Synthesis of 4(5)-[5-(Aminomethyl)tetrahydrofuran-2-yl- or 5-(Aminomethyl)-2,5-dihydrofuran-2-yl]imidazoles by Efficient Use of a PhSe Group:  Application to Novel Histamine H₃-Ligands¹

Abstract

(+)-4(5)-[(2R,5S)-(5-Aminomethyl)tetrahydrofuran-2-yl]imidazole 1 and its C2‘ epimer (−)-2, which are the 5‘-amino derivatives of a novel imidazole C-nucleoside, were synthesized via β- and α-2‘-phenylselenenyl nucleosides 15 and 16. The anomers 15 and 16 were provided by a new synthetic method for C-nucleosides via the elimination of PhSeCl and selenocyclization from diol intermediates 12 and 14, starting from l-glutamic acid. Their ent-1 and ent-2 (imifuramine), the latter of which was indicated as a novel type of histamine H3-agonist confirmed by an in vivo brain microdialysis method, were synthesized by the same methodology from d-glutamic acid. The four isomers (3, 4, ent-3, and ent-4) of a 4(5)-[(5-aminomethyl)-2,5-dihydrofuran-2-yl]imidazole were also synthesized via the oxidative elimination of the PhSe group of the key intermediates (15, 16, ent-15, and ent-16). In connection with this study, 4(5)-(5-aminomethylfuran-2-yl)-1H-imidazole (5) was also synthesized starting from d-ribose.

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

“…Detritylation of 31 with Pd(OH) 2 -C in cyclohexene gave the desirable (Ϫ)-5 (57%) and 4-(5-hydroxymethyltetrahydrofuranyl)-imidazole 33 (37%), the latter of which could revert to 5 by N-ethoxycarbonylation. 12) In a similar manner, cis-isomer (Ϫ)-6 (63%) and 34 (25%) were obtained from 32.…”

“…The conversion of 5 or 6 into trans-1 or its cis-isomer 2 has already been described in our previous report. 12) Accordingly, the present method may become a more efficient stereodivergent synthetic route to the trans-and cis-amino compounds than the previous method using the PhSe group.…”

“…We recently reported that intramolecular Mitsunobu reaction of a diol 14ab 17) (1 : 1 diastereomeric mixture), which was prepared starting from (R)-benzyloxymethyl-g-butyrolactone (12), 18) with N,N,NЉ,NЉ-tetramethylazodicarboxamide (TMAD) 19) and Bu 3 P followed by desilylation affords trans-and cis-cyclization products 15 (47%, 9% ee) and 16 (53%, 20% ee) with low optical purities (Chart 2). The low optical purities were attributed to indistinguishable activities between two hydroxy groups of 14ab.…”

“…Debenzylation of 19ab using H 2 /Pd-C and subsequent Mitsunobu phthaloylimination afforded crude phthalimides. After chromatographic separation of the trans-isomer 21 contaminated by diethyl 1,2-hydrazine-dicarboxylate formed in the Mitsunobu reaction, deprotection of the crude 21 with hydrazine hydrate and purification yielded (ϩ)-1, imifuramine, 12) in 37% overall yield 21) from the diol intermediate 17ab. Similarly, cis-(Ϫ)-2 12) was obtained from crude 22 in 6% overall yield from 17ab.…”

“…After chromatographic separation of the trans-isomer 21 contaminated by diethyl 1,2-hydrazine-dicarboxylate formed in the Mitsunobu reaction, deprotection of the crude 21 with hydrazine hydrate and purification yielded (ϩ)-1, imifuramine, 12) in 37% overall yield 21) from the diol intermediate 17ab. Similarly, cis-(Ϫ)-2 12) was obtained from crude 22 in 6% overall yield from 17ab. This synthetic process allows the synthesis of the enantiomer (Ϫ)-1 by simply switching the starting material to (ϩ)-12.…”