Synthesis of Enantiomerically Pure 4-Substituted Riboses

Abstract

An efficient and flexible synthesis of 4-substituted ribose analogues is described. The key step involves the simple addition of a Grignard reagent to a ketone derived from a commercially available ribose. The addition of a range of Grignard reagents proceeded in high yield and with complete stereocontrol, to provide a single enantiomer in every case, the identity of which was confirmed by single-crystal X-ray crystallography. This addition is unaffected by substitution at the 2-position of the starting ribose.

ribose - deoxyribose - nucleosides - antivirals - stereocontrol

References and Notes

1 Dan A. Iino T. Yoshimura Y. Minakawa N. Tanaka M. Saraki T. In Nucleosides and Nucleotides as Anti-Tumor and Anti-Viral Agents   Chu C. Baker DC. Plenum Publishing Co.; New York: 1993. 

2a See, for example: el Kouni MH. Curr. Pharm. Des.  2002,  8:  581 ; and references therein

2b For a recent review of ribose-modified nucleosides, see: Ichikawa E. Kato K. Synthesis  2002,  1 

3 Klumpp K. Leveque V. Le Pogam S. Ma H. Jiang W.-R. Kang H. Granycome C. Singer M. Laxton C. Hang JQ. Sarma K. Smith DB. Heindl D. Hobbs CJ. Merrett JH. Symons J. Cammack N. Martin JA. Devos R. Najera I. J. Biol. Chem.  2006,  281:  3793 

4 Summerer D. Marx A. Bioorg. Med. Chem. Lett.  2005,  15:  869 

5 Wainwright P. Maddaford A. Bissell R. Fisher R. Leese D. Lund A. Runcie K. Dragovich PS. Gonzalez J. Kung P. Middleton DS. Pryde DC. Stephenson PT. Sutton SC. Synthesis  2007,  1378 

6 Alberto MJ. Miguel C. Florenci G. Santiago R. Encarna C. Juan M. J. Org. Chem.  1998,  63:  698 

7 Vorbrueggen H. Ruh-Pohlenz C. In Handbook of Nucleoside Synthesis   John Wiley & Sons, Inc.; Chichester (UK): 2001. 

8 For a range of protection/deprotection methods and primary references, see: Greene TW. Wuts PGM. In Protecting Groups in Organic Synthesis   3rd ed.:  John Wiley & Sons, Inc.; New Jersey (USA): 1999. 

9

Crystal data for 21: C₁₂H₁₇N₃O₅, orthorhombic, P2₁2₁2₁, a = 15.1487(16), b = 24.363(3), c = 6.9867(8) Å, Z = 8, V = 2578.6(5) ų, D _c = 1.459 Mg/m³, Mo-K_α radiation, λ = 0.71073 Å, 5.4 2θ 44.6. Bruker AXS SMART-APEX diffractometer was used to collect the data; 21867 reflections were collected of which 5995 unique reflections [I >2σ(I)] were used for refinement (401 parameters), converging to R = 0.058 and R _w = 0.1297. The configuration of 21 was determined relative to the known configuration of the starting material and was not determined directly from the X-ray diffraction data. CCDC 662745 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, fax: [phone].

10 See, for example: Eldrup AB. Prhavc M. Brooks J. Bhat B. Prakash TP. Song Q. Bera S. Bhat N. Dande P. Cook PD. Bennett CF. Carroll SS. Ball RG. Bosserman M. Burlein C. Colwell LF. Fay JF. Flores OA. Getty K. LaFemina RL. Leone J. MacCoss M. McMasters DR. Tomassini JE. Von Langen D. Wolanski B. Olsen DB. J. Med. Chem.  2004,  47:  5284 ; and references therein

11a Bio MM. Xu F. Waters M. Williams JM. Savary KA. Cowden CJ. Yang C. Buck E. Song ZJ. Tschaen DM. Volante RP. Reamer RA. Grabowski EJJ. J. Org. Chem.  2004,  69:  6257 

11b Girardet J.-L. Gunic E. Esler C. Cieslak D. Pietrzkowski Z. Wang G. J. Med. Chem.  2000,  43:  3704 

11c Punzo F. Watkin DJ. Hotchkiss D. Fleet GWJ. Acta Crystallogr., Sect. E: Struc. Rep. Online  2006,  62:  o98 

11d Jenkinson SF. Jones NA. Moussa A. Stewart AJ. Heinz T. Fleet GWJ. Tetrahedron Lett.  2007,  48:  4441 

