A General and Scalable\nMethod toward Enantioenriched\nC2-Substituted Azetidines Using Chiral <i>tert</i>-Butanesulfinamides

Diverse ranges of chiral nitrogen-containing heterocycles\nserve\nas a molecular toolbox for modulating a wide array of biological processes,\nbut enantioenriched production of smaller chiral heterocycles is a\nbottleneck. There is a lack of general approaches for the stereoselective\npreparation of chiral 4-membered monocyclic C2-substituted azetidines,\nwhere many routes to different substitution types are possible, but\nno simple and common approach exists. To bridge this gap, inexpensive\nand widely available chiral <i>tert</i>-butanesulfinamides\nare harnessed for chiral induction with 1,3-bis-electrophilic 3-chloropropanal,\nproviding a three-step approach to C2-substituted azetidines with\naryl, vinyl, allyl, branched alkyl, and linear alkyl substituents.\nEleven azetidine products are produced, and the approach is shown\nto be effective on a gram-scale with a single purification of the\nprotected azetidine product in 44% yield over three steps in an 85:15\ndiastereomeric ratio. In most cases, the diastereomers are separable\nusing normal phase chromatography, often resulting in previously elusive\nenantiopure azetidine products. Protected azetidines were shown to\nundergo rapid and efficient sulfinamide cleavage, producing an azetidine\nhydrochloride salt that was subjected to derivatization reactions,\nhighlighting the method’s applicability to medicinal chemistry\napproaches.