SYNTHESIS OF A STRUCTURALLY AND STEREOCHEMICALLY DIVERSE SPIROKETAL LIBRARY USING NOVEL STEREOSELECTIVE SPIROCYCLIZATIONS OF C1-SUBSTITUTED GLYCAL EPOXIDES
A chemical genetic approach that uses small organic molecules to modulate protein function has the potential to overcome the limitations of classical genetic techniques for the study of biological processes. However, acquiring the features of broad applicability and specificity that are inherent to traditional genetics is still a challenge in chemical genetics. The impact that chemical genetics will have on our understanding of biological systems depends on a steady supply of biologically active small molecules with novel targets or improved specificity for known targets. Diversity-oriented synthesis (DOS) of small molecule libraries is an emerging method to identify new probes for biological studies and potential therapeutic lead compounds. We have explored the use of an approach that employs structural features commonly found in natural products as starting points for library design. Our library incorporates spiroketal motifs, but is otherwise stereochemically and structurally diverse to address a wide range of biological targets. Although many efforts have been made to synthesize members of the spiroketal class of natural products, traditional methods are not suitable for generating stereochemical diversity in DOS. Therefore, we have developed a strategy to create stereochemical diversity by using novel stereocontrolled spiroketalization reactions that provide access to both spiroketal stereoisomers from a common C1-substituted glycal epoxide precursor. Our route has allowed the synthesis of a library of diastereomeric spiroketals in which we control the stereochemical configuration not only at the quaternary spiroketal carbon, but also at multiple ring carbons. The library will ultimately be screened against a number of biological targets to evaluate the effectiveness of the design strategy, and potentially identify new biological probes or lead compounds for drug development.
spiroketal; small molecule library; glycal; glycoside; diversity-oriented synthesis
dissertation or thesis