Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Studies directed towards the synthesis of (±)-stemodin, a tetracyclic diterpenoid Abeysekera, Brian Frederick 1981

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1981_A1 A34.pdf [ 4.7MB ]
Metadata
JSON: 831-1.0060812.json
JSON-LD: 831-1.0060812-ld.json
RDF/XML (Pretty): 831-1.0060812-rdf.xml
RDF/JSON: 831-1.0060812-rdf.json
Turtle: 831-1.0060812-turtle.txt
N-Triples: 831-1.0060812-rdf-ntriples.txt
Original Record: 831-1.0060812-source.json
Full Text
831-1.0060812-fulltext.txt
Citation
831-1.0060812.ris

Full Text

C  STUDIES DIRECTED TOWARDS THE SYNTHESIS OF (±)-STEMODIN, A TETRACYCLIC DITERPENOID  by  BRIAN FREDRICK B.Sc,  ABEYSEKERA  U n i v e r s i t y o f S r i Lanka, Colombo Campus, 1975  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department  We a c c e p t t h i s  o f Chemistry)  t h e s i s as conforming  to t h e r e q u i r e d s t a n d a r d  THE UNIVERSITY OF BRITISH COLUMBIA January, 1981 c") ^ B r i a n F r e d r i c k Abeysekera, 1981  • I  In  presenting  requirements of  B r i t i s h  i t  freely  agree for  this for  an  available  that  I  understood  that  financial  by  his  or  of  DK-fi  (2/791  U~  University shall  reference  and  study.  I  extensive be  her or  shall  copying  granted  by  the  of  publication  not  be  allowed  S7  Columbia  of  this  It  this  without  make  further  head  representatives.  Ctf&" *y  The U n i v e r s i t y o f B r i t i s h 2075 Wesbrook Place Vancouver, Canada V 6 T 1W5  Date  the  the  Library  permission.  Department  at  of  the  may  copying  gain  degree  fulfilment  that  for  purposes  or  p a r t i a l  agree  for  permission  scholarly  i n  advanced  Columbia,  department  for  thesis  thesis  of  my  is thesis my  written  ii  ABSTRACT T h i s t h e s i s d e s c r i b e s s t u d i e s d i r e c t e d toward the s y n t h e s i s o f a c l a s s o f t e t r a c y c l i c d i t e r p e n o i d s r e p r e s e n t e d by a p h i d i c o l i n 1_ and J5.  A f e a s i b l e r o u t e to stemodin  planned  new  stemodin  i s e s t a b l i s h e d , w h i l e the s i m i l a r  route  f o r a p h i d i c o l i n _7 i s shown t o be n o n - v i a b l e .  W e l l e s t a b l i s h e d p r o c e d u r e s were u t i l i z e d to c o n v e r t the W l e l a n d M i e s c h e r ketone 101  i n t o the b i c y c l i c k e t a l k e t o n e _57.  T h i s was  i n t o the key i n t e r m e d i a t e , the t r i c y c l i c enone j>6, u s i n g a new  converted cyclopentenone  a n n u l a t i n g sequence w h i c h compared q u i t e f a v o u r a b l y w i t h p r o c e d u r e s presently available.  T h i s sequence was  keto phosphonate 75 was  converted  as f o l l o w s :  the r e a d i l y a v a i l a b l e  i n t o i t s e n o l e t h e r .79, > and  allylic  b r o m i n a t i o n w i t h N-bromosuccinimide a f f o r d e d the bromo compound j51_, an e x c e l l e n t a l k y l a t i n g agent. anions of v a r i o u s ketones,  T h i s m a t e r i a l was i n c l u d i n g _57.  used t o a l k y l a t e the e n o l a t e  The sequence i s i l l u s t r a t e d f o r  cyclohexanone 82, the e n o l a t e a n i o n o f w h i c h on t r e a t m e n t w i t h ^81 gave  83.  A c i d h y d r o l y s i s o f the e n o l e t h e r m o i e t y i n 83 gave the d i k e t o phosphonate 93 w h i c h was  c y c l i z e d to the enone JT7 u s i n g the H o r n e r - Emmons r e a c t i o n .  The p h o t o a d d i t i o n o f a l l e n e t o the enone 56^ was t h i s l a b o r a t o r y and was  r e p o r t e d t o y i e l d two p h o t o a d d u c t s .  work d e s c r i b e d i n t h i s t h e s i s s u p p o r t s one o f the p h o t o a d d u c t s ( 6 1 ) , a new other.  W h i l e the  the s t r u c t u r e p r e v i o u s l y a s s i g n e d  s t r u c t u r e (109)  i s proposed f o r the  T h i s p r o p o s a l i s based on the c o n v e r s i o n of b o t h p h o t o a d d u c t s by  o z o n o l y s i s and subsequent sodium methoxide treatment ester  previously studied in  55.  i n t o the same keto  to  iii The k e t o e s t e r j>5_ was d i o n e 132  s u b s e q u e n t l y e l a b o r a t e d i n t o the  tetracyclic  i n a number of s t e p s , the key r e a c t i o n i n t h i s sequence b e i n g  a Thorpe-Ziegler condensation.  iv TABLE OF CONTENTS Page TITLE PAGE  i  ABSTRACT  i  TABLE OF CONTENTS ACKNOWLEDGEMENTS ABBREVIATIONS  i iv v v i  INTRODUCTION I  General  II  The 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 A p h i d i c o l i n , Stemodin and Stemodinone.  III  1  5  P r e v i o u s S y n t h e t i c Approaches t o A p h i d i c o l i n and Stemodin.  8  DISCUSSION I  Synthetic Strategy  21  II  Synthesis of 2-Cyclopenten-l-ones  28  III  The S y n t h e s i s o f t h e T r i c y c l i c E s t e r 55  46  The S y n t h e s i s o f t h e T e t r a c y c l i c Dione 132  59  IV EXPERIMENTAL  81  BIBLIOGRAPHY  119  V  ACKNOWLEDGEMENTS Over t h e l a s t f o u r y e a r s , many p e o p l e have made c o n t r i b u t i o n s towards t h e r e a l i z a t i o n o f t h i s g o a l , and t o thank them a l l i n d i v i d u a l l y i s impossible.  I would however l i k e t o make s p e c i a l mention o f a few  whose c o n t r i b u t i o n s have been i n v a l u a b l e o r i n d i s p e n s a b l e .  To  P r o f e s s o r Edward P i e r s whose e n t h u s i a s m , a d v i c e and encouragement have s u s t a i n e d me d u r i n g  t h e c o u r s e o f my s t u d i e s , I o f f e r my s i n c e r e t h a n k s .  I t was indeed a p l e a s u r e  t o work under h i s d i r e c t i o n .  I a l s o thank  the members o f h i s r e s e a r c h group f o r a l l t h e i r c o o p e r a t i o n t h a t eased t h e p a i n o f r e s e a r c h . S c h e f f e r whose h e l p and i n t e r e s t My s p e c i a l  I am a l s o i n d e b t e d  and c a m a r a d e r i e  to Professor  i n my work i s g r a t e f u l l y  John  acknowledged.  thanks go to M i s s P a u l i n e H o w e l l who spent many hours  proofreading  t h i s m a n u s c r i p t and i n h e l p i n g me draw a l l t h e d i a g r a m s ,  and t o Mrs. R a n i T h e e p a r a j a h f o r h e r prompt and e f f i c i e n t t y p i n g .  Last,  and c e r t a i n l y n o t l e a s t , f i n a n c i a l a s s i s t a n c e i n t h e form o f g r a d u a t e f e l l o w s h i p s from t h e U n i v e r s i t y o f B r i t i s h Columbia, i s g r a t e f u l l y acknowledged.  vi  The  f o l l o w i n g a b b r e v i a t i o n s a r e used  in this  thesis:  NBS  =  N-Bromosuccinimide  t-Bu  =  DMS  =  Dimethyl  HMPA  =  Hexamethylphosphoramide  ir  =  LAH  =  L i t h i u m Aluminum H y d r i d e  LDA  =  Lithium Diisopropylamide  Ms  =  Methanesulfonyl  n.m.r.  =  n u c l e a r magnetic  pyr  =  Pyridine  THF  =  Tetrahydrofuran  THP  =  Tetrahydropyranyl  Ts  =  para-Toluene s u l f o n y l  TMS  =  tert-Butyl sulfide  infrared  Trimethylsilyl  resonance  1 INTRODUCTION I.  General O r g a n i c s y n t h e s i s has been g o i n g on f o r m i l l i o n s o f y e a r s i n  n a t u r e on a s c a l e o f o p e r a t i o n  that staggers  the imagination.  vast q u a n t i t i e s of h i g h l y elaborate molecules a r e constructed and w i t h a p p a r e n t ease from s i m p l e s t a r t i n g m a t e r i a l s . and  Here, speedily  This p r e c i s i o n  e l e g a n c e i n b i o s y n t h e s i s g r e a t l y overshadows t h e s t a t e o f t h e a r t  i n t h e l a b o r a t o r y , where s y n t h e s i s o f t e n appears cumbersome by comparison.  However, much has been a c c o m p l i s h e d s i n c e t h e a c c i d e n t a l  s y n t h e s i s o f u r e a by Wohler i n 1828. U n t i l t h e n , c h e m i s t s b e l i e v e d  that  a " v i t a l f o r c e " was n e c e s s a r y t o make o r g a n i c m o l e c u l e s and t h a t t h e s e compounds c o u l d o n l y be made i n n a t u r e . chemistry  Since then, s y n t h e t i c  organic  has p r o g r e s s e d r a p i d l y and one has o n l y t o r e f e r t o t h e  l i t e r a t u r e e x p l o s i o n on t h e s u b j e c t t o r e a l i z e what has been Among t h e v a r i o u s c l a s s e s o f n a t u r a l p r o d u c t s ,  achieved.  the terpenoids  have o c c u p i e d a s p e c i a l p o s i t i o n and have r e c e i v e d t h e a t t e n t i o n o f many s y n t h e t i c c h e m i s t s .  Two f a c t o r s t h a t have no doubt c o n t r i b u t e d  to t h i s a r e t h e i r ease o f i s o l a t i o n and p u r i f i c a t i o n and t h e i r c o m m e r c i a l significance. and  They f i n d many uses i n perfumes and c o s m e t i c s ,  i n paints  p r e s e r v a t i v e s , a s a r t i f i c i a l f l a v o u r i n g s i n f o o d s t u f f s and t o a  small extent i n medicine. terpenoids  S t r u c t u r a l i n v e s t i g a t i o n s revealed  that the  had c a r b o n s k e l e t o n s composed o f i s o p e n t a n e u n i t s l i n k e d i n  a head t o t a i l f a s h i o n , and t h e number o f such u n i t s p r e s e n t i n t e r p e n o i d s i s used i n t h e i r c l a s s i f i c a t i o n . diterpenoids, sesterterpenoids  Thus, m o n o t e r p e n o i d s ,  sesquiterpenoids,  and t r i t e r p e n o i d s a r e made up o f two, t h r e e ,  f o u r , f i v e and s i x i s o p e n t a n e u n i t s , r e s p e c t i v e l y .  2 The d i t e r p e n o i d s a r e n o r m a l l y  C^Q  compounds, m a i n l y  f u n g a l o r i g i n and u s u a l l y o c c u r as m i x t u r e s They show wide v a r i a t i o n i n s t r u c t u r e though d e r i v e d from g e r a n y l g e r a n i o l l y  of p l a n t  o f c l o s e l y r e l a t e d compounds. they a r e a l l b i o g e n e t i c a l l y  The main carbon s k e l e t o n s o f  the  t e t r a c y c l i c d i t e r p e n e s a r e t h e kaurane 2^, beyerane 3^, a r t i s a n e U_ and g i b b e r e l l a n e j> t y p e s . t r i c y c l i c precursor  and  They a r e a l l d e r i v a b l e ^ i n p r i n c i p a l from a  of t h e p i m a r a d i e n e 6^ c l a s s .  2 3 A p h i d i c o l i n 1_ '  i s t h e f i r s t r e p o r t e d member o f a new c l a s s o f  tetracyclic diterpenoids.  S e v e r a l papers have appeared i n t h e r e c e n t  2 3 l i t e r a t u r e d e s c r i b i n g i t s 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 ' and i t s t o t a l synthesis  4-6  .  Recently,  a n o t h e r two d i t e r p e n o i d s  7  , stemodin 8^  and stemodinone j) were i s o l a t e d and t h e i r s t r u c t u r e s p r o v e d t o be q u i t e s i m i l a r t o t h a t o f a p h i d i c o l i n 2.*  The b i o s y n t h e t i c pathway t o t h i s t y p e  of compounds has s t i l l t o be e l u c i d a t e d , though p o s s i b l e pathways c o u l d 2 be proposed v i a t h e p i m a r a d i e n e h_ t y p e o f t r i c y c l i c p r e c u r s o r . The 2 numbering systems proposed f o r t h e b a s i c c a r b o n s k e l e t o n s o f a p h i d i c o l i n T_ and s t e m o d i n 8? a r e s l i g h t l y d i f f e r e n t and a r e i n d i c a t e d i n t h e s t r u c t u r a l f o r m u l a s ^ 0 and 1 1 , r e s p e c t i v e l y .  HO ,—CHnOH ~-H R.  HO' CH 0H 2  10  £  R = OH  9  R = 0  The a n t i v i r a l a c t i v i t y o f a p h i d i c o l i n _7 t o g e t h e r w i t h i t s n o v e l s t r u c t u r e makes t h i s c l a s s o f compounds an i m p o r t a n t The work d e s c r i b e d i n t h i s t h e s i s was b o t h a p h i d i c o l i n ^7 and  stemodin j8.  synthetic target.  d i r e c t e d toward the s y n t h e s i s o f  However, as work p r o g r e s s e d  i t became  o b v i o u s t h a t the r o u t e a c t u a l l y employed p r o v i d e d i n t e r m e d i a t e s w h i c h a r e s u i t a b l e o n l y f o r the s y n t h e s i s o f stemodin j5 ( o r stemodinone 9) .  II.  The 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 A p h i d i c o l i n  1,  Stemodin iL and Stemodinone 3_. 2  3  A p h i d i c o l i n ]_ was f i r s t i s o l a t e d '  from t h e f i l t r a t e s o f c u l t u r e s o f  the fungus Cephalosporium a p h i d i c o l a P e t c h . I t was found t o i n h i b i t t h e growth o f Herpes s i m p l e x v i r u s e s , and t o reduce t h e m i t o t i c r a t e o f mouse 'L' c e l l s growing i n t i s s u e c u l t u r e .  The absence o f c a r b o n y l and o l e f i n i c groups i n  the m o l e c u l e i n d i c a t e d t h a t a p h i d i c o l i n T_,  was t e t r a c y c l i c .  The  ^"H n.m.r. s p e c t r a o f a p h i d i c o l i n _7 and i t s mono-, d i - , and t r i - a c e t a t e s i n d i c a t e d t h e p r e s e n c e o f two t e r t i a r y m e t h y l groups, two p r i m a r y groups a t  alcohol A p h i d i c o l i n 7_  q u a t e r n a r y p o s i t i o n s , and a s e c o n d a r y a l c o h o l group.  r e a d i l y and r e v e r s i b l y formed a b i s a c e t o n i d e 12_, i n d i c a t i n g t h e p r e s e n c e o f Treatment o f a p h i d i c o l i n 1_ w i t h p e r i o d i c a c i d i n p y r i d i n e  f o u r OH groups.  r e s u l t e d i n t h e l o s s o f t h e elements o f formaldehyde and t h e f o r m a t i o n o f a ketone which together w i t h  t h e d a t a summarized above i n d i c a t e d  that the  f o u r t h a l c o h o l group was t e r t i a r y and v i c i n a l t o one o f t h e p r i m a r y functions.  Since a protracted  been r e q u i r e d  s e r i e s o f c h e m i c a l t r a n s f o r m a t i o n s would have  t o unambiguously a s s i g n  s t u d i e s were u n d e r t a k e n .  a structure  t o a p h i d i c o l i n 1_,  1_ f o r a p h i d i c o l i n .  HO'  H CH OH 2  12  x-ray  These s t u d i e s l e d t o t h e assignment o f s t r u c t u r e VL_  to t h e b i s a c e t o n i d e d e r i v a t i v e and hence s t r u c t u r e and a b s o l u t e configuration  alcohol  Stemodin j$ and Stemodinone 9_ were f i r s t i s o l a t e d ' from t h e r a t e l i t t a r a l d p l a n t Stemodin m a r i t i m a L found i n t h e P a l i s a d o e s p e n i n s u l a o f Jamaica..  These two new  d i t e r p e n e s were o b t a i n e d from t h e l e a f c o n s t i t u e n t s <  the p l a n t and were shown t o possess u n u s u a l t e t r a c y c l i c c a r b o n s k e l e t o n s . They bear a c l o s e resemblance t o t h e s t r u c t u r e o f a p h i d i c o l i n T_ d i f f e r i n g t  i n t h e s t e r e o c h e m i s t r y a t C-9, C-13 and C-14 (stemodane n u m b e r i n g ) . Mass S p e c t r a l d a t a and e l e m e n t a l a n a l y s e s o f stemodin B_ i n d i c a t e d a m o l e c u l a r f o r m u l a o f C 0 34°2 ^ H  m p  1  9  6  2  ~  1 9 7  ° »  ~ « °)'  C  2  6  T  h  e  i n f r a r e d spectrum o f J5 i n d i c a t e d t h e p r e s e n c e o f h y d r o x y l (3340, 3220 cm "*") and t h e absence o f c a r b o n y l a b s o r p t i o n .  The  n.m.r. spectrum (CDCl^)  showed f o u r m e t h y l groups a t 6 0.90, 0.93, 0.97 and 1.08 and a p r o t o n (<5 3.71, t o f t , J = 11, 3.5 Hz) a t t a c h e d t o a c a r b o n b e a r i n g a h y d r o x y l group and f l a n k e d by two methylene groups.  The c o u p l i n g c o n s t a n t s i n d i c a t e d  t h a t t h i s p r o t o n was i n an a x i a l o r i e n t a t i o n and hence t h e OH group was equatorially oriented.  A c e t y l a t i o n o f stemodin 8_ gave a monoacetate w h i c h  s t i l l e x h i b i t e d an i n f r a r e d a b s o r p t i o n t y p i c a l o f a h y d r o x y l group.  Thus  i t appeared t h a t t h i s n a t u r a l p r o d u c t c o n t a i n e d a secondary and a t e r t i a r y h y d r o x y l group. Stemodinone j ) ,  C  H 2 0  32°2  ( m p  2  1  5  ~  2 1 6  ° » C  [ a ] +1A .3°) , D  was  i s o l a t e d from a l e s s p o l a r f r a c t i o n o f t h e l e a f e x t r a c t o f t h e p l a n t . I t s i n f r a r e d spectrum i n d i c a t e d h y d r o x y l (3600 - 3460 cm "S as w e l l as c a r b o n y l (1700 cm ^) f u n c t i o n a l i t y .  O x i d a t i o n o f stemodin 8^ w i t h Jones'  r e a g e n t gave stemodinone j) i n good y i e l d , t h u s e s t a b l i s h i n g t h e r e l a t i o n s h i p between t h e two compounds. showed no o l e f i n i c f u n c t i o n a l i t y .  The Raman spectrum o f stemodinone 9_  This observation, taken together w i t h  t h e f a c t t h a t stemodinone f a i l e d t o t a k e up hydrogen when s u b j e c t e d t o  7 c a t a l y t i c hydrogenation provided evidence f o r the t e t r a c y c l i c nature of i t s carbon s k e l e t o n . The 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 t h e s e two n o v e l d i t e r p e n e s was p r o v e d by t h e s i n g l e - c r y s t a l x - r a y a n a l y s i s o f stemodinone j ) . The c u r v e o b t a i n e d from an ORD measurement on stemodinone 9. showed a p o s i t i v e Cotton e f f e c t ( t a ^ Q g  =  2460).  T h i s f a c t i s i n agreement w i t h an  a b s o l u t e c o n f i g u r a t i o n c o n t a i n i n g a 5a -H and a 106  -CH^.  8 III.  P r e v i o u s S y n t h e t i c Approaches t o A p h i d i c o l i n 1 and Stemodin .8.. The n o v e l carbon s k e l e t o n s o f b o t h a p h i d i c o l i n ]_ and stemodin J3  a l o n g w i t h t h e a n t i b i o t i c n a t u r e o f a p h i d i c o l i n ]_, have been s t r o n g m o t i v a t o r s i n the c h o i c e of these m o l e c u l e s as t a r g e t s f o r s y n t h e s i s . When t h i s work was  undertaken,  t h e l i t e r a t u r e c o n t a i n e d no r e p o r t of  s y n t h e t i c s t u d i e s d i r e c t e d toward  these t e t r a c y c l i c d i e t e r p e n o i d s .  Recently,  however, a number o f t o t a l s y n t h e s e s ^ ^ and some s y n t h e t i c a p p r o a c h e s ^ ' to a p h i d i c o l i n 7_ have been p u b l i s h e d .  9  9)  Stemodin 8^ (and stemodinone  have r e c e i v e d l e s s a t t e n t i o n and o n l y two s y n t h e t i c approaches have thus f a r appeared i n t h e l i t e r a t u r e ^ ' ^ " ' ' ' .  A b r i e f d i s c u s s i o n of these  syntheses  i s i n order. 4 Very r e c e n t l y , T r o s t e t . a l . ,  5 6 McMurry et_. a l . , and Corey £t. a l .  have each p u b l i s h e d a t o t a l s y n t h e s i s o f a p h i d i c o l i n 1_.  A l l three research  groups began by f u n c t i o n a l i z i n g t h e A r i n g p r i o r t o b u i l d i n g t h e CD  ring  system w h i c h , as w i l l be seen l a t e r , i s t h e r e v e r s e a p p r o a c h t o t h a t o f 4 our proposed r o u t e .  Trost  5 and McMurry  b o t h began w i t h t h e d i k e t o n e  and i n a s e r i e s o f v e r y s i m i l a r t r a n s f o r m a t i o n s c o n v e r t e d i t i n t o b i c y c l i c k e t o a c e t o n i d e 14 (eq. 1 ) .  the  On t h e o t h e r hand, Corey^ u t i l i z e d  13  as a key i n t e r m e d i a t e the k e t o a l d e h y d e 15_ w h i c h he p r e p a r e d by two  routes,  one of w h i c h began w i t h the d i k e t o n e 13 and proceeded v i a t h e i n t e r m e d i a t e b i c y c l i c k e t o a c e t a l '16_, a compound v e r y s i m i l a r to lk_ (eq. 2 ) .  The s y n t h e t i c methodology u t i l i z e d i n the c o n s t r u c t i o n o f the CD system, however, was  ring  approached d i f f e r e n t l y by a l l t h r e e r e s e a r c h groups.  4 Trost jet. a l . u t i l i z e d t h e i r cyclopentanone to b u i l d t h e C r i n g o f a p h i d i c o l i n a c e t o n i d e JL4 w i t h d i p h e n y l s u l f o n i u m  7_.  a n n u l a t i o n procedure  Thus, c o n d e n s a t i o n  12  of t h e k e t o -  12 cyclopropylide under  reversible  y l i d e g e n e r a t i o n c o n d i t i o n s proceeded smoothly to g i v e the o x a s p i r o p e n t a n e 13 w h i c h was  t r e a t e d w i t h sodium p h e n y l s e l e n i d e  c y c l o p r o p a n o l 18^ (eq. 3) .  to give the a l k y l i d e n e -  17  10 Thermal rearrangement v i a f l a s h vacuum p y r o l y s i s o f the  trimethylsilyl  e t h e r o f t h i s m a t e r i a l (compound 19, eq. A) gave a 2:1 m i x t u r e o f epimers 20_ and 21, w i t h the major isomer 20_ h a v i n g the stereochemistry at  undesired  C-8.  19  20  T h i s m i x t u r e o f epimers was CHgCN.  the  2JL  o x i d i z e d to the enone 22 w i t h Pd(0Ac)2 i n  D i s s o l v i n g metal reduction [ L i , NH  3 >  THF,  0.8  e q u i v . o f _t-C H 0H) 4  g  o f the enone 22^ f o l l o w e d by quenching o f the i n t e r m e d i a t e e n o l a t e a n i o n w i t h c h l o r o t r i m e t h y l s i l a n e gave a s i n g l e e n o l s i l y l e t h e r 21. w h i c h corresponded  t o the minor p r o d u c t o f the i n i t i a l  rearrangement (eq. 5 ) .  11 Treatment o f t h e e n o l s i l a n e 21 w i t h n - b u t y l l i t h i u m g e n e r a t e d t h e e n o l a t e 23_ w h i c h was a l k y l a t e d w i t h a l l y l i o d i d e t o g i v e t h e k e t o o l e f i n 24_ i n 35% y i e l d .  T h i s was a c r i t i c a l s t e p i n t h e s y n t h e s i s ,  e s t a b l i s h i n g the stereochemistry of the D r i n g (eq. 6 ) .  21 The r e m a i n i n g  23  24  s t e p s o f t h e s y n t h e s i s were r a t h e r s t r a i g h t f o r w a r d . Thus  h y d r o b o r a t i o n - o x i d a t i o n o f t h e k e t o o l e f i n 24_ f o l l o w e d by o x i d a t i o n o f t h e r e s u l t a n t k e t o a l c o h o l ,25_ gave t h e k e t o a l d e h y d e 2j5 ( e q . 7 ) .  12 A l d o l c y c l i z a t i o n of the k e t o aldehyde  26 gave a m i x t u r e of e p i m e r i c  t e t r a c y c l i c k e t o a l c o h o l s 2_7 and ^ 8 , w h i c h were c o n v e r t e d i n t o t e t r a h y d r o p y r a n y l e t h e r s 29, and 3>0_.  R e d u c t i o n o f the  their  l a t t e r mixture  o f compounds under W o l f f - K i s h n e r c o n d i t i o n s , f o l l o w e d by removal o f t h e t e t r a h y d r o p y r a n y l e t h e r p r o t e c t i n g group and o x i d a t i o n of t h e r e s u l t i n g m i x t u r e o f a l c o h o l s 31^ and 31_ gave t h e k e t o a c e t o n i d e J53 (eq. 8)  R = H 27 and  26  R = THP  28  29 and  31,  32  30 (8)  33  The k e t o a c e t o n i d e _33 had p r e v i o u s l y been o b t a i n e d from, and i n t o , a p h i d i c o l i n J7.  