828
L.P. Tardibono Jr. et al. / Tetrahedron 67 (2011) 825e829
purified by column chromatography (silica gel; eluted with 6e8%
concentrated under high vacuum. A dilute solution of hydro-
chloric acid (0.5 M, 4 mL) was added and the mixture was stirred
at rt for 1 h. The mixture was neutralized to pH 8 with 1 M sodium
hydroxide and concentrated to solids. The crude material was
adsorbed on silica gel and purified by column chromatography
20
CH3OH/CH2Cl2) to give 21 mg of (þ)-4b as a clear oil (90%). [
a]
D
þ33 (c 0.1, CH3OH); 1H NMR (600 MHz, CD3OD)
d 0.58e0.62 (m,
2H), 0.82e0.86 (m, 2H), 1.57e1.64 (m, 1H), 1.74e1.81 (m, 1H),
2.13e2.16 (m, 2H), 2.88e2.95 (m, 1H), 3.10e3.18 (m, 1H), 3.60e3.70
(m, 2H), 5.50e5.54 (m, 1H), 5.91 (ddd, J¼2.4, 2.4, 5.4 Hz, 1H), 6.28
(ddd, J¼1.8, 1.8, 6.0 Hz, 1H), 7.59 (s, 1H); 13C NMR (150 MHz, CD3OD)
(silica gel; eluted with 8% CH3OH/CH2Cl2) to afford 70 mg of
20
(ꢀ)-14 as white powder (72%). Mp 70e71 ꢂC; [
a
]
ꢀ112 (c 0.1,
D
d
7.75, 24.5, 39.3, 39.7, 42.9, 60.6, 61.6, 115.1, 129.2, 137.1, 143.6, 151.7,
CH3OH); 1H NMR (600 MHz, CD3OD)
d 1.59e1.66 (m, 2H),
157.7, 162.1; IR (thin film) 1485, 1596, 3200, 3325 cmꢀ1; HRMS (ESI)
m/z [MþH]þ: calcd for C15H21N6Oþ, 301.1771; found, 301.1788.
1.81e1.87 (m, 1H), 2.85 (ddd, J¼7.8, 7.8, 13.2 Hz, 1H), 2.92e2.99 (m,
1H), 3.60e3.69 (m, 2H), 5.55e5.60 (m, 1H), 5.90 (ddd, J¼2.4, 2.4,
5.4 Hz, 1H), 6.24 (ddd, J¼2.4, 2.4, 5.4 Hz, 1H), 8.03 (s, 1H); 13C NMR
4.1.5. (þ)-2-((1R,4R)-4-(2-Amino-6-chloropyrimidin-4-ylamino)cy-
clopent-2-enyl)ethanol (12). To an EtOH (6.5 mL) solution of (ꢀ)-11
(720 mg, 3.17 mmol) was added 12 M HCl (0.33 mL, 3.80 mmol) and
the reaction was stirred at 80 ꢂC for 4 h. The reaction mixture was
concentrated to a light brown oil. To a solution of the oil and 2-
amino-4,6-dichloropyrimidine (574 mg, 3.33 mmol) in n-BuOH
(6.5 mL) was added triethylamine (1.10 mL, 7.92 mmol). The re-
action was stirred in a sealed tube at 110 ꢂC for 4 days. The reaction
mixture was concentrated to a solid. The crude material was
adsorbed on silica gel, and purified by column chromatography
(silica gel; eluted with 1e2% CH3OH/CH2Cl2 to remove unreacted 2-
amino-4,6-dichloropyrimidine, then 5% CH3OH/CH2Cl2 to elute
(150 MHz, CD3OD) d 39.5, 39.7, 43.3, 61.5, 61.6, 125.4, 129.0, 142.5,
142.6, 151.6, 155.1, 161.7; IR (thin film) 1402, 1468, 1507, 1562, 1612,
2928, 3211, 3331 cmꢀ1; HRMS (ESI) m/z [MþNa]þ: calcd for
C12H14ClN5ONaþ, 302.0772; found, 302.0785.
