C-10 CARBON-SUBSTITUTED ARTEMISININ-LIKE TRIOXANE COMPOUNDS HAVING ANTIMALARIAL, ANTIPROLIFERATIVE AND ANTITUMOUR ACTIVITIES

Abstract: The present invention provides a two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin by a variety of carbon nucleophiles, resulting in the novel C-10 carbon-substituted trioxanes of structure (1), wherein, when n is 1, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, acetylenics, or benzoy methylenes, or alkanoymethylenes; or when n is 2, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes; or when n is 3, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes.

Description: C-10 Carbon-Substituted Artemisinin-Like Trioxane Compounds Having Antimalarial, Antiproliferative and Antitumor Activities Description This study was supported in-part by National Institutes of Health grant Al 34885 ( to G.H.P.) and NCRROPTD-GCRC RR00722 (to T.A.S.) and joint inventors G.H.P., T.A.S., S.H.W., M.H.P. and P.P., have assigned their rights to the Johns Hopkins University. Cross-Reference to Related Patent Applications This patent application references Disclosure Document entitled "A Novel Class of 12-C Artemisinin Dimers,"No.: 392,815, filed February 23, 1996, and is a continuation-in-part of U.S. Patent Application No. 09/001,242, filed December 30, 1997 and entitled "C-10 Carbon- Substituted Artemisinin-Like Trioxane Compounds Having Antimalarial, Antiproliferative and Antitumor Activities. Technical Field The present invention relates to a direct two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin by various carbon nucleophiles without the destruction of the trioxane peroxidic bond. The present invention further relates to the formation of monomeric and dimeric C-10 carbon-substituted (rather than oxygen substituted) derivatives of the trioxane 10- deoxoartemisinin which demonstrate potent and potentially therapeutically valuable antimalarial, and antiproliferative and antitumor activities. 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 Plasmodiumfalciparum 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. Artemisinin in methanol is reduced with sodium borohydride to an equilibrium mixture of α- 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 dihydroartemisinin), 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 1 R=H 2 R=CH 3 3 = H 2 H 3 4 R=COCH 2 CH 2 COONa 5 R=CH 2 C 6 H 4 COOH 6 R=CH 2 CC 6 H 4 COONa 7 R= artemether (compound II-2), arteether (II-3), sodium artesunate (II-4), artelinic acid (II-5), sodium artelinate (II-6), dihydroartemisinin condensation by-product (II- 7) and the olefinic compound, structure πi, in have been produced. Artemether (II-2) is produced by reacting β-dihydroartemisinin with boron trifluoride (BF 3 ) etherate or HCl in methanohbenzene (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 (H-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, (HI), and the dihydroartemisinin condensation by-product (H-7), formed on addition of dihydroartemisinin to (III), M. Cao, et al., 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. Venugopalan, "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 artemisinin 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 HI is inactive against P. berghei- infected mice, whereas the dihydroartemisinin condensation by-product (H-7) has an SD 90 of 10 mg/Kg in P. berghei- infected 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 (π, R = alkyl) < esters [H, R=C(=0)-alkyl or -aryl] < carbonates [H, 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 number 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., etal, J. Med. Chem., 35:2459-2467 (1992), incorporated 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 (π-3), one of the antimalarial derivatives discussed previously, was rapidly converted by rat liver microsomes into dihydroartemisinin (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 (H-1) suggest that they were prodrugs for (H-1). The controlled slow formation of (H-1), 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., 743-744 (1990); and Haynes, R.K., et al, Synlett., 481-484 (1992). 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 artemisinin-related endoperoxides were tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolum (MTT) assay, H. J. Woerdenbag, etal. "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 (HI-3), sodium artesunate (H-4), artelinic acid (H-5) and sodium artelinate (H-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 (H 1-6) discussed above demonstrated zero to slight antiproliferative and antitumor activity, it has been discovered that a class of artemisinin dimer compounds exhibits antiproliferative and antitumor activities that are, in vitro, equivalent to or greater than known antiproliferative and antitumor agents. See, U.S. Patent Number 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 a more efficient method for the formation of hydrolytically more stableC-10 carbon-substituted deoxoartemisinin compounds and structural analogs thereof having antimalarial, and antiproliferative and antitumor activities that are equivalent to or greater than those of known antimalarial, and antiproliferative and antitumor agents, respectively. Disclosure of Invention Accordingly, it is an object of this invention to provide a class of artemisinin related dimers which demonstrate antiproliferative and antitumor activities. More specifically, it is an object of this invention to provide a class of trioxane dimers which demonstrate antiproliferative 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 10-deoxoartemisinin (VII) of the following structure or diastereomers thereof, having antimalarial, and antiproliferative and antitumor activities; VII wherein, the monomers of the present invention are formed when n is 1 and R is an unsubstituted or substituted aryl, heteroaryl, polyethylene glycol, acetylenic, aroylmethylene or alkanoylmethylene group or the dimers of the present invention are formed when n is 2 and R is a linker such as an unsubstituted or substituted alkyl, alkenyl, aryl, heteroaryl, polyethylene glycol, diketone, or a bis-acetylene group or the trimers of the present invention are formed when n is 3 and R is a linker such as an unsubstituted or substituted alkyl, alkenyl, aryl, heteroaryl, polyethylene glycol, diketone, or a bis-acetylene group. Brief Description of the Drawings The accompanying drawings, which are incorporated 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 drawings, Figures 1-5, 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 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C-10 carbon-substituted trioxane dimers 38 and 39 of the present invention versus calcitriol and versus a control using only a solvent. Figure 2 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C-10 carbon-substituted trioxane dimers 43, 44 and 45 of the present invention versus calcitriol and versus a control using only a solvent. Figure 3 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C-10 carbon-substituted trioxane monomer 27 of the present invention versus calcitriol and versus a control using only a solvent. Figure 4 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C- 10 carbon-substituted trioxane dimer 47 of the present invention versus calcitriol and versus a control using only a solvent. Figure 5 depicts the dose response curves generated by exposing murine keratinocytes to various concentrations of the C-10 carbon-substituted trioxane dimer 48 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 cell 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 38 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 39 of the present invention. Figure 6e depicts the dose response curves generated by exposing various leukemia cancer cell lines to various concentrations of compound VI. 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 38 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 39 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 compound VI. 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 38 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 39 of the present invention. Figure 8e depicts the dose response curves generated by exposing various colon cancer cell lines to various concentrations of compound VI. 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 38 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 39 of the present invention. Figure 9e depicts the dose response curves generated by exposing various CNS cancer cell lines to various concentrations of compound VI. Figure 10a depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of paclitaxel. Figure 1 Ob 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 38 of the present invention. Figure 1 Od depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of the C-10 carbon-substituted dimer 39 of the present invention. Figure 1 Oe depicts the dose response curves generated by exposing various melanoma cancer cell lines to various concentrations of compound VI. 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 11 c depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of the C-10 carbon-substituted dimer 38 of the present invention. Figure l id depicts the dose response curves generated by exposing various ovarian cancer cell lines to various concentrations of the C-10 carbon-substituted dimer 39 of the present invention. Figure 12a depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of paclitaxel. Figure 12b depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of artemisinin. Figure 12c depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of the C-10 carbon-substituted dimer 38 of the present invention. Figure 12d depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of the C-10 carbon-substituted dimer 39 of the present invention. Figure 12e depicts the dose response curves generated by exposing various renal cancer cell lines to various concentrations of compound VI. 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 38 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 39 of the present invention. Figure 13e depicts the dose response curves generated by exposing various prostate cancer cell lines to various concentrations of compound VT. 