Special Seminar in Organic Chemistry: Dr. Martin Tomanik (Scripps Research Institute)

Title: Synthetic routes to (–)-myrocin G, (–)-euonyminol, and Pd(II)-catalyzed synthesis of bicyclo[3.2.1] lactones.

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Abstract: In the first part of my seminar, I will focus on the synthesis of two natural products:myrocin G and euonyminol.  Myrocin G is a pimarane diterpene that was originally proposed to react with DNA.  Our short synthesis of this natural product was enabled by the development of a highly convergent fragment coupling–ring closure cascade reaction.  In collaboration with the Adibekian lab, we elucidated the X-ray repair cross-complementing protein 5 (XRCC5) as the cellular target for myrocin, making it the first reported inhibitor of this protein essential for the non-homologous end joining (NHEJ) repair machinery.  Euonyminol is the most highly oxygenated member of the dihydro-β-agarofuran sesquiterpenes.  We developed the first enantioselective synthesis of this nonahydroxylated natural product using a highly diastereoselective alkene oxyalkylation, a radical-mediated ene–yne cyclization, and a late-stage diastereoselective α-ketol rearrangement. In the second part of my seminar, I will highlight the discovery and development of an intramolecular β-C(sp3)–H olefination and lactonization of free carboxylic acids as a means to efficiently access bicyclo[3.2.1] lactones.  This transformation features a broad substrate scope, shows excellent functional group compatibility, and can be extended to the preparation of the related seven-membered bicyclo[4.2.1] lactones.