Asymmetric Hydrogenation of Acetamidoacrylates

The rhodium complexes with hydroxyphospholane ligand 125663 or 126660 catalyze the asymmetric hydrogenation of a-acetamidoacrylates with ee values in excess of 98%. System 125 is also very effective in the asymmetric hydrogenation of P-acetamidoacrylates (up to 99.6% ee).664 The planar-chiral heterocyclic ligand 127 complexed with rhodium(I) catalyzes the hydrogenation of a-acetamidoacrylates in excellent yields and ee values from 79-96% under mild conditions.665 

Other systems that prove successful in the highly enantioselective hydrogenation of a-acetamidoacrylates include the spirophosphinites 128 (94.2-97.2% ee)666 and the Josiphos ligands 129 with rhodium(I) (84-96% ee). Excellent 

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In the asymmetric hydrogenation of acetamidoacrylate in water with this cationic (HO)4-BASPHOS catalyst (S)-N-acetyl alanine was obtained in quantitative yield and in more than 99% ee. Noteworthy is the unusually short time necessary in or-... 

Enamides, in addition to the acrylates shown above, are also asymmetrically hydrogenated with many of the same systems that prove useful for the acetamidoacrylate reductions. The Rh(I)/BICP (2(/J)-2/(i)-bis(dipenylphosphino)-1(R),] (R)-dicyclopenlane) 132 and Rh(I)/DuPHOS systems work well (>90% ee) for the asymmetric hydrogenation of /3-acctamidovinyl methoxymethyl ethers... 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

Table 12.5 Asymmetric hydrogenation of a-acetamidoacrylates using the (S)-(R)-diamino FERRIPHOS ligand.

Furthermore FERRIPHOS ligands bearing alkyl groups instead of dimethy-lamino substituents proved to be excellent ligands in the asymmetric hydrogenation of a-acetamidoacrylic acids[34] and acetoxy acrylic esters[35l Their air stability and the easy modification of their structure make the FERRIPHOS ligands particularly useful tools for asymmetric catalysis. 

Furanoside diphosphinite ligands 10 and 11 (Fig. 11) were applied in the Ir-catalyzed asymmetric hydrogenation of several dehydroaminoacid derivatives [25]. The best enantioselectivities (ee s up to 78%) were obtained in the reduction of methyl W-acetamidoacrylate with ligand 10. These results using the lr/10-11 catalysts precursor show that enantiomeric excesses are strongly dependent on the absolute configuration of the C-3 stereocenter of the carbohydrate backbone. The best enantioselectivity were therefore obtained with ligand 10 with an... 

In asymmetric hydrogenation of olefins, the overwhelming majority of the papers and patents deal with hydrogenation of enamides or other appropriately substituted prochiral olefins. The reason is very simple hydrogenation of olefins with no coordination ability other than provided by the C=C double bond, usually gives racemic products. This is a common observation both in non-aqueous and aqueous systems. The most frequently used substrates are shown in Scheme 3.6. These are the same compounds which are used for similar studies in organic solvents salts and esters of Z-a-acetamido-cinnamic, a-acetamidoacrylic and itaconic (methylenesuccinic) acids, and related prochiral substrates. The free acids and the methyl esters usually show appreciable solubility in water only at higher temperatures, while in most cases the alkali metal salts are well soluble. 

Wan and Davis135,138 modified rhodium complexes with the water soluble chiral tetrasulfonated binap ligand 26 (Table 2) and used them as catalysts in the asymmetric hydrogenation of 2-acetamidoacrylic acid in aqueous media. The e.e. observed in neat water using Rh/26 was approximately the same as that obtained with the unsulfonated Rh/binap in ethanol (68-70% versus 67%).135... 

The new ligands were evaluated in the Rh-catalyzed asymmetric hydrogenation of benchmark substrates methyl a-N-acetamidoacrylate (7), methyl a-(2)-N-acetamidocinnamate (8) and dimethyl itaconate (9) (Table 2.3). For all three substrates, catalyst performance was superior in CH2CI2. Differences of up to 83% ee compared to otherwise identical reactions conducted in MeOH could be noted, giving... 

Figure 8.12 U rea functionalized phosphate ligands for asymmetric hydrogenation of dimethyl itaconate (DMI), N-(3,4-dihydronaphthalen-2-yl)acetamide (DNA) and methyl 2-acetamidoacrylate (MAA).

Water-soluble chelating diphosphines. This amine hydrochloride has been used to prepare water-soluble ligands for transition metals, particularly Rh(I). Thus, the complex Rh(I) -2 is a highly active catalyst for homogeneous hydrogenation, and Rh(I)-3 combines with the glycoprotein avidin to form an effective asymmetric catalyst lor hydrogenation of -acetamidoacrylic acid. 

Table 3 The Rh(l -SpirOP) -catalyzed asymmetric hydrogenation of 2-acetamidoacrylic acid with different S/C ratio ...

Table 7.2 Asymmetric hydrogenation of methyl a-acetamidoacrylate with Rh(l)-Et-DuPhos complex the effect of the miscibility of ionic liquid with an organic solvent on catalytic activity.

Table 6.11 Catalyst screening for the asymmetric hydrogenation of methyl-2-acetamidoacrylate (127).

More recently, de Bellefon and co-workers [74] demonstrated the asymmetric hydrogenation of methyl-2-acetamidoacrylate (127) to 128, within a glass capillary reactor (530 pm i.d.). Employing MeOH as the reaction solvent, H2 (1-5 bar), and a residence time of 1 min, the chiral phosphines (R,R)-DIOP (129), (R)-PHANPHOS (130), and (R,S)-Cy,Cy-J OSIPHOS (131) were evaluated as chiral promoters in the model reaction (Table 6.11). Using this approach, the authors were able to screen the catalysts using only 100 pi of reaction mixture, readily identifying 130 as the most suitable catalyst for the transformation. 

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