Nucleoside and nucleotide analogues by catalyst free Huisgen nitrile oxide–alkyne1,3-dipolar cycloaddition

Algay, Virginie; Singh, Ishwar; Heaney, Frances

doi:10.1039/b917450h

Cited by 26 publications

(19 citation statements)

References 27 publications

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“…Steroidal glycoconjugate formation is demonstrated by the regioselective formation of 23 (85 %) by the reaction of putative nitrile oxide p-17 with protected d-galactose 22 as a model sugar dipolarophile. [17] The selective tethering of one or two cholesterol units to a thymidine skeleton was demonstrated by trapping of the same dipole by 5Ј-protected mono-or bis-propargylated thymidines 24 or 26 [18] to give conjugates 25 and 27 in 81 and 68 % yields, respectively (Scheme 5). The mono-and bis-steroidal conjugates are potentially useful building blocks for the formation of syn-thetic oligonucleotides with tuneable amphiphilic properties.…”

Section: Resultsmentioning

confidence: 99%

“…), thymidine mono-alkyne 24 (0.75 equiv. ), or thymidine bis-alkyne 26 [18] (1.5 equiv.) was put into a round-bottomed flask, and a solution of oxime p-16 and Ch-T (1.5 equiv.…”

Section: General Procedures For the Preparation Of Oximes 16mentioning

confidence: 99%

“…The organic layer was dried with anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The crude reaction product was purified by flash column chromatography (hexane/EtOAc 0-10 %) to give compound p- 18 General Procedure for the Nitrile Oxide-Alkyne Cycloaddition with Sugar and Nucleoside Substrates: Alkylated sug ar 22 [ 2 1 ] (0.75 equiv. ), thymidine mono-alkyne 24 (0.75 equiv.…”

Section: General Procedures For the Preparation Of Oximes 16mentioning

confidence: 99%

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C‐3β‐Tethered Functional Cholesterol Conjugates by Nitrile Oxide Alkyne Cycloaddition (NOAC)

2014

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Section: Resultsmentioning

confidence: 99%

“…), thymidine mono-alkyne 24 (0.75 equiv. ), or thymidine bis-alkyne 26 [18] (1.5 equiv.) was put into a round-bottomed flask, and a solution of oxime p-16 and Ch-T (1.5 equiv.…”

Section: General Procedures For the Preparation Of Oximes 16mentioning

confidence: 99%

Section: General Procedures For the Preparation Of Oximes 16mentioning

confidence: 99%

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C‐3β‐Tethered Functional Cholesterol Conjugates by Nitrile Oxide Alkyne Cycloaddition (NOAC)

2014

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“…In one elegant example Pezacki et al circumvents this problem by employing nitrones as more reactive dipole partners. 14 We and others have recently discovered nitrile oxide click conjugation to alkenes 15,16 and to terminal alkynes [17][18][19] as a highly effective approach to chemical modification of oligonucleotides. Nitrile oxides are reactive 1,3-dipoles, and in the absence of an effective dipolarophile side reactions, including dimerisation leading furoxans, 1,2,4-oxadiazole-4-oxides or 1,4,2,5-dioxadiazines could be problematic.…”

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confidence: 99%

Solid phase strain promoted “click” modification of DNAvia[3+2]-nitrile oxide–cyclooctyne cycloadditions

Singh

Heaney

2011

Chem. Commun.

