The History of Ergot

Years ago a review on ergot alkaloids (EA) appeared with the title: “The biosynthesis of ergot alkaloids; the story of the unexpected” (Floss, 1980). I don’t believe that any other title could be more appropriate since the entire history of EA research, from the discovery of ergotamine almost a century ago until the present, has truly been the history of the unexpected. The beginning of modern ergot alkaloid research dates back to 1918 when A.Stoll isolated in crystalline form ergotamine (Stoll, 1945), an alkaloid present in the sclerotia of the Claviceps purpurea fungus and patented it. In 1917 the Sandoz pharmaceutical company of Basel granted Stoll, then a young Swiss chemist and student of R.Willstaetter, already distinguished in the field of natural products, the responsibility of setting up a laboratory and developing new drug research (Stoll, 1965). Stoll proposed the goal of isolating the oxytocic active principle present in Claviceps sclerotia, universally used in post partum hemorrhages and now known as ergometrine. He hoped to do exactly as Sertumer had done a century earlier in isolating the active principle morphine from opium. Unfortunately, unlike morphine, ergometrine was not easily extractable with solvents due to its tendency to remain in the aqueous phase and, above all, because it was present in scarce quantities in the mixture of alkaloids produced by the Claviceps sclerotia: often one tenth in comparison with the production of ergotamine (Hofmann, 1964). This explains how Stoll ended up finding ergotamine, the major and the most lipophilic alkaloid in the extracted mixture, while looking for ergometrine. Nevertheless, ergotamine was used for some time as an oxytocic drug but with poor results. In fact, the crude drug (ground sclerotia) was used for many years in spite of serious dosage problems. Stoll was credited with being able to isolate in the pure state the first alkaloid of a series of almost one hundred products the majority of which were present in traces in the sclerotia collected in the Black Forest region. Stoll isolated from the mother liquor of ergotamine, also ergotaminine, a more liposoluble alkaloid of the same elementary composition as ergotamine, but which was dextrorotatory. At the beginning of research on EA scientists had the following means for characterizing a product: elemental analysis, melting point, characteristic chromatic reactions and measurement of optical rotation. Elemental analyses