Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
J Am Chem Soc. 2023 May 3;145(17):9708-9717. doi: 10.1021/jacs.3c01303. Epub 2023 Apr 20.
The controlled programming of regiochemical outcomes in nucleophilic fluorination reactions with alkali metal fluoride is a problem yet to be solved. Herein, two synergistic approaches exploiting hydrogen bonding catalysis are presented. First, we demonstrate that modulating the charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. Moreover, we report a urea-catalyzed formal dyotropic rearrangement, a thermodynamically controlled regiochemical editing process consisting of C-F bond scission followed by fluoride rebound. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor, and more generally, new opportunities in regiodivergent asymmetric ()urea-based organocatalysis.
利用碱金属氟化物进行亲核氟化反应时，对区域化学产物的控制是一个尚未解决的问题。在此，我们提出了两种协同利用氢键催化的方法。首先，我们证明通过氢键供体脲催化剂调节氟化物的电荷密度可以直接影响带有芳基和酯基取代基的不对称氮丙啶盐氟化的动力学区域选择性。此外，我们还报道了脲催化的形式双角重排，这是一个热力学控制的区域化学编辑过程，包括 C-F 键断裂和随后的氟离子回弹。这些发现为从单个氯胺前体获得对映富集的氟胺区域异构体提供了一种途径，更广泛地说，为基于 ()脲的手性有机催化的区域发散不对称反应提供了新的机会。