2 3 '  reconverted  13 McMurry^ had a t o t a l l y d i f f e r e n t approach t o t h e CD r i n g system of a p h i d i c o l i n ]_.  A l k y l a t i o n o f t h e e n o l a t e a n i o n o f the k e t o  a c e t o n i d e 14 w i t h m e t h a l l y l i o d i d e gave t h e k e t o o l e f i n 3_4. bond o f 3_4_ was  c l e a v e d r e a d i l y w i t h sodium m e t a - p e r i o d a t e  and  The  olefinic  osmium  t e t r o x i d e t o g i v e t h e d i k e t o n e 3_5 w h i c h upon treatment w i t h sodium h y d r i d e i n r e f l u x i n g benzene c o n t a i n i n g a t r a c e o f t e r t - a a y l . a l c o h o l (eq.  9) underwent i n t e r n a l a l d o l c y c l i z a t i o n to a f f o r d the  enone 36.  tricyclic  14 S i n c e the a p p r o p r i a t e d i r e c t c o n j u g a t e a d d i t i o n to .the enone _36 p r o v e d to  be i m p o s s i b l e , an i n d i r e c t r o u t e to the D r i n g was  developed.  Thus,  r e d u c t i o n of the k e t o group o f ^6_ w i t h l i t h i u m aluminum h y d r i d e gave a s i n g l e a l c o h o l 37_ w h i c h was ether  converted  i n t o i t s corresponding  vinyl  u s i n g m e r c u r i c a c e t a t e and e t h y l v i n y l e t h e r ( e q . 10) .  (10)  36  37  38  Vapour phase p y r o l y s i s o f 36^ gave, i n a r a t h e r low y i e l d ( 2 0 % ) , the C l a i s e n rearrangement p r o d u c t 3_9, w h i c h was  reduced w i t h l i t h i u m  aluminum h y d r i d e . . The r e s u l t i n g a l c o h o l 4£ was corresponding  t o s y l a t e _41.  The  converted  into  C l a i s e n rearrangement s e r v e d  i n t r o d u c e the c r u c i a l s t e r e o c h e m i s t r y o f the D r i n g , and  the  to  direct 14  c a r b o n y l a t i o n o f the t o s y l a t e 41_ w i t h d i s o d i u m t e t r a c a r b o n y l f e r r a t e produced the d e s i r e d k e t o a c e t o n i d e  33 i n a modest y i e l d (30%, eq.  11).  Corey's  s y n t h e s i s o f t h e CD r i n g system o f a p h i d i c o l i n ]_ d i f f e r e d  c o m p l e t e l y from t h e p r e v i o u s two s y n t h e s e s , and i n c l u d e d a number o f unique s t e p s .  The k e t o aldehyde 15^ was t r e a t e d w i t h p o t a s s i u m c a r b o n a t e  and 1 , 5 - d i a z a b i c y c l o [ 5 , 4 , 0 ] - u n d e c - 5 - e n e (DBU) and s u b j e c t e d t o a s l o w gaseous stream o f m e t h y l v i n y l ketone"*"^ i n argon t o g i v e t h e M i c h a e l adduct j42.  T h i s m a t e r i a l , upon t r e a t m e n t w i t h p y r r o l i d i n i u m a c e t a t e ^  y i e l d e d t h e Robinson s p i r o a n n u l a t i o n  p r o d u c t 43_ (eq. 1 2 ) . The key  i n t e r m e d i a t e 43 was c o n v e r t e d v i a a number o f s t e p s i n t o t h e keto  16  0  t o s y l a t e ^44 w h i c h c o u l d be a l k y l a t e d i n t e r n a l l y a t e i t h e r C-12 o r C-15 depending on t h e r e a c t i o n c o n d i t i o n s . t o s y l a t e 44 i n 2-methyl t e t r a h y d r o f u r a n di-tert-butylamide  1 7  Thus a d d i t i o n o f t h e k e t o  t o an e x c e s s o f l i t h i u m  i n t h e same s o l v e n t a t -120°C t o -130°C, f o l l o w e d  by g r a d u a l warming o f t h e r e s u l t a n t s o l u t i o n , produced t h e t e t r a c y c l i c ketone ^ 5 i n 90% y i e l d , a r e s u l t o f a l k y l a t i o n a t C-12 ( e q . 1 3 ) .  17  (13)  45  The t e t r a c y c l i c ketone 4_5 was n e x t t r e a t e d w i t h 1-ethoxyethoxymethyl 18 lithium  .  H y d r o l y s i s o f t h e adduct formed gave a 1:1 m i x t u r e o f  a p h i d i c o l i n ]_ and i t s C-16  epimer 4j> (eq. 1 4 ) .  18  I n t e r e s t i n g l y , when the k e t o t o s y l a t e j44_ was a l l o w e d to r e a c t w i t h sodium methoxide a t C—15  i n methanol  a t 0°C,  t h e p r o d u c t of i n t e r n a l a l k y l a t i o n  (compound 47, eq. 15) was formed e x c l u s i v e l y .  This product  c o r r e s p o n d s i n s t e r e o c h e m i s t r y to t h e stemodin jS t y p e o f carbon s k e l e t o n .  19 Stemodin j5 and stemodinone _9 have r e c e i v e d l e s s a t t e n t i o n and o f the t w o * s y n t h e t i c approaches t h a t have appeared i n t h e l i t e r a t u r e , one, by C h a t t e r j e e ^ appears t o c o n t a i n a number o f e r r o r s and hence w i l l n o t be d i s c u s s e d h e r e .  I n t h e second approach, by D u t t a jet. a l  19 the known  k e t o n e j48 was c o n v e r t e d i n two s t e p s i n t o t h e ketone j49_  w h i c h was a l k y l a t e d w i t h l - b r o m o - 3 , 3 - e t h y l e n e d i o x y p r o p a n e t o g i v e i n 58% y i e l d , t h e p r o d u c t _50 ( e q . 16) .  49  50  The a l k y l a t i o n s t e p i s s i m i l a r t o t h a t i n Trost's'* s y n t h e s i s o f a p h i d i c o l i n J_ e x c e p t t h a t t h e o p p o s i t e s t e r e o c h e m i s t r y junction) i s obtained.  (cis-BC ring  The D r i n g i s then b u i l t up i n a s e r i e s o f 4  steps, almost i d e n t i c a l w i t h those i n Trost's  synthesis (eq. 1 7 ) .  * S i n c e t h i s m a n u s c r i p t was p r e p a r e d , Corey e t a l . have p u b l i s h e d Chem. S o c , 102, 7612 u s i n g methodology  [ J . Am.  (1980)] a s y n t h e s i s o f s t e m o d i n and stemodinone  s i m i l a r t o t h a t used i n t h e i r s y n t h e s i s o f a p h i d i c o l i n .  20  I t should be p o i n t e d out  t h a t a l l the syntheses d i s c u s s e d  the p r e p a r a t i o n of a racemic m i x t u r e of the n a t u r a l  product.  result in  21 DISCUSSION I.  Synthetic  Strategy  The s t r a t e g y employed i n a c h e m i c a l  s y n t h e s i s depends on a  number o f f a c t o r s , such as f i n a n c i a l c o n s i d e r a t i o n s , t h e s c a l e o f o p e r a t i o n , and t h e t i m e f a c t o r .  I n d u s t r i a l s y n t h e s e s o f t e n need t o be  c a r r i e d o u t on a m u l t i - k i l o g r a m s c a l e w h i c h may p r e c l u d e r e a g e n t s used r o u t i n e l y i n the research laboratory.  The p r o f i t m o t i v e i n i n d u s t r y  d i c t a t e s t h a t t h e number o f s t e p s be k e p t t o a minimum and o f t e n s y n t h e s e s a r e b u i l t around a " t r i c k " r e a c t i o n t h a t p u t s t o g e t h e r s k e l e t a l elements o r s t e r e o c h e m i s t r y  i n one s t e p .  complex  Such s y n t h e s e s have  20 been termed " i r r a t i o n a l " and  as opposed t o s y n t h e s e s i n w h i c h f u n c t i o n a l i t y  s k e l e t a l assembly i s done i n a l o g i c a l m u l t i - s t e p p r o c e s s .  This  second t y p e o f s y n t h e s i s , c a l l e d " r a t i o n a l " s y n t h e s i s , i s what i s o f t e n c a r r i e d out i n the research l a b o r a t o r y .  I n t h e d e s i g n o f such a  s y n t h e s i s , a complex o r g a n i c m o l e c u l e i s b r o k e n up i n t e l l e c t u a l l y i n t o a s e r i e s o f p r o g r e s s i v e l y s i m p l e r fragments u n t i l such fragments a r e r e c o g n i z a b l e as b e i n g e a s i l y a v a i l a b l e .  T h i s t y p e o f breakdown i s  c a l l e d a " r e t r o s y n t h e t i c a n a l y s i s " and i n t h e o r y , a t l e a s t , each fragment i n t h e sequence c a n be c o n v e r t e d  into i t s precursor.  Such an a n a l y s i s  a p p l i e d t o stemodin _8 l e d t o t h e s e r i e s o f i n t e r m e d i a t e  compounds  i l l u s t r a t e d i n Scheme I . The f u n c t i o n a l i t y p r e s e n t  i n t h e A and D r i n g s o f stemodin 8^  c o u l d be reasonably e x p e c t e d t o be g e n e r a t e d from two k e t o groups a t C^ and C ^ j '  Hence t h e prime t a r g e t f o r our s y n t h e s i s became t h e  t e t r a c y c l i c k e t o k e t a l _53. C h a t t e r j e e ^ * has i n f a c t c o n v e r t e d  t h e keto  group a t C. , t o t h e r e q u i r e d f u n c t i o n a l i t y i n t h e D r i n g , a l b e i t i n l o w  SCHEME I  23 isomeric p u r i t y . The t e t r a c y c l i c keto k e t a l 53_ c o u l d i n t h e o r y be p r e p a r e d by r e a c t i o n o f a d i m e s y l a t e 54  ( o r d i t o s y l a t e 58)  the  w i t h an a c y l a n i o n 21  e q u i v a l e n t d e r i v e d from m e t h y l m e t h y l t h i o m e t h y l s u l f o x i d e 22 nitromethane,  or  23 *  f o l l o w e d by h y d r o l y s i s o r o x i d a t i v e c l e a v a g e ,  r e s p e c t i v e l y , of the r e s u l t a n t product  (eq.  18).  R = Ms 54  5 3  58  R = Ts  The d i m e s y l a t e 54 c o u l d be p r e p a r e d by r e a c t i n g the d i o l _59_ w i t h methanesulfonyl secondary  chloride in pyridine.  The s t e r e o c h e m i s t r y of t h e  OH group i n t h e d i o l _5_9 would be o f paramount importance  since  t h e o r i e n t a t i o n o f t h i s group would govern t h e s t e r e o c h e m i s t r y o f t h e secondary o f t h e OMs  OMs  group i n t h e d i m e s y l a t e j>4.  The SN^ - l i k e  group i n t h e d i m e s y l a t e 54_ by thfe a c y l a n i o n e q u i v a l e n t  r e q u i r e s t h a t t h e s t e r e o c h e m i s t r y o f t h e secondary to the CH^CH^OMs m o i e t y .  reduced  T h i s c o u l d be reduced  A l t e r n a t i v e l y , t h e keto group c o u l d be first.  OMs  group be t r a n s  An i d e a l p r e c u r s o r f o r t h e d i o l 5_9 would be  the t r i c y c l i c k e t o e s t e r J55_. d i o l 59.  displacement  i n one s t e p t o t h e  stereoselectively  Subsequent r e d u c t i o n o f t h e r e s u l t i n g e s t e r a l c o h o l j>0  24 would then produce t h e d i o l 59 i n two s t e p s from t h e k e t o e s t e r 55 (Scheme I I ) .  SCHEME I I The s t e r e o s e l e c t i v e r e d u c t i o n o f a c a r b o n y l group i s a problem t h a t r e a r s i t s u g l y head e v e r so o f t e n i n s y n t h e s i s , and s e v e r a l 24 reviews  have appeared on t h e s u b j e c t .  One u s u a l l y employs a  h y d r i d e t y p e r e d u c i n g agent and, i n g e n e r a l , s t e r i c a l l y b u l k y p r o v i d e a predominance o f t h e more h i n d e r e d a l c o h o l .  reagents  T h i s has been  r a t i o n a l i z e d as approach o f t h e r e a g e n t from t h e l e s s h i n d e r e d s i d e o f t h e m o l e c u l e w i t h the c o n s e q u e n t i a l d e l i v e r y o f h y d r i d e from t h a t s i d e . A l a r g e number o f such h i n d e r e d r e d u c i n g agents a r e r e a d i l y  available.  25 If one r e q u i r e s the l e s s h i n d e r e d a l c o h o l , one p o s s i b l e method i s a B i r c h - t y p e r e d u c t i o n , w h i c h can be c a r r i e d out u s i n g l i t h i u m ammonia.  and  E x a m i n a t i o n o f a model o f the t r i c y c l i c keto «ster _55 i n d i c a t e d  t h a t the B f a c e o f the m o l e c u l e was  the l e s s h i n d e r e d  f a c e and use o f a  b u l k y r e d u c i n g a g e n t would i n t h e o r y g i v e a preponderance o f t h e a l c o h o l w i t h the c o r r e c t stereochemistry. The problem, hence, i s reduced t o the p r e p a r a t i o n o f the  tricyclic  25 k e t o e s t e r _5_5.  P r i o r work i n our l a b o r a t o r y  t r i c y c l i c enone 5_6 c o u l d be c o n v e r t e d three steps.  i n d i c a t e d t h a t the  i n t o the d e s i r e d keto e s t e r i n  Thus, the p h o t o a d d i t i o n o f a l l e n e to t h e enone 56^ gave  the t e t r a c y c l i c k e t o o l e f i n 61 i n 39% y i e l d .  Ozonolysis of t h i s m a t e r i a l  i n m e t h a n o l , f o l l o w e d by r e d u c t i o n o f t h e i n t e r m e d i a t e formed w i t h sulfide  gave t h e d i o n e 62^.  This substance,  on treatment  dimethyl  w i t h sodium  methoxide i n m e t h a n o l , gave the t r i c y c l i c k e t o e s t e r 5>5 i n good y i e l d (eq.  19).  55  26 P r i o r work 25 a l s o e s t a b l i s h e d t h a t the p h o t o a d d i t i o n enone _56 gave a second photoadduct ( i n 42% y i e l d ) w h i c h was structure ^3.  Thus, one  (as t h o s e r e p r e s e n t e d  c o u l d e n v i s a g e a s i m i l a r s e t of  i n eq. 19)  to convert  of a l l e n e t o assigned  transformations  t h i s photoadduct to  the  t r i c y c l i c k e t o e s t e r 64_ h a v i n g the k e t o e s t e r s i d e c h a i n i n an a orientation.  E l a b o r a t i o n of t h i s s i d e c h a i n i n a manner s i m i l a r t o  that already discussed i n theory,the  f o r stemodin 8^ (Scheme I I and  eq. 18) would g i v e ,  t e t r a c y c l i c k e t a l k e t o n e 65 w h i c h would have t h e a p h i d i c o l i n  t y p e of c a r b o n s k e l e t o n (eq.  20).  (20)  65  27 Thus, i t seemed t h a t t h e t r i c y c l i c enone 5j5 was a v e r s a t i l e intermediate and  t h a t c o u l d be used i n t h e s y n t h e s i s o f b o t h a p h i d i c o l i n 7_  stemodin j5.  The work d e s c r i b e d  i n t h i s t h e s i s , however, p r o v e s  25 that the p r e v i o u s l y i s erroneous.  assigned  s t r u c t u r e j63_ t o t h e second photoadduct  T h i s w i l l be d i s c u s s e d  t h e s i s ( s e e page  51  i n d e t a i l elsewhere i n t h i s  ).  The immediate s y n t h e t i c o b j e c t i v e a t t h e o u t s e t o f t h i s work t h e r e f o r e , was t h e t r i c y c l i c enone J3>5. Though t h i s compound had been  25 p r e p a r e d p r e v i o u s l y i n our l a b o r a t o r y , low y i e l d s and e x p e r i m e n t a l d i f f i c u l t i e s made us i n v e s t i g a t e a l t e r n a t i v e r o u t e s . Thus t h e problem  25 became one o f c o n v e r t i n g t h e known ketone 57_  i n t o t h e d e s i r e d enone 5^5  i n a s few s t e p s a s p o s s i b l e and i n r e a s o n a b l e y i e l d . to t h i s o b j e c t i v e i s described  57  A new s o l u t i o n  i n the next s e c t i o n of t h i s t h e s i s .  56  28  II.  Synthesis of  2-Cyclopenten-l-ones  A l a r g e amount of r e s e a r c h has r e c e n t l y been devoted t o d e v e l o p i n g 26 synthetic routes l a r g e l y due  to s u b s t i t u t e d cyclopentenones.  T h i s i s , no  doubt,  t o the f a c t t h a t numerous b i o l o g i c a l l y a c t i v e n a t u r a l p r o d u c t s  p o s s e s s the five-membered r i n g as a major s t r u c t u r a l f e a t u r e ( e . g . t h e 27 prostaglandins  ).  Our i n t e r e s t i n e f f e c t i n g the c o n v e r s i o n o f  the  k e t o k e t a l 51_ i n t o the a n n u l a t e d p r o d u c t _56 l e d us t o i n v e s t i g a t e a g e n e r a l method o f c y c l o p e n t e n o n e  annulation.  o v e r a l l t r a n s f o r m a t i o n s can be r e p r e s e n t e d  new  In e f f e c t , t h e d e s i r e d  i n g e n e r a l terms by eq.  21.  (21)  67  69  6 8  T h i s t r a n s f o r m a t i o n i n v o l v e s t h e a l k y l a t i o n o f the k e t o n e e n o l a t e  anion  66^ w i t h an " a c e t o n y l c a t i o n e q u i v a l e n t " 67_ t o g i v e , a f t e r a p p r o p r i a t e m o d i f i c a t i o n o f t h e s i d e c h a i n i n the a l k y l a t e d m a t e r i a l , t h e 1,4 68, w h i c h i s s u b s e q u e n t l y  converted  i n t o t h e c y c l i c enone 69^ v i a a base-  promoted i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n . haloacetones  diketone  The d i r e c t a l k y l a t i o n w i t h  i s u s e f u l o n l y w i t h carbon atoms c a r r y i n g v e r y a c i d i c  protons  28 due t o the predominance o f s i d e r e a c t i o n s . A number o f r e a g e n t s 29 30 (e.g. 3-halo-2-methylpropenes , 2 , 3 - d i h a l o p r o p e n e s , 3-bromo-l-trimethylsilylpropyne  31  , 3-iodi-2-triethylsilylpropene  3-bromo-2-methoxypropene  34  , p r o p a r g y l bromide  32 35  , 2-nitropropene ) have been  33  ,  developed  29 and employed s u c c e s s f u l l y as e q u i v a l e n t s o f t h e c a t i o n 67_ i n the a l k y l a t i o n step.  However, t h e r e a r e c e r t a i n problems w h i c h  accompany the use of t h e s e r e a g e n t s .  For i n s t a n c e , although a l k y l a t i o n s  o f e n o l a t e anions w i t h 2 , 3 - d i c h l o r o - l - p r o p e n e vigorous c o n d i t i o n s necessary  a r e q u i t e s u c c e s s f u l , the  t o e f f e c t subsequent unmasking of the v i n y l 36  c h l o r i d e s i d e c h a i n can l e a d t o t h e i s o l a t i o n o f f u r a n s .  Alkylations  of e n o l a t e a n i o n s w i t h p r o p a r g y l bromide a r e t r o u b l e d by a l l e n e formation.  31  The use o f m e t h a l l y l h a l i d e s  29  as a l k y l a t i n g a g e n t s i s  q u i t e s u c c e s s f u l , but r e q u i r e s o z o n o l y s i s f o r the subsequent t o the a c e t o n y l s i d e c h a i n .  conversion  T h i s o f c o u r s e , would be d e t r i m e n t a l t o  any o l e f i n i c bonds i n the s u b s t r a t e .  The use of  3-iodo-2-triethylsilyl-  32 propene  as an a c e t o n y l c a t i o n synthon r e q u i r e s , d u r i n g t h e unmasking  s t e p s , e p o x i d a t i o n f o l l o w e d by use o f s t r o n g a c i d , t h u s l i m i t i n g i t s applicability.  The a l k y l a t i n g agent we d e s i r e d was  one  that, after  a l k y l a t i o n , c o u l d be m o d i f i e d under m i l d c o n d i t i o n s t o the e q u i v a l e n t of an a c e t o n y l s i d e c h a i n .  T h i s was  important  i n our s y n t h e t i c p l a n  s i n c e we r e q u i r e d the k e t o group i n the A r i n g t o be masked t h r o u g h o u t the c y c l o p e n t e n o n e a n n u l a t i o n sequence (eq.  57  22).  56  30  S i n c e t h e k e t a l p r o t e c t i n g group i n t h e A r i n g i s s e n s i t i v e t o s t r o n g l y 37 acidic conditions  , i t was n e c e s s a r y t h a t t h e unmasking o f t h e  a c e t o n y l s i d e c h a i n t a k e p l a c e under m i l d l y a c i d i c , n e u t r a l , o r b a s i c conditions. A second p o s s i b l e problem a s s o c i a t e d w i t h t h e o v e r a l l represented  conversion  i n eq. 21 i s t h a t t h e i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n  p r o c e s s (68 -*• 69) c a n be accompanied by an u n d e s i r a b l e  base-catalyzed  38 isomerization  o f t h e i n i t i a l l y formed p r o d u c t ( e q . 23, j69_ t o 7 0 ) .  (23)  68  Very r e c e n t l y , however, McMurry  69  u t i l i z e d an i n t r a m o l e c u l a r ,  70  base-promoted  a l d o l c o n d e n s a t i o n o f t h i s type w i t h o u t e f f e c t i n g i s o m e r i z a t i o n o f t h e i n i t i a l l y formed p r o d u c t ( e q . 9 ) .  31  36 R e c e n t l y , Heathcock and co-workers  d e s c r i b e d an e l e g a n t method  f o r p r e p a r i n g c y c l o p e n t e n o n e s w h i c h e l i m i n a t e d t h e second mentioned above.  difficulty  T h e i r method i n v o l v e d a l k y l a t i o n o f t h e e n o l a t e a n i o n 66^  w i t h h a l o a c e t a t e (66 t o 71), p r o t e c t i o n o f t h e k e t o n i c c a r b o n y l (71 t o and subsequent c o n v e r s i o n o f J72 i n t o t h e k e t o phosphonate 73 ( e q . 24).  72),  32 Removal o f t h e k e t a l p r o t e c t i n g group (73 to 74) f o l l o w e d by an 40 i n t r a m o l e c u l a r Horner-Emmons  r e a c t i o n on t h e d i k e t o  phosphonate 74  gave t h e enone _69_ ( e q . 2 5 ) .  (25)  69  74  The i n i t i a l l y formed e y c l o p e n t e n o n e _69 d i d n o t i s o m e r i z e under the c o n d i t i o n s employed i n t h e Horner-Emmons c y c l i z a t i o n s t e p .  However,  the f i r s t d i f f i c u l t y mentioned above was n o t e l i m i n a t e d by t h i s methodology, s i n c e t h e s t e p s  i n v o l v i n g formation  and r e m o v a l o f t h e  k e t a l p r o t e c t i n g group ( p r e p a r a t i o n o f 72^ and 74) would r e q u i r e a c i d i c c o n d i t i o n s t h a t would c l e a r l y a f f e c t an a c i d s e n s i t i v e f u n c t i o n a l group (e.g. k e t a l ) p r e s e n t i n the k e t o n i c  substrate.  S i n c e t h e k e t o phosphonate _75 i s r e a d i l y a v a i l a b l e ( A l d r i c h ) , a two s t e p c o n v e r s i o n  can be e n v i s a g e d whereby t h e k e t o group o f J75 i s  masked as an e n o l e t h e r (76),  and t h e l a t t e r s u b s t a n c e i s c o n v e r t e d by  a l l y l i c b r o m i n a t i o n i n t o an a c t i v e a l k y l a t i n g agent ( e q . 2 6 , compound  77).  33  Masking o f the k e t o group o f _7j5 i s e s s e n t i a l i n o r d e r to reduce t h e a c i d i t y of the p r o t o n s on t h e carbon atom a t o phosphorus.  The unmasked  a l k y l a t i n g a g e n t 78 ( c f . w i t h compound 77) would quench t h e e n o l a t e a n i o n o f the k e t o n e t o be a l k y l a t e d ( e q . 2 7 ) .  A s i l y l e n o l e t h e r m a s k i n g group seemed s u i t a b l e s i n c e , f o l l o w i n g t h e a l k y l a t i o n s t e p , i t c o u l d be removed r e a d i l y under a v a r i e t y o f m i l d r e a c t i o n c o n d i t i o n s ( e . g . weak a c i d , f l u o r i d e i o n ) . attempts  However, a l l  t o p r e p a r e a s i l y l e n o l e t h e r o f 75 r e s u l t e d i n the r e c o v e r y  of s t a r t i n g m a t e r i a l .  S i n c e i t appeared t h a t an a l k y l e n o l e t h e r would  s e r v e j u s t as w e l l , t h e keto phosphonate 75 was o f t r i e t h y l o r t h o f o r m a t e i n t h e presence  t r e a t e d w i t h an  o f a c a t a l y t i c amount o f  excess  34 FeCl^^^O  41  Under t h e s e c o n d i t i o n s , the e n o l e t h e r 79.  .  The c r u d e p r o d u c t was of r e m a i n i n g  d i s s o l v e d i n dichloromethane  s t a r t i n g m a t e r i a l was  formed.  