Regioselective asymmetric α,α-bisalkylation of ketones via complex-induced syn-deprotonation of chiral N-amino cyclic carbamate hydrazones.

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.

Citation

Sarah E Wengryniuk, Daniel Lim, Don M Coltart. Regioselective asymmetric α,α-bisalkylation of ketones via complex-induced syn-deprotonation of chiral N-amino cyclic carbamate hydrazones. Journal of the American Chemical Society. 2011 Jun 8;133(22):8714-20

PMID: 21510644

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