WO1988004660A2 - Synthesis process and oxygen-containing heterocyclic products thereof - Google Patents

Abstract

A process for synthesizing oxygen-containing analogs of the antimalarial agent known as quinghaosu or artemisinin, and in particular compounds of formulae (I) and (II). The process employs as a reactant a vinylsilane that is subjected to an ozonolysis/acidification step which closes the oxygen-containing ring structure. The various products are claimed as aspects of this invention as is their use as antimalarials.

Description

SYNTHESIS PROCESS AND OXYGEN-CONTAINING

HETEROCYCLIC PRODUCTS THEREOF

This invention was made during the course of work on a United States Government contract issued by the Department of the Army (DAMD - 1785-C-5011). The United States Government may hold rights under this patent.

Background of the Invention 1. Field of the Invention

This invention is in the field of organic chemistry. More particularly it relates to a process for the synthesis of oxygen-containing heterocyclic organic compounds and to materials formed by this process. In one application, this process is used to prepare the antimalarial agent qinghaosu (artemisinin) and a variety of analogs.

2. Background References

One key step of the present process is the ozonolysis of a vinylsilane to introduce an oxygen functionality. A reference which involves ozonolysis of a vinylsilane and can lead to an alpha-hydroxyperoxy aldehyde is that of George Buchi, et al., Journal of the American Chemical Society, Vol 100, 294 (1978). This reference illustrates this reaction but in different settings. Another reference is by R. Ireland et al., Journal of the American Chemical Society, Vol 106, 3668 (1984), which relates to silylation.

In another aspect, this invention employs unsaturated bicyclic ketones as reactants. References relating to such materials and to methods for forming some of them include W. Clark Still, Synthesis, Number 7, 453-4 (1976); Kazuo Taguchi et al., Journal of the American Chemical Society. Vol. 95, 7313-8 (1973); and E.W. Warnhoff et al., Journal of Organic Synthesis, Vol 32, 2664-69 (1967).

Other art of interest to the present invention relates to the antimalarial natural product, qinghaosu. The antimalarial qinghaosu has been used in China in the form of crude plant products since at least 168 B.C.

Over the last twenty years, there has been an extensive interest in this material. This has led to an elucidation of its structure as

The modern chemical name is artemisinin.

The carbons in the artemisinin structure have been numbered as set forth above. When reference is made to a particular location in a compound of this general type, it will, whenever possible, be based on this numbering system. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having dif ferent bridge-length structures in which these carbons would properly be otherwise numbered.

Some of the present products are seco analogs, that is, the 1,2,3,4-ring structure seen in artemisinin is not closed in such compounds. However, again, the artemisinin numbering will be used with these seco analogs.

References to artemisinin and derivatives include the May 31, 1985 review article by Daniel L.

Klayman appearing in Science, Vol 228, 1049, (1985); and the article appearing in the Chinese Medical Journal, Vol 92, No. 12, 811 (1979). Two syntheses of artemisinin have been reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, Vol 58 (5), 817, (1986); and by G. Schmid et al, Journal of the American Chemical Society, Vol 105, 624 (1983). Neither of these syntheses employs ozonolysis.

The interest in artemisinin has prompted a desire for an effective and efficient method for synthesis of the material and its analogs (including radio-labeled analogs). This invention satisfies this need.

Statement of the Invention

A new process for synthesizing multiple ring compounds having a plurality of ring oxygens has now been discovered. This process involves the ozonolysis of a vinylsilane with resulting formation of the desired multiple ring material.

In one embodiment, the process is directed to the preparation of polyoxa tetracyclic compounds such as artemisinin of the following General Formula I.

General Formula I. in General Formula I., X is a heteroatom bridge selected from -O-, -S-, and R₁ is an organic

bridge which can be a methylene (-CH₂-) unit or a two or three carbon atom long chain with or without substituents; R₂ is an organic bridge which can be a covalent single bond or a methylene unit through five carbon atom long chain with or without substituents; R₃ is an organic bridge which can be a methylene unit through three carbon chain with or without substituents; R₄ is a hydrogen or an alkyl group, with or without substituents; R₅ and R₆ can together be a carbonyl oxygen or R₅ can be a hydrogen, an alkyl or a substituted alkyl while R₆ is a hydrogen, a hydroxyl, an alkyl ether, a carboxylic ester, a carbonate, a carbamate, an amide, or a urea, and R₁₀ is a hydrogen or an alkyl or aryl with or without substituents.

The synthesis process of this invention when used to prepare the tetracycles of General Formula I includes subjecting to ozonolysis a vinylsilane compound of General Formula II.

General Formula II. In General Formula II., R₁ through R₆ and X are as defined with the polyoxa tetracyclic compounds of General Formula I and R₇, R₈ and R₉ are independently selected from lower hydrocarbyls. in one specific aspect, this invention provides a method for synthesizing artemisinin by ozonolysis of the vinylsilane

The process of this invention can also be applied to prepare seco analogs of artemisinin which substantially retain the activity of the more complicated parent compound. These analogs have the structure shown in General Formula III.

General Formula III.

In General Formula III., R¹ and R² are independently hydrogen, methyl or α-unsubstituted organic moieties containing up to about 12 carbon atoms, with the total size of R¹ plus R² being not greater than about 20 carbons; R⁶ is hydrogen, alkyl, or a substituted alkyl while R⁷ is hydrogen, hydroxyl, alkyl ethers, carboxylic ester, carbonate, carbamate, amide, or urea or R⁶ and R⁷ together form a carbonyl oxygen; R⁸ and R⁹ are independently hydrogen, alkyl, or substituted alkyl or R⁸ and R⁹ together form an organic ring; and R¹⁰ and R^{1 1} are independently hydrogen or organic groups.

These seco materials can be prepared by the process described above, which involves ozonolysis of a vinylsilane and acid-catalyzed condensation of the hydroperoxide compound which result with a carbonyl (aldehyde or ketone). This process involves a. subjecting a vinylsilane of General Formula IV to ozonolysis to yield a hydroperoxide of General Formula V, and

General Formula IV. General Formula V. b. reacting the hydroperoxide of Formula V. and a carbonyl of General Formula VI. in the presence of an acid catalyst to yield the desired seco analog.

General Formula VI. In a further embodiment the vinylsilane itself is a bridged (bicyclic) material of General Formula VII. dervied from a bicyclic bridging ketone of General Formula VIII. having non-enolizable bridgehead moieties for both of its alpha positions.

General Formula VII. General Formula VIII.

In these formulas m is an integer - either 0 or 1; n is an integer - either 0, 1, 2, 3, or 4; and the various R's are each independently selected from hydrogens, alkyls and substituted alkyls. This vinylsilane is subjected to ozonolytic cleavage of its olefinic bond to yield a member of a family of unique carboxyl/carbonyl-substituted vinylsilanes which may in turn optionally be subjected to a wide range of reactions prior to a final ozonolysis/acidification step which closes the oxygen-containing ring structure. This variation of the process can yield desired artemisinin analogs and the like in several fewer steps. It can yield artemisinin analogs not easily obtainable otherwise. The process is also characterized by permitting control of the stereochemistry of the "1", "4", "5", "6", and "7" centers (as these positions are defined in artemisinin).

This embodiment of the invention offers additional versatility in that its intermediates can be protected and modified by alkylation or chain extension techniques so as to yield as ultimate products artemisinin analog tetracycles represented by General Formula IX.

General Formula IX. In this formula, X and Y together can equal a carbonyl oxygen or X can be hydrogen, while Y is selected from hydrogen, hydroxyl, or alkyl ethers; carboxylic esters; carbonates, carbamates, amides and ureas; m is 0 or 1, n is 0, 1, 2, 3 or 4, p is 0, 1 or 2 with the sum of m plus p equal to 0, 1 or 2, and the R's are independently hydrogen, lower alkyl or substituted lower alkyl.

In other aspects, this invention provides antimalarial pharmaceutical compositions incorporating the oxygen-substituted products set forth above.

Detailed Description of the Invention Brief Description of the Drawings

In the drawings:

Figure 1 is a flow diagram showing the total synthesis of an artemisinin analog,

Figure 2 is a flow diagram showing a total synthesis of artemisinin,

Figures 3, 4, and 5 are each a flow diagram showing routes to artemisinin analogs,

Figure 6 is a flow diagram for preparing seco compounds,

Figure 7 is a flow diagram for introducing substituents into the seco compounds,

Figures 8 and 9 are each a flow diagram for preparing artemisinin analogs using vinylsilanes of ketones with nonenolizable bridgeheads.

Description of Preferred Embodiments

In accord with this invention, polyoxa artemisinin analog compounds are prepared by ozonolysis of vinylsilanes. These artemisinin analog compounds can be tetracycles of General Formula I., seco analogs of General Formula III. or bridgehead-substituted analogs of General Formula IX., depending upon the particular materials upon which the ozonolysis is carried out. In defining the groups represented by the various X's, R's in these General Formulas and likewise in General Formulas II. and IV-VIII., reference is made to the possibility of "substituting" these groups. The limits of this possible substituting can be spelled out in functional terms as follows: A possible substituent is a chemical group, structure or moiety which, when present in the compounds of this invention, does not substantially interfere with the preparation of the compounds or which does not substantially interfere with subsequent reactions of the compounds. Thus, suitable substituents include groups that are substantially inert at the various reaction conditions presented after their introduction such as the ozonolysis and acidification. Suitable substituents can also include groups which are predictably reactive at the conditions to which they are exposed so as to reproducably give rise to desired moieties.

These possible substituents will from time to time be referred to as R* such that R₁, R₂ or the like will be described as including one or more R* substituents. R* can be any substituent meeting the above functional definition. Common R* groups include saturated aliphatic groups including linear and branched alkyls of 1 to 20 carbon atoms such as methyl, ethyl isopropyl, n-butyl, t-butyl, the hexyls including cyclohexyl, decyl, hexadecyl, eicosyl, and the like. R* can also include aromatic groups generally having from 1 to 20 aromatic carbon atoms; for example aryls such as quinolines, pyridines, phenyls, naphthyls, and aralkyls of up to about 20 total carbon atoms such as benzyls, phenylethyls and the like, and alkaryls of up to about 20 total carbon atoms such as the xylyls, ethylphenyls and the like. These various hydrocarbon structures of the R* substituents may themselves include olefinic carbon-carbon double bonds, subject to the understanding that the ozonolysis may attack and oxidatively cleave this unsaturation if it is present during that reaction, amides, sulfonates, carbonyls, carboxyls, alcohols, esters, ethers, sulfonamides, carbamates, phosphates, carbonates, sulfides, sulfhydryls, sulfoxides, sulfones, nitro, nitroso, amino, imino, oximino, *a*, B-unsaturated variations of the above, and the like, subject to the understanding that many of these functional groups may be subject to attack during the overall reaction sequence and thus may need to be appropriately protected. They can then be deprotected at some later stage as desired. In General Formula I.,

R₁ is an organic covalent bridge joining the "7" and "12" carbon atoms. The R₁ bridge can be a methylene (-CH₂-) unit or a two or three carbon atom long alkylene chain, (-CH₂-CH₂-, or -CH₂-CH₂-CH₂-) with or without R* substituents. When R₁ is substituted, the substituents replace hydrogens. Preferably, R₁ is a one or two carbon alkylene, with up to two lower alkyl R* substituents. The term "lower" when used as a qualifier of organic group size means from one to ten carbons. More preferably R₁ is a one carbon alkylene, especially with a lower alkyl substituent, e.g., methyl.

The R₂ bridge can be a covalent single bond between the "1" and "7" carbons or a one carbon atom through five carbon atom long alkylene chain, that is a -(CH₂)n=1-5-, between these two carbons with or without R* substituents. More preferred R₂ groups are three through five carbon atom long alkylene bridges having from zero through two alkyl substituents. R₃ is a one carbon atom through three carbon atom long alkylene chain, between the "1" and "4" carbons. The carbon atom of the R₃ chain which is adjacent to the "4" carbon can be substituted with one or two R* groups when R₃ is two or three carbon atoms long. Preferred R* groups for substituenting R₃ are lower alklys. Preferred R₃ groups are the one or two carbon atom long alkylenes with two carbon atom long alkylenes being most preferred.

R₄ is a hydrogen, a methyl or a methyl substituted with an R*. Methyl and methyl substituted with a lower alkyl are preferred with methyl being most preferred.

R₅ and R ₆ can together be a carbonyl oxygen attached to the "12" carbon position. Alternatively, R₅ can be a hydrogen, a methyl or an R*-substituted methyl while R₆ is a hydrogen, a hydroxyl, an alkyl—preferably lower alkyl—ether, an ester formed by the hydroxyl with a carboxylic acid of the formula HOOC-CH₃ or HOOC-CH₂R* (i.e., acetic acid or a substituted acetic acid), a carbonate, a carbamate, an amide, or a urea. Carbonyl is preferred. When R₆ is hydroxyl, hydrogen, methyl and lower alkyl-substituted methyl are preferred R₅ groups.