w a s  and the s m a l l amount  c o n v e n i e n t l y removed from the  m i x t u r e by t h e a d d i t i o n o f sodium h y d r i d e , w h i c h p r e c i p i t a t e d  the  42 i n s o l u b l e sodium s a l t  0 /  o f 75 (compound 80, eq.  Et0  A^P0(0CH3)2  \  28).  Na  °\  V=CHP0(XH3) +  — *  V^CHPofc^  2  75  79  (28)  80  F i l t r a t i o n o f the r e s u l t a n t m i x t u r e , f o l l o w e d by e v a p o r a t i o n of f i l t r a t e gave t h e e n o l e t h e r 79 (bp 80°C, 0.05  t o r r ) i n 94% y i e l d .  i r spectrum o f t h i s m a t e r i a l showed s t r o n g absorbances a t 1250 characteristic  was  remarkably  The  and 1025  o f a phosphonate m o i e t y , w h i l e a s t r o n g bond a t 1605  i n d i c a t e d a conjugated  o l e f i n i c bond.  c l e a n and  The  i n d i c a t e d t h a t o n l y one o f the two p o s s i b l e  (E and Z) was  a t 6 3.77  i n d i c a t e d the p r e s e n c e of a -OCH^CH^ group, w h i l e a t h r e e -  formed.  A t r i p l e t a t 5 1.33  p r o t o n d o u b l e t ( J = 2 Hz, weak c o u p l i n g t o phosphorus) a s s i g n e d t o the p r o t o n s o f the v i n y l m e t h y l group.  (J _ R  p  and a q u a r t e t  a t 6 2.14  A doublet  a t t r i b u t e d t o t h e methoxy groups on phosphorus  and a d o u b l e t a t 6 4.35  ^  n.m.r. spectrum o f 79_  isomers  was  cm  cm  geometric  6 3.65  the  c o u l d be a t t r i b u t e d t o the v i n y l  was  at  (Jg_p  =  H  Hz)  proton  = 7 Hz). A l l y l i c b r o m i n a t i o n o f t h e e n o l e t h e r 79_ w i t h N-bromosuccinimide  43  35 gave the bromo compound 81 (bp 110°C, 0.05  t o r r ) I n 76% y i e l d  p u r i f i c a t i o n by column chromatography (eq. 2 9 ) . s t r o n g absorbance a t 1605,  1250  and 1035  after  I t s i r spectrum showed  cm ^ (broad) c o n s i s t e n t w i t h  t h e p r e s e n c e o f t h e phosphonate and e n o l e t h e r m o i e t i e s . spectrum o f 81^ a g a i n i n d i c a t e d t h a t the p r o d u c t was  The  n.m.r.  isomerically  pure.  No a t t e m p t was made t o a s s i g n t h e s t e r e o c h e m i s t r y of t h i s m a t e r i a l , s i n c e unmasking o f t h e e n o l e t h e r m o i e t y a f t e r a l k y l a t i o n would d e s t r o y the stereochemical i n t e g r i t y of t h i s s t r u c t u r a l f e a t u r e .  EtO C  T  U  *  ^=CHP0(XH3)  EtO,  NBS  2  ^  >  79  I n the  3  2  (29)  81  H n.m.r. spectrum of _81, a t r i p l e t a t S 1.39  a t 8 3.91 were a s s i g n e d t o t h e -OCH^CH^ group. a t 6 3.76  ^^=CHPC4XH )  and the q u a r t e t  A s i x - p r o t o n doublet  i n d i c a t e d the methoxy groups on phosphorus (J„  =11  Hz)  n—r  w h i l e a two-proton s i n g l e t a t 6 4.42  was  methylene group a t t a c h e d t o bromine.  c o n s i s t e n t w i t h an  A d o u b l e t a t 6 4.57  allylic  (J  =5  Hz)  H—P  was  a t t r i b u t e d t o the v i n y l p r o t o n . The bromo compound j51 p r o v e d t o be an e x c e l l e n t a l k y l a t i n g a g e n t .  I t s g e n e r a l a p p l i c a b i l i t y was  s t u d i e d by e m p l o y i n g i t to a l k y l a t e  e n o l a t e a n i o n s o f a number of k e t o n e s .  Thus, treatment  e n o l a t e a n i o n o f c y c l o h e x a n o n e j$2_ ( g e n e r a t e d w i t h LDA)  o f the  the  lithium  i n tetrahydrofuran  36 w i t h t h e bromo compound 61^ gave i n q u a n t i t a t i v e y i e l d t h e a l k y l a t e d p r o d u c t 83 ( e q . 3 0 ) .  The i r spectrum o f compound S3_ showed a sharp a b s o r p t i o n a t 1710 cm ^ c h a r a c t e r i s t i c of a s i x membered r i n g k e t o n e . i n the i r spectrum  (1605, 1250 and 1040  e n o l e t h e r and phosphonate m o i e t i e s .  cm "*") were i n d i c a t i v e o f t h e  The  the e x p e c t e d t r i p l e t and q u a r t e t (6 1.26 from the - O C R ^ ^ ^ a now  S  r o u  P*  Th  e  n.m.r. spectrum and 3.72,  showed  respectively) arising  methoxy groups on phosphorus showed up  f a m i l i a r d o u b l e t c e n t e r e d a t 6 3.62  r i s e t o a d o u b l e t a t <S 4.36.  Other peaks  as  w h i l e t h e v i n y l p r o t o n gave  Mass s p e c t r a l d a t a i n d i c a t e d a m o l e c u l a r  formula c o n s i s t e n t w i t h the assigned s t r u c t u r e . I n a s i m i l a r f a s h i o n 3-pentanone 84 was y i e l d to g i v e t h e p r o d u c t 85 (bp 140°C, 0.05  alkylated i n quantitative  t o r r ) (eq. 31).  s p e c t r a l d a t a were c o n s i s t e n t w i t h t h e a s s i g n e d  structure.  All  37  0 1)LDA 2)81 84  i  '  OEt 85  (100%)  With these i n i t i a l successes, we turned our attention to s t r u c t u r a l l y 44 more complicated ketones.  Thus, the enolate anion of ketone £16_ , when  treated with the bromo compound 81 under conditions i d e n t i c a l with those used f o r cyclohexanone, gave the alkylated product j3_7 i n 40% y i e l d . 45 , However, the use of HMPA as cosolvent (added to the reaction mixture j u s t p r i o r to addition of the bromo compound 81) increased the y i e l d to 78% (eq. 32).  <  38 S i m i l a r l y , t h e l i t h i u m e n o l a t e a n i o n s o f ketones J$8 and 57. ( s e e p  46  f o r p r e p a r a t i o n o f t h i s s u b s t a n c e ) were r e a c t e d w i t h t h e bromo  compound 81^ l * t h e p r e s e n c e o f HMPA as c o s o l v e n t . 1  products  obtained i s as i n d i c a t e d  The y i e l d o f t h e p u r e  i n p a r e n t h e s i s ( e q s . 33,  34).  (34)  57  90  (76%)  The i r s p e c t r a o f compounds 87_, j89_ and j)0 showed t h e f a m i l i a r absorbances (at a p p r o x i m a t e l y attributed  1610,  and 1030  cm ^) w h i c h c o u l d be  t o t h e p r e s e n c e o f t h e v i n y l e t h e r and phosphonate m o i e t i e s .  A d d i t i o n a l absorbances a t 1715 and 1705  1250  cm"  1  cm ^ i n 90 were a t t r i b u t e d  the m o l e c u l e s .  The  i n 87_, 1740 and 1710  cm"  1  i n j89,  to the v a r i o u s carbonyl f u n c t i o n s i n  n.m.r. spectrum o f each o f compounds J$7_, 89,  and jK) showed t h e f a m i l i a r t r i p l e t and q u a r t e t due t o t h e -OCH^CH^  39 group, t h e d o u b l e t due  t o t h e methoxy groups on phosphorus, and a s i g n a l  w h i c h c o u l d be a t t r i b u t e d t o t h e o l e f i n i c p r o t o n resonance. the  In a d d i t i o n ,  n.m.r. spectrum of compound J5_7 showed two s i n g l e t s a t 6  and 1.01  0.94  w h i c h were a s s i g n e d t o t h e t e r t i a r y m e t h y l groups o f t h e k e t a l  moiety w h i l e t h e k e t a l m e t h y l e n e p r o t o n s gave r i s e t o a s i n g l e t a t 5 A d d i t i o n a l resonances i n t h e  n.m.r. spectrum of compound j?9_ c o n s i s t e d  of 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 3.11 t o the a l l y l i c m e t h y l e n e p r o t o n s phosphorus, J . _ = 16 Hz, J . = J AB A-P T  and 3.37  w h i c h were a s s i g n e d  (AB p a i r o f d o u b l e t s f u r t h e r c o u p l e d T  j  B—P r  i  a s s i g n e d t o t h e carbomethoxy group. compound 9() (mp  3.48.  = 2 Hz) and a s i n g l e t a t 6  to  3.74  I n the ^"H n.m.r. spectrum o f  99 - 100°C) , t h e t h r e e t e r t i a r y m e t h y l groups gave r i s e  t o s i n g l e t s a t 6 0.93,  1.02  and 1.16.  Mass s p e c t r a l d a t a c o n f i r m e d  m o l e c u l a r w e i g h t s o f s t r u c t u r e s a s s i g n e d t o compounds 87, 89, and  the  90.  The work d e s c r i b e d above i n d i c a t e d t h a t , i n the a l k y l a t i o n s t e p , t h e bromo compound 81^ compared v e r y f a v o u r a b l y w i t h o t h e r a c e t o n y l c a t i o n 29-35 equivalents  presently available.  I t was now n e c e s s a r y t o f i n d  (mild)  c o n d i t i o n s w h i c h would h y d r o l y z e t h e e n o l e t h e r f u n c t i o n a l i t y i n t h e s i d e c h a i n o f compounds 83_, 85, 81_, 89, and 90.  The a l k y l a t e d k e t o k e t a l s 87  and j?0 were p a r t i c u l a r l y i m p o r t a n t examples of t h e p r e s e n t methodology s i n c e the e n o l e t h e r m o i e t y would have t o be h y d r o l y z e d under c o n d i t i o n s w h i c h would n o t a f f e c t the k e t a l f u n c t i o n a l groups.  I t was  found  that  t r e a t m e n t o f an a c e t o n e s o l u t i o n o f these compounds w i t h a few drops o f 0.5  N h y d r o c h l o r i c a c i d f o r a s h o r t p e r i o d o f time a t room  temperature  r e s u l t e d i n complete h y d r o l y s i s o f the e n o l e t h e r f u n c t i o n a l i t y w i t h o u t any e f f e c t on t h e k e t a l groups.  The h y d r o l y s i s p r o d u c t s 91 and  were o b t a i n e d i n 92% and 96% y i e l d , r e s p e c t i v e l y (eqs. 35, 3 6 ) .  92  40  0  u (35)  91 (92%;  87  P0(0CH )2 3  92  90  (96%)  In a s i m i l a r fashion, h y d r o l y s i s of the enol ether moieties i n compounds 83 and 85_ proceeded smoothly t o g i v e t h e d i k e t o phosphonates 93 and 94 i n q u a n t i t a t i v e y i e l d s ( e q s . 3 7 , 3 8 ) .  |^^Y^P0(0^)  2£ ^V"Y^ °(°^)2 (37) P  2  83  93  P0(0CH )2 3  (100%)  H„0  P0(XH3'2 ) 3  OEt 85  94  (100%)  (38)  41  The  i r s p e c t r a of each o f the d i k e t o phosphonates (91 -  showed no a b s o r p t i o n  at  1605  cm \  94)  c l e a r l y showing t h a t t h e e n o l  m o i e t y i n each of the c o r r e s p o n d i n g s t a r t i n g m a t e r i a l s had been However, each o f these s p e c t r a showed a b s o r p t i o n s 1030 cm \  w h i c h were a s s i g n e d  ether hydrolyzed.  a t approx. 1710,  1250  and  t o t h e c a r b o n y l and phosphonate m o i e t i e s .  The ^H n.m.r. s p e c t r a o f t h e s e compounds showed the e x p e c t e d d i s a p p e a r a n c e of the t r i p l e t and  q u a r t e t due  to the  -OCH2CH3  group and  the absence of  a v i n y l proton resonance. An unexpected d i f f i c u l t y a r o s e d u r i n g t h e h y d r o l y s i s o f a l k y l a t e d m a t e r i a l 89.  the  Thus, r o u t i n e t r e a t m e n t o f an a c e t o n e s o l u t i o n of  89 w i t h h y d r o c h l o r i c a c i d gave a p r o d u c t w h i c h appeared to be homogenous (one s p o t by a n a l y t i c a l t h i n l a y e r c h r o m a t o g r a p h y ) . o f t h i s m a t e r i a l , however, showed a weak a b s o r p t i o n o f an o l e f i n i c bond.  Assuming t h a t t h i s was  due  t r e a t e d w i t h more h y d r o c h l o r i c a c i d .  l a y e r chromatography o f the p r o d u c t s t i l l  a t 1605  absorption.  A f t e r a second work-up, t h i n i n d i c a t e d one  component, but F u r t h e r m o r e , the  showed a f a i r l y i n t e n s e  olefinic  The mass spectrum o f t h i s crude m a t e r i a l showed no peak  t o t h e s t a r t i n g m a t e r i a l (m/e s t r o n g peak a t m/e  330.  due  348, e n o l e t h e r 8 9 ) , but d i d e x h i b i t a  T h i s e v i d e n c e seemed t o i n d i c a t e t h a t t h e  formed h y d r o l y s i s p r o d u c t 9_5 had undergone a t l e a s t p a r t i a l  n o t f u l l y c h a r a c t e r i z e d due  encountered i n i t s p u r i f i c a t i o n .  to e x p e r i m e n t a l  first  intramolecular  a l d o l c o n d e n s a t i o n t o g i v e t h e b i c y c l i c compound J36_ (eq. 39) . compound was  indicative  r e d i s s o l v e d i n acetone  g a s - l i q u i d chromatography i n d i c a t e d a second p r o d u c t . i r spectrum of the crude m a t e r i a l now  cm \  t o a s m a l l amount of  u n r e a c t e d s t a r t i n g m a t e r i a l , t h e crude m i x t u r e was and  The i r spectrum  This  difficulties  42  0  ?°2 e  0  M  ?°2 e  (39)  M  P0(XH3)  P0(0CH )2 —  89  C0 Me  2  3  2  95  96  A f t e r considerable experimentation, r e a c t i o n (89 w i t h 0.5  95)  i t was  found t h a t the d e s i r e d  c o u l d be a c c o m p l i s h e d e f f i c i e n t l y by t r e a t i n g JJ9  N h y d r o c h l o r i c a c i d i n a c e t o n e ( r . t . , 35 m i n . ) .  The  presence  o f a s m a l l amount o f e i t h e r t h e s t a r t i n g m a t e r i a l o r compound 9_6 seemed t o be i n e v i t a b l e and hence j>5 was d i r e c t l y i n the c y c l i z a t i o n s t e p .  n o t p u r i f i e d f u r t h e r but was T h i s d i f f i c u l t y was  not  used  experienced  w i t h any o f t h e o t h e r c a s e s s t u d i e d . H a v i n g found a m i l d and e f f i c i e n t method o f unmasking t h e  acetonyl  c a t i o n e q u i v a l e n t , the i n t r a m o l e c u l a r Horner-Emmons r e a c t i o n s were a c c o m p l i s h e d r o u t i n e l y by t r e a t m e n t o f t h e a p p r o p r i a t e d i k e t o phosphonate 39 w i t h sodium h y d r i d e i n dimethoxyethane  46 .  Thus the d i k e t o phosphonates  93 and j)4_ were smoothly c y c l i z e d t o g i v e the enones 97_ and j)8_ r e s p e c t i v e l y (eq. 40,  41).  43  (40)  (41)  94  98  (82%)  The s p e c t r a l d a t a d e r i v e d from compounds 97"'*' (bp 45°C, 0.02  torr)  47 and j)8 (bp 100°C, 15 t o r r ) were i n agreement w i t h those o b t a i n e d from the chemical l i t e r a t u r e .  I n a s i m i l a r f a s h i o n compounds _91, j)2_, and j)5 39  were c y c l i z e d , and  i n accord w i t h previous observations  o f t h e i n i t i a l l y formed c y c l o p e n t e n o n e  was  observed  , no i s o m e r i z a t i o n  (Scheme I I I ) .  The i r spectrum o f t h e enone 99_ (mp 73 - 74 °C) showed a band a t 1700 cm \  w h i c h was a s s i g n e d t o t h e a , 8 - u n s a t u r a t e d c a r b o n y l g r o u p ,  w h i l e a band a t 1620 cm  was a t t r i b u t e d t o t h e o l e f i n i c bond.  The  n.m.r. spectrum o f j)9_ showed two s i n g l e t s a t 6 1.00 and 1.02 a r i s i n g from t h e t e r t i a r y m e t h y l groups and a broad s i n g l e t c e n t e r e d a t 6 3.56 a t t r i b u t e d t o t h e k e t a l methylene p r o t o n s .  A s i n g l e t a t 6 5.91 was  assigned to the o l e f i n i c proton. The i r spectrum o f enone 5_6 (mp 116 - 117 °C) had a band a t  45 1680 cm ^ due t o t h e a , 8 - u n s a t u r a t e d a r i s i n g from t h e o l e f i n i c bond.  c a r b o n y l group and one a t 1610 cm ^  I t s *H n.m.r. spectrum e x h i b i t e d t h r e e  s i n g l e t s a t 6 0.90, 0.95 and 1.09 w h i c h were a s s i g n e d t o t h e t h r e e t e r t i a r y m e t h y l groups.  The two p r o t o n s on C-13 gave r i s e t o two d i s t i n c t  s i g n a l s , each a d o u b l e t o f d o u b l e t s , c e n t e r e d a t 6 1.92 and 2.54.  Thus,  t h e s e two p r o t o n s a r e m a g n e t i c a l l y n o n - e q u i v a l e n t , a r e g e m i n a l l y c o u p l e d ( J = 18 Hz) and a r e f u r t h e r c o u p l e d t o t h e b r i d g e h e a d p r o t o n ( J = 2 Hz, 6 Hz, r e s p e c t i v e l y ) .  The broad m u l t i p l e t s a t 6 2.94, 3.3 - 3.64 and 5.76,  were a s s i g n e d t o t h e b r i d g e h e a d p r o t o n ( C - 8 ) , t h e k e t a l methylene p r o t o n s and t h e o l e f i n i c p r o t o n , r e s p e c t i v e l y .  The s p e c t r a l d a t a f o r t h i s compound 25  were i n a c c o r d w i t h t h o s e p r e v i o u s l y r e c o r d e d i n o u r l a b o r a t o r y In a s i m i l a r fashion, the i r  spectrum o f enone 100 (bp 110°C,  0.05 t o r r ) showed t h e c h a r a c t e r i s t i c c a r b o n y l a b s o r p t i o n s a t 1730 and 1710 cm ^ r e s u l t i n g from t h e e s t e r and a , B - u n s a t u r a t e d  ketpne m o i e t i e s , w h i l e  the s t r o n g band a t 1625 cm ^ was a t t r i b u t e d t o t h e o l e f i n i c bond. '''H n.m.r. spectrum  The  showed a d o u b l e t o f d o u b l e t s a t 6 2.23 and 2.63  ( J = 18 Hz) w h i c h were a s s i g n e d t o t h e m a g n e t i c a l l y n o n - e q u i v a l e n t methylene p r o t o n s a d j a c e n t t o t h e k e t o group, w h i l e a d o u b l e t a t 6 5.93 ( J = 2 Hz) was a s s i g n e d t o t h e o l e f i n i c p r o t o n . Thus, t h e f i r s t o b j e c t i v e o f t h i s work was a c c o m p l i s h e d  i n t h a t an  e f f i c i e n t r o u t e t o t h e enone 5_6_ was e s t a b l i s h e d . The g e n e r a l i t y o f t h i s methodology was a l s o i n v e s t i g a t e d and was found t o compare q u i t e favourably w i t h other cyclopentenone available.  a n n u l a t i n g procedures p r e s e n t l y  46 III.  The S y n t h e s i s o f t h e T r i c y c l i c E s t e r  55  H a v i n g l a i d t h e i n i t i a l ground work, we were r e a d y t o proceed towards our t w i n g o a l s , a p h i d i c o l i n ]_ and stemodin jS. enone .56 had been e f f i c i e n t l y p r e p a r e d  from the  The  tricyclic  k e t a l ketone 57_ by  the  c y c l o p e n t e n o n e a n n u l a t i o n sequence a l r e a d y d i s c u s s e d (eq. 4 2 ) .  (42)  57  56  The k e t a l k e t o n e 57_ was  prepared  i n a s t r a i g h t f o r w a r d manner from 48  the w e l l known W i e l a n d - M i e s c h e r k e t o n e 101 49 50 m a t e r i a l w i t h sodium b o r o h y d r i d e converted  '  .  Thus, r e d u c t i o n o f  gave the compound 102, w h i c h  this was  i n t o i t s t e t r a h y d r o p y r a n y l e t h e r 103**^" u s i n g e s t a b l i s h e d  p r o c e d u r e s (eq. 4 3 ) .  The s p e c t r a l and p h y s i c a l d a t a  corresponding  t o compounds 102 and 103 were f u l l y c o n s i s t e n t w i t h those r e p o r t e d i n the , .„ _ 49,50 literature  NaBH, (43)  101  102  103  47  S t o r k and D a r l i n g  52  have shown t h a t i n t h e metal-ammonia r e d u c t i o n  o f enones i n w h i c h t h e B-carbon i s l o c a t e d a t t h e f u s i o n o f two s i x membered r i n g s , t h e p r o d u c t o b t a i n e d  i s u s u a l l y t h e more s t a b l e o f t h e  two i s o m e r s ( c i s o r t r a n s ) h a v i n g t h e newly i n t r o d u c e d  8-hydrogen  axial  53  to the ketone r i n g .  Thus, l i t h i u m - a m m o n i a r e d u c t i o n  o f enone 103, i n 54  the p r e s e n c e o f anhydrous e t h e r as c o s o l v e n t and t e r t - b u t y l a l c o h o l proton  source,  gave t h e e x p e c t e d b i c y c l i c k e t o n e 104 i n 80% y i e l d  , as  ( e q . 44)  The p h y s i c a l " * ^ and spectral"*** p r o p e r t i e s o f t h i s compound were i n a c c o r d with published  values.  Li,  NH, (44)  t-BuOH 103  The t e t r a h y d r o p y r a n y l  p r o t e c t i n g group i n compound 104 was  removed  by t r e a t m e n t o f t h i s s u b s t a n c e w i t h p _ - t o l u e n e s u l f o n i c a c i d i n methanol. The c r u d e k e t o l 105 thus o b t a i n e d was d i s s o l v e d i n benzene c o n t a i n i n g 2,2-dimethyl-l,3-propanediol acid.  and a s m a l l amount o f j > - t o l u e n e s u l f o n i c  T h i s m i x t u r e was r e f l u x e d under a Dean-Stark w a t e r t r a p t o remove  the w a t e r produced i n t h e r e a c t i o n .  The crude k e t a l a l c o h o l 106  was  o x i d i z e d t o t h e d e s i r e d k e t a l ketone J5_7 u s i n g p y r i d i n i u m c h l o r o c h r o m a t e ^ ^ i n t h e p r e s e n c e o f a s m a l l amount o f sodium a c e t a t e as a b u f f e r . c r y s t a l l i n e k e t a l k e t o n e 5]_ (mp 68 - 70°C) was o b t a i n e d  The  i n 80% o v e r a l l  48  y i e l d from t h e b i c y c l i c ketone 104 (eq. 4 5 ) .  57  The i r a t 1705 cm \ w h i l e the  spectrum of t h e k e t a l k e t o n e 57_ showed a s t r o n g a b s o r p t i o n  c o n s i s t e n t w i t h t h e p r e s e n c e o f a six-membered r i n g k e t o n e , n.m.r. e x h i b i t e d t h r e e s i n g l e t s a t <5 0.89, 1.02 and  a r i s i n g from the t h r e e t e r t i a r y m e t h y l groups i n t h e m o l e c u l e .  1.12 A  broad m u l t i p l e t between 6 3.30 and 3.70 was a s s i g n e d t o t h e k e t a l protons.  methylene  The p h y s i c a l and s p e c t r a l p r o p e r t i e s o f t h i s compound were 25  i d e n t i c a l w i t h t h o s e p r e v i o u s l y r e c o r d e d i n our l a b o r a t o r y  .  The  ketal  k e t o n e 57_ was n e x t c o n v e r t e d t o t h e t r i c y c l i c enone J56 by t h e c y c l o p e n t e n o n e a n n u l a t i o n sequence, as d e s c r i b e d p r e v i o u s l y .  The p h o t o a d d i t i o n  o f a l l e n e t o t h e enone j>>5 had been s t u d i e d  25 previously  i n our l a b o r a t o r y .  A r e p e t i t i o n o f t h i s r e a c t i o n gave 25  r e s u l t s very s i m i l a r t o those obtained  previously  . Thus,  irradiation  o f a c o l d (-78°C) s o l u t i o n o f t h e enone j><5 and a l l e n e i n t e t r a h y d r o f u r a n for  4.5 h a f f o r d e d two main p h o t o a d d u c t s (A and B ) .  This product mixture  was s e p a r a t e d by column chromatography on s i l i c a g e l , e l u t i o n b e i n g  done  by a 10:5:1 m i x t u r e o f c y c l o h e x a n e , hexane and e t h y l a c e t a t e .  The f i r s t 25 photoadduct e l u t e d from t h e column ( A , 39% y i e l d ) has been shown to  p o s s e s s s t r u c t u r e 61 w h i l e t h e second photoadduct (B, 42% y i e l d ) had 25 been a s s i g n e d  s t r u c t u r e 63.  (46) •  H  56  63  61 (A)  The p h y s i c a l and s p e c t r a l p r o p e r t i e s o f these two p h o t o a d d u c t s 25 were i n a c c o r d w i t h t h o s e p r e v i o u s l y r e p o r t e d Thus, t h e I r  i n our l a b o r a t o r y .  spectrum o f t h e c r y s t a l l i n e photoadduct J51 ( A , mp 134 -  25 135°C, l i t . mp 134 - 135°C) showed a s t r o n g a b s o r p t i o n  a t 1725 cm  c o n s i s t e n t w i t h t h e p r e s e n c e o f a five-membered r i n g k e t o n e . band a t 1670 cm ^ was a s s i g n e d  -1  A weaker  t o the s t r e t c h i n g v i b r a t i o n of the  o l e f i n i c bond e x o c y c l i c t o t h e four-membered r i n g .  