Configuration 6-aminopenicillanic acid

Let us look at the common substracture of the penicillin antibiotics, namely 6-aminopenicillanic acid, to illustrate some aspects of working out whether a chiral centre is allocated the I or 6 configuration. 

N, in a cell-free extract of Cephalosporium acremonium.154 Only the naturally occurring tripeptide with the LLD-configuration was utilized for biosynthesis, from which it is clear that L-valine is built into the tripeptide with inversion of configuration and that later formation of penicillin N involves an epimerization in the a-aminoadipyl moiety. Although in these experiments only the valine fragment of the precursor was labelled, intact incorporation is indicated by the failure of L-cysteinyl-D-valine or 6-aminopenicillanic acid (160) to act as penicillin precursors, and by the observation that the formation of labelled valine could not be detected in the feeding experiment with (159). 

The synthesis of (6S)-cephalosporins from 6-aminopenicillanic acid derivatives 90 has been achieved by two routes. The Morin penam sulfoxide-cephem rearrangement was shown to be a practical method for the preparation of cephalosporins 91 with unnatural configurations <00T6053>. 

Treatment of 6-aminopenicillanic acid with excess benzaldehyde at pH 7.5 led to direct 6a-hydroxybenzylation in the form of imine 264. Mild acid hydrolysis of this material followed by phenylacetylation provided a single, poorly active product (265) of undefined configuration. 

---