Phenylalanine asymmetric synthesis

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). 

An interesting aspect of the benzofuran cationic polymerization was uncovered by Natta, Farina, Peraldo and Bressan who reported in 196160,61 that an asymmetric synthesis of an optically active poly(benzofuran) could be achieved by using AlCl2Et coupled with (-)j3-phenylalanine, (+)camphorsulphonic acid or with (-)brucine. The optical activity was definitely due to the asymmetric carbon atoms in the polymer chain, indicating that at least some of the polymer s macromolecules possessed a di-isotactic structure, v/ z.62 ... 

The vinylcyclopropane 10 is a useful chiral building block for organic synthesis, as the vinyl group can be oxidatively cleaved if desired and further functionahzed (Scheme 14.1). Either diastereomer 20 or 21 of the cyclopropane analog of phenylalanine can be readily prepared from 10 [40]. Corey has reported another elegant appHcation of the vinylcyclopropane 10 in the asymmetric synthesis of the antidepressant (-i-)-sertraline 22 [52]. 

Closely related in topographical structure, but with different and quite unique torsional properties, are the (3-isopropyl-substituted analogues of tyrosine 41,421 and phenylalanine. 43,441 All four isomers of each amino acid analogue have been prepared by asymmetric synthesis. In addition, the highly topographically constrained amino acid 3-isopropyl-2, 6 -dimethyl-tyrosine has been prepared by asymmetric synthesis/451... 

The asymmetric synthesis of the C(2) diastereomer of amprenavir was also accomplished, similarly starting from N-tert-butoxycarbonyl-(S)-phenylalaninal (19), where the requisite chiral ammonium fluoride 4e was generated in situ from the corresponding bromide 3e in the initial nitro aldol process (Scheme 9.8) [18]. 

Reductive amination reactions of keto acids are performed with amino acid dehydrogenases. NAD-dependent leucine dehydrogenase from Bacillus sp. is of interest for the synthesis of (S)-fert.-leucine [15-17]]. This chiral compound has found widespread application in asymmetric synthesis and as a building block of biologically active substances. The enzyme can also be used for the chemoenzy-matic preparation of (S)-hydroxy-valine [18] and unnatural hydrophobic bran-ched-chain (S)-amino acids. NAD-dependent L-phenylalanine dehydrogenase from Rhodococcus sp. [19] has been used for the synthesis of L-homophenyl-alanine ((S)-2-Amino-4-phenylbutanoic acid) [9]. These processes with water-soluble substrates and products demonstrate that the use of coenzymes must not... 

MIP catalyst 76 also performs enantioselective hydrolysis of non-activated d-and L-phenylalanine ethyl ester 78 at pH 7.4, with characteristic saturation kinetics (Scheme 13.19). While this catalyst does not have the precise shape complementarity to ester 78, a threefold enhancement compared to the blank reaction was observed. Furthermore, enantiodiscrimination was obtained, as compound 78 was hydrolyzed 1.44-fold faster than ent-78. Although the reported rate enhancement was modest compared to the standards in asymmetric synthesis, it can be considered as a first step in the development of imprinted polymers for enantioselective catalysts. 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

Sometimes the natural products that are needed are immediately obvious from the structure of the target molecule. An apparently trivial example is the artificial sweetener aspartame (marketed as Nutrasweet), which is a dipeptide. Clearly, an asymmetric synthesis of this compound will start with the two members of the chiral pool, the constituent (natural) (S)-amino acids, aspartic acid and phenylalanine. In fact, because phenylalanine is relatively expensive for an amino acid, significant quantities of aspartame derive from synthetic (S)-phenylalanine made by one of the methods discussed later in the chapter. 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

It seems that the syn selectivity in the nitroaldol reaction can best be explained as arising from steric hindrance in the bicyclic transition state it seems that the greater stereoselectivity obtained by use of catalysts 27 and 28 can be ascribed to increased catalyst stability, even in the presence of an excess of highly acidic nitroalkanes. The syn-selective asymmetric nitroaldol reaction was successfully applied to the catalytic asymmetric synthesis of t/zreo-dihydrosphingosine 45, which elicits a variety of cellular responses by inhibiting protein kinase C. An efficient synthesis of erythro-AHPA 42 from L-phenylalanine was, moreover, achieved by using LLB (Sch. 9) [59],... 

The situation may be exemplified by showing the different catalytic methods of asymmetric synthesis of L-phenylalanine, starting from six different substrates (Fig. 7-2). Additionally, fermentation processes, using glucose as the carbon and energy source, have been developed130-321. 

Sulfinimines (Thiooximine S-Oxides) Asymmetric Synthesis of (R)-(+)-(3-Phenylalanine from (S)-(+)-N-(Benzylidene)-p-Toluenesulfinamide. 

This efficient asymmetric synthesis was used to convert (3) into (4) with an optical purity of 86%. In this case L-phenylalanine proved to be much more efficient than L-proline. The optically active product (4) was converted into optically active estrone (6) in overall yield of 13% from (2). The intermediate... 

Cyclic olefins afford optically active polymers by asymmetric synthesis polymerization. The first example was the polymerization of benzofuran (265) with AlEtCl2 or AICI3 in the presence of optically active cocatalysts such as p-phenylalanine and 10-CSA the polymer is considered to possess the chiral erythro- or threodiisotactic structure (266a or 266b)... 

A simple extension of the foregoing synthesis was also shown to be usefrd for making phenylalanine asymmetrically deuterated in the CHD group [68], Azido substituted boronic esters have been mentioned in passing in Section 8.3.5 in conjunction with another synthesis (Scheme 8.22) [54]. 

Finally, several other animal tissues yield useful enzymes that have been employed in S5mthesis. Pepsin is an important digestive protease from animal stomach whose native role is hydrolyzing amide bonds involving hydrophobic, aromatic amino adds, for example, phenylalanine, tyrosine, and tryptophan. Acylase from pordne kidney sdectivdy hydrolyzes N-acetyl amino adds and is commercially available. It has long been used for kinetic resolutions of amino adds. In addition to hydrolases, other animal enzymes have found important applications in biocatalysis. Rabbit musde aldolase is commerdally awiilable and was shown to catalyze aldol condensations between dihydroxyacetone phosphate and various nonnatural aldehydes by the Whitesides group in 1989 [10]. This seminal report touched off an avalanche of new applications for this and related enzymes in asymmetric synthesis. 

The asymmetric synthesis via a-transaminases was described for L-phenylalanine and L-homophenylalanine in several reports and reviews [17,62,86]. Herein the focus is on ffl-transaminases that catalyzed the asymmetric synthesis of optically pure nonproteinogenic amino acids as building blocks for peptidomimetic and other pharmaceutical compounds. The overall advantage of -transaminase-catalyzed reactions is the ability to use achiral amino donors like benzylamine, which thermodynamically favors the equilibriinn toward the product side. 

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