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Total synthesis of (+)-8-isocyano-10-cycloamphilectene Schindeler, Todd W. 1998

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T O T A L SYNTHESIS OF (+)-8-ISOCYANO-10-CYCLOAMPHILECTENE by TODD W. SCHTNDELER B . Sc., The University of British Columbia, 1990  A THESIS S U B M I T T E D I N P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FORTHE D E G R E E OF D O C T O R OF PHILOSOPHY in T H E F A C U L T Y OF G R A D U A T E STUDIES D E P A R T M E N T OF C H E M I S T R Y  We accept this thesis as conforming to the required standard.  T H E U N I V E R S I T Y OF BRITISH C O L U M B I A January 1998 © Todd W . Schindeler  In  presenting  degree freely  this  at the  thesis  in  partial  University  of  British Columbia, I agree  available for reference  copying  of  department  this or  publication of  thesis for by  his  or  of  and study. I further  the  her  representatives.  The University of British Columbia Vancouver, Canada  that the  be  It  this thesis for financial gain shall not  Department  requirements  agree  scholarly purposes may  permission.  DE-6 (2/88)  fulfilment  is  for  an  Library shall make  that permission for granted  by the  understood  be  advanced  allowed  extensive  head  that  without  it  of  copying  my or  my written  11  Abstract  A 36-step synthesis o f the tetracyclic diterpene (+)-8-isocyano-10-cycloamphilectene (11) from (i?)-pulegone (40) is described. A n efficient four-step process gave 38 from 40 with complete  regioselectivity  in  the  introduction  of  the  carbon-carbon  double  bond.  Methoxycarbonylation and reduction were followed by stereocontrolled alkylation and produced 16.  Treatment o f the enol trifluoromethanesulfonate  derived from 16 under conditions  (Pd(PPh )4, L i C l , T H F , reflux) appropriate for an intramolecular Stille-type coupling gave the 3  bicyclic compound 18.  A highly face- and regioselective D i e l s — A l d e r cycloaddition process  gave the tricyclic compound 54.  The bromine atom in 54 was reductively removed in a  samarium(II) induced protiodebromination process, and three further synthetic steps gave compound 21. A t this point, the configurations at four o f the seven stereocentres had been set and attention was turned towards the introduction o f the fourth required carbocyclic ring. A l l y l i c oxidation, reduction o f the carbon-carbon double bond by catalytic hydrogenation and a two-step methoxycarbonylation process gave the intermediate 65 which was transformed into 32 by an efficient  five-step  synthetic  sequence in which the  introduction o f C-7 o f the  cycloamphilectane skeleton was an important step. A n aldol condensation reaction followed by a chemoselective reduction gave compound 30 which was  subjected  to an alkylation,  epimerization, alkylation sequence wherein the ge/w-dimethyl function was installed yielding the ketone 81. A t this point, the complete carbon skeleton with the correct configuration at each stereogenic centre for the natural product was in hand. Deoxygenation and degradation o f the ester function to an isocyanide group completed the synthesis o f 11.  iv  TABLE OF CONTENTS Abstract  ii  Table of Contents  iv  List of Tables  viii  List of Figures  ix  List of Abbreviations and Acronyms  x  Acknowledgements Introduction  xii 1  General Introduction  1  Background  4  Objective and Goals  Discussion  11  14  Isolation and Characterization of (-)-8-Isocyano-10-cycloamphilectene (11)  14  Retrosynthetic Analysis  15  Introduction of Enantiomeric Excess  18  Preparation of the P-Keto Ester 35  23  Preparation of the Iodide 15  35  Preparation of the Tricyclic Diester 55  38  Preparation of the Ester 21  55  Preparation of the a,B-Unsaturated Ester 65  60  Preparation of the Keto Aldehyde 32  72  Preparation of the Ketone 81  81  Preparation of (+)-8-Isocyano-10-cycloamphilectene (11)  90  Conclusions Experimental Section General  103 105 105  Data Acquisition and Presentation  105  Solvents and Reagents  108  Procedures Preparation of Methyl 6-Chloro-2-hexynoate (49)  110 110  Preparation of Methyl (£)-6-Chloro-3-(trimethylstannyl)-2-hexenoate (50) Preparation of (£)-6-Chloro-3-(trimethylstannyl)-2-hexen-l-ol (52) Preparation of (E)-6-Chloro-1 -[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-3-(trimethylstannyl)-2-hexene (53) Preparation of ( £ ) - 1 -[[(1,1 -Dimethylethyl)dimethylsilyl]oxy]-6-iodo-3-(trimethylstannyl)-2-hexene (15) Preparation of {(li?,4/?)-4,8-Epoxy-3-oxo-p-menthane and (li?,4o")-4,8-Epoxy-3oxo-/?-menthane} (41) Preparation of {(2i?,5i?)-5-Methyl-2-(phenylthio)cyclohexanone and (2S,5R)-5Methyl-2-(phenylthio)cyclohexanone} (39) Preparation of {(2i?,5i?)-5-Methyl-2-(phenylsulfinyl)cyclohexanone and (2S,5R)-5Methyl-2-(phenylsulfinyl)cyclohexanone} (42) Preparation of (5i?)-(-)-5-Methyl-2-cyclohexenone (38) Preparation of Methyl (5i?)-5-Methyl-2-cyclohexenone-6-carboxylate (44) Preparation of Methyl (3i?)-3-Methylcyclohexanone-2-carboxylate (35) Preparation of Methyl (2R, 3i?)-2-[( &)-6-[[(l,l-Dimethylethyl)dimethylsilyl]oxy]-4(trimethylstannyl)-4-hexenyl]-3-methylcyclohexanone-2-carboxylate (16) J  Purification of Commercial A^-Phenyltrifluoromethanesulfonimide Preparation of Methyl (3R, 4i?)-3-[(^)-6-[[(l,l-Dimethylethyl)dimethylsilyl]oxy]-4(trimethylstannyl)-4-hexenyl]-4-methyl-2-[(trifluoromethanesulfonyl)oxy]cyclohexene-3-carboxylate (17) Preparation of Tetrakis(triphenylphosphine)palladium(0) Preparation of the Methyl (4aa,5a)-(+)-l,2,3,4,4a,5,6,7-Octahydro-l-[( E)-2-[[(l,ldimethylethyl)dimethylsilyl]oxy]ethylidene]-5-methyl-4a-naphthalenecarboxylate (18) J  Preparation of Methyl 2-Bromoacrylate Preparation of {Dimethyl (la,3p,6aa,7a,9aa)-2,3,4,5,6,6a,7,8,9,9a-Decahydro-lbromo-3-[[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]-7-methyl-1,6a[\H\phenalene-dicarboxylate Dimethyl (lB,3(3,6aa,7a,9aa)-2,3,4,5,6,6a,7,8,9,9a-Decahydro-l-bromo-3-[[[(l,ldimethylethyl)dimethylsilyl]oxy]methyl]-7-methyl-l,6a[l//]-phenalenedicarboxylate} (54) Preparation of Samarium Diiodide Preparation of {Dimethyl (la,3a,3aB,6p,6a6)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-6-methyl-3,6a[ l//]-phenalenedicarboxylate and Dimethyl (la,3p,3aB,6p,6aB)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-  vi  l-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-6-m phenalenedicarboxylate} (55) Preparation o f M e t h y l  134  (la,3p,3ap,6|3,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-  [[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-3-(hydroxymethyl)-6-methyl-6a[ltfj-phenalenecarboxylate (56) and M e t h y l ( l a , 3 a , 3 a p , 6 p , 6 a P ) - ( - ) - 2 , 3 , 3 a , 4 , 5 , 6 , 6 a , 7 , 8 , 9 - D e c a h y d r o - 1 -[[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]-3 (hydroxymethyl)-6-methyl-6a[l//]-phenalenecarboxylate (57); R e d u c t i o n o f the Diesters 55 Preparation o f M e t h y l  137 (la,3p,3ap,6p,6aP)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-  dimethylethyl)dimethylsilyl]oxy]methyl]-3 -formyl-6-methyl-6a[ l / / ] - p h e n a l e n e carboxylate (20) and M e t h y l  (la,3a,3ap,6p,6ap)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-  1"[[[(1 > • 1 -dimethylethyl)dimethylsilyl]oxy]methyl]-3 -formyl-6-methyl-6a[ 1H]phenalenecarboxylate (58); O x i d a t i o n o f the A l c o h o l 57  139  Preparation o f the A l d e h y d e s 20 and 58, E p i m e r i z a t i o n o f the A l d e h y d e 58  141  Preparation o f the A l c o h o l 56; R e d u c t i o n o f the A l d e h y d e 20  142  Preparation o f M e t h y l  (la,3P,3ap,6p,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-  [[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]-6-methyl-3-[[[(p-methylphenyl)sulfonyl]oxy]methyl]-6a[l/7]-phenalenecarboxylate Preparation o f M e t h y l  (59)  144  (la,3p,3ap,6p,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-  [[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-6a[l//]-phenalenecarboxylate (21) Preparation o f M e t h y l  146 (la,3p,3ap,6p,6aP)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-  [[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-9-oxo-6a[l//]phenalenecarboxylate (22)  148  Preparation o f M e t h y l ( l a , 3 p , 3 a p , 6 p , 6 a p , 9 a p , 9 b a ) - ( - ) - P e r h y d r o - l - [ [ [ ( l , l - d i m e t h y l ethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-9-oxo-6a[li/]-phenalenecarboxylate (23) Preparation o f M e t h y l  150 (la,3p,3ap,6p,6ap,9ap,9ba)-(-)-2,3,3a,4,5,6,6a,7,9a,9b-  D e c a h y d r o - 1 -[[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-9[[(trifluoromethyl)sulfonyl]oxy]-6a[l//]-phenalenecarboxylate Preparation o f D i m e t h y l  (64)  152  (la,3p,3ap,6p,6ap,9ap,9ba)-(-)-2,3,3a,4,5,6,6a,7,9a,9b-  Decahydro-l-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-6a,9[ l//]-phenalenedicarboxylate (65)  154  Preparation o f D i m e t h y l (la,3P,3aP,6P,6ap,9ap,9ba)-2,3,3a,4,5,6,6a,7,9a,9bD e c a h y d r o - l - ( h y d r o x y m e t h y l ) - 3 , 6 - d i m e t h y l - 6 a , 9 [ l / / ] - p h e n a l e n e d i c a r b o x y l a t e (66) Preparation o f D i m e t h y l  156  (la,3P,3ap,6p,6ap,9ap,9ba)-2,3,3a,4,5,6,6a,7,9a,9b-  D e c a h y d r o - 1 - f o r m y l - 3 , 6 - d i m e t h y l - 6 a , 9 [ l / / ] - p h e n a l e n e d i c a r b o x y l a t e (68)  157  Preparation o f M e t h y l ( l a , 3 P , 3 a p , 6 p , 6 a p , 9 a p , 9 b a ) - ( - ) - 2 , 3 , 3 a , 4 , 5 , 6 , 6 a , 7 , 9 a , 9 b D e c a h y d r o - l - a c e t y l - 9 - f o r m y l - 3 , 6 - d i m e t h y l - 6 a [ l / / ] - p h e n a l e n e c a r b o x y l a t e (32)  159  vii  Preparation o f Methyl (la,3aa,4a,5ap,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,10,1 Oa, 1 Ob, 1 Oc-Dodecahydro-1,4-dimethyl-6-oxo-1 Oa-pyrenecarboxylate (76) Preparation o f Methyl ( l a , 3 act, 4 a , 5 act, 10aa,10bp, 10ca)-(-)-1,2,3,3a,4,5,5a, 6,7,8,10,1 Oa, 1 Ob, 1 Oc-Tetradecahydro-1,4-dimethyl-6-oxo-1 Oa-pyrenecarboxylate (30)  163 165  Preparation o f Methyl (la,3aa,4a,5aP,7p,10aa,10bp,10ca)-l,2,3,3a,4,5,5a,6,7,8,10,10a, 10b, 1 Oc-Tetradecahydro-1,4,7-trimethyl-6-oxo-l Oa-pyrenecarboxylate (79) and Methyl (la,3aa,4a,5ap,7a,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,7,8,10,1 Oa, 1 Ob, 1 Oc-Tetradecahydro-1,4,7-trimethyl-6-oxo-1 Oa-pyrenecarboxylate (80); Alkylation o f the Ketone 30  168  Preparation o f the C-7p Ketone 80; Epimerization o f the C - 7 a Ketone 79  170  Preparation of Methyl (la,3aa,4a,5ap,10aa,10bp,10ca)-(+)-l,2,3,3a,4,5,5a,6,7,8,10,1 Oa, 1 Ob, 1 Oc-Tetradecahydro-1,4,7,7-tetramethyl-6-oxo-1 Oapyrenecarboxylate (81)  172  Preparation of Methyl (la,3aa,4a,5ap,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,7,8,10,1 Oa, 1 Ob, 1 Oc-Tetradecahydro-1,4,7,7-tetramethyl-1 Oa-pyrenecarboxylate (29)  174  Preparation o f (3p,3ap,8aa,10p,10aP,10ba,10cp)-(-)-l,2,3,3a,4,6,7,8,8a,9,10,10a,10b, 10c-Tetradecahydro-3a-carboxy-3,7,7,10-tetramethylpyrene  (85)  180  Preparation o f Diphenylphosphoryl Azide  182  Preparation o f Acetic Formic Anhydride  183  Preparation o f (3p,3ap,8aP,10p,10aP,10ba,10cp)-(+)-l,2,3,3a,4,6,7,8,8a,9,10,10a,10b, 10c-Tetradecahydro-3a-isocyano-3,7,7,10-tetramethylpyrene (11) ((+)-8isocyano-10-cycloamphilectene)  184  References and Notes Appendix  189 197  viii  List of Tables page Table I: Comparison of C nmr Data for the Natural 8-Isocyano-10cycloamphilectene ((-)-ll) and the Synthetic 8-Isocyano-10cycloamphilectene ((+)-! 1) 1 3  102  ix  L i s t of Figures page Figure 1: Possible Arrangements of Isoprene Units Leading to the Cycloamphilectane Carbon Skeleton  6  Figure 2: Equilibrium o f the Epimers o f a P-Keto Ester Through Its Enol Form  20  Figure 3: Conjugate Addition to a,P-Unsaturated Carbonyl Compounds  21  Figure 4: The Equilibrium Between the 2 Lowest Energy Conformations of the Potassium Enolate Anion of the P-Keto Ester 35 Figure 5: Endo Approach of the Dienophile from the Face Bearing the  43  Angular Ester  48  Figure 6: Conformational Diagram of the Enolate A n i o n Intermediate  53  Figure 7: Conformational Diagram o f 22  63  Figure 8: 400 M H z * H nmr Spectrum of the Diene 18 Recorded in C D C 1  198  3  Figure 9: 400 M H z *H nmr Spectrum of the Ketone 23 Recorded in C D C 1  199  3  Figure 10: 400 M H z *H nmr Spectrum of the Enol Trifluoromethanesulfonate 64 Recorded in C D C 1  200  3  Figure 11: 400 M H z H nmr Spectrum of the Keto Aldehyde 32 Recorded X  in C D C I 3  201  Figure 12: 400 M H z *H nmr Spectrum of the Dienone 76 Recorded in C D C 1  3  Figure 13: 400 M H z *H nmr Spectrum o f (+)-8-Isocyano-10-cycloamphilectene (11) Recorded in C D C 1 3  202  203  List of Abbreviations and Acronyms  Ac  acetyl ( C H C O - )  DMSO  dimethyl sulfoxide  AIBN  2,2'-azobisisobutyronitrile  equiv  equivalent(s)  Anal.  elemental analysis  et al.  (Latin) A n d others.  aq  aqueous  eV  electron volt  bp  boiling point  EI  electron ionization  br  broad  Et  ethyl ( C H - )  Bu  butyl (C4H9-)  ga  gauge  c  concentration in g per 100 m L  glc  gas—liquid chromatography  h  hour(s)  H-x  hydrogen on carbon number x  cat.  3  2  5  catalytic  C-x  carbon number x  calcd  calculated  HMPA  hexamethylphosphor amide  m-CPBA  7w-chloroperoxybenzoic acid  hplc  high performance liquid chromatography  firms  high resolution mass spectrum (Latin) In its original position.  5  chemical shift  d  doublet  DCI  desorption chemical ionization  in situ.  DD3AL-H  diisobutylaluminum hydride  L-Selectride® lithium triethylborohydride  DMAP  A^A^-dimethylaminopyridine  lrms  low resolution mass spectrum  DMP  3,5 -dimethylpyrazole  LDA  lithium diisopropylamide  m  multiplet  it  ambient temperature  m  meta  s  singlet  Me  methyl ( C H - )  sec  secondary (as an alkane)  min  minute(s)  t  triplet  MOM  methoxymethyl (CH OCH -) melting point  TBAF  tetra-«-butylammonium fluoride  TBS  ferf-butyldimethylsilyl  tert  tertiary (as an alkane)  Tf  trifluoromethanesulfonyl (CF S0 -)  3  3  mp n  NMO  2  normal (as an alkane) TV-methylmorpholine TV-oxide  3  [0]  oxidation  P  pseudo  PCC  pyridinium chlorochromate  Ph  phenyl ( C H - )  ppm  part per million  Pr  6  5  2  THF  tetrahydrofuran  tic  thin layer chromatography  TMS  tetramethylsilane  TPAP  tetra-w-propylariimonium perruthenate  Ts  tosyl (p-CH C4H4S0 -)  uv  ultraviolet  xs.  excess  3  propyl ( C H - ) 3  7  psi  pounds per square inch  q  quartet  2  Xll  Acknowledgements  I would like to take this opportunity to express my gratitude to my professor D r . Edward Piers. I have admired his dedication to science, his ongoing commitment to his students' success and his willingness to share his wisdom; I consider myself fortunate to have worked under his direction. The generous gift o f an authentic sample o f the naturally occurring (-)-8-isocyano10-cycloamphilectene ((-)-ll) and accompanying spectra from Professor T. H i g a o f the Department o f Marine Sciences, University o f the Ryukyus, Nishihara, Okinawa, Japan is gratefully acknowledged. The equipment used to develop the hydrogenation chemistry employed in the stereoselective reduction o f the a , P-unsaturated ketone 22 was lent by D r . Brian Cliff o f the U B C Chemistry department. W e greatly appreciate the loan o f this equipment. I am personally indebted to the members o f the Piers research group with whom I have had the pleasure o f working.  Their friendship, thoughtful discussions and kind  advice have enriched my time at U B C , and were instrumental in the successful conclusion of my research. Finally, financial support in the form of Research and Teaching Assistantships from the University of British Columbia is gratefully acknowledged.  1  Introduction  General Introduction The synthesis o f organic molecules o f all levels o f complexity involves the conversion o f available substances o f known structure, through a sequence o f particular, controlled chemical reactions, into other substances bearing a desired molecular structure.  Through the process o f  rational synthetic design, organic chemists can create molecules designed to test structural theory or a theoretical hypothesis, or to be tested for medicinal value or for commercial use. The tools o f the synthetic organic chemist are the chemical transformations that are at one's disposal. Broadly speaking, these chemical transformations can be classified as either those in which a new carbon-carbon bond is formed or those in which functional groups are changed or interconverted. Over the years, a vast array o f chemical reactions have been developed to carry out these transformations in the laboratory. These reactions vary in nature from those involving simple organic reactants to more complicated clusters o f ligands around transition metals. Some reactions may be carried out under standard conditions whereas others require conditions that rigorously exclude atmospheric oxygen, moisture or both. It has long been the practice o f synthetic organic chemists to use the tools o f organic chemistry to attempt the synthesis o f natural products. The synthesis o f substances occurring in nature provides a measure o f the conditions and powers o f science. The synthesis o f a natural product has traditionally served as an independent proof o f its proposed structure.  Now,  synthesis often serves as an artificial source o f the material i f the isolation o f the material from the natural source is not viable. Furthermore, it is through synthetic chemistry that analogues o f natural products can be prepared.  It is through studies o f these compounds that the key  2 structural features responsible for the biological reactivity o f natural products, such as analgesics and insect antifeedants, can and have been elucidated. Finally, natural product synthesis provides the student o f organic chemistry with a wide range o f experience in the laboratory with various chemical reaction conditions as well as practical techniques, and as such, it serves as excellent training. Synthetic organic chemistry also plays a key role in the development o f medicinal substances such as anticancer and antibiotic and antiviral antiinfective agents. It is often stated by organic chemists that synthetic organic chemistry drives the pharmaceutical industry. Indeed a primary source o f employment for chemists trained in the field o f organic synthesis is with the major drug houses.  These companies often have extensive and well funded research programs  that have led to many interesting and useful discoveries.  But to what extent does synthetic  organic chemistry actually play a role in the design and development o f medicinal substances?  A  recent article published in the Journal o f Natural Products serves to illustrate this role very well. 1  In their article, the authors conducted a survey o f anticancer and antiinfective agents approved for use by either the United States Food and Drug Administration or comparable agencies in other countries during the period o f 1983 to 1994.  Their data shows that nearly 90% o f the 2  substances considered could be traced in origin or in their development to synthetic organic chemistry. M o r e specifically, the authors found that new approved drugs, for the period of 1983 to 1994, that are classified as analgesics, antidepressants,  antihistamines,  antihypertensives,  anxiolytics, cardiotonics, hypnotic drugs and antifungal agents were all exclusively synthetic in origin. origin.  In addition, over two thirds o f the new antiinflammatory substances were synthetic in  3  Compounds in the pre-New Drug Application phase up to the end o f 1995 were also included in the survey.  F o r these substances, the author's survey shows that more than half 2  could be traced in origin or in their development to synthetic organic chemistry. For the period o f 1959 to 1973, an article published in the American Journal o f 3  Pharmacology reveals, in a survey similar to that in the Journal o f Natural Products article, that approximately 60% o f all substances prescribed by physicians in the United States were of synthetic origin. So it can be seen that synthetic organic chemistry does indeed play a leadership role in the development o f medicinal substances.  Although natural products chemists, molecular biologists  and pharmacologists also play a key role in the discovery o f chemotherapeutics, analgesics,  antiallergics, antiinflamatories,  antivirals, immunosuppressants,  such as  anesthetics  and  coronary drugs to name only a few, it is synthetic organic chemists that see the majority o f these medicinal agents through their various levels o f development and finally to public availability. Synthetic organic chemistry also has had dramatic effects on other industrial areas. Developments in the fields o f insect antifeedants and selective pesticides have made agricultural operations more efficient and environmentally friendly.  Advances in polymer chemistry have  resulted from improvements in monomer synthesis and reaction catalysis.  Thermoplastic and  thermosetting polymers have resulted from research in organic chemistry. These polymers have afforded substances with such varied uses as synthetic fibers, films, pipes coatings, molded articles and so forth.  4  Background Previous work in our laboratories has been directed towards, among other things, the total synthesis o f racemic modifications o f the amphilectane diterpenoids 8,15-diisocyano-l 1(20)amphilectane ( l ) , whose levorotatory antipode has been isolated from the marine sponge 4  Hymemiacidon amphilecta, and 8-isocyano-10,14-amphilectadiene 5  ( 2 ) , whose levorotatory 6  antipode has been isolated from the Palauan sponge Halichondria sp. These compounds share 7  the amphilectane carbon skeleton 3 and contain the somewhat uncommon isocyanide moiety.  The largest group o f naturally occurring isocyanides discovered so far has come from marine organisms.  These compounds often display marked cytotoxic activity. '  5 8  naturally occurring isocyanides have been reported to date. 9  M o r e than 40  The isocyanides are often found  with the corresponding isothiocyanate, formamide and amine derivatives. '  8 10  A diterpene isocyanide from the structurally similar adocaine family, which share the carbon skeleton 4, (+)-7,20-diisocyanoadociane (5) was isolated from a sponge o f the genus  5  Amphimedon,  11  and has been synthesized by Corey and Magriotis, thus allowing assignment o f 12  its absolute configuration.  A group o f diterpene isocyanides and formamides, bearing the carbon skeleton 6, have been isolated from a marine sponge Adocia Halichondra  1  sp.,  5  from a Palauan sponge o f the genus  and from the dorsal mantle o f nudibranchs that feed upon Halichondrid sponges. '  7 13  These compounds have been named the cycloamphilectanes and include such compounds as 7isocyano-l-cycloamphilectene cycloamphilectene (9), amphilectene (11).  (7), 7-isocyano-ll-cycloamphilectene  8-formamido-l(12)-cycloamphilectene  (10)  (8),  8-isocyano-l(12)-  and 8-isocyano-10-cyclo-  Mixtures containing the compounds 9, 10 and 11 displayed marked in vitro  antimicrobial activity, particularly against gram positive bacteria, but showed no in vivo activity 5  6  17  H  2  18  5  6 III  19  -c  6  11  other than marked toxicity.  5  Bergquist has proposed  14  that the presence o f isocyanides, as well  as the corresponding isothiocyanate, formamide and amine derivatives, in marine organisms may confer an advantage by helping to preserve the specificity o f association o f the sponge and its preferred microfloral symbionts. 8-Isocyano-10-cycloamphilectene ( 1 1 ) can be seen as a regular diterpene arising from a formal cyclization o f an isoprene derived 20 carbon precursor as shown in Figure l .  1 5  The  isoprene subunits are indicated by the heavy bonds. Their connectivity is shown as normal bonds and the theoretical cyclizations are shown with broken-line bonds.  A t least three different  foldings o f the C o precursor can lead to the required skeleton. 2  Figure 1 : Possible Arrangements of Isoprene Units Leading to the Cycloamphilectane Carbon Skeleton Although the syntheses o f ( ± ) - l and (±)-2 have been delineated elsewhere, '  4 6  a brief  summary o f the synthetic route to ( ± ) - l will be presented at this point, as a portion o f the  7  synthesis o f (+)-ll was based thereupon. ( ± ) - l was synthesized from cyclohexanone in 24 steps (see Scheme 1). Cyclohexanone was transformed into the P-keto ester 14 by a four step process. Methoxycarbonylation o f cyclohexanone by the method 12.  16  o f Ruest et al. gave the P-keto ester  Benzeneselenation, followed by oxidation—elimination o f the selenide gave 2-(methoxy-  carbonyl)-2-cyclohexenone (13).  2-(Methoxycarbonyl)-3-methylcyclohexanone (14) was pre-  pared by reaction o f the P-keto ester (13) with either lithium methyl(phenylthio)cuprate more recently with lithium methyl(cyano)cuprate. 4  17  or  18  The P-keto ester 14 was transformed into the diene 18 by an efficient two step process. Alkylation o f the potassium enolate anion o f the P-keto ester 14 in refluxing toluene with the iodide 15 proceeded regio- and stereo selectively and the ketone 16 was isolated in 70% yield. The conversion o f the ketone 16 into the diene 18 was accomplished by conversion o f the ketone 16 into the corresponding enol trifluoromethanesulfonate catalyzed intramolecular coupling process.  19  17, followed by a palladiums-  These latter two stages were carried out in a one-  pot process and proceeded in 86% overall yield. Diels—Alder reaction o f the diene 18 with acrolein proceeded regioselectively but, unfortunately, gave all four o f the possible diastereomeric adducts. Equilibration o f this mixture, with sodium methoxide—methanol, followed by chromatographic separation gave two isomeric aldehydes, 19 (minor) and 20 (major).  The ratio o f the two substances was approximately 3:7,  respectively. The synthesis was continued with the major component, aldehyde 20, whereas the minor product, aldehyde 19 was not synthetically useful. Conversion o f the formyl function in aldehyde 20 to a methyl group was accomplished efficiently by known methods, giving the ester 21 in 79% overall yield.  8  O  O (a)  O  O (we) ^  MeO  M  e  f  o  y  o  MeO"  (d)  12  >U  O  14  13  o  MesSn'  (e)  MeC^C  17 I  Me Sn  — Ck  /  /  3  1  15  separation  20  19 R = ct-H, R ' = B - C H O T B S , R " = a - C H O 2  20 R = p - H , R ' = a - C H O T B S , R " = p - C H O  (h) ,  2  X  (i) , (j)  /  Si  Scheme 1: (continued next page)  (±) 1  28  27  Scheme 1: Synthesis of (±) 1 Reagents (a) N a H , cat. K H , dimethylcarbonate, T H F ; (b) K H , T H F ; PhSeBr; (c) w - C P B A , T H F ; (d) M e C u ( C N ) L i , T H F ; (e) K H , toluene; 15 (f) L D A , T H F ; P h N T f ; Pd(PPh ) ; (g) acrolein, benzene; N a O M e , M e O H ; (h) D I B A L - H , 2  3  4  T H F ; (I) TsCl, D M A P , C H C 1 ; (j) Super-Hydride®, T H F ; (k) Cr0 —3,5-dimethylpyr2  2  3  azole, C H C 1 ; (1) N a , tert-BuOH,  N H ; (m) Z n , C H B r , T i C l , C H C 1 ; (n) « - B u N F ,  THF;  2  2  2  (o) ( C O C l ) , 2  Me SO, 2  3  2  CH C1 ; Et N; 2  3  2  4  2  2  4  (p) N a O M e , M e O H ;  (q)  [(MeO) 2  P O C ( M e ) C 0 M e ] K , 18-Crown-6, T H F ; separation; (r) PhSeNa, T H F , H M P A ; (s) L i , 2  N H ; (t) xs. L D A , T H F ; xs. M e l ; (u) diphenylphosphoryl 3  azide, toluene; M e S i 3  ( C H ) O H , E t N ; « - B u N F , T H F ; acetic formic anhydride, E t 0 ; (v) P P h , CC1 , E t N . 2  2  3  4  2  3  4  3  10  Treatment o f the ester 21 with chromium trioxide—3,5-dimethylpyrazole complex in methylene chloride served to introduce an oxygen function at C - l l (amphilectane numbering) and the a,B-unsaturated ketone 22 was isolated in 77% yield.  Stereoselective reduction o f the  C-12 to C-13 carbon-carbon double bond was accomplished by alkali metal—ammonia reduction. The best and most consistent results were obtained with the use o f an excess o f sodium metal as the reductant.  Thus, treatment o f the oc,B-unsaturated ketone 22 with 15 equiv o f  sodium and 2 equiv o f tert-butyl alcohol in ammonia—diethyl ether gave the ketone 23 with the correct stereochemistry at C-12 and C-13, (amphilectane numbering). Treatment o f the ketone 23 with the reagent provided the required alkene 24.  The correct  20  derived from zinc dust, C H B r and T i C l 2  stereochemistry  2  4  was established at C - l  (amphilectane numbering) by a deprotection, oxidation, epimerization sequence and gave the aldehyde 25. of  trimethyl  Subjection o f the aldehyde 25 to a Wittig-Horner reaction with the potassium salt 2-phosphonopropionate  gave  a  mixture  of  the  geometrically  isomeric  a,B-unsaturated esters 26, which were separated by column chromatography on silica gel. Treatment o f the (£)-isomer o f the a, B-unsaturated esters 26 with the highly nucleophilic reagent sodium benzeneselenide  in THF—hexamethylphosphoramide degraded  both ester  functions to their corresponding carboxylic acids and the carbon-carbon double bond on the C - l (amphilectane numbering) side chain was then reduced utilizing a dissolving metal reduction. In a subsequent step, alkylation o f the trianion derived from reaction o f the dicarboxylic acid with an excess o f L D A with methyl iodide gave the dicarboxylic acid 28, thus introducing the final required carbon atom for the amphilectane carbon skeleton.  11  To complete the total synthesis, the acid functions o f 28 were converted into isocyanide groups. This transformation was accomplished by an efficient three stage process that had been developed for this purpose in our laboratories. The details o f this process will be discussed later.  in " C  -  1 Thus, the synthetic efforts described above resulted in the first total synthesis o f (±)-8,15diisocyano-10(20)-amphilectene (1).  The key features o f the described total synthesis were the  reactions which formed the second and third rings, namely an intramolecular Stille type coupling and a Diels—Alder reaction, respectively.  The configurations at C - l and C-3 (amphilectane  numbering) were established under thermodynamic control whereas those o f C-4, C-l, C-8, C-12 and C - l 3 were established under conditions o f kinetic control.  Objective and Goals The overall objective o f the work described in this thesis was to complete a total synthesis of 8-isocyano-10-cycloamphilectene (11).  The facts that the diterpene isocyanide 11 possesses a  synthetically challenging structure (a tetracyclic compound with an array o f seven contiguous stereogenic centres), and that it is an antimicrobial compound made it a tempting target for total  12  synthesis. In the course o f the planning o f the synthetic route, a number o f additional sub-goals became apparent.  In their communication disclosing the structure o f (-)-8-isocyano-10-cycloamphilectene 5  ( 1 1 ) , the authors were able to determine the relative stereochemistry o f 1 1 , from X-ray diffraction data, but were unable to provide the absolute configuration o f the molecule. Thus, it was decided to use a synthetic sequence that would determine the absolute configuration o f (-)8-isocyano-10-cycloamphilectene ( 1 1 ) . T o achieve this goal, the synthetic plan was to synthesize a single enantiomer o f the diterpene isocyanide 1 1 and to compare the optical rotations o f the synthetic and natural materials. F o r this plan to be successful, the absolute configuration o f the intermediate at the point where the enantiomeric excess would be introduced into the synthesis would have to be known unambiguously. U p o n examination o f the previous syntheses, especially that o f (±)-8,15-diisocyano10(20)-amphilectene (1), with an eye towards the planned total synthesis, two further goals were apparent. Firstly, it was hoped that the synthetic route could be made more efficient at the stage where the third carbocyclic ring, (ring C ) , o f the skeleton was formed. In the previous syntheses, the Diels—Alder chemistry employed for this purpose gave facial selectivity that were at best 7:3  13  in favour o f the required isomer.  Thus, a second goal for this synthesis was to modify this  chemistry to improve the facial selectivity o f this reaction. Secondly, in the stages where the allylic oxidation served to functionalize C - l l (amphilectane numbering) and subsequently where an alkali metal—ammonia reduction served to saturate the C - l 2 to C - l 3 carbon-carbon double bond and set the stereochemistry at these centres, it was not unusual, especially when working on larger or preparative scales, for each reaction to proceed in only about 60% yield. This gave an overall yield for this two step process in the range o f 30 to 35%. In the planned synthesis, this transformation would occur at a point where a considerable amount o f chemistry remained to be done.  Clearly, the loss o f a large  amount o f material, as much as 70%, at this point would be both inconvenient and discouraging. Thus, a third goal for this synthesis was to attempt to find a more efficient method o f effecting the overall transformation from the alkene 21 to the ketone 23. Finally, in the data reported for the natural product, the absorption for the isocyanide 5  function in the ir spectrum, 2245 cm" , seems anomalous. The accepted range for this absorption 1  is 2100 to 2180 cm" . 1  21  A fourth and final (minor) goal for this synthesis was to attempt to  confirm the reported value and thus determine whether this compound displays abnormal behaviour, or if the reported value was in error.  14  Discussion  Isolation and Characterization of (-)-8-Isocyano-10-cycloamphilectene (11)  5 In  11  1980 Kaslauskas and coworkers,  at the Roche Research  Institute o f Marine  Pharmacology, reported the isolation o f 6 new tri- and tetracyclic diterpene isocyanides from a marine sponge o f the genus Adocia.  5  The mother liquors from the direct crystallization o f  diisocyanoadocaine (5), representing about 1% o f the dry weight o f the sponge, contained a highly complex mixture o f mono- and diisocyanides. separated by silica gel column chromatography.  The mono- and diisocyanides were  The monoisocyanides were then purified by  exhaustive hplc on a Magnum® 9 silica gel column using methylene chloride and then 4:1 hexane—diisopropyl ether as the eluents. The diisocyanides were purified using the same column and 3:2 hexane—diisopropyl ether as the eluting solvent. Although most o f the compounds were not obtained in sufficient quantity to allow chemical correlation spectroscopy, some o f the compounds were highly crystalline. The  diterpene  (-)-8-isocyano-10-cycloamphilectene  (11)  possessed  spectral  data  5  requiring 7 degrees o f unsaturation, suggesting a tetracyclic carbon skeleton, a single isocyanide group, and a single trisubstituted carbon-carbon double bond. These features were confirmed by single crystal X-ray analysis, which also gave the relative stereochemistry  at the  seven  15  stereogenic centres. The colourless solid has a melting point o f 88 - 89 °C, an optical rotation o f -21.7° (c = 2, chloroform), a peak at m/z = 297 amu (5% relative intensity) in the mass spectrum and an absorption at 2245 cm" in the ir spectrum. 1  singlet at 5 = 5.20 ppm while the  1 3  The ' H nmr spectrum displayed a broad  C nmr spectrum showed signals at 5 = 154.4, 137.5, 115.2,  62.8, 49.0, 47.6, 46.2, 44.0, 43.1, 42.7, 40.6, 38.0, 37.7, 37.2, 32.2, 31.6, 29.8, 29.5, 25.1, 19.5 f  and 15.2 ppm.  Retrosynthetic Analysis The strategy for the construction o f 8-isocyano-10-cycloamphilectene (11) was based upon the recognition that the diene 18, previously prepared in our laboratories, a suitable intermediate.  22  would serve as  A possible retrosynthetic pathway, leading to this proposed starting  material, the diene 18, is outlined in Scheme 2. Since it has been demonstrated by Piers et al. ' that a methoxycarbonyl group at C-8 4  6  (cycloamphilectane numbering), in systems similar to 11, can be efficiently converted into the isocyanide function required for the natural product, it seemed highly probable that 8-isocyano10-cycloamphilectene (11) would be available from the ester 29.  This signal was not mentioned in the data reported by Kazlauskas et al. but was present  1  in the  5  1 3  C nmr spectrum o f an authentic sample o f (-)-8-isocyano-10-cycloamphilectene. The  spectrum and the sample were provided to us by Prof. T. Higa o f the Department of Marine Sciences, University o f the Ryukyus, Nishihara, Okinawa, Japan.  16  17  Disconnection o f the methyl groups at C - l 5 and introduction o f an oxygen function at C-14 would give an intermediate such as the ketone 30. Synthetically, introduction o f the methyl groups was expected to be accomplished by an alkylation, epimerization, alkylation sequence. The C-14 carbonyl oxygen would then be removed by a suitable reduction protocol. Theoretical disconnection o f the bond between C - l 5 and C-20 (cycloamphilectane numbering) o f the ketone 30 would lead to a tricyclic synthon such as 31, o f which compounds such as the keto aldehyde 32 or the ketone 33 would be the synthetic equivalents.  The ring  closure could be accomplished by an intramolecular alkylation or aldol condensation process. Either o f the compounds 32 or 33 should be readily available from the diester 34 by an appropriate sequence o f reactions o f which the introduction o f the C - l 5 carbon atom would be the key step. The diester 34 could, in turn, be made from the ketone 23 in a few synthetic steps in which the addition o f the C-20 carbon atom would be an important step. It has already been shown ' that the ketone 23 can be prepared from the alkene 21 in two 4  synthetic steps.  6  Allylic oxidation followed by stereoselective reduction o f the C-12 to C-13  (amphilectane numbering) carbon-carbon double bond has been employed to achieve this transformation.  A s alluded to in the introduction section, the efficiency o f this two-step  transformation was inconsistent, due to the capricious nature o f the individual steps. Therefore, at this stage o f the present work a more efficient overall conversion o f the ester 21 to the ketone 23 would be sought. Disconnection o f the bonds between C - l and C-2 (amphilectane numbering) and between C-3 and C-4 would lead to the diene 18 and some suitable 3 carbon moiety. It was expected from previous w o r k done in the racemic series, that a Diels—Alder cycloaddition reaction 4  would proceed to give the desired regiochemical outcome, but that the facial selectivity o f the  18  process would be less than desired. It was hoped that the C-8 ester function could be used to provide a steric driving force and that a suitable dienophile could be found to give a high proportion o f products resulting from the required facial selectivity. A s stated above, the diene 18 had previously been prepared in our laboratories, in racemic form, from 2-(methoxycarbonyl)3-methylcyclohexanone (14).  Introduction of Enantiomeric Excess There are two methods available to the organic chemist for the introduction o f an enantiomeric excess into a synthetic organic molecule.  One method is to use, as the initial  starting material or as a substrate at some suitable step, a chiral building block that is either enriched in, or exclusively, a single enantiomer.  