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Enantioselective synthesis of the sesterterpenoid (-)-dysidiolide and structurally related analogues Caillé, Sébastien 2002

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E N A N T I O S E L E C T I V E S Y N T H E S E S O F T H E S E S T E R T E R P E N O J X ) ( - ) - D Y S I D I O L I D E A N D S T R U C T U R A L L Y R E L A T E D A N A L O G U E S by S E B A S T L E N C A I L L E B.Sc. (Hons.), Universite de Sherbrooke, 1997 A THESIS S U B M I T T E D FN 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 conforming 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 September, 2002 © Sebastien Caille, 2002 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 ^L^^^h^j The University of British Columbia Vancouver, Canada Date c^f/g-o / p a DE-6 (2/88) ii ABSTRACT The enantioselective total synthesis of the marine natural product (-)-dysidiolide (1) is described in this thesis. In addition, six structural analogues of the sesterterpenoid were synthesized in their enantiomerically pure forms. These substances are (-)-6-epidysidiolide (25), (-)-4,6-bisepidysidiolide (148), (-)-15-epidysidiolide (26), (-)-4,15-bisepidysidiolide (181), (-)-6,15-bisepidysidiolide (27), and (-)-4,6,15-trisepidysidiolide (194) The synthesis o f (-)-dysidiolide (1) started with the conversion of known racemic alcohol 35 into a,(3-unsaturated ketone 38. Diastereoselective addition of cyanocuprate 33 to the conjugated enone function of racemic 38 provided ketone 46. Ozonolytic cleavage o f the alkenic bond of 46 yielded dione 59, which underwent an aldol condensation-dehydration process to afford bicyclic conjugated enone 60. A stereospecific Claisen rearrangement using allylic alcohol 64 (available from 60) as starting material produced racemic tertiary amide 80. A series of transformations were used to obtain racemic alcohol 29 from 80. The two enantiomers o f 29 were separated, and enantiomerically pure alcohol (-)-29 was employed to continue the synthetic endeavor towards (-)-l. The mixture of nitriles 28 was synthesized from (-)-29 via a sequence of reactions. Diastereoselective alkylation of the anion o f 28 with iodide 119 afforded nitrile (-)-120, which was converted into aldehyde (-)-6 in several steps. (-)-Dysidiolide (1) was constructed from (-)-6 according to a known procedure. The anion of 28 was alternatively alkylated with methyl iodide to produce nitrile (—)-118. Ill Structural analogues (-)-25 and (-)-148 were constructed from the latter material. Enantiomerically pure alcohol (+)-35 was synthesized and converted into (-)-60 as described above for its racemic counterpart. A stereospecific Claisen rearrangement using allylic alcohol (-)-63 (available from (-)-60) as starting material provided tertiary amide (-)-149. The remaining four structural analogues of (-)-l, namely (-)-26, (-)-181, (-)-27, and (-)-194 were constructed from (-)-149 using sequences of reactions similar to those that were used to synthesize (-)-l, (-)-25, and (-)-148. (-)-118 (+)-35 « - 6 0 (-)-63 (-)-149 iv T A B L E O F C O N T E N T S A B S T R A C T i i T A B L E O F C O N T E N T S iv L I S T O F T A B L E S v i i i L I S T O F F I G U R E S ix L I S T O F A B B R E V I A T I O N S x A C K N O W L E D G E M E N T S xiv 1. I N T R O D U C T I O N 1 1.1 General introduction 1 1.2 Isolation and biological activity of the sesterterpenoid (-)-dysidiolide .. 5 1.2.1 Isolation of (-)-dysidiolide (1) and elucidation of its structure 5 1.2.2 Biological properties of (-)-dysidiolide (1) 7 1.3 Other synthetic approaches to (-)-dysidiolide 9 1.3.1 The initial approach to (-)-dysidiolide (1) 10 1.3.2 Synthetic approaches to dysidiolide (1) via Diels-Alder reactions . . . 13 1.4 Proposals 19 2. D I S C U S S I O N 22 2.1 Retrosynthetic analysis 22 2.2 Synthesis of (-)-dysidiolide 24 2.2.1 Synthesis o f the racemic ketone 37 24 2.2.2 Synthesis of the racemic a, P-unsaturated ketone 38 27 2.2.3 Synthesis of the racemic cyclohexanone 46 by a conjugate addition reaction 31 2.2.4 Synthesis o f the racemic bicyclic a, P-unsaturated ketone 60 37 2.2.5 Synthesis o f the racemic allylic alcohol 64 40 2.2.6 Synthesis o f the racemic tertiary amide 80 51 2.2.7 Synthesis of the racemic ether 81 56 . 2.2.8 Synthesis o f the racemic secondary alcohol 29 67 2.2.9 Synthesis of the enantiomerically pure alcohol (-)-29 67 2.2.10 Synthesis of the diastereomeric mixture of nitriles 28 75 2.2.11 Synthesis of the enantiomerically pure nitrile (-)-118 82 2.2.12 Synthesis of the iodide 119 87 2.2.13 Synthesis o f the enantiomerically pure nitrile (-)-120 88 2.2.14 Synthesis of the enantiomerically pure primary alcohol (-)-122 91 2.2.15 Synthesis of the enantiomerically pure primary alcohol (-)-131 93 2.2.16 Synthesis of the enantiomerically pure aldehyde (-)-6 98 2.2.17 Synthesis of (-)-dysidiolide (1) 102 2.3 Syntheses of (-)-6-epidysidiolide and (-)-4,6-bisepidysidiolide 117 2.3.1 Synthesis of the enantiomerically pure aldehyde (-)-141 118 2.3.2 Synthesis of the enantiomerically pure (-)-6-epidysidiolide (25) 122 2.3.3 Synthesis o f the enantiomerically pure (-)-4,6-bisepidysidiolide (148). 127 2.4 Syntheses of (-)-15-epidysidiolide and (-)-4,15-bisepidysidiolide 130 vi 2.4.1 Synthesis o f the enantiomerically pure ketone (+)-34 132 2.4.2 Synthesis of the enantiomerically pure alcohol (+)-35 determination of its absolute configuration 138 2.4.3 Synthesis o f the enantiomerically pure tertiary amide (-)-149 143 2.4.4 Syntheses of enantiomerically pure (—)-15-epidysidiolide (26) and (-)-4,15-bisepidysidiolide(181) 144 2.4.5 Determination of the absolute configuration (at C-4) of the alcohols (-)-179 and (-)-180 149 2.5 Syntheses of (-)-6,15-bisepidysidiolide and (-)-4,6,15-trisepidysidiolide .. 153 2.5.1 Synthesis of enantiomerically pure alcohols (-)-186 and (-)-187 154 2.5.2 Determination of the absolute configuration o f alcohol (-)-187 156 2.5.3 Synthesis of the enantiomerically pure secondary alcohol (-)-186 . . . . 162 2.5.4 Synthesis of enantiomerically pure (—)-6,15-bisepidysidiolide (27) . . . 163 2.5.5 Synthesis of enantiomerically pure (-)-4,6,15-trisepidysidiolide (194). 165 3. CONCLUSION 167 4 . BIOLOGICAL ACTIVITY STUDIES 169 5. EXPERIMENTAL 170 5.1 General experimental 170 5.1.1 Data Acquisition and Presentation 170 5.1.2 Solvents and Reagents 173 5.2 Synthesis of (-)-dysidioIide 176 5.3 Syntheses of (-)-6-epidysidiolide and (-)-4,6-bisepidysidiolide 239 5.4 Syntheses of (-)-15-epidysidiolide and (-)-4,15-bisepidysidiolide 252 vii 5.5 Syntheses of (-)-6,15-bisepidysidiolide and (-)-4,6,15-trisepidysidiolide ... 294 6. REFERENCES AND FOOTNOTES 312 7. APPENDIXES 320 7.1 * H nmr spectra 320 7.2 X-ray crystallographic data 327 LIST OF TABLES Table 1. lH nmr (400 M H z , CDC1 3 ) spectral data for the alcohol 35: decoupling experiments 25 Table 2. ' H nmr (400 M H z , CDC1 3 ) spectral data for the alcohol 63: decoupling and nOe difference experiments 43 Table 3. *H nmr (400 M H z , CDC1 3 ) spectral data for the alcohol 64: decoupling and nOe difference experiments 45 Table 4. Comparison of the [ H nmr spectral data of our aldehyde (-)-6 (400 M H z , CDCI3) with those reported by Corey and Roberts for the aldehyde (-)-6 (500 M H z , CDCI3) 100 Table 5. Comparison of the 1 3 C nmr spectral data of our aldehyde (-)-6 (75 M H z , C D C I 3 ) with those reported by Boukouvalas and coworkers for the aldehyde (-)-6 (500 M H z , CDC1 3 ) 101 Table 6. Comparison of the lH nmr spectral data of our synthetic (-)-l (400 M H z , DMSO-fife) with those reported for naturally occurring (-)-l (500 M H z , DMSO-ck) I l l Table 7. Comparison of the 1 3 C nmr spectral data of our synthetic (-)-l (75 M H z , DMSO-^k) with those reported for naturally occurring (-)-l (125.7 M H z , DMSO-tfk) 112 Table 8. *H nmr (400 M H z , CDC1 3 ) spectral data for the amide 80: C O S Y experiment 196 ix LIST OF FIGURES Figure 1 6 Figure 2 25 Figure 3 42 Figure 4. O R T E P representation of the alcohol 85 60 Figure 5. O R T E P representation of the alcohol (-)-147 125 Figure 6. O R T E P representation of the mandelate ester (+)-167 140 Figure 7 141 X LIST OF ABBREVIATIONS A - angstrom a - below the plane of a ring or a 1,2-relative position A c - acetyl A I B N - 2,2'-azobis(isobutyronitrile) anal. - anal. ax - axial P - above the plane of a ring or a 1,3-relative position B n - benzyl bp - boiling point br - broad B u - butyl B z - benzoyl °C - degrees Celsius calcd. - calculated cm - centimeter (s) C O S Y - ( ' H - ' H ) homonuclear correlation spectroscopy C-x - carbon number x d - doublet 5 - chemical shifts in parts per mill ion from tetramethylsilane or a 1,5-relative position A - heat D C C - 1,3-dicyclohexylcarbodiimide D C I - desorption chemical ionization D E A D - diethyl azodicarboxylate D L B A L H - diisobutylaluminum hydride D M E - 1,2-dimethoxyethane D M F - dimethylformamide D M A P - 4-(dimethylamino)pyridine D M S O - dimethyl sulfoxide D D Q - 2,3-dichloro-5,6-dicyano-l,4-benzoquinone ed. - edition Ed. , Eds - editor, editors E I - electron impact ionization epi - epimeric eq - equatorial equiv. - equivalent (s) Et - ethyl g - gram or gaseous glc - gas-liquid chromatography Y - a 1,4-relative position h - hour (s) hv - light H M P A - hexamethylphosphoramide H P L C - high performance liquid chromatography H-x - hydrogen number x H z - hertz / - iso I B X - o-iodoxybenzoic acid IC50 - inhibitory concentration (for 50% of a biological sample) ER. - infrared J - coupling constant K D A - potassium diisopropylamide L D A - lithium diisopropylamide m - multiplet m - meta M - molar M e - methyl mg - milligram (s) ug microgram (s) M H z megahertz min minute (s) m L milliliter (s) u L microliter (S) mm millimeter (s) mmol millimole (s) mol mole (s) mp melting point n normal N M P A /-methylpyrrolidinone nmr nuclear magnetic resonance nOe nuclear Overhauser effect O R T E P - Oak Ridge Thermal Ell ipsoid Plot P page P para Ph phenyl P M B /7-methoxybenzyl ppm parts per million PPTS pyridinium />-toluenesulfonate Pr propyl q quarter R rectus (configuration) rt room temperature s singlet S sinister (configuration) sec secondary t triplet t tertiary T B A F - tetrabutylammonium fluoride T f trifluoromethanesulfonyl T H F tetrahydrofuran T F A trifluoroacetic acid TIPS - triisopropylsilyl T L C thin layer chromatography p - T s C l - /?-toluenesulfonyl chloride v/v volume-to-volume ratio w/v weight-to-volume ratio • - coordination or complex ± racemic xiv ACKNOWLEDGEMENTS I would like to thank Professor Edward Piers, my research supervisor, for his guidance over the years. In particular, his dedication to excellence in research has been a great source of inspiration. In addition, the professional support of the members of the Piers group, past and present, is sincerely appreciated. The assistance of the technical staff of the nmr (in particular Marietta Austria and Lianne Darge), mass spectroscopy, and elemental analysis laboratories is gratefully acknowledged. I want to acknowledge several persons with whom I developed solid personal ties during this stay at U B C . Shawn, Jim, Cris, Gang, A i l i , thank you. A special thank you to Dr. Cerrie Rogers for proofreading this thesis and simply for being herself. Y o u gave me the most important thing, mon amour. Finally, this thesis is dedicated to my parents, for their constant support, and to the memory of Jean-Paul Caille. X V Heureux qui comme Ulysse, a fait un beau voyage Heureux qui comme Ulysse, a vu cent paysages Georges Brassens 1 1. INTRODUCTION 1. 1. General introduction The research discipline of synthetic organic chemistry is centered upon the construction of structurally complex molecules from simple, inexpensive and readily available starting materials. The architecturally complex substances pursued by synthetic chemists may have been isolated in nature, but they can also emanate entirely from one's imagination. Over the last few decades, the pharmaceutical industry has exhibited a growing interest in the production of the latter class of compounds. Indeed, an increasing number of substrates that are not found in nature have been shown to exhibit potent biological activity and have been employed in the composition of a number of prescribed and non-prescribed medications. The pharmaceutical industry experiences a great need to employ synthetic organic chemists that are able to fabricate these complex substances. The organic chemist uses a collection of tools to effect the synthesis of structurally convoluted substances. These tools are chemical transformations. Some of these transformations are closely related to the biosynthetic processes that occur in nature. Other chemical transformations used by synthetic organic chemists are discovered through investigations carried out in this research area. These transformations do not have an equivalent process in nature and often involve reagents that contain heteroatoms (boron, silicon, phosphorus, sulfur, etc.) or metal atoms. To design a chemical transformation unknown in nature and employ it to solve an intricate obstacle in the 2 construction of a structurally complex compound remains an important goal for a synthetic organic chemist and represents one of the most gratifying experiences that she or he can enjoy. In general, the field of synthetic organic chemistry can be divided into two subdivisions. The first subdivision is concerned with the study of particular chemical transformations. Thus, novel chemical processes are thoroughly examined in terms of the reagents and the solvents used, the reaction temperature and the reaction time. The reagents employed in these transformations are often subject to structural changes (when metal complexes are used, for instance). These efforts are all aimed at designing "ideal" experimental conditions for a particular chemical process. These processes can then be utilized with a series of different substrates in order to determine the scope and the limitations of the synthetic method. The second research area that concerns the synthetic organic chemist involves the design and execution of the total synthesis of naturally occurring compounds. A s many of these substances possess complex carbon frameworks, the value of the new methodologies developed (see preceding paragraph) is often assessed by examining their efficacy in the construction of natural products. A vast number of the latter compounds show interesting biological properties. Hence, not only does the synthetic elaboration of naturally occurring substances allow the evaluation of the efficiency o f novel synthetic methods, but it also provides these natural products in sufficient amounts to complete investigations of their biological profile. Moreover, structurally related analogues of these 3 naturally occurring compounds can be prepared through the use of the same synthetic approaches that were designed to construct the natural products. These analogues may exhibit a biological potential that surpasses the one displayed by the natural product. Terpenoids constitute an important family of natural products. These compounds are produced from a common biosynthetic precursor, isopentenyl diphosphate.1 isopentenyl diphosphate c ^ P P = diphosphate In general, these substances are composed of five-carbon units. 2 Terpenoids are classified according to the number of carbon atoms that they possess. Monoterpenoids (Cio), sesquiterpenoids (C15), diterpenoids (C20), sesterterpenoids (C25) and triterpenoids (C30) form the different classes of terpene natural products.1 Dysidotronic acid, 3 xeniaoxolane, 4 umbraculolide B 5 and 3-bromobarakoxide 6 are all examples of diterpene (C20) naturally occurring substances (see Scheme 1). One of the principal interests of the research group led by Dr. Edward Piers is the construction of terpenoids, and the main focus of the research program detailed in this thesis is the total synthesis of a medicinally relevant sesterterpenoid (C25). 4 dysidotronicacid xeniaoxolane Scheme 1 5 1. 2. Isolation and biological activity of the sesterterpenoid (-)-dysidiolide 1.2. 1. Isolation of (-)-dysidiolide (1) and elucidation of its structure Marine sponges are a rich source of architecturally complex and biologically active natural products. Despite their structural complexity, the scarcity o f these substances, in conjunction with their potential medicinal importance, continues to prompt interest in their elaboration via synthesis. (-)-Dysidiolide 7 (1) is a particularly interesting representative of this class of compounds (natural products isolated from marine sponges). This y-hydroxybutenolide terpenoid (1) was isolated from the marine sponge Dysidea etheria de Laubenfels and, in 1996, its structure was reported by Gunasekera, McCarthy, Kelly-Borges, Lobkovsky and Clardy. 7 The sponge specimen was collected by scuba diving at a depth of sixty feet off the coast of Long Island, Bahamas. (-)-! (-)-Dysidiolide (1) exhibits a unique carbon skeleton with an array of carbon chirality centers, including two quaternary carbon centers. The structure of this sesterterpenoid ((-)- l) was determined through an X-ray crystallographic study effected with the isolated substance.7 The perspective drawing of the X-ray structure of 1 is shown 6 in Figure 1. A s can be seen in this perspective drawing, the two large appendages located on the decalin core of 1 (one is constituted of carbons 1, 2, 3, 4, 5 and 25, and the other contains carbons 16, 17, 18, 19, 20 and 21) occupy pseudo-axial and axial positions on the same side of the molecule. The extended conformation of these two substituents lead to the projection of two parallel arms from one of the two sides of the decalin network of the natural product (1). The drawing displays (+)-l, the antipode of the naturally occurring enantiomer of dysidiolide. In fact, the isolation report defined only the relative configuration of the terpenoid (1). The absolute stereochemistry of the isolated species ((-)-l) was determined when the first total synthesis of the natural product ((-)-l) had been completed. 8 In the crystalline form, the relative configuration at C-25 of (-)-dysidiolide (1) is the one depicted in Figure 1 (Figure 1 shows a representation of (+)-l).7 However, the authors of the isolation report7 concluded that the isoprenoid ((-)-l) exists in solution as a mixture of epimers at C-25. This conclusion originated from the doubled signals observed in the  l H nmr and 1 3 C nmr spectra of (-)-l for H a , H-4, C - l , C-2, C-3, C-4 and C-25 (Figure 1). C13 C12 Figure 1 7 1.2.2. Biological properties of (-)-dysidiolide (1) A s disclosed by Gunasekera and coworkers, 7 natural (-)-dysidiolide (1) inhibited the dephosphorylation of /7-nitrophenol phosphate by the human cdc25A protein phosphatase (IC50 o f 9.4 pM) . This enzyme (cdc25A) is expressed early in the G\ phase ( G stands for growth) of the cell cycle and is responsible for the G i / S transition 9 (S stands for synthesis). Synthetic (-)-dysidiolide (1) has also demonstrated notable inhibitory activity against cdc25A (IC50 o f 35 p:M). 1 0 Moreover, this substance (synthetic (-)- l ) has been shown to inhibit the dephosphorylation of /7-nitrophenol phosphate by the human cdc25B protein phosphatase (IC50 of 87 pM) , one of the homologues of the human cdc25A protein phosphatase.1 0 This other enzyme (cdc25B) is considered to be a regulator of the G2 /M transition ( G stands for growth; M stands for mitosis) of the cell cycle. 9 Enforced expression of either of these enzymes (cdc25A or cdc25B) causes cellular transformations that may contribute to the growth of certain types of cancer. In fact, inappropriate amplification of cdc25A or cdc25B is characteristic of a number of human cancers, including breast cancers.9 For that reason, it is believed that inhibitors of these enzymes (human cdc25A and cdc25B) may possess novel antitumor properties. Natural (-)-dysidiolide (1) halted the growth of the A-549 human lung carcinoma and the P388 murine leukemia cell lines with IC50 values of 4.7 p M and 1.5 p M , respectively. 7 This dramatic anticancer activity was corroborated by experiments effected 8 with synthetic (-)-l10 and (±)-l. n Synthetic (-)-l was subsequently tested along with the human cdc25A and cdc25B protein phosphatases and did not exhibit significant inhibitory activity against these two enzymes (cdc25A and cdc25B). 1 2 Hence, even though (-)-dysidiolide (1) has established itself as a potent anticancer agent, its biological mode of action remains unexplained. 9 1. 3. Other synthetic approaches to (-)-dysidiolide The report7 concerning the isolation and structure elucidation of the sesterterpenoid (-)-dysidiolide (1) generated a considerable interest in the synthetic organic chemistry community. As a matter of fact, the [4.4.0] bicyclic nucleus, along with the appendant side chains located at C-6 and C-15 of (-)-l, defined a type of structure not previously encountered in a natural product. 7 Moreover, (-)-dysidiolide (1) exhibits potent antitumor act ivi ty 7 , 1 0 ' 1 1 (see section 1.2) and, thus, this substance might be an important lead for the treatment of cancer or other proliferative disorders. It appeared profitable to design a way to obtain (-)-l in significant amounts in order to pursue the investigation of its biological profile. Thus, several research groups embarked on programs aimed at developing an efficient synthetic route to the natural product ((-)-l) from simple, commercially available starting materials. Three enantioselective total syntheses ' ' and one enantioselective formal total synthesis 1 5 o f (-)-dysidiolide (1) have been reported to date. The antipode of the naturally occurring enantiomer of dysidiolide, (+)-l, has also been synthesized 1 6 via a different approach. Finally, two total syntheses 1 1 ' 1 7 and two formal total syntheses 1 8 ' 1 9 of 10 dysidiolide (1) in its racemic form have been published. The firm interest in this natural product ((-)-l) demonstrated by synthetic organic chemists has been the subject of an article 2 0 published in Chemical & Engineering News. 1. 3. 1. The initial approach to (-Vdysidiolide (1) The first total synthesis of (-)-l reported in the literature was carried out by Corey and Roberts. 8 These researchers synthesized the natural enantiomer of dysidiolide from the known enantiomerically pure bicyclic conjugated enone (+)-221 (see Scheme 2). The alcohol (-)-3 was derived from (+)-2 via a series of chemical steps. A key step of this synthetic effort was the transformation of the tertiary alcohol (-)-3 into the alkene 4. This process permitted the formation of both the C-9,C-10 alkenic bond and the quaternary carbon center at C-15 of (-)-l. Thus, the intermediate (-)-3 was allowed to react with boron trifluoride (BF 3 ) in CH2CI2 at -78 °C for 3 h to afford the alkene 4 (see Scheme 2). 11 (-)-3 1) B F 3 (g), CH 2 C1 2 , -78 °C, 3 h 2) E t 3 N , T H F , H 2 0 , Scheme 2 12 The mechanism proposed by the authors8 to account for the conversion o f (-)-3 into 4 is depicted in Scheme 3. (r-Bu)Me2SiO^ (f-Bu)Me2SKX r Me3Sj ^ \ B F 3 L\OH r i H (f-Bu)Ph2SiCr (-)-3 Me3Si ^ B F 2 (f-Bu)Ph2SiO' H |0 (f-Bu)Me2SiO Me3SiF (f-Bu)Ph2SiO OSiMe2(f-Bu) (f-Bu)Ph2SiCT + HO—BF2 - — - HO=BF2 Scheme 3 Thus, reaction of the hydroxyl function of (-)-3 with boron trifluoride (BF3) forms the intermediate 7. Heterolysis of one of the C - 0 bonds of 7 affords the tertiary carbocation 8. Finally, a stereospecific 1,2-shift (Wagner-Meerwein rearrangement)2 2 of the angular 13 methyl group of 8, along with simultaneous elimination of the trimethylsilyl (MesSi) function, converts adduct 8 into the alkene 4. The alkene 4 was treated with pyridinium /?-toluenesulfonate2 3 (PPTS) in ethanol at 55 °C for 2.5 h (see Scheme 2). This reaction effected the cleavage of /-butyldimethylsilyl ether function of 4 and furnished the primary alcohol (-)-5. The latter substance was obtained in 70% yield from (-)-3. The aldehyde (-)-6 was constructed from the alcohol (-)-5 through a series of reactions. The former pivotal synthetic intermediate ((-)-6) appears in each of the reported synthetic approaches 8 ' 1 1 ' 1 3 ' 1 4 ' 1 6 ' 1 7 ' 1 8 to dysidiolide (1). Corey and Roberts synthesized the sesterterpenoid ((-)- l) from (-)-6 via an efficient two-step sequence of transformations (see section 2.2.17 for details, vide infra). 1. 3.2. Synthetic approaches to dysidiolide (1) via Diels-Alder reactions The majority of the subsequent syntheses of dysidiolide (1) disclosed in the literature employed a Diels-Alder reaction to assemble the bicyclic core of this naturally occurring substance. In every case, the six-membered ring containing the endocyclic C-9,C-10 alkenic bond of 1 was formed in this chemical s tep. 1 1 ' 1 3 ' 1 4 , 1 5 ' 1 6 14 Magnuson, Sepp-Lorenzino, Rosen and Danishefsky 1 1 used such a strategy to achieve a total synthesis of 1 in its racemic form. In the key step of this synthesis, the racemic conjugated diene 9 was allowed to react with the oxolenium type 1 1 dienophile (intermediate 13 in Scheme 4, p. 15) derived by treatment of 10 with MeaSiOTf at low temperature (-90 °C). This intermolecular [2+4] cycloaddition reaction generated the bicyclic intermediate 11 in 67% yield (equation 1). Racemic dysidiolide (1) was subsequently constructed 1 1 from the substance 11. 10 The mechanism ' ' proposed for this Diels-Alder transformation is described Scheme 4. Scheme 4 16 Reaction of one of the oxygen atoms of the acetal function of 10 with trimethylsilyl trifluoromethanesulfonate (MesSiOTf) produces the cationic intermediate 12. Ring opening of the latter species generates the a, P-unsaturated oxolenium 1 1 cation 13. At this stage, an intermolecular [2+4] cycloaddition reaction occurs between intermediate 13 and diene 9 to afford the bicyclic adduct 14. This Diels-Alder reaction proceeds via approach of the dienophile 13 to the P face of 9 (as drawn in Scheme 4) and in an endo fashion relative to the oxolenium function of 13. The acetal product 11 is finally obtained from the bicycle 14 (via intermediate 15) as illustrated in Scheme 4. It should be noted that MesS iOTf is regenerated at the end of the process and is typically used in catalytic • ?S Of\ 77 amounts in this type of transformation. ' ' Boukouvalas, Cheng and Robichaud 1 6 employed a Diels-Alder reaction related to the one utilized by Danishefsky and coworkers 1 1 to build the bicyclic network of (+)-dysidiolide (1). In the work reported by Boukouvalas and coworkers, 1 6 the enantiomerically pure conjugated diene (-)-16 was treated with the doubly activated dienophile 17 in the presence of ethylaluminum dichloride (E tAlCb) at low temperature in CH2CI2 (Scheme 5). This experiment afforded a mixture of the diastereomers (+)-18 and 19 (ratio of (+)-18/19 was 2.3/1) in 76% yield. Thus, the intermolecular [2+4] cycloaddition reaction between (-)-16 and 17 proceeded in an endo fashion relative to the aldehyde function of 17. The mixture of (+)-18 and 19 was treated with lithium triethylborohydride (Super-hydride®, L i E t 3 B H ) in T H F at -78 °C to provide the diols (+)-20 and (-)-21. These substances were easily separable by chromatography on silica gel and were isolated in yields of 43% and 18%, respectively, from the diene (-)-16. The 17 antipode of the natural enantiomer of dysidiolide, (+)-l, was synthesized from the diol (+)-20 via a series of chemical transformations.1 6 (+)-20 (_)-21 Scheme 5 Miyaoka, Kajiwara, Hara and Yamada 1 4 utilized an intramolecular Diels-Alder reaction to construct the decalin core of the naturally occurring substance ((-)- l) . In this work, a solution of enantiomerically pure phenyl sulfoxide 22, pyridine and ethyl 18 propiolate was heated to reflux for 8 h, to afford the lactone 23 in 89% yield. A s depicted in Scheme 6, elimination of the sulfoxide function of the substrate 22 generated the conjugated diene 24. This intermediate, under the reaction conditions, underwent an intramolecular [2+4] cycloaddition reaction to provide the lactone 23. The natural enantiomer of dysidiolide, ( - ) - l , was elaborated from the enantiomerically pure lactone Scheme 6 19 1. 4. Proposals The initial goal of the research program described in this thesis was to achieve a total synthesis o f the naturally occurring enantiomer of the sesterterpenoid (-)-dysidiolide (1) via an approach different from those described 8 ' 1 1 ' 1 4 ' 1 6 in the preceding section of the Introduction (1.3). The key steps of our synthetic plan to construct ( - ) - l involved highly diastereoselective or stereospecific carbon-carbon bond forming processes. In addition, enantioselective syntheses of selected analogues of the sesterterpene natural product ( - ) - l were contemplated. It was suggested by Gunasekera and coworkers 7 in their isolation and structural elucidation report that the spatial proximity (see section 1.2.1, X-ray model of 1 in Figure 1) of the y-hydroxybutenolide-containing side chain of the terpenoid (1) (including C - l - C-5 and C-25) and the aliphatic appendage of the same substance (including C-16 - C-21) could play an important role in the inhibitory activity observed for (-)-dysidiolide (1) (IC50 o f 9.4 u.M) when it was tested against the human cdc25A protein phosphatase. If this hypothesis is correct, the spatial proximity between these two large substituents might also be essential to the potent antitumor activity displayed by ( - ) - l . 7 , 1 0 ' 1 1 We aimed at developing a flexible approach to the natural product ((-)- l ) that would allow us to examine the preceding theory. The structurally related analogues of ( - ) - l which we planned to synthesize to investigate this hypothesis would possess opposite absolute configurations at C-6 and/or C-15 compared to the sesterterpenoid ((-)-!)• 20 Diastereomers of (-)-l in which C-6, C-15 or both of these quaternary carbon centers have absolute configurations opposite to those present in the natural product ((-)-l) would not enjoy close spatial proximity between their two large appendages but would still possess the main structural features of (-)-l. Hence, the synthesis of such structurally related analogues and the evaluation of their respective biological properties should allow us to corroborate or refute the suggestion brought forward by Gunasekera and coworkers 7 concerning the spatial proximity of these two large substituents. The antitumor activity of these selected analogues could also be determined in order to reveal the scope of their biological potential. In brief, the goals of the research program detailed in this thesis were to conceive and execute the enantioselective total syntheses of (-)-dysidiolide (1), 6-epidysidiolide (25), 15-epidysidiolide (26) and 6,15-bisepidysidiolide (27) (see Scheme 7). 26 Scheme 7 22 2. DISCUSSION 2. 1. Retrosynthetic analysis Our strategy for the construction of (-)-dysidiolide (1) was quite different from the synthetic routes to ( - ) - l 8 , 1 1 , 1 4 , 1 6 described in the Introduction (section 1.3). As a matter of fact, we hoped to devise a versatile synthetic approach which would allow us to obtain, along with (-)-l, structurally related analogues of the naturally occurring substance ((-)-l) (see section 1.4). A s described previously (section 1.3.1), the enantiomerically pure aldehyde (-)-6 had already been converted into (—)-dysidiolide via an efficient sequence of reactions.8 We intended to prepare (-)-6 from the nitrile 28 through the use of a series of transformations that would include the diastereoselective alkylation of the anion o f 28 (see Scheme 8). The nitrile 28 would be made from the enantiomerically pure secondary alcohol 29. The enantiomers of the racemic alcohol 29 would be separated to afford the synthetic intermediate (29) in its enantiomerically pure form. The racemic alcohol 29 would be constructed from the ester (or amide) 30. A stereospecific Claisen 28 rearrangement effected with a suitable derivative of the racemic allylic alcohol 31 as starting material would provide the racemic ester (or amide) 30. This 3,3-sigmatropic rearrangement would generate the C-9,C-10 alkenic bond and the quaternary center at C-15 of dysidiolide. A diastereoselective conjugate addition of the cyanocuprate 33 to the racemic a,(3-unsaturated ketone 32 would be the key transformation of the annulation 23 sequence proceeding from 32 to the racemic allylic alcohol 31. Finally, the conjugated enone 32 would be synthesized from the known racemic ketone 34 29 OH H (±)-31 X = O R o r N R 2 (R = alkyl group) P = Protecting group OP (±)-32 + CuCNLi OH enantiomerically pure 29 33 Scheme 8 24 2. 2. Synthesis of (-)-dysidiolide 2. 2. 1. Synthesis o f the racemic ketone 37 The initial step of the total synthesis of (—)-dysidiolide (1) was the diastereoselective reduction of the known racemic ketone 34. 2 9 The reduction of cyclohexanone derivatives with lithium tri-sec-butylborohydride (L-Selectride®) was reported in 1972 by Brown and Krishnamurthy. 3 0 It is well established that this reagent delivers the hydride anion from the equatorial side of the carbonyl group, to yield the corresponding product with an axial hydroxyl group. The reagent usually provides the secondary alcohol adduct with excellent diastereoselectivity. The reduction of ketone 34 with L-Selectride® at low temperature (-78 °C) produced alcohol 35 as a single diastereomer, as depicted in equation 2. Alcohol 35 was isolated as a white crystalline solid (mp 101-102 °C) in quantitative yield. The IR spectrum of 35 possessed a strong O - H stretching absorption at 3458 cm"1 and a ketal C - O - C stretching absorption at 1114 cm"1. The ! H nmr spectrum o f 35 showed a 1-proton signal at 5 3.74-3.78, attributed to the carbinol proton, as well as the characteristic resonances of the ketal function. The relative configuration of 35 was confirmed by a series o f ' H nmr decoupling experiments. Irradiation of the signal corresponding to M e e (5 0.96) (see Figure 2 and Table 1) sharpened the signal at 8 1.81 (loss of 7 = 7.0 Hz) and allowed the identification o f H b . H d O H 35 Figure 2 Table 1: *H nmr (400 M H z . C D C K ) spectral data for the alcohol 35: decoupling experiments Signal irradiated Signals observed Assign-ment 5 (mult., 7 (Hz)) 5 (initial mult., 7 (Hz), assignment) to mult, after irradiation, 7 (Hz). H a 3.74-3.78 (m) 1.81 (dddq, 7 = 2.4, 4.0, 12.8, 7.0, Hb) to ddq,7=4.0, 12.8, 7.0. H b 1.81 (dddq, 7 = 2.4, 4.0, 12.8, 7.0) 3.74-3.78 (m, Ha) to sharpened m 1.90 (dd,7=4.0, 13.1, He) to d , 7 = 13.1. 1.46 (dd ,7= 12.8, 13.1, H j ) to d , 7 = 13.1. 0.96 ( d , 7 = 7 . 0 , M e e ) to s He 1.90 (dd, 7=4.0 , 13.1) 1.81 (dddq, 7 = 2.4, 4.0, 12.8, 7.0, H b ) to ddq,7=2.4, 12.8, 7.0. 1.46 (dd,7= 12.8, 13.1, Hd) to d , 7 = 12.8. H d 1.46 (dd, 7 = 12.8, 13.1) 1.81 (dddq, 7 = 2.4, 4.0, 12.8, 7.0, Hb) to ddq,7=2.4, 4.0, 7.0. 1.90 (dd, 7=4 .0, 13.1, He) to d ,7=4.0 . M e e 0.96 (d,7=7.0) 1.81 (dddq, 7 = 2.4, 4.0, 12.8, 7.0, Hb) to ddd, 7 = 2.4, 4.0, 12.8. 26 Irradiation of Hb (5 1.81) sharpened the signals at 5 3.74-3.78 (sharpened multiplet), 8 1.90 (loss of J= 4.0 Hz) , and 5 1.46 (loss of J= 12.8 Hz) and enabled the identification of H a , He, and Ha, respectively. The multiplet at 5 3.74-3.78 was easily assigned to H a (the carbinol proton) based on its chemical shift. Irradiation o f Ha sharpened the signal associated with Hb (loss of J= 12.8 Hz). The magnitude of the coupling constant between Hb and H d ( J = 12.8 Hz) indicated that both are axial protons. Irradiation of H a sharpened the signal at 5 1.81 (loss of 7 = 2.4 Hz). The magnitude of the coupling constant between H a and Hb (J= 2.4 Hz) revealed that H a is an equatorial proton. From these results, the cis relationship between M e e and the O H group was demonstrated. The hydroxyl function of 35 was protected as a p-methoxybenzyl ( P M B ) ether, as shown in Scheme 9. O C H 3 OCH3 36 37 Scheme 9 The sodium alkoxide of 35 was prepared using N a H and the former intermediate was allowed to react with PMJ3C1 in presence of a catalytic amount of BU4NI to furnish ether 36. The latter substance was treated with a small amount of concentrated hydrochloric 27 acid in acetone to effect the hydrolysis of the ketal function. This sequence afforded ketone 37 in 81% yield from 35. The IR spectrum of ketone 37 displayed a strong C=0 stretching absorption at 1712 cm"1 and an aromatic carbon-carbon stretching absorption at 1613 cm"1. The lH nmr spectrum of 37 revealed, in addition to a 1-proton signal at 5 3.59-3.63, attributed to H a , multiplets at 5 7.25-7.29 and 8 6.86-6.90, associated with the four aromatic protons, doublets at 8 4.60 and 8 4.43, attributed to the two diastereotopic benzylic protons, and a 3-proton singlet at 8 3.79, corresponding to the CH3O- group. 2. 2. 2. Synthesis of the racemic a, (3-unsaturated ketone 38 The next challenge at hand was to synthesize the a,P-unsaturated ketone 38. This substance was required to undertake the annulation sequence which would hopefully lead to the construction of the decalin network of (-)-dysidiolide. O O P M B 38 A sequence was developed in 1992 by Magnus, Evans and Lacour 3 1 to transform a ketone into the corresponding conjugated enone. This process involved reaction of alkenyl triisopropylsilyl (TIPS) ethers with Me3SiN3 and iodosobenzene (PhIO), thus producing P-azido alkenyl silyl ethers. These substrates were treated with T B A F , to furnish the corresponding conjugated enones. Hence, the alkenyl silyl ethers 40 and 41 were 28 obtained from deprotonation of the ketone 37 with a strong base, followed by treatment of the resultant enolate anions with TLPSOTf, as portrayed in Scheme 10. O OTIPS OTIPS 1) (Me 3 Si) 2 NK, T H F PhIO, M e 3 S i N 3 , -78 °c r I + r 1 cH2ci2 N * A 2) TIPSOTf, E t 3 N , ^ ^ ^ n - 2 5 ° C t o - 1 8 ° C OPMB OPMB OPMB T H F , -78 °C 37 40 41 OTIPS OTIPS O O 42 43 38 39 Scheme 10 Preliminary investigations showed that (Me 3Si)2NK was the base that offered the highest 40/41 ratio (3.3/1) for the conversion of 37 into these alkenyl triisopropylsilyl (TIPS) ethers. Substances 40 and 41 were not separable by chromatography on silica gel and were treated without further purification with M e 3 S i N 3 and PhIO to provide the corresponding P-azido alkenyl silyl ethers 42 and 43. The mixture of 42 and 43, upon treatment with T B A F in T H F at -40 °C and subsequent separation of the products by flash chromatography on silica gel, generated the conjugated enones 38 and 39. The sequence furnished enone 38 in 59% yield and enone 39 in 20% yield from ketone 37. The T B A F treatment had to be carried out at low temperature (-40 °C) and the resultant reaction mixture had to be filtered through silica gel prior to the aqueous workup, in order to avoid the appearance of baseline material upon analyses of the crude product by thin layer chromatography. The presence of this baseline material was accompanied by a 29 significant reduction in the yields of substances 38 and 39. In fact, compounds 38 and 39 decomposed and produced the same baseline material when treated with T B A F in T H F at room temperature. The IR spectra of enones 38 and 39 revealed strong C=0 stretching absorptions at 1681 cm"1 and 1674 cm"1, respectively, characteristic of a,(3-unsaturated ketone functions. The  l H nmr spectrum of 38 possessed a doublet of doublets at 5 6.81 and a doublet at 8 5.97, derived from the two alkenyl protons. The ! H nmr spectrum of 39 displayed a singlet at 8 5.81, attributed to its alkenyl proton, and a 3-proton singlet at 8 1.95, due to the allylic methyl group. Despite the fact that the method described above afforded enone 38 in a reasonable yield, a recent report by Nicolaou, Zhong, and Baran 3 2 prompted us to investigate a more efficient route to 38. Nicolaou and coworkers 3 2 used o-iodoxybenzoic acid ( IBX) to generate, in a single step, conjugated enones from secondary alcohols and ketones. The proposed mechanism 3 2 for the conversion of ketones into conjugated enones is depicted in Scheme 11. 