Iterative Assembly of Polycyclic Saturated Heterocycles from Monomeric Building Blocks

Polycyclic saturated heterocycles with predictable shapes and structures are assembled by iterative couplings of bifunctional stannyl amine protocol (SnAP) reagents and a single morpholine-forming assembly reaction. Combinations of just a few monomers enable the programmable construction of rotationally restricted, nonplanar heterocyclic arrays with discrete sizes and molecular shapes. The three-dimensional structures of these constrained scaffolds can be quickly and reliably predicted by DFT calculations and the target structures immediately decompiled into the constituent building blocks and assembly sequences. As a demonstration, in silico combinations of the building blocks predict saturated heptacyclic structures with elementary shapes including helices, S-turns and U-turns, which are synthesized in 5–6 steps from the monomers using just three chemical reactions.