Studies in asymmetric synthesis

Abstract

It has been shown by McKenzie and his school that when optically active esters of alpha-keto-acids and a Grignard reagent (RgX) interact the diastereo-isomerides are produced in unequal amounts. The substituted glycollic acids, obtained by hydrolysis, were optically active, although not optically pure. The analogous reactions using optically active esters of gamma-, delta-, epsilon- ..... keto-acids had virtually not been studied. In the present investigation the interaction of (-)-menthyl esters of o-acetyl fatty acids and phenyl magnesium bromide has been studied with a view to obtaining asymmetric synthesis and to relating this to the length of the chain intervening between the carbonyl and carbomenthoxy groups. The investigation has entailed the preparation of the above type of esters when n = 0, 2, 3, 4 and 8, and their treatment with phenyl magnesium bromide. The hydroxy-acids or (with n = 2 and 3) lactones, obtained after hydrolysis of the resulting esters, were opticallyactive, except in the case of n = 8. With n = 2 or 3, the degree of asymmetric synthesis was dependent on reaction conditions. The addition of a Grignard reagent to a carbonyl group has previously been found to occur asymmetrically only when the carbonyl group is in a molecule containing, a "fixed centre of asymmetry". It has now been found that an asymmetric reaction occurs when an optically active organo-metallic compound adds to a ketone. This type of reaction has been studied using (-)-menthyl bromoacetate, acetophenone and zinc. The B -hydroxy acid obtained on hydrolysis was optically active. The extent of the asymmetric synthesis was found to be remarkably constant, irrespective of a wide variation in reaction conditions.Theories of asymmetric synthesis are discussed and a theory involving energy differences of two transition states is proposed as an explanation of the results obtained in this investigation. Hydroxy-V-phenyl-n-valeric acid (n = 2) has been prepared and resolved.