Asymmetric hydrogenation 2-acetamidoacrylic acids

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)] ... 

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. 

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. 

Some researchers have begun to explore the possibihty of combining transition metal catalysts with a protein to generate novel synthetic chemzymes . The transition metal can potentially provide access to novel reaction chemistry with the protein providing the asymmetric environment required for stereoselective transformations. In a recent example from Reetz s group, directed evolution techniques were used to improve the enantioselectivity of a biotinylated metal catalyst linked to streptavidin (Scheme 2.19). The Asn49Val mutant of streptavidin was shown to catalyze the enantioselective hydrogenation of a-acetamidoacrylic acid ester 46 with moderate enantiomeric excess [21]. 

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... 

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. 

Kumada et al. have examined a number of chiral ferrocenylphosphines as ligands for asymmetric reactions catalyzed by transition metals. They are of interest because they contain a planar element of chirality as well as an asymmetric carbon atom. They were first used in combination with rhodium catalysts for asymmetric hydrosilylation of ketones with di- and trialkylsilanes in moderate optical yields (5-50%). High stereoselectivity was observed in the hydrogenation of a-acetamidoacrylic acids (equation 1) with rhodium catalysts and ferrocenylphosphines. ... 

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

Asymmetric hydrogenation. This diphosphinite has been incorporated into a cationic rhodium catalyst (2) by reaction of 1 with chloronorbornadienerho-dium(I) dimer, [(NBD)RhCl]2, and AgPFe in acetone. Use of 2 in the hydrogenation of a-acetamidoacrylic acids and esters results in amino acids with the natural... 

The NP2 unit and the resultant achiral [Rh(NP2)(NBD)] moiety can also be attached easily at a specific site in a protein. The protein structure then provides the chirality required for enantioselective hydrogenation. Thus, hydrogenation of a-acetamidoacrylic acid to A/ -acetylalanine catalyzed by [Rh(NP2)(NBD)] bound to avidin at RT and 1.5 atm of H2 showed —40% S enantiomeric excess. Although these hydrogenation results with avidin are modest, it does demonstrate that asymmetric synthesis is accomplished by the -phosphine rhodium catalyst attached covalently to a protein. 

One of the strongest noncovalent interactions between a small molecule and a protein is found in the biotin-(strept)avidin association. This strong supramolecular interaction (K 10 M ) was first utilized by Wilson and White-sides in 1978 to prepare an asymmetric Rh(I) catalyst for the hydrogenation of olefins. They demonstrated that the biotinylated Rh(f)(ndb) diphosphine complex (3a in Figure 10.9) at 0.2 mol% loading catalyzed the quantitative hydrogenation of Af-acetamidoacrylic acid, affording the (S)-form of iV-acetamidoalanine with 41% ee, while the product was obtained in racemic form in the absence of avidin (Scheme 10.12) [42]. 

Scheme 10.12 Asymmetric hydrogenation of /V-acetamidoacrylic acid by a biotin-linked Rh(l) diphosphine complex bound to avidin [42].

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