UBC Theses and Dissertations

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UBC Theses and Dissertations

An approach to the synthesis of neoclovene Mar, Andrew 1974

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AN APPROACH TO THE SYNTHESIS OF NEOCLOVENE  BY  ANDREW MAR B.Sc.  (Hons.), U n i v e r s i t y o f B r i t i s h Columbia, 1971.  A THESIS SUBMITTED I N PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE  i n t h e Department of CHEMISTRY  We accept t h i s t h e s i s as c o n f o r m i n g t o t h e required standard  THE UNIVERSITY OF BRITISH COLUMBIA August, 1974  In  presenting  this  an a d v a n c e d  degree  the  shall  I  Library  f u r t h e r agree  for  scholarly  by h i s of  this  written  thesis at  it  purposes  for  may  financial  is  flex:. <\  of  Columbia,  British  by  for  gain  Columbia  shall  the  that  not  requirements I  agree  r e f e r e n c e and copying  t h e Head o f  understood  of  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada  of  for extensive  be g r a n t e d  It  fulfilment  available  permission.  Department  D a t e  freely  permission  representatives. thesis  partial  the U n i v e r s i t y  make  that  in  of  this  or  that  study. thesis  my D e p a r t m e n t  copying  for  or  publication  be a l l o w e d w i t h o u t  my  ABSTRACT  ,  T h i s t h e s i s d e s c r i b e s t h e i n v e s t i g a t i o n o f two s y n t h e t i c approaches to  t h e keto t o s y l a t e 90_, a key i n t e r m e d i a t e i n a proposed  neoclovene.  The f i r s t  approach i n v o l v e d an e f f i c i e n t  the epoxy a c e t a l s 152 and 153 from i n d a n - l - o n e  142.  synthesis of  9-step  synthesis of  D i a l k y l a t i o n o f 142  with methyl i o d i d e f o l l o w e d by t h e r e a c t i o n o f t h e d i m e t h y l ketone 143 w i t h d i e t h y l cyanomethylphosphorane gave t h e n i t r i l e s s u b j e c t i o n o f the n i t r i l e s in  144 and 145.  to h y d r o l y s i s , hydrogenation,  the f o r m a t i o n o f t h e a r o m a t i c a l c o h o l 141.  and r e d u c t i o n r e s u l t e d  Treatment o f the l a t t e r  l i t h i u m i n l i q u i d ammonia f o l l o w e d by r e g i o s e l e c t i v e h y d r o g e n a t i o n d i s u b s t i t u t e d double bond o f 149 w i t h the homogeneous c a t a l y s t phosphine)chlororhodium  gave t h e o l e f i n a l c o h o l 150.  bond o£ t h e o l e f i n a c e t a l m-chloroperbenzoic  The 179,  second  a proposed  tris(triphenyl-  E p o x i d a t i o n o f t h e double  t o o b t a i n t h e keto  tosylate  to give s y n t h e t i c a l l y useful y i e l d s of  T h i s p r e c l u d e d f u r t h e r use o f t h i s  approach.  approach i n v o l v e d t h e s y n t h e s i s o f t h e o l e f i n a l c o h o l i n t e r m e d i a t e i n t h e s y n t h e s i s o f t h e keto t o s y l a t e 90_.  a l k y l a t i o n of i s o b u t y r o n i t r i l e of  of the  o f epoxy a c e t a l s 152 and 153 i n  However, a l l attempts  90 from t h e epoxy a c e t a l s f a i l e d the d e s i r e d p r o d u c t s .  with  151, c o r r e s p o n d i n g t o .the a l c o h o l 150, w i t h  a c i d gave a m i x t u r e  quantitative yield.  Successive  the a l k y l a t i o n product  165 w i t h a l l y l  Thus,  bromide f o l l o w e d by o z o n o l y s i s  gave t h e a l d e h y d i c n i t r i l e  167.  Successive  treatment  with c y c l o p e n t y l i d e n e t r i p h e n y l p h o s p h o r a n e , p o l y p h o s p h o r i c a c i d , and a l c o h o l i c sodium h y d r o x i d e  a f f o r d e d t h e ketone 170.  The ketone 170 was  c o n v e r t e d i n t o t h e epoxy ketone 171 and t h e l a t t e r was r e a c t e d w i t h methylenetriphenylphosphorane  to y i e l d  t h e epoxy o l e f i n  173.  The  latter  was  subjected  to h y d r o b o r a t i o n - o x i d a t i o n  174  and  175.  The  and  the  epoxide was  g i v e the o l e f i n acetate with  t o produce the epoxy a l c o h o l s  a l c o h o l i c f u n c t i o n a l i t y was reduced w i t h  acetate  178  protected  as the  acetate  tungsten h e x a c h l o r i d e - n - b u t y l l i t h i u m  i n 90%  yield.  R e d u c t i o n o f the  olefin  l i t h i u m aluminum h y d r i d e y i e l d e d the o l e f i n a l c o h o l  Unfortunately,  due  to the  c o n c l u d e d at t h i s p o i n t .  to  l a c k o f time and m a t e r i a l , t h i s p r o j e c t  179. was  A p o s s i b l e s y n t h e t i c r o u t e t o the keto t o s y l a t e  90 from the o l e f i n a l c o h o l 179  i s given.  - iv -  TABLE OF CONTENTS  TITLE PAGE .  ABSTRACT TABLE OF CONTENTS  1  .  »  ACKNOWLEDGEMENTS INTRODUCTION 1.  Diorganocopper Reagents  2.  Intramolecular A l k y l a t i o n  3.  O r i g i 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 Neoclovene . . . . o  4.  Other S y n t h e t i c Approaches  t o Neoclovene .....  DISCUSSION 1.  General  2.  Attempted S y n t h e s i s o f Keto T o s y l a t e 90 ......  3.  Second Attempted 90  EXPERIMENTAL BIBLIOGRAPHY  S y n t h e s i s o f Keto T o s y l a t e  - V -  ACKNOWLEDGEMENT I would like to express my thanks to Dr. Edward Piers for his encouragement, invaluable advice, and consistent interest during the course of this research and the preparation of this manuscript. I would also like to thank a l l the members of Dr. Piers' research group (past and present.) for their many helpful discussions and suggestions. Special thanks are  to Mrs. Diane Gray for the very capable typing  and to Mr. Marston Lee for drawing the many structural diagrams in this thesis.  INTRODUCTION 1.  Diorganocopper Reagents The use of a catalytic amount of a copper salt in the reaction  of an a,8-unsaturated carbonyl compound with an organometallic reagent  o' all H  \ V  . C  _ =  CH / 3  C  1 -i—.  / C C H ,  R 4  A  R  2  M E T A L  — — * -  C H J  C H  C H = C - C H O  \H . .  .  R H 0  -  C H  3  n  .  j_  C  I  3  MLTAL  o  I' C H C H  2  IIII C C H  3  3.  to achieve a Michael (1,4) addition has been known since 1941.* It was not until twenty-five years later that House, Respess, and 2 Whitesides  experimentally showed that the reactive intermediate was  in fact an organocopper derivative.  This derivative, preformed from  Cu(I) and an organometallic reagent or formed from the same reagents in situ gave the same product upon reaction with E-3-penten-2-one 1.  3 Since 1966, extensive research  has shown that diorganocopper  reagents can be used with a wide variety of substrates other than a,8unsaturated carbonyl compounds. The coupling reaction of organo4-8 9 11 cuprates with alkyl halides " and tosylates has been shown to _  H&Ua  CuLi  6,0%  M  0= c  6.5 %  &/t  6 0 %  s  9  15% 11  CH =CKCH 0T 2  2  S  ^  C  " 89%  L  V  CH  12  2  = CHCH  15  CuLi  4  CH oTs  14  3  15  9 8 % 16  E ^ C H ^ C H o . 0T«. IS O JL "  9 C CH  a  19 CH^ OTs  20  2  MeoCuti  — — — « ~  O , II  9CCH2CH2CH3  21  - 3proceed n o t o n l y i n h i g h y i e l d but i n some cases selectivity  (see C h a r t 1 ) . Other  with high stereo-  l e a v i n g groups have a l s o been  d i s p l a c e d by organocuprate r e a g e n t s .  In t h e case o f e t h y n y l c a r b i n o l  12 acetates, allenes  a r e formed. 13  O l e f i n s a r e formed  stereoselectively  acetates and B-alkoxy- and 3 - a l k y l t h i o - a , B - u n s a t u r ' a t e d 14 15 c a r b o n y l compounds ' (see C h a r t 2) and ketones a r e formed from from a l l y l i c  carboxylic acid chlorides'^  (see C h a r t 3 ) . Epoxide r i n g s can a l s o be 17-19  opened i n a n u c l e o p h i l i c manner by  organocuprates.  Although  organocuprate r e a g e n t s r e a c t w i t h t h e a f o r e m e n t i o n e d s u b s t r a t e s , o r g a n i c chemists have found t h e s e r e a g e n t s t o be most u s e f u l i n t h e i r ' 2' unusually e f f e c t i v e conjugate a d d i t i o n to a,8-unsaturated aldehydes, ketones,^' ^  esters,^' ^  involves either p a r t i a l cuprate,  [RCu(I)Y]  and n i t r i l e s ^ ' ^ 3  o r complete  (see C h a r t s 2 and 3 ) .  e l e c t r o n t r a n s f e r from  organo-  , t o u n s a t u r a t e d s u b s t r a t e f o r m i n g e i t h e r a charge-  t r a n s f e r complex o r a r a d i c a l a n i o n .  Subsequent t r a n s f e r o f an o r g a n i c  r a d i c a l from a t r a n s i e n t o r g a n o c o p p e r ( I I ) s p e c i e s t o t h e end o f t h e c o n j u g a t e d a n i o n r a d i c a l o r c o l l a p s e o f the charge t r a n s f e r  R:Cu(II)Y  [R:Cu(I)Y]  0  I)  -C-C=C-  -C=C-C-  I I  55  54  complex  Cu(I)Y  0  R  -C-C=C56  Y = R, halogen, CN  would complete  t h e a d d i t i o n sequence and g e n e r a t e e n o l a t e 56 which i s  - 4 -  24  25  CHART  2  -  5 -  CN ( CH</) CoR.  CN C C H o ) C o C l ' a ' 10  lo  l o  R = 7lE>U 95%  3£>  -nC Hcj 0 C C H C H C o C | 4  2  2  n  1  CoCl  l o  So»  R = nBu 93%  •?8 I (CH^  *7 *C  0 CCH CH CoR  4  a  1 CCH ) a  PL-nE>u 93%  a  10  2  CoR •  41  40 M e CuLi 9  88%  OH 43  42-  f>-CCH ) CoCH 2  8  C H C H C H CCH^g C0CH3  a  3  2  OH 44  45  yy  •o  84%  46  4_7_  •5>7%  49  46  \  c  =  =  /  c  MegCuLi,  cHo  50 CH ^  CH  3  / C H  C =  C0 CH 2  G CH  3  CHART 3  2  c H  3  - 6 quenched on subsequent aqueous workup.  The  apparent requirements  a net n e g a t i v e charge on the copper complex f o r e f f i c i e n t a d d i t i o n has  r e c e n t l y been  Although  confirmed.  of  conjugate  26,27  e n o l a t e s such as 56_ have been trapped  as e n o l d e r i v a t i v e s  2 with a c e t y l c h l o r i d e , a c e t i c anhydride,  and d i e t h y l  phosphorochLori-  28 date  and  CH  have been found  t o g i v e o n l y one  double bond isomer,  ccH ) ca 3  3  /  \  H  cH  /  2  H  ccH,  few  II o  57  (C H 0) Po 2  5  a  3°)  r e s e a r c h e r s have,* u n t i l r e c e n t l y , a l k y l a t e d these to  f u r t h e r e l a b o r a t e the c a r b o n y l Last year,  Boeckman and  enolates i n s i t u  substrate.  Coates i n d e p e n d e n t l y  copper e n o l a t e s can be r e g i o s e l e c t i v e l y and,  showed t h a t organo-  i n some c a s e s ,  34 s e l e c t i v e l y a l k y l a t e d to y i e l d a - d i s u b s t i t u t e d and carbonyl  stereo-  a,8-disubstituted  compounds.  To date, the d i r e c t a l k y l a t i o n o f the i n t e r m e d i a t e magnesium e n o l a t e formed from the c o p p e r - c a t a l y z e d conjugate a d d i t i o n o f G r i g n a r d r e a g e n t s t o a,8-unsaturated ketones has been a c h i e v e d by Stork * and K r e t c h m e r . > The a l k y l a t i o n o f c o p p e r - l i t h i u m malonates has been r e p o r t e d by G r i e c o . 2 9  3 0  3 1  3 2  3 3  34-36  In his first' paper on this subject, Boeckman ' was able to successfully J  >  react some regio-stable copper enolates with various a-trimethyls i l y l a,B-unsaturated ketones.  It was found that in the case of  cyclic a,B-unsaturated ketones, the incoming a-trimethylsilyl vinyl ketones add predominately anti to the previously introduced (from the cuprate addition) alkyl group and therefore the overall annelation reaction produces a highly stereoselective product.  In the case of  enolate 6_2, the cyclohexene skeleton assumes a half-chair conformation in which the a l l y l i c methyl group i s in a pseudoaxial position to . fl 2) relieve A  ' ' strain.  In this conformation, the steric requirements  favor alkylation on the a face.  