Synthetic Studies Toward Indole Alkaloids Spirotryprostatin B And Communesin F

There is growing interest in the field of natural product synthesis by developing asymmetric catalysis for rapid construction of chiral quaternary carbon centers and polycyclic frameworks to facilitate natural products synthesis.The indole alkaloids spirotryprostatin B and communesin F possess polycyclic skeleton and chiral quaternary carbon center（s）with good physiological activity,which have received much attention from synthetic chemists.Although plethora of strategies have been reported,construct of quaternary carbon centers relying on asymmetric catalysis are limited.In this dissertation,synthetic studies toward these two natural products have been carried out based on the asymmetric catalysis developed by our group.Spirotryprostatin alkaloids bear a spiro[pyrrolidine-3,3’-oxindole]backbone and diketopiperazine skeleton with potent anticancer activities.The synthesis of spirotryprostatin alkaloids have been achieved by several research groups.However,the construction of the core spiro[pyrrolidine-3,3’-oxindole]framework mostly takes advantage of oxidative rearrangement reaction of tetrahydro-β-carbaline.Our group has developed an catalytic asymmetric tandem double Michael addition of oxindole to alkynone,which provides a convenient access to spiro[pyrrolidine-3,3’-oxindole].We initially synthesized oxindole incorporated with diketopiperazine from L-tryptophan derivatives and L-proline,which was subjected to the action of Sc（OTf）₃/chiral N,N’-dioxide.After screening ligands and reaction conditions,the diastereoselectivity was improved to 2.6:1,overcoming the adverse effect of substrate control on the diastereoselectivity.Next,addition of methyl Grignard to the methyl ketone produced tertiary alcohol,which was smoothly dehydrated by employing Burgess reagent after reaction condition optimization to inhibit the racemization of the spiro carbon center.Finally,the complete formal synthesis of spirotryprostatin B was completed in eight steps using Ru Cl₃ mediated double bond migration.Communesin alkaloids are a class of indole alkaloids with polycyclic skeletons and continuous C₂-symmetric quaternary carbon centers,which displayed broad anti-tumor activity.Biosynthetically,communesins are derived from the rearrangement of dimeric cyclotryptamine alkaloids.We have developed the catalytic asymmetric conjugation addition reaction of 3-substituted oxidized indole to indole-3-one catalyzed by Ni（II）/chiral N,N’-dioxide,which enabled constructing C₂ symmetric continuous quaternary carbon centers in excellent enantioselectivities.Starting from the obtained enantioenriched bisoxindole,activation of unprotected oxindole with Meerwein salt delivered imine ester.Subsequently,removal of phthaloyl protection mediated with hydrazine triggered the cascade of ring opening/ring closure,which establishing the pentacyclic skeleton of communesin.