Synthesis and HHDH‐Catalyzed Kinetic Resolution of Propargylic Epoxides

Abstract

The versatile reactivity of propargylic epoxides and alcohols, due to the presence of a triple bond, is used in the synthesis of various organic compounds and building blocks. However, there are not many known methods for the preparation of optically pure propargylic epoxides and alcohols, and the existing ones often require specific reagents. Halohydrin dehalogenases (HHDHs) can be used to obtain enantiomerically pure compounds from racemic epoxides. These important biocatalysts facilitate epoxide ring‐opening reactions with unnatural nucleophiles such as azides. Here we report the first biocatalytic transformation of propargylic epoxides using HHDHs. Six propargylic epoxides with different substituents were synthesized. Kinetic resolution reactions catalyzed by HHDHs in the presence of azide were performed. Two enzymes with opposite stereoselectivities, HheC and HheA2‐N178A were used and yielded azido alcohols (98 ‐ >99% ee, E‐value >200) and epoxides (up to 88% ee). Best performing p‐tolyl propargylic epoxide derivative was used in a sequence of two enzymatic reactions to obtain both enantiomers of the secondary alcohol and (R)‐primary alcohol in > 99% ee, respectively, through complete conversion of the starting epoxide. The obtained azido alcohols were used in further transformations. Click reactions with terminal acetylenes gave triazolyl propargylic alcohols (>99% ee, up to 98% yield). In the case of primary azido alcohol, the click reaction was followed by intramolecular cyclization to form the dihydrofuranyl triazole motif that is found in biologically active compounds.