The 71 syntheses of physostigmine yield 33 racemic mixtures and 38 products of a single enantiomer. The first total synthesis of physostigmine was achieved by Julian and Pikl in 1935. The main goal of Julians formal physostigmine synthesis was to prepare the key 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.
The bean was studied throughout the 1860s by a few different Edinburgh scientists, including Douglas Argyll Robertson who wrote a paper on the use of Calabar bean extract on the eye and was the first to use it medicinally, and Thomas Richard Fraser, who researched how to best extract the active principle, which was later determined to be physostigmine. Fraser also studied the antagonism between physostigmine and atropine extremely rigorously, at a time when the concept of antagonism had little if any experimental support. Frasers research is still the basis of todays knowledge about the interactions between atropine and physostigmine at many different and specific doses. Physostigmines first use as a treatment for glaucoma was by Ludwig Laqueur in 1876. Laqueur himself had glaucoma so, like Christison, he experimented on himself, although Laqueur was much more scientific and methodical in his self-treatment. In the 1920s, Otto Loewi determined the biomechanical mechanism for the effects of physostigmine on the body. Loewi was studying how actions that we now consider to be controlled by the parasympathetic nervous system, were directed by chemicals. During his studies, Loewi discovered acetylcholine and that physostigmine acted by preventing acetylcholine inhibition. In 1936, Loewi was awarded the Nobel Prize for his work on discovering acetylcholine and biological chemical transmitters. More important discoveries surrounding physostigmine were made at the University of Edinburgh in 1925. Edgar Stedman and George Barger determined the structure of physostigmine using a method called chemical degradation. In 1935 Percy Lavon Julian was later the first to synthesize physostigmine.