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Asymmetric syntheses in the alkylation of substituted acetic esters Rolston, John Henry 1963

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ASYMMETRIC SYNTHESES IN THE ALKYLATION OF SUBSTITUTED ACETIC ESTERS by JOHN HENRY ROLSTON B. Se Honours, The University of B r i t i s h Columbia, 1962 0  -A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department ,of CHEMISTRY  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA August, 1963  In presenting t h i s  thesis in p a r t i a l fulfilment  of  the requirements for an advanced degree at the U n i v e r s i t y o f : B r i t i s h Columbia,' I agree a v a i l a b l e for .reference  that  the L i b r a r y s h a l l make i t  and study.  I f u r t h e r agree  mission for extensive copying of t h i s  t h e s i s for  freely-  that p e r -  scholarly  purposes may be granted by the Head of my Department or by h i s representatives,,  It  i s understood that copying, or p u b l i - . ' .  c a t i o n of t h i s t h e s i s for f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n p e r m i s s i o n .  ABSTRACT  An attempt has been made to develop a model f o r p r e d i c t i n g the course of an asymmetric a l k y l a t i o n .  Thus,  by considering the influence of an asymmetric center upon a reaction center located i n an adjoining plane, a preferred conformation of the intermediate anion i s selected©  This  conformation i s used to predict the stereochemistry of the product.  The model c o r r e c t l y predicts the stereochemical  r e s u l t of several reactions known i n the l i t e r a t u r e . The (-) isobornyl and (-) menthyl esters of 2-methylbutyric acid were alkylated with 1-bromobutane i n 42% y i e l d .  Both of the alkylated esters were reduced with  l i t h i u m aluminium hydride and the 2-me thyl-2-ethylhexan-l-ol i s o l a t e d by gas-liquid chromatography was shown to be o p t i c a l l y inactive.  The lack of an observable r o t a t i o n does not permit a  c r i t i c a l evaluation of the proposed model i n these instances. The major impurities present i n the a l k y l a t i o n of the aforementioned  esters, namely the n-butyl ether of the o p t i c a l l y  active alcohol, have been i d e n t i f i e d by independent syntheses.  ACKNOWLEDGMENTS  The writer wishes to express h i s thanks to Dr» R, E« Pincock f o r h i s understanding, advice and i n s p i r a t i o n during the experimental stages and the writing of t h i s t h e s i s .  TABLE OF CONTENTS  Page. PART I  PART I I (a)  A MODEL FOR PREDICTING THE STEREOCHEMICAL RESULT OF AN ALKYLATION REACTION  1  AN ATTEMPTED EXPERIMENTAL VERIFICATION OF THE MODEL EXPERIMENTAL Preparation of (-) Isobornyl 2-Methylbutyrate  8  Preparation of (-) Menthyl 2-Methylbutyrate  9  A l k y l a t i o n o f (-) Isobornyl 2-Methylbutyrate  10  A l k y l a t i o n of (-) Menthyl 2-Methylbutyrate  12  Reduction of (-) Isobornyl 2-Methyl-2-ethylhexanoate 14 Reduction of (-) Menthyl 2-Methyl-2-ethylhexanoate  15  Alternate preparation of (-) Isobornyl 2-Methyl-2-ethylhexanoate 16 Alternate preparation of (-) Menthyl 2-Methyl-2-ethylhexanoate  17  Preparation of (-) Isobornyl-n-butyl ether  18  Preparation of (-) Menthyl-n-butyl ether  19  Hydrolysis of (.-) Menthyl 2-Methyl-2-ethylhexanoate  19  Cleavage of (-) Menthyl 2-Methyl-2-ethylhexanoate  (b)  with NaNHg  20  I s o l a t i o n of 2-Methyl-2-ethylhexanoic acid  21  A l k y l a t i o n of E t h y l Proprionate  22  RESULTS AND DISCUSSION  25  PART I I I APPLICATION OF THE MODEL TO OTHER REACTIONS  2Q  PART IV  34  ,BIBLIOGRAPHY  LIST OF FIGURES  Page  Table I  E q u i l i b r i u m Ratio of Diastereomeric Esters  Table I I  A l k y l a t i o n Conditions f o r (-) Isobornyl 2-Methylbutyrate  Table I I I  5  11  A l k y l a t i o n Conditions f o r (-) Menthyl 2-Methylbutyrate  13  Diagram I  Resume of Syntheses  24  Equation I  Mechanism of A l k y l a t i o n  26  Equation I I Mechanism of A l k y l a t i o n  26  Diagram I I  31  Summary of Prelog's Rule  PART I  A MODEL FOR PREDICTING THE STEREOCHEMICAL RESULT OF AN ALKYLATION REACTION. Preliminary work (1)  has shown that i t i s possible to  alkylate esters, possessing a weakly a c i d i c o^-proton, with 1-bromobutane, using sodium hydride dispersed i n diglyme as the basic medium.  In order to investigate the p o s s i b i l i t y of an  asymmetric synthesis by t h i s method the a l k y l a t i o n of two esters prepared from 2-methylbutanoic a c i d was studied.  This a c i d was  selected because i t would provide, upon a l k y l a t i o n of the ester, a series of t r i - a l k y l substituted acetates i n which a l l three a l k y l substituents were d i f f e r e n t .  Furthermore, i n view of the p a r t i a l  separation of the diastereomers of (-) menthyl 2-methylbutyrate by d i s t i l l a t i o n (2) and the recent successful application of g a s - l i q u i d chromatography i n separating diastereomeric mixtures, (3) (4), a separation of the diastereomers of the (-) menthyl and (-) isobornyl esters, obtained from the a l k y l a t i o n , appeared f e a s i b l e .  E a r l y work by Prelog (5), concerning the asymmetric addition of Grignard reagents too£-keto e s t e r s . ( I l l ) bears some resemblance to the present study.  Thus both reactions  involve the addition of an a l k y l group to an sp* hybridized 1  carbon atom situated the same number of carbon atoms away from the asymmetric group.  The reactants f o r the two reactions  are considered to be represented as I H and IV r e s p e c t i v e l y .  