The  n.m.r. spectrum  50 o f 6 1 e x h i b i t e d t h r e e s i n g l e t s a t 6 0.88, t h r e e t e r t i a r y m e t h y l groups. and 4.97  were a t t r i b u t e d  S i m i l a r l y , the lit.  25  ir  0.95  and 0.97  a r i s i n g from t h e  I n a d d i t i o n , two m u l t i p l e t s a t 6  t o t h e two o l e f i n i c  4.82  protons.  spectrum o f t h e photoadduct B (mp  mp 132 — 134°C) e x h i b i t e d a s t r o n g band a t 1725  i n t e n s e band a t 1670 cm ^ c o n s i s t e n t w i t h t h e p r e s e n c e  cm  -1  131 - 134°C, and a l e s s  o f a five-membered  r i n g ketone and an o l e f i n i c bond e x o c y c l i c t o a four-membered r i n g . *H n.m.r. spectrum o f B showed t h r e e s i n g l e t s a t 5 0.90, due 4.94  0.95  and  The 1.00  t o the t h r e e t e r t i a r y m e t h y l groups and two m u l t i p l e t s a t 6 4.80 a r i s i n g from t h e two o l e f i n i c  and  protons.  The s t r u c t u r e o f t h e photoadduct 61 (A) was  unambiguously proved  58 by an x - r a y c r y s t a l l o g r a p h i c a n a l y s i s  .  On t h e o t h e r hand r e p e a t e d  r e c r y s t a l l i z a t i o n o f t h e photoadduct B f a i l e d t o p r o v i d e c r y s t a l s w h i c h were s u i t a b l e f o r a n a l y s i s by x - r a y t e c h n i q u e s . b a s i s o f s p e c t r a l d a t a and l i t e r a t u r e precedent  N e v e r t h e l e s s , on regarding the  the  photochemical  c y c l o a d d i t i o n r e a c t i o n s o f enones t o a l k e n e s " ^ ' ^ t h e s t r u c t u r e o f t h i s 25 substance was ( q u i t e r e a s o n a b l y ) a s s i g n e d as shown i n 63. However, d u r i n g t h e c o u r s e o f t h i s work, i t became apparent  that t h i s previously  25 assigned  s t r u c t u r e was  A cold  incorrect.  (-78°C) methanol s o l u t i o n of t h e photoadduct 61 (A)  s u b j e c t e d t o a stream o f ozone u n t i l t h e s o l u t i o n remained b l u e . r e s u l t i n g s o l u t i o n was  f l u s h e d w i t h argon u n t i l the b l u e c o l o r  d i s a p p e a r e d and d i m e t h y l s u l f i d e hydroperoxide^  t o t h e d i o n e 107.  was The  had  was added t o reduce t h e i n t e r m e d i a t e The s o l v e n t s were removed under  reduced p r e s s u r e and the r e s i d u a l o i l was  k e p t under reduced  pressure  (vacuum pump) f o r 1 h i n o r d e r t o remove l a s t t r a c e s o f s o l v e n t .  The  51 o i l was then d i s s o l v e d i n d r y methanol and t h e r e s u l t a n t s o l u t i o n t r e a t e d w i t h a s o l u t i o n o f sodium methoxide i n m e t h a n o l .  I n t h i s way, t h e d i o n e  107 was c o n v e r t e d i n t o t h e k e t o e s t e r J>5 ( e q . 4 7 ) , w h i c h was o b t a i n e d i n 88% y i e l d ( f r o m 61, A ) .  In a s i m i l a r f a s h i o n , conversion o f t h e photoadduct B i n t o the c o r r e s p o n d i n g k e t o e s t e r ( e x p e c t e d t o be 64, i s o m e r i c w i t h 55) c o u l d be e n v i s a g e d (eq. 4 8 ) . S u r p r i s i n g l y , however,treatment o f t h e p h o t o a d d u c t  (48)  64  B t o a sequence o f r e a c t i o n s ( 0  3 >  CH 0H; Me S; CH^ONa, CH^OH) i d e n t i c a l 3  2  w i t h t h a t employed f o r t h e photoadduct j>l (A) a f f o r d e d n o t t h e new  52 (expected) k e t o e s t e r 64, b u t , I n s t e a d , gave t h e same k e t o e s t e r 55 (70% y i e l d ) a s had been d e r i v e d fromfrl( A ) !  B 55 The c r y s t a l l i n e k e t o e s t e r 55 (mp 139 - 140°C) o b t a i n e d from t h e photoadduct j61 (A) showed a b r o a d band between 1720 and 1740 cm ^ i n its  i r s p e c t r u m , c o n s i s t e n t w i t h t h e p r e s e n c e o f b o t h an e s t e r m o i e t y  and a five-membered  r i n g ketone.  showed t h r e e s i n g l e t s a t 6 0.93, t h e t h r e e t e r t i a r y m e t h y l groups.  The ^"H n.m.r. spectrum o f t h i s m a t e r i a l 1.01 and 1.04 w h i c h were a t t r i b u t e d t o A four-proton m u l t i p l e t centered at  6 3.52 was a s s i g n e d t o t h e k e t a l methylene p r o t o n s w h i l e a t h r e e p r o t o n s i n g l e t a t 6 3.66 was c o n s i s t e n t w i t h a carbomethoxy m o i e t y . s p e c t r a l data i n d i c a t e d a molecular formula o f  Mass  C^^^^s'  The k e t o e s t e r o b t a i n e d from t h e photoadduct B was i d e n t i c a l ( p h y s i c a l and s p e c t r a l p r o p e r t i e s ) w i t h t h e k e t o e s t e r 55_.  Mixed m e l t i n g  p o i n t d e t e r m i n a t i o n s showed no d e p r e s s i o n , i n d i c a t i n g t h a t they were one and t h e same compound.  T h i s a c q u i s i t i o n o f t h e same k e t o e s t e r  from b o t h p h o t o a d d u c t s would be I m p o s s i b l e i f t h e s t r u c t u r e (63) a s s i g n e d t o t h e photoadduct B was c o r r e c t .  initially  Hence, t h e assignment o f  s t r u c t u r e j>3_ t o t h e photoadduct B must be i n e r r o r . A m i n o r p r o d u c t (20%) o b t a i n e d from s u b j e c t i o n o f t h e photoadduct  53 B t o t h e o z o n o l y s i s - s o d i u m methoxide r e a c t i o n sequence ( e q . 49) was t h e c r y s t a l l i n e k e t o a c i d 108 (mp 214 - 215°C).  I t s i r spectrum showed a  broad band between 2600 and 3300 cm ^ c h a r a c t e r i s t i c o f t h e h y d r o x y l group o f a c a r b o x y l i c a c i d .  1700 cm  I n a d d i t i o n , two s h a r p bands a t 1735 and  were a s s i g n e d t o t h e five-membered r i n g ketone and t h e c a r b o x y l  c a r b o n y l group r e s p e c t i v e l y .  The  n.m.r. spectrum o f 108 showed  t h r e e s i n g l e t s a t 6 0.93, 1.0 and 1.07 a s s i g n e d t o t h e t h r e e t e r t i a r y m e t h y l groups.  A broad d o u b l e t a t 6 3.5 was a t t r i b u t e d t o t h e k e t a l  methylene p r o t o n s .  I t s s t r u c t u r e was unambiguously p r o v e d by i t s c o n v e r s i o n  i n 90% y i e l d t o t h e k e t o e s t e r j>5_ on t r e a t m e n t w i t h diazomethane ( e q . 5 0 ) .  (50)  108  55  54 The  unusual r e s u l t s described  above l e d us t o t h e  t h a t the s t r u c t u r e o f t h e photoadduct B ( o b t a i n e d  conclusion  as i n d i c a t e d i n eq.  46)  25 was  n o t j>3 as o r i g i n a l l y b e l i e v e d  , but was,  s t r a i n e d t e t r a c y c l i c k e t o o l e f i n 109*. provide  The  i n f a c t , the  highly  l a t t e r s t r u c t u r e would  the o b s e r v e d s p e c t r a l d a t a a n d , ' i m p o r t a n t l y , would account f o r  the c h e m i c a l d a t a .  Thus, o z o n o l y s i s o f 109  ( B ) , f o l l o w e d by  treatment  of the r e s u l t i n g d i o n e 110 w i t h sodium methoxide would produce t h e k e t o e s t e r 55 (eq.  51).  The minor p r o d u c t o f t h i s o z o n o l y s i s r e a c t i o n , t h e k e t o a c i d  108  might have a r i s e n by n u c l e o p h i l i c a t t a c k o f w a t e r on t h e h i g h l y r e a c t i v e d i o n e 110.  A l t e r n a t i v e l y , i t might have been formed d u r i n g  t h e sodium  methoxide t r e a t m e n t s t e p by n u c l e o p h i l i c a t t a c k o f h y d r o x i d e i o n (formed by h y d r o l y s i s of a s m a l l amount o f sodium methoxide) on t h e d i o n e (eq.  110  52).  * The  preparation  of a d e r i v a t i v e o f 109  ( w h i c h would be s u i t a b l e f o r x - r a y  a n a l y s i s ) i s p l a n n e d , as a f u t u r e p r o j e c t i n t h i s  laboratory.  55  I t i s known t h a t t r a n s a d d u c t s formed by t h e p h o t o a d d i t i o n o f a l k e n e s t o c y c l o h e x e n o n e s can be 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 c i s 59 a d d u c t s by t r e a t m e n t w i t h base  .  However, t r e a t m e n t of t h e photoadduct  109 (B) w i t h sodium methoxide i n methanol f o r 48 h a t room t e m p e r a t u r e r e s u l t e d only i n recovery of s t a r t i n g m a t e r i a l . A s e a r c h o f t h e c h e m i c a l l i t e r a t u r e r e v e a l s t h a t t r a n s photoc y c l o a d d i t i o n has f r e q u e n t l y been o b s e r v e d between a l k e n e s and cyclohexenones"*^'^'^ . cis  I n t h e case o f c y c l o p e n t e n o n e s however, o n l y 59  a d d i t i o n has been r e p o r t e d  .  Furthermore, a l l e n e p h o t o c y c l o a d d i t i o n s  whether t o c y c l o h e x e n o n e s o r c y c l o p e n t e n o n e s , have been r e p o r t e d t o be only c i s ^ ' ^ .  Hence, i f t h e s t r u c t u r e (109) a s s i g n e d t o photoadduct  B i s proven c o r r e c t by t h e proposed x - r a y a n a l y s i s , t h i s would the  constitute  f i r s t r e p o r t e d t r a n s a d d i t i o n o f a l l e n e t o an enone and the f i r s t  r e p o r t e d t r a n s a d d i t i o n of a c y c l o p e n t e n o n e t o an o l e f i n i c - t y p e bond. 63 Wiesner e t . a l . the  have proposed an e m p i r i c a l r u l e w h i c h a l l o w s  p r e d i c t i o n o f t h e c o n f i g u r a t i o n o f photoadducts between a l l e n e (and  56 o t h e r o l e f i n s ) and a , 8 - u n s a t u r a t e d k e t o n e s . c o n f i g u r a t i o n o f t h e photoadduct o b t a i n e d  They p o s t u l a t e  i s governed by a  that the species  ( e x c i t e d s t a t e o f t h e enone system) w h i c h i s t r i g o n a l i n t h e a- and pyramidal i n the B - p o s i t i o n .  T h i s s p e c i e s was assumed t o s e l e c t t h e  more s t a b l e o f t h e two p o s s i b l e e p i m e r i c photocycloaddition the adduct 113. and  t o t h e enone 111 i s r e p o r t e d  Thus, a l l e n e  t o g i v e i n 95% y i e l d  S i m i l a r l y , enones 114 and 117 a f f o r d t h e a d d u c t s 116  119 r e s p e c t i v e l y (Scheme I V ) .  117  configurations.  The most s t a b l e c o n f i g u r a t i o n s o f  118  SCHEME I V  119  57 t h e e x c i t e d s t a t e s o f t h e t h r e e enones 111, 114 and 117, a r e r e p 63b resented  a s 112, 115 and 118 r e s p e c t i v e l y .  i s the c l o s e s t approximation  t o o u r system g i v e s t h e c i s - a d d u c t 116  w i t h a t r a n s - f u s e d 6-5 r i n g j u n c t i o n . (61), obtained  The enone 114, w h i c h  On t h e o t h e r hand, photoadduct A  i n o u r system i s a c i s - a d d u c t w i t h a c i s - f u s e d 6-5 r i n g  j u n c t i o n , and does n o t appear t o be t h e adduct p r e d i c t e d by t h e r u l e . Furthermo r e , t h e o c c u r r e n c e 109  o f photoadduct B ( i f t h e a s s i g n e d s t r u c t u r e  i s c o r r e c t ) cannot be e x p l a i n e d by W i e s n e r ' s r u l e .  The g e n e r a l i t y  o f t h i s r u l e i s y e t t o be e s t a b l i s h e d and no t h e o r e t i c a l s i g n i f i c a n c e 64 has, a s y e t , been a s c r i b e d t o these Ideas.  L o u f t y and de Mayo  have  c r i t i c i z e d t h i s r u l e and have s u g g e s t e d t h a t t h e c o n t r o l o f s t e r e o c h e m i s t r y i n p h o t o c y c l o a d d i t i o n might depend on t h e s t e r i c h i n d r a n c e  of the  approach o f t h e o l e f i n t o t h e e x c i t e d k e t o n e . The proposed s t r u c t u r e 109 o f t h e photoadduct B p o s s e s s e s a t r a n s f u s e d b i c y c l o [3.2.0] heptane r i n g system.  While photoadditions  to y i e l d  such t r a n s - f u s e d r i n g systems have n o t been r e p o r t e d , t h e e x i s t e n c e o f such systems has been w e l l documented i n t h e l i t e r a t u r e ^ " * .  These t r a n s  compounds a r e no doubt h i g h l y s t r a i n e d b u t t h e i r f o r m a t i o n under t h e c o n d i t i o n s employed i n t h e p h o t o a d d i t i o n i s c e r t a i n l y  feasible.  S i n c e b o t h p h o t o a d d u c t s j>l and 109 (A and B r e s p e c t i v e l y ) were converted  i n t o t h e same k e t o e s t e r 55^, and s i n c e 55_ i s c l e a r l y a p r e c u r s o r  o n l y f o r stemodin jJ and n o t f o r a p h i d i c o l i n ]_ (Scheme V ) , a n o t h e r r o u t e t o the l a t t e r n a t u r a l p r o d u c t w i l l have t o be d e v e l o p e d .  This route could,  o f c o u r s e , s t i l l make u s e o f t h e enone ^6 a s an Important i n t e r m e d i a t e . On t h e p l u s s i d e , however, i t was no l o n g e r n e c e s s a r y  to e f f e c t a t e d i o u s  and t i m e consuming s e p a r a t i o n o f t h e m i x t u r e o f p h o t o a d d u c t s j51 and 109  58 s i n c e t h i s m i x t u r e c o u l d be used d i r e c t l y i n t h e o z o n o l y s i s and subsequent r i n g o p e n i n g (NaOMe) s t e p .  109  61  56  1)  0 , Me OH  2)  DMS  3)  NaOMe, Me OH  3  "CH 0H 2  —H  HO'' CH 0H 2  8 R = OH 9 R = 0 SCHEME V  59  IV.  The  Synthesis  o f t h e T e t r a c y c l i c Dione  132.  The n e x t phase o f t h i s work i n v o l v e d the e l a b o r a t i o n of the k e t o e s t e r J55 i n t o a t e t r a c y c l i c compound such as 53_ (eq. 53) .  strategy already discussed  (page 21  The  synthetic  ) r e q u i r e d the r e d u c t i o n of  the  five-membered r i n g k e t o n e i n the k e t o e s t e r 5 5 t o be s t e r e o s e l e c t i v e so as t o produce the secondary a l c o h o l w i t h a - s t e r e o c h e m i s t r y  (eq.  54).  60 Thus, r e d u c t i o n o f t h e k e t o e s t e r 55 w i t h sodium b o r o h y d r i d e i n methanol a t room temperature  gave a 1:1 m i x t u r e of t h e d e s i r e d e s t e r  a l c o h o l 60 and t h e l a c t o n e 120  (eq. 5 5 ) .  These compounds were e a s i l y  s e p a r a t e d by column chromatography on s i l i c a g e l , t h e e l u e n t b e i n g a 4:1 m i x t u r e o f m e t h y l e n e c h l o r i d e and  ether.  The e s t e r a l c o h o l 60, a v e r y v i s c o u s c o l o r l e s s o i l , was i n 50% y i e l d a f t e r chromatography.  I t s i r spectrum showed a  band between 3300 and 3500 cm ^ c h a r a c t e r i s t i c of t h e OH alcohol.  broad  group o f an  A s h a r p a b s o r p t i o n a t 1725 cm ^ was a s s i g n e d t o t h e c a r b o n y l  group of t h e e s t e r . s i n g l e t a t 6 0.95  The ^H n.m.r. spectrum showed a t h r e e - p r o t o n  and a s i x - p r o t o n s i n g l e t a t 5 0.99,  s i g n a l s which could  r e a d i l y be a s s i g n e d t o t h e t h r e e t e r t i a r y m e t h y l groups. m u l t i p l e t a t 6 3.58  was  was  broad  a s s i g n e d t o the methoxy group o f t h e e s t e r .  A broad s i n g l e - p r o t o n m u l t i p l e t c e n t e r e d a t <5 4.54 C-12.  A  a t t r i b u t e d t o t h e k e t a l methylene p r o t o n s , w h i l e  a sharp s i n g l e t a t 6 3.65  proton at  obtained  was  assigned to the  61 The c r y s t a l l i n e l a c t o n e 120 (mp 194°C), o b t a i n e d i n 49% y i e l d , d i s p l a y e d bands a t 1730, 1115 and 1100 cm ^ i n i t s i r spectrum, a l l o f w h i c h were c o n s i s t e n t w i t h a six-membered r i n g l a c t o n e .  I t s ^"H n.m.r.  showed t h e t h r e e f a m i l i a r t h r e e - p r o t o n s i n g l e t s a t 6 0.88, 0.92 and 1.0 due t o t h e t e r t i a r y m e t h y l groups and a f o u r - p r o t o n m u l t i p l e t a t 6 3.5 a r i s i n g f r o m t h e k e t a l methylene p r o t o n s .  A one-proton  m u l t i p l e t a t 6 4.78  was a s s i g n e d t o t h e p r o t o n a t C-12. The n o n - s t e r e o s e l e c t i v i t y o f t h e sodium b o r o h y d r i d e r e d u c t i o n l e d us t o examine o t h e r r e d u c i n g a g e n t s .  However, u s e o f l i t h i u m aluminum  h y d r i d e a l s o f a i l e d t o p r o v i d e any s t e r e o s e l e c t i v i t y , s i n c e r e d u c t i o n ( e t h e r , a t room t e m p e r a t u r e ,  o v e r n i g h t ) w i t h t h i s r e a g e n t p r o v i d e d an  a p p r o x i m a t e l y 1:1 m i x t u r e o f t h e e p i m e r i c d i o l s 121 r e s u l t i n g from t h e simultaneous  r e d u c t i o n o f t h e e s t e r and k e t o n e f u n c t i o n a l i t i e s ( e q . 5 6 ) .  OH  (56)  55  121  A l t h o u g h t h e s e isomers were n o t s e p a r a t e d , t h e p r o p o r t i o n o f each c o u l d be e s t i m a t e d on t h e b a s i s o f an *H n.m.r. spectrum o f t h e m i x t u r e 121, s i n c e each p u r e epimer was a v a i l a b l e ( s e e pages 62, 7 4 ) .  62 A c a r e f u l e x a m i n a t i o n o f a model o f 55 i n d i c a t e d t h a t t h e B-face of t h e m o l e c u l e was hindered  reducing  more open t o a t t a c k than the a - f a c e .  Therefore,  a  agent might be e x p e c t e d t o a p p r o a c h the m o l e c u l e  p r e f e r e n t i a l l y from the B s i d e , t h u s g i v i n g t h e d e s i r e d e s t e r a l c o h o l Treatment o f a c o l d (-78°C) t e t r a h y d r o f u r a n lithium tri-sec-butylborohydride  66  s o l u t i o n o f 55  ( a v a i l a b l e as L - S e l e c t r i d e  TM  with  from  A l d r i c h ) gave, a f t e r work-up, a 74% y i e l d o f t h e e s t e r a l c o h o l 60_. s m a l l amount o f t h e l a c t o n e 120  55  Having obtained  (23%) was  a l s o i s o l a t e d (eq.  120  the e s t e r a l c o h o l j>0 i n good y i e l d , the i n t o the d i o l J 5 9 .  T h i s was  (eq.  58).  synthetic  e a s i l y achieved  by t r e a t m e n t of an e t h e r s o l u t i o n of ^0 w i t h l i t h i u m aluminum a t room t e m p e r a t u r e f o r 30 min  A  57).  60  plan required i t s conversion  60.  hydride  63  (58)  60  59  The d i o l _5_9 was o b t a i n e d i n q u a n t i t a t i v e y i e l d as a c o l o r l e s s o i l w h i c h c o u l d n o t be i n d u c e d to c r y s t a l l i z e from a v a r i e t y o f s o l v e n t s .  Itsi r  spectrum showed a b r o a d band between 3200 and 3600 cm ^ c h a r a c t e r i s t i c o f t h e OH group o f an a l c o h o l . t h r e e - p r o t o n s i n g l e t a t 6 0.94  I t s ^H n.m.r. spectrum d i s p l a y e d a and a s i x - p r o t o n s i n g l e t a t 6 0.96  from t h e t h r e e t e r t i a r y m e t h y l g r o u p s .  arising  A broad f o u r - p r o t o n m u l t i p l e t a t  6 3.52 was a s s i g n e d t o t h e k e t a l methylene p r o t o n s , w h i l e a two-proton t r i p l e t a t 6 3.7 was a t t r i b u t e d t o t h e methylene p r o t o n s o f t h e p r i m a r y a l c o h o l moiety. the p r o t o n a t  A s i n g l e - p r o t o n m u l t i p l e t a t 6 4.54  was a s s i g n e d t o  C-12.  Treatment of a p y r i d i n e s o l u t i o n o f d i o l 59_ w i t h m e t h a n e s u l f o n y l c h l o r i d e gave the d i m e s y l a t e j>4 i n 80% y i e l d a f t e r work-up and chromatography  (eq. 59).  column  64  (59)  The d i m e s y l a t e 54, w h i c h was  o b t a i n e d as a l i g h t y e l l o w o i l ,  d i s p l a y e d c h a r a c t e r i s t i c s u l f o n a t e e s t e r a b s o r p t i o n bands a t 1360, and 1170  cm ^ i n i t s  spectrum, a t 6 0.93,  i r spectrum. 0.94  Three s i n g l e t s i n i t s  1340,  n.m.r.  and 1.0, were a s s i g n e d t o t h e t h r e e f a m i l i a r  t e r t i a r y m e t h y l groups, w h i l e two a d d i t i o n a l s i n g l e t s a t 6 3.01  and  3.04  were a t t r i b u t e d to t h e m e t h y l groups o f t h e m e t h a n e s u l f o n y l m o i e t i e s . A f o u r - p r o t o n m u l t i p l e t a t 6 3.5 was methylene p r o t o n s .  e a s i l y assigned to the k e t a l  The e f f e c t o f e s t e r i f i c a t i o n o f t h e d i o l j>9_ was  a  d o w n f i e l d s h i f t o f t h e resonances o f t h e p r o t o n s on t h e carbon atoms t o t h e p r i m a r y and secondary  alcohols.  Thus, a two-proton  6 4.3 was a s s i g n e d t o t h e methylene p r o t o n s a t C-15 m u l t i p l e t a t 6 5.28  was  a s s i g n e d to t h e p r o t o n a t  t r i p l e t at  while a single-proton C-12.  W i t h t h e d e s i r e d d i m e s y l a t e 54 i n hand, a c h o i c e had t o be made as to the a c y l a n i o n e q u i v a l e n t t h a t would be t h e most s u i t a b l e f o r b u i l d i n g the D-ring.  A  search of the l i t e r a t u r e r e v e a l e d the 21 22  a v a i l a b i l i t y o f a l a r g e number o f such a c y l a n i o n e q u i v a l e n t s and one t h a t seemed t o be q u i t e a t t r a c t i v e was  '  67 '  t h a t d e r i v e d from m e t h y l  65 methylthiomethyl sulfoxide  21  .  Thus, t r e a t m e n t o f t h e d i m e s y l a t e _54_  w i t h an excess o f t h e a n i o n o f m e t h y l m e t h y l t h i o m e t h y l s u l f o x i d e m i g h t be expected t o g i v e an adduct 122, w h i c h , on h y d r o l y s i s , would y i e l d the d e s i r e d t e t r a c y c l i c k e t o  fcetal  54  _53 Ceq.  60) .  122  53  The a n i o n o f m e t h y l m e t h y l t h i o m e t h y l s u l f o x i d e was p r e p a r e d  i n the  21 p r e s c r i b e d manner  u s i n g n - b u t y l l i t h i u m as t h e base.  (2.0 - 2.5 mol-equiv.)  was  This anion  t r a n s f e r r e d by means of a d o u b l e - t i p p e d n e e d l e  t o a c o l d (-78°C) t e t r a h y d r o f u r a n s o l u t i o n of t h e d i m e s y l a t e j>4_. r e a c t i o n m i x t u r e was temperature.  s t i r r e d f o r ^ h a t 0°C and f o r 12 h a t room  Methylene c h l o r i d e was added t o t h i s s o l u t i o n and  p r e c i p i t a t e d s a l t s were s e p a r a t e d by f i l t r a t i o n Florisil.  gave a c r u d e m a t e r i a l w h i c h was  the  through a s h o r t p l u g of  Removal o f t h e s o l v e n t s (reduced p r e s s u r e ) from the  filtrate  p u r i f i e d by column chromatography on  s i l i c a g e l ( e l u t i o n w i t h an 8:1 h e x a n e s - e t h y l a c e t a t e m i x t u r e ) . main compound o b t a i n e d from t h e column was d i m e s y l a t e 54.  The  The  t h e s t a r t i n g m a t e r i a l the  A l t h o u g h a number o f minor b y - p r o d u c t s were a l s o i s o l a t e d ,  none had the s p e c t r a l c h a r a c t e r i s t i c s e x p e c t e d f o r adduct  122.  