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Monday, May 17, 2004
Douglass Taber
University of Delaware

Adventures in Polycarbocyclic Construction

As the computational methods used in pharmaceutical development have improved, receptor binding analysis has led to many potential new drug candidates that are polycyclic. Such leads are often not pursued, however, because of the perception that even if it turned out to be active, an enantiomerically-pure polycyclic agent would be too expensive to manufacture. Taking this as a challenge, academic research groups continue to develop clever approaches for the efficient synthesis of complex polycarbocyclic target structures. Three recent approaches are outlined here.

Hee-Yoon Lee of the Korea Advanced Institute of Science & Technology (KAIST) in Daejon reported (J. Am. Chem. Soc. 2003, 125, 10156. ) that on heating, the imine 1 is cleanly converted into the tricyclic 2. The reaction presumably proceeds via insertion of the alkylidene carbene 3 into the alkene, to give the unstable alkylidene cyclopropane 4. The authors suggest that 4 opens to the diradical 5, which then cyclizes. It is striking that the geometry of the starting alkene 1 is retained in the product 2. It is possible that in fact there is a concerted pathway for the opening of 4 and simultaneous insertion, to give 2.

Hiroto Nagaoka of Meiji Pharmaceutical University has reported (Tetrahedron Lett. 2003, 44, 4649. ) the tandem reduction - Dieckmann cyclization of the esters 6 and 9. It is striking that the geometry of the starting alkene dictates the ring fusion of the product. Both 5/5 and 6/5 systems can be prepared this way.

The furanoterpene 15-acetoxytubipofuran 12 shows cytotoxicity against B-16 melanoma cells. E. Peter Kündig of the University of Geneva has reported (J. Am. Chem. Soc. 2003, 125, 5642. ) a concise asymmetric synthesis of 12, based on the addition of lithio ethyl vinyl ether to the chromium tricarbonyl-activated benzaldehyde imine 10. In the course of the organometallic addition, five carbon-carbon bonds are formed.

D. F. Taber, Org. Chem. Highlights 2004, May 17.