Facile Cu-free Sonogashira cross-coupling of nucleoside C-6 arylsulfonates with terminal alkynes
Graphical abstract
Introduction
The acetylenic moiety is commonly found in a number of natural products and biologically active molecules.1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i) Once incorporated in organic molecules, the acetylenic core can serve as important synthetic intermediates because alkynes can undergo a wide variety of reactions. As a result, this has prompted interest in the design of efficient synthetic methods for the incorporation of the acetylenic unit in organic molecules. One such method for the incorporation of the acetylenic unit in organic molecules is the Sonogashira cross-coupling method.2, 2(a), 2(b), 2(c), 2(d), 2(e) In recent years, the Sonogashira reaction has undoubtedly become one of the most widely used reactions in organic synthesis for the formation of a C(sp)–C(sp2) bond. In the original Sonogashira cross-coupling reaction, a terminal alkyne is coupled with an aryl or vinyl halide or triflate, using a palladium catalyst and a Cu(I) salt as co-catalyst.3, 3(a), 3(b), 3(c), 3(d) Various modifications of the original Sonogashira cross-coupling reaction have been reported in the past decade.4, 5, 6, 7, 8, 9, 10, 10(a), 10(b), 10(c), 10(d), 10(e), 10(f), 11, 12, 12(a), 12(b), 12(c), 13, 14, 15
The modification of nucleosides continues to be an important area in organic research due to the wide variety of applications that modified nucleosides possess and the biological importance of nucleosides in general. For example, modified nucleosides have been shown to act as enzyme inhibitors and antagonists, and have the potential to be lowly toxic, yet effective as antiviral and anticancer agents.16, 17 Modified nucleoside analogs, substituted at the C-6 position, have been reported to possess a wide range of biological activities.18, 19, 20, 21, 22 The alkynylation of nucleosides by the Sonogashira cross-coupling reaction is well documented in the literature.15, 21, 23, 24, 25, 26 However, most of the successful Sonogashira cross-coupling alkynylation of nucleosides, reported thus far, have involved the use of halopurine nucleosides as electrophiles reacting with terminal alkynes.
An important modification of the Sonogashira cross-coupling reaction we have been exploring in our lab, for the synthesis of modified nucleosides, is the Cu-free method.15 The use of copper is sometimes limited by the formation of insoluble copper acetylides, which are potentially explosive. In addition, Buchwald and co-workers reported the potential oligomerization of the alkyne starting material when using a copper co-catalyst in the conventional Sonogashira cross-coupling method.4 Historically, the identity of the group being displaced in a Sonogashira-type cross-coupling has been a halide. However, examples have been cited in the literature in which the halogen has been replaced with a sulfonate as the leaving group in the synthesis of modified nucleosides. For example, the facile displacement of a sulfonate on the C-6 position of nucleosides by oxygen and nitrogen nucleophiles has been reported.27 An analogous Suzuki-type cross-coupling has been developed in which nucleoside arylsulfonates were reacted with arylboronic acids to create a new C–C bond at the C-6 position of 2′-deoxyguanosine.28
The use of tosylates as the leaving group in a Sonogashira-type cross-coupling, especially in the coupling of non-nucleosidic aromatic compounds with terminal acetylenes, has been reported.4, 29 A Cu-free Pd-catalyzed cross-coupling of vinyl tosylates with terminal acetylenes has been reported by Fu and co-workers.29 Similarly, Gelman and co-workers reported the first Sonogashira-type cross-coupling of aryl tosylates with terminal alkynes under Cu-free conditions.4 However, to the best of our knowledge, there has been no literature precedence on the displacement of sulfonates in general, and tosylates in particular, on nucleosides using terminal alkynes through a Sonogashira-type cross-coupling.
To add to the current state of knowledge in the field, our group has been particularly interested in investigating the development of efficient methods to synthesize C-6-alkynyl-substituted nucleosides. As a part of our ongoing interest in transition metal-mediated syntheses of modified nucleosides,30 we recently reported a modified Sonogashira-type cross-coupling in the C-6-alkynylation of protected 2′-deoxyadenosine.15 Therefore, in this work, we set out to evaluate both the conventional Sonogashira cross-coupling method and the modified versions, in the coupling of protected 2′-deoxyguanosine sulfonates with terminal acetylenes, toward the synthesis of C-6-alkynylated deoxynucleosides. Herein, we report our initial results that show a convenient Sonogashira-type cross-coupling of protected 2′-deoxyguanosine sulfonates with terminal acetylenes to afford C-6-alkynyl-substituted nucleosides.
Section snippets
Results and discussion
Our synthetic strategy toward the C-6-alkynylated deoxyribonucleoside derivatives involved a Sonogashira-type cross-coupling of protected 2′-deoxyguanosine sulfonates with terminal acetylenes. Initial attempts to sulfonate the unprotected 2′-deoxyguanosine resulted in a complex mixture of products probably due to the reactivity of the polar hydroxyl groups with the sulfonyl chloride. We then decided to protect the hydroxyl groups prior to sulfonation. In order to obtain the deoxyribonucleoside
Conclusion
In summary, we have developed a Cu-free Sonogashira-type cross-coupling of terminal acetylenes of varying functionality with the O6-arylsulfonyl derivative of 2′-deoxyguanosine. The reactions generally proceed to completion within 24 h, afford moderate to good yields, and are tolerant to different functional groups. Efforts are underway to optimize the reaction conditions further and expand the scope to incorporate other nucleosides and terminal acetylenes.
General methods
All reactions were carried out in oven-dried glassware under a nitrogen atmosphere. All the reagents were obtained from commercial sources and were used without further purification. Thin-layer chromatography was performed on silica gel plates containing fluorescent indicator. Column chromatographic separation was performed using 230–400 mesh silica gel. 1H NMR spectra (300 MHz) and 13C data (75 MHz) were obtained in CDCl3 or DMSO-d6. Coupling constants (J) are reported in Hertz (Hz). The sugar
Acknowledgements
We acknowledge the generosity of the Chemistry Department at GVSU through the use of its instrumentation facilities. We also thank the Chemistry Department for providing financial support through the Weldon Fund.
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