The resulting ratio (97:3) of the cis  octalone 64 to the trans octalone 65_ respectively shows the potential of the conjugate addition-anneiation sequence in organic synthesis. Boeckman has also added an isopropenyl group via the cuprate as shown by his synthesis of hydrindenone 68_ (see Chart 4). In his second 36 paper on the alkylation of organocopper enolates,  Boeckman turned his  attention toward the use of alkyl halides as the alkylating agents (see Chart 4). This work showed that these metal enolates (formed in a regioselective manner), because of the covalent nature of the copper37 oxygen bond,  may be alkylated regiospecifically in unhindered cases  without a significant amount of polyalkylation. the  If the B position of  carbonyl substrate is sterically hindered, as in ketone 71_ (see  Chart 4),the metal enolates w i l l undergo equilibration* at a significant _ Boeckman also proposed that reduction in the size of the alkyl halide would increase the ratio of alkylation to equilibration.  - 9 r a t e r e l a t i v e t o the r a t e o f a l k y l a t i o n r e s u l t i n g  i n loss of regio-  * specificity,, In  a v e r y s i m i l a r s t u d y , Coates  i n v e s t i g a t e d the  conjugate  2 - n - b u t y l t h i o m e t h y l e h e ketones as w e l l  addition-alkylation of o t h e r a,B-unsaturated  34  ketones.  as  A l t h o u g h the r e s u l t s o b t a i n e d d i d not  show as h i g h a degree o f s t e r e o s e l e c t i v i t y as Boeckman s work, he  has  1  demonstrated  a new  method o f a c q u i r i n g  a , a - d i s u b s t i t u t e d ketones.  Thus,  37 double c o n j u g a t e a d d i t i o n for  example ketone  2.  (see  7£, Chart 4 ) , f o l l o w e d by a l k y l a t i o n o f the  lithium enolate resulted disubstituted  t o 2 - n - b u t y l t h i o m e t h y l e n e ketones  copper-  i n the f o r m a t i o n . o f c x - i s o p r o p y l - a - a l k y l -  ketones.  Intramolecular Aikylations Intramolecular a l k y l a t i o n s p l a y a very important r o l e i n s y n t h e t i c 38  organic chemistry.  With the advent  and  r e f i n e m e n t o f chromato-  g r a p h i c t e c h n i q u e s , p.m.r. s p e c t r o m e t e r s , and X-ray t e c h n i q u e s chemists are now of  crystallographic  a b l e t o i s o l a t e and determine  many n a t u r a l p r o d u c t s i n a r e l a t i v e l y s h o r t t i m e .  compounds have complex, p o l y c y c l i c s t r u c t u r e s .  the  structure  Most o f t h e s e  In o r d e r t o s y n t h e s i z e  t h e s e compounds from s i m p l e r mono-,.di-, o r t r i - c y c l i c p r e c u r s o r s , more and more c h e m i s t s have used integral  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 as an  s t e p i n t h e i r s y n t h e t i c sequence.  a t t r a c t i v e because  o f the f a c i l i t y  since i t i s k i n e t i c a l l y  controlled,  This type of a l k y l a t i o n i s  of intramolecular reactions.  Also,  t h i s p r o c e s s can l e a d to v e r y  _ I t must be remembered t h a t o t h e r s t e r i c f a c t o r s i n the system a l s o c o n t r i b u t e t o the r a t e o f a l k y l a t i o n .  cis-decalin  - 10 -  s t r a i n e d r i n g systems  (vide i n f r a ) .  In the s y n t h e s i s o f  sesquiterpenes,  the f i r s t good examples o f i n t r a m o l e c u l a r a l k y l a t i o n a r e to be i n McMurry's s y n t h e s i s of  (i)-copaene  and  been used not o n l y  39  of  ( i ) - s a t i v e n e and  (i)-ylangene.  Heathcock's s y n t h e s i s  Intramolecular  40  '  41  c y c l i z a t i o n s have  i n the s y n t h e s i s o f s e s q u i t e r p e n e s  synthesis of s t e r o i d s , diterpene  found  but  a l s o i n the  a l k a l o i d s , t r i t e r p e n e s , and a l k a l o i d s .  42 In P i e r s ' s y n t h e s i s (see Chart  ( i ) - s e y c h e l l e n e 81_, the keto t o s y l a t e 79_  5 ) , upon treatment w i t h base, gave i n e x c e l l e n t y i e l d  norseychellanone into  of  80.  T h i s ketone was  ( i ) - s e y c h e l l e n e 81_.  then c o n v e r t e d  In the f i e l d  of diterpene  by standard  (±)methods  a l k a l o i d s Nagata  43 and co-workers, i n the s y n t h e s i s o f the p e n t a c y c l i c compound employed an i n t r a m o l e c u l a r a l k y l a t i o n o f ketone 82^ t o form the  atisine, C-D  44 r i n g system o f t h i s complex compound. demonstrated the use  P i e r s and  co-workers  again  o f t h i s t y p e o f a l k y l a t i o n i n the s y n t h e s i s  (+)-copacamphor 85_ by base treatment o f the k e t o - t o s y l a t e 84.  example i s taken from Corey's r e c e n t The  keto t o s y l a t e 8_6 was  the r e q u i r e d t r i c y c l i c e s t a b l i s h e d to y i e l d  converted  skeleton.  synthesis of  The  t h e s e two  aspects  step.  " t r a p " an organocopper e n o l a t e  of the"conjugate  the importance o f the  intramolecular  were i n t e r e s t e d i n combining  That i s to say,  i t was  formed from a c u p r a t e  an i n t r a m o l e c u l a r a l k y l a t i o n s t e p . t h i s r e a c t i o n , we  then  88.  s y n t h e s i s , we  i n one  final 45  ( t ) - q - c o p a e n e 88.  i s o p r o p y l s u b s t i t u e n t was  In view o f the p o t e n t i a l s y n t h e t i c u t i l i t y  a l k y l a t i o n i n organic  The  to the ketone 87^ thus e s t a b l i s h i n g  (t)-q-copaene  a d d i t i o n - a l k y l a t i o n r e a c t i o n and  of  proposed to  addition via  To demonstrate the a p p l i c a t i o n o f  proposed to s y n t h e s i z e neoclovene 89.  The  key  -11 -  - 12 -  r e a c t i o n f o r t h e proposed s y n t h e s i s was t h e f o r m a t i o n o f t h e t r i c y c l i c s k e l t o n v i a t h e organocopper e n o l a t e 91_. of the a d d i t i o n product,  The expected  stereochemistry  i n t e r m e d i a t e £1_ w i l l be d i s c u s s e d at a l a t e r  time  (see p.  23 ) .  3.  O r i g i 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 Neoclovene S i n c e t h i s t h e s i s i s p a r t i a l l y concerned  s y n t h e s i s o f neoclovene,  i t i s p e r t i n e n t t o d i s c u s s t h e o r i g i n and  the work which l e d t o t h e e s t a b l i s h m e n t chemistry o f t h i s  w i t h an approach t o t h e  o f t h e s t r u c t u r e and s t e r e o -  compound. 46  Neoclovene was f i r s t  i s o l a t e d by P a r k e r ,  Raphael, and R o b e r t s ,  when, i n an attempt to o b t a i n a pure sample o f ( i ) - c l o v e n e by t h e 48 well-known s u l p h u r i c a c i d - c a t a l y z e d rearrangement o f c a r y o p h y l l e n e ,  '  they d i s c o v e r e d a t h e n unknown hydrocarbon as one o f t h e two main products i n t h i s r e a c t i o n .  They s u b s e q u e n t l y c h a r a c t e r i z e d  this  hydrocarbon and showed i t s 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 t o be as d e p i c t e d i n s t r u c t u r e 89_.  T h i s s t r u c t u r a l d e t e r m i n a t i o n by  IO II  8<3?  Raphael and co-workers w i l l be summarized i n t h e f o l l o w i n g p a r a g r a p h s . Neoclovene  fC, „.H„ . ) was shown to be t r i c y c l i c by c a t a l y t i c  h y d r o g e n a t i o n over 10% p a l l a d i u m on c h a r c o a l t o a f u l l y  saturated  d i h y d r o d e r i v a t i v e , n e o c l o v a n e 93. The p.m.r. spectrum o f n e o c l o v e n e i n d i c a t e d one v i n y l p r o t o n a t x 4.19, t h r e e t e r t i a r y methyl a t x 8.80(3H) and x 8.99 (J = 1.5 H z ) .  (6H) and a v i n y l i c methyl group  groups  at x 8.41  H y d r o b o r a t i o n f o l l o w e d by Jones o x i d a t i o n gave two  e p i m e r i c ketones 9_4 whose c a r b o n y l a b s o r p t i o n s a t 1712 cm * were i n d i c a t i v e o f cyclohexanones  (see Chart 6 ) . , Treatment  o f neoclovene  w i t h osmium t e t r o x i d e f o l l o w e d by sodium m e t a p e r i o d a t e c l e a v a g e o f t h e diol resulted  i n t h e k e t o - a l d e h y d e 9_5,  showed a sharp s i n g l e t a t x 7.98 v i n y l i c methyl group. as a t r i p l e t i n g methylene  (J = 2 . 5 group.  t h e p.m.r. spectrum o f which  (3H) c o n f i r m i n g t h e p r e s e n c e o f t h e  F u r t h e r , t h e a l d e h y d i c p r o t o n a t x 0.2  appeared  Hz) thus i n d i c a t i n g t h e p r e s e n c e o f a n e i g h b o u r -  - 14 -  CHART  £»  - 15 -  When t h e k e t o - a l d e h y d e trioxide,  diazomethane, and  acetoxy-methyl due  e s t e r 9>6 was  t o a l a c k o f resonance  the t h r e e t e r t i a r y methyl shift  t o be  expected  95 was  s e q u e n t i a l l y t r e a t e d w i t h chromium  t r i f l u o r o p e r a c e t i c a c i d , the shown to p o s s e s s i n the x 5-6  i f one  o r two  a t e r t i a r y acetoxy  region.  groups showed any  resultant group  In a d d i t i o n , none o f  appreciable downfield  o f them were s u b s t i t u t e d on  the  carbon b e a r i n g the a c e t o x y - f u n c t i o n .  97_ c o r r e s p o n d i n g t o 96^ w i t h  Treatment o f the h y d r o x y - e s t e r  p h e n y l magnesium bromide, f o l l o w e d by a c e t i c a n h y d r i d e gave the d i p h e n y l e n e was  (J  j u x t a p o s i t i o n o f a methylene group. n«-,  n ;  „it  r,f  J. Uli.U-.lvX. \_i  .14 * w 5 A~  -.»,)!,.r..i'i  \J S-  L^ill  \A  f o l l o w e d by m e t h a n o l i c  n-r\A  JL \J S*. JL. \JL ^  dehydration  The v i n y l i c p r o t o n s i g n a l a t T  a c e t a t e 98.  c l e a r l y resolved into a t r i p l e t  UlV/Ul ^  = 8 Hz)  demonstrating  Treatment o f 98_ w i t h a  3.89  the catalytic  ,„X .-.U (-.il..-.J1 ^V ClWl Uil fA\.VJO . .Jv.UU I L.a^^.i.  r, „  ,-,  ••  ,. .C  -«4 r. A  .1 4  \J JL.  sodium hydroxide, h y d r o l y s i s and  gave the n o r - h y d r o x y - e s t e r  excess  ~  esterification  99. 49  A second initially  B a r b i e r - W i e l a n d sequence  the nor-diphenyleneacetate  performed  100  the p.m.r. spectrum  r e v e a l e d the v i n y l i c p r o t o n as a sharp s i n g l e t a neighbouring quaternary c e n t e r methyl  at T  In a d d i t i o n , one  3.62  p r o b a b l y a methyl 101  was  o f the  group.  C o n v e r s i o n o f t h i s . p r o d u c t to the  of  tertiary 100  o f the s u b s t i t u e n t s a t t h i s q u a t e r n a r y c e n t e r  was  hydroxy-  a c h i e v e d i n the same manner as f o r the h i g h e r homologue.  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 101 102.  l e d t o a 1 , 3 - d i o l which  transformed  to t h e mono-tosylate  102  4-isopropenyl-3,3-dimethylcyclohex-2-enone  yielded  o f which,  indicative  groups had moved d o w n f i e l d i n the c o n v e r s i o n o f 98_ t o  s u g g e s t i n g t h a t one  ester  on 99_ a f f o r d e d  Base i n d u c e d f r a g m e n t a t i o n 103.  This  was of  t ^.  - 16 -  e s t a b l i s h e d the t r i c y c l i c  system o f n e o c l o v e n e .  The assignment o f t h e r e l a t i v e group at  w i t h r e s p e c t to the gem-dimethyl  by t h e f o l l o w i n g method. epimeric alcohols the  c o n f i g u r a t i o n o f the t e r t i a r y methyl group a t C  g  was  H y d r o b o r a t i o n o f n e o c l o v e n e gave  proven  two  104 and 105 which were shown by p.m.r. t o have  s t r u c t u r e shown.  Jones o x i d a t i o n o f 104 gave ketone 106 t h e o . r . d .  c u r v e o f which showed a marked n e g a t i v e C o t t o n e f f e c t which i s  c o n s i s t e n t with the p r e d i c t i o n o f the octant r u l e .  '  If this  ketone  had p o s s e s s e d a s t r u c t u r e i n which the C^ methyl group were a n t i t o t h e C  c  8  gem-dimethyl  show a p o s i t i v e  group then t h e C o t t o n c u r v e would be e x p e c t e d t o effect.  