Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor.
Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor.
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DOI：
10.1039/c1sc00061f
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发表时间：
2011-01-01
期刊：
影响因子：
8.4
通讯作者：
Johnston JN
中科院分区：
文献类型：
--
作者：
Davis TA;Johnston JN
首次报道了芳基硝基甲烷亲核试剂与芳基醛亚胺的高度非对映和对映选择性加成反应。鉴定这种氮杂-亨利变体的富电子手性双（脒）催化剂是这一发展的关键，最终导致在两个步骤中差异保护的顺式二苯乙烯二胺。然后，该方法成为（-）-Nutlin-3（Hoffmann-LaRoche）的对映选择性合成的关键，Nutlin-3是p53-MDM 2的有效顺式咪唑啉小分子抑制剂，广泛用作细胞生物学探针，目前用于药物开发。
The first highly diastereo- and enantioselective additions of aryl nitromethane pronucleophiles to aryl aldimines are described. Identification of an electron rich chiral Bis(Amidine) catalyst for this aza-Henry variant was key to this development, leading ultimately to differentially protected cis-stilbene diamines in two steps. This method then became the lynchpin for an enantioselective synthesis of (–)-Nutlin-3 (Hoffmann-LaRoche), a potent cis-imidazoline small molecule inhibitor of p53-MDM2 used extensively as a probe of cell biology and currently in drug development.