P450-Catalyzed Intramolecular C-S Bond Formation: Mechanistic Dichotomy Directed by Cyclization.

Abstract

While biocatalysis excels at controlling reaction selectivity, the detailed mechanisms by which heme enzymes govern C-S cyclization patterns remain largely uncharted. Herein, the potential energy landscape for P450-catalyzed intramolecular C-S bond formation in brassinin is mapped by using DFT calculations on cluster models. The computations predict a mechanistic divergence dictated by the mode of substrate activation. The epoxidation pathway is proposed to proceed via a rate-determining epoxide ring-opening step to yield a zwitterionic intermediate, favoring the construction of a six-membered thiazine scaffold. In contrast, the hydrogen abstraction pathway─characterized by a stepwise hydrogen atom transfer and proton transfer─is shown to generate a radical intermediate that would steer cyclization toward a five-membered thiazolidine ring. Notably, the radical pathway is predicted to be kinetically favored with a lower overall activation barrier. These findings offer a theoretical framework for understanding the competition between zwitterionic and radical manifolds, providing a rationale for the bioengineering of P450 enzymes toward programmable heterocycle synthesis.

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