Total synthesis of analogues of the β-lactam antibiotics. Part 1. Isoclavam-3-carboxylates

Abstract

4-Hydroxymethylazetidin-2-one (15a), prepared from 4-vinylazetidin-2-one (16) by reductive ozonolysis, was converted into 4-iodomethylazetidin-2-one (15c) by sequential reactions involving toluene-p-sulphonyl chloride and sodium iodide. Compound (15c) reacted with methyl glyoxylate hydrate in the presence of triethylamine to give methyl hydroxy-(2-iodomethyl-4-oxoazetidin-1-yl) acetate (13b) as a 1:1 mixture of diastereoisomers, which was transformed into methyl 7-oxo-3-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate (12a), as a single exo-diastereoisomer, by the action of sodium hydride. The t-butyl, p-nitrobenzyl, and benzyl esters of 7-oxo-3-oxa-1-azabicyclo[3.2.0]heptane-2-exo-carboxylic acid, i.e.(12d–f), were similarly prepared.

Brief treatment of the t-butyl ester (12d) with trifluoroacetic acid resulted in β-lactam cleavage to give (2-t-butoxycarbonyl-3-trifluoroacetyloxazolidin-4-yl)acetic acid (19c) which reacted further with trifluoroacetic acid to give (2-carboxy-3-trifluoroacetyloxazolidin-4-yl)acetic acid (19d). Hydrogenolysis of the benzyl ester (12f), in the presence of sodium hydrogen carbonate, afforded the sodium salt (12b) which underwent rapid β-lactam cleavage in aqueous solution.