Study Based On Multi-component Reactions Involved Active Ylides For Effective Construction Of Bioactive Compounds

Multi-component Reactions (MCRs) is a novel strategy for efficient synthesis of poly-functional compound from three or more simple materials in one-pot. As their simple, highly efficient, convergent and atom-economic, Multi-component Reactions attract more and more attention from both academic and industrial community. Furthermore, the combination of multicomponent reactions and cascade processes in one system would enable the organic synthesis in the least number of steps.Diazo compounds are one of most important species in synthesis chemistry and they are widely used in organic synthesis due to their special reactivity. Recently, our group successively developed a series of diazo participated multi-component reactions and multi-component cascade reactions based on trapping active ylide intermediates. However, because of the narrow scope of substrates and the limitation of the efficient chiral catalyst in most cases by now, there are still many new opportunities and challenges on these new reactions.In this dissertation, we designed and implemented three types of ylide trapping multi-component reactions or multi-component cascade reactions. One was based on the multi-component reactions of ammonium ylides with imines to construct α, β-amino ester derivatives through the co-catalytic strategy; another was based on oxonium ylides nucleophilic additions and their cascade reactions; the last one based on1,3-dipolar cycloaddition of carbonyl ylides to construct polysubstituted tetrahydrofuran derivatives, and attempt [3+2] cycloaddition/Michael addition of multi-component cascade reaction. The value of our partial synthesized compounds has been demonstrated in exploring biological activity. And we proposed a preliminary structure activity relationship (SAR) between compounds and biological activity.Chapter1is the short review of relevant literatures, including co-catalysis; diazo compound, carbene and yilde chemistry; ylide involved multi-component reactions, multi-component cascade reactions and cross-dehydrogenative coupling reaction etc. At the end of this chapter is a brief introduction of design strategies and content of this dissertation.In chapter2, for the first time we have discovered an efficient squaramide and dirhodium(II)-cocatalyzed synthesis of α,β-diamino acid derivatives starting from aryl diazoacetates, arylamines and N-sulfonyl aldimines under mild conditions. The research showed that squaramide catalyst containing a double hydrogen bond can effectively activate the substrate N-sulfonyl aldimines to capture the active ammonium ylides intermediate which were in situ generated from anilines and metal carbenoids.The research of chapter3was based on the previous study, we have successfully developed a protocol for the three-component conjugate addition of aryl diazoacetates, alcohols and β,γ-unsaturated ketimines to build γ-dehydro-a-hydroxyl-δ-amino esters derivatives. Broad functional group tolerance is exhibited, and a wide range of substrates can be efficiently converted into the desired products in high yields with excellent regio-and diastereselectities under mild reaction condition. And the product can be readily converted into a-hydroxyl-δ-amino adipic acid compounds and polysubstituted2,3-dihydrofuran derivatives.In chapter4, for the first time, we achieved an one-pot, oxidative, chemselective and enantioselective multi-component cross-dehydrogenative coupling reaction of N-substituted glycine esters with diazoketone and water catalyzed by Rh2(OAc)4and chiral phosphoric acid, which provides a rapid and efficient access to synthesis of various chiral β-hydroxy-a-amino acid derivatives. And this is the first example of emplyed chiral phosphoric acid to realized asymmetric multi-component cross-dehydrogenative coupling reaction with water involved.In chapter5, for the first time, we have developed a cascade transformation that enables the efficient preparation of polysubstituted seven-membered-ring O,O-acetals in moderate yields with excellent diastereo-and enantioselectivities. The method described herein is based on Rh2(OAc)4and chiral Br(?)nsted acids-cocatalyzed Mannich/base-catalyzed oxy-Michael addition reaction of aryl diazoesters, water, anilines and methyl3-(2-formylphenoxy)propenoates. In chapter6, we have developed a three-component1,3-dipolar cycloaddition (DC) reactions of aryl diazoesters with cinnamaldehydes and β-nitrostyrenes. The presented reaction performed well over a broad range of substrates to give the desired multisubstituted tetrahydrofuran products. On this basis, we have designed an efficient pattern of one-pot cascade reaction of [3+2] cycloaddition/Michael addition which provides a rapid and efficient access to highly substituted tetrahydrofuran-chroman frameworks.In chapter7, the value of our partial synthesized compounds has been demonstrated in exploring biological activity. We propose a preliminary structure activity relationship (SAR) based on the test of biological activity on PTP1B, SIRT1and B16-F10-XBP1-DBD-Luc target.