Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

Herein we report our efforts to develop a continuous flow methodology for the efficient preparation of pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Appropriate design of a supported base permitted the continuous production of the macrocycles even at large scales, taking advantage of the positive template effect promoted by the bromide anions. In addition, the use of flow protocols allowed a ca. 20-fold increase in productivity as well as reducing the environmental impact almost 2 orders of magnitude, in comparison with the related batch macrocyclization process.