Total synthesis of β-lactamase inhibitors based on the 4-oxa-1-azabicyclo[3.2.0]heptan-7-one ring system

Abstract

4-(2-Bromoethoxy)azetidin-2-one (4), 4-(1,3-dibromoisopropoxy)azetidin-2-one (5), 4-(1-benzyloxy-3-chloroisopropoxy)azetidin-2-one (6), 4-[(1-bromomethyl)prop-2-enoxy]azetidin-2-one (7), and 4-[3-bromo-1(bromomethyl)propoxy]azetidin-2-one (8) have been synthesised and their use for the preparation of bicyclic β-lactam compounds has been investigated. On treatment with base, (4) gave 4-oxa-1-azabicyclo[3.2.0]heptan-7-one, (5) gave (3RS, 5SR)-3-(bromomethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (9) and its (3RS, 5RS)isomer (21), and (6) gave (3RS, 5SR)-3-(benzyloxymethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (10) and its (3RS, 5RS)-isomer (22). Compound (7) did not undergo cyclisation; instead elimination occurred to give a conjugated diene, 4-(1-methylene-prop-2-enoxy)azetidin-2-one. Cyclisation of (8) gave not only the fivemebered-ring compound but also the six-membered-ring compound, 4-(bromomethyl)-5-oxa-1-azabicyclo[4.2.0]octan-8-one.

Compounds (9) and (21) reacted with a variety of nucleophilic reagents to give products derived by displacement of bromide. Catalytic hydrogenation of (10) removed the benzyl group to give the hydroxymethyl compound. Removal of the benzyl group from (22) under these conditions gave a hydroxymethyl compound which rearranged on silica gel to give 3,9-dioxa-7-azabicyclo[4.2.1]nonan-4-one.

Differences in the ¹H n.m.r, spectra of pairs of stereoisomers such as (9) and (21), and (10) and (22), are discussed. Relative stereochemistries have been deduced for two natural products previously isolated from Streptomyces clavuligerus. Compound (9) and some of its relatives have been found to be β-lactamase inhibitors.