-1.60 (m, 3H, H-3, H-7, H-9'), 1.61-1.72 (m, 2H, H-7', -OH), 1.88 (dd, 1H, / = 7.0, 12.5 Hz, H-3'), 1.93-2.00 (m, 1H, H-6), 2.20 (dddd, 1H, / = 0.5, 7.5, 7.5, 13.0 Hz, H-5'), 2.37 (ddd, 1H, / = 7.5, 7.5, 12.0 Hz, H-l), 2.64-2.74 (m, 1H, H-8), 4.21-4.36 (m, 1H, H-4). 1 3 C NMR (75.5 MHz, CDC13) 5: 24.0 (-ve), 28.3 (-ve), 30.4 (-ve), 40.8, 40.8, 41.9, 42.1 (-ve), 43.4, 47.8, 48.5 (-ve), 50.9, 51.4, 54.8 (-ve), 73.4 (-ve). HRMS calcd for Ci4H2 40:208.1827; found: 208.1825. Anal, calcd for C 1 4 H 2 4 0 : C 80.71, H 11.61; found: C 80.79, H 11.68. 189 Table 14. *H NMR (400 MHz, CDC13) data for the alcohol 196: COSY Experiment. OH Assignment 'H NMR COSY Correlations H-x 8 (multiplicity, 7 (Hz)) H - l 2.37 (ddd, 7=7.5, 7.5, 12.0) H-8, H - l l , H - l l ' H-3 part of mat 1.42-1.60 H-3', H-4 H-3' 1.88 (dd, 7=7.0,12.5) H-3, H-4 H-4 4.21-4.36 (m) H-3, H-3', H-5, H-5' H-5 part of mat 1.25-1.40 H-4, H-5', H-6 H-5' 2.20 (dddd, 7= 0.5, 7.5, 7.5, 13.0) H-4, H-5, H-6 H-6 1.93-2.00 (m) H-5, H-5', H-7, H-7' H-7 part of mat 1.42-1.60 H-6, H-7', H-8 H-7' part of mat 1.61-1.72 H-6, H-7, H-8 H-8 2.64-2.74 (m) H - l , H-7, H-7', H-9, H-9' H-9 1.09 (dd,7=6.5, 13.0) H-8, H-9' H-9' part of mat 1.42-1.60 H-8, H-9' H - l l 1.14-1.25 (m) H-1,H-11" H - l l ' part of mat 1.25-1.40 H - l , H - l l OH part of m at 1.61-1.72 Me-12, Me-13, 0.88,0.91, 1.02 Me-14 190 Preparation of (IS* 2S* 6R* 8R*)-2,10,10-trimethyltricyclo[6.3.0.02,6]undecan-4-one (174) To a stirred solution of the alcohol 196 (817 mg, 3.92 mol) in dry C H 2 C 1 2 (50 mL) at room temperature was added oven-dried Celite® (1.69 g) and P C C (1.69 g, 7.84 mmol). The dark brown mixture was stirred at room temperature for 3 h. Dry E t 2 0 (150 mL) was added and the mixture was stirred for 1 h at room temperature. The mixture was filtered through a column of Florisil® (-60 g) and the column was eluted with E t 2 0 (-1.5 L ) . The filtrate was concentrated under reduced pressure. Purification of the crude material by flash column chromatography (50 g of silica gel, 1:4 Et 20-petroleum ether), followed by bulb-to-bulb distillation (99-102 °C/0.4 torr) of the acquired liquid, provided 756 mg (93%) of the ketone 174 as a colourless oil . IR(neat): 1746, 1461, 1407, 1366, 1170, 1133 c m 1 . X H N M R (500 M H z , CDC1 3 ) 8: 0.86 (s, 3H, -CH3), 0.97-1.01(m, 1H, H-9; s, 3H, -CH3 (8 0.99)), 1.02 (s, 3H , -CH3), 1.18 (br dd, 1H, / = 11.5, 12.0 H z , H - l l ) , 1.38 (ddd, 1H, / = 2.5, 8.0, 12.0 Hz , H - l l ' ) , 1.46-1.58 (m, 1H, H-7), 1.65 (ddd, 1H, / = 2.0, 8.0, 14.0 Hz , H-7'), 1.72 (ddd, 1H, / = 2.5, 9.0, 12.5 Hz , H-9'), 1.98 (br d, 1H, / = 18.5 H z , H-3), 2.05-2.12 (m, 1H, H-5; d, 1H, / = 18.5 Hz , H-3' , (8 2.09)), 2.30-2.40 (m, 2 H , H-5*, H-6), 2.53 (ddd, 1H, / = 8.0, 9.0, 11.5 Hz , H - l ) , 2.65-2.75 (m, 1H, H-8). O H O 196 174 191 1 3 C NMR (75.5 MHz, CDC13) 5: 22.2 (-ve), 26.1 (-ve), 29.0 (-ve), 39.7, 40.9, 41.3 (-ve), 43.0, 43.5, 44.6 (-ve), 49.0, 49.6, 51.5, 52.9 (-ve), 220.6. HRMS calcd for Ci 4H 2 20:206.1671; found: 206.1674. Anal, calcd for C i 4 H 2 2 0 : C 81.50, H 10.75; found: C 81.70, H 10.63. Table 15. lH NMR (400 MHz, CDC13) data for the ketone 174: COSY Experiment. O Assignment H-x 'H NMR 8 (multiplicity, / (Hz)) COSY Correlations H - l 2.53 (ddd,/=8.0, 9.0, 11.5) H-8, H - l l , H - l l ' H-3 1.98 (br d, / = 18.5) (d of AB quartet) H-3', H-5' H-3* 2.09 (br d, / = 18.5) (d of AB quartet) H-3, H-5' H-5 2.05-2.12 (m) H-5', H-6, H-7 H-5' part ofm at 2.30-2.40 H-3, H-3', H-5 H-6 part of mat 2.30-2.40 H-5, H-5', H-7, H-7' H-7 • 1.46-1.58 (m) H-5, H-6, H-7', H-8 H-7' 1.65 (ddd,/=2.0, 8.0, 14.0) H-6, H-7, H-8 H-8 2.65-2.75 (m) H - l , H-7, H-7', H-9, H-9' H-9 0.97-1.01 (signal under Me peak at 0.99) H-8, H-9' H-9' 1.72 (ddd,/= 2.5, 9.0, 12.5) H-8, H-9 H - l l 1.18 (brdd,/= 11.5, 12.0) H-I.H-H' H-ll' 1.38 (ddd,/=2.5, 8.0, 12.0) H - l , H - l l Me-12, Me-13, Me-14 0.86, 0.99, 1.02 192 Table 16. 