Study On The Synthesis Of Macrocycles Based On L-hydroxyproline

Macrocyclic compounds because of its synthesis, structure and properties ofspecificity, in great attention since1970s, especially in the enzyme simulation, ioniccarrier, the immune system and antibacterial properties of increasingly in-depth study;show its potential prospects in the field of pharmaceutical chemistry research anddevelopment, supramolecular broad application.Related research of macrocycles containing hydroxyproline increasingly active inrecent years, based on the analysis of literature achievements, and computer aidedmolecular design taking L-hydroxyproline macrocycles as building core fragmentdesign the a series of macrocyclic compounds with the core of hydroxyproline,aryl-alkyl ether macrocycle chain and focuses on the general method of synthesis ofthis class of macrocyclic compounds, as well as for the study of the biological activityof new active pilot found foundation compounds.The details are shown as followings were done:Based on the analysis of literature achievements, and computer aided moleculardesign,we designed a small L-hydroxyproline as the core of macrocyclic compoundlibrary. And in which the L-hydroxyproline core containing aryl-alkyl ether chainstarget macrocycles as the main research object of this paper, the synthesis of the targetcompounds inverse analysis; according to different ring strategies designed threegeneral synthetic route with the class of macrocyclic compounds.Cyclization method is the key to the synthesis of macrocyclic compounds, thisarticle explores the feasibility of the synthesis of macrocyclic compounds cyclizationmethod, respectively, to try the Mitsunobu cyclization reaction, amidation cyclizationreaction and ring-closing olefin metathesis reactions method;Eventually found usingMitsunobu reaction and amidation reaction can form a ring, while using olefinmetathesis reactions cannot form a ring;On this basis, the L-hydroxyproline,1,4-butanediol,1,5-butyl glycol,1,6-adipic between alcohol and hydroxy benzoic acid asinitial raw materials, adopt the Mitsunobu reaction and amidation reaction wassuccessfully synthesized with L-hydroxyproline skeleton and aryl-alkyl ether chain13,14,15-membered ring compounds9-a,9-b,9-c, confirmed that the two methods ofcyclization synthesis class13to15yuan ring macrocyclic compounds is generic.During the experiments,we also studied amide cyclization reaction conditions and Mitsunobu cyclization reaction in detail; discussed the influences of differentcondensing agent for amidation effects and different catalysts on Mitsunobu reaction;For amidation reaction using EDC HCl-HOBT as condensing agent cyclization yieldwas61.5%, significantly higher than the DCC and the cyclization of ethylchloroformate yields make the condensing agent; for mitsunobu reaction: when usedADDP-TBP as catalyst yield of cyclization up to69.8%, significantly higher than usedDEAD-TBP and TMAD-TBP as catalysts. Concurrent synthesis are13and15-membered rings, the synthetic by amidation cyclization reaction yield higher thanmitusunobu cyclization reaction yield, and in the synthesis of14-membered ringmacrocyclic compounds, the result just the opposite.