Catalytic enantioselective nucleophilic addition of organolithium derivatives: pitfalls and opportunities

Abstract

Organolithium reagents in solution are known to adopt oligomeric structures that are highly sensitive to the presence and nature of additives. In particular, the addition of lithium halides, chalcogenides or pnictogenides leads, in many cases, to well-defined complexes having the effect of decreasing the degree of aggregation of the original oligomer and often increasing the reactivity of the lithiated species itself. Incorporating a stereogenic element through the additive may allow the resulting complexes to be employed in stereochemically controlled reactions. In this context, two strategies can be applied that are the usual picture of a single metal in interaction with σ-donor (non-metalated) ligand(s) e.g. spartein, or, the possibility for the main group organolithium to be associated with another chiral lithiated partner forming organo(-bi-)metallic entities in which nucleophilicity and asymmetry are coupled. To date, engaging lithio reactants in the very classical enantioselective nucleophilic addition process with aldehydes remains a challenge due to the high intrinsic reactivity of the two partners. Nevertheless, taking advantage of a thorough understanding of the aggregation phenomena between the lithiated dipolar entities all along the catalytic cycle allows the fine-tuning of a substoichiometric enantioselective hydroxyalkylation of an aldehyde by an alkyllithium. We show the application of such a strategy to an example described recently.