The Journal of Organic Chemistry
ARTICLE
(d, JP,C = 142.6 Hz, PCH2), 62.2 (d, JP,C = 1.9Hz, OCH2), 62.3 (d, JP,C =1.9
Hz, OCH2), 74.7 (C-40), 79.2 (d, JP,C = 3.1 Hz, C-20), 84.2 (d, JP,C = 2.1 Hz,
C-30), 87.7 (C-10), 123.7 (C-5), 125.0 (d, JP,C = 10.9 Hz, CHdCH), 127.9
(Bz, C), 128.7 (Bz, C), 128.8 (Bz, C), 128.9 (Bz, C), 129.8 (Bz, C), 129.9
(Bz, C), 130.1 (Bz, C), 130.4 (d, JP,C = 14.6 Hz, CHdCH), 132.9 (Bz, C),
133.7 (Bz, C), 133.8 (Bz, C), 134.0 (Bz, C), 141.9 (C-8), 149.9 (C-4), 151.9
(C-6), 153.1 (C-2), 164.6 (Bz, CdO), 164.7 (Bz, CdO), 165.2 (Bz,
CdO); 31P NMR (121.5 MHz, CDCl3) δ 25.4; HRMS calcd for
C37H37N5O9P [M þ H]þ 726.2329, found 726.2319.
16.3 (CH3), 16.4 (CH3), 61.9 (OCH2), 62.0 (OCH2), 71.6 (C-40), 74.3
(C-20), 92.2 (C-10), 118.3 (d, JP,C = 190.3 Hz, C-70), 119.7 (C-5), 123.6
(d, JP,C = 28 Hz, C-50), 138.3 (C-8), 143.8 (d, JP,C = 6.8 Hz, C-60), 145.8
(C-30), 149.2 (C-4), 152.8 (C-2), 155.5 (C-6); 31P NMR (121.5 MHz,
MeOD) δ 18.6; HRMS calcd for C16H23N5O5P [M þ H]þ 396.1437,
found 396.1427. Data for 23c: 1H NMR (600 MHz, CDCl3) δ
1.32ꢀ1.35 (m, 6H, CH3), 4.07ꢀ4.12 (m, 4H, OCH2), 4.97 (s, 2H,
0
0
H4), 5.20 (s, 1H, H2 ), 5.77 (d, J = 6.2 Hz, 1H, H1 ), 5.79 (d, J = 17.8 Hz,
0
0
1H, H7 ), 6.27 (br, 2H, NH2), 6.41 (d, J = 11.5 Hz, 1H, H5 ), 6.99 (ddd,
0
J1 = 20.5 Hz, J2 = 16.7 Hz, J3 = 11.5 Hz, 1H, H6 ), 7.94 (s, 1H, H8), 8.22
1-(Thymin-1-yl)-2,3-O-dibenzoyl-(E)-3-(diethylphospho-
no)allyl-β-D-erythrofuranose (22). Thymine (46 mg, 0.36 mmol),
ammonium sulfate (1.4 mg, 0.011 mmol), and 6 mL of HMDS were
added to a dried flask. The mixture was refluxed overnight under N2.
HMDS was removed in vacuo. To the flask with the residue was added a
solution of compound 20 (109 mg, 0.18 mmol) in 9 mL of dried
CH3CN, followed by dropwise addition of SnCl4 (64 μL, 0.54 mmol) at
room temperature under N2. The reaction mixture was allowed to stir for
1 h. The reaction was quenched with cold saturated NaHCO3 and
partitioned between H2O (10 mL) and EtOAc (80 mL). The organic
layer was washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by chromatography on a
silica gel column (CH2Cl2/MeOH = 49:1) to afford 22 (48 mg, 0.078
(s, 1H, H2); 13C NMR (150 MHz, CDCl3) δ 16.3 (CH3), 16.4 (CH3),
61.9 (d, JP,C = 9.8 Hz, OCH2), 62.0 (OCH2), 69.0 (C-40), 76.0 (C-20),
90.5 (C-10), 119.0 (d, JP,C = 189.9 Hz, C-70), 119.6 (C-5), 122.0 (d,
JP,C = 27.5 Hz, C-50), 138.6 (C-8), 142.7 (d, JP,C = 5.8 Hz, C-60), 145.7
(C-30), 149.1 (C-4), 152.6 (C-2), 155.6 (C-6); 31P NMR (121.5 MHz,
MeOD) δ 18.1; HRMS calcd for C16H23N5O5P [M þ H]þ 396.1437,
found 396.1434.
1-(Thymin-1-yl)-3-(diethylphosphono)allyl-β-D-erythro-
furanose (24). A solution of 22 (48 mg, 0.078 mmol) in methanol
saturated with ammonia (3 mL) was stirred at room temperature over-
night. The mixture was concentrated, and the residue was purified by
chromatography on a silica gel column (CH2Cl2/MeOH = 19:1) to
afford a crude product, which was further purified by HPLC on a C18
column to provide 24 in trace amount. HRMS calcd for C16H26N2O8P
[M þ H]þ 405.1427, found 405.1421.
