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We thank the Spanish Ministerio de Economia y Competitividad (MINECO, Project CTQ2012-35790), and MINECO/FEDER, UE (Project CTQ2015-66954-P) for financial support. E.H. thanks the Gobierno Vasco for a predoctoral fellowship. N.R. thanks the MICINN for a Ramon y Cajal contract and the European Commission for a Marie Curie Foundation (CIG: CHAAS-304085). We also thank the Centro de Computacion Cientifica de la UAM for their generous allocation of computer time.

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Palladium-Catalyzed Carbonylative Cyclization of Amines via gamma-C(sp(3))-H Activation: Late-Stage Diversification of Amino Acids and Peptides

Publicat a:Acs Catalysis. 6 (10): 6868-6882 - 2016-10-01 6(10), DOI: 10.1021/acscatal.6b01987

Autors: Hernando, Elier; Villalva, Julia; Manu Martinez, Angel; Alonso, Ines; Rodriguez, Nuria; Gomez Arrayas, Ramon; Carretero, Juan C

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The selective gamma-C(sp(3))-H carbonylation of N-(2-pyridyl)sulfonyl (N-SO2Py)-protected amines has been accomplished by using palladium catalysis and Mo(CO)(6) as carbonyl source. The reaction provides a powerful approach for derivatization of amine-based moieties, including amino acids, into richly functionalized gamma-lactams. Not only methyl groups, but also methylene C-H bonds of cyclopropanes and conformationally biased molecules can be activated to provide ring-fused gamma-lactam derivatives. This carbonylation protocol is also amenable to the late-stage diversification of more-complex multifunctional molecules such as dipeptides and tripeptides, demonstrating the key role of the N-SO2Py as directing group and its capacity to override other inherent substrate coordinating elements. In addition to providing an attractive solution to the difficulties in handling hazardous CO gas, the use of Mo(CO)(6) as an air-stable solid source of CO in substoichiometric amount (0.33 equiv) ensures Pd-II-catalytic activity by preventing its decomposition or deactivation under excess of CO via reduction of Pd-II to Pd-0 or saturation of the metal coordination sphere. Indeed, significantly lower efficiency is observed when the reactions are carried out under CO atmosphere (1 atm), or in the presence of increased amounts of Mo(CO)(6). A series of experimental and DFT mechanistic studies provide important insights about the reaction mechanism.

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