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Total synthesis of (±)-palauolide, (±)-isolinaridiol and (±)-isolinaridiol diacetate Wai, John Sui Man 1988

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TOTAL SYNTHESIS OF (±)-PALAUOLIDE, (±)-ISOLINARIDIOL AND (±)-ISOLINARIDIOL DIACETATE  By  JOHN SUI MAN  WAI  B . S c , U n i v e r s i t y o f Hong Kong, 1982 M . P h i l . , U n i v e r s i t y o f Hong Kong, 1984  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY  We a c c e p t t h i s t h e s i s as conforming to the r e q u i r e d  standard  THE UNIVERSITY OF BRITISH COLUMBIA February 1988  ©  J o h n S u i Man WAI, 1988  In  presenting  degree  at  this  the  thesis  in partial  University of  freely available for reference copying  of  department publication  this or of  thesis by  for  his  this thesis  or  British Columbia, and study.  her  The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3  DE-6(3/81)  n  requirements  for  an  Library shall make it  I further agree that permission for  representatives.  may be It  is  granted  advanced  by the  understood  that  extensive  head  of my  copying  or  for financial gain shall not be allowed without my written  Department  2 (  the  I agree that the  scholarly purposes  permission.  Date  fulfilment of  ii  ABSTRACT  This thesis describes (±)-palauolide  (55)  and  the the  (±)-isolinaridiol d i a c e t a t e I n the was  by  a  followed  ketone 121.  by  The  nitrile  transformed verted with  bromide-dimethyl  reagent 40  to  via  the  which  was  to p r o v i d e  naridiol  114  173.  The  diacetate  (61),  C o n v e r s i o n o f 276  the  provided  developed i n  the  product. linaridiol  phosphonate 261,  provided  Diisobutylaluminum hydride (64).  with  substance which was  (61).  con107  (64)  and  of  the Z l a c t o n e  r e d u c t i o n o f 279  (±)-isoli-  was  prepared  by  (±)-palauolide  f o l l o w e d by with  (55).  treatment  the 279  anion  of of  as the major  yielded  (±)-iso-  B i s - a c e t y l a t i o n o f the l a t t e r m a t e r i a l p r o v i d e d  i s o l i n a r i d i o l diacetate  was  s t e r e o s e l e c t i v e l y the  synthesis  t h i s m a t e r i a l , under c a r e f u l l y d e f i n e d c o n d i t i o n s , 7-lactone  alkylated  latter  substance 276  i n t o the aldehyde 234,  into  (±)-palauolide  (±)-isolinaridiol bicyclic  converted  J u l i a o l e f i n a t i o n of  photooxygenated to p r o v i d e  f o l l o w i n g the c h e m i s t r y  the  was  stereoselectively  the n i t r i l e  t o t a l syntheses o f  catalyzed  a l k y l a t i o n o f the r e s u l t a n t c h l o r o  l i t h i u m s a l t o f the s u l f o n e 223  In the  substructure  sulfide  a s e r i e s o f r e a c t i o n s i n t o compound 175  which was  and  3,6-dimethyl-2-cyclohexen-1-one  i n t o the a . ^ - u n s a t u r a t e d aldehyde 107.  t r i e n e 216,  (55).  (±)-isolinaridiol (64)  r e s u l t a n t annulation product  ICH2CH2CH2OCH2OCH3  sesterterpenoid  (±)-palauolide, the d e c a l i n  intramolecular  112,  the  (61).  copper(I)  a d d i t i o n o f the G r i g n a r d  the  diterpenoids  t o t a l synthesis of  constructed  (115),  t o t a l syntheses o f  (±) -  iii  iv  TABLE OF CONTENTS  Page  ABSTRACT  i i  TABLE OF CONTENTS  iv  LIST OF TABLES  v i i  LIST OF FIGURES  viii  ABBREVIATIONS  ix  ACKNOWLEDGEMENTS  x i i  INTRODUCTION  1  I.  General  1  II.  P r e v i o u s Work  9  III.  I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n o f P a l a u o l i d e (55)  IV.  V.  I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n o f I s o l i n a r i d i o l (64) and I s o l i n a r i d i o l d i a c e t a t e  13  (61)  P r e v i o u s Syntheses o f C l e r o d a n e - t y p e D i t e r p e n o i d s  . . . .  15  . . . .  17  DISCUSSION  29  I.  T o t a l S y n t h e s i s o f (±)-Palauolide  29  A.  Retrosynthetic  29  B.  S y n t h e s i s o f the n i t r i l e  Analysis 112  31  V  C.  S y n t h e s i s o f the h o m o a l l y l i c i o d i d e 113  41  D.  A l k y l a t i o n o f the n i t r i l e 113. Attempts to prepare  112 w i t h the i o d i d e compound 145  48  A l k y l a t i o n o f the n i t r i l e 172. P r e p a r a t i o n o f the aldehyde 107  112 w i t h the i o d i d e a,^-unsaturated  E.  F.  S y n t h e s i s o f the phosphonium s a l t  G.  C o n v e r s i o n o f 7-methoxybutenolides 7-hydroxybutenolides  H.  I.  J.  K.  II.  67 188  80  into 88  R e a c t i o n o f a.^-unsaturated aldehydes w i t h phosphoranes and phosphonate anions d e r i v e d from 4 - ( h a l o m e t h y l ) - b u t e n o l i d e s  91  R e a c t i o n o f aunsaturated phosophoranes d e r i v e d from trimethylsilylfurans  96  aldehydes w i t h 4-(halomethyl)-2-  R e a c t i o n o f g e r a n i a l (211) w i t h the s u l f o n e P h o t o s e n s i t i z e d o x i d a t i o n o f the r e s u l t a n t t r i e n e 221 to the c o r r e s p o n d i n g b u t e n o l i d e  223. 99  R e a c t i o n o f the aldehyde 107 w i t h the s u l f o n e 223. P h o t o s e n s i t i z e d o x i d a t i o n o f the r e s u l t a n t t r i e n e 216 to (±)-palauolide (55)  T o t a l s y n t h e s i s o f (±)-Isolinaridiol (64)  104  and  (±)-Isolinaridiol d i a c e t a t e (61)  110  A.  Retrosynthetic analysis  110  B.  Z s e l e c t i v e Horner-Wittig o l e f i n a t i o n s 1.  2.  O l e f i n a t i o n s with a c y c l i c ethyl)phosphonates  112  O l e f i n a t i o n s w i t h 7 - l a c t o n e a-phosphonates  C.  S y n t h e s i s o f the aldehyde  D.  S y n t h e s i s o f (±)-isolinaridiol (64) i t s geometric isomer 278  E.  112  bis(trifluoro-  . . . .  234  118 126  and  S y n t h e s i s o f (±)-isolinaridiol d i a c e t a t e (61)  132 . . . .  139  vi F.  Attempt t o oxidize (±)-isolinaridiol (64)  to (±)-isolinaridial (60)  III.  Miscellaneous  144  l +7 /  EXPERIMENTAL  152  REFERENCES  240  vii  LIST OF TABLES  Table  1  2  3  4  5  6  Page  nmr s p e c t r a l d a t a o f n a t u r a l p a l a u o l i d e and s y n t h e t i c (±)-palauolide (55)  106  R e a c t i o n o f 3-methylbutanal w i t h the 7 - l a c t o n e phosphonate 261  121  R e a c t i o n o f aldehydes w i t h the 7 - l a c t o n e phosphonate 261  123  Partial nmr and i n f r a r e d d a t a f o r o l e f i n a t i o n p r o d u c t s d e r i v e d from r e a c t i o n s o f aldehydes w i t h the 7 - l a c t o n e phosphonate 261  127  nmr s p e c t r a l d a t a o f i s o l i n a r i d i o l  (64)  nmr s p e c t r a l d a t a r e p o r t e d f o r n a t u r a l i s o l i n a r i d i o l d i a c e t a t e , and those d e r i v e d from our s y n t h e t i c (±)-isolinaridiol d i a c e t a t e (61) and the d i a c e t a t e 281  137  143  viii  LIST OF FIGURES  Figure  Page  1  The 400 MHz  2  The 400 MHz  l  3  The 270 MHz  4  The H  5  The 400 MHz (55)  7  8  9 10  11  X  nmr  X  H  nmr  spectrum o f 111  50  H  nmr  spectrum o f 175  75  ^H nmr  spectrum o f 107  81  spectrum o f n a t u r a l p a l a u o l i d e X  H  nmr  (±)-palauolide 108  The 400 MHz H isolinaridiol  nmr  The 400 MHz (64)  nmr  X  The  spectrum o f  107  X  H  spectrum o f n a t u r a l 135 spectrum o f  (±)-isolinaridiol 136  300 MHz  %  nmr  spectrum o f 278  The 300 MHz H nmr d i a c e t a t e (61)  spectrum o f  The 300 MHz  s p e c t r a o f 281  X  X  H  nmr  138  (±)-isolinaridiol 140 142  ix  LIST OF ABBREVIATIONS  Ac  -  AIBN  -  2,2'-azobisisobutyronitrile  br  -  broad  Bu  -  butyl  Bn  -  benzyl  Bz  -  benzoyl  d  -  doublet  DBU  -  DEG  -  DIBAL-H -  acetyl  l,8-diazobicyclo[5.4.0]undec-7-ene diethylene glycol diisobutylaluminum  hydride  DMAP  -  4-N,N-dimethylaminopyridine  DME  -  1,2-dimethoxyethane  DMF  -  N,N-dimethylformamide  DMSO  -  dimethylsulfoxide  equiv  -  equivalent(s)  Et  -  ethyl  glc  -  g a s - l i q u i d chromatography  h  -  hour(s)  HMPA  -  hexamethylphosphoramide  ir  -  infrared  LAH  -  l i t h i u m aluminum h y d r i d e  LDA  -  l i t h i u m diisopropylamide  m  -  multiplet  X  Me  -  methyl  min  -  minute(s)  mp  -  melting  Ms  -  methanesulfonate  NBS  -  N-bromosuccinimide  nmr  -  nuclear magnetic  nOe  -  nuclear  PCC  -  pyridinium chlorochromate  Ph  -  phenyl  PPTS  -  pyridinium  Pr  -  propyl  Py  -  pyridine  q  -  quartet  rt  -  s  -  singlet  t  -  triplet  tert  -  tertiary  TBAF  -  tetra-n-butylammonium  TBDMS  -  tert-butyldimethylsilyl  THF  -  tetrahydrofuran  THP  -  tetrahydropyranyl  tic  -  thin layer  TMEDA  -  N,N,N',N'-tetramethylenediamine  TMS  -  trimethylsilyl  TosMIC  -  (p.-toluenesulfonyl) methyl  TPP  -  point  resonance  Overhauser enhancement  p.-toluenesulfonate  room t e m p e r a t u r e  fluoride  chromatography  tetraphenylphorphin  isocyanide  xi  p.-TsOH  -  para- toluenesulfonic  Ts  -  para-toluenesulfonvl  v  -  very  A  -  heat  acid  xii  ACKNOWLEDGEMENTS  This  t h e s i s i sbased on t h e  Department 1985  of  Chemistry,  research  work  carried  out  i n the  U n i v e r s i t y o f B r i t i s h Columbia from January,  t o November, 1987, u n d e r t h e s u p e r v i s i o n o f P r o f e s s o r Edward I would l i k e  t o express  my d e e p e s t g r a t i t u d e  to  Piers.  Professor  Piers  f o r h i s i n v a l u a b l e guidance, encouragement and d i s c u s s i o n throughout t h e course our  o f t h e r e s e a r c h w o r k , a n d f o r h i s immense e f f o r t  problem sets t o f u r t h e r educate us i n t h e science  try.  H i s advice  on w r i t i n g t h i s  I would l i k e group  Montse  o f organic  shared  the pleasure  and t h e j o y o f success.,  chemis-  research  of discussion, the frustra-  S p e c i a l t h a n k s a r e due t o D r .  L l i n a s - B r u n e t , Mr. F r a s e r F l e m i n g ,  their careful proofreading,  up  appreciated.  t o t h a n k a l l t h e members o f P r o f e s s o r P i e r s '  w i t h whom I h a v e  tion of failure,  thesis i sgreatly  i n setting  and Miss  Betty-Anne Story f o r  a n d t o P r o f e s s o r J.R. S c h e f f e r  f o r showing  me how t o do MM2 c a l c u l a t i o n s . Thanks  are  also  extended t o the t e c h n i c a l s t a f f s  o f the nuclear  m a g n e t i c r e s o n a n c e a n d mass s p e c t r o s c o p y  services for their  usually  Rani  efficient  s e r v i c e , and t o Mrs.  r e l i a b l e and  Theeparajah f o r typing the  thesis. The ride"  generosity  o f t h e S w i r e Company (HK)  t o Vancouver i s acknowledged w i t h  thanks.  f o r providing  a  "free  xiii  TO MY WIFE  JENNY  - 1INTRODUCTION  I.  General  The  achievement  of  molecule involves  the  synthetic  When  plan.  synthetic  broken tally  chemical  development the  synthesis  and  chemical  i f  necessary,  until  a synthesis,  the  complex  target  to construct  synthesis  is  i n s u c h a way the  greatly  target  by  conceivable  synthons. The nature.  synthetic operations.  In  Thus,  is  theoretically  r e j o i n e d experimenthe  recognizing, synthesized  planning w i t h i n the  and  Such fragments are  r e a c t i o n s most f r e q u e n t l y u s e d i n o r g a n i c They  usually sites  used  to  o r an  electrophilic  one  success i s accomplished.  of  a  target  j o i n e d by  known  r e f e r r e d to  as  1  electrophilic  reactive  the is  molecule  the  a  plan  molecule.  facilitated  of  compounds i n  expected,  t h a t t h e y m i g h t be  m o l e c u l e , c e r t a i n f r a g m e n t s w h i c h c a n be or  was  organic  execution  b e h a v i o u r o f the  repeatedly  into pieces  o f a complex  experimental  sequence i s d i f f e r e n t from what  modified, planning  the  c a r r y out  sites,  incorporated  in  nucleophilic  to form bonds.  center. two one  whole  more c o m p l e x s y s t e m , a r e  H o w e v e r , some c h e m i c a l  electrophilic i n part  are p o l a r  interacting chemical  in  with  reagents  have e i t h e r a n u c l e o p h i l i c s i t e  nucleophilic sites,  or  sites  Thus, most o f the  synthetic operations  e.g.  n u c l e o p h i l i c and  involve  synthesis  site.  two  reagents possess  electrophilic  These s p e c i e s ,  two  sites  i f they  or are  i n t o a s u b s t r a t e molecule to give  commonly r e f e r r e d t o as  "bifunctional  a  conjunc-  - 2 -  t i v e reagents".  Examples o f  some  simple  bifunctional  reagents  are  g i v e n below. Dialkyl  malonates  conjunctive reagents. equivalents  of  and d i t h i a n e s a r e well-known, simple They have  donor-donor  malonate (1) has been used valuable  effectively  (d,d) synthons. in  the  For  preparation acid  of  (2)^  as  example, the  synthetic diethyl  synthetically  ( e q u a t i o n 1),  while  (3) had been employed i n the p r e p a r a t i o n o f d i t h i o k e t a l s 4.  Hydrolysis  of  the l a t t e r m a t e r i a l s p r o v i d e s  of d i f f e r e n t ring sizes^ 3  used  cyclopropane-1,1-dicarboxylic  1,3-dithiane  and  been  examples o f  serve  as  ( e q u a t i o n 2).  synthetic  access  I n these  equivalents  of  t o c y c l i c ketones 5  reactions,  reagents  1  the d,d synthons 6 and 7,  respectively. In organic synthesis, annulation r e a c t i o n s are i n the c o n s t r u c t i o n o f a t a r g e t m o l e c u l e . reagents  have  occasions,  been  used  to  effect  the b i f u n c t i o n a l reagents  frequently  involved  Many b i f u n c t i o n a l c o n j u n c t i v e  annulation  reactions.  On  such  react with a s u i t a b l e substrate v i a  an i n t e r m o l e c u l a r c o u p l i n g s t e p , f o l l o w e d by an i n t r a m o l e c u l a r  cycliza-  Heteroatoms i n an o r g a n i c molecule impose an a l t e r n a t i n g a c c e p t o r and donor r e a c t i v i t y p a t t e r n (as shown) upon the carbon skeleton. Thus, carbons •^ are acceptors ( a t t a c k by donors) and carbons a r e donors ( a t t a c k by a c c e p t o r s ) ; the heteroatom X ° i s a donor c e n t e r . 1  2  X = 0,N  [For a d e t a i l e d d i s c u s s i o n , see D. Seebach, Angew. Chem. I n t . E n g l . , 18, 239 (1979)] .  Ed  - 3 -  /° c  \  • r  2Et  LLot*  Br  >  _ f ! i ^  Triethylbenzylammonium c h l o r i d e  ^^Br  tx~ u 2  ^  1  2  r y ^ >r Y s  ^U^H  H  s  N - S3A H  <CH2)nCt  \-sAcH2)nCI  2 . cn=2-7 i cH ) ci (  2  n  o=  2  >  x  r )G ^ s  -^->  S  H  4  GH  HgCl ,H 0 2  H  )n  (2)  C0 Et 2  t i o n step.  S e l e c t e d examples o f such reagents  Condensation THF-HMPA  at  of  -60°  Decarboxylation valuable  equivalent intermediate  of  to  and  octalone  the  dianion  -80°C  gave  with the  ethyl  diester  below.  4-bromobutanoate 9  i n  60%  i n  yield.  5  s a p o n i f i c a t i o n o f the l a t t e r material provided the  10 ( e q u a t i o n  the  8  are given  d,d  3).  I n t h i s case 8 a c t s as  synthon 11.  i n sesquiterpene  a  synthetic  The k e t o n e 10 h a s b e e n u s e d a s a n  syntheses.**  - 4-  fi  The  aryllithium  s y n t h o n 13.  The  resulting  14  sulfones  is  in  annulation  a s y n t h e t i c e q u i v a l e n t o f the  undergo  For example, r e a c t i o n diethyl  a n n u l a t i o n p r o d u c t 15 lene  12  r e a g e n t h a s b e e n shown t o a d d  a-lithio  alkylation.? sulfone  reagent  11  ether  of  spontaneous the  sequence  Compounds s u c h a s 16  synthons  by  could  have  to  be  For example,  2-cyclopenten-l-one  equivalents  s t r u c t u r e 17.  very  effective  treatment (19)  of  This  considerable  of The  12  i n the presence  with  the  afforded  the  tetrahydronapthaapplication  M = SI  or  Sn)  were  synthetically former  i n the  acetoxy  first  valuable  substances  f o r the syntheses o f the  the  systems.  (X = l e a v i n g group; as  a  o f the general  demonstrated rings.  Trost^  aryllithium  i n 78% y i e l d ( e q u a t i o n 4).  and  intramolecular  (-78°C t o room t e m p e r a t u r e )  s y n t h e s i s o f s t e r o i d s and o t h e r p o l y c y c l i c  described  to v i n y l sulfones  d,a  have  d,a been  five-membered  allylsilane  18  o f c a t a l y t i c amount o f  with tetra-  - 5 -  k i s ( t r i p h e n y l p h o s p h i n e ) p a l l a d i u m and b i s ( d i p h e n y l p h o s p h i n o ) e t h a n e in 5).  refluxing O D  THF  for  T h i s r e a c t i o n was  hirsutene  (21).  8c  20  h gave  t h e k e t o n e 20  one  of the key steps  i n 56% y i e l d  i n an e l e g a n t  [dppe]  (equation  synthesis of  - 6Mechanistically, of the  complex bond of  above r e a c t i o n i n v o l v e s f i r s t l y  acetoxyallysilane  7r-allylpalladium species  the  on  the  23,  18  with  intermediate  silyl which  22  group r e s u l t s  palladium(O) and  acetate  i n the  pane a n n u l a t i o n p r o d u c t  k e t o n e 19  to  Attack  of the  ion.  formation  20  (Scheme  l).  to a f f o r d 8  c  *  Scheme 1  ,  e  interaction  complexes  a t t a c k s the e l e c t r o n d e f i c i e n t  t h e a,ji-unsaturated  the  the  of  the  give  a  latter  palladium  carbon-carbon  double  methylenecyclopro-  - 7An  alternative  reagents cases, 17. with  approach  which i n v e r t s the e l e c t r o n i c sense o f  o f g e n e r a l s t r u c t u r e 16 the  reagents 16 s t i l l  has  also  been  enolate  3-iodo-2-(trimethylsilylmethyl)-1-propene 26.  F l u o r i d e i o n induced c y c l i z a t i o n  a f f o r d e d the a l c o h o l 27  (equation 6 ) . ^  SiMe3  of  (25) of  the  gave the  the  latter  these synthon  ketone  24  alkylation material  c  KH DME  SPh  SPh  25  24  In  f u n c t i o n as e q u i v a l e n t s to the d,a  For example, r e a c t i o n o f the potassium  product  reported.  the  26  OH n-Bu.NF — 4  26  (6)  THF, l h  SPh 27  OH  >-  (6)  SPh  Recently, a l l e n e s 28 as  Danheiser  has  described  synthetic  equivalents  of  the  17  use  the  d,a  example,  r e a c t i o n o f 2-cyclohexen-1 -one  a l l e n e 31  i n the presence o f t i t a n i u m t e t r a c h l o r i d e  at  -78°C  of  (trimethylsilyl)-  synthon  (30) w i t h the in  29.^  For  (trimethylsilyl)dichloromethane  f o r 1 h gave r e g i o s e l e c t i v e l y the ( t r i m e t h y l s i l y l ) c y c l o p e n t e n e  annulation product  34 i n 85% y i e l d  (equation 7 ) .  - 8 -  The  r e a c t i o n i s thought to i n v o l v e  tetrachloride  w i t h the  firstly  enone to generate the  32,  which i s r e g i o s e l e c t i v e l y a t t a c k e d by  to  afford  the  a c t i o n w i t h the trimethylsilyl c a t i o n by  the  (Scheme 2 ) .  v i n y l c a t i o n 33. adjacent group, titanium  the  enolate,  alkoxy a l l y l i c  titanium carbocation  (trimethylsilyl)allene  Such a c a t i o n i s s t a b i l i z e d by  carbon-silicon  followed  complexation of  by  bond.  A  1,2-shift  i n t e r c e p t i o n o f the  produces  the  interof  isomeric  annulated  31  the vinyl  product  34  - 9 -  SiMe3  TiCl  31  32  SiMe3 \-SiMe3  4-  33  34  Scheme 2  II.  P r e v i o u s Work  Previous s t a n n y l ) copper 1-alkynes treatment  36  in  our  reagent  35  (X  =  l a b o r a t o r i e s had shown t h a t the ( t r i m e t h y l adds  leaving  regioselectively  -78°C  u>-substituted Thus,  f o r 6 h p r o v i d e d e f f i c i e n t l y the  2 - ( t r i m e t h y l s t a n n y l ) - 1 - a l k e n e s 37 ( e q u a t i o n 8 ) . ^  vinylstannanes  37  have  been  p r e c u r s o r s o f a number o f b i f u n c t i o n a l synthetic  to  group o r p o t e n t i a l l e a v i n g group).  o f 36 w i t h 35 i n THF a t  corresponding The  work  equivalents  to  the  shown  to  conjunctive  donor-acceptor  serve  as  reagents  synthons 3 8 .  effective that  i X  '  i 2  are Thus,  - 10 -  /SnMe3  Me.SnCu.Me.S (35, 2equiv.)  HC=C(CH 2 ) n X  ^  2  :—  1>  =< \CH 2 )nX  MeOH (60equiv.), THF 3  (8)  -63°C, 12h  6  37 _d  transmetalation methyllithium  /SnMB3  ^CH2)n-lCH2  XCH 2 ) 3 Cl  38  39  of  5-chloro-2-(trimethylstannyl)-1-pentene  i n THF  at  magnesium b r o m i d e - e t h e r a t e , 40.  I n t h e presence  -78°C,  followed  by  addition  a d d i t i o n o f boron t r i f l u o r i d e - e t h e r a t e o f t h e r e a c t i o n s ( e q u a t i o n 9).12  t o enones  reagent  s u l f i d e complex, 41.  In  with  o f anhydrous  p r o v i d e d the c o r r e s p o n d i n g G r i g n a r d  o f c o p p e r ( I ) bromide-dimethyl  reagent underwent conjugate  addition  (39)  some  this  cases,  s i g n i f i c a n t l y improved the y i e l d s  11  The c o n j u g a t e a d d i t i o n p r o d u c t s 42 ment w i t h p o t a s s i u m h y d r i d e i n THF  were r e a d i l y c y c l i z e d  ( e q u a t i o n 10).  As e x p e c t e d ,  such c o n d i t i o n s , the " k i n e t i c " p r o d u c t s p o s s e s s e d a and  in  each case i n which subsequent  s i n g l e , c i s - f u s e d annulated 45  adduct  cyclized  to  product  give  only  by  cis  e q u i l i b r a t i o n was was  obtained.  the  cis-decalone  ring  treat1 2 a  under  junction  not p o s s i b l e ,  For  example  46  i n 78%  a  the yield  ( e q u a t i o n 11).  Cl^O  me KH,  THF  ^  ^  '  (11)  r t , 2h  In  o t h e r c a s e s , v a r y i n g degrees  conditions gave the conjugate  of  THF.  addition  After  methanol,  equilibration  occurred  c y c l i z a t i o n and f o r the d e c a l o n e s , f u r t h e r  t r a n s -decalones  d e c a l o n e s 48  of  and 49,  product  the 47  major  products.  equilibration  For  c y c l i z e d t o g i v e a 3.5:1  the  example  the  m i x t u r e o f the  r e s p e c t i v e l y on treatment w i t h p o t a s s i u m h y d r i d e i n  further  a 1:2.8  as  under  equilibration  with  m i x t u r e o f the ketones 48  sodium and  methoxide i n b o i l i n g 49,  respectively  o b t a i n e d ( e q u a t i o n 12).  A8  47 before further e q u i l i b r a t i o n a f t e r further e q u i l i b r a t i o n  49  3.5  :  1  1  :  2.8  was  12 -  It  c a n be seen t h a t , i n the above r e a c t i o n s ,  stannyl)-1-pentene 1-pentene  d ,a-* 2  (39)  serves  synthon ( 5 0 ) .  as  synthetic  equivalent  of  the  Use o f the former substance as shown i n  the above examples p r o v i d e d a v a l u a b l e sequence.  a  5-chloro-2-(trimethyl-  methylenecyclohexane  annulation  The methylenecyclohexane moiety i s a f a i r l y common s t r u c t u r a l  f e a t u r e i n the t e r p e n o i d f a m i l y o f n a t u r a l p r o d u c t s .  53 R=-NHCH0.  Scheme 3  54 R = -N=C  - 13 -  The  utility  demonstrated and  of  by  this  methylenecyclohexane  process  was  i t s a p p l i c a t i o n to the s y n t h e s i s o f (±)-axamide-1  (53)  (±)-axisonitrile-1  addition  of  the  (54).  G r i g n a r d reagent  (51), f o l l o w e d by treatment annulation c h a i n and and  product  52  w i t h potassium  in  85% y i e l d .  1982  compound,  x  indicated  collected which  formula  C25H36O3.  5.83  indicated triene  the  unit.  nm  to two  J = 11 Hz),  p a l a u o l i d e and  (±)-axamide-1  i s o l a t e d a new  growth  Infrared  7.16  s e s t e r t e r p e n o i d from  of  Bacillus  bands  at  (s,  3500  1H),  and  a resonance a t S stereochemistry  6.26 15.18  the  and  the  in  the  and the cm"-'-  ultraviowas  Signals at S  5.95  6.28  (d, nmr  ^ C  substitution  new  butenolide  ( s , 1 H ) i n the % (q)  1740  moiety and an  11 Hz),  This  I t had  and  carbon-carbon double bonds. J - 15.5,  species  subtilis  named p a l a u o l i d e .  (e 17,000) i n d i c a t e d t h a t  (dd, 1H,  (53)  (55)  Palauolide  P a l a u , Western C a r o l i n e I s l a n d s . the  the  (Scheme 3 ) .  the p r e s e n c e o f a 7 - h y d r o x y b u t e n o l i d e  Hz),  afforded  A f t e r i n c o r p o r a t i o n o f the s i d e  aureus a t 1 0 / i g / d i s c , was  f u r t h e r conjugated  15.5  from  inhibited  l e t a b s o r p t i o n a t 322  (d, 1H,  i n THF,  e x t r a c t of a mixture of at l e a s t three d i f f e r e n t  Straphvlococcus molecular  hydride  E l u c i d a t i o n of  S u l l i v a n and F a u l k n e r ^  the m e t h a n o l i c sponges  Structural  catalyzed  to 2 - m e t h y l - 2 - c y c l o p e n t e n - l - o n e  a p p r o p r i a t e f u n c t i o n a l group m a n i p u l a t i o n s ,  I s o l a t i o n and  In  CuBr.Me2S-BF3.Et2O  (40)  (±)-axisonitrile (54) were o b t a i n e d  III.  of  Thus,  1 3  annulation  3  1H,  J  =  spectrum o f  nmr  spectrum  pattern of  this  - 14 Comparison o f the remaining s i g n a l s i n the ^ C (55)  palauolide  substances have supported  with the  those same  of illimaquinone  bicyclic  ring  (56)  system.  and  nmr s p e c t r a o f  indicated that This  was  both  further  by the f a c t that chemical degradations o f both substances l e d  t o t h e same d i k e t o n e  57.  Thus, t h e s t r u c t u r e  of  palauolide  (55)  was  established.  Although palauolide carbon the  the carbon skeleton  i s relatively  common among  framework o f p a l a u o l i d e  literature.  that comprises the b i c y c l i c  (55)  sponge  metabolites,  had n o t been r e p o r t e d  portion of the  entire  previously i n  15 -  IV.  I s o l a t i o n and  S t r u c t u r a l E l u c i d a t i o n of I s o l i n a r i d i a l  I s o l i n a r i d i o l diacetate  In  1982,  San  ent-clerodane  type  The cm"  1  new  1H,  in  Portugal.  of  the  new  aerial  The  chemical  and  composition  of  (L.) had not been s t u d i e d p r e v i o u s l y .  compound showed two  The  r e p o r t e d the i s o l a t i o n o f a  1  ( L . ) . a p l a n t which grows i n the n o r t h e r n  i n d i c a t i n g the presence  moieties.  et__al. ^  d i t e r p e n o i d from the hexane e x t r a c t  c e n t r a l p a r t o f S p a i n and Linaria saxatilis  and  (61)  Feliciano  part of L i n a r i a s a x a t i l i s  (60)  s t r o n g i n f r a r e d bands a t 1725  o f s a t u r a t e d and  s i g n a l s a t 6 9.93  ( s , 1H),  and  a, (3-unsaturated  9.45  carbonyl  (br s, 1H),  sharpened on i r r a d i a t i o n a t 6 9.93-9.45 and 6.41), 2.57  1675  6.41 (m,  (br s, 2H) CHO  in  I the -41  nmr  spectrum  indicated  moiety i n the molecule. and  the  ir  spectrum  clerodane-type transformed the  bicyclic  The of  the  remaining the  new  substructure.  i n t o s o l i d a g o l a c t o n e (62)  presence  of  a (Z)-RCH2CH=CCH2CHO  s i g n a l s i n the  ^H  spectrum  compound i n d i c a t e d the presence T h i s new  substance  (see Scheme 4 ) , an  s t r u c t u r e and a b s o l u t e s t e r e o c h e m i s t r y o f which had  e s t a b l i s h e d by Okazaki  nmr  e t a l . ^ Thus, s t r u c t u r e 60 was 1  was  of  chemically  ent-clerodane. already  been  proposed f o r the  A c c o r d i n g to Rowe's nomenclature, s t r u c t u r e s 5 8 and 5 9 with absolute s t e r e o c h e m i s t r y i n d i c a t e d are r e f e r r e d to as c l e r o d a n e and ent-clerodane. respectively. For detailed d i s c u s s i o n , see F. P i o z z i , H e t e r o c v c l e . 15, 1489 (1981). D  58  59  - 16 -  Scheme 4  new compound and i t was named i s o l i n a r i d i a l , closely  related  since  t o the d i t e r p e n o i d l i n a r i d i a l  e a r l i e r by Kitagawa e t a l .  1  8  from L i n a r i a  structurally  ( 6 3 ) , which was  japonica  In 1985, the same S p a n i s h group r e p o r t e d  i t is  isolated  (Scheme 4 ) .  the i s o l a t i o n from  Linaria  - 17 saxatllis  (L.) o f another  skeleton i d e n t i c a l with showed  ir  absorptions  I n the H nmr  new  the  diterpene  (60)  that of i s o l i n a r i d i a l  presence  1.91  and l i t h i u m aluminum h y d r i d e  each)  x  also  Saponification of this  64 (Scheme 5 ) , which was named  isolineridiol.  V.  Syntheses o f C l e r o d a n e - t y p e  in  3H  cm" .  isolinaridial  diacetate.  diol  compound  of  isolinaridiol  terpenoids,  (s,s,  reduction  Thus s t r u c t u r e 61 was proposed f o r the new  The  T h i s new  x  o f two a c e t a t e groups.  l e d to the same d i o l  Previous  (60). ^  a carbon  due to acetoxy groups a t 1745, 1240, 1030  spectrum, s i g n a l s a t S 1.97,  X  indicated  e n t - c l e r o d a n e - type d i t e r p e n o i d h a v i n g  diterpenoid  and  was  named  Diterpenoids  p a l a u o l i d e (55), i s o l i n a r i d i o l  (64) and i s o l i n a r i -  d i a c e t a t e (61) had n o t been s y n t h e s i z e d p r i o r t o the work d e s c r i b e d this  thesis.  clerodane theses (67),  of 2 2  type  However,  the  syntheses  o f a number o f t r a n s - f u s e d  d i t e r p e n o i d s had been r e p o r t e d .  (±)-annonene  (65), ^ 2  (±)-4-epi-ajugarin,  (-)-methyl k o l a v e n a t e  (69)  2 4 d  23c  Thus,  (±)-ajugarin-IV ( 6 6 ) , (±)-maingayic  had been c a r r i e d out.  acid  the 2 x  total  syn-  (±)-ajugarin-I (68),  2 4 a  and  - 18 -  In  the  following  discussion,  which  reviews  briefly  s y n t h e s e s , the s t r a t e g i e s employed f o r the c o n s t r u c t i o n o f substructure Kende  et  al.. ^ 2  derivative  a l k y l a t i o n provided stereochemistry  and de Groot e t a l . .  2 3  at  of a  the  Wieland-Miescher  trans-ring C-9.  junction  and  Starting  ketone  with  a  (70), r e d u c t i v e  produced  the  desired  A s u i t a b l e sequence o f r e a c t i o n s t h e n i n t r o For example,  in  the  s y n t h e s i s o f (±)-ajugarin-IV, ^ r e d u c t i v e a l k y l a t i o n o f the enone 2  71 w i t h a l l y l bromide a f f o r d e d the ketone 72. converted  The l a t t e r  i n t o the c o n j u g a t e d ketone 73 i n f i v e s t e p s .  r e d u c t i o n o f 73 i n the absence o f an a l c o h o l p r o v i d e d was  decalin  employed b a s i c a l l y the same  duced the r e q u i r e d secondary methyl group a t C-8. total  the  above  o f the c l e r o d a n e d i t e r p e n o i d s w i l l be emphasized.  approach f o r the c o n s t r u c t i o n o f the d e c a l i n moiety. suitable  the  c o n v e r t e d i n t o (±)-ajugarin-IV  (66) (Scheme 6 ) .  material  was  Lithium-ammonia  ketone  74,  which  - 19 -  Scheme 6  on  Kakisawa  et a l .  a starting material more,  they  also  u  a l s o employed t h e Wieland-Miescher ketone  f o r the syntheses o f  (i)-annonene  (65).  (70) as Further-  used an a l k a l i metal-ammonia r e d u c t i o n t o p r o v i d e t h e  trans-fused ring junction  (Scheme 7 ) .  However, t h e y employed a  Claisen  rearrangement  p r o c e s s t o i n t r o d u c e t h e r e q u i r e d s i d e c h a i n a t C-9.  r e a c t i o n was  found  alkylation  mentioned  to  be  less  above  h y d e s 75 a n d 7 6 , r e s p e c t i v e l y . the carbon-carbon double bond converted into  stereoselective  than  the  This  reductive  and p r o v i d e d a n 85:15 m i x t u r e o f t h e a l d e Subsequent i n 75 p r o v i d e d  (±)-annonene ( 6 5 ) (Scheme 7 ) .  catalytic  hydrogenation  the aldehyde  of  7 7 , w h i c h was  - 20 -  / Claisen  Scheme 7  Ley e t _ a l . required  2 2  employed a v e r y d i f f e r e n t approach  decalin  system  and  built  from the keto d i t h i o a c e t a l 78.  In this  the n e c e s s a r y C-8 and C-9 s u b s t i t u e n t s were a l r e a d y p r e s e n t i n 78  and  skeleton  an of  annulation ring  CHCH2CH2)2CuMgBr  A. to  sequence Thus,  provide  was  compound  up  the case,  compound  employed t o c o n s t r u c t the carbon 78  was  treated  with  (CH2=  the o l e f i n 79, which was t r e a t e d s u c c e s s -  - 21 i v e l y with borane-dimethyl hydroxide  to  the aldehyde enone  82  s u l f i d e complex and hydrogen  g i v e the a l c o h o l 80.  The  81 which underwent an a l d o l  (Scheme 8 ) .  l a t t e r m a t e r i a l was condensation  to  o x i d i z e d to provide  the  The r e m a i n i n g appendages were added s t e r e o s e l e c -  t i v e l y t o the a n n u l a t e d p r o d u c t 82 t o g i v e 83, which was (±)-ajugarin-I (67)  peroxide-sodium  (Scheme 8 ) .  Scheme 8  converted  into  - 22 -  A  slightly  d i f f e r e n t approach was employed by Tokoroyama e t a l .  i n the t o t a l s y n t h e s i s o f (±)-maingayic a c i d methyl-2-cyclohexen-l-one  (84) w i t h  (68).  the  alcohol  85.  Mesylation  of  anion the  compound 86 which was t r e a t e d s u c c e s s i v e l y w i t h m e t h a n o l i c hydrogen c h l o r i d e ,  addition  reagent,  with  m a t e r i a l gave +  87 (Scheme 9 ) . The  choice  F o r example, treatment  2  l,8-diazabicyclo[5.4.0]undec-7-ene ( e q u a t i o n 13).  formaldehyde  [RCH2COCH~CC>2CH3]Na and  By a p r o p e r  M e C u L i , formaldehyde,  of  conjugate  On the o t h e r hand, treatment  87b R=Me  Scheme 9  product  o f t h e enone  methanesulfonyl  p r o v i d e d the  a  complex,  e i t h e r the t r a n s - f u s e d o r c i s - f u s e d b i c y c l i c  c o u l d be o b t a i n e d s e l e c t i v e l y . successively  latter  t o a f f o r d the decalone  C-5 s u b s t i t u e n t was then i n t r o d u c e d .  with  4  3,4-di-  CH2=CHMgBr.(n-Bu^PCuI)^  f o l l o w e d by t r a p p i n g o f the r e s u l t i n g e n o l a t e provided  Reaction of  2  c h l o r i d e , and  cis-fused  o f 87b w i t h  87a  decalone  88  diethylaluminum  - 23 -  c y a n i d e p r o v i d e d the t r a n s - f u s e d decalone 10).  Thus,  this  c l e r o d a n e systems. (68)  89  stereoselectively  (Scheme  approach p r o v i d e d access t o b o t h the t r a n s - and c i s The n i t r i l e  89 was c o n v e r t e d i n t o  (±)-maingayic a c i d  (Scheme 10).  Scheme 10  Recently, the  bicyclic  the  Japanese group employed the same method t o c o n s t r u c t  substructure  of  (-)-methyl  kolavenate  s t a r t i n g m a t e r i a l was the e n a n t i o m e r i c a l l y pure  (69). ^k  (R)-3,4-dimethyl-2-cyclo-  hexen-l-one ( 9 0 ) , which was c o n v e r t e d i n t o the o p t i c a l l y a c t i v e 91 .  Hydrocyanation  of  which was c o n v e r t e d i n t o In  decalone  the l a t t e r m a t e r i a l p r o v i d e d the n i t r i l e  (-)-methyl k o l a v e n a t e  et a l .  2 5  92,  (69) (Scheme 11).  a d d i t i o n t o the syntheses o f c l e r o d a n e - t y p e  r i z e d above, G o l d s m i t h  The  2  diterpenoids  summa-  and Kato e t a l . ^ have r e p o r t e d p r e l i m i 2  - 24  nary studies the  on  the  construction  -  p o t e n t i a l a p p l i c a t i o n of a Diels-Alder of  the  clerodane decalin substructure.  chose the  s u b s t i t u t e d q u i n o n e 93  as  the  starting  structed  the  in  the  first  Diels-Alder suitable  decalin  quent s u c c e s s f u l nitrile  97  clerodanes  skeleton  r e a c t i o n o f the  reductions  (Scheme  up  with  the  a new  of  95  into  step.  the  the  Both  material  q u i n o n e 93,  e q u i l i b r a t i o n , provided  2  con-  example,  6 followed  k e t o n e 95. 96  ketone  p o t e n t i a l r o u t e to the  groups  and  For  in  total  a by  Subseand  synthesis  the of  12). different  c l e r o d a n e s has  been reported  the  i n t o the  side chain  d i e n e 94  transformation  opened  A distinctly  and  reaction  synthetic by  approach  ApSimon e t _ a l . ^  d e c a l i n by  2  to  the  Instead  synthesis of  a l k y l a t i o n , t h e y made u s e  of  introducing of  the  - 25 -  Scheme 12  c l e a v a g e o f the c y c l i c h e m i a c e t a l 98 t o mediate of  98  was p r e p a r e d i n f i v e  2-methyl-l,3-cyclohexadione  ketone  101, the c a t a l y t i c  prepare  The  key  inter-  s t e p s , which i n c l u d e d the c o n d e n s a t i o n  (100) w i t h  the  hydroxy  a,^-unsaturated  h y d r o g e n a t i o n o f the c o n d e n s a t i o n p r o d u c t 102,  the a d d i t i o n o f methyl magnesium bromide t o 103,  99.  the  hydrogenation  product  d e h y d r a t i o n o f the r e s u l t a n t a l c o h o l 104, and the h y d r a t i o n o f the  e n o l e t h e r f u n c t i o n i n 105 (see Scheme 13). vicinal tively,  methyl  groups  at  compound 98 would be  synthesis of clerodanes.  C-8 a  P r o v i d e d t h a t the n e c e s s a r y  and C-9 can be i n t r o d u c e d s t e r e o s e l e c valuable  intermediate  for  the  total  - 26 -  Scheme 13  -  VI.  27  Aim  As  mentioned  previously,  a  new  sequence had been developed i n our noted  earlier,  terpenoids carbon  there  a  laboratory.  hexen-l-one  Furthermore,  f a i r number o f k n o w n n a t u r a l l y  (106)  as  I n the a n n u l a t i o n and the  the  Grignard  major  product  reagent (Scheme  stereochemistry  same  methylenecyclohexane  moiety  (55),  isolinaridiol to  attempt  the  as  the  and i s o l i n a r i d i o l total  40, 14).  the  a key  role.  occurring of  1 2  The  decalone latter  their  49  is  material  a t the r i n g j u n c t i o n and natural products diacetate  (61).  the  palauolide  T h u s , i t was  syntheses of these n a t u r a l products v i a  r e a c t i o n sequences i n which the methylenecyclohexane a n n u l a t i o n would p l a y  also  14  p o s s e s s e s t h e same r e l a t i v e  (64)  as  r e a c t i o n between 3-methyl-2-cyclo-  Scheme  decided  annulation  t h a t p o s s e s s a m e t h y l e n e c y c l o h e x a n e m o i e t y as p a r t  skeleton.  obtained  are  methylenecyclohexane  process  - 28 -  61  - 29 -  DISCUSSION  I.  Total  A.  Retrosynthetic  Our  Analysis  retrosynthetic  premise  (55)  S y n t h e s i s o f (±)-Palauolide  that  the  analysis  decalin by  substructure  prepared  readily  discussed  i n the Introduction  (55)  o f (±)-palauolide of  this  was b a s e d  substance  along  with  section  suitable  ments, would p r o v i d e phosphorane with  108.  of this  which,  108  i n turn,  Recently,  Suitable aldehyde  I t was e x p e c t e d t h a t  thesis.  suitable  provide the  the  butenolide frag-  desired  108 w o u l d E  couple  olefin.  The  from the c h l o r i d e  109,  s h o u l d be p r e p a r a b l e from t h e 2 - t r i m e t h y l s i l y l f u r a n  110.  derivatives  t o a f f o r d 7-hydroxy  would  provide  the  group  nitrile  the l a t t e r  been  of  the  successfully  2 8  interconversions 111.  resultant iodide  substance would,  of  the  Disconnection a t the  c h a i n and the b i c y c l i c  112 a n d t h e h o m o a l l y l i c  112 w i t h  have  butenolides.  functional  functionalization  the n i t r i l e  nitrile  the  t o be a v a i l a b l e  carbon-carbon bond j o i n i n g the side with  the phosphorane  primarily  was a n t i c i p a t e d  retrosynthetic  107  method  functionalization of the resultant  2-trimethylsilylfuran  photo-oxygenated  be  t h e o , / 3 - u n s a t u r a t e d a l d e h y d e 107 a n d t h e s t a b i l i z e d  t h e a l d e h y d e 107 t o g i v e  phosphorane  would  use o f the methylenecyclohexane annulation  D i s c o n n e c t i o n o f t h e carbon-carbon double bond a t o moiety,  on t h e  113.  system,  fragments,  along would  Alkylation  forsteric  of  r e a s o n s , be  - 31 -  e x p e c t e d to take p l a c e w i t h the required  nitrile  111.  114.  The  functional  l a t t e r m a t e r i a l was  m i c a l l y most s t a b l e p r o d u c t d e r i v e d tion the  reaction  interconversions  would  the  to  involving  a,y9-acetylenic may  reaction  conditions. ^  be  controlled  the  thermodynaannula-  enone 115.  chiral  Thus,  centers  in  annulation  the  homoallylic  This  e s t e r was  iodide  113,  expected  to  P r e v i o u s work i n our  esters by  and a  be  t h a t the  judicious  group  would p r o v i d e be  available  laboratories  added  regioselec-  stereochemistry of choice  of  had  such  reagents  and  2  S y n t h e s i s o f the n i t r i l e  112  3-Methyl-2-cyclohexen-1-one  (106)  was  k i n e t i c a l l y deprotonated  treatment w i t h l i t h i u m d i i s o p r o p y l a m i d e i n THF  basis  the  i n s t a l l e d a t the  elements o f t r i m e t h y l s t a n n a n e can  additions  enolate  along  along with s u i t a b l e f u n c t i o n a l  c h l o r o pentynoate 117.  shown t h a t the tively  the  provide  from a methylenecyclohexane  expected to be  disconnection,  Z c h l o r o pentenoate 116. the  form  synthesis.  A retrosynthetic  from  to  group o f 112,  a n t i c i p a t e d to be  i n v o l v i n g the v i n y l s t a n n a n e 39 and  b i c y c l i c r i n g system was  stage o f the  B.  group,  c o r r e c t r e l a t i v e s t e r e o c h e m i s t r y o f t h r e e o f the  the  the  stereochemistry  D i s c o n n e c t i o n o f the n i t r i l e  with i n t r o d u c t i o n of a s u i t a b l e ketone  desired  anion  was  at  -78°C.  The  resultant  a l l o w e d to r e a c t w i t h iodomethane to a f f o r d , on  o f a g l c a n a l y s i s and  ^H nmr  s p e c t r o s c o p y , e x c l u s i v e l y the  3 , 6 - d i m e t h y l - 2 - c y c l o h e x e n - l - o n e (115)  i n 93%  yield  by  (equation 1 4 ) .  the  desired 3 0  The  - 32 -  ir  spectrum o f 115 e x h i b i t e d an a b s o r p t i o n a t 1672  presence  of  an  a,^-unsaturated  cm"!,  six-membered r i n g ketone.  spectrum o f 115 e x h i b i t e d a b r o a d s i n g l e t a t 6 1.96 methyl  group  methyl  group.  