Serofendic acids A and B, possessing atisane skeleton, isolated from fetal calf serum (FCS) show potent protective action against neurotoxicity induced by glutamete and an No donor. Due to its scarce availability from nature, the development of efficient synthesis is highly demanded. Eisai group synthesized serofendic acids from (-)-isosteviol through methyl atisienoate and established its absolute configuration including the stereochemistry about sulfoxide. Tohoku group studied four approaches for the synthesis of atisane derivatives. The first approach using intramolecular Diels-Alder reaction resulted in a non stereoselective production of atisane skeleton. The second approach utilizing intramolecular double Michael reaction provided the required atisane derivative in a highly stereoselective manner. However, the transformation of the product into natural diterpenes required a number of steps for the removal of ester group and introduction of C_1, unit. In order to prepare a bicyclo[2.2.2]octane ring system carrying exo olefin part, cyclization of vinyl radical was next examined. Although total synthesis of (±)-gumiferolic acid showing potent growth-regulatory activity was achieved by the third approach, the yield of the key step was low. Finally, the bicyclo[3.2.1]octane possessing exo olefin part and oxygen functionality was prepared by cycloalkenylation reaction using catalytic amount of palladium(II) acetate in DMSO under oxygen atmosphere and converted into methyl atisienoate via intramolecular Diels-Alder reaction and homoallyl-homoallyl radical rearrangement. Thus, (-)-enantiomer of atisane diterpene convertible to serofendic acids was effectively synthesized.
