Chirospecific Syntheses of Nitrogen and Side-Chain Modified Anatoxin Analogues. Synthesis of (1R)-Anatoxinal and (1R)-Anatoxinic Acid Derivatives

Article abstract of DOI:10.1021/jo00296a050

A straightforward and good yielding route to side-chain analogues of the potent neurotoxin and neurotransmitter (+)-anatoxin (1) has been developed.Peroxy acid oxidation of the (silyloxy)butadiene 43 derived from readily synthesized, optically pure (1R)-t-BOC-anatoxin (42) affords silyloxy ketone 44.Fluorolysis of 44 followed by oxidative cleavage of the resultant α-hydroxy ketone 45 gives a mixture of α,β-unsaturated acid 46 and ester 41 in 57percent combined yield.Other approaches to these compounds, based on literature precedent, failed. (1R)-t-BOC-anatoxinic acid (46) then serves as educt for the synthesis of a wide variety of anatoxin derivatives with modified side-chain functionality.These analogues, designed to serve as probes of the antagonist binding site of the nicotinic acetylcholine receptor, include alcohol, aldehyde, amide, hydroxamate, and oxime ether functional groups.