The mechanism p r o p o s e d ^ f o r t h e rearrangement o f c a r y o p h y l l e n e i n t o neoclovene i n v o l v e s i n i t i a l l y the i s o m e r i z a t i o n o f the e x o c y c l i c double-bond f o l l o w e d by an a c i d - c a t a l y z e d c y c l i z a t i o n t o t h e  tricyclic  cation  would  109.  A Wagner-Meerwein rearrangement o f t h i s c a t i o n  produce the b r i d g e - h e a d c a t i o n 110.  A final  Wagner-Meerwein r e a r r a n g e -  ment and subsequent p r o t o n l o s s would then g e n e r a t e n e o c l o v e n e .  lo9  108  t  89  4.  89  Other S y n t h e t i c Approaches  t o Neoclovene  There has been a number o f approaches t o t h e t o t a l 52 neoclovene  will  synthesis  53 '  but, f o r the sake o f b r e v i t y , the o n l y s u c c e s s f u l 53  be d i s c u s s e d .  P a r k e r and co-workers  neoclovene by u t i l i z i n g  (vide supra).  one  succeeded i n s y n t h e s i z i n g  a s y n t h e t i c scheme which a l s o added s u p p o r t  t o h i s proposed mechanism f o r t h e rearrangement o f c a r y o p h y l l e n e neoclovene  of  into  Thus, the t r i - s u b s t i t u t e d double bond o f  - 18 c a r y o p h y l l e n e 107 vv'as e p o x i d i z e d w i t h m - c h l o r o p e r b e n z o i c a c i d f o l l o w e d by o x i d a t i v e c l e a v a g e o f t h e e x o c y c l i c double bond w i t h osmium t e t r o x i d e - s o d i u m p e r i o d a t e t o g i v e t h e epoxy-ketone  111  (see C h a r t 7 ) .  Treatment  o f the l a t t e r w i t h p o t a s s i u m h y d r o x i d e produced  112.  carbonate e s t e r  The  113,  formed  112 w i t h e t h y l c h l o r o f o r m a t e , was m i x t u r e o f ketones  114  and  the k e t o l  from the r e a c t i o n o f the  p y r o l y z e d a t 350° t o g i v e a  115 r e s p e c t i v e l y .  Hydrogenation  m i x t u r e over 10% p a l l a d i u m on c h a r c o a l y i e l d e d t h e s a t u r a t e d 116.  Treatment  iodide afforded  o f the t r i c y c l i c  ketone  the t e r t i a r y a l c o h o l  ketol 3:1  of this ketone  116 w i t h methylmagnesium  117 which,  when t r e a t e d  with concentrated s u l p h u r i c a c i d rearranged to neoclovene.  i n ether  JL  laVH^  - 61 -  DISCUSSION  1.  General At t h e o n s e t o f t h i s p r o j e c t , we  wished t o a p p l y  the  conjugate  a d d i t i o n - i n t r a m o l e c u l a r a l k y l a t i o n sequence t o the s y n t h e s i s neoclovene.  Because o f the g r e a t  d i v e r s i t y i n the number o f t h e o r e t i c a l  pathways i n which t h i s complex m o l e c u l e c o u l d be d i s c u s s i o n o f s y n t h e t i c s t r a t a g e m and The  first  order of business  m o l e c u l e must be  by  constructed,  methodology i s  i n planning  a s y n t h e s i s o f a complex  A l e s s complex r i n g s t r u c t u r e may  the t h e o r e t i c a l c l e a v a g e o f a bond i n a complex  structure.  The  intermediate  a brief  appropriate.  the r e d u c t i o n o f the complex framework to  rational precursors.  of  be  simpler obtained  bridged-ring  c y c l i z a t i o n o f the a p p r o p r i a t e l y f u n c t i o n a l i z e d  would r e g e n e r a t e the d e s i r e d p o l y c y c l i c s k e l e t o n .  This  54 approach i s w e l l i l l u s t r a t e d by Corey and synthesis  o f l o n g i f o l e n e 118.  The  co-workers,  i n the  t h e o r e t i c a l c l e a v a g e o f the  bond i n l o n g i f o l e n e 118  produced a s i m p l i f i e d  compared w i t h  appropriately f u n c t i o n a l i z e d intermediate  underwent an diketone  121.  118.  The  intramolecular Michael  s t r u c t u r e . 119  C^-C^  cyclization  as  to produce the  120  tricyclic  - 21 -  T h i s same b a s i c approach was  used by McMurry i n h i s s y n t h e s i s  39 of  ( t ) - s a t i v e n e 122.  The key s t e p  i n this synthesis  involved the  i n t r a m o l e c u l a r a l k y l a t i o n o f an a p p r o p r i a t e l y f u n c t i o n a l i z e d the b i c y c l i c  keto t o s y l a t e 123, t o a f f o r d t h e t r i c y c l i c  123  intermediate,  ketone  124.  111  - 22 -  Following  t h i s general  o u t l i n e , t h e t h e o r e t i c a l c l e a v a g e o f two  .carbon-carbon bonds i n n e o c l o v e n e 89_ were c o n s i d e r e d  (see Chart 8 ) .  Cleavage o f t h e C^-C.^ and C ^ - C ^ bonds o f n e o c l o v e n e 89_ (see numbering below) would l e a d t o t h e h y p o t h e t i c a l 126  respectively.  Bearing  intermediates  125 and  i n mind t h a t the c o n j u g a t e a d d i t i o n -  c y c l i z a t i o n sequence i n v o l v e s , i n i t i a l l y ,  .  t h e a d d i t i o n o f a methyl  group by an organocuprate r e a g e n t , t h e a p p r o p r i a t e l y f u n c t i o n a l i z e d intermediates required  t h a t might be e n v i s a g e d f o r the r e g e n e r a t i o n  tricyclic  Upon a n a l y z i n g  skeleton  o f the  were 90, 127, 128, and 129.  t h e proposed i n t e r m e d i a t e s ,  r e j e c t e d f o r l a c k o f a " h a n d l e " on  keto t o s y l a t e 127 was  f o r the i n t r o d u c t i o n o f t h e C^^  v i n y l methyl group. The e s t e r t o s y l a t e 128 was a l s o r e j e c t e d not o n l y because o f the- o b v i o u s d i f f i c u l t y i n • s y n t h e s i z i n g t h i s intermediate  but a l s o o f the uncertainty  the c y c l i z e d p r o d u c t . 90 and 129.  complex  i n the decarboxylation  Thus, our a t t e n t i o n was f o c u s e d  on  of  intermediates  There was an o b v i o u s l i m i t a t i o n i f 129 were t o be t h e  b i c y c l i c precursor  t o neoclovene, s i n c e conjugate a d d i t i o n  could  produce not o n l y t h e d e s i r e d t r a n s hydrindenone 130 but a l s o t h e c i s isomer 131.  Therefore,  we b e l i e v e d  t h a t t h e k e t o t o s y l a t e 9_0 s h o u l d  be our o b j e c t i v e . In a s e a r c h  o f the current  l i t e r a t u r e , s e v e r a l examples were found,  which l e d us t o b e l i e v e t h a t c o n j u g a t e a d d i t i o n would o c c u r a n t i t o t h e two  carbon c h a i n .  synthesis  In an i n v e s t i g a t i o n on some approaches t o t h e  o f cadinene s e s q u i t e r p e n e n e s , P h i l l i p s  a d d i t i o n t o t h e dienones 132 and 135 o c c u r r e d  found that, c o n j u g a t e  a n t i to the a x i a l  b r i d g e h e a d s u b s t i t u e n t s ^ ^ t o a f f o r d ketones 134 and 135.  In a r e c e n t  - 23 -  130  paper,  Z i e g l e r and W e n d e r °  u  dimethylcyclohex-2-en-l-one  r e p o r t e d t h a t upon treatment 136 w i t h l i t h i u m d i v i n y l  b u t y l p h o s p h i n e complex, the v i n y l yield  131  free of i t s diastereomer.  have added a p t ! to the p x i a l  ketone  137 was  fl  v  '  2")  3,4-  cuprate-tri-n-  produced  The c u p r a t e reagent was  (due t o A  of  i n good proposed  to  i n t e r a c t i o n " ) C,4 methyl -  group. An examination  o f m o l e c u l a r models o f keto t o s y l a t e 9_0  showed t h a t , although the two  carbon s i d e c h a i n i s i n a p s e u d o - a x i a l  and not a p u r e l y a x i a l o r i e n t a t i o n , approach from the 3 f a c e would cause the r e a g e n t C^Q  methylene group.  clearly  This s t e r i c  o f the c u p r a t e reagent  t o be almost  e c l i p s e d w i t h the  i n t e r a c t i o n s h o u l d be  almost  comparable i n magnitude t o the i n t e r a c t i o n e x p e r i e n c e d by the c u p r a t e reagent i n the above examples  (see Chart 9) and  thus, a t t a c k from  the  a f a c e would be p r e d i c t e d .  T h i s would produce,  a l k y l a t i o n o f the i n i t i a l l y  formed e n o l a t e , the r e q u i r e d s t e r e o c h e m i s t r y  i n the p r o d u c t , ketone  97.  The  v i a the a l c o h o l 138  neoclovene.  to  after intramolecular  l a t t e r c o u l d be e a s i l y  transformed  - 25 -  CHART «D  - 26  2.  Attempted S y n t h e s i s  -  o f Keto T o s y l a t e  At the o u t s e t o f t h i s work, we methoxy a l c o h o l 139 keto a l c o h o l 140. 57 reduction,  which we  had  90  a v a i l a b l e a sample* o f  attempted to reduce and h y d r o l y z e  Unfortunately,  the  lithium-liquid  the to  the  ammonia  5 8 " '  when attempted under a v a r i e t y o f c o n d i t i o n s  temperature, amount o f l i t h i u m and  (varying  i n v e r s e a d d i t i o n ) , e i t h e r gave no  r e d u c t i o n p r o d u c t s u s i n g m i l d r e a c t i o n c o n d i t i o n s or a complex m i x t u r e of saturated l i t h i u m and  and  unsaturated  a higher  p r o d u c t s u s i n g a g r e a t e r amount o f  r e a c t i o n temperature.  the aromatic a l c o h o l 141,  We  therefore  the demethoxy analogue o f 139  synthesized i n the hopes  * We  thank Dr.  F.  Kido f o r a generous sample o f t h i s  compound.  - 27 of introducing an oxygen functionality at the  carbon atom of the  indane system at a later stage in the synthesis.  |39  UO  \M  We chose as our starting material, indan-l-one 142 which was alkylated with methyl iodide in the presence of potassium t-butoxide to give an 86% yield of 2,2-dimethylindan-l-one 143 (see Chart 10). The keto group of 145 was then used as a "handle" for the introduction of the two carbon side chain.  I n i t i a l l y considered for this purpose  was the reaction of 143 with the modified Wittig reagent, triethyl 59 phosphonoacetate.  However, this reaction proved very sluggish and  even when carried out at elevated temperatures, produced no synthetically useful results.  Since i t was felt that the failure of this  reaction was due, at least in part, to the sterically hindered nature of the carbonyl group in 145, i t was decided to attempt the use of a reagent which was sterically less demanding, namely, diethyl cyanomethylphosphonate.^"^  This approach proved successful.  reaction of ketone 143 with diethyl cyanomethylphosphonate  Thus,  in the 63 presence of methyl-sulfinyl carbanion in dimethyl sulfoxide at 105° for twenty hours produced a mixture* of Z and E isomers 144 and 145 _ A 65:35 mixture of the Z 144 and E 145 isomers was obtained as judged by g.l.c. analysis and by integration of the signals at T 4.36 and T 4.87 in the p.m.r. spectrum.  - 29 respectively in 93% yield. The physical and spectral properties of the n i t r i l e s were in agreement with structures 144 and 145.  Thus the infrared spectrum  showed a n i t r i l e absorption at 2238 cm * and olefinic absorptions at 1615 and 1600 cm *. This mixture of isomers were partially separated by column chromatography to give a fraction that contained the major^* Z_ isomer in 96% purity.  From the p.m.r. spectrum of this fraction,  the proton resonances of the E isomer could be deduced.  Of particular  64 interest was the anisotropic effect the p.m.r. spectrum.  of the cyano group shown in  The C.7 proton (see Chart 10) of the Z_ isomer  was deshielded by the cyano group and appeared as a multiplet at x 1.53-1.83. in the  The gem dimethyl group appeared as a singlet at T 8.73  isomer while i t appeared at lower f i e l d (T 8.54), due to the  deshielding effect of the n i t r i l e group, i n the E isomer.  