ARTEMISININ ANALOGS HAVING ANTIMALARIAL, ANTIPROLIFERATIVE, AND ANTITUMOR ACTIVITIES AND CHEMOSELECTIVE METHODS OF MAKING THE SAME

Abstract: Methods for producing novel artemisinin analogs and artemisinin dimers having antimalarial, antiproliferative and antitumor activities are described herein. These novel artemisinin analogs and artemisinin dimers have structure (VII) or diastereomers thereof, having antimalarial, and antiproliferative and antitumor activities wherein, the monomers of the present invention are formed when n is 1 and R is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl. The dimers of the present invention are formed when n is 2 and R is a linker including, but not limited to, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl.

Description: ARTEMISININ ANALOGS HAVING ANTIMALARIAL, ANTIPROLIFERATIVE, AND ANTITUMOR ACTIVITIES AND CHEMOSELECTIVE METHODS OF MAKING THE SAME Description Technical Field The present invention relates to a procedure for the production of enantiomerically pure monomeric and dimeric C-10 non-acetal derivatives of natural trioxane artemisinin having high in vitro antimalarial, antiprohferative and antitumor activities. The present invention further relates to the formation of a novel trioxane aldehyde compound produced via a chemoselective C-C bond formation at the C-10 position upon reaction of artemisinin trioxane lactone with lithiothiazole or lithiobenzothiazole. This trioxane aldehyde may then be reacted with organolithium, Grignard, and phosphorus ylide nucleophiles exclusively via carbonyl addition. Background Art Each year approximately 200-300 million people experience a malarial illness and over 1 million individuals die. In patients with severe and complicated disease, the mortality rate is between 20 and 50%. Plasmodium is the genus of protozoan parasites which is responsible for all cases of malaria and Plasmodium falciparum is the species of parasite that is responsible for the vast majority of fatal malaria infections. Malaria has traditionally been treated with quinolines such as chloroquine, quinine, mefloquine, and primaquine and with antifolates such as sulfadoxine-pyrimethamine. Unfortunately, most P. falciparum strains have now become resistant to chloroquine, and some, such as those in Southeast Asia, have also developed resistance to mefloquine and halofantrine; multidrug resistance is developing in Africa also. The endoperoxides are a promising class of antimalarial drugs which may meet the dual challenges posed by drug-resistant parasites and the rapid progression of malarial illness. The first generation endoperoxides include artemisinin and several synthetic derivatives, discussed in further detail below. Artemisia annua L., also known as qinghao or sweet wormwood, is a pervasive weed that has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. Its earliest mention, for use in hemorrhoids, occurs in the Recipes for 52 Kinds of Diseases found in the Mawangdui Han dynasty tomb dating from 168 B.C. Nearly five hundred years later Ge Hong wrote the Zhou Hou Bei Ji Fang (Handbook of Prescriptions for Emergency Treatments) in which he advised that a water extract of qinghao was effective at reducing fevers. In 1596, Li Shizhen, the famous herbalist, wrote that chills and fever of malaria can be combated by qinghao preparations. Finally, in 1972, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This crystalline compound, called qinghaosu, also referred to as QHS or artemisinin, is a sesquiterpene lactone with an internal peroxide linkage. Artemisinin is a member of the amorphane subgroup of cadinenes and has the following structure (I). I Artemisinin or QHS was the subject of a 1979 study conducted by the Qinghaosu Antimalarial Coordinating Research Group involving the treatment of 2099 cases of malaria (P. vivax and P. falciparum in a ratio of about 3:1) with different dosage forms of QHS, leading to the clinical cure of all patients. See, Qinghaosu Antimalarial Coordinating Research Group, Chin. Med. J., 92:811 (1979). Since that time artemisinin has been used successfully in many thousand malaria patients throughout the world including those infected with both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. Assay of artemisinin against P. falciparum in vitro revealed that its potency is comparable to that of chloroquine in two Hanian strains (Z. Ye, et al., J. Trad. Chin. Med., 3:95 (1983)) and of mefloquine in the Camp (chloroquine-susceptible) and Smith (chloroquine-resistant) strains, D.L. Klayman, et al, J. Nat. Prod., 47:715 (1984). Although artemisinin is effective at suppressing the parasitemias of P. vivax and P. falciparum, the problems encountered with recrudescence, and the compound's insolubility in water, led scientists to modify artemisinin chemically, a difficult task because of the chemical reactivity of the peroxide linkage which is believed to be an essential moiety for antimalarial activity. Reduction of artemisinin in the presence of sodium borohydride results in the production of dihydroartemisinin (II-l) or DHQHS, (illustrated in structure II below), in which the lactone group is converted to a lactol (hemiacetal) function, with properties similar to artemisinin. Artemisiiiin in methanol is reduced with sodium borohydride to an equilibrium mixture of a- and β-isomers of dihydroartemisinin. The yield under controlled conditions is 79% (artemisinin, 0.85M with NaBH 4 - 6:34M, 7:5 equivalents in methanol, 12 L at 0-5 °C for about 3 hours followed by quenching with acetic acid to neutrality at 0-5 °C and dilution with water to precipitate dibydroartermsinin), A. Brossi, et al, Journal of Medicinal Chemistry, 31:645-650 (1988). Using dihydroartemisinin as a starting compound a large number of other derivatives, such as, II 2 R=CH 3 3 R=CH 2 CH 3 4 R=COCH 2 CH 2 COONa 5 R=CH 2 C 6 H 4 COOH 6 R=CH 2 H 4 COONa artemether (compound II-2), arteether (II-3), sodium artesunate (H-4), artelinic acid (II-5), sodium artelinate (II-6), dihydroartemisinin condensation by-product (II-7) and the olefinic compound, structure III, III have been produced. Artemether (II-2) is produced by reacting β-dihydroartemisinin with boron trifluoride (BF 3 ) etherate or HC1 in methanol :benzene (1:2) at room temperature. A mixture of β- and α-artemether (70:30) is obtained, from which the former is isolated by column chromatography and recrystallized from hexane or methanol, R. Haynes, Transactions of the Royal Society of Tropical Medicine and Hygiene, 88(1): S1/23-S1/26 (1994). For arteether (II-3), (Brossi, et al., 1988), the α-isomer is equilibrated (epimerized) to the β-isomer in ethano benzene mixture containing BF 3 etherate. Treatment of dihydroartemisinin with an unspecified dehydrating agent yields both the olefinic compound, (III), and the dihydroartemisinin condensation by-product (II-7), formed on addition of dihydroartemisinin to (III), M. Cao, etal, Chem. Abstr., 100:34720k (1984). Until recently, the secondary hydroxy group in dihydroartemisinin (II-l) provided the only site in an active artemisinin- related compound that had been used for derivatization. See B. Nenugopalan, "Synthesis of a Novel Ring Contracted Artemisinin Derivative," Bioorganic & Medicinal Chemistry Letters , 4(5):751-752 (1994). The potency of various artemisinin-derivatives in comparison to arter isinin as a function of the concentration at which the parasitemia is 90 percent suppressed (SD 90 ) was reported by D. L. Klayman, "Qinghaosu (Artemisinin): An Antimalarial Drug from China ' Science 228:1049-1055 (1985). Dr. Klayman reported that the olefinic compound III is inactive against P. berghei-ϊnϊecteά mice, whereas the dihydroartemisinin condensation by-product (II-7) has an SD 90 of 10 mg/Kg in_P. berghei-infβcted mice. Thus, the dihydroartemisinin ether dimer proved to be less potent than artemisinin, which has an SD 90 of 6.20 mg/Kg. Following, in order of their overall antimalarial efficacy, are the three types of derivatives of dihydroartemisinin (II-l) that have been produced: (artemisinin) < ethers (II, R = alkyl) < esters [II, R = C(=0)-alkyl or -aryl] < carbonates [II, R = C(=0)0-alkyl or -aryl]. Other rational design of structurally simpler analogs of artemisinin has led to the synthesis of various trioxanes, some of which possess excellent antimalarial activity. Posner, G.H., et al, reported the chemistry and biology of a series of new structurally simple, easily prepared, racemic 1,2,4- trioxanes (disclosed in U.S. Patent No. 5,225,437 and incorporated herein by reference) that are tricyclic (lacking the lactone ring present in tetracyclic artemisinin I) and that are derivatives of trioxane alcohol IV IV having the relative stereochemistry shown above. Especially attractive features of trioxane alcohol IV are the following: (1) its straightforward and easy preparation from cheap and readily available starting materials, (2) its availability on gram scale, and (3) its easy one-step conversion, using standard chemical transformations, into alcohol derivatives such as esters and ethers, without destruction of the crucial trioxane framework. See, Posner, G.H., et al, J. Med. Chem., 35:2459-2467 (1992), incoφorated herein by reference. The complete chemical synthesis of artemisinin and a variety of other derivatives is reviewed by Sharma, R.P., et al, Heterocycles, 32(8):1593-1638 (1991), and is incorporated herein by reference. Metabolic studies by Baker, et al, demonstrated that β-arteether (II-3), one of the antimalarial derivatives discussed previously, was rapidly converted by rat liver microsomes into dmydroartemisinin (II-l). See Baker, J.K., et al, Biol. Mass Sped, 20: 609-628 (1991). This finding and the fact that the most effective artemisinin derivatives against malaria have been ethers or esters of (II-l) suggest that they were prodrugs for (II-l). The controlled slow formation of (II-l), however, is not desirable in view of its short half-life in plasma (less than two hours) and relatively high toxicity. The successful synthesis of anticancer and antiviral drugs by replacing a carbon-nitrogen bond in nucleosides by a carbon-carbon bond (C-nucleosides) prompted the preparation of several 10- alkyldeoxoartemisinins, V, wherein R is 1-allyl, propyl, methyl, or ethyl. Typically, these syntheses involved five or six steps and the reported yields were only about 12 percent. See, Jung, M., et al, Synlett., 143-144 (1990); and Haynes, R.K., et al, Synlett., 481-484 (1992). Heterolytic cleavage of the peroxide 0-0 bond via S N 2 attack of nucleophiles is well documented., see Adam, W. et al, J. Am. Chem. Soc, 114:5591 (1992) and Razuvaev, G. A.,et al, T. G. In Organic Peroxides; D. Swern, Ed., John Wiley & Sons, New York, 3:141-270, (1972). For example, tert-butyl ethers are conveniently prepared by Grignard nucleophilic attack on the 0-0 bond in tert-butyl peresters, see Lawesson, S.