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 38 of the present invention. Figure 14d depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of he C-10 carbon-substituted dimer 39 of the present invention. Figure 14e depicts the dose response curves generated by exposing various breast cancer cell lines to various concentrations of compound VI. Best Mode for Carrying out the Invention The present invention provides a direct two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin (II-l) by a variety of carbon nucleophiles, resulting in the novel C-10 carbon-substituted monomeric and dimeric (VH) compounds; VII wherein, the monomers of the present invention are formed when n is 1 and R is an unsubstituted or substituted aryl, heteroaryl, polyethylene glycol, acetylenic, aroylmethylene, or alkanoylmethylene group or the dimers of the present invention are formed when n is 2 and R is a linker such as an unsubstituted or substituted alkyl, alkenyl, aryl, heteroaryl, polyethylene glycol, diketone, or a bis-acetylene group, the trimers of the present invention are formed when n is 3 and R is a linker such as an unsubstituted or substituted alkyl, alkenyl, aryl, heteroaryl, polyethylene glycol, diketone, or a bis-acetylene group. The synthesis of the C- 10 carbon-substituted monomeric and dimeric compositions VH of the present invention have not been accomplished previously. Although they might be synthesized by other means, the present invention offers an efficient two-step process as described in further detail below. Preferably, the compounds of the present invention are synthesized by the two-step chemical operation illustrated below. (II-l) (VI) (VH) This process involves mild diethylaminosulfur trifluoride (DAST) fluorination of dihydroartemisinin (II-l), wherein R; = H and R 2 = OH, followed by the facile substitution of the anomeric fluorine atom in pyranosyl fluoride (VI) by various alkyl, alkenyl, alkynyl, aryl and heteroaryl nucleophiles (R) to form either α- or β-oriented C-10 carbon-substituted deoxoartemisinin monomeric or dimeric (VII ) compounds. The simplicity and high chemical yields in this process of the present invention indicate that it can be used for the synthesis of a wide variety of other saturated, unsaturated, aromatic and heteroaromatic C- 10 carbon-substituted analogs of the present invention. Several aspects of the process of the present invention are surprising and of value. In general, the first step of the preferred process of the present invention, fluorination of the pyranose anomeric 10-OH group in dihydroartemisinin is accomplished by using an effective amount of a fluorinating agent. Effective fluorinating agents include, but are not limited to, 2-fluoropyridinium salts, hydrogen fluoride-pyridine, hexafluoropropene-amine complex and diethylaminosulfur trifluoride (DAST). An effective amount of one or more oxidizing agents can be utilized. In particular, one or more fluorinating agents from the above list can be employed, although diethylaminosulfur trifluoride is the preferred fluorinating agent. The relative effectiveness of the various possible fluorinating agents depends upon the concentration employed and other conditions of the reaction. Various amounts of the fluorinating agent can be employed, but generally it should be present in the range of 1 to 10 molar equivalents of fluorinating agent per mole of dihydroartemisinin (π-1). Preferably, at least 1 equivalent of fluorinating agent per molar equivalent of dihydroartemisinin is needed for the reaction to proceed to completion. To facilitate mixing of the starting materials, the fluorination is preferably accomplished utilizing an effective dissolution amount of a dihydroartemisinin solvent which is compatible with the particular fluorinating agent or agents employed. Typical solvents include tetrahydrofuran, water, acetone, aqueous dioxane, or mixtures thereof or other dihydroartemisinin solvents known to one of ordinary skill in the art. In the preferred embodiment of the invention the fluorination of the pyranose anomeric 10-OH group in dihydroartemisinin is accomplished by dissolving the dihydroartemisinin using tetrahydrofuran and utilizing diethylaminosulfur trifluoride as the fluoridizing agent. The pyranose anomeric 10-OH group is fluorinated over a temperature range of -30°C to 25°C for 15 minutes to 24 hours for solutions which are approximately 1 to 2 mg/ml of dihydroartemisinin using 1 to 10 molar equivalents of the fluorinating reagent. The second step of the process of the present invention, facile substitution of the anomeric fluorine atom in pyranosyl fluoride (VI) by various alkyl, alkenyl, alkynyl, aryl and heteroaryl carbon nucleophiles to form either or β oriented C- 10 carbon-substituted deoxoartemesinin (VH) compounds of the present invention is accomplished by dissolving the desired nucleophile and pyranose fluoride (VI) in a solvent which is compatible with the particular carbon nucleophiles employed. Typical solvents include dry methylene chloride, tetrahydrofuran or mixtures thereof or other solvents known to one of ordinary skill in the art. In the preferred embodiment of the invention facile substitution of the anomeric fluoride atom in pyranosyl fluoride (VI) is accomplished by dissolving 1 to 10 molar equivalents and preferably 2 molar equivalents of an alkyl, alkenyl, alkynyl, aryl or heteroaryl carbon nucleophile with pyranosyl fluoride (VI) and cooling the mixture to -70 to -90°C and preferably -78°C. Coupling of the carbon nucleophile with the pyranosyl fluoride occurs in the presence of boron trifluoride-etherate over a temperature range of -70°C to room temperature. Fluorination of readily available dihydroartemisinin lactol (II-l) where R ! = H and R 2 = OH with DAST proceeded in high yield on a gram-scale to form a mixture of anomeric fluorides, with the β-fluoride VI vastly predominating and easily separated from the α-fluoride by immediate application of the crude product mixture to chromatography using a Florisil® column; exposure to water caused hydrolysis of these pyranosyl fluorides back into the reactant lactol II-l. After purification, however, lOβ-fluoride VI is a stable crystalline solid. Coupling of either the α-fluoride or the β-fluoride VT with trimethylaluminum in the presence of boron trifluoride-etherate gave lOβ-methyl derivative VII where n=l and R = CH 3 with almost complete stereoselectivity, thereby implicating a common oxygen- stabilized C-10 carbocation intermediate. The relative stereochemistry at carbons 9 and 10 was established by the characteristic 'HNMR chemical shifts and coupling constants of the methine hydrogen atoms at these positions (J 9 10 = 10-11 Hz for trans and J 9 10 = 5.6-6.7 Hz for cis). Based on the characteristic Η NMR chemical shifts for analogous C-9, 10-disubstituted systems, we conclude that the structure is a lOβ-methyl derivative (not shown) (rather than as 9α, 1 Oα-dimethyl) and, therefore, that the reaction probably does not proceed via the intermediacy of a C-9, 10-olefϊn {i.e., via the dehydrofluorinated intermediate). Several dimethyl aluminum acetylides, prepared from Me 2 AlCl and the corresponding lithium acetylides, coupled smoothly to form exclusively the lOβ-acetylenic derivatives. Di- and tri-methoxylated benzenes and heteroaromatic N-methylpyrrole and furan coupled to produce exclusively, in stereochemical contrast, the 1 Oα-oriented derivatives. Apparently, relatively small nucleophiles approach the intermediate cation from the β-face of the molecule, whereas relatively large aryl and heteroaryl nucleophiles approach from the α-face {i.e. directed by and trans to the C-9 methyl group). Coupling of pyranosyl fluoride VI with N-methylpyrrole proceeded equally well on 400 mg scale as on 20 mg scale, and larger scale executions of this and of the other coupling reactions reported here are not expected to be a problem. In the course of these studies, it was also discovered that dihydroartemisinin (π-1) itself, like many 1 -hydroxy carbohydrates, can be used directly as an electrophile donor in the presence of boron trifluoride-etherate for Friedel-Crafts arylation of reactive aromatics and heteromatics. Consequently, the C- 10 carbon-substituted trioxanes of the present invention may be formed according to an alternative embodiment wherein convesion of the pyranose anomeric 10-OH group in dihydroartemisinin with a carbon nucleophile is accomplished by contacting dihydroartemisinin with an electron-rich aromatic or heteroaromatic nucleophile. The chemical yields of the process according to the preferred embodiment versus the second embodiment compare as follows: C-lOα glycoside formation using the process of the second embodiment proceeded in 56% yield with 1 ,3 -dimethoxybenzene {vs. 71 % using glycosy 1 fluoride VI) and in 75% yield with N-methylpyrrole {vs. 86% using glycosyl fluoride VI). Although furan did not couple with lactol H-1, furan did couple in 31 % yield with fluoride VI. Neither lactol H-1 nor fluoride VI, however, coupled with thiophene. In summary, it was surprising to learn that the dihydroartemisinin lactol (H-1) as a pyranose sugar with a free anomeric hydroxyl group has led to this two-step protocol involving direct fluorination of readily available lactol H-1 and then C-glycoside formation for easy semi-synthesis of various artemisinin C-10 derivatives VH without destruction of the critical trioxane ring system. These C-10 carbon-substituted trioxanes are expected to be considerably more stable toward hydrolysis than the corresponding ether and ester derivatives (C-10 acetals) of dihydroartemisinin that are currently used clinically as chemotherapeutic antimalarial drugs. The biological activities of C-10 carbon-substituted trioxanes 38 and 39 disclosed below in Table II, are discussed in further detail below. TABLE I Monomers of the Present Invention (see formula VH) TABLE π Dimers and Trimers of the Present Invention (see formula VII) ( i ) and ( ) designates the point of attachment. 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 CsA. 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 Corp. (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 Figures 1-5, for PE cells treated with calcitriol and the C-10 carbon-substituted dimers 38, 39, 43, 44, 45, 47 and 48, and monomer 27 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 38, 39, 43, 44, 45, 47, and 48, and monomer 27 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. Antiproliferative activities, measured in vitro using murine keratinocytes as described previously, are shown in Figures 1-5. Note that the trioxane dimers 38, 39, 43, 44, 45, 47 and 48, even at physiologically relevant 100 nanomolar concentrations, are at least as antiproliferative as calcitriol ( 1 α, 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 38 and 39 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 38 and 39 are summarized in Tables III, IV and V (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 antiproliferative 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 * 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 interpolated 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 zero 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 III. A drug effect of this intensity is interpreted 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 IV. 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 V. This is interpreted as cytotoxicity. TABLE HI TABLE IV *NCI indicates these values are not relevant TABLE V The C- 10 carbon-substituted trioxane dimer 38 of the present invention and compound VI of the present invention in most instances are as potent and in some instances more potent than paclitaxel. The data in Tables III, IV and V 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, compound VI and the C-10 carbon-substituted trioxane dimers 38 and 39 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 "u 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 38 and 39 dose response curves in Figures 3c and 3d, respectively, the leukemia cell line MOLT-4 displays primary growth inhibition at drug concentrations that are less than 10 "7 and greater than 10 "4 , respectively, and compound VI displays primary growth inhibition at a concentration of about 10 "7 molar. 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 38 and 39 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. Compound VI reaches cytostasis at a concentration between 10 "4 M andlO "3 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, compound VI, and for both C-10 carbon-substituted trioxane dimers 38 and 39. The potency of the C-10 carbon-substituted trioxane dimer 38 of the present invention, and compound VI, 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 III, IV and V and the C-10 carbon-substituted trioxane dimer 38 of the present invention and compound VI 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 D.L. 