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A Versatile Approach to CF3‐Containing 2‐Pyrrolidones by Tandem Michael Addition–Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors |
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| Authors: | Dr. Natalia Mateu Myriam Ciordia Dr. Oscar Delgado Dr. María Sánchez‐Roselló Dr. Andrés A. Trabanco Dr. Michiel Van Gool Dr. Gary Tresadern Laura Pérez‐Benito Prof. Dr. Santos Fustero |
| Affiliation: | 1. Departamento de Química Orgánica, Universidad de Valencia, 46100‐Burjassot (Spain);2. Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe (CIPF), 46012‐Valencia (Spain);3. Neuroscience Medicinal Chemistry Department, Janssen Research and Development, E‐45007‐Toledo (Spain);4. Departamento de Química y Bioquímica, Facultad de Farmacia Universidad CEU San Pablo, Urbanización Monteprincipe Ctra., Boadilla del Monte Km 5,3, 28668 Madrid (Spain) |
| Abstract: | The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition–lactamization sequence is described. The resulting CF3‐containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β‐secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery. |
| Keywords: | cyclization drug discovery enzymes fluorine inhibitors |