Studies in the Total Synthesis of (+)-Lysergic Acid and (+)-Lysergol: A Direct Approach for the Construction of the Tetracyclic core of Ergot Alkaloids

The ergot alkaloids are a class of compounds which were isolated from fungus Claviceps Purpurea, For several decades, several researches have demonstrated that these natural products, and some semisynthetic derivatives have wide biological activites. Among the most representative ergot alkaloids, (+)-lysergic acid and (+)-lysergol have been synthetic targets in organic synthesis for years. Thirteen syntheses have been reported for (+)- Lysergic acid and three for (+)-Lysergol. Herein, we show how we accomplished the synthesis of key tetracyclic core of these alkaloids and how we will employ it to complete the diasteroselective total syntheses of (+)-lysergic acid and (+)-lysergol. Our synthesis started with an aminoaldehyde derived from 4-bromotryptophan (synthesized in 7 steps from L-serine). From this aldehyde the key reactions involved a Horner-Wadsworth-Emmons olefination, Cu-catalyzed NH Insertion and intramolecular Heck Reaction.