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(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.

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An automated process research approach to reaction optimization was developed. Chemical process research can be greatly accelerated by coupling automated synthesis equipment with statistical design of experiments (DoE). With the use of an automated process approach, multiple experiments can be performed in parallel on an automated platform, and multiple parameters that may influence process performance can be examined within one set of experiments generated from statistical design. We have successfully applied an automated process research approach to optimize the Friedel-Crafts acylation reaction that was used in our total synthesis of (+)-calanolide A, a potential anti-HIV agent currently in clinical trials. The in situ yield for a coumarin product was successfully optimized, increasing from 70% to 97% by HPLC analysis.

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