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Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction
Author(s) -
Bock Christina M.,
Parameshwarappa Gangajji,
Bönisch Simon,
Neiss Christian,
Bauer Walter,
Hampel Frank,
Görling Andreas,
Tsogoeva Svetlana B.
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201504798
Subject(s) - domino , combinatorial chemistry , chemistry , cascade reaction , electrophile , catalysis , reaction conditions , computational chemistry , organic chemistry
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 (EC 50 up to 0.071 μ m for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC 50 2.6 μ m ).