Synthesis of (±)-Actinophyllic Acid and Analogs: Applications of Cascade Reactions and Diverted Total Synthesis

Abstract

Actinophyllic acid is a biologically active indole alkaloid with a unique structural framework that incorporates five contiguous stereocenters. A total synthesis of (±)-actinophyllic acid has been completed that proceeds in only 10 steps from readily available, known compounds and with the isolation of nine intermediates. The synthesis features a novel cascade of reactions of N-stabilized carbocations with π-nucleophiles to create the tetracyclic core of actinophyllic acid in a single chemical operation. This pivotal cascade sequence generates substructures of the actinophyllic acid core that are not otherwise accessible, and one key intermediate was modified to furnish several novel compounds having potentially promising anticancer activity, one of which induces cell death in a wide range of cancer cell lines.

An Oxidation–Amidation Approach for the Synthesis of Glycuronamides

“…Thus, we required a method for the formation of a glucuronamide that did not involve a carboxylic acid intermediate. Although methods for the direct conversion of primary alcohols to amides have been described,25–36 in our hands these were unsuccessful.…”

Concise total synthesis of (±)-actinophyllic acid

“…Toward identifying novel, biologically-active compounds, several intermediates were diverted to prepare analogs for biological evaluation, 34 and a number of tetracyclic derivatives of 28 were found to exhibit significant anticancer activity as reported elsewhere. 20 Notably, these compounds are not readily accessible by known synthetic pathways, including those that have been reported for the synthesis of actinophyllic acid. Accordingly, this discovery of promising anticancer leads underscores the value, which is not universally acknowledged, of developing alternative entries to complex natural products as a strategy to generate compounds for biological screening that would not be otherwise accessible.…”

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…These findings have been used in a crucial step toward the racemic synthesis of actinophyllic acid 16 a carboxypeptidase U inhibitor useful for the treatment of thrombotic diseases (Scheme ) …”