CHAAS · New tools for assembling complex molecules

New tools for assembling complex molecules

Over the past few decades, Bergman, Hartwig, Davies, and many others have demonstrated that the selective and efficient functionalization of non-activated C(sp3)-H bonds of simple aliphatic substrates can be achieved through diverse metal-catalyzed reactions.[1] However, achieving catalyst-controlled selective C(sp3)-H bond functionalization of more complex substrates such as alpha-amino acids remains a challenging task. In this regard, within this project, we aimed at studying the catalytic functionalization of inert C(sp3)-H bonds assisted by sulfur-tethered directing groups paying particular attention to the straightforward chemical modification of amino acids and peptides. Amino acids are versatile chiral building blocks in total synthesis and ligand design.[2] However, the limited number of amino acids genetically encoded is rather limited and therefore there is a need for new methodologies to achieve their straightforward chemical modification. The most relevant results are presented in Scheme 1. We have developed an efficient protocol to perfom the remote palladium-catalyzed gamma-C(sp3) C-H arylation of N (2 pyridyl)sulfonyl amino acid derivatives (Phase I: Chem. Sci., 2013, 4, 175);[3] as well as a selective gamma-C(sp3)-H carbonylation of N-(2-pyridyl)sulfonyl (N-SO2Py)-protected amines by using palladium-catalysis and Mo(CO)6 as carbonyl source (Phase II: Full Paper in preparation, 2016).[4] Both functionalization processes have been applied to the post-synthetic modification of small peptides as a means of optimizing their molecular function or discovering new biologically active candidates.[5] This extension to the late-stage functionalization of more complex molecules not only adds more weight to the functional group tolerance of the methods, but also illustrates the capacity of the bidentate N-SO2Py directing group to act in the presence of other coordinating elements. The ability to induce site-specific reactivity on a given molecule at otherwise unreactive sites in complex settings has tremendous significance to the field of complex molecule synthesis. In any case, general aspects of each type of C-H functionalization, including remaining challenges as well as mechanistic details, have been explored. Bibliography [1] (a) Bergman, R. G. Nature 2007, 446, 391. (b) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. [2] Rodríguez, N.; Romero-Revilla, J. A.; Fernández-Ibáñez, M. A.; Carretero, J. C. Chem. Sci. 2013, 4, 175. [3] Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids; Wiley: New York, 1987. [4] Hernando, E.; Villalva, J.; Martínez, Á. M.; Alonso, I.; Rodríguez, N.; Gómez Arrayás, R.; Carretero, J. C. Manuscript in preparation, 2016. [5] For selected recent examples, see: (a) Simmons E. M.; Hartwig, J. F. Nature 2012, 483, 70. (b) McNally, A.; Haffemayer, B.; Collins B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. (c) Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 16940. (d) Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z.-J. Angew. Chem. Int. Ed. 2014, 53, 3899. (e) He, J.; Hamann, L. G.; Davies, H. M. L.; Beckwith, R. E. J. Nat. Commun. 2015, 6, 5943. (f) Huang, X.; Bergsten, T. M.; Groves, J. T. J. Am. Chem. Soc., 2015, 137, 5300. (g) Durak, L. J.; Payne, J. T.; Lewis, J. C. ACS Catal. 2016, 6, 1451. (h) Peng, J.; Chen, C.; Xi, C. Chem. Sci. 2016, 7, 1383.

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