Stereoselective conjugate cyanation of enals by combining photoredox and organocatalysis Thomas Wong, Martin Berger, Dengke Ma, Yann Baumgartner, Paolo Melchiorre Institute of Chemical Research of Catalonia, Spain ICIQ - Institute of Chemical Research of Catalonia, The Barcelona Institute of Science and Technology, SpainUniversity of Bologna, Department of Industrial Chemistry ‘Toso Montanari’, Italy Precise control over the selectivity of a reaction is a fundamental target of a synthetic chemist. While great advances have been obtained in achieving stereocontrol 1 , the selective manipulation of functional groups within a substrate (chemoselectivity) is still a challenge 2 . The cyanation of aldehydes offers an illustrative example: the 1,2-addition of nucleophilic cyanide to the aldehydic group was one of the first examples of an enantioselective catalytic process 3 . By contrast, the parent 1,4-cyanation is complicated by chemoselectivity issues: as previously described, the combination of nucleophilic cyanide and enals delivered 1,2-addition cyanohydrin as the sole product 4 . To date, there is no general 1,4-cyanation procedure that can override the intrinsic selectivity for enals through polar pathways 5 . We report an asymmetric catalytic method to achieve the exclusive conjugate cyanation of enals 6 through radical reactivity. The synergistic action of a chiral organocatalyst with a visible-light-activated photoredox catalyst promotes the single-electron reduction of enals, inducing a formal inversion of polarity. The resulting chiral 5π-enaminyl radical, being nucleophilic in character, is then intercepted by an electrophilic cyanide source with perfect 1,4-chemoselectivity and good stereocontrol. The β-cyanoaldehydes products are of great synthetic value, as shown in the short preparation of an unnatural chiral γ-amino acid after redox manipulation steps. The generality of the method, which induces "umpolung" 7 within enals to enable a cross-electrophile coupling, is further demonstrated by the chemo- and stereo-selective β-alkylation with Michael acceptors, affording 1,6-dicarbonyl compounds with β-stereocenter. References 1. Fundamentals of Asymmetric Catalysis, ed. Walsh, P. J. & Kozlowski M. C. University Science Books (2009). 2. Shenvi, R. A., O’Malley, D. P. & Baran, P. S. Chemoselectivity: the mother of invention in total synthesis. Acc. Chem. Res. 42 , 530–541 (2009). 3. Bredig G. & Fiske, P. S. Beiträge zur chemischen Physiologie und Pathologie. Biochem. Z. 46 , 7 (1912). 4. Prelog, V. & Wilhelm, M. Untersuchungen über asymmetrische Synthesen VI). Der Reaktionsmechanismus und der sterische Verlauf der asymmetrischen Cyanhydrin-synthese. Helv. Chim. Acta . 37 , 1634–1660 (1954). 5. a) Kagan, H. B. Historical perspectives, in Comprehensive Asymmetric Catalysis, ed. Jacobsen, E. N., Pfaltz A. & Yamamoto, H. Springer-Verlag, Berlin 1, 4-22 (1999). b) Zeng, X.-P., Sun, J.-C., Liu, C.-, Ji, C.-B. & Peng, Y.-Y. Catalytic asymmetric cyanation reactions of aldehydes and ketones in total synthesis . Adv. Synth. Catal. 361 , 3281–3305 (2019). 6. Berger, M., Ma, D., Baumgartner, Y., Wong, T.H.-F., Melchiorre, P. Stereoselective conjugate cyanation of enals by combining photoredox and organocatalysis. Nat. Catal. 6 , 332-338 (2023). 7. Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Ed. Eng. 18 , 239–258 (1979).
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