These building blocks typically are compounds  derived from natural sources and include simple terpenoids, amino acids and carbohydrates. The other method is to carry out an enantioselective chemical reaction, one in which the reagent or substrate itself is chiral, by virtue, for example, o f it possessing a chiral auxiliary. Both  o f these  methods  were  considered  for  the  total  synthesis  of  8-isocyano-10-  cycloamphilectene (11). A third method that one could use to secure a single enantiomer o f a natural product is to prepare the racemic modification o f the natural material and then carry out a resolution as the final step. Although this method is not technically a chiral method o f synthesis, it does offer the advantage o f producing, for comparative study, both enantiomers o f the natural product.  It  should be noted, however, that the resolution o f a racemate still requires either introduction o f a chiral auxiliary, yielding diastereomers  that can (hopefully) be separated  by conventional  19  chromatography, or by direct chromatographic separation o f the enantiomers, utilizing a chiral stationary or mobile phase.  Furthermore, because one does not know i f a resolution will be  successful until it is attempted, there is much more uncertainty involved in attempting to obtain an enantiomerically pure synthetic material in this manner. The first option that was considered for the synthesis o f enantiomerically pure 8isocyano-10-cycloamphilectene (11) was to carry out early in the synthetic sequence an enantioselective chemical reaction.  A convenient point at which to carry out such a reaction  would be the conjugate addition o f the methyl group to the unsaturated keto ester 13. This was considered a favourable point for two reasons. Firstly, the unsaturated keto ester 13 is achiral. Thus the facial selectivity o f the conjugate addition process would be the only factor that would need to be considered.  Secondly, and as importantly, the unsaturated keto ester 13 could be  readily made in large quantities by known methods.  O  4  O  13  Conjugate addition to the unsaturated keto ester 13 would in fact introduce two stereogenic centres into the product, the P-keto ester 14, and it would thus seem that diastereoselectivity would be important.  However, it is known that both epimeric forms o f the P-keto  ester function o f compounds such as the P-keto ester 14 are readily available to the molecule (see Figure 2). These epimeric forms inter-convert through its tautomeric form, the enol 36, and this  20  enol form is readily accessible to the molecule. Therefore, the stereochemistry o f the molecule at C-2 cannot be defined, as the two epimers at that centre are in equilibrium, and the absolute configuration o f the P-keto ester 14 is simply a function o f the stereochemistry at C-3. Furthermore, the configuration o f the carbon atom bearing the methoxycarbonyl moiety would be set by an alkylation process as the next synthetic step and the stereochemical outcome o f this process was well known to be dictated by the orientation o f the methyl group at the adjacent carbon atom, C-3. Thus it was obvious that the only stereogenic centre that needed to be considered in the production o f a single enantiomer o f the P-keto ester 14, and in the planned synthesis o f 8-isocyano-10-cycloamphilectene (11), was that bearing the methyl group, C-3.  O  O  O  14  OH  36  O  O  14  Figure 2: Equilibration of the Epimers of a P-Keto Ester Through Its Enol Form  In the racemic syntheses o f 8,15-diisocyano-10(20)-amphilectene (l) and o f 8-isocyano4  10(14)-amphilectadiene (2), the methyl group at C-3 o f the P-keto ester 14 was introduced by 6  conjugate addition, using an organocuprate reagent, o f a methyl group to the unsaturated keto ester 13. It was clear that i f the introduction o f this methyl group, to give the p-keto ester 14, could be controlled in an enantioselective sense, then the desired enantiomeric excess for the synthesis could be introduced in this way (see Equation 1). The necessary transformation could be carried out by treatment o f the P-keto ester 13 with an appropriate chiral cuprate reagent to produce a single, desired isomer such as the P-keto ester 35.  Conjugate addition o f organometallic reagents such as organocuprates and Grignard reagents to a, P-unsaturated carbonyl compounds is an important and well known method o f assembling organic molecules.  In these reactions, the organic portion o f the organometallic  reagent adds to the p-carbon atom of the a,P-unsaturated aldehyde, ester or ketone, giving first a resonance stabilized a-carbanion and then, after protonation or some other form o f quenching, the P-substituted product (see Figure 3).  This methodology has also been applied to other  systems yielding resonance stabilized oc-carbanions upon conjugate addition, such as 1-nitro- or 1-sulfinylalkenes.  The primary advantage o f these reactions is that they allow the direct  introduction o f non-stabilized organic moieties into an organic structure with high chemo- and regioselectivity, starting from substrates which are generally readily available.  E Figure 3: Conjugate Addition to a,P-Unsaturated Carbonyl Compounds  22  Enantioselective conjugate addition can be achieved either by reacting an achiral reagent with a chiral substrate or by reacting a chiral reagent with a prochiral substrate. F o r the present requirements, it was clear that the latter alternative would have to be employed. Thus, a method was sought in which a prochiral substrate, the P-keto ester 13, would be treated with a chiral reagent which would induce the enantioselective conjugate addition o f a methyl group onto the substrate. This subject has been thoroughly reviewed  23  by Rossiter and Swingle. Although much  has been established on the utility o f such chiral cuprate reagents, the reported  enantio-  selectivities were typically poor. Furthermore, the chemical yields o f the reported reactions were highly variable.  Consequently it was decided to attempt to introduce the required chirality  through a method in which the starting material for the synthesis was drawn from the pool o f chiral substrates. A retrosynthetic analysis o f the keto ester 35 (see Scheme 3 ) suggested that this compound could be prepared by C-methoxycarbonylation o f the enolate anion derived from 3-methylcyclohexanone (37). The enantiomer o f the ketone 37 with the ^-configuration at C - 3 is commercially available as a single stereoisomer and it seemed at first glance that this compound would serve as a good starting point for our synthesis. It was recognized, however, that it might be difficult to chemoselectively methoxycarbonylate the ketone 37 as there is little chemical difference between the protons on either side o f the carbonyl group in terms o f their accessibility to a base. Indeed, initial attempts at the selective deprotonation o f 37, using L D A as the base under various conditions and monitoring o f the generated enolate anion by its reaction with triisopropylsilyl chloride, gave essentially a 1:1 mixture o f silyl enol ethers. Producing a mixture  23  of methoxycarbonylated products was undesirable as the chromatographic separation of P-keto esters is hampered by their tendency to 'streak' rather than to run as discrete bands on silica gel.  O  O *Ph  35 Scheme 3: Retrosynthetic analysis of 35  The same retrosynthetic disconnection could also lead to 5-methyl-2-cyclohexenone (38). It was expected that the deprotonation o f this compound could be kinetically controlled and that methoxycarbonylation o f the appropriate enolate anion, followed by hydrogenation o f the C-2 to C-3 carbon-carbon double bond, would give the desired B-keto ester 35. been shown previously, by w o r k  24  Furthermore, it had  done in our research laboratories as well as w o r k  25  found in  the chemical literature, that the a,B-unsaturated ketone 38 was readily accessible in an enantiomerically pure form from pulegone (40), a commercially available monoterpene isolated from oils derived from plants o f the Labiatae family. Thus, work was started upon the synthesis o f a single enantiomer o f the required B-keto ester 35 from pulegone.  Preparation of the P-Keto Ester 35 The first key intermediate required for synthesis o f 8-isocyano-10-cycloamphilectene (11) was the P-keto ester 35. The P-keto ester 35 was prepared according to the synthetic sequence outlined in Scheme 4. A solution o f (l/?)-(+)-pulegone (40) in methanol was treated with 30%  24  aqueous hydrogen peroxide in 25% aqueous potassium hydroxide solution by a modification o f the method * o f Katsuhara to provide a mixture o f the cis- and toms-pulegone epoxides (41).  It  25  was found that proper temperature control was essential for the success o f the reaction.  The  oxidation reaction is quite exothermic and, in order to avoid the formation o f by-products, the addition o f the base solution to the reaction mixture was carried out dropwise such that the temperature o f the reaction mixture did not rise above 10 °C. Work-up o f the reaction mixture gave the desired product in nearly quantitative yield as a mixture o f diastereomers.  The ir  spectrum o f the product mixture showed a strong absorption at 1740 cm" consistent with the 1  carbon-oxygen stretching o f a ketone carbonyl function and absorptions at 1260 and 919 cm" for 1  the epoxide function, indicating the successful formation o f the product, the epoxides 41. The sulfides 39 were prepared from the mixture o f the epoxides by a modification o f the  35  44  Scheme 4: Synthesis o f 35  Reagents (a) H 0 , N a O H , M e O H , water; (b) PhSNa, 2  T H F ; (c) CH3CO3H, C H C 1 ; (d) C a C 0 ; 2  T H F ; (f) H , P d / C , E t 0 . 2  2  38  2  3  2  (e) L D A -  HMPA,  THF; Me0 CCN, 2  25  method  o f Avery et al.  25b  Thus, thiophenoxide opening o f the epoxides 41 with concomitant  retro-aldol expulsion o f acetone gave the regioisomerically pure sulfides 39 in nearly quantitative yield as a mixture o f diastereomers, which could be carried on to the next step directly. In their work,  25b  Avery et al. used an excess o f sodium thiophenoxide to open the epoxide moiety;  however, in our studies it was found that i f very pure reagents were employed, the reaction could be accomplished with equimolar quantities o f the reactants.  This change produced a much  cleaner reaction and allowed the reaction to be carried out at a concentration much higher than that previously reported.  25b  The mixture o f products 39 showed, in the ir spectrum, an  absorption at 3059 cm" for the aromatic carbon-hydrogen stretch, a strong absorption at 1  1713 cm" for the carbonyl function and an absorption at 692 cm" for the carbon-sulfur linkage. 1  It is well k n o w n  1  26  that sulfides can be oxidized to sulfoxides by many different oxidizing  agents. Further oxidation o f the sulfoxide, to yield the sulfone, is normally a slower process and is competitive only when fairly strong oxidants are employed (see Equation 2). to oxidize the sulfides 39 by the method  27  Early attempts  o f Oppolzer and Petrizilka gave varying results.  Commercial /w-chloroperoxybenzoic acid (TW-CPBA) is sold as a mixture o f m - C P B A and w-chlorobenzoic acid, with the peracid making up between 57 and 86% by weight. The reagent also tends to be quite wet and methylene chloride solutions o f the reagent often freeze at the temperatures required for the selective oxidation reaction. A s a result o f these two factors it was difficult to consistently obtain the desired amount o f oxidant for the reaction and, as / w - C P B A is a strong enough oxidant to efficiently carry out the oxidation o f the sulfoxide to the sulfone, the over-oxidized by-product, sulfone 43, often contaminated the product mixture.  Although the  sulfone contaminant could be removed from the desired sulfoxide by column chromatography on  26  silica gel, this process was inconvenient, especially on larger scales, and an alternative oxidation method was sought.  o  o  O Ph  Ph  [O]  42  39  Avery et al. have reported peroxyphthalic acid hexahydrate  28  o  II  [O]  Ph  2  43  the synthetic utility o f the magnesium salt o f mono-  to carry out this oxidation. This reagent is provided in known  concentration but is not especially soluble in the water—ethanol mixtures required for the oxidation reaction. Thus, on larger scale quantities, the volume o f the reaction mixture made its handling somewhat difficult.  Furthermore, upon completion o f the extractive work-up, large  amounts o f drying agent were required to dry the ether—ethanol solution and the mixture was often difficult to filter.  So, although the over-oxidation problem had been addressed by the use  of this method, it was still hoped that an operationally more convenient method might be found to carry out the desired oxidation. When the oxidation o f the sulfide 39 was attempted with peracetic acid, the desired sulfoxide 42 was isolated in essentially quantitative yield. The oxidant is commercially available as a 32% solution by weight in aqueous acetic acid and typically contains about 6% hydrogen peroxide.  The presence o f the hydrogen peroxide contaminant, however, did not seem to  interfere with the desired reaction as none o f the over-oxidized product sulfone 43 was detected. Thus one equivalent o f peracetic acid was added to a well stirred methylene chloride solution o f the sulfide 39 that had been cooled to 0 °C. The reaction was very rapid as demonstrated by tic  27  analysis o f aliquots from the reaction mixture.  Saturated aqueous sodium thiosulfate solution  was then added to reduce excess oxidant (mostly hydrogen peroxide). T o facilitate the work-up of the reaction mixture, the two phase system was poured into about two volumes o f diethyl ether. Acetic acid was removed from the organic phase as its sodium salt by washing the organic phase with saturated aqueous sodium bicarbonate.  Removal o f the solvent from the dried  organic phase gave the sulfoxide 42 as a yellow oil which solidified upon standing. This material showed, in the ir spectrum, a strong absorption at 1046 cm" for the sulfoxide function as well as 1  absorptions at 3051 and 1704 cm" for the aromatic C - H and carbonyl stretches, respectively. 1  The solidified material was sufficiently pure to be carried directly on to the next step. It is well k n o w n  29  that sulfoxides bearing a P-hydrogen undergo elimination upon  pyrolysis in the presence o f a base and this method has been used for the conversion o f many ketone, aldehydes and esters into their a,P-unsaturated derivatives.  29  A temperature o f about  80 °C is required to effect the elimination reaction. The elimination is a syn process, proceeding through a pseudo 5-membered ring internal elimination mechanism, analogous to that o f the Cope reaction (see Equation 3).  C  C  H  >  \  Ph  o  •  X—C H  C  \  .S  Ph  o  Previously in our laboratories, the conversion o f the sulfoxide 42 into (5i?)-5-methyl-2cyclohexenone (38) had been accomplished by heating a mixture o f the sulfoxide 42, calcium carbonate and carbon tetrachloride to its boiling point.  Filtration o f the reaction mixture  28  followed by careful removal o f the carbon tetrachloride by distillation gave the product, the a,P-unsaturated ketone 38. Carbon tetrachloride is a poisonous substance,  30  a carcinogen and 30  has recently been listed under the Canadian Chlorofluorocarbon Control A c t as an ozone depleting substance.  31  Thus it was considered appropriate to seek an alternative preparation o f  the a,P-unsaturated ketone 38. The first concerns in finding an alternative solvent for the elimination reaction were 1) the solubility of the sulfoxide 42 in the solvent, as it was believed that the reaction would be faster in the solution state, and, 2) the boiling point o f the solvent.  Because it was known that the  pyrolysis reaction required a temperature o f about 80 °C to proceed, solvents with boiling points of greater than that temperature were initially considered. The first solvent tried was butanone, which has a boiling point o f 80 ° C The sulfoxide 42 was found to be very soluble in butanone, thus a mixture o f the sulfoxide 42, calcium carbonate and butanone were heated to the boiling point and stirred under reflux. G l c analysis o f the liquid phase showed, after as little as 15 min, the presence o f the desired product.  After 16 h o f heating, the mixture was cooled to it and  isolation o f the product as described for the carbon tetrachloride procedure was attempted. Unfortunately, although there is a large difference in the boiling points o f the a,P-unsaturated ketone 38 and butanone (approximately 120 °C), it proved impossible to separate these materials completely by fractional distillation, presumably due to the formation o f an azeotrope.  A s the  next step o f the sequence called for a reaction o f the ketone function o f the a,P-unsaturated ketone 38, the presence o f butanone in the product mixture would clearly interfere i f not removed. Thus, although butanone seemed initially promising as an environmentally innocuous alternative to carbon tetrachloride, for the present purpose it did not prove to be appropriate.  29  It was noted that the sulfoxide 42 was also soluble in some o f the low molecular mass hydroxylic solvents. Although the boiling points o f ethanol, 78 °C, and propanol, 97 °C, would likely have been suitable for the facilitation o f the pyrolysis reaction, it was feared that the separation of these solvents from the product would prove problematic. Because the presence o f an alcohol would be detrimental to the course o f the next reaction in the sequence and it seemed likely that it would be difficult to obtain the desired a, P-unsaturated ketone 38 in a pure form, the elimination reaction was not attempted in these solvents. The sulfoxide 42 is very soluble in methylene chloride. The boiling point o f this solvent (40 °C), is however insufficient to facilitate the elimination reaction. A n attempt was made to carry out the desired elimination reaction in a sealed tube, thus allowing the contents to be heated above the boiling point o f the solvent. For this reaction, a soluble base that could not react with a proton source to form a gas was thought to be more appropriate than calcium carbonate, and imidazole was chosen as a suitable candidate.  Equimolar amounts o f the sulfoxide 42 and  imidazole were dissolved in methylene chloride and placed in a sealed tube. The tube was heated to 90 °C and this temperature was maintained for a period o f 8 h. The tube was cooled to rt and opened. A two phase system had formed, the upper phase being a clear, yellow liquid and the lower being a more viscous, dark yellow oil. The top layer was carefully removed by pipette and the methylene chloride was evaporated under a stream o f argon. The residue, upon distillation, provided the desired a,P-unsaturated ketone 38 in 90% yield. Although this method proved an excellent one for the production o f the a,P-unsaturated ketone 38 on a relatively small scale, the requirement for specialized equipment, to safely handle the pressures developed by the reaction on preparative scales, precluded its use as a method for the large scale production o f the a,P-unsaturated ketone 38.  30  Running the elimination reaction in solvents less volatile than the a , 3-unsaturated ketone 38 was also considered as an alternative.  It was hoped that the product o f the elimination  reaction could then be distilled directly from the reaction mixture. 285 °C, was first considered as reaction medium for this purpose.  Tri(ethylene glycol), bp  Although the sulfoxide 42 is  not especially soluble in tri(ethylene glycol), it was hoped that the reaction could be carried out at a temperature above the melting point o f the sulfoxide 42.  Thus a mixture o f the sulfoxide 42,  calcium carbonate and tri(ethylene glycol) was heated to 120 °C. The reaction's progress was monitored in the following manner.  A sample o f the liquid phase was removed and partitioned  between water and diethyl ether and then glc analysis was carried out on the diethyl ether phase. The presence o f the desired product was noted after 1 h and the reaction mixture was heated for 8 h. Unfortunately, attempts to distill the product from the reaction mixture gave only low yields of the  desired a,f3-unsaturated  ketone  contaminated with tri(ethylene glycol).  38.  Furthermore,  this material was invariably  This is not surprising as the difference in the boiling  points of the a , P-unsaturated ketone 38 and tri(ethylene glycol) is only about 80 °C. Attempts at running the reaction for longer periods o f time did not significantly affect the yield o f the product.  A s it was unlikely that subsequent work on this reaction could provide an efficient  process for the production o f the a,P-unsaturated ketone 38, this method for its preparation was not investigated further. A logical extension o f the above attempt was to carry out the elimination reaction in the absence o f a solvent, and this method in the end proved to be the best choice for running the elimination reaction without using carbon tetrachloride. Thus, 1 equiv o f the sulfoxide 42 and 2 equiv o f dry calcium carbonate were ground together in a mortar, to ensure that they were thoroughly mixed, and the mixture was transferred to a round-bottomed flask. The flask was  31  fitted with a vacuum trap and the apparatus was placed under reduced pressure (about 0.3 Torr). The flask containing the sulfoxide-base mixture was heated (90 °C) to facilitate the elimination reaction while the vacuum trap was cooled (-78 C ) to trap the product.  The reaction was  allowed to proceed for 3 hours after which time the apparatus was brought to atmospheric pressure and then allowed to come to rt. condensate was often found to be wet.  Although the base was dried prior to use, the The condensate was dissolved in pentane and the  solution was dried over magnesium sulfate.  The pentane was then removed by distillation and  the residue was distilled to give an excellent yield (91%) o f the desired ct,P-unsaturated ketone 38.  Gratifyingly, this material proved to be identical with that previously produced in our  laboratory by the method using carbon tetrachloride as the solvent. With the a , P-unsaturated ketone 38 in hand, attention was turned towards the synthesis of the required P-keto ester 44.  It was expected that the excellent methodology for the  regioselective synthesis o f these systems by reaction o f the lithium enolate anions o f ketones with methyl cyanoformate, as developed  32  by Mander and Sethi, would serve to accomplish this  transformation (see Scheme 5). Methyl cyanoformate (Mander's reagent) reacts smoothly with lithium enolate anions o f ketones, prepared directly or through the corresponding trimethylsilyl enol ether, in the presence o f hexamethylphosphoramide to provide, after appropriate work-up, the desired P-keto esters.  Whereas the reaction o f lithium enolate anions with alkyl halo-  formates, or with O-alkoxycarbonyl carbonates  also serves to accomplish the  described  transformation, the product is invariably a mixture o f O- and C-alkoxycarbonylated products  33  with the exact product composition being dependent upon such factors as the reaction temperature, stoichiometry, solvent, the counter-ion to the enolate anion, the leaving group in the reagent and steric congestion in the substrate.  32  Mander's reagent, on the other hand, reacts with  32  I  •C-H  LDA  O  y \  MeLi TMSO^  - O  Me0 CCN 2  \  V  HMPA  •H  o  C0 Me  + Li  2  ^  Scheme 5:Methoxycarbonylation with Mander's reagent  lithium enolate anions o f ketones exclusively on the carbon o f the enolate anion; none o f the enol carbonate that would result from the reaction occurring at the oxygen o f the enolate anion is observed. The a,3-unsaturated ketone 38 was chosen as the substrate for this reaction because the required lithium enolate 45, as opposed to lithium enolate 46, was readily available by reaction o f the a,3-unsaturated ketone 38 with L D A under conditions o f kinetic control (see equation 4). A s L D A can add in a conjugate fashion to ct,3-unsaturated ketones, the base actually employed was a complex o f L D A and hexamethylphosphoramide. This complex, when used as a base, is more basic and less nucleophilic than is L D A alone.  34  Because hexamethylphosphoramide was  introduced at the enolate anion formation stage, none was added prior to the introduction o f the Mander's reagent, as would be typical for Mander and Sethi's protocol. This modification to the procedure did not seem to affect the course o f the reaction.  O xs. L D A , T H F not HMPA  38  45  46  +  L i  33  Thus, addition o f a solution o f Mander's reagent in T H F to a solution o f the lithium enolate anion 45, prepared by reaction o f the ct,P-unsaturated ketone 38 and L D A — h e x a methylphosphoramide complex in T H F solution at -48 °C, gave, after work-up and purification of the crude product by column chromatography on silica gel, the B-keto ester 44 in 78% yield. The product exists as a mixture o f epimers at C-6. This material showed, in the ir spectrum, strong absorptions at 1742 and 1678 cm" and weaker absorptions at 1650 and 1622 cm" , for the 1  1  B-keto ester functions o f the two epimers o f the product. In the H nmr spectrum, two singlets J  were observed at 5 3.67 and 3.74 ppm representing the protons from the methoxy groups o f the minor and major epimers, respectively. Comparison o f the integrals for these resonances showed that the epimers o f the product existed in the ratio o f about 5:1. A l l that now remained to complete the synthesis o f the P-keto ester 35 was the hydrogenation o f the carbon-carbon double bond in the p-keto ester 44. Hydrogenation over a platinum metal catalyst was expected to be the most effective method for this transformation. O f the metals considered as catalysts, including platinum, palladium, rhodium and ruthenium, palladium seemed to be the candidate most likely to give a high yield o f the desired product. Platinum black, prepared from Adam's catalyst in situ, was thought to be too reactive a catalyst, as it is known to hydrogenate the carbon-oxygen double bonds o f ketones under relatively mild conditions,  35  while supported platinum catalysts tend to be as reactive or more reactive than is  platinum black.  36  Rhodium catalysts are most often used for hydrogenation o f aromatic and  heteroaromatic systems at relatively low temperatures and pressures. catalysts are more readily poisoned than are palladium catalysts.  38  37  Furthermore, rhodium  Finally, ruthenium catalysts  were also thought to be too reactive for the desired transformation. Ruthenium catalysts, similar to platinum catalysts, are known to hydrogenate aliphatic ketones under relatively mild  34 conditions. '  Palladium on charcoal was selected to effect the desired reduction as this catalyst  is known to be the best catalyst for the reduction o f olefins and acetylenes.  39  Disubstituted  carbon-carbon double bonds, in most cases, are hydrogenated at rt and just above atmospheric pressure.  Furthermore, palladium on charcoal seems to be the most effective o f the platinum  metal catalysts for the reduction o f olefins conjugated to carbonyl groups, especially ketones.  40  Thus, the P-keto ester 44 was hydrogenated under hydrogen at atmospheric pressure and at 0 °C, using 5 mol % o f 10% palladium on charcoal. The reaction was run using diethyl ether as the solvent and was complete within 30 min.  For this reaction, it was essential that the  catalyst be saturated with hydrogen thoroughly prior to the introduction o f the substrate. Failure to do so resulted in the production o f significant amounts o f a fairly polar compound that displayed, in the *H nmr spectrum, three one-proton signals in the aromatic region o f the spectrum. This material was assumed to be the phenol 47, the product o f dehydrogenation o f the enol form o f the P-keto ester 44.  OH  O  47  Filtration o f the reaction mixture through a short pad o f Celite  to remove the catalyst,  followed by removal o f the solvent from the filtrate and distillation o f the residue gave the desired P-keto ester 35 in nearly quantitative yield. This material existed as a mixture o f epimers at the C-2 position. P-Keto ester 35 displayed, in the ir spectrum, four strong absorptions at 1748, 1714, 1651 and 1615 cm" , representing the P-keto ester functions o f the two epimers o f 1  35 the product. The H nmr spectrum of this material showed no resonances in the olefinic region l  of the spectrum, indicating that the carbon-carbon double bond reduction had gone to completion. Furthermore, resonances were observed at 8 3.71 and 3.75 ppm for the protons of the methoxy groups of the minor and major epimers, respectively.  Integration of these  resonances showed the epimers to exist, in chloroform solution, in the ratio of about 9:1. Some nmr samples, especially those that had been left standing at rt for extended periods of time, showed a resonance at approximately 8 12 ppm, presumably for the hydroxylic proton of the enol form of the B-keto ester function.  A signal at m/z = 170 amu was observed in the mass  spectrum, confirming the molecular mass of the product. Thus, the B-keto ester 35 was prepared from the naturally occurring (i?)-pulegone (40) by a 6 step series of reactions that proceeded in 65% overall yield.  Preparation of the Iodide 15 The next step in the synthesis called for the alkylation of some suitable enolate anion derivative of the P-keto ester 35 with (£)-l-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-6-iodo-3(trimethylstannyl)-2-hexene (15). The iodide 15 had been previously prepared in our laboratory  41  and, for the present study, the iodide 15 was prepared by a modification of this method (see Scheme 6). Methyl 6-chloro-2-hexynoate (49) was prepared by a modification of the method Piers et al.  413  of  In this modified procedure, the base employed was fert-butyllithium instead of  methyllithium. feft-Butyllithium takes on a deep yellow colour in THF solution. The advantage of this procedural change was that this property could be used to indicate when exactly one equiv  36  (a)  97%  C0 Me 2  48  49 (b)  cr  -  Me Sn  OH  ^  82%  (c)  ,C0 Me 2  97%  Me Sn 3  3  50  52  (d)  95%  K  Me^Sn  97%  15  Scheme 6: Synthesis o f 15  Reagents (a)  tert-BuU,  T H F ; M e 0 C C l ; (b) 2  Me SnCu3  ( C N ) L i , M e O H , T H F ; (c) D I B A L - H , E t 0 ; (d) T B S C 1 , imidazole, C H C 1 ; (e) N a l , 2  2  2  acetone.  o f the base had been added to the reaction mixture. slowly to a solution o f 5-chloro-l-pentyne (48)  Thus,  tert-butyllithium  solution was added  in T H F at -78 ° C until a v e r y pale y e l l o w c o l o u r  persisted for a p e r i o d o f 1 m i n after the addition o f the base was terminated.  U p o n completion o f  the reaction and subsequent w o r k - u p , a cleaner crude p r o d u c t was generated than was the case when methyllithium was e m p l o y e d as the base. In fact, tic and glc analyses s h o w e d that the only detectable organic component in the crude product was the desired alkynic ester 49, c o l u m n c h r o m a t o g r a p h y step, w h i c h was required in the previous m e t h o d , Distillation o f the crude product gave the alkynic ester 49  4 1 a  and the  c o u l d be eliminated.  in nearly quantitative yield.  This  37  compared to a yield o f 8 1 % from the previous method.  The distillate produced ir and T i nmr  spectra which were identical with those previously reported  413  for the alkynic ester 49.  Methyl (£)-6-chloro-3-(trimethylstannyl)-2-hexenoate (50) was prepared from the alkynic ester 49 by the method o f Piers et al.  4U  methylstannyl)(cyano)cuprate  Thus, reaction o f the alkynic ester 49 with lithium (tri-  in the presence  required a,3-unsaturated ester 50.  o f methanol provided, stereoselectively,  the  After chromatographic separation and distillation o f the  resulting crude material, the a,B-unsaturated ester 50 was isolated in 82% yield. Also isolated was the isomeric methyl (Z)-6-chloro-3-(trimethylstannyl)-2-hexenoate (51) in 8% yield. Both o f these materials showed T i nmr spectra identical with those previously reported  413  for these  compounds. ( E)-6-Chloro-3-(trimethylstannyl)-2-hexen-l-ol (52) was prepared from the a,B-unsatJ  urated ester 50 by the method  410  o f Piers and Friesen.  Thus, D I B A L - H reduction o f the  ct,B-unsaturated ester 50, followed by appropriate work-up gave the alcohol 52 in nearly quantitative yield. The alcohol 52 displayed ir and H nmr spectra identical with those previously l  reported for this compound.  410  (£)-6-Chloro-1 -[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-3 -(trimethylstannyl)-2-hexene (53) was prepared from the alcohol 52 by a modification o f a standard technique.  In this  modification, methylene chloride was used to replace the standard A^A'-dimethylformamide as reaction solvent.  The result o f this modification was to eliminate the usual aqueous work-up  required to remove the A(,A^-dimethylformamide.  Under the present modification, all that was  required was simple filtration o f the reaction mixture through a short pad o f silica gel, to remove the imidazole—HC1 salt by-product o f the reaction. Removal o f the solvent gave the product, which was sufficiently pure to be carried on to the next step without further purification. Thus,  38  reaction o f the alcohol 52 with slight excesses o f imidazole and fert-butyldimethylsilyl chloride in methylene chloride gave, after appropriate work-up, the desired chloride 53 in nearly quantitative yield. This material produced ir and H nmr spectra identical with those reported X  410  previously  for this compound. (£)-l-[[(l,l-Dimethylethyl)dimethylsilyl]oxy]-6-iodo-3-(trimethylstannyl)-2-hexene was prepared from the chloride 53 by a standard halide exchange reaction.  (15)  Thus, treatment o f  the chloride 53 with an excess o f sodium iodide in acetone gave, after appropriate work-up o f the reaction mixture and distillation o f the crude product, the desired iodide 15 in nearly quantitative yield. The distillate produced ir and T i nmr spectra identical with those reported  410  previously  for this compound. Thus the required alkylating agent, iodide 15, was prepared from 5-chloro-l-pentyne (48), in 7 1 % overall yield, by an efficient 5 stage process.  Preparation of the Tricyclic Diester 55  The next key intermediate required for the synthesis o f 8-isocyano-10-cycloamphilectene (11), according to the retrosynthetic plan, was the tricyclic diester 55.  This compound was  prepared according to the route summarized in Scheme 7. The first step was the alkylation o f an appropriate derivative of the B-keto ester 35 with iodide 15 to produce methyl (2i?,3i?)-2-[(£)-6[[(l,l-dimethylethyl)dimethylsilyl]oxy]-4-(trimethylstannyl)-4-hexenyl]-3-methylcyclohexanone2-carboxylate (16).  P-Keto esters are known to be especially difficult to alkylate due to the  stability o f the enolate anions derived from them.  Lithium and sodium enolates o f p-keto  39  esters often exhibit very little reactivity with normal electrophiles, such as alkyl halides. Potassium enolates tend to be more reactive towards alkylations; however, the product is often a mixture o f reaction o f the electrophile at the carbon and the ketonic oxygen o f the enolate anion. The product o f (9-alkylation is o f course an enol ether and as such is sensitive to acid hydrolysis; the P-keto ester portion o f the starting material can be thus regenerated and recovered to be used again. Therefore, i f the alkylating agent is readily available and the compound is not sensitive to the conditions required for the acid hydrolysis, the competition between C- and O-alkylation does not present a serious problem for the synthetic plan.  However, in the present example, the  planned reaction failed to meet both of the above mentioned criteria. The alkylating agent, iodide 15, whereas it could be prepared readily in quantity, was the product o f a five-step process and thus represented a fair investment o f time and resources.  Furthermore, the alkylation product,  ketone 16, contains an alkenylstannane function, a group that is well known to be quite sensitive to acid hydrolysis. The conditions that would be required to hydrolyze the enol ether product o f (3-alkylation would almost certainly result in protiodestannylation o f the product.  Scheme 7: Synthesis of 55 PhNTf , 2  THF; (c)  reagents (a) K H , toluene; 15; (b) L D A , THF;  Pd(PPh ) , 3  benzene; (e) Sml , MeOH, THF. 2  4  LiCl,  THF; (d)  methyl  2-bromoacrylate,  41  Additives may be employed to increase the reactivity o f these enolate anions, such as hexamethylphosphoramide or a crown ether such as 18-crown-6 or 15-crown-5. These additives make the enolate anions more reactive by selectively complexing with the cation, providing a more exposed, and thus more reactive, anion. Unfortunately, these additives also tend to make the enolate anion harder, increasing the likelihood o f reaction on the oxygen atom o f the enolate anion.  42  Thus, whereas additives often increase the overall yield o f alkylated product, a  concomitant increase in the proportion o f O-alkylated product may result. The alkylation o f the P-keto ester 35 with the iodide 15 had been attempted under a variety o f conditions.  4  Lithium enolates were found to be unreactive even under forcing  conditions. The use o f sodium hydride as the base and T H F or 1,2-dimethoxyethane as solvent gave good conversions o f the starting material (as high as 75%), but the reaction times tended to be very long, running to several days at reflux on occasion. The product mixture, upon analysis, was found to contain about 20% o f the unwanted O-alkylated material. The use o f potassium hydride as the base and the same solvents as above gave about the same yield o f alkylated products by a considerably faster reaction, being complete in 36 to 48 h.  Perhaps  not  surprisingly, however, the product mixture was found to contain about 25% o f the O-alkylated material. The use o f potassium hydride as base in T H F solvent in the presence o f 2 equiv o f 18crown-6 gave complete conversion within 24 h, but in this case, the O-alkylated material was the major isolated product. Eventually it was found that the use o f an aromatic hydrocarbon solvent promoted the C-alkylation process.  4  The use o f potassium hydride as base and benzene as solvent at reflux  gave an extremely sluggish reaction but when toluene was substituted for benzene, the reaction  42  was found to be complete within 4 days.  The product mixture was found to contain less than  10% o f the O-alkylated product and the isolated yield o f the ketone 16 was 66%. For the present work, an experiment was attempted in which o-xylene was substituted for the toluene solvent. It was hoped that reaction at the higher temperature (xylene has a boiling point o f 140 °C whereas that o f toluene is 110 °C), would accelerate the reaction while maintaining the low proportion o f 0-alkylation that had been observed in other hydrocarbon solvents.  F r o m the previous work, an inverse correlation between the isolated yield o f the  product and the duration o f the reaction was noted. It seems likely that some decomposition o f the product was occurring over time in the reaction mixture, thus it was hoped that a shorter reaction time would give a better isolated yield o f the desired ketone 16. This optimism was, o f course, balanced against the realization that the planned higher reaction temperature could itself lead to decomposition o f the product. In the event, the use o f potassium hydride as the base and o-xylene as the solvent gave complete reaction within 16 h.  