Synthesis and Application of Constrained Amidoboronic Acids Using Amphoteric Boron-Containing Building Blocks

Amidoboronic acid-containing peptidomimetics are an important class of scaffolds in chemistry and drug discovery. Despite increasing interest in boron-based enzyme inhibitors, constrained amidoboronic acids have received little attention due to the limited options available for their synthesis. We describe a new methodology to prepare both alpha- and beta-amidoboronic acids that impose restrictions on backbone angles. Lewis acid-promoted Boyer-Schmidt-Aube lactam ring expansions using an azidoalkylboronate enabled generation of constrained alpha-amidoboronic acid derivatives, whereas assembly of the homologous beta-amidoboronic acids was achieved through a novel boronic acidmediated lactamization process stemming from an alpha-boryl aldehyde. The results of quantum chemical calculations suggest carboxylate-boron coordination to be rate-limiting for small ring sizes, whereas the tetrahedral intermediate formation is rate limiting in the case of larger rings. As part of this study, an application of beta-amidoboronic acid derivatives as novel VIM-2 metallo-beta-lactamase inhibitors has been demonstrated.

Automated summary

Amidoboronic acid-containing peptidomimetics, a crucial scaffold in chemistry and drug discovery, have been synthesized using a new methodology to prepare constrained alpha- and beta-amidoboronic acids. Quantum chemical calculations have revealed rate-limiting steps for different ring sizes, and a potential application of beta-amidoboronic acid derivatives as novel VIM-2 metallo-beta-lactamase inhibitors has been demonstrated.