Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E.
Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6pi-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Domostoj
Mathias M
MM
Scheiper
Bodo
B
D000577:Amides / Q000737:chemistry; D016227:Benzoquinones / Q000737:chemistry; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D003432:Cross-Linking Reagents / Q000737:chemistry; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006219:Halogens / Q000737:chemistry; D026121:Indole Alkaloids / Q000138:chemical synthesis; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry; D010777:Photochemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013463:Sulfuric Acid Esters / Q000737:chemistry; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014025:Titanium / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D000577:Amides; D016227:Benzoquinones; D002227:Carbazoles; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D006219:Halogens; D026121:Indole Alkaloids; D011758:Pyrroles; D013463:Sulfuric Acid Esters; C505029:dictyodendrin B; C523041:dictyodendrin C; C523042:dictyodendrin E; C041514:carbazole; C004532:quinone; D010165:Palladium; D014025:Titanium; D019098:Telomerase; D015032:Zinc