Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes

Stefano Bonciolini, Antonio Pulcinella, Matteo Leone, Debora Schiroli, Adrián Luguera Ruiz, Andrea Sorato, Maryne A. J. Dubois, Ranganath Gopalakrishnan, Geraldine Masson, Nicola Ca’, Stefano Protti, Maurizio Fagnoni, Eli Zysman-Colman, Magnus Johansson and Timothy Noël ()
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Stefano Bonciolini: University of Amsterdam
Antonio Pulcinella: University of Amsterdam
Matteo Leone: University of Amsterdam
Debora Schiroli: University of Amsterdam
Adrián Luguera Ruiz: University of Amsterdam
Andrea Sorato: University of Amsterdam
Maryne A. J. Dubois: AstraZeneca
Ranganath Gopalakrishnan: AstraZeneca
Geraldine Masson: Univ. Paris-Saclay
Nicola Ca’: University of Parma
Stefano Protti: University of Pavia
Maurizio Fagnoni: University of Pavia
Eli Zysman-Colman: North Haugh University of St Andrews
Magnus Johansson: AstraZeneca
Timothy Noël: University of Amsterdam

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)−C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic β-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.

Date: 2024
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DOI: 10.1038/s41467-024-45804-z

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