Chemoenzymatic formal total synthesis of (−)-bestatin

A highly stereoselective, enzymatic reduction of an α-chloro-β-keto ester provided the key intermediate for a total synthesis of the α-hydroxy-β-amino acid moiety of (−)-bestatin. The reduction product was cyclized to a glycidic ester that was opened in a Ritter reaction with benzonitrile, affording a trans-oxazoline, which was hydrolyzed under acidic conditions to the target molecule.

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Ethyl (2R,3S)-2-chloro-3-hydroxy-4-phenylbutyrateC12H15ClO3Ee > 98%[α]D = +24 (c 0.7, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: (2R,3S)

Ethyl (2S,3S)-cis-4-phenyl-2,3-oxiranebutanoateC12H14O3Ee > 98%[α]D = +37 (c 3.0, CHCl3)Source of chirality: prior enzymatic reductionAbsolute configuration: (2S,3S)

(4S,5R)-4,5-Dihydro-2-phenyl-4-carboethoxy-5-benzyl-1,3-oxazoleC19H19NO3Ee > 98%[α]D = −57 (c 2.0, CHCl3)Source of chirality: prior enzymatic reductionAbsolute configuration: (4S,5R)

(2S,3R)-2-Hydroxy-3-amino-4-phenylbutyric acid hydrochlorideC10H13NO3·HClEe > 98%[α]D = +23 (c 1.3, 1 M HCl)Source of chirality: prior enzymatic reductionAbsolute configuration: (2S,3R)