9.51 (1 H, s, imide NH), 8.90 (1 H, s, amide NH), 7.61 (1 H, d,
solvent was evaporated under reduced pressure and the residue
J 12.2, COCH᎐CHOEt), 7.35–7.22 (10 H, m, ArH), 5.31 (1 H,
was partitioned between CH2Cl2 (15 cm3) and water (15 cm3).
The two layers were separated and the aqueous layer was
extracted with CH2Cl2 (2 × 25 cm3). The organic phase was dried
(MgSO4) and the solvent evaporated. The residue was purified
by flash column chromatography (silica gel, 5% MeOH in
CH2Cl2) to give compound 25 (0.064 g, 34%) as a colourless
syrup; [α]2D4 Ϫ36.1 (c 1, CHCl3); νmax(neat)/cmϪ1 3609–3445,
2924, 1771 and 1605; δH (CDCl3, Me4Si) 7.35–7.20 (11 H, m, 6Ј-
H, ArH), 5.48 (1 H, d, J 7.3, 5Ј-H), 4.51 (2 H, s, PhCH2O), 4.40
(2 H, s, PhCH2O), 3.94 (1 H, d, J 6.5, 3-H), 3.70 (2 H, m,
CH2O), 2.42 (1 H, irregular t, J ca. 6.2, 4-H), 2.31 (2 H, m, 2-
H), 1.60 (1 H, dd, J 9.4, 4.7, 5-H), 1.48 (1 H, t, J 5.2, 6-Hendo),
1.01 (1 H, m, 6-Hexo). A fraction of this syrup (0.050 g, 0.119
mmol) was dissolved in CH2Cl2 (5 cm3) and treated with BCl3 (1
in CH2Cl2; 0.96 cm3) using the same protocol employed for
the deprotection of 24. The target compound 8 (0.025 g, 89%)
was obtained as a white powder after crystallization from
MeOH–CH2Cl2; mp 261–262 ЊC; [α]2D5 Ϫ30 (c 0.18, MeOH);
δH (CDCl3, Me4Si) 8.02 (1 H, d, J 7.7, 6Ј-H), 6.02 (1 H, d, J 7.7,
5Ј-H), 4.21 (1 H, d, J 6.9, 3-H), 3.71 (2 H, br d, J 5.51, CH2OH),
2.40 (1 H, ddd, J 13.5, 7.0, 1.9, 2-Hβ), 2.18–2.04 (2 H, m, 2-Hβ,
4-H), 1.70 (1 H, ddd, J 9.7, 4.9, <1, 5-H), 1.52 (1 H, t, J 5.2, 6-
Hendo), 1.21 (1 H, m, 6-Hexo); δC(CD3OD) 19.36 (6-C), 28.92 (5-
C), 40.91 (2-C), 51.16 (1-C), 54.10 (4-C), 64.87 (CH2OH), 75.49
(3-C), 94.74 (5Ј-C), 168.88 (6Ј-C); m/z (FAB) (relative intensity)
238 (MHϩ, 100), 112 (B ϩ 2 H, 25) [Found: (FAB): 238.1221.
Calc. for MHϩ, 238.1192].
᎐
d, J 12.2, COCH᎐CHOEt), 4.53 (2 H, AB q, J 11.9, PhCH O),
᎐
2
4.40 (2 H, AB q, J 12.1, PhCH2O), 3.90 (3 H, m, 3-H,
OCH2CH3), 3.60 (2 H, m, CH2O), 2.41 (2 H, m, 4-H, 2-Hβ),
2.21 (1 H, d, J 13.8, 2-Hα), 1.41 (1 H, dd, J 9.0, 4.4, 5-H), 1.28 (1
H, t, J 4.9, 6-Hendo), 1.21 (3 H, t, J 7.0, OCH2CH3), 0.97 (1 H, m,
6-Hexo). Without further purification, a stirred solution of 22
(0.340 g, 0.73 mmol) in ethanol (15 cm3) was treated with 2
HCl (2.5 cm3) and cyclization to the pyrimidine ring was per-
formed in a similar manner as for 23. After work-up and purifi-
cation by column chromatography (silica gel, acetone–CH2Cl2,
5:1), compound 24 (0.2609 g, 85%) was obtained as a colour-
less syrup; [α]D24 Ϫ22.7 (c 1 in CHCl3); νmax(neat)/cmϪ1 3200,
2960, 1710 and 1600; δH (CDCl3, Me4Si) 8.80 (1 H, br s, NH),
7.40–7.20 (11 H, m, 6Ј-H, ArH), 5.39 (1 H, dd, J 7.9, 2.2, 5Ј-H),
4.52 (2 H, AB q, J 11.4, PhCH2O), 4.40 (2 H, AB q, J 12.4,
PhCH2O), 3.95 (1 H, d, J 6.3, 3-H), 3.71 (2 H, m, CH2O), 2.42
(1 H, t, J 5.5, 4-H), 2.35–2.20 (2 H, m, 2-H), 1.65 (1 H, t, J 4.5,
5-H), 1.55 (1 H, t, J 5.3, 6-Hendo), 1.11 (1 H, m, 6-Hexo) (Found:
