A Flexible, Efficient Synthesis of (±)-Carbocyclic Phosphonic Acid Nucleoside Derivatives

Abstract

An efficient and flexible synthesis of cyclopentane and hydroxylated cyclopentane phosphonic acid analogues is described. The key step involves the opening of an epoxide with either a nu­cleoside base or a selenyl anion to access the target molecules.

Key words

phosphonic acids - ribose analogues - nucleosides - ­epoxide

References

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• 2 See for example: el Kouni MH. Curr. Pharm. Des.  2002,  8:  581 ; and references therein
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• 3b Erion MD. Raja Reddy K. Boyer SH. Matelich MC. Gomez-Galeno J. Lemus RH. Ugarkar BG. Colby TJ. Schanzer J. van Poelje PD. J. Am. Chem. Soc.  2004,  126:  5154 
• 4 Dando T. Plosker G. Drugs  2003,  63:  2215 
• 5 For a recent review of ribose-modified nucleosides, see: Ichikawa E. Kato K. Synthesis  2002,  1 
• 6 Ravenscroft P. Newton RF. Scopes DIC. Tetrahedron Lett.  1986,  27:  747 
• 7a Ogawa A. Shuto S. Tanaka M. Sasaki T. Mori S. Shigeta S. Matsuda A. Chem. Pharm. Bull.  1999,  47:  1000 
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• 7d Crimmins MT. King BW. Zuercher WJ. Choy AL. J. Org. Chem.  2000,  65:  8499 
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• 8b Depres J.-P. Greene AE. J. Org. Chem.  1984,  49:  928 
• 9 Agrofoglio L. Condom R. Guedj R. Tetrahedron Lett.  1992,  33:  5503 
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• 11 Asami M. Takahashi J. Inoue S. Tetrahedron: Asymmetry  1994,  5:  1649 
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• 13 Assumed to be the diastereoisomer shown by direct analogy to literature reports for such π-allyl Pd-mediated base attachments.⁷

14

Assignment of facial selectivity for the initial osmylation, and cis- and trans-diols was made by proton NMR methods (Figure [2] ), by firstly rigorously assigning each proton using COSY, followed by NOE experiments (vide infra).

Figure 2 NOE assignments for the cis-diol 27 and the trans-diol 30.

15

Experimental Procedure, Preparation of 19.
To a solution of 6-amino-purine (1 g, 7.4 mmol) in N,N-dimethylformamide (160 mL) was added Cs₂CO₃ (4.82 g, 14.8 mmol, 2 equiv), Kryptofix 2.2.2 (279 mg, 0.74 mmol, 0.1 equiv) and 4a (4.27 g, 16.3 mmol, 2.2 equiv). The reaction mixture was stirred under argon at 120 °C for 4 d. After this time, HPLC analysis indicated that the reaction was 20% complete, therefore a further 1.94 g (1 equiv) 4a were added and stirring continued at 120 °C for a further 5 d. The reaction mixture was then cooled, concentrated in vacuo purified by flash chromatography (silica, 5-20% MeOH in CH₂Cl₂) to give 1.2 g (41%) of the phosphonate ester as a yellow solid; mp 157-159 °C. ¹H NMR (CD₃OD): δ = 1.31 (d, 12 H), 1.90-2.20 (m, 5 H), 2.60-2.80 (m, 2 H), 4.65 (m, 2 H), 8.16 (2 × s, 2 H); LRMS (ES⁺): m/z (rel. int.) = 398.24 [M + H]⁺. Chemical purity by HPLC, Synergy Hydro RP18 4.6 × 150 mm, 0-40% MeCN over 20 min then held for 5 min, aq phase 20 mM NaH₂PO₄, pH 2, 93.7% (260 nm). Bromotrimethylsilane (4.9 mL, 3.7 mmol, 3.3 equiv) was added to a portion of this ester (450 mg, 1.13 mmol) in MeCN (10 mL) and then stirred overnight at r.t. The reaction mixture was concentrated in vacuo, added to H₂O (10 mL) and adjusted to pH 4.5 with 1 M NaOH solution. After removing the solvent in vacuo the residue was added to H₂O (3 mL). Then, 5 drops of TFA were added and the resultant solution purified by preparative HPLC. Freeze drying gave 260 mg (74%) of 19 as a white solid. ¹H NMR (18% DCl in D₂O): δ = 0.15-0.40 (m, 5 H), 0.75-0.90 (m, 2 H), 2.90 (m, 1 H), 3.25 (m, 1 H), 6.85 (s, 1 H), 7.85 (s, 1 H). R _f = 0.6 (1:1:1:1:1 toluene-acetone-BuOH-H₂O-HOAc). LRMS (ES⁺): m/z (rel. int.) = 314.10 [M + H]⁺. Chemical purity by HPLC, Synergy Hydro RP18 4.6 × 150 mm, 0-20% MeCN over 20 min then held for 5 min, aq phase 20 mM NaH₂PO₄, pH 7, 96.97% (261 nm).

