A New Efficient Stereoselective Debromination Reaction with Trialkylgermanium Hydrides Useful in the Design of Short Synthetic Routes to β-Lactamase Inhibitor Prodrugs

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Prodrugs derived from the β-lactamase inhibitor 6-β-hydroxymethylsulbactam can be synthesized efficiently in a three-step process by making use of the highly stereoselective radical debromination utilizing tri-n-butylgermanium hydride. This reagent is capable of abstracting bromine from the C-6 position of pairs of epimers 6-hydroxymethyl-6-bromo-penicillate-1,1-dioxide esters and functionalized esters suitable for prodrug use in high yields. The bromine abstraction usually results in favoured formation of the 6-β-hydroxymethyl epimer relative to the 6-α-hydroxymethyl epimer in ratios that exceed 97:3. Reaction of pure 6-α-hydroxymethyl-6-β-bromo-penicillate-1,1-dioxide ester results in almost exclusive formation of 6-β-hydroxymethylsulbactam ester. This methodology conserves the C−C bond formation at C-6 by making use of both epimers resulting from formylation, which is difficult and nonstereoselective in the β-hydroxymethylsulbactam prodrug synthesis.