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Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters
Author(s) -
Qu Shen,
Smith Samuel M.,
LainaMartín Víctor,
Neyyappadath Rifahath M.,
Greenhalgh Mark D.,
Smith Andrew D.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202004354
Subject(s) - stereocenter , chemistry , kinetic resolution , steric effects , enantioselective synthesis , catalysis , substituent , selectivity , diastereomer , acylation , tertiary alcohols , organic chemistry , combinatorial chemistry
A highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.