-O, et al, J. Am. Chem. Soc, 81:4230, (1959). Also, 3,3- disubstituted-l,2-dioxetanes react with organolithium reagents primarily via S N 2 0-0 bond cleavage (with regioselective attack at the sterically less encumbered 0 atom) to form β -hydroxy ethers (Adam, W., et al. , Chem. Ber, 125:235, (1992)) and bicyclic endoperoxides likewise react with lithium and magnesium organometallics to produce 0-0 bond-cleaved hydroxy ethers. See, Schwaebe, M. K., et al, Tetrahedron Lett., 37:6635 (1996). When a dialkyl peroxide 0-0 bond is sterically hindered, then nucleophilic attack by a reactive organometallic reagent is made more difficult; an excellent example of this phenomenon leading to chemoselective nucleophilic addition of an organolithium reagent to the aldehyde carbonyl group in a peroxy aldehyde. See, Dussault, P., et al, T. J. Org. Chem., 58:5469 (1993) and Dussault, P., Synlett, 997 (1995). 1,2,4-Trioxanes in the artemisinin family undergo peroxide 0-0 bond cleavage when exposed to dimethylcopperlithium and to trityllithium; in these two cases, however, single-electron-reductive cleavage of the peroxide bond is likely occurring. See, Posner, G. H. et al., J. Am. Chem. Soc, 114:8328 (1992). Sodium borohydride chemoselectively reduces artemisinin (I) into its lactol (II-l), but more potent lithium aluminum hydride reduces both the lactone carbonyl group and the trioxane 0-0 bond. See, Wu, Y, et al, Youji Huaxue, 153, (1986); Chem. Abstr. 1986, 105, 191426n. Based on these published precedents, it seemed that it would be very difficult to find any reactive organometallic reagents that would add chemoselectively to the lactone carbonyl group (less electrophilic than an aldehyde) of trioxane lactone artemisinin (I) without also cleaving the trioxane O- O bond. In fact, exposing artemisinin to 1.2 equivalent of phenyllithium in THF at -78 °C produced at least three major products (not characterized). Over the past thirty years only a few drugs isolated from higher plants have yielded clinical agents, the outstanding examples being vinblastine and vincristine from the Madagascan periwinkle, Catharanthus roseus, etoposide, the semi-synthetic lignan, from Mayapple Podophyllum peltatum and the diterpenoid taxol, commonly referred to as paclitaxel, from the Pacific yew, Taxus brevifolia. Of these agents, paclitaxel is the most exciting, recently receiving approval by the Food and Drug Administration for the treatment of refractory ovarian cancer. Since the isolation of artemisinin, there has been a concerted effort by investigators to study other therapeutic applications of artemisinin and its derivatives. National Institutes of Health reported that artemisinin is inactive against P388 leukemia. See NCI Report on NSC 369397 (tested on 25 October 1983). Later anticancer studies that have been conducted on cell line panels consisting of 60 lines organized into nine, disease-related subpanels including leukemia, non-small-cell lung cancer, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers, further confirm that artemisinin displays very little anticancer activity. A series of artemismin-related endoperoxides were tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolum (MTT) assay, H. J. Woerdenbag, et al, "Cytotoxicity of Artemisinin-Related Endoperoxides to Ehrlich Ascites Tumor Cells," Journal of Natural Products, 56(6):849-856 (1993). The MTT assay, used to test the artemisinin-related endoperoxides for cytotoxicity, is based on the metabolic reduction of soluble tetrazolium salts into insoluble colored formazan products by mitochondrial dehydrogenase activity of the tumor cells. As parameters for cytotoxicity, the IC 50 and IC 80 values, the drug concentrations causing respectively 50% and 80% - growth inhibition of the tumor cells, were used. Artemisinin (I) had an IC 50 value of 29.8 μM. Derivatives of dihydroartemisinin (II-l) being developed as antimalarial drugs (artemether (II-2), arteether (III-3), sodium artesunate (II-4), artelinic acid (II-5) and sodium artelinate (II-6)), exhibited a somewhat more potent cytotoxicity. Their IC 50 values ranged from 12.2 μM to 19.9 μM. The dihydroartemisinin condensation by-product dimer (II-7), disclosed previously by M. Cao, et al, 1984, was the most potent cytotoxic agent, its IC 50 being 1.4 μM. At this drug concentration the condensation by-product (H-7) is approximately twenty-two times more cytotoxic than artemisinin and sixty times more cytotoxic than dihydroartemisinin (II-l), the parent compound. While artemisinin and its related derivatives (II 1-6) discussed above demonstrated zero to slight antiprohferative and antitumor activity, it has been discovered that a class of artemisinin dimer compounds exhibits antiprohferative and antitumor activities that are, in vitro, equivalent to or greater than known antiprohferative and antitumor agents. See, U.S. Patent No. 5,677,468 incorporated herein by reference. Unfortunately, while the in vitro results of these artemisinin compounds are encouraging these compounds do not appear to have significant antitumor activity on the treatment of tumor cells in mice. There is still a need, therefore, to develop methods for the formation of hydrolytically stable C- 10 carbon-substituted artemisinin compounds and structural analogs thereof having antimalarial, and antiprohferative and antitumor activities that are equivalent to or greater than those of known antimalarial, and antiprohferative and antitumor agents, respectively, wherein the method does not result in cleavage of the trioxane 0-0 bond. Disclosure of Invention Accordingly, it is an object of this invention to provide a class of artemisinin related dimers which demonstrate antiprohferative and antitumor activities. More specifically, it is an object of this invention to provide a class of trioxane dimers which demonstrate antiprohferative and antitumor activities and that are considerably more stable than artemether and related C-10 ethers and esters toward hydrolysis. A further object of this invention is to provide artemisinin dimers to be used clinically as chemotherapeutic anticancer drugs. An additional object of this invention is to provide a class of trioxane monomers to be used clinically as chemotherapeutic antimalarial drugs. Additional objects, advantages and novel features of this invention shall be set forth in part in the description and examples that follow, and in part will become apparent to those skilled in the art upon examination of the following specification or may be learned by the practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims. To achieve the foregoing and other objects and in accordance with the purposes of the present invention, as embodied and broadly described therein the compositions of this invention comprise C-10 carbon-substituted derivatives of the trioxane exocyclic alkene (VII) of the following structure VII or diastereomers thereof, having antimalarial, and antiprohferative and antitumor activities wherein, the monomers of the present invention are formed when n is 1 and R is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl. The term "alkyl" includes straight chain or branched alkyl compounds comprising 1-20 carbon atoms and cyclic alkyl compounds comprising 5-10 carbon atoms. The term "heteroalkyl" includes polyalkylene glycols such as polyethylene glycol (PEG). The term "aryl"means a phenyl or phenyl group substituted by 1 or more substituents selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "heteroaryl" includes 5 or 6 membered heteroaromatic rings comprising one or more heteroatoms selected from N, O or S, unsubstituted or substituted by halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "lower alkyl" means straight or branched hydrocarbon radicals comprising 1-20 carbon atoms and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like. "Halogen" is fluorine, chlorine, bromine or iodine. The dimers of the present invention are formed when n is 2 and R is a linker including, but not limited to, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl. The term "alkyl" includes straight chain or branched alkyl compounds comprising 1-20 carbon atoms and cyclic alkyl compounds comprising 5-10 carbon atoms. The term "heteroalkyl" includes polyalkylene glycols such as polyethylene glycol (PEG). The term "aryl"means a phenyl or phenyl group substituted by 1 or more substituents selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "heteroaryl" includes 5 or 6 membered heteroaromatic rings comprising one or more heteroatoms selected from N, O or S, unsubstituted or substituted by halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "lower alkyl" means straight or branched hydrocarbon radicals comprising 1-20 carbon atoms and include, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like. "Halogen" is fluorine, chlorine, bromine or iodine. Brief Description of the Drawings The accompanying drawings, which are incoφorated in and form a part of the specification, illustrate the preferred embodiments of the present invention, and together with the description serve to explain the principles of the invention. In the drawing, Figure 5, the horizontal axis depicts various dilutions of the test compounds, ranging from 10 "6 to 7 x 10 "9 molar, that were exposed to murine keratinocytes. The vertical axis (cell number) depicts the number of murine keratinocyte cells present after exposure to a specific concentration of the tested compound as compared to the cell number at time zero. In the drawings, Figures 6-14, the horizontal axis depicts various dilutions of the test compound, ranging from 10 "4 to 10 '9 molar, that were exposed to the specified cancer cell lines. The vertical axis (percentage growth) depicts the growth of the specified cancer cell line when exposed to a specific concentration of the tested compound as compared to the growth of the same cancer cell line not exposed to any compound. In the Drawings: Figure 1 schematically depicts the method of converting artemisinin I into the 9,10-unsaturated C-10 alkylidenated aldehyde VII of the present invention. Figure 2 schematically depicts the method of converting artemisinin I into an alkene benzothiazole- 4 artemisinin analogue of the present invention. Figure 3 schematically depicts the formation of artemisinin analogues of the present invention by organometallic nucleophilic addition to the carbonyl group of the trioxane enal Ie. Figure 4 schematically depicts the formation monomeric and dimeric exocyclic alkene analogues of artemisinin by reacting nucleophilic phosphonium ylides with the trioxane enal Ie. Figure 5 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C-10 carbon-substituted trioxane dimers VH-f, VH-g, and Vll-h of the present invention versus calcitriol and versus a control using only a solvent. Figure 6a depicts the dose response curves generated by exposing various leukemia cancer «ell lines to various concentrations of paclitaxel. Figure 6b depicts the dose response curves generated by exposing various leukemia cancer cell lines to various concentrations of artemisinin. Figure 6c depicts the dose response curves generated by exposing various leukemia cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure 6d depicts the dose response curves generated by exposing various leukemia cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-g of the present invention. Figure 6e depicts the dose response curves generated by exposing various leukemia cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-h. Figure 7a depicts the dose response curves generated by exposing various non-small cell lung cancer cell lines to various concentrations of paclitaxel. Figure 7b depicts the dose response curves generated