The azetidine (azacyclobutane) heterocycle, a four-membered saturated cyclic amine, is found in various natural and synthetic compounds with unique biological activities. The azetidine's physicochemical properties make it an increasingly popular scaffold in drug discovery despite being known since the 1950's. Azetidines can be used as bioisosteric replacements for more common saturated heterocycles such as piperazines, piperidines, pyrrolidines, leading to improved drug-like properties including lipophilicity, solubility, and in vitro metabolism. Indeed, numerous approved drugs such as delafloxacin, azelnidipine, tebanicline, baricitinib, cobimetinib, tebipenem, and siponimod feature an azetidine. Increasingly complex substituted azetidines, such as ones containing 2,3-disubstitution, have become commonplace (Figure ). Azetidines have also prominently featured in the context of chemical proteomic studies. Notwithstanding the relevance of azetidines in drug discovery and recent innovation in synthetic methodology, a need remains for new methods of azetidine construction that allow access to expanded chemical space, ideally in an expeditious fashion. Indeed, current approaches to synthesizing more complex azetidines in enantiopure form either employ multistep ring-synthesis strategies (which are not amenable to library synthesis) or C-H functionalization of a preformed azetidine, which is inherently limited to arylation (Figure ). Disclosed herein is a different approach for rapid, modular synthesis of enantio-and diastereopure azetidines that capitalizes on simple strain release functionalization of pre-formed 1-azabicyclobutanes (ABBs). 5d, The developed chemistry can be employed to generate libraries of diverse optically active azetidines. Chemical proteomic profiling of stereoisomeric sets of cysteine-reactive acrylamides derived from the new azetidine library reveals ligandable protein sites distinct from those of azetidine probes synthesized using C-H arylation. These findings illustrate the potential for the method of azetidine synthesis reported herein to facilitate the discovery of chemical probes and drug leads. As the number of substituents increases on the azetidine ring, simplified and modular access can be challenging. Indeed, the common route to such scaffolds involves cyclization from acyclic precursors already bearing terminal substitution, which in turn require multistep routes for preparation. An alternative approach to modularly access 2,3-disubstitution relies on C-H activation approaches (Figure ) but so far these are limited to (hetero)arene substitution at C-3 followed by directing group cleavage. 5a, 5c That approach delivers cis-2,3 substitution and if the trans-stereochemistry is desired an additional epimerization step is required. The Didier group reported an innovative approach to access cis-2,3 substitution utilizing azetinyl-carboxylic acid followed by asymmetric reduction. 5b Previously, our group reported a general strategy for the direct functionalization of strained C-C and C-N bonds, including that of azabicyclo [1.1.0]butanes (ABBs). 6b Since then, numerous reports have appeared on both the polar and radical functionalization of ABBs. 5d