1 3 C (125.8 MHz, CDC13) and *H NMR (500 MHz) data for the ketone 174: H M Q C Experiment O 174 Assignment 1 3 C N M R APT H M Q C C-x 8 ppm X H NMR Correlations (8 ppm) Me 22~2 CH or CH 3 Me (0.99) Me 26.1 C H or CH 3 Me (0.86) Me 29.0 C H or CH 3 Me (1.02) C-7 39.7 C or CH 2 H-7 (1.46-1.58), H-7'(1.65) C-10 40.9 C or C H 2 C-8 41.3 CH or C H 3 H-8 (2.65-2.75) C-5 43.0 C or CH 2 H-5 (2.05-2.12), H-5' (part of m at 2.30-2.40) C - l l 43.5 C or CH 2 H - l l (1.18), H-ll'(1.38) C-6 44.6 CH or C H 3 H-6 (part of m at 2.30-2.40) C-2 49.0 C or C H 2 C-9 49.6 C or CH 2 H-9 (0.97-1.01), H-9'(1.72) C-3 51.5 C or CH 2 H-3 (1.98), H-3' (2.05-2.12) C - l 52.9 CH or C H 3 H - l (2.53) C-4 220.6 C or C H 2 193 Preparation of (IS* 2R*, 8S*)-2,10,10-trimethyltricyclo[6.3.0.02,6]undec-5-en-4-one (197) 174 197a/b 197 Following a procedure reported by Little, 8 7 to a cold (-78 °C), stirred solution of lithium tetramethylpiperidide (from tetramethylpiperidine (1.23 mL, 7.26 mmol) and n-BuLi (4.09 mL, 1.6 M in hexane, 6.54 mmol)) in dry THF (10 mL), was added, with a gas-tight syringe, freshly distilled chlorotrimethylsilane (1.84 mL, 14.5 mmol). A solution of the ketone 174 (300 mg, 1.45 mmol) in dry THF (10 mL) was added. After about 5 minutes, triethylamine (3.04 mL, 21.8 mmol) was added via a syringe. The reaction mixture was warmed slowly to room temperature over a period of 1 h. Et 2 0 (100 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgS0 4), and the solvent was removed under reduced pressure. The crude material was placed under reduced pressure (vacuum pump) for about 4 hours to remove remaining amines and traces of solvent. The crude rnixture contained a 3:2 mixture of silyl enol ethers, which was determined by the 1 H NMR integration of olefinic signals at 5 4.48 (br unresolved d, / = 2.0 Hz) and 4.45 ppm (s). Based on the appearance of the olefinic signal, the major product (S 4.48) is the desired silyl enol ether, formed by abstraction of the less hindered proton. The crude mixture of silyl enol ethers 197a/b was dissolved in a rnixture of acetonitrile (12 mL) and CH 2 C1 2 (6 mL). Palladium acetate (Aldrich, 99.9%, 391 mg, 1.74 mmol) was added to this solution and the mixture was stirred for 12 h at room temperature. The solvent was removed under reduced pressure and Et 2 0 (50 ml) was added to the residual 194 material. The mixture was filtered through a column of silica gel (-30 g), and the products were eluted with E t 2 0 . The combined eluate was concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (50 g of silica gel, 1:4 Et 20-petroleum ether) to yield 155 mg (52%) of the enone 197 as a colourless oil , as well as 120 mg of the ketone 174. The overall yield of 197, based on the recovered 174, was 87%. IR(neat): 1713, 1636, 1466, 1367, 1242, 1189, 844 c m 1 . *H N M R (400 M H z , CDC1 3 ) 8: 0.93 (s, 3H, -CH3), 1.06 (s, 3H, - C H , ) , 1.08 (s, 3 H , -CH3), 1.19 (dd, 1H, / = 11.0, 12.0 Hz , H-9), 1.42 (dd, 1H, / = 9.0, 13.0 H z , H - l l ) , 1.49 (ddd, 1H, / = 1.5, 9.0, 13.0 Hz , H - l l 1 ) , 1.76 (ddd, 1H, / = 1.5, 7.0, 12.0 H z , H-9'), 2.17-2.31 (m, 3H , H-3, H-7, H-7'), 2.36 (ddd, 1H, / = 9.0, 9.0, 11.0 Hz , H - l ) , 2.70-2.83 (m, 2H, H-3' , H-8), 5.65 (d, 1H, / = 2.0 Hz , H-5). 