Indirect Evidence for the Biosynthesis of (1S,2S)-1,2-Epoxypropylphosphonic Acid as a Co-Metabolite of Fosfomycin [(1R,2S)-1,2-Epoxypropylphosphonic Acid]by Streptomyces fradiae

Abstract

Treatment of the culture broth of fosfomycin (1) producing Streptomyces fradae with ammonia gives 2−3% of the C‐1 epimeric compound 5, as well as the known (1R,2R)‐2‐amino‐1‐hydroxypropylphosphonic acid (3) derived from fosfomycin. The configuration of 5 was determined by capillary electrophoresis employing a quinine carbamate‐type chiral selector and by synthesis from a monoprotected 1,2‐dihydroxypropylphosphonate of known absolute configuration. It is postulated that (1S,2R)‐2‐amino‐1‐hydroxypropylphosphonic acid (5) is derived by ring opening of a trans‐epoxide, formed as a co‐metabolite of fosfomycin (cis‐epoxide), with ammonia. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Steric Enforcement of cis-Epoxide Formation in the Radical C–O-Coupling Reaction by Which (S)-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin

“…Although published work has established that the predominant outcome in the oxidation of 1 by HppE is, effectively, replacement of the C1 pro-R hydrogen by the C2 oxygen with inversion of configuration at C1 (producing cis -Fos, 2 ; Scheme A and Figure A), , one study examining production of Fos in vivo reported observation of a small quantity of the trans -epoxide, [( 1S , 2S )-epoxypropylphosphonic acid; trans -Fos, 3 ], potentially arising from competing retention at C1 in the HppE-catalyzed cyclization (Scheme B, blue arrows, and Figure A). Because even a small degree of stereoambiguity in this step would rule out the mechanism enforcing inversion (Scheme B, purple arrows), we deemed it important to test directly for in vitro production of 3 by HppE.…”

Steric Enforcement of cis-Epoxide Formation in the Radical C–O-Coupling Reaction by Which (S)-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin

“…Although published work has established that the predominant outcome in the oxidation of 1 by HppE is, effectively, replacement of the C1 pro-R hydrogen by the C2 oxygen with inversion of configuration at C1 (producing cis -Fos, 2 ; Scheme A and Figure A), , one study examining production of Fos in vivo reported observation of a small quantity of the trans -epoxide, [( 1S , 2S )-epoxypropylphosphonic acid; trans -Fos, 3 ], potentially arising from competing retention at C1 in the HppE-catalyzed cyclization (Scheme B, blue arrows, and Figure A). Because even a small degree of stereoambiguity in this step would rule out the mechanism enforcing inversion (Scheme B, purple arrows), we deemed it important to test directly for in vitro production of 3 by HppE.…”

Steric Enforcement of cis-Epoxide Formation in the Radical C–O-Coupling Reaction by Which (S)-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin

“…Although published work has established that the predominant outcome in the oxidation of 1 by HppE is, effectively, replacement of the C1 pro-R hydrogen by the C2 oxygen with inversion of configuration at C1 (producing cis -Fos, 2 ; Scheme A and Figure A), , one study examining production of Fos in vivo reported observation of a small quantity of the trans -epoxide, [( 1S , 2S )-epoxypropylphosphonic acid; trans -Fos, 3 ], potentially arising from competing retention at C1 in the HppE-catalyzed cyclization (Scheme B, blue arrows, and Figure A). Because even a small degree of stereoambiguity in this step would rule out the mechanism enforcing inversion (Scheme B, purple arrows), we deemed it important to test directly for in vitro production of 3 by HppE.…”

Steric Enforcement of cis-Epoxide Formation in the Radical C–O-Coupling Reaction by Which (S)-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin

“…Although published work has established that the predominant outcome in the oxidation of 1 by HppE is, effectively, replacement of the C1 pro-R hydrogen by the C2 oxygen with inversion of configuration at C1 (producing cis -Fos, 2 ; Scheme A and Figure A), , one study examining production of Fos in vivo reported observation of a small quantity of the trans -epoxide, [( 1S , 2S )-epoxypropylphosphonic acid; trans -Fos, 3 ], potentially arising from competing retention at C1 in the HppE-catalyzed cyclization (Scheme B, blue arrows, and Figure A). Because even a small degree of stereoambiguity in this step would rule out the mechanism enforcing inversion (Scheme B, purple arrows), we deemed it important to test directly for in vitro production of 3 by HppE.…”