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

Abstract

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 α- and β-amidoboronic acids that impose restrictions on backbone angles. Lewis acid-promoted Boyer–Schmidt–Aube lactam ring expansions using an azidoalkylboronate enabled generation of constrained α-amidoboronic acid derivatives, whereas assembly of the homologous β-amidoboronic acids was achieved through a novel boronic acid-mediated lactamization process stemming from an α-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 β-amidoboronic acid derivatives as novel VIM-2 metallo-β-lactamase inhibitors has been demonstrated.

Recent advances in the synthesis and reactivity of MIDA boronates

“…Recently, the Yudin group reported Lewis acid-promoted Boyer–Schmidt–Aube lactam ring expansions using azidomethyl MIDA boronate and cyclic ketones to afford diverse constrained α-amido-MIDA-boron compounds in good yields (Scheme 12(d)). 83…”

Exploiting Enantiopure β‐Amino Boronic Acids in Isocyanide‐Based Multicomponent Reactions

“…[8,9] Remarkable exceptions come from the impressive work of Professor Yudin and his research group, which, over the last few years, exploited various borylated reagents [10,11] and, in particular, both αand βamino boronic acids, [12][13][14] even coming to the discovery of boron-based peptidomimetics endowed with relevant biolog-ical activities. [7,[15][16] Quite recently, from the same group, amidoboronic acid-containing peptidomimetics with constrained backbone were also achieved, and successfully demonstrated as novel VIM-2 metallo-β-lactamase inhibitors [17] (Figure 1).…”

Towards depeptidized aminoboronic acid derivatives through the use of borylated iminium ions

“…Furthermore, we also impose a rotational constraint on the C-N bond, which represents an underexplored area of the aminoboronic acid chemical space. 20 This type of change can only be done thorough deep-seated changes to the b-aminoboronic acid motif rather than late-stage peripheral modifications. 21 Our initial strategy for depeptidizing branched b-aminoboronates was to consider only free amines rather than amides.…”