Highly Selective Anion Template Effect in the Synthesis of Constrained Pseudopeptidic Macrocyclic Cyclophanes

Herein, we report
the synthesis of a novel family of constrained
pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo­[3,4-f]­isoindolocyclophane scaffold and involving four coupled
substitution reactions in the macrocyclization process. Although the
increase in the number of steps involved in the macrocyclization could
lead to a larger number of possible side products, the optimization
of the methodology and the study of the driving forces have made it
possible to obtain the desired macrocycles in excellent yields. A
thorough computational study has been carried out to understand the
macrocyclization process, and the results obtained nicely agree with
experimental data. Moreover, the bromide anion had a clear catalytic
template effect in the macrocyclization reaction, and surprisingly,
the chloride anion had a negative template effect in opposition to
the results obtained for analogous macrocycles. The parameters responsible
for the specific kinetic template effect observed have been studied
in detail.