X is a heteroatom bridge selected from -O-, -S-, and R₁₀ is hydrogen or R*. The preferred

X groups are -O-, -S-, and wherein

R₁₀ is a lower alkyl. The most preferred X is -O-.

The vinylsilanes from which the Formula I. polyoxa tetracyclics are prepared are represented by

General Formula II. In General Formula II., R₁ through

R₄ and X have the meanings set forth above with reference to General Formula I., R₅ and R₆ are a carbonyl oxygen and R₇, R₈ and R₉ are lower hydrocarbyls. Typical hydrocarbyls for this application are lower alkyls, aryls, alkaryls and aralkyls. In selecting these three R's, generally two or three of them are methyls. Typical silyl groups include trimethyl silyl, t-butyl dimethyl silyl and phenyldimethyl silyl.

When the Formula II. vinylsilanes are subjected to ozonolysis, two transitory primary ozonide and dioxetane intermediates are formed,

In the seco analog compounds of General Formula III., R¹ and R² are independently selected from hydrogens, methyls and alpha-unsubstituted organic moieties containing up to about 12 carbon atoms subject to the proviso that the total size of R¹ and R² is not greater than about 20 carbons as noted. These moieties are unsubstituted at the alpha position but can be substituted in other positions. Typical R¹ and R² groups include the alkyls; unsaturated groups such as alkenyls, hexyls and the like; hydroxy-subst ituted alkyls; aryls such as benzyls; fluorinated, sulfonated or phosphorated alkyls and the like. Simple lower alkyls are preferred. R⁶ and R⁷ are selected as set forth for R₅ and

R₆ in Formula 1. R⁸ and R⁹ are hydrogen, lower alkyls or substituted lower alkyls and can in addition be joined into an alkylene chain linking the "1" and "7" carbons into a cycloalkylene ring such as of 3 to 8 carbons. A preferred configuration for R⁸ and R⁹ is to have them joined into a 6-membered cycloalkylene ring, with or without substituents.

R¹⁰ and R¹¹ are independently selected f rom hydrogen , lower alkyls and substituted lower alkyls. It is often attractive to be able to alter the hydrophobicity/hydrophilicity of the seco analogs. Alkyls in these positions will decrease hydrophilicity and increase hydrophobicity. Alkyl substituents which are themselves substituted with an ionic group such as a carboxylic acid or sulfonic acid group will enhance hydrophilicity. In preferred embodiments, R¹⁰ is a lower alkyl, and especially a methyl, and R¹¹ is a hydrogen.

A vinylsilane of General Formula IV. is subjected to ozonolysis in the preparation of the seco analogs. In this silane R³, R⁴ and R⁵are hydrocarbyls like R₇ , R₈ and R₉ in Formula II. The ozonolysis produces the silyloxy-hydroperoxides represented by General Formula V. In General Formula V. , R³ through R and R⁸ through R¹¹ have the meanings set forth above.

Carbonyl compounds of General Formula VI. are reacted with the hydroperoxide in the preparation of the seco compounds. R¹ and R² are as defined with reference to General Formula III. Thus the carbonyl includes ketones and aldehydes.

In a third embodiment, the ozonolysis process of this invention is used with bridgehead ketones of Formula VIII. to yield tetracyclic artemisinin analogs of Formula IX.

In the bridgehead ketones defined by General Formula VIII., m is an integer - either 0 or 1; n is an integer - either 0, 1, 2, 3, or 4; and the various R's are each independently selected from hydrogens, alkyls and substituted alkyls.

Preferably n is 1 or 2 or 3. Preference is also given to materials wherein the various R's are selected from hydrogen, lower alkyls and substituted lower alkyls. Materials wherein at most one or two of the R's in the m methylenes and at most one of the R's in the m methylenes are other than hydrogen are especially preferred.

The bridgehead ketones are shown in more detail by General Formula VIII*. in which m, n and the R's are as previously described.

General Formula VIII*. Several of the materials encompassed by General Formulas VIII. and VIII*., are known compounds. (See Still, supra, for a disclosure of materials wherein n is 1, m is 1 and all the R's are hydrogen; wherein n is 2, m is 1 and all the R's are hydrogen; wherein n is 3, m is 1 and all the R's are hydrogen; and wherein n is 2 , m is 1 and all the R's are hydrogen except for one R^Cl, which is a methyl.)

The bridgehead ketone materials of General Formulas I. and I*, can be prepared as follows: When both of the R^B substituents are hydrogen, the materials can be prepared by the cyclodialkylation of appropriate enamines. The pyrrolidine enamines are a well-known family of materials whose preparation from commercial cyclic ketones is well documented, and for this reason they are preferred. In a typical representative reaction cyclohexanone is converted to the cyclohexeneamine, which is then reacted with a l,4-dichlorobut-2-ene to give a bicyclic ketone as shown in Reaction 1.

Reaction 1 The reaction of the dialkylation reagent and the enamine is carried out under effective alkylation conditions. These include anhydrous conditions; an aprotic reaction medium such as dimethylformamide, tetrahydrofuran, or the like; and the general exclusion of oxygen from the reaction vessel such as by an inert gas cap. The reaction is generally promoted by the addition of a base such as an amine or the like, for example a trialkyl amine, and by the presence of a halide alkylation promoter such as an alkali metal iodide. In the reaction, approximately equimolar amounts of the dialkylation reagent and the enamine are employed. A representative preparation taken from Still (supra) is provided in Example 15.

In those cases where the bridgehead ketones have R^B substituents other than hydrogen, they can be prepared using the methods set forth by Taguchi et al (supra) and Warnhoff et al (supra). In Taguchi et al saturated bridgehead ketones containing a carboxylic acid functionality at one of the bridgeheads are prepared. The carboxyl group can be used as a point of attachment for other R^B substituents as called for. The Warnhoff et al work discloses a method for introducing carboxyl and halo substituents on both of the bridgehead carbons of saturated bicyclic ketones. Again, these groups can serve as active sites for the coupling of other R^B groups as desired. With suitable modification, the desired olefinic bond can be introduced into the bicyclic structure.

The bicyclic bridgehead ketones of Formula VI I I . are converted to the v inyls i lanes of Formula VII. The three R^S substituents in the silyl functionality are independently selected from lower hydrocarbyls as previously defined. The vinylsilanes can also be represented by General Formula VII*.

General Formula VII*. When this vinylsilane is treated with ozone formation of the mixed carbonyl/ester vinylsilanes of Formula X*, by differential ozonolytic cleavage of the olefinic double bond (instead of the bridging vinylsilane) of Formula II. occurs.

General Formula X*. R^E is a protective esterifymg group.

The vinylsilanes of Formula VIII. are versatile intermediates. The carbonyl-containing arm can be extended using conventional chain-extension techniques such as the Wittig reaction. This introduces a

unit wherein R is a hydrogen, an alkyl or a substituted alkyl and p is an integer of from 0 to 2, subject to the proviso that p plus m has a value not greater than 2. The product of this chain extension has the structure shown in Formula XI*.

General Formula XI*. These chain extension products can be deprotected and subjected to ozonolysis and acidification to yield the desired tetracyclic structure. Alternatively, after protecting the carbonyl group such as an acetal or ketal, these materials can be derivatized to modify their structure and give rise to numerous other substitution patterns. In another variation, the acid functionality and the carbonyl functionality can be protected (such as by esterif ication and by conversion to an acetal or ketal, respectively) and the product then alkylated to add an R^F group and deprotected to give a product as shown in General Formula XII*.

General Formula XII*. In this formula the R^F group is a lower alkyl or substituted lower alkyl.

Deprotection, ozonolysis and acidification of any of these vinylsilanes yield desired tetracycles. These tetracycles are defined structurally by means of General Formula IX. (or General Formula IX*., below).

General Formula IX*. The Ozonolysis Reaction

The process of this invention employs an ozonolysis reaction in its formation of the desired artemisinin analogs. This reaction is carried out at low temperatures in a liquid reaction medium. Ozone is extremely reactive and it is advantageous to employ low temperatures to avoid side reactions between the ozone and other regions of the vinyl silane molecule. The low temperature can range from a high of about 15° to a low equal to the freezing point of the reaction solvent, which can be as low as -100° C or lower. Excellent results are obtained at dry ice/acetone bath temperatures (-78°C) and a preferred temperature range is from -100°C to about -25°C, with most preferred temperatures being in the range of from -70°C to -80°C.

The reaction solvent employed in this reaction is selected to assure compatibility with the highly reactive ozone. As a general rule, ethers, both linear and cyclic, are to be avoided as they are likely to be converted to peroxides which present an explosion hazard. The solvents employed are polar organics, preferably lower alcohols such as methanol, ethanol, the propanols and ethylene and propylene glycols; lower ketones such as acetone and methyl-ethyl ketone; and the and liquid esters such as ethyl acetate. Of these solvents, the lower alcohols, and especially methanol, are preferred.

The reaction is carried out by mixing the vinyl silane in the reaction medium and then adding the ozone. The amount of ozone preferably is controlled so that excesses are avoided. Good results are obtained when the amount of ozone is limited to not more than 1.25 equivalents, based on the amount of vinyl silane present, with ozone levels of from about 0.75 to about 1.25 equivalents based on the amount of vinyl silane present being preferred. Lower ozone levels can be used, but are not preferred because of the lower yields which result from them.

The reaction is very quick, being complete in a few minutes at most. Excellent results are obtained at times in the range of 15 seconds to about 15 minutes. It is advantageous to limit this reaction period.

The reaction product is then treated with acid. In the case where the ultimate product is a non-bridgehead substituted tetracycle the product contains a dioxetane which is isolated and then treated. This can be carried out by stripping the solvent off with vacuum or other like processes which minimize the possibility of degradative reaction. In the case of the seco materials or the bridgehead-substituted tetracycles the acidification can be carried -out without isolating the intermediate.

The ozonolysis reaction product or isolated dioxetane is treated with acid to bring about rearrangement of these transitory intermediates and give rise to the desired product tetracycles or seco analogs. This reaction can be carried out in an nonaqueous liquid reaction phase with halohydrocarbons such as chloroform and the like being preferred. The acid employed should be of at least moderate strength as shown by a pKa of from about 5 to about 0.1 and can be an organic or an inorganic acid. Mixtures of acids can be used, if desired. Typical acids include acetic acid; the substituted acetic acids such as trichloroacetic acid, trifluoroacetic acid and the like, and other strong organic acids such as alkyl sulfonic acids and the like. The mineral acids such as the hydrohalic acids, e.g., HCl, HBr, etc., the oxyhalo acids such as HCIO₃ and the like; sulfuric acid and phosphoric acid and the like may be used as well but should be checked before use to assure that they do not cause unwanted side reactions.

The rearrangement reaction is merely catalyzed by the acid, thus in principle only a trace amount of acid is needed. However, the use of more than a trace amount of acid may be preferred. In practice, the best approach is to monitor the course of the reaction and add acid as needed to achieve and sustain a reasonable reaction rate. In particular, the amount of acid added is generally at least about one equivalent based on the amount of product present. Large excesses while not needed, can be used, and the preferred amount of acid is from about one to about ten, and especially from about one to about two, equivalents based on the amount of product present. This reaction does not require high temperatures. It will go to completion overnight at room temperature. The reaction may also proceed to completion either more rapidly or more slowly, depending on the acid and solvent system employed. Higher temperatures may be employed, if desired and if it is ascertained that they do not give unacceptable yield losses. Temperatures from about -100°C to about +50°C can be used with temperatures of from about-20°C to about +30°C being preferred and temperatures of from about 0°C to about +20°C being more preferred. As would be expected, times are inversely related to temperature with times in the range of 1 hour to about 24 hours being useful.

The product of the acid-catalyzed rearrangement can be worked up and purified using chromatographic techniques and the like.

To obtain products where the 12 substituent is other than a carbonyl oxygen, the techniques illustrated in Figure 5 can be used. As shown in that figure, the carbonyl can be reduced without affecting the reduction-sensitive peroxy group by the use of sodium borohydride as reported by M.-m Liu et al. in Acta Chim Sinica, Vol 37, 129 (1979). This reduction converts the carbonyl into a lactol. The lactol hydroxyl can be converted to an ester by reaction with an appropriate acid anhydride or acid halide or active ester. Typical examples of these reactants include acetic anhydride, propionic anhydride, maleic anhydride and substituted analogs thereof, alkanoyl chlorides, and the like. This reaction is carried out in an aprotic solvent such as an ether or halohydrocarbon (for example, dichloromethane) at a moderate temperature of from about 0°C to room temperature in from about 0.5 to 5 hours. An ether can also be formed such as by contacting the alcohol with methanol or a R*-CH₂-OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF3. The BF₃ is presented as an etherate and forms a complex with the alcohol and effects the ether formation at -10°C to room temperature in from 0.5 to 5 hours. The added alcohol is a good solvent. A carbonate can be formed from the alcohol such as by reacting it with an organic chloroformate such as an alkyl chloroformate. This is again carried out at -10°C to room temperature in from 0.5 to 5 hours in an aprotic solvent such as was used in the formation of the ester. All of these products can be recovered using a conventional organic workup. The Overall Process

The ozonolysis reaction is incorporated into an overall synthesis scheme to provide the desired artemisinin analogs.

