Total syntheses of indolactam alkaloids (−)-indolactam V, (−)-pendolmycin, (−)-lyngbyatoxin A, and (−)-teleocidin A-2

Abstract

We report the total syntheses of (–)-indolactam V and the C7-substituted indolactam alkaloids (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The strategy for preparing indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish the C4–N linkage, in addition to an intramolecular conjugate addition to build the conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage sp2–sp3 cross-couplings on an indolactam V derivative are used to introduce the key C7 substituents and the necessary quaternary carbons. These challenging couplings, in addition to other delicate manipulations, all proceed in the presence of a basic tertiary amine, an unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform for probing complexity-generating and chemoselective transformations in the context of alkaloid total synthesis.

Synthetic Indolactam V Analogues as Inhibitors of PAR2‐Induced Calcium Mobilization in Triple‐Negative Breast Cancer Cells

“…Our initial task was to prepare substantial amounts (gram scale) of indolactam V ( 1 ) as a precondition for the planned structural variation. Careful analysis of the published syntheses of 1 prompted us to consider the strategy of Kogan et al . and Xu et al .…”

“…Having successfully developed an efficient synthetic scheme allowing us to prepare indolactam V ( 1 ) in gram amounts, we next turned our attention to the synthesis of various derivatives (Scheme ) . For this purpose, we preferentially used the TBS‐protected compound 17 a as a safe (biologically inactive) key intermediate.…”

“…As also shown in Scheme , a variety of C7‐substituted derivatives were synthesized starting from TBS‐protected indolactam V ( 17 a ). Using the iodinated compound 26 as a key intermediate, palladium‐catalyzed cross‐coupling and carbonylation methods were applied to introduce various substituents at C7. As before, the silyl protecting group was cleaved off only in the final step under standard conditions (TBAF).…”

Tandem Palladium Catalysis for Rapid Construction of 3,4‐Fused Tricyclic Indoles

“…[13] In recent decades, great efforts have been made to explore effective methods for the rapid construction of 3,4-fused tricyclic indoles. These methods include intramolecular Fischer indole syntheses, [14] Pictet-Spengler reactions, [15] Witkop photocyclizations, [16] addition of indolynes, [17] and dipolar cycloadditions. [18] In spite of such important advances, two challenges that remain include the multistep synthesis of the synthetic precursors and the selective installation of functional groups at the C4 position of indoles, which is not a preferred reaction site for electrophilic substitution.…”

PIII‐Chelation‐Assisted Indole C7‐Arylation, Olefination, Methylation, and Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis

“…[2] To date,the CÀHfunctionalization of indole at the C3 or C2 position has been successfully achieved by transition metal catalysis. [4] Tr aditional methods to synthesize indole C7linkage natural compounds mainly rely on the prefunctionalization of the C7 position in the form of leaving groups (such as Br, OTf,B R 2 ,S nR 3 ) [5] with coupling partners using transition metal catalysis.F or instance,apalladium-mediated intramolecular Stille reaction between the 7-stannylindole and iodoarene was used as ak ey step in total synthesis of Chloropeptin I-a na nti-HIV agent ( Figure 1a). [4] Tr aditional methods to synthesize indole C7linkage natural compounds mainly rely on the prefunctionalization of the C7 position in the form of leaving groups (such as Br, OTf,B R 2 ,S nR 3 ) [5] with coupling partners using transition metal catalysis.F or instance,apalladium-mediated intramolecular Stille reaction between the 7-stannylindole and iodoarene was used as ak ey step in total synthesis of Chloropeptin I-a na nti-HIV agent ( Figure 1a).…”