American Chemical Society
ja202267k_si_001.pdf (3.64 MB)

Regioselective Asymmetric α,α-Bisalkylation of Ketones via Complex-Induced Syn-Deprotonation of Chiral N-Amino Cyclic Carbamate Hydrazones

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journal contribution
posted on 2011-06-08, 00:00 authored by Sarah E. Wengryniuk, Daniel Lim, Don M. Coltart
The first general method for the asymmetric α,α-bisalkylation of ketones having both α- and α′-protons is described. Both excellent regio- and stereoselectivity result. The transformation is enabled by complex-induced syn-deprotonation (CIS-D), which completely reverses the inherent preference of lithium diisopropylamide (LDA) to remove the less sterically hindered of two similarly acidic protons. CIS-D also overrides the normal tendency of LDA to remove the more strongly acidic proton in a substrate having protons differing significantly in their acidity. The regiochemical outcome is, thus, the opposite of that normally obtained for kinetic LDA-mediated deprotonation of ketones and (S)-1-amino-2-methoxymethylpyrrolidine/(R)-1-amino-2-methoxymethylpyrrolidine (SAMP/RAMP)hydrazones. Conveniently, this strategy allows access to either ketone enantiomer using a single enantiomer of the auxiliary. The utility of this method is demonstrated by a concise and highly efficient formal synthesis of both (R)- and (S)-stigmolone.