30 45 Scheme 11 It is suggested that the enol form of the ketone (44) reacts with the protonated form of o-iodoxybenzoic acid to produce, after a proton transfer and the loss of a molecule of H 2 0 , the intermediate 45. The latter adduct then undergoes an elimination step to afford the conjugated enone. 31 Ketone 37 was treated with two equivalents of D3X in a mixture of toluene and D M S O at 70 °C for 48 hours, as shown in equation 3. This reaction furnished the enones 38 and 39 in isolated yields of 58% and 14%, respectively. Consequently, the regioselectivity of the transformation (ratio 38/39 = 4/1) was improved in comparison to the Magnus protocol and the overall yield of 38 remained virtually the same. The single-step procedure developed by Nicolaou and coworkers 3 2 for the synthesis o f conjugated enones from ketones presented obvious advantages in terms of time compared to the Magnus three-step protocol. 3 1 The conversion of 37 into 38 had to be effected on a large scale (-15 g of 37) since a relatively large amount (25 g) of compound 38 had to be synthesized. The economy in time provided by the use of the method elaborated by Nicolaou and coworkers 3 2 was particularly apparent when the transformation was performed on large scale. O O p IBX, DMSO, x,,^/ toto'7°°C, + 1 J P ) OPMB OPMB 37 38 2. 2. 3. Synthesis of the racemic cyclohexanone 46 by a conjugate addition reaction The initial step of the annulation sequence which would bring about the construction of the decalin core of (-)-l involved the synthesis of the functionalized cyclohexanone 46. 32 O O P M B 46 Addition of a cuprate reagent to the ct,P-unsaturated ketone 38 was deemed to be a suitable method to obtain 46. It has been suggested that the preferred mode of attack of organometallic reagents to a, P-unsaturated ketones is perpendicular to the n system of the enone so that continuous interaction of the developing sigma bond with the % system is possible through the transition state.3 3 As conjugate addition reactions are typically under kinetic control, 3 4 the stereochemical outcome has often been explained on the basis of attack of the nucleophile perpendicular to the % system of the enone (stereoelectronic control) and from the least hindered side of the molecule (steric control). 3 5 Two possible half-chair conformations that the enone 38 can adopt are 47 and 48, as described in Scheme 12. 33 " chair " conformer 48 » boat " Scheme 12 Attack of a cuprate nucleophile (Y") perpendicular to the n system of the enone from the top face of 47 (path A ) proceeds through a chair-like transition state to give the enolate 49. On the other hand, approach of the nucleophile in a perpendicular fashion to the enone from the bottom face o f 47 (path B) proceeds through a boat-like transition state to provide the enolate 50. Clearly, the transition state leading from 47 to the intermediate 50 is energetically less favorable than the corresponding transition state proceeding from 47 to the enolate 49. As a matter of fact, the transition structure leading to 50 has a boat-like conformation and is further destabilized by the steric interactions between the incoming nucleophile and the /7-methoxybenzyl ( P M B ) ether substituent. Approach of the cuprate nucleophile (Y") from the bottom face of conformer 48 (path C) proceeds through a chair-like transition state to furnish the enolate 51. However, attack of the nucleophile from the top face of 48 (path D) proceeds through a boat-like transition state to afford the enolate 52. The transition states leading from 48 to the 34 intermediates 51 and 5 2 are both energetically disfavored compared to the transition state proceeding from 4 7 to the enolate 49 . Indeed, the transition structure leading to 5 2 has a boat-like conformation and the transition structure leading to 5 1 is destabilized by the steric interactions between the incoming nucleophile and the two ring substituents (y>methoxybenzyl ether and Me a ) . Therefore, the transition state leading to the enolate 4 9 is the energetically most favorable of the four possible transition states (paths A , B , C, and D) and 4 9 should be the predominant adduct obtained from the addition of the cuprate nucleophile on the enone 38 . The enolate 4 9 gives rise to the trans isomer 46 . As wi l l be detailed below, the cyclohexanone 4 6 was the only diastereomer furnished by the conjugate addition reaction. The lower order cyanocuprate 3 3 was the reagent chosen to transform the conjugated enone 3 8 into the functionalized cyclohexanone 4 6 (Scheme 13). The iodide 5 3 , necessary for the formation of the cuprate 3 3 , was prepared from the known primary 36 alcohol 54 , as presented in Scheme 13. Treatment of 54 withp-TsC\ and Et3N afforded the crude tosylate 55 , which was allowed to react with N a l in acetone at 50 °C to generate 5 3 in 78% yield from 54 . The ' H nmr spectrum of 5 3 showed a 2-proton triplet at 8 3.16, attributed to the methylene protons of the -CH2I group. The 1 3 C nmr spectrum of 5 3 displayed a carbon signal at 8 6.4, ascribed to the carbon of the - C H 2 I group. 35 OPMB 38 cuprate 33 OPMB 46 OH 54 /?-TsCl E t 3 N C H 2 C 1 2 rt 55 Nal , acetone, 50 °C Cu(CN)Li 33 53 OTs Scheme 13 First attempts to prepare the cuprate 33 employed a procedure similar to that developed by Piers and Mara is . 3 7 However, attempts to generate the primary alkyllithium 56 (Scheme 14) by treatment of 53 at low temperature (-78 °C) with 2 equivalents of M3uLi in T H F resulted in the formation of a large amount of the Wurtz-type coupling product 57 (equation 4). 2 equiv. J-BuLi THF, -78 °C 53 (4) The same undesirable result, involving the use of T H F as solvent in the lithium-iodine exchange of primary iodides with / - B u L i , was noticed by Bailey and Punzalan. 3 8 36 They proposed the use of a mixture of pentane and E t 2 0 as solvents to circumvent this problem. In agreement with the protocol reported by Bailey and coworker 3 8 for lithium-iodine exchange reactions, the iodide 53 was treated with two equivalents of 7-BuLi in a mixture of pentane and E 1 2 O (9:1, respectively) at low temperature (-78 °C), to afford a solution of the alkyllithium 56 (Scheme 14). 2 equiv. f-BuLi Li pentane, E t 2 0, 53 -78 °C 56 CuCN, E t 2 0, -40 °C, 10 min ,Cu(CN)Li 33 Scheme 14 This solution was cannulated into a cold (-60 °C) slurry of C u C N in E t 2 0 and the resultant mixture was warmed to -40 °C for 10 min to form the cyanocuprate reagent 33. Trimethylsilyl bromide ( M e 3 S i B r ) 3 9 and the conjugated enone 38 were added to the solution of 33 at low temperature (-78 °C) and the resultant mixture was stirred for 2 h. The reaction mixture was treated with aqueous NH4CI-NH3 (pH 8), warmed to room temperature, and stirred open to the atmosphere until the aqueous phase became deep blue. A n aqueous workup was effected and the crude alkenyl trimethylsilyl ether 58 was obtained. This material was dissolved in T H F and was allowed to react with T B A F at room temperature. The latter treatment, after an aqueous workup and chromatography of the resultant crude residue on silica gel, furnished the cyclohexanone 46 as a single diastereomer in 84% yield from 38 (Scheme 15). The JR spectrum of 46 possessed a 37 strong C = 0 stretching absorption at 1713 cm"1, characteristic of a cyclohexanone derivative. The lH nmr spectrum of 46 showed 1-proton singlets at 8 4.69 and 8 4.63, attributed to the two alkenyl protons. The same spectrum also displayed a 3-proton singlet at 8 1.68, attributed to the allylic methyl group. The stereochemical assignment of 46 was confirmed at a later stage of the synthesis. O S i M e 3 1) Me 3 SiBr, 38, E t 2 0 , 7 8 o r / ^ C u C N L i 33 2) Aqueous N H 4 C I/NH3 (pH8),rt O P M B 58 TBAF, THF, rt O P M B 46 Scheme 15 2. 2. 4. Synthesis o f the racemic bicyclic a.P-unsaturated ketone 60 The keto alkene 46 was treated with ozone (O3) and Sudan Red 7B in a mixture of CH2CI2 and C H 3 O H ( C H 2 C 1 2 / C H 3 0 H : 2/1) at -78 °C (see equation 5). O 1 \ r\ c J r>„J -7T3 O O 1) 0 3 , Sudan Red 7B, CH 2 C1 2 , C H 3 O H , -78 °C M e a (5) O P M B 2) M e 2 S O P M B 46 59 38 This treatment effected the ozonolytic cleavage of the alkenic bond of 46. Veysoglu, Mitscher and Swayze 4 0 initially reported the use of Sudan Red 7B in carbon-carbon double bond ozonolysis reactions. Sudan Red 7B Sudan Red 7B is a red dye and therefore confers a deep red color to the reaction mixture to which it is added. One of the nitrogen-nitrogen double bonds o f Sudan Red 7B reacts with O3 and the products of this reaction are colorless. Thus, a colorless solution is obtained when Sudan Red 7B has been entirely consumed by the reagent (O3). In the present case (equation 5), Sudan Red 7B reacts with O 3 at a rate substantially lower than that of reaction of O 3 with the alkenic bond o f 46. Therefore, the disappearance of the red color of the reaction mixture (implying complete disappearance of Sudan Red 7B) meant that the alkenic bond of 46 had entirely reacted with O 3 and the color change was used as an end-point indicator of the ozonolysis process. After a colorless solution had been obtained, dimethyl sulfide (Me2S) was added and the reaction mixture was warmed to room temperature. The solution was stirred for 12 h at room temperature and concentrated in vacuo. The resultant crude residue was purified by chromatography on silica gel to furnish the dione 5 9 in 93% yield. The ' H nmr spectrum of 5 9 showed a 3-proton singlet at 8 2.10, attributed to M e a . The 1 3 C nmr 3 9 spectrum of 5 9 displayed signals at 5 211.3 and 8 208.2, due to the two carbonyl carbon atoms. The dione 59 was allowed to react with sodium hydroxide (NaOH) in CH3OH at reflux for 48 h to provide the bicyclic a,J3-unsaturated ketone 60 (equation 6). 59 60 This transformation finalized the annulation sequence that had been started with conjugate addition of the lower order cyanocuprate 33 to the a,(3-unsaturated ketone 38. O 33 O P M B 38 The aldol condensation-dehydration process afforded the conjugated enone 60 in 92% yield. The IR spectrum of 60 displayed a strong C = 0 stretching absorption at 1682 cm"1, characteristic o f a conjugated enone. The ! H nmr of spectrum of 60 showed a 3-proton singlet at 8 1.81, attributed to M e a . 2. 2. 5. Synthesis of the racemic allylic alcohol 64 40 Two notable features of the structure of (-)-dysidiolide (1) are the C-9,C-10 carbon-carbon double bond and the adjacent quaternary center at C-15 (see Scheme 16). 64 Intermediate 61 3,3-sigmatropic rearrangement Scheme 16 41 As mentioned previously (see section 2.1), it was proposed that these structural entities could be generated through a Claisen rearrangement41 involving an intermediate such as 61 . This 3,3-sigmatropic rearrangement would furnish a product ( 62 ) that possesses the required C-9,C-10 alkenic bond and the quaternary carbon chirality center at C-15. The adduct 6 2 would be a useful intermediate for the construction of (-)-dysidiolide (1). Considering that this sigmatropic rearrangement was expected to be a stereospecific process, it was necessary to carry out the sequence starting with the allylic alcohol 6 4 (and not with its epimer at the carbinol center, the allylic alcohol 6 3 ) in order to synthesize the product (62) with the correct relative configuration at C-15. Thus, the bicyclic enone 6 0 had to be reduced diastereoselectively to afford 64 . Reduction o f the carbonyl function of 6 0 using D I B A L H at low temperature (-98 °C) gave a mixture of the allylic alcohols 6 3 and 6 4 (equation 7). 1) D I B A L H , THF, -98 °C, l h I I ' I + I I I ( 7 ) 2 ) N a 2 S 0 4 - 10H 2 O, ™ E t 2 0 , it, 1 h 6 0 2 6 3 The diastereomeric alcohols 6 3 and 6 4 were easily separated by chromatography on silica gel and were isolated in yields of 47% and 51%, respectively. The LR spectra of 6 3 and 6 4 displayed strong O - H stretching absorptions. The relative configurations of 6 3 and 6 4 were ascertained by the following : H nmr experiments (see Tables 2 and 3). Initially, H a , Hb, He and Med were identified in the ! H nmr spectra of 6 3 and 6 4 (see Figure 3). O C H 3 O C H 3 63 64 Figure 3 H a in compounds 63 and 64 are carbinol protons and thus were easily assigned by their chemical shifts (8 4.51-4.55 for 63 and 8 4.68-4.73 for 64). The 3-proton doublets at 8 0.98 and 8 1.13 in the spectra of 63 and 64, respectively, were attributed to Mea in these two substances. He gave rise to a doublet of doublets at 8 3.49 in the spectrum of 63 and to a doublet of doublets at 8 3.11 in the spectrum of 64. In order to identify Hb in the *H nmr spectra of 63 and 64, proton decoupling experiments were performed. Irradiation of H c (8 3.49) in the *H nmr spectrum of 63 generated sharpened multiplets at 8 2.14-2.25 and 8 2.44-2.56 (see entry 4, Table 2). Irradiation of Mea (8 0.98) in the same spectrum caused sharpening of the signal at 8 2.44-2.56 but did not affect the signal at 8 2.14-2.25 (see entry 5, Table 2). Moreover, irradiation o f the multiplet at 8 2.44-2.56 in the spectrum of 63 (see entry 3, Table 2) caused the 3-proton signal at 8 0.98 (Med) to appear as a singlet (loss of J- 7.0 Hz) and the 1-proton signal at 8 3.49 (He) to show as a doublet (loss of one coupling constant, J= 7.4 Hz). Finally, irradiation of the multiplet at 8 2.14-2.25 in the spectrum of 63 (see entry 1, Table 2) caused the signal at 8 3.49 (FL) to show as a doublet (loss of one coupling constant, J = 11.6 Hz) but did not alter the 3-proton signal at 8 0.98 (Me d ) . Hence, the signal at 8 2.14-2.25 in the ! H nmr spectrum of 63 was assigned to Hb and the signal at 8 2.44-2.56 in the same spectrum was attributed to He. Table 2: *H nmr f400 M H z . C D C M data for the alcohol 63: decoupling and nOe difference experiments OCH3 63 Entry Signals irradiated Decoupling experiments (signals observed) nOe cor-relations 3 Assign-ment 8 ppm (mult., J (Hz)) 8 ppm (initial mult., / (Hz), assignment) to mult, after irradiation, J (Hz). 1 H b 2.14-2.25 (m) 3.49 (dd, 7=7.4 , 11.6, H c ) to d, .7=7.4 H a , M e d 2 H a , Hf 4.51-4.55 (m) H b , M e d 3 He 2.44-2.56 (m) 3.49 (dd,7=7.4, 11.6, H=)tod, 7 = 11.6, 0.98 (d, J = 7 . 0 , M e d ) to s 4 He 3.49 (dd, .7=7.4, 11.6) 2.14-2.25 (m, H b ) to sharpened m 2.44-2.56 (m, He) to sharpened m 5 M e d 0.98 (d, .7=7.0) 2.44-2.56 (m, He) to sharpened m H a , Hb, He "Only those nOe correlations that could be unambiguously assigned are recorded. 44 Irradiation of H c (8 3.11) in the [ H nmr spectrum of 64 produced a sharpened multiplet at 8 2.61-2.69 (see entry 3, Table 3). Irradiation of Med (8 1.13) in the same spectrum (see entry 4, Table 3) did not affect the signal at 8 2.61-2.69. Finally, irradiation of the multiplet at 8 2.61-2.69 in the spectrum of 64 (see entry 1, Table 3) brought about the loss o f one of the coupling constant (J = 10.6 Hz) of the signal at 8 3.11 (He) but did not alter the signal at 8 1.13 (Mea). The signal at 8 2.61-2.69 in the  l H nmr spectrum of 64 was therefore assigned to Hb. 45 Table 3: *H nmr (400 M H z . C D C h ) data for the alcohol 64: decoupling and nOe difference experiments OCH3 64 Entry Signals irradiated Decoupling experiments (signals observed) nOe cor-relations 3 Assign-ment 5 ppm (mult., 7 (Hz)) 5 ppm (initial mult., 7 (Hz), assignment) to mult, after irradiation, 7 (Hz). 1 H b 2.61-2.69 (m) 3.11 (dd,7=4.2, 10.6, H e ) t o d , 7 = 4.2 M e d 2 H a 4.68-4.73 (m) M e ; 3 H c 3.11 (dd, 7=4 .2 , 10.6) 2.61-2.69 (m, H b ) to sharpened m 4 M e d 1.13 (d,7=7.2) N o sharpening of the H b signal H b a Only those nOe correlations that could be unambiguously assigned are recorded. The coupling constant (7) between Hb and H c is 11.6 H z in the spectrum of 63 and 10.6 H z in the spectrum of 64. This indicates that Hb and H c are axial protons and that they have a trans relationship with one another (as shown in Figure 3). The preceding conclusions imply that the relative configuration of the carbon bearing Hb in 63 and 64 is the one depicted in Figure 3, and, consequently, that the conjugate addition of the lower order cyanocuprate 33 on the a,P-unsaturated ketone 38 proceeded with the expected diastereoselectivity. 46 O .Cu(CN)Li 6 33 O P M B 38 The signals corresponding to H a , Hb, H c and Mea had been identified in the *H nmr spectra of 63 and 64. Therefore, it was possible to ascertain the relative configurations of these two substances. The following *H nmr nOe difference experiments were used to achieve this objective. Irradiation of the signal at 8 2.14-2.25 (Hb) in the J H nmr spectrum of 63 (see entry 1, Table 2) caused an enhancement of the signal at 8 0.98 (Mea) and vice versa (see entry 5, Table 2). Furthermore, irradiation of the same signal (8 2.14-2.25) (see entry 1, Table 2) generated an enhancement of the signal at 8 4.51-4.55 (the part of the multiplet attributed to H a ) and vice versa (see entry 2, Table 2). Finally, irradiation of the signal at 8 0.98 (Mea) in the same spectrum (see entry 5, Table 2) produced an enhancement of the signal at 8 4.51-4.55 (the part of the multiplet associated with H a ) and vice versa (see entry 2, Table 2). In the *H nmr spectrum of 64, irradiation of the doublet at 8 1.13 (Mea) (see entry 4, Table 3) brought about an enhancement of the signal at 8 2.61-2.69 (Hb) and vice versa (see entry 1, Table 3). On the other hand, irradiation of the multiplet at 8 2.61-2.69 (H b ) (see entry 1, Table 3) or the doublet at 8 1.13 (Mea) (see entry 4, Table 3) in the same spectrum (64) did not cause an enhancement of the signal at 8 4.68-4.73 (H a ) , nor did irradiation of the signal at 8 4.68-4.73 (H a ) (see entry 2, Table 3) give rise to enhancement of the multiplet at 8 2.61-2.69 (Hb) or the doublet at 8 1.13 (Mea). 47 Irradiation of the doublet associated with Mea (5 0.98) (see entry 5, Table 2) or the multiplet derived from Hb (5 2.14 :2.25) (see entry 1, Table 2) in the *H nmr spectrum of 63 generated an enhancement of the part of the multiplet (5 4.51-4.55) corresponding to H a . A s detailed above, no such signal enhancements were observed in the experiments conducted with alcohol 64. Consequently, the ! H nmr nOe difference experiments described above collectively allowed the determination of the relative configurations of allylic alcohols 63 and 64. The conclusions drawn from these nOe experiments were corroborated by X-ray crystal structures of subsequent intermediates in the synthesis. Reduction of the carbonyl group of the a , (3-unsaturated ketone 60 was investigated with a series of different reducing agents. The diastereoselective reduction of the conjugated enone 60 to generate the allylic alcohol 64 was required. Lansbury and M a c L e a y 4 2 reported that the reduction of cyclohexanone derivatives with LiAlELt or NaBH4 proceeds primarily by delivery of hydride from the axial side of the carbonyl function to provide the corresponding product with an equatorial hydroxyl group. This adduct was the major product of the reaction in all the cases studied. 4 2 In agreement with these results, treatment of the conjugated enone 60 with L i A l H 4 in T H F at -78 °C afforded the alcohols 63 (equatorial hydroxyl group) and 64 (axial hydroxyl group) in isolated yields of 72% and 18%, respectively (Scheme 17). 48 N a H C 0 3 , rt Scheme 17 When the enone 60 was allowed to react with NaBFL; in C H 3 O H at -78 °C, in the presence of C e C b • 7 H2O, the allylic alcohol 63 was obtained as the exclusive product of the reaction (93%). The C e C h • 7 H 2 0 reagent was used in this case to avoid reduction of the alkenic bond o f the conjugated enone function. 4 3 Amann et al.44 reported that the reduction of the enone function of 65 using the conditions described by Luche and coworkers 4 3 (NaBFLi, C e C l 3 • 7 H 2 0 , C H 3 O H , T H F , room temperature) afforded exclusively the allylic alcohol 66 (see Scheme 18). This substance (66) contains a pseudo-equatorial hydroxyl group. 49 Scheme 18 A s demonstrated by Brown and Krishnamurthy, lithium tri-sec-butylborohydride (L-Selectride®), in the absence of other important effects, reduces cyclohexanone derivatives predominantly from the equatorial side of the carbonyl function to yield the corresponding substance with an axial hydroxyl group as the major product. When the conjugated enone 65 was allowed to react with lithium tri-sec-butylborohydride (L-Selectride®) in T H F (see Scheme 18), and the reaction mixture was then treated with basic aqueous hydrogen peroxide (NaOH, H2O2, H 2 O , room temperature), the allylic alcohol 67 was produced as a single diastereomer. 4 4 The allylic alcohol function generated in this reaction possesses a pseudo-axial hydroxyl group. Thus, the reduction of the conjugated enone function of 65 with NaBH4 and the reduction of the same function with L-Selectride® proceeded from opposite faces o f the carbonyl group of the substrate to provide the epimers 66 and 67, respectively. 4 4 50 Bearing in mind the aforementioned results (Scheme 18) and considering that the reduction of the bicyclic enone 60 with N a B F L provided exclusively the allylic alcohol 63 (Scheme 17), the reduction of the carbonyl group of the enone 60 with L-Selectride® was investigated. However, treatment of 60 with lithium tri-sec-butylborohydride (L-Selectride®) in T H F at -78 °C (equation 8) generated, after the requisite basic aqueous hydrogen peroxide treatment, the alcohol 63 as a single diastereomer in 91% yield. Examination o f molecular models of the a,(3-unsaturated ketone 60 did not lead to a conclusive rationale concerning the result of this experiment (equation 8). The allylic alcohol 64 was the intermediate substance required to pursue our synthetic efforts towards (-)-dysidiolide (1) and, as detailed above, it had not been possible to synthesize this intermediate (64) through a diastereoselective reduction of the carbonyl group of 60. Therefore, a Mitsunobu sequence 4 5 was carried out starting with the allylic alcohol 63. The intermediate 63 was allowed to react with triphenylphosphine (PPI13), benzoic acid (PhCOaH) and diethyl azodicarboxylate ( D E A D ) in T H F at room temperature for 6 h (Scheme 19). This reaction afforded, after an aqueous workup, the benzoate 68. Without further purification, crude 68 was treated with L i A l F L in Et20 at 0 °C for 1 h to provide, subsequent to an aqueous workup and purification of the resultant crude material by chromatography on silica gel, the alcohol 64 in 72% yield from 63. A combination of reduction of the conjugated enone 60 using D D 3 A L H in T H F at low H 2 0 , r t P M B O P M B O 60 63 51 temperature (-98 °C) (see equation 7) and the Mitsusobu sequence presented here, allowed the overall conversion of 60 into allylic alcohol 64 in 80% yield. P M B O 63 68 1) L i A l H 4 , E t 2 0 , 0 °C, 1 h 2) H 2 0 , rt i f Scheme 19 2. 2. 6. Synthesis of the racemic tertiary amide 80 The 3,3-sigmatropic rearrangement proposed previously (see Scheme 16) was now required, using the allylic alcohol 64 as starting material. This important step would introduce the requisite C-9,C-10 alkenic bond and the quaternary carbon center at C-15 with the correct relative configuration for the synthesis of dysidiolide (1) (see Scheme 16). The protocol developed by Johnson and coworkers 4 6 for the rearrangement of ketene acetals into y,5-unsaturated esters was the initial method considered to effect this Claisen rearrangement.41 This protocol involves the treatment of an allylic alcohol intermediate (69) with excess ethyl orthoacetate ( (E tO^CMe) in the presence o f a catalytic amount of 52 propionic acid (EtCChH) at high temperature (-140 °C). A s shown in Scheme 20, the formation of the ketene acetal intermediate (70) precedes the 3,3-sigmatropic rearrangement. The latter process then affords the y,5-unsaturated ester product (71). This practical method allows the preparation of the precursor (70) and the subsequent 3,3-sigmatropic rearrangement to take place in the same reaction vessel. O H R (EtO) 3CMe, cat. E t C 0 2 H R 5 69 -140 °C OEt A R OEt 3,3-sigmatropic rearrangement Rj and R 2 = alkyl groups R 2 70 Scheme 20 The allylic alcohol 64 was treated with excess ( E t O ) 3 C M e at 135 °C in the presence of a catalytic amount of E t C C h H (equation 9) to provide the ester 72 in 59% yield and the conjugated diene 73 in 30% yield. C k JX^ . M e , (EtO) 3CMe, cat. E t C 0 2 H 135 °C + (9) P M B O 64 72 73 The ER spectrum of 72 showed a strong C=0 stretching absorption at 1743 cm"1, characteristic o f an ester function. The ' H nmr spectrum of 72 exhibited a 1-proton multiplet at 5 5.34-5.39, attributed to the alkenyl proton, a 2-proton quartet at 5 4.03, associated with the Hb protons, a 3-proton triplet at 6 1.32, corresponding to M e c , and a 3-53 proton singlet at 8 1.15, derived from the tertiary methyl group (Me a ) . The *H nmr spectrum of 73 displayed a 1-proton doublet at 5 5.44 and a 1-proton multiplet at 8 5.53, corresponding to the two alkenyl protons. The same ' H nmr spectrum showed a 3-proton singlet at 8 1.76, due to the allylic methyl group. The alcohol 64, when stored at 0 °C, slowly loses water to form the diene 73. However, this reaction does not take place i f 64 is stored over K 2 C O 3 (as a solution in E t 2 0 ) . The preceding observations suggest (not surprisingly) that the formation of the diene 73 is an acid-catalyzed process. If this is correct, treatment of 64 under acidic conditions should be avoided unless the conjugated diene 73 is the desired reaction product. Eschenmoser and coworkers 4 7 designed a method to perform Claisen rearrangements which is similar to the protocol elaborated by Johnson and coworkers. 4 6 This former method involves treatment of a substrate containing an allylic alcohol function (74) with excess AyV-dimethylacetamide dimethyl acetal (Me2NC(OMe)2Me) in toluene at high temperature (-140 °C). A ketene A^O-acetal intermediate (75) is formed during the course of the reaction (Scheme 21) and undergoes a 3,3-sigmatropic rearrangement to yield a y,8-unsaturated amide product (76). In contrast with the protocol developed by Johnson and coworkers, 4 6 the method elaborated by Eschenmoser and coworkers 4 7 to effect Claisen rearrangements does not include acid catalysis. 54 OH R 74 Me 2 NC(OMe) 2 Me toluene • i -140 °C N M e , R. R? 75 N M e , 3,3-sigmatropic rearrangement R l and R 2 = alkyl groups Scheme 21 The efficacy of the latter method was exemplified in the elegant total synthesis of the Stemona alkaloid (-)-stenine (Scheme 22) reported by Wipf, K i m and Goldstein. 4 8 In one of the key sequences of the synthesis, the tertiary amide 79 was obtained in 77% yield from the conjugated enone 77. H 1) NaBFL,, C e C l 3 • 7 H 2 0 0 M e C H 3 O H , T H F , 4 0 ° C 2) aqueous N a H C 0 3 , rt HO 77 Me 2 NC(OMe) 2 Me, xylenes, 130 °C O Me 2 N N OMe 79 Scheme 22 55 In view of the result described above (equation 9), it seemed likely that the "acid free" method developed by Eschenmoser and coworkers 4 7 would represent a more suitable protocol to effect the desired 3,3-sigmatropic rearrangement than the method designed by Johnson and coworkers. 4 6 Gratifyingly, treatment of the allylic alcohol 64 with excess Me 2 NC(OMe)2Me in toluene at 100 °C for 4 h afforded the tertiary amide 80 in 93% yield (equation 10). This reaction yielded only trace amounts of the diene 73. The JR spectrum of 80 revealed a strong C=0 stretching absorption at 1646 cm"1, characteristic of an amide function. The  l H nmr spectrum of 80 displayed a signal at 5 5.38-5.43, attributed to the alkenyl proton, and a 3-proton singlet at 5 1.16, corresponding to the tertiary methyl group (Me a ) . The protons Hb and Hb' gave rise to doublets at 5 2.42 and 5 2.37 and the two methyl groups on the amide nitrogen produced 3-proton singlets at 8 2.95 and 5 2.87. 100 ° C , 4 h (10) = H k H PMBO PMBO 64 80 56 2. 2. 7. Synthesis o f the racemic ether 81 (-)-Dysidiolide (1) possesses an aliphatic appendage that is attached to the decalin core of the natural product ((-)-l) at C-15 (see Scheme 23). This appendage possesses six of the carbons of the sesterterpenoid (C-16, C-17, C - l 8, C - l 9 , C-20 and C-21). The next task presented by our synthetic enterprise towards (-)-l was the completion of the construction of this aliphatic substituent. Hence, it was necessary to generate the ether 81 from the tertiary amide 80 (see Scheme 23). (-)-l Scheme 23 The initial step of the synthesis o f 81 was the reduction of the amide function of 80. This substance (80) was allowed to react with L i E t 3 B H (Super-Hydride®) 4 9 in T H F at 57 room temperature for 2 h to provide, after the required basic aqueous H 2 O 2 treatment, the primary alcohol 82 in 94% yield (equation 11). A strong O - H stretching absorption at 3400 cm"1 was apparent in the ER. spectrum of 82. The lH nmr spectrum of 82 exhibited a 2-proton triplet at 8 3.55, associated with the carbinol protons. ^ N M e 2 ^ O H 1) L i E t 3 B H , THF, rt, 2 h 2) N a O H , H 2 0 2 , H 2 0 , 50 °C, 2 h (11) 80 82 The alcohol function of 82 was cleanly oxidized using the Dess-Martin periodinane 5 0 to afford the aldehyde 83 in quantitative yield (equation 12). .OH P M B O Dess-Martin periodinane CH 2 C1 2 , rt (12) P M B O 82 83 Dess-Martin periodinane = OAc A c O I O A c The IR spectrum of 83 revealed a strong C=0 stretching absorption at 1719 cm"1, characteristic o f an unconjugated aldehyde function. A 1-proton triplet at 8 9.58 was observed in the *H nmr spectrum of 83, ascribed to the aldehydic proton. 58 The next transformation undertaken for the synthesis of the ether 81 was the attachment of four of the carbons ( C - l 8, C - l 9, C-20 and C-21) of the aliphatic appendage of ( - ) - l to the aldehyde substrate (83). Araki , Ito and Butsugan 5 1 elaborated a protocol to obtain homoallylic alcohols by reaction of allylic halides (bromides and iodides) with aldehydes or ketones in the presence of indium metal. This procedure was employed to achieve the aforementioned objective. Hence, reaction of 83 with methallyl bromide and indium metal in D M F at room temperature for 1 h provided the diastereomeric homoallylic alcohols 84 and 85 in 83% and 15%> isolated yields, respectively (see equation 13). O (-)-i 59 The IR spectra of 84 and 85 each displayed a strong O - H stretching absorption. This absorption was seen at 3484 cm"1 in the IR spectrum o f 84 and at 3412 cm"1 in the IR spectrum of 85. In the  l H nmr spectrum of 84, Hb and Hy were observed as singlets at 5 4.81 and 5 4.71 (not assigned specifically). The analogous protons appeared as singlets at 5 4.71 and 8 4.64 (not assigned specifically) in the } H nmr spectrum of 85. The J H nmr spectra of 84 and 85 each showed a 3-proton singlet associated with M e a . This signal was seen at 5 1.73 in the  l H nmr spectrum of 84 and at 8 1.71 in the ! H nmr spectrum of 85. Finally, the spectra of 84 and 85 each exhibited a 1-proton multiplet attributed to the. carbinol proton. This signal was detected at 8 3.60-3.64 in the  l H nmr spectrum of 84 and at 8 3.82-3.86 in the ! H nmr spectrum o f 85. The secondary alcohol 85 was isolated as a white solid which, upon recrystallization from heptane, provided crystals (mp 90-92 °C) suitable for an X-ray crystallographic study. 5 2 The perspective drawing of this substance (85) is shown in Figure 4. B y this means, the relative configurations of 84 and 85, as well as those of previous intermediates in the synthetic sequence, were conclusively established. 60 CI .7 PC16 C I 5 C 2 6 Alcoho l 85 Figure 4 O R T E P representation of the alcohol 85 (note that this structure (85) is drawn as the enantiomer to that which was presented in equation 13) Homoallylic alcohols 84 and 85 were readily converted into the desired ether 81 (see Scheme 23, p. 56) through the radical deoxygenation method developed by Barton and M c C o m b i e . 5 3 In this protocol, a xanthate intermediate (87), prepared from the corresponding alcohol (86), is allowed to react with tributylstannane (BuaSnH) in the presence of a catalytic amount of 2,2'-azobis(isobutyronitrile) ( A I B N ) at high 61 temperature to generate the deoxygenation product (88) (Scheme 24). „ R 2 R 2 S Bu^SnH F*2 R l > ^ u R ' ^ A _ _ _ _ _ _ R OH • R ^ O ^ S C H 3 • R H A 86 87 88 R = Alkyl R i = Alkyl or H R 2 = Alkyl or H Scheme 24 A s indicated in Scheme 24, the protocol designed by Barton and coworker 5 3 has been used to effect the deoxygenation of primary, secondary and tertiary alcohol functions. Nevertheless, the method has been more broadly applied to the deoxygenation of secondary alcohol substrates than to the deoxygenation of primary or tertiary alcohols. 5 4 Indeed, in the case of secondary alcohol starting materials, the method developed by Barton and M c C o m b i e 5 3 offers both the ease of preparation of the xanthate intermediate (87) and the efficiency of the radical step that affords the deoxygenation product (88) (see Scheme 24). The proposed mechanism for the free-radical process that yields 88 is presented in Scheme 2 5 . 5 4 ' 5 5 62 CN CN -N=N— A I B N CN + N 2 90 > H ——SnBu 3 90 R R, S SnBu 3 J!Q 89 R O ^ S C H 3 87 CN -H + Bu 3Sn 89 R2 , H — Q n B u 3 path A ) 91 O x B u 3 S n S " ^ S C H 3 93 + 1 > . v H SnBu 3 R v — / 92 R \ 2 R-|v 88 + • SnBu 3 89 (path B \ R, S' ,SnBu 3 R ^ O " "SCHq + H 94 aqueous workup or chromatography on silica gel R 2 R ' ^ O H 86 • SnBu 3 89 R = Alkyl Rj = Alkyl o r H R 2 = Alkyl o r H Scheme 25 63 The tributyltin radical (89) is produced by the reaction of tributylstannane (Bu3SnH) with the initiator radical (90). The radical 89 then adds to the xanthate function of 87 (see also Scheme 24), to afford the intermediate radical 91. Fragmentation of 91 (path A) yields the carbon radical 92 along with the carbonodithioate 93. Finally, the radical 92 abstracts a hydrogen atom from BusSnH to provide the desired deoxygenation product (88) and the tributyltin radical (89). However, i f the fragmentation of radical 91 (path A) is slow, this intermediate may abstract a hydrogen atom from BU3S11H (path B ) to furnish the adduct 94 and the radical 89. The intermediate 94, after aqueous workup or chromatography on silica gel, gives rise to the alcohol 86. This substance (86) is the precursor of the xanthate 87 (see Scheme 24). The rate of fragmentation of the radical 91 (path A) depends to a large extent on the stability o f the carbon radical 92. 5 4 Primary carbon radicals are known to be less stable than their secondary counterparts.5 6 Hence, the free-radical process displays great efficiency when secondary alcohol substrates are used as starting materials of the 2-step procedure. On the other hand, when primary alcohols are used as starting materials o f the sequence, path B becomes a valid competitor to path A and appreciable amounts of the primary alcohol substrate (86) are recovered from the free-radical process. This radical deoxygenation method elaborated by Barton and M c C o m b i e 5 3 (see Scheme 24) was used to synthesize the ether 81 from the homoallylic alcohol 84. 64 Initially, the xanthate intermediate 95 was prepared from 84 (Scheme 26). E. H PMBO 84 P - O H 85 a - O H 1) H-BuLi, THF, rt, 10 min 2) CS 2 , rt, 30 min 3) Mel , rt, 20 min 4) aqueous N a H C 0 3 , rt k H PMBO 95 p -OR 96 a - O R Bu 3 SnH, cat. A I B N , toluene, reflux, 15 min 81 Scheme 26 Thus, the alcohol 84 was allowed to react with «-BuLi in T H F at room temperature. The reaction mixture was stirred for 10 min and carbon disulfide ( C S 2 ) was added. The mixture was stirred for another 30 min at room temperature and methyl iodide (Mel) was added. Finally, the solution was stirred for 20 min and treated with saturated aqueous N a H C 0 3 . A n aqueous workup was effected and the crude xanthate 95 was obtained. This substance (95) was treated, without further purification, with tributylstannane (Bu 3 SnH) in the presence of a catalytic amount of 2,2'-azobis(isobutyronitrile) ( A I B N ) in toluene at 65 reflux for 15 min. The solution was cooled to room temperature and concentrated in vacuo. The resultant crude material was purified by chromatography on silica gel to provide the ether 81 in 79% yield from 84. As indicated in Scheme 26, the ether 81 was also synthesized in the same manner from the alcohol 85 (77%). The ! H nmr spectrum o f 81 contained 1-proton singlets at 8 4.63 and 8 4.60, corresponding to Hb and Hy (not assigned specifically). It also included a 3-proton singlet at 8 1.64, associated with M e a . Despite the fact that ether 81 had been constructed in a straightforward manner and in appreciable yield (77%) from the primary alcohol 82 (see equation 12, equation 13 and Scheme 26), a more expeditious route to 81 was subsequently elaborated. This improved procedure involves the preparation of the ether 81 from 82 via a 2-step sequence. The initial reaction of this synthetic sequence features the conversion of the alcohol 82 into the primary iodide 97. Hence, 82 was treated with triphenylphosphine (PPh 3), imidazole and iodine (I 2) in a mixture of C H 3 C N and E t 2 0 ( C H 3 C N / E t 2 0 : 2/3) at room temperature for 2 h to afford the iodide 97 in 92% yield (equation 14). 1-Proton multiplets associated with the - C H 2 I group were observed at 8 2.96-2.98 and 8 2.85-2.89 in the *H nmr spectrum of 97. ^ O H 1) PPh 3 ,1 2 , imidazole, C H 3 C N , E t 2 0 , rt, 2 h E H PMBO 82 2)aqueous N a H C 0 3 , rt (14) 97 A copper-catalyzed Grignard reaction 5 7 was employed to generate the ether 81 from the primary iodide 97. The latter material was allowed to react with 66 methallylmagnesium chloride 5 8 and copper(I) iodide (Cul) in the presence o f lithium iodide 5 9 (L i l ) in T H F at -40 °C. The reaction mixture was warmed to room temperature over the course of 6 h and stirred at this temperature for 10 h (equation 15). k H P M B O 97 I 1) methallylmagnesium chloride Cul, L i l , THF, -40 °Ctor t , lOhatr t 2) aqueous N H 4 C I / N H 3 (pH 8), rt (15) 81 methallylmagnesium chloride ,MgCI The suspension was treated with aqueous NH4CI-NH3 (pH 8) and the resultant biphasic mixture was stirred open to the atmosphere until the aqueous phase became deep blue. A n aqueous workup was conducted and the resultant crude residue was purified by chromatography on silica gel to give the ether 81 in 99% yield. The 2-step sequence presented in equations 14 and 15 allowed the preparation of the ether 81 from 82 in 91% yield. In comparison, the initial series of transformations used to construct 81 from 82 (see equation 12, equation 13 and Scheme 26) provided a 77% overall yield. 67 2. 2. 8. Synthesis o f the racemic secondary alcohol 29 The synthetic intermediate 81 was treated with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone 6 0 (DDQ) in wet C H 2 C 1 2 (CH 2 C1 2 /H 2 0: 18/1) at room temperature for 1 h to effect the cleavage of its /?-methoxybenzyl ( P M B ) ether function (equation 16). This reaction afforded the secondary alcohol 29 in 97% yield. The X H nmr spectrum of 29 exhibited a 1-proton multiplet at 5 3.43-3.51 due to the carbinol proton. The IR spectrum of 29 displayed a strong O - H stretching absorption at 3365 cm"1. 2. 2. 9. Synthesis o f the enantiomerically pure alcohol (-)-29 One of the goals of this research program was the total synthesis o f natural (-)-dysidiolide (1). A t this stage of the work, as indicated in Scheme 27, the racemic ketone (±)-34 had been successfully converted into the racemic bicyclic alcohol (±)-29. In order to achieve the goal stated above, it was necessary to generate an enantiomerically pure intermediate along the synthetic pathway. In other words, the two enantiomers of one of the synthetic intermediates of the sequence had to be separated. The racemic secondary alcohol (±)-29 was the substance chosen to pursue this endeavor (see Scheme 27). 68 (±)-29 Separation of enantiomers t The two separated enantiomers of the secondary alcohol 29 Scheme 27 The use of diastereomeric mandelate esters for the resolution (separation) of the enantiomers of secondary alcohols was initially reported by Whitesell and Reynolds, 6 1 who treated racemic secondary alcohols with (+)- or (-)-mandelic acid in the presence o f /?