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Rapid, catalyst free, solid phase modification of DNA by strain promoted cyclooctyne-nitrile oxide click chemistry is reported; the reaction is characterised by mild conditions, occurring in an aqueous environment under atmospheric conditions at room temperature and is complete in 10 minutes.Chemically modified oligonucleotide-based drugs are promising therapeutic candidates, 1 however clinical applications are limited by poor cellular uptake. 2 The conjugation of oligonucleotides to molecules expected to facilitate their internalization, e.g. cell penetrating peptides or lipids, offers an attractive way to combat these shortcomings. 3 The Cu(I) catalysed azide and alkyne cycloaddition (CuAAC) reported by Meldal et al. 4 and Sharpless et al. 5 has been extensively used in synthetic chemistry and in chemical biology. 6,7 It is a high yielding and efficient reaction, however, for certain applications the requirement for the catalyst can be limiting. 6 The added metal can be cytotoxic 8 and can upset the metabolic balance of the systems under study, thus, a need exists to expand the field of metal free biocompatible chemistry. Approaches to-date include the photoinduceable cycloadditions of tetrazines 9b or nitrile imines to alkenes, 9a and the [3+2]-azide-cyclooctyne cycloaddition developed by Bertozzi et al. 10,11 and Boons et al. 12 The latter, exploiting the intrinsic ring strain of cyclooctynes 13 is a powerful reaction, yet it can require several hours to reach completion at room temperature. In one elegant example Pezacki et al. circumvents this problem by employing nitrones as more reactive dipole partners. 14 We and others have recently discovered nitrile oxide click conjugation to alkenes 15,16 and to terminal alkynes 17-19 as a highly effective approach to chemical modification of oligonucleotides. Nitrile oxides are reactive 1,3-dipoles, and in the absence of an effective dipolarophile side reactions, including dimerisation leading furoxans, 1,2,4-oxadiazole-4-oxides or 1,4,2,5-dioxadiazines could be problematic. 20 However, we anticipated high chemoselectivity for the desired cycloaddition with a very reactive strained cycloalkyne partner. Whilst there are numerous applications of cyclooctynes in the context of biological systems 21 to the best of our knowledge there are currently no reports describing their reaction with nitrile oxide dipoles, nor are there any reports on solid phase conjugation of oligonucleotides with ring strained alkynes. In the present communication we report the first preparation of a DNA ligated cyclooctyne and demonstrate its utility in strain promoted nitrile oxide click cycloadditions.The desired DNA-cyclooctyne was constructed by manual solid phase synthesis employing the phosphoramidite building block 4. Synthesis of this key intermediate, shown in Scheme 1, was achieved in three steps from the dibromobicycle 1, itself obtained by a known procedure 22 from commercially available cis-cycloheptene. Ring opening of 1 with 1,4-butanediol in the presence of silver perchlorate a...

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“…We and others have reported the application of nitrile oxide derivatives to the modification of nucleosides, oligonucleotides and polymers bearing alkene/alkyne functions. [13][14][15][16][17][18][19] Other metal-free strategies include Diels-Alder cycloadditions, 20 photoinduceable cycloadditions of tetrazines or nitrile imines to alkenes 21,22 and strain-promoted azide-alkyne cycloaddition (SPAAC) reactions.…”

Section: Introductionmentioning

confidence: 99%

Fast RNA conjugations on solid phase by strain-promoted cycloadditions

et al. 2012

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Strain promoted cycloaddition is presented as a tool for RNA conjugation on the solid phase; RNA-cyclooctyne conjugates are prepared by cycloaddition to both azide (strain-promoted azide-alkyne cycloaddition, SPAAC) and nitrile oxide dipoles (strain-promoted nitrile oxide-alkyne cycloaddition, SPNOAC). The conjugation is compatible with 2′-OMe blocks and with 2′-O-TBDMS protection on the ribose moieties of the sugar. Nitrile oxide dipoles are found to be more reactive click partners than azides. The conjugation proceeds within 10 min in aqueous solvents, at room temperature without any metal catalyst and tolerates dipoles of varying steric bulk and electronic demands, including pyrenyl, coumarin and dabcyl derivatives.

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Nucleoside and nucleotide analogues by catalyst free Huisgen nitrile oxide–alkyne1,3-dipolar cycloaddition

Cited by 26 publications

References 27 publications

C‐3β‐Tethered Functional Cholesterol Conjugates by Nitrile Oxide Alkyne Cycloaddition (NOAC)

C‐3β‐Tethered Functional Cholesterol Conjugates by Nitrile Oxide Alkyne Cycloaddition (NOAC)

Solid phase strain promoted “click” modification of DNAvia[3+2]-nitrile oxide–cyclooctyne cycloadditions

Fast RNA conjugations on solid phase by strain-promoted cycloadditions

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