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

Abstract

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.

Keywords: Cooperative Catalysis; Cycloaddition; Isothiourea; Palladium Catalysis; α,β-Unsaturated Acyl Ammonium.

Figure 1

[a] Previous cooperative catalysis using isothiourea derived C(1)‐ammonium enolates. [b] State of the art cooperative catalysis using enals and vinylcyclopropanes [c] Proposed use of α,β‐unsaturated acyl ammonium intermediates in cooperative catalysis using isothioureas.

Scheme 1

Effect of olefin configuration on product outcome and isomerization studies.

Scheme 2

Derivatization studies.

Scheme 3

Proposed mechanism and tentative stereochemical rationale.