Spiroketals are privileged substructures found in numerous natural products. Even relatively simple spiroketals exhibit a range of biological activities. In more complex structures, spiroketals often serve as rigid scaffolds to present sidechains along well-defined three-dimensional vectors. Thus, spiroketals are attractive targets for diversity-oriented synthesis. In particular, they allow extensive use of stereochemical diversity to enhance three-dimensional structural diversity.
Target-oriented synthesis of spiroketal-containing natural products has commonly relied upon thermodynamically-controlled spiroketalization reactions. However, in such reactions, the stereochemical outcome at the anomeric carbon is influenced by multiple, sometimes competing factors that govern product stability. Thus, to synthesize systematically stereodiversified spiroketal libraries, new kinetically-controlled spiroketal-forming reactions are required.
We have developed a new synthetic route to spiroketals that provides stereocontrolled access to either of the two anomeric stereoisomers. Our approach also uses four adjacent stereogenic centers to present functional groups and sidechains along diverse three-dimensional vectors. This project has also provided us with many exciting opportunities to develop new synthetic methodologies. Our current efforts involve exploring the efficiency and flexibility of this diversity-oriented synthesis route and using it to generate libraries of stereodiverse spiroketals for high-throughput screening.
