compound (L)-eseroline (compound 10 in the adjacent diagram), the conversion of which to physostigmine would be straightforward. In one of his earlier works Julian synthesized the ring of physostigmine from 1-methyl-3-formyl-oxindole as starting material, which was discovered by Paul Friedländer. However, the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of compound 6 to give compound 7 in the diagram) with sodium and alcohol did not proceed in good yield. In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen. Although he succeeded in the synthesis of the target compound, the route had several drawbacks. First, the chemical resolution of compound 8 is unreliable, and the chemical resolution of rac-eserethole gives optically pure product only after eight recrystallizations of its tartrate salt. Second, the reductive amination going from compound 8 to compound 9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to construct the ring system and showcase new synthetic methods. Biosynthesis Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme: History The Calabar bean The Efik people, living in Cross River State and the Ibibio people in Akwa Ibom State, in what is now the south-south of Nigeria, were the first to come in contact with physostigmine, the active ingredient in the Calabar bean. The Calabar bean, or chopping nut, was very prevalent in Efik culture as an ordeal poison. Individuals accused of witchcraft would drink the white, milky extract of the bean, made by crushing the bean in a mortar and soaking the remains in water. If the accused died, it was considered proof of their use of witchcraft. If they lived, usually due to vomiting up the poison, then they were declared innocent and sent free. Western medicine's discovery In 1846, European missionaries arrived in what was referred to as Old Calabar, now part of Nigeria. These missionaries wrote about the use of the Calabar bean as a test for witchcraft. These beans eventually made their way back to Scotland, the home of these particular missionaries, where in 1855 Robert Christison, a toxicologist, tested the toxicity of the poison on himself by eating one. He survived to document the experience. The bean was studied