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

Abstract

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.

Macrocyclization Reactions at High Concentration (≥0.2M): The Role of Catalysis

“…Bromide anions as a template have also been very recently used for the preparation of pseudopeptidic macrocycles containing the hexahydropyrrolo-[3,4-f ]-isoindolocyclophane scaffold, in a continuous flow methodology. 46 The macrocyclization reaction involves four coupled substitution reactions, and the implementation 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.…”

“…Bromide anions as a template have also been very recently used for the preparation of pseudopeptidic macrocycles containing the hexahydropyrrolo-[ 3,4-f ]-isoindolocyclophane scaffold, in a continuous flow methodology . The macrocyclization reaction involves four coupled substitution reactions, and the implementation of flow protocols allowed a ca.…”

Basically, nucleophilicity matters little: towards unravelling the supramolecular driving forces in enzyme-like CO2 conversion

“…Macrocyclic compounds 1, 2, and 3 were synthesized according to literature procedures. 28,29 CO 2 cycloaddition reaction 8.7 mmol of styrene oxide (SO), 0.087 mmol of tetrabutyl ammonium halide (TBAX)and 0.0087 mmol of the corresponding pseudopeptide (1, 2, or 3) were added to a 25 mL twin-necked round bottom flask. The system was purged with dry N 2 and CO 2 , leaving two CO 2 balloons as gas supply.…”