Oxetanes have recently attracted interest in drug discovery programs for their ability to enhance physicochemical properties. They also provide potential replacement groups for carbonyl and <i>gem</i>-dimethyl motifs. However, their incorporation is limited by the synthetic methods available.<br/>3-Aryloxetane-3-carboxylic acid derivatives represent an attractive building block to access a wide variety of medicinally valuable functionalities through the acid moiety. In addition, recently published patents display biologically active molecules containing this motif. The similarity between 3-aryl-oxetane-3-carboxylic acids and 2-arylalkanoic acids, such as ibuprofen, represents an interesting opportunity for medicinal chemists. However, there are only a small number of commercial available examples, at significant cost. Their synthesis is limited to ring closure and subsequent reduction/oxidation strategies, which can be both lengthy and low yielding.<br/>This poster will disclose a simple two-step strategy to synthesize novel 3-aryloxetane-3-carboxylic acids from readily accessible oxetan-3-ols. This involves the incorporation of a furan moiety via a lithium-catalyzed Friedel-Crafts arylation of oxetan-3-ols, followed by oxidative cleavage. A range of oxetane-carboxylic acids are obtained in high yield, including oxetane-containing analogues of drugs such as Ibuprofen and Felbinac. Triflate, benzyl and TIPS protecting groups were tolerated under the reaction conditions, providing additional synthetic handles. Chemoselective functionalization of these oxetane building blocks was demonstrated through amidation, Suzuki-cross coupling and alkylation reactions, showing the high stability of the oxetane and providing a broader range of derivatives.

3-Aryloxetane-3-carboxylic acids: Two step process towards novel versatile building blocks for drug discovery programs

2019 Fall National Meeting

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