Heck and Sonogashira couplings in aqueous media – application to unprotected nucleosides and nucleotides
© Herve and Len; licensee Springer. 2016
Received: 7 October 2014
Accepted: 13 February 2015
Published: 19 March 2015
Amongst all synthetic nucleosides having high potential biological activities, C5-modified pyrimidines and C7-deaza or C8-modified purines have been particularly studied. These main chemical modifications have been developed using palladium cross-coupling reactions. This review focus on both Heck and Sonogashira cross-coupling of nucleosides using different aspects of the twelve principles of green chemistry: use of aqueous medium and no protection/deprotection steps.
Nucleoside analogues having modifications of the glycone moiety [1-3] (eg AZT ) and/or the nucleobase [5-7] (eg BVDU [8,9]) are of great biological importance due to their high effectiveness as antiviral and antitumor agents. Among all the potent modifications, introduction of aryl, polyaryl, heteroaryl, heteropolyaryl, alkenyl and alkynyl groups on either the pyrimidine or the purine moiety via C-C cross-coupling was described for the study of biological environments such as DNA and RNA structural probes, protein–DNA complexes, DNA damage, mutation and cancers [10,11]. The most efficient C-C cross-coupling strategies are the palladium-catalyzed reactions such as (i) Suzuki–Miyaura, Stille, Negishi and Hiyama reactions for the formation of aromatic C sp2 – C sp2; (ii) Heck reaction for the formation of vinyl derivatives and (iii) Sonogashira reaction for the formation of acetylenyl derivatives. These cross-coupling reactions were realized most often in organic solvents with protected nucleoside analogues. In order to use safer solvents and auxiliaries, to limit the risks and hazards, different groups have reported recently those cross-couplings in greener solvents such as water without the need for protection and deprotection steps. Since recent developments and a complete review on Suzuki-Miyaura reaction applied to unprotected nucleosides were reported by our group [7,12-15], this paper will focused on the Heck reactions and Sonogashira reactions applied to unprotected nucleosides and nucleotides in aqueous media or water as sole solvent. For the sake of clarity, this review has been arranged to describe the Heck reaction and then the Sonogashira reaction. For each part, the different methodologies by varying the palladium source and nature with respect to Pd(0) and Pd(II), the nature of the base will be discussed.
Heck cross-coupling reaction in aqueous solution was developed using only Pd(II) as a pre-catalyst in water and in CH3CN/H2O.
Pd(II)-catalyzed Heck cross-coupling in CH3CN/H2O
Coupling of nucleoside analogue 1 with butyl acrylate (4) in the absence of ligand gave the target product 7 in 64% yield, while a higher yield (74%) was achieved when TPPTS (10 mol%) was used (Table 1, entries 1 and 2). Cyclohexenone (5) and styrene (6) were coupled with iodo derivative 1, under ligand free conditions, to afford 8 and 9 in 72% and 82% yields, respectively (Table 1, entries 3 and 5). These yields were similar to those achieved when TPPTS (10 mol%) was used (Table 1, entries 4 and 6). Aromatic styrene (6) gave higher yields than those obtained with alkenes 4 and 5. Based on these results, Heck couplings of 5-bromo-2’-deoxyuridine as pyrimidine analogue, 8-bromo-2’-deoxyguanosine and 8-bromo-2’-deoxyadenosine as purine analogues were explored but without success.
Synthesis of butyl acrylate uridine and cytosine analogues 7, 15-19
Pd(II)-catalyzed Heck cross-coupling in H2O
In 2014, for the first time, Len et al. reported a palladium catalyzed Heck cross-coupling reaction between 5-iodo-2ʹ-deoxyuridine and various acrylate derivatives using ligand-free conditions and assisted-microwaves in pure water . Those new conditions allowed a totally aqueous access to antiviral BVDU. Heck cross-coupling of 5-iodo-2ʹ-deoxyuridine (1) with various acrylate derivatives was carried out using Pd(OAc)2 (10 mol%) alone in presence of Et3N (2 eq) as base in H2O as solvent at 80°C.
Sonogashira cross-coupling reaction in aqueous solution was developed using both Pd(0) as catalyst in water or in CH3CN/H2O and Pd(II) as a pre-catalyst only in CH3CN/H2O.
Pd(0)-catalyzed Sonogashira cross-coupling in CH3CN/H2O
In 1990, Casalnuovo et al. undertook the Sonogashira coupling of unprotected nucleosides and nucleotides with acetylene derivatives . Reactions were conducted in a mixture of CH3CN/H2O (various proportion) as solvent using a self-made water-soluble Pd(0) complex (10 to 20 mol%): Pd(PPh2(m-C6H4SO3M))3 (M = Na+, K+) (10 to 20 mol%) in presence of CuI (0.2 eq to 0.5 eq) and NEt3 (2 eq to 10 eq).