1 3 C N M R (75.5 M H z , CDC1 3 ) 8: 24.6 (-ve), 27.4 (-ve), 29.0 (-ve), 32.9, 40.2, 43.8, 44.4 (-ve), 49.2, 49.5, 50.5 (-ve), 52.7, 122.0 (-ve), 195.8, 210.8. H R M S calcd for C i 4 H 2 0 O : 204.1514; found: 204.1519. Anal , calcd for C 1 4 H 2 0 O : C 82.30, H 9.87; found: C 82.15, H 9.89. 195 Table 17. *H NMR (400 MHz, CDC13) data for the enone 197: COSY Experiment. O 13 Assignment 'H NMR COSY Correlations H-x 5 (multiplicity, / (Hz)) H - l 2.36 (ddd, 1H, / = 9.0, 9.0, 11.0) H-8, H - l l , H- l l* H-3 part ofm at 2.17-2.31 H-5, H-3' H-3' part of mat 2.70-2.83 H-3 H-5 5.65 (d, lH,/=2.0). H-3 and/or H-7 or H-7' H-7, H-7' part of mat 2.17-2.31 H-8, long range to H-9 and H-9' H-8 part ofm at 2.70-2.83 H - l , H-7, H-7', H-9, H-9' H-9 1.19 (dd, 1H,7= 11.0, 12.0) H-8, H-9', long range to H-7 or H-7' H-9' 1.76 (ddd, l H , / = 1.5, 7.0, 12.0) H-8, H-9, long range to H-7 or H-7' H - l l 1.42 (dd, lH, /=9.0 , 13.0) H-1,H-11' H-1T 1.49 (ddd, l H , / = 1.5, 9.0, 13.0) H - l , H - l l Me-12, Me-13, 0.93, 1.06, 1.08 Me-14 196 Preparation of (IS* 2S* 8S*)-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.02,6Jundec-5-en-4-one (198) O O Q 197 198c 198 To a cold (-78 °C), stirred solution of L D A (0.308 mmol) in dry T H F (2 mL) was added, dropwise via a syringe, a solution of the enone 197 (31.5 mg, 0.154 mmol) in dry THF (2 mL). After 15 minutes, the mixture was warmed to -30 °C, and formaldehyde gas (formed from paraformaldehyde) was passed into the stirred reaction mixture in a stream of argon gas for 5 minutes. Saturated aqueous NH4C1 (5 mL) was added, followed by Et 2 0 (10 mL), and the mixture was warmed to room temperature. The layers were separated and the aqueous phase was extracted with Et 2 0 (2 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4), and concentrated under reduced pressure. The crude material was purified by flash column chromatography (15 g of silica gel, 1:1 Et20-petroleum ether) to provide 26.2 mg (73%) of a mixture of the alcohols 198c as a colourless oil. The ratio of diastereomers, determined from the *H NMR integration of olefinic signals, was 1:4.6. The mixture of the alcohols 198c and tosyl chloride (70 mg) was dissolved in dry CH 2 C1 2 (1 mL) and pyridine (0.070 mL). The reaction mixture was stirred at room temperature for 4 days. DBU (0.140 mL) was added and the mixture was stirred for additional 2 h. Brine (10 mL) and water (10 mL) were added and the aqueous layer was extracted with Et 2 0 (4x10 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4) and concentrated under reduced pressure. The crude material was purified 197 hrrmediately by flash column chromatography (15 g of silica gel, 1:4 Et20-petroleum ether) to yield 18.5 mg (76%) of the dienone 198 as a colourless oil. IR (neat): 1702, 1623, 1462, 1368, 1259, 1153 cm'1. *H NMR (400 MHz, CDC13) 5: 0.93 (s, 3H, -CH3), 1.11 (s, 3H, -CH3), 1.14 (s, 3H, -CH3), 1.23 (brdd, 1H, 7=11.0, 12.0 Hz, H-9), 1.51-1.60 (m, 2H, H- l l ) , 1.78 (dd, 1H, 7=9.0, 12.0 Hz, H-9'), 2.20-2.31 (m, 1H, H-7), 2.39 (ddd, 1H, 7= 9.0, 9.0, 11.0 Hz, H-l), 2.70-2.81 (m, 2H, H-8, H-7'), 5.11 (s, 1H, H-15), 5.85 (s, 1H, H-15'), 5.86 (d, 1H, 7= 1.5 Hz, H-5). 