Synthesis of Some Novel 1,2,3-Triazole-Fused Oligonucleoside and Oligosaccharide Analogues

Pei-Yuan Jin; Peng Jin; Yi-An Ruan; Yong Ju; Yu-Fen Zhao

doi:10.1055/s-2007-992357

LETTER

Synthesis of Some Novel 1,2,3-Triazole-Fused Oligonucleoside and Oligosaccharide Analogues

Pei-Yuan Jin^a, Peng Jin^a, Yi-An Ruan^a, Yong Ju*^a,b, Yu-Fen Zhao^a
^a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China
^b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(10)62781695; e-Mail: juyong@tsinghua.edu.cn;

Abstract

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Abstract

Several 1,2,3-triazole-fused oligonucleoside and oligosaccharide analogues were synthesized by involving a Cu(I)-catalyzed 1,3-dipolar cycloaddition as the key step. The structures of the products were confirmed on the basis of the ¹H NMR and ESI-MS methods.

Key words

1,3-dipolar cycloaddition - catalysis - AZT - oligonucleosides - oligosaccharides

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References

References and Notes

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15

Typical Procedure for the Preparation of 4: 1,2-Ethylene-diamine (120 mg, 2 mmol) was dissolved in MeCN (10 mL). Crushed KOH (493 mg, 8.8 mmol) was added and after 15 min of stirring an 80% propargyl bromide solution in toluene (0.76 mL, 8.8 mmol) was slowly added via syringe. The mixture was stirred for 6 h. The reaction mixture was reduced to a brown oil to which ice-water (15 mL) was added and the mixture was subsequently extracted with CH₂Cl₂ (3 × 15 mL). The combined extracts were washed with H₂O, dried over anhyd MgSO₄, filtered, and reduced to a brown syrup. Flash column chromatography using hexanes-EtOAc (20:1) yielded the alkyne 4 (339 mg, 80%) as a pale yellow. ¹H NMR (300 MHz, CDCl₃): δ = 3.48 (d, J = 2.4 Hz, 8 H, 4 × CH₂), 2.72 (s, 4 H, 2 × CH₂), 2.22 (t, J = 2.4 Hz, 4 H, 4 × CH). ESI-MS (+): m/z = 213 [M + H]⁺, 235 [M + Na]⁺.
Compound 5: ESI-MS (+): m/z = 227 [M + H]⁺, 249 [M + Na]⁺, 265 [M + K]⁺.
Compound 6: ESI-MS (+): m/z = 269 [M + H]⁺, 307 [M + K]⁺.
Compound 12: ESI-MS (+): m/z = 294 [M + H]⁺, 316 [M + Na]⁺, 332 [M + K]⁺.
Compound 13: ESI-MS: m/z = 321 [M + H]⁺, 360 [M + K]⁺.

