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 alpha,alpha-bisalkylation of ketones having both alpha- and alpha'-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 dfisopropylamide (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.