1
mmol) as a colorless amorphous solid in 43% yield. Data for 22: H
NMR (300 MHz, CDCl3) δ 1.18ꢀ1.24 (m, 6H, CH3), 1.97 (s, 3H,
CH3), 2.61 (dAB, JAB = 7.1 Hz, JP,H = 22.0 Hz, 2H, PCH2), 4.00ꢀ4.04
1-(Adenin-9-yl)-(E)-3-phosphonoallyl-β-D-erythrofuranose
(1e). To a solution of compound 23a (52 mg, 0.125 mmol) and 2,6-
lutidine (1 mL, 8.61 mmol) in 8 mL of dry CH2Cl2 was added bromo-
trimethylsilane (293 μL, 2.52 mmol) at room temperature under
nitrogen. The reaction mixture was continuously stirred for 2 days in
the darkness. The reaction mixture was concentrated under high vacuum
at room temperature, and the residue was coevaporated with MeOH and
0.5 M TEAB solution. Purification by HPLC using reverse phase C18
column (mobile phase A: MeCN þ 50 mM TEAB; mobile phase B:
H2O þ 50 mM TEAB) and ion exchange with Dowex-Naþ resin offered
1e (26 mg, 0.064 mmol) as a colorless solid after lyophilization in 51%
yield. Data for 1e: 1H NMR (600 MHz, D2O) δ 2.46 (dAB, JAB = 7.7 Hz,
0
(m, 4H, OCH2), 4.53 (d, J = 10.7 Hz, 1H, H4 a), 4.83 (d, J = 10.7 Hz, 1H,
0
0
H4 b), 5.73 (d, J = 5.8 Hz, 1H, H2 ), 5.98ꢀ6.08 (m, 1H, CHdCH), 6.12
(dd, J1 = 15.9 Hz, J2 = 4.5 Hz, 1H, CHdCH), 6.21 (d, J = 5.8 Hz, 1H,
0
H1 ), 7.19 (s, 1H, H6), 7.31ꢀ7.62 (m, 6H, Ar-H), 7.90ꢀ8.10 (m, 4H, Ar-
H), 9.28 (br, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 12.6 (CH3), 16.4
(CH3), 16.5 (CH3), 29.6 (d, JP,C = 138.5 Hz, PCH2), 62.2 (OCH2), 62.3
(OCH2), 74.3 (C-40), 78.9 (d, JP,C = 3.0 Hz, C-20), 82.9 (d, JP,C = 2.0 Hz,
C-30), 88.5 (C-10), 112.1 (C-5), 124.5 (d, JP,C = 11.0 Hz, CHdCH),
128.6 (Bz, C), 128.7 (Bz, C), 128.8 (Bz, C), 128.9 (Bz, C), 129.7 (Bz, C),
129.8 (Bz, C), 130.0 (Bz, C), 130.1 (Bz, C), 131.5 (d, JP,C = 14.6 Hz,
CHdCH), 133.6 (Bz, C), 133.9 (Bz, C), 135.7 (C-6), 150.6 (C-2),
163.7 (C-4), 164.6 (Bz, CdO), 165.5 (Bz, CdO); 31P NMR (121.5
MHz, CDCl3) δ 25.5; HRMS calcd for C30H34N2O10P [M þ H]þ
613.1951, found 613.1957.
0
JP,H = 20.8 Hz, 2H, PCH2), 4.01 (d, J = 10.2 Hz, 1H, H4 a), 4.43 (d, J =
0
0
10.2 Hz, 1H, H4 b), 4.89 (d, J = 7.6 Hz, 1H, H2 ), 5.72 (dd, J1 = 15.6 Hz,
0
J2 = 4.7 Hz, 1H, H5 ), 5.93 (ddt, J1 = 13.9 Hz, J2 = 13.9 Hz, J3 = 7.5 Hz,
1-(Adenin-9-yl)-(E)-3-(diethylphosphono)allyl-β-D-ery-
throfuranose (23a). A solution of 21 (180 mg, 0.248 mmol) in
methanol saturated with ammonia (4 mL) was stirred at room tem-
perature overnight. The mixture was concentrated, and the residue was
purified by chromatography on a silica gel column (CH2Cl2/MeOH=
19:1 and 9:1) to afford a crude product, which was further purified by
HPLC on a C18 column to give 23a (18 mg, 0.043 mmol) as colorless oil
in 17% yield. Data for 23a: 1H NMR (300 MHz, MeOD) δ 1.29ꢀ1.34
(m, 6H, CH3), 2.70 (dAB, JAB = 7.0 Hz, JP,H = 22.1 Hz, 2H, PCH2), 3.91
0
0
1H, H6 ), 6.03 (d, J = 7.6 Hz, 1H, H1 ), 8.16 (s, 1H, H2), 8.30 (s, 1H, H8);
13C NMR (150 MHz, D2O) δ 32.3 (d, JP,C = 129 Hz, PCH2), 76.6 (C-
20), 77.5 (C-40), 79.0 (C-30), 87.4 (C-10), 118.9 (C-5), 126.2 (d, JP,C
=
0
0
10.5 Hz, H6 ), 129.7 (d, JP,C = 12 Hz, H5 ), 140.6 (C-8), 148.9 (C-4),
152.7 (C-2), 155.5 (C-6); 31P NMR (121.5 MHz, D2O) δ 19.7; HRMS
calcd for C12H15N5O6P [M ꢀ H]ꢀ 356.0761, found 356.0758.
