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Tuesday, June 6, 2023

Stereoselective conjugate cyanation of enals by combining photoredox and organocatalysis

  Being one of many first uneven organocatalytic response ever reported1, the uneven cyanation of carbonyl compounds has been extensively studied2,3. Though examples for 1,2-cyanation of α,β-unsaturated aldehydes exist, the father or mother 1,4-cyanation is difficult by chemoselectivity points: as Prelog and Wilhelm described, mixture of nucleophilic cyanide and enals delivered the 1,2-addition cyanohydrin as the only product4. Due to digital and steric components, nucleophilic cyanide has an amazing choice for the carbonyl carbon of enals. Up to now, there isn’t a basic 1,4-cyanation process that may override the intrinsic selectivity for enals by way of polar pathways5.

  We had been intrigued by the longstanding problem in natural synthesis, and approached the issue with a “radically” completely different technique. A radical cyanation was conceptualized, utilizing an electrophilic cyanide supply and a 5π-enaminyl radical, which was beforehand reported to be nucleophilic in nature6. Knowledgeable by our earlier investigations on photochemistry of chiral iminium ions7, we reasoned that their electron-poor nature might be leveraged for a facile single electron switch (SET) discount to kind a chiral nucleophilic radical, which then could be intercepted in uneven trend with electrophilic tosyl cyanide, a longtime regent for radical nitrile switch8. By reversing the polarity of the enal part, the cyano group switch to the β-position of an enal ought to unlock an answer to this drawback and allow additional transformations by such cross electrophile coupling strategy.

  We got down to discover the concept utilizing our difluorinated pyrrolidine catalyst, which is amenable to radical uneven iminium ion catalysis7, an exterior photocatalyst and a 1,4-dihydropyridine as sacrificial reductant. We had been happy to see the β-cyanoaldehyde product shaped with unique 1,4-chemoselectivity and good enantioselectivity over quite a lot of aliphatic enals bearing various useful teams, resembling alkyne and phthalimide. Extra advanced enals, together with pure product derived scaffolds, is also remodeled, with out altering the pre-installed alkene and ketone functionalities. Moreover, stereoinduction of the cyanation is dictated by the aminocatalyst and never influenced by the pre-existing stereocenters within the beginning supplies. The cyanoaldehyde merchandise are of nice artificial worth, as proven within the quick preparation of an unnatural chiral γ-amino acid after redox manipulation steps.

  We then looked for different reactivities utilizing this umpolung platform, resembling a cross-electrophile coupling of two Michael acceptors to kind synthetically difficult linear 1,6-dicarbonyl compounds9. Certainly, the response delivered the specified product with persistently good yields and excessive stage of enantioinduction. An analogous stage of useful group tolerance as noticed for the β-cyanation was additionally discovered, since reactive handles resembling alkyl chloride, ester and aryl fluoride had been unaffected. Terminal and inner alkenes, which frequently take part in radical transformations, had been retained with out double bond isomerization. Though the merchandise had been obtained as combination of inseparable diastereomers, they might be separated upon international discount to the corresponding alcohols.

  In conclusion, we demonstrated that the synergy of photoredox catalysis and uneven organocatalysis could be a basic, versatile technique for exerting enantiocontrol over novel radical reactions. Inspired by the preliminary success, we consider that there’s unexplored potential with our present strategies. Investigations to increase this idea is at the moment in progress.


  1. Bredig, G. & Fiske, P. S. Beiträge zur chemischen Physiologie und Pathologie. Biochem. Z. 46, 7-23 (1912).
  2. Kurono, N. & Ohkuma, T. Catalytic uneven cyanation reactions. ACS Catal. 6, 989–1023 (2016).
  3. Zhou, H., Zhou, Y., Bae, H. Y., Leutzsch, M., Li, Y., De, C. Ok., Cheng, G.-J., Record, B. Organocatalytic Stereoselective Cyanosilylation of Small Ketones. Nature, 605, 84–89 (2022).
  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. Zeng, X.-P., Solar, J.-C., Liu, C.-, Ji, C.-B. & Peng, Y.-Y. Catalytic uneven cyanation reactions of aldehydes and ketones in whole synthesis. Adv. Synth. Catal. 361, 3281–3305 (2019).
  6. Terrett, J. A., Clift, M. D. & MacMillan, D. W. C. Direct β-alkylation of aldehydes through photoredox organocatalysis. J. Am. Chem. Soc. 136, 6858–6861 (2014).
  7. Silvi, M., Verrier, C., Rey, Y. P., Buzzetti, L. & Melchiorre, P. Seen-light excitation of iminium ions allows the enantioselective catalytic β-alkylation of enals. Nat. Chem. 9, 868–873 (2017).
  8. Barton, D.H.R., Jaszberenyi, J. & Theodorakis, E.A. The invention of radical reactions. half XXIII new reactions: Nitrile and thiocyanate switch to carbon radicals from sulfonyl cyanides and sulfonyl isothiocyanates. Tetrahedron, 48, 2613 (1992).
  9. Seebach, D. Strategies of reactivity umpolung. Angew. Chem. Int. Ed. 18, 239–258 (1979).

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