Mechanistic manifold in a hemoprotein-catalyzed cyclopropanation reaction with diazoketone

Donggeon Nam, John-Paul Bacik, Rahul L. Khade, Maria Camila Aguilera, Yang Wei, Juan D. Villada, Michael L. Neidig (), Yong Zhang (), Nozomi Ando () and Rudi Fasan ()
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Donggeon Nam: University of Rochester
John-Paul Bacik: Cornell University
Rahul L. Khade: Stevens Institute of Technology
Maria Camila Aguilera: University of Rochester
Yang Wei: Stevens Institute of Technology
Juan D. Villada: University of Rochester
Michael L. Neidig: University of Oxford
Yong Zhang: Stevens Institute of Technology
Nozomi Ando: Cornell University
Rudi Fasan: University of Rochester

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Hemoproteins have recently emerged as promising biocatalysts for new-to-nature carbene transfer reactions. However, mechanistic understanding of the interplay between productive and unproductive pathways in these processes is limited. Using spectroscopic, structural, and computational methods, we investigate the mechanism of a myoglobin-catalyzed cyclopropanation reaction with diazoketones. These studies shed light on the nature and kinetics of key catalytic steps in this reaction, including the formation of an early heme-bound diazo complex intermediate, the rate-determining nature of carbene formation, and the cyclopropanation mechanism. Our analyses further reveal the existence of a complex mechanistic manifold for this reaction that includes a competing pathway resulting in the formation of an N-bound carbene adduct of the heme cofactor, which was isolated and characterized by X-ray crystallography, UV-Vis, and Mössbauer spectroscopy. This species can regenerate the active biocatalyst, constituting a non-productive, yet non-destructive detour from the main catalytic cycle. These findings offer a valuable framework for both mechanistic analysis and design of hemoprotein-catalyzed carbene transfer reactions.

Date: 2023
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DOI: 10.1038/s41467-023-43559-7

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