The vinyl  proton of the E_ isomer, deshielded by the aromatic ring,appeared as a singlet at T 4.36 while i t appeared at x 4.87 i n the £_ isomer. The mixture of nitriles 144 and 145 was hydrolyzed^^ to a mixture of unsaturated acids 146 and 147 using a refluxing mixture of ethylene glycol, water, and sodium hydroxide. The white crystalline product exhibited physical properties in accord with those expected for a mixture of compounds 146 and 147. Of particular interest i n the infrared spectrum was the absence of the n i t r i l e absorption, the presence of the hydroxyl absorption at 3600-2400 cm absorption at 1690 cm . -1  and an unsaturated carbonyl  Again, the presence of the Z. 146 and  isomers were evident in the p.m.r. spectrum.  147  The deshielding effect  of the acid group and the aromatic ring system caused the resonances of the gem dimethyl group (x 8.45) and the vinyl proton (x 3.62) to appear  - 30 at lower f i e l d in the E_ isomer as compared to the corresponding signals (T 8.72 and 4.15 respectively) of the Z_ isomer.  The  proton of the  Z isomer was also deshielded by the acid functionality and appeared as a multiplet at T 1.14-1.42. Hydrogenation of the mixture of acids (one equivalent of hydrogen) over palladium on charcoal gave a 94% yield of the saturated acid 148. The physical and spectral properties of the acid were in agreement with structure 148.  Thus the infrared spectrum showed a hydroxyl  absorption at 3500-2400 cm \ 1705 cm  and a saturated carbonyl absorption at  The presence of the acidic proton was evidenced in the  p.m.r. spectrum by a broad singlet at T -1.08. at T 6.73  The doublet of doublets  ( J = 6 Hz) was assigned to the benzylic methine proton and  the unresolved multiplet (AB of ABM system) between T 7.16 and T 7.68 wa readily attributable to the methylene protons adjacent to the acid functionality.  The magnetic nonequivalence of methylene protons found  in an asymmetric environment is a well-established phenomenon,^ and this therefore deserves no further comment. The sharp singlets at x 9.08 and T 8.82 were attributed to the tertiary methyl groups. The reduction of the aromatic acid 148 to the aromatic alcohol 141 67 68 was achieved by the reaction of the former with diborane tetrahydrofuran.  in  The physical and spectral properties of the resulting  product (93% yield) were in accord with structure 141. group was evident  '  The hydroxyl  due to an absorption at 3360 cm * in the infrared  spectrum and an exchangeable hydroxyl proton (broad singlet, T 6.506.93) in the p.m.r. spectrum. singlet at T 2.98.  The aromatic protons appeared as a  The triplet at T 6.27  (J = 6 Hz) was assigned to  the methylene protons a to the hydroxyl group.  The geminal dimethyl  - 31 group appeared as singlets at x 8.89 and 9.05 while the singlet at T 7.38 was attributed to the C methylene protons. 3  With the achievement of our f i r s t synthetic objective, the next step involved the reduction of the aromatic system and hopefully the introduction of an oxygen functionality at the  carbon atom  69 (vide supra).  Since previous work 70  'the a l l y l i c oxidation  in this laboratory showed that  of the alcohol 154, under a variety of conditions,  yielded a number of a,6-unsaturated carbonyl products, we decided to synthesize the epoxy ethers 152 and 153 (see Chart 10) and introduce  +  OTHER PRODUCT'S  the oxygen functionality via an a l l y l i c alcohol (vide infra). Reaction of the aromatic alcohol 141 with lithium in liquid 72 ammonia  afforded the diene alcohol 149 in 90% yield.  This compound  showed the expected spectral properties. The infrared spectrum showed a hydroxyl absorption at 3365 cm~* and an olefinic absorption at 1645 cm  In the p.m.r. spectrum the vinyl protons were evident  as a singlet at x 4.25.  The C^ methylene protons appeared as a singlet  at T 7.38 while the triplet* at x 6.33 (J = 7 Hz) was assigned to the methylene protons adjacent to the hydroxyl group.  The exchangeable  hydroxyl proton appeared as a singlet at x 7.05, and the geminal methyl group as singlets at v.  T  8.92 and 9.03.  - 32 -  R e g i o s e l e c t i v e h y d r o g e n a t i o n o f d i e n e 149 was use o f the homogeneous c a t a l y s t  a c h i e v e d by the  t r i s (triphenylphosphine)chloro-  72 rodiunu  A f t e r the uptake o f one e q u i v a l e n t o f hydrogen, t h e o l e f i n i c  alcohol  150 was  i s o l a t e d i n 95% y i e l d .  The 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 i n complete agreement There was  an absence o f o l e f i n i c a b s o r p t i o n s due t o the d i s u b s t i t u t e d  double bond i n the i n f r a r e d spectrum. appeared at 3370 cm \  The h y d r o x y l a b s o r p t i o n  In the p.m.r. spectrum, the complete  o f the d i s u b s t i t u t e d double bond was  reduction  e v i d e n t due t o the l a c k o f  resonances i n the v i n y l p r o t o n r e g i o n . 7 Hz) was  w i t h the a s s i g n e d s t r u c t u r e .  The t r i p l e t  a t x 6.45  (J =  a s s i g n e d t o t h e methylene p r o t o n s a d j a c e n t t o the h y d r o x y l  group w h i l e the s i n g l e t s at x 8.95 gsminal methyl group. broad s i n g l e t a t x 6.05  and x 9.08  were a t t r i b u t e d t o the  The exchangeable h y d r o x y l p r o t o n appeared as a . t o x 6„28.  The hydroxy f u n c t i o n a l i t y o f 150 was Thus treatment o f the o l e f i n i c  alcohol  p r o t e c t e d as an  acetal.  150 w i t h c h l o r o m e t h y l methyl  73 74 ether  '  i n the p r e s e n c e o f excess p o t a s s i u m t - b u t o x i d e a f f o r d e d ,  i n 92% y i e l d ,  the o l e f i n i c  acetal.  The p h y s i c a l and  p r o p e r t i e s o f t h i s p r o d u c t were i n agreement i n t e r e s t was spectrum. at T 6.73  The p<,m r. spectrum showed the methoxy group as a 0  Of  singlet  w h i l e the methylene p r o t o n s a d j a c e n t to the methoxy group  a t t r i b u t e d t o the  and x 9.07  w i t h s t r u c t u r e 151.  the absence o f h y d r o x y l a b s o r p t i o n s i n the i n f r a r e d  appeared as a s i n g l e t a t x 5.48. was  spectral  The m u l t i p l e t a t x 6.20  methylene p r o t o n s .  a r e due to the geminal methyl  The epoxy a c e t a l s  The two  to x  6.66  s i n g l e t s at x  group.  152 and 153 were formed by treatment o f t h e  8.95  - 33 76 o l e f i n i c acetal  151 w i t h m - c h l o r o p e r b e n z o i c a c i d .  had s p e c t r a l p r o p e r t i e s t h a t  chromatographic  except f o r the p r e s e n c e o f the  i n the i n f r a r e d  152 and  spectrum.  153 r e s p e c t i v e l y .  isomer  152.  -CH OCH a  Gas-liquid  This  assignment  The  epoxidizing  assumed t o have a t t a c k e d from the l e s s h i n d e r e d s i d e o f  the double bond, a n t i to the two  R-  151,  based on the s t e r i c approach c o n t r o l p r i n c i p l e .  r e a g e n t was  This mixture  a n a l y s i s o f the p r o d u c t r e v e a l e d an 80:20 m i x t u r e o f the  e p i m e r i c epoxy a c e t a l s was  cm  '  were almost i d e n t i c a l w i t h those o f  the c o r r e s p o n d i n g o l e f i n i c a c e t a l epoxy a b s o r p t i o n a t 740  77  3  carbon c h a i n , thus forming the major  -  34  -  With the achievement o f our second o b j e c t i v e , we now wished to i n t r o d u c e an oxygen s u b s t i t u e n t a t the  position.  We t h e r e f o r e 77-79  r e a c t e d t h e epoxy a c e t a l s 152 and 153 w i t h l i t h i u m d i e t h y l a m i d e in  t e t r a h y d r o f u r a n t o produce  a mixture o f a l l y l i c  d i a s t e r e o m e r s ) and 157 (two d i a s t e r e o m e r s ) . assignment  T  The above t e n t a t i v e  was supported by a h y d r o x y l a b s o r p t i o n a t 3480 cm * i n t h e  i n f r a r e d spectrum at  a l c o h o l s 156 (two  and a broad  s i n g l e t , assigned to the v i n y l  4.62 i n the p.m.r. spectrum.  by g a s - l i q u i d chromatographic  Although  analysis,  proton,  the f o u r p r o d u c t s ,  showed t h a t t h i s  evidenced  sequence  would p r o b a b l y be s y n t h e t i c a l l y u n p r o d u c t i v e , we n e v e r t h e l e s s d e c i d e d to  c o n t i n u e w i t h the sequence. 80 Upon treatment  o f t h i s m i x t u r e w i t h aqueous h y d r o c h l o r i c a c i d ,  a d i a s t e r e o m e r i c m i x t u r e o f the r e a r r a n g e d a l l y l i c  a l c o h o l s 158 (two  d i a s t e r e o m e r s ) and 159 (two d i a s t e r e o m e r s ) were formed. assignment  was based  on the d i s a p p e a r a n c e  o f the v i n y l  This tentative proton  resonance i n the p.m.r. spectrum and the p r e s e n c e o f a m u l t i p l e t a t x 5.84-6.17 which was a s s i g n e d t o the p r o t o n a d j a c e n t t o the h y d r o x y l group.  When the a l c o h o l s 158 and 159 were o x i d i z e d w i t h  Collins  8182 reagent,  '  a m i x t u r e o f ketones  t e n t a t i v e assignment  160 and 161 were formed.  was s u s t a i n e d by the p r e s e n c e o f an  ketone a b s o r p t i o n a t 1665 and 1630 c m The presence  i n the i n f r a r e d  a,3-unsaturated spectrum.  o f two major p r o d u c t s were e v i d e n t by g a s - l i q u i d  chromatographic Although  - 1  This  analysis.  t h i s sequence produced  t h e d e s i r e d ketone  not s y n t h e t i c a l l y u s e f u l due to t h e poor o v e r a l l y i e l d e x p e c t a t i o n t h a t the d e s i r e d ketone  160, i t was and the  160 was the minor component. The  - 35  above e x p e c t a t i o n  was  due  -  t o the f a c t ,  e s t a b l i s h e d by  Rickborn,  t h a t the base induced rearrangement o f epoxides o c c u r s w i t h a b s t r a c t i o n of a proton that o f a p r o t o n at  by  2.  should  be  difficulties  a l c o h o l 139  and  group at the  the minor isomer.  o f Keto T o s y l a t e  achieved 162.  the  the base Therefore,  Thus, we  attempted  sequence.  o f the methoxy  i n t r o d u c t i o n o f an o x y g e n - c o n t a i n i n g f u n c t i o n a l  p o s i t i o n o f the  epoxy acetals  s u b s t i t u e n t at C. and  152  the f o r m a t i o n  r e a l i z e d i n the  through the b a s e - c a t a l y z e d  and  153  l e d us  Two  there  are  initially  o f the  same r e a c t i o n .  and  This could  A l d o l c y c l i z a t i o n o f the  be  diketone  four possible c y c l i z a t i o n  Since  o n l y the k e t o l 163  the , ^ - u n s a t u r a t e d ketone 164, a  ketone 164,  would be  under the p r o p e r  f  of  be  in their a,8-  dehydrated to  the t h e r m o d y n a m i c a l l y f a v o r e d  r e a l i z e d i f the  conditions.  can  the  products.  the t h i r d p r o d u c t cannot be d e h y d r a t e d t o g i v e an  u n s a t u r a t e d ketone.  oxygen  desired  o f these p r o d u c t s have a f o u r membered r i n g i n c o r p o r a t e d  skeleton  to  i n t r o d u c t i o n o f the  Upon examination o f the p o s s i b l e c y c l i z e d i n t e r m e d i a t e s  d i k e t o n e 162,  two  90  encountered i n the r e d u c t i o n  i n the  b i c y c l i c system was  by  f o r o n l y t h i s compound.  i n v e s t i g a t e a s y n t h e t i c sequence i n which the containing  Abstraction  the a t t a c k by  the keto t o s y l a t e 90_ by a n o t h e r s y n t h e t i c  Second Attempted S y n t h e s i s The  epoxide.  s t e r i c a l l y hindered  i s epoxy a c e t a l 153,  i s h i g h l y favored  the d e s i r e d ketone 160 to s y n t h e s i z e  to the  the  s i n c e t h i s s t e r i c i n t e r a c t i o n i s more pronounced  i n the minor epoxide, t h a t psotion  syn  the base would be  carbon s i d e c h a i n but,  a t the  i s a and  77  product,  c y c l i z a t i o n were c a r r i e d out  - 36 -  I&4  163  We chose, as our f i r s t objective, the ketone 170, which would be an intermediate to the diketone 162. was  The starting material chosen  isobutyronitrile 165 which was alkylated with  a l l y l bromide in the presence of lithium diisopropylamide to give a 83% yield of 2,2-dimethyl-4-pentenenitrile 166 (see Chart 11).  