by exposing various non-small cell lung cancer cell lines to various concentrations of the artemisinin. Figure 7c depicts the dose response curves generated by exposing various non-small cell lung cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-f of the present invention. Figure 7d depicts the dose response curves generated by exposing various non-small cell lung cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-g of the present invention. Figure 7e depicts the dose response curves generated by exposing various small cell lung cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-h. Figure 8a depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of paclitaxel. Figure 8b depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of artemisinin. Figure 8c depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure 8d depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-g of the present invention. Figure 8e depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Figure 9a depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of paclitaxel. Figure 9b depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of artemisinin. Figure 9c depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure 9d depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-g of the present invention. Figure 9e depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Figure 10a depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of paclitaxel. Figure 10b depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of artemisinin. Figure 10c depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-f of the present invention. Figure lOd depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-g of the present invention. Figure 1 Oe depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Figure 11a depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of paclitaxel. Figure 1 lb depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of artemisinin. Figure l ie depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure lid depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-g of the present invention. Figure l ie depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Figure 12a depicts the dose response curves generated by exposing various renal cancer cell lines o various concentrations of paclitaxel. Figure 12b depicts the dose response curves generated by exposing various renal cancer cell lines o various concentrations of artemisinin. Figure 12c depicts the dose response curves generated by exposing various renal cancer cell lines o various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure 12d depicts the dose response curves generated by exposing various renal cancer cell lines o various concentrations of the C-10 carbon-substituted dimer VH-g of the present invention. Figure 12e depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Figure 13a depicts the dose response curves generated by exposing various prostate cancer cell lines to various concentrations of paclitaxel. Figure 13b the response curves generated by exposing various prostate cancer cell lines to various concentrations of artemisinin was not evaluated. Figure 13c depicts the dose response curves generated by exposing various prostate cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-f of the present invention. Figure 13d depicts the dose response curves generated by exposing various prostate cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-g of the present invention. Figure 13e depicts the dose response curves generated by exposing various prostate cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-h. Figure 14a depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of paclitaxel. Figure 14b the dose response curves generated by exposing various breast cancer cell lines to various concentrations of artemisinin was not evaluated. Figure 14c depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of the C-10 carbon-substituted dimer VH-f of the present invention. Figure 14d depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-g of the present invention. Figure 14e depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of the C-10 carbon-substituted dimer Vll-h. Best Mode for Carrying out the Invention The present invention provides a direct method for reacting an organometallic reagent that chemoselectively adds to the lactone group of trioxane lactone artemisinin (I) without cleaving the trioxane bond. The resulting trioxane aldehyde Ie may then be further reacted with organolithium, Grignard, and phosphorous ylide nucleophiles exclusively via carbonyl addition. Also, a trioxane ketone product may be reacted with phenyllithium via only carbonyl addition. These chemoselective lactone, aldehyde, and ketone carbonyl addition reactions produced a series of new, enantiomerically pure, C-10 non-acetal derivatives of natural trioxane artemisinin having high in vitro antimalarial, antiprohferative and antitumor activities. In general, the first step of the preferred process of the present invention, conversion of artemisinin (I) into trioxane enal Ie, is accomplished by using an effective amount of an organometallic reagent which chemoselectively reacts at the C-10 position of the artemisinin skeleton without disrupting the 0-0 bond in this trioxane. Effective organometallic reagents include, but are not limited to heteroaryllithium reagents, and preferably lithiothiazole and lithiobenzothiazole. The relative amounts of the various possible organometallic reagents depends upon the concentration employed and other conditions of the reaction. Various amounts of the organometallic reagent can be employed, but generally it should be present in the range of 1.0 to 1.5 molar equivalents of organometallic reagent per molar equivalent of artemisinin for the reaction to proceed to completion. Based on the published precedents discussed previously in the background section of the present application, it seemed that it would be very difficult to find any reactive organometallic reagents that would add chemoselectively to the lactone carbonyl group (less electrophilic than an aldehyde) of trioxane lactone artemisinin (I) without also cleaving the trioxane 0-0 bond. In fact, exposing artemisinin to 1.2 equivalent of phenyllithium in THF at -78 °C produced at least three major products (not characterized). However, suφrisingly after in situ 0-acetylation, thiazole carbonyl adduct la was isolated in 95% yield! See Figure 1. Mass spectrometry confirmed that the trioxane unit was intact, thereby establishing that this new C-C bond-forming reaction had occurred with very high chemoselectivity at C-10 of the artemisinin skeleton without rupturing the 0-0 bond in this trioxane. Alternatively, as shown in Figure 2 a similar chemoselective result was obtained using lithiobenzothiazole as the nucleophile Interestingly, other «... 17 heteroaryllithium reagents (e.g. 2-lithiothiophene, 2-lithiobenzoxazole) failed to react with artemisinin under conditions in which lithiothiazole and lithiobenzothiazole did react. The next step in the production of the novel trioxane enal Ie involves the elimination of acetic acid from the artemisinin thiazole acetate la product to form the 9, 10 alkene lb product. Methods for effecting this elimination are well known in the art. Preferably the artemisinin thiazole acetate la product is reacted with triethylsilane and trimethylsilyl triflate (TMS-OTf) to form only the corresponding product 9, 10 alkene lb. This elimination may also be achieved by treating the artemisinin thiazole acetate la product with TMS-OTf over molecular sieves or alternatively (as shown in Figure 2) this elimination may also be accomplished using triethylsilyl triflate (TES-OTf) over molecular sieves. Next, the alkene thiazole lb was N-methylated, reduced, and then hydrolyzed without purification of intermediates following standard procedures well known in the art (see Dondoni, A.; Marra, A.; Perrone, D. J. Org. Chem. 1993, 58, 275) incoφorated herein by reference, to form 9, 10-unsaturated C-10 aldehyde Ie. The three separate steps shown in Figure 1 allowed conversion of artemisinin (I) into trioxane 9-en-10-al Ie in 69% overall yield. This addition-elimination sequence overall represents addition of a formyl anion unit at C- 10 of artemisinin followed by dehydration. Demonstration of further high chemoselectivity in organometallic reactions with such artemisinin trioxane analogs was achieved by organometallic nucleophilic addition to the carbonyl group of enal Ie. As shown in Figure 3, organometallic reagents or Grignard reagents such as, but not limited to n- butyllithium, phenyllithium, and phenyl magnesium bromide, added exclusively (and in some cases stereoselectively) to only the aldehyde carbonyl group of trioxane enal Ie to form allylic alcohols 1-1 and 1-2, without rupturing the trioxane 0-0 bond. «-Butyllithium added to enal Ie to give a roughly 2:1 diastereomeric mixture of allylic alcohols 1-1. Whereas phenyllithium added to aldehyde Ie to produce a 3.2:1.0 mixture of allylic alcohol diastereomers 1-2, phenylmagnesium bromide formed the same benzylic alcohols 1-2 in a 7.6: 1.0 ratio, presumably due to magnesium coordination also to one or more of the non- aldelydic oxygen atoms in polyoxygenated aldehyde Ie. When excess phenylmagnesium bromide was used, however, the peroxide 0-0 bond in trioxane alcohol 1-2 underwent nucleophilic rupture. Oxidation of alcohols 1-1 and 1-2 produced enones 1-3 and 1-4. This oxidation step can be accomplished using standard procedures suchastetrapropylammomumperruthenate (TPAP) andN-methylmoφholineN-oxide (NMO) disclosed by Ley, S.V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639 and incoφorated herein by reference. Phenyl enone 1-4 reacted with phenyllithium exclusively via carbonyl addition to form tertiary alcohol trioxane 1-5. Other artemisinin analogues were obtained by converting the aldehyde Ie using standard Wittig reagents to form a mixture of geometric isomers of monomeric or dimeric exocyclic alkenes VH without cleaving the trioxane 0-0 bond as shown in Figure 4. The monomeric exocyclic alkenes (VII, where n = 1) may be produced by reacting Ie with RCH=PPh 3 wherein R is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl. The term "alkyl" includes straight chain or branched alkyl compounds comprising 1-20 carbon atoms and cyclic alkyl compounds comprising 5-10 carbon atoms. The term "heteroalkyl" includes polyalkylene glycols such as polyethylene glycol (PEG). The term "aryP'means a phenyl or phenyl group substituted by 1 or more substituents selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "heteroaryl" includes 5 or 6 membered heteroaromatic rings comprising one or more heteroatoms selected fromN, O or S, unsubstituted or substituted by halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "lower alkyl" means straight or branched hydrocarbon radicals comprising 1-20 carbon atoms and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like. "Halogen" is fluorine, chlorine, bromine or iodine. The dimeric artemisinin analogues may be produced by reacting Ie with PPh 3 =CH-R-CH=PPh 3 where R is a linker group including, but not limited to, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl. The term "alkyl" includes straight chain or