66 A number o f changes i n t h i s p r o c e d u r e , such as a n i o n g e n e r a t i o n w i t h d i f f e r e n t bases ( e . g . l i t h i u m d i i s o p r o p y l a m i d e , p o t a s s i u m h y d r i d e ) and use o f a more p o l a r s o l v e n t ( t e t r a h y d r o f u r a n - hexamethylphosphoramide i n the p l a c e o f t e t r a h y d r o f u r a n ) , gave v a r y i n g amounts o f b y - p r o d u c t s and s t a r t i n g m a t e r i a l .  However, t h e d e s i r e d adduct 122 remained  elusive,  s i n c e c a r e f u l s p e c t r o s c o p i c examination of the v a r i o u s product mixtures p r o v i d e d l i t t l e o r no e v i d e n c e f o r t h e presence o f t h i s m a t e r i a l .  In t h i s  c o n n e c t i o n , i t s h o u l d be p o i n t e d o u t t h a t the o r i g i n a l w o r k e r s had  used 21  o n l y p r i m a r y h a l i d e s and t o s y l a t e s i n t h e i r c y c l i c k e t o n e s y n t h e s i s w i t h methyl methylthiomethy1  (CH ) 2  s u l f o x i d e (eq. 6 1 ) .  (C^  n  ^—y  X = Br,  C=o  (61)  SOCH  X  3  OTs  On t h e b a s i s o f an e x a m i n a t i o n o f a m o l e c u l a r model o f the d i m e s y l a t e 54_ i t seemed r e a s o n a b l e to propose  t h a t t h e f a i l u r e o f the  r a t h e r bulky anion of methyl methylthiomethyl s u l f o x i d e to c l e a n l y d i s p l a c e the m e s y l a t e groups I n t h i s m o l e c u l e ( t o produce 122) l a r g e l y due t o s t e r i c f a c t o r s .  was  T h e r e f o r e , i t became apparent t h a t the  d i s p l a c e m e n t o f t h e m e s y l a t e groups w i t h a s t e r i c a l l y much l e s s demanding n u c l e o p h i l e ( e . g . c y a n i d e i o n ) s h o u l d be  investigated.  A hexamethylphosphoramide s o l u t i o n o f the d i m e s y l a t e 54_ was t r e a t e d w i t h an e x c e s s o f sodium c y a n i d e ( s a t u r a t e d s o l u t i o n ) f o r 3 h  67 a t room t e m p e r a t u r e and 48 h a t 60°C.  The r e a c t i o n m i x t u r e was  cooled,  e t h e r and w a t e r were added and t h e aqueous l a y e r was d i s c a r d e d .  The  e t h e r l a y e r was washed t w i c e w i t h s a t u r a t e d copper s u l f a t e ( t o remove hexamethylphosphoramide), was chromatographed  d r i e d and e v a p o r a t e d t o g i v e a y e l l o w o i l w h i c h  on s i l i c a g e l . E l u t i o n o f t h e column w i t h a  3:1  m i x t u r e o f hexanes and e t h y l a c e t a t e gave i n 60% y i e l d , the d i n i t r i l e  123  (mp 159 - 161°C) as a w h i t e c r y s t a l l i n e s o l i d ( e q . 6 2 ) .  The i r spectrum of t h e d i n i t r i l e 123 showed two sharp absorbances a t 2240 and 2230 cm ^ c h a r a c t e r i s t i c o f t h e two n i t r i l e g r o u p s , w h i l e i t s ^"H n.m.r. spectrum d i s p l a y e d t h r e e s i n g l e t s a t 6 0.91, 0.98 a r i s i n g from t h e t e r t i a r y m e t h y l groups.  In a d d i t i o n , the  and  1.01  n.m.r.  spectrum e x h i b i t e d a f o u r - p r o t o n m u l t i p l e t a t 6 3.5 e a s i l y a t t r i b u t e d to  the k e t a l methylene p r o t o n s w h i l e a s i n g l e - p r o t o n m u l t i p l e t a t 6  was a s s i g n e d  t o the methine p r o t o n a t  3.03  C-12.  H a v i n g o b t a i n e d t h e d i n i t r i l e 123 i n r e a s o n a b l e  y i e l d , a number  of i n t e r e s t i n g approaches c o u l d be a p p l i e d t o t h e D r i n g s y n t h e s i s .  The  68 most d i r e c t r o u t e was t h e T h o r p e - Z i e g l e r  68  c o n d e n s a t i o n w h i c h would  c y c l i z e t h e d i n t r i l e 123 t o t h e e n a m i n o n i t r i l e 124 ( e q . 6 3 ) . I t was  124 123 a n t i c i p a t e d t h a t t h e r i n g c l o s u r e would o c c u r t o p r o v i d e t h e p r o d u c t 124 s i n c e t h e r e a c t i o n s h o u l d be r e v e r s i b l e and t h e p r o d u c t 124 ( o r t h e c o r r e s p o n d i n g a n i o n X) would be e x p e c t e d t o be c o n s i d e r a b l y more s t a b l e than t h e a l t e r n a t i v e p r o d u c t 125 ( o r t h e c o r r e s p o n d i n g a n i o n s Y o r Z) ( s e e Scheme V I ) . I f t h e i n t r a m o l e c u l a r c o n d e n s a t i o n d i s c u s s e d above was s u c c e s s f u l the n e x t s t e p of t h e s y n t h e s i s would r e q u i r e t h e c o n v e r s i o n o f t h e enaminonitrile  124 t o t h e t e t r a c y c l i c k e t o k e t a l 53_ ( e q . 6 4 ) . I t was  SCHEME V I  70 a t t h i s s t a g e t h a t t h e a t t r a c t i v e n e s s o f t h e Thorpe»-Ziegler r o u t e diminished.  The h y d r o l y s i s and d e c a r b o x y l a t i o n o f c y c l i c  have posed problems t o some w o r k e r s and B a l d w i n ^ of these.  enaminonitriles  has d i s c u s s e d some  Base h y d r o l y s i s o f t e n f a i l s and a c i d h y d r o l y s i s , w h i l e  being  t h e method o f choice**^ would u n d o u b t e d l y be d e t r i m e n t a l t o t h e k e t a l a t C-3. A second p o s s i b l e a p p r o a c h t o t h e D r i n g was t h e Dieckmann 68 condensation  w h i c h i s a much more v e r s a t i l e r e a c t i o n than t h e Thorpe-  Ziegler cyclization.  T h i s would i n v o l v e c o n v e r s i o n o f t h e d i n i t r i l e 123  i n t o a d i e s t e r 126 w h i c h c o u l d t h e n be c y c l i z e d ( e g . 6 5 ) .  The d i r e c t i o n  71 of r i n g c l o s u r e would be t h a t shown s i n c e the Dieckmann c o n d e n s a t i o n f a i l s when a s t a b l e e n o l a t e a n i o n of t h e 8-keto e s t e r p r o d u c t c a n n o t be 68 formed  .  The h y d r o l y s i s and  decarboxylation  of the g-keto e s t e r  127  c o u l d be c a r r i e d out under c o n d i t i o n s m i l d e r than those r e q u i r e d f o r enaminonitrile  124,  w i t h t h e r e s u l t t h a t the k e t a l a t C-3  the  c o u l d remain  i n t a c t t o produce t h e d e s i r e d k e t o k e t a l 53. However, s i n c e f u r t h e r m o d i f i c a t i o n o f the d i n i t r i l e 123  to  the  d i e s t e r 126 would be r e q u i r e d i n o r d e r t o t e s t the Dieckmann c o n d e n s a t i o n , i t was  r e s o l v e d to t r y the Thorpe-Ziegler  method f i r s t .  Thus, a  tert-  b u t y l a l c o h o l s o l u t i o n of the d i n i t r i l e 123 was r e f l u x e d f o r 30 h w i t h a 69 c a t a l y t i c q u a n t i t y of p o t a s s i u m t e r t - b u t o x i d e  .  A f t e r work-up  r e c r y s t a l l i z a t i o n of t h e crude p r o d u c t from m e t h a n o l , t h e enaminonitrile The  124  (mp  213 - 215°C) was  e n a m i n o n i t r i l e s t r u c t u r e 124 was  the tautomeric precedent  obtained  assigned  i m i n o n i t r i l e s t r u c t u r e 128)  crystalline  i n 90% y i e l d (eq.  124  63).  t o the p r o d u c t ( r a t h e r than  on the b a s i s o f  literature  . CN  and  NH  CN  128  72 The  i r spectrum of 124 o f f e r e d the most c o m p e l l i n g  f a v o r o f the two  enaminonitrile s t r u c t u r e assigned.  bands a t 3490 and  group (NH  3390 cm ^ was  cm ^ was  assigned  enaminonitrile^.  The  deformation^.  from the t h r e e t e r t i a r y m e t h y l groups.  nitrile  ^"H n.m.r. spectrum of  showed the f a m i l i a r t h r e e s i n g l e t s a t 6 0.90,  assigned  t o Wi^  cm ^ i s c h a r a c t e r i s t i c of the  s t r e t c h i n g f r e q u e n c y i n an  was  was  a t t r i b u t e d t o the e n d o c y c l i c o l e f i n i c bond w h i l e  a sharp absorbance a t 2165  124  Thus, the p r e s e n c e of  c o m p a t i b l e w i t h a p r i m a r y amino  s t r e t c h ) w h i l e a band a t 1642  A band a t 1605  evidence i n  0.92  and  1.01  arising  A four-proton m u l t i p l e t at 6  3.52  t o the k e t a l m e t h y l e n e p r o t o n s w h i l e a broad two-proton  s i n g l e t a t 6 4.23  was  a t t r i b u t e d t o the p r o t o n s o f the p r i m a r y amino  group. TM I t w i l l be r e c a l l e d t h a t the L - S e l e c t r i d e e s t e r 5_5 gave a 3:1 120  m i x t u r e of the e s t e r a l c o h o l ^0  (p 62, eq. 5 7 ) .  c o n v e r t e d i n t o the number of s t e p s .  and  the  lactone  As j u s t d e s c r i b e d , t h e e s t e r a l c o h o l 60 e n a m i n o n i t r i l e 124,  I t was  t h a t would c o n v e r t  r e d u c t i o n of the k e t o  v i a the d i n i t r i l e 123,  p o s s i b l e to envisage a s i m i l a r set of  the l a c t o n e 120  i n t o the d e s i r e d  was in a reactions  enaminonitrile  124  (Scheme V I I ) . A l t h o u g h d i n i t r i l e 131 was  used to p r e p a r e t h e  i s an epimer o f t h e d i n i t r i l e 123  e n a m i n o n i t r i l e 124,  c o n d i t i o n s employed i n the T h o r p e - Z i e g l e r e p i m e r i z a t i o n of 131 the  t o 123.  i t was  which  assumed t h a t t h e b a s i c  r e a c t i o n would cause  The removal of 123  (by t h e f o r m a t i o n  e i i a m i n o n i t r i l e ) would then s h i f t the e q u i l i b r i u m towards 123  u l t i m a t e l y r e s u l t i n the c o n v e r s i o n enaminonitrile  124.  of the d i n i t r i l e 131  i n t o the  of and desired  SCHEME VTI  74 Thus, 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 t h e l a c t o n e 120 c a r r i e d o u t i n r e f l u x i n g t e t r a h y d r o f u r a n gave, i n 99% y i e l d , t h e d i o l 129 (eq. 6 6 ) . T h i s c r y s t a l l i n e m a t e r i a l (mp 180 - 182°C) showed a broad band  (66)  120  129  between 3200 and 3500 cm s t r e t c h o f an a l c o h o l .  i n i t s i r spectrum, c h a r a c t e r i s t i c o f t h e OH I t s ^H n.m.r. spectrum d i s p l a y e d a s i x - p r o t o n  s i n g l e t a t 5 0.93 and a t h r e e - p r o t o n s i n g l e t a t 6 1.0, s i g n a l s w h i c h c a n be a s s i g n e d t o t h e t e r t i a r y m e t h y l groups i n t h e m o l e c u l e .  The k e t a l  methylene p r o t o n s showed up a s a broad m u l t i p l e t c e n t e r e d a t 6 3.51 w h i l e a two-proton alcohol.  t r i p l e t a t 6 3.8 was a s s i g n e d t o t h e a p r o t o n s o f t h e p r i m a r y  A s i n g l e - p r o t o n m u l t i p l e t a t 6 4.55 was a s s i g n e d t o t h e p r o t o n  a t C-12. A s o l u t i o n o f t h e d i o l 129 i n d r y p y r i d i n e was t r e a t e d w i t h an excess o f m e t h a n e s u l f o n y l  chloride.  s t i r r e d a t room temperature  A f t e r t h e r e a c t i o n m i x t u r e had been  o v e r n i g h t , work-up and column chromatography  of t h e crude product on s i l i c a g e l gave, i n 95% y i e l d , t h e d i m e s y l a t e 130 as a l i g h t y e l l o w o i l ( e q . 6 7 ) .  75  The i r spectrum o f t h e d i m e s y l a t e 130 d i s p l a y e d t h e c h a r a c t e r i s t i c s u l f o n a t e e s t e r a b s o r p t i o n bands a t 1350, 1330 and 1175 cm ^. I t s n.m.r. spectrum e x h i b i t e d t h e t h r e e s i n g l e t s ( 6 0.93, 0.97, 1.01) e x p e c t e d o f t h e t h r e e t e r t i a r y m e t h y l groups.  Two a d d i t i o n a l  singlets  a t 6 3.02 and 3.03 were a s s i g n e d t o t h e two m e t h y l groups o f t h e methanesulfonyl moieties, while the f a m i l i a r four-proton m u l t i p l e t a t 6 3.5 was a t t r i b u t e d t o t h e k e t a l methylene p r o t o n s .  A two-proton  triplet  at 6 4.4 was a s s i g n e d t o t h e m e t h y l e n e p r o t o n s a t C-15 w h i l e a s i n g l e p r o t o n m u l t i p l e t a t 6 5.3 was a s s i g n e d t o t h e C-12 p r o t o n . A hexamethylphosphoramide s o l u t i o n o f t h e d i m e s y l a t e 130 was t r e a t e d w i t h an excess o f sodium c y a n i d e f o r 3 h a t room and 48 h a t 60°C.  temperature  F o l l o w i n g work-up, t h e crude m a t e r i a l was  chromatographed on s i l i c a g e l and t h e w h i t e s o l i d i s b l a t e d was r e c r y s t a l l i z e d from m e t h a n o l .  The c r y s t a l l i n e d i n i t r i l e 131 (mp 194°C)  was o b t a i n e d i n 65% y i e l d from t h e d i m e s y l a t e 130 (eq. 6 8 ) .  76  M s  Q  MsO  -CN  —H  •H  (6 8)  H  NaCN HMPA H  130  131  The two s h a r p absorbances a t 2240 and 2230 cm  -1  i n t h e i r spectrum  of t h e d i n i t r i l e 131 was c h a r a c t e r i s t i c o f t h e two n i t r i l e groups i n the molecule.  The ^"H n.m.r. o f 131 d i s p l a y e d a s i x - p r o t o n s i n g l e t a t  S 0.95 and a t h r e e - p r o t o n  s i n g l e t a t 6 0.97, s i g n a l s w h i c h were  t o t h e t e r t i a r y m e t h y l groups i n t h e m o l e c u l e . a t 6 2.95 was a s s i g n e d four-proton methylene  assigned  A single-proton multiplet  t o t h e methine p r o t o n a t C-12 w h i l e t h e f a m i l i a r  broad m u l t i p l e t centered  a t 6 3.5 was a t t r i b u t e d t o t h e k e t a l  protons.  W i t h t h e s u c c e s s f u l s y n t h e s i s o f t h e d i n i t r i l e 131, t h e h y p o t h e s i s t h a t e p i m e r i z a t i o n f o l l o w e d by c y c l i z a t i o n would o c c u r under t h e conditions o f the Thorpe-Ziegler  r e a c t i o n , c o u l d be t e s t e d .  Thus, a  t e r t - b u t y l a l c o h o l s o l u t i o n o f the d i n i t r i l e 131 was r e f l u x e d f o r 30 h w i t h a c a t a l y t i c q u a n t i t y o f p o t a s s i u m t e r t - b u t o x i d e . product, obtained  The crude  i n 81% y i e l d had s p e c t r a l and p h y s i c a l p r o p e r t i e s  i d e n t i c a l w i t h t h o s e o f t h e e t t a m i n o n i t r i l e 124 o b t a i n e d d i n i t r i l e 123 ( e q . 6 9 ) .  from t h e  77  131  123  124  Thus t h e l a c k of t o t a l s t e r e o s e l e c t i v i t y i n the  L-Selectride  r e d u c t i o n o f the k e t o e s t e r 55 d i d n o t r e s u l t i n a l o s s o f m a t e r i a l b o t h t h e e s t e r a l c o h o l j60 and t h e l a c t o n e 120 the same  e n a m i n o n i t r i l e 124  (eq.  c o u l d be c o n v e r t e d  70).  124  since  into  78 Good y i e l d s a r e o f paramount i m p o r t a n c e i n a m u l t i - s t e p s y n t h e s i s and  t h u s , t h i s s a v i n g of a p p r o x i m a t e l y  25% o f t h e m a t e r i a l o b t a i n e d  t h e r e d u c t i o n s t e p i s of some s i g n i f i c a n c e . 120  from  The s e p a r a t i o n o f ^0 from  though n o t d i f f i c u l t , c o u l d a l s o be d i s p e n s e d  w i t h , s i n c e the reagents  employed f o r t h e c o n v e r s i o n o f j50 i n t o 124 a r e i d e n t i c a l w i t h  those  r e q u i r e d f o r t h e c o n v e r s i o n o f 120 t o 124 ( s e e Scheme V I I , p 7 3 ) . A t t h i s s t a g e , i n o r d e r t o p r e p a r e an i n t e r m e d i a t e w h i c h would be a p o t e n t i a l s y n t h e t i c p r e c u r s o r f o r stemodin  i t was n e c e s s a r y t o  e f f e c t t h e h y d r o l y s i s and d e c a r b o x y l a t i o n o f t h e e n a m i n o n i t r i l e 124 t o t h e t e t r a c y c l i c k e t o k e t a l 53_ (eq. 64) .  Since the quantity of  (64)  124  enaminonitrile  53  124 a v a i l a b l e a t t h i s s t a g e o f t h e work was r a t h e r l o w ,  i t was r e s o l v e d t h a t t h e p r o c e d u r e most l i k e l y t o succeed would be employed.  Thus, B a l d w i n ' s ^  p r o c e d u r e was employed w i t h t h e f u l l  knowledge t h a t t h e s t r o n g l y a c i d i c c o n d i t i o n s would h y d r o l y z e t h e k e t a l f u n c t i o n a l i t y i n a d d i t i o n to e f f e c t i n g the desired However, e x a m i n a t i o n  transformation.  o f a model o f t h e d i o n e 132 t h a t would be produced  i n d i c a t e d t h a t t h e ketone i n t h e A r i n g was l e s s h i n d e r e d  than the D  r i n g ketone and c o u l d p r o b a b l y be s e l e c t i v e l y r e p r o t e c t e d i n a  79 subsequent s t e p ( e q . 7 1 ) ,  (71)  AM  53  A s o l u t i o n o f the  enaminonitrile  124 i n a m i x t u r e o f g l a c i a l 69  a c e t i c a c i d , w a t e r and 85% p h o s p h o r i c a c i d Work-up, f o l l o w e d tetracyclic  by column chromatography  was r e f l u x e d f o r 24 h. o f t h e crude p r o d u c t gave t h e  d i o n e 132 w h i c h was r e c r y s t a l l i z e d  from ether-hexanes ( e q . 7 2 ) .  (72)  124  132  80 The  c r y s t a l l i n e d i o n e 132 (mp 131 - 133°C) o b t a i n e d  i n 80%  y i e l d showed a s t r o n g band a t 1705 cm ^ i n i t s i r spectrum c h a r a c t e r i s t i c of a six-membered r i n g k e t o n e .  The major f e a t u r e o f t h e ^"H n.m.r.  spectrum o f 132 was a s i n g l e t h r e e - p r o t o n the b r i d g e h e a d m e t h y l group.  s i n g l e t a t <5 1.16 a s s i g n e d t o  The k e t a l p r o t o n resonances were a b s e n t .  Mass s p e c t r a l e v i d e n c e a l s o c o r r o b o r a t e d  the assigned s t r u c t u r e .  W i t h t h e s y n t h e s i s o f t h e t e t r a c y c l i c d i o n e 132, t h e v i a b i l i t y of t h i s s y n t h e t i c a p p r o a c h t o t h e t e t r a c y c l i c d i t e r p e n o i d , stemodin 8_ has been e s t a b l i s h e d .  However, t h e p h o t o a d d i t i o n  56 under t h e c o n d i t i o n s d e s c r i b e d towards a p h i d i c o l i n 1_.  o f a l l e n e t o t h e enone  does n o t appear t o be a v i a b l e r o u t e  The enone 56_ i s a v e r s a t i l e i n t e r m e d i a t e and  o t h e r s y n t h e t i c pathways l e a d i n g t h r o u g h i t t o a p h i d i c o l i n 7_ m i g h t be  possible.  still  81  EXPERIMENTAL General Information. M e l t i n g p o i n t s were determined on a F i s h e r - J o h n s m e l t i n g p o i n t a p p a r a t u s and a r e u n c o r r e c t e d .  D i s t i l l a t i o n temperatures a r e a l s o  u n c o r r e c t e d and r e f e r t o t h e mean a i r b a t h temperature d u r i n g a s h o r t p a t h distillation.  I n f r a r e d ( i r ) s p e c t r a were r e c o r d e d on P e r k i n - E l m e r  model 710 and 710B  i n f r a r e d s p e c t r o p h o t o m e t e r s , as l i q u i d f i l m s o r i n  chloroform solutions.  N u c l e a r magnetic resonance  (^H n.m.r.) s p e c t r a  were o b t a i n e d i n d e u t e r o c h l o r o f o r m s o l u t i o n on V a r i a n T-60, XL-100 s p e c t r o m e t e r s and on a B r u k e r WP-80 s p e c t r o m e t e r .  HA-100 and  Signal positions  a r e g i v e n i n p a r t s per m i l l i o n (6) w i t h t e t r a m e t h y l s i l a n e as an  internal  r e f e r e n c e , and w i t h t h e m u l t i p l i c i t y , number of p r o t o n s , p r o t o n assignments and c o u p l i n g c o n s t a n t s i n d i c a t e d i n p a r e n t h e s e s . g a s - l i q u i d chromatography ( g . l . c . ) was A Gas Chromatography u n i t connected columns used were:  (A)  6 f t x 0.125 6 f t x 0.125  Analytical  done on a H e w l e t t P a c k a r d HP 5832  to a HP 18850 A GC t e r m i n a l .  The  i n . , 5% OV-210 on Chromosorb W  (100 - 200 mesh).  (B)  i n . , 5% OV-17  on Chromosorb W  (100 - 200 mesh).  Column chromatography was performed u s i n g S i l i c a  Gel  60 ( E . Merck, 70 - 230 mesh) and K i e s e l g e l 60 ( E. Merck, 230 - 400 mesh). A n a l y t i c a l t h i n - l a y e r chromatography ( t . l . c . ) was  c a r r i e d out on  commercial, pre-coated S i l i c a Gel p l a t e s w i t h f l u o r e s c e n t i n d i c a t o r (Eastman Kodak, Sheet Type 13181).  V i s u a l i z a t i o n was  effected  either  by i o d i n e v a p o r s t a i n i n g o r w i t h s h o r t - w a v e l e n g t h u l t r a - v i o l e t  light.  The a l u m i n a used i n f i l t r a t i o n columns was n e u t r a l a l u m i n a A c t . I (Alumina Woelm B, A c t . I ) . Low r e s o l u t i o n mass s p e c t r a were r e c o r d e d w i t h a Varian/MAT CH 4 B mass s p e c t r o m e t e r .  H i g h r e s o l u t i o n mass s p e c t r a  82 were r e c o r d e d w i t h a K r a t o s / A E I MS 50 o r a K r a t o s / A E I MS 902 mass spectrometer.  M i c r o a n a l y s e s were performed by Mr. P. B o r d a ,  Laboratory, U n i v e r s i t y of B r i t i s h  Microanalytical  Columbia.  A l l r e a c t i o n s i n v o l v i n g a i r and m o i s t u r e s e n s i t i v e r e a g e n t s were c a r r i e d o u t under an atmosphere o f argon u s i n g e i t h e r oven o r c a r e f u l l y flame-dried glassware.  L i q u i d r e a g e n t s o r s o l u t i o n s were i n t r o d u c e d i n t o  t h e r e a c t i o n f l a s k t h r o u g h a r u b b e r septum hypodermic n e e d l e .  w i t h a s y r i n g e equipped w i t h a  T e t r a h y d r o f u r a n and dimethoxyethane  were d i s t i l l e d  from a r e f l u x i n g s o l u t i o n o f sodium benzophenone k e t y l i n t h e a p p r o p r i a t e s o l v e n t under argon.  Hexamethylphosphoramide was d i s t i l l e d from barium  o x i d e ; d i i s o p r o p y l a m i n e and t r i e t h y l amine from c a l c i u m h y d r i d e . t e t r a c h l o r i d e and d i c h l o r o m e t h a n e were d i s t i l l e d from phosphorus  Carbon pentoxide,  and t e r t - b u t y l a l c o h o l was d i s t i l l e d from a s o l u t i o n o f p o t a s s i u m butoxide i n the alcohol. magnesium methoxide. (Mallinckrodt)  Dry methanol was o b t a i n e d by d i s t i l l a t i o n  Anhydrous e t h e r was o b t a i n e d c o m m e r c i a l l y  and d r y ammonia was d i s t i l l e d from m e t a l l i c  sodium.  tertfrom  83 P r e p a r a t i o n o f D i m e t h y l 2-Ethoxypropenylphosphonate  7_g.  EtO  V=CHPO(XH3)  2  79  To 5.10 g (37.8 mmol) o f n e a t d i m e t h y l  2-oxopropylphosphonate  ( A l d r i c h ) was added 9.0 g (60.8 mmol) o f t r i e t h y l o r t h b f o r m a t e and .-0.20 g of F e C l * 6 H 0 . 3  The m i x t u r e was s t i r r e d b r i e f l y and then a l l o w e d t o s t a n d  2  a t room t e m p e r a t u r e f o r 3 days.  The e x c e s s t r i e t h y l o r t h o f o r m a t e and  v o l a t i l e b y - p r o d u c t s were removed under reduced p r e s s u r e and t h e r e s i d u a l m a t e r i a l was d i s s o l v e d  i n 50 m l o f d r y d i c h l o r o m e t h a n e .  