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. 2019 Jan 16;141(2):774-779.
doi: 10.1021/jacs.8b12035. Epub 2019 Jan 3.

Direct Carbon Isotope Exchange through Decarboxylative Carboxylation

Cian Kingston  1 , Michael A Wallace  2 , Alban J Allentoff  2 , Justine N deGruyter  1 , Jason S Chen  3 , Sharon X Gong  2 , Samuel Bonacorsi Jr  2 , Phil S Baran  1
Affiliations

Direct Carbon Isotope Exchange through Decarboxylative Carboxylation

Cian Kingston et al. J Am Chem Soc. .

Abstract

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol were demonstrated by its use in an industrial carbon-14 radiolabeling setting.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(A) A new approach to carbon-14 radiolabeling inspired by hydrogen isotope exchange. NHPI = N-hydroxyphthalimide. (B) Potential pitfalls of Ni-mediated carboxylation of redox-active ester substrates.
Scheme 1.
Scheme 1.
(A) Initial investigation with 12CO2. (B) Development, optimization and analysis with 13CO2. a0.1 mmol. b1H NMR yield with 1,3,5-trimethoxybenzene as an internal standard. cCalculated from high-resolution mass spectrometry data in MassWorks (Cerno Bioscience) and confirmed by 13C NMR. dIsolated yield. DSPR = deck screening pressure reactor.
Scheme 2.
Scheme 2.
(A) Scope of the Ni-mediated decarboxylative carboxylation with 13CO2. Reaction conditions: RAE (1.0 equiv.), NiBr2•glyme (1.0 equiv.), neocuproine (2.2 equiv.), Mn (2.2 equiv.), 13CO2 (50 psi), DMF (0.1 M), rt, 20 h. a1H NMR yield with 1,3,5-trimethoxybenzene as an internal standard. LSC = liquid scintillation counting, AMS = accelerator mass spectrometry, HPLC = high-performance liquid chromatography. (B) Translation to a 14CO2 radiochemistry setup. Reaction conditions: RAE (1.0 equiv.), NiBr2•glyme (1.0 equiv.), neocuproine (2.2 equiv.), Mn (2.2 equiv.), 14CO2 (1 atm, 5.5–32 equiv.), DMF (0.03–0.05 M), −25° C (1h) to rt, 20 h.
Scheme 3.
Scheme 3.
Comparative studies on the synthesis of biologically-relevant compounds. Reactions conditions as in Scheme 2.
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