De-epimerizing DyKAT of β-Lactones Generated by Isothiourea-Catalysed Enantioselective [2+2] Cycloaddition

29 January 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Moderate diastereoselectivity (typically 70:30 dr) is observed in the isothiourea-catalysed [2+2]-cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones to generate spirocyclic β lactones, but subsequent ring-opening with morpholine generatesβ hydroxyamide products with enhanced stereoselectivity (up to >95:5 dr). Stereoconvergence is observed in the ring-opening of diastereoisomeric β-lactones, leading to a single product (>95:5 dr, >99:1 er). Mechanistic studies and DFT analysis indicate a substrate controlled Dynamic Kinetic Asymmetric Transformation (DyKAT) involving epimerisation at C(3) of the β-lactone under the reaction conditions, coupled with a hydrogen bond-assisted nucleophilic addition to the Si face of the β-lactone and stereodetermining ring-opening. The scope and limitations of a one-pot protocol consisting of isothiourea-catalysed enantio-determining [2+2] cycloaddition followed by diastereo-determining ring-opening is subsequently developed. Variation within the anhydride ammonium enolate precursor, as well as N(1)- and C(3)- within the pyrazol-4,5-dione scaffold is demonstrated, giving a range of functionalised β hydroxyamides with high diastereo- and enantiocontrol (>20 examples, up to >95:5 dr and >99:1 er) via this DyKAT.


DFT analysis

Supplementary materials

Supporting Information
Supporting information for publication


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