16

Typical Procedure for the Preparation of 7a: Triazole 7a was prepared from azide a (0.4 mmol) and alkyne 4 (21 mg, 0.1 mmol) with CuSO₄ (5 mg, 5% equiv of azide) and sodium ascorbate (8 mg, 10% equiv of azide) in THF-H₂O (1:1, 10 mL) at r.t. for 12 h. Then the solvent was removed and the residue was purified by column chromatography over silica gel using CH₂Cl₂-MeOH (4:1) as eluent; white solid; yield: 42%; mp 246-249 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.28 (s, 4 H, triazole-H), 7.82 (s, 4 H, H-6), 7.70 (m, 4 H, H-3), 6.43 (t, J = 6.0 Hz, 4 H, H-1′), 5.36 (m, 4 H, H-3′), 4.21 (m, 4 H, H-4′), 3.68 (m, 8 H, 4 × CH₂), 3.59-3.63 (m, 8 H, H-5′), 2.59-2.74 (m, 12 H, H-2′, NCH₂), 1.81 (s, 12 H, Me-5). ESI-MS (+): m/z = 1281 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₅₄H₆₉N₂₂O₁₆: 1281.5256; found: 1281.5269.
Compound 7b: white solid; yield: 60%; mp 198-201 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.98-8.19 (m, 4 H, triazole-H), 5.90-5.98 (m, 4 H, H-1), 5.25-5.65 (m, 12 H, H-2, H-3, H-4), 4.02-4.30 (m, 12 H, H-5, H-6), 3.73-3.87 (br, 8 H), 2.60-2.86 (br, 4 H), 1.83-2.06 (m, 48 H, 16 × COMe). ESI-MS (+): m/z = 1705 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₀H₉₃N₁₄O₃₆: 1705.5871; found: 1705.5857.
Compound 8a: yield: 38%; mp 253-255 °C. ESI-MS (+): m/z = 1295 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₅₅H₇₁N₂₂O₁₆: 1295.5413; found: 1295.5436.
Compound 8b: yield: 65%; mp 190-195 °C. ESI-MS (+): m/z = 1719 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₁H₉₅N₁₄O₃₆: 1719.6028; found: 1719.6008.
Compound 9a: yield: 41%; mp 257-260 °C. ESI-MS (+): m/z = 1359 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₅₈H₇₆N₂₂NaO₁₆: 1359.5702; found: 1359.5702.
Compound 9b: yield: 51%; mp 190-193 °C. ESI-MS (+): m/z = 1761 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₄H₁₀₁N₁₄O₃₆: 1761.6497; found: 1761.6482.
Compound 14a: yield: 48%; mp 270-273 °C. ESI-MS (+): m/z = 1651 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₆₉H₈₈N₂₈NaO₂₀: 1651.6622; found: 1651.6630.
Compound 14b: yield: 70%; mp 206-211 °C. ESI-MS (+): m/z = 2159 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₈₉H₁₁₉N₁₈O₄₅: 2159.7571; found: 2159.7588.
Compound 15a: yield: 39%; mp 266-269 °C. ESI-MS (+): m/z = 1657 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₁H₉₃N₂₈O₂₀: 1657.7115; found: 1657.7117.
Compound 15b: yield: 63%; mp 211-216 °C. ESI-MS (+): m/z = 2187 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₉₁H₁₂₃N₁₈O₄₅: 2187.7884; found: 2187.7838.

17a Lelong I. Luu B. Mersel M. Rottem S. FEBS Lett. 1988, 232: 35

17b Jin PY. Liu K. Ji SH. Ju Y. Zhao YF. Synthesis 2007, 407

18

Typical Procedure for the Preparation of 18: Amine 16 (472 mg, 1 mmol) was dissolved in MeCN (10 mL). Crushed K₂CO₃ (304 mg, 2.2 mmol) was added and after 15 min of stirring an 80% propargyl bromide solution in toluene (0.19 mL, 2.2 mmol) was slowly added via syringe. The mixture was allowed to stir overnight and until TLC analysis revealed the reaction to be complete. The reaction mixture was reduced to a brown oil to which ice-water (15 mL) was added and the mixture was subsequently extracted with CH₂Cl₂ (3 × 15 mL). The combined extracts were washed with H₂O, dried over anhyd MgSO₄, filtered, and reduced to a brown syrup. Flash column chromatography using CH₂Cl₂-MeOH (80:1) yielded the alkyne 18 (389 mg, 71%) as a pale yellow; mp 122-125 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.36 (m, 1 H, H-6′′), 5.05 (br, 1 H, CONH), 4.49 (m, 1 H, H-3′′), 3.44 (d, J = 2.4 Hz, 4 H, NCH₂), 3.27 (q, J = 5.7 Hz, 2 H, NHCH₂), 2.69 (t, J = 5.7 Hz, 2 H, NCH₂), 2.32 (br, 2 H, H-7′′), 2.23 (t, J = 2.4 Hz, 2 H), 1.01-2.02 (br, 26 H, other protons of steroidal moiety), 1.00 (s, 3 H, Me-19′′), 0.90 (d, J = 6.5 Hz, 3 H, Me-21′′), 0.86 (m, 6 H, Me-26′′, Me-27′′), 0.67 (s, 3 H, Me-18′′). ESI-MS (+): m/z = 549 [M + H]⁺, 571 [M + Na]⁺, 587 [M + K]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₅₇N₂O₂: 549.4415; found: 549.4422.
Compound 19: mp 124-127 °C. ESI-MS (+): m/z = 605 [M + H]⁺, 627 [M + Na]⁺, 643 [M + K]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₆₅N₂O₂: 605.5041; found: 605.5041.
Compound 24: mp 114-117 °C. ESI-MS (+): m/z = 630 [M + H]⁺, 652 [M + Na]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₁H₆₄N₃O₂: 630.4993; found: 630.4999.
Compound 25: mp 125-129 °C. ESI-MS (+): m/z = 658 [M + H]⁺, 680 [M + Na]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₁H₆₈N₃O₂: 658.5306; found: 658.5310.

