Introduction of fluorine is a common practice in drug discovery to improve the metabolic stability and brain penetration of bioactive molecules. During our development of a novel series of fused pyrrolidine BACE1 inhibitors for the potential treatment of Alzheimer’s disease, we were interested in exploring SAR around the number and position of fluorine atoms on the phenyl ring that would occupy the S1 subsite of the enzyme. As part of this effort, we encountered two major, unexpected synthetic hurdles imposed by changes in the fluorine substitution pattern – (i) an unexpected reversal in regioselectivity in the methanolysis of cyclic anhydrides 1 and (ii) irreversible formation of intramolecular adducts 3 during Curtius rearrangement of acids 2. Solutions to these synthetic challenges and our current understanding of the effects of fluorine that led to these unexpected hurdles will be presented.

Unexpected changes in reactivity arising from fluorine substitution in the synthesis of BACE inhibitors

255th National Meeting (2018)

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