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 

机构地区：[1]State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201 [2]School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137 [3]University of Chinese Academy of Sciences,Beijing 10049

出　　处：《CCS Chemistry》2024年第10期2529-2536,共8页中国化学会会刊（英文）

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).

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 phlegmaria.Spectroscopic 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 yield.An 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 step.During our semisynthesis attempts,a novel transformation was developed to constructα-aminoketone from enamine N-oxide.Moreover,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.

关 键 词：Lycopodium alkaloids phlegmine A total synthesis ASIC1a inhibitor ANALGESIC 

分 类 号：O62[理学—有机化学]