Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]‐ and Calix[12]pyrrole Analogues

• Published in: Angewandte Chemie International Edition 2023-04, Vol.62 (15), p.e202301460-n/a
• Main Authors: Inaba, Yuya, Yang, Jian, Kakibayashi, Yu, Yoneda, Tomoki, Ide, Yuki, Hijikata, Yuh, Pirillo, Jenny, Saha, Ranajit, Sessler, Jonathan L., Inokuma, Yasuhide
• Format: Article
• Language: English
• Subjects: Calixarenes; Chirality; Macrocycles; Racemization Kinetics; Ring Expansion
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202301460

Chiral pyrrolic macrocycles continue to attract interest. However, their molecular design remains challenging. Here, we report a calixpyrrole‐based chiral macrocyclic system, calix[1]furan[1]pyrrole[1]thiophene (1), synthesized from an oligoketone. Macrocycle 1 adopts a partial cone conformation in the solid state, and undergoes racemization via ring inversion. Molecular dynamics simulations revealed that inversion of the thiophene is the rate determining step. Pyrrole N‐methylation suppressed racemization and permitted chiral resolution. Enantioselective N‐methylation also occurred in the presence of a chiral ammonium salt, although the stereoselectivity is modest. A unique feature of 1 is that it acts as a useful synthetic precursor to yield several calix[n]furan[n]pyrrole[n]thiophene products (n=2–4), including a calix[12]pyrrole analogue that to our knowledge constitutes the largest calix[n]pyrrole‐like species to be structurally characterized. An inherently chiral calix[3]pyrrole derivative was synthesized from a polyketone precursor. Although the macrocycle racemizes through ring inversion at room temperature, N‐methylation effectively suppressed the racemization, allowing chiral resolution of the enantiomers. Ring expansion reaction allowed access to calix[9]‐ and calix[12]pyrrole‐type macrocycles, the largest of which was characterized by an X‐ray diffraction analysis.