Enantioselective Giese additions of prochiral α-amino radicals via chiral phosphoric acid catalysis Bacoș, P. David, Lahdenperӓ, Antti S. K. and Phipps, Robert J. * University of Cambridge, UK
Amines that feature an adjacent stereocentre are important chemical building blocks in a range of applications. 1 Recent years have seen a dramatic increase in methods that form these via α-amino radical intermediates, but very few can exert control over the newly formed stereocentre. 2,3 Because stereochemistry can have profound impact on the interactions of small molecules with biological systems, this represents a huge barrier to the wider adoption of these methodologies. We have designed a strategy to overcome this challenge in the context of one of the most important radical carbon-carbon bond forming reactions, the Giese reaction. 4 Incorporation of a removable basic heteroarene motif into the amine partner enables a network of attractive non-covalent interactions between a phosphoric acid catalyst, the subsequently formed α-amino radical, and the Giese acceptor, allowing the catalyst to exert very high levels of control during the C−C bond forming step. 5 Furthermore, the chiral catalyst is also able to control the facial selectivity of attack on the Giese acceptor, allowing control of chirality originating from the acceptor β-position. The reaction products are of particular importance as they are analogues of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system, and we further demonstrate the concise synthesis of a leading pharmaceutical and a natural product. We anticipate that our strategy of using a heteroaryl motif to enable hydrogen bonding with a chiral catalyst will not only to be applicable to other α-amino radical functionalisation processes but could also be expanded more broadly to other asymmetric radical transformations. References 1. Q. Yin, Y. Shi, J. Wang, and X. Zhang, Chem. Soc. Rev , 2020, 49 , 6141-6153. 2. S. Mondal, F. Dumur, D. Gigmes, M. P. Sibi, M. P. Bertrand, and M. Nechab, Chem. Rev. , 2022, 122 , 5842-5976.
3. M. H. Shaw, J. Twilton, and D. W. C. MacMillan, J. Org. Chem. , 2016, 81 , 6898-6926. 4. A. L. Gant Kanegusuku and J. L. Roizen, Angew. Chem. Int. Ed. , 2021, 60 , 21116-21149. 5. R. S. J. Proctor, A. C. Colgan, and R. J. Phipps, Nat. Chem. , 2020, 12 , 990-1004.
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