title: Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal-Free Six-Step Domino Reaction.
abstract: Aza- and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six-step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult-to-access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X-ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 μM for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 μM).
authors.affiliation: Institute of Organic Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054, Erlangen, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Bock
authors.affiliation: Institute of Organic Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054, Erlangen, Germany.
authors.forename: Gangajji
authors.initials: G
authors.lastname: Parameshwarappa
authors.affiliation: Chair of Theoretical Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstrasse 3, 91058, Erlangen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Bönisch
authors.affiliation: Chair of Theoretical Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstrasse 3, 91058, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Neiss
authors.affiliation: Institute of Organic Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054, Erlangen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Bauer
authors.affiliation: Institute of Organic Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054, Erlangen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Hampel
authors.affiliation: Chair of Theoretical Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstrasse 3, 91058, Erlangen, Germany. andreas.goerling@fau.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Görling
authors.affiliation: Institute of Organic Chemistry and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054, Erlangen, Germany. svetlana.tsogoeva@fau.de.
authors.forename: Svetlana B
authors.identifier: http://orcid.org/0000-0003-4845-0951
authors.initials: SB
authors.lastname: Tsogoeva
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D003587:Cytomegalovirus / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic
keywords: antiviral agents; density functional calculations; domino reaction; medicinal chemistry; organocatalysis