Exploring the synthesis of aminal guanidine-based molecules

A novel approach has been developed for the efficient synthesis of the unsymmetrical (2-aminopyrrolidin-1-yl)carboxamidine alkaloidal core found in cernumidine (1) and its analogs (20a, 20c, 20f, 20i-o). The key transformation in this process involves the utilization of the Curtius rearrangement, which plays a pivotal role in constructing the aminal moiety. One of the major challenges encountered during this synthesis was the instability of the free aminal core intermediate. Furthermore, a noteworthy observation during the synthesis was the racemization process that occurred during the isocyanate trapping by organometallic reagents. Detailed DFT calculations shed light on this phenomenon, revealing a neighboring coordination-induced mechanism. The resulting compounds were subjected to evaluation for their anti-inflammatory properties using lipopolysaccharide-stimulated human THP1 cells. Notably, compounds featuring the guanidine moiety and electron-donating groups exhibited significant anti-inflammatory activity. These findings suggest that these compounds hold promise as potential candidates for further development as anti-inflammatory agents.

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C. S. B. Gomes acknowledges the XTAL – Macromolecular Crystallography group (UCIBIO and i4HB) for granting access to the X-ray diffractometer. X-Ray infrastructure was financed by FCT-MCTES through project RECI/BBBBEP/0124/2012. Publisher Copyright: © 2024 The Royal Society of Chemistry.