The amount o f O-alkylated material was comparable to that  formed when toluene was employed as the solvent. The required ketone 16 was isolated, after appropriate work-up and distillation o f the crude product, in 77% yield, representing a modest increase over that observed with the previous conditions. The distillate displayed ir, ^  nmr and  mass spectral data identical with those previously observed for the racemic modification o f this 4  compound. In addition, a hexane solution o f 16 displayed an [ a ]  D  of-126°.  Thus, it would seem that the hypothesis that some decomposition o f the product with time under the conditions o f the reaction was probably correct. Furthermore it would seem that if this decomposition was occurring, it must be due to the continued exposure to the base and  43 that any thermal effect must be of lesser importance as in these experiments the factor varied had been the reaction temperature. The stereochemical outcome of this alkylation reaction, as depicted in 16, was known from precedent and can be explained in the following manner. 4  The two lowest energy  conformations of the potassium enolate anion derived from the P-keto ester 35 are depicted in Figure 4 as structures 35a and 35b. These conformations are in equilibrium under the conditions of the alkylation reaction.  H  H  35a  35b  Figure 4: The Equilibrium Between the 2 Lowest Energy Conformations of the Potassium Enolate Anion of the P-Keto Ester 35  The conformer 35a suffers from a severe steric interaction between the methoxycarbonyl group on C-2 and the secondary methyl group. As a result of this allylic strain, the equilibrium shown favours conformer 35b, despite the axial orientation of the methyl group in this conformation. The presence of this axial methyl group effectively blocks access to the enolate anion from the top face, (as shown in Figure 4), and the approach of the electrophile, iodide 15, occurs from the bottom face.  On the basis of this simple steric argument, the expected  stereochemical outcome of the alkylation reaction would be that shown in 16, that is with the alkyl chain on C-2 trans to the C-3 methyl group.  44  Considering the effect o f stereoelectronic control, on the other hand, one would also predict the alkylation o f the enolate anion 35b from the bottom face (as shown in Figure 4), i f the reaction has a late or product-like transition state.  43  Approach o f the iodide 15 from the bottom  face leads to a product in a chair conformation through a chair-like transition state whereas approach from the top face leads to a product in a twist boat conformation through a boat-like transition state. The chair-like transition state is lower in energy than is the boat-like transition state and thus, would be the favoured reaction pathway.  Based upon this stereoelectronic  argument and the above steric argument, the configuration o f the product 16 was assigned with confidence. The next step in the synthesis called for the formation o f the enol trifluoromethanesulfonate o f the ketone 16, methyl (37?,4i?)-3-[(£)-6-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-4(trimethylstannyl)-4-hexenyl)-4-methyl-2-[(trifluoromethanesulfonyl)oxy]cyclohexene-3-carboxylate (17).  This procedure was carried out using conditions developed by M c M u r r y and Scott. 44  The reagent employed was /V-phenyltrifluoromethanesulfonimide (PhNTf ), 2  available trifluoromethanesulfonating agent.  a commercially  It is often contaminated with a small amount o f  unknown material. The presence o f this contaminant does not seem to affect the course o f the reaction and excellent conversions o f a ketone into the corresponding enol trifluoromethanesulfonate are possible by simply utilizing a slight excess o f the reagent. For the present reaction, however,  a problem arose in that the  trifluoromethanesulfonate  trifluoromethanesulfonating  agent and  the  enol  17 proved to be almost inseparable by column chromatography, and  separation o f the excess reagent from the product, especially on large scales, was inconvenient. Fortunately, the contaminant in the A^-phenyltrifluoromethanesulfonimide was readily detectable, either by the observance o f any pale gray or yellow colour in the reagent or, even  45  better, by the detection o f any amine odour in the reagent. In such cases, the reagent could be readily purified before use by column chromatography on silica gel. The purified reagent, when stored in the dark in tightly stoppered vials, seemed to be stable indefinitely. When the purified reagent was used in the reaction, it was found that equimolar quantities o f the ketone 16 and the reagent could be employed and only a slight excess o f the base was required. Thus,  sequential  treatment  phenyltrifluoromethanesulfonimide trifluoromethanesulfonate  in  of  the  ketone  T H F gave,  17 in 88% yield.  16  after  with  L D A and  appropriate  purified  work-up,  the  Nenol  This material displayed, in the ir spectrum, an  absorption at 1216 cm" characteristic o f the sulfonate function. The H nmr spectrum exhibited 1  !  a multiplet around 8 6 ppm that integrated to 1 proton for the newly formed olefinic proton. In the  1 3  C nmr spectrum, 4 resonances were observed for the olefinic carbons, at 5 120, 140, 144  and 148 ppm, and a quartet was observed at 8 118 ppm for the carbon o f the trifluoromethyl group.  The molecular ion was not observed in the mass spectrum; however, peaks for the  molecular weight minus a methyl group and the molecular weight plus an ammonium cation were observed by desorption chemical ionization. Elemental analysis for carbon, hydrogen and sulfur gave results within acceptable limits. Finally, a hexane solution produced o f 17 an [ a ] o f -150°. D  The next step o f the synthesis called for an intramolecular Stille type coupling reaction in which a carbon-carbon single bond is formed between the olefinic carbons o f the compound 17 bearing the trifluoromethanesulfonate and trimethylstannyl functions, yielding the diene 18.  The  methodology  our  laboratory  4111  for ' ' 410  45  this  ring forming reaction  and by others  to be as shown in Scheme 8.  46  has  been  extensively investigated  in  in recent years. The overall pathway for this process is thought  46  The starting point for the catalytic cycle is believed to be the dissociation o f two o f the triphenylphosphine ligands from the tetrakis(triphenylphosphine)palladium(0) to give the coordinatively unsaturated active catalyst, bis(triphenylphosphine)palladium(0).  This catalyst then  Scheme 8: Reaction Pathway for the Palladium Catalyzed Coupling Reaction  47  oxidatively inserts into the carbon-oxygen bond o f the enol trifluoromethanesulfonate moiety. The next step is a transmetalation reaction at the olefinic carbon bearing the trimethylstannyl function.  This forms a 'trans' bis(vinyl) palladium(II) species and gives the by-product o f the  reaction, trimethylstannyl trifluoromethanesulfonate.  After a rearrangement o f the ligands on the  palladium dication, the coupled reaction product, diene 18, is formed by a reductive elimination process, which concomitantly regenerates the active catalyst. A high quality catalyst is essential for coupling reactions o f this type, and since tetrakis(triphenylphosphine)palladium(0) is quite sensitive to oxidation, the catalyst required for this synthesis was prepared  from palladium(II) chloride.  A high yield o f the  catalyst  tetrakis(triphenylphosphine)palladium(0) was obtained in one step from palladium(II) chloride following the procedure  47  o f Coulson et al.  Treatment o f a T H F solution o f the enol trifluoromethanesulfonate  17 with 10 mol  percent o f tetrakis(triphenylphosphine)palladium(0) at reflux under an atmosphere o f argon provided, after appropriate work-up, chromatographic purification and distillation o f the crude product, the diene 18 in 87% yield. The distillate produced ir, H nmr, !  1 3  C nmr and mass spectral  data identical with those from the previously produced racemic modification o f this compound. 4  In addition, a hexane solution o f 18 showed an [OC]D o f +236°. The 400 M H z *H nmr spectrum of the diene 18 is included in the Appendix as Figure 8. The formation o f the third ring o f the required tetracyclic skeleton was to be achieved through a Diels—Alder reaction o f the diene 18.  In previous work in our laboratories, the  necessary cycloaddition reaction had been carried out using either methyl acrylate  48  or acrolein.  4  Both dienophiles gave high yields o f Diels—Alder adducts; however, the reaction utilizing acrolein as the dienophile proceeded much more rapidly than that with methyl acrylate.  48  Unfortunately, neither reaction proceeded with a high degree o f facial selectivity, although both proceeded with complete regioselectivity. The best results were achieved by treating the diene with an excess o f acrolein in refluxing benzene.  In this case, all four o f the possible (regioselective) Diels—Alder adducts  were formed. The desired face from which the dienophile was to approach was that opposite the angular methoxycarbonyl group.  It was hoped that the presence o f this angular group would  effectively block the approach o f the dienophile from what is shown as the top face (see Figure 5).  Indeed, i f the reaction were to occur through the endo transition state, examination o f  molecular models suggests that approach o f the dienophile from this face would be hindered by the angular methoxycarbonyl group.  In fact, a 7:3 mixture, in terms o f facial selectivity, was  OR  Figure 5: Endo Approach of the Dienophile from the Face Bearing the Angular Ester  observed in favour o f the methoxycarbonyl group.  dienophile approaching from  the  side opposite the  angular  O f the minor component o f this mixture, 93% was found to be to  product o f Diels—Alder reaction through an exo transition state whereas only 7% was that from an endo transition state.  4  Because the stereochemistry at C-4 (cycloamphilectane numbering) was set during the course o f this reaction, and the synthetic plan did not allow for an opportunity to correct for the  49  introduction o f the wrong stereochemistry at this centre, a 7:3 mixture o f products due to the partial lack o f facial selectivity o f the Diels—Alder reaction meant that fully 30% o f the material had to be discarded at this point in the synthesis. Examination o f the results o f the experiment described above did however suggest a remedy for this situation. The results suggested that the angular methoxycarbonyl group was capable o f acting as a blocking group.  O f the product  mixture, only about 2% (7% o f 30%) arose from the top face endo transition state. Thus, when the dienophile approached such that the aldehyde was oriented towards the angular ester, a steric repulsion was encountered and the cyclization reaction was unlikely to proceed.  When the  dienophile approached from the top face in a manner leading towards an exo transition state, the group that was oriented towards the angular ester was a proton. This interaction must lead to considerably less steric repulsion as this arrangement led to reaction 14 times more often than did the opposite arrangement.  It was proposed that i f the proton were to be replaced with a group  large enough to produce a considerable steric repulsion with the angular ester, then the Diels— Alder reaction through the top face would be effectively eliminated. Introducing a bromine atom on the a-carbon o f the dienophile seemed to be an ideal choice. A bromine atom is much larger than a hydrogen atom required steric demand on the approach o f the dienophile.  49  and was expected to provide the  Furthermore, the product o f the  Diels—Alder reaction would then be an oc-bromo carbonyl compound and many methods o f effecting the reduction o f an a-bromo carbonyl compound to the parent carbonyl compound are known. The best choice for the dienophile proved to be methyl 2-bromoacrylate. This compound was readily synthesized from methyl acrylate, which is commercially available and inexpensive.  50  o  O (a)  OMe  o OMe  (b)  Br  81% Br  OMe  overall  Scheme 9: Synthesis o f Methyl 2-Bromoacrylate Reagents (a) B r , C H C 1 ; (b) E t N , E t 0 , pentane. 2  3  3  2  Also, as will be discussed later, the Diels—Alder adduct 54, an a-bromo ester was conveniently reduced to the parent ester in a straightforward manner. The preparation o f methyl 2-bromoacrylate was modeled upon a literature procedure  50  for the preparation o f 2-bromoacrolein (see Scheme 9). Methyl 2-bromoacrylate was prepared from methyl acrylate by an efficient, two step addition—elimination process. Thus, treatment o f methyl acrylate with 1 equiv o f bromine in chloroform solution provided methyl 2,3-dibromoacrylate which was immediately dehydrobrominated by treatment with 1 equiv o f triethylamine in 1:1 ether—pentane. Filtration o f the reaction mixture to remove the triethylamine hydrobromide salt, followed by removal o f the solvent from the filtrate and distillation o f the derived residue gave the desired methyl 2-bromoacrylate in good yield. material showed, in the  A deuteriochloroform solution o f this  nmr spectrum, a three proton singlet at 5 3.8 ppm and 2 one proton  doublets at 8 6.2 and 6.9 ppm. This material was found to be prone to polymerization as a neat liquid, even at low temperatures; however, it could be stored for extended periods o f time at -35 °C as a solution in dry benzene. Treatment o f the diene 18 with an excess o f methyl 2-bromoacrylate in refluxing benzene, gave, after  removal o f the  solvent and purification o f the  derived residue by column  chromatography on silica gel, a nearly quantitative yield o f the Diels—Alder adducts.  This  51  material displayed, in the ir spectrum, strong absorptions at 1740 and 1732 era" for the 2 ester 1  functions. Examination o f the H nmr spectrum o f the product showed it to be a mixture o f a X  major and a minor isomer.  Comparison o f the integrals for the broad doublets at 5 2.81 and  2.86 ppm, arising from the minor and major isomers, respectively, showed the isomers to be in the ratio o f about 4:1. It was satisfying to note that, using the distinctive pairs o f singlets arising from the methoxy protons o f each isomer as a diagnostic tool, the product mixture comprised only 2 isomers, suggesting that the introduction o f the bromine atom into the dienophile had had the desired effect o f controlling the facial selectivity o f the reaction.  Because the synthetic plan  required this synthesis and that o f 8,15-diisocyano-ll(20)-amphilectene to converge in a few 4  synthetic steps, further proof o f the structure o f the Diels—Alder adducts was not sought at this point. The next step in the synthetic plan called for the reduction o f the carbon-bromine bond o f the diesters 54. The methodology chosen to carry out this transformation was that introduced by Girard et al.  51  and developed by others.  52  A wide range o f a-heterosubstituted ketones and  esters have been reduced under extremely mild conditions by the action o f samarium diiodide, providing the unsubstituted carbonyl compound in good to excellent yields.  53  The samarium diiodide reagent required for this step was prepared from samarium metal and methylene iodide following a slight modification o f the procedure o f Molander and H a h n .  54  For the success o f this preparation, both high quality samarium metal and oxygen free, dry T H F are required and conditions had to be maintained such that atmospheric oxygen was rigorously excluded.  Thus, addition o f 1 equiv o f methylene iodide to a stirred suspension o f -40 mesh  samarium metal in an appropriate amount o f T H F produced, after 16 h o f stirring, a deep blue  52 solution o f samarium diiodide. The concentration o f the derived reagent was taken to be that o f the limit o f solubility o f samarium diiodide in T H F , about 0.1 M .  5 5  A method  55  to determine the  actual concentration o f a T H F solution o f samarium diiodide has been disclosed by W i p f and Venkatraman. Since esters do not undergo reduction with samarium diiodide, the mechanism o f the 51  reduction o f ct-halo esters is presumably direct reduction o f the halide (see Scheme 10).  Br  O  Br)  O  •OMe  OMe SmOI)  H  52  O  Sm(m)  O  MeOH  4_ O M e  OMe  Scheme 10: Mechanism of the Samarium(II) Reduction of an a-Halo Ester  Samarium(II) acts as a one electron reducing agent and gives samarium(III) as a stable by-product.  The first equiv o f the samarium diiodide donates an electron to the halide atom,  producing a radical anion. Homolytic cleavage o f the halogen carbon bond splits off a bromide anion and leaves a resonance stabilized radical.  The second equiv o f the samarium diiodide  donates an electron to the radical, giving an enolate anion, which is then protonated by the methanol co-solvent, providing the reduced product.  53  Addition o f a solution o f the diesters 54 in 3:1 THF—methanol to 2 equiv o f a T H F — samarium diiodide solution at -78 °C gave, after appropriate work-up and purification by column chromatography, a residue that provided, upon distillation, the diesters 55 in nearly quantitative yield.  The distillate displayed, in the ir spectrum, a strong absorption at 1735 cm" for the  carbonyl functions. Apparently the absorptions for the 2 different esters overlap. The molecular ion was observed in the mass spectrum, at m/z = 450 amu, and high resolution measurement o f this mass confirmed the expected molecular formula.  Elemental analysis for carbon and  hydrogen produced results within accepted limits. Thus it was clear that the desired reduction had taken place. Examination o f the *H nmr spectrum produced from the distillate showed that the product was a mixture o f two compounds, presumably epimers at C-3 (amphilectane numbering).  By  comparison o f the integrals o f pairs o f signals that could be assigned to the same function in the two epimers with confidence, such as the doublets at 5 = 1.0 and 1.1 ppm, corresponding to the secondary methyl group at C-7, the ratio o f the epimers was found to be 1:1. This result was not surprising. Examination o f molecular models o f the enolate anion intermediate in the reduction pathway (see Figure 6) demonstrated that the two faces o f the enolate anion were equally accessible to a proton source.  Thus, this protonation was not expected to occur stereo-  selectively.  .  l~C0 Me 2  Figure 6: Conformational Diagram of the Enolate Anion Intermediate Hydrogen atoms have been omitted.  55  54  Examination o f molecular models o f the two epimers o f the product did suggest, however, that the epimer with the methoxycarbonyl group in the p orientation would be the thermodynamically more stable epimer. In this system, the P orientation at C-3 (amphilectane numbering) puts the methoxycarbonyl group in a pseudo-equatorial position.  The epimeric  position has the methoxycarbonyl in a pseudo axial position, where it experiences an eclipsing steric interaction with the silyloxymethyl group at C - l , which also occupies a pseudo axial position. Thus, epimerization o f the product o f the reduction reaction, the diesters 55, should yield material that is enriched in the C-3P epimer. It is this epimer which was required for the continuation o f the synthesis. Attempts to epimerize the product mixture under normal conditions for epimerization o f aldehydes and ketones, sodium methoxide in methanol at reflux, however, did not lead to any substantial enrichment o f either epimer, as judged by *H nmr and glc analyses. Apparently, the relatively low acidity o f the proton a to the secondary methoxycarbonyl group makes the deprotonation o f the ester unfavourable and the epimerization reaction is exceedingly slow. Attempts to epimerize the product mixture under more forcing conditions, potassium fert-butoxide in fert-butanol - T H F mixtures, led to some enrichment o f one epimer, as judged by H nmr analysis.  l  Unfortunately, after a short period o f time, the product mixture began to  become contaminated with additional compounds. Judging from the appearance o f new singlets in the *H nmr spectrum at around 8 1.1 ppm, these new compounds were probably tert-butyl esters o f the diesters 55, presumably arising from transesterification. A s a result o f the problems associated with epimerization o f 55, this approach to enrich the composition o f the desired isomer was abandoned.  55  Thus, the tricyclic diesters 55 were synthesized from the B-keto ester 35 by a 5 step sequence that proceeded in 57% overall yield.  Preparation of the Ester 21  21 Although  the  diesters  55  formed  a  mixture that  was  inseparable  by column  chromatography on silica gel, it was known from the previous synthetic work that the corresponding epimers with an aldehyde moiety at C - 3 (amphilectane numbering), aldehydes 20 and 58, instead o f the secondary methoxycarbonyl group, were easily separated by this technique. Thus, the synthetic plan was modified in the following way. The diesters 55 would be reduced to the alcohols 56 and 57. The hindered nature o f the angular ester function at C - 8 was expected to make a chemoselective reduction o f the C - 3 methoxycarbonyl group straightforward.  I f the  alcohols 56 and 57 proved to be separable, then the alcohol 56, bearing the required C-3P hydroxymethyl group, a known compound and thus readily identified by comparison o f H nmr 4  X  data, would be set aside. The epimeric alcohol 57 would be converted to the required alcohol 56 by an oxidation, epimerization and reduction sequence as outlined in Scheme 11. I f the alcohols  56  56 and 57 did not prove to be separable, the mixture would be oxidized to the separable aldehydes 20 and 58.  The C-3 6 epimer would be reduced to the required alcohol 56 while the  C-3 a epimer would be subjected to an epimerization - reduction sequence to maximize the yield of the required stereoisomer.  Scheme 11: Synthesis o f 56  Reagents (a) D I B A L - H , Et20; work-up; (b) oxalyl chloride,  D M S O , C H C 1 ; E t N ; (c) N a O M e , M e O H ; D I B A L - H , E t 0 ; work-up. 2  2  3  2  The diesters 55 were reduced to a mixture o f the alcohols 56 and 57 by standard methodology.  Thus reduction o f the esters with D D 3 A L - H led to a 90% yield o f the two  57  epimeric alcohols. These alcohols proved to be readily separable by column chromatography on silica gel.  The less polar isomer proved to be, upon comparison o f T i nmr data, the C-3P  epimer, alcohol 56, which was isolated in 50% yield. This material produced ir, H nmr, J  1 3  C nmr  and mass spectra which proved to be identical with those previously reported for the racemic 4  modification o f this compound. In addition, a hexane solution o f 56 displayed an [ a ]  D  o f -88°.  The more polar isomer, alcohol 57 was isolated in 40% yield. This material displayed, in the ir spectrum, absorptions at 3410 and 1729 cm" for the O H and carbonyl stretches, respectively, 1  confirming that the reaction had succeeded.  Elemental analysis for carbon and hydrogen gave  results within accepted limits. A hexane solution o f 57 displayed an [a]n o f -87°. Following the above described plan, alcohol 57 was subjected to the following oxidation, epimerization, reduction sequence to convert it into the alcohol 56. The most consistent results for the oxidation step o f this sequence were obtained using the Swern method.  56  Appropriate  work-up and purification o f the crude product by column chromatography on silica gel gave the aldehyde 20 in 7 1 % yield and the aldehyde 58 in 20% yield. Although the starting material for this oxidation reaction was a single isomer, the product was invariably the above described mixture o f aldehydes. Apparently, the aldehyde 58, assumed to be the first formed product o f the reaction, epimerizes during the final stage o f the  Swern protocol, where an excess of  triethylamine is employed. The aldehyde 58 was taken up in dry methanol and, at 0 °C, a small amount o f sodium hydride was added.  The solution o f the aldehyde and sodium methoxide thus obtained was  allowed to warm to rt. When the epimerization was judged to be complete, typically overnight, the sodium methoxide was quenched with aqueous citric acid solution. Appropriate work-up and purification o f the crude product by column chromatography on silica gel gave the aldehyde 20 in  58  88% yield and the aldehyde 58 in 8% yield.  These materials, as well as the above isolated  aldehyde 20 produced *H nmr spectra identical with those reported for the racemic materials. 4  The alcohol 56 was derived from the aldehyde 20 by a standard reduction protocol. Thus, reaction o f the aldehyde 20 with 1 equiv o f D I B A L - H produced, after appropriate workup, the desired alcohol 56 in nearly quantitative yield.  This material produced ir, *H nmr and  mass spectra identical with those from the above described alcohol 56, produced directly from the reduction o f the diesters 55.  59  With the alcohol 56 in hand, the stage was set for the reduction o f the C-3 (amphilectane numbering) hydroxymethyl group to a methyl group, (see Scheme 12). This transformation was accomplished efficiently by known methods. p-toluenesulfonyl  chloride in methylene  Thus, treatment o f the  alcohol 56 with  chloride containing 4-(/Y,A -dimethylamino)pyridine /  provided the /?-toluenesulfonate 59 in 94% yield, after appropriate work-up and purification by column chromatography on silica gel.  This material, in the ir spectrum, displayed a strong  absorption at 1178 cm" for the sulfonate function. 1  The H nmr spectrum showed a 3 proton l  singlet at 5 = 2.46 ppm and 2 two proton doublets at 8 = 7.36 and 7.80 ppm. These data support the introduction o f the /?-toluenesulfonate  moiety into the molecule.  Desorption chemical  ionization mass spectrometry produced masses corresponding to the molecular ion plus a proton and the molecular ion plus an ammonium cation, and a high resolution measurement o f the former mass confirmed the molecular formula o f the product.  A hexane solution o f the p-  toluenesulfonate 59 produced an [ a ] o f -63°. D  Reaction o f the /?-toluenesulfonate 59 with excess Super-Hydride® in T H F  5 7  afforded the  tricyclic ester 21 in 95% yield, based on recovered /?-toluenesulfonate 59 (10%). This material produced ir, H nmr, l  racemic material.  1 3  C nmr and mass spectra identical with those previously reported for the 4  In addition, a hexane solution o f the distilled product produced an [ a ]  D  of  -74°. Thus the desired ester 21 was prepared from the diesters 55 by a three step process that proceeded in 70% overall yield. The yield o f the diesters 55 was optimized through the use o f an epimerization sequence which converted the alcohol 57 into the alcohol 56.  60  Preparation of the a,p-Unsaturated Ester 65  A t this stage o f the synthesis, a carbonyl function had to be introduced at C - l l (amphilectane numbering) o f the intermediate tricyclic ester 2 1 .  A carbonyl function at C - l 1 was  envisioned to serve as the necessary 'handle' for the construction o f the fourth ring required for the completion o f the functionalize C - l l .  cycloamphilectane  skeleton.  A n allylic oxidation was chosen  to  This transformation had, in the previous work, been accomplished by the 4  action o f chromium trioxide—dimethylpyrazole complex.  The use o f this oxidant system was  reported by Corey and Fleet in 1973 for oxidation o f many primary and secondary alcohols. In 58  1978, it was discovered,  59  by Salmond et al,  that this methodology could be applied to the  oxidation o f allylic methylene groups (see Equation 5).  X/  ^ S i  X/  ^ S i  61  A s stated in the introduction section, the yield o f this reaction was highly variable, especially on larger scales.  The reaction itself seemed to proceed smoothly; analysis o f the  reaction mixture by tic showed the tricyclic ester 21 was converted to a single, more polar component.  The success o f the reaction seemed to be linked to the dryness to the diethyl ether  required for the work-up. The procedure called for the reaction mixture, at the completion o f the oxidation, to be poured into dry diethyl ether to precipitate the reagent complex. The mixture o f product and reagent, which is used in vast excess to achieve a reasonable reaction rate, was separated by column chromatography o f this slurry on Florisil®. The column was eluted with dry diethyl ether and the product was isolated from the appropriate fractions o f the eluate. The use of diethyl ether dried by distillation from sodium metal, as described in the general experimental section, produced the best results. small scales.  However, this was only convenient for reactions on fairly  F o r example, on a 200 mg scale, much less than 1 mmol, about 0.5 L o f diethyl  ether was required for the dilution o f the reaction mixture and to run the column. The use o f diethyl ether that was less dry seemed to promote degradation o f the product, presumably by further oxidation by the chromium reagent. Crude products isolated from reactions where nondried diethyl ether was employed were strongly coloured and had a burnt odour. These reactions invariably suffered from low yields. Although it would have been advantageous to find an alternative method o f carrying out this allylic oxidation, no suitable procedure was identified. balance between the efficiency o f the transformation  The best results, considering a  on small scales and the  logistical  considerations o f the reaction on a preparative scale, were obtained when the reaction was carried out on a scale o f about 600 mg or 1.5 mmol o f 21. Thus, treatment o f the tricyclic ester  62  21 with chromiurn trioxide—3,5-dimethylpyrazole complex  59  in methylene chloride solution  afforded, after work-up and distillation o f the crude product, the desired a , P-unsaturated ketone 22 in 73% yield.  This material produced ir, ^  nmr,  1 3  C nmr and mass spectra identical with  those from the previously reported racemic material. In addition, a hexane solution o f distilled 4  22 produced an [ a ] o f -43°. D  A s no method was found to improve the above-described allylic oxidation, which was seen as a limitation in the previous synthetic work, attention was focused on the next stage o f 4  the synthesis. The synthetic plan now called for the reduction o f the C-12 to C - l 3 carbon-carbon double bond (amphilectane numbering). This reduction had to occur stereoselectively at C - l 3 to provide the correct configuration at this centre. A s the carbonyl function at C - l l could be used to correct the configuration at C-12, and the required configuration was the thermodynamically more stable one (assuming the required orientation o f the C - H bond at C - l 3), the stereochemical outcome o f the reduction reaction at this centre was o f less concern. In the previous synthesis, the conversion o f the ct,P-unsaturated ketone 22 into the 4  ketone 23 was accomplished by a dissolving metal reduction using sodium in liquid ammonia diethyl ether solution in the presence o f fer/-butyl alcohol. the product was obtained in good yield.  60  O n small scales, up to about 20 mg,  O n preparative scales, however, the reaction gave  inconsistent results and often gave significant amounts o f by-products.  In some cases, the by-  products made up the major portion o f the product mixture and, in all cases, represented an irretrievable loss o f material.  4  The capricious nature o f this reaction was discouraging and an  alternative method o f achieving this transformation was sought. Examination o f molecular models o f the oc,P-unsaturated ketone 22 suggested that the side opposite to the angular methoxycarbonyl group at C-8 (amphilectane numbering) is more  63  open in terms o f approach o f a reagent to the C-12 to C-13 carbon-carbon double bond, (see Figure 7).  Approach from the top face o f the molecule is hindered by the methoxycarbonyl  function whereas  approach from the bottom face is hindered by the pseudoaxial tert-  butyldimethylsilyloxymethyl group at C - l . Both o f these groups are attached to carbons allylic to the  double bond.  However, the  geometry  o f the  ring system  forces  the  fert-butyl-  dimethylsilyloxymethyl group to be splayed out somewhat from what is a normal axial position. The methoxycarbonyl group at C-8, on the other hand, is rigidly held in an orientation almost perpendicular to the double bond.  Thus, the bottom face o f the molecule seems to be more  Figure 7: Conformational Diagram of 22 Some hydrogen atoms have been omitted.  X/  ^•Si  X/ ^Si  X/  ^-Si  Scheme 13: Synthesis o f 23 Reagents (a) hydrogenation; (b) epimerization; (c) H , 10% Pd/C. 0.3 M methanolic K O H , 45 psi. 2  64  open than is the top. It was decided to attempt a direct hydrogenation o f the a , |3-unsaturated ketone 22, and hoped that the angular ester at C-8 could be relied upon, as it was in the Diels— Alder step, to provide the necessary steric influence and set the correct configuration at C-13, (see Scheme 13). Hydrogenation is well known to give the product o f syn addition o f the elements o f hydrogen to an unsaturated system. Thus, i f the hoped for steric control would be exerted and the required configuration were to be established at C-13 (amphilectane numbering), then the "wrong" configuration would be produced at C-12. However, the stereochemical outcome at C-12 was not an immediate concern because, as explained above, the carbonyl function at C - l l could be used to correct the configuration at this centre. Of  more immediate concern was whether  or not  any reaction in the  planned  transformation would take place. Whereas mono- and disubstituted double bonds tend to add hydrogen, under conditions o f catalytic hydrogenation, readily, at it and just over 1 atm o f hydrogen, trisubstituted carbon-carbon double bonds often require pressures o f 100 atm or more and tetrasubstituted double bonds often require elevated temperatures and pressures, on the order o f 275 °C and 100 atm.  61  Double bonds common to two rings, as is the case in the desired  reaction, are the most difficult to hydrogenate and often prove to be inert to catalytic hydrogenation.  61  Preliminary attempts to achieve this transformation with heterogeneous  catalysts,  palladium and platinum black, palladium on carbon and activated charcoal, and the homogenous Crabtree  62  and Wilkinson  63  all and the a,P-unsaturated attempt.  catalysts, were not successful. In fact, no reaction was observed at ketone 22 was recovered in nearly quantitative yield after each  65  It is known that the acidity or basicity o f the reaction medium can have a profound effect on the efficiency or rate o f hydrogenation reactions.  35  The effect o f the p H o f the reaction  medium is not predictable, however. In some cases addition o f a base will give an increase in the rate o f hydrogenation whereas in others a sharp decrease is observed. During the course o f a literature search, a particularly encouraging example was noted (see Equation 6). 64  6  In this example, the conjugated carbon-carbon double bond o f epi cyperone (60) was chemoselectively hydrogenated in preference to the C-l vinyl group when the reaction was run in a moderately basic medium. In this case, the addition o f the base gave a rate enhancement for the hydrogenation o f the enone function sufficient to allow isolation o f the ketone 61 without any reduction o f the more sterically accessible vinyl group. The example does not exactly model the planned transformation in that the double bond that was hydrogenated in 60 was not common to two rings. However, the double bond was tetrasubstituted and the rate enhancement was quite remarkable. These observations made a trial reaction seem worthy o f investigation. A n attempt to carry out the hydrogenation o f the a , |3-unsaturated ketone 22 under the conditions o f H o w e and McQuillan, 5 mol % o f 10% palladium on charcoal, rt, 0.3 M sodium 64  hydroxide in methanol, 1 atm H , did not lead to any hydrogenated product. This result was not 2  too discouraging as the enone system in the ct,p-unsaturated ketone 22 is more sterically hindered than that in epi cyperone.  When the reaction was repeated  at 45 psi, the  66  a, P-unsaturated ketone 22 was consumed after about 8 days.  The reaction was monitored  periodically by tic analysis and 2 products, one o f polarity similar to that o f ct,P-unsaturated ketone 22 and the other o f much higher polarity, were observed. The spot for the more polar product seemed to increase in intensity with time.  When the spot corresponding to the  a,P-unsaturated ketone 22 had disappeared completely, the reaction was stopped. The catalyst was removed by filtration and water was added to the filtrate. The filtrate was neutralized by addition o f 1 M aqueous citric acid, and after an aqueous work-up and separation o f the product mixture by column chromatography on silica gel, the two products were isolated. One product was o f polarity similar to that of the a, P-unsaturated ketone 22 and made up about 70% o f the weight o f the product mixture. Comparison o f a H nmr spectrum produced J  from this material with that o f the known racemic ketone 23 showed that these materials were spectroscopically identical.  Apparently, the hydrogenation reaction had been successful and,  under the basic conditions o f the reaction, the first formed product, presumably ketone 62, had epimerized to the thermodynamically more stable ketone 23.  HO  The second product, the more polar material, made up about 30% o f the weight o f the product mixture and was not especially stable in its pure state.  In the ir spectrum, a strong  absorption was observed at 3400 cm" , indicating that the material was an alcohol. 1  It seemed  67  likely that the material was alcohol 63.  This assumption was confirmed in that reaction o f the  more polar component with fcrt-butyldimethylsilyl chloride and imidazole in methylene chloride produced the ketone 23.  Clearly, the fert-butyldimethylsilyl protecting group is not completely  stable to the conditions o f the hydrogenation reaction. Although it was reasonably straightforward to reprotect any material that had been deprotected during the course o f the reaction, it was desirable to find conditions such that a reprotection step would not be necessary. Furthermore, the total amount o f material isolated, the desired product plus the 'reprotected' product, did not account for all o f the expected material. It was clear from the data accumulated during the course o f the reaction that the alcohol 63 was forming more slowly than was the ketone 23. It was hoped that the overall rate o f the reaction could be increased such that the reduction reaction would be complete before the de-silylation reaction had proceeded to a significant extent. The first factor to be varied was the amount o f the catalyst employed.  