Synthesis of Artemisinin

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

The entire biosynthesis pathway of artemisinin has not been elucidated yet. The first committed step is conversion of FPP to amorphadiene via the cyclization catalyzed by ADS [102] followed by further oxidations of amorphadiene to artemisinic acid. Artemisinic acid can be used as a precursor for semi-synthesis of artemisinin and related chemicals [88]. 

Scheme 10. Total synthesis of artemisinin by Schmid and Hofheinz. Conditions (i) ClCH20Me, PhN(CH3)2, DCM, rt. (ii) B2H6/THF, H2O2 (iii) PhCHzBr, KH, THF/DMF (iv) HCl, MeOH (v) PCC, DCM, rt. (vi) LDA, (E)-(3-iodo-l-methyl-l-propenyl)-trimethylsilane (vii) lithium methoxy(trimethylsily)methyhde (viii) Li/NH3 (ix) PCC DCM (x) m-CPBA, DCM (xi) -Bu4NF, THF, rt. (xii) O2 (methylene blue, DCM, rt.) (xiii) HCOOH, DCM.

The total synthesis of artemisinin via conventional chemistry has also been achieved. In 1983, Schmid and Hofheinz pubhshed a paper showing the complete synthesis of artemisinin from (-)-Isopulegol (Scheme 10), with 5% overall yield. Since then, several other total synthesis of arteminisin... 

Ravindranathan T, Knmar MA, Menon RB, Hiremath SV. (1990) Stereoselective synthesis of artemisinin. Tetrahedron Lett 31 755-758. 

Ekthawatchai S, Kamchonwongpaisan S, Kongsaeree P, Tamchompo B, Thebtaranonth Y, Yuthavong Y. (2001) C-16 artemisinin derivatives and their antimalarial and cytotoxic activities Synthesis of artemisinin monomers, dimers, trimers and tetramers by nucleophilic additions to artemisitene. JMed Chem 44 4688 695. 

The biosynthesis of artemisinin3 is of interest in that it provides clues to the chemical synthesis of artemisinin from its more abundant precursor in A. annua, artemisinic acid 2. Conjugate reduction of the acrylate double bond of 2 followed by singlet oxygenation leads,... 

To better understand the importance of optical activity towards antimalarial activity and to further improve this CoMFA study, the synthesis of (-)-artemisinin and various other analogues having unnatural configuration are underway. In addition, further analogues needed to complete this study are (3-face substituents in the B and C rings of artemisinin, or primarily the axial positions at C-5, C-7, and C-8. Analogues such as 422 pave the way for the latter of these cases, C-83 substituted analogues. 

Avery, M. A. Chong, W. K. M. Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L. /. Am. Chem. Soc. 1992,... 

The key intermediate for the synthesis of artemisinine is the acid 80, which has been used to build-up the peroxide linkage resulting in the formation of 7. Schmid and Hofheinz [92] obtained 80 starting from (-)-isopulegol (72) (Scheme 7), while the Chinese scientists have synthesized it starting from R(+)-citronellal (81) (Scheme 8) [93]. 

Recently Avery et al [94] have developed a stereoselective total synthesis of (+)-artemisinine starting from (R)-(+)-pulegone (92). Elaboration of 92 gives the known sulphoxide 93, which was allowed to undergo dianion alkylation and desul-phurisation to yield disubstituted-cyclohexanone (95). Homologation of the latter afforded the aldehyde % in two steps. This product was then converted into the silyl acetate (97), which underwent Tandem Claisen ester-enolate rearrangement to give the vinylsilane 98. Ozonolysis and cyclisation of 98 provided 7 (Scheme 10). 

Dihydroqinghaosu (32) (Scheme 1) is a key intermediate in the synthesis of artemisinin analogues / derivatives, which have shown antimalarial activity. Following the Chinese scientists s work, Lin et al. [95] synthesized a series of water soluble derivatives of artemisinin of which artenilic acid (36d) was found to exhibit activity and better stability than artemisinin or artesunate. Brossi et al. [96] reported the synthesis of arteether (36b), which after preclinical studies is now in clinical evaluation in India [96a], Deoxyqinghaosu described in scheme 11 has been reported to have high antimalarial activity. Synthesis of (+)-12-butyldeoxoartemisinin (99) and some tricyclic analogues (100) of artemisinin has recently been achieved [97,98]. 

In this chapter, we first describe the peculiar electronic structure of 2 and its impact on its chemical reactivity that is opposite from that of ordinary oxygen 02-Then, we compare the respective advantages and limitations of photochemical and chemical methods to generate 2 in a context of industrial development. In particular, we detail the criteria for choosing a reaction medium compatible with both the organic substrate and water-soluble chemical sources of 02- Finally, the main reactions of 2 in organic chemistry are listed and illustrated with two industrially relevant examples recently developed in the fields of perfumery (synthesis of rose oxide) and pharmacy (synthesis of artemisinin). 

Bhisutthibhan, J., Pan, X.-O., Hossler, P.A., Walker, D.J., Yowell, C.A., Carlton, J., Dame, J.B., and Meshnick, S.R. The plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin, /. Biol. Chem., 273,16192,1998. 21. Avery, M.A., Chong, W.K.M., and Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L., /. Am. Chem. Soc., 114,974,1992. Avery, M.A., Bonk, J.D., and Bupp, J. Radiolabeled antimalarials synthesis of 14C-artemisinin, /. Labelled Comp. Radiopharm., 38, 263, 1996. 

The total and partial synthesis of artemisinin, a potent antimalarial agent, investigated in the last three decades (14SC1987), and the evolution of synthetic strategies, mainly modern approaches focused on step economy and overall cost, and new reaction developments (14SL751) were reviewed. 

The Claisen rearrangement of the enolate of the ester 12 generated with LDA, afforded the y,<5-unsaturated acid 13 which served as an intermediate in the total synthesis of (+)-artemisinin (Scheme 5.1.17) [28]. 

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