Bicyclic sp -enriched systems have gained much attention in design of biologically active compounds as structural analogs of common rings (e.g., benzene, pyridine, piperidine). In particular, 3-azabicyclo[3.1.1]heptane (1) was proposed to be a bicyclic saturated isostere of pyridine and piperidine two heterocycles most widely used in drug discovery (Figure ). Some known biologically active 3-azabicyclo[3.1.1]heptane derivatives include potent aromatase inhibitors or purinergic receptor P2Y14 antagonists (Figure ). Reported methods for the construction of 3-azabicyclo[3.1.1]heptane system (Scheme 1) relied on thermal (A), photochemical (B), or metal-catalyzed intramolecular [2+2] cycloaddition, recyclization of 2-oxaspiro [3.3]heptanes (C), double Mannich reaction of cyclobutanone, or cyclization of 1,3-substituted cyclobutane-derived amino esters (D). Herein, we report very efficient approach to the multigram synthesis of 3-azabicyclo[3.1.1]heptanes based on the cyclization of cyclobutane-derived 1,3-dicarboxylic acid derivative 1 (Scheme 1, E). Notably, somewhat related approach, i.e., cyclization of truxillic acid amides, was used in the very first synthesis of 3azabicyclo[3.1.1]heptane system reported over a century ago. The key intermediate obtained in our workbicyclic imide 2was transformed into a series of 1-amino-3-azabicyclo[3.1.1]heptane derivatives, including monoprotected diamine building blocks 3 and 4, as well as bicyclic analogs of Thalidomide. This classical medication is currently used to treat a variety of cancers; recently, it has attracted much attention in design of proteolysis-targeting chimeras (PROTACs) due to its action as a cereblon E3 ligase ligand.