Evaluation and optimization of synthetic routes from dihydroartemisinin to the alkylamino-artemisinins artemiside and artemisone: A test of N-glycosylation methodologies on a lipophilic peroxide

Wing Chi Chan, Dennis Ho Wai Chan, Kin Wo Lee, Wing Shan Tin, Ho Ning Wong, Richard K. Haynes

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

10-Alkylamino-artemisinins including artemiside and artemisone display enhanced activities against malaria. Earlier, dihydroartemisinin (DHA) TMS ether was converted by trimethylsilyl bromide into the 10-β-bromide that with amine nucleophiles provided the amino-artemisinins. In an attempt to develop more economic approaches, direct N-glycosylation of DHA was examined but 2-deoxyartemisinin was invariably obtained. However, hydroxyl group activation by conversion into the 10β-halide in non-polar solvents with anhydrous HCl and Group I and II metal halides, oxalyl chloride or thionyl chloride with catalytic DMSO, and oxalyl bromide did succeed. The β-halides were converted in situ by thiomorpholine into artemiside, and by thiomorpholine-1,1-dioxide into artemisone respectively in scalable reactions. Hydrogen peroxide-acetonitrile or the urea-hydrogen peroxide complex efficiently oxidized the sulfide artemiside to the sulfone artemisone. Overall, a generalized approach to 10-alkylamino-artemisinins is now available.
Original languageEnglish
Pages (from-to)5156-5171
Number of pages16
JournalTetrahedron
Volume74
Issue number38
Early online dateApr 2018
DOIs
Publication statusPublished - 20 Sept 2018

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