Abstract

The gukulenins are complex, cytotoxic bis(tropolone) tetraterpenoids that contain a pseudo-C2-symmetric structure comprising highly-functionalized cyclopentanes and α-tropolone rings, and an electrophilic α-acetoxyaldehyde residue. In this lecture I will describe a synthetic route to gukulenin A. Key steps include a directed C–H arylation and tandem Grob fragmentation–alkylation to establish the substituted cyclopentane residues, a method for the synthesis of highly-substituted α-troplones by the ring expansion of ortho-quinone monoketal intermediates, a site-selective three-component cross-coupling reaction using the novel reagent (E)-1,2-di(tributylstannyl)-1-ethoxyethylene, and a thermal carbonyl–ene reaction to complete the carbon skeleton of the target. Through the synthesis and evaluation of 15 analogs we establish the dimeric α-tropolone structure as a critical driver of cytotoxicity and much of the peripheral functionality as dispensable. Gukulenin A demonstrated antitumor activity in vivo, and our studies set the stage to evaluate the activity of synthetic analogs in murine models.

Biography

Prof. Seth Herzon completed his undergraduate studies at Temple University, obtained a PhD in 2006 from Harvard University under the guidance of Professor Andrew G. Myers, and was an NIH postdoctoral fellow with Professor John F. Hartwig at the University of Illinois, Urbana–Champaign. He began at Yale in 2008 and is currently the Milton Harris ’29 Ph.D. Professor of Chemistry. He holds joint appointments in the Departments of Pharmacology and Therapeutic Radiology at the Yale School of Medicine and is a Member of the Yale Cancer Center. Herzon’s research is centered on organic synthesis with an emphasis on the molecular mechanism of action and structure–function studies of anticancer and microbiome-derived natural products. Since 2018 he has served as an Associate Editor for The Journal of Organic Chemistry.

He has been recognized for his accomplishments by a number of awards, including an NSF CAREER Award, a Searle Scholar Award, a Fellowship from the David and Lucile Packard Foundation, a Fellowship from the Alfred P. Sloan Foundation, a Cottrell Scholar Award of the Research Corporation for Scientific Advancement, a Research Scholar Award from the American Cancer Society, the Arthur C. Cope Scholar Award of the American Chemical Society, the Novartis Chemistry Lectureship, the Synthesis/Synlett Award in Organic Chemistry, the Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, the Thieme–IUPAC Award, the Tetrahedron Young Investigator Award in Organic Synthesis, the Wilson Prize, a Yale Faculty Innovation Award, and a Creativity Extension Award from the National Science Foundation. From 2018–2019 he was a member of the United States Defense Science Study Group, Sponsored by the Institute for Defense Analyses.