De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition

Abstract

An enantioselective isothiourea-catalysed [2 + 2] cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones is used to construct spirocyclic β-lactones in good yields, excellent enantioselectivity (99 : 1 er) but with modest diastereocontrol (typically 70 : 30 dr). Upon ring-opening with morpholine or alternative nucleophilic amines and alcohols β-hydroxyamide and β-hydroxyester products are generated with enhanced diastereocontrol (up to >95 : 5 dr). Control experiments show that 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 are 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.

Fig. 1. [A] Previous work. [B] DyKAT type III de-epimerization processes. [C] This work: coupling an enantioselective catalytic [2 + 2]-cycloaddition with a DyKAT type III ring-opening process.

Scheme 1. Reactions performed on 0.25 mmol scale with 1.0 equiv. of 3-methyl-1-phenylpyrazol-3,4-dione and 1.5 equiv. of homoanhydride. Product dr assessed by ¹H NMR analysis of the crude reaction mixture. Yields are isolated yields after chromatographic purification; all product ers are determined by HPLC analysis on a chiral stationary phase.

Fig. 2. DFT analysis of pathways from the interconvertible (3R,4R)-7 and (3S,4R)-8 β-lactone diastereoisomers. M06-2X_SMD/def2-TZVP//M06-2X_SMD/def2-SVP Gibbs free energies (ΔG₂₉₈) are shown in kcal mol⁻¹ and selected hydrogen atoms have been removed for clarity.

Scheme 2. All reactions performed on 0.25 mmol scale with 1.0 equiv. of dione and 1.5 equiv. of anhydride. Product dr assessed by ¹H NMR analysis of the crude reaction mixture. Yields are isolated yields after chromatographic purification; all product ers are determined by HPLC analysis on a chiral stationary phase.