Studies On Regio-/Stereoselective Addition And Cyclization Reactions Of Functionalized Alkynes

Background and PurposesPolysubstituted olefins are the core frameworks of many bioactive small molecules,so the development of synthetic methods to efficiently construct such frameworks has received great attention.Meanwhile,the addition reaction and cyclization reaction of alkynes are ideal strategies for constructing polysubstituted olefins due to high economic atomicity and few by-products.However,conventional alkynes are difficult to obtain single-configuration compounds due to small polarity difference in C–C tribonds,resulting in less than ideal regional/stereoselectivity.In view of this key problem,it is envisaged to introduce a functional group at the alkyno-based end to precisely regulate the regional/stereoselectivity of the reaction with the unique electronic and spatial effects of the functional group.In addition,the introduced functional group can also be subsequently modified.More importantly,the functional group can act as a good pharmacopore and accelerate the rapid construction and discovery of lead drugs.Based on this,combined with the accumulation of our group’s previous work,we synthesized two kinds of stable and representative functional alkynes(including electron-rich alkynes ynamides and electron-deficient alkynesα,α-difluoromethylene alkynes)and envisaged them as coupling reagents to develop novel reaction modes and construct a library of drug-like compounds.Methods1.Considering the weak acidity characteristics of phenolic compounds,a hydrophenoxylation strategy of ynamides was developed without external mediators,and the reaction was carried out with toluene as a solvent for 12 hours at 80 ~oC.Deuterated experiments,control experiments and nucleophilic competition experiments were used to explore the reaction mechanism.In addition,the deuterated phenoxylation reaction was realized by using cheap and easily available deuterated methanol as a solvent.The aim products can also be further transformed to construct drug-like heterocyclic compounds.2.Under the catalysis of cyclopentadienyl rhodium catalyst,the cyclization reaction ofα,α-difluoromethylene alkynes and sulfonimides were carried out,1-adamantanecarboxylic copper was used as base,1-adamantanecarboxylic acid and4?MS were used as additives and methanol was used as the solvent.The reaction was reacted at 80 ~oC for 24 hours.Combining deuteration experiments,intermediate experiments and DFT calculations to explore the reaction mechanism,a highly chemical/regio/stereoselective[4+1]cyclization reaction was achieved,rapid construction of a single non enantiomer containing both the chirality of the quaternary carbon center and the sulfur atom center provides a compound basis for subsequent bioactivity screening.Results1.We developed a regional/stereospecific cis-phenoxylation reaction without mediation promotion,efficiently constructing the N,O-enamide frameworks of a series of common intermediates of bioactive molecules.The reaction requires no external mediators and reagents,the reaction conditions are mild,easy to operate and easy to scale,solvents are easy to recover,and are resistant to common functional groups,which is well in line with modern green chemistry.In addition,further intramolecular Heck conjugation of the product can be converted into a drug-like framework 2-aminobenzofuran derivative,which enhances its potential synthetic applications and is expected to be applied to the design and development of drugs frameworks.2.We developed a highly diastereoselective rhodium(III)catalyzed redox-neutral C–H/[4+1]cyclization reaction between sulfonimide andα,α-difluoromethylene alkynes to directly obtain benzisothiazole 1-oxide with a bipalm-centered carbon center and a high(E)-configuration,which can be used as an important pathway for the synthesis of novel cyclofluoride sulfonimide frameworks.Mechanistically,the reaction is activated by sulfoxideamine-assisted C–H bond,migration insertion,diastereotypical-determinedβ-F elimination,amino metallization,and termination by rapid proton dissolution.This method uses stable and easily available materials,has high atom economy and is compatible with various common functional groups,which has certain scalability and practicality.Meanwhile,the obtained compounds provide a molecular basis for later biological activity screening.ConclusionIn summary,based on the unique structure of functional alkynes(ynamides andα,α-difluoromethylene alkynes),we aim to achieve excellent regional/stereoselective addition/cyclization reactions.These reactions started from stable and readily available materials,the reaction conditions were relatively mild,and a variety of high value-added N,O-enamides and fluorinated benzoisothiazole 1-oxides products were constructed economically with high atomic economy.At the same time,the development of these strategies has further expanded the field of synthetic chemistry,enriched the reaction mode of functional alkynes and constructed a variety of drug-like molecules with potential application value,which provides guidance and reference for the subsequent development of novel reaction modes and asymmetric catalytic versions.