Amstein tripeptide

J.E. Baldwin (1975, 1976A) has developed a biomimetic synthesis which is loosely analogous to the biosynthetic pathway which starts with the so-called Amstein tripeptide. Baldwin used bicyclic dipeptides more suitable for stereoselective in vitro syntheses. 

The elucidation of the mechanism of biosynthesis of penicillin stemmed from the discovery that isotopically labelled cysteine and valine were used in the assembly of penicillin by Penicillium chrysogenum (Amstein and Grant, 1954 Amstein and Clubb, 1957). Cysteine and valine together with a-aminoadipic acid are used by Cephalosporium acremonium to synthesise penicillin N (8.27) and cephalosporin C (8.28). Evidence was accumulated that a tripeptide, h-(f.-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV) was formed as an intermediate. Since this tripeptide is not transported into mycelial cells, it must be synthesised intracellularly and synthesis of penicillin from the isotopically labelled tripeptide was demonstrated using a cell-free system. Clearly, ACV is not produced by a ribosomal synthesis of a protein followed by proteolytic processing. The enzyme involved, ACV synthetase, not only forms the two peptide bonds but also epimerises the valine residue. Thus, incubation of [2-2H]-valine with purified ACV synthetase completely removed deuterium... 

The intCTvening steps between the tripeptide or amino-acid constituents and p-lactam products remain a mystery. Closely related proposals involving a dehydrovaline tripeptide by Amstein (Scheme 1) and Baldwin (Scheme 2) have been advanced. Thioaldehyde (5), a postulated intermediate in Scheme 1 and one which by simple tautomerism could afford the... 

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