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Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies
Author(s) -
Sun Zhankui,
Winschel Grace A.,
Zimmerman Paul M.,
Nagorny Pavel
Publication year - 2014
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.201405128
Subject(s) - enantioselective synthesis , oxocarbenium , chemistry , stereoselectivity , acetal , phosphoric acid , enantiomer , enol , organocatalysis , chiral auxiliary , combinatorial chemistry , organic chemistry , stereochemistry , catalysis , nucleophile
An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S N 2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations.