Study On Tandem Cyclizations Of Tryptamine-Ynamides Toward Two Indole Alkaloid Frameworks

As versatile building blocks for organic synthesis,ynamides display an exceptionally fine balance between stability and reactivity.They have drawn more and more attentions from synthetic chemists.Ynamides can participate in a series of reactions,such as addition,reduction,oxidation,cycloaddition,ring-closing metathesis and cycloisomerization.Two kinds of polycyclic indoline motifs,namely 1H-pyrrolo[2,3-d]carbazole and spiro[pyrrolidine-3,3’-oxindoles],were synthesized via a pathway-controllable sequential transformation from common tryptamine-ynamides.Ulteriorly,we have also researched the asymmetric synthesis of the tetracyclic framework.Various indole alkaloids with abundant bioactivities and synthetic values share a common 1H-pyrrolo[2,3-d]carbazole scaffold.We developed a tryptamine-ynamide-based Br?nsted acid-catalyzed tandem cyclization to this tetracyclic indoline framework.With a wide substrate scope,this cascade reaction was concise and efficient.A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate.As the pivotal intermediate in the synthesis of vindorosine,Büchi ketone was synthesized by utilizing our newly developed methodology.It is expected that this methodology should find broad applications in the synthesis of various indole alkaloids with diverse structures.The spiro[pyrrolidine-3,3’-oxindoles]-containing alkaloids often show diverse bioactivities.We developed a tryptamine-ynamide-based silica gel and alumina-mediated approach to synthesize the tricyclic oxindoles.The mechanism of the cascade reaction was studied by isotope-labeled and crossover experiments.The application of the methodology was demonstrated by the formal syntheses of two natural products,(±)-coerulescine and(±)-horsfiline.The total synthesis of(±)-elacomine through this methodology is in process.The cytotoxicity evaluation results showed that almost all the compounds synthesized in the substrate scope exhibited inhibitory activities against A549 cell line in vitro.During the research on asymmetric synthesis of the tetracyclic framework,we have screened a series of chiral catalysts and reaction conditions.In order to improve the asymmetric selectivity,we optimized diversified protecting groups and synthesized various tetracyclic indolines.We summarized the primary rules of asymmetric selectivity influenced by protecting groups on the substrates,which provides a direction for further optimization and development of this methodology.