Discovery and Asymmetric Total Synthesis of Phlegmine A as a Selective Inhibitor of ASIC1a

作     者：Zai-Feng Yuan Fei Liu Yu-Fei Ou Wen-Yan Li Li-Yan Peng Xiao-Nian Li Qin-Shi Zhao 

作者机构：State Key Laboratory of Phytochemistry and Plant Resources in West ChinaKunming Institute of BotanyChinese Academy of SciencesKunming 650201 School of PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137 University of Chinese Academy of SciencesBeijing 10049 

出 版 物：《CCS Chemistry》 (中国化学会会刊（英文）)

年 卷 期：2024年第6卷第10期

页      面：2529-2536页

核心收录：

学科分类：081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：the National Natural Science Foundation of China(NSFC grant no.21837003) the Joint Foundation of NSFC-Yunnan Province(grant no.U1502223) the Yunnan Revitalization Talent Support Program“Young Talent”Project,NSFC(grant no.81903521) the Natural Science Foundation of Yunnan Province,China(grant no.202001AT070067) 

主　　题：Lycopodium alkaloids phlegmine A total synthesis ASIC1a inhibitor analgesic 

摘      要：Phlegmine A(1),a novel type of Lycopodium alkaloid with a unique skeleton,was isolated from the rare and endangered herbal medicinal plant,Phlegmariurus *** methods and X-ray diffraction analysis were employed to unambiguously elucidate the structure of phlegmine A(1).Furthermore,we realized the asymmetric total synthesis of the natural product phlegmine A(1)in 18 linear steps from commercial ingredients,achieving a 1.3%overall *** intramolecular carbene cyclization,dimethyldioxirane(DMDO)enamine oxidation,and Stevens rearrangement were exploited to establish the sterically congested vicinal quaternary centers,and an epimerization/aldol condensation/deacetylation reaction was utilized for the rapid assembly of enone at the final *** our semisynthesis attempts,a novel transformation was developed to constructα-aminoketone from enamine ***,the synthetic sample obtained from this work enabled the successful verification of phlegmine A(1)as a new type of highly selective acidsensing ion channel 1a(ASIC1a)inhibitor,which also exerted an in vivo analgesic effect,rendering it a promising lead compound.