Engineering metalloenzymes for new-to-nature carbene and nitrene transfer biocatalysis

Abstract

Biocatalysis, which involves using enzymes to address synthetic challenges of significance to humans, has rapidly developed into a pivotal technology for chemical innovation. Over the past decade, there has been a notable increase in the use of metalloproteins as catalysts for abiotic, synthetically valuable carbene and nitrene transfer reactions. This trend highlights the adaptability of protein-based catalysts and our growing ability to harness this potential for novel enzyme chemistry. This review focuses on the most recent advancements in metalloenzyme-catalyzed carbene and nitrene transfer reactions, including cyclopropanation, carbene Y–H and C–H insertions, Doyle-Kirmse reactions, aldehyde olefinations, nitrene azide-to-aldehyde conversions, and nitrene C–H insertion. A variety of protein scaffolds have been engineered to offer varied levels of reactivity and selectivity towards pharmaceutically relevant compounds. The application of these new catalysts in preparative-scale synthesis underscores their emerging biotechnological significance. Furthermore, insights into key intermediate and determining factors in stereochemistry are offering valuable guidance for engineering metalloproteins, thereby expanding the scope and utility of these non-natural activities.