Organocatalytic Access to Enantioenriched Spirooxindole-Based 4-Methyleneazetidines

Abstract

This work describes the synthesis of enantioenriched spiro compounds, incorporating the azetidine and the oxindole motifs. The preparation relies on a formal [2 + 2] annulation reaction of isatin-derived N-tert-butylsulfonyl ketimines with allenoates. The asymmetric induction is secured by an organocatalytic strategy, exploiting a bifunctional cinchona-type β-isocupridine-based catalyst. Some post-transformation products, including unexpected spiropyrroline and 3,3-disubstituted oxindole derivatives, are also presented.

Keywords: azetidines; cinchona-based catalysts; organocatalysis; spirooxindoles.

Scheme 1

(a) Our previous diastereoselective strategy to chiral spirooxindole-based 4-methyleneazetidines; (b) Reported organocatalyzed formal [2 + 2] cycloadditions of aldimmines and ketimines with allenoates; (c) Organocatalysed enantioselective strategy to chiral spirooxindole-based 4-methyleneazetidines.

Scheme 2

Substrate scope for the reaction of various ketimines 1a–j with allenoates 4a,b, catalyzed by catalyst 5g. Reactions conditions: ketimine 1a–j (0.15 mmol), 4a,b (0.30 mmol), 5g (0.03 mmol) in THF (1.5 mL). Isolated yields, after purification by column chromatography on silica gel, are reported. Er was determined by HPLC, on a chiral stationary phase. Trt = Trityl; nd = not detected.

Scheme 3

Chemical correlation for the assignment of absolute configuration of compound 6a. For comparison of the chiral HPLC chromatograms of 6a and 6a′, see the Supporting Information.

Scheme 4

Possible transition state for reaction of ketimine 1b with allenoate 4a, under catalysis of 5g. Ketimine 1b is reported without the condensed phenyl ring for clarity.

Scheme 5

Reactions performed from compound 6a.