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Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines
Author(s) -
Um Joann M.,
Kaka Naeem S.,
Hodgson David M.,
Houk K. N.
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201000046
Subject(s) - chemistry , substituent , asymmetric induction , enamine , isopropyl , steric effects , alkylation , piperidine , transition state , stereochemistry , stereoselectivity , intermolecular force , alkyl , nucleophile , density functional theory , computational chemistry , medicinal chemistry , organic chemistry , enantioselective synthesis , molecule , catalysis
The asymmetric C ‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A 1, 3 strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.