Enantioselective reactions amino acid synthesis

Nelson SG, Spencer KL (2000) Enantioselective (3-amino acid synthesis based on catalyzed asymmetric acyl halide-aldehyde cyclocondensation reactions. Angew Chem Int Ed 39 1323-1325... 

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

This reaction was first reported by Corey and T.ink in 1992. It is an enantioselective synthesis of a -amino acids by means of the asymmetric reduction of trichloromethyl ketones from catechoiborane in the presence of either (/ )- or (5)-oxazaborolidine, followed by the treatment of the resulting alcohols with base and sodium azide and subsequently the reductive conversion of the azido group into an amino group. Therefore, this reaction is generally known as the Corey-Link reaction. Occasionally, it is also referred to as the Corey-Link amino acid synthesis, Corey-Link procedure, etc. 

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... 

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemic mixture into its pure enantiomers (Section 9.8). A more direct approach, however, is to use an enantioselective synthesis to prepare only the desired 5 enantiomer directly. As discussed in the Chapter 19 Focus Oil, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that chiral environment, the substrate may be more... 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

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]. 

By employing A-acetamidoacrylates, rhodium-catalyzed 1,4-addition reactions can be applied to the enantioselective synthesis of a-amino acids. Unlike other typical 1,4-addition reactions, which install a stereogenic center at the p-position of the 1,4-adducts, this process deals with the formation of a stereocenter at the a-position, and thus the protonation (hydrolysis) step becomes an important step... 

A new stereocenter is formed when a synthon 143 with umpoled carbonyl reactivity (d reactivity) is introduced into aldehydes or imines. The enantioselective variant of this type of reaction was a longstanding problem in asymmetric synthesis. The very large majority of a-hetero-snbstitnted carbanions which serve as eqnivalents for synthons like 142 and 143 lead to racemic products with aldehydes or imines. However, enantiomerically pnre acylions and a-hydroxy carboxylic acids or aldehydes (144 and ent-144, respectively) as well as a-amino acids and aldehydes (145 and ent-145) are accessible either by nsing chiral d reagents or by reacting the components in the presence of chiral additives (Scheme 18). 

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