954 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
EVans et al.
meso-1-[(7-Benzyloxymethyl-9-deaza-6-methoxypurin-9-yl)m-
ethyl]azetidine-2,4-dimethanol Hydrochloride (37). To a stirred
solution of aldehyde 36 (277 mg, 0.93 mmol) in EtOH (3 mL) at
ambient temperature was added 3·HCl (143 mg, 0.93 mmol)
followed after 5 min by NaBH3CN (88 mg, 0.48 mmol). The
mixture was left to stir overnight, after which time all of the starting
aldehyde had dissolved. The reaction mixture was absorbed onto
silica gel, the volatiles were removed under reduced pressure, and
the product was purified by flash chromatography (CHCl3/MeOH
) 95:5 to 80:20) to give colorless crystals, which were taken up in
water. Concentrated HCl was added and the mixture was then
concentrated under reduced pressure to dryness to afford 37 (70
mg, 54%). 1H NMR (300 MHz, D2O): δ 8.61 (s, 1H), 8.02 (s, 1H),
7.25–7.07 (m, 5H), 5.90 (s, 2H), 4.68 (s, 2H), 4.58 (s, 2H),
4.54–4.43 (m, 2H), 4.24 (s, 3H), 3.72 (dd, J ) 13.2, 5.7 Hz, 2H),
3.61 (dd, J ) 13.2, 3.2 Hz, 2H), 2.47 (dt, J ) 12.1, 9.0 Hz, 1H),
2.28 (dt, J ) 9.6, 9.0 Hz, 1H). 13C NMR (75 MHz, D2O): δ 159.4,
148.4, 142.5, 139.9, 137.0, 128.8, 128.6, 128.2, 116.7, 102.6, 78.7,
72.0, 66.6, 60.2, 56.5, 47.3, 20.4. ESI-HRMS for C21H27N4O4 [M
+ H+] calcd, 399.2032; found, 399.2046.
meso-[(9-Deazahypoxanthin-9-yl)methyl]azetidine-2,4-dimeth-
anol Hydrochloride (40). A solution of 37 (114 mg, 0.26 mmol)
in concentrated HCl (3 mL) was heated under reflux for 3 h and
then cooled to room temperature. The mixture was evaporated to
dryness under reduced pressure, and residual HCl was removed by
the addition and evaporation of acetonitrile several times. The
residue was absorbed onto silica and purified by flash chromatog-
raphy (2-propanol/H2O/NH4OH ) 9:1:1) to give a colorless gum.
This was converted to its hydrochloride salt for characterization
by the addition and evaporation of concentrated HCl, yielding 40
as a colorless solid (53 mg, 67%) after trituration with 2-propanol.
HPLC purity: 99.5% (220 nm). 1H NMR (300 MHz, D2O): δ
8.21–8.15 (m, 1H), 7.75–7.72 (m, 1H), 4.57 (s, 2H), 4.50 (dddd, J
) 9.0, 9.0, 5.5, 3.6 Hz, 2H), 3.69 (13.3, 5.5 Hz, 2H), 3.58 (dd, J
) 13.3, 3.6 Hz, 2H), 2.48–2.36 (m,1H), 2.28 (dt, J ) 12.1, 9.0,
Hz, 1H). 13C NMR (75 MHz, D2O, freebase): δ 155.9, 144.2, 142.9,
130.2, 117.5, 111.5, 64.5, 62.7, 49.1, 24.0. ESI-HRMS for
C12H17N4O3 [M + H+] calcd, 265.1301; found, 265.1316. Anal.
(C12H16N4O3 ·2.6H2O) C, H, N.
Hz, 1H), 2.54–2.37 (m, 2H). 13C NMR (75 MHz, D2O): δ 154.2,
144.7, 137.7, 132.4, 118.6, 104.1, 67.8, 64.7, 60.0, 58.8, 42.5, 20.6.
ESI-HRMS for C12H17N4O3 [M + H+] calcd, 265.1301; found,
265.1316.
