Abstract

Structural modification or analogue synthesis, one of the cornerstones in drug discovery, is essential for leadoptimization and development of analog drugs and follow-on drugs. Among various structural modificationapproaches, those that can directly manipulate or derivatize lead compounds are most attractive to medicinal chemists, as such“late-stage” modifications would allow divergent synthesis of a number of analogues from a common advanced intermediate. Currently, most late-stage modification methods are based on transforming existing more reactive functional groups or functionalizing C−H bonds. In contrast, transformations that are not intuitive or obvious have been rarely used for analog synthesis. This lecture focuses on three strategies that can realize non-obvious transformations for structural modification, which provide more direct access to valuable analogues that are eitherchallenging or tedious to prepare. The first strategy is based on boron-insertion into ether C-O bonds via Ni/Zn tandem catalysis.The reaction goes through a cleavage-and-then-rebound mechanism.This method enables one-carbon ring expansion and swapping oxygen to nitrogen in cyclic ethers. The second strategy is based on the carbonyl 1,2-transposition enabled by the palladium/norbornene cooperative catalysis.This approach first converts the ketone to the corresponding alkenyl triflate that can then undergo the palladium/norbornene-catalyzed regioselective α-amination/ipso hydrogenation enabled by a bifunctional H/N donor. The resulting “transposed enamine” intermediate can subsequently be hydrolyzed to give the 1,2-carbonyl-migrated product. This method allows rapid access to unusual bioactive analogues through late-stage functionalization. The third approach is centered ona hook-and-slide strategy for homologation of tertiary amidesand carboxylic acidswith tunable lengths of the inserted carbon chain. Alkylation at the α-position of the amide (hook) is followed by highly selective branched-to-linear isomerization (slide) to effect amide migration to the end of the newly introduced alkyl chain; thus, the choice of alkylation reagent sets the homologation length. The key step involves a carbon–carbon bond activation process by a carbene-coordinated rhodium complex with assistance from a removable directing group. The approach is demonstrated for introduction of chains as long as 16 carbons and is applicable tohomologation of complex bioactive molecules.

Biography

Professor Guangbin Dong received his B.S. degree from Peking University and completed his Ph.D. degree in chemistry from Stanford University with Professor Barry M. Trost, where he was a Larry Yung Stanford Graduate fellow. In 2009, he began to research with Professor Robert H. Grubbs at California Institute of Technology, as a Camille and Henry Dreyfus Environmental Chemistry Fellow. In 2011, he joined the department of chemistry and biochemistry at the University of Texas at Austin as an assistant professor and a CPRIT Scholar. Since 2016, he has been a Professor of Chemistry at the University of Chicago. Now, he is the first chair of the Weldon G. Brown Professorship.

His researchfocuses on 1) pushing the boundary of C-C bond activation for efficient synthesis of complex organic molecules; 2) rendering the metal/norbornene cooperative catalysis as a useful tool for pharmaceutical research; 3) tackling challenges in synthesis of complex bioactive natural products; 4) developing compact molecular synthesizers for automated organic synthesis and 5) realizing programmable synthesis of monodisperse sequence-defined graphene nanoribbonand conjugated polymericmaterials.

His previous recognitions includeElias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator (2024), Tetrahedron Young Investigator Award (2021), Chan Memorial Award in Organic Synthesis (2018), Blavatnik National Awards for Young Scientists, Finalist (2020, 2022), Arthur C. Cope Scholar (2017) and Sloan Research Fellow (2014).

His representative works include:

1.Zhang, Rui; Yu Tingting; and Dong, Guangbin* “Rhodium catalyzed tunable amide homologation through a hook-and-slide strategy” Science 2023, 382, 951-957.

2.Wu, Zhao; Xu, Xiaolong; Wang, Jianchun and Dong, Guangbin* “Carbonyl 1,2-transposition through triflate-mediated α-amination”Science 2021, 374, 734-740.

3.Hairong Lyu; Kevlishvili, Ilia; Yu, Xuan; Liu, Peng* and Dong, Guangbin* “Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis” Science 2021, 372, 175-182.

4.Xu, Yan; Qi, Xiaotian; Zheng, Pengfei; Berti, Carlo C.; Liu, Peng;* Dong, Guangbin* "Deacylative transformations of ketones via aromatization-promoted C–C bond activation" Nature, 2019, 567, 373-378.

5.Xia, Ying; Lu, Gang; Liu, Peng* and Guangbin Dong* “Catalytic Carbon–Carbon Bond Activation of Cyclopentanones”Nature,2016, 546-550.

6.Mo, Fanyang; Dong, Guangbin* “Regioselective Ketone α-Alkylation with Simple Olefins via Dual Activation”,Science,2014,345, 68-72.

Others:A motto of Guangbin’s favorites is “Hire the best people…..then get out of their way” (from Arnold Beckman). He enjoys most sports, fishing,Karaoke, and cooking. HisE-mail address is gbdong@uchicago.edu.