A Novel Asysmetric Synthesis Route To Enantiopureisopavine Alkaloids

Life phenomenon is closely related to chirality,as a result the asymmetric synthesis have been the research focus in the field of organic chemistry in recent years.This thesis just includes two parts,the first part is the exploration of novel asymmetric synthesis route of enantiopure isopavine alkaloids;the other part is the preliminary study on novel substrates for asymmetric MBH reaction.The isopavine alkaloids are a class of natural products originally isolated from Papaveraceae.It can be analgesic,antitussive and sedative.It has also reported that the isopavines and non-natural analogues exhibit important pharmacological activities for the treatment of the nerve system disorders,such as Hungtington's chorea,Parkinson's and Down's syndromes.However,the content of natural isopavine alkaloids in plants of Papaveraceae family is very low,so it's expensive and lengthy to obtain the enantiopure isopavine alkaloids relying on natural product extraction.So the researchers began to explore the chemical synthesis route to enantiopure isopavine alkaloids.In half a century,the synthesis of racemic isopavine alkaloids have been reported nearly twenty times,while relatively few total syntheses of enantiopure isopavine alkaloids have been reported.The already known methods have traditionally resorted tooptical resolution,or starting with naturally occurring compounds,or utilizing chiral auxiliaries.So it's urge to find a simple,efficient and general route to optically active isopavine alkaloids.The main content includes the following several parts:(1)we made a retrosynthetic of the doublybenz-annulatedazabicyclo[3.2.2]nonane,and designed the synthetic route,which includes two key steps: one is the enantioselective addition of arylboronic acids to 2-nitrostyrenes,the other is the intramolecular Pictet�Spengler cyclization reaction.(2)Through repeated study on asymmetric addition reaction and substrate designs,we eventually finished the construction of chiral center.(3)we carried out the exploration of Pictet-Spengler intramolecular cyclization reaction.We exchanged the route three times and finally found the simple,efficient and general route to enantiopure isopavine alkaloids based on Pictet-Spengler reaction.(4)We used the new way synthetized seven enatiopure isopavine alkaloids and their relevant racemic compounds.At the same time,we establish the chiral HPLC method for determination of optical purity,.Above all,a simple,efficient novel route to optically active isopavine alkaloids with the use of efficiency asymmetric catalysis reaction has been explorded.The aromatic aldehyde was used as the starting material to obtain the final product by ten steps.34 new compounds were obtained.The second chapter of this thesis is a study on the new substrates of asymmetric MBH reaction.Asymmetric MBH reaction is a classic method for the synthesis of chiral C-C bond,with the advantages of high atom economy,easy derivatization and so on.Nitro derivatives is a kind of important structural type in the field of drug research.It has obvious bactericidal and antitumor effects and can be targeted to tubulin.The product of the MBH reaction has not only maintained the structure of the conjugated nitro group,but also introduced hydroxyl functional groups.This can be further derived a variety of structural types of compounds,which undoubtedly provides a great convenience for the transformation of the drug structure.However,there are few reports on the MBH reaction of nitro and electrophilic reagents.This thesis first explored the asymmetric MBH reaction of electrophilic aldehydes with nitro compounds.The catalytic activity and asymmetric induction of 21 kinds of organic small molecule chiral catalysts were investigated in this reaction,and determined that small molecule catalyst of cinchona alkaloids framework(DHQ)2AQN have better catalytic effect on asymmetric MBH reaction of ?-nitrostyrene with ethyl glyoxylate.Then effect of temperature,solvent,and substrate ratio on the catalytic reaction was also investigated,and the optimal catalytic condition was disclosed: In the presence of cinchona alkaloid catalyst(DHQ)2AQN,?-nitrostyrene reacted with ethyl glyoxylate in toluene under 0�C affording the MBH adduct in 60% yield with good enantioselectivity(up to 56.9% ee).