Uno Hiroto, Kawai Koki, Araki Taichi, Shiro Motoo, Shibata Norio
Department of Nanopharmaceutical Sciences & Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan.
Rigaku Corporation, 3-9-12, Matsubara-cho, Akishima-shi, Tokyo, 196-8666, Japan.
Angew Chem Int Ed Engl. 2022 Jun 13;61(24):e202117635. doi: 10.1002/anie.202117635. Epub 2022 Apr 13.
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 and gem-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, the gem-difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α-difluorinated β-ketoester, and a β-ketosulfone are suitable substrates for this method.
偕二氟亚甲基部分在药物化学中具有吸引力，因为它们能够模拟其他更常见的官能团。因此，非常需要有效的不对称构建方法，特别是用于手性药物的工业生产。通过钯催化的取代-2-亚烷基三亚甲基碳酸酯与偕二氟烷基酮之间的不对称[4+2]环加成反应，我们能够轻松获得在环状和非环状骨架中含有四取代偕二氟烷基立体中心的手性1,3-二氧杂环己烷。开发了一种新型亚磷酰胺配体，其含有庞大的1,1-二萘基甲氨基部分，以高产率提供具有优异对映选择性、非对映选择性和区域选择性的产物。引人注目的是，偕二氟取代模式促进了反应，五氟乙基酮、α,α-二氟代β-酮酯和β-酮砜是该方法的合适底物。