R  0 C—C *  R-0  ,R'  0  Na  c—c  0  R'  R-0 IV  Prelog was able, on the assumption that the two carbonyl groups preferred a trans orientation with respect to each other, to successfully predict the configuration of the ^-hydroxy a c i d obtained a f t e r removing the asymmetric group by hydrolysis. However, i t i s not possible to apply this model d i r e c t l y to the present a l k y l a t i o n since such an assumption i s not j u s t i f i e d f o r compounds of type IV. In a recent paper (6)  a t h e o r e t i c a l model has been  developed, to explain the influence of an asymmetric carbon atom, R^  9  substituted by large ( L ) , medium (M) and small (S) groups (a) upon an adjacent s p hybridized reaction center.  I t i s found  2  that there are two preferred conformations, represented by V.A and V.B, of the possible r o t a t i o n a l isomers.  The former i s the preferred conformation when R  2  i s slightly  larger than R-^ and the l a t t e r i s preferred when R^ i s much larger than R^«  Since, the preferred orientation of the plane  defined by groups R-^ and R^, can be s p e c i f i e d by applying these models, the d i r e c t i o n of attack (see arrows) upon a center i n t h i s plane can be estimated.  These ideas were used with success  by Zimmerman i n several examples where the center of attack was the carbon atom to which R^ and R  2  were attached.  In the a l k y l a t i o n of an ester of the general structure  (a)  The l a r g e , medium and small groups are assigned to atoms  l a b e l l e d a, b and c, respectively, i n the diagrams T and IT.  V I the resonance requirements of the anion formed by removal of the proton w i l l place both of the groups ^  and R  2  i n coplanarity  Pi with the -0-C=  grouping.  c-o  /  \' R  3T Thus,, the o r i e n t a t i o n of t h i s plane may be s p e c i f i e d with respect to the asymmetric center, and by using the models V.A and V.B  a  preferred conformation f o r the anion derived from VI can be selected.  9 I t i s noted that the introduction of the -0-C*  grouping  has separated the reaction center from the asymmetric center by the length of these bonds.  However, t h i s f a c t , which tends to lessen  the influence of asymmetric center upon the reaction center, does not remove i t completely since equilibrium mixtures of various o p t i c a l l y active esters show a preference diastereomer.  f o r formation of  one  Five such esters were studied by McKenzie (7) and  the equilibrium r a t i o of the diastereomers are l i s t e d i n table  1.  The absolute configurations of these acids studied by McKenzie are known.  The levo-rotating chloro and bromo phenyl acetic acids  have been correlated with (+) hydrotropic a c i d (8) and with  (-) mandelic acid (9). Mislow has a l s o , i n turn, correlated (-) mandelic acid to (-) l a c t i c acid (10)• TABLE 1 Alcohol  R  E q u i l i b r i u m Ratio (+) Acid (-) Acid  2  *  5%  47%  CI  M%  53%  (-) Menthol  CI  42%  58%  4.  [-) Menthol  Br  Mfo  5%  5.  [-) Menthol  OH  54%  Wo  1.  {+) Borneol  CI  2.  (-) Borneol  3.  t  I t i s i n t e r e s t i n g , that i f the model V.B i s used with the assumption that Rg))  then the predicted absolute configuration of the acid  agrees with that obtained experimentally f o r examples 1 to 4 l i s t e d i n Table 1.  With the mandelic ester, example 5  t  a preponderance of the (-) a c i d .  model V.B predicts  However, t h i s f a c t might be  expected since the p o s s i b i l i t y of a hydrogen bonded hydroxyl group might e a s i l y reverse the r e l a t i v e sizes of the R^ and R  2  groups.  In the a l k y l a t i o n of the (-) menthyl and (-) isobornyl esters of ( d l ) 2-raethylbutanoic acid the r e l a t i v e s i z e of the groups R]_ and Rg are very nearly the same, hence, i t i s necessary to use model V.A.  The preferred conformation of the anion, f o r a l k y l a t i o n  of either (-) isobornyl or (-) menthyl 2-methylbutyrate, can then be represented as 711.  L  Thus the predicted configuration of the products from reduction of both the (-) menthyl ester and the (-) isobornyl ester i s represented  as T i l l .  CH  3  i I  C H F=-h== CH 0H J  4  2  9  I I I  C H 2  5  -On the basis of Brewster's Rules (11)  t h i s configuration i s expected  to have a p o s i t i v e sign of r o t a t i o n . In order to obtain and to measure the o p t i c a l r o t a t i o n of pure samples of p o t e n t i a l l y asymmetrically  synthesized material  i t was necessary to remove the o p t i c a l l y active alcohol from the . t r i a l k y l substituted acetic esters 1 and 11.  This was accomplished  by reducing the ester with l i t h i u m aluminium hydride to give the o p t i c a l l y active alcohol and 2-methyl-2-ethylhexan-l-ol.  This  procedure avoided the low y i e l d s accompanying hydrolysis of such highly hindered esters and permitted the use of gas-liquid chromatography to p u r i f y the 2-methyl-2-ethylhexan-l-ol ((Vlll).  -8PART I I  AN ATTEMPTED EXPERIMENTAL VERIFICATION OF THE MODEL.  (a)  EXPERIMENTAL  Preparation of (-) Isobornyl 2-Methylbutyrate. The  (-) isoborneol (b) (11.0 g. .072 moles) was  dissolved i n 50 ml* of anhydrous p y r i d i n e .  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 continuously during the dropwise addition of 9,4 (.080  g.  moles) of (dl) 2-methyroutyryl c h l o r i d e . When the addition  was completed the temperature was r a i s e d t o , and maintained at 85° f o r 48 hours.  The reaction mixture was  allowed to c o o l to  room temperature whereupon 300 ml. of water were added. solution was  then a c i d i f i e d to pH 6 with concentrated B  The  hydrochloric  a c i d and extracted with 30-60° petroleum ether (2x75 ml©).  The  combined ether l a y e r s were washed well with 5% hydrochloric a c i d (5x50 ml.) and with water (2x25 ml.).  A f t e r drying over anhydrous  sodium sulphate the solvent was removed under water-tap vacuum. The o i l obtained was c a r e f u l l y sublimed at 2 mm of Hg with temperatures up to 95°.  This sublimation was repeated several  times i n order to remove any unreacted (-) isoborneol. d i s t i l l a t i o n gave 3.5 g. (50$) at 2 mm.  (b)  A final  of the required ester B.pt. 100-101°  Gas-liquid chromatography of t h i s material showed the  The (-) isoborneol was prepared from reduction of (+) camphor  according to the method of W. G. Brown (12) M.pt. r  I  213-214°  2 6  L<A>J  =  -29.06° c ° 2,67  i n ethanol.  The l i t e r a t u r e (13) reports ethanol.  presence of a 5% impurity.  A sample, free of t h i s impurity,  was obtained by gas-liquid chromatography on a 10 foot Carbowax column a t 80°  o  An i n f r a r e d spectrum showed peaks a t 2960 c m ( s )  2880 cm~'(m) 1775 cm'(s) 1460 cm'(m) 1265 cm'(w) 1185 cm'(m) 1155 cnf'(m) !080 cm'(w) 1050 cm'(w) and 1015 cm'(w). Analysis Calculated f o r C-^HggOg Found  C, 75.58£  H, 10.99^  C, 75.39%  H, 11.06?$  Preparation of (-) Menthyl 2HTCethylbutyrate The (-) menthyl ester was prepared i n 81% y i e l d using the procedure outlined f o r the (-) isobornyl ester.  However,  10.0 g. (.064 moles) of (-) menthol (c) and 7.7 g. (.064 moles) of the acid chloride were used. at 100°.  The reaction was run f o r 25 hours  Some unreacted (-) menthol was removed by passing the  o i l , obtained after removal of the solvent, through an alumina column, using 30-60 petroleum ether as the e l u t i n g solvent.  The  alcohol remained on the column while the ester passed through, close to the solvent f r o n t .  The f r a c t i o n s containing "the ester  were combined, dried over magnesium sulphate and evaporated to give an o i l .  D i s t i l l a t i o n afforded a center f r a c t i o n (9.4 g.)  B.pt 102-104° a t 1 mm.  (c)  The i n f r a r e d spectrum showed peaks' a t  The (-) menthol was obtained from F i s h e r S c i e n t i f i c Co.,  Fairlawn, N. J .  [j 1  » -40.8 c - 2.34 i n chloroform.  . -10-  2930 cm'(s) 2860 cm'(m) 1725 cm (s) 1460 cm'(broad) 1385 cm'(w) 1370 cm'(w) 1275 cm'(w) 1240 cnf'(wj 1185 cm'(s) and 1150 cm^m). Analysis C, 74.95??  H, 11.74??  C, 74.53??  H, 11.84??  A l k y l a t i o n of (-) Isobornyl 2-Methylbutyrate. A three-necked reaction f l a s k equipped with a reflux condensor and two dropping funnels was set up after c a r e f u l l y drying i n an oven at 110°.  T h i r t y m i l l i l i t e r s of diglyme (d)  f r e s h l y d i s t i l l e d from l i t h i u m aluminium hydride through an 18" Vigereux column were introduced into the f l a s k along with 2.0 g. of sodium hydride (e) free of o i l . ;  The o i l was conveniently removed  by washing with anhydrous ether and f i l t e r i n g under suction.  Under  continuous s t i r r i n g , 7.5 g. (.032 moles) of (-) isobornyl 2-methylbutyrate and 8.6 g. (.064 moles) of 1-bromobutane were added from the dropping funnels.  The temperature was raised to 1 0 0 % ° f o r 24 hours. The  reaction was then cooled to room temperature and a 1 ml. portion was removed,.  This sample was treated according to the procedure  given below f o r the f i n a l work up, using however, appropriately reduced  (d)  The diglyme, bis-(2-methoxyethyl) ether, was obtained from  Eastman Organic Chemicals, Rochester, 3, New York. (e)  A 51% dispersion of sodium hydride i n mineral o i l was supplied  by Metal Hydrides Incorporated, Beverly, Mass.  quantities of reagents.  The course of the reaction was easily-  followed by analyzing t h i s and subsequent samples by g a s - l i q u i d chromatography on a 5 foot Ucon Polar column at  130°.  In a l l attempts l i t t l e , i f any, a l k y l a t i o n occurred i n the f i r s t 24 hours, however, upon the addition of more sodium hydride and 1-bromobutane the a l k y l a t i o n proceeded to give f a i r yields.  The times of the additions and amounts of reagents are  summarized i n Table 11.  Time (hours)  ,  TABLE 11  NaH  (grams)  0  . C^H^Br (moles)  2.0  .064  24  -  .064  48  1.0  .096  72  1.0  .096  96  1.0  .096  120  1.0  .096  The reaction was  cooled to room temperature a f t e r each 24 hour period,  at which time a sample was  taken f o r analysis and the additions of  reagents were made. After a t o t a l reaction time of 144 hours the work up commenced by slowly adding 500 ml. of water.  The s o l u t i o n was  with d i l u t e sulphuric acid and extracted with ether aqueous phase was  was acidified  (2x75 ml.).  The  divided into two parts and to each an additional  500 ml. of water were added.  The solutions were then separately  extracted with ether (2x50 ml.).  The combined ether extracts were  washed well with water (5x50 ml.), dried over magnesium sulphate and evaporated to an o i l . Vacuum distillations of this o i l provided further purification.  Several impurities (1.4 g.) were removed by d i s t i l l i n g  with a pressure of 25 mm of Hg and temperatures up to 1 6 5 ° . The f i n a l d i s t i l l a t i o n gave 3.8 g. (42%) of a clear liquid Bpt. 120-130° at 1 mm. This was shown by gas-liquid chromatography to contain only one component which had the same retention time and infrared spectrum as authentic (-) isobornyl 2-methyl-2-ethylhexanoate ( f ) . Analysis Calculated for \^y^  c  2  Found  > 77.49??  H, 11.64??  G, 77.51??  H , 11.53??  The major component present in the i n i t i a l fraction was further purified by gas-liquid chromatography and comparison of its retention time and infrared spectra with those of a known sample of (-) isobornyl n-butyl ether proved i t s identity Analysis  (f).  .  Calculated for C-^HggO Found  C, 79.94??  H , 12.46??  C, 80.47??  H, 12.86??  Alkylation of (-) Menthyl 2-Methylbutyrate The alkylation was carried out using the procedure outlined  (f)  The reference sample was prepared as shown i n diagram T,  f o r the (-) isobornyl ester.  However, 16.0  g. (.066  was used i n 50 ml. of f r e s h l y d i s t i l l e d diglyme.  moles) of ester  I t was  also necessary,  as i n the previous a l k y l a t i o n to make several additions of sodium hydride and 1-bromobutane i n order to force the reaction to completions additions are summarized i n table  These  111.  • -TABLE 111 Time (hours)  NaH  0  (grams)  C  A a H  B r  (moles)  3.4  .132  20  -  .132  36  3.4  .132  56  1.7  .132  72  1.7  .132  The reaction was  run at 100-5  l a s t addition l i s t e d i n table  and i t was  terminated 20 hours a f t e r the  111.  