Jacob P Sorrentino1, Brett R Ambler1,2, Ryan A Altman1. 1. Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States. 2. Department of Discovery Chemistry MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
Abstract
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.
We report the conversion of aryl methyl ethers and n class="Chemical">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.
Authors: Li Xing; David C Blakemore; Arjun Narayanan; Ray Unwalla; Frank Lovering; R Aldrin Denny; Huanyu Zhou; Mark E Bunnage Journal: ChemMedChem Date: 2015-03-06 Impact factor: 3.466
Authors: Eric P Gillis; Kyle J Eastman; Matthew D Hill; David J Donnelly; Nicholas A Meanwell Journal: J Med Chem Date: 2015-07-22 Impact factor: 7.446