The behaviour of qinghaosu (artemisinin) in the presence of non-heme Iron(II) and (III)

In aprotic solvents with FeCl3, FeCl3/N-Acetyl cysteine or FeCl2, qinghaosu (artemisinin) undergoes rearrangement to give the tetrahydrofuran acetate, 4-hydroxydesoxoqinghoasu or the enol lactone as the major product depending on the amount of catalyst used and the polarity of the reaction medium

The behaviour of qinghaosu (artemisinin) in the presence of heme Iron(II) and (III)

With hemin [chloroprotoporphyrin IX iron(III)] or hemin/cysteine in aqueous MeCN, oxygen loss from the peroxide bridge of qinghaosu takes place to give a precursor to desoxoqinghaosu, a known malaria-inactive metabolite, in low yield. Ring-opened forms of qinghaosu such as the free hydroperoxide or peroxyhemiacetal react with hemin and heme to give predominantly the diketone resulting from oxygen loss from the peroxide bridge followed by deformylation

EXTRACTION OF ARTEMISININ AND ARTEMISINIC ACID - PREPARATION OF ARTEMETHER AND NEW ANALOGS

The preparation of artemether from artemisinin is reviewed. Firstly, the extraction of artemisinin from Artemisia annua is described and an estimation of the yield per hectare based on literature data is given. Artemisinin is reduced with sodium borohydride to produce dihydroartemisinin as a mixture of epimers. The mixture is treated with methanol and an acid catalyst to provide artemether. Increasing demand for use of artemether places pressure on the supply of artemisinin, and an alternative means of preparing the drug from artemisinic acid, an abundant constituent of A. annua, which could triple current yields, is described. In anticipation of problems of drug resistance emerging with the continued use of artemether and artesunate to treat malaria, development of new derivatives of artemisinin which have enhanced stability is required. Examples of such derivatives which have been prepared in our laboratories, or proposed, are described

PREPARATION OF A BICYCLIC ANALOG OF QINGHAO (ARTEMISINIC) ACID VIA A LEWIS-ACID CATALYZED IONIC DIELS-ALDER REACTION INVOLVING A HYDROXY DIENE AND CYCLIC ENONE AND FACILE CONVERSION INTO (+/-)-6,9-DESDIMETHYLQINGHAOSU

Treatment of 6-methylcyclohex-2-enone (8) and hexa-3,5-dien-1-ol (14) either in dichloromethane at -20 to 0 degrees C with aluminum chloride (1 equiv) or in acetonitrile at -20 degrees C with Cu(II) trifluoromethanesulfonate (1 equiv) rapidly provides in a highly stereoselective reaction the hemiacetal Diels-Aider adduct 15, which with a trans ring junction and anti methyl group is considered to arise via an ionic Gassman-type Diels-Alder reaction involving prior formation of a hemiacetal between the alcohol and enone followed by generation of an allylic cation from the hemiacetal mediated by the Lewis acid. The adduct 15 is then converted in straightforward fashion into the methyl ester of the desdimethyl analogue of qinghao (artemisinic) acid, which upon sequential photosensitized oxygenation and then Fe(phen)(3)(PF6)(3)/copper(II) triflate catalyzed cleavage-oxygenation provides (+/-)-6,9-desdimethylqinghaosu

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

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 CH2Cl2 or copper(II) trifluoromethanesulfonate [Cu(OTf)(2)] in MeCN farms a thermally labile intermediate. Chromatographic isolation of the intermediate at low temperature and analysis by low-temperature H-1 and C-13 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 degrees 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

The formation of a peracetal and trioxane from an enol ether with copper(II) triflate and oxygen: Unexpected oxygenation of aldol intermediates

The enol ether 7 undergoes rapid conversion into a 2:3 mixture of cis aldol 9 and trans aldol 11 in the presence of copper(II) triflate (0.1 equiv) and water (1 equiv) in MeCN with no intermediate formation of the corresponding ketoaldehyde 12. In the presence of oxygen, slow oxygenation of the aldols takes place to give the peracetal 13 and trioxane 14 (93:7, 47\% combined yield), and the methoxyaldehyde 8 in 12\% yield. It is proposed that retroaldolisation to an enol or Cu(II) enolate which is oxidised to an enol radical is the key step. Oxygenation of trans aldol 11 with Cu(II)/O-2 in the presence of MeOH gave the peracetal (37\%), trioxane (2\%), and the methoxyaldehydes 8 (4\%) and 10 (4\%). The cis aldol 9 reacted, by comparison, very slowly under the same conditions. (C) 1997 Elsevier Science Ltd