Amino acids by asymmetric hydrogenation

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. 

Following the success in producing amino acids by asymmetric hydrogenation, this research has been extended to dipeptides. Using rhodium complexes of the same or similar ligands to those above, the hydrogenation of dehydrodipeptides is also possible in optical yields in the range of 90-98% (equation 51).261"264... 

Asymmetric hydrogenations are often used at this scale because the methodology accommodates a wide variety of substrates. In addition, the technique has been scaled. In-depth discussions on the synthesis of amino acids by asymmetric hydrogenations can be found in Chapters 12-15. Resolution techniques, including SMB, are also viable options. 

Kreuzfeld, H.J., Doebler, C., Schmidt, U. and Krause, H.K. (1996) Synthesis of nonpro-teinogenic (D)- or (L)-amino acids by asymmetric hydrogenation. Amino Acids, 11, 269-82. 

Fig. 20. Synthesis of an optically active amino acid by asymmetric hydrogenation of an azomethine bond.

One of the first asymmetric catalysts to be successfully employed for asymmetric synthesis was the rhodium complex of (12.372a), due to Knowles [12,56], This ligand, which contains two asymmetric P atoms, was used in the Monsanto process for the production of L-amino acids by asymmetric hydrogenation of acylamino-acrylic acids. Only the L isomer, namely L-dopa is effective in the treatment of Parkinson s disease, and the synthesis of this compound by the route (12.374) represents an early commercial success [48]. The synthesis of L-dopa in yields of up to 95% optical purity can also be secured with the rhodium complex of (12.372b), the asymmetry of the catalyst in this case arising from the C atoms. 

The preparation of optically pure a-amino-acids by asymmetric hydrogenation of their a,/S-unsaturated derivatives catalysed by chiral rhodium(l) diphosphine complexes continues to be actively pursued. In an outstanding paper, Fryzuk and Bosnich have described the preparation and use of the rhodium(l) complex of (i )-l,2-bis(diphenylphosphino)propane ( R-prophos ) which catalyses the reduction of (Z)-N-acylaminoacrylic acids to (5)-a-amino-acids in ca. 90%... 

Table 2 Asymmetric Synthesis of Amino Acids by Catalytic Hydrogenation ...

Kitamura, M., Yoshimura, M., Tsukamoto, M., Noyori, R. Synthesis of a-amino phosphonic acids by asymmetric hydrogenation. Enantiomer 1996, 1, 281-303. 

Fryzuk, M. D. and Bosnich, B. (1977) Asymmetric synthesis of optically active amino acids by catalytic hydrogenation, J. Am. Chem. Soc. 99,62S1 2S1. 

The complexes (72) and (73) are octahedral and, as described in section 6.1.2, can exist in two enantiomeric forms, A and A. In this case, the / -BINAP forms exclusively the R-A diastereomer, and the S-BINAP the S-A. A catalytic quantity (1 mol % or even less) promotes the asymmetric hydrogenation of a wide variety of alkenes bearing nearby polar groups, such as amides, alcohols, esters, etc., which are necessary for high e.e.s. An important application of this is in the synthesis of amino acids by asymmetric reduction of amidoacrylates (74). 

Fryzuk, M. D., and B. Bosnich Asymmetric Synthesis. Production of Optically Active Amino Acids by Catalytic Hydrogenation. J. Amer. Chem. Soc. 99, 6262 (1977). 

The enantioselective synthesis of the jS-amino acid ester shown in Figure 1.6 has recently been reported by Kubryk and Hansen (Merck) where good ees were obtained by asymmetric hydrogenation. Using an in-situ reaction with diBoc-anhydride to protect the amine group a crystalline product was obtained that was recrystallized to the required 99 % + ee purity very easily. 

Asymmetric Hydrogenation. Asymmetric hydrogenation with good enantio-selectivity of unfunctionalized prochiral alkenes is difficult to achieve.144 145 Chiral rhodium complexes, which are excellent catalysts in the hydrogenation of activated multiple bonds (first, in the synthesis of a-amino acids by the reduction of ol-N-acylamino-a-acrylic acids), give products only with low optical yields.144 146-149 The best results ( 60% ee) were achieved in the reduction of a-ethylstyrene by a rhodium catalyst with a diphosphinite ligand.150 Metallocene complexes of titanium,151-155 zirconium,155-157 and lanthanides158 were used in recent studies to reduce the disubstituted C—C double bond with medium enantioselectivity. 

The carbon-carbon double bond of an enamine is also applicable for asymmetric hydrogenation leading to chiral amino acids. For example, hydrogenation of 13 by rhodium catalyst with ferrocenyl diphosphine 15 as a ligand was successful for the synthesis of methyl 3-amino-4-polyfluorophenylbutanoate 14 with excellent stereoselectivity (see Scheme 9.5) [15]. 

The approach can be coupled with other methods to prepare amino acids, such as to access [3-substituted a-amino acids. The methodology gives a way to prepare all four possible isomers of (3-aryl a-amino acids by a combination of asymmetric hydrogenation and the use of the deracem-ization process to invert the a-center (Scheme 9.36)." "°... 

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