Pd(0)-catalyzed Sonogashira cross-coupling in H2O
Pd(II)-catalyzed Sonogashira cross-coupling in CH3CN/H2O
The expected bicyclic products 104–110 were isolated in moderate to good yields (33-57%) with alkynes substituted with electron-rich aryl core (Table 11, entries 2–4). Concerning alkynes substituted with electron-poor aryl moiety, only one product was obtained (Table 11, entry 5). The bicyclic scaffold has already been observed before, but only as a by-product .
The principal objective of this review was to describe the Heck and Sonogashira couplings of nucleosides in accordance with the 12 principles of green chemistry. To date, the majority of the works involved the synthesis (i) of alkenes in 5-position of pyrimidines and 7-position of 7-deazapurines and (ii) of alkynes in position 5 of pyrimidines, in position 7 of 7- deazapurines and in position 8 position of purines. The usual starting materials used were 5-iodo, 7- and 8-bromo analogues. The review encompasses variations of the starting materials, alkene and alkyne, nature of the solvent, palladium source and ligand at either room temperature or higher temperature.
Concerning the Heck cross-couplings, only palladium Pd(II) such as Na2PdCl4 (80 mol%) and Pd(OAc)2 (5–10 mol%) was used. Most of the reactions were realized in presence of TPPTS as ligand in a mixture of CH3CN/H2O and in sole water. Using these procedures, the yields were low to good (4-98%). It is noteworthy that recent results of Len’s group starting from 5-iodo-2’-deoxyuridine furnished, in pure water, in presence of Pd(OAc)2 (10 mol%) and NEt3 without any ligand at 80°C under microwave irradiation the heterocyclic targets in 35-90% yields.
Concerning the Sonogashira cross-couplings, the reported procedures were similar (alkyne, NEt3, CuI) excepted for the nature of the palladium (Pd(0) and Pd(II)) and the nature of the solvent (CH3CN/H2O and sole water). Pd(0) was used in aqueous media or in pure water while Pd(II) was used only in a mixture of CH3CN/H2O. The yields of the target nucleoside analogues were comprised between 16-98%. It is noteworthy that nucleotide analogues having either mono- and triphosphate as starting material afforded the corresponding cross-coupling adducts in presence of Pd(0) in water or in presence of Pd(II) in CH3CN/H2O.
In the future, the Heck and Sonogashira cross-coupling reactions of nucleoside analogues, in ligand-free conditions, as reported by Len with recycling of the catalytic system will open a new avenue for the green chemistry applied to heterocyclic chemistry.
- Lebreton J, Escudier JM, Arzel L, Len C. Synthesis of bicyclonucleosides having a C-C bridge. Chem Rev. 2010;110:3371–418.View ArticleGoogle Scholar
- Len C, Mondon M, Lebreton J. Synthesis of cyclonucleosides having a C-C bridge. Tetrahedron. 2008;64:7453–75.View ArticleGoogle Scholar
- Len C, Mackenzie G. Synthesis of 2’,3’-didehydro-2’,3’-dideoxynucleosides having variations at either or both of the 2’- and 3’-positions. Tetrahedron. 2006;62:9085–107.View ArticleGoogle Scholar
- Wright K. AIDS Therapy. First tentative signs of therapeutic promise. Nature. 1986;323:283.Google Scholar
- Agrofoglio LA, Gillaizeau I, Saito Y. Palladium-assisted routes to nucleosides. Chem Rev. 2003;103:1875–916.View ArticleGoogle Scholar
- Fairlamb IJS. Regioselective functionalisation of unsaturated halogenated nitrogen, oxygen and sulfur heterocycles by Pd-catalysed cross-coupling and direct arylation processes. Chem Soc Rev. 2007;36:1036–45.View ArticleGoogle Scholar
- Hervé G, Sartori G, Enderlin G, Mackenzie G, Len C. Palladium-catalyzed Suzuki reaction in acqueous solvents applied to unprotected nucleosides and nucleotides. RSC Adv. 2014;4:18558–94.View ArticleGoogle Scholar
- De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS, Walker RT. (E)-5-(2- Bromovinyl)-2’-deoxyuridine: A potent and selective anti-herpes agent. Proc Natl Acad Sci U S A. 1979;76:2947–51.View ArticleGoogle Scholar
- Ashwell M, Jones AS, Kumar A, Sayers JR, Walker RT, Sakuma T, et al. The synthesis and antiviral properties of (E)-5- (2-bromovinyl)-2’-deoxyuridine-related compounds. Tetrahedron. 1987;43:4601–8.View ArticleGoogle Scholar
- Kuwahara M, Sugimoto N. Molecular evolution of functional nucleic acids with chemical modifications. Molecules. 2010;15:5423–44.View ArticleGoogle Scholar