-toluenesulfonic acid (TsOH) and separated the resultant diastereomeric mandelate esters by fractional crystallization or high-performance liquid chromatography (HPLC) . 69 (R)-(-)-mandelic acid = P n O H O H (S)-(+)-mandelic acid = P n O H O H O-Acetylmandelate esters have also been employed to carry out the same operation. 6 1 This resolution technique was employed by Steel, M i l l s , Parmee and Thomas in their total synthesis o f (+)-milbemycin E . 6 2 Thomas and coworkers 6 2 treated the racemic diol 98 with (i?)-(-)-0-acetylmandelic acid, 1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine ( D M A P ) at room temperature in C H 2 C I 2 . This reaction provided a mixture of the diastereomeric esters (-)-99 and (-)-100 (Scheme 28). C 0 2 E t (/?)-( _)-0-acetyl-mandelic acid D C C , D M A P , C H 2 C 1 2 , rt C 0 2 E t CQ2Et A c C T ^ P h (-)-99 A c C T ^ P h (-)-100 crystallization of (-)-99 upon trituration of the mixture of (-)-99 and (-)-100 with hexane K 2 C 0 3 , ethanol, rt Me 3Si HQ C 0 2 E t '""Me Scheme 28 70 The O-acetylmandelate ester (-)-99 crystallized upon trituration of the mixture ((-)-99 and (-)-100) with hexane and was isolated in 33% yield from racemic 98. The ester (-)-99 was allowed to react with potassium carbonate (K2CO3) in ethanol at room temperature to furnish the diol (+)-98 in 97%> yield. The total synthesis of (+)-milbemycin E was completed with the use of (+)-98 as an enantiomerically pure building block. (+)-milbemycin E Separation of the enantiomers of the secondary alcohol 29 (see Scheme 27) was achieved through the use of a protocol closely related to the one employed by Steel et al62 in their enantioselective total synthesis of (+)-milbemycin E (Scheme 28). Hence, the diastereomeric O-acetylmandelate esters (+)-101 and (+)-102 were obtained from the treatment of racemic alcohol 29 with (5)-(+)-0-acetylmandelic acid, 1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine ( D M A P ) in C H 2 C I 2 at low temperature (-20 °C) for 24 h, as depicted in Scheme 29. 71 (±) -29 (S)-(+)-0-acetyl-mandelic acid DCC, D M A P , CH 2 C1 2 , -20 °C, 24 h + A c O ^ P h H b (+)-101 H < * » H A c O ^ P h H b (+)-102 separation of (+)-101 and (+)-102 by chromatography on silica gel K 2 C 0 3 , C H 3 O H , rt, 1 h K 2 C 0 3 , C H 3 O H , rt, 1 h (-)-29 Scheme 29 The O-acetylmandelate esters (+)-101 and (+)-102 were separated by chromatography on silica gel and isolated in 46% and 45% yields, respectively, from the racemic alcohol 29. The IR spectra of (+)-101 and (+)-102 exhibited strong C = 0 stretching absorptions (at 1746 cm"1 for both substances) characteristic o f an ester function. The lH nmr spectra of (+)-101 and (+)-102 each exhibited a 1-proton doublet of doublets (8 4.78 and 5 4.72, respectively) corresponding to IL.. The same spectra each displayed a 1-proton singlet (at 5 5.87 for (+)-101 and at 6 5.89 for (+)-102) attributed to H b and a 3-proton singlet (at 5 72 2.17 for (+)-101 and at 8 2.16 for (+)-102) associated with the methyl group of the acetate function. Finally, the lH nmr spectra of (+)-101 and (+)-102 both possessed five aromatic proton resonances. The ester (+)-101 was allowed to react with potassium carbonate 6 3 (K2CO3) in C H 3 O H at room temperature for 1 h to furnish the alcohol (-)-29 in 91% yield (see Scheme 29). In the same manner, (+)-29 was generated from (+)-102 (89%). The lH nmr and IR spectra of (-)-29 and (+)-29 were identical with those of racemic 29. The specific optical rotation of (-)-29 was found to be [a]23 -70 .0° at a concentration of 2.20 g/lOOmL in C H 3 O H , whereas the specific optical rotation recorded for (+)-29 was [ a ] " +69.7° at a concentration of 2.50 g/lOOmL in C H 3 O H . Dale, Du l l and Mosher 6 4 demonstrated the suitability of (+)- and (-)-2-methoxy-2-phenyl-2-trifluoromethylacetic acids as reagents for the determination of the enantiomeric composition of secondary alcohols and amines. O (5)-(-)-2-methoxy-2-phenyl- _ II p h 2-trifluoromethylacetic acid HO F 3 C t )Me O (/?)-(+)-2-methoxy-2-phenyl- _ II p h 2-trifluoromethylacetic acid HO j£ MeO 1bF3 Alcohols (-)-29 and (+)-29 were separately treated with (5)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride, triethylamine (Et3N) and 4-(dimethylamino)pyridine 73 ( D M A P ) in C H 2 C I 2 at room temperature for 15 min to afford the diastereomeric esters 103 and 104 (see Scheme 30). Reagent A , E t 3 N , D M A P C H 2 C I 2 , rt, 15 min Reagent A , E t 3 N, D M A P CH 2 C1 2 , rt, 15 min H F 3 C ^ i ^ P h OMe 104 (one enantiomer) Reagent A = (5)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride CI Ph MeO u F 3 Scheme 30 The  l H nmr spectrum of 103 included a 1-proton doublet of doublets at 8 4.93 due to H a and a 3-proton singlet at 5 3.48 due to the CH3O- function. These signals could not be observed in the  l H nmr spectrum of 104, which showed the corresponding resonances at 5 4.91 and 5 3.53. The latter signals could not be seen in the  l H nmr spectrum of 103. 74 Hence, the alcohols (-)-29 and (+)-29 were considered to be "enantiomerically pure" materials. 6 5 The alcohol (-)-29 was chosen to continue our synthetic endeavor towards dysidiolide in view of the fact that the sign of the specific optical rotation of the naturally occurring enantiomer of 1 is negative.8 75 2. 2. 10. Synthesis of the diastereomeric mixture of nitriles 28' As mentioned previously (section 2.1), one of the key transformations in the construction of the southwestern section of ( - ) - l was foreseen to be the alkylation of the anion formed by deprotonation of the nitrile 28 (see Scheme 31). ( - ) - l Scheme 31 This conversion was required to generate the quaternary carbon center (at the position of C-6 in 1) of the alkylated substance in a diastereoselective fashion. (-)-Dysidiolide (1) would subsequently be constructed from this alkylated material. 76 The next objective of our synthetic approach to (-)-l was therefore to synthesize the nitrile 28 from the enantiomerically pure alcohol (-)-29 (see Scheme 29). It was conceived that a carbonyl homologation protocol, starting from ketone 105, would be utilized to attach the necessary carbon atom of the nitrile function of 28 (see Scheme 31). This carbonyl homologation protocol would initially produce aldehyde 106. 105 The alcohol (-)-29 was allowed to react with the Dess-Martin periodinane in C H 2 C I 2 at room temperature to provide the ketone (-)-105 in 92% yield (equation 17). (-)-29 (-)-105 The IR spectrum of (-)-105 revealed a strong C=0 stretching absorption at 1712 cm"1, characteristic o f a ketone function. The 1 3 C nmr spectrum of (-)-105 showed a signal at 8 215.5, associated with the carbon of the ketone function. 77 67 Magnus and Roy elaborated a synthetic method that proved to be suitable for the homologation of sterically hindered ketones. In this protocol, (methoxymethyl)trimethylsilane (107) is treated with sec-BuLi in T H F -78 °C. The reaction mixture is warmed to -25 °C and stirred for 30 min at that temperature to afford a solution of (methoxy(trimethylsilyl)methyl)lithium (108) (see Scheme 32). H M e 3 S r " O M e 107 sec-QuU, THF -78 °C to -25 °C, 30 min at -25 °C Li Rj = Alkyl , alkenyl or aryl R 2 = Alkyl (ketone) or H (aldehyde) M e 3 S r " O M e 108 1) R 1 - ^ R 2 109 THF, -35 °C 2) aqueous N a H C 0 3 , R 1-hT ^ O 112 R 1 \ / R 2 OMe 111 H C 0 2 H , r t ,2h H O ^ / R l \£—r-A , M e 3 S r ^ O M e 110 Scheme 32 The solution of 108 is cooled to -35 °C and treated with a T H F solution of a ketone or an aldehyde substrate (109). After the starting material (109) has been consumed, the reaction mixture is treated with saturated aqueous N a H C 0 3 . A n aqueous workup is conducted and a crude alcohol intermediate (110) is obtained. This crude adduct (110) is 78 dissolved, without further purification, in formic acid ( H C O 2 H ) and the resultant solution is stirred at room temperature for 2 h. The formic acid treatment initially generates an alkenyl ether intermediate (111), which is subsequently hydrolyzed in the same reaction vessel (and under the same experimental conditions) to provide an aldehyde product (112). The reaction mixture (containing 112) is concentrated in vacuo and the resultant crude material is purified by chromatography on silica gel to yield the aldehyde product (112). The protocol reported by Magnus and R o y 6 7 (Scheme 32) was applied to the homologation of the ketone (-)-105. Hence, a cold (-35 °C) solution of (methoxy(trimethylsilyl)methyl)lithium (108) was prepared as described above and treated with a T H F solution of (-)-105. The resultant heterogeneous mixture was stirred for 1 h at -35 °C and treated with saturated aqueous NaHCC>3. A n aqueous workup was effected and the crude tertiary alcohol 113 was obtained (see Scheme 33). 79 H M e 3 S r OMe 107 sec-BuLi, THF -78 °C to -25 °C, 30 min at -25 °C Li M e 3 S r " O M e 108 1) (-)-105, THF, -35 °C, 1 h 2) aqueous N a H C 0 3 , rt M e 3 S i ' "OMe 113 Scheme 33 The crude alcohol (113) was dissolved in formic acid ( H C O 2 H ) and the resultant solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the resultant crude material was purified by chromatography on silica gel. Unfortunately, the formic acid treatment did not afford the aldehyde 106 (see Scheme 34). Instead, the reaction furnished the formate ester 114 as a diastereomeric mixture in 82% yield. Hence, although the required aldehyde function was generated by the formic acid treatment, the C a ,Cb alkenic bond of 113 also reacted with the organic acid under these conditions. 80 Scheme 34 The ' H nmr spectrum of 114 revealed signals corresponding to both diastereomers of the mixture. Thus, the spectrum exhibited doublet signals at 5 9.77 and 5 9.71, associated with the aldehydic proton of each diastereomer. In addition, the spectrum displayed singlet resonances at 5 8.00 and 5 7.98, attributed to H a o f the two isomers. Finally, the ' H nmr spectrum of 114 showed singlets at 5 1.44 and 8 1.41, corresponding to the protons of the two Meb groups present in both diastereomers. A n alternative approach was examined to produce the aldehyde 106 from the tertiary alcohol 113. Thus, the crude alcohol (113) was dissolved in a biphasic mixture 6 8 of trifluoroacetic acid (TFA) , H 2 O and C H C I 3 (1:1:8, respectively) and the resultant mixture was stirred at 0 °C for 30 min. Gratifyingly, this procedure afforded the 81 diastereomeric mixture of aldehydes 106 6 9 in 88% yield from (-)-105 (equation 18). TFA, H 2 0 , CHC1 3 (1:1:8) 0 °C, 30 min (18) Me 3 Si ' "OMe 113 OHC 106 The IR spectrum of 106 exhibited a strong C=0 stretching absorption at 1723 cm"1, distinctive of an aldehyde function. The ^ and 1 3 C nmr spectra of 106 revealed signals corresponding to both diastereomers of the mixture. The J H nmr spectrum of 106 possessed doublet resonances at 8 9.76 and 8 9.70, attributed to the aldehydic protons of the two isomers. The 1 3 C nmr spectrum of 106 displayed signals at 8 207.4 and 8 205.3, associated with the carbons of the aldehyde functions present in the products. The nitrile 28 (see Scheme 31) was synthesized from the mixture of aldehydes 106 through the use of a procedure developed by Sampath Kumar, Subba Reddy, Tirupathy Reddy and Yadav. 7 0 This group reported the 1-step conversion of aldehyde substrates into the corresponding nitriles. In this procedure, an aldehyde substrate (115) is treated with hydroxylamine hydrochloride ( N H 2 O H • HC1) in 7V-methylpyrrolidinone ( N M P ) at 115 °C for several hours (see Scheme 35). The hydroxylamine hydrochloride treatment initially generates an oxime intermediate (116), which undergoes a dehydration process to afford a nitrile product (117). 82 HO. O N A RA, N H 2 O H • HCI H R' H R 115 N M P , 115 °C, several hours 116 117 R = Alkyl Scheme 35 The aldehyde 106 was allowed to react with N H 2 O H • H C I in N M P at 115 °C for 4 h (equation 19) to provide the diastereomeric mixture of nitriles 2 8 6 6 in 96% yield. The IR spectrum of 28 exhibited a weak C=N stretching absorption at 2236 cm"1, characteristic of a nitrile function. The ! H and 1 3 C nmr spectra of 28 revealed signals corresponding to both diastereomers of the mixture. The 1 3 C nmr spectrum of 28 displayed signals at 8 121.4 and 8 120.9, attributed to the carbon of the nitrile function present in the two isomers. 2. 2. 11. Synthesis of the enantiomerically pure nitrile (-)-118 Alkylation of the anion derived from the mixture of nitriles 28 was the next goal in our synthetic endeavor towards ( - ) - l (see Scheme 31). This process was studied in a systematic manner. Methyl iodide (Mel) was chosen as a suitable electrophile to (19) 106 28 83 investigate the alkylation reaction since this reagent is readily available and very reactive. To prepare the anion of 28, a T H F solution of the nitrile (28) was added to a solution of lithium diisopropylamide ( L D A ) in T H F at 0 °C (equation 20). 1) L D A , THF, 0 °C, 1 h 2) Mel, -98 °C to it, 6 h H M L C L r t ? R CN CN (20) 28 28 The resultant solution was stirred for 1 h at 0 °C, cooled to -98 °C and treated with M e l . The mixture was warmed to room temperature over the course of 6 h and treated with saturated aqueous NFLtCl. A n aqueous workup was effected and a ! H nmr spectrum of the crude residue was obtained. This *H nmr spectrum revealed that the experiment afforded only starting material (28). The alkylation of the anion of 28 was undertaken again, although in this second attempt hexamethylphosphoramide ( H M P A ) was added to the reaction mixture. Indeed, H M P A has been demonstrated to promote the formation of the anions of organic substances (compounds that contain specific functional groups; for example carboxylic acids, esters, nitriles, etc) as well as their alkylation. 7 1 Thus, to a solution of 28 and lithium diisopropylamide ( L D A ) in T H F at 0 °C was added four equivalents of hexamethylphosphoramide ( H M P A ) and the resultant mixture was stirred for 1 h (equation 21). The solution acquired an orange coloration during this time. The mixture was cooled to -98 °C and M e l was added. Upon addition of the reagent (Mel), the 84 solution immediately lost its orange coloration. A n investigation by thin layer chromatography ( T L C ) of the reaction mixture, done 5 min after the addition of M e l , indicated disappearance of the starting material (28). The mixture was treated with saturated aqueous NH4CI, an aqueous workup was conducted, and the resultant crude residue was purified by chromatography on silica gel to furnish the nitrile (-)-118 as a single enantiomer in 88% yield. The IR spectrum of (-)-118 displayed a weak C=N stretching absorption at 2231 cm"1, indicative of a nitrile function. The *H nmr spectrum of (-)-118 revealed a 3-proton singlet at 5 1.22, derived from M e a . 1) L D A , H M P A , THF, 0 °C, 1 h 2) Mel , -98 °C, 5 min 3) aqueous NH4CI, rt (21) 28 (-)-118 The nitrile (-)-118 was converted into the /?-nitrobenzoate (-)-147 at a later stage of our synthetic studies (vide infra, see sections 2.3.1 and 2.3.2). (-)-118 (-)-147 85 A n X-ray crystallographic study effected with benzoate (-)-147 unambiguously ascertained the relative configuration of this substance ((-)-147) at C-7 (see Figure 5, section 2.3.2) and, consequently, determined the relative configuration of compound (-)-118atC-5. Examination of the molecular model of the anion of nitrile 28 led to a rationale for the observed diastereoselectivity of the transformation presented in equation 21. At first, one has to appreciate that the transition state leading from the anion of 28 to the product (-)-118 is probably represented most accurately by the former reaction intermediate. This suggestion emanates from the exothermic nature of the alkylation process (see Hammond's postulate) 7 2 and signifies that the most stable transition state for this alkylation process structurally resembles the most stable conformation of the anion of 28. The most stable conformation of the anion of 28 (as determined using computerized molecular modeling) 7 3 is shown in Scheme 36. In this conformation, the approach of the electrophile (Mel) from the p face (see drawing on the left, Scheme 36) of the anion of 28 (pseudo-equatorial approach) is considerably hindered by the methylene group associated with C-4. On the other hand, in the same conformation, the attack of the electrophile from the a face of the anion of 28 is hindered only by the pseudo-axial hydrogen attached to C-7. Owing to its pseudo-axial nature (as opposed to axial), this hydrogen (H? a ) does not significantly encumber the attack trajectory on the a 86 face of the anion of 28. This analysis rationalizes the formation of (—)-118 depicted in equation 21. Anion of 28 L i Anion of 28 (only one resonance form) Scheme 36 The nitrile (-)-118 was not an intermediate suitable for completion of the total synthesis of (-)-dysidiolide (1). On the other hand, alkylation of the anion of 28 from its a face (see Scheme 36) with an electrophile such as iodide 119 would afford the nitrile 120 (equation 22), from which ( - ) - l could be synthesized. iodide 119 H 3 C O — < f ^ > — C H 2 O C H 2 C H 2 l Anion of 28 M = L i or K 120 87 2. 2. 12. Synthesis o f the iodide 119 The iodide 119 was synthesized in order to attempt the transformation presented in equation 22. The construction of 119 was effected as described below (see equations 23 and 24). Ethylene glycol (in excess) was treated with sodium hydride (NaH) in the presence of a catalytic amount of tetrabutylammonium iodide (BU4NI) in D M F at 0 °C. The reaction mixture was stirred for 15 min and /?-methoxybenzyl chloride (PMBC1) was added. The suspension was warmed to room temperature, stirred for 12 h and treated with saturated aqueous NH4CI. A n aqueous workup was effected and the resultant crude material was purified by chromatography on silica gel to furnish the primary alcohol 121 in 74% yield (equation 23). 1) NaH, B114NI, ^ \ / O C H 3 u n ^ / O H DMF, 0°C, 15 min | |j H ° * H O - ^ V 0 ^ ^ ( 2 3 ) (in excess relative to 2) PMBC1, 0 °C to rt, n w / \ NaHandPMBCl) 12hatrt H a H a 3) aqueous 121 N H 4 C I , rt The IR spectrum of 121 showed a strong O - H stretching absorption at 3437 cm"1 and an aromatic carbon-carbon stretching absorption at 1614 cm"1. The  l H nmr spectrum of 121 revealed a 2-proton triplet at 5 3.56, attributed to the H a protons, and a 2-proton signal at 5 3.70-3.77, corresponding to the carbinol protons. The same ! H nmr spectrum displayed a 1-proton triplet at 5 1.97; this signal disappeared upon addition of a few drops of D 2 0 to the nmr solvent (CDCI3) and was therefore assigned to the proton of the hydroxyl group. Finally, the ! H nmr spectrum of 121 exhibited a 2-proton singlet at 8 4.48, derived from the two benzylic protons, a 3-proton singlet at 8 3.79, ascribed to the 88 CH3O- group, and 2-proton resonances at 5 7.23-7.27 and 8 6.85-6.89, associated with the four aromatic protons. The primary alcohol 121 was allowed to react with triphenylphosphine (PPh 3), imidazole and iodine (I 2) in a mixture of C H 3 C N and E t 2 0 ( C H 3 C N / E t 2 0 : 2/3) at 0 °C for 1 h to afford the iodide 119 in 95% yield (equation 24). The *H nmr spectrum of 119 exhibited a 2-proton triplet at 8 3.24, derived from the - C H 2 I group. The 1 3 C nmr spectrum of 119 featured a signal at 8 3.2, ascribed to the carbon of the - C H 2 I group. . O C H 3 !) PPh 3 , imidazole, QCH3 r r I 2 , C H 3 C N , E t 2 0 , ( 2 4 ) 0 °c, 1 h 1^^°^KJ HO 1 2 1 2)aqueous NaHC03, rt 2. 2. 13. Synthesis of the enantiomerically pure nitrile (-)-120 The alkylation of the anion o f nitrile 28 with iodide 119 was now investigated. Experimental conditions identical with those employed to prepare nitrile (—)-118 (equation 21) were used. Thus, the anion of 28 was prepared by treatment of the nitrile substrate (28) with lithium diisopropylamide ( L D A ) in the presence of hexamethylphosphoramide ( H M P A ) in T H F at 0 °C for 1 h. The cold (0 °C) solution of the resultant anion (28) was cooled to -98 °C and iodide 119 was added. The reaction mixture was warmed to room temperature over the course of 6 h and then was treated with saturated aqueous NH4CI (equation 25). Unfortunately, this experiment yielded only the starting material 28. 89 7 1) L D A , H M P A , THF, 0 °C, 1 h 2) iodide 119, -98 °C to rt, 6 h 3) aqueous (25) C N C N 28 NH 4 C1, rt 28 Since the reaction of 28 with L D A undoubtedly produced the corresponding anion (vide supra, equation 21), it was evident that the alkylation process between the anion of 28 and the iodide 119 was the faulty step in this experiment (equation 25). Thus, it was decided to examine the alkylation of the anion o f 28 prepared by treatment of this substance (28) with potassium diisopropylamide 7 4 ( K D A ) . The resultant anion with a potassium counterion was expected to be more nucleophilic than the corresponding anion with a lithium counterion. A mixture of diisopropylamine ((z-Pr) 2NH) and potassium 7-butoxide (7-BuOK) in T H F at -78 °C was treated with «-butyllithium («-BuLi), in accordance with the reported procedure, 7 4 and the resultant gold colored solution was stirred for 20 min to afford a cold (-78 °C) solution of potassium diisopropylamide ( K D A ) in T H F (equation 26). A T H F solution of 28 was added to the cold (-78 °C) solution of potassium diisopropylamine ( K D A ) and the resultant orange colored mixture was stirred for 30 min at -78 °C. The iodide 119 was added and the orange solution was stirred at -78 °C for 30 min. The mixture was warmed to -40 °C, stirred for 1 h, and treated with saturated (/-Pr) 2NH + r-BuOK rc-BuLi, THF, -78 °C, 20 min (/-Pr) 2NK (KDA) + r-BuOLi (26) 90 aqueous NH4C1. However, this experiment also provided exclusively the starting material, nitrile 28 (equation 27). 1) K D A , THF, -78 °C, 30 min 28 2) iodide 119, -78 °C, 30 min 3) -40 °C, 1 h 4) aqueous NH4CI, rt (27) 28 The alkylation process was studied again, using experimental conditions similar to those described in equation 27. However, the alkylation step of this new experiment was carried out in the presence of hexamethylphosphoramide 7 1 ( H M P A ) . Thus, the anion of 28 was prepared as described above (28, K D A , T H F , -78 °C, 30 min; equation 27) and four equivalents of H M P A were added to the resultant orange colored solution. The iodide 119 was immediately added and the orange coloration of the mixture disappeared. A n investigation by thin layer chromatography ( T L C ) of the reaction mixture, done 5 min after the addition o f 119, revealed that the starting material (28) had been completely consumed. The solution was treated with saturated aqueous NH4CI, an aqueous workup was effected, and the resultant crude material was purified by chromatography on silica gel to afford the nitrile (-)-120 as a single enantiomer in 88% yield (equation 28). 91 (-)-120 The IR spectrum of (-)-120 showed a weak O N stretching absorption at 2230 cm" and an aromatic carbon-carbon stretching absorption at 1614 cm -1. The  lH. nmr spectrum of (-)-120 revealed a 2-proton signal at 5 3.65-3.74, attributed to H a and H a ' , and 1-proton doublets at 8 4.45 and 8 4.39, derived from the diastereotopic benzylic protons. The same ' H nmr spectrum exhibited a 3-proton singlet at 8 3.78, associated with the C H 3 0 - group, and 2-proton multiplets at 8 7.22-7.26 and 8 6.83-6.87, due to the four aromatic protons. 2. 2. 14. Synthesis o f the enantiomerically pure primary alcohol (-)-122 The next objective in our synthetic endeavor towards (-)-dysidiolide (1) was conversion of the nitrile function of (-)-120 into a primary alcohol function (see substance 122 in equation 29). 92 7 7 (29) H 3 CO' B-120 122 This goal was achieved as described below and as depicted in Scheme 37. The nitrile (-)-120 was allowed to react with diisobutylaluminum hydride 7 5 ( D I B A L H ) in 1,2-dimethoxyethane ( D M E ) at room temperature for 30 min and the resultant solution was treated with I N aqueous citric acid. The biphasic mixture thus produced was stirred at room temperature for 3 h. The imine function (see adduct 123) initially generated by the aqueous acidic treatment ( I N aqueous citric acid) slowly hydrolyzed (under the same experimental conditions) to afford the corresponding aldehyde function (see intermediate 124). A n aqueous workup was effected and the resultant crude aldehyde 124 was allowed to react, without further purification, with sodium borohydride (NaBFL) in C H 3 O H at room temperature for 20 min. The reaction mixture was treated with saturated aqueous N H 4 C 1 and an aqueous workup was conducted. The resultant crude material was purified by chromatography on silica gel to provide the primary alcohol (-)-122 in 79% yield from (-)-120. The IR spectrum of (-)-122 exhibited a strong O - H stretching absorption at 3437 cm" 1. The *H nmr spectrum of (-)-122 revealed a 3-proton multiplet at 8 3.40-3.65, associated with H a , Ha> and Hb'. The same spectrum showed a 1-proton signal at 8 3.84-3.90, derived from Hb. 93 (-)-122 124 Scheme 37 2. 2. 15. Synthesis of the enantiomerically pure primary alcohol (-)-131 The next task in our synthetic enterprise towards (-)-l was the transformation of the primary alcohol (-)-122 into the /?-methoxybenzyl (PMB) ether 125 (equation 30). 94 (-)-122 125 The method developed by Barton and McCombie for the radical deoxygenation of alcohol substrates (see section 2.2.7, Scheme 24) was contemplated to accomplish this transformation. Unfortunately, poor yields of deoxygenated product are generally reported when primary xanthates are used as starting materials of the free-radical process 5 4 (see section 2.2.7). Large amounts of the primary alcohol precursor (adduct 86 in Schemes 24 and 25, section 2.2.7) are recovered from the free-radical process in these cases. The use of a higher temperature (150 °C) in the radical deoxygenation step, however, brought about an improvement in the efficiency of the protocol elaborated by Barton and M c C o m b i e 5 3 to effect the deoxygenation of primary alcohols. For example, using this procedure, the xanthate 126 was allowed to react with tributylstannane (Bu3SnH) in the presence of a catalytic amount of 2,2'-azobis(isobutyronitrile) (AIBN) in /?-cymene at 150 °C. Under these conditions, the deoxygenation product 127 was produced in a moderate 51% yield (equation 31). 7 6 95 HO r C 0 2 CH 3 Bu 3 SnH, AIBN, /7-cymene, 150 °C r C 0 2 CH 3 (31) 126 127 Barton and coworkers subsequently reported an improved protocol for the deoxygenation of primary alcohols. In this method, tributylstannane (BU3S11H) and 2,2'-azobis(isobutyronitrile) (AIBN) were replaced with diphenylsilane (Ph 2 SiH 2 ) and benzoyl peroxide in the free-radical deoxygenation step. These changes in the method (in conjunction with the use of an elevated temperature (150 °C) in the free-radical deoxygenation step) resulted in conversion of primary xanthates into the corresponding deoxygenation products in acceptable to good yields. For example, treatment of the xanthate 128 with P h 2 S i H 2 in the presence of a catalytic amount of benzoyl peroxide at 150 °C in o-xylene provided the benzoate 129 in 91% yield, as illustrated in equation 32. o-xylene, 150 °C Ph2SiH2, benzoyl peroxide 129 (32) S C H 3 128 benzoyl peroxide = 96 The efficiency of this novel experimental procedure developed by Barton and coworkers 7 7 for the radical deoxygenation of primary alcohol substrates prompted us to employ this procedure to convert the primary alcohol (-)-122 into the /?-methoxybenzyl ( P M B ) ether 125. Initially, the xanthate 130 was synthesized from (-)-122 (see Scheme 38). Hence, the alcohol (-)-122 was allowed to react with sodium hydride 7 8 (NaH) in the presence of a catalytic amount of imidazole in T H F at 60 °C for 2 h and the resultant suspension was cooled to room temperature. Carbon disulfide (CS2) was added and the yellow colored reaction mixture was stirred for 1 h. Methyl iodide was finally added and the suspension was stirred at room temperature for 30 min. The mixture was treated with saturated aqueous NaHCO-3 and an aqueous workup was effected. The resultant crude xanthate 130 was treated, without further purification, with diphenylsilane (Ph2SiH2) in the presence of a catalytic amount of benzoyl peroxide in o-xylene at 150 °C for 45 min. The solution was cooled to room temperature and the solvent was evaporated in vacuo, to provide a crude mixture of the /7-methoxybenzyl ether 125 and the primary alcohol (—)-131. Thus, it was clear that the p-methoxybenzyl ( P M B ) ether function was partially cleaved under the experimental conditions of the free-radical process. The crude mixture of 125 and (-)-131 was allowed to react with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone 6 0 (DDQ) in wet C H 2 C 1 2 ( C H 2 C 1 2 / H 2 0 : 18/1) at room temperature for 1 h and the resultant solution was treated with H 2 0 . A n aqueous workup was conducted and the residual material was purified by chromatography on silica gel, to furnish the primary alcohol (-)-131 in 80% yield from (-)-122 (Scheme 38). The IR spectrum of (-)-131 displayed a strong O - H stretching absorption at 3318 cm"1. The : H nmr spectrum of 97 (—)-131 revealed a 2-proton signal at 8 3.61-3.70, derived from the carbinol protons, and 3-proton singlets at 8 0.97 and 8 0.85, associated with the tertiary methyl groups. Scheme 38 125 2. 2. 16. Synthesis of the enantiomerically pure aldehyde (-)-6 98 The alcohol function of (-)-131 was oxidized with the Dess-Martin periodinane in C H 2 C I 2 at room temperature to afford the aldehyde (-)-6 in 95% yield (equation 33). The IR spectrum of (-)-6 disclosed a strong C=0 stretching absorption at 1719 cm"1, characteristic of an aldehyde function. The lH nmr spectrum of (-)-6 showed a 1-proton triplet at 5 9.90, attributed to the aldehydic proton. A s described previously (section 1.3.1), Corey and Roberts reported the first total synthesis of (-)-dysidiolide (1). During the course of this synthesis, the enantiomerically pure aldehyde (-)-6 was constructed from the primary alcohol (-)-132 in several steps. Corey and Roberts 8 also synthesized the bis(3,5-dinitrobenzoate) 133 from the alcohol (-)-132. A n X-ray crystallographic study conducted on compound 133 allowed these workers to establish the absolute configuration of each of the four chirality centers located on the decalin core of 133 (Scheme 39). Considering that Corey and Roberts 8 made the aldehyde (-)-6 from (-)-132, the absolute configurations of the four chirality centers of intermediate (-)-6 obtained by these researchers was also unambiguously established. 99 O (-)-6 Scheme 39 A s can be observed in Table 4, the ' H nmr spectral data derived from our sample of aldehyde (-)-6 agree very well with those reported by Corey and Roberts 8 for (-)-6. The aldehyde (-)-6 was also made by Boukouvalas, Cheng and Robichaud 1 6 during the course of their total synthesis o f (-)-l. The 1 3 C nmr spectral data reported by Boukouvalas and coworkers 1 6 for (-)-6 agree very well with the 1 3 C nmr spectral data acquired from our sample of aldehyde (-)-6, as can be seen by the data summarized in Table 5. Thus, it may be concluded that the compound (aldehyde (-)-6) obtained in our synthetic work is identical with that constructed by Corey 8 and Boukouvalas. 1 6 On the basis of this conclusion, the absolute configurations o f alcohol (-)-29, ketone (-)-105, nitrile (-)-120, alcohol (-)-122 and alcohol (-)-131 (see Scheme 29, equation 17, 100 equation 28, Scheme 37 and Scheme 38, respectively), which had not been unambiguously established before, could now be assigned with confidence. Table 4: Comparison of the *H nmr spectral data of our aldehyde (-)-6 (400 M H z , CDC1V) with those reported by Corey and Roberts 8 for the aldehyde ( - V 6 (500 M H z . CDCJ3) (-)-6 *H assignment H-x ! H nmr signals of the aldehyde (-)-6 (5, multiplicity, J (Hz)) Our aldehyde (-)-6 Aldehyde (-)-6 made by Corey H-10 9.90, t, J = 3 . 2 9.90, t, .7=3.1 H-8 5.31-5.35, m 5.33, m H-15 4.67, s 4.67, s H-15' 4.64, s 4.64, s H-9 2.33, dd, J = 2.8, 14.4 2.33, dd, J= 1.9, 14.2 H-9' 2.24, dd, J = 3 . 6 , 14.4 2.24, dd, J = 3 . 4 , 14.2 4 unassigned protons 1.90-2.09, m 1.90-2.08, m 1 unassigned proton 1.76-1.82, m 1.77-1.82, m 6 unassigned protons 1.50-1.74, m 1.51-1.74, m Me-16 1.68, s 1.68, s 5 unassigned protons 1.08-1.35, m 1.09-1.35, m tertiary M e 1.07, s 1.07, s tertiary M e 0.99, s 0.99, s Me-18 0.84, d, .7=6.4 0.84, d, J = 6 . 5 101 Table 5: Comparison of the C nmr spectral data of our aldehyde (-)-6 (75 M H z , C D C M with those reported by Boukouvalas and coworkers 1 6 for the aldehyde (-)-6 (75 M H z . C D C M (->6 1 3 C assignment C-x 1 3 C nmr signals of the aldehyde (-)-6 (8) Our aldehyde (-)-6 Aldehyde (-)-616 made by Boukouvalas C-10 204.4 204.4 C-8 117.1 117.1 C-15 109.7 109.7 the remaining 18 carbon signals were not assigned 146.2 146.2 145.1 145.0 47.3 47.1 42.5 42.5 42.0 42.0 40.0 40.0 38.6 38.6 37.6 37.6 37.0 37.0 33.0 33.0 31.6 31.6 29.3 29.4 26.0 26.0 23.0 23.0 22.5 22.5 22.4 22.4 22.3 22.3 14.9 14.8 102 2. 2. 17. Synthesis o f (-Vdysidiolide (I) Corey and Roberts 8 synthesized ( - ) - l from the aldehyde (-)-6 via a 2-step sequence. Considering that the method employed by this group 8 to construct the y-hydroxybutenolide moiety of the natural product ((-)-l) was efficient, it was decided to use the same protocol to complete our synthesis o f (-)-!• Corey and Roberts prepared a cold (-78 °C) solution of 3-lithiofuran in T H F by treatment of 3-bromofuran with «-butyllithium (rc-BuLi) at low temperature (-78 °C), as depicted in Scheme 40. The aldehyde (-)-6 was allowed to react with the 3-lithiofuran species at low temperature (-78 °C) to afford the diastereomeric alcohols (-)-134 and (-)-135 in isolated yields of 50% and 48%>, respectively. y-hydroxybutenolide moiety of ( - ) - l 103 (-)-134 (-)-135 Scheme 40 Corey and Roberts 8 used a protocol elaborated by Kernan and Faulkner 7 9 to effect the last step of their total synthesis of (-)-dysidiolide (1). Faulkner and coworker 7 9 irradiated dichloromethane (CH2CI2) solutions of 3-alkylfuran substrates (136), Rose Bengal and diisopropylethylamine ((/-Pr) 2EtN) with a 200-W tungsten incandescent lamp under an O2 atmosphere at -78 °C to generate the corresponding 3-alkyl-4-hydroxybutenolide products (137) (see equation 34). 104 I The proposed mechanism for this photochemical process is detailed below and depicted in Scheme 41. First, the triplet sensitizer (S), Rose Bengal, absorbs one of the photons emitted by the tungsten incandescent lamp. This process promotes the sensitizer (S) from its ground state (lS) to its first excited singlet state ( 1 S*). 8 0 The sensitizer (S) in its excited singlet state ( 1S*) then undergoes intersystem crossing to provide a sensitizer molecule (S) in its excited triplet state ( 3S*). Finally, energy transfer occurs between the sensitizer (S) in its excited triplet state ( 3S*) and an oxygen molecule (O2) in its ground state (302). The quantum of energy transferred is lost by the sensitizer molecule (S) and gained by the oxygen molecule (O2). This exchange o f energy produces a sensitizer molecule (S) in its ground state (*S) and an oxygen molecule (O2) in its first excited singlet state (102*). 105 hv Rose Bengal = Sensitizer = S 1„* intersystem crossing 3 C * b • o Y + Jo 2 energy transfer \ s + o2 Oj = singlet oxygen = O ^ ^ ^ O N R = Alkyl group O OH 137 . 0 . 138 C H N-139 Scheme 41 This "singlet oxygen" species ( 1 0 2 * ) then undergoes a [2+4] cycloaddition reaction with the furan function of the substrate 136, as shown in Scheme 4 1 , to afford the endoperoxide intermediate 138. This adduct (138) is subsequently deprotonated by diisopropylethylamine ((/-Pr) 2EtN). The proton is removed by this bulky base ((/-PfhEtN) from the less sterically hindered side 7 9 o f the substrate (138) (the side 106 opposite to the alkyl group, R) to generate the alkoxide intermediate 1 3 9 . A t last, a proton transfer affords the 3-alkyl-4-hydroxybutenolide product ( 137) . Taking advantage of this elegant protocol developed by Kernan and Faulkner, Corey and Roberts 8 obtained (-)-dysidiolide (1) in 98% yield from the alcohol ( - ) - 1 3 4 (equation 35). Corey and Roberts also converted the alcohol ( - ) - 1 3 5 into the diastereomeric substance ( - ) - 1 3 4 via the 2-step sequence shown in Scheme 42. Hence, the alcohol function of ( - ) - 1 3 5 was oxidized with the Dess-Martin periodinane 5 0 to provide the ketone 1 4 0 in quantitative yield. The ketone function of 1 4 0 was subsequently reduced with BH3 • M e 2 S in presence of the oxazaborolidine catalyst A 8 1 in toluene at -30 °C to furnish the secondary alcohol ( - ) - 1 3 4 in a diastereoselective manner and in 91% yield. 107 (-)-134 Scheme 42 The method reported by Corey and Roberts 8 (vide supra, Scheme 40 and equation 35) was employed to complete our synthetic enterprise towards (-)-dysidiolide (1). A solution of 3-lithiofuran in T H F at -78 °C was prepared as mentioned previously (see Scheme 40). A T H F solution of aldehyde (-)-6 was then added to the cold (-78 °C) solution of 3-lithiofuran in T H F (equation 36). The resultant mixture was stirred at -78 °C for 30 min and treated with saturated aqueous NH4CI. After an aqueous workup, 108 the crude product was purified by chromatography on silica gel to afford the diastereomeric secondary alcohols (-)-134 and (-)-135 in 50% and 46% isolated yields, respectively. The IR spectra of (-)-134 and (-)-135 revealed strong O - H stretching absorptions, at 3392 cm"1 and 3345 cm" 1, respectively. The J H nmr spectrum of (-)-134 exhibited a 1-proton multiplet at 6 4.82-4.88, attributed to the carbinol proton, and a 1-proton singlet at 5 6.38, corresponding to H c . The same spectrum showed 1-proton singlets at 5 7.34 and 8 7.33, associated with H a and Hb (not assigned specifically). The lH nmr spectrum of (-)-135 disclosed a 1-proton multiplet at 8 4.81-4.89, derived from the carbinol proton, a 1-proton singlet at 8 6.39, attributed to He, and a 2-proton singlet at 8 7.35, due to H a and Hb. (-)-134 (-)-135 Following the method developed by Kernan and Faulkner, diisopropylethylamine ((/-Pr) 2EtN) and Rose Bengal were added to a CH2CI2 solution of the alcohol (-)-134. The resultant pink colored suspension was cooled to -78 °C and irradiated with a 200-W tungsten incandescent lamp under an O2 atmosphere, as illustrated in equation 37. After a period of time which was dependant on the reaction scale (2 h for 13 mg of (-)-134), the irradiation was stopped and the reaction mixture was warmed to room temperature. The heterogeneous mixture was treated with saturated 109 aqueous NH4CI, an aqueous workup was effected, and the resultant crude product was purified by chromatography on silica gel to provide (-)-l in 93% yield. The physical properties and spectral data exhibited by this substance were, as detailed below, in full accordance with those reported for naturally occurring (-)-l. The ! H nmr spectrum o f our synthetic sample of (-)-l is shown in Appendix 1. 1) 0 2 , hv, Rose Bengal, (/-Pr)2EtN, CH 2 C1 2 , -78 °C 2) aqueous N H 4 C I , rt ( - ) -134 OH H O ^ O H ° (-)"! (37) Table 6 compares the ! H nmr spectral data of our synthetic sample of (-)-l with the *H nmr spectral data of the sample of (-)-l isolated from nature.7 Only selected signals from the ! H nmr spectrum of the latter sample of (-)-l are listed in the literature.7 A s can be observed in Table 6, the *H nmr spectral data obtained from our synthetic sample of (-)-l agree very well with the data derived from the sample of natural (-)-l.7 The two ' H nmr spectra display slight differences in chemical shifts and coupling constants for the signals corresponding to H-25 and O H a (C-25). However, these observations are not surprising, since the chemical shifts and shapes of these *H nmr resonances are dependant on the concentrations of (-)-l and on the presence (or absence) of moisture in the nmr sample. Table 7 compares the 1 3 C nmr spectral data of our synthetic sample of (-)-l with the 1 3 C nmr spectral data of the sample of natural (-)-! . 