and  Reaction  of  a  the  5-chloro-l-pentyne  d o u b l e t a t 8 1.13  due  (J - 7 Hz) due  (trimethylstannyl)copper(I)  (118)* i n THF  indicating The  nmr  the  vinyl  to  t o the secondary  reagent  35  with  i U  a t -78°C f o r 6 h a f f o r d e d , on the b a s i s  o f a g l c a n a l y s i s , a mixture o f the d e s i r e d c h l o r o v i n y l s t a n n a n e 39 its  isomer  119 ^ 3  in  a  ratio  of  F o r t u n a t e l y , when t h i s mixture was graphy  on  silica  (62% y i e l d ) . ^ chromatography, separated. als  85:15, r e s p e c t i v e l y  s u b j e c t e d to (slow) column  However, when the m i x t u r e was isomers  and  ( e q u a t i o n 15). chromato-  g e l , o n l y the d e s i r e d v i n y l s t a n n a n e 39 was  both  the  recovered  subjected to f l a s h  column  c o u l d be r e c o v e r e d , but were not  cleanly  A f t e r a s o l u t i o n o f a m i x t u r e o f these two  isomeric  materi-  i n aqueous a c e t i c acid-THF had been s t i r r e d a t room temperature f o r  12 h, o n l y the v i n y l s t a n n a n e indicated  total  39  disappearance  was  recovered  (30%).  o f the o t h e r isomer.  i n d i c a t e d that while both  isomers  d e s t a n n y l a t i o n , the minor  isomer 119  are  susceptible  Glc  These to  analysis  experiments  acid-catalyzed  i s more l a b i l e .  * T h i s m a t e r i a l i s c o m m e r c i a l l y a v a i l a b l e from A l d r i c h Chemical Company.  - 33 The (H H z  A  >  spectrum o f 39  nmr  and Hg) ^Sn-H  showed s i g n a l s due  to two  olefinic  as a p a i r o f d o u b l e t o f t r i p l e t s a t 6 5.71 =  1  5  0  H z  >  a  n  d  5  -  <i  2 3  = 2.5,  0.8  Hz,  J  (J S  .  n  =  2.5,  = 70  H  protons  Hz),  1.2 3 2  respectively. 1. Me SnCu.Me S (35) 3  2  Me Sn  THF, -78°C, 6h  HC=C(CH ) Cl 2 3  3  /^CH ) CI  2. HOAc, aq NHjCl  2  118  39 The v i n y l s t a n n a n e 39  solution  of  was  methyllithium  to  reagent  40  by  a  THF  120 was  119  85:15  s o l u t i o n o f 39 converted  was  s t i r r e d a t -78°C f o r 3 h.  two  e p i m e r i c c h l o r o ketones 121 was  ethereal  at -78°C.  a d d i t i o n o f s o l i d magnesium  t r i f l u o r i d e - e t h e r a t e and the enone 115  an  i n t o the  S u c c e s s i v e a d d i t i o n o f c o p p e r ( I ) bromide-dimethyl  ,,K  2 3  t r a n s m e t a l a t e d by a d d i t i o n o f  r e s u l t a n t v i n y l l i t h i u m reagent Grignard  HcH , C,  +  3  The  1 2  corresponding  bromide-etherate.  s u l f i d e complex, b o r o n  gave a b r i g h t y e l l o w s l u r r y which  A f t e r a p p r o p r i a t e workup, o b t a i n e d i n 77% y i e l d  a  mixture  of  ( e q u a t i o n 16).  1. CuBr.Me S 2  BF .Et 0 3  'SnMe  MeLi.THF  MgBr .Et 0  -78°C  -78°C  3  2  ketone 115  2  -MgBr  120  The  ir  i n d i c a t i n g the presence  Upon  exposure  to  2  -  a  l  N H  (16)  C 1 4  40  spectrum o f 121  t e r m i n a l double bond,  2  e x h i b i t e d a b s o r p t i o n s a t 1705  and 905  cm" ,  o f a s a t u r a t e d six-membered c y c l i c ketone and  1  a  respectively. potassium  tert-butoxide i n t e r t - b u t y l a l c o h o l at  - 34 -  30°C f o r 12 h, the c h l o r o ketones 121 underwent tion  and  brated  the i n i t i a l l y  to  produce  respectively was  in  a  formed a n n u l a t i o n p r o d u c t ( s ) was 94:6  89% y i e l d  mixture  chromatography on s i l i c a  i  H  nmr  broad  (5  J  Hz)  singlet). the  =  6  the  singlet), and  alkyla-  (were) e q u i l i 114  and  122,  A pure sample o f each isomer  spectrum o f the major p r o d u c t  doublet,  ketones  crude  g e l impregnated w i t h 25%  (5 4.70,  0.99,  the  ( e q u a t i o n 17).  the o l e f i n i c p r o t o n s  of  of  o b t a i n e d by s u b j e c t i n g a p o r t i o n o f  The  intramolecular  114  product  silver  to  column  nitrate.  showed s i g n a l s due  the secondary  methyl group  the a n g u l a r methyl group (5  By c o r r e l a t i o n o f the l a t t e r v a l u e w i t h the  to  chemical  a n g u l a r methyl groups i n t r a n s - and c i s - 1 - d e c a l o n e s  0.87, shifts  (6 0.75-0.9  and 1.05-1.20, r e s p e c t i v e l y ) , as r e p o r t e d by Boeckman e t a l . .  114  was  o l e f i n i c s i g n a l s at S  4.74  3 3  t e n t a t i v e l y assigned a trans-fused r i n g j u n c t i o n . The  ^H nmr  and 4.63. groups  The  spectrum o f 122 s i g n a l s due  appeared  at  S  to  1.31  e x h i b i t e d two the  angular  and  0.98  (J  and  the  = 6 Hz),  c o r r e l a t i o n o f the former v a l u e w i t h Boeckman's  data,  secondary  methyl  respectively. 122  was  By  tenta-  t i v e l y assigned a cis-fused ring j u n c t i o n . Since  there  are  two  e p i m e r i z a b l e c h i r a l c e n t r e s i n the a n n u l a t i o n  p r o d u c t ( s ) , f o u r i s o m e r i c p r o d u c t s , p o s s e s s i n g s t r u c t u r e s 114,  123,  and  analysis,  124,  could  have been produced.  Based on c o n f o r m a t i o n a l  122,  - 35 structures expected 123a  114 to  and  an  be  124a).  structure mol'l.  and  114  (see  conformations  114a  more s t a b l e t h a n s t r u c t u r e s 123  and and  would  be  more  energy  ratio  of  stable  124  114  1Ka  94:6,  the trans  isomer  123a  122a  yield  i s p r i m a r i l y due  (equation  attack  is  reduction min  (calcium,  afforded  18).  The  i s h i n d e r e d by  relatively  unhindered.  stereoselectively i n 75%  114  (diethylether  s t e r e o s e l e c t i v i t y of this  yield  the  alcohol  reduction  of the h y d r i d e reagent to  the angular methyl On  the  1 2 4 a  group, whereas  the /3  the o t h e r hand, d i s s o l v i n g metal  l i q u i d ammonia) o f t h e k e t o n e  e q u a t o r i a l a l c o h o l 126  kcal  124  3 h) a f f o r d e d e x c l u s i v e l y the a x i a l  to the f a c t t h a t approach  a-face of the ketone  b y -0.7  that  114.  L i t h i u m aluminum h y d r i d e r e d u c t i o n o f the ketone  125  predicted  the c a l c u l a t i o n d i d i n d i c a t e t h a t  122  room t e m p e r a t u r e ,  be  (conformations  t h a n s t r u c t u r e 122  123  solution,  3 4  would  d i f f e r e n c e i s n o t l a r g e enough t o r e s u l t i n  a n n u l a t i o n p r o d u c t s h o u l d be  i n 84%  122a)  M o l e c u l a r mechanics c a l c u l a t i o n s (MM2)  Although this  equilibrium  major  122  114  at  thermodynamically  (equation  19).  -33°C more  for  10  stable  36 -  The  i r spectrum  o f 125 showed  i n d i c a t i n g t h e presence  a  broad  absorption  o f an a l c o h o l group.  at  3490  The f a c t t h a t  t h i s p r o t o n was o n l y weakly c o u p l e d w i t h i t s v i c i n a l n e i g h b o r i n g  i t e d a broad  equatorially o r i e n t e d .  i r absorption  a t 3300 cm" . 1  o f 125  The ^H nmr spectrum  e x h i b i t e d a b r o a d s i n g l e t a t S 3.56 f o r the >CH0H p r o t o n .  i n d i c a t e d t h a t i t was  cm" ,  The  3 4 a  The a l c o h o l 126 exhib-  ^H nmr spectrum  t r i p l e t a t J 3.04 ( J = 9 Hz) f o r the >CH0H p r o t o n .  protons  showed a  Thus, i n t h i s  case, 34a  i t was c l e a r t h a t t h e c a r b i n o l p r o t o n was i n an a x i a l  o f t h e a l c o h o l 126 w i t h j > - t o l u e n e s u l f o n y l  Treatment presence  of  temperature  4-N,N-dimethylaminopyridine f o r 12  ( e q u a t i o n 20). in  HMPA  orientation.  at  (equation 21).  c h l o r i d e i n the  i n dichloromethane  h a f f o r d e d the p.-toluenesulfonate 127  f o r 3 h p r o v i d e d t h e a x i a l n i t r i l e 112a  room  i n 83% y i e l d  R e a c t i o n o f the l a t t e r m a t e r i a l 127 w i t h sodium  80°C  at  cyanide  i n 44% y i e l d  37 -  112a  127 The In  i r s p e c t r u m o f 112a e x h i b i t e d a n i t r i l e  the  nmr s p e c t r u m o f 112a t h e >CH-CN p r o t o n  of doublets  a t 5 2.60 ( J = 4.5, 1.3 H z * ) ,  equatorially orientated.  appeared  at  angular  supported since  5  1.24.  the  on  These  triplet  that this proton i s m e t h y l g r o u p was  r e l a t i o n s h i p ) and  s h i f t may b e c o m p a r e d w i t h  m e t h y l g r o u p o f 126 (6 0.98).  observations  that of further  a s s i g n m e n t o f a t r a n s - f u s e d r i n g j u n c t i o n t o k e t o n e 114,  successive  formation  indicating  g r o u p (1,3 d i a x i a l  This chemical  a t 2225 cm'^.  appeared as a  The s i g n a l due t o t h e a n g u l a r  strongly deshielded by the n i t r i l e  the  absorption  metal-ammonia  reduction,  tosylation,  and  nitrile  t h e c i s - f u s e d 1 - d e c a l o n e 122 w o u l d n o t g i v e a n i t r i l e i n  which the angular  m e t h y l group c o u l d be d e s h i e l d e d b y t h e n i t r i l e  group  (Scheme 15). The  The  preparation  of the desired n i t r i l e  o r i g i n of the small coupling  112 f r o m t h e k e t o n e 114 v i a  ( J - 1.3 H z ) i s n o t known.  - 38 -  122  Scheme 15  the a  route more  described direct  r o u t e was i n v e s t i g a t e d .  t h e k e t o n e s 114 isocyanide  a b o v e was b o t h t e d i o u s  and  122,  respectively,  and low y i e l d i n g .  Therefore,  T r e a t m e n t o f a 94:6 m i x t u r e o f with  p.-toluenesulfonylmethyl  a n d p o t a s s i u m t e r t - b u t o x i d e i n HMPA a t 45°C f o r 88 h g a v e ,  3 5  b a s e d o n a g l c a n a l y s i s , a 15:85 m i x t u r e respectively,  i n 68% y i e l d  of  nitriles  112a  and  112b,  ( e q u a t i o n 22).  CN CH3-Q-SO2CH2NSC  tert-BuOK, HMPA  114  122  112a  112b 15:85  Column  chromatography  of  a  p o r t i o n o f t h i s mixture  i m p r e g n a t e d w i t h 25% s i l v e r n i t r a t e compound. the  The  axial nitrile  major  isomer  minor  a  pure  sample  of  gel each  isomer e x h i b i t e d s p e c t r a i d e n t i c a l w i t h those o f  112a o b t a i n e d  exhibited  afforded  on s i l i c a  a  from t h e route  nitrile  described  absorption  at  earlier.  The  2225 c m " i n t h e i r 1  - 39 -  spectrum. for  The H nmr s p e c t r u m s h o w e d a t r i p l e t  t h e >CH-CN p r o t o n ,  tated,  indicating  that this proton  a n d a s i n g l e t a t 5 0.96 f o r t h e a n g u l a r  t h a t t h e m e t h y l g r o u p was n o t 1,3 d i a x i a l angular nmr  methyl  of  i s o m e r was a s s i g n e d The  similar  was  axially  methyl group,  to the n i t r i l e  112a a p p e a r e d a t 5 1.24).  s p e c t r u m was v e r y  in  a t 6 2.08 ( J = 1 1 . 5 H z )  i  Since  t o that o f the minor  group  orien-  indicating (cf.  the  t h e r e s t o f t h e ^H isomer,  the  major  s t r u c t u r e 112b.  exclusive formation  of the trans-fused n i t r i l e s  112a a n d 112b i s  accord w i t h reports that trans -1-decalones u s u a l l y r e a c t f a s t e r  nucleophiles  than  the corresponding  cis-l-decalones.  r e a c t i o n c o n d i t i o n s i n w h i c h t h e two k e t o n e s products  are  expected  trans-1-decalone. ^  For  3  treatment  to  o f a 2:1 m i x t u r e  be  derived  example,  are  mainly  Marshall  Therefore,  et  a l . ^  alkenes  trans-  and  c i s - fused  respectively  (equation  23).  the  96  p_-toluenesulfonylmethylisocyanide  ketone  with  reported  that  o f t h e 1 - d e c a l o n e s 128 a n d 129, r e s p e c t i v e l y ,  87:13  the  the  o r even s o l e l y from the  sulfoxide  of  under  i n equilibrium,  with methylene-triphenylphosphorane i n dimethyl mixture  with  Kato et__al., 6b reported 2  t e r t - b u t o x i d e produced only the trans-fused n i t r i l e  afforded 130  and  an 131,  that treatment and  of  potassium  97 ( e q u a t i o n 24).  (23) 128  129  130  131 87:13  - 40 -  96 When was the  a  97 15:85  deprotonated  mixture  of then i t r i l e s  112a a n d 112b, r e s p e c t i v e l y ,  with lithium diisopropylamide  i n HMPA -THF a t  0°C  and  r e s u l t a n t a n i o n was a l k y l a t e d w i t h n - b u t y l i o d i d e , o n l y t h e n i t r i l e  132 was o b t a i n e d supported epimeric  i n 92%  yield  the earlier only a t  stereoselectivity  conclusion  the carbon of  (equation  bearing  the alkylation  the n i t r i l e i sprobably  anion from t h e a  sterically  the angular  by  r e l a t i v e l y unhindered. nitrile  132 w o u l d b e  1120.  This  that the n i t r i l e s  alkylation of then i t r i l e hindered  25).  face  result  further  112a a n d 112b a r e group.  The  high  due t o t h e f a c t  that  of  the molecule  i s  methyl group whereas t h e p face i s  Thus, predominant o r e x c l u s i v e f o r m a t i o n o f t h e expected.  112b 15:85  Treatment o f a THF s o l u t i o n o f 15:85 m i x t u r e o f t h e a x i a l a n d e q u a t o r i a l n i t r i l e s 112a a n d 112b, r e s p e c t i v e l y , w i t h l i t h i u m d i i s o propylamide i n t h e a b s e n c e o f HMPA, f o l l o w e d b y a d d i t i o n o f i o d o m e t h a n e , p r o v i d e d a 15:85 m i x t u r e o f t h e a l k y l a t e d p r o d u c t and the original e q u a t o r i a l n i t r i l e 112b, r e s p e c t i v e l y . T h u s , u n d e r t h e s e c o n d i t i o n s , o n l y t h e a x i a l n i t r i l e 112a u n d e r w e n t d e p r o t o n a t i o n .  - 41 -  The angular  nmr spectrum o f 132 e x h i b i t e d a s i n g l e t a t 6 1.26 due to methyl  group,  diaxial relationship). groups  which I t may  is  d e s h i e l d e d by the a x i a l n i t r i l e (1,3  be  recalled  that  the  angular  methyl  o f the a x i a l and e q u a t o r i a l n i t r i l e s 112a and 112b appeared a t S  1.24 and 0.96, r e s p e c t i v e l y . strated  the  that  a  high  The  exclusive  stereochemical  formation  control  of  132  demon-  o f the d e s i r e d r e l a t i v e  s t e r e o c h e m i s t r y o f the newly formed c h i r a l c e n t r e i s p o s s i b l e .  C.  S y n t h e s i s o f the h o m o a l l y l i c i o d i d e 113  Reaction of 3-butyn-l-ol formamide  38  at  (133) w i t h phosphorus  room temperature f o r 40 min a f f o r d e d , a f t e r two c a r e f u l  f r a c t i o n a l d i s t i l l a t i o n s of alkyne reagents  134^  i  n  42%  yield  crude  i r spectrum o f 134  of  134  product,  ( e q u a t i o n 26). purified  the  volatile  I t was n e c e s s a r y  before  use,  chloro t h a t the  otherwise  no  obtained.  i n d i c a t i n g the presence spectrum  the  and s o l v e n t be c a r e f u l l y  d e s i r e d m a t e r i a l was  The  trichloride-dimethyl-  e x h i b i t e d a b s o r p t i o n s a t 3000 and 2120 cm"--, 1  of a  showed  terminal  alkyne  function.  The  ^-H  nmr  a t r i p l e t a t 6 3.63 ( J = 7 Hz) f o r the -CH2CI  T h i s a l c o h o l i s commercially  a v a i l a b l e from A l d r i c h Chemical  Company.  - 42  protons,  a  doublet  of  -CH CH2C1 p r o t o n s and  a  2  acetylenic A  triplets triplet  at at  of  the  chloro  at  2.68 2.11  (J = 2.5, (J  =  chromatography  of  the  a c e t y l e n i c e s t e r 117 spectrum  134  i n THF  -78°C.  The  was  of  117  cnT^,  crude  was  A f t e r appropriate  product  obtained  showed the  Reaction  m i x t u r e o f the  of  on  i n 63%  acetylene  ester  silica  yield and  — 114  114  (equation  carbonyl  Hz  an  acetylenic  -20°C f o r 1 h  gel,  and the  and  column required  27).  The  absorptions  ir  a t 2235  THF  d e s i r e d e s t e r 116  and  (equation  a t 1704  cnT^,  The  to the due  ^H  nmr  28).  obtained.  at  -48°C f o r 4 h  2 9  135with  afforded a  the b i s ( t r i m e t h y l s t a n n y l ) When t h i s m i x t u r e was  4:1  compound  subjected  to  column chromatography, a pure sample The  ir  spectrum  i n d i c a t i n g the p r e s e n c e o f spectrum o f 116  C l C ^ - p r o t o n s and  ( 2 ? )  117  2  in  was  Hz)  treated with  workup  ClC0 Et  117  compound  group. due  the  ^C02Et  f r a c t i o n a l d i s t i l l a t i o n and  absorption  3.56  ester  respectively  each  the  for  of l i t h i u m (trimethylstannyl)(phenylthio)cuprate  acetylenic  careful  for  respectively.  2.  136,  Hz)  resultant  1. MeLi, T H F  the  7 Hz)  2.5  a l l o w e d to r e a c t w i t h e t h y l c h l o r o f o r m a t e a t  t h e n a t room temperature f o r 1 h.  1710  5  alkyne  e t h e r e a l s o l u t i o n of methyllithium  and  8  proton.  solution  a n i o n was  -  an  showed  a t 8 6.43  The  coupling  i n d i c a t e d t h a t t h i s p r o d u c t p o s s e s s e d the Z  an  a,/9-unsaturated  e x h i b i t e d a broad t r i p l e t  a triplet  to the o l e f i n i c p r o t o n .  o f 116  ( J = 1.1 constant  geometry.  32  Hz,  at 8 J_s _H n  J_s _H n  of  - 43  nMe  3  1. [Me SnCuSPh]Li 3  2  116  THE, -48°C, 4h  -C02Et  ci-  C0 Et  CI  (135)  2.  A  (28)  +-  aq. NH C1  1  4  117  nMe  3  MejSn  ^/C0 Et 2  136 The while  i r spectrum o f 136 e x h i b i t e d the  nmr  trimethylstannyl Me3SnCH.2CH2-  spectrum showed two s i g n a l s  groups.  group.  (5 0.22,  a t 1702  0.12)  Furthermore, a m u l t i p l e t a t 5 0.83  protons i n d i c a t e d that  trimethylstannyl  a carbonyl absorption  This  was  supported  r e s o l u t i o n mass spectrum o f 136 which i n d i c a t e d t h a t  1  due to the due t o  the c h l o r i n e had been r e p l a c e d  conclusion  cm"  by  the  the by a high  the M -CH3 peak had +  a mass c o r r e s p o n d i n g to C j 2 H 2 5 0 2 ^ ^ n • 2  T h i s n u c l e o p h i l i c s u b s t i t u t i o n o f a c h l o r i d e by group  had not been observed p r e v i o u s l y  reactions  the  u  synthetic  modified group  j  n  o r d e r to e l i m i n a t e  route  for  by r e p l a c i n g  preparing  trimethylstannyl  i n our l a b o r a t o r i e s when s i m i l a r  had been c a r r i e d out on h i g h e r homologues  e s t e r 117.^  a  of  the  acetylenic  the u n d e s i r e d s u b s t i t u t i o n the  homoallylic  reaction,  iodide  113  was  the c h l o r i n e atom by a t e r t - b u t y l d i m e t h y l s i l y l o x y  (Scheme 16).  O^CK  nMe;  CO^t  ^C0 Et 2  Scheme 16  139  - 44 -  Reaction of 3-butyn-l-ol  (133) w i t h t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e  i n the p r e s e n c e o f i m i d a z o l e i n dimethylformamide for  12  h a f f o r d e d the alkyne  137 i n 98% y i e l d  at  room  (equation 2 9 ) .  spectrum o f 137 showed a b s o r p t i o n s a t 3300 and 2100 cm" ,  to  r e a c t with e t h y l chloroformate  room temperature f o r 1 h. 90%  yield  2230 and conjugated  1705  cm" , 1  The  resultant  anion  was  a t -20°C f o r 1 h and then a t  The r e q u i r e d pentynoate 138 was  ( e q u a t i o n 30).  The i r  A s o l u t i o n o f the l a t t e r m a t e r i a l 137 i n  THF was t r e a t e d w i t h m e t h y l l i t h i u m a t -78°C. allowed  4 1  i n d i c a t i n g the  1  presence o f a terminal alkyne.  temperature  obtained  in  The i r spectrum o f 138 showed a b s o r p t i o n s a t  indicating  the  presence  of  an  alkyne  and  a  e s t e r c a r b o n y l group, r e s p e c t i v e l y .  TBDMSCl,  imidazole  (29)  DMF  133  1.  C02Et  MeLi, THF  (30)  2. C l C 0 E t 2  Treatment  of  the  pentynoate  nyl) (phenylthio)cuprate 1 3 5  3 9  139 e x h i b i t e d a s i n g l e t a t 6 0.18  presence  of  with  lithium  i n THF a t -40°C f o r 9  workup, the Z e s t e r 139 i n 91% y i e l d of  138  ( e q u a t i o n 31). (J.s -H  a t r i m e t h y l s t a n n y l group.  n  =  h  (trimethylstanafforded,  after  The H nmr spectrum 1  52/54 H z ) , i n d i c a t i n g  the  The o l e f i n i c p r o t o n appeared a t  - 45  nMe3  [Me SnCuSPhjLi  C02Et  \  aq. NH CI  2.  139  8  6.40  as  a  triplet  (J = 1 Hz, Js -H n  c o n f i r m e d the Z geometry o f the showed  singlets  at  5  0.90  ester.  =  1  2  0  H  z  )•  The  3 2  T  ^H  n  e  v a l u e o f l^n-W  nmr  spectrum  also  and 0.04 due t o t h e methyl p r o t o n s o f the  t e r t - b u t y l s i l y l o x y group, c o n f i r m i n g t h a t the e t h e r l i n k a g e was i n t a c t . D i i s o b u t y l a l u m i n u m h y d r i d e r e d u c t i o n o f the -78°C  139  i n THF a t  f o r 1 h and then a t 0°C f o r 1 h p r o v i d e d the a l l y l i c  a l c o h o l 140  i n 96% y i e l d absorption  ( e q u a t i o n 32). at  3350  The i r spectrum  cm"-'-,  a  broad  i n d i c a t i n g the presence o f a hydroxy  group.  The ^H nmr spectrum o f 140 showed a collapsed allylic  to  ^  i  0  /  at  R e a c t i o n o f the a l c o h o l  nMe3  / ^ ^ C 0  triplet  of  140  8  showed  4.08  (J =  6  Hz,  a d o u b l e t on D2O exchange), i n d i c a t i n g t h e p r e s e n c e o f an  a l c o h o l group.  .  ester  2  140  DIBAL-H, THF  with  chloromethyl  .  > > 4 i 0 ^ > ^ 0 H  E t  /  139  <32>  methyl e t h e r i n t h e presence o f d i i s o p r o p y l e t h y l a m i n e i n dichloromethane at  room temperature f o r 12  (equation for  33).  The  h  afforded  the  ether  141  i n 90%  yield  ^H nmr spectrum o f 141 showed a s i n g l e t a t 8 4.63  the a c e t a l p r o t o n s and a s i n g l e t a t 5 3.38 f o r the methoxy  i n d i c a t i n g t h a t the methoxymethoxy group had been  installed.  protons,  - 46 -  SnMe CH 0CH C1 3  2  i,-Pr NEt, CH C1 2  2  The v i n y l s t a n n a n e 141 was at  -78°C.  iodomethane nmr  The  resultant  ->  (33)  >-SiO "  2  /  141  transmetalated with methyllithium vinyllithium  t o g i v e the E o l e f i n 142  reagent  i n 90% y i e l d  was  in  treated  ( e q u a t i o n 34) .  spectrum o f 142 e x h i b i t e d a b r o a d s i n g l e t a t S 1.69  THF with  The  ^H  due t o the v i n y l  m e t h y l group.  The s i l y l this  e t h e r l i n k a g e i n compound 142 was  material  with  tetra-n-butylammonium  fluoride  THF  spectrum o f 143 e x h i b i t e d a b r o a d a b s o r p t i o n a t  3400 cm"  1  due t o the hydroxy group.  p_-toluenesulfonyl  chloride  in  the  R e a c t i o n o f the presence  of  workup  p.- t o l u e n e s u l f onate decomposed  on  and column chromatography 144  heating  in  75%  yield  alcohol  98%  143  yield  with  4-N .N-dimethylamino-  p y r i d i n e i n d i c h l o r o m e t h a n e a t room temperature f o r appropriate  in  room  (Scheme  ir  produced  at  The a l c o h o l  The  was  in  of  temperature f o r 40 min. 17).  143  c l e a v e d by treatment  12  h  gave,  after  o f the crude p r o d u c t , the  (Scheme  17).  This  material  under vacuum and s l o w l y t u r n e d brown on s t o r a g e  - 47  Scheme  under argon i n a f r e e z e r . doublets  at  6  7.83  The  -"-H  17  nmr  spectrum  ( J = 8 Hz) and 7.37  of  144  The  was  113 by treatment  converted  into  the  iodide  p.-toluenesulf onate with  i o d i d e i n dimethylformamide a t room temperature i n the dark f o r (91%  yield,  Scheme  17).  The  m/e  144  sodium 4  days  o v e r a l l y i e l d f o r the s y n t h e s i s o f the  h o m o a l l y l i c i o d i d e 113, based on the s t a r t i n g 42%.  two  ( J - 8 Hz) and a s i n g l e t a t 5  2.48 due t o the p_-toluenesulf onate group. readily  showed  3-butyn-l-ol  (133),  The h i g h r e s o l u t i o n mass spectrum o f 113 showed a m o l e c u l a r 270.0111, c o n s i s t e n t w i t h a formula  was  i o n at  o f C3HJ5O2I.  An attempt t o by-pass the p . - t o l u e n e s u l f o n a t i o n s t e p by c o n v e r s i o n o f the  alcohol  143  d i r e c t l y i n t o the i o d i d e 113 u s i n g  triphenylphosphine  d i i o d i d e gave the d e s i r e d m a t e r i a l 113 i n o n l y 21% y i e l d  ( e q u a t i o n 35).  - 48 -  D.  A l k y l a t i o n o f the n i t r i l e 112 w i t h the i o d i d e 113.  Attempts t o  p r e p a r e compound 145  Treatment o f respectively  a  15:85  mixture  of  the  nitriles  homoallylic  iodide  113  (1.3  g r a d u a l l y warmed t o room temperature. starting nitrile  material, 111  and  112b,  (1 mmol), i n THF a t 0°C w i t h l i t h i u m d i i s o p r o p y l a m i d e  mmol) i n the p r e s e n c e o f HMPA f o r 15 min, was f o l l o w e d the  112a  (0.69  112a  and  112b  mmol;  94%  yield  mmol). Workup  by  addition  (1.2 of  The r e s u l t a n t s o l u t i o n was gave  a  mixture  of  the  (0.23 mmol), the d e s i r e d a l k y l a t e d based  on  recovery  m a t e r i a l ) , and the diene 146 ( e q u a t i o n 36).  146  of  starting  - 49  The  presence o f the diene  in  competition  f u n c t i o n e d not  also  as  iodide  i n d i c a t e d t h a t an e l i m i n a t i o n r e a c t i o n  w i t h the d e s i r e d a l k y l a t i o n process.  anion  a  146  base  o n l y as a n u c l e o p h i l e  that  nmr  e f f e c t e d dehydrohalogenation  compound ( F i g . 1 ) .  m e t h y l g r o u p a p p e a r e d a t 6 1.27, diaxial  to  relative  s t e r e o c h e m i s t r y had  and  the  1.68  nitrile  w e r e due  methyl protons,  group  ^H  due  nmr  Hp)  but  of the h o m o a l l y l i c  and  a t 1671  and  1638  showed  the  The  to the  at  methoxy p r o t o n s The  cm*-'-, i n d i c a t i n g  i t  angular was  w i t h the  singlets  side chain.  that  methyl  t h a t the product  to the a c e t a l protons, the  111  1,3  expected 6  4.62,  and  vinyl  i r spectrum of  111  the presence of  the  the e x o c y c l i c double bond, r e s p e c t i v e l y .  s p e c t r u m o f 146  showed t h r e e s i n g l e t s  a t S 4.65,  3.40  and  t o t h e a c e t a l , methoxy and v i n y l m e t h y l p r o t o n s , r e s p e c t i v e l y ,  a doublet  remaining 1H,  nitrile  of iodide),  s i g n a l s due that  been obtained.  t r i s u b s t i t u t e d d o u b l e bond and The  The  indicating  r e s p e c t i v e l y , on  showed a b s o r p t i o n s  and  (displacement  spectrum of the a l k y l a t e d m a t e r i a l  c o n s i s t e d o f o n l y one  1.80  Thus, the  was  113.  The  3.38  -  a t 5 4.22  signals  J = 7 Hz,  Hg),  indicated  ( J = 7 Hz)  at  5  5.23  the  6.43  (dd,  ( d , 1H,  presence  due  to  1H,  the  -CH 0M0M  J = 11,  17 Hz,  J = 17 Hz, of  a diene  H ), c  protons.  2  5.05  H ), A  ( d , 1H,  u n i t w i t h the  5.63  The (br t ,  J = 11  Hz,  stereochemistry  shown. It  i s evident  produced  a  four c h i r a l been  product centres  correctly  conversion  that  the  111 on  in  synthetic  sequence  w h i c h the r e l a t i v e  discussed  stereochemistry  the d e c a l i n s u b s t r u c t u r e o f p a l a u o l i d e  established.  o f the n i t r i l e  The  next  above of  (55)  r e q u i r e d t r a n s f o r m a t i o n was  group i n t o a methyl  group.  had the had the  - 51 -  When  the n i t r i l e  111 was  room temperature i n benzene, occurred  and  the n i t r i l e  when the r e d u c t i o n was starting  material  treated with diisobutylaluminum hydride at e t h e r , THF o r dimethoxyethane,  111 was  recovered i n t a c t .  On the o t h e r hand,  c a r r i e d out i n benzene a t 80°C f o r 8 h,  was  consumed.  o b t a i n e d , on the b a s i s o f  s p e c t r o s c o p y , a 4:1 mixture o f two aldehydes.  The ^H nmr  t h i s m i x t u r e showed two aldehyde p r o t o n s i g n a l s a t S 9.98 former s i g n a l was the the  structure  nitrile  of  the  No f u r t h e r work was minor component.  i n dimethoxyethane  aqueous 147  due to the major component which was  d e s i r e d aldehyde 147.  a t 60°C  for  i n 87% y i e l d  ( e q u a t i o n 37).  to  the  aqueous  The acid  and 9.93.  imine 148 The  ir  1713  cm"  at  c a r r i e d out t o  determine  F o r t u n a t e l y , r e d u c t i o n o f the 6  h  gave,  after  workup  i n t e r m e d i a t e imine 148 workup,  and  temperature  f o r 12 h.  showed a b r o a d a b s o r p t i o n a t 3254 cm" spectrum  1  room  of  the aldehyde 147  due t o the c a r b o n y l .  In the  The  l a t e r found to be  the  1  The  and  aldehyde  was  rather  aldehyde 147  o b t a i n e d o n l y a f t e r the imine had been s t i r r e d i n an aqueous solution  -^H  spectrum o f  a c i d h y d r o l y s i s o f the crude p r o d u c t , o n l y the d e s i r e d  insensitive  acid  a l l the  A f t e r aqueous workup and aqueous a c i d  h y d r o l y s i s o f the crude p r o d u c t , t h e r e was nmr  no r e d u c t i o n  was  THF-acetic  i r spectrum o f the  due t o the  N-H  group.  exhibited a strong absorption at ^  nmr  spectrum  of  147,  the  - 52 -  1. DIBAL-H, DME,  60°C  148  111  (37)  aldehyde group  proton  gave r i s e  To  appeared  a t 5 9.98  to a singlet at S  as a s i n g l e t and  0.96.  generate the r e q u i r e d methyl s u b s t i t u e n t ,  treated  with  an  under r e f l u x broad  excess  f o r 24 h .  absorption  hydroxide  o f anhydrous  The  at  cm'^,  was  the  149, w h i c h  turned  chromatography  from  colorless  to  147  was  exhibited  allowed to react with  i n d i e t h y l e n e g l y c o l a t 210°C f o r 3 h .  gradually  aldehyde  h y d r a z i n e (10 e q u i v ) i n m e t h a n o l  r e s u l t a n t hydrazone  3250  the angular methyl  dark  The  o f t h e c r u d e p r o d u c t p r o v i d e d two  potassium  reaction  brown.  mixture  Workup and  different  a  oils  column (equa-  t i o n 38) . The were  more  p o l a r c o m p o n e n t was  consistent  material singlets methyl  145.  protons,  at  those  Thus,  a t 6 4.63,  broad s i n g l e t signals  with  and  nmr 1.66  respectively,  a t S 4.51 6  expected  the  3.37  1.05  due  isolated  due  i n 10% y i e l d a n d  for  spectrum  the  desired  of  i t s spectra deoxygenated  this material  t o the a c e t a l , methoxy  on t h e s i d e c h a i n .  and  0.82  (doublet,  vinyl  I t also exhibited  t o the e x o c y c l i c o l e f i n i c p r o t o n s and  (singlet),  showed  J  =  6 Hz),  a  methyl  and  0.74  53  (singlet).  The c h e m i c a l  decalin  substructure  reported  for palauolide  (d,  shifts  of  145  (55)  3H, J = 7 H z ) , a n d 0.74  1 4  were  signals  almost  [ c f . S 4.51  I t e x h i b i t e d an i r band  a t S 6.45  ( d d , 1H, J = 1 0 , 16 H z , H ) , 5.20  (d,  J - 10 H z , H ) , 4.97  vinyl  moiety. ^ 4  This  at  o f a diene  m e t h y l ) i n t h e ^H nmr  with  t h e same a s  ( s , 2H) , 1.05  (s,  3H),  1594  r e d u c t i o n was cm" ,  c o n c l u s i o n was  A  c  exactly  the Wolff-Kishner  presence  1H,  associated  the those 0.82  (s, 3H)].  The l e s s p o l a r p r o d u c t . f r o m i n 45% y i e l d .  o f these  1  indicating  supported  B  D  m a t e r i a l and the  the  by s i g n a l s  ( d , 1H, J = 16 H z , H ) ,  ( b r t , 1H, J - 6 H z , H ) , 1.70  spectrum of t h i s  isolated  ( b r s,  5.04 3H,  - 54 -  disappearance o f the signals methyl 0.82  groups o f the d e c a l i n  (doublet,  similar 145.  (singlet).  analysis  t e m p e r a t u r e was s l o w l y  of aliquots  reaction until  the reaction  less polar  out  material.  in  diethylene  The  3-proton  spectrum o f the leading  to  vinyl diene  this  methyl 150  group  be a c c o u n t e d f o r b y p o s t u l a t i n g  in  which  hydrazone group a b s t r a c t s five-membered  cyclic  i s correct, transition  that  Tic  t h e r e was no  160°C.  Furthermore,  that  a t 5 1.70 i n t h e ^H nmr  the  elimination  regioselective.  an i n t r a m o l e c u l a r  This  reaction  selectivity  reaction  mechanism  carbanion r e s u l t i n g from decomposition o f the an a l l y l i c  transition  competes  p r o t o n from the s i d e  state  i t i s apparent that state  reached  signal  indicated  s u b s t a n c e was h i g h l y  incipient  indicated  base,  simultaneously.  can  the  r a i s e d f r o m 110° t o 180°C.  temperature  were  i n t h e ^H nmr s p e c t r u m o f  carried  of the reaction mixture  b o t h p r o d u c t s 145 a n d 150 a p p e a r e d  cyclic  These c h e m i c a l s h i f t s  150 was a s s i g n e d t o t h i s  o f 147 was  (singlet),  i n t h e presence o f anhydrous potassium carbonate, a m i l d e r  the reaction  ulate  The t h r e e  a p p e a r e d a t 5 1.06  to those o f the corresponding s i g n a l s  Wolff-Kishner reduction  glycol and  substructure  J = 6 H z ) a n d 0.78  Thus, s t r u c t u r e  The  due t o t h e m e t h o x y m e t h o x y g r o u p .  ( s e e Scheme 1 8 ) .  chain I f this  the e l i m i n a t i o n reaction relatively  well  with  via a post-  v i a the  the desired  - 55 -  150  145  Scheme 18  intermolecular protonation glycol  by the  solvent,  diethylene  (Scheme 18).  When  the  hydrazone 149 was t r e a t e d w i t h p o t a s s i u m t e r t - b u t o x i d e i n  dimethylsulfoxide isolated,  In  o f the c a r b a n i o n  an  to c o n v e r t  at  i n 36% y i e l d  room  temperature,  43  only  the  diene  150  was  ( e q u a t i o n 39).  attempt to slow down the e l i m i n a t i o n p r o c e s s , the methoxymethoxy group on the hydrazone 149  i t was to  a  decided hydroxy  - 56 group.  Thus,  the aldehyde  i n dichloromethane (equation 1714 cm" The  1  -41  40).  (-78°C, 1 h) to a f f o r d the a l c o h o l 151 i n The  spectrum  72%  i r spectrum o f 151 showed a b s o r p t i o n s a t  due to the hydroxy nmr  147 was t r e a t e d w i t h d i m e t h y l b o r o n b r o m i d e  of  group  and the c a r b o n y l group,  4 4  yield  3366  and  respectively.  151 e x h i b i t e d a s i n g l e t a t 5 9.98 due to the  aldehyde p r o t o n and a d o u b l e t a t J 4.14  ( J - 8 Hz) due  to  the  ^CCH^OH  protons.  The  aldehyde  151  r e f l u x i n g methanol f o r hydrazone  was a l l o w e d to r e a c t w i t h anhydrous h y d r a z i n e i n 24  h.  However,  treatment  of  the  resultant  w i t h potassium h y d r o x i d e o r potassium carbonate i n d i e t h y l e n e  g l y c o l a t 170°C f o r 3 h a f f o r d e d the diene  150  as  the  only  isolable  product (equation 41).  Since  a l l these  attempts  to  convert  the  aldehyde  147 i n t o the  - 57 b i c y c l i c d i e n e 145 u s i n g the W o l f - K i s h n e r r e d u c t i o n , f a i l e d t o g i v e t h e desired  product  i n synthetically  useful  y i e l d s , other  methods were i n v e s t i g a t e d .  Thus, the aldehyde  lithium  (ether  aluminum  hydride  a l c o h o l 152 (93%, e q u a t i o n 42). absorption  at  solution,  147 room  was  deoxygenation reduced  temperature)  The i r spectrum o f 152 showed  3469 cm" due t o the hydroxy 1  group.  a  12  Hz)  due  ( J = 12 Hz) on  D2O  exchange.  These  positive  enhancement  in a  nuclear  Overhauser  was  i n which the s i g n a l  irradiated.  broad  1  (J =  t o t h e -CH2OH p r o t o n s , and each o f them c o l l a p s e d t o a  doublet  experiment  t o the  The H nmr spectrum  o f 152 e x h i b i t e d a p a i r o f d o u b l e t o f d o u b l e t s a t S 3.80 and 3.70 6,  with  This  signals  also  showed  enhancement d i f f e r e n c e  (5 1.06) due t o the a n g u l a r methyl  experiment  confirmed  a  group  the e x p e c t a t i o n t h a t the  -CH2OH and a n g u l a r methyl groups a r e i n 1,3 d i a x i a l r e l a t i o n s h i p i n the a l c o h o l 152.  The and  alcohol  the l a t t e r  conditions. in  152  substance  was  subjected  t o Barton's  deoxygenation  Thus, s u c c e s s i v e treatment o f a s o l u t i o n o f t h e a l c o h o l 152  dimethylformamide  disulfide,  was c o n v e r t e d i n t o the c o r r e s p o n d i n g xanthate 153  with  1,8-diazabicyclo[5.4.0]undec-7-ene,  carbon  and iodomethane a f f o r d e d , a f t e r column chromatography o f the  crude p r o d u c t on s i l i c a g e l , the xanthate  153  (100%,  equation  43).  4 5  - 58 -  The  -"-H nmr  spectrum o f 153 high  showed a s i n g l e t a t 8 2.57  protons.  The  r e s o l u t i o n mass spectrum o f 153  i o n a t m/e  440.2410, c o n s i s t e n t w i t h a formula  F o l l o w i n g the c o n d i t i o n s n o r m a l l y tion, ^  a  hydride  in  4  refluxed 153 and  was  toluene the  for  solution  presence  4 h.  recovered  of  of  4  s o l u t i o n of solution  be  of  the  and  in  t h a t the n e o p e n t y l  hydride  corresponding  the s o l u t i o n  reported  deoxygenated  tri-n-butyltin  conditions, hydride  can  contains  that  deoxygena-  tri-n-butyltin  the  both  was  xanthate Barton -' 4  o f some p r i m a r y a l c o h o l s  that  is  added  xanthates a  sterically  efficiently  very  the case o f our xanthate r a d i c a l 154  molecular  deoxygenation.  R e c e n t l y , B a r t o n e t a l . - * have alcohols  and  o c c u r r e d and  4  primary  showed a  Barton  153  I t i s p e r t i n e n t to note  to undergo the d e s i r e d  -SCH3  the  2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e (AIBN)  F r a s e r - R e i d ^ have r e p o r t e d t h a t x a n t h a t e s  failed  of  for  xanthate  However, no deoxygenation  intact.  to  o f £24^40^2^3•  employed  the  due  low 153,  when  a  p.-cymene  to  a  Q-cymene  slowly at  hindered  150°C.  Under  concentration  these of  tin  i t i s certainly possible  formed would c y c l i z e onto the double bond  the s i d e c h a i n b e f o r e i t would a b s t r a c t a hydrogen atom from the t i n  hydride. compounds  Nevertheless, was  the r e a c t i o n was  obtained.  On  the  c a r r i e d out and  basis  of  ^H nmr  a  mixture  of  spectroscopy,  the  - 59 -  154 m i x t u r e c o n s i s t e d o f a t l e a s t f o u r compounds w h i c h w e r e n o t s e p a r a b l e b y column chromatography  on s i l i c a  gel.  No  f u r t h e r w o r k was  c a r r i e d out to  d e t e r m i n e t h e s t r u c t u r e o f t h e s e compounds. More  recently,  Robins et a l . * *  reported that phenylthionocarbonate  4  e s t e r s o f a l c o h o l s u n d e r g o d e o x y g e n a t i o n more r e a d i l y ponding  xanthates.  Furthermore,  the  than  the  deoxygenation reaction could  c a r r i e d o u t i n t h e p r e s e n c e o f an e x c e s s o f t i n h y d r i d e .  Thus,  felt  154,  that, under.these conditions,  formed, might Treatment acetonitrile  a b s t r a c t a hydrogen o f t h e a l c o h o l 152  the neopentyl r a d i c a l  from n-B^SnH r a t h e r than with  phenoxythiocarbonyl  i n the presence of 4-N N-dimethylaminopyridine  thionocarbonate  >  155  (40%,  equation  e x h i b i t e d a n a b s o r p t i o n a t 1729  cm" . 1  corres-  44).  The  The  nmr  i r  i t  be was  i f i t was cyclize.  chloride  in  p r o v i d e d the  spectrum  s p e c t r u m o f 155  of  155  showed  - 60 -  a 2-proton  triplet  a t 8 7.40  ( J = 8 Hz), a 1-proton  = 8 Hz), and a 2-proton d o u b l e t a t 8 7.40 group, been  indicating  that  triplet  (J = 8 Hz)  the p h e n y l t h i o n o c a r b o n a t e  due  a t 8 7.27  to  the  phenyl  f u n c t i o n a l group had  installed. R e a c t i o n o f the t h i o n o c a r b o n a t e 155 w i t h t r i - n - b u t y l t i n h y d r i d e  equiv.,  0.41  M  solution  i n t o l u e n e ) i n the presence  i n i t i a t o r ) a t 70°C f o r 3 h a f f o r d e d c l e a n l y , the methyl  The 10 Hz)  e t h e r 156  -"-H nmr  at  spectrum  o f 156  o f 156  (J = 10 Hz)  8  but  o f AIBN  rather  (10  (radical  surprisingly,  (75%, e q u a t i o n 45).  spectrum  and 3.21  singlets  C  (J  3.38  showed a p a i r o f d o u b l e t s a t 8 3.39  due  to the MeOCH C< p r o t o n s and two  3-proton  2  and 3.74  due  to the two methoxy groups.  showed a m o l e c u l a r i o n  consistent  with  a  (J =  The mass  formula  of  23 40°3H  The  formation  of  156  can  postulated reaction  mechanism  Recently,  et  Beckwith  the deoxygenation O-alkyl-S-methyl  al.  4 9  be of  rationalized Barton  species,  dithiocarbonate(xanthate)  has  of  alcohols.  have g a t h e r e d e v i d e n c e t h a t suggests  proceeds v i a the f o l l o w i n g pathway:  which  the b a s i s o f the  deoxygenation  157  r a d i c a l a f f o r d s an a l k o x y t h i o c a r b o n y l r a d i c a l 158 latter  on  been  detected  with  Reaction a  of  that an  trialkyltin  (see Scheme 19).  by e l e c t r o n s p i n  The  resonance  - 61 -  s (1)  R>sn  ROCSMe  ——•  ROC=S  157  R SnSMe 3  158 slow  (2)  +  ^-fission  R0C=S  •  R-  158  +  COS  159  160  R"SnH 3  (3)  R-  •  159  Scheme  spectroscopy  undergoes  hydride If 155 the was  to give this  the alkane  mechanism  w i t h n-B^SnH, the  161  (Scheme  operates substrate  carried  n-B^SnH  out  thioacetal  M),  the  ( t o g i v e 163)  corresponding  159  alkyl  radical  would a f f o r d  rather radical  165,  the  162  converted  ( s e e Scheme 2 0 ) .  than 164.  secondary, t e r t i a r y  and  156  undergo  166,  thionocarbonate initially  Since  high  (slow)  the  into  reaction  concentration  ^-fission  reduction  and  (Scheme  o f 163  the a l k o x y a l k y l  of from  to  the  via  the  radical  20).  that irradiation  some h i g h l y h i n d e r e d  hexamethylphosphoramide s o l u t i o n  and  trialkyltin  c o u l d a b s t r a c t a h y d r o g e n atom  Further  thioacetal  P e t e e t a l . -*Q h a v e r e p o r t e d  with  159  19).  w o u l d be  162  the methyl ether  alkyl radical  i n the r e a c t i o n o f our 155  radical  3  reacts  i n the presence o f a r e l a t i v e l y  (0.4  R Sn-  t o g i v e an  alkyl radical  alkoxythiocarbonyl radical  n-B^SnH  167  The  +•  161  19  slow /3-fission  c a r b o n o x y s u l f i d e 160.  RH  of acetates  alcohols i n  with ultraviolet  light  a (254  of  primary,  5%  aqueous  nm)  at  room  - 62 -  Scheme 20  - 63 -  temperature g i v e s products.  