Cooperative Palladium/Isothiourea Catalyzed Enantioselective Formal (3+2) Cycloaddition of Vinylcyclopropanes and α,β‐Unsaturated Esters

• Published in: Angewandte Chemie International Edition 2022-06, Vol.61 (25), p.e202202621-n/a
• Main Authors: Bitai, Jacqueline, Nimmo, Alastair J., Slawin, Alexandra M. Z., Smith, Andrew D.
• Format: Article
• Language: English
• Subjects: Ammonium; Catalysis; Cooperative Catalysis; Cycloaddition; Enantiomers; Esters; Intermediates; Isothiourea; Lithium chloride; Palladium; Palladium Catalysis; Transition metals; α,β-Unsaturated Acyl Ammonium
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202202621

A protocol for the enantioselective synthesis of substituted vinylcyclopentanes has been realised using cooperative palladium and isothiourea catalysis. Treatment of vinylcyclopropanes with Pd(PPh3)4 generates a zwitterionic π‐allyl palladium intermediate that intercepts a catalytically generated α,β‐unsaturated acyl ammonium species prepared from the corresponding α,β‐unsaturated para‐nitrophenyl ester and the isothiourea (R)‐BTM. Intermolecular formal (3+2) cycloaddition between these reactive intermediates generates functionalised cyclopentanes in generally good yields and excellent diastereo‐ and enantiocontrol (up to >95 : 5 dr, 97 : 3 er), with the use of LiCl as an additive proving essential for optimal stereocontrol. To the best of our knowledge a dual transition metal/organocatalytic process involving α,β‐unsaturated acyl ammonium intermediates has not been demonstrated previously. Cooperative palladium and isothiourea catalysis allows the formal (3+2) cycloaddition of vinylcyclopropanes and α,β‐unsaturated esters to generate functionalized cyclopentanes via an α,β‐unsaturated acyl ammonium intermediate with the addition of LiCl crucial to obtain high product diastereo‐ and enantioselectivity.