# Fused 3D boron heterocycles via EnT catalysis: synthesis, modification and validation as beta-lactamase inhibitors

## TL;DR

A new method to create complex 3D boron structures mimics antibiotic resistance inhibitors and could aid drug development.

## Contribution

A visible light-mediated EnT catalysis strategy enables [2 + 2] cycloadditions of boron heterocycles to form 3D frameworks.

## Key findings

- The EnT catalysis strategy allows synthesis of angularly fused boron heterocycles with high structural complexity.
- The 3D boron frameworks mimic structural motifs of the β-lactamase inhibitor Xeruborbactam.
- NMR titration and co-crystallisation confirmed enantiospecific binding and hydrogen bonding with β-lactamase.

## Abstract

The installation of a boron unit into bioactive scaffolds continues to unlock novel modes of molecular recognition in drug discovery. As such, de novo strategies to access 3D boron-containing frameworks, that modulate the intrinsic reactivity at boron, are being intensively pursued. Herein, we report a visible light-mediated energy transfer (EnT) catalysis strategy that enables the [2 + 2] cycloaddition of boron-containing heterocycles to construct 3D frameworks with high structural complexity. Leveraging both inter- and intramolecular cycloadditions, a suite of angularly fused boron heterocycles was accessed, offering enhanced steric shielding and modular handles for additional interactions. A boron deletion strategy permits the synthesis of benzofuran scaffolds, otherwise inaccessible via direct EnT. Crucially, the resulting 3D architectures mimic structural motifs found in the potent β-lactamase inhibitor Xeruborbactam. The biological relevance of these frameworks was validated by NMR titration, pKa analysis, and co-crystallisation with serine β-lactamase CTX-M-14, revealing enantiospecific binding and a well-defined hydrogen bonding network. These results establish a versatile platform for the synthesis of functionalised boron heterocycles with direct translational potential in medicinal chemistry.

An energy transfer catalysis strategy enables [2 + 2] cycloadditions of boron heterocycles, yielding 3D frameworks that mimic β-lactamase inhibitors. These structures show promise for medicinal chemistry and can be used in boron deletion strategies.