D-Phenylglycine amide

PGA D-Phenylglycine amide PGME D-Phenylglycine methyl ester PhAc Phenylacetic acid... 

Enantiopure (/D-phenylglycine amide [abbreviated ( )-PGA] (1) has become readily accessible at DSM as a result of its application on industrial scale as a key intermediate in enzymatic routes for the preparation of fS-lactam antibiotics (Scheme 25.1).10... 

Scheme4.6 The side chains D-phenylglycin amide and D-p-hydroxyphenyl-glycin — accessible by bio-transformation (C) — are coupled by penicillin acylases, which alleviates the need for protective group chemistry (D).

An approach to L-terMeucine (9) is based on the use of a cheap chiral template, D-phenylglycine amide (8) in an asymmetric Strecker reaction with pivaldehyde, and HCN generated in situ from sodium cyanide and acetic acid in water gave the aminonitrile 10 in high yield and diastereoisomeric excess (Scheme 9.10). ... 

An efficient synthesis of P-lactam with D-phenylglycine or its derivatives as a side chain can be accomplished only by using a kinetically controlled approach via acyl group transfer from an activated side chain donor, and D-phenylglycine can be used as ester, usually methyl (PGM) or ethyl (PGE), or as amide (PGA). As a... 

In subsequent process generations, peniciUin G acylase derived enzymes were also used to couple the synthetic side chains, such as D-phenylglycine (ampicillin, cephalexin) and D-p-hydroxyphenylglycine (amoxicillin, cephadroxil) in the form of amino acid amides or esters to 6-APA and 7-ADCA (Scheme 4.6D). Biotransformation routes to the n-phenylglycine and n-p-hydroxyphenylglycine side chains were also developed (Scheme 4.6C), but the enzymatic process towards n-phenyl-glycine amide has been substituted by a classical resolution. 

Figure 12.2-9. Enzymatic conversion of 6-APA and 7-ADCA into ampicillin and cephalexin using penicillin amidase. The side chain is introduced using an activated form of D-(-)-phenylglycine, either the amide (R = NH3) or the ester (R = OCH3> OC2H5).

Sugie and Suzuki11671 demonstrated the occurrence of D-aminoacylase, which specifically hydrolyzes the amide bond of N-acyl-D-amino acids, in actinomycetes, and applied the enzyme to the production of D-phenylglycine. Recently, a new d-aminopeptidase was found in Alcaligenes denitrijicans, and shown to act on various N-acyl-D-amino acids including N-acetyl-D-methionine[168, 1691. 

Schiff base of D,L-phenyl-glycine amide Base, L-mandelic acid D-Phenylglycine [178]... 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

Unlike the Cu(II) complexes of other L-amino acids, that of L-histidine yields a positive d-d Cotton effect. Also, on the basis of the CD spectra of L-proline, L-hydroxyproline, and L-phenylglycine amide complexes of Cu(II) and Ni(II), which show positive Cotton effects in the d-d transition region, the adequacy of the hexadecant rule has been questioned (Wellman et ai, 1969) together with the planar rule (C2h), quadrant rule (C2v), and octant rule (/>2h) The several sector rules have been compared and discussed by Martin (1974, pp. 129-156). 

Remarkable is DSM s process for the preparation of (D)-phenylglycine by classical resolution with in situ racemisation. The imine of phenylglycinamide, prepared in a Strecker reaction, is readily racemised, so that in the presence of (R)-mandelic acid, the (D)-phenylglycinamide crystallises out almost quantitatively. In acidic medium, the mandehc acid is separated off and recycled the remaining amide is cleaved to yield free (D)-phenylglycine. 

In 2002, Sheldon et al. reported a two-step, one-pot enzymatic synthesis of cephalexin from o-phenylglycine nitrile. The nitrile hydratase-catalysed hydration of D-phenylglycine nitrile to the corresponding amide was combined with the penicillin G acylase-catalysed acylation of 7-aminodesace-toxycephalosporanic acid (7-ADCA) to afford, in one pot, enantiopure cephalexin in 79% yield, as shown in Scheme 4.19. 

Synthesis of the 3-methoxy-7-amino-3-cephem-4-carboxylic acid (149) was of practical importance, since it enabled the Swiss chemists to prepare a number of amide derivatives for biological testing. Thus, for example, acylation of the amino group of the 3-methoxy nucleus (149) with D-phenylglycine or with d-2-( 1,4-cyclohexadienyl)glycine afforded two orally active cephalosporins, CGP 3940 and CGP 9000. 

Thus, the mixture of a solution of roc-phenylglycine methyl ester in CHjClj and a yellow solution of 3-hexadecanoyl-(4/ )-methoxycarbonyl-l,3-thiazolidine-2-thione (14a) in the same solvent was stirred at room temperature in nitrogen until the original yellow color of the medium vanished. A usual workup gave an optically active amide 16 in 93.7% yield [enantiomeric excess percent (ee%) = 64.4 (S excess [ ]d +50.35°) based on the pure amide 16] (82TL201). The N-acylation of (4R)-MCTT (1) was carried out by its treatment with hexadecanoyl chloride in the presence of EtjN in tetrahydrofuran (THF) or by treatment of the thallium salt with hexadecanoyl chloride in THF. 

Resolution of a,a-disubstituted a-amino acids (but also of a,a-disubstituted a-hydroxy acids [51]) can also be performed on their esters. We have used pig liver esterase (PLE) for resolution of a variety of a,a-disubstituted esters. Although all substrates tested are hydrolyzed, only for a-substituted phenylglycine esters (17, X = NH2) and a-substituted mandelic esters (17, X = OH) reasonable enanlioselectivities are observed for hydrolysis of the (S) enantiomer (E = 2-114) [44]. For these types of amino acids and hydroxy acids the PLE resolution forms a valuable extension of the M. neoaurum resolution technology, since the corresponding racemic amides are hydrolyzed sluggishly (Scheme 8). The PLE resolution of a-allylphenylglycine ethyl ester has been applied in the synthesis of D-a-phenylproline (vide infra). 

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