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

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.