Multigram Synthesis and Physicochemical Evaluation of (Oxa)Azaspiro[2.n]alkane Building Blocks

Abstract

An efficient and scalable approach to (oxa)azaspiro[2.n]alkane building blocks has been developed, starting from commercially available N-Boc-protected lactams and lactones. Tebbe olefination followed by cyclopropanation as the key step enabled the construction of spirocyclic cores containing five-to seven-membered heterocycles, with scalability demonstrated up to 62 g. Subsequent diastereomeric separation and straightforward functional group interconversions provided a diverse set of derivatives, including carboxylic acids, amines, and gem-difluorinated analogues, thereby extending access to scarcely explored larger-ring scaffolds. Experimental lipophilicity measurements demonstrated that spiroannelation of the gem-diflurocyclopropane ring significantly increased LogP values; the effect was similar to that of CF3 group. Structural characterization by single-crystal X-ray diffraction studies and exit vector plot (EVP) analysis confirmed the three-dimensional architecture of representative compounds and suggested potential applications for isosteric replacements. Together, these results establish a robust platform for the multigram preparation and physicochemical profiling of spirocyclic building blocks, which are of high relevance to medicinal chemistry.