Synthesis and HHDH-Catalyzed Kinetic Resolution of Propargylic Epoxides

Kolman, Robert Junior; Švaco, Petra; Majerić Elenkov, Maja; Dokli, Irena (2024) Synthesis and HHDH-Catalyzed Kinetic Resolution of Propargylic Epoxides. Advanced Synthesis & Catalysis, 366 (24). pp. 5066-5072. ISSN 1615-4169

Microsoft Word - Accepted Version - article Restricted to Closed Access until 21 August 2025. Download (277kB) | Request a personal copy from author

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 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 (29–88% ee). The best performing p-tolyl propargylic epoxide derivative was used in a sequence of two enzymatic reactions to obtain both enantiomers of the β-azido alcohol and the (R)-enantiomer of the α-azido alcohol, each in >99% ee, through complete conversion of the starting epoxide. The obtained azido alcohols were used in further transformations. The click reactions with terminal acetylenes gave triazolyl propargylic alcohols (>99% ee, 90–98% yield). In the case of the α-azido alcohol, the click reaction was followed by intramolecular cyclization to form the dihydrofuranyl triazole motif that is found in biologically active compounds.

Item Type:	Article
Uncontrolled Keywords:	Biocatalysis; Halohydrin dehalogenases; Kinetic resolution; Propargylic epoxides; Propargylic alcohols
Subjects:	NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Enzimska sinteza fluoriranih kiralnih građevnih blokova-EnzyFluor Maja Majerić-Elenkov; Zvjezdana Findrik Blažević; Martina Sudar; Nevena Milčić IP-2018-01-4493 HRZZ
Depositing User:	Irena Dokli
Date Deposited:	28 Jan 2025 08:21
URI:	http://fulir.irb.hr/id/eprint/9509
DOI:	10.1002/adsc.202400734

Actions (login required)

View Item