Far Away from Flatland. Synthesis and Molecular Structure of Dihetera[3.3.<i>n</i>]propellanes and Trihetera[3.3.<i>n</i>]propellanes: Advanced Analogues of Morpholine/Piperazine

Abstract

An approach to di- and trihetera[3.3.<i>n</i>]propellanes (<i>n</i> = 2-4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3 + 2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and <i>in situ</i> generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3-5 steps on a multigram scale with 10-72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.<i>n</i>]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat-chair, twist chair-chair, and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).