COPPER-CATALYZED, ENANTIOSELECTIVE CONJUGATE ADDITION

INTRODUCTION Conjugate addition of carbon nucleophiles to α,β-unsaturated electrophiles is an essential carbon-carbon bond forming process in synthetic organic chemistry. Organocuprates, which are derived from organolithium or Grignard reagents, are the most commonly used nucleophiles for this transformation. The utility of cuprate conjugate addition has been broadened through the development of enantioselective variants. However, the modified cuprates require stoichiometric amounts of chiral ligands and copper, which prompted the development of more efficient systems. The development of methods that require catalytic amounts of copper and chiral ligands for conjugate addition of carbon nucleophiles (Scheme 1) is evolving into two competing systems. The first employs dialkylzinc reagents as the nucleophiles; the second uses Grignard reagents. Although the use of Grignard reagents was the first to be applied to enantioselective conjugate addition, dialkylzinc reagents have dominated the field since their first application in the mid-1990s. Copper-catalyzed dialkylzinc additions have been applied to conjugated cyclic substrates such as cyclohexenones, cyclopentenones, as well as unsaturated lactones, and lactams. The extension to acyclic substrates is more complex because they can exhibit s-cis/s-trans conformational equilibria. More recently, progress has been made on these more challenging acyclic substrates such as chalcones, benzylideneacetones, and aliphatic α,β-unsaturated enones. Other acyclic substrates which do not undergo conformational equilibria, such as malonates and nitroolefins, have also been surveyed. A mechanism for the copper-catalyzed addition of dialkylzinc reagents is proposed. Although it historically has been difficult to achieve high enantioselectivity and chemioselective 1,4-addition with Grignard reagents, much progress has been made recently. Copper-catalyzed enantioselective conjugate addition has broad synthetic potential for diverse targets from anti-tumor agents to perfumes.