branched alkyl compounds comprising 1-20 carbon atoms and cyclic alkyl compounds comprising 5-10 carbon atoms. The term "heteroalkyl" includes polyalkylene glycols such as polyethylene glycol (PEG). The term "aryP'means a phenyl or phenyl group substituted by 1 or more substituents selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "heteroaryl" includes 5 or 6 membered heteroaromatic rings comprising one or more heteroatoms selected from N, O or S, unsubstituted or substituted by halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. The term "lower alkyl" means straight or branched hydrocarbon radicals comprising 1-20 carbon atoms and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like. "Halogen" is fluorine, chlorine, bromine or iodine. The Z- and E-geometric isomers of these monomeric and dimeric exocyclic alkenes VHa-h were separated from each other chromatographically. In the case of Vll-e, only the more soluble major isomer Z- VH-e remained in solution when a 1 : 1 mixture of the two isomers selectively precipitated out of solution from ethyl acetate/hexane solvent. Assignment of exocyclic alkene geometry was achieved reliably by Η NMR spectroscopy with the E-isomers having considerably larger vicinal H-H coupling constants than those of the corresponding Z-isomers. Determination of Antimalarial Activity To determine the antimalarial effect of various C-10 carbon-substituted monomers of the present invention, screening assays were performed against chloroquine-sensitiveR. falciparum (NF54), according to the method described below their IC 50 values are included in Table I. Strikingly, seven of the eleven C- 10 trioxane analogs are at least as potent as artemisinin. The most potent of these analogs is 1-3, with an IC 50 of 1.4 nM relative to artemisinin's IC 50 of 10 nM. Activity was determined by measuring the incoφoration of [ 3 H]hypoxanthine, by the methods of Desjardins and Milhouse, with the following modifications, see Desjardins, R.Ε.; Canfield, C.J.; Haynes, J.D.; Chulay, J.D. Antimicrob. Agents Chemother., 16: 710 (1979); Milhous, W.K.; Weatherly, N.F.; Bowdre, J.H.; Desjardins, R.; Antimicrob. Agents Chemother., 27: 525 (1985). Chloroquine-sensitive P. falciparum (NF54 strain)were maintained in a 2.4% suspension of type 0 + human erythrocytes (obtained weekly from a rotating pool of screened healthy volunteers) in RPMI 1640 (Gibco BRL #13200-076), supplemented with 25 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES; Calbiochem #391338), 27 mM ΝaHC0 3 (Gibco BRL #11810-025), and 10% heat-inactivated human type 0 + serum (Interstate Blood Bank, Inc.), under 3% 0 2 , 4% C0 2 , and 93%N 2 . Parasitemia was maintained at 0.05-3% and doubling time at approximately 15 hours by twice weekly change of medium and replenishment with fresh erythrocytes. Stock solutions (approximately 2.5 mg/mL of HPLC-purified or recrystallized test compound) were prepared in dimethyl sulfoxide (DMSO; Sigma-Aldrich #27,043-1). DMSO solutions were diluted 500-fold in medium, serially diluted in 0.2% DMSO in medium (to maintain constant solvent concentration), then 100 μL aliquots were pipetted into microtiter plate wells (Costar 3595). Provisional EC 50 values were obtained in a survey of seven 5 -fold dilutions yielding final concentrations (in triplicate) of 0.16-2500 ng/mL. Assays were later expanded to include ten concentrations (in quadruplicate) of approximately 1.8-fold dilutions which flank the provisional EC 50 . Plates included at least 8 wells of no drug controls (4 with and 4 without DMSO) and 4 wells of uninfected erythrocytes. Parasite culture (0.25%) parasitemia in 2.4% hematocrit; 100 μL per well) was added and the plate was incubated for 48 hours prior to the addition of 25 μL [ 3 H]hypoxanthine (14.1 Ci/mmol, 1 mCi/mL in 70% ethanol, New England Nuclear NET - 177, diluted to 25 μCi/mL with medium) and subsequent 20 hour incubation. Cells were harvested (Brandel MB-48R) onto GF-C glass filters (Brandel). The filters were washed five times with 3 mL water per sample spot, dried under a heat lamp, and counted (Beckman Model LS-6500) in scintillation cocktail (ICN Cytoscint). Decays per minute (dpm) values were downloaded and analyzed (Power Macintosh 7200/90; Microsoft Excel 5.0), to yield the mean and standard deviation at each drug concentration. Dose-response curves were fit to the experimental data (Delta Point DeltaGraph 3.5.3) by means of the Marquardt algorithm, were solved for the drug concentration that kills 50% of parasites, and were analyzed for goodness of fit (R 2 value). TABLE I "Antimalarial activity against Plasmodium falciparum was determined as reported previously. 32 The standard deviation for each set of quadruplicates was an average of 9.8% (<32%) of the mean. R 2 values for the fitted curves were <0.990. Artemisinin is ± standard deviation of concurrent control (n = 11). Antimalarial testing in vitro against Plasmodium falciparum NF54 malaria parasites, according to the procedure discussed above showed that C-9,10-unsaturated, C-10 carbon-substituted heteroaryl artemisinin analogs lb and benzo-4, ketones 1-3 and 1-4, tertiary alcohol 1-5 and exocyclic alkenes Vll-a,- c, and -d, are all similar to clinically used natural artemisinin (I) in antimalarial potency (Table 1). The high antimalarial activities of these C-10 carbon-substituted artemisinin analogs in Table I provide biological evidence that the trioxane 0-0 bond in these semi-synthetic analogs is intact; artemisinin derivatives lacking this 0-0 linkage are not antimalarially active. Several of the CIO derivatives in Table I as well as other analogs available easily via this new synthetic methodology may have especially desirable solubility and pharmacological properties. Determination of Antiproliferative and Antitumor Activities To determine the inhibitory effect of the compositions of the present invention on cell proliferation, screening assays were performed on a murine keratinocyte cell line PE. Cell line PE was chosen for its particular sensitivity to the induction of ornithine decarboxylase (ODC) activity by the extensively characterized tumor promoter TPA. Cell line PE was derived from a papilloma-induced in female SENCAR mice by a standard skin initiation/promotion protocol, see Yuspa, S .H, et al., Carcinogenesis, 7:949-958 (1986). PE cell culture medium consisted of Eagle's minimal essential medium without calcium chloride (Whittaker Bioproducts, Walkersville, MA) supplemented with 8% chelexed fetal calf serum and 1% antibiotic-antimycotic (Gibco BRL) and the addition of CaCl 2 to 0.05 mM Ca" . MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetraxolium bromide] was purchased from Sigma Chemical Co. (St. Louis, MO), and TPA was supplied by L.C. Services (Woburn, MA). L-[ 14 C]ornithine (56 μCi/mol) was from Amersham/Searle Coφ. (Arlington Heights, IL). Chemical solvents used in all assays of biological activity were of the highest grade commercially available. Growth Inhibition. Growth curves, shown in Figure 5, for PE cells treated with calcitriol and the C-10 carbon-substituted dimers VH-g, VH-h and VH-h generated by assay for the reduction of the tetrazolium-based compound MTT, see Charmichael, et al., Cancer Res., 47:936-942 (1987). A mitochondrial dehydrogenase reduces MTT to a blue formazan product with an absorbance maximum of 505 nm in DMSO; the number of viable cells can thus be determined spectrophotometrically. PE cells were seeded at a density of 5,000 cells/well in 50 μL of medium into 96-well microtiter plates. Twelve hours later, the medium was removed, and cells were treated with 100 μL of fresh medium into which the appropriate amount of calcitriol or analog dissolved in dimethyl sulfoxide (DMSO) had been added, with the concentration of DMSO held constant at 0.1%. The plates were fed once at 48 hours, with the readdition of the C-10 carbon-substituted trioxane dimers Vll-g, VH-h and VH-h at this time. At 24-hour intervals following the initial treatment of the cells with compounds, 0.1 mg (50 μL of a 2 mg/mL solution) of MTT was added to each well. After 4 hours, the MTT was removed and DMSO added to dissolve the blue formazan dye. Using a microtiter plate reader, the A 505 was then determined and cell number calculated from blank-subtracted absorbance values . Results from the MTT assay for the inhibition of cell growth were independently confirmed by treating 100-cm 2 dishes of cells in an analogous manner for 96 hours, whereupon the cells were harvested by trypsinization and counted. Further, the viability of the cells treated with calcitriol or trioxane dimers was determined to be identical to control cells at 96 hours by trypan blue exclusion. Antiprohferative activities, measured in vitro using murine keratinocytes as described previously, are shown in Figure 5. Note that the trioxane dimers VH-g, VH-h and VH-h even at physiologically relevant 100 nanomolar concentrations, are at least as antiprohferative as calcitriol (lα, 25- dihydroxyvitamin D 3 ) that is the hormonally active form of vitamin D and that is used clinically as a drug to treat psoriasis, a skin disorder characterized by uncontrolled proliferation of cells. To determine the cytotoxicity of the C-10 carbon-substituted trioxane dimers VH-g, Vll-h and Vll-h of the present invention, screening assays were performed by the National Cancer Institute using a 60 cell line panel; some of these activities of trioxane dimers Vll-g, VH-h and Vll-h are summarized in Tables II, III and IV (set out below). The screening assay is performed on 96-well microtitre plates. Relatively high initial inoculation densities are used, in order to permit measurement of "time-zero" values and to enhance the screen's ability to detect and provide some differentiation between antiprohferative and cytotoxic response parameters. The specific inoculation densities (which range from 5,000 to 40,000 cells/well) used for each cell line are those which, for the respective line, were determined to give an optical density signal for both the "time-zero" value (at 24 hours) and the "no-drug" control (at 72 hours) above the noise level and within the linear range of the end-point assay (which measures cellular protein). The inoculated microtitre plates are pre-incubated for 24 hours at 37 ° C prior to drug additions . The five drug dilutions tested routinely range from 10 "4 to 10 "8 molar. Higher or lower concentration ranges may be selected on a nonroutine basis if appropriate solubility and/or prior biological information or other screening data so dictate. Duplicate wells are prepared for all concentrations, (concentration is often denoted by placing brackets around a number); "time-zero" and "no drug" controls are also provided for each test. The minimum amount of compound required for a one-time evaluation in the routine screen can be calculated from the knowledge that each test requires a total of approximately 40 ml (0.04 liter) of cell culture medium containing the highest desired drug concentration. Thus, the amount (grams) of sample required (assuming an upper test concentration limit of 10 "4 M) is: molecular weight of compound x 10 "4 x 0.04. After a 48 hour incubation (37°C) with the test compound, the cells are fixed in situ to the bottoms of the microtitre wells by addition of 50 ul of either 