Nitrile biotransformations for the synthesis of enantiomerically enriched β2-, and β3-hydroxy and -alkoxy acids and amides, a dramatic O-substituent effect of the substrates on enantioselectivity

Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing microbial whole cell catalyst, is able to catalyze the hydrolysis of a number of β-hydroxy and β-alkoxy nitriles under very mild conditions. Both the efficiency and enantioselectivity of the biocatalysis, however, were strongly dependent upon the structures of both nitrile and amide substrates. When biotransformations of racemic 3-hydroxy-3-phenylpropionitrile and 2-hydroxymethyl-3-phenylpropionitrile gave low enantioselectivity, their O-methylated isomers underwent highly efficient and enantioselective biocatalytic reactions to afford highly enantioenriched β2- and β3-hydroxy amide and acid derivatives in excellent yield. The study has provided an example of simple and very convenient substrate engineering method to increase the enantioselectivity of the biocatalytic reaction.

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(S)-2-Hydroxymethyl-3-phenylpropionamideC10H12NO2Ee = 65.4%[α]D25=-31.3 (c 6.08, EtOH)Source of chirality: enzymatic synthesisAbsolute configuration: (S)

(R)-2-Hydroxymethyl-3-phenylpropionic acidC10H12O3Ee = 86.4%[α]D25=+13.5 (c 3.10, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (R)

(S)-2-Methoxymethyl-3-phenylpropionamideC11H15NO2Ee = 96.2%[α]D25=-9.7 (c 3.91, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (S)

(R)-2-Methoxymethyl-3-phenylpropionic acidC11H14O3Ee = 96.2%[α]D25=+4.0 (c 6.74, cyclohexane)Source of chirality: enzymatic synthesisAbsolute configuration: (R)

(S)-2-Allyloxymethyl-3-phenylpropionamideC13H17NO2Ee = 57.6%[α]D25=+2.8 (c 4.27, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (S)

(R)-2-Allyloxymethyl-3-phenylpropionic acidC13H16O3Ee = 54.6%[α]D25=0 (c 3.10, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (R)

(S)-2-Benzyloxymethyl-3-phenylpropionamideC17H19NO2Ee = 68.4%[α]D25=-10.0 (c 2.39, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (S)

(R)-2-Methoxymethyl-3-phenylpropionamideC10H13NO2Ee >99.9%[α]D25=+111.9 (c 3.20, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (R)

(S)-2-Hydroxymethyl-3-phenylpropionic acidC10H12O3Ee = 64.5%[α]D25=-41 (c 1.83, CHCl3)Source of chirality: enzymatic synthesisAbsolute configuration: (S)