The Total Synthesis Of Cannabinol

Marijuana is recognized as one of the world’s three largest drugs. However due to the important pharmacological and physiological activities of cannabinoids which are the active ingredient of marijuana, scientists pay more and more attention to them. Cannabinol,△9-tetrahydrocannabinol, and cannabinodiol are prominent members of this family. Recent study has found that cannabinol can selectively bind to CB2receptors to produce unique pharmacological activity. This discovery attracts the interest of chemists to study it, At the same time, It also brings new challenges to chemists to explore simple, convenient and high yielding synthetic strategies.Based on the new discoveries of our research group,we designed a new approach to synthesize cannabinol.First, the key step of intramolecular Diels-Alder reaction was studied. We constructed2-pyrones through simple reaction, then explored their [4+2] cycloaddition as dienes with acetylenic dienophiles to obtain the optimal reaction conditions.The synthesis of cannabinol:Starting from3,5-dihydroxy benzoic aci, we got the important intermediate of1,3-dimethoxy-5-amyl benzene through a series of reactions. It underwent acylation through the method found by our team, Michael addition, ester hydrolysis, decarboxylation, ring-closing and oxidation to get the derivative of2-pyrone. The skeleton structure known as6#-dibenzo[b,d]-pyran-6-one was then constructed using the above-mentioned optimal conditions to intramolecular Diels-Alder reaction. Further oxidization and nucleophilic addition gave the target molecule.The structures of new synthetic intermediates were confirmed by HRMS,1H-NMR and13C-NMR.