50% trichloroacetic acid (for adherent cell lines) or 80% trichloroacetic acid (for settled cell suspension lines), followed by incubation for 60 minutes at 4°C. The cellular protein in each well is assayed using a sulforhodamine B (SRB) stain procedure. Briefly, after discarding the supernatants, the microtitre plates are washed 5 times with deionized water and air-dried. One hundred microliters of SRB solution (0.4% w/v in 1% acetic acid) is added to each microtitre well and incubated for 10 minutes at room temperature. Unbound SRB is removed by washing 5 times with 1% acetic acid. The plates are air-dried, the bound stain is solubilized with Tris buffer, and the optical densities read at 515nm. SRB is a bright pink anionic dye which, in dilute acetic acid, binds electrostatically to the basic amino acids of TCA-fixed cells. Cryopreserved master stocks of all the lines are maintained, and cultures used for screening are replaced from the master stock after no more than twenty passages in the screening laboratory. The cell line panel consists of 60 lines, organized into nine, disease-related subpanels including leukemia, non-small-cell lung cancer, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers. The response parameters GI 50 and LC 50 are inteφolated values representing the concentrations at which the percentage growth (PG) is +50 and -50, respectively: GI 50 is the concentration for which the PG = +50. At this value the increase from time t zao in the number or mass of cells in the test well is only 50% as much as the corresponding increase in the control well during this period of the experiment, see Table II. A drug effect of this intensity is inteφreted as primary growth inhibition. TGI is the concentration for which PG = 0. At this value the number or mass of cells in the well at the end of the experiment equals the number or mass of cells in the well at time t^, see Table III. A drug effect of this intensity is regarded as cytostasis. LC 50 is the concentration for which the PG=-50. At this value, the number or mass of cells in the test well at the end of the experiment is half that at time t^, see Table IN. This is inteφreted as cytotoxicity. TABLE π LogioGIjo C-10 Carbon-Substituted Trioxane Dimers Panel/ Artemisinin vπ-f vπ-g vπ-h Paclitaxel Cell line Breast Cancer MCF7 > -4.00 -6.06 -6.63 -7.33 -11.69 NCI/ADR- RES -5.29 -5.27 -5.76 -8.48 MDA- MB231/ -4.20 -5.67 -6.07 -6.49 -8.54 ATCC > -4.00 -6.13 -7.10 -7.31 HS 578T -5.94 -7.14 -7.41 < -13.00 MDA-MB- > -4.00 -5.86 -6.57 -7.29 < -13.00 435 -4.06 -5.74 -6.82 -7.33 -9.31 MDA-N -6.50 -7.51 < -8.00 -9.81 BT-549 T-47D MG MID -5.73 -6.58 -7.03 Delta -4.07 0.98 0.93 0.97 -10.15 Range 0.73 2.71 2.60 4.00 8.00 TABLE m *NCI indicates these values are not relevant TABLE IV The C-10 carbon-substituted trioxane dimers Vll-g, Vll-h and Vll-h of the present invention in most instances are as potent and in some instances more potent than paclitaxel. The data in Tables II, III and IV are graphically represented in Figures 6a, b, c, d, and e through Figures 14e. Dose response curves, shown in the above mentioned Figures, are obtained by exposing various cancer cell lines to compounds having a known concentration ([log 10 M]), as discussed in detail above, and then plotting the percentage growth of each cell line for each concentration. The drug concentration limits that are tested are between 10 "4 or -4.00M and 10 "9 or -9.00M. The -4.00M value being the high concentration and the -9.00M value being the low concentration. Percentage growth is determined by dividing the number or mass of cells in the test well by the number or mass of cells in a control well. Referring to the leukemia cell line MOLT-4 in Figures 6a, 6b, 6c, 6d, and 6e the first comparison that is made between artemisinin, paclitaxel, and the C-10 carbon-substituted trioxane dimers Vll-g, Vll-h and Vll-h of the present invention are the drug concentrations which are necessary to inhibit growth, graphically represented in Figures 6a, 6b, 6c, 6d, and 6e as the concentration necessary to achieve the percentage growth value of +50. As discussed previously, the five drug dilutions routinely tested range from 10 "4 to 10 '9 molar. Therefore, concentrations less than or greater than 10 "9 and 10 "4 molar, respectively, that are required to achieve a desired result are not determined. Referring now to Figure 6a, some concentration of paclitaxel that is less than 10 "8 M is necessary to achieve primary growth inhibition; in fact the lower concentrations have been determined for this drug and the concentration at which primary growth inhibition occurs using paclitaxel is at 10 "π molar. Figure 6b indicates that some concentration of artemisinin that is greater than 10 '4 molar is necessary to achieve primary growth inhibition. Referring to the C-10 carbon-substituted trioxane dimers Vll-f, Vll-g, and Vll-h dose response curves in Figures 6c, 6d and 6e, respectively, the leukemia cell line MOLT-4 displays primary growth inhibition at drug concentrations that are greater than 10 "6 , 10 "7 and greater than 10 s , respectively. The drug concentration at which artemisinin is considered cytostatic, i.e. percentage growth is equal to 0, is at a concentration greater than 10 "4 molar. The C-10 carbon-substituted trioxane dimers Vll-g, Vll-h and Vll-h reach cytostasis at drug concentrations of approximately 10 "4 M, and at some concentration greater than 10 "4 M, respectively, while the paclitaxel concentration necessary to achieve cytostasis is some value greater than 10 "4 M. Cytotoxicity, i.e., the concentration for which the percentage growth is equal to -50, occurs at a concentration greater than 10 "4 M for paclitaxel, artemisinin, and for both C-10 carbon-substituted trioxane dimers Vll-g, Vll-h and Vll-h. The potency of the C-10 carbon-substituted trioxane dimer Vll-g, Vll-h and Vll-h of the present invention as compared to artemisinin and paclitaxel varies from cell line to cell line. The mean values for each drug are presented at the end of Tables II, III and IV and the C-10 carbon-substituted trioxane dimer Vll-g, Vll-h and Vll-h of the present invention are more potent than artemisinin and equivalent to and in many instances higher in potency than paclitaxel. The dihydroartemisinin condensation by-product disclosed by M. Cao et al., and tested by DX. Klayman and H. J. Woerdenbag, discussed previously, was approximately twenty-two times more potent at causing 50% growth inhibition in one cancer cell line than artemisinin. With respect to the drug concentrations causing 50% growth inhibition, the dimers Vll-g, Vll-h and Vll-h were at least 100 times more potent than artemisinin. When inteφreting the mean values, it is important to take into consideration that drug concentrations less than 10 "9 M and greater then 10M were not collected, and this factor is reflected in the range. For a further comparison on the effects of the trioxane dimers of the present invention on various cancer cell lines versus the effects of artemisinin and paclitaxel on the same cell lines see Figures 7a, b, c, d and e for non-small cell lung cancer cell lines, Figures 8a, b, c, d and e for colon cancer cell lines, Figures 9a, b, c, d and e for CNS cancer cell lines, Figures 10a, b, c, d and e for melanoma cancer cell lines, Figures 11a, b, c, d and e for ovarian cancer cell lines Figures 12a, b, c, d and e for renal cancer cell lines, Figures 13a, c, d and e for prostate cancer cell lines and Figures 14a, c, d and e for breast cancer cell lines. In summary, the peroxide bond in artemisinin itself and in artemisinin-derived trioxane aldehyde Ie has been shown for the first time to withstand exposure to powerful organometallic nucleophiles like heteroaryllithium and aryllithium reagents, «-butyllithium, a phenyl Grignard reagent, and phosphonium ylides . Several of these nucleophiles added with high chemoselectivity to the lactone carbonyl group of artemisinin and to the aldehyde and ketone carbonyl groups of artemisinin-derived aldehyde Ie and ketone 1-4. In this way, a series of new, enantiomerically pure, C-10 carbon-substituted derivatives of natural artemisinin was prepared. Antimalarial testing in vitro of these semi-synthetic, C-10 non-acetal analogs of artemisinin showed them to have high antimalarial activities The foregoing description is considered as illustrative only of the principles of the invention. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and processes shown as described above. Accordingly, all suitable modifications and equivalents may be resorted to falling within the scope of the invention as defined by the claims which follow.. The invention is further illustrated by the following non-limited examples. All scientific and technical terms have the meanings as understood by one with ordinary skill in the art. The specific examples which follow illustrate the synthesis of representative compounds of the instant invention and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variation in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different fashion will be evident to one skilled in the art. The synthetic descriptions and specific examples that follow are only intended for the puφoses of illustration, and are not to be construed as limiting in any manner to make compounds of the present invention by other methods. EXAMPLES Unless otherwise noted, reactions were run in oven-dried glassware under an atmosphere of argon. Diethyl ether (ether) and tetrahydrofuran (THF) were distilled from sodium benzophenone ketyl prior to use. Methylene chloride (CH 2 C1 2 ) was distilled from calcium hydride prior to use. All other compounds were purchased from Aldrich Chemical Company and used without further purification. Analytical thin-layer chromatography (TLC) was conducted with Silica Gel 60 F 254 plates (250 mm thickness, Merck). Column chromatography was performed using flash silica gel (partical size 400-230 mesh). Yields are not optimized. Purity of final products was judged to be >95% based on their chromatographic homogeneity. High performance liquid chromatography (HPLC) was carried out with a Rainin HPLX system equipped with two 25 mL/min preparative pump heads using a Rainin Dynamax 10 mm x 250 mm (semi-preparative) column packed with 60 A silica gel (8 μm pore size) as bare silica. Melting points were measured using a Mel-Temp metal-block apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were obtained either on a Varian XL-400 spectrometer, operating at 400 MHZ for 'H and 100 MHZ for 13 C. Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. Splitting patterns are described- as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad (br) . Infrared (IR) spectra were obtained using a Perkin-Elmer 1600 FT-IR spectrometer. Resonances are reported in wavenumbers (cm 1 ). Low and high resolution mass spectra (LRMS and HRMS) were obtained with electronic or chemical ionization (El or CI) either (1) at Johns Hopkins University on a VG Instruments 70-S Spectrometer run at 70 eV for El and run with ammonia (NH 3 ), butane (C 4 H 10 ) or methane (CH 4 ) as carrier gas for CI or (2) at the University of Illinois at Champaign-Urbana on a Finnigan-MAT CH5 , a Finnigan-MAT 731 , or a VG Instruments 70-VSE spectrometer run at 70 eV for El and run with methane (CH 4 ) for CI. Combustion analyses were conducted by Atlantic Microlab (Norcross, GA). Various methods of purifying the products of the present invention are known and understood by those skilled in the art and the purification methods presented in the Examples is solely listed by way of example and is not intended to limit the invention. EXAMPLE I Preparation of 10-Formylanhydroartemisinin of the Present Invention a) Synthesis of 10-Acetyl-10-(2'-thiazolyl)artemisinin (la) 2-Bromothiazole (90 μL, 1.0 mmol) in Et^O (1 mL) at -78 °C was treated with n-BuLi (1.6 M in hexanes, 0.70 mL, 1.1 mmol). The reaction mixture was stirred for 30 minutes at -78 °C and then artemisinin (I, 0.20 g, 0.71 mmol, in 1 mL THF) was added via cannula. The reaction mixture was stirred for 30 minutes at -78 °C and then for 30 minutes at -65 °C. At -65 °C, acetic anhydride (0.67 mL, 7.1 mmol) was added, after being stirred for 10 minutes at -65 °C the reaction mixture became viscous. The reaction mixture was warmed to room temperature, diluted (CH 2 C1 2 ) then poured into pH 7 phosphate buffer (100 mL) and extracted (CH 2 C1 2 ). The organic layer was dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 50% EtOAc/hexanes as eluent to give 0.28 g of the desired product la as a white solid (0.68 mmol, 95%); mp 128 °C (dec); [α] D 23 +232 ° (c 0.55, EtOAc); 'H NMR (CDC1 3 ) δ 0.94-1.08 (m, 1 H), 0.98 (d, J= 6.4 Hz, 3 H), 1.11 (d, J= 7.2 Hz, 3 H), 1.3-1.7 (m, 4 H), 1.49 (s, 3 H), 1.7-1.8 (m, 2 H), 1.9-2.1 (m, 3 H), 2.10 (s, 3 H), 2.35-2.45 (m, 1 H), 2.60-2.68 (m, 1 H), 5.54 (s, 1 H), 7.3 (d,J= 3.2 Hz, 1 H), 7.7 (d, J= 3.2 Hz, 1 H); 13 C NMR (CDC1 3 ) δ 11.6, 20.0, 21.7, 23.4, 24.5, 25.6, 34.3, 35.91, 35.96, 37.3, 45.5, 51.7, 79.7, 89.1, 101.4, 104.4, 119.9, 141.5, 167.2, 170.2; HRMS calcd for C 20 H 27 NO 6 S: 409.1559, found: 409.1554. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 25% EtOAc/hexanes at 3 mL/min, Rj 12 min); characteristic data were identical to those given above, b) Synthesis of 10-(2'-Thiazolyl)anhydroartemisinin (lb) TMSOTf 4A Sieves Acetate la (0.11 g, 0.27 mmol) and powdered 4A MS (185 mg) in CH 2 C1 2 (2.5 mL) at room temperature were treated with triethylsilane (0.43 mL, 2.7 mmol) followed by trimethylsilyl triflate (0. 14 mL, 0.76 mmol). The reaction mixture was stirred at room temperature for 30 minute then quenched with triethylamine (2 mL), filtered through celite and concentrated. The crude product was chromatographed on a flash silica gel column with 15% EtOAc/hexanes as eluent to give 82 mg of the desired product lb as a white solid (0.23 mmol, 87%); mp 164-167 °C; [ ] D 23 +42 °(c 0.56, EtOAc); ΗNMR (CDC1 3 ) δ 1.0 (d, J = 5.6 Hz, 3 H), 1.1-1.2 (m, 1 H), 1.25-1.40 (m, 1 H), 1.40-1.64 (m, 3 H), 1.45 (s, 3 H), 1.65-1 75 ( , 1 H), 1.9-2.0 (m, 2 H), 2.00-2.15 (m, 2 H), 2.25 (s, 3 H), 2.38-2.43 (m, 1 H), 5.77 (s, 1 H), 7.3 (d, J= 3.2 Hz, 1 H), 1.1 (d,J= 3.2Hz, 1 H); 13 C NMR (CDC1 3 ) δ 17.1, 20.1, 24.4, 25.6, 29.0, 34.1, 36.0, 37.5, 47.9, 50.6, 78.3, 90.2, 104.5, 110.6, 118.3, 138.0, 142.7, 165.0; HRMS calcd for C 18 H 23 N0 4 S: 349.1348, found: 349.1354. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 5% EtOAc/hexanes at 3 mL/min, R t 13 minute); characteristic data were identical to those given above. c.) Synthesis of 10-FormyIanhydroartemisinin (Ie) Reaction was performed under an atmosphere of air. Thiazole Ib(128 mg, 0.37 mmol) and powdered 4A MS (0.75 g) in acetonitrile (4 mL) at room temperature were treated with methyl triflate (80 μL, 0.71 mmol), the suspension was stirred for 15 min and then concentrated to dryness. The crude N-methylthiazolium salt was suspended in methanol (4 mL), cooled to 0 °C and then treated with sodium borohydride (60 mg, 1.6 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min, then quenched at 0 °C with acetone (8 mL). The crude reaction mixture was filtered through celite and then concentrated. The reduced product was then dissolved in acetonitrile (4 mL) and treated with HgCl 2 (140 mg) followed by H 2 0 (0.4 mL), the mixture was stirred for 15 min at room temperature then filtered through celite and concentrated. The crude product was dissolved (THF, CH 2 C1 2 , E^O) and washed with (20% aq. KI soln. (twice), H 2 0, brine). The organic layer was dried (Νa 2 S0 4 ) and concentrated. The crude product was chromatographed on a Florisil (-200 mesh) column with 25% EtOAc/hexanes as eluent to give 90 mg of the desired aldehyde Ie s a white solid (0.31 mmol, 87%); mp 115-117 °C; [α] D 23 +102° (c 0.33, EtOAc); 'H NMR (CDC1 3 ) δ 1.0 (d, J = 6.0 Hz, 3 H), 1. 10- 1.32 (m, 2 H), 1.38-1.64 (m, 3 H), 1.43 (s, 3 H), 1.7-1.8 (m, 1 H), 1.88-1.98 (m, 2 H), 2.0-2.1 (m, 2 H), 2.10 (s, 3 H), 2.34-2.44 (m, 1 H), 5.7 (s, 1 H), 9.8 (s, 1 H); 13 C NMR (CDC1 3 ) δ 14.8, 20.0, 24.2, 25.6, 28.7, 34.0, 36.0, 37.4, 47.8, 50.5, 78.0, 90.0, 104.7, 126.7, 142.8, 184.2; HRMS calcd for C 16 H 22 0 5 : 294.1467, found: 294.1474. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 30% EtOAc/hexanes at 3 mL/min, R t 9 min); characteristic data were identical to those given above. EXAMPLE II Preparation of the Exocyclic Alkenes of the Present Invention 10-Acetyl-10-(2'-benzothiazolyl)artemisinin (Benzo-3) - Benzothiazole (76 μL, 0.10 mmol) in THF (1 mL) at -78 °C was treated with «-BuLi (1.6 M in hexanes, 0.44 mL, 1.1 equiv.). The reaction mixture was stirred for 30 min at -78 °C, then artemisinin (I, 0.14 g, 0.50 mmol, in 1.5 mL THF) was added via canula. The reaction mixture was stirred for 30 min at -78 °C and then for 30 min at -65 °C. At -65 °C, acetic anhydride (0.50 mL, 10 equiv.) was added, after being stirred for 10 min at -65 °C the reaction mixture became viscous. The reaction mixture was warmed to room temperature, diluted (CH 2 C1 2 ) then poured into pH 7 phosphate buffer (100 mL) and extracted (CH 2 C1 2 ). The organic layer was dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 20-40% EtOAc hexanes as eluent to give 0.21 g of the desired product Benzo-3 as a white solid (0.45 mmol, 91%); mp 129-131 °C; [α] D 23 +183 ° (c 0.46, EtOAc); 'HNMR (CDC1 3 ) δ 0.94-1.08 (m, 1 H), 0.99 (d, J = 6.0 Hz, 3 H), 1.18 (d, J= 7.2 Hz, 3 H), 1.28-1.84 (m, 6 H), 1.55 (s, 3 H), 1.90-2.14 (m, 3 H), 2.15 (s, 3 H), 2.38-2.48 (m, 1 H), 2.70-2.80 (m, 1 H), 5.57 (s, 1 H), 7.35 (m, 1 H), 7.43 (m, 1 H), 7.88 (m, 1 H), 7.99 (m, 1 H); 13 C NMR (CDC1 3 ) δ 11.7, 20.1, 21.8, 23.6, 24.7, 25.8, 34.5, 35.3, 36.1, 37.5, 45.6, 51.8, 79.9, 89.3, 101.4, 104.7, 121.6, 123.3, 124.9, 125.5, 135.8, 152.7, 167.4, 171.0 EXAMPLE in 10-(2'-BenzothiazoIyl)anhydroartemisinin (Benzo-4) - Acetate Benzo-3 (0.10 g, 0.22 mmol) and powdered 4 A MS (160 mg) in CH 2 C1 2 (3 mL) at room temperature were treated with triethylsilyl triflate (0.14 mL, 0.62 mmol). The mixture was stirred at room temperature for 1 h then quenched with triethylamine (2 mL), filtered through celite and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtOAc/hexanes as eluent to give 65 mg of the desired product Benzo-4 as a white solid (0. 16 mmol, 74%); mp 155-158 °C; [α] D 23 +36 ° (c 0.46, EtOAc); ΗNMR (CDC1 3 ) δ 0-99 (d, J= 6.0 Hz, 3 H), 1.1-1.2 (m, 1 H), 1.25-1.40 (m, 1 H), 1.40-1.64 (m, 3 H), 1.47 (s, 3 H), 1.68- 1.75 (m, 1 H), 1.9-2.0 (m, 2 H), 2.00-2.14 (m, 2 H), 2.35 (s, 3 H), 2.36-2.46 (m, 1 H), 5.80 (s, 1 H), 7.34 (m, 1 H), 7.44 (m, 1 H), 7.88 (m, 1 H), 8.01 (m, 1 H); 13 C NMR (CDC1 3 ) δ 17.4, 20.1, 24.4, 25.6, 28.9,- 34.1, 36.0, 37.5, 48.1, 50.5, 78.3, 90.4, 104.6, 113.7, 121.3, 123.0, 124.7, 125.6, 134.5, 138.1, 153.7, 165.0; HRMS calcd for C 22 H 25 N0 4 S: 399.1504, found: 399.1501. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 10% EtOAc hexanes at 3 mL/min, R t 10 min); characteristic data were identical to those given above. EXAMPLE IV 10-(l'-Pentanoyl)anhydroartemisinin (1-3) - Aldehyde Ie (80 mg, 0.27 mmol) in THF (2 mL) at - 78 °C was treated with fl-BuLi (1.6 M in hexanes, 0.20 mL, 1.2 equiv.). The reaction mixture was stirred for 2 h at -78 °C then warmed to room temperature, diluted (Et 2 θ), washed (aq. NH 4 C1, aq. NaHC0 3 , brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtOAc/petroleum ether as eluent to give 73 mg of the desired products I - 1 as an oil (0.21 mmol, 77%), a ca. 1:1.5 mixture of diastereomers (as determined by *H NMR). The mixture of alcohols (73 mg, 0.21 mmol), powdered 4A MS (150 mg) and NMO (50 mg, 0.43 mmol) in CH 2 C1 2 (1.5 mL) at room temperature was treated with TPAP (catalytic amount, ca. 5 mg). The reaction mixture was stirred for 2h, then filtered through celite and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtO Ac/petroleum ether as eluent to give 56 mg of the desired product I - 3 as an oil (0.16 mmol, 76%); [α] D 23 +149 ° (c 0.43, EtOAc); Η NMR (CDC1 3 ) δ 0-91 (t, J= 7.6 Hz, 3 H), 0.99 (d, J = 6.0 Hz, 3 H), 1.06-1.28 (m, 3 H), 1.30-1.40 (m, 2 H), 1.43 (s, 3 H), 1.46-1.64 (m, 5 H), 1.82 (dd, J- 4.4, 12.4 Hz, 1 H), 1.90-2.10 (m, 3 H), 2.00 (s, 3 H), 2.36-2.45 (m, 1 H), 2.63 (dt, J= 7.6, 16.4 Hz, 1 H), 2.77 (dt, J= 7.6, 16.4 Hz, 1 H), 5.66 (s, 1 H); 13 C NMR (CDC1 3 ) δ 14.0, 17.2, 20.1, 22.5, 24.4, 25.6, 25.8, 28.9, 34.1, 36.1, 37.6, 39.8, 48.4, 50.4, 78.0, 90.0, 104.5, 117.3, 142.5, 199.8; HRMS calcd for C 20 H 30 O 5 : 350.2093, found: 350.2096. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 10% EtOAc/hexanes at 3 mL/min, R t 9 min); characteristic data were identical to those given above. EXAMPLE V 10-Benzoylanhydroartemisinin (I - 4) - Aldehyde Ie (68 mg, 0.23 mmol) in THF (2 mL) at -78 °C was treated with PhMgBr (1.0 M in THF, 0.30 mL, 1.3 equiv.). The reaction mixture was stirred for 2 h at -78 °C, warmed to room temperature, diluted (Et 2 θ), washed (aq. NH4C1, aq. NaHCO 3 , brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtOAc/petroleum ether as eluent to give 75 mg of the desired products I - 2 as an oil (0.20 mmol, 87%), a ca. 1:7.5 mixture of diastereomers. The mixture of alcohols (75 mg, 0.20 mmol), powdered 4A MS (150 mg) and NMO (50 mg, 0.43 mmol) in CH 2 C1 2 (1.5 n-mL) at room temperature was treated with TPAP (catalytic amount, ca. 5 mg). The reaction mixture was stirred for 2h, then filtered through celite and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtO Ac/petroleum ether as eluent to give 72 mg of the desired product I - 4 as an white solid (0.19 mmol, 97%); mp ~ 155 °C (dec); [ ] D 23 +244 ° (c 0.42, EtOAc); Η NMR (CDC1 3 ) δ 1.00 (d, J= 6.4 Hz, 3 H , 1.10-1.22 (m, 1 H), 1.24-1.38 (dq, J= 3.2, 12.8 Hz, 1 H), 1.38- 1.64 (m, 3 H), 1.46 (s, 3 H), 1.68-1.78 (m, 1 H), 1.86 (s, 3 H), 1.88-2.00 (m, 2 H), 2.04-2.16 (m, 2 H), 2.40-2.50 (m, 1 H), 5.66 (s, 1 H), 7.38- 7.44 (m, 2 H), 7.48-7.56 (m, 1 H), 8.16-8.22 (m, 2 H); ,3 C NMR (CDC1 3 ) δ 16.5, 20.1, 24.3, 25.5, 29.3, 34.0, 36.1, 37.4, 47.3, 50.8, 78.3, 90.1, 104.6, 114.6, 127.8, 130.4, 132.8, 136.6, 142.5, 191.4; HRMS calcd for C22H2605: 370.1780, found: 370.1788. