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Synthesis and biocatalysis of propargylic epoxides

Halohydrin dehalogenases (HHDHs) are important biocatalysts that facilitate the reversible conversion between halohydrins and epoxides. Their ability to catalyze enantioselective epoxide ring- opening reactions with different nucleophiles (azide, cyanide, cyanate, thiocyanate etc.) can be used in synthesis of optically active epoxides, β- substituted alcohols and heterocyclic compounds. Further transformation (hydrolysis, reduction, intermolecular click reactions) gives rise to valuable building blocks (e. g. amino alcohols, aziridines, triazoles, oxazolidinones) in synthesis of pharmaceutical and natural compounds. [1] Propargylic epoxides and alcohols, owing to the presence of a triple bond, undergo various intermolecular and intramolecular reactions.[2, 3] Unfortunately, there are few described methods for enantioselective synthesis of these compounds, and those available require expensive or custom-made catalysts. However, halohydrin dehalogenases can be used to obtain enantiomerically pure starting compounds from racemic propargylic epoxides for triple bond and/or nucleophile transformations. Therefore, the synthesis of mono- and disubstituted propargylic epoxides and subsequent enantioselective ring opening by halohydrin dehalogenases (HheC and HheA-N178A) was described (Figure 1). Internal propargylic epoxides were synthesized from the corresponding terminal acetylenes by introduction and epoxidation of a double bond (cyclopentyl, tert-butyl and phenyl). Also, p- and m-tolyl derivatives were synthesized in a similar reaction sequence, starting from the corresponding iodotoluene and trimethylsilylacetylene. 2, 2-Disupstituted epoxides were prepared from corresponding methyl ketones. Biocatalytic kinetic resolution reactions in the presence of sodium azide were catalyzed by two HHDHs with opposite stereopreference (HHeC and HheA-N178A). With both enzymes reactions yielded enantiomerically pure secondary azido alcohols (ee > 99%, E > 200). While HheC yielded almost exclusively (R)-β-azido alcohol (up to 99:1), HheA-N178A gave mostly (S)-β-azido alcohol (β : α ratio between 90:10 and 54:46).

halohydrin dehalogenase ; propargylic epoxide ; biocatalysis ; kinetic resolution

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