Large screening of DNA-compatible reaction conditions for Suzuki and Sonogashira cross-coupling reactions and for reverse amide bond formation

Nicholas Favalli; Gabriele Bassi; Davide Bianchi; Jörg Scheuermann; Dario Neri

doi:10.1016/j.bmc.2021.116206

Large screening of DNA-compatible reaction conditions for Suzuki and Sonogashira cross-coupling reactions and for reverse amide bond formation

Bioorg Med Chem. 2021 Jul 1:41:116206. doi: 10.1016/j.bmc.2021.116206. Epub 2021 May 9.

Authors

Nicholas Favalli¹, Gabriele Bassi¹, Davide Bianchi², Jörg Scheuermann³, Dario Neri⁴

Affiliations

¹ ETH Zürich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland; Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland.
² ETH Zürich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
³ ETH Zürich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland. Electronic address: joerg.scheuermann@pharma.ethz.ch.
⁴ ETH Zürich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland; Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland. Electronic address: dario.neri@pharma.ethz.ch.

PMID: 34038862
DOI: 10.1016/j.bmc.2021.116206

Abstract

Progress in DNA-encoded chemical library synthesis and screening crucially relies on the availability of DNA-compatible reactions, which proceed with high yields and excellent purity for a large number of possible building blocks. In the past, experimental conditions have been presented for the execution of Suzuki and Sonogashira cross-coupling reactions on-DNA. In this article, our aim was to optimize Suzuki and Sonogashira reactions, comparing our results to previously published procedures. We have tested the performance of improved conditions using 606 building blocks (including boronic acids, pinacol boranes and terminal alkynes), achieving >70% conversion for 84% of the tested molecules. Moreover, we describe efficient experimental conditions for the on-DNA synthesis of amide bonds, starting from DNA derivatives carrying a carboxylic acid moiety and 300 primary, secondary and aromatic amines, as amide bonds are frequently found in DNA-encoded chemical libraries thanks to their excellent DNA compatibility.

Keywords: DNA-compatible reactions; DNA-encoded libraries; Reverse amide bond formation; Sonogashira cross-coupling; Suzuki cross-coupling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemistry
Catalysis
Combinatorial Chemistry Techniques / methods*
DNA / chemistry*
Drug Discovery / methods*
Molecular Structure
Small Molecule Libraries*

Substances

Amides
Small Molecule Libraries
DNA