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Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

ABSTRACT: The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels-Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels-Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels-Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels-Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geometries indicates that the enzyme may prearrange the substrate within the active site to accelerate the [4+2] cycloaddition and impede the [6+4] cycloaddition through interactions with active-site residues. Judging from partial charge analysis, we find that the hydrogen bond between the Thr196 residue of SpnF and the substrate C15 carbonyl group contributes to the enhancement of the rate of the Diels-Alder reaction. QM/MM simulations show that the substrate can easily adopt a reactive conformation in the active site of SpnF because interconversion between the C5-C6 s-trans and s-cis conformers is facile. Our QM/MM study suggests that the enzyme SpnF does behave as a Diels-Alderase.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC5735378 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

Zheng Yiying Y Thiel Walter W

The Journal of organic chemistry 20171129 24

The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels-Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels-Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predi ...[more]

PMID: 29131960

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Project description:Copper(I) [Cu2(μ-Br)2(tBuImCH2pyCH2L)] n (L = OMe, NEt2, NHtBu) compounds supported by flexible functionalized NHC-based polydentate ligands have been prepared in a one-pot procedure by reacting the corresponding imidazolium salt with an excess of copper powder and Ag2O. An X-ray diffraction analysis has revealed that [Cu2(μ-Br)2(tBuImCH2pyCH2NEt2)] n is a linear coordination polymer formed by bimetallic [Cu(μ-Br)]2 units linked by the lutidine-based NHC-py-NEt2 ligand, which acts as a heteroditopic ligand with a 1κC-2κ2 N,N' coordination mode. We propose that the polymeric compounds break down in the solution into more compact tetranuclear [Cu2(μ-Br)2(tBuImCH2pyCH2L)]2 compounds with a coordination mode identical to the functionalized NHC ligands. These compounds have been found to exhibit high catalytic activity in the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In particular, [Cu2(μ-Br)2(tBuImCH2pyCH2NEt2)]2 efficiently catalyzes the click reaction of a range of azides and alkynes, under an inert atmosphere at room temperature in neat conditions at a very low catalyst loading, to quantitatively afford the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in a few minutes. The cycloaddition reaction of benzyl azide to phenylacetylene can be performed at 25-50 ppm catalyst loading by increasing the reaction time and/or temperature. Reactivity studies have shown that the activation of the polynuclear catalyst precursor involves the alkyne deprotonation by the NHC moiety of the polydentate ligand to afford a copper(I)-alkynyl species bearing a functionalized imidazolium ligand. DFT calculations support the participation of the dinuclear species [(CuBr)2(μ-tBuImCH2pyCH2NEt2)], resulting from the fragmentation of the tetranuclear compound, as the catalytically active species. The proposed reaction pathway proceeds through zwitterionic dinuclear intermediates and entails the active participation of both copper atoms, as well as the NHC moiety as an internal base, which activates the reacting alkyne via deprotonation.

Dataset Information

Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

Publications

Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

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