New Synthesis of 2′,4′-Functionalized Nucleotides via Stereospecific Hydrogenation and Azidation Reactions

This paper is dedicated to Professor E. J. Corey, without whom our chemistry world would not be what it is today.

Abstract

The synthesis of an anti-infective nucleoside derivative was accomplished through selective hydrogenation using an achiral ligand to establish the stereochemistry of the 2′ stereogenic center. The quaternary 4′ center was introduced through stereoselective epoxidation with dimethyl dioxirane followed by a regioselective, stereospecific epoxide opening with trimethylsilyl azide.

Key words

homogeneous hydrogenation - nucleotide synthesis - dimethyl dioxirane - azides

• References and Notes

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• 9 Representative Procedures: [Rh(nbd)₂]BF₄ (0.04 kg) and 12 (0.05 kg) were mixed in MeOH (57.9 kg) and Ar was bubbled through the solution. The solution was transferred to a mixture of compound 3 (27.7 kg) in MeOH (57.9 kg), which had also been degassed by bubbling Ar. The reaction was hydrogenated for 3 h at 43–47 °C (20 bar H₂) until HPLC analysis indicated complete consumption of compound 3 (conversion >98%). The reaction mixture was cooled to 20–25 °C and filtered, the filtrate was concentrated to give a solution of the product in MeOH (80.3 kg, containing 27.37 kg of 4 by HPLC quantitative assay), and the solution was used directly in the next step. Yield: 98.0%; purity: 99.7% (HPLC); 98.6% de. For the synthesis from 4 → 5 see the method developed by Campeau and O’Shea.⁵ A mixture of 5 (1000 g, 1.0 equiv), imidazole (454 g, 1.5 equiv) and DMF (2000 mL, 2V) was placed under nitrogen. A solution of TBSCl (941 g, 1.4 equiv) in DMF (8 L, 8V) was added dropwise at 25–30 °C over 1 h. The mixture was stirred at 25–30 °C for 16 h until HPLC analysis indicated complete consumption of 4 (conversion >99.5%). The mixture was added to H₂O (11 L, 11V) dropwise at 10–20 °C to form a precipitate. The reaction mixture was stirred for 2 h, then the precipitate was filtered, washed with H₂O (2 L) and then dried under vacuum to give an off-white solid. Yield of 5a: 91%; purity: 97% (HPLC); off-white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.29 (s, 1 H, NH), 7.26 (d, J = 8 Hz, 1 H, CH), 6.13 (d, J = 7.2 Hz, 1 H, CH), 5.50 (d, J = 8 Hz, 1 H, CH), 4.43 (d, J = 8 Hz, 1 H, CH), 4.29 (s, 1 H, CH₂), 3.97 (s, 1 H, CH₂), 2.42 (m, 1 H, CH), 0.75 (s, 9 H, t-Bu), 0.71 (d, J = 7.2 Hz, 3 H, CH₃), 0.00 (s, 6 H, CH₃). ¹³C NMR (DMSO-d ₆): δ = 162.9, 162.6, 150.3, 141.2, 101.8, 87.5, 83.5, 75.0, 43.2, 30.6, 25.5, 17.5, 10.7, –4.53, –4.58. HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₆N₂O₄Si: 339.1735; found: 339.1740. A solution of 5a (45.8 g, 1.0 equiv) in CH₂Cl₂ (687 mL, 15V) was treated with NaHCO₃ (170.6 g, 15.0 equiv), H₂O (458.1 mL, 10V) and acetone (314.4 g, 40 equiv). The mixture was cooled to 0 °C and treated with a solution of oxone (283.4 g) in H₂O (1428.2 mL, 31V) added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h until HPLC analysis indicated complete consumption of 5a (conversion >99%). The mixture was filtered below 5 °C and the cake was washed with pre-cooled CH₂Cl₂ (91.6 mL, 2V). The organic layer was washed with saturated Na₂SO₃ solution (458 mL, 10V), brine (458 mL, 10V), and then dried with Na₂SO₄ (4 × 1832 g) below 5 °C. After filtration, the solution was distilled below 0 °C at constant volume until GC analysis indicated the acetone was removed (<0.1% by volume). The volume of CH₂Cl₂ was adjusted (458 mL, 10V) and the mixture was cooled to –10 °C followed by addition of neat TMSN₃ (15.6 g, 1.0 equiv). A ZnCl₂ solution (41.5 g, 46.7% in Me-THF, 1.05 equiv) was added at –10 °C dropwise, then the reaction mixture was stirred at –10 °C for 1 h until HPLC analysis indicated complete consumption of 6 (conversion >99%). Propylamine (80.0 g, 10 equiv) was added dropwise at –10 °C and then the mixture was warmed to 0 °C slowly. H₂O (229.1 mL, 5V) was added at 0 °C and the mixture was stirred for 30 min. The mixture was warmed to 25 °C slowly, separated, and the organic layer was washed with H₂O (3 × 5V). The CH₂Cl₂ solution was exchanged with toluene to form a heavy suspension. The precipitate was filtered, washed with toluene (2 × 1V) and then dried in vacuum to give 7 (43 g, 84%, 98.5% HPLC purity) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.33 (s, 1 H, NH), 7.66 (d, J = 8 Hz, 1 H, CH), 6.17 (d, J = 8 Hz, 1 H, CH), 5.75 (s, 1 H, OH), 5.58 (d, J = 8 Hz, 1 H, CH), 4.12 (d, J = 10 Hz, 1 H, CH), 3.68 (dd, J = 12, 5.2 Hz, 1 H, CH₂), 3.59 (dd, J = 12, 5.2 Hz, 1 H, CH₂), 2.40 (m, 1 H, CH), 0.78 (s, 9 H, t-Bu), 0.76 (d, J = 6.4 Hz, 3 H, CH₃), 0.01 (s, 6 H, CH₃). ¹³C NMR (DMSO-d ₆): δ = 162.8, 150.4, 101.7, 98.3, 84.6, 75.7, 60.6, 41.2, 25.4, 17.5, 10.9, –4.5, –4.6. HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₇N₅O₅Si: 420.1674; found: 420.1673.