Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles
Angewandte Chemie International Edition
Bioconjugation, Enantioselective α-thiolation, Organocatalysis, Oxidative thiolation, Umpolung
Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.
Blom, J., Reyes-Rodriguez, G. J., Tobiesen, H. N., Lamhauge, J. N., Iversen, M. C., Barløse, C. L., Hammer, N., Rusbjerg, M., & Jørgensen, K. A. (2019). Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.201911793. Retrieved from https://nsuworks.nova.edu/cnso_chemphys_facarticles/264