Ynamide Hydroalkoxylation Initiated Rearrangement Reaction:Efficient Construction Of Medium-Sized Lactams

Alkoxylation/rearrangement of alkyne is a tandem reaction with atom economy and high bond-forming efficiency.Because of its synthetic value,this reaction is a very hot research topic in alkyne chemistry recently.If suitable substrate and catalyst design is achieved,some multi-step reactions would be enormous simplified through this strategy,to realize "Green Chemistry".Because of above reasons,people reported a series of noble metal-catalyzed alkyne alkoxylation/rearrangement reactions and their asymmetry versions by desylmetry strategy,to achieve the facile synthesis of 5-7 membered rings.However,non-noble metal-catalyzed or metal-free alkyne alkoxylation/rearrangement reaction,and its application in medium-sized ring synthesis,is rarely reported to date.Inspired by our previous work in ynamide chemistry,we took advantage of the special properties of ynamide,to design non-noble metal-catalyzed or metal-free alkyne alkoxylation/rearrangement reactions.What's more,some useful medium-sized lactams were constructed by this reaction.Main contents of this thesis include following three sections:In the first part,we introduced the classification,development and mechanism of rearrangement reactions;the synthesis and application of medium-sized compounds;the reactive nature and application of ynamides.Thus,we reached research methods and targets after summarizing the backgrounds.In the second part,hydroalkoxylation/Claisen rearrangement of ynamides,which include intramolecular and intermolecular reaction were studied.(1)In yttrium-catalyzed tandem intramolecular hydroalkoxylation/Claisen rearrangement of ynamides,we used Y(OTf)3 as non-noble metal-catalyst to get the efficient synthesis of 8-19 membered lactams.Besides,most medium-sized lactams were synthesized in almost quantitative yields.We successfully synthesized bioactive 8-membered lactam,after product derivatization.Finally,key intermediate was separated in mechanism study,which strongly proved our proposed reaction pathway.(2)Corresponding intermolecular hydroalkoxylation/Claisen rearrangement reaction was achieved,furnishing highly selective synthesis of various ?,?-unsaturated amides,which can be easily converted into useful ?,?-unsaturated acids and ?-lactones.In the third part,Br(?)osted acid-catalyzed hydroalkoxylation/[1,3]-rearrangement of ynamides was studied.We developed a metal-free catalytic system to realize this reaction,and further achieved its asymmetric version.(1)By a series of reaction conditions optimization,0.5 mol%of HOTf was found to be efficient for this cascade,in which benzo[d]azocinones were achieved with high yield and diastereoselectivity.Moreover,we got the hydroalkoxylation intermediate to testify the mechanism.Finally,bioactivity study on medium-sized lactams obtained indicated these compounds display some anti-tumor activity.(2)Based on the racemic results,asymmetric hydroalkoxylation/[1,3]-rearrangement of ynamides was actualized by chiral spiro DTBM-phosphoramide.Various of chiral medium-sized lactams were synthesized with up to 96:4 e.r.and>50/1 d.r.through this method.Importantly,the chiral Br(?)nsted acid catalyst can be recycled in our reaction.In addition,mechanism study showed that the stereoselectivity was achieved by kinetic resolution.