The development of new chemical motifs with appropriate physicochemical properties that access new chemical space can provide valuable opportunities in drug discovery. Azetidines have recently attracted interest in medicinal chemistry but their incorporation remains limited by the available synthetic methods. We have targeted 3,3-disubstituted azetidines as polar and achiral linker groups, with defined exit vectors and low molecular weight as fragments and building blocks. In particular we required divergent synthetic routes to incorporate medicinally relevant substituents.<br/>This presentation will describe the versatile synthesis of 3,3-disubstituted azetidines: 3,3-diarylazetidines, 3-arylazetidine ethers and 3-arylazetidine sulfides. An azetidine carbocation intermediate is formed from azetidin-3-ols using calcium or iron catalysis. The reactions proceed in high yields under mild conditions with (hetero)aromatics, phenols and thiols as nucleophiles, opening possibilities to apply the methodology to late stage functionalization. Notably, the Cbz group is essential to enhance the reactivity of the substrate; while the Boc derivative is unreactive. Finally, further derivatization of the new azetidines motifs, via deprotection, S<sub>N</sub>Ar, oxidation and cross-coupling reactions, demonstrate their potential for incorporation in drug discovery programs.

Synthesis of novel 3,3-disubstituted azetidines for medicinal chemistry: Divergent catalytic functionalization of 3-aryl-3-azetidinols

2019 Fall National Meeting

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