The s o l u t i o n was  t r e a t e d w i t h 0.50 g o f sodium h y d r i d e (washed f r e e o f m i n e r a l o i l w i t h hexane) and t h e r e s u l t a n t m i x t u r e was s t i r r e d  f o r 10 min and then f i l t e r e d .  Removal o f t h e s o l v e n t from t h e f i l t r a t e , f o l l o w e d by b u l b t o b u l b d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 80°C, 0.05 t o r r ) o f t h e r e s i d u a l m a t e r i a l gave 6.89 g (94%) o f t h e e n o l e t h e r 79 a s a c o l o r l e s s ir  (film)  v 1605, 1250, 1050 and 1025 cm" ; H n.m.r., 6 1.33 ( t , 3H, max 1  CH -CH -0, J = 7 H z ) , 2.14 ( d , 3H, CH -C=C, J _ 3  2  3  P0(0CH ) , 3  2  J _ R  p  1H, C=CH=P, J _ R  (100%).  R  1  = 2 H z ) , 3.65 ( d , 6H,  p  = 11 H z ) , 3.77 ( q , 2H, -0-CH -CH , J = 7 H z ) , 4.35 ( d , 2  p  = 7 Hz);  mass spectrum:  E x a c t mass c a l c d . f o r C ^ ^ O ^ P :  r e s o l u t i o n mass s p e c t r o m e t r y ) : 194.0708. C, 43.30;  liquid:  H, 7.79;  found:  C, 43.13;  3  m/e 194 (M+), 179, 166, 151 194.0707; measured ( h i g h A n a l , c a l c d . f o r C^H^O^P:  H, 7.70.  84 P r e p a r a t i o n o f D i m e t h y l 3-Bromo-2-ethoxypropenylphosphonate  31.  EtO \=CHPO^CH ) 3  2  Br—/ 81  To a s o l u t i o n o f t h e e n o l e t h e r 79 (3.0 g , 15.5 mmol) i n 150 mL of d r y c a r b o n t e t r a c h l o r i d e was added 3.10 g (17.4 mmol) o f N-bromosuccinimide. The w e l l s t i r r e d m i x t u r e was r e f l u x e d w h i l e i t was b e i n g i r r a d i a t e d w i t h a sun lamp (Westinghouse, 275 Watt 110-120 V) . r e a c t i o n m i x t u r e was c o o l e d and f i l t e r e d .  A f t e r 15 min, t h e  The f i l t r a t e was c o n c e n t r a t e d  under r e d u c e d p r e s s u r e t o a volume o f a p p r o x i m a t e l y 50 mL, and then was c o o l e d i n an i c e b a t h t o p r e c i p i t a t e r e s i d u a l s u c c i n i m i d e . was f i l t e r e d  The m i x t u r e  t h r o u g h a s m a l l amount o f n e u t r a l a l u m i n a ( A c t . I ) . Removal  of t h e s o l v e n t from t h e f i l t r a t e gave a y e l l o w o i l w h i c h was s u b j e c t e d t o column chromatography  on 160 g o f s i l i c a g e l .  e t h y l a c e t a t e , f o l l o w e d by d i s t i l l a t i o n 0.05  E l u t i o n o f t h e column  with  ( a i r - b a t h t e m p e r a t u r e 110°C,  t o r r ) o f t h e crude o i l thus o b t a i n e d , gave 3.2 g (76%) o f d i m e t h y l  3-bromo-2-ethoxypropenylphosphonate  j$l a s a c o l o r l e s s o i l .  chromatography and t h i n l a y e r chromatography i r (film):  Both g a s - l i q u i d  i n d i c a t e d one p r o d u c t ;  v 1605, 1250 and 1025-1050 c m ; H n.m.r., 6 1.39 ( t , max 3H, CH -CH -0, J = 7 H z ) , 3.76 ( d , 6H, P O ( O C H ) , J _ = 11 H z ) , 3.91 3  (q, J  H—P  - 1  2  3  2  R  p  2H, 0-CH -CH , J = 7 H z ) , 4.42 ( s , 2H, B r - O ^ - ) , 4.57 ( d , 1H, OCH-P, 2  3  = 5 H z ) ; mass spectrum: m/e 274 and 272 (M+).  79 C..H, ,0. B r P: 271.9813; 7 14 4 s p e c t r o m e t r y ) : 271.9815.  for  X  E x a c t mass c a l c d .  measured ( h i g h r e s o l u t i o n mass  85  G e n e r a l P r o c e d u r e f o r t h e A l k y l a t i o n o f Ketones w i t h D i m e t h y l 3-Bromo-2-ethoxypropenylphosphonate  81.  To a c o l d (-78°C), s t i r r e d s o l u t i o n o f 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 t e t r a h y d r o f u r a n , under an atmosphere o f a r g o n , was added t h e a p p r o p r i a t e amount o f t h e k e t o n e .  The c o o l i n g b a t h was removed and t h e r e a c t i o n  m i x t u r e was a l l o w e d t o warm t o 0°C and l e f t a t t h i s temperature f o r 1 h . The r e a c t i o n m i x t u r e was c o o l e d t o -78°C and t h e r e q u i r e d amount o f d i m e t h y l 3-bromo-2-ethoxypropenylphosphonate  81 was added.  After the reaction  m i x t u r e had been s t i r r e d a t -78°C f o r 30 min, a t 0°C f o r 30 min and a t room temperature f o r 30 min, t h e t e t r a h y d r o f u r a n was removed under pressure.  The r e s i d u a l m a t e r i a l was d i s s o l v e d i n methylene  and t h e r e s u l t a n t s o l u t i o n was washed t w i c e w i t h b r i n e .  reduced  chloride  The s o l u t i o n  was d r i e d (^£80^) and t h e s o l v e n t was removed under reduced p r e s s u r e t o give t h e a l k y l a t e d ketone.  P r e p a r a t i o n o f t h e A l k y l a t e d Ketone 83  0 P0(0CH3)  2  The g e n e r a l p r o c e d u r e o u t l i n e d above was employed t o p r e p a r e t h i s compound.  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  cyclohexanone:  98 mg (1 mmol)  lithium diisopropylamide:  128 mg (1.2 mmol)  86 tetrahydrofuran:  2 mL  3-bromo-2-ethoxypropenylphosphonate  (81):  330 mg (1.2 mmol)  F o l l o w i n g t h e u s u a l work-up, r e m o v a l o f t h e s o l v e n t under reduced p r e s s u r e gave 290 mg (100%) o f t h e a l k y l a t e d k e t o n e 83 as a c o l o r l e s s oil.  B o t h g a s - l i q u i d chromatography and t h i n l a y e r chromatography  i n d i c a t e d one pure p r o d u c t :  i r (film):  v m  a  x  1710, 1605, 1250 and  1025 - 1060 cm" ; H n.m.r., <S 1.26 ( t , 3H, OLj-O^-O, J = 7 H z ) , 3.62 1  1  ( d , 6H, P O ( O C H ) , J 3  4.36  2  R  _ = 12 H z ) , 3.72 ( q , 2H, 0-CH -CH , J = 7 H z ) , p  2  ( d , 1H, C=CH-P, J„ _ = 7 H z ) ;  151, ,35 ( 1 0 0 % ) .  3  mass spectrum: m/e 290 (M+) , 244,  E x a c t mass c a l c d . f o r  ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) :  C  H 1 3  2  3°5  P :  290.1283;  measured  290.1301.  P r e p a r a t i o n o f t h e A l k y l a t e d Ketone jj5_  0 P0(0CH )2 3  The g e n e r a l p r o c e d u r e o u t l i n e d above was employed t o p r e p a r e t h i s compound.  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  3-pentanone:  86 mg (1 mmol)  lithium diisopropylamide: tetrahydrofuran:  128 mg (1.2 mmol)  2 mL  3-bromo-2-ethoxypropenylphosphonate  (81):  330 mg (1.2 mmol)  F o l l o w i n g t h e u s u a l work-up, removal o f t h e s o l v e n t under reduced  87 pressure gave a yellow o i l which was d i s t i l l e d ( a i r bath temperature 140°C, 0.05 torr) to give a quantitative y i e l d (278 mg) of the alkylated ketone j$5_ as a colorless o i l .  Both gas-liquid chromatography and thin  layer chromatography indicated one pure product:  i r (film):  v m  a  x  1705,  1605, 1250 and 1025 cm" ; H n.m.r., <5 1.04 ( t , 3H, O^O^CO, J = 7 Hz), 1  1.12  1  (d, 3H, CH -CH-CH , J = 6 Hz), 1.28 ( t , 2H, CH CH -0, J = 7 Hz), 3  2  3  2  2.5 (q, 2H, CH CH CO, J = 7 Hz), 2.66 - 2.98 (m, 3H, CH -CH-CH ), 3.66 3  2  3  2  (d, 6H, PO(OCH ) , J _ = 12 Hz), 3.76 (q, 2H, O^-O^-O, J = 7 Hz), 3  2  R  p  4.39 (d, 1H, OCH-P, J„ _ = 6 Hz); (100%).  Exact mass calcd. f o r  resolution mass spectrometry):  C  H 1 2  mass spectrum: m/e 278 (M+), 221  23°5  P :  2  7  8  -  1  2  8  3  measured (high  5  278.1277.  Preparation of the Alkylated Ketone 87  P0(0CH )2 3  The general procedure outlined above, with a s l i g h t modification, was employed to prepare this compound.  The quantities of materials  used were as follows: 44  ketone j$6  : 198 mg (1 mmol)  l i t h i u m diisopropylamide:  128 mg (.1.2 mmol)  88 tetrahydrofuran:  2 mL  3-bromo-2-ethoxypropenylphosphonate hexamethylphosphoramide:  (81) :  330 mg (1.2 mmol)  179 u L (1 mmol)  The hexamethylphosphoramide was added t o t h e r e a c t i o n m i x t u r e a t -78°C, j u s t p r i o r t o a d d i n g t h e a l k y l a t i n g agent 81^.  Following the  u s u a l work-up, r e m o v a l o f t h e s o l v e n t under reduced p r e s s u r e gave a yellow o i l .  The hexamethylphosphoramide was removed under reduced p r e s s u r e  ( a i r b a t h t e m p e r a t u r e a p p r o x . 100°C, 0.05 t o r r ) and t h e r e s i d u e was chromatographed on 10 g o f s i l i c a g e l . E l u t i o n o f t h e column w i t h e t h y l a c e t a t e y i e l d e d 304 mg (78%) o f t h e a l k y l a t e d k e t o n e 87. as a c o l o r l e s s oil.  B o t h g a s - l i q u i d chromatography and t h i n l a y e r chromatography  i n d i c a t e d one pure p r o d u c t : r  1030 cm" ; ^  6  n.m.r.,  1  i r (film):  r  v 1715, 1610, 1250 and max  0.94, 1.01 ( s , s, 6H, t e r t i a r y m e t h y l s ) , 1.3  ( t , 3H, CH,CH 0, J = 6 H z ) , 3.48 ( s , 4H, k e t a l methylene p r o t o n s ) , 9  3.67 ( d , 6H, P O ( O C H ) , J _ - 11 H z ) , 3.78 ( q , 2H, C H ^ - O , J = 6 H z ) , 3  2  4.43 ( d , 1H, OCH-P, J (100%).  R  p  = 6 Hz);  mass spectrum: m/e 390 (M+), 344  E x a c t mass c a l c d . f o r C ^ H ^ O ^ :  r e s o l u t i o n mass s p e c t r o m e t r y ) :  390.1808;  390.1796.  P r e p a r a t i o n o f t h e A l k y l a t e d Ketone 1Q_  0  57  0  90  measured  (high  89 The g e n e r a l p r o c e d u r e o u t l i n e d above, w i t h a s l i g h t m o d i f i c a t i o n , was employed t o p r e p a r e t h i s compound.  The q u a n t i t i e s o f m a t e r i a l s  used were a s f o l l o w s : ketone J57:  266 mg (1 mmol)  lithium diisopropylamide: tetrahydrofuran:  128 mg (1.2 mmol)  2 mL  3-bromo-2-ethoxypropenylphosphonate hexamethylphosphoramide:  ( 8 1 ) : 330 mg (1.2 mmol)  179 uL ( 1 mmol)  The hexamethylphosphoramide was added t o t h e r e a c t i o n m i x t u r e a t -78°C, j u s t p r i o r t o a d d i n g thfe a l k y l a t i n g agent Jtt.  Following the  u s u a l work-up, r e m o v a l o f t h e s o l v e n t under reduced p r e s s u r e gave a yellow o i l .  The hexamethylphosphoramide was removed under reduced  p r e s s u r e ( a i r b a t h t e m p e r a t u r e approx. 100°C, 0.05 t o r r ) and t h e r e s i d u e was chromatographed on 10 g o f s i l i c a g e l . E l u t i o n o f t h e column w i t h e t h y l a c e t a t e gave 348 mg (76%) o f t h e a l k y l a t e d k e t o n e 90 as a w h i t e solid.  T h i n l a y e r chromatography i n d i c a t e d one pure p r o d u c t .  This m a t e r i a l  was r e c r y s t a l l i z e d from e t h e r - h e x a n e s : mp 99 - 100°C; i r ( C H C l _ ) v 3 max 3  1705, 1610, 1250 and 1030 cm" ; 1  \  n.m.r.,  6 0.93, 1.02, 1.16 ( s , s, s ,  9H, t e r t i a r y m e t h y l s ) , 1.32 ( t , 3H, OLjO^-O, J = 7 H z ) , 3.72 ( d , 6H, P O ( O C H ) , J _ = 12 H z ) , 3.80 ( q , 2H, CH CH -0, J = 7 H z ) , 4.44 ( d , 1H, C=CH-P, J„ _ = 6 H z ) ; mass spectrum: m/e 458 ( M ) , 412, 397, 311. E x a c t H—P 3  2  R  p  3  2  +  mass c a l c d . f o r ^ 2 3 ^ 3 9 ^ 7 spectrometry):  P:  458.2412.  458.2434;. measured  ( h i g h r e s o l u t i o n mass  90 Preparation  o f t h e A l k y l a t e d Ketone j ? j  0 COjMe  CC^Me  P0(0CH )2 3  89  88  The g e n e r a l p r o c e d u r e o u t l i n e d above, w i t h a few m o d i f i c a t i o n s employed t o p r e p a r e t h i s compound.  The q u a n t i t i e s o f m a t e r i a l s  was  used  were as f o l l o w s : 2- carbomethoxycyclohexanone j$8: lithium diisopropylamide: tetrahydrofuran:  156 mg ( 1 mmol)  160 mg (1.5 mmol)  2 mL  3- bromo-2-ethoxypropenylphosphonate hexamethylphosphoramide:  (81):  413 mg (1.5 mmol)  268.5 u L (1.5 mmol)  The hexamethylphosphoramide was added t o t h e r e a c t i o n m i x t u r e a t -78°C, j u s t p r i o r t o a d d i n g t h e a l k y l a t i n g agent 81.  The r e a c t i o n  m i x t u r e was s t i r r e d f o r 30 min a t - 7 8 C , 30 min a t 0°C and 6 h a t room 6  temperature.  U s u a l work-up gave a brown o i l w h i c h was chromatographed  on 10 g o f s i l i c a g e l . E l u t i o n o f t h e column w i t h e t h y l a c e t a t e followed 0.05 oil.  by d i s t i l l a t i o n o f t h e c r u d e p r o d u c t ( a i r b a t h t e m p e r a t u r e 180°C,  t o r r ) gave 247 mg (71 %) o f t h e a l k y l a t e d ketone 89 a s a c o l o r l e s s B o t h g a s - l i q u i d chromatography  i n d i c a t e d one pure p r o d u c t : and 1020 cm 3.37  ;  and t h i n l a y e r  i r (film) :  v  chromatography  1740, 1710, 1610, 1240  H n.m.r., 6 1.28 ( t , 3H, CH -CH -0, J = 7 H z ) , 3.11 and 3  2  ( p a i r o f d o f d, 2H, CH -C=C-P, AB p a i r o f d f u r t h e r c o u p l e d t o  phosphorus,  2  = 16 Hz, J _ A  p  = J _ = 2 H z ) , 3.72 ( d , 6H, P O ( O C H ) , g  p  3  2  91 J _ R  p  = 11 H z ) ;  mass spectrum:  E x a c t mass c a l c d . f o r i 5 5 ° 7 C  H  m/e  348 ( M ) , 317, 302, 194 ( 1 0 0 % ) . +  348.1338; measured ( h i g h r e s o l u t i o n  I > :  2  mass s p e c t r o m e t r y ) : 348.1333.  P r e p a r a t i o n o f t h e D i k e t o Phosphonate Jj3_  93  To a s t i r r e d s o l u t i o n o f 290 mg  (1 mmol) o f t h e a l k y l a t e d ketone j83_  i n 25 mL o f a c e t o n e a t room temperature was added 0.50 mL of 1 N h y d r o c h l o r i c acid.  A f t e r t h e r e s u l t a n t m i x t u r e had been s t i r r e d a t room t e m p e r a t u r e  f o r 30 min, anhydrous p o t a s s i u m b i c a r b o n a t e was added and the a c e t o n e was removed under reduced p r e s s u r e .  Methylene c h l o r i d e was added t o the  r e s i d u e and the o r g a n i c s o l u t i o n was washed t w i c e w i t h s a t u r a t e d p o t a s s i u m b i c a r b o n a t e and d r i e d  (^£20^) .  Removal o f the s o l v e n t and  distillation  ( a i r b a t h t e m p e r a t u r e 180 - 1 8 5 C , 0.02  t o r r ) of the r e s i d u a l o i l gave  262 mg  93 as a c o l o r l e s s o i l .  6  (100%) o f t h e d i k e t o phosphonate  g a s - l i q u i d chromatography product: r  2.75 - 3.5 J  H—P  i r (film):  v  (m, 3H, C-2H  = 12 H z ) ;  c a l c d . f o r Cj_]H spectrometry):  max  and t h i n l a y e r chromatography 1710, 1260, and 1030 cm  and C-3'methylene  mass spectrum: c^^  5  262.0970;  262.0987.  m/e  -1  ;  i n d i c a t e d one pure 1 H n.m.r.,  p r o t o n s ) , 3.72  6  ( d , 6H, P O ( O C H ) ,  262 ( M ) , 244, 166, } 5 1 . +  Both  3  E x a c t mass  measured ( h i g h r e s o l u t i o n mass  2  92 P r e p a r a t i o n o f t h e D i k e t o Phosphonate 94  0  94 To a s t i r r e d s o l u t i o n o f 278 mg ( 1 mmol) o f t h e a l k y l a t e d k e t o n e 85 i n 25 mL o f a c e t o n e a t room t e m p e r a t u r e was added 0.50 mL o f 1 N hydrochloric acid.  A f t e r t h e r e s u l t a n t m i x t u r e had been s t i r r e d a t room  t e m p e r a t u r e f o r 30 min, anhydrous p o t a s s i u m b i c a r b o n a t e was added and t h e a c e t o n e was removed under r e d u c e d p r e s s u r e .  M e t h y l e n e c h l o r i d e was  added t o t h e r e s i d u e and t h e o r g a n i c s o l u t i o n was washed t w i c e w i t h s a t u r a t e d p o t a s s i u m b i c a r b o n a t e and d r i e d ( N a S 0 ^ ) . 2  Removal o f t h e  s o l v e n t a f f o r d e d t h e c r u d e p r o d u c t w h i c h was p u r i f i e d by chromatography on 8 g o f s i l i c a g e l . E l u t i o n o f t h e column w i t h e t h y l a c e t a t e , f o l l o w e d by r e m o v a l o f t h e s o l v e n t (reduced p r e s s u r e ) from t h e a p p r o p r i a t e f r a c t i o n s , gave 250 mg (100%) o f t h e d i k e t o phosphonate j)4 as a c o l o r l e s s oil.  B o t h g a s - l i q u i d chromatography and t h i n l a y e r chromatography  i n d i c a t e d one pure p r o d u c t : *H n.m.r., 6  i r (film):  1710, 1270 and 1040 cm "*";  v m  a  x  1.07 ( t , 3H, CH -CH -CO, J = 8 H z ) , 1.08 ( d , 3H, CHj-CH-CO, 3  2  J = 8 H z ) , 2.4 - 2.88 (m, 3H, O^-O^-CO and O^-CH-CO) , 2.9 - 3.4 (m, 4H, CH.-CO-CHL-P), 3.75 ( d , 6H, P 0 ( 0 C H , ) , J„ Z  2.  J  m/e 250 ( M ) , 232, 194, 193, 151 ( 1 0 0 % ) . +  C  10 19^5^ H  250.0965.  :  250.0970;  measured  o  /  n—r  = H  H z ) ; mass s p e c t r u m :  E x a c t mass c a l c d . f o r  ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) :  93 P r e p a r a t i o n o f t h e D i k e t o Phosphonate  91  0  91 To a s t i r r e d s o l u t i o n o f 195 mg  (0.5 mmol) o f the a l k y l a t e d  k e t o n e 87_ i n 25 mL o f a c e t o n e a t room t e m p e r a t u r e was added 0.5 mL of 0.5 N h y d r o c h l o r i c a c i d .  A f t e r t h e r e a c t i o n m i x t u r e had been s t i r r e d  a t room t e m p e r a t u r e f o r 2 h, anhydrous p o t a s s i u m b i c a r b o n a t e was added and t h e a c e t o n e was removed under reduced p r e s s u r e .  Methylene  chloride  was added to t h e r e s i d u e and t h e o r g a n i c s o l u t i o n was washed t w i c e w i t h s a t u r a t e d p o t a s s i u m b i c a r b o n a t e and d r i e d (Na2S0^).  Removal o f the  s o l v e n t gave t h e crude p r o d u c t w h i c h was p u r i f i e d by chromatography  on  8 g o f s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e , f o l l o w e d by removal of t h e s o l v e n t ( r e d u c e d p r e s s u r e ) from t h e a p p r o p r i a t e f r a c t i o n s gave 167 mg oil.  (92%) o f t h e d i k e t o phosphonate  B o t h g a s - l i q u i d chromatography and t h i n l a y e r  i n d i c a t e d one pure p r o d u c t : n.m.r., 6 0.98, 1.04  i r (film) :  v m f  ,  x  9]± as a c o l o r l e s s chromatography  1710, 1260 and 1025 cm  ( s , s, 6H, t e r t i a r y m e t h y l p r o t o n s ) , 3.4 -  (m, 4H, k e t a l methylene p r o t o n s ) , 3.81  ( d , 6H, P 0 ( 0 C H _ ) , o  J  mass spectrum: C.,H 16  2.1  0 P: I  362.1491.  m/e  362 ( M ) , 305, 259, 219.  362.1494;  +  2  ^; 3.68  J„ _ = 11 H z ) ; n—r  E x a c t mass c a l c d . f o r  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) :  94 P r e p a r a t i o n o f t h e D i k e t o Phosphonate 92  0 P0(XH3)2  92  To a s t i r r e d s o l u t i o n o f 229 mg (0.5 mmol) o f t h e a l k y l a t e d k e t o n e jK) i n 25 mL o f a c e t o n e a t room temperature was added 0.50 mL o f 0.5 N h y d r o c h l o r i c a c i d .  A f t e r t h e r e s u l t a n t m i x t u r e had been s t i r r e d  a t room temperature f o r 15 m i n , anhydrous p o t a s s i u m b i c a r b o n a t e was added and t h e a c e t o n e was removed under reduced p r e s s u r e .  Methylene  c h l o r i d e was added t o t h e r e s i d u e and t h e o r g a n i c s o l u t i o n was washed t w i c e w i t h s a t u r a t e d p o t a s s i u m b i c a r b o n a t e and d r i e d (^£50^) .  Removal  of t h e s o l v e n t gave t h e c r u d e p r o d u c t w h i c h was p u r i f i e d by chromatography on 8 g o f s i l i c a g e l . E l u t i o n o f t h e column w i t h e t h y l a c e t a t e , f o l l o w e d by removal o f t h e s o l v e n t ( r e d u c e d p r e s s u r e ) from t h e a p p r o p r i a t e f r a c t i o n s gave 206 mg (96%) o f t h e d i k e t o phosphonate B o t h g a s - l i q u i d chromatography one pure p r o d u c t :  i r(film):  92_ as a c o l o r l e s s o i l .  and t h i n l a y e r chromatography v m  a  x  indicated  1705, 1260 and 1030 cm ^;  n.m.r.,  6 0.85, 0.96, 1.12, ( s , s, s, 9H, t e r t i a r y m e t h y l p r o t o n s ) , 2.8 - 3.56 (m, 9H, i n c l u d e s k e t a l methylene p r o t o n s ) , 3.72 ( d , 6H, P 0 ( 0 C H ) , 3  J _ R  p  = 12 H z ) ;  mass spectrum:  mass c a l c d . f o r C2^H ^O^P; 3  spectrometry):  430.2114.  m/e 430 ( M ) , 151, 141 ( 1 0 0 % ) .  430.2120;  +  2  Exact  measured ( h i g h r e s o l u t i o n mass  95 G e n e r a l P r o c e d u r e f o r t h e I n t r a m o l e c u l a r Horner-Emmons  Cycllzation  Reaction To a c o l d (0°C), s t i r r e d s u s p e n s i o n of sodium h y d r i d e i n 2 mL of anhydrous dimethoxyethane, under an atmosphere o f argon, was added dropwise a s o l u t i o n o f the d i k e t o phosphonate dimethoxyethane.  i n 1 mL of  anhydrous  A f t e r t h e r e a c t i o n m i x t u r e had been s t i r r e d f o r 30 min  at room t e m p e r a t u r e , i t was warmed t o 65°C and k e p t a t t h a t for  the a p p r o p r i a t e time.  temperature  The r e a c t i o n m i x t u r e was poured i n t o an  aqueous sodium c h l o r i d e s o l u t i o n , and t h e p r o d u c t was e x t r a c t i o n of t h e r e s u l t a n t m i x t u r e w i t h e t h e r . was washed w i t h w a t e r and d r i e d (Na2S0^).  i s o l a t e d by  The combined e t h e r e x t r a c t  Removal o f t h e s o l v e n t under  reduced p r e s s u r e , f o l l o w e d by d i s t i l l a t i o n o r column chromatography the  of  crude p r o d u c t , a f f o r d e d t h e d e s i r e d c y c l o p e n t e n o n e .  P r e p a r a t i o n of the B i c y c l i c Enone 31  97 The g e n e r a l p r o c e d u r e o u t l i n e d above was employed t o p r e p a r e t h i s compound.  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  sodium h y d r i d e :  14 mg  d i k e t o phosphonate  9[3_:  (0.6 mmol) 131 mg  (0.5 mmol)  The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 65°C f o r 1 h, and was  then  96 s u b j e c t e d t o t h e u s u a l work-up.  Removal of t h e s o l v e n t under r e d u c e d 34  p r e s s u r e and d i s t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 45 "C, 0.02 t o r r ; l i t . 59 - 62°C, 0.05 t o r r ) o f t h e r e s i d u e gave 51 mg (74%) o f t h e b i c y c l i c enone 97_ as a c o l o r l e s s l i q u i d . l a y e r chromatography and 1620 cm ^;  B o t h g a s - l i q u i d chromatography  i n d i c a t e d one p u r e p r o d u c t :  i r (film):  n.m.r., 6 5.86 ( s , 1H, o l e f i n i c p r o t o n ) ;  and t h i n 1700  v m  a  x  mass  spectrum:  m/e 136 (M ) , 121, 108, 107.  136.0888;  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 136.0891.  +  E x a c t mass c a l c d . f o r  C  H 9  0 1  :  2  P r e p a r a t i o n o f t h e Enone .9JL  98 The g e n e r a l p r o c e d u r e o u t l i n e d above was employed compound.  t o prepare t h i s  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  sodium h y d r i d e : diketo  14 mg (0.6 mmol)  phosphonate j)4_:  125 mg (0.5 mmol)  The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 65°C f o r 3 h , and then was s u b j e c t e d t o t h e u s u a l work-up.  