Identification of Readily Accessible Manganese Catalysts Enables Multi-gram Scale Enantioselective γ-C(sp ³ )‒H Lactonization of Carboxylic Acids
- 1Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat De Girona
Abstract
Selective C‒H bond functionalization is a powerful tool to access complex molecules within a minimal number of synthetic steps, but its applicability on a large scale is often hampered by the requirement of harsh reaction conditions and costly catalysts. Among the existing C‒H bond functionalization portfolio, carboxylic acid directed C‒H lactonization has emerged as a particularly valuable transformation since it provides access to synthetically versatile lactone products from readily available carboxylic acids. Aiming at identifying catalysts that facilitate scalability of the reaction, herein, a collection of simple manganese complexes bearing triazacyclononane, picolinic acid, bipyridine and minimal N-based tetradentate ligands, which are established oxidation catalysts, have been screened in a model carboxylic acid directed C‒H lactonization reaction. While most of them proved ineffective, we identified two catalysts bearing simple N-based tetradentate ligands, Mn-(OTf) 2 (meb) (Mn-meb) and ( R,R )-Mn-(OTf) 2 (mcb) (Mn-( R,R -mcb)), which are far more easily accessible than previously reported best-in-class sterically encumbered catalysts and provide lower yet still comparable performance under mild reactions conditions. Remarkably, high levels of enantioselectivity can be obtained in some relevant directed C‒H bond oxidation reactions. Even though these simplified complexes still operate in fluorinated solvents like hexafluoroisopropanol (HFIP), we demonstrate that solvent usage can be minimized with respect to previously adopted protocols by working at up to 30-fold higher concentrations and recycling the solvent over at least three catalytic runs. The effectiveness of this approach is demonstrated on a small scale using seven highly diversified substrates and on a five gram scale by the lactonization of a cycloalkyl carboxylic acid and a protected amino acid via secondary and primary C(sp 3 )‒H bond oxidation, respectively. More than two grams of a highly enantioenriched lactone could be isolated using only ~100 mL of HFIP, 1.5 equiv. of H 2 O 2 and ~15 mg of an inexpensive and air-stable manganese catalyst (TON ≈ 1000).
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BibTeX
@misc{zaccaria2026identification,
title = {{Identification of Readily Accessible Manganese Catalysts Enables Multi-gram Scale Enantioselective γ-C(sp ³ )‒H Lactonization of Carboxylic Acids}},
author = {Francesco Zaccaria and Lluc Vila and Arnau Call and Miquel Costas},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010445/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010445/v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Identification of Readily Accessible Manganese Catalysts Enables Multi-gram Scale Enantioselective γ-C(sp ³ )‒H Lactonization of Carboxylic Acids
AU - Francesco Zaccaria
AU - Lluc Vila
AU - Arnau Call
AU - Miquel Costas
PY - 2026
DA - 2026/10/14
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010445/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010445/v1
AB - Selective C‒H bond functionalization is a powerful tool to access complex molecules within a minimal number of synthetic steps, but its applicability on a large scale is often hampered by the requirement of harsh reaction conditions and costly catalysts. Among the existing C‒H bond functionalization portfolio, carboxylic acid directed C‒H lactonization has emerged as a particularly valuable transformation since it provides access to synthetically versatile lactone products from readily available carboxylic acids. Aiming at identifying catalysts that facilitate scalability of the reaction, herein, a collection of simple manganese complexes bearing triazacyclononane, picolinic acid, bipyridine and minimal N-based tetradentate ligands, which are established oxidation catalysts, have been screened in a model carboxylic acid directed C‒H lactonization reaction. While most of them proved ineffective, we identified two catalysts bearing simple N-based tetradentate ligands, Mn-(OTf) 2 (meb) (Mn-meb) and ( R,R )-Mn-(OTf) 2 (mcb) (Mn-( R,R -mcb)), which are far more easily accessible than previously reported best-in-class sterically encumbered catalysts and provide lower yet still comparable performance under mild reactions conditions. Remarkably, high levels of enantioselectivity can be obtained in some relevant directed C‒H bond oxidation reactions. Even though these simplified complexes still operate in fluorinated solvents like hexafluoroisopropanol (HFIP), we demonstrate that solvent usage can be minimized with respect to previously adopted protocols by working at up to 30-fold higher concentrations and recycling the solvent over at least three catalytic runs. The effectiveness of this approach is demonstrated on a small scale using seven highly diversified substrates and on a five gram scale by the lactonization of a cycloalkyl carboxylic acid and a protected amino acid via secondary and primary C(sp 3 )‒H bond oxidation, respectively. More than two grams of a highly enantioenriched lactone could be isolated using only ~100 mL of HFIP, 1.5 equiv. of H 2 O 2 and ~15 mg of an inexpensive and air-stable manganese catalyst (TON ≈ 1000).
ER -