Quantifying possible routes for SpnF-catalyzed formal Diels-Alder cycloaddition

Medvedev, M.G.; Zeifman, A.A.; Novikov, F.N.; Bushmarinov, I.S.; Stroganov, O.V.; Titov, I.Y.; Chilov, G.G.; Svitanko, I.V.

Авторы: Medvedev Michael G., Zeifman Alexey A., Novikov Fedor N., Bushmarinov Ivan S., Stroganov Oleg V., Titov Ilya Yur‘evich, Chilov Ghermes G., Svitanko Igor V.
Журнал: Journal of the American Chemical Society
Год издания: 2017
Издательство: American Chemical Society
Местоположение издательства: United States
DOI: 10.1021/jacs.6b13243
Аннотация: The Diels-Alder reaction is a cornerstone of modern organic synthesis. Despite this, it remains essentially inaccessible to biosynthetic approaches. Only a few natural enzymes catalyze even a formal [4+2] cycloaddition, and it remains uncertain if any of them proceed via the Diels-Alder mechanism. In this study, we focus on the [4+2] cycloaddition step in the biosynthesis of spinosyn A, a reaction catalyzed by SpnF enzyme—one of the most promising “true Diels-Alderase” candidates. The four currently proposed mechanisms (including the Diels-Alder one) for this reaction in water (as a first-order approximation of the enzymatic reaction) are evaluated by an exhaustive quantum mechanical search for possible transition states (728 were found in total). We find that the line between the recently proposed bis-pericyclic [J. Am. Chem. Soc. 2016, 138 (11), 3631] and Diels-Alder routes is blurred, and favorable transition states of both types may coexist. Application of the Curtin-Hammett principle, however, reveals that the bis-pericyclic mechanism accounts for ≈83% of the reaction flow in water, while the classical Diels-Alder mechanism contributes only ≈17%. The current findings provide a route for modeling this reaction inside the SpnF active site and inferring the catalytic architecture of possible Diels-Alderases.
Добавил в систему: Медведев Михаил Геннадьевич

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Quantifying possible routes for SpnF-catalyzed formal Diels-Alder cycloadditionстатья

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