Xiong-Wei Liu,Zhen Yao,Jun Yang,Zhi-Yong Chen,Xiong-Li Liu,Zhi Zhao,Yi Lu,Ying Zhou,Yu Cao
A facile and efficient methodology was developed for the synthesis of isoxazole-fused spiropyrrolidine oxindoles 3–5 via a 1,3-dipolar cycloaddition reaction of 3-methyl-4-nitro-5-alkenyl-isoxazoles with azomethine ylides (thermally generated in situ from isatin derivatives and proline or thioproline or sarcosine). Products bearing adjacent quaternary-tertiary centers were smoothly obtained in high yields (up to 90% yield) with good diastereoselectivity (up to 20:1). Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3, human lung cancer cells A549 and human leukemia cells K562 by the MTT-based assays using the commercially available standard drug Cisplatin as a positive control. These results suggested that most of isoxazole-fused spiropyrrolidine oxindoles 3–5 showed considerable cytotoxicities to these three cell lines K562, A549 and PC-3, and that isoxazole-fused spiropyrrolidine oxindoles may be potential leads for further biological screening.
Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3′-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3′-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis.Keywords:1,3-dipolar cycloaddition;azomethine ylide;one pot synthesis;maleimide;succinimide-fused spiro[pyrrolidine-2,3′-oxindole]
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