The work up followed the previous procedure and the r e s u l t i n g o i l was vacuum d i s t i l l e d .  The i n i t i a l f r a c t i o n (3.3 g.) was c o l l e c t e d  between 145-150° at 20 mm.  A sample was  p u r i f i e d by g a s - l i q u i d  chromatography on a 10 foot Carbowax column at 100°.  This sample was  shown to be i d e n t i c a l with (-) menthyl n-butyl ether by comparison with authentic material, prepared as shown i n diagram 1. Analysis Calculated f o r C,,H  0  C, 79.18#  H, 13.29#  C, 80.69^  H, 12.94?$  27 Found  The second f r a c t i o n (8.3 g.) d i s t i l l e d between 178-182° at 20 mm  of Hg  -14-  and was  shown to be free of any impurity*  t h e o r e t i c a l amount.  The y i e l d was 42% of the  An i n f r a r e d spectrum was  obtained and i t was  superimposable with that of an authentic sample of (-) menthyl 2-methyl-2-ethylhexanoate ( f ) . Reduction of (-) Isobornyl The reduction was  2-Ifethyl-2-ethylhexanoate. accomplished by slowly adding 3,8  g.  (©013 moles) of the (-) isobornyl ester to a s t i r r e d dispersion of ,40 g, (,38 ether.  moles) of l i t h i u m aluminium hydride i n 75 ml, of anhydrous  The temperature was  r e f l u x i n g was maintained  increased so as to r e f l u x the ether, and  f o r 24 hours.  The reaction vessel was  i n an i c e - 3 a l t bath, whereupon 50 ml. of water were added.  cooled  The  aqueous s o l u t i o n was c a r e f u l l y a c i d i f i e d to pH 6, with d i l u t e a  hydrochloric a c i d , and extracted with ether.  The ether extracts  were dried over magnesium sulphate and evaporated The mixture of the two alcohols was  to an o i l (3.6 g.).  separated by gas-liquid chromatography o  on a 5 foot Apiezon J preparative column at 130 ,  The s p e c i f i c r o t a t i o n  of the (-) isoborneol was unchanged from that used i n the o r i g i n a l preparation of the (-) isobornyl 2-methylbutyrate.  In order to ensure  complete removal of any o p t i c a l l y active impurities the 2-methyl2-ethylhexan-l-ol was  rechromatographed on the same column.  Subsequent  analysis by g a s - l i q u i d chromatography using the most s e n s i t i v e conditions available indicated only one component was present.  The  absolute  r o t a t i o n of t h i s twice p u r i f i e d material was determined on a "neat"  -15-  sample with an automatic polarimeter (g) using a .5 cm. c e l l .  This  was shown t o be 0.000 - .001° and indicates the 2-methyl-2-ethylhexanl - o l was o p t i c a l l y i n a c t i v e .  A sample (.5 ml. i n .2. ml. MeOH) showed  no o p t i c a l a c t i v i t y between 700 and 320 vyi. Analysis  Calculated f o r C H 0  C, 74.93?$  H, 13.97?$  Found  C, 74.91??  H, 14.32?$  g  2 0  Reduction of (-) Menthyl 2-Methyl-2-ethylhexanoate. An 8.0 g. (.027 moles) sample of the ester was reduced by l i t h i u m aluminium hydride according t o the procedure outlined f o r the :(-) isobornyl e s t e r . 7.0 g.  The o i l , , i s o l a t e d from the work up, weighed  The alcohols were separated on a 10 foot Apiezon J column  at 160°.  The s p e c i f i c rotation of the recovered (-) menthol was  unchanged from that of the o r i g i n a l material.  The absolute r o t a t i o n  of the 2-methyl-2-ethylhexan-l-ol was taken after a second p u r i f i c a t i o n on a 5 foot Apiezon J column at 140°.  This was 0.000 - .001°. An  O.R.D. curve (700 - 320 m/) of a neat sample showed no o p t i c a l a c t i v i t y . The i n f r a r e d spectrum was superimposable with that of the 2-methyl-2ethylhexan-l-ol obtained from the (-) isobornyl ester and showed bands at 3350 cm"'(broad) 2950 cm'(s) 2915 cm (s) 2860 cm (m) 1465 cm'(s) 1395 cm'(m) and 1035 cm'(s). Analysis  (g)  Calculated f o r C H 0  C, 74.93?$  H, 13.97?$  Found  C, 74.99^  H, 13.96?$  g  2 0  An ETL-NPL Automatic polarimeter Type 143A, with a mercury l i g h t  SPurce, (5461 2) was used.  -15-  sample with an automatic polarimeter (g) , using a .5 cm, c e l l .  This  o was shown to be 0,000-,00l and indicates the 2-nBthyl-2-ethylhexan-l-ol +  was optically inactive. Analysis Calculated for C H 0 g  2(  Found  C, 74.9$  H, 13,97??  C, 74.91??  H, 14.32??  Reduction of (-) Menthyl 2rM8thyl-2-ethylhexanoate. An 8,0 g, (,027 moles) sample of the ester was reduced by lithium aluminium hydride according to the procedure outlined for the (-) isobornyl ester. 7.0 g. at 1 6 0 ° .  The o i l , isolated from the work up, weighed  The alcohols were separated on a 10 foot Apiezon J column The specific rotation of the recovered (-) menthol was  unchanged from that of the original material.  The absolute rotation  of the 2-methyl-2-ethylhexan-l-ol was taken after a second purification on a 5 foot Apiezon J column at 1 4 0 ° . optically inactive material.  This was 0 . 0 0 0 - . 0 0 i ° indicating  The infrared spectrum was superimposable  with that of the 2-methyl-2-ethylhexan-l-ol obtained from the (-<) isobornyl ester and showed bands at 3350 cm'(broad) 2950 cm'(s) 2915 cm'(s) 2860 cm'(m) 1465 cm'(s) 1395 cm'(m) and 1035 cm'(s). " Analysis Calculated for Found  (g)  C, 74.93??  H, 13.97??  C, 74.99??  H, 13.9^?  An ETL-NPL Automatic Polarimeter Type 143A, with a mercury light  source, (5461 1) was used.  -16-*  Alternate preparation  of (-) Isobornyl  2-Methyl-2rethylhexanoate.  The acid chloride of 2-methyl-2-ethylhexanoic acid  was  prepared, from the acid i t s e l f , by treatment with t h i o n y l chloride as described  i n an e a r l i e r manuscript (1).  (2.3 g. .013  moles) was  (.013  The acid chloride  added dropwise to a s t i r r e d solution of 2.0  g.  moles) of (-) isoborneol dissolved i n 10 ml. of an anhydrous o  pyridine.  The temperature was  f o r 24 hours.  increased to and maintained at 80  The work up followed that outlined f o r the  of (-) isobornyl 2-methylbutyrate and 3.5 isolated.  