After some  experimentation, it was found that i f between 20 and 25 mol % o f the catalyst was employed, the reaction was complete after 48 h and no material corresponding to the alcohol 63 was detected. Thus, reaction o f the a, P-unsaturated ketone 22 with hydrogen at 45 psi with 25 mol % o f 10% palladium on charcoal in 0.3 M methanolic potassium hydroxide led to the ketone 23 in 88% yield. This reaction could readily be performed on a multi-gram scale. The work-up o f the hydrogenation reaction deserves comment.  O n larger scales, the  amount o f methanol present during the aqueous work-up tended to carry over a fair amount of water into the organic phase. The high water content made the organic phase difficult to dry and the dried solutions were often difficult to filter. It was desirable to remove the methanol by evaporation prior to the aqueous work-up and after the mixture had been filtered; however, it  68  was feared that concentrating the mixture in the presence o f the potassium hydroxide would lead to decomposition o f the product.  The methanol could be evaporated after the potassium  hydroxide was neutralized, but this was not seen as a significant improvement. In the end, ethyl acetate was added to the filtered reaction mixture and the mixture was stirred for 1 h.  The potassium hydroxide saponified the ethyl acetate, giving ethanol and  relatively harmless potassium acetate. The solvent was then evaporated and the residue, which was taken up in diethyl ether, washed once with saturated aqueous sodium chloride and dried, gave the product in a straightforward manner. The recrystallized product produced ir, *H nmr,  C nmr and mass spectra identical with  , 3  those previously reported for the racemic ketone 23.  In addition, a hexane solution o f the  4  product 23 produced an [ a ]  D  o f -36°.  The 400 M H z H nmr spectrum o f the ketone 23 is l  included in the Appendix as Figure 9. With the ketone 23 in hand, attention was turned to the completion o f the synthesis o f the diester 65.  This material was prepared in two steps from the ketone 23 (see Scheme 14). The  first step in this sequence called for the preparation o f the enol trifluoromethanesulfonate 64.  o  (b)  Me0 C 2  92%  23  64  65  Scheme 14: Synthesis o f 65 Reagents (a) L D A , T H F ; PhNTf , T H F ; 2  (b) C O , L i C l , E t N , P d ( P P h ) , M e O H . 3  3  4  69  The enol trifluoromethanesulfonate 64 was prepared from the ketone 23 by the method  20  o f M c M u r r y and Scott, in a manner similar to that used for the preparation o f the enol trifluoromethanesulfonate  17.  In this case, the temperature o f the reaction mixture had to be  raised to between -30 and -20 °C in order to attempt to drive the formation o f the enolate anion towards completion, and 1.35 equiv o f L D A was employed.  Even so, there was always  unreacted starting material in the product mixture. The use o f larger excesses o f the base led to extensive decomposition o f the starting material.  Although this result was dissatisfying, the  described conditions led to an excellent mass balance for the reaction and, thus, very little material was lost at this step as a result o f the incomplete formation o f the enolate anion. In the event, the ketone 23 was deprotonated by L D A in T H F solution and reaction o f the enolate anion with A'-phenyltrifluoromethanesulfonimide led to, after appropriate work-up and purification by column chromatography on silica gel, the enol trifluoromethanesulfonate 64 in 84% yield.  Removal o f the solvent from those fractions o f the eluate from the column that  contained the unreacted  starting material produced  13% o f the ketone  23.  The enol  trifluoromethanesulfonate 64 displayed, in the ir spectrum, a strong absorption at 1211 cm" for 1  the sulfonate function. The *H nmr spectrum showed a new 1 proton doublet at 5 = 5.8 ppm. These data showed that the desired reaction had taken place. In the mass spectrum, a mass o f m/z = 554 amu was detected for the molecular ion and a high resolution measurement o f this mass confirmed the expected molecular formula. In addition, a hexane solution o f the product 64 produced an [a]o o f -39°. The 400 M H z *H nmr spectrum o f the enol trifluoromethanesulfonate 64 is included in the Appendix as Figure 10. The enol trifluoromethanesulfonate 64 was converted into the diester 65 by a palladium catalyzed methoxycarbonylation reaction. This reaction was modeled upon chemistry  65  described  70  by Schoenberg et al. in which the alkoxycarbonylation reaction is carried out with aryl, benzyl and vinylic halides. These halides react with carbon monoxide and an alcohol at or below 100 °C in  the  presence  of  a  fert-amine  and  a  catalytic  amount  of  a  tris-  or  tetrakis-  (triphenylphosphine)palladium(O) complex (see Scheme 15).  X  A  .X  Pd(0)L  2  Y  A  OA  \  y  -R NHX 3  Pd \  co  X  7  \S^y  O A = oxidative addition R E = reductive elimination Scheme 15: Palladium(O) Catalyzed Methoxycarbonylation Pathway  A s was the case in the palladium(0)-catalyzed Stille-type coupling, which was described for the preparation o f the diene 18, the first step in this alkoxycarbonylation process is an oxidative addition o f the carbon-halide bond.  The carbon monoxide then coordinates to the  71  palladium centre, and rapidly inserts into the carbon-palladium single bond. pathways are possible, both leading to the same product.  A t this point, two  The palladium atom may reductively  eliminate, leaving an acyl halide. This acyl halide would rapidly react with the alcohol, usually used as the solvent, to give the product and a tert-amme—HX salt.  Alternatively, a solvent  molecule may displace the halide bound to the palladium atom, splitting off F I X as the tertamine—HX salt. Reductive elimination at this point gives the product. Because palladium(O), derived from tetrakis(triphenylphosphine)palladium(0), is known to oxidatively add the carbon-oxygen bond o f an enol trifluoromethanesulfonate, the analogous reaction with an enol trifluoromethanesulfonyl ether, such as the trifluoromethanesulfonate should be straightforward.  64,  A s is common practice with intermolecular Stille type couplings  involving enol trifluoromethanesulfonyl ethers, lithium chloride was added to the reaction mixture.  This  soluble  source  of  chloride  ion  aids  the  reaction  by  displacing  the  trifluoromethanesulfonate on the palladium atom after the initial oxidative addition. The complex with the trifluoromethanesulfonate  tends to decompose to insoluble material, removing the  palladium from the catalytic cycle as well as destroying the substrate.  The complex with the  chloride ligand is more stable under the reaction conditions and gives a more efficient reaction. Thus, reaction o f the enol trifluoromethanesulfonate 64 with carbon monoxide at 1 atm in methanol solvent in the presence o f triethylamine and a catalytic amount  o f tetrakis(tri-  phenylphosphine)palladium(O) at 70 °C gave, after appropriate work-up, purification by column chromatography on silica gel and distillation o f the oil obtained, the diester 65 in 92% yield. In the ir spectrum, this material displayed a strong absorption at 1723 cm" for the (coincident) 1  carbonyl stretches. The *H nmr spectrum showed 2 three proton singlets at 5 = 3.6 and 3.7 ppm for the 2 methoxy groups and a 1 proton resonance at 8 = 6.8 ppm for the olefinic proton o f the  72  a,|3-unsaturated ester.  These data support the conclusion that the desired reaction had taken  place. In the mass spectrum, a mass o f m/z = 464 amu was observed for the molecular ion and a high resolution measurement o f this mass confirmed the molecular formula. Elemental analysis o f the distilled product for carbon and hydrogen gave results within accepted limits. In addition, a hexane solution o f the product 65 produced an [ct] o f -90°. D  Thus, the diester 65 was prepared, based upon recovered starting material in the formation o f the enol trifluoromethanesulfonate step, in 57% overall yield in four steps from the ester 21. The second step o f the conversion o f the ester 21 into the ketone 23 was carried out by catalytic hydrogenation, replacing the previous dissolving metal reduction method that had been problematic. The third goal for the synthetic work, therefore, had been at least partially realized, (see page 13).  Preparation of the Keto Aldehyde 32 A t this stage, the synthetic plan called for the conversion o f the diester 65 into a substrate that would be suitable to undergo reaction to form the fourth ring required for the synthesis o f the cycloamphilectane carbon skeleton. It was envisaged that this ring would be constructed through an intramolecular aldol condensation reaction. In order to carry out this transformation, the keto aldehyde 32 was required. The keto aldehyde 32 was prepared from the diester 65 in 5 synthetic steps (see Scheme 16). The first step o f this process required the removal o f the fert-butyldimethylsilyl protecting  73  Scheme 16: Synthesis of 32 Reagents (a) Pd(OAc) , water, acetone; (b) cat. TPAP, 2  N M O , 4 A mol. sieves, CH C1 ; (c) MeMgBr, E t 0 ; (d) xs. DIBAL-H, E t 0 ; work-up. 2  2  2  2  74  group from the C - l (amphilectane numbering) fer^-butyldimethylsilyloxymethyl group. Attempts to remove the protecting group using fluoride ion, derived form tetra-«-butylammonium fluoride, in wet T H F solvent did not lead to any o f the expected alcohol 66.  The only organic product  isolated from this reaction displayed, in the H nmr spectrum, the typical hallmarks o f the l  expected carbon skeleton, the 2 three-proton doublets for the secondary methyl groups and the olefinic proton for the a , p-unsaturated ester, but only one signal that could be attributed to methoxy protons. In the ir spectrum, the product did not show the expected absorption around 3400 cm" for the hydroxyl group. 1  lactone 67.  Thus, it is likely that the product o f this reaction was the  Apparently, under the conditions o f the reaction, the fert-butyldimethylsilyl group  was cleaved and the intermediate alkoxide anion (or the alcohol 66, formed by protonation o f the intermediate alkoxide anion by the solvent) reacts further in a lactonization process with the methoxycarbonyl group at C - l l to give the lactone 67 and an equiv o f methanol. Even though the product o f the lactonization gives a 6 membered ring, this lactonization process was expected to be slow under neutral conditions. However, the conditions described above are fairly basic and the fluoride ion from the reagent, which was used in slight excess, was undoubtedly catalyzing the lactonization reaction.  Clearly, an alternative method to accomplish the  deprotection reaction was required. Attempts to remove the protecting group under acidic conditions, 1 M hydrochloric acid in aqueous T H F at rt, did lead to some o f the desired product, the alcohol 66, but this process was fairly slow and the product mixture was invariably contaminated with the above described lactone 67. Evidently, the acidic conditions o f this process were also catalyzing the lactonization reaction. Because the lactone 67 represented a significant portion o f the reaction mixture and a  75  loss o f the material that was not easily recovered, this method o f carrying out the desired deprotection reaction was also abandoned. Recent w o r k  66  by Wilson et al. has led to the development o f a method for the cleavage  of fert-butyldimethylsilyl protecting groups to form alcohols under nearly neutral conditions. This interesting process involves using a palladium(II) complex in wet acetone as solvent and proton source. The optimal conditions were found to be 5 mol % o f the catalyst and 5 equiv o f water at rt with the apparatus protected from light and under these conditions, several primary and secondary alcohols were prepared from their silyl protected derivatives. These results were encouraging and when the described conditions were applied to the present reaction, the desired alcohol 66 was obtained in excellent yield without contamination by the lactone 67. Thus, a solution o f the diester 65 in acetone was treated with water and 6 mol % o f chlorobis(acetonitrile)palladium(II) in the dark for a period o f 18 h.  Appropriate work-up  followed by purification o f the crude product by column chromatography on silica gel, gave the required alcohol 66 in nearly quantitative yield.  In the ir spectrum, the product displayed an  absorption at 3422 cm" for the primary alcohol O H stretch. 1  The *H nmr spectrum displayed  three-proton singlets at 8 = 3.6 and 3.7 ppm for the 2 methoxy groups.  A s this material was  prone to lactonization upon standing, further characterization was not carried out. The next step in the synthetic plan called for the oxidation o f the primary alcohol 66 to give the aldehyde 68.  The oxidation conditions had to be carefully chosen so that the  lactonization o f the starting material, known from the above work to be a relatively facile process, would be avoided. Oxidation using the previously described Swern conditions was not attempted as the reagent is known to be fairly acidic and it was feared that the acidity o f the reagent would tend to catalyze the undesired lactonization process.  76  The oxidation method that was used was that employing tetra-«-propylammonium perruthenate, a mild and convenient oxidant for alcohols developed by Griffith and Ley. Tetra67  rc-propylammonium  perruthenate is a commercially available, air-stable  and non-volatile  substance which readily converts primary alcohols to aldehydes and secondary alcohols to ketones without competing carbon-carbon double bond cleavage for unsaturated systems.  67  catalytically.  In the  presence  o f TV-methylmorpholine TV-oxide, the  or allylic  reagent can be  used  67  In the event, treatment o f the alcohol 66 with 7 mol % o f tetra-w-propylammonium perruthenate in methylene chloride in the presence o f /V-methylmorpholine JV-oxide and 4 A molecular sieves gave, after appropriate work-up, the required aldehyde 68 in 90% yield. This material displayed in the ir spectrum an absorption at 2722 cm" for the aldehydic C - H stretch. In 1  the TL nmr spectrum, this material displayed a 1 proton singlet at 8 = 9.6 ppm for the aldehyde proton.  These data indicated the desired transformation had taken place.  Since this material  quickly began to yellow upon standing, it was used in the next reaction without delay and, thus, it was not further characterized. A t this point in the synthesis, the introduction o f the C - l 5 carbon atom (amphilectane numbering) into the carbon skeleton was undertaken.  This carbon was to be added by reaction  of the aldehyde with an appropriate nucleophilic organometallic reagent such as a methyllithium or a methyl Grignard reagent, to provide, after appropriate work-up, the alcohols 69.  The  primary factor that had to be considered in the planning o f this transformation was the selectivity o f the addition.  The chosen reagent had to be chemoselective for addition to the aldehyde  function over either 1,2- or 1,4-addition to the a, P-unsaturated ester function. The carbon atom of an aldehyde carbonyl is more electrophilic than that o f an ester and much more electrophilic  77 than that of an ct,(3-unsaturated ester. Thus, chemoselectivity in this reaction was not expected to be problematic. The nucleophile chosen was methylmagnesium bromide. This reagent is a good nucleophile and is less reactive than methyllithium, thus, the addition reaction was expected to be controllable in a chemoselective sense. The best conditions found for this reaction were as follows. A solution of the aldehyde 68 in diethyl ether was treated with 3 equiv of methylmagnesium bromide solution at -78 °C for a period of 30 min. Quenching of the reaction mixture at -78 °C, followed by appropriate work-up and removal of the solvent gave a colourless oil. Analysis of this oil by tic showed it to be a mixture of two major and two minor components. The major components were both more polar than the minor components. All four were uv active. Although initially disconcerting, the presence of four products in the reaction mixture was not entirely unexpected. The nucleophilic addition of the Grignard reagent to the carbon atom of the aldehyde carbonyl was not expected to proceed with any great degree of face selectivity. Examination of molecular models did not suggest that the aldehyde 68 would adopt any particular conformation that would lead to the reagent being added selectively to one face of the aldehyde versus the other. Thus, the initial reaction was expected to lead to 2 epimeric alkoxide anions that, upon protonation, would give two epimeric alcohols, 69. It was known from the work done on the de-silylation reaction, (diester 65 -> alcohol 66) that the alcohol 66 tended to lactonize readily. Intramolecular cyclization of the 2 epimeric alkoxide anions described above, in a manner like that observed with the alcohol 66, would lead to 2 epimeric lactones, 70. Therefore, the presence of 4 components in the product mixture isolated from this reaction could easily be rationalized. The major two products, the more polar two components observed by tic analysis, were taken to be the alcohols 69, whereas the two  78  minor products were taken to be the lactones 70.  Both o f these materials contain a,0-  unsaturated ester-type functions, and thus, both sets o f compounds would be expected to be uv active. N o further spectroscopic evidence in support o f the products' identities was gathered. The presence o f 4 components in the product mixture from the Grignard addition was o f little synthetic consequence as the next step in the sequence called for reduction o f the above product mixture to provide the diols 74. It was believed that reduction o f either the alcohols 69 or the lactones 70 would lead to the diols 74 and it was hoped that the predicted product mixture could be characterized at this point. The product mixture derived from the above reaction was dissolved in diethyl ether and treated with an excess o f D I B A L - H .  Work-up o f the reaction mixture, under appropriate  conditions, led to a semi-solid foam as the crude product. Analysis o f this product by tic, quite surprisingly, showed it to be a mixture o f four components, similar to the product mixture isolated from the Grignard reaction.  A s was the case for the Grignard product mixture, the  product mixture o f this reduction reaction consisted o f two more polar compounds and two less polar compounds. The more polar compounds appeared to be the major components while the less polar compounds were the minor components.  The minor components were uv active,  whereas the major components were not. These observations led to the conclusion that the product was a mixture o f the expected diols 74 and the aldehydes 73. A rationalization o f this conclusion is as follows. Reaction o f the alcohols 69 with 3 equiv o f D I B A L - H , the first to deprotonate the alcohol and the second and third to reduce the ester moiety at C - l 1 (amphilectane numbering) would lead to, after work-up, the diols 74.  Because the alcohols 69 were epimeric at C-14, the product o f this reaction, the  diols 74, would also be epimeric. Furthermore, as the alcohols 69 were the major components o f  79  the Grignard product mixture, it is reasonable that their reduction products would constitute the  Scheme 17: Formation of 73 from 70  major portion o f the reduction product mixture. The diols 74 would not be expected to be uv active at 254 nm. Whereas it was expected that the lactones 70 would react with 2 equiv o f D D 3 A L - H to provide the diols 74, the formation o f the aldehydes 73 is readily explained (see Scheme 17). Delivery o f a hydride ion to C-20 (amphilectane numbering) would lead to the aluminum alkoxide salt 71. Apparently, this salt was stable under the reaction conditions. U p o n work-up, the salt was hydrolyzed to give the lactols 72. The lactols 72 were o f course in equilibrium with the open hydroxy aldehyde form, the aldehydes 73, and the equilibrium apparently favours the latter  80  form. That the equilibrium favours the open form is clear in that the a,P-unsaturated aldehyde function present in this form would explain the observed uv activity. A s above, two epimeric aldehydes were formed from the lactones 70. The complexity o f the above product mixture was disappointing, but again was o f little synthetic consequence.  The next step o f the synthetic plan called for an oxidation reaction that  would provide a single compound from the four components o f the product mixture, i f the above conclusions had been drawn correctly.  Thus, no attempt was made to further purify or  characterize this mixture and it was taken directly on to the next step. The product mixture from the reduction reaction was oxidized using the previously described method  67  o f Griffith and Ley. Thus, the product mixture was treated with a catalytic  amount o f tetra-«-propylammonium perruthenate in methylene chloride in the presence o f Nmethylmorpholine A^-oxide and 4 A molecular sieves.  Gratifyingly, analysis o f the reaction  mixture showed that it contained a single major component that was less polar than any o f the four starting materials. After appropriate work-up and purification by column chromatography on silica gel, the product was obtained as a clear, colourless oil. The keto aldehyde 32 was isolated in 65% yield. This yield is for the 3 steps from the aldehyde 68. Given the complexity o f the intermediate reaction mixtures and the lack o f full purification at each intermediate step, this efficiency was highly satisfying. The product 32 displayed, in the ir spectrum, an absorption at 2715 cm" , for the aldehydic C - H stretch and strong absorptions at 1723 and 1683 cm" , for the 1  1  carbonyl stretches o f the ketone and ester (coincident, 1723) and aldehyde (1683). The ^  nmr  spectrum showed a one-proton singlet at 8 = 9.3 ppm for the proton o f the aldehyde and a 3proton singlet at 8 = 2.0 ppm, within the 8 = 1.96 to 2.10 ppm multiplet, for the protons o f the methyl ketone. In the mass spectrum, a mass o f m/z = 332 amu was observed for the molecular  81  ion and a high resolution measurement confirmed the expected molecular formula. A chloroform solution of the product 32 gave an [a] of -44°. D  Thus, the keto aldehyde 32 was prepared from the diester 65 in 5 synthetic steps. The overall yield of this process was 59%. The 400 MHz H nmr spectrum of the keto aldehyde 32 is l  included in the Appendix as Figure 11.  Preparation of the Ketone 81  81 With the keto aldehyde 32 in hand, the closure of the fourth ring and the introduction of the last 2 required carbon atoms for the synthesis of the cycloamphilectane carbon skeleton could finally be addressed.  The synthetic plan called for the ring closure to proceed by an intra-  molecular aldol condensation.  After a selective reduction of the C-l5 to C-20 carbon-carbon  double bond of 76 (cycloamphilectane numbering), the C-l6 and C-l7 carbons would be installed into 30 by an alkylation, epimerization, alkylation reaction protocol (30-^79->80->81, see Scheme 18). After some experimentation, the best conditions for the ring closure reaction were found to be as follows.  The aldol condensation was carried out under conditions of basic catalysis in  82  Scheme 18: Synthesis o f 81  Reagents (a) 2.5 M methanolic K O H , M e O H , 4 A mol.  sieves; (b) ( P P h ) R h C l , E t S i H ; 6 M HC1, T H F ; cat. T P A P , N M O , 4 A mol. sieves, 3  3  3  C H C 1 ; (c) L D A , T H F ; H M P A ; M e l ; (d) N a O M e , M e O H . 2  2  methanol as solvent in the presence o f dry 4 A molecular sieves to absorb the liberated water. The most consistent results, in terms o f efficiency o f the process, were obtained when the aldol was allowed to form for extended periods o f time at rt followed by a brief period o f heating to drive the dehydration reaction to completion. When the heating period was omitted, the reaction invariably produced mixtures o f the desired product and unreacted starting material, despite tic analysis o f the reaction mixture suggesting the reaction had gone to completion. Presumably, the dehydration reaction was driven to completion when the sample o f the reaction mixture was applied to the tic plate by the silica gel, which is itself a good desiccant.  83  Thus, a suspension o f the keto aldehyde 32 and crushed 4 A molecular sieves was made basic by the addition o f a few drops o f 2.5 M methanolic potassium hydroxide and stirred at rt for 18 h before being warmed to 50 °C and stirred at that temperature for 2 h.  Appropriate  work-up, purification by column chromatography on silica gel and recrystallization o f the derived crude product, gave the dienone 76 in 72% yield.  This material displayed, in the ir spectrum,  strong absorptions at 1711 and 1676 cm" , for the carbonyl stretches for the ester and ketone 1  functions, respectively, and a strong absorption at 1638 cm" , for the carbon-carbon double 1  bonds. The H nmr spectrum showed 3 one-proton resonances at 8 = 5.9, 6.1 and 6.9 ppm for X  the 3 olefinic protons.  In the mass spectrum, a mass at m/z = 314 amu was observed for the  molecular ion and a high resolution measurement o f this mass confirmed the expected molecular formula.  Elemental analysis for carbon and hydrogen gave results within accepted limits.  A  chloroform solution o f the recrystallized product produced an [CX]D o f -215°. The 400 M H z T4 nmr spectrum o f the dienone 76 is included in the Appendix as Figure 12. A t this point, the synthetic plan called for a chemoselective reduction o f the C - l 5 to C-20 (cycloamphilectane numbering) carbon-carbon  double bond.  It was imagined that this  transformation would be difficult to achieve. The cycloamphilectane skeleton required that the C-10 to C - l l double bond be left untouched. Previously in this work, a catalytic hydrogenation process was used to effect the reduction o f an ct,P double bond o f an ct,p-unsaturated ketone. A search o f the chemical literature revealed that it is known that catalytic hydrogenation can be used to effect the reduction o f the y,8 double bond o f an a,p-y,8-dienone.  68  This, o f course is the  exact opposite o f the required result. The a,P-unsaturation, however, was a disubstituted double bond at the edge o f the molecule, whereas the y,8-unsaturation is trisubstituted and more internal. The a,P-unsaturation was, therefore, more accessible to the surface o f a heterogenous catalyst  84  and it was possible that the rate o f its hydrogenation might have been significantly higher than that o f the y,8-unsaturation. Thus, a small amount o f the dienone 76 was treated with palladium on charcoal under an atmosphere o f hydrogen in methanol for 10 min. Filtration, followed by removal o f the solvent led to a virtually quantitative mass recovery o f material that did not show any signals whatsoever in the olefinic region o f its ^  nmr spectrum.  Clearly, another method o f effecting this trans-  formation was required. Fortunato and Ganem have reported  69  an interesting method for the conversion o f  a,3-unsaturated ketones and esters into synthetically useful enolate anions.  P-Unsubstituted  cyclic a,P-unsaturated ketones, especially those in 6 membered rings, upon treatment with lithium or potassium tri-sec-butylborohydride, were shown to undergo selective 1,4-reduction to ketone enolate anions which could then be reacted with various electrophiles.  Acyclic  a, P-unsaturated ketones, on the other hand, displayed mainly 1,2-reduction products. The report of these results was quite encouraging. Unfortunately, treatment o f the dienone 76 under the conditions authors led only to the isolation o f the alcohol 77.  69  described by the  Presumably, the presence  o f the  y,5-unsaturation in some way makes the dienone less prone to 1,4-reduction and the reagent delivers the hydride in a 1,2-fashion.  85  Other reagents or methods attempted for the selective reduction included diimide, generated from potassium azodicarboxylate, palladium catalyzed conjugate reduction with tri-«70  butyltin hydride  71  and a copper(I) bromide—lithium trimethoxyaluminum hydride complex.  72  In  each case, the reaction returned only starting material. After much experimentation, the method that was chosen to effect the selective reduction of the dienone 76 involved rhodium catalyzed hydrosilation by the method authors found that, in the presence o f Wilkinson's catalyst,  63  73  o f Ojima et al. The  a , P-unsaturated ketones react with  triethylsilane to provide the corresponding enol silyl ethers in good to excellent yields; only conjugated double bonds are affected. reaction was reported  73  Saturated ketones react to give alkyl silyl ethers. This  to work best when run without a solvent.  Thus, the dienone 76 was suspended in triethylsilane and the suspension was heated to 60 °C.  A t this temperature, the starting material dissolved and a pale yellow solution was  obtained. The catalyst was added as a solution in methylene chloride and the methylene chloride added was immediately driven off by evaporation under a stream o f dry argon. The reaction was allowed to proceed for 30 min after which time the mixture was cooled to rt. Work-up o f the reaction mixture gave an oil which, by tic analysis, was a mixture o f compounds o f similar polarity to the starting material and compounds much less polar than the starting material. The above crude product, assumed to be a mixture o f silyl enol ethers and their corresponding hydrolysis products, was taken up in T H F and treated with aqueous hydrochloric acid to hydrolyze any silyl ethers that were present.  Analysis o f this mixture, again by tic,  showed it to consist o f compounds o f polarity similar to that o f the starting material and o f compounds o f polarity greater than that o f the starting material. This material was taken to be a  86  mixture o f the desired product and products o f the hydrosilation o f the dienone carbonyl. Appropriate work-up o f the hydrolysis reaction mixture gave an oily solid. This solid was immediately treated under the above described  67  tetra-«-propylammonium  perruthenate oxidation conditions. Gratifyingly, analysis o f this reaction mixture, by tic, showed it to consist o f a single component in addition to the starting material, dienone 76. The r f o f the new material was similar to that o f the starting material. Work-up o f this reaction, followed by purification o f the crude product by column chromatography on silica gel and recrystallization o f the resulting solid, gave the ketone 30 in 79% yield from the dienone 76. Also isolated was 11% of the starting material, dienone 76. The ketone 30 displayed, in the ir spectrum, a strong absorption at 1712 cm" , for the 1  (coincident) carbonyl stretches. The H nmr spectrum showed a single resonance in the olefinic X  region, a doublet o f doublets at 8 = 5.6 ppm. A mass o f m/z = 316 amu was observed in the mass spectrum, for the molecular ion, and a high resolution measurement o f this mass confirmed the expected molecular formula. A chloroform solution o f the recrystallized product produced an [ a ]  D  of-37°. The gem-dimethyl function, representing the last two carbon atoms missing from the  cycloamphilectene skeleton, was introduced by standard alkylation chemistry. Thus, treatment o f the  ketone  30  with 2  equiv  o f L D A in T H F at  -78 °C  followed by  addition  of  hexamethylphosphoramide and methyl iodide, gave, after appropriate work-up and separation by column chromatography on silica gel, two products in a ratio o f about 5:2.  Both products  showed, in the H nmr spectrum, a new 3 proton doublet for the introduced secondary methyl X  group.  The major component showed the new resonance at 8 = 1.09 ppm while the minor  component showed the new resonance at 8 = 0.99 ppm.  87  Treatment o f the major component under epimerizing conditions (sodium methoxide, methanol, rt) cleanly converted it into the minor component.  Thus, the major component from  the alkylation reaction was the ketone 79 while the minor component was the thermodynamically more stable ketone 80.  After appropriate work-up, the material isolated from the epimerization  reaction was combined with the minor component  isolated from the alkylation reaction.  Recrystallization gave the ketone 80 in 90% yield from the ketone 30. This material displayed, in the ir spectrum, a strong absorption at 1713 cm" , for the (coincident) carbonyl stretches. The TI 1  nmr spectrum displayed three 3-proton doublets at 5 = 0.86, 0.97 and 0.99 ppm for the three secondary methyl groups and a 1 proton resonance at 8 = 5.6 ppm for the olefinic proton.  A  mass o f m/z = 330 amu was observed in the mass spectrum for the molecular ion and a high resolution measurement o f this mass confirmed the expected molecular formula for the ketone 80.  A n elemental analysis for carbon and hydrogen produced results within accepted limits.  A  chloroform solution o f the recrystallized material produced an [OC]D o f -28°. Treatment o f the ketone 80 with 3 equiv o f L D A in T H F at -48 °C followed by addition of hexamethylphosphoramide and methyl iodide gave, after appropriate work-up and purification by column chromatography on silica gel, the ketone 81 as a colourless oil in 78% yield.  This  material displayed, in the ir spectrum, strong absorptions at 1720 and 1705 cm" , for the carbonyl 1  stretches. In the H nmr spectrum, two 3-proton singlets were observed at 8 = 1.0 and 1.1 ppm l  for the gem-dimethyl function. A mass o f m/z = 344 amu was observed in the mass spectrum for the molecular ion and a high resolution measurement o f this mass confirmed the expected molecular formula. A chloroform solution o f the product gave an [OC]D o f +5°. A t this point, it was possible to assign the stereochemistry at C - l (cycloamphilectane numbering). With the introduction o f the second methyl group o f the gem-dimethyl function, the  88  *H nmr spectrum o f the ketone 81 was simplified considerably, compared to those o f the ketones 30, 79 or 80, in that only a single proton remained a to the C - l 4 carbonyl group. A sample o f the ketone 81 was dissolved in methyl alcohol-^ and the solution was treated with a small amount of sodium hydride. The resulting very pale yellow solution was heated to reflux and maintained at this temperature for 16 h. A H nmr spectrum o f the worked-up and purified product lacked !  the ddd at 6 = 2.3 ppm that was previously present in the spectrum o f the ketone 81. signal at 6 = 2.3 ppm could be assigned to H - l with confidence.  Thus the  Inspection o f the coupling  constants for this signal, J= 12, 12 and 3 H z , suggested that the orientation o f this proton had to be a.  In this orientation, two large coupling constants, to H-2f3 and H - l 2 , and one smaller  coupling constant, to H-2ot, would be expected.  In the  approximately equal coupling constants would be expected.  3-orientation,  3 smaller and  Clearly, the configuration at C - l  was that with the proton in the ct-orientation. This is the required configuration for the carbon skeleton o f 8-isocyano-10-cycloamphilectene (11). With the peak pattern for H - l established, it was possible to look back at the H nmr !  spectra o f the ketones 30, 79 and 80 to attempt to establish the C - l stereochemistry in these compounds.  In the * H nmr spectrum o f the C-150 methyl compound, ketone 80, a ddm was  observed at 5 = 2.1 ppm, within the 8 = 1.93 to 2.15 ppm multiplet, that showed the same coupling constants for the large couplings, J= 12 H z , as that observed for H - l in the ketone 81. In the *H nmr spectrum o f the C - l 5 a methyl compound, ketone 79, a ddd was observed at 5 = 2.2 ppm, within the 5 = 2.12 to 2.26 ppm multiplet, that also showed the same coupling constants as did H - l from the ketone 81. Similarly for the ketone 30, a ddd was observed at 8 = 2.1 ppm with coupling constants J = 12, 12 and 3 H z , again the same as those for the ketone 81.  89  These data suggest that the configuration at C - l for each o f these compounds was that with H - l in the a-orientation. These observations were the basis for the assignment o f the configuration at C - l in the ketones 30, 79 and 80. U p o n examination o f molecular models o f the dienone 76, it seemed that the epimer with H - l in the a-orientation would show a pattern o f coupling constants similar to that observed for the a,P-saturated compounds.  U p o n similar examination o f the other C - l epimer, it was not  clear what conformation the molecule would adopt. In any case, upon examination o f the *H nmr spectrum o f the dienone 76 it was not possible to assign the C - l proton with any degree of certainty. Comparison o f the two molecular models o f the C - l epimers o f the dienone (76 and 78) did suggest, however, that the C - l a epimer (76) had a lower energy ground state than did the C-13 epimer (78). The C - i p epimer suffers from a severe eclipsing interaction along the C - l to C-12 carbon-carbon single bond as well as a 'flagpole' type interaction across the (boat-like) C-ring. The C - l a epimer, on the other hand, lacks these steric interactions. Thus, on the basis of these arguments, and the fact that the ring closure reaction was run under conditions that could equilibrate the two epimers, the configuration at C - l for the product o f this reaction was assigned as a .  90  Thus the ketone 81 was prepared from the keto aldehyde 32 in 5 synthetic steps in 44% overall yield, based on recovered starting material for the selective reduction step. A t this point, the carbon skeleton with the correct configuration for the target molecule at each stereogenic centre, was complete.  Preparation of (+)-8-Isocyano-10-cycloamphilectene (11)  -C 11  With the required carbon skeleton constructed, all that remained for the total synthesis o f the diterpene isocyanide 11 was the reduction o f the C-14 (cycloamphilectane numbering) ketone function to a methylene group and the conversion o f the methyl ester moiety attached to C-8 into an isocyanide group (see Scheme 19). A s the C-14 ketone is fairly hindered, flanked on one side by a gem-dimethyl group and on the other by a tertiary carbon, the method o f effecting its reduction had to be one that was not sensitive to steric crowding. The procedure chosen for this reduction involved, as the key step, the excellent deoxygenation methodology  74  developed by  Barton and McCombie. Numerous methods have been developed for the deoxygenation o f alcohols. For primary alcohols, reduction o f  a suitable derivative o f the alcohol is common.  The Super-Hydride®  91  - C 11 Scheme 19: Completion o f the Total Synthesis o f 11 Reagents (a) NaBFL,, M e O H ; (b) L D A , T H F ; H M P A ; C S ; M e l ; (c) n - B u S n H , cat. A T R N , toluene; (d) PhSeNa, H M P A , 2  3  T H F ; (e) ( P h O ) P O N , E t N , toluene; 2-trimethylsilylethanol, E t N ; (f) « - B u N F , T H F ; 2  3  3  3  4  work-up; acetic formic anhydride, E t 0 ; work-up; P P h , C C U , E t N , CH C1 . 2  3  3  2  2  92  reduction o f the p-toluenesulfonate 59 to the ester 21 was an example o f this methodology. Many primary alcohols have also been converted to their corresponding halides. The alkane is then available by hydrogenolysis o f the halide. alcohols where  processes take place readily.  