A comprehensive overview of recent literature from 2003 concerning advances in enantioselective copper catalysed 1,4-addition of organometallic reagents to alpha,beta-unsaturated compounds is given in this critical review. About 200 ligands and catalysts are presented, with a focus on stereoselectivities, catalyst loading, ligand structure and substrate scope. A major part is devoted to trapping and tandem reactions and a variety of recent synthetic applications are used to illustrate the practicality and current state of the art of 1,4-addition of organometallic reagents. Finally several mechanistic studies are discussed (162 references).

Monodentate phosphoramidites are excellent ligands for Rh-catalyzed asymmetric hydrogenations of substituted olefins. Enantioselectivities between 95 and 99% were obtained in the asymmetric hydrogenation of protected alpha- and beta-dehydroamino acids and esters, itaconic acid and esters, aromatic enamides, aromatic enol esters, aromatic and aliphatic enol carbamates, and alpha-substituted cinnamic acids. An iridium catalyst Ir(L*)(COD)Cl was developed that contains only a single bulky phosphoramidite based on 3,3'-disubstituted BINOL or bisphenol as a chiral ligand. With this catalyst, acetylated dehydroamino acid esters could be hydrogenated with very good enantioselectivity. Most reactions have turnover frequencies of 250-1600 h (-1), depending upon the hydrogen pressure. The enantioselectivity is unaffected by the pressure over a wide range. Because of their modularity and easy synthesis, parallel ligand synthesis is possible. Results obtained with these library ligands deviate only slightly from those obtained with purified ligands. Using this instant ligand library protocol, DSM has developed catalysts for industrial processes. These MonoPhos ligands are currently used in production for pharmaceutical intermediates by DSM. It is possible to use catalysts based on a mixture of two different monodentate ligands, such as two different monodentate phosphoramidites or one phosphoramidite and one achiral phosphine ligand. Dependent upon the substrate, the "mixed" catalyst may lead to higher enantioselectivity and rate than the "homocatalysts".

Monodentate phosphoramidites based on BINOL or substituted BINOL are excellent ligands for the rhodium-catalysed asymmetric hydrogenation of olefins. Very high enantioselectivities were obtained with MonoPhos (7a) the simplest member of this class, a ligand that is prepared in a single step from BINOL and HMPT. Turnover numbers up to 6000 have been obtained in the hydrogenation of dehydroamino acid derivatives. Enantioselectivities in the hydrogenation of dehydroamino acids are solvent dependent; in non-protic solvents they range from 95 ± 99%. Itaconic acid and its dimethyl ester could be hydrogenated with 96 and 94% e.e., respectively. Hydrogenation of aromatic enamides gave the corresponding acylated amines in 86 ± 94% e.e. Several analogous phosphoramidite ligands have been prepared. Surprisingly, bidentate ligands gave poorer results, both in terms of rate as well as enantioselectivity. Taddol-based phosphoramidites led to poor e.e. and slow rates. Methyl substituents at the 3,3'-position of BINOL led to a sharply reduced rate and a somewhat lower enantioselectivity. Bromo substituents at the 6,6'-position led to a slightly reduced rate but little effect was seen on enantioselectivity. Use of octahydro-MonoPhos (11) gave results that were very similar to those obtained with 7a. The rate of the reaction is dependent on the hydrogen pressure, however, the enantioselectivity is not affected. The rate of the dehydroamino acid hydrogenation also increases if the ligand to rhodium ratio is reduced from 2.2 to 1.5 or even to 1.0; yet, there is no deleterious effect on the enantioselectivity. Catalytic activity ceases with L/Rh 3 when dehydroamino acid derivatives were used as substrate. The reaction shows a positive non-linear effect, which confirms the presence of Rh-complexes with more than one ligand. Following the hydrogenation of methyl 2-acetamidocinnnamate with Rh(nbd) 2 BF 4 /7a by electrospray mass spectrometry showed the presence of several rhodium species. Notable are the presence of [Rh(7a)] 3 and [Rh(7a)] 4 . There is at present insufficient evidence to conclude if the active catalytic species carries one or two ligands. In view of the low cost of MonoPhos this invention might well lead to a broader application of asymmetric olefin hydrogenation for the production of enantiopure amino acids and amines.

The first total synthesis of phthioceranic acid (1) has been achieved by an iterative catalytic asymmetric 1,4-addition protocol. This method provides a robust and high-yielding route for the preparation of 1,3-oligomethyl (deoxypropionate) arrays. After the desired number of methyl groups has been introduced, these arrays can be further functionalized at both ends to polymethyl-substituted lipids such as phthioceranic acid, a heptamethyl-branched fatty acid from the virulence factor Sulfolipid-I (2), found in Mycobacterium tuberculosis.