Racemization of Optically Active Aromatic N-Acetylamino Acids and Asymmetric Transformation of N-Acetyl-2-(4-hydroxyphenyl)glycine via Salt Formation with Optically Active α-Methylbenzylamine

Abstract

The racemization rates of N-acetyl-(S)-tyrosine, N-acetyl-(S)-phenylalanine, N-acetyl-(R)-2-(4-hydroxyphenyl)glycine [(R)-AcHpg], N-acetyl-(R)-2-phenylglycine, and N-acetyl-(S)-alanine were measured by use of (RS)-α-methylbenzylamine [(RS)-MBA] as a base-catalyst. The first-order rate constant for racemization tended to increase with an increase in the polar substituent constant of the N-acetylamino acid side chain. The racemization appeared to be subject to the inductive effect by the side chain. An asymmetric transformation of (RS)-AcHpg by using (R)-MBA, based on the result of racemization, gave an optically pure salt of (R)-AcHpg with (R)-MBA by successive use of the filtrate as the solvent. Optically pure (R)-2-(4-hydroxyphenyl)glycine [(R)-Hpg] was separated from the salt in 87–90% yield based on the starting (RS)-AcHpg. In addition, the asymmetric transformation of (R)-AcHpg was achieved by using (S)-MBA to give optically pure (S)-Hpg in 80% yield after purification of the salt of (S)-AcHpg with (S)-MBA followed by hydrolysis.

Crystallization-Induced Diastereomer Transformations

“…20 p-Hydroxyphenylglycine 43 has attracted special attention from various groups, due to its utility as a side chain in semisynthetic penicillins and cephalosporins such as amoxicillin, cefadroxil, cefatrizine, cefaparole, and cefoperazon. In a systematic study Shiraiwa and co-workers 89 found that the rate of racemization of N-acetyl-amino acids increases proportionally with Taft's polar substituent constant (σ*) of the amino acid side chain and also with increasing amounts of the (R)-R-methylbenzylamine (R*NH 2 ) resolving agent. On this basis they developed a CIDT in which racemic N-acetyl-4-hydroxyphenylglycine 42 is converted in 95% yield to the (R,R)-salt (90-93% de) via heating with at least a 5-fold excess of the amine in a 5:1 mixture of cumene and 1-hexanol at reflux (150 °C) for 3 h (Scheme 25).…”

Process Paths of Kinetically Controlled Crystallization: Enantiomers and Polymorphs

“…Investigations of the reaction kinetics of free amino acids in buffered aqueous solutions indicate that reversible first-order rate laws are valid; however, some peptides and proteins have more complex kinetics . Rate constants for racemization have been measured for several molecules, − with additional values cited in the review by Bada . Typical values of the rate constant k r range from 1 × 10 -4 to 1 × 10 -1 s -1 .…”