Studies related to penicillins. Part 22. Mechanistic aspects of β-elimination reactions involving penicillanate 1,1-dioxides

Abstract

In the presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)(0.5 mol equiv.) and deuterium oxide, methyl benzylpenicillinate 1,1-dioxide (1a) was converted into its 3,6-dideuteriated derivative (3a), its 3,6-dideuteriated 6-epimer (3b), and (2R,3S)-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-oxo-3-phenylacetamido[3-²H]azetidine-2-sulphinic acid (2b). Under similar conditions, methyl penicillanate 1,1-dioxide (1c) afforded its 3-deuteriated derivative (3c) which was then transformed into (2R)-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-oxoazetidine-2-sulphinic acid (2c). The aforementioned results indicate that the β-elimination reactions occur by E1cB pathways, in which C-3 anionic intermediates, i.e.(4a) and (4b), are formed reversibly.

Methyl benzyl[2β-methyl-²H₃]penicillinate 1,1-dioxide (7a) and methyl [2β-methyl-²H₃]penicillanate 1,1-dioxide (7b) were transformed by DBN into the corresponding sulphinic acids, in which the deuterium label was located exclusively in the methyl group anti with respect to the methoxycarbonyl moiety, i.e. compounds (12a) and (12b). These findings suggest that the carbanionic intermediates (4a) and (4b) undergo the β-elimination reactions by way of the conformers (5a) and (5b).

p-Nitrobenzyl penicillanate 1,1-dioxide (13b) was converted into [3-²H]penicillanic acid 1,1-dioxide (18a) by deuterium-exchange and hydrogenolysis steps. The last mentioned compound was comparable to sulbactam (17a) in its ability to synergise the antibacterial activity of ampicillin against β-lactamase-producing bacteria.