The scheme set out in Figure 1 is a stereoselective total synthesis of artemisinin 18. (Qinghaosu) and 13-desmethylartemisinin 13 starting from the known sulfoxide 1. (available from R(+)-pulegone, William R. Roush and Alan E. Walts, J. Amer. Chem. Soc. 106, 721 (1984)). Treatment of the dianion derived from 1. with the known bromide 2. afforded a mixture of diastereomeric sulfoxides 3. which was reduced directly in wet THF with aluminum-mercury amalgam to give the ketone 4. The ketone 4, was reacted with p-toluenesulfonylhydrazide to give the hydrazone 5.. Reaction of the hydrazone 5 in N,N,N',N'-tetramethyl- ethylenediamine with n-butyllithium and quenching of the resultant vinyl anion with dimethylformamide afforded the unsaturated aldehyde 6 .

Straightforward reduction of the aldehyde 6 with diisobutyl-aluminum hydride gave the allylic alcohol 2 which was silylated with trimethylsilyl chloride and imidazole to give the silyl ether 8. Deprotonation of the allylic ether 8 with tertbutyllithium in THF gave the product, from Brook rearrangement product, 9. Acetylation of 9 then gave the acetate 10. Deprotonation of the ester 10 with lithium N-cyclohexyl-N-isopropylamide (LICA) followed by in situ ester-enolate Claisen rearrangement gave the carboxylic acid 11.

The carboxylic acid 11 could be converted to 13-desmethylartemisinin 13 in the following manner. Treatment of 11 with oxalic acid impregnated silica gel gave the keto-acid 12. Ozonolysis of 12 at low temperature in methanol gave an unstable intermediate dioxetane which was treated immediately with CF₃CO₂H in CDCI₃ to afford (Scheme I) the nor analog of artemisinin, 13.

Alternatively, (Scheme II, Figure 2.) 11 could be esterified to give the ester 14. which could be methylated to provide a mixture of monomethylated products, 15 and 16, in a 3:1 ratio respectively. This ester mixture was sequentially treated with KOH in methanol followed by oxalic acid on wet silica gel to provide, after chromatography, the stereoisomerically pure keto-acid 17.

Finally, ozonolysis of 17 in methanol at -78°C gave an unstable dioxetane intermediate which, after evaporation of the methanol, was treated with dilute moist CF₃CO₂H in CDCI₃, affording optically pure artemisinin 18. As will be shown in the Examples, the synthetic material 18. was identical to naturally derived qinghaosu. Such synthetic material would be useful as an antimalarial.

In one important application, this synthetic sequence can be modified slightly to produce radiolabelled artemisinin. This can be carried out effectively and simply by using carbon 14-based CH₃I in the alkylation of compound 14. This will insert the radiolabel at the 13 position where it is stable and nonlabile. The product of this synthesis is of particular usefulness in biological testing of artemisinin where its metabolic fate, absorption and the like can be easily tracked because of the added radiolabel. As shown in General Formula I., the present invention permits the stereospecif ic synthesis of many polyoxa tetracyclic compounds beyond artemisinin. In these cases, one could use the synthetic schemes set forth in the Figures with appropriate modifications. For example, to vary R₁ from the one carbon alkylene bridge shown in Figures 1 and 2 to a two or three carbon bridge by homologating the -CH₂-COOH group in compound 11. or compound 15 to the corresponding higher analogs. The Ri bridge can be substituted with R* groups by alkylation with X-R* where X is a leaving group such as a halide (e.g. I or Br) a tosylate, a mesylate or the like. This alkylation can take place before or after the homolόgation, depending upon the particular site on the R₁ group sought to be substituted.

The R₂ bridge is set by the ring structure in compound 1. In Figure 1, compound 1, is shown as a cyclohexanone-based material. One could as well start with cyclopropanone (thereby obtaining a carbon-carbon single bond R₂). cyclobutanone (thereby obtaining a -CH₂ R₂), cyclopentanone, etc. In every case, the carbons of the starting aldehyde can be substituted with R* groups as desired on R₂.

R₃ is determined by the nature of the leaving- group containing side chain in alkylation agent 2 in Figure 1. Thus, if this side chain is varied in length or substitution, so is R₃.

Similarly, R₄ can be altered by varying the other substituent on the carbon atom between the two ether oxygens on compound 2 . In compound 2 this group is a methyl and R₄ is a methyl. If this group is altered to be a hydrogen or an R* substituted methyl, R₄ will follow accordingly. The preparation schemes set forth on Figures 1 and 2 result in products of General Structures 1-4 where X is -O-. In Figure 3, a variation of the scheme of Figure 1 is depicted which will produce compounds where X is -S- or The scheme of Figure 3 begins with

acid 11. This material is converted to the acid chloride 19 by conventional treatment with oxalyl chloride ClCOCOCl, thionyl chloride, or the like. Acid chloride 19. can then enter into a nucleophilic substitution with H2S or the amine NH₂R₁₀ to insert an

-S- or as X in compounds 20a and 20b,

respectively. These compounds of General Formula II. can be further processed by the ozonolysis of the invention to yield corresponding X=-S- and materials of General Formula I.

Turning to Figure 4, a preparation is shown for inserting -S- and into the artemisinin

structure. In one scheme, the mixture of esters 15 and

16 produced as in Figure 2 is contacted with primary amine to give the mixture of amides 21 and 22.

Alternatively, esters 15/16 can be hydrolyzed with methanolic KOH to the mixture of acids 25 and 26. This mixture can be converted to the corresponding mixed acid chlorides by the method described with Figure 3 and the acid chlorides reacted with to give the mixture of amides 21. and 22.

The mixture of amides 21 and 22 is then treated with methanolic base followed by treatment with oxalic acid-impregnated silica gel to yield the keto-amide 23 of the General Formula II. This material is subjected to ozonolysis to yield the NR₁₀ analog 24 of arteminisin.

To insert a sulfur X into the structure, the mixed acid chlorides 25 and 26 are reacted with H₂S to yield 21 and 28. When this material is treated with the oxalic acid on silica gel, the sulfur compound 29 of General Formula II. is formed. When subjected to ozonolysis, compound 30 of General Formula I. results. R₅ and R₆ are together a carbonyl oxygen in compounds 13 and 18 in Figures 1 and 2. This carbonyl can be reduced, without affecting the reductionsensitive peroxy group, by the use of sodium borohydride, as reported by M.-m. Liu et al., in Acta Chim. Sinica, Vol. 37, 129 (1979). This reduction converts the carbonyl to a lactol (hemiacetal wherein R₅ is H and R₆ is OH. The R₅ hydrogen can be replaced with an R* group by alkylation with X-R*. An R₆ OH can be converted to an ether or ester by art known techniques.

The other possible configuration for R₅ and R₆, as set forth in General Formula I., can be produced as shown in Figure 5. In each of the five sequences given in Figure 5, the reaction with oxalic acid to cleave the side-chain protection and form the ketone as shown in Figure 1 , 2 , and 4 has been omi tted for brevity and replaced by "...".

In one of these sequences, the mixed esters 15 and 16 are reduced with lithium aluminum hydride to alcohols 31 and 32. After side-chain deprotection, ozonolysis yields compound 33 where R₅ and R₆ are hydrogen. In the next variation, 31 and 32 are oxidized into aldehyde 34 which after deprotection and ozonolysis yields 35 where R₅ and R₆ equal OH and H.

Aldehyde 34 can be alkylated with Grignard reagent to give alcohol 36. This alcohol can be carried forward to give compound 37 of Formula I., where R₅ and R₆ are R* and H.

Alcohol 36 can be oxidized to aldehyde 38. This material can be deprotected and subjected to oxonolysis to give 39 where R₅ and R₆ are R* and OH.

In another variation, aldehyde 38 can be treated again with Grignard to add an additional R* group (the same or different than the R* of 38), and this product can be deprotected and ozonized to give 40. It will be appreciated in this last sequence that if the two R*s are identical, one could add them at once to esters 15 and 16 by using excess Grignard reagent.

It will also be appreciated that the reactions of Figure 5 could be run on the acid chloride of acid compound 11 of Figure 1 to give the corresponding desmethyl materials.

Figure 6 illustrates a preparation scheme in which two representative seco derivatives are prepared. In this scheme an unsaturated (allylic) alcohol (shown representatively in Figure 6 as cyclohexenylmethanol) is converted to the corresponding silyl ether 5. Allylic silyl ether 5 is then deprotonated in TMEDA with s-butyllithium to afford a Brook rearrangement product 6. The hydroxyl of 6 is then esterified (such as acetylated) to yield ester 7. Ester 7 is then deprotonated such as with lithium N-cyclohexyl-N-isopropylamide (LICA) in THF followed by in situ ester/enolate Claisen rearrangement to give carboxylic acid-substituted vinylsilane 8.

This vinylsilane 8 is then subjected to ozonolysis. The ozonolysis reaction product contains a transitory dioxetane which is observable spectroscopically. The dioxetane material rearranges to give the hydroperoxide 1. The hydroperoxide is converted to the desired seco analog by reaction with a ketone of General Formula IV. in the presence of acid as previously described.

As shown in General Formula III., the present invention provides a range of seco analogs of artemisinin wherein R⁶ and R⁷ together are a carbonyl oxygen. To achieve the full range of these materials, one could use the synthetic scheme set forth in the Figure with appropriate modifications. For example, to vary R¹ and R² from the one or two carbon alkyls shown in Figure 6, one can use the corresponding

carbonyl in the reaction with hydroperoxide 1.

Similarly, R⁸ and R⁹ are set by the structure of allyl alcohol 4. One could as well start with other ring structures such as cyclopentene or with separate R⁸ and R⁹ groups attached on either side of the olefinic bond of compound 4. R¹⁰ and R¹¹ are determined by the nature of the esterifying group reacted with the hydroxyl group of compound 6. With the propionic anhydride shown in Figure 6, one obtains a methyl and a hydrogen in these positions. With acetic anhydride one obtains two hydrogens. When these esterifying agents are replaced by agents having other substituted and unsubstituted groups, the R¹⁰ and R¹¹ groups are altered correspondingly. It is also possible to alter the R¹⁰ and R¹¹ groups by alkylation and the like.

To obtain analogs where R⁶ and R⁷ are other than a carbonyl oxygen, the techniques illustrated in Figure 7 can be used. The carbonyl can be reduced as previously described. An ether such as ether 11 can also be formed such as by contacting the alcohol 9 with methanol or a R*-CH₂-OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF₃. The BF₃ is presented as an etherate and forms a complex with the alcohol and effects the ether formation at -10°C to room temperature in from 0.5 to 5 hours. The added alcohol is a good solvent. A carbonate such as carbonate 12 can be formed from 9 or the like such as by reacting 9 with an organic chloroformate such as an alkyl chloroformate. This is again carried out at -10°C to room temperature in from 0.5 to 5 hours in an aprotic solvent such as was used in the formation of ester 10. All of these products can be recovered using a conventional organic work up.

When the process involves bridgehead- substituted materials, the reactions of Figures 8 and 9 can be used. In the reactions shown there the conversion of the ketone to the vinylsilane can be carried out using any of the art-known methods for silylating a carbonyl functionality. In this case a method which proceeds with good efficiency and yield involves the straightforward use of bis(trialkylsilyl) methyllithium. This reagent can be prepared by the method of Grobel and Seebach, Chem. Ber, 110, 852 (1977). The silylation is carried out by contacting the ketone and the silylation reagent at about equimolar levels (0.75 to about 1.33 equivalents of silylation complex based on the ketone present) at low temperatures such as -100°C to about 0°C, once again in an aprotic anhydrous reaction phase. The product of this silyation can be extracted into a nonpolar organic phase and can be worked up by rinsing with water, brine, and the like. The product can be purified, such as by chromatographic techniques.

The ozonolytic cleavage reaction employed in Figures 8 and 9 is an adoption of the method described by R.E. Claus and S.L. Schreiber, Org. Syn., 64, 150 (1985). This reaction is carried out at essentially the conditions used in the ozonolysis. The reaction solvent employed in this reaction is similar to the materials used in the ozonolysis and is selected to assure compatibility with the highly reactive ozone. Of these solvents, the lower alcohols, especially methanol mixed with halohydrocarbons and especially dichloroethylene, are preferred. In the case shown in Figure 8 an optimum solvent was a 5:1 volume ratio of methylene chloride and methanol, respectively. The solvent plus the presence of an acid acceptor such as alkali metal carbonate or bicarbonate gave best results. This acid acceptor is useful to prevent the alcohol of the react ion medium f rom combining with an aldehyde of the reaction product. The acid acceptor can be employed to advantage if, as in the case of Figure 8, this reaction is undesired.

