Asymmetric abstraction of two chemically-equivalent methylene hydrogens: significant enantioselectivity of endoperoxide presented by fumitremorgin B endoperoxidase

作者：Ji, Jian-Nan; Chen, Shi-Lu^*

来源：Physical Chemistry Chemical Physics, 2018, 20(41): 26500-26505.

DOI：10.1039/c8cp05637d

• COFACTOR-INDEPENDENT DIOXYGENATION
• NONHEME IRON ENZYMES
• ENZYMATIC-REACTIONS
• C-H
• STRUCTURAL BASIS
• ACTIVE-SITES
• MECHANISMS
• ACTIVATION
• INSIGHTS
• EPOXIDATION

The combination of the inert C-H bond activation and asymmetric synthesis, especially the transformation of prochiral sp(3) precursors to chiral sp(3) centers, is a profound challenge. In the present DFT calculations, the unique enantioselectivity in verruculogen biosynthesis catalyzed by fumitremorgin B endoperoxidase (FtmOx1) has been mechanistically investigated, where a prochiral methylene in fumitremorgin B is dominantly converted to an R-chiral eight-membered endoperoxy ring. FtmOx1 is the first-reported mononuclear -ketoglutarate-dependent non-heme iron enzyme responsible for chiral endoperoxide formation, which handles the substrate using a Tyr224 radical resulting from the hydrogen abstraction by an Fe-IV?O species. It is demonstrated that the perfect enantioselectivity of the R-endoperoxy ring originates from the asymmetric abstraction of two chemically-equivalent methylene hydrogens from substrate chain A by the Tyr224 radical and the high conformation stability of the resultant chain A radical due to steric effects. The barrier difference in the abstraction of two hydrogens is 5.6 kcal mol(-1). The hydrogen abstraction by the Tyr224 radical is rate-limiting in the FtmOx1 reaction with an overall barrier of 18.6 kcal mol(-1). The results obtained here advance the understanding of the chemistry in enantioselectivity, providing a potentially general way for the transformation of prochiral sp(3) precursors to chiral sp(3) centers.

• 出版日期2018-11-7
• 单位北京理工大学