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Regioselective Catalytic Asymmetric C‐Alkylation of Isoxazolinones by a Base‐Free Palladacycle‐Catalyzed Direct 1,4‐Addition
Author(s) -
Hellmuth Tina,
Frey Wolfgang,
Peters René
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201410933
Subject(s) - stereocenter , regioselectivity , chemistry , steric effects , nucleophile , catalysis , combinatorial chemistry , enantioselective synthesis , stereochemistry , nucleophilic addition , alkylation , organic chemistry
Isoxazolinones constitute a class of heterocycles utilized for the development of novel drug candidates. The cyclic oxime ester motif is also synthetically useful as it contains functional handles which have previously been used to provide access to an assortment of valuable compound classes not easily accessible by alternative approaches. However, asymmetric methods towards isoxazolinones are notoriously scarce. Herein we report the first catalytic asymmetric alkylations of isoxazolinones forming all‐C‐substituted quaternary stereocenters. The present studies were driven by the question of how to control the regioselectivity in the competition of different nucleophilic positions. The investigation of a direct 1,4‐addition uncovered that a sterically demanding palladacycle catalyst directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900.