The proposed research program would develop methods, based on alkoxycarbinyl radicals, for the asymmetric synthesis of highly oxygenated cyclic and acyclic systems. These methods would be applied to the synthesis of natural products, designed biological probes, and enzyme inhibitors, and thus would be of benefit in the medicinal chemistry arena in general. Specific research areas to be addressed include: 1. Development of new methods to synthesize highly oxygenated bridged ring systems using alkoxycarbinyl radicals. These methods would be applied to the total synthesis of zaragozic acid (squalestatin). Ready access to the zaragozic acid ring system would allow the design and synthesis of novel inhibitors of enzymes that utilize diphosphate- containing substrates. 2. Development of new methods for the synthesis of complex spirocyclic ring systems, including spiroethers and spiroketals, based on alkoxycarbinyl radicals. These methods would be applied to the synthesis of conformationally constrained glycopeptides which, in turn, would be useful for probing glycoprotein structure and function in biological systems. These compounds would be particularly useful for investigations into biological processes involving carbohydrate recognition.