The  physical and spectral properties of the olefinic n i t r i l e were in agreement with structure 166, and with the data reported in the 83 84 literature  '  for this compound.  Thus the infrared spectrum showed  the presence of the terminal olefinic functionality as bands at 3090, 1640, and 920 cm * and a n i t r i l e absorption at 2245 cm  In the p.m.r.  spectrum of 166, the vinyl group exhibited a multiplet at T 3.75-4.45 for the C  4  proton and a multiplet at x 4.63-5.06 for the C  5  protons.  The doublet (J = 7 Hz) at x 7.72 was assigned to the a l l y l i c C, protons  - 37 -  - 38 -  while, t h e s i n g l e t a t T 8.67 was a s s i g n e d t o t h e t e r t i a r y  methyl  groups. Cleavage  o f t h e double  bond o f compound  166 was e f f e c t e d by 85  o z o n o l y s i s i n 1% pyridine- d i c h l o r o m e t h a n e  solution  at -78°, followed 86  by d e c o m p o s i t i o n The  resulting  o f the r e s u l t i n g  crude  aldehyde  ozonide  nitrile  with  from  further p u r i f i c a t i o n .  t h e crude p r o d u c t  infrared  i n the next  reaction  However, t h e s p e c t r a l d a t a  supported  obtained  t h e a s s i g n e d s t r u c t u r e 167.  spectrum showed t h e p r e s e n c e  acid.  167 was somewhat u n s t a b l e and  prone t o a u t o x i d a t i o n and was t h e r e f o r e used without  z i n c and a c e t i c  The  o f the a l d e h y d i c carbonyl  f u n c t i o n a l i t y w i t h "absorptions a t 2750 and 1720 cm ^ w h i l e the a b s o r p t i o n band a t 2250 cm * i n d i c a t e d  the p r e s e n c e  o f the n i t r i l e  m u l t i p l e t a t T 0.10 i n the p.m.r. spectrum c o n f i r m e d the aldehyde sharp  functionality.-  singlet  multiplet The  reagent  group.  A  the presence o f  The t e r t i a r y methyl groups appeared as a  a t T 8.50 w h i l e t h e methylene p r o t o n s  were e v i d e n t as a  a t x 7.26. crude  aldehyde  nitrile  was then r e a c t e d w i t h t h e W i t t i g 87  cyclopentylidenetriphenylphosphorane  i n dimethoxyethane t o  g* i v e , i n 87% y i e l d , t h e o l e f i n i c n i t r i l e 168.* T h i s compound showed We attempted to s y n t h e s i z e compound 168 by an a l t e r n a t e r o u t e . U n f o r t u n a t e l y , even a t low temperatures, t h e W i t t i g r e a g e n t a c t e d  o <T 3 H  ^ 3  as a base c a u s i n g t h e f o r m a t i o n o f t h e A l d o l c o n d e n s a t i o n 1-cyclopentylidenec.yclopentanone.  product  - 39 -  the expected s p e c t r a l p r o p e r t i e s .  The n i t r i l e  by t h e a b s o r p t i o n a t 2255 cm * i n the i n f r a r e d o l e f i n i c a b s o r p t i o n appeared  a t 1680 cm  group was spectrum  as a m u l t i p l e t  while the  The p.m.r. spectrum  a sharp s i n g l e t a t x 8.65 f o r the t e r t i a r y methyl v i n y l p r o t o n appeared  evidenced  groups  showed  w h i l e the  a t T 4.37-4.90. 88 8!  When t h e o l e f i n i c n i t r i l e was t r e a t e d w i t h p o l y p h o s p h o r i c a c i d , i t underwent c y c l i z a t i o n and formed  the b i c y c l i c  imine 169.*  '  The crude  imine was immediately h y d r o l y z e d u s i n g a m e t h a n o l i c sodium h y d r o x i d e s o l u t i o n t o a f f o r d a 70% ( o v e r a l l ) y i e l d  o f the d e s i r e d product.  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 i n complete a c c o r d w i t h s t r u c t u r e 170. a b s o r p t i o n a t 248 mu substituted infrared  The u l t r a v i o l e t  spectrum  (e = 14,300) which i s t y p i c a l  ft-unsaturated  ketone.  e x h i b i t e d an  of a f u l l y  T h i s was s u p p o r t e d by t h e  spectrum w i t h a b s o r p t i o n s a t 1660 and 1640 cm  p.m.r. spectrum,  t h e t e r t i a r y methyl  groups  appeared  In the  as a s i n g l e t a t  x 8.90. Having accomplished  our f i r s t  o b j e c t i v e , we next wished t o  i n t r o d u c e a two carbon c h a i n a t t h e c a r b o n y l c a r b o n . t h i s problem  seemed t o be t h e use o f t h e m o d i f i e d W i t t i g  t r i e t h y l phosphonoacetate. o f t h e ketone  'Die s o l u t i o n t o  U n f o r t u n a t e l y , a l l attempts  reagent at the r e a c t i o n  170 w i t h t h i s r e a g e n t o r t h e l e s s s t e r i c a l l y demanding  reagent d i e t h y l cyanomethylphosphonate f a i l e d  due t o the e n o l i z a t i o n  In our hands, i t was found t h a t t h e use o f 10% phosphorous p e n t o x i d e m e t h a n e s u l f o n i c acid^O was s u p e r i o r t o t h a t o f p o l y p h o s p h o r i c a c i d due t o t h e d i f f i c u l t y i n s t i r r i n g a s o l u t i o n o f the l a t t e r . The y i e l d s o f ketone 170 was a p p r o x i m a t e l y t h e same i n b o t h c a s e s .  - 40 -  of  t h e ketone.  V a r i o u s o t h e r attempts a t the i n t r o d u c t i o n o f o n l y  one carbon atom a t t h e c a r b o n y l carbon a l s o f a i l e d .  We,  therefore,  d e c i d e d t o p r e v e n t t h e e n o l i z a t i o n o f t h e ketone 170 by " b l o c k i n g " the  double bond.  The b l o c k i n g group chosen had t o p r o h i b i t  enolization  and had t o be s u s c e p t i b l e to^removal t o r e f o r m t h e double bond. -The epoxide moiety seemed t o meet b o t h r e q u i r e m e n t s .  Thus treatment o f t h e 91  ketone 170 w i t h a m i x t u r e o f hydrogen p e r o x i d e and sodium h y d r o x i d e gave, i n 76% y i e l d ,  t h e epoxy ketone 171.  An a n a l y t i c a l sample o f  t h i s m a t e r i a l was o b t a i n e d by p r e p a r a t i v e g . l . c . and e x h i b i t e d data i n agreement  w i t h the a s s i g n e d s t r u c t u r e .  Most n o t a b l e i n the  i n f r a r e d spectrum was t h e c a r b o n y l a b s o r p t i o n a t 1700 cm p.m.r..spectrum,  spectral  In t h e  t h e t e r t i a r y methyl groups now appeared as two  s i n g l e t s a t Y 9.07 and T 5.92.  One o f t h e methyl groups was a p p a r e n t l y 92  s h i e l d e d by t h e oxygen atom o f t h e epoxide r i n g resonate a t a higher  thus c a u s i n g it. t o  field.  With t h e e s t a b l i s h m e n t o f t h e b l o c k i n g group, we a g a i n attempted to the  i n t r o d u c e the two carbon c h a i n v i a t h e W i t t i g r e a c t i o n .  Although  r e a c t i o n o f t h e epoxy ketone w i t h t r i e t h y l phosphonoacetate was  u n s u c c e s s f u l , we were a b l e t o r e a c t t h e former w i t h d i e t h y l methylphosphonate  a t an e l e v a t e d  However, when we t r i e d  temperature  cyano-  (see page 27).  t o hydrogenate t h e double bond o f t h e epoxy  Q nitrile of  172 (see Chart 11) w i t h a v a r i e t y o f c a t a l y s t s , h y d r o g e n o l y s i s  the a l l y l i c  double bond.  C-0 bond o c c u r r e d  c o n c u r r e n t l y with the reduction o f the  We t h e r e f o r e d e c i d e d t o i n s e r t t h e two carbon c h a i n v i a  two one-carbon h o m o l o g a t i o n s . The f i r s t  carbon atom was i n t r o d u c e d by means o f t h e W i t t i g  - 41 reaction.  Thus, reaction of the epoxy ketone 171 with methylenetri-  phenylphosphorane resulted in an 88% yield of the epoxy olefin 173. The spectral properties of this product were consistant with the assigned structure. Of interest was the complete disappearance of the carbonyl absorption and the presences of olefinic absorptions at 3120, 1635, and 890 cm"  1  in the infrared spectrum.  The vinyl protons  in the p.m.r; spectrum were evident as a singlet at x 4.73.  The  signals at x 9.05 and 8.87 were assigned to the tertiary methyl groups. In accord with our plans to convert this compound into the next higher homologue, i t was necessary at this stage of the synthesis to functionalize the terminal double bond into a primary alcohol functionality.  This was achieved by subjecting the epoxy  olefin 173 to hydroboration with diborane in tetrahydrofuran followed by decomposition of the intermediate alkylborane with alkaline hydrogen peroxide.  The resultant ratio of the products (epoxy  alcohols 174 and 175) varied somewhat.from reaction to reaction but the mixture of products, as judged by gas-liquid  chromatographic  analysis, never contained less than 75% of the major isomer,* epoxy alcohol 175.  An analytical sample of this major isomer, collected  by preparative g . l . c , exhibited spectral properties in accord with structure 175.  Thus, the infrared spectrum showed a hydroxyl  absorption at 3460 cm  In the p.m.r. spectrum, the tertiary methyl  groups were evident as sharp singlets at x 9.30 and  9.00.  _ The assignment of the stereochemistry ot the two epimeric epoxy alcohols 174 and 175 is tentative and was based on examination of molecular models and the application of the steric approach control principle.  v.  -  The at T  protons  adjacent  to T  5.84  The  42  -  t o t h e h y d r o x y l group appeared as a m u l t i p l e t  6.57.  a l c o h o l f u n c t i o n a l i t y was p r o t e c t e d a s a n e s t e r b y  o f t h e e p o x y a l c o h o l s 174 a n d 175 w i t h a c e t i c a n h y d r i d e  treatment  i n dry  p y r i d i n e t o g i v e , i n 92% y i e l d ,  a mixture  177o  a c e t a t e s was d e p e n d e n t o n t h e r a t i o  The r a t i o o f t h e e p i m e r i c  o f e p o x y a l c o h o l s 174 a n d 175 u s e d .  of the mixture  sample o f t h e major isomer exhibited The 1740  177, o b t a i n e d  spectral properties i n accord  presence  to the acetate f u n c t i o n a l i t y .  at  spectrum.  Although olefins  structure.  I n t h e p.m.r.  to the protons  The t e r t i a r y m e t h y l  spectrum,  adjacent  groups appeared as  group appeared as a  7.97.  T  At t h i s the double  g.l.c,  with absorptions at  s i n g l e t s a t f 9.27 and T 8.97 w h i l e t h e a c e t o x y singlet  analytical  with the assigned  a t T 5 . 4 7 - 6 . 4 0 was a s s i g n e d  the m u l t i p l e t  An  by p r e p a r a t i v e  o f t h e a c e t a t e g r o u p was a p p a r e n t  a n d 1230 cm * . . i n t h e i n f r a r e d  176 a n d  o f epoxy a c e t a t e s  t i m e , we f e l t  t h a t i t would be a p p r o p r i a t e t o r e i n t r o d u c e  bond by t h e r e d u c t i o n o f t h e e p o x i d e  functionality.  t h e r e w e r e many e x a m p l e s o f t h e r e d u c t i o n o f e p o x i d e s i n the l i t e r a t u r e ,  t h e r e w a s , a p p a r e n t l y , no e x a m p l e o f t h e  reduction of a tetrasubstituted t h e epoxy a c e t a t e  epoxide.  94  95  with  at elevated temperatures  also failed  able to effect  reduction of  ethylenediamine  yielded only starting material.  r e d u c t i o n o f the epoxide  epoxy a c e t a t e s  The a t t e m p t e d  176 a n d 177 w i t h c h r o m i u m ( I I )  complex i n dimethylforinamide  We w e r e f i n a l l y  to  zinc-copper*'  or zinc-silver  96  t o p r o d u c e any r e d u c t i o n  t h e r e d u c t i o n by t h e treatment  176 a n d 177 w i t h t u n g s t e n  The  couple product. of the  h e x a c h l o r i d e and . n - b u t y l -  lithium in refluxing tetrahydrofuran. 178  was  thus o b t a i n e d  i n 90% y i e l d .  were i n agreement w i t h the a s s i g n e d  J 1  The  The p h y s i c a l and s t r u c t u r e 178.  spectrum showed c a r b o n y l a b s o r p t i o n s a t 1740 p a r t i c u l a r i n t e r e s t was  desired o l e f i n i c  and  spectral properties  Thus, the  1230  cm  *.  