1 110 A s can be seen in this table, the 1 3 C nmr spectral data obtained from our synthetic sample of ( - ) - l agree very well with the data derived from the sample of natural ( - ) - l . 7 I l l Table 6: Comparison of the ' H nmr spectral data of our synthetic (-)-l (400 M H z , D M S O - 6 ^ with those reported for naturally occurring ( - V 1 7 (500 M H z . DMSO-fik) (-)-l *H nmr assignment H-x *H nmr signals of (-)-dysidiolide (5, multiplicity, J (Hz)) Our synthetic (-)-l Naturally occurring (-)-l H-2 5.91, b r s 5.91, s H-4 4.48-4.54 (4.34-4.41), am 4.51 (4.38) , a dt ,y=5.7, 8.6 O H b (C-4) part of mat 5.23-5.33 (5.12-5.18) a 5.23 (5.12), ad, J = 5 . 7 H-9 part of m at 5.23-5.33 omitted in the literatureb Me-20 1.62, s 1.62, s H-21 4.63, s 4.63, s H-21' 4.60, s 4.60, s Me-22 0.93, s 0.93, s Me-23 0.81, d, 7=6 .7 0.81, d, .7=6.7 Me-24 part of mat 1.42-2.04 1.51, b r s H-25 6.09, br d, 7=6 .8 6.08, d, .7=6.0 O H a (C-25) 7.84, br d, .7=6.8 7.80, d, J = 6 . 0 a Doubled H nmr signals were observed for H-4 and OHb (C-4). These doubled signals are due to the two epimers (at C-25) of (-)-l that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. b This signal was omitted in the list of ' H nmr resonances given for naturally occurring (-)-l.7 However, this signal was reported 1 6 in the *H nmr spectrum of synthetic (-)-l prepared by Boukouvalas et al.16 112 Table 7: Comparison of the 1 3 C nmr spectral data of our synthetic (-)-l (75 M H z , DMSO-afV) with those reported for naturally occurring ( - V 1 7 (125.7 M H z . DMSO-firV) OH R 1 2 n 2 4 13 C nmr assignment C-x 1 3 C nmr signals o f (-)-dysidiolide (5) Our synthetic (-)-l Naturally occurring (-)-l7'a C - l 170.5 (170.4) b 170.5 (170.4) b C-2 115.8 (116.1) b 115.9 (116.2) b C-3 175.7 (173.7) b(br) 175.5 (173.5) b (br) C-4 64.3 (62.9) b 64.4 (63.0) b C-7 33.0 33.0 C-9 115.5 115.5 C-10 142.1 (br) 142.3 C-19 145.3 145.3 C-20 22.0 22.0 C-21 110.0 110.0 C-22 25.9 25.9 C-23 14.9 14.9 C-24 22.0 22.0 C-25 97.6 (98.0) b 97.6 (98.0) b the remaining 11 carbon signals were 41.0 (br) 41.0 (br) not assigned 39.0 (br) 39.0 (br) 37.8 37.9 36.5 (br) 36.6 (br) 31.1 (br) 31.0 (br) 29.8 (br) 29.8 (br) 113 End of Table 7 1 3 C nmr signals of (-)-dysidiolide (5) Our synthetic (-)-l Naturally occurring (-)-l 27.0 (br) 27.0 (br) 23.4 (br) 23.5 (br) 21.7 21.7 21.6 21.6 21.4 (br) 21.5 (br) a The C nmr assignments related to carbons 1-4, 7, 9, 10, and 19-25 were determined by use of H M Q C and H M B C experiments.7 b Doubled 1 3 C nmr signals were observed for C - l , C-2, C-3, C-4, and C-25. These doubled signals are due to the two epimers (at C-25) of (-)-l that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. The IR spectral data acquired from our synthetic sample of (-)-l agree well with the IR spectral data reported for naturally occurring (-)-l.7 The IR spectrum o f synthetic (-)-l displayed, among other absorption bands, a strong O - H stretching absorption at 3392 cm"1 and a strong C=0 stretching absorption at 1741 cm"1. Recrystallization of a sample of our synthetic (-)-l from a mixture of C H 3 O H and CH2CI2 (CH30H:CH2Ci2, 2:98) provided white crystals which exhibited a melting point of 182-183 °C. This melting point compares well with the one reported for naturally occurring (-)-l (186-187 °C). Finally, the specific optical rotation recorded with our synthetic (-)-l ([a]^ 2 - 12 .0° at a concentration of 1.40 g/lOOmL in a l.T mixture of C H 3 O H and CH2CI2) agrees well with the specific optical rotation value reported for naturally occurring (-)-l ([a]^ -11 .1° at a concentration of 0.6 g/lOOmL in a 1:1 mixture of C H 3 O H and CH2CI2).7 The sign of the specific optical rotation of our synthetic (-)-l, confirmed that we had constructed the naturally occurring enantiomer of dysidiolide. 114 Scheme 43 presents a summary of the synthesis of (-)-dysidiolide (1 ) from the known racemic ketone (+)-34 29 1) L-Selectride, THF, -78°C,2 h 2) IN aqueous NaOH, 30% aqueous H2O2, rt, 16 h 99% 1) NaH, Bu 4NI, PMBC1, DMF, 50 °C, 3 h 2) HC1, acetone, rt, 30 min 3) IBX, DMSO, toluene, 70 °C, 48 h ©PMB (±)-38 47% 53 1) 2 eq. / -BuLi, pentane, E t 2 0 , -78 °C, 1 h i 2) CuCN, E t 2 0 , -40 °C, 10 min NaOH, C H 3 O H (±)-60 reflux, 48 h 92% CuCNLi 33 1) 33, Me3SiBr, E t 2 0, -78 °C, 2 h 2) aqueous N H 4 C I / N H 3 (pH 8), rt 3) TBAF , THF, rt 84%o OPMB (±)-59 1) D IBALH, THF, -78 °C, 1 h 2) N a 2 S 0 4 - 10 H 2 0 , E t 2 0 , rt, 1 h 47% of 63 and 51% of 64 (±)-63 1) PPh 3 , P h C 0 2 H , DEAD, THF, rt, 6 h 2) L i A l H 4 , E t 2 0 , 0 °C, 1 h 3) H 2 0 , rt 72% 1) 0 3 , Sudan Red 7B, CH 2 C1 2 , CH3OH, -78 °C 2) Me 2 S, rt, 12 h at rt 93% O OPMB (±)-46 Me 2 NC(OMe) 2 Me toluene, 100 °C,4 h 93% NMe2 k H PMBO (±)-80 Scheme 43 NMe2 1) LiEt3BH, THF, rt,2h ) 2) IN aqueous NaOH, 30% aqueous H2O2, 50 °C, 2 h 94% imidazole CH 3 CN, Et 20 rt, 2h 92% (±)-82 (±)-97 1) methallylmagnesium chloride, Cul, Lil, THF, -40 °C to rt, 10 hatrt 2) aqueous N H 4 C I / N H 3 (pH 8), rt 99% (+)-101 46% AccT > h (+)-102 45% (±)-29 (±)-81 K 2 C 0 3 , CH 3 OH, rt, 1 h 91% H Me 3 SK OMe 107 sec-BuLi, THF ] -78 °C to -25 °C, 30 min at -25 °C QH (-)-29 CH 2C1 2, rt, 30 min 92% (-)-105 1) 108, THF, -35 °C, 1 h 2) aqueous NaHC0 3, rt ! 3) TFA, H 2 0, CHC13(1:1:8) 0 °C, 30 min 88% 106 Scheme 4 3 (second page) 116 106 28 Dess-Martin periodinane, CH 2C1 2, rt 30 min 9 5 % (-)-131 1) 3-lithiofuran, THF, -78 °C, 30 min 2) aqueous NH4C1, rt A V // 1) KDA, THF, -78 °C, 30 min 2) HMPA, iodide 119, -78 °C, 5 min > 3) aqueous NH4C1, rt (-)-120 1) DIBALH, DME, rt, 30 min 2) IN aqueous citric acid, rt, 3 h 3) NaBH 4, CH 3 OH, rt, 20 min 4) aqueous NH4C1, rt 7 9 % 1) NaH, THF, catalytic imidazole, 60 °C, 2 h 2) CS 2 ) rt, 1 h 3) Mel, rt, 30 min 4) Ph 2SiH 2, catalytic benzoyl peroxide, o-xylene, 150 °C, 45 min 5) DDQ, CH 2C1 2, H 2 0 , rt, 1 h 80% n-BuLi, THF, -78 °C, 30 min A w // Br 3-bromofuran Li 3-lithiofuran 0 2 , hv, Rose Bengal, (i-Pr)2EtN, CH 2C1 2, -78 °C » 9 3 % (only alcohol (-)-134 in this reaction) Scheme 43 (third page) 117 2. 3. Syntheses of (-)-6-epidysidiolide and (-)-4,6-bisepidysidioIide A s mentioned previously (see section 1.4 of the Introduction), the synthesis of analogues structurally related to (-)-dysidiolide (1) was planned. One of these analogues has the opposite absolute configuration at C-6 compared with the natural product ((-)- l) (see Scheme 44). It was envisaged that this diastereomer of ( - ) - l , which we wi l l henceforth call 6-epidysidiolide (25), could be made from the nitrile (-)-118. The synthesis of (-)-118 has already been described in section 2.2.11 (equation 21). O 25 (-H Scheme 44 118 2. 3. 1. Synthesis of the enantiomerically pure aldehyde (-V141 The initial steps of the synthesis of 6-epidysidiolide (25) from (-)-118 involve the transformation of the nitrile (-)-118 into the aldehyde (—)-141. The nitrile function of (-)-118 was reduced to afford the corresponding product with the aldehyde function. Substance (-)-118 was allowed to react with diisobutylaluminum 75 hydride ( D I B A L H ) in 1,2-dimethoxyethane ( D M E ) at room temperature for 1 h and the resultant solution was treated with I N aqueous citric acid. The biphasic mixture thus obtained was stirred at room temperature for 2 h, an aqueous workup was effected, and the resultant crude residue was purified by chromatography on silica gel to provide the aldehyde (-)-142 in 86% yield (equation 38). The IR spectrum of (-)-142 showed a strong C = 0 stretching absorption at 1726 cm"1, characteristic of an aldehyde function. The ' H nmr spectrum of (-)-142 revealed a 1-proton singlet at 8 9.65, derived from the aldehydic proton. (-)-118 (-)-141 119 1) D I B A L H , D M E , rt, l h (38) C N 2) IN aqueous citric acid, rt, 2 h H O (-)-118 (-)-142 The aldehyde (-)-142 was converted into the corresponding homologated aldehyde (-)-141. The method developed by Magnus and R o y 6 7 (see section 2.2.10, Scheme 32) was chosen to effect this 1-carbon homologation. Hence, (methoxymethyl)trimethylsilane (107) was treated with sec-BuLi in T H F at low temperature (-78 °C). The reaction mixture was warmed to -25 °C and stirred for 30 min, to generate a solution of (methoxy(trimethylsilyl)methyl)lithium (108) in T H F (see Scheme 45). The solution of 108 was cooled to -35 °C and a T H F solution of the aldehyde (-)-142 was added. The resultant heterogeneous mixture was stirred at -35 °C for 30 min and treated with saturated aqueous NaHC03 . A n aqueous workup was conducted and the crude product (143) was dissolved in CHCI3. The solution thus obtained was cooled to 0 °C and a 1:1 mixture of trifluoroacetic ac id 6 8 (TFA) and H 2 0 was added (ratio of CHCI3 /TFA /H2O was 8/1/1). The biphasic mixture was stirred for 30 min at 0 °C, warmed to room temperature, stirred for 2 h, and then was treated with H 2 0 (Scheme 45). Unfortunately, treatment of the adduct 143 under these acidic conditions yielded only the starting material of the experiment, compound 143. 120 S i M e 3 S i M e 3 143 143 Scheme 45 Magnus and Roy described an alternative procedure in which the alcohol intermediate of the homologation protocol (143 in this case) is allowed to react under basic conditions to generate the corresponding alkenyl ether adduct (compound 144 in Scheme 46 in our case). To that end, a T H F solution of the crude intermediate 143 was treated with potassium hydride (KH) . The reaction mixture was warmed to 60 °C and stirred at this temperature for 30 min (Scheme 46). The suspension was then cooled to room temperature and treated with saturated aqueous N a H C 0 3 . A n aqueous workup was effected and the substance 144 was obtained as a crude residue. This residue (144) was dissolved in a mixture of acetic acid (CH3CO2H) and H2O (ratio of CH3CO2H/H2O was 121 4/1) and the resultant solution was stirred at room temperature for 3.5 h. The homogenous mixture was subsequently treated with H2O and an aqueous workup was conducted. Chromatography of the crude material on silica gel afforded the aldehyde (-)-141 in 54% yield from (-)-142. The IR spectrum of (-)-141 revealed a strong C = 0 stretching absorption at 1719 cm"1 due to the aldehyde function. The ! H nmr spectrum of (-)-141 showed a 1-proton triplet at 5 9.92, corresponding to the aldehydic proton. The same ' H nmr spectrum also exhibited a 2-proton resonance at 5 2.28-2.34, associated with H a and H a . . 1) C H 3 C 0 2 H , H 2 0 , rt, 3.5 h 2) H 2 0 , rt V (-)-141 Scheme 46 122 2. 3. 2. Synthesis o f enantiomerically pure (-)-6-epidysidiolide (25) The final steps for the synthesis of (-)-6-epidysidiolide (25) involved conversion of aldehyde (-)-141 into the target substance. The protocol that was previously employed for the synthesis of ( - ) - l from the aldehyde (-)-6 (see section 2.2.17, equations 36 and 37) was utilized. (-)-25 A solution of 3-lithiofuran in T H F at -78 °C was prepared as described previously in section 2.2.17 (see Scheme 40). A T H F solution of the aldehyde (-)-141 was then added to the cold (-78 °C) solution of 3-lithiofuran (equation 39). The homogenous mixture was stirred at -78 °C for 30 min and then was treated with saturated aqueous N H 4 C I . After an aqueous workup, the crude residue was purified by chromatography on silica gel to furnish the diastereomeric secondary alcohols (-)-145 and (-)-146, in 28% and 65% isolated yields, respectively. The IR spectra of (-)-145 and (-)-146 revealed strong O - H stretching absorptions at 3398 cm"1 and 3359 cm" 1, respectively. The lH nmr spectrum of (-)-145 exhibited a 1-proton multiplet at 6 4.83-4.90, attributed to the carbinol proton, a 2-proton resonance at 5 7.36-7.39, derived from H a and Hb, and a 1-proton singlet at 5 123 6 . 4 4 , associated with H c . The ! H nmr spectrum of (-)-146 displayed a 1-proton multiplet at 8 4 . 8 0 - 4 . 8 7 , corresponding to the carbinol proton, 1-proton resonances at 8 7 . 3 8 and 8 7 . 3 7 , due to FL. and H b (not assigned specifically), and a 1-proton singlet at 8 6 . 4 3 , associated with H e . (-)-145 B - 1 4 6 At this stage, the absolute configurations at C - 4 o f (-)-145 and (-)-146 (see equation 3 9 ) were not known. This absolute configuration was determined for the secondary alcohol (-)-146 as described below. The alcohol (-)-146 was allowed to react with 4-nitrobenzoyl chloride, triethylamine (Et3N) and 4-(dimethylamino)pyridine ( D M A P ) in C H 2 C I 2 at room temperature for 3 0 min to provide the benzoate (-)-147 in 9 5 % yield (equation 4 0 ) . The I R spectrum of (-)-147 displayed a strong C = 0 stretching absorption at 1 7 2 1 cm"1, corresponding to the ester function. The ! H nmr of (-)-147 exhibited a 1-proton doublet of doublets at 8 6 . 2 6 , associated with H a , and 2-proton multiplets at 8 8 . 2 3 - 8 . 2 7 and 8 8 . 1 6 - 8 . 2 0 , due to H b , H e , H d and H e (not assigned specifically). 124 r 1) 4-nitrobenzoyl chloride E t 3 N, D M A P , CH 2 C1 2 , rt, 30 min 2) aqueous N a H C 0 3 , rt (-)-146 The benzoate (-)-147 was isolated as a white solid and, upon recrystallization from hexanes, provided colorless crystals (mp 109-111 °C) suitable for an X-ray crystallographic study. 8 2 The perspective drawing of this substance ((-)-147) is shown in Figure 5. Considering that the absolute configurations at C-7, C-8, C-12, and C-16 of the benzoate (-)-147 were known, the absolute configuration at C-5 of this substance was ascertained through analysis of this X-ray crystal structure. Since (-)-147 was synthesized from (-)-146, the absolute configuration at C-4 (which corresponds to C-5 in (-)-147) was established as R for the alcohol (-)-145 and as S for the alcohol (-)-146. 125 (-)-147 Figure 5 O R T E P representation of the benzoate (-)-147 126 The alcohol (-)-145 was converted into (-)-6-epidysidiolide (25) via a protocol essentially identical to that utilized for the construction of (-)-dysidiolide (1) from (-)-134 (see section 2.2.17, equation 37). Thus, diisopropylethylamine ((z'-PfhEtN) and Rose Bengal were added to a CH2CI2 solution of the alcohol (-)-145. The resultant pink colored suspension was cooled to -78 °C and irradiated with a 200-W tungsten incandescent lamp under an O2 atmosphere, as depicted in equation 41. After a period of time dependant on the reaction scale (30 min for 3.2 mg of (-)-145), the irradiation was discontinued. The reaction mixture was warmed to room temperature and treated with saturated aqueous N H 4 C 1 . A n aqueous workup was effected and the crude residue was purified by chromatography on silica gel to afford (-)-6-epidysidiolide (25) in 68% yield. The IR spectrum of (-)-25 displayed a strong C=0 stretching absorption at 1762 cm"1, corresponding to the carbonyl function of the y-hydroxybutenolide moiety. The same spectrum also revealed a strong O - H stretching absorption at 3307 cm' "\ The ! H nmr spectrum of (-)-25 exhibited 1-proton singlets at 8 6.21 and 5 6.03, derived from Hb and H c (not assigned specifically), and a 1-proton resonance at 5 4.75-4.81, attributed to H a . The l¥L nmr spectrum of (-)-25 is shown in Appendix 1. The 1 3 C nmr spectrum o f (-)-25 showed doubled signals for C - l (5 170.6 and 5 170.4), C-2 (5 116.0 and 8 115.9), C-3 (5 176.0 and 5 173.9), C-4 (5 64.0 and 5 62.6) and C-25 (6 98.2 and 5 97.5). These doubled signals are due to the two epimers (at C-25) of (-)-25 that exist in solution. A similar observation was made upon examination of the 1 3 C nmr spectrum of (-)-l (see section 2.2.17). 127 B - 2 5 2. 3. 3. Synthesis of enantiomerically pure (-)-4.6-bisepidysidiolide (148) Considering that the secondary alcohol (-)-146 was readily available from the aldehyde (-)-141 (see equation 39), it was decided to synthesize 4,6-bisepidysidiolide (148) (see equation 42) from substance (-)-146 and to investigate the biological activity profile of this structural analogue (148) of (-)-dysidiolide (1). The alcohol (-)-146 was thus converted into (-)-4,6-bisepidysidiolide (148) using a procedure essentially identical with that employed to synthesize (-)-25 from (-)-145. This experiment afforded (-)-4,6-bisepidysidiolide (148) in 63% yield (equation 42). The IR spectrum of (-)-148 revealed a strong C = 0 stretching absorption at 1748 cm"1, corresponding to the carbonyl function of the y-hydroxybutenolide moiety. The same spectrum also showed a strong O - H stretching absorption at 3398 cm"1. The lH nmr spectrum of (-)-148 exhibited a 2-proton multiplet at 6 5.98-6.30, due to Hb and He, and a 1-proton resonance at 8 4.80-4.88, * 1 13 associated with H a . The H nmr spectrum of (-)-148 is shown in Appendix 1. The C nmr spectrum of (-)-148 displayed doubled signals for C - l (8 170.6 and 8 170.4), C-2 (8 128 116.1 and 5 115.7), C-3 (8 176.0 and 8 174.0), C-4 (8 64.4 and 8 64.1) and C-25 (8 98.2 and 8 97.5). These doubled signals are caused by the two epimers (at C-25) of (-)-148 that exist in solution. Similar observations were made when the 1 3 C nmr spectra of ( - ) - l (see section 2.2.17) and (-)-25 (see section 2.3.2) were examined. 1) 0 2, hv, Rose Bengal, (7-Pr) 2EtN, CH 2 C1 2 , -78 °C * 2) aqueous NH 4 C1, rt (42) (-)-148 129 Scheme 47 presents a summary of the synthesis o f (-)-6-epidysidiolide (25) and (-)-4,6-bisepidysidiolide (148) from the enantiomerically pure nitrile (—)-118. (-H18 1) DIBALH, DMR rt, 1 h 2) IN aqueous citric acid, rt,2h 8 6 % 1) 108, THF,-35 °C, 30 min 2) aqueous NaHC0 3 , rt 3) K H , THF, 60 °C, 30 min 4) aqueous NaHC0 3 , rt 5) C H 3 C 0 2 H , H 2 0 , rt, 3.5 h 6) H 2 0,rt 54% H Li 1 sec-BuLi, THF x M e 3 S i ' / ^ O M e Me3Si OMe -78 °C to -25 °C, 107 30 min at -25 °C -108 1) 3-lithiofuran, THF, -78 °C, 30 min 2) aqueous NH 4C1, rt 0 2 , hv, Rose Bengal, (7-Pr)2EtN, CH 2C1 2 , -78 °C 6 3 % (-)-145 2 8 % w // n-BuLi, THF, -78 °C, 30 min w // Br 3-bromofuran Li 3-lithiofuran 0 2 , hv, Rose Bengal, (;-Pr)2EtN, CH 2 C1 2 > -78 "C 6 8 % Scheme 47 130 2. 4. Syntheses of (-)-15-epidysidioIide and (-)-4,15-bisepidysidiolide The synthesis of another structural analogue of (-)-dysidiolide (1) was considered at this point (see section 1.4). This substance possesses at C-15 the absolute configuration opposite to that of C-15 in ( - ) - l (Scheme 48). It was planned that this compound, 15-epidysidiolide (26), would be constructed from tertiary amide 149. The latter material is the epimer of the amide 80, from which (-)-dysidiolide (1) had been elaborated previously. 26 0 ^ / N M e 2 7 =. H PMBO 80 (-)- l Scheme 48 131 Initially, the racemic tertiary amide 149 was constructed from (±)-enone 60, the synthesis of which is detailed in section 2.2.4. Thus, as discussed previously (see section 2.2.5, Scheme 17), the enone 60 was treated with sodium borohydride in the presence of cerium trichloride heptahydrate4 3 (CeCl 3 • 7 H 2 0 ) in C H 3 O H at -78 °C to furnish the alcohol 63 in 93% yield (equation 43). O i O H P M B O 60 1) N a B H 4 , C e C l 3 • 7 H 2 0 , C H 3 O H , -78 °C 2) aqueous N a H C 0 3 , rt (43) 63 The racemic allylic alcohol 63 was allowed to react with excess N,N-dimethylacetamide dimethyl acetal (Me2NC(OMe)2Me) in toluene at 110 °C for 5 h (in accordance with the procedure reported by Eschenmoser and coworkers 4 7), to provide the racemic tertiary amide 149 in a stereospecific manner and in 91% yield (equation 44). The IR spectrum of 149 revealed a strong C=0 stretching absorption at 1646 cm"1, characteristic o f an amide function. The lH nmr spectrum of 149 displayed a resonance at 5 5.16-5.21, attributed to the alkenyl proton, and a 3-proton singlet at 5 1.17, corresponding to the tertiary methyl group (Me a ) . The Hb protons appeared as a 2-proton singlet at 8 2.45 and the two methyl groups on the amide nitrogen produced 3-proton singlets at 5 3.03 and 5 2.92. Me 2 NC(OMe) 2 Me toluene i 1 1 0 ° C , 5 h (44) 63 149 132 2. 4. 1. Synthesis of the enantiomerically pure ketone (+)-34 At this stage of our studies, the tertiary amide 149 had to be made in large amounts from the ketone 34 2 9 (see sections 2.1 and 2.2.1 for the original references to substance 34) in order to supply enough of 149 to complete the synthesis of 15-epidysidiolide (26). Hence, it was thought worthwhile to design a method to produce ketone 34 in its enantiomerically pure form and then to effect the construction of enantiomerically pure 15-epidysidiolide (26) from this material. Indeed, using such a strategy, it would be possible to synthesize 15-epidysidiolide (26) in its enantiomerically pure form without having to achieve a resolution of the enantiomers of one of the synthetic intermediates leading to 26. The natural enantiomer of dysidiolide ((-)-l) had been elaborated via such an enantiomeric separation (see section 2.2.9). It was planned that ketone 34 8 3 would be made in its enantiomerically pure form from the commercially available ketone 150 (equation 45), via the method designed by Enders and coworkers 8 4 to generate enantiomerically pure aldehyde and ketone products. 150 34 This protocol, illustrated in general terms in Scheme 49 (page 134), includes the construction of an enantiomerically pure hydrazone intermediate (154) by treatment of a ketone or an aldehyde (151) with (5)-(-)-l-amino-2-(methoxymethyl)pyrrolidine (152). 133 This substance (154) is then allowed to react with lithium diisopropylamide ( L D A ) in T H F at 0 °C. The resultant anion is alkylated at low temperature (typically -95 °C) with a suitable electrophile (a primary iodide in most cases). 8 4 This process occurs in a diastereoselective manner to afford an alkylated hydrazone adduct (155); a model has been proposed to explain the diastereoselectivity of this alkylation process. 8 5 ' 8 6 Finally, the hydrazone function of 155 is cleaved, via any of a number of available methods, 8 7 to yield the alkylated ketone or aldehyde product (156). The ketone and aldehyde products (156) are prepared in good enantiomeric excesses (85-99% ee) in the majority of the cases studied. 8 4 The enantiomer of 152, (i?)-(-)-l-amino-2-(methoxymethyl)pyrrolidine (153), is used to prepare the hydrazone intermediate (enantiomer of 154) i f the synthesis of a ketone or an aldehyde of absolute configuration opposite to that shown in Scheme 49 is required. 134 R? N H 2 i N .Ri O 151 152 N H 3 C O N-154 1) L D A , THF, 0 ° C >I -95 °C R, = Alkyl (ketone) or H (aldehyde) R 2 = Alkyl R 3 = Alkyl R? R 3 \v^' .R i R? N R 3 W Cleavage of the hydrazone function N -O 156 H3CO 155 Scheme 49 It was decided to use this protocol for the synthesis of ketone 34 in its enantiomerically pure form. Results obtained by Tokoroyama et a / . 8 8 suggested that 152 was the enantiomer of the reagent necessary to effect the synthesis o f the enantiomer of 34 depicted in equation 45. Hence, the commercially available ketone 150 was treated with ( 1S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine 8 9 (152) in benzene at 80 °C for 2 h with the use of a Dean-Stark trap (equation 46). The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by bulb-to-bulb distillation (265-280 °C/0.3 Torr) and the hydrazone (+)-157 was obtained 135 in 98% yield. The IR spectrum o f (+)-157 displayed a strong C=N stretching absorption at 1471 cm"1, characteristic of a hydrazone function. The lH nmr spectrum of (+)-157 revealed a 1-proton doublet of doublets at 8 3.39, attributed to H a , and 1-proton multiplets at 8 3.19-3.24 and 8 3.11-3.18, derived from H a ' and Hb (not assigned specifically). The same *H nmr spectrum exhibited 1-proton doublets of triplets at 8 3.03 and 8 2.76, due to H c and FL^ a 3-proton singlet at 8 3.31, associated with the C H 3 0 - group, as well as the characteristic resonances of the ketal function. The anion of the hydrazone (+)-157 was alkylated with methyl iodide (Mel) according to the procedure reported by Ziegler and coworker. 9 0 This anion was prepared by treatment of a cold (0 °C) T H F solution of lithium diisopropylamide ( L D A ) with a solution of (+)-157 in T H F (see Scheme 50). The reaction mixture was stirred for 1 h at 0 °C and cooled to -95 °C. Methyl iodide (Mel) was added and the homogenous mixture was stirred for 15 min at -95 °C. The solution was treated with saturated aqueous NH4CI and an aqueous workup was conducted. The resultant crude alkylated hydrazone (158) was dissolved in C H 2 C I 2 and the mixture was cooled to -78 °C. Ozone (O3) was bubbled through the mixture for 5 h. The suspension was then warmed to room temperature and (46) (+)-157 136 the solvent was evaporated in vacuo. The crude residue was purified by chromatography on silica gel to furnish the ketone (+)-34 in 87% yield from the hydrazone (+)-157. The ketone (+)-34 displayed spectral data (IR and ! H nmr) that were in good agreement with those reported for racemic 34. 2 9 The specific optical rotation recorded for (+)-34 was [<X]D +1.56° at a concentration of 4.20 g/lOOmL in C H 2 C 1 2 . (+)-157 158 0 3 , CH 2 C1 2 , -78 °C, 5 h 1 o (+)-34 Scheme 50 In the above reaction sequence (Scheme 50), the carbon-nitrogen double bond of hydrazone 158 was cleaved by treatment of this material (158) with O 3 . The proposed 87 mechanism for this transformation is depicted in Scheme 51. Ozone (O3) initially reacts with the carbon-nitrogen double bond of the hydrazone 158 via a 1,3-dipolar 137 cycloaddition to afford the intermediate 159. The five-membered ring thus formed subsequently undergoes a ring-opening process to generate the adduct 160. Fragmentation of 160 furnishes the diazene 161, the ketone (+)-34, and a molecule of oxygen (02). Scheme 51 It is proposed that the diazene 161 reacts with another equivalent of ozone (O3) to provide the dipolar intermediate 162 (see Scheme 52). Finally, fragmentation of this intermediate (162) produces a molecule of oxygen (02) as well as the nitrosamine 163. 138 Recovery o f 163 from this ozonolysis process has been reported. 8 7 Moreover, studies have demonstrated that two equivalents of ozone (O3) are necessary to consume one equivalent of the hydrazone starting material. This observation is also in agreement with the proposed mechanism. 8 7 161 162 0 2 Scheme 52 2. 4. 2. Synthesis o f the enantiomerically pure alcohol (+)-35 and determination of its absolute configuration The enantiomeric purity and the absolute configuration of the ketone (+)-34, which had been synthesized through the use of the method developed by Enders and coworkers 8 4 (see previous section), had to be determined. This objective was achieved in the following manner. The previously prepared racemic alcohol 35 was allowed to react with (iS)-(+)-0-acetylmandelic ac id 6 1 in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine ( D M A P ) in C H 2 C 1 2 at -20 °C, as depicted in Scheme 53. The heterogeneous mixture was stirred for 24 h at -20 °C and filtered. The filtrate was concentrated and the crude residue containing the O-acetylmandelate esters 164 and 165 was treated, without further purification, with potassium carbonate (K2CO3) 139 in C H 3 O H at 0 ° C . 6 3 The suspension was stirred at 0 °C for 20 min and fdtered. The fdtrate was concentrated and the residual crude material was purified by chromatography on silica gel to provide the diastereomeric mandelate esters (+)-166 and (+)-167 in isolated yields o f 45% and 43%, respectively, from the racemic alcohol 35. w OH (±)-35 0S)-(+)-O-acetyl-mandelic acid DCC, D M A P , CH 2 C1 2 , -20 °C, 24 h v>'' O + A c O ^ ^ P H 164 K 2 C 0 3 , C H 3 O H , 0 °C, 20 min + (+)-166 separation of (+)-166 and (+)-167 by chromatography on silica gel Scheme 53 The IR spectra of (+)-166 and (+)-167 exhibited strong O - H stretching absorptions at 3452 cm"1 and 3446 cm" 1, respectively, as well as strong ester C = 0 140 stretching absorptions at 1725 cm" 1 and 1726 cm" 1, respectively. The ! H nmr spectra of (+)-166 and (+)-167 revealed 1-proton resonances corresponding to H a at 5 4.93-4.97 and 8 4.93-4.98, respectively. The same spectra displayed 1-proton doublets at 8 5.13 and 8 5.16, respectively, attributed to Hb in these substances. Finally, the lH nmr spectra of (+)-166 and (+)-167 each possessed five aromatic proton resonances. The mandelate ester (+)-167 was isolated as a crystalline solid that, upon recrystallization from E t 2 0 , provided crystals (mp 105-107 °C) suitable for an X-ray crystallographic study. 9 1 The perspective drawing of this substance ((+)-167) is shown in Figure 6. 9 2 S Figure 6 O R T E P representation of the mandelate ester (+)-167 The absolute configuration of the ester (+)-167 at C - l was established by the reagent, (5)-(+)-0-acetylmandelic acid, used for the preparation of this substance. 141 Therefore, the absolute configurations at C-9 and C-10 in (+)-167 could be unambiguously assigned and are as shown in Figure 6. These assignments dictate that the absolute configurations at C-2 and C-3 in the diastereomeric ester (+)-166 are as depicted in Figure 7. The corresponding alcohol 35 is the starting material required for the planned synthesis of 15-epidysidiolide (26) (depicted in Figure 7). To provide the optically active secondary alcohol (+)-35 (equation 47), ketone (+)-34 (vide supra, Scheme 50) was reduced as described previously for its racemic counterpart (section 2.2.1, equation 2). The alcohol (+)-35 displayed spectral data (IR and ! H nmr) identical to those exhibited by racemic 35. The specific optical rotation recorded with (+)-35 was [ a ] 2 0 +28.1° at a concentration of 4.00 g/lOOmL in C H 2 C 1 2 . 26 Figure 7 . O 2 ) N a O H , H 2 0 2 , H 2 0 , r t 1) L-Selectride, THF, -78 °C O O ,0 O H (47) (+)-34 (+)-35 142 At this point, we were able to determine whether or not the enantiomer of 35 synthesized (equation 47) was the one required to effect the construction of the desired enantiomer of 26 (Figure 7). Alcohol (+)-35 was converted into mandelate ester (+)-166 (Scheme 54) in 89% yield via the same method used for the synthesis of (+)-166 and (+)-167 from racemic 35 (vide supra, Scheme 53), and, consequently, (+)-35 was the enantiomer required to pursue the synthesis o f 15-epidysidiolide (26). OH (+)-35 (S)-(+)-0-acetyl-mandelic acid DCC, D M A P , CH 2 C1 2 , -20 °C, 24 h AcO x X Ph 164 K 2 C 0 3 , C H 3 O H , 0 °C, 20 min H O ^ P h (+)-166 Scheme 54 143 Moreover, using this series of experiments, we were able to determine the enantiomeric purity of alcohol (+)-35. The *H nmr spectrum of a crude sample of (+)-166 (Scheme 54) was devoid of any signal present in the spectrum of (+)-167. 9 3 Thus, the alcohol (+)-35 was considered to be an enantiomerically pure material. 9 4 2. 4. 3. Synthesis of the enantiomerically pure tertiary amide (-1-149 Tertiary amide (-)-149 was synthesized from enantiomerically pure alcohol (+)-35 according to the same protocol that allowed the construction of racemic 149 from racemic 35 (vide supra, Scheme 43, equation 43 and equation 44). The IR and *H nmr spectra of the enantiomerically pure synthetic intermediates leading from (+)-35 to (-)-149 were, as expected, identical to those obtained for the corresponding racemic intermediates. The specific optical rotations of these intermediates are included in the Experimental section of the thesis (see section 5.4). (+)-35 (-)-149 144 2. 4. 4. Synthesis o f enantiomerically pure (-)-15-epidysidiolide (26) and (—)-4,15-bisepidysidiolide (181) The parallel construction of (-)-15-epidysidiolide (26) and (—)-4,15-bisepidysidiolide (181) from the enantiomerically pure tertiary amide (-)-149 is described in Scheme 55 (vide infra, pages 147 and 148). The sequence of reactions presented therein is similar to that employed to synthesize (-)-dysidiolide (1) from racemic tertiary amide 80 (vide supra, Scheme 43). The amide function of (-)-149 was cleanly reduced using L i E t 3 B H (Super-Hydride®) 4 9 to furnish primary alcohol (-)-168 (94%). The latter material was converted into the corresponding iodide, (-)-169, and this substance was treated with methallylmagnesium chloride 5 8 in the presence of C u l and L i l 5 9 at -40 °C to provide ether (-)-170 in 86% yield from (-)-168. Cleavage of the /7-methoxybenzyl ( P M B ) ether function o f (-)-170 with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone 6 0 (DDQ) was followed by oxidation of the hydroxyl function of the resultant material ((-)-171) employing the Dess-Martin periodinane, 5 0 to afford ketone (-)-172 in 84%> overall yield. Substance (-)-172 was treated with (methoxy(trimethylsilyl)methyl)lithium 6 7 (108) at -40 °C and the resultant crude material was allowed to react in a biphasic mixture 6 8 of trifluoroacetic acid (TFA) , H 2 O , and CHCI3 at 0 °C, to generate the diastereomeric mixture of aldehydes 173 in 74%> yield. The epimeric mixture of nitriles 174 was prepared by treatment of 173 with hydroxylamine hydrochloride 7 0 ( N H 2 O H • HC1) in 7V-methylpyrrolidinone ( N M P ) at 115 °C (93%). Nitrile 174 was treated with potassium disopropylamide 7 4 ( K D A ) at -78 °C and the resultant anion was allowed to react with iodide 119 in the presence of hexamethylphosphoramide 7 1 ( H M P A ) to furnish nitrile (-)-145 175 as a single enantiomer in 91% yield. Nitrile (-)-175 was the product anticipated from this alkylation process, based on previous results (section 2.2.13, equation 28). 75 Nitrile (-)-175 was allowed to react with diisobutylaluminum hydride ( D I B A L H ) in 1,2-dimethoxyethane ( D M E ) and the resultant solution was treated with I N aqueous citric acid. The crude aldehyde thus generated was treated with sodium borohydride ( N a B H 4 ) to afford primary alcohol (-)-176 in 82% yield from (-)-175. The hydroxyl group of (-)-176 was transformed into the corresponding xanthate function (NaH, catalytic imidazole, T H F , 60 °C; C S 2 , rt; M e l , rt). 7 8 The xanthate intermediate was subjected to radical deoxygenation conditions 7 6 (BU3S11H, A I B N , o-xylene, 150 ° C ) , 9 5 to provide, after treatment of the resultant crude material with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone 6 0 (DDQ), primary alcohol (-)-177 in 85% yield from alcohol (-)-176. Facile oxidation of the alcohol function of (-)-177 with the Dess-Martin periodiane 5 0 yielded aldehyde (-)-178 (91%). The latter substance was treated with 3-lithiofuran 8 in T H F at -78 °C to generate the epimeric secondary alcohols (-)-179 (41%) and (-)-180 (49%>), which were easily separable by chromatography on silica gel. Finally, (-)-15-epidysidiolide (26) was prepared by irradiation 7 9 o f a solution of (-)-179, diisopropylethylamine ((z'-Pr^EtN) and Rose Bengal in C H 2 C I 2 with a 200-W tungsten incandescent lamp under an O 2 atmosphere at -78 °C (85%). Employing a similar protocol, (—)-4,15-bisepidysidiolide (181) was obtained from (-)-180 in 83% yield. It was thought of interest to synthesize this structural analogue ((-)-181) of (-)-dysidiolide and to investigate its biological profile. 146 The intermediates of the sequence of reactions leading from (-)-149 to (-)-26 and (-)-181 displayed spectral data (IR, lH nmr, 1 3 C nmr) that correlated well with their respective structures (see Experimental, section 5.4). The specific optical rotations of the intermediates (except for 173 and 174) of this reaction sequence were recorded and are included in the Experimental section of the thesis. The lH nmr spectra of (-)-15-epidysidiolide (26) and (—)-4,15-bisepidysidiolide (181) are presented in Appendix 1. 147 ,NMe 2 i H PMBO ( - M 4 9 (-)-172 1) LiEt 3 BH, THF, rt,2h 1 2) IN aqueous NaOH, 30% aqueous H 2 0 2 , 60 °C, 3 h 94% Dess-Martin periodinane CH 2 C1 2 , rt, 30 min 90% 1) 108, THF, -40 °C, l h 2) aqueous NaHC0 3 , rt 3) TFA, H 2 0 , CHC1 3 (1:1:8) 0 ° C , 30 min 74% PPh 3,1 2, imidazole PMBO C H 3 C N , Et 2 0 rt, 1 h 94% = H PMBO (-)-168 (-)-169 1) methallylmagnesium chloride Cul, Li l , THF, -40 °C, 5 h 2) Aqueous N H 4 C 1 / N H 3 (pH 8), rt 92% (-)-171 2,3-dichloro-5,6-dicyano-1,4-benzo-quinone (DDQ) CH 2 C1 2 , H 2 0 , rt, 1 h 93% k H PMBO (-)-170 H Me 3Sr OMe 107 sec-BuLi, THF * -78 °C to -25 °C, 30 min at-25 °C Li Me 3Sr OMe 108 173 174 1) KDA, THF, -78 °C, 30 min 2) HMPA, iodide 119, -78 °C, 5 min »» 3) aqueous NH 4C1, rt 91% Scheme 55 148 C N V ^ ^ Z — O C H 3 4) aqueous NFLCl, rt (-)-175 82% 1) DIBALH, DME, rt, 30 min 2) IN aqueous citric acid, rt,3h ^ 3) NaBH), CH 3 OH, 0 rt, 20 min 0 2 , hv, Rose Bengal. 0-Pr)2EtN, CH 2C1 2 , -78 °C 85% 0 2 , hv, Rose Bengal, (j-Pr)2EtN, CH 2C1 2, -78 °C 83% O ^ O H 1) NaH, THF, catalytic imidazole, 60 °C, 2 h 2) CS 2 , rt, 1 h 3) Mel, rt, 30 min » 4) aqueous NaHC0 3 , rt 5) Bu3SnH, AIBN, o-xylene, 150 °C, 15 min 6) DDQ, CH 2C1 2 , H 2 0 , rt, 1 h 85% (-)-177 Dess-Martin periodinane CH 2C1 2 , rt, 30 min 91% 1) 3-lithiofuran, THF, -78 °C, 30 min 2) aqueous NH4C1, rt A w // n-BuLi, THF, -78 °C,30 min A w // Br 3-bromofuran 3-lithiofuran (-)-26 (-)-181 Scheme 55 (second page) 149 2. 4. 5 . Determination of the absolute configuration (at C-4) of the alcohols (-)-179 and B - 1 8 0 The absolute configuration at C-4 of secondary alcohols (-)-179 and (-)-180 was determined as follows. First, these two substances were compared with their diastereomers, (-)-134 and (-)-135 (see section 2.2.17, equation 36). The absolute configuration at C-15 of (-)-134 is opposite to that at C-15 of (-)-179, as shown below. This is the only structural difference between these two compounds. Similarly, the unique structural distinction between (-)-135 and (-)-180 is the absolute configuration at C-15. (-)-134 (_)_135 (_)_179 (-)-180 To evaluate the validity of these assignments, the ' H nmr spectra of (-)-179 and (-)-180 were compared with the lH nmr spectra of (-)-134 and (-)-135. It was anticipated that the chemical shifts of the lH nmr signals corresponding to Me-23 in these four diastereomers would be essentially unaffected by the absolute configuration at C-15. This prediction was based on the fact that in all of these substances, C-15 is located on the decalin framework at an appreciable distance from Me-23. On the other hand, the chemical shifts of the lH nmr signals attributed to Me-23 in these molecules could be significantly influenced by their absolute configuration at C-4, because this chirality 150 center is located in the vicinity of Me-23. Therefore, it would be anticipated that the chemical shifts of the *H nmr signals associated with Me-23 in the spectra of (-)-134 and (-)-179 would be similar. In the same manner, one would expect to find comparable chemical shifts for the *H nmr signals derived from Me-23 in the spectra of (-)-135 and (-)-180. Indeed, the chemical shift of Me-23 in (-)-134 (5 0.87) is very similar to the chemical shift of Me-23 in (-)-179 (5 0.85). Moreover, the chemical shift of Me-23 in (-)-135 (5 0.77) is comparable to the chemical shift o f Me-23 in (-)-180 (5 0.75). However, i f the compounds with an R configuration at C-4 ((-)-134 and (-)-179) are compared with the compounds with an S configuration at C-4 ((-)-135 and (-)-180), there is a significant chemical shift difference (0.1 ppm) between the two sets of signals corresponding to Me-23. This suggestion concerning the absolute configurations of alcohols (-)-179 and (-)-180 based on their respective *H nmr spectra was corroborated by the results of an oxidation-reduction sequence conducted using alcohol (-)-180 as starting material. As described earlier (see Scheme 42 in section 2.2.17), Corey and Roberts 8 treated the ketone 140 with B H 3 • M e 2 S in the presence of a catalytic amount of the enantiomerically pure oxazaborolidine catalyst A in toluene at -30 °C to afford the alcohol (-)-134 as a single diastereomer in 91% yield (Scheme 56). It was believed that reduction of the ketone function of 182 (which could be obtained by oxidation of the alcohol function of (-)-180) under the same experimental conditions should furnish the alcohol (-)-179 as the major product. As depicted in Scheme 56, the only difference in structure between the ketones 140 and 182 is their absolute configuration at C-15. Since in each of compounds 151 140 and 182, C-15 is located at an appreciable distance from the carbonyl group, the absolute configuration at this chirality center was not anticipated to have an important influence on the outcome of the reduction process. C H 3 oxazaborolidine catalyst A Scheme 56 Alcohol (-)-180 was treated with the Dess-Martin periodinane 5 0 in C H 2 C I 2 at room temperature to afford ketone (-)-182 in 96% yield (see Scheme 57). The IR 152 spectrum of (-)-182 revealed a strong C = 0 stretching absorption at 1672 cm"1. The 1 3 C nmr spectrum of (-)-182 displayed a signal at 5 195.0, associated with the carbon of the ketone function. Next, the ketone (-)-182 was treated with BH3 • Me2S in the presence of a catalytic amount of oxazaborolidine A in toluene at -30 °C for 10 h to provide the alcohol (-)-179 as a single diastereomer in 94% yield (Scheme 57). The result of this reduction process provided very strong corroborative evidence for the stereochemical assignment of alcohols (-)-179 and (-)-180. (-)-179 Scheme 57 153 2. 