A facile and efficient synthesis of polycyclic spiropyrrolidine oxindoles bearing mesityl oxide unit via a three-component 1,3-dipolar cycloaddition reaction

Abstract

A facile and efficient methodology was developed for the synthesis of multifunctional polycyclic spiropyrrolidine oxindoles bearing mesityl oxide unit via a three-component 1,3-dipolar cycloaddition reaction of dienones 2 with azomethine ylides (thermally generated in situ from isatin derivatives and proline or thioproline). Products bearing adjacent four chiral carbon centers were smoothly obtained in high yields (up to 98% yield) with diastereoselectivities up to >20:1. Furthermore, the key structural characteristic of the products of such a reaction is the natural product ingredient turmerone motif fused at the 3-position of the spirooxindole core, with varying degrees of substitution around it. In addition, 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 drugs Cisplatin as a positive control. These results suggested there is a trend that lipophilicity groups improve the potency, and also suggested an mesityl oxide moiety located in the polycyclic spiropyrrolidine oxindoles is beneficial for the activity. The results also demonstrated that most of the compounds showed considerable cytotoxicities to these three cell lines K562, A549 and PC-3, and indicated that polycyclic spiropyrrolidine oxindole analogs bearing mesityl oxide unit may be potential leads for further antitumor activity screenings.