The Synthetic Studies Of (+)-Pleuromutilin

The discovery of lead compounds from active natural products is one of the effective means for drug development.The diterpene fungal secondary metabolites（+）-pleuromutilin inhibits the growth of Gram-positive pathogens significantly,which has been served as several antibiotic synthesis such as tiamulin(DENGEAR^?),valnemulin(ECONOR^?)and human antibiotics retapamulin（ALTABAX（?））,lefamulin(XENLETA^?).Its 5/6/8 tricyclic structure is necessary to biological activity but also a significant challenge for synthetic chemist to construct.This thesis aims at the synthetic studies of（+）-pleuromutilin along with the related design methodologies.The strategy of“overbred intermediate fragmentation”is designed to construct eight-membered ring,which is based on the interconnection among oxidation state and diastercenter in（+）-pleuromutilin.The following three parts are mainly included in this thesis:Part 1:The isolation,structure elucidation,biosynthetic pathway and structure–activity relationships of（+）-pleuromutilin were presented.Then we focued on the published synthetic works.Part 2:Focusing on the strategy of“overbred intermediate fragmentation”,a linear retrosynthtic analyses of（+）-pleuromtuilin was demonstrated,which was based on the classification of stereocenters.By simplifying the target molecules,a simulation route was designed to verify the feasibility of key reaction,which contained“Michael addition,Conia-ene cyclization,MHAT cyclization,formal[2+2]cycloaddition”.Part 3:On the basis of part 2,the synthesis route was adjusted,in which two chiral synthons could be prepared at 10 gram scale from cheap（-）-citronellol in 4 and 8 steps,respectively.