4.1.8. (þ)-tert-Butyl (1R,4S)-4-(2-hydroxyethyl)cyclopent-2-enylcar-
bamate (17). A solution of (þ)-16 (390 mg, 1.16 mmol) in anhydrous
THF (3.5 mL) was cooled to e78 ꢂC. The mixture was treated
dropwise with DIBAL-H (1 M in THF)(3.5 mL, 3.5 mmol) and stirred
for 3 h while warming to rt. To the mixture was added 50 mL of satd
Rochelle salt solution and 20 mL of EtOAc and the mixture was
stirred for 1 h. The organic layer was separated and the aqueous
phase was washed with EtOAc (3ꢃ20 mL). The combined organics
were then washed with satd NaCl, dried over anhydrous sodium
sulfate and concentrated to an oil. Purification by column chro-
matography (silica gel; eluted with 60% EtOAc/hexanes) provided
product) to afford 375 mg of (þ)-12 as a tan solid (50%). Mp
20
85ꢀ87 ꢂC; [
a
]
D
þ180 (c 0.05, CH3OH); 1H NMR (600 MHz, CDCl3)
d
1.27 (ddd, J¼6.6, 6.6,13.2 Hz,1H),1.39 (br s,1H),1.57e1.64 (m, 3H),
1.75e1.81 (m, 1H), 2.64 (ddd, J¼7.8, 7.8, 13.2 Hz, 1H), 2.78e2.84 (m,
1H), 3.68e3.78 (m, 2H), 4.82 (br s, 2H), 5.73 (ddd, J¼1.8, 1.8, 5.4 Hz,
1H), 5.8 (s, 1H), 5.92e5.96 (m, 1H); 13C NMR (150 MHz, CDCl3)
190 mg of (þ)-17 as a clear oil (75%). [
a
]
20 þ138 (c 0.05, CH2Cl2); 1H
D
NMR (600 MHz, CDCl3)
d
1.20e1.27 (m, 1H), 1.44 (s, 9H), 1.52e1.60
d
38.4, 39.0, 41.3, 57.1, 61.2, 130.5, 138.6, 162.3, 163.5; IR (thin film)
(m, 1H), 1.66e1.72 (m, 1H), 1.80e1.87 (m, 1H), 1.88e1.94 (m, 1H),
2.89e2.96 (m, 1H), 3.64e3.75 (m, 2H), 4.44e4.51 (m, 1H),
4.69e4.77 (m, 1H), 5.70 (ddd, J¼2.4, 2.4, 5.4 Hz, 1H), 5.89 (dddd,
1574, 3317 cmꢀ1; HRMS (ESI) m/z [MþH]þ: calcd for C11H16ClN4Oþ,
255.1013; found, 255.1013; HRMS (ESI) m/z [MþNa]þ: calcd for
C11H15ClN4ONaþ, 277.0832; found, 277.0827.
J¼1.8, 1.8, 1.8, 5.4 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 28.4, 38.4,
38.6, 40.7, 56.2, 61.5, 79.3, 131.1, 138.6, 155.3; IR (thin film) 1521,
1684, 2929, 3330 cmꢀ1; HRMS (ESI) m/z [MþH]þ: calcd for
C12H22NOþ3 , 228.1600; found, 228.1597; HRMS (ESI) m/z [MþNa]þ:
calcd for C12H21NO3Naþ, 250.1419; found, 250.1414.