C, 65.99; H, 5.88. C25H26N2O4ؒH2O requires C, 66.06; H,
6.65%). A fraction of this syrup (0.080 g, 0.191 mmol) was
dissolved in CH2Cl2 (4 cm3), cooled to Ϫ78 ЊC, and treated
under a blanket of argon with a solution of BCl3 (1 in
CH2Cl2; 1.53 cm3). The reaction mixture was stirred at Ϫ78 ЊC
for 6 h, and then for 1 h at Ϫ30 ЊC. The mixture was cooled
again to Ϫ78 ЊC then MeOH (6 cm3) was added to it and the
mixture was stirred at Ϫ78 ЊC for 1 h and then allowed to reach
room temperature conditions. The solvent was removed under
reduced pressure and the residue was evaporated thrice after the
addition of 5 cm3 portions of MeOH. The crude foam was
dissolved in MeOH (1.2 cm3) and treated with CH2Cl2 (2.5 cm3)
until cloudiness was observed. After the solution had been left
to stand in the freezer, the precipitated solid was separated and
washed with CH2Cl2 (1.5 cm3) and petrol (3 cm3) to give the
target compound 7 (0.015 g, 33%) as a white powder; mp 212–
214 ЊC; [α]2D5 Ϫ33.6 (c 0.25 in MeOH); δH (CD3OD, Me4Si) 7.68 (1
H, d, J 7.9, 6ЈH), 5.61 (1 H, d, J 7.9, 5Ј-H), 4.21 (1 H, d, J 6.9,
3-H), 3.70 (2 H, m, CH2OH), 2.36 (1 H, ddd, J 13.4, 6.9, 2.2, 2-
Hβ), 2.06 (2 H, m, 2-Hα, 4-H), 1.74 (1 H, ddd, J 9.7, 4.9, 1.1,
5-H), 1.45 (1 H, t, J 5.2, 6-Hendo), 1.15 (1 H, ddd, J 9.7, 5.4, 2.3,
6-Hexo); δC(CD3OD) 19.18 (6-C), 28.96 (5-C), 41.19 (2-C), 54.00
(4-C), 65.09 (CH2OH), 75.48 (3-C), 102.58 (5Ј-C), 147.80 (6Ј-
C), 153.20 (2Ј-C), 165.40 (4Ј-C); m/z (FAB) (relative intensity)
239 (MHϩ, 100), 113 (B ϩ 2 H, 15) [Found (FAB): 239.1039.
Calc. for MHϩ, 239.1032].
(1S,3S,4R,5S)-3-Benzyloxy-4-(benzyloxymethyl)-1-(6-chloro-
purin-9-yl)bicyclo[3.1.0]hexane 27
A stirred solution of carbocyclic amine 20 (0.025 g, 0.077
mmol), 4,6-dichloro-5-formamidopyrimidine14 (0.015 g, 0.087
mmol) and triethylamine (183 mm3, 1.314 mmol) in 1,4-dioxane
(4 cm3) was stirred under gentle reflux for 24 h. After cooling,
the solvent was removed under reduced pressure and the resi-
due was purified by column chromatography (silica gel,
hexane–EtOAc, 3:1) to give compound 26 as a clear yellow
syrup (0.034 g, 92%). This compound was immediately reacted
with triethyl orthoformate (2 cm3) and 12 hydrochloric acid
(43 mm3) in DMF (0.7 cm3), and the reaction mixture was
stirred at room temperature for 2 days. The reaction was
quenched with triethylamine (0.3 cm3) and the solvent was
evaporated. The residue was purified by column chroma-
tography [silica gel, hexane–EtOAc, 4:1 (200 cm3) and hexane–
EtOAc, 3:1 (100 cm3)] to give the chloro compound 27 (0.034 g,
47%) as a yellow syrup; [α]2D4 Ϫ31.5 (c 0.6 in CHCl3); νmax(neat)/
cmϪ1 2926, 1590 and 1557; δH (CDCl3, Me4Si) 8.69 (1 H, s, 8Ј-
H), 8.11 (1 H, s, 2Ј-H), 7.40–7.20 (10 H, m, ArH), 4.61 (2 H, s,
PhCH2O), 4.43 (2 H, s, PhCH2O), 4.02 (1 H, br t, 3-H), 3.75 (2
H, m, CH2O), 2.55 (1 H, t, J 6.2, 4-H), 2.49 (2 H, br d, J 3.2, 2-
H), 1.85 (1 H, dd, J 9.2, 4.7, 5-H), 1.76 (1 H, t, J 5.2, 6-Hendo),
1.40 (1 H, dd, 9.2, 5.6, 6-Hexo) (Found: C, 67.19; H, 5.46.
