Modular photocatalytic synthesis of α-trialkyl-α-tertiary amines Georgia Harris, J. H. Blackwell 1 , M. A. Smith, A. D. Trowbridge 1 , M. J. Gaunt University of Cambridge, UK
Alkyl α-tertiary amines (ATA) are important pharmacophores in biologically active small molecules due to their high density of structural information, hydrogen-bonding capabilities, and diverse three-dimensional architectures. 1,2 However, these highlyhindered scaffolds represent an area of chemical space that is challenging to access through conventional methods. 3,4 While numerous strategies have been developed for the synthesis of these compounds, a general and modular platform remains elusive. 1,5 Seeking to address this methodological deficiency, we have developed a multicomponent platform for synthesis of ATAs employing primary amine, ketone, and olefin feedstocks. 6 The strategy relies on use of an iridium photocatalyst which, upon absorption of visible light, readily generates a key α-amino radical intermediate from an in situ formed imine; this highly reactive species undergoes subsequent Giese-type addition with a variety of olefins forging the α-tertiary centre. Moreover, we have demonstrated that asymmetric induction can be achieved in this transformation by exploiting a chiral amine transfer (CAT) reagent, derived from readily available phenyl glycinol, to relay stereochemical information to the developing quaternary centre. Mechanistic analysis highlights the importance of an intramolecular 1,5-hydrogen atom transfer, a process which drives the overall redox neutral biomimetic transamination. This operationally simple methodology gives access to a range of functionally and structurally diverse ATA derivatives under exceptionally mild conditions, enabling the rapid generation of chemical complexity from simple building blocks. References 1. A. Hager, N. Vrielink, D. Hager, J. Lefranc and D. Trauner, Nat. Prod. Rep ., 2016, 33 , 491–522. 2. M. Sanford, Drugs , 2014, 74 , 1411–1433. 3. D. A. Cogan, G. Liu and J. Ellman, Tetrahedron , 1999, 55 , 8883–8904. 4. G. Stork and S. R. Dowd, J. Am. Chem. Soc ., 1963, 85 , 2178–2180. 5. J. Clayden, M. Donnard, J. Lefranc and D. J. Tetlow, Chem. Commun ., 2011, 47 , 4624–4639. 6. J. H. Blackwell, G. R. Harris, M. A. Smih and M. J. Gaunt, J. Am. Chem. Soc ., 2021, 143 , 15946–15959.
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