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The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH2 initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH2 for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N-benzyldihydronicotinamide (BNAH) in situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA-MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of twoelectron reduction products from the artemisinins; regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is enhance

The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous - in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70\% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known arternisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t(1/2) 26 min, and at pH 7.4, t(1/2) is about 10 hours. With a pK(a), of 4.6, over 99\% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of arternisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the `druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristi

Artemisinin - the next generation: Efficacies of artemisone against the malaria parasite are substantially greater than those of the current artemisinin "gold standard", artesunate. Also, in contrast to most current artemisinins it displays low lipophilicity and negligible neuro- and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin-based combination therapy. (Chemical Equation Presented). © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Artemisinins are the most important class of antimalarial drugs. They specifically inhibit PfATP6, a SERCA-type ATPase of Plasmodium falciparum. Here we show that a single amino acid in transmembrane segment 3 of SERCAs can determine susceptibility to artemisinin. An L263E replacement of a malarial by a mammalian residue abolishes inhibition by artemisinins. Introducing residues found in other Plasmodium spp. also modulates artemisinin sensitivity, suggesting that artemisinins interact with the thapsigargin-binding cleft of susceptible SERCAs.

An economical phase-transfer method is used to prepare 10-arylaminoartemisinins from DHA and arylamines, and artemether, arteether, and artelinate from the corresponding alcohols. In vivo sc screens against Plasmodium berghei and R yoelii in mice reveal that the p-fluorophenylamino derivative 5g is some 13 and 70 times, respectively, more active than artesunate; this reflects the very high sc activity of 10-alkylaminoartemisinins. However, through the po route, the compounds are less active than the alkylaminoartemisinins, but still approximately equipotent with artesunate.

Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced.

A new chiral tertiary aminonaphthol ligand 3b served as a highly efficient ligand for the asymmetric catalytic phenyl transfer to aromatic aldehydes and a variety of chiral diarylmethanols was prepared in high ee values (ee up to 99\%) and chemical yields. The straightforward syntheses of both 3b and its enantiomer provide an excellent opportunity for large-scale applications.

New leads for antimalarial drugs? 10-Alkylaminoartemisinin derivatives like that shown display in vivo antimalarial activities greater than those of the parent artemisinin. Previous conclusions regarding the chemical basis for the antimalarial activity of these compounds must be reconsidered.

Artemisinins form the most important class of antimalarial currently available, particularly because they are effective against parasites resistant to almost all the other classes. Their mechanism of action is controversial. Some aspects of this controversy are reviewed here. Whilst there is no clinical resistance yet identified to artemisinins, the potential to examine the relationship between polymorphisms in PfATP6 (a target of artemisinins) in multidrug resistant isolates of Plasmodium falciparum, is also discussed. (C) 2004 Elsevier Ltd. All rights reserved.

Interaction of PdCl2(MeCN)(2) with 2 equiv of (S-P)-(BuPhP)-Bu-t(O)H (1H) followed by treatment with Et3N gave [Pd{(1)(2)H}](2)(mu-Cl)(2) (2). Reaction of 2 with Na[S2CNEt2] or K[N(PPh2S)(2)] afforded Pd[(1)(2)H](S2CNEt2) (3) or Pd[(1)(2)H)[N(PPh2S)(2)] (4), respectively. Treatment of 3 with V(O)(acac)(2) (acac = acetylacetonate) and CuSO4 in the presence of Et3N afforded bimetallic complexes V(O)[Pd(1)(2)(S2CNEt2)](2) (5) or Cu[Pd(1)(2)(S2CNEt2)](2) (6), respectively. X-ray crystallography established the S-P configuration for the phosphinous acid ligands in 3 and 6, indicating that 1H binds to Pd(II) with retention of configuration at phosphorus. The geometry around Cu in 6 is approximately square planar with the average Cu-O distance of 1.915(3) Angstrom. Treatment of 2 with HBF4 gave the BF2-capped compound [Pd{(1)(2)BF2}](2)(mu-Cl)(2) (7). The solid-state structure of 7 containing a PdP2O2B metallacycle has been determined. Chloride abstraction of 7 with AgBF4 in acetone/water afforded the aqua compound [Pd{(1)(2)BF2}(H2O)(2)][BF4] (8) that reacted with [NH4](2)[WS4] to give [Pd{(1)(2)BF2}(2)](2)[mu-WS4] (9). The average Pd-S and W-S distances in 9 are 2.385(3) and 2.189(3) Angstrom, respectively. Treatment of [(eta-p-cymene)RuCl2](2) with 1H afforded the phosphinous acid adduct (eta(6)-p-cymene)RuCl2(1H) (10). Reduction of [(CpRuCl2)-Ru-star](x) (Cp-star = eta(5)-C5Me5) with Zn followed by treatment with 1H resulted in the formation of the Zn(II) phosphinate complex [{(CpRu)-Ru-star(eta(6)-C6H5)}(BuPO2)-Bu-t\}](2)(ZnCl2)(2) (11) that contains a Zn2O4P2 eight-membered ring.

