TY - DATA T1 - Quantifying Possible Routes for SpnF-Catalyzed Formal Diels–Alder Cycloaddition PY - 2017/02/27 AU - Michael G. Medvedev AU - Alexey A. Zeifman AU - Fedor N. Novikov AU - Ivan S. Bushmarinov AU - Oleg V. Stroganov AU - Ilya Yu. Titov AU - Ghermes G. Chilov AU - Igor V. Svitanko UR - https://acs.figshare.com/articles/journal_contribution/Quantifying_Possible_Routes_for_SpnF-Catalyzed_Formal_Diels_Alder_Cycloaddition/4731703 DO - 10.1021/jacs.6b13243.s001 L4 - https://ndownloader.figshare.com/files/7724971 KW - SpnF enzyme KW - biosynthetic approaches KW - enzymes catalyze KW - Diel KW - transition states KW - bis-pericyclic mechanism accounts KW - reaction flow N2 - 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. ER -