Synthesis of optically active α-methylamino acids and amides through biocatalytic kinetic resolution of amides

Catalyzed by Rhodococcus sp. AJ270, a nitrile hydratase and amidase containing microbial whole-cell catalyst, under very mild conditions, a number of racemic α-methylamino amides were resolved into the corresponding optically active (S)-(+)-α-methylamino acids and (R)-(−)-α-methylamino amides. The steric requirement of the amidase against α-amino phenylacetamides bearing methyl group(s) at α-amino nitrogen and/or α-carbon was also studied. Coupled with the chemical hydrolysis of amide, the biotransformation process provided a direct synthesis of α-methylamino acids in both enantiomeric forms from readily available racemic amides.

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(R)-(−)-α-Methylamino phenylacetamideC9H12N2OEe = 99%[α]D25=-98.4 (c 0.5, MeOH)Source of chirality: enzymatic synthesisAbsolute configuration: R

(R)-(−)-α-Methylamino-4-fluorophenylacetamideC9H11N2OFEe = 93%[α]D25=-82.0 (c 0.5, MeOH)Source of chirality: enzymatic synthesisAbsolute configuration: R

(R)-(−)-α-Methylamino-4-methylacetamideC10H14N2OEe = 85%[α]D25=-81.6 (c 0.5, MeOH)Source of chirality: enzymatic synthesisAbsolute configuration: R

(R)-(−)-α-Methylamino-4-methoxyphenylacetamideC10H14N2O2Ee = 95%[α]D25=-75.9 (c 0.5, MeOH)Source of chirality: enzymatic synthesisAbsolute configuration: R

(S)-(+)-α-Methylamino phenylacetic acidC9H11NO2Ee = 96%[α]D25=+116.4 (c, 0.5, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: S

(S)-(+)-α-Methylamino-4-fluorophenylacetic acidC9H10NO2FEe = 83%[α]D25=+78.4 (c 0.5, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: S

(S)-(+)-α-Methyl-4-chlorophenylacetic acidC9H10NO2ClEe = 85%[α]D25=+67.3 (c 0.5, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: S

(S)-(+)-α-Methylamino-3-methylphenylacetic acidC10H13NO2Ee = 81%[α]D25=+83.2 (c 0.5, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: S

C9H17NO2(+)-α-Methylamino-α-cyclohexyl-acetic acidEe = 96%[α]D25=+46.2 (c 1.0, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: unknown

(R)-(−)-α-Methylamino-phenylacetic acidC9H11NO2Ee = 87%[α]D25=-101.7 (c 0.5, 1 M HCl)Source of chirality: enzymatic synthesisAbsolute configuration: R