Mandelic Acid Amides

Cefonicid (55) is synthesized conveniently by nucleophilic displacement of the C-3 acetoxy moiety of with the appropriately substituted tetrazole thiol (54).The mandelic acid amide C-7 side chain is reminiscent of cefamandole. 

The purified enzyme displays its highest activity at 50°C. Furthermore, the enzyme is fairly stable because more than 90% of the activity is retained after a preincubation for 30 min up to 55°C. The L-aminoamidase is active between pH values of 6.5-11.0, with a broad pH optimum at pH values of 8.0-9.5 (Fig. 9). Determination of the substrate specificity of the purified enzyme showed that this amide hydrolase was active toward a rather broad range of bodi a-H- and a-alkyl-substituted amino acid amides (Table 8). Within these two substrate classes, highest activity is observed for file cyclic amino acid amide DL-proline amide and the a-alkyl-substituted amino acid amides DL-isovaline amide and DL-a-allylalanine amide. Furthermore, this enzyme displays modest activity toward a number of simple amides (e.g., acetamide and propionamide). The enzyme appears to be inactive with the a-hydroxy acid amide DL-mandelic acid amide and with the dipeptide L-Phe-L-Leu. These results clearly show that this purified amide hydrolase belongs to the group of aminoamidases. 

By this procedure three microorganisms could be identified that hydrolyzed DL-mandelic acid amide completely L-enantiospecific. The most interesting one of these three strains, based on its high cellular activity, could be identified as an Ochrobactrum anthropi strain, and this strain has been deposited at the NCIMB culture collection as NCIMB 40321. 

Inclusion of the amide in oxazolidinone functionality can be used to overcome diene statial disposition issues, for example in the conversion of 19 into 20 yields of 20 were generally high (Table 2). Ring opening of the oxazolidine moiety with or without loss of the mandelic acid moiety then afforded the corresponding azepin-2-ones <06TL3625>. 

The principles outlined above were allied by Marckwald and McKenzie 18 for the partial resolution of a racemic acid with an active alcohol. Thus When df-mandelic acid was heated with less than one equivalent of 1-menthol, the resulting ester contained somewhat more J-menthyl-d-mandelate than f-menthyl-L-mandelate and the unesterified acid contained a corresponding excess of i-mandelic acid. Also, when a mixture of equal amounts of the two diastereoisomeric esters was partially hydrolyzed, the regenerated acid and that still combined in the residual ester contained unequal amounts of the two antipodes. The process has been extended to the resolution of acids and amines through the formation and hydrolysis of amides.89... 

The high-yield synthesis of the racemate via a Strecker synthesis is elegantly combined with the asymmetric transformation process. Addition of the resolving agent (S)-mandelic acid results in the formation of both diastereoisomeric salts. In the presence of benzaldehyde these salts are in equilibrium with the Schiff base, which racemizes readily. The low solubility of the diastereoisomeric salts (in apolar solvents) eventually allows obtainment of a >95% yield of the (/f) (.S )-salt in more than 99% diastereoisomeric excess. After decomposition of this salt by hydrochloric acid, pure (Ah-phenylglycine amide is obtained, and the resolving agent can be recycled. 

Either (S)-specific aminopeptidase catalyzed hydrolysis of racemic PGA11 or crystallization-induced asymmetric transformation of racemic PGA with (.S l-mandelic acid as resolving agent12 can be used to prepare (R)-PGA. As a result of its ready availability on large scale within DSM, we envisaged the application of (R)-PGA for the production of enantiomerically pure amine functionalized compounds using the chirality transfer concept. Obviously, (S)-phenylglycine amide is also available and can be used for the preparation of the opposite enantiomer of the amines described. 

Independent synthesis of the crystalline amide LXVII established its identity and its configurational relationship to L-(+)-mandelic acid. The latter acid was converted to ethyl L-(+)-mandelate (LXVIII), and the ether linkage introduced by reaction with ethyl bromoacetate in the presence of silver carbonate, under conditions such that Walden inversion was impossible. The resulting ethyl D-(+)-2-phenyldiglycolate (LXVI), was subjected to ammonolysis, giving a crystalline product, m. p. 174-174.5°, [a]26D 106.2°. This showed no mixed melting point depression and an identical infrared absorption spectrum with the sample of LXVII obtained from /3-D-xylopyranosylbenzene. The enantiomorphic l-(—)-2-phenyldiglycolamide was also prepared by identical synthetic steps from d-( —)-mandelic acid. 

A striking solvent effect was observed in the reduction of a chiral a-keto amide, C6H5-CO-CO-NR2 (NR2 = (5)-proline methyl ester), with sodium tetrahy-dridoborate, leading to mandelic acid after hydrolysis [704]. When the a-keto amide was reduced in pure tetrahydrofuran or methanol, the resulting enantiomeric excess of (5)-mandelic acid produced was 36% and 4%, respectively. However, when a tetrahydrofuran/methanol (99 1 cL/L) solvent mixture was used, the enantiomeric excess increased to 64% ( ). In other solvent mixtures, a catalytic amount of a protic solvent (CH3OH or H2O) was found to be necessary for good asymmetric induction [704]. 

The catalytic hydrogenation of the benzoylformic acid amides of optically active amino acid esters was carried out. When the (5)-amino acid ester was used, the resulting mandelic acid had the (R)-con-figuration. When pyruvic acid amides of optically active benzylic amines were hydrogenated over palladium, optically active lactic acid was obtained in relatively high enantiomeric excess (ee 60%). The... 

Blaschke, G. Chromatographic resolutions of racemates. III. Chromatography of racemic mandelic acid on polyacrylic esters and amides of optically active ephedrine derivatives, Chem. Ber., 1974, 107, 237-252. 

Since racemic monomer was used to prepare 1 and 3 it is quite possible that only one of the two enantiomeric forms can be attacked by the enzyme. Earlier we found that the poly(amide-urethane) derived from natural mandelic acid was degraded more readily by both enzymes and fungi than the corresponding nonsubstituted poly(amide-urethane) derived from glycolic acid (6J. ... 

By the lithium aluminum hydride reduction of amides, amino alcohols (and their derivatives) can be obtained, which have a different arrangement of amino and hydroxy groups to those derived from amino acids. Thus, (5)-2-amino-l-phenylethanol is obtained by reduction of (S)-mandelic acid amide1. 

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

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

Oxadiazoles can be prepared by acylation of amidoximes. A variation of this method gives a one-pot synthesis from the amidoxime, an organic acid and a peptide coupling agent the method is sufficiently mild that there is no racemisation when mandelic acid is used. 1,2,4-Oxadiazoles can also be prepared from amides via acylamidines, " or via the cycloaddition of nitrile oxides to nitriles, as illustrated, or to 6>-methyl oximes. ... 

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