Asymmetric Hydrogenation Using Monodentate Phosphoramidite Ligands

Abstract

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".

Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes of Monodentate BINOL‐Derived Phosphoramidites

“…[12] Monodentate phosphoramidite ligands have the advantage of being readily accessible, highly diverse, air stable and inexpensive compared to most bidentate ligands. [13] In addition, they are amenable to parallel synthesis. [14] We have developed the use of monodentate phosphoramidites as ligands for asymmetric hydrogena-tion, [15][16][17] conjugate addition [18] , allylic alkylation, [19] asymmetric arylation of aldehydes, [20] ketones [21,22] and substituted imines.…”

Homogeneous palladium-catalyzed asymmetric hydrogenation

“…42 Two isotopic labeling experiments were carried out to confirm that the simple unprotected indole can be activated by a Brønsted acid to form iminium in situ, which was then hydrogenated by the Pd-catalyst. The use of deuterated TFE afforded the product with two deuterium atoms incorporated to the 3-position which indicated that a reversible process of protonation and deprotonation existed (eqn (9)). Owing to the fact that equilibrium was faster than hydrogenation, thus two deuterium atoms were imported to the 3-position of the 2-methylindoline before hydrogenation occurred.…”

Ruthenacycles and Iridacycles as Catalysts for Asymmetric Transfer Hydrogenation and Racemisation

“…To counter this problem, we have developed a new class of low cost ligands for asymmetric hydrogenation that can be prepared in just two steps. Binol-based monodentate phosphoramidites can be synthesised in a mere 2 steps, making them not only highly cost-effective but also readily prepared in a short period of time even in kg amounts [4]. In addition, their easy preparation allows the parallel synthesis of 96 ligands simultaneously in high throughput equipment, enabling the synthesis and testing of these ligands within 2 days [5].…”