## 2 The Phytochemistry of _Artemisia annua_ L. (Qinghao)
### Sesquiterpenenoids
#### 2.6.3.2. Cadinanes, Muurolanes and Amorphanes
annua_ being studied, artemisininic acid (**473**) can be present at ten times the concentrations of artemisinin (**495**). For this reason, much research has been undertaken into the chemical conversion of artemisininic acid (**473**) to artemisinin (**495**), which can be achieved with an efficiency of greater than 40% [156, 157] (see also Section 4.4 for an application of this conversion to the production of artemisinin). By varying the conditions for the oxidation step, artemisininic acid (**473**) can be converted to various other sesquiterpenes from _A. annua_, including: arteannuin B (**462**) [158, 159], deoxyarteannuin B (**477**) [160] and _epi_-deoxyarteannuin B (**478**) [161, 162] (note that deoxyarteannuin B (**477**) [129, 161], _epi_-deoxyarteannuin (**478**) [68, 158, 160, 163, 164] and 6, 7-dehydroartemisinic acid (**476**) [165] have all also been obtained independently by chemical synthesis). Dihydroartemisinic acid (**480**), which is the 11,13-dihyro analogue of artemisininic acid (**473**) in Table 36, was first isolated as a natural product several years after artemisininic acid [166, 167] and it has also been chemically synthesised [168, 169]. It is particularly significant that dihydroartemisinic acid hydroperoxide (**481**), the tertiary allylic hydroperoxide from dihydroartemisinic acid, has also been isolated as a natural product from _A. annua_ [170]. This has led to the suggestion that dihydroartemisinic acid (**480**) might be converted to its tertiary hydroperoxide (**481**) in the living plant by a non-enzymatic process as shown in Scheme 5. This hypothesis has apparently been confirmed by recent _in vivo_ and _in vitro_ experiments [155, 185] (see Section 3.3) which also suggested that (**481**) can undergo further non-enzymatic conversion to (**495**). Although both artemisininic acid (**473**) and dihydroartemisinic acid (**480**) are the most signifcant amorphane sesquiterpenes from _A. annua_ in regard of the biosynthesis of artemisinin (**495**), several other amorphanes from this species have also been implicated in this process (see Section 3.3). These amorphane sesquiterpenes appear amongst the alphabetical listings in Table 36. Arteannuin A (**461**) was one of the first sesquiterpenes to be reported from _A. annua_ and it has since been synthesized on two occasions [171, 172]. The structure of arteannuin B (**462**) was determined in 1972 by X-ray crystallography [173] in combination with 1D- [174] and 2D- [175] NMR spectroscopy, and it has also been confirmed by chemical reactions [176]. Several syntheses of arteannuin B are reported [158, 171, 177-179] and areannuin C [180] is now thought to be identical with arteannuin B [175]. Syntheses have also been reported of arteannuin E (**463**) [181] and arteannuin F (**464**) [182] (which is also referred to as artemisinincone) [171]. The structures of arteannuin H (**465**) [166, 183], arteannuin I (**466**) [166], arteannuin J (**467**) [166], arteannuin K (**468**) [166, 184], arteannuin L (**469**) [166, 184] and arteannuin M (**470**) [166, 184] were all deduced by 2D-NMR spectroscopy, when they were first described as natural products from _A. annua_. All of these compounds have been reported as metabolites of dihydroartemisinic acid (**480**) _in vivo_ (Scheme 5) [185], and there is evidence from _in vitro_ studies to support the biogenetic proposal that arteannuin H (**465**) might be produced by spontaneous autoxidation reactions involving a secondary allylic hydroperoxide, which is derived from dihydroartemisinic acid (**480**) as shown in Scheme 5 [183]. The stereochemistry of the 5-hydroxyl group was wrongly assigned when arteannuins K (**468**), L (**469**) and M (**470**) were first reported as natural products [166]. The correct stereochemistry at the 5-OH group has now been established as \(a\) (as drawn) by 2D-NMR studiesinvolving derivitization of synthetic aretannuins K, L and M as their Mosher esters [184]; and by chemical synthesis of both natural (-)-arteannuin M [184] and its (+)-enantiomer [186-188].