(()-1-[(7-Benzyloxymethyl-9-deaza-6-methoxypurin-9-yl)m-
ethyl]azetidine-2-methanol (39). To a stirred solution of 30 (162
mg, 0.86 mmol) dissolved in MeOH (2 mL) was added concentrated
HCl (1 mL). The reaction mixture was stirred for 20 min and then
concentrated under reduced pressure. Residual HCl was removed
by the addition and evaporation of acetonitrile several times to
afford 5 as the HCl salt, which was committed to the next step
without purification or characterization. The gumlike hydrochloride
salt 5 was taken up in EtOH (10 mL) and aldehyde 36 (197 mg,
0.66 mmol) followed by the addition of NaBH3CN (63 mg, 0.99
mmol). The reaction mixture was allowed to stir overnight and then
acidified to pH 1 using concentrated HCl. A small amount of HCN
was evolved at this point. The reaction mixture was absorbed onto
silica under reduced pressure and the product purified by flash
chromatography (CHCl3/MeOH/NEt3 ) 90:10:0.5) to give 39 as a
colorless solid (170 mg, 69%), mp 214–216 °C. 1H NMR (300
MHz, CDCl3): δ 8.52 (s, 1H), 7.33 (s, 1H), 7.31–7.20 (m, 5H),
5.70 (s, 2H), 4.45 (s, 2H), 4.09 (s, 3H), 3.97 (d, J ) 13.5 Hz, 1H),
3.80 (d, J ) 13.5 Hz, 1H), 3.68 (br s, 1H), 3.55–3.46 (m, 1H),
3.45–3.42 (m, 2H), 3.34 (ddd, J ) 8.8, 6.9, 2.5 Hz, 1H), 3.01 (ddd,
J ) 8.7, 8.7, 7.3 Hz, 1H), 2.14–2.00 (m, 1H), 1.90 (dddd, J )
10.1, 8.1, 8.1, 2.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 156.2,
149.9, 149.8, 136.7, 131.5, 128.3, 127.8, 127.5, 115.8, 114.0, 76.8,
70.0, 66.6, 64.0, 53.5, 51.3, 50.6, 18.7. ESI-HRMS for C20H25N4O3
[M + H+] calcd, 369.1927; found, 369.1948.
(()-1-[(9-Deazahypoxanthin-9-yl)methyl]azetidine-2-metha-
nol (42). A solution of 39 (68 mg, 0.18 mmol) was heated to reflux
in concentrated HCl (3 mL) for 2 h. The mixture was concentrated
under reduced pressure and then azeotropically dried by the addition
and evaporation of acetonitrile. The residue was purified by flash
chromatography on silica (CHCl3/MeOH/H2O/NH4OH ) 65:35:
7:1) to give 42 as an amorphous white solid (33 mg, 76%), mp
213–216 °C. HPLC purity: 98.9% (220 nm). 1H NMR (300 MHz,
60:40 CD4OD/D2O): δ 8.03 (s, 1H), 7.60 (s, 1H), 4.23 (d, J )
13.8 Hz, 1H), 4.08 (d, J ) 13.5 Hz, 1H), 4.10–3.98 (m, 1H),
3.65–3.49 (m, 4H), 2.27–2.11 (m, 2H). 13C NMR (75 MHz, 60:40
CD4OD/D2O): δ 156.1, 144.9, 143.6, 130.8, 118.7, 109.9, 68.3,
63.4, 51.1, 49.4, 20.0; ESI-HRMS for C11H15N4O2 [M + H] calcd,
235.1195; found, 235.1196.
