Enantio-, Diastereo- and Regioselective Synthesis of Chiral Cyclic and Acyclic gem-Difluoromethylenes by Palladium-Catalyzed [4+2] Cycloaddition
Enantio-, Diastereo- and Regioselective Synthesis of Chiral Cyclic and Acyclic gem-Difluoromethylenes by Palladium-Catalyzed [4+2] Cycloaddition
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钯催化的对映体、非对映体和区域选择性合成手性环状和无环偕二氟亚甲基 [4 2] 环加成
DOI：
10.1002/anie.202117635
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Norio Shibata
中科院分区：
文献类型：
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作者：
Hiroto Uno;Koki Kawai;Taichi Araki;Motoo Shiro;Norio Shibata
宝石-二氟亚甲基在药物化学中很有吸引力，因为它们能够模仿其他更普遍的官能团。因此，有效的不对称构造方法是非常需要的，特别是对于手性药物的工业生产。利用Pd催化的不对称[4+2]环加成反应，在取代- 2 -烷基二烯碳酸酯和gem -二氟烷基酮之间，我们可以很容易地获得手性1,3 -二恶烷，它们在环和非环骨架中含有四取代的二氟烷基立体中心。一种新型的磷酰胺配体，含有大量的1,1 -二萘基甲基氨基片段，为高收率的产品提供了良好的对映、非对映和区域选择性。引人注目的是，宝石-二氟取代模式促进了反应，而五氟乙基酮、α、α -二氟化β -酮酯和β -酮砜是该方法的合适底物。
gem‐Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd‐catalyzed asymmetric [4+2] cycloaddition between substituted‐2‐alkylidenetrimethylene carbonates andgem‐difluoroalkyl ketones, we were able to easily access chiral 1,3‐dioxanes that contain a tetrasubstituted difluoroalkyl stereogenic center in cyclic and acyclic skeletons. A novel phosphoramidite ligand, which contains a bulky 1,1‐dinaphthylmethanamino moiety, was developed to provide the products in high yield with excellent enantio‐, diastereo‐, and regioselectivity. Strikingly, thegem‐difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α‐difluorinated β‐ketoester, and a β‐ketosulfone are suitable substrates for this method.