19

Typical Procedure for the Preparation of 20a: Triazole 20a was prepared by heating azide a (53 mg, 0.2 mmol) and alkyne 18 (55 mg, 0.1 mmol) with CuSO₄ (2.5 mg, 5% equiv of azide) and sodium ascorbate (4 mg, 10% equiv of azide) in THF-H₂O (1:1, 10 mL) at 50 °C for 12 h. Then the solvent was removed and the residue was purified by column chromatography over silica gel using CH₂Cl₂-MeOH (7:1) as eluent; white solid; yield: 46%; mp 301-305 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.33 (br, 2 H, H-3), 8.31 (s, 2 H, triazole-H), 7.89 (s, 2 H, H-6), 6.44 (t, J = 6.5 Hz, 2 H, H-1′), 5.47 (m, 2 H, H-3′), 5.32 (m, 1 H, H-6′′), 4.58 (br, 1 H, CONH), 4.51 (m, 1 H, H-3′′), 3.58-3.75 (m, 6 H, H-4′, H-5′), 3.37 (s, 4 H, NCH₂), 3.16 (m, 2 H, NHCH₂), 2.54-2.80 (m, 6 H, H-2′, NCH₂), 2.34 (br, 2 H, H-7′′), 1.83 (s, 6 H, Me-5), 0.97-1.99 (br, 26 H, other protons of steroidal moiety), 0.96 (s, 3 H, Me-19′′), 0.87 (d, J = 6.5 Hz, 3 H, Me-21′′), 0.84 (m, 6 H, Me-26′′, Me-27′′), 0.66 (s, 3 H, Me-18′′). ESI-MS (+): m/z = 1083 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₅₆H₈₃N₁₂O₁₀: 1083.6350; found: 1083.6373.
Compound 20b: white solid; yield: 65%; mp 220-223 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.88 (s, 2 H, triazole-H), 5.85 (t, J = 4.2, 4.8 Hz, 2 H, H-1′), 5.30-5.55 (m, 4 H, H-2′, H-3′), 5.25 (m, 1 H, H-6′′), 4.53 (br, 1 H, CONH), 4.51 (m, 1 H, H-3′′), 4.00-4.27 (m, 8 H, H-4′, H-5′, H-6′), 3.73 (s, 4 H, NCH₂), 3.23 (m, 2 H, NHCH₂), 2.61 (m, 2 H, NCH₂), 2.34 (br, 2 H, H-7′′), 2.02-2.09 (s, 24 H, 8 × COMe), 0.96-1.99 (br, 26 H, other protons of steroidal moiety), 1.09 (s, 3 H, Me-19′′), 0.95 (d, J = 6.5 Hz, 3 H, Me-21′′), 0.85 (m, 6 H, Me-26′′, Me-27′′), 0.67 (s, 3 H, Me-18′′). ESI-MS (+): m/z = 1295 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₆₄H₉₅N₈O₂₀: 1295.6657; found: 1295.6638.
Compound 21a: yield: 51%; mp 286-290 °C. ESI-MS (+): m/z = 1139 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₆₀H₉₁N₁₂O₁₀: 1139.6976; found: 1139.6960.
Compound 21b: yield: 58%; mp 215-218 °C. ESI-MS (+): m/z = 1351 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₆₈H₁₀₃N₈O₂₀: 1351.7283; found: 1351.7267.
Compound 26a: yield: 36%; mp 307-310 °C. ESI-MS (+): m/z = 1431 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₁H₁₀₃N₁₈O₁₄: 1431.7896; found: 1431.7893.
Compound 26b: yield: 59%; mp 222-227 °C. ESI-MS (+): m/z = 1749 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₈₃H₁₂₁N₁₂O₂₉: 1749.8357; found: 1749.8346.
Compound 27a: yield: 45%; mp 311-314 °C. ESI-MS (+): m/z = 1459 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₇₃H₁₀₇N₁₈O₁₄: 1459.8209; found: 1459.8216.
Compound 27b: yield: 55%; mp 229-232 °C. ESI-MS (+): m/z = 1777 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₈₅H₁₂₅N₁₂O₂₉: 1777.8670; found: 1777.8680.