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Organocatalyzed Enantioselective Michael Addition of 2‐Hydroxypyridines and α,β‐Unsaturated 1,4‐Dicarbonyl Compounds
Author(s) -
Wu YuChun,
Jhong Yi,
Lin HuiJie,
Swain Sharada Prasanna,
Tsai HuiHsu Gavin,
Hou DuenRen
Publication year - 2019
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201900997
Subject(s) - enantioselective synthesis , chemistry , cinchona , bifunctional , michael reaction , organocatalysis , catalysis , adduct , organic chemistry , cinchona alkaloids , combinatorial chemistry
The framework of 2‐pyridones is prevalent in biologically and medicinally important molecules. Here we report that chiral N ‐substituted 2‐pyridones were prepared by enantioselective, organocatalytic aza‐Michael additions of halogenated 2‐hydroxypyridines (pyridin‐2(1 H )‐ones) to α,β‐unsaturated‐1,4‐dketones or 1,4‐ketoesters. The reactions were optimized by the choice of solvents and systematic screening of Cinchona alkaloid‐based bifunctional catalysts to achieve excellent yields and enantioselectivities (up to 98% yield and >99% ee). Density functional theory calculations provided rationales for the observed enantioselectivity. Formal synthesis of a human rhinovirus protease inhibitor was achieved using the chiral Michael adduct generated by this method.