To set the stage for azetidine library synthesis, a variety of nucleophiles and conditions were screened and optimized conditions were developed (Figure ). When exposed to acidic conditions the ABBs were found to be unstable and dimerization was observed. In the literature, exposure of ABBs to weak acid leads to incorporation of the nucleophilic counterion at the C-3 position (e.g. AcOH). 8 With this data in mind, two sets of conditions were employed depending on the pKa of the nucleophile: (1) acidic nucleophiles e.g. carboxylic acids, phenols, thiophenols, and phosphates were added in directly (THF at rt) or ( ) basic nucleophiles such as anilines, alcohols, and alkyl amines added in smoothly with the addition of TfOH (0.9-1 equiv, CH3CN or toluene, -78 to -40 °C followed by stirring at rt). TfOH was chosen due to its non-nucleophilic conjugate base. In accord with prior studies, strong nucleophiles (Grignard reagents) could also be added stereospecifically to generate C-C linkages at C-3. 9 Finally, by utilizing both the acidity of C-3 and the basicity of the amine, a C-3 double functionalization could be achieved as a result of sequential deprotonative functionalization followed by acid-catalyzed strain-release opening. With the optimized set of conditions (Methods A and B) in hand, the scope of this method was investigated as outlined in Table . Numerous nucleophiles were enlisted such as amines, alcohols, thiols, carboxylic acids, and phosphates. Acidic and basic nucleophiles as well as Grignard reagents, amino acid functionalization and double C3 functionalization were successfully demonstrated. An electrophilic quenching agent (Boc anhydride) was utilized to simplify purification. The products were obtained in 36-87% yields with excellent diastereoselectivities (>20:1), on scales ranging from 0.1 to 0.8 mmol. The stereochemical outcomes of these reactions were verified by X-ray crystallography (2b', 2d, 13-trans, 18-cis, 18-trans, 21-trans, and 28'). Thus, when the starting material carries an acidic proton, Method A enabled ring opening using phenols (14 and 26), thiophenol (20) carboxylic acids (19 and 25), and phosphate (10). Using Method B, basic or neutral e.g. amines (8, 22, and 23), anilines (6 and 7) and alcohols (11-12) led to smooth ring opening. Despite the fact that TfOH is a strong acid, the chemoselectivity and functional-group tolerance was high, enabling use of acid-sensitive groups such as tert-butyl ethers and esters. Additionally, select previously reported nucleophiles were found to successfully undergo C-3 strain release nucleophilic substitution, for example Grignard reagents (15, 16 and 17) and azides (9). 10 Finally, stereospecific double functionalization at the C3 position was investigated. This was achieved by treating the ABB (3b-c) with tBuLi to deprotonate the C3 site, resulting in ABB lithium (ABB-Li). 10b, c Table . Scope of stereospecific strain release opening of enantiopure ABBs. All products were obtained with dr >20:1. This species was then quenched with D2O to give a C3 deuterium labeled ABB, which was further reacted with 4methoxythiophenol (method A) to afford compound 27. Similar sequential deprotonative functionalization was utilized to form compounds 28 and 29 by using methyl cyanoformate as the electrophile (see SI for support for stereochemical outcome).