1 3 C NMR (100.6 MHz, CDCI3) 8: 23.5 (-ve), 27.4 (-ve), 29.0 (-ve), 32.7, 40.3, 44.1, 44.9 (-ve), 48.2 (-ve), 49.7, 51.8, 112.8, 123.1 (-ve), 154.3 (-ve), 189.8, 197.8. HRMS calcd for Ci5H2 00:216.1514; found: 216.1518. Preparation of (IS*, 2S* 5R*, 67?* 8S*)-5,6-epoxy-3-methylidene-2,10,10-trimethyl-tricyclof 6.3.0.02,6Jundecan-4-one [ (±)-l-Desoxyhypnophilin J (61) O O 198 61 To a mixture of the dienone (198) (10 mg, 0.046 mmol), sodium bicarbonate (50 mg), water (1 mL) and THF (1 mL) at 0 °C was added a 30% solution of aqueous hydrogen peroxide (0.10 mL). The mixture was stirred for 8 h at 0 °C, and the progress of the 198 reaction was monitored by T L C . Et 2 0 (20 mL) and saturated aqueous NH4CI (10 mL) were added. The layers were separated and the organic layer was washed with brine (10 mL), dried (MgSCU) and concentrated under reduced pressure. The crude material was immediately purified by flash column chromatography on iatrobeads (5 g of iatrobeads, 1:5 Et20-petroleum ether), to yield 6 mg (56%) of (±)-1-desoxyhypnophilin (61) as a clear oil, along with 2 mg of unreacted starting material. The comparison of the spectral data of the synthetic and isolated natural product44 is presented in Tables 18 and 19. Since the numbering system used in naming the synthetic intermediates and (±)-1-desoxyhypnophilin (61) is different from that generally employed for the hirsutane family of sesquiterpene ids, both are shown in Tables 18 and 19 for comparison of spectral data of synthetic and natural (±)- 1-desoxyhypnophilin. IR (neat): 1730, 1642, 1466, 1367, 1259, 1124 cm"1. J H NMR (400 MHz, CDC13) 5: 0.90 (s, 3H, -CH3, H-12), 1.10 (s, 3H, -CH3, H-13), 1.12-1.15 (m, 1H, H-9'; s, 3H, -CH3, H-14 (5 1.14)), 1.43-1.58 (m, 2H, H - l l , H-ll') , 1.77 (ddd, 1H, / = 1.5, 8.0, 12.0 Hz, H-9), 1.97 (d, 2H, / = 9.0 Hz, H-7), 2.37 (ddd, 1H, / = 9.0, 9.0, 11.5 Hz, H-l), 2.65-2.75 (m, 1H, H-8), 3.41 (s, 1H, H-5), 5.42 (s, 1H, H-15), 6.03 (s, 1H, H-15'). 1 3 C NMR (100.6 MHz, CDC13) 5: 17.5, 27.3, 28.9, 30.1, 39.2, 40.1, 42.5, 46.5, 49.5, 49.9, 61.1, 76.6, 119.9, 153.4, 198.1. HRMS calcd for Ci 5H 2 0O 2:232.1463; found: 232.1459. 199 Table 18. Comparison of C NMR data for synthetic (±)-l-desoxyhypnophillin 61 (100.6 MHz, CDC13) with those reported for natural (-)-l-desoxyhypnophilin44 (75.5 MHz, CDCI3). (±)-61 Hirsutane numbering (-)-61 1 3 C assignments C-x 8 (ppm) Hirsutane numbering C-x T T Lit. C signals and DEPT-135 data3 C - l 49.9 C-2 49.8 + C-2 46.5 C-3 46.5 0 C-3 153.4 C-4 153.4 0 C-4 198.1 C-5 198.1 0 C-5 61.1 C-6 61.1 + C-6 76.6 C-7 76.6 0 C-7 30.1 C-8 30.1 -C-8 39.2 C-9 39.2 + C-9 49.5 C-10 49.5 -C-10 42.5 C - l l 42.5 0 C - l l 40.1 C - l 40.1 -C-12 17.5 C-12 17.5 + C-13 28.9 C-13 28.9 + C-14 27.3 C-14 27.3 + C-15 119.9 C-15 119.9 -Amplitude of signals in DEPT-135 spectrum (CH3 or CH = +, CH 2 = -, C = 0) 200 Table 19. Comparison of *H NMR data for synthetic (±)-l-desoxyhypnophillin 61 with those reported for natural (-)-l-desoxyhypnophilin44 (400 MHz, CDC13). O Q (±)-61 Hirsutane numbering (-)-61 8, multiplicity, Hirsutane Lit. *H assignments *H assignment /(Hz) numbering of H 8, multiplicity, 7 (Hz) H-x H - l 2.37 ddd H-2 2.40 dt 7=9.0, 9.0, 11.5 7= 12,9 H-5 3.41 s H-6 3.44 s H-7 1.97 d H-8 2.00 d 7=9.0 7=9 H-8 2.65-2.75 m H-9 2.73 ddtd 7= 8, 12,9, 12 H-9 1.77 ddd H-10 1.80 ddd 7= 1.5, 8.0, 12.0 7= 1,8, 12 H-9' 1.14m H-10' 1.17 dd 7= 12, 12 H - l l part of 1.43-1.58 m H - l 1.54 dd 7=9, 13 H - i r part of 1.43-1.58 m H- l ' 1.48 ddd 7= 1,9, 13 H-12 0.90 s H-12 0.92 s H-13 1.10s H-13 1.12 s H-14 1.14s H-14 1.16s H-15 5.24 s