The  good t o e x c e l l e n t y i e l d s o f the radical  mechanism  they  propose  s i m i l a r t o t h a t o f B a r t o n deoxygenation. w i t h a c e t i c anhydride i n p y r i d i n e pyridine  The due  (catalyst) afforded  group.  f o r t h i s process i s  i n the presence o f 4-N,N-dimethylamino-  the a c e t a t e  The  deoxygenated  Treatment o f the a l c o h o l 152  168 (95%, e q u a t i o n 4 6 ) .  i r spectrum o f 168 e x h i b i t e d a s t r o n g  t o the c a r b o n y l  desired  absorption  at  1741  cm"  1  nmr spectrum o f 168 showed a 3-proton  s i n g l e t a t 8 2.06 due t o the a c e t y l p r o t o n s , i n d i c a t i n g t h a t the a c e t a t e had  been formed. However,  when  the  deoxygenation c o n d i t i o n s  acetate  168  described  was  subjected  above f o r 3 h,  no  t o the p h o t o l y t i c reaction  occurred  (tic analysis). Since  a l l of  the  above-described  attempts  to  deoxygenate  a l c o h o l 152 f a i l e d t o g i v e u s e f u l y i e l d s o f the d e s i r e d m a t e r i a l was  decided  Ireland's and  to  investigate  procedure,-'  2  the  Ireland  deoxygenation.  the a l c o h o l 152 was t r e a t e d  with  the  145,  i t  Following  n-butyllithium  b i s ( d i m e t h y l a m i n o ) p h o s p h o r o c h l o r i d a t e i n a 4:1 m i x t u r e o f dimethoxy-  ethane and N,N,N',N'-tetramethylethylenediamine (TMEDA) a t room temperature  f o r 12  material  was  h.  However,  recovered.  no  reaction  L i u et  al.-*  3  took  place  and the s t a r t i n g  have  reported  the  use  of  - 64 -  dimethylaminophosphorodichloridate highly hindered alcohols. mixture  of  h  phosphorodiamidates  and  TMEDA  was  4:1  treated successively  with  and then w i t h anhydrous dimethylamine  Column chromatography o f the crude p r o d u c t on s i l i c a  the phosphorodiamidate  The 5 2.69  i  H  nmr  and  spectrum  2.66  phosphorodiamidate  due  169  of  in a  f o r 30 min and d i m e t h y l a m i n o p h o s p h o r o d i c h l o r i d a t e  a t room temperature,  2 h.  prepare  Thus, a s o l u t i o n o f the a l c o h o l 152  dimethoxyethane  n-butyllithium  to  for  12  a t 0°C f o r  gel  provided  (71%, e q u a t i o n 47).  o f 169 to the  e x h i b i t e d two b r o a d 6-proton 0 -P(NMe2)2  group had been  protons,  s i n g l e t s at  indicating  that  the  installed.  R e a c t i o n o f 169 w i t h a s o l u t i o n o f l i t h i u m i n anhydrous ethylamine i n the p r e s e n c e reduction o f 170  o f t e r t - b u t y l a l c o h o l a t 0°C  product  170  i n 75% y i e l d  showed a q u a r t e t a t S 5.16  f o r 30 min a f f o r d e d  ( e q u a t i o n 48).  ( J = 7 Hz)  due  The  the  nmr  t o the o l e f i n i c 1.58  4.50  over-  spectrum proton  - 65 in  the  side  chain,  a  broad doublet  a t 6 1.55  ( J = 7 Hz) and a b r o a d  s i n g l e t a t 6 1.58 due t o the v i n y l methyl groups. with  the  present,  and  ether  linkage  had  ( s , 3H), 0.82  (d, 3H, J = 6 H z ) , 0.74  the same as those r e p o r t e d 3H),  been  cleaved.  the c h e m i c a l s h i f t s o f the s i g n a l s due t o the o l e f i n i c  the methyl groups on the d e c a l i n p o r t i o n o f 170  1.05  0.82  along  f a c t t h a t resonances due to the methoxymethoxy group were n o t  i n d i c a t e d t h a t the a l l y l i c  However,  These s i g n a l s ,  f o r palauolide  (d, 3H, J - 7 Hz), 0.74  the r e l a t i v e s t e r e o c h e m i s t r y  [6  (s,  ( s , 3H)] were almost  (55) [S 4.51  (s, 3 H ) ] .  4.50  protons 2H),  exactly  ( s , 2H), 1.05 ( s ,  These d a t a i n d i c a t e d t h a t  1 4  o f the d e c a l i n s u b s t r u c t u r e  o f 170 was  the  same as t h a t o f p a l a u o l i d e ( 5 5 ) .  4.51  In  an attempt t o a v o i d the r e d u c t i v e  c l e a v a g e o f the methoxymethoxy  group, the r e a c t i o n o f the phosphorodiamidate 169 lithium  with  a  of  i n e t h y l a m i n e i n the presence o f t e r t - b u t y l a l c o h o l was c a r r i e d  out  a t -48°C and was quenched p r e m a t u r e l y a f t e r 15 minutes.  of  the  starting  material  A  mixture  161 and a new compound was o b t a i n e d .  The ^H  nmr spectrum o f the l a t t e r m a t e r i a l showed t h a t group  solution  the  phosphorodiamidate  was i n t a c t w h i l e the methoxymethoxy group had been c l e a v e d .  suggested that occurring  reductive  preferentially  cleavage to  the  of  the  reductive  methoxymethoxy  group  This was  removal o f the phosphoro-  - 66 -  d i a m i d a t e group. I n an attempt to a v o i d the  side chain,  the  l o s s o f the a l l y l i c  the a c e t a l l i n k a g e  on 169  was  d i n g a l c o h o l 171.  I t was  hoped t h a t , d u r i n g  alcohol  function  would  exist  would be  less susceptible  group.  Thus, the phosphorodiamidate 169  bromide  a l c o h o l 171  The The the  (65%,  to r e d u c t i v e  ir nmr  equation  spectrum  olefinic  proton  side chain,  to the "CCH^OH p r o t o n s , and  Hz)  and  Treatment  of  171  due with  two  170  the  (equation  i r and 50).  ^H nmr  corresponthe  therefore,  methoxymethoxy  t r e a t e d with dimethylboron h  to  afford  the  allylic  to the  a t 3350  ( J •= 7 Hz)  a d o u b l e t a t S 4.13  6-proton d o u b l e t s a t 6 2.66  cm" . 1  due  to  (J = 7 (J  Hz) =  4  -P0(NMe )2 p r o t o n s . 2  a s o l u t i o n o f l i t h i u m i n e t h y l a m i n e i n the  p r e s e n c e o f t e r t - b u t y l a l c o h o l a t 0°C product,  and,  c l e a v a g e than the was  on  reduction process,  showed a t r i p l e t a t 6 5.40  i n the  ( J = 4 Hz)  to the  e x h i b i t e d a broad absorption  due  2.64  the  function  49).  o f 171  spectrum o f 171  cleaved  l a r g e l y as an a l k o x i d e  i n dichloromethane a t -78°C f o r 1  4 4  oxygen  also  led  to  an  over-reduction  s p e c t r a o f which were i d e n t i c a l w i t h t h a t  of  - 67 -  E.  A l k y l a t i o n o f the n i t r i l e t h e a.ft-unsaturated  Of it  the  various  -CH2OH  yield.  d e o x y g e n a t i o n methods t r i e d  (see p r e v i o u s  I r e l a n d d e o x y g e n a t i o n was  group  on  the  capable  C l e a r l y this undesired  b o n d was  modified  to the  be  stereoselective.  phosphorodiamidate  deoxygenation. a l d e h y d e 107  following plan  substance  would  be  Conversion  174,  expected  followed to  to the  s i d e r e a c t i o n c o u l d be  i n s t a l l e d a f t e r the  according  of  section),  of  reducing  synthetically  side chain attached  expected t h a t a l k y l a t i o n of the n i t r i l e  the  Preparation  107  p l a n t o c o n s t r u c t t h e a,0-unsaturated  would  i o d i d e 172.  group t o a m e t h y l group i n a c l e a n and  alkoxy  structure.  was  the  However, t h i s method a l s o r e s u l t e d i n r e d u c t i v e c l e a v a g e  allylic  double  with  aldehyde  appeared t h a t o n l y the  the  112  112  afford  avoided  Thus, the  synthetic  Scheme 2 1 ) .  w i t h the  alkyl  reduction the  of  the  i f the  from the n i t r i l e  (see  cleanly  of  d e c a l i n sub-  112  It  iodide  of the r e s u l t a n t product by  useful  the ether  173  was 172 into  latter 175.  A  - 68 -  Scheme 21  - 69 -  s t r a i g h t f o r w a r d sequence o f r e a c t i o n s would e f f e c t into  the  anion o f  methyl a  ketone  trialkyl  a,/S-unsaturated  176.  R e a c t i o n o f the l a t t e r m a t e r i a l w i t h the  phosphonoacetate  ester  was  expected  177 as the major p r o d u c t .  the e s t e r 177 would g i v e the d e s i r e d aldehyde worked  very  well  and  the c o n v e r s i o n o f 175  i t s execution  is  to  Finally,  107.  give  E  reduction of  Indeed,  described  the  this  plan  i n the f o l l o w i n g  paragraphs. Reaction o f 3-chloro-1-propanol in  the  presence  of  (178) w i t h c h l o r o m e t h y l methyl  diisopropylethylamine  3-chloro-l-methoxymethoxypropane 179 ( 8 0 % ) .  ether  i n dichloromethane Treatment  of  the  gave latter  m a t e r i a l w i t h sodium i o d i d e i n acetone  a t 60°C i n the dark f o r 30 h gave  3-iodo-l-methoxymethoxypropane  in  Vigorous  reflux  of  the  (172)  reaction  70%  mixture  yield  (equation  51).  5 4  l e d t o a low y i e l d o f the  i o d i d e 172 and the f o r m a t i o n o f s i d e p r o d u c t s .  CH 0CH C1 3  2  i-Pr NEt, CH C1  U  2  2  2  178  179 Nal,  179  60°C  acetone  The 3.40 at  • H nmr spectrum L  •  172  o f 172 e x h i b i t e d two s i n g l e t s a t 5  due t o the a c e t a l and methoxy p r o t o n s , r e s p e c t i v e l y .  S 3.60 ( J = 6 Hz) and 3.30 ( J = 6 Hz) were due t o the  -CH I 2  protons,  respectively,  (51)  l^s^O^O'  4.63  and  5  The t r i p l e t s -CH CH 02  2  and  and the q u i n t e t a t 5 2.05 ( J = 6 Hz) was  - 70 -  due t o the -CH2CH2CH2- p r o t o n s . A  15:85  mixture  of  the n i t r i l e s  112a and 112b, r e s p e c t i v e l y ,  was  t r e a t e d w i t h l i t h i u m d i i s o p r o p y l a m i d e i n THF a t 0°C i n the  presence  of  hexamethylphosphoramide.  followed  by  stirring  Addition  o f the r e s u l t a n t s o l u t i o n  temperature  for  ( e q u a t i o n 52).  1  h,  gave  at  the 0°C  iodide for  alkylated  30  nitrile  G l c a n a l y s i s and ^H nmr s p e c t r o s c o p y  one a l k y l a t i o n p r o d u c t had been  112a  the  of  172, min  and  at  room  173 i n 99% y i e l d showed  that  only  formed.  173  112b  15:85  The  i r spectrum o f 173 showed a b s o r p t i o n s a t 2228 and 1638 cm"  to the n i t r i l e spectrum  group and the e x o c y c l i c o l e f i n ,  o f 173 e x h i b i t e d  respectively.  nitrile  function.  (Note  acetal  protons  and  The ^H nmr  one  relationship  to  t h a t the a n g u l a r methyl p r o t o n s o f 112a  and 112b appeared a t 5 1.24 and 0.96, r e s p e c t i v e l y ) . the  due  a s i n g l e t a t S 1.27 due t o the a n g u l a r methyl  group, i n d i c a t i n g t h a t t h i s group was i n a 1,3 d i a x i a l the  1  of  the  The s i g n a l s due to  o l e f i n i c p r o t o n s o v e r l a p p e d and  appeared a t S 4.59. F o l l o w i n g the p r o c e d u r e s developed e a r l i e r f o r the t r a n s f o r m a t i o n o f the  nitrile  111  into  the phosphorodiamidate  169, the n i t r i l e  c o n v e r t e d i n t o the c o r r e s p o n d i n g phosphorodiamidate.  173 was  71 -  Thus, d i i s o b u t y l a l u m i n u m dimethoxyethane of  at  the r e s u l t a n t  hydride  reduction of  the  nitrile  173  in  60°C f o r 6 h, f o l l o w e d by a c i d c a t a l y z e d h y d r o l y s i s  product,  provided  the  aldehyde  180  in  85%  yield  (equation 53).*  The  ir  spectrum  o f 180 e x h i b i t e d a s t r o n g a b s o r p t i o n a t 1713  due t o the c a r b o n y l group.  nmr spectrum 180 showed a s i n g l e t  The  8 9.53 due t o the aldehyde p r o t o n , the secondary methyl p r o t o n s , methyl The lithium  a d o u b l e t a t 6 1.02  cm"  1  at  ( J = 6 Hz) due to  and a s i n g l e t a t 5 0.98 due to the a n g u l a r  protons. aldehyde 180 was t r e a t e d w i t h an e t h e r e a l s o l u t i o n - s u s p e n s i o n o f aluminum  hydride  at  room  temperature.  After  An attempt t o deoxygenate the aldehyde 180 u s i n g the reduct ion f a i l e d . No d e s i r e d p r o d u c t was i s o l a t e d .  workup,  the  Wolff-Kishner  - 72 -  alcohol  181  was  o b t a i n e d i n 91% y i e l d  ( e q u a t i o n 54).  o f 181 e x h i b i t e d a broad a b s o r p t i o n a t 3462 cm" group.  The  nmr spectrum  (J «= 12 Hz) and S 3.70  aminophosphorodichloridate. anhydrous dimethylamine of  hydroxyl  2  mixture  of  at  53  0°C  The  at  and  room  dimethyl-  r e s u l t a n t s o l u t i o n was t r e a t e d w i t h  for  2  h.  After  workup  the crude product on s i l i c a g e l , the  date 174 was o b t a i n e d i n 88% y i e l d  dimethoxyethane  respectively,  was t r e a t e d s u c c e s s i v e l y w i t h n - b u t y l l i t h i u m  chromatography  the  ( J = 12 Hz) due t o the -CH 0H p r o t o n s .  N,N,N',N'-tetramethylethylenediamine,  temperature,  to  o f 181 showed a p a i r o f d o u b l e t s a t 5 3.78  A s o l u t i o n o f the a l c o h o l 181 i n a 4:1 and  due  1  The i r spectrum  and  column  phosphorodiami-  ( e q u a t i o n 55).  0  The 4.00  • H nmr spectrum  (J  protons.  L  -  4,  12  Hz)  o f 174 showed a p a i r o f d o u b l e t o f d o u b l e t s a t 6 and  6 3.95 ( J = 4, 12 Hz) due to the -CH 0P0-  I t a l s o showed a p a i r o f d o u b l e t s a t 5 2.66  2  (J  =  4  Hz)  and  - 73 2.64  (J  = 4 Hz) due t o the -PO(NMe2)2 p r o t o n s , i n d i c a t i n g the presence  o f the phosphorodiamidate The phosphorodiamidate Reaction  group. 174 was s u b j e c t e d t o  o f 174 w i t h an anhydrous  Ireland  deoxygenation.  ethylamine s o l u t i o n o f l i t h i u m i n the  p r e s e n c e o f t e r t - b u t y l a l c o h o l a t 0°C f o r 10 min-*  2  gave a 1:1 m i x t u r e o f  the d e s i r e d deoxygenated m a t e r i a l 175 and an o v e r - r e d u c e d p r o d u c t 182 i n which the carbon-carbon double bond on also 2:1, min.  been reduced ( e q u a t i o n 56).  the  bicyclic  substructure  had  The r a t i o o f p r o d u c t s was improved t o  i n f a v o u r o f 175, when the r e a c t i o n was c a r r i e d o u t a t -10°C f o r 5 T h i s experiment suggested t h a t the phosphorodiamidate  be reduced s e l e c t i v e l y under s u i t a b l e c o n d i t i o n s . ethylamine  solution  of  lithium  was  s e l e c t i v i t y improved t o 25:1 i n f a v o u r However,  when  this  s e l e c t i v i t y dropped.  reaction  was  employed of  carried  the  When  a  group more  could dilute  f o r the r e a c t i o n , the desired  material  175.  out on a l a r g e r s c a l e , the  F o r t u n a t e l y , when the r e d u c t i o n was c a r r i e d o u t i n  (56)  182  174  - 74 -  anhydrous  methylamine i n the absence o f t e r t - b u t y l a l c o h o l a t -20°C f o r  10 min, the phosphorodiamidate group was reduced s e l e c t i v e l y and 175 was o b t a i n e d i n 81% y i e l d The to  ir  (equation 5 7 ) .  spectrum o f 175 showed a b s o r p t i o n s a t 1636 and 891 cm"  the e x o c y c l i c double bond.  exhibited  The  nmr  spectrum  of  175  6 Hz) due t o the methyl s u b s t i t u e n t s on the b i c y c l i c moiety.  methyl p r o t o n s (8 0.73) was p r o b a b l y due t o the  due  ( F i g . 2)  two s i n g l e t s a t 8 1.04 and 0.73, and a d o u b l e t a t 8 0.80  C-5 a n g u l a r methyl p r o t o n s appeared a t lower f i e l d  1  That  (J = the  (8 1.04) than the C-9  fact  that  the  former  e x p e r i e n c e d a d e s h i e l d i n g a n i s o t r o p i c e f f e c t from the a d j a c e n t e x o c y c l i c olefin. at  The ^H nmr spectrum o f 175 a l s o showed t h r e e  (br d, 1H, J = 12 H z ) .  another  and  were  well  d e c o u p l i n g experiment,  H  These s i g n a l s  separated  from  did the  i r r a d i a t i o n a t 8 4.49  s i g n a l a t 8 2.28 t o sharpen.  s i g n a l was due t o an a l l y l i c J  overlap  with  remaining s i g n a l s . protons)  one In a  caused  T h i s r e s u l t suggested t h a t the l a t t e r  p r o t o n , and based on i t s appearance  (br d t ,  On i r r a d i a t i o n o f p r o t o n  a t 8 2.28, the b r o a d d o u b l e t a t 8 2.09 became a b r o a d s i n g l e t and was  therefore the  not  (olefinic  = 5 , 13.5 H z ) , i t was a s s i g n e d t o p r o t o n A. A  signals  6 2.28 (br d t , 1H, J = 5, 13.5 Hz), 2.09 ( b r d, 1H, J = 13.5 Hz), and  1.87  the  distinct  assigned  to  p r o t o n B.  I r r a d i a t i o n of proton H  b r o a d d o u b l e t a t 8 1.87 t o sharpen and,  assigned  to  HQ.  thus,  this  A  a l s o caused  resonance  The ^H nmr s p e c t r a o f o t h e r compounds i n t h i s  was  series  e x h i b i t e d s i m i l a r s i g n a l s i n the r e g i o n 8 2.3-1.8 and these s i g n a l s were assigned  on  the  basis  of  the  compound 175, as d e s c r i b e d above.  d e c o u p l i n g experiments c a r r i e d out on  - 76 -  A  pure  sample  of  the o v e r - r e d u c t i o n p r o d u c t 182 was o b t a i n e d by  treatment  o f t h e phosphorodiamidate  solution  o f l i t h i u m i n t h e presence  min  174  with  an  anhydrous  ethylamine  o f t e r t - b u t y l a l c o h o l a t 0°C f o r 20  (equation 58).  The  i r spectrum  o f t h e o v e r r e d u c t i o n p r o d u c t 182 d i d n o t  show t h e  characteristic  absorptions  a t -1635 and -890 cm"-*- due t o t h e e x o c y c l i c  olefin.  The  nmr spectrum  o f 182 e x h i b i t e d two d o u b l e t s a t 8 0.78 and  5  due t o t h e secondary methyl p r o t o n s , and two s i n g l e t s a t 5 0.77  0.73  and 8 0.70 due t o t h e t e r t i a r y methyl p r o t o n s . assumed reduction The  to  be  i n an  equatorial  u s u a l l y lead to the  orientation  thermodynamically  h i g h r e s o l u t i o n mass spectrum  The C-4 methyl  group was  s i n c e d i s s o l v i n g metal more  stable  product.  o f 182 showed a peak a t m/e 296.2707,  c o r r e s p o n d i n g t o the m o l e c u l a r i o n w i t h a formula o f C19H36O2. Treatment  o f 175 w i t h p y r i d i n i u m  p.-toluenesulf onate  i n tert-butyl  alcohol  at  3 3  Vigorous  70°C  to  The  the  the  h gave the a l c o h o l 183  i n which the o l e f i n i c double bond had  i r spectrum o f 183  hydroxyl  exocyclic  The  12  showed a broad  59).  the  cm~^  due  891  cm'^  due  to  the  chlorochromate  in  olefin.  a l c o h o l 183,  presence  spectrum  and  of  of  upon o x i d a t i o n w i t h  anhydrous  184  c a r b o n y l group. ( J = 2 Hz)  sodium  pyridinium  acetate  showed The  due  nmr  a  strong  dichloromethane  (99%, e q u a t i o n  a b s o r p t i o n a t 1728  spectrum o f 184  to the aldehyde  in  exhibited  60).  cm'^  a  (room The i r  due  to the  triplet  o f e p i m e r i c a l c o h o l s 185  at  S  proton.  R e a c t i o n o f the aldehyde 184 w i t h m e t h y l l i t h i u m i n e t h e r a t 0°C a mixture  of  isomerized into  a b s o r p t i o n a t 3319  group and a b s o r p t i o n s a t 1635  temperature, 1 h ) , a f f o r d e d the aldehyde 184  9.74  (91%, e q u a t i o n  r e f l u x o f the r e a c t i o n s o l u t i o n l e d to a s i g n i f i c a n t amount  a s i d e product ring.  for  (see e q u a t i o n 61).  The  ir  gave  spectrum  - 78 -  o f the l a t t e r m a t e r i a l showed a b r o a d s b s o r p t i o n a t 3349 cm" hydroxy group. at  m/e <  with  corresponding  Subsequent  )  pyridinium  to  o x i d a t i o n o f the m i x t u r e o f e p i m e r i c  chlorochromate  in  (from  the  aldehyde  184)  the  H  1  nmr  spectrum  of  peak  1  alcohols  185  p r e s e n c e o f sodium a c e t a t e i n  (equation  e x h i b i t e d a s t r o n g a b s o r p t i o n a t 1718 cm" The  a  a molecular i o n with a formula o f  d i c h l o r o m e t h a n e p r o v i d e d the methyl ketone 176 i n an 97%  due t o the  The h i g h r e s o l u t i o n mass spectrum o f 185 showed  264.2455,  C^8^32 - -  1  61).  overall  yield  of  The i r spectrum o f 176  due to  the  carbonyl  group.  176 e x h i b i t e d a s i n g l e t a t 5 2.13 due to the  -COCH3 p r o t o n s , i n d i c a t i n g the p r e s e n c e o f a methyl ketone. I t s h o u l d be n o t e d t h a t the ketone 176 has been p r e p a r e d et  al.-*6  nmr  and  by  Sharma  v i a a r o u t e v e r y d i f f e r e n t from t h a t d e s c r i b e d above. ir  spectroscopic  data  reported ^  for  5  this  The  material  1  H  were  i d e n t i c a l w i t h those d e r i v e d from our m a t e r i a l . It  is  w e l l - known  t h a t under s u i t a b l e c o n d i t i o n s , treatment o f an  unsymmetrical ketone w i t h the s a l t o f a phosphonoacetate g i v e s the t r a n s ester  as  Atmol)  with  temperature  the  major product.^7  [Et0 CCHPO(OEt) ]K 2  for  2  15  h  +  Indeed, r e a c t i o n o f the ketone 176 (65 (0.7  provided,  mmol)  in  THF  (3  mL)  at  i n nearly quantitative yield,  m i x t u r e o f 177 and i t s geometric isomer 186.  These  two  products  room  a 10:1 were  - 79 -  2.14  readily  separable  Both the cm"l 177, 2.14  due  i r s p e c t r a o f 177  the v i n y l methyl protons J  hand, the  ^H  at  and  = 1.5 nmr  Hz)  and  and  5 2.32  s p e c t r u m o f 186  ( J - 5,  experience  12 Hz)  protons.  d o u b l e b o n d as  the  The  Since  the  and 5  4.12  I n the  nmr  -CH.2(CH3)C= p r o t o n s  (J  the a l l y l i c in  protons  an  12 on  Hz)  the  the Z  was  assigned  S  On  the  other  ( J = 1.3 of  Hz)  triplets  due  to  the  same s i d e o f  a,/3-unsaturated  ester  the E s t e r e o c h e m i s t r y ,  while  the  would  carbonyl 186  was  stereochemistry.  a,/?-unsaturated i n THF  e s t e r 177,  upon treatment  a t -78°C f o r 1 h  a l c o h o l 187  group.  ( J = 8 Hz)  1718  appeared at  a t 5 1.85  5,  at  of  respectively.  =  62).  spectrum  a p a i r of broad doublets  2.24  group  gel (equation  e x h i b i t e d an a b s o r p t i o n  showed a d o u b l e t  i n 98%  yield  and  The due  ^H  nmr  0°C  2  with diisobutylalumi2 The  i n d i c a t i n g the  s p e c t r u m o f 187  t o t h e =CCH 0H  for  (equation 63).  s h o w e d a b r o a d a b s o r p t i o n a t 3327 cm'^ hydroxyl  silica  an a n i s o t r o p i c m a g n e t i c d e s h i e l d i n g e f f e c t f r o m t h e  hydride  allylic  and  ester  g r o u p , compound 177 assigned  186  6 2.02-1.78 (m),  to the v i n y l methyl protons  -CFJ2(CH3)C=  num  c o l u m n c h r o m a t o g r a p h y on  t o the c a r b o n y l group o f the e s t e r .  (d,  due  by  1.85  protons.  h,  afforded  i r spectrum of presence  the 187  of  the  e x h i b i t e d a doublet  at 6  - 80 -  Manganese(IV) oxide o x i d a t i o n o f the a l c o h o l 187 the  key  intermediate,  ( e q u a t i o n 64). cm"  due  1  The  doublet  a t 8 9.97 at  a.^-unsaturated  i r spectrum o f 107  to the c o n j u g a t e d  showed a d o u b l e t broad  the  5  5.86  aldehyde 107,  (J = 8 Hz)  due  The  nmr  yield  at  1676  spectrum o f  to the aldehyde p r o t o n  due  provided  i n 88%  e x h i b i t e d an a b s o r p t i o n  c a r b o n y l group.  ( J - 8 Hz)  i n hexane  and  to the o l e f i n i c p r o t o n on  107 a the  s i d e c h a i n ( F i g . 3).  F.  S y n t h e s i s o f the phosphonium s a l t  Recently,  188  Katsumura e t a l . ° r e p o r t e d a v e r y e f f i c i e n t  7-hydroxybutenolides  by  photosensitized  oxygenation  of  synthesis  of  substituted  - 82 -  2-trimethylsilylfurans.  For  example  the  transformed r e a d i l y i n t o the butenolide  silylfuran  189a  190a i n 91% y i e l d  could  (equation 65).  I t was e x p e c t e d t h a t the phosphonium s a l t 188 c o u l d be s y n t h e s i z e d the  chloro  butenolide  109,  and  that  the  latter  p r e p a r e d from 4 - c h l o r o m e t h y l - 2 - t r i m e t h y l s i l y l f u r a n  .  X  ^  O  S  i  —  MejSl^^so^  al.  5 9  steps (189)  ,  the  (110) (Scheme 2 2 ) .  , i o d o - h a l o g e n lamp  _ 7 8  ° ' c  C H  2 2' C 1  5  t=\  110  was  \  O  ^  v / r i  190a  m i n  t h e c h e m i s t r y r e p o r t e d by G o l d s m i t h e t a l . furan  from  m a t e r i a l c o u l d be  tetraphenylphorphin  189a  Following  0  be  3 8  and T a n i s  et  p r e p a r e d from 3-furanmethanol (189) i n s i x  i n an o v e r a l l y i e l d o f 45% (equations  66 t o 71).  (6 mmol) was t r e a t e d w i t h n - b u t y l l i t h i u m  3-Furanmethanol  (13 mmol) i n THF a t 0°C.  The  r e s u l t a n t d i a n i o n was t r e a t e d w i t h d i p h e n y l d i s u l f i d e a t 0°C f o r 12 h  to  g i v e r e g i o s e l e c t i v e l y the f u r a n a l c o h o l 190 (81%,  e q u a t i o n 66).  ^H nmr spectrum o f 190 e x h i b i t e d two d o u b l e t s a t 6 7.59 ( J = 2  The  Hz) and  - 83 -  8  6.65  (J  — 2 Hz) due t o the f u r a n p r o t o n s , a 5-proton m u l t i p l e t a t 8  7.25-7.15 due t o the p h e n y l t h i o Hz)  due  to  the  hydroxyl  group, and a t r i p l e t a t 5 1.62  proton.  The  latter  (J  -  5  s i g n a l underwent D 0 2  exchange.  -OH  1. n-BuLi[2 e q u i v . ) ,  THF  (66)  2. PhSSPh, 0°C, 12h  190  189  The  a l c o h o l 190 was t r e a t e d w i t h t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e i n  the  presence  of  give  the f u r a n  191 (95%, e q u a t i o n 67).  exhibited  a  imidazole  9-proton  i n dimethylformamide a t room temperature t o  singlet  and  The  ^H  nmr  of  191  a 6-proton s i n g l e t a t 8 0.91 and 5  0.07, r e s p e c t i v e l y , due t o the s i l y l p r o t e c t i n g group, the  spectrum  indicating  that  l a t t e r had been i n s t a l l e d .  TBDMSCl, DMF,  Ny^sPh  imidazole  (67)  rt  190  An  191  ethereal  n-butyllithium  solution  (5.2 mmol).  o f the f u r a n 191 (4.7 mmol) was t r e a t e d w i t h The  resultant  mixture  t r i m e t h y l s i l y l c h l o r i d e a t 0°C f o r 48 h t o g i v e e q u a t i o n 68).  was  treated  with  the s i l y l f u r a n 192 (83%,  The -41 nmr spectrum o f 192 e x h i b i t e d a b r o a d s i n g l e t a t 5  84 -  6.85  due  t o t h e f u r a n p r o t o n and 9-proton s i n g l e t a t 8 0.38 due t o the  trimethylsilyl  group.  1. n - B u L i , E t 0  ±  2. TMSCl, 0°C, 48h  SPh  MesSi  191  192  An e t h a n o l i c s o l u t i o n o f the p h e n y l t h i o f u r a n 192 refluxed  i n the presence o f Raney n i c k e l  f u r a n d e r i v a t i v e 193 i n 90% y i e l d nickel spectrum  l e d to  (7 g)  (2.6 mmol)  was  f o r 3 h t o p r o v i d e the  ( e q u a t i o n 69).  An  excess  an o v e r - r e d u c e d t e t r a h y d r o f u r a n d e r i v a t i v e .  of  Raney  The  nmr  193 showed two b r o a d s i n g l e t s a t 6 7.56 and 8 6.60 due  t o the  furan protons.  .—X^OSi-^:  jrA  \  Me3Si-^cr^SPh  Ra-Ni, EtOH  >  r e f l u x , 3h  _ / ^ 0 5 i - ^  .jr\  c  (69)  Me Si-^s X 3  192 Treatment  \  0  193 o f compound 193 w i t h a 3:1:1 mixture o f a c e t i c a c i d ,  and THF, r e s p e c t i v e l y , ^ ^ a t room  temperature  f o r 12  h  water  p r o v i d e d the  Raney n i c k e l i s commercially a v a i l a b l e as a 50% s l u r r y i n water, pH 10, from Aldrich Chemical Co. The reagent was washed t h r e e times w i t h d i s t i l l e d water and s i x times w i t h d i s t i l l e d absolute ethanol before use. The r e q u i r e d q u a n t i t y (-2.7 g p e r mmol o f the p h e n y l t h i o f u r a n 192) o f R a n e y - n i c k e l was o b t a i n e d by w e i g h i n g together w i t h a minimum amount o f e t h a n o l under an atmosphere o f argon.  - 85 -  alcohol  194  (99%, e q u a t i o n 70).  a b s o r p t i o n a t 3326 cm'^ of  194  showed  two  The  i r spectrum o f 194 showed a b r o a d  due t o the hydroxy group.  b r o a d s i n g l e t s a t 5 7.60  p r o t o n s , and a s i n g l e t a t 6 0.30  0Si-<  The  nmr  and 6.66  spectrum  due t o the f u r a n  due to the t r i m e t h y l s i l y l  group.  /--OH  H0Ac-H 0-THF  170)  2  Me3Si  rt,  Me Si""\ r  12h  3  l  194  193  The a l c o h o l 194 was  treated with  lithium  chloride,  s - c o l l i d i n e and m e t h a n e s u l f o n y l c h l o r i d e i n dimethylformamide  a t 0°C f o r  2 h t o g i v e the c h l o r i d e 110  a  mixture  i n 79% y i e l d  of  (equation  spectrum o f 110 e x h i b i t e d a s i n g l e t a t S 4.45  71).  2  s-collidine,  (71)  DMF  110  194  the  stage  Following  the a c q u i s i t i o n o f 4 - c h l o r o m e t h y l - 2 - t r i m e t h y l s i l y l f u r a n (110), was  set  for  the  critical  photosensitized  the c o n d i t i o n s r e p o r t e d by Katsumura e t a l . . ^  d i c h l o r o m e t h a n e s o l u t i o n o f 110 of  nmr  due t o the - C H 2 C I p r o t o n s .  L i C l , MeS0 Cl, 0 C  JTS  With  The  t e t r a p h e n y l p o r p h i n , was  (325W) w h i l e oxygen was  8  oxygenation. a cold  (-78°C)  (10 mmol), c o n t a i n i n g a c a t a l y t i c amount  irradiated  with  a  h a l o g e n - t u n g s t e n lamp  bubbled through the s o l u t i o n .  After a  reaction  - 86 -  time  of  27  min,  the  d i s s o l v e d i n methanol. room  temperature.  product 78%  solution  was  c o n c e n t r a t e d and the r e s i d u e was  The r e s u l t a n t s o l u t i o n was s t i r r e d f o r 12  (equation  72).  The  i r spectrum  of  109  a b s o r p t i o n a t 3357 cm"! due t o the hydroxy group and cm"l due t o t h e c a r b o n y l group.  a 2-proton whose  broad  signals  at  A f t e r workup and column chromatography o f t h e crude  on s i l i c a g e l , the ( c h l o r o m e t h y l ) b u t e n o l i d e 109 was o b t a i n e d  yield  1736  h  The  an  hydroxy and - C H 2 C I p r o t o n s  with  one  showed a broad absorption  at  nmr spectrum o f 109 showed  s i n g l e t a t 6 6.21 due t o the v i n y l and overlapped  in  another.  >CH0H  protons,  The s i g n a l s due t o the  appeared a t 6 4.80 and S 4.37, r e s p e c t i v e l y .  1. 0 , l i g h t 2  /^*CI  tetraphenylphorphin  o  CH C1 , -78°C 2  —  >  -jQg  2. MeOH, r t  Recently, tion  of  amine a t  Faulkner e t a l . ^ ^  reported that  photosensitized  3-substituted  f u r a n s 195 i n the presence  0°C  regioselectively  butenolides  provides  196 ( e q u a t i o n 73).  (72)  ~ J r \ . O ^ Q / ^ O H  2  oxygena-  of diisopropylethyl-  the corresponding  -y-hydroxy  T h i s approach makes t h e presence  o f the  - 87 -  t r i m e t h y l s i l y l group on the f u r a n r i n g  unnecessary  and  thus  with  a  shortens  s u b s t a n t i a l l y the route to 7-hydroxybutenolides. The  7-hydroxybutenolide  109,  upon  treatment  s o l u t i o n o f p _ - t o l u e n e s u l f o n i c a c i d a t room temperature readily  transformed  ( e q u a t i o n 74). 1768  cm"  1  into  the methoxybutenolide  The i r spectrum  due  to  the  The  c a r b o n y l group.  nmr spectrum  f o r 12  197  i n 92%  The  spectrum  was yield  I t i s known t h a t t h e c a r b o n y l  i n t h e presence  of  an  a  vinyl  o f 197 showed a m u l t i p l e t a t 8 6.20 and a  b r o a d s i n g l e t a t 8 5.80 due t o the v i n y l p r o t o n and t h e >CH0Me respectively.  h,  o f 197 e x h i b i t e d a b s o r p t i o n s a t 1800 and  absorption o f a 6-butenolide i s s p l i t proton.^  methanolic  proton,  a l s o showed a s i n g l e t a t 6 3.61 due t o the  methoxy group.  Treatment o f the c h l o r i d e 197 w i t h t r i p h e n y l p h o s p h i n e benzene  provided  the phosphonium s a l t 188 i n 70% y i e l d  in  (equation 75).  4-  /—CI  Ph„P, b e n z e n e  P P h CI 3  O^Q^OMe 197  reflux  O^^^iOMe 188  refluxing  - 88 -  The  nmr spectrum +  the -CH.2PPh  3  With  o f 188 e x h i b i t e d  the  phosphonium  a,^-unsaturated  salt the  188  to  studied.  the  (±)-palauolide aldehyde  investigation  butenolide  of This  phosphorane  with  some  aldehydes.  aldehydes w i t h conversion  now a v a i l a b l e , i t was p o s s i b l e t o  corresponding  C o n v e r s i o n o f -Y-methoxybutenolides  Prior  to  protons.  i n v e s t i g a t e the r e a c t i o n o f  G.  a b r o a d m u l t i p l e t a t S 6.00 due  i n t o -y-hvdroxvbutenolides  o f the o l e f i n a t i o n o f  phosphoranes  7-methoxybutenolides  and into  phosphonate  a,0-unsaturated anions,  the  7-hydroxybutenolides  was  type o f r e a c t i o n was t o be employed i n the g e n e r a t i o n (55)  from  the  of  p r o d u c t 198 o f the r e a c t i o n between the  107 and the phosphorane 108 (Scheme 23).  Scheme 23  - 89 -  Recently,  Wernuth  7-ethoxybutenolide  et  199.  al.^3  reported  Their  procedure  p r e p a r a t i o n o f the 7-methoxybutenolide 200, model  for  studying  the  7 - h y d r o x y b u t e n o l i d e s . Thus, in  the  presence  the  preparation was  which  transformation of  modified was  of  the  for  the  employed  as  7-methoxybutenolides  r e a c t i o n o f g l y o x y l i c a c i d 201 w i t h  a  into  propanal  o f morpholine hydrogen c h l o r i d e i n aqueous dioxane a t  room temperature f o r 1 h and a t r e f l u x temperature f o r 24 h p r o v i d e d the 7-hydroxybutenolide  202^  i n 63% y i e l d  (see e q u a t i o n 76).  the l a t t e r m a t e r i a l w i t h m e t h a n o l i c hydrogen c h l o r i d e hydrogen  chloride  gas i n 150 mL  o f dry methanol)  p r o v i d e d the 7-methoxybutenolide 200  i n 47% y i e l d  (-7  Treatment g  of  anhydrous  under r e f l u x f o r 16 h ( e q u a t i o n 76).  199 R=Et 200 R = Me  The due  i r spectrum o f 200 e x h i b i t e d a b s o r p t i o n s a t 1797  t o the c a r b o n y l group.  s i n g l e t s a t 8 5.89 respectively,  a  d o u b l e t a t 5 2.06  and 5.60 singlet  The due at  nmr to  8  the 3.58  spectrum o f 200 olefinic due  and  and  1769  cm"  1  showed two b r o a d >CH0CH3  protons  to the methoxy p r o t o n s and a  ( J = 2 Hz) due to the v i n y l methyl  group.  - 90 -  Wermuth e t a l . ^ 3 r e p o r t e d concentrated  hydrochloric  that  acid  treatment  (2  ml  r e g e n e r a t e d the 7 - h y d r o x y b u t e n o l i d e 202 thought  that  under  gram  199  with  of  199)  ( e q u a t i o n 77).  refluxing f o r 15  min  However, i t  was  such d r a s t i c c o n d i t i o n s , the o l e f i n i c double bonds  p r e s e n t i n the p a l a u o l i d e s k e l e t o n tions.  per  of  would  undergo  rearrangement  T h e r e f o r e , m i l d e r r e a c t i o n c o n d i t i o n s would have to be  reac-  developed  f o r our s y n t h e s i s .  A c i d h y d r o l y s i s o f the 7-methoxybutenolide conditions 202.  failed  However,  to  203  Larcheveque may  204 by treatment w i t h h y d r o x i d e  et  al.^  reported  4  be c o n v e r t e d i n t o the i o n (equation  i n f o r m a t i o n on the e x p e r i m e n t a l c o n d i t i o n s was  203  After  a  variety  of  p r o v i d e u s e f u l y i e l d s o f the 7 - h y d r o x y b u t e n o l i d e  recently,  7-methoxybutenolide  200 under  78).  that  the  7-hydroxybutenolide Unfortunately,  no  reported.  204  some  experimentation,  7-methoxybutenolide  it  was  found  200 w i t h sodium h y d r o x i d e  t h a t treatment  o f the  i n aqueous a c e t o n i t r i l e a t  - 91 -  room temperature f o r 30 min produced the a c i d aldehyde 2 0 5 (see e q u a t i o n 79).  When d i l u t e h y d r o c h l o r i c a c i d  solution,  was  added  to  the  ir  product  7 - h y d r o x y b u t e n o l i d e 2 0 2 c o u l d be o b t a i n e d d i r e c t l y  the  w i t h o u t i s o l a t i o n o f the i n t e r m e d i a t e a c i d aldehyde 2 0 5 The  above  and  nmr  (equation  s p e c t r a l d a t a o f the l a t t e r m a t e r i a l were  (see e q u a t i o n 76, p. 89).  hydroxy  group  and  and  cm"  the c a r b o n y l groups, r e s p e c t i v e l y .  spectrum o f 2 0 5 showed a s i n g l e t a t 8 9.60 two b r o a d s i n g l e t s a t 8 6.53  due to  and 8 2.21  the  earlier  The i r spectrum  o f the a c i d aldehyde 2 0 5 showed a b s o r p t i o n s a t 3034 and 1698 the  79).  identical  w i t h those o f the 7 - h y d r o x y b u t e n o l i d e 2 0 2 p r e p a r e d as d e s c r i b e d i n t h i s s e c t i o n o f the t h e s i s  (70%)  1  The  aldehyde  due to nmr proton  due t o the o l e f i n i c and the  v i n y l methyl p r o t o n s , r e s p e c t i v e l y .  Thus, a method  for  the  conversion  of  7-methoxybutenolides  into  7 - h y d r o x y b u t e n o l i d e s under m i l d r e a c t i o n c o n d i t i o n s had been developed.  H.  R e a c t i o n o f a.B-unsaturated  aldehydes w i t h phosphoranes  and  phosphonate  anions d e r i v e d from 4-("halomethvDbutenolides  Recently,  Thaller  s y n t h e s i s o f a new  et  al.  3  reported  monoterpene, s c o b i n o l i d e  the (206).  isolation In t h e i r  and  total  synthesis,  - 92 the phosphonium of  sodium  isolated  s a l t 207 was  hydroxide as  and  t r e a t e d w i t h an aqueous m e t h a n o l i c  the  a yellow s o l i d  resultant  (see e q u a t i o n 80).  t h e n a l l o w e d t o r e a c t w i t h the aldehyde for  3  mixture  h.  Preparative  gave s c o b i n o l i d e  stable  solution  phosphorane  208  The phosphorane 208  209 i n r e f l u x i n g  y i e l d s o f 4 7 % and 11%, r e s p e c t i v e l y  corresponding  was  dichloromethane  t h i n l a y e r chromatography o f the crude (206) and the  was  Z-isomer  product 210  in  ( e q u a t i o n 80).  F o l l o w i n g the c h e m i s t r y r e p o r t e d by Boeckman e t a l .  b b  and T h a l l e r e t  a l . , * ' ' the phosphorane 208 was p r e p a r e d and i s o l a t e d .  When we  the  t o the c o n d i t i o n s  3  above  olefination  reported, ^  most  of  olefination  product  reaction the  exactly  phosphorane  mixture  was  208  according was  recovered  i s o l a t e d i n o n l y 10% y i e l d .  when the r e a c t i o n mixture was r e f l u x e d f o r 24 h, s c o b i n o l i d e  repeated  and  the  However, (206)  was  isolated i n 48% y i e l d . Treatment  of  geranial  (211) w i t h the phosphorane 208 i n r e f l u x i n g  - 93 -  dichloromethane products.  (bp 40°C) f o r 24 h d i d n o t g i v e much o f the  However,  1,2-dichloroethane yield  when  the  reaction  was  carried  olefination  out  i n boiling  (bp 80°C) f o r 16 h, compound 212 was i s o l a t e d i n  ( e q u a t i o n 81).  46%  These r e s u l t s suggest t h a t the phosphorane 208 i s  not v e r y r e a c t i v e and t h a t the o l e f i n a t i o n i s changes i n the a,unsaturated  sensitive  to  structural  aldehyde.  211 The  i r spectrum  o f 212 showed a b s o r p t i o n s a t 1778 and 1747 cm"l due  to the c a r b o n y l group.  I n the ^H nmr  spectrum  of  212,  the  p r o t o n s appeared  a t 6 6.75  16 Hz, Hg), 5.97  (d, 1H, J = 12 Hz, H ) , 5.84 ( b r s, 1H, H ) ,  (br  s,  and the methyl  1.63  (br s ) .  1H, H ) E  (dd, 1H, J - 12, 16 Hz, H ) , 6.35  (d, 1H, J =  A  c  olefinic  and  D  groups a t S 1.85  ( b r s ) , 1.69  5.07  ( b r s) and  In o r d e r to by-pass the i s o l a t i o n o f the phosphorane, the b u t e n o l i d e phosphonium  salt  207  was  amount o f d i m e t h y l s u l f o x i d e . 1,2-dichloroethane  solution  r e f l u x e d f o r 17 h.  Workup  product  on  treated  w i t h d i m s y l potassium  i n a minimum  The r e s u l t a n t s o l u t i o n was t r e a t e d w i t h a of and  geranial column  (211)  and  chromatography  the of  s i l i c a g e l p r o v i d e d compound 212 i n 47% y i e l d .  showed t h a t the o l e f i n a t i o n c o u l d be c a r r i e d  out  mixture the  was  crude  This result  successfully  without  - 94 -  i s o l a t i o n o f the phosphorane  208.  However, when the r e a c t i o n o f g e r a n i a l n o l i d e phosphonium  s a l t 188 was  with  described, geranial  those  just  (211) w i t h the 7-methoxybute-  attempted  under  (211) was  conditions  identical  r e c o v e r e d i n t a c t and no  o l e f i n a t i o n p r o d u c t c o u l d be d e t e c t e d by g l c and t i c a n a l y s i s  (equation  82) .  (82)  no reaction  In  view  of  this  failure,  a t t e n t i o n was  t u r n e d t o the use o f the  b u t e n o l i d e phosphonate 213, the a n i o n o f which was expected reactive prepared  than  197  ( e q u a t i o n 83). 4.15  c o r r e s p o n d i n g phosphorane.  i n 78% y i e l d by h e a t i n g  butenolide  6  the  and  purified  The ^H nmr  a  mixture  of  triethylphosphite  to  be  more  The phosphonate 213 the at  /3-(chloromethyl)  -  150°C  h  for  18  spectrum o f 213 e x h i b i t e d a b r o a d q u i n t e t  ( J = 7 Hz) due t o the -P(0CH CH3) 2  2  protons, a s i n g l e t  at S  due t o the methoxy p r o t o n s , and a p a i r o f d o u b l e t o f d o u b l e t s a t 5 (J  -  16,  21  Hz)  and  6 2.89  at 3.60 3.01  ( J = 16, 21 Hz) due to the - C H P 0 ( 0 E t ) 2  protons.  (83)  197  was  213  2  95 -  The phosphonate 214 was prepared according to the procedure reported by  Boeckman  et a l . . ^ and was  olefination  of an a,B-unsaturated  conditions,  as  reported by fi  Masamune e t a l . . esters  with  employed as a model f o r studying the aldehyde.  Boeckman  et a l . . ^  a  variety  of  Corey et a l . . ^ and  b  ft  0 0  f o r coupling  of 7-phosphonates  of a,yS-unsaturated  a.^-unsaturated aldehydes, no o l e f i n a t i o n product could be  i s o l a t e d from the r e a c t i o n of g e r a n i a l phosphonate repeated  Under  214  with  (equation 8 4 ) .  (211) with  the anion  of the  Nevertheless, the reactions  the 7-methoxybutenolide  phosphonate  213,  and  were not  s u r p r i s i n g l y , no o l e f i n a t i o n product could be i s o l a t e d (equation 8 5 ) .  213  Without  any success  i n olefination  of a,^-unsaturated  using the 7-methoxybutenolide phosphonium s a l t 188 213, other means of o l e f i n a t i o n were i n v e s t i g a t e d .  or the  aldehydes phosphonate  - 96 I.  