Sureshan et al.
860.2904, found 860.2910. Anal. Calcd for C43H46ClN5O12‚1/4C7H8
C, 60.86; H, 5.48; N, 7.93. Found: C, 60.60; H, 5.56; N, 7.58.
2-Amino-6-chloro-9-{5′-O-benzyl-3′-O-[2′′,6′′-di-O-benzyl-r-
D-glucopyranosyl]-â-D-ribosyl}purine (12). A solution of triacetate
11 (30 mg, 0.035 mmol) in methanol (2 mL) was saturated with
ammonia (bubbled at rt for 5 min), and the solution was stirred at
rt. When TLC showed complete disappearance of the starting
material (12 h), the solvent was evaporated and the residue was
dissolved in DCM, washed with water (3 times) to remove the
acetamide and then with brine, and the solution dried over anhyd
MgSO4. The gummy residue obtained after evaporation was
chromatographed using ethyl acetate as eluent to afford 12 (21 mg,
82%) as a colorless solid. Scale up using 11 (380 mg) and methanol
(15 mL) provided 293 mg of 12 (90.4%): mp 97 °C; [R]D -73.6
0.3 mmol) at rt and the mixture stirred overnight and then at 80 °C
for 3 h. When the TLC showed transformation of the starting
material into a single new spot, the mixture was diluted with
dichloromethane, washed with water and brine, dried over MgSO4,
and evaporated. Benzyl alcohol was removed by chromatography
using 35% ethyl acetate-hexane as eluent. Further elution with
ethyl acetate-methanol (95:5, v/v) gave an inseparable mixture of
two products. Further purification of this mixture by reversed-phase
column chromatography (in RP-18) using water-acetonitrile as
eluent provided the expected 16 (20 mg, 43%) and the degluco-
sylated product 17 (11 mg, 41%).
Method B. To a solution of nucleoside 11 (50 mg, 0.058 mmol)
in benzyl alcohol (0.5 mL) was added NaH (4.8 mg, 0.12 mmol)
at rt and the mixture stirred at 120 °C overnight. Usual workup in
ethyl acetate followed by column chromatography (elution with
35% EtOAc-hexane to remove the benzyl alcohol and then with
5% MeOH in EtOAc) provided pure 16 (41 mg, 88%) as a colorless
gum: 1H NMR (400 MHz, CDCl3) δ 3.48 (dd, 1H, 9.79, 3.43 Hz,
H-2′′), 3.51-3.62 (m, 3H, H-5A′, H-5B′, H-6A′′), 3.62-3.71 (m,
2H, H-4′′, H-6B′′), 3.80-3.87 (m, 1H, H-5′′), 4.08-4.19 (m, 2H,
H-3′ and H-3′′), 4.28-4.32 (m, 1H, H-4′), 4.42-4.58 (m, 5H, H-2′,
2 × PhCH2), 4.73 (ABq, 2 H, 38.64, 11.69 Hz, PhCH2), 4.86 (d,
1H, 3.56 Hz, H-1′′), 5.60 (AB q, 19.45, 2.33 Hz, c-6-OCH2Ph),
5.90 (br s, 2H, NH2), 6.07 (d, 1H, 6.10 Hz, H-1′), 7.20-7.50 (m,
20H, 4 × Ph), 7.89 (s, 1H, H-8); 13C NMR (100 MHz, CDCl3) δ
68.68 (C-6-OCH2Ph), 68.81 (C-6′′), 69.35 (C-4′′), 69.96 (C-5′),
71.92 (C-3′′), 72.41 (C-5′′), 73.75 (PhCH2), 73.82 (PhCH2), 74.41
(PhCH2), 77.20 (C-2′), 79.36 (C-2′′), 80.85 (C-3′), 82.84 (C-4′),
86.40 (C-1′), 99.82 (C-1′′), 115.17 (C-5), 127.75, 127.78, 128.02,
128.05, 128.37, 128.40, 128.64, 128.67, 129.07 (aromatic carbons),
136.12, 136.26 (ipso carbons), 137.06 (C-8), 137.22, 137.71 (ipso
carbons), 154.09 (C-4), 159.47 (C-2), 161.25 (C-6); m/z (ES+) )
806.4 [(M + H)+, 100], 828.4 [(M + Na)+, 80]; HRMS mass calcd
for C44H47N5O10 [M + H]+ 806.3396, found 806.3404.