5. Syntheses of (-)-6,15-bisepidysidiolide and (-)-4,6,15-trisepidysidiolide The subsequent structural analogue of (-)-dysidiolide (1) that we endeavored to synthesize was 6,15-bisepidysidiolide (27) (Scheme 58). It was anticipated that this substance could be made from the mixture of nitriles 174 in a manner very similar to that used for the synthesis of (-)-6-epidysidiolide (25) from the mixture of nitriles 28 (see equation 21, section 2.2.11 and Scheme 47, section 2.3). The synthesis of 174 was described above (see Scheme 55 in section 2.4.4). Scheme 58 154 2. 5. 1. Synthesis o f enantiomerically pure alcohols (-V186 and (-)-187 Secondary alcohol (-)-186 (an advanced intermediate in the synthesis of 27) and its C-4 epimer (-)-187 were constructed from the mixture of nitriles 174 as shown in Scheme 59 (vide infra, page 156). The anion of 174 was prepared by treatment of this substance with lithium diisopropylamide ( L D A ) in the presence of hexamethylphosphoramide 7 1 ( H M P A ) in T H F at 0 °C. The intermediate thus formed was allowed to react with methyl iodide (Mel) at -98 °C to provide nitrile (-)-183 as a single enantiomer and in 92% yield. The diastereoselectivity of this alkylation process was predicted from results obtained earlier (vide supra, section 2.2.11, equation 21). Compound (-)-183 was allowed to react with diisobutylaluminum hydride 7 5 in 1,2-dimethoxyethane ( D M E ) and the resultant solution was treated with I N aqueous citric acid at room temperature for 3 h to afford aldehyde (-)-184 (90%). The latter material was allowed to react with (methoxy(trimethylsilyl)methyl)lithium 6 7 (108) in TFfF at -35 °C and the resultant crude tertiary alcohol was treated with potassium hydride 6 7 (KH) in T H F at 60 °C. The alkenyl ether function of the crude intermediate thus produced was hydrolyzed under acidic conditions (oxalic acid, acetone:H20 (2:1), rt, 1 h) to furnish homologated aldehyde (-)-185 in 79% yield from (-)-184. The aldehyde (-)-185 was allowed to react with 3-lithiofuran 8 in T H F at -78 °C to afford a mixture of secondary alcohols (-)-186 and (-)-187 (1:6.7 ratio, respectively) in 92% yield (the absolute configuration at C-4 of (-)-187 was determined as explained below, see section 2.5.2). The latter two substances were difficult to separate by 155 chromatography on silica gel but following several chromatographic steps, pure (-)-187 was isolated in 74% yield along with a mixture of (-)-186 and (-)-187 (2:1 ratio, respectively, 18% yield). Secondary alcohol (-)-186 was subsequently constructed in synthetically useful amounts through a Mitsunonu sequence 4 5 employing (-)-187 as starting material (vide infra, section 2.5.3). The intermediates of the sequence of reactions leading from 174 to (-)-186 and (-)-187 displayed spectral data (IR, ' H nmr, 1 3 C nmr) that correlated well with their respective structures (see Experimental, section 5.5). The specific optical rotations of the intermediates (except for 174) of this reaction sequence were recorded and are included in the Experimental section of the thesis. 156 CN lH 174 1) LDA, HMP A, THF, 0 °C, 1 h • 2) Mel, -98 °C, 5 min 3) aqueous NH 4 Cl,rt W^'l T\ 9 2 / 0 (-)-183 H Li 1 sec-BuLi, THF x M e 3 S r OMe »- M e 3 S r T>Me -78 °C to -25 °C, 107 30 min at -25 °C 108 A w // «-BuLi, THF, -78 °C, 30 min 1) DIBALH, DME, rt, 1 h 1 2) IN aqueous citric acid, rt, 2h 90% h f (-)-184 1) 108, THF,-35 °C, 30 min 2) aqueous NaHC0 3 , rt 3) K H , THF, 60 °C, 30 min 4) aqueous NaHC0 3 , rt 5) oxalic acid, acetone :H 2 0 (2:1), rt, 1 h 79% 1) 3-lithiofuran, THF, -78 °C, 30 min 2)aqueous NH 4C1, rt A w // Br 3-bromofuran Li 3-lifhiofuran Scheme 59 2. 5. 2. Determination of the absolute configuration of alcohol (-)-187 at C-4 The absolute configuration of the carbinol chirality center (C-4) of alcohol (-)-187 (see Scheme 59) had to be ascertained. This objective was accomplished using the method elaborated by Dale and Mosher 9 6 for the determination of the absolute 157 configuration of the carbinol center of chiral secondary alcohol substrates. Dale and Mosher 9 6 separately treated chiral secondary alcohols (188) with (-)- and (+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride to afford diastereomeric pairs o f 2-methoxy-2-phenyl-2-trifluoromethylacetate esters (189 and 190, respectively), as illustrated in Scheme 60 (vide infra, page 159). Examination of the  lH nmr spectra of the pairs of esters thus prepared, and comparison of the  l H nmr resonances observed in these spectra with an empirical model allowed Dale and Mosher to ascertain the absolute configuration of the carbinol center of the secondary alcohol starting materials (188). The empirical model designed by Mosher and coworker 9 6 employs the conformations of esters 189 and 190 shown in Scheme 60. These conformations, which locate H a , the two oxygen atoms of the ester function and the carbon of the CF3 group all in the same plane, were not designated by the authors as undoubtedly the most stable ones but were utilized because they were suitable to explain the experimental results obtained. In the Newman projection of 189 (Scheme 60), it can be easily recognized that the R2 group is juxtaposed with the phenyl group (Ph) and that the R i group is juxtaposed with the methoxy group (MeO). These correlations are reversed for the ester 190, namely the R i group is juxtaposed with the phenyl group (Ph) and the R2 group is juxtaposed with the methoxy group (MeO) in this other diastereomer. The protons of the R2 group in 189 (facing Ph) are thought to be shielded by the anisotropic effect of the aromatic substituent. These protons (R2 group) are thus expected to be found at higher field in the *H nmr spectrum of 189 than in the ! H nmr spectrum of 190. Similarly, the protons of the R i group are expected to be found at higher field in the ' H nmr spectrum of 190 (in which 158 R i faces Ph) than in the  l H nmr spectrum of 189. Dale and Mosher 9 6 studied the nmr resonances of the protons (in R i and R 2 ) attached to the carbons that were in a and P positions relative to the carbinol center of the secondary alcohol starting materials (188) in order to reach conclusions concerning the absolute configurations of these alcohol substrates. In a later report, Ohtani, Kusumi, Kashman and Kak i sawa 9 7 extended the utilization of this model to the determination of the absolute configurations of the carbinol chirality centers of complex natural products that possess secondary hydroxyl functions. Kakisawa et al91 suggested that any proton present in the R i and R 2 groups (see Scheme 60) o f esters 189 and 190 can experience the shielding effect of the phenyl group and can therefore be used to determine the absolute configuration of the carbinol center of 188, no matter how far from the carbinol center of the alcohol starting material this proton sits. Kakisawa and coworkers 9 7 considered their improved model to be more reliable than the one put forward by Dale and Mosher 9 6 because their conclusions concerning the absolute configurations of the carbinol centers of alcohol starting materials relied on the examination of a larger number of data points ( ' H nmr resonances). Kakisawa et al. demonstrated the reliability of their supplemented method by determining the absolute configurations of the carbinol centers of a series of structurally intricate terpene natural products. 159 O 189 190 (i?)-(-)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride O MeO iph (5)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride O Ph / C F 3 t>Me Scheme 60 In the present work, alcohol (-)-187 was separately treated with (-)- and (+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride in the presence of triethylamine (Et3N) and 4-(dimethylamino)pyridine ( D M A P ) in C H 2 C I 2 at room temperature for 15 min to provide the diastereomeric esters 191 and 192 in 87% and 83% isolated yields, respectively (Scheme 61). The IR spectra of 191 and 192 each displayed a strong C=0 160 stretching absorption, characteristic of an ester function (at 1746 cm"1 for both substances). The ! H nmr spectra of 191 and 192 each showed a 1-proton resonance (at 5 6.10-6.14 for 191 and at 8 6.07-6.12 for 192), corresponding to FL, and a 3-proton singlet (at 8 3.40 for 191 and at 8 3.44 for 192), attributed to the M e O - group. Employing the supplemented model reported by Kakisawa and coworkers, 9 7 the chemical shifts of the resonances corresponding to H a , Hy, M e c and Mea in the *H nmr spectra of 191 and 192 were compared. The chemical shift o f the resonance associated with H a was observed, as expected, at higher field in the *H nmr spectrum of 192 (8 6.29) than in the  l H nmr spectrum of 191 (8 6.44). Moreover, the chemical shifts of the resonances derived from Hb', M e c and Mea were observed, as anticipated, at higher field in the *H nmr spectrum of 191 (8 1.64, 8 0.68 and 8 0.59, respectively) than in the *H nmr spectrum of 192 (8 1.74, 8 0.76 and 8 0.73, respectively). The differences in chemical shifts observed between these two ! H nmr spectra were of comparable magnitudes to those reported by Mosher 9 6 and Kakisawa 9 7 for other pairs of 2-methoxy-2-phenyl-2-trifluoromethylacetate esters. Hence, the absolute configuration of the carbinol chirality center (C-4) of (-)-187 was established as S (as depicted in Scheme 61). 161 (-)-187 (-)-187 CI CF-, MeO Ph Et 3 N, DMAP, CH 2 C1 2 , rt, 15 min CI CF-, Ph "OMe Et 3 N, DMAP, CH 2 C1 2 , rt, 15 min (i?)-(-)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride 0 MeO (lS)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride 0 c i - ^ S Ph* / C F 3 t)Me 4 C F 3 MeC7 'Ph 191 C F 3 R 1 Ph t ) M e 192 R 2 = Mec\vvl" 'XT Me d Scheme 61 162 2. 5. 3. Synthesis o f the enantiomerically pure secondary alcohol (-V186 It was necessary at this stage to construct secondary alcohol (-)-186 (Scheme 59) in sufficient amounts to complete the synthesis o f 6,15-bisepidysidiolide (27). The alcohol (-)-186 was made from (-)-187 via a Mitsunobu 4 5 inversion sequence. Secondary alcohol (-)-187 was allowed to react with triphenylphosphine (PPh 3), /?-nitrobenzoic acid and diethyl azodicarboxylate ( D E A D ) in T H F at room temperature (Scheme 62). The heterogeneous mixture was stirred for 2 h and treated with saturated aqueous NaHCCb. A n aqueous workup was conducted and the crude /?-nitrobenzoate 193 was obtained. This residual material was treated, without further purification, with diisobutylaluminum hydride ( D I B A L H ) in T H F at room temperature for 1 h to afford the secondary alcohol (-)-186 in 82% yield from (-)-187. The IR spectrum of (-)-186 showed a strong O - H stretching absorption at 3413 cm' 1 . The *H nmr spectrum of (-)-186 revealed a 2-proton resonance at 5 7.35-7.39, attributed to H a and Hb. The same spectrum exhibited a singlet at 5 6.41, derived from H c , and a multiplet at 8 4.85-4.92, associated with the carbinol proton. 163 (-)-187 1) /7-nitrobenzoic acid, PPh 3 , D E A D , THF, r t ,2h 2) aqueous N a H C 0 3 , rt 193 1) D I B A L H , THF, rt, 1 h 2) N a 2 S 0 4 '10 H 2 0 , E t 2 0 , rt, 1 h (-)-186 Scheme 62 2. 5. 4. Synthesis of enantiomerically pure (—)-6,15-bisepidysidiolide (27) (-)-6,15-Bisepidysidiolide (27) was synthesized from secondary alcohol (-)-186 using a method identical to that employed for the construction of ( - ) - l from (-)-134 (see equation 37, section 2.2.17). Specifically, a C H 2 C I 2 solution of alcohol (-)-186, 164 diisopropylethylamine ((/-Pr) 2EtN) and Rose Bengal at -78 °C was placed under an O2 atmosphere and irradiated with a 200-W tungsten incandescent lamp to provide (-)-6,15-bisepidysidiolide (27) in 79% yield (equation 48). The IR spectrum of (-)-27 revealed a strong C=0 stretching absorption at 1747 cm"1, associated with the carbonyl function of the y-hydroxybutenolide moiety. The same spectrum showed a strong O-H stretching absorption at 3326 cm"1. The  l H nmr spectrum of (-)-27 displayed a 1-proton singlet at 5 5.95, associated with Hb. The same  l H nmr spectrum exhibited doubled signals for H a (multiplets at 5 4.49-4.57 and 8 4.36-4.46), H c (doublet at 5 6.12 and multiplet at 5 5.98-6.08) and H4 (doublets at 5 7.90 and 8 7.82). The 1 3 C nmr spectrum of (-)-27 revealed doubled signals for C - l (5 170.7 and 5 170.4), C-2 (8 116.2 and 5 115.8), C-3 (5 175.8 and 5 173.8), C-4 (5 64.5 and 8 62.6) and C-25 (8 98.3 and 8 97.6). These doubled : H and 1 3 C nmr signals correspond to the two epimers (at C-25) of (-)-27 that exist in solution. The ! H and 1 3 C nmr spectra of (-)-l also showed doubled signals for H a , Ci, C2, C3, C 4 and C25 (see section 2.2.17, Tables 6 and 7). The : H nmr spectrum of (-)-6,15-bisepidysidiolide (27) is presented in Appendix 1. O B -186 1) 0 2 , hv, Rose Bengal, 2) aqueous N H 4 C I , rt ( / -Pr ) 2 EtN,CH 2 Cl 2 , -78 °C HdQ (48) 165 2. 5. 5. Synthesis of enantiomerically pure (—)-4.6.15-trisepidysidiolide (194) Considering that alcohol (-)-187 was readily available via the reaction sequence employed to construct (-)-27 (vide supra, Scheme 59), it was thought worthwhile to synthesize (-)-4,6,l 5-trisepidysidiolide (194) from (-)-187 and to evaluate the biological potential of this structural analogue of (-)-dysidiolide. Thus, a solution of (-)-187, diisopropylamine ((/-PrhEtN) and Rose Bengal in C H 2 C I 2 was irradiated 7 9 with a 200-W tungsten incandescent lamp under an O 2 atmosphere at -78 °C to generate (-)-4,6,15-trisepidysidiolide (194) (88%), as depicted in equation 49. The LR spectrum of (-)-194 revealed a strong C = 0 stretching absorption at 1747 cm"1, corresponding to the carbonyl function of the y-hydroxybutenolide moiety. The same spectrum also showed a strong 0 - H stretching absorption at 3332 cm"1. The : H nmr spectrum of (-)-194 displayed a 1- proton singlet at 5 5.95, associated with H b . The same * H nmr spectrum exhibited doubled signals for H a (multiplets at 6 4.54-4.61 and 5 4.39-4.48), H c (multiplet at 5.98-6.04 and doublet at 6.11) and H d (doublets at 8 7.89 and 5 7.77). The ! H nmr spectrum of (-)-4,6,l 5-trisepidysidiolide (194) is presented in Appendix 1. The 1 3 C nmr spectrum of (-)-194 revealed doubled signals for C - l (5 169.9 and 5 169.7), C-2 (5 115.4 and 5 115.1), C-3 ( 5 175.3 and 5 173.3), C-4 (5 63.4 and 5 62.1) and C-25 (5 97.5 and 5 96.9). These doubled signals are caused by the two epimers (at C-25) of (-)-194 that exist in solution. The  l H and 1 3 C nmr spectra of (-)-27 also showed doubled signals for H a , H e , H d , C i , C 2 , C3, C4 and C25 (see section 2.5.4). 167 3. CONCLUSION In summary, the research program detailed in this thesis culminated in the enantioselective synthesis o f the sesterterpenoid (-)-dysidiolide (1). Key steps of the synthetic pathway towards (-)-l thus developed involve highly diastereoselective or stereospecific carbon-carbon bond forming processes. This synthetic strategy is entirely different from those employed in previous total synthesis o f (-)-dysidiolide (1) (see Introduction). 8 ' 1 1 ' 1 3 ' 1 4 ' 1 6 Moreover, the transformations included in the synthetic sequence leading to (-)-l provided chemical yields that range from acceptable to excellent. The vast majority o f the experimental procedures corresponding to these transformations are easy to perform in the laboratory. Finally, our particularly versatile approach to the natural product allowed the enantioselective syntheses of structural analogues of (-)-l, namely (-)-6-epidysidiolide (25), (-)-4,6-bisepidysidiolide (148), (-)-15-epidysidiolide (26), (-)-4,15-bisepidysidiolide (181), (-)-6,15-bisepidysidiolide (27), and (-)-4,6,15-trisepidysidiolide (194) (Scheme 63). 168 169 4. BIOLOGICAL ACTIVITY STUDIES (-)-Dysidiolide (1) and the structural analogues (-)-25, (-)-26, (-)-27, (-)-148, (-)-181 and (-)-194 were submitted to biological activity assays. These studies were conducted by Dr. Michel Roberge and his coworkers in the Department of Biochemistry of the University o f British Columbia. A s specified in the Introduction (section 1.4), one of the objectives of the research program detailed in this thesis was the evaluation of the hypothesis brought forward by Gunasekera et al1 concerning the importance of the spatial proximity of the two large substituents of (-)-dysidiolide (1) for the biological activity displayed by the sesterterpenoid ((-)-l). It was believed that investigation of the biological profiles of the analogues of (-)-l synthesized could help clarify this question. Our sample of (-)-dysidiolide (1) and the structural analogues of (-)-l mentioned above were tested for antimitotic activity. Substances (-)-25, (-)-26, (-)-27, (-)-148, (—)-181 and (-)-194 showed antimitotic activities noticeably higher than that of (-)-dysidiolide (1) in several assays. 9 8 It was shown that the antimitotic activities observed did not arise from cytotoxic effects. These preliminary results indicate that the spatial proximity between the two large substituents of (-)-dysidiolide (1) is not crucial to the antimitotic activity exhibited by the natural product. Inhibition studies done with the enzyme cdc25, which w i l l be conducted shortly, 9 9 might corroborate these results. The latter studies could also help elucidate the biological mode of action o f (-)-dysidiolide (1), which remains unexplained (see Introduction, section 1.2.2). 170 5. EXPERIMENTAL 5. 1. General experimental 5. 1. 1. Data Acquisition and Presentation Proton nuclear magnetic resonance (*H nmr) spectra were recorded on Bruker models WH-400 (400 M H z ) and AV-400 (400 M H z ) spectrometers using deuteriochloroform (CDCI3) as a solvent unless stated otherwise. Signal chemical shifts (8) are reported in parts per million (ppm) from tetramethylsilane and were measured relative to that of chloroform (CHCI3) (8 7.24) unless stated otherwise. In the *H nmr spectra recorded in hexadeuteriodimethylsulfoxide (DMSO-ck), signal positions were measured relative to that of dimethylsulfoxide ( D M S O ) (8 2.54). The multiplicity, number of protons, coupling constants and assignments (when known) are given in parentheses. Diastereotopic protons located on the same carbon are designated by H x and H X ' , with H x being the proton resonating at lower field. When mixtures o f diastereomers are present, ratios of integration are reported. The abbreviations used in describing multiplicity are: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet, br-broad. Coupling constants (J) are given in Hertz (Hz). Decoupling experiments ( 1 H - 1 H ) , nuclear Overhauser enhancement (nOe) difference experiments, and ^ - ^ H homonuclear correlation experiments ( C O S Y ) were recorded on a Bruker model WH-400 (400 M H z ) spectrometer. The ' H nmr spectra were recorded employing a 30° radio frequency pulse and a delay o f one second between pulses. 171 Carbon nuclear magnetic resonance ( 1 3 C nmr) spectra were recorded on Bruker models A V - 3 0 0 (75 M H z ) and A M - 4 0 0 (100.6 M H z ) spectrometers or a Varian model X L - 3 0 0 (75 M H z ) spectrometer using deuteriochloroform (CDCI3) as a solvent unless stated otherwise. Signal chemical shifts (5) are reported in parts per mill ion (ppm) from tetramethylsilane and were measured relative to that of deuteriochloroform (CDCI3) (5 77.0) unless stated otherwise. In the 1 3 C nmr spectra recorded in hexadeuteriodimethylsulfoxide (DMSO-fifc), signal positions were measured relative to that of hexadeuteriodimethylsulfoxide (DMSO-d6) (5 40.5). The 1 3 C nmr spectra were recorded employing a 30° radio frequency pulse and a delay of two seconds between pulses. Infrared (IR) spectra were recorded from liquid films between sodium chloride plates or from potassium bromide pellets using a Perkin-Elmer 1710 Fourier Transform spectrophotometer with internal calibration. Elemental analysis were performed on a Carlo Erba C H N model 1106 or on a Fisons E A model 1108 elemental analyzer by the U B C Microanalytical Laboratory. L o w and high resolution electron impact ionization (EI) mass spectra were recorded on a Kratos Concept II H Q mass spectrometer or on a Kratos M S 80 mass spectrometer by the U B C M S Laboratory. For these high resolution spectra, the molecular ion ( M + ) masses are given. High resolution desorption chemical ionization (DCI) mass spectra were recorded on a Delsi Nermag R-10-10 C mass spectrometer. For 172 these high resolution spectra, [M+H] + and [M+NrL;] + ions were detected and are reported. Optical rotations were measured with a Perkin-Elmer model MC-241 polarimeter at 589 nm (sodium D line). Melting points were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures refer to air-bath temperatures of Kugelrohr (bulb-to-bulb) distillations and are uncorrected. Gas-liquid chromatography (glc) analyses were performed on Hewlett-Packard model 5890 capillary gas chromatograph, equipped with a flame ionization detector and a fused silica column. The dimensions of this capillary column are ~25 m x 0.20 mm (HP-5, cross-linked with 5% phenylmethyl silicone). Thin layer chromatography (TLC) was carried out on commercially available aluminum-based silica gel 60 F 2 5 4 plates (E. Merck, type 5554, thickness 0.2 mm). Visualization was accomplished using ultraviolet light (254 nm), followed by heating the chromatogram after staining with one of the following solutions: (a) vanillin (3-methoxysalicylaldehyde) in a sulfuric acid-ethanol mixture (6% vanillin w/v, 4% sulfuric acid v/v, and 10% water v/v in ethanol), (b) phosphomolybdic acid in ethanol (20% phosphomolybdic acid w/v, Aldrich). Flash chromatography was performed with 230-400 mesh silica gel (E. Merck, Silica Gel 60) using the technique described by S t i l l . 1 0 0 173 Concentration and evaporation of solvent under reduced pressure (water aspirator) refers to solvent removal via a Buchi rotary evaporator at ~15 Torr. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been oven (-140 °C) or flame dried and cooled under a stream of dry argon. The glass syringes, stainless steel needles, and Teflon® cannulae used to handle anhydrous solvents and reagents were oven dried, cooled in a desiccator, and flushed with dry argon prior to use. The plastic syringes were flushed with dry argon before use. Unless stated otherwise, solutions of crude products were dried using magnesium sulfate after each aqueous work-up. Cold temperatures were maintained by the use of the following cold baths: 0 °C, ice-water; -25 °C and -35 °C, aqueous calcium chloride-dry ice (31 and 39 g of CaCl 2 /100 m L H 2 0 , respectively); 1 0 1 -40 °C, acetonitrile-dry ice; -60 °C, chloroform-dry ice; -78 °C, acetone-dry ice; -98 °C, methanol-liquid nitrogen. 5. 1.2. Solvents and Reagents A l l solvents and reagents were purified and dried using known procedures. 1 0 2 Diethyl ether and tetrahydrofuran were distilled from sodium benzophenone ketyl, while benzene and dichloromethane were distilled from calcium hydride. These four solvents were distilled under an atmosphere of dry argon and used immediately. Acetonitrile, pentane, dimethyl sulfoxide (DMSO) , 1,2-dimethoxyethane ( D M E ) , and toluene were 174 distilled under an atmosphere of dry argon, from calcium hydride. Magnesium was added to methanol and, after refluxing the mixture, the methanol was distilled from the resultant magnesium methoxide solution under an atmosphere of dry argon. A l l other solvents were obtained commercially and used without further purification. Petroleum ether refers to a hydrocarbon mixture with a boiling point range of 30-60 °C. A^Af-diisopropylethylamine, A /,A /-diisopropylamine, hexamethylphosphoramide ( H M P A ) , triethylamine, (methoxymethyl)trimethylsilane, carbon disulfide (CS2), and trimethylsilyl bromide (MesSiBr) were distilled under an atmosphere of dry argon, from calcium hydride. These reagents were stored under an atmosphere of dry argon except for trimethylsilyl bromide (MesSiBr), which was used immediately. Solutions of n-butyllithium in hexanes, sec-butyllithium in cyclohexane, and t-butyllithium in pentane were obtained from Aldrich Chemical Co. and were standardized according to the method reported by Chong . 1 0 3 Lithium diisopropylamide ( L D A ) was prepared by adding a solution of n-butyllithium (1.0 equiv.) in hexanes to a solution of diisopropylamine (1.1 equiv.) in dry T H F at 0 °C. The resultant solution was stirred at 0 °C for 30 min prior to use. 175 Argon was dried by bubbling it through concentrated sulfuric acid and then by passing it through a drying tube filled with Drierite® and potassium hydroxide ( K O H ) . Iodine was purified via sublimation by warming (-60 °C) the iodine under reduced pressure (-15 Torr). Methyl iodide was passed through a short column o f basic alumina (activity I) which had been oven dried (-140 °C) and allowed to cool in a desiccator prior to use. A l l other reagents were commercially available and were used without further purification. 176 5. 2. Synthesis of (-)-dysidiolide (1) Preparation of (2R* . S^^^.g.g-trimethvl-y.ll-dioxaspirofS.SJundecan-S-ol (35) To a cold (-78 °C), stirred solution of L-Selectride (217 mL, 217 mmol) in T H F was added, via a cannula, a cold (-78 °C) solution of ketone 342 9 (34.0 g, 160 mmol) in dry T H F (300 mL). The homogeneous mixture was stirred at -78 °C for 2 h and treated with I N aqueous N a O H (570 mL) and 30% aqueous H2O2 (430 mL). The mixture was vigorously stirred at room temperature open to the atmosphere for 16 h. Water (500 mL) and E t O A c (1 L ) were added, the phases were separated, and the aqueous phase was extracted with E tOAc . The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (1.1 kg of silica gel, 3:2 petroleum ether-Et20) of the crude material yielded 34.0 g (99%) of 35 as a crystalline white solid, mp 101-102 °C. I R ( K B r ) : 3458, 1114, 1086 cm"1. 34 35 ! H N M R (400 M H z ) : 5 3.74-3.78 (m, 1 H , H a ) , 3.54 (d, 1 H , J= 11.6 Hz , C H H O ) , 3.50 (d, 1 H , J= 11.6 Hz , C H H O ) , 3.47 (d, 1 H , J= 11.6 Hz , C H H O ) , 3.44 (d, 1 H , J= 11.6 177 Hz, C H H O ) , 2.03-2.08 (m, 1 H) , 1.90 (dd, 1 H , J= 4.0, 13.1 Hz , H c ) , 1.81 (dddq, 1 H , J = 2.4, 4.0, 12.8, 7.0 Hz , H b ) , 1.58-1.75 (m, 3 H) , 1.46 (dd, 1 H , J = 12.8, 13.1 Hz , H d ) , 1.22-1.25 (m, 1 H , O H ; exchanges with D 2 0 ) , 0.98 (s, 3 H , CH3CCH3), 0.96 (d, 3 H , J = 7.0 Hz , Me e ) , 0.94 (s, 3 H , CH3CCH3). 1 3 C N M R (75 M H z ) : 5 97.9, 70.1, 69.9, 69.5, 34.5, 32.6, 30.2, 29.4, 25.3, 22.8, 22.7, 17.6. H R M S (EI) Calcd for C12H22O3: 214.1569. Found: 214.1567. Anal . Calcd for C12H22O3: C, 67.26; H , 10.35. Found: C, 66.98; H , 10.21. 178 Preparation of (3R*, 4£*)-4-(4-methoxybenzyloxy)-3-methylcyclohexanone (37) To a stirred solution of alcohol 3 5 (52.6 g, 246 mmol) in D M F (850 mL) were sequentially added solid N a H (19.7 g, 492 mmol) and solid B u 4 N I (2 g, 5.4 mmol). The mixture was stirred at room temperature for 15 min and neat P M B C 1 (50.0 mL, 369 mmol) was added via a syringe. The reaction mixture was warmed to 50 °C, stirred for 3 h, cooled to room temperature, and treated with saturated aqueous NH4CI (500 mL). The resultant mixture was extracted with E tOAc . The combined extracts were washed with brine, dried, and concentrated. The residue (36) was dissolved in acetone (1 L ) and concentrated hydrochloric acid (80 mL) was slowly poured into the resultant solution. The mixture was stirred at room temperature for 30 min. Water (800 mL) and E t O A c (1 L ) were added, the phases were separated, and the aqueous phase was extracted with E tOAc . The combined organic phases were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (1.5 kg of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 49.4 g (81%) of 3 7 as a clear oil . JPv(neat): 1712, 1613, 1248, 1035 cm' 179 } H N M R (400 M H z ) : 5 7.25-7.29 (m, 2 H , H b ) , 6.86-6.90 (m, 2 H , He), 4.60 (d, 1 H , J = 11.3 Hz , H a ) , 4.43 (d, 1 H , J = 11.3 Hz , H a ) , 3.79 (s, 3 H , C H 3 0 ) , 3.59-3.63 (m, 1 H , C H O C H 2 ) , 2.44-2.59 (m, 2 H) , 2.12-2.32 (m, 3 H) , 2.02-2.09 (m, 1 H) , 1.65-1.74 (m, 1 H) , 1.03 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 211.8, 159.1, 130.7, 129.1 (2 carbons), 113.8 (2 carbons), 75.2, 70.6, 55.3, 44.9, 37.3, 36.0, 28.2, 17.5. H R M S (EI) Calcd for C i 5 H 2 o 0 3 : 248.1413. Found: 248.1405. Anal . Calcd for C i 5 H 2 0 O 3 : C, 72.55; H , 8.12. Found: C, 72.51; H , 7.99. 180 Preparation of (4R*. 5i?*)-4-(4-methoxybenzyloxy)-5-methylcyclohex-2-en-l-on^ (38) and 4-(4-methoxybenzyloxy)-3-methylcyclohex-2-en-l-one (39) O C H 3 O C H 3 OCH3 37 38 39 To a stirred solution of ketone 37 (14.0 g, 56.5 mmol) in dry toluene (300 mL) and dry D M S O (150 mL) was added D 3 X 1 0 4 (31.6 g, 113 mmol) in one solid portion. The reaction mixture was warmed to 70 °C and stirred for 48 h. The mixture was cooled to room temperature, diluted with E t 2 0 (500 mL), washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (700 g of silica gel, 3:2 petroleum ether-Et 20) of the crude material yielded 8.0 g (58%) o f 38 as a clear oil and 1.9 g (14%) o f 39 as a clear oil . Characterisation for conjugated enone 38: IR(neat): 1681, 1613, 1248, 1085 cm"1. lH N M R (400 M H z ) : 5 7.25-7.29 (m, 2 H , H b ) , 6.86-6.90 (m, 2 H , IL ) , 6.81 (dd, 1 H , J = 3.0, 10.3 Hz , HC=CH-C=0) , 5.97 (d, 1 H , J= 10.3 Hz , HC=CH-C=0) , 4.58 (d, 1 H , J = 181 11.6 Hz , H a ) , 4.51 (d, 1 H , J= 11.6 Hz , H a ) , 4.18-4.22 (m, 1 H , C H O C H 2 ) , 3.78 (s, 3 H , C H 3 0 ) , 2.36-2.57 (m, 3 H , C H 3 C H C H 2 ) , 1.04 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 199.0, 159.4, 148.5, 129.9, 129.5, 129.3 (2 carbons), 113.9 (2 carbons), 74.2, 70.9, 55.3, 42.7, 33.4, 13.9. H R M S (EI) Calcd for C i 5 H i 8 0 3 : 246.1256. Found: 246.1252. Anal . Calcd for C i 5 H 1 8 0 3 : C, 73.15; H , 7.37. Found: C, 72.95; H , 7.43. Characterisation for conjugated enone 39 : IR(neat): 1674, 1614, 1250, 1083 cm"1. *H N M R (400 M H z ) : 8 7.23-7.27 (m, 2 H , H b ) , 6.84-6.88 (m, 2 H , H c ) , 5.81 (s, 1 H , HC=C), 4.63 (d, 1 H , J= 11.3 Hz , H a ) , 4.46 (d, 1 H , J= 11.3 Hz , H a .) , 3.98-4.04 (m, 1 H , C H O C H 2 ) , 3.78 (s, 3 H , C H 3 0 ) , 2.51-2.60 (m, 1 H), 2.15-2.31 (m, 2 H) , 2.01-2.10 (m, 1 H) , 1.95 (s, 3 H , C = C C H 3 ) . 1 3 C N M R (100.6 M H z ) : 5 198.4, 161.2, 159.2, 129.7, 129.3 (2 carbons), 127.4, 113.7 (2 carbons), 74.3, 71.3, 55.1, 34.2, 27.3, 20.9. H R M S (EI) Calcd for C i 5 H i 8 0 3 : 246.1256. Found: 246.1254. 182 Anal. Calcd for C , 5 H 1 8 0 3 : C, 73.15; H , 7.37. Found: C, 73.29; H , 7.32. Preparation of 5-iodo-2-methylpent-l-ene (53) X ^ •OH X ^ .OTs J 54 55 53 To a stirred solution of 4-methylpent-4-en-l-ol (54) (21.7 g, 217 mmol) in dry C H 2 C I 2 (300 mL) at room temperature were added neat E t 3 N (39.2 mL, 282 mmol), via a syringe, and solid /?-TsCl (49.6 g, 260 mmol). The reaction mixture was stirred at room temperature for 2 h and treated with saturated aqueous N H 4 C 1 (200 mL). The phases were separated and the aqueous phase was extracted with C H 2 C I 2 . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. The residual material (55) was dissolved in acetone (500 mL) and solid N a l (65.1 g, 434 mmol) was added to the resultant solution. The reaction mixture was warmed to 50 °C and stirred for 3 h. The mixture was cooled to room temperature and filtered. Most of the acetone was evaporated from the filtrate and E 1 2 O (400 mL) was added to the residue. The mixture was filtered. The filtrate was washed twice with I N aqueous NaHSCM and once with brine, dried, and concentrated (no use of high vacuum). Flash chromatography (200 g of silica gel, petroleum ether) of the crude material yielded 35.6 g (78%) of 53 as a clear oil. IR(neat): 1650, 1217, 892 cm' 183 lH N M R (400 M H z ) : 5 4.74 (s, 1 H , C=CHH), 4.71 (s, 1 H , C=CHH) , 3.16 (t, 2 H , J = 6.9 Hz , CH 2 I ) , 2.10 (t, 2 H , J = 6.9 Hz , C = C C H 2 ) , 1.94 (quintet, 2 H , J = 6.9 Hz, C H 2 C H 2 I ) , 1.70 (s, 3 H , Me). 1 3 C N M R (75 M H z ) : 5 143.6, 111.1,38.2,31.2, 22.2, 6.4. H R M S (EI) Calcd for C 6 H n I : 209.9906. Found: 209.9910. Anal . Calcd for C 6 H n I : C, 34.31; H , 5.28. Found. C, 34.30; H , 5.30. 184 Preparation of (3R*, 4R*, 5i?*>4-(4-methoxybenzyloxy)^ l-yl)cyclohexanone (46) 38 46 To a cold (-78 °C), stirred solution of / - B u L i (3.37 mL, 5.49 mmol ) 1 0 5 in dry pentane (24 mL) was added, dropwise via a syringe, a solution of iodide 53 (0.576 g, 2.745 mmol) in dry E t 2 0 (3.5 mL). The mixture was stirred at -78 °C for 1 h. A white precipitate formed after about 15 min. To a separate 3-necked flask containing solid C u C N (0.25 g, 2.745 mmol) was added dry E t 2 0 (38 mL) and the stirred suspension was cooled to -60 °C. Stirring was ceased in the original flask and the white precipitate was allowed to settle to the bottom of the flask. The solution of 5-lithio-2-methylpent-l-ene was rapidly cannulated into the stirred suspension of C u C N and the resultant mixture was immediately warmed to -40 °C. After 10 min, the cuprate solution was cooled to -78 °C. Freshly distilled M e 3 S i B r (0.97 mL, 7.32 mmol) and a solution of the enone 38 (0.225 g, 0.915 mmol) in dry E t 2 0 (5.0 mL) were sequentially added via syringes. The reaction mixture was stirred at -78 °C for 2 h and treated with aqueous NH4CI-NH3 (pH 8, 40 mL). The resultant mixture was stirred at room temperature open to the atmosphere until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined extracts were concentrated and the residual 185 material was dissolved in T H F (25 mL). To the resultant stirred solution was added, via a syringe, a solution of FJU4NF (8.0 mL, 8.0 mmol) in T H F . The mixture was stirred at room temperature for 1 h and treated with saturated aqueous N a H C 0 3 (20 mL). The phases were separated and the aqueous phase was extracted with Et.20. The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (50 g of silica gel, 4:1 petroleum ether-Et 20) of the crude material yielded 0.254 g (84%) of 46 as a clear oil . IR(neat): 1713, 1613, 1249, 1037 cm"1. ! H N M R (400 M H z ) : 8 7.25-7.29 (m, 2 H , H b ) , 6.86-6.90 (m, 2 H , He), 4.69 (s, 1 H , C=CHH), 4.63 (s, 1 H , C=CHH), 4.58 (d, 1 H , J= 11.3 Hz , H a ) , 4.47 (d, 1 H , J= 11.3 Hz , H a ) , 3.80 (s, 3 H , C H 3 0 ) , 3.34-3.39 (m, 1 H , CHOCH 2 ) , 2.66 (dd, 1 H , J= 5.8, 14.0 Hz), 2.12-2.45 (m, 4 H), 2.06 (dd, 1 H , J = 4.3, 14.0 Hz), 1.96 (m, 2 H , C=CCH 2), 1.68 (s, 3 H , C=CCH 3 ), 1.44-1.56 (m, 1 H) , 1.11-1.35 (m, 3 H) , 1.01 (d, 3 H , J = 6.6 Hz, CH 3 CH). 1 3 C N M R (75 M H z ) : 5 211.7, 159.1, 145.3, 130.6, 129.2 (2 carbons), 113.7 (2 carbons), 110.1, 79.7, 70.9, 55.2, 45.0, 41.5, 38.4, 37.6, 32.6, 31.6, 24.9, 22.2, 16.9. HRMS (EI) Calcd for C21H30O3: 330.2195. Found: 330.2192. Anal. Calcd for C 2 1 H 3 0 O 3 : C, 76.33; H , 9.15. Found: C, 76.35; H , 9.16. 46 5 9 To a stirred solution of ketone 46 (6.0 g, 18.2 mmol) in a mixture of dry CH2CI2 (300 mL) and dry C H 3 O H (150 mL) was added Sudan Red 7B (6 mg, 0.015 mmol) as a solid. The red solution was cooled to -78 °C. Ozone was bubbled through the solution until the mixture became colorless. Neat Me2S (13.3 mL, 182 mmol) was added via a syringe and the mixture was warmed to room temperature. The mixture was stirred at room temperature under an A r atmosphere for 12 h and concentrated. Flash chromatography (180 g of silica gel, 3:2 petroleum ether-Et20) o f the crude material yielded 5.6 g (93%) of 5 9 as a clear oil . IR(neat): 1713, 1613, 1249, 1035 cm"1. ! H N M R (400 M H z ) : 8 7.24-7.28 (m, 2 H , H b ) , 6.85-6.89 (m, 2 H , H c ) , 4.55 (d, 1 H , J = 11.3 Hz , H a ) , 4.47 (d, 1 H , J = 11.3 Hz , H a .), 3.79 (s, 3 H , CH 3 0) , 3.35-3.41 (m, 1 H , CHOCH2), 2.66 (dd, 1 H , J= 5.6, 14.0 Hz), 2.32-2.44 (m, 3 H) , 2.12-2.30 (m, 3 H) , 2.10 187 (s, 3 H , C H 3 C = 0 ) , 2.04 (dd, 1 H , J = 4.0, 14.0 Hz), 1.44-1.62 (m, 2 H) , 1.23-1.35 (m, 1 H) , 1.07-1.19 (m, 1 H), 1.00 (d, 3 H , J = 6 . 6 H z , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 5 211.3, 208.2, 159.1, 130.5, 129.1 (2 carbons), 113.6 (2 carbons), 79.4, 70.9, 55.1, 44.9, 43.3, 41.5, 38.4, 32.5, 31.4, 29.8, 21.0, 16.7. H R M S (EI) Calcd for C 2 0 H 2 8 O 4 : 332.1988. Found: 332.1991. Anal . Calcd for C 2 0 H 2 8 O 4 : C, 72.26; H , 8.49. Found: C, 71.99; H , 8.47. 188 Preparation of (3R*. 4R*. 4a^*)-4-(4-methoxybenzyloxyV3.8-dimethyl-3.4.4a.5.6.7-hexahydronaphthalen-1 (2H)-one (60) To a stirred solution of dione 5 9 (6.1 g, 18.4 mmol) in dry C H 3 O H (200 mL) was added a solution of N a O H (1.88 g, 47.0 mmol) in dry C H 3 O H (200 mL) via a cannula. The mixture was stirred at reflux for 48 h. The solution was cooled to room temperature and treated with saturated aqueous N H 4 C 1 (150 mL). Most of the C H 3 O H was evaporated under reduced pressure and the resultant mixture was extracted with E t O A c . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (300 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 5.32 g (92%) of 6 0 as a clear oil . IR(neat): 1682, 1614, 1248, 1037 cm"1. lU N M R (400 M H z ) : 6 7.24-7.28 (m, 2 H , H b ) , 6.85-6.89 (m, 2 H , H c ) , 4.57 (d, 1 H , J = 11.2 Hz , H a ) , 4.38 (d, 1 H , J= 11.2 Hz , H a ) , 3.79 (s, 3 H , C H 3 0 ) , 3.41 (dd, 1 H , J = 4 . 1 , 10.0 Hz , C H O C H 2 ) , 2.33-2.58 (m, 4 H) , 1.98-2.27 (m, 3 H) , 1.81 (s, 3 H , C = C C H 3 ) , 1.69-1.79 (m, 1H) , 1.36-1.49 (m, 1 H) , 1.07-1.19 (m, 1 H) , 0.99 (d, 3 H , 7 = 7.0 Hz , C H 3 C H ) . 189 UC N M R (100.6 M H z ) : 5 203.3, 159.2, 145.1, 131.6, 130.6, 129.4 (2 carbons), 113.8 (2 carbons), 82.1, 70.7, 55.3, 46.6, 39.0, 33.6, 30.4, 29.7, 27.5, 21.1, 15.2. H R M S (EI) Calcd for C 2 oH 2 60 3 : 314.1882. Found: 314.1876. Anal . Calcd for C 2 0 H 2 6 O 3 : C, 76.40; H , 8.33. Found: C, 76.63; H , 8.34. 190 Preparation of ( I R * . 3R*. 4R*. 4aig*)-4-(4-methoxybenzyloxy)-3.8-dimethyl-1.2.3.4.4a.5.6.7-octahydronaphthalen-l-ol (63) and (IS*. 3R*. 4R*. 4a/?*)-4-(4-methoxybenzyloxy)-3,8-dimethyl-l,2.3.4.4a.5.6,7-octahydronaphthalen-l-ol (64) To a cold (-98 °C), stirred solution of enone 60 (0.83 g, 2.64 mmol) in dry T H F (60 mL) was added, via a syringe, a solution of D I B A L H (7.92 mL, 7.92 mmol) in hexanes. The solution was stirred at -98 °C for 1 h and diluted with dry Et20 (120 mL). Solid Na2SC>4 #10 H 2 0 (3.0 g, 9.31 mmol) was added and the mixture was warmed to room temperature. The suspension was stirred at room temperature open to the atmosphere for 1 h and filtered through Celite®. The Celite® cake was rinsed with E12O and the filtrate was concentrated. Flash chromatography (85 g of silica gel, 4:1 petroleum ether-Et 20) of the residue yielded 0.39 g (47%) of 63 as a clear oil and 0.43 g (51%) of 64 as a clear oil. Characterisation for alcohol 63: IR(neat): 3421, 1613, 1248, 1076, 1037 cm"1. 191 *H N M R (400 M H z ) : 8 7.24-7.28 (m, 2 H , H g ) , 6.83-6.87 (m, 2 H , H h ) , 4.51-4.55 (m, 2 H , H a and H f ) , 4.29 (d, 1 H , J= 11.1 Hz, H f ) , 3.78 (s, 3 H , CHaO), 3.49 (dd, 1 H , J = 7.4, 11.6 Hz , He), 2.44-2.56 (m, 1 H , H e ) , 2.14-2.25 (m, 1 H , H b ) , 1.87-2.12 (m, 5 H) , 1.74 (s, 3 H , MeO, 1 61 (s, 1 H , O H ; exchanges with D20), 1.35-1.48 (m, 2 H) , 1.03-1.15 (m, 1 H), 0.98 (d, 3 H , J= 7.0 Hz , Me d). 