H-15' 5.27 s H-15' 6.03 s H-15 6.05 s 201 Preparation of (IS*, 2S* 4S* 5S* <5R* 8S*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[ 6.3.0. &,L'Jundecan-4-ol) [ (±)-6,7-epoxy-4( 15)-hirsuten-5-ol ](62)44 O OH a 12 13 61 62 To a cool (0°C), stirred mixture of (±)-1-desoxyhypnophilin (61) (3.7 mg, 0.016 mmol) in absolute ethanol (0.5 mL) was added sodium borohydride (0.9 mg, 0.023 mmol) and the reaction mixture was stirred for 15 min. Water (10 mL) was added, and the mixture was extracted with E t 2 0 (3 x 10 mL). The combined organic extracts were washed with water (10 mL) , brine (10 mL) , dried (MgS04), and concentrated under reduced pressure. The crude material was immediately purified by flash column chromatography on iatrobeads (1 g of iatrobeads, 1:2 Et 20-petroleum ether), to afford 2.5 mg (68%) of the alcohol 62 as a colourless oil . IR (film): 3436, 1465, 1107, 1066, 886 cm" 1. *H N M R (400 M H z , CDC1 3 ) 5: 0.89 (s, 3H , -CH3, H-12), 1.01 (s, 3H , -CH3, H-14), 1.07 (s, 3H , - C H , , H-13), 1.06-1.14 (m, 1H, H-9), 1.41 (d, 2H , / = 9.0 Hz , H - l l ) , 1.63 (d, 1H, / = 11.0 H z , -OH) , 1.72 (dd, 1H, / = 8.0, 12.0 Hz , H-9'), 1.84 (d, 2 H , / = 8.5 H z , H-7), 2.27 (dt, 1H, / = 11.0, 9.0 Hz , H - l ) , 2.55-2.70 (m, 1H, H-8), 3.45 (d, 1H, / = 2.0 H z , H -5), 4.59 (dddd, 1H, / = 2.0, 2.0, 2.0, 11.0 Hz , H-4), 4.96 (d, 1H, / = 2.0 H z , H-15), 5.23 (d, 1H, 7=2 .0 Hz , H-15'). 202 1 3 C NMR (100.6 MHz, CDC13) 5: 17.1, 27.4, 28.9, 30.3, 39.1, 39.8, 42.4, 48.7, 48.7, 49.6, 63.6, 74.2, 75.4, 111.3, 159.3. HRMS calcd for C 1 5H 2 20 2:234.1620; found: 234.1620. 203 Table 20. Comparison of 1 J C N M R data for synthetic (15*, 25* 45* 55* 6f l* 85*)-5.6- epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.02'6]undecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) (100.6 M H z , CDC1 3 ) with those reported for natural (+)-6.7- epoxy-4(15)-hirsuten-5-ol 4 4 (75.5 M H z , CDC1 3 ) (±)-62 Hirsutane numbering (+)-62 1 3 C assignments C-x 8 (ppm) Hirsutane numbering C-x 1 3 C signals and DEPT-135 data3 C - l 48.7 C-2 48.7 + C-2 48.7 C-3 48.7 0 . C-3 159.3 C-4 159.3 0 " C-4 74.2 C-5 74.2 + C-5 63.6 C-6 63.6 + C-6 75.4 C-7 75.4 0 C-7 30.3 C-8 30.3 -C-8 39.1 C-9 39.1 + C-9 49.6 C-10 49.6 -C-10 42.4 C - l l 42.4 0 C - l l 39.8 C - l 39.8 -C-12 17.1 C-12 17.1 + C-13 28.9 C-13 28.9 + C-14 27.4 C-14 27.4 + C-15 111.3 C-15 111.3 -Amplitude of signals in DEPT-135 spectrum (CH 3 or C H = +, C H 2 = -, C = 0) 204 Table 21. Comparison of *H NMR data for synthetic (15*, 25* 45* 55* 6R*, 85*)-5,6-epoxy-3-methylidene-2,10,10-trimethyltricyclo[6.3.0.02'6]vindecan-4-ol) [(±)-6,7-epoxy-4(15)-hirsuten-5-ol] (62) with those reported for natural (+)-6,7-epoxy-4(15)-hirsuten-5-0144(400 MHz, CDC13). OH OH (±)-62 Hirsutane numbering (+)-62 *H assignment 8, multiplicity, 7 (Hz) Hirsutane numbering of H Lit. *H assignments 8, multiplicity, 7 (Hz) H - l 2.27 dt 7 = 11.0, 9.0 H-2 2.27 dt 7= 11,9 H-4 4.59 dddd 7=2.0,2.0, 2.0, 11.0 H-5 4.59 dddd 7=2,2, 2, 10.8 H-5 3.45 d 7=2.0 H-6 3.45 d 7=5 H-7 1.84 d 7= 8.5 H-8 1.84 d 7= 8.5 H-8 2.55-2.70 m H-9 2.65 ddtd 7=7.5, 11, 8.5,11 H-9 1.06-1.14m H-10' 1.10 dd 7= 11, 12 H-9' 1.72 dd 7=7.5, 12.0 H-10 1.72 dd 7=7.5, 12.0 H - l l 1.41 d 7=9.0 H - l 1.42 d 7=9 H-12 0.89 s H-12 0.89 s H-13 1.07 s H-13 1.07 s H-14 1.01 s H-14 1.01 s H-15 4.96 d 7=2.0 H-15' 4.96 d 7=2 H-15" 5.23 d 7=2.0 H-15 5.23 d 7=2 OH 1.63 d 7= 11.0 OH not reported 205 APPENDIX X-ray crystalllographic data for the dione alcohol 