the p.m.r. spectrum i n which, due  removal o f the s h i e l d i n g e f f e c t  acetate  Of  to  o f the oxygen atom o f the  infrared  the  epoxide  r i n g , t h e t e r t i a r y methyl groups appeared as s i n g l e t s a t x. 9.07 9.03.  The  acetoxy  group was  m u l t i p l e t a t T 5.66-6.31 was acetate  a t T 8.04  assigned to the protons  while  adjacent  another  a c e t a t e p r o t e c t i n g group was acetate with  to  carbon  atom to the s i d e c h a i n ,  the  removed by the r e a c t i o n o f the  l i t h i u m aluminium hydride..  The  product,  olefinic  obtained i n  97%  e x h i b i t e d s p e c t r a l p r o p e r t i e s i n agreement with s t r u c t u r e  179.  Thus, the i n f r a r e d spectrum showed a h y d r o x y l a b s o r p t i o n at 3410 In the p.m.r. spectrum,'the s i n g l e t s a t x 9.14  and x 9.08  a s s i g n e d to the t e r t i a r y methyl grups w h i l e the d o u b l e t at x 6.40 hydroxyl  was  a t t r i b u t e d t o t h e methylene p r o t o n s  cm  were (J = 4  a d j a c e n t to  Hz) the  group.  At t h i s p o i n t i n the s y n t h e s i s , we alcohol  the  functionality.  In o r d e r t o add  yield,  e v i d e n t as a s i n g l e t  and  179  wished to homologate the  a c c o r d i n g to the scheme shown i n C h a r t  12.  The  s y n t h e s i s o f the keto t o s y l a t e 90_ i n v o l v e d r e a c t i o n o f the t o s y l a t e 180,  corresponding  to t h e o l e f i n i c a l c o h o l 179,  olefinic  proposed olefinic  w i t h sodium  99 cyanide  i n dimethyl  t o g i v e the o l e f i n i c n i t r i l e  181.  Base h y d r o l y s i s o f the l a t t e r would a f f o r d t h e o l e f i n i c a c i d  182.  S u b j e c t i o n o f 182  sulfoxide  t o o z o n o l y s i s and  base-catalyzed  cyclization''' ^ <  ,  - 44 would produce the  keto a c i d  functionality with  alcohol Chart  179,  12,  due the  was  the  to the  carried  Thus, i n c o n c l u s i o n , to the  synthesis  application of successful  desired  of the  some r e c e n t  an  acid  resultant  product, keto t o s y l a t e  90.  starting material,  k e t o t o s y l a t e 90,  quite  as  the  proposed  olef on  o f f e r s the  The  s e c o n d and  possibility  sequence could  future.  f e a s i b l e approach  been developed which i n c l u d e d  s y n t h e t i c methods.  synthetic near  t o s y l a t i o n of the  a t t r a c t i v e and  approach described  neoclovene i n the  of the  out.  o f n e o c l o v e n e has  development of the  by  l a c k o f t i m e and  synthesis  not  Selective reduction  diborane followed  a l c o h o l would then g i v e Unfortunately  184.  lead  that  to the  the  most  further  syntheses  of  - 45 -  C H A R T \Z  EXPERIMENTAL  General M e l t i n g p o i n t s , which  were d e t e r m i n e d  boiling points are uncorrected.  on a K o f l e r b l o c k , and  Ultraviolet  i n methanol s o l u t i o n on e i t h e r a Cary, model SP  800, spectrophotometer.  Oxj.JLCJ.iic:  u a i j . i c u  I v C x J .  Refractive  u u l i l c t C J .  *  s p e c t r a were measured 14, o r a U n i c a m , m o d e l  i n d i c i e s were t a k e n on a  J V U U L J . J J C  i j i i i u i .  U u  II^A  r e c o r d e d o n a P e r k i n - E l m e r model 710 s p e c t r o p h o t o m e t e r s p e c t r a w e r e r e c o r d e d o n a P e r k i n - E l m e r m o d e l 457 The  while  tetra-  s o l u t i o n o n V a r i a n A s s o c i a t e s s p e c t r o m e t e r s m o d e l s T-60  a n d / o r HA-100, X L - 1 0 0 .  Line positions  with t e t r a m e t h y l s i l a n e as i n t e r n a l  are given i n the Tiers T  parentheses.  G a s - l i q u i d chromatography  e i t h e r an Aerograph The f o l l o w i n g  Autoprep  are indicated i n  ( g . I . e . ) was c a r r i e d  m o d e l 700 o r a V a r i a n A e r o g r a p h ,  columns were  scale,  standard; the m u l t i p l i c i t y ,  i n t e g r a t e d peak a r e a s , and p r o t o n assignments  90-P.  comparison  spectrophotometer.  p.m.r. s p e c t r a w e r e t a k e n i n d e u t e r o c h l o r o f o r m o r c a r b o n  chloride  V.  employed:  o u t on model  - 47 -  Column  Length  A  10 f t x 1/4 i n  B  S t a t i o n a r y Phase 20% SE 30  C  "  10% SE 30  D  "  10% FFAP  E  "  10% O V - 2 1 0  10 f t x 3/8  G  11  H  5 f t x 1/4  in  60/80  11  11  II  .  "  20% SE 30  " '  "  "  11  "  20% SE 30  "  "  "  The s p e c i f i c column used a l o n g w i t h column t e m p e r a t u r e and gas  . II  '  11  10% OV-210 in  Mesh  Chromosorb W  20% Carbowax 20 M  11  F  Support  carrier  (helium) f l o w - r a t e ( i n ml/min), are i n d i c a t e d i n parentheses.  chromatography  was -performed u s i n g f l o r i s i l  n e u t r a l s i l i c a g e l (Camag o r Macheray, (Ca ap o r Macher^yj Nagel and Co.) < m  Column  (Fisher S c i e n t i f i c Co.),  Nagel and Co.) o r n e u t r a l a l u m i n a  The alumina was d e a c t i v a t e d as  r e q u i r e d by a d d i t i o n o f the c o r r e c t amount o f w a t e r . mass s p e c t r a were r e c o r d e d on an AEI t y p e MS-9  High r e s o l u t i o n  mass s p e c t r o m e t e r .  Micro-  a n a l y s e s were p e r f o r m e d by Mr. P. Borda, M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y o f B r i t i s h Columbia,  Vancouver.  P r e p a r a t i o n o f 2 , 2 - D i m e t h y l i n d a n - l - o n e 143 To an i c e - c o o l e d , s t i r r e d s u s p e n s i o n o f powdered p o t a s s i u m t b u t o x i d e (156.8 g, 1.4 moles) i n 1 £ o f d r y dimethoxyethane, kept under an atmosphere  o f d r y n i t r o g e n , was added a s o l u t i o n o f 79.2 g  mole) o f 1-indanone  142 i n 200 ml o f d r y dimethoxyethane.  The  (0.60 resulting  m i x t u r e was s t i r r e d f o r 10 min, and t h e n a s o l u t i o n o f 426 g (3 moles) of methyl i o d i d e i n 300 ml o f d r y dimethoxyethane was added.  The  m i x t u r e was warmed t o room t e m p e r a t u r e and a l l o w e d t o s t i r f o r 3 h. The r e s u l t i n g m i x t u r e was d i l u t e d w i t h w a t e r and t h o r o u g h l y e x t r a c t e d  -  with ether.  48  -  The ethereal e x t r a c t s were combined, washed with b r i n e ,  and d r i e d over anhydrous magnesium s u l f a t e .  Removal of the solvent  gave an o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded 78.2 g (86%) of the desired a l k y l a t e d product 143, b.p. 47-49° at 0.2 mm [ l i t .  b.p. 87-89° at 0.6 mm; n  1.5383]; m.p. 37-38°; n  p  1.5442; u l t r a v i o l e t , X 246 my (e = 12,800); i n f r a r e d ( f i l m ) , v max max 1706,  1610 cm \; p.m.r., T 8.80 ( s i n g l e t , 6H, t e r t i a r y methyls),  7.OS ( s i n g l e t s , 2H, methylene protons), 2.17-2.85 ( m u l t i p l e t , 4H, aromatic protons). Anal. Calcd. f o r  C  H 1 1  0 : 1 2  C >  82  - > ' ' * 46  H  7  5 5  F o u n d :  c  > 82.43;  H, 7.56.  Preparation of N i t r i l e s 144 and 14b A s t i r r e d suspension of sodium hydride (16.8 g, 0.35 mole) i n 400 ml of dry dimethyl s u l f o x i d e was slowly heated, under an atmosphere of dry n i t r o g e n , to 75° and kept at t h i s temperature u n t i l f r o t h i n g had ceased (approximately 30 min).  The s o l u t i o n was cooled  to room temperature and a s o l u t i o n o f d i e t h y l cyanomethylphosphonate (67.5 g, 0.38 mole) i n 100 ml of dry dimethyl s u l f o x i d e was added. The r e s u l t i n g s o l u t i o n was s t i r r e d f o r 15 min, and then a s o l u t i o n of the ketone 143 (11.2 g, 70 mmole) i n 50 ml of dimethyl s u l f o x i d e was added.  The r e a c t i o n mixture was heated (bath temperature 105°) f o r  20 h, then cooled, d i l u t e d with water and thoroughly extracted with ether.  The combined e x t r a c t s were washed- with water, saturated b r i n e ,  and then d r i e d over anhydrous magnesium s u l f a t e .  Removal of the  solvent, followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced  - 49 pressure afforded 11.75 g (93%) of a 65:35 mixture of £ and E^ isomers respectively as judged by p.m.r. and gas-liquid chromatographic analysis (column E, 125°, 100).  This mixture exhibited b.p. 96-98° at 0.25  infrared (film) v 2238, 1615, 1600 cm \ max J  mm;  A sample was subjected to . r  column chromatography using Camag Kieselgel for TLC (without binder) and 98:2 petroleum ether (b.p. 68°)-ether as eluting solvent.  A  positive pressure (air) was required to maintain a reasonable flow rate. The ratio of compound to s i l i c a gel was 1:100. The major Z_ isomer was thus obtained in 96% purity. tertiary methyls), 7.13  It exhibited p.m.r., T 8.73  (singlet, 6H,  (singlet, 2H, methylene protons), 4.87  (singlet,  1H, vinyl proton),-2.49-2.91 (multiplet, 3H, aromatic protons), 1.83  (multiplet, 1H,  proton).  From the above, the p.m.r. spectrum  of the minor E^ isomer could be deduced. (singlet, 6H, tertiary methyls), 7.08 4.36  1.53-  It showed p.ni.r.. 7  8.54  (singlet, 2H, methylene protons),  (singlet, 1H, vinyl proton), 2.43-2.90 (multiplet, 4H, aromatic  protons). Anal. Calcd. for C^H^N: C, 84.90; H, 7.08; N,  C, 85.21; H, 7.15; N, 7.64.  Found:  7.51.  Preparation of Acids 146 and 147 A mixture of n i t r i l e s 144 and 145 (24 g, 135 mmoles) was dissolved in 540 ml of 5:1 ethylene glycol-water containing 100 g (2.5 mole) of sodium hydroxide.  The resulting solution was refluxed (bath temperature  140°) under an atmosphere of nitrogen for 20 h and then cooled to room temperature.  This mixture was diluted with 600 ml of saturated brine  and extracted with ether.  The aqueous residue was acidified to pH 2  - 50 with 6 N hydrochloric acid and the resulting mixture was  thoroughly  extracted with 600 ml of 1:1 petroleum ether (b.p. 68°)-ether.  The  combined extracts were washed twice with brine and then dried over anhydrous magnesium sulfate. of white crystals.  An analytical sample, obtained by recrystallization  from hexane, exhibited m.p. I960, 1625 cm" ; 1  Removal of the solvent gave 19 g (95%)  114-115°; infrared  ultraviolet, A  276 my  (CHCl,), v  3600-2400,  (e = 12,150), 286 (e = 11,660),  1H3-X  302 (e = 10,400). isomers.  The p.m.r. spectrum showed a 81:19 ratio of Z to E  The major 2_ isomer exhibited p.m.r., T 8.72  tertiary methyls), 7.12  (singlet, 6H,  (singlet, 2H, methylene protons), 4.15  (singlet,  IH, vinyl proton)2.35-2.85 (multiplet, 3H, aromatic protons), 1.42  (multiplet,  IH, Cj  proton).  The E_ isomer had p.m.r., T 8.45  (singlet, 6H, tertiary methyls), 7.01 3.62  1.14-  (singlet, 2H, methylene protons),  (singlet, IH, vinyl proton), 2.46-2.96 (multiplet, 4H, aromatic  protons). Anal. Calcd. for H,  C  H 1 3  0 1 4  : 2  c  » 77.20; H, 6.98.  Found:  C, 77.04;  7.20.  Hydrogenation of Acids 146 and  147  The acids 146 and 147. (16 g, 0.89 mole) in 350 ml of ethyl acetate were hydrogenated over 2.0 g of 10% palladium on charcoal at room temperature until the uptake of hydrogen was complete (approximately 10 h).  The reaction mixture was filtered through celite and the  f i l t r a t e was evaporated to dryness to give a yellow o i l which was d i s t i l l e d under reduced pressure (b.p. 140-142° at 0.05 mm).  The  resulting pale yellow o i l (17.0 g, 94%) crystallized upon standing.  v  - 51 An analytical sample, obtained by recrystallization from hexane, exhibited m.p. r  ultraviolet X  74.5-75.5°; infrared (film) v 3500-2400, 1705 • ' *• max  nicLX  p.m.r., x 9.08  260 my  (e = 615), 267 my  2H, -CH C0 H), 6.73 2  6.0 Hz), 2.88  (e = 992), 273 my  (singlet, 3H, tertiary methyl), 8.82  tertiary methyl), 7.32 2  cm" ; 1  3  (singlet, 2H, C  3  (e = 1145);  (singlet, 3H,  protons), 7.16-7.68 (multiplet,  (doublet of doublets, 1H, methine proton, J =  (singlet, 4H, aromatic protons), -1.08  (broad singlet, 1H,  -C00H).  