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

Stefano Bonciolini; Antonio Pulcinella; Matteo Leone; Deborah Schiroli; Adrian Luguera Ruiz; Andrea Sorato; Maryne A.J. Dubois; Ranganath Gopalakrishnan; Geraldine  Masson; Nicola Della Ca'; Stefano Protti; Maurizio Fagnoni; Eli Zysman-Colman; Magnus Johansson; Timothy Noël

doi:10.1038/s41467-024-45804-z

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

Stefano Bonciolini
, Antonio Pulcinella
, Matteo Leone
, Deborah Schiroli
, Adrian Luguera Ruiz
, Andrea Sorato
, Maryne A.J. Dubois
, Ranganath Gopalakrishnan
, Geraldine Masson
, Nicola Della Ca'
, Stefano Protti
, Maurizio Fagnoni
, Eli Zysman-Colman
, Magnus Johansson
, Timothy Noël^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	1509
Number of pages	9
Journal	Nature Communications
Volume	15
Early online date	19 Feb 2024
DOIs	https://doi.org/10.1038/s41467-024-45804-z
Publication status	E-pub ahead of print - 19 Feb 2024

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H2020 MSC-ITN Eli Zysman-Colman: Photocatalysis as a tool for synthetic organic chemistry (PhotoReAct)
Zysman-Colman, E. (PI)
Joint Research Centre European Commission
1/01/21 → 31/12/24
Project: Standard

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Bonciolini, S., Pulcinella, A., Leone, M., Schiroli, D., Ruiz, A. L., Sorato, A., Dubois, M. A. J., Gopalakrishnan, R., Masson, G., Ca', N. D., Protti, S., Fagnoni, M., Zysman-Colman, E., Johansson, M., & Noël, T. (2024). Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes. Nature Communications, 15, Article 1509. Advance online publication. https://doi.org/10.1038/s41467-024-45804-z

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

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.",

author = "Stefano Bonciolini and Antonio Pulcinella and Matteo Leone and Deborah Schiroli and Ruiz, \{Adrian Luguera\} and Andrea Sorato and Dubois, \{Maryne A.J.\} and Ranganath Gopalakrishnan and Geraldine Masson and Ca', \{Nicola Della\} and Stefano Protti and Maurizio Fagnoni and Eli Zysman-Colman and Magnus Johansson and Timothy No{\"e}l",

note = "Authors are grateful to have received generous funding from the European Union H2020 research and innovation program under the Marie S. Curie Grant Agreement (PhotoReAct, No 956324, S.B., M.L., A.L., G.M., E.Z.C., T.N.; CHAIR, No 860762, A.P., M.J., T.N.)",

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Bonciolini, S, Pulcinella, A, Leone, M, Schiroli, D, Ruiz, AL, Sorato, A, Dubois, MAJ, Gopalakrishnan, R, Masson, G, Ca', ND, Protti, S, Fagnoni, M, Zysman-Colman, E, Johansson, M & Noël, T 2024, 'Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes', Nature Communications, vol. 15, 1509. https://doi.org/10.1038/s41467-024-45804-z

TY - JOUR

T1 - Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes

AU - Bonciolini, Stefano

AU - Pulcinella, Antonio

AU - Leone, Matteo

AU - Schiroli, Deborah

AU - Ruiz, Adrian Luguera

AU - Sorato, Andrea

AU - Dubois, Maryne A.J.

AU - Gopalakrishnan, Ranganath

AU - Masson, Geraldine

AU - Ca', Nicola Della

AU - Protti, Stefano

AU - Fagnoni, Maurizio

AU - Zysman-Colman, Eli

AU - Johansson, Magnus

AU - Noël, Timothy

N1 - Authors are grateful to have received generous funding from the European Union H2020 research and innovation program under the Marie S. Curie Grant Agreement (PhotoReAct, No 956324, S.B., M.L., A.L., G.M., E.Z.C., T.N.; CHAIR, No 860762, A.P., M.J., T.N.)

PY - 2024/2/19

Y1 - 2024/2/19

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-45804-z

DO - 10.1038/s41467-024-45804-z

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 1509

ER -

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

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H2020 MSC-ITN Eli Zysman-Colman: Photocatalysis as a tool for synthetic organic chemistry (PhotoReAct)

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