preparation  g. of a yellow o i l were  An i n f r a r e d spectrum of t h i s o i l indicated the presence  of unreacted alcohol and acid chloride as well as the required ester. The  acid chloride was  removed by d i s s o l v i n g the o i l i n 20 ml.  of  dimethyl sulfoxide and 5 ml. of 50% aqueous potassium hydroxide and warming the r e s u l t i n g solution f o r 15 minutes on a steam bath. cooling, 150 ml. of water were added and the s o l u t i o n was with concentrated hydrochloric  acid.  After  acidified  The a c i d i f i e d solution  was  extracted with 30-60° petroleum ether and the combined ether extracts were washed well with 5% sodium bicarbonate and f i n a l l y with water. After drying over magnesium sulphate and removing the solvent an o i l (2.8 g.) was  obtained, the i n f r a r e d of which showed the absence of  the acid chloride.  The  (-)  isoborneol was  r e s i d u a l o i l at a pressure of 1 mm A f i n a l d i s t i l l a t i o n gave 1.3 129-130° at 1 mm. only one peak.  then sublimed from t h i s  of Hg and temperatures up to 40°.  g. (35%)  of a c l e a r white l i q u i d  Gas-liquid chromatography of t h i s material  B.pt. indicated  Further attempts were made to separate the diastereomeric  -17-  aixture on a 5 foot column (20?? Ucon Polar on f i r e b r i c k ) and on a 10 foot column (20% Carbowax 20-M on f i r e b r i c k ) . No separation was -i  \  obtained.  -i  The i n f r a r e d spectrum had bands at 2960 cm (s) 2885 cm (m)  1725 cm'(s) 1465 cm'(m) 1380 cm'(w) 1150 cm'(m) and 1050 cm'(w). Analysis Calculated f o r ^ ^ 1  3  5  °  2  Found  C, 77.49??  H, 11.64??  C, 77,77??  H, 11.28??  Alternate preparation of (-) Menthyl 2-Methyl-2-8thylhexanoate. The procedure was s i m i l a r to that outlined f o r the preparation of (-) isobornyl 2~methyl-2-ethylbutyrate, however 4.1 g. (.027 moles) of (-) menthol and 4.3 g. (.024 moles) of the 2-methyI-2-ethylhexanoyl chloride were used.  The reaction was run at 105° f o r 24 hours. The  011 i s o l a t e d a f t e r removal of the solvent contained some unreacted (-) menthol. This was removed by placing the o i l on an alumina column and e l u t i n g with 30-60° petroleum ether.  The ester passed through the  column e a s i l y , the (-) menthol remained on the column. A f t e r combining the f r a c t i o n s containing the ester and removing the solvent a vacuum d i s t i l l a t i o n afforded 3.7 g. (48??) of the (-) menthyl-2-aethyl-2-ethyl hexanoate.  The i n f r a r e d spectrum showed c h a r a c t e r i s t i c peaks at  2925 cm'Cs) 2855 cm'(m) 1715 cm'(s) 1460 cm'(s) 1380 cm'(m) 1370 cm (sh) 1160 cm'(sh) and 1145 cm'(s). Analysis Calculated f o r C Found  l 9  H  3 6  o  2  C, 76.97??  H, 12.24??  C, 77.02??  H, 11.75??  •IS-  Attempts to separate the mixture of diastereomers were unsuccessful. Columns of 20$ Ucon Polar (5 f o o t ) , 20$ S i l i c o n e GE-SF-96 (10 foot) and  20$ Apiezon J (10 foot) on f i r e b r i c k were used.  Preparation of (-) Isobornyl-n-butyl ether. The  (-) isoborneol (5,0 g. ,032 moles) was dissolved i n  15 ml, of diglyme containing 1.5 g, of sodium hydride (e) which had been washed with anhydrous e t h y l ether to remove the hydrocarbon o i l . Following t h i s , 8,8 g  8  (©064 moles) of 1-bromobutane were added and o  the  reaction temperature was increased to 100 f o r 24 hours.  After  cooling, 150 ml, of water were added. The r e s u l t i n g solution was a c i d i f i e d with concentrated hydrochloric acid.and extracted twice with ether.  The combined ether extracts were washed f i v e times with water,  dried over magnesium sulphate and evaporated to an o i l .  The unreacted  (-) isoborneol (,.75 g,) was removed by room temperature sublimation a t 15 mm of Hg, The f i n a l d i s t i l l a t i o n gave 1,2 g. of a water white l i q u i d B p t 116-118? at 15 mm. e  This was 21$ of the t h e o r e t i c a l amount  based upon the (-) isoborneol consumed. a 5 foot Apiezon J column at 180°.  The compound was p u r i f i e d on  The i n f r a r e d spectrum showed peaks  at 2940 cm'(s) 1870 cm'(m) 1475 cm'(sh) 1455 cm'(m) 1390 cm (w) 1370 em'(w) 1115 cm"'(s) and 1095 cm"'(s). Analysis C, 79.94$  H, 12.46$  C, 80.02?$  H, 12.61$  -19-  Preparation of (-) Menthyl-n-butyl ether. The (-) menthyl-n-butyl ether was prepared using the procedure described f o r the (-) isobornyl ether. were used, however the reaction was run at 120 24 hours.  o  The same quantities instead of 100  o  for  The crude material i s o l a t e d as an o i l was shown by gas-  l i q u i d chromatography to contain some unreacted (-) menthol.  This  was removed by passing the o i l through an alumina column as described i n the p u r i f i c a t i o n of,(-) menthyl-2-methyl-2-ethylhexanoate.  The  o i l i s o l a t e d from the chromatography was vacuum d i s t i l l e d , the main f r a c t i o n was c o l l e c t e d at 76-77° at 1 mm of Hg and weighed 2.5 g.., representing 37?? of the t h e o r e t i c a l amount. showed bands at 2950 cm'(s) 2910  The i n f r a r e d spectrum  cm"'(s) 2860 cm'(s) 1640 cm'(broad)  1375 cm'(w) and 1110 cm'(s). Analysis Calculated f o r Cj^H Found  0  C, 79.18??  H , 13.29??  C, 79.82??  H , 12.68??  Hydrolysis of (-)-Menthyl-2-Methyl-2-sthylhexanoate. Basic hydrolysis of the (.-) menthyl ester was attempted using the procedure of Brandstrom (14). However, even a f t e r an extended run of 24 hours at 110° the ester was recovered i n d i c a t i n g v i r t u a l l y no hydrolysis had  occurred.  The next attempt at hydrolyzing the ester involved a c i d i c hydrolysis.  A sample (1.0 g.  .0034 moles)  of -the ester was dissolved  i n 5 ml. of diglyme, f r e s h l y d i s t i l l e d from sodium metal.  To t h i s  •20-  solution was added 5 ml. of concentrated hydrochloric a c i d and the temperature  was raised to 180°.  cooled to room temperature  A f t e r 24 hours the solution was  and 75 ml. of water were added.  s o l u t i o n was then extracted three times with ether.  