H,  Anal. Calcd. for (L-H-.O.,: IS ID I 8.10.  C, 76.44; H, 7.90.  Found:  C, 76.70;  Preparation of Aromatic Alcohol 141 To a stirred solution cf acid 14S (16.2 g, 79 mmcles) in 30 ml of dry tetrahydrofuran, cooled to 0°, was added 75 ml (100 mmoles) of borane in tetrahydrofuran.  The ice bath was removed and the resulting  solution was stirred under nitrogen for 1 h.. The excess hydride was destroyed by careful addition of 50 ml of 1:1 tetrahydrofuranwater and the aqueous phase was saturated with 15 g of anhydrous potassium carbonate.  The layers were separated and the aqueous phase  was extracted four times with 50 ml portions of ether.  The combined  organic extracts were dried over anhydrous magnesium sulfate.  The  concentrated yellow o i l was d i s t i l l e d under reduced pressure to afford 20 14.0 g (93%) of the desired alcohol b.p. 106-108° at 0.55 mm; I. 5318; ultraviolet  A  M  A  X  261 my  (e = 668), 267 my  n  Q  (e = 1055), 274 my  (e = 1270); infrared (film) v 3360, 3110, 3060, 1040, 1010 cm" ; max p.m.r., T 9.05 (singlet, 3H, tertiary methyl), 8.89 (singlet, 3H, 1  3  - 52 t e r t i a r y methyl), 7.38 ( s i n g l e t , 2H,  methylene protons), 6.50-6.93  (broad s i n g l e t , IH, exchangeable, -OH), 6.27 ( t r i p l e t , 2H, -CH^OH, J = 6.0 Hz), 2.98 ( s i n g l e t , 4H, aromatic protons). Anal. Calcd. f o r n  HO:  IS  C, 82.06; H, 9.53.  Found:- C, 81.95;  lo  H, 9.56.  Preparation of Diene Alcohol 149 To a s t i r r e d s o l u t i o n of l i t h i u m (2.15 g, 310 mmoles) i n 350 ml of l i q u i d ammonia ( d i s t i l l e d from sodium metal) cooled t o -78° was added a s o l u t i o n of 11.8 g (62 mmole) aromatic a l c o h o l i n 20 ml of dry dimethyoxyethane and 8 ml o f 95% ethanol.  This s o l u t i o n was  s t i r r e d at -78° f o r 45 min aid then at -33° f o r 30 min. The blue c o l o r was Hi scharged by the a d d i t i o n of  1Q  ml of 95% ethanol.  was allowed to evaporate and 360 ml of.water was added. was t h r i c e extracted with ether.  The ammonia This mixture  The combined organic e x t r a c t s were  washed with saturated b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal o f the solvent, followed by d i s t i l l a t i o n of the r e s i d u e , gave 10.5 g (90%) of the diene a l c o h o l 149_ as a c o l o r l e s s o i l , b.p. 92-94° at 0.2 mm.  An a n a l y t i c a l sample, obtained by preparative g . l . c .  (column A, 160°, 100) e x h i b i t e d i n f r a r e d (film) v 1045,  1015 cm ; p.m.r., -1  T  m a x  3365, 3055, 1645,  9.03 (singlet,- 3H, t e r t i a r y methyl), 8.92  ( s i n g l e t , 3H, t e r t i a r y methyl), 7.38 ( s i n g l e t , 2H, C„ methylene protons), 7.05 ( s i n g l e t , III, exchangeable, -OH), 6.33 ( t r i p l e t , 2H, -CH_ 0H, J = 7.0 Hz), 4.25 ( s i n g l e t , 2H, v i n y l protons). 2  Anal. Calcd. f o r C jH^O: ' C, 81.20; H, 10.48. H, 10.30.  Found: .C, 81.27  - 53 -  Hydrogenation of Diene Alcohol  149  The hydrogenation of diene a l c o h o l 149  (10.0 g, 52 mmoles) was  c a r r i e d out i n benzene (200 ml) at room temperature and atmospheric pressure using t r i s ( t r i p h e n y l p h o s p h i n e ) c h l o r o r h o d i u m (2.0 g) as c a t a l y s t . One  equivalent of hydrogen was consumed a f t e r 11 h.  The r e a c t i o n  mixture was f i l t e r e d through a column of Camag K i e s e l g e l a c t i v i t y I I I neutral alumina (360 g) and eluted with 1 £ of ether.  Removal of the  solvent and d i s t i l l a t i o n under reduced pressure afforded 9.5 g of the o l e f i n i c alcohol as a c o l o r l e s s o i l , b.p.  (95%)  94-96° at 0.5 mm.  An  a n a l y t i c a l sample obtained by preparative g'.l.c. (column B, 200°, 100) exhibited infrared"(film) v  3370, 1040,  1005 cm" ; 1  p.m.r., x  9.08  max ( s i n g l e t , 3H, t e r t i a r y methyl), 8.95 6.45  ( s i n g l e t , 3H, t e r t i a r y methyl),  ( t r i p l e t , 2H, -Ch\,GH, J = 7.0 Hz), 6.05-G.28 (broad s i n g l e t , III,  exchangeable,  -OH).  Mol. Wt. Calcd. f o r mass spectrometry):'  C  H 1 3  22  194.1670.  0 :  Found (high r e s o l u t i o n  194.1614.  Preparation of O l e f i n i c A c e t a l  151  To an i c e bath cooled s t i r r e d s l u r r y of 8.27  g (72 mmoles) of  powdered potassium t-butoxide i n 200 ml of a7.hydrous ether was added a s o l u t i o n of 7.4 g (38 mmoles) of o l e f i n i c a l c o h o l 150 i n 50 ml of anhydrous ether. of 6.45  A f t e r s t i r r i n g i n the cold f o r 15 min, a s o l u t i o n  g (80 mmoles) of chloromethyl methyl ether i n 30 ml of anhydrous  ether was added.  The i c e water bath was removed and the r e a c t i o n  mixture was s t i r r e d under nitrogen f o r a f u r t h e r 15 min.  Water  then added and t h i s mixture was thoroughly extracted w i t h ether.  was The  - 54  combined e t h e r e a l  extracts  -  were washed w i t h s a t u r a t e d  over anhydrous magnesium s u l f a t e .  The  the  g  residue d i s t i l l e d  to y i e l d " 8 . 3  as a c o l o r l e s s o i l , b.p. o b t a i n e d by p r e p a r a t i v e 1.4820; i n f r a r e d  (film) v J  x 9.07  ( s i n g l e t , 3H,  m e t h y l ) , 6.73 2  2  3  An  (column D,  r  and  acetal  151  100)  20 n^  exhibited cm" ; 1  ( s i n g l e t , 3H,  p.m.r., tertiary 2H,  -Oq^OCIij). C,  75.58; H,  10.99.  Found:  C,  75.62;  10.91.  P r e p a r a t i o n of Epoxy A c e t a l s To acetal (5.25  a cooled 151  (0°)  i n 5 ml  stirred  152  and  153  s o l u t i o n o f 500  o f methylene c h l o r i d e was  mmoles) m ~ c h l o r o p e r b e n z o i c a c i d  T h i s m i x t u r e was  h.  The  i n 10 ml  s o l u t i o n was  the  extract  sodium s u l f i t e  washed with a 10%  compounds as  a quantitative  a c o l o r l e s s o i l b.p.  l i q u i d chromatographic a n a l y s i s product to be respectively*,  an An  mmoles) o l e f i n i c  f o r 0.5  (hot box) (column E,  h and  then at  The  of  D i s t i l l a t i o n of  100)  brine  the  desired  130-135° at 125°,  20%  organic  s o l u t i o n , saturated  y i e l d o f the  mg  chloride.  poured onto 10 ml  l a y e r s were s e p a r a t e d .  d r i e d over anhydrous magnesium s u l f a t e .  concentrated o i l afforded  (2„10  o f methylene  at 0°  sodium h y d r o x i d e s o l u t i o n and was  mg  added a s o l u t i o n o f 905  s t i r r e d under d r y n i t r o g e n  room temperature f o r 2.5  and  olefinic  -Ci^OCH.,), 6.29-6.66 ( m u l t i p l e t ,  ( s i n g l e t , 2H,  dried  a n a l y t i c a l sample,  130°,  t e r t i a r y m e t h y l ) , 8.95  Anal. Calcd. f o r C , H . , 0 _ : l b 26 2 H,  o f the  mm.  and  removed in_ vacuo  3060, 1140, 1100, 1025 ' ' '  max  ( s i n g l e t , 3H,  -CH OCH OCH ), 5.48  (92%)  92-94° at 0.4 g.l.c.  e t h e r was  brine  0.4  mm.  showed  80:20 m i x t u r e o f e p i m e r i c epoxy a c e t a l s  152  a n a l y t i c a l sample o f t h i s m i x t u r e , o b t a i n e d  Gas-  the and by  153  - 55 -  preparative g. I.e. (column G, 160°, 200), e x h i b i t e d i n f r a r e d v  (film)  2990, 1140, 1100, 1030, 740 cm" ; p.m.r., T 9.02, 9.07  (singlet,  1  JHclX  s i n g l e t , 6H, t e r t i a r y methyls), 6.70 ( s i n g l e t , 3H, -CH OCH_ ), 6.17-6.59 2  3  ( m u l t i p l e t , 2H, -CH^OCH^Ciy, 5.47 ( s i n g l e t s , 2H, -OCH_ OCH ). 2  Mol. Wt. calcd. f o r C mass spectrometry):  H  0^:  2 3 8  •  1 9 3 2  •  3  Found (high r e s o l u t i o n  238.1937.  Preparation of 2,2-Dimet.hyl-4-pentenenitrile 166 To an i c e water bath cooled, s t i r r e d s o l u t i o n of diisopropylamine (45.5 g, 0.45 moles) i n 75 ml of dry benzene was added 150 ml (0.375 moles) n - b u t y l l i t h i u m i n hexane.  A f t e r s t i r r i n g i n an i n e r t atmosphere  for 5 min, a s o l u t i o n of 20.7 g (0.30 moles) of i n 45 ml of d r y benzene was added dropwise.  i s o b u t y r o n i t r i l e 165  The c o o l i n g bath was  removed and t h i s mixture was s t i r r e d a t room temperature f o r 5 min. The r e a c t i o n was again cooled t o 0° and a s o l u t i o n of a l l y l bromide (72.6 g, 0.6 mole) i n 75 ml dry benzene was added.  The r e s u l t i n g  mixture was r e f l u x e d f o r 1.5 h and then cooled to room Water was added and the layers were separated. thoroughly extracted with ether.  temperature.  The aqueous layer was  The organic e x t r a c t s were combined,  washed with water, saturated b r i n e , and d r i e d over anhydrous magnesium sulfate.  The solvent was removed under reduced pressure and the  residue d i s t i l l e d to give 27.0 g (83%) of the desired product b.p. 147-148°; n£ (film) V  1.4191 [ l i t .  b.p/ 147-148.5°, n  D  1.4180]; i n f r a r e d  3090, 2245, 1640, 920 cm" ; p.m.r., T 8.67 ( s i n g l e t , 6H, 1  IT13.X  t e r t i a r y methyls), 7.72 (doublet, 2H, methylene protons, J = 7 Hz), 4.63-5.06 ( m u l t i p l e t , 2H, C proton)„  5  pi'otons), 3.75-4.45 ( m u l t i p l e t , 1H, C  4  - 56 -  Preparation of 3-Cyano-3,3-dimethyl propanal  1.67  A s o l u t i o n of 5 g (46 mmoles) of o l e f i n i c n i t r i l e 166 i n 80 ml of a 1% pyridine-dichloromethane  s o l u t i o n was t r e a t e d with ozone at  u n t i l the s o l u t i o n turned blue.  The excess ozone was removed by bubbling  dry nitrogen through the s o l u t i o n . (370 mmoles) of zinc dust. immediately  This mixture was poured onto 24 g  A c e t i c acid (46 ml, 810 mmoles) was  added and the r e s u l t i n g s l u r r y was  temperature.  -78°  slowly warmed to room  A f t e r the s o l u t i o n had been s t i r r e d f o r 1 h, i t was  f i l t e r e d , d i l u t e d with b r i n e and extracted with methylene c h l o r i d e . The organic phase was washed with water, saturated sodium bicarbonate s o l u t i o n , saturated b r i n e , and d r i e d over anhydrous magnesium s u l f a t e . The solvent was removed to a f f o r d 3.5 g (70%) of the crude aldehyde Due to t h e i n s t a b i l i t y of t h i s compound, i t was used  n i t r i l e .167immediately  i n the next r e a c t i o n without f u r t h e r p u r i f i c a t i o n .  A small  sample of the aldehyde n i t r i l e 167 was d i s t i l l e d and e x h i b i t e d b.p. 91° at 19 mm;  i n f r a r e d (film) v  2750,. 2250, 1720 cm" ; 1  90-  p.m.r.,  max x 8.50  ( s i n g l e t , 6H, t e r t i a r y methyls), 7.26  protons), 0.10  ( m u l t i p l e t , IH, -CHO).  This compound was c h a r a c t e r i z e d as i t s d e r i v a t i v e , r e c r y s t a l l i z e d from ethanol, m.p. Anal. Calcd. f o r C -H 2  Found:  ( m u l t i p l e t , 2H, methylene  C, 49.66; H, 4.47;  N 0 :  2,4-dinitrophenylhydrazone 153-154°.  C, 49.48; H, 4.50;  N, 23.85.  N, 24.04.  - 57 -  Preparation of Cycloperityltripheriylphdsphdriium Iodide To a s o l u t i o n of 13.6 g (70 mmoles) of c y c l o p e n t y l i o d i d e i n 50 ml of xylene was added 39.3 g (150 mmole) of triphenylphosphine.  This  mixture was r e f l u x e d f o r 17 h and then cooled to room temperature. The p r e c i p i t a t e d s a l t was f i l t e r e d , washed with benzene, and d r i e d under vacuum overnight to a f f o r d 28.6 g (90%) of the desired compound as a pale yellow c r y s t a l . V  max  1590, 1440, 1110  I t e x h i b i t e d m.p„ 238-240°; i n f r a r e d (CHCl^)  cm" ,  Anal. Calcd. f o r C  1  H IP: 24  C, 60.28; H, 5.28; I , 27.68.  Found:  C, 60.46; H, 5.55; I, 27.32.  