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 10% EtOAc/hexanes at 3 mL, R t 11 min); characteristic data were identical to those given above. EXAMPLE VI 10-(Benzhydryl)anhydroartemisinin (I - 5) - Ketone I - 4 (60 mg, 0.16 mmol) in THF (2 mL) at -78 C C was treated with PhLi (1.8 M in cyclohexane-ether, 70 to 30, 0.14 mL, 1.5 equiv.). The reaction mixture was stirred at -78 °C for 2 h, then slowly warmed to room temperature (1 h), diluted (Et j O), washed (brine, aq. NH_,C1, aq. NAHC0 4 , brine), dried (Na^O.,) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtO Ac/petroleum ether as eluent to give 63 mg of the desired product I - 5 as an oil (0.15 mmol, 91%); mp 152-155 °C (dec); [α] D 23 23 +146 ° (c 0.51, EtOAc); ΗNMR (CDC1 3 ) δ 0.97 (d, J = 6.0 Hz, 3 H), 1.03 (s, 3 H), 1.04-1.14 (m, 1 H), 1.22-1.56 (m, 4 H), 1.33 (s, 3 H), 1.64-1.72 (m, 2 H), 1.90-2.06 (m, 3 H), 2.34-2.44 (m, 1 H), 4.20 (br s, 1 H), 5.65 (s, 1 H), 7.20-7.49 (m, 10 H); ,3 C NMR (CDC1 3 ) δ 16.8, 20.1, 24.4, 25.5, 28.4, 34.1, 36.1, 37.6, 48.0, 50.4, 78.4, 80.1, 90.3, 104.4, 106.6, 127.17, 127.25, 127.59, 127.81, 127.86, 128.5, 144.9, 145.1, 146.0; HRMS calcd for C 28 H 32 0 5 : 448.2250, found: 448.2259. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 10% EtOAc/hexanes at 3 mL/min, R t 13 min); characteristic data were identical to those given above. EXAMPLE VII 10-VinyIanhydroartemisinin (VH-a) - Methyltriphenylphosphonium bromide (0.71 g, 2.0 mmol) was dried under vacuum/low heat for 2 days. The Wittig salt was suspended in THF (4 mL) and at 0 °C treated with H-BuLi (1.6 M in hexanes, 1.4 mL, 2.4 mmol). The solution was stirred at room temperature for 1 h. Aldehyde Ie (0.15 g, 0.50 mmol) in THF (3 mL) at -78 °C was treated with a portion of the prepared ylide solution (ca. 0.33 M, 2 mL, ca. 0.70 mmol) transferred via syringe. The mixture was stirred at -78 °C for 1 h then warmed to room temperature and stirred for 15 min; a precipitate was observed. The reaction was quenched (H 2 0), extracted (El^O), washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 5-10% EtOAc/hexanes as eluent to give 112 mg of the desired product Vll-a as an oil (0.38 mmol, 77%); [α] D 23 23 +81 ° (c 0.49, EtOAc); ΗNMR (CDC1 3 ) δ 0.98 (d, J = 6.0 Hz, 3 H), 1.04-1.30 (m, 2 H), 1.42 (s, 3 H). 1.44-1.80 (m, 5 H), 1.76 (s, 3 H), 1.88-2.08 (m, 3 H), 2.34-2.44 (m, 1), 5.10 (dd, J= 2.0, 10.8 Hz, 1 H), 5.62 (dd, J= 2.0, 10.8 Hz, 1 H), 5.66 (s, 1 H), 6.50 (dd, J= 10.8, 16.8 Hz, 1 H); ,3 C NMR (CDC1 3 ) δ 15.7, 20.2, 24.5, 29.3, 34.2, 36.2, 37.6, 46.7, 51.0, 78.7, 90.0, 104.3, 107.5, 113.2, 127.7, 141.7; HRMS calcd for C 17 H 24 0 4 : 292.1675, found: 292.1678. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 5% EtOAc/hexanes at 3 mL/min, R j 9 min); characteristic data were identical to those given above. EXAMPLE VIII 10-(l-PropenyI)anhydroartemisinin (Vll-b) - Ethyltriphenylphosphonium bromide (0.74 g, 2.0 mmol) was dried under vacuum/low heat for 2 days. The Wittig salt was suspended in THF (4 mL) and at 0 °C treated with «-BuLi (1.6 M in hexanes, 1.4 mL, 2.4 mmol). The solution was stirred at room temperature for 2 h. Aldehyde Ie (0.20 g, 0.67 mmol) in THF (3 mL) at -78 °C was treated with a portion of the prepared ylide solution (ca. 0.33 M, 5 mL, ca. 1.7 mmol) transferred via syringe. The reaction mixture was stirred at -78 °C for 30 min then warmed to room temperature and stirred for 1 h; a precipitate was observed. The reaction was quenched (H 2 0), extracted (EtjO), washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 5% EtOAc/hexanes as eluent to give 170 mg of the desired product Z-VII-b as an oil (0.55 mmol, 83%); [α] D 23 +52 ° (c 0.50, EtOAc); 'H NMR (CDC1 3 ) δ 0.98 (d, J = 6.0 Hz, 3 H), 1.02-1.28 (m, 3 H), 1.42 (s, 3 H), 1.50-1.78 (m, 4 H), 1.73 (s, 3 H), 1.80 (d, J = 6.0 Hz, 3 H), 1.88-2.08 (m, 3 H), 2.34-2.44 (m, 1), 5.64 (s, 1 H), 6.07-6.22 (m, 2 H); 13 C NMR (CDC1 3 ) δ 15.6, 18.2, 20.2, 24.5, 25.8, 29.4, 34.2, 36.2, 37.6, 46.6, 51.0, 78.8, 89.9, 104.3, 104.7, 122.3, 125.3, 141.4; HRMS calcd for C 18 H 26 0 4 : 306.1831, found: 306.1833. The product was further purified prior to antimalarial testing using HPLC (Silica semipreparative column, 2% EtOAc/hexanes at 3 mL/min, R t 15 min); characteristic data were identical to those given above. EXAMPLE IX 10-(Styryi)anhydroartemisinin Z/E-(YIl-c) - Benzyltriphenylphosphonium bromide (0.43 g, 1.0 mmol) was dried under vacuum/low heat for 3 h. The Wittig salt was suspended in THF (4 mL) and at 0 °C treated with w-BuLi (1.6 M in hexanes, 0.75 mL, 1.2 mmol). The solution was stirred at room temperature for 1 h. Aldehyde Ie (21 mg, 71 μmol) in THF (1.5 mL) at -78 C C was treated with a portion of the prepared ylide solution (ca. 0.16 M, 0.6 mL, ca. 1.5 equiv.) transferred via syringe. The reaction mixture was stirred at -78 C C for 30 min then warmed to room temperature and stirred for 30 min. The reaction was quenched (H 2 0), extracted (Et^O), washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtOAc/hexanes as eluent to give 20 mg of the desired products Z/E-YlI-c as an oil (54 μmol, 76%), Z:E = 1.2: 1 (as determined by 'H NMR). The 2 isomers were separated by HPLC (Silica semipreparative column, 1% EtOAc/hexanes at 5 mL/min), Z R t 20 min, E R t 22 min. Z-VII-c: oil, [α] D 23 +42 ° (c 0.48, EtOAc); Η NMR (CDC1 3 ) δ 0.98 (d, J= 6.0 Hz, 3 H), 1.02-1.28 (m, 2 H), 1.416 (s, 3 H), 1.422 (s, 3 H), 1.40-1.74 (m, 5 H), 1.88-2.08 (m, 3 H), 2.36-2.46 (m, 1), 5.64 (s, 1 H), 6.03 (d, J = 12.0 Hz, 1 H), 6.50 (d, J= 12.0 Hz, 1 H), 7.15-7.22 (m, 1 H), 7.23-7.30 (m, 2 H), 7.53 (d, J= 7.2 Hz, 2 H); 13 C NMR (CDC1 3 ) δ 16.4, 20.3, 24.5, 25.8, 29.3, 34.1, 36.4, 37.6, 45.9, 51.2, 78.8, 90.0, 104.4, 105.6, 122.5, 127.1, 127.8, 129.2, 132.3, 137.2, 141.4; HRMS calcd for C 23 H 28 0 4 . 368.1988, found: 368.1986. E-VII-c: oil, [α] D 23 +150 ° (c 0.51, EtOAc); Η NMR (CDCl 3 ) δ l.00 (d, J = 6.0 Hz, 3 H), 1.02-1.28 (m, 2 H), 1.45 (s, 3 H), 1.40-1.74 (m, 4 H), 1.86 (s, 3 H), 1.80-2.10 (m, 4 H), 2.36-2.46 (m, 1), 5.72 (s, 1 H), 6.87 (d, J = 16.0 Hz, 1 H), 6.99 (d, J = 16.0 Hz, 1 H), 7.17-7.24 (m, 1 H), 7.27-7.34 (m, 2 H), 7.43-7.50 (m, 2 H); I3 C NMR (CDC1 3 ) δ 16.1, 20.2, 24.5, 25.8, 29.4, 34.2, 36.2, 37.6, 47.0, 51.0, 78.7, 90.1, 104.4, 108.5, 119.6, 126.6, 127.2, 127.6, 128.4, 137.7, 142.0; HRMS calcd for C 23 H 28 0 4 368.1988, found: 368.1983. EXAMPLE X 10-(p-NitrostyryI)anhydroartemisinin _Z/£'-(VII-d) (p-Nitrobenzyl)triphenylphosphonium bromide (0.96 g, 2.0 mmol) was dried under vacuum overnight. The Wittig salt was suspended in THF (4 mL) and at 0 °C treated with (1.6 M BuLi in hexanes, 1.4 mL, 2.2 mmol). The solution was stirred at room temperature for 30 min. Aldehyde Ie (83 mg, 0.28 mmol) in THF (2 mL) at -78 °C was treated with a portion of the prepared ylide solution (ca. 0.33 M, 1.4 mL, ca. 1.5 equiv.) transferred via syringe. The reaction mixture was stirred at room temperature for 90 min. The reaction was quenched (H 2 0), extracted (E^O), washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 5-15% EtOAc/hexanes as eluent to give 80 mg of the desired products Z/E-Vll-d as a yellow oil (0. 19 mmol, 69%), Z:E = 1 :4 (as determined by 'H NMR). The 2 isomers were separated by HPLC (Silica semipreparative column, 5% EtOAc/hexanes at 3 mL/min), Z R t 18 min, E R t 21 min. Z-VII-d: yellow oil, [α] D 23 +105 ° (c 0.40, EtOAc); 'HNMR (CDC1 3 ) δ 0.98 (d, J= 6.0 Hz, 3 H), 1.06-1.32 (m, 2 H), 1.39 (s, 3 H), 1.40-1.76 (m, 4 H), 1.50 (s, 3 H), 1.84-2.10 (m, 4 H), 2.36-2.46 (m, 1), 5.61 (s, 1 H), 6.25 (d, J = 12.0 Hz, 1 H), 6.51 (d, J = 12.0 Hz, 1 H), 7.69 (d, J= 8.8 Hz, 2 H), 8.13 (d, J= 8.8 Hz, 2 H); ,3 C NMR (CDC1 3 ) δ 16.4, 20.2, 24.4, 25.8, 29.4, 34.0, 36.3, 37.6, 46.0, 51.2, 78.8, 90.1, 104.5, 108.2, 123.0, 125.7, 129.3, 130.1, 141.0, 144.1; HRMS calcd for C 23 H 27 N0 6 : 413.1838, found: 413.1841. E-Vll-ά: yellow oil, [ ] D 23 +53 ° (c 0.51, EtOAc); 'H NMR (CDCl 3 ) δ 1.00 (d, J = 6.0 Hz, 3 H), 1.06-1.32 (m, 2 H), 1.46 (s, 3 H), 1.40-1.74 (m, 4 H), 1.90 (s, 3 H), 1.84-2.10 (m, 4 H), 2.36-2.46 (m, 1), 5.73 (s, 1 H), 7.02 (s, 2 H), 7.55 (d, J= 8.8 Hz, 2 H), 8.17 (d, J= 8.8 Hz, 2 H); I3 C NMR (CDC1 3 ) δ 16.2, 20.1, 24.4, 25.8, 29.2, 34.0, 36.1, 37.5, 47.0, 50.8, 78.6, 90.1, 104.5, 112.2, 123.7, 123.9, 125.3, 126.8, 141.7, 144.4, 146.4; HRMS calcd for C 23 H 27 N0 6 : 413.1838, found: 413.1845. EXAMPLE XI 10-(p-ChlorostyryI)anhydroartemisinin Z Z?-(VII-e) ( ?-Chlorobenzyl)triphenylphosphonium bromide (0.85 g, 2.0 mmol) was dried under vacuum overnight. The Wittig salt was suspended in THF (4 mL) and at 0 °C treated with «-BuLi (1.6 M in - hexanes, 1.4 mL, 2.2 mmol). The solution was stirred at room temperature for 30 min. Aldehyde Ie (97 mg, 0.33 mmol) in THF (2 mL) at -78 °C was treated with a portion of the prepared ylide solution (ca. 0.33 M, 2.1 mL, ca. 0.69 mmol) transferred via syringe. The reaction mixture was stirred at -78 °C for 30 min, warmed to room temperature and stirred for 10 min. The reaction was quenched (H 2 0), extracted (El^O), washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 5% EtOAc/hexanes as eluent to give 78 mg of the desired products Z/EWII-e as an oil (0.19 mmol, 58%), Z:E = 2.2: 1 (as determined by Η NMR). Upon storage at -15 °C in ca. 0.2 M solution of EtOAchexanes, - 1:10, a 1:1 complex of Z:E crystallized out. The mother liquor was concentrated to give 30 mg of Z-VII-e as an oil; [α] D 23 +119 ° (c 0.52, EtOAc); Η NMR (CDC1 3 ) δ 0.98 (d, J= 6.0 Hz, 3 H), 1.02-1.28 (m, 2 H), 1.41 (s, 3 H), 1.44 (s, 3 H), 1.40-1.74 (m, 5 H), 1.88-2.08 (m, 3 H), 2.36-2.46 (m, 1), 5.63 (s, 1 H), 6.04 (d, J= 12.0 Hz, 1 H), 6.43 (d, J = 12.0 Hz, 1 H), 7.23 (d, J= 8.4 Hz, 2 H), 7.49 (d, J= 8.4 Hz, 2 H); 13 C NMR (CDC1 3 ) δ 16.3, 20.3, 24.4, 25.8, 29.4, 34.1, 36.3, 37.6, 45.9, 51.2, 78.8, 90.0, 104.4, 106.2, 123.0, 127.9, 130.6, 130.8, 132.7, 135.6, 141.1. The remaining mixture oϊE/Z (1:1) resisted attempts at chromatographic separation by HPLC. EXAMPLE XII Preparation of 7-Benzene dimer VH-i Ie VH-i / Xylylenebis(triphenylphosphonium bromide) (0.79 g, 1.0 mmol) was dried under vacuum/low heat for 3 h. The Wittig salt was suspended in THF (2 mL) and at 0 °C treated with «-BuLi (1.6 M in hexanes, 1.4 mL, 2.2 mmol). The solution was stirred at room temperature for 1 h to give a black solution. Aldehyde Ie (50 mg, 0. 17 mmol) in THF (1.0 mL) at -78 °C was treated with a portion of the prepared bis-ylide solution (ca. 0.25 M, 0.34 mL, ca. 0.085 mmol) transferred via syringe. The reaction mixture was stirred at -78° C for 30 min then warmed to room temperature and stirred for 30 min. The reaction was quenched ( H 2 0), extracted (Et^O), washed (brine), dried (Na^O.,) and concentrated. The crude product was chromatographed on a flash silica gel column with 8-15% EtOAc/hexanes as eluent to give 35 mg of the desired product VH-i as a mixture of all 3 possible Z/E isomers as an oil (53 gmol, 63%), EE:EZ.-ZZ = 3:2:1 (as determined by 'H NMR). The 3 isomers were separated by HPLC: Silica semipreparative column, 10% EtOAc/hexanes at 3 mL/min, gave ZZ/EZ (mixture); R t 13 min, EE R t 15 min. Silica semipreparative column, 100% CH 2 C1 2 at 3 mL/min, gave separation of the ZZ/EZ: mixture; EZR t 8 min, ZZ R t 13 min.; VH-i [EE] [α] D 23 +31 ° (c 0.47, EtOAc); 'H NMR CDC1 3 δ 0.98 (d, J = 6.0 Hz, 6 H), 1.02-1.28 (m, 6 H), 1.45 (s, 6 H), 1.45-1.72 (m, 6 H), 1.86 (s, 6 H), 1.80-2.08 (m, 8 H), 2.36-2.46 (m, 2), 5.71 (s, 2 H), 6.86 (d, J= 15.6 Hz, 2 H), 6.97 (d, J = 15.6 Hz, 2 H), 7.39 (s, 4 H); 13 C NMR (CDC1 3 ) δ 16.1, 20.2, 24.5, 25.8, 29.3, 34.1, 36.2, 37.6, 46.9, 50.9, 78.7, 90.1, 104.4, 108.5, 119.1, 126.7, 127.3, 136.7, 142.0; HRMS calcd for C 40 H 50 O 8 : 658.3506, found: 658.3515; VH-i [EZ] [α] D 23 +144° (c 0.48, EtOAc); ΗNMR (CDC1 3 ) δ 0.98 (d, J= 5.6 Hz, 3 H), 0.99 (d, J = 5.6 Hz, 3 H), 1.02-1.28 (m, 6 H), 1.42 (s, 6 H), 1.45 (s, 3 H), 1.45-1.76 (m, 6 H), 1.86 (s, 3 H), 1.80-2.08 (m, 8 H), 2.35-2.48 (m, 2), 5.66 (s, 1 H), 5.70 (s, 1 H), 6.00 (d, J= 12.0 Hz, 1 H), 6.46 (d, J= 12.0 Hz, 1 H), 6.85 (d, J= 16.0 Hz, 1 H), 6.95 (d, J = 16.0 Hz, 1 H), 7.35 (d, J- 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H); 13 C NMR (CDC1 3 ) δ 16.1, 16.5, 20.2, 20.3, 24.5, 25.8, 29.3, 29.4, 34.10, 34.15, 36.2, 36.4, 37.6, 45.9, 47.0, 51.0, 51.2, 78.7, 78.8, 90.0, 90.1, 104.37, 104.40, 105.6, 108.4, 119.2, 122.2, 126.1, 127.5, 129.5, 132.0, 136.2, 136.5, 141.4, 142. 