ZIPPER-MODE CASCADE CARBOMETALLATION FOR CONSTRUCTION OF POLYCYCLIC STRUCTURES

A novel concept for the synthesis of polycyclic compounds via "zipper"-mode cyclic carbometallation reactions has been introduced. The Zr-promoted bicyclization-carbonylation of enynes can be highly diastereoselective, leading to the formation of stereoisomerically homogeneous bicyclic ketones. The reaction has been applied to a total synthesis of pentalenic acid with essentially complete control of stereo- and regiochemistry. In contrast to the ZrCp2-promoted methodology, whose applicability is limited to bicyclization, cyclic carbopalladation can repeat itself to produce three or more rings in one step, provided that beta-elimination or other decomposition paths are not available. Alkynes and 1,1-disubstituted alkenes can serve as relay functionalities. With 1,1-disubstituted alkenes, however, the regiochemistry of cyclization can be complicated by cyclopropanation. Efforts have been made to delineate the scope of cyclopropanation. Finally, cyclic acylpalladation followed by intramolecular trapping by O-enolates can give enol lactones via bicyclization. This bicyclization process has been applied to an expeditious synthesis of a tricyclic intermediate for a promising anti-ulcer agent U-68,215.