One-Pot Total Synthesis Of Natural Products And New Synthetic Methodology Of Relative N-Containing Heterocycles From Amino Acids

The research of facile total synthesis of natural products always promotes the development of organic synthesis,drug discovery and green chemistry.Traditional design and execution of total synthesis usually rely on the retrosynthetic analysis which defined by Prof.E.J.Corey.Through searching a series of chemical transformations,people assemble their target molecules step by step.Since the twentieth century,the tendency to pursue the limits of structural complexity has changed by means of the motivation behind and the standards for total synthesis.Chemists are paying more attention to finish a total synthesis with more efficient and easier protocols.The concepts of chemical ideality and pot economy have emerged to fulfill these needs.Based on the self-sorting behavior of molecules,we attempt to use rational retrosynthetic analysis to arrange a series of self-organized reaction sequence,which can be integrated compatibly under a common condition such that the entire sequence proceeds in one pot.If it works,we can achieve self-sorting synthesis from artificial step-by-step synthesis.This rational design high-level synthetic strategy is more consistent with biogenetic pathway of natural products compare with traditional synthetic approaches,and it is an effective strategy to construct natural products especially alkaloids.Parallelly,it is a stimulating way to lead the synthesis of natural products-like skeletons or new structures.However,it is a challenging research topic.The examples of self-sorting one-pot total synthesis are rather rare.The targets of this topic are usually structurally simple compounds with multi synthetic limitations.Notably,there is no theoretical basis for guiding the regularity of this strategy.Through rational design of substrates,conditions and reaction pathways,this thesis developed many examples of self-sorting one-pot total synthesis and new synthesis methodology of heterocyclic rings from amino acids.We attempted to add some interesting examples for self-sorting one-pot total synthesis and to search the answers of above challenging issues.The main content is as follows:In chapter one,a brief introduction of the background and tendency of natural products total synthesis has been given.We summarized the examples of one-pot total synthesis in recent years,which included(a)one-pot multi-steps total synthesis;(b)microwave assisted one-pot total synthesis;(c)self-sorting one-pot total synthesis.In this chapter,we demonstrated the design,research background and challenge of this area.At last,we proposed the main idea and research project of this thesis.In chapter two,we give a introduction of the total synthesis of 5-(3-indolyl)oxazoles alkaloids and attempt to find a solution to achieve one-pot total synthesis of this natural products family.We proposed that this kind of alkaloids might biogenerated from corresponding amino acids.Though rational retrosynthetic analysis,we used amino acids to afford pimprinine,pimprinethine,pimprinaphine,WS-30581A,WS-30581B,laboradorin 1,uguenenazole,balsoxine and texamine in one-pot protocol.Notably,we achieve the first total synthesis of chiral alkaloid pimprinol A and provide a facile synthetic approach for its alkaloid family.In chapter three,based on the above research,we studied deep into the by-reaction which amino acids transform into aldehyde.We developed a decarboxylative deaminative dual-coupling reaction of amino acids with indoles to afford BIM scaffolds and its further application to the one-pot total synthesis of natural products.This endeavour also established a convenient one-pot total synthesis of seven BIM natural products,Streptindole,Arsindoline B,tris(3-indoly l)methane,3,3’-bisindolylphenylmethane,vibrindole A,arundine,and 1,1-(3,3’-diindolyl)-2-phenylethane.The synthesis greatly shortened the traditional approaches and improved the synthesis efficiency.In chapter four,through analyzing the structure of sophodibenzosides natural product family,we found that they all have a 4-hydroxybenzil core backbone.With the combination of Diversity-Oriented Synthesis and self-sorting one-pot total synthesis,we directly build the 4-hydroxybenzil backbone via rational retrosynthetic analysis.Using 4-hydroxybenzil products as platform molecule,we finished the collective total synthesis of sophodibenzosides natural products family.Through para-selective C-C bond coupling between phenols C(sp2)and aryl methyl ketones C(sp3),we realized one-pot synthesis of 4-hydroxybenzil derivatives.This synthetic method has good substrate compatibility which can tolerate sensitive groups such as halogen and hydroxyl groups.Aglycones of the sophodibenzoside D-I,which are biogenerated precursor of sophodibenzoside family can be formed through gram-scale synthesis.After modification,we finished the first total synthesis of sophodibenzoside F and I.In chapter five,we combined Biology-Oriented Synthesis with self-sorting one-pot total synthesis.Through rational design,an expeditious one-step synthesis of the imidazopyridoindole scaffold was achieved through the C-H oxidation/biscyclization reaction of methyl ketone and tryptamine derivatives.Compared with traditional synthetic pathway,our protocol shows facile and effective advantages.The trapping strategy of 2H-β-carboline-N-acylimine intermediate will also give inspirations to prepare other indole alkaloid-like molecules.In chapter six,during the study of one-pot total synthesis,we realized that to mimic biogeneration pathway is an effective method to achieve self-sorting one-pot total synthesis.Amino acids are basic unit of life.In organic synthesis,the reaction mode of amino acids participated transformation can be classed into four types:Ugi multi components reactions,decarboxylation coupling reactions,C-H activation reactions and other.This chapter reviewed the examples of amino acids participated transformations and make a conclusion that there is no reaction using bio-inspired catabolism and reconstruction mode.It is a blank point of amino acid chemistry research.In chapter seven,we used amino acids and acetophenone as substrates to afford 2,6-disubstituted and 2,4,6-trisubstituted pyridines through I2 promoted decarboxylation,deamination and reconstruction of amino acids.This successful execution proved that,the bio-mimic catabolism and reconstruction process of amino acids can be used to develop synthetic method.Based on this,we expand the utility of this concept to achieve the novel synthesis of pyridines through homo-dimerization,β-carboline through cross-dimerization,thiazole and oxazole through hetero-dimerization,pyridines through homo-trimerization,pyridines through cross-trimerization,hydropyridine through tetramerization,which enrich the examples of amino acids synthetic methodologies.In chapter eight,we considered that,with the dwindling of fossil carbon sources such as crude oil,synthetic method of valuable heterocyclic molecules from biomass transformation might have positive effect to sustainable chemistry.Based on our study in the catabolism and reconstruction process of amino acids,we developed a functionalized quinolines synthesis from two distinct amino acids and aniline.From divergent amino acids substrates,we provide a biomass transformation method for 2,3-disubstituted,2-substituted and 3-substituted quinolines which will be useful in pharmaceutical discovery,photochemical application.It is an interesting supplement to the method of quinoline synthesis.In chapter nine,we summarized our works in this thesis and make some predictions and prospects for future research topics.