Studies on the biosynthesis of β-lactam antibiotics. Part I. Stereospecific syntheses of (2RS,3S)-[4,4,4-2H3]-, (2RS,3S)-[4-3H]-, (2RS,3R)-[4-3H]-, and (2RS,3S)-[4-13C]-valine. Incorporation of (2RS,3S)-[4-13C]-valine into penicillin V

Abstract

Syntheses of the title compounds are described. (–)-(2R,3S)-trans-2,3-Epoxybutyric acid was esterified and reduced to (2R,3S)-trans-2,3-epoxybutan-1-ol, which with lithium iodide-free [²H₃]methyl-lithium gave (2R,3S)-3-methyl[4,4,4-²H₃]butane-1,2-diol. Treatment of this with sodium metaperiodate gave [3,3,3-²H₃]-isobutyraldehyde (not isolated) which was converted into the aminonitrile, and thence into (2RS,3S)-[4,4,4-²H₃]valine. N.m.r. studies on the enzymatically resolved valine and its acetate established the stereochemical homogeneity of the labelling. (2RS,3S)-[4-¹³C]- and (2RS,3S)-[4-³H]-Valine were synthesized by the same route, by using [¹³C]methyl-lithium and [³H]methyl-lithium respectively. Similarly, (2RS,3R)-[4-³H]valine was synthesized from (2S,3R)-trans-2,3-epoxybutyric acid.

(2RS,3S)-[4-¹³C]Valine was incorporated into phenoxymethylpenicillin, the ¹³C n.m.r. spectrum of which showed an enhanced signal for the α-methyl group.