same absolute configuration about these three centers. The carbon atom bearing the acylamino group (C-6) has the l configuration, whereas the carbon to which the carboxyl group is attached has the d configuration. Thus, the acylamino and carboxyl groups are trans to each other, with the former in the a and the latter in the 33 orientation relative to the penam ring system. The atoms composing the 6-aminopenicillanic acid (6-APA) portion of the structure are derived biosyntheti-cally from two amino acids, l-cysteine (S-1, C-5, C-6, C-7, and 6-amino) and l-valine (2,2-dimethyl, C-2, C-3, N-4, and 3-carboxyl). The absolute stereochemistry of the penicillins is designated 3S:5R:6R, as shown below.
Examination of the structure of the penicillin molecule shows that it contains a fused ring system of unusual design, the 3-lactam thiazolidine structure. The nature of the 3-lactam ring delayed elucidation of the structure of penicillin, but its determination resulted from a collaborative research program involving groups in Great Britain and the United States during the years 1943 to 1945.14 Attempts to synthesize these compounds resulted, at best, in only trace amounts until Sheehan and Henery-Logan15 adapted techniques developed in peptide synthesis to the synthesis of penicillin V. This procedure is not likely to replace the established fermentation processes because the last step in the reaction series develops only 10% to 12% penicillin. It is of advantage in research because it provides a means of obtaining many new amide chains hitherto not possible to achieve by biosynthetic procedures.
Two other developments have provided additional means for making new penicillins. A group of British scientists, Batchelor et al.16 reported the isolation of 6-APA from a culture of P. chrysogenum. This compound can be converted to penicillins by acylation of the 6-amino group. Sheehan and Ferris17 provided another route to synthetic penicillins by converting a natural penicillin, such as penicillin G potassium, to an intermediate (Fig. 8.1), from which the acyl side chain has been cleaved and which then can be treated to form biologically active penicillins with various new side chains. By these procedures, new penicillins, superior in activity and stability to those formerly in wide use, were found, and no doubt others will be produced. The first commercial products of these research activities were phenoxyethylpenicillin (phenethicillin) (Fig. 8.2) and dimethoxyphenylpenicillin (methicillin).
The early commercial penicillin was a yellow-to-brown amorphous powder that was so unstable that refrigeration was required to maintain a reasonable level of activity for a short time. Improved purification procedures provided the white
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