Thiamine-inspired novel organocatalytic reactions with heterazolium precatalysts
Final Report Abstract
Within the collaborative research of the Forschergruppe FOR1296 “Thiamine” we could develop novel organocatalytic C-C bond fragmenting transformations to generate versatile α,ω-functionalized building blocks from cyclic diketones and vinylogous trilfate hemiacetals. Most importantly these unprecedented transformations are bioinspired by the activity of the thiamine dependent enzyme cyclohexane-1,2-dione hydrolase (CDH). The employment of chiral NHC catalysts now allows for highly enantioselective catalytic domino transformation by merging the original transformation with a highly selective cross aycloin reaction. The power of NHC catalysis for trapping instable intermediates was also demonstrated. Furthermore, we could design a novel carborane-based zwitterionic NHC precatalyst. Its distinct catalytic activity provides further evidence for the importance of the N-aryl substituent in triazolium derived NHC catalysts. While in thiamine dependent enzymes reactivity (and selectivity) often seems to be controlled by the close environment of the thiamine cofactor, reactivity differences in NHC organocatalysts rather stem from the N-substitutents of the heterazolium precatalysts. The carborane substituent as an aryl mimetic strongly influences the reactivity of the NHC catalyst; comparison with typical electron-rich or electron poor aryl substituted NHCs reveals its electronically interjacent character which also may allow to draw conclusions for the characterization of such ortho-carboranes. This work was featured as a cover page of Chemistry – A European Journal in 2017 and was also initiative for a recent highlight in the Laborzeitschrift GIT ( Jan. 2018, German and English version 01/2018). The cooperative action of NHC catalysis with thiourea-based H-bond catalysts could be demonstrated for nitro-Stetter reactions. This approach allows to employ nitro alkenes as versatile 1,2-biselectrophilic alkene synthons; due to base-mediated elimination of HNO2 the nitro group can here be considered as a traceless activation group. We have used this concept for the synthesis of 1,4-diketones and polysubstituted pyrroles allowing for uncommon heteroaryl substituents and for the enantioselective synthesis of 3,5,6-trisubstituted 3,4-dihydropyranones providing access to a previously problematic substitution pattern.
Publications
- A versatile combined N-heterocyclic carbene and basecatalyzed multiple cascade approach for the synthesis of functionalized benzofuran-3-(2H)- ones. Tetrahedron Lett. 2011, 52: 6952–6956
Franz JF, Fuchs PJW, Zeitler K
(See online at https://doi.org/10.1016/j.tetlet.2011.10.078) - NHC-catalysed, chemoselective crossed-acyloin reactions. Chem. Sci. 2012, 3: 735–740
Rose CA, Gundala S, Fagan C, Franz JF, Connon SJ, Zeitler K
(See online at https://doi.org/10.1039/c2sc00622g) - Stereoselective synthesis of bulky 1,2-diols with alcohol dehydrogenases. Catal Sci Technol 2012, 2: 1580–1589
J. Kulig, R. C. Simon, C. A. Rose, S. M. Husain, M. Häckh, S. Lüdeke, K. Zeitler, W. Kroutil, M. Pohl, D. Rother
(See online at https://doi.org/10.1039/c2cy20120h) - An N-Heterocyclic Carbene-Mediated, Enantioselective and Multicatalytic Strategy to Access Dihydropyranones in a Sequential Three-Component One-Pot Reaction. Org. Lett. 2017, 19: 6076–6079
Fuchs PJW, Zeitler K
(See online at https://doi.org/10.1021/acs.orglett.7b02889) - Carboranes as Aryl Mimetics in Catalysis: A Highly Active Zwitterionic NHC-Precatalyst", Chem. Eur. J. 2017, 23: 7932–7937
Selg C, Neumann W, Lönnecke P, Hey-Hawkins E, Zeitler K
(See online at https://doi.org/10.1002/chem.201700209) - Nitroalkenes as latent 1,2-biselectrophiles – A multicatalytic approach for the synthesis of 1,4-diketones and their application in a 4-step one-pot reaction to polysubstituted pyrroles", J. Org. Chem. 2017, 82: 7796–7805
Fuchs PJW, Zeitler K
(See online at https://doi.org/10.1021/acs.joc.7b00830)
