Abstract: Carbonyl-tethered alkylidenecyclopropanes can react with aryl isocyanates in presence of Pd(0)-phosphoramidite catalysts to give seven-membered heterobicyclic products in a formal [3+2+2] cycloaddition process. The reaction involves the formation of a palladium π-allyl complex intermediate (A), which behaves as a formal 1,5-dipole, and can be trapped by externally added isocyanates. This report also includes preliminary assays of asymmetric variants, as well as DFT computational studies that shed some light on the nature of the catalytic cycle.

Abstract: Optically active 2-aminobiaryls are valuable chiral frameworks with broad applications in catalysis, synthetic chemistry, and materials science. Here, we present a simple and practical methodology for their asymmetric synthesis via enantioselective palladium catalyzed C−H arylations or alkenylations of racemic precursors. The methodology utilizes a kinetic resolution strategy, producing two highly valuable enantioenriched axially chiral molecules: the C−C coupling product and the unreacted starting material. Notably, we have established reaction conditions that enable the in situ regeneration of the active Pd(II) catalyst using atmospheric air as the sole oxidant. Finally, we showcase the synthetic utility of this approach by preparing several derivatives relevant to the field of asymmetric catalysis.

External link: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202425512

We are really pleased to announce here that our research article at ChemCatChem, entitled "Photocatalytic Arylations with Diazonium Salts in Aqueous and Biorelevant Media" and authored by X. Fernández, J. Miguel, J. L. Mascareñas and M. Tomás-Gamasa has been accepted and it's already on-line.

Abstract: Performing designed, abiotic chemical transformations in live environments represents a powerful approach to interrogate and manipulate biology, and to uncover new types of biomedical tools. Despite significant advances in the area, the list of bioorthogonal reactions so far available is still very short, and mainly restricted to the use of strained reactants, or metal-promoted processes. En route to further expanding the repertoire of biocompatible reactions, we demonstrate here that aryldiazonium salts, well-established as radical precursors, can react with unsaturated systems in biologically relevant media under photocatalytic conditions, to give either addition or cycloaddition products, depending on the reactants.

External link: https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202401778

We are so pleased to announce here that our last paper at Org. Lett., entitled "Assembly of 2-Substituted Tetrahydroquinolines from ortho-Methylbenzenesulfamides and Dienes, Using a C(sp3)–H Activation/Annulation Sequence" and authored by I. Huertas-Morales, B. Cendón, D. Costa, J. L. Mascareñas and M. Gulías, has been accepted and it's already on-line.

Abstract: 1,2,3,4-Tetrahydroquinolines (THQs) are essential structural cores in many natural products and pharmaceutical drugs. Especially relevant are those presenting substitutions at position 2, yet practical methods for their one-step assembly from acyclic precursors are very scarce. Herein, we present a straightforward approach to assembling these skeletons from ortho-methylanilines using a palladium-catalyzed C(sp3)–H activation/formal cycloaddition sequence. Key for the success of the approach is the use of dienes as partners, since they lead to stable π–allyl palladium intermediates that prevent β-hydride elimination processes and allow installation of versatile alkenyl handles at position 2. Moreover, installing a perfluorobenzenesulfonyl substituent at the amine not only facilitates the C–H activation but also allows for an easy recovery of the free amine.

External link: https://pubs.acs.org/doi/10.1021/acs.orglett.4c02292

We are so pleased to announce here that our last minireview at Angew. Chem. Int Ed., entitled "Bioorthogonal Synthetic Chemistry Enabled by Visible-Light Photocatalysis" and authored by M. Mato, X. Fernández-González, C. D'Avino, M. Tomás-Gamasa and J. L. Mascareñas, has been accepted and it's already on-line (gold Open Access).

Abstract: The field of bioorthogonal chemistry has revolutionized our ability to interrogate and manipulate biological systems at the molecular level. However, the range of chemical reactions that can operate efficiently in biological environments without interfering with the native cellular machinery, remains limited. In this context, the rapidly growing area of photocatalysis offers a promising avenue for developing new type of bioorthogonal tools. The inherent mildness, tunability, chemoselectivity, and external controllability of photocatalytic transformations make them particularly suitable for applications in biological and living systems. This minireview summarizes recent advances in bioorthogonal photocatalytic technologies, with a particular focus on their potential to enable the selective generation of designed products within biologically relevant or living settings.

External link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202413506

We are so proud to announce here that our collaborative research article at JACS Au, entitled "De Novo Engineering of Pd-Metalloproteins and Their Use as Intracellular Catalysts" and authored by S. Learte-Aymamí, L. Martínez-Castro, C. González-González, M. Condeminas, P. Martin-Malpartida, M. Tomás-Gamasa, S. Baúlde, J. R. Couceiro, J.-D. Maréchal, M. J. Macias, J. L. Mascareñas and M. E. Vázquez, has been accepted and it's already on-line (gold Open Access) also being selected as "Editors' Choice".

Abstract: The development of transition metal-based catalytic platforms that promote bioorthogonal reactions inside living cells remains a major challenge in chemical biology. This is particularly true for palladium-based catalysts, which are very powerful in organic synthesis but perform poorly in the cellular environment, mainly due to their rapid deactivation. We now demonstrate that grafting Pd(II) complexes into engineered β-sheets of a model WW domain results in cell-compatible palladominiproteins that effectively catalyze depropargylation reactions inside HeLa cells. The concave shape of the WW domain β-sheet proved particularly suitable for accommodating the metal center and protecting it from rapid deactivation in the cellular environment. A thorough NMR and computational study confirmed the formation of the metal-stapled peptides and allowed us to propose a three-dimensional structure for this novel metalloprotein motif.

External link: https://pubs.acs.org/doi/10.1021/jacsau.4c00379