The  The combined  ether layers were i n turn extracted with 5% sodium bicarbonate s o l u t i o n , d r i e d over magnesium sulphate, and evaporated to an o i l . The o i l was shown by g a s - l i q u i d chromatography to contain diglyme and s t a r t i n g ester.  There was no (-) menthol detected.  The  bicarbonate solution was c a r e f u l l y a c i d i f i e d with hydrochloric acid and extracted with ether.  The ethereal solution a f t e r being  washed with water, was dried and the solvent was removed. material was  No a c i d i c  i s o l a t e d and the hydrolysis was considered unsuccessful.  Cleavage of (-) Menthyl-2-Methyl-2-ethylhexanoate  with sodium amide.  A s o l u t i o n of sodium amide i n 10 ml, of diglyme was  prepared  from 10 ml. of l i q u i d ammonia according to a standard procedure (15), After removal of any excess ammonia the e s t e r , (-) menthyl-2-methyl-2ethylhexanoate (1.0 g.) dissolved i n 5 ml. of diglyme, was added. reaction mixture was heated under s t i r r i n g at 150° f o r 4 hours. cooling, 150 ml, of water were added and the s o l u t i o n was with concentrated hydrochloric a c i d .  The  After  acidified  An ether extraction was done and  the ethereal layer was dried after being washed with water.  Evaporation  of the ether afforded a brownish o i l , the i n f r a r e d spectrum of which indicated a mixture of (—) menthol and the amide of hexanoic  acid.  2-methyl-2-ethyl  -21-  I s o l a t i o n of 2-Methyl-2-ethylhexanoic  acid*  The o i l obtained from the sodium amide cleavage of the (-) menthyl ester was dissolved i n 10 ml. of benzene, d r i e d over sodium wire.  The solution was saturated with hydrogen chloride  gas f o r 15 minutes and following t h i s 1,0 g. of n - b u t y l n i t r i t e (h) was added over 10  minutes.  The s t i r r e d solution was allowed to stand at room temperature f o r 2 hours, during which time the solution turned red and a considerable amount of gas was evolved. hours on a steam bath.  The f l a s k was heated f o r an a d d i t i o n a l 2  A f t e r cooling, the reaction mixture  extracted with 5% potassium hydroxide.  was  The combined basic layers  were back extracted with benzene, treated with charcoal and a c i d i f i e d with concentrated sulphuric a c i d . extracted into ether.  The o i l which separated was  The ethereal s o l u t i o n was dried over magnesium  sulphate and evaporated to an o i l (.53 g,).»  An i n f r a r e d  spectrum  indicated the presence of (-) menthol as well as the free acid, The o i l was dissolved i n ether and extracted three times with 5% sodium bicarbonate s o l u t i o n .  The bicarbonate extracts,=after  a c i d i f i c a t i o n with hydrochloric acid and extraction with ether, gave 150 mg. of a clear o i l . This was 28?£ of the t h e o r e t i c a l amount based on the (—) menthyl 2-methyl-2-ethylhexanoate  (h)  used.  The i n f r a r e d spectra  The n - b u t y l n i t r i t e was prepared according to the procedure given i n  Org. Syn. c o l l , v o l , 2, page 108, using  the quantities l i s t e d .  indicated that no alcohol was present and the spectrum was superimposable with the spectrum of 2-methyl-2-ethylhexanoic acid obtained by a s i m i l a r method ( 1 ) , A l k y l a t i o n of E t h y l Proprionate. The general procedure used was s i m i l a r -to that described f o r the a l k y l a t i o n of (-) isobornyl 2-methylbutyrate. However, the 1-bromobutane and the ethyl proprionate were added i n equal amounts (.098 moles) to one equivalent of sodium hydride dispersed i n 35 ml. of diglyme.  The reaction was run at room temperature f o r 48 hours.  A second addition of .0Q8 moles of both sodium hydride and 1-bromobutane was made a f t e r 24 hours.  The workup followed the previous procedure.  The o i l i s o l a t e d after removal of the solvent was vacuum d i s t i l l e d . The main f r a c t i o n , c o l l e c t e d between 50° and 60° at 8 mm of Hg weighed 1,4 g. and was shown by gas-liquid chromatography to contain 80$ of ethyl 2-methylhexanoate.  This compound was characterized, after  further p u r i f i c a t i o n on a 5 foot Apiezon J column at 140°, by i t s _/  i n f r a r e d spectrum.  -i  Peaks appeared at 2975 cm (s) 2870 cm (m) 1730 cm (s)  1465 cm'^m) 1375 cnf'(m) 1350 cm (w). 1180 cm'(s) 1145 cm'(s) 1095 cm'(w) 1045 cm'(w) 1025 cm'(w) and 860 cm'(w). Analysis Calculated f o r CgH^O^ Found  C, 68.31$  H, 11.47$  C, 69.07$  H, 11.61$  A second run was made with 2 molar equivalents of 1-bromobutane o added i n i t i a l l y . The reaction was run f o r 5 hours at 100 • The o i l  •23'  . i s o l a t e d a f t e r removal of the solvent was d i s t i l l e d at. room temperature f o r 1 hour.  The unreacted ethyl proprionate and 1-bromobutane were  thus removed.  The d i s t i l l a t i o n was continued and the f i r s t f r a c t i o n  (2,5 g») was c o l l e c t e d between 50° and 60° at 8 mm of Hg, This was shown by the r a t i o s of the peak areas of a gas-liquid chromatogram to contain 93$ o f the mono-alkylation product.  The percentage y i e l d ,  based upon the amount of ethyl proprionate consumed, was 20$ of the t h e o r e t i c a l amount,  A second f r a c t i o n (.3 g,) was c o l l e c t e d at  approximately 120° at 8 mm of Hg. This was i d e n t i f i e d by i t s infrared spectrum and a carbon and hydrogen analysis as a condensation product of ethyl-2-methylhexanoate, namely, ethyl-2,4-dimethyl-2-(n-butyl)3-keto-octanoate.  The i n f r a r e d spectrum showed bands at 2940 cm'(s)  2870 cm'(m) 1735 cm'(s) 1705 cm'(s) 1465 cm"'(m) 1380 cm'(w) and 1145 cm'(w). Analysis Calculated f o r C ^ K ^ O ^ Found  C, 71.02$  H, 1 1 . 1 ^  C, 71,22$  H, 10.60$  -24-  CH,  /0-C,H C  NaH  4  H — C - C  CH.  NaOH  o  C H Br 4  5  9  C H 2  0-C,H 2' ' 5  CH-  5  GJi,— C-CO H  H — C - C  CH 2  £  CH  5  CH  5  4  CH 2  I  H-C-COCI I C H *  •  2  'CH, C H -C-C0CI  2  4  9  Z '5  ROH  %  \  C4H9— c—C NaH  CH  CH 2  H-C-C  O-R'  5  UAIH4  +  C H -0-R 4  9  NaH  C4H96Y  O - R  C H 2  5  S0CI  £  CH.  