Multidrug-resistant malaria caused by Plasmodium falciparum has severely limited treatment options over recent years. Artemisinins are still effective for treating uncomplicated as well as severe malaria, because resistance is not yet clinically apparent. This article reviews some clinically useful properties of artemisinins and how they might work. (C) 2004 Elsevier SAS. All rights reserved.

Lewis acid-catalysed arylation of the 100-benzoate and, less effectively, the 10alpha-benzoate of dihydroartemisinin [DHA] with activated aromatic compounds, including naphthalenes, stereoselectively, provides 10alpha-aryl derivatives including di-substituted naphthalene derivatives. 2-Methoxynaphthalene provides the 1-, rather than the 3-substituted derivative. In contrast, 10beta-aryl derivatives are obtained stereoselectively from the 10beta-bromide, generated in situ from trimethylsilyl bromide and the TMS ether of 10alpha-DHA, and the corresponding aryl Grignard reagents. The 10alpha-aryl compounds are shown by NMR spectroscopy and X-ray crystallographic analysis to possess a chair pyranose ring with equatorial aryl group, whereas the 10beta-aryl derivatives have a twist-boat pyranose ring with equatorial aryl group. The stereochemistry of the Lewis acid-catalysed arylations, which is common to that observed for the Lewis acid-catalysed arylation of pyranosyl glycosides with axial anomeric leaving groups in general, may be rationalized in terms of axial attack from the a or si face of the half-chair oxonium ion intermediate. On the other hand, the Grignard reagents activate the axial bromide to elimination through complexation, and thereby the aryl nucleophile attacks the incipient oxonium ion from the P or re face. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

The cyclic decapeptides Loloatin A (cyclic L-valyl-L-ornithyl-L-leucyl-D-tyrosyl-L-prolyl-L-phenylalanyl-D-phenylal anyl-L- asparaginyl-L-aspartyl-L-tyrosyl), loloatin B (cyclic L-valyl-Lornithyl-L-leucyl-D-tyrosyl-L-prolyl-L-phenylalanyl-D- phenylalanyl-L-asparaginyl-L-aspartyl-L-trytophanyl) and loloatin C (cyclic L-valyl-L-ornithyl-L-leucyl-D-tyrosyl-L-prolylL-tryptophanyl-D-phenylala nyl-L- asp araginyl-L-aspartyl-L-tryptophanyl) have been synthesized by Fmoc-based solid-phase peptide synthesis, commencing with Asp linked to polystyrene RAM resin through its side chain, and by on resin cyclization of the linear decapeptide through Asp and Asn, followed by cleavage of Asp from the resin. Through the use of a unique combination of DMF/dichloroethane solvent mixture in the coupling steps, and careful monitoring of both coupling and Fmoc deprotection steps, the final cyclic peptides were obtained in overall yields of 31-37\%. (C) Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

We recently described a screening system designed, to detect neurotoxicity of artemisinin derivatives based on primary neuronal brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity Res. 2:3749, 2000). Here, we probe possible mechanisms of this brain stem-specific neurodegeneration, in which artemisinin-sensitive neuronal brain stem cell cultures are compared with nonsensitive cultures (cortical neurons, astrocytes). Effects on the cytoskeleton of brain stem cell cultures, but not that of cortical cell cultures, were visible after 7 days. However, after a recovery period of 7 days, this effect also became visible in cortical cells and more severe in brain stem cell cultures. Neurodegeneration appears to be induced by effects on intracellular targets such as the cytoskeleton, modulation of the energy status by mitochondrial or metabolic defects, oxidative stress or excitotoxic events. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range in all three cell cultures, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Artemisinin additionally induces oxidative stress, as observed as an increase of reactive oxygen species and of lipid peroxidation in both neuronal cell types. Interestingly, an induction of expression of AOE was only seen in astrocytes. Here, manganese superoxide dismutase (MnSOD) expression was increased more than 3-fold and catalase expression was increased more than 1.5-fold. In brain stem neurons, MnSOD expression was dose dependently decreased. Copper-zinc superoxide dismutase and glutathione peroxidase, two other antioxidant enzymes that were investigated, did not show any changes in their mRNA expression in all three cell types after exposure to artemisinin.

