Synthesis of Unnatural C-2 Amino Acid Nucleosides Using NIS-Mediated Ring Opening of 1,2-Cyclopropane Carboxylated Sugar Derivatives

Abstract

We have developed a general and efficient method for the stereoselective construction of pyrimidine-based pyranosyl C-2 amino acid nucleosides using NIS-mediated ring opening of 1,2-­cyclopropanated sugar derivatives. This methodology has been successfully extended to the synthesis of furanosyl nucleosides, which have potential applications in the development of novel, nontoxic antifungal therapeutics.

Key words

amino acid nucleoside - donor-acceptor - polyoxin - purine - pyrimidine

References and Notes

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10

Addition of further equivalence of the reagents did not result in any noticeable increase in the yield. The use of excess NIS in the presence of stoichiometric amount of nucleobase was not effective as the reaction was found to be incomplete even after 48 h.

11

CCDC 706702 contains the supplementary crystallographic data for the azide 5.

21

General Procedure for the NIS-Mediated Ring Opening of Cyclopropyl Carboxylates; Synthesis of Iodide 4: To a solution of cyclopropyl carboxylate 2 (0.488 g, 1 mmol) in CH₂Cl₂ (10 mL), freshly prepared TMS-activated thymine 3 (0.675 g, 2.5 mmol) and NIS (0.562 g, 2.5 mmol) were added under an argon atmosphere at r.t. (25 ˚C). After 48 h the reaction mixture was diluted with CHCl₃ (10 mL) and then neutralized with dilute Na₂S₂O₃ solution. Insoluble material was removed by filtration. The organic layer was separated and dried over anhyd Na₂SO₄.The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (230-400 mesh) using 40% EtOAc-PE, which gave the corresponding iodide 4 as a gummy solid (0.606 g, 82%).
Compound 4: R _f (EtOAc-PE, 2:3) 0.35; [α]_D +31.0 (c = 2, CHCl₃). IR (neat): 3214, 3064, 3032, 1721, 1714, 1694, 1454, 1368, 1267, 1027, 736, 698 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 9.05 (s, 1 H), 7.10-7.34 (m, 18 H), 5.97 (d, J = 9.9 Hz, 1 H), 5.00 (d, AB type, J = 10.5 Hz, 1 H), 4.74 (d, AB type, J = 10.5, 1 H), 4.31 (d, AB type, J = 10.2 Hz, 1 H), 4.46-4.63 (m, 3 H), 3.98 (q, J = 7.8 Hz, 2 H), 3.81 (dd, J ₁ = 3.6 Hz, J ₂ = 11.1 Hz, 1 H), 3.62-3.71 (m, 2 H), 3.84 (s, 3 H), 1.94 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.2, 163.1, 150.2, 137.9, 137.7, 137.4, 134.9, 128.4, 127.7, 127.5, 112.3, 82.0, 78.9, 77.4, 74.7, 74.6, 73.4, 68.3, 53.6, 48.8, 23.3, 12.5. HRMS: m/z [M + Na] calcd for C₃₅H₃₇IN₂O₈: 763.1492; found: 763.1559.
General Procedure for the Preparation of Azides; Synthesis of Azide 5: To a stirred solution of iodide 4 (0.236 g, 0.31 mmol) in anhyd DMF (2 mL) was added sodium azide (0.040 g, 0.62 mmol) and the reaction was stirred for 24 h at r.t. (25 ˚C). Most of the DMF was removed under vacuum followed by dilution with CHCl₃ (10 mL), which was washed with H₂O. The organic layer was separated and dried over anhyd Na₂SO₄. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (230-400 mesh) using 40% EtOAc-PE to obtain the corresponding azide 5 as a pale yellow solid (0.200 g, 96%).
Compound 5: mp 182 ˚C; R _f (EtOAc-PE, 2:3) 0.3; [α]_D +42.22 (c = 1.8, CHCl₃). IR (neat): 2114, 1744, 1713, 1693, 1496, 1265, 737, 699 cm^-¹. ^¹H NMR (400 MHz, CDCl₃):
