Synthesis of 1,3-diaryl-spiro[azetidine-2,3'-indoline]-2',4-diones via the Staudinger reaction: cis- or trans-diastereoselectivity with different addition modes

Abstract

A new synthetic approach for realizing biologically relevant bis-aryl spiro[azetidine-2,3'-indoline]-2',4-diones was developed based on Staudinger ketene-imine cycloaddition through the one-pot reaction of substituted acetic acids and Schiff bases in the presence of oxalyl chloride and an organic base. A series of [azetidine-2,3'-indoline]-2',4-diones were synthesized using this method. For comparison, the same compounds were obtained using a known technique, where ketene is generated from pre-synthesized acyl chloride. It was shown that the use of oxalyl chloride for ketene generation in the one-pot reaction at room temperature allows for the reversal of the diastereoselectivity of spiro-lactam formation, unlike previously described procedures.

Fig. 1. Spiro-oxindoles SAR405838 and APG-115, which are currently under clinical trials, and dispiro-oxindole KM-140 have successfully completed preclinical studies.

Scheme 1. The possible mechanisms for the Staudinger reaction.

Fig. 2. Molecular docking of 1,3-bis(4-chlorophenyl)spiro[azetidine-2,3′-indoline]-2′,4-dione stereoisomers on MDM2 active site: (a) (2R,3R), (b) (2R,3S), (c) (2S,3R), (d) (2S,3S).

Scheme 2. Staudinger synthesis of bis-aryl spiro[azetidine-2,3′-indoline]-2′,4-diones using pre-synthesized acyl chloride.

Scheme 3. Staudinger synthesis of bis-aryl spiro[azetidine-2,3′-indoline]-2′,4-diones without using presynthesized acyl chloride.

Scheme 4. The proposed mechanism for acid activation and ketene formation.

Scheme 5. Generalization of two approaches for spirocyclic oxindolo-β-lactams synthesis by Staudinger ketene imine-cycloaddition applied in the present work (predominantly formed diastereomers are indicated).

Fig. 3. Molecular structures spiro-oxindolo-β-lactams: (a) compound 22a (CCDC 1963622); (b) compound 22b (CCDC 1963623); (c) compound 25a (CCDC 1963617); (d) compound 28b (CCDC 1963625); (e) compound 29b (CCDC 1963624).

Fig. 4. Schiff base attacking a ketene carbonyl: (a) E-imine attacks from the hydrogen side; (b) E-imine attacks from the phenyl side; (c) Z-imine attacks from the hydrogen side; (d) Z-imine attacks from the phenyl side.