Institute of Chemistry and Cell Biology
Harvard University Medical School
A robust, practical synthesis platform has been developed to maximize the opportunities offered by Diversity-Oriented Synthesis (DOS). While combinatorial chemistry has become quite common in academia and in the pharmaceutical industry, DOS represents a new discovery tool for chemical genetics that focuses on preparing small molecules of maximum structural variation, with the aim of 'populating' previously vacant areas of 'chemical space.' Our approach relies on cheminformatics for pre-synthesis library enumeration and a robust solid-phase chemistry platform for preparing large numbers of small molecules. In addition, our "bead, one stock solution" approach requires chemical encoding during synthesis, and the challenge of automating this process has recently been met through the development of new software tools. The biggest challenge for DOS lies in the development of efficient and selective chemical reactions that produce compounds with highly varied three-dimensional structures. Several approaches to this challenge will be presented.