Year: 2023

Title:
Rapid Access to Carbon-Isotope-Labeled Alkyl and Aryl Carboxylates Applying Palladacarboxylates

Abstract:
Herein, we report a strategy for the formation of isotopically labeled carboxylic esters from boronic esters/acids using a readily accessible palladium carboxylate complex as an organometallic source of isotopically labeled functional groups. The reaction allows access to either unlabeled or full ¹³C- or ¹⁴C-isotopically labeled carboxylic esters, and the method is characterized by its operational simplicity, mild conditions, and general substrate scope. Our protocol is further extended to a carbon isotope replacement strategy, involving an initial decarbonylative borylation procedure. Such an approach allows access to isotopically labeled compounds directly from the unlabeled pharmaceutical, which can have implications for drug discovery programs.

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Title:
Multi-carbon labelling of active pharmaceutical ingredients enabled by a three-gas surrogate hydroformylation

Abstract:
Drug metabolism and pharmacokinetic studies play a crucial role in drug discovery and development programmes, assessing a lead drug candidate’s efficacy and safety profile. Quantitative bioanalytical assessment of analytes with mass spectrometry requires the use of stable carbon-13-labelled compounds with a molecular mass difference of ≥3 daltons. The incorporation of three or more carbon isotopes into drug candidates is not trivial, often requiring lengthy and costly syntheses. Here we report a dual catalytic strategy for the synthesis of multi-carbon-labelled isotopologues of active pharmaceutical ingredients. This approach uses isotopically labelled gas surrogates in a three-chamber reactor for sequential release of alkenes, carbon monoxide and hydrogen followed by low-pressure hydroformylation to generate multi-labelled alkyl aldehydes. The method’s utility has been demonstrated through the synthesis of multiple labelled N-alkyl bioactive compounds, site-selective carbon-13 and deuterium introduction and for triple-carbon labelling of small molecules combined with α-functionalization.

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