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Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert ‐Butyl Isostere
Author(s) -
Mukherjee Paramita,
Pettersson Martin,
Dutra Jason K.,
Xie Longfei,
am Ende Christopher W.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700333
Subject(s) - oxetane , trifluoromethyl , isostere , chemistry , lipophilicity , stereochemistry , context (archaeology) , organic chemistry , alkyl , paleontology , biology
The synthesis of a new trifluoromethyl oxetane was developed using a Corey–Chaykovsky epoxidation/ring‐expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert ‐butyl isostere in the context of the γ‐secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane‐containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert ‐butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert ‐butyl isostere.