This method can be extended to secondary Tertiary alcohols can usually be dehydrated  readily and the hydrocarbon is then accessible through hydrogenation o f the olefin. These processes, except o f course for the hydrogenation processes, are ionic in principle. They have limitations and disadvantages as soon as complex, polyfunctional compounds, where competing processes may detract from the yield o f the desired reduction reaction, are used as substrates.  Furthermore, when secondary or tertiary alcohols are used as the substrate, the  reduction reaction tends to be more difficult.  The main reason for this is that, in cases o f high  steric demand, nucleophilic substitution reactions take place in l o w yields i f at all.  Also,  rearrangements and eliminations are common side reactions when carbocations appear as intermediates. Thus, the above described reaction protocols tend to fail especially in cases where secondary alcohols are the required reduction substrates. Radical reactions offer themselves as alternatives to ionic reactions. Radicals are not solvated, to the extent that ions are, and as such are less susceptible to steric factors.  Moreover, radical reactions take place under neutral  conditions and so are ideally suited for application to sensitive, polyfunctional molecules.  The  method o f Barton and M c C o m b i e describes deoxygenation reactions in which the carbon-oxygen bond is cleaved through a homolytic process, giving carbon based radicals that are subsequently quenched by a hydrogen atom donor. When O-alkyl thiobenzoates  and O-alkyl S-methyl dithiocarbonates  derived from  secondary alcohols were heated with tri-77-butylstannane, in a suitable solvent, the corresponding  93  alkanes were isolated in high yield.  74  The mechanism for the reduction reaction is shown in Scheme 20. butylstannane provides a source o f tri-n-butylstannyl radicals.  74  Heating o f tri-«-  The stannyl radical adds to the  thiocarbonyl, forming a thermodynamically stable tin-sulfur single bond and a radical on the thiocarbonyl carbon.  Fragmentation o f this radical leads to the alkyl radical (R-) and the  ^SR' «-Bu Sn  R  3  «-Bu Sn 3  fragmentation  O  SR'  «-Bu SnH 3  RH  +  «-Bu Sn ' 3  ~<  R-  +  «-Bu Sn' 3  Scheme 20: Mechanism of the Barton Deoxygenation of a Dithiocarbonate  tributylstannyl thiol acid ester. The major driving force for this reaction is obtained in going from thiocarbonyl to carbonyl.  74  Tri-«-butylstannane then donates a hydrogen atom to the alkyl radial  in a chain propagating step, giving the reduced product and a tri-«-butylstannyl radical.  94  The  Barton  method  has  been  applied  thioimidazolides and O-alkyl dithiocarbonates.  to  various  Excellent results  O-alkyl  75  thioesters,  (9-alkyl  have been obtained using the  (3-alkyl S-methyl dithiocarbonate derivative in toluene and 2,2'-azobisisobutyronitrile as a radical initiator. To apply the Barton method to the present problem, the ketone function at C-14 (cycloamphilectane numbering) o f the ketone 81 had to be reduced to an alcohol. This reduction was carried out by a standard technique. reacted with sodium borohydride at rt.  The ketone 81 was dissolved in dry methanol and Appropriate work-up led to the isolation o f a nearly  quantitative yield o f the alcohols 82 and 83, epimers at C-14. In the ir spectrum, this mixture displayed an absorption at 3502 cm" , for the secondary alcohol O H stretch and a strong 1  absorption at 1723 cm" , for the ester carbonyl stretch. 1  A mass spectrum, taken on the mixture,  showed a mass at m/z = 346 amu for the molecular ion and a high resolution measurement o f this mass confirmed the expected molecular formula. In the *H nmr spectrum o f the mixture o f 82 and 83, two resonances were observed at 8 = 3.1 and 3.2 ppm for the carbinol protons o f the two epimers. The resonance at 5 = 3.1 ppm was a doublet with a coupling constant o f 11 H z . That at 8 = 3.2 ppm was a broad singlet. Integration o f these signals showed the epimers to be present in a ratio o f - 5 : 2 , respectively. The signal at 8 = 3.1 ppm could be assigned to the alcohol 82 with confidence; similarly, the signal at 8 = 3.2 ppm was assigned to the alcohol 83.  Examination o f molecular models shows that the  alcohol 82, with the hydroxyl group in the equatorial orientation, has the carbinol proton anti to the proton at C - l (cycloamphilectane numbering). The alcohol 83, with the hydroxyl in the axial orientation, has the carbon-hydrogen bond o f the carbinol proton roughly perpendicular to that o f the C - l proton.  Referring to the vicinal Karplus correlation,  76  one would expect the carbinol  95  proton o f the alcohol 82 to show a large coupling while that o f the alcohol 83 would show little or no coupling.  The data from the T i nmr spectrum bears out these expectations.  Thus the  reduction reaction gave the alcohol 82 as the major product and the alcohol 83 as the minor product. The mixture was carried on to the next step. After some experimentation, the best conditions found for the formation o f the required 0-alkyl ^-methyl dithiocarbonates 84 were as follows.  A solution o f the alcohols 82 and 83 in  T H F was added to a solution o f L D A in the same solvent and allowed to react at -48 °C. Addition o f dry hexamethylphosphoramide, followed by dry carbon disulfide, gave, in situ, the O-alkyl  dithiocarbonate  dithiocarbonates 84.  anion which  was  treated  with  methyl iodide to  provide  the  After appropriate work-up and purification by column chromatography on  silica gel, the dithiocarbonates 84 were isolated as a yellow oil in 92% yield. In the ir spectrum, the product mixture displayed strong absorptions at 1723 and 1196 cm" , for the carbonyl and thiocarbonyl stretches, respectively. 1  The H nmr spectrum :  showed a doublet at 8 = 5.7 ppm ( J = 13 H z ) and a broad singlet at 8 = 5.8 ppm for the carbinol protons o f the epimers o f the product. Integration o f these resonances showed them to be in the ratio o f - 5 : 2 , as was the ratio for the alcohols 82 and 83. The dithiocarbonates 84 were carried on to the Barton deoxygenation protocol as a mixture. The dithiocarbonates 84 were deoxygenated under the conditions described by Tatsuta 75  et al. Thus, slow addition o f a solution o f 2,2'-azobisisobutyronitrile in toluene to a hot solution of the dithiocarbonates 84 in toluene led to, after appropriate work-up and purification by column chromatography on silica gel, the deoxygenated ester 29 in good yield.  In the ir  spectrum, this material displayed a strong absorption at 1724 cm" , for the carbonyl stretch. 1  A  mass o f 330 amu was observed in the mass spectrum for the molecular ion and a high resolution  96  measurement o f this mass confirmed the expected molecular formula. A chloroform solution o f the purified product produced an [a]o o f - 5 3 ° . The successful deoxygenation reaction, leading to the ester 29, represented the completion o f the carbon skeleton o f the cycloamphilectanes, with the configuration correct at each stereogenic centre for the target natural product, 8-isocyano-10-cycloamphilectene (11).  With  the ester 29 in hand, the only chemistry remaining to complete the total synthesis o f the diterpene isocyanide was the conversion o f the methyl ester moiety attached to C-8 (cycloamphilectane numbering) into an isocyanide group. The first step in this transformation called for the conversion o f the C-8 ester moiety into the corresponding carboxylic acid.  It was anticipated that the ester 29 would be relatively 4  unreactive under normal saponification conditions. The mechanism o f saponification requires the addition o f hydroxide ion to the carbonyl carbon and the resultant formation o f a tetrahedral intermediate.  There already exists a relatively high degree o f steric hindrance around the C-8  (cycloamphilectane  numbering)  methoxycarbonyl  group,  and  formation  of a  tetrahedral  intermediate from the ester would result in severe steric interactions. To alleviate this expected problem, the reagent chosen for the hydrolysis o f the C-8 (cycloamphilectane numbering) ester was the highly nucleophilic phenyl selenide anion.  77  This  reagent cleaves esters by ON2 cleavage o f the carbon-oxygen bond between the methyl group and the oxygen. During the course o f the reaction, the carboxylate function remains trigonal. Since no new steric interactions are introduced, the reaction tends to proceed smoothly. Phenyl selenide anion seemed to be an ideal reagent for the required reaction. polarizability makes it a powerful nucleophile.  77  Its high  A powerful nucleophile is required to overcome  the relatively poor leaving group tendencies o f the carboxylate, which is displaced in the reaction.  97  Sodium phenyl selenide is an extremely weak base and is relatively easy to generate, either by deprotonation o f benzeneselenol with sodium hydride in a suitable solvent or by reduction o f diphenyldiselenide with sodium metal. Sodium borohydride may also be employed as the reductant but, in this case a relatively unreactive phenyl selenide—borane complex is formed.  77  In the event, conversion o f the ester 29 into the carboxylic acid 85 was carried out by heating a solution o f the ester 29 and sodium phenyl selenide in THF—hexamethylphosphoramide solution to reflux for 72 h.  After appropriate work-up and purification o f the crude  product mixture by column chromatography on silica gel, the acid 85 was isolated in 56% yield. Also isolated was 3 3 % o f the unreacted ester 29.  In the ir spectrum, the product displayed  absorptions at 3400-2450 and 1692 cm" , due to the carboxyl function. A chloroform solution o f 1  the product produced an [ a ] o f -70°. D  With the acid 85 in hand, the stage was set for the conversion o f the acid to the required isocyanide function and the completion o f the total synthesis o f 8-isocyano-10-cycloamphilectene (11). Fortunately, methodology appropriate for this transformation had been well worked out in 4  our laboratories for the previous syntheses o f the amphilectane diterpenoids.  The individual  stages o f this efficient, two pot process are given in Scheme 21. A solution o f the acid 85 in dry toluene was treated sequentially with triethylamine and diphenylphosphoryl azide  78  and stirred at 85 °C for a period o f 22 h. During this time aliquots o f  the reaction mixture were removed periodically and checked by ir analysis. The peaks due to the acid function, 3400-2450 and 1692 cm" , disappeared within 2 h and were replaced by a peak at 1  1766 cm" , presumably due to the acyl azide intermediate. 1  After 22 h, the peak at 1766 cm" had 1  itself disappeared and had been replaced by a peak at 2250 cm" , from the isocyanate 86. 1  2-(Trimethylsilyl)ethanol and additional triethylamine were added and the temperature was raised  98  to 100 °C. After 20 h at this temperature, additional portions o f these latter two reagents were added and the reaction was allowed to proceed for a further 24 h.  Appropriate work-up,  followed by purification o f the crude product by column chromatography on silica gel, gave the  11  89  88  Scheme 21: Intermediates in the Conversion o f 85 into 11 Reagents (a) ( P h O ) P O N , 2  3  E t N , toluene; (b) 2-trimethylsilylethanol, E t N ; (c) T B A F , T H F ; work-up; (d) acetic 3  3  formic anhydride, E t 0 ; (e) P P h , CCL,, E t N , CH C1 . 2  carbamate 87 in 80% yield.  3  3  2  2  This material displayed, in the ir spectrum, absorptions at 3446,  1736 and 1508 cm" , for the carbamate function, and was taken directly onto the next step. 1  The next step in the sequence involved treatment o f the carbamate 87 with tetra-rcbutylammonium fluoride in T H F . The product amine 88 was isolated after an aqueous work-up.  99  This material was treated immediately with acetic formic anhydride, which was prepared by the method  79  of Huffman.  The crude formamide 89, isolated after an aqueous work-up of the  reaction mixture, was immediately treated with triphenylphosphine, carbon tetrachloride and triethylamine, to effect the dehydration—deprotonation reaction and generate the isocyanide function.  PPh,  +  Ph PCl C C I 3  CCL,  3  + Ph PCl CC1 3  3  RNHCHO  R-  -N =  C;  \  91  R-  + -N  :  + ;C  +  Et NHCl 3  R-  + -N  PPh  3  CI +  CHC1  CI +  PPh 0  3  H  •C  :  H  3  92 S c h e m e 22: Mechanism of the Stepwise Dehydration of a Formamide  The dehydration reaction is believed to proceed in a stepwise manner (see Scheme 22).  80  The triphenylphosphine and the carbon tetrachloride react to form a salt which reacts with the formamide to give the intermediate 91 and an equiv of chloroform. Elimination of an equiv of triphenylphosphine oxide gives the intermediate 92. The isocyanide is formed by deprotonation of the intermediate 92 by triethylamine. Evidence for this mechanism exists in that deuterium labeling experiments have shown that the proton on the chloroform formed in the reaction comes exclusively from the N - H moiety.  80  After appropriate work-up, followed by purification of the crude product by column  100  chromatography on silica gel and recrystallization o f the solid thus obtained from methanol— water, 8-isocyano-10-cycloamphilectene (11) was obtained in 74% yield from the carbamate 87. The spectral and physical data recorded for this material, along with the data reported for the natural material, are presented in Table I. The melting point o f the recrystallized material was 87-89 °C.  Satisfyingly, in the ir spectrum, the product displayed a strong absorption at  2133 cm" , for the isocyanide, indicating the success o f the functional group transformation. The 1  T-I nmr spectrum showed only one resonance above 8 = 2.5 ppm, a broad doublet at 5.22 that integrated for one proton.  The  1 3  C nmr spectrum showed resonances for 21 carbons.  In the  mass spectrum, a mass o f m/z = 297 amu was observed and a high resolution measurement o f this mass confirmed the expected molecular formula. A chloroform solution o f the recrystallized material produced an [ a ] o f +23°. The 400 M H z T4 nmr spectrum o f (+)-8-isocyano-10-cycloD  amphilectene (11) is included in the Appendix as Figure 13. The melting point,  !  H nmr and mass spectral data are in exact accord with those  published for the natural product. The ir and 5  1 3  C nmr data for the synthetic material do not fully  agree with those published for the natural material. For comparative purposes, the  1 3  C nmr data  for the natural and synthetic 8-isocyano-lO-cycloamphilectenes are collected in Table I. 5  The  absorption in the ir spectrum for the isocyanide function determined for the synthetic material is in the range one would expect for an isocyanide function.  21  That reported for the natural  material does not fall within the expected range for an isocyanide. Clearly the reported value was in error. Curiously the value reported, 2245 cm" , does fall exactly within the range one would 1  expect for a cyanide. A s for the synthetic material displayed 21.  1 3  C nmr data, Kaslauskas et al. reported 20 resonances and the 5  It should be noted that the 20 resonances reported for the  natural material are in exact accord with 20 o f the signals found for the synthetic material and  101  that one would expect to observe 21 resonances i f all o f the carbons had significantly different chemical shifts. The extra resonance observed for the synthetic material was at 5 = 37.2 ppm. It seems likely that the extra resonance was omitted in the communication disclosing the natural material. The [CX]D values for the natural and synthetic material agreed in magnitude but differed in sign. Thus, it was clear that the enantiomer o f the natural material had been synthesized. In other  words,  the  structure  that was  depicted  as the  natural  product,  cycloamphilectene (11), is actually the other enantiomer o f the natural material. sample  81  o f (-)-8-isocyano-10-cycloamphilectene ((-)-ll), displayed H and l  1 3  8-isocyano-10A n authentic  C nmr spectra in  exact accord with the synthetic material. Thus, the dextrorotatory antipode o f the natural material was prepared from the ketone 81 in 6 synthetic steps and 46% overall yield. The above described synthetic efforts culminated in the total synthesis o f (+)-8-isocyano-10-cycloamphilectene (11) in 32 steps and 2% overall yield from the P-keto ester 35. T o our knowledge, this work represents the first total synthesis of a cycloamphilectane diterpenoid and, specifically, the first total synthesis o f (+)-8-isocyano-10cycloamphilectene (11).  102  Table I: Comparison o f C nmr Data for the Natural 8-Isocyano-10-cycloamphilectene ((-)-ll) and the Synthetic 8-Isocyano-10-cycloamphilectene ((+)-! 1)  Chemical Shift Observed in a  ( - ) - H (ppm) 15.2  Chemical Shift Observed in (+)-ll (ppm) 15.2  b  19.5  19.5  c  25.1  25.1  d  29.5  29.5  e  29.8  29.8  f  31.6  31.7  g  32.2  32.2  h  37.2*  37.2  i  37.7  37.7  j  38.0  38.0  k  40.6  40.6  1  42.7  42.7  m  43.1  43.0  n  44.0  43.9  o  46.2  46.2  P  47.6  47.6  q  49.0  49.0  r  62.8  62.8  s  115.2  115.2  t  137.5  137.6  u  154.4  154.4  5  Resonance  *  This resonance, absent from the reported data, was observed in the C nmr spectrum o f 5  an authentic sample o f the natural product. 81  1 3  103  Conclusions  11  The work described in the discussion section o f this thesis constitutes the successful total synthesis o f (+)-8-isocyano-10-cycloamphilectene (11).  This compound was synthesized in 32  steps from the p-keto ester 35 which in turn was synthesized in four steps from commercially available (5i?)-(+)-pulegone (40).  Overall, the 36 step linear sequence proceeded in approx-  imately 2% yield. The synthesis was convergent at two points, one involving the iodide 15, prepared from commercially available 5-chloro-l-pentyne by a 5 stage process that proceeded in 71% overall yield and the other involving methyl 2-bromoacrylate, prepared from commercially available methyl acrylate by a one pot two-step process that proceeded in 81% yield. T o our knowledge, this was the first total synthesis o f this biologically active and structurally interesting natural product. The key features o f the described total synthesis were the reactions which formed the second, third and fourth rings, namely an intramolecular Stille-type coupling, a Diels - Alder reaction and an intramolecular aldol condensation reaction, respectively. The configurations at C - l , C-3 and C-12 (cycloamphilectane numbering) were established under thermodynamic  104  control whereas those o f C-4, C-8 and C-13 were established under kinetic control.  The  configuration at C-l was that from the commercially obtained starting material for the synthesis, (5i?)-(+)-pulegone  (40).  Because the optical rotation o f the natural and synthetic materials agreed in magnitude but differed in sign, it was clear that the synthetic material was the other enantiomer o f the natural product.  Thus, the first goal o f the synthesis (see page 12) to establish the absolute  configuration o f the natural product, was realized.  The absolute configuration o f the natural  product is opposite to that depicted in structure 11. A t the stage where the C-ring o f the carbon skeleton was formed, the facial selectivity o f the Diels - Alder process was improved over that employed in the amphilectane syntheses. The previous syntheses showed, at best, a 7:3 facial selectivity whereas the Diels - Alder process in the synthetic efforts described herein proceeded with complete facial selectivity.  Thus, the  second goal o f the synthesis was also realized (see page 12). The third goal o f the synthesis (see page 13) to improve the efficiency o f the somewhat problematic process wherein the ester 21 was converted into the ketone 23, was only partly realized. Here, a more efficient and convenient process was found to carry out the reduction step of the sequence, but no alternative for the allylic oxidation step was found. Finally, the reported value for the ir absorption o f the isocyanide function o f 8-isocyano10-cycloamphilectene (11) would seem to be in error.  The value determined for the synthetic  material was in the expected range for this absorption, and the natural product does not display any abnormal behaviour. page 13).  Thus the fourth and final goal o f the synthesis was also realized (see  105  Experimental Section  General  Data Acquisition and Presentation Melting points were measured on a Fisher-Johns melting point apparatus and are uncorrected.  Distillation temperatures  distillations and are uncorrected.  refer to air bath temperatures  o f Kugelrohr type  Boiling points refer to wet-bulb stillhead temperatures,  measured with a thermometer, and are uncorrected. Pressures quoted (reduced pressures) refer to that o f the manifold to which the apparatus was attached. Infrared spectra were recorded either on thin films between sodium chloride plates (liquid samples) or on 1 to 2 weight percent potassium bromide pellets (solid samples) using a PerkinElmer model 1600 Fourier transform infrared spectrometer with internal calibration. Proton nuclear magnetic resonance ( T i nmr) spectra were recorded on Bruker model AC-200,  WH-400  or  AVA-500  spectrometers  at  200.132 M H z ,  400.100 M H z ,  or  500.130 M H z , respectively, using deuteriochloroform ( C D C K ) as the solvent unless otherwise noted.  Signal positions (5 values) are given in ppm from T M S and were measured relative to  that o f chloroform (5 7.26 ppm).  Coupling constants (J values) are given in H z .  The  multiplicity, integration, coupling constant(s) and assignment (when known) are given in parenthesis. T i n - hydrogen and tin - carbon coupling constants quoted are the average for those displayed by  1 1 7  S n and  119  Sn.  106  Carbon nuclear magnetic resonance ( C nmr) were recorded on Bruker model AC-200, 1 3  Varian model X L - 3 0 0 , Bruker models A M - 4 0 0 or A V A - 5 0 0 spectrometers at 50.323 M H z , 75.4 M H z , 100.614 M H z or 125.757 M H z , respectively, using C D C 1 otherwise noted.  3  as the solvent unless  Signal positions (8 values) are given in ppm from T M S and were measured  relative to that o f C D C 1 (8 77.0 ppm). 3  L o w and high resolution electron impact (EI) mass spectra were recorded on Kratos M S 5 0 or M S 8 0 mass spectrometers at 70 eV. L o w and high resolution desorption chemical ionization (DCI) mass spectra were recorded with a Delsi Nermag model R-10-10C mass spectrometer using either ammonia, isobutane or methane or mixtures o f these materials as the ionizing gas. These analyses were performed by the U B C Mass Spectrometry Laboratory. Elemental analyses were performed on a Carlo Erba model 1106 C H N elemental analyzer or on a Fisons E A model 1108 elemental analyzer or using standard micro-analytical techniques. These analyses were carried out by M r . P. Borda o f the U B C Microanalytical Laboratory. Optical rotations o f samples were measured with a Perkin-Elmer model M C - 2 4 1 polarimeter at 589 nm (sodium ' D ' line) and 436 nm. High  performance  liquid  chromatography was performed  using a Waters  600E  Multisolvent Delivery System connected in series to a Waters 486 Tunable Absorbance Detector and a Waters 410 Differential Refractometer. Preparative liquid chromatography was done on a Waters Prep 500 system using normal phase silica gel columns. analyses  were  performed  on  Hewlett-Packard models  Gas-liquid chromatographic  5880A  or  5890  capillary  gas  chromatographs employing commercial fused silica columns (20 m x 0.21 mm x 30 urn) coated with cross-linked 5% phenyl 95% methyl silicone. Thin layer chromatography was carried out on commercial aluminum backed silica gel 60 plates (E. Merck, type 5554, 0.2 mm on aluminum).  107  Visualization  was  accomplished by  ultraviolet light  (254 nm),  commercial 20%  w/v  phosphomolybdic acid in ethanol, aqueous eerie ammonium molybdate, basic aqueous potassium permanganate and/or iodine.  Liquid—solid chromatography (column chromatography) was  performed with either 230-400 mesh silica gel (E. Merck, silica gel 60) using apparatus described  823  by Still et al. and the method described by Williams et al.  82b  silica gel (Sigma, tic grade silica) using the method described by Taber.  or type H 5 - 25 um  82c  Compounds that were submitted for high resolution mass spectrometry and elemental analysis were typically homogenous by tic analysis and/or greater than 95% pure by gle analysis. In a few cases, these analyses were carried out on mixtures that other analytical methods had shown to be epimeric in nature. A l l reactions were carried out under an atmosphere o f dry argon using glassware that had been thoroughly flame or oven dried, unless otherwise stated.  Glass syringes, stainless steel  needles and Teflon® cannulae were oven dried prior to use. Plastic syringes were flushed with dry argon. Removal o f solvent refers to concentration using a rotary evaporator at - 1 5 Torr, followed  by evacuation under  reduced  pressure  (rotary vacuum pump, -0.05 Torr) i f  appropriate. Cold temperatures were maintained by use o f the following baths: 0 °C, ice—water; -10 °C, ice—acetone; -20 °C, -30 °C, -40 °C and -48 °C, D r y Ice®—aqueous calcium chloride (27, 35, 41 and 47 g o f C a C l -198 °C, liquid nitrogen.  2  per 100 ml o f H 0 ) , respectively; -78 °C, D r y Ice®—acetone; 2  108  Reference to a glove box and operations carried out in a glove box refer to a Vacuum Atmospheres Company Dri-Box.  The glove box allows storage and manipulation o f materials  under an atmosphere o f dry argon.  Solvents and Reagents The argon gas used was commercial grade and was purchased from either Matheson Gas Products  or Praxair Canada Incorporated.  D r y argon refers to  argon passed  through  concentrated sulfuric acid, potassium hydroxide pellets and Drierite® prior to use. Solvents and reagents were purified and dried using accepted procedures. ether refers to a hydrocarbon mixture with bp 35-60° C.  Petroleum  Aqueous N H C 1 — N H 4 O H ( p H 8) 4  refers to saturated NH4CI (aq) adjusted to p H 8 ( p H paper) by the addition o f 30% N H 4 O H (aq). Dry T H F , ether or toluene refer to T H F , ether or toluene heated to reflux over and distilled from sodium metal under an atmosphere o f dry argon. D r y methylene chloride, benzene or methanol refer to methylene chloride, benzene or methanol heated to reflux over and distilled from calcium hydride under an atmosphere o f dry argon. Lithium diisopropylamide solution was prepared by dropwise addition o f a solution o f fer/-butyllithium  in pentane to a stirred solution o f diisopropylamine (1.0 equiv) in dry T H F at  -78 °C until a pale yellow colour persisted for 1 minute.  Addition o f 0.1 equiv o f additional  diisopropylamine gave a colourless solution o f the base, which was then ready for immediate use. Methyl iodide was dried and purified by filtration through oven dried basic alumina followed by distillation from calcium hydride.  Samarium metal (-40 mesh) was purchased from  Cerac Specialty Inorganics and stored in a glove box.  (/?)-(+)-Pulegone was 'purem' grade  109  purchased from Fluka Chemie A G and was used as received. triethylborohydride solution in T H F .  Super-Hydride® is lithium  Carbon monoxide was C . P. grade purchased from  Matheson Gas Products. Apiezon® is a registered trademark o f the Shell Chemical Company.  Celite® is a  registered trademark o f the Celite Corporation. Drierite® is a registered trademark o f the W . A . Hammond Drierite Company. Corporation.  D r y Ice® is a registered trademark o f the Union Carbide  Florisil® is a registered trademark o f the U . S . Silica Company.  registered trademark o f the Hamilton Company. Whatman International Limited.  Gastight® is a  Magnum® is a registered trademark o f  PYREX® is a registered trademark o f Corning Incorporated.  Selectride® and Super-Hydride® are a registered trademarks o f the Aldrich Chemical Company, Incorporated. Incorporated.  Teflon® is a registered trademark o f E . I . du Pont de Nemours & Company, Tygon®  is  a  registered  trademark  of  the  Norton  Company.  110  Procedures  Preparation o f Methyl 6-Chloro-2-hexynoate (49)  83  C l ^ ^ N ^ C0 Me 2  49  A solution o f 5-chloro-l-pentyne (48) (24.38 g, 237.6 mmol) in dry T H F (600 m L ) was stirred magnetically and cooled to -78 °C. A solution o f fert-butyllithium in pentane (188 m L , 1.26 M ) was added by syringe. yellow colour.  A t the end o f the addition, the solution took on a very pale  The reaction mixture was stirred for an additional 5 min and then methyl  chloroformate (22.0 m L , 285 mmol) was added by syringe. The yellow colour disappeared but returned a few minutes later. After the mixture had been stirred for 10 min, the cooling bath was removed and the mixture was allowed to warm to rt. The solvent was removed from the yellow reaction mixture.  The residue was suspended in diethyl ether (300 m L ) and then poured into  saturated NH4CI (aq) (25 m L ) and water (75 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with saturated N a C l (aq) (3 x 100 mL), dried over M g S 0 4 and filtered. Removal o f the solvent gave the crude product which was essentially homogenous by glc and tic (developed with 10:1 petroleum ether - diethyl ether, visualized with the phosphomolybdic acid dip) analyses. Distillation o f the crude product (bp 61-63 °C at 0.17 Torr) gave the alkynic ester 49 (37.19 g, 97%) as a clear, colourless oil. This material displayed ir and H nmr spectra identical with those l  previously reported  413  for this compound.  Ill Preparation o f Methyl (£)-6-Chloro-3-(trimethylstannyl)-2-hexenoate (50)  C0 Me 2  CI  CI  Me Sn  Me Sh  3  C0 Me  3  50  2  51  A solution o f hexamethyldistannane (57.6 m L , 90.4 g, 276 mmol) in dry T H F (1.10 L ) was stirred magnetically and cooled to -78 °C.  A solution o f methyllithium in diethyl ether  (181 m L , 1.4 M ) was added by syringe and the resulting pale yellow, cloudy mixture was stirred for 25 min. Copper(I) cyanide (24.7 g, 276 mmol) was added in 1 portion. The resulting bright yellow mixture was warmed to -40 °C and stirred at that temperature for 30 min. The colour changed from yellow through orange to deep red during the stirring time.  The solution was  cooled to -78 °C and dry methanol (11.6 m L , 287 mmol) was added by syringe. A solution o f the alkynic ester 49 (36.92 g, 229.9 mmol) in dry T H F (100 mL) was added to the reaction flask by cannula. The resulting yellow solution was stirred for 4 h. The reaction vessel was opened to the atmosphere and aqueous NH4CI - N H 4 O H ( p H 8) (600 mL) was added.  The cold bath was  removed and the mixture was allowed to warm to rt and then vigorously stirred for 16 h. The phases were separated and the deep blue aqueous phase was extracted with diethyl ether (3 x 500 mL). The flocculent purple precipitate was kept with the organic phase.  The combined  organic phases were washed with saturated N a C l (aq) (3 x 500 m L ) , dried over M g S 0 filtered. analysis  4  and  Removal o f the solvent gave the crude product (90 g) as a clear, yellow oil. U p o n tic (developed  with  19:1  petroleum  ether  -  diethyl  ether,  visualized with  the  phosphomolybdic acid dip), this material proved to be a mixture o f a major component and a slightly less polar minor component.  Separation and purification was achieved by preparative  112 liquid chromatography (two 8 cm (width) by 32 cm (length) silica gel columns, 2% diethyl ether in petroleum ether, flow rate 200 mL/min, refractive index detection) on 8 to 10 m L portions o f the crude product. Combination o f appropriate fractions followed by removal o f the solvent and distillation (bp 124-128 °C at 1.20 Torr) o f the residue gave the cc,P-unsaturated ester 50 (61.30 g, 82%) as a clear, colourless oil. Similar treatment (bp 120-124 °C at 1.20 Torr) gave the minor component, which proved to be methyl (Z)-6-chloro-3-(trimethylstannyl)-2-hexenoate (51), (7.81 g, 10%) also as a clear, colourless oil. These materials showed *H nmr spectra identical with those previously reported for these compounds. " 41  Preparation o f (£)-6-Chloro-3-(trimethylstannyl)-2-hexen-l-ol (52)  Me Sn 3  52 A solution o f the a,3-unsaturated ester 50 (37.08 g, 114.0 mmol) in dry diethyl ether (700 mL) was stirred magnetically and cooled to -78 ° C  A solution o f D I B A L - H in hexanes  (239 m L , 1.0 M ) was added in 50 m L portions by syringe and the colourless solution was stirred for 1 h after which time tic analysis (developed with 4:1 petroleum ether - diethyl ether; visualized with the phosphomolybdic acid dip) showed the reaction to be complete.  The cold  bath was removed and the solution was allowed to warm to rt. The reaction vessel was opened to the atmosphere and diethyl ether (500 m L ) was added.  Saturated  NH4CI  (aq) (20 mL) was  added, cautiously at first, and the mixture was vigorously stirred for 4 h, after which time a thick,  113  white slurry had formed. Magnesium sulfate (2 g) and Celite" (5 g) were added and the mixture was stirred for an additional 10 min.  A short column (5 cm high in a 10 cm (width) coarse  sintered glass funnel) o f 230-400 mesh silica gel was prepared  and this was topped with a thin  (1 cm) layer o f Celite®. The reaction mixture was filtered through the column and the column was washed with diethyl ether (300 m L ) . Removal o f the solvent from the combined filtrates, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the alcohol 52 (32.79 g, 97%) as a clear, very pale yellow oil. This material could be used without further purification. reported  84  Ir and  X  H nmr spectra o f this material were identical with those previously  for this compound.  Preparation o f (E)-6-Chloro-l-[[(l, 1-dimethylethyl)dimethylsilyl]oxy]-3-(trimethylstannyl)-2hexene (53)  53 A solution o f the alcohol 52 (19.36 g, 65.10 mmol) in dry methylene chloride (1 L ) was stirred magnetically and cooled to -10 °C. Imidazole (5.76 g, 84.6 mmol) was added, followed by fert-butyldimethylsilyl chloride (10.8 g, 71.7 mmol). A white precipitate formed immediately. The mixture was stirred for 3 h, during which time the cold bath was allowed to melt and the mixture was allowed to warm to it.  The reaction vessel was opened to the atmosphere and  petroleum ether (500 m L ) was added.  A short (5 cm high in a 10 cm (width) coarse sintered  glass funnel) column o f 230-400 mesh silica gel was prepared. The reaction mixture was filtered  114  t h r o u g h the c o l u m n a n d the c o l u m n w a s w a s h e d w i t h p e t r o l e u m ether (250  solvent  from  c m (length) silica gel c o l u m n s , 0 . 2 5 %  liquid chromatography  ethyl acetate  in p e t r o l e u m  (two  appropriate  (vacuum  pump)  fractions,  g a v e the  followed  c h l o r i d e 53  by treatment  (25.40 g, 95%)  c o u l d be u s e d without further purification.  with those previously reported  8 4  o f the  Purification  of  8 c m (width) by  32  ether, f l o w  r e f r a c t i v e i n d e x d e t e c t i o n ) o n 8 t o 10 m L p o r t i o n s o f t h e c r u d e p r o d u c t .  the  R e m o v a l o f the  the filtrate g a v e the c r u d e p r o d u c t (28 g) as a clear, c o l o u r l e s s oil.  this material w a s a c c o m p l i s h e d b y preparative  from  mL).  rate 2 0 0  mL/min,  R e m o v a l o f the  residue under  reduced  as a c l e a r , c o l o u r l e s s o i l .  solvent  pressure  This  material  T h i s m a t e r i a l s h o w e d ir a n d T i n m r s p e c t r a i d e n t i c a l  for this c o m p o u n d .  Preparation o f ( £ ) - ! - [ [ ( ! , l - D i m e t h y l e t h y l ) d i m e t h y l s i l y l ] o x y ] - 6 - i o d o - 3 - ( t r i m e t h y l s t a n n y l ) - 2 -  hexene  (15)  15 A  307 mmol)  3 days.  solution  of  the  in acetone (300  chloride  53  mL)  stirred magnetically  was  (25.20 g,  61.21  mmol)  and  and heated  sodium  to reflux  iodide  for  (46.0  g,  a period  of  A t this t i m e , the m i x t u r e c o n t a i n e d a w h i t e precipitate a n d g l c analysis o f the liquid p h a s e  s h o w e d that the  starting  solvent w a s r e m o v e d .  material had been c o n s u m e d .  W a t e r (200  mL)  T h e mixture was  a n d diethyl ether (300  T h e mixture w a s shaken and the layers w e r e separated.  mL)  c o o l e d to it  w e r e a d d e d to the  and  residue.  T h e aqueous phase was extracted  d i e t h y l e t h e r (3 x 1 0 0 m L ) a n d t h e c o m b i n e d o r g a n i c p h a s e s w e r e d r i e d o v e r  MgSGv  the  The  with  dried  s o l u t i o n w a s filtered a n d the s o l v e n t w a s r e m o v e d to isolate the c r u d e p r o d u c t (32 g) as a clear,  115  very pale yellow oil. Distillation (180-190 °C at 0.12 Torr) gave the iodide 15 (29.87 g, 97%) as a clear, colourless oil. Ir and ' H nmr spectra o f this material were identical with those previously reported  84  for this compound.  Preparation o f {(li?,4i?)-4,8-Epoxy-3-oxo-/?-menthane and (li?,45)-4,8-Epoxy-3-oxo-/?menthane} (41)  41 A solution o f (7?)-(+)-pulegone (40) (47.13 g, 309.7 mmol) in methanol (250 mL) was stirred magnetically and cooled in an ice - water bath until its temperature had fallen below 4 °C. Aqueous hydrogen peroxide (30% by wt, 125 m L , 1.10 mol) was added and the temperature again was allowed to fall below 4 °C. A solution o f potassium hydroxide (37.5 g, 0.67 mol) in water (125 m L ) was prepared and cooled to it. The potassium hydroxide solution was added, dropwise from an addition funnel over a period o f about 1 h, to the pulegone solution, at a rate such that the temperature o f the reaction mixture did not rise above 10 °C. The mixture was stirred for an additional 4.5 h, maintaining the temperature between 4 and 10 °C. A t this time, glc analysis o f the reaction mixture showed that the starting material had been consumed.  The  mixture was poured into saturated N a C l (aq) (500 mL) and this mixture was extracted with diethyl ether (3 x 500 m L ) . The combined organic phases were washed with saturated N a C l (aq) (2 x 200 m L ) and dried over M g S 0  4  for a period o f 6 h. Removal o f the solvent followed by  116  treatment o f the residue under reduced pressure (vacuum pump) gave the epoxides 41 (50.01 g, 96%) as a clear, colourless oil. Analysis o f the oil by glc showed it to be a mixture o f the two expected diasteriomers in a ratio o f - 6 5 : 35. This ratio is in agreement with that previously reported for this mixture.  This material, which could be used without further purification,  85  displayed:  ir(film): 1740, 1260, 919 cm" . 1  J  H nmr (400 M H z ) : 5 = {(1.04 (d, J= 7 H z ) , 1.06 (d, J= 6 Hz)), 3 H , C - l - C H } , {(1.18 (s), 3  1.19 (s)), 3 H , 3° - C H } , 1.40 (s, 3 H , 3° - C H ) , 1.70 - 2.05 (m, 4 H ) , {(2.12 - 2.22 (m), 3  3  2.57 (ddd, J= 13, 3, 3 Hz)), 1 H } , 2.38 (br s, 2 H ) . Anal, calcd. for C i H O : C 71.39, H 9.59; found: C 71.55, H 9.65. 0  16  2  Preparation o f {(2i?,5 rv)-5-Methyl-2-(phenylthio)cyclohexanone and (2 S,5i?)-5-Methyl-2J  1  (phenylthio)cyclohexanone) (39)  O  39 Sodium hydride (7.49 g, 312 mmol) was placed in a dry 3 necked 2 L round-bottomed flask.  The flask was equipped with a condenser and the ports were capped with rubber septa.  Dry T H F (900 m L ) was added and the suspension was stirred magnetically at it. The reaction vessel was equipped with a vent, by piercing the septum on the condenser with a 16 ga needle,  117  and benzenethiol (32.1 m L , 312 mmol) was added, slowly, by syringe.  