Enantioselective hydrogenation, amino acid synthesis

Rh(COD)(/ ,/ -DIPAMP)]+BF4- (13) has shown remarkable activity and enantioselectivity in the asymmetric hydrogenation of various enamides, enol acetates, and unsaturated olefins.20 26 For the past 20 years, 13 has been the premier asymmetric homogeneous catalyst for amino acid synthesis, but a new generation of catalysts based on novel bisphosphines (vide infra) has surpassed it in versatility. 

Knowles amino acid synthesis (Section 26.3) an enantioselective method of amino acid synthesis by hydrogenation of a Z enamido acid with a chiral hydrogenation catalyst. 

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). 

Depending on the stereoselectivity of the reaction, either the or the 5 configuration can generated at C-2 in the product. This corresponds to enantioselective synthesis of the d md L enantiomers of a-amino acids. Hydrogenation using chiral catalysts has been carefully investigated. The most effective catalysts for the reaction are ihodiiun... 

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. 

There is little doubt that the hydrogenation of dehydro a-amino acids is the best-studied enantioselective catalytic reaction. This was initiated by the successful development of the L-dopa process by Knowles (see below) and for many years, acetylated aminocinnamic acid derivatives were the model substrates to test most newly developed ligands. As can be seen below, this is the transformation most often used for the stereoselective synthesis of a variety of pharma and... 

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]. 

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

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. 

---