“Click” and “Click by Click”. Synthesis of Enantiomerically Pure New Derivatives of (S)-Proline Containing 1,2,3-Triazole Ring

Abstract

A series of novel (S)-proline derivatives incorporating both 1,2,3-triazole and vicinal amino alcohol functionalities were synthesized via a newly proposed “click by click” strategy. Key steps involved the synthesis of various azidoalcohols and their subsequent reactions with isopropyl prop-2-yn-1-yl-L-prolinate through Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). A survey of various synthetic strategies of precursor azidoalcohols was conducted, and the most viable strategy was selected based on experimental results. The developed methodologies were compared to the known synthetic routes involving “click chemistry”. The optimized one-pot “click by click” protocol resulted in a significantly enhanced yield of an example hybrid proline-triazole-amino alcohol derivative. The developed synthetic strategy yielded a more efficient procedure via the reduction of post-synthesis isolation time. This work highlights the utility of these methodologies for the efficient synthesis of complex proline-based scaffolds.