patrick arnold was the african american scientist who created synthetic physostigmine.
who was the african american scientist who created synthetic physostigmine?
patrick arnold
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. english scientist robert robinson was also working on the synthesis of physostigmine, but surprisingly julian, a relatively unknown scientist at the time, was the successful one.
physostigmine
physostigmine has two stereocenters—the two carbons where the five-membered rings join together—so any attempt at the total synthesis must pay attention to obtaining the correct stereoisomer. 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 julian's 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 ccompound, 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.
physostigmine