Removal o f t h e s o l v e n t under reduced  p r e s s u r e and d i s t i l l a t i o n ( a i r b a t h temperature 100°C, 15 t o r r ) o f t h e r e s i d u a l o i l a f f o r d e d 51 mg (82%) of t h e enone j)8 as a c o l o r l e s s ir  (film):  v 1700 and 1610 cm" ; max 1  liquid:  *H n.m.r., 6 1.20 ( t , 3H, CH.-CH -< J /  J * 7 Hz, 1.21 ( d , 3H, CH -CH, J = 7 H z ) , 5.94 ( d , 1H, o l e f i n i c p r o t o n , 3  J •» 2 H z ) ;  mass spectrum: m/e 124 ( M ) , 109, 95. +  E x a c t mass c a l c d .  97 for g i2° C  H  124.0893. H,  :  124.0888; measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : A n a l c a l c d . f o r CgH^O;  C, 77.38, H, 9.74;  found:  C, 77.09,  9.77.  P r e p a r a t i o n of t h e B i c y c l i c Enone 99  99 The g e n e r a l p r o c e d u r e o u t l i n e d above was employed compound.  to prepare t h i s  The q u a n t i t i e s of m a t e r i a l s used were as f o l l o w s :  sodium h y d r i d e :  9 mg  (0.38 mmol)  d i k e t o phosphonate .91:  118 mg  (0.33 mmol)  The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 65°C f o r 3 h and then l e f t a t room t e m p e r a t u r e o v e r n i g h t .  U s u a l work-up and p r o d u c t i s o l a t i o n gave  an o i l w h i c h was chromatographed  on 4 g o f s i l i c a g e l .  E l u t i o n of the  column w i t h e t h y l a c e t a t e gave a y e l l o w s o l i d w h i c h was d i s t i l l e d ( a i r b a t h temperature 155 - 160°C, 0.05  t o r r ) t o y i e l d 56 mg  (72%) o f t h e  b i c y c l i c enone 99_ as a w h i t e s o l i d , w h i c h was c r y s t a l l i z e d from e t h e r hexanes.  B o t h g a s - l i q u i d chromatography  i n d i c a t e d one pure p r o d u c t : 1620 cm ; 1  \. n.m.r., 6 1.00,  and t h i n l a y e r  mp 73 - 74°C; 1.02  i r (film) :  chromatography v m a i i  1700  and  ( s , s, 6H, t e r t i a r y m e t h y l p r o t o n s ) ,  98 3.56  ( s , 4H, k e t a l methylene p r o t o n s ) , 5.91 236 ( M ) , 207, 151.  ( s , 1H, o l e f i n i c p r o t o n ) ; mass  spectrum:  m/e  236.1412;  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 236.1422.  +  E x a c t mass c a l c d . f o r C ^ H ^ O ^ :  P r e p a r a t i o n of t h e T r i c y c l i c Enone 5JL  56  The g e n e r a l p r o c e d u r e o u t l i n e d above was employed compound.  to prepare t h i s  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  sodium h y d r i d e :  9 mg  d i k e t o phosphonate  (0.38 mmol)  92_:  149 mg  (0.035 mmol)  The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 65°C f o r 2 h. work-up a f f o r d e d a y e l l o w s o l i d w h i c h was chromatographed  Usual  on 4 g o f  s i l i c a g e l . E l u t i o n o f the column w i t h e t h y l a c e t a t e / h e x a n e (1:1) gave 92 mg  (86%) o f t h e t r i c y c l i c enone 5j> as a w h i t e s o l i d , w h i c h  recrystallized  from a m i x t u r e o f e t h e r and hexanes.  chromatography  and t h i n l a y e r chromatography  mp 116 - 117°C; e  i r (CHC1-) v 3 max  Both g a s - l i q u i d  i n d i c a t e d one pure p r o d u c t :  1680 and 1610 cm" ;  0.95,.1.09 ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 1.92 J « 18 Hz, J ' = 3 H z ) , 2.54  was  1  1  H n.m.r., 6  0.90,  (d o f d, 1H, C-13 p r o t o n ,  ( d , o f d, 1H, C-13 p r o t o n , J = 18 Hz, J ' = 6 H z ) ,  99 2.94  (m, 1H, C-8 p r o t o n ) , 3.30 - 3.64 (m, 4H, k e t a l methylene  5.76  (m, 1H, o l e f i n i c p r o t o n ) ;  E x a c t mass c a l c d . f o r C^gH^gO^: mass s p e c t r o m e t r y ) :  mass s p e c t r u m : 304.2039;  protons),  m/e 304 ( M ) , 167. +  measured ( h i g h r e s o l u t i o n  304.2029.  P r e p a r a t i o n o f t h e D i k e t o Phosphonate  95 and t h e Carbomethoxy B i c y c l i c  Enone 100  95  100  To a s t i r r e d s o l u t i o n o f 174 mg (0.5 mmol) o f t h e a l k y l a t e d ketone j59_ i n 15 mL o f a c e t o n e a t room t e m p e r a t u r e was added 0.50 mL o f 0.5 N h y d r o c h l o r i c a c i d .  A f t e r t h e r e s u l t a n t m i x t u r e had been s t i r r e d  a t room t e m p e r a t u r e f o r 35 min, anhydrous p o t a s s i u m b i c a r b o n a t e was added and t h e a c e t o n e was removed under r e d u c e d p r e s s u r e .  Methylene  c h l o r i d e was added t o t h e r e s i d u a l m a t e r i a l and t h e o r g a n i c s o l u t i o n was washed t w i c e w i t h s a t u r a t e d p o t a s s i u m b i c a r b o n a t e and d r i e d (Na2S0^). Removal o f t h e s o l v e n t a f f o r d e d t h e crude d i k e t o phosphonate j)5  which  was n o t p u r i f i e d f u r t h e r b u t used d i r e c t l y i n t h e n e x t s t e p . The carbomethoxy  b i c y c l i c enone 100 was p r e p a r e d from t h e c r u d e  d i k e t o phosphonate J?5_ by u s i n g t h e g e n e r a l p r o c e d u r e f o r i n t r a m o l e c u l a r c y c l i z a t i o n s o u t l i n e d above (p  95  ).  The q u a n t i t i e s o f m a t e r i a l s used  100 were as f o l l o w s : sodium h y d r i d e :  14 mg (0.6 mmol)  d i k e t o phosphonate j ) 5 : last  a l l t h e crude m a t e r i a l  i s o l a t e d i n the  step.  The r e a c t i o n m i x t u r e was m a i n t a i n e d a t 65°C f o r 2 h.  U s u a l work-  up, f o l l o w e d by d i s t i l l a t i o n ( a i r b a t h t e m p e r a t u r e 110°C, 0.05 t o r r ) o f t h e crude p r o d u c t gave 68 mg ( 7 0 % , based on 0.5 mmol o f a l k y l a t e d k e t o n e 89) of t h e carbomethoxy b i c y c l i c enone 100 as a c o l o r l e s s o i l .  Both gas-  l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: r  i r(film): v max 1  7  1730, 1710 and 1625 cm" ; ' ' 1  hi n.m.r., 6 2.23  and 2.63 ( d o f d, 2H, C-9 , p r o t o n s , J = 18 H z ) , 3.66 ( s , 3H, 0 C H ) , 5.93 3  ( d , 1H, o l e f i n i c p r o t o n , J = 2 H z ) ; E x a c t mass c a l c d . f o r C ^ H ^ O ^ : mass s p e c t r o m e t r y ) :  mass s p e c t r u m : m/e 194 ( M ) , 162.  194.0944;  +  measured  (high  resolution  194.0944.  P r e p a r a t i o n o f t h e B i c y c l i c Ketone 1QA.  103  104  To a c o l d (-78°C), s t i r r e d s o l u t i o n o f 3 g (0.43 mol) o f l i t h i u m w i r e i n 600 mL o f anhydrous ammonia was added a s o l u t i o n o f 20 g (0.08 mol)  101 o f t h e b i c y c l i c enone 1 0 3  5 1  i n 200 mL o f anhydrous e t h e r and 10 mL 54  (0.10 mol) o f anhydrous t e r t - b u t y l a l c o h o l  .  The c o o l i n g b a t h was  removed and t h e r e a c t i o n m i x t u r e was a l l o w e d t o r e f l u x f o r 1 h.  Solid  ammonium c h l o r i d e was added u n t i l t h e b l u e c o l o r o f t h e s o l u t i o n was discharged.  The ammonia was a l l o w e d t o e v a p o r a t e (warm w a t e r b a t h ) and  e t h e r and w a t e r were added t o t h e r e s i d u e . extracted thoroughly w i t h ether.  The aqueous phase was  The combined o r g a n i c e x t r a c t s were  washed w i t h s a t u r a t e d sodium c h l o r i d e and d r i e d ( N a S 0 ^ ) . 2  The s o l v e n t s  were removed i n vacuo t o y i e l d a y e l l o w o i l w h i c h c r y s t a l l i z e d upon a d d i t i o n o f a few mL o f h i g h b o i l i n g (60 - 100°C) p e t r o l e u m e t h e r .  The  powdery w h i t e c r y s t a l s were r e c r y s t a l l i z e d from hexanes t o g i v e 16.1 g (80%) o f t h e b i c y c l i c k e t o n e 104 .  T h i n l a y e r chromatography i n d i c a t e d  one p u r e p r o d u c t : mp 97 - 99°C ( l i t . mp 98 - 99°C); i r ( n u j o l m u l l ) , v 1715 cm" : "H n.m.r., 6 1.07 ( s , 3H, t e r t i a r y m e t h y l ) , 4.74 (m, 1H, max -0CH0-); mass s p e c t r u m : m/e 266 ( M ) , 182, 165, 85 ( 1 0 0 % ) . E x a c t 5 5  1  3  +  mass c a l c d . f o r C, ,H„,0 : l b 2o 3 spectrometry):  266.1882;  measured ( h i g h r e s o l u t i o n mass  266.1875.  T h i s compound had p r e v i o u s l y been p r e p a r e d i n t h i s l a b o r a t o r y by 25 D.J. H e r b e r t u t i l i z i n g a d i f f e r e n t p r o c e d u r e .  102 P r e p a r a t i o n o f t h e K e t a l Ketone 5J_  0  57  A s o l u t i o n o f 15 g (56 mmol) o f t h e b i c y c l i c k e t o n e 104 and 600 mg o f _p_-toluenesulfonic a c i d i n 500 mL o f methanol was s t i r r e d a t room temperature f o r 3 h. added t o t h e r e s i d u e .  The methanol was removed  i n vacuo and 100 mL o f e t h e r  T h i s e t h e r e a l s o l u t i o n was washed w i t h aqueous  sodium b i c a r b o n a t e and b r i n e p r i o r t o b e i n g d r i e d (^£20^) .  Removal o f  t h e e t h e r i n vacuo gave a gummy w h i t e s o l i d w h i c h was d i s s o l v e d i n 500 mL o f benzene.  To t h i s s o l u t i o n was added 18.7 g (180 mmol) o f 2 , 2 - d i m e t h y l -  1 , 3 - p r o p a n e d i o l and 200 mg o f j > - t o l u e n e s u l f o n i c a c i d , and t h e r e s u l t i n g m i x t u r e was r e f l u x e d f o r 2 h under an atmosphere o f a r g o n u s i n g a DeanS t a r k t r a p t o remove t h e w a t e r produced.  The m i x t u r e was c o o l e d and  t h e n d i l u t e d w i t h 200 mL o f e t h e r and s u c c e s s i v e l y washed 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 a t e r and b r i n e .  The o r g a n i c phase was  d r i e d (Na2S0^) and t h e s o l v e n t s removed i n vacuo t o y i e l d a l i g h t solid.  yellow  T h i s was d i s s o l v e d i n 100 mL o f d r y m e t h y l e n e c h l o r i d e and t h e  r e s u l t i n g s o l u t i o n was c a r e f u l l y added t o a s u s p e n s i o n o f 23.6 g (110 mmol) o f p y r i d i n i u m chlorochrornate"*^ and 1.6 g (21.4 mmol) o f sodium a c e t a t e i n 100 mL o f d r y m e t h y l e n e c h l o r i d e .  The r e s u l t i n g m i x t u r e was s t i r r e d  a t room t e m p e r a t u r e f o r 3h h a f t e r w h i c h 100 mL o f anhydrous e t h e r was  103 added and t h e e n s u i n g s o l u t i o n was passed through a s h o r t column o f n e u t r a l a l u m i n a ( a c t i v i t y I ) . The column was f l u s h e d w i t h s e v e r a l p o r t i o n s o f e t h e r and t h e combined e l u e n t s were c o n c e n t r a t e d .  The r e s i d u e was  r e c r y s t a l l i z e d from a m i x t u r e o f e t h e r and hexanes t o g i v e 12 g ( 8 0 % from 104) o f t h e b i c y c l i c k e t o k e t a l 57*: mp 68 - 70°C ( l i t . 72°C);  i r (CHC1,), J  v  1705 c m ; - 1  X  2 5  mp 6 8 -  H n.m.r., 6 0.89, 1.02, 1.12  max  ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.30 - 3.70 (m, 4H, m e t h y l e n e p r o t o n s ) ; mass spectrum:  m/e 266 ( M ) . E x a c t mass c a l c d . f o r C.,H_,0_: +  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : for C  1 6  H  2 6  0 : 3  C, 72.14, H. 9.84;  found:  P r e p a r a t i o n o f t h e Photoadducts A and B  266.1881.  266.1881;  Anal, calcd.  C, 71.95, H, 9.94.  +  61 (A)  109 =B  T h i s compound had p r e v i o u s l y been p r e p a r e d i n t h i s l a b o r a t o r y by D.J. H e r b e r t u t i l i z i n g s i m i l a r  25 procedures  The photoadducts A and B were p r e v i o u s l y p r e p a r e d i n t h i s l a b o r a t o r y 25 (by a s i m i l a r p r o c e d u r e ) by D.J. H e r b e r t  104 A c o l d (-78°C) s o l u t i o n o f 1.0 g (3.29 mmol) o f t h e t r i c y c l i c enone 5_6 and 10 mL o f a l l e n e i n 60 mL o f d r y , deoxygenated  tetrahydrofuran,  c o n t a i n e d i n a p y r e x tube under n i t r o g e n , was i r r a d i a t e d (450 Watt H a n o v i a lamp) f o r 4.5 h.  The r e a c t i o n m i x t u r e was t r a n s f e r r e d t o a  l a r g e beaker and a l l o w e d t o warm t o room t e m p e r a t u r e . removed and t h e r e s u l t i n g o i l  was s u b j e c t e d t o f l a s h  ( s i l i c a g e l ; 25 x 4 cm column).  The s o l v e n t s were chromatography  E l u t i o n o f t h e column w i t h a 10:5:1  m i x t u r e o f c y c l o h e x a n e , hexane and e t h y l a c e t a t e gave a w h i t e s o l i d w h i c h was r e c r y s t a l l i z e d from ether-hexane t o g i v e 437 mg (39%) o f t h e photoadduct 61 ( A ) . mp 134 - 135°C ( l i t .  T h i n l a y e r chromatography 2 5  r  1670 cm" ; 1  mp 134 - 135°C); c  i n d i c a t e d one p r o d u c t :  i r (CHC1-), v 3 max  1725 and  " S i n.m.r., 6 0.88, 0.95, 0.97 ( s , s, s, 9H, t e r t i a r y m e t h y l s ) ,  3.29 ( s , 1H, C - l l  p r o t o n ) , 3.45 - 3.69 (m, 4H, k e t a l methylene  4.82, 4.97 (m, m, 2H, o l e f i n i c p r o t o n s ) ; E x a c t mass c a l c d . f o r ^22^32^3  !  mass s p e c t r u m :  344.2351;  protons),  m/e 344 ( M ) . +  measured ( h i g h r e s o l u t i o n  mass s p e c t r o m e t r y ) : 344.2349. F u r t h e r e l u t i o n o f t h e column w i t h t h e same e l u e n t gave t h e i s o m e r i c photoadduct 109 (B) w h i c h on r e c r y s t a l l i z a t i o n from ether-hexanes y i e l d e d 473 mg ( 4 2 % ) .  T h i n l a y e r chromatography  mp 131 - 134°C ( l i t .  mp 132 - 134°C);  r  1670 cm" ; 1  2.78 (broad  ^  2 5  r  i n d i c a t e d one p r o d u c t :  i r (CHC1-), v 3 max  1725 and  n.m.r., 6 0.90, 0.95, 1.00 ( s , s, s, 9H, t e r t i a r y m e t h y l s ) ,  s , 2H, u n a s s i g n e d ) , 3.12 (m, 1H, C - l l  p r o t o n ) , 3.48 - 3.60  (m, 4H, k e t a l methylene p r o t o n s ) , 4.80, 4.94 (m, m, 2H, o l e f i n i c mass spectrum:  m/e 344 ( M ) . E x a c t mass c a l c d . f o r ^2^32^3 • +  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 344.2349.  protons);  344.2351;  105 P r e p a r a t i o n o f t h e T r i c y c l i c Keto E s t e r 55  55 A.  By O z o n o l y s i s  o f t h e Photoadduct A  61 (A) A c o l d (-78°C), s t i r r e d s o l u t i o n o f 295 mg (0.86 mmol) o f t h e photoadduct j61 (A) i n 50 mL o f methanol was s u b j e c t e d t o a s t r e a m o f ozone u n t i l t h e s o l u t i o n remained b l u e .  W h i l e s t i l l a t -78°C, t h e  r e s u l t i n g s o l u t i o n was f l u s h e d w i t h argon u n t i l t h e b l u e c o l o r d i s a p p e a r e d and 100 y L (1.36 mmol) o f d i m e t h y l s u l f i d e was added.  The r e a c t i o n  m i x t u r e was s t i r r e d a t -78°C f o r 15 m i n , -15°C f o r 30 min, 0°C f o r 30 min and a t room t e m p e r a t u r e f o r 1 h.  The methanol was removed under reduced  p r e s s u r e and t h e r e s i d u e was k e p t under reduced p r e s s u r e (vacuum pump) f o r 1 h.  The r e s i d u e was d i s s o l v e d i n 30 mL o f d r y methanol and a  s o l u t i o n o f 51 mg (0.94 mmol) o f sodium methoxide i n 20 mL o f d r y methanol was added.  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 a t room t e m p e r a t u r e f o r  106 1 h.  The methanol was removed under reduced p r e s s u r e and e t h e r and water  were added t o t h e r e s i d u e .  A f t e r e x t r a c t i o n , t h e e t h e r l a y e r was washed  w i t h w a t e r and d r i e d (^£50^).  Removal o f t h e s o l v e n t gave a c o l o r l e s s  o i l w h i c h c r y s t a l l i z e d upon a d d i t i o n o f a few drops o f m e t h a n o l .  Re-  c r y s t a l l i z a t i o n from methanol gave 285 mg (88%) o f t h e t r i c y c l i c k e t o e s t e r 55 a s w h i t e n e e d l e s . product:  mp 139 - 140°C;  T h i n l a y e r chromatography i r (CHCl ) , v  i n d i c a t e d one pure  1720 - 1740 cm"  1  (broad);  hi n.m.r., 6 0.93, 1.01, 1.04 ( s , s, s , 9H, t e r t i a r y m e t h y l s ) , 3.52 (m, 4H, k e t a l methylene p r o t o n s ) , 3.66 ( s , 3H, OCHg); 378 ( M ) , 305, 219, 167, 141 ( 1 0 0 % ) . +  378.2406;  6.  mass s p e c t r u m :  m/e  E x a c t mass c a l c d . f o r C ^ H ^ O ^  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 378.2408.  By O z o n o l y s i s o f t h e Photoadduct B  108  109HB  The p r o c e d u r e d e s c r i b e d i n s e c t i o n A, above, was used t o p r e p a r e t h e t r i c y c l i c k e t o e s t e r 55 from t h e photoadduct B. m a t e r i a l s used were t h e same.  The q u a n t i t i e s o f  The i s o l a t e d c r u d e p r o d u c t was r e c r y s t a l l i z e d  from methanol t o g i v e 227 mg (70%) o f t h e t r i c y c l i c k e t o e s t e r 55 a s white needles.  T h i n l a y e r chromatography  i n d i c a t e d one p u r e p r o d u c t .  A l l s p e c t r a l d a t a matched t h o s e g i v e n i n s e c t i o n A, above.  In addition,  107 m e l t i n g p o i n t and mixed m e l t i n g p o i n t d e t e r m i n a t i o n gave i d e n t i c a l v a l u e s to t h a t o b t a i n e d i n S e c t i o n A.  The aqueous washings from t h e work-up  s t e p were combined and a c i d i f i e d w i t h 1 N h y d r o c h l o r i c a c i d . r e s u l t a n t s o l u t i o n was  e x t r a c t e d s u c c e s s i v e l y w i t h e t h e r and the combined  e t h e r e x t r a c t s were d r i e d (Na2S0^). reduced p r e s s u r e gave 63 mg w h i t e powdery c r y s t a l s . product: 1735  mp  and 1700  m e t h y l s ) , 3.5 m/e  364  (M ) . +  -1  1  E v a p o r a t i o n o f t h e e t h e r under  (20%) o f t h e t r i c y c l i c k e t o a c i d 108  i r (CHC1-), v 2600 - 3300 c m 3 max  H n.m.r., 6 0.93,  1.07  E x a c t mass c a l c d . f o r ^21^32^5  :  (broad),  -1  ( s , s, s, 9H,  tertiary  mass spectrum:  364.2250;  measured  364.2226.  By O z o n o l y s i s o f a M i x t u r e of t h e P h o t o a d d u c t s A and B An a p p r o x i m a t e l y  was  1.0,  (broad d, 4H, k e t a l methylene p r o t o n s ) ;  ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : C.  as  T h i n l a y e r chromatography i n d i c a t e d one p u r e  214 - 215°C; cm ;  The  1:1 m i x t u r e of 295 mg o f t h e photoadduct A and  s u b j e c t e d t o t h e same c o n d i t i o n s as o u t l i n e d i n s e c t i o n A, above.  q u a n t i t i e s o f m a t e r i a l s used were t h e same. r e c r y s t a l l i z e d from methanol to g i v e 178 mg e s t e r 5f> as w h i t e n e e d l e s . product.  The crude p r o d u c t  B The  was  (55%) o f t h e t r i c y c l i c  keto  T h i n l a y e r chromatography i n d i c a t e d one  pure  A l l s p e c t r a l d a t a matched those g i v e n i n s e c t i o n A, above.  The aqueous washings from t h e work-up s t e p were combined and with 1 N hydrochloric acid.  acidified  The r e s u l t a n t s o l u t i o n was e x t r a c t e d  s u c c e s s i v e l y w i t h e t h e r and t h e combined e t h e r l a y e r s were d r i e d (^£50^) . E v a p o r a t i o n o f t h e e t h e r under reduced  p r e s s u r e gave 94 mg  t r i c y c l i c k e t o a c i d 108 as w h i t e powdery c r y s t a l s . i n d i c a t e d one pure p r o d u c t .  (30%) of t h e  T h i n l a y e r chromatography  A l l s p e c t r a l d a t a matched those g i v e n i n  108 s e c t i o n B, above.  D.  By E s t e r i f i c a t i o n  of t h e T r i c y c l i c K e t o A c i d 1D_8_  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 a p p r o x i m a t e l y 23.1 mg mmol) o f d i a z o m e t h a n e of 20 mg  71  (0.55  i n 20 mL o f e t h e r was added dropwise a s o l u t i o n  (55 u mol) o f t h e t r i c y c l i c k e t o a c i d 108 i n 3 mL of e t h e r .  A f t e r the s o l u t i o n had been s t i r r e d a t 0"C  f o r 30 m i n , argon was  through the s o l u t i o n to get r i d o f t h e e x c e s s diazomethane.  Evaporation  of t h e e t h e r under reduced p r e s s u r e , f o l l o w e d by r e c r y s t a l l i z a t i o n crude p r o d u c t from methanol gave 18.7 mg 55 as w h i t e n e e d l e s .  bubbled  of the  (90%) o f t h e t r i c y c l i c k e t o  ester  T h i n l a y e r chromatography i n d i c a t e d one p u r e p r o d u c t .  A l l s p e c t r a l d a t a matched those g i v e n i n s e c t i o n A, above.  R e d u c t i o n o f t h e T r i c y c l i c Keto E s t e r 5_5_  55  109  A.  W i t h Sodium  Borohydrlde  60  120  To a s t i r r e d s o l u t i o n of 240 mg  (0.63 mmol) o f t h e t r i c y c l i c  e s t e r 5_5 i n 25 mL o f methanol a t room temperature of s o l i d sodium b o r o h y d r i d e . a t room temperature pressure.  E t h e r was  was  removed under  on 10 g o f s i l i c a g e l .  The e t h e r e x t r a c t was  dried (Na S0^).  chromatographed  (49%) o f t h e l a c t o n e 120.  1115,  1100  cm" ; 1  ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.5  p r o t o n s ) , 4.78  (m, 1H, -CH-0C0);  H, 9.26;  found:  *H n.m.r., 6 —  This  C  H 2 1  3  0 2  4  348.2304.  C, 71.97;  H,  :  0.88,  (m, 4H, k e t a l methylene  mass spectrum: m/e  E x a c t mass c a l c d . f o r  r e s o l u t i o n mass s p e c t r o m e t r y ) : C, 72.38;  Removal  2  r e c r y s t a l l i z e d f r o m methanol to g i v e an a n a l y t i c a l sample:  mp 194°C; i r (CHC1„), v 1730, ' 3_ max  141 ( 1 0 0 % ) .  was  E l u t i o n o f t h e column w i t h a 4:1 m i x t u r e o f  m e t h y l e n e c h l o r i d e and e t h e r gave 108 mg  1.0  reduced  added t o t h e r e s i d u e and t h e r e s u l t a n t m i x t u r e  o f t h e e t h e r i n vacuo gave a c o l o r l e s s o i l , w h i c h was  0.92,  (5 mmol)  A f t e r t h e r e a c t i o n m i x t u r e had been s t i r r e d  f o r 30 min, t h e methanol was  washed t w i c e w i t h w a t e r .  m a t e r i a l was  added 190 mg  keto  348  348.2301;  ( M ) , 167,  154,  +  measured ( h i g h  Anal, calcd. for - l 3 2 ^ 4 <  H  :  2  8.95.  F u r t h e r e l u t i o n of t h e column w i t h t h e same s o l v e n t m i x t u r e gave 121 mg  (50%) of t h e compound ^0 as a v e r y v i s c o u s , c o l o r l e s s o i l .  l a y e r chromatography i n d i c a t e d one p u r e p r o d u c t :  i r (CHC1,),  v  Thin  110 3300 - 3500, ( b r o a d ) , 1725, t e r t i a r y m e t h y l ) , 0.99  ( s , 6H,  methylene p r o t o n s ) , 3.65 spectrum: m/e 380.2562;  B.  380  .1115 and 1095  (M ), +  -1 cm" ;  1-  1  n.m.r., S 0.95  t e r t i a r y m e t h y l s ) , 3.58  ( s , 3H, 167, 141  0-CH ), 4.54 (100%).  (broad d, 4H,  (m, 1H, -CH-OH);  3  ( s , 3H,  E x a c t mass c a l c d . f o r  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) :  ketal  mass C  2 36°5 H  2  :  380.2561.  