Development of novel domino and sequential one-pot multi-step synthesis of bioactive heterocyclic compounds
Final Report Abstract
Organocatalytic domino transformations offer enormous potential of generating sophisticated structures with low manual efforts, in contrast to the conventional stop-and-go synthesis. By lowering costs, working time, and waste, domino reactions contribute to the aim of economically and ecologically compatible modern synthetic chemistry. Within the funding period we developed unprecedented environmentally friendly multi-step domino reactions that employ non-covalent catalysis and use versatile nitroolefins, aldehydes, and malononitrile as readily available starting compounds. We developed and computationally studied a novel sustainable and atom efficient organocatalytic six-step domino process for the facile preparation of azabicycles and carbobicycles, which otherwise are difficult to access via traditional methods. Remarkably, in vitro tests against P. falciparum 3D7 strains and human cytomegalovirus (HCMV) revealed several highly functionalized and artemisinin-containing domino products as highly active compounds, outperforming the clinical reference drugs. We further developed an organocatalyzed four-component five-step branched domino reaction, which can be combined with subsequent linear domino reactions in one-pot, providing a straightforward multi-step onepot route to new multichromophoric 2,6-dicyanoanilines and fluorescent antiviral quinazolines with only a single work-up procedure and starting from simple and readily available compounds. Fluorescence of new antiviral hybrids and quinazolines have potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers. Furthermore, we demonstrated a novel three-component two-step Knoevenagel/vinylogous Michael domino reaction starting from easily accessible arylacetaldehydes, malononitrile and nitroolefins towards diarylsubstituted dicyanonitroolefins, using imidazole as a cheap and commercially available organocatalyst. Merging this two-step domino reaction with a facile CuBr2/DABCO co-catalyzed three-step domino reaction in one-pot resulted in challenging highly functionalized o-terphenyls, which are of potential importance for synthetic and medicinal chemistry. Very recently we developed a facile direct C-H oxidation of cyclic tertiary amines at ambient conditions, employing organic dyes as photocatalysts and LED. Tolerance of this new environmentally compatible domino reaction to various side-chain derivatizations of tryptoline and tetrahydroisoquinoline substrates was demonstrated. The developed method provides a straightforward and sustainable route towards Strychnocarpine alkaloid derivatives, which feature strong antiviral properties against human cytomegalovirus (HCMV).
Publications
- Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation via a Metal-Free Six-Step Domino Reaction. Chem. Eur. J., 2016, 22, 5189-5197
C. M. Bock, G. Parameshwarappa, S. Bönisch, C. Neiss, W. Bauer, F. Hampel, A. Görling, S. B. Tsogoeva
(See online at https://doi.org/10.1002/chem.201504798) - Deeper Insight into the Six-Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products. ChemistryOpen, 2017, 6, 364-374
C. M. Bock, G. Parameshwarappa, S. Bönisch, W. Bauer, C. Hutterer, M. Leidenberger, O. Friedrich, M. Marschall, B. Kappes, A. Görling, S. B. Tsogoeva
(See online at https://doi.org/10.1002/open.201700005) - Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metalfree domino reactions. Nature Commun., 2017, 8: 15071
F. E. Held, A. A. Guryev, T. Fröhlich, F. Hampel, A. Kahnt, C. Hutterer, M. Steingruber, H. Bahsi, C. von Bojničić-Kninski, D. S. Mattes, T. C. Foertsch, A. Nesterov-Mueller, M. Marschall, S. B. Tsogoeva
(See online at https://doi.org/10.1038/ncomms15071) - Three-Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o-Terphenyls. Chem. Eur. J., 2018, 24, 6551-6556
D. Grau, B. W. Grau, F. Hampel, S. B. Tsogoeva
(See online at https://doi.org/10.1002/chem.201800048) - Facile Access to Challenging ortho-Terphenyls via Merging Two Multi-Step Domino Reactions in One- Pot: A Joint Experimental/ Theoretical Study. ChemCatChem, 2019, 11, 3982-3992
B. W. Grau, S. Bönisch, A. Neuhauser, F. Hampel, A. Görling, S. B. Tsogoeva
(See online at https://doi.org/10.1002/cctc.201900746) - Visible-Light-Driven C-H Oxidation of Cyclic Tertiary Amines: Access to Synthetic Strychnos Alkaloids with Antiviral Activity. Chem. Eur. J., 2019, 25, 4062-4066
A. A. Guryev, F. Hahn, M. Marschall, S. B. Tsogoeva
(See online at https://doi.org/10.1002/chem.201900078)
