Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products
Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products
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DOI：
10.1038/nchem.730
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发表时间：
2010-09-01
期刊：
影响因子：
21.8
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
--
作者：
Antonchick, Andrey P.;Gerding-Reimers, Claas;Waldmann, Herbert
在面向生物学的合成中，在进化中选择的天然产物的基础支架类用于定义化学结构空间中的生物相关起点，以合成具有集中结构多样性的化合物集合。在这里，我们描述了一个高对映选择性的合成天然产物启发的3，3 '-吡咯烷基螺吲哚-它含有一个全碳季中心和三个叔立体中心。该合成通过使用1-3摩尔%的由N，P-二茂铁基配体和CuPF（6）（CH（3）CN）（4）形成的手性催化剂，偶氮甲碱叶立德与取代的3-亚甲基-2-羟吲哚的不对称刘易斯酸催化的1，3-偶极环加成进行。细胞评价已经确定了一种分子，该分子可以阻止有丝分裂，诱导多个微管组织中心和多极纺锤体，在有丝分裂期间引起染色体聚集缺陷，并抑制细胞中微管蛋白的再生长。我们的研究结果支持这样的概念，即基于天然产物启发的支架构建复杂的立体化学的化合物集合将是具有不同生物活性的化合物的丰富来源。
In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3'-pyrrolidinyl spirooxindoles-which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1-3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF(6)(CH(3)CN)(4). Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.