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

A strategy for the creation of sp(3)-rich, non-planar scaffolds for drug discovery is described. Stereo-controlled 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 CeN 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. (C) 2020 Elsevier Ltd. All rights reserved.

Automated summary

This study presents a strategy for drug discovery by creating sp(3)-rich, non-planar scaffolds using stereo-controlled reactions to generate 1,2-diazetidines. The resulting chemical library is characterized by significant sp(3)-character with nitrogen substituents in an anti-configuration.