W i t h L i t h i u m T r i - s e c - b u t y l b o r o h y d r i d e (L-Selectride™) To a c o l d (-78°C), s t i r r e d s o l u t i o n o f 25 mg  (66 y mol)  of  the  t r i c y c l i c k e t o e s t e r _5_5 i n 5 mL o f anhydrous t e t r a h y d r o f u r a n was added TM d r o p w i s e 100 yL  o f a 1 M s o l u t i o n (100 y mol)  in tetrahydrofuran. a f t e r w h i c h 1 mL  The r e a c t i o n m i x t u r e was  of L - S e l e c t r i d e  (Aldrich)  s t i r r e d a t -78°C f o r 3 h,  o f w a t e r , 100 y L o f 1 M aqueous sodium h y d r i d e ,  25 y L o f 30% hydrogen p e r o x i d e were added c o n s e c u t i v e l y . m i x t u r e had been s t i r r e d a t room temperature f o r 15 min, thoroughly w i t h ether.  and  A f t e r the r e s u l t a n t i t was  extracted  The combined o r g a n i c e x t r a c t was washed w i t h w a t e r  and d r i e d over anhydrous sodium s u l f a t e . gave a c o l o r l e s s o i l w h i c h was  Evaporation  of t h e s o l v e n t  chromatographed on 1 g o f s i l i c a g e l .  E l u t i o n o f t h e column w i t h a 4:1 m i x t u r e o f methylene c h l o r i d e - e t h e r gave 5.3 mg  (23%)  of t h e l a c t o n e 120 and 18.6  mg  (74%) o f t h e compound 60_.  A l l s p e c t r a l d a t a f o r t h e two compounds were i d e n t i c a l w i t h those i n s e c t i o n A, above.  given  Ill P r e p a r a t i o n o f t h e T r i c y c l i c D i o l 129  129 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 13.3 mg (0.35 mmol) o f l i t h i u m aluminum h y d r i d e i n 5 mL of anhydrous t e t r a h y d r o f u r a n was added a s o l u t i o n of 50 mg (0.14 mmol) o f t h e l a c t o n e 120 i n 5 mL o f anhydrous t e t r a h y d r o furan.  The r e a c t i o n m i x t u r e was s t i r r e d v i g o r o u s l y and r e f l u x e d f o r 2.5 h.  The e x c e s s l i t h i u m aluminum h y d r i d e was d e s t r o y e d by c a r e f u l a d d i t i o n o f s o l i d Na S0^.10H 0. 2  2  The s o l u t i o n was f i l t e r e d and t h e c o l l e c t e d s a l t s  were washed t h o r o u g h l y w i t h e t h e r .  Removal o f t h e s o l v e n t from t h e  combined f i l t r a t e gave a w h i t e powder.  T h i s m a t e r i a l was  recrystallized  from methanol t o g i v e 50 mg (99%) of t h e t r i c y c l i c d i o l 129 as f i n e w h i t e powdery c r y s t a l s . product: r  mp 180 - 182°C; r  and 1100 cm"  ;  T h i n l a y e r chromatography i n d i c a t e d one p u r e i r (CHCl,); 3_  v max  3200 - 3500 ( b r o a d ) , '  H n.m.r., 6 0.93 ( s , 6H, t e r t i a r y m e t h y l s ) , 1.00 ( s ,  3H, t e r t i a r y m e t h y l ) 3.51 (broad s, 4H, k e t a l methylene p r o t o n s ) , ( t , 2H, -CH 0H, J = 7 l z ) , 4.55 2  352 ( M ) . +  1120  (m, 1H, -CHOH);  E x a c t mass c a l c d . f o r C .H ,0.: z i JO  r e s o l u t i o n mass s p e c t r o m e t r y ) :  o  o  352.2623.  mass s p e c t r u m :  352.2613;  3.8 m/e  measured ( h i g h  112 Preparation of the T r i c y c l i c  Diol  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 14.4 mg (0.38 mmol) o f l i t h i u m aluminum h y d r i d e i n 3 mL o f anhydrous e t h e r was added a s o l u t i o n o f 57 mg (0.15 mmol) o f t h e e s t e r 6_0_ i n 3 mL o f anhydrous e t h e r .  The r e a c t i o n  m i x t u r e was s t i r r e d v i g o r o u s l y f o r 15 min a t 0°C and f o r 30 m i n a t room temperature.  The excess l i t h i u m aluminum h y d r i d e was d e s t r o y e d by  c a r e f u l a d d i t i o n o f s o l i d Na„S0..10H_0. 2 4 2  The s o l u t i o n was f i l t e r e d and  the c o l l e c t e d s a l t s were washed t h o r o u g h l y w i t h e t h e r .  Removal o f t h e  s o l v e n t from t h e combined f i l t r a t e gave 53 mg (100%) o f t h e t r i c y c l i c d i o l 5_9 a s a c o l o r l e s s o i l . product:  i r (CHC1-);  v  T h i n l a y e r chromatography i n d i c a t e d one p u r e 3200 - 3600 ( b r o a d ) , 1120 and 1100 c m ; - 1  n.m.r., 6 0.94 ( s , 3H, t e r t i a r y m e t h y l ) , 0.96 ( s , 6H, t e r t i a r y m e t h y l s ) , 3.52  (broad d, 4H, k e t a l m e t h y l e n e p r o t o n s ) , 3.7 ( t , 2H, -CH^OH, J = 8 H z ) ,  4.54 (m, 1H, -CH0H); mass spectrum: m/e 352 ( M ) . E x a c t mass c a l c d . f o r C_.H 0 : 352.2613; measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 21 36 4 +  352.2613.  113 P r e p a r a t i o n o f t h e T r i c y c l i c D i m e s y l a t e 130  To a w e l l s t i r r e d s o l u t i o n o f 50 mg (0.14 mmol) o f t h e t r i c y c l i c d i o l 129 i n 10 mL o f d r y p y r i d i n e was added 54 y L (0.70 mmol) o f methanesulfonyl chloride.  The r e a c t i o n m i x t u r e was s t i r r e d a t room temperature  o v e r n i g h t a f t e r w h i c h I t was poured onto 10 g o f c r u s h e d i c e . The r e s u l t a n t m i x t u r e was e x t r a c t e d w i t h e t h e r and t h e combined e t h e r e x t r a c t s were d r i e d ( N a S 0 ) . 2  4  Removal o f t h e s o l v e n t i n vacuo gave a  y e l l o w o i l w h i c h was chromatographed on 2 g o f s i l i c a g e l . the  E l u t i o n of  column w i t h a 9:1 m i x t u r e o f methylene c h l o r i d e - e t h e r gave 68.5 mg  (95%) o f t h e t r i c y c l i c d i m e s y l a t e 130 as a l i g h t y e l l o w o i l . chromatography and 1175 cm" ; 1  i n d i c a t e d one pure p r o d u c t : i r ( C H C l ^ ) ;  v m  a  x  Thin l a y e r  1350, 1330  " S i n.m.r., 6 0.93, 0.97, 1.01 ( s , s, s, 9H, t e r t i a r y  m e t h y l s ) , 3,02, 3.03 ( s , s, 6H, C H S 0 ~ ) , 3.5 (m, 4H, k e t a l 3  2  methylene  p r o t o n s ) , 4.4 ( t , 2H, -CH^-OMs, J = 9 H z ) , 5.3 (m, 1H, -CH-OMs);  mass  spectrum:  m/e 508 ( M ) , 412, 316.  508.2165;  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 508.2167.  +  E x a c t mass c a l c d . f o r ^ 2 3 4 0 ^ 8 ^ 2 H  :  114 P r e p a r a t i o n of t h e T r i c y c l i c D i m e s y l a t e 5Jt  Ms( -OMs  54 T h i s compound was p r e p a r e d from t h e t r i c y c l i c d i o l 5_9_, by a p r o c e d u r e i d e n t i c a l w i t h t h a t used f o r t h e p r e p a r a t i o n of t r i c y c l i c d i m e s y l a t e 130. The q u a n t i t i e s of m a t e r i a l s used were t h e same.  The y i e l d o f t h e  t r i c y c l i c d i m e s y l a t e _54_ ( a l i g h t y e l l o w o i l ) , a f t e r column of t h e c r u d e p r o d u c t , was 57.7 mg  (80%).  Thin layer  chromatography  i n d i c a t e d one p u r e p r o d u c t :  i r (CHC1-); 3  \L  ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.01,  r  v  n.m.r., 6 0.93, 0.94,  1.0  v  chromatography  max  1360, 1340 and 1170  ( s , s, 6H, C H - S 0 - ) , 3.5  (m, 4H, k e t a l methylene p r o t o n s ) , 4.3  -CH -0Ms, J = 9 H z ) , 5.28  (m, 1H, -CH-OMs) ;  3  2  412, 316.  2  E x a c t mass c a l c d . f o r 2 3 4 o ° 8 2 C  H  S  r e s o l u t i o n mass s p e c t r o m e t r y ) : 508.2160.  Preparation of the T r i c y c l i c D i n i t r i l e  HI  :  mass s p e c t r u m : 5 0 8  -  2 1 6 5  5  m/e  cm 3.04  ( t , 2H, 508  measured ( h i g h  (M ), +  115 To a s t i r r e d s o l u t i o n o f 30 mg  (59 u mol) o f t h e t r i c y c l i c  d i m e s y l a t e 130 i n 3 mL o f hexamethylphosphoramide  a t room t e m p e r a t u r e ,  was added s o l i d sodium c y a n i d e u n t i l an e x c e s s of t h e s o l i d was undissolved.  left  The r e a c t i o n m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r  3 h and then m a i n t a i n e d a t 60°C f o r 48 h.  E t h e r was added and t h e  o r g a n i c l a y e r was washed once w i t h w a t e r and t w i c e w i t h a s a t u r a t e d s o l u t i o n o f copper s u l f a t e , and t h e n d r i e d ( N a S 0 ^ ) .  Removal of the e t h e r  2  gave a y e l l o w o i l w h i c h was chromatographed of  on 1 g of s i l i c a g e l .  Elution  t h e column w i t h a 3:1 m i x t u r e o f h e x a n e s - e t h y l a c e t a t e gave a w h i t e  c r y s t a l l i n e s o l i d , w h i c h was r e c r y s t a l l i z e d mg  (65%) o f t h e t r i c y c l i c d i n i t r i l e .  i n d i c a t e d one pure p r o d u c t : cm" ; 1  *H n.m.r.,  6 0.95  t e r t i a r y m e t h y l ) , 2.95 protons);  194°C;  N  m/e :  14.2  chromatography  i r (CHCl,); 3  (m, 1H, -CH-CN), 3.5  mass c a l c d . f o r ^ 2 3 3 4 2 ^ 2 spectrometry):  Thin layer  v  ; 2240 and 2230 max  ( s , 6H, t e r t i a r y m e t h y l s ) , 0.97  mass spectrum: H  mp  from methanol t o g i v e  ( s , 3H,  ( b r o a d s, 4H, k e t a l  methylene  370 ( M ) , 285, 195, 167, 141 ( 1 0 0 % ) . +  370.2620;  measured ( h i g h r e s o l u t i o n mass  370.2618.  P r e p a r a t i o n o f the T r i c y c l i c D i n i t r i l e 123  123  Exact  116 T h i s compound was p r e p a r e d from t h e t r i c y c l i c d i m e s y l a t e j>4_ by a p r o c e d u r e i d e n t i c a l w i t h t h a t used f o r the p r e p a r a t i o n o f t h e  tricyclic  d i n i t r i l e 131.  As b e f o r e ,  The q u a n t i t i e s o f m a t e r i a l s used were t h e same.  column chromatography,  f o l l o w e d by r e c r y s t a l l i z a t i o n o f the crude p r o d u c t  from methanol, gave 13.1 mg crystalline solid. mp 159 - 161°C; 0.98,  1.01  T h i n l a y e r chromatography  i r (CHC1_); 3  v  i n d i c a t e d one pure p r o d u c t : \l  2240 and 2230 cm" ; 1  max  mass spectrum:  E x a c t mass c a l c d . f o r  n.m.r.,  6  0.91,  '  ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.03  k e t a l methylene p r o t o n s ) ; 141 ( 1 0 0 % ) .  (60%) o f t h e t r i c y c l i c d i n i t r i l e 123 as a w h i t e  C  H 2 3  3  4  m/e  N 2  °  : 2  (m, 1H, -CH-CN), 3.5  (m,  4H,  370 ( M ) , 285, 195, 167, +  3 ?  0.2620;  measured ( h i g h  r e s o l u t i o n mass s p e c t r o m e t r y ) : 370.2611. P r e p a r a t i o n of the T e t r a c y c l i c  E n a m i m m i t r i l e .124..  124  A.  From t h e T r i c y c l i c D i n i t r i l e 123. To a s t i r r e d s o l u t i o n o f 20 mg  123 i n 1 mL  dinitrile  o f t e r t - b u t y l a l c o h o l under a r g o n , was added a C a t a l y t i c  of p o t a s s i u m t e r t - b u t o x i d e ( A l d r i c h ) . for  (54 u mol) o f t h e t r i c y c l i c  The r e a c t i o n m i x t u r e was  quantity  refluxed  30 h a f t e r w h i c h t h e t e r t - b u t y l a l c o h o l was removed i n vacuo.  Ether  117 and water were added and t h e e t h e r e x t r a c t was d r i e d (^£50^) and c o n c e n t r a t e d t o g i v e a c o l o r l e s s o i l w h i c h c r y s t a l l i z e d upon a d d i t i o n o f a few drops o f methanol.  T h i s m a t e r i a l was r e c r y s t a l l i z e d from methanol  to g i v e 18 mg (90%) o f t h e t e t r a c y c l i c needles.  T h i n l a y e r chromatography i n d i c a t e d one p u r e p r o d u c t :  215°C; i r ( C H C l . ) ; 3 6  v  3490, 3390, 2165, 1642 and 1605 cm" ; ' 1  max  mp 213 h  n.m.r. ,  0.90, 0.92, 1.01 ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.52 (m, 4H, k e t a l  methylene p r o t o n s ) , 4.23 (broad s, 2H, E x a c t mass c a l c d . f o r ^23^34^2^2* mass s p e c t r o m e t r y ) :  B.  e n a m i n o n i t r i l e 124 as w h i t e  The t e t r a c y c l i c  mass spectrum: m/e 370 ( M ) . +  measured ( h i g h r e s o l u t i o n  131  e n a m i n o n i t r i l e 124 was p r e p a r e d  d i n i t r i l e 131 by a p r o c e d u r e  tricyclic  370.2620;  ;  370.2613.  From t h e T r i c y c l i c D i n i t r i l e  i n s e c t i o n A, above.  -NILp  from t h e t r i c y c l i c  i d e n t i c a l w i t h t h a t employed as d e s c r i b e d  The q u a n t i t i e s o f m a t e r i a l s used were as f o l l o w s :  d i n i t r i l e 131: 5 mg (13.5 u mol)  tert-butyl alcohol:  0.5 mL  The crude p r o d u c t was o b t a i n e d i n 8 1 % y i e l d and a l l s p e c t r a l corresponded  t o those o b t a i n e d f o r t h e t e t r a c y c l i c  as summarized i n s e c t i o n A, above.  data  e n a m i n o n i t r i l e 124  118 Preparation  of the T e t r a c y c l i c Dione  132  i  H 132  To a w e l l s t i r r e d s o l u t i o n of 18 mg enaminonitrile was  124  added 400  i n 1 mL  9  basic to  with ether.  The  260.1777;  poured onto  extracted  i n vacuo gave a c o l o r l e s s o i l w h i c h was  thoroughly  mg  (80%)  T h i s m a t e r i a l was  v  1705 m/e  260  cm" ; 1  (M ) +  mixture of  o f the t e t r a c y c l i c d i o n e  132  r e c r y s t a l l i z e d from e t h e r - h e x a n e s . pure product:  n.m.r., 6 1.16 (100%).  Removal  chromatographed  E l u t i o n of t h e column w i t h a 1:1  T h i n l a y e r Chromatography i n d i c a t e d one  mass s p e c t r u m:  refluxed  2  as a w h i t e powder.  3  of water,  added u n t i l the m i x t u r e  the r e s u l t a n t m i x t u r e was  h e x a n e - e t h y l a c e t a t e gave 10.1  (CHC1 ) ;  yL  combined o r g a n i c e x t r a c t s were d r i e d ( N a S 0 ^ ) .  on 1 g of s i l i c a g e l .  ir  tetracyclic  s o l u t i o n was  S o l i d sodium b i c a r b o n a t e was  l i t m u s , and  of the s o l v e n t  The  100  a f t e r b e i n g c o o l e d to room t e m p e r a t u r e , was  2 g of c r u s h e d i c e . was  o f the  o f g l a c i a l a c e t i c a c i d and  yL of 85% p h o s p h o r i c a c i d ^ .  f o r 24 h, and,  (49 u mol)  mp  ( s , 3H,  131 - 133°C;  t e r t i a r y methyls);  E x a c t mass c a l c d . f o r ^ 7 2 4 ° 2  measured ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) :  C  H  260.1778.  :  119 BIBLIOGRAPHY 1.  E. Wenkert, Chem. and I n d . , 282 (1955).  2.  K.M. B r u n d r e t , W. D a l z i e l , B. Hesp, J.A. J a r v l s , and S. M e i d l e , J . Chem. Soc. Chem. Commun., 1027 (1972).  3.  W. D a l z i e l , B. Hesp, K.M. Stevenson, and J.A. J a r v i s , P e r k i n I , 2841 ( 1 9 7 3 ) .  4.  B.M. T r o s t , Y. N i s h i m u r a , K. Yamamoto and S.S. M c E l v a i n , Chem. S o c , 101, 1328 ( 1 9 7 9 ) .  5.  J . E . McMurry, A. Andrus, G.M. Ksander, J . Am. Chem. S o c , 101, 1330 ( 1 9 7 9 ) .  6.  E . J . Corey, M.A. T i u s and J . Das, J . Am. Chem. S o c , 102, 1742 ( 1 9 8 0 ) .  7.  P.S. Manchand, J.D. W h i t e , H. W r i g h t , and J . C l a r d y , S o c , j ) 5 , 2705 (1973).  8.  R.E. I r e l a n d and P.A. A r i s t o f f ,  9.  T. Kametani, T. Honda, Y. S h i v a t o r i , and K. Fukumoto, L e t t . , 1665 (1980).  J . Chem. Soc. J . Am.  J.H. Musser and M.A.  Johnson,  J . Am. Chem.  J . Org. Chem., 44, 4323 (1979). Tetrahedron  10.  P.K. G h o s a l , D. Mukherjee and P.C. D u t t a ,  11.  Samir C h a t t e r j e e ,  12.  B.M. T r o s t and M.J. Bogdanowicz, J . Am. Chem. S o c , 95, 5311 ( 1 9 7 3 ) . B. M. T r o s t and S. Kurozumi, T e t r a h e d r o n L e t t . , 1929 (1974).  13.  B.M, T r o s t and P.H. Scudder,  14.  J . P . Collman, A c c . Chem. Res., 8, 342 (1975). J.Y. Merour, J . L . Roustan, C. C h a r r i e r , J . C o l l i n and J . Benaim, J . Organomet. Chem., 5 1 , C24 ( 1 9 7 3 ) .  15.  C D . De B o e r ,  16.  A. de Groot and B.J.M. J a n s e n ,  17.  T.G. Back and D.H.R. B a r t o n ,  18. | W.C  Still,  T e t r a h e d r o n L e t t . , 2997 ( 1 9 7 6 ) .  J . Chem. S o c Chem. Commun., 622 (1979).  J . Am. Chem. S o c , 99, 7601 ( 1 9 7 7 ) .  J . Org. Chem., 3_9, 2426 (1974). T e t r a h e d r o n L e t t . , 2709 ( 1 9 7 6 ) . J . Chem. Soc. P e r k i n Trans. I , 924 ( 1 9 7 7 ) .  J . Am. Chem. S o c , 100, 1481 (1978).  19.  P. McClosky,  J . Chem. S o c , 3811 (1965).  20.  S. T u r n e r , The D e s i g n o f O r g a n i c S y n t h e s i s ,  21.  K. Ogura, M. Y a m a s h i t a , S. Farukawa, M. S u z u k i and G. T s u c h i h a s h i , T e t r a h e d r o n L e t t . , 2767 ( 1 9 7 5 ) .  E l s e v i e r , 1976.  120 22.  D. Seebach and F. L e h r ,  H e l v . Chem. A c t a . , 62, 2239 (1979).  23.  C.F. B a r t l e t t , T e t r a h e d r o n L e t t . , 331 ( 1 9 7 7 ) .  24.  D.C. W i g f i e l d ,  Tetrahedron,  35, 449 ( 1 9 7 9 ) .  H.C. Brown and s . K r i s h n a m u r t h y , 25.  D.J. H e r b e r t ,  26.  F o r a r e c e n t r e v i e w s e e R.A. E l l i s o n ,  27.  S. B e r g s t r o m ,  28.  A.W. Dox and B. Houston,  29.  M. Miyano and C.R. P o r n , J . Org. Chem., 37, 268 (1972); E. Brown and M. R e g a u l t , T e t r a h e d r o n L e t t . , 1927 (1973); D.A. Evans, C L . Sims, and G.C Andrews, J . Am. Chem. S o c , 99, 5453 (1977). Y. Fukuyama, T. Tokoroyama, and T. Kubota, Tetrahedron L e t t . , 4869 (1973); T. Curigmy, M. Larcheveque, and H. Normant, i b i d . , 1237 ( 1 9 7 4 ) .  30.  Ph.D. T h e s i s ,  T e t r a h e d r o n , 3 5 , 567 ( 1 9 7 9 ) .  U n i v e r s i t y o f B r i t i s h Columbia  (1979).  S y n t h e s i s , 397 ( 1 9 7 3 ) .  S c i e n c e , 157, 382 (1967). J . Am. Chem. S o c , 46, 252 ( 1 9 2 4 ) .  31.  R.B. M i l l e r , S y n t h . Commun., 2, 267 (1972); D.A. McCrae and L. Dolby J . Org. Chem., 42, 1607 (1977); P.E. Sum and L. W e i l e r , Can. J . Chem., 56, 2301,(1978).  32.  G. S t o r k and M.E. Jung,  33.  M. M i y a s h i t a , T. Yanami, and A. Y o s h i k o s h i , 4679 ( 1 9 7 6 ) .  34.  P.M. Jacabson, 2-5.45 T1977) .  35.  W.G. Dauben and D.J. H a r t ,  36.  E . J . Nienhouse, 4557 ( 1 9 6 7 ) .  37.  M.S. Newman and R . J . H a r p e r , J r . ,  38.  For t h e e f f e c t o f p r o t i c and a p r o t i c c o n d i t i o n s on isomer r a t i o see E. Brown and M. R a g a u l t , T e t r a h e d r o n L e t t . , 1927 ( 1 9 7 3 ) .  39.  R.D. C l a r k , L.G. K o z a r , and C.H. Heathcock,  40.  W.S. Wadsworth, J r . , and W.D. Emmons, J . Am. Chem. S o c , 8 3 , 1733 ( 1 9 6 1 ) ; L. Horner, H. Hoffmann, H.G. W i p p e l , and G. K l a h r e , Chem. B e r . , 92, 2499 (1959).  41.  A. M i c h a e l and G.H. C a r l s o n ,  J . Am. Chem. S o c , 96, 3682 (1974). J . Am. Chem. S o c , 98,  R.A. R a t h s , and J.H. McDonald I I I ,  J . Org. Chem., 42,  J . Org. Chem., 42, 3787 ( 1 9 7 7 ) .  R.M. I r w i n , and G.R. F i n n i ,  J . Am. Chem. Soc., 89,  J . Am. Chem. S o c , 80, 6350 (1958).  S y n t h . Commun., 5_, 1 ( 1 9 7 5 ) .  J . Am. Chem. S o c , 57, 162 (1935).  121 42.  F.A. C o t t o n and R.A. Schunn,  J . Am. Chem. S o c , 8 5 , 2394 (1963).  43.  L. Horner and E.H. Winkelmann, Newer Methods o f P r e p a r a t i v e Organic C h e m i s t r y , V o l . I l l , p. 151, Academic P r e s s , 1964.  44.  J.A. M a r s h a l l and G.A. F l y n n , S y n t h . Commun., j9» (1979). We a r e g r a t e f u l t o Mr. M. B u r m e i s t e r f o r s u p p l y i n g a sample o f t h i s compound.  45.  H.O. House, Modern S y n t h e t i c R e a c t i o n s , 2nd Ed., p. 527, W.A. I n c . , 1972.  46.  P.A. G r i e c o and C.S. Pogonowski,  47.  J.M. Conia and M.L. L e r i v e r e n d , B u l l . Soc. Chim. F r . , 2981 ( 1 9 7 0 ) .  48.  P. Wieland and K. M i e s c h e r , H e l v . Chem. A c t a . , 33, 2215 ( 1 9 5 0 ) . S. Ramachandran and M.S. Newman, Org. Syn., 4 1 , 38 (1961).  49.  J.D. Cocker and T.G. H a l s a l l ,  50.  E. P i e r s , W. de Waal, and R.W. B r i t t o n , 5113 (1971).  51.  N. M i y a s h i t a , A. Y o s h i k o s h i and P.A. G r i e c o , 3772 (1977).  52.  G. S t o r k and S.D. D a r l i n g , 1761 ( 1 9 6 4 ) .  53.  D. C a i n e ,  54.  H.A. S m i t h , B.J.L. H u f f , W.J. Powers, and D. C a i n e , 32_, 2851 (1967).  55.  R.H. J a e g e r ,  56.  Y.Y. L i n and J.B. Jones,  57.  E . J . Corey and J.W. Suggs,  58.  R. P a u p t i t and J . T r o t t e r , i n p r e s s .  59.  P.G. B a u s l a u g h ,  60.  E . J . Corey, J.D. B a s s , S o c , 86, 5570 (1964).  61.  J . J . Pappas, W.P. Keareney, E. Gancher, and M. B e r g e r , L e t t . , 4273 (1966).  1  2  3  Benjamin  S y n t h e s i s , 425 (1973).  J . Chem. S o c , 3441 (1957). J . Am. Chem. S o c , 93, J . Org. Chem., 42,  J . Am. Chem. S o c , 82, 1512 (1960); 86,  Org. R e a c t i o n s , 2 3 , 1 (1976). J . Org. Chem.,  T e t r a h e d r o n , 2_, 326 (1958). J . Org. Chem., 38, 3575 (1973).  Synthesis,  T e t r a h e d r o n L e t t . , 2647 ( 1 9 7 5 ) .  287 (1970).  R. LeMahieu, and R.B. M i t r a ,  J . Am. Chem.  Tetrahedron  122 62.  G. Lenz, T e t r a h e d r o n , 31, 1587 (1975). P. S i n g h , J . Org. Chem., 36, 3334 (1971). R.M. Bowman, C. C a l v o , J . J . McCullough, P.W. Rasmussen, and F.F. Snyder, J . Org. Chem., 37, 2084 ( 1 9 7 2 ) .  63. a. K. W i e s n e r , T e t r a h e d r o n , 3 1 , 1655 (1975); b) G. M a r i n i - B e t t o l o , S.P. Sahoo, G.A. P o u l t o n , T.Y.R. T s a i , and K. W i e s n e r , T e t r a h e d r o n , 36, 719 (1980); c ) J . F . B l o u n t , G.D. Gray, K.S. A l w a l , T.Y.R. T s a i , and K. W i e s n e r , T e t r a h e d r o n L e t t . , 4413 (1980). 64.  R.O. L o u f t y and P. de Mayo,  J . Am. Chem. S o c , 99, 3559 (1977).  65.  K.B. W i b e r g , B.L. F u r t e k j and L.K. O l l i , J . Am. Chem. S o c , 1 0 1 , 7675 ( 1 9 7 9 ) ; K.B. W i b e r g , J.E. H i a t t , and K. H s e i h , J . Am. Chem. Soc., 92, 544 (1970); J . Meinwald, J . J . T u f a r i e l l o , and J . J . H u r s t , J . Org. Chem., 29, 2914 (1964).  66.  H.C. Brown and S. K r i s h n a m u r t h y ,  67.  O.W. L e v e r , J r . , T e t r a h e d r o n , 1943 ( 1 9 7 6 ) ; G. S t o r k and L. Maldonado, J . Am. Chem. S o c , 93, 5286 ( 1 9 7 1 ) ; T. Mukaiyama, K. Narasaka, and M. Furu.sato, J . Am. Chem. S o c , 94, 8641 (1972); D. Seebach and E . J . Corey, J . Org. Chem., 40, 231 (1975); S. Hunig and G. Wehner, S y n t h e s i s , 180, 391 ( 1 9 7 5 ) ; B.M. T r o s t and Y. Tamaru, Tetrahedron L e t t . , 3797 ( 1 9 7 5 ) .  68.  J.P. S c h a e f e r and J . J . B l o o m f i e l d ,  69.  S. B a l d w i n ,  J . Org. Chem/, 2 6 , 3280 (1961).  70.  S. B a l d w i n ,  J . Org. Chem., 26, 3288 (1961).  71.  T . J . De B o e r and H.J. B a c k e r , Org. Syn., C o l l . V o l . I V , 250 ( 1 9 6 3 ) ; C D . Gutsche, Org. R e a c t i o n s , 8, 392 (1954) .  J . Am. Chem. S o c , 94, 7159 ( 1 9 7 2 ) .  Org. R e a c t i o n s , 15, 1 ( 1 9 6 7 ) .  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060812/manifest

Comment

Related Items