16

Experimental Procedure, Preparation of 21.
To a stirred solution of diphenyl diselenide (180 g, 0.58 mol, 1 equiv) in EtOH (8 L) at 0 °C was slowly added in small portions NaBH₄ over 70 min. Compound 4b (262 g, 1.15 mol, 2 equiv) was then added dropwise to the reaction mixture over 15min and the solution was allowed to warm to r.t. The reaction mixture was subsequently heated at reflux for 1 h, air was blown over the cooled solution, and the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ (2 L), the organic fraction was washed with H₂O (2 × 300 mL) and brine (300 mL), dried over MgSO₄, and the solvent was removed in vacuo. The crude hydroxy-selenide (39 g, 88.7 mmol, 1 equiv) was subsequently dissolved in CH₂Cl₂ (400 mL) and Et₃N (12.7 mL, 90.9 mmol, 1 equiv) and 4-(dimethylamino)pyridine (4 mg, 0.033 mmol) were added. The reaction mixture was then cooled to 0 °C and acetic anhydride (8.5 mL, 90.1 mmol, 1 equiv) was added dropwise over 15 min. The reaction mixture was then stirred at r.t. overnight. Then, CH₂Cl₂ (1 L) and H₂O (1 L) were added, the organic layer was separated, washed with H₂O and brine, and the solvent was removed in vacuo to give crude 20 (450 g, 100%) as an oil. ¹H NMR (CDCl₃): δ = 0.02 (s, 6 H), 0.87 (s, 9 H), 1.43 (m, 1 H), 1.83 (m, 1 H), 1.92 (s, 3 H), 2.02 (m, 1 H), 2.26-2.39 (m, 2 H), 3.51 (d, 2 H), 3.64 (m, 1 H), 5.11 (m, 1 H), 7.22-7.29 (m, 3 H), 7.51-7.62 (m, 2 H). A portion of crude 20 (20 g, 48.2 mmol, 1 equiv) was taken up and stirred in CH₂Cl₂ (150 mL) at 0 °C and to this was added 35% aq H₂O₂ (50 mL) and N,N-diisopropyl-ethylamine (18.5 mL, 106 mmol, 2.2 equiv). After stirring for 15 min, 1-BuOH (75 mL) was added and the reaction mixture was heated at 50 °C for 40 min. The reaction mixture was then allowed to cool to r.t. and 1 M citric acid (200 mL) was added. The organic layer was washed with sat. NaHCO₃ (200 mL) and brine (200 mL), and was then concentrated in vacuo. The residue was dissolved in hexane (500 mL) and washed with H₂O (2 × 500 mL). The organic phase was filtered and concentrated under vacuum to give 21 (10 g, 79%) as a brown oil. ¹H NMR (CDCl₃): δ = 0.06 (s, 6 H), 0.85 (s, 9 H), 1.49 (dt, 1 H), 2.02 (s, 3 H), 2.39 (dt, 1 H), 2.80 (m, 1 H), 3.52 (d, 2 H), 5.62 (m, 1 H), 5.84 (m, 1 H), 6.02 (m, 1 H).

17

Experimental Procedure, Preparation of 31.
The cyclopentene 24 (1.63 g, 4.60 mmol) was dissolved in acetone (5 mL) and to this NMO (539 mg, 9.2 mmol) was added followed by 1% OsO₄ in H₂O (2.5 mL). This mixture was heated at 50 °C overnight. More NMO (50 mg, 0.85 mmol) was added and stirred for a further 2 h at 50 °C. The solution was then concentrated by evaporation and purified by flash chromatography (85:15 CH₂Cl₂-MeOH) to give 27 (220 mg, 0.56 mmol, 12%) and 30 (530 mg, 1.36 mmol, 29%). Analytical data for 27: R _f = 0.3 (10% MeOH in CH₂Cl₂). ¹H NMR (CD₃OD): δ = 1.30 (d, 12 H), 1.70 (m, 1 H), 1.90 (m, 1 H), 2.15 (m, 2 H), 2.30 (m, 1 H), 4.05 (t, 1 H), 4.20 (dd, 1 H), 4.65 (m, 2 H), 5.10 (m, 1 H), 5.65 (d, 1 H), 7.90 (d, 1 H). Analytical data for 30: R _f = 0.2 (10% MeOH in CH₂Cl₂). ¹H NMR (CD₃OD): δ = 1.30 (d, 12 H), 1.60 (m, 1 H), 1.80 (m, 1 H), 2.15 (m, 2 H), 2.35 (m, 1 H), 3.80 (t, 1 H), 4.20 (t, 1 H), 4.45 (m, 1 H), 4.65 (m, 2 H), 5.65 (d, 1 H), 7.60 (d, 1 H). Trimethylsilylbromide (1.8 mL, 13.6 mmol) was added to a stirred solution of 30 (530 mg, 1.36 mmol) in MeCN (20 mL) under an atmosphere of nitrogen, the reaction mixture was stirred overnight at r.t. The reaction was not complete and therefore more trimethylsilylbromide (2 mL) was added. This mixture was left at r.t. for a further 2 d. The solvent was then removed under vacuum. Then, H₂O (10 mL) was added to the reaction mixture, which was basified with 1 M aq NaOH and subsequently acidified with TFA. The solvent was removed under reduced pressure and H₂O (10 mL) was added. The crude product was purified by HPLC (0.1% TFA in H₂O 10 min, then 10% MeCN, Atlantis) and freeze dried to give 31 (245 mg, 0.80 mmol, 59%). R _f = 0.30 (1:1:1:1:1 toluene-acetone-butan-1-ol-H₂O-HOAc). ¹H NMR (D₂O): δ = 1.30-1.60 (m, 2 H), 1.70-2.00 (m, 2 H), 2.15 (m, 1 H), 3.80 (m, 1 H), 4.00 (dd, 1 H), 4.90 (q, 1 H), 5.50 (d, 1 H), 7.80 (d, 1 H), 11.10 (s, 1 H). LRMS (ES⁺): m/z (rel. int.) = 307.12 [M + H]⁺. Chemical purity by HPLC, Synergy Hydro 4.6 × 150 mm, 1.0 mL/min, 0- 40% MeCN over 20 min then to 70% over 5 min, held at 70% for 5 min, aq phase 20 mM NaH₂PO₄, pH 2.5, 97.82% (270 nm).