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 dimer 38 was at least 100 times more potent than artemisinin. When interpreting 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 1 la, b, c, d and e for ovarian cancer cell lines Figures 12a, b, c, d and e for renal cancer cell lines, Figures 13 a, c, d and e for prostate cancer cell lines and Figures 14a, c, d and e for breast cancer cell lines. To determine the antimalarial effect of various C-10 carbon-substituted monomers, and dimers 38 and 39 of the present invention, screening assays were performed against chloroquine-sensitive P. falciparum (NF54), according to the method described below their IC 50 values are included in Table I and summarized in Table VI. Strikingly, twelve of the thirteen C-10 aryl and heteroaryl analogs are at least as potent as artemisinin. The most potent of these analogs is C-lOα furan 17a, with an IC 50 of 1.4 nM relative to artemisinin's IC 50 of 10 nM. Determination of Antimalarial Activity Activity was determined by measuring the incorporation of [ 3 H]hypoxanthine, by the methods of Desjardins and Milhouse, with the following modifications, see Desjardins, R.E.; Canfield, C.J.; Haynes, J.D.; Chulay, i.O.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 mMNaHC0 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 priorto the addition of25 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). The preliminary data summarizing the activities of C-10 carbon-substituted monomers 8-11 and 13a, 13b, 14, 15, 16a-16d, 17a-17d, 18, 19, 20a-20c, and dimers 38 and 39 are represented in Table VI, below. TABLE VI t = to be tested Εxpansion data, ^survey data (preliminary). Artemether and the C- 10 carbon-substituted trioxane monomers 13 a, 16a and 17a, and dimers 38 and 39 have IC 50 values lower than that of artemisinin thus indicating that these compounds are more potent than artemisinin. As we have done before using in vitro antimalarial potencies as a reliable guide, three of these C- 10 analogs were selected for in vivo evaluation; their in vivo antimalarial activities are summarized below in Table VII, including subcutaneous and oral administration routes. Hydrolytically stable C-10 dihydroartemisinin furan 17a, methylfuran 17b and N-methylpyrrole 16a are more potent in vivo than artemisinin and than chloroquine when administered subcutaneously. Recent preliminary in vivo acute toxicity testing results highlight the relative safety of furan derivatives 17a and 17b. TABLE VII The current understanding of the trioxanes' fundamental chemical and biological mechanism(s) of action support the following sequence of events in killing malaria parasites: (1) heme iron-activation {i.e. reductive cleavage) of the peroxidic O-O bond to form initially an oxy radical; (2) reorganization of this oxy radical into one or more carbon-centered radicals; and finally (3) formation of an alkylating epoxide and of an oxidizing high-valent iron-oxo species. Any one or a combination of these reactive and cytotoxic intermediates may kill the malaria parasites. Recent evidence has confirmed the intermediacy of an epoxide and of carbon-centered radicals; isolation of a covalent adduct between the trioxane skeleton and a porphyrin unit was observed when artemisinin (I) was treated with a heme model, /wesø-tetraphenylporphyrin. Therefore, following our previous protocol, we have exposed methylfuran 5b to iron (II) and have found evidence for the intermediacy of a C 4 -carbon radical intermediate {i.e. a C 4 -hydroxylated product was isolated) and for a high-valent ironoxo intermediate {i.e. rearrangement of hexamethyl Dewar benzene into hexamethylbenzene was observed). Thus, the chemical mechanism of action of these C-10 carbon-substituted 10-deoxoartemisinin compounds seems to be the same as that of natural artemisinin (I) itself and of its clinically used semi-synthetic ether derivatives {e.g. artemether, arteether). Often, solubility in water is a desirable feature of a new drug candidate. Since organic compounds bearing one or more carboxylic acid groups or phenolic groups are usually water soluble at physiological pH, we have prepared a series of 10-carbon-substituted trioxane carboxylic acids via alkene oxidation and ester saponification. Also, bisphenol (34) was prepared by hydrolysis of the corresponding bis-silyl ether. The water solubility of some of these trioxanes at pH 7.4 is as follows: compound 33: 0.03 M; compound 16e: 0.01 M; bis-phenol compound 13d: less than 0.003 M. In summary, very short semi-synthesis has generated a series of enantiomerically pure, C-10 non- acetal carbon analogs of dihydroartemisinin (II-l) having high in vitro antimalarial activities. Several of these new 10-deoxoartemisinin trioxanes are highly efficacious in vivo, even when administered orally to rodents. These potent trioxanes in the artemisinin family, therefore, are now excellent candidates for further preclinical evaluations as part of the worldwide effort to combat malaria via chemotherapy. Drawing 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. EXAMPLES Unless otherwise noted, reactions were run in flame-dried round-bottomed flasks under an atmosphere of ultra high purity (UHP) argon. Diethyl ether (ether) and tetrahydrofuran (THF) were distilled from sodium benzophenone ketyl prior to use. Dichloromethane (CH 2 C1 2 ) and triethylamine (TEA) were distilled from calcium hydride prior to use. All other compounds were purchased from Aldrich Chemical Company and used without further purification. All temperatures are understood to be in Centigrade (0°C) when not specified. Analytical thin- layer chromatography (TLC) was conducted with Silica Gel 60 F 254 plates (250 micrometer thickness, Merck). Column chromatography was performed using short path silica gel (particle size < 230 mesh), flash silica gel (particle size 400-230 mesh), or Florisil® (200 mesh). Yields are not optimized. High performance liquid chromatography (HPLC) was carried out with a Rainin HPLX system equipped with two 25 mL/min preparative pump heads using Rainin Dynamax 10mm x 250mm (semi-preparative) columns packed with 60 A silica gel (8 μm pore size), either as bare silica or as C- 18-bonded 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 Η and 100 MHz for 13 C or a varian XL-500 spectrometer, operating at 500 Mhz for 'H and 125 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 (b). The solvents employed for taking NMR spectra are DMSO-d 6 (perdeuterodimethysulfoxide), D 2 0 (deuterated water), CDC1 3 (deuterochloroform) and other conventional deuterated solvents. Combination of CH 3 CN and H 2 0 in different concentrations are used as HPLC solvent system. Infrared (IR) spectra were obtained using a Perkin-Elmer 1600 FT-IR spectrometer. Resonances are reported in wavenumbers (cm 1 ). Low resolution (LRMS) and high resolution (HRMS) mass spectra were obtained on a VG Instruments 70-S spectrometer run at 70 eV for electronic ionization (El) and run with ammonia (NH 3 ) as a carrier for chemical ionization (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. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the present invention by other methods. EXAMPLE I Preparation of C-10 carbon-substituted Dimer 38 of the Present Invention a) Synthesis of artemether To a solution of artemisinin (0.34 g, 1.24 mmol) in methanol (25 mL) and THF (5 mL) at - 15 °C was added sodium borohydride (0.34 g, 9.30 mmol) in four equal portions over 1 hour. The resulting reaction mixture was stirred at -15°C for 2 hours and quenched with glacial acetic acid (0.55 mL, 9.60 mmol) at -15°C. To the mixture at room temperature was added water (30 mL) and CH 2 C1 2 (30 mL). The two layers were separated, and the aqueous phase was extracted with CH 2 CI 2 (30 x 2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude dihydroartemisinin white solid: mp 149°-153°C. To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0°C. The reaction was stirred at 0 ° C for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30 x2 mL) . The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemether isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73 °-74.5 °C; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a X H NMR spectrum identical to that reported in the literature. b) Synthesis of Bis-TMS-enol ether of 1,4-Diacetylbenzene To a stirred solution of diacetylbenzene (1 eq.), ether and THF at room temperature was added TEA (2.2 eq.) via gas-tight syringe. Trimethylsilyl trifluoromethanesulfonate (TMSOTf; 2.2 eq.) was slowly added to the reaction mixture at room temperature via gas-tight syringe. The resulting mixture was stirred at room temperature for 2 hours. The two layers were separated, and the top layer was concentrated under reduced pressure. The mixture was diluted with dry ether (30 mL) and filtered. The resulting filtrate was concentrated under reduced pressure to provide crude product as light yellow oil. Purification by Kϋgelrohr afforded the desired product that was used immediately for coupling with β-artemether. bis-TMS-enol ether of 1 ,4- diacetylbenzene (1.50 g, 4.89 mmol, 49% yield) was prepared as a colorless oil: 'HNMR(CDC1 3 ) δ 7.56 (s, 4H), 4.95 (d, J= 1.8 Hz, 2H) 4.45 (d, J= 1.8 Hz, 2H), 0.29 (s, 18H); 13 C NMR (CDC1 3 ) δ 155.26, 137.22, 124.88, 91.30, 0.11. c) Synthesis of >-Dimer 38 To a stirred solution of β-artemether (1 eq.) in CH 2 C1 2 at -78°C added a 1M solution of TiCl 4 in CH 2 C1 2 (1.1 eq.) via gas-tight syringe. A solution of the bis-TMS-enol ether (0.55 eq.) in CH 2 C1 2 at room temperature was then added to the reaction mixture via gas-tight syringe. The resulting reaction mixture was stirred at -78 °C for 1 hour. The reaction was quenched at -78 °C with water (3 mL) and diluted with ether (5 mL). The two layers were separated, and the aqueous phase was extracted with ether (10 x 2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product. Column chromatography on Florisil (l%-30% EtOAc/hexanes) afforded the desired product as a solid. The material was further purified using HPLC. /--dimer 38 (13 mg, 0.019 mmol, 13%) was obtained after HPLC (silica, 25% EtOAc/hexanes, 3 mL/min, 254 nm, R, = 18.5 min) as a white solid: mp 87° -88°C; Η NMR (CDC1 3 ) δ 8.02 (s, 4H), 5.33 (s, 2H), 5.1 1-5.06 (m, 2H), 3.20 (d ABq, Jd = 5.6 Hz, Δ AB = 84.5 Hz, J AB = 16 Hz, 4H), 2.84-2.75 (m, 2H), 2.35-2.27 (m, 2H), 2.02-1.97 (m, 2H), 1.96-1.89 (m, 2H), 1.87-1.80 (m, 2H), 1.77-1.67 (m, 4H), 1.47-1.23 (m, 10H), 1.31 (s, 6H), 0.98 (d, J= 6 Hz, 6H), 0.90 (d, J= 7.6 Hz, 6H); 13 C NMR (CDC1 3 ) δ 197.58, 139.98, 128.39, 102.93, 89.56, 80.83, 70.00, 52.00, 44.01, 40.50, 37.54, 36.51, 34.41, 29.92, 25.80, 24.79, 20.11, 12.97; HRMS (CI) m/z calculated for C 40 H 58 NO 10 (M + NH 4 + ) 712.4061, found 712.4054. EXAMPLE II Preparation of C-10 Carbon-Substituted Dimer 39 of the Present Invention a) Synthesis of Artemether Step (a) from Example 1 is followed. b) Synthesis of Bis-TMS-enol ether of 1,3-Diacetylbenzene To a stirred solution of diacetylbenzene (1 eq.), ether and THF at room temperature was added triethylamine (2.2 eq.) via gas-tight syringe. Trimethylsilyl trifluoromethanesulfonate (TMSOTf; 2.2 eq.) was slowly added to the reaction mixture at room temperature via gas-tight syringe. The resulting mixture was