The product of the ozonolytic cleavage can be worked up and recovered. In the case of sensitive products, the workup is carried out under reductive conditions, for example in the presence of an alkylamine and an anhydride such as acetic anhydride. In cases where the product is less sensitive, the conditions need not be reductive.

The recovered product can then be treated with a strong acid such as a mineral acid and preferably hydrochloric acid to yield the tetracycles of Formula VI. This product can be recovered by extraction into an organic layer which is then washed, dried and, if desired, subjected to column chromatography and the like. The optional chain extension and alkylation steps can be carried out as previously described.

7. Use of the Products

The compounds of this invention all contain the peroxy linkage which can lead to free radical intermediates in vivo and have antiprotozoan activities against a broad range of parasites such as Toxoplasma, Leishmania, Trypanosoma, etc., in addition to Plasmodia. In tests, they have been demonstrated to have high activity in this application. They offer activity against drug-resistant forms of malaria and can even intervene in cerebral malaria, where they can interrupt coma and reduce fever. These materials should also have anthelminthic activity against such diseases as Schistosoma and Trichinella, etc. (R. Docampo et al., Free Radicals in Biology, Vol. VI, Chapter 8, p. 243, 1984, Academic Press, Inc.). In this application, the compounds are generally compounded into vehicles or carriers known in the art for administration to patients in need of such treatment. The mode of administration can be oral or by injection. Typical vehicles are disclosed in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro, ed., Mack Publishing Company, Easton, PA. (1985). For oral administration, the compounds can be prepared as elixirs and suspensions in sterile aqueous vehicles, and also can be presented admixed with binders, carriers, diluents, disintegrants and the like as powders, as pills, or as capsules. Typical liquid vehicles include sterile water and sterile sugar syrup. Typical solid materials include starch, dextrose, mannitol microcrystalline cellulose and the like.

For administration by injection, the materials can be presented as solutions/suspensions in aqueous media such as injectable saline, injectable water and the like. They can also be presented as suspensions or solutions in nonaqueous media such as the injectable oils including injectable corn oil, peanut oil, cotton seed oil, mineral oil, ethyl oleate, benzyl benzoate and the like. The nonaqueous media can, in some cases, permit substantial quantities of the medication to be administered as a depot in the patient's fat layer so as to obtain a prolonged release of the agent to the patient.

The materials of this invention are used in fairly large doses. Commonly, dose levels of from about 100 mg/day to as much as 10,000 mg/day are employed. The actual use level will vary depending upon the particular patient's response to the drug and to the patient's degree of affliction. In a particularly preferred utility, the compounds are used against Plasmodia and, in that use, require dosages from 0.1 to 10 times that used with the natural product artemisinin.

The peroxide link presented by all of these compounds and the free radicals it can produce are useful in a range of industrial chemical settings, as well. Example 1

2,5,5-Trimethyl-2-(2'-(1"R-methyl-3"-oxocyclohex-2"- yl)-ethyl-1,3-dioxane (4)

5R-Methyl-2-phenylsulfinylcyclohexanone ( 1 , Figure 1) (7.14 g, 30.0 mmoles) in dry THF (75 ml) at -30°C under argon was treated with a solution of lithium diisopropylamide (prepared from 9 ml or 64.5 mmoles of diisopropylamine and 41.6 ml of 1.55 M solution of n-BuLi in hexane) in dry THF (75 ml) followed by dry hexamethylphosphoramide (HMPA) (30 ml). The mixture was stirred at -30 °C for 3 hr and then 2-(2'bromoethyI)- 2,5,5trimethyl-1,3-dioxane (2, Figure 2) (8.42 ml. 36.0 mmoles) was added dropwise via syringe. The mixture was stirred at -30°C for 1 hr and then was allowed to warm to room temperature over 1 hr. The mixture was poured into ice-cold, saturated ammonium chloride solution (100 ml) and was extracted with diethyl ether (2 x 100 ml). The organic layers were washed with water (3 x 100 ml) and brine (100 ml), dried (MgSO₄), and evaporated in vacuo to give 15.1 g of crude alkylation product (3, Figure 1). This was dissolved in THF (675 ml) to which was added water (75 ml) followed by 7.5 g of amalgamated aluminum foil strips (prepared by dipping aluminum foil strips in 2% aqueous mercuric chloride for 15 sec followed by washing with absolute ethanol and diethyl ether). The mixture was stirred at room temperature for 2 hr and then was filtered under reduced pressure while the solids were being washed with diethyl ether (500 ml). The filtrate was washed with 5% sodium hydroxide solution (3 x 500 ml), water (500 ml), and brine (500 ml). The aqueous phases were sequentially extracted with diethyl ether (500 ml) and the combined organic phases were dried (MgSO₄) and evaporated in vacuo to give 10.35 g of crude material. This was purified by flash chromatography on 207 g silica gel 60 (230-240 mesh), eluting with EtOAc/hexane (10:90) → (15:85) to give the product 4 (Figure 1) (4.0 g, 50%) as a colorless oil. IR (thin film): 2960 (s), 2940 (m), 2880 (m), 1716 (s) cm^-1. NMR (400 MHz, CDCI₃): δ 3.501 (1 H, d, J 11 Hz), 3.496 (1 H, d, J 11 Hz), 3.454 (1 H, d, J 11 Hz), 3.450 (1 H, d, J 11 Hz), 2.30 (3 H, m), 2.01 (2 H, m), 1.83 (1 H, m), 1.65 (6 H, m), 1.34 (3 H, s), 1.03 (3 H, d, J 7 Hz), 0.93 (6 H, s). C₁₃ NMR (400 MHz, CDCI₃): δ 213.2, 99.1, 70.5, 70.3, 57.1, 41.6,

41.4, 38.4, 33.5, 33.3, 29.9, 25.6, 22.7, 21.7, 20.8,

20.5. MS (m/e): 268 (M⁺), 253 (M-Me). Analysis: Found: C, 71.73; H, 10.33. C₁₆H₂₈O₃ requires C, 71.64; H, 10.45%

Example 2

2,5,5-Trimethyl-2-[2'-(l"R-methyl-3"-oxocyclohex-2"-yl)-ethyl]-1,3-dioxane p-tosylhydrazone (5)

A mixture of the ketone (4, Figure 1) (3.60 g, 13.44 mmoles), dry THF (100 ml), p-tosylhydrazine (2.49 g, 13.44 mmoles), and pyridine allowed to cool and then was evaporated in vacuo, giving 8.5 g of crude material. This was purified by flash chromatography on 170 g silica gel 60 (230-400 mesh) and elution with EtOAc/hexane (25:75) → (40:60) to give the product 5 (Figure 1) (5.5 g, 94%) as a gummy solid. IR (CHCI₃): 3120 (m), 2955 (s), 2875 (s), 1735 (m), 1635 (2), 1605 (w), 1500 (w) cm^-1. NMR (CDCI₃): δ 8.53 (1 H, broad), 7.81 (2 H, d, J 8 Hz), 7.20 (2 H, d, J 8 Hz), 3.44 (4 H, s), 2.39 (3 H, s), 2.19 (3 H, m), 1.54 (8 H, m), 1.27 (3 H, s), 1.24 (3 H, d, J 5 Hz), 0.97 (3 H, s), 0.93 (3 H, s). MS (m/e): 437 (M+H⁺), 421 (M-Me).

Example 3

2,5,5-Trimethyl-2-[2'(1"R-methyl-3"-3"-formylcvclohex-3"-en-2"-yl)-ethyl]-1,3-dioxane (6)

To a solution of the hydrazone (5, Figure 1) (220 mg, 0.505 mmole) in dry TMEDA (10 ml) at -20°C under argon was added n-BuLi (1.30 ml of 1.55 M solution in hexane, 2.02 mmoles). The mixture was stirred at room temperature for 30 min and then was cooled to 0°C. After addition of dry DMF (0.5 ml), by drops, the mixture was stirred at 0°C for 30 min and then was poured into ice-cold saturated ammonium chloride solution (20 ml). This was extracted with ethyl acetate (2 x 20 ml) and washed with saturated ammonium chloride solution (20 ml), water (20 ml), and brine (20 ml). The combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give 175 mg of crude material, which was purified by preparative TLC, eluting with EtOAc/hexane (15:85), to give the product 6 (Figure 1) (77 mg, 55%) as a pale yellow oil. IR (thin film): 2960 (s), 2870 (m), 2710 (w), 1685 (s), 1635 (w) cm^-1. NMR (400 MHz, CDCI₃): δ 9.38 (1 H,s), 6.73 (1 H, t, J r Hz), 3.472 (1 H, d, J 11 Hz), 2.28 (2 H, m), 1.91 (1 H, m), 1.71 (5 H, m), 1.39 (2 H, m), 1.31 (3 H, s), 0.94 (3 H, s), 0.89 (3 H, s), 0.86 (3 H, d, J 7 Hz). C₁₃ NMR (400 MHz, CDCI₃): δ 194.7, 151.2, 99.0, 70.3, 41.6, 37.7, 35.0, 29.9, 28.5, 27.5, 26.1, 23.9, 23.0, 22.7, 21.0, 18.6, 14.1. MS (m/e): (M-Me). Example 4

2,5,5-Trimethyl-2-(2'-(1"R-methyl-3"hydroxymethyl- cyclohex-3"-en-2"-yl)-ethyl)-1,3-dioxane (7)

The aldehyde (6, Figure 1) (1.1 g, 4.04 mmoles) in dry THF (10 ml) was added dropwise via syringe to diisobutylaluminum hydride (DIBAL) (4.21 ml of 1.2 M solution in toluene, 5.05 mmoles) in dry THF (30 ml) at -78°C under argon. The mixture was stirred at -78°C for 30 min. and then was allowed to warm to room temperature over 30 min. The mixture was poured into ice-cold, saturated potassium sodium tartrate solution (50 ml) and was extracted with ethyl acetate (2 x 50 ml). The organic extracts were washed with saturated potassium sodium tartrate solution, dried (MgSO₄), and evaporated in vacuo to give the product 7 (Figure 1) (1.14 g, 100%) as a colorless oil. IR (CHCI₃): 3580 (m), 3430 (m, broad), 2990 (s), 2945 (s), 2915 (s), 2855 (s), 1660 (w) cm^-1. NMR (CDCI₃): δ 5.68 (1 H, m), 3.99 (2 H, s), 3.53 (2 H, d, J 11 Hz), 3.35 (2 H, d, J 11 Hz), 1.94 (3 H, m), 1.61 (8 H, m), 1.30 (3 H, s), 0.98 (3 H, s), 0.88 (3 H, d, J 6 Hz), 0.81 (3 H, s). MS (m/e): 267 (M-Me). Analysis: Found: C, 72.60; H, 10.53. C₁₇H₃₀O₃ requires C, 72.34; H, 10.64%.

Example 5

2,5,5-Trimethyl-2-(2'-(l"R-methyl-3"-trimethylsilyloxy- methylcyclohex-3"-en-2"-yl)-ethyl)-1,3-dioxane (8)

To the alcohol 7 (Figure 1) (100 mg, 0.355 mmole) in dry DMF (4 ml) at 0°C under argon was added imidazole (242 mg, 3.55 mmoles) and trimethylchlorosilane (116 mg, 1.065 mmole). The mixture was stirred at 0°C for 1 hr, then poured into ice-cold water (20 ml) and extracted with diethyl ether (2 x 20 ml). The organic extracts were washed with water (20 ml) and brine (20 ml), dried (MgSO₄), and evaporated in vacuo to give the product 8 (Figure 1) (126 mg, 100%) as a colorless oil. 1R (CHCI₃): 3000 (s), 2950 (s), 2920 (s), 2860 (s) cm^-1. NMR (CDCI₃): δ 5.60 (1 H, m), 3.98 (2 H, s), 3.48 (2 H, d, J 11 Hz), 3.32 (2 H, d, J 11 Hz), 1.92 (3 H, m), 1.54 (7 H, m), 1.25 (3 H, s), 0.92 (3 H, s), 0.85 (3 H, d, J 7 Hz), 0.80 (3 H, s), 0.05 (9 H, s). MS (m/e): 354 (M+), 339 (M-Me).