12 Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis  2004,  639 

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Representative Experimental Procedure for the Preparation of 30: To a solution of 27 (19.9 g, 36 mmol) in THF (300 mL) at -78 °C, was added a 3 M solution of MeMgBr in THF (17.8 mL, 53 mmol) over 10 min. The reaction mixture was stirred for 15 min and allowed to self warm to r.t. After 30 min, the reaction mixture was quenched with MeOH and diluted with EtOAc. The mixture was washed with 1 N HCl, dried over MgSO₄ and evaporated to give 28 (18.7 g, 91%). This was used crude without further purification; R _f = 0.55 (hexane-EtOAc, 8:1). To a solution of 28 (18.7 g, 32 mmol) in THF (200 mL) was added a 1 M solution of TBAF in THF (35.7 mL, 35 mmol). The mixture was stirred for 3 h at r.t., diluted with EtOAc and washed with brine-H₂O (1:1, 3 ×). The organics were dried over MgSO₄, filtered and evaporated to give 29 (15.6 g) which was used without further purification; R _f = 0.34 (hexane-EtOAc, 2:1). To a solution of 29 (15.6 g, 34 mmol) in CH₂Cl₂ (600 mL) was added NMO (13.8 g, 120 mmol), TPAP (0.25 g, 0.7 mmol) and 4 Å MS (100 g). The mixture was then stirred for 6 h at r.t., filtered and washed with H₂O. The organics were dried over MgSO₄ and evaporated to provide a residue that was purified by flash column chromatography eluting with CH₂Cl₂-hexane (7:3) to give 30 (9.8 g, 66% over two steps); R _f = 0.60 (CH₂Cl₂-hexane, 7:3). ¹H NMR (CDCl₃): δ = 1.40 (s, 3 H), 1.43 (s, 3 H), 1.45 (s, 3 H), 1.47 (s, 3 H), 3.21 (d, 1 H), 3.28 (d, 1 H), 3.72 (s, 1 H), 7.25-7.38 (m, 15 H).

14

Experimental Procedure for the Preparation of 35: A suspension of N-benzoyladenine (1.6 g, 6.7 mmol) and bis(trimethylsilyl)acetamide (3.3 mL, 13.4 mmol) in MeCN (40 mL) was heated at reflux for 40 min. The mixture was cooled to r.t., and 33 (2.0 g, 3.4 mmol) was added followed by TMSOTf (1.8 mL, 10 mmol). The resulting mixture was heated at reflux for 6 h, cooled to r.t., diluted with EtOAc and washed with sat. NaHCO₃. The organics were dried over MgSO₄ and evaporated to give a residue that was purified by flash column chromatography eluting with 2% MeOH-CH₂Cl₂ to provide 34 (1.6 g, 67%) as a white foam; R _f = 0.41 (2% MeOH-CH₂Cl₂). ¹H NMR (CDCl₃): δ = 1.62 (s, 3 H), 1.66 (s, 3 H), 4.76 (dd, 2 H), 6.27 (s, 1 H), 6.81 (s, 1 H), 7.30-7.60 (m, 12 H), 7.96-8.10 (m, 8 H), 8.30 (s, 1 H), 8.86 (s, 1 H), 9.33 (br s, 1 H, NH).
A mixture of 34 (1.6 g, 2.2 mmol) and 16% NH₃-MeOH (50 mL) was left standing at r.t. for 3 d. After concentration in vacuo, the residue obtained was stirred in MeOH-CH₂Cl₂ (1:1; 15 mL) and the resulting white solid was filtered and dried to give 35 (0.37 g, 56%) as a white solid. ¹H NMR (D₂O): δ = 0.78 (s, 3 H), 1.20 (s, 3 H), 3.56 (dd, 2 H), 4.09 (s, 1 H), 6.06 (s, 1 H), 8.05 (s, 1 H), 8.25 (s, 1 H). MS: m/z (%) = 296.01 [M + H]⁺. Chemical purity by HPLC: Atlantis dC18, 3 × 150 mm, 3 µM, 0-50% MeCN over 15 min, then 50-95% MeCN over 5 min then held for 5 min (aqueous phase containing 0.1% TFA in H₂O), 98.43% (257 nm).

15

Representative Experimental Procedure for the Preparation of 20a: Bis(trimethylsilyl)acetamide (3.8 mL, 16 mmol) was added to a suspension of N-benzoylcytosine (1.67 g, 8 mmol) in MeCN (30 mL) under argon and the reaction mixture was heated at reflux temperature for 30 min. After cooling to r.t., 19 (2.0 g, 4 mmol) was added followed by TMSOTf (2.1 mL, 12 mmol). The reaction mixture was then heated at reflux for 1.5 h, allowed to cool, diluted with EtOAc and sat. NaHCO₃ and stirred for 5 min. The mixture was filtered and the organic phases were separated, dried over MgSO₄ and concentrated in vacuo. The resulting white foam was further purified by flash silica chromatography eluting with CH₂Cl₂-EtOAc-MeOH (1:1:0.1) to give 20a (0.52 g, 31%) as a white foam and the corresponding α-anomer (0.49 g, 30%) as a white foam. Data for β-anomer: R _f = 0.59 (CH₂Cl₂-EtOAc-MeOH, 1:1:0.1). ¹H NMR (MeOD-d ₃): δ = 0.34-0.43 (m, 2 H), 0.50-0.60 (m, 2 H), 0.96-1.06 (m, 1 H), 1.36 (s, 3 H), 1.58 (s, 3 H), 3.68 (s, 2 H), 4.88-4.94 (m, 2 H), 5.85 (d, 1 H), 7.50-7.67 (m, 4 H), 7.96 (d, 2 H), 8.40 (d, 1 H). Data for α-anomer: R _f = 0.40 (CH₂Cl₂-EtOAc-MeOH, 1:1:0.1). ¹H NMR (MeOD-d ₃): δ = 0.41-0.50 (m 2 H), 0.55-0.73 (m, 2 H), 1.10-1.20 (m, 1 H), 1.30 (s, 3 H), 1.35 (s, 3 H), 3.62 (s, 2 H), 4.83-4.87 (m, 1 H), 5.08 (dd, 1 H), 6.34 (d, 1 H), 7.50-7.67 (m, 4 H), 7.95 (d, 2 H), 8.06 (d, 1 H).