(()-(2R,4R)-1-[(7-Benzyloxymethyl-9-deaza-6-methoxypurin-
9-yl)methyl]azetidine-2,4-dimethanol Hydrochloride (38). To a
stirred solution of aldehyde 36 (210 mg, 0.70 mmol) in EtOH (7
mL) at ambient temperature was added 4·HCl (100 mg, 0.65 mmol)
followed after 5 min by NaBH3CN (67 mg, 1.0 mmol). The mixture
was left to stir overnight, after which time most of the starting
aldehyde had dissolved. The reaction mixture was absorbed onto
silica gel under reduced pressure and the product purified by flash
chromatography (CHCl3/MeOH ) 95:5 to 80:20) to give colorless
crystals, which were taken up in water. Concentrated HCl was
added, and then the mixture was concentrated under reduced
pressure to afford 38 as a colorless hygroscopic solid (235 mg,
1-[(9-Deazaadenin-9-yl)methyl]-3-methylthiomethylazetidine-
3-methanol Hydrochloride (43). NaOAc (134 mg, 1633 µmol)
was added to a solution of 9·HCl (300 mg, 1.6 mmol) in water (4
mL) and 1,4-dioxane (2 mL), and the resulting suspension was
stirred at room temperature for 5 min. Formaldehyde solution (0.131
mL, 1.6 mmol) was then added dropwise followed by 9-deazaad-
enine (241 mg, 1.8 mmol), and the resulting suspension was heated
to 95 °C (bath temperature). After 2 h, the crude reaction was
absorbed onto silica and concentrated in vacuo. Chromatography
(NH4OH/MeOH/CH2Cl2 ) 2:48:50) of the resulting residue af-
1
83%). H NMR (300 MHz, D2O): δ 8.78 (s, 1H), 8.13 (s, 1H),
7.20–7.04 (m, 5H), 5.86 (s, 2H), 4.62 (s, 2H), 4.62–4.47 (m, 3H),
4.27 (s, 3H), 4.26–4.04 (m, 2H), 3.57 (br d, J ) 10.5 Hz, 1H),
3.30 (br d, J ) 10.5 Hz, 1H), 2.46 (t, J ) 8.1 Hz, 2H). 13C NMR
(75 MHz, D2O): δ 160.0, 147.4, 140.2, 140.1, 136.9, 128.9, 128.7,
128.3, 116.8, 102.3, 78.8, 72.1, 68.4, 65.0, 60.2, 58.8, 57.0, 42.2,
20.8. ESI-HRMS for C21H27N4O4 [M + H+] calcd, 399.2032;
found, 399.2014.
1
forded 43 as a syrup (180 mg, 33.4%). H NMR (D2O): δ 7.88
(brs, 1H), 7.29 (brs, 1H), 3.81 (s, 2H), 3.46 (s, 2H), 3.37 (dd, J )
17.5, 9.8 Hz, 4H), 2.46 (s, 2H), 2.55 (m, 2H), 1.83 (s, 3H). 13C
NMR (D2O): δ 150.5, 150.2, 145.2, 130.5, 113.8, 106.2, 64.2, 57.8,
48.3, 39.8, 38.6, 16.5. HRMS for C13H19N5OS [MH+] calcd,
294.1388; found, 294.1388. Anal. (C13H19N5OS) C, H, N.
(()-(2R,4R)-[(9-Deazahypoxanthin-9-yl)methyl]azetidine-2,4-
dimethanol Hydrochloride (41). A solution of 38 (60 mg, 0.13
mmol) was heated to reflux in concentrated HCl (5 mL). After 3 h,
the mixture was concentrated under reduced pressure and the residue
purified by successive flash chromatography on silica (9:1:1
2-propanol/H2O/NH4OH and then 65:35:7:1 CHCl3/MeOH/H2O/
NH4OH). The isolated product was dissolved in 1 M HCl (2 mL)
and again concentrated in vacuo to give 41 as a hygroscopic
colorless gum (35 mg, 84%). HPLC purity: 96% (290 nm). 1H NMR
(300 MHz, D2O): δ 8.57 (s, 1H), 7.72 (s, 1H), 4.65 (d, J ) 6.9 Hz,
2H), 4.60–4.48 (m, 2H), 4.21 (dd, J ) 14.2, 6.4 Hz, 1H), 14.2, 3.0
Hz, 1H), 3.52 (dd, J ) 13.2, 4.6 Hz, 1H), 3.22 (dd, J ) 13.2, 3.4
1-[(9-Deazaadenin-9-yl)methyl]-3-methylthiomethylazeti-
dine (44). NaOAc (0.048 g, 0.586 mmol) was added to a solution
of 10·HCl (0.09 g, 0.586 mmol) in water (2 mL) and stirred for
15 min. Formaldehyde solution (0.047 mL, 0.586 mmol), 9-dea-
zaadenine (86 mg, 0.644 mmol), and 1,4-dioxane (1 mL) were
added consecutively, and the resulting suspension was stirred at
95 °C for 3 h. The crude reaction was absorbed onto silica and
concentrated in vacuo. Chromatography (NH4OH/MeOH/CH2Cl2
) 2:48:50) of the resulting residue afforded product contaminated
with ammonium acetate. Further chromatography using Amberlyst
15 (H2O f 2% aqueous NH4OH) afforded 44 as a syrup (80 mg,
1
52%). H NMR (D2O): δ 8.06 (s, 1H), 7.34 (s, 1H), 3.71 (s, 2H),