Asymmetric Divergent Total Syntheses Of Hydroindole Alkaloids

Aspidosperma and Catharanthus hydroindole alkaloids are two types of biologically active natural products.For instance,tabersonine inhibits SK-BR-3human cancer cell line better than cisplatin,jerantinine E has a strong in vitro cytotoxicity against human KB cells(IC₅₀<1μg/m L).Vinblastine and vincristine have been widely used as well-known anticancer drugs for chemotherapy.Therefore,the total synthesis of these natural products has become a hot research area.After more than 50 years of hard work by chemists,the contradiction of total synthesis of these natural products has changed from"whether synthesis can be achieved"to"whether divergent synthesis can be achieved".Among of them,the construction of"common intermediate skeleton"and"all-carbon quaternary stereocenter"have become the hot spots and difficulties.This dissertation mainly focuses on the asymmetric total synthesis of several Aspidosperma and Catharanthus hydroindole alkaloids.Commercially and inexpensively available materials,common high-level intermediates on gram-scale quantities,and efficient synthetic routes all define this synthetic route as a potential and promising path for new drug discovery and process.Part 1:Studies on a Stereoselective Intermolecular Inverse-Electron-Demand[4+2]Cycloaddition of Pyrones and Chiral Five-Membered Endocyclic EnecarbamatesWe anticipated to develop a divergent strategy for collective total synthesis of Aspidosperma and Catharanthus hydroindole alkaloids,which contain the same pentacyclic（ABCDE[6-5-6-6-5]ring system）core structure.From our point of view,the biggest challenge is the construction of hydroindole skeleton（CE rings）,including multiple contiguous cis-stereocenters of the C ring with two all-carbon quaternary stereocenters（C5 and C12）.We employed a stereoselective intermolecular inverse-electron-demand[4+2]cycloaddition of pyrones and chiral five-membered endocyclic enecarbamates,which provided straightforward access to the core hydroindole skeleton（CE rings）bearing four contiguous cis-stereocenters with one all-carbon quaternary stereocenter（C-5）.These consecutive cis-stereocenters were induced by amino acid chirality（pyroglutamic acid）.Part 2:Total Syntheses of Fourteen Unsubstituted or Ortho-Substituted Aspidosperma Hydroindole AlkaloidsAfter completing the construction of CE rings,we achieved total synthesis of the natural products via the construction of D ring followed by the introduction of AB rings.Firstly,we used an efficient Pd/C-catalyzed cascade reaction to construct the D ring.Then,we utilized Fischer indolization to build AB rings with one all-carbon quaternary stereocenter（C12）.Finally,we obtained three unsubstituted or ortho-substituted Aspidosperma hydroindole alkaloids（（+）-dehydroaspidospermidine,（+）-dehydrodeacetylaspidospermine,and（+）-dehydrodeacetylpyrfolidine）in 9-longest linear step sequence from known pyrones and enecarbamates.We achieved divergent syntheses of 11 Aspidosperma hydroindole alkaloids（（+）-aspidospermidine,（-）-aspidospermine,（+）-vincadifformine,（-）-quebrachamine,（-）-pyrifolidine,etc.）in1-2 steps starting from these three alkaloids.Part 3:Total Syntheses of Seven Meta-Substituted Aspidosperma and Catharanthus Hydroindole AlkaloidsFurthermore,five meta-substituted Aspidosperma hydroindole alkaloids（（-）-jerantinines A,C,and E,（-）-16-methoxytabersonine,（-）-vindoline）and two Catharanthus hydroindole alkaloids（（+）-leurosidine and（+）-vinblastine）have been also synthesized,via a challengingα,β-unsaturated ketone Fischer indolization rearrangement with excellent regio-and stereoselectivity,an efficient Pd/C-catalyzed cascade reaction,and late-stage oxidative functionalization.