Example 6

2,5,5-Trimethyl-2-(2'-(1"R-methyl-3"-trimethylsilyl- hydroxymethylcyclohex-3"-en-2"-yl)-ethyl)-1,3-dioxane

(9)

To a solution of the silyl ether 8 (Figure 1) (7.20 g, 20.3 mmoles) in dry THF (100 ml) at -78°C under argon was added t-BuLi (23.9 ml of 1.7 M solution in pentane, 40.6 mmoles). The mixture was stirred at -30° to -40°C for 2-1/2 hr and then was recooled to -78°C. A mixture of acetic acid (15 ml) and THF (50 ml) was added slowly and the resulting mixture was poured into ice-cold, saturated sodium bicarbonate solution (200 ml). This was extracted with chloroform (3 x 200 ml) and washed with brine (200 ml). The combined organic extracts were dried (MgSO₄) and evaporated in vacuo to give 8.20 g of crude material. This was purified by flash chromatography on 246 g silica gel 60 (230-400 mesh), eluting with EtOAc/hexane (10:90) → (30:70) to give the product 9 (Figure 1) (2.60 g, 36%) as well as the alcohol 7 (2.50 g, 44%). IR (CHCI₃): 3550 (w, broad), 3000 (s), 2955 (s), 2935 (s), 2870 (s) cm^-1. NMR (CDCI₃): δ 5.53 (1 H, m), 3.84 (1 H, m), 3.57 (2 H, d, J 11 Hz), 3.37 (2 H, d, J 11 Hz), 2.01 ( 3 H, m) , 1 . 63 ( 8 H, m) , 1 . 34 ( 3 H, s ) , 1 . 01 ( 3 H , s ) , 0 . 92 (3 H, d, J 7 Hz), 0.85 (3 H, s), 0.04 (9 H, s). MS (m/e): 354 (M+), 353 (M-H), 337 (MOH). Analysis: Found: C, 66.02; H, 10.58; Si, 6.87. C₂OH₃₈SiO₃.1/2EtOAc requires C, 66.33; H, 10.55; Si, 7.04%.

Example 7

2,5,5-Trimethyl-2-(2'-(1"R-methyl-3"-trimethylsilyl-hydroxymethylcyclohex-3"-en-2"-yl)-ethyl)-1,3-dioxaneacetate ester (10)

To a solution of the alcohol 9 (Figure 1) (354 mg, 1.00 mmole) in diethyl ether (10 ml) at room temperature under argon was added dry pyridine (0.17 ml, 2.00 mmoles), acetic anhydride (0.14 ml, 1.50 mmole), and 4-dimethylaminopyridine (10 mg). The mixture was stirred at room temperature for 16 hr and then was poured into ice-cold water (20 ml). This was extracted with diethyl ether (2 x 20 ml). The combined organic layers were dried (MgSO₄) and evaporated in vacuo to give the product 10 (Figure 1) (376 mg, 95%) as a colorless oil. IR (CHCI₃): 3000 (m), 2960 (s), 2930 (s), 2875 (s), 1725 (s), 1645 (w) cm^-1. NMR (CDCI₃): δ 5.34 (1 H, m), 5.08 (1 H, m), 3.40 (4 H, m), 2.06 (3 H, s), 2.05-1.20 (10 H, m), 1.35 (3 H, s), 1.01 (3 H, s), 0.88 (6 H, m), 0.01 (9 H, s). MS (m/e): 396 (M+), 395 (M-H). Analysis: Found: C, 65.24; H, 10.13. C₂₂H₄₀SiO₄.1/2 H₂O requires C, 65.19; H, 10.12%. Example 8

2,5,5-Trimethyl-2-(2'-(4"-carboxymethyl-1"R-methyl-3"-trimethylsilylmethylenecyclohex-2"-yl)-ethyl)-1,3-dioxane (11)

To freshly distilled dry cyclohexylisopropyl- amine (0.51 ml, 3.076 mmole) in dry distilled THF (5 ml) at 0°C under argon was added n-BuLi (1.92 ml of 1.6 M solution in hexane, 3.076 mmoles). The mixture was stirred at 0°C for 10 min. and then was cooled to -78°C. The ester 10 (Figure 1) (609 mg, 1.538 mmole) in dry distilled THF (5 ml) was added dropwise over 30 min and the mixture was stirred at -78°C for 3 hr followed by room temperature for 4 days. Then the mixture was poured into ice-cold, saturated ammonium chloride solution (20 ml) with 38 drops of 5N hydrochloric acid, and extracted with chloroform (3 x 20 ml). The organic extracts were washed with brine (20 ml), dried (MgSO₄), and evaporated in vacuo to give 754 mg of crude material. This was purified by flash chromatography on 76 g silica gel 60 (230-400 mesh), eluting with (1% HOAc/EtOAc)//hexane (7:93) → (50:50) to give the product 11 (Figure 1) (361 mg, 59%). IR (CHCI₃): 3575 (w), 3030 (w, broad), 3000 (m), 2955 (s), 2870 (m), 1710 (s), 1610 (w) cm^-1. NMR (CDCI₃): δ 8.17 (1 H, broad), 5.21 (1 H, s), 3.28 (4 H, m), 2.38 (2 H, m), 2.00-1.00 (11 H, m), 1.12 (3 H, s), 0.75 (9 H, m), -0.12 (9 H, s). MS (m/e): 396 (M⁺), 381 (M-Me). High-resolution MS: Found: 396.270. C₂₂H₄₀SiO₄ requires 396.269. Example 9

4R-Methyl-3-(3'-oxobutyl)-2-trimethylsilylmethylene- cyclohexylacetic acid (12)

To silica gel 60 (70-230 mesh, 400 mg) in dichloromethane (4 ml) was added 10% aqueous oxalic acid (4 drops), with stirring. The mixture was stirred at room temperature for 5 min. Then the ketal 11 (Figure 1) (150 mg, 0.38 mmole) in dichloromethane (4 ml) was added and the mixture was stirred for a further 6 hr. The mixture was filtered under suction while the solid was being washed with dichloromethane (8 ml). The filtrate was evaporated in vacuo to give 131 mg of crude material. This was purified by flash chromatography on 13 g silica gel 60 (230-400 mesh), eluting with (1% HOAc/EtOAc)/hexane (50:50) → (90:10) to give the product 12 (Figure 1) (77 mg, 65%) as a solid. IR (CHCI₃): 3580 (w), 3040 (m, broad), 2970 (s), 1710 (s), 1610 (m) cm^-1. NMR (CDCI₃): δ 8.53 (1 H, broad), 54.0 (1 H, s), 2.70 (1 H, m), 2.47 (5 H, m), 2.10 (3 H, s), 1.75 (7 H, m), 0.85 (3 H, d, J 7 Hz), 0.03 (9 H, s). MS (m/e): 310 (M+), 295 (M-Me), 277 (M-Me-H₂O). High-resolution MS: Found: 310.197. C₁₇H₃₀SiO₃ requires 310.196.

Example 10

13-desmethylartemisinin (13)

Ozonized oxygen (7.0 psi, 0.4 L/min, 70 V) was bubbled through a sintered-glass frit into a solution of the ketone 12 (Figure 1) (77 mg, 0.248 mmole) in dry methanol (20 ml) at -70°C for 68 seconds. The mixture was evaporated in vacuo to give 84 mg of material, which was dissolved in deuterochloroform (0.4 ml) in an NMR tube. Ten drops of a ten percent solution of trifluoroacetic acid in deuterochloroform were added and the mixture was kept at room temperature for 5 hr followed by 4°C for 16 hr followed by room temperature for 6 hr. The mixture was purified by flash filtration on 7.7 g silica gel 60 (230400 mesh) covered with a layer of sodium bicarbonate, eluting with EtOAc/CHCl₃ (10:90) to give 13-desmethylartemisinin (13, Figure 1) (26 mg, 39%). IR (CHCI₃): 2990 (w), 2950 (m), 2920 (m), 2855 (m), 1735 (s) cm^-1. 400 MHz NMR (CDCI₃): δ 5.89 (1 H, s), 3.18 (1 H, dd, J 7, 18 Hz), 2.40 (1 H, ddd, J 4, 11, 13 Hz), 2.25 (1 H, dd, J 1, 18 Hz), 2.02 (1 H, m), 1.87 (1 H, m), 1.83 (1 H, m), 1.66 (2 H, m), 1.45 (3 H, s), 1.33 (5 H, m), 0.99 (3 H, d, J 5 Hz). MS (m/e): 268 (M+), 253 (M-Me).

Example 11

2,5,5-Trimethyl-2-(2'-(4"-carbomethoxymethyl-1"R-methyl- 3"-trimethylsilylmethylenecyclohex-2"-yl)-ethyl)-1,3- dioxane (14)

To the carboxylic acid 11 (Figure 2) (59 mg, 0.149 mmole) in dry acetone (5 ml) was added powdered anhydrous potassium carbonate (21 mg, 0.15 mmole) followed by dimethyl sulfate (14 μl, 0.15 mmole). The mixture was heated under reflux for 3 hr, then poured into ice-cold 0.1 M sodium carbonate solution (20 ml) and extracted with diethyl ether (2 x 20 ml). The organic extracts were washed with brine (20 ml), dried (Mg SO₄), and evaporated in vacuo to give 57 mg of crude material. This was purified by preparative TLC, eluting with EtOAc/hexane (10:90) to give the product 14 (Figure 2) (39 mg, 64%). NMR (CDCI₃): δ 5.30 (1 H, s), 3.58 (3 H, s).

Example 12

2,5,5-Trimethyl-2-(2'-4''-(1'''-carbomethyloxyethyl)- 1''R-methyl-3''-trimethylsilylmethylenecyclohex-2''yl)— ethyl)1,3-di oxane (15/16)

To a solution of dry THF (3 ml) and dry isopropylcyclohexylamine (280 μl or 1.697 μmol) under argon at 0-5°C was added n-butyllithium (1.6 M in hexane, 1.06 ml, or 1.697 mmol). After 10 min at 0-5°C, 400 μl of the resultant lithium amide solution (0.24 mmol) was added to a 0°C solution of the ester 14 (Figure 2) (35 mg or 0.0854 mmol) in dry THF (1 ml). After 1 hr at 0°C, the ester enolate solution was treated with CH₃I (30 μl or 0.482 mmol). After 1 hr at 0°C, the reaction mixture was poured into saturated aqueous NH₄CI (30 ml) and extracted 2 x 25 ml EtOAc. The combined organic layer was washed 1 x 20 ml H₂O, dried over anhydrous MgSO₄, filtered, and the solvent removed on a rotovap. The residual glass was chromatographed on a TLC plate (250 micron, silica gel) with 10% Et₂O-pentane to afford a 3:1 mixture of 15:16 (Figure 2) (respectively) as a clear glass, 25 mg or 69% yield. NMR (400 MHz, CDCI₃): δ 5.30 (s, 1 H), 3.5 (s, 3 H), 3.5 (m, 1 H), 1.33 (s, 3 H), 1.05 (d, J = 6.8 Hz, 3 h), 0.98 (s, 3 H), 0.91 (d J = 7.2 Hz, 3 H), 0.87 (s, 3 H), 0.090 (s, 9 H). Example 13

3S-(3'-oxobutyl)-2-trimethyIsilyImethylene-1R,4R,7S- menthan-8-oic acid (17)

To a solution of the ester 15/16 (Figure 2) (21 mg or 0.0495 mmole) dissolved in reagent grade methanol (3 ml) under argon at room temperature was added 10% aqueous KOH (20 μl). The mixture was refluxed until the hydrolysis was complete (about 6 hrs, as determined by TLC). The reaction mixture was cooled to room temperature and poured into 1% aqueous HOAc (25 ml) and extracted 3 x 20 ml EtOAc. The combined organic layer was washed 2 x 15 ml H₂O, dried over anhydrous MgSO₄, filtered and the solvent removed on a rotovap. The resultant crude acid was dissolved in CH₂CI₂ (about 0.5 ml) and added to a well-stirred slurry of silica gel, (50 mg, 70-230 mesh Keiselgel 60) in CH₂CI₂ (0.5 ml) which had been treated with 10% aqueous oxalic acid (20 μl). After 18 hrs at room temperature under argon, the slurry was filtered and washed with CH₂CI₂ (10 ml). The solvent was evaporated to give the crude acid 17 (Figure 2) (21 mg). The crude acid was purified on a TLC plate (250 micron, silica gel) eluting with 40% EtOAc/hexane (containing 0.4% HOAc). This gave 17 (Figure 2) (13 mg or 81% yield) with about 25% isomeric contamination (the 7R analog). The isomeric acid mixture was rechromatographed as before and pure 17 (Figure 2) was isolated as a white solid (8.4 mg or 52% overall yield from 15/16). NMR (400 MHz, CDCI₃): δ 5.35 (s, 1 H), 2.73 (dq, J = 6.8, 12 Hz, 1 H), 2.3-2.6 (m, 3 H), 2.13 (s, 3 H), 1.10 (d, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.087 (s, 9 H). Example 14

Artemisinin (18)

The keto-acid 17 (Figure 2) (3.5 mg or 0.0108 mmol) was dissolved in dry methanol (1 ml) and placed in a 1 dram vial under argon with a screw cap. The solution was cooled at -78°C, the cap removed, and a stream of O₃/O₂ (7 psi, 0.4 1/min, 70 v) was bubbled in until a faint blue color was seen (about 10 sec). The cap was replaced and the solution stood at -78°C for 5 min. The solution was then purged with argon (5 min.) and warmed to room temperature. The solvent was carefully removed under high vacuum (0.02 mm Hg), and the resultant solid was kept under high vacuum for 30 min. This product was dissolved in CDCI₃ (0.75 ml) and CF₃CO₂H (10 μl) was added. The mixture was kept at room temperature for 4 hrs and then at -20°C for 18 hrs. The reaction mixture was evaporated to dryness under high vacuum and then chromatographed on TLC (250 micron, silica gel) with 20% EtOAc/hexane to give pure 18 (Figure 2) (1 mg or 33% yield). The synthetic 18 (Figure 2) was identical, by proton and carbon NMR (400 MHz), to authentic materials. It was also identical by TLC in several solvent systems.

