Ergot alkaloids possess perhaps a greater diversity of bioactivity than any other class of natural products. They and their semisynthetic derivatives are exceptionally active as dopamine and serotonin receptor agonists and antagonists, having found utility in treating Parkinson's disease and migraines. We have engineered an efficient library-optimized route to underrepresented ergolines with diversity in the 'A' (phenyl) ring.  In addition, the route allows for the incorporation of conjugated unsaturated systems for tuning of the natural fluorescence wavelengths of ergolines to yield a set of biological probes with fluorescent properties. A highly functionalized pyridine derivative is the key to the efficiency of the route, allowing for introduction of 'A'-ring molecular diversity as late as possible in the synthetic route. Utilizing this derivative, a functionalized ergoline skeletal framework has been synthesized via a key intramolecular Heck cyclization in seven steps from readily available starting materials.

Ergot alkaloid analogs: Engineering a library-optimized route

243rd National Meeting (2012)

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