2-Amino-6-O-benzyl-9-{5′-O-benzyl-2′-O-(dibenzyloxyphos-
phoryl)-3′-O-[2′′,6′′-di-O-benzyl-3′′,4′′-bis(dibenzyloxyphospho-
ryl)-r-D-glucopyranosyl]-â-D-ribosyl}purine (18). A solution of
the triol 16 (40 mg, 0.05 mmol), bis(benzyloxy)(diisopropylami-
no)phosphine (82 mg, 0.24 mmol), and imidazolium triflate (68
mg, 0.31 mmol) in anhydrous DCM (3 mL) was stirred at room
temperature under a nitrogen atmosphere for 45 min. The reaction
mixture was cooled to -78 °C, m-CPBA (84 mg) was added, and
the mixture stirred for 1.5 h, gradually allowing the temperature to
attain rt. Usual workup in ethyl acetate followed by chromatography
using ethyl acetate-hexane-Et3N (55:43:2; v/v/v) afforded pure
18 (65 mg, 82%) as a colorless gum: [R]D +28.8 (c 1.4, CHCl3);
1H NMR (400 MHz, CDCl3) δ 3.50 (dd, 1H, 10.37, 3.02 Hz, H-5A′),
3.56-3.68 (m, 4H, H-5B′, H-2′′, H-6A′′, H-6B′′), 3.80-3.86 (m,
1H, H-5′′), 4.32 (dd, 1H, 6.05, 3.02 Hz, H-4′), 4.32 (AB q, 2H,
48.17, 11.88 Hz, CH2Ph), 4.35 (AB q, 2H, 14.04, 11.88 Hz, CH2Ph),
4.43-4.66 (m, H, H-4′′, CH2Ph), 4.68 (dd, 1H, 4.75, 3.02 Hz, H-3′),
4.71-4.79 (m, H, CH2Ph), 4.84-5.04 (m, H-3′′, CH2Ph), 5.36 (d,
1H, 3.46 Hz, H-1′′), 5.50 (s, 2H, CH2Ph), 5.56 (ddd, 1H, 8.64,
4.75, 6.05 Hz, H-2′), 6.18 (d, 1H, 6.05 Hz, H-1′), 6.96-7.50 (m,
50H, 10 × Ph), 7.68 (s, 1H, H-8); 13C NMR (100 MHz, CDCl3) δ
67.80 (C-6-OCH2Ph), 68.18 (C-6′′), 68.97 (C-5′), 68.91, 69.06,
69.18, 69.23, 69.33, 69.39, 69.43, 69.49, 69.63, 69.69, 71.37, 73.15,
73.42 (CH2Ph, 31P coupled), 69.87 (C-5′′, 31P coupled), 73.33 (C-
3′, 31P coupled), 74.24 (C-4′′, 31P coupled), 76.60-76.71 (m, C-2′,
C-2′′, 31P coupled), 77.98 (C-3′′, 31P coupled), 81.91 (C-4′), 85.00
(C-1′, 31P coupled), 95.10 (C-1′′), 115.52 (C-5), 127.40, 127.49,
127.54, 127.63, 127.71, 127.74, 127.81, 127.91, 127.93, 127.94,
128.07, 128.16, 128.17, 128.20, 128.24, 128.30, 128.33, 128.37,
128.40 (aromatic carbons), 134.87, 134.95, 135.02, 135.50, 135.58,
135.64, 135.71, 135.99, 136.08, 136.30, 137.24, 137.56, 137.88
(ipso carbons, 31P coupled), 137.78 (C-8), 153.97 (C-4), 159.03
(C-2), 160.74 (C-6); 31P NMR (161.94 MHz, CDCl3) δ -1.40,
-1.967, -2.101; m/z (ES+) ) 1587.8 [(M + H)+, 100]; HRMS
1
(c 1.06, CHCl3); H NMR (400 MHz, CDCl3) δ 3.19 (br s, 4′′-
OH), 3.45-3.66 (m, 6H, H-2′′, H-5A′, H-5B′, H-4′′, H-6A′′, H-6B′′),
3.80 (ddd, 1H, 9.78, 4.90, 2.16 Hz, H-5′′), 4.11-4.18 (m, 2H, H-3′
and H-3′′), 4.21 (m, 1H, H-4′), 4.35-4.50 (m, 6H, H-2′, 2′′-OH
and 2 × PhCH2), 4.83 (ABq, 2 H, 20.94, 11.55 Hz, PhCH2), 4.86
(d, 1H, 3.52 Hz, H-1′′), 5.76 (dd, 1H, 5.09, 2.74 Hz, H-1′), 6.01
(d, 4.70 hz, 3′′-OH), 6.88 (br s, 2H, NH2), 7.13-7.33 (m, 15H, 3
× Ph), 7.96 (s, 1H, H-8); 13C NMR (100 MHz, CDCl3) δ 69.02
(C-6′′), 69.60 (C-4′′), 70.04 (C-5′), 72.37 (C-3′′), 72.51 (C-5′′),
73.65 (PhCH2), 74.01 (PhCH2), 75.30 (PhCH2), 77.42 (C-2′), 79.36
(C-2′′), 81.44 (C-3′), 83.28 (C-4′), 86.43 (C-1′), 100.45 (C-1′′),
124.86 (C-5), 127.67, 127.77, 127.84, 127.95, 128.22, 128.33,
128.41, 128.76, 128.83, 128.89, 129.21 (aromatic carbons), 135.80,
137.02, 137.99 (ipso carbons), 140.29 (C-8), 151.48 (C-4 or C-6),
154.33 (C-6 or C-4), 159.84 (C-2); m/z (FAB+) ) 734.2 [(M H)+,
100]; HRMS mass calcd for C37H4135ClN5O9 [M + H]+ 734.25928,
found 734.26378. Anal. Calcd for C37H40ClN5O9: C, 60.53; H, 5.49;
N, 9.54. Found: C, 60.30; H, 5.63; N, 9.43.
