Divergent Syntheses of Carbazole Alkaloids Clausenapin, Indizoline, Claulansine M, and Clausenaline D

Abstract

We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.

Palladium‐Catalyzed Regioselective Synthesis of 1‐Hydroxycarbazoles Under Aerobic Conditions

“…[7][8][9] Thus, regioselective synthesis of 1-oxygenated carbazoles from this type of C3'-substituted substrate remains an unresolved challenge. In view of their prevalence in bioactive molecules [1] and their utility for further transformation into carbazolequinones, biscarbazoles, and other alkaloids, [3,[10][11][12] development of such a synthetic method is of great importance to provide straightforward access to a diverse range of 1-oxygenated carbazoles.…”

Total synthesis of naturally occurring 1-oxygenated carbazole alkaloids - clausine E, clausenapin, indizoline and formal synthesis of clausenaline D

“…The combined organic extract was washed with water, brine and dried over sodium sulfate. The organic layer was concentrated in vacuo and the crude residue was purified by flash chromatography on silica gel using hexane : ethyl acetate (80 : 20) Methoxy-3-methyl-2-(3-methylbut-2-en-1-yl)-9H-carbazole (3). To a suspension of LAH (0.126 g, 0.0033 mol) in anhydrous CH2Cl2/Et2O (6 mL, 1:1) was added drop wise compound 10 (0.09 g, 0.000278 mol) dissolved in anhydrous CH2Cl2/Et2O (4 mL, 1:1) under an argon atmosphere at ambient temperature and stirring was continued for 5 hours.…”

“…The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel using hexane : ethyl acetate (80 : 20) …”

“…19 Intermediate 10 was utilized for accomplishing the first total synthesis of (±)-mafaicheenamine A. Chang and coworkers described synthesis of the intermediate 10 using O-allylation of clausine E and olefin metathesis as the key steps and used it as a precursor for getting indizoline. Further they also synthesized Clausenapin, claulansine M and clausenaline D from clausine E. 20 Clausine E was synthesized by TFAA-mediated annulation of (E)-4-(1′H-indol-3′-yl)-3-(methoxycarbonyl)but-3-enoic acid, obtained from Stobbe condensation of indole-3-carbaldehyde, 21 with dimethyl succinate using sodium hydride as a base. 20 Argade's group accomplished the synthesis of intermediate 10 by prenylation of the Wittig adduct dimethyl (E)-2-((1-tert-butoxycarbonyl)-1H-indol-3-yl)methylene)succinate followed by selective hydrolysis, triphosgene-induced intramolecular acylation and methylation.…”

“…Further they also synthesized Clausenapin, claulansine M and clausenaline D from clausine E. 20 Clausine E was synthesized by TFAA-mediated annulation of (E)-4-(1′H-indol-3′-yl)-3-(methoxycarbonyl)but-3-enoic acid, obtained from Stobbe condensation of indole-3-carbaldehyde, 21 with dimethyl succinate using sodium hydride as a base. 20 Argade's group accomplished the synthesis of intermediate 10 by prenylation of the Wittig adduct dimethyl (E)-2-((1-tert-butoxycarbonyl)-1H-indol-3-yl)methylene)succinate followed by selective hydrolysis, triphosgene-induced intramolecular acylation and methylation. The intermediate 10 was then transformed to indizoline, mafaicheenamine A, claulamine A, claulansine A and claulamine E.…”