Synthesis and Physicochemical Properties of Cryptophazane—A Soluble and Functionalizable C₁‐Symmetrical Cryptophane

Abstract

The first example of a cryptophazane, a cryptophane functionalized with a nitrogen atom replacing one of the methylene bridges, is obtained with a 28 % overall yield over 8 steps, through the preparation of a C 1 -symmetrical aza-cyclotriveratrylene (aza-CTV). Herein, we demonstrate that the introduction of a nitrogen atom on this part of the cryptophane core enhances the solubility in organic media of both the cryptophane and the synthetic intermediates, while presenting the same conformation as known cryptophanes. Cryptophazane was prepared on a multigram scale and easily functionalized. We also investigated its ability to encapsulate xenon atoms using hyperpolarized 129 Xe (HP 129 Xe) NMR spectroscopy. We found that both its affinity and exchange kinetics were in the appropriate range for applications in 129 Xe magnetic resonance imaging (MRI). Combined with the wide range of possible functionalization, this makes cryptophazane an excellent candidate for targeted HP 129 Xe MRI.

Synthesis of Cryptophanes: Recent Advances

“…Dubost and Cailly demonstrated the synthesis of cryptophazane, a cryptophane in which one of the axial methylene bridges has been replaced with an À NH group (Scheme 14). [62] The 2-amino-benzyl alcohol derivative 89 was first protected with TBDMS group before subjecting it to Buchwald-Hartwig amination (BHA) with 90 which afforded in six linear steps from 2-amino-5-methoxybenzoic acid. The bromo-compound 90 for BHA was prepared by Barluenga Boronic Coupling (BBA).…”

“…Dubost and Cailly demonstrated the synthesis of cryptophazane, a cryptophane in which one of the axial methylene bridges has been replaced with an −NH group (Scheme 14). [62] The 2‐amino‐benzyl alcohol derivative 89 was first protected with TBDMS group before subjecting it to Buchwald‐Hartwig amination (BHA) with 90 which afforded 91 . Deprotection followed by cyclization in HClO 4 resulted in the formation of intermediate 92 , a C 1 ‐symmetrical CTB‐1 N in 60 % overall yield in six linear steps from 2‐amino‐5‐methoxybenzoic acid.…”

31st Annual GP2A Medicinal Chemistry Conference

“…In this communication, we will present the synthesis of a new type of cyclotriveratrylenes, which are key intermediates in the preparation of cryptophanes, using either Barluenga Boronic Coupling [63] or Burchwald-Hartwig amination [64], according to the methodology described by our group (Figure 17) [65]. Magnetic Resonance Imaging is a technology frequently used in the medical imaging field thanks to the high resolution and the excellent tissue contrast it provides.…”

“…In this communication, we will present the synthesis of a new type of cyclotriveratrylenes, which are key intermediates in the preparation of cryptophanes, using either Barluenga Boronic Coupling [63] or Burchwald-Hartwig amination [64], according to the methodology described by our group (Figure 17) [65].…”

Self-assembled tetrazine cryptophane for ion pair recognition and guest release by cage disassembly

“…These molecular hosts attract great interest as they display remarkable recognition properties toward small molecules like epoxides, 5 methane and halogenomethane, 2 a ,6 anions, 7 cations, 8 or even atoms like radon or xenon. 7 b ,9 However, cryptophanes have not yet been used for ion-pair recognition due to their homotopicity. Promising related applications are currently being investigated; for instance, the development of hyperpolarized 129 Xe biosensors for MRI, 10 the design of devices for methane sensing, 11 and the trapping of radioactive Cs + found in nuclear waste.…”