1; HRMS calcd for C 40 H 50 O 8 : 658.3506, found: 658.3501; Vϊl-i fZZJ 'H NMR (CDC1 3 ) δ 0.98 (d, J = 6.0 Hz, 6 H), 1.02-1.28 (m, 6 H), 1.39 (s, 6 H), 1.42 (s, 6 H), 1.38-1.72 (m, 8 H), 1.86-2.08 (m, 6 H), 2.36-2.46 (m, 2), 5.66 (s, 2 H), 6.00 (d, J= 12.0 Hz, 2 H), 6.46 (d, J= 12.0 Hz, 2 H), 7.43 (s, 4 H). EXAMPLE XIII Preparation of n-Benzene dimers VH-f, -g, and -h, m-Xylylenebis(triphenylphosphonium bromide (0. 13 g, 0. 17 mmol), aldehyde Ie (0.10 g, 0. 34 mmol) in EtOH (1.0 mL) at 0°C was treated with lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.68 mL, 4.0 equiv.). The reaction was stirred for 10 min at 0 °C, then for 10 min at room temperature. The reaction was concentrated then diluted in ether, washed (brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtOAc/hexanes as eluent to give 111 mg of the desired product (VII-f,-g, and -h) as a mixture of all 3 possible Z/E isomers as an oil (0.17 mmol, 99%), ZE:EE:ZZ - 6:3:2 (as determined by Η NMR). The 3 isomers were separated by HPLC: Silica semipreparative column, 10% EtOAc/hexanes at 3 mL/min, gave ZZ R t 11 min, EE/EZ (mixture); R t 13 min. Silica semipreparative column, 80% CH 2 Cl 2 /hexanes at 3 mL/min, gave separation of the EE EZ: mixture; EE R t 9 min, EZ R t 19 min.; VH-f [EE] [ ] D 23 0° (c 0.48, EtOAc); Η NMR (CDC1 3 ) δ 0-99 (d, J = 5.6 Hz, 6 H), 1.02-1.32 (m, 6 H), 1.46 (s, 6 H), 1.40-1.72 (m, 8 H), 1.87 (s, 6 H), 1.80-2.08 (m, 6 H), 2.36-2.46 (m, 2), 5.72 (s, 2 H), 6.87 (d, J = 15.6 Hz, 2 H), 6.99 (d, J = 15.6 Hz, 2 H), 7.22 (m, 3 H), 7.53 (s, br, 1 H); 13 C NMR (CDC1 3 ) δ 16.1, 20.2, 24.5, 25.8, 29.4, 34.2, 36.2, 37.6, 47.0, 51.0, 78.7, 90.1, 104.4, 108.5, 119.6, 125.1, 125.4, 127.6, 128.5, 137.9, 142.0; HRMS calcd for C 40 H 50 O 8 : 658.3506, found: 658.3515; VH-g [EZ] [α] D 23 +77° (c 0.49, EtOAc); 'H NMR (CDC1 3 ) δ 0.97 (d, J = 6.0 Hz, 3 H), 0.99 (d, J= 5.6 Hz, 3 H), 1.02-1-30 (m, 6 H), 1.40 (s, 3 H), 1.41 (s, 3 H), 1.44 (s, 3 H), 1.38- 1.74 (m, 8 H), 1.86 (s, 3 H), 1.80-2.08 (m, 8 H), 2.35-2.46 (m, 2), 5.65 (s, 1 H), 5.70 (s, 1 H), 6.05 (d, _/= 12.0 Hz, 1 H), 6.50 (d, J = 12.0 Hz, 1 H), 6.85 (d, J = 15.6 Hz, 1 H), 6.96 (d, J= 15.6 Hz, 1 H), 7.19- 7.24 (t, J= 7.6 Hz, 1 H), 7.27-7.31 (m, 1 H), 7.42-7.45 (m, 1 H), 7.49 (s, br, 1 H); ,3 C NMR (CDC1 3 ) δ 16.1, 16.5, 20.2, 20.5, 24.5, 25.8, 29.2, 29.4, 34.1, 34.2, 36.2, 36.3, 37.6, 45.9, 46.9, 51.0, 51.1, 78.695, 78.704, 89.9, 90.0, 104.3, 104.4, 105.5, 108.2, 119.3, 122.8, 125.4, 127.2, 127.8, 128.0, 128.2, 132.3, 137.2, 137.5, 141.3, 142.0; HRMS calcd for C 40 H 50 O 8 : 658.3506, found: 658.3508; Vll-h [ZZ] [α] D 23 +228° (c 0.49, EtOAc); 'HNMR (CDC1 3 ) δ 0.98 (d, J= 5.6 Hz, 6 H), 1.02-1.28 (m, 4 H), 1.36 (s, 6 H), 1.41 (s, 6 H), 1.38-1.70 (m, 10 H), 1.88-1.96 (m, 4 H), 2.00-2.08 (m, 2 H), 2.36-2.46 (m, 2), 5.66 (s, 2 H), 5.99 (d, J = 12.0 Hz, 2 H), 6.48 (d, J = 12.0 Hz, 2 H), 7.15-7.20 (t, J= 8.0 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.43 (d, J= 7.6 Hz, 1 H), 7.50 (s, br, 1 H); 13 C NMR (CDC1 3 ) δ 16.5, 20.3, 24.5, 25.9, 29.2, 34.1, 36.4, 37.6, 45.9, 51.2, 78.7, 89.9, 104.4, 105.0, 122.5, 127.6, 128.0, 129.8, 132.7, 136.8, 141.4; HRMS calcd for C 4O H 50 O 8 : 658.3506, found: 658.3515. EXAMPLE Xr 10 -(Trichloroimidate)dihydroartemisinin (VIII) II-l VIII Dihydroartemisinin (II-l, 0.30 g, 1.1 mmol), potassium carbonate (600 mg, 4.4 mmol) in CH 2 C1 2 (6.0 mL) at room temperature were treated with trichloroacetonitrile (0.51 mL, 5.1 mmol). The reaction was stirred for 6 h, then filtered and concentrated to give the crude product VIII as a foamy solid (0.48 g, ca. 100%). The crude material was unstable to chromatography (silica gel/Florisil) and resisted attempts at recrystallization. NMR confirmed desired product VIII was formed in sufficient purity for further use; ] H NMR (CDC1 3 ) δ 0.97 (d, J= 7.2 Hz, 3 H), 0.98 (d, J = 6.0 Hz, 3 H), 1.0-2.0 (m, 8 H), 1.43 (s, 3 H), 2.0- 2.2 (m, 2 H), 2.3-2.5 (m, 1), 2.6-2.8 (m, 1), 5.50 (s, 1 H), 5.85 (d, J= 9.6 Hz, 1 H), 8.56 (s, br, 1 H); 13 C NMR (CDC1 3 ) δ 12.0, 20.1, 21.9, 24.5, 25.8, 32.1, 34.0, 36. 1, 37.1, 45.2, 51.5, 79.9, 91.4, 96.3, 104.3, 161.5. EXAMPLE XV 10β-(Hydroperoxy)dihydroartemisinin IX VIII IX Imidate VIII (0.30 g, 0.70 mmol) in CH 2 C1 2 (10 mL) at -78 °C was treated with H 2 0 2 (ca. 1.8 M in acetonitrile, 2.0 mL, 5 equiv.), followed by TMSOTf (100 μL, catalytic amoimt). The reaction was stirred for 20 min at -78° C, then for 10 min at room temperature. The reaction was diluted in ether, washed (sat. aq. NaHCO, brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 25% EtO Ac/petroleum ether as eluent to give 153 mg of the desired product IX as a solid (0.51 mmol, 73%); 'H NMR (CDC1 3 ) δ 0.97 (d, _/= 6.0 Hz, 3 H), 0.99 (d, J= 7.2 Hz, 3 H), 1.18- 1.56 (m, 6 H), 1.46 (s, 3 H), 1.60-1.80 (m, 2 H), 1.88-1.98 (m, 1), 2.01-2.09 (m, 1), 2.35-2.45 (m, 1), 2.76-2.86 (m, 1), 5.33 (d, J= 4.4 Hz, 1 H), 5.62 (s, 1 H), 9.77 (s, br, 1 H); Η NMR also shows broad singlets at δ 6.1 (1 H) and 6.6 (1 H) which slowly disappear under vacuum - product appears to be isolated as a monohydrate; 13 C NMR (CDC1 3 ) δ 12.7, 20.2, 24.7, 24.8, 25.9, 30.9, 34.3, 36.2, 37.4, 43.8, 52.2, 80.7, 88.1, 104.5, 106.3. EXAMPLE XVI Bis-lOβ-dihydroartemisinin (X) IX VIII X Imidate VIII (32 mg, 75 μmol), hydroperoxide IX (31 mg, 0.10 mmol, 1.3 equiv.) in CH 2 C1 2 (1.0 mL) at - 78 °C was treated with TMSOTf (14 μL, 75 μmol, 1.0 equiv.). The reaction was stirred for 30 min at -78 °C, then diluted in ether, washed (sat. aq. NaHC0 3 , brine), dried (Na 2 S0 4 ) and concentrated. The crude product was chromatographed on a flash silica gel column with 10% EtO Ac/petroleum ether as eluent to give 22 mg of the desired product X as a solid (39 μmol, 52%); Η NMR (CDC1 3 ) δ 0.94 (d, J = 6.4 Hz, 6 H), 0.95 (d, J- 7.6 Hz, 6 H), 1.18-1.28 (m, 2 H), 1.36-1.74 (m, 14 H), 1.43 (s, 6 H), 1.82-1.92 (m, 2H), 2.00-2.08 (m, 2) 2.32-2.42 (m, 2), 2.74-2.84 (m, 2), 5.32 (d, J= 4.4 Hz, 2 H) 5.67 (s, 2 H); 13 C NMR (CDC1 3 ) δ 13.0, 20.2, 24.7, 24.9, 26.0, 31.2, 34.4, 36.4, 37.1, 44.0, 52.4, 81.0, 88.0, 103.76, 103.86.

Claims: Claims The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 1. An artemisinin dimer of formula: or an isomer thereof wherein R is alkylene, alkylene comprising one or more substituents, heteroalkylene, alkenylene, alkenylene comprising one or more substituents, alkynylene, arylene, arylene comprising one or more substituents, heteroarylene, heteroarylene comprising one or more substituents, wherein said substituents are selected from the group comprising halogen, N0 2 , OH, SH, NHC^O, NH 2 , COOH, C(=)ONH 2 , COOR 2 . 2. The dimer according to claim 1, wherein R is m-phenyl 3. The dimer according to claim 2, wherein the artemisinin dimer is the [E,E] dimer. 4. The dimer according to claim 2, wherein the artemisinin dimer is the [E,Z] dimer. 5. The dimer according to claim 2, wherein the artemisinin dimer is the [Z,Z] dimer. 6. The dimer according to claim 1, wherein R is p-phenyl 7. The dimer according to claim 2, wherein the artemisinin dimer is the [E,EJ dimer. 8. The dimer according to claim 2, wherein the artemisinin dimer is the [E,Zj dimer. 9. The dimer according to claim 2, wherein the artemisinin dimer is the [Z,Z] dimer. 10. An artemisinin compound having the formula wherein R is CHO, C(=)OX, wherein X is alkyl, alkenyl, alkynyl, aryl or heteroaryl, C(OH)X 2 , wherein X is alkyl, alkenyl, alkynyl, aryl or heteroaryl, alkyl, alkyl comprising one or more substituents, heteroalkyl, alkenyl, alkenyl comprising one or more substituents, alkynyl, aryl, aryl comprising one or more substituents, heteroaryl, or heteroaryl comprising one or more substituents, wherein said substituents are selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. 11. The artemisinin compound according to claim 10 wherein R is 2'-thiazolyl. 12. The artemisinin compound according to claim 10 wherein R is 2'-benzothiazolyl. 13. The artemisinin compound according to claim 10 wherein R is CHO. 14. The artemisinin compound according to claim 10 wherein R is C(0)«-Bu. 15. The artemisinin compound according to claim 10 wherein R is C(0)Ph. 16. The artemisinin compound according to claim 10 wherein R is C(OH)Ph 2 . 17. The artemisinin compound according to claim 10 wherein R is CH=CH 2 . 18. The artemisinin compound according to claim 10 wherein R is CH=CHPh. 19. The artemisinin compound according to claim 18 wherein the compound is the [E,E]. isomer. 20. The artemisinin compound according to claim 18 wherein the compound is the _Z,Z . isomer. 21. The artemisinin compound according to claim 10 wherein R is CH=CHPh-/?-N0 2 . 22. The artemisinin compound according to claim 21 wherein the compound is the [EE] isomer. 23. The artemisinin compound according to claim 21 wherein the compound is the [Z, Z] . isomer. 24. A method of producing a novel artemisinin analogue comprising: reacting artemisinin (I) with an organolithium reagent to afford the intermediate (la) having the structure treating said intermediate (la) with a reagent which eliminates HO Ac from (la) to form the 9, 10 alkene (lb) having the structure and converting said 9,10 alkene (lb) to enal (Ie) having the structure 25. A method for treating malaria comprising administering an effective amount of an artemisinin analog having the structure wherein R is CHO, C(=)OX, wherein X is alkyl, alkenyl, alkynyl, aryl or heteroaryl, C(OH)X 2 , wherein X is alkyl, alkenyl, alkynyl, aryl or heteroaryl, alkyl, alkyl comprising one or more substituents, heteroalkyl, alkenyl, alkenyl comprising one or more substituents, alkynyl, aryl, aryl comprising one or more substituents, heteroaryl, or heteroaryl comprising one or more substituents, wherein said substituents are selected from the group comprising halogen, nitro, amino, hydroxy, thiohydroxy, lower alkoxy, lower thioalkyl, lower alkyl, NHC(=0)R wherein R is aryl or lower alkyl, COOH, or COOR wherein R is aryl or lower alkyl. 26. A method for treating cancer comprising administering an effective amount of an artemisinin dimer having the structure or an isomer thereof wherein R is alkylene, alkylene comprising one or more substituents, heteroalkylene, alkenylene, alkenylene comprising one or more substituents, alkynylene, arylene, arylene comprising one or more substituents, heteroarylene, heteroarylene comprising one or more substituents, wherein said substituents are selected from the group comprising halogen, N0 2 , OH, SH, NHC(=)0, NH 2 , COOH, CBONH 2 , COOR 2 .

Inventors: MURRAY CHRISTOPHER, O'DOWD HARDWIN, POSNER GARY H, SHAPIRO THERESA A, XIE SUJI, MURRAY, CHRISTOPHER, O'DOWD, HARDWIN, POSNER, GARY, H., SHAPIRO, THERESA, A., XIE, SUJI
Applicants: HAUSER INC, UNIV JOHNS HOPKINS, HAUSER, INC., JOHNS HOPKINS UNIVERSITY
Application year: 2000
Main classification: C07D493
IPC codes: C07D493, C07D519