Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University Chikusa, Nagoya, 464-8601, Japan.
Chem Asian J. 2023 May 16;18(10):e202300211. doi: 10.1002/asia.202300211. Epub 2023 Apr 19.
Despite the significant advances in trifluoromethylation methods, the synthesis of complex trifluoromethylated molecules, bearing a natural-product-like three-dimensional framework, remains as a formidable challenge. Therefore, the cycloaddition of unprecedented CF -substituted oxidopyridinium betaines was investigated. After the methylation of trifluoromethylated pyridin-3-ols with methyl triflate, pyridinium ions generated in-situ were treated with triethylamine in the presence of N-methylmaleimide to produce trifluoromethylated 8-azabicyclo[3.2.1]octane derivatives via (5+2) cycloaddition of the corresponding oxidopyridinium betaines. Exo/endo-selectivity varied depending on the positions of the CF substituents; endo-products were preferred in the reactions of oxidopyridinium betaines with the CF group at the 2- or 6-positions, whereas the 5-CF -substituted betaine exclusively produced an exo-product. Moreover, unique regio- and stereoselectivities have been observed in the reactions of 2- or 6-CF -substituted oxidopyridinium betaines with vinyl sulfones and trans-1,2-disubstituted alkenes. To gain insight into the reactivity of trifluoromethylated oxidopyridinium betaines, computational investigations were also conducted.
尽管三氟甲基化方法取得了重大进展，但合成具有天然产物样三维骨架的复杂三氟甲基化分子仍然是一个艰巨的挑战。因此，研究了前所未有的 CF-取代氧化吡啶𬭩甜菜碱的环加成反应。三氟甲基化吡啶-3-醇用甲基三氟甲磺酸酯甲基化后，原位生成的吡啶鎓离子在三乙胺存在下与 N-甲基马来酰亚胺反应，通过相应氧化吡啶𬭩甜菜碱的（5+2）环加成反应生成三氟甲基化 8-氮杂双环[3.2.1]辛烷衍生物。根据 CF 取代基的位置，外消旋/内消旋选择性有所不同；在氧化吡啶𬭩甜菜碱与 2-或 6-位 CF 基团的反应中，内产物占优势，而 5-CF-取代的甜菜碱则仅产生外产物。此外，在 2-或 6-CF-取代的氧化吡啶𬭩甜菜碱与乙烯基砜和反式 1,2-二取代烯烃的反应中观察到独特的区域和立体选择性。为了深入了解三氟甲基化氧化吡啶𬭩甜菜碱的反应性，还进行了计算研究。
