Novel chiral imidazole cyclophane receptors: synthesis and enantioselective recognition for amino acid derivatives

Abstract

Novel chiral imidazole cyclophane receptors were synthesized by highly selective N-alkylation of the imidazolyl 1N-position of the bridged histidine diester 2 with the dibromide in the presence of NaH; these receptors exhibit good chiral recognition toward the enantiomers of L-and D-amino acid derivatives (up to K D /K L = 3.52, DDG 0 = 23.11 kJ mol 21 ) in CHCl 3 at 25.0°C.Molecular recognition between molecules is one of the most fundamental processes in biochemical systems. The study of synthetic model systems could contribute to the understanding of these processes and, at the same time, offer new perspectives for the development of pharmaceuticals, enantiomer-selective sensors, catalysts and molecular devices. 1 One area that has proven especially challenging is the creation of enantioselective artificial receptors. 2 Cyclophanes have gained considerable interest because of their potential applications in artificial enzymes, host-guest complexes, molecular self-assembly, selective catalysis and material science. 3 A variety of cyclophanes with novel structures and properties have been reported. However, inspecting the impressively long list, examples dealing with histidine are quite rare. 4 Imidazole and histidine derivatives are generally considered to be difficult to prepare, so this makes the development of imidazole-containing receptors much more challenging. Our interest has been focused on the synthesis of imidazolium and imidazole cyclophanes. 5 Recent work aimed to synthesize chiral macrocyclic tetraoxo polyamines containing two functional imidazole arms that are oriented in an anti fashion, and to develop a convenient and efficient method for the synthesis of bridged histidine derivatives. 6 On the basis of this method, we herein report the synthesis of novel chiral imidazole cyclophane receptors from L-histidine (Scheme 1), and their enantioselective recognition for amino acid methyl esters. To our knowledge, this is the first example of a chiral imidazole cyclophane from L-histidine as a chiral recognition receptor.We have previously synthesized chiral macrocyclic tetraoxo polyamines containing two functional imidazole arms via aminolysis of the dihistidine dimethyl esters 2 with commerically available polyamines. 6 The key intermediate 2 was directly used without protection of the imidazole ring. Herein four novel chiral imidazole cyclophanes 3-6 were obtained by highly selective N-alkylation of the imidazolyl 1N-position of 2 with the corresponding dibromides in the presence of a slight excess of NaH in DMF under dry and oxygen-free conditions at 25-0°C. The reaction conditions have a significant influence on the macrocyclization because the bridged compound 2 possesses several active functional groups, and the N-alkylation of imidazole groups usually leads to serious side reactions such as the quaternization reaction of imidazole and the elimination reaction of halides. 5,7 To minimize these side reactions and competitive reactions between the imidazolyl 1N-position and the NH of CONH, 8 th...

Synthesis and Crystal Structure of Novel Benzimidazole Cyclophanes

“…Table 1 Selected bond lengths (Å) and bond angles (°) S(1)-C(1) 1.732(6) N(1)-C (7) 1.385(6) N(2)-C(2) 1.388 (6) …”

“…苯并咪唑环蕃是 环蕃化学领域中新型的模拟酶模型, 一方面环蕃的环形 空腔具有疏水性, 另一方面苯并咪唑环上的氮原子具有 良好的反应活性, 可以通过氮原子的质子化、季胺化等 引入活性基团 [5] , 从而改善该类化合物的性质, 形成不 同包结性能的主体, 俘获不同种类的客体分子, 与客体 分子形成超分子体系, 实现酶功能模拟与分子识别 [6] .…”

Chiral Heterocycle-Based Receptors for Enantioselective Recognition

“…Xie et al [34] synthesized the chiral imidazole containing cyclophanes, 149-152 by highly selective N-alkylation of the imidazolyl 1N-position of 148 with the corresponding dibromides (Scheme 26).…”

“…The present review article presents a detailed account of the recent developments in the design and synthesis of various chiral receptors with heterocyclic motif such as pyridine [18], chromene [32,33], imidazole [34], benzimidazole [35,36], furan [37], thiophene [38], oxazole [22][23][24][25] etc. and its application in the enantioselective recognition of different classes of chiral analytes [39,40].…”

Facile Synthesis of Optically Active Imidazole Derivatives

“…The application of imidazoles in medicinal chemistry [4] or chemistry of natural products/alkaloids [5][6] or of 1,3-disubstituted imidazole salts as ionic liquids [7][8] are also well known. Although a few examples of the synthesis and applications of optically active imidazole derivatives have been published [9][10][11][12][13], development of an efficient synthesis of such derivatives still requires more attention. Recently, we have published the synthesis and application of enantiopure 2-phenylimidazoles starting from the commercially available α-amino acids as a source of chirality [14][15].…”