Studies toward the Total Synthesis of (±)-Lysergic Acid

Ergoline alkaloids are a class of compounds that can act as agonists or antagonists of adrenergic, dopaminergic, and serotonergic receptors. Among them, (±)-lysergic acid (1) is of particular interest as a precursor for new pharmaceuticals. This work aims to develop a synthetic route to (±)-lysergic acid (1) without using indole derivatives as starting materials. The first route failed to afford intermediate 4 via Mizoroki-Heck or Heck-Matsuda coupling between compounds 2 and 3. The second route provided intermediate 6 in 41% yield over four steps, but the subsequent Diels-Alder and rearomatization reactions upon aryne generation did not produce intermediate 7. A third route is currently under investigation, starting from p-toluenesulfonylamide 8 to afford compound 9, which is expected to undergo a nucleophilic addition/Diels-Alder cascade reaction with the domino aryne precursor 10.