stirred at room temperature for 2 hours. The two layers were separated, and the top layer was concentrated under reduced pressure. The mixture was diluted with dry ether (30 mL) and filtered. The resulting filtrate was concentrated under reduced pressure to provide crude product as light yellow oil. Purification by Kϋgelrohr afforded the desired product that was used immediately for coupling with β-artemether. bis-TMS-enol ether of 1,3- diacetylbenzene (1.80 g, 5.87 mmol, 59% yield) was obtained as a colorless oil: 'H NMR (CDC1 3 ) δ 7.83-7.82 (m, IH), 7.53-7.50 (m, 2H), 7.29-7.25 (m, IH), 4.93 (d, J= 1.6 Hz, 2H), 4.44 (d, J= 1.6 Hz, 2H), 0.27 (s, 18H); 13 C NMR (CDC1 3 ) δ 155.49, 137.27, 127.78, 125.06, 122.10, 91.18, 0.13. c) Synthesis of m-Dimer 39 To a stirred solution of β-artemether (1 eq.) in CH 2 C1 2 at -78 °C added a 1M solution of TiCl 4 in CH 2 C1 2 (1.1 eq.) via gas-tight syringe. A solution of the bis-TMS-enol ether (0.55 eq.) in CH 2 C1 2 at room temperature was then added to the reaction mixture via gas-tight syringe. The resulting reaction mixture was stirred at -78 °C for 1 hour. The reaction was quenched at -78°C with water (3 mL) and diluted with ether (5 mL). The two layers were separated, and the aqueous phase was extracted with ether (10 x 2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product. Column chromatography on Florisil (l%-30% EtOAc/hexanes) afforded the desired product as a solid. The material was further purified using HPLC. w-dimer 39 (45 mg, 0.065 mmol, 33%) was obtained after HPLC (silica, 25% EtOAc/hexanes, 3 mL/min, 254 run, R, = 19.4 min) as a white solid: mp 78°-79°C; 'H NMR (CDC1 3 ) δ 8.52-8.50 (m, IH), 8.15-8.13 (m, 2H), 7.59-7.54 (m, IH), 5.34 (s, 2H), 5.11-5.05 (m, 2H), 3.11 (d ABq, Jd = 6.4 Ηz, Δυ Aa = 93.4 Hz, JAB = 16.4 Hz, 4H), 2.86-2.77 (m, 2H), 2.34-2.26 (m, 2H), 2.02- 1.97 (m, 2H), 1.96- 1.89 (m, 2H), 1.86- 1.82 (m, 2H), 1.73-1.67 (m, 4H), 1.45-1.22 (m, 10H), 1.30 (s, 6H), 0.97 (d, J= 6 Hz, 6H), 0.91 (d, J= 8 Hz, 6H); 13 C NMR (CDC1 3 ) δ 197.28, 137.15, 132.37, 128.93, 102.99, 89.40, 80.82, 70.17, 52.04, 44.11, 40.00, 37.45, 36.49, 34.40, 29.88, 25.81, 24.76, 20.11, 13.07; LRMS (CI, rel intensity) 712 (M + NH 4 +, 1), 620 (28), 446 (37), 400 (97), 383 (100), 369 (28), 365 (95), 284 (30), 270 (28), 222 (14), 183 (17); HRMS (CI) m/z calculated for C 40 H 58 NO 10 (M + NH 4 + ) 712.4061, found 712.4069. EXAMPLE HI Preparation of the C-10 Carbon-Substituted Dimer 45 of the Present Invention a) Synthesis of 1,4-diethynylbenzene A 100 mL round-bottomed flask was charged with THF (55 mL) and lithium diisopropylamide (LDA; 1.5 M in cyclohexane, 8.70 mL, 12.9 mmol, Aldrich) at -78 °C. To this mixture was added a solution of 1,4-diacetylbenzene (1.00 g, 6.17 mmol, Aldrich) in THF (10 mL) at -78°C. The resulting yellow slurry was stirred at -78 °C for 1 hour. Diethyl chlorophosphate (1.96 mL, 13.6 mmol, Aldrich) was then added to the mixture via syringe. The resulting orange-brown mixture was stirred at -78 °C for 15 minutes and then slowly warmed up to room temperature and stirred for 15 minutes. To a solution of LDA (18.5 mL, 27.8 mmol) in THF (60 mL) at -78°C was added the above orange-brown mixture via cannula. The resulting dark blue-green reaction mixture was stirred at -78 °C for 40 minutes and slowly warmed up to room temperature. The reaction was monitored by thin layer chromatography until all starting material diketone was consumed (3.5 hours at room temperature). The reaction was quenched with 1 N HCl (3 mL) and diluted with water (25 mL). Two layers were separated and the aqueous was extracted with ether (25 mL x 2). The combined organic layers were washed with 1 N HCl (25 mL), water (25 mL) and saturated NaHC0 3 (25 mL). The organic phase was dried over MgS0 4 , filtered and concentrated under reduced pressure to give a crude product. Column chromatography on silica (flash, 1% EtOAc/hexanes) afforded 1, 4 diethynylbenzene (0.620 g, 4.91 mmol, 80%) as a white crystalline solid: - mp 91-92°C (lit. 96.5°C) With Η and 13 C NMR spectra identical to those reported in the literature. b) Synthesis of C-l 0 />-DiethynyIbenzene 10-deoxoartemisinin Dimer 45 A 10 mL round-bottomed flask was charged with 1 ,4-diethynylbenzene (0.013 g, 0.1 mmol) and ether (1 mL) at 0°C. To this mixture was added n-BuLi (1.6 M in hexanes, 0.13 mL, 0.21 mmol, Aldrich). The resulting white slurry was stirred at 0°C for 30 minutes. Dimethyl aluminum chloride (1.0 M in hexanes, 0.21 mL, 0.21 mmol, Aldrich) was then added to the reaction mixture at 0 σ C. The resulting yellowish mixture was stirred at 0 °C for 0.5 hours. To this reaction mixture at -78 °C was added boron trifluoride diethyl etherate (BF 3 .Et 2 O; 0.027 mL, 0.21 mmol, Aldrich) and a solution of C-10 β- fluorodeoxoartemisinin (0.060 g, 0.21 mmol) in CH 2 C1 2 (2 mL). The reaction mixture was stirred at - 78°C for 30 minutes, slowly warmed up to -50°C and stirred for 2 hours. The reaction was finally warmed up to -40 °C and stirred for 12 hours. The reaction was quenched with water (3 mL) and diluted with ether (10 mL). Two layers were separated and the aqueous was extracted with ether (10 mL x 2). The combined organic layers were washed with brine, dried over MgS0 4 , filtered, and concentrated under reduced pressure to provide a crude product. Purification by column chromatography (Florisil®, l%-5% ethyl acetate/hexanes) gave dimer 45 (0.010 g, 0.015 mmol, 15%) as a white solid: ΗNMR (CDC1 3 ) δ 7.34 (s, 4 H), 5.62 (s, 2 H), 4.96 (d, J= 5.6 Hz, 2H), 2.85 (m, 2H, 2.38 (ddd, J= 14.4, 13.6, 4.0 Hz, 2 H), 2.19 (apparent dq,Jd = 3.3 Hz, Jq = 13.6 Hz, 2 H, 2.06 (m, 2 H), 1.92-1.78 (m, 6 H, 1.70-1.51 (m, 6 H), 1.45 (s, 6 M, 1.42-1.25 (m, 4 M, 1.04 (d, JI = 7.6 Hz, 6 H) 0.96 (d,J= 6.4 Hz, 6 H), 13 C NMR (CDC13) δ 131.4, 122.7, 104.3, 89.6, 88.9, 88.3, 80.9, 67.8, 52.7, 45.4, 37.4, 36.3, 34.6, 30.3, 26.1, 24.6, 23.0, 20.3, 13.9. EXAMPLE IV Preparation of C-10 carbon-substituted Dimer 43 of the Present Invention a) Preparation of 10α-(l',3'-Dimethoxyphenyl) deoxoartemisininin Monomer 13a b) Preparation of 1,3-Dimethoxybezene dimer 43 Dimer 43 10α-(l ',3 '-Dimethoxyphenyl) deoxoartemisininin monomer 13a (64.6 mg, 0.16 mmol, 2 equiv) and the 10-deoxoartemisinin β-fluoride (22.9 mg, 0.08 mmol) were dissolved in dry CH 2 C1 2 (0.8 mL) and cooled to -78°C. BF 3 Et,0 (14μL, 0.11 mmol) was then added, and the mixture was stirred at -70°C for 1 hour and then allowed to warm to -40 °C over 1 hour. After being stirred at this temperature for additional 4 hours, the reaction was quenched with saturated aqueous NaHC0 3 solution (1 mL) and then diluted with CH 2 C1 2 (10 mL) and water (5 mL). The organic phase was separated, and aqueous phase was extracted with CH 2 C1 2 (10 mL x 2). The organic portion was combined, washed with water, dried over anhydrous MgS0 6 , filtered, and concentrated under reduced pressure. Purification by column chromatography (flash gel, 33% EtOAc / hexanes) gave the desired 1,3 -dimethoxybenzene dimer 43 (39.8 mg, 0.059 mmol, 74%) as a white solid. m.p. = 168 - 169.2°C; 'HNMR (300 MHz, CDCl 3 ) δ 7.91 (br s, 1H), 6.31 (s. IH), 5.39 (s. 2H), 4.91 (d, J= 9.9 Hz, 2H), 3.76 (s, 6H), 2.56 (m, 2H), 2.33 (m, 2H, 1.99 (m, 2H), 1.89- 0.88 (m, 18H) 1.43 (s. 6H), 0.95 (d, J= 6.2 Hz, 6H), 0.58 (s. 6H), 13 C NMR (75MH 2 , CDC1 2 ) δ 157.14, 127.8, 122.8, 104.4, 94.2, 92.4, 80.6, 70.0, 56.1, 52.5, 46.8, 37.3, 36.9, 34.8, 34.8, 26.4, 25.3, 22.0, 20.8, 13.9; IR(KBr) 2934, 2868, 1608, 1509, 1457, 1377, 1294, 1201, 1068, 883, 847 cm "1 . Note. * 77ze stereochemistry of anomeric centers was assigned based upon the proton NMR coupling constant (J=9.9Hz). EXAMPLE V Monomer 12 Compound dihydroartemisinin (π-1) was treated with trimethylallylsilane, BF 3 Et,0 to form 10-β allyldeoxoartemisinin. 10-β allyldeoxoartemisinin was then converted to 10-β hydroxyethylartemisinin via oxidation (0 3 ) and reduction (LiBH 4 ). TsCl will then be reacted with this alcohol to form a tosylate. Triethylene glycol (TEG) is reacted with this tosylate to form dimer 35 (ββ) and monomer 12. EXAMPLE VI Preparation of the pyranosyl fluoride intermediate used to form C-10 carbon-substituted derivatives of the trioxane 10-deoxoartemisinin of the present invention A representative fluorination is as follows: A 250 mL flame-dried round-bottomed flask was charged with dihydroartemisinin (H-1, 1.30 g, 4.57 mmol) and dry tetrahydrofuran (100 mL). To this mixture at -30°C was added diethylaminosulfur trifluoride (DAST, 1.34 mL, 6.82 mmol). The resulting reaction mixture was stirred at -30°C for 15 minutes, slowly warmed up to room temperature and stirred for 1 hour. The reaction was concentrated under reduced pressure. The crude product was purified immediately without aqueous workup by column chromatography (Florisil®, 1%→5% ethyl acetate/hexanes) to give lOβ-fluoride VI (1.08 g, 3.75 mmol, 82%) and lOα-fluoride (0.102 g, 0.366 mmol, 8%) as white solids. lOβ-fluoride VI: mp = 108.0-109.0°C; 'HNMR (300 MHz, CDC1 3 ) δ 5.60 (dd, J H . F = 54.4 Hz, J H . H = 2.3 Hz, IH), 5.56 (d, J H . F = 1.9 Hz, IH), 2.63 (d of m, J H . F = 33.3 Hz, IH), 2.38 (m, 1 H), 2.03 (m, 1 H), 1.93-1.80 (in, 2 H), 1.73-1.21 (in, 7 H), 1.43 (s, 3 H), 1.00 (d, J= 7.4 Hz, 3 H), 0.96 (d, J= 6.2 Hz, 3 H); 13 C NMR (75 MHz, CDC I3 ) δ 111.2 (d, J c . F = 223 Hz), 104.9, 89.1, 80.9, 52.6, 43.8 (d, J c . F = 1.8 Hz), 37.8, 36.6, 34.9, 31.1 (d, J C . F = 22.7 Hz), 26.2, 25.0, 24.6 (d, J C . F = 5.9 Hz), 20.6, 12.7; 19 F NMR (282 MHz, CDC 13 , CFC 13 (ex)) ♦ 134.7 (dd,J= 53.7, 36.7 Hz); IR(KBr) 2947, 2871, 1453, 1381, 1181, 11, 1040, 982, 950, 914, 867 cm "1 . lOα-fluoride: mp = 99.0-100.0°C; Η NMR (300 MHz, CDC1 3 ) δ 5.44 (s, 1 H), 5.27 (dd, J H . F = 53.6 Hz, J H . H - 9.1 Hz, 1 H), 2.53 (m, 1 H), 2.40 (n, 1 H), 2.03 (m, 1 H), 1.94-1.05 (m, 9 H), 1.46 (s, 3 H), 0.99 (d, J= 7.1 Hz, 3 H), 0.96 (d, J= 7.1 Hz, 3 H); 13C NMR (75 MHz, CDC13) δ 108.8 (d, J C . F = 209 Hz), 105.0, 91.7 (d. J CH . F = 5.8 Hz), 80.2, 51.7, 45.4 (d,J c . F 9.6 Hz), 37.7, 36.5, 34.5, 33.2 (d, J C . F = 19.0 Hz), 26.2, 25.0, 22.5, 20.6, 12.0; 19 F NMR (282 MHz, CDC1 3 , CFC1 3 (ex)) Φ-140.7 (ddd, J= 53.7, 10.8, 4.6 Hz); IR (KBr) 2946, 2880, 1456, 1380, 1205, 1111, 1042, 878, 846 cm "1 . EXAMPLE VH Preparation of C-10 Carbon-Substituted Monomer 9 of the Present Invention 10β-(4'-Chlorophenylethynyl) deoxoartemisinin: 4-Chlorophenylacetylene (0.520 g, 3.84 mmol) was dissolved in dry diethyl ether (10 mL) and the solution was cooled to -78°C. Methyllithium (1.4 M in diethyl ether, 2.49 mL, 3.49 mmol) was added slowly by syringe. The clear solution was warmed to 0°C and stirred for 30 min. Dimethyl aluminum chloride ( 1.0 M in hexanes, 3.49 mL, 3.49 mmol) was added slowly by syringe. The resulting cloudy white suspension was stirred at 0°C for 30 minutes. The reaction was then cooled to -78°C. 1 Oβ-Fluorodeoxoartemisinin (0.500 g, 1.75 mmol) in dry dichloromethane (50 mL) at -78°C was added by cannula. Boron trifluoride diethyl etherate (0.300 g, 2.10 mmol) was added slowly by syringe. The reaction was warmed to -50°C and stirred for 3 hours. Distilled water (50 mL) was added and the separated aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried over magnesium sulfate and concentrated under vacuum. The remaining oil was purified by column chromatography (Florisil ® , 5% ethyl acetate/hexanes) to provide monomer 9 (0.588 g, 1.46 mmol, 83%) as a colorless oil [α] 25 D = +64.5 (c = 1.33, CHC1 3 ). HPLC: 10:90 ethyl acetate: hexanes, 3 mL/min., R t = 12.1 min. Η NMR (CDC1 3 400 Mhz) δ 7.27 - 7.34 (4H, m), 5.64 (IH, s), 4.96 (IH, d, J= 5.6 Hz), 2.85 (IH, m), 2.38 (IH, ddd, J= 4.0, 13.2, 14.4 Hz), 2.19 (IH, ddd, J = 3.2, 13.6, 13.6Hz) 2.06 (IH, ddd, J= 2.8, 4.8, 14.4, Hz), 1.78 - 1.94 (2H, m), 1.45 (3H, s, 1.20 - 1.72 (6H, m), 1.04 (3H, d, J= 7.2 Hz), 0.96 (3H, d, J= 6.0 Hz). 