Adventures in Polycyclic Ring Construction

The development of efficient strategies for the construction of designed polycyclic systems is one of the more challenging and intriguing activities of organic synthesis. The three approaches outlined here each depend on a planned sequence of events.

The intramolecular Diels-Alder reaction has long been a powerful method for polycyclic ring construction. Al Padwa of Emory University reports (J. Org. Chem. 2003, 68, 227. DOI: 10.1021/jo020413d) that on Rh catalysis, a diazoalkyne such as 1 is smoothly converted into the reactive furan 2. Cyclization of 2 leads via 3 to the angularly-arylated product 4.

Scott Denmark of the University of Illinois reports (J. Org. Chem. 2003, 68, 8015. DOI: 10.1021/jo034853w) a hetero intramolecular Diel-Alder reaction of a nitro alkene 5, followed by intramolecular dipolar cycloaddition of the resulting nitronate 6, to give the tricycle 7. Raney nickel reduction effected cleavage of the N-O bonds and reductive amination of the liberated aldehyde, to give, after acetylation, the angularly substituted cis-decalin 8.

Sam Zard of the Ecole Polytechnique in Paliseau has developed elegant and affordable free-radical methods for C-C bond construction. In the context of the total synthesis of pleuromutilin, he recently reported (Org. Lett. 2003, 5, 325. DOI: 10.1021/ol027312m) that the free radical cyclization of 12 proceeded smoothly to give the eight-membered ring product 13. The ketone 12 is easily prepared from m-toluic acid. It is a tribute to the efficacy of the cyclization procedure that the conformation drawn, the conformation required for cyclization, is the less stable chair available to 12.