Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert‐Butyl Isostere

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.

[1]  K. F. Morgan,et al.  Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry. , 2016, Chemical reviews.

[2]  Gregory W. Kauffman,et al.  Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability. , 2015, ACS medicinal chemistry letters.

[3]  E. Carreira,et al.  Evaluation of tert‐Butyl Isosteres: Case Studies of Physicochemical and Pharmacokinetic Properties, Efficacies, and Activities , 2015, ChemMedChem.

[4]  Gregory W. Kauffman,et al.  Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators. , 2014, Journal of medicinal chemistry.

[5]  Monish Jain,et al.  Metabolically Stable tert-Butyl Replacement. , 2013, ACS medicinal chemistry letters.

[6]  G. Kay,et al.  A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. , 2011, British journal of clinical pharmacology.

[7]  Erick M. Carreira,et al.  Oxetane als vielseitige Bausteine in der Wirkstoff‐Forschung und Synthese , 2010 .

[8]  E. Carreira,et al.  Oxetanes as versatile elements in drug discovery and synthesis. , 2010, Angewandte Chemie.

[9]  A. A. Fokin,et al.  Stereospecific consecutive epoxide ring expansion with dimethylsulfoxonium methylide. , 2010, The Journal of organic chemistry.

[10]  C. Molinaro,et al.  Resolution of 2,2-disubstituted epoxides via biocatalytic azidolysis. , 2010, Organic letters.

[11]  Franz Schuler,et al.  Oxetanes in drug discovery: structural and synthetic insights. , 2010, Journal of medicinal chemistry.

[12]  P. Verhoest,et al.  Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. , 2010, ACS chemical neuroscience.

[13]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[14]  Dafydd R Owen,et al.  Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. , 2009, Bioorganic & medicinal chemistry letters.

[15]  S. Matsunaga,et al.  Catalytic asymmetric synthesis of 2,2-disubstituted oxetanes from ketones by using a one-pot sequential addition of sulfur ylide. , 2009, Angewandte Chemie.

[16]  Bo Feng,et al.  In Vitro P-glycoprotein Assays to Predict the in Vivo Interactions of P-glycoprotein with Drugs in the Central Nervous System , 2008, Drug Metabolism and Disposition.

[17]  Y. Shishido,et al.  Synthesis of aromatic compounds containing a 1,1-dialkyl-2-trifluoromethyl group, a bioisostere of the tert-alkyl moiety. , 2007, Bioorganic & medicinal chemistry letters.

[18]  E. Carreira,et al.  Oxetanes as promising modules in drug discovery. , 2006, Angewandte Chemie.

[19]  R. Austin,et al.  A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES , 2005, Drug Metabolism and Disposition.

[20]  K. Okuma,et al.  Reaction of dimethyloxosulfonium methylide with epoxides. Preparation of oxetanes , 1983 .

[21]  D. Dess,et al.  Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones , 1983 .

[22]  B. Landrum,et al.  Synthesis of partially fluorinated oxetanes , 1965 .

[23]  E. Corey,et al.  Dimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic Synthesis , 1965 .

[24]  Martin Pettersson,et al.  γ-Secretase Modulators as Aβ42-Lowering Pharmacological Agents to Treat Alzheimer’s Disease , 2017 .

[25]  Ramesh Krishnamurti,et al.  Synthetic methods and reactions. 141. Fluoride-induced trifluoromethylation of carbonyl compounds with trifluoromethyltrimethylsilane (TMS-CF3). A trifluoromethide equivalent , 1989 .

[26]  I. Ruppert,et al.  Die ersten CF3-substituierten organyl(chlor)silane , 1984 .