The resulting white  suspension was stirred for 1 h and then a solution o f the epoxide 41 (50.0 g, 297 mmol) in dry T H F (100 m L ) was added by cannula. The vent was removed. The mixture was heated to reflux for a period o f 16 h after which time the yellow solution was cooled to rt and poured into water (500 mL). Diethyl ether (300 mL) was added and the layers were separated. The aqueous phase was extracted with diethyl ether (3 x 200 mL). The combined organic phases were dried over MgS0  4  and filtered. Removal o f the solvent from the dried solution, followed by treatment o f  the residue under reduced pressure (vacuum pump), gave the sulfides 39 (65.1 g, 99%), as a mixture o f a yellow oil and a white solid. The title compound exists as a mixture o f epimers at C-2.  Analysis o f the mixture by glc showed the diastereomers to be in the ratio o f - 6 5 : 35,  consistent with that o f the starting material, the epoxides 41.  This material, which was used  without further purification, displayed:  !  H nmr (400 M H z ) : 5 = 0.98 - 1.08 (m, 3 H ) , 1.33 - 1.47 (m, 1 H ) , 1.60 - 2.36 (m, 5 H ) , 2.62 2.82 (m, 1 H ) , 3.70 - 3.90 (m, 1 H ) , 7.18 - 7.53 (m, 5 H ) .  lrms (EI): m/z = 220 (23%, M ) . +  A small amount o f the mixture was washed with pentane to separate the liquid phase from the solid phase. Removal o f the solvent from both fractions followed by treatment o f the residual oil and solid (separately) under reduced pressure (vacuum pump) gave samples that displayed:  ir (film): 3059, 1713, 750, 692 cm" , 1  ir ( K B r ) : 3068, 1704, 754, 692 cm" . 1  118  Preparation o f {(2i?,5i?)-5-Methyl-2-(phenylsulfinyl)cyclohexanone and (2o ,5^)-5-Methyl-2,  (phenylsulfinyl)cyclohexanone} (42)  O  O  42 A solution o f the sulfides 39 (65.33 g, 296.6 mmol) in methylene chloride (1 L ) was stirred magnetically and cooled to 0 °C.  Peracetic acid (32% by wt in dilute acetic acid,  70.5 m L , 297 mmol) was added dropwise over a period o f 10 min from an addition flannel and the mixture was stirred for an additional 10 min. A t this time, tic analysis o f the reaction mixture (developed with 4:1 petroleum ether - diethyl ether, visualized with the phosphomolybdic acid dip) showed the reaction to be complete. Saturated Na S2C«3 (aq) (100 m L ) was added and the 2 2  phase system was stirred vigorously for 5 min. The mixture was poured into diethyl ether (2.3 L ) and the layers were separated. The organic phase was washed successively with water (500 mL), 1:1 saturated N a H C 0 (aq) - water (3 x 350 m L ) and finally with saturated N a C l (aq) (2 x 3  100 mL). The organic phase was dried over MgSCu, filtered and the solvent was removed. The resulting viscous yellow oil was placed under reduced pressure (vacuum pump) to remove the last traces o f solvent and, upon standing, it solidified to give a pale yellow mass.  This material,  the sulfoxides 42, weighed 70.74 g (-100%), and was used without further purification. The title compound is a mixture o f diastereomers both at C-2 and at the sulfoxide sulfur. displayed:  ir ( K B r ) : 3051, 1704, 1046 cm" . 1  This material  119  Preparation o f (5i?)-(-)-5-Methyl-2-cyclohexenone (38) O  38 D r y calcium carbonate was prepared in the following manner. Calcium carbonate (-20 g) was placed in a beaker and heated in an oven at 140 °C for a period o f 16 hr. The beaker was transferred to a vacuum desiccator containing a beaker o f phosphorus pentoxide. The desiccator was placed under reduced pressure (vacuum pump) and maintained under static vacuum for a period o f 16 h and then brought to atmospheric pressure with a supply o f dry argon. The sulfoxides 42 (11.74 g, 49.68 mmol) and dry calcium carbonate (9.95 g, 99.4 mmol) were mixed thoroughly and then placed in a 250 m L round-bottomed flask. The flask was fitted with a vacuum trap and the apparatus was evacuated to a pressure o f 0.070 Torr. The vacuum trap flask was cooled to -78 °C and the reaction flask was heated in an oil bath to 90 °C. This temperature was maintained for 3 h. The oil and cooling baths were removed and the apparatus was brought to rt and atmospheric pressure. The crude product, 5.5 g o f a clear, colourless oil was taken up in pentane (75 m L ) and the solution was dried over M g S D , .  This material was  filtered and the pentane was removed by distillation at atmospheric pressure though a Vigreux column. The residue was distilled (60 - 70 °C at 16 Torr) to provide the a,P-unsaturated ketone 38 (4.98 g, 91%) as a clear, colourless oil. This oil produced ir and those previously reported  86  nmr spectra identical with  for this compound. In addition, this material displayed:  120  optical rotation: [ a ] [a]  2 5 D  2 6 D  -90° (c = 7.8, chloroform),  [a] 6  2 6  4 3  -2 1 9° (c = 7.8, chloroform); lit. : 87  -90° (c = 2.6, chloroform).  Preparation o f Methyl (57?)-5-Methyl-2-cyclohexenone-6-carboxylate (44)  O  O  44 A solution o f L D A in dry TFfF (40 mL) was prepared at -78 °C in the usual way from dry diisopropylamine (4.07 mL, 29.1 mmol) and a solution o f fert-butyllithium in pentane (16.5 mL, 1.76 M ) . D r y H M P A (4.74 m L , 27.3 mmol) was added rapidly, by syringe, and the resulting pale yellow solution was stirred for 15 min. A solution o f the ct,P-unsaturated ketone 38 (2.00 g, 18.2 mmol) in dry T H F (10 mL) was added by cannula and the mixture was stirred for 90 min. A solution o f methyl cyanoformate (2.16 m L , 27.2 mmol) in dry T H F (10 m L ) was added by cannula and the resulting yellow solution was stirred for 2 h. The reaction vessel was opened to Diethyl ether (20 m L ) and saturated NH4CI (aq) (20 m L ) were added.  the atmosphere.  mixture was allowed to warm to rt with efficient stirring.  The layers were separated.  The The  aqueous phase was extracted with diethyl ether (3 x 50 mL). The combined organic phases were dried over M g S 0 , filtered, and the solvent was removed. The crude product, a yellow oil, was 4  purified by column chromatography (180 g o f 230-400 mesh silica gel, 7 cm (width) column, 5:4 petroleum ether - diethyl ether). The appropriate fractions were combined and concentrated to provide the P-keto ester 44 (2.38 g, 78%) as a clear, colourless oil which solidified upon  121  standing. The title compound exists as a mixture o f epimers at the C-6 position. The ratio o f the epimers varied from experiment to experiment. Upon prolonged standing, especially in solution, the enol form o f the keto ester function, as well as the two C-6 epimers, could be observed in the *H nmr spectrum.  The solid material from the above described experiment, which was used  without further purification, displayed:  mp: 71-73 °C. ir (KBr): 1742, 1678, 1650, 1622, 1589, 1438 cm" . 1  T i nmr (400 M H z ) : 5 = 1.05 (d, 2.5 H , J= 7 H z , C-5 - C H : major isomer), 1.01 (d, 0.5 H , J = 3  7 H z , C-5 - C H : minor isomer), 2.10 (ddddd, 1 H , J = 10, 10, 10, 3, 3 H z , H - 4 B : both 3  isomers), 2.40 -2.65 (m, 2 H , H-4ct and H - 5 : both isomers), 3.10 (d, 0.82 H , J=  12 H z ,  H - 6 : major isomer), 3.37 (d, 0.18 H , J= 3 H z , H - 6 : minor isomer), 3.67 (s, 0.5 H , C H 0 - : 3  minor isomer), 3.74 (s, 2.5 H , C H 0 - : major isomer), 6.04 (ddd, 1 H , J = 10, 3, 1 H z , H - 2 : 3  both isomers), 6.95 (ddd, 0.82 H , J= 10, 6, 3 H z , H - 3 : major isomer), 7.02 (ddd, 0.18 H , J = 10, 6, 3 H z , H - 3 : minor isomer).  Preparation o f Methyl (3i?)-3-Methylcyclohexanone-2-carboxylate (35)  O  O  35  122  Palladium on activated charcoal (10% by wt, 1.13 g, 1.06 mmol) was placed in a roundbottomed flask which was then thoroughly flushed with argon and capped with a rubber septum. D r y diethyl ether (90 m L ) was added by syringe.  Magnetic stirring was started and the  suspension was cooled to -78 °C. The catalyst was presaturated by 3 cycles o f evacuating the flask (water aspirator) and then refilling it with hydrogen.  The reaction flask was warmed to  0 °C. A solution o f the 3-keto ester 44 (3.57 g, 21.3 mmol) in dry diethyl ether (10 mL) was added to the reaction flask by cannula. A positive pressure o f hydrogen was maintained (balloon) and the mixture was stirred vigorously for 30 min. The septum was removed and the atmosphere of hydrogen was displaced with a stream o f argon. Celite® (3 g) was added and the mixture was filtered through a short column (1.5 cm in a 150 m L medium sintered glass funnel) o f Celite®. The solid was washed with diethyl ether (50 mL). Removal o f the solvent from the combined filtrates, followed by distillation (60 - 80 °C, 0.30 Torr) o f the residue, gave the P-keto ester 35 (3.68 g, 97%) as a clear, colourless oil which semi-solidified on standing to give a mixture o f a clear, colourless oil and a colourless, crystalline solid. The ratio o f the epimers varied over time and from experiment to experiment.  The title compound exists as a mixture o f epimers at the  C-6 position. The liquid phase produced the following ir data:  ir(film): 1748, 1714, 1651, 1615, 1440, 1285, 1223 cm" . 1  The product mixture was well stirred to produce a suspension o f the solid and liquid phases. A sample o f the mixture displayed:  nmr (400 M H z ) : 5 = 1.03 (d, 2.7 H , J= 8 H z , C-3 - C H : major isomer), 1.06 (d, 0.3 H,J = 3  8 H z , C-3 - C H : minor isomer), 1.42 (ddd br d, 0.9 H , J= 12, 12, 12, 4 H z , major isomer), 3  123  1.48 - 1.55 (m, 0.1 H , minor isomer), 1.73 (ddddd, 0.9 H , J=  13, 13, 13, 4, 4 H z , major  isomer), 1.85 - 1.97 (m, 1 H , both isomers), 2.00 - 2.17 (m, 1 H , both isomers), 2.22 - 2.38 (m, 2 H , H-3 and one undetermined proton: both isomers), 2.47 (d br dd, 0.9 H , J= 13, 4, 4 H z , major isomer), 2.63 - 2.82 (m, 0.1 H , minor isomer), 3.05 (d, 0.9 H , J= 13 H z , H - 2 : major isomer), 3.58 (d, 0.1 H , J= 3 H z , H - 2 : minor isomer), 3.71 (s, 0.3 H , C H 0 - : minor 3  isomer), 3.75 (s, 2.7 H , C H 0 - : major isomer), 3  lrms (EI): m/z = 170 (38%, WT). hrms (EI): calcd. for C H i 0 : 170.0943; found: 170.0939. 9  4  3  A small sample o f the solid was removed and washed with hexane (to remove the liquid phase) and placed under reduced pressure (vacuum pump).  The *H nmr spectrum was run  immediately after the sample was made up. The solid material displayed the following data:  mp: 35 - 37 °C. T i nmr (400 M H z ) : 5: = 1.03 (d, 3 H , J = 8 H z , - C H ) , 1.42 (ddd br d, 1 H , J = 12, 12, 12, 3  4 H z ) , 1.73 (ddddd, \ H,J=  13, 13, 13,4, 4 H z ) , 1.88 - 1.97 (m, 1 H ) , 2.00 - 2.09 (m (10  lines), 1 H ) , 2.22 - 2.34 (m, 2 H ) , 2.47 (d br dd, 1 H , J= 13 H z , H - 2 proton), 3.75 (s, 3 H , C H 0 - ) . 3  13, 4, 4 H z ) , 3.05 (d, 1 H , J =  124  Preparation of Methyl (2R, 3i?)-24(£)-6-[[(l,l-Dimethylethyl)dimethylsilyl]oxy]-4-(trimethylstannyl)-4-hexenyl]-3-methylcyclohexanone-2-carboxylate  15  (16)  16  35  A suspension o f potassium hydride (0.32 g, 8.0 mmol) in dry o-xylene (20 mL) was stirred magnetically and cooled to 0 °C. A solution of the P-keto ester 35 (1.36 g, 8.00 mmol) in dry o-xylene (20 m L ) was added to the reaction vessel by cannula. The mixture was stirred for 15 min to obtain a colourless solution. A solution o f the iodide 15 (4.07 g, 8.00 mmol) in dry o-xylene (10 m L ) was added to the reaction vessel by cannula. The solution was heated to reflux for a period o f 16 h. During the first hour o f the heating period the solution became cloudy, cleared and then again became cloudy. A t the end o f the heating period, the reaction mixture was composed o f a white solid and a yellow solution. The mixture was cooled to rt and the solvent was removed under reduced pressure (vacuum pump).  The residue was treated with  saturated N F L C l (aq) (20 mL), water (20 m L ) and diethyl ether (50 m L ) .  The layers were  separated and the aqueous phase was extracted with diethyl ether (2 x 20 mL). The combined organic phases were dried over M g S 0 , filtered and the solvent was removed. 4  The crude  product, 4.45 g o f a clear yellow oil, was purified by column chromatography (230 g o f 230400 mesh silica gel, 5.5 cm (width) column, 12:1 petroleum ether - diethyl ether). Combination  125 of the appropriate fractions and removal o f the solvent, followed by distillation (160-180 °C at 0.10 Torr) of the residue gave the ketone 16 (3.37 g, 77%) as a clear, very pale yellow oil. This material displayed ir, *H nmr, low and high resolution ( D O ) mass spectra identical with those previously reported  1 3  43  for this compound. In addition, this material displayed:  C nmr (100 M H z ) : 5 = -9.3 (Un-c = 340 H z ) , -5.0 (2 carbons), 16.8, 18.4, 24.8, 25.4 ( J . = 4  S n  15 H z ) , 26.1 (3 carbons), 30.2, 31.6, 33.9 71 H z ) , 64.3, 140.5  (Vsn-c =  (V „s  C  c  = 45 H z ) , 39.3, 40.2, 51.6, 60.1 (V s „.c =  36 H z ) , 145.0, 171.8, 207.6.  optical rotation: [CX]D -126° (c = 1.9, chloroform). 25  Also isolated during the column chromatography procedure, from the earlier fractions of eluate, was 0.65 g (16%) of the iodide 15. None of the 3-keto ester 35 was recovered.  Purification of Commercial A^-Phenyltrifluoromethanesulfonimide  A column was prepared employing 120 g of 230-400 mesh silica gel as the stationary phase and 10:1 petroleum ether - diethyl ether as the mobile phase. Commercial A^-phenyltrifluoromethanesulfonimide (5.0 g) was dissolved in the minimum amount o f methylene chloride and this solution was loaded onto the top o f the column. The column was eluted, with the above mentioned solvent mixture, and fractions were collected. Those fractions in which a colourless compound was observed to be crystallizing were pooled. Removal o f the solvent, followed by  126  brief treatment under reduced pressure (vacuum pump), gave the title compound (4.8 g, 96% recovery) as a colourless, crystalline solid.  mp: 101 - 103 °C; l i t .  88  mp: 101 - 103 °C.  Preparation o f Methyl (3R, 4/?)-3-[(£)-6-[[(l,l-Dimethylethyl)dimethylsilyl]oxy]-4-(trimethylstannyl)-4-hexenyl]-4-methyl-2-[(trifluoromethanesulfonyl)oxy]cyclohexene-3-carboxylate  (17)  Me Sh 3  17  A solution o f L D A in dry TFfF (30 m L ) was prepared in the usual way at -78 °C from dry diisopropylamine (0.410 m L , 2.93 mmol) and a solution o f feAt-butyllithium (1.72 m L , 1.7 M ) in pentane. A solution o f the ketone 16 (1.52 g, 2.79 mmol) in dry T H F (20 m L ) was added to the base solution by cannula.  The very pale yellow solution was stirred for a period o f 2 h.  A -Phenyltrifluoromethanesulfonimide (1.00 g, 2.79 mmol) was added and the solution was /  stirred for 15 min. The mixture was warmed to 0 °C and stirred at this temperature for 15 min. The reaction vessel was opened to the atmosphere and ether (10 m L ) was added.  The solvent  was removed and the crude product, 3.02 g o f a clear, yellow oil, was purified by column chromatography (125 g o f 230-400 mesh silica gel, 4 cm (width) column, 12:1 petroleum ether -  127  diethyl ether). Combination o f the appropriate fractions, followed by removal o f the solvent and treatment  of  the  residue  under  reduced  pressure  (vacuum  pump)  gave  the  enol  trifluoromethanesulfonate 17 (1.67 g, 88%) as a clear, colourless oil. This material displayed:  ir(film): 1740, 1417, 1216 cm" . 1  T i nmr (400 M H z ) : 5 = 0.08 (s, 6 H , - ( C H ) S i - ) , 0.12 (s, 9 H , J „ . = 54 H z , (CH ) Sn-), 0.90 2  3  2  S  H  3  3  (s, 9 H , ( C H ) C S i - ) , 0.93 (d, 3 H , J= 8 H z , C-5 - C H ) , 1.18-1.30 (m, 2 H ) , 1.53 - 1.60 3  3  3  (m, 1 H ) , 1.69 -1.97 (m, 4 H ) , 2.12 -2.33 (m, 4 H ) , 3.71 (s, 3 H , C H 0 - ) , {(4.26 (dd, 1 H , 3  J = 13, 6 H z ) , 4.30 (dd, 1 H , J = 13, 6 Hz)), C-12 protons}, 5.68 (dd, 1 H , J = 6, 6 H z , Vsn-H = 78 H z , H - l l ) , 5.98 - 6.02 (m, 1 H , H - l ) . 1 3  C nmr (75 M H z ) : 8 = -9.9  (V „s  = 329 H z ) , -5.5 (2 carbons), 16.3, 18.0, 23.1, 24.3, 25.6 (3  C  carbons), 25.8, 30.6, 33.1 ( J „-c = 42 H z ) , 34.8, 51.5, 54.3, 59.5 ( V - c = 70 H z ) , 118.0 3  s  Sn  (q, V . = 313 H z ) , 120.4, 140.4 (Un-c = 29 H z ) , 144.0, 148.0, 171.0. F  C  lrms (EI): m/z = 663 (56%, M ^ M e ) . lrms (DCI): m/z = 663 (58%, M ^ M e ) , 694 (13%, (M+NH4) ). +  Anal, calcd. for CssH^FjOsSSiSn: C 44.32, H 6.70, S 4.73; found: C 44.44, H 6.81, S 4.86. optical rotation: [a]o -150° (c = 2.7, chloroform). 25  Preparation o f Tetrakis(triphenylphosphine)palladium(0)  47  For this reaction, all solvents were deoxygenated by sparging with helium gas at a rate o f 100 m L per min for a period o f 2 h.  128 An oven dried, 1 L round-bottomed flask equipped with 2 female and 1 male B 24 ground glass joints was brought into a glove box and charged with palladium(II) chloride (10.0 g, 56.4 mmol), triphenylphosphine (74.0 g, 282 mmol) and a magnetic stirrer bar. The 2 female joints were capped with rubber septa and the male joint with a 25 mL round-bottomed flask. The apparatus was removed from the glove box and connected to an argon line by a needle tipped Tygon® hose. Dimethyl sulfoxide (700 mL) was added by cannula. The suspension was stirred magnetically and placed in an oil bath. The oil bath was heated, gradually to 140 °C and the mixture was stirred at this temperature for 30 min. A burgundy solution was produced. The oil bath was removed and stirring was restored as quickly as was possible. A vent was installed by piercing one of the septa with a 16 ga needle, and hydrazine hydrate (11.0 mL, 226 mmol) was added by syringe. The solution darkened in colour to a redder burgundy upon addition of the reducing agent. The mixture was stirred until the product began to crystallize. The unstirred reaction mixture was allowed to cool to it. The 25 mL round-bottomedflaskwas replaced with a filtering funnel comprised of a 1 Lflaskfused to a coarse sintered glass funnel. The contents of the reactionflaskwere tipped into the filter and the solvent was allowed to run through the sinter under a positive pressure of argon. Thefiltrand,a yellow, crystalline solid, was washed with absolute ethanol (3 x 50 mL) followed by dry diethyl ether (4 x 50 mL) and then dried overnight in the filtering funnel under a positive pressure of argon. The filtering funnel was brought back into the glove box and the product, 63.2 g (97%) of yellow crystals was placed in foil wrapped vials for storage. The title compound could be kept in the glove box for periods of between 3 and 6 months, depending on the frequency of use, without significant loss of catalytic activity. For longer term storage, the vials were stored in a glove box freezer (-35 °C). prepared complex displayed:  The freshly  129  Anal, calcd. for C H oP4Pd: C 74.84, H 5.23; found: C 74.82, H 5.36; l i t . : C 75.3, H 5.36. 47  72  6  Preparation o f the Methyl ( 4 a a , 5 a ) - ( + ) - l , 2 , 3 , 4 , 4 a , 5 , 6 , 7 - O c t a h y d r o - l - [ ( £ ) - 2 - [ [ ( l , l dimethylethyl)dimethylsilyl]oxy]ethylidene]-5-methyl-4a-naphthalenecarboxylate (18)  18  A mixture o f the enol trifluoromethanesulfonate  17 (2.70 g, 3.99 mmol), tetrakis-  (triphenylphosphine)palladium(O) (0.230 g, 0.199 mmol) and dry T H F (40 m L ) was stirred magnetically and heated to reflux for a period o f 24 h. The resulting black solution was cooled to rt and additional catalyst (0.200 g, 0.173 mmol) was added. The mixture was heated to reflux and heating was continued for an additional 24 h. The reaction mixture was cooled and most o f the solvent was removed by rotary evaporation.  The resulting black oil was prepurified by  filtration through a short column (25 g in a 150 m L medium sintered glass funnel) o f 230400 mesh silica gel. The silica gel was washed with 1:1 petroleum ether - diethyl ether (220 mL) and the solvent was removed from the combined filtrates to isolate the crude product (1.45 g) as a clear, yellow oil. Purification by column chromatography (27 g o f tic grade silica gel, 3.5 cm (width) column, 9:1 petroleum ether - diethyl ether) provided, after removal o f the solvent from  130  the appropriate fractions, 1.35 g o f a clear, very pale yellow oil. This material was further purified by distillation (125-130 °C at 0.015 Torr) to finally yield the diene 18 (1.27 g, 87%) as a clear, colourless oil. This material displayed:  ir (film): 1728, 1432 cm" . 1  T i nmr (400 M H z ) : 8 = 0.05 (s, 6 H , - ( C H ) S i - ) , 0.75 - 0.92 (a singlet (at 0.89 for the 3  2  ( C H ) S i - ) overlapped with a doublet (for the C-5 2° - C H ) , 1 2 H ) , 1.14 (ddd, 1 H , J = 13, 3  3  3  13, 4 H z ) , 1.42 - 1.63 (m, 4 H ) , 1.70 - 1.83 (m, 2 H ) , 2.12 - 2.17 (m, 2 H ) , 2.51 (br d, 1 H , J= 15 H z ) , 2.64 (br d, 1 H , J= 14 H z ) , 3.62 (s, 3 H ) , {(4.15 (ddd, 1 H , J= 13, 6, 2 H z ) , 4.22 (ddd, 1 H , J= 13, 6, 2 Hz)), C-2'protons}, 5.43 (ddd, 1 H , J= 6, 6, 2 H z , H - l ' ) , 5.75 (dd, 1 H , J = 4, 4 H z , H-8). 1 3  C nmr (50 M H z ) : 8 = -5.04, -4.96, 17.2, 18.2, 23.4, 25.5, 25.9 (3 carbons), 26.8, 28.6, 35.4, 39.4, 51.3, 52.6, 59.9, 124.1, 124.6, 140.7, 141.0, 173.6.  lrms (EI): m/z = 364 (8%, M+). hrms (EI): calcd. for C i H 0 S i : 364.2434; found: 364.2426. 2  3 6  3  Anal, calcd. for C i H 0 S i : C 69.18, H 9.95; found: C 69.35, H 10.00. 2  optical rotation: [ a ]  3 6  2 3 u  3  +236 (c=5.0, hexane); [ct] 6 +5 47 (c=5.0, hexane).  Preparation o f Methyl 2-Bromoacrylate  23  43  50  A 250 m L round-bottomed flask equipped with a condenser was charged with a solution of methyl acrylate (18.7 m L , 208 mmol) in chloroform (82.5 m L ) and the solution was stirred  131  magnetically at it.  Bromine (10.7 m L , 207 mmol) was added, dropwise by syringe, and the  resulting deep red solution was stirred for 3 h. The solvent was removed by rotary evaporation and the crude dibromide, a clear, yellow-orange oil, was transferred with diethyl ether (125 mL) to a 500 m L round-bottomed flask. Pentane (125 mL) was added and the solution was stirred at it.  D r y triethylamine (29.0 m L , 208 mmol) was added by syringe.  immediately and the solution rapidly became turbid; thick, white suspension.  The colour was destroyed  After 10 min, the reaction mixture was a  The mixture was stirred for 16 h and then suction filtered through a  medium sintered glass filter funnel. The white solid was washed with pentane (100 mL) and the solvent was removed from the combined filtrates by rotary evaporation.  For this operation, the  bath in which the evaporating flask was immersed was filled with water at 15 °C. The residue was distilled (bp 69-71 °C at 48 Torr, l i t .  50  6 5 °C at 50 Torr) to provide 27.56 g (81%) o f the  title compound as a clear, colourless oil. This material displayed:  *H nmr (400 M H z ) : 5 = 3.80 (s, 3 H ) , 6.23 (d, 1 H , J= 2 H z ) , 6.90 (d, 1 H , J= 2 H z ) .  This material was diluted with dry benzene to provide a stock solution o f methyl 2-bromoacrylate (0.50 g per m L o f solution) and the solution was stored sealed under an atmosphere o f argon at -35 °C. The solution showed no loss o f activity (as a dienophile) after a period o f 18 months although it had, after this time, taken on a pale yellow colour.  Preparation o f {Dimethyl  (la,3P,6aa,7a,9aa)-2,3,4,5,6,6a,7,8,9,9a-Decahydro-l-bromo-3-  [[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-7-methyl-l,6a[l//]-phenalenedicarboxylate and  132  Dimethyl (lB,3p,6aa,7a,9aa)-2,3,4,5,6,6a,7,8,9,9a-Decahydro-l-bromo-3-[[[(l,ldimethylethyl)dimethylsilyl]oxy]methyl]-7-methyl-1,6a[l//]-phenalenedicarboxylate}  (54)  A solution o f the diene 18 (0.841 g, 2.31 mmol) and methyl 24>romoacrylate (1.52 m L o f 0.50 g/mL in benzene, 4.61 mmol) in dry benzene (25 m L ) was stirred magnetically and was heated to reflux for a period o f 44 h. The solvent was removed and the crude product, 1.74 g o f a clear, yellow oil and a pasty white solid, was purified by column chromatography (130 g o f 230-400 mesh silica gel, 4 cm (width) column, 12:1 petroleum ether - diethyl ether). Removal o f the solvent, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the epimeric product mixture 54 (1.17 g, 96%) as a clear, very pale yellow oil. Analysis o f the TL nmr spectrum, by comparison o f the integrals for the signals at 8 = 0.85 (minor epimer) and 0.92 (major epimer), representing the tert-butyl protons from the 2 epimers, suggested the ratio of the products was about 4:1, but the identity o f the major isomer was unknown. A sample o f the product mixture displayed:  ir(film): 1740, 1732, 1447 cm" . 1  133  *H nmr (400 M H z ) : 6 = 0.03 - 0.10 (m, 6 H , - ( C H ) S i - ) , {(0.85 (s) and 0.92 (s)), 9 H , 3  ( C H ) C S i - } , 1.10 (d, 3 H , J= 3  2  8 H z , C-7 - C H ) , 1.15 - 1.29 (m, 2 H ) , 1.31 - 1.47 (m,  3  3  2 H ) , 1.55 - 2.10 (m, 5 H ) , 2.13 - 2.55 (m, 4 H ) , 2.81 (br d, 1 H , J=  13 H z ) , 2.86 (br d,  1 H , J= 13 H z ) , 3.50 - 3.89 (m, 8 H , contains singlets at 3.66, 3.69, 3.73 and 3.89 for the C H 0 - functions). 3  lrms (DCI): m/z = 530, 532 (55%, M ) . 4  Anal, calcd. for C H 4 i 0 B r S i : C 56.70, H 7.80; found: C 56.34, H 7.83. 2 5  5  Preparation o f Samarium Diiodide  54  A 0.10 M solution o f the title compound in oxygen free, dry T H F was prepared in the following manner. A n oven dried B 19, B 24 two-necked 300 m L round-bottomed flask and solvent transfer bridge were brought into a glove box. The flask was charged with -40 mesh samarium metal powder (4.51 g, 30.0 mmol) and a magnetic stirrer bar. The B 19 joint was fitted with a rubber septum capped, vacuum stopcock equipped, straight inlet adapter and the solvent transfer bridge was fitted to the B 24 joint. The free end o f the solvent transfer bridge was capped with a 25 m L round-bottomed flask. A l l o f the ground glass joints were greased with Apiezon® type N vacuum grease and the apparatus was removed from the glove box.  The solvent transfer bridge was  connected to a double manifold argon - vacuum line and a positive pressure o f argon was applied. The cap on the solvent transfer bridge was removed quickly and was replaced with a glass solvent bomb.  The apparatus was evacuated and, under static vacuum, oxygen free, dry  134  T H F (270 m L ) was transferred from the bomb to the flask containing the samarium. T o facilitate the transfer, the flask containing the samarium was cooled to -198 °C and the solvent bomb was stirred and heated to 30 °C. When the transfer was complete, the cooling bath was removed. The apparatus was opened to the argon side o f the line and was allowed to warm to rt.  The  solvent transfer bridge was removed quickly and was replaced with a stopper. The mixture was stirred magnetically and methylene iodide (2.21 m L , 27.5 mmol) was added by Gastight® syringe through the inlet adapter. The reaction flask was wrapped in foil and the mixture was stirred for a period o f 16 h. The resulting deep blue solution was ready for immediate use and could be stored indefinitely at rt in the dark.  Preparation o f {Dimethyl  (la,3a,3ap,6p,6ap)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-  dimethylethyl)dimethylsilyl]oxy]methyl]-6-methyl-3,6a[l//]-phenalenedicarboxylate and Dimethyl (la,3p,3ap,6p,6ap)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-6-methyl-3,6a[l//]-phenalenedicarboxylate}  C0 Me 2  55  (55)  135  A solution o f samarium diiodide in oxygen free, dry T H F (73 m L , 0 . 1 0 M ) was transferred to a dry, thoroughly argon flushed, round-bottomed flask by Gastight® syringe, stirred magnetically and cooled to -78 °C. A solution o f the diesters 54 (1.83 g, 3.45 mmol) in 3:1 dry T H F - dry methanol (20 m L ) was added, dropwise by cannula, to the samarium diiodide solution. A t the end o f the addition, the reaction mixture was pale green. The reaction mixture was stirred for a period o f 5 minutes and the reaction flask was then opened to the atmosphere. A gentle stream o f compressed air was blown into the flask until the reaction mixture was yellow in colour and the cooling bath was then removed.  The reaction mixture was poured into  saturated K2CO3 (aq) (20 m L ) and shaken with diethyl ether (20 m L ) . separated.  The layers were  The aqueous phase was extracted with diethyl ether (3 x 20 m L ) and the combined  organic phases were dried over M g S 0  4  and filtered. Removal o f the solvent from the filtrate  provided the crude product, 1.73 g o f a clear, amber oil, which was purified by column chromatography (50 g o f tic grade silica gel, 4 cm (width) column, 4:1 petroleum ether - diethyl ether).  The product epimers were isolated together. Combination o f the appropriate fractions,  followed by removal o f the solvent and distillation (210 - 220 °C at 0.094 Torr) o f the residue gave the diesters 55 (1.55 g, 100%) as a clear, very viscous, very pale yellow oil. Analysis o f the X  H nmr spectra derived from this material, by comparison o f the integrals for the C H 0 3  fiinctions from the 2 epimers o f the product, suggested the ratio o f the products was about 1:1. The mixture 55 displayed:  ir(film): 1735, 1447, 1434 cm" . 1  T i nmr (400 M H z ) : 5 = {(0.044 (s), 0.045 (s), 0.060 (s)),6 H , - ( C H ) S i - } , {(0.86 (s), 0.90 (s)), 3  2  9 H , ( C H ) C S i - } , {(1.00 (d, J= 8 H z ) , 1.10 (d, J= 8 Hz)), 3 H , C-6 - C H } , 1.16 - 1.27 3  3  3  136  (m, 1 H ) , 1.28 - 1.40 (m, 2 H ) , 1.44 - 1.52 (m, 1 H ) , 1.56 - 1.78 (m, 4 H ) , 1.80 - 2.06 (m, 3 H ) , 2.13 - 2.28 (m, 2 H ) , {(2.35 - 2.43 (m, 7 lines), 2.47 (br d, J = 13 Hz)), 1 H } , {(2.53 - 2.60 (m), 2.70 (ddd, J= 14, 2, 2 Hz)), 1 H } , 2.78 - 2.88 (m, 1 H ) , 3.47 (dd, 1 H , J= 11, 9 H z , one o f H - l ' ) , 3.63 - 3.71 (m, contains singlets at 3.666, 3.673 (two overlapping), and 3.68 for the C H 0 - functions, and the other o f H - l ' , 7 H ) . 3  X  H nmr ( C D , 400 M H z ) : 6 = {(0.050 (s), 0.090 (s), 0.10 (s)), 6 H , - ( C H ) S i - } , {(0.96 (s), 0.99 6  6  3  2  (s)), 9 H , ( C H ) C S i - } , {(1.07 (d, J= 8 H z ) , 1.21 (d, J= 8 Hz)), 3 H , C-6 - C H } , 111 3  3  3  1.17 (m, 1 H ) , 1.25 - 1.63 (m, 4 H ) , 1.65 - 2.12 (m, 7 H ) , 2.17 (br s, 1 H ) , {(2.27 (ddd, J = 14, 2, 2 H z ) , 2.32 (br d, J=  13 Hz)), 1 H } , {(2.57 (br d, J=  15 H z ) , 2.61 - 2.69 (m, 7  lines)), 1 H } , {(2.80 - 2.88 (m, 5 lines), 3.00 (br d, J= 12 Hz)), 1 H } , {(3.29 (s), 3.33 (s), 3.36 (s), 3.40 (s)), 6 H , C H 0 - functions}, 3.48 - 3.70 (m, 2 H , C - l ' protons). 3  lrms (EI): m/z = 450 (0.3%, M ) . 4  hrms (EI): calcd. for CzsHaOsSi: 450.2802; found: 450.2795. Anal, calcd. for C z s ^ O s S i : C 66.63, H 9.39; found: C 66.76, H 9.27.  137  Preparation o f Methyl (la,3p,3ap,6p,6aB)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,ldimethylethyl)dimethylsilyl]oxy]methyl]-3-(hydroxymethyl)-6-methyl-6a[l//]phenalenecarboxylate (56) and Methyl  (la,3a,3aP,6P,6aP)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-  l-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]- 3-(hydroxymethyl)-6-methyl-6a[l.r7]phenalenecarboxylate (57); Reduction o f the Diesters 55  A solution o f the diesters 55 (2.82 g, 6.27 mmol) in dry diethyl ether (50 m L ) was stirred magnetically and cooled to -78 °C. A solution o f D J J B A L - H in hexanes (13.2 m L , 1.0 M ) was added in 3 portions at 1 min intervals by syringe and the colourless solution was stirred for 1 h. The cooling bath was removed and the reaction mixture was allowed to warm to rt and stirred at this temperature for 20 min. Saturated NH4CI (aq) (0.5 m L ) was added, dropwise at first, and, after the effervescence had subsided, diethyl ether (50 m L ) was added.  The two-phase system  was stirred vigorously until a thick, white slurry had formed (about 20 min). Magnesium sulfate (1 g) and Celite® (2 g) were added to the slurry and the mixture was stirred for 2 h. A short column o f Florisil® (3 cm high in a 150 m L medium sintered glass funnel) was prepared and the reaction mixture was filtered through the column. The solid material was washed with diethyl  138 ether (100 m L ) and the solvent was removed from the combined filtrates.  The crude product  was separated and purified by column chromatography (50 g o f tic grade silica gel, 4 cm (width) column, 1:1 petroleum ether - diethyl ether). After combination o f appropriate fractions, removal o f the solvent and treatment o f the residues under reduced pressure (vacuum pump), 2 compounds were isolated. The first component eluted was the 3 f 3 - C H O H compound, alcohol 2  56 (1.06 g, 40%) as a clear, colourless oil. The second component eluted was the 3 a - C H O H 2  compound, alcohol 57 (1.33 g, 50%) also as a clear, colourless oil.  The alcohol 56 displayed:  ir (film): 3494, 1723, 1463, 1084, 837 cm" . 1  H nmr (400 M H z ) : 8 = 0.060 (s, 6 H , - ( C H ) S i - ) , 0.92 (s, 9 H , ( C H ) C S i - ) , 1.06 (d, 3 H , J =  l  3  2  3  3  9 H z , C-6 C H - ) , 1.08-1.17 (m, 1 H ) , 1.27 (ddd, 1 H , J = 13, 13, 3 H z ) , 1.36 - 1.68 (m, 3  8 H ) , 1.84 - 1.96 (m, 3 H ) , 2.10 - 2.23 (m, 3 H ) , 2.36 (br d, 1 H , J= 15 H z ) , 3.46 - 3.60 (m, 7 lines, 2 H ) , 3.63 - 3.74 (m, 5 H , contains a singlet at 3.64 for the C H 0 - function). 3  1 3  C nmr (50 MHz): 5 = -5.9, -5.2, 17.6, 18.1, 20.6, 26.2 (3 carbons), 31.0, 31.52, 31.54, 32.9, 34.5, 38.6, 42.1, 44.1, 45.2, 49.8, 53.1, 62.4, 65.2, 130.4, 135.8, 175.4.  lrms (DCI): m/z = 423 (100%, (JVf+H), 440 (50%, ( M + N H / ) ) . hrms (DCI): calcd. for C H430 Si: 423.2931; found: 423.2936. 24  4  Anal, calcd. for C ^ H ^ S i C 68.20, H 10.02; found: C 67.99, H 10.01. optical rotation: [ct]  22 D  -88° (c=1.8, hexane); [ c t ]  The alcohol 57 displayed:  22 436  -192° (c=1.8, hexane).  139  ir (film): 3417, 1723, 1450, 1039 cm" . 1  *H nmr (400 M H z ) : 5 = 0.040 (s, 6 H , - ( C H ) S i - ) , 0.90 (s, 9 H , ( C H ) C S i - ) , 1.10 (d, 3 H , J = 3  2  3  3  8 H z , C-6 - C H ) , 1.16 - 1.40 (m, 6 H ) , 1.52 - 1.71 (m, 5 H ) , 1.80 - 2.10 (m, 3 H ) , 2.18 3  2.30 (m, 3 H ) , 3.54 (dd, 1 H , J= 12, 8 H z ) , 3.60 - 3.72 (m, 6 H , contains a singlet at 3.65 for the C H 0 - function). 3  Anal, calcd. for C z ^ C ^ S i C 68.20, H 10.02; found: C 68.37, H 10.03. optical rotation: [ a ]  2 9 D  Preparation o f Methyl  -87° (c=6.4, hexane); [ a ] e 43  29  -192° (c=6.4, hexane).  (la,33,3af3,6p,6ap)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-  dimethylethyl)dimethylsilyl]oxy]methyl]-3-formyl-6-methyl-6a[l//]-phenalenecarboxylate and Methyl  (20)  (la,3a,3ap,6p,6ap)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-dimethyl-  ethyl)dimethylsilyl]oxy]methyl]-3-formyl-6-methyl-6a[l//]-phenalenecarboxylate (58); Oxidation o f the Alcohol 57  A  20  H  58  A solution o f oxalyl chloride in methylene chloride (0.41 m L , 2.0 M ) was diluted with dry methylene chloride (15 m L ) . The solution was stirred magnetically and cooled to -48 °C. D r y  140 dimethyl sulfoxide (0.115 m L , 1.61 mmol) was added, dropwise, by syringe and, after the evolution o f gas had ceased, the colourless solution was stirred for 2 min. A solution o f the alcohol 57 (0.310 g, 0.734 mmol) in dry methylene chloride (5 m L ) was added to the reaction flask by cannula. A white suspension was formed and the mixture was stirred for 15 min. Dry triethylamine (0.51 mL, 3.7 mmol) was added by syringe and the resulting colourless solution was stirred for 5 min. The cooling bath was removed and the reaction mixture was allowed to warm to rt.  The contents o f the reaction flask were added to water (5 m L ) , the mixture was  shaken and the layers were separated. The aqueous phase was extracted with methylene chloride ( 3 x 5 mL) and the combined organic phases were washed with saturated N a C l (aq) ( 1 x 1 0 mL). The washed solution was dried over M g S 0 , filtered and the solvent was removed to give the 4  crude product (0.34 g) as a clear, yellow oil. This oil was taken up in dry methanol (20 mL). The pale yellow solution was stirred magnetically and cooled to 0 °C. Sodium hydride (5 mg, 0.2 mmol) was added in 1 portion and the solution was stirred for 5 min. The cooling bath was removed. The reaction mixture was stirred at rt for a period o f 16 h and then diluted with water (30 mL).  The mixture was neutralized ( p H paper) by dropwise addition o f a 1.0 M citric  acid (aq) solution and the methanol was removed by rotary evaporation. Diethyl ether (50 mL) was added to the residue, the mixture was shaken and the layers were separated. The organic phase was washed with saturated N a C l (aq) ( 3 x 1 0 m L ) , dried over M g S 0 4 , filtered and the solvent was removed. The crude product, 0.32 g o f a clear, pale yellow oil, was separated and purified by column chromatography (27 g o f tic grade silica gel, 3'/2cm (width) column, 6:1 petroleum ether - diethyl ether). Removal o f the solvent from the appropriate fractions, followed by treatment o f the residues under reduced pressure (vacuum pump), gave 0.218 g (71%) o f the desired P - C H O product, aldehyde 20 and 0.061 g (20%) o f the epimeric ct-CHO product,  141  aldehyde 58, both as clear, pale yellow oils. These compounds displayed H nmr spectra identical X  with those o f the racemic material and could be used without further purification. 43  Preparation o f the Aldehydes 20 and 58, Epimerization o f the Aldehyde 58  A solution o f the aldehyde 58 (0.282 g, 0.671 mmol) in dry methanol (7 m L ) was stirred magnetically and cooled to 0 °C. Sodium hydride (5 mg, 0.2 mmol) was added and the solution was stirred for 3 min. The cooling bath was removed and the solution was stirred at rt for a period o f 16 h. The reaction mixture was poured into saturated N a C l (aq) (10 m L ) and saturated N F L C l (aq) (5 mL) was added.  This mixture was extracted with ethyl acetate (5 x 25 mL) and  the solvent was removed from the extract.  The residue was taken up in diethyl ether (90 mL)  and this mixture was washed with saturated N a C l (aq) ( 1 x 1 0 m L ) . The organic phase was dried over M g S 0 , filtered and the solvent was removed to provide 0.29 g o f a clear, pale yellow oil. 4  This material was separated and purified by column chromatography (27 g o f tic grade silica gel, 3V2 cm (width) column, 6:1 petroleum ether - diethyl ether). Removal o f the solvent from the appropriate fractions, followed by treatment o f the residues under reduced pressure (vacuum  142  pump), gave 0.248 g (88%) o f the desired B - C H O product, aldehyde 20 and 0.023 g (8%) o f recovered starting material, aldehyde 58.  Aldehyde 20, which was used without  further  purification, displayed: ir (film): 2858, 1724, 838, 776 cm" . 1  *H nmr (400 M H z ) : 8 = 0.060 (s, 6 H , - ( C H ) S i - ) , 0.90 (s, 9 H , ( C H ) C S i - ) , 1.02 (d, 3 H , J = 3  2  3  3  7 H z , C-6 - C H ) , 1.05 - 1.16 (m, 1 H ) , 1.18 - 1.28 (m, 1 H ) , 1.34 - 1.42 (m, 1 H ) , 1.45 3  1.70 (m, 5 H ) , 1.80 - 1.90 (m, 2 H ) , 1.98 (ddd, 1 H , J= 13, 4, 4 H z ) , 2.10 - 2.31 (m, 3 H ) , 2.46 (br d, 1 H , J=  13 H z ) , 2.83 (br s, 1 H ) , 3.50 (dd, 1 H , J=  10, 8 H z , one o f H - l ' ) ,  3.67 (s, 3 H , C H 0 - ) , 3.68 (dd, 1 H , / = 10, 4 H z , the other o f H - l ' ) , 9.62 (d, 1 H , J = 3  3 Hz, CHO-). 1 3  C nmr (50 M H z ) : 8 = -5.4 (2 carbons), 18.1, 18.5, 20.7, 25.8 (3 carbons), 31.0, 31.4, 31.5, 31.7, 34.3, 35.1, 41.5, 42.3, 42.5, 51.0, 52.1, 64.7, 129.5, 134.0, 175.6, 199.2.  lrms (EI): m/z = 420 (12%, M ) . +  hrms (EI): calcd. for C H 4 o 0 S i : 420.2695; found: 420.2693. 24  4  Anal, calcd. for C H 4 o 0 S i : C 68.53, H 9.58; found: C 68.78, H 9.59. 