A-Acetamidoacrylic acid

A very interesting development is the incorporation of an achiral di-phosphinerhodium(I) moiety at a specific site in the protein avidin (268). The protein binds biotin, which was first converted to the cationic rhodium complex shown in 42. a-Acetamidoacrylic acid was converted to N-acetylalanine with 40% ee in aqueous solution at pH 7 (0°C, 1.5 atm H2). 

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. 

Arobs increased from 0.21 to 60 s. a-Acetamidoacrylic acid has a pAa of 3.26, so it is probable that at pH 3.2 it undergoes protonation in the intermediate complex to a certain extent, but why should this result in such a dramatic increase ofthe rate of hydrogenation remains elusive. 

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]. 

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. ... 

Similarly to the purely organic solutions, the most widely studied alkeneic substrates are (Z)-a-acetamidocinnamic and (Z)-a-acetamidoacrylic acids and their salts. The corresponding methyl and ethyl esters are often studied in aqueous/or-ganic biphasic systems, one of the organic solvents most often employed being ethyl acetate. 

Quaternization of the ligand (3R,4R)-3,4-bis(diphenylphosphino)-l-methylpyrro-lidone, bound in the complex [Rh(cod)L]+, (L = 39) yielded a highly active and selective catalyst for hydrogenation (Z)-a-acetamidocinnamic acid (S)-N-acetylphe-nylalanine was obtained in 88-96% enantiomeric excess [91]. The 4-dimethylami-no derivatives of CHIRAPHOS (33), BDPP (34, 35) and DIOP (36) showed similarly high activities and enantioselectivities (up to 97% ee) for the reduction of (Z)-a-acetamidoacrylic acid either in aqueous slurries or in biphasic systems [92],... 

In the aforementioned work, ligands are attached covalently to a polymer. An interesting non-covalent attachment was reported early on by Wilson and Whitesides [15]. An achiral phosphine ligand linked to a biotin unit (Structure 6) interacted specifically with the protein avidin in aqueous solution to impose stereoselectivity in catalytic hydrogenation. In the rhodium-catalyzed hydrogenation of a-acetamidoacrylic acid in buffered aqueous solution, ee values of up to 40% were observed at TONs of 500 in a 48 h mn. Catalyst recovery was not a motivation for this work, but during workup the catalyst was separated from the low molecular weight products by ultrafiltration. 

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... 

Rhodium and ruthenium complexes associated with water-soluble BINAP 6 gave enantioselectivities up to 88% in the reduction of a-acetamidoacrylic acid and its methyl ester [10,11], quite close to the values obtained in organic solvents [Eq. (2)] it is to be noted in these cases that the direction of enantioselection was the opposite using the rhodium or the ruthenium catalyst, as in organic solvents. 

Other protein-rhodium conjugates containing cationic rhodium catalysts have also been prepared using bis(diphenylphosphino-ethyl)amino derivatives 5-7 and solutions of these bis(phosphine) ligands in the presence of carbonic anhydrase, a-chymotrypsin and bovine serum albumin (47). However, the exact nature of the complexes formed has not been discerned in any of these cases, and these latter enzyme-transition metal complexes evidently do not exhibit enantioselectivity in hydrogenation of a-acetamidoacrylic acid. 

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. 

Chiral diphosphinite ligands derived from D-glucose (c/. 3, 324, 325) can be used in the hydrogenation of a-acetamidoacrylic acids leading to a-amino-acids of >80% optical purity. Optimized conditions have been worked out for the large-scale resolution of the useful ligand diphos. ... 

Full details have been published on the use of chiral rhodium catalysts to effect catalytic reduction of / -substituted a-acetamidoacrylic acids optical yields of 70-80% are obtained. The requisite a-(A -acyl)acrylic acids... 

In this procedure the diphosphine intermediate serves as the basis for the elaboration of a water-soluble rhodium-based homogeneous hydrogenation catalyst. The enantioselectivity of the catalyst was tested by the reduction of a-acetamidoacrylic acid to iV-acetylalanine. The presence of avidin resulted in a definite increase in activity of the catalyst and in the production of the S-enantiomer (natural amino acid) in 40% excess. 

The preparation of (silyloxy)rhodium complexes of the type [Rh2(fi-OSiR3)2(Ti -COD)2l (R = Me, Ph), which could serve as models of rhodium complexes bound to silica, has been reported238. The synthesis of the water-soluble complex [Rh(Ti -COD)(DPPETS)]+[Cl]" (DPPETS = l,2-bis bis(m-sodiosulfonatophenyl)phosphino ethane) has been reported and its catalytic activity in two-phase hydroformylation reactions investigated. The mechanism of the homogeneous reduction of (Z)-a-acetamido and (Z)-a-benzamidocinnamic acid methyl ester and a-acetamidoacrylic acid methyl ester in an organic-water medium in the presence of catalysts derived from [Rh2(lt-Cl)2(Ti -COD)2] and chiral sulphonated phosphines has been investigated W. ... 

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