The Stereochemistry of β‐Lactam Formation in Penicillin Biosynthesis

Abstract

(2R,3S)‐[U‐14C,3‐3H1]‐ and (2R,3R)‐[U‐14C,2,3‐3H2] Cysteine hydrochlorides have been separately synthesised. The latter compound has been shown to have uniform distribution of tritium between C‐2 and C‐3. The above cysteines and (2R)‐[U‐14C,3,3,3′,3′‐3H4]cystine have been converted to samples of penicillin G by Penicillium chrysogenum. Incorporation results indicate that all but 14% of the tritium is lost from the (2R,3S)‐[3‐3H1]isomer; that 42% of tritium is retained by the non‐stereospecifically C‐3 tritiated cystine; and that 58% of tritium is retained by the (2R,3R)‐[2,3‐3H2]isomer on conversion to penicillin G. Degradation of the penicillin G derived from (2R,3R)‐[U‐14C,2,3‐3H2]cysteine hydrochloride has indicated that in fact about 87% of the original C‐3 tritium of cysteine is retained at C‐5 of penicillin G. The results indicate stereospecificity in the cyclisation giving rise to the β‐lactam ring in penicillin G in nature with loss of the 3‐pro‐S‐hydrogen and retention of the 3‐pro‐R‐hydrogen of cysteine. Thus there is net retention of stereochemistry in the cyclisation. Copyright © 1977, Wiley Blackwell. All rights reserved