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On-DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA-Encoded Chemical Libraries

Lookup NU author(s): Harriet Stanway-Gordon, Jessica Graham, Professor Mike Waring

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

DNA-encoded libraries (DELs) are an increasingly popular approach to finding small molecule ligands for proteins. Many DEL synthesis protocols hinge on sequential additions of monomers using split-pool combinatorial methods. Therefore, compatible protecting group strategies that allow the unmasking of reactive functionality (e.g. amines and alcohols) prior to monomer coupling, or the removal of less desirable functionality (e.g., alkenes and alkynes) are highly desirable. Hydrogenation / hydrogenolysis procedures would achieve these ends but have not been amenable to DEL chemistry. We report a catalytic hydrogen transfer reaction using Pd / C, HCONH4 and the micelle-forming surfactant, TPGS-750-M, which gives highly efficient conversions for hydrogenolysis of Cbz-protected amines and benzyl protected alcohols and hydrogenation of nitros, halides, nitriles, aldehydes, alkenes and alkynes. Application to multicycle synthesis of an encoded compound was fully compatible with DNA-amplification and sequencing, demonstrating its applicability to DEL synthesis. This method will enable synthetic DEL sequences using orthogonal protecting groups.


Publication metadata

Author(s): Stanway-Gordon HA, Graham JS, Waring MJ

Publication type: Article

Publication status: Published

Journal: Angewandte Chemie International Edition

Year: 2022

Volume: 61

Issue: 3

Print publication date: 10/01/2022

Online publication date: 08/11/2021

Acceptance date: 08/11/2021

Date deposited: 16/11/2021

ISSN (print): 0044-8249

ISSN (electronic): 1521-3757

Publisher: Wiley-VCH

URL: https://doi.org/10.1002/anie.202111927

DOI: 10.1002/anie.202111927


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Funding

Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)
EP/R51309X/1
EP/S022791/1EPSRC

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