Example 15

1. The total synthesis of racemic 13,14-des-methylartemisinin 1, as shown in Figure 1.

The bicyclic ketone 2 , available in good yield from cyclohexanone by the method of Still (W.C. Still, Synthesis, 453 (1976)), was treated with bis(trimethylsilyl)methyl lithium to give the diene 3 in 56% yield. The disubstituted double bond of 3 was selectively converted to the ozonide by treatment with ozone in methanol:dichloromethane (1:5, v/v) in the presence of sodium bicarbonate. The crude ozonolysis product was then reacted with Et₃N/Ac₂O to afford the ester-aldehyde 4 in 43% yield. This unstable aldehyde was used immediately in the reaction with lithium methoxyethyldiphenylphosphine oxide (S. Warren et al, J.C.S. Perkin I , 3099 (1979)) to give a complex diastereomeric mixture of phosphine oxides 5. It was more convenient and efficient to convert 5 without prior purification to the enol ether 6 by treatment of 5 with NaH/THF. Thus, the enol ether 6 was produced from the aldehyde 4 with 54% yield. Ester hydrolysis of 6 gave the acid 7 , acidification of which afforded the keto-acid 8, in 54% overall yield from 6. Finally, low temperature ozonolysis of 8 in methanol followed by careful evaporation of solvent gave an intermediate dioxetane which was treated immediately in moist CDCI₃ with CF₃CO₂H to give the analog 1 in 33% isolated yield.

Example 16

Preparation of 10-Trimethylsilylmethylenebicyclo[4.3.1] dec-2-ene (3)

Bis(trimethylsilyl)methyllithium was prepared according to a procedure of Grobel and Seebach (B.Th. Grobel and D. Seebach, Chem. Ber., 110, 852 (1977)); to a solution of bis(trimethylsilyl)methane (2.85 ml, 13.3 mmol) in THF (20 ml) and HMPT (5 ml) at -78°C was added dropwise via syringe a solution of s-BuLi (7.66 ml of 1.74 M in pentane). The resultant pale green solution was allowed to warm to -40°C. After 8 h at -40°C, the resultant red solution was cooled to -78°C and a solution of bicyclo[4.3.1]dec-2-ene-10-one ( 2 , Figure 3) (2.00 g, 13.3 mmol) in THF (5 ml) was added. The reaction was allowed to warm to 5°C over 13 h, then stirred with H₂O (50 ml) and extracted into hexane (2 x 50 ml). The combined hexane layers were washed with H₂O (4 x 100 ml) and brine (100 ml), dried over Na₂SO₄ and evaporated to give 3.00 g of yellow oil, which was purified via column chromatography with silica gel. After elution with EtOAc/hexane, some starting ketone, 0.35 g, was recovered and the desired diene 2 (Figure 8) was isolated as a colorless oil, 1.64 g (56.0% yield). NMR (400 MHz): δ 5.67 (AB pattern, 2 H, CH = CH-), 5.18 (s, 1 H, =CH(TMS)), 2.85 (bs, 1 H, bridgehead H), 2.26 (m, 4 H, =CH-CH₂-). 2.05 (m, 1 H), 1.79-1.55 (m, 3 H) 1.41 (s, 1 H), 1.28 (m, 1 H), 0.07 (s, 9 H, SiCH₃).

Example 17

Preparation of Methyl syn-2(3-(2-Acetaldehyde)-2(E.Z)— trimethylsilylmethylenecyclohexyl)acetate (4)

As per Schreiber's procedure (R.E. Claus and S.L. Schreiber, Org. Syn., 64, 150 (1985)), through a stirring suspension of NaHCO₃ (12 mg) in a solution of 10-trimethylsilylmethylenebicyclo[4.3.1]dec-2-ene (400 mg, 1.82 mmol), dry CH₂CI₂ (15 ml) and absolute methanol (3 ml) at -78°C was passed a stream of O₃/O₂. The disappearance of starting material was monitored by periodic TLC (SiO₂ in EtOAc/hex) before the mixture was purged with inert gas, allowed to warm to ambient temperature, filtered, diluted with dry benzene (30 ml) and concentrated at reduced pressure to a colorless solution of approximately 10 ml. This concentrate was diluted with dry CH₂CI₂ (15 ml) and treated successively with triethylamine (0.39 ml) and acetic anhydride (0.58 ml). After 4 h at ambient temperature, the reaction was stirred with 10% aq. HCl (3 ml) and H₂O (20 ml). The aqueous layer was separated and extracted with Et₂O (2 x 25 ml). The combined organic layers were washed with H₂O (25 ml), sat. aq. NaHCO₃ (2 x 30 ml) and brine (2 x 60 ml), dried over Na₂SO₄ and evaporated to give a yellow oil, which was purified via column chromatography with silica gel. After elution with EtOAc/hex, the unstable aldehyde 4. (Figure 8) was obtained as a colorless oil, 215 mg (43.7% yield) which consisted of a 1:1 mix of E:Z isomers by NMR (90 MHz) and was used immediately.

NMR (90 MHz): delta 9.70 (m, 1 H, -CHO), 5.30 (s, 1 H, =CH(TMS)), 3.65 (d, 3 H, -CO₂CH₃), 3.50-2.05 (m, 6 H), 1.90-1.10 (bm, 6 H), 0.12 (d, 9 H, SiCH₃).

Example 18

Preparation of Methyl syn-2(3-Methoxy-2(E,Z)-butenyl-2- (E,Z)trimethylsilylmethylene cyclohexyl)acetate (6)

To a solution of diisopropylamine (0.184 ml, 1.31 mmol) in THF (10 ml) at 0°C was added dropwise a solution of nBuLi (0.821 ml of 1.6 M in hexanes). After 10 min at 0°C, a solution of (1-methoxyethyl)diphenyl phosphine oxide (S. Warren et al, J.C.S. Perkin I, 3099 (1979)) (307 mg, 1.19 mmol) in THF (5 ml) was added via cannula. After 10 min at 0°C, the resultant brick red solution was cooled to -78°C, and a solution of aldehyde 4 (Figure 3) (215 mg, 0.796 mmol) in THF (5 ml) was added via cannula. After 1 h at -78°C, the resultant yellow solution was allowed to warm to ambient temperature, stirred with sat. aq. NH₄CI (20 ml) and extracted with Et₂O (2 x 20 ml). The combined ethereal layers were washed with sat. aq. NH₄CI (20 ml, brine (820 ml), sat. aq. NaHCO₃ (2 x 15 ml) and brine (2 x 25 ml), dried over Na₂SO₄ and evaporated to provide 483 mg of yellow foam, from which a purified sample of diastereomeric adduct mixture 5 (Figure 8) was obtained and spectrally scrutinized.

NMR (90 MHz): δ 8.25-7.24 (bm, 10 H, ArH), 5.75-4.90 (m, 3 H, HO-CH), 3.67 (q, 3 H, -CO₂CH₃), 3.30 (q, 3 H -OCH₃), 3.30-0.69 (m, 15 H), 0.70 (q, 9 H, SiCH₃).

The crude adduct mixture 5 (Figure 8) was placed in THF (4 ml) and added via cannula to a stirring suspension of NaH (24 mg of an 80% oil dispersion, 0.80 mmol) in THF (8 ml). After 3 h at ambient temperature, the resultant suspension was stirred with sat. aq. NH₄CI (15 ml) and hexane (50 ml). The separated organic layer was washed with sat. aq. NH₄CI (15 ml) and brine (25 ml), dried over Na₂SO₄ and evaporated to afford 344 mg of orange oil, which was purified by column chromatography with silica gel. After elution with EtOAc/hexane, enol ether 6 (Figure 3) was obtained as a colorless oil, 140 mg (54.3% yield from 4) , which was a mix of four diastereomers as reflected in the NMR and TLC (SiO₂ in EtOAc/hexane).

NMR (90 MHz): δ 5.10 (m, 1 H, -CH), 4.18 (bm, 1 H, -CH(OMe)), 4.48 (m, 3 H, OCH₃), 3.17-0.90 (m, 15 H), 0.07 (d, 9 H, SiCH₃). Example 19

Preparation of syn-2(3(3-Oxobutyl)-2(E,Z)-trimethylsilylmethylenecyclohexyl)acetic Acid (8)

To a solution of ester 6 (Figure 3) (90.0 mg, 0.278 mmol) in MeOH (10 ml) was added 6 N KOH (0.69 ml, 15 equiv). The solution was heated at reflux for 12 h and allowed to stir at ambient temperature for an additional 12 h. The resultant yellow solution was acidified with sat. aq. NH₄CI (35 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (2 x 30 ml), dried over Na₂SO₄ and evaporated to give acid 2 (Figure 3 ) as a yellow oil, which was a fairly pure E:Z mix by NMR and used without further purification.

NMR ( 90 MHz ) : δ 5.23 (m, 1 H, = CH) , 4. 26 (bt, 1 H, MeO-C=CH), 3.48 (m, OCH₃), 3.40-0.90 (m, 15 H), 0.07 (d, 9 H, SiCH₃).

The yellow oil was placed in CH₂CI₂ (10 ml) and stirred with silica gel (70-230 mesh) while adding freshly prepared 10% aq. oxalic acid (50 ml). After 2 h at ambient temperature, the solid was filtered off and rinsed with CH₂CI₂ (100 ml). The filtrate was concentrated in vacuo to afford a yellow oil, which was purified by column chromatography with silica gel. After elution with HOAc/EtOAc/hexane, ketoacid 8 (Figure 8) was obtained as a yellow oil, 77 mg (93.9% yield from enol 7).

NMR (90 MHz): delta 5.23 (d, 1 H, =CH), 3.30-2.30 (m, 6 H), 2.13 (s, 3 H, COCH₃ ), 2.00-1.00 (bm, 8 H), 0.07 (d, 9 H, SiCH₃). Example 20

Preparation of (+)-13,14-Desmethylartemisinin (1)

Through a solution of ketoacid 8 (Figure 8) (17 mg, 0.057 mmol) in absolute MeOH (2 ml) at -78°C was passed a stream of O₃/O₂ until no starting material could be detected by TLC (HOAc/EtOAc/hexane). The resultant pink solution was allowed to warm to ambient temperature and concentrated in vacuo to a yellow foam, which was placed in CDCI₃ (2 ml). After treatment with 10% trifluoroacetic acid in CDCI₃ (20 microliter), the formation of cyclization product 8 was monitored by NMR (90 MHz). After 8.5 h at ambient temperature, the solution was stirred with NaHCO₃ (25 mg), filtered, and evaporated to give 17 mg of yellow oil, which was purified by PTLC with silica gel. After development with 5% EtOAc/CHCl₃, the major component was isolated and reapplied to PTLC plates for development in 35% EtOAc/hexane. In this manner, (±) 13,14-desmethylartemisinin (1, Figure 8) was isolated as white needles which were recrystallized with EtOAc/hexane to give 4.8 mg, mp 130-130.5°C.

¹H NMR (400 MHz): δ 5.90 (s, 1 H, H5), 3.18 (dd, 1 H, J = 18.3, 7.1 Hz, H_11α), 2.42 (dt, 1 H, J = 13.5, 3.8 Hz, H₁)m 2.25 (dd, 1 H, J = 18.3, 1.3 Hz, H_11β), 2.02 (ddd, 1 H, J = 15.3, 4.9, 2.7 Hz, H_3α), 1.96-1.48 (m, 10 H), 1.44 (s, 3 H, -CH₃). ¹³C NMR: δ 168.7, 105.4, 93.2, 78.1, 43.9, 38.4, 36.0, 32.1, 31.6, 30.2, 26.6, 25.5, 25.4, 24.7. IR (KBr) 2925, 1735, 1210, 1005 cm^-1. CIMS (⁺NH₄) m/e 272 (M + ⁺NH₄), 255 (M + ⁺H). Example 21

1-t-Butyldimethylsilyloxymethylcyclohexene (5).

