Efficiency has become a key organizing principle in modern natural product synthesis. In assessing a synthetic target, practical criteria such as time, cost, and effort invariably track with step-count and production scale. Therefore, the principle of minimum chemical distance must be employed. Access to bioactive Aspidosperma-aspidosperma bis-indole alkaloid scaffolds have been limited due to low isolation yields and long synthetic routes. In 2011, Kam and coworkers isolated (–)-melodinine K, a promising anti-cancer agent, from Melodinus tenuicaudatus leaves, in 0.001% yield. Through a combination of chemistry and biochemistry, the first novel semi-synthesis of (–)-melodinine K is reported in eight steps from a commercially available mono-indole alkaloid, (–)-tabersonine. This monomeric alkaloid can be isolated from Voacanga Africana seeds in a staggering 1.3% yield, eliminating the need for a multistep total synthesis. This efficient route utilizes an enzymatic biotransformation in yeast to perform site-selective C-H oxidation which enables multigram quantities of late-stage monomers. Synthetic reactions then allow coupling of the two monomers through a key Polonovski-Potier reaction. Evaluation of semi-synthetic (–)-melodinine K by the National Cancer Institute found that it was potent against various colon cancer and melanoma cell lines. This novel synthetic route establishes a template for fast access to diverse scaffolds of various bioactive bis-indole alkaloid natural products as well as new bis-indole alkaloid analogs to probe biological activity.

Semi-synthesis and biological evaluation of bis-indole alkaloid (–)-melodinine K: Case study in efficiency

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.