Preparation of O l e f i n i c N i t r i l e 168 To a cooled (0°), s t i r r e d s l u r r y of 45.8 g (100 mmoles) of cyclopentyltriphenylphosphonium  i o d i d e i n 250 ml of dry dimethoxy-  ethane was added 48.2 ml (92 mmoles) of a 1.9 M s o l u t i o n of n - b u t y l l i t h i u m i n hexane.  The r e s u l t i n g blood red s o l u t i o n was s t i r r e d ,  under dry nitrognen, at room temperature f o r 15 min.  A s o l u t i o n of  3.0 g (27 mmole) of crude aldehyde n i t r i l e 167 i n 20 ml of dimethoxyethane was added.— A f t e r s t i r r i n g f o r 30 min, the mixture was poured i n t o 300 ml of water and thoroughly extracted with petroleum ether (b.p. 30-60°).  The organic e x t r a c t s were combined, washed with  saturated b r i n e , and d r i e d over anhydrous magnesium s u l f a t e .  Removal  of the solvent and d i s t i l l a t i o n of the residue gave 3.8 g (87%) of the desired compound.  An a n a l y t i c a l sample, obtained by preparative 2] ^  g . l . c . (column H, 135°, 100) e x h i b i t e d b.p. 52-54° at 0.35 mm; n 1.4699; i n f r a r e d (film) v  2255, 1680 cm ^; p.m.r., T 8.65  (singlet,  - 58 -  6H, t e r t i a r y methyls), 4.37-4.90 ( m u l t i p l e t , 1H, v i n y l proton). Anal. Calcd. f o r C  H^N:  C, 80.93; H, 10.50.  Found:  C, 80.95;  H, 10.72.  Preparation of Ketone 170 A s t i r r e d s o l u t i o n of 5.0 g (30.5 mmoles) of the o l e f i n i c n i t r i l e and 75 g of polyphosphoric a c i d was heated, i n an i n e r t atmosphere, at 125-130° f o r 30 min.  This mixture was poured onto i c e , b a s i f i e d with a  20% sodium hydroxide s o l u t i o n , and extracted with chloroform..  The  organic extract was washed with saturated b r i n e and concentrated y i e l d the crude imine 169 which e x h i b i t e d i n f r a r e d ( f i l m ) v max J  1650, '  J  1600 cm ^.  The imine 169 was immediately  to  added to a s o l u t i o n of 184 ml  of ^0% sodium hydroxide s o l u t i o n and 180 ml of methanol and r e f l u x e d . under a nitrogen atmosphere, f o r 2.5 h.  The r e a c t i o n mixture  cooled and the methanol was removed at a s p i r a t o r pressure.  was  The  residue  was d i l u t e d with water and a c i d i f i e d w i t h 6 N h y d r o c h l o r i c a c i d .  This  mixture was thoroughly extracted with ether, the ether layer was washed with saturated b r i n e and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent, f i l t r a t i o n through a column of Camag K i e s e l g e l a c t i v i t y I I I n e u t r a l alumina (15 g ) , and e l u t i o n with ether gave a yellow o i l .  D i s t i l l a t i o n of t h i s m a t e r i a l under a s p i r a t o r pressure  gave 3.5 g (70%) of the ketone 170, b.p.  108-109° at 10 mm.  An  a n a l y t i c a l sample was obtained by preparative g . l . c . (column A, 120), and i t e x h i b i t e d n J  i n f r a r e d (film) v t e r t i a r y methyls).  19,5  D  1660,  1.5079; ultraviolet X 1640,  1390 cm" ; 1  max  p.m.r.,  248 my 8.90  155°,  (e = 14,300) ^ ' J  ( s i n g l e t , 611,  - 59  A n a l . C a l c d . f o r C -.H.' 0: 1116 H,  -  C,  80.44; H,  Found:  C,  80.19;  9.60.  Preparation  o f Epoxy Ketone  To a s t i r r e d (45.8  171  s o l u t i o n o f 2.5  mmoles) o f 30% ml  g  (15.3  hydrogen p e r o x i d e  was  added 15.3  The  r e s u l t i n g m i x t u r e was  was  then added and  The  organic  (76.3  thoroughly  ketone 1 7 i , b.p.  6i>-67° at  preparative g.l.c.  max  1700  cm" ;  1.2  (column G,  mm.  3H,  tertiary  Mol.  Wt.  Calcd. f o r C ^ H ^ C y  mass s p e c t r o m e t r y ) :  Preparation To  200)  hexane.  ml  (76%)  3H,  of the  epoxy  sample o b t a i n e d  by  (film)  t e r t i a r y methyl),  8.92  180.1149.  Found  (high r e s o l u t i o n  180.1140.  173  (0°), s t i r r e d  s l u r r y o f 19.1  (50 mmoles) o f a 2.4  (53.5  mmoles) o f  o f anhydrous e t h e r  was  M solution of n-butyllithium i n at room temperature, under  an  atmosphere o f d r y n i t r o g e n , f o r 10 min,  a s o l u t i o n o f epoxy ketone  171  g,  16.7  s o l u t i o n was  ml  g  stirred  (3.0  A f t e r the  g  Distillation  exhibited infrared  m e t h y l t r i p h e n y l p h o s p h o n i u m bromide i n 200 added 20.8  ether.  methyl).  o f Epoxy O l e f i n  a cooled  in_ vacuo.  analytical  (singlet,  (singlet,  Water  s a t u r a t e d b r i n e , d r i e d over  a f f o r d e d 2.1  An  130°,  p.m.r., x 9.07  1  e x t r a c t e d with  concentrated  o f the r e s i d u e under r e d u c e d p r e s s u r e  5 ml  sodium h y d r o x i d e s o l u t i o n .  washed t w i c e w i t h and  and  o f methanol  s t i r r e d a t room temperature f o r 2 h.  the m i x t u r e was  l a y e r was  mmoles) o f ketone 170  s o l u t i o n i n 50 ml  mmoles) o f 20%  anhydrous magnesium s u l f a t e ,  v  9.82.  mmoles) i n 20 ml  o f dry  e t h e r was  added.  This mixture  - 60  was  -  r e f l u x e d f o r 4 h, c o o l e d , poured i n t o water, and  extracted with  ether.  s a t u r a t e d b r i n e , and  The  e t h e r e a l e x t r a c t s were combined, washed  d r i e d over anhydrous magnesium s u l f a t e .  o f the s o l v e n t and  distillation  epoxy o l e f i n  T h i s sample was  173.  (column E, 115°, infrared  t e r t i a r y methyl), 2H,  110).  (film) v  vinyl  8.87  1635,  (singlet,  H 0: 12 l o  C,  of Epoxy A l c o h o l s  174  1 0  1 0  Removal  (88%)  of  the  shown to be pure by g . l . c . a n a l y s i s 105-108°  (hot box)  p.m.r., T 9.05  890  cm ;  3H,  t e r t i a r y methyl),  -1  at 10  mm;  (singlet,  4.73  3H,  (singlet,  80.85; H, -10.18.  Found:  C,  80.68;  10.33.  To a s o l u t i o n o f 2.3  g  o f dry t e t r a h y d r o f u r a n  was  added 5.6  ml  T h i s s o l u t i o n was  (12.9  at 0° and  then s t i r r e d  s o l u t i o n was  ml  r e s u l t i n g m a t e r i a l was with  ether.  The  stirred  added s l o w l y ,  The  16 ml  f o r 1 h, then c o n c e n t r a t e d .  of  warmed The  extracted  e x t r a c t s were washed w i t h a  (b.p.  nitrogen  f o l l o w e d by a d d i t i o n  d r i e d over anhydrous magnesium  m a t e r i a l under reduced p r e s s u r e  h.  r e a c t i o n m i x t u r e was  Removal o f the s o l v e n t , f o l l o w e d by d i s t i l l a t i o n  80  tetrahydrofuran.  d i l u t e d w i t h water then t h o r o u g h l y  combined e t h e r  b r i n e s o l u t i o n , and  M borane i n  The  in  atmosphere o f dry  c o o l e d t o i c e temperature, and  o f 30% hydrogen p e r o x i d e .  room temperature and  173  at room temperature f o r 1.5  20%  sodium h y d r o x i d e  175  under an  (7.4 mmoles) o f 1.33  again  o f 26.6  and  mmoles) o f epoxy o l e f i n  r e a c t i o n m i x t u r e was  to  g  with  protons).  Preparation  ml  o f the r e s i d u e gave 2.6  I t e x h i b i t e d b.p.  _ 3120,  Anal. Calcd. f o r C H,  thoroughly  saturated  sulfate.  o f the r e s i d u a l  105-107° at 0.4  mm)  afforded  - 61 -  2.6 g (93%) o f the d e s i r e d oil.  nicix  9.00  174 and 175 as a c o l o r l e s s  An a n a l y t i c a l sample o f the major isomer was o b t a i n e d  preparative v  epoxy a l c o h o l s  3460,  by  g . l . c . (column G, 165°, 200) and e x h i b i t e d i n f r a r e d 1035 cm" ; 1  (singlet,  p.m.r., x 9.30  ( s i n g l e t , 3H, t e r t i a r y  3H, t e r t i a r y m e t h y l ) , 5.84-6.57 ( m u l t i p l e t ,  (film),  methyl), 2H,  -CH 0H). 2  Mol.  Wt.  Calcd.  mass s p e c t r o m e t r y ) :  Preparation  for  C  H 1 2  20°2  :  1  9  6  -  1  4  6  3  -  Found  (high r e s o l u t i o n  196.1459.  o f Epoxy A c e t a t e s  176 and  177  To a s o l u t i o n o f 2.1 g (10.7 mmoles) o f epoxy a l c o h o l s  174 and  175 i n 14 ml d r y p y r i d i n e was added 5.6 g (56 mmoles) o f a c e t i c anhydride.  This  s o l u t i o n v as :  then d i l u t e d w i t h water.  irrpri  The e t h e r e a l  combined, washed w i t h s a t u r a t e d magnesium s u l f a t e .  ^i-  rp.nm  ip>m'nr'TT?i"iirf^ -  fcv* P. Ti  e x t r a c t s o f t h i s m i x t u r e were  b r i n e , and d r i e d over anhydrous  The s o l v e n t was removed under reduced p r e s s u r e  the r e s i d u e was d i s t i l l e d  a t 99-101° a t 0.5 mm t o g i v e  o f the d e s i r e d p r o d u c t s .  An a n a l y t i c a l sample o f the major isomer  obtained  by p r e p a r a t i v e  (film) v  1740,  m e t h y l ) , 8.97 -0C0CH ), 3  Anal. H,  9.50.  1230,  (singlet,  g . l . c . (column G, 1030 cm" ; 1  for C  H^o  :  and  2.3 g (92%)  180°, 200) e x h i b i t e d i n f r a r e d  p.m.r., x 9.27  3H, t e r t i a r y m e t h y l ) , 7.97  5.47-6.40 ( m u l t i p l e t , 2H, Calcd.  ?rnd  (singlet,  3H,  tertiary  ( s i n g l e t , 3H,  -CH_ 0Ac). 2  C, 70.56; H, 9.30.  Found:  C, 70.43;  - 62 -  Preparation of O l e f i n i c Acetate  178  To a s t i r r e d s o l u t i o n of 12.0 g (30 mmoles) of tungsten hexachlorid i n 40 ml of dry t e t r a h y d r o f u r a n , cooled to -78°, and under an atmosphere of nitrogen was added 25 ml (60 mmoles) of 2.4 M i i - b u t y l l i t h i u m i n hexane.  The s o l u t i o n was then warmed to room temperature  over a 20 min p e r i o d .  A s o l u t i o n of 1.9 g (8 mmoles) of epoxy acetates  176 and 177 i n 5 ml of dry tetrahydrofuran was then added. s o l u t i o n was r e f l u x e d f o r 7 h, cooled to room temperature, i n t o 350 ml of a s o l u t i o n that was i n sodium hydroxide.  This green and poured  1.5 M i n sodium t a r t r a t e and 2 M  This mixture was thoroughly extracted with ether  and the ethereal e x t r a c t s were combined.  This organic e x t r a c t was  washed with saturated b r i n e , d r i e d over anhydrous magnesium s u l f a t e , and then concentrated.  The residue was d i s t i l J e d to a f f o r d 1.6 g  of the o l e f i n i c acetate 178^, b.p. 87-90° at 0.5 mm.  An a n a l y t i c a l  sample, obtained by p r e p a r a t i v e g . l . c . (column F, 180°, infrared (film) v v  ;  1740, m  a  1230,  1  and  9.03  x  ( s i n g l e t s , 6H, t e r t i a r y methyls), 8.04 6.31  200) e x h i b i t e d  p.m.r., T 9.07  1025 cm" :  (90%)  ( s i n g l e t , 3H, ~0C0CH ), 3  5.66-  ( m u l t i p l e t , 2H, -CH_ 0Ac). 2  Mol. Wt. c a l c d . f o r mass spectrometry):  C  H ] 4  2 2  °2  :  222  .1619.  Found (high r e s o l u t i o n  222.1583.  Preparation of the O l e f i n i c Alcohol 179 To a s t i r r e d s o l u t i o n of 1.2 g (5.4 mmole) of o l e f i n i c acetate 178 i n 10 ml of dry ether was added 100 mg aluminum hydride.  (2.6 mmole) l i t h i u m  This mixture was r e f l u x e d , under an atmosphere of  dry n i t r o g e n , f o r 1 h then cooled to room temperature.  The  excess  - 63 -  hydride was destroyed by the a d d i t i o n o f powdered sodium s u l f a t e decahydrate and the r e a c t i o n mixture was f i l t e r e d through  celite.  The f i l t r a t e was concentrated and d i s t i l l e d at reduced pressure to a f f o r d 900 mg (97%) of the o l e f i n a l c o h o l 179, b.p. (hot-box) 8285° at 0.3 mm.  An a n a l y t i c a l sample, obtained by p r e p a r a t i v e g . l . c .  (column G, 160°, 200) e x h i b i t e d i n f r a r e d ( f i l m ) v 3410, 1025 cm" max  1  p.m.r., x 9.14 and 9.08 ( s i n g l e t s , 6H, t e r t i a r y methyls), 6.40 (doublet, 2H, -CH^OH, J = 4 Hz). Mol. Wt. calcd. f o r C mass spectrometry):  H 0:. 180.1514. Q  180.1511.  Found (high r e s o l u t i o n  - 64 -  BIBLIOGRAPHY 1.  M.S. Kharasch and P.O. Tawney, J . Amer. Chem. S o c , 63, 2508 (1941).  2.  H.O. House, W.L. Respess, and G.M. Whitesides, J . Org. Chem., 31, 3128 (1966).  3.  G.H. 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