24  4  Preparation o f the Alcohol 56; Reduction o f the Aldehyde 20  56  143  A solution o f the aldehyde 20 (0.889 g, 2.11 mmol) in dry diethyl ether (20 mL) was stirred magnetically and cooled to -78 °C. A solution o f D I B A L - H in hexanes (2.50 m L , 1.0 M ) was added by syringe and the colourless solution was stirred for a period o f 30 min. The cooling bath was removed and the reaction mixture was allowed to warm to rt and stirred at this temperature for 20 min. Saturated N H C 1 (aq) (0.2 mL) was added, and, after the effervescence 4  had subsided, diethyl ether (20 mL) was added. The 2 phase system was stirred vigorously until a thick, white slurry had formed (about 20 min). Magnesium sulfate (0.5 g) and Celite® (1 g) were added to the slurry and the mixture was stirred for 2 h. A column o f 22 g o f 230-400 mesh silica gel supported in a 4 cm (width) column topped by a 1 cm thick layer o f Florisil® was prepared and the reaction mixture was filtered though the column. The column was washed with diethyl ether (200 m L ) and the solvent was removed from the combined filtrates. The residual oil was treated under reduced pressure (vacuum pump) to provide the title compound (0.901 g, -100%) as a clear, very pale yellow oil. This material produced ir, ' H nmr and mass spectra identical with that o f the above described alcohol 56, prepared by reduction o f the diesters 55 and was used without further purification.  144  Preparation o f Methyl  (la,3p,3ap,6p,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-  dimethylethyl)dimethylsilyl]oxy]methyl]-6-methyl-3-[[[(/j-methylphenyl)sulfonyl]oxy]methyl]6a[li?]-phenalenecarboxylate (59)  A solution o f the alcohol 56 (0.890 g, 2.11 mmol) in dry methylene chloride (18 m L ) was stirred magnetically at rt. 4-(A ,A -Dimethylamino)pyridine (0.310 g, 2.53 mmol) was added in 1 r  7  portion followed by p-toluenesulfonyl chloride (0.443 g, 2.32 mmol), also in 1 portion. reaction mixture was stirred for a period o f 16 h and then poured into saturated N a H C 0  The 3  (aq)  (20 mL) and diethyl ether (50 m L ) . The mixture was shaken and the layers were separated. The organic layer was washed with saturated N a H C 0 (aq) (1 x 20 m L ) and saturated N a C l (aq) (1 x 3  20 m L ) before being dried over M g S 0 . 4  removed.  The dried solution was filtered and the solvent was  The crude product, 1.29 g o f a clear, pale yellow oil, was purified by column  chromatography (50 g o f tic grade silica gel, 4 cm (width) column, 4:1 petroleum ether - diethyl ether).  Removal o f the solvent from the appropriate fractions, followed by treatment o f the  residue under reduced pressure (vacuum pump), gave the /7-toluenesulfonate 59 (1.15 g, 94%) as a clear, very pale yellow oil. This material displayed:  145  ir (film): 1723, 1178, 837, 776 cm" . 1  X  H nmr (400 M H z ) : 5 = -0.040 (s, 6 H , - ( C H ) S i - ) , 0.86 (s, 9 H , ( C H ) C S i - ) , 1.02 (d, 3 H , J = 3  2  3  3  7 H z , 2° - C H ) , 1.22 (ddd, 1 H , J = 13, 13, 4 H z ) , 1.29 - 1.40 (m, 2 H ) , 1.41 - 1.57 (m, 3  2 H ) , 1.59 - 1.68 (br s, 1 H ) , 1.70 - 1.78 (m, 2 H ) , 1.78 - 1.89 (m, 3 H ) , 2.00 - 2.17 (m, 4 H ) , 2.36 (br d, 1 H , J = 13 H z ) , 2.46 (s, 3 H , A r - C H ) , 3.43 (dd, 1 H , J= 10, 8 H z , one 3  of H - l ' or H - l " ) , 3.59 (dd, 1 H , J= 10, 4 H z , one o f H - l ' or H - l " ) , 3.64 (s, 3 H , C H 0 - ) , 3  3.91 (dd, 1 H , J= 10, 8 H z , the other o f H - l ' or H - l " ) , 4.05 (dd, 1 H , J=  10, 4 H z , the  other o f H - l ' or H - l " ) , 7.36 (d, 2 H , J= 8 H z , A r - H ) , 7.80 (d, 2 H , J= 8 H z , A r - H ) . 1 3  C nmr (50 M H z ) : 5 = -5.5 (2 carbons), 17.0, 18.2, 19.5, 21.6, 25.3, 25.8 (3 carbons), 30.4, 31.3, 33.4, 34.5, 36.66, 36.73, 41.9, 44.0, 51.1, 51.5, 64.3, 73.2, 127.9 (2 carbons), 129.7 (2 carbons), 130.9, 132.9, 133.2, 144.5, 175.1.  lrms (DCI): m/z = 577 (11%, ( M + l ) ) , 594 (100%, ( M + N H ) ) . +  +  4  hrms (DCI): calcd. for CsiHjsAsSiS ( ( M + l ) ) : 577.3019; found: 577.3028. +  optical rotation: [ a ]  2 2 D  -63° (c=1.8, hexane); [cx] 6 -137° (c=1.8, hexane). 22  43  146  Preparation o f Methyl (la,3P,3aP,6p,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9^^ dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-6a[l//]-phenalenecarboxylate (21)  X/  X/  ^Si  ^Si  21  90  A solution o f the /?-toluenesulfonate 59 (3.50 g, 6.07 mmol) in dry T H F (30 m L ) was stirred magnetically at rt. A solution o f Super-Hydride® in T H F (12 m L , 1.0 M) was added by syringe and the solution was stirred for a period o f 24 h. Water was cautiously added (until the effervescence had ceased) and then 30% aqueous  H2O2  (1.5 m L ) and 15% aqueous N a O H  (1.5 m L ) were added. The mixture was stirred for 40 min and then the contents o f the reaction flask were poured into water (120 m L ) and pentane (50 mL). The mixture was shaken and the layers were separated.  The aqueous phase was extracted with pentane (3 x 50 mL).  The  combined organic phases were dried over MgSCu, filtered and the solvent was removed. The crude product, 2.87 g o f a clear, pale yellow oil, was separated and purified by column chromatography (100 g o f tic grade silica gel, 5.5 cm (width) column, 12:1 petroleum ether diethyl ether until the product had eluted then 4:1 petroleum ether - diethyl ether to elute the unreacted starting material). Removal o f the solvent from the fractions containing the least polar compound, followed by distillation o f the residue (145-150 °C at 0.040 Torr) gave the ester 21  147  (2.12 g, 86%) as a clear, colourless oil. Removal o f the solvent from the fractions containing the unreacted starting material, followed by treatment o f the residue under reduced pressure (vacuum pump), gave 0.366 g (10%) o f the /?-toluenesulfonate 59.  Also isolated, from the fractions o f  polarity between that o f the product and the starting material, was 0.0402 g (2%) o f a clear, colourless oil, presumed to be the alcohol 90.  The ester 21 displayed:  ir(film): 1725, 1462 cm" . 1  T i nmr (400 M H z ) : 5 = 0.060 (s, 6 H , - ( C H ) S i - ) , 0.90 (s, 9 H , ( C H ) C S i - ) , 0.96 (d, 3 H , J = 3  6 Hz, 2° - C H ) , 1.02 (d, 3 H , J= 3  7 H ) , 1.76 (ddd, \H,J=  2  3  3  6 H z , 2° - C H ) , 1 . 2 0 - 1 . 3 1 (m, 2 H ) , 1.32 - 1.68 (m, 3  13, 4, 4 H z ) , 1.87 (br d, 1 H , J=  2.10 (br s, 1 H ) , 2.14 - 2.26 (m, 1 H ) , 2.41 (br d, 1 H , J=  16 H z ) , 1.93 - 2.06 (m, 2 H ) , 13 H z ) , 3.45 (dd, 1 H , J=  10,  9 H z , one of H - l ' ) , 3.65 (s, 3 H , C H 0 - ) , 3.67 (dd, 1 H , J = 10, 5 H z , the other of H - l ' ) . 3  1 3  C nmr (100 M H z ) : 5 = -5.39, -5.36, 17.2, 18.3, 19.7, 20.6, 26.0 (3 carbons), 31.1, 31.36, 31.42, 31.5, 33.3, 34.5, 43.0, 43.78, 43.84, 50.8, 51.4, 64.9, 130.8, 134.0, 175.3.  lrms (EI): m/z = 406 (7.2%, M*). hrms (EI): calcd. for C H 4 2 0 S i : 406.2903; found: 406.2907. 24  3  Anal, calcd. for C H 4 0 S i : C 70.88, H 10.41; found: C 71.11, H 10.59. 2 4  optical rotation: [ a ]  2  2 5 D  3  -73.8° (c=4.0, hexane); [ a ]  The alcohol 90 displayed:  ir(film): 3335, 1467, 1040 cm" . 1  2 5 4 3 6  -158° (c=4.0, hexane).  148  *H nmr (400 M H z ) : 5 = 0.050 (s, 6 H , - ( C H ) S i - ) , 0.83 (d, 3 H , J= 3  2  6 Hz, 2° - C H ) , 0.90 (s, 3  9 H , ( C H ) C S i - ) , 0.97 (d, 3 H , / = 6 H z , 2° - C H ) , 1.00 - 1.08 (m, 1 H ) , 1.12 (ddd, 1 H , J 3  3  3  = 13, 13, 4 H z ) , 1.26 (s, 1 H ) , 1.35 - 1.59 (m, 7 H ) , 1.69 - 1.77 (m, 1 H ) , 1.82 (ddd, 1 H , J = 13, 3, 3 H z ) , 1.86 - 1.98 (m, 2 H ) , 2.04 (br d, 1 H , J= 14 H z ) , 2.10 - 2.20 (m, 2 H ) , 3.33 (br d, 1 H , J= 10 H z ) , 3.47 (dd, 1 H , J= 10, 10 H z ) , 3.68 (dd, 1 H , J— 11, 4 H z ) , 3.84 (d, 1 H , y = 11 H z ) .  Preparation o f Methyl  (la,3p,3a(3,6p,6ap)-(-)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-l-[[[(l,l-  dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-9-oxo-6a[l^T]-phenalenecarboxylate  (22)  22 A magnetically stirred suspension o f chromium trioxide (3.92 g, 39.2 mmol) in dry methylene chloride (100 mL) was cooled to -20 °C. 3,5-Dimethylpyrazole (3.77 g, 39.2 mmol) was added in 1 portion and the mixture was stirred for a period o f 20 min. A deep red solution was produced.  A solution o f the ester 21 (0.637 g, 1.57 mmol) in dry methylene chloride  (15 mL) was added to the chromium reagent by cannula.  The solution was warmed to 0 °C,  stirred at this temperature for a period o f 2 h and then poured into diethyl ether (200 mL). A  149  column o f Florisil® (9 cm high supported in an 8 cm (width) column) was prepared and the reaction mixture was filtered through the column. The column was washed with diethyl ether (600 mL) and the solvent was removed from the combined eluents. The crude product, 0.55 g o f a brown, oily solid, was purified immediately by column chromatography (26 g o f tic grade silica gel, 3!/2 cm (width) column, 4:1 petroleum ether - diethyl ether). Removal o f the solvent from the appropriate fractions followed by distillation (155-160 °C at 0.037 Torr) o f the residue gave the a,P-unsaturated ketone 22 (0.480 g, 73%) as a clear, colourless oil which solidified on standing to provide a colourless, crystalline solid. This material displayed:  mp: 54 - 56 °C. i r ( K B r ) : 1726, 1674, 1462 cm" . 1  :  H nmr (400 MHz): 5 = 0.026 (s, 3 H , one o f - ( C H ) S i - ) , 0.053 (s, 3 H , the other o f 3  2  - ( C H ) S i - ) , 0.89 (s, 9 H , ( C H ) C S i - ) , 1.02 (d, 3 H , J = 6 H z , 2° - C H ) , 1.03 (d, 3 H J = 3  2  3  3  3  ;  6 H z , 2° - C H ) , 1.07 (ddd, 1 H , J= 12, 12, 5 H z ) , 1.14 (ddd, 1 H , J= 13, 13, 5 H z ) , 1.50 3  1.62 (m, 4 H ) , 1.66 (ddd, 1 H , J = 14, 14, 8 H z ) , 1.95 (ddd, 1 H , J = 12, 2, 1 H z ) , 2.16 2.30 (m, 2 H ) , 2.36 - 2.57 (m, 2 H ) , 2.67 (ddd, 1 H , J= 13, 2, 1 H z ) , 2.97 (br dd, 1 H , J = 5, 3 H z ) , 3.31 (dd, 1 H , J= 9, 9 H z ) , 3.60 (dd, 1 H , J= 9, 4 H z ) , 3.69 (s, 3 H , C H 0 - ) . 3  1 3  C nmr (50 MHz): 5 = -5.4, -5.2, 17.1, 18.3, 20.7, 26.0 (3 carbons), 30.2, 30.5, 31.0, 31.2, 31.9, 34.8 (2 carbons), 43.4, 44.8, 51.7, 51.8, 64.8, 133.6, 158.9, 172.1, 197.9.  lrms (EI): m/z = 420 (0.63%, M*). hrms (EI): calcd. for C H4o0 Si: 420.2696; found: 420.2693. 24  4  Anal, calcd. for C H4o0 Si: C 68.52, H 9.59; found: C 68.31, H 9.67. 24  optical rotation: [a] D  4  21  -43° (c = 1.0, hexane); [ a ] 6 43  21  -55° (c = 1.0, hexane).  150  Preparation o f Methyl  (la,3p,3af3,6p,6arj,9ap,9ba)-(-)-Perhydro-14[[(l,l-dimethylethyl)-  dimethylsilyl]oxy]methyl]-3,6-dimethyl-9-oxo-6a[l//]-phenalenecarboxylate (23)  o,  23 A  suspension o f 10% palladium on activated charcoal (0.490 g, 0.461 mmol) in  methanolic potassium hydroxide (11 m L , 0.30 M ) in a PYREX® reaction bomb was stirred magnetically on a Humboldt Vortex Hydrogenator and evacuated to water aspirator pressure (-25 Torr). The reaction bomb was compressed with hydrogen gas to a pressure o f 45 psi and stirred for a period o f 15 min. The stirrer was stopped and the pressure was released. The oc,Punsaturated ketone 22 (0.775 g, 1.84 mmol) was added in 1 portion, the stirrer was restarted and the bomb was repressurized with hydrogen as above. 48 h.  The mixture was stirred for a period o f  The pressure was released and the catalyst was removed by filtration through a short  column o f Celite® (2 cm high supported in a 2 cm (width) column). The column was washed with methanol (15 m L ) . Ethyl acetate (20 m L ) was added to the combined filtrates and the mixture was stirred for 1 h. The solvent was removed. The residue was taken up in diethyl ether (100 mL) and washed with saturated N a C l (aq) (1 x 20 mL). The organic phase was dried over M g S C u , filtered and the solvent was removed.  The residue, a clear, colourless oil which  151  solidified to a colourless, oily solid was recrystallized from pentane to provide the ketone 23 (0.684 g, 88%) as a colourless, crystalline solid. This material displayed:  mp: 7 9 - 8 1 °C. i r ( K B r ) : 1723, 1464 cm" . 1  !  H nmr (400 M H z ) : 5 = 0.00 (s, 3 H , - ( C H ) S i - ) , 0.020 (s, 3 H , - ( C H ) S i - ) , 0.84 - 0.92 (m 3  2  3  2  (overlapping d (2° - C H ) and s ( ( C H ) C S i - ) , 12 H ) , 0.95 (d, 3 H , J= 6 H z , 2° - C H ) , 1.12 3  (ddd, 1 H,J=  3  3  3  13, 13, 5 H z ) , 1.22 - 1.59 (m, 7 H ) , 1.75 (dddd, 1 H , J=  1.87 (ddd, 1 H , J=  13, 3, 3 H z ) , 2.07 (br dd, 1 H , J=  11, 11, 11, 4 H z ) ,  13, 3 H z ) , 2.31 (dd, 1 H , J=  13,  4 H z ) , 2.34 - 2.48 (m, 2 H ) , 2.49 - 2.56 (m, 1 H ) , 2.61 (ddd, 1 H , J = 13, 7, 3 H z ) , 3.56 -  3.67 (m, (7 lines), 2 H), 3.67 (s, 3 H , C H 0 - ) . 3  1 3  C n m r (50 M H z ) : 6 = -5.53, -5.45, 17.0, 18.2, 19.8, 25.9 (3 carbons), 30.6, 30.8, 32.3, 32.7, 36.1, 36.5, 37.8, 42.2, 42.9, 47.3, 50.5, 50.9, 51.2, 61.6, 173.6, 211.1.  lrms (DCI): m/z = 422 (15%, M ) . +  firms (DCI): calcd. for C 4 H 4 0 S i : 422.2853; found: 422.2845. 2  2  4  Anal, calcd. for C 4 H 4 0 S i : C 68.20, H 10.02; found C 68.17, H 10.13. 2  optical rotation: [ a ]  2  2 5 D  4  -36° (c = 2.4, hexane); [oc]  25 436  -48° (c = 2.4, hexane).  152  Preparation o f Methyl (la,3B,3aB,6p,6aB,9a(3,9ba)-(-)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l[[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-9-[[(trifluoromethyl)sulfonyl]oxy]eafl/TI-phenalenecarboxylate (64)  A solution o f L D A in dry T H F (10 mL) was prepared at -78 °C in the usual way using dry diisopropylamine (0.134 m L , 0.958 mmol) and a solution o f tert-butyllithium (0.614 m L , 1.56 M ) in pentane. A solution o f the ketone 23 (0.300 g, 0.711 mmol) in dry T H F (3 mL) was added to the reaction flask by cannula. The pale yellow solution was stirred for 5 min and then warmed to -30 °C and stirred for a period o f 3 h maintaining the temperature between -30 °C and -20 °C. A solution o f A'-phenyltrifluoromethanesulfonimide (0.279 g, 0.781 mmol) in dry T H F (2 mL) was added to the reaction flask by cannula. The mixture was stirred for 10 min and then allowed to warm to rt. The pale yellow solution was diluted with diethyl ether (10 m L ) and the solvent was removed. The crude product, 0.70 g o f a clear, yellow oil, was purified by column chromatography (40 g o f tic grade silica gel, 4 cm (width) column, methylene chloride to elute the product and then 9:1 petroleum ether - diethyl ether to elute the unreacted starting material). Removal o f the solvent from the appropriate fractions, followed by treatment o f the residues  153  under reduced pressure (vacuum pump), gave the enol trifluoromethanesulfonate 64 (0.331 g, 84%) and recovered ketone 23 (0.039 g, 13%), both as clear, colourless oils.  The title  compound displayed:  ir(film): 1726, 1444, 1420, 1211 cm . -1  T I nmr (400 M H z ) : 5 = 0.030 (s, 6 H , - ( C H ) S i - ) , 0.34 - 0.96 (contains 2 d (from the 2° - C H ) 3  2  3  overlapping with each other and 1 s (from the ( C H ) C S i - ) , 15 H ) , 1.19 (ddd, 111,/= 13, 3  3  13, 5 H z ) , 1.23 - 1.51 (m, 6 H ) , 1.70 (dddd, 1 H , J = 13, 13, 13, 3 H z ) , 1.79 (dd, 1 H , J = 18, 3 H z ) , 1.94 (br d, 1 H , J = 14 Hz), 2.07 (br dd, 1 H , J = 13, 2 Hz), 2.21 (br s, 1 H ) , 2.55 - 2.63 (m, 1 H ) , 3.01 (dd, 1 H , J = 18, 8 H z ) , 3.53 - 3.69 (m, 5 H , contains a singlet at 3.65 for the C H 0 - function), 5.77 (d, 1 H , J= 8 H z ) . 3  1 3  C nmr (50 M H z ) : 8 = -5.6, -5.5, 16.9, 18.1, 19.5, 25.8 (3 carbons), 29.9, 30.2, 33.2, 34.2, 35.4, 36.5, 40.9, 42.3, 42.4, 46.3,49.8, 51.1, 61.3, 118.5 (q, J . = 320 H z ) , 118.6, 149.7, l  ? c  172.9. lrms (EI): m/z = 554 (3%, N f ) . hrms (EI): calcd. for C 5H4i0 F SSi: 554.2346; found: 554.2360. 2  6  3  optical rotation: [CX]D -39° ( c = l l , hexane); [a]4 6 -68° ( c = l l , hexane). 25  25  3  154  Preparation o f Dimethyl (la,3p,3aP,6p,6ap,9ap,9ba)-(-)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l[[[(l,l-dimethylethyl)dimethylsilyl]oxy]methyl]-3,6-dimethyl-6a,9[l//]-phenalenedicarboxylate (65)  A dry 50 m L B 1 4 3-necked round-bottomed flask was brought into a glove box and charged with dry lithium chloride (0.049 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.067 g, 0.058 mmol) and a magnetic stirrer bar. septum capped condenser.  The middle joint was fitted with a rubber  One outer joint was fitted with a Teflon® stopcock equipped inlet  adapter and the other outer joint was fitted with a rubber septum. The stopcock was closed and the apparatus removed from the glove box. The inlet adapter was connected to a low pressure supply o f carbon monoxide and the septum on the condenser was pierced with a 16 ga needle connected to a Tygon® hose connected to an oil bubbler. D r y methanol (15 m L ) was added by syringe to the reaction flask and the mixture was stirred magnetically. The stopcock was opened and the apparatus was purged with a gentle flow o f carbon monoxide for a period o f 30 min. D r y triethylamine (0.161 m L , 1.16 mmol) was added by syringe, followed by a solution o f the enol trifluoromethanesulfonate 64 (0.320 g, 0.578 mmol) in dry methanol (5 m L ) , by cannula.  155  The yellow suspension was heated to 70 °C and stirred at this temperature for a period o f 3 h. The mixture was cooled to rt, opened to the atmosphere and filtered through a short column o f Celite® (1 cm high supported in a 2 cm (width) column). The column was washed with methanol (10 m L ) and the solvent was removed from the combined filtrates. The residue was taken up in diethyl ether (50 m L ) and shaken with saturated N a C l (aq) (10 m L ) . The organic phase was separated, dried over M g S 0 , filtered and the solvent was removed. The crude product, 0.35 g 4  of a clear, yellow oil, was purified by column chromatography (10 g o f 230-400 mesh silica gel, 2 cm (width) column, 9:1 methylene chloride - diethyl ether).  Removal o f the solvent from the  appropriate fractions, followed by distillation (160-165 °C at 0.050 Torr) o f the residue, gave the a,B-unsaturated ester 65 (0.247 g, 92%) as a clear, colourless oil. This material displayed:  ir (film): 1723, 1254 cm" . 1  *H nmr (400 M H z ) : 6 = -0.020 (s, 6 H , - ( C H ) S i - ) , 0.82 - 0.87 (contains a singlet at 0.85 (for 3  2  the ( C H ) C S i - protons) overlapping with a doublet (for a 2° - C H ) , 12 H ) , 0.88 (d, 3 H , J 3  3  3  = 6 H z , 2° - C H ) , 1.18 - 1.50 (m, 7 H ) , 1.64 (dddd, 1 H , J= 3  10, 10, 10, 4 H z ) , 1.75 (ddd,  l H , y = 18, 4, 2 Hz), 1.85 (dd, 1 H , J= 10, 2 Hz), 2.06 (dd, 1 H , J= 2.52 (m, 1 H ) , 2.59 (br d, 1 H,J 10, 5 H z ) , 3.53 (dd, 1 H , J=  = 11 H z ) , 3.02 (dd, 1 H , J=  13, 4 Hz), 2.44 -  18, 6 H z ) , 3.43 (dd, 1 H , J =  10, 9 Hz), 3.62 (s, 3 H , C H 0 - ) , 3.68 (s, 3 H , C H 0 - ) , 6.77 3  3  (ddd, 1 H , J= 7, 2, 2 H z , H-8). 1 3  C nmr (50 M H z ) : 5 = -5.5 (2 carbons), 16.2, 17.0, 19.7, 25.9 (3 carbons), 30.0, 30.4, 33.5, 36.1, 36.2, 37.7, 39.8, 41.2, 42.5, 45.4, 49.7, 51.0, 51.2, 62.0, 133.3, 137.5, 167.6, 173.6.  lrms (EI): m/z = 464 (13%, \ f ) . hrms (EI): calcd. for CzeHwOjSi: 464.2959; found 464.2933.  156  Anal, calcd. for CMHLUOSSI: C 67.20, H 9.54; found C 67.19, H 9.45. optical rotation: [ a ]  2 5 D  -90° (c = 9.2, hexane); [a] 6  Preparation o f Dimethyl  43  25  -185° (c = 9.2, hexane).  (la,3p,3ap,6|3,6aP,9aP,9ba)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l-  (hydroxymethyl)-3,6-dimethyl-6a,9[l//]-phenalenedicarboxylate  (66)  HO  A solution o f the a,P-unsaturated ester 65 (0.0314 g, 0.0676 mmol) in acetone (2 mL) was stirred magnetically at rt and the reaction flask was wrapped in foil. A single drop o f water was added by Pasteur  pipette  followed by bis(acetonitrile)dichloropalladium(II) (1.0 mg,  0.0039 mmol). The red solution was stirred for a period o f 18 h at the end o f which time the reaction mixture was a yellow solution with a small amount o f black precipitate. solvent was removed by rotary evaporation.  M o s t of the  For this operation, the evaporating flask was not  immersed in a warm water bath, but rather periodically warmed in a cool water bath as frost began to accumulate on the evaporating flask. The crude product, a clear, brown oil, was purified immediately by column chromatography (2 g o f tic grade silica gel, IV2 cm (width) column, 1:2 petroleum ether - diethyl ether). The product-containing fractions were pooled and their solvent was removed as described above. The product, the alcohol 66, 0.0242 g (-100%) was isolated  157  as a clear, colourless oil. This material, which was carried on to the next step without delay, displayed:  ir(film): 3422, 1721, 1436, 1253 c m . -1  H nmr (400 M H z ) : 8 = 0.85 (d, 3 H , J= 6 H z , 2° - C H ) , 0.92 (d, 3 H , J= 6 H z , 2° - C H ) , 1.12  l  3  3  - 1.23 (m, 1 H ) , 1.25 - 1.52 (m, 7 H ) , 1.66 (dddd, 1 H , J = 12, 12, 12, 4 H z ) , 1.73 - 1.83 (m, 2 H ) , 2.06 (dd, 1 H , J= 18, 3 H z ) , 2.53 - 2.67 (m, 2 H ) , 3.04 (dd, 1 H , J= 18, 8 H z ) , 3.52 - 3.59 (m, 2 H ) , 3.62 (s, 3 H , C H 0 - ) , 3.70 (s, 3 H , C H 0 - ) , 6.82 (br d, 1 H , J = 3  3  1 Hz, H-8).  Preparation o f Dimethyl  (la,3p,3ap,6fj,6ap,9af3,9ba)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l-  formyl-3,6-dimethyl-6a,9[l//]-phenalenedicarboxylate (68)  O  To the alcohol 66 (0.233 g, 0.666 mmol) in a 25 m L round-bottomed flask was added Nmethylmorpholine ./V-oxide (0.160 g, 1.35 mmol) and dry powdered 4 A molecular sieves (0.50 g).  The flask was purged with argon and fitted with a rubber septum.  D r y methylene  chloride (10 m L ) was added by syringe and the mixture was stirred magnetically. The suspension  158  was cooled to 0 °C and tetra-«-propylammonium peraithenate (0.016 g, 0.046 mmol) was added in 1 portion. The reaction mixture was warmed to 8 °C, stirred at this temperature for a period o f 1 h and then filtered through a short column (5 g supported in a 2 cm (width) column) o f tic grade silica gel. The column was washed with methylene chloride and fractions were collected. Those fractions containing the major component (tic developed with 2:1 petroleum ether diethyl ether, visualized with uv light and the K M n 0  4  dip, (rf: -0.7)) were pooled. Removal o f  the solvent, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the aldehyde 68 (0.209 g, 90%) as a clear, colourless oil. This material, which was used without further purification, displayed:  ir (film): 2722, 1723, 1436, 1254 cm" . 1  T i nmr (400 M H z ) : 6 = 0.85 (d, 3 H , J = 6 H z , 2° - C H ) , 0.92 (d, 3 H , J = 6 H z , 2° - C H ) , 1.03 3  3  - 1.17 (m, 1 H ) , 1.23 - 1.50 (m, 6 H ) , 1.69 (dddd, 1 H , J= 12, 12, 12, 4 H z ) , 1.84 (br d, 1 H , J= 20 Hz), 2.02 (br dd, 1 H , J= 17, 3 H z ) , 2.12 (ddd, 1 H , J= 17, 2, 2 Hz), 2.69 (br d, 1 H , J = 13 H z ) , 3.09 (dd, 1 H , J = 20, 7 Hz), 3.31 - 3.37 (m, 1 H ) , 3.61 (s, 3 H , C H 0 - ) , 3.70 (s, 3 H , C H 0 - ) , 7.00 (ddd, 1 H , J= 7, 2, 2 H z , H-8), 9.62 (s, 1 H , - C H O ) . 3  3  159  Preparation o f Methyl (la,3p,3ap,6f3,6a(3,9a(3,9ba)-(-)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-lacetyl-9-formyl-3,6-dimethyl-6a[l^T]-phenalenecarboxylate (32) O  Step 1: Preparation o f {Dimethyl (la,3p,3ap,6p,6aP,9ap,9ba)-2,3,3a,4,5,6,6a,7,9a,9bDecahydro-l-[(l'i?)-r-hydroxyethyl]-3,6-dimethyl-6a,9[l//]-phenalenedicarboxylate and Dimethyl (la,3p,3aP,6p,6ap,9ap,9ba)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l-[(l' S)-l'1  hydroxyethyl]-3,6-dimethyl-6a,9[l//]-phenalenedicarboxylate} (69) and {Methyl [(5i?)-5Methylpentanolido]-[4,3,2-c,d]-(la,3a,3aa,6aa,7a,9aa,9bp)-2,3,3a,6,6a,7,8,9,9a,9bdecahydro-l,7-dimethyl-6a[l//]-phenalenecarboxylate and Methyl [(5,S)-5-Methyl-pentanolido][4,3,2-c,d]-(la,3a,3aa,6aa,7a,9aa,9bp)-2,3,3a,6,6a,7,8,9,9a,9b-decahydro-l,7-dimethyl6a[l//]-phenalenecarboxylate} (70)  160  A solution of the aldehyde 68 (0.209 g, 0.601 mmol) in dry diethyl ether (10 mL) was stirred magnetically and cooled to -78 °C.  A solution of methylmagnesium bromide (0.60 mL,  3.0 M) in diethyl ether was added by syringe and the solution was stirred for a period of 30 min. The cooling bath was removed and the reaction vessel was opened to the atmosphere. Saturated NFLCl (aq) (0.5 mL) was added, dropwise by pipette, and the mixture was allowed to warm to rt with efficient stirring. At rt, the mixture was comprised of a clear, colourless liquid and a white, pasty solid. The contents of the flask were triturated and small portions of  MgSO*4  were added  until a readilyfilterablemixture was obtained. Filtration followed by removal of the solvent from the filtrate gave the crude product, 0.219 g of a clear, colourless oil. For this operation, the evaporating flask was not immersed in a warm water bath, but rather periodically warmed in a cool water bath as frost began to accumulate in the evaporating flask. Analysis of this material by tic (developed with 1:1 petroleum ether - diethyl ether, visualized with uv light and the K M n 0 dip) showed it to be a mixture of 4 major components. 4  The 2 major components of  lower polarity, (rf: -0.25 and -0.22), were assigned to the lactones 70 while those of higher polarity, (rf: -0.11 and -0.08), were assigned to the alcohols 69. This material was carried on to the next step without delay.  Step 2: Preparation of {Methyl (3aa,4a,6aa,7a,9p,9aa,9bp)-3a,4,5,6,6a,7,8,9,9a,9bDecahydro-1 -formyl-9-[(1 'R)~1'-hydroxyethyl]-4,7-dimethyl-3a[3//]-phenalenecarboxylate and Methyl  (3aa,4a,6aa,7a,93,9aa,9b(3)-3a,4,5,6,6a,7,8,9,9a,9b-Decahydro-l-formyl-9-[(l' S)-l'-  hydroxyethyl]-4,7-dimethyl-3a[3//]-phenalenecarboxylate}  1  (73) and {Methyl  (la,3p,3aP,6p,6ap,9aP,9ba)-2,3,3a,4,5,6,6a,7,9a,9b-Decahydro-l-[(l'i?)-l'-hydroxyethyl]-9(hydroxymethyl)-3,6-dimethyl-6a[ li/j-phenalenecarboxylate and Methyl  161  (la,3B,3aB,6p,6aP,9aB,9ba)-2,3,3a,^^ (hydroxymethyl)-3,6-dimethyl-6a[l//]-phenalenecarboxylate}  OH  (74)  HO  A solution of the above crude product (0.219 g) in dry diethyl ether (10 mL) was stirred magnetically and cooled to -78 °C.  A solution of D I B A L - H (2.0 mL, 1.0 M) in hexanes was  added by syringe and the solution was stirred for a period of 5 h. The cooling bath was removed, the reaction vessel was opened to the atmosphere and saturated NH4CI (aq) (6 drops) was added by pipette.  Diethyl ether (10 mL) was added and the mixture was stirred vigorously for 3 h.  Magnesium sulfate (0.5 g) and Celite® (1 g) were added, the mixture was stirred for 20 min and then was filtered through a pad of Celite® (1 cm high supported in a 2 cm (width) column). The solid was washed with diethyl ether (10 mL) and ethyl acetate (5 mL). The solvent was removed from the combined filtrates to isolate the crude product (0.181 g) as a clear, very pale yellow oil which formed a semi-solid foam under reduced pressure (vacuum pump).  Analysis of this  material by tic (developed with 1:2 petroleum ether - diethyl ether, visualized with uv light and the KMn04 dip) showed it to be a mixture of 4 major components. The 2 major components of higher polarity, (rf: - 0 . 1 0 and - 0 . 1 8 ) , were assigned to the diols 74 while those of lower polarity, (uv active spots of rf: - 0 . 2 5 and - 0 . 3 2 ) , were assigned to the aldehydes 73. used without further purification.  The mixture was  162  S t e p 3:  P r e p a r a t i o n o f the K e t o A l d e h y d e  32  O  To  (0.25  the  above crude product (0.181 g)  g) and A f - m e t h y l m o r p h o l i n e N - o x i d e (0.35  and capped with a rubber septum.  was  added dry p o w d e r e d  g , 3.0 m m o l ) .  D r y methylene  Tetra-«-propylammonium  f o r 2 h.  A  diethyl ether as the m o b i l e p h a s e .  T h e reaction mixture  column was  collected and those  Fractions were  perruthenate  column was constructed  68)  methylene chloride -  w a s l o a d e d onto the c o l u m n and  c o n t a i n i n g the  R e m o v a l o f t h e s o l v e n t g a v e t h e k e t o a l d e h y d e 32  as a c l e a r , c o l o u r l e s s o i l .  ir (film): 2 7 1 5 ,  1723,  1683,  product  (rf:  (m, 1 H ) ,  - C O C H  3  1.45  function),  (0.132 g, 6 5 % ,  the  -0.65,  4  tic  dip)  overall  from  6 Hz, 2° -CH ),  0.96  T h i s material displayed:  1190 cm" . 1  * H n m r (400 M H z ) : 5 = 0.86  - 1.06  was  employing  d e v e l o p e d w i t h 1:2 p e t r o l e u m e t h e r - d i e t h y l e t h e r , v i s u a l i z e d w i t h u v l i g h t a n d t h e K M n 0  were combined.  The  T h e reaction mixture  2 3 0 - 4 0 0 m e s h s i l i c a g e l ( 1 0 g ) s u p p o r t e d i n a 3 c m ( w i d t h ) c o l u m n a n d 9:1  run.  sieves  T h e flask was purged with argon  m m o l ) w a s a d d e d and the c o o l i n g bath w a s r e m o v e d .  w a r m e d t o 8 ° C a n d s t i r r e d at t h i s t e m p e r a t u r e  molecular  c h l o r i d e (5 m L ) w a s a d d e d b y s y r i n g e .  suspension w a s stirred magnetically and c o o l e d to 0 ° C .  (0.042 g, 0.12  4 A  ( d , 3 H , J=  6 H z , 2 ° - C H ) , 0.90  - 1.66 ( m , 6 H ) ,  2.10  (ddd,  1 H, J  3  1.96  =  ( d , 3 H , J=  3  - 2 . 0 6 ( m , 6 H , c o n t a i n s a s i n g l e t at 2 . 0 3  19, 4,  2 Hz),  2.34  (br  d,  1 H , J=  f o r the  11 H z ) ,  3.21  163 (ddd, 1 H , J = 19, 6, 1 H z ) , 3.58 (s, 3 H , C H 0 - ) , 3.96 (m, 1 H ) , 6.81 (ddd, 1 H , J= 6, 2, 3  2 H z , H-8), 9.28 (s, 1 H , - C H O ) . 1 3  C nmr (50 M H z ) : 8 = 16.9, 19.4, 29.1, 29.8, 30.0, 34.6, 36.6, 37.2, 37.9, 41.2, 42.4, 44.6, 47.8, 50.0, 51.0, 142.0, 152.7, 173.7, 194.7, 211.4.  lrms (EI): 332 (11%, M ^ ) . hrms (EI): calcd. for optical rotation: [ct]  C20H28O4:  25 D  Preparation o f Methyl  332.1988; found: 332.1987.  -44° (c = 1.4, chloroform);  [oc] 36 4  2 5  -75° (c = 1.4, chloroform).  (la,3aa,4a,5ap,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,10,10a,10b,10c-  Dodecahydro-l,4-dimethyl-6-oxo-lOa-pyrenecarboxylate (76)  A solution o f the keto aldehyde 32 (0.220 g, 0.663 mmol) in dry methanol (12 mL) was stirred magnetically at rt. Powdered dry 4 A molecular sieves (0.5 g) were added followed by 5 drops o f 2.5 M methanolic sodium hydroxide by Pasteur pipette. The suspension was stirred at rt for a period o f 18 h and then warmed to 50 °C and stirred at this temperature for 2 h.  The  cooled mixture was filtered through a short column (1 cm high supported in a 2 cm (width) column) o f Celite®. The solid was washed with methanol (15 m L ) and the solvent was removed from the combined filtrates. The residue was taken up in diethyl ether (40 mL) and the solution  164  was washed with portions (5 m L ) o f water until the last washing was neutral ( p H paper). organic phase was dried over MgSCU, filtered and the solvent was removed.  The  The residue was  purified by column chromatography (20 g o f 230-400 mesh silica gel, 3 cm (width) column, 19:1 methylene chloride - diethyl ether). Removal o f the solvent from the appropriate fractions gave pale yellow residue which was recrystallized from hexane to provide the dienone 76 (0.151 g, 72%) as a colourless, crystalline solid. This material displayed:  mp: 172 - 174 °C. ir ( K B r ) : 1711, 1676, 1638, 1457, 1436 1241, 1199, 810, 780 cm" . 1  H nmr (400 M H z ) : 5 = 0.86 (d, 3 H , J= 6 H z , 2° - C H ) , 0.92 (ddd, 1 H , J= 12, 12, 6 H z ) , 1.00  l  3  (d, 3 H , J= 4 H z , 2° - C H ) , 1.03 - 1.14 (m, 2 H ) , 1.31 (dd, 1 H , J= 3  11, 11 H z ) , 1.40 -  1.70 (m, 4 H ) , 1.90 (br d, 1 H , J = 21 H z ) , 2.04 - 2.21 (m, 4 H ) , 3.18 (dd, 1 H , J = 21, 6 H z ) , 3.63 (s, 3 H , C H 0 - ) , 5.85 (d, 1 H , J = 10 H z , H-7), 6.08 (br d, 1 H , J = 6 H z , 3  H-9), 6.93 (d, 1 H , J = 10 H z , H-8). 1 3  C nmr (100 M H z ) : 5 = 16.9, 19.5, 30.0, 30.3, 33.9, 37.1, 37.6, 40.6, 41.3, 41.7, 49.1, 49.6, 50.2, 51.2, 125.7, 132.6, 134.4, 146.0, 173.9, 200.6.  lrms (EI): m/z = 314 (13.5%, M * ) . hrms (EI): calcd for C H O : 314.1882; found: 314.1879. 2 0  2 6  3  Anal, calculated for C H O : C 76.40, H 8.33; found: C 76.10, H 8.30. 2 0  optical rotation: [ a ]  2 5 D  2 6  3  -215° (c = 0.61, chloroform); [ a ] 6 43  25  -311° (c = 0.61, chloroform).  165  Preparation o f Methyl  (la,3aa,4a,5aa,10aa,10bP,10ca)-(-)-l,2,3,3a,4,5,5a,6,7,8,10,10a,-  1 Ob, 1 Oc-Tetradecahydro-1,4-dimethyl-6-oxo-1 Oa-pyrenecarboxylate (30)  O  [[HTH J Me0 C 2  J  30 Step 1: Preparation o f the Intermediate A ; Rhodium Catalyzed Reduction o f the Dienone 76  A  10 m L B I O round-bottomed  0.438 mmol) and a magnetic stirrer bar.  flask was charged with the dienone 76 (0.139 g, A rubber septum was fitted and the flask was  thoroughly flushed with argon. D r y triethylsilane (1.5 mL) was added by syringe. Stirring was started and the suspension was heated to 60 °C. A t this temperature, the starting material had dissolved to provide a pale yellow solution. The flask was vented by piercing the septum with an 18 ga needle.  A solution o f chlorotris(triphenylphosphine)rhodium(I) (0.042 g, 0.045 mmol) in  dry methylene chloride (0.20 mL) was added to the reaction mixture by Gastight® syringe. The reaction mixture was stirred for 2 min (to allow the methylene chloride to be blown off) after which time the vent was removed. The mixture was stirred for a period o f 1.5 h. The reaction mixture was cooled to 8 °C and then added to hexane (20 mL) by Pasteur pipette. The resulting suspension was allowed to stand for 15 min and then filtered through a fine sintered glass funnel. The solid was washed with hexane ( 2 x 5 mL) and the filtrates were combined. Removal o f the solvent from the filtrates, followed by treatment o f the residue under reduced pressure (vacuum  166  pump), gave the intermediate A (0.36 g) as a viscous, clear, yellow oil. This material was carried on to the next step immediately.  Step 2: Preparation o f the Intermediate B; Hydrolysis o f the Intermediate A  The above residue, intermediate A, was taken up in T H F (25 m L ) and the solution was stirred magnetically. Aqueous hydrochloric acid (0.3 m L , 6 M ) was added by pipette and the yellow solution was stirred at rt for a period o f 16 h. The mixture was then poured into diethyl ether (50 m L ) and saturated N a C l (aq) (10 mL). separated.  The mixture was shaken and the layers were  The organic phase was washed successively with saturated NaHC03 (aq) (10 m L )  and saturated N a C l (aq) (10 m L ) , dried over M g S 0 and finally filtered. Removal o f the solvent, 4  followed by treatment o f the residue under reduced pressure (vacuum pump), gave the intermediate B (0.32 g) as a yellow, oily solid. immediately.  This material was carried on to the next step  167  Step 3: Preparation o f the Ketone 30; Oxidation o f the Intermediate B  To the above residue, intermediate B, in a 25 m L B 14 round43ottomed flask was added powdered dry 4 A molecular sieves (0.6 g), /V-methylmorpholine-Af-oxide (0.100 g) and a magnetic stirrer bar. A rubber septum was fitted and the flask was thoroughly flushed with dry argon. D r y methylene chloride (7 m L ) was added and the suspension was stirred magnetically. Tetra-n-propylammonium perruthenate (0.015 g, 0.043 mmol) was added and the suspension was stirred for a period o f 1 h. A column o f 230 - 400 mesh silica gel (10 g supported in a 3 cm (width) column) was prepared and the reaction mixture was filtered through the column. column was washed with methylene chloride and fractions were collected.  The  Removal o f the  solvent from the appropriate fractions gave a pale yellow solid residue which was recrystallized once from 4:1 methanol - water to provide the ketone 30 (0.110 g, 79%, overall from 76) as a colourless, crystalline solid.  The column was further washed with 9:1 methylene chloride -  diethyl ether and fractions containing the unconverted starting material were pooled. Removal o f the solvent from these fractions, followed by treatment o f the residue under reduced pressure (vacuum pump), provided the dienone 76 (0.015 g, 11%) as a pale yellow solid. recrystallized ketone 30 displayed: mp: 147 - 149 °C.  The  168  i r ( K B r ) : 1712, 1458, 1439, 1203, 1147 cm" . 1  J  H nmr (400 M H z ) : 5 = 0.86 (d, 3 H , J= 6 H z , 2° - C H ) , 0.87 - 0.95 (m, 1 H ) , 0.97 (d, 3 H , J = 3  6 H z , 2° - C H ) , 0.98 - 1.09 (m, 1 H ) , 1.12 - 1.70 (m, 6 H ) , 1.78 (br d, 1 H , J= 3  17 H z ) ,  1.89 (ddd, 1 H , J= 13, 3, 3 H z ) , 1.96 - 2.06 (m, 2 H ) , 2.10 (ddd, 1 H , J = 12, 12, 3 H z ) , 2.32 - 2.43 (m, 3 H ) , 2.47 - 2.56 (m, 1 H ) , 2.93 (dd, 1 H , J = 17, 6 H z ) , 3.61 (s, 3 H , C H 0 - ) , 5.56 (dd, 1 H , J= 6, 2 H z , H-9). 3  1 3  C nmr (50 M H z ) : 5 = 17.0, 19.5, 30.2, 30.3, 33.7, 33.9, 36.2, 38.0, 41.0, 41.4, 41.7, 45.3, 49.8, 50.9, 51.8, 53.4, 121.0, 134.7, 174.2, 212.1.  lrms (EI): m/z = 316 (23%, M " ) . hrms (EI): calculated for C H 8 O : 316.2039; found: 316.2033. 2 0  optical rotation: [ a ]  2 4 D  Preparation o f Methyl  2  3  -37° (c = 1.8, chloroform); [ a ]  2 4 4 3 6  -48° (c = 1.8, chloroform).  (la,3aa,4a,5ap,7p,10aa,10bp,10ca)-l,2,3,3a,4,5,5a,6,7,8,10,10a,-  10b,10c-Tetradecahydro-l,4,7-trimethyl-6-oxo-10a-pyrenecarboxylate (79) and Methyl (la,3aa,4a,5ap,7a,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,7,8,10,10a,10b,10c-Tetradecahydrol,4,7-trimethyl-6-oxo-10a-pyrenecarboxylate (80); Alkylation o f the Ketone 30  169  A solution o f L D A in dry T H F (2 m L ) was prepared at -78 °C in the usual way from dry diisopropylamine (0.0190 m L , 0.137 mmol) and a solution o f  tert-butyllithium  (0.0810 m L ,  1.70 M ) in pentane. A solution o f the ketone 30 (0.0217 g, 0.0686 mmol) in dry T H F (1 mL) was added to the L D A solution by cannula. The pale yellow solution was stirred for 2 h and then warmed to 0 °C.  D r y hexamethylphosphoramide  (0.0360 m L , 0.206 mmol) was added by  syringe and the reaction mixture was recooled immediately to -78 °C and stirred at this temperature for 30 min. Methyl iodide (0.0210 m L , 0.343 mmol) was added by syringe and the solution was stirred for 30 min. The cooling bath was removed and the reaction mixture was allowed to warm to rt.  The reaction mixture was stirred at this temperature for 20 min after  which time it was poured into a mixture o f diethyl ether (10 m L ) , saturated N a C l (aq) (3 mL) and water (3 m L ) . The mixture was shaken and the layers were separated. The aqueous phase was extracted with diethyl ether ( 3 x 5 m L ) . The combined organic phases were dried over M g S 0 , 4  filtered and the solvent was removed.  Analysis o f this material by tic (developed with 4:1  petroleum ether - diethyl ether, visualized with the eerie ammonium molybdate dip) showed the reaction had produced 2 products less polar than the starting material as well as a spot on the baseline.  The crude product, 0.033 g o f a clear, yellow film, was separated and purified by  column chromatography (2 g o f 230-400 mesh silica gel, 1.5 cm (width) column, 9:1 hexane diethyl ether). Removal o f the solvent from the fractions containing the less polar product gave a colourless solid (0.0060 g, 26%), which proved to be the C-7f3 ketone 80. This material was not purified further at this point.  Removal o f the solvent from the fractions containing the more  polar product, followed by treatment o f the residue under reduced pressure (vacuum pump), gave a clear, colourless film (0.0147 g, 65%) which proved to be the C - 7 a ketone 79.  This  170  material was carried onto the next step without further purification. The material represented by the spot on the baseline was not isolated. The C - 7 a ketone 79 displayed:  ir(film): 1718, 1194, 1457, 1378, 1266, 737 cm" . 1  T i nmr (400 M H z ) : 5 = 0.85 (d, 3 H , J= 6 H z , 2° - C H ) , 0.87 - 0.95 (m, 1 H ) , 0.96 (d, 3 H , J = 3  6 H z , 2° - C H ) , 1.09 (d, 3 H , J= 7 H z , 2° - C H ) , 1.16 - 1.27 (m, 2 H ) , 1.37 - 1.55 (m, 3  3  3 H ) , 1.56 - 1.70 (m, 2 H ) , 1.79 (br d, 1 H , J= 17 H z ) , 1.93 (ddd, 1 H , J= 13, 3, 3 H z ) , 1.96 - 2.10 (m, 2 H ) , 2.12 - 2.26 (m, 2 H ) , 2.47 - 2.57 (m, 2 H ) , 2.94 (dd, 1 H , J=  17,  6 H z ) , 3.61 (s, 3 H , C H 0 - ) , 5.54 (br dd, 1 H , J= 6, 2 H z , H-9). 