Nondirected C–H/C–F Coupling for the Synthesis of α‑Fluoro Olefinated Arenes

The fluorinated entities are considered a privileged
structure
class in the field of medicinal chemistry because of the amplified
bioactivity they exhibit. In this regard, developments in C–H
fluorination and trifluoromethylation have been mostly targeted. The
α-fluoro olefins also show potential applications as bioisosteres
of amides and are also prevalent in drug candidates, but their synthetic
accessibility by a C–H activation strategy remains an elusive
domain. The assistance of the directing group (DG) does enable the
fluoroalkenylation but also constrains the scope in terms of expansion
of chemical space for drug development programs. The nondirected strategy
is a “one-shot” solution to the existing issues on the
use of DGs. With this perspective, we herein report the nondirected
protocol on Pd-catalyzed C–H/C–F coupling for accessing
α-fluoro olefins in a regioselective fashion. The transformation
is governed by the dual control of a pyridine and amino acid-based
ligand, which dictate the complementary selectivity achieved. The
protocol allows for the late-stage derivatization of drugs and natural
products and also enables the conjugation of the drug with the natural
product by means of a fluoro-olefin bridge. The incorporation of these
fluorinated moieties can potentially modulate the parent bioactivity
of drugs. Mechanistic investigations and DFT calculations suggest
the vital role of monoprotected amino acid ligand in the C–H
activation step through concerted metalation deprotonation, which
is the overall turnover frequency-determining state of the catalytic
cycle.

在药物化学领域，氟化物实体因其所展现的增强生物活性而被视为一种特权结构类别。在此方面，C-H氟化和三氟甲基化的进展主要集中于此。α-氟烯烃也显示出作为酰胺的生物等位体的潜在应用，且在药物候选物中亦普遍存在，但通过C-H活化策略的合成可及性仍是一个难以触及的领域。导向基团（DG）的辅助虽能实现氟烯烃化，但也限制了在药物开发项目中化学空间扩展的范畴。非导向策略是对现有导向基团使用问题的一种“一劳永逸”的解决方案。在此视角下，本文报道了一种非导向Pd催化的C-H/C-F偶联的非定向方案，以区域选择性地获取α-氟烯烃。该转化受基于吡啶和氨基酸的配体的双重控制，这些配体决定了所获得的互补选择性。该方案允许药物和天然产物的后期衍生化，并可通过氟烯烃桥将药物与天然产物进行偶联。这些氟化基团的引入有可能调节药物母体的生物活性。机理研究和DFT计算表明，单保护氨基酸配体在C-H活化步骤中的重要作用，通过协同金属化去质子化，这是催化循环整体周转频率决定的状态。