Enantioselective Hydrogenation of Prochiral Substrates

In the pioneering studies of Homer et al. [57] and Knowles and Sabacky [58], chirally modified Wilkinson catalysts were introduced in the homogeneous enantioselective hydrogenation of prochiral olefins. To this end, in Wilkinson-type catalysts the triphenylphosphine ligand was replaced by the optically active phosphine ligands (-i-)-PMePr Ph and H-PMePfPh, chiral at the phosphoms atom. 

In these 1968 papers, the substrates to be hydrogenated were a-ethylstyrene, a-methoxystyrene, a-phenylacrylic acid, itaconic acid, etc. The hydrogenation of dehydroamino acid derivatives entered the literature with the papers of Kagan and co-workers [59, 60] and Knowles et al. [61]. Actually, the hydrogenation of (Z)-c -acetamidocinnamic acid to give A-acetylphenylalanine (eq. (3)) became the most frequently studied test system for the evaluation of new catalysts. 

Up to the mid-1980s the field of enantioselective hydrogenation had been dominated by the Rh-based Wilkinson-type catalysts. Then, Noyori et al. introduced a new family of Ru-based catalysts, which showed a wider applicability than the Rh catalysts. a, ff-Unsaturated acids other than dehydroamino acids became substrates which could be hydrogenated with high enantioselectivity 

In the enantioselective hydrogenation of yS-keto esters optically active 3-hydro-xyalkanoic esters, important compounds in the synthesis of natural products, are 

Enantioselective hydrogenation of prochiral carbonyl compounds with Wilkinson-type catalysts is less successful than the hydrogenation of prochiral olefins. Both rates and enantioselectivities are greatly diminished in the hydrogenation of ketones, compared with olefins. Enantioselectivities only occasionally reach 80% ee, e. g., in the hydrogenation of acetophenone with the in-situ catalyst [Rh(nbd)Cl]2/DIOP, where nbd = norbomadiene [71]. The Ru-based BINAP catalysts improved this situation, by allowing the hydrogenation of a variety of functionalized ketones in enantioselectivities close to 100% ee [72]. 

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As enantioselective hydrogenations of prochiral substrates are undoubtedly the most common applications of chiral diphosphine ligands, a broad screening of our ligands was undertaken with some commonly used standard substrates. As substrates for the hydrogenation of C=C double bonds dimethyl itaconate (DlMl), methyl 2-acetamidoacrylate (MAA), methyl acetamidocinnamate (MAC) as an a-amino acid precursor, and ethyl (Z)-3-acetamidobutenoate ( 3-ENAM1DE) as a p-amino acid precursor were chosen (see Eig. 1.4.5). 

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