A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: key intermediates for taxol side chain and phenylnorstatine

Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo-α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.

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Ethyl (2S,3R)-3-bromo-2-hydroxyphenylbutanoateC12H15BrO3Ee = 96%[α]D20=-16.8 (c 2.1, CHCl3)Source of chirality: S. cerevisiae reductionAbsolute configuration: (2S,3R)

Ethyl (2S,3S)-3-bromo-2-hydroxyphenylpropanoateC11H13BrO3Ee >99%[α]D20=+42.0 (c 1.3, CHCl3)Source of chirality: S. cerevisiae reductionAbsolute configuration: (2S,3S)

Ethyl (2S,3S)-3-bromo-2-hydroxy-5-methylhexanoateC9H17BrO3Ee >99%[α]D20=+3.8 (c 1.7, CHCl3)Source of chirality: S. cerevisiae reductionAbsolute configuration: (2S,3S)

Ethyl (2S,3S)-3-bromo-2-hydroxyoctanoateC9H17BrO3Ee >99%[α]D20=-18.1 (c 1.6, CHCl3)Source of chirality: S. cerevisiae reductionAbsolute configuration: (2S,3S)

Ethyl (2R,3S)-3-phenyl-2,3-oxiranepropanoateC11H12O3Ee >99%[α]D20=+15.0 (c 1.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

Ethyl (2R,3R)-4-phenyl-2,3-oxiranebutanoateC12H14O3Ee = 96%[α]D20=+4.2 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

Ethyl (2R,3R)-5-methyl-2,3-oxirane-hexanoateC9H16O3Ee >99%[α]D20=-3.0 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

Ethyl (4S,5R)-2,4-diphenyl-4,5-dihydroxazole-5-carboxylateC18H17NO3Ee >99%[α]D20=+20.0 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

Ethyl (4S,5R)-4-benzyl-2-methyl-4,5-dihydrooxazole-5-carboxylateC14H17NO3Ee = 96%[α]D20=-14.5 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

Ethyl (4S,5R)-4-isopropyl-2-methyl-4,5-dihydrooxazole-5-carboxylateC11H19NO3Ee >99%[α]D20=-3.2 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

Ethyl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoateC18H19NO4Ee = >99%[α]D20=-21.7 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

Ethyl (2R,3S)-3-acetylamino-2-hydroxy-4-phenylbutanoateC14H19NO4Ee = 96%[α]D20=-38.0 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

Ethyl (2R,3S)-3-acetylamino-2-hydroxy-5-methylhexanoateC11H21NO4Ee = >99%[α]D20=+13.0 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)