S. Mukarram, H. Chavan, I. Khan
Oct 1, 2011
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Indian journal of applied research
Abstract
A practical and efficient protocol is described for the synthesis of ethyl-3-[(4R)-2,2-dimethyl-1,3-dioxolan4-yl]-2,2-difluoro-3-hydroxypropanoate (2), which is an important intermediate for the preparation gemcitabine hydrochloride. Literature survey reveals that this diastereomer exists with its other stereomer ethyl 3-[(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-difluoro-3-hydroxypropanoate in 3:1 ratio. Our observations on differences in physical properties of diastereomers lead us to purify and characterize this important diastereomer in high optical purity that could be readily adaptable on industrial scale. Introduction The drive towards higher levels of achievement in organic synthesis both in terms of methodology and complexity of target remains unabated. The science is driven by the continuous discovery of novel and complex structures from nature that fascinates and challenges synthetic organic chemists, while the need to improve our ability to synthesize organic molecules in more efficient and economic ways (1). Contemporary asymmetric synthesis is a widely used method for stereocontrolled creation of C-C bonds in organic molecules (2). During recent years, this approach to organic synthesis greatly contributed to progress in the directed introduction of various functionalities, and in the highly controlled formation of new centres of chirality. Preparation of the desired optical isomers by application of chiral starting materials is very advantageous, enabling precise planning and efficient realization of synthesis pathways (Chiron approach) (3). Many monosaccharides and their readily available derivatives are versatile substrates for the synthesis of optically active target molecules (4). Besides the great diversity and important structural array offered by these monosaccharides also poses a problem of separation of these structurally related isomers. These challenges trigger the creativity of a synthetic chemist to devise a process to separate the desired molecule with the correct stereochemistry. A typical mixture of ethyl-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-difluoro-3-hydroxypropanoate (2) and ethyl 3-[(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-difluoro3-hydroxypropanoate (3) is one of such problems; The separation of these diastreomers with high purity might be of advantage as it is characterized by (a) ready availability from natural sources, (b) by pronounced versatility due to the presence of the ester functionality, protected diol functionality, biologically more important difluoro functionality and a free hydroxyl group with defined stereochemistry for further functional group manuplations (Figure 1). O O