1 3 C N M R (100.6 M H z ) : 5 159.0, 133.7, 131.9, 131.0, 129.3 (2 carbons), 113.6 (2 carbons), 79.8, 71.4, 66.3, 55.2, 37.1, 36.5, 32.4, 26.7, 26.4, 21.6, 18.9, 15.1. H R M S (EI) Calcd for C 2 oH 2 8 0 3 : 316.2039. Found: 316.2042. Anal. Calcd for C 2 0 H 2 8 O 3 : C, 75.91; H , 8.92. Found: C, 75.67; H , 8.88. Characterisation for alcohol 64: IR(neat): 3422, 1613, 1248, 1082, 1037 cm"1. X H N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H g ) , 6.83-6.87 (m, 2 H , H h ) , 4.68-4.73 (m, 1 H , H a ) , 4.49 (d, 1 H , J= 11.2 Hz , H f ) , 4.39 (d, 1 H , J= 11.2 Hz , H f ) , 3.78 (s, 3 H , CH 30), 3.11 (dd, 1 H , J =4 .2 , 10.6 Hz , H c ) , 2.61-2.69 (m, 1 H , H b ) , 1.87-2.12 (m, 3 H) , 1.78-1.84 (m, 1 H), 1.52-1.76 (m, 3 H) , 1.67 (s, 3 H , Mei), 1.41 (s, 1 H , O H ; exchanges with D20), I. 25-1.37 (m, 2 H) , 1.13 (d, 3 H , J = 7.2 Hz , Me d). U C N M R (100.6 M H z ) : 5 159.2, 132.5, 130.8, 130.7, 129.4 (2 carbons), 113.8 (2 carbons), 83.9, 70.5, 66.1, 55.2, 37.0, 34.6, 32.5, 29.1, 27.1, 21.2, 19.0, 15.6. H R M S (EI) Calcd for C 2 0 H 2 8 O 3 . 316.2039. Found: 316.2038. Anal . Calcd for C 2 0 H 2 8 O 3 : C, 75.91; H , 8.92. Found: C, 76.09; H , 8.97. 193 Preparation of (\S*. 3R*. 4R*. 4a^*V4-r4-methoxvbenzvloxyV3.8-dimethyl-1.2.3.4.4a.5.6.7-octahydronaphthalen-l-ol (64) from alcohol 63 To a cold (0 °C), stirred solution of alcohol 63 (0.39 g, 1.23 mmol), P P h 3 (0.39 g, 1.48 mmol), and benzoic acid (0.18 g, 1.48 mmol) in dry T H F (30 mL) was added, via a syringe, neat D E A D (0.23 mL, 1.48 mmol). The reaction mixture was stirred at 0 °C for 15 min and warmed to room temperature. The mixture was stirred at room temperature for 6 h and treated with saturated aqueous N a H C 0 3 (25 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed with brine, dried, and concentrated. The residue (68) was dissolved in dry Et20 (20 mL) and the resultant stirred solution was cooled to 0 °C. Solid L i A l H 4 (76 mg, 2.00 mmol) was added and the mixture was stirred at 0 °C for 1 h. The reaction mixture was carefully treated with water (20 mL), the phases were separated, and the aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (40 g of silica gel, 3:2 petroleum ether-Et 20) of the crude material yielded 0.28 g (72%) of 64 as a clear oil. O C H 3 63 OCH3 68 O C H 3 64 194 Preparation of (}S*. 4aR*. 5R*. 6i?*Vl-(A^.A^-dimethylcarbamoynmethyl-5-(;4-methoxybenzyloxy)-1,6-dimethyl-1.2.3 A 4 a . 5.6,7-octahydronaphthalene (80) O H | M e 2 N ^ £ > To a stirred solution of alcohol 64 (0.62 g, 1.96 mmol) in dry toluene (50 mL) was added neat A^TV-dimethylacetamide dimethyl acetal (2.87 mL, 19.60 mmol) via a syringe. The reaction mixture was stirred at 100 °C for 4 h, cooled to room temperature and concentrated. Flash chromatography (30 g of silica gel, 1:1 petroleum ether-EtOAc) of the crude material yielded 0.75 g (93%) of 80 as a clear oil. FR (neat): 1646, 1514, 13 92, 1249, 1084 cm"1. • H N M R (400 M H z ) : 5 7.22-7.26 (m, 2 H , Hj), 6.82-6.86 (m, 2 H , Hi), 5.38-5.43 (m, 1 H , Hh), 4.51 (d, 1 H , J= 11.3 Hz , He), 4.36 (d, 1 H , J = 11.3 Hz , He), 3.77 (s, 3 H , C H 3 0 ) , 3.18 (dd, 1 H , J= 3.2, 6.5 Hz , Ha), 2.95 (s, 3 H , C H 3 N ) , 2.87 (s, 3 H , C H 3 N ) , 2.42 (d, 1 H,J= 14.2 Hz , H b ) , 2.37 (d, 1 H , J= 14.2 Hz , Hy), 1.90-2.22 (m, 6 H) , 1.54-1.74 (m, 2 H), 1.16 (s, 3 H , MeO, 1.05-1.13 (m, 1 H) , 0.87-0.99 (m, 1 H) , 0.88 (d, 3 H , J = 6.6 Hz , Me,). 195 C N M R (100.6 M H z ) : 5 171.7, 159.0, 143.4, 131.1, 129.3 (2 carbons), 116.5, 113.6(2 carbons), 83.4, 70.4, 55.2, 39.2, 39.1, 38.4, 38.3, 36.9, 35.3, 32.6, 30.6, 27.7, 25.8, 21.6, 13.4. H R M S (DCI) Calcd for C24H36NO3 [M+H] + : 386.2695. Found: 386.2692. Anal . Calcd for C24H35NO3: C, 74.77; H , 9.15; N , 3.63. Found: C, 74.49; H , 9.14; N , 3.80. 196 Table 8: *H nmr (400 M H z . C D C M spectral data for the amide 80: C O S Y Experiment M e 2 N ^ O O C H 3 80 Assignment 5 ppm (multiplicity, J (Hz)) C O S Y Correlations Hj 7.22-7.26 (m) Hi H i 6.82-6.86 (m) Hj H h 5.38-5.43 (m) H g , H g ' H c 4.51 (d, J= 11.3) H c . H c . 4.36 ( d , J = 11.3) H c H d 3.18 (dd, J = 3.2, 6.5) H e , Hf H b 2.42 (d,J= 14.2) H b . Hb- 2.37 ( d , J = 14.2) H b He part of the mat 1.90-2.22 H d H f part of the mat 1.90-2.22 H d , H g , M e a H g part of the m at 1.90-2.22 Hf, H g ' Hg' part of the mat 1.90-2.22 H g M e a 0.88 (d, .7=6.6) H f 197 Preparation of (15*. 4aR*. 5R*. 6^*Vl-(2-hvdroxvethvlV5-(4-methoxybenzyloxyV1.6-dimethyl-1.2.3.4.4a.5,6,7-octahydronaphthalene (82) To a stirred solution of amide 80 (0.66 g, 1.71 mmol) in dry T H F (50 mL) at room temperature was added a solution of L i E t s B H (6.84 mL, 6.84 mmol) in T H F via a syringe. The reaction mixture was stirred at room temperature for 2 h and treated with I N aqueous N a O H (57 mL) and 30% aqueous H2O2 (43 mL). The mixture was vigorously stirred open to the atmosphere at 50 °C for 2 h and cooled to room temperature. Water (100 mL) and E t O A c (100 mL) were added, the phases were separated, and the aqueous phase was extracted with E t O A c . The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (30 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 0.55 g (94%) of 82 as a clear oil . IR(neat): 3400, 1613, 1248, 1040 cm"1. OCH3 80 OCH3 82 lH N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H b ) , 6.82-6.86 (m, 2 H , H e ) , 5.36-5.41 (m, 1 H , C=CH), 4.46 (d, 1 H , J= 11.3 Hz , H a ) , 4.42 (d, 1 H , J= 11.3 Hz , H a ) , 3.78 (s, 3 H , 198 C H 3 0 ) , 3.55 (t, 2 H , J = 6.6 Hz , C H 2 O H ) , 3.18 (dd, 1 H , 7 = 2.5, 4.8 Hz , C H O C H 2 ) , 2.29-2.38 (m, 1 H) , 2.10-2.19 (m, 1 H), 1.88-2.08 (m, 4 H) , 1.52-1.78 (m, 2 H) , 1.13-1.36 (m, 3 H) , 1.01 (s, 3 H , tertiary Me), 0.92-0.98 (m, 2 H) , 0.89 (d, 3 H , J = 6.5 Hz , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 8 159.0, 143.1, 131.2, 129.4 (2 carbons), 117.5, 113.6 (2 carbons), 82.9, 70.7, 60.1, 55.2, 41.7, 39.8, 38.3, 37.4, 33.0, 30.2, 28.1, 26.3, 21.7, 15.4. H R M S (EI) Calcd for C 2 2 H 3 2 0 3 : 344.2351. Found: 344.2349. Anal . Calcd for C 2 2 H 3 2 0 3 : C, 76.70; H , 9.36. Found: C, 76.88; H , 9.36. 199 Preparation of (IS*, 4aR\ 5R*. 6ig*Vl-f2-iodoethyl)-S-f4-methoxybenzvloxyV1.6-dimethyl-l,2.3.4.4a.5.6.7-octahvdronaphthalene (97) O C H 3 OCH3 82 9 To a cold (0 °C), stirred solution of P P h 3 (0.21 g, 0.82 mmol) and imidazole (0.11 g, 1.64 mmol) in dry C H 3 C N (3 mL) and dry E t 2 0 (4.5 mL) was added solid I 2 (0.21 g, 0.82 mmol). The reaction mixture was stirred at 0 °C for 20 min and a solution of alcohol 82 (0.14 g, 0.41 mmol) in dry E t 2 0 (1.5 mL) was added via a syringe. The mixture was warmed to room temperature, stirred for 2 h, and treated with saturated aqueous N a H C 0 3 (6 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (15 g of silica gel, 20:1 petroleum ether-Et 20) of the crude material yielded 171 mg (92%) of 97 as a clear oil . IR(neat): 1613, 1514 cm"1. *H N M R (400 M H z ) : 5 7.24-7.28 (m, 2 H , H b ) , 6.85-6.89 (m, 2 H , H c ) , 5.27-5.32 (m, 1 H , C=CH), 4.49 (d, 1 H , J= 11.1 Hz , H a ) , 4.38 (d, 1 H , J = 11.1 Hz , H a .) , 3.79 (s, 3 H , 200 C H 3 0 ) , 3.18 (dd, 1 H , 7 = 3.0, 5.9 Hz , C H O C H 2 ) , 2.96-2.98 (m, 1 H , CHHI) , 2.85-2.89 (m, 1 H , CHHI) , 2.38 (dt, 1 H , J= 13.2, 4.4 Hz), 1.89-2.12 (m, 5 H) , 1.46-1.76 (m, 5 H), 1.17 (dt, 1 H , J = 13.2, 4.6 Hz), 0.97 (s, 3 H , tertiary Me) , 0.90 (d, 3 H , J = 6.6 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 159.1, 141.4, 131.1, 129.5 (2 carbons), 117.9, 113.8 (2 carbons), 83.2, 70.8, 55.3, 42.5, 41.7, 40.8, 37.0, 32.7, 30.6, 27.8, 25.1, 21.4, 15.3, 4.0. H R M S (EI) Calcd for C 2 2 H 3 i I 0 2 : 454.1365. Found: 454.1369. Anal . Calcd for C 2 2 H 3 i I 0 2 : C, 58.15; H , 6.88. Found: C, 58.45; H , 6.97. 2 0 1 Preparation of (IS*. 4aR*. 5R*. 67^*)-5-(4-methoxybenzylox rnethylpent-4-en-l-yn-1.2.3.4,4a,5,6,7-octahydronaphthalene (81) 97 81 To a cold (-40 °C), stirred solution of L i l (4.72 g, 35.2 mmol) and C u l (0.84 g, 4.4 mmol) in dry T H F (30 mL) were sequentially added a solution of methallylmagnesium chloride 5 8 (16.0 mL, 8.8 mmol) in dry T H F and a solution of iodide 97 (0.20 g, 0.44 mmol) in dry TFfF (5 mL), both via a cannula. The reaction mixture was warmed to room temperature over the course of 6 h and stirred at this temperature for 10 h. The mixture was treated with aqueous NH4CI-NH3 (pH 8, 30 mL) and stirred at room temperature open to the atmosphere until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted with Et20. The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (20 g of silica gel, 20:1 petroleum ether-Et^O) of the residual material yielded 166 mg (99%) of 81 as a clear oil . IR(neat): 1613, 1247, 1087, 1040 cm"1. 202 X H N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H b ) , 6.82-6.86 (m, 2 H , I L ) , 5.25-5.29 (m, 1 H , C = C H - C H 2 ) , 4.63 (s, 1 H , C=CHH), 4.60 (s, 1 H , C=CHH), 4.50 (d, 1 H , J= 11.2 Hz , H a ) , 4.35 (d, 1 H , J= 11.2 Hz , H a ) , 3.78 (s, 3 H , C H 3 0 ) , 3.17 (dd, 1 H, J = 3.4, 6.7 Hz, C H O C H 2 ) , 2.05-2.17 (m, 5 H) , 1.89-1.97 (m, 4 H) , 1.64 (s, 3 H , C = C C H 3 ) , 1.46-1.63 (m, 4 H) , 1.15-1.38 (m, 2 H) , 1.01-1.11 (m, 1 H) , 0.94 (s, 3 H , tertiary Me) , 0.88 (d, 3 H , J = 6.8 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 8 159.0, 146.1, 143.2, 131.2, 129.3 (2 carbons), 116.0, 113.6 (2 carbons), 109.7, 83.7, 70.4, 55.2, 40.8, 38.7, 38.6, 36.8, 36.5, 32.8, 30.9, 27.6, 25.9, 22.3, 22.1, 21.2, 13.6. H R M S (EI) Calcd for C 2 6 H 3 8 0 2 : 382.2872. Found: 382.2872. Anal . Calcd for C 2 6 H 3 8 0 2 : C, 81.62; H , 10.01. Found: C, 81.59; H , 10.17. 203 Preparation of (IS*. 4aR*. 57?*. 6/?*V1.6-dimethvl-l-(4-methylpent-4-en-l-ylV 1.2.3.4.4a,S.6.7-octahydronaphthalen-5-ol (29) O C H 3 81 To a stirred solution of ether 81 (0.11 g, 0.29 mmol) in C H 2 C I 2 (10 mL) and water (0.5 mL) at room temperature was added solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (79 mg, 0.35 mmol). The biphasic mixture was stirred at room temperature for 1 h, water (10 mL) was added, the phases were separated, and the aqueous phase was extracted with C H 2 C I 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (10 g of silica gel, 4:1 petroleum ether-Et20) o f the crude material yielded 73.7 mg (97%) of 29 as a clear oil . IR (neat): 3365, 1077, 1047 cm"1. [ H N M R (400 M H z ) : 5 5.28-5.34 (m, 1 H , C = C H - C H 2 ) , 4.66 (s, 1 H , C=CHH) , 4.62 (s, 1 H , C=CHH), 3.43-3.51 (m, 1 H , C H O H ) , 2.02-2.19 (m, 2 H) , 1.78-2.01 (m, 5 H) , 1.61-I. 75 (m, 3 H) , 1.66 (s, 3 H , C = C C H 3 ) , 1.01-1.38 (m, 7 H), 0.96 (s, 3 H , tertiary Me) , 0.93 (d, 3 H , J = 6 . 7 H z , C H 3 C H ) . 204 1 3 C N M R (75 M H z ) : 5 146.0, 143.1, 116.3, 109.8, 76.2, 41.0, 40.6, 38.8, 38.4, 36.5, 32.9, 30.5, 29.8, 25.8, 22.3, 22.0, 21.5, 15.0. H R M S (EI) Calcd for C i 8 H 3 0 O : 262.2297. Found: 262.2295. Anal. Calcd for C i 8 H 3 0 O : C, 82.38; H , 11.52. Found: C, 82.65; H , 11.53. 205 Preparation of 4aR. 5R. 6i?V5-(^-2-acetoxy-2-phenyl)acetoxy-1.6-dimethyl-l-(4-methvlpent-4-en-l-ylV1.2.3.4.4a.5.6.7-octahvdronaphthalene (101) and (+)-(lR. 4 a £ 5S. 6S)-5 -(>S'-2-acetoxy-2-pheny 1) acetoxy-1,6-dimethyl-1 -(4-methy lpent-4-en-1 -yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (102V06 (+)-101 (+)-102 To a cold (-20 °C), stirred solution of racemic alcohol 29 (0.17 g, 0.63 mmol). in dry CH2CI2 (8 mL) was added, via a cannula, a cold (-20 °C) solution of (S)-(+)-0-acetylmandelic acid (0.25 g, 1.3 mmol), D C C (0.27 g, 1.4 mmol), and D M A P (12 mg, 0.1 mmol) in dry C H 2 C 1 2 (2 mL). The mixture was stirred at -20 °C for 24 h and filtered. The filtrate was concentrated. Flash chromatography (60 g of TLC-grade silica gel, benzene) of the crude material afforded 0.13 g (46%) of (+)-101 as a clear oil and 0.12 g (45%) of (+)-102 as a clear oil . Characterisation for ester (+)-101: [a]n +40.2° (c 1.50 C H 3 O H ) IR(neat): 1746, 1456, 1233, 1059 cm"1. 206 *H N M R (400 M H z ) : 5 7.40-7.48 (m, 2 H), 7.32-7.38 (m, 3 H) , 5.87 (s, 1 H , O - C H -C=0), 5.26-5.31 (m, 1 H , C = C H - C H 2 ) , 4.78 (dd, 1 H , J= 3.2, 6.0 Hz , CH-CH-OC=0), 4.63-4.69 (m, 2 H , C=CH 2 ) , 2.17 (s, 3 H , CH 3C=0), 2.09-2.19 (m, 1 H) , 1.69 (s, 3 H , C = C C H 3 ) , 1.45-2.05 (m, 10 H) , 0.96 (s, 3 H , tertiary Me) , 0.88-1.26 (m, 5 H) , 0.52 (d, 3 H , J= 8.8 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 170.1, 168.7, 146.3, 142.6, 134.3, 129.0, 128.6 (2 carbons), 127.6 (2 carbons), 116.6, 109.6, 79.8, 74.6, 40.9, 39.0, 38.4, 37.8, 36.5, 32.5, 29.7, 28.6, 25.8, 22.4, 22.1,21.4, 20.7, 15.1. H R M S (DCI) Calcd for C28H 3 9 0 4 [M+H] + : 439.2848. Found: 439.2831. Anal . Calcd for C 2 8 H 3 8 0 4 : C, 76.68; H , 8.73. Found: C, 77.05; H , 8.63. Characterisation for ester (+)-102: [a ] D ' +50.0° (c 3.30 C H 3 O H ) IR(neat): 1746, 1456, 1233, 1057 cm"1. ' H N M R (400 M H z ) : 5 7.41-7.48 (m, 2 H), 7.31-7.38 (m, 3 H) , 5.89 (s, 1 H , O - C H -C=0), 5.26-5.32 (m, 1 H , C = C H - C H 2 ) , 4.72 (dd, 1 H , J= 3.2, 6.8 Hz , CH-CH-OC=0), 2 0 7 4.67 (s, 1 H , C - C H H ) , 4.62 (s, 1 H , C=CHH), 2.16 (s, 3 H , CH 3C=0), 2.09-2.14 (m, 1 H) , 1.82-2.07 (m, 6 H), 1.66 (s, 3 H , C = C C H 3 ) , 1.64-1.72 (m, 1 H) , 1.32-1.58 (m, 5 H) , 1.01-1.25 (m, 3 H), 0.92 (s, 3 H , tertiary Me), 0.90 (d, 3 H , J= 8.0 H z , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 8 170.1, 168.7, 145.8, 142.6, 134.0, 129.0, 128.6 (2 carbons), 127.4 (2 carbons), 116.5, 109.7, 80.4, 74.7, 40.1, 38.6, 38.3, 36.9, 36.3, 32.2, 30.1, 28.8, 25.7, 22.3,21.7,21.1,20.6,14.8. H R M S (DCI) Calcd for C28H3904 [M+H] + : 439.2848. Found: 439.2850. Anal . Calcd for C28H3804: C, 76.68; H , 8.73. Found: C, 76.89; H , 8.67. 208 Preparation of ( - ) - ( ! £ 4a/?. 5R. 6it)-1.6-dimethyl-l-(4-methylpent-4-en-l-yl)-1.2.3.4.4a.5.6.7-octahvdronaphthalen-5-ol (29) 1 0 6 (+)-101 To a stirred solution of ester (+)-101 (0.13 g, 0.30 mmol) in dry C H 3 O H (4 mL) at room temperature was added solid K 2 C O 3 (0.53 g, 3.84 mmol). The suspension was stirred at room temperature for 1 h and filtered. The filtrate was concentrated. Flash chromatography (6 g of silica gel, 4:1 petroleum ether-Et20) of the crude material afforded 72 mg (91%) of (-)-29 as a clear oil . [ a ] £ -70 .0° (c 2.20 C F L O H ) The nmr and IR spectra of (-)-29 were identical with those of racemic 29. 209 Preparation of (+)-(!/?. 4aS. 5S. 65)-1.6-dimethyl-l-(4-methylpent-4-en-l-ylV 1.2.3.4.4a.5.6.7-octahydronaphthalen-S-ol (29V06 (+)-102 To a stirred solution of ester (+)-102 (0.10 g, 0.23 mmol) in dry C H 3 O H (3 mL) at room temperature was added solid K 2 C O 3 (0.40 g, 2.92 mmol). The suspension was stirred at room temperature for 1 h and filtered. The filtrate was concentrated. Flash chromatography (5 g of silica gel, 4:1 petroleum ether-Et.20) o f the crude material afforded 60 mg (89%) of (+)-29 as a clear oil . [a]*2 +69.7° (c 2.50 C H 3 O H ) The ' H nmr and IR spectra of (+)-29 were identical with those of racemic 29. 210 Preparation of (IS, 4a/?, 5R, 67^)-5-(5'-2-methoxy-2-phenyl-24rifluoromethyl)acetoxy 1.6-dimethvl-l-(4-methylpent-4-en-l-yn-1.2.3.4.4a.5.6.7-octahydronaphthalene (103) 1 0 6 103 To a stirred solution of alcohol (-)-29 (0.5 mg, 2 pmol), dry E t 3 N (4 pL , 28.7 pmol), and D M A P (1 mg, 7.8 pmol) in dry C H 2 C I 2 (0.5 mL) at room temperature was added neat (1S)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride (2 pL, 10.7 pmol), via a syringe. The reaction mixture was stirred at room temperature for 15 min, treated with C H 3 O H (0.5 mL), and concentrated. Flash chromatography (1 g of silica gel, 9:1 petroleum ether-Et20) of the crude material yielded 0.9 mg (95%) of 103 as a clear oil . ! H N M R (400 M H z ) : 5 7.48-7.54 (m, 2 H), 7.35-7.41 (m, 3 H) , 5.31-5.35 (m, 1 H , C = C H - C H 2 ) , 4.93 (dd, 1 H , J - 3.4, 6.5 Hz , CH-OC=0) , 4.62 (s, 1 H , C=CHH) , 4.56 (s, 1 H , C=CHH) , 3.48 (s, 3 H , C H 3 0 ) , 2.10-2.26 (m, 2 H), 1.75-2.10 (m, 4 H) , 1.62 (s, 3 H , C = C C H 3 ) , 1.43-1.60 (m, 5 H) , 1.00-1.31 (m, 5 H) , 0.95 (s, 3 H , tertiary Me) , 0.90 (d, 3 H , .7=8.9 Hz , C H 3 C H ) . 211 Preparation of(\R, 4 a £ 5S. 65)-5-(5-2-methoxy-2-phenyl-24rifluoromethynacetoxy dimethyl-l-(4-methylpent-4-en-l-yl)-L2,3,4,4a,5,6J-octahydronaphthalene (104)106 104 To a stirred solution of alcohol (+)-29 (0.8 mg, 3.2 umol), dry E t 3 N (6.4 uL, 45.9 u,mol), and D M A P (1.5 mg, 12.5 pmol) in dry C H 2 C I 2 (0.8 mL) at room temperature was added neat (iS)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride (3.2 u.L, 17.1 umol), via a syringe. The reaction mixture was stirred at room temperature for 15 min, treated with C H 3 O H (0.5 mL), and concentrated. Flash chromatography (1 g of silica gel, 9:1 petroleum ether-Et.20) of the crude material yielded 1.5 mg (92%) of 104 as a clear oil . ! H N M R (400 M H z ) : 5 7.48-7.54 (m, 2 H) , 7.34-7.39 (m, 3 H) , 5.34-5.38 (m, 1 H , C - C H - C H 2 ) , 4.91 (dd, 1 H , J= 2.4, 4.6 Hz , CH-OC=0) , 4.63 (s, 1 H , O C H H ) , 4.57 (s, 1 H , C=CHH) , 3.53 (s, 3 H , C H 3 0 ) , 2.25-2.33 (m, 1 H), 2.05-2.14 (m, 1 H), 1.81-2.00 (m, 5 H), 1.62 (s, 3 H, C = C C H 3 ) , 1.43-1.71 (m, 4 H), 1.00-1.34 (m, 5 H) , 0.97 (s, 3 H, tertiary Me) , 0.73 (d, 3 H , J = 6.7 Hz, C H 3 C H ) . 212 Preparation of (-)-(!5. 4a/?. 6/c)-1.6-dime^yl-l-(4-methylpent-4-en-l-yl)-1.2.3.4.6.7-hexahydronaphthalen-5(4a//)-one (105) To a stirred solution of alcohol (-)-29 (75 mg, 0.29 mmol) in dry C H 2 C 1 2 (8 mL) at room temperature was added solid Dess-Martin reagent5 0 (0.15 g, 0.35 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 min, diluted with E t 2 0 (20 mL), and treated with saturated aqueous N a H C 0 3 (15 mL). Solid N a 2 S 2 0 3 (0.44 g, 2.80 mmol) was immediately added and the mixture was stirred at room temperature open to the atmosphere for 30 min. The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (8 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 69 mg (92%) of (-)-105 as a clear oil . [a]o -162 .6° (c 1.70 C F L O H ) IR(neat): 1712, 1650, 1200 cm"1. *H N M R (400 M H z ) : 6 5.45-5.48 (m, 1 H , C = C H - C H 2 ) , 4.66 (s, 1 H , C=CHH) , 4.61 (s, 1 H , C=CHH), 2.66-2.74 (m, 2 H), 2.49 (dt, 1 H , J = 16.9, 6.4 Hz), 1.89-2.10 (m, 4 H) , (-)-29 (-)-105 213 1.55-1.78 (m, 3 H), 1.68 (s, 3 H , C = C C H 3 ) , 1.21-1.35 (m, 5 H) , 1.04-1.12 (m, 1 H) , 1.05 (d, 3 H , / = 6.5 Hz , C H 3 C H ) , 1.01 (s, 3 H , tertiary Me) . 1 3 C N M R (75 M H z ) : 5 215.5, 145.9, 144.8, 117.0, 109.9, 48.0, 40.4, 39.8, 38.6, 38.3, 36.0, 33.7, 33.3, 25.9, 22.3, 21.8, 21.3, 13.9. H R M S (EI) Calcd for C i 8 H 2 8 0 : 260.2140. Found: 260.2147. Anal . Calcd for C i 8 H 2 8 0 : C, 83.00; H , 10.84. Found: C, 83.02; H , 10.85. 214 Preparation of (IS. 4 a £ 5RS. 6^V5-formyl-1.6-dimethyl-l-(4-methylpent-4-en-l-ylV 1.2.3.4,4a.5.6.7-octahydronaphthalene (106) (mixture of diastereomers) To a cold (-78 °C), stirred solution of dry (methoxymethyl)trimethylsilane (0.48 mL, 3.08 mmol) in dry T H F (4 mL) was added, dropwise via a syringe, a solution of sec-B u L i (2.37 mL, 3.08 mmol) in cyclohexane. The solution was warmed to -25 °C and held at this temperature for 30 min. The reaction mixture was cooled to -35 °C and a solution of ketone (-)-105 (40 mg, 0.15 mmol) in dry T H F (1 mL) was added via a syringe. The mixture was stirred at -35 °C for 1 h and treated with saturated aqueous N a H C 0 3 (5 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried, and concentrated. The residue (113) was immediately dissolved in C H C I 3 (10 mL), the resultant stirred solution was cooled to 0 °C, and a solution of T F A (1.2 mL) in water (1.2 mL) was added via a syringe. The biphasic mixture was stirred at 0 °C for 30 min and treated with water (10 mL). The phases were separated and the aqueous phase was extracted with CH2CI2. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (8 g of silica gel, 19:1 petroleum ether-Et20) of the crude material yielded 37 mg (88%) of 106 (mixture of diastereomers) as a clear oil . 215 IR(neat): 2705, 1723, 1654, 1458 cm"1. : H N M R (400 M H z ) : 5 9.76 (d, 0.4 H , J = 4.0 Hz , C H O ) , 9.70 (d, 0.6 H , J = 2.1 Hz , C H O ) , 5.32-5.38 (m, 1 H , C = C H - C H 2 ) , 4.62-4.71 (m, 2 H , C=CH 2 ) , 2.42-2.52 (m, 1 H , C H - C H O ) , 2.05-2.36 (m, 4 H) , 1.88-2.00 (m, 3 H) , 1.48-1.86 (m, 4 H) , 1.67 (s, 1.2 H , C = C C H 3 ) , 1.66 (s, 1.8 H , C = C C H 3 ) , 1.01-1.38 (m, 5 H) , 0.97 (s, 3 H , tertiary Me) , 0.95 (d, 1.8 H , J= 6.6 Hz , C H 3 C H ) , 0.89 (d, 1.2 H , J= 6.8 Hz , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 5 207.4, 205.3, 146.1, 146.0, 144.4, 143.6, 117.5, 166.7, 109.8, 109.7, 57.9, 57.1, 41.3, 40.9, 39.7, 39.3, 38.6, 38.4, 36.8, 36.6, 34.7, 34.4, 33.3, 32.7, 30.8, 30.7, 30.3, 26.4, 26.0, 25.9, 25.0, 22.4, 22.3, 22.2, 21.9, 21.5, 19.5, 15.9. H R M S (EI) Calcd for C i 9 H 3 0 O : 274.2297. Found: 274.2296. Anal . Calcd for C i 9 H 3 0 O : C, 83.15; H , 11.02. Found: C, 83.15; H , 11.10. 216 Preparation of (\S, 4 a £ 5RS. 6i?)-5-cyano-1.6-dimethyl-l-(4-methylpent-4-en-l-yl)-l,2,3,4,4a,5,6,7-octahydronaphthalene (28) (mixture of diastereomers) To a stirred solution of the mixture of aldehydes 106 (59 mg, 0.22 mmol) in N-methylpyrrolidinone (7 mL) was added solid N H 2 O H • HC1 (46 mg, 0.66 mmol). The reaction mixture was warmed to 115 °C, stirred for 4 h, cooled to room temperature, and treated with saturated aqueous N a H C 0 3 (20 mL). The mixture was extracted with E t O A c and the combined extracts were washed with brine, dried, and concentrated. Flash chromatography (10 g of silica gel, 15:1 petroleum ether-Et20) of the crude material yielded 56 mg (96%) of 28 (mixture of diastereomers) as a clear oil . IR (neat): 2236, 1649 cm"1. : H N M R (400 M H z ) : 5 5.35-5.40 (m, 0.7 H , C = C H - C H 2 ) , 5.30-5.34 (m, 0.3 H , C = C H -C H 2 ) , 4.67 (s, 1 H , C=CHH), 4.63 (s, 1 H , C=CHH), 2.48-2.57 (m, 1 H) , 2.32-2.42 (m, 1 H) , 2.12-2.29 (m, 1 H) , 1.86-2.09 (m, 5 H) , 1.50-1.78 (m, 3 H) , 1.68 (s, 2.1 H , C = C C H 3 ) , 1.67 (s, 0.9 H , O C C H 3 ) , 1.01-1.38 (m, 6 H) , 1.09 (d, 0.9 H , 7 = 6.2 Hz , C H 3 C H ) , 1.05 (d, 2.1 H , J= 6.4 Hz , C H 3 C H ) , 0.97 (s, 2.1 H , tertiary Me), 0.96 (s, 0.9 H , tertiary Me) . 217 1 3 C N M R (100.6 M H z ) : 5 145.9, 145.8, 143.5, 142.3, 121.4, 120.9, 117.1, 116.9, 109.9, 109.8, 41.2, 40.7, 39.8, 39.3, 38.9, 38.8, 38.5, 38.3, 36.5, 36.4, 35.8, 34.5, 34.3, 32.9, 31.4, 30.9, 26.9, 26.8, 25.8, 25.7, 22.3, 22.2, 22.1, 22.0, 21.6, 21.5, 19.7, 17.4. H R M S (EI) Calcd for C i 9 H 2 9 N : 271.2300. Found: 271.2305. Anal . Calcd for C , 9 H 2 9 N : C, 84.07; H , 10.77; N , 5.16. Found: C, 84.28; H , 10.77; N , 4.99. 218 Preparation of ( - ) - ( ! £ 4aR, 5S, 6./?)-5-cyano-1.5.6-trimethyl-l-(4-meth^ 1.2.3.4.4a.5.6.7-octahydronaphthalene (118) To a cold (0 °C), stirred solution of L D A (0.28 mmol, 2.0 equiv) in dry T H F (1.5 mL) were sequentially added, via syringes, a solution of the mixture of nitriles 28 (38 mg, 0.14 mmol) in dry T H F (1 mL) and dry H M P A (neat liquid) (0.10 mL, 0.56 mmol). The reaction mixture was stirred at 0 °C for 1 h and cooled to -98 °C. Neat M e l (35 pL , 0.56 mmol) was added via a syringe and the solution was stirred at -98 °C for 10 min. The reaction mixture was treated with saturated aqueous NH4CI (3 mL), the phases were separated and the aqueous phase was extracted with Et20. The combined organic phases were washed sequentially with 10% aqueous CuSCu and brine, dried, and concentrated. Flash chromatography (5 g of silica gel, 19:1 petroleum ether-Et.20) o f the crude material yielded 35 mg (88%) of (-)-118 as a clear oil. [ a ] 2 ; - 81 .7° (c 4.90 C H 3 O H ) IR(neat): 2231, 1650, 1451, 887 cm"1. ] H N M R (400 M H z ) : 5 5.27-5.31 (m, 1 H , C = C H - C H 2 ) , 4.67 (s, 1 H , C=CHH) , 4.62 (s, 1 H , C=CHH) , 2.09-2.26 (m, 3 H), 1.90-2.08 (m, 6 H) , 1.60-1.79 (m, 3 H) , 1.66 (s, 3 H , 28 H - H * 219 C = C C H 3 ) , 1.48-1.57 (m, 2 H ) , 1.12-1.42 (m, 2 H ) , 1.22 (s, 3 H , M e a ) , 1.04 (d, 3 H , J = 6.6 H z , C H 3 C H ) , 0.97 (s, 3 H , M e * ) . 1 3 C N M R (75 M H z ) : 5 145.9, 142.5, 124.2, 116.4, 109.9, 42 .1 , 41.5, 40 .5 , 39.8, 38.5, 36.5, 31.9, 30.4, 30.0, 25.9, 22.3 , 22.1 , 21.8, 19.0, 16.2. H R M S (EI) C a l c d for C 2 0 H 3 i N : 285.2456. Found : 285.2458. A n a l . C a l c d for C 2 0 H 3 i O : C , 84.15; H , 10.95; N , 4 .91. F o u n d : C , 84.30; H , 10.92; N , 5.00. 220 Preparation of 2-(4-methoxybenzyloxy)ethanol (121) O C H 3 121 To a cold (0 °C), stirred solution of ethylene glycol (8.9 g, 160 mmol) in D M F (70 mL) were sequentially added solid N a H (2.56 g, 64.0 mmol) and solid FJU4NI (0.20 g, 0.54 mmol). The mixture was stirred at 0 °C for 15 min and neat P M B C 1 (4.33 mL, 32.0 mmol) was added via a syringe. The reaction mixture was warmed to room temperature, stirred for 12 h, and treated with saturated aqueous N H 4 C 1 (75 mL). The resultant mixture was extracted with E t O A c . The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (400 g of silica gel, 1:1 petroleum ether-EtOAc) of the crude material yielded 4.3 g (74%) of 121 as a clear oil . IR(neat): 3437, 1614, 1515, 1250, 1034 cm"1. lH N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H b ) , 6.85-6.89 (m, 2 H , H c ) , 4.48 (s, 2 H , H a ) , 3.79 (s, 3 H , Me), 3.70-3.77 (m, 2 H , C H 2 O H ) , 3.56 (t, 2 H , J = 5.6 Hz , C H 2 C H 2 O H ) , 1.97 (t, 1 H , J= 6.4 Hz , O H ; exchanges with D 2 0 ) . 1 3 C N M R (75 M H z ) : 5 158.6, 129.6, 128.8 (2 carbons), 113.1 (2 carbons), 72.1, 70.7, 60.8, 54.5. 221 H R M S (EI) Calcd for C i 0 H i 4 O 3 : 182.0943. Found. 182.0946. Anal . Calcd for C i 0 H i 4 O 3 : C, 65.91; H , 7.74. Found: C, 65.96; H , 7.80. Preparation of 2-iodo-l-(4-methoxybenzyloxy)ethane (119) 121 119 To a cold (0 °C), stirred solution of P P h 3 (3.58 g, 13.7 mmol) and imidazole (1.86 g, 27.3 mmol) in dry C H 3 C N (50 mL) and dry E t 2 0 (75 mL) was added solid I 2 (3.47 g, 13.7 mmol). The reaction mixture was stirred at 0 °C for 20 min and a solution of alcohol 121 (1.65 g, 9.1 mmol) in dry E t 2 0 (25 mL) was added via a cannula. The mixture was stirred at 0 °C for 1 h and treated with saturated aqueous N a H C 0 3 (100 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (200 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 2.53 g (95%) of 119 as a clear oil . IR(neat): 1614, 1511, 1250, 1106, 1035 cm"1. lH N M R (400 M H z ) : 5 7.24-7.28 (m, 2 H , H b ) , 6.85-6.89 (m, 2 H , He), 4.49 (s, 2 H , H a ) , 3.79 (s, 3 H , Me), 3.69 (t, 2 H , J = 6.8 Hz , O C H 2 C H 2 ) , 3.24 (t, 2 H , J= 6.8 Hz , CH 2 I ) . 1 J C N M R (75 M H z ) : 5 158.9, 129.5, 129.0 (2 carbons), 113.4 (2 carbons), 72.0, 70.0, 54.9, 3.2. H R M S (EI) Calcd for C i 0 H i 3 I O 2 : 291.9960. Found: 291.9955. Anal . Calcd for C i 0 H 1 3 I O 2 : C, 41.12; H , 4.49. Found: C, 41.41; H , 4.47. 223 Preparation of ( - ) - ( ! £ 4aR, 5S. 6/^)-5-cyano-5-[2-(4-methoxybenzyloxy)ethyl]-L6-dimethyl-l-(4-methylpent-4-en-l-yl)-1.23A4a,5A7-octah^ (120) H-120 To a cold (-78 °C), stirred solution of / - B u O K (31 mg, 0.28 mmol) in dry T H F (2 mL) was added dry / P r 2 N H (43 pL , 0.33 mmol) as a neat liquid and via a syringe. A solution of «-BuLi (0.14 mL, 0.22 mmol) in hexanes was added, dropwise via a syringe, and the reaction mixture was stirred at -78 °C for 20 min. A solution of the mixture of nitriles 28 (30 mg, 0.11 mmol) in dry T H F (1 mL) was added via a syringe and the homogeneous mixture was stirred at -78 °C for 30 min. Dry H M P A (77 pL , 0.44 mmol) and iodide 119 (86 mg, 0.295 mmol) were sequentially added as neat liquids and via syringes. The mixture was stirred vigorously at -78 °C for 5 min. The reaction mixture was treated with saturated aqueous N H 4 C 1 (5 mL), the phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic phases were washed sequentially with 10% aqueous C u S 0 4 and brine, dried, and concentrated. Flash chromatography (10 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 42 mg (88%) of (-)-120 as a clear oil . [aJo -30 .2° (c 1.60 C H 3 O H ) 224 IR(neat): 2230, 1614, 1249, 1038 cm"1. *H N M R (400 M H z ) : 6 7.22-7.26 (m, 2 H , H b ) , 6.83-6.87 (m, 2 H , H e ) , 5.30-5.38 (m, 1 H , C = C H - C H 2 ) , 4.64 (s, 1 H , C=CHH), 4.59 (s, 1 H , C=CHH), 4.45 (d, 1 H , J= 11.1 Hz , H a ) , 4.39 (d, 1 H , J= 11.1 Hz , H,.), 3.78 (s, 3 H , C H 3 0 ) , 3.65-3.74 (m, 2 H , C H 2 C H 2 0 ) , I. 98-2.20 (m, 3 H) , 1.48-1.94 (m, 7 H), 1.65 (s, 3 H , C = C C H 3 ) , 1.17-1.44 (m, 3 H) , 0.93-1.13 (m, 5 H), 1.04 (br s, 3 H , C H 3 C H ) , 0.96 (s, 3 H , tertiary Me) . 1 3 C N M R (100.6 M H z ) : 5 159.2, 146.0, 143.1, 130.3, 129.3 (2 carbons), 122.6, 116.7, 113.8 (2 carbons), 109.8, 73.1, 67.4, 55.3, 43.7, 41.7, 39.8, 39.2, 38.4, 36.6, 32.2, 30.4, 30.0, 29.7, 28.2, 25.9, 22.4, 22.2, 21.8. H R M S (EI) Calcd for C 2 9 H 4 1 N 0 2 : 435.3137. Found: 435.3132. Anal . Calcd for C29H41NO2: C, 79.94; H , 9.49; N , 3.22. Found: C, 79.69; H , 9.35; N , 3.34. 225 Preparation of ( - M i f f . 4aR. 5S, 6ffi-5-hydroxymethyl-5-[2-(4-methoxybenzyloxy)ethyl]-L6-dimethyl-l-(4-methylpent-4-en-l-yl)-1.2,3.4.4a.5.6J-octahydronaphthalene (122) To a stirred solution of nitrile (-)-120 (30 mg, 0.07 mmol) in dry D M E (4 mL) at room temperature was added, via a syringe, a solution of D T B A L H (0.16 mL, 0.16 mmol) in hexanes. The reaction mixture was stirred at room temperature for 30 min and treated with I N aqueous citric acid (15 mL). The mixture was stirred at room temperature open to the atmosphere for 3 h and extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. The residue was immediately dissolved in dry C H 3 O H (5 mL) and solid N a B H 4 (6 mg, 0.16 mmol) was added to the resultant solution. The solution was stirred at room temperature for 20 min and treated with saturated aqueous NH4CI (4 mL). The resultant mixture was extracted with Et20. The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 3:1 petroleum ether-EtiO) of the crude material yielded 24 mg (79%) of (-)-122 as a clear oil. [ a ] " - 50 .0° (c 0.04 C H 3 O H ) 226 IR(neat): 3437, 1614, 1250, 1038 cm"1. *H N M R (400 M H z ) : 8 7.21-7.25 (m, 2 H , H b ) , 6.84-6.88 (m, 2 H , H e ) , 5.21-5.31 (m, 1 H , C = C H - C H 2 ) , 4.64 (s, 1 H , C=CHH), 4.60 (s, 1 H , C=CHH) , 4.44 (s, 2 H , H a ) , 3.84-3.90 (m, 1 H , C H H O H ) , 3.78 (s, 3 H , CH 3 0), 3.40-3.65 (m, 3 H , C H 2 C H 2 0 and C H H O H ) , 1.96-2.12 (m, 2 H) , 1.82-1.94 (m, 4 H) , 1.45-1.81 (m, 8 H) , 1.66 (s, 3 H , C = C C H 3 ) , 1.02-1.34 (m, 5 H) , 0.94 (s, 3 H , tertiary Me) , 0.78 (d, 3 H , J = 6.6 Hz , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 5 159.4, 146.2, 145.2, 129.5 (2 carbons), 129.4, 117.0, 113.9 (2 carbons), 109.6, 73.1, 67.7, 66.4, 55.3, 42.2, 40.1, 40.0, 38.7, 38.6, 37.3, 31.9, 30.3, 29.1, 26.1, 22.6, 22.5, 22.4, 15.3, 14.9. H R M S (DCI) Calcd for C 2 9 H 4 5 0 3 [M+H] + : 441.3369. Found: 441.3364. Anal . Calcd for C29H44CV C, 79.04; H , 10.06. Found: C, 78.84; H , 9.62. 227 Preparation of (-)-(!& 4 a £ 5R. 6^V5-(2-hydroxyethylV1.5.64rimethyl-l-(4-methvlpent-4-en-l-yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (131) To a stirred solution of alcohol (-)-122 (21 mg, 0.05 mmol) in dry T H F (4 mL) were added solid imidazole (4 mg, 0.05 mmol) and solid N a H (10 mg, 0.24 mmol). The reaction mixture was warmed to 60 °C and stirred for 2 h. The mixture was cooled to room temperature and neat C S 2 (14 u.L, 0.24 mmol) was added via a syringe. The reaction mixture was stirred at room temperature for 1 h and neat M e l (19 uL, 0.30 mmol) was added via a syringe. The mixture was stirred at room temperature for 30 min and treated with saturated aqueous N a H C 0 3 (5 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed with brine, dried, and concentrated. The crude xanthate was dissolved in o-xylene (5 mL) and the resultant stirred solution was warmed to 150 °C. Neat P h 2 S i H 2 (0.07 mL, 0.38 mmol) and a solution of benzoyl peroxide (4 mg, 0.017 mmol) in o-xylene (0.4 mL) were sequentially added via syringes. The reaction mixture was stirred at 150 °C for 45 min during which time a fresh solution of benzoyl peroxide (4 mg, 0.017 mmol) in o-xylene (0.4 mL) was added every 15 min (total of 12 mg of benzoyl peroxide added). The reaction mixture was cooled to 0 °C and concentrated. The residue was dissolved in C H 2 C b (5 mL) and water (0.25 mL). Solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone 228 (23 mg, 0.10 mmol) was added to the resultant mixture. The biphasic mixture was stirred at room temperature for 1 h, water (5 mL) was added, the phases were separated, and the aqueous phase was extracted with CH2CI2. The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 12 mg (80%) of (-)-131 as a clear oil. [ a ] " -89 .0° (c0.40 C H C I 3 ) IR(neat): 3318, 1650, 1030, 886 cm"1. ] H N M R (400 M H z ) : 5 5.28-5.31 (m, 1 H , C = C H - C H 2 ) , 4.67 (s, 1 H , C=CHH) , 4.66 (s, 1 H , C=CHH) , 3.61-3.70 (m, 2 H , C H 2 O H ) , 1.93-1.98 (m, 2 H) , 1.89 (d, 1 H , 7 = 12.3 Hz), I. 45-1.78 (m, 9 H) , 1.70 (m, 3 H , C = C C H 3 ) , 1.03-1.37 (m, 7 H) , 0.97 (s, 3 H , tertiary Me) , 0.85 (s, 3 H , tertiary Me), 0.81 (d, 3 H , J= 6.8 Hz, C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 146.8, 145.2, 116.9, 109.4, 59.7, 41.9, 41.2, 39.8, 38.7, 37.2, 35.6, 33.0, 31.5, 29.2, 29.0, 26.0, 22.6, 22.5, 22.5, 22.4, 14.8. H R M S (DCI) Calcd for C21H40NO [ M + N H 4 ] + : 322.3110. Found: 322.3110. 229 Preparation of ( - ) - ( ! £ 4a£. 5R. 6^V1.5.6-trimethyl-l-r4-methylpent-4-en-l-ylV5-(2-oxoethyl)-l,2.3.4.4a.5.6.7-octahydronaphthalene (6) To a stirred solution of alcohol (-)-131 (12 mg, 0.04 mmol) in dry CH2CI2 (4 mL) at room temperature was added solid Dess-Martin reagent5 0 (34 mg, 0.08 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 min, diluted with E t 2 0 (10 mL), and treated with saturated aqueous N a H C 0 3 (8 mL). Solid N a 2 S 2 0 3 (0.10 g, 0.64 mmol) was immediately added and the mixture was stirred at room temperature open to the atmosphere for 30 min. The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (4 g of silica gel, 19:1 petroleum ether-Et20) of the crude material yielded 11 mg (95%) of (-)-6 as a clear oil. [oc]D - 7 4 . 0 ° (c 0.50 CDC13) IR(neat): 2726, 1719, 1650, 886 cm"1. 230 *H N M R (400 M H z ) : 5 9.90 (t, 1 H , 7 = 3.2 Hz , C H O ) , 5.31-5.35 (m, 1 H , C = C H - C H 2 ) , 4.67 (s, 1 H , C=CHH), 4.64 (s, 1 H , C=CHH), 2.33 (dd, 1 H , 7 = 2.8, 14.4 Hz , C H H -C H O ) , 2.24 (dd, 1 H , J = 3.6, 14.4 Hz , C H H - C H O ) , 1.90-2.09 (m, 4 H) , 1.76-1.82 (m, 1 H), 1.50-1.74 (m, 6 H) , 1.68 (s, 3 H , C = C C H 3 ) , 1.08-1.35 (m, 5 H) , 1.07 (s, 3 H , tertiary Me) , 0.99 (s, 3 H , tertiary Me), 0.84 (d, 3 H , J= 6.4 Hz, C H 3 C H ) . 1 3 C N M R (75 M H z ) : 8 204.4, 146.2, 145.1, 117.1, 109.7, 47.3, 42.5, 42.0, 40.0, 38.6, 37.6, 37.0, 33.0, 31.6, 29.3, 26.0, 23.0, 22.5, 22.4, 22.3, 14.9. H R M S (DCI) Calcd for C 2 i H 3 5 0 [M+H] + : 303.2688. Found: 303.2680. 231 Preparation of (-)-(!& 4aS. 5R. 6fl)-5-ffi-2-(3-faryl)-2-hy^^ C4-methvlpent-4-en-l-ylV1.2.3.4.4a.5.6.7-octahvdronaphthalene (134) and (-)-(lS. 4aS. 5R. 67?)-5-[5-2-(3-furyl)-2-hydroxyemyll-lJ.6-tr^ 1.2.3.4.4a.5.6.7-octahydronaphthalene (135) (-)-135 To a cold (-78 °C), stirred solution of 3-bromofuran (63 uL, 0.70 mmol) in dry T H F (1.2 mL) was added a solution of «-BuLi (0.44 mL, 0.70 mmol) in hexanes via a syringe. The reaction mixture was stirred at -78 °C for 30 min and a solution of aldehyde (-)-6 (21 mg, 0.07 mmol) in dry T H F (2 mL) was added via a syringe. The mixture was stirred at -78 ° C for 30 min and treated with saturated aqueous NH4CI (5 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 9:1 petroleum ether-E12O) of the crude material yielded 13 mg (50 %) of (-)-134 as a clear oil and 12 mg (46%) of (-)-135 as a clear oil . Characterisation for alcohol (-)-134: 232 [<X]D -48 .0° (c 0.20, CDC1 3 ) IR(neat): 3392, 1650, 1455, 1024, 875 cm' 1 . ' H N M R (400 M H z ) : 8 7.34 (s, 1 H) , 7.33 (s, 1 H) , 6.38 (s, 1 H , H a ) , 5.31 (s, 1 H , C = C H -C H 2 ) , 4.82-4.88 (m, 1 H , C H O H ) , 4.65 (s, 1 H , C=CHH), 4.58 (s, 1 H , C=CHH) , 1.47-1.93 (m, 14 H), 1.64 (s, 3 H , C = C C H 3 ) , 0.98-1.33 (m, 8 H) , 0.95 (s, 3H, tertiary Me) , 0.87 (d, 3H,J = 6.4 Hz, C H 3 C H ) . 1 3 C N M R (75 M H z ) : 8 146.8, 145.9 (br), 143.2, 138.4, 131.1, 117.2 (br), 109.7, 108.7, 64.0, 41.4 (br), 39.9 (br), 38.4, 37.2, 36.9 (br), 36.3 (br), 34.5, 33.4 (br), 31.5, 29.7 (br), 26.0, 23.4 (br), 22.4, 22.3, 21.9, 14.9. H M R S Calcd for C 2 5 H 3 8 0 2 : 370.2872. Found: 370.2871. Characterisation for alcohol ( - ) - 1 3 5 : [a ] 2 1 - 80 .0° (c 2.40, CHC1 3 ) IR(neat): 3345, 1650, 1456, 1025, 875 cm"1. ' H N M R (400 M H z ) : 8 7.35 (s, 2 H , H a and H b ) , 6.39 (s, 1 H , H c ) , 5.33 (s, 1 H , C = C H -C H 2 ) , 4.81-4.89 (m, 1 H , C H O H ) , 4.65 (s, 1 H , C=CHH), 4.63 (s, 1 H , C=CHH) , 1.47-233 2.00 (m, 13 H), 1.67 (s, 3 H , C = C C H 3 ) , 1.01-1.40 (m, 6 H), 0.99 (s, 3 H , tertiary Me) , 0.94 (s, 3 H , tertiary Me) , 0.77 (d, 3 H , J = 8.0 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 146.6, 146.5 (br), 143.2, 138.4, 131.3, 117.0 (br), 109.5, 108.6, 64.7 (br), 42.4 (br), 41.9 (br), 40.0 (br), 38.6, 38.2 (br), 37.3 (br), 36.0 (br), 32.9, 31.6 (br), 29.7, 29.3 (br), 26.1, 22.5, 22.4, 22.3, 14.6. H R M S (EI) Calcd for C 2 5 H 3 8 0 2 : 370.2872. Found: 370.2873. 234 Preparation of (-)-dysidiolide (1) 'OH (-)-134 OH ( - ) - l To a stirred solution of fiiran (-)-134 (13 mg, 0.035 mmol) and dry / -Pr 2 NEt (61 pL, 0.35 mmol) in dry CH2CI2 (8 mL) was added Rose bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and O2 was bubbled through the solution for 15 min. The solution was placed under an 0 2 atmosphere and irradiated with a 200-W tungsten filament lamp. The solution was stirred at -78 °C for 2 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous NH4CI (10 mL). The phases were separated and the aqueous phase was extracted with CH2CI2. The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (10 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 13 mg (93%) of ( - ) - l as a white solid, mp 182-183 °C (186-187 °C in literature). [a]£ - 12 .0° (c 1.40 1:1 CH3OH-CH2CI2) ([a] 2 ; -11 .1° (c 0.6 1:1 C H 3 0 H - C H 2 C 1 2 ) in literature) I R ( K B r ) : 3392, 1741, 1649, 1445, 1250, 1132, 1075, 945 cm"1. 235 Doubled ' H and 1 3 C nmr signals were observed for selected protons and carbons. These doubled signals are due to the two epimers (at C-25) of (-)-l that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. ! H N M R (400 M H z , D M S O - ^ ) : 5 7.84 (br d, 1 H , J = 6.8 Hz , O - C H O H ) , 6.09 (br d, 1 H , J= 6.8 Hz , O - C H O H ) , 5.91 (br s, 1 H , C=CH-C=0), 5.23-5.33 (m, 2 H , C = C H - C H 2 and C H 2 C H O H ) (5.12-5.18 for C H 2 C H O H ) , 4.63 (s, 1 H , C=CHH) , 4.60 (s, 1 H , C=CHH) , 4.48-4.54 (m, 1 H , C H 2 C H O H ) (4.34-4.41), 1.42-2.04 (m, 12 H), 1.62 (s, 3 H , C = C C H 3 ) , 0.84-1.29 (m, 9 H) , 0.93 (s, 3 H , Me,), 0.81 (d, 3 H , J = 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z , D M S O - ak ) : 5 175.7 (173.7) (br), 170.5 (170.4), 145.3, 142.1 (br), (116.1) 115.8, 115.5, 110.0, (98.0) 97.6, 64.3 (62.9), 41.0 (br), 39.0 (br), 37.8, 36.5 (br), 33.0, 31.1 (br), 29.8 (br), 27.0 (br), 25.9, 23.4 (br), 22.1, 22.0, 21.7, 21.6, 21.4 (br), 14.9. H R M S (DCI) Calcd for C 2 5 H 3 9 0 4 [M+H] + : 403.2848. Found: 403.2858. 