The Stereochemistry of beta-Lactam Formation in Penicillin Biosynthesis

Abstract

1 (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. 2 The above cysteines and (2R)-[U-¹⁴C,3,3,3′,3′-³H₄]cystine have been converted to samples of penicillin G by Penicillium chrysogenum. 3 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. 4 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. 5 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.