直接获取 N-三氟甲基酰胺、氨基甲酸酯、硫代氨基甲酸酯和尿素,Nature

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直接获取 N-三氟甲基酰胺、氨基甲酸酯、硫代氨基甲酸酯和尿素
Nature ( IF 50.5 ) Pub Date : 2019-09-04 , DOI: 10.1038/s41586-019-1518-3
Thomas Scattolin ₁ , Samir Bouayad-Gervais ₁ , Franziska Schoenebeck ₁

Affiliation

酰胺和相关的羰基衍生物在整个物理和生命科学领域 1、2 中具有重要意义。作为关键的生物结构单元，酰胺的稳定性和构象影响肽和蛋白质的结构及其生物学功能。此外，酰胺键的形成是最常用的化学转化之一 3,4。鉴于它们无处不在，一种能够在不影响稳定性的情况下改变酰胺的基本性质的技术可能在制药、农业化学和材料科学中具有相当大的潜力。为了影响有机分子的物理性质——例如溶解度、亲油性、构象、pK a 和（代谢）稳定性——氟化方法已被广泛采用 5-7。相似地，使用等排体和肽模拟物 8 或特别是通过 N-甲基化 9 进行位点特异性修饰已被用于改善化合物的稳定性、物理性质、生物活性和细胞渗透性。然而，由于缺乏有效的合成方法，尚未探索结合 N-甲基化和氟化方法的 N-三氟甲基羰基基序。在这里，我们报告了一种直接获取酰胺和相关羰基化合物的 N-三氟甲基类似物的方法。该策略依赖于操作简单的台式氨基甲酰氟结构单元的制备，可以很容易地多样化为相应的 N-CF3 酰胺、氨基甲酸酯、硫代氨基甲酸酯和脲。这种方法可以容忍丰富的功能和立体化学，我们展示了许多高度功能化的化合物的例子——包括广泛使用的药物、抗生素、激素和聚合物单元的类似物。酰胺和相关羰基化合物的 N-三氟甲基类似物是通过实验室稳定的氨基甲酰氟结构单元制备的。

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Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas

Amides and related carbonyl derivatives are of central importance across the physical and life sciences1,2. As a key biological building block, the stability and conformation of amides affect the structures of peptides and proteins as well as their biological function. In addition, amide-bond formation is one of the most frequently used chemical transformations3,4. Given their ubiquity, a technology that is capable of modifying the fundamental properties of amides without compromising on stability may have considerable potential in pharmaceutical, agrochemical and materials science. In order to influence the physical properties of organic molecules—such as solubility, lipophilicity, conformation, pK a and (metabolic) stability—fluorination approaches have been widely adopted5–7. Similarly, site-specific modification with isosteres and peptidomimetics8, or in particular by N-methylation9, has been used to improve the stability, physical properties, bioactivities and cellular permeabilities of compounds. However, the N-trifluoromethyl carbonyl motif—which combines both N-methylation and fluorination approaches—has not yet been explored, owing to a lack of efficient methodology to synthesize it. Here we report a straightforward method to access N-trifluoromethyl analogues of amides and related carbonyl compounds. The strategy relies on the operationally simple preparation of bench-stable carbamoyl fluoride building blocks, which can be readily diversified to the corresponding N–CF3 amides, carbamates, thiocarbamates and ureas. This method tolerates rich functionality and stereochemistry, and we present numerous examples of highly functionalized compounds—including analogues of widely used drugs, antibiotics, hormones and polymer units. N-trifluoromethyl analogues of amides and related carbonyl compounds are prepared via bench-stable carbamoyl fluoride building blocks.

更新日期：2019-09-04

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