13 C NMR (CDC1 3 , 100 MHz) δ 134.4, 132.6, 128.6, 121.1, 104.2, 89.5, 87.9, 87.6, 80.9, 67.8, 52.6, 45.3, 37.4, 36.2, 34.6, 30.3, 26.1, 23.0, 20.3, 13.9, IR (neat): 2940, 1488, 1377, 1227, 1188, 1089, 1052, 1014, 990, 960, 924, 873, 825 cm "1 . EXAMPLE Vm Preparation of C-10 Carbon Substituted Monomer 15 of the Present Invention A flame-dried 10 mL round-bottomed flask was charged with 2,7-dimethoxynaphthalene (0.113 g, 0.601 mmol) and β fluoride VI (0.034 g, 0.119 mmol) in dried dichloromethane (1 mL). To this mixture at -78 °C was added boron trifluoride diethyl etherate (0.018 mL, 0.143 mmol) via gas-tight syringe. The mixture turned bright yellow and then dark orange in 20 minutes at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. TLC indicated no starting material fluoride. The reaction was quenched at -78 °C with distilled water (2 mL) and diluted with chloroform (4 mL). The two layers were separated and the aqueous phase was extracted with chloroform (4mLx3). The combined organic layers were washed with brine (2 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (flash gel, 1% -5% ethyl acetate/hexanes) to give the monomer 15 (0.044 g, 0.095 mmol, 80%) with 'H NMR similar to that of subsequent material after HPLC. Further purification by HPLC (silica, 15% ethyl acetate/hexanes, 3.0 mL/min, 264 nm, room temperature = 11.1 min) afforded white solid 10α-(2',7'-dimethoxynaphth-3'-yl)deoxoartemisinin monomer 15: mp = 149.0-151.0°C; [α] D 25 = +246.4° (c = 1.29, CHCI 3 ); 'H NMR (400 MHz, CDC1 3 ) δ 8.39 (d, J= 2.4 Hz, 1 H), 7.67 (d, J= 8.8 Hz, 1 H), 7.62 (d, J= 8.8 Hz, 1 H), 7.05 (d, J= 2.4 Hz, 1 H), 6.99 (dd, J= 8.8, 2.4 Hz, 1 H), 5.69 (d, J= 11.2 Hz, 1 H), 5.50 (s, 1 H), 4.02 (s, 3 H), 3.90 (s, 3 H), 3.38 (m, 1 H), 2.43 (apparent dt, J = 4.0, 14.0 Hz, 1 H), 2.09 (ddd, J = 16.0, 4.0, 2.8 Hz, 1 H), 1.94 (m, I H), 1.82-1.54 (m, 7 H), 1.44 (s, 3 H), 1.35 (m, 1 H), 1.02 (d, J= 6.4 Hz, 3 H), 0.47 (d, J= 7.2 Hz, 3 H); 13 C NMR(100MHz, CDCl 3 )δ 157.8, 155.3, 134.0, 129.52, 129.48, 125.4, 119.3, 116.9, 110.2, 104.6, 104.1, 93.0, 81.3, 70.2, 56.7, 56.1, 52.4, 46.3, 37.4, 36.4, 34.3, 30.4, 26.2, 24.8, 21.3, 20.4, 13.2; IR (CHC1 3 ) 3011, 2930, 2883, 1627, 1248, 1216, 1210, 1043, 784, 768, 748; cm "1 analysis calculated for C 27 H 34 O e : C 71.34, H 7.54, found: C 71.27, H 7.52. EXAMPLE IX Preparation of C-10 Carbon Substituted Monomer 16a of the Present Invention β fluoride VI (0.400 g, 1.40 mmol) and N-methylpyrrole (0.568 g, 7.00 mmol) were dissolved in dry dichloromethane (25 mL) and the solution was cooled to -78 °C. Boron trifluoride diethyl etherate (0.238 g, 0.206 mL, 1.68 mmol) was added slowly by syringe. The reaction was stirred for 30 minutes at -78°C and then the temperature was raised to -40°C. After 5 hours at -40C, the reaction was quenched with distilled water (10 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL x 2). The combined organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by column chromatography (Florisil ® , 10% ethyl acetate/hexanes) to provide the product (0.417 g, 1.20 mmol, 86%) 10α-(N- methylpyrrol-2'-yl)deoxoartemisininmonomer 16a as a white foam: [α] D 25 =+105.8° (c = 1.65, CHC1 3 ); HPLC: silica, 10% ethyl acetate/hexanes, 3 mL/min, 254 nm, Rt = 12.5 min; Η NMR (400 MHz, CDC1 3 ) δ 6.55 (dd, J = 2.0, 2.4 Hz, 1 H), 6.00-5.97 (in, 2 H), 5.39 (s, 1 H), 4.50 (d, J = 11.2 Hz, 1 H), 3.84 (s, 3 H), 2.90-2.78 (m, 1 H), 2.39 (dt, J = 4.0, 14.0 Hz, 1 H), 2.04 (ddd, J= 14.4, 4.8, 2.8 Hz, 1 H), 1.94 - 1.87 (m, 1 H), 1.40 (s, 3 H), 0.99 (d, J = 6.4 Hz, 3 H), 1.80-0.80 (in, 8 H), 0.61 (d, J= 7.2 Hz, 3 H); I3 C NMR (100 MHz, CDCl 3 ) δ 129.6, 123.6, 109.4, 106.0, 104.0, 91.8, 80.6, 72.4, 51.9, 45.8, 37.3, 36.2, 35.0, 34.1, 30.8, 26.0, 24.7, 20.9, 20.3, 14.3; IR (CHC1 3 ) 2927, 1454, 1377, 1321, 1042, 927, 880, 828, 711 cm "1 . EXAMPLE X Preparation of C-10 Carbon-Substituted Monomer 13a of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 0.026 g, 0.090 mmol) and 1,3 -dimethoxybenzene (0.063 g, 0.454 mmol) were dissolved in dry dichloromethane (1 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.013 mL, 0.109 mmol) was added slowly by syringe. After 15 minutes, the reaction was warmed to -40 °C and stirred for 2 hours. Saturated aqueous sodium bicarbonate (1 mL) was added. The solution was extracted with dichloromethane (3 x 2 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, chromatographed on Florisil ( 10% ethyl acetate in hexanes), and then crystallized from pentane to provide 13a (0.026 g, 0.064 mmol, 71%) as a white solid. Mp: 136-138 °C. [α] D 25 = +94.6 (c = 0.67, CHC1 3 ). HPLC: 10:90 ethyl acetate:hexanes, 3 mL/min, 264 nm, R, = 21.6 min. ΗNMR (CHCl 3 , 400 MHz) δ: 7.54 (lH, d, J= 8.4 Hz), 6.54 (IH, dd, J= 2.4, 8.4 Hz), 6.39 (IH, d, J= 2.4 Hz), 5.40 (IH, s), 4.94 (IH, d, J= 10.4 Hz), 3.79 (3H, s), 3.76 (3H, s), 2.45 - 2.58 (IH, in), 2.40 (IH, dt,J = 4.0, 13.6 Hz), 2.03 (IH, ddd,J = 3.2, 5.2, 14.8 Hz), 1.86 - 1.93 (IH, m), 1.42 (3H, s), 1.0 - 1.8 (8H, m), 0.98 (3H, d, J = 6.0 Hz), 0.57 (3H, d, J = 7.6 Hz). 13 C NMR (CHC1 3 , 100 MHz) δ: 159.8, 157.5, 128.6, 122.3, 105.0, 104.0, 97.7, 92.1, 80.7, 69.1, 55.4, 55.3, 52.0, 46.2, 37.4, 36.4, 34.7, 34.3, 26.0, 24.8, 21.6, 20.4, 13.2. IR CHC1 3 : 2933, 1614, 1509, 1378, 1278, 1156, 1128, 1041, 880, 838 cm- 1 . Anal, calcd for C 23 H 32 0 6 : C 68.21, H 7.97, found: C 68.19, H 7.93. EXAMPLE XI Preparation of C-10 Carbon-Substituted Monomer 17a of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 0.386 g, 1.35 mmol) and furan (0.459 g, 6.75 mmol) were dissolved in dry dichloromethane (5 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.020 mL, 0.159 mmol) was added very slowly by syringe. The reaction was warmed to -50 °C and stirred for 4 hours. Saturated aqueous sodium bicarbonate (5 mL) was added. The solution was extracted with dichloromethane (2 x 15 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (1% to 5% ethyl acetate in hexanes) to provide 17a (0.325 g, 0.972 mmol, 72%) as a white solid. Mp: 97-98 °C. [α] D 25 = +72.9 (c = 0.28, CHC1 3 ). HPLC: 20:80 ethyl acetate: hexanes, 3 mL/min, 264 nm, R, = 6.3 min. Η NMR (CDC1 3 , 400 MHz) δ: 7.36 (IH, d, J= 1.2 Hz), 6.28 - 6.30 (2H, m), 5.35 (IH, s), 4.43 (IH, d, J= 10.8 Hz), 2.79 - 2.88 (IH, m), 2.36 (IH, dt, 4.0, 14.0 Hz), 2.00 (IH, dt, J= 3.8, 14.4 Hz), 1.83 - 1.90 (IH, m), 1.67 - 1.76 (2H, m), 1.56 - 1.64 (IH, m), 1.38 (3H, s), 1.20 - 1.55 (3H, m), 0.94 (3H, d, J= 6.4 Hz), 0.8 - 1.1 (2H, m), 0. 60 (3H, d, J= 7.2 Hz). 13 C NMR (CDC1 3 , 100 MHz) δ: 153.1, 142.0, 110.0, 108.3, 104.2, 92.2, 80.3, 71.1, 52.0, 45.7, 37.3, 36.3, 34.1,21.5, 26.1,24.7, 21.3, 20.3, 13.7. IR(CHC1 3 ): 2926, 2872, 1455, 1377, 1196, 1153, 1127, 1100, 1043, 924, 880, 848, 741 cm '1 . Anal, calcd for C 19 H 26 0 5 : C 68.24, H 7.84, found: C 68.38, H 7.80. EXAMPLE Xπ Preparation of C-10 Carbon-Substituted Monomer 18 of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 0.110 g, 0.384 mmol) and thiophene (0.162 g, 1.92 mmol) were dissolved in dry dichloromethane (1 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.071 mL, 0.576 mmol) was added very slowly by syringe. The reaction was warmed to -50 °C and stirred for 4 hours. Saturated aqueous sodium bicarbonate (1 mL) was added. The solution was extracted with dichloromethane (3 2 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (3% ethyl acetate in hexanes) to provide 18 (0.047 g, 0.134 mmol, 35%) as a colorless oil. [α] D 25 = +83.4 (c = 0.54, CHC1 3 ). HPLC: 50:50 dichloromethane:hexanes, 3 mL/min, 235 nm, R t = 7.7 min. Η NMR (CDC1 3 , 400 MHz) δ: 7.25 (IH, dd, J = 1. 2, 5.2 Hz), 7. 00 (IH, dd, J = 1. 2, 3.6 Hz), 6.93 (IH, dd, J= 3.6, 5.2 Hz), 5.40 (IH, s), 4.67 (IH, d, J= 10.8 Hz), 2.58 - 2.67 (IH, m), 2.40 (IH, dt, J = 4.0, 14.0 Hz), 2.04 (IH, ddd, J = 2.8, 4.8, 14.4 Hz), 1.87 - 1.94 (IH, m), 1.71 - 1.80 (2H, m), 1.42 (3H, s), 1.2 - 1.7 (4H, m), 0.98 (3H, d, J= 6.0 Hz), 0.8 - 1.2 (2H, m), 0.64 (3H, d, J= 7.2 Hz) 13 C NMR (CDC1 3 , 100 MHz) δ: 126.0, 125.2, 125.0, 104.3, 92.0, 80.4, 73.9, 51.9, 46.0, 37.4, 36.3, 35.0, 34.2, 26.0, 24.8, 21.5, 20.3, 14.1. IR CHC1 3 ): 2924, 2871, 2360, 1455, 1276, 1196, 1126, 1100, 1056, 927, 880, 830, 695 cm "1 . HRMS (CI,NH 4 + ): m/z calcd for C 19 H 30 NO 4 S : (M+NH 4 + ) 368.1896, found 368.1901. EXAMPLE Xπi Preparation of C-10 Carbon-Substituted Monomer 19 of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 0.038 g, 0.133 mmol) and N-methylindole (0.087 g, 0.664 mmol) were dissolved in dry dichloromethane (2 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.020 mL, 0.159 mmol) was added slowly by syringe. The reaction was warmed to -40 °C and stirred for 4 hours. Saturated aqueous sodium bicarbonate (2 mL) was added. The solution was extracted with dichloromethane (3 x 3 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (15% ethyl acetate in hexanes) to provide 19 (0.038 g, 0.096 mmol, 72%) as a white foam. [α] D 25 = +126.7 (c = 1.06, CHC1 3 ). HPLC: 25:75 ethyl acetate:hexanes, 3 mL/min, 257 nm, R t = 9.3 min. 'HNMR (CHC1 3 , 400 MHz) δ: 8.04 (IH, d, J= 7.6 Hz), 7.26 (IH, d, J = 8.0 Hz), 7.20 (IH, dd, J= 7.2, 8.0 Hz), 7.10 (IH, dd, J= 7.2, 7.6 Hz), 7.02 (IH, s), 5.46 (IH, s), 5.67 (IH, d, J = 10.4 Hz), 3.73 (3H, s), 2.92 - 3.15 (IH, m), 2.43 (IH, dt, J = 4.0, 14.0 Hz), 2.05 (IH, ddd, J = 3.0, 4.8, 14.4 Hz), 1.88 - 1.95 (IH, m), 1.73 - 1.80 (2H, m), 1.42 (3H, s), 0.99 (3H, d, J = 6.0 Hz), 0.8 - 1.6 (6H, m), 0.60 (3H, d, J= 7.2 Hz). 13 C NMR (CDC1 3 , 100 MHz) δ: 137.4, 127.0, 126.5, 121.5, 121.0, 119.0, 114.4, 108.9, 104.2, 92.0, 80.7, 72.3, 52.0, 46.1, 37.4, 36.4, 34.3, 32.6, 26.1, 24.8, 21.2, 20.3, 14.5. IR (CHC1 3 ): 2926, 2871, 1476, 1375, 1128, 1100, 1057, 1042, 880, 741 cm- 1 . Anal, calcd for C 24 H 31 N0 4 : C 72.52, H 7.86, N 3.52, found: C 72.36, H 7.94, N 3.40. EXAMPLE XIV Preparation of C-10 Carbon-Substituted Monomer 20a of the Present Invention l-Chloro-4-ethynylbenzene (0.111 g. 0.810 mmol) was dissolved in dry diethyl ether (1 mL). The solution was cooled to 0 °C . Methyllithium (1.4 M in diethyl ether, 0.550 mL, 0.770 mmol) was added slowly by syringe and the clear solution was stirred at 0 °C for 30 min. Dimethylaluminum chloride (1.0 M in hexanes, 0.770 mL, 0.770 mmol) was added by syringe. The cloudy white suspension was stirred at 0 °C for 2 hours. The solution was cooled to -78 °C and a solution of 1 Oβ-fluoro- 10-deoxoartemisinin (VI, 0.116 g, 0.405 mmol) in dry dichloromethane (10 mL) was added by cannula. Boron trifluoride diethyl etherate (0.060 mL, 0.486 mmol) was immediately added and the reaction was stirred for 15 minutes at -78 °C. The solution was then warmed to -40 °C and stirred for 4 hours. Distilled water (5 mL) was added and the reaction was extracted with dichloromethane (3 x 10 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (10%) ethyl acetate in hexanes) to provide 20a (0.123g, 0.316 mmol, 78%) as a colorless oil. [α] D 25 = +64.5° (c = 1.33, CHC1 3 ). HPLC: 10:90 ethyl acetate:hexanes, 3 mL/min, 264 nm, R t = 12.1 min. Η NMR (CDC1 3 , 400 MHz) δ: 7.23 - 7.38 (4H, m), 5.61 (IH, s), 4.95 (IH, d, J = 5.6 Hz), 2.83 (IH, m), 2.37 (IH, m), 2.45 (3H, s), 1.11 - 2.22 (10H, m), 1.02 (3H, d, J= 7.3 Hz), 0.95 (3H, d, J= 6.2 Hz). 