3  Preparation o f the C-70 Ketone 80; Epimerization o f the C - 7 a Ketone 79  A solution o f the C - 7 a ketone 79 (0.0147 g, 0.0445 mmol) in dry methanol (2 m L ) was stirred magnetically and cooled to 0 °C. Sodium hydride (a spatula tip, about 0.5 mg) was added and the pale yellow solution was stirred for 10 min. The cooling bath was taken away and the mixture was stirred for a period o f 16 h after which time the solvent was removed. The residue was taken up in diethyl ether (10 mL) and added to water (5 m L ) . A solution o f citric acid (aq)  171  (2 drops, 1 M ) was added by Pasteur pipette, the mixture was shaken and the layers were separated.  The aqueous phase was extracted with diethyl ether ( 2 x 1 0 m L ) . The combined  organic phases were dried over M g S 0 , filtered and the solvent was removed. 4  The crude  product, 0.018 g o f a clear, yellow film, was purified by column chromatography (0.50 g o f tic grade silica gel, 8 mm (width) column, 4:1 hexane - diethyl ether). Removal o f the solvent from the appropriate fractions gave the title compound (0.0145 g, 99%) as a colourless solid.  This  material was combined with the C-7[3 ketone isolated in the previous step and the lot was recrystallized once from 4:1 methanol - water to provide the C-7P ketone 80.  The product  (0.0204 g, 90%> from the ketone 30) exists as a colourless, crystalline solid.  This material  displayed: mp: 171 - 172 °C. ir ( K B r ) : 1713, 1457, 1376, 1195, 1175, 1147, 737 cm" . 1  X  H nmr (400 M H z ) : 5 = 0.86 (d, 3 H , J= 6 H z , 2° - C H ) , 0.87 - 1.11 (m, 2 H ) , 0.97 (d, 3 H , J = 3  6 H z , 2° - C H ) , 0.99 (d, 3 H , J= 6 H z , 2° - C H ) , 1.21 (dd, 1 H , J= 13, 11 H z ) , 1.24 (dd, 3  3  1 H , J=  11, 10 Hz), 1.35 - 1.52 (m, 3 H ) , 1.62 (ddd, 1 H , J = 11, 11, 4 H z ) , 1.78 (dm,  1 H , J=  17 H z ) , 1.85 (ddd, 1 H , J=  14, 3, 3 H z ) , 1.93 - 2.15 (m, 4 H ) , 2.39 - 2.53 (m(9  lines)d, 1 H , J = 1 H z ) , 2.54 (dd, 1 H , J= 14, 6 H z ) , 2.92 (dddd, IH,J=  17, 6, 2, 2 Hz),  3.59 (s, 3 H , C H 0 - ) , 5.55 (ddd, 1 H , J= 6, 4, 2 H z , H-9). 3  1 3  C nmr (100 M H z ) : 5 = 14.3, 17.0, 19.5, 30.2, 30.4, 34.0, 36.2, 38.1, 41.4, 41.7, 43.4, 44.4, 46.3, 49.7, 50.9, 51.9, 53.6, 120.6, 135.0, 174.2, 213.1.  lrms (EI): m/z = 3 3 0 (1 %, NT). hrms (EI): calculated for C i H O : 330.2195; found 330.2188. 2  3 0  3  Anal, calculated for C H O : C 76.33, H 9.15; found C 76.15, H 9.07. 2 1  3 0  3  172  optical rotation: [CX]D -28° (c = 1.1, chloroform);  Preparation o f Methyl  [a]436  -30° (c = 1.1, chloroform).  (la,3aa,4a,5aP,10aa,10bp,10ca)-(+)-l,2,3,3a,4,5,5a,6,7,8,10,-  10a, 10b, 1 Oc-Tetradecahydro-1,4,7,7-tetramethyl-6-oxo-l Oa-pyrenecarboxylate (81)  O  [f H T  H  Me0 C  J  2  81 A solution o f L D A in dry T H F (2 m L ) was prepared at -78 °C in the usual way from dry diisopropylamine (0.0510 m L , 0.360 mmol) and a solution o f 1.50 M ) in pentane.  fert-butyllithium  (0.247 m L ,  A solution o f the C-7p ketone 80 (0.0395 g, 0.120 mmol) in dry T H F  (2 m L ) was added to the L D A solution by cannula. After it had been stirred for 10 min, the pale yellow solution was warmed to -48 °C and stirred at this temperature for a period o f 2.5 h. D r y hexamethylphosphoramide (0.0840 m L , 0.480 mmol) was added by syringe and the pale yellow solution was stirred for 30 min. Methyl iodide (0.0370 m L , 0.600 mmol) was added by syringe, the mixture was stirred for 20 min and then the reaction mixture was warmed to 0 °C. Diethyl ether (2 m L ) and water (1 m L ) were added, the cooling bath was removed and the mixture was allowed to warm to rt. The contents o f the reaction flask were poured into diethyl ether (10 mL) and water (5 m L ) . The mixture was shaken and the layers were separated.  The aqueous phase  was extracted with diethyl ether ( 2 x 5 m L ) and the combined organic phases were washed successively with water ( 2 x 5 m L ) and saturated N a C l (aq) ( 1 x 5 m L ) before being dried over  173  MgS0 . 4  Filtration, followed by removal o f the solvent, gave the crude product (0.045 g) as a  clear, very pale yellow oil. Analysis o f the oil by tic (developed with 9:1 petroleum ether diethyl ether, visualized with the eerie ammonium molybdate dip) showed that the reaction had produced 1 major and 1 minor component, both less polar than the starting material. The crude product was purified by column chromatography (0.80 g o f tic grade silica gel, 8 mm (width) column, 47:3 hexane - diethyl ether).  Removal o f the solvent from the fractions containing the  major product, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the ketone 81 (0.0324 g, 78%) as a clear, colourless oil. This material displayed: ir(film): 1720, 1705, 1457, 1441, 1384, 1192, 1144 cm" . 1  *H nmr (400 M H z ) : 5 = 0.86 (d, 3 H , J= 6 H z , 2° - C H ) , 0.87 - 1.09 (m, 2 H ) , 0.97 (d, 3 H , J = 3  6 H z , 2° - C H ) , 1.02 (s, 3 H , 3° - C H ) , 1.10 (s, 3 H , 3° - C H ) , 1.15 (dd, 1 H , J = 13, 3  3  3  2 Hz), 1.25 (dd, 1 H , J = 10, 10 Hz), 1.35 - 1.53 (m, 3 H ) , 1.61 (dddm, 1 H , J = 9, 9, 9 H z ) , 1.82 ( b r d , 1 H , J= 17 Hz), 1.85 (ddd, 1 H , J= 13, 3, 3 H z ) , 1.93 (br dd, l H , / = . 11, 11 H z ) , 2.06 (br dd, 1 H , J= 13, 4 Hz), 2.13 - 2.24 (m, 2 H ) , 2.31 (ddd, 1 H , J= 12, 12, 3 H z ) , 2.92 (br dd, 1 H , J= 17, 6 H z ) , 3.61 (s, 3 H , C H 0 - ) , 5.54 (br dd, 1 H , J= 6, 3  1 H z , H-9). 1 3  C nmr (100 M H z ) : 5 = 17.0, 19.5, 24.5, 26.0, 30.2, 30.4, 34.4, 36.2, 38.3, 41.4, 41.7, 45.1, 46.2, 48.7, 49.2, 49.8, 50.9, 52.0, 121.9, 133.9, 174.2, 215.6.  lrms (EI): m/z = 344 (8.1%, M ) . 4  hrms (EI): calculated for C H 0 : 344.2351; found 344.2344. 2 2  3 2  3  optical rotation: [ct]n +5° (c = 1.3, chloroform); [ a ] 6 25  43  25  +47° (c = 1.3, chloroform).  174 j Preparation o f Methyl  (la,3aa,4a,5ap,10aa,10bp,10ca)-(-)-l,2,3,3a,4,5,5a,6,7,8,10,10a,-  1 Ob, 1 Oc-Tetradecahydro-1,4,7,7-tetramethyl-1 Oa-pyrenecarboxylate (29)  Step 1: Preparation o f M e t h y l  (lp,5aa,6a,8aa,9a,10ap,10ba,10cp)-l,2,3,5,5a,6,7,8,8a,9,-  10,1 Oa, 1 Ob, 1 Oc-Tetradecahydro-1 -hydroxy-2,2,6,9-tetramethyl-5a-pyrenecarboxylate (82) and Methyl  (la,5aa,6a,8aa,9a,10ap,10ba,10cp)-l,2,3,5,5a,6,7,8,8a,9,10,10a,10b,10c-  Tetradecahydro-l-hydroxy-2,2,6,9-tetramethyl-5a-pyrenecarboxylate  A  (83)  solution o f the ketone 81 (0.0324 g, 0.0940 mmol) and  2.3 mmol) in dry methanol (3 m L ) was stirred magnetically at rt.  1-pentene (0.250 mL,  Sodium borohydride (7.0 mg,  0.19 mmol) was added and the solution was stirred for 45 min. Analysis o f the reaction mixture by tic (developed with 9:1 petroleum ether - diethyl ether, visualized with the eerie ammonium molybdate dip) showed that the starting material had been consumed. Solid ammonium chloride (10 mg) was added in several small portions and the mixture was stirred until the effervescence  175  had ceased. The solvent was removed. The residue was taken up in diethyl ether (10 m L ) and water (2 m L ) and the layers were separated. The aqueous phase was extracted with diethyl ether ( 3 x 2 m L ) and the combined organic phases were washed with water ( 2 x 2 m L ) before being dried over MgSCu.  Filtration, followed by removal o f the solvent, gave the crude product  (0.037 g) as a clear, colourless oil. Analysis o f this oil by tic (developed with 4:1 petroleum ether - diethyl ether, visualized with the eerie ammonium molybdate dip) showed it to contain 2 major components, both more polar than the starting material, along with a trace o f material o f similar i f to the starting material. This material was purified by column chromatography (0.25 g o f tic grade silica gel, 7.5 mm (width) column, 19:1 chloroform - diethyl ether).  Fractions containing  the 2 major components were pooled and produced, after removal o f the solvent and treatment o f the residue under reduced pressure (vacuum pump),a mixture o f the title compounds (0.0327 g, -100%) as a clear, colourless oil. This material could be used without further purification. Comparison o f the integrals o f the signal for the carbinol proton in the ' H nmr spectrum (5 = 3.05 (for 82) and 3.17 (for 83)) gave the ratio o f the products to be - 5 : 2 in favour o f the alcohol 82. The mixture displayed:  ir (film): 3502, 1723 (with a shoulder on the low frequency side), 1457, 1382, 1268, 1193, 758 cm" , 1  lrms (EI): m/z = 346 (21%, M*). hrms (EI): calculated for  C22H34O3:  346.2508; found: 346.2509.  A small amount o f the mixture was separated under the chromatographic conditions listed above to provide samples o f the 2 epimers o f the title compound for H nmr analysis. !  176  The alcohol 82 (the less polar epimer) displayed:  T i nmr (400 M H z ) : 8 = 0.77 (s, 3 H , 3° - C H ) , 0.82 - 1.80 (m, 12H), 0.86 (d, 3 H , J= 6 H z , 2° 3  - C H ) , 0.97 (d, 3 H , J = 6 H z , 2° - C H ) , 1.00 (s, 3 H , 3° - C H ) , 1.87 (br s, 2 H ) , 2.03 (br 3  3  3  d, 1 H , J= 12 Hz), 2.06 (ddd, 1 H , J = 12, 12, 3 H z ) , 2.84 (dd, 1 H , J=  17, 6 Hz), 3.05  (d, 1 H , J= 11 H z , H - l ) , 3.62 (s, 3 H , C H 0 - ) , 5.34 (br d, 1 H , J= 6 H z , H-4). 3  The alcohol 83 (the more polar epimer) displayed:  T i nmr (400 M H z ) : 8 = 0.81 (s, 3 H , 3° - C H ) , 0.82 - 1.75 (m, 12 H ) , 0.85 (d, 3 H , J= 6 H z , 2° 3  - C H ) , 0.97 (d, 3 H , J= 6 H z , 2° - C H ) , 0.99 (s, 3 H , 3° - C H ) , 1.80 - 1.90 (m, 1 H ) , 2.01 3  3  3  - 2.10 (m, 2 H ) , 2.22 (br d, 1 H , J= 15 H z ) , 2.85 (dd, 1 H , J= 17, 6 H z ) , 3.17 (br s, 1 H , H - l ) , 3.62 (s, 3 H , C H 0 - ) , 5.34 (dd, 1 H , J= 6, 2 H z , H-4). 3  Step 2: Preparation o f {Methyl  (la,3aa,4a,5ap,6a,10aa,10bp,10ca)-l,2,3,3a,4,5,5a,6,7,8,10,-  10a, 10b, 1 Oc-Tetradecahydro-1 ^JJ-tetramethyl-e-^-methyl-O-dithiocarbonato)-1 Oapyrenecarboxylate and Methyl (la,3aa,4a,5aP,6a,10aa,10bp,10cct)-l,2,3,3a,4,5,5a,6,7,8,10,10a, 10b, 1 Oc-Tetradecahydro-1 ,4,7,7-tetramethyl-6-(S-methyl-0-ditliiocarbonato)-1 Oapyrenecarboxylate) (84)  177  S  A solution o f L D A in dry T H F (1 mL) was prepared at -78 °C in the usual way from dry diisopropylamine (0.0200 m L , 0.142 mmol) and a solution o f 1.70 M ) in pentane.  fert-butyllithium  (0.0850 m L ,  A solution o f alcohols 82 and 83 (0.0246 g, 0.0710 mmol) in dry T H F  (1.5 mL) was added to the L D A solution by cannula. The pale yellow solution was warmed to 48 °C and stirred at this temperature for 30 min. D r y hexamethylphosphoramide (0.0370 m L , 0.213 mmol) was added, by syringe, followed by dry carbon disulfide (0.0210 m L , 0.355 mmol), by syringe.  The mixture was stirred for 2 min and then the cooling bath was removed.  The  contents o f the reaction flask were allowed to warm to rt. A t rt, analysis o f the reaction mixture by tic (developed with 4:1 petroleum ether - diethyl ether, visualized with the eerie ammonium molybdate dip) showed that the starting materials had been consumed and replaced with baseline material. Methyl iodide (0.0220 m L , 0.355 mmol) was added by syringe and the reaction mixture was heated to reflux and stirred at this temperature for 20 min. T o the cooled reaction mixture was added glacial acetic acid (5 drops), by Pasteur pipette, followed by diethyl ether (2 mL). The resulting yellow, cloudy mixture was poured into diethyl ether (10 m L ) and water (5 mL). The mixture was shaken and the layers were separated. The aqueous phase was extracted with diethyl ether ( 2 x 1 0 m L ) and the combined organic phases were washed successively with water ( 1 x 5 m L ) and saturated N a C l (aq) ( 1 x 5 m L ) before being dried over M g S 0 . 4  Filtration,  178  followed by removal o f the solvent, gave the crude product (0.036 g) as a clear, yellow oil. Analysis o f this oil by tic (developed with 9:1 petroleum ether - diethyl ether, visualized by sight and then with the eerie ammonium molybdate dip) showed 2 major components had been produced. These spots were yellow and were less polar than the starting materials. Purification was accomplished by column chromatography (0.45 g o f tic grade silica gel, 8 mm (width) column, 15:1 hexane - diethyl ether). The fractions containing the product epimers were pooled. Removal o f the solvent, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the dithiocarbonates 84 (0.0286 g, 92%) as a clear, yellow oil. This material, which was sufficiently pure to be carried on to the next step directly, displayed: ir(film): 1723, 1457, 1225, 1203, 1196, 1052 cm- . 1  selected H nmr (400 M H z ) : 5 = 0.85 - 0.95 (5 lines, 12 H , methyl groups), {2.57 (s) and 2.59 :  (s), 3 H , S - C H -OCH  3  3  from the P- and a-epimers, respectively}, {3.63 (s) and 3.65 (s), 3 H ,  from the a - and P-epimers, respectively}, 5.39 (br s, 1 H , H-9), {5.67 (d, J =  13 H z ) and 5.78 (br s), 1 H , H - 6 from the a - and P-epimers, respectively}. lrms (EI): m/z = 328 (33%, ( M - H O C ( S ) S C H ) . +  3  179  A solution o f the dithiocarbonates 84 (0.0404 g, 0.0925 mmol) and tri-«-butylstannane (0.0500 m L , 0.185 mmol) in dry toluene (5 mL) was stirred magnetically and heated to reflux. A solution o f 2,2'-azobisisobutyronitrile (0.100 m L , 0.033 M ) in toluene was added to the yellow solution, dropwise by syringe, over a period o f 1 min. The yellow colour had disappeared 1 min later, and after 4 min, a gray colour had started to develop. Heating was discontinued and the mixture was immediately cooled to ~8 °C. Analysis o f the reaction mixture by tic (developed with 9:1 petroleum ether - diethyl ether, visualized by sight and the eerie ammonium molybdate dip) showed that the starting materials (yellow) had been consumed and a single major component had formed. This material was less polar than the starting materials. The solvent was removed from the reaction mixture to isolate the crude product (0.089 g) as a dark oil. This material was purified by column chromatography (1 g o f tic grade silica gel, 8 mm (width) column, 49:1 hexane - diethyl ether). Removal o f the solvent from the appropriate fractions gave the ester 29 (0.0312 g, -100%) as a clear, colourless oil. This material was rigorously purified by hplc (100:1 hexane - diethyl ether, Econosil 5 u, silica gel, 4.6 by 250 mm column, 0.75 mL/min, uv detection at A, = 220 nm).  The product was dissolved in hexane (-0.40 mL) and  aliquots (0.025 m L , about 3 mg o f compound) were injected for each run. The product proved to be a mixture o f a major and a minor component.  Removal o f the solvent from the fractions  containing the major component, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the ester 29 (0.0220 g, 72%) as a clear, colourless oil which slowly solidified on standing.  Removal o f the solvent from the fractions containing the minor  component, followed by treatment o f the residue under reduced pressure (vacuum pump), gave 0.0012 g (~4%>) o f a clear, colourless oil. The proton nmr spectrum o f this material was similar  180  to that o f the title compound except that it did not show a signal in the olefinic region. The ester 29 displayed: mp: 8 0 - 8 1 °C. i r ( K B r ) : 1724, 1457, 1441, 1383, 1192, 1177 c m . -1  *H nmr (400 M H z ) : 5 = 0.78 (s, 3 H , 3° - C H ) , 0.84 (d, 3 H , J= 6 H z , 2° - C H ) , 0.85 - 0.88 (m, 3  3  1 H ) , 0.88 (s, 3 H , 3° - C H ) , 0.91 (d, 3 H , J = 6 H z , 2° - C H ) , 0.93 (dd, l H , / = 12, 3  3  12 H z ) , 1.04- 1.10 (m, 2 H ) , 1.17- 1.28 (m, 4 H ) , 1.34 - 1.46 (m, 3 H ) , 1.50 (ddd, 1 H , J = 13, 3, 3 H z ) , 1.66 (ddd, 1 H , J= 11, 11, 4 H z ) , 1.70 (dm, 1 H , 7 = 16 H z ) , 1.77 (s, 2 H ) , 2.05 (d br ddd, 1 H , J = 12, 3, 3, 3 H z ) , 2.82 (dd, 1 H , J = 16, 6 Hz), 3.61 (s, 3 H , C H 0 - ) , 5.29 (d br dd, 1 H , J= 6, 2, 2 H z , H-9). 3  1 3  C nmr (100 M H z ) : 5 = 17.1, 19.6, 25.2, 29.7, 30.67, 30.70, 31.7, 32.4, 36.1, 39.1, 41.5, 42.5, 43.2, 45.2, 46.4, 48.0, 49.9, 50.7, 50.8, 118.9, 137.7, 174.8.  lrms (EI): m/z = 330 (14%, M ) . 4  hrms (EI): calculated for C ^ H ^ C ^ : 330.2559; found: 330.2551. optical rotation: [ a ]  2 5 D  -53° (c = 2.2, chloroform); [ a ]  2 5 4 3 6  -112° (c = 2.2, chloroform).  Preparation o f (3p,3ap,8aa,10p,10ap,10ba,10cp)-(-)-l,2,3,3a,4,6,7,8,8a,9,10,10a,10b,10cTetradecahydro-3a-carboxy-3,7,7,10-tetramethylpyrene  85  (85)  181  A suspension o f sodium hydride (0.0160 g, 0.666 mmol) in dry T H F (1 m L ) was stirred magnetically at rt.  Freshly distilled benzeneselenide  dropwise by syringe.  (0.0710 m L , 0.666 mmol) was added,  A thick, white slurry was formed and was stirred for 5 min.  hexamethylphosphoramide  Dry  (0.232 m L , 1.33 mmol) was added by syringe and the resulting  orange solution was stirred for 1 h. A solution o f the ester 29 (0.0220 g, 0.0666 mmol) in dry T H F (1.5 m L ) was added to the reaction flask by cannula. The solution was heated to reflux for a period o f 72 h. The cooled mixture was poured into water (5 m L ) and acidified ( p H ~2, p H paper) by dropwise addition o f 1.0 M HC1 (aq). Diethyl ether (10 m L ) was added, the mixture was shaken and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 10 m L ) and the combined organic phases were dried over M g S C V removal  o f the  solvent,  gave  the  crude  product  (0.15 g)  as  Filtration, followed by  a yellow  solid  (mostly  diphenyldiselenide). This material was separated by repeated column chromatography on 230400 mesh  silica gel,  firstly  with 9:1  petroleum  ether - diethyl ether to  separate  the  diphenyldiselenide and unreacted starting material from the product and then secondly with 8:1 petroleum ether - methylene chloride to separate the diphenyldiselenide from the unreacted starting material. Removal o f the solvent from the fractions containing the product, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the carboxylic acid 85 (0.0119 g, 56%) as a colourless, crystalline solid.  Removal o f the solvent from the  fractions  containing the unreacted starting material gave 0.0073 g (33%) o f the ester 29 as a clear, colourless oil which solidified upon standing. The title compound displayed:  mp: 1 7 9 - 1 8 1 °C. ir (KBr): 3400 - 2450 (very br), 1692, 1457, 1384, 1364, 1272, 1220, 909, 735 cm" . 1  182  T4 nmr (400 M H z ) : 6 = 0.80 (s, 3 H , 3° - C H ) , 0.83 - 0.91 (m, 1 H ) , 0.92 (s, 3 H , 3° - C H ) , 0.95 3  3  (d, 3 H , J = 6 H z , 2° - C H ) , 0.96 (d, 3 H , J = 6 H z , 2° - C H ) , 1.00 (dd, 1 H , J = 13, 3  3  13 H z ) , 1.07 - 1.17 (m, 2 H ) , 1.20 - 1.33 (m, 3 H ) , 1.40 - 1.57 (m, 5 H ) , 1.64 (dddd, 1 H , J = 13, 13, 13, 4 Hz), 1.77 (br d, 1 H , J = 17 Hz), 1.83 (br s, 2 H ) , 2.07 (dm, 1 H , J = 13 H z ) , 2.81 (dd, 1 H , J= 17, 6 H z ) , 5.33 (br d, 1 H , J = 6 H z , H-5). 1 3  C nmr (100 M H z ) : 5 = 17.0, 19.6, 25.2, 29.7, 30.2, 30.6, 31.9, 32.3, 36.2, 39.1, 41.3, 42.2, 43.1, 45.1, 46.4, 48.0, 49.5, 50.5, 118.8, 138.0, 178.6.  lrms (EI): m/z = 316 (4%, M ). 4  hrms (EI): calculated for C i H 0 : 316.2403; found: 316.2402. 2  optical rotation: [ a ]  2 5 D  3 2  2  -70° (c = 1.2, chloroform); [ a ]  Preparation of Diphenylphosphoryl A z i d e  2 5 4 3 6  -142° (c = 1.2, chloroform).  78  To a magnetically stirred suspension o f sodium azide (0.627 g, 9.65 mmol) in dry acetone (10 m L ) was added diphenyl chlorophosphate (2.00 m L , 9.65 mmol) by syringe. suspension was stirred for a period o f 1 h.  The white  The reaction flask was fitted with a short path  distillation apparatus and the solvent was distilled at atmospheric pressure.  The receiver flask  was replaced with a fresh flask and the apparatus was placed under reduced pressure (vacuum pump, -0.1 Torr). The heating mantle was heated rapidly to 190 °C and then slowly to 225 °C. The product (1.95 g, 73%), which distilled when the heating mantle was between  215 and  225 °C, was obtained as an odourless, clear, colourless oil. This material showed, in the ir spectrum, a strong, sharp absorption at 2175 cm" (for the azide function). 1  183  Preparation o f Acetic Formic Anhydride  Sodium formate (20 g) was ground thoroughly with a mortar and pestle and then dried in an oven at 140 °C for a period o f 18 h. A dry, 3 necked, 100 m L , round-bottomed flask was charged with dry sodium formate (15.0 g, 0.221 mol), dry diethyl ether (12.5 m L ) and a magnetic stirrer bar. The centre port was equipped with a septum capped, pressure equalizing dropping funnel charged with freshly distilled acetyl chloride (13.3 m L , 0.188 mol). One side port was equipped with a C a C l drying 2  tube topped condenser; the other with a thermometer.  The contents o f the flask were stirred and  the acetyl chloride was added as rapidly as was possible, keeping the temperature o f the reaction mixture in the range o f 23 - 27 °C. After the addition was complete, the suspension was stirred for 5.5 h maintaining the temperature between 25 and 27 °C. The mixture was suction filtered and the solid was washed with diethyl ether ( 1 x 5 m L ) . The combined filtrates were transferred to a Vigreux column equipped distillation apparatus and most o f the diethyl ether was distilled at atmospheric pressure. The flask containing the diethyl ether was replaced with a fresh flask and the cooled apparatus was placed under aspirator pressure.  The residue was distilled.  The  product (10.3 g, 62%) was collected at 43 - 45 °C (41 Torr) and exists as a clear, colourless oil. This material was stored in a refrigerator in a polyethylene stoppered, round-bottomed flask and was used within 3 days o f its preparation. The stopper was loosened daily to relieve any pressure that had built up.  184  Preparation o f (3P,3aP,8ap,10p,10aP,10ba,10cP)-(+)-l,2,3,3a,4,6,7,8,8a,9,10,10a,10b,10cTetradecahydro-3a-isocyano-3,7,7,10-tetramethylpyrene  (11) ((+)-8-isocyano-10-  cycloamphilectene)  Step 1: Preparation o f  (la,3aa,4a,5ap,10aa,10bp,10ca)-l,2,3,3a,4,5,5a,6,7,8,10,10a,10b,10c-  Tetradecahydro-l,4,7,7-tetramethyl-10a-[O-[(2-trimethylsilyl)ethyl]-A -carbamato]pyrene  (87)  /  Me Si 3  87 A  solution o f the carboxylic acid 85 (0.0110 g, 0.0348 mmol), dry triethylamine  (0.010 m L , 0.070 mmol) and diphenylphosphoryl azide (0.011 m L , 0.052 mmol) in dry toluene (0.40 m L ) was stirred magnetically and heated to 85 °C.  After 2 h, analysis o f the reaction  mixture by ir spectroscopy showed that the absorptions due to the carboxylic acid function (3400 - 2450 and 1692 cm" ) had disappeared and an absorption at 1766 c m 1  -1  was now apparent.  Heating was continued and the mixture was periodically checked by ir analysis. A n absorption at 2250 c m was observed to increase in intensity at the expense o f the peak at 1766 c m . -1  -1  After  185 22 h, the peak at  1766 cm"  1  had completely disappeared.  D r y triethylamine (0.10 m L ,  0.70 mmol) and 2-(trimethylsilyl)ethanol (0.10 m L , 0.70 mmol) were added, both by syringe, and the colourless solution was heated to 100 °C. After 20 h at this temperature, additional 0.10 m L portions o f dry triethylamine and 2-(trimethylsilyl)ethanol were added by syinge and heating was continued for an additional 24 h. A t this time analysis by ir spectroscopy showed the absorption at 2250 cm" to have disappeared and a new absorption at 1736 cm" was now observed. 1  1  The  solvent and excess reagents were removed from the cooled reaction mixture and the residue was prepurified by filtration through 230-400 mesh silica gel (1.0 g, supported in a TA mm (width) column). The column was washed with diethyl ether (10 m L ) . Removal o f the solvent from the filtrate gave 0.022 g o f a clear, amber oil. This oil was purified by column chromatography (0.6 g o f tic grade silica gel, 8 mm (width) column, 9:1 hexane - diethyl ether). Removal o f the solvent from the appropriate fractions, followed by treatment o f the residue under reduced pressure (vacuum pump), gave the carbamate 87 (0.0120 g, 80%) as a clear, colourless oil. This material was used immediately in the next step. A sample displayed: ir (film): 3446, 1736, 1508 cm" . 1  Step 2: Preparation o f (+)-8-isocyano-10-cycloamphilectene (11)  -C 11  186  To the carbamate 87 (0.0100 g, 0.0232 mmol) and a solution o f tetra-w-butylammonium fluoride (0.20 m L , 1.0 M ) in T H F was added dry T H F (0.50 mL). The pale yellow solution was stirred and heated to 60 °C for a period o f 1.5 h, and then cooled to rt. The solvent and volatile materials were removed under reduced pressure. (15 m L ) and 4:1 saturated  NH4CI  (aq) - 30% N H  The residue was partitioned between hexane 3  (aq) (5 mL). The layers were separated. The  aqueous phase was extracted with hexane ( 3 x 5 mL). The combined organic phases were dried over M g S 0 , filtered and the solvent was removed. 4  The residue, a clear, colourless oil, was  dissolved immediately in dry diethyl ether (0.50 mL) and the solution was stirred magnetically at rt.  Acetic formic anhydride (0.040 m L , 0.23 mmol) was added by syringe, the solution was  stirred for 2 h and then an additional portion o f acetic formic anhydride (0.020 m L , 0.11 mmol) was added by syringe. The solution was stirred for a further h and then the solvent and excess reagent were removed under reduced pressure.  The residue, a clear, pale yellow oil was  partitioned between diethyl ether (5 mL) and water (3 mL). The layers were separated and the organic phase was washed with saturated N a C l (aq) (3 mL) before being dried over M g S 0 . 4  Filtration, followed by removal o f the solvent, gave a clear, pale yellow oil. T o this residue was added immediately triphenylphosphine (0.015 g, 0.057 mmol). The mixture was dissolved in dry methylene chloride (0.50 m L ) and stirred at rt. D r y triethylamine (0.020 m L , 0.14 mmol) and dry carbon tetrachloride (0.0060 m L , 0.062 mmol) were added, both by syringe. The solution was heated to reflux and maintained at this temperature for 2 h. The solvent was removed from the cooled reaction mixture and the resulting yellow residue was washed with 97:3 hexane - diethyl ether (10 mL) in several small portions. The solvent was removed from the washings to isolate the crude product (0.0096 g) as a pale yellow, oily solid. This residue was purified by column chromatography (0.3 g o f tic grade silica gel, 8 mm (width) column, the column was prepared  187  and loaded with hexane but eluted with 97 : 3 hexane - diethyl ether). Removal o f the solvent from the appropriate fractions, followed by recrystallization o f the resulting residue from 4:1 methanol - water, gave (+)-8-isocyano-10-cycloamphilectene (11) (0.0051 g, 74% from the carbamate 87) as a colourless, crystalline solid. This material displayed:  mp: 87 - 89 ° C ; lit. 88 - 89 ° C (for (-)-8-isocyano-10-cycloamphilectene). 5  ir ( K B r ) : 2912, 2864, 2133, 1454 cm" . 1  T i nmr (400 M H z ) : 5 = 0.81 (s, 3 H , 3° - C H ) , 0.86 - 0.97 (m, 2 H ) , 0.94 (d, 3 H , J = 7 H z , 2° 3  - C H ) , 0.95 (s, 3 H , 3° - C H ) , 1.03 (d, 3 H , J= 7 H z , 2° - C H ) , 1.04 - 1.13 (m, 3 H ) , 1.19 3  3  3  - 1.29 (m, 1 H ) , 1.31 - 1.43 (m, 2 H ) , 1.46 (dddd, 1 H , J = 13, 13, 13, 4 H z ) , 1.54 - 1.62 (m, 4 H ) , 1.89 (dd, 1 H , J= 14, 2 Hz), 1.95 (br d, 1 H , J= 15 H z ) , 1.96 - 2.07 (m, 2 H ) , 2.45 (br dd, 1 H , J= 17, 5 H z ) , 5.22 (br d, 1 H , J= 5 H z , H-5). 1 3  C nmr (125 M H z ) : 5 = 15.2, 19.5, 25.1, 29.5, 29.8, 31.7, 32.2, 37.2, 37.7, 38.0, 40.6, 42.7, 43.0, 43.9, 46.2, 47.6, 49.0, 62.8, 115.2, 137.6, 154.4.  lrms (EI): m/z = 297 (4.5%, M ) . +  hrms (EI): calculated for C i H i N : 297.2456; found: 297.2453. 2  optical rotation: [ a ]  2 4 D  3  +23° (c = 0.38, chloroform); [ a ]  2 4 4 3 6  +42° (c = 0.38, chloroform); lit.  [CX]D -21.7° (c = 2, chloroform, for (-)-8-isocyano-10-cycloamphilectene). 20  5  188  The  and  1 3  C nmr spectra as well as the low resolution mass spectral data for the  (synthetic) (+)-8-isocyano-10-cycloamphilectene ((+)-ll) were identical to those reported the (natural) (-)-8-isocyano-10-cycloamphilectene ((-) 11).  5  for  189  References and Notes  1  G . M . Cragg, D J . Newman, and K . M . Snader. J. Nat. Prod. 60, 52 (1997).  2  The actual figures are as follows. F o r new approved drugs (1983 to 1994) a total o f 520  substances were considered. The authors divided these into categories: substances o f biologic derivation, unmodified natural products, compounds derived from a natural product, purely synthetic materials and finally synthetic materials that were modeled on a natural product as the parent compound. The latter three categories involve synthetic organic chemistry to varying degrees. O f the 520 substances, 462 (89%) fall into these three categories. F o r available anticancer drugs (through 1993) a total o f 93 substances were considered under the above described system o f categories. O f these 72 (77%) can be seen to be derived from synthetic organic chemistry. F o r pre-New Drug Approval substances (1989 to 1995) the authors considered 299 substances. O f these, 161 (54%) have their origin or can trace their development through synthetic organic chemistry. 3  N R . Farnsworth and R . W . Morris. Amer. J. Pharm. 148, 46 (1976).  4  (a) E . Piers and M . Llinas Brunet. J. Org. Chem. 54, 1483 (1989); (b) E . Piers, M . Llinas-  Brunet, and R . M . Oballa. Can. J. Chem. 71, 1484 (1993). 5  R. Kazlauskas, P . T . Murphy, R.J. Wells, and J.F. Blount. Tetrahedron Lett. 21, 315  (1980). 6  E . Piers and M A . Romero. Tetrahedron. 49, 5791 (1993).  190  T.F. Molinski, D . J . Faulkner, G . D . V a n Duyne, and J. Clardy. J. Org. Chem. 52, 3334  7  (1987). 8  D . J . Faulkner. Tetrahedron. 33, 1421 (1977).  9  M . S . Edenborough, B . Herbert. Nat. Prod. Rep. 5, 211 (1988); Acta C r y s t , Sect. C:  Cryst. Struct. Comm. C52, 2601 (1996); H . A . Sharma, J. Tanaka, T. Higa, A . Lihgow, G . Bernardinelli, and C . Jefford. Tetrahedron Lett. 33, 1593 (1992); G . M . Konig, A D . Wright, and C . K . Angerhofer. J. Org. Chem. 61, 3259 (1996). 1 0  D . J . Faulkner. Nat. Prod. Rev. 1, 251, 551 (1984); N . K . Gulavita, E . de Silva, M . R .  Hegadone, P. Karuso, P.J. Scheuer, G . D . V a n Duyne, and J. Clardy. J. Org. Chem. 51, 5136 (1986); A . Patra, C . W . J . Chang, P.J. Scheuer, G . D . V a n Duyne, G . K . Matsumoto, and J. Clardy. J. A m . Chem. Soc. 106, 7981 (1984). 1 1  M . J . Garson. J. Chem. Soc. Chem. Commun. 35 (1986).  1 2  E . J . Corey and P . A . Magriotis. J. A m . Chem. Soc. 109, 287 (1987).  13  F o r reviews o f natural products containing isocyanides, isothiocyanates and formamides  see: G . R . Shulte, P.J. Schearer. Tetrahedron 38, 1857 (1982); J.E. Thompson, R . P . Walker, S.J. Wratten, and D . J . Faulkner. Tetrahedron 38, 1865 (1982). 1 4  P R . Bergquist. "Sponges," Hutchinson, London (1978).  15  C.J.R. Fookes, M . J . Garson, J . K . M a c L e o d , B . W . Skelton, and A . H . White. J. Chem.  Soc. Perkin Trans. I. 1003 (1988). 1 6  L . Ruest, G . Blouin, and P. Deslongchamps. Synth. Commun. 6, 169 (1976).  1 7  G H . Posner, C E . Whitten, and J.J. Sterling. J. A m . Chem. Soc. 95, 7788 (1973).  191  1 8  J.-P. Gorlier, L . Hamon, J. Levisalles, and J. Wagnon. J. Chem. Soc. Chem. Commun. 88  (1973); L . Hamon and J. Levisalles. J. Organomet. Chem. 251, 133 (1983). 1 9  E . Piers, R . W . Friesen, and S.J. Rettig. Can. J. Chem. 70, 1385 (1992). See also E.Piers,  R . W . Friesen, a n d B . A . Keay. Tetrahedron, 47, 4555 (1991). 2 0  (a) L . Lombardo. Tetrahedron Lett. 23, 4293 (1982);(b) J.E. M c M u r r y and W . J . Scott.  Tetrahedron Lett. 24, 979 (1983); 21, 4313 (1980); R . E . Ireland, S. Thiasrivongs, P H . Dussault. J. A m . Chem. Soc. 110, 5768 (1988). 2 1  D . Dolphin and A . Wick. "Tabulation o f Infrared Spectra", John Wiley & Sons, N e w  Y o r k (1977). 2 2  E . Piers and R . W . Friesen. Can. J. Chem. 65, 1681 (1987).  2 3  B E . Rossiter and N . M . Swingle. Chem. Rev. 92, 771 (1992).  2 4  R. Andrade, L . Breau, and Y . Han. Unpublished results.  2 5  (a) J. Katsuhara. J. Org. Chem. 32, 797 (1967); (b) M . A . Avery, W . K . M . Chong, and  C. Jennings-White. J. A m . Chem. Soc. 114, 974 (1992). 2 6  J. March. "Advanced Organic Chemisty." 3rd E d . , John Wiley & Sons, N e w York. pp.  1089 - 1090 and references quoted therein. 2 7  W . Oppolzer and M . Petrizilka. Helv. Chim. Acta. 61, 2755 (1978).  2 8  P. Brougham, M . S . Cooper, D . A . Cummerson, H . Heany, and N . Thompson. Synthesis.  1015 (1987). 2 9  For an excellent review o f this and related methods, see B . Trost. A c c . Chem. Res. 11,  453 (1978).  192  3 0  S. Budavari, E d . "The M e r c k Index, 11 E d " , M e r c k & C o . , Rahway, N e w Jersey, th  monograph 1822, pg. 276 (1989). 3 1  Communique, Ministry o f the Environment, Government o f Canada (1996).  3 2  L . N . Mander and S.P. Sethi. Tetrahedron Lett. 24, 5425 (1983).  3 3  For reviews o f alkylation o f enolate anions on the oxygen versus the carbon atom see  H . O . House, "Modern Synthetic Reactions", 2nd ed., W . A . Benjamin, Menlo Park, California (1972), pp. 735 - 760 and D . Caine in "Carbon-Carbon B o n d Formation", V o l . 1, R . L . Augustine ed., Marcel Dekker, N e w Y o r k (1979), pp. 250 - 258. 3 4  When the methoxycarbonylation reaction was attempted in the absence of H M P A , the  major isolated product was 3-(A ,A -diisopropylamino)-5-methylcyclohexanone. /  /  3 5  R . L . Augustine, "Catalytic Hydrogenation", Marcel Dekker, N e w Y o r k (1965), pg. 34.  3 6  R . L . Augustine, "Catalytic Hydrogenation", Marcel Dekker, N e w Y o r k (1965), pg. 35.  3 7  G . Gilman and G.Cohn. Advances in Catalysis, 9, 733 (1957).  3 8  R . L . Augustine, "Catalytic Hydrogenation", Marcel Dekker, N e w Y o r k (1965), pg. 40.  3 9  R . L . Augustine, "Catalytic Hydrogenation", Marcel Dekker, N e w Y o r k (1965), pg. 36.  4 0  P . N . Rylander. "Catalytic Hydrogenation Over Platinum Metals", Academic Press, N e w  Y o r k (1967), pp. 81-107. 4 1  (a) E . Piers, T. Wong, and K . A . Ellis. Can. J. Chem. 70, 2058 (1992); (b) E . Piers, R . W .  Friesen, and S.J. Rettig. Can. J. Chem. 70, 1385 (1992); (c) E . Piers and R . W . Friesen. Can. J. Chem. 65, 1681 (1987). 4 2  For a monograph on the hard—soft acid base concept see T. H o . "Hard and Soft Acids  and Bases Principle in Organic Chemistry", Academic Press, N e w Y o r k , 1977.  193  4 3  P. Deslongchamps. "Stereoelectronic Effects in Organic Chemistry. - (Organic Chemistry  Series: V o l . 1)". Pergamon Press, Oxford, pp. 280-1 (1983); H . O . House. "Modern Synthetic Organic Reactions", 2  nd  E d . , W . A . Benjamin Inc., Menlo Park, pp. 586-95 (1972).  4 4  J.E. M c M u r r y and W.J. Scott, Tetrahedron Lett. 24, 979 (1987).  4 5  E . Piers, R . W . Friesen, and B A . Keay. Tetrahedron 47, 4555 (1991); J. Chem. S o c ,  Chem. Commun. 809 (1980). 4 6  W . J . Scott, G T . Crisp, and J.K. Stille. J. A m . Chem. Soc. 106, 4630 (1984); W.J. Scott  and J.K. Stille. J. A m . Chem. Soc. 108, 3033 (1986); J.K. Stille. Angew. Chem., Int. E d . Engl. 25, 508 (1986). 4 7  D . R . Coulson, L . C . Satek, and S.O. Grim. Inorg. Synth. 13, 121 (1972).  4 8  See reference 22.  4 9  The V a n der Waals radius o f a bromine atom is 1.95 A ; that o f a hydrogen atom is  1.20 A . The covalent radius o f a carbon-bromine bond is 1.91 A ; that o f a carbon-hydrogen bond is 1.03 A . Thus the 'reach' o f a carbon-bromine bond is about 3.86 A whereas the 'reach' of a carbon-hydrogen bond is about 2.23 A . 5 0  J. Rachon, V . Goedken, and H . M . Walborsky. J. Org. Chem. 54, 1006 (1989); see also  E . W . Delia and P . E . Pigou. Aust. J. Chem. 36, 2261 (1983). 5 1  P. Girard, J . L . Namy, and H . B . Kagan. J. A m . Chem. Soc. 102, 2693 (1980).  5 2  G . A . Molander and G . Hahn. J. Org. Chem. 51, 1135 (1986); A B . Smith III, N . K .  Dunlap, and G . A . Sulikowski. Tetrahedron Lett. 29, 439 (1988); J. Castro, H . Sbrenson, A . Riera, C . M o r i n , A . Moyano, M . A . Pericas, and A . E . Greene. J. A m . Chem. Soc. 112, 9388 (1990).  194  5 3  F o r a review o f the use o f lanthanide reagents in organic synthesis see: G . A . Molander.  Chem. Rev. 92, 29 (1992). 5 4  G . A . Molander and G . Hahn. J. A m . Chem. Soc. 51, 1135 (1986).  5 5  P. W i p f and S. Venkatraman. J. Org. Chem. 58, 3445 (1993).  5 6  A . J . Mancuso, S.-L. Huang, and D . Swern. J. Org. Chem. 43, 2480 (1978).  5 7  S. Krishnamurthy and H . C . Brown. J. Org. Chem. 41, 3064 (1976).  5 8  E . J . Corey and W.J. Fleet. Tetrahedron Lett. 4499 (1973).  5 9  W . J . Salmond, M . A . Barta, and J.L. Havens. J. Org. Chem. 43, 2057 (1978).  6 0  F o r a reviews o f dissolving metal reductions o f this type, see: H . O . House. "Modern  Synthetic Reactions", 2nd ed., Benjamin/Cummins, N e w Y o r k , (1972), pp. 173-183; D . Caine. Org. React. 23, 1 (1976). 6 1  J. March. "Advanced Organic Chemistry", 3rd ed. John Wiley & Sons, N e w Y o r k ,  (1985), pg. 693. 6 2  The Crabtree catalyst is (l,5-cyclooctadiene)(tricyclohexylphosphine)(pyridine)iridium(I)  hexafluorophosphate. Preparation: R. H , Crabtree and G . E . Morris. J. Organomet. Chem. 135, 395 (1977). 6 3  The Wilkinson catalyst is chlorotris(triphenylphosphine)rhodium(I). Preparation: J.F.  Young, J . A . Osborn, F . H . Jardine, and G . Wilkinson. Chem. Commun. 131 (1965). 6 4  R. H o w e and F.J. McQuillan. J. Chem. Soc. 1194 (1958).  6 5  A . Schoenberg, I. Bartoletti, and R . F . Heck. J. Org. Chem. 39, 3318 (1974).  6 6  N . S . Wilson and B A . Keay. J. Org. Chem. 61, 2918 (1996).  6 7  W . P . Griffith and S.V. Ley. Aldrichim. Acta. 23, 1 (1990).  195  6 8  R . L . Augustine. "Catalytic Hydrogenation", Marcell Decker, N e w Y o r k , (1965), pg. 62.  6 9  J . M . Fortunato and B . Ganem. J. Org. Chem. 41, 2194 (1976).  7 0  J.W. Hamersma and E.I. Snyder. J. Org. Chem. 30, 3985 (1965).  7 1  E . Keinan and P . A . Gleize. Tetrahedron Lett. 23, 477 (1982); P.Four and F. Guibe.  Tetrahedron Lett. 23, 1825 (1982). 7 2  M . F . Semmelhack, R . D . Stauffer, and A . Yamashita. J. Org. Chem. 42, 3180 (1977).  7 3  I. Ojima, R. Kogure, and Y . Nagai. Tetrahedron Lett. 5035 (1972).  7 4  D . H . R . Barton and S.W. McCombie. J. Chem. Soc. Perkin 1. 1574 (1975). For an  excellent review o f radical reduction o f alcohols see: W . Hartwig. Tetrahedron. 16, 2609 (1983). 7 5  K . Tatsuta, K . Akimoto and M . Kinoshita. J. A m . Chem. Soc. 101, 6116 (1979).  7 6  M . Karplus. J. Chem. Phys. 30, 11 (1959); R . J . Abraham in "Nuclear Magnetic  Resonance For Organic Chemists", D . W . Mathieson e d , Academic Press, London (1967), pp. 138-144. 7 7  D . Liotta, U . Sunay, H . Santiesteban, and W . Markiewicz. J. Org. Chem. 46, 2605  (1981). 7 8  T. Shiori, K . Ninomiya, and S. Yamada. J. A m . Chem. Soc. 94, 6203 (1972).  7 9  C . W . Huffman. J. Org. Chem. 23, 727 (1958).  8 0  R. Appel, R. Kleinstuck, and K . - D . Ziehn. Angew. Chem. Int. E d . Engl. 10, 132 (1971).  8 1  W e are indebted to Professor T. Higa o f the Department o f Marine Sciences, University  of the Ryukyus, Okinawa, Japan for a sample o f the natural occurring (-)-8-isocyano-10-cycloamphilectene ((-)-ll) and accompanying *H and  1 3  C nmr spectra.  196  8 2  (a) W . C . Still, M . Kahn, and A . Mitra. J. Org. Chem. 43, 2923 (1978); (b) H . P . Williams,  D . H . Moore, and F A . Byrd, J. Chem. E d . 51, 370 (1974); (c) D . H . Taber. J. Org. Chem. 47, 1351 (1982). 8 3  The names o f the compounds that appear in the titles o f the procedures in the  experimental section were assigned based upon the rules set out in "The International Union o f Pure and Applied Chemistry Nomenclature o f Organic Chemistry." Butterworths, London (1969). 8 4  R . W . Friesen. P h . D . Thesis, The University o f British Columbia, (1988), pgs. 47-8, 188.  8 5  J. Katsuhara. J. Org. Chem. 32, 797 (1967).  8 6  J. Y . Roberge. P h . D . Thesis, The University o f British Columbia, (1992), pg. 180.  8 7  W . Oppolzer and M . Perzilka. Helv. Chim. Acta. 61, 2755 (1978).  8 8  Aldrich® Catalogue Handbook o f Fine Chemicals 1996-1997. pg. 1175.  197  Appendix  in  200  

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