Skip to main content

New tools for assembling complex molecules

Final Report Summary - CHAAS (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.


[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.