## 2 The Phytochemistry of _Artemisia annua_ L. (Qinghao)
### Sesquiterpenenoids
#### 2.6.3.3 Seco-Cadinanes  
Artemisinin (**495**) is a _seco_-cadinane sesquiterpene, which was first isolated from _A. annua_ in 1972. The unusual endoperoxide group in artemisinin has been confirmed by a variety of means [219-226] and the absolute stereochemistry of artemisinin has been established by X-ray crystallography [227]. Many total [171,228-235] and partial syntheses [236-239] of artemisinin have been reported and the various synthetic strategies have been reviewed [144]. Artemisitene (**497**), the 11,13-dehydro analogue of artemisinin, is present in _A. annua_ at much lower levels than artemisinin (typically concentrations in the order of 0.01%, as compared with 1%) [240], although artemisinin can be obtained readily by chemical transformations of artemisinin [165,213,241,242]; and a partial synthesis of artemisinin from artemisinin acid (**473**) has also been reported [243]. Artemisinin (**495**) is believed to be localized primarily within the glandular trichomes of _A. annua_, which are loosely attached to the leaf surface [244]. Perhaps because of this highly accessible location, it has been claimed that artemisinin can be extracted in 97% yield simply by dipping a leaf in chloroform for 5 seconds! \begin{table}
\begin{tabular}{|p{113.8 pt}|p{113.8 pt}|p{113.8 pt}|} \hline
**Name** & **Alternative Name(s)** & **CAS Number** & **References** \\ \hline
1\(\alpha\)-Aldehyde-2\(\beta\)-[3-butanone]-3\(\alpha\)-methyl-6\(\beta\)-[2-propanoic acid]-cyclohexane (**493**) 1\(\alpha\)-Aldehyde-2\(\beta\)-[3-butanone]-3\(\alpha\)-methyl-6\(\beta\)-[2-propenoic acid]-cyclohexane (**494**) 2\(\alpha\)-Artemisinin (**495**) 3\(\alpha\)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2,benzodoxepin-10(_3H_)-one & [9] \\ \hline Artemisitene (**497**) Artemisinten (**497**) Artemisinin, 11,13-didehyde 89-7) 3\(\alpha\)-Hydroxy-deoxyxartemisinin (8[7\(\rightarrow\)6]-abeo-amorphane (**500**) 1\(\alpha\)-Norannuic acid (**501**) 15-nornor10-Hydroxy-colonan-3\(\alpha\)-methyl-6\(\beta\)-[2-propanol formyl ester]-cyclohexane (**505**) & 4,5-Dioxo-4,5-_seco_-11(13)cadinen-12-oic acid & [9, 217] \\ \hline \end{tabular}
\end{table} 
Table 38: _Seco_-Cadinane, _nor_-Cadinane and _abeo_-Cadinane Sesquiterpenoids. Deoxyartemisinin (**499**) is some 100-300 times less potent than artemisinin (**495**) as an antimalarial drug, which demonstrates that the peroxy linkage in artemisinin is indeed necessary for its biological activity. Several syntheses of deoxyartemisinin have been reported [171,229,236,254,255]. Fully assigned 2D-NMR data are available for artemisinin (**495**) [221], the _seco_-cadinane **493**[9] and deoxyartemisinin (**499**) [165]. The formyl ester in _nor_-amorphane **502** is thought to have been derived from the carbon at the 12-position of an amorphane precursor by oxidative rearrangements. This group has been lost altogether, presumably as the result of ester hydrolysis, in the bis-_nor_-amorphane sesquiterpene, norannuic acid **501**[66,199]. Similarly, the formyl group in 1-oxo-2\(\beta\)-[3-butanone]-3\(\alpha\)-methyl-6\(\beta\)-[2-propanol formyl ester]-cyclohexane (**505**) [218] is probably also derived from oxidative rearrangements, this time deriving from the 5-position of an appropriate bicyclic precursor (the related _seco_-cadinane natural product **504** has also been reported from the _in vitro_ autoxidation of dihydroartemisinin acid in organic solution) [193]. It seems likely that the ethyl substituent in artemisinin G (**496**) might be derived from the 4- and 15-positions of a conventional amorphane precursor. \begin{table}
\begin{tabular}{c c}  & **Table 38**. _Cont._ \\ \end{tabular}
\end{table} 
Table 38: _Cont._The novel carbon skeleton of compound **500** is thought to be derived from the amorphane skeleton by migration of C-8 from C-7 to C-6 (_i.e._, compound **500** is an 8(7\(\rightarrow\)6) _abeo_ amorphane), which results in a contraction of the B ring from six atoms to five.