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The Size‐Accelerated Kinetic Resolution of Secondary Alcohols
Author(s) -
Pölloth Benjamin,
Sibi Mukund P.,
Zipse Hendrik
Publication year - 2021
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.202011687
Subject(s) - steric effects , chemistry , enantiomer , kinetic resolution , catalysis , kinetic energy , stacking , covalent bond , kinetics , alcohol , pyridine , computational chemistry , stereochemistry , organic chemistry , enantioselective synthesis , physics , quantum mechanics
Abstract The factors responsible for the kinetic resolution of alcohols by chiral pyridine derivatives have been elucidated by measurements of relative rates for a set of substrates with systematically growing aromatic side chains using accurate competitive linear regression analysis. Increasing the side chain size from phenyl to pyrenyl results in a rate acceleration of more than 40 for the major enantiomer. Based on this observation a new catalyst with increased steric bulk has been designed that gives enantioselectivity values of up to s=250. Extensive conformational analysis of the relevant transition states indicates that alcohol attack to the more crowded side of the acyl‐catalyst intermediate is favoured due to stabilizing CH‐π‐stacking interactions. Experimental and theoretical results imply that enantioselectivity enhancements result from accelerating the transformation of the major enantiomer through attractive non‐covalent interactions (NCIs) rather than retarding the transformation of the minor isomer through repulsive steric forces.