R e a c t i o n o f a.fl-unsaturated aldehydes w i t h phosphoranes d e r i v e d  from  4- (halomethyl') - 2 - t r i m e t h y l s i l v l f u r a n s  Our a t t e n t i o n was t u r n e d t o the use o f the phosphonium s a l t s from  4-(halomethyl)-2-trimethylsilylfurans.  phosphonium  salts  would  provide  Scheme 2 4 ) .  The  latter  material  a,/9-unsaturated product. of  216  aldehyde  107  to  the was give  Deprotonation  of  such  s t a b i l i z e d phosphorane 215 (see expected the  to  react  with  the  E o l e f i n 216 as the major  S e l e c t i v e p h o t o s e n s i t i z e d o x y g e n a t i o n o f the s i l y l f u r a n moiety would  provide  (±)-palauolide  (55)  (Scheme 24).  c h e m o s e l e c t i v e p h o t o s e n s i t i z e d o x y g e n a t i o n was expected tion  derived  o f s i l y l f u r a n s proceeds a t a r a t e f a s t e r  The d e s i r e d  since  than the a l l y l i c  oxygenaoxygena-  28 t i o n o f alkenes. is  not  likely  Furthermore,  the diene moiety  i n the s i d e c h a i n o f 216  t o undergo a [2+4] c y c l o a d d i t i o n w i t h g e n e r a t e d  oxygen, s i n c e t h i s r e a c t i o n would r e q u i r e the diene moiety s t e r i c a l l y congested c i s o i d conformation.  Scheme 24  to  singlet adopt  a  - 97 -  In  an  attempt  to prepare  the r e q u i r e d phosphonium s a l t ,  m e t h y l - 2 - t r i m e t h y l s i l y l f u r a n (110) was i n r e f l u x i n g benzene f o r 24 h.  monohydrate  and  furan  with  triphenylphosphine  However, no p r o d u c t was  s t a r t i n g m a t e r i a l s were r e c o v e r e d Treatment o f the  treated  110  o b t a i n e d and  The  with  a  mixture  of  calcium  tetra-n-butylammonium bromide ( c a t a l y s t ) * ^  6.64  due  protons  ^H nmr  spectrum o f 217  e x h i b i t e d two  •CI  due  9  bromide  i n hexane a t  217  (equation  s i n g l e t s a t S 7.65  to the f u r a n p r o t o n s , a s i n g l e t a t 6 4.37 and a s i n g l e t a t 6 0.28  due  to  to the t r i m e t h y l s i l y l  the  protons.  2  (86)  Me3Si--^cr  hexane, 50°C  217  110  R e a c t i o n o f the bromide 217  with triphenylphosphine i n e t h e r  r e f l u x f o r 24 h p r o v i d e d the phosphonium s a l t 218  as a white,  solid  The  (77%  and 6 -C^Br  n-Bu^NBr, CaBr.H 0  Me3S'r  the  intact.  50°C f o r 2 h p r o v i d e d the c o r r e s p o n d i n g bromo d e r i v a t i v e 86).  4-chloro-  from  the  f u r a n 110,  e q u a t i o n 87).  / u  under  amorphous  -^H spectrum o f  + e x h i b i t e d a 2-proton  m u l t i p l e t a t S 5.30  due  to the -CH^PPl^ p r o t o n s .  218  - 98 -  S i m i l a r l y the  phosphonium  iodide  219  was  prepared  as  follows.  Treatment o f the c h l o r i d e 110 w i t h sodium i o d i d e i n acetone a t 60°C gave the  i o d i d e 220.  phine i n ether  With  R e a c t i o n o f the l a t t e r afforded  bromide  (211)  218  solution of phenyllithium^ resultant  was  studied.  To  a  solution  i n e t h e r was added, s u c c e s s i v e l y , 1  and a dichloromethane s o l u t i o n o f  geranial.  the  Workup  nmr s p e c t r o s c o p y and a g l c a n a l y s i s , a  When the phosphonium i o d i d e 219 was s u b j e c t e d  3:2  (equation  t o the same r e a c t i o n  s t e r e o s e l e c t i v i t y o f the o l e f i n a t i o n improved  to 2:1 i n f a v o u r o f 221 ( e q u a t i o n 90).  the  an e t h e r e a l  o f the o l e f i n a t i o n p r o d u c t s 221 and 222, r e s p e c t i v e l y  conditions,  of  m i x t u r e was s t i r r e d a t room temperature f o r 1 h.  p r o v i d e d , on the b a s i s o f  89).  triphenylphos-  b o t h phosphonium s a l t s 218 and 219 a v a i l a b l e , t h e i r use i n the  phosphonium  mixture  with  the phosphonium s a l t 219 ( e q u a t i o n 88).  o l e f i n a t i o n of geranial  The  substance  slightly  - 99 -  Me Si-^ 3  +  PPh l  1.  3  +  2. OHC^i  Me Si 3  2  221  PhLi, ether  1  219 Me Si 3  222  The silica  o l e f i n a t i o n p r o d u c t s 221  and 222 were u n s t a b l e and decomposed on  g e l d u r i n g chromatography.  Attempts t o s e p a r a t e them on  v a t e d n e u t r a l alumina were not s u c c e s s f u l . was  l a t e r c o n f i r m e d to be the E o l e f i n It  222 the  was  olefin.  However,  m i x t u r e underwent slow  product  102).  stereoselective,  and  o f i o d i n e would c o n v e r t the Z o l e f i n  little  stereomutation  was  to  d e t e c t e d and  the  decomposition.  S i n c e the o l e f i n a t i o n s another  with method  (±)-palauolide s y n t h e s i s was  J.  (see p.  major  e x p e c t e d t h a t r e f l u x i n g a s o l u t i o n o f the m i x t u r e o f 221  i n n-hexane i n the presence E  However, the  deacti-  Reaction of geranial  the  phosphorane  215  were  not  very  t h a t might e v e n t u a l l y be used f o r the  investigated.  (211) w i t h the s u l f o n e 223.  o x i d a t i o n o f the r e s u l t a n t t r i e n e 221  Photosensitized  to the c o r r e s p o n d i n g  butenolide  Our  a t t e n t i o n turned to  olefination.  In  general,  the  possibility  of  employing  the  Julia  the  s y n t h e s i s of 1 , 2 - d i s u b s t i t u t e d alkenes  - 100 -  u s i n g t h i s method p r o v i d e e x c l u s i v e l y the the  sulfone  olefins.72 224  example,  o r  treatment  benzaldehyde  and a c e t i c anhydride p r o v i d e d the  The  m a t e r i a l underwent smooth r e d u c t i v e e l i m i n a t i o n w i t h sodium  xhe  stereochemistry  of  the  n-butyllithium,  a-acetoxy  amalgam t o g i v e s t e r e o s e l e c t i v e l y the diene 226 91).72  with  p  successive  latter  of  E  i n 93%  reaction  sulfone  yield  can be  225.  (equation  rationalized  by  3. Ac 0  224  225  proposing that generates  an  the anion  reductive which  cleavage  226  of  the  phenylsulfonyl  assumes the lowest energy  s t r u c t u r e 225a) from which the E-alkene  group  conformation  (see  i s formed.  225a Recently, sis  of  i n c o n n e c t i o n w i t h work d i r e c t e d toward the t o t a l  indanomycin,Ley  structurally  complex  and produced  employed the J u l i a o l e f i n a t i o n to c o u p l e  a,@-unsaturated  f u n c t i o n a l i z e d s u l f o n e 228.  synthe-  The  aldehyde  o l e f i n a t i o n was  o n l y the E , E - l , 3 - d i e n e 229  227  with  totally  ( e q u a t i o n 92).  the  the  highly  stereoselective  - 101 -  C"^V^CH0 C0 M  227  PhS0  228  2  2  1. a. n - B u L i , THF, -78°C  SEM=CHOCH2CH2SiMe  b. b e n z o y l c h l o r i d e 2. Na(Hg), MeOH-THF  2  3  V  (92) 229  The s u l f o n e 223 r e q u i r e d f o r our work mixture  of  The  in  dimethylformamide  at  80-90°C  for  nmr spectrum o f 223 showed a s i n g l e t  to t h e -CH S02Ph p r o t o n s . 2  prepared  by  4 - ( c h l o r o m e t h y l ) - 2 - t r i m e t h y l s i l y l f u r a n (110)  benzenesulfinate equation 93).  was  The h i g h  resolution  mass  heating and  2.5  h  a  sodium (72%,  a t S 4.15 due  spectrum  of  223  S0 Ph 2  (93)  80-90°C  110  223  102  showed  a  formula of The The  molecular  ion  at  m/e  -  294.0744, c o n s i s t e n t w i t h a m o l e c u l a r  Ci^H-LgSC^Si.  sulfone  resultant  223 was  treated with n-butyllithium  solution  was  treated  (-78°C to r t , 1.5  benzoyloxy  The  230.  sodium amalgam (4%) i n m e t h a n o l i c stereoselectively  the  94).  In the ^-H nmr  6.65  (dd, 1H,  1H,  J = 11 Hz,  formed  J = 11, H) c  H ), A  at  bond  -20°C  6.26  (d, 1H, H ), D  had  -78°C.  for  3  h  (211)  afford  treated with  7 3  to  223,  afford equation  s i g n a l s appeared  J = 16 Hz,  indicating  the  Hg),  that  at  5.90  the  5 (d,  newly  the d e s i r e d E s t e r e o c h e m i s t r y .  i d e n t i c a l w i t h the major  previously described  at  to  m a t e r i a l was  the o l e f i n i c  (br s, 1H,  double  h)  (68% y i e l d from s u l f o n e  o f 221,  16 Hz,  and 5.07  carbon-carbon  T h i s m a t e r i a l was  t r i e n e 221  spectrum  latter  THF  THF  successively with geranial  (-78°C, 3 h) and b e n z o y l c h l o r i d e phenylsulfone  in  W i t t i g r e a c t i o n (see p.  product  obtained  from  the  99).  S0 Ph 2  S0£Ph Me3Si-'**\0 223  1.  n-BuLi,  THF  >  2. O H C - ^ V ^ ^ V ^ 3.  Me3Si  0  PhCOCl  Na(Hg), MeOH-THF  (94)  221  - 103 -  The  furan  triene  221  was  then used as a model t o i n v e s t i g a t e  p h o t o s e n s i t i z e d oxygenation r e a c t i o n . methane  When  s o l u t i o n o f the f u r a n t r i e n e 221,  o f t e t r a p h e n y l p o r p h i n , was the m i x t u r e ,  cold  (-78°C) a  i r r a d i a t e d w h i l e oxygen was  methanolic  catalytic  (-78°C)  amount  solution of  dichloro-  c o n t a i n i n g a c a t a l y t i c amount  a t e r r i b l e m i x t u r e o f p r o d u c t s was  when a c o l d containing  a  of  bubbled  obtained. the  Fortunately,  furan  Rose Bengal, was  through  triene  221,  i r r a d i a t e d with a  t u n g s t e n - h a l o g e n lamp (325W) through an aqueous sodium  nitrite  while  solution,^  oxygen  was  7-hydroxybutenolide spectrum  of  231  bubbled 231 was exhibited  through  the  methanolic  o b t a i n e d i n 70% y i e l d  The  -41 nmr  J = 11, 16 Hz, H ) , A  Hz,  H ), c  6.00  spectrum 6.30  cm"  1  due  to  1  the  (d, 1H, J = 16 Hz, H ), fi  (d, 1H, J = 11 Hz, H ) , D  and 5.87  6.23  (d, 1H,  ( s , 1H, H ) E  These  the  The i r  due  t o the  carbonyl  o f 231 e x h i b i t e d s i g n a l s a t 5 7.18  p r o t o n s on the diene b u t e n o l i d e moiety o f 231. were  filter,  ( e q u a t i o n 95).  a b r o a d a b s o r p t i o n a t 3343 cm"  hydroxy group and a s t r o n g a b s o r p t i o n a t 1744 group.  the  (dd,  1H,  -  8.5  J due  chemical  to the shifts  almost e x a c t l y the same as those r e p o r t e d f o r the diene b u t e n o l i d e  These r e a c t i o n c o n d i t i o n s are i d e n t i c a l w i t h those used f o r c o n v e r t ing 4 - ( c h l o r o m e t h y l ) - 2 - t r i m e t h y l s i l y l f u r a n (110)to the c o r r e s p o n d i n g 7 - h y d r o x y b u t e n o l i d e 109.  110  109  - 104 -  moiety o f p a l a u o l i d e 15.5 Hz), 6.26  K.  (55) [5 7.16 (dd, J - 11, 15.5 Hz), 6.28  ( s ) , 5.95 (d, J = 11 Hz), 5.83  (s)].  R e a c t i o n o f the aldehyde 107 w i t h the s u l f o n e  (d,  J  -  1 4  223.  Photosensitized  o x i d a t i o n o f the r e s u l t a n t t r i e n e 216 t o (±)-palauolide (55)  With  suitable  conditions  developed  o l e f i n a t i o n and p h o t o s e n s i t i z e d these  reactions  n-butyllithium.  The  1.5  o f (±)-palauolide ( 5 5 ) . To  223 i n THF a t -78°C was added  resultant  solution  u n s a t u r a t e d aldehyde 107 (-78°C, 3 h) and temperature,  J ) f o r the r e q u i r e d  oxygenation, the stage was s e t t o employ  to e f f e c t a t o t a l synthesis  a s o l u t i o n o f the s u l f o n e  room  (section  h).  was  treated  benzoyl  solution  with  chloride  the (-78°C  of a,fito  The r e s u l t a n t b e n z o y l o x y p h e n y l s u l f o n e 232  was a l l o w e d t o r e a c t w i t h sodium amalgam (4%) i n a 3:1 and  a  methanol, r e s p e c t i v e l y , a t -20°C f o r 3 h.  mixture  Workup a f f o r d e d  t r i e n e 216 (51% from the aldehyde 107, e q u a t i o n 96).  of  THF  the f u r a n  105 -  The H  nmr  i  to  the  spectrum o f 216 e x h i b i t e d s i n g l e t s a t 5 7.58  furan protons H  t r i m e t h y l s i l y l group. at  6 6.56  (d,  J  -  10  molecular S i 0  ion  Hz,  H ),  indicating  E  bond  6.30  m/e  the  appeared  newly  5.89  introduced  i n the diene moiety p o s s e s s e s the d e s i r e d E  424.3161, which  216  showed  the  i s c o n s i s t e n t with a formula of  (-78°C) dichloromethane-methanol  s o l u t i o n o f the f u r a n  c o n t a i n i n g a c a t a l y t i c amount o f Rose Bengal, was  minutes w i t h a h a l o g e n - t u n g s t e n lamp (325W) through nitrite  filter,  while  r e s u l t a n t s o l u t i o n was the  chain  n  The h i g h r e s o l u t i o n mass spectrum o f at  due t o the  (d, 1H, J = 16 Hz, H ) , that  due  -  A cold 216,  The o l e f i n i c p r o t o n s i n the s i d e  double  stereochemistry.  H  r e s p e c t i v e l y , and a t 6 0.27  c  1H,  28 44  and Hg,  (dd, 1H, J = 10, 16 Hz, H ) ,  carbon-carbon  c  A  and 6.76  dark  f o r 3 h.  oxygen  was  bubbled  an  triene  irradiated for 8 aqueous  sodium  through the m i x t u r e .  The  purged w i t h argon and kept a t room temperature i n  A f t e r workup and column chromatography  o f the crude  - 106 -  The  s y n t h e t i c m a t e r i a l was s p e c t r o s c o p i c a l l y i d e n t i c a l w i t h n a t u r a l  palauolide  ( F i g s . 4 and  s p e c t r a l data reported our  5).  For  comparison  f o r the n a t u r a l m a t e r i a l  purposes, 1 4  the  1  H  and those d e r i v e d  nmr from  s y n t h e t i c m a t e r i a l a r e compiled i n T a b l e 1.  T a b l e 1:  A  H nmr s p e c t r a l d a t a o f n a t u r a l p a l a u o l i d e and s y n t h e t i c (±)-palauolide (55)  R e p o r t e d Data H nmr (CDC1 ) 6: 7.16 (dd, 1H, J = 15.5, 11 Hz, H ) , 6.28 (d, 1H, J = 15.5 Hz, Hg), 6.26 ( s , 1H, H ) , 5.95 (d, 1H, J - 11 Hz, H ) , 5.83 ( s , 1H, Hg), 4.51 ( s , 2H, Hp), 1.86 ( s , 3H, v i n y l methyl p r o t o n s ) , 1.05 ( s , 3H, methyl p r o t o n s ) , 0.82 (d, 3H, J = 7 Hz, methyl p r o t o n s ) , 0.74 ( s , 3H, methyl p r o t o n s ) . A  3  A  c  Our  D  data  H nmr (400 MHz, CDCI3) 5: 7.14 (dd, 1H, J_ - 15.5, 11 Hz, H ) , 6.29 (d, 1H, J - 15.5 Hz, H ) , 6.26 (d, J = 8.5 Hz, c o l l a p s e d t o s on D 0 exchange, H ) , 5.97 (d, 1H, J = 11 Hz, H ) , 5.87 ( s , 1H, Hg), 4.51 ( s , 2H, H ) , 1.88 ( s , 3H, v i n y l methyl p r o t o n s ) , 1.06 ( s , 3H, methyl p r o t o n s ) , 0.82 (d, 3H, J •= 6 Hz, methyl p r o t o n s ) , 0.74 ( s , 3H, methyl protons). A  A  B  c  2  D  F  We of  are g r a t e f u l to Professor palauolide (55) .  D.J. F a u l k n e r f o r the H nmr spectrum A  Figure 4  : The  H nmr  spectrum of n a t u r a l  palauolide  - 109 -  The w o r k s u m m a r i z e d a b o v e c o n s t i t u t e s t h e s u c c e s s f u l t o t a l of  (±)-palauolide  i n a  cyclohexen-1-one w i t h an represents  the  biologically  first  total overall  reported  interesting  o f seventeen steps yield  total  natural  of  5%  from  3,6-dimethyl-2-  ( s e e Scheme  synthesis of this  synthesis  25) and  structurally  product.  i,n 115 iv(-»173 v ( - » > 180 vi(->)181 vii (•*) 174 viii(-*-) 175  ixC-*-) 183 x(-*)184 xi{-»-) 185 x(-»176 183 R = H , R = H . 0 H 184 R = H . R'=0 185 R = M e . R ' = H . 0 H 176 R = M e . R ' = 0  173 180 181 174 175  x i i i * ) 177 xiiil-*-) 187 x i v ( - * ) 107  177 187 107  Li  R=C02Et R=CH20H R=CH0  f~  Me3Si-^0-'  223a  Scheme 25  R=CN R=CH0 R = CH20H R=CH20P0(NMe2)2 R = Me  and  109a Reagents  and  CuBr-Me S,  3  30°C,  Bu^K,  i , 2 - ( 5 - c h l o r o p e n t - l - e n y l ) m a g n e s i u m bromide,  B F - E t 0 , THF, -78°C, 3  2  Bu^H,  conditions: 2  10  h,  82%;  h;  NH Cl,  0°C; I [ C H ] 0 C H 0 M e , 2  3  77%;  2  i i i , (p.-tolylsulphonyl)methyl  Bu^-OH-HMPA, 40-55°C, 3 days, 64%;  THF-HMPA,  H 0,  4  2  i v , lithium  i i ,  isocyanide,  diisopropylamide,  0°C - room temp., 99%; v, B u A l H , DME, i  2  60°C, 6 h; H0Ac-H 0, THF, room temp., 10 h, 85%; v i , L 1 A I H 4 ,  Et 0,  2  temp.,  91%; v i i , B u L i , DME-TMEDA; Cl P0NMe , n  2  0°C, 2 h, 88%; v i i i ,  2  L i , MeNH , -20°C, 10 Bu^-OH,  2  room  room temp., 10 h; Me NH, 2  min,  2  toluene-p_-sulphonate ,  Bu^K,  81%;  i x , pyridinium  70°C, 91%; x, p y r i d i n i u m chlorochromate ,  NaOAc, C H C 1 , 99%; x i , MeLi, E t Q , 98%; x i i , [ E t 0 C C H P 0 ( 0 E t ) ] K , THF, 2  2  2  room temp., 18 h, 88%; x i i i , hexane, room  2  Bu AlH, i  2  Et 0, 2  -78 -+ 0°C, 98%; x i v , Mn0 , 2  room temp., 88%; xv, 223a, THF, -78°C, 3  temp.;  halogen  lamp,  Me0H-CH Cl , 2  2  Na(Hg),  MeOH-THF,  aqueous -78°C,  8  NaN0  2  -20°C,  filter,  3 0 , 2  2  h,  h;  PhCOCl,  -78°C  51%; x v i , hu ( t u n g s t e n  Rose  Bengal  (catalyst),  min; purge r e a c t i o n m i x t u r e w i t h argon and then  keep a t room temp, i n the dark f o r 3 h, 68%.  - 110  II.  T o t a l Synthesis of Diacetate  A.  retrosynthetic  the  carbon-carbon  double  7 4  aldehydes. nate  For  236  in  the  236  234 the  and  (±)-palauolide  It  may  be  61  to  side chain  of  the  to e f f e c t h i g h l y  resultant  m i x t u r e o f the 97).  It  was  Z and  involving  latter  Further,  it  that  the  of  64 the  substance,  fragments,  would et  bis(trifluoroethyl)-  stereoselective Z olefination  that  p r e p a r a b l e by m o n o a l k y l a t i o n hoped  64.  of  phospho-  -78°C i n the p r e s e n c e o f 18-crown-6  s h o u l d be  was  and  Recently, S t i l l  methyl  E esters,  expected  San  (60)  disconnection o f the  the  isolinaridol  example, r e a c t i o n o f the potassium s a l t o f the at  of  that  of i s o l i n a r i d i a l  the phosphonate 235.  use  noted  group i n t e r c o n v e r s i o n s  of  (55),  interconversions  Retrosynthetic  w i t h n - h e p t a n a l i n THF  gave a 46:1 (equation  bond  and  thesis.  reduction  functionalization  reported  phosphonoacetate  223.  of  group  64.  (64)  the methodology employed  diacetate  functional  aldehyde  have  the  natural  ester  along with s u i t a b l e the  diol  have r e p o r t e d  9  would p r o v i d e  al.  based on  functional  61 would p r o v i d e the  retrosynthetic  provide  (±)-Isolinaridiol  (±)-isolinaridiol  d e c a l i n substructure  s a p o n i f i c a t i o n o f the  Further  (61) was  retrosynthetic  F e l i c i a n o et a l . ^ the  o f the  of  i n a previous s e c t i o n of t h i s  Suitable diacetate  analysis  diacetate  construction  as d i s c u s s e d  and  Analysis  (±)-isolinaridiol i n the  (±)-Isolinaridiol (64)  (61)  Retrosynthetic  Our  -  of  237  and  238,  respectively  the analogous phosphonate 239  reaction  with of  the  the  iodide  a n i o n o f 235  235 240. with  - Ill -  - 112  (CF CH 0) P(jHC0 Me 3  2  2  18-crown-6  aldehyde 234  (236)  2  ether,  -  -78  C  238  237  would g i v e p r i m a r i l y the Z o l e f i n  223.  S u i t a b l e r e t r o s y n t h e t i c f u n c t i o n a l group i n t e r c o n v e r s i o n s the  aldehyde  234  would p r o v i d e  the n i t r i l e  c a r b o n - c a r b o n bond j o i n i n g the s i d e c h a i n and with  241.  Disconnection  the b i c y c l i c  at  system,  the  along  the s u i t a b l e f u n c t i o n a l i z a t i o n o f the fragments, would p r o v i d e  nitrile already  112  and  been  the i o d i d e 240. demonstrated  p r e p a r a t i o n o f the n i t r i l e (±)-palauolide  Alkylation  to 112  be  of  completely  the  nitrile  had been developed f o r the  synthesis  1.  O l e f i n a t i o n s with a c y c l i c b i s ( t r i f luoroethvDphosphonates  of  distilled  phosphorus p e n t a c h l o r i d e ^ provided  m a t e r i a l was presence  of  the had the of  (55).  Z S e l e c t i v e Horner-Wittig o l e f i n a t i o n s  Treatment  112  s t e r e o s e l e c t i v e and  B.  h,  involving  4  with  phosphonoacetate  a t room temperature f o r 1 h and  the d i c h l o r i d e 243 treated  trimethyl  i n 99% y i e l d  in  with  a t 75°C f o r 3  ( e q u a t i o n 98).  2,2,2-trifluoroethanol  diisopropylethylamine  (242)  The  benzene  a t room temperature f o r 2 h.  latter in  the  Column  113 -  (MeO) $CH C02Me 2  —  2  >  CI 2^CH2C0 Me  242  2  chromatography  of  t h e crude  239  bis(trifluoroethyl)phosphonate of 0 (CF3CH20)2P-  239  spectrum  and  exhibited  protons,  product  a  A  3  silica  g e l provided  (57%, equation  99).  The  0  CF CH OH 3  2  a t 6 3.75 d u e  nmr  protons,  0  (2.3 equiv.)  CI PCH C02Me  >  2  (99)  (CRC^bPCHbCOjMf  i - P r N E t , benzene  L  the  ( J = 8 H z ) due t o t h e  t o t h e methoxy 0 a t 8 3.15 ( J = 20 H z ) due t o t h e -PCH2- p r o t o n s .  a doublet  2  on  q u i n t e t a t 8 4.44  a singlet  (98)  2  c  L  7  "  2 4 3  Reaction the  o f 2-chloroethanol  presence  temperature 100). sodium  of gave  / \ / 0 H  iodide  60°C i n t h e d a r k  (240)  C1CH_0CH 3 2  CH CI 2  2  i n dichloromethane  2-chloro-l-methoxymethoxyethane  at  i.-Pr NEt 2AA  w i t h chloromethyl methyl  diisopropylethylamine  (50%,  equation  with  at  (80%, see  an  acetone  ether i n room  equation  solution  of  f o r 30 h a f f o r d e d 2 - i o d o - 1 - m e t h o x y -  100).  The ^H  nmr  spectrum  of  240  7  2  l  (244)  Treatment o f t h e l a t t e r m a t e r i a l  methoxyethane  C  239  2  >  „  Cl^s/O^O^  NaT  (100)  >  acetone  1  v  2A0  x  - 114  exhibited  two  singlets  methoxy p r o t o n s , 5  3.30  at  6  respectively,  ( J - 6 Hz)  due  to the  -  4.68 and  and  two  triplets  -OCH2CH2-  The (0.71 The  (0.63  239  mmol) i n dimethylformamide  resultant  s o l u t i o n was  60°C  239,  for  the  4 h.  245,  mmol) (2 mL)  was  phosphonate  respectively  ion  g e l or  at  m/e  t r e a t e d w i t h sodium h y d r i d e  mmol).  (H  235, nmr  X  f o r 15  The m i x t u r e  and  min.  (47 umol)^^ was  and  heated  o f the phosphonate the  di-alkylated  spectroscopy,  equation  However, these compounds were not s e p a r a b l e by chromatography on silica  and  respectively.  a t room temperature  (0.47  (240)  and  (J = 6 Hz)  showed a m o l e c u l a r  Workup p r o v i d e d a 6 : 2 0 : 1 m i x t u r e  mono-alkylated  phosphonate  a t 6 3.82  t r e a t e d w i t h 18-crown-6 e t h e r  2-iodo-l-methoxymethoxyethane at  t o the a c e t a l  formula o f C ^ H g I 0 2 .  with a molecular  phosphonate  due  ICH2- protons,  and  The h i g h r e s o l u t i o n mass spectrum o f 240 215.9649, c o n s i s t e n t  6 3.40,  101). either  alumina.  2.  ICH CH OCH OCH 2  2  2  3  239 18-crown-6  I t was  expected  that  employing  ether  239 235 245  R=R>H R=H,R=CH CH OCH OMe R=R=CH CH20CH20Me 2  of  2-chloroethanol  2-iodo-l-benzyloxymethoxyethane  (244)  c h l o r o m e t h y l e t h e r i n the presence methane  at  room temperature  with  freshly  2  2  as the a l k y l a t i n g reagent would p r o v i d e a s e p a r a b l e m i x t u r e Treatment  2  (246)  of products.  distilled  benzyl  of diisopropylethylamine i n dichloro-  provided  2-chloro-1-benzyloxymethoxyethane  - 115 -  (247)  i n 86% y i e l d  (see e q u a t i o n 102).  The  nmr  spectrum  of  247  e x h i b i t e d two s i n g l e t s a t 5 4.81 and 6 4.63 due t o t h e b e n z y l and a c e t a l protons, r e s p e c t i v e l y . described  I n the H nmr s p e c t r a o f a number  i n t h i s t h e s i s t h a t c o n t a i n the -OCH2OCH3 group,  s h i f t s o f the a c e t a l protons i n v a r i a b l y S Hz)  of  A  4.56.  The spectrum  appeared  compounds  the chemical  between  6  4.68 and  o f 247 a l s o showed two t r i p l e t s a t 6 3.83 ( J = 6  and 6 3.63 ( J = 6 Hz) due t o the C1CH CH 0- and C1CH CH 02  2  2  2  protons,  respectively. Treatment provided  of  the  resolution  247  iodide  with  sodium  246  mass spectrum  i n 77%  i o d i d e i n acetone yield  (equation  a t 60°C f o r 40 h 102).  The  high  o f 246 showed a m o l e c u l a r i o n a t m/e 291.9966,  c o r r e s p o n d i n g to a m o l e c u l a r formula o f C^oH^30 I. 2  d^Ss/OH  ClCH OCH Ph 2  244  2 CH C1 P  r  2  Nal,  247  2  N  E  t  247  2  acetone  (102) >  P^X/O^O^Pn 246  F o l l o w i n g c o n d i t i o n s i d e n t i c a l w i t h those d e s c r i b e d i n the page, a dimethylformamide 239 the  s o l u t i o n o f the b i s ( t r i f l u o r o e t h y l ) p h o s p h o n a t e  was t r e a t e d s u c c e s s i v e l y w i t h sodium h y d r i d e , 18-crown-6 e t h e r , iodide  246.  After  70%  yield  (equation  and  workup and column chromatography o f the crude  p r o d u c t on s i l i c a g e l , pure mono-alkylated in  previous  phosphonate 248 was  103). The ^H nmr spectrum  isolated  o f 248 e x h i b i t e d a  5-proton m u l t i p l e t a t 5 7.34 due t o the aromatic p r o t o n s , a  singlet  at  - 116 -  6 3.75 due t o the methoxy p r o t o n s , and a d o u b l e t o f d o u b l e t o f d o u b l e t s 0 o f d o u b l e t s a t S 3.39 ( J = 4, 10, 22 Hz) due to the >CHP(0R) p r o t o n . 2  9  1-  >  N a H  D  M  ^  F  (CF,CH 0)2F CH2C02Me  %  '  >  7  2  9  (103)  > (CF CH 0)2PCHC0 Me 3  2  2  CH2CH 0CH20CH Ph  ' ^H CH 0CH 0CH Ph 2  2  2  2  2  2  18-crown-6 e t h e r  *~  2A8  With  the  available,  desired  the  use  substituted  of  this  b u t a n a l was i n v e s t i g a t e d . the  phosphonate  potassium  b i s ( t r i f l u o r o e t h y l ) p h o s p h o n a t e 248  reagent f o r the o l e f i n a t i o n o f 3-methyl-  Following S t i l l ' s procedure,  (0.74  7  of  248 (0.58 mmol) i n THF (10 mL) a t 0°C was t r e a t e d w i t h  b i s ( t r i m e t h y l s i l y l ) amide (0.64  complex *"  a solution  7 4  g) .  The  t r e a t e d w i t h 3-methylbutanal stirred  a t -78°C f o r 4 h.  esters,  249  and  250,  resultant (0.46  mmol),  and  18-crown-6 .nC^CN  s o l u t i o n was c o o l e d t o -78°C and  mmol).  The  reaction  Workup p r o v i d e d a 3:1 mixture  respectively  (87%,  equation  mixture  was  o f the Z and E 104).  Column  C02Me I (CF CH 0)2PCHC0 Me 3  2  2  lm  K  N(TMS) ,THF 2  CH2CH 0CH20CH Ph— 2  * 248  ^  ?  c  c  2.  ^ 0 - ^ P h  —  3-methylbutanal 18-crown-6 e t h e r -78°C  >  +  ( 1 0 A )  - 117 -  chromatography  of  this  material  on  silica  gel  (4 g, 230-400 mesh,  e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 9:1 v/v) a f f o r d e d a pure  sample  of  each compound f o r c h a r a c t e r i z a t i o n . The at  i r spectrum o f the l e s s p o l a r Z e s t e r 249 e x h i b i t e d a b s o r p t i o n s  1719  and 1644  tively.  The  Hz) due to  cm"'-  ^H  nmr  due  to the c a r b o n y l  spectrum o f 249  i-PrCH.2 p r o t o n s .  The  e x h i b i t e d a b s o r p t i o n s a t 1713 olefin  groups,  2.12  (J  olefinic  and 1646 The  cm"^^H  due  nmr  to  spectrum  the  i-PrCH^-  and thus r e s o n a t e a t lower f i e l d  Z  Hz)  due  carbonyl  protons  250 and  o f 250 showed a  based on comparison o f the c h e m i c a l and  (J = 7  a  triplet  The assignment  2  shifts  o f the two  i-PrCH.2-protons o f the Z isomer are d e s h i e l d e d by the  isomer.  (J = 7  the  = 7 Hz) due to the i - P r C H - p r o t o n s .  protons  respec-  showed a t r i p l e t a t 6 6.01  (J = 7 Hz) due t o the o l e f i n i c p r o t o n , and  s t e r e o c h e m i s t r y was  isomer  groups,  i r spectrum o f the more p o l a r E e s t e r  respectively.  t r i p l e t a t 6 6.90 5  alkene  t o the o l e f i n i c p r o t o n , and a t r i p l e t a t S 2.35  the  at  and  of  of  the  isomers.  The  cis  C^Me  group  than the c o r r e s p o n d i n g p r o t o n s o f the E  On the o t h e r hand, as expected, the o l e f i n i c p r o t o n produces a s i g n a l a t lower f i e l d  of  the  E  than the o l e f i n i c p r o t o n o f the  isomer. The Z s e l e c t i v i t y  o f the o l e f i n a t i o n  bis(trifluoroethyl)phosphonate contrast, S t i l l 236  with  comparison lower  et a l . .  various  7 4  248  of  (3:1,  3-methylbutanal Z:E)  was  had r e p o r t e d t h a t r e a c t i o n o f the  aldehydes  gave h i g h Z s e l e c t i v i t y  o f the s t r u c t u r e s o f the two phosphonates,  selectivity  rather  w i t h 248 must be due  s i d e c h a i n (Me vs C ^ C l ^ O C ^ O C l ^ P h ) .  with  the  low.  In  phosphonate  (>30:1, Z:E). 236  and  248,  On the  t o the presence o f a more b u l k y  I t was  thought t h a t  reducing  the  - I n e f f e c t i v e s i z e o f t h i s s i d e c h a i n by u s i n g improve the Z  phosphonate  251  might  selectivity.  (CF CH 0)2PCHC02Me 3  the  (CF CH 0) PCHC02Me  2  3  2  2  CH2CH20CH20CH Ph  Me  2  248  235  (CF CH 0) R 3  2  2  251 2.  O l e f i n a t i o n s w i t h -y-lactone q-phosphonates  It  was  expected  p r e p a r a b l e from the  that  the  reaction  7-lactone  of  tris(2,2,2-trifluoroethyl)phosphite o f these substances  phosphonate  a-bromo-7-butyrolactone (253).*  was  be with  desired  intact.  130°C  no reaction 252  thought  no-7-butyrolactone  Both 252  recovered  3  253  It  (252)*  a t 130°C f o r 2 days d i d not g i v e any o f the  (CF CH 0) P 2  would  However, h e a t i n g a mixture  p r o d u c t and most o f the bromo l a c t o n e 252 was  3  251  and 253  t h a t 251 might be a c c e s s i b l e from (254)  by  substituting  the  a-diethylphospho-  ethoxy  groups  are c o m m e r c i a l l y a v a i l a b l e from A l d r i c h Chemical  with  Co.  - 119  trifluoroethoxy  groups.  Treatment  t r i e t h y l p h o s p h i t e a t 140°C (equation  105).  for  However,  5  o f the d e s i r e d phosphonate  +  of h  the  bromo  provided  the  subsequent treatment  w i t h p h o s p h o r u s p e n t a c h l o r i d e and  EW3P  -  lactone  I  prepare decided  to investigate  f o r aldehyde  the use  olefinations,  i n order  reported  o f Z and  E e s t e r s o b t a i n e d from  reagents,  the  ratio  Furthermore, reagents  255  i s sensitive  nature  of  Nagaoka and  R  the  Kishi  groups  106). 260  provided On  a  1:9  mixture  256  o f 258  and  t h e o t h e r h a n d , r e a c t i o n o f 256  p r o v i d e d a 9:1  mixture  o f 258  Thus, o l e f i n a t i o n o f aldehydes  and  the  259, with  259,  simpler determine et  al.  7  8  phosphonate temperature.  general,  phosphonate  to give predomi-  reagents  Z o.^-unsaturated  with  251  Horner-Wittig  the r e a c t i o n  phosphonate  predominantly  example, r e a c t i o n o f the aldehyde 257  and  reported that i n  esters, while  provide  to  to the s t r u c t u r e o f the  solvent  7 9  a  Recently, K i s h i  w i t h b u l k y R groups r e a c t w i t h aldehydes  n a n t l y E a.^-unsaturated small  (105)  of  achieved.  r e a c t i o n s of aldehydes  any  the b i s ( t r i f l u o r o e t h y l ) p h o s p h o n a t e  c o u l d be  the  provide  (EtOljUL  whether h i g h Z s e l e c t i v i t y that  254  25A  to  phosphonate  7 7  251.  >  w e r e u n s u c c e s s f u l , i t was 7-lactone  254  of the phosphonate  t r i f l u o r o e t h a n o l d i d not  B r ^ ,  attempts  with  phosphonate  252  Since  252  255  esters.  with For  diisopropylphosphonate  respectively the  (see  equation  dimethylphosphonate  respectively  (equation  with dimethyl 7-butyrolactone  106).  phosphonate  - 120 -  261 was  investigated.  [(R0)PCC02Et]M  255  +  2  CH3  (RO)  PCHCO E t ,  THF  Me  CHO  C0 Et 2  tert-BuOK,  -78  C  C0 Et 2  256  259  258  The  phosphonate 261 was  butyrolactone 8  h.  A  to  OfcOjP  bulb  provide  •+-  to  carbonyl  1  9  260  R=Me  9  1  p r e p a r e d by h e a t i n g a m i x t u r e  the  s u b j e c t e d to column  group.  o f a-bromo-7a t 150°C  pure phosphonate 261  15  °°  C  chromatography  for  on  silica  (30%, e q u a t i o n 107).  The i r  > W-Ojy^  252  o f 261  262  (106)  b u l b d i s t i l l a t i o n o f the r e s u l t a n t o i l p r o v i d e d the  B r - J L  262  spectrum  R=jrPr  (252) w i t h p u r i f i e d t r i m e t h y l p h o s p h i t e  crude p r o d u c t , which was gel  257  261  showed a s t r o n g a b s o r p t i o n The H  (107)  spectrum  1772  cm"  1  due  o f 261  to  the  e x h i b i t e d two d o u b l e t s a t 5 0 3.77 ( J = 10 Hz) and 5 3.73 (J = 10 Hz) due t o the - P ( 0 C H ) p r o t o n s , 0 and a t r i p l e t of doublets a t 6 3.03 (J - 8, 24 Hz) due to the -PCH< X  nmr  at  3  2  - 121 -  proton. a t m/e  The h i g h r e s o l u t i o n mass spectrum o f 261 showed a m o l e c u l a r i o n 194.0352, c o n s i s t e n t w i t h a m o l e c u l a r f o r m u l a o f  The  reaction  o f 3-methylbutanal  C^il^O^.  w i t h the 7 - l a c t o n e phosphonate 261  ( e q u a t i o n 108), under a v a r i e t y o f e x p e r i m e n t a l c o n d i t i o n s , was gated.  investi-  The r e s u l t s a r e summarized i n T a b l e 2.  263  (108)  (MeO) P^^> 2  CHO  261  T a b l e 2:  =\  3-methylbutanal w i t h the 7 - l a c t o n e phosphonate 261  Reaction of  Reaction Conditions  Entry  Product r a t i o 263 : 264  1  NaH/benzene/rt^  2  tert-BuOK/THF/- 7 8 C  3  te r t-BuOK/THF-HMPA/-7 8 C  4  KN(TMS) /THF/18-crown-6/-78°C  5  0  c  0  2  J 264  d  3  Total isolated y i e l d (%)  64 : 36  69  73 : 27  81  77 : 23  80  >99 : <1  86  The p r o d u c t r a t i o s were determined by g l c a n a l y s i s o f the crude p r o d u c t m i x t u r e s , and were s u p p o r t e d by ^H nmr s p e c t r o s c o p y . See r e f e r e n c e 80. See r e f e r e n c e 79. See r e f e r e n c e 74.  - 122  Treatment  of  the  phosphonate  -  261 w i t h sodium h y d r i d e  i n benzene,  f o l l o w e d by a d d i t i o n o f 3-methylbutanal, gave a 64:36 mixture o f and  E  lactones,  263  and  l a c t o n e s were s e p a r a t e d spectrum and  1670  of cm"  at  S  due  1  by column chromatography on s i l i c a g e l .  The  X  H  nmr  7 Hz)  ( J = 7 Hz)  spectrum o f 263 due  due  the  olefinic  showed a t r i p l e t o f  to the o l e f i n i c p r o t o n and  to the i-PrCH^- p r o t o n s .  the more p o l a r E l a c t o n e 264  exhibited absorptions  due  alkene  to  the  carbonyl  spectrum o f 264 to  the  and  a broad t r i p l e t  out  i n THF  the Z s e l e c t i v i t y Addition  However,  base and  1681 The  X  cm"  H  nmr  7 Hz)  (J = 7 Hz)  1  due  due to  the  phosphonate  261  was  i n the presence o f potassium t e r t - b u t o x i d e a t -78°C,  improved m a r g i n a l l y  to  73:27  (Table  2,  entry  2).  o f hexamethylphosphoramide to the r e a c t i o n m i x t u r e r e s u l t e d i n  a further slight 3).  triplet  protons.  When the r e a c t i o n o f 3-methylbutanal w i t h carried  and  (J = 3,  a t S 2.09  bond,  i r spectrum of  functions, respectively.  showed a t r i p l e t o f t r i p l e t s a t 6 6.78  o l e f i n i c p r o t o n and  the i-PrCH2-  a t 1757  1752  triplets  a broad  The  ir  at  double  Z The  The  exhibited absorptions  to the c a r b o n y l group and  ( J = 4.5,  2.60  r e s p e c t i v e l y (Table 2, e n t r y 1).  the l e s s p o l a r Z l a c t o n e 263  respectively. a t 6 6.27  264,  the  improvement i n the Z:E when  the r e a c t i o n  ratio  (77:23)  potassium b i s ( t r i m e t h y l s i l y l ) a m i d e was was  carried  out  in  THF  in  18-crown-6 a t -78°C f o r 4 h, o n l y the Z l a c t o n e 263 the crude p r o d u c t .  (Table  T h i s m a t e r i a l was  the  entry  used as  the  presence  of  c o u l d be  i s o l a t e d i n 86%  2,  yield  detected  in  (Table  2,  entry 4). Employing Table  reaction  2, e n t r y 4,  conditions  identical  the o l e f i n a t i o n o f a  number  with of  those  summarized i n  aldehydes  with  the  - 123  7-lactone  phosphonate 261 was  are summarized i n T a b l e  -  investigated  ( e q u a t i o n 109).  The  results  3.  (109)  T a b l e 3:  R e a c t i o n o f aldehydes w i t h the 7 - l a c t o n e phosphonate  Aldehyde  Product r a t i o Z lactone : E lactone  Total isolated y i e l d (%)  (267)  265a :: 266a, >99:1  94%  265b :: 266b, 83:17  68%  265c :: 266c, 97:3  78%  265d :: 266d, 50:50  91%  a  Entry  261  1  heptanal  2  cyclohexanecarboxaldehyde ( 2 6 8 )  3  (E)-2-hexenal  4  benzaldehyde  b  (269) (270)  b  c  b  The p r o d u c t r a t i o s were determined by glc p r o d u c t m i x t u r e , and were s u b s t a n t i a t e d by These aldehydes were d i s t i l l e d use. T h i s aldehyde was torr).  distilled  analysis of the crude nmr s p e c t r o s c o p y .  (atmospheric p r e s s u r e ) j u s t p r i o r to  under reduced  pressure  (bp  40-45°C/15  124  In  the  reactions  aldehydes 267, described, vity.  the  268  and  of 269  products  the  -  phosphonate  (Table 3, e n t r y 1-3),  to  with under  the the  aliphatic conditions  were formed w i t h good to e x c e l l e n t Z  However, w i t h benzaldehyde, no  interesting  261  s e l e c t i v i t y was  selecti-  observed.  It  is  note t h a t Minami e t al.^Q r e p o r t e d t h a t r e a c t i o n o f  the  sodium s a l t o f the d i e t h y l phosphonate 254 w i t h benzaldehyde i n gave o n l y the E l a c t o n e 266d ( e q u a t i o n  The 7-lactone selective rane 272  Z  selective  olefination  phosphonate 261 olefination  of  benzene  110).  of  d e s c r i b e d above  aliphatic is  aldehydes  complimentary  with to  the  the E  the a l i p h a t i c aldehyde 271 w i t h the phospho-  r e p o r t e d r e c e n t l y by S e c r i s t e t a l . * *  1  (equation  111).  - 125 -  A pure sample o f each o f the l a c t o n e s 256b and 266b ( T a b l e 3, 2) was  o b t a i n e d by column chromatography o f the crude p r o d u c t mixture  s i l i c a g e l (70-230 mesh, e l u t i o n w i t h petroleum Similarly,  the  lactones  e t h e r - e t h e r , 8:2  on  v/v).  265d and 266d (Table 3, e n t r y 4) were r e a d i l y  s e p a r a b l e by column chromatography silica  entry  of  the  crude  product  g e l (230-400 mesh, e l u t i o n w i t h benzene-ether,  sample o f the E l a c t o n e 266a was  30:1  o b t a i n e d as f o l l o w s .  mixture v/v).  Treatment  on  A  pure  of  the  phosphonate 261 w i t h a s u s p e n s i o n o f sodium h y d r i d e i n benzene, f o l l o w e d by a d d i t i o n o f h e p t a n a l lactones,  265a  and  (267), gave  266a.  These  chromatography on s i l i c a g e l . the  phosphonate  mixture was  261 w i t h  a  1:1  mixture  by  Z  and  (269)  of  the  crude  E  column  S i m i l a r l y , r e a c t i o n o f the sodium s a l t  (E)-2-hexenal  subjection  the  substances were s e p a r a t e d by  i n benzene p r o v i d e d a  o f the Z and E l a c t o n e s , 265c and 266c.  obtained  of  of 1:3  The pure E l a c t o n e 266c p r o d u c t mixture  t o column  chromatography on s i l i c a g e l . The  assignment  i n T a b l e 3 was, of  o f s t e r e o c h e m i s t r y o f the o l e f i n a t i o n p r o d u c t s  i n each case, based on comparison  the o l e f i n i c p r o t o n s  and/or  the  allylic  7'-protons  s t r u c t u r e s A and B) o f the two p o s s i b l e geometric  A Z-lactone general structure A  o f the c h e m i c a l (see  isomers.  B E-lactone general structure B  listed shifts general  - 126 -  The  olefinic  protons  of  the  E isomers a r e d e s h i e l d e d by the c i s  c a r b o n y l group o f t h e l a c t o n e moiety and thus r e s o n a t e than the corresponding protons o f the Z isomers. the Z isomers, t h e a l l y l i c 7'-protons, field  at  lower  On t h e o t h e r h a n d , f o r  i f present,  resonate  at  obtained from t h e experiments Table  4  (page  127).  spectra o f the lactones, at  -0.50-0.56  isomers. these  ppm  materials,  I t i spertinent  Z  interesting to point out that,  On  stretching vibrations defined  C.  the  other  o f the Z and  i n t h e -^H nmr resonate  i n the i r spectra o f  double bond s t r e t c h i n g v i b r a t i o n s o f  hand, E  (-5-11 cm"'-) t h a n  those  of  the positions o f the carbonyl  isomers  do  not  show  any  well  differences.  S y n t h e s i s o f the aldehyde  A  that,  than the corresponding protons o f the Z  the carbon-carbon  lactones.  t o note  the o l e f i n i c protons o f the E isomers  lower f i e l d  I t i s also  products  summarized i n Tables 2 and 3 a r e t a b u l a t e d  t h e E l a c t o n e s a p p e a r a t h i g h e r wavenumbers the  lower  than those o f the E isomers.  Some o f t h e s p e c t r o s c o p i c d a t a d e r i v e d f r o m t h e o l e f i n a t i o n  in  field  15:85  mixture  of  234  the n i t r i l e s  112a a n d 112b, r e s p e c t i v e l y , was  t r e a t e d w i t h l i t h i u m d i i s o p r o p y l a m i d e i n THF-HMPA a t l-Iodo-2-methoxymethoxyethane was s t i r r e d  f o r 15  (240) was a d d e d a n d t h e r e s u l t a n t  a t 0°C f o r 30 m i n a n d a t r o o m t e m p e r a t u r e  provided the n i t r i l e  0°C  241 i n 99% y i e l d  ( e q u a t i o n 112).  for 1  h.  min.  solution Workup  - 127 -  T a b l e 4:  P a r t i a l '•H nmr and i n f r a r e d  data f o r o l e f i n a t i o n  products  d e r i v e d from r e a c t i o n s o f aldehydes w i t h the 7 - l a c t o n e phosphonate 261  Lactone  a  3  Chemical s h i f t s (5) o l e f i n i c p r o t o n aH y l i c 7 ' - p r o t o n ( s )  b  i r absorptions (cm"') uC=0 i/C=C  263  6.35  2.60  1752  1670  264  6.85  2.09  1757  1681  265a  6.24  2.70  1757  1672  266a  6.76  2.20  1757  1681  265b  6.03  3.45  1756  1669  266b  6.54  2.11  1757  1678  265c  6.57  d  1747  1647  266c  7.09  1751  1652  265d  7.02  1747  1641  266d  7.58  1742  1651  A l l compounds analysis.  d  -  c  e x h i b i t e d one peak on g l c a n a l y s i s and one spot by t i c  See s t r u c t u r e s A and B. A l l i n f r a r e d s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r spectrophotometer w i t h i n t e r n a l c a l i b r a t i o n . T h i s compound c o n t a i n s no a l l y l i c  7'-proton.  model  1710  128 -  CN  CN  1. LDA, THF-HMPA  (112) 2. ICH CH OCH OCH (240) 2  112a  2  2  3  241  112b  15:85  The  i r spectrum  due t o the n i t r i l e spectrum  of  and  olefinic  groups,  respectively.  