Arnold Vlietinck

Preparation of 6-epi-phenoxymethyl- and 6-epi-benzyl-penicillin

Base-catalysed epimerisation at position 6 of N-trimethylsilyl derivatives of phenoxymethylpenicillin benzyl ester in the presence of triethylamine and DBN has been investigated. When triethylamine was used as catalyst a 1,4-thiazepine was obtained in addition to a mixture of the penicillin ester with natural configuration and its 6-epimer. No 1,4-thiazepine was formed when DBN was used as an epimerisation catalyst. The method was also extended to the trimethylsilyl esters of phenoxymethyl- and benzyl-penicillin. The 6-epimers of both penicillins were isolated in ca. 70% yield.

Preparation and deoxygenation of 6-epi-penicillin S-oxides

6-epi-Phenoxymethyl- and 6-epi-benzylpenicillin and their benzyl esters have been prepared by deoxygenation of the corresponding 6-epi-S-oxides. The latter are obtained by epimerisation of the sulphoxides with normal configuration. Various reaction conditions were investigated for this purpose.

Intramolecular nucleophilic attack in 6-epi-ampicillin

6-Epi-hetacillin slowly hydrolyses in neutral aqueous solution to 6-epi-ampicillin, which then gradually cyclizes to 2-(3,6-dioxo-5-phenylpiperazin-2-yl)-5,5-dimethylthiazolidine-4-carboxylic acid by intramolecular nucleophilic attack of the side-chain amino-group upon the β-lactam carbonyl; under the same conditions hetacillin readily hydrolyses to yield ampicillin as sole product.

Isomerisation of benzyl 6-phenoxyacetoxypenicillanates and their S-oxides.

The preparation of benzyl 6α- and 6β-phenoxyacetoxypenicillanate and their (S)- and (R)-S-oxides is described. No epimerisation was observed when benzyl 6α- or 6β-phenoxyacetoxypenicillanate or benzyl 6α- or 6β-trimethylsiloxypenicillanate was treated with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Benzyl 6β-phenoxyacetoxypenicillanate (S)-S-oxide was transformed into the 6α-isomer with DBN as catalyst; the converse reaction was not observed. With both isomers in these experiments, the phenoxyacetoxy side chain was hydrolysed to a large extent.