Asymmetric Total Synthesis Of Vicinal Allcarbon Quaternary Type Cyclotryptamine Alkaloids Mediated By Novel Spirocyclic Amides Chiral Catalysts

Chiral phenomena are widely present in bioactive natural products and drug molecules and profoundly affect the properties of these compounds.The construction of chiral structural units is often the key to the total synthesis of natural products from a synthetic perspective.In the past two decades,with the development of new chiral catalysts and the exploration of new catalytic principles,the field of asymmetric catalysis has achieved rapid progress,which has basically met the needs of the construction of simple chiral center in most elementary reactions.Based on this,synthetic chemists have realized the construction of simple chiral structural units in a variety of natural products and active drugs.However,for the construction of complex chiral structural units in natural products and active drugs,most of the current reports are based on key intermediates containing simple chiral centers,and are realized through multi-step transformation,while reports on the efficient synthesis of such structural units using catalytic asymmetry are quite rare.Taking cyclotryptamine alkaloids with C_3a-C_3a'vicinal all-carbon quaternary carbon chiral structural unit as an example,due to their unique and complex stereo structure and rich biological activity,many famous chemists including Larry E.Overman and Movassaghi have been attracted to their synthesis.However,to date,the efficient synthesis of such alkaloids is still subject to the catalyzed asymmetric construction of a crowded C_3a-C_3a'vicinal all-carbon quaternary stereocenters.This paper is dedicated to solving this specific scientific problem.In order to achieve high-efficiency construction of C_3a-C_3a'vicinal all-carbon quaternary carbon stereocenters required for the total synthesis of corresponding cyclotryptamine alkaloids,a catalytic asymmetric dialkylation reaction strategy of bisoxindoles was proposed at the beginning of our study.Inspired by the recently developed 1-azaspiro[4.4]-nonane skeleton catalyst in our group,a series of novel chiral spiro amide 1,2,3-triazolium catalysts were developed for the proposed synthetic strategy.With these catalysts,we have successfully achieved the catalytic asymmetric dialkylation of bisoxindoles and completed the asymmetric synthesis of several corresponding natural products.This dissertation is divided into four parts:1.Summary of asymmetric synthesis of vicinal all-carbon quaternary type cyclotryptamine alkaloids;2.The design and synthesis of novel chiral spiro amide1,2,3-triazolium catalyst;3.Catalytic asymmetric homo/hetero dialkylation of bisoxindoles;4.Synthesisof?-?-Chimonanthidine,?-?-Folicanthine,?-?-Chimonanthine,?+?-Calycanthine and?-?-Ditryptophenaline.In the first chapter,we briefly introduced the vicinal all-carbon quaternary type cyclotryptamine natural products,and reviewed the progress of their asymmetric synthesis research according to the different synthetic strategies.In the second chapter,the research background of spiropyrrolidine chiral skeleton and 1,2,3-triazolium catalyst was introduced.The chiral spirocyclic amide1,2,3-triazolium catalyst was designed and synthesized and its catalytic properties were explored.In the third chapter,using the catalysts above,we efficiently achieved the catalytic asymmetric homo/hetero dialkylation reaction with excellent results of up to82%yield,99%ee and>20:1 dr.In addition,based on the experimental data obtained and related control experiments,we also explored and analyzed the catalytic mechanism and stereo control model of the above reactions.In the fourth chapter,using this methodology,we finally realized the first asymmetric total synthesis of?-?-Chimonanthidine and efficiently completed the formal synthesis of active natural products?-?-Folicanthine,?-?-Chimonanthine,?+?-Calycanthine and?-?-Ditryptophenaline.