title: Quantifying Possible Routes for SpnF-Catalyzed Formal Diels-Alder Cycloaddition.
abstract: 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.
authors.affiliation: X-ray Structural Laboratory, A.N. Nesmeyanov Institute of Organoelement Compounds RAS , 119991 Moscow, Russian Federation.|N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.
authors.forename: Michael G
authors.identifier: 0000-0001-7070-4052
authors.initials: MG
authors.lastname: Medvedev
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Zeifman
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.|MolTech Ltd. , Leninskie gory, 1/75 A, 119992 Moscow, Russian Federation.
authors.forename: Fedor N
authors.initials: FN
authors.lastname: Novikov
authors.affiliation: X-ray Structural Laboratory, A.N. Nesmeyanov Institute of Organoelement Compounds RAS , 119991 Moscow, Russian Federation.
authors.forename: Ivan S
authors.identifier: 0000-0002-6534-4133
authors.initials: IS
authors.lastname: Bushmarinov
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.|MolTech Ltd. , Leninskie gory, 1/75 A, 119992 Moscow, Russian Federation.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Stroganov
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.|MolTech Ltd. , Leninskie gory, 1/75 A, 119992 Moscow, Russian Federation.
authors.forename: Ilya Yu
authors.initials: IY
authors.lastname: Titov
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.|MolTech Ltd. , Leninskie gory, 1/75 A, 119992 Moscow, Russian Federation.
authors.forename: Ghermes G
authors.initials: GG
authors.lastname: Chilov
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry RAS , 119991 Moscow, Russian Federation.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Svitanko