Development of an asymmetric alkene hydroheteroarylation methodology
Timothy P Aldhous 1 , Paul Kemmitt 2 , Natalie Fey 1 , John F. Bower 3 1 University of Bristol, UK 2 AstraZeneca, UK 3 University of Liverpool, UK
The Suzuki reaction has become a mainstay of the pharmaceutical industry for the formation of planar “2D” biaryl structures. While chiral alkyl nucleophiles (e.g. 2 ) can be used to access “3D” benzylic stereocentres (e.g. 3 ), this approach can often lead to isomeric side-products. 1 An “ideal” alternate approach is to form benzylic stereocentres directly via the enantioselective addition of aryl C-H bonds ( 4 ) across alkenes ( 5 ). 2 To develop this, the Bower group recently reported enantioselective Ir-catalysed hydroarylations of alkenes with acetanilides to provide tertiary benzylic stereocenters. 3 The focus of my work has been to broaden the scope of this methodology by designing new chiral catalyst systems ( Scheme 1B ). I have developed enantioselective protocols that provide tertiary benzylic stereocentres via the hydroarylation of mono-substituted alkenes 7 with a wide range of benzenoid and heterocyclic ( 6 ) arenes ( Scheme 1C ). By employing 1,1-disubstituted alkenes in this protocol, a broad range of products bearing challenging quaternary benzylic centres can be accessed in an atom and step economical manner. 4 In a recent advancement, I have achieved exciting preliminary results which show that enantioenriched quaternary stereocentres can be accessed through this reaction manifold.
References 1. D. Leonori, V. K. Aggarwal, Angew. Chem. Int. Ed. 2015 , 54 , 1082.
2. T. P. Aldhous, R. W. M. Chung, A. G. Dalling, J. F. Bower, Synthesis , 2021 , 53 , 2961–2975. 3. S. Grélaud, P. Cooper, L. J. Feron, J. F. Bower, J. Am. Chem. Soc., 2018 , 140 , 9351. 4. P. Cooper, A. G. Dalling, E. H. E. Farrar, T. P. Aldhous, S. Grélaud, E. Lester, L. J. Feron, P. D. Kemmitt, M. N. Grayson, J. F. Bower, Chem. Sci. , 2022 , Advance Article .
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© The Author(s), 2022
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