147. OH 147 Formula Crystal System Space Group Lattice Parameters Z value Number of reflections used in refinement R Rw C14H20O3 Monocyclic P2j/n (#14) a (A) = 6.9319 (10) b (A) = 16.678 (4) c (A) = 10.9304 (6) P(°)= 101.4844(14) V (A 3) =1238.4 (3) 4 3034 0.090 0.089 X-ray crystalllographic data for the dione alcohol 148. Q V Me Formula Ci3H 1 803 Crystal System Space Group P2i /n (#14) Lattice Parameters a (A) = 6.9319 (10) b (A) = 16.678 (4) c (A) = 10.9304 (6) P(°)= 101.4844(14) V (A 3) =1238.4 (3) Z value ' _^ 4 Number of reflections* used in refinement 3034 R 0.090 R w 0.089 X-ray crystalllographic data for the alcohol 196. Formula C14H24O Crystal System Monocyclic Space Group C2/c (#15) Lattice Parameters a (A) = 20.437 (3) b (A) = 14.387 (3) c (A) = 9.7108 (3) P O 92.9752 (7) V (A 3) =2557.8 (5) Z value 4 Number of reflections used in refinement 3244 R 0.053 R w 0.087 REFERENCES (1) Roberts, R. M . Serendipity: accidental discoveries in science; John Wiley and Sons, Inc.: New York, 1989; pp 42-48. (2) Corey, E. J. Angew. Chem. Int. Ed. Engl. 1991, 30, 455. (3) Corey, E. J.; Cheng, X . - M . The Logic of Chemical Synthesis; Wiley: New York, 1989. (4) Seebach, D. Angew. Chem. Int. Ed. Engl. 1990, 29, 1320. (5) Nicolau, K. C ; Sorensen, E. J. Classics in Total Synthesis; V C H : Weinheim, 1996. (6) Nicolau, K. C ; Sorensen, E. J.; Winssinger, N. / . Chem. Ed. 1998, 75, 1225. (7) Nicolaou, K. C ; Vourloumis, D.; Wissinger, N.; Baran, P. S. Angew. Chem. Int. Ed. Engl. 2000, 39, 44. (8) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon Press: Oxford, U. K., 1992. (9) Jung, M . E . ; in Comprehensive Organic Chemistry; Trost, B. M . and Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4; Semmelhack, M . F., Ed.; pp 1-67. (10) Lee, V. J. ; in Comprehensive Organic Chemistry; Trost, B. M . and Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4; Semmelhack, M . F., Ed.; pp 69-168. (11) Lipshutz, B.; Sengupta, S. Org. React. 1992, 41, 135. (12) Guevel, A . - C ; Hart, D. J. J. Org. Chem. 1996, 61, 465. (13) Guevel, A . - C ; Hart, D. J. / . Org. Chem. 1996, 61,473. (14) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. / . Org. Chem. 1997, 62, 1305. (15) Little, R. D.; Masjedizadeh, M . R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47, 315. (16) Wender, P. A.; Eck, S. L. Tetrahedron Lett. 1977,14, 1245. (17) Wender, P. A.; White, A. W. / . Am. Chem. Soc. 1988,110, 2218. (18) Cooke, M . P. / . Org. Chem. 1984,49, 1144. (19) Cooke, M . P.; Widener, R. K. / . Org. Chem. 1987, 52, 1381. (20) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 5209. (21) Kocovsky, P.; Srogl, J. / . Org. Chem. 1992, 57, 4565. 209 (22) Bronk, B. S.; Lippard, S. J.; Danheiser, R. L. Organometallics 1993,12, 3340. (23) Piers, E . ; Wong, T. / . Org. Chem. 1993, 58, 3609. (24) Wong, T. Ph.D. Thesis; The University of British Columbia: Vancouver, B. C , 1993. (25) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508. (26) Duncton, M . A. J.; Pattenden, G. / . Chem. Soc, Perkin Trans. 1 1999, 1235. (27) Piers, E . ; Friesen, R. W.; Keay, B. A. J. Chem. Soc, Chem. Commun. 