C-Nucleosides belong to the category of nucleoside derivatives in which the ribofuranosyl moiety is linked to the heterocyclic base with a carbon-carbon bond, in contrast to the abundant naturally occurring N-nucleosides with a carbon-nitrogen bond. N-nucleosides are the major components in nucleic acids and also play a wide range of important roles in many biological processes essential to life. A handful of naturally occurring C-nucleosides have been found in nature and identified to possess a wide variety of biological activities. C-Nucleosides remain the structural features of the N-nucleoside congeners, but the nucleosidic C-C bond is resistant to non-enzymatic hydrolysis and enzymatic degradation, which provide substantial stabilities under physiological condition. Moreover, replacement of the nitrogen with carbon alters the π-electron distribution on the heterocyclic bases, which changes the acid-base properties, hydrogen-bond capabilities, as well as the π-π stacking interactions. By virtue of the structural resemblances, C-nucleoside analogs become a straightforward bioisosteric substitution of biological active N-nucleosides and received significant attentions. However, the chemical synthesis of C-nucleosides continues to be challenging and the development of efficient synthesis for C-nucleosides still remains an ongoing task. Owing to a wide range of biological and medicinal interests, we would like to initiate a study to investigate the stereoselective synthesis of C-nucleosides. The objective of this proposal is to explore generally applicable approaches and potentially new strategies for the stereoselective C-glycosylation of pentofuranose derivatives. Theoretically, direct condensation of a carbohydrate and a heterocycle to form the nucleosidic bond should offer a shorter route toward the target C-nucleosides. The inherent problem is that this approach usually results in a mixture of different regioisomers and stereoisomers, which tremendously restricts the reaction scale and limited the product scopes as well as synthetic practicalities. In this proposal, we will start with the evaluation of an intramolecular strategy for the nucleosidic bond formation to control the stereochemistry and enhance the reactivities for C-glycosylation. The synthetic strategy will utilize the β-hydroxyl groups on the pentofuranosides as guiding groups for stereospecific C-glycosylation reaction. Thus, the aglycones will be installed onto the sugar precursors with covalent linkages bonded to theβ-hydroxyl groups of the sugars. Subsequently, the aglycones are anticipated to react with the sugar acceptors intramolecularly with designated regio- and stereo-selectivity to afford the desired carbon-carbon nucleosidic bond. We have completed preliminary studies to demonstrate the feasibility of this proposal. The intramolecular strategy is compatible with conventional intermolecular synthetic methodologies and has the potential to provide a collective library of natural and synthetic C-nucleoside derivatives for further biological evaluation.
|Effective start/end date||2018/08/01 → 2020/03/31|
- Heck reaction
- Friedel-Crafts reaction
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