Preparative and stereochemical aspects of reactions providing new C-10 ester and ether derivatives of the antimalarial drug dihydroartemisinin (DHA, 2) have been examined. beta-Artesunate has been prepared for the first time, and has been differentiated from the antimalarial alpha-artesunate; the latter has been incorrectly designated as the beta-epimer in Chemical Abstracts and some primary literature. New ester and ether derivatives bearing potential intercalating groups have been synthesised by means of the Schmidt, Mitsunobu and DCC coupling procedures, by acylation in the presence of DMAP, or by hydroxy activation with BF3 as catalyst. When the hydroxy group of DHA acts as a nucleophile towards activated carboxy groups in acylating agents or the DCC intermediate, alpha-esters are obtained exclusively. When the hydroxy group is activated for displacement by nucleophiles, as in the Schmidt or Mitsunobu procedures, beta-esters and beta-ethers are obtained either exclusively or predominantly. An exception is represented by the Mitsunobu procedure involving DHA and 1- and 2-naphthols, in which mixtures of epimers are obtained; however, exclusive formation of beta-aryl ethers takes place when the Schmidt procedure is used, with activation of the intermediate trichloracetimidate by SnCl2. The latter method is therefore superior to patented procedures for the preparation of beta-aryl ethers from nonbasic aryl alcohols without detectable rearrangement to C-aryl compounds. However, the Mitsunobu procedure is better when basic aromatic alcohols are used as nucleophiles. The formation of alpha-products in which the hydroxy group of DHA acts as a nucleophile is of biological significance in relation to enzyme-mediated Phase II glucuronidation of DHA, in which only the alpha-DHA glucuronide is formed.

Upon treatment with LDA or alkyllithium, enantiomers of P-chiral phosphinates, phosphinothioates, phosphinoamidates, thionophosphinates, thionophosphinothioates and thionophosphinoamidates undergo clean [1,3]- and [1,2]-rearrangements with complete stereoselectivity, with retention of configuration at phosphorus, to provide functionalised tertiary phosphine oxides and phosphine sulfides; the [1,2]-rearrangements of the phosphinoamidates are previously unrecorded. (C) 2001 Elsevier Science Ltd. All rights reserved.

Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.

Reaction of (R-P)- and (S-P)-tert-butylphenylphosphinobromidates and tert-butylphenylthionophosphinochloridates with metallated phenol and BINOL alkoxides, thioalkoxides, amides and enolates leading with clean inversion at phosphorus to phosphinates, phosphinothiolates and phosphinoamidates, and the corresponding thionophosphorus compounds are described. (C) 2001 Elsevier Science Ltd. All rights reserved.

The isolation in 1972 of artemisinin by Chinese scientists, and their development of all the derivatives now used in the treatment of malaria today, were of outstanding importance. The results which have accumulated both from the Chinese work and from that subsequently conducted on a worldwide basis provide for a relatively comprehensive understanding of the chemistry, pharmacological profiles, toxicology, metabolism, and effects on the malaria parasite. The optimal regimens for use in the field are also apparent, particularly in combinations with longer half-life quinoline antimalarials. Thus the future use of the artemisinin class of drug appears assured. However, the mechanism of action needs to be clarified. More importantly from a clinical viewpoint, problems inherent in the current derivatives must be addressed, particularly that of neurotoxicity, if new artemisinin derivatives are to be introduced in a normal drug regulatory environment. The application of established principles of modern drug design should indeed allow for the first truly rationally designed, in so far as the target is still unknown, derivatives to come to hand. Curr Opin Infect Dis 14:719-726, (C) 2001 Lippincott Williams & Wilkins.

P-Chiral tertiary phosphane oxides have been prepared from each of the secondary phosphane oxides racemic 1, (S-p)-(-)-4 and (R-p)-(+)-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 alpha,omega-dihalide bears an embedded heteroatom (O or Si), yields are diminished. The enantiomeric purity of each of the products was assessed through admixture with (R-p)- and (S-p)-tert-butyl(phenyl)phosphanylthioic acids and measurement of the tert-butyl resonances in the H-1-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.

In CH2Cl2 in the presence of benzylamine, artemisinin transfers an oxygen atom from the intermediate open hydroperoxide to tertiary amines to form N-oxides and N-benzyl-11-azadesoxyartemisinin Base-catalyzed side reactions interfere with the corresponding reaction involving dihydroartemisinin. The reactions serve as a model for biological activity in which the act of binding to a protein liberates hydroperoxide. (C) 1999 Elsevier Science Ltd. All rights reserved.

