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A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold

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An enantioselective methodology to construct trans-Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans-Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels–Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN2-like reaction at a tertiary center to obtain the trans-Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

OriginalsprogEngelsk
TidsskriftAngewandte Chemie - International Edition
Vol/bind60
Nummer33
Sider (fra-til)18318-18327
Antal sider10
ISSN1433-7851
DOI
StatusUdgivet - aug. 2021

Bibliografisk note

Funding Information:
K.A.J. thanks Villum Investigator grant (no. 25867), the Carlsberg Foundation “Semper Ardens” and Aarhus University. Thanks are expressed to Dr. Joseph Anthony Izzo, Dr. Christina Hope McCulley and Frank Jensen for computational guidance and discussions, as well as Peter Nørby and Mathias Kirk Thøgersen for performing X‐ray analysis.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

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