- Hollenstein M. Nucleoside triphosphates – Building blocks for the modification of nucleic acids. Molecules. 2012;17:16569–3591.View ArticleGoogle Scholar
- Sartori G, Enderlin G, Hervé G, Len C. Highly effective synthesis of C-5-substituted 2’-deoxyuridine using Suzuki-Miyaura cross-coupling in water. Synthesis. 2012;44:767–72.View ArticleGoogle Scholar
- Sartori G, Hervé G, Enderlin G, Len C. New efficient approach of ligand-free Suzuki-Miyaura reaction applied to 5-iodo-2’-deoxyuridine in neat water. Synthesis. 2013;45:330–3.View ArticleGoogle Scholar
- Gallagher-Duval S, Hervé G, Sartori G, Enderlin G, Len C. Improved microwave-assisted ligand-free Suzuki-Miyaura cross-coupling of 5-iodo-2’-deoxyuridine in pure water. New J Chem. 2013;37:1989–95.View ArticleGoogle Scholar
- Enderlin G, Sartori G, Hervé G, Len C. Synthesis of 6-aryluridines via Suzuki-Miyaura cross-coupling reaction at room temperature under aerobic ligand-free conditions in neat water. Tetrahedron Lett. 2013;54:3374–7.View ArticleGoogle Scholar
- Sakthivel K, Barbas III CF. Expanding the potential of DNA for binding and catalysis: Highly Functionalized dUTP Derivatives that are substrates for thermostable DNA polymerase. Angew Chem Int Ed. 1998;37:2872–5.View ArticleGoogle Scholar
- Lee SE, Sidorov A, Gourlain T, Mignet N, Thorpe SJ, Brazier JA, et al. Enhancing the catalytic repertoire of nucleic acids: a systematic study of linker length and rigidity. Nucleic Acids Res. 2001;29:1565–73.View ArticleGoogle Scholar
- Cho JH, Shaughnessy KH. Aqueous-phase Heck couplings of 5-iodouridine and alkenes under phosphine-free conditions. Synlett. 2011;20:2963–6.Google Scholar
- Dadová J, Vidláková P, Pohl R, Havran L, Fojta M, Hocek M. Aqueous Heck cross-coupling preparation of acrylate-modified nucleotides ans nucleoside triphosphates for polymerase synthesis of acrylate-labeled DNA. J Org Chem. 2013;78:9627–37.View ArticleGoogle Scholar
- Hervé G, Len C. First ligand-free, microwaves-assisted, Heck cross-coupling reaction in sole water on nucleoside - Application to the synthesis of antiviral BVDU. RSC Adv. 2014;4:46926–9.View ArticleGoogle Scholar
- Casalnuovo AL, Calabrese JC. Palladium-catalyzed alkylynations in aqueous media. J Am Chem Soc. 1990;112:4324–30.View ArticleGoogle Scholar
- Thoresen LH, Jiao GS, Haaland WC, Metzker ML. Rigid, conjugated, fluoresceinated thymidine triphosphates: syntheses and polymerase mediated incorporation into DNA analogues. Chem Eur J. 2003;9:4603–10.View ArticleGoogle Scholar
- Bong DT, Ghadiri MR. Chemoselective Pd(0)-catalyzed peptide coupling in water. Org Lett. 2011;16:2509–11.Google Scholar
- Vrábel M, Pohl R, Klepetářvá B, Votruba I, Hocek M. Synthesis of 2’-deoxyadenosine nucleosides bearing bipyridine-type ligands and their Ru-complexes in position 8 trough cross-coupling reactions. Org Biomol Chem. 2007;5:2849–57.View ArticleGoogle Scholar
- Brázdilová P, Vrábel M, Pohl R, Pivoňková H, Havran L, Hocek M, et al. Ferrocenylethynyl derivatives of nucleosides triphosphates: synthesis, incorporation, electrochemistry, and bioanalytical applications. Chem Eur J. 2007;13:9527–33.View ArticleGoogle Scholar
- Čapek P, Cahová H, Pohl R, Hocek M, Gloeckner C, Marx A. An efficient method for the construction of functionalized DNA bearing amino acid group through cross-coupling reactions of nucleoside triphophates followed by primer extension or PCR. Chem Eur J. 2007;13:6196–203.View ArticleGoogle Scholar
- Vrábel M, Pohl R, Votruba I, Sajadi M, Kovalenko SA, Ernsting NP, et al. Synthesis and photophysical properties of 7-deaaza-2’-deoxyadenosines bearing bupyridine ligands and their Ru(II)-complexes in position 7. Org Biomol Chem. 2008;6:2852–60.View ArticleGoogle Scholar
- Kalachova L, Pohl R, Hocek M. Synthesis of 2’-deoxyuridine and 2’-deoxycytidine nucleosides bearing bipyridine and terpyridine ligands at position 5. Synthesis. 2009;1:105–12.Google Scholar
- Cho JH, Prickett CD, Shaughnessy KH. Efficient Sonogashira coupling of unprotected halonucleosides in aqueous solvents using water-soluble palladium catalysts. Eur J Org Chem. 2010;19:3678–83.View ArticleGoogle Scholar
- Fresneau N, Hiebel MA, Agrofoglio LA, Berteina-Raboin S. One-pot Sonogashira-cyclization protocol to obtain substituted furopyrimidine nucleosides in aqueous conditions. Tetrahedron Lett. 2012;53:1760–3.View ArticleGoogle Scholar
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