A sensitive, selective, and reproducible GC-MS-SIM method was developed for determination of artemether (ARM) and dihydroartemisinin (DHA) in plasma using artemisinin (ART) as internal standard. Solid phase extraction was performed using C-18 Bond Elut cartridges. The analysis was carried out using a HP-5MS 5\% phenylmethylsiloxane capillary column. The recoveries of ARM, DHA and ART were 94.9+/-1.6\%, 92.2+/-4.1\% and 81.3+/-1.2\%, respectively. The limit of quantification in plasma was 5 ng/ml (C.V.less than or equal to 17.4\% for ARM and 15.2\% for DHA). Calibration curves were linear with R(2)greater than or equal to 0.988. Within day coefficients of variation were 3-10.4\% for ARM and7.7-14.5\% for DHA. Between day coefficients of variations were 6.5-15.4\% and 7.6-14.1\% for ARM and:DHA. The method is currently being used for pharmacokinetic studies. Preliminary data on pharmacokinetics showed C-max of 245.2 and 35.6 nglml reached at 2 and 3 h and AUC(0-8h), of 2463.6 and 111.8 ngh/ml for ARM and DHA, respectively. (C) 1999 Elsevier Science B.V. All rights reserved.

The trimethylsilyl triflate catalysed DA reaction of the 3,5-hexadien-1-ol TMS ether with (+/-)-6-methylcyclohexenone efficiently gives the trans-fused adduct acetal, whose controlled hydrolysis converts it into (3aRS,6aSR,9SR,9aSR,9bRS)-9a-hydroxy-9-,3a6,6a,7,8,9,9a,9b-decahydro-1ox a-1-H-phenalene. An efficient sequence involving hydrogenation, stereoselective reduction with lithium tri-tert-butoxyaluminohydride to the alcohol, selective protection of the primary hydroxyl group with tert-butyldimethylsilyl chloride, dehydration of the secondary alcohol to the alkene, deprotection and oxidation of the primary alcohol group to the carboxylic acid provides the desmethyl qinghao acid analogue which has been converted previously into (+/-)-6,9-desmethylqinghaosu. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

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.

Whereas oxidative dimerization of each of the lithiated reagents (R-p)- and (S-p)-tert-butylphenylphosphane oxides 1 Li and 2 Li by means of oxygen in THF at low temperature led cleanly to meso-1,2-di-tert-butyl-1,2-diphenyldiphosphane dioxide (3), the respective nucleophilic substitution reactions of 1 Li and 2 Li with the (R-p)- and (S-p)-tert-butylphenylphosphinic bromides (4 and 6) in THF under argon led to the corresponding (S-p,S-p)- and (R-p,R-p)-1,2-di-tert-butyl-1,2-diphenyldiphosphane dioxides (5 and 7) in good yields, together with the meso-diphosphane dioxide 3. The structures of 3 and 5 were established by X-ray crystallography. Similarly, the reaction of lithiated (R-p)-phosphane oxide 1 Li with diphenylphosphinic bromide (8) or of achiral lithiated diphenylphosphane oxide 10 Li with (R-p)-tert-butylphenylphosphinic bromide (4) provided (S-p)-tert-butyltriphenyldiphosphane dioxide (9).

Syntheses of bi- and tridentate doubly P-chiral diphosphine dioxides through reaction of the individual enantiomers of optically pure lithiated tert-butylphenylphosphine oxide with different bifunctional electrophiles are described. Copyright (C) 1996 Elsevier Science Ltd

Nucleophilic carbonyl and conjugate addition reactions of configurationally stable lithiated P-chiral tert-butylphenylphosphine oxide with aldehydes and alpha,beta-unsaturated carbonyl compounds occur in good yields with diastereoselectivities ranging from 33 to greater than or equal to 98\%. Copyright (C) 1996 Elsevier Science Ltd

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.

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.

The trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS) ethers of hexa-3,5-dien-1-ol react with cyclohexenones and an acyclic enone, methyl vinyl ketone (MVK), in the presence of 5-10 mol\% of Me(3)SiOSO(2)CF(3) (TMSOTf) in MeCN to provide trans-fused adducts arising via ionic (Gassman-type) Diels-Alder reactions; structural confirmation for adduct stereochemistry for this type of reaction is provided by an X-ray structural determination.

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.

NMR studies of the solution structures of lithiated (E)-1-(t-butylthio)but-2-ene (4) and lithiated (E)-1-(phenylthio)but-2-ene (6) are reported. The structure of lithiated (E)-1-(t-butylthio)but-2-ene (4) is best described as a transoid carbanion with the allylic carbons C1, C2, and C3 having intermediate sp(2)-sp(3) hybridization. In (4) the heteroatom and non-allylic substituent do not play any significant role in carbanion stabilization. Lithiated (E)-1-(phenylthio)but-2-ene (6) differs from (4) in that it exhibits cis geometry about the C1-C2 bond and the phenylthio group participates in helping to stabilize allylic charge. There is a discrepancy between the geometry about the C1-C2 bond in the solution and solid structures of (4) in the presence of TMEDA.

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.