13 C NMR (CDCl j , 100 MHz) δ: 134.4, 132.6, 128.6, 121.1, 104.2, 89.5, 87.9, 87.6, 80.9, 67.8, 52.6, 45.3, 37.4, 36.2, 34.6, 30.3, 26.1, 24.6, 23.0, 20.3, 13.9. IR (CHC1 3 ): 2940, 1488, 1377, 1277, 1 188, 1090, 1052, 1014, 990, 960, 924, 874, 825 cm- 1 . HRMS (CI, NH 4 + ): m/z calcd for C 23 H 31 C1N0 4 (M+NH 4 + ) 420.1942, found 420.1950. EXAMPLE XV Preparation of C-10 Carbon-Substituted Monomer 21 of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 50 mg, 0.175 mmol) and 1,3-diallyloxybenzene (166 mg, 0.873 mmol) were dissolved in dry dichloromethane (10 mL) and the solution was cooled to -78 °C. Boron trifluoride diethyl etherate (30 mg, 0.210 mmol) was added slowly by syringe. The reaction was stirred for 30 minutes at -78 °C and then the temperature was raised to -50 °C. After 7 hours at -50 °C, the reaction was quenched with distilled water (10 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL x 2). The combined organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by column chromatography on Florisil (3 to 5% ethyl acetate in hexanes) to provide the diallyoxy analog 21 (46 mg, 58% yield) as a colorless oil. [α] D 25 = +81.8 (c = 0.81, CHC1 3 ). HPLC: 10:90 ethyl acetate:hexanes, 3 mL/min, 255 nm, R t = 11.2 min. 'H NMR (CDCl 3 , 400 MHz) δ: 7.54 (d, J= 8.4 Hz, 1 H), 6.55 (dd, J= 2.4, 8.4 Hz, 1 H), 6.41 (d, J= 2.4 Hz, 1 H), 5.97-6.10 (m, 2 H), 5.36-5.43 (m, 3 H), 5.23-5.29 (m, 3 H), 5.01 (d, J = 11.0 Hz, 1 H), 4.51 (dt, J = 1.2, 4.8 Hz, 2 H), 4.78 (d, J= 4.8 Hz, 2 H), 2.45-2.55 (m, 1 H), 2.40 (dt, J = 4.0, 14.0 Hz, 1 H), 2.04 (ddd, J= 2.8, 4.8, 14.4 Hz, 1 H), 1.86-1.93 (m, 1 H), 1.70-1.81 (m, 2 H), 1.43 (s, 3 H), 1.0-1.6 (m, 6 H), 0.97 (d, J = 6.4 Hz, 3 H), 0.59 (d, J= 7.2 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 159.8, 157.5, 133.4, 133.3, 128.6, 117.6, 116.6, 106.3, 105.1, 99.6, 92.2, 80.7, 69.2, 68.9, 68.8, 52.0, 46.2, 37.4, 36.3, 35.0, 34.3, 26.0, 24.8, 21.5, 20.3, 13.2. IR (neat): 2925, 1612, 1506, 1377, 1260, 1177, 1128, 1100, 1060, 1041, 928 cm-'. HRMS (El): mlz calcd for C 27 H 36 0 6 : 456.2512, found 456.2518. EXAMPLE XVI Preparation of C-10 Carbon-Substituted Monomer 22 of the Present Invention lOβ-Fluoro-10-deoxoartemisinin (VI, 43 mg, 0.149 mmol) and N-benzylpyrrole (1 17 mg, 0.744 mmol) were dissolved in dry dichloromethane (2 mL) and the solution was cooled to -78 °C. Boron trifluoride diethyl etherate (25 mg, 0.179 mmol) was added slowly by syringe. The temperature was raised to -45 °C. After 4 hours at -45 °C, the reaction was quenched with distilled water (5 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL x 3). The combined organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed on Florisil (10% ethyl acetate in hexanes) to provide the pyrrole 22 (56 mg, 88% yield) as a white solid. Mp: 139-140 °C. [α] D 25 = +56.6 (c = 1.49, CHC1 3 ). HPLC: 10:90 ethyl acetate: hexanes, 3 mL/min, 254 nm, R x = 10.1 min. 'HNMR ^DC^, 400 MHz) δ: 7.13-7.30 (m, 5 H), 6.60 (s, 1 H), 6.06-6.08 (m, 2 H), 5.51 (s, 2 H), 5.36 (s, 1 H), 4.52 (d, J= 11.2 Hz, 1 H), 2.59-2.68 (m, 1 H), 2.35 (dt, J = 4.0, 14.4 Hz, 1 H), 1.96-2.02 (m, 1 H), 1.84-1.89 (m, 1 H), 1.63-1.72 (m, 2 H), 1.21 (s, 3 H), 0.95 (d, J= 6.4 Hz, 3 H), 0.8-1.6 (m, 6 H), 0.48 (d, J= 6.8 Hz, 3 H). 13 C NMR (100 MHz, CDC1 3 ) δ: 139.7, 130.1, 128.3, 126.8, 126.6, 123.4, 109.2, 106.9, 104.1, 91.7, 80.6, 72.6, 51.9, 50.6, 45.8, 37.4, 36.2, 34.1, 31.1, 29.7, 25.724.8, 20.9, 20.3, 14.3. IR(CHC1 3 ): 2922, 1496, 1453, 1377, 1296, 1126, 1054, 927, 879, 713 cm "1 . Anal, calcd for C 26 H 33 N0 4 : C 73.73, H 7.85, N 3.30, found: C 73.18, H 7.76, N 3.21. EXAMPLE XVπ Preparation of C-10 Carbon-Substituted Monomer 23 of the Present Invention Dihydroartemisinin (II-l, 1.00 g, 3.52 mmol) and N-benzylpyrrole (2.76 g, 17.6 mmol) were dissolved in dry dichloromethane (50 mL). The solution was cooled to -50 °C and boron trifluoride diethyl etherate (0.599 g, 0.519 mL, 4.22 mmol) was added slowly by syringe. The reaction was stirred at -50 °C for 4 hours and then quenched with saturated aqueous sodium bicarbonate. The solution was extracted with dichloromethane (3 x 50 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (10 to 20% ethyl acetate in hexanes) to provide the 2-substituted pyrrole 22 (1.064 g, 2.50 mmol, 71% yield) as a white solid and the 3-substituted pyrrole 23 (0.059 g, 0.137 mmol, 4% yield) as a white foam. [α] D 25 = +41.7 (c = 1.25, CHC1 3 ). HPLC: 15:85 ethyl acetate: hexanes, 3 mL/min, 254 nm, R t = 12.7 min. 'H NMR (CDC 1 3 , 400 MHz) δ: 7.26-7.33 (m, 3 H), 7.11-7.13 (m, 2 H), 6.69 (t, J = 2.0 Hz, 1 H), 6.59 (t, J= 2.6 Hz, 1 H), 6.23 (dd, J = 1.6, 2.4 Hz, 1 H), 5.36 (s, 1 H), 5.00 (s, 2 H), 4.34 (d, J = 10.4 Hz, 1 H), 2.53-2.62 (m, 1 H), 2.35 (ddd, J = 4.0, 13.6, 14.4 Hz, 1 H), 2.02 (ddd, J= 2.8, 4.8, 14.4 Hz, 1 H), 1.85-1.91 (m, 1 H), 1.69-1.75 (m, 2 H), 1.34-1.62 (m, 4 H), 1.40 (s, 3 H), 1.24-1.32 (m, 1 H), 0.95-1.10 (m, 1 H), 0.97 (d, J= 6.4 Hz, 3 H), 0.65 (d,J= 7.2 Hz, 3 H). 13 C NMR(100 MHz, CDCl 3 ) δ: 138.2, 128.6, 127.5, 127.0, 124.0, 120.9, 119.6, 107.6, 104.0, 92.0, 80.7, 72.3, 53.3, 52.1, 46.1, 37.4, 36.4, 34.3, 33.7, 26.1, 24.8, 21.4, 20.3, 14.5. IR (CHC1 3 ): 2925, 2870, 1560, 1498, 1453, 1158, 1126, 1100, 1058, 1042, 880, 708 cm- 1 . Anal, calcd for C 26 H 33 N0 4 : C 73.73, H 7.85, N 3.30, found: C 73.64, H 7.80, N 3.32. EXAMPLE XVIH Preparation of C-10 Carbon-Substituted Monomer 24 of the Present Invention Following the procedure for 22, lOβ-fluoro-10-deoxoartemisinin (VI, 50mg,0.176mmol) and N- (ethoxycarbonylmethyl)pyrrole (135 mg, 0.880 mmol) provided the ester 24 (41 mg, 56% yield) as a colorless oil. [α] D 25 = +97.2 (c = 1.61, CHC1 3 ). HPLC: 3:97 ethano hexanes, 3 mL/min, 235 nm, R t = 8.0 min. ΗNMR (CDC1 3 , 400 MHz) δ : 6.59 (dd,J= 1.6, 2.8 Hz, 1 H), 6.07 (dd, J= 2.8, 3.6 Hz, 1 H), 5.99 (dd, J = 1.6, 3.6 Hz, 1 H), 5.44 (d, J= 18.0 Hz, 1 H), 5.36 (s, 1 H), 4.83 (d, J = 18.0 Hz, 1 H), 4.52 (d, J = 11.2 Hz, 1 H), 4.15-4.27 (m, 2 H), 2.55-2.64 (m, 1 H), 2.39 (ddd, J = 4.0, 13.2, 14.4 Hz, 1 H), 2.03 (ddd, J= 2.8, 4.8, 14.4 Hz, 1 H), 1.85-1.92 (m, 1 H), 1.69-1.76 ( , 2 H), 1.40 (s, 3 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.0-1.6 (m, 6 H), 0.97 (d, J= 6.4 Hz, 3 H), 0.61 (d, J= 7.2 Hz, 3 H). 13 C NMR (100 MHz, CDC1 3 ) δ: 170.0, 129.7, 124.0, 109.5, 107.4, 104.3, 91.8, 80.6, 72.8, 61.1, 51.8, 48.9, 45.8, 37.4, 36.2, 34.1, 31.4, 26.0, 24.8, 20.9, 20.3, 14.3, 14.2. IR (neat): 2928, 2872, 1753, 1376, 1300, 1197, 1126, 1099, 1042, 880, 712 cm "1 . HRMS (El): m/z calcd for C 23 H 33 N0 6 S (M + ) 419.2308, found 419.2300. EXAMPLE XIX Preparation of C-10 Carbon-Substituted Monomer 25 of the Present Invention Following the procedure for 22, 10β-fluoro-10-deoxoartemisinin (VI, 50 mg, 0.176 mmol) and N- furfurylpyrrole (129 mg, 0.879 mmol) provided the furfurylpyrrol analog 25 (54 mg, 74% yield) as a white solid. Mp: 135-136 °C. [α] D 25 = +68.5 (c = 1.09, CHC1 3 ). HPLC: 3:97 isopropanol: dichloromethane, 3 mL/min, 235 nm, R t = 5.2 min. Η NMR (CDC1 3 , 400 MHz) δ: 7.32 (dd, J = 0.8, 1.6 Hz, 1 H), 6.67 (dd, J = 2.0, 2.8 Hz, 1 H), 6.27 (dd, J = 2.0, 3.2 Hz, 1 H), 6.22 (dd, J = 0.4, 3.2 Hz, 1 H), 6.00 (dd, J= 2.8, 3.6 Hz, 1 H), 5.96 (dd, J= 2.0, 3.2 Hz, 1 H), 5.60 (d, J= 16.4 Hz, 1 H), 5.38 (s, I H), 5.29 (d, J= 16.4 Hz, 1 H), 4.53 (d, J = 11.6 Hz, 1 H), 2.74-2.84 (m, 1 H), 2.37 (dt, J = 4.0, 14.0 Hz, 1 H), 2.01 (ddd, J= 2.8, 5.0, 14.4 Hz, 1 H), 1.84-1.91 (m, 1 H), 1.66- 1.74 (m, 2 H), 1.34 (s, 3 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.8-1.6 (m, 6 H), 0.51 (d, J= 7.2 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 152.2, 142.1, 129.5, 123.0, 110.2, 109.3, 107.6, 107.0, 104.3, 91.9, 80.8, 72.8, 51.9, 45.9, 43.8, 37.4, 36.3, 34.1, 31.4, 25.9, 24.8, 20.9, 20.3, 14.3. IR (CHC1 3 ): 2926, 2872, 1449, 1377, 1288, 1196, 1150, 1126, 1042, 927, 879, 828, 713 cm- 1 . Anal, calcd for C 24 H 31 N0 5 : C 69.71, H 7.56, N 3.38, found: C 69.88, H 7.66, N 3.32. EXAMPLE XX Preparation of C-10 Carbon-Substituted Monomer 26 of the Present Invention 10β-Fluoro-10-deoxoartemisinin (2, 0.038 g, 0.133 mmol) and N-methylindole (0.087 g, 0.664 mmol) were dissolved in dry dichloromethane (2 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.020 mL, 0.159 mmol) was added slowly by syringe. The reaction was warmed to -40 °C and stirred for 4 hours. Saturated aqueous sodium bicarbonate (2 mL) was added. The solution was extracted with dichloromethane (3 x 3 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (15% ethyl acetate in hexanes) to provide the indole 26 (0.038 g, 0.096 mmol, 72%) as a white foam. [α] D 25 = +126.7 (c = 1.06, CHC1 3 . HPLC: 25:75 ethyl acetate:hexanes, 3 mL/min, 257 nm, R t = 9.3 min. Η NMR (CDC1 3 , 400 MHz) δ: 8.04 (IH, d, J= 7.6 Hz), 7.26 (IH, d, J = 8.0 Hz), 7.20 (IH, dd, J= 7.2, 8.0 Hz), 7.10 (IH, dd, J= 7.2, 7.6 Hz), 7.02 (IH, s), 5.46 (IH, s), 5.67 (IH, d,J= 10.4 Hz), 3.73 (3H, s), 2.92 - 3.15 (IH, m), 2.43 (IH, dt,J= 4.0, 14. 0 Hz), 2.05 (lH, ddd,J = 3.0, 4.8, 14.4 Hz), 1.88 - 1.95 (lH, m), 1.73 - 1.80 (2H, m), 1.42 (3H, s), 0.99 (3H, d, J = 6.0 Hz), 0.8 - 1.6 (6H, m), 0.60 (3H, d, J = 7.2 Hz). 13 C NMR (CDC1 3 , 100 MHz) δ: 137.4, 127.0, 126.5, 121.5, 121.0, 119.0, 114.4, 108.9, 104.2, 92.0, 80.7, 72.3, 52.0, 46.1, 37.4, 36.4, 34.3, 32.6, 26.1, 24.8, 21.2, 20.3, 14.5. IR (CHC1 3 ): 2926, 2871, 1476, 1375, 1128, 1100, 1057, 1042, 880, 741 cm "1 . Anal, calcd for C 24 H 31 N0 4 C 72.52, H 7.86, N 3.52, found: C 72.36, H 7.94, N 3.40. EXAMPLE XXI Preparation of C-10 Carbon-Substituted Monomer 27 of the Present Invention 10β-Fluoro-10-deoxoartemisinin (VI, 50 mg, 0.175 mmol) and 2-methylfuran (72 mg, 0.87 mmol) were dissolved in dry dichloromethane (2 mL). The solution was cooled to -78 °C and boron trifluoride diethyl etherate (0.030 mg, 0.210 mmol) was added very slowly by syringe. The reaction was warmed to -50 °C and stirred for 4 hours. Saturated aqueous sodium bicarbonate (5 mL) was added. The solution was extracted with dichloromethane (2 5 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil (3% ethyl acetate in hexanes) to provide the methylfuran analog 27 (43 mg, 71% yield) as a white solid. Mp: 96.5-98 °C [α] D 25 = +62.4 (c = 2.13, CHC1 3 ). HPLC: 2:98 ethanokhexanes, 3 mL/min, 235 nm, R t = 7.8 min. ] H NMR (CDC1 3 , 400 MHz) δ: 6.19 (d, J= 3.2 Hz, 1 H), 5.88 (d, J= 3.2 Hz, 1 H), 5.36 (s, 1 H), 4.38 (d, J = 11.2 Hz, 1 H), 2.78-2.88 (m, 1 H), 2.37 (ddd, J = 4.0, 14.0, 14.4 Hz, 1 H), 2.27 (s, 3 H), 2.02 (ddd, J= 2.8, 3.2, 14.4 Hz, 1 H), 1.85-1.92 (m, 1 H), 1.68-1.76 (m, 2 H), 1.40 (s, 3 H), 1.0-1.7 (m, 6 H), 0.96 (d, J= 6.0 Hz, 3 H), 0.64 (d, J= 7.2 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 151.7, 151.3, 109.2, 106.0, 104.2, 92.2, 80.4, 71.2, 52.0, 45.8, 37.3, 36.3, 34.1, 31.2, 26.1, 24.7, 21.3, 20.3, 13.9, 13.7. IR (neat): 2924, 2872, 1566, 1452, 1376, 1126, 1099, 1085, 1043, 1020, 880, 784 can -1 . Anal, calcd. for C 20 H 28 O 5 : C 68.84, H 8.10, found: C 69.36, H 8.12. EXAMPLE XXH Preparation of C-10 Carbon-Substituted Monomer 29a of the Present Invention l-Ethynyl-4-fluorobenzene (37 mg, 0.307 mmol) was dissolved in dry diethyl ether ( 1 mL). The solution was cooled to 0 °C. Methyllithium (1.4 M in diethyl ether, 0.199 mL, 0.279 mmol) was added slowly by syringe. After 30 minutes at 0 °C, dimethylaluminum chloride (1.0 M in hexanes, 0.279 mL, 0.279 mmol) was added, leading to a cloudy white suspension. The reaction was stirred for 2 hours at 0 °C. The solution was cooled to -50 °C and 10β-fluoro-10-deoxoartemisinin (VI, 40 mg, 0.140 mmol) in dichloromethane (5 mL) was