engleski

Kinetic resolution of mono- and 2,2-disubstituted propargylic epoxides

Propargylic epoxides and alcohols, owing to the presence of a triple bond, undergo various intermolecular and intramolecular reactions. [1, 2]. Halohydrin dehalogenases can be used to obtain enantiomerically pure starting compounds from racemic propargylic epoxides for triple bond and/or nucleophile transformations. [3] Therefore, the synthesis of mono- and disubstituted propargylic epoxides and subsequent enantioselective ring opening by halohydrin dehalogenases (HheC, HheAN178A and HheB-4x mutant) was described (Figure 1). Internal propargylic 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. 2, 2-Disubstituted epoxides were prepared from corresponding methyl ketones, starting with selective α-halogenation, followed by triple bond introduction though a Grignard reaction and Williamson-type cyclisation. Kinetic resolution reactions in the presence of sodium azide were catalyzed by three HHDHs. Reactions of monosubstituted substrates with HheC and HheA-N178A 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). For disubstituted epoxides, reactions with HheC and HheB-4x yielded tertiary azido alcohols almost regiospecifically (β : α ratio >99:1) with excellent to very good enantioselectivities(ee between >99 and 91%, E between >200 and 60).

halohydrin dehalogenase ; propargylic epoxide ; kinetic resolution

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