Ergot alkaloids, isolated from fungi of the claviceps genus, exhibit a wide spectrum of structural diversity, biological activity and therapeutic uses. The common structural element is the tetracyclic ergoline ring system (1). Ergot alkaloids with dopaminomimetic properties have attracted significant interest because of their potential to treat neurological and endocrine disorders. The industrial synthesis of the most important commercial ergot alkaloids starts from naturally occurring lysergic acid obtainable by fermentation. Lysergic acid already contains the full ergoline skeleton and therefore does not allow the introduction of substituents at the C4-position in the ergoline scaffold. Presented here is our work on the asymmetric synthesis of the tricyclic core of the ergoline skeleton (4) with, for the first time, substitution in the C4-position. By using bisoxazoline ligands (5) in the Zn(II)-catalysed asymmetric Friedel-Crafts (FC) alkylation of 4-substituted indole derivatives (2) with nitrostyrene derivatives (3), a tandem FC-alkylation/Michael addition sequence was developed, installing three contiguous chiral centres with high levels of enantioselectivity (up to &gt;99% ee, 20 examples). The resulting products of this reaction have been used to synthesise novel C4-substituted tetracyclic ergoline derivatives, in a total of 5-6 steps from commercially available starting materials.

Development of an asymmetric synthesis of ergoline derivatives

2019 Fall National Meeting

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