X  H  nmr  triplet  o f d o u b l e t s a t 6 2.15 ( J =  7,  15  Hz) and  ( J - 7, 15 Hz) due t o the -CH CH 0- p r o t o n s . 2  Treatment  of  dimethoxyethane a t  the n i t r i l e 60°C  113).  The i r spectrum  2  241  for 6  c a t a l y z e d h y d r o l y s i s o f the crude  with diisobutylaluminum hydride i n  h  afforded,  after  imine, the aldehyde  workup  A  S 9.97 due t o the aldehyde  at  acid  1713  cm"  1  exhibited a singlet  proton.  1. DIBAL-H, DME, 60°C  (113)  2. H0Ac-H 0-THF, r t 2  241  and  273 (92%, e q u a t i o n  o f 273 showed a s t r o n g a b s o r p t i o n  due t o the c a r b o n y l group, w h i l e the H nmr spectrum at  The  1  241 showed a s i n g l e t a t 5 3.34 due t o the methoxy p r o t o n s ,  and a p a i r o f b r o a d 2.09  o f 241 e x h i b i t e d a b s o r p t i o n s a t 2228 and 1638 cm"  273  - 129 -  R e d u c t i o n o f the aldehyde 273 w i t h l i t h i u m aluminum h y d r i d e i n e t h e r at  room  114). to  temperature  provided  the  a l c o h o l 274 i n 95% y i e l d  (equation  The i r spectrum o f 274 showed a b r o a d a b s o r p t i o n a t 3443 cm"'- due  the  hydroxy  group.  d o u b l e t s a t 5 3.77  The  nmr spectrum o f 274 showed a p a i r o f  ( J = 11 Hz) and 6 3.68  ( J = 11 Hz) due t o the  -CH OH 2  protons.  Successive mixture with  of  J  of  dimethoxyethane  n-butyllithium  dichloridate 0°C)-'  treatment  a and  solution  of  the a l c o h o l 274 i n a 4:1  N,N,N',N'-tetramethylethylenediamine  (15 min, room t e m p e r a t u r e ) , dimethylaminophosphoro-  (12 h, room temperature), and anhydrous  afforded,  after  column  chromatography  dimethylamine  (2 h,  o f the crude p r o d u c t on  s i l i c a g e l , the phosphorodiamidate 275 (63%, e q u a t i o n 115).  The '-H  nmr  - 130 -  o f 275  spectrum  e x h i b i t e d a p a i r o f d o u b l e t s o f d o u b l e t s a t 6 4.00 ( J = 0 and S 3.94 ( J = 4, 11 Hz) due t o the -CH 0P(NMe )2 p r o t o n s ,  4, 11 Hz) and  2  2  a p a i r o f d o u b l e t s a t 6 2.67 ( J = 6 Hz) and 2.65 ( J = 6 Hz) due t o 0  the  -0P(NMe )2 p r o t o n s .  These  2  diamidate  group had been  Treatment  of  the  s p e c t r a l d a t a showed t h a t the phosphoro-  installed. phosphorodiamidate  amine s o l u t i o n o f l i t h i u m ,  i n the  -20°C  the  for  10  min  ( e q u a t i o n 116). 1.04  and  6  gave  275  absence  of  deoxygenated  The H nmr spectrum L  o f 276  w i t h an anhydrous tert-butyl  compound  276  methyl-  alcohol,  at  i n 80% y i e l d  e x h i b i t e d two s i n g l e t s a t  5  0.75, and a d o u b l e t a t 6 0.85 (J' - 6 Hz) due t o the methyl  groups i n the d e c a l i n s u b s t r u c t u r e .  The  e t h e r 276  was  tert-butvlalcohol  5 5  treated at  70°C  for  e q u a t i o n 117).  The i r spectrum  cm" .  nmr spectrum  1  due  The  X  H  with  pyridinium 12  o f 277  o f 277  h  p_-toluenesulfonate  t o g i v e t h e a l c o h o l 277  in  (91%,  showed a b r o a d a b s o r p t i o n a t 3375  e x h i b i t e d a b r o a d s i n g l e t a t S 4.50  t o the e x o c y c l i c o l e f i n i c p r o t o n s , and a p a i r o f d o u b l e t o f t r i p l e t s  a t 6 3.61 ( J = 5.5, 10 Hz) and 6 3.52 ( J = 5.5, 10 Hz) due t o the -CH 0H 2  protons.  131 -  OH PPTS,  >  tert-BuOH  70°C, 1 2 h  (117)  277  276  When t h e a l c o h o l 277 was o x i d i z e d w i t h p y r i d i n i u m c h l o r o c h r o m a t e the  presence  temperature, the  alcohol  oxalyl  of  anhydrous  sodium  a mixture o f products 277  acetate i n dichloromethane  was  obtained.  w i t h a dichloromethane  However, t r e a t m e n t o f  by  of  provided  spectrum  o f 234 e x h i b i t e d a s t r o n g a b s o r p t i o n a t 1 7 1 8 cm"'group.  234 c l e a n l y  addition  mine, ^  carbonyl  the aldehyde  T h e '-H nmr s p e c t r u m  ( J = 3.5 H z ) due t o t h e a l d e h y d e doublets  triethyla-  (85%, equation 118). due  o f 234 s h o w e d a t r i p l e t  proton,  a t room  solution of dimethylsulfoxide-  c h l o r i d e r e a g e n t a t -78°C, f o l l o w e d  8  i n  and  a  pair  of  The i r to the  a t 6 9.78  doublet  of  a t S 2.41 ( J = 3.5, 14.5 H z ) a n d 6 2.29 ( J = 3.5, 14.5 H z ) due  t o t h e -CH CHO p r o t o n s . 2  OH  1. DMSO,  (C0C1)  C H C 1 , -78°C 2  2. E t N , 3  277  2  CHO  2  >  (118)  -78°C t o r t  234  132 -  D.  S y n t h e s i s o f (±)-isolinaridiol (64) and i t s geometric isomer 278  With s u i t a b l e c o n d i t i o n s developed f o r the (Section  B)  and  required  Z  olefination  w i t h the a c q u i s i t i o n o f the aldehyde 234 ( S e c t i o n C ) ,  the stage was s e t t o e f f e c t the s y n t h e s i s o f (±)-isolinaridiol ( 6 4 ) . cold  (0°C) THF (1.9 mL) s o l u t i o n o f the phosphonate 261 (0.11 mmol) was  t r e a t e d with a toluene s o l u t i o n o f (0.12  potassium  bis(trimethylsilyl)amide*  mmol) and then 18-crown-6.nCH^CN complex (0.16 g) was added.  r e s u l t a n t s o l u t i o n was c o o l e d t o -78°C, a THF s o l u t i o n o f 234  A  (85  /imol)  of  aldehyde  was added, and s t i r r i n g was c o n t i n u e d a t -78°C f o r 4 h.  G l c a n a l y s i s o f the crude p r o d u c t showed t h a t mixture  the  The  the  olefination  products.  i t consisted  of  a  3:1  S u b j e c t i o n o f t h i s mixture to  column chromatography on s i l i c a g e l p r o v i d e d b o t h the pure Z l a c t o n e 279 (58%) and the pure E l a c t o n e 280 (19%, e q u a t i o n 119).  This reagent Chemical Co.  solution  i s commercially  available  from  Aldrich  - 133 -  The at  i r spectrum o f the l e s s p o l a r l a c t o n e 279 e x h i b i t e d  1753 cm"  the o l e f i n i c  absorptions  due t o t h e c a r b o n y l group and a t 1666 and 1635 cm"  1  linkages.  The H nmr spectrum o f 279 e x h i b i t e d a  due t o  1  1-proton  X  t r i p l e t o f t r i p l e t s a t 6 6.24 ( J •= 2.8 Hz) due t o t h e o l e f i n i c p r o t o n on the s i d e c h a i n , and a p a i r o f t r i p l e t o f d o u b l e t o f d o u b l e t s a t  S  2.89  and S 2.65 ( J = 2.5, 8, 17 Hz) due t o t h e -CH CH= p r o t o n s . 2  The  i r spectrum o f the more p o l a r l a c t o n e 280 showed a b s o r p t i o n s a t  1758 cm"  due t o t h e c a r b o n y l group and a t 1676 and 1635 cm"  1  carbon-carbon  double  bonds.  The  L  H  proton  on  the  side  due t o the  nmr spectrum o f 280 e x h i b i t e d a  1-proton t r i p l e t o f t r i p l e t s a t 8 6.76 ( J - 2.5, olefinic  1  chain,  and  a  6.5  Hz)  due  t o the  pair of multiplets at 5  2.30-2.22 and 5 2.18-2.10 due t o the -CH CH= p r o t o n s . 2  Since a v i c i n a l as  the carbonyl  o l e f i n i c p r o t o n on the same s i d e o f the double group i n an a,/9-unsaturated  a n i s o t r o p i c magnetic d e s h i e l d i n g e f f e c t lactone  279  was  bond  e s t e r would e x p e r i e n c e an  from  the c a r b o n y l  group,  the  a s s i g n e d t h e Z s t e r e o c h e m i s t r y , w h i l e the l a c t o n e 280  was a s s i g n e d the E s t e r e o c h e m i s t r y . The with  Z selectivity  t h e potassium  observed Table  (3:1, Z:E) o f the o l e f i n a t i o n o f t h e aldehyde  s a l t o f t h e phosphonate 261 was n o t as h i g h as those  i n the o l e f i n a t i o n  2,  of  e n t r y 4) and h e p t a n a l  3-methylbutanal  potassium  proved The THF  (>99% Z  (>99% Z s e l e c t i v i t y ,  Attempts t o improve the Z s e l e c t i v i t y the  234  by changing  the  selectivity,  T a b l e 2, e n t r y 1 ) . concentration  of  s a l t o f the phosphonate 261, and t h a t o f t h e aldehyde 234  t o be f r u i t l e s s . Z l a c t o n e 279, upon treatment  with diisobutylaluminum  hydride i n  a t -78°C f o r 1 h and 0°C f o r 2 h, a f f o r d e d (±)-isolinaridiol (64) i n  - 134 -  96% y i e l d  ( e q u a t i o n 120).  absorption 1636  at  3328  and 891 cm"  spectrum  of  cm"  The i r spectrum  1  the  this  material  was  shown  Feliciano* different  X  1  9  F o r comparison  purposes,  data r e p o r t e d f o r n a t u r a l i s o l i n a r i d i o l , San  l 9  those  Feliciano,  those o b t a i n e d from our s y n t h e t i c (±)-isolinaridiol a r e compiled i n  Table  5.  Reduction THF  afforded  cally diol  X  However, these H nmr d a t a a r e s l i g h t l y  spectral  broad  The H nmr  p r o v i d e d by P r o f e s s o r A. San  d e r i v e d from the a u t h e n t i c sample p r o v i d e d by P r o f e s s o r and  a  t o be i d e n t i c a l w i t h t h a t o f a  r e p o r t e d by San F e l i c i a n o e t a l .  nmr  exhibited  due t o the e x o c y c l i c t e r m i n a l double bond.  1  F i g s . 7 and 8 ) .  from those  64  due t o the hydroxy groups and a b s o r p t i o n s a t  sample o f n a t u r a l i s o l i n a r i d i o l (see  of  o f the E l a c t o n e 280 w i t h the  distinctly  diol  diisobutylaluminum  hydride  in  278 (89%, e q u a t i o n 121), which i s s p e c t r o s c o p i -  d i f f e r e n t from i s o l i n a r i d i o l  64.  The  X  H  nmr  of  the  64 (see F i g . 9) e x h i b i t e d a 1-proton t r i p l e t a t 6 5.52 ( J = 7.5 Hz)  due  t o the o l e f i n i c  proton,  a broad  s i n g l e t a t 6 4.05 due t o the =CCH.20H  *  We are g r a t e f u l t o P r o f e s s o r A. San F e l i c i a n o f o r a sample o f i s o l i n a r i d i o l and f o r c o p i e s o f i t s H nmr, i r , and mass s p e c t r a . X  137  T a b l e 5:  I.  1  H nmr s p e c t r a l d a t a o f i s o l i n a r i d i o l ( 6 4 )  Reported  Data  -41 nmr ( 2 0 0 MHz, C D C 1 ) 8: 5.32 ( t , 1H, J = 7.5 Hz, olefinic proton), 4.49 ( d , 2H, J = 1.4 Hz , o l e f i n i c p r o t o n s ) , 3.68 ( t , 2H, J = 5.7 H z , - C H C H O H ) , 2.34 ( t , 2H, 5.7 H z , -CH CH OH), 2.10 (m, 2H, - C H C H = ) , 1.04 ( s , 3H, m e t h y l p r o t o n s ) , 0.82 ( d , 3H, J = 6 H z , m e t h y l p r o t o n s ) , 0.75 ( s , 3H, m e t h y l p r o t o n s ) . 3  3  2  2  2  2  b  2  II.  Data d e r i v e d from t h e sample p r o v i d e d  by Professor  San F e l i c i a n o  -41 nmr ( 4 0 0 MHz, CDCI3) 6: 5.36 ( b r t , 1H, J = 8 Hz, olefinic proton), 4.50 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 4 . 1 8 , 4.15 ( d , d, 1H e a c h , J = 12 H z , = C C H 0 H ) , 3.74 ( b r t , 2H, J = 6 Hz, -CH CH 0H), 2.39 ( t , 2H, J = 6 H z , - C H C H 0 H ) , 2.09 (m, 2H, -CH CH=), 1.80 ( b r s, 2H, D 0 e x c h a n g e d , -OH), 1.05 ( s , 3H, m e t h y l p r o t o n s ) , 0.83 ( d , 3H, J = 7 H z , m e t h y l p r o t o n s ) , 0.77 ( s , 3H, m e t h y l p r o t o n s ) . 2  2  2  2  2  2  2  Ill.  Data d e r i v e d from our s y n t h e t i c m a t e r i a l  41 nmr ( 4 0 0 MHz, CDCI3) 5: 5.36 ( b r t , 1H, J = 8 H z , o l e f i n i c p r o t o n ) , 4.50 ( b r s , 2H, o l e f i n i c p r o t o n s ) , 4.18, 4.15 ( d , d, 1H each, J = 12 H z , = C C H 0 H ) , 3.74 ( b r t , 2H, J = 6 H z , - C H C H 0 H ) , 2.39 ( t , 2H, J = 6 H z , - C H C H 0 H ) , 2.09 (m, 2H, -CH CH=), 1.80 ( b r s, 2H, D 0 e x c h a n g e d , -OH), 1.05 ( s , 3H, m e t h y l p r o t o n s ) , 0.84 ( d , 3H, J = 7 H z , m e t h y l p r o t o n s ) , 0.77 ( s , 3H, m e t h y l p r o t o n s ) . 2  2  2  2  2  2  2  The s i g n a l s a t 6 4.2-4.1 w e r e n o t r e p o r t e d , however t h e "41 nmr s p e c t r u m o f i s o l i n a r i d i o l p r o v i d e d b y P r o f e s s o r San F e l i c i a n o showed t h a t t h e r e i s a b r o a d s i n g l e t a t -6 4.12. No h y d r o x y l  p r o t o n s were  reported.  139 protons,  a triplet  and  a triplet  E.  Synthesis of  Treatment  a t S 3.71  a t S 2 A3  (J = 6 Hz)  ( J - 6 Hz),  of  (±)-isolinaridiol  of  amount  the d i a c e t a t e 61 i n 90% y i e l d  61 e x h i b i t e d a b s o r p t i o n s a t 1742  groups and  the e x o c y c l i c o l e f i n i c  (see F i g . 10)  o f our  synthetic  and  to  t o the  (±)-isolinaridiol d i a c e t a t e  pyridine containing a catalytic provided  due  due  (64) of  -CH2CH2OH  the  -CH CH20H p r o t o n s . 2  (61)  with  acetic  anhydride  in  4-N,N-dimethylaminopyridine  ( e q u a t i o n 122).  1635  protons,  cm'  double bond.  due  1  The  (±)-isolinaridiol  X  H  The  to nmr  i r spectrum  the  carbonyl  spectral  diacetate  (61)  data were  Fig.  10  : The  300  MHz  H nmr  spectrum of  synthetic  isolinaridiol  diacetate  - 141  found  to  be  somewhat  isolinaridiol  diacetate  different (vide  Treatment o f the d i o l presence  of  281  (78%,  e q u a t i o n 123).  and  1635  278  -  from  those  w i t h a c e t i c anhydride i n p y r i d i n e  H  L  nmr  d i f f e r e n t from those r e p o r t e d For comparison, the isolinaridiol  Comparison isolinaridiol  A  n a t u r a l product.  for natural i s o l i n a r i d i o l  and and nmr  spectral  the d i a c e t a t e 281 spectral  and  o f our  Thus f a r , we  this  material  case, t h e r e our  San so  synthetic materials  little are  1747  were a l s o 1 9  natural  synthetic  (±)-iso-  are compiled i n T a b l e  data  reported  synthetic materials  natural  synthetic  (±)-iso-  does  not  show  i s i d e n t i c a l with  diacetate.  6.  for  have not been s u c c e s s f u l i n our  the  attempts  However, we  a b l e to send us a s m a l l  t h a t a p r o p e r comparison can be  seems to be  281  at  for  the racemic d i a c e t a t e 281  F e l i c i a n o w i l l be  the  diacetate  diacetate.  reported  those d e r i v e d from our  to o b t a i n a sample o f n a t u r a l i s o l i n a r i d i o l that Professor  data  w i t h those d e r i v e d from our  (61) one  ( c a t a l y s t ) gave the  s p e c t r a l d a t a (see F i g . 11)  nmr  H  diacetate  that  H  1 9  (61)  o f the  l i n a r i d i o l diacetate conclusively  1  diacetate,  l i n a r i d i o l diacetate  in  This material exhibited i r absorptions  The  1  for natural  1 9  infra).  4-N,N-dimethylaminopyridine  cm' • .  reported  amount  of  In  any  doubt t h a t the s t r u c t u r a l assignments  of  correct.  c a r r i e d out.  hope  - 143 -  T a b l e 6:  I.  H nmr s p e c t r a l data r e p o r t e d f o r n a t u r a l i s o l i n a r i d i o l d i a c e t a t e , and those d e r i v e d from our s y n t h e t i c <±)-isolinarid i o l d i a c e t a t e (61) and the d i a c e t a t e 281  i  S p e c t r a l data reported f o r n a t u r a l i s o l i n a r i d i o l diacetate •4" nmr (50 MHz, C D C l ) S: 5.45 (m, 1H, o l e f i n i c p r o t o n ) , 4.47 2H, =CCH 0Ac), 4.43 (br s, 2H, o l e f i n i c p r o t o n s ) , 4.04 ( t , 2H, J Hz, -CH CH 0Ac), 2.38 ( t , 2H, J = 6 Hz, -CH CH OAc), 1.97, 1.91 s, 3H each, a c e t y l p r o t o n s ) , 1.03 ( s , 3H, methyl p r o t o n s ) , 0.81 d , 3H, methyl p r o t o n s ) , 0.75 ( s , 3H, methyl p r o t o n s ) . 3  2  2  2  2  2  (s, = 6 (s, (br  a  I I . Data d e r i v e d from our s y n t h e t i c (±)-isolinaridiol d i a c e t a t e (61) H nmr (300 MHz, CDCI3) 5: 5.44 ( t , 1H, J = 7.5 Hz, o l e f i n i c p r o t o n ) , 4.61 ( b r s, 2H, = C C H 0 A c ) , 4.49 ( b r s, 2H, olefinic protons ), 4.13 (m, 2H, -CH CH OAc), 2.40 ( t , 2H, J - 7 Hz, -CH CH 0Ac), 2.06, 2.03 ( s , s, 3H each, a c e t y l p r o t o n s ) , 1.04 ( s , 3H, methyl p r o t o n s ) , 0.81 (d, 3H, J = 6 Hz, methyl p r o t o n s ) , 0.75 (s, 3H, methyl p r o t o n s ) . X  b  2  b  2  2  Ill.  2  2  Data d e r i v e d from the s y n t h e t i c d i a c e t a t e 281 '-H nmr (300 MHz, CDCI3) 8: 5.57 ( t , 1H, J = 7.5 Hz, olefinic proton), 4.50 ( b r s, 4H, =CCH 0Ac and o l e f i n i c p r o t o n s ) , 4.10 ( t , 2H, J = 7.5 Hz, -CH CH 0Ac), 2.43 ( t , 2H, J - 7.5 Hz, -CH CH OAc), 2.06, 2.04 ( s , s, 3H each, a c e t y l p r o t o n s ) , 1.04 ( s , 3H, methyl p r o t o n s ) , 0.82 (d, 3H, J = 6 Hz, methyl p r o t o n s ) , 0.77 ( s , 3H, methyl p r o t o n s ) . 2  2  2  No c o u p l i n g c o n s t a n t was  2  2  given.  The assignment i s based on the f a c t t h a t the o l e f i n i c p r o t o n s o f compounds d e s c r i b e d i n t h i s t h e s i s b e a r i n g the g e n e r a l structure C invariably appear a t 8 4.49 t o 4.52 i n the ^H nmr s p e c t r a and the =CCH 0Ac p r o t o n s o f compound 282 (prepared by r e d u c t i o n o f the lactone 263, T a b l e 2, f o l l o w e d by b i s - a c e t y l a t i o n o f the p r o d u c t ) appears a t 6 4.63 ( s ) . 2  general structure C  282  144 -  F.  Attempts t o o x i d i z e  (±)-isolinaridiol  (64) to (±)-Isolinaridial  R e c e n t l y , i n c o n n e c t i o n w i t h work d i r e c t e d toward the t o t a l sis  of  polygodial  (284),  Lallemand  et  al.**  3  employed  o x i d a t i o n t o o x i d i z e the d i o l 283 to the d i a l d e h y d e 284 124).  It  was  (±)-isolinaridiol  expected  synthe-  the  (75%,  (60)  Swern  equation  t h a t t h i s method c o u l d be employed t o o x i d i z e  (64) t o (±)-isolinaridial (60).  D i i s o b u t y l a l u m i n u m h y d r i d e r e d u c t i o n o f the l a c t o n e 263 p r o v i d e d the diol the  285  (85%,  e q u a t i o n 125), which was employed f o r a model study o f  o x i d a t i o n o f the d i o l 64 to the d i a l d e h y d e 60.  285 showed a b r o a d a b s o r p t i o n a t 3336 cm" a weak a b s o r p t i o n a t 1656 cm" spectrum  of  285  exhibited  The p r e p a r a t i o n thesis.  of  1  a  spectrum  of  due t o the hydroxy groups and  due to the o l e f i n i c  1  The i r  t r i p l e t a t 8 5.42  the l a c t o n e 263 was  linkage.  The -^H  nmr  ( J — 6 Hz) due t o the  d e s c r i b e d i n p. 116 o f t h i s  - 145 -  o l e f i n i c p r o t o n , a s i n g l e t a t 6 4.15 due t o the =CCH OH p r o t o n s , and two 2  t r i p l e t s a t « 3.73 ( J = 6 Hz) and S 2.39 ( J = 6 Hz) due t o the -CH CH OH 2  and  -CH2CH OH p r o t o n s , 2  Treatment Swern  respectively.  o f the d i o l 285 w i t h a  addition of t r i e t h y l a m i n e ^ mixture  ( e q u a t i o n 126). 1674  cm"  1  triplet  on  a  n  (  j column  at  solution  The i r spectrum  respectively.  o f the  reagent a t -78°C, f o l l o w e d by chromatography  s i l i c a g e l , p r o v i d e d the aldehyde  of  and the aunsaturated  The H nmr spectrum A  the  crude  286 i n 58% y i e l d  o f 286 showed a b s o r p t i o n s a t  due t o t h e s a t u r a t e d aldehyde  c a r b o n y l groups,  9.48  dichloromethane  dimethylsulfoxide-oxalyl chloride  product  2  1728 and aldehyde  o f 286  exhibited  a  S 9.60 ( J - 2 Hz) due t o the -CH CH0 p r o t o n , a s i n g l e t a t S 2  due t o the =CCH0 p r o t o n , and a t r i p l e t a t S 6.83 ( J = 8 Hz) due t o  the o l e f i n i c  proton.  0  H  1. D M S O - ( C O C l ) , C H C l , -78°C 2  2. Et,N,  285  X  0H  3  2  2  )  v  /CHO  (126)  v_run  -78°C t o 0°C  286  L  M  U  - 146  However, conditions  The  and  been g e n e r a t e d . successful. 64 had  (60)  were not  of  cm"',  at  this  stage  been used, f u r t h e r  overall  (see page  of  a t e r r i b l e mixture showed  the of  absorphad  o f the work, a l l o f the  attempts  to  prepare  available  (±)-isolinaridial  possible.  yield  (±)-isolinaridiol (64) identity  under  s u g g e s t i n g t h a t the d e s i r e d d i a l d e h y d e  work summarized above c o n s t i t u t e s the  an  (64)  However, a l l attempts to p u r i f y the d i a l d e h y d e were not  (±)-isolinaridiol (64)  with  (±)-isolinaridiol  above p e r s i s t e n t l y p r o v i d e d  1673  Since,  diol  oxidize  i r spectrum o f the crude p r o d u c t m i x t u r e  a t 1727  The  to  described  products. tions  attempts  -  successful total  i n a t o t a l o f n i n e steps from the n i t r i l e of  19%  provided  (see  Scheme 26).  112  B i s - a c e t y l a t i o n of  (±)-isolinaridiol d i a c e t a t e  t h i s m a t e r i a l w i t h n a t u r a l 61 has  141).  synthesis  (61).  The  not y e t been e s t a b l i s h e d  146a  H-*)  241 273  61 R=Ac  Scheme 26  Reagents and c o n d i t i o n s : i , l i t h i u m diisopropylamide, THF-HMPA, 0°C; I(CH ) 0CH 0Me, 0°C -+ room temp., 99%; i i , B u A l H , DME, 60°C, 6 h ; H O A c - H 0 , THF, r o o m temp., 10 h , 9 2 % ; i i i , LiAlH^, Et 0, room temp., 95%; i v , B u L i , DME-TMEDA; C l P O N M e , room temp., 10 h ; M e N H , 0°C, 2 h , 6 3 % ; v , L i , M e N H , -20°C, 10 m i n , 8 0 % ; v i , p y r i d i n i u m p.-to l u e n e s u l f o n a t e , B u 0 H , 70°C, 9 1 % ; v i i , D M S O - ( C 0 C 1 ) , C H C 1 , -78°C; E t N , -78°C t o room temp., 8 5 % ; v i i i , d i m e t h y l - y - b u t y r o l a c t o n e p h o s p h o n a t e ( 2 6 1 ) , lithium bis(trimethylsilyl)amide, THF, 0°C; 1 8 - c r o w n - 6 • n C H C N c o m p l e x , -78°C, 4 h , 5 8 % ; i x , B u A l H , THF, -78 -+ 0°C, 9 6 % ; x, A c 0 , DMAP, p y r i d i n e , 90%. i  2  2  2  2  2  2  n  2  2  2  2  t  2  2  2  3  3  i  2  2  - 147  III.  Miscellaneous  In the chemical l i t e r a t u r e , reported  diterpenoid  which the d e c a l i n instead  natural  there  are a  products  substructure  has  fairly  bearing  an  a general  endocyclic  (64).  Examples i n c l u d e  the  acid  289,  8 6  the furano-olefin  kolav-3-en-15-oic a c i d  (292),  287 R=C02H R'=H 288 R=CH 0HR'=H 289 R=H R=C02H 2  kolavenic  8 9  acid  (287),  290,  and k o l a v e l o o l  8 7  number  8 4  function  (55) a n d i s o l i n a r kolavenol  junceic (293).  of  structure i n  olefinic  o f an e x o c y c l i c double bond as i n p a l a u o l i d e  idiol  large  acid  8 5  290 R=Me 291 R=C02H  (288),  8 5  (291),  8 8  - 148 -  In order i n our t o t a l for  the  t o employ t h e m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n sequence used s y n t h e s i s o f (±)-palauolide  construction  natural products, double bond i n t o  of  ( 5 5 ) a n d (±)-isolinaridiol ( 6 4 )  the decalin substructure  o f t h i s category  of  c o n d i t i o n s w o u l d have t o be d e v e l o p e d t o i s o m e r i z e t h e the ring  (Scheme 2 8 ) .  Scheme 28  - 149 -  In  connection  with  a v a r o l , Sarma e t a l .  work  directed  toward  r e p o r t e d t h a t rhodium  9 0  i s o m e r i z a t i o n o f a -2:1 mixture  the t o t a l  synthesis of  (III) chloride  catalyzed  o f 294 and 295 f u r n i s h e d e x c l u s i v e l y the  d i m e t h y l e t h e r 294 ( e q u a t i o n 127).  MeO  MeO  MeO  OMe  OMe  RhCl , 3  EtOH  reflux  295  Attempts were made t o i s o m e r i z e number  of  palauolide 114  intermediates prepared (55) and i s o l i n a r i d i o l  the  exocyclic  d u r i n g the course (64).  o b t a i n e d i n each case  3  complicated  EtOH, r e f l u x  or £-TsOH, EtOH, r e f l u x  (KAPA)  9 i  of  of  a  o f the s y n t h e s i s o f  o f rhodium ( I I I ) c h l o r i d e mixture  of  products  9 0  was  ( e q u a t i o n 128).  RhCl ,  Treatment  bond  When a s o l u t i o n o f the decalone  i n e t h a n o l was r e f l u x e d i n the presence  or o f p_-toluenesulfonic a c i d , a  double  the  alcohol  126  with  complicated  (128)  mixture  potassium  i n 3-aminopropylamine (APA), o r w i t h rhodium  3-aminopropylamide (III) chloride  9 0  - 150 -  in  ethanol,  gave, i n each case, o n l y r e c o v e r e d s t a r t i n g m a t e r i a l .  same r e s u l t was  observed when the n i t r i l e  112  was  subjected  to  The  similar  reaction conditions.  During  the  investigation  o f the use o f d i m e t h y l b o r o n bromide^  c l e a v e the methoxymethyl group o f compound 276, desired nmr  277  material  d i m e t h y l b o r o n bromide (6 h ) , the a l c o h o l 296 The a l c o h o l 296 hydroxy  group.  a t 6* 5.18 8  1.57  due due  e x h i b i t e d two 6  Hz)  mixture  Thus, i t appeared  was  that  due  in  dichloromethane  was  o b t a i n e d i n 84% y i e l d  ' H nmr  spectrum  o f 296  (^H  reaction Indeed,  treated  wtih  equiv.) a t -78°C f o r a p r o l o n g e d p e r i o d o f  time  ( e q u a t i o n 130).  e x h i b i t e d an i r a b s o r p t i o n a t 3304 cm"'  The  the  obtained  this  was  due  to  showed a v e r y broad  the  singlet  t o the e n d o c y c l i c o l e f i n i c p r o t o n , and a b r o a d s i n g l e t to  the  vinyl  methyl  s i n g l e t s a t 8 1.00 to  the  methyl  protons.  and 0.73,  The  ' H nmr  i n the f u r a n o - o l e f i n  s u b s t i t u e n t s on the b i c y c l i c moiety.  290.  8 7  at  spectra also  and a d o u b l e t a t 8 0.87  c h e m i c a l s h i f t s are v e r y s i m i l a r to those r e p o r t e d f o r the protons  of  be used to e f f e c t the d e s i r e d double bond i s o m e r i z a t i o n .  when a s o l u t i o n o f the e t h e r 276  (6  3:1  and the i s o m e r i z e d m a t e r i a l 296  s p e c t r o s c o p y , e q u a t i o n 129).  could  a  to  (J  «=  These  corresponding  - 151 -  1.56 br s  290  - 152 -  EXPERIMENTAL  General  Proton  n u c l e a r magnetic resonance ( H nmr) s p e c t r a were r e c o r d e d on X  e i t h e r a Bruker model WP or  Bruker  model  WH  80, Bruker model HXS  400  spectrometers  270, V a r i a n model  using deuterochloroform  s o l v e n t and t e t r a m e t h y l s i l a n e (TMS) as the i n t e r n a l dard.  Signal  positions  Coupling constants of  protons,  or  given i n parts per m i l l i o n  ( J - v a l u e s ) a r e g i v e n i n Hz.  A b b r e v i a t i o n s used a r e :  s,  stan-  (5) from  The m u l t i p l i c i t y ,  singlet;  300  as the  external  assignments ( i f p o s s i b l e ) , and c o u p l i n g c o n s t a n t s  i n parentheses. triplet;  are  XL  d,  TMS.  number  are given  doublet;  t,  q, q u a r t e t ; m, m u l t i p l e t ; b r , broad; v, v e r y .  Carbon n u c l e a r magnetic resonance ( C nmr) s p e c t r a were r e c o r d e d i 3  a B r u k e r model WH 400 spectrometer 300 TMS  spectrometer  a t 75.3 Hz u s i n g d e u t e r o c h l o r o f o r m  as the i n t e r n a l s t a n d a r d .  million  (5) from  Infrared  model  as the s o l v e n t and  S i g n a l p o s i t i o n s are given i n  parts  ( i r ) s p e c t r a were r e c o r d e d e i t h e r on a P e r k i n - E l m e r  Perkin-Elmer  XL  per  TMS.  1710 F o u r i e r t r a n s f o r m a  a t 100.6 Hz o r on a V a r i a n  on  model  spectrophotometer w i t h i n t e r n a l c a l i b r a t i o n o r on  model 710B spectrophotometer u s i n g the 1601 cm"  1  band o f  polystyrene f i l m f o r c a l i b r a t i o n . Low r e s o l u t i o n mass s p e c t r a (LRMS) were CH4B spectrometer.  recorded  on  a  Varian/MAT  High r e s o l u t i o n mass s p e c t r a (HRMS) were r e c o r d e d on  a K r a t o s / A E l MS 50 o r MS 902 spectrometer.  I n cases  of  compounds  with  - 153 -  trimethylstannyl based on ' 2 0 g  n  groups  a n (  j  w  e  r  e  m  a  the m o l e c u l a r weight d e t e r m i n a t i o n s (HRMS) were d  on the (M -15) peak. +  e  G a s - l i q u i d chromatography  ( g l c ) was performed on e i t h e r  a  Packard model 5880 o r model 5890 c a p i l l a r y gas chromatograph, a flame i o n i z a t i o n d e t e c t o r and a 25 m x 0.21  mm  fused  Hewlett-  both using  silica  column  c o a t e d w i t h c r o s s - l i n k e d SE-54. Thin  layer  chromatography  a v a i l a b l e aluminum backed  silica  ( t i c ) was  performed  gel plates  on  commercially  ( E . Merck,  type  V i s u a l i z a t i o n was accomplished w i t h i o d i n e vapor, u l t r a v i o l e t 5% s o l u t i o n o f ammonium molybdate Conventional  column  i n 10% aqueous  chromatography  sulfuric  9  silica  g e l ( E . Merck, S i l i c a G e l 60).  s i l v e r n i t r a t e was p r e p a r e d a c c o r d i n g t o solution  of  12.5  homogeneous.  over  (w/v).  w  a  s done  on  230-400  S i l i c a g e l impregnated  the  following  with  procedure.  A  gel with s t i r r i n g u n t i l  the  slurry  Most o f the water was removed under reduced p r e s s u r e  (20 t o r r ) and the s i l i c a torr)  acid  g o f s i l v e r n i t r a t e i n 100 mL o f d i s t i l l e d water was  added t o 50 g o f 70-230 mesh s i l i c a was  l i g h t or a  was done on 70-230 mesh s i l i c a (E.  Merck, S i l i c a G e l 60) w h i l e f l a s h chromatography ^ mesh  5554).  g e l was  dried  under  reduced  pressure  (0.02  D r i e r i t e o v e r n i g h t a t room temperature w i t h p r o t e c t i o n  from  light. Melting melting  points  point  (uncorrected)  apparatus.  were  measured  on  D i s t i l l a t i o n temperatures  i n d i c a t e d as a i r - b a t h temperatures o f K u g e l r o h r U n l e s s o t h e r w i s e s t a t e d , a l l r e a c t i o n s were  a  Fischer-Johns  (uncorrected) are  distillations. carried  out  under  an  atmosphere o f d r y argon, w i t h d r y s o l v e n t s i n flame d r i e d glassware. C o l d temperatures were m a i n t a i n e d by the use o f the f o l l o w i n g b a t h s :  - 154 -  aqueous c a l c i u m c h l o r i d e / C 0 (-48°C), All  chloroform/C0  2  (-20°C, -30°C,  (-63°C),  2  2  (-78°C).  2  Reagents  Petroleum  ether  r e f e r s t o a h y d r o c a r b o n m i x t u r e w i t h b.p.  Ether r e f e r s to d i e t h y l ether. benzene  were  distilled  Tetrahydrofuran, ether,  Iodomethane  was  30-60°C.  dimethoxyethane  from sodium benzophenone k e t y l .  methane and c a r b o n t e t r a c h l o r i d e were d i s t i l l e d xide.  acetonitrile/C0  9 3  temperatures r e c o r d e d were i n degrees C e l s i u s .  S o l v e n t s and  and  acetone/C0  -40°C),  passed  from  Dichloro-  phosphorus  pento-  through a s h o r t colum o f b a s i c alumina  ( a c t i v i t y I) b e f o r e use. Diisopropylamine,  triethylamine,  hexamethylphosphoramide, distilled sieves.  dimethyl  sulfoxide,  E t h a n o l and methanol was  dried  Dimethylformamide  was  Ethylamine was  were  over dried  distilled  activated over  4A  were  molecular  t o l u e n e and dimethylamine  distilled from  4A  from l i t h i u m .  magnesium. 3A  powdered  activated  lutidine,  acetonitrile  activated  N,N,N',N'-Tetramethylethylenediamine, from sodium.  collidine, and  from c a l c i u m h y d r i d e and s t o r e d over  were d i s t i l l e d  alcohol  pyridine,  tert-Butvl  molecular  molecular  sieves.  sieves  9 4  and  d i s t i l l e d b e f o r e use. p_-Toluenesulfonyl  c h l o r i d e - * was  chloroform-petroleum ether. chloride was  9  p u r i f i e d by r e c r y s t a l l i z a t i o n from  Phosphorus  t r i c h l o r i d e and  were f r e s h l y d i s t i l l e d b e f o r e use.  d i s t i l l e d under reduced p r e s s u r e (~55°C/16  Boron  trimethylsilyl-  trifluoride-etherate  torr).  Benzyl  chloro-  - 155 -  methyl  e t h e r was  d i s t i l l e d under reduced p r e s s u r e (-120°C/16 t o r r ) .  Triethylphosphite  and  trimethylphosphite  decanted and d i s t i l l e d b e f o r e use. s t o r e d under  bromide-dimethyl  method d e s c r i b e d by Wats *" and 9  described  Hexamethylditin  by P o s n e r .  sulfide  by removal  complex  phenylthiocopper  was  distilled  was was  prepared  and  with  magnesium  by  prepared  Magnesium b r o m i d e - e t h e r a t e  9 7  by the r e a c t i o n o f 1,2-dibromoethane followed  d r i e d over sodium,  argon.  Copper(I)  method  were  was  metal  o f e t h e r under reduced p r e s s u r e (0.02  by  the the  prepared  in  ether,  t o r r ) a t room  temperature. T r i p h e n y l p h o s p h i n e was ethyl  acetate.  p u r i f i e d by r e c r y s t a l l i z a t i o n from  N-Bromosuccinimide  18-Crown-6 e t h e r was  was  recrystallized  under reduced p r e s s u r e (0.02 Tetra-n-butylammonium  r e c r y s t a l l i z e d from h o t water.  from  torr). * 7  fluoride,  dry  acetonitrile  and  freeze  dried  dried  p r e p a r e d by the t i t r a t i o n o f hydro-  under reduced p r e s s u r e (0.02  a m i n o p h o s p h o r o d i c h l o r i d a t e was  and  1  f l u o r i c a c i d w i t h tetra-n-butylammonium h y d r o x i d e , was -0°C  methanol-  crystallized torr).  at  Dimethyl-  p r e p a r e d by the method d e s c r i b e d by Walsh  op et  al.  Phenoxythiocarbonyl  d e s c r i b e d by M i y a z a k i . "  chloride  was  u  was  by  P y r i d i n i u m p_-toluenesulf onate was  the method d e s c r i b e d by M i y a s h i t a e t a l . ' ^ phosphonoacetate  prepared  Methyl  the method prepared  bis(trifluoroethyl)-  p r e p a r e d by the method d e s c r i b e d by S t i l l  Manganese(IV) o x i d e was  p r e p a r e d by the r e a c t i o n  permanganate and manganese s u l f a t e . ' ^ ' by m i x i n g sodium and mercury.'^2  by  between  Sodium amalgam (4%) was  et  al.  7  4  potassium prepared  - 156 -  S o l u t i o n s o f m e t h y l l i t h i u m i n e t h e r and were  obtained  from  Aldrich  Chemical  u s i n g the procedure o f K o f r o n e t a l . ' hydride  u 3  n-butyllithium  i n hexanes  Co., I n c . and were s t a n d a r d i z e d Potassium  hydride  and  were washed f r e e o f o i l w i t h d r y e t h e r , d r i e d under  sodium  a stream o f  argon and weighed b e f o r e u s e . All  o t h e r r e a g e n t s were c o m m e r c i a l l y  without f u r t h e r  available  THF The  a cold  -78°C.  solution  was  (115)  (42 mmol) as a s o l u t i o n i n hexanes.  s t i r r e d a t 0°C f o r 15 min and r e c o o l e d t o  3-Methyl-2-cyclohexen-l-one  (4.5 mL, 40 mmol) was added  and t h e m i x t u r e was s t i r r e d f o r 30 min a t -78 C. C  to  overnight. with  water.  warm  gradually  once  room temperature,  The r e a c t i o n mixture was d i l u t e d w i t h  mixture  was  and then was s t i r r e d pentane,  and  washed  The o r g a n i c l a y e r was s e p a r a t e d and the aqueous l a y e r was  e x t r a c t e d twice w i t h washed  to  dropwise  To the r e s u l t a n t white  s l u r r y was added iodomethane (5 mL, 80 mmol), the r e a c t i o n allowed  utilized  (-78°C) s o l u t i o n o f d i i s o p r o p y l a m i n e (8.4 mL, 60 mmol) i n  (50 mL) was added n - b u t y l l i t h i u m resulting  were  purification.  P r e p a r a t i o n o f 3.6-dimethyl-2-cyclohexen-1-one  To  and  with  pentane.  The  organic  extracts  were  combined,  2N h y d r o c h l o r i c a c i d and t h r e e times w i t h b r i n e , and  - 157 -  then were d r i e d  (MgSO^), f i l t e r e d and c o n c e n t r a t e d .  Distillation the  remaining  [bp 40-42°C/0.02 t o r r  (lit.  3 0  bp 95-100°C/22 t o r r ) ] , o f  o i l y i e l d e d 4.6 g (93%) o f the cyclohexenone 115.  m a t e r i a l was homogeneous by g l c a n a l y s i s and e x h i b i t e d i r ( f i l m ) : 1672,  1635 c m ; H nmr (80 MHz) 5: -1  This 3031,  5.83 (m, l H , o l e f i n i c p r o t o n ) , 3.72  X  (m, 1H, H ) , 2.50-1.40 (m, 4H, methylene p r o t o n s ) , 1.96 ( b r s, 3H, v i n y l A  methyl p r o t o n s ) , 1.13 (d, 3H, J = 7 Hz, methyl p r o t o n s ) .  P r e p a r a t i o n o f 5 - c h l o r o - 2 - t r i m e t h y l s t a n n v l - l - p e n t e n e (39)  H  To THF The  a  cold  B  SnMe  3  (-20°C) s o l u t i o n o f h e x a m e t h y l d i t i n  (16 mL, 70 mmol) i n  (500 mL) was added m e t h y l l i t h i u m (80 mmol) as a s o l u t i o n resulting  then was  cooled  complex  to  -78°C.  Solid  copper(I)  bromide-dimethylsulfide  (14.8 g, 60 mmol) was added i n one p o r t i o n and the mixture was  reddish  brown  s o l u t i o n was r e c o o l e d t o -78°C.  ml, 60 mmol) was added and the r e a c t i o n mixture h.  ether.  p a l e y e l l o w s o l u t i o n was s t i r r e d a t -20°C f o r 20 min and  s t i r r e d a t -78°C f o r 5 min and then a t -63°C f o r 30 min.  6  in  Acetic  acid  s t i r r e d f o r 10 min. petroleum  ether  (3.4 mL,  60  added.  resulting  5-Chloro-1-pentyne (6.4 was s t i r r e d a t -78°C f o r  mmol) was added and the mixture was  S a t u r a t e d aqueous  were  The  ammonium  The mixture  chloride  (pH  8) and  was a l l o w e d t o warm t o room  - 158 -  temperature and was s t i r r e d v i g o r o u s l y w i t h exposure t o a i r . aqueous  layer  was  s e p a r a t e d and e x t r a c t e d twice w i t h p e t r o l e u m  The combined e x t r a c t was washed once chloride  (pH  8)  and  twice  f i l t e r e d and c o n c e n t r a t e d . column  chromatography  ether).  Distillation  of of  The  with The  on  with  saturated  brine,  material  g e l (450  [bp 95-100°C/15 t o r r  was  1  0  (MgSO^),  subjected  g, e l u t i o n w i t h  (lit.  to  petroleum  bp 80-85°C/25  4  ether.  ammonium  and then was d r i e d  residual  silica  aqueous  blue  torr)]  the o i l o b t a i n e d from the a p p r o p r i a t e f r a c t i o n s p r o v i d e d 9.6 g (62%) the c h l o r i d e 39 as a c o l o r l e s s o i l .  glc  3040, 930 cm* ; H nmr (80 MHz) 6:  a n a l y s i s and e x h i b i t e d i r ( f i l m ) :  5.71  ( d t , 1H, J = 2.5, 1.2 Hz, J  2.5,  0.8  (br  Hz,  Isn-H  t , 2H, J <= 7 Hz,  =  7  0  H z  >  H  B>•  allylic  -CH CH CH C1), 0.15 ( s , 9H, J 2  2  2  Preparation  of  S n  3  5  1  2  1  5  0  H z  >  H  X  A>' 5.23 ( d t ,  1H,  J  =  2H, J = 7 Hz, - C H C l ) , 2.43 2  CH ), S n  1  -H = -  T h i s m a t e r i a l was homogeneous by  1.89  (quintet,  2H,  J  -  7  Hz,  - H = 52/54 Hz, -SnMe ). 3  5-f 2 - ( 5 - C h l o r o - l - p e n t e n v l ) 1 - 2 . 5 - d i m e t h v l c v c l o h e x a n o n e  (121)  To a c o l d (39)  (1.7  g,  (-78°C) s o l u t i o n o f 5 - c h l o r o - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n e 6.4  mmol)  i n THF  m e t h y l l i t h i u m i n e t h e r (7.1 mmol).  (50 mL)  was  added  A f t e r the mixture h a d  a solution of been  stirred  - 159 -  at  -78°C f o r 20 m i n , s o l i d m a g n e s i u m b r o m i d e - e t h e r a t e  was a d d e d i n o n e p o r t i o n a n d t h e r e s u l t i n g m i l k y for  an  additional  20  min.  S o l i d copper(I)  c o m p l e x ( 0 . 2 8 g, 1.4 m m o l ) , b o r o n mmol)  and  After 3  the  ( 1 . 7 g, 6.6 mmol)  solution  was  stirred  bromide-dimethyl  sulfide  trifluoride-etherate  ( 0 . 7 1 mL,  k e t o n e 115 ( 0 . 7 5 mL, 5.3 mmol) w e r e a d d e d s u c c e s s i v e l y .  the r e s u l t i n g b r i g h t yellow mixture  h a d b e e n s t i r r e d a t -78°C  h , s a t u r a t e d a q u e o u s ammonium c h l o r i d e (pH 8) was a d d e d .  was w a r m e d t o r o o m t e m p e r a t u r e a n d s t i r r e d v i g o r o u s l y w i t h air.  The  petroleum aqueous  blue  aqueous  ether.  layer  was s e p a r a t e d  The c o m b i n e d o r g a n i c  ammonium  chloride  colorless showed -2:1. nmr  oil.  torr)  of  the  6":  4.93  (br  s,  to with  once  with  times w i t h b r i n e , and then (air-bath  o i l provided  temperature  0.93 g ( 7 7 % ) o f a nmr  spectroscopy  o f e p i m e r s o f 121 i n t h e r a t i o o f  This material exhibited i r (film): MHz)  mixture  exposure  washed  A n a l y s i s o f t h i s m a t e r i a l by g l c and  that i t consisted of a mixture  (80  was  Distillation  remaining  The  for  and e x t r a c t e d t w i c e  extract  (pH 8) a n d t h r e e  was d r i e d (MgSO^) a n d c o n c e n t r a t e d . 88-89°C/0.02  5.8  3 0 9 8 , 1 7 0 5 , 1 6 4 0 , 905 c m " ; 1  -1.3H, o l e f i n i c  (br  2H, - C H C 1 ) , 2.9-1.2 (m, 1 1 H ) , 1.15 ( s , -1H, t e r t i a r y m e t h y l o f  -2H,  tertiary  isomer),  3.59  2  1.05 ( d , -2H, J = 7 H z , -CHCH3 o f m a j o r i s o m e r ) , methyl o f major isomer),  of minor isomer). 228.1276.  minor  o f the major  4.80 (m, -0.7 H, o l e f i n i c  minor isomer),  of the  H  isomer), t,  protons  protons  X  1.03 ( s ,  1.00 ( d , -1H, J = 7 H z , -CHCH3)  E x a c t Mass c a l c d . f o r C  1 3  H2i  3 5  C10:  228.1281;  found:  160  Preparation  o f the ketones 114 and  -  122  114 To  a  s o l u t i o n o f potassium t e r t - b u t o x i d e  butyl alcohol  (40 mL)  was  f o r 12 h.  The  with  (10 mL)  r e a c t i o n mixture was  cooling  and  The  brine  dried  then  was  and  neutralized  combined e x t r a c t was (MgSO^)  and  g (89%)  t h i s m a t e r i a l was  chromatography  o f the  three  times  washed t h r e e  times  with  Distillation  remaining  oil  cm" ; 1  The X  H  by  concentration  5H), 3H),  and  t r a n s ketone 114 nmr  yielded  A  (400 1.96  MHz)  (0.22  g) on s i l i c a  ( d t , 1H,  1.32-1.15 (m,  o f the a p p r o p r i a t e  Thus column  g e l impregnated w i t h  t r a c e amounts of the l e s s p o l a r  4.70  (br s, 2H,  J - 4 Hz,  1H),  0.99  (d, 3H,  3086, 1713,  cis 1638,  o l e f i n i c protons),  13 Hz),  25:1,  f r a c t i o n s provided  exhibited i r (film):  5:  portion  to column chromatography, so t h a t a pure  available for characterization.  of this material  t r a n s ketone 114  122.  (m,  extracted  s i l v e r n i t r a t e (25 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r ,  followed  (m,  hydrochloric  compounds i n a r a t i o o f 94:6.  subjected  sample o f each compound was  25%  2N  o f a c o l o r l e s s o i l . G l c a n a l y s i s o f t h i s o i l showed t h a t i t  c o n s i s t e d o f a m i x t u r e o f two of  with  (6.3  s t i r r e d a t 30°C  concentrated.  ( a i r - b a t h temperature 80-85°C/0.02 t o r r ) o f the 4.6  g, 55 mmol) i n t e r t -  the s o l u t i o n was  the r e s u l t a n t m i x t u r e was  with petroleum ether. and  (6.2  added a s o l u t i o n o f the c h l o r o ketone 121  g, 27 mmol) i n t e r t - b u t a n o l  acid  122  1.90-1.78 (m,  J = 6.0  Hz,  v/v)  0.17  g  ketone 895,  876  2.40-2.04  2H) , 1.69-1.50  methyl  protons),  - 161 -  0.87  ( s , 3H,  a n g u l a r methyl p r o t o n s ) .  ( c a r b o n y l c a r b o n ) , 155.85 ary  olefinic  carbon),  1 3  (quaternary o l e f i n i c  c a r b o n ) , 58.01, 44.51 ( t e r t i a r y  (methyl  carbons).  found:  192.1515.  Exact  Mass  1  l  ti  nmr  (400 MHz)  p r o t o n s ) , 2.39-2.25 (s,  c a r b o n s ) , 35.92  calcd.  The c i s ketone 122 e x h i b i t e d i r ( f i l m ) : 8:  (second-  (quaternary  carbons),  f o r C H2oO:  18.91,  192.1514;  13  3084, 1708, 1639,  894,  4.74, 4.63 ( b r s, b r s, 1H each,  (m, 4H), 2.17-2.08  204.46  c a r b o n ) , 105.54  35.92, 32.19, 31.75, 26.61, 21.05 (secondary  14.36  cm' ;  C nmr (100.6 MHz) 6:  874  olefinic  (m, 2H), 1.92-1.55 (m, 6H),  1.31  3H, a n g u l a r methyl p r o t o n s ) , 0.98 (d, 3H, J - 6 Hz, methyl p r o t o n s ) .  E x a c t Mass c a l c d . f o r C H o O : 13  2  192.1514;  found:  192.1517.  P r e p a r a t i o n o f the a l c o h o l 125  To a s o l u t i o n - s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e mmol)  mg,  0.57  i n e t h e r (2 mL) was added dropwise a s o l u t i o n o f the t r a n s ketone  114 (91 mg, 0.47 mmol) i n d r y e t h e r (0.5 mL). stirred  The r e a c t i o n mixture  was  f o r 3 h and then was t r e a t e d w i t h s o l i d sodium s u l f a t e decahy-  d r a t e u n t i l the e v o l u t i o n o f gas ceased. the  (22  residue  was  washed  three  times  c o n c e n t r a t e d and the r e s i d u a l o i l was  The mixture was with  ether.  distilled  filtered  and  The f i l t r a t e was  (air-bath  temperature  - 162 -  110-115°C/0.5  torr)  to  yield  76  mg  (84%) o f the a l c o h o l 125.  m a t e r i a l was homogeneous by g l c a n a l y s i s and e x h i b i t e d i r (br),  This  (film):  3490  3075, 1637, 895 c m ; H nmr (400 MHz) 5: 4.55 ( t , 1H, J = 1.5 Hz, -1  X  o l e f i n i c p r o t o n ) , 4.53 ( b r s, 1H, o l e f i n i c p r o t o n ) , 2.40  (br dt,  1.95-1.80 angular  1H  J  =  4,  (m, 2H), 1.70-1.30  12  3.56 ( b r s, 1H, H ) , A  Hz, Hg), 2.14 ( b r d, 1H, J 12 Hz, H ) , c  (m, 7H), 1.20 ( b r s,  2H),  1.17  ( s , 3H,  methyl p r o t o n s ) , 0.98 (d, 3H, J = 6 Hz, methyl p r o t o n s ) .  Mass c a l c d . f o r C  1 3  H  2 2  0:  194.1670;  found:  Exact  194.1670.  P r e p a r a t i o n o f the a l c o h o l 126  L i q u i d ammonia containing reflux the  (15 mL) was condensed i n t o a c o l d  calcium  (55  ketone  114  r e f l u x e d f o r 45 min. (150 The  mg, 14 mmol) and the mixture  ( d r y i c e - a c e t o n e condenser) f o r 10 min.  trans  (-78°C) d r i e d f l a s k was s t i r r e d under  An e t h e r e a l s o l u t i o n  (50 mg, 1.3 mmol) was added and the mixture  The r e a c t i o n mixture  was  quenched  with  ul,) and water (2 mL) and then was e x t r a c t e d t h r e e times w i t h combined o r g a n i c e x t r a c t was washed t h r e e times  (MgSO^) 80-82°C/0.5 solidified  and  concentrated.  torr)  yielded  on c o o l i n g .  38  Distillation mg  (75%) o f  with  brine,  (air-bath the  alcohol  of was  ethanol ether. dried  temperature 126  which  R e c r y s t a l l i z a t i o n from e t h e r a f f o r d e d c o l o r l e s s  - 163  prisms, and  m.p.  129-130°C.  T h i s m a t e r i a l was  homogeneous by  e x h i b i t e d i r (CHC1 ): 3300 ( b r ) , 3080, 1642, 3  (400 MHz)  5:  = 1.4  o l e f i n i c p r o t o n ) , 3.04  Hz,  J = 4, (m,  -  4.62  12 Hz,  1H),  ( t , 1H,  Hg),  2.14  1.71-1.14 (m,  ( s , 3H,  angular  J = 1.7  Hz,  9H),  methyl  1.05  J = 9 Hz,  J - 12 Hz,  (d, 3H,  protons).  895  H ), c  J = 6 Hz,  Exact  Mass  ^  1  H ),  2.35  1.99  (m,  A  analysis  cm" ;  o l e f i n i c p r o t o n ) , 4.59  ( t , 1H,  (br d, 1H,  1035,  glc  nmr  ( t , 1H,  J  (br d t ,  1H,  1H),  1.88  methyl p r o t o n s ) , calcd.  for  0.98  C13H22O:  194.1670; found: 194.1670.  P r e p a r a t i o n o f the t o s y l a t e  127  OTs  A  s o l u t i o n o f the a l c o h o l 126  chloride mmol) h.  in  The  sodium trated. silica  (26 mg,  0.13  (22 mg,  0.11  mmol), p . - t o l u e n e s u l f o n y l  mmol) and 4-N,N-dimethylaminopyridine (16 mg,  dichloromethane  (2 mL)  was  s t i r r e d a t room temperature f o r 12  s o l u t i o n was  d i l u t e d w i t h e t h e r , washed w i t h  bicarbonate  and  The  brine,  r e s i d u a l m a t e r i a l was  and  then was  saturated  d r i e d (MgSO^) and  e t h e r - e t h e r , 8:1  v/v).  t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s p r o v i d e d the t o s y l a t e 127 which  1600,  1496,  exhibited 898  cm" ; 1  X  H  aqueous concen-  s u b j e c t e d to column chromatography  g e l (4 g, e l u t i o n w i t h petroleum  83%)  0.13  one  spot  on t i c ;  nmr  (80 MHz)  8:  Concen(32  i r (CHCI3): 3089, 3032,  7.75,  7.31  on  mg, 1638,  (d, d, 2H each, J  -  8  Hz,  aromatic  CHOTs), 2.44 (s,  3H,  ( s , 3H,  angular  protons).  p r o t o n s ) , 4.60  - 164  -  (m,  2H,  aromatic methyl p r o t o n s ) , 2.5-1.0  methyl  protons),  E x a c t Mass c a l c d . f o r  Preparation of n i t r i l e  mg,  52  (d, S :  3H,  dried  to  petroleum  ether-ether,  collected  (9 mg,  25 jimol)  was  Hz,  found:  methyl  348.1756.  and  sodium  cyanide  heated a t 80°C f o r 3 h. e t h e r and washed  column  and  (MgSO,^) and c o n c e n t r a t e d chromatography 19:1  v/v).  concentrated.  on  and  silica  The  112a  Distillation  as a c o l o r l e s s o i l which was  exhibited i r (film): ( t , 1H,  p r o t o n ) , 2.60 14.Hz, Hg),  3070, 2225, 1638,  J - 1.5  ( d t , 1H,  2.16  Hz,  once  The with  ( b r d, 1H,  4.5  Hz,  J - 14 Hz,  residue  was  fractions  (air-bath 2.3  mg  were  temperature  (44%)  of  the  homogeneous by g l c a n a l y s i s  998,  H ), A  H ), c  The  g e l (1 g, e l u t i o n w i t h  895  cm" ; 1  o l e f i n i c p r o t o n ) , 4.56  J = 1.3,  the  appropriate  65-68°C/0.02 t o r r ) o f the remaining o i l y i e l d e d  4.61  J - 7.5  1.00  112a  d i l u t e d w i t h petroleum  subjected  6:  12H),  1H,  t w i c e w i t h aqueous c o p p e r ( I I ) s u l f a t e and twice w i t h b r i n e .  o r g a n i c l a y e r was  nitrile  (m,  (m,  348.1759;  2  /imol) i n d r y HMPA (1 mL)  r e a c t i o n m i x t u r e was water,  0.82  C oH28°3  A s o l u t i o n o f the t o s y l a t e 127 (2.5  o l e f i n i c p r o t o n s ) , 4.38  2.41  1  H  nmr  (400  (br s, 1H,  ( t d t , 1H,  2.00-1.87 (m,  MHz)  olefinic  J = 1.5,  2H),  and  5,  1.75-1.30  165 -  (m,  8 H ) , 1.24 ( s , 3 H , a n g u l a r methyl p r o t o n s ) , 1.14 (d, 3 H , J = 6.4  methyl  protons).  Exact  Mass  f o r C14H21N:  calcd.  203.1674;  Hz,  found:  203.1676.  P r e p a r a t i o n o f the n i t r i l e s  112a and 112b  112 b To a c o l d (2.9  g,  (0°C)  s o l u t i o n o f ( p . - t o l u e n e s u l f o n y l ) methyl  94:6  (0.47 mL, 5 mmol) and the ketones  15  min.  tert-Butyl  114 and 122 (0.96 g, 5 mmol;  r e s p e c t i v e l y ) , were added and the r e s u l t a n t mixture was s t i r r e d  room temperature  f o r 1 h and a t 45°C f o r 88 h.  poured  i n t o c o o l IN h y d r o c h l o r i c a c i d  three  times w i t h petroleum  ether.  and  then  was  dried  (MgSO^)  the mixture  was  ether-ether,  collected  and  65-68°C/0.02 colorless o i l .  19:1  concentrated.  torr)  of  the  extracted  The combined e x t r a c t was washed once  and  concentrated.  s u b j e c t e d t o f l a s h chromatography on s i l i c a petroleum  at  The r e a c t i o n mixture was  w i t h water, twice w i t h aqueous c o p p e r ( I I ) s u l f a t e and twice and  3  15 mmol) i n d r y HMPA (17 mL) was added potassium t e r t - b u t o x i d e  (4.0 g, 36 mmol) and the s o l u t i o n was s t i r r e d f o r alcohol  isocyanide-*-  v/v).  The  gel  remaining  brine  The r e s i d u a l o i l was (40  appropriate  Distillation  with  g,  elution  with  fractions  were  (air-bath  o i l yielded  temperature  0.69 g (68%) o f a  G l c a n a l y s i s o f t h i s o i l showed t h a t i t c o n s i s t e d  of  a  - 166 -  mixture  of  two compounds, 112a and 112b, i n a r a t i o o f 15:85, r e s p e c t -  ively.  Column chromatography  silica  gel  impregnated  with  petroleum ether-ether, 2 5 : 1 , for  less  polar  silver  nitrate  material  on  (55 g, e l u t i o n w i t h  v/v) a f f o r d e d pure samples  minor  those o f the a x i a l n i t r i l e more  polar  895 cm' ; 1  4.62  1  (br  component  H nmr  component  o f each  compound  112b e x h i b i t e d i r ( f i l m ) :  (400 MHz)  6:  4.68  1.78-1.25 angular  203.1674; found:  (m, 8 H ) , 1.17 methyl  (see  above).  The  3070, 2225, 1638, 998,  ( t , 1 H , J •= 1.7 Hz, o l e f i n i c p r o t o n ) ,  s, 1 H , o l e f i n i c p r o t o n ) , 2.36 c  3H,  exhibited spectra i d e n t i c a l with  112a p r e p a r e d p r e v i o u s l y  d, 1 H , J - 12 Hz, H ) , 2.08  2H), (s,  25%  ( 0 . 1 g) o f t h i s  characterization. The  (br  of a portion  ( b r t , 1 H , J = 12 Hz, Hg), 2.17  ( t , 1 H , J = 11.5 Hz, H ) , A  (d, 3 H , J - 6 . 2  protons).  Exact  2.0-1.85  (m,  Hz, methyl p r o t o n s ) , 0.96  Mass  calcd.  for  C14H21N:  203.1676.  P r e p a r a t i o n o f 4 - c h l o r o - l - b u t v n e (134)  CI  To  dimethylformamide  wise, phosphorus stirred l-ol  for  (6.7 mL,  (50  trichloride  90 min.  mL) a t room temperature was added, drop-  (2.5 mL,  69  //mol)  and  the  mixture  To the r e s u l t a n t y e l l o w s l u r r y was added  0.2 mol) and s t i r r i n g was c o n t i n u e d f o r 40 min.  p r o d u c t was d i s t i l l e d  was  3-butynThe crude  (70-110°C) from the r e a c t i o n m i x t u r e and c o l l e c t e d  - 167 -  as a c o l o r l e s s o i l , which was then f r a c t i o n a l d i s t i l l e d t o r r ) t o a f f o r d 7 g (42%) o f the c h l o r i d e 650  cm" ; H nmr (80 MHz) 6: 1  2H,  J  proton).  2.5,  7  Hz,  I r ( C H C 1 ) : 3300, 2120, 2  2  2  -CH CH C1), 2.11 ( t , 1H, J = 2.5 Hz, a c e t y l e n i c 2  2  E x a c t Mass c a l c d . f o r C ^ ^ C l :  88.0079; found:  P r e p a r a t i o n o f e t h v l 5-chloro-2-pentvnoate  To a c o l d  80-85°C/760  3.63 ( t , 2H, J = 7 Hz, -CH C1), 2.68 ( d t ,  1  =  134.  (bp  88.0074.  (117)  (-78°C) s o l u t i o n o f 4 - c h l o r o - l - b u t y n e  (134)  (4.4  g,  50  mmol) i n THF (100 mL) was added m e t h y l l i t h i u m (55 mmol) as a s o l u t i o n i n d i e t h y l ether.  A f t e r the mixture had been s t i r r e d a t -78°C f o r 10  and  f o r 1 h, e t h y l c h l o r o f o r m a t e  at  and  -20°C  (5.7 mL, 60 mmol) was added  the r e s u l t a n t mixture was s t i r r e d a t -20°C f o r 1 h, and then a t room  temperature  f o r an  a d d i t i o n a l hour.  The r e a c t i o n mixture was d i l u t e d  w i t h e t h e r , washed twice w i t h aqueous sodium b i c a r b o n a t e and twice brine,  and  then  was  dried  (MgSO^) and c o n c e n t r a t e d .  with  petroleum  e t h e r - e t h e r , 9:1 v/v)  c o l l e c t e d and c o n c e n t r a t e d . 0.02  torr)  of  Distillation  o i l which  was  g,  elution  and the a p p r o p r i a t e f r a c t i o n s were  the remaining o i l y i e l d e d  as a c o l o r l e s s  with  The r e s i d u e was  s u b j e c t e d t o f l a s h column chromatography on s i l i c a g e l (300  117  min  ( a i r - b a t h temperature  80-82°C/  5.0 g (63%) o f the pentynoate  homogeneous  by  g l c analysis  and  - 168 -  exhibited 6:  1  4.20 ( q , 2H, J - 7 Hz, -0CH -), 3.65 ( t , 2H, J = 7 Hz, C1CH -)., 2.83 2  (t,  2  2H, J = 7 Hz, C1CH CH -), 1.32 ( t , 3H, J = 7 Hz, C H - ) . 2  calcd.  for C H 0 5  3 5  4  To a c o l d THF  (50  2  E x a c t Mass  3  C 1 0 (M -0Et):  Preparation of ethyl  The  ' H nmr (80 MHz)  i r ( f i l m ) : 2235, 1710, 1258, 1090, 760 cm" ;  +  114.9950;  found:  114.9950.  ( Z ) - 5 - c h l o r o - 3 - t r i m e t h v l s t a n n v l - 2 - p e n t e n o a t e (116)  (-20°C) s o l u t i o n o f h e x a m e t h y l d i t i n (1.1 mL, 4.9 mmol)  mL) was added m e t h y l l i t h i u m (4.9 mmol) as a s o l u t i o n i n e t h e r .  r e s u l t i n g p a l e y e l l o w s o l u t i o n was s t i r r e d a t -20°C f o r 20  then s o l i d p h e n y l t h i o c o p p e r  (0.84 g, 4.9 mmol) was added.  min and  The r e s u l t i n g  r e d s o l u t i o n was s t i r r e d a t -20°C f o r an a d d i t i o n a l 15 min and then c o o l e d t o -78°C. and  The c h l o r o pentynoate  Saturated  aqueous ammonium c h l o r i d e  (pH 8) and petroleum  separated,  washed  twice  through a s h o r t pad o f F l o r i s i l  of  r e s i d u e showed t h a t i t c o n s i s t e d o f a mixture  Careful fractional d i s t i l l a t i o n of  this  material  afforded  and c o n c e n t r a t e d .  ( a i r - b a t h temperature  0.39  h.  The o r g a n i c  w i t h b r i n e and the d r i e d  filtered the  for 4  e t h e r (300 mL)  were added, and the mixture was warmed t o room temperature. was  was  117 (0.74 g, 4.6 mmol) was added  the m i x t u r e was s t i r r e d a t -78°C f o r 15 min and a t -48°C  layer  in  (MgSO^),  Glc analysis  o f two compounds. 60-62°C/0.02 t o r r )  g (26%) o f the more v o l a t i l e d e s i r e d  169  e s t e r 116.  This material exhibited i r  cm' ;  nmr  ^-H  1  olefinic Hz,  proton),  C1CH -),  3 5 1 6  C10  4.19  1 2 0 2  Sn  5:  6.43  1704,  1603,  ( t , 1H, J = 1.1 H z , J  ( q , 2H, J = 7 H z ,  - 0 C H - ) , 3.56 2  _H  S n  = 52/54 H z ,  (M -CH ):  310.9859;  +  3  Exact  3  found:  _H  =  774 H  >  z  7  ( t , 3H, J = 7 H z ,  2  -SnMe ).  S n  1207,  ( b r t , 2H, J =  2  ( t , 2H, J = 7 H z , C 1 C H C H - ) , 1-29  ( s , 9H, J  3  9  MHz)  2.86  2  C H - ) , 0.21 C H  (80  (film):  Mass  calcd.  for  310.9866.  1 36  The  residual  m a t e r i a l from t h e above d i s t i l l a t i o n  f l a s h chromatography on  silica  gel  (300  elution  100:1 v / v ) .  distillation  ( a i r - b a t h t e m p e r a t u r e 75-78°C/0.02 t o r r ) o f  gave  a  small  exhibited i r (film): 1H,  Hz,  - 0 C H ) , 2.55  7  2  12 25°2 H  1 2  °  S n  0.83  3  2  2  0  (m, 2H,  J_s -H  ( s , 9H,  3  1  H z  >  olefinic  n  (M -CH ): +  3  =  2  440.9897;  -SnMe ) .  found:  3  the  (80  MHz)  4.18  ( s , 9H, Exact  440.9900.  S n  petroleum  remaining 136, w h i c h 5:  ( q , 2H,  1.28  J  to  f r a c t i o n s and  product  protons),  - S n C H - ) , 0.22  50/52 H z ,  E  l  proton),  ( b r t , 2H, J = 7 H z , a l l y l i c  -0CH CH ),  - S n M e ) , 0.12 c  1  Sn  2  Hz,  1 7 0 2 , 1 6 0 1 , 1 2 0 0 , 770 c m " ;  J = 1.1 H z , J - H =  (t,  o f the appropriate  sample o f the l e s s v o l a t i l e  subjected  with  ether-ether,  material  Concentration  g,  was  .  H  6.34  J = 7  ( t , 3H, J = 52/54  Mass c a l c d .  =  Hz, for  - 170  -  Preparation of l-tert-butyldimethylsilvloxy-3-butyne  A  solution  silyl  of  3-butyn-l-ol  c h l o r i d e (9 g, 60  dimethylformamide  (17  mmol) mL)  Aqueous sodium b i c a r b o n a t e times  and  was was  (3.8 mL,  added and  with petroleum ether.  The  the s i l y l 1  1  H  nmr  J = 2.5, 0.90  e t h e r 137  the m i x t u r e was  Distillation  7 Hz, -CH C=), 2  ( s , 9H,  6":  3.72  1.92  ( t , 2H,  ( t , 1H,  t e r t - b u t y l p r o t o n s ) , 0.07  2.5  ( s , 6H,  extracted  a  in  c o l d (-78°C) s o l u t i o n o f the alkyne  three  [bp 55-60°C/15  torr  2100,  1110,  -0CH -), 2.37  Hz,  h.  with  2  acetylenic  (dt,  of 632 2H,  proton),  methyl p r o t o n s ) .  Preparation of e t h y l 5-tert-butyldimethvlsilyloxv-2-pentvnoate  To  mmol)  washed twice  3300,  J = 7 Hz,  J =  125  o i l y i e l d e d 9 g (98%)  which e x h i b i t e d i r ( f i l m ) :  (80 MHz)  g,  a t room temperature f o r 12  bp 45-46°C/2.5 t o r r ) ] o f the remaining  4 1  cm" ;  (8.5  combined e x t r a c t was  b r i n e , d r i e d (MgSO,^) and c o n c e n t r a t e d . (lit.  50 mmol), t e r t - b u t y l d i m e t h y l -  imidazole  stirred  (137)  (137)  (9.2  (138)  g, 50 mmol) i n  - 171 -  THF  (180 mL) was added m e t h y l l i t h i u m (55 mmol) as a s o l u t i o n  After  t h e s o l u t i on had been s t i r r e d  1 h, e t h y l c h l o r o f o r m a t e  in  ether.  a t -78°C f o r 10 min and a t -20°C f o r  (5.7 mL, 60 mmol) was added and t h e m i x t u r e was  stirred  a t -20°C f o r 1 h, and a t room temperature  mixture  was d i l u t e d w i t h e t h e r , washed t w i c e w i t h aqueous sodium b i c a r b o -  nate  and t w i c e w i t h b r i n e ,  and then was d r i e d  Distillation  ( a i r - b a t h temperature  oil  11.5 g (90%)  yielded  exhibited  i r (film):  f o r 1 h.  The r e a c t i o n  (MgSO^) and c o n c e n t r a t e d .  75-78°C/ 0.02 t o r r ) o f t h e  o f the pentynoate  remaining  138 as a c o l o r l e s s o i l which  2230, 1705, 1250, 1110, 1080 c m ; -1  X  H nmr (80 MHz)  6:  4.20  2.52  ( t , 2H, J = 7 Hz, -,CH Cs) , 1. 8  (s,  9H, t e r t - b u t y l p r o t o n s ) , 0.07 ( s , 6H, s i l y l methyl p r o t o n s ) .  ( q , 2H, J = 7 Hz, -OCH CH ), 3.76 ( t , 2H, J = 7 Hz, 2  2  Mass c a l c d .  for C  1 2  Preparation of ethyl  H  2 1  0 Si 3  3  ( t , 3H, J = 7 Hz,  2  (M -CH ): +  3  241.1260; found:  Si0CH -), 2  -0CH CH ), 2  0.90  3  Exact  241.1256.  (Z)-5-tert-butyldimethvlsilyloxv-3-trimethyl-  s t a n n y l - 2 - p e n t e n o a t e (139)  SnMe3  ^  To a c o l d THF The then  (120  i 0  ^vA^C0 Et 2  (-20°C) s o l u t i o n o f h e x a m e t h y l d i t i n (2.6 mL, 12  in  mL) was added m e t h y l l i t h i u m (13 mmol) as a s o l u t i o n i n e t h e r .  r e s u l t i n g p a l e y e l l o w s o l u t i o n was s t i r r e d solid  mmol)  phenylthiocopper  a t -20°C f o r 20  (2.1 g, 12 mmol) was added.  min and  The r e d s o l u -  - 172  t i o n was  stirred  to r78°C. was  The  stirred  mixture,  a t -20°C f o r an a d d i t i o n a l 15 rain and  pentynoate 138  saturated  petroleum  ether  was  mixture  was  added  separated,  (91%)  o f the e s t e r 139, nmr  (80  6.5  S i 0 C H - ) , 2.63  4.18  5:  (q, 2H,  -OCH CH -), 0.90  J  52/54  H  "  2  penten-l-ol  of  room  most  of  the  cooled  the  mixture  the  reaction  petroleum  ether  temperature.  More  phenylthiocopper  concentrated.  Hz, 1 5  H  6.40 J -  J  The  had  organic  Distillation  0 Si 3  1 2 0  Sn  1600,  -0CH CH ), 3.63  - 6.5  (s, 6H,  3  1700,  J = 1 Hz,  1H, 2  Hz,  tert-butyl  -SnMe ), 0.04 3 1  (t, 7 Hz,  ( s , 9H,  3  Mass c a l c d . f o r C  Preparation  to  and  (br t , 2H,  2  J = 7 Hz, _  warmed  which e x h i b i t e d i r ( f i l m ) :  MHz)  proton),  S N  8) and  was  (air-  91-95°C/0.02 t o r r ) o f the r e m a i n i n g o i l y i e l d e d 3.8  olefinic Hz,  To  l a y e r became n e a r l y c o l o r l e s s .  of F l o r i s i l  temperature  'H  added and  at -40°C f o r 9 h.  until  then  washed twice w i t h b r i n e , d r i e d (MgSO^), f i l t e r e d  bath  -1  and  was  the o r g a n i c  through a s h o r t pad  cm ;  g, 10 mmol) was  aqueous ammonium c h l o r i d e (pH  the  p r e c i p i t a t e d and layer  (2.6  a t -78°C f o r 15 min  were added, and  -  J_ n-H  1110, =  0.18  +  3  J  (s,  s i l y l methyl p r o t o n s ) .  ( M - C H ) : 407.1063;  Hz  (t,  2  protons),  0  2H,  S i O C H C H - ) , 1.28 2  2  1052  S  (t,  3  1  SnMe3  > 3H, 9H,  Exact  found: 407.1058.  (Z)-5-tert-butvldimethvlsilyloxv-3-trimethylstannyl-2-  (140)  g  - 173 -  To a c o l d  (-78°C) s o l u t i o n o f the pentynoate 138 (3.8 g, 9 mmol)  in  THF (90 mL) was added a s o l u t i o n o f d i i s o b u t y l a l u m i n u m h y d r i d e (27 mmol) i n hexanes. 0°C  A f t e r the m i x t u r e had been s t i r r e d a t -78°C f o r 1 h and a t  f o r 1 h, i t was t r e a t e d w i t h aqueous ammonium c h l o r i d e  d i l u t e d with ether. min,  dried  lation  (MgSO/^), f i l t e r e d through F l o r i s i l  3.3  olefinic  change, 2  H),  -CH 0H), 2  SiOCH CH -), 2  4.08  1  6H,  (M -CH ): +  3  the  3.57 ( t , 2H, J - 7 Hz, S i O C H - ) , 2  1.18  ( t , 1H, J = 6 Hz, exchanged  silyl  methyl p r o t o n s ) .  365.0958;  Preparation of  found:  S  n  .  H  Distil-  residual o i l  i r (film):  6.26 ( b r t , 1H,  J  3350 =  6  t o a d on D2O ex-  ( t , 2H, J = 6 Hz, c o l l a p s e d  9H, t e r t - b u t y l p r o t o n s ) , 0.19 ( s , 9H, J (s,  torr) of  g (96%) o f the a l c o h o l 140 which e x h i b i t e d -1  for 5  and c o n c e n t r a t e d .  1621, 1090, 1010 c m ; H nmr (80 MHz) 6:  (br), Hz,  The mixture was s t i r r e d a t room temperature  ( a i r - b a t h temperature 104-105°C/0.02  yielded  (1.6 mL) and  2.43 ( t , 2H, J - 7 Hz,  w i t h D 0, -OH), 0.89 ( s ,  = 52/54  2  Hz,  -SnMe ), 3  Exact Mass c a l c d . f o r C i H 9 0 S i 3  2  0.05 1 2 0  2  Sn  365.0959.  (Z)-5-tert-butyldimethylsilvloxy-3-trimethvlstannvl-l-  methoxymethoxv-2-pentene (141)  /  To a c o l d  (-20°C) s o l u t i o n o f the a l c o h o l 140 (3.3 g, 8.7 mmol)  diisopropylethylamine  and  (2.3 mL, 13 mmol) i n dichloromethane (25 mL) was  - 174 -  added c h l o r o m e t h y l methyl e t h e r (1 mL, stirred  a t room temperature  13  f o r 12 h.  mmol)  and  the  ether.  The  The  combined  through  extract  9:1  g  cm ; -1  (s,  X  (90%) H nmr  2H,  (decantation)  concentrated gel  and  (75  with  elution  90-93°C/0.02 t o r r ) o f the  (80 MHz) 5:  6.21  3.38  (s,  (d, 2H, J = 6 Hz, =CCH 0-),  3H,  2  -OCH ), 3  2.45  ( s , 9H, t e r t - b u t y l p r o t o n s ) , 0.20  Hz, -SnMe3), 0.06  ( s , 6H, s i l y l methyl p r o t o n s ) .  15 33°3 H  S i l 2  °  with  remaining  -CH CH C=), 0.91 2  S n  ether. filtered petroleum  o i l yielded  (M -CH ): +  3  1100, 1040  ( t , 1H, J - 6 Hz, o l e f i n i c p r o t o n ) ,  a c e t a l p r o t o n s ) , 4.01 2  c  petroleum  o f the d i e t h e r 141, which e x h i b i t e d i r ( f i l m ) :  J - 7 Hz, S i 0 C H - ) , 2  and the r e m a i n i n g  the r e s i d u e was  g,  with  v / v ) . The f i l t r a t e was c o n c e n t r a t e d and d i s t i l l a t i o n  ( a i r - b a t h temperature 3.3  was  a s h o r t column o f s i l i c a  ether-ether,  triturated  o r g a n i c s o l u t i o n was decanted  s o l i d was washed t h r e e more times  was  The r e a c t i o n mixture was concen-  t r a t e d under reduced p r e s s u r e and the r e s i d u a l o i l was petroleum  mixture  409.1220;  found:  ( t , 2H, ( s , 9H, I  3.58 J S  = n  .  H  4.63 ( t , 2H, 7  = 52/54  Exact Mass c a l c d .  409.1228.  Preparation of (E)-5-tert-butvldimethvlsilyloxv-3-methyl-1-methoxymethoxy-2-pentene (142)  /  Hz,  for  - 175 -  To in  a cold  (-78°C) s o l u t i o n o f the v i n y l s t a n n a n e 141 (3.3 g, 8 mmol)  THF (65 mL) was added m e t h y l l i t h i u m  ether.  After  the  solution  had  (9 mmol) as a s o l u t i o n i n d i e t h y l  been  stirred  at  -78°C f o r 30 min,  iodomethane (1.2 mL, 20 mmol) was added and the m i x t u r e was s t i r r e d a  further  90  min.  The r e s u l t a n t  s o l u t i o n was d i l u t e d w i t h p e t r o l e u m  e t h e r , washed t h r e e times w i t h b r i n e , Distillation o i l yielded by  (air-bath 2 g (90%)  g l c analysis  (80 MHz) 6: acetal Hz,  dried  (MgSO,^)  and  o f the alkene 142.  and e x h i b i t e d  4.04  concentrated.  temperature 81-83°C/0.02 t o r r ) o f the r e m a i n i n g  i r (film):  This material  was  homogeneous  2725, 1100, 1050 cm" ; H nmr 1  5.36 ( b r t , 1H, J - 7 Hz, o l e f i n i c p r o t o n ) ,  protons),  for  4.61  1  ( s , 2H,  (d, 2H, J - 7 Hz, =CCH 0-), 3.68 ( t , 2H, J = 7 2  - S i 0 C H - ) , 3.35 ( s , 3H, -0CH ), 2.23 ( t , 2H, J = 7 2  3  Hz,  =CCH CH -), 2  2  1.69  ( b r s, 3H, v i n y l methyl p r o t o n s ) , 0.88 ( s , 9H, t e r t - b u t y l p r o t o n s ) ,  0.03  ( s , 6H, s i l y l methyl p r o t o n s ) .  (M -0CH 0CH ): +  2  3  213.1674;  found:  Exact  Mass  calcd.  f o r C^ ^25 - ^ (  )  1  2  213.1671.  P r e p a r a t i o n o f (E)-3-methyl-5-methoxymethoxy-3-penten-l-ol (143)  To THF 142  a s o l u t i o n o f tetra-n-butylammonium f l u o r i d e (5.6 g, 20 mmol) i n  (35 mL) a t room temperature was added a s o l u t i o n o f the s i l y l (2 g, 7.2 mmol) i n THF.  After  ether  the s o l u t i o n had been s t i r r e d f o r 40  - 176 -  min,  i t was d i l u t e d w i t h e t h e r , washed t h r e e  (MgSC^)  and  concentrated.  Distillation  0.02 t o r r ) o f the r e m a i n i n g alcohol X  H nmr  2H,  acetal  protons),  2  1.72 6  of  ( a i r - b a t h temperature 81-83°C/ the  homoallylic  3400 ( b r ) , 2760, 1040, 922  cm ; -1  2  (s,  3H,  -0CH ),  2.30  3  ( t , 2H,  J  -  6.5  ( b r s, 4H, v i n y l methyl and h y d r o x y l p r o t o n s ) .  Mass c a l c d . f o r C H  Preparation  dried  4.11 (d, 2H, J = 7 Hz, =CCH 0), 3.73 ( t , 2H, J =  2  2  brine,  5.48 (br t , 1H, J - 7 Hz, o l e f i n i c p r o t o n ) , 4.65 ( s ,  6.5 Hz, H0CH -), 3.40 ~CCH CH -),  with  o i l y i e l d e d 1.1 g (98%) o f  143 which e x h i b i t e d i r ( f i l m ) : (80 MHz) 6:  times  1 1  0  (M -CH 0CH ): +  2  2  3  115.0759;  Hz, Exact  found: 115.0762.  (E)-3-methvl-5-methoxymethoxv-3-penten-l-yl  tosylate  (1*4)  A  s o l u t i o n o f the a l c o h o l 143 (0.84 g, 5.3 mmol), p _ - t o l u e n e s u l f o n y l  chloride mmol) h.  (1.2 g, 6.3 mmol) and 4-N,N-dimethylaminopyridine (0.77 g,  i n dichloromethane (15 mL) was s t i r r e d a t room temperature f o r 12  The s o l u t i o n was d i l u t e d w i t h e t h e r , washed w i t h  sodium  6.3  bicarbonate  and  brine,  dried  (MgSO^)  saturated  aqueous  and c o n c e n t r a t e d .  The  r e s i d u a l m a t e r i a l was s u b j e c t e d t o f l a s h column chromatography on s i l i c a gel  (75 g, e l u t i o n w i t h petroleum  e t h e r - e t h e r , 1:1 v / v ) .  c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s  provided  the  C o l l e c t i o n and tosylate  144  - 177  (1.2  g,  75%)  1180,  1100  aromatic 2H,  as a c o l o r l e s s o i l which e x h i b i t e d  cm" ;  '-H nmr  1  protons),  a c e t a l protons),  6.5  Hz,  2.39  ( t , 2H,  J = 6.5  4.14  ( t , 2H,  J = 7 Hz,  To  J - 7 Hz,  2  1 4  H  1 8  4  of  +  4  light.  (MgS0 ) 4  2  ( s , 3H,  (s,  (d, 2H,  J =  benzylic  protons),  vinyl  methyl  protons).  282.0926;  found:  282.0930.  slowly  turned  freezer.  t o s y l a t e 144  added sodium i o d i d e  The and  was  combined  (1.27  g, 4.04  (1 g,  the mixture was  extract  concentrated.  oil  m a t e r i a l was  added and  6.6  mmol) i n  mmol) and  was  washed  extracted twice  (113)  dimethylfor-  the  resultant  was  homogeneous by  from  t h r e e times w i t h  with  brine,  dried  D i s t i l l a t i o n ( a i r - b a t h temperature 48-51°C/  r e m a i n i n g o i l y i e l d e d 1 g (91%)  which  Hz,  4.64  s t i r r e d a t room temperature f o r 4 days w i t h p r o t e c t i o n  t o r r ) o f the  colorless  o l e f i n i c proton), 2  1360,  each, J = 8  decomposed on h e a t i n g under vacuum and  was  Water  pentane.  2H  1600,  (E)-5-iodo-l-methoxvmethoxv-3-methyl-2-pentene  (8 mL)  m i x t u r e was  (d, d,  ( s , 3H,  (M -CH 0):  i r (film):  -OCH CH -), 4-03  3  2  0 S  Hz,  -0CH ), 2.48  -OCH CH -), 1-65  a s o l u t i o n o f the  mamide  0.02  ( s , 3H,  s t o r a g e under argon i n a  Preparation  7.37  ( t , 1H,  E x a c t Mass c a l c d . f o r C  brown on  7.83,  5.38  2  tosylate  6:  (80 MHz)  =CCH 0-). 3.40  This  -  stored  o f the  iodide  113  over copper dust i n a f r e e z e r .  glc analysis  and  exhibited  i r (film):  as  a  This 2770,  - 178 1040  cm ;  E  -1  nmr  L  (80  MHz)  5.41 ( b r t , 1 H , J = 7 Hz, o l e f i n i c  6:  p r o t o n ) , 4.63 ( s , 2 H , a c e t a l p r o t o n s ) , 4.07 (d, 2 H , J = 7 3.38  (s, 3H, - 0 C H ) , 3  2  -CH2CH2I),  1.68 ( b r s, 3 H , v i n y l  for  C H  270.0116;  1 5  I0 : 2  found:  P r e p a r a t i o n o f the n i t r i l e  To  a  cold  methyl p r o t o n s ) .  111  (-78°C) s o l u t i o n o f d i i s o p r o p y l a m i n e  hexanes and t h e m i x t u r e was s t i r r e d  (1.2  mmol)  stirred added  15:85,  respectively)  a t 0°C f o r 15 min. the  iodide  (0.17 mL, 1.2 mmol) as  a t 0°C f o r 15 min.  mmol) and a s o l u t i o n o f a m i x t u r e o f t h e n i t r i l e s mmol;  E x a c t Mass c a l c d .  270.0111.  i n THF (10 mL) was added n - b u t y l l i t h i u m  1  -CC^O),  3.23 ( t , 2 H , J = 8 Hz, - C H I ) , 2.58 ( t , 2 H , J = 8  Hz,  8  Hz,  a  solution  in  HMPA (0.34 mL, 2  112a and 112b (0.2 g,  i n THF were added and the s o l u t i o n was  To t h e r e s u l t a n t y e l l o w s o l u t i o n a t 0°C  113 (0.35 g, 1.3 mmol).  The s o l u t i o n was a l l o w e d t o  warm g r a d u a l l y  t o room  temperature  solution  diluted  w i t h petroleum e t h e r , washed w i t h water, aqueous  was  copper(II) s u l f a t e , twice with b r i n e , The  and  was  was  dried  r e s i d u a l o i l was s u b j e c t e d t o f l a s h  stirred  (MgSO^)  overnight.  and  The  concentrated.  column chromatography on s i l i c a  - 179 -  gel  (35 g, e l u t i o n w i t h petroleum  of  the  ether-ether,  3:1 v/v)  and  collection  a p p r o p r i a t e f r a c t i o n s a f f o r d e d 0.24 g [94% based on r e c o v e r y o f  47 mg o f t h e s t a r t i n g m a t e r i a l and the n i t r i l e s , (respectively)]  of  the  nitrile  111  1 1 2 a and  112b,  which e x h i b i t e d i r ( f i l m ) :  2780, 2227, 1671, 1638, 1150, 1103, 1045, 2045, 895 cm' ; 1  X  H  nmr  (60:40 3086, (400  MHz)  6:  4.60,  4 . 5 5 ( s , s, 1H each, e x o c y c l i c o l e f i n i c p r o t o n s ) , 4.05 (d, 2 H , J =  5.35  ( t , 1H, J = 6 . 5 Hz, H ) , 4.62 ( s , 2 H , a c e t a l p r o t o n s ) , A  6.5  Hz, <=CCH 0-), 3.38 ( s , 3 H , - O C H 3 ) ,  2.40 ( b r d t , 1H, J = 5 , 1 3 . 5 Hz,  Hg),  2.14 ( b r dd, 1 H , J - 4 , 1 3 . 5 Hz, H ) , 2.0-1.82 (m, 5H) , 1 . 8 - 1 . 5 (m,  2  c  9H),  1.68  (s, 3H,  v i n y l methyl p r o t o n s ) , 1.27 ( s , 3 H , a n g u l a r  p r o t o n s ) , 1 . 1 1 (d, 3 H , J = 6 Hz, methyl p r o t o n s ) . C  22 35 H  N 0  2  :  methyl  Exact Mass c a l c d .  for  345.2668; found: 345.2668.  P r e p a r a t i o n o f the aldehyde 147  K'C  To  a  solution  ethane (7 mL) solution  was  o f the n i t r i l e added  i n hexanes  and  111 (0.17 g, 0.5 mmol) i n dimethoxy-  diisobutylaluminum  hydride  t h e m i x t u r e was h e a t e d  r e a c t i o n m i x t u r e was c a u t i o u s l y poured i n t o  water,  (2  mmol)  as  a t 60°C f o r 6 h. and  a The  the r e s u l t a n t  180 -  mixture  was  neutralized  times w i t h e t h e r . (Na2S0 )  The e x t r a c t s were combined, washed w i t h b r i n e ,  and c o n c e n t r a t e d .  4  of THF-acetic temperature pressure  w i t h IN h y d r o c h l o r i c a c i d and e x t r a c t e d  acid-water for  12  h.  (0.02 t o r r ) ,  concentrated  material  (4 mL,  3:1:0.16 by volume) and s t i r r e d a t  After  removal  the r e s i d u e was d i s s o l v e d i n e t h e r .  to a f f o r d 0.15 g  (87%)  The  solution  and b r i n e , then d r i e d of  the  aldehyde  (MgS0 ) 4  147.  This  was homogeneous by t i c a n a l y s i s and e x h i b i t e d i r ( f i l m ) : 1  1H,  aldehyde  proton),  a c e t a l p r o t o n s ) , 4.58  X  H nmr  (400 MHz) A  (br s, 2H, o l e f i n i c p r o t o n s ) , 4.06  =CCH 0-),  ( s , 3H, -0CH ), 2.27  2.12  ( b r d, 1H, J = 13 Hz, H ) , 2.0-1.1 (m, 14H),  3  protons),  1.03  angular  methyl p r o t o n s ) .  found:  348.2658.  P r e p a r a t i o n o f the a l c o h o l 152  K'C  Mass  9.98  ( s , 2H,  (d, 2H, J  1.69  (s,  (d, 3H, J = 7 Hz, methyl p r o t o n s ) , Exact  3086,  =  7  ( b r d t , 1H, J = 5, 13 Hz, Hg),  c  methyl  6":  ( t , 1H, J = 7 Hz, H ) , 4.62  Hz,  2  3.37  5.36  room  o f the s o l v e n t s under reduced  2776, 2736, 1713, 1671, 1637, 1149, 893 cm' ; (s,  dried  The r e s i d u a l o i l was d i s s o l v e d i n a mixture  was washed w i t h aqueous sodium b i c a r b o n a t e and  three  calcd.  for  C22 36°3 H  3H,  0.96 :  vinyl ( s , 3H,  348.2664;  - 181 -  To  a  solution-suspension  mmol) i n e t h e r  o f l i t h i u m aluminum h y d r i d e  (3 mL) was added an e t h e r e a l s o l u t i o n o f the aldehyde 147  (99 mg, 0.28 mmol) and the mixture h.  Sodium s u l f a t e decahydrate  s t i r r e d mixture and  was  washed  f i l t r a t e was c o n c e n t r a t e d exhibited i r (film): 1  X  H  nmr  was s t i r r e d a t room temperature f o r 1  was  added  in  small  u n t i l e v o l u t i o n o f gas ceased.  the r e s i d u e  cm" ;  (16 mg, 0.42  three  times  portions  The mixture  with  t o a f f o r d 92 mg (93%)  ether.  was f i l t e r e d The  combined  o f the a l c o h o l 152 which  3469 ( b r ) , 3085, 1669, 1635, 1150, 1103, 1043, 6:  (400 MHz)  892  5.47 ( t , 1H, J - 7 Hz, H ) , 4.63 ( s , 2H, A  a c e t a l p r o t o n s ) , 4.52 ( b r s, 2H, e x o c y c l i c o l e f i n i c p r o t o n s ) , 2H,  t o the  4.06 ( d ,  J = 7 Hz, =CCH 0-), 3.80, 3.70 (dd, dd, 1H each, J = 6, 12 Hz; each 2  c o l l a p s e s t o d, J = 12 Hz on D 0 exchange, -CH 0H), 3.38 ( s , 3H, -0CH ), 2  2.27  ( b r d t , 1H,  J  2  - 4, 14 Hz, Hg), 2.11 ( b r d, 1H, J = 14 Hz, H ) , c  1.93-1.40 (m, 12H), 1.71 ( s , 3H, v i n y l methyl 2H),  1.06  1.27-1.11  (m, 2  2  3.70  protons),  ( s , 3H, a n g u l a r methyl p r o t o n s ) , 1.02 ( t , 1H, J = 6 Hz, D 0  exchanged, -CH 0H), 0.94 (d, 3H, difference  3  spectrum  showed  J  =  positive  6.5  Hz,  methyl  protons);  s i g n a l enhancement a t 6" 3.80 and  (-CH 0H) on i r r a d i a t i o n a t 6 1.06 ( a n g u l a r methyl p r o t o n s ) . 2  Mass c a l c d f o r C ] H 2  3 5  0  (M -0CH ): +  2  3  nOe  319.2637;  found:  319.2636.  Exact  - 182 -  P r e p a r a t i o n o f t h e x a n t h a t e 153  H 'C  To a s o l u t i o n o f the a l c o h o l 152 (67 mg, 0.2 mmol) i n dimethylformamide (1 mL) was added 1 , 8 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 7 - e n e mmol)  and  the  solution  Carbon d i s u l p h i d e nued  at  room  was  stirred  at  room temperature  (0.93 mL, 15 mmol) was added and s t i r r i n g  temperature  f o r 1 h.  f o r t h r e e more hours a t room temperature.  s o l v e n t were removed under was  on s i l i c a  p e t r o l e u m e t h e r - e t h e r , 6:4 v / v ) .  C o l l e c t i o n and  appropriate  86  fractions  afforded  v i s c o u s y e l l o w o i l which 894  cm" ; ^-H nmr (400 MHz) 8: 1  2  was  conti-  solution  was  Excess r e a g e n t s and and the r e s i d u e  g e l (3 g, e l u t i o n w i t h concentration  3085,  o f the  1669,  1635, 1219,  5.36 ( t , 1 H , J - 7 Hz, H ) , 4.69, 4.64 (d, A  4.63 ( s , 2 H ,  acetal  protons),  4.54  s, 2 H , e x o c y c l i c o l e f i n i c p r o t o n s ) , 4.07 (d, 2 H , J •= 7 Hz, = C C H 0 - ) , 2  3.39  (s, 3H, - 0 C H ) ,  Hz,  Hg), 2.13 ( b r d, 1 H , J - 1 3 . 5 Hz, H ) , 1 . 9 7 - 1 . 4 8  3H,  f o r 5 min.  mg (100%) o f the x a n t h a t e 153 as a  exhibited i r (film):  d, 1H each, J = 12 Hz, - C H 0 C S 2 - ) , (br  The  reduced p r e s s u r e (0.02 t o r r ) ,  s u b j e c t e d t o column chromatography  1.3  The r e s u l t a n t r e d s o l u t i o n t u r n e d  y e l l o w on a d d i t i o n o f iodomethane (1.8 mL, 29 mmol). stirred  (0.17 mL,  3  2.57  (s, 3H, - S C H 3 ) ,  2.29  (br dt, 1H, J =  c  vinyl  methyl p r o t o n s ) , 1 . 3 5 - 1 . 1 5  (m,  3H),  1.17  5,  13.5  (m, 1 1 H ) , 1.71 ( s , (s, 3H,  angular  - 183 -  methyl  protons),  0.93  calcd. f o r C24H 0 S2: 40  (d,  3H, J = 6 Hz, methyl p r o t o n s ) .  440.2419;  3  found:  P r e p a r a t i o n o f the t h i o n o c a r b o n a t e  (10  ph, 68 umol)  mmol) i n a c e t o n i t r i l e The  solution  dried  was  9:1 v / v ) . afforded (film): 7.40  aromatic J  The r e s i d u e  was  (40%)  of  the  of  the  proton),  7.10  = 7 Hz, H ) , 4.65 A  8  Hz,  aromatic  48  0.13 h.  X  H  nmr  2  fractions  MHz)  p r o t o n s ) , 5.35  ( s , 3H, -0CH ), 2.28 3  6:  ( t , 1H, J - 8 Hz, ( t , 1H,  (d, d, 1H each,  ( b r s, 2H, e x o c y c l i c o l e f i n i c p r o t o n s ) ,  (d, 2H, J = 7 Hz, =CCH 0-), 3.40 2  ether-ether,  (400  ( s , 2H, a c e t a l p r o t o n s ) , 4.63, 4.52  J - 10 Hz, -CH 0C0S-), 4.54  column  155 which e x h i b i t e d i r  p r o t o n s ) , 7.27  (d, 2H, J - 8 Hz, aromatic  to  appropriate  thionocarbonate 1  J  subjected  s i l i c a g e l (2 g, e l u t i o n w i t h petroleum  3085, 1729, 1635, 1592, 1491, 894 cm" ;  ( t , 2H,  phenoxythiocarbonyl  d i l u t e d w i t h e t h y l a c e t a t e , washed t w i c e w i t h b r i n e ,  on  mg  57 fimol),  (1 mL) was s t i r r e d a t room temperature f o r  C o l l e c t i o n and c o n c e n t r a t i o n 11  440.2410.  and 4-N,N-dimethylaminopyridine (15 mg,  (MgSO^ and c o n c e n t r a t e d .  chromatography  Mass  155  A s o l u t i o n o f the a l c o h o l 152 (20 mg, chloride  Exact  4.07  ( b r d t , 1H, J = 4,  - 184 -  14 Hz, Hg), 2.13 ( b r d, 1H, J = 14 Hz, H ) , 1.95-1.49  (m, 11H), 1.69 ( s ,  c  3H,  vinyl  methyl  protons),  methyl p r o t o n s ) , 0.89  1.35-1.18  (m,  pyridine and  1  mmol)  and  with  brine,  1104,  Hz, H ) , 4.65 A  1044, (s,  olefinic  protons),  =CCH 0-),  3.40  2  methyl  acetic (2 mg,  The e t h e r e a l  893 cm" ; 1  2H,  X  acetal  4.16  protons),  (s,  2H,  -CH 0Ac), 2  ( s , 3H, -0CH ), 2.4-1.1  protons),  3  1.70  (s,  a n g u l a r methyl p r o t o n s ) , 0.90  3H,  4.54  vinyl  methyl  was  washed  The r e s i d u e showed  5.35 (br  4.07  (m, 16H),  Solvent  (0.02 t o r r ) and  3086, 1741, 1669,  H nmr (270 MHz) 6:  16 /xmol) i n  solution  d r i e d (MgSO^j and c o n c e n t r a t e d .  anhydride  min.  were removed under reduced p r e s s u r e  one s p o t on t i c and e x h i b i t e d i r ( f i l m ) : 1150,  /imol),  4-N,N-dimethylaminopyridine  the r e s i d u e was d i s s o l v e d i n e t h e r . twice  29  (0.4 mL) was s t i r r e d a t room temperature f o r 90  excess reagents  angular  168  A s o l u t i o n o f the a l c o h o l 152 (10 mg, mL,  ( s , 3H,  ( s , 3H, methyl p r o t o n s ) .  P r e p a r a t i o n o f the a c e t a t e  (0.1  3H), 1.09  1635,  1240,  ( t , 1H, J - 6.8  s,  2H,  exocyclic  (d, 2H, J = 6.8 Hz,  2.06  (s,  3H,  acetyl  p r o t o n s ) , 1.09  ( s , 3H,  ( b r s, 3H, methyl p r o t o n s ) .  - 185 -  P r e p a r a t i o n o f the phosphorodiamidate  To a s o l u t i o n o f the a l c o h o l 152 dimethoxyethane mL)  a t 0°C was  After  the  (1  mL)  was  had  been  stirred  mixture  (40 LIL, 0.32  silica  The  of  -1  X  H  nmr  2.69, 3H, (br  the  The r e a c t i o n m i x t u r e  was  with  (1 mL) was  brine,  dried  (MgS04)  and  s u b j e c t e d to column chromatography Collection  on and  the a p p r o p r i a t e f r a c t i o n s gave the phosphorodiamidate  (270  MHz)  6:  3085, 1667,  5.34  1634,  ( t , 1H, J = 6.8  1224,  1041,  Hz, H ) , A  994,  4.63  ( s , 2H, e x o c y c l i c o l e f i n i c p r o t o n s ) , 4.06  Hz, =CCH 0-), 4.00  2.66  ( b r s, b r s, 6H each, - N ( C H ) ) ,  2  (br m,  2H, 3  methyl  added and  diluted  6.8  vinyl  hexanes.  had been s t i r r e d a t 0°C f o r 2 h, i t was  residue  a c e t a l p r o t o n s ) , 4.53 =  (0.25  After  174 which e x h i b i t e d i r ( f i l m ) : cm ;  mmol) was  g e l (2 g, e l u t i o n w i t h e t h e r - a c e t o n e 10:1 v / v ) .  concentration  of  added.  w i t h e t h e r , and then was washed twice concentrated.  mixture  (73 /imol) i n  s t i r r e d a t room temperature f o r 12 h.  resultant  a  a t room temperature f o r 30 min,  c o o l e d t o 0°C, and anhydrous dimethylamine  the  J  66 Ltmol) i n  added a s o l u t i o n o f n - b u t y l l i t h i u m  mixture  was  (23 mg,  and N,N,N',N'-tetramethylethylenediamine  dimethylaminophosphorodichloridate mixture  174  p r o t o n s ) , 1.08  s, 3H, methyl p r o t o n s ) .  - P 0 C H - ) , 3.39 2  2  2  ( s , 3H,  2.30-1.10 (m, 16H),  891  ( s , 2H, (d,  2H,  -0CH ), 3  1.70  ( s , 3H, a n g u l a r methyl p r o t o n s ) ,  (s, 0.93  - 186 -  P r e p a r a t i o n o f 3-lodo-l-methoxvmethoxypropane  To a c o l d and was  (-20°C) s o l u t i o n o f 3 - c h l o r o - 1 - p r o p a n o l  d i i s o p r o p y l e t h y l a m i n e (28 mL, added c h l o r o m e t h y l methyl  solution  had  been s t i r r e d  w i t h dichloromethane once  with  (172)  dried  pressure  via  e t h e r (11.4  0.10  i n dichloromethane  mL,  0.15  a t room temperature  mol).  mol)  (200  After  f o r 12 h, i t was  The  Vigreux  s o l u t i o n was  diluted  hydrochloric  column  concentrated  (10 cm).  t o r r ) o f the r e m a i n i n g o i l a f f o r d e d 11 g  at  Distillation  (80%)  of  mL) the  acid,  aqueous sodium b i c a r b o n a t e , twice w i t h b r i n e ,  (MgSO^). a  mol)  and washed t h r e e times w i t h IN  saturated  then was  0.16  (8.4 mL,  and  atmospheric  (bp 73-80°C/15  3-chloro-l-methoxy-  methoxypropane. A  solution  sodium i o d i d e for  30  h.  o f 3-chloro-l-methoxymethoxypropane (11 g, 80 mmol) and  (47 g, 0.32 The  mol)  s o l u t i o n was  c o n c e n t r a t e d a t atmospheric Distillation  [bp  i n acetone  torr  via (lit.  a 5 4  Vigreux  was  stored  m a t e r i a l was 6:  4.63  (s,  3H,  over  stirred  copper  dust  column  under  as  a  2H,  a c e t a l p r o t o n s ) , 3.60  methoxy p r o t o n s ) , 3.30  ( t , 2H,  (10  colorless  argon i n a f r e e z e r .  