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

Abstract

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.

Application of Cyclohexane‐1,3‐diones in the Synthesis of Six‐Membered Nitrogen‐Containing Heterocycles

“…Biologically active quinolone and benzoacridinones, pyridine derivatives synthesized from cyclohexane-1,3-dione derivatives. [70,78,87,88]…”

“…Benzoacridinones are another significant six‐membered nitrogen heterocycles that have tricyclic moiety containing acridine skeleton and showed different kinds of biological activities (Figure 3). [70] There are several methods in literature which provide benzoacridinones in the presence of catalysts such as N , N ‐disulfo‐1,1,3,3‐tetramethylguanidinium carboxylate ionic liquids, [71] sulfonic acid functionalized boron nitride, [72] and succinimide‐ N ‐sulfonic acid [73] . However, in spite of many advantages of these methods, they also have their limitations such as low yield and prolonged reaction time.…”

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Alcyopterosin O

“…Illudalic acid was isolated from the toxic eastern jack o’lantern mushroom, Omphalatus illudens , and was later discovered to be a selective phosphatase inhibitor . We recently reported that its congener, illudinine, is a monoamine oxidase inhibitor . The alcyopterosins are cytotoxic illudalanes from deep water Antarctic Alcyonium corals, which have received considerable attention from natural products researchers .…”

“…Notable illudalane syntheses include that of illudalic acid and illudinine by Woodward and Hoye in 1977, that of illudinine by Teske and Deiters in 2008, that of alcyopterosin A by Sato in 2002 and by Iglesias in 2006, and those of several other alcyopterosins by Witulski in 2010 . We reported syntheses of alcyopterosin A in 2016 and illudinine in 2017, with the latter synthesis updated in 2020 . Eight additional publications on the synthesis of illudalane sesquiterpenes have appeared since the beginning of 2018, as these targets increasingly attract attention for natural product synthesis.…”

“…This 1-indanone-based approach to the 2,2-dimethylindane core was employed previously for the syntheses of illudinine, illudalic acid, and alcyopterosin A . The neopentylene ring fusion was then truncated or omitted for synthetic expediency in follow-up medicinal chemistry efforts, , despite evidence that the intact neopentylene ring fusion can be important for potency. , Here we assemble the fully substituted arene, including the neopentylene fusion, in one regioselective intermolecular [2+2+2] cyclotrimerization, having prepared the nonsymmetrical diyne alcohol substrate ( 9 ) in four steps (59% overall) from dimedone.…”