added very slowly by syringe. Then boron trifluoride diethyl etherate (24 mg, 21 μL, 0.168 mmol) was added by syringe. The reaction was stirred for three hours at -50 °C, and then saturated aqueous sodium bicarbonate (5 mL) was added. The reaction was warmed to room temperature and the aqueous phase was separated and extracted with dichloromethane (3 x 5 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil ( 10% ethyl acetate in hexanes) to provide the alkyne 29a (40 mg, 74% yield) as a colorless oil. [α] D 25 = +77.9 (c = 1.57, CHC1 3 ). HPLC: 10:90 ethyl acetate: hexanes, 3 mL/min, 264 nm, Λ, = 11.5 min. »H NMR (CDC1 3 , 400 MHz) δ: 7.37 (dd, J= 5.6, 8.8 Hz, 2 H), 7.00 (t, J= 8.8 Hz, 2 H), 5.62 (s, 1 H), 4.95 (d, J = 5.6 Hz, 1 H), 2.80-2.88 (m, 1 H), 2.37 (dt, J = 4.0, 13.6 Hz, 1 H), 2.20 (dq, J= 3.6, 14.0 Hz, 1 H), 2.05 (ddd, J= 3.2, 4.8, 14.4 Hz, 1 H), 1.79-1.92 (m, 2 H), 1.68 (dq, J= 3.2, 12.8 Hz, 1 H), 1.44 (s, 3 H), 1.2-1.6 (m, 5 H), 1.03 (d, J= 7.6 Hz, 3 H), 0.95 (d, J = 6.0 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 162.5 (d, J= 248 Hz), 133.3 (d, J = 35 Hz), 118.7, 115.6 (d, J= 22 Hz), 104.3, 89.5, 87.7, 86.5, 80.9, 67.8, 52.6, 45.3, 37.4, 36.2, 34.6, 30.3, 26.1, 24.6, 23.0, 20.3, 13.9. IR (neat): 2941, 1506, 1377, 1228, 1136, 1089, 1051, 990, 874, 839 cm -1 . HRMS (El): m/z calcd for C 24 H 27 F0 4 (M + ) 386.1893, found 386.1897. EXAMPLE XXm Preparation of C-10 Carbon-Substituted Monomer 29b of the Present Invention Following the procedure for 29a, 4-(methylthio)-l-ethynylbenzene (46 mg, 0.307 mmol) and 1 Oβ-fluoro- 10-deoxoartemisinin (VI, 40 mg, 0.140 mmol) provided the product alkyne 29b (11 mg, 19% yield) as a colorless oil and deoxodidehydroartemisinin (23 mg, 62% yield). [α] D 25 = +63.8 (c 0.76, CHC1 3 ). HPLC: 10:90 ethyl acetate: hexanes, 3 mL/minutes, 264 nm, R t = 14.7 minutes. Η NMR (CDC1 3 , 400 MHz) δ: 7.30 (dt, J= 8.8, 2.0 Hz, 2 H), 7.17 (dt, J= 8.8, 2.0 Hz, 2 H), 5.63 (s, 1 H), 4.95 (d, J = 5.6 Hz, 1 H), 2.80-2.88 (m, 1 H), 2.48 (s, 3 H), 2.38 (ddd, J= 14.8, 13.6, 4.0 Hz, 1 H), 2.23 (dq,J = 3.6, 13.6 Hz, 1 H), 2.06 (ddd, J= 2.4, 4.4, 14.0 Hz, 1 H), 1.78-1.92 (m, 2 H), 1.45 (s, 3 H), 1.2-1.7 (m, 3 H), 1.04 (d, J= 7.2 Hz, 3 H), 0.95 (d, J= 6.4 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 139.6, 131.7, 125.8, 118.9, 104.2, 89.5, 88.5, 86.9, 81.0, 67.9, 52.7, 45.4, 37.4, 36.3, 34.6, 30.3, 26.1, 24.6, 23.0, 20.3, 15.4, 14.0. IR (neat): 2922, 1491, 1369, 1188, 1135, 1090, 1050, 990, 924, 874, 821 cm -1 . HRMS (El): m/z calcd for C 24 H 30 O 4 S (M + ) 414.1865, found 414.1868. EXAMPLE XXIV Preparation of C-10 Carbon-Substituted Monomer 30 of the Present Invention 10α-Acetoxy-10-deoxoartemisinin (55 mg, 0.169 mmol) and 2-trimethylsilyloxyfuran (79 mg, 85 μm, 0.506 mmol) were dissolved in dry dichloromethane (2 mL). The solution was cooled to -78 °C and trimethylsilyl triflate (45 mg, 37 μm 0.203 mmol) was added slowly by syringe. The solution turned bright yellow then faded to pale pink. The reaction was warmed to -50 °C and stirred for two hours. The solution was diluted with dichloromethane (5 mL) and saturated aqueous sodium bicarbonate (5 mL), then warmed to room temperature. The aqueous phase was separated and extracted with dichloromethane (3 x 5 mL). The combined organic phase was dried over magnesium sulfate, concentrated under reduced pressure to give a yellow oil, and then chromatographed through Florisil (20% ethyl acetate in hexanes) to provide a mixture of two diastereomers of the lactone 30 (16 mg, 31 % yield of the less polar isomer as a white solid; 32 mg, 63% of the more polar isomer as a color less oil). Less polar isomer: Η NMR (CDC1 3 , 40OMHz) δ: 7.79 (dd, J = 5.6, 1.2 Hz, 1 H), 6.15 (dd, J= 5.6, 1.2 Hz, 1 H), 5.35 (s, 1 H), 5.01 (dt, J = 9.6, 1.6 Hz, 1 H), 4.29 (dd, J= 9.6, 6.0 Hz, 1 H), 2.61-2.70 (m, 1 H), 2.24-2.32 (m, 1 H), 1.94- 2.04 (m, 2 H), 1.80-1.87 (m, 2 H), 1.65-1.72 (m, 1 H), 1.32 (s, 3 H), 1.2-1.4 (m, 5 H), 1.10 (d,J= 7.6 Hz, 3 H), 0.97 (d, J= 5.6 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 173.0, 157.2, 121.5, 102.3, 90.7, 81.5, 72.9, 51.4, 42.9, 37.5, 36.3, 34.1, 29.6, 25.7, 24.88, 24.86, 19.9, 11.8. IR (neat): 2933, 1778, 1752, 1093, 1011 cm- 1 EXAMPLE XXV Preparation of C-10 Carbon-Substituted Monomer 31 of the Present Invention 10α-Acetoxy-I0-deoxoartemisinin (50 mg, 0.153 mmol) was dissolved in dry dichloromethane (10 mL). The solution was cooled to -78 °C. l,3-Bis(trimethylsilyloxy)benzene (195 mg, 0.766 mmol) was added. Then trimethylsilyl trifluoromethanesulfonate (37 mg, 0.168 mmol) was added slowly by syringe. The reaction was warmed to -50 °C and stirred for 5 hours. Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.53 mL, 1.53 mmol) was added by syringe. After 10 minutes, saturated aqueous sodium bicarbonate (5 mL) was added. The aqueous layer was separated and extracted with dichloromethane (3 x 5 mL). The combined organic layer was dried over MgS04, concentrated, and chromatographed on Florisil (15% ethyl acetate in hexanes) to give the phenol 31 (36 mg, 0.099 mmol, 65% yield) as a white solid. Mp: 159-161 °C. [α] D 25 = +134.3 (c = 1.30, CHC1 3 ). Η NMR (CDC1 3 , 400 MHz) δ: 7.11 (t, J= 8.0 Hz, 1 H), 6.65-6.67 (m , 2 H), 6.48 (ddd, J= 8.4, 2.4, 0.8 Hz, 1 H), 5.51 (s, 1 H), 5.46 (d, J = 3.2 Hz, 1 H), 2.75-2.83 (m, 1 H), 2.38 (ddd,J = 4.0, 13.6, 14.8 Hz, 1 H), 1.85-2.06 (m, 4 H), 1.69 (ddd, J= 12.8, 3.6, 3.2 Hz, 1 H), 1.55-1.61 (m, 1 H), 1.2-1.5 (m, 4 H), 1.44 (s, 3 H), 1.00 (d, J= 7.2 Hz, 3 H), 0.96 (d, J= 6.4 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 158.7, 156.7, 130.1, 109.2, 109.1, 104.3, 104.2, 100.5, 88.3, 81.0, 52.5, 44.4, 37.4, 36.3, 34.6, 31.0, 26.0, 24.6, 24.4, 20.3, 12.9. IR (CHC1 3 ): 3450, 2925, 1597, 1281, 1148, 1094, 1034, 981, 875, 757 cm-'. HRMS: (El) calcd for C 21 H 28 0 6 376.1886, found 376.1878. EXAMPLE XXVI Preparation of C-10 Carbon-Substituted Monomer 16e of the Present Invention 10a-(l'-(Ethoxycarbonylmethyl)pyrrol-2'-yl)-10-deoxoartemisinin (24, 28 mg, 0.067 mmol) was dissolved in tetrahydrofuran (5 mL). Distilled water (1 mL) and then lithium hydroxide monohydrate (14 mg, 0.333 mmol) were added. The reaction was stirred for 3 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and diluted with diethyl ether (5 mL). The aqueous layer was separated and extracted with dichloromethane (3 x 5 mL). The combined organic layer was dried over MgS0 4 , concentrated, and chromatographed on Florisil (20% ethyl acetate in hexanes) to give the carboxylic acid 16e (23 mg, 0.059 mmol, 88% yield) as a white foam. Η NMR (CD 3 OD, 400 MHz) δ: 6.59 (t, J= 1.8 Hz, 1 H), 6.05 (dd,J= 3.6, 2.0 Hz, 1 H), 5.96 (t, J = 3.0 Hz, 1 H), 5.45 (s, 1 H), 4.67 (d, J= 17.2 Hz, 1 H), 4.57 (d, J= 17.2 Hz, 1 H), 4.55 (d, J= 10.8 Hz, 1 H), 2.72-2.81 (m, 1 H), 2.30 (dt, J = 4.0, 14.4 Hz, 1 H), 1.98-2.20 (m, 1 H), 1.84-1.92 (m, 1 H), 1.30 (s, 3 H), 1.0- 1.7 (m, 8 H), 0.95 (d, J = 6.0 Hz, 3 H), 0.72 (d, J= 7.2 Hz, 3 H). IR (neat): 3752, 3406, 2926, 1604, 1396, 1310, 1125, 1039 cm- 1 . EXAMPLE XXVII Preparation of C-10 Carbon-Substituted Monomer 33 of the Present Invention 10α-(2'-Furyl)- 10-deoxoartemisinin (17a, 160 mg, 0.478 mmol) was dissolved in acetonitrile (5 mL) and then carbon tetrachloride (3 mL) and distilled water (3 mL) were added. To the heterogeneous mixture was added sodium periodate (1.023 g, 4.78 mmol) and then a catalytic amount of ruthenium dioxide (-6 mg, -0.05 mmol). The reaction mixture was stirred at room temperature and a white precipitate slowly formed. After about 8 hours, the reaction was diluted with dichloromethane (5 mL) and distilled water (5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3 x5 mL). The combined organic layer was filtered through a short plug of Celite to remove the black solid. The filtrate was dried over magnesium sulfate, concentrated, and chromatographed on Florisil to give the carboxylic acid 33 (149 mg, 0.478 mmol, 100%) as a white solid. Mp: 146-149 °C. [α] D 25 = +79.4 {c = 0.70, CHC1 3 ). ΗNMR (CDC1 3 , 400 MHz) δ: 5.36 (s, 1 H), 3.90 (d, J= 10.8 Hz, 1 H), 2.48-2.56 (m, IH), 2.31 (dt, J = 14.0, 3.6 Hz, 1 H), 2.01-2.07 (m, 1 H), 1.87-1.94 (m, 1 H), 1.70-1.76 (m, 1 H), 1.38- 1.56 (m, 4 H), 1.38 (s, 3 H), 1.18-1.30 (m, 1 H), 0.98-1.12 (m, 1 H), 0.97 (d, J= 6.0 Hz, 3 H), 0.86 (d, J= 6.8 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ 53.6, 47.4, 38.5, 37.5, 35.4, 32.2, 26.1, 26.0, 22.6, 20.9, 14.2. IR (CHC1 3 ): 3443, 2927, 1603, 1444, 1379, 1195, 1129, 1087, 1043, 912, 878, 732 cm "1 . HRMS (El): m/z calcd for C 16 H 26 N0 5 (M-H 2 0+NH 4 + ) 312.1811, found 312.1818. EXAMPLE XXVm Preparation of C-10 Carbon-Substituted Monomer 34 of the Present Invention The carboxylic acid 33 (23 mg, 0.074 mmol), potassium carbonate (20 mg, 0.147 mmol), and benzyl bromide (25 mg, 0.147 mmol) were dissolved in dry N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with diethyl ether (2 mL) and distilled water (3 mL). The aqueous layer was separated and extracted with diethyl ether (3 x 5 mL). The combined organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and then chromatographed through Florisil ( 10% ethyl acetate in hexanes) to provide the ester 34 (20 mg, 67% yield) as a white solid. Mp: 84-86 °C. [α] D 25 = +52.5 (c = 1.21, CHC1 3 ). HPLC: 15:85 ethyl acetate: hexanes, 3 mL/minutes, 254 nm, R t 3.4 minutes. Η NMR (CDC1 3 , 400 MHz) δ: 7.28-7.40 (m, 5 H), 5.27 (s, 1 H), 5.23 (d, J= 12.8 Hz, 1 H), 5.18 (d,J= 12.8 Hz, 1 H), 4.06 (d, J= 11.2 Hz, 1 H), 2.68- 2.77 (m, 1 H), 2.37 (ddd, J = 4.0, 13.6, 14.8 Hz, 1 H), 2.03 (ddd, J= 2.8, 4.8, 14.4 Hz, 1 H), 1.85-1.91 (m, 1 H), 1.68-1.73 (m, 2 H), 1.52-1.59 (m, 1 H), 1.44 (s, 3 H), 1.21-1.50 (m, 4 H), 0.98-1.08 m, 1 H), 0.95 (d, J= 6.4 Hz, 3 H), 0.75 (d, J= 7.2 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 169.7, 135.6, 128.5, 128.3, 128.2, 104.3, 91.9, 79.9, 75.6, 66.5, 51.9, 45.5, 37.2, 36.1, 33.9, 30.5, 25.9, 24.6, 21.2, 20.2, 13.0. IR (CHC1 3 ): 2926, 1752, 1456, 1376, 1280, 1183, 1088, 1048, 879 cm "1 . EXAMPLE XXIX Preparation of C-10 Carbon-Substituted Dimer 46 of the Present Invention The carboxylic acid 34 (21 mg, 0.067 mmol), potassium carbonate (19 mg, 0.134 mmol), and 1,4- di(bromomethyl)benzene (9 mg, 0.034 mmol) were dissolved in dry N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with diethyl ether (2 mL) and distilled water (3 mL). The aqueous layer was separated and extracted with diethyl ether (3 x 5 mL). The combined organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and then chromatographed through Florisil (20% ethyl acetate in hexanes) to provide the diester 46 (20 mg, 67% yield) as a colorless oil. [α] D 25 = +58.5 (c = 0.86, CHC1 3 ). HPLC: 30:70 ethyl acetate: hexanes, 3 mL/min, 254 nm, R t = 12.1 min. 