The Stereochemistry of beta-Lactam Formation in Penicillin Biosynthesis

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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.

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