To a solution of 1-hydroxymethylcyclohexene 4 (Figure 6) (46.6 ml, 44.8 g, 400 mmoles) in dry dichloromethane (250 ml) at 0°C under argon was added N,N-diisopropylethylamine (76.6 ml, 440 mmoles) followed by a solution of t-butyldimethylchlorosilane (66.3 g, 440 mmoles) in dry dichloromethane (100 ml). The mixture was stirred at room temperature for 2 hr and then was poured into ice cold, saturated ammonium chloride solution (100 ml). The organic layer was separated and washed with saturated ammonium chloride solution (100 ml) and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried (K₂CO₃) and evaporated in vacuo to give 89.7 g of crude material. This was fractionally distilled under reduced pressure to give the product 5 (Figure 6) (81.8 g, 90%) as a colorless liquid, bp 94º-100°C/6 mm Hg. IR (thin film): 3000 (m), 2950 (s), 293) (s), 2880 (s), 2855 (s), 1680 (w) cm^-1. NMR (CDCI₃): delta 5.62 (1 H, m), 3.97 (2 H, s), 1.93 (4 H, m), 1.56 (4 H, m), 0.88 (9 H, s), 0.03 (6 H, s). MS (m/e): 226 (M⁺), 211 (M-Me).

Example 22

1-(t-Butyldimethylsilylhydroxy-methyl)cyclohexene (6).

To the silyl ether (5, Figure 6) (26.0 ml, 22.6 g, 100 mmoles) in dry THF (250 ml) at -78°C under argon was added dry TMEDA (24.0 ml, 160 mmoles) followed by s-BuLi (154 ml of 1.3 M solution in cyclohexane, 200 mmoles). The mixture was stirred at -30°C for 3 hr and then recooled to -78°C. A mixture of acetic acid (20 ml) and THF (80 ml) was slowly added. The mixture was poured onto ice cold, saturated sodium bicarbonate. solution (200 ml), which was extracted with dichloromethane (2 x 300 ml). The organic extracts were washed with brine (200 ml), dried (MgSO₄), and evaporated in vacuo to give 26.7 g of crude material. This was purified by flash chromatography on 267 g silica gel 60 (230-400 mesh), eluting with EtOAc/hexane (5:95) → (7:93) to give the product 6 (Figure 6) (11.65 g, 52%) as a colorless oil. IR (thin film): 3580 (w), 3460 (m, broad), 3040 (w), 2940 (s), 2900 (s), 2870 (s), 1670 (w) cm^-1. NMR (CDCI₃): δ 5.53 (1 H, m), 3.92 (1 H, s), 1.97 (4 H, m), 1.58 (4 H, m), 0.94 (9 H, s), -0.01 (3 H, s), -0.11 (3 H, s). MS (m/e): 226 (M⁺), 225 (M-H).

Example 23

1-(1'-t-Butyldimethylsilyl-1'-propionoxymethyl) cyclohexene (7).

To a solution of the alcohol (6, Figure 6) (11.3 g, 50.0 mmoles) in diethyl ether (100 ml) at room temperature under argon was added dry pyridine (8.10 ml, 100 mmoles) followed by propionic anhydride (7.70 ml, 60.0 mmoles). 4-Dimethylaminopyridine (610 mg, 5.0 mmoles) was added and the mixture was stirred at room temperature for 16 hr. The mixture was poured into ice cold water (100 ml) and extracted with diethyl ether (2 x 100 ml). The organic extracts were washed with saturated ammonium chloride solution (100 ml), dried (MgSO₄), and evaporated in vacuo to give 18.7 g of crude material. This was purified by flash filtration through 100 g silica gel 60 (230-400 mesh), eluting with 500 ml of EtOAc/hexane (7:93) to give the product 7 (Figure 6) (13.9 g, 99%) as a colorless oil. IR (thin film): 3030 (w), 2925 (s), 2885 (m), 2850 (s), 2770 (w), 1740 (s), 1660 (w) cm^-1. NMR (CDCI₃): δ 5.44 (1 H, m), 5.05 (1 H, s), 2.25 (2 H, q, J 7 Hz), 1.88 (4 H, m), 1.49 (4 H, m), 1.05 (3 H, t, J 7 Hz), 0.83 (9 H, s), -0.03 (3 H, s), -0.12 (3 H, s). MS (m/e): 282 (M⁺), 253 (M-Et), 225 (M-EtCO).

Example 24

1-(1'-Carboxyethyl)-2-t-butyldimethylsilyl-methylene- cyclohexane (8).

To dry cyclohexylisopropylamine (2.17 ml, 13.0 mmole) in dry THF (20 ml) at 0°C under argon was added n-BuLi (8.13 ml of 1.6 M solution in hexane, 13.0 mmoles). The mixture was stirred at 0°C for 10 min and then was cooled to -78°C. The ester (2, Figure 6) (3.08 ml, 2.82 g, 10.0 mmoles) was added dropwise and the mixture was stirred at room temperature for 18 hr. The mixture was poured into ice-cold saturated ammonium chloride solution (50 ml), and extracted with diethyl ether (2 x 50 ml), the organic extracts were washed with brine (50 ml), dried (MgSO₄), and evaporated in vacuo to give 4.0 g of crude material. This was purified by flash chromatography on 200 g silica gel 60 (230-400 mesh), eluting with (1% HOAc/EtOAc)/hexane (15:85) → (20:80) to give the undesired isomer (161 mg, 6%) and the desired product 8 (Figure 6) (1.70 g, 68%) as a crystalline solid, mp 106-109°C. IR (CHCI₃): 3500 (w), 3030 (m, broad), 2930 (s), 2860 (s), 2650 (m, broad), 1710 (s), 1620 (s) cm^-1. NMR (CDCI₃): delta 5.23 (1 H,s), 2.72 (1 H, m), 2.31 (3 H, m), 1.64 (6 H, m), 1.06 (3 H, d J 6 Hz), 0.88 (9 H, s), 0.07 (6 H, s). MS (m/e): 257 (M-Me), 255 (M-OH), 225 (M-Bu^t). Analysis: Found: C, 68.11; H, 10.45; Si, 9.56. C₁₆H₃₀SiO₂ requires C, 68.09; H, 10.64; Si, 9.93%.

Example 25

1-t-Butyldimethylsilyloxy-8-hydroperoxy-4-methyl8- hexahydroisochroman-3-one (1).

Ozonized oxygen (7.0 psi, 0.41/min, 70 V) was bubbled through a sintered-glass frit into a solution of the carboxylic acid (8, Figure 6) (500 mg, 1.77 mmole) in dry methanol (20 ml) at -70°C for 6 min 40 sec. The mixture was evaporated in vacuo to give 651 g of crude material, which was purified by flash chromatography on 65 g silica gel 60 (230-400 mesh), eluting with EtOAc/hexane (25:75) to give the product 1 (Figure 4) (334 mg, 57%) as a white solid. IR (CHCI₃): 3520 (m), 3340 (m,broad), 2950 (s), 2900 (m), 2890 (m), 2870 (s), 1740 (s) cm^-1. NMR (400 MHz, CDCI₃): delta 8.06 (1 H, broad), 5.74 (1 H, s), 2.99 (1 H, dq, J 7, 7 Hz), 2.21 (1 H, ddd, J 7,7,12 Hz), 1.91 (1 H, m), 1.67 (5 H, m), 1.28 (2 H, m), 1.16 (3 H, d, J 7 Hz), 0.92 (9 H, s), 0.20 (3 H, s), 0.17 (3 H, s). C₁₃ NMR (400 MHz, CDCI₃): delta 173.6, 138.3, 99.5, 83.2, 41.1, 35.5, 29.2, 25.6, (3 C), 25.5, 23.7, 23.1, 21.0, 17.9, 12.4. MS (m/e): 331 (M + H⁺), 315 (M-Me), 297 (M-O₂H), 285 (M-CO₂), 273 (M-Bu^t). The stereochemistry of 1 (Figure 6) was determined as follows: Treatment of 1 with triphenylphosphine in THF gave the alcohol 1a (Figure 4). After careful chromatographic purification and multiple crystallizations, 1a was analyzed by X-ray crystallographic analysis (Crystallytics, Inc., Lincoln, Nebraska) and shown to have the structure and relative stereochemistry given in Figure 1. From this information, the structure of 1 can be inferred as shown in the Figure 6.

Example 26

14-Desmethyl-2-nor-1,2-secoartemisinin (2).

To a solution of the hydroperoxide 1. (Figure 6) (133 mg or 0.403 mmol) in dry, distilled acetone (6 ml) under argon was added trifluoroacetic acid (0.54 ml). The mixture was magnetically stirred overnight at room temperature under argon, poured into sat. aq. NaHCO₃ and extracted 3 x 25 ml Et₂O. The combined organic layer was washed 1 x 40 ml H₂O and 1 x 40 ml saturated aqueous NaCl. The organic phase was dried over MgSO₄, filtered, and the solvent evaporated in vacuo. The crude product was placed on one preparative TLC plate (1.5 mm silica gel) and eluted with 20% EtOAc/hexane to give 2 (Figure 4) as a white solid (75 mg or 73% yield), m.p. 111-112°C. IR (CCI₄): 2960, 2880, 1755, 1460, 1390, 1220, 1180, 1100, 1020 cm^-1. Compound 2 displays unusual NMR behavior. ¹H NMR (CDCI₃) at 25°C: δ 0. 92 (d, J = 8.8 Hz, 2H), 1.18 (br s, 3H), 1.38 (br s, 3H), 2.70 (br s, 0.5H), 3.10 (br s, 0.5H), 5.50 (br s, 1H); at 60°C: 0.95 (dq, J = 4.7, 13.3 Hz, 1H), 1.18 (d, J = 6.8 Hz , 3H) , 1.43 (br s , 3H) , 1.54 (br s , 3H), 2.5 (very br s, 1H), 3.2 (br s, 1H), 5.60 (s, 1H); at 3.5°C: 0.9 (m, 1.5H), 1.60 (d, J = 7.2 Hz, 3H), 1.37 (s, 3H), 1.61 (s, 3H), 2.69 (d, J = 13 Hz, 0.8H), 3.09 (dq, J = 6.6, 13 Hz, 0.8H), 3.5 (m, 0.4H), 5.59 (s, 0.8H), 5.68 (s, 0.2H). ¹³C NMR (CDCI₃) at 60°C: δ 12.0, 23.0, 23.6, 24.9, 25.1, 31.3, 34.0, 71.8, 76.0, 76.5, 92.9, 94.8, 172.0. Mass spectrum (DCI-NH₃): 274 (M+NH₄ ⁺), 257 (M+H⁺), 198, 181, 170, 153.

Example 27

The preparation of Examples 20-24 is repeated with the change that in Example 20 in place of 1-hydroxymethyl cyclohexene 4 (Figure 6), 400 mmole of 1-hydroxymethylcyclopentene is used. This gives rise to artemisinin analogs similar to compounds 2 and 3 but having one less carbon in the alkylene bridge between the "1" and "7" carbons.

Example 28

The preparation of Examples 20-24 is repeated with the change that in Example 20 in place of 1-hydroxymethyl cyclohexene 4 (Figure 4), 400 mmole of 1-hydroxy-2-ethylhex-2-ene is used. This gives rise to artemisinin analogs similar to compounds 2 and 3 but having an ethyl as R⁸ and a butyl as R⁹.

Example 29

Biological Results

(A) The analog 1 (Figure 8) was sent to Walter Reed Army Institute of Research (WRAIR) for in vitro testing against P. falciparum using modifications of the procedures of Desjardins et al, 1979, and Milhous et al, 1985, (Desjardins, R.E., C.J. Canfield, D.E. Haynes, and J.D. Chulay, Antimicrob. Angents Chemother., Vol. 16, 710-718 (1979); Milhous, W.K., N.F. Weatherly, J.H. Bowdre, and R.E. Desjardins, Antimicrob. Agents Chemother. Vol. 27, 525-530, 1985.) to assess the intrinsic activity of compound 1 (Figure 8) as an anti-malarial drug relative to simultaneous known controls such as chloroquine, mefloquine, pyrimethamine, sulfadoxine, tetracycline, qinghaosu or quinine. Since some anti-malarials are more static than cidal in action, it is necessary to extend the incubation period to assess the effects of such drugs on parasite growth rates. In order to insure exponential parasite growth and maximum uptake of radioisotope throughout the extended incubation, reduced starting parasitemias (0.2%) and reduced red cell hematocrits (1.0%) are required. As a result, drugs which are actively incorporated into erythrocytes (such as chloroquine or qinghaosu) will have slightly lower 50% inhibitory concentrations than in other assay systems employing higher red cell hematocrits. Except for the contribution from the 10% normal pooled human plasma and added 10^-10M (0.014 ng/ml) PABA, the culture medium is folate-free. The trace amount of PABA insures exponential growth of the sulfonamide-susceptible parasite clone without antagonizing the activity of antifol anti-malarials. Sulfonamides and sulfones are 1, 000-10, 000-fold more active and DHFR inhibitors are 5-200-fold more active in this medium than in normal RPMI 1640 culture medium.