236 Table 6: Comparison of the  l H nmr spectral data of our synthetic (-)-(l) (400 M H z . DMSO-cfo with those reported for naturally occurring (-)-l 7 (500 M H z . DMSO-fik) (-)-l ! H nmr assignment H-x : H nmr signals of (-)-dysidiolide (5, multiplicity, . / (Hz)) Our synthetic (-)-l Naturally occurring (-)-l7 H-2 5.91, b rs 5.91, s H-4 4.48-4.54 (4.34-4.41), am 4.51 (4.38), a dt,7=5.7, 8.6 O H b (C-4) part of mat 5.23-5.33 (5.12-5.18) a 5.23 (5.12), a d ,7=5 .7 H-9 part of m at 5.23-5.33 omitted in the literature13 Me-20 1.62, s 1.62, s H-21 4.63, s 4.63, s H-21' 4.60, s 4.60, s Me-22 0.93, s 0.93, s Me-23 0.81, d, 7=6 .7 0.81, d ,7=6 .7 Me-24 part of m at 1.42-2.04 1.51, b r s H-25 6.09, br d ,7=6.8 6.08, d ,7=6 .0 O H a (C-25) 7.84, br d, 7=6 .8 7.80, d ,7=6 .0 a Doubled J H nmr signals were observed for H-4 and OT b (C-4). These doubled signals are due to the two epimers (at C-25) of (-)-l that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. b This signal was omitted in the list of } H nmr resonances given for naturally occurring (-)-l.7 However, this signal was reported 1 6 in the ! H nmr spectrum of synthetic (-)-l prepared by Boukouvalas et al.16 2 3 7 Table 7: Comparison of the C nmr spectral data of our synthetic (-)-l (75 M H z . DMSO-<^) with those reported for naturally occurring ( - V 1 7 (125.7 M H z . D M S O - ^ 1 (-)-l 13 C nmr assignment C-x 1 3 C nmr signals of (-)-dysidiolide (5) Our synthetic (-)-l Naturally occurring ( - ) - l 7 ' a C - l 170.5 (170.4) b 170.5 (170.4) b C-2 115.8 (116. l ) b 115.9 (116.2) b C-3 175.7 (173.7) b(br) 175.5 (173.5) b(br) C-4 64.3 (62.9) b 64.4 (63.0) b C-7 33.0 33.0 C-9 115.5 115.5 C-10 142.1 (br) 142.3 C-19 145.3 145.3 C-20 22.0 22.0 C-21 110.0 110.0 C-22 25.9 25.9 C-23 14.9 14.9 C-24 22.0 22.0 C-25 97.6 (98.0) b 97.6 (98.0) b the remaining 11 carbon signals were not assigned 41.0 (br) 41.0 (br) 39.0 (br) 39.0 (br) 37.8 37.9 36.5 (br) 36.6 (br) 31.1 (br) 31.0 (br) 29.8 (br) 29.8 (br) 2 3 8 End of Table 7 I 3 C nmr signals of (-)-dysidiolide (5) Our synthetic (-)-l Naturally occurring (-)-l 27.0 (br) 27.0 (br) 23.4 (br) 23.5 (br) 21.7 21.7 21.6 21.6 21.4 (br) 21.5 (br) a The C nmr assignments related to carbons 1-4, 7, 9, 10, and 19-25 were determined by use of H M Q C and H M B C experiments.7 b 13 Doubled C nmr signals were observed for C - l , C-2, C-3, C-4, and C-25. These doubled signals are due to the two epimers (at C-25) of (-)-l that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. 239 5. 3. Syntheses of (-)-6-epidysidiolide and (-)-4,6-bisepidysidiolide Preparation of ( - ) - ( ! £ 4aR. 5S. 6i?V5-formyl-1.5.6-trimethyl-l-r4-methvlpent-4-en-l-ylV1.2.3.4.4a.5.6.7-octahvdronaphthalene (142) To a stirred solution of nitrile (-)-118 (36 mg, 0.13 mmol) in dry D M E (4 mL) at room temperature was added, via a syringe, a solution of D I B A L H (0.26 mL, 0.26 mmol) in hexanes. The reaction mixture was stirred at room temperature for 1 h and treated with aqueous I N citric acid (6 mL). The mixture was stirred at room temperature open to the atmosphere for 2 h and extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 19:1 petroleum ether-Et,20) of the crude material yielded 31 mg (86%) of (-)-142 as a clear oil. [ a ] 2 ; -104 .0° (c 3.00 C H 3 O H ) IR(neat): 2708, 1726, 1650, 1452 cm"1. ! H N M R (400 M H z ) : 5 9.65 (s, 1 H , C H O ) , 5.32-5.37 (m, 1 H , C = C H - C H 2 ) , 4.66 (s, 1 H , C - C H H ) , 4.62 (s, 1 H , C=CHH), 2.08-2.19 (m, 2 H) , 1.90-2.04 (m, 3 H) , 1.45-1.78 (m, 7 (-)-118 B - 1 4 2 240 H), 1.66 (s, 3 H , C = C C H 3 ) , 1.13-1.41 (m, 2 H), 0.98-1.11 (m, 2 H) , 0.97 (s, 3 H , tertiary Me) , 0.92 (s, 3 H , tertiary Me), 0.82 (d, 3 H , J = 6.8 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 209.8, 146.0, 143.6, 117.1, 109.8, 50.2, 42.9, 41.8, 39.8, 38.6, 36.6, 31.0, 30.4, 28.1, 26.1, 22.3, 22.1, 22.0, 16.0, 14.0. H R M S (DCI) Calcd for C 2 0 H 3 3 O [M+H] + : 289.2531. Found: 289.2530. Anal . Calcd for C 2 0 H 3 2 O : C, 83.27; H , 11.18. Found: C, 83.31; H , 11.14. 241 Preparation of (-)-(lS. 4aS. 5S. 6/t)-l.S.64rimethyl-l-(4-methylpent-4-en-l-yl)-5-(2-oxoethyl)-!,2,3.4,4a.5.6.7-octahydronaphthalene ( 1 4 1 ) To a cold (-78 °C), stirred solution of dry (methoxymethyl)trimethylsilane (0.07 mL, 0.45 mmol) in dry T H F (1 mL) was added, dropwise via a syringe, a solution of sec-B u L i (0.35 mL, 0.45 mmol) in cyclohexane. The solution was warmed to -25 °C and held at this temperature for 30 min. The reaction mixture was cooled to -35 °C and a solution of aldehyde ( - ) - 1 4 2 (13 mg, 0.045 mmol) in dry T H F (0.5 mL) was added via a syringe. The mixture was stirred at -35 °C for 30 min and treated with saturated aqueous N a H C 0 3 (3 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried, and concentrated. The residue (143 ) was immediately dissolved in dry T H F (2 mL) and solid K H (9.2 mg, 0.23 mmol) was added to the resultant stirred solution. The mixture was warmed to 60 °C, stirred for 30 min, cooled to room temperature, and treated with saturated aqueous NaHCOa (3 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C C h and brine, dried, and concentrated. The residue (144) was dissolved in acetic acid (1.2 mL) and water (0.3 mL) and the resultant solution was stirred at room temperature for 3.5 h. Water (5 mL) and Et20 (10 mL) were added, the phases were separated, and the aqueous phase 242 was extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (3 g of silica gel, 15:1 petroleum ether-Et20) of the crude material yielded 7.3 mg (54%) o f (-)-141 as a clear oil . [a]" - 8 0 . 4 ° (c 4.00 C H 3 O H ) IR(neat): 2730, 1719, 1456, 885 cm - 1 . *H N M R (400 M H z ) : 5 9.92 (t, 1 H , J = 3.0 Hz , C H O ) , 5.25-5.30 (m, 1 H , C = C H - C H 2 ) , 4.66 (s, 1 H , C=CHH) , 4.62 (s, 1 H , C=CHH), 2.28-2.34 (m, 2 H , C H 2 C = 0 ) , 1.88-2.08 (m, 4 H), 1.44-1.81 (m, 8 H), 1.67 (s, 3 H , C = C C H 3 ) , 0.97-1.33 (m, 4 H) , 1.00 (s, 3 H , tertiary Me), 0.96 (s, 3 H , tertiary Me), 0.80 (d, 3 H , J = 6.6 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 204.5 , 146.2, 144.8, 116.8, 109.7, 51.3, 43.5, 42.0, 39.9, 38.6, 37.8, 36.8, 31.8, 31.6, 30.0, 26.1 , 22.4, 22.2, 22.1 , 19.4, 15.2. H R M S ( D C I ) Calcd for C 2 i H 3 5 0 [M+H] + : 303.2688. Found: 303.2685. Anal. Calcd for C 2 i H 3 4 0 : C, 83.38; H , 11.33. Found: C, 83.46; H , 11.48. 243 Preparation of (-)-(!& 4 a £ 5S. 6fl)-5- r^2-(3-furyl)-2-hydro^^ r4-methylpent-4-en-l-yn-1.2.3.4.4a.5.6.7-octahydronaphthalene (145) and (-)-(lS. 4aS. 5S. 6^V545-2-r3-furylV2-hydroxvethvll-1.5.64rimethyl-l-(4-methylpent-4-en-l-yn 1.2.3.4.4a.5.6.7-octahydronaphthalene (146) (-)-145 (-)-146 To a cold (-78 °C), stirred solution of 3-bromofuran (30 uL, 0.33 mmol) in dry THF (0.6 mL) was added, via a syringe, a solution of «-BuLi (0.21 mL, 0.33 mmol) in hexanes. The reaction mixture was stirred at -78 °C for 30 min and a solution of aldehyde (-)-141 (10 mg, 0.033 mmol) in dry TFTF (1 mL) was added via a syringe. The mixture was stirred at -78 °C for 30 min and treated with saturated aqueous NH4CI (3 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed sequentially with saturated aqueous NaHC03 and brine, dried, and concentrated. Flash chromatography (5 g of silica gel, 9:1 petroleum ether-Et20) of the crude material yielded 3.4 mg (28%) of (-)-145 as a clear oil and 8.0 mg (65%o) of (-)-146 as a clear oil. Characterisation for alcohol (-)-145: 244 [a] 2 ; - 27 .0° (c 2.90 C H 3 O H ) IR (neat): 3398, 1648, 1451, 1025, 874 cm"1. r H N M R (400 M H z ) : 5 7.36-7.39 (m, 2 H , H a and H b ) , 6.44 (s, 1 H , He), 5.20-5.24 (m, 1 H , C = C H - C H 2 ) , 4.83-4.90 (m, 1 H , C H O H ) , 4.65 (s, 1 H , C=CHH) , 4.62 (s, 1 H , C=CHH), 1.43-2.02 (m, 13 H) , 1.66 (s, 3 H , C = C C H 3 ) , 0.99-1.32 (m, 6 H) , 0.95 (s, 3H, Mea), 0.79 (d, 3 H , 7 - 6.3 Hz, C H 3 C H ) . 0.73-0.78 (br s, 3 H , Me e ) . 1 3 C N M R ( 7 5 M H z ) : 8 146.3, 145.3 (br), 143.4, 138.8, 131.2, 116.2, 109.7, 108.7, 63.8, 44.1, 43.4, 42.1 (br), 39.9, 38.7, 37.2, 36.3, 32.2, 32.0, 29.5 (br), 26.1, 22.9, 22.5, 22.4, 22.2, 15.4. H M R S Calcd for C 2 5 H 3 8 0 2 : 370.2872. Found: 370.2874. Characterisation for alcohol ( - ) -146: [a] 2 ? - 55 .6° (c 5.90 C H 3 O H ) FR (neat): 3359, 1649, 1458, 1024, 875 cm"1. lH N M R (400 M H z ) : 5 7.38 (m, 1 H) , 7.37 (m, 1 H) , 6.43 (s, 1 H , H a ) , 5.23-5.28 (m, 1 H , C = C H - C H 2 ) , 4.80-4.87 (m, 1 H , C H O H ) , 4.67 (s, 1 H , C=CHH) , 4.65 (s, 1 H , C=CHH) , 245 1.66-2.07 (m, 6 H) , 1.69 (s, 3 H , C = C C H 3 ) , 1.45-1.64 (m, 8 H) , 0.97-1.34 (m, 5 H) , 0.96 (s, 3 H , tertiary Me) , 0.93 (s, 3 H , tertiary Me), 0.80 (d, 3 H , J = 6.6 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 8 146.3, 145.3 (br), 143.4, 138.4, 131.2, 116.8, 109.7, 108.6, 63.8, 45.1, 42.8, 42.4, 40.1, 38.7, 37.0, 36.6, 32.3, 32.2, 30.0 (br), 26.1, 22.5, 22.4, 22.2, 18.6 (br), 15.2. H R M S (EI) Calcd for C 2 5 H 3 8 O 2 : 370.2872. Found: 370.2873. 246 Preparation of (-)-(!& 4 a £ 5S. 6itV5-[^-2-f3-iurylV2-r4-nitrobenzoyloxyN)ethyl]-1.5.6-trimethyl-l-(4-methylpent-4-en-l-yl)-1.2,3,4,4a,5,6,7-octahydronaphthalene (147) (-)-147 To a stirred solution of alcohol (-)-146 (11 mg, 0.03 mmol), E t 3 N (13 pL , 0.09 mmol), and D M A P (1.2 mg, 0.01 mmol) in dry C H 2 C I 2 (2 mL) at room temperature was added solid 4-nitrobenzoyl chloride (11 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 30 min and treated with saturated aqueous N a H C 0 3 (3 mL). The phases were separated and the aqueous phase was extracted with C H 2 C I 2 . The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (3 g of silica gel, 20:1 petroleum ether-Et^O) of the crude material yielded 14.6 mg (95%) of (-)-147 as a white solid, mp 109-111 °C. [ a ] * -31 .3° (c I .3OCH3OH) I R ( K B r ) : 1721, 1530, 1460, 1273, 1101 cm"1. 247 ' H N M R (400 M H z ) : 5 8.23-8.27 (m, 2 H) , 8.16-8.20 (m, 2 H) , 7.50 (s, 1H), 7.35-7.38 (m, 1 H) , 6.46 (s, 1 H , H a ) , 6.26 (dd, 1 H , J= 2.1, 9.2 Hz , C H 2 C H - 0 ) , 5.21-5.26 (m, 1 H , C = C H - C H 2 ) , 4.56 (s, 1 H , C=CHH), 4.51 (s, 1 H , C=CHH), 2.31 (dd, 1 H , J= 9.2, 15.2 Hz) , 1.48-2.11 (m, 10 H), 1.52 (s, 3 H , C = C C H 3 ) , 0.96-1.29 (m, 7 H) , 0.95 (s, 3 H , Me b ) , 0.84 (d, 3 H , J = 6.7 Hz, C H 3 C H ) . 0.78 (s, 3 H , Me c ) . H R M S (EI) Calcd for C 3 2 H 4 i N 0 5 : 519.2985. Found: 519.2979. 248 Preparation of (-)-6-epidysidiolide (25) To a stirred solution of furan ( - ) -145 (3.2 mg, 0.009 mmol) and dry z'-P^NEt (16 u.L, 0.09 mmol) in dry C H 2 C I 2 (2 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and O 2 was bubbled through the solution for 15 min. The solution was placed under an O 2 atmosphere and irradiated with a 200-W tungsten filament lamp. The solution was stirred at -78 °C for 0.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous NH4CI (3 mL). The phases were separated and the aqueous phase was extracted with C H 2 C I 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (3 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 2.2 mg (63%) of ( - ) -25 as a clear oil . [a]2° - 44 .4° (c 3.80 C H 3 O H ) TR (neat): 3307, 1762, 1650, 1456, 1138, 1026 cm"1. 249 *H N M R (400 M H z ) : 5 6.21 (s, 1 H) , 6.03 (s, 1 H) , 5.25-5.29 (m, 1 H , C = C H - C H 2 ) , 4.78 (d, 1 H , J= 9.0 Hz , C H 2 C H O H ) , 4.66 (s, 1 H , C=CHH), 4.63 (s, 1 H , C=CHH) , 1.90-2.10 (m, 4 H) , 1.46-1.82 (m, 10 H), 1.68 (s, 3 H , C = C C H 3 ) , 1.00-1.31 (m, 6 H) , 0.97 (s, 3 H , tertiary Me), 0.95 (s, 3 H , tertiary Me), 0.79 (d, 3H,J= 6.6 Hz , C H 3 C H ) . Doubled 1 3 C nmr signals were observed for selected carbons. These doubled signals are due to the two epimers (at C-25) of (-)-25 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. 1 3 C N M R (75 M H z , DMSO-c4) : 5 176.0 (173.9), (170.6) 170.4, 145.4, 145.2 (br), (116.0) 115.9, 115.8, 110.0, (98.2) 97.5, 64.0 (62.6), 42.3, 42.1, 41.9, 41.4, 38.1, 36.4, 36.3, 31.8, 31.7, 29.4 (br), 25.9, 22.7, 22.1, 21.7, 20.0, 14.9. H R M S (DCI) Calcd for C 2 5 H 3 9 0 4 [M+H] + : 403.2848. Found: 403.2859. 250 Preparation of (-)-4,6-bisepidysidiolide (148) rr rr i H i H (-)-146 o. 'OH OH (-)-148 To a stirred solution of furan (-)-146 (3.5 mg, 0.009 mmol) and dry z'-P^NEt (16 pL, 0.09 mmol) in dry CH2CI2 (2 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and O2 was bubbled through the solution for 15 min. The solution was placed under an O2 atmosphere and irradiated with a 200-W tungsten filament lamp. The solution was stirred at -78 °C for 0.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous NH4CI (3 mL). The phases were separated and the aqueous phase was extracted with CH2CI2. The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (3 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 2.5 mg (68%) of (-)-148 as a clear oil . [<X]D -5.4° (c 2.5OCH3OH) IR(neat): 3398, 1748, 1650, 1455, 1137, 952 cm"1. 251 lH N M R (400 M H z ) : 8 5.98-6.30 (m, 2 H , O - C H O H and C=CH-C=0), 5.24-5.30 (m, 1 H , C = C H - C H 2 ) , 4.80-4.88 (m, 1 H , C H 2 C H O H ) , 4.66 (s, 1 H , C=CHH) , 4.63 (s, 1 H , C=CHH) , 1.86-2.12 (m, 4 H) , 1.47-1.78 (m, 10 H) , 1.67 (s, 3 H , C = C C H 3 ) , 1.04-1.34 (m, 6 H) , 0.96 (br s, 6 H , 2 tertiary Me), 0.82 (d, 3 H , J= 6.4 Hz , C H 3 C H ) . Doubled 1 3 C nmr signals were observed for selected carbons. These doubled signals are due to the two epimers (at C-25) of (-)-148 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. 1 3 C N M R ( 7 5 M H z , D M S O - ^ ) : 8 176.0 (174.0), (170.6) 170.4, 145.5 (br), 145.3, (116.1) 115.7, 114.2, 110.2, (98.2) 97.5, (64.4) 64.1, 42.5 (br), 41.8, 41.0, 38.1, 36.3, 36.0, 31.9, 31.5 (br), 31.4, 30.4, 29.0 (br), 22.3, 22.1, 21.1, 19.4 (br), 14.9. H R M S (DCI) Calcd for C25H42N04 [ M + N H 4 ] + : 420.3114. Found: 420.3094. 252 5. 4. Syntheses of (-)-15-epidysidiolide and (-)-4,15-bisepidysidiolide Preparation of hydrazone (+V157 (+)-157 To a stirred solution of ketone 150 (45.5 g, 0.23 mol) in dry benzene (350 mL) was added, via a syringe, neat ( 1S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine 8 9 (32.9 g, 0.25 mol). The reaction mixture was warmed to 80 °C and stirred, with the use of a Dean-Stark trap, for 2 h. The solution was cooled to room temperature and concentrated. The residue was distilled bulb-to-bulb (265-280 °C/0.3 Torr) to provide 70.0 g (98%) of (+)-157 as a clear oil . [a]n +190.3° (c 8.00 CH 2 C1 2 ) IR(neat): 1641, 1471, 1364, 1122, 1020 cm"1. lR N M R (400 M H z ) : 5 3.45-3.56 (m, 4 H , C H 2 0 - C - O C H 2 ) , 3.39 (dd, 1 H , J = 4.0, 9.5 Hz , CHH - O C H 3 ) , 3.31 (s, 3 H , CH3O), 3.19-3.24 (m, 1 H), 3.11-3.18 (m, 1 H) , 3.03 (dt, 1 H , J= 5.8, 9.2 Hz , C H H - N ) , 2.76 (dt, 1 H , J= 5.8, 14.3 Hz , C H H - N ) , 2.27-2.48 (m, 4 H , 253 2 x CH 2C=N) 2.08-2.17 (m, 1 H), 1.89-2.04 (m, 2 H), 1.59-1.86 (m, 5 H), 0.99 (s, 3 H, CH3CCH3), 0.93 (s, 3 H, CH3CCH3). 1 3 C N M R (75 MHz): 5 167.1, 96.7, 75.0, 70.0, 69.9, 65.8, 58.9, 54.7, 31.7, 31.3, 30.8, 29.9,26.3,24.3,22.5,22.3,21.8. HRMS (EI) Calcd for C 1 7 H 3 0 N 2 O 3 : 310.2353. Found: 310.2358. Anal. Calcd for C17H30N2O3 : C, 65.77; H, 9.74; N, 9.02. Found: C, 65.83; H, 9.77; N, 8.82. 254 Preparation of (+)-(2i?)-2,9,94rimethyl-7.11-dioxaspiro[5.5]undecan-3-one (34) To a cold (0 °C), stirred solution of L D A (0.27 mol, 1.2 equiv) in dry T H F (300 mL) was added a cold (0 °C) solution of hydrazone (+)-157 (70.0 g, 0.226 mol) in dry T H F (150 mL), via a cannula. The reaction mixture was stirred at 0 °C for 1 h and cooled to -98 °C. Neat M e l (21.1 mL, 0.34 mol) was added, via a syringe, and the mixture was stirred at -98 °C for 15 min. The reaction mixture was treated with saturated aqueous N H 4 C 1 (200 mL), the phases were separated, and the aqueous phase was extracted with Et20. The combined extracts were washed sequentially with saturated aqueous NaHCOa and brine, dried, and concentrated. The residue (158) was dissolved in dry CH2CI2 (500 mL) and the resultant stirred mixture was cooled to -78 °C. O 3 was bubbled through the heterogeneous mixture for 5 h. The mixture was placed under an A r atmosphere, warmed to room temperature, and concentrated. Flash chromatography (1.5 kg of silica gel, 4:1 petroleum ether-Et20) of the crude material yielded 41.7 g (87%) of (+)-34 as a white solid. This substance ((+)-34) displayed spectral data (IR and *H nmr) that were in good agreement with those reported for racemic 34. 2 9 (+)-34 (+)-157 158 [CX]D +1.56° (c4.20 CH2CI2) 255 Preparation of (+)-(2R. 3^-3-r5'-2-hydroxy-2-phenylacetoxyV2.9.9-trimethvl-7.11-dioxaspiro[5.5]undecane (166) and (+)-(2S. 3.R)-3-(S-2-hydroxv-2-phenvlacetoxv)-2.9.9-trimethyl-7.1 l-dioxaspiro[5.5]undecane (167) (+)-166 (+)-167 To a cold (-20 °C), stirred solution of racemic alcohol 35 (1.00 g, 4.67 mmol) in dry C H 2 C 1 2 (20 mL) was added a cold (-20 °C) solution of 0S)-(+)-O-acetylmandelic acid (1.81 g, 9.34 mmol), D C C (2.07 g, 10.06 mmol), and D M A P (0.11 g, 0.93 mmol) in dry C H 2 C I 2 (5 mL), via a cannula. The mixture was stirred at -20 °C for 24 h and filtered. The fdtrate was concentrated. The residue was dissolved in dry C H 3 O H (30 mL) and the resultant solution was cooled to 0 °C. Solid K2CO3 (3.0 g, 22 mmol) was added and the suspension was stirred at 0 °C for 20 min. The reaction mixture was filtered and the filtrate was concentrated. Flash chromatography (150 g of silica gel, 3:2 petroleum ether-E t 2 0 ) of the crude material afforded 0.73 g (45%) of (+)-166 as a white solid, mp 152-154 °C, and 0.70 g (43%) of (+)-167 as a white solid, mp 105-107 °C. Characterisation for ester (+)-166: [ a ] £ +74.5° (c I . 5 O C H 2 C I 2 ) 256 IPv(KBr): 3452, 1725, 1455, 1206, 1112 cm"1. LH N M R (400 M H z ) : 5 7.38-7.42 (m, 2 H), 7.24-7.35 (m, 3 H) , 5.13 (d, 1 H , J = 5.2 Hz , C H O H ) , 4.93-4.97 (m, 1 H , C H - O C O ) , 3.35-3.57 (m, 5 H , C H 2 0 - C - O C H 2 and O H ; exchanges w i t h D 2 0 ) , 2.10-2.17 (m, 1 H) , 1.75-1.90 (m, 3 H) , 1.68 (ddt, 1 H , J = 2.4, 4.3, 14.0 Hz), 1.48 (dt, 1 H , J = 4.3, 13.4 Hz), 1.13-1.25 (m, 1 H), 0.95 (s, 3 H , CH3CCH3), 0.91 (s, 3 H , CH3CCH3), 0.33 (d, 3 H , J = 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 173.6, 138.7, 128.4, 128.3 (2 carbons), 126.5 (2 carbons), 97.3, 74.9, 73.0, 70.1, 70.0, 35.4, 31.6, 30.2, 26.8, 25.9, 22.7, 22.6, 16.6. H R M S (DCI) Calcd for C 2 0 H 2 9 O 5 [M+H] + : 349.2015. Found: 349.2020. Anal . Calcd for C 2 0 H 2 8 O 5 : C, 68.94; H , 8.10. Found: C, 69.32; H , 8.14. Characterisation for ester (+)-167: [a] 2, 2 +7.5° (c 1.20 CH 2 C1 2 ) IR (KBr) : 3446, 1726, 1456, 1213, 1108 cm"1. 257 lU N M R (400 M H z ) : 5 7.27-7.41 (m, 5 H , aromatic protons), 5.16 (d, 1 H , J = 7.1 Hz, C H O H ) , 4.93-4.98 (m, 1 H , CH-OC=0), 3.50 (d, 1 H , J = 7.1 Hz , O H ; exchanges with D 2 0), 3.42-3.45 (s, 2 H , C H 2 0 - C - O C H 2 ) , 3.35-3.38 (s, 2 H , C H 2 0 - C - O C H 2 ) , 1.76-2.02 (m, 3 H), 1.48-1.61 (m, 3 H), 1.33 (t, 1 H , J= 16.4 Hz) , 0.95 (s, 3 H , CH3CCH3), 0.92 (d, 3 H , J= 8.9 Hz , C H 3 C H ) , 0.87 (s, 3 H , CH3CCH3). , 3 C N M R (75 M H z ) : 5 173.6, 138.6, 128.6 (2 carbons), 128.4, 126.3 (2 carbons), 97.3, 75.0, 72.8, 70.1, 69.9, 35.5, 31.4, 30.1, 26.4, 25.4, 22.7, 22.6, 17.5. H R M S (DCI) Calcd for C 2 0 H 2 9 O 5 [M+H] + : 349.2015. Found: 349.2014. Anal . Calcd for C 2 0 H 2 8 O 5 : C, 68.94; H , 8.10. Found: C, 68.92; H , 8.22. 258 Substances (+)-35, (+)-37, (+)-38, (-)-39, (-)-46, (-)-59, and (-)-60 were synthesized starting from (+)-34 according to the procedures detailed in section 5.2 for the construction of their racemic counterparts. The IR and  l H nmr spectra of the enantiomerically pure synthetic intermediates leading from (+)-35 to (-)-60 were, as expected, identical to those obtained for the corresponding racemic intermediates. The specific optical rotations of these intermediates are reported below. (+)-35: [a]2? +28.1° (c 4.00 CH 2 C1 2 ) (+)-37: [ a ] 2 2 +37.3° (c 1.85 CH 2 C1 2 ) (+)-38: [a]2? +127.7° (c 1.50 CH 2 C1 2 ) (-)-39: [ a ] 2 3 - 11 .4° (c 5.00 CH 2 C1 2 ) (-)-46: [a]2,3 - 2 . 8 ° (c 5.00 CH 2 C1 2 ) (-)-59: [ a ] 2 3 - 1 .0 ° (c 3.50 CH 2 C1 2 ) (-)-60: [ a ] 2 3 - 136 .8° (c 5.00 CH 2 C1 2 ) 259 Preparation of (-)-(\R, 3R. 4R. 4ai?)-4-(4-methoxybenzyloxy)-3,8-dimethyl-1.2.3.4.4a.5,6.7-octahydronaphthalen-f-ol (63) O C H 3 O C H 3 (_).60 (-)-63 To a cold (-20 °C), stirred solution of enone (-)-60 (3.80 g, 12.1 mmol) in dry C H 3 O H (300 mL) were added C e C l 3 • 7 H 2 0 (9.02 g, 24.2 mmol) and N a B H 4 (0.92 g, 24.2 mmol) as solids. The solution was stirred at -20 °C for 1 h and treated with saturated aqueous N a H C 0 3 (100 mL). Most of the C H 3 O H was evaporated and the resultant mixture was extracted with E tOAc . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (175 g of silica gel, 3:1 petroleum ether-Et 20) of the residue yielded 3.55 g (93%) of (-)-63 as a clear oil. This substance ((-)-63) displayed spectral data (IR and  l H nmr) that were identical with those detailed above (section 5.2) for racemic 63. [ a ] £ - 84 .7° (c 8.00 C D C I 3 ) 260 Preparation of (-)-(\R. 4aR. 5R. 6ffl-l-(iV;#-dimethylcarbamoy methoxybenzyloxyVl,6-dimethyl-1.2,3.4.4a.5.6.7-octahydronaphthalene (149) To a stirred solution of alcohol (-)-63 (3.55 g, 11.2 mmol) in dry toluene (300 mL) was added neat AfJV-dimethylacetamide dimethyl acetal (14.9 mL, 112.0 mmol) via a syringe. The reaction mixture was stirred at 110 °C for 5 h, cooled to room temperature, and concentrated. Flash chromatography (180 g of silica gel, 1:1 petroleum ether-EtOAc) of the crude material yielded 3.92 g (91%) of (-)-149 as a clear oil. [a ] 2 ; -31 .0° (c 7.00 CH 2 C1 2 ) IPv(neat): 1646, 1514, 1393, 1248, 1087 cm"1. lU N M R (400 M H z ) : 6 7.23-7.27 (m, 2 H , H b ) , 6.82-6.86 (m, 2 H , H c ) , 5.16-5.21 (m, 1 H , C=CH), 4.52 (d, 1 H , J= 11.3 Hz , H,) , 4.36 (d, 1 H , J = 11.3 Hz , H a . ) , 3.78 (s, 3 H , C H 3 0 ) , 3.19 (dd, l H , / = 3.4, 7.0 Hz , C H O C H 2 ) , 3.03 (s, 3 H , C H 3 N ) , 2.92 (s, 3 H , C H 3 N ) , 2.45 (s, 2 H , C H 2 C = 0 ) , 2.24-2.34 (m, 1 H) , 2.03-2.22 (m, 3 H), 1.88-1.97 (m, 1 B - 6 3 O C H 3 B - 1 4 9 261 H), 1.72-1.79 (m, 1 H) , 1.58-1.66 (m, 3 H) , 1.42-1.53 (m, 1 H) , 1.17 (s, 3 H , tertiary Me) , 0.87 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 5 172.1, 159.1, 144.5, 131.3, 129.3 (2 carbons), 114.0, 113.7(2 carbons), 83.3, 70.5, 55.3, 42.5, 39.1, 38.3, 37.4, 36.7, 35.5, 32.2, 30.9, 27.6, 24.4, 21.5, 13.3. H R M S (EI) Calcd for C24H35NO3: 385.2613. Found: 385.2617. Anal . Calcd for C24H35NO3: C, 74.77; H , 9.15; N , 3.63. Found: C, 74.62; H , 9.23; N , 3.68. 262 Preparation of (-)-(\R, 4aR. 5R, 6i?Vl-(2-hydroxyethyl)-5-(4-methoxybenzyloxy)-l,6-dimethy 1-1,2,3,4,4a,5,6,7-octahydronaphthalene (168) To a stirred solution of amide (-)-149 (1.50 g, 3.90 mmol) in dry T H F (110 mL) at room temperature was added a solution of L i E t s B H (15.6 mL, 15.6 mmol) in T H F via a syringe. The reaction mixture was stirred at room temperature for 2 h and treated with I N aqueous N a O H (125 mL) and 30% aqueous H 2 O 2 (95 mL). The mixture was vigorously stirred open to the atmosphere at 60 °C for 3 h and then was cooled to room temperature. Water (220 mL) and E t O A c (220 mL) were added, the phases were separated, and the aqueous phase was extracted with E t O A c . The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (30 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 1.26 g (94%) of (-)-168 as a clear oil. (-)-149 (-)-168 [ a ] £ -40 .4° (c 6.00 C H 2 C I 2 ) IR(neat): 3400, 1614, 1249, 1038 cm' 263 *H N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H b ) , 6.83-6.87 (m, 2 H , H c ) , 5.28-5.33 (m, 1 H , C=CH), 4.53 (d, 1 H , J= 11.3 Hz , Ha), 4.35 (d, 1 H , J= 11.3 H z , H a ) , 3.78 (s, 3 H , C H 3 0 ) , 3.71-3.74 (m, 2 H , C H 2 O H ) , 3.17 (dd, 1 H , J = 3.4, 7.3 Hz , C H O C H 2 ) , 2.19-2.28 (m, 1 H), 2.05-2.18 (m, 3 H), 1.87-1.96 (m, 1 H) , 1.67-1.82 (m, 2 H) , 1.53-1.64 (m, 3 H) , I. 41-1.48 (m, 1 H) , 1.18-1.30 (m, 2 H) , 1.00 (s, 3 H , tertiary Me) , 0.86 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 159.0, 143.6, 131.2, 129.4 (2 carbons), 114.7, 113.7 (2 carbons), 83.3, 70.4, 59.7, 55.3, 44.0, 37.9, 36.5, 32.3, 30.9, 29.7, 27.5, 25.2, 21.5, 13.1. H R M S (DCI) Calcd for C 2 2 H 3 6 N 0 3 [ M + N H 4 ] + : 362.2695. Found: 362.2706. Anal . Calcd for C 2 2 H 3 2 0 3 : C, 76.70; H , 9.36. Found: C, 76.50; H , 9.50. 264 Preparation of (-)-(LR. 4aR. 5R. 6/gVl-(2-iodoeMyl)-S-(4-methoxybenzyloxy)-1.6-dimethyl-l,2,3A4a.5,6,7-octahydronaphthalene (169) (-)-l68 (_)_: To a cold (0 °C), stirred solution of P P h 3 (2.21 g, 8.44 mmol) and imidazole (1.15 g, 16.88 mmol) in dry C H 3 C N (30 mL) and dry E t 2 0 (45 mL) was added solid I 2 (2.14 g, 8.44 mmol). The reaction mixture was stirred at 0 °C for 20 min and a solution of alcohol (-)-168 (1.45 g, 4.22 mmol) in dry E t 2 0 (15 mL) was added via a cannula. The mixture was warmed to room temperature, stirred for 1 h, and treated with saturated aqueous N a H C 0 3 (60 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (150 g of silica gel, 20:1 petroleum ether-Et 20) of the crude material yielded 1.80 g (94%) of (-)-169 as a clear oil . [a]' - 39 .0° ( c 3 . 5 0 C H 2 C l 2 ) IR(neat): 1613, 1514 cm' 265 *H N M R (400 M H z ) : 5 7.23-7.27 (m, 2 H , H b ) , 6.83-6.87 (m, 2 H , H c ) , 5.21-5.27 (m, 1 H , C=CH), 4.52 (d, 1 H , J= 11.3 Hz , Ha), 4.34 (d, 1 H , J = 11.3 Hz , H a ) , 3.78 (s, 3 H , C H 3 0 ) , 3.14-3.24 (m, 3 H , C H O C H 2 a n d CH 2 I ) , 2.04-2.24 (m, 6 H) , 1.88-1.96 (m, 1 H) , I. 54-1.63 (m, 2 H) , 1.36-1.43 (m, 1 H), 1.21-1.28 (m, 2 H) , 0.97 (s, 3 H , tertiary Me), 0.85 (d, 3 H , J = 7.0 Hz, C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 159.1, 142.4, 131.1, 129.4 (2 carbons), 115.0, 113.7 (2 carbons), 83.1, 70.4, 55.3, 46.8, 41.6, 37.0, 36.6, 32.2, 31.0, 27.5, 25.0, 21.4, 13.1, 2.0. H R M S (EI) Calcd for C 2 2 H 3 i I 0 2 : 454.1365. Found: 454.1369. Anal . Calcd for C 2 2 H 3 i I 0 2 : C, 58.15; H , 6.88. Found: C, 58.51; H , 6.95. 266 Preparation of (-)-(\R, 4aR, 5R, 6i?)-5-(4-methoxybenzyloxy)-L6-dimethyl-l-(4-methylpent-4-en-l-yl)-l,2,3,4,4a,5,6,7-octahydronaphthalene (170) To a cold (-40 °C), stirred solution of L i l (40.2 g, 0.30 mol) and C u l (7.12 g, 37.4 mmol) in dry T H F (250 mL) were sequentially added a solution of methallylmagnesium chloride 5 8 (135 mL, 74.8 mmol) in dry T H F and a solution of iodide (-)-169 (1.70 g, 3.74 mmol) in dry T H F (40 mL), both via a cannula. The reaction mixture was stirred at -40 °C for 5 h, treated with aqueous N H 4 C 1 - N H 3 (pH 8, 250 mL), and stirred open to the atmosphere at room temperature until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted with Et20. The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (150 g of silica gel, 20:1 petroleum ether-Et20) of the residual material yielded 1.31 g (92%) of (-)-170 as a clear oil . O C H 3 (-)-169 OCH3 (-)-170 [ a ] £ -29 .6° ( c 2 . 5 0 C H 2 C l 2 ) IR(neat): 1614, 1249, 1089, 1040 cm"1. 267 *H N M R (400 M H z ) : 5 7.24-7.28 (m, 2 H , H b ) , 6.83-6.87 (m, 2 H , H c ) , 5.21-5.27 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH), 4.66 (s, 1 H , C=CHH), 4.53 (d, 1 H , J= 11.3 Hz , H a ) , 4.35 (d, 1 H , J= 11.3 Hz , H a ) , 3.78 (s, 3 H , CH 3 0), 3.17 (dd, 1 H , 7 = 3.4, 7.6 Hz, C H O C H 2 ) , 2.19-2.27 (m, 1 H) , 2.05-2.18 (m, 3 H) , 1.96-2.02 (m, 2 H) , 1.86-1.94 (m, 1 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.53-1.61 (m, 3 H), 1.36-1.47 (m, 5 H), 1.13-1.25 (m, 1 H), 0.96 (s, 3 H , tertiary Me) , 0.86 (d, 3 H , 7 = 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 159.0, 146.2, 144.2, 131.3, 129.4 (2 carbons), 114.2, 113.7 (2 carbons), 109.7, 83.5, 70.3, 55.2, 40.9, 38.8, 38.2, 37.5, 36.7, 32.4, 31.0, 27.5, 25.0, 22.4, 21.7, 15.3, 13.1. H R M S (EI) Calcd for C 2 6 H 3 8 0 2 : 382.2872. Found: 382.2870. Anal . Calcd for C 2 6 H 3 8 0 2 : C, 81.62; H , 10.01. Found: C, 81.79; H , 10.04. 268 Preparation of (-)-(lR. 4 a/?. SR. 6ii)-1.6-dimethyl-l-(4-methylpent-4-en-l-yl)-1.2.3.4.4a.S.6.7-octahydronaphthalen-5-ol (171) O C H 3 (-)-170 To a stirred solution of ether (-)-170 (1.315 g, 3.44 mmol) in C H 2 C 1 2 (120 mL) and water (6 mL) at room temperature was added 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (0.86 g, 3.78 mmol) as a solid. The biphasic mixture was stirred at room temperature for 1 h, water (100 mL) was added, the phases were separated, and the aqueous phase was extracted with C H 2 C 1 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (100 g of silica gel, 4:1 petroleum ether-Et 20) of the crude material yielded 0.84 g (93%) of (-)-171 as a clear oil. [a]*1 - 42 .2° (c 1.00 CH 2 C1 2 ) IR(neat): 3400, 1078, 1048 cm"1. 269 l H N M R (400 M H z ) : 5 5.17-5.24 (m, 1 H , C = C H - C H 2 ) , 4.62 (s, 1 H , C=CHH) , 4.60 (s, 1 H , C=CHH), 3.35-3.41 (m, 1 H , C H O H ) , 2.01-2.16 (m, 3 H) , 1.90-1.98 (m, 3 H) , 1.70-I. 83 (m, 2 H) , 1.63 (s, 3 H , C = C C H 3 ) , 1.51-1.59 (m, 2 H) , 1.30-1.45 (m, 6 H), 1.07-1.16 (m, 1 H), 0.93 (s, 3 H , tertiary Me) , 0.84 (d, 3 H , J= 6.4 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 145.8, 143.9, 114.6, 109.6, 75.9, 40.8, 40.1, 38.7, 38.2, 38.1, 32.7, 30.9, 30.2, 24.2, 22.3, 21.9, 21.6, 14.2. H R M S (EI) Calcd for C i g H 3 0 O : 262.2297. Found: 262.2295. Anal . Calcd for C i 8 H 3 0 O : C, 82.38; H , 11.52. Found: C, 82.31; H , 11.68. 270 Preparation of (-)-( lR. 4a/?. 6it)-1.6-dimethyl-l-(4-methylpent-4-en-l-yl)-1.2.3.4.6.7-hexahydronaphthalen-5(4a//)-one (172) (-)-171 (-)-172 To a stirred solution of alcohol (-)-171 (0.86 g, 3.28 mmol) in dry C H 2 C 1 2 (90 mL) at room temperature was added the Dess-Martin reagent 5 0 (1.53 g, 3.61 mmol) in one solid portion. The reaction mixture was stirred at room temperature for 30 min, diluted with E t 2 0 (200 mL), and treated with saturated aqueous N a H C 0 3 (150 mL). Solid N a 2 S 2 0 3 (4.58 g, 29.0 mmol) was immediately added and the mixture was stirred at room temperature open to the atmosphere for 30 min. The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed sequentially with saturated aqueous NaHCCh and brine, dried, and concentrated. Flash chromatography (90 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 0.77 g (90%) of (-)-172 as a clear oil . [<x]£ -156 .6° (c 5.00 CH 2 C1 2 ) IR(neat): 1713, 1650, 1201 cm"1. } H N M R (400 M H z ) : 5 5.45-5.51 (m, 1 H , O C H - C H 2 ) , 4.70 (s, 1 H , C=CHH) , 4.68 (s, 1 H , C=CHH) , 2.85-2.92 (m, 1 H), 2.59-2.69 (m, 1 H) , 2.49 (dt, 1 H , J = 6.7, 16.8 Hz), 271 1.92-2.06 (m, 4 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.63-1.69 (m, 2 H) , 1.40-1.56 (m, 5 H), 1.19-1.31 (m, 2 H), 1.05 (d, 3 H , J= 6.4 Hz , C H 3 C H ) , 0.98 (s, 3 H , tertiary Me), 1 3 C N M R (75 M H z ) : 5 215.0, 145.7, 145.0, 115.5, 109.9, 48.0, 40.7, 39.8, 38.6, 38.0, 37.5, 33.6, 33.2, 23.5, 22.3, 21.8, 21.4, 13.8. H R M S (EI) Calcd for C i 8 H 2 8 0 : 260.2140. Found: 260.2142. Anal. Calcd for C i 8 H 2 8 0 : C, 83.00; H , 10.84. Found: C, 82.99; H , 10.94. 272 Preparation of (\R. 4aS, 5RS, 67?)-5-formyl-l,6-dimethyl-l-(4-methylpent-4-en-l-y^ 1,2,3A4a,5,6,7-octahydronaphthalene (173) (mixture of diastereomers) (-)-172 173 To a cold (-78 °C), stirred solution of dry (methoxymethyl)trimethylsilane (4.49 mL, 28.8 mmol) in dry T H F (37 mL) was added, dropwise via a syringe, a solution of sec-BuLi (22.2 mL, 28.8 mmol) in cyclohexane. The solution was warmed to -25 °C and held at this temperature for 30 min. The reaction mixture was cooled to -40 °C and a solution of ketone (-)-172 (0.75 g, 2.88 mmol) in dry T H F (9 mL) was added via a syringe. The mixture was stirred for 1 h at -40 °C and treated with saturated aqueous N a H C 0 3 (40 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic phases were washed with brine, dried, and concentrated. The residue was immediately dissolved in C H C I 3 (50 mL) , the resultant stirred solution was cooled to 0 °C, and a solution of T F A (6 mL) in water (6 mL) was added via a syringe. The biphasic mixture was stirred for 30 min at 0 °C and treated with water (50 mL). The phases were separated and the aqueous phase was extracted with C H 2 C I 2 . The combined extracts were washed sequentially with saturated aqueous NaHCC«3 and brine, dried, and concentrated. Flash chromatography (80 g of silica gel, 19:1 petroleum ether-E 1 2 O ) of the residual material yielded 0.58 g (74%) of 173 (mixture of diastereomers) as a clear oil . 273 IR(neat): 2708, 1719, 1650, 1456 cm"1. ' H N M R (400 M H z ) : 5 9.74 (d, 0.55 H , J = 4.0 Hz , C H O ) , 9.69 (d, 0.45 H , J= 2.1 Hz , C H O ) , 5.29-5.37 (m, 1 H , C = C H - C H 2 ) , 4.63-4.69 (m, 2 H , C=CH 2 ) , 2.56-2.66 (m, 2 H) , 2.13-2.34 (m, 4 H) , 1.95-2.11 (m, 4 H), 1.78-1.89 (m, 2 H) , 1.56-1.72 (m, 1 H) , 1.69 (s, 3 H , C = C C H 3 ) , 1.35-1.51 (m, 3 H) , 1.12-1.30 (m, 1 H) , 1.01 (s, 1.35 H , tertiary Me) , 1.00 (s, 1.65 H , tertiary Me) , 0.94 (d, 1.65 H , J= 6.4 Hz , C H 3 C H ) , 0.84 (d, 1.35 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R (100.6 M H z ) : 5 207.2, 205.2, 145.9, 145.8, 144.9, 144.3, 115.9, 114.7, 109.8, 109.7, 57.6, 56.8, 40.8, 40.7, 38.9, 38.7, 38.6, 38.5, 37.6, 34.1, 33.9, 32.7, 32.6, 31.0, 30.9, 30.5, 26.2, 25.3, 24.5, 23.9, 22.3, 22.2, 22.1, 21.8, 21.6, 21.5, 19.4, 15.2. H R M S (EI) Calcd for C i 9 H 3 0 O : 274.2297. Found: 274.2299. Anal . Calcd for C i 9 H 3 0 O : C, 83.15; H , 11.02. Found: C, 82.98; H , 11.09 274 Preparation of (IR. 4aS. 5RS. 6i^)-5-cyano-1.6-dimethyl-l-(4-methylpent-4-en-l-yl)-l,2,3.4.4a.5.6.7-octahydronaphthalene (174) (mixture of diastereomers) 173 174 To a stirred solution of the mixture of aldehydes 173 (0.52 g, 1.90 mmol) in N-methylpyrrolidinone (60 mL) was added solid N H 2 O H • HC1 (0.40 g, 5.70 mmol). The reaction mixture was warmed to 115 °C, stirred for 3 h, cooled to room temperature, and treated with saturated aqueous N a H C 0 3 (150 mL). The mixture was extracted with E t O A c and the combined extracts were washed with brine, dried, and concentrated. Flash chromatography (85 g of silica gel, 15:1 petroleum ether-Et 20) of the crude material yielded 0.48 g (93%) of 174 (mixture of diastereomers) as a clear oil . IR (neat): 2236, 1650, 1458, 886 cm"1. *H N M R (400 M H z ) : 5 5.30-5.37 (m, 1 H , C = C H - C H 2 ) , 4.69 (s, 1 H , C=CHH) , 4.66 (s, 1 H , C=CHH), 2.44-2.58 (m, 3 H), 2.28 (dt, 0.5 H , J = 5.2, 17.7 Hz) , 2.14-2.23 (m, 0.5 H) , I. 86-2.09 (m, 6 H) , 1.62-1.74 (m, 2 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.32-1.50 (m, 4 H) , 1.11-1.23 (m, 1 H), 1.09 (d, 1.5 H , J = 6.7 Hz , C H 3 C H ) , 1.06 (d, 1.5 H , J= 7.0 Hz , C H 3 C H ) , 1.00 (s, 1.5 H , tertiary Me) , 0.99 (s, 1.5 H , tertiary Me) . 275 1 3 C N M R (75 M H z ) : 5 146.0, 145.9, 144.1, 143.1, 121.7, 121.0, 115.3, 115.2, 109.9, 109.8, 40.7, 40.6, 39.0, 38.9, 38.7, 38.6, 37.7, 35.2, 34.4, 34.3, 33.9, 32.4, 31.8, 31.0, 30.9, 30.3, 29.7, 27.1, 27.0, 24.2, 23.5, 22.4, 21.9, 21.7, 21.6, 21.5, 19.4, 16.6. H R M S (EI) Calcd for C i 9 H 2 9 N : 271.2300. Found: 271.2300. Anal. Calcd for d 9 H 2 9 N : C, 84.07; H , 10.77; N , 5.16. Found: C, 84.20; H , 10.75; N , 5.20. 276 Preparation of (-)-(}R, 4a/?. 5S. 6i?)-5-cyano-5-[2-(4-methoxybenzyloxy)ethyl]-1.6-dimethyl-1 -(4-methylpent-4-en-1 -yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (175) (-)-175 To a cold (-78 °C), stirred solution o f / - B u O K (176 mg, 1.58 mmol) in dry T H F (11 mL) was added, via a syringe, dry / - P r 2 N H (0.25 mL, 1.89 mmol) as a neat liquid. A solution of «-BuLi (0.79 mL, 1.26 mmol) in hexanes was added, dropwise via a syringe, and the reaction mixture was stirred at -78 °C for 20 min. A solution of the mixture of nitriles 174 (170 mg, 0.63 mmol) in dry T H F (5 mL) was added via a syringe and the homogeneous mixture was stirred at -78 °C for 30 min. Dry H M P A (0.44 mL, 2.52 mmol) and iodide 119 (0.37 g, 1.26 mmol) were sequentially added via syringes, as neat liquids. The mixture was stirred vigorously at -78 °C for 5 min. The reaction mixture was treated with saturated aqueous N F L C l (20 mL), the phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic phases were washed sequentially with 10% aqueous C U S O 4 and brine, dried, and concentrated. Flash chromatography (25 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 0.25 g (91%) of (-)-175 as a clear oil . [ a ] " -31 .0° (c 1.00 CH 2 C1 2 ) 277 IR(neat): 2229, 1614, 1514, 1248, 1102, 1037 cm"1. lH N M R (400 M H z ) : 5 7.22-7.26 (m, 2 H , H b ) , 6.83-6.87 (m, 2 H , He), 5.28-5.34 (m, 1 H , C = C H - C H 2 ) , 4.69 (s, 1 H , C=CHH), 4.66 (s, 1 H , C=CHH), 4.44 (s, 2 H , H a ) , 3.79 (s, 3 H , C H 3 0 ) , 3.67 (t, 2 H , J= 8.6 Hz , C H 2 C H 2 0 ) , 2.22-2.39 (m, 2 H) , 1.95-2.10 (m, 4 H), I. 56-1.92 (m, 3 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.11-1.52 (m, 9 H) , 0.99 (d, 3 H , J= 9.2 Hz, C H 3 C H ) , 0.90 (s, 3 H , tertiary Me). 1 3 C N M R ( 7 5 M H z ) : 5 159.2, 146.0, 143.2, 130.2, 129.3 (2 carbons), 122.7, 114.9, 113.8 (2 carbons), 109.9, 72.9, 67.0, 55.3, 43.6, 41.2, 40.7, 39.2,'39.1, 39.0, 38.7, 31.3, 30.2, 30.1, 23.5, 22.4, 22.1, 21.6, 15.1. H R M S (DCI) Calcd for C 2 9 H 4 5 N 2 0 2 [ M + N H 4 ] + : 453.3481. Found: 453.3487. Anal . Calcd for C 2 9 H 4 i N 0 2 : C, 79.94; H , 9.49; N , 3.22. Found: C, 79.99; H , 9.56; N , 3.30. 278 Preparation of (-)-(li?. 4a/?. 5S, 6i?V5-hydroxymethyl-5-[2-(4-methoxybenzyloxy)eth^ 1.6-dimethyl-1 -(4-methylpent-4-en-1 -yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (176) (-)-175 (_)-176 To a stirred solution of nitrile (-)-175 (120 mg, 0.28 mmol) in dry D M E (16 mL) at room temperature was added, via a syringe, a solution of D I B A L H (1.12 mL, 1.12 mmol) in hexanes. The reaction mixture was stirred at room temperature for 30 min and then was treated with I N aqueous citric acid (60 mL). The mixture was stirred at room temperature open to the atmosphere for 3 h and then was extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. The residue was immediately dissolved in dry C H 3 O H (20 mL) and solid N a B H 4 (24 mg, 0.64 mmol) was added to the resultant solution. The solution was stirred at room temperature for 20 min and then was treated with saturated aqueous NH4CI (15 mL). The resultant mixture was extracted with Et20. The combined organic extracts were washed with brine, dried, and concentrated. Flash chromatography (25 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 101 mg (82%) of (-)-176 as a clear oil . [ a ] £ -18 .9° (c 1.00 CH2CI2) 279 IR(neat): 3435, 1613, 1514, 1249, 1038 cm"1. *H N M R (400 M H z ) : 5 7.22-7.26 (m, 2 H , H b ) , 6.84-6.88 (m, 2 H , H c ) , 5.22-5.29 (m, 1 H , O C H - C H 2 ) , 4.68 (s, 1 H , C - C H H ) , 4.66 (s, 1 H , C=CHH), 4.47 (d, 1 H , J = 11.6 Hz , H a ) , 4.43 (d, 1 H , J= 11.6 Hz , H a ) , 3.85 (t, 1 H , J = 7.0 Hz , C H H O H ) , 3.78 (s, 3 H , CH3O), 3.50-3.57 (m, 2 H , C H 2 C H 2 0 ) , 3.40-3.47 (m, 1 H , C H H O H ) , 1.95-2.16 (m, 4 H) , I. 78-1.89 (m, 2 H) , 1.31-1.76 (m, 10 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.01-1.28 (m, 3 H) , 0.93 (s, 3 H , tertiary Me) , 0.75 (d, 3 H , J = 6.7 Hz , C H 3 C H ) 1 3 C N M R (75 M H z ) : 5 159.4, 146.3, 145.2, 129.6 (2 carbons), 129.4, 115.2, 113.9 (2 carbons), 109.7, 73.0, 67.8, 66.2, 55.3, 42.7, 41.0, 40.2, 39.3, 39.1, 38.8, 31.2, 28.9, 25.7, 22.9, 22.5, 22.4, 21.7, 17.6, 14.6. H R M S (DCI) Calcd for C^HtsOs [M+H] + : 441.3369. Found: 441.3367. Anal . Calcd for C29H44O3: C, 79.04; H , 10.06. Found: C, 78.84; H , 10.10. 280 Preparation of(-)-(\R. 4aS. 5R. 6^V5-r2-hydroxvethvlV1.5.64rimethvl-l-(4-methvlpent-4-en-1 -y lV 1.2.3.4.4a.5.6.7-octahydronaphthalene (1771 (-)-176 (-)-177 To a stirred solution of alcohol (-)-176 (80 mg, 0.18 mmol) in dry T H F (15 mL) were added imidazole (4 mg, 0.18 mmol) and N a H (34 mg, 0.86 mmol) as solids. The reaction mixture was warmed to 60 °C and stirred for 2 h. The mixture was cooled to room temperature and neat C S 2 (52 u.L, 0.86 mmol) was added via a syringe. The reaction mixture was stirred at room temperature for 1 h and neat M e l (67 uL, 1.08 mmol) was added via a syringe. The mixture was stirred at room temperature for 30 min and treated with saturated aqueous N a H C 0 3 (15 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed with brine, dried, and concentrated. The crude xanthate was dissolved in o-xylene (14 mL) and the resultant stirred solution was warmed to 150 °C. Neat BU3S11H (0.19 mL, 0.72 mmol) and a solution of 2,2'-azobisisobutyronitrile (2 mg, 0.012 mmol) in o-xylene (0.35 mL) were sequentially added via syringes. The reaction mixture was stirred at 150 °C for 15 min, cooled to 0 °C, and concentrated. The residue was dissolved in C H 2 C 1 2 (15 mL) and water (0.75 mL) was added. Solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (57 mg, 0.25 mmol) was added to the resultant mixture. The biphasic 281 mixture was stirred at room temperature for 1 h, water (15 mL) was added, the phases were separated, and the aqueous phase was extracted with C H 2 C I 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (20 g of silica gel, 3:1 petroleum ether-Et20) of the crude material yielded 46 mg (85%) of (-)-177 as a clear oil. [<X]D - 71 .3° (c 0.50 C H 2 C I 2 ) IR(neat): 3349, 1650, 1046, 886 cm"1. lH N M R (400 M H z ) : 5 5.24-5.30 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH) , 4.67 (s, 1 H , C=CHH), 3.63-3.75 (m, 2 H , C H 2 O H ) , 1.95-2.11 (m, 3 H) , 1.34-1.77 (m, 14 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.15 (dt, 1 H , J= 5.5, 13.1 Hz), 1.03 (dd, 1 H , J= 4.6, 12.2 Hz) , 0.98 (s, 3 H , tertiary Me) , 0.85 (s, 3 H , tertiary Me), 0.79 (d, 3 H , J= 6.7 Hz , CH3CH). 