co9b00164_si_001.pdf (11.62 MB)
An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis
journal contribution
posted on 2020-02-27, 13:06 authored by Yves Ruff, Roberto Martinez, Xavier Pellé, Pierre Nimsgern, Pascale Fille, Maxim Ratnikov, Frédéric BerstThe use of DNA-encoded
libraries has emerged as a powerful hit
generation technology. Combining the power of combinatorial chemistry
to enumerate large compound collections with the efficiency of affinity
selection in pools, the methodology makes it possible to interrogate
vast chemical space against biological targets of pharmaceutical relevance.
Thus, the chemical transformations employed for the synthesis of encoded
libraries play a crucial role in the identification of diverse and
drug-like starting points. Currently established transformations have
mostly been limited to water-compatible reactions to accommodate the
growing oligonucleotide tag. Herein, we describe the development of
a practical catch-and-release methodology utilizing a cationic, amphiphilic
PEG-based polymer to perform chemical transformations on immobilized
DNA conjugates under anhydrous conditions. We demonstrate the usefulness
of our APTAC (amphiphilic polymer-facilitated transformations under
anhydrous conditions) approach by performing several challenging transformations
on DNA-conjugated small molecules in pure organic solvents: the addition
of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran,
the synthesis of saturated heterocycles using the tin (Sn) amine protocol
(SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox
decarboxylative cross-coupling of carboxylic acids to DNA-conjugated
aryl halides in DMSO. In addition, we demonstrate the feasibility
of the latter in multititer-plate format.