C-Nucleosides: Synthetic Strategies and Biological Applications

Abstract

Introduction 6729 2. C-Nucleosides in Chemical Biology 6730 2.1. Extension of the Genetic Alphabet 6730 2.1.1. Artificial Base-Pairs Based on Hydrogen Bonding 6731 2.1.2. Artificial Base-Pairs Based on Hydrophobic Interactions 6733 2.1.3. Artificial Base-Pairs Based on Metal Bridges 6735 2.1.4. Conclusions and Outlook of Artificial Base-Pairs 6736 2.2. Other Applications in Chemical Biology 6736 3. Medicinal Chemistry of C-Nucleosides 6736 3.1. Natural C-Nucleosides 6736 3.2. Mechanism-Based Biologically Active C-Nucleosides 6737 3.2.1. Inhibitors of Nucleolytic Enzymes 6737 3.2.2. Inhibitors of Oxidoreductases 6738 3.2.3. Conclusions and Outlook in Medicinal Chemistry 6738 4. Synthesis of C-Nucleosides 6738 4.1. Construction of an Aglycon Unit upon a Carbohydrate Moiety 6738 4.1.1. Introduction of the Nitrile Group and its Heterocyclizations 6738 4.1.2. Wittig-Type Reactions 6740 4.1.3. Cycloadditions 6741 4.1.4. Other Methods for the Construction of the Aglycon Unit 6744 4.2. Construction of a Carbohydrate Moiety upon an Aglycon Unit 6744 4.3. Direct Coupling of a Carbohydrate Moiety with a Preformed Aglycon Unit 6749 4.3.1. Nucleophilic Addition to the Aldehyde Function of a Carbohydrate 6749 4.3.2. Nucleophilic Addition to 1,2-Anhydrofuranoses 6750 4.3.3. Couplings of Nucleophiles with Halogenoses 6750 4.3.4. Nucleophilic Addition to Furanolactones 6751 4.3.5. Heck Coupling 6752 4.3.6. Lewis Acids-Mediated Electrophilic Substitutions 6753 4.4. Modification of the Existing C-Nucleosides 6754 4.5. Modular Approaches 6757 5. Conclusions 6759 6. Acknowledgments 6759 7. References 6759

Efficient synthesis of fluorescent alkynyl C-nucleosides via Sonogashira coupling for the preparation of DNA-based polyfluorophores

“…The ethynyl functionalized deoxyribose derivative 8 , which served as a central building block for the synthesis of all fluorophore- C -nucleosides, 36, 37 was prepared by following previously reported procedures (Scheme 1). 38–41 The α-anomer 8 is readily available on multi-gram scale as the major isomer from inexpensive 2-deoxy-D-ribose ( 1 ) through a 7 step procedure.…”

Synthesis of 2′-Deoxy-9-deaza Nucleosides Using Heck Methodology

“…7,9,27–29 To our delight, the use of Pd(OAc) 2 increased the yield to 76%, which is a dramatic improvement. It should be noted that the combination of Pd(OAc) 2 and tetrabutylammonium chloride (TBAC) for use in Heck coupling is also known as Jeffery conditions.…”

“…5–9 In addition to imparting resistance to hydrolytic and enzymatic cleavage resulting from the more stable carbon–carbon glycosidic bond, 7,9,10 this change also results in altering H-bond accepting N7 to NH, an H-bond donor, for 2′-deoxy-9-deaza nucleosides such as 1 and 2 (Figure 1). This allows these compounds to engage in alternative hydrogen-bonding patterns such as Hoogsteen base pairing, which may find use in complex oligonucleotide structures or in the investigation of polymerases.…”

“…It should be noted that triphenylarsine (AsPh 3 ) was utilized instead of the more standard triphenylphospine (PPh 3 ) because of its intrinsically higher nucleophilicity. 8,9,21 Although the reactions using Pd 2 dba 3 ·CHCl 3 turned black, which is typical of palladium-catalyzed reactions, 8 and 7 and 10 were successfully coupled to give a stable and isolatable enol-ether intermediate 18 , the yields remained consistently low at only 10–17% even with the addition of more portions of catalyst. Although we considered that the nitrogens might be interfering, because products were forming, albeit in low yields, a more effective catalyst was sought.…”

Expanding a fluorescent RNA alphabet: synthesis, photophysics and utility of isothiazole-derived purine nucleoside surrogates

“…4 From a synthetic perspective, the construction of purine-like isomorphic nucleoside mimics, particularly C-nucleoside analogues, presents formidable difficulties in linking the heterocycle to the ribose moiety. 5 From a photophysical viewpoint, the unpredictable nature of fluorescent molecules, particularly within the context of nucleic acids, propagates a trial and error approach. 6 Taken together, the compounded challenges have resulted in very few analogues which are truly isomorphic and isofunctional.…”