Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction. Issue 15 (26th February 2016)

• Record Type: Journal Article
• Authors: Bock, Christina M.; Parameshwarappa, Gangajji; Bönisch, Simon; Neiss, Christian; Bauer, Walter; Hampel, Frank; Görling, Andreas; Tsogoeva, Svetlana B.
• Is Part Of: Chemistry. Volume 22:Issue 15(2016)
• Page Start: 5189
• Page End: 5197
• Publication Date: 2016-02-26
• Subjects: antiviral agents -- density functional calculations -- domino reaction -- organocatalysis -- medicinal chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201504798
• Languages: English
• ISSNs: 0947-6539

Abstract

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 ). Abstract : Six steps in one go ! An unprecedented two component six‐step domino reaction, providing a straightforward and atom economical route to bioactive azabicycles and carbobicycles is presented. DFT calculations accounting for dispersion interactions revealed that chemoselectivity might result from small differences in transition state and reaction energies of the branching step. This reaction opens up a new vista of generating, in a single operation, new antivirals outperforming clinically used drugs.