Synthesis of sp3-rich chemical libraries based upon 1,2-Diazetidines

Abstract A strategy for the creation of sp 3 -rich, non-planar scaffolds for drug discovery is described. Stereocontrolled ring opening of homochiral 1,2-epoxides by hydrazine monohydrate followed by selective protection of both nitrogen atoms and Mitsunobu ring closure gives differentially protected, enantiomerically pure 1,2-diazetidines (up to 98% ee) bearing a variety of C-3 substituents. Iterative C–N functionalization at the two nitrogen atoms using a range of chemistries and coupling partners produces a 1,2-diazetidine based chemical library. Crystallographic data confirm that these frameworks display significant sp 3 -character with the nitrogen substituents adopting an anti-configuration.