References and Notes
<A NAME="RD31707ST-1">1</A>
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.
<A NAME="RD31707ST-2A">2a</A> See, for example:
el Kouni MH.
Curr. Pharm. Des.
2002,
8:
581 ; and references therein
<A NAME="RD31707ST-2B">2b</A> For a recent review of ribose-modified nucleosides, see:
Ichikawa E.
Kato K.
Synthesis
2002,
1
<A NAME="RD31707ST-3">3</A>
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.
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<A NAME="RD31707ST-4">4</A>
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Marx A.
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<A NAME="RD31707ST-5">5</A>
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.
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<A NAME="RD31707ST-6">6</A>
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Miguel C.
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<A NAME="RD31707ST-7">7</A>
Vorbrueggen H.
Ruh-Pohlenz C. In
Handbook of Nucleoside Synthesis
John Wiley & Sons, Inc.;
Chichester (UK):
2001.
<A NAME="RD31707ST-8">8</A> For a range of protection/deprotection methods and primary references, see:
Greene TW.
Wuts PGM.
In Protecting Groups in Organic Synthesis
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1999.
<A NAME="RD31707ST-9">9</A>
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) Å3, D
c = 1.459 Mg/m3, Mo-Kα 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 data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK, fax: +44(1223)336033.
<A NAME="RD31707ST-10">10</A> 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
<A NAME="RD31707ST-11A">11a</A>
Bio MM.
Xu F.
Waters M.
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Savary KA.
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<A NAME="RD31707ST-11B">11b</A>
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<A NAME="RD31707ST-11C">11c</A>
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Hotchkiss D.
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Acta Crystallogr., Sect. E: Struc. Rep. Online
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o98
<A NAME="RD31707ST-11D">11d</A>
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<A NAME="RD31707ST-12">12</A>
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<A NAME="RD31707ST-13">13</A>
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).
<A NAME="RD31707ST-14">14</A>
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).
<A NAME="RD31707ST-15">15</A>
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).