Preparation of the four stereoisomers of isoleucine.

L-Isoleucine was discovered in 1904 by Ehrlich (l), and its constitution established 3 years later (a) by degradation to d-isoamylamine and (b) by synthesis through the Strecker reaction with d-isovaleraldehyde (2). The synthetic product, however, appeared on fractional crystallization to be optically inhomogeneous, and Ehrlich attributed this to the presence in nearly equal parts of natural isoleucine and of a diastereoisomer, to which he gave the designation of alloisoleucine (2).’ A similar epimeric mixture could also be obtained by subjecting naturally occurring L-isoleucine to the prolonged action of hot concentrated baryta under pressure (2). With either of these procedures, followed by digestion of the products by yeast, which converts n-isoleucine into d-isoamyl alcohol, etc., the alloisoleucine could subsequently be readily isolated. This isomer, which in the present nomenclature would be called n-alloisoleucine, possessed an [a], at 20” = -36.80” in comparison with the value of [cu], at 20” = f36.80” for Lisoleucine (both in 20 per cent HCl) (1). These two stereoisomers differed in the configuration at the Qbut possessed the same configuration at the P-carbon atom. Together with their enantiomorphs, the theoretical number of stereoisomers of isoleucine is therefore four. A total synthesis of isoleucine by Bouveault and Locquin (4) was followed by the resolution of the racemate by Locquin through the fractional crystallization of the brucine salts of the corresponding N-formyl derivatives (5) ; [a], at 20” for L-isoleucine was +40.61” and for n-isoleucine was -40.86” (in 6.1 N HCl). Shortly thereafter Ehrlich developed a synthesis of isoleucine based on the reaction between malonic ester and secbutyl iodide (6), and, after digestion of the synthetic product with yeast, obtained a n-isoleucine preparation with [o& at 20” = -40.07” (7). The possibility that total synthetic routes to isoleucine might lead to a