ROH  t  2  5  NQNH  5  CH  9  HCI  9  3  2  4  C H -C-CONH  C H 0H 2  C H 0N0  CH,  5  R-OH  C H —C-CH,OH 4  9  CH 2  R = (-) menthyl or (-) isoborrvy] DIAGRAM 1  5  PART II  AN ATTEMPTED EXPERIMENTAL VERIFICATION OF THE MODEL,  (b) RESULTS AND DISCUSSION  The synthesis of a t r i - s u b s t i t u t e d acetic a c i d , 2-methyl2-ethylhexanoic a c i d , has been accomplished by a l k y l a t i o n of the hindered  (-) menthyl ester of 2-methylbutyrate.  The acid was  shown to be i d e n t i c a l with that obtained from an alternate path (see diagram I ) . was  In both syntheses the t h i r d a l k y l substituent  introduced by a l k y l a t i o n of an ester using sodium hydride  dispersed i n diglyme.  The e t h y l , (-) menthyl and (-)  isobornyl  esters used, vary widely i n structure and the successful a l k y l a t i o n of these esters demonstrates the usefulness o f sodium hydride f o r such r e a c t i o n s  8  Thus, a convenient synthetic route to a t r i -  substituted acetic acid involves the a l k y l a t i o n of an ester by an a l k y l halide using sodium hydride as the base. The mechanism, (see equations £ and I I ) , of the a l k y l a t i o n reaction i s considered to involve an S 2 N  anion on an a l k y l h a l i d e .  attack of a  sodio-enolate  The t r a n s i t i o n state involved i n  equation I I w i l l require the close approach of the a l k y l halide and the anion. R  Hence, i f the anion possesses a dissymmetric center  the approach of the 1-bromobutane i n forming the t r a n s i t i o n  state may  well be favoured i n one p a r t i c u l a r d i r e c t i o n .  -26-  CH  Na  3  I  • H:  C — H *NaH I  C H 2  5  EQUATION 1  |X*C H Br 4  I\  A  9  X.  Q  C - C  '  CH, Q,H  EQUATION For example, i n equation 1,  9  n  the preferred d i r e c t i o n f o r approach of  the 1-bromobutane w i l l be that indicated by arrow A.  Attack from  any other d i r e c t i o n (arrow B) w i l l be l e s s favoured and the r e s u l t i n g product w i l l be of the opposite configuration.  Thus, an asymmetric  synthesis would be expected since the diastereomeric  products w i l l  be formed i n unequal amounts. The absence of an observable r o t a t i o n i n the samples of 2-methyl-2=ethylhexan-l-ol obtained from reduction of the (-) isobornyl and  (-) menthyl esters can be interpreted by s t a t i n g that the amount of  asymmetric induction i n the aforementioned alkylations i s n e g l i g i b l e . Several factors might contribute to t h i s lack of asymmetric synthesis.  -27-  F i r s t l y , the small differences i n free energy between two conformations tend to become of less importance as the temperature i s increased. out  Since McKenzie's equilibrations (7) are c a r r i e d  at lower temperatures than the a l k y l a t i o n s , small differences  i n the free energy of the anions w i l l play a larger part i n determining the r a t i o of the products. A second f a c t o r , inherent i n the p a r t i c u l a r system chosen, may also have disfavoured the predicted asymmetric a l k y l a t i o n .  Thus, there i s probably l i t t l e  difference i n the e f f e c t i v e size of an ethyl and methyl group and, as a r e s u l t , the s t e r i c i n t e r a c t i o n of either group with the asymmetric environment w i l l be very nearly the same.  This f a c t  would tend to remove any free energy difference between two conformations such as IX A and IX B, and i t would be d i f f i c u l t .to predict which of these would be the preferred conformation.  Thus the number of anions with either of these conformations w i l l be the  same and racemic material w i l l r e s u l t .  T h i r d l y , the distance of  the  carbon atom from the asymmetric group may have been s u f f i c i e n t  T28-  i n t h i s instance to remove the influence of the asymmetric group on the two groups attached to the reaction center.  In the e q u i l i b r a t i o n  of 2-phenyl-2-chloro acetates of (-) menthol and (-) borneol c i t e d e a r l i e r , the larger sizes of the groups would s t i l l produce s u f f i c i e n t i n t e r a c t i o n at these distances to permit a preferred conformation be assigned,  to  A fourth f a c t o r which might explain the absence of an  observed r o t a t i o n , even i f an asymmetric a l k y l a t i o n occurred, l i e s i n the magnitude of the r o t a t i o n i t s e l f . of 2-methyl-2-ethylhexan-l-ol  The  ^ / ^ j o f a resolved sample  might well be very small and hence i f  the amount of asymmetric induction was also small, then the r o t a t i o n of the prepared sample could have been l e s s than that detectable with the automatic polarimeter. I d e n t i f i c a t i o n of the (-) isobornyl and (-) menthyl n-butyl ethers as side products to the a l k y l a t i o n r a i s e s the question of t h e i r formation.  Although every reasonable precaution was taken to ensure  anhydrous conditions i t i s not inconceivable a trace of water may have been present.  Thus the formation of sodium hydroxide i n the reaction  media would be expected to hydrolyze the ester and generate the acid and sodium alkoxide. subsequent S 2 N  The ether i t s e l f would then be formed by a  attack of the alkoxide on 1-bromobutane.  A second alternative involves the reduction of the ester with sodium hydride.  This i s seemingly l e s s l i k e l y i n view of the known  inertness of esters to reduction by sodium hydride. The a l k y l a t i o n of e t h y l proprionate was attempted i n order  r  2 9  to determine the course of the reaction when twod-hydrogen atoms were a v a i l a b l e .  As can be seen from the experimental data, the  a l k y l a t i o n proceeded much more r a p i d l y and e a s i l y than with the more highly hindered esters.  The mono-alkylation product appeared  as the major product with none of the d i - a l k y l a t e d ester being detected.  