Highly Enantioselective Ni(0)-Catalyzed Cascade Reductive Syn-Arylative Cyclization for Five-membered Heterocyclics Bearing Chiral Quaternary Carbon Stereocenters of Tetrasubstituted Allylic Alcohols

24 November 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Construction of chiral quaternary carbon stereocenters is a significant challenge of asymmetric synthesis. Catalytic synthesis of these structures with trisubstituted allylic alcohols is highly important. However, most of reported methodologies required precious transition-metal catalyst. Herein we reported the first highly enantioselective synthesis of five-membered heterocyclics bearing chiral quaternary carbon stereocenters of tetrasubstituted allylic alcohols by cascade reductive syn-arylative cyclization of hetereo 1,6-alkynones with aryl boronic acids catalyzed by the earth-abundant Nickel catalysis Ni(cod)2 and P-chiral monophosphine ligand (S)-BIDIME applying proton solvent tert-butanol. Various multi-substituted functionalized pyrrolidines and tetrahydrofurans were achieved in high yield (up to 98%), excellent enantioselectivity (>99:1 er) with broad substrate scope. Totally thirty-seven examples were successfully applied for this transformation. The catalytic cycle and the role of proton solvent was proposed, modified and confirmed first time by detailed density functional theory (DFT) calculations, and further clarified the ligand-control for the excellent enantioselectivity initiated by Ni(0) precursor. Ligand effects, gram scale reaction and control experiments were carried out. New reaction design was proposed for further application of this methodology. This developed methodology and mechanism study is anticipated to find wider applications in organic synthesis and chemical biology.

Keywords

Enantioselective Synthesis
Ni(0)-Catalyzed Reaction
Cascade Reaction
Reductive Syn-Arylative Cyclization
Five-membered Heterocyclics
Chiral Quaternary Carbon Stereocenters
Tetrasubstituted Allylic Alcohol

Supplementary materials

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Supporting Information
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Experimental procedures and compound characterization
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CCDC 2073755.cif
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cif file of CCDC 2073755
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Checkcif of CCDC 2073755.pdf
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Checkcif of CCDC 2073755.pdf
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