Total Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E

Abstract

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.

Azahelicenes and other similar tri and tetracyclic helical molecules

“…This synthesis could be applied only for obtaining the racemic aza [7]helicene 16 from the reaction of aniline with racemic 4,4'-biphenanthryl-3,3'-ylene ditriflate (Scheme 13). Furstner and coworkers described the total synthesis of dictyodendrin B 18 16 and, in another paper, the total synthesis of dictyodendrins C and E. 17 The synthesis of dictyodendrin B consists of 13 steps, affording the target compound in an 8% overall yield. The key steps are the titanium catalyzed synthesis of the 2,3,7-trisubstituted indole ring and the photochemical cyclization and concomitant aromatization using Pd/C in nitrobenzene leading to the substituted pyrrolo[2,3-c]carbazole scaffold in multigram quantities.…”

A formal total synthesis of the telomerase inhibitor dictyodendrin B

“…Thereafter, they extended this strategy to the total syntheses of dictyodendrin C (3) and E (5). 4 Two groups including us recently reported the synthesis of core structures of dictyodendrin. Álvarez and co-workers reported a synthesis of the pyrrolo [2,3-c]carbazole core of dictyodendrin based on a Suzuki-Miyaura cross-coupling reaction of a 3-arylpyrrole-4-boronate with a 3-bromoindole derivative and tandem photochemical 6-electrocyclization/aromatization.…”

“…A palladium-catalyzed cross-coupling reaction of the triflate 10 with the indole-3-boronate 11 using 10 mol% of Pd(PPh 3 ) 4 and K 2 CO 3 as the base in refluxing DME furnished 9 in 72% yield (Scheme 3). Alkaline hydrolysis of the diester 9 proceeded with concomitant removal of the TBS protecting group to give hydroxy-diacid 20 in quantitative yield.…”

Recent Accomplishments in the Total Synthesis of Natural Products Through C–H Functionalization Strategies

“…Between 2005 and 2006, Fuerstner and coworkers reported the first total syntheses of dictyodendrins B, C, and E [48,49] followed by Tokuyama and coworkers in 2010 with the first total synthesis of dictyodendrin A and the syntheses of the B-E analogs [50,51].…”