Amino acid enantioselective hydrogenation

Examples of commercial syntheses of a-amino acids by hydrogenation catalyzed by rhodium-DuPhos complexes, including data on the activities and selectivities, are shown in Figure 15.10. Notice that several of these processes occur with high enantioselectivities and turnover numbers ranging from 1000 to 50,000. " ° In general, turnover numbers of 1000 or 5000 are needed for the cost of the catalyst to become a minor contributor to the cost of the overall process. 

Depending on the stereoselectivity of the reaction, either the R or the 5 configuration can be generated at C-2 in the product. This corresponds to enantioselective synthesis of the D and l enantiomers of a-amino acids. The hydrogenation using stereoselective chiral catalysts has been carefully investigated. The most effective catalysts for the reaction are rhodium complexes with chiral phosphine ligands. Table 2.1 records some illustrative results. The details of the catalytic mechanism need not be considered here. The fundamental point is that the chiral environment at the catalytic... 

What has been described for Norphos containing Rh catalysts is not unique but typical for the situation at present. A variety of optically active chelating phosphines developed in the last 20 years allows the synthesis of natural and unnatural amino acids by hydrogenation of the corresponding dehydroamino acid derivatives. The hydrogenation of dehydroamino acid derivatives is one of the most successful reaction types in enantioselective catalysis with transition metal compounds [5]. 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

William Knowles at the Monsanto Company discovered some years ago that u-amino acids can be prepared enantioselectively by hydrogenation of a Z enam-ido acid with a chiral hydrogenation catalyst. (S)-Phenylalanine, for instance, is prepared in 98.7% purity contaminated by only 1.3% of the (H) enantiomer when a chiral rhodium catalyst is used. For this discovery, Knowles shared the 2001 Nobel Prize in chemistry. 

Racemic a-amino amides and a-hydroxy amides have been hydrolyzed enantio-selectively by amidases. Both L-selective and o-selective amidases are known. For example, a purified L-selective amidase from Ochrobactrum anthropi combines a very broad substrate specificity with a high enantioselectivity on a-hydrogen and a,a-disubstituted a-amino acid amides, a-hydroxyacid amides, and a-N-hydroxya-mino acid amides [102]. A racemase (a-amino-e-caprolactam racemase, EC 5.1.1.15) converts the o-aminopeptidase-catalyzed hydrolysis of a-amino acid amides into a DKR (Figure 6.38) [103]. 

In an indirect amination process, acyl halides are converted to amino acids. Reaction of the acyl halide with a chiral oxazolidinone leads to a chiral amide, which reacts with the N=N unit of a dialkyl azodicarboxylate [R"02C—N=N—CO2R ]. Hydrolysis and catalytic hydrogenation leads to an amino acid with good enantioselectivity. ... 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

As expected initial examination of the hydrogenation of this substrate revealed its relatively low activity compared to dehydroamino acids that provide 3-aryl-a-amino acids. By carrying out the hydrogenation at an elevated temperature, however, the inherent low activity could be overcome. A screen of the Dowpharma catalyst collection at S/C 100 revealed that several rhodium catalysts provided good conversion and enantioselectivity while low activity and selectivity was observed with several ruthenium and iridium catalysts. Examination of rate data identified [(l )-PhanePhos Rh (COD)]Bp4 as the most active catalyst with a rate approximately... 

When we first contemplated thermochemical products available from Glu, a search of the literature revealed no studies expressly directed at hydrogenation to a specific product. Indeed, the major role that Glu plays in hydrogenation reactions is to act as an enantioselectivity enhancer (17,18). Glu (or a number of other optically active amino acids) is added to solutions containing Raney nickel, supported nickel, palladium, or ruthenium catalysts and forms stereoselective complexes on the catalyst surface, leading to enantioselective hydrogenation of keto-groups to optically active alcohols. Under the reaction conditions used, no hydrogenation of Glu takes place. 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

Oheme and co-workers investigated335 in an aqueous micellar system the asymmetric hydrogenation of a-amino acid precursors using optically active rhodium-phosphine complexes. Surfactants of different types significantly enhance both activity and enantioselectivity provided that the concentration of the surfactants is above the critical micelle concentration. The application of amphiphilized polymers and polymerized micelles as surfactants facilitates the phase separation after the reaction. Table 2 shows selected hydrogenation results with and without amphiphiles and with amphiphilized polymers for the reaction in Scheme 61.335... 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

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