Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds.

Abstract

Lipophilic yeasts of the genus Malassezia are commensal fungi that constitute the normal skin microbiota but may become pathogenic. These fungi, especially M. furfur, convert tryptophan into various alkaloid indoles such as malassezione, which may serve as virulence factors. To facilitate testing of malassezione as an aryl hydrocarbon receptor agonist and potential glucokinase activator, we developed a convenient synthetic route from commercially available indole-3-acetic acid. Treatment of the N-Boc-protected indole-3-acetic acid with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of DMAP generates the N,N'-Boc-protected malassezione, which upon deprotection yields malassezione in an overall yield of ca. 20%. This is an improvement over the preparation of the isonitrile followed by an Fe hydride initiated isonitrile-olefin intramolecular coupling reaction, which generated malassezione with an overall yield of ca. 5%. Furthermore, the present method may also be used to prepare related compounds.