'HNMR (CDC1 3 , 400 MHz) δ: 7.38 (s, 4 H), 5.27 (s, 2 H), 5.21 (d, J= 12.0 Hz, 2 H), 5.18 (d, J 12.0 Hz, 2 H), 4.06 (d, J = 10.8 Hz, 2 H), 2.67-2.76 (m, 2 H), 2.38 (ddd, J = 4.0, 13.6, 14.4 Hz, 2 H), 2.03 (ddd, J= 2.8, 4.8, 14.4 Hz, 2 H), 1.85-1.92 (m, 2 H), 1.66-1.74 (m, 4 H), 1.4-1.6 (m, 4 H), 1.44 (s, 6 H), 1.2- 1.4 (m, 6 H), 0.95- 1.08 m, 2 H), 0.96 (d, J = 6.0 Hz, 6 H), 0.74 (d, J= 7.2 Hz, 6 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 169.6, 135.6, 128.4, 104.4, 91.9, 80.0, 75.6, 66.1, 51.9, 45.5, 37.2, 36.1, 33.9, 30.5, 25.9, 24.6, 21.3, 20.2, 13.0. IR(CHC1 3 ): 2926, 1752, 1456, 1376, 1180, 1088, 1048 cm- 1 EXAMPLE XXX Preparation of C-10 Carbon-Substituted Trimer 49 of the Present Invention The carboxylic acid 34 (37 mg, 0.118 mmol), potassium carbonate (82 mg, 0.592 mmol), 1,3,5- tri(bromomethyl)benzene (14 mg, 0.0395 mmol), and tetrabutylammonium iodide (4 mg, 0.012 mmol) were dissolved in dry N,N-dimethylformamide (2 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with diethyl ether (2 mL) and distilled water (3 mL). The aqueous layer was separated and extracted with diethyl ether (3 x 5 mL). The combined organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and then chromatographed through Florisil (40% ethyl acetate in hexanes) to provide the triester 49 (28 mg, 69% yield) as a colorless oil. HPLC: 40:60 ethyl acetate: hexanes, 3 mL/min, 254 nm, R t = 8.9 min. Η NMR (CDC1 3 , 400 MHz) δ: 7.36 (s, 3 H), 5.29 (s, 3 H), 5.21 (d, J = 12.0 Hz, 3 H), 5.14 (d, J= 12.0 Hz, 3 H), 4.08 (d, J = 11.2 Hz, 3 H), 2.64-2.76 (m, 3 H), 2.38 (ddd, J = 4.0, 13.6, 14.4 Hz, 3 H), 2.00 (ddd, J= 2.8, 4.8, 14.4 Hz, 3 H), 1.88-1.94 (m, 3 H), 1.66-1.74 (m, 6 H), 1.4-1.6 (m, 6 H), 1.44 (s, 9 H), 1.2-1.4 (m, 9 H), 0.95-1.08 (m, 3 H), 0.95 (d, J= 6.0 Hz, 9 H), 0.76 (d, J= 7.2 Hz, 9 H). IR (CHC1 3 ): 2926, 1752, 1456, 1376, 1180, 1088, 1048 cm- 1 . EXAMPLE XXXI Preparation of C-10 Carbon-Substituted Dimer 47 of the Present Invention 10α-(2'-Furyl)- 10-deoxoartemisinin (22 mg, 0.066 mmol) and 1 Oβ-fluoro- 10-deoxo-artemisinin ( 19 mg, 0.066 mmol) were dissolved in dry dichloromethane (1 mL) and the solution was cooled to -78 °C. Boron trifluoride diethyl etherate (11 mg, 10 μL, 0.079 mmol) was added and the reaction was warmed to -50 °C for 4 hours. Saturated aqueous sodium bicarbonate (1 mL) was added. The solution was extracted with dichloromethane (3 x 2 mL). The combined organic solution was dried with magnesium sulfate, concentrated under vacuum, and chromatographed on Florisil to provide the dimer 47 (22 mg, 56% yield) as a white foam. [α] D 25 = +56.8 (c = 1.20, CHC1 3 ). HPLC: 1 :99 isopropanol: dichloromethane, 3 mL/min, 236 nm, R t 5.0 min. 'H NMR (CDC1 3 , 400 MHz) δ: 6.33 (s, 2 H), 5.35 (s, 2 H), 4.46 (d, J = 10.8 Hz, 2 H), 2.70-2.80 (m, 2 H), 2.37 (ddd, J= 14.4, 13.6, 4.0 Hz, 2 H), 2.01 (ddd, J = 14.4, 4.8, 2.8 Hz, 2 H), 1.84-1.91 (m, 2 H), 1.70-1.75 (m, 4 H), 1.40 (s, 6 H), 1.0-1.6 (m, 12 H), 0.96 (d, J= 6.0 Hz, 6 H), 0.66 (d,J= 7.2 Hz, 6 H). 13 CNMR(CDC1 3 , 100 MHz) δ: 152.9, 108.6, 104.1, 92.1, 80.4, 71.2, 52.0, 45.9, 37.3, 36.3, 34.1, 32.0, 26.0, 24.7, 21.3, 20.3, 13.8. IR(CHC1 3 ): 2926, 2873, 1452, 1377, 1197, 1127, 1042, 926, 879, 754 cm- 1 . EXAMPLE XXXH Preparation of C-10 Carbon-Substituted Dimer 48 of the Present Invention 10-( 1 '-Methylpyrrol-2'-yl)- 10-deoxoartemisinin ( 16, 45 mg, 0.130 mmol) and benzaldehyde (7 mg, 0.065 mmol) were dissolved in tetrahydrofuran (2 mL). Hydrochloric acid (cone, one drop) was added. The reaction was stirred overnight at room temperature, with the color gradually becoming dark purple. Saturated aqueous sodium bicarbonate (5 mL) and diethyl ether (5 mL) were added. The aqueous phase was extracted with diethyl ether (3 x 5 mL). The combined organic phase was dried over magnesium sulfate and concentrated to a brown oil that was chromatographed over Florisil (5% to 20% ethyl acetate in hexanes) to provide the dimer 48 (25 mg, 49% yield, 63% based on recovered starting material) as a white solid and the starting material (7 mg, 16% recovery). Mp: 130-135 °C. [α] D 25 = +43.0 (c = 0.56, CHC1 3 ). HPLC: 15:85 ethyl acetate: hexanes, 3 mL/min, 254 nm, R t = 11.5 minutes. ΗNMR (CDC1 3 , 400 MHz) δ: 7.06-7.25 (m, 5 H), 5.86 (d, J= 3.6 Hz, 1 H), 5.83 (d, J= 3.6 Hz, 1 H), 5.35 (s, 3 H), 5.21 (d, J = 3.6 Hz, 1 H), 5.19 (s, 1 H), 4.45 (d, J= 2.8 Hz, 1 H), 4.42 (d, J= 2.8 Hz, 1 H), 3.63 (s, 3 H), 3.50 (s, 3 H), 2.81-2.86 (m, 1 H), 2.69-2.74 (m, 1 H), 2.29-2.39 (m, 2 H), 1.97-2.02 (m, 2 H), 1.82-1.89 (m, 2 H), 1.64-1.75 (m, 4 H), 1.4-1.6 (m, 8 H), 1.36 (s, 3 H), 1.35 (s, 3 H), 0.95 (d, J= 6.4 Hz, 3 H), 0.93 (d, J= 6.4 Hz, 3 H), 0.8-1.3 (m, 4 H), 0.56 (d, J= 7.2 Hz, 3 H), 0.52 (d, J= 7.2 Hz, 3 H). 13 C NMR (CDC1 3 , 100 MHz) δ: 141.6, 135.9, 135.2, 129.9, 129.5, 128.9, 128.1, 126.3, 108.5, 108.2, 107.5, 107.1, 104.1, 91.9, 91.9, 80.7, 80.6, 73.2, 72.9, 52.0, 51.9, 45.9, 42.2, 37.4, 36.3, 34.2, 31.9, 31.8, 30.9, 30.7, 26.0, 25.9, 24.7, 20.8, 20.3, 14.5, 14.4. IR(CHC1 3 ): 2926, 2872, 1458, 1377, 1197, 1126, 1100, 1041, 926, 755 cm 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.

Claims: Claims The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 1. An artemisinin compound of formula: and the enantiomers and diastereomers thereof, wherein: a.) n is 1, and R is selected from the group consisting ofan unsubstituted or substituted aryl, heteroaryl, acetylenic, polyethylene glycol, aroylmethylene, or alkanoylmethylene group; or b.) n is 2, and R is selected from the group consisting ofan unsubstitued or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group; or c.) n is 3, and R is selected from the group consisting ofan unsubstitued or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group. 2. The compound according to claim 1, wherein n is 1 and R is selected from the group consisting of: wherein R' is Me, R' is allyl, R' is C-COOH, or R' is -OH; wherein R' is Me, R' PhCH 2 , R' is is EtOOCCH 5 , R' is C-COOH, R' is Benzene; wherein R' is H, R' is Me, R' is Et, R' is t-butyl; wherein R' is CI, R' is F, R' is SMe; 2, 4-di(allyoxy)phenyl; l-benzyl-2-pyrrolyl; l-benzyl-3-pyrrolyl; 1 -(ethoxycarbonylmethyl)-2-pyrrolyl; 1 -furfuryl-2-pyrrolyl; 1 -methyl-3-indolyl; 5-methyl-2-furyl; 2-thienyl; 5 C^= R/ wherein R' is 4-fluorophenyl, R' is 4-(thiomethyl)phenyl; 2, 5-dihydro-5-oxo- 2-furyl; 2, 4-dihydroxyphenyl; COOH; or wherein 1 designates the point of attachment. 3. The compound according to claim 1, wherein n is 2 and R is selected from the group consisting of: or wherein, x is 0 - 2. 4. The compound according to claim 1, wherein n is 3 and R is selected from the group consisting of R is a linker such as an unsubstituted or substituted alkyl, alkenyl, aryl, heteroaryl, polyethylene glycol, diketone, or a bis-acetylene group. 5. The compound according to claim 4, wherein R is 6. A compound useful for the production of C-10 carbon-substituted trioxanes or entantiomers thereof comprising: 7. A method for treating cancer, which comprises administering to a patient suffering from said cancer a C-10 carbon-substituted trioxane of the formula: and the enantiomers and diastereomers thereof, wherein: a.) n is 1, and R is selected from the group consisting of an unsubstituted or substituted aryl, heteroaryl, acetylenic, polyethylene glycol, aroylmethyl or alkanoylmethylene group; b.) n is 2, and R is selected from the group consisting of an unsubstituted or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group; or c.) n is 3, and R is selected from the group consisting of an unsubstitued or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group. 8. The method according to claim 7, wherein n is 1 and R is selected from the group consisting of: wherein R' is Me, R' is allyl, R' is C-COOH, or R' is -OH; wherein R' is Me, R' is PhCH 2 , R' is R' is EtOOCCH 5 , R' is C-COOH, R' is Benzene; wherein R' is H, R' is Me, R' is Et, R' is t-butyl; ; wherein R' is C1, R' is F, R' is SMe; 2, 4-di(allyoxy)phenyl; l-benzyl-2-pyrrolyl; l-benzyl-3-pyrrolyl; l-(ethoxycarbonylmethyl)-2-pyrrolyl;l-furfuryl-2-pyrrolyl; l-methyl-3-indolyl; 5-methyl-2-furyl; 2-thienyl;> C = ^ = R wherein R' is 4-fluorophenyl, R' is 4-(thiomethyl)phenyl; 2, 5-dihydro- wherein i designates the point of attachment. 9. The method according to claim 7, wherein n is 2 and R is selected from the group consisting of: 10. The compound according to claim 4, wherein R is 11. The method according to claim 7, wherein said cancer is selected from the group of cancers consisting of leukemia, non-small-cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. 12. The method according to claim 8, wherein said cancer is selected from the group of cancers consisting of leukemia, non-small-cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. 13. The method according to claim 9, wherein said cancer is selected from the group of cancers consisting of leukemia, non-small-cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. 11. A method for treating malaria, which comprises administering to a patient suffering from said malaria a C-10 carbon-substituted trioxane of the formula: and the enantiomers and diastereomers thereof, wherein: a.) n is 1, and R is selected from the group consisting of an unsubstituted or substituted aryl, heteroaryl, acetylenic, polyethylene glycol, aroy methylene, or alkanoylmethylene group; or b.) n is 2, and R is selected from the group consisting of an unsubstituted or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group; or c.) n is 3, and R is selected from the group consisting of an unsubstitued or substituted aryl, heteroaryl, alkenyl, alkyl, diketone, polyethylene glycol, or bis-acetylene group. 15. The method according to claim 14, wherein n is 1 and R is selected from the group consisting of: or wherein I designates the point of attachment. 16. A process for converting the pyranose anomeric 10-OH group in dihydroartemesinin with a carbon nucleophile comprising the steps of: contacting dihydroartemisinin with diethylaminosulfur trifluoride to produce β pyranosyl fluoride; purifying said β pyranosyl fluoride; and reacting said β pyranosyl fluoride with a carbon nucleophile. 17. A process for converting the pyranose anomeric 10-OH group in dihydroartemesinin with a carbon nucleophile comprising the step of: contacting dihydroartemisinin with an electron-rich aromatic or heteroaromatic nucleophile. 18. A process for converting the pyranose anomeric 10-OH group in dihydroartemesinin with a carbon nucleophile comprising the step of: contacting dihydroartemisinin with alcohol under acidic conditions to produce the corresponding C- 10 ether; reacting said C- 10 ether with an enol derivative. 19. The process according to claim 18,wherein said enol derivative is bis-enol silyl ether. 20. The process according to claim 18,wherein said enol derivative is mono-enol silyl ether. 21. The process according to claim 18, wherein said alcohol is methanol and said corresponding C- 10 ether is artm ether. 22. The process according to claim 18, wherein said alcohol is ethanol and said corresponding C-10 ether is arteether. 23. A process for converting the 10-OMe group in artemether with a carbon nucleophile comprising the step of: reacting artemether with an enol derivative. 24. The method according to claim 21, wherein said enol derivative is bis-enol silyl ether. 25. The method according to claim 21 ,wherein said enol derivative is mono-enol silyl ether. 26. A mehtod of treating cancer , which comprises administering to a patient suffering from said cancer a compound of formula: 27. The method according to claim 26, wherein said cancer is selected from the group of cancers consisting of leukemia, non-small-cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.

Inventors: DAUGHENBAUGH RANDALL J, ELIAS JEFFREY S, MURRAY CHRISTOPHER, NORTHRUP JOHN, PARKER MICHAEL H, PLOYPRADITH POONSAKDI, POSNER GARY H, SHAPIRO THERESA A, WOO SOON HYUNG, ZHENG QUN Y, DAUGHENBAUGH, RANDALL, J., ELIAS, JEFFREY, S., MURRAY, CHRISTOPHER, NORTHRUP, JOHN, PARKER, MICHAEL, H., PLOYPRADITH, POONSAKDI, POSNER, GARY, H., SHAPIRO, THERESA, A., WOO, SOON, HYUNG, ZHENG, QUN, Y.
Applicants: HAUSER INC, UNIV JOHNS HOPKINS, HAUSER, INC., JOHN HOPKINS UNIVERSITY
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, A61K33, A61P35, C07D493, C07D519, C07F7, C07F17