Application of vicarious nucleophilic substitution to the total synthesis of dl-physostigmine.
A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively simple method that should be adaptable to the synthesis of homologous members of this type of alkaloid. The key step in the synthesis is a new vicarious nucleophilic substitution reaction between p-nitroanisole and a C-silylated derivative of N-methylpyrrolidinone. Subsequent conversion of the initial adduct to the tricyclic framework of physostigmine follows a well-established protocol and provides the key intermediate 8 in high yield. The vicarious nucleophilic substitution reaction has also been extended to six-membered lactams, with encouraging results.
Rege
Pankaj D
PD
Departments of Chemistry and Pharmacological Sciences, State University of New York, Stony Brook, New York 11790, USA.
Johnson
Francis
F
D001966:Bromine / Q000737:chemistry; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D007887:Fabaceae / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010830:Physostigmine / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013302:Streptomyces / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007202:Indicators and Reagents; D010830:Physostigmine; D001966:Bromine