Artemisinin Artemisinic acid

Experiments with and -labelled precursors provided unambiguous evidence, that there are several branch points in the biosynthesis of artemisinin. The most prominent sesquiterpene metabolites in sweet wormwood are, aside from artemisinin, artemisinic acid and arteannuin B, which branch off at the artemisinic aldehyde stage. [465]... 

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]. 

Artemisinic acid can indeed be easily converted to artimisinin using conventional chemistry in three steps via reduction of the exocyclic methylene group and photooxidation of the resulting dihydroartemisinic acid, with 30% overall yield (see Scheme 9) Other artemisinin derivatives have also been prepared using artemisinic acid as the starting material. ... 

Roth RJ, Acton N. (1989) A simple conversion of artemisinic acid into artemisinin. J Nat Prod 52 1183-1185. 

Haynes RK, Vonwiller SC. (1994) Extraction of artemisinin and artemisinic acid Preparation of artemether and new analognes. Trans R Soc Trap Med Hyg 88 23-26. 

Using various derivatives of artemisinic acid, the methodology onthned in Scheme 184 was extended to the synthesis of a nnmber of modified artemisinin-type tetracychc trioxanes. For example, the syntheses of 6,9-desdimethylartemisinin 586a , A-fi-hydroxyartemisinin , and C9-alkylated artemisinin analognes were reported . In some cases it is possible to avoid the lactonization step while preserving the ester fnnctionality and interrnpting the cychzation of aldehyde-peroxyhemiacetals of type 652, at the step of formation of tricyclic 5-hydroxy-1,2,4-trioxane . ... 

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,... 

Vroman, J.A., Khan, I., and Avery, M.A. Copper (I) catalyzed conjugate addition of Grignard reagents to acrylic acids homologation of artemisinic acid and subsequent conversion to 9-substituted artemisinin analogs, Tetrahedron Lett., 38, 6173, 1997. 

In conclusion, the vast literature and its derivatives, particularly artesunate, artemether, and arteether, point out to the need to make these derivatives in quantities that would reduce their current production cost to make these drugs accessible to the economically underprivileged societies that are often the victims of malaria. A recent promising method in which artemisinic acid, a precursor to artemisinin, has been produced in engineered yeast. Therefore, microbially produced artemisinic acid holds promise to the syntheses of antimalarial drugs at affordable prices <2006N940>. Furthermore, anticancer activities of artemisinin 1 and its derivatives have been reviewed <2005MI995>. 

Haynes, R. K. Vonwiller, S. C. Catalysed oxygenation of allyhc hydroperoxides derived from Qinghao (artemisinic) acid. Conversion of qinghao acid into dehydroqinghaosu (artemisitene) and qinghaosu (artemisinin). J. Chem. Soc. Chem. Commun., 1990, 451 53. 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

All structural modulations described above are concerned with the C-10 site. Artemisinin derivatives functionalized at C-16 (7, 8) are more difficult to prepare, and the natural precursors, artemisitene and artemisinic acid, are less readily available than artemisinin [18c, 28, 29],... 

Surprisingly, the allylic radical bromination of the nonfluorinated glycal 10 had not been reported, although the allyl bromide could obviously provide a shorter route to 16-substituted derivatives than the previously described approaches from artemisitene or artemisinic acid [28, 29, 59a, 65, 66], Conversely, reactivity of 10 toward electrophilic brominating agents was well documented. Dibromides [44,67] and bromohydrins [68,69] have been used for the introduction of ionizable functions in artemisinin at C-10 and C-9. 

Figure 6.13 Principle of an evaporative light-scattering detector and its application for plant constituents. (Chromatograms after J. L Veuthey, Analytical Pharmaceutical Chemistry, University of Geneva.) Conditions sample, extract of Artemisia annua (sweet wormwood) column, 12.5cm x 4mm i.d. stationary phase, Nucleosil 100 Cqg/ 5pm mobile phase, 1 ml min water with trifluoroacetic acid (pH 3)/acetonitrile (39 61). Peaks 1 = artemisinin 2 = artemisinic acid.

Kohler M, Haerdi W, Christen P, Veuthey JL. Extraction of artemisinin and artemisinic acid from Artemisia annua L. using supercritical carbon dioxide. J Chromatogr 1997 785 353-360. 

---