C26H25ClN4O2ؒ0.1H2O requires C, 67.40; H, 5.48).
(1S,3S,4R,5S)-3-Hydroxy-4-hydroxymethyl-1-(4-amino-2-oxo-
1,2-dihydropyrimidin-1-yl)bicyclo[3.1.0]hexane 8
A solution of 24 (0.190 g, 0.454 mmol), triethylamine (1.45
mm3, 10.44 mmol) and 1H-1,2,4-triazole (0.705 g, 10.22 mmol)
in acetonitrile (10 cm3) was treated at room temperature with
POCl3 (104 mm3, 1.11 mmol). The reaction mixture was stirred
for 2 h at room temperature and then poured onto a mixture of
CH2Cl2 (51 cm3), triethylamine (5.1 cm3) and saturated aqueous
NaHCO3 (15.5 cm3). The organic layer was separated, dried
(MgSO4), filtered and evaporated under reduced pressure to
give a residue that was chromatographed through a short col-
umn (silica gel, ether) to give the triazole intermediate as a
white foam; δH (CDCl3, Me4Si) 9.21 (1 H, s, triazole), 8.09 (1 H,
s, triazole), 7.98 (1 H, d, J 7.1, 6Ј-H), 7.35–7.22 (10 H, m, ArH),
6.70 (1 H, d, J 7.1, 5Ј-H), 4.55 (2 H, AB q, PhCH2O), 4.41 (2 H,
AB q, PhCH2O), 4.01 (1 H, d, J 5.4, 3-H), 3.80 (2 H, m, CH2O),
2.49 (1 H, t, J 5.5, 4-H), 2.40 (2 H, m, 2-H), 1.70 (2 H, m, 5-H,
6-Hendo), 1.20 (1 H, m, 6-Hexo). This material was dissolved in
dioxane (6 cm3) and stirred with concentrated aqueous ammo-
nia (1.5 cm3) for 24 h at 40 ЊC. After such time, analysis by TLC
still showed unreacted starting material. Additional concen-
trated aqueous ammonia (1.6 cm3) was added and stirring was
continued for an additional 24 h to complete the reaction. The
(1S,3S,4R,5S)-3-Benzyloxy-4-(benzyloxymethyl)-1-(6-amino-
purin-9-yl)bicyclo[3.1.0]hexane 28
A solution of 27 (0.034 g, 0.074 mmol) in saturated methanolic
ammonia (5 cm3) was heated in a sealed tube at 80 ЊC for 12 h.
After cooling to room temperature, the solvent was removed
under reduced pressure and the residue was purified by column
chromatography (silica gel, 3% MeOH in EtOAc) to give 28
(0.031 g, 97%) as a white solid; mp 179–181 ЊC; [α]2D4 Ϫ35.7 (c 0.21
in CHCl3); νmax(KBr)/cmϪ1 3299, 2862 and 1601; δH (CDCl3,
Me4Si) 8.31 (1 H, s, 8Ј-H), 7.79 (1 H, s, 2Ј-H), 7.39–7.25 (10 H,
m, ArH), 5.52 (2 H, br s, NH2), 4.61 (2 H, s, PhCH2O), 4.42 (2
H, s, PhCH2O), 4.02 (1 H, br t, 3-H), 3.78 (2 H, m, CH2O), 2.54
(1 H, t, J 6.4, 4-H), 2.49 (2 H, d, J 3.2, 2-H), 1.85–1.67 (2 H, m,
5-H, 6-Hendo), 1.38 (1 H, dd, J 9.4, 5.5, 6-Hexo) (Found: C, 70.55;
H, 6.21. C26H27N5O2 requires C, 70.72; H, 6.16%).
J. Chem. Soc., Perkin Trans. 1, 1997
1077