Preparation of 2′-Alkylselenouridine Derivatives via a 2-(Trimethyl­silyl)ethylselenation Approach

Shota Fukuno; Masayuki Ninomiya; Mamoru Koketsu

doi:10.1055/s-0036-1588937

Synlett, Inhaltsverzeichnis

Synlett 2017; 28(07): 831-834
DOI: 10.1055/s-0036-1588937

letter

Preparation of 2′-Alkylselenouridine Derivatives via a 2-(Trimethylsilyl)ethylselenation Approach

Shota Fukuno

^aDepartment of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan eMail: koketsu@gifu-u.ac.jp

,

Masayuki Ninomiya

^aDepartment of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan eMail: koketsu@gifu-u.ac.jp

^bDepartment of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan

,

Mamoru Koketsu*

^aDepartment of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan eMail: koketsu@gifu-u.ac.jp

^bDepartment of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan

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Abstract

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Abstract

2′-O-Methylation of nucleotides is well-known to increase siRNA stability against nuclease activities. Recently, selenium-containing biomolecules have been recognized as unique biological and medicinal agents for humans. In this study, 2′-alkylselenouridine derivatives were prepared through 2-(trimethylsilyl)ethylselenation at the C2′ position of 5′-DMT-2,2′-O-cyclouridine, followed by alkylation with various haloalkanes utilizing the characteristics of a Si atom. Overall, we demonstrated the versatility of a 2-(trimethylsilyl)ethylselenyl group for the synthesis of 2′-alkylselenouridines.

Key words

selenium-containing biomolecule - 2-(trimethylsilyl)ethylselenyl group - selenation - 2′-alkylselenouridine derivative - phosphoramidite monomer

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Referenzen

References and Notes
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22 Synthesis of 5′-(4,4′-Dimethoxytrityl)-2′-trimethylsilylethyluridine (4) After stirring of 2-(trimethylsilyl)ethyl diselenide (1, 1.14 mmol), NaBH₄ (1.14 mmol), and EtOH (2.85 mmol) in DMF (5 mL) at 0 °C for 30 min, 3 (0.95 mmol) was added to the solution, and the reaction was continued at 60 °C for an additional 1 h. The resultant solution was quenched by 5% NH₃Cl aq, and then was poured into distilled water, partitioned with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with n-hexane–EtOAc (3:1 to 1:1) to afford 4 (98% yield) as a white amorphous powder. [α]_D +79.39 (c 0.64, CHCl₃). IR (film): ν_max = 3407, 2924, 1685 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 8.79 (br s, 1 H, NH), 7.89 (d, 1 H, J = 7.6 Hz, H5), 7.36 (d, 2 H, J = 6.8 Hz, Ph), 7.30 (t, 2 H, J = 7.6 Hz, Ph), 7.26–7.23 (m, 5 H, Ph), 6.84 (d, 4 H, J = 8.9 Hz, Ph), 6.19 (d, 1 H, J = 8.3 Hz, H1′), 5.36 (d, 1 H, J = 8.2 Hz, H6), 4.37 (dd, 1 H, J = 2.8, 4.8 Hz, H3′), 4.18 (d, 1 H, J = 2.7 Hz, H4′), 3.79 (s, 6 H, 2 OMe), 3.66 (dd, 2 H, J = 4.8, 7.6 Hz, H2′), 3.51 (dd, 1 H, J = 2.7, 11.0 Hz, H5′a), 3.47 (dd, 2 H, J = 2.7, 11.0 Hz, H5′b), 2.85 (d, 1 H, J = 3.5 Hz, OH), 2.78–2.71 (m, 2 H, SeCH₂ CH₂TMS), 1.03–0.95 (m, 2 H, SeCH₂CH₂ TMS), 0.008 (s, 9 H, SiMe₃). ¹³C NMR (150 MHz, CDCl₃): δ = 163.1, 158.9, 150.4, 144.4, 140.0, 135.2, 135.0, 130.21, 130.16, 128.2, 127.4, 113.5, 102.7, 88.1, 87.4, 84.7, 71.6, 63.5, 55.4, 50.4, 20.8, 19.2, –1.8. ⁷⁷Se NMR (115 MHz, CDCl₃): δ = 150.3. HRMS (ESI, TOF): m/z calcd for C₃₅H₄₂N₂O₇SeNa, 733.1824; found: 733.1816 [M + Na]⁺.
23 Alkylation of 6 TBAF (1.0 M in THF, 0.15 mmol) was added to a solution of 6 (0.05 mmol) and MeI (0.25 mmol) in DMF (0.5 ml). After stirring at 40 °C for 5 h, the resultant solution was poured into distilled water, partitioned with EtOAc twice, and washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with n-hexane–EtOAc (3:1 to 2:1) to afford 7a (92% yield) as a white amorphous powder. Reaction parameters are given in Tables 1 and 2. The operation procedures for 7b–s are exactly the same with 7a. [α]_D +52.18 (c 0.62, CHCl₃). IR (film): ν_max = 3398, 2925, 1713, 1661 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, 1 H, J = 8.0 Hz, H5), 7.38–7.25 (m, 14 H, Ph), 6.84 (d, 4 H, J = 8.9 Hz, Ph), 6.21 (d, 1 H, J = 6.7 Hz, H1′), 5.47 (s, 2 H, CH₂OCH₂ Ph), 5.40 (d, 1 H, J = 8.1 Hz, H6), 4.69 (s, 2 H, CH₂ OCH₂Ph), 4.38 (d, 1 H, J = 5.4 Hz, H3′), 4.15 (d, 1 H, J = 3.5 Hz, H4′), 3.79 (s, 6 H, 2 OMe), 3.55–3.46 (m, 3 H, H2′ and H5′), 2.75 (d, 1 H, J = 4.0 Hz, OH), 2.14 (s, 3 H, SeMe). ¹³C NMR (100 MHz, CDCl₃): δ = 162.7, 158.9, 151.3, 144.3, 138.5, 138.0, 135.3, 135.1, 130.2, 128.4, 128.2, 127.8, 127.4, 113.4, 102.4, 102.3, 88.8, 87.4, 84.5, 72.3, 71.3, 70.5, 63.0, 55.4, 51.0, 4.9. ⁷⁷Se NMR (75 MHz, CDCl₃): δ = 27.9. HRMS (ESI, TOF): m/z calcd for C₃₉H₄₀N₈O₇SeNa: 767.1848; found: 767.1860 [M + Na]⁺.
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Supporting Information

Preparation of 2′-Alkylselenouridine Derivatives via a 2-(Trimethyl­silyl)ethylselenation Approach

Preparation of 2′-Alkylselenouridine Derivatives via a 2-(Trimethylsilyl)ethylselenation Approach