2-Amino-6-chloro-9-{5′-O-benzyl-2′-O-(dibenzyloxyphospho-
ryl)-3′-O-[2′′,6′′-di-O-benzyl-3′′,4′′-bis-(dibenzyloxyphosphoryl)-
r-D-glucopyranosyl]-â-D-ribosyl}purine (13). A solution of the
triol 12 (297 mg, 0.405 mmol), bis(benzyloxy)(diisopropylamino)-
phosphine (602 mg, 1.744 mmol), and imidazolium triflate (480
mg, 2.202 mmol) in anhydrous DCM (10 mL) was stirred at room
temperature under N2 for 30 min. The reaction mixture was cooled
to -78 °C, and then m-CPBA (685 mg, 60-70%) was added and
the mixture stirred for 45 min at this temperature and then at rt for
an additional 30 min. Usual workup in ethyl acetate followed by
column chromatography using ethyl acetate-hexane-Et3N (55:
43:2; v/v/v) provided pure 13 (575 mg, 94%) as a gum: [R]D +31.7
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.48 (dd, 1H, 10.47,
2.56 Hz, H-5A′), 3.56-3.70 (m, 4H, H-2′′, H-5B′, H-6A′′, H-6B′′),
3.81-3.85 (m, 1H, H-5′′), 4.24-4.80 (m, 11H, H-3′, H-4′, H-4′′
and 4 × PhCH2), 4.70-4.79 (m, 2 H, PhCH2), 4.80-5.02 (m, 9H,
H-3′′ and 4 × PhCH2), 5.34 (d, 1H, 3.72 Hz, H-1′′), 5.50 (ddd,
1H, 8.61, 4.70, 6.26 Hz, H-2′), 6.17 (d, 1H, 6.51 Hz, H-1′), 6.97-
7.40 (m, 45H, 9 × Ph), 7.84 (s, 1H, H-8); 13C NMR (100 MHz,
CDCl3) δ 66.30 (C-6′′), 68.93 (C-5′), 68.97, 69.03, 69.19, 69.25,
69.38, 69.43, 69.54, 69.59, 69.67, 69.73, 69.80 (6 × PhCH2OP,
31P coupled), 69.92 (C-5′′), 71.37 (PhCH2OC), 73.19 (PhCH2OC),
73.46 (PhCH2OC and C-3′), 74.25 (C-4′′), 76.69 (C-2′′), 76.76 (C-
2′), 77.93 (C-3′′), 82.20 (C-4′), 85.07 (C-1′), 95.15 (C-1′′), 127.41,
127.53, 127.56, 127.64, 127.70, 127.78, 127.85, 127.88, 127.94,
127.97, 128.10, 128.17, 128.19, 128.22, 128.25, 128.32, 128.39,
128.47, 128.55 (aromatic carbons), 134.68, 134.75, 134.83, 134.89,
135.47, 135.54, 135.61, 135.67, 135.94, 135.97, 136.02, 136.05 (6
× POCH2C, 31P coupled), 137.07, 137.57, 137.82 (3 × COCH2C),
140.57 (C-8), 151.03 (C-4 or C-6), 153.58 (C-6 or C-4), 158.89
(C-2); 31P NMR (161.94 MHz, CDCl3) δ -2.04, -1.93, -1.217;
m/z (FAB+) ) 1514.6 [(M + H)+, 10]; HRMS mass calcd for
C79H8035ClN5O18P3 [M + H]+ 1514.4394, found 1514.4396.
2-Amino-6-O-benzyl-9-{5′-O-benzyl-3′-O-[2′′,6′′-di-O-benzyl-
r-D-glucopyranosyl]-â-D-ribosyl}purine (16). Method A. To a
solution of nucleoside 11 (50 mg, 0.058 mmol) and benzyl alcohol
(36.5 µL, 0.35 mmol) in DMF (0.5 mL) was added NaH (12 mg,
1690 J. Org. Chem., Vol. 73, No. 5, 2008