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A New Synthetic Approach toward Ring-Expanded ("Fat") Purine Nucleobases: Synthesis and Use of 5-Dichloromethyl-1-p-methoxybenzyl-4-nitroimidazole as a Versatile Intermediate.
Published: 01 November 1999 by MDPI in The 3rd International Electronic Conference on Synthetic Organic Chemistry session General Organic Synthesis
Abstract: ing expanded ("fat") purine nucleosides are of chemical, biochemical, biophysical, and medicinal interest.1-12 The majority of "fat" nucleosides reported from this laboratory in recent yeas were synthesized using the common imidazole precursor, namely 1-benzyl-5-nitro-imidazole- 4-carboxylic acid (I).5-11 However, the synthesis of I suffered from a number of drawbacks, including multi-step procedures, prolonged reaction periods (sometimes days), poor yields, tedious work-ups, and the necessity of separation of regioisomers, all of which contributed to the difficulty in preparing I on a reasonably large scale. We present here an efficient, convenient, and a versatile alternative for I in 5-dichloromethyl-1-p-methoxybenzyl -4-nitroimidazole (II). The latter has a number of novel features which will potentially not only enable the efficient resynthesis of the previously reported "fat" nucleosides from this laboratory, but will also open new ways for the synthesis of a wide variety of novel "fat" nucleosides that would otherwise be difficult to prepare using I. The novel features of II include (a) the presence of a versatile, highly reactive dichloromethyl functional group which can serve as the site of both nucleophilic and electrophilic attacks for further annulation of the appropriate side chain , (b) the potentially facile conversion of the above dichloromethyl group into a wide variety of other reactive functional groups including, but not limited to, a carboxylic acid, a carboxaldehyde, or an iminomethylene functionality, and (c) the attachment of the more conveniently removable p-methoxybenzyl protecting group at the 1-position as compared to the unsubstituted benzyl group of I. In addition, the synthesis of II is brief, convenient, reasonably good-yielding, and can be prepared on a reasonably large scale from readily available and inexpensive starting materials.