Enantioselective hydrogenation, amino

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... 

Excellent asymmetric hydrogenation of amino ketones has been applied for the syntheses of many chiral drugs. For example, the enantioselective hydrogenation of 3-aryloxy-2-oxo-l-propylamine derivatives can directly afford the l-amino-3-aryloxy-2-propanol derivatives as chiral / -adrenergic blocking agents. This has been successfully accomplished with a neutral MCCPM-Rh complex as the catalyst. With 0.01 mol.% of an (A,A)-MCCPM-Rh complex,... 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Fig. 31.11 I intermediates in the enantioselective hydrogenation of /7-amino ester precursors.

Scheme 33.13 Some applications of the enantioselective hydrogenation of a-amino ketones.

The (2S,4S)-MCCPM-Rh(I) complex was found previously by Achiwa and colleagues to be an efficient catalyst for the enantioselective hydrogenation of /9-amino ketone derivatives, leading to a practical enantioselective synthesis of (F)-fluoxetine [N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine] hydrochloride [22 b]. Moreover, the use of AMPP ligands again proved to be efficient for these substrates, as exemplified in Table 33.6 [15 i],... 

Enantioselective hydrogenation of prochiral ketones has rarely been studied in aqueous biphasic media. In addition to the chiral bisphosphonic acid derivatives of 1,2-cyclohexanediamine [130], the protonated 4,4 -, 5,5 -, and 6,6 -amino-methyl-substituted BINAP (diamBINAP 2HBr) ligands (Scheme 38.7) served as constituents of the Ru(II)-based catalysts in the biphasic hydrogenations of ethyl acetoacetate [131, 132]. These catalysts were recovered in the aqueous phase and used in at least four cycles, with only a marginal loss of activity and enantio-selectivity. 

A breakthrough in this area came when Dang and Kagan3 synthesized DIOP, a C2 chiral diphosphine obtained from tartaric acid (Fig. 6-1). DIOP-Rh(I) complex catalyzed the enantioselective hydrogenation of a-(acylamino)acrylic acids and esters to produce the corresponding amino acid derivatives with up to 80% ee. These achievements stimulated research on a variety of bidentate chiral diphosphines, and numerous chiral ligands bearing C2 symmetry have been developed as a result (see Fig. 6-1 for examples). 

Homogeneous enantioselective hydrogenation constitutes one of the most versatile and effective methods to convert prochiral substrates to valuable optically active products. Recent progress makes it possible to synthesize a variety of chiral compounds with outstanding levels of efficiency and enantioselectivity through the reduction of the C=C, C=N, and C=0 bonds. The asymmetric hydrogenation of functionalized C=C bonds, such as enamide substrates, provides access to various valuable products such as amino acids, pharmaceuticals, and... 

One of the important conclusions of the early attempts was that it is fruitful to place the functionality near an optically active support. Already in 1958, Isoda and coworkers reported for the first time the enantioselective hydrogenation with a Raney nickel catalyst modified with optically pure amino acids. Optical yields reported at that time were from low (2.5%) to moderate (36%) values (for references see [12]). Subsequently, in 1963, Izumi and coworkers [100] initiated an extended study of the modified Raney nickel system with TA. As a result of their initial researches, this system was the first heterogeneous chiral catalyst to give high enantioselectivities in the hydrogenation of / -ketoesters (95%) [101,102],... 

Enantioselective synthesis of /1-amino acids is important as they are present in various natural products and in many biologically active compounds [26,27]. Several methods exist for the enantioselective synthesis of -substituted /1-amino acids (/l3-amino acids) however, synthesis of a-substituted /1-amino acids (/l2-amino acids) is very limited [28,29]. A report on highly enantioselective hydrogen atom transfer reactions to synthesize /l2-amino acids (Scheme 9) has recently been described [30]. 

Cyclic a-amino acids with an enamine pattern can be obtained upon enantioselective hydrogenation followed by a hydroformylation/cyclization sequence in a single-pot version Rh(I)-DuPHOS acts as a catalyst for both steps, the enantioselective hydrogenation of prochiral dienamides and the hydroformylation of the resulting homoallylic amines (Scheme 13) [52,53]. 

General Procedure for the Enantioselective Hydrogenation/Hydroformylation/Enamine Formation. Synthesis of Cyclic Enamine Amino Acids. Prochiral dieneamide (1 eq) and... 

An especially important case is the enantioselective hydrogenation of a-amidoacrylic acids, which leads to a-amino acids.14 A particularly detailed study has been carried out on the mechanism of reduction of methyl Z-a-acetamidocinnamate by a rhodium catalyst with a chiral disphosphine ligand.15 It has been concluded that the reactant can bind reversibly to the catalysts to give either of two complexes. Addition of hydrogen at rhodium then leads to a reactive rhodium hybride and eventually to product. Interestingly, the addition of hydrogen occurs most rapidly in the minor isomeric complex, and the enantioselectivity is... 

As enantioselective hydrogenations of prochiral substrates are undoubtedly the most common applications of chiral diphosphine ligands, a broad screening of our ligands was undertaken with some commonly used standard substrates. As substrates for the hydrogenation of C=C double bonds dimethyl itaconate (DlMl), methyl 2-acetamidoacrylate (MAA), methyl acetamidocinnamate (MAC) as an a-amino acid precursor, and ethyl (Z)-3-acetamidobutenoate ( 3-ENAM1DE) as a p-amino acid precursor were chosen (see Eig. 1.4.5). 

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