Copper-catalyzed asymmetric alkylation of imines with dialkylzinc and related reactions.

The catalytic asymmetric addition reactions of organometallic reagents to CdN double bonds of imines are fundamentally important processes, which provide convenient and versatile routes to optically active amines bearing a stereogenic center at the R-position. Optically active R-branched amines are important chiral building blocks, and are abundantly present in biologically active compounds, such as methoxyphenamine (a 2-adrenergic antagonist for treatment of asthma), rivastigmine (an AcCh esterase inhibitor for treatment of Alzheimer’s disease), tamsulosin (a selective R1-adrenergic antagonist to improve urinary trouble due to prostatic hyperplasia), and repaglinide (a blocker of ATP-dependent K channels in cells used as a hypoglycemic agent) (Figure 1). Asymmetric addition to CdN double bonds has been achieved based on the use of a chiral auxiliaries or chiral ligands. In 1982, Takahashi and co-workers reported the pioneering work of a chiral auxiliary-controlled asymmetric addition of organolithium reagents to imines 1 derived from aldehydes and valinol or phenylglycinol (Scheme 1). The chiral auxiliary strategy is still an important technology from a practical point of view because separation of the diastereomeric products prior to cleavage of the chiral auxiliary provides enantiomerically pure products. In the past two decades, the asymmetric additions of organometallic reagents to the CdN double bonds of imines in the presence of a stoichiometric or catalytic amount of a chiral ligand have been developed as a new technology for the synthesis of optically active amines, including alkaloids. The ligandinduced enantioselective synthesis has the potential for direct recovery and reuse of the unchanged chiral ligands. In 1990, Tomioka and co-workers reported the first chiral ligandcontrolled asymmetric addition reaction of organometallic compounds to CdN double bonds of imines with organolithium reagents activated by a chiral amino ether ligand 5 (Scheme 2). Even with 5 mol % of ligand 5, enantiomerically enriched amine 6 was produced, though with moderate ee, opening up the door to catalytic asymmetric addition reactions of organometallic reagents to a CdN double bond of an imine. Denmark and co-workers also showed the excellent ability of asymmetric induction of (-)-sparteine and bisoxazoline ligands and the catalytic use of these ligands for addition of organolithium reagents to imines (Scheme 3). In 1992, Soai and co-workers reported the first catalytic asymmetric addition reaction of a dialkylzinc reagent to a CdN double bond. In the presence of chiral amino alcohol 11, addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines proceeded with high enantioselectivity (Scheme 4). Surprisingly good enantioselectivity was observed even with 10 mol % of the amino alcohol, although the chemical yield was not satisfactory. Since these early examples, considerable energetic approaches toward the catalytic asymmetric addition of organometallic reagents to CdN double bonds of imines have appeared. Among these, chiral π-allylpalladium-catalyzed allylation with allylstannane or allylsilane, and rhodiumMOP-based phosphine-catalyzed arylation with arylstannanes showed impressive early success. A key concept is catalytic generation of reactive organometal-chiral ligand complexes from corresponding less reactive organometallic reagents in situ. Excellent feature articles have been published on this exciting topic. However, in great contrast to the chiral amino alcohol catalyzed asymmetric alkylation of aldehydes with organozinc reagents, which has become a very effective and general method, the catalytic asymmetric * To whom correspondence should be addressed. Tel: 81-(0)75-753-4553. Fax: 81-(0)75-753-4604. E-mail: tomioka@pharm.kyoto-u.ac. jp. Chem. Rev. 2008, 108, 2874–2886 2874