Nordic Consortium for CO2 Conversion

Title:
Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent

Abstract:
Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal-mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting-group strategies.

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Title:
Synergetic effects on the capture and release of CO₂ using guanidine and amidine superbases

Abstract:
The capture of CO₂ from air is of utmost importance, not only to reduce its impact on climate change but also for its utilisation as a tremendous, renewable source of C1 building blocks for sustainable chemical synthesis. Novel and known superbase structures are compared in a new selection of solvents for CO₂ capture and release. Bicyclic amidine and guanidine superbases with 6–5, 6–6 and 6–7 configurations and many methylated analogues are investigated. As reported here, identified superbase/solvent combinations offer a highly efficient, reversible, and kinetically favourable CO₂ capture process from air. The two most beneficial superbase/solvent synergic combinations identified are 1,5,7-triazabicyclo[4.3.0]non-6-ene (TBN) in butyl acetate and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in acetonitrile. They reach saturation after 15 min with pure CO₂ and after 24 hours under open-air conditions and release CO₂ with a CO₂/superbase molar ratio of 0.41 and 0.25, respectively. Due to the favourable thermodynamics of the systems, quantitative CO₂ release for TBN and DBN occurs under mild conditions at 90 °C and 60 °C within 20 minutes. The required time for a complete absorption–desorption cycle for both TBN-butyl acetate and DBN-acetonitrile was only 48.5 and 38.5 minutes respectively. Superbase–solvent mixtures are recyclable and the system retains its initial CO₂ capturing capability after 5 cycles. As this apparently easy emerging system design allows the direct capture of CO₂ from air, it has potential for positive utilization on the global scale.

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Title:
Asymmetric Boracarboxylation of Styrenes Using Carbon Dioxide

Abstract:
The boracarboxylation reaction has potential for the production of natural products and drug candidates, but the development of an asymmetric version of this transformation is challenging. We report an enantioselective boracarboxylation of styrenes, enabled by a copper catalyst containing chiral phosphines. Our experimental conditions provide yields between 31–76% and enantiomeric ratios from 80:20 up to 98:2 for electron-rich styrenes. Oxidation of a boracarboxylation product gives (S)-tropic acid, an intermediate towards several tropane alkaloids. A computational analysis of the mechanistic details shows a complex pattern of competing reaction pathways, highlighting challenges encountered when developing asymmetric reactions using CO₂.

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Title:
Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

Abstract:
Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO₂. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO₂, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric ¹⁴CO₂ generated from the primary carbon-14 source Ba¹⁴CO₃, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

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Title:
Kinetically-Controlled Ni-Catalyzed Direct Carboxylation of Unactivated Secondary Alkyl Bromides without Chain Walking

Abstract:
Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO₂ at the initial C(sp³)–Br site by the rapid formation of Ni(I)–alkyl species, thus avoiding undesired β-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

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