Asymmetric synthesis of (−)-fosfomycin and its trans-(1S,2S)-diastereomer using a biocatalytic reduction as the key step

Fosfomycin is a gram positive and gram negative antibiotic that contains an asymmetric epoxide. An enzyme library was screened for its ability to reduce dimethyl(1-chloro-2-oxopropyl)phosphonate to the corresponding asymmetric chlorohydrin. Homology models were built in MOE, which were shown to accurately model the enzyme–substrate complex displaying the stereoselectivity that we observed. Two enzymes, YDR368w and YHR104w, were chosen for the scale up and synthesis of fosfomycin and its trans-(1S,2S)-diastereomer.

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syn-(1R,2S)-1,2-Epoxypropylphosphonic acidC3H5O4PNa2[α]36522 = −17 (c 1, H2O)Absolute configuration: (1R,2S)

anti-(1S,2S)-Dimethyl-1-chloro-2-hydroxypropanephosphonateC5H12O4PCl[α]36522 = −17 (c 1, H2O)Absolute configuration: (1S,2S)

anti-(1S,2S)-1-Chloro-2-hydroxypropane phosphonic acidC3H6O4PClNa2[α]36522 = −31.5 (c 1, H2O)Absolute configuration: (1S,2S)

syn-(1R,2S)-Dimethyl-1-chloro-2-hydroxypropanephosphonateC5H12O4PCl[α]36522 = +2.8 (c 1, H2O)Absolute configuration: (1R,2S)

syn-(1R,2S)-1-Chloro-2-hydroxypropane phosphonic acidC3H6O4PClNa2[α]36522 = +4 (c 1, H2O)Absolute configuration: (1R,2S)

trans-(1S,2S)-1,2-Epoxypropylphosphonic acidC3H5O4PNa2[α]36522 = +5.2 (c 1, H2O)Absolute configuration: (1S,2S)