Studies On Gold-catalyzed Reactions Of Indoles With Alkynes And Its Applications In The Total Synthesis Of Lundurine C

Azocinoindole,a featuring unique indole fused with an eight-membered ring,is the common skeleton core of deoxyisoaustamide,oaramine N,grandilodine,lapidilectine B and lundurine A-D.These alkaloids not only present complex structural characteristics,but also exnibit potent anti-tumor and antiflammatory biological activitives.Therefore exploration of the total synthesis of azocinoindole alkaloids,as well as development of efficient methodologies for constructing the tricyclic skeleton,is of extreme value in organic synthesis.Gold catalysis is now a prevailing method for the assembly of polyclic and spiro indole heterocycles with advantages of mild condition and benign functional group compatibility.Because gold can selectively activate alkynes towards nucleophilic attack by indoles,proper design of substrates will enable cascade multiple-bond-forming reactions to produce polycyclic ring in one step.Although a few methods have been developed for the synthesis of azocinoindoles with gold-catalyzed cyclization reactions between indoles with alkynes,poor selectivity and narrow substrates still remain as problems and limit the scope of application.It is of urgent to develope more efficient methodology for the synthesis of azocinoindoles and further application to the total synthesis of natural azocinoindole alkaloids.In this thesis,the following topics were studied:(1)A conceptually new approach has been developed to assemble azocinoindoles from 2-propargyl-?-tetrahydrocarbolines by means of a gold-catalyzed ring expansion.The mechanism of the ring expansion was proposed which includes intramolecular Friedel-Crafts reaction,[1,2]-alkenyl miragation,Grob fragamentation and enamine-imine tautomerization.The presence of electron-withdrawing group at Cl position of?-tetrahydrocarboline is critical for the ring expansion.(2)Further investigations led us to find that methanesulfonic acid is helpful for the gold-catalyzed ring expansion of 2-propargyl-?-tetrahydrocarbolines,and the scope of the substrates free of electron-withdrawing group at C1 position was expanded.Meanwhile,a dual reaction patterns including ring expansion and Alder-ene-type cycloisomerization were disclosed.For the internal alkyne substrates,the ring expansion is exclusive.For the terminal alkyne substrates,the Alder-ene-type cycloisomerisation is predominant.DFT calculations were performed to understand the chemoselectivity as well as the role of MsOH played in the reactions.(3)A new concise total synthesis route of lundurine C was designed,in which the newly developed gold-catalyzed azocinoindole synthesis was successfully applied as key step.The further steps to complete the total synthesis of lundurine C is now in progress in this laboratory.