Synthesis of Antisense Oligonucleotides:  Replacement of 3H-1,2-Benzodithiol-3-one 1,1-Dioxide (Beaucage Reagent) with Phenylacetyl Disulfide (PADS) As Efficient Sulfurization Reagent:  From Bench to Bulk Manufacture of Active Pharmaceutical Ingredient

Cheruvallath, Zacharia S.; Carty, Recaldo L.; Moore, Max N.; Capaldi, Daniel C.; Krotz, Achim H.; Wheeler, Patrick; Turney, Brett; Craig, Stephen R.; Gaus, Hans; Scozzari, Anthony N.; Cole, and Douglas L.; Ravikumar, Vasulinga T.

doi:10.1021/op990077b

Cited by 50 publications

(14 citation statements)

References 40 publications

(45 reference statements)

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“…The methods currently applied to preparation of oligonucleotides in the laboratory [ 1 , 2 ] as well as in large-scale production [ 3 , 4 , 5 ], consist of stepwise addition of nucleoside phosphoramidites to a growing oligomer chain on a solid support. While solid-supported phosphoramidite chemistry undoubtedly is the method of choice for small-scale synthesis of oligonucleotides, solution phase synthesis may well challenge it in cases where multikilogram quantities are needed for clinical phase trials of therapeutic oligonucleotides or as starting materials for the construction of nanomaterials.…”

Section: Introductionmentioning

confidence: 99%

Acetylated and Methylated β-Cyclodextrins as Viable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution

et al. 2012

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Novel soluble supports for oligonucleotide synthesis 11a–c have been prepared by immobilizing a 5′-O-protected 3′-O-(hex-5-ynoyl)thymidine (6 or 7) to peracetylated or permethylated 6-deoxy-6-azido-β-cyclodextrins 10a or 10b by Cu(I)-promoted 1,3-dipolar cycloaddition. The applicability of the supports to oligonucleotide synthesis by the phosphoramidite strategy has been demonstrated by assembling a 3′-TTT-5′ trimer from commercially available 5′-O-(4,4′-dimethoxytrityl)thymidine 3′-phosphoramidite. To simplify the coupling cycle, the 5′-O-(4,4′-dimethoxytrityl) protecting group has been replaced with an acetal that upon acidolytic removal yields volatile products. For this purpose, 5′-O-(1-methoxy-1-methylethyl)-protected 3′-(2-cyanoethyl-N,N-diisopropyl-phosphoramidite)s of thymidine (5a), N4-benzoyl-2′-deoxycytidine (5b) and N6-benzoyl-2′-deoxyadenosine (5c) have been synthesized and utilized in synthesis of a pentameric oligonucleotide 3′-TTCAT-5′ on the permethylated cyclodextrin support 11c.

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Section: Introductionmentioning

confidence: 99%

Acetylated and Methylated β-Cyclodextrins as Viable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution

et al. 2012

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“…These products were immediately hydrolyzed by addition of approximately 2 equiv of aqueous triethylammonium bicarbonate (TEAB) to give the H -phosphonate 16 . Treatment of 16 with approximately 4 equiv of phenylacetyl disulfide (PADS) [ 57 ] gave the known dinucleoside phosphorothioate 17 [ 26 , 58 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

Hersh¹

2015

Beilstein J. Org. Chem.

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SummaryThe reaction of the diamidite, (iPr2N)2PH, with acyl chlorides proceeds with the loss of HCl to give the corresponding acyl diamidites, RC(O)P(N(iPr)2)2 (R = Me (7), Ph (9)), without the intervention of sodium to give a phosphorus anion. The structure of 9 was confirmed by single-crystal X-ray diffraction. The coupling of the diamidites 7 and 9 with 5′-O-DMTr-thymidine was carried out with N-methylimidazolium triflate as the activator to give the monoamidites 3′-O-(P(N(iPr)2)C(O)R)-5′-O-DMTr-thymidine, and further coupling with 3′-O-(tert-butyldimethylsilyl)thymidine was carried out with activation by pyridinium trifluoroacetate/N-methylimidazole. The new dinucleoside acylphosphonites could be further oxidized, hydrolyzed to the H-phosphonates, and sulfurized to give the known mixture of diastereomeric phosphorothioates. The goal of this work was the measurement of the barrier to inversion of the acylphosphonites, which was expected to be low by analogy to the low barrier found in acylphosphines. However, the barrier was found to be high as no epimerization was detected up to 150 °C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol.

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“…0.2 M PADS in 1:1 3-picoline/CH 3 CN were used as a sulfurization reagent with 3 minutes contact time. [16] A solution of tertbutyl hydroperoxide/acetonitrile/water (10:87:3) was used to oxidize inter nucleosidic phosphite to phosphate. The step-wise coupling efficiencies were more than 97%.…”

Section: Synthesis Of Oligonucleotides 7-15mentioning

confidence: 99%

Activity of siRNAs with 2-Thio-2′-O-Methyluridine Modification in Mammalian Cells

Prakash

Naik

Sioufi

et al. 2009

Nucleosides, Nucleotides and Nucleic Acids

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Synthesis of Antisense Oligonucleotides: Replacement of 3H-1,2-Benzodithiol-3-one 1,1-Dioxide (Beaucage Reagent) with Phenylacetyl Disulfide (PADS) As Efficient Sulfurization Reagent: From Bench to Bulk Manufacture of Active Pharmaceutical Ingredient

Cited by 50 publications

References 40 publications

Acetylated and Methylated β-Cyclodextrins as Viable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution

Acetylated and Methylated β-Cyclodextrins as Viable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

Activity of siRNAs with 2-Thio-2′-O-Methyluridine Modification in Mammalian Cells

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