Studies toward the asymmetric total synthesis of frondosin A through oxydopyrylium [5+2] cycloaddition reaction

Abstract

Cycloaddition reaction, which can make two new bonds in regio- and stereocontrolled fashion, are very useful methods in organic synthesis. Among the various types of cycloadditions, dipolar cycloadditions of oxidopyrylium species and the related carbonyl ylides have proved to be a powerful methodology for the synthesis. The intramolecular [5+2] cycloaddition reaction of oxidopyrylium ion generated from acetoxypyranone produced fuzed 6 and 7-membered ring regio- and stereoselectively. This method provides a good synthetic strategy to construct norsesquiterpenoid core structure like biological active frondosins. Asymmetric total synthesis of frondosin A, which is fuzed 6 and 7-membered ring and cis-phenyl and contain methyl functional group, was successfully utilized regio- and stereoselectively by using oxidopyrylium ion [5+2] cycloaddition. In our synthetic trials, we could know that gem-dimethyl group affected reaction rate and diastereomer ratio, and aromatic group affected the face selectivity of cycloaddition. Specially, methoxy group of ortho-position in aromatic substituent was very important in view of face selectivity during [5+2] cycloaddition reaction of oxidopyrylium. Azabicyclo[3.3.0]octane derivative, which exhibit nicotinic pharmacology with a beneficial effect, but without significant associated side effect was successfully synthesized through 5 step from isobutyric acid. Design of processes is to maximize the amount of raw material that ends up in the product and the design of energy efficient processes.