Efficient Synthesis of trans- or cis-4(5)-(5-Aminomethyltetrahydrofuran-2-yl)imidazoles via Diazafulvene Intermediates: Synthetic Approach toward Human Histamine H4-Ligands

Abstract

Histamine H 4 (H 4 )-receptor is the most recently discovered histamine receptor which has approximately 35% overall homology to the human histamine H 3 (H 3 )-receptor.1-7) However, the tissue distribution of the two receptors is quite different. The H 3 -receptor is mainly found in the central nervous system, whereas the mRNA of the H 4 -receptor is expressed exclusively in peripheral tissues, such as bone marrow, 1,4) small intestine, 1,6,7) spleen, 4,6,7) and leukocytes.7) The physiological and pathophysiological functions of the receptor are unknown. However, the abundant expression of human H 4 -receptor mRNA in the hematopoietic and lymphatic tissues indicates that the receptor might be related to regulation of hematopoiesis and/or an immune function. To investigate the pharmacology of the receptor, specific ligands are indispensable, but most H 3 -ligands are active at the H 4 -receptor as well and no specific ligands for the H 4 -receptor are available. 8)We very recently examined the binding affinity and functional activity of 2,5-disubstituted tetrahydrofuranylimidazoles for human H 3 -and H 4 -receptors expressed in SK-N-MC cells.10,11) exhibited potent agonistic activities for the H 3 -receptor, while its enantiomer (Ϫ)-1 was found to be a selective H 3 -agonist, which was approximately 300-fold more active at the H 3 -receptor than the H 4 -receptor (Fig. 1). It is of particular interest to find that methylcyanoguanidine derivatives (Ϫ)-3 (OUP-16) and (ϩ)-4 (OUP-13) exhibited full agonistic activities for the H 4 -receptor with 40-to 45-fold selectivity over the H 3 -receptor. Hence, the two OUP compounds would be lead compounds to develop selective human H 4 -receptor ligands. 8)We previously reported a stereodivergent synthesis of trans-or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl-or 5-aminomethyl-2,5-dihydrofuranyl)imidazoles, which is characterized by use of a-or b-phenylselenenyl nucleosides 7 or 8 as key intermediates (Fig. 1).10-12) Although the synthetic strategy was effective as an initial step for accessing these compounds, it lacks the stereoselective formation of 7 or 8 and, further, requires phenylselenenylation and deselenenylation steps in the synthetic sequence. On the other hand, we reported an efficient and stereoselective synthesis of b-imidazole C-nucleosides bearing 4(5)-substituted imidazole as a Sciences; 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan: b R&D Division, AZWELL, Inc.; 2-24-3, Sho, Ibaraki, Osaka 567-0806, Japan: and c Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University; 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan. Received March 17, 2003; accepted

Metalated Heterocycles in Organic Synthesis: Recent Applications

“…Frequently, this metalation-blockage at C-2 is produced by an easily removable trialkylsilyl group, the formed 5-lithiated imidazole thus being suitable as nucleophile, for instance, in addition reactions to aldehydes 66 or ring-opening of lactones. 67 Isoxazoles can not be lithiated at C-5 by deprotonation with alkyllithiums, as the resulting anion suffers fragmentation to benzonitrile and ethynolate ion or enaminones, depending on the alkyllithium and the substituents present on the ring. 68 When the 5-position is blocked, lithiation of the ring is possible, as in the case of the treatment of 3,5-disubstituted isoxazole 19 with nbutyllithium generating 4-isoxazolyllithium species 20, which added to amino acrylate 21 in a Michael fashion affording trisubstituted isoxazole 22 in the search of agonists at AMPA receptors (Scheme 7).…”

Development of New Synthetic Reactions Using Hetero-Heavy Atoms and Their Application to Synthesis of Biofunctional Molecules

“…[70][71][72] We thus directed our attention to synthesizing 4(5)-(β-D-ribofuranosyl) imidazole (127) having the imidazole in place of nucleo-base, as shown in Chart 34. 75,76) The The stereoselective synthetic method of C-nucleosides via diazafulvene intermediates was further applied to synthesis of various C-nucleosides: β-ribofuranosylimidazoles exhibiting antiulcer activity 77) ; α-L-arabinofuranosylimidazoles 78) ; tetrahydrofuranylimidazoles 79,80) ; α-D-xylofuranosylimidazoles 81) ; trans-or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl) imidazoles for histamine H 4 -ligands 82) ; and pyrazole C-nucleosides. 83) 6.…”

“…110) In relation to the development of selective H 4 R ligands, improved synthesis of imifuramine and its derivatives was achieved via cyclization of a diazafulvene intermediate generated by Bu 3 P/TMAD treatment of a diol intermediate. 82) 7.3. Development of Novel H 3 R Antagonists OUP-133 and 153 The (2R,5S)-trans-and (2S,5S)-cis-stereoisomers 174a and 174b of 4(5)-(5-aminotetrahydropyanyl-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were efficiently synthesized via cyclization of diol intermediate 170 using L-glutamine as starting material, as shown in Chart 41.…”