All test compounds are solubilized in DMSO and diluted 400-fold (to rule out a DMSO effect) in culture medium with plasma for a starting concentration of at least 12,500 ng/ml. Drugs are subsequently diluted fivefold using the Cetus Pro/Pette system utilizing a range of concentrations from 0.8 ng/ml to 12,500 ng/ml. Fifty percent inhibitory concentrations are reported in ng/ml.

Table 1 summarizes differences in the susceptibility profiles of the two control P. falciparum clones (Oduola, A.M.J., N.F. Weatherly, J.H. Bowdre, R.E. Desjardins, Thirty-second Annual Meeting, American Society of Tropical Medicine and Hygiene, San Antonio, Texas, December 4-8, 1983) and provides results of testing. The W-2 Indochina P. falciparum clone is resistant to chloroquine, pyrimethamine and sulfadoxine but susceptible to mefloquine. The D-6 African P. falciparum clone is susceptible to chloroquine, pyrimethamine and sulfadoxine but resistant to mefloquine.

(±)-13,14-Desmethyl-artemisinin (1)

The data shown in Table 1 indicate that compound 1 (Figure 8) is approximately 1/2 as active as the natural product Qinghaosu against the W-2 Indochina strain of P. falciparum. Against this same strain, compound 1 (Figure 8) was about three times as potent as the classical antimalarial agent chloroquine. While it can be seen from the table that the antimalarial efficacy of 2 varies with strain, the potency of 1 versus the other five compounds is still in the nanogram range and this is highly significant. These data show that compound 1 (Figure 3) is a highly active antimalarial agent.

B. The WRAIR in vitro antimalarial screen was used to assess the intrinsic activity of compounds (2, Figure 6) and (3, Figure 6) as antimalarial drugs relative to simultaneous known controls such as chloroquine, mefloquine, pyrimethamine, sulfadoxine, tetracycline, qinghaosu or quinine.

Table 2 summarizes differences in the susceptibility profiles of the two control P. falciparum clones.

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a polyoxa artemisinin analog compound which comprises subjecting an appropriately substituted vinylsilane compound to ozonolysis and thereafter acidifying the product generated by the ozonolysis.

2. The process of claim 1 wherein the artemisinin analog is a compound of the formula

wherein R₁ is selected from the group consisting of one carbon atom long through three carbon atom long alkylene bridges and substituted one carbon atom long through three carbon atom long alkylene bridges,

R₂ is a covalent bridge selected from the group consisting of a covalent single bond and one carbon atom through five carbon atom long alkylene bridges and substituted one carbon atom through five carbon atom long alkylene bridges,

R₃ is a covalent bridge selected from the group consisting of one carbon atom through three carbon atom long alkylene bridges and one carbon atom through three carbon atom long alkylene bridges having substitution on their carbon atom adjacent to the carbonyl, R₄ is selected from the group consisting of hydrogen, methyl and substituted methyl,

R₅ and R₆ are selected such that they together are a carbonyl oxygen or separately R₅ is selected from the group consisting of hydrogen, methyl and substituted methyl and R₆ is selected from the group consisting of hydrogen, hydroxyl, alkyl esters, carboxylic acid esters, carbonate, carbamates, amides, and urea, and X is a heteroatom group selected from -O-, -S- and wherein R₁₀ is selected from the group

consisting of hydrogen, alkyls, substituted alkyls, aryls and substituted aryls, and wherein the vinylsilane is a compound of the formula

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₁₀, and X are as defined and R₇, R₈ and R₉ are independently selected from lower hydrocarbyls.

3. The process of claim 1 wherein the ozonolysis is conducted in a liquid reaction medium at a temperature of from about 15°C to the freezing temperature of the liquid reaction medium; and wherein the ozonolysis is conducted with from 0.75 to 1.25 equivalents of ozone per mole of vinyl silane.

4. The process of claim 3 wherein the acidification is carried out with an acid having a pKa of 5 or less.

5. The process of claim 4 wherein the liquid reaction medium is a one through ten carbon atom alkanol.

6. A polyoxa tetracyclic compound of the formula

wherein R₁ is selected from the group consisting of one carbon atom long through three carbon atom long alkylene bridges and substituted one carbon atom long through three carbon atom long alkylene bridges,

R₂ is a covalent bridge selected from the group consisting of a covalent single bond and one carbon atom through five carbon atom long alkylene bridges and substituted one carbon atom through five carbon atom long alkylene bridges,

R₃ is a covalent bridge selected from the group consisting of one carbon atom through three carbon atom long alkylene bridges and one carbon atom through three carbon atom long alkylene bridges having substitution on their carbon atom adjacent to the carbonyl,

R₄ is selected from the group consisting of hydrogen, methyl and substituted methyl,

R₅ and R₆ are selected such that they together are a carbonyl oxygen or separately R₅ is selected from the group consisting of hydrogen, methyl and substituted methyl and R₆ is selected from the group consisting of hydrogen, hydroxyl, alkyl esters, carboxylic acid esters, carbonate, carbamates, amides, and urea, and X is a heteroatom group selected from -O-, -S- and wherein R₁₀ is selected from the group

consisting of hydrogen, alkyls, substituted alkyls, aryls and substituted aryls, subject to the proviso that R₁ can not be a methyl-substituted methylene when R₂ is a 3-methyl propylene, R₃ is an ethylene, and R₄ is a methyl and R₅ and R₆ are together a carbonyl oxygen or R₅ is a hydrogen and R₆ is a hydroxyl.

7. The polyoxa tetracyclic compound of claim 9 wherein R₁ is a one to two carbon atom long alkylene;

R₂ is a three to five carbon atom long alkylene;

R₃ is a one to two carbon atom long alkylene; and R₅ and R₆ together are a carbonyl oxygen.

8. A vinyl silane of the formula

wherein R₁ is selected from the group consisting of one carbon atom long through three carbon atom long alkylene bridges and substituted one carbon atom long through three carbon atom long alkylene bridges,

R² is a covalent bridge selected from the group consisting of a covalent single bond and one carbon atom through five carbon atom long alkylene bridges and substituted one carbon atom through five carbon atom long alkylene bridges,

R₃ is a covalent bridge selected from the group consisting of one carbon atom through three carbon atom long alkylene bridges and one carbon atom through three carbon atom long alkylene bridges having substitution on their carbon atom adjacent to the carbonyl,

R₄ is selected from the group consisting of hydrogen, methyl and substituted methyl,

R₅ and R₆ are selected such that they together are a carbonyl oxygen or separately R₅ is selected from the group consisting of hydrogen, methyl and substituted methyl and R₆ is selected from the group consisting of hydrogen, hydroxyl, alkyl esters, carboxylic acid esters, carbonate, carbamates, amides, and urea, and X is a heteroatom group selected from -O- , -S- and wherein R₁₀ is selected from the group

consisting of hydrogen, alkyls, substituted alkyls, aryls and substituted aryls, and R₇, R₈ and R₉ are independently selected from lower hydrocarbyls.

9. The process of claim 1 wherein the artemisinin analog is a seco analog of artemisinin of the formula

wherein R¹ and R² are independently selected from hydrogens, methyls and alpha-unsubstituted organic moieties containing up to about 12 carbon atoms, subject to the proviso that the total size of R¹ and R² is not greater than about 20 carbons; R⁶ is selected from hydrogen, while R⁷ is selected from hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamates, amides, and ureas or together R⁶ and R⁷ are a carbonyl oxygen; R⁸ and R⁹ are independently selected from hydrogen, alkyls, and substituted alkyls or together form an organic ring; and R¹⁰ and R¹¹ are independently selected from hydrogen, lower alkyls wherein the vinylsilane is of the formula

wherein R³, R⁴ and R⁵ are independently selected from hydrocarbyls and R⁸, R⁹, R¹⁰ and R¹¹ are as previously defined, thereby yielding a silyloxy-hydroperoxide of the formula

and wherein the acidification is carried out to react said silyloxy-hydroperoxide with a ketone of the formula

in the presence of an acid.

10. The process of claim 9 comprising the additional step of reducing the product of the acidification with a borohydride.

11. A seco analog of artemisinin of the formula

wherein R¹ and R² are independently selected from hydrogens, methyls and alpha-unsubstituted organic moieties containing up to about 12 carbon atoms, subject to the proviso that the total size of R¹ and R² is not greater than about 20 carbons; R⁶ is selected from hydrogen, while R⁷ is selected from hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamates, amides, and ureas or together R⁶ and R⁷ are a carbonyl oxygen; R⁸ and R⁹ are independently selected from hydrogen, alkyls, and substituted alkyls or together form an organic ring; and R¹⁰ and R¹¹ are independently selected from hydrogen, lower alkyls and substituted lower alkyls.

12. A seco analog compound of claim 11 of the formula

13. A seco analog compound of claim 11 of the formula

14. A vinylsilane of the formula

wherein R³, R⁴ and R⁵ are independently selected from hydrocarbyls; R⁸ and R⁹ are independently selected from hydrogen, alkyls, and substituted alkyls or are joined together to form an alkylene ring; and R¹⁰ and R¹¹ are independently selected from hydrogen, lower alkyls, and substituted lower alkyls.

15. The process of claim 1 wherein the artemisinin analog is a polyoxatetracyclic compound of the formula

wherein m is an integer selected from 0 and 1; n is an integer selected from 0, 1, 2, 3, and 4; p is an integer selected from 0, 1 and 2, subject to the proviso that the sum of m plus p has a value from 0 through 2 inclusive; R^F is selected from hydrogen, lower alkyls and substituted lower alkyls; the remaining R's are each independently selected from hydrogens, alkyls and substituted alkyls; and X and Y are selected such that they together equal a carbonyl oxygen or X is hydrogen, while Y is selected from the group consisting of hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamate, amides and ureas ; and wherein the vinylasilane is a carbonyl/ester vinylsilane of the formula

16. The process of claim 1 wherein the artemisinin analog is a polyoxatetracyclic compound of the formula

wherein m is an integer selected from 0 and 1; n is an integer selected from 0, 1, 2, 3, and 4; the R's are each independently selected from hydrogens, alkyls and substituted alkyls; and X and Y are selected such that they together equal a carbonyl oxygen or X is hydrogen, while Y is hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamate, amides and ureas; and wherein the vinylsilane is a carbonyl/ester vinylsilane of the formula

wherein the R^S's are lower hydrocarbyls; and R^E is a protecting esterifying group

17. The process of claim 1 wherein the artemisinin analog is a polyoxatetracyclic compound of the formula

wherein m is an integer selected from 0 and 1; n is an integer selected from 0, 1, 2, 3, and 4; p is an integer selected from 0, 1 and 2, subject to the proviso that the sum of m plus p has a value from 0 through 2 inclusive; the R's are each independently selected from hydrogens, alkyls and substituted alkyls; and X and Y are selected such that they together equal a carbonyl oxygen or X is selected from the group consisting of hydrogen, alkyls, and substituted alkyls and Y is selected from the group cons isting of hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamate, amides and ureas; and wherein the vinylsilane is a carbonyl/ester vinylsilane of the formula

wherein the R^S's are lower hydrocarbyls; and R^E is a protecting esterifying group.

18. A polyoxatetracyclic compound of the formula

wherein m is an integer selected from 0 and 1; n is an integer selected from 0, 1, 2, 3, and 4; p is an integer selected from 0, 1 and 2, subject to the proviso that the sum of m plus p has a value from 0 through 2 inclusive; R^F is selected from hydrogen, lower alkyls and substituted lower alkyls; the remaining R's are each independently selected from hydrogens, alkyls and substituted alkyls subject to the proviso that at least one of the R^A1, R^A2, R^C1 and R^C2 substituents is other than hydrogen; and X and Y are selected such that they together equal a carbonyl oxygen or X is a hydrogen while Y is selected from the group consisting of hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamate, amides and ureas.

19. A vinylsilane of the formula

wherein m is an integer selected from 0 and 1; n is an integer selected from 0, 1, 2, 3, and 4; the R's are each independently selected from hydrogens, alkyls and substituted alkyls and the R^S's are each independently selected from lower hydrocarbyls.

20. Artemisinin radiolabeled with carbon-14 at its 13-carbon position.

21. The polyoxatetracyclic compound of claim 1 of the formula

22. The polyoxatetracyclic compound of claim 1 of the formula

wherein R₁₀ is methyl.

23. The polyoxatetracyclic compound of claim 1 of the formula

24. The polyoxatetracyclic compound of claim 1 of the formula

wherein R is a lower alkyl.

25. The polyoxatetracyclic compound of claim 1 of the formula

wherein R is a lower alkyl.

26. The polyoxatetracyclic compound of claim 1 of the formula

wherein R is a lower alkyl

27. The polyoxatetracyclic compound of claim 1 of the formula

28. An antimalarial composition comprising a compound of claim 6 in a pharmaceut ically acceptable carrier.

29. An antimalarial composition comprising a compound of claim 11 in a pharmaceutically acceptable carrier.

30. An antimalarial composition comprising a compound of claim 18 in a pharmaceutically acceptable carrier.