3‑((Hetera)cyclobutyl)azetidines, “Stretched” Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery

Four
3-((hetera)­cyclobutyl)­azetidine-based isosteres of piperidine,
piperazine, and morpholine were designed and synthesized on up to
gram scale. The key step of the synthetic sequence included cyclization
of N-protected 2-(azetidin-3-yl)­propane-1,3-diol
or the corresponding 1,3-dibromide. X-ray diffraction studies of the
products obtained, followed by exit vector plot analysis of their
molecular geometry, demonstrated their larger size and increased conformational
flexibility as compared to the parent heterocycles and confirmed their
potential utility as building blocks for lead optimization programs.