Synthesis of Illudinine from Dimedone and Identification of Activity as a Monoamine Oxidase Inhibitor

• Published in: Journal of organic chemistry 2020-11, Vol.85 (21), p.13429-13437
• Main Authors: Gaston, Robert, Geldenhuys, Werner J, Dudley, Gregory B
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.0c01301

The fungal metabolite illudinine is prepared in seven steps and ca. 55% overall yield from dimedone using an “open and shut” (ring-opening and ring-closing) strategy. Tandem ring-opening fragmentation and olefination of dimedone establishes alkyne and vinylarene functionality linked by a neopentylene tether. Oxidative cycloisomerization then provides the illudinine framework. The key innovation in this second-generation synthesis of illudinine is the use of the nitrile functional group, rather than an ester, as the functional precursor to the carboxylic acid of illudinine. The small, linear nitrile (CN) is associated with improved selectivity, π-conjugation, and reactivity at multiple points in the synthetic sequence relative to the carboxylic acid ester. Preliminary assays indicate that illudinine and several related synthetic analogues are monoamine oxidase inhibitors, which is the first reported indication of biological activity associated with this natural product. Illudinine was found to inhibit monoamine oxidase B (MAO-B) with an IC50 of 18 ± 7.1 μM in preliminary assays.