Collective Total Syntheses Of 4N-Featured Dimeric Alkaloids

The-4N-containing-dimeric-alkaloids-are-known-to-be-derived-from-biosynthetic tryptamine/tryptophan,in-which-the-4N-is-converted-from“N”of-indole-and“N”of-side-chain.In-nature,enzymes-assemble-symmetric-4N-and-unsymmetric-4N-specifically,delivering-dimeric-natural-products-with-diverse-connection-ways.It-is-the-varied-dimerization-linkages-that-create-specific-biological-activities.The-unique-structures-and-activities-of-this-family-have-attracted-significant-attention-from-many-chemists.The-construction-of-all-carbon-quaternary-stereocenter-and-the-control-of-dimerization-linkage-sites-with-high-stereoselectivity-have-become-a-hot-and-challenging-research-area.In-comparison-with-2N-featured-bioinspired-tryptamine/tryptophan-in-traditional-researches,this-thesis-designed-and-synthesized-a-library-of-2N-featured-aniline-enamine-monomers.Metal-catalyzed-stereoselective-oxidative-dimerization-for-controllable-assembling-symmetric-4N-and-unsymmetric4N-were-achieved,which-established-a-series-of-nature-products-scaffold-libraries-efficiently.Collective-total-syntheses-of-4N-featured-dimeric-alkaloids-were-fulfilled-in-a-concise-and-efficient-manner,which-defined-this-synthetic-strategy-as-a-potential-and-promising-path-for-the-bioactivity-research-and-drug-discovery.Part-Ⅰ:Total-Synthesis-of(-)-Calycanthine-via-Iron-Catalyzed-Stereoselective-Oxidative-DimerizationDimeric-cyclotryptamine-alkaloids-typically-feature-vicinal-all-carbon-quaternary-stereocenters-and-four-nitrogen-atoms.Compared-with-the-actual-biosynthetic-tryptophan-derivatives,we-designed-the-2N-featured-monomer,aiming-to-construct-vicinal-all-carbon-quaternary-stereocenters-via-a-one-step-dimerization-process-to-access-the-4N-featured-isomeric-members-of-this-family.In-this-thesis,we-disclose-the-first-synthetic-route-to-access-the-skeleton-of(-)-iso-calycanthine,featuring-an-iron-catalyzed-oxidative-dimerization-reaction-in-a-catalytic-single-step-operation-with-overwhelming-control-of-absolute-and-relative-stereochemistry.This-strategy-has-been-successfully-applied-to-the-total-synthesis-of(-)-calycanthine-and-sixteen-isocalycanthine-derivatives,which-demonstrates-a-new-synthetic-pathway-for-dimeric cyclotryptamine alkaloids.Part-Ⅱ:Total-Synthesis-of(+)-Asperazine-A:A-Stereoselective-Domino-DimerizationThe-concise-total-synthesis-of(+)-asperazine-A-bearing-unsymmetrical-C3-N1’ linkage-was-achieved-stereoselectively-via-an-unprecedented-4N-based-cascade-linkage.Umpolung-from-nucleophilic-aniline(N~1)to-electrophilic-N-iodoaniline-was-implemented-via-oxidant-iodine-cation,released-steadily-by-Ni-catalyzed-keto/enol-tautomerism-ring-opening-of-1,3-dicarbonyl-iodomethylcyclopropane.It-triggered-the-condensation-via-endo-attack-by-enamine(N~2)followed-by-addition-of-aniline(N~3)for-the-key-quaternization-at-C3-position.The-proton-generated-in-the-first-cyclization-initiate-the-isomerism-from-enamine(N~4)to-iminium,followed-by-the-addition-from-aniline(N~1).The-unsymmetrical-dimer-was-acquired-via-ring-reopening(N~4)driven-by-thermodynamic-stability-of-indole-aromatization.This-domino-process-assembles-four-distinct“N”s-in-sequence-to-achieve-the-aniline-dihydro-pyrrole-dimerization-isomerization,establishing-a-22-membered-library-of-asperazine-A-scaffolds-efficiently.Control-experiments-and-density-functional-theory-calculations-supported-the-electrophilic-N-iodoaniline-pathway-and-elucidated-the-highly-endo-selective-preference.