Asymmetric hydrogenation trisubstituted

M., Humphrey, G.R. et al. on the long term factory process for the production of a prostaglandin D2 receptor antagonist - unprecedented asymmetric hydrogenation of an indole Fxo-Cyclic Trisubstituted a,(i-Unsaturated Acid. 

TABLE 6-1. Asymmetric Hydrogenation of Trisubstituted Acrylic Acids Catalyzed by Chiral Ferrocenylphosphine-Rhodium Complexes... 

Broene and Buchwald37 synthesized chiral titanocene compound 22 for the asymmetric hydrogenation of trisubstituted olefins. 

TABLE 6-3. Chiral Titanocene-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Trisubstituted Olefins... 

Asymmetric Hydrogenation of Trisubstituted Alkenes 3.1 Asymmetric Hydrogenation of Standard Test Substrates... 

Asymmetric Hydrogenation of Trisubstituted Olefins with Heteroatoms... 

Chiral l,T-diphosphetanylferrocene Et-FerroTANE serves as an effective ligand for the rhodium-catalyzed hydrogenation of y9-aryl- and /9-alkyl-substituted monoamido ita-conates (Eqs. 19 and 20) [54]. The Et-DuPhos-Rh catalyst was utihzed for the asymmetric hydrogenation of the trisubstituted olefin derivative in the preparation of an important intermediate for the drug candoxatril (>99% ee) [110]. 

Only limited successful examples of asymmetric hydrogenation of acrylic acids derivatives have included the use of chiral Rh complexes (Scheme 1.17). The diamino phosphine (28) utilizes selective ligation of the amino unit to a Rh center and also exerts electrostatic interaction with a substrate. Its Rh complex catalyzes enantioselective hydrogenation of 2-methylcinnamic acid in 92% optical yield [116], Certain cationic Rh complexes can attain highly enantioselective hydrogenation of trisubstituted acrylic acids [ 1171. 2-(6 -Methoxynaphth-2 -yl)acrylic acid is hydrogenated by an (.S ..S )-BIPNOR- Rh complex in methanol at 4 atm to give (.S)-naproxen with 98% ee but only in 30% yield [26]. 

Asymmetric hydrogenation has been reported to occur in excellent yield and ee when a trisubstituted alkene is hydrogenated with a chiral titanocene catalyst (equation 84)334. A similar reaction, but with variable enantioselectivity, may also be obtained with chiral Rh, Ru and Co catalysts335-338. Disubstituted alkenes (mainly 1,1-disubstituted) may also be... 

Asymmetric hydrogenation of trisubstituted alkenes without a chelating effect of functional groups is not easy with Ru catalysts. Hydrogenation of 1,2-diphenylpro-... 

Asymmetric Hydrogenations. Catalytic asymmetric hydrogenations of p-disubstituted-a-phenylacrylic acids have been achieved using the Rh complex of (4) (eq 9). Asymmetric hydrogenation of unsymmetrically substituted trisubstituted acrylic acids leads to the formation of two stereocenters in high ee. The variation of the terminal dialkylamino substituents has little effect on enantioselectivity. A study of a Ru° complex of (1) was reported as a model for understanding the stereoselective transition state of asymmetric hydrogenations. ... 

Asymmetric hydrogenation of trisubstituted aryl alkenes and aryl alkene esters using iridium-phosphine thiazole complexes 220 have been reported <06JA2995>. The tetrahydrobenzo[rf]thiazole complex (220b) delivers higher enantioselectivity than the cyclopenta[(7]thiazole and cyclohepta[r/]thiazole counterparts (220a and 220c), and replacement of thiazole moiety with oxazole dramatically reduces the enantioselectivity. The... 

The 7 -symmetric complex ethylene bis(tetrahydroindenyl) titanium l,T-binaphth-2,2 -dithiolate has been used to catalyze the asymmetric hydrogenation of unfunctionalized trisubstituted olefins.1680 The kinetic resolution of racemic disubstituted 1-pyrrolidines via asymmetric reduction has been described.1681... 

Quite a considerable number of papers deal with the effect of structure of olefinic substrates on their reactivity in the catalytic hydrogenation 65). Lebedev 66) attempted a generalization of the problem. His conclusion that the rate of hydrogenation of olefins decreases in the order monosubstituted - symmetric disubstituted - asymmetric disubstituted - trisubstituted tet-rasubstituted ethylene derivatives is called the Lebedev rule. Campbell 67) supplemented it by demonstrating that the rate of hydrogenation decreases with the number and size of substituents on carbon atoms of the double bond, cis isomers are usually hydrogenated more quickly than trans isomers, and olefins containing the terminal double bond are more reactive than those with the double bond inside the chain. 

The invention of Ru-binap dicarboxylate complexes extends the scope of asymmetric hydrogenations . Simple acyclic acids are hydrogenated with enantioselectivities from 80 to 100%. The procedure is applicable to /3,y-unsaturated carboxylic acids with about 80% e.e. . Deuterium incorporation indicates that a mechanism involving a metal monohydride complex operates. An amino group on the chiral phosphine ligand enhances the efficacy of ferrocenylphosphine-Rh complexes toward trisubstituted acyclic acids . 

Asymmetric hydrogenation of trisubstituted a,P-unsaturated acids 7.11 is catalyzed by cationic Rh(I) complexes, and can be performed with ferrocenyl-diphosphines 3.41 as ligands [169, 752, 1063], These reactions are run under elevated pressure and are highly enantioselective (Figure 7.9). 

A binaphthol titanocene catalyst has been proposed by Buchwald and Broene for use in asymmetric hydrogenation of nonfimctionalized trisubstituted olefins [829], These reactions take place undo- H2 pressure at 65°C. Acydic or cyclic olefins lead to saturated, branched alkanes with high chemical yield and enantiose-lectivity (ee 83 - 99%). Unfortunately, in most of the cases, the absolute configuration of the product has not yet been determined. 

Asymmetric hydrogenation. (R,/f)-Binaphane (1) is prepared from l,l -bi-2,2 -naphthol in five steps. Its Ru complex is useful for asymmetric hydrogenation of trisubstituted enamides. 

The asymmetric hydrogenation of various trisubstituted enamides in methanol by H2, catalysed by [RuCl(5 )-Synphos)(p-cym)]+Cr((S)-synphos, 238) to optically active 3-aminochroman derivatives in yields up to 97% and up to 96% ee was... 

The complex [Ir(cod)(L)]BarF, (cod= 1,5-cyclooctadiene BArp = tetrakis[bis-3,5-(trifluorome thyl)phenyl]borate and L = (250) or (251)), has been used in asymmetric hydrogenation of several E- and Z-trisubstituted and disubstituted functionalized olefins. The proper choice of ligand components gave up to 99% ee under unoptimized reaction conditions. ... 

The cationic Rh and Ir complexes with chiral (iminophosphoranyl)ferrocene ligands (107) and (108) were found to be very powerful catalysts for asymmetric hydrogenation of a series of unfunctionalized di- and trisubstituted olefins with almost perfect enantiomeric excesses (up to 99% ee) under mild conditions. In some cases the rhodium complexes were even better catalysts than their iridium counterparts. ... 

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