Please join Yale Chemistry for a Silliman Seminar in Organic Chemistry with Prof. Doron Pappo, Professor of Chemistry, Ben-Gurion University of the Negev.
Abstract: Metal-catalyzed oxidative phenol coupling offers a direct route to biphenols and diaryl ethers from simple phenolic precursors. Although substantial progress has been made in controlling chemoselectivity (cross-coupling vs. homocoupling and C–C coupling vs. C–O coupling) and stereoselectivity (axial chirality), other aspects of selectivity remain largely unexplored.
In nature, the biosynthesis of glycopeptide antibiotics, including vancomycin, and other biologically active macrocyclic peptides, relies on enzymatic oxidative phenol macrocyclizations of linear precursors to form biaryl and diaryl ether-linked macrocyclopeptides. Despite their synthetic importance, biomimetic and step-economical chemical counterparts of these transformations remain underdeveloped.
A major limitation of oxidative phenol coupling is its narrow substrate scope: the reaction is typically restricted to phenols having multiple electron-donating substituents that block reactive positions, or to 2-naphthol derivatives. As a result, unsubstituted phenols and ortho- or meta-monosubstituted phenols that are expected to yield a mixture of biphenol isomers have largely remained inaccessible.
To address these long-standing challenges, we have developed hydroxo multicopper(II) clusters, such as Cu2(tmeda)2(μ-OH)2(μ-OTf)](OTf) and [Cu4(pmbma)4(µ3-OH)4](OTf)4 (pmbma = N-(2-pyridinylmethylene)benzenemethanamine) that, in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), enable the oxidative macrocyclization of linear peptides and mediate the oxidative coupling of simple unsubstituted as well as mono- and polysubstituted phenols with complete ortho–ortho selectivity.
In this talk, I will highlight the unique reactivity and selectivity of hydroxo multicopper(II) clusters and discuss key mechanistic features that enable them to promote redox transformations inaccessible to conventional, mononuclear metal catalysts.
Biography: Doron Pappo earned his Ph.D. from Tel Aviv University in 20006 under the guidance of Yoel Kashman. He subsequently conducted postdoctoral work with Prof. K. C. Nicolaou at The Scripps Research Institute, La Jolla, and the Biopolis Chemical Synthesis Laboratory, ICES (A*STAR), Singapore (2006–2007). From 2007–2009, he was a senior researcher in Prof. Keinan’s group at the Technion and then held a team-leader position at Makhteshim-Agan (currently ADAMA; 2010). He joined the Ben-Gurion University of the Negev faculty in 2010 as an assistant professor. He was promoted in 2016 to an associate professor and in 2020 to the rank of a full professor. The Pappo group’s primary research interest is developing and designing novel redox systems for selective oxidation and dehydrogenation reactions based on earth-abundant metal catalysts such as iron, copper, cobalt, and manganese. Doron was awarded in 2016 The Israeli Chemical Society Award for Outstanding Young Scientist for his group research achievements and, in 2023, The Israel Chemical Society-Adama Prize for Technological Innovation. For more information on Prof. Pappo’s research: Home Page | pappogroup
Hosted by Prof. Scott Miller.
Sponsored by the Mrs. Hepsa Ely Silliman Memorial Fund
References:
(1) Libman, A.; Ben-Lulu, M.; Gaster, E.; Bera, R.; Shames, A. I.; Shaashua, O.; Vershinin, V.; Torubaev, Y.; Pappo, D. Multicopper Clusters Enable Oxidative Phenol Macrocyclization (OxPM) of Peptides. J. Am. Chem. Soc. 2023, 145 (38), 21002-21011.
(2) Bera, R.; Shaashua, O.; Libman, A.; Derks, M. T.G.M.; Yuan, B.; Pereverzev, A. Y.; Kapanaiah, R.; Ben Lulu, M.; Kertzman, L.; Vainer, Y.; Torubaev, Y. V.; Roithová, J.; Pappo, D. Ortho-Ortho Selective Oxidative Coupling of Phenols by Hydroxo Multicopper(II) Clusters, J. Am. Chem. Soc. 2025, ASAP.
(3) Bera, R.; Kapanaiah, R.; Pappo, D. Regioselective Oxidative Coupling of Mono-Halogenated Phenols, Under review.