Lewis Acid-Catalyzed 2,3-Dihydrofuran Acetal Ring-Opening Benzannulations toward Functionalized 1-Hydroxycarbazoles.

The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-ß-indolyl-ß-ketoesters. To highlight the method's synthetic utility, a formal total synthesis of murrayafoline A, a bioactive carbazole-containing natural product, was undertaken.

Synthetic methodology-enabled discovery of a tunable indole template for COX-1 inhibition and anti-cancer activity.

Establishing structure-activity relationships (SAR) for privileged pharmacophores, such as the indole scaffold, is a key step in the early stages of drug discovery. Herein, we report the synthesis and preliminary SAR studies on substituted 6-hydroxyindole-7-carboxylates as a tunable framework for COX inhibition and anti-cancer activity. To facilitate the SAR discovery, a modular synthetic methodology was employed which enabled the synthesis of the substituted indoles. From the synthesized compounds, five displayed COX-1 inhibition activity in a colorimetric assay with their intracellular activity further confirmed by a cell-based target validation assay. Following molecular docking analyses, key interactions between the active compounds and the COX enzymes were elucidated. In addition to the identified COX inhibitors, two compounds showed selective cytotoxicity against Hep-G2, MCF-7, and LnCaP. The mechanism of cell death was investigated and found to include induction of Caspase-3 activation and cleavage, down-regulation of anti-apoptotic proteins Bcl-xL and Bcl-2, and upregulation of Bax. Finally, two representative compounds were confirmed to induce cell cycle arrest at the G1/G0 stage. In summary, the 6-hydroxyindole-7-carboxylate framework shows promising versatility as a template for the discovery of anti-inflammation or anti-cancer agents, given the evidence of its COX inhibitory and anti-cancer activities herein presented.

Catalyst-Controlled Chemodivergent Reactions of 2-Pyrrolyl-α-diazo-ß-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran Acetals and Highly Substituted Indoles.

A catalyst-controlled, chemodivergent reaction of pyrrolyl-α-diazo-ß-ketoesters with enol ethers is reported. While Cu(II) catalysts selectively promoted a [3 + 2] cycloaddition to provide pyrrolyl-substituted 2,3-dihydrofuran (DHF) acetals, dimeric Rh(II) catalysts afforded 6-hydroxyindole-7-carboxylates via an unreported [4 + 2] benzannulation. The choice of enol ether proved to be crucial in determining both regioselectivity and yield of the respective products (up to 91% yield for Cu(II) and 82% for Rh(II) catalysis). Furthermore, the DHF acetals were shown to serve as precursors to 7-hydroxyindole-6-carboxylates (isomeric to the indoles formed from Rh) and highly substituted furans in the presence of Lewis acids. Thus, from a common pyrrolyl-α-diazo-ß-ketoester, up to three unique heterocyclic scaffolds can be achieved based on catalyst selection.