Scalable Synthesis of β-Lactamase Inhibitor QPX7728 by Sequential Nickel-Catalyzed Boron Insertion into a Benzofuran Substrate and Enantioselective Cyclopropanation of the Resulting Vinylboronate

Abstract

We report the scalable, high-yielding, and highly selective synthesis of the β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion of benzofuran 1 followed by enantioselective cyclopropanation of the resulting cyclic vinylboronate 2. The identification of the key reagents (catalyst and chiral auxiliary) for both steps relied on the use of high-throughput experimentation. Further optimization allowed for the cost-effective and scalable production of QPX7728.

Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors

“…However, DBO and VAB do not inhibit any metallo-carbapenemases. Compared with the clinical success of SβL inhibitors, there are no equivalent inhibitors in the clinic for MβLs, − which can hydrolyze almost all β-lactams including carbapenems and the first-generation β-lactamase inhibitors clavulanate, tazobactam, and sulbactam. ,, The continuous emergence and dissemination of MDR Gram-negative pathogens with acquired serine and metallo-carbapenemase genes has led to an urgent need for the development of broad-spectrum, dual-action inhibitors to conquer carbapenem resistance. ,, …”

“…34,51,52 The continuous emergence and dissemination of MDR Gram-negative pathogens with acquired serine and metallo-carbapenemase genes has led to an urgent need for the development of broad-spectrum, dual-action inhibitors to conquer carbapenem resistance. 44,53,54 Many review articles about β-lactamases, including carbapenemases, as well as about β-lactamase inhibitors have been published previously. 55−57 This Perspective focuses on inhibitors that deactivate the most prevalent mechanism of antibiotic resistance in Gram-negative opportunistic pathogens, for example, carbapenemases, and specifically, both serine and metallo-carbapenemases simultaneously.…”

Nickel-Catalyzed Ring-Opening of Benzofurans for the Divergent Synthesis of ortho-Functionalized Phenol Derivatives

“…The ring-opening transformations of benzofurans provide an efficient and highly atom-economical strategy to construct ortho -alkenyl-/alkyl-substituted phenol derivatives, which are the basic structures of many drug molecules and bioactive natural products . However, such transformations were comparatively scarce, especially for 2,3-disubstituted benzofuran, due to the high C–O bond strength, steric hindrance, and confronted aromatic stabilization (Scheme a right)…”

Haloboration of o‐Alkynyl Phenols Generates Halogenated Bicyclic‐Boronates**

“…Recently, a novel approach to form the BLI Xeruborbactam was reported. [15] This method proceeds via benzoxaborinine A (Figure 2, top) which was accessed by a nickel catalysed boron insertion into benzofuran B. While notable, this approach has functional group limitations and it does not tolerate substituents at the C3 position of the benzofuran.…”