Simone Charlotte Vonwiller

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

Abstract 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.

Reaction of Metallated tert‐Butyl(phenyl)phosphane Oxide with Electrophiles as a Route to Functionalized Tertiary Phosphane Oxides: Alkylation Reactions

P-Chiral tertiary phosphane oxides have been prepared from each of the secondary phosphane oxides racemic 1, (SP)-(−)-4 and (RP)-(+)-tert-butylphenylphosphane oxide (5) by lithiation with LDA or nBuLi, or sodiation with sodium hydride, in THF, and then by treatment with a series of primary alkyl halides. Doubly P-chiral ditertiary bis(phosphane oxides) are also obtained from these metallated secondary phosphane oxides by treatment with electrophiles based on straight-chain, tartrate-derived, and bishalomethylarene dihalides. In general, the bis-phosphane oxides are obtained in good yields. However, when the α,ω-dihalide bears an embedded heteroatom (O or Si), yields are diminished. The enantiomeric purity of each of the products was assessed through admixture with (RP)- and (SP)-tert-butyl(phenyl)phosphanylthioic acids and measurement of the tert-butyl resonances in the 1H-NMR spectra. In all cases, the act of metallation of the enantiomerically pure secondary phosphane oxide followed by its alkylation is not accompanied by detectable racemization. This method for preparing P-chiral tertiary phosphane oxides is therefore more straightforward than those described previously.

Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues

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.

The diastereospecific aprotic conjugate addition reactions of carbanions derived from allylic sulfoxides and allylic phosphine oxides

Abstract The title carbanions undergo conjugate addition to cyclic enones in THF to deliver vinylic sulfoxides and vinylic phosphine oxides as single diastereomers.

The diastereospecific aprotic conjugate addition reactions of allylic anions-mechanistic aspects.

Abstract A ten-membered cyclic “chair-chair” - or “ trans -decalyl”-like TS is proposed to account for the diastereospecific aprotic conjugate addition reactions of allylic carbanions bearing polar, charge-stabilizing groups.

The preparation of D-ring-contracted analogues of Qinghaosu (Artemisinin) from Qinghao (Artemisinic) acid and their In vitro activity against Plasmodium falciparum

Abstract Qinghao (Artemisinic) acid was converted into dihydroqinghao aldehyde and then submitted to copper(II)-catalysed oxidative deformylation. The resulting ketone was reduced to the diastereomeric alcohols which were submitted to photooxygenation, and then cleavage-oxygenation-cyclisation, catalysed by Cu(II)(OSO 2 CF 3 ) 2 , to give the title compounds. In vitro testing results for antrimalarial activity indicated a remarkable dependence on the stereochemistry of the 9-methyl-substituent.

Preparation of hydrindenones from 2-methylcyclopent-2-enone and the carbanion of (E)-but-2-enyldiphenylphosphine oxide: efficient enolate trapping with β-sulphonylvinyl ketones

The β-sulphonylvinyl ketones (5), (7), (9), and (10), easily prepared from β-(phenylthio)propionyl chloride or from methyl vinyl ketone, react efficiently with the enolate produced by the conjugate addition of the carbanion of (E)-but-2-enyldiphenylphosphine oxide to 2-methylcyclopent-2-enone to provide in highly stereoselective fashion vinylogous β-diketones, two of which upon hydrogenation and aldol ring closure have been converted into hydrindenones in high yields.

Tandem Wagner-Meerwein rearrangement-carbocation trapping in the formation of chiral heterocyclic ring systems

Abstract Ortho lithiated protected anilines and phenols undergo exclusive addition to fenchone from the exo face. The corresponding adducts, under acidic conditions undergo cationic rearrangement followed by internal trapping of the new cation with amino, hydroxyl or methoxyl substituents to give enantiomerically pure chiral heterocyclic ring systems. The nature of the rearrangement is dependent on the donor group and its ability to stabilise a positive charge. With an amino donor group a product due to Wagner-Meerwein rearrangement is formed while with a methoxy donor group Nametkin rearrangement is the preferred pathway.

Iron(III) and copper(II) catalysed transformations of fatty acid hydroperoxides: efficient generation of peroxy radicals with copper(II) trifluoromethanesulphonate

Whereas methyl (9Z,11E,13S)-13-hydroperoxyoctadeca-9,11-dienoate (3) and methyl (9Z,11E,13S,15Z)-13-hydroperoxyoctadeca-9,11, 15-trienoate (4) are converted by FeCl3 dietherate into epoxy alcohols and chloroepoxides, catalytic amounts of copper(II) trifluoromethanesulphonate in the presence of octanoic acid under oxygen efficiently convert the second compound into hydroperoxy dioxolanes and dioxabicycloheptanes, and methyl (5Z,8Z,11Z,13E,15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate (15-HPETE methyl ester, 18) into hydroperoxy bisdioxolanes via an 11-peroxy radical.

Catalysed oxygenation of allylic hydroperoxides derived from qinghao (artemisinic) acid. Conversion of qinghao acid into dehydroginghaosu (artemisitene) and qinghaosu (artemisinin)

Photo-oxygenation of ginghao acid and its dihydro analogue provides allylic hydroperoxides which are converted either indirectly via the corresponding esters, or directly into dehydroginghaosu (artemisitene) and the antimalarial ginghaosu (artemisinin), by treatment with a catalytic amount of copper(II) trifluoromethanesulphonate with or without an iron(III) co-catalyst in dichloromethane-acetonitrile under oxygen.