' Structural Differentiation in Asymmetric Reactions 173 



found in certain addition reactions to carbonyl groups. An analogy 

 between asymmetric additions and the differentiation of identical sub- 

 stituents has been pointed out by Schwartz and Carter, 4 who suggest 

 that the "two bonds" linking C and a in a = Cbc (or perhaps more 

 appropriately the two layers of high electron density occupied by the 

 7r electrons) could be considered to correspond to the two a groups of 

 the ordinary meso carbon atom. The following example has been 

 studied most thoroughly. The symmetric a-keto acid RiCOCOOH is 

 esterified with the optically active alcohol H (OH) Cab; the resulting 

 ester XXIII is treated with the Grignard reagent R 2 MgX and then 



j> -• OM.X 



A _A„/ H A_/V/ H 



COOH 



R. C C *- R, C C »-HO— C»-R, 



II / \ II / \ : 



O a b O a b R, 



XXIII XXIV XXV 



hydrolyzed to furnish the hydroxy acid XXV, which generally is found 

 to consist of an unequal mixture of the two antipodes. Their propor- 

 tion does not depend on the relative stabilities of the intermediate 

 Grignard complexes XXIV, since an exchange of the alkyl groups 

 between the keto acid and the Grignard reagent alters the sign of rota- 

 tion of the resulting hydroxy acid. The steric result, therefore, is 

 determined not by the nature of the product but by the mechanism 

 of the addition reaction. Prelog et al. 14 were able to relate the direct- 

 ing influence of the alcohol H(OH)Cab to the bulk and orientation 

 of the alkyl substituents a and b and therefore presumably to their 

 differential ability to block the approach of the Grignard reagent to 

 the keto group. Although the distance between the blocking group 

 and the site of the reaction is rather large, the steric selectivity went 

 as high as 69% excess. Even greater predominance of one isomer 

 may result if the keto group and the directing asymmetric center are 

 adjacent to each other. 1 ' 15 



These results seem sufficiently encouraging to warrant the view that 

 even a single linkage between an enzyme and its substrate might ex- 

 plain a substantially complete differentiation of identical groups. This 

 seems conceivable also in terms of a modified Ogston scheme if one 

 assumes that the steric hindrance effects near the catalytic center are 

 so graded and so distributed that only one of the two a groups can 

 approach. As these mechanistic details may well be quite variable 



