John C. Sheehan

THE CHEMISTRY OF SYNTHETIC AND SEMISYNTHETIC PENICILLINS

The “semisynthetic” penicillins constitute the outstanding example of the significant improvement in clinical effectiveness of an antibiotic by chemical alterations of the molecular structure. More than 4,000 new penicillins have been prepared by chemical acylation of the “penicillin nucleus,” or 6-aminopenicillanic acid (6APA). In 1957, my laboratory at Massachusetts Institute of Technology completed the first rational total synthesis of a natural penicillin (penicillin V).l This synthesis was the culmination of a nine-year research project and was supported financially by Bristol Laboratories, Syracuse, N. Y. Two routes were used, one involving the cyclization to a p-lactam by our carbodiimide method of an intermediate which carried the “side-chain” (phenoxyacetyl) . In the second scheme, “side-chains” were attached by chemical acylating agents to 6APA, the penicillin nucleus. The second route constitutes the first, and to this date the only, total general synthesis of the penicillins. The concept of synthesizing both natural and side-chain modified penicillins by chemical acylation of 6APA, as originally conceived and carried out in my laboratory, has been exceedingly fruitful. The original successful experiments were the subject of a patent application dated March 1, 1957, and since issued as the broad, basic patent covering both synthetic and semisynthetic penicillins (J. C. Sheehan, U.S. 3,159,617). At a Ciba Conference in London in March, 1958, (published later that same year2) I announced, “we have prepared this compound (6APA) via a totally synthetic route . . . We have shown that one can acylate with various acid chlorides and obtain the corresponding penicillins.” Details of the general penicillin synthesis have been reported by Sheehan and Henery-Logan3 in 1959 and 1962. The general total synthesis of the penicillins solved a classic problem dating from the extensive and intensive World War 11 effort* and is the most elegant from an organic chemical point of view. Also, in principle, total synthesis affords an opportunity for extensive modifications of the ring system, which biochemical methods in general do not. However, a total synthesis is necessarily a multistep process, and, although each step proceeds in good yield, the process is not competitive industrially with subsequently developed biochemical and microbiological methods. A major practical contribution5 came from a group at Beecham Laboratories in England (1959) who made the important observation that Penicillium chrysogenum, cultured in the absence of side-chain precursors, produced substantial quantities of the same key intermediate we had made by total synthesis, namely 6APA. In the next year (1960), four laboratories5-* developed independently enzymatic methods for side-chain removal from natural penicillins ( G and V.) to yield the same nucleus (6APA). These low-cost biochemical methods, together with the chemical acylation procedure for 6APA first devised and applied in my laboratory, provided the thrust for the spectacular growth of the “semisynthetic” penicillins. It is of interest to note that two independent Japanese investigators had previously reportedS1O evidence for the existence of a “penicillin nucleus,” but their observations were not further pursued.