1 3 C N M R ( 7 5 M H z ) : 5 146.3, 145.4, 114.9, 109.7, 59.8,41.3, 41.0, 39.1, 38.8, 37.3, 35.7, 33.0, 31.1, 29.7, 28.8, 24.5, 22.7, 22.5, 22.4, 21.8, 14.7. H R M S (DCI) Calcd for C21H37O [M+H] + : 305.2845. Found: 305.2842. Anal . Calcd for C 2 i H 3 6 0 : C, 82.83; H , 11.92. Found: C, 82.64; H , 11.81. 2 8 2 Preparation of (-)-(!& 4aS. 5R. 6^V1.5.64rimethyl-l-r4-methvlpent-4-en-l-vlV5-r2-oxoethyl)-L2,3,4,4a,5,6J-octahydronaphthalene (178) H-177 (-)-178 To a stirred solution of alcohol (-)-177 (46 mg, 0.15 mmol) in dry C H 2 C 1 2 (12 mL) at room temperature was added the Dess-Martin reagent 5 0 (95 mg, 0.23 mmol) in one solid portion. The reaction mixture was stirred at room temperature for 30 min, diluted with E t 2 0 (30 mL), and treated with saturated aqueous NaHCC«3 (25 mL). Solid Na 2S 2C>3 (0.29 g, 1.84 mmol) was immediately added and the mixture was stirred at room temperature open to the atmosphere for 30 min. The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (12 g of silica gel, 19:1 petroleum ether-Et 20) of the crude material yielded 41 mg (91%) of (-)-178 as a clear oil. [a]? - 5 6 . 3 ° (c 0.50 CH 2 C1 2 ) IR (neat): 2850, 1720, 886 cm"1. 283 *H N M R (400 M H z ) : 5 9.87 (t, \H,J= 3.3 Hz , C H O ) , 5.26-5.35 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH) , 4.67 (s, 1 H , C=CHH), 2.33 (dd, 1 H , J = 3.3, 13.9 Hz , C H H -C H O ) , 2.19 (dd, 1 H , J = 3 . 3 , 13.9 Hz , C H H - C H O ) , 1.96-2.15 (m, 4 H) , 1.32-1.82 (m, 10 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.02-1.21 (m, 2 H), 1.06 (s, 3 H , tertiary Me) , 0.98 (s, 3 H , tertiary Me), 0.83 (d, 3 H , J = 6.6 Hz, C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 204.8, 14'6.2, 145.9, 115.2, 109.8, 48.3, 42.5, 40.9, 39.4, 39.3, 38.8, 37.8, 33.1, 31.4, 29.4, 23.7, 23.1, 22.7, 22.4, 21.7, 14.9. H R M S (EI) Calcd for C 2 i H 3 4 0 : 302.2610. Found: 302.2615. Anal . Calcd for C 2 i H 3 4 0 : C, 83.38; H , 11.33. Found: C, 83.51; H , 11.46. 284 Preparation of (-UIR. 4aS. 5R. 6/^V54^-2-(3-miylV2-hydroxyethyl]-1.5.6-trimethyl^ r4-methylpent-4-en-l-yn-1.2.3.4.4a.5.6.7-octahvdronaphthalene (179) and (-)-(!& 4 a £ 5R. 6R)-5- [S-2-(3 -furyl)-2-hydroxy ethyl] -1.5.6-trimethyl-1 - (4-methy lpent-4-en-1 -y 1)-1.2.3.4.4a.5.6.7-octahydronaphthalene (180) (-)-179 (-)-180 To a cold (-78 °C), stirred solution of 3-bromofuran (0.04 mL, 0.42 mmol) in dry THF (0.8 mL) was added a solution of n-BuLi (0.27 mL, 0.42 mmol) in hexanes via a syringe. The reaction mixture was stirred at -78 °C for 30 min and a solution o f aldehyde (-)-178 (25 mg, 0.084 mmol) in dry THF (1.3 mL) was added via a syringe. The mixture was stirred at -78 °C for 30 min and then was treated with saturated aqueous N F L C l (3 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed sequentially with saturated aqueous NaHC03 and brine, dried, and concentrated. Flash chromatography (5 g of silica gel, 9:1 petroleum ether-Et20) o f the crude material yielded 12.7 mg (41%) of (-)-179 as a clear oil and 15.2 mg (49%) of (-)-180 as a clear oil. Characterisation for alcohol (-)-179: 285 [cc]o -52.8° (c I.OOCH2CI2) FR (neat): 3391, 1649, 1459, 1025, 875 cm"1. lU N M R (400 MHz): 5 7.31-7.35 (m, 2 H, H a and H b), 6.34 (s, 1 H, H c), 5.23-5.29 (m, 1 H, C=CH-CH 2), 4.82-4.88 (m, 1 H, CHOH), 4.68 (s, 1 H, C=CHH), 4.66 (s, 1 H, C=CHH), 1.96-2.08 (m, 3 H), 1.33-1.81 (m, 14 H), 1.69 (s, 3 H, C=CCH 3), 0.89-1.07 (m, 2 H), 0.95 (br s, 3 H, tertiary Me), 0.93 (s, 3H, tertiary Me), 0.84 (d, 3 H, J = 6.4 Hz, CH3CH). 1 3 C N M R (75 MHz): 5 146.3, 145.7 (br), 143.3, 138.4, 131.3, 115.0, 109.7, 108.6, 64.4, 41.6 (br), 41.0, 40.5 (br), 39.1, 39.0 (br), 38.8, 36.2, 35.0, 32.8, 31.0 (br), 23.5 (br), 22.7, 22.6, 22.4, 21.7, 14.7. HMRS Calcd for C 2 5 H 3 8 O 2 : 370.2872. Found: 370.2887. Characterisation for alcohol (-)-180: [aJo -73.4° (c I.5OCH2CI2) IR (neat): 3436, 1649, 1460, 1025, 875 cm"1. 286 ! H N M R (400 M H z ) : 5 7.34-7.36 (m, 2 H , H a and H b ) , 6.38 (s, 1 H , H c ) , 5.28-5.32 (m, 1 H , C = C H - C H 2 ) , 4.82-4.88 (m, 1 H , C H O H ) , 4.69 (s, 1 H , C=CHH) , 4.67 (s, 1 H , C=CHH), 1.96-2.14 (m, 3 H) , 1.34-1.87 (m, 14 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.15-1.21 (m, 1 H) , 1.02-1.11 (m, 1 H) , 1.00 (s, 3 H , tertiary Me) , 0.95 (s, 3 H , tertiary Me) , 0.74 (d, 3 H , 7 = 6.7 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 8 146.2, 145.0 (br), 143.3, 138.4, 131.4, 115.3, 109.7, 108.6, 64.2, 41.3 (br), 41.0, 39.2, 38.8, 36.1, 33.3 (br), 33.2, 31.3 (br), 29.7, 29.3 (br), 25.1, 22.8, 22.6, 22.4,21.7,14.8. H R M S (EI) Calcd for C 2 5 H 3 8 0 2 : 370.2872. Found: 370.2884. 2 8 7 Preparation of (-)-15-epidysidiolide (26) (-)-179 (-)-26 To a stirred solution of furan (-)-179 (7.2 mg, 0.019 mmol) and dry / -Pr 2 NEt (33.6 pL , 0.19 mmol) in dry CH2CI2 (6 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and O2 was bubbled through the solution for 15 min. The solution was placed under an O2 atmosphere and irradiated with a 200-W tungsten fdament lamp. The solution was stirred at -78 °C for 1.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous N H 4 C 1 (6 mL). The phases were separated and the aqueous phase was extracted with CH2CI2. The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 6.6 mg (85%) of (-)-26 as a clear oil . [OC]D - 9 . 3 ° ( C 1.00 CH2CI2) IR(neat): 3392, 1747, 1649, 1456, 1136, 952 cm"1. 288 Doubled XH and 1 3 C nmr signals were observed for selected protons and carbons. These doubled signals are due to the two epimers (at C-25) of (-)-26 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. *H N M R (400 M H z , DMSO-fife): 8 7.91 (d, 1 H , J = 7.9 Hz , O - C H O H ) (7.83), 6.05-6.17 (m, 1 H , O - C H O H ) , 5.95 (s, 1 H , C=CH-C=0) , 5.29 (d, 1 H , J = 6.3 Hz , C H 2 C H O H ) (part of the 5.14-5.25 multiplet), 5.14-5.25 (part of this multiplet, 1 H , C = C H - C H 2 ) , 4.65 (s, 1 H , C=CHH) , 4.62 (s, 1 H , C=CHH), 4.47-4.56 (m, 1 H , C H 2 C H O H ) (4.35-4.44), 1.86-2.07 (m, 3 H) , 1.40-1.85 (m, 9 H), 1.64 (s, 3 H , C = C C H 3 ) , 1.01-1.29 (m, 6 H) , 0.94 (s, 3 H , tertiary Me) , 0.91 (s, 3 H , tertiary Me), 0.74 (br d, 3 H , J = 6.3 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z , DMSO - r f * ) : 8 175.2 (173.2), (170.0) 169.7, 144.7, 144.6 (br), 115.4, (115.2) 115.1, 109.3, (97.5) 96.8, 63.4 (61.9), 41.4 (br), 41.2, 40.7, 37.4, 35.7, 35.6, 35.3, 31.1, 31.0, 28.7, 28.1 (br), 25.2, 21.4, 21.0, 17.7 (br), 14.2. H R M S (EI) Calcd for C 2 5 H 3 8 0 4 : 402.2770. Found: 402.2779. 289 Preparation of (—)-4.15-bisepidysidiolide (181) (-)-180 (_)_181 To a stirred solution of furan (-)-180 (3.0 mg, 0.008 mmol) and dry / -Pr 2 NEt (14 u.L, 0.08 mmol) in dry C H 2 C 1 2 (2 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and 0 2 was bubbled through the solution for 15 min. The solution was placed under an 0 2 atmosphere and irradiated with a 200-W tungsten filament lamp. The solution was stirred at -78 °C for 0.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous N H 4 C 1 (3 mL). The phases were separated and the aqueous phase was extracted with C H 2 C 1 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (2 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 2.7 mg (83%) of (-)-181 as a clear oil . [ a ] " -44 .3° (c 0.80 CH 2 C1 2 ) IR(neat): 3368, 1752, 1649, 1455, 1136, 952 cm"1. 290 Doubled ! H and 1 3 C nmr signals were observed for selected protons and carbons. These doubled signals are due to the two epimers (at C-25) of (-)-181 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. *H N M R (400 M H z , DMSO-d6): 5 7.74-7.81 (m, 1 H , O - C H O H ) (7.86-7.92), 5.97-6.13 (m, 1 H , O - C H O H ) , 5.92 (s, 1 H , C=CH-C=0) , 5.19-5.28 (m, 2 H , C = C H - C H 2 and C H 2 C H O H ) (5.14, C H 2 C H O H ) , 4.68 (br s, 1 H , C=CHH), 4.66 (br s, 1 H , C=CHH), 4.46-4.53 (m, 1 H , C H 2 C H O H ) (4.34-4.42), 1.92-2.10 (m, 4 H) , 1.30-1.84 (m, 13 H), 1.66 (s, 3 H , C = C C H 3 ) , 1.05-1.17 (m, 1 H) , 0.97 (br s, 3 H , tertiary Me) , 0.91 (br s, 3 H , tertiary Me) , 0.78 (br d, 3 H , J = 6.2 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z , DMSO-d6): 5 175.9(174.0), (170.6) 170.4, 145.3, 144.6 (br), (116.1) 115.7, 113.9, 110.2, (98.3) 97.6, 64.4 (64.1), 42.5 (br), 41.8, 38.1, 36.3, 36.1, 31.9, 31.5, 31.3 (br), 30.4, 29.0, 28.7 (br), 22.3, 22.1, 21.1, 21.0, 14.9. H R M S (EI) Calcd for C25H 3 8 0 4 : 402.2770. Found: 402.2774. 291 Preparation of (-)-(\R. 4 a £ SR. 67?)-5-[2-(3-furyl)-2-oxoethyl]-1.5.6-trimethyl-^ methylpent-4-en-l-ylVl,2,3.4.4a,5,6,7-octahydronaphthalene (182) (-)-180 (-)-182 To a stirred solution of alcohol (-)-180 (10 mg, 0.027 mmol) in dry C H 2 C 1 2 (3 mL) at room temperature was added the Dess-Martin reagent 5 0 (25 mg, 0.06 mmol) in one solid portion. The reaction mixture was stirred at room temperature for 15 min, diluted with E t 2 0 (10 mL), and treated with saturated aqueous NaHCCb (8 mL). Solid N a 2 S 2 0 3 (66 mg, 0.42 mmol) was immediately added and the mixture was stirred at room temperature open to the atmosphere for 30 min. The phases were separated and the aqueous phase was extracted with E t 2 0 . The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (8 g of silica gel, 15:1 petroleum ether-Et 20) of the crude material yielded 9.5 mg (96%) of (-)-182 as a clear oil . [a] 2 ; -32 .8° ( c 0 . 5 0 C H 2 C l 2 ) FR(neat): 1672, 1456, 1157, 874 cm"1. 292 *H N M R (400 M H z ) : 5 7.95-7.97 (dd, 1 H , J= 0.9, 1.8 Hz , H a ) , 7.39 (t, 1 H,J= 1.8 Hz , H b ) , 6.73 (dd, 1 H , J= 0.9, 1.8 Hz , H e ) , 5.24-5.29 (m, 1 H , C = C H - C H 2 ) , 4.69 (s, 1 H , C=CHH) , 4.67 (s, 1 H , C=CHH), 2.79 (d, 1 H , J = 16.8 Hz , CHHC=0), 2.61 (d, 1 H , / = 16.8 Hz , CHHC=0), 2.36-2.45 (m, 1 H), 1.96-2.11 (m, 3 H), 1.35-1.80 (m, 9 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.22-1.32 (m, 1 H) , 0.99-1.19 (m, 2 H) , 1.01 (s, 3 H , tertiary Me) , 1.00 (s, 3 H , tertiary Me) , 0.82 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 195.0, 146.5, 146.3, 144.4, 129.3, 114.6 (br), 114.2, 109.7, 108.7, 45.8, 41.9, 41.0, 39.3 (br), 39.1, 38.8, 37.8, 31.8, 31.6, 30.3, 29.7, 29.2 (br), 22.6, 22.4, 21.8, 15.2. H R M S (EI) Calcd for C 2 5 H 3 6 0 2 : 368.2715. Found: 368.2722. 293 Preparation of (-)-(\R. 4 a £ 5R. 6/?V54^-2-(3-mrylV2-hydroxyethyl]-1.5.6-trimethyl-l^ (4-methylpent-4-en-l-yl)-1.2,3,4,4a.5.6.7-octahydronaphthalene (179) To a cold (-78 °C), stirred solution of ketone (-)-182 (8 mg, 0.022 mmol) in dry T H F (2 mL) was added, via a syringe, a solution of oxazaborolidine catalyst A (0.88 mL, 0.044 mmol) in toluene. The solution was stirred at -78 °C for 15 min and a cold (-78 °C) solution of B H 3 • M e 2 S (88 uL, 0.044 mmol) in toluene was added via a cannula. The reaction mixture was warmed to -30 °C and stirred for 10 h. Water (10 mL) and E t 2 0 (10 mL) were added, the phases were separated, and the aqueous phase was extracted with E t 2 0 . The combined extracts were washed with brine, dried, and concentrated. Flash chromatography (5 g of silica gel, 9:1 petroleum ether-Et 20) of the crude material yielded 7.6 mg (94%) of (-)-179 as a clear oil. (-)-182 (-)-179 294 5. 5. Syntheses of (-)-6,15-bisepidysidiolide and (-)-4,6,15-trisepidysidiolide Preparation of (-)-(\R, 4aR, 5S, 67?)-5-cyano-L5,6-trimethyl-l-(4-methylpent-4-en-l-yl)-1.2.3.4.4a.5.6,7-octahydronaphthalene (183) To a cold (0 °C), stirred solution of L D A (1.38 mmol, 1.5 equiv) in dry T H F (7 mL) were sequentially added, via syringes, a solution of the mixture of nitriles 174 (250 mg, 0.92 mmol) in dry T H F (7 mL) and dry H M P A (neat liquid) (0.48 mL, 2.76 mmol). The reaction mixture was stirred at 0 °C for 1 h and cooled to -98 °C. Neat M e l (0.17 mL, 2.76 mmol) was added via a syringe and the solution was stirred at -98 °C for 10 min. The reaction mixture was treated with saturated aqueous N H 4 C I (15 mL), the phases were separated and the aqueous phase was extracted with Et20. The combined organic phases were washed sequentially with 10% aqueous C U S O 4 and brine, dried, and concentrated. Flash chromatography (25 g of silica gel, 19:1 petroleum ether-Et 20) of the crude material yielded 242 mg (92%>) of (-)-183 as a clear oil. [<X]D -120 .2° (c 1.00 CH 2 C1 2 ) IR(neat): 2231, 1650, 1456, 886 cm' 295 ! H N M R (400 M H z ) : 5 5.27-5.32 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH) , 4.65 (s, 1 H , C=CHH) , 2.30 (dt, 1 H , 7 = 4.3, 18.0 Hz), 2.06-2.17 (m, 2 H) , 1.89-2.01 (m, 3 H) , I. 56-1.76 (m, 3 H), 1.68 (s, 3 H , C = C C H 3 ) , 1.28-1.52 (m, 6 H) , 1.23 (s, 3 H , Me a ) , 1.12-1.22 (m, 1 H) , 0.98 (d, 3 H , J= 7.0 Hz , C H 3 C H ) , 0.95 (s, 3 H , Mo, ) . 1 3 C N M R (75 M H z ) : 5 145.9, 142.9, 124.2, 114.7, 109.9, 41.4, 40.8, 40.6, 39.0, 38.6, 38.5,31.4,31.2,30.1,23.6,22.3,22.0,21.5,19.8,15.4. H R M S (EI) Calcd for C 2 0 H 3 i N : 285.2457. Found: 285.2454. Anal. Calcd for C 2 0 H 3 i O : C, 84.15; H , 10.95; N , 4.91. Found: C, 84.07; H , 11.01; N , 4.86. 296 Preparation of f - ) - ( lR. 4a/?. 55. 6ffl-5-formvl-1.5.64rimethvl-l-f4-methylpent-4-en-l-yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (184) (-)-183 (-)-184 To a stirred solution of nitrile (-)-183 (192 mg, 0.67 mmol) in dry D M E (20 mL) at room temperature was added, via a syringe, a solution of D I B A L H (1.34 mL, 1.34 mmol) in hexanes. The reaction mixture was stirred at room temperature for 1 h and treated with I N aqueous citric acid (30 mL). The mixture was stirred at room temperature open to the atmosphere for 2 h and extracted with Et20. The combined extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (18 g of silica gel, 19:1 petroleum ether-Et20) o f the crude material yielded 174 mg (90%) of (-)-184 as a clear oil . [a] 2, 3 - 92 .3° (c 1.00CH 2 C1 2 ) IR(neat): 2703, 1724, 1650, 1455 cm"1. *H N M R (400 M H z ) : 5 9.67 (s, 1 H , C H O ) , 5.33-5.38 (m, 1 H , C = C H - C H 2 ) , 4.69 (s, 1 H , C=CHH), 4.67 (s, 1 H , C=CHH), 2.14-2.24 (m, 2 H), 1.97-2.09 (m, 3 H), 1.67-1.72 (m, 2 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.56-1.63 (m, 2 H), 1.38-1.49 (m, 5 H), 1.12-1.32 (m, 2 H), 0.99 (s, 3 H , tertiary Me) , 0.94 (s, 3 H , tertiary Me) , 0.83 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 297 1 3 C N M R (75 M H z ) : 5 209.7, 146.0, 144.3, 115.4, 109.8, 50.2, 42.0, 40.9, 39.0, 38.8, 38.7, 30.9, 30.1, 29.1, 23.7, 22.4, 22.3, 21.6, 16.0, 14.7. H R M S (EI) Calcd for C20H32O: 288.2453. Found: 288.2452. Anal . Calcd for C 2 o H 3 2 0 : C, 83.27; H , 11.18. Found: C, 83.07; H , 11.19. 298 Preparation of (-)-( lR. 4 a £ 5S. 6^V1.5.6-trimethyl-l-(4-methylpent-4-en-l-vn-5-r2-oxoethyO-1.2.3.4.4a.5.6,7-octahydronaphthalene (185) To a cold (-78 °C), stirred solution of dry (methoxymethyl)trimethylsilane (0.59 mL, 3.80 mmol) in dry T H F (5 mL) was added, dropwise via a syringe, a solution of sec-B u L i (2.92 mL, 3.80 mmol) in cyclohexane. The solution was warmed to -25 °C and held at this temperature for 30 min. The reaction mixture was cooled to -35 °C and a solution of aldehyde (-)-184 (115 mg, 0.38 mmol) in dry T H F (2 mL) was added via a syringe. The mixture was stirred at -35 °C for 30 min and treated with saturated aqueous N a H C C h (6 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried, and concentrated. The residue was immediately dissolved in dry T H F (10 mL) and solid K H (76 mg, 1.90 mmol) was added to the resultant stirred solution. The mixture was warmed to 60 °C, stirred for 30 min, cooled to room temperature, and treated with saturated aqueous NaHCCb (10 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined extracts were washed sequentially with saturated aqueous NaHCC>3 and brine, dried, and concentrated. The residue was dissolved in acetone (4 mL) and water (2 mL). Solid oxalic acid (103 mg, 1.14 mmol) was added and the resultant mixture was stirred at room temperature for 1 h. Water (10 mL) and Et20 (20 mL) were added, the phases were separated, and the aqueous phase was extracted with Et20. The combined extracts were 299 washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (11 g of silica gel, 15:1 petroleum ether-Et20) o f the crude material yielded 91 mg (79%) of (-)-185 as a clear oil. [<X]D -66 .4° (c 1.50CH 2 C1 2 ) IR (neat): 2723, 1720, 1457, 886 cm"1. *H N M R (400 M H z ) : 5 9.92 (t, 1 H , J = 3.0 Hz , CHO) , 5.25-5.31 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH), 4.66 (s, 1 H , C=CHH), 2.35 (dd, 1 H , J = 3.0, 15.0 Hz , C H H C = 0 ) , 2.24 (dd, 1 H , J= 3.0, 15.0 Hz , C H H C = 0 ) , 2.04-2.16 (m, 3 H), 1.96-2.02 (m, 2 H) , 1.52-1.78 (m, 5 H) , 1.70 (s, 3 H , C = C C H 3 ) , 1.34-1.48 (m, 4 H) , 1.04-1.20 (m, 2 H), 1.03 (s, 3 H , tertiary Me) , 0.97 (s, 3 H , tertiary Me), 0.80 (d, 3 H , J = 6.7 Hz , C H 3 C H ) . 1 3 C N M R (75 M H z ) : 5 204.6, 146.2, 145.0, 115.0, 109.8, 50.9, 42.9, 40.9, 39.0, 38.9, 38.8, 37.8, 32.5, 31.1, 29.3, 24.4, 22.5, 22.4, 21.2, 20.5, 15.0. H R M S (EI) Calcd for C21H34O: 302.2610. Found: 302.2613. Anal . Calcd for C 2 i H 3 4 0 : C, 83.38; H , 11.33. Found: C, 83.47; H , 11.37. 300 Preparation of ( - U 1 R . 4aS. 5S. 6^V5-[^-2-(3-mrylV2-hydroxyethyl1-1.5.6-trimethyl-l-(4-methylpent-4-en-l-yl)-l,2,3,4,4a,5,6,7-octahydronaphthalene (187) H-187 To a cold (-78 °C), stirred solution of 3-bromofuran (0.12 mL, 1.30 mmol) in dry T H F (2.5 mL) was added, via a syringe, a solution of «-BuLi (0.81 mL, 1.30 mmol) in hexanes. The reaction mixture was stirred at -78 °C for 30 min and a solution of aldehyde (-)-185 (78 mg, 0.26 mmol) in dry T H F (4 mL) was added via a syringe. The mixture was stirred at -78 °C for 30 min and treated with saturated aqueous NH4CI (10 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed sequentially with saturated aqueous N a H C 0 3 and brine, dried, and concentrated. Flash chromatography (20 g of silica gel, 99:1 benzene-CH3CH20H) o f the crude material yielded 71 mg (74 %) of (-)-187 as a clear oil and 17 mg (18%) of a 1:2 mixture of (-)-187 and (-)-186, respectively, as a clear oil . Characterisation for alcohol (-)-187: [ajo -62 .3° (c 1.00 CH 2 C1 2 ) 301 IR(neat): 3401, 1650, 1456, 1025, 875 cm"1. *H N M R (400 M H z ) : 5 7.37 (s, 2 H , H a and H b ) , 6.42 (s, 1 H , H c ) , 5.24-5.28 (m, 1 H , C = C H - C H 2 ) , 4.82-4.87 (m, 1 H , C H O H ) , 4.68 (s, 1 H , C=CHH), 4.67 (s, 1 H , C=CHH), 2.04-2.17 (m, 2 H) , 1.95-2.03 (m, 3 H) , 1.87 (dd, 1 H , 7 = 8.0, 15.0 Hz), 1.54-1.77 (m, 6 H), 1.70 (s, 3 H , C = C C H 3 ) , 1.35-1.51 (m, 5 H) , 1.02-1.19 (m, 2 H) , 1.00 (s, 3 H , tertiary Me), 0.90 (s, 3 H , tertiary Me) , 0.79 (d, 3 H , J= 6.7 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 146.3, 145.7 (br), 143.4, 138.4, 131.2, 114.9, 109.7, 108.6, 63.8, 44.7, 43.8, 42.7, 41.0, 39.5 (br), 39.2, 38.8, 36.5, 32.4, 31.9, 30.3, 29.7, 22.7, 22.4, 21.8, 15.1. H R M S (EI) Calcd for C 2 5 H 3 8 O 2 : 370.2872. Found: 370.2869. 302 Preparation of (IR. 4aS. 5S. 6^V5-[5-2-r3-mrylV2-(5-2-methoxy-2-phenyl-2-trifluoromethyl)acetoxy]ethyl-1,5,6-trimethyl-1 -(4-methylpent-4-en-1 -yl)-1.2.3 A4a.5.6.7-octahydronaphthalene (191) 191 To a stirred solution of alcohol (-)-187 (1.1 mg, 0.003 mmol), dry E t 3 N (4 uL, 0.029 mmol), and D M A P (1 mg, 0.008 mmol) in dry C H 2 C 1 2 (0.5 mL) at room temperature was added neat (i?)-(-)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride (2 uL, 0.011 mmol), via a syringe. The reaction mixture was stirred at room temperature for 15 min, treated with C H 3 O H (0.5 mL), and concentrated. Flash chromatography (1 g of silica gel, 15:1 petroleum ether-Et 20) of the crude material yielded 1.6 mg (87%) of 191 as a clear oil. IR(neat): 1746, 1453, 1170 cm *H N M R (400 M H z ) : 5 7.50 (s, 2 H , H a and H b ) , 7.26-7.42 (m, 5 H , aromatic protons), 6.44 (s, 1 H , He), 6.09-6.14 (m, 1 H , CH-OC=0), 5.18-5.22 (m, 1 H , C = C H - C H 2 ) , 4.69 (s, 1 H , C=CHH), 4.67 (s, 1 H , C=CHH), 3.40 (s, 3 H , C H 3 0 - ) , 1.95-2.15 (m, 4 H) , 1.70 303 (s, 3 H , C = C C H 3 ) , 1.64 (dd, 1H, J= 3.2, 15.2 Hz , H d .), 1.22-1.62 (m, 12 H) , 1.08-1.16 (m, 1 H) , 0.97 (s, 3 H , Me e ) , 0.68 (d, 3 H , J= 6.4 Hz , C H 3 C H ) , 0.59 (s, 3 H , Me f ) . H R M S (EI) Calcd for C 3 5 H 4 5 F 3 0 4 : 386.3270. Found: 386.3269. 304 Preparation of (IR. 4 a £ 5S. 6it)-54^-2-(3-mryl)-2-(i?-2-methoxy-2-phenyl-2-trifluoromethyl)acetoxy]ethyl-1.5,6-trimethyl-1 -(4-methylpent-4-en-1 -yl)-1.2.3.4.4a.5.6.7-octahydronaphthalene (192) 192 To a stirred solution of alcohol (-)-187 (2 mg, 0.005 mmol), dry E t 3 N (7 pL , 0.05 mmol), and D M A P (1.8 mg, 0.014 mmol) in dry CH2CI2 (1.0 mL) at room temperature was added neat (/S)-(+)-2-methoxy-2-phenyl-2-trifluoromethylacetyl chloride (3.5 pL, 0.02 mmol), via a syringe. The reaction mixture was stirred at room temperature for 15 min, treated with C H 3 O H (1.0 mL), and concentrated. Flash chromatography (2 g of silica gel, 15:1 petroleum ether-Et20) of the crude material yielded 2.6 mg (83%) of 192 as a clear oil . IR(neat): 1745, 1454, 1165 cm"1. ' H N M R (400 M H z ) : 5 7.27-7.44 (m, 7 H , H a , H b , and 5 aromatic protons), 6.29 (s, 1 H , H e ) , 6.07-6.11 (m, 1 H , CH -OC=0), 5.23-5.26 (m, 1 H , C = C H - C H 2 ) , 4.68 (s, 1 H , C=CHH), 4.66 (s, 1 H , C = C H H ) , 3.44 (s, 3 H , CH3O-), 1.97-2.17 (m, 4 H) , 1.74 (dd, 1H, J= 5.6, 14.8 Hz , Ha), 1.70 (s, 3 H , C = C C H 3 ) , 1.24-1.61 (m, 13 H), 0.99 (s, 3 H , Me e ) , 0.76 (d, 3 H , J= 6.7 Hz , C H 3 C H ) , 0.73 (s, 3 H , Me f ) . H R M S (EI) Calcd for C 3 5 H 4 5 F 3 O 4 : 386.3270. Found: 386.3278. 306 Preparation of (-)-(LR. 4 a £ 55. 6^V5-[^-2-(3-mrylV2-hvdroxvethyl]-1.5.6-trimethvl-l-(4-methylpent-4-en-l-yl)-f 2,3,4,4a,5,6,7-octahydronaphthalene (186) To a cold (0 °C), stirred solution of alcohol (-)-187 (19 mg, 0.05 mmol), P P h 3 (20 mg, 0.075 mmol), and /?-nitrobenzoic acid (13 mg, 0.075 mmol) in dry T H F (1.5 mL) was added, via a syringe, neat D E A D (12 uL, 0.075 mmol). The reaction mixture was stirred at 0 °C for 15 min and warmed to room temperature. The mixture was stirred at room temperature for 2 h and treated with saturated aqueous N a H C 0 3 (3 mL). The phases were separated and the aqueous phase was extracted with Et20. The combined organic extracts were washed with brine, dried, and concentrated. The residue (193) was dissolved in T H F (4 mL) and a solution of D I B A L H (0.20 mL, 0.20 mmol) in hexanes was added, via a syringe, to the resultant stirred solution. The reaction mixture was stirred at room temperature for 1 h and diluted with dry E t 2 0 (8 mL). Solid N a 2 S 0 4 • 10 H 2 0 (0.1 g, 0.30 mmol) was added and the mixture was stirred at room temperature open to the atmosphere for 1 h. The resultant thick slurry was filtered through Celite®, the Celite® cake was rinsed with E t 2 0 and the filtrate was concentrated. 307 Flash chromatography (5 g of silica gel, 7:1 petroleum ether-Et20) of the residue yielded 15.5 mg (82%) of (-)-186 as a clear oil. [a] 2, 2 - 31 .7° (c 1.40 CH 2 C1 2 ) FR(neat): 3413, 1650, 1456, 1025, 875 cm"1. *H N M R (400 M H z ) : 5 7.37 (s, 2 H , H a and H b ) , 6.41 (s, 1 H , H c ) , 5.21-5.26 (m, 1 H , C = C H - C H 2 ) , 4.85-4.92 (m, 1 H , C H O H ) , 4.67 (s, 1 H , C=CHH), 4.66 (s, 1 H , C=CHH), 1.95-2.11 (m, 4 H) , 1.51-1.92 (m, 6 H) , 1.69 (s, 3 H , C = C C H 3 ) , 1.36-1.47 (m, 7 H) , 1.04-1.23 (m, 2 H), 0.97 (s, 3H, tertiary Me) , 0.87-0.92 (br s, 3 H , tertiary Me) , 0.80 (d, 3 H , J = 8.7 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z ) : 5 146.3, 145.4 (br), 143.4, 138.6, 131.3, 114.5, 109.7, 108.6, 64.0, 43.8, 43.1, 42.7 (br), 40.9, 39.2, 39.0, 38.8, 36.5, 36.3, 32.4, 31.3, 22.7 (br), 22.6, 22.4, 21..7, 15.1. H M R S Calcd for C 2 5 H 3 g 0 2 : 370.2872. Found: 370.2871. 308 Preparation of (-)-6.15-bisepidysidiolide (27) (-)-186 OH (-)-27 To a stirred solution of furan ( - ) - 1 8 6 (9 mg, 0.024 mmol) and dry / -Pr 2 NEt (42 pL , 0.24 mmol) in dry C H 2 C 1 2 (5 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and 0 2 was bubbled through the solution for 15 min. The solution was placed under an 0 2 atmosphere and irradiated with a 200-W tungsten fdament lamp. The solution was stirred at -78 °C for 1.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous NH4CI (8 mL). The phases were separated and the aqueous phase was extracted with C H 2 C 1 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (6 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 7.7 mg (79%) of (-)-27 as a clear oil . [a]2° - 15 .1° (c 0.90 CH 2 C1 2 ) IR(neat): 3326, 1747, 1650, 1456, 1137, 952 cm" 309 Doubled *H and 1 3 C nmr signals were observed for selected protons and carbons. These doubled signals are due to the two epimers (at C-25) of (-)-27 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. *H N M R (400 M H z , DMSO-fik): 5 7.90 (d, \H,J= 7.7 Hz , O - C H O H ) (7.82), 6.12 (d, 1 H , J= 1.1 Hz , O - C H O H ) (5.98-6.08), 5.95 (s, 1 H , C=CH-C=0), 5.30 (d, 1 H , J= 6.2 Hz , C H 2 C H O H ) (part of the 5.17-5.26 multiplet), 5.17-5.26 (part of this multiplet, 1 H , C = C H - C H 2 ) , 4.68 (br s, 1 H , C=CHH), 4.66 (br s, 1 H , C=CHH) , 4.49-4.57 (m, 1 H , C H 2 C H O H ) (4.36-4.46), 1.92-2.21 (m, 4 H), 1.31-1.80 (m, 12 H) , 1.66 (s, 3 H , C = C C H 3 ) , 1.05-1.20 (m, 2 H) , 0.97 (s, 3 H , tertiary Me) , 0.90 (br s, 3 H , tertiary Me) , 0.71-0.79 (m, 3 H , C H 3 C H ) . 1 3 C N M R (75 M H z , DMSO-<4): 5 175.8 (173.8), (170.7) 170.4, 145.4, 145.1 (br), (116.2) 115.8, 115.4, 110.0, (98.3) 97.6, 64.5 (62.6), 42.9 (br), 41.7 (br), 38.1, 36.8 (br), 36.4, 36.1, 35.1, 31.6 (br), 31.4, 31.3, 28.8 (br), 25.9, 22.2, 22.0 (br), 21.8, 15.3. H R M S (EI) Calcd for C25H 3 80 4: 402.2770. Found: 402.2770. 310 Preparation of (-V4.6.15-trisepidysidiolide (194) (-)-194 To a stirred solution of fiiran (-)-187 (3.7 mg, 0.010 mmol) and dry /'-Pr 2NEt (17.3 uL , 0.10 mmol) in dry C H 2 C 1 2 (2 mL) was added Rose Bengal (1 mg, 0.001 mmol) as a solid. The reaction mixture was cooled to -78 °C and 0 2 was bubbled through the solution for 15 min. The solution was placed under an 0 2 atmosphere and irradiated with a 200-W tungsten filament lamp. The solution was stirred at -78 °C for 0.5 h and irradiation was stopped. The mixture was placed under an A r atmosphere, warmed to room temperature, and treated with saturated aqueous N H 4 C 1 (3 mL). The phases were separated and the aqueous phase was extracted with C H 2 C 1 2 . The combined organic phases were washed with brine, dried, and concentrated. Flash chromatography (2 g of silica gel, 49:1 C H 2 C 1 2 - C H 3 0 H ) of the crude material yielded 3.5 mg (88%) of (-)-194 as a clear oil . [a]2,1 - 53 .4° (c 1.00 CH 2 C1 2 ) IR (neat): 3332, 1747, 1649, 1456, 1137, 952 cnf 1 . 311 Doubled *H and 1 3 C nmr signals were observed for selected protons and carbons. These doubled signals are due to the two epimers (at C-25) of (-)-194 that exist in solution. In these cases, the signal corresponding to the minor isomer is reported in brackets. ! H N M R (400 M H z , DMSO-4?): 5 7.89 (d, 1 H , J= 8.1 Hz , O - C H O H ) (7.77), 5.98-6.04 (m, 1 H , O - C H O H ) (6.11), 5.95 (s, 1 H , C=CH-C=0) , 5.17-5.33 (m, 2 H , C H 2 C H O H and C = C H - C H 2 ) , 4.67 (br s, 1 H , C=CHH), 4.66 (br s, 1 H , C=CHH) , 4.54-4.61 (m, 1 H , C H 2 C H O H ) (4.39-4.48), 1.81-2.20 (m, 5 H), 1.47-1.79 (m, 10 H) , 1.66 (s, 3 H , C = C C H 3 ) , 1.39 (br s, 3 H , tertiary Me), 1.10-1.21 (m, 1 H) , 0.88-1.03 (m, 2 H) , 0.95 (s, 3 H , tertiary Me) , 0.77 (d, 3 H , J= 6.2 Hz , C H 3 C H ) . 1 3 C N M R ( 7 5 M H z , DMSO-<4): 5 175.3 (173.3), (169.9) 169.7, 144.7 (br), 144.6, (115.4) 115.1, 113.5, 109.5, (97.5) 96.9, 63.4 (62.1), 41.1, 40.4, 37.4, 35.6, 35.5 (br), 35.3, 31.2, 30.7, 28.3, 28.0 (br), 23.2 (br), 21.6, 21.4, 20.4, 18.7 (br), 14.2. H R M S (EI) Calcd for C 2 5 H 3 8 0 4 : 402.2770. Found: 402.2773. 312 6. REFERENCES AND FOOTNOTES 1) Dewick, P. M . Nat. Prod. Rep. 2002, 19, 181. 2) Nakanishi, K . ; Goto, T.; Ito, S.; Natori, S.; Nozoe, S. "Natural Products Chemistry", 1 s t ed. Academic Press, New York, 1974,1, 4. 3) Giannini, C ; Debitus, C ; Posadas, I.; Paya, M . ; D 'Aur i a , M . V . Tetrahedron Lett. 2000, 41, 3257. 4) Miyaoka, H . ; Mitome, H . ; Nakano, M ; Yamada, Y . Tetrahedron, 2000, 56, 7737. 5) Subrahmanyam, C ; Ratnakumar, S.; Ward, R. S. Tetrahedron, 2000, 56, 4585. 6) Kuniyoshi, M . ; Marma, M . S.; Higa, T.; Bernardinelli, G ; Jefford, C. W . J. Chem. Soc, Chem. Commun. 2000, 1155. 7) Giinasekera, S. P.; McCarthy, P. I ; Kelly-Borges, M . ; Lobkovsky, E . ; Clardy, J. J. Am. Chem. Soc. 1996, 118, 8759. 8) Corey, E . J.; Roberts, B . E . J. Am. Chem. Soc. 1997,119, 12425. 9) Peng, H . ; Xie , W. ; Otterness, D . M . ; Cogswell, J. P.; McConnel l , R. T.; Carter, H . L . ; Powis, G ; Abraham, R. T.; Zalkow, L . H . ; Med. Chem. 2001, 44, 834. 10) Takahashi, M . ; Dodo, K . ; Sugimoto, Y . ; Aoyagi, Y . ; Yamada, Y . ; Hashimoto, Y . ; Shirai, R. Bioorg. Med. Chem. Lett. 2000,10, 2571. 11) Magnuson, S. R.; Sepp-Lorenzino, L . ; Rosen, N ; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1615. 12) Blanchard, J. L . ; Epstein, D . M . ; Boisclair, M . D . ; Rudolph, J.; Pal, K . Bioorg. Med. Chem. Lett. 1999, 9, 2537. 13) Takahashi, M . ; Dodo, K . ; Hashimoto, Y . ; Shirai, R. Tetrahedron Lett. 2000, 41, 2111. 313 14) Miyaoka, H . ; Kajiwara, Y . ; Hara, Y . ; Yamada, Y . J. Org. Chem. 2 0 0 1 , 66, 1429. 15) Jung, M . E . ; Nishimura, N . Org. Lett. 2 0 0 1 , 3, 2113. 16) Boukouvalas, J.; Cheng, Y . - X . ; Robichaud, J.; J. Org. Chem. 1998 , 63, 228. 17) Forsyth, C. J.; Demeke, D . Org. Lett. 2 0 0 0 , 2, 3177. 18) Piers, E . ; Caille, S.; Chen, G . Org. Lett. 2 0 0 0 , 2, 2483. 19) Paczkowshi, R.; Maichle-Mossmer, C ; Maier, M . E . Org. Lett. 2 0 0 0 , 2, 3967. 20) Rouhi, A . M . Chemical & Engineering News, Apr i l 6 t h 1998 , 76 (number 14), 42. 21) Hagiwara, H . ; Uda, H . J. Org. Chem. 1988 , 53, 2308. 22) Smith, M . B . ; March. J. "March's Advanced Organic Chemistry", 5 t h ed. John Wiley & Sons, New York, 2 0 0 1 , 1393. 23) Prakash, C ; Saleh, S.; Blair, I. A . Tetrahedron Lett. 1 9 8 9 , 30, 19. 24) Gassman, P. G . ; Singleton, D. A . ; Wilwerding, J. J.; Chavan, S. P. J. Am. Chem. Soc. 1 9 8 7 , 109, 2182. 25) Gassman, P. G . ; Chavan, S. P. J. Org. Chem. 1988 , 53, 2392. 26) Sammakia, T.; Berliner, M . A . J. Org. Chem. 1994 , 59, 6890. 27) Gassman, P. G . ; Chavan, S. P. Tetrahedron Lett. 1988 , 29, 3407. 28) For a review on the Claisen rearrangement, see Blechert, S. Synthesis, 1 9 8 9 , 71. 29) Piers, E . ; Friesen, R. W. Can. J. Chem. 1992 , 70, 1204. 30) Brown, H . C ; Krishnamurthy, S. J. Am. Chem. Soc. 1972 , 94, 7159. 31) Magnus, P.; Evans, A . ; Lacour, J. Tetrahedron Lett. 1992 , 33, 2933. 32) Nicolaou, K . C ; Zhong, Y . - L . ; Baran, P. S. J. Am. Chem. Soc. 2 0 0 0 , 122, 7596. 33) Boeckman, R. K . Jr; Silver, S. M . Tetrahedron Lett. 1973,14, 3497 and references therein. 314 34) House, H . O.; Thompson, H . W. J. Org. Chem. 1963, 28, 360. 35) Allinger, N . L . ; Riew, C. K . Tetrahedron Lett. 1966, 7, 1269. 36) Pirrung, M . C. J. Am. Chem. Soc. 1981,103, 82. 37) Piers, E . ; Marais, P. C. J. Org. Chem. 1990, 55, 3454. 38) Bailey, W. R.; Punzalan, E . R. J. Org. Chem. 1990, 55, 5404. 39) Bergdahl, M . ; Lindstedt, E . - L . ; Nilsson, M ; Olsson, T. Tetrahedron 1989, 45, 535. 40) Veysoglu, T.; Mitscher, L . A . ; Swayze, J. K . Synthesis 1980, 807. 41) Claisen, L . ; Ber. Dtsch. Chem. Ges. 1912, 45, 3157. For a review on the Claisen rearrangement, see Blechert, S. Synthesis, 1989, 71. 42) Lansbury, P. T.; MacLeay, R. E . J. Org. Chem. 1963, 28, 1940. 43) Luche, J .-L. J. Am. Chem. Soc. 1978, 100, 2226. 44) Amann, A . ; Ourisson, G. ; Luu, B . Synthesis, 1987, 1002. 45) Hughes, D . L . Org. React. 1992, 42, 635. 46) Johnson, W. S.; Werthemann, L . ; Bartlett, W. R.; Brocksom, T. J.; L i , T.; Faulkner, D . J.; Peterson, M . R. J. Am. Chem. Soc. 1970, 92, 741. 47) Wick, A . E . ; Felix, D . ; Steen, K . ; Eschenmoser, A . Helv. Chim. Acta 1964, 47, 2425. 48) Wipf, P.; K i m , Y . ; Goldstein, D . M . J. Am. Chem. Soc. 1995, 117, 11106. 49) Brown, H . C ; K i m , S. C ; Krishnamurthy, S. J. J. Org. Chem. 1980, 45, 1. 50) Dess, D . B . ; Martin, J. C. J. Org. Chem. 1983, 48, 4155. 51) Araki , S.; Ito, H . ; Butsugan, Y . J. Org. Chem. 1988, 53, 1831. 52) This study was carried out by Dr. Brian Patrick, Manager, U B C X-ray Crystal Structure Laboratory. The X-ray crystallographic report is provided in Appendix 2. 53) Barton, D . H . R.; McCombie, S. W. J. Chem. Soc, Perkin Trans. 1 1975, 1574. 315 54) McCombie, S. W. In Comprehensive Organic Synthesis; Trost, B . M . ; Fleming, I. Eds.; 1 s t ed. Pergamon Press, Oxford, 1991, vol. 8, section 4.2.2.4, 818. 55) Barton, D . H . R.; Crich, D . ; Lobberding, A . ; Zard, S. Z . J. Chem. Soc, Chem. Commun. 1985, 646. 56) Smith, M . B . ; March. J. "March's Advanced Organic Chemistry", 5 t h ed. John Wiley & Sons, New York, 2001, 241. 57) Derguini-Boumechal, F.; Lome, R.; Linstrumelle, G. Tetrahedron Lett. 1977, 18, 1181. 58) Benkeser, R. A . Synthesis 1971, 347. 59) Kleijn, H . ; Westmijze, H . ; Vermeer, P. Tetrahedron Lett. 1978,19, 1133. 60) Oikawa, Y . ; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885. 61) Whitesell, J. K . ; Reynolds, D . J. Org. Chem. 1983, 48, 3548. 62) Steel, P. G. ; M i l l s , O. S.; Parmee, E . R.; Thomas, E . J. J. Chem. Soc, Perkin Trans. 1 1997, 391. 63) Tang, C ; Rapoport, H . J. Am. Chem. Soc 1972, 94, 8615. 64) Dale, J. A ; Dul l , D . L . ; Mosher, H . S. J. Org. Chem. 1969, 34, 2543. 65) Similar ' H nmr studies were effected with 2-methoxy-2-phenyl-2-trifluoromethylacetate esters to determine the enantiomeric purity of a secondary alcohol substrate by Grubbs and coworkers: Moore, J. S.; Gorman, C. B . ; Grubbs, R. H . J. Am. Chem. Soc. 1991, 113, 1704. The absence of the 3-proton singlet resonance corresponding to the methoxy group of one of the diastereomeric esters prepared from their racemic alcohol substrate into the  l H nmr spectrum of the 2-methoxy-2-phenyl-2-trifluoromethylacetate ester prepared from their optically active 316 alcohol starting material made Grubbs and coworkers conclude that this optically active alcohol substrate was present in >95% enantiomeric excess. 66) Even though 28 existed as a diastereomeric mixture, each diastereomer of the mixture was an enantiomerically pure material. 67) Magnus, P.; Roy, G. Organometallics 1982, 1, 553. 68) Ellison, R. A . ; Lukenbach, E . R.; Chiu, C. Tetrahedron Lett. 1975, 16, 499. 69) Even though 106 existed as a diastereomeric mixture, each diastereomer of the mixture was an enantiomerically pure material. 70) Sampath Kumar, H . M . ; Subba Reddy, B . V . ; Tirupathy Reddy, P.; Yadav, J. S. Synthesis 1999, 586. 71) Pfeffer, P. E . ; Silbert, L . S. J. Org. Chem. 1970, 35, 262 (carboxylic acids); Cregge, R. J.; Herrman, J. L . ; Lee, C. S.; Richman, J. E . ; Schlessinger, R. H . Tetrahedron Lett. 1973,14, 2425 (esters); Piers, E . ; Breau, M . L . ; Han, Y . ; Plourde, G. L . ; Yeh, W . - L . J. Chem. Soc., Perkin Trans. 1 1995, 963 (nitriles). 72) Carey, F. A . ; Sundberg, R. J. "Advanced Organic Chemistry, Part A : Structure and Mechanisms", 3 t h ed. Plenum Press, New York, 1990, 211. 73) The computer program used was Chem3D Pro by CambridgeSoft Corporation. 74) Raucher, S.; Koolpe, G. A . J. Org. Chem. 1978, 43, 3794. 75) Winterfeldt, E . Synthesis 1975, 617. 76) Barton, D . H . R ; Motherwell, W. B . ; Stange, A . Synthesis 1981, 743. 77) Barton, D . H . R.; Blundell, P.; Dorchak, J.; Jang, D . O.; Jaszberenyi, J. S. Tetrahedron 1991, 46, 8969. 78) Huffman, J. W. ; Raveendranath, P. C. J. Org. Chem. 1986, 57, 2148. 317 79) Kernan, M . R.; Faulkner, D . J. J. Org. Chem. 1988, 53, 2773. 80) Foote, C. S.; Wexler, S. J. Am. Chem. Soc. 1964, 86, 3880. 81) Corey, E . J.; Bakshi, R. K . ; Shibata, S. J. Am. Chem. Soc. 1987,109, 5551. 82) This study was carried out by Dr. Brian Patrick, Manager, U B C X-ray Crystal Structure Laboratory. The X-ray crystallographic report is provided in Appendix 2. 83) The enantiomer of 34 presented in equation 45 was the enantiomer required for the synthesis of 15-epidysidiolide (26). 84) Enders, D . In Asymmetric Synthesis; Morrison, J. D . Ed. ; Academic Press, New York, 1984, 3, 275 85) Collum, D . B . ; Kahne, D . ; Gut, S. A ; DePue, R. T.; Mohamadi, F . ; Wanat, R. A ; Clardy, J. C ; Van Duyne, G. J. Am. Chem. Soc. 1984,106, 4865. 86) Wanat, R. A . ; Collum, D . B . J. Am. Chem. Soc. 1985,107, 2078. 87) Enders, D . ; Wortmann, L . ; Peters, R. Acc. Chem. Res. 2000, 33, 157. 88) L i o , H . ; Monden, M . ; Okada, K ; Tokoroyama, T. J. Chem. Soc, Chem. Commun. 1987, 358. 89) (S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine was synthesized on large scale (120 g) through the following procedure: Enders, D. ; Fey, P.; Kipphardt, H . Organic Syntheses 1987, 65, 173. 90) Ziegler, F. E . ; Becker, M . R. J. Org. Chem. 1990, 55, 2800. 91) This study was carried out by Dr. Brian Patrick, Manager, U B C X-ray Crystal Structure Laboratory. The X-ray crystallographic report is provided in Appendix 2. 92) The numbering system used in Figure 6 for (+)-167 is different than the one employed in the Experimental section of the thesis. 318 93) ' H nmr studies were effected with mandelate esters to determine the enantiomeric purity o f secondary alcohol substrates: Whitesell, J. K . ; Reynolds, D . J. Org. Chem. 1983, 48, 3548. 94) B y analogy with the report by Grubbs and coworkers mentioned in Reference 65 (Moore, J. S.; Gorman, C. B . ; Grubbs, R. H . J. Am. Chem. Soc. 1991,113, 1704), alcohol (+)-35 was determined to be present in >95% enantiomeric excess. 95) BU3S11H and A I B N were used in the conversion of (-)-176 to (-)-177 instead of Ph2SiH-2 and benzoyl peroxide (as in the synthesis of (-)-l) because it simplified the purification of the primary alcohol (-)-177. 96) Dale, J. A . ; Mosher, H . S. J. Am. Chem. Soc. 1973, 95, 512. 97) Ohtani, I.; Kusumi, T.; Kashman, Y . ; Kakisawa, H . J. Am. Chem. Soc. 1991,113, 4092. 98) The details of these assays are not presented here but wi l l be reported in due course. 99) Dr. Roberge and his coworkers wi l l effect these inhibition studies. 100) Still, W. C ; Kahn, M . ; Mitra, A . J. Org. Chem. 1978, 43, 2923. 101) Bryan, W. P.; Byrne, R. H . J. Chem. Ed. 1970, 47, 361. 102) Perrin, D . D . ; Armarego, W. L . ; Perrin, D . R. "Purification o f Laboratory Chemicals", 3 r d ed. Pergamon Press, Oxford, 1988. 103) Burchat, A . F. ; Chong, M . I ; Nielsen, N . J. Organomet. Chem. 1997, 542, 281. 104) I B X was synthesized as described in the following report: Frigerio, M . ; Santagostino, M . ; Sputore, S. J. Org. Chem. 1999, 64, 4537. 105) This procedure was conducted on a larger scale than that reported here. 319 106) The procedures leading to the isolation of substances (+)-101, (+)-102, (-)-29, (+)-29, 103 and 104, as well as those described in section 5.3 (synthesis o f 6-epidysidiolide (25)) were effected in the laboratory by Dr. Gang Chen. 7. A P P E N D I X E S 321 322 323 324 7. 2. X - r a y crystallographic data X-ray data for secondary alcohol 8 5 : Formula: C 2 6 H 3 8 O 3 Crystal color, Habit: clear, platelet Crystal system: orthorhombic Lattice type: primitive Lattice parameters: a= 7.6675(3) A b = 13.5690(8) A c = 21.604(2) A V = 2247.6(2) A3 Space group: P2,2i2i (#19) Z value: 4 Number of reflections used in refinement: 3681 Residuals: R = 0.031 R w = 0.037 X-ray data for benzoate ( - ) -147 : Formula: C 3 2 H 4 1 N O 5 Crystal color, Habit: clear, block Crystal system: monoclinic Lattice type: primitive Lattice parameters: a = 10.2261(4) A b = 9.4757(4) A c = 14.8572(8) A V = 1429.1(1) A 3 Space group: P2, (#4) Z value: 2 Number of reflections used in refinement: 4417 Residuals: R = 0.035 R w = 0.042 X-ray data for mandelate ester (+)-167: Formula: C20H28O5 Crystal color, Habit: clear, platelet Crystal system: orthorhombic Lattice type: primitive Lattice parameters: a = 6.0289(3) A b = 14.0122(6) A c = 23.118(2) A V = 1952.9(2) A3 Space group: P2 i2 x 2 i (#19) Z value: 4 Number of reflections used in refinement: 2458 Residuals: R = 0.027 R w = 0.032 

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