I t i s moteworthy that condensation of the mono-alkylation  product was responsible f o r the major impurity.  This may  be  r a t i o n a l i z e d on the basis of the a c c e s s i b i l i t y of the carbonyl group of ethyl proprionate r e l a t i v e to that of the more highly hindered (-) isobornyl and (-) menthyl esters.  Thus attack of an ambident  anion on the carbonyl group would be expected to be much easier with the e t h y l ester than with either of the l a t t e r mentioned esters. By way of summation i t can be stated that the a l k y l a t i o n did not produce asymmetric material, hence no c r i t i c a l evaluation of the approximations involved i n extending Zimmerman's models can be made.  The i s o l a t i o n and i d e n t i f i c a t i o n of the major impurities  present i n the a l k y l a t i o n products serves to complete the e a r l i e r study  (1).  -30  PART I I I  APPLICATION OF THE MODEL TO OTHER REACTIONS.  The extension of the model developed i n t h i s manuscript to other reactions i s somewhat l i m i t e d by the amount of pertinent experimental data available i n the l i t e r a t u r e .  However, as out-  l i n e d i n PART X , the work of McKenzie on the e q u i l i b r a t i o n of the esters l i s t e d i n table I can be interpreted i n terms of t h i s model i f the r e l a t i v e sizes of the two groups R^ and Rg  can be assignede  I t i s noted that Zimmerman's o r i g i n a l model assumes that only s t e r i c interactions e x i s t between the asymmetrically substituted carbon atom and the groups R  1  and R .  2  Thus, i f no other interactions are  present which a l t e r the preferred conformation of the reacting species, the model i s successful i n p r e d i c t i n g the stereochemical outcome of several reactions, eg. examples 1 to 4 of table I f however, additional forces are present, which i n t e r f e r e with the assignment of a preferred conformation on s t e r i c grounds alone, then the model w i l l be of l i t t l e value.  Thus, example 5  l i s t e d i n table I. w i l l not permit an assignment of a preferred conformation of the anion on the basis of the proposed model, since hydrogen bonding of the (/-hydroxy group introduces a non-steric interaction. Several other examples of reactions which can be interpreted i n terms of the proposed model are found i n the addition of  Grignard  reagents t o , and reduction of, o p t i c a l l y active ^-keto esters.  Prelog,  on the strength of his empirical r u l e was able to p r e d i c t the configuration of the predominent diastereomer i n these reactions. He assumed a trans orientation of the two carbonyl groups and considers three r o t a t i o n a l conformers of the molecule.  The pre-  dominent diastereomer can be predicted from that conformer which has theo^-keto group e c l i p s i n g the smallest substituent on the asymmetric center.  The preferred d i r e c t i o n of attack i s assumed  to be from the l e a s t hindered side as shown i n diagram I I .  DIAGRAM I I The examples,, taken from Prelog's paper (5), i n which the absolute configuration of each product i s known, are l i s t e d i n table IJF along with the observed and predicted signs of rotations of the most abundant a c i d obtained after hydrolysis.  -3.2'  TABLE 17 Alcohol  Observed Rotation  Prelog s Prediction  H  H  (-) L a c t i c  /  ( )  (+) A t r o l a c t i c  A  (-) Menthol  CH  3  (-)• Menthol  CH  3  (-) Menthol  2  +  1  (-) Mandelic  H j  (-) A t r o l a c t i c  (-) Menthol  i  CH, 3  1  (-) Borneol  CH, 3  H  (")  (-) L a c t i c  (+)  (+) A t r o l a c t i c  (")  (-) A t r o l a c t i c  (+)  (+) A t r o l a c t i c  (-) Borneol (-) Borneol  C H  t  (-) 2-0ctanol (-) 2-0ctanol  3  C H  i  C H  3  3  rf  mm  CH  (-) A t r o l a c t i c  The model developed i n t h i s thesis predicts the same conf i g u r a t i o n as Prelog»s Rule f o r a l l those reactions l i s t e d i n table I V i f the following assumptions  are made.  much larger than the,/-keto oxygen.  f  F i r s t , that therfgroup i s very-  Second, that the p^-keto oxygen i s  only s l i g h t l y larger than a methyl group.  Third, that the solvation  of the o^-keto oxygen w i l l not a l t e r the above assignments. In addition to those reactions l i s t e d i n table IV there are several others l i s t e d by Prelog f o r which the absolute configuration of the products are at present unknown. In a l l these cases the present model predicts the same configuration f o r the predominent diastereomer as Prelog's Rule. Thus the present model supplements Prelog*s o r i g i n a l suggestions by allowing a preferred conformation to be selected f o r anions of type IV  as well as f o r o^-keto esters.  Furthermore, i t concurs with the  predictions of Prelog*s Rule i n a l l examples to which the l a t t e r has been applied.  -34-  BIBLIOGRAPHY  1.  Rolston, J . H«, Bo Sc. Thesis, University of B r i t i s h Columbia, May 1962.  2.  B a i l e y , M. E . and Hass, H. B., J . Am. Chem. Soc. 63_, 1969 (1941).  3.  Corey, E . J . and Casanova, J . , Chem. and Ind. 1664 (1961.  4.  Gil-Av, E . and Nurok, D., Proc. Chem. Soc. 146 (1962).  5.  Prelog, V„, Helv. Chim. Acta. 3_6, 308 ( 1 9 5 3 ) .  6. Zimmerman, H. F . and Chang, W. H., J . Am. Chem. Soc. 81, 3634 (1950). 7.  McKenzie, A and Smith, I . A., Ber. 5_8, 894 (1925).  8.  Mislow, K  9.  Hughes, E. D. and Ingold, C. K., e t a l , Nature Lon. 166. 1 7 9  e  and H e f f l e r , M., J . Am. Chem. Soc. J±, 3668 (1952).  (1950). 10.  Mislow, K., J . Am. Chem. Soc. 7_3_, 3954 (1951).  11.  Brewster, J . H., J . Am. Chem. Soc., 81, 5475 (1949).  12.  Brown, W. G., J . Am. Chem. Soc., 71., 1675 (1949).  13.  Lipp, M., Ber. J l , 8 (1941).  14.  Brandstrom, A. and Forsblad, I . , Arkiv f u r Kemi, J5, 361. (1953). Hauser, C.R., e t a l , Org. Rxns., 8, 1 2 2 (1954).  15.  

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