Regioselective Catalytic Asymmetric C-Alkylation of Isoxazolinones by a Base-Free Palladacycle-Catalyzed Direct 1,4-Addition

• Published in: Angewandte Chemie International Edition Vol. 54; no. 9; pp. 2788 - 2791
• Main Authors: Hellmuth, Tina, Frey, Wolfgang, Peters, René
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 23-02-2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Accessibility; Alkylation; ambidoselectivity; asymmetric catalysis; Asymmetry; Catalysis; Catalysts; Competition; Cyclization; Esters; ferrocene; Handles; Isoxazoles - chemistry; Molecular Structure; Organometallic Compounds - chemistry; Oximes; palladacycles; Palladium - chemistry; quaternary stereocenters; Stereoisomerism; asymmetric catalysis; palladacycles; quaternary stereocenters; ferrocene; ambidoselectivity
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201410933

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.
Control freak: Enantio‐ and regioselective C‐alkylations of isoxazolinones to form products with all‐carbon‐substituted quaternary stereocenters are now possible. The controlled reaction was conducted with a sterically demanding planar‐chiral palladacycle catalyst (TON up to 1900) in the absence of any other reagent.