Stereogenic center asymmetric hydrogenation

In the case of tri-substituted alkenes, the 1,3-syn products are formed in moderate to high diastereoselectivities (Table 21.10, entries 6—12). The stereochemistry of hydrogenation of homoallylic alcohols with a trisubstituted olefin unit is governed by the stereochemistry of the homoallylic hydroxy group, the stereogenic center at the allyl position, and the geometry of the double bond (Scheme 21.4). In entries 8 to 10 of Table 21.10, the product of 1,3-syn structure is formed in more than 90% d.e. with a cationic rhodium catalyst. The stereochemistry of the products in entries 10 to 12 shows that it is the stereogenic center at the allylic position which dictates the sense of asymmetric induction... 

As described hitherto, diastereoselectivity is controlled by the stereogenic center present in the starting material (intramolecular chiral induction). If these chiral substrates are hydrogenated with a chiral catalyst, which exerts chiral induction intermolecularly, then the hydrogenation stereoselectivity will be controlled both by the substrate (substrate-controlled) and by the chiral catalyst (catalyst-controlled). On occasion, this will amplify the stereoselectivity, or suppress the selectivity, and is termed double stereo-differentiation or double asymmetric induction [68]. If the directions of substrate-control and catalyst-control are the same this is a matched pair, but if the directions of the two types of control are opposite then it is a mismatched pair. 

In chiral ligand 24, the two cyclopentane rings restrict the conformational flexibility of the nine-membered ring, and the four stereogenic centers in the backbone dictate the orientation of the four R-phenyl groups. Scheme 6 15 shows the application of Rh-24 in the asymmetric hydrogenation of dehy-droacylamino acids. 

The asymmetric hydrogenation of yS,yS-disubstituted a-dehydroamino acids, in which the yS-substituents are nonequivalent, provides the opportunity to selectively construct two stereogenic centers. The Me-DuPhos or Me-BPE ligands facilitate the rhodium-catalyzed hydrogenation of the E- and Z-isomers of yS,yS-disubstituted a-dehydroamino acid... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

As mentioned elsewhere, the development of transition metal catalysts that allowed for high enantioselectivity in reduction reactions showed that chemists could achieve comparable yields and ee s to enzymes. A large number of transition metal catalysts and ligands are now available. A number of reactions have been scaled up for commercial production that use an asymmetric hydrogenation (Chapters 12-18) or a hydride delivery (Chapters 12, 16, and 17) for the key step that forms the new stereogenic center. 

Because a comprehensive review on the catalytic performance of Josiphos ligands has been published,20 we restrict ourselves to a short overview on the most important fields of applications. Up to now, only the (7 )-(S)-family (and its enantiomers) but not the (R)-(R) diastereoisomers have led to high enantioselectivities (the first descriptor stands for the stereogenic center, and the second stands for the planar chirality). The most important application is undoubtedly the hydrogenation of C = N functions, where the effects of varying R and R1 have been extensively studied (for the most pertinent results see Table 15.5, Entries I—4). Outstanding performances are also observed for tetrasubstituted C = C bonds (Entry 5) and itaconic and dehydroamino acid derivatives (Entries 6 and 7). A rare example of an asymmetric hydrogenation of a heteroaromatic compound 36 with a respectable ee is depicted in Scheme 15.6.10b... 

In addition to carbon-carbon bond formation, transition metal catalysts can also generate a stereogenic center. The first reaction of this type in which useful amounts of asymmetric induction were observed was an asymmetric hydrogenation to make phenylalanine and the method has been used for many years to synthesize the anti-Parkinsons drug, L-Dopa (3) (Fig. 7) (142, 143). 

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