1985, 809. (28) Piers, E. ; Friesen, R. W.; Keay, B. A. Tetrahedron 1991, 47, 4555. (29) Piers, E. ; Romero, M . A ; Walker, S. D. Synlett 1999, 1082. (30) Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L . ; Moretti, R.; Koerner, M . ; Lipshutz, B. H. / . Am. Chem. Soc. 1988,110, 2641. (31) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C ; Liebeskind, L. S. / . Org. Chem. 1994, 59, 5905. (32) Alfred, G.; Liebeskind, L. S. / . Am. Chem. Soc 1996,118, 2748. (33) Tanaka, FL; Kameyama, Y.; Sumida, S.; Torii, S. Tetrahedron Lett. 1992, 33, 7029. (34) Piers, E. ; McEachern, E. J.; Burns, P. A. / . Org. Chem. 1995, 60, 2322. (35) McEachern, E. J. Ph.D. Thesis; The University of British Columbia: Vancouver, B.C., 1997. (36) Piers, E. ; McEachern, E. J.; Burns, P. A. Tetrahedron 2000, 56, 2753. (37) Burfield, D. R.; Smithers, R. S. / . Org. Chem. 1978,43, 3966. (38) Piers, E. ; Boehringer, E. M . ; Yee, J. G. K. / . Org. Chem. 1998, 63, 8642. (39) Boehringer, E. M . M. Sc. Thesis; The University of British Columbia: Vancouver, B. C.,1996. (40) Piers, E . ; McEachern, E. J. Synlett 1996, 1087. (41) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881. (42) Molander, G. Acc Chem. Res. 1998, 31, 603. (43) Wallace, D. J. "Postdoctoral Report", The University of British Columbia, 1996. (44) Abate, D.; Abraham, W.-R. / . Antibiotics 1994, 47, 1348. (45) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671. 210 (46) Mulzer, J. ; in Organic Synthesis Highlights; Mulzer, J., Altenbach, H.-J., Braun, M . , Krohn, K. and Reissig, H.-U., Eds.; V C H Publishers, Inc.: New York, 1991; pp 323-334. (47) Stork, G.; Danheiser, R. L. / . Org. Chem. 1973, 38, 1775. (48) Stork, G.; Danheiser, R. L. ; Ganem, B. / . Am. Chem. Soc. 1973, 95, 3414. (49) Piers, E . ; Tse, H. L. A. Can. J. Chem. 1993, 71, 983. (50) Piers, E . ; Romero, M . A. / . Am. Chem. Soc. 1996,118, 1215. (51) Panouse, J.; Sanie, C. Bull. Soc. Chim. Fr. 1956, 1272. (52) Pereyre, M . ; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987; p 6. (53) Stiles, M . ; Longroy, A. L. / . Org. Chem. 1967, 32, 1095. (54) Burns, P. A. "Postdoctoral Report", The University of British Columbia, 1995. (55) Yee, J. G. K. Ph.D. Thesis; The University of British Columbia: Vancouver, B.C., 2000. (56) Snieckus, V. Chem. Rev. 1990, 90, 880. (57) Meyer, K ; Seebach, D. Chem. Ber. 1980,113, 1304. (58) Wiley, G. A.; Hershkowitz, R. L. ; Rein, B. M . ; Chung, B. C. / . Am. Chem. Soc. 1964, 86, 964. (59) Schaefer, J. P.; Higgins, J. / . Org. Chem. 1967, 32, 1607. (60) Urabe, H.; Suzuki, K.; Sato, F. / . Am. Chem. Soc. 1997,119, 10014. (61) Petasis, N. A.; Patane, M . A. Tetrahedron 1992, 48, 5757. (62) Paquette, L. A.; Nakatani, S.; Zydowsky, T. M . ; Edmondson, S. D.; Sun, L.-Q.; Skerlj, R. / . Org. Chem. 1999, 64, 3244. (63) Paquette, L. A. / . Org. Chem. 1999, 64, 3255. (64) Faulkner, D. J. Nat. Prod. Rep. 1984,1, 251. (65) Iwagawa, T.; Nakamura, K.; Hirose, T.; Okamura, H.; Nakatani, M . J. Nat. Prod. 2000, 63, 468. (66) Mehta, G.; Krishnamurthy, N. / . Chem. Soc, Chem. Commun. 1986, 1319. (67) Mehta, G.; Murthy, A. N. / . Org. Chem. 1987, 52, 2875. (68) Little, R. D.; Ott, M . M . / . Org. Chem. 1997, 62, 1610. (69) Galatsis, P.; Manwell, J. J. Tetrahedron 1995, 51, 665. 21 (70) Criegee, R. Angew. Chem. Int. Ed. Engl. 1975,14, 745. (71) Odinokov, V. N.; Tolstikov, G. A. Russ. Chem. Rev. 1981, 50, 636. (72) Bailey, P.; Lane, A. G. / . Am. Chem. Soc. 1967, 89, 4473. (73) Lee, D. G.; Van den Engh, M . ; in Oxidation in Organic Chemistry; Trahanovsky, W. S., Ed.; Academic Press: New York, 1973; pp 177-186. (74) Schroder, M . ; Stephenson, T. A.; in Comprehensive Coordination Chemistry; Wilkinson, G., Gillard, R. and McCleverty, J., Eds.; Pergamon Press: Oxford, 1987; Vol. 4; pp 277-518. (75) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936. (76) Pretsch, E.; Seibl, J.; Clerc, T.; Simon, W. Tables of Spectral Data for Structure Determination of Organic Compounds; Springer-Verlag: New York, 1989. (77) Cheng, X . - C ; Varoglu, M . ; AbreU, L.; Crews, P.; Lobkovsky, E . ; Clardy, J. J. Org. Chem. 1994, 59, 6344. (78) Wang, G.