Macrocycle and medium ring structures are found in diverse natural products and approved drugs with a wide range of compelling biological activities.  However, access to libraries of these molecules for high-throughput screening in probe and drug discovery poses a major challenge in diversity-oriented synthesis.  Conventional macrocyclization-based approaches to macrocycles and medium rings are generally unsuitable for library synthesis due to their high sensitivity to substrate structure, including chain length, substituent patterns, and stereochemistry, resulting in unpredictable, often low efficiency.  To address this problem, we are developing alternative ring expansion-based approaches in which polycyclic substrates are assembled rapidly using flexible synthetic pathways, then undergo efficient ring-expansion reactions to provide diverse macrocycles and medium rings.  We leverage multidisciplinary collaborations with biologists to evaluate the libraries that we synthesize with the long-term goals of probing important biological processes and exploring promising new therapeutic opportunities in cancer and infectious diseases.

Ring expansion approaches to macrocycle and medium ring library synthesis

248th National Meeting (2014)

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