Synthesis and Applications of β‐Aminoalkylboronic Acid Derivatives

Abstract

α‐Aminoalkylboronic acids display a distinct role in medicinal chemistry, and their utility has been demonstrated by the successful commercialization of three drugs: bortezomib, ixazomib, and vaborbactam. Just as α‐aminoalkylboronic acids are a bioisostere of α‐amino acids, β‐aminoalkylboronates are a bona fide bioisostere of β‐amino acids, thus they also hold promising potential in drug discovery. Moreover, β‐aminoalkylboronates are versatile synthetic intermediates that are amenable to many of the established C−B bond derivatization reactions of chiral optically enriched alkylboronates, leading to the stereocontrolled preparation of valued classes of products such as β‐amino alcohols, 1,2‐diamines, and hemiboronic acid heterocycles. In addition, β‐aminoalkylboronates were shown to act as catalysts in certain organic reactions. This review presents an overview of the strengths and limitations of current preparative methods to access β‐aminoalkylboronic acid derivatives stereoselectively with various substitution patterns. Strategically, several disconnections can be exploited to establish both functional groups. Some of the key methods include the classical Matteson asymmetric homologation chemistry, transition metal‐catalyzed aminoboration of alkenes and formal hydroboration of enamine derivatives, nucleophilic additions of boryl‐substituted carbanions onto N‐functionalized imines, borylative ring openings of aziridines, and functionalization of alpha‐boryl aldehydes.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Boronic derivatives have been also elaborated as prodrugs (through biooxidation of the CÀ B bond) and used for reversible covalent inhibition of biomolecules with hydroxyl groups. [49] Figure 3 shows some approved boron-containing drugs; so far, they all fall into one of two chemotypes, namely, aminoboronic acids or their derivatives, [50][51][52] as well as benzoxaboroles. [53] Alternatively, (hetero)aliphatic boronates and trifluoroborates are widely used to create the C(sp 3 )À C or C-(sp 3 )À heteroatom bonds in early drug discovery.…”

Aza-Matteson Reactions via Controlled Mono- and Double-Methylene Insertions into Nitrogen–Boron Bonds

“…Such so-called “aza-Matteson” reactions would provide a rapid and modular approach to access boron-substituted alkyl amines, thus offering a new avenue to derivatize or prepare functionalized nitrogen-containing molecules. Herein we report our preliminary development of the controlled carbenoid insertions into aminoboranes for the one-step preparation of various α- and β-boron-substituted tertiary amines (Scheme c) . Unlike traditional Matteson reactions, both mono- and double-methylene insertions can be selectively realized in one step by judicious choices of leaving groups and Lewis-acid activators.…”

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

“…Most of these transformations are aminoborations; they were covered recently in a review section by Li and Hall. [23] Thus, if O-benzoyl hydroxylamine derivatives are involved into the Cu-catalyzed borylation reaction shown in Scheme 52 instead of the Celectrophile, β-amino boronic derivatives can be obtained. The first examples of this strategy implementation were described by Hirano, Miyura, and co-workers in 2013-2015; they employed styrene derivatives 248 (A), [303,304] strained bicyclic alkenes 250 (B), [305] and non-activated monosubstituted alkenes (C) [242,304] as the substrates (Scheme 70).…”

“…As might be anticipated from Figure 1, two boron-based chemotypes are currently predominant in drug discovery: i) aminoboronic acids or their derivatives (typically chiral); ii) benzoxaboroles-cyclic arylboronates that are beyond the scope of this review. Recently, αand β-aminoboronic acids and their derivatives were surveyed comprehensively; [21][22][23] a number of more general reviews on organoboron compounds in medicinal chemistry were also published. [2,[11][12][13][14][15][16][17][18] Therefore, we shall limit further discussion by overview of recent approaches to the synthesis of enantiopure α-aminoboronic acids or their derivatives.…”