homogeneous by g l c a n a l y s i s and e x h i b i t e d  (s,  at  60°C and cm).  bp 87-85°C/1.87 kPa)] o f the  r e m a i n i n g o i l y i e l d e d 13 g (70%) o f the i o d i d e 172 which  was  d i l u t e d w i t h petroleum e t h e r , f i l t e r e d  pressure  80-85°C/15  (150 mL)  ( t , 2H,  J = 6 Hz,  nmr  J = 6 Hz, -CH I), 2  (80  -CH 0-),  2.05  2  oil This MHz) 3.40  (quintet,  187  2H, J = 6 Hz,  -CH CH CH I). 2  2  2  P r e p a r a t i o n o f the n i t r i l e 173  CN  H  ft  To  a  cold  (-78°C) s o l u t i o n o f d i i s o p r o p y l a m i n e  i n THF (11 mL) was added n - b u t y l l i t h i u m hexanes  and  (1.5 mmol)  g,  1.1  mmol;  15:85,  s o l u t i o n was s t i r r e d a t solution  was  added  0°C  the n i t r i l e s  respectively) f o r 15  the i o d i d e  min.  acid, was  was  (MgSO^,  filtered  the  analysis 1039,  desired  nitrile  and e x h i b i t e d  921,  894  through  173.  i r (film):  a  112a  To  the  1  and 112b  resultant  temperature  for 1  yellow  small  pad  brine of  This  material  h.  The  hydrochloric and  then  F l o r i s i l and  (0.02 t o r r ) t o a f f o r d 0.34  g  (99%)  was homogeneous by g l c  3086, 2766, 2228,  c m ; H nmr (400 MHz) 6: -1  in  HMPA (0.4 mL,  d i l u t e d w i t h petroleum e t h e r , washed w i t h IN  c o n c e n t r a t e d under reduced p r e s s u r e of  solution  i n THF were added and the  t w i c e w i t h aqueous copper s u l f a t e and twice w i t h dried  a  172 (0.35 g, 1.5 mmol) and the s o l u t i o n  was s t i r r e d a t 0°C f o r 30 min and a t room solution  as  the s o l u t i o n was s t i r r e d a t 0°C f o r 15 min.  2.2 mmol) and a s o l u t i o n o f a mixture o f (0.23  (0.24 mL, 1.7 mmol)  1638,  1153, 1112,  4.59 ( b r s, 3H, o l e f i n i c and  - 188 -  a c e t a l p r o t o n s ) , 4.55 ( b r s, 1H, o l e f i n i c p r o t o n ) , 3.43 ( t , 2H, Hz,  J  -  6  -CH CH 0-), 3.35 ( s , 3H, - O C H 3 ) , 2.34 ( b r d t , 1H, J = 5, 12 Hz, H ) , 2  2.14  2  A  ( b r d, 1H, J - 12 Hz, Hg), 2.00-1.20 (m, 14H), 1.27 ( s , 3H, a n g u l a r  methyl  protons),  calcd. for C  1 9  H  1.11  N0 :  3 1  2  (d, 3H, J = 6 Hz, methyl p r o t o n s ) .  305.2355;  found:  Exact Mass  305.2356.  P r e p a r a t i o n o f the aldehyde 180  To a s o l u t i o n o f the n i t r i l e 173 (0.34 g, 1.1 ethane  (11  mL)  was  added  mmol)  diisobutylaluminum hydride  in  (4.4 mmol) as a  s o l u t i o n i n hexanes and the s o l u t i o n was warmed a t 60°C f o r reaction mixture  mixture was  extracted  was  cautiously  neutralized  three  times  with  with ether.  with brine, dried  (Na2S0 )  dissolved  mixture  in a  IN  4  and of  removal  of  the  6  h.  The  i n t o water, and the r e s u l t a n t  hydrochloric  acid,  and  then  was  The e x t r a c t s were combined, washed  concentrated.  THF-acetic  volume) and t h e s o l u t i o n was s t i r r e d After  poured  dimethoxy-  at  The  acid-water room  residual  (8 mL, 1:1:0.16 by  temperature  s o l v e n t under reduced p r e s s u r e  r e s i d u e was d i s s o l v e d i n e t h e r and the  resultant  o i l was  f o r 12  h.  (0.02 t o r r ) , the  solution  was  washed  - 189 -  with and  aqueous  concentrated  exhibited 921, (s,  sodium  i r  893 c m ; -1  bicarbonate  t o a f f o r d 0.29 g  (film):  3086,  and b r i n e , and then was d r i e d (MgSO^) (85%)  of  the  aldehyde  180,  2766, 2740, 1713, 1636, 1153, 1112, 1039,  '-H nmr (400 MHz) 6:  9.52 ( s , 1H, aldehyde p r o t o n ) ,  2H, a c e t a l p r o t o n s ) , 4.58 ( b r s, 2H, o l e f i n i c p r o t o n s ) ,  J - 6 Hz, -CH 0-), 3.35 ( s , 3H, -OCH3), 2  H ),  which  4.60  3.50 ( t , 2H,  2.26 ( b r d t , 1H, J - 5,  12  Hz,  2.11 ( b r d, 1H, J = 12 Hz, Hg), 1.95-1.10 (m, 14H), 1.02 (d, 3H, J  A  •= 6 Hz, methyl p r o t o n s ) , 0.98 ( s , 3H, angular Mass c a l c d . f o r C H 3 2 0 : 1 9  3  308.2351;  methyl  found:  protons).  Exact  308.2359.  P r e p a r a t i o n o f the a l c o h o l 181  To  a  solution-suspension  mmol) i n e t h e r 180 for  (0.28 1 h.  of  l i t h i u m aluminum h y d r i d e  (10 mL) was added an e t h e r e a l s o l u t i o n  g, 0.9 mmol) and the m i x t u r e was s t i r r e d  the c o l l e c t e d m a t e r i a l was  combined  the  1.8  aldehyde  a t room temperature  Sodium s u l f a t e decahydrate was added i n s m a l l p o r t i o n s t o the  s t i r r e d m i x t u r e u n t i l e v o l u t i o n o f gas ceased. and  of  (70 mg,  washed  f i l t r a t e was c o n c e n t r a t e d  three  to y i e l d  The m i x t u r e was f i l t e r e d times  with  ether.  The  0.25 g (91%) o f the a l c o h o l  - 190 -  181 which e x h i b i t e d i r ( f i l m ) : 921, (br  891  cm* ; 1  %  s, 2H, o l e f i n i c  -CH 0H),  3462 ( b r ) , 3085, 1635, 1152, 1111, 1039,  nmr (400 MHz) 5: 4.62 ( s , 2H, a c e t a l p r o t o n s ) , 4.51 p r o t o n s ) , 3.78, 3.70 (d, d, 1H  each,  J  -  12  Hz,  3.51 ( t , 2H, J - 6.5 Hz, -CH CH 0-), 3.37 ( s , 3H, -0CH ), 2.26  2  2  2  3  (br  d t , 1H, 1 - 5 , 12 Hz, H ) , 2.10 (br d, 1H, J - 12 Hz, Hg), 1.87 ( b r  d,  1H,  A  I - 12 Hz, H ) , 1.70-1.10 (m, 14H), 1.06 ( s , 3H, a n g u l a r methyl c  p r o t o n s ) , 0.94 (d, 3H, J = 6 Hz, methyl p r o t o n s ) . C  19 34°3 H  :  310.2508;  found:  Exact Mass c a l c d . f o r  310.2509.  P r e p a r a t i o n o f the phosphorodiamidate 174  To  a s o l u t i o n o f the a l c o h o l 181 (0.22 g, 0.7 mmol) i n a m i x t u r e o f  dimethoxyethane at  0°C  was  (6 mL) and N,N,N',N'-tetramethylethylenediamine  added n - b u t y l l i t h i u m  A f t e r the m i x t u r e had been s t i r r e d dichloridate stirred to  (0.77 mmol) as a s o l u t i o n i n hexanes. f o r 15  min,  dimethylaminophosphoro-  (0.45 mL, 3.6 mmol) was added and the r e a c t i o n m i x t u r e was  a t room temperature f o r 12 h.  0°C,  (1.5 mL)  anhydrous  dimethylamine  c o n t i n u e d a t 0°C f o r 2 h.  The r e a c t i o n m i x t u r e  (10  mL) was added,  was  cooled  and s t i r r i n g was  The s o l u t i o n was d i l u t e d w i t h  ether,  washed  - 191 -  twice  with  brine,  dried  (MgS0 )  and  4  concentrated.  s u b j e c t e d to column chromatography on s i l i c a g e l ether-acetone  10:1  v/v).  The  g  (88%)  920,  888  (s, 2H,  -1  1  H  nmr  3084, 1635,  (400 MHz)  o l e f i n i c p r o t o n s ) , 4.00,  -CH 0P), 2  2.64  cm ;  3.48  ( t , 2H,  2.11  A  (br  d,  lH,  2  -PNMe ), 2.26 2  Hg),  444.3117;  P r e p a r a t i o n o f the e t h e r  Liquid  methylamine  -30°C  for  30  min.  To  with  torr)  to  and  yield  1152,  1H each, J ( s , 3H,  1.9-1.1 (m,  found:  1037,  acetal protons),  (br d t , 1H,  J = 6 Hz,  1111,  4,  14H),  12  -OCH3),  J = 5, 1.06  methyl p r o t o n s ) .  4.51 Hz, 2.66,  12  Hz,  (s,  3H,  Exact  444.3119.  175  (7  c o n t a i n i n g l i t h i u m metal  ( s , 2H,  2  Mass c a l c d .  2  1215,  -CH CH 0-), 3.35  (d, 3H,  4 5  elution  was  as a c o l o r l e s s v i s c o u s o i l  (dd, dd,  a n g u l a r methyl p r o t o n s ) , 0.93 2 3  174  6: 4.60  J - 12 Hz,  for C H N 04P:  then 0.02  1305,  3.95  J = 6 Hz,  (d, d, 6H each, J = 4 Hz,  H ),  (16 t o r r ,  o f the phosphorodiamidate  which e x h i b i t e d i r ( f i l m ) :  g,  residue  a p p r o p r i a t e f r a c t i o n s were combined  c o n c e n t r a t e d under reduced p r e s s u r e 0.27  (10  The  mL)  (9 mg,  was 1.3  condensed i n t o a c o l d  (-78°C) f l a s k  mmol) and the mixture was  the r e s u l t a n t  s t i r r e d at  dark b l u e s o l u t i o n was  added an  - 192 -  e t h e r e a l s o l u t i o n o f the phosphorodiamidate the  mixture  174 (99 mg, ' 0.2  s t i r r e d a t -20°C f o r e x a c t l y 10 min.  was c a u t i o u s l y b u t q u i c k l y t r e a t e d w i t h aqueous the  resultant  mixture  was  extracted  times  e t h e r e a l e x t r a c t s were combined, washed w i t h b r i n e , concentrated. silica  gel  The  residue  was  g,  elution  with  (4  and  The r e a c t i o n mixture  ammonium  three  mmol)  chloride  and  ether.  The  (MgS0 )  and  with dried  4  s u b j e c t e d t o column chromatography on petroleum  ether-ether,  20:1 v / v ) .  C o l l e c t i o n and c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 48 mg (81%) o f the e t h e r 175 as a c o l o r l e s s o i l which 3085,  2767,  1636,  1147,  exhibited  1112, 1078, 1039, 922, 891 cm" ; 1  ir X  (film):  H nmr (400  MHz) 6: 4.60 ( s , 2H, a c e t a l p r o t o n s ) , 4.49 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 3.44 J  -  ( t , 2H, J - 6 Hz, -CH CH 0-), 3.36 ( s , 3H,-0CH ), 2.'28 ( b r d t , 1H, 2  2  3  = 5, 13.5 Hz, H ) , 2.09 ( b r d, 1H, J = 13.5 Hz, Hg), 1.87 A  12 Hz, H ) , 1.63-1.00 (m, 13H), 1.04 ( s , 3H, a n g u l a r methyl p r o t o n s ) , c  0.80 (d, 3H, J - 6 Hz, methyl p r o t o n s ) , 0.73 ( s , Irradiation  at  8  4.49  2.34-2.23 t o sharpen; 2.14-2.06  to  to sharpen; to  ( b r d, 1H, J  collapse  (olefinic  protons)  3H,  caused  methyl the  protons).  signal  at 8  i r r a d i a t i o n a t 5 2.28 ( H ) caused the s i g n a l a t A  8  c o l l a p s e t o a b r o a d s i n g l e t and the s i g n a l a t 8 1.91-1.82  i r r a d i a t i o n a t 8 2.09 (Hg) caused the s i g n a l a t 8 to  a  broad  doublet  (J =  2.34-2.23  13.5 Hz) and the s i g n a l a t 5  1.91-1.82 t o sharpen t o a q o f d ( J = 3.5 Hz, J = 12 Hz); i r r a d i a t i o n a t 5  1.87  triplet d  (HQ) caused  the  s i g n a l a t 8 2.34-2.23 t o c o l l a p s e t o a b r o a d  ( J = 13.5 Hz) and the s i g n a l a t 8 2.14-2.06 t o sharpen t o a d o f  ( J - 4, 13.5 H z ) .  294.2557.  Exact Mass c a l c d . f o r C  1 9  H 40 : 3  2  294.2559;  found:  -  P r e p a r a t i o n o f the e t h e r  Dry  a t 0°C  alcohol  of  r e s u l t a n t mixture were  trated.  condensed i n t o a c o l d  0.29  mmol) and  The  the mixture  was was  treated  the mixture  was  with  (13 mg,  combined,  washed  s t i r r e d a t 0°C  1151,  1112,  3.46  ( t , 2H,  Hz,  1 9  a  ether.  1039  cm ; -1  X  H  J - 7 Hz,  H  3 6  protons),  0 : 2  0.70  296.2715;  nmr  chromatography  e t h e r - e t h e r , 30:2  (400 MHz) 2  ( s , 3H, (s,  found:  3H,  The  v/v).  6:  4.62  ( s , 2H, 20H),  methyl p r o t o n ) , 0.73 methyl p r o t o n ) .  296.2707.  the  ethereal  w i t h b r i n e , d r i e d (MgSO^) and  -CH CH 0-), 1.8-0.8 (m, 2  THF  tert-butyl  The  concen-  on  silica  Collection mg  (80%)  c o l o u r l e s s o i l which e x h i b i t e d i r ( f i l m ) :  methyl p r o t o n s ) , 0.77  methyl C  as  added a  f o r 20 min.  c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 6.8 182  stirred  aqueous ammonium c h l o r i d e and  s u b j e c t e d to column  (1 g, e l u t i o n w i t h petroleum  was  29 pmol) and  e x t r a c t e d t h r e e times w i t h  r e s i d u e was  ether  (-78°C) f l a s k  the r e s u l t a n t dark b l u e s o l u t i o n was  mmol) and  mixture  extracts  To  was  the phosphorodiamidate 174  (0.11  reaction  (1 mL)  l i t h i u m m e t a l (11 mg,  f o r 20 min.  solution  gel  182  l i q u i d ethylamine  containing  193  and  of  1463,  the 1383,  a c e t a l protons), 0.78  (d, 3H,  (d, 3H,  J - 7  J •= 7  Hz,  Exact Mass c a l c d . f o r  194 -  P r e p a r a t i o n o f the a l c o h o l 183  A mixture  o f the  p _ - t o l u e n e s u l f onate heated  ether  (0.55  a t 70°C f o r 12  pressure ether.  (0.02  (65  mg,  was  of  removal  891  r e s i d u e was t r i t u r a t e d t h r e e times w i t h d r y  column  solvent  and  concentrated,  chromatography  e t h e r - e t h e r , 7:3 v / v ) .  under  reduced  and the  on s i l i c a g e l (1 g,  C o l l e c t i o n and c o n c e n t r a -  a p p r o p r i a t e f r a c t i o n s p r o v i d e d 50 mg (91%) o f the a l c o h o l 3319 (br) , 3085, 1635,  c m ; H nmr (400 MHz) 5: 4.50 ( b r s, 2H, o l e f i n i c -1  X  3.57 ( t , 2H, J = 6 Hz, -CH CH OH), 2.29 ( b r d t , 1H, J = 5, 12 2  2.10  pyridinium  the  to  of  183 as a c o l o r l e s s o i l which e x h i b i t e d i r ( f i l m ) : 1055,  and  After  subjected  the  mmol)  h.  torr)  e l u t i o n w i t h petroleum  0.22  g, 2.2 mmol) i n t e r t - b u t y l a l c o h o l (5 mL) was  The e t h e r e a l s o l u t i o n was f i l t e r e d  residue  tion  175  ( b r d,  1H,  J  =  2  12  Hz,  Hg),  protons), Hz,  H ), A  1.87 ( b r d, 1H, J = 12 Hz, H ) , c  1.65-1.00 (m, 14H), 1.05 ( s , 3H, a n g u l a r methyl p r o t o n s ) , 0.80 (d, 3H, J =  6  Hz,  methyl  calcd. f o r C  1 7  H  3 0  0:  protons), 250.2296;  0.75  ( s , 3H, methyl p r o t o n s ) .  found:  250.2295.  Exact Mass  - 195  P r e p a r a t i o n o f the aldehyde  -  184  CHO  To a s t i r r e d mg,  0.32  solution-suspension of  mmol)  and  d i c h l o r o m e t h a n e (5 mL) 0.24  mmol).  1 h,  i t was  short  pad  (99%)  2714,  2 Hz, H  A  and H ), c  (d,  sodium  acetate  A f t e r the mixture  Florisil.  1728,  1635,  The  892  2  1.70-1.15 (m, J = 6 Hz,  then  f i l t r a t e was  cm" ; 1  1  H  nmr  (br s, 2H,  was  61  filtered  concentrated  (400 MHz)  /xmol) i n (60  J = 12 Hz,  11H),  ( s , 3H,  1.05  5:  248.2140;  Hg),  a  to a f f o r d 58  mg  9.74  1.88  angular  methyl p r o t o n s ) , 0.79 2  mg,  through  (film):  ( t , 1H,  o l e f i n i c p r o t o n s ) , 2.30-2.16  (br d, 1H,  Exact Mass c a l c d . f o r C H 8 0 : 1 7  mg,  as a c o l o r l e s s o i l which e x h i b i t e d i r  -CH CH0), 2.10  3H,  (5  (70  had been s t i r r e d a t room temperature f o r  d i l u t e d w i t h dry e t h e r , and of  chlorochromate  added a s o l u t i o n o f the a l c o h o l 183  aldehyde p r o t o n ) , 4.50  12 Hz, 0.81  was  o f the aldehyde 184  3085,  3H,  anhydrous  pyridinium  ( s , 3H,  found:  (br d, 1H,  methyl  J = (m, J =  protons),  methyl p r o t o n s ) .  248.2145.  - 196 -  P r e p a r a t i o n o f the ketone 176  •0 H "" A  To a c o l d (0°C) s t i r r e d s o l u t i o n o f the ^imol)  i n ether  i n ether. h,  (1 mL) was added m e t h y l l i t h i u m  concentrated  to  give  a  mixture o f e p i m e r i c 1  found: mixture  acetate  and  1 8  H  3 2  0:  264.2455. o f alcohols obtained  as d e s c r i b e d above was added t o a  (3 mg, 36 /xmol) i n dichloromethane  14  mmol)  and  (1 mL) a t 0°C and the The  reaction  mixture  d i l u t e d w i t h d r y e t h e r and then was f i l t e r e d through a s h o r t pad o f  Florisil.  Concentration  which  MHz) 8:  o f the f i l t r a t e  exhibited i r (film):  gave 22 mg (97%)  1  4.51 ( b r s, 2H, o l e f i n i c p r o t o n s ) ,  Hz,  H ) , 1.65-1.10 (m, 13H), 1.05 ( s , 3H, a n g u l a r  methyl p r o t o n s ) ,  3H, J = 7 Hz, methyl p r o t o n s ) , 0.78 ( s , 3H, methyl p r o t o n s ) . 1 8  H  3 0  O:  5,  12  2.21-2.05 (m, 1H), 1.88 ( b r d, 1H, J - 12  c  Mass c a l c d . f o r C  ketone  X  2.28 ( b r d t , 1H, J =  H ) , 2.13 ( s , 3H, -COCH3), A  o f the  3085, 1718, 1635, 891 cm* ; H nmr (400  Hz,  (d,  evolu-  filtered  Exact Mass c a l c d . f o r C  m i x t u r e was s t i r r e d a t room temperature f o r 1 h.  176  88  a l c o h o l s , which showed i r  s o l u t i o n - s u s p e n s i o n o f p y r i d i n i u m chlorochromate (31 mg,  was  mg,  (0.28 mmol) as a s o l u t i o n  The s o l u t i o n was d i l u t e d w i t h e t h e r ,  3349 ( b r ) , 3085, 1635, 891 cm" .  264.2453;  sodium  (22  s u l f a t e decahydrate was added i n s m a l l p o r t i o n s u n t i l  t i o n o f gas ceased.  The  184  A f t e r the mixture had been s t i r r e d a t room temperature f o r 3  sodium  (film):  aldehyde  262.2297;  found:  262.2298.  0.80 Exact  - 197 -  P r e p a r a t i o n o f the e s t e r s 186 and 177  R 186 R=H. R=C0?Et 177 R=C0 Et,R=H  Hi  2  H  A  To a s u s p e n s i o n o f p o t a s s i u m h y d r i d e (30 mg, 0.75 mmol; washed ether  and d r i e d under a stream o f argon)  t u r e was added t r i e t h y l phosphonoacetate m i x t u r e was s t i r r e d f o r 30 min.  i n THF (3 mL) a t room (140  uL,  0.7  15 h .  concentrated.  Glc  were  analysis  of  the  of  the  The l e s s p o l a r 890  of  50:1  v/v).  2  ddd,  3  1:10.  2.55  The  two  on s i l i c a g e l  Collection  and  (Z) e s t e r 177, 19 mg (88.3%).  X  3085, 1718, 1648,  5.60 ( b r s, 1H, o l e f i n i c p r o t o n ) ,  4.50 ( b r s, 2H, t e r m i n a l o l e f i n i c p r o t o n s ) , 4.12 ( q , 2H, -0CH CH ),  filtrate  r e s i d u a l o i l showed t h a t i t  (Z) e s t e r 186 e x h i b i t e d i r ( f i l m ) :  cm" ; H nmr (400 MHz) 6: 1  decahy-  a p p r o p r i a t e f r a c t i o n s a f f o r d e d b o t h the pure (Z)  e s t e r 186, 2.5 mg (11.6%) and the pure  1151,  The  r e a d i l y s e p a r a b l e by column chromatography  (2 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , concentration  and the  temperature  sulfate  Celite.  c o n s i s t e d o f a m i x t u r e o f two compounds i n a r a t i o products  room  The r e a c t i o n mixture was t r e a t e d w i t h sodium  d r a t e , d i l u t e d w i t h e t h e r , and f i l t e r e d through was  tempera-  A s o l u t i o n o f the ketone 176 (17 mg, 65  /jmol) i n THF was added and the mixture was s t i r r e d a t for  mmol)  with  J  =  7.5  Hz,  ( b r d t , 1H, J = 4, 12 Hz, H ) , 2.32, 2.24 ( b r ddd, b r A  2H, J - 5, 12, 12 Hz, -CH (CH )C=), 2.11 ( b r d, 1H, J - 12 Hz, Hg), 2  3  - 198 -  1.90  1H,  (m,  1.74-1.22 angular (s,  1.85  H ), c  3H,  J = 1.5 Hz, v i n y l  (m, 1 1 H ) , 1.25 ( t , 3 H , J - 7.5 Hz, methyl  methyl  -OCH CH ), 2  3  protons),  1.05  Exact Mass  calcd.  for  C22H36O2:  3H,  (s,  0.85 (d, 3 H , J = 6 Hz, methyl p r o t o n s ) ,  protons),  3H, methyl p r o t o n s ) .  found:  (d,  0.73  332.2715;  332.2721.  The  more p o l a r  (E) e s t e r 177 e x h i b i t e d i r ( f i l m ) :  1224, 1148, 892, 871 c m ; -1  4.51  proton),  (br  X  H nmr  (400 MHz)  S:  5.63  3085, 1718, 1646,  (br s, 1 H , o l e f i n i c  s, 2 H , t e r m i n a l o l e f i n i c p r o t o n s ) , 4.14 (q, 2 H , J =  7.5 Hz, - 0 C H C H ) ,  2.29 (br d t , 1 H , J - 5, 13.5 Hz, H ) , 2.14 (d, 3 H ,  =  methyl p r o t o n s ) ,  2  1.5  3H,  Hz,  3  vinyl  and H ) , 1 . 6 6 - 1 . 2 2  -CH (CH )C= 2  3  -0CH CH ), 2  3  c  1.05 ( s , 3 H , a n g u l a r  methyl p r o t o n s ) , C  22 36°2 H  A  0.74  332.2715;  :  2.15-2.07  (m, 1 1 H ) , 1.28  methyl p r o t o n s ) ,  ( s , 3 H , methyl p r o t o n s ) . found:  P r e p a r a t i o n o f the a l l y l i c  (m, 1 H , Hg), 2 . 0 2 - 1 . 7 8 ( t , 3H, J  =  J (m,  7.5  Hz,  0.81 (d, 3 H , J = 6 Hz,  Exact  Mass  calcd.  for  332.2715.  a l c o h o l 187  OH  To  a  c o l d (-78°C) s t i r r e d  ^mol) i n e t h e r as  a  s o l u t i o n o f the (E) e s t e r 177 (19 mg,  (1 mL) was added d i i s o b u t y l a l u m i n u m  s o l u t i o n i n hexanes.  hydride  (0.25  A f t e r the s o l u t i o n had been s t i r r e d  57  mmol)  for 1 h  - 199 -  a t -78°C and 2 h a t 0°C, i t was t r e a t e d w i t h s a t u r a t e d aqueous chloride  (0.1  mL)  and then d i l u t e d w i t h e t h e r .  was s t i r r e d f o r 5 min a t room temperature, through  a  pad  of  (98%) o f the a l l y l i c 3085,  Florisil.  (MgSO^  -1  X  H nmr  (400 MHz) 6:  J = 8 Hz, •=CCH 0H), 2.29 2  p r o t o n s ) , 1.03  f o r C20H34O:  290.2610;  A  h.  ( b r s,  3H,  vinyl  (d, 3H, J =  E x a c t Mass  calcd.  290.2614.  a l c o h o l 187 (15.8 mg,  (1.5 mL) was s t i r r e d a t room temperature w i t h 3  ( t , 1H, J -  107  A s o l u t i o n o f the a l l y l i c  for  5.37  (br d t , 1H, J = 5, 13.5 Hz, H ) , 2.10  ( s , 3H, methyl p r o t o n s ) .  found:  P r e p a r a t i o n o f the aldehyde  mg)  3327 ( b r ) ,  ( s , 3H, a n g u l a r methyl p r o t o n s ) , 0.81  8 Hz, methyl p r o t o n s ) , 0.72  filtered  ( b r s, 2H, t e r m i n a l o l e f i n i c p r o t o n s ) , 4.12  (br d, 1H, J - 13.5 Hz, Hg), 1.93-1.18 (m, 15H), 1.65 methyl  and  C o n c e n t r a t i o n o f the f i l t r a t e gave 16 mg  1668, 1636, 1000, 891 c m ;  2H,  The r e s u l t i n g mixture  a l c o h o l 187 which e x h i b i t e d i r ( f i l m ) :  8 Hz, o l e f i n i c p r o t o n ) , 4.50 (d,  dried  ammonium  55 /xmol) i n n-hexane  manganese(IV)  oxide  (70  The mixture was f i l t e r e d through a pad o f C e l i t e .  The  c o l l e c t e d m a t e r i a l was washed f o u r more times w i t h d i e t h y l  ether.  The  - 200 -  combined f i l t r a t e  was c o n c e n t r a t e d  to a f f o r d 14 mg  107 as a c o l o r l e s s o i l which e x h i b i t e d  ir  1611,  MHz)  1195,  891  aldehyde p r o t o n ) , 2H,  terminal  protons), (d,  cm" ; 1  5.86  H  nmr  (270  (film):  3084,  8: 9.97  1676,  protons),  (m, 16H), 1.06  2.16  Mass c a l c d . f o r C20H32O:  0.77  288.2453;  ( b r s,  (d, 3H, J = 0.8 Hz, v i n y l methyl  ( s , 3H, a n g u l a r  3H, J = 8 Hz, methyl p r o t o n s ) ,  1633,  (d, 1H, J = 8 Hz,  (br d, 1H, J= 8 Hz, o l e f i n i c p r o t o n ) , 4.51  olefinic  2.4-1.1  1  (88%) o f the aldehyde  methyl  protons),  0.81  ( s , 3H, methyl p r o t o n s ) .  found:  Exact  288.2446.  P r e p a r a t i o n o f 2 - t r i m e t h y l s i l v l - 4 - ( c h l o r o m e t h y l ) f u r a n (110)  190X=OH, Y=SPh.Z=H 191 X=OTBDMS,Y=SPh,Z=H 192 X=0TBDMS,Y=SPh,Z=TMS 193 X=0TBDMS.Y=H, Z=TMS 194 X=0H, Y=H, Z=TMS 110 X=Cl, Y=H, Z=TMS  2 - T r i m e t h y l s i l y l - 4 - ( c h l o r o m e t h y l ) f u r a n (110) was furanmethanol al  5  as  described  by  Goldsmith  et  al  prepared  from  3-  and  Tanis  et  5  8  v i a 190, 191, 192, 193, and 194.  9  Compound 190 e x h i b i t e d ^-H nmr furan  a-proton),  7.25-7.15  Hz, f u r a n y3-proton),  4.66  (80 MHz) 8: 7.59  (d, 1H,  (m, 5H, p h e n y l p r o t o n s ) ,  6.65  (d, 2H, J = 5 Hz, -CH 0H), 1.62 2  J  =  2  Hz,  (d, 1H, J = 2 ( t , 1H, J =  5  Hz, exchanged w i t h D2O, -OH). Compound  191  exhibited  l  U  nmr  (80 MHz) 8: 7.55  (d, 1H, J = 2 Hz,  - 201 f u r a n a-proton), Hz,  furan  7.23-7.13 (m, 5H, phenyl p r o t o n s ) ,  0-proton),  4.66  ( s , 2H,  -CH 0),  6.61 (d, 1H, J  =  2  0.91 ( s , 9H, t e r t - b u t y l  2  p r o t o n s ) , 0.07 ( s , 6H, s i l y l methyl p r o t o n s ) . Compound 192 e x h i b i t e d ^-H nmr (80 MHz) 8: 7.35-7.15 (m, protons),  6.85  5H,  phenyl  (br s, 1H, f u r a n p r o t o n ) , 4.70 ( s , 2H, -CH 0), 0.99 ( s , 2  9H, t e r t - b u t y l p r o t o n s ) , 0.38 ( s , 9H, s i l y l  t r i m e t h y l p r o t o n s ) , 0.13 ( s ,  6H, s i l y l methyl p r o t o n s ) . Compound a-proton),  193  exhibited  X  H  nmr  (80 MHz) 8: 7.56 ( b r s, 1H, f u r a n  6.60 (br s, 1H, f u r a n /3-proton),  4.63  (br  0.97 ( s , 9H, t e r t - b u t y l p r o t o n s ) , 0.30 ( s , 9H, s i l y l  s,  2H,  -CH 0-), 2  trimethyl protons),  0.13 ( s , 6H, s i l y l methyl p r o t o n s ) . Compound 194 e x h i b i t e d H nmr (80 MHz) 8: X  a-proton),  6.66  (br  s,  1H, f u r a n /9-proton),  7.60  (br  s,  1H,  furan  4.55 ( b r s, 2H, -CH 0H), 2  1.58 (br s, 1H, D 0 exchange, -OH), 0.30 ( s , 9H, s i l y l methyl p r o t o n s ) . 2  Compound 110 e x h i b i t e d H nmr (270 MHz) 8: 1  a-proton),  7.61 ( b r  s,  1H,  furan  6.62 ( s , 1H, f u r a n 0 - p r o t o n ) , 4.45 ( s , 2H, -CH C1), 0.25 ( s , 2  9H, s i l y l methyl p r o t o n s ) .  P r e p a r a t i o n o f the c h l o r o b u t e n o l i d e  0  :  109  202 -  While  oxygen  was  bubbled  through  f u r a n d e r i v a t i v e 110 (2 g, 10 mmol) and a phenylporphin  (1  mmol)  a cold  (-78°C) s o l u t i o n o f the  catalytic  i n dichloromethane  amount  of  tetra-  (120 mL), i t was i r r a d i a t e d  w i t h a h a l o g e n - t u n g s t e n lamp (650 W, 110 V o p e r a t e d a t 50 V) f o r 27 min. The  disappearance  of  starting  material  was  s o l u t i o n was a l l o w e d t o warm t o room temperature trated.  The r e s i d u e was d i s s o l v e d i n methanol  a t room temperature  f o r 12 h.  was  flash  subjected  to  1  1  H  column  chromatography  nmr  (80 MHz) 5:  6.21 ( b r s, 2H, H  A  C H  146.9849;  3 5  C10  (M -l): +  3  on s i l i c a v/v).  concenstirred  g e l (250 g,  Collection  3357 ( b r ) , 1763,  -OH), 4.37 ( s , 2H, - C H 2 C I ) .  4  was  then  and  o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 1.27 g (78%) o f the  exchanged w i t h D2O, 5  and  A f t e r removal o f the s o l v e n t , the r e s i d u e  b u t e n o l i d e 109, which e x h i b i t e d i r ( f i l m ) : cm" ;  by g l c . The  and the s o l u t i o n  e l u t i o n w i t h p e t r o l e u m e t h e r - e t h y l a c e t a t e , 6:5 concentration  monitored  found:  1660, 1139  and Hg), 4.80 ( b r s, 1H, E x a c t Mass  calcd.  for  146.9843.  P r e p a r a t i o n o f the methoxy b u t e n o l i d e 197  0  :  OMe  A s o l u t i o n o f the b u t e n o l i d e 109 (0.1 g, 0.67 mmol) and p_-toluenesulf o n i c a c i d monohydrate (30 mg, 0.16 mmol) i n d r y methanol  (10  mL)  was  - 203 stirred and  a t room temperature f o r 2 days.  The s o l u t i o n  was  concentrated  t h e r e s i d u e was s u b j e c t e d t o column chromatography on s i l i c a e t h e r - e t h y l acetate 3:1 v / v ) .  g, e l u t i o n w i t h petroleum concentration  of  1662,  1120 cm" . 1  1  H nmr (80 MHz) 6:  s, 1 H , Hg), 4.31 ( b r s, 2 H , - C H C 1 ) , 2  calcd. for C H 6  3 5 6  Collection  and  t h e a p p r o p r i a t e f r a c t i o n s a f f o r d e d 0 . 1 g (92%) o f the  methoxy b u t e n o l i d e 197 which e x h i b i t e d i r ( f i l m ) : 1768,  g e l (5  C10  3  (M+-1):  2845,  6 . 2 0 (m, lH,' H ) , A  3.61 ( s , 3 H ,  161.0005;  3113,  found:  -OCH3).  1800,  5.80 ( b r  Exact  Mass  160.9999.  P r e p a r a t i o n o f t h e phosphonium s a l t 188  0' H  A solut ion phine  o f the b u t e n o l i d e 197 (0.4 g, 2.5 mmol) and t r i p h e n y l p h o s -  (1 g, 3.9 mmol) i n benzene (8 mL) was r e f l u x e d f o r  resultant  slurry  decanted.  The r e s i d u e was washed  dried  under  CD C1 ) 2  6:  1H each, H -OCH3).  A  was  centrifuged  reduced p r e s s u r e  phosphonium s a l t 2  B  188.  and  the  supernatant  2  days.  The  s o l u t i o n was  t h r e e times w i t h benzene and then  was  (0.02 t o r r ) t o a f f o r d 0.74 g (70%) o f the  T h i s white f i n e s o l i d e x h i b i t e d ^H nmr  8.2-7.5 (m, 15H, aromatic and Hg), 5.80 (d, 2H, J  =  (80  MHz,  p r o t o n s ) , 6.00,5.98 ( b r s, b r s, 16  Hz,  -CH P), 2  3.30  ( s , 3H,  - 204 -  H y d r o l y s i s o f the methoxy b u t e n o l i d e 200 to the hydroxy b u t e n o l i d e 202  200  To  a  mixture  sodium h y d r o x i d e solution  was  of  (4 M,  clear  202  the b u t e n o l i d e 200 (0.13 g, 1 mmol) and aqueous 1.1  (-7  mmol)  was  added  acetonitrile  treated  with  dilute  s o l u t i o n turned c o l o r l e s s . triturated  with  ether.  the  m l ) . The s o l u t i o n , which was s t i r r e d a t room  temperature f o r 0.5 h, g r a d u a l l y t u r n e d y e l l o w . was  until  hydrochloric  acid  The r e s u l t a n t (2  M, 1.2 mmol) and the  A f t e r removal o f s o l v e n t s , the The  ethereal  solution  solution  was  residue  filtered,  was dried  (MgS04) and c o n c e n t r a t e d t o p r o v i d e 68 mg (60%) o f the h y d r o x y b u t e n o l i d e 202  6 3  5.94  which  exhibited  i r (film):  3350, 1730 c m ; ^-H nmr (80 MHz) 6: -1  ( b r s, 1H, OCHOH), 5.79 (m, 1H, o l e f i n i c p r o t o n ) , 5.48 (v b r s, 1H,  D 0 exchanged, -OH), 2.06 (d, 3H, J = 2H, methyl p r o t o n s ) . 2  - 205 -  P r e p a r a t i o n o f the phosphonate 213  t0Et)2 Me  0"  A  mixture  o f the b u t e n o l i d e  triethylphosphite  (5  mL)  was  (197) (0.11 g, 0.68 mmol) and p u r i f i e d  heated  at  -150°C  f o r 18  t r i e t h y l p h o s p h i t e was removed under reduced p r e s s u r e  h.  (0.02 t o r r ) and the  r e s i d u a l o i l was s u b j e c t e d t o column chromatography on s i l i c a elution  with  ether).  Excess  g e l (10 g,  C o l l e c t i o n and c o n c e n t r a t i o n o f the a p p r o p r i a t e  f r a c t i o n s a f f o r d e d 0.14 g (78%) o f the phosphonate 213 as a c o l o r l e s s o i l which  exhibited  i r (film):  nmr (400 MHz) 6:  3107, 2846, 1796, 1767, 1651, 1250 cm" ; 1  6.11 ( b r d, 1H, J = 4.5 Hz, H  A  X  H  o r Hg), 5.82 ( b r d, 1H,  J - 3 Hz, Hg o r H ) , 4.15 ( b r q u i n t e t , 4H, J - 7 Hz, -0CH CH ), 3.60 ( s , A  3H, (dt,  2  -0CH ), 3.01, 2.89 (dd, dd, 1H each, J - 16, 3  6H,  264.0762;  J  =  found:  2.7, 7 Hz, -0CH CH ). 2  3  Hz,  -CH P),  P r e p a r a t i o n o f the s u l f o n e 223  •S0 Ph 2  1.35  2  Exact Mass c a l c d . f o r C  264.0756.  Me3Si  21  3  1 Q  H  1 7  0 P: 6  - 206  A s t i r r e d mixture o f the benzenesulfinate  (0.58  g,  h e a t e d a t 80-90°C f o r 2.5 ether,  washed  trated.  The  twice  3.5  h.  with  r e s i d u e was  furan  -  110  (0.56  mmol) and  The  2.95  mmol),  sodium  dimethylformamide (2.5  resultant  brine,  g,  dried  solution  was  mL)  diluted  (MgSo ), f i l t e r e d and  s u b j e c t e d t o column chromatography  on  neutral  g, e l u t i o n w i t h p e t r o l e u m e t h e r - d i e t h y l  2:8  concentration  C o l l e c t i o n and  afforded  0.62  3065, 1681, 7.8-7.3  g  1587,  (m,  C  1 4  H  0 SSi:  P r e p a r a t i o n o f the  THF  (0.9  and  the  (10 mg,  a cold mL)  sulfone  1310,  protons),  was  Limol)  the  (223)  1251,  1152 6.45  s i l y l methyl p r o t o n s ) . found:  triene  appropriate  which e x h i b i t e d cm" ; 1  (s,  1H,  nmr H ), A  fractions ir  (film): 8:  (80 MHz) 4.15  Mass  (s,  calcd.  2H, for  216  sulfone  s t i r r e d f o r 20 min. was  H  Exact  223  added a s o l u t i o n o f n - b u t y l l i t h i u m  i n THF  X  ether,  294.0744.  (-78°C) s o l u t i o n o f the  s o l u t i o n was 35  1448,  294.0746;  3  To  o f the  aromatic ( s , 9H,  2  1 8  1479,  6H,  - C H S 0 - ) , 0.25 2  (72%)  of  with  concen-  4  alumina ( a c t i v i t y I I I , 20 v/v).  was  added and  the  (25.5  mg,  (77  Ltmol)  A s o l u t i o n o f the s o l u t i o n was  87  Ltmol)  in  i n hexanes  aldehyde  s t i r r e d at  107  -78°C  - 207 for  3  h.  Benzoyl c h l o r i d e  m i x t u r e was The  solution  was  twice  with  The  methanol (1 mL,  3:1 v/v) and was  The  mixture  was  neutral  pentane-ether,  50:1  v/v).  afforded  mg  1H,  H ), A  olefinic  d, 1H,  methyl 6 Hz,  6.76  J - 16 Hz,  terminal (br  (51%)  was  J = 13.5  D  p r o t o n s ) , 1.05  3  (MgSO^  i n a mixture  c o o l e d to  h.  and  of  -20°C.  THF-  Sodium  s t i r r e d a t -20°C f o r 2  residue (2  5.89  H ), G  was  continued  g,  subjected  activity  of  the  891,  Hg),  844  6.56  (d, 1H,  cm" ;  (dd, 1H,  X  H  nmr  for  (br dt, 1H,  (400 MHz)  3H,  methyl  Exact Mass c a l c d . f o r C 8H44Si0: 2  4.50  1.80  Hz,  6.30  s,  2H,  Hp),  2.12  c  3H,  vinyl  (d, 3H,  0.27  found:  7.58  H ),  (br  (s,  protons),  424.3161;  6:  16 Hz,  a n g u l a r methyl p r o t o n s ) , 0.82  (s,  fractions  which e x h i b i t e d i r  J «= 5, 13.5  14H),  column  I I I , e l u t i o n with  J = 10,  J = 10 Hz, Hg),  1.97-1.20 (m,  ( s , 3H,  1  to  appropriate  the d e s i r e d t r i e n e 216,  1250,  methyl p r o t o n s ) , 0.74  -SiMe ).  The  p r o t o n s ) , 2.30 Hz,  dissolved  Collection  ( s , 1H,  H ),  dried  added and s t i r r i n g was  alumina  of  3085, 3034, 1635,  1H,  reaction  d i l u t e d w i t h pentane, washed t w i c e w i t h b r i n e ,  on  (s,  was  added and the mixture was  chromatography  (film):  the  over a p e r i o d o f 1.5  then  the s o l u t i o n was  (MgSO^) and c o n c e n t r a t e d .  7.5  and  o i l was  A d d i t i o n a l amalgam (13 mg)  dried  (d,  brine  residual  amalgam (4%, 23 mg)  h.  added and  d i l u t e d w i t h e t h e r , washed once w i t h s a t u r a t e d sodium  concentrated.  1  87 umol) was  a l l o w e d to warm to room temperature  b i c a r b o n a t e and  h.  (10 uL,  (s,  J = 9H,  424.3161.  - 208 -  P r e p a r a r i o n o f (±)-Palauolide  (55)  0  HG  1  A  solution  of  .the  triene  216  amount o f Rose Bengal (1.7 /imol) methane was  (1 mL,  10:3 v/v) was  b u b b l e d through the s o l u t i o n ,  sodium n i t r i t e purged  with  filter  subjected  to  (74 g per  (br),  column  1H,  1614, A  H ),  5.87  D  (br  1634,  (4.4  J = 11, 15.5 Hz, H ) ,  = 8.5 Hz;  i t was  (m,  with  The  resultant  solution  E  1.88  1  H  nmr  (400 MHz)  6:  7.14  (d, 1H, J = 15.5 Hz, Hg), 6.23 exchange,  (br s, 2H,  H ),  was  was  5.97  3340 (dd,  (d, 1H, J 11  Hz,  terminal o l e f i n i c protons),  2.30  c  (d, 1H, J =  (br d, 1H, J = 13.5 Hz, H ) ,  ( s , 3H, v i n y l methyl p r o t o n s ) , 1.06 (d, 3H, J = 6 Hz, methyl p r o t o n s ) ,  The ^H nmr  a  fractions  68%) which e x h i b i t e d i r . ( f i l m ) : -1  6.29  ( s , 1H, H ) , 4.51  protons).  min  on s i l i c a g e l (1.5 g, e l u t i o n w i t h  890 cm ;  2  methyl p r o t o n s ) , 0.82 methyl  8  C o l l e c t i o n o f the a p p r o p r i a t e mg,  c o l l a p s e d to s on D 0  15H),  While a stream o f oxygen  a l l o w e d to s t a n d a t room temperature i n  d t , 1H, J = 5, 13.5 Hz, Hp), 2.12  1.10  of methanol-dichloro-  irradiated for  litre).  chromatography  (±)-palauolide  3083, 1757,  mixture  Removal o f s o l v e n t p r o v i d e d a crude p r o d u c t which  h e x a n e - e t h y l a c e t a t e , 7:3 v / v ) . provided  17 /xmol) and a c a t a l y t i c  110 V o p e r a t e d a t 50 V) through an aqueous  argon and then was  dark f o r 3 h.  a  c o o l e d to -78°C.  h a l o g e n - t u n g s t e n lamp (650 W,  the  in  (7.5 mg,  G  2.07-  ( s , 3H, a n g u l a r 0.75  spectrum o f t h i s m a t e r i a l was  (s,  3H,  i d e n t i c a l to  - 209 -  t h a t o f the n a t u r a l l y o c c u r r i n g  sesterterpene  Mass c a l c d . f o r C 2 5 H 0 : 384.2664; 3 6  3  found:  (+)-palauolide.*  Exact  384.2660.  P r e p a r a t i o n o f 2-iodo-l-benzyloxvmethoxvethane (246)  I^N/°\/ N/Ph 0  To  a  cold  (0°C) s o l u t i o n o f 2 - c h l o r o e t h a n o l  diisopropylethylamine added  benzyl  stirred  (1.0 mL, 15 mmol) and  (5.2 mL, 30 mmol) i n dichloromethane  chloromethyl  ether  (33  mL)  (3.8 mL, 27 mmol) and the s o l u t i o n was  a t room temperature f o r 12 h.  The r e a c t i o n mixture  was  diluted  w i t h e t h e r , washed once w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e , w i t h 2N h y d r o c h l o r i c a c i d , twice w i t h s a t u r a t e d aqueous sodium nate  and  three  concentrated. the  remaining  ethane  with  Distillation  brine,  and  then  was  dried  twice  bicarbo-  (MgSO^) and  ( a i r - b a t h temperature 90-95°C/0.02 t o r r )  o i l y i e l d e d 2.6 g (86%) o f  of  2-chloro-l-benzyloxymethoxy-  (247).  The 1118,  times  was  c h l o r i d e 247 e x h i b i t e d i r ( f i l m ) : 1075,  aromatic  1041,  1002  cm" ; 1  X  3095, 3064, 3032, 1498, 1161,  H nmr (270 MHz) 6:  p r o t o n s ) , 4.81 ( s , 2H, b e n z y l p r o t o n s ) ,  We a r e g r a t e f u l t o  Professor  spectrum o f p a l a u o l i d e .  D.  John  4.63  Faulkner  7.35-7.20 (m, 5H, ( s , 2H,  f o r the  acetal  -41 nmr  - 210 -  p r o t o n s ) , 3.83 ( t , 2H, J = 6 Hz, -CH C1).  Exact  2  Mass  calcd.  -CH 0-),  3.63  2  for C  H 1 0  13  3 5 c l o  ( t , 2H, 2  J  -  200.0604;  :  6  Hz,  found:  200.0600. A s t i r r e d s o l u t i o n o f the c h l o r i d e 247 (2.0 g, 10 mmol) iodide  (6 g, 40 mmol) i n acetone (20 mL) was h e a t e d  f o r 40 h. material  The r e s u l t a n t s o l u t i o n was  was  concentrated  t r i t u r a t e d t h r e e times w i t h petroleum  the  ether.  (air-bath  temperature 105-110°C/0.02 t o r r ) o f the r e m a i n i n g  The 1152,  and  and  were  g (77%)  filtered  i o d i d e 246 e x h i b i t e d i r ( f i l m ) : 1114,  aromatic protons),  concentrated.  o f 2-iodo-l-benzyloxymethoxyethane  1066,  1027  cm" ; 1  X  H  residual  The o r g a n i c Distillation o i l yielded  (246).  3095, 3064,  nmr  sodium  a t 60°C i n the dark  solutions  2.5  combined,  and  3030,  1497, 1455,  (270 MHz) 8 7.35-7.20 (m, 5H,  p r o t o n s ) , 4.78 ( s , 2H, b e n z y l p r o t o n s ) ,  4.63  ( s , 2H,  acetal  3.83 ( t , 2H, J = 6 Hz, -CH 0-), 3.26 ( t , 2H, J = 6 Hz, - C H I ) . 2  Exact Mass c a l c d . f o r C  H 1 0  13  I O  2  291.9959;  :  2  found:  291.9966.  P r e p a r a t i o n o f the phosphonate 248  0  To a s t i r r e d s u s p e n s i o n with  diethyl  ether  o f sodium h y d r i d e  (35 mg, 1.46 mmol;  washed  and d r i e d ) i n dimethylformamide (4.4 mL) was added  methyl b i s ( 2 , 2 , 2 - t r i f l u o r o e t h y l ) p h o s p h o n o a c e t a t e (0.42 g, 1.32 mmol) and  - 211 -  the m i x t u r e was s t i r r e d a t room temperature  f o r 15 min.  (25 mg, 95 j*mol) and 2-iodo-l-benzyloxymethoxyethane mmol)  were  added.  pad  pressure column  of  Florisil.  (16 t o r r ,  The  e t h e r - e t h e r , 4:6 v / v ) .  on  ether  and  silica  g e l (160  reduced flash  C o l l e c t i o n and c o n c e n t r a t i o n o f t h e a p p r o p r i a t e  ir  1743, 1499, 1299, 1264, 1174, 1068, 964  0.45 g (70%) o f t h e phosphonate 248 which cm ; -1  X  H  exhibited nmr  (400  7.34 (m, 5H, a r o m a t i c p r o t o n s ) , 4.71, 4.70 (d, d, 1H each, J =  7 Hz, b e n z y l p r o t o n s ) , 4.58, 4.57 (d, d, 1H, each, J = 11.5 protons),  4.40  (ra, 4H,  CF CH 0-), 3  2  -CH CH 0-), 3.39 (ddd, 1H, J = 4, 2  a  g, e l u t i o n w i t h p e t r o l e u m  provided  6:  through  The r e s i d u e was s u b j e c t e d t o  fractions  MHz)  filtered  f i l t r a t e was c o n c e n t r a t e d under  then 0.02 t o r r ) .  chromatography  (film):  (246) (0.28 g, 0.98  A f t e r the r e a c t i o n m i x t u r e had been h e a t e d a t 60°C  f o r 4 h, i t was d i l u t e d w i t h anhydrous small  Then 18-crown-6  10,  2  PCHCH -). 2  Exact  found:  375.0425.  Mass  calcd.  for C  Hz,  acetal  3.75 ( s , 3H, - O C H 3 ) , 3.64 (m, 2H, 22 1 0  H  Hz, 1 4  F 0 P 6  6  -PCH-),  2.25  (M -0CH ^): +  2  (m,  2H,  375.0432;  P r e p a r a t i o n o f the phosphonate 261  A mixture o f the commercially a v a i l a b l e a-bromo-7-butyrolactone g,  (7.4  45 mmol) and p u r i f i e d t r i m e t h y l p h o s p h i t e (8.3 g, 67 mmol) was h e a t e d  - 212 -  a t 150°C  f o r 8 h.  pressure  (0.02 t o r r ) and the crude p r o d u c t was  distillation material.  Excess t r i m e t h y l p h o s p h i t e was  The crude p r o d u c t was  appropriate  were  s u b j e c t e d t o f l a s h column  collected  ( a i r - b a t h temperature 120-130°C/0.02 g  1236, (d,  (30%) 1034  d,  the ti  cm" ;  each,  -PCH-), 2.50  (m,  phosphonate  nmr  l  1  3H  194.0344;  of  J  (270 MHz) =  2H,  10 Hz,  7:3,  and c o n c e n t r a t e d .  residual  chromatograv/v).  The  Distillation  t o r r ) o f the r e m a i n i n g o i l  yielded  261 which e x h i b i t e d i r ( f i l m ) :  6:  4.30  (m, 2H,  -P(0CH ) ), 3  -CH CH 0-). 2  reduced  t o r r ) o f the  g e l (150 g, e l u t i o n w i t h e t h e r - a c e t o n e , fractions  under  obtained v i a a short path  ( a i r - b a t h temperature 120-160°C/0.02  phy on s i l i c a  2.6  removed  2  Exact  2  3.03 Mass  -CH 0-), 2  1772,  3.77,  3.73  ( t d , 1H, J = 8, 24 calcd.  for  C H 6  1 1  Hz, 0 P: 5  found: 194.0352.  G e n e r a l procedure A:  reaction  o f the phosphonate  s a l t s 248a and  261a  w i t h aldehydes  261a  248a  To 261  a cold  (0 C) C  s t i r r e d s o l u t i o n o f the r e q u i r e d phosphonate  (0.57 mmol) i n THF  bis(trimethylsilyl)amide complex (0.85 g ) .  After  (10  mL)  (0.63  was mmol)  added  a  solution  of  248  or  potassium  i n t o l u e n e and 18-crown-6 .nC^CN  the s o l u t i o n had been s t i r r e d f o r  15  min,  it  - 213 -  was  cooled  to  -78°C  and the r e q u i r e d aldehyde (0.45 mmol) was added.  S t i r r i n g was c o n t i n u e d a t -78°C f o r 4 h. treated  with  combined  solution  was  b r i n e and then was e x t r a c t e d t h r e e times w i t h e t h e r .  The  extract  concentrated.  was  The  washed  residue  twice was  The  with  brine,  dried  (MgS0 ) 4  and  s u b j e c t e d t o column chromatography on  s i l i c a g e l (2 g, e l u t i o n w i t h e i t h e r petroleum benzene-ether, 30:1 v / v ) .  resultant  e t h e r - e t h e r , 8:2  v/v or  C o l l e c t i o n and c o n c e n t r a t i o n o f the a p p r o p r i -  a t e f r a c t i o n s y i e l d e d pure sample(s) o f the o l e f i n a t i o n p r o d u c t ( s ) .  General  procedure B:  r e a c t i o n o f the phosphonate s a l t 261b w i t h  aldehyde  (Me0) P~a^2  To a s u s p e n s i o n ether  and  dried  o f sodium h y d r i d e under  o  N  (14 mg,  „e  0.58  mmol;  washed  with  a stream o f argon) i n benzene (2.7 mL) a t room  temperature was added the phosphonate 261 (0.1 g, s o l u t i o n was s t i r r e d a t 50°C f o r 30 min.  0.53  mmol)  and the  The a p p r o p r i a t e aldehyde (0.42  mmol) was added and the s o l u t i o n was s t i r r e d a t room temperature f o r 15 h.  