Artemisine

The Karplus equation predicts that J is largest when the two CH bonds are staggered anti (0=180") or eclipsed (0=0°), and J is smallest when the two bonds are perpendicular (0=90"). Because of J s dependence on dihedral angle, it can be used to distinguish between isomers such as artemisin acetate and 6-epiartemisin acetate. 

For each molecule (isomer A and isomer B), obtain dihedral angles for the following pairs of vicinal hydrogens Hg-Hy, H Hg, Hy-Hn, and Hg-Hyaxiai- Use the Karplus equation to estimate coupling constants for each pair, and then compare your predictions to the experimental coupling constants (see above). Which molecule is artemisin acetate and which is 6-epiartemisin acetate ... 

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]. 

M. Gabriels and J. Plaizier-Vercammen, Development of a reversed-phase thin-layer chromatographic method for artemisin and its derivatives. J. Chromatogr. Sci. 42 (2004) 341-347. 

Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD. (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440 940-943. 

Scheme 8. Summary of the biosynthetic pathway to artemisinin through artemisinic alcohol in Artemisia annua.

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. ... 

Scheme 9. Conversion of artemisinic acid to artimisinin by Roth and Acton. Conditions (i) NaBH4/NiCl2, (ii) O2 (-78°C), (iii) O2 (trace of TFA).

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. 

Artemisia ketone (2) Artemisinic alcohol (3) Arteannuin B (4) 1,8-Cineole (5) Camphor (6) Fig. 2. Examples of some secondary metabolites isolated from Artemisia annua. 

Artemisinic acid is a cw-fused decalin we can still deduce its shape from the steroid approach. Note that both hydrogens at the ring fusion are down, whereas we have been looking at systems where the ring fusion substituents are up. We shall need to change ring B rather than ring A. 

Ro DK, Paradise EM, Ouellet M, et ai. Production of the antimalatial drug precursor artemisinic acid in engineered yeast. Nature 440 940-943, 2006. 

Quinghaosu is the latest fundamental discovery in this area and is a heterocyclic compound that does not have a nitrogen atom in its structure. It is taken from a Chinese folk medicine. It is isolated from the plmt Artemisia annua. It is amazing that this compound, which is completely different than the other drugs described in this chapter in terms of structure, exhibits the exact same therapeutic effect. The main interest in quinoghaosu is based on the fact that it is active against resistant forms of malaria caused by P falciparum, and even its cerebral forms. Synonyms of this drug are artemisine, artemisinin, and others. 

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 . ... 

Table 28 Photooxygenation of methyl artemisinate derivatives 294 <2001JNP1201 >...

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