4.1.6. (ꢀ)-2-((1R,4R)-4-(2,5-Diamino-6-chloropyrimidin-4-ylamino)
cyclopent-2-enyl)ethanol (13). A solution of p-chloroaniline
(125 mg, 0.981 mmol) in 3 N HCl (2 mL) was stirred at 0 ꢂC. To this
solution was added
a solution of sodium nitrite (68 mg,
0.981 mmol) in water (0.8 mL) and the mixture was allowed to stir
at 0 ꢂC for 10 min. The resultant diazonium salt solution was added
to a mixture of cyclopentene (þ)-12 (200 mg, 0.785 mmol), acetic
acid (4 mL), water (4 mL), and sodium acetate trihydrate (1.6 g). The
reaction mixture was stirred overnight at rt. The yellow precipitate
was filtered and washed with cold water until the eluting filtrate
was pH 7. The solids were dried under vacuum to yield 260 mg of
product (84%). A portion (180 mg) of the material was dissolved in
water/i-PrOH (5 mL/5 mL) and Zn dust (296 mg, 4.53 mmol) was
added. The mixture was stirred at 90 ꢂC for 4 h. The reaction
mixture was concentrated to a solid. The crude material was
adsorbed on silica gel and purified by column chromatography
(silica gel; eluted with 2e5% CH3OH/CH2Cl2 to remove p-chlor-
oaniline and other impurities, then 6e7% CH3OH/CH2Cl2 to elute
4.1.9. (þ)-2-((1S,4R)-4-(2-Amino-6-chloropyrimidin-4-ylamino)cy-
clopent-2-enyl)ethanol (18). To an EtOH (1.6 mL) solution of (þ)-17
(180 mg, 0.791 mmol) was added 12 M HCl (0.079 mL, 0.791 mmol)
and the reaction was stirred at 80 ꢂC for 4 h. The reaction mixture
was concentrated to a light brown oil. To a solution of the oil and 2-
amino-4,6-dichloropyrimidine (143 mg, 0.831 mmol) in n-BuOH
(2 mL) was added triethylamine (0.275 mL, 1.98 mmol). The re-
action was stirred in a sealed tube at 110 ꢂC for 4 days. The reaction
mixture was concentrated to a solid. The crude material was
adsorbed on silica gel and purified by column chromatography
(silica gel; eluted with 1e3% CH3OH/CH2Cl2 to remove unreacted 2-
amino-4,6-dichloropyrimidine, then 3e4% CH3OH/CH2Cl2 to elute
product) to afford 125 mg of (þ)-18 as a tan oil (60%). [
a
]
20 þ42 (c
D
0.1, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
1.54e1.65 (m, 3H),
product) to afford 93 mg of (ꢀ)-13 as a pink oil (76%). [
a
]
20 ꢀ36 (c
1.68e1.77 (m, 1H), 1.87e1.99 (m, 3H), 2.94e3.03 (m, 1H), 3.67e3.77
(m, 2H), 4.80 (br s, 2H), 5.76 (ddd, J¼2.4, 2.4, 5.4 Hz,1H), 5.79 (s,1H),
D
0.05, CH3OH); 1H NMR (600 MHz, CD3OD)
d
1.28 (ddd, J¼6.6, 6.6,
13.2 Hz, 1H), 1.54e1.61 (m, 1H), 1.75e1.81 (m, 1H), 2.66 (ddd, J¼7.8,
7.8, 13.2 Hz, 1H), 2.73e2.80 (m, 1H), 3.60e3.68 (m, 2H), 5.09e5.13
(m,1H), 5.77 (ddd, J¼1.8,1.8, 5.4 Hz,1H), 5.91 (ddd, J¼1.8,1.8, 5.4 Hz,
5.98e6.01 (m, 1H); 13C NMR (150 MHz, CDCl3)
d 38.4, 38.5, 41.2,
57.0, 61.8, 130.4, 140.1, 162.5, 163.8; IR (thin film) 1576, 2921 cmꢀ1
;
HRMS (ESI) m/z [MþNa]þ: calcd for C11H16ClN4Oþ, 255.1013; found,
1H); 13C NMR (150 MHz, CD3OD)
d
39.7, 40.5, 42.6, 58.3, 61.6, 114.6,
255.1013.
132.7,138.6,143.0, 157.3, 158.2; IR (thin film) 1440, 1502,1571, 2925,
3329 cmꢀ1; HRMS (ESI) m/z [MþH]þ: calcd for C11H17ClN5Oþ,
270.1132; found, 270.1122.
4.1.10. (þ)-2-((1S,4R)-4-(2,5-Diamino-6-chloropyrimidin-4-ylamino)
cyclopent-2-enyl) ethanol (19). A solution of p-chloroaniline (125 mg,
0.981 mmol) in 3 N HCl (2 mL) was stirred at 0 ꢂC. To this solution
was added a solution of sodium nitrite (68 mg, 0.981 mmol) in water
(0.8 mL) and the mixture was allowed to stir at 0 ꢂC for 10 min. The
resultant diazonium salt solution was added to a mixture of cyclo-
pentene (þ)-18 (200 mg, 0.785 mmol), acetic acid (4 mL), water
4.1.7. (ꢀ)-2-((1R,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)cyclo-
pent-2-enyl)ethanol (14). A mixture of (ꢀ)-13 (93 mg,
0.345 mmol), triethyl orthoformate (2 mL), and 12 M HCl
(0.087 mL) was stirred overnight at rt. The suspension was