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J Am Chem Soc. 2018 Feb 14;140(6):2272-2283. doi: 10.1021/jacs.7b12137. Epub 2018 Jan 24.

Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions.

Author information

1
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, PR China.

Abstract

An unprecedented ligand-controlled regiodivergent Cu(I)-catalyzed asymmetric intermolecular (3 + 2) cycloaddition reaction of α-substituted iminoesters with β-fluoromethyl β,β-disubstituted enones was developed. This novel strategy provides an efficient method for the enantioselective regiodivergent synthesis of pyrrolidines bearing two adjacent quaternary stereocenters or two discrete quaternary stereocenters, opening up a new era for medicinal chemistry and diversity-oriented synthesis. DFT calculations showed that the P,N-ligand L2 acts as a pseudobidentate ligand. The formation of a O-Cu bond with the carbonyl oxygen atom of the enone and dissociation of the amine nitrogen of L2 from the Cu(I) center occurs during the catalytic cycle; this is the main reason for the tuning the regioselectivity of the cycloaddition reaction caused by switching of the ligand. The salient features of this work include high yields (up to >99%), a general substrate scope, the use of commercially available ligands, and high regio-(up to >20:1 rr), diastereo- (up to >20:1 dr), and enantioselectivity (up to >99% ee).

PMID:
29303569
DOI:
10.1021/jacs.7b12137

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