engleski

Synthesis and kinetic resolution of propargylic epoxides

Halohydrin dehalogenases (HHDHs) are versatile biocatalysts that facilitate the conversion between halohydrins and epoxides in both directions. 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. Using propargylic epoxides as substrates of HHDHs, enantiomerically pure starting compounds for triple bond and/or nucleophile transformations, such as intramolecular click reactions, can be obtained. Therefore, the synthesis of substituted propargylic epoxides and subsequent enantioselective ring opening by halohydrin dehalogenases (HheA-N178A and HheC) was described (Figure 1). Phenyl-, tert-butyl- and cyclopentyl- substituted epoxides were synthesized from the corresponding terminal acetylenes by introduction and epoxidation of a double bond. Also, p- and m- tolyl derivatives were synthesized in a similar reaction sequence, starting from the corresponding iodotoluene and trimethylsilylacetylene. Kinetic resolution reactions in the presence of sodium azide were catalyzed by two HHDHs with opposite stereopreference. With both enzymes reactions yielded enantiomerically pure secondary azido alcohols (e.e. > 99%, E > 200). While HheA- N178A gave mostly (S)-β-azido alcohol (β : α ratio between 90:10 and 54:46), HheC yielded almost exclusively (R)-β-azido alcohol (up to to 99:1).

halohydrin dehalogenase ; propargylic epoxide ; biocatalysis ; kinetic resolution

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