Guanacastepene was originally isolated from a fungus growing on a tree in Costa Rica in the year 2000 and was reported to be an antibiotic active against methicillin-resistant Staphylococcus and vancomycin-resistant Enteroccus. Since drug-resistant bacteria have become a major problem, guanacastepene attracted great interest. Since guanacastepene is not readily available from natural sources, there was thus a great interest in many laboratories in the synthesis of this natural product so that the biology of guanacastepene could be further studied. Our 2001 Organic Letters paper describes the first report of a route to a portion of the skeleton of guanacastepene. The synthesis of guanacastepene has since been completed by both Danishefsky in 2002 and by our laboratory in 2003 and now numerous other laboratories are working on this target.

Guanacastepene has an unusual tricyclic-fused core. The chemistry in our paper describes a novel and practical route to the central seven-membered ring and a very unusual new route to the cyclopentanone.

  Could you summarize the significance of your paper in layman’s terms?

Natural products often have interesting biological properties that are of interest for drug development. However, their availability from natural sources may be very limited (as in this case) so that total synthesis in the laboratory is the only way to make enough material for further biological evaluation. However, the structures of natural products, such as guanacastepene, are often very different than those of man-made compounds, and new techniques have to be invented and perfected to manufacture these compounds in the laboratory. This paper describes several new methods that are useful for the synthesis of the guanacastepene family of natural products so that their biological activity can be fully evaluated.

  How did you become involved in the research?

We became interested in this research because it offered an opportunity to exploit and further develop a cyclopentanone synthesis, which we had first developed several years earlier.