Copper(II) Trifluoromethanesulfonate-Induced Cleavage Oxygenation of Allylic Hydroperoxides Derived from Qinghao Acid in the Synthesis of Qinghaosu Derivatives: Evidence for the Intermediacy of Enols
Abstract
The semisynthesis of qinghaosu (artemisinin) derivatives from qinghao (artemisinic) acid and related compounds is gaining increasing importance despite the fact that the key step in the transformation, the cleavage oxygenation of the intermediate allylic hydroperoxides to form peroxy hemiacetals, is not well understood. It has been found that the allylic hydroperoxide 10 derived from the methyl ester of qinghao acid under catalysis by trifluoromethanesulfonic acid (TfOH) in CH2Cl2or copper(II) trifluoromethanesulfonate [Cu(OTf)2] in MeCN forms a thermally labile intermediate. Chromatographic isolation of the intermediate at low temperature and analysis by low-temperature 1H and 13C NMR spectroscopies showed it to be the simple enol 16a, a compound possessing unexpected stability. The enol 16a undergoes autoxidation at room temperature or facile oxygenation at —20 °C in the presence of Cu(II) and oxygen to give the peroxy hemiacetal 12. Thus, the catalyzed cleavage of cyclic allylic hydroperoxides proceeds via enol intermediates and it would seem that the propensity for subsequent oxygenation is related to the stability of the enol.
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Quantitative studies monitoring the decline of dihydroartemisinic acid (480) and increase of artemisinin (495) during leaf development and senescence have confirmed that an intermediate such as 481 is probably involved in this conversion.
“quantitative studies, which monitored the decline of dihydroartemisinic acid (480) and the increase of artemisinin (495) during leaf development and senescence have confirmed that an intermediate, such as 481, is probably involved in this conversion [301]”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [301]
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- Authors
- Vonwiller, S. C., Warner, J. A., Mann, S. T., & Haynes, R. K.
- ORCID
- Haynes, Richard K.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 1995-11
- Volume
- 117
- Issue
- 45
- Pages
- 11098-11105
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2020500709
- Cited by
- 48
- References
- 0
- Citations by year
- 2025: 3 · 2024: 2 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Oxidative Organic Chemistry Reactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Physical Sciences › Chemistry › Organic Chemistry › Organic Chemistry Synthesis Methods
- Keywords
- artemisinin, artemisinin derivatives, artemisinic acid, allylic hydroperoxides, enol intermediate, autoxidation, semisynthesis
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