## 2 The Phytochemistry of _Artemisia annua_ L. (Qinghao)
### Monoterpenoids
#### 2.5.2 Irregular Acyclic Monoterpenes  
Phytochemists were interested in _A. annua_ before the discovery of artemisinin because it is a rich source of unusual irregular acyclic monoterpenoids, such as artemisinin ketone (**276**) [115-120], which is the major constituent of the essential oil in some varieties of _A. annua_[29,37,42,73], and can account for up to 50% of the total [22,25,33,43,45,53]. It is often found in conjunction with smaller amounts of artemisinin alcohol (**273**) [22,33,38,121]. Artemisia ketone (**276**) is formed by a non-standard \"head-to-middle\" condensation of DMAPP [104,122-126], which is thought to proceed as shown in Scheme 2 via chrysanthemyl pyrophosphate, an intermediate containing a three-membered ring. The mechanism for the formation of this unusual intermediate [127], is believed to mimic the formation of presqualene, another naturally-occuring cyclopropane, which is involved in the biosynthesis of the triterpene precursor, squalene (see Section 2.7.2) [128]. Two other classes of irregular cyclic monoterrepenoids, the lavandulanes **279)-281** and the santolinanes **282** and **283**, are also known from _A. annua_. The formation of all three skeletons has been explained in terms of different cleavage reactions occurring at each of the three carbon-carbon bonds in the cyclopropyl ring of the common precursor, chrysanthemyl pyrophosphate (Scheme 2) [126].  
**Scheme 2.** Formation of the irregular artemisyl, lavandulyl and santolinyl skeletons in _A. annua_ by \"head-to-middle\" condensation of a DMAPP (C\({}_{5}\)) precursor and subsequent carbon-carbon cleavage reactions of the resulting intermediate, chyvanthemyl pyrophosphate.  
\begin{table}
\begin{tabular}{|l|l|l|l|} \hline
**Name** & **Alternative Name(s)** & **CAS Number** & **References** \\ \hline _Artemisates_ & & & \\ \hline Artemisia alcohol (**273**) & 3,3,6-Trimethyl-1,5-heptadiene-4-ol & [29887-38-5] & [19, 23, 29, 33, 38, 40, 43, 45, 27644-04-8] & 48, 51, 66, 73, 121] \\  & & [7736-36-67] & \\ Artemisyl acetate (**274**) & Artemisia alcohol acetate & [34658-88-1] & [25, 40, 43, 45, 72, 112, 113] \\  & 3,3,6-Trimethyl-1,5-heptadiene-4-ol acetate & [29887-38-5] & \\ (_E_)-2-Butenoic acid, 2-methyl-, 2,2-dimethyl-1-(2-methyl-1-propenyl)-3-butenyl ester (**275**) & & [62594-30-3] & [30] \\ Artemisia ketone (**276**) & 3,3,6-Trimethyl-1,5-heptadiene-4-one & [546-49-6] & [19, 21-24, 26, 29, 31, 33, 36, 38, 40-45, 49, 53, 66, 72, 73, 112, 113, 121] \\  & & & [19, 32, 38, 45] \\  & & [29548-02-5] & [23] \\ \hline \end{tabular} \
\begin{tabular}{|l|l|l|} \hline _Lavandulanes_ & & \\ \hline _trans_-5-Hydroxy-2-isopropyl-5-methylhex-3-en-1-ol (**279**) & 3-Hexene-1,5-diol, 5-methyl-2-(1-methyl- & [403797-33-1] & [129] \\  & & \(\rm{ethenyl}\))- & [9] \\  & & \(\rm{ethenyl}\)- & [20777-39-3] & [19] \\  & & \(\rm{ethenyl}\)- & [20777-39-3] & [19] \\ \hline \end{tabular}
\begin{tabular}{|l|l|l|} \hline _Santolinanes_ & & \\ \hline Santolina alcohol (**282**) & 3-Ethenyl-2,5-dimethyl-4-hexen-2-ol & [35671-15-9] & [19, 32, 43] \\  & 3-Ethenyl-1,2,5-dimethyl-1,4-hexadiene & [70005-95-7] & [23, 25, 43, 45, 50] \\  & & [2153-66-4] & \\ \hline \end{tabular}
\end{table}
Table 24: Irregular Acyclic Monoterpenoids.  
Both the lavandulane tertiary allylic alcohol **279** and its secondary allylic alcohol analogue **280** have been proposed to be derived from the precursor, lavandulol, by spontaneous autoxidation reactions which yield allylic hydroperoxide intermediates as shown in Scheme 3[129]. This suggestion was supported by a biomimetic synthesis, in which photooxygenation of racemic lavandulol yielded both of the hydroperoxide intermediates expected from the reaction of singlet oxygen with the tri-substituted double bond in this precursor. Reduction of the tertiary allylic hydroperoxide product then resulted in a tertiary allylic alcohol identical with the natural product **279**.  
**Scheme 3.** Proposed formation of lavandulanes **279** and **280** by spontaneous autoxidation reactions.