Research on selective protection and deprotection of the diethylenetriamine skeleton for efficient synthesis

Polyprotected diethylenetriamine derivatives represent valuable building blocks for the fabrication of targeted antitumor candidates and molecular imaging probes. Nevertheless, precise site-selective modification of their multiple amine moieties still remains a major synthetic challenge. In this study, we adopted diethylenetriamine as the core structural framework and employed Fmoc and Cbz groups as amine protecting groups to develop a cost-effective continuous-flow synthetic methodology. Notably, the entire synthetic procedure avoids traditional column chromatography purification. Tubular and microchannel reactors were applied to realize site-selective Fmoc protection and deprotection. Target products were efficiently afforded by low-temperature DBU-mediated Fmoc deprotection coupled with citrate salt purification, without the addition of any dibenzofulvene (DBF) scavenger. This synthetic strategy features high efficiency and promising scalability, offering a concise and practical new route for the site-specific functionalization of diethylenetriamine-based polyamines.