Asymmetric Total Syntheses And Biological Studies Of Tuberostemoamide And Sessilifoliamide A

Radix Stemonae,known as “Baibu”,which is one of the traditional Chinese medicines included in all versions of ancient Chinese medical literatures and Chinese Pharmacopoeia,has been clinically used as the indigenous system of medicine for treating antitussive and insecticide.Numerous researches show that the alkaloids unique to the Stemonaceae family are believed to be responsible for its bioactivities.Up to now,more than 215 alkaloids with a great variety and structural complexity have been isolated from this genus.Research papers revealed that most of these alkaloids exhibit various important bioactivities including antitussive,anti-inflammatory,insecticidal,antitumor and acetylcholinesterase(AChE)inhibition activity.However,a single Stemona alkaloid is seldom developed for further clinical use,mainly due to the lack of comprehensive biological profiling,which is largely hampered by isolation and synthetic accessibility.Stemona alkaloids have attracted wide attention from a variety of research areas,such as natural product chemistry,medicinal chemistry and organic synthetic chemistry,due to many existing scientific problems in their intricate molecular structure,important biological activity,interesting biosynthetic pathway and challenging organic synthesis.In this thesis,Stemona alkaloids tuberostemoamide and sessilifoliamide A which both contain an oxaspirolactone moiety are selected as our target molecules for asymmetric total syntheses and biological studies.This paper consists of the following three parts.Chapter ?: Review of Stemona alkaloidsThe structural characteristics as well as classification,biogenesis,bioactivity and progress on the total synthesis in recent years of Stemona alkaloids are described.Chapter ?: Asymmetric total syntheses of Tuberostemoamide and Sessilifoliamide ATuberostemoamide(2-1)and sessilifoliamide A(2-2)were isolated from the roots of S.tuberosa,and S.sessilifolia,respectively.These two naturally occurring molecules possess a 5/7/5 tricycle skeleton as well as an oxaspirolactone moiety and contain 5-6 contiguous stereogenic centers,one of which is quaternary spirocenter.Their intricate structures present a great challenge for organic synthesis,therefore,there have been no reported total syntheses of these two alkaloids.Herein,we efficiently accomplished the first asymmetric total syntheses of tuberostemoamide,sessilifoliamide A,and their four epimers,using ethylstemoamide(2-4)which is similar to stemoamide(2-5)as the common intermediate.The synthesis started with L-pyroglutamic derivative 2-8 as the chiral pool,in the hope of accessing serviceable stereocontrol and the key reactions included intramolecular SmI2 promoted radical cyclization as well as lactonechemoselective nucleophilic addition.Notably,after adopting new reduction conditions,the kinetic and thermodynamic process of ethylstemoamide in C=C bond reduction is different from the case of stemoamide.The stereochemistry control relationship at C8/C9/C10 is clearly revealed for the first time and a subtle difference of substituent at the C10 position between stemoamide and ethylstemoamide(Me vs Et)drastically changes the stereoselectivity,which is significantly valuable for syntheses of ethylstemoamide structurally related Stemona alkaloids.Chapter ?: Biological Studies of Tuberostemoamide and Sessilifoliamide AOn the basis of activities of Stemonaceae plants and the existing biological studies of some other Stemona alkaloids,we performed antitumor,AChE inhibition and antiinflammatory biological evaluation of several compounds possessing a similar 5/7/5 tricycle-skeleton(compound 2-1,2-2,2-4,2-12,2-11 a,2-19,2-20,2-21)with stemoamide.Biological studies reveal that 11,13-Bis-epi-sessilifoliamide A(2-20)is expected to be a selective and reversible BChE inhibitor for the treatment of neurodegenerative diseases,and sessilifoliamide A(2-2)may be a part of the antiinflammatory substances in Stemonaceae plants.