## 3 The Biosynthesis of Artemisinin (Qinghaosu)
### Phase 3 (Dihydroartemisinin acid to Artemisinin)
#### 3.3.2 Artemisinic Acid (**473**) as a Late-Stage Precursor to Artemisinin
In conclusion, although the absence for any detectable transformation of artemisinin acid into artemisinin in the most recent study [155] is at variance with the earlier literature (pre-1990's) [281,284,286] for the biosynthesis of artemisinin, it is consistent with much of the more recent literature (post-1990's), in which there is now a gathering consensus that dihydroartemisinin acid (**480**), rather than artemisinin acid (**473**), is the true late-stage precursor to artemisinin (**495**). 3.3 Arteannuin B (**462**) and Dihydroarteannuin B (**479**) as Late-Stage Precursors to Artemisinin  
As noted above, in the most recent study of the metabolism of artemisinin acid, arteannuin B (**462**) was obtained as the major metabolite of artemisinin acid (**473**), without any evidence for the accompanying formation of artemisinin (**495**) [155]. However, because both arteannuin B (**462**) and artemisinin (**495**) were often reported together from \"older\" biosynthetic studies with artemisinin acid (**473**), some authors have previously proposed that arteannuin B (**462**) might be an intermediate in the proposed conversion of artemisinin acid (**473**) [215,251] to artemisinin (**495**) [203,248,285]. It is indeed possible to convert artemisinin B into artemisinin by chemical transformations [239] and there have been various suggestions as to mechanisms by which this transformation might also occur _in vivo_[209,217]. A microbial system which is capable of converting artemisinin B (**462**) to artemisinin (**495**) has recently been described [309] and an enzyme with the appropriate activity has also been purified [310,311]. On the other hand, a study which found that epoxyartemisinic acid (**487**) could be converted to artemisinin B (**462**) also stated that epoxyartemisinic acid (**487**) could not be transformed into artemisinin (**495**) and therefore - by implication - arteannuin B cannot be a precursor to artemisinin [284]. It has also been claimed that the 11,13-dihydro analogue of artemisinin B (**462**), dihydroarteannuin B (**479**), can be converted into artemisinin by cell free extracts of _A. annua_[249,312]. 3.4 epi-Deoxyarteannuin B (**478**) and Dihydro-epi-deoxyarteannuin B (**485**) as Late-Stage Precursors to Artemisinin  
_epi_-Deoxyarteannuin B (**478**) was obtained as a minor metabolite of artemisinin acid (**473**), without any evidence for the accompanying formation of artemisinin (**495**), in the most recent study of the metabolism of artemisinin acid [155]. However, experiments in the \"older\" literature (1990's and before), using radiolabelled forms of both _epi_-deoxyarteannuin B (**478**) and its 11,13-dihydro analogue, dihydro-_epi_-deoxyarteannuin B (**485**), have suggested that both were intermediates [286] in the respective biotransformations of artemisinin acid (**473**) and dihydroarteramisinic acid (**480**) to artemisinin (**495**) [284]. However, once again, more recent experiments using dihydro-_epi_-deoxyarteannuin B (**485**) which had been labelled with a stable isotope [169] and fed to an intact plant system have shown no detectable incorporation into artemisinin (**495**); although three novel hydroxylated metabolites were obtained in significant quantities from this feeding experiment [190]. 3.3.5 The seco-Cadinane (**494**) and Artemisitene (**497**) as Late-Stage Precursosr to Artemisinin  
The _seco_-cadinane aldehyde (**494**) has been hypothesized to be a precursor to artemisinin (**495**) via its end tautomer, which undergoes reaction with molecular oxygen * to produce artemisinin (**497**), the 11,13-dehydro analogue of artemisinin (this reaction was proposed to occur in a similar manner to the transformations which have now been established experimentally for the end in steps iii) and iv) in Scheme 12 [217,313]).