Transition states and origins of 1,4-asymmetric induction in alkylations of 2,2,6-trialkylpiperidine enamines.
The asymmetric C-alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6-trialkylpiperidides has previously been shown to provide alpha-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.
Um
Joann M
JM
Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095-1569, USA.
Kaka
Naeem S
NS
Hodgson
David M
DM
Houk
K N
KN
D000447:Aldehydes / Q000737:chemistry; D000478:Alkylation; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry*
D000447:Aldehydes; D010880:Piperidines; C032727:piperidine
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