Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

Destro, Gianluca; Horkka, Kaisa; Loreau, Olivier; Buisson, David‐Alexandre; Kingston, Lee P.; Vecchio, Antonio Del; Schou, Magnus; Elmore, Charles S.; Taran, Frédéric; Cantat, Thibault

doi:10.1002/ange.202002341

Cited by 13 publications

(16 citation statements)

References 75 publications

(60 reference statements)

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“…C(sp 3 ) acids that form stabilized carbanions upon ionic decarboxylation can undergo exchange with CO2 spontaneously at high temperatures in the solid state 29 or in solution. [30][31][32].In contrast, compounds that lack strong anion stabilizing groups like nitro-or cyanoaryl acetate groups require high reaction temperatures (³150 ºC), long reaction times (³24 hours), or are simply inert towards exchange. Audisio and co-workers demonstrated the 11 C-labelling of the arylacetate drugs Flurbiprofen and Tolmetin by uncatalyzed exchange with [ 11 C]CO2, although slow kinetics and harsh conditions resulted in low radiochemical yields (RCY) (7% and 3% respectively at 150 ºC).…”

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“…Audisio and co-workers demonstrated the 11 C-labelling of the arylacetate drugs Flurbiprofen and Tolmetin by uncatalyzed exchange with [ 11 C]CO2, although slow kinetics and harsh conditions resulted in low radiochemical yields (RCY) (7% and 3% respectively at 150 ºC). 30 With the goal of developing a mild method for direct carboxylate exchange at rates appropriate for 11 C-labelling, we considered alternative strategies for C(sp 3 )-carboxylate bond cleavage and subsequent CO2 recapture. Here we show that a family of organic photocatalysts mediate the exchange of CO2 groups without the need for prior stoichiometric carboxylate activation or high temperatures (Fig 1B).…”

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Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

et al. 2021

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Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp 3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [ 11 C]CO2 is demonstrated.The synthesis of isotopically labelled molecules is essential to drug development and nuclear medicine. As drug candidates move towards clinical research and human trials, absorption, distribution, metabolism, and excretion (ADME) studies require compounds enriched with long-lived radioisotopes like 3 H and 14 C. 1 Positron emission tomography (PET) techniques that probe the advance of disease states and can determine the efficacy of drug treatment require molecular targets radiolabelled with short-lived positron-emitting isotopes such as 11 C or 18 F. 2 The limited availability and high cost of isotopically enriched precursors make the preparation of complex targets challenging. For PET studies, compounds must be synthesized and purified within a few half-lives of the radiolabel ( 11 C t1/2 = 20.3 minutes). Approaches that selectively introduce isotopic labels from feedstock sources with compatibility towards common structural motifs found in clinical candidates will have a positive impact on both drug discovery efforts and medical imaging.Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. [3][4][5][6][7][8][9] The loss of 3 H labels through (bio)chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labelling approachs. 10-11 ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels. 12 Similarly, 11 C-isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. 13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ). [27][28] These reactions are limited to primary alkyl or cyclic secondary a...

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Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

et al. 2021

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“…14 The pioneering methods from Gauthier, 15 Baran, 16 and Cantat/Audisio 17 using 13 CO or 13 CO2, to facilitate CIE showed the power of utilizing transition metal catalysts to achieve C-C bond activation, allowing for a sustainable late-stage carbon isotope enrichment strategy for pharmaceutically relevant small molecules. Despite added progress in this arena [18][19][20][21][22] , CIE labeling approaches are limited to carboxylic acids, revealing the unmet need for new CIE methods to address the diverse functional groups present in pharmaceuticals and natural products, and ideally employing easily handleable solid labeling sources (Figure 2A). 23 Herein we report a novel CIE strategy which is the first to employ Ar-CN exchange and demonstrate its utility for incorporating 13 C or 14 C labels (Figure 2B).…”

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Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

et al. 2021

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A facile one-pot strategy for 13 CN and 14 CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh3 is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)2 to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating de novo synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [ 14 C]belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh3 is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of 14 C labeled tracers for clinical development.This methodology was successfully applied to doravirine (3e) despite the presence of the Ar-Cl moiety, delivering 4e with

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Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

Reilly

Lam

Ren

et al. 2021

Preprint

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<div> A facile one-pot strategy for 13CN and 14CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh3 is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)2 to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating de novo synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [14C]<a>belzutifan</a> to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh3 is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of 14C labeled tracers for clinical development. </div>

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Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

Cited by 13 publications

References 75 publications

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

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