Total synthesis of analogues of the β-lactam antibiotics. Part 6. (6R*)-4(t-butoxycarbonyl)-2-methoxycarbonyl-3-oxacepham 1,1-dioxides

Abstract

The (2S*,4R*)/(2R*,4R*)- and (2R*,4S*)/(2S*,4S*)-diastereoisomers of the title compound, i.e. compounds 6b/7b and 22/23, have been prepared by a strategy involving final closure of the 2,3-bond in which a novel carbenoid-insertion reaction is implicated. Thus, in the presence of rhodium(II) acetate, t-butyl (αR*)-α-{(4R*)-4-[diazo(methoxycarbonyl)methylsulphonyl]-2-oxoacetidin-1-yl}-α-(tetrahydropyran-2-yloxy)acetate 8c(both as a 3 : 1 and as a 1 : 2 mixture of epimers) afforded a 3 : 1 mixture of the oxacepham dioxides 6b/7b. Under similar conditions, the (αS*)-diastereoisomer of compound 8c, i.e. 9c(as a 2 : 1 mixture of epimers), gave rise to a 2 : 1 mixture of the oxacepham dioxides 22/23. The diazo compounds 8c and 9c were prepared from methyl α-[(2R*)-4-oxoazetidin-2-ylthio]acetate 12a by sequential reactions with t-butyl α,α-dihydroxyacetate (to give 17a/18a), acidic dihydropyran (to furnish 17e/18e), potassium permanganate (to yield 15d/16d), and p-carboxybenzenesulphonyl azide.

Deprotection of the t-butyl ester moiety of compounds 6b/7b was achieved by using trifluoroacetic acid but the derived sodium salts 6a/7a failed to synergise the action of ampicillin against β-lactamase producing bacteria.