Novel synthon for incorporating 1,3-dimethyl-imidazolium group into molecular architecture

Abstract

The synthesized 1,3-dimethylated imidazolium carbaldehydes serves as synthons for incorporating a permanently cationic imidazolium group into molecular framework. The utility of new synthon was demonstrated in a variety of reactions: Knoevenagel, Wittig, Schiff base formation, based mediated electrophilic substitution and oxidation, including synthesis of the natural product norzooanemonin.Imidazole is an important functionality in biological systems and 5-imidazole-carbaldehydes, including their mono-N-methylated analogs are often used as building blocks in medicinal chemistry. Because methylation is the major histamine catabolic pathway in mammalian tissues, mono-N-methylated imidazole derivatives are commonly found in imidazole metabolites. Beside natural occurrence, other compounds bearing this group have been widely studied due to their anticancer, 1 antimalarial, 2 antibacterial, 3 antifungal, 4 and ocular antihypertensive 5 properties. In addition, several drugs and drug candidates (pilocarpine, tipifarnib) that incorporate N-methyl imidazoles have been developed. These findings have been facilitated by the commercial availability of suitable synthons such as 1-methyl-1H-imidazole-5-carbaldehyde for inclusion in SAR studies.Although rare, di-N-methylated imidazolium occurs in natural compounds. Some examples include 1,3-dimethylhistidine, zooanemonin, 6 norzooanemonin, methyl ester of norzooanemonin, (+)-echinobetaine B, 7 Chrysophysarin A, 8 and the insect peptide extracted from Heliothis virescens 9 (Fig. 1). These compounds have some promising biological properties such as antiviral, 9 nematocidal, and antifouling 10 activities. Biologically, 1,3-dimethylimidazolium group is metabolically stable. For example, the methyl groups in 1,3-dimethylhistidine-1,3-(C 14 H 3 ) 2 were not eliminated in a variety of animals studies. 11 Considering the potential usefulness of imidazolium-containing compounds, the availability of a suitable building block for its incorporation into diverse molecules would add an important functionality to a variety of compound libraries.Unfortunately, 1,3-dimethyl-5-imidazolium-carbaldehyde suitable for facile incorporation of di-N-methylated imidazolium is unknown. With a few exceptions that include their use as protective agents against chemical weapons (soman), 12 non-natural basic amino acidcontaining peptides, 13 and antibacterial compounds 3 , the literature is sparse on the use of dimethylated imidazolium-containing molecules in biological applications. There are number of synthetic 14 and enzymatic 15 methods available for methylation of imidazoles. The most E-mail: achilefus@mir.wustl.edu Fax : +1 314-747-5191, Tel : +1 314-362-8599 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please ...

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