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Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α‐Fluorinated Ketones
Author(s) -
Thomson Connor J.,
Barber David M.,
Dixon Darren J.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201916129
Subject(s) - aldol reaction , enantioselective synthesis , oxetane , bifunctional , aryl , chemistry , catalysis , combinatorial chemistry , superbase , organocatalysis , ketone , diol , organic chemistry , alkyl
The catalytic enantioselective synthesis of α‐fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi‐gram scalability has been demonstrated along with catalyst recovery and recycling. 1 H NMR studies identified a 1400‐fold rate enhancement under BIMP catalysis, compared to the prior state‐of‐the‐art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3‐aminoalcohol, 1,3‐diol, oxetane, and isoxazoline derivatives.