Quaternary carbon stereogenic centers through copper-catalyzed enantioselective allylic substitutions with readily accessible aryl- or heteroaryllithium reagents and aluminum chlorides.

Abstract

Catalytic enantioselective allylic substitution (EAS) reactions[i] are among the most versatile classes of transformations in organic chemistry: such processes convert readily available achiral substrates to enantiomerically enriched products bearing a stereogenic center adjacent to a readily functionalizable alkene. We have devised chiral amino acid-based[ii] and bidentate N-heterocyclic carbene (NHC) Cu complexes[iii] that promote EAS processes with dialkylzinc reagents and generate quaternary carbon stereogenic centers[iv] with high site- and enantioselectivity. Catalytic enantioselective Cu-free additions of alkylmagnesium halides to allylic halides,[v] as well as dialkylzinc and trialkylaluminum reagents[vi] to phosphates, have also been developed. Nonetheless, significant and compelling problems remain unaddressed. Catalytic EAS transformations involving aryl nucleophiles and which deliver quaternary carbon centers are notoriously scarce, and protocols that involve hetero-arylmetals do not exist (including those that furnish tertiary C–C bonds). The only reported cases of aryl additions by catalytic EAS that generate quaternary carbons correspond to Si-substituted alkenes and involve diarylzinc reagents,[vii] which are relatively difficult to prepare in high purity and offer only one of the two aryl units. Such considerations underline a shortcoming in the state-of-the-art: the absence of EAS methods that deliver quaternary carbon stereogenic centers through reactions with mono-arylmetal reagents, in particular those that are easily accessible and atom-economical.[i]