Catalytic Asymmetric Synthesis of Tertiary Alkyl Fluorides: Negishi Cross-Couplings of Racemic α,α-Dihaloketones

The
development of new approaches to the construction of fluorine-containing
target molecules is important for a variety of scientific disciplines,
including medicinal chemistry. In this Article, we describe a method
for the catalytic enantioselective synthesis of tertiary alkyl fluorides
through Negishi reactions of racemic α-halo-α-fluoroketones,
which represents the first catalytic asymmetric cross-coupling that
employs geminal dihalides as electrophiles. Thus, selective reaction
of a C–Br (or C–Cl) bond in the presence of a C–F
bond can be achieved with the aid of a nickel/bis­(oxazoline) catalyst.
The products of the stereoconvergent cross-couplings, enantioenriched
tertiary α-fluoroketones, can be converted into an array of
interesting organofluorine compounds.

新型含氟目标分子构建方法的研发，对于包括药物化学（medicinal chemistry）在内的诸多学科均具有重要意义。本文报道了一种通过外消旋α-卤代-α-氟代酮的根岸偶联（Negishi reaction）反应，实现叔烷基氟化物催化对映选择性合成的方法——这是首例以偕二卤代物作为亲电试剂的催化不对称交叉偶联反应。借助镍/双恶唑啉（bis(oxazoline)）催化剂的辅助，可在C-F键共存的条件下实现C-Br（或C-Cl）键的选择性活化与反应。该立体汇聚型交叉偶联反应的产物为对映富集的叔α-氟代酮，可进一步转化为一系列颇具研究价值的有机氟化合物（organofluorine compounds）。