title: Regioselective asymmetric α,α-bisalkylation of ketones via complex-induced syn-deprotonation of chiral N-amino cyclic carbamate hydrazones.
abstract: 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.
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wengryniuk
authors.forename: Daniel
authors.initials: D
authors.lastname: Lim
authors.forename: Don M
authors.initials: DM
authors.lastname: Coltart