The r e a c t i o n mixture  was d i l u t e d w i t h petroleum  e t h e r , washed t h r e e  times w i t h b r i n e , and was d r i e d (MgSO^ and c o n c e n t r a t e d . was  The  residue  s u b j e c t e d t o column chromatography on s i l i c a g e l (2 g, e l u t i o n w i t h  - 214 -  e i t h e r petroleum  e t h e r - e t h e r , 8:2,  Collection  c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s y i e l d e d pure  and  v/v  or  benzene-ether,  30:1 v / v ) .  sample(s) o f o l e f i n a t i o n p r o d u c t ( s ) .  P r e p a r a t i o n o f the Z and E e s t e r s 249 and 250  F o l l o w i n g the g e n e r a l procedure A, r e a c t i o n o f the potassium  salt of  the phosphonate 248 w i t h i s o v a l e r a l d e h y d e a f f o r d e d a 3:1 mixture e s t e r 249 and the E e s t e r 250, r e s p e c t i v e l y . reagents  were  potassium  used:  the  The f o l l o w i n g  bis(trimethylsilyl)amide  by column chromatography o f the w i t h petroleum  (0.64  mmol);  crude  product  Both  glc  analysis  and  m a t e r i a l c o n s i s t e d o f a mixture in  a  ratio  o f 3:1.  ^-H  on  Workup,  silica  nmr  (87%) o f  spectroscopy  a  (2  g,  concentracolorless  showed t h a t t h i s  F u r t h e r column chromatography on s i l i c a  isomers.  followed  gel  o f the Z e s t e r 249 and the E  230-400 mesh, e l u t i o n w i t h petroleum samples o f each  of  18-crown-6 .nC^CN  e t h e r - e t h e r , 8:2 v/v) and c o l l e c t i o n ,  t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 122 mg oil.  amounts  phosphonate 248 (0.58 mmol) i n THF (10 mL);  complex (0.74 g ) ; i s o v a l e r a l d e h y d e (49 pL, 0.46 mmol).  elution  o f the Z  ester  250  g e l (4 g,  e t h e r - e t h e r , 9:1 v/v) p r o v i d e d pure  - 215 -  The  less  polar  Z  e s t e r 249 e x h i b i t e d i r ( f i l m ) : 1719, 1644, 1498  cm" ; --H nmr (300 MHz) 6: 1  7.35 (m, 5H, aromatic p r o t o n s ) ,  6.01 ( t , 1H,  J = 7 Hz, o l e f i n i c p r o t o n ) , 4.73 ( s , 2H, b e n z y l i c p r o t o n s ) , 4.58 ( s , acetal protons), -CH2CH2O-),  3.72 ( s , 3H, methoxy p r o t o n s ) ,  2.57  proton),  calcd. f o rC The cm" ; 1  7  2  isopropyl  1 8  H  2 6  Hz,  Hz,  Me CHCH C=), 2  2  0 : 4  306.1831;  found:  '-H nmr (300 MHz) S:  protons),  irradiation  at  benzylic  =  7  (ra, 1H,  Hz,  collapsed  1646,  1498  6.90 ( t ,  protons),  3.73 ( s , 3H, methoxy p r o t o n s ) ,  2  at 6  Exact Mass  1713,  7.35 (m, 5H, aromatic p r o t o n s ) ,  -CH CH 0-). 2.64 ( t , 2H, J 2  Hz,  306.1826.  more p o l a r E e s t e r 250 e x h i b i t e d i r ( f i l m ) :  acetal  1.69  0.92 (d, 6H, J = 7 Hz, methyl p r o t o n s ) .  J = 7 Hz, o l e f i n i c p r o t o n ) , 4.75 ( s , 2H, 2H,  7  ( t , 2H, J = 7 Hz, c o l l a p s e d t o s on i r r a d i a t i o n  3.68, -CH CH 0-). 2.35 ( t , 2H, J = 2  3.68 ( t , 2H, J =  2H,  1H,  4.58 ( s ,  3.62 ( t , 2H, J = 7 to  a  singlet  on  6 3.62, -CH CH 0-), 2.12 ( t , 2H, J = 7 Hz, Me CHCH C=), 2  2  1.75 (m, 1H, i s o p r o p y l p r o t o n ) , Exact Mass c a l c d . f o r C  1 8  H  2 6  0 : 4  2  0.93 (d, 6H, J •= 7 Hz, methyl 306.1831;  found:  P r e p a r a t i o n o f the Z and E l a c t o n e s 263 and 264  263  306.1835.  2  protons).  - 216 Procedure I  Following  the  general  the phosphonate 261 w i t h •'•H nmr s p e c t r o s c o p y 263  were  i s o v a l e r a l d e h y d e a f f o r d e d , by g l c a n a l y s i s  o f the crude p r o d u c t ,  and the E l a c t o n e  reagents  264,  used:  mmol).  product v/v),  Workup  on s i l i c a and  a 2:1 mixture o f the Z l a c t o n e  respectively.  The  (14 mg, 0.58 mmol);  followed  g e l (2 g,  collection  a f f o r d e d 30 mg (46%)  and  following  amounts  of  the phosphonate 261 (0.1 g, 0.53 mmol) i n benzene  (2.7 mL); sodium h y d r i d e 0.42  procedure B, r e a c t i o n o f the sodium s a l t o f  and  by  elution  column with  concentration  isovaleraldehyde  (45 /zL,  chromatography o f the crude petroleum  ether-ether,  8:2  o f the a p p r o p r i a t e f r a c t i o n s  o f the Z l a c t o n e 263 and  15  mg  (23%) o f  the E  l a c t o n e 264.  Procedure I I  To  a c o l d (0°C)  s o l u t i o n o f the phosphonate 261 (0.11 g, 0.57 mmol)  i n THF (3.8 mL) was added s o l i d potassium mmol)  and  the  mixture  was  tert-butoxide  (57  was  added  and  stirring  was  continued  w i t h b r i n e , d r i e d (MgS0 ) and c o n c e n t r a t e d . 4  washed  chromatography on s i l i c a  three  The times  G l c a n a l y s i s o f the r e s i d u e  showed t h a t i t c o n s i s t e d o f a mixture o f the Z l a c t o n e 264 i n a r a t i o o f 73:27.  The  (30 /*L, 0.28  a t -78°C f o r 4 h.  r e a c t i o n m i x t u r e was d i l u t e d w i t h p e t r o l e u m e t h e r ,  lactone  0.51  s t i r r e d a t room temperature f o r 1 h.  r e s u l t a n t s o l u t i o n was c o o l e d t o -78°C and i s o v a l e r a l d e h y d e mmol)  mg,  263  and  T h i s m a t e r i a l was s u b j e c t e d  g e l (2 g, e l u t i o n w i t h  petroleum  the E  t o column  ether-ether,  - 217 8:2  v/v).  Collection  a f f o r d e d 26 mg (61%)  and  c o n c e n t r a t i o n o f the a p p r o p r i a t e  o f the Z l a c t o n e 263 and 8.6  mg  fractions  (20%) o f  the E  l a c t o n e 264.  Procedure I I I  To  a cold  (0°C)  s o l u t i o n o f the phosphonate 261 (0.11 g, 0.57 mmol)  i n THF (3.3 mL) was added s o l i d potassium mmol)  and  t h e mixture  mg,  0.51  was s t i r r e d a t room temperature f o r 1 h.  HMPA  (0.6 mL) was added and the Isovaleraldehyde was The  (30  resultant  tert-butoxide  solution  was  (57  cooled  to  ul, 0.28 mmol) was added and the r e a c t i o n mixture  s t i r r e d a t -78°C f o r 4 h, and then was d i l u t e d w i t h petroleum resultant  mixture  aqueous c o p p e r ( I I ) (MgS0 ) 4  and  was  c o n s i s t e d o f a 77:23 mixture  silica  washed  once  s u l f a t e , and twice w i t h  concentrated.  respectively.  This  -78°C.  ether.  w i t h b r i n e , t h r e e times brine  and  then  was  with dried  G l c a n a l y s i s o f the r e s i d u e showed t h a t i t o f the Z l a c t o n e 263 and the E l a c t o n e 264,  m a t e r i a l was s u b j e c t e d t o column chromatography on  g e l (2 g, e l u t i o n w i t h petroleum  e t h e r - e t h e r , 8:2 v / v ) .  Collec-  t i o n and c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 27 mg (62%) o f t h e Z l a c t o n e 263 and 7.7 mg (18%)  o f the E l a c t o n e 264.  Procedure IV  F o l l o w i n g the g e n e r a l procedure A, r e a c t i o n o f the potassium the  phosphonate  l a c t o n e 263.  261  with  salt of  i s o v a l e r a l d e h y d e a f f o r d e d p r a c t i c a l l y pure Z  The f o l l o w i n g amounts o f reagents  were used: the  phospho-  - 218 -  nate  261 (0.57 mmol) i n THF (10 mL); p o t a s s i u m b i s ( t r i m e t h y l s i l y l ) a m i d e  (0.62  mmol); 18-crown-6-nCH CN complex (0.85 g ) ;  fih,  3  0.45  mmol).  G l c a n a l y s i s o f the crude p r o d u c t  o n l y the Z l a c t o n e 263. of  isovaleraldehyde  short  pad  silica  v/v).  Concentration  The crude p r o d u c t  was  (49  a f t e r workup showed  then  passed  through  g e l (1 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r ,  a 8:2  o f the e l u a n t a f f o r d e d 60 mg (86%) o f the Z l a c t o n e  263. The nmr  l e s s p o l a r Z l a c t o n e 263 e x h i b i t e d i r ( f i l m ) :  (270 MHz) 8:  1752, 1670 cm" ; '-H 1  6.27 ( t t , 1H, J = 4.5 Hz, o l e f i n i c p r o t o n ) ,  4.29 ( t ,  2H, J = 7 Hz, -CH 0-), 2.90 ( b r t , 2H, J = 7 Hz, -CH CH 0-), 2.60 ( b r t , 2  2  2H, J = 7 Hz, -CH C=), 2  6H,  J  •=  154.0994; The nmr  7  Hz,  1.71 ( q u i n t e t , 1H, J = 7 Hz,  methyl  found:  protons).  Exact  Mass  2  Me CH-), 2  calcd.  0.95 (d,  f o r CgH]_ 0 : 4  2  154.0995.  more p o l a r E l a c t o n e 264 e x h i b i t e d i r ( f i l m ) :  (270 MHz) 6:  1757, 1681 cm" ; H 1  1  6.78 ( t t , 1H, J = 3, 7 Hz, o l e f i n i c p r o t o n ) , 4.36 ( t ,  2H, J = 7 Hz, -CH 0-), 2.85 ( b r t , 2H, J = 7 Hz, -CH CH 0-), 2.09 ( b r t , 2  2H,  J  =  2  7 Hz, -CH C=), 2  1.71 ( q u i n t e t , 1H, J - 7 Hz, Me CH-), 0.95 (d,  6H, J = 7 Hz, methyl p r o t o n s ) . found:  154.0993.  2  2  Exact Mass c a l c d . f o r CgH^O;^: 154.0994;  - 219 -  P r e p a r a t i o n o f t h e Z a n d E l a c t o n e s 265a a n d 266a  0  O  266a  265a  Procedure I  F o l l o w i n g t h e g e n e r a l p r o c e d u r e A, r e a c t i o n o f t h e p o t a s s i u m s a l t o f the  phosphonate  265a. (0.57  261 w i t h n - h e p t a n a l a f f o r d e d p r a c t i c a l l y  The f o l l o w i n g amounts o f r e a g e n t s were u s e d : mmol) i n THF (10 m L ) ; p o t a s s i u m  t h e phosphonate  bis(trimethylsilyl)amide  (0.62  mmol).  G l c a n a l y s i s o f t h e c r u d e p r o d u c t a f t e r workup showed o n l y t h e Z  silica tration  The c r u d e  product  n-heptanal  261  18-crown-6-nC^CN  265a.  (0.85 g) ;  lactone  mmol);  lactone  complex  pure Z  (61 uL, 0.45  was p a s s e d t h r o u g h a s h o r t p a d o f  g e l (1 g , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 8:2 v / v ) .  Concen-  o f t h e e l u a n t a f f o r d e d 78 mg (94%) o f t h e Z l a c t o n e 265a.  Procedure I I  Following the  phosphonate  crude  product,  the general  p r o c e d u r e B, r e a c t i o n o f t h e s o d i u m  261 w i t h n - h e p t a n a l a f f o r d e d , b y  o fthe  a 1:1 m i x t u r e o f t h e Z l a c t o n e 265a a n d E l a c t o n e 266a.  The  f o l l o w i n g amounts o f r e a g e n t s were used:  g,  0.53  mmol)  g l c analysis  salt of  t h e phosphonate  261 (0.1  i n b e n z e n e (2.7 m L ) ; s o d i u m h y d r i d e (14 mg, 0.58 m m o l ) ;  - 220 -  n - h e p t a n a l (57 (ML, 0.42 mmol). phy  of  / )•  v  the crude p r o d u c t  gave,  v  fractions,  after 30  Workup, f o l l o w e d by column  chromatogra-  (2 g, e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r ,  collection  and  concentration  of  the  mg (39%) o f the Z l a c t o n e 265a and 289 mg  8:2  appropriate  (36%) o f the E  l a c t o n e 266a. The  l e s s p o l ar Z l a c t o n e 265a e x h i b i t e d i r ( f i l m ) :  --H nmr (300 MHz) 6: (t, (br  1757, 1672  cm" ,  6.24 ( t t , 1H, J = 2.5, 7 Hz, o l e f i n i c p r o t o n ) ,  2H, J = 7 Hz, -CH 0-), 2.90 ( b r t , 2H, J = 7 2  Hz,  -CH CH 0-), 2  4.30 2.70  2  q, 2H, J - 7 Hz, -CH C=), 1.50-1.20 (m, 8H), 0.90 ( t , 3H, J = 6 Hz, 2  methyl p r o t o n s ) .  Exact Mass c a l c d .  for  c  ll l8 2• H  0  182.1307;  found:  182.1308. The 1  more p o l a r E l a c t o n e 266a e x h i b i t e d i r ( f i l m ) :  H nmr (300 MHz) 6:  (t,  2H,  J  6.76  1757, 1681  cm" ; 1  ( t t , 1H, J = 2.5, 7 Hz, o l e f i n i c p r o t o n ) ,  = 7 Hz, -CH 0-), 2.88 ( b r t , 2H, J = 7 Hz, -CH CH 0-), 2.20 2  2  2  (br q, 2H, J - 7 Hz, -CH C=), 1.70-1.20 (m, 8H), 0.90 ( t , 3H, J - 6 2  methyl  4.38  protons).  Exact  Mass  calcd. f o r C^H^sO^  182.1307;  182.1307.  P r e p a r a t i o n o f the Z and E l a c t o n e s 265b and 266b  0  265b  266b  Hz,  found:  - 221 -  F o l l o w i n g the g e n e r a l procedure A, r e a c t i o n o f the p o t a s s i u m s a l t o f the  phosphonate  a n a l y s i s and the  261  with  cyclohexanecarboxaldehyde  nmr s p e c t r o s c o p y  o f the crude product,  a f f o r d e d , by g l c a 5:1 m i x t u r e  Z l a c t o n e 265b and the E l a c t o n e 266b, r e s p e c t i v e l y .  amounts o f reagents mmol)  in  THF  were used:  the  phosphonate  (261)  The f o l l o w i n g (0.11  (10 mL); potassium b i s ( t r i m e t h y l s i l y l ) a m i d e  mmol).  After  workup,  chromatography on s i l i c a 8:2  v/v).  (56%)  H  g e l (2 g, e l u t i o n w i t h  Concentration  of  the a p p r o p r i a t e  o f the Z l a c t o n e 265b and 10 mg  The 1  the crude p r o d u c t  (270  MHz)  8:  6.03  ( t , 2H, J - 8 Hz, -CH 0-), 3.45 ( b r m, 1H,  (dt,  2H, J = 2.5, 8 Hz, -CH CH 0-),  2  C  1 1  H  1 6  0 : 2  180.1150;  found:  1.9-0.9 (m, 10H).  H  nmr  (270 MHz) 8:  (t,  2H, J •= 7 Hz, -CH 0-), 2.80 ( d t , 2H, J = 3, 7 Hz,  C  1 1  m, H  1 6  1H,  0 : 2  allylic  180.1150;  proton), found:  1  proton),  proton),  2.87  Exact Mass c a l c d .  1757, 1678  ( t d , 1H, J - 3, 10 Hz, o l e f i n i c p r o t o n ) ,  2  (br  cm" ;  180.1150.  l e s s p o l a r E l a c t o n e 266b e x h i b i t e d i r ( f i l m ) : 6.54  1756, 1669  allylic  The X  to column  ether-ether,  ( t d , 1H, J = 2.5, 10 Hz, o l e f i n i c  2  (56 u~L,  (12%) o f the E l a c t o n e 266b.  4.29  2  0.57  f r a c t i o n s a f f o r d e d 45 mg  l e s s p o l a r Z l a c t o n e 265b e x h i b i t e d i r ( f i l m ) :  nmr  for  was s u b j e c t e d petroleum  g,  (0.62 mmol),  18-crown-6-nCl^CN complex (0.85 g) ; eye l o h e x a n e c a r b o x y a l deny de 0.45  of  1.9-0.9 (m, 10H).  180.1150.  -CH CH 0-), 2  2  cm" ; 1  4.29 2.11  Exact Mass c a l c d . f o r  - 222 -  P r e p a r a t i o n o f the Z and E l a c t o n e s 265c and 266c  H  C  H  B  ft  Hg  p  265c  Procedure  I  F o l l o w i n g the g e n e r a l procedure A, r e a c t i o n o f the p o t a s s i u m the  s a l t of  phosphonate 261 w i t h (E)-2-hexenal a f f o r d e d , by g l c a n a l y s i s o f the  crude p r o d u c t , a 97:3 mixture o f the Z l a c t o n e 265c and 266c,  respectively.  phosphonate 261  The  (E)-2-hexanal  (0.62  to  petroleum  ether-ether  column  8:2  lactone  mmol);  v/v).  (10 mL);  bis(tri-  18-crown-6-nCH3CN complex  (0.85 g ) ;  A f t e r workup, the crude on  silica  Concentration  product  was  g e l (2 g, e l u t i o n w i t h of  the  appropriate  (78%) o f the Z l a c t o n e 265c.  II  Following  the  general  procedure  B, r e a c t i o n o f the sodium s a l t o f  the phosphonate 261 w i t h (E)-2-hexenal a f f o r d e d , by g l c a n a l y s i s o f crude  the  potassium  chromatography  f r a c t i o n s a f f o r d e d 52 mg  Procedure  mmol) i n THF  (52 pL, 0.45 mmol).  subjected  E  f o l l o w i n g amounts o f r e a g e n t s were used:  (0.11 g, 0.57  trimethylsilyl)amide  the  product,  a  1:3  the  mixture o f the Z l a c t o n e 265c and the E l a c t o n e  266c. The f o l l o w i n g amounts o f reagents were used:  the phosphonate  261  - 223 -  (0.1  g,  mmol);  0.53  mmol)  (E)-2-hexenal  chromato-graphy  of  in  (49 LIL, 0.42 mmol). the  petroleum ether-ether,  H nmr  (270 MHz) 5:  -CH CH 0-), 2  2.95  2  a l l y l i c protons), CH -).  H  nmr  column  g e l (2 g, e l u t i o n w i t h and  concentra-  (21%) o f the Z l a c t o n e 265c and  1747, 1647  7.42 (dd, 1H, J = 10, 16 Hz, H ) , 6.57 A  ( t d , 1H, J = 7, 16 Hz, H ) , 4.33 c  cm  ;  ( t d , 1H, J =  ( t , 2H, J =  7  Hz,  ( t , 2H, J = 7 Hz, -CH CH 0-), 2.18 (q, 2H, J = 7 Hz, 2  1.47  2  (m, 2H, J = 7 Hz, CH CH CH -), 3  H 1 0  14°2  :  2  2  0.93  166.0994;  (270 MHz) 5:  ( t , 3H, J = 7  found: 166.0994.  more p o l a r E l a c t o n e 266c e x h i b i t e d i r ( f i l m ) :  1751, 1652  cm" ;  7.09 ( t d , 1H, J = 2.5, 10 Hz, Hg), 6.3-6.0 (m,  c  Hz,  for  15 mg  by  0.58  1  2H,  and H ) , 4.39 ( t , 2H, J = 7 Hz, -CH CH 0-), 2.96 ( d t , 2H, J = 2.5, 7  A  =  fractions,  Exact Mass c a l c d . f o r C  3  The %  followed  l e s s p o l ar Z l a c t o n e 265c e x h i b i t e d i r ( f i l m ) :  2, 10 Hz, Hg), 6.00  Hz,  on s i l i c a  (14 mg,  (60%) o f the E l a c t o n e 266c.  The X  crude p r o d u c t  Workup,  8:2 v / v ) , gave, a f t e r c o l l e c t i o n  t i o n o f the a p p r o p r i a t e 42 mg  benzene (2.7 mL); sodium h y d r i d e  2  2  -CH CH 0-), 2.19 (q, 2H, J = 7 Hz, a l l y l i c 2  7 C  2  Hz, 1 0  CH CH CH -), 3  H 40 : 1  2  2  2  166.0994;  protons),  0.93 ( t , 3H, J = 7 Hz, C H - ) . 3  found:  166.0992.  1.48  (m, 2H,  J  Exact Mass c a l c d .  - 224  -  P r e p a r a t i o n o f the Z and E l a c t o n e s 265d and  266d  0 o  o 26 5d  266d  F o l l o w i n g the g e n e r a l procedure A, the  phosphonate  nmr  261  spectroscopy  265d  and  used:  the  r e a c t i o n o f the p o t a s s i u m s a l t  of  w i t h benzaldehyde a f f o r d e d by g l c a n a l y s i s and  -^H  o f the crude product, E  l a c t o n e 266d.  the phosphonate 261  (0.11  bis(tri-methylsilyl)amide g);  benzaldehyde  was  subjected  (46 juL, 0.45  mixture of  the  Z  lactone  f o l l o w i n g amounts o f reagents  g, 0.57  (0.62  mmol) i n THF  (10 mL);  were  potassium  mmol); 18-crown-6-nC^CN complex  mmol).  A f t e r workup,  the  crude  (0.85  product  to column chromatography on s i l i c a g e l (2 g, 230-400 mesh,  e l u t i o n w i t h benzene-ether, 30:1 fractions  The  a 1:1  a f f o r d e d 38 mg  (48%)  v/v).  Concentration  o f the  o f the Z l a c t o n e 265d and  appropriate  34 mg  (43%)  of  the E l a c t o n e 266d. The X  H  nmr  l e s s p o l a r Z l a c t o n e 265d e x h i b i t e d i r ( f i l m ) : (300  aromatic 2H,  J  MHz)  6:  protons), -  7  Hz,  7.82 7.02  (dd, 2H, ( t , 1H,  -CH CH 0-), 2  E x a c t Mass c a l c d . f o r C  H  1 0  °2  J = 2.5 3.15  2  1 1  J = 2,  :  7.5  Hz,  H ),  J = 2.5,  E  nmr  (300 MHz)  (m,  5H,  aromatic  7.58  ( t , 1H,  p r o t o n s ) , 4.48  J = 3 Hz,  ( t , 2H,  1  7 Hz,  4.41  3H, (t,  -CH CH 0-). 2  2  found: 174.0683.  more p o l a r E l a c t o n e 266d e x h i b i t e d i r ( f i l m ) : 5:  cm" ;  7.42-7.32 (m,  A  The L  1641  o l e f i n i c proton),  ( d t , 2H,  174.0681;  Hz,  1747,  1742,  1651  o l e f i n i c proton),  J - 7 Hz,  2  1  7.54-7.38  -CH CH 0-), 3.26 2  cm" ;  (dt,  - 225 -  2H,  J - 3, 7 Hz,  found:  -CH CH 0-)2  Exact Mass c a l c d .  2  To a c o l d  mL,  0.18  mol)  had  been s t i r r e d  w i t h dichloromethane saturated dried  pressure  via  0.113  0.168  a t room temperature  mol).  f o r 12 h,  4  The  a  Vigreux  column  t o r r ) o f the r e m a i n i n g o i l a f f o r d e d  was  concentrated  (10 cm). 11.2  g  (80%)  the  diluted  acid,  under  Distillation  mL)  After  sodium b i c a r b o n a t e , twice w i t h b r i n e , solution  mol)  (250  i t was  washed t h r e e times w i t h IN h y d r o c h l o r i c  aqueous  (MgS0 ).  mL,  i n dichloromethane  added c h l o r o m e t h y l methyl e t h e r (12.8 mL,  solution  was  174.0681;  2  (240)  (-20°C) s o l u t i o n o f 2 - c h l o r o e t h a n o l (7.35  and d i i s o p r o p y e t h y l a m i n e (31.4  with  1Q  174.0680.  P r e p a r a t i o n o f 2-iodo-l-methoxymethoxyethane  was  f o r CnU 0 :  and  once then  atmospheric  (bp 50-54°C/15  of  2-chloro-l-  methoxymethoxyethane. A  solution  sodium i o d i d e for  30  h  o f 2-chloro-1-methoxymethoxyethane (4.0 g, 32 mmol) and  (20 g, 0.13  with  protection  pentane and f i l t e r e d . pressure  via  a  mol)  The  Vigreux  i n acetone  (64 mL)  from l i g h t .  f i l t r a t e was column  t o r r ) o f the r e m a i n i n g o i l y i e l d e d  stirred  s o l u t i o n was  concentrated  (10 cm). 3.5  The  was  under  Distillation  at  60°C  d i l u t e d with atmospheric  (bp 58-60°C/15  g (50%) o f the i o d i d e  240  as  a  - 226 -  colorless freezer. (film):  o i l which This material 1144,  was  stored  over  copper  dust  under argon i n a  was homogeneous by g l c a n a l y s i s  and e x h i b i t e d i r  1115, 1065, 1030 c m ; '-H nmr (270 MHz) 6:  4.68 ( s ,  -1  2H,  a c e t a l p r o t o n s ) , 3.82 ( t , 2H, J = 6 Hz, -OCH CH -), 3.40 ( s , 3H, -0CH ), 2  3.30  ( t , 2H, J = 6 Hz, - C H I ) .  3  Exact Mass c a l c d .  2  found:  2  f o r C H I 0 : 215.9646; 4  9  2  215.9649.  P r e p a r a t i o n o f the n i t r i l e 241  CN  0\/0\  HA"'  To in  a cold  THF  (40  (-78°C) s o l u t i o n o f d i i s o p r o p y l a m i n e mL)  was  added n - b u t y l l i t h i u m  (0.83 mL,  (0.89  mmol)  and  a  solution  g, 3.9 mmol; 15:85,  solution  was  stirred  at  stirred  at  0°C  respectively) 0°C  f o r 15  i n THF min.  were  t h e n was d r i e d  added  and the  To the r e s u l t i n g y e l l o w  240 (1.15 g, 5.5 mmol)  and  the  solution  f o r 30 min and a t room temperature f o r 1 h.  s o l u t i o n was d i l u t e d w i t h petroleum e t h e r , washed once chloric acid,  HMPA (1.37 mL,  o f a mixture o f the n i t r i l e s 112a and 112b  s o l u t i o n was added the i o d i d e was  mmol)  (5.7 mmol) as a s o l u t i o n i n  hexanes and the s o l u t i o n was s t i r r e d a t 0°C f o r 15 min. 7.9  5.9  with  IN  The  hydro-  twice w i t h aqueous copper s u l f a t e and twice w i t h b r i n e and (MgS0 ), and f i l t e r e d through a s m a l l 4  pad  of  Florisil.  - 227  The  f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e  t o r r ) t o a f f o r d 1.12 g (99%) o f the d e s i r e d n i t r i l e was  homogeneous  1638, 1H,  by  (16 t o r r , 241.  This  g l c a n a l y s i s and e x h i b i t e d i r ( f i l m ) :  4.59 ( b r s,  1  proton),  4.57  material  3086, 2228,  1153, 1110, 1070, 1041, 895 cm" ; '-H nmr (400 MHz) 5: olefinic  then 0.02  ( s , 2H, a c e t a l p r o t o n s ) , 4.55 ( b r s, 1H,  o l e f i n i c p r o t o n ) , 3.50 (m, 2H, -CH CH 0-), 3.34 ( s , 3H, -0CH ), 2.40 ( b r 2  dt,  2  3  1H, J - 5.5, 13.5 Hz, H ) , 2.15, 2.09 ( b r t d , b r t d , 1H each, J - 7, A  15 Hz, -CH CH 0-), 2.13-1.10 (m, 2  2  11H),  1.27  ( s , 3H,  p r o t o n s ) , 1.15 ( d , 3H, J = 6 Hz, methyl p r o t o n s ) . C  1 8  H  2 9  N0 :  291.2198;  2  found:  angular  methyl  Exact Mass c a l c d . f o r  291.2205.  P r e p a r a t i o n o f the aldehyde 273  To a s o l u t i o n o f the n i t r i l e ethane  (40  mL)  was  241 (1.12 g, 3.86 mmol)  added d i i s o b u t y l a l u m i n u m h y d r i d e  in  (15.4 mmol) as a  s o l u t i o n i n hexanes and the s o l u t i o n was warmed a t 60°C f o r 6 reaction  mixture  was  cautiously  poured  and t h e r e s u l t a n t mixture was n e u t r a l i z e d  acid,  and then was e x t r a c t e d t h r e e times w i t h e t h e r . brine,  dried  h.  The  i n t o water under a b l a n k e t o f  argon,  combined, washed w i t h  dimethoxy-  (Na S0 ) 2  4  with  and  IN h y d r o c h l o r i c The e x t r a c t s were  concentrated.  The  - 228 -  residual  o i l was  d i s s o l v e d i n a mixture o f T H F - a c e t i c  mL, 1:1:0.16 by volume) and the s o l u t i o n was s t i r r e d for  12  torr),  h.  After  removal o f the s o l v e n t under reduced p r e s s u r e (0.02  with  aqueous  sodium  (MgS04) and c o n c e n t r a t e d exhibited i r (film):  protons),  -CH CH 0-), Hz,  and b r i n e , and then was d r i e d  3086, 2767, 2737, 1713, 1637, 1153, 1109, 1044, 893 9.97 ( s , 1H, aldehyde p r o t o n ) , 4.56  1  acetal  bicarbonate  t o a f f o r d 1.04 g (92%) o f the aldehyde 273 which  c m ; H nmr (400 MHz) 6:  2  a t room temperature  t h e r e s i d u e was d i s s o l v e d i n e t h e r and the r e s u l t a n t s o l u t i o n was  washed  -1  a c i d - w a t e r (100  4.55  ( b r s,  2H,  olefinic  protons),  ( s , 2H,  3.46 (m, 2H,  3.32 ( s , 3H, -0CH ), 2.30-1.1 (m, 14H), 1.04 ( d , 3H, J  2  =  3  methyl p r o t o n s ) , 0.99 ( s , 3H, a n g u l a r  calcd. f o r C  1 8  H  3 0  0 : 3  294.2195;  found:  methyl p r o t o n s ) .  Exact  7  Mass.  294.2200.  P r e p a r a t i o n o f the a l c o h o l 274  H ' B  To a s o l u t i o n - s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e mmol)  i n ether  1 h.  6.8  (40 mL) was added an e t h e r e a l s o l u t i o n o f the aldehyde  273 (1.04 g, 3.54 mmol) and the mixture was s t i r r e d for  (0.26 g,  a t room  temperature  Sodium s u l f a t e decahydrate was added i n s m a l l p o r t i o n s t o the  s t i r r e d mixture u n t i l e v o l u t i o n o f gas ceased.  The m i x t u r e was f i l t e r e d  - 229 -  and  the  combined 274  collected  material  was  (br  1  2H,  1  olefinic  The  alcohol  3443 ( b r ) , 3085, 2775, 1635, 1152, 1108,  892 cm" ; H nmr (400 MHz) 8: s,  t h r e e times w i t h e t h e r .  f i l t r a t e was c o n c e n t r a t e d t o a f f o r d 1.0 g (95%) o f the  which e x h i b i t e d i r ( f i l m ) :  1039,  washed  protons),  4.59 ( s , 2H, a c e t a l p r o t o n s ) ,  4.50  3.77, 3.68 (d, d, 1H each, J = 11 Hz,  -CH 0H), 3.50 (m, 2H, -CH CH 0-), 3.34 ( s , 3H, -0CH ), 2.27 ( b r d t , 2  J  2  2  3  1H,  = 5, 13.5 Hz, on i r r a d i a t i o n a t 8 4.50, sharpened t o a d o f t , J = 5,  13.5 Hz, H ) , 2.10 ( b r d, 1H, J - 12 Hz, Hg), 1.95-1.00 (m,  13H), 1.05  A  ( s , 3H, a n g u l a r methyl p r o t o n s ) , 0.99 (d, 3H, J = 6 Hz, methyl p r o t o n s ) . Exact Mass c a l c d . f o r C  1 8  H  3 2  0 : 3  296.2351;  found:  296.2355.  P r e p a r a t i o n o f the phosphorodiamidate 275  0 \ / 0 \  To a s o l u t i o n o f the a l c o h o l 274 (0.31 g, 1 mmol) i n a dimethoxyethane  (4  mixture  mL) and N,N,N',N'-tetramethylethylenediamine  a t 0°C was adeed n - b u t y l l i t h i u m  (1.26 mmol) as a  solution  in  of  (1 mL)  hexanes.  A f t e r t h e m i x t u r e had been s t i r r e d f o r 15 min, dimethylaminophosphorodichloridate stirred  (0.4 mL, 3.2 mmol) was added and  at  room temperature f o r 12 h.  to 0°C, anhydrous  dimethylamine (5  mL)  the  reaction  mixture  was  The r e a c t i o n m i x t u r e was c o o l e d was  added,  and  stirring  was  - 230 -  continued  at  0°C f o r 2 h.  w i t h water, t w i c e w i t h residue  was  The s o l u t i o n was d i l u t e d w i t h e t h e r , washed  brine,  combined  and  10:1  concentrated  viscous  concentrated.  The  protons),  v/v).  The  appropriate  fractions  (16 t o r r ,  the phosphorodimmidate  275  then as  a  3085, 1635, 1213, 895  4.58 ( s , 2H, a c e t a l p r o t o n s ) , 4.51 ( b r s, 2H,  1  3.53,  and  o i l which e x h i b i t e d i r ( f i l m ) :  cm" ; ^-H nmr (400 MHz) 5: olefinic  4  under reduced p r e s s u r e  0.02 t o r r ) t o y i e l d 0.27 g (63%) o f colorless  (MgS0 )  s u b j e c t e d t o f l a s h column chromatography on s i l i c a g e l (30  g, e l u t i o n w i t h e t h e r - a c e t o n e , were  dried  4.00, 3.94 (dd, dd, 1H each, J = 4, 11 Hz, -CH 0P), 2  3.45 ( t d , t d , 1H each, J = 8, 10  Hz,  -CH CH 0-). 2  2  3.33  (3H, s,  -0CH ), 2.67, 2.65 ( d , d, 6H each, J - 6 Hz, -PNMe ), 2.27 ( b r d t , 1H, J 3  =5,  2  14 Hz, H ) , 2.11 ( b r d, 1H, J = 14 Hz, H ) , 1.93 ( t , 2H, J = 8 A  -CH CH 0-), 2  C  2 2  H  2.04-1.40  2  0.99 4 3  fi  ( d , 3H,  J  N 0 P:  430.2960;  2  4  =  (m,  6  10H), 1.06 ( s , 3H, a n g u l a r methyl p r o t o n s ) ,  Hz,  P r e p a r a t i o n o f the e t h e r  methyl  found:  protons).  Liquid  methylamine  c o n t a i n i n g l i t h i u m metal  Exact  Mass  calcd.  for  430.2966.  276  0 \ / 0  HB  Hz,  x  ;  (10 mL) was condensed i n t o a c o l d (12 mg, 1.7 mmol) and the m i x t u r e  (-78°C) f l a s k was  stirred  231 -  at  -30°C  f o r 30 min.  To the r e s u l t a n t dark b l u e s o l u t i o n was added an  e t h e r e a l s o l u t i o n o f the phosphorodiamidate the  mixture  mixture  was  was  stirred  cautiously  at but  -20 C  275 (0.13 g, 0.3  f o r e x a c t l y 10 min.  C  quickly  treated  with  mmol)  and  The r e a c t i o n  aqueous  ammonium  c h l o r i d e and the r e s u l t a n t mixture was e x t r a c t e d t h r e e times w i t h e t h e r . The e t h e r e a l e x t r a c t s were combined, washed w i t h and c o n c e n t r a t e d . s i l i c a gel  (4  brine,  dried  (MgS0 ) 4  The r e s i d u e was s u b j e c t e d t o column chromatography  g,  elution  with  petroleum  ether-ether,  on  100:8 v / v ) .  C o l l e c t i o n and c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 67 mg (80%) o f the e t h e r 276 as a c o l o r l e s s o i l which 3085,  exhibited  (film):  1636, 1149, 1109, 1078, 1040, 891 cm" ; *H nmr (400 MHz) 8: 1  ( s , 2H, a c e t a l p r o t o n s ) , 4.49 ( b r s, 2H, o l e f i n i c p r o t o n s ) , (dt,  i r  dt,  1H  3.47,  4.57 3.38  each, J = 6, 10 Hz, -CH CH 0-), 3.34 ( s , 3H, - O C H 3 ) , 2.29 2  2  (br t d t , 1H, J = 1.3, 5, 13.5 Hz, H ) , 2.10 ( b r dd, 1H, J = 4, 13.5 Hz, A  Hg),  1.88  ( b r d, 1H, J - 12 Hz, H ) , 1.72-1.20 (m, 11H), 1.04 ( s , 3H, c  a n g u l a r methyl p r o t o n s ) , 0.85 (d, 3H, J = 6 Hz, (s,  3H,  methyl  protons).  Irradiation  at  methyl  irradiation  at  6  2.29  ( J •=  5,  13.5  ( H ) caused the s i g n a l a t 8 2.14-2.06 t o A  c o l l a p s e t o a b r o a d s i n g l e t and the s i g n a l a t 8 irradiation  0.75  8 4.49 ( o l e f i n i c p r o t o n s )  caused t h e s i g n a l a t 8 2.34-2.25 t o sharpen t o a d o f t Hz);  protons),  1.93-1.83  to  sharpen;  a t 6 2.10 (Hg) caused the s i g n a l a t 8 2.34-2.25 to c o l l a p s e  to a b r o a d d o u b l e t ( J = 13 Hz) and s i g n a l a t 8 1.93-1.83 t o sharpen t o a q o f d ( J = 3, 12 Hz); i r r a d i a t i o n a t 5 1.88 (H^) caused the s i g n a l a t 5 2.34-2.25 t o c o l l a p s e t o a b r o a d t r i p l e t 2.14-2.06 C  18 32°2 H  :  ( J •= 13 Hz)  t o sharpen t o a d o f d ( J = 4, 13 H z ) . 280.2402;  found:  280.2412.  and  signal  at 5  E x a c t Mass c a l c d . f o r  - 232 -  P r e p a r a t i o n o f the a l c o h o l 277  OH  He-.. HBH  A s o l u t i o n o f the e t h e r 2-toluenesulfonate heated  ether.  (0.02  gel  torr),  h.  After  The  mg,  0.13  mmol)  and  pyridinium  residue  removal  of  solvent  under  reduced  the r e s i d u e was t r i t u r a t e d t h r e e times w i t h d r y  The e t h e r e a l s o l u t i o n s  trated.  (37  (0.33 g, 1.3 mmol) i n t e r t - b u t y l a l c o h o l (6 mL) was  a t 70°C f o r 12  pressure  276  were  combined,  filtered,  and  concen-  was s u b j e c t e d t o column chromatography on s i l i c a  (4 g, e l u t i o n w i t h petroleum  ether-ether,  7:3 v / v ) .  Collection  and  c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 25 mg (91%, based on recovery o f 5 exhibited  mg  of  i r (film):  starting  material)  of  the  alcohol  277  3375 ( b r ) , 3085, 1636, 892 c m ; H nmr (300 MHz) -1  1  6: 4.50 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 3.61, 3.52 ( d t , d t , l H each, 5.5, 1H,  10  2  fi  12H),  16 28 H  0 :  =  A  c  1.72-1.18  1.04 (s, 3H, a n g u l a r methyl p r o t o n s ) , 0.86 (d, 3H, J = 6 Hz,  methyl p r o t o n s ) , 0.75 ( s , 3H, methyl p r o t o n s ) . C  J  Hz, -CH 0H), 2.29 ( t d t , 1H, J - 2, 5.5, 14 Hz, H ) , 2.10 ( t d d ,  J = 4.5, 4.5, 14 Hz, H ) , 1.88 ( b r d, 1H, J = 13 Hz, H ) ,  (m,  which  236.2140;  found:  236.2144.  Exact  Mass  calcd. f o r  - 233  P r e p a r a t i o n o f the aldehyde  -  234  CHO  He-.  HH B  To  a  cold  (-78°C) s o l u t i o n o f d i m e t h y l s u l f o x i d e  i n d i c h l o r o m e t h a n e ( 0 . 6 mL) and mg,  the  mixture  55 jumol) was  Triethylamine  was  was  stirred  added o x a l y l c h l o r i d e a t -78°C f o r 20 m i n .  a d d e d a n d t h e m i x t u r e was  (35 /JL, 0.25  mmol) was  stirred  ( 5 . 6 mg, (9  The  under  r e s i d u e was  times w i t h pentane concentrated ir (t,  (film): 1H,  2.41, 1H,  and the pentane a f f o r d 11 mg  3085, 2724, 1718,  J = 3.5  2.29  Hz,  2.11  A  c  ( d , 3H,  1.80-1.18 (m, J - 6.6  E x a c t Mass c a l c d .  1 6  H  2 6  then  was  1636,  892  triturated filtered  cm ;  ^-H nmr  - 1  14.5  ( 3 0 0 MHz)  ( b r s, 2H, Hz,  olefinic  -CH CH0), 2  2.29  1.89  9H),  methyl  0:  min.  ( s , 3H,  234.1984;  angular  0.83  234.1992.  three and  9.78  protons), (br  dt,  ( b r d, 1H,  ( s , 3H, m e t h y l  found:  was  exhibited 6:  ( b r d, 1H, J = 13 Hz, H g ) , 1.06  (13  concentrated  ( 8 5 % ) o f t h e a l d e h y d e 234 w h i c h  Hz, m e t h y l p r o t o n s ) ,  for C  a l c o h o l 277  s o l u t i o n were combined,  ( d d , d d , 1H e a c h , J = 3.5,  H ),  The  a l d e h y d e p r o t o n ) , 4.52  J = 5, 13 H z , H ) ,  = 13 H z , 0.96  to  (0.02 t o r r ) .  /imol)  added and the r e a c t i o n m i x t u r e and  pressure  66  a t -78°C f o r 30  a l l o w e d t o warm s l o w l y t o room t e m p e r a t u r e reduced  mg,  71 /imol)  J  protons), protons).  - 234 -  P r e p a r a t i o n o f the Z and E l a c t o n e s 279 and 280  To a c o l d (-0°C) s o l u t i o n o f the phosphonate 261 (0.11 mmol) i n THF (1.9  mL)  was,added potassium b i s ( t r i m e t h y l s i l y l ) a m i d e  (0.12 mmol) as a  s o l u t i o n i n toluene  and 18-crown-6-nC^CN complex (0.16 g) .  mixture  stirred  had  been  f o r 15  and  was added  and  the m i x t u r e  The r e s u l t a n t s o l u t i o n was t r e a t e d w i t h  t h e n was e x t r a c t e d t h r e e times w i t h petroleum e t h e r .  extract  was  washed  twice  v/v).  Collection  and  showed  that  5 mg The  1635,  i t consisted  The crude m a t e r i a l was s u b j e c t e d petroleum  891 c m ; H nmr (400 MHz) 8: -1  1  t o column  ether-ether,  3084, 1753,  1666,  6.24 ( t t , 1H, J - 2, 8 Hz, o l e f i n i c  4.52 ( b r s, 2H, o l e f i n i c p r o t o n s ) , 4.28 ( b r t , 2H, J = 7.5 Hz,  2  2  each,  two  (19%).  -CH 0-), 2.91 ( b r t , 2H, J = 7.5 Hz, -CH CH 0-), 2.89, 2.65 1H  of  and the pure E l a c t o n e  l e s s p o l a r Z l a c t o n e 279 e x h i b i t e d i r ( f i l m ) :  proton),  combined  c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s  a f f o r d e d b o t h the pure Z l a c t o n e 279, 15 mg (58%) 280,  brine  4  chromatography on s i l i c a g e l (2 g, e l u t i o n w i t h 8:2  The  was  w i t h b r i n e , d r i e d (MgS0 ) and c o n c e n t r a t e d .  G l c a n a l y s i s o f the crude m a t e r i a l compounds i n a r a t i o o f 3:1.  the  min, i t was c o o l e d t o -78°C, a THF  s o l u t i o n o f the aldehyde 234 (85 nmol) s t i r r e d a t -78°C f o r 4 h .  After  J  2  (tdd,  tdd,  = 2.5, 8, 17 Hz, -CH C=), 2.30 ( b r d t , 1H, J = 5, 13.5 Hz, 2  - 235 -  H ),  2.10 ( b r d, 1H, J - 13.5 Hz, Hg), 1.87 (br d, 1H, J - 12.5 Hz, H ) ,  A  c  1.7-1.1  (m, 9H), 1.05 ( s , 3H, a n g u l a r  6.5 Hz, methyl p r o t o n s ) , c a l c d . f o r C20H30O2: The 1635,  0.82  methyl p r o t o n s ) , 0.87 (d, 3H, J =  ( s , 3H,  302.2246;  found:  methyl  protons).  -1  olefinic  1  Mass  302.2239.  more p o l a r E l a c t o n e 280 e x h i b i t e d i r ( f i l m ) :  892 c m ; H nmr (400 MHz)  Exact  6: 6.76 ( t t , 1H,  J  3084, 1758, 1676, =  2.5,  6.5  Hz,  p r o t o n ) , 4.51 (br. s, 2H, o l e f i n i c p r o t o n s ) , 4.36 ( t , 2H, J = 6  Hz,  -CH 0-), 2.85 ( b r t , 2H, J = 6 Hz, -CH CH 0-), 2.27 ( b r d t , 1H, J  5,  13  1H,  J - 13 Hz, Hg), 1.87 ( b r d, 1H, J - 13 Hz, H ) , 1.65-1.10  2  2  Hz,  2  H ) , 2.30-2.22, 2.18-2.10 (m, 1H each, -CH C=), 2.11 ( b r d, A  2  c  1.05  ( s , 3H,  protons), 302.2246;  =  angular  methyl p r o t o n s ) ,  0.82 ( s , 3H, methyl p r o t o n s ) . found:  (m, 9H),  0.86 (d, 3H, J = 6.5 Hz, methyl Exact Mass c a l c d . f o r C20H30O2:  302.2238.  P r e p a r a t i o n o f (±)-isolinaridiol (64) and the d i o l 278  To ether  a c o l d (-78°C) s o l u t i o n o f the Z l a c t o n e 279 (15 mg, 50 umol) i n (1 mL) was  solution  added  i n hexanes.  diisobutylaluminum  hydride  (0.2 mmol)  A f t e r the mixture had been s t i r r e d  h and a t 0°C f o r 1 h, i t was t r e a t e d  with  saturated  as  a  a t -78°C f o r 1  aqueous  ammonium  - 236 -  chloride stirred  (10  LIL) and  then  was  a t room temperature f o r 5 min, d r i e d (MgS0 ) , and c o n c e n t r a t e d  to a f f o r d  (64) which e x h i b i t e d i r ( f i l m ) :  through  o f (±)-isolinaridiol  3328 ( b r ) , 3086, 1636, 891 cm" ; H 1  MHz) S 5.36 ( b r t , 1H, J - 8 Hz, o l e f i n i c  olefinic t,  14.5 mg (96%)  The mixture was filtered  4  Florisil  (400  d i l u t e d with ether.  nmr  1  p r o t o n ) , 4.50 ( b r s, 2H,  p r o t o n s ) , 4.19, 4.15 (d, d, 2H, J = 12 Hz, =CCH 0H), 2  3.74 ( b r  2H, J = 6 Hz, -CH CH 0H), 2.39 ( t , 2H, J = 6 Hz, -CH CH OH), 2.30 ( b r 2  dt,  2  2  2  1H, J - 6, 14 Hz, H ) , 2.09 (m, 2H, -CH C=), 1.9-1.0 (m, A  2H,  D 0  2  (br  s,  0.83  ( d , 3H, J = 7 Hz, methyl p r o t o n s ) , 0.76 (s,  The  '•H  2  nmr  7H), 1.78  exchanged,-OH), 1.05 ( s , 3H, a n g u l a r methyl p r o t o n s ) , 3H,  methyl  protons).  spectrum o f t h i s m a t e r i a l was i d e n t i c a l t o t h a t o f n a t u r a l  isolinaridiol  (64).*  Exact Mass c a l c d . f o r C  2 0  H  3 2  0  (H -H 0): +  2  288.2453;  found: 288.2451. Similarly,  the E  lactone  280 (10 mg, 33 ^tmol) was reduced  diol  278 (9 mg, 89%), which e x h i b i t e d i r ( f i l m ) :  891  c m ; H nmr (300 MHz) 6 5.52 ( t , 1H, J = 7.5 Hz, o l e f i n i c  4.51  ( b r s, 1H, o l e f i n i c  2H,  J  -1  dt,  2  H  3 2  0  We  ( t,  2  2  2  A  protons),  different 2 0  proton),  6 Hz, -CH CH 0-), 2.43 ( t , 2H, J - 6 Hz, -CH CH 0-), 2.30 ( b r  methyl p r o t o n s ) .  C  1636,  p r o t o n s ) , 4.05 ( b r s, 2H, =CCH 0H), 3.71  1H, J = 5, 14 Hz, H ) , 2.14-1.10 (m,  methyl  3309 ( b r ) , 3085,  1  -  t o the  from  0.82 The that  ^H of  +  2  natural  ( s , 3H,  angular  (d, 3H, J •= 6 Hz, methyl p r o t o n s ) , 0.76 ( s , 3H,  ( H - H 0 ) : 288.2453;  are g r a t e f u l  11H), 1.04  2  to  isolinaridiol.  nmr  spectrum  isolinaridiol  of  this  (64).  material  was  Exact Mass c a l c d .  very for  found: 288.2448.  Professor  A.  San  F e l i c i a n o f o r a sample o f  - 237 -  P r e p a r a t i o n o f the d i a c e t a t e 61 and 281  OAc  OAc OAc  OAc  HA"  A solution of i s o l i n a r i d i o l (5  (64) (4 mg,  13 umol),  solution  a t room  temperature  for  column  chromatography  ether-ethyl acetate, fractions  silica  8:2 v / v ) .  The  resultant  4.5  mg  (90%)  ( t , 1H, J = 7.5 Hz, o l e f i n i c  2H,  J  =  2.16-1.96 1H,  protons), protons).  7  Hz,  -CH CH 0Ac), 2  2  (m, 3H) , 2.06, 2.03  2.29  (m, 2H, (br  H nmr  appro-  (300  MHz)  =CCH 0Ac), 2  2.40  2  A  (d, 3H, J - 6 Hz, methyl p r o t o n s ) ,  1.84  Exact Mass c a l c d . f o r C the  2 2  diol  H  3 4  0  278  9  (M -H0Ac): +  2  1  (4  mg,  for  (br  ( s , 3H, a n g u l a r  methyl  0.75  methyl  (s,  3H,  ^H nmr s p e c t r a l d a t a o f t h i s m a t e r i a l i s d i f f e r e n t a l  (t,  d t , 1H, J = 5, 13.5 Hz, H ) ,  ( s , s, 3H each, a c e t y l p r o t o n s ) ,  r e p o r t e d by San F e l i c i a n o e t  Similarly,  X  (br s, 2H, 2  c  The  of  -CH CH 0Ac),  J = 13.5 Hz, H ) , 1.54-1.0 (m, 9H), 1.04 0.81  petroleum  o f the d i a c e t a t e (61) which  p r o t o n ) , 4.61  p r o t o n s ) , 4.13  times  subjected  C o l l e c t i o n and c o n c e n t r a t i o n  1  ( b r s, 2H, o l e f i n i c  was  g e l (1 g, e l u t i o n w i t h  3083, 1742, 1635, 1234, 892 cm' ;  4.49  those  on  afforded  exhibited i r (film): 6: 5.44  h.  The r e s i d u e  4  priate  1.5  was d i l u t e d w i t h e t h y l a c e t a t e and then was washed t h r e e  w i t h b r i n e , d r i e d (MgS0 ) and c o n c e n t r a t e d .  d,  anhydride  /iL, 52 umol) and 4-N,N-dimethylaminopyridine ( c a t a l y s t ) i n p y r i d i n e  (0.5 mL) was s t i r r e d  to  acetic  isolinaridiol  330.2559;  found:  from  diacetate. 330.2560.  14 umol) was c o n v e r t e d  i n t o the  - 238  d i a c e t a t e 281 1230,  892  (4 mg,  cm' ; 1  p r o t o n ) , 4.50 -  7.5  dt,  Hz,  1H,  each, 9H),  2  protons),  (300 MHz)  13.5  Hz,  0.77  1 9  ( t , 1H,  J = 7.5  H ),  ( t , 2H,  J = 7.5  2.15-2.02 (m,  A  1.85  (br d, 1H,  3H,  different  Exact  Mass  from  0.82  those  calcd.  for  2  Hz,  ^H nmr  reported  C H340 2 2  s,  3H  1.56-1.1  (m,  J = 6 Hz,  s p e c t r a l data  for  of  isolinaridiol  (M -H0Ac): +  2  methyl  330.2559;  330.2557.  296  in  dichloromethane  (1 mL)  was  mmol) as a s o l u t i o n i n dichloromethane. at  -78°C  m i x t u r e o f THF was  c  (s,  J (br  2  H ),  (d, 3H,  The  olefinic ( t , 2H,  2.04  To a c o l d (-78°C) s o l u t i o n o f the e x o c y c l i c alkene  stirred  Hz,  1635,  -CH CH 0Ac), 2.29  2.06,  J = 13.5  methyl p r o t o n s ) .  is  Hz,  3H),  methyl p r o t o n s ) ,  P r e p a r a t i o n o f the e n d o c y c l i c alkene  umol)  1747,  2  angular (s,  6: 5.57  3085,  =CCH 0Ac and o l e f i n i c p r o t o n s ) , 4.10  protons),  material  found:  nmr  2  ( s , 3H,  diacetate.  which e x h i b i t e d i r ( f i l m ) :  -CH CH 0Ac), 2.43  acetyl  this  H  78%)  (br s, 4H,  J = 5,  1.04  X  -  and  f o r 6 h,  i t was  (20  mg,  added d i m e t h y l b o r o n bromide After  cannulated  s a t u r a t e d aqueous sodium  e x t r a c t e d t h r e e times w i t h e t h e r .  276  The  the  solution  had  into a vigorously  bicarbonate.  The  combined e x t r a c t s was  71 (0.43 been  stirred mixture washed  - 239 -  w i t h b r i n e , d r i e d (MgSO^) and c o n c e n t r a t e d . to  column  chromatography  e t h e r - e t h e r , 7:3 v / v ) . fractions  afforded  exhibited i r (film):  14  on  silica  The r e s i d u e  was  g e l (1 g, e l u t i o n w i t h  C o l l e c t i o n and c o n c e n t r a t i o n o f the mg  (84%)  3304 ( b r ) cm" ; 1  subjected  of  the  petroleum  appropriate  e n d o c y c l i c alkene  296 which  '-H nmr (400 MHz) 6: 5.18 (v  br  s,  1H, o l e f i n i c p r o t o n ) , 3.62 (m, 2H, -CH 0H), 1.57 ( b r s, 3H, v i n y l methyl 2  p r o t o n s ) , 2.1-1.1 (m, 13H), 1.00 ( s , 3H, a n g u l a r methyl (d,  protons),  3H, J = 6 Hz, methyl p r o t o n s ) , 0.73 ( s , 3H, methyl p r o t o n s ) .  Mass c a l c d . f o r C  1 6  H  2 g  O:  236.2140;  found: 236.2143.  0.87 Exact  - 240 -  REFERENCES  1. E . J . Corey, 2.  (a) E. P i e r s and V. Karunaratne, (b)  3.  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