Sorrentino Jacob P, Ambler Brett R, Altman Ryan A
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States.
Department of Discovery Chemistry MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
J Org Chem. 2020 Apr 17;85(8):5416-5427. doi: 10.1021/acs.joc.0c00125. Epub 2020 Mar 27.
We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.
我们报道了通过一种天然产物衍生的、经美国食品药品监督管理局（FDA）批准的治疗药物的后期官能团化反应，将芳基甲基醚和苯酚转化为六种氟烷基类似物。这一系列简短的合成步骤结合了现代方法和传统方法，并且表明一些最近报道的方法在类似天然产物的骨架上并不总是能如预期那样有效。尽管如此，反应优化可为药物化学目的提供足够量的每种目标类似物。在某些情况下，经典反应和合成步骤仍然比现代有机氟转化反应更具优势，这应该会促使人们继续寻找改进的反应。总体而言，该项目为药物化学家提供了一条有价值的合成路线图，以获得一系列相对于原始基于氧的类似物具有不同物理化学性质的氟化治疗候选物。
