| Chemical Genetics is a powerful approach to modulating protein function, through the direct interaction of small molecules with protein targets. Diversity-oriented synthesis (DOS) has emerged as a powerful approach to generate libraries of small molecules that explore underrepresented regions of chemical structure space. In particular, diverse libraries of natural product-like small molecules may leverage the proven ability of natural products to influence biology with the ease of accessibility inherent in DOS.; The spiroketal structural motif is found in a wide range of natural products with diverse biological activities. In many cases, the spiroketal structure itself is directly associated with the biological activity of the molecule. In other natural products, spiroketals can serve as rigid scaffolds to present sidechains along well-defined vectors in three-dimensional space.; Previous methods for the synthesis of spiroketals were unsuitable for DOS. Thus, we have developed several novel reactions to access systematically stereodiversified spiroketals, including a new cross coupling reaction of glycal iodides, and two remarkable stereoselective kinetic spirocyclization reactions. With this new chemistry in hand, we have synthesized our first small library of 48 stereochemically diverse spiroketals. We have also developed methods to add increased functionality to our spiroketal libraries via the incorporation of azides and alkyl chlorides into the library design. Our first-generation library has been deposited in the NIH Small Molecule Repository and Screening Center Network, and we have begun biological screening of our compounds. |
