Approaches towards the biomimetic synthesis of 9-hydroxypinoresinol analogs: a stepping point in the development of a new anti-seizure drug

A recently isolated natural compound, Petaslignolide A, from the leaves of Petasites japonicas, has shown to be an effective neuroprotecting agent because of its antioxidant and anti-seizure activity. Recent studies have shown that the anti-seizure activity is dependent upon a metabolite of the natural product, 9-hydroxypinoresinol. Thus, the first total biomimetic synthesis was proposed to obtain 9-hydroxypinoresinol while employing metal-free organocatalysis. The synthesis utilizes the known Sonogashira Coupling reaction followed by hydrogenation using Lindlar's catalyst, epoxidation with mCPBA then ending with the highly complex step of metal-free organocatalysis to obtain 9-hydroxypinoresinol. Preliminary research in the use of metalfree organocatalysis approach were unsuccessful, thus a revised biomimetic synthesis was proposed. Previous reactions yielding the epoxide is further tosylated followed by coupling with 1-phenyl-3-butene-1-ol utilizing alkylation conditions. Further oxidation of the alkene using ozonolysis conditions then ends with metal-free organocatalysis. This revised synthesis provides promise to understanding the structure-activity relationship of the analogs to 9-hydroxypinoresinol and in turn, elucidating the mechanism of activity. The first total synthesis of 9-hydroxypinoresinol will allow the creation of a class of new novel anti-epileptic pharmaceuticals