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Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases

2019; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41557-019-0370-2

1755-4349

Michael J. Black, Kyle F. Biegasiewicz, Andrew J. Meichan, Daniel G. Oblinsky, Bryan Kudisch, Gregory D. Scholes, Todd K. Hyster,

Sulfur-Based Synthesis Techniques

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-haloamides. This transformation is a C–C bond-forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis. Flavin-dependent ‘ene’-reductases have now been shown to catalyse redox-neutral radical cyclizations of α-haloamides to form enantioenriched oxindoles. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where a ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the radical formed after cyclization.