Programming Selectivity of Aliphatic C-H Bond Functionalization through Innovative Auxiliary Reagents

Summary

Currently, organic synthesis relies on sequential transformations of functional groups, which typically generate stoichiometric amounts of non-productive waste. Consequently, fine-chemical production involves tedious multi-step procedures with poor atom-economy and low energy efficiency. The selective functionalization of C-H bonds has the potential to revolutionize synthetic planning, allowing for dramatic simplification of complex-molecule synthesis. However, the low reactivity of C-H bonds imposes significant obstacles to develop such transformations, with the improvement of selectivity as the main focus of the current efforts.
In this project, I propose to develop an innovative strategy to develop site-selective reactions for challenging unactivated C(sp3)-H bonds. The strategy relies on the use of ?auxiliary reagents? that bear (i) a substrate-binding site that binds to a functional group of a substrate, and (ii) a directing group for coordination to a catalyst. Upon formation of the substrate-auxiliary reagent architecture, and its coordination to the catalyst, one specific C-H bond will be selectively activated and functionalized. Importantly, site-selectivity can be controlled by crafting the auxiliary reagent framework. Furthermore, the chiral auxiliaries will allow for unprecedented enantioselective functionalization of unactivated C(sp3)-H bonds. This will significantly contribute to the development of sustainable methods for synthesis of fine-chemicals, such as pharmaceuticals, agrochemicals and materials.

Output

Scientific article

  • D. S. Clark, J. F. Hartwig, H. M. Key, P. Dydio(2016): Artificial Catalysis by Heme Proteins Containing Noble Metal Porphyrins Nature pp. 534 - 537
  • J.F. Hartwig, P.F. Dydio, H.M. Key(2016): An artificial metalloenzyme with the kinetics of native enzymes. Science pp. 102 - 106
  • H.M. Key, J.F. Hartwig, P.F. Dydio(2017): Chemoselective, Enzymatic Cā€“H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor J. Am. Chem. Soc., 2017, 139 (5), pp 1750ā€“1753 pp. 1750 - 1753
  • P.F. Dydio, H.M. Key, J.F. Hartwig(2017): Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes ACS Cent. Sci., 2017, 3 (4), pp 302ā€“308 10.1021/acscentsci.6b00391 pp. 302 - 308

Details

Project number

680-50-1306

Main applicant

Dr. P.F. Dydio

Affiliated with

Universiteit van Amsterdam, Faculteit der Natuurwetenschappen, Wiskunde en Informatica, Van 't Hoff Institute for Molecular Sciences (HIMS)

Team members

Dr. P.F. Dydio

Duration

19/06/2014 to 03/11/2016