A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids

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Showing functional group metathesis between in situ chlorinated carboxylic acids can offer a straightforward approach to carbon isotope labelling. Carbon isotope labeling of pharmaceuticals, particularly with carbon-14, is crucial for studying drug metabolism and pharmacokinetics. However, incorporating 14C into complex drug molecules is challenging, often requiring de novo synthesis using radioactive reagents. This creates safety concerns and is expensive.

Existing methods for 14C labeling of carboxylic acids typically use radioactive gases like 14CO2 or 14CO. While effective, these methods have limitations:

- Require handling of toxic, radioactive gases

- Need specialized gas handling equipment

- Often involve harsh reaction conditions

- May be limited to specific types of carboxylic acids

The authors sought to develop a new approach that could directly label existing carboxylic acid-containing drugs without radioactive gases, using mild conditions and simple setups. The paper introduces a novel strategy using metal-catalyzed functional group metathesis to exchange the carbonyl group between carboxylic acid derivatives. This allows isotopic labeling using a single, easy-to-handle 14C source, without radioactive gases.

Designing this functional group exchange reaction presented several challenges:

1. Reductive elimination of acid chlorides from transition metals is thermodynamically unfavorable

2. The reaction requires quantitative CO transfer between metal centers without loss

3. The catalyst must enable reversible CO insertion/de-insertion while avoiding unwanted β-hydride elimination

Initial studies with palladium catalysts showed promise for aromatic acid chlorides but led to alkene formation with alkyl substrates due to β-hydride elimination.

The authors hypothesized nickel catalysts may be more suitable:

- Nickel binds CO more tightly, potentially preventing its loss

- Nickel is less prone to β-hydride elimination

- Nickel can mediate decarbonylative transformations

Two effective nickel catalyst systems were developed:

1. Ni(COD)2 with a chloride source

2. Air-stable (CO)3Ni(P(O-2,4-tBuC6H3)3) (L1Ni(CO)3)

Both catalysts enabled rapid 13C exchange at room temperature without β-hydride elimination. The nickel-catalyzed exchange reaction showed broad applicability across diverse carboxylic acid substrates. Several experiments provided insights into the reaction mechanism. Based on these observations, the authors proposed a mechanism involving:

1. Single electron transfer from Ni(0) to acid chloride, forming an acyl radical

2. Rapid recombination to form a nickel-acyl complex

3. Reversible CO de-insertion/insertion on nickel, incorporating the isotopic label

4. Rapid acid chloride elimination to regenerate Ni(0)

The presence of multiple CO ligands on nickel likely facilitates rapid CO insertion, inhibiting β-hydride elimination. High levels of 13C incorporation were achieved without racemization. The method was also demonstrated with 14C labeling of perillic acid, ramatroban, and lonazolac using 14C-4-biphenylcarboxylic acid as the isotope donor, achieving high specific activities.

This paper introduces a novel approach to carbon isotope labeling of carboxylic acids using metal-catalyzed functional group metathesis. The method employs readily available nickel catalysts to enable isotope exchange under mild conditions without radioactive gases or specialized equipment.

The reaction shows broad applicability across diverse carboxylic acid structures, including complex pharmaceuticals. It offers a straightforward alternative to existing labeling methods, potentially simplifying the process of preparing radiolabeled compounds for drug metabolism studies.

The mechanistic insights provided may also contribute to the broader understanding of nickel-catalyzed carbonyl chemistry and open avenues for developing new transformations.

This work addresses a significant challenge in pharmaceutical development by providing a simpler, safer method for incorporating carbon isotopes into drug candidates. The ability to directly label existing molecules without de novo synthesis could accelerate the preparation of radiolabeled compounds for ADME studies.

The broad scope and mild conditions make this approach potentially valuable for late-stage isotopic labeling of complex molecules. This could enable more efficient and cost-effective production of labeled compounds for various applications in drug discovery and development.

While not explicitly stated in the paper, potential areas for future research could include:

1. Further optimization to expand the substrate scope

2. Exploration of other metal catalysts or ligand systems

3. Application to other types of functional group exchanges

4. Development of asymmetric variants for synthesizing chiral labeled compounds

5. Scaling up the process for larger-scale production of radiolabeled drugs

6. Investigating the potential for site-selective labeling in more complex molecules

https://www.nature.com/articles/s41557-024-01447-7