Synthetic Study Of Several Qinghaosu Analogues

Qinghaosu（artemisinin）is a natural product isolated from traditional Chinese herb Artemisia annua L.by Chinese scientists in early 1970’s.Because of the excellent antimalarial activity of Qinghaosu,many Qinghaosu-containing agents have been recommended as the first-line antimalarial drugs by WHO.The1,2,4-trioxane core in Qinghaosu is the pharmacore for its antimalarial activity.Construction of the peroxide bridge in Qinghaosu has been a serious challenge in synthesis,because of the involvement of attaching a peroxy group onto the C-12,a quaternary carbon with excessive steric crowding.Previously,this task was achieved almost entirely by photosensitized oxygenation.In this thesis,several Qinghaosu analogues carrying a linear chain at the C-10 position were constructed using dark singlet oxygen as the key reagent.The side chain was then further elaborated to afford various functionalized Qinghaosu analogues.The first part of this thesis describes conversion of dihydroqinghao acid several Qinghaosu analogues with a side chain at the C-10 position via a four-step reactions,including esterification,reduction,oxidation,and ketal formation.The dark singlet oxygen generated by Na₂ MoO₄ catalyzed disproportionation of H₂O₂ was used to activate the substrate.The unstable hydroperoxide was then treated with Cu（OTf）₂ and triplet oxygen to incorporate a hydroperoxyl group onto the C-12.The resulting intermediate then underwent multiple ketal/acetal reactions to construct 1,2,4-trioxane and from the desired C-10 substituted Qinghaosu with an overall yield of up to 48%.The second part of this thesis is based on the exchange of decomposition with the acrylic ester,ester hydrolysis reaction and with the selected amine for acylation.Artemisinin analogs with carbon chains at the C-10 carbon chain are further prepared into a variety of artemisinin analogs with potentially biological activities.Artemisinin analogs containing biotin structures were also prepared.