-Y.-.S.; Abrell, L. M . ; Avelar, A.; Borgeson, B. M . ; Crews, P. Tetrahedron 1998, 54, 7335. (79) Morris, L. A.; Jaspars, M . Tetrahedron 1998, 54, 12953. (80) Paquette, L. A. Recent Synthetic Developments in Polyquinane Chemistry; Springer-Verlag: Heidelberg, 1984; Vol. 119. (81) Piers, E. ; Karunaratne, V. Tetrahedron 1989, 45, 1089. (82) Piers, E. ; Renaud, J.; Rettig, S. J. Synthesis 1998, 590. (83) Nishimura, Y.; Koyama, Y.; Umezawa, J. / . Antibiot. 1980, 33, 404. (84) Singh, V.; Samanta, B. Tetrahdron Lett. 1999, 40, 383. (85) Mizuno, H ; Domon, K.; Masuya, K.; Tanino, K.; Kuwajima, I. / . Org. Chem. 1999, 64, 2648. (86) Kupka, L ; Anke, T.; Giannetti, B. M . ; Steghch, W. Arch. Microbiol. 1981,130, 223. (87) Van Hijfte, L. ; Little, R. D.; Petersen, J. L. ; Moeller, K. D. / . Org. Chem. 1987, 52, 4647. (88) Stone, K. J.; Little, R. D. J. Org. Chem. 1984, 49, 1849. (89) Ito, Y.; Saegusa, T. / . Org. Chem. 1978, 43, 1011. 212 (90) Fevig, T. L.; Elliott, R. L.; Curran, D. J. Am. Chem. Soc. 1988,110, 5064. (91) Kocovsky, P.; Dunn, V.; Gogoll, A.; Langer, V. J. Org. Chem. 1999, 64, 101. (92) Devin, P.; Fensterbank, L. ; Malacria, M . J. Org. Chem. 1998, 63, 6764. (93) Dvorak, C. A.; Dufour, C ; Iwasa, S.; Rawal, V. H. / . Org. Chem. 1998, 63, 5302. (94) Hashimoto, H.; Tsuzuki, K.; Sakan, F ; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1974, 43, 3745. (95) Froborg, J.; Magnusson, G. J. Am. Chem. Soc. 1978,100, 6728. (96) Veschambre, H ; Vocelle, D. Can. J. Chem. 1969, 47, 1981. (97) Rosenberger, M . ; Yates, P. Tetrahedron Lett. 1964, 33, 2285. (98) Piers, E . ; Wong, T.; Ellis, K. A. Can. J. Chem. 1992, 70, 2058. (99) Whitesides, G. M . ; Ehmann, W. J. / . Org. Chem. 1970, 35, 3565. (100) Thompson, H. W.; McPherson, E. ; Lences, B. L. / . Org. Chem. 1976, 41, 2903. (101) Brown, J. Angew. Chem. Int. Ed Engl. 1987, 26, 190. (102) Thompson, H. W.; McPherson, E. / . Am. Chem. Soc. 1974, 96, 6232. (103) Brown, J. M . ; Naik, R. G. / . Chem. Soc, Chem. Comm. 1982, 348. (104) Crabtree, R. H ; Davis, M . W. / . Org. Chem. 1986, 51, 2655. (105) Chaloner, P. A ; Esteruelas, M . A.; Joo, F.; Oro, L. A. Homogenous Hydrogenation; Kluwer Academic Publishers: Dordrecht, 1994; pp 133-142. (106) Ryu, I.; Murai, S.; Hatayama, Y.; Sonoda, N. Tetrahedron Lett. 1978, 37, 3455. (107) Fleming, I.; Paterson, I. Synthesis 1979, 736. (108) Harmon, A. D.; Hutchinson, C. R. / . Org. Chem. 1975, 40, 3474. (109) Danishefsky, S.; Schuda, P. F ; Kitahara, T.; Etheredge, S. J. / . Am, Chem. Soc 1977, 99, 6066. (110) Schreiber, J.; Maag, H ; Hashimoto, N.; Eschenmoser, A. Angew. Chem. Int. Ed Engl. 1971,10, 330. (111) Roberts, J. L. ; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett. 1977,19, 1621. (112) Danishefsky, S.; Zamboni, R.; Kahn, M . ; Etheredge, S. J. / . Am. Chem. Soc 1981, 103, 3460. (113) Perrin, D. D.; Armarego, W. L.; Perrin, D. R. Purification of Laboratory Chemicals; Pergamon Press: Oxford, 1988. 213 (114) Kofron, W. G . ; Baclawski, L . M . / . Org. Chem. 1976, 41, 1879. (115) Koreeda, M . ; Jiang, Y . ; Akagi , H . / . Chem. Soc, Chem. Commun. 1979, 449. 214 

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