Phosphoramidite ligands, based on a chiral amine and atropoisomerically flexible biphenols, induce high enantioselectivities (ee's up to 98%) in the copper-catalyzed conjugate addition of dialkyl zinc reagents to a variety of Michael acceptors.There have been many efforts in the field of asymmetric conjugate addition through copper-catalysis. 1 Among the various ways to introduce the chiral information, we demonstrated that trivalent phosphorous ligands were particularly efficient. 2 Later on, we introduced the use of diorganozinc reagents as primary organometallics, 3 and since this first report, in 1993, 3 this combination of a chiral phosphorus ligand and dialkyl zincs has found widespread use, 4-8 although the reaction could be also promoted by non-phosphorus ligands. 9 Typically, cyclohexenone has served as representative Michael acceptor (Scheme 1) with most often Cu(OTf) 2 as copper source (catalyst loading 0.5-2%), in toluene or CH 2 Cl 2 as solvent. Scheme 1Among the many ligands, which have been shown to be efficient, the ones based on a modular concept are of prime importance. Thus, a TADDOL or binaphthol moiety forms a ring with the phosphorus atom, whereas a chiral alcohol or amine is fixed on the exocyclic position ( Figure 1). This combination of two chiral moieties around the phosphorus atom allows for the formation of two diastereomeric ligands. The experimental results show that only one diastereomeric combination affords high enantioselectivities (the matched series) whereas the other one (the mismatched series) does not.For example, ligand L1 affords 96% ee for the conjugate addition of diethylzinc onto cyclohexenone (Scheme 1), whereas the mismatched ligand L1' affords a racemic product. 4d,4e Similarly, ligand L2 affords 98% ee 5 (75% for the mismatched L2') and ligand L3 52% ee 6 (9% for the mismatched L3') for the same reaction. Both mismatched ligands afforded, however, the opposite enantiomer, showing that the binaphthol unit is imposing the absolute stereochemistry of the conjugate adduct. Such behavior of diastereomeric ligands is not unknown and some examples have been reported. 10In the course of our studies to find new ligands, we prepared an equimolecular mixture of ligands L2 and L2', starting from racemic binaphthol. When the reaction was performed using this mixture (Scheme 2), ethyl cyclohexanone was obtained in quantitative yield and with an ee of 66%, corresponding to the enantiomer given by L2! Thus, although each ligand should afford an opposite enantiomer, the matched ligand L2 is largely more efficient and overcomes the mismatched L2'. 11

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.

The asymmetric conjugate addition of diethyl zinc to acyclic enones is described. With 1% Cu(OTf) 2 and 2% of a chiral phosphite ligand, the catalyst allowed ee's up to 92% to be obtained. The addition of dimethyl zinc to a macrocyclic 15-membered ring enone lead to optically active R-(-)-muscone, in 53% yield and 79% enantiomeric excess.

The copper-catalyzed asymmetric conjugate addition of dialkyl zinc leads to homochiral zinc enolates. These intermediates were trapped in situ with activated allylic electrophiles, without the need of additional palladium catalysis. High trans selectivity (85/15 to 100/0) and excellent enantioselectivities (up to 99%) could be attained. The functionalized nature of the electrophiles makes the new synthons potential candidates for further elaboration.

A tandem asymmetric conjugate addition-cyclopropanation was developed, in which a cyclic or linear enone was converted to a TMS-protected 3-substituted-cyclopropanol in an efficient one-pot reaction. These compounds were then selectively cleaved to yield alpha-methyl-beta-alkyl ketones, alpha-methylene-enones, or chain extended gamma-alkyl-enones. This methodology was applied to the formal total synthesis of (-)-(S,S)-clavukerin A and (+)-(R,S)-isoclavukerin.