δ = 8.45 (s, 1 H), 7.22-7.37 (m, 15 H), 6.99 (s, 1 H), 5.77 (d, J = 7.1 Hz, 1 H), 5.00 (d, J = 11.6 Hz, 1 H), 4.32 (d, J = 10.4 Hz, 1 H), 4.66 (dd, J = 4.8 Hz, J ₂ = 17.2 Hz, 2 H), 4.57 (d, J = 12.4 Hz, 1 H), 4.49 (d, J = 12.4 Hz, 1 H), 4.39 (d, J = 1.8 Hz, 1 H), 3.83-3.72 (m, 3 H), 3.64-3.66 (m, 1 H), 3.55 (m, 4 H), 2.51 (br s, 1 H), 1.91 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 163.0, 149.4, 137.6, 137.5, 137.4, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 110.8, 79.0, 78.4, 77.3, 75.2, 74.8, 73.4, 68.0, 57.9, 52.7, 47.3, 22.5. HRMS: m/z [M + Na] calcd for C₃₅H₃₇N₅O₈: 678.2540; found: 678.2554.
General Procedure for the Reduction of Azides Using Zn; Synthesis of Amino Acid Nucleoside 6: To a stirred solution of azide 5 (0.105 g, 0.16 mmol) in AcOH-THF (1:1, 5 mL) was added zinc (0.0009 g, 10 mmol%) and the reaction was stirred for 3 h at r.t. (25 ˚C). After the disappearance of the starting material (by TLC), Zn was removed by filtration and the filtrate was diluted with EtOAc (15 mL). The organic layer was thoroughly washed with NaHCO₃ solution. It was separated and dried over anhyd Na₂SO₄. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (230-400 mesh) using 20% MeOH-CHCl₃ to obtain the corresponding C-2 amino acid nucleoside 6 as a colorless gummy solid (0.080 g, 80%).
Compound 6: R _f (MeOH-CHCl₃, 4:1) 0.35; [α]_D +12 (c = 2, CHCl₃). IR neat): 3584, 3064, 3031, 2953, 2919, 1739, 1733, 1694, 1455, 1368, 1267, 1155, 1111, 736, 698, 666 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.92 (br s, 1 H), 7.21-7.33 (m, 15 H), 7.06 (s, 1 H), 5.77 (d, J = 10.4 Hz, 1 H), 4.99 (d, J = 11.6 Hz, 1 H), 4.86 (d, J = 11.2 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 4.65 (d, J = 11.2 Hz, 1 H), 4.50-4.60 (m, 3 H), 4.10-4.04 (m, 1 H), 3.61-3.80 (m, 6 H), 3.46 (s, 3 H), 2.41 (m, 1 H), 1.93 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 176.0, 163.8, 150.7, 138.5, 138.3, 136.0, 129.0, 128.9, 128.4, 128.3, 128.2, 111.6, 80.0, 79.5, 75.7, 75.3, 73.8, 68.8, 52.5, 51.0, 49.9, 30.8, 12.9. HRMS: m/z [M + Na] calcd for C₃₅H₃₉N₃O₈: 652.2635; found: 652.2662.
General Procedure for the Reduction of Azide 10 Using Pd/C: A suspension of 10% Pd/C (0.040 g) and azide 10 (0.040 g, 0.06 mmol) in MeOH (2 mL) under hydrogen atmosphere was stirred for 12 h at ambient temperature (25 ˚C). The catalyst was filtered and washed with MeOH (20 mL). The filtrate was concentrated and the crude product was purified by flash column chromatography (10% CHCl₃-MeOH) to get the corresponding amino triol 27 as a gummy solid (0.017 g, 82%).
Compound 27: R _f (MeOH-CHCl₃, 1:9) 0.2; [α]_D +6.5 (c = 2, DMF). IR (neat): 3417, 1659, 1651, 1644, 1049, 1026, 1004, 826, 764 cm^-¹. ^¹H NMR (400 MHz, DMSO): δ = 10.32 (s, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 5.60 (d, J = 8.0 Hz, 1 H), 5.56 (d, J = 10.0 Hz, 1 H), 4.45 (t, J = 6.0 Hz, 1 H), 3.73 (d, J = 12.0 Hz, 1 H), 3.53-3.66 (m, 5 H), 3.20-3.35 (m, 2 H), 1.89-2.13 (m, 5 H). ^¹³C NMR (100 MHz, DMSO): δ = 177.2, 163.8, 151.5, 141.9, 103.0, 81.1, 79.9, 72.0, 61.9, 52.6, 51.1, 50.1, 21.6. HRMS: m/z [M + Na] calcd for C₁₃H₁₉N₃O₈: 368.1070; found: 368.1065.