Asymmetric Synthesis of α‑Fluoro-β-Amino-oxindoles with Tetrasubstituted C–F Stereogenic Centers via Cooperative Cation-Binding Catalysis

Biologically relevant chiral 3,3-disubstituted
oxindole products
containing a β-fluoroamine unit are obtained in high yields
and with excellent stereoselectivity (up to 99% ee, dr >20:1 for syn) through the organocatalytic direct Mannich reaction
of 3-fluoro-oxindoles as fluoroenolate precursors and α-amidosulfones
as the bench-stable precursors of sensitive imines by using a chiral
oligoethylene glycol and KF as a cation-binding catalyst and base,
respectively. This protocol can be easily scaled without compromising
the asymmetric induction. Furthermore, this protocol was also successfully
extended to generate tetrasubstituted C–Cl and C–Br
stereogenic centers.

以3-氟氧化吲哚作为氟烯醇前体、α-酰胺砜作为敏感亚胺的稳定前体，采用手性低聚乙二醇作为阳离子结合型催化剂、氟化钾作为碱，通过有机催化直接曼尼希反应（Mannich reaction），可获得含有β-氟胺单元的具有生物相关性的手性3,3-二取代氧化吲哚（oxindole）产物，该反应兼具高收率与优异的立体选择性：对映体过量值（ee）最高可达99%，syn型产物的非对映选择性比例（dr）大于20:1。该反应体系可轻松放大，且不会削弱不对称诱导效果。此外，该策略还可成功拓展用于构建四取代的碳-氯与碳-溴手性中心。