Click Chemistry in Lead Optimization of Boronic Acids as ß-Lactamase Inhibitors.

Boronic acid transition-state inhibitors (BATSIs) represent one of the most promising classes of ß-lactamase inhibitors. Here we describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic acids, which were synthesized by combining the asymmetric homologation of boronates with copper-catalyzed azide-alkyne cycloaddition for the stereoselective insertion of the amido group and the regioselective formation of the 1,4-disubstituted triazole, respectively. This synthetic pathway, which avoids intermediate purifications, proved to be flexible and efficient, affording in good yields a panel of 14 BATSIs bearing three different R1 amide side chains (acetamido, benzylamido, and 2-thienylacetamido) and several R substituents on the triazole. This small library was tested against two clinically relevant class C ß-lactamases from Enterobacter spp. and Pseudomonas aeruginosa. The K(i) value of the best compound (13a) was as low as 4 nM with significant reduction of bacterial resistance to the combination of cefotaxime/13a.

Synthesis of highly-substituted enantiomerically pure allylboronic esters and investigation of their stereoselective addition to aldehydes.

Diastereomerically pure allylboronates bearing the readily available tartrate derivative were obtained via sigmatropic rearrangement. Allyl additions were performed, and the influence of γ-disubstituted allylboronates was studied. Highly γ-substituted boronic esters were found to lead to the corresponding enantiomerically enriched homoallyl alcohols with exclusively E configuration; their synthesis and the mechanism of the reaction is proposed here.