Development of a practical solid-phase synthesis approach to 1,3,5-triazepan-2,6-diones

1,3,5-Triazepan-2,6-diones are a class of conformationally restricted heterocycles derived from dipeptides. With the aim to develop a general and practical method useful for library production, three polymer-assisted syntheses, all based on a catch and release approach, have been evaluated and compared. The method involving a Hofmann rearrangement of N-Boc dipeptide carboxamides and subsequent trapping of the isocyanate on polymer-supported N-hydroxysuccinimide (PS-HOSu) was found to be the most reliable and versatile, allowing rapid access to the 1,3,5-triazepan-2,6-dione skeleton.