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Origins of Stereoselectivity in the α-Alkylation of Chiral Hydrazones

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journal contribution
posted on 17.12.2010, 00:00 by Elizabeth H. Krenske, K. N. Houk, Daniel Lim, Sarah E. Wengryniuk, Don M. Coltart
Density functional theory calculations and experiment reveal the origin of stereoselectivity in the deprotonation−alkylation of chiral N-amino cyclic carbamate (ACC) hydrazones. When the ACC is a rigid, camphor-derived carbamate, the two conformations of the azaenolate intermediate differ in energy due to conformational effects within the oxazolidinone ring and steric interactions between the ACC and the azaenolate. An electrophile adds selectively to the less-hindered π-face of the azaenolate. Although it was earlier reported that use of ACC auxiliaries led to α-alkylated ketones with er values of 82:18 to 98:2, B3LYP calculations predict higher stereoselectivity. Direct measurement of the dr of an alkylated hydrazone prior to removal of the auxiliary confirms this prediction; the removal of the auxiliary under the reported conditions can compromise the overall stereoselectivity of the process.