## 2 The Phytochemistry of _Artemisia annua_ L. (Qinghao)
### Sesquiterpenenoids
#### 2.6.3.2. Cadinanes, Muurolanes and Amorphanes
* The most significant products from this feeding study were dihydroarteannuin B (**479**), dihydro-_epi_-deoxyarteannuin B (**485**) and the dihydro _seco_-cadinane (**493**). The pattern of transformations of dihydroartemisinin acid (**480**) which was observed _in vivo_ very closely paralleled the spontaneous autoxidation chemistry for dihydroartemisinin acid which had previously been demonstrated _in vitro_[193,218]. This has lead to the proposal that the main metabolic route to all three of these metabolites and artemisinin (**495**) in _A. annua_ involves the spontaneous autoxidation of dihydroartemisinin acid (**480**) and the subsequent chemical reactions of the derived tertiary allylic hydroperoxide (**481**), as is shown in Scheme 6. **Scheme 6. ** The most dominant products from metabolism of dihydroartemisinin acid (**480**)  
_in vivo_ in _A. annua_ plants. When labeled artemisinin acid (**473**), the 11,13-dehydro analogue of dihydroartemisinin acid (**480**), was fed to intact _A. annua_ plants, slightly fewer labeled metabolites were isolated [155]. However, all seven metabolites from this experiment are also known as natural products from _A. annua_ and six of the seven feature in the pairs of metabolites discussed in Table 37. The most abundant metabolite from feeding artemisinin acid (**473**) was arteannuin B (**462**), followed by _epi_-deoxyarteannuin B (**478**) and the _seco_-cadinane (**494**) as shown in Scheme 7 (the remaining four metabolites are: annulide (**457**), isoannulide (**490**), deoxyarteannuin B (**477**) and artemisinin acid methyl ester (**474**), which were all isolated in trace amounts. It is intriguing to note that there are exact structural homologies between six of the seven highly oxygenated 11,13-dehydro sesquiterpenes which have been isolated as metabolites of artemisinin acid (**473**) and a subset of the sixteen 11,13-dihydro metabolites which were obtained in the preceding study with dihydroartemisinin acid (**480**) (see Table 37). Clearly, the _in vivo_ transformations of artemisinin acid (**473**) closely parallel those of its 11,13-dihydro analogue, dihydroartemisinin acid (**480**), as is shown by Schemes 5, 6 and 7. (However, note that in the case of artemisinin acid (**473**), no allylic hydroperoxide analogous to (**481**) in Scheme 6 was isolated _in vivo_ as a natural product, and its existence as an intermediate in Scheme 7 must therefore be inferred. Such an allylic hydroperoxide can, however, be produced in the laboratory by chemical reactions with \({}^{1}\)O\({}_{2}\) and it is known to undergo _in vitro_ several of the transformations which are depicted _in vivo_ in Scheme 7). **Scheme 7. ** The most dominant products from metabolism of artemisinin acid (**473**) _in vivo_ in _A. annua_ plants. It seems likely therefore that similar mechanisms are operative in the metabolism of both dihydroartemisinin acid (**480**) and artemisinin acid (**473**). These biological transformations have been proposed to involve spontaneous autoxidation of the \(\Delta^{4,5}\) double bond in (**473**)/(**480**) and subsequent rearrangements of the resultant allylic hydroperoxides [155,185]. In addition, feeding experiments with both labeled precursors appear to show that artemisinin acid (**473**) and dihydroartemisinin acid (**480**) are NOT mutually interconvertible; rather, each is the committed precursor to the two large families of highly oxygenated 11,13-dehydro and 11,13-dihydro sesquiterpene metabolites which are known from this species (see, for example, the nine pairs of compounds in Table 37). This observation fits well with the reported occurrence of two chemical races of _A. annua_: a low-yielding-artemisinin chemotype, which is rich in artemisinin acid; and a high-yielding-artemisinin chemotype, which also contains significant quantities of dihydroartemisinin acid, as discussed in Section 4.1.