Studies related to penicillins. Part 26. Conversion of potassium benzylpenicillinate into 1-substituted derivatives of 3-phenylacetamidoazetidine-2,4-dione

Abstract

A new method for the synthesis of azetidine-2,4-diones, involving a Norrish Type II photoreaction of 4-pyruvolyazetidin-2-ones, has been devised. The process features in two strategies in which potassium benzylpenicillinate (17a) is converted into 1-substituted 3-phenylacetamidoazetidine-2,4-diones.

In one strategy, (1R,5S)-3-benzyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-ones substituted at position 6 by methyl, p-nitrobenzyl, and methoxymethyl esters of a 1-carboxy-2-methylprop-1-enyl moiety [i.e. compounds (14a–c)] were treated with pyruvic acid. A displacement reaction ensued in which the acid cleaved the C-5–O-4 bond of the substrate with an inversion of configuration to give the corresponding 1-substituted (3R,4R)-3-phenylacetamido-4-pyruvoyloxyazetidin-2-ones (10a–c). Under photolytic conditions, compounds (10a–c) were converted into the 1-substituted 3-phenylacetamidoazetidine-2,4-diones (15a,b,e). The oxadiazabicycloheptenones (14a–c) were derived from the corresponding 1-substituted (2R,3S)-4-oxo-3-phenylacetamidoazetidine-2-sulphinic acids (19a–c) by a novel oxidative desulphinytation induced by lead (IV) acetate.

In the second strategy, (1S,5R)-3-benzyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-ones substituted at position 6 by 1-methoxycarbonyl-2-methylprop-1-enyl, (1S)-1-methoxycarbonyl-2-methyl-2-methylthiopropyl, and (3R)-4,4-dimethyl-2-oxothietan-3-yl entities [i.e. compounds (13a), (18a), and (25)] were treated with pyruvic acid to give the corresponding (3S,4S)-3-phenylacetamido-4-pyruvoyloxyazetidin-2-ones (9a), (22), and (24). Whereas the photolyses of compounds (9a) and (24) proceeded in the expected manner to give the azetidinediones (15a) and (23), loss of methanethiol accompanied the Norrish Type II reaction of the pyruvate (22) to give the azetidinedione (15a).

The methoxymethyl ester (15e) was transformed into the carboxylic acid (15c) by the action of trifluoroacetic acid. Compound (15c) lacked antibacterial activity and β-lactamase inhibitory properties.