1,2,3-O-Tribenzoyl-3-(diethylphosphono)propyl-D-ery-
throfuranose (25). To a solution of 20 (613 mg, 1.01 mmol) in
methanol (20 mL) was added Pd/C (106 mg, 0.1 mmol) under Ar. The
reaction mixture was stirred under hydrogen atmosphere for 21 h. The
mixture was filtered through a Celite pad to remove the catalyst and
purified on a silica gel column (EtOAc/n-hexane = 1:1 and 2:1) to afford
25 (571 mg, 0.935 mmol) as an anomeric mixture (25a and 25b) in 92%
yield. Data for 25a: 1H NMR (300 MHz, CDCl3) δ 1.19ꢀ1.25 (m, 6H,
CH3), 1.71ꢀ2.05 (m, 4H, (H5, 2H), (H6, 2H)), 2.51ꢀ2.67 (m, 2H,
PCH2), 3.96ꢀ4.09 (m, 4H, OCH2), 4.59 (s, 2H, H4), 5.89 (d, J = 0.6 Hz,
1H, H2), 6.60 (d, J = 0.6 Hz, 1H, H1), 7.30ꢀ7.62 (m, 9H, Ar-H),
7.86ꢀ8.10 (m, 6H, Ar-H); 13C NMR (75 MHz, CDCl3) δ 16.3 (CH3),
16.4 (CH3), 17.2 (d, JP,C = 4.7 Hz, C-6), 24.7 (d, JP,C = 140.7 Hz,
PCH2), 34.8 (d, JP,C = 15.3 Hz, C-5), 61.5 (OCH2), 61.6 (OCH2), 76.6
(C-4), 78.8 (C-2), 85.2 (d, JP,C = 1.6 Hz, C-3), 100.1 (C-1), 128.4 (Bz,
C), 128.5 (Bz, C), 128.6 (Bz, C), 128.9 (Bz, C), 129.2 (Bz, C), 129.3 (Bz,
C), 129.6 (Bz, C), 129.8 (Bz, C), 129.9 (Bz, C), 133.4 (Bz, C), 133.6 (Bz,
C), 133.7 (Bz, C), 164.9 (Bz, CdO), 165.0 (Bz, CdO), 165.1 (Bz, CdO),
0
(d, J = 9.5 Hz, 1H, H4 a), 4.06ꢀ4.16 (m, 4H, OCH2), 4.44 (d, J = 9.5 Hz,
0
0
1H, H4 b), 4.98 (d, J = 7.1 Hz, 1H, H2 ), 5.87ꢀ5.97 (m, 2H, CHdCH),
6.00 (d, J = 7.1 Hz, 1H, H1 ), 8.20 (s, 1H, H2), 8.30 (s, 1H, H8); 13C
0
NMR (75 MHz, MeOD) δ 16.7 (CH3), 16.8 (CH3), 29.5 (d, JP,C
=
138.4 Hz, PCH2), 63.7 (OCH2), 63.8 (OCH2), 78.2 (d, JP,C = 3.6 Hz,
C-40), 79.3 (C-20), 80.3 (d, JP,C = 2.3 Hz, C-30), 90.7 (C-10), 120.8 (C-5),
122.2 (d, JP,C = 10.9 Hz, CHdCH), 135.9 (d, JP,C = 14.2 Hz, CHdCH),
142.1 (C-8), 150.8 (C-4), 153.8 (C-2), 157.3 (C-6); 31P NMR (121.5
MHz, MeOD) δ 28.2; HRMS calcd for C16H25N5O6P [M þ H]þ
414.1543, found 414.1542.
1
Data for 23b: H NMR (600 MHz, CDCl3) δ 1.29ꢀ1.31 (m, 6H,
0
CH3), 4.03ꢀ4.06 (m, 4H, OCH2), 4.79 (d, J = 14.9 Hz, 1H, H4 a), 4.87
0
0
(d, J = 14.9 Hz, 1H, H4 b), 5.45 (s, 1H, H2 ), 5.69 (dd, J1 = 18.3 Hz, J2 =
0
0
17.6 Hz, 1H, H7 ), 6.03 (s, 1H, H1 ), 6.21 (br, 2H, NH2), 6.25 (d, J = 9.1
0
Hz, 1H, H5 ), 7.63 (ddd, J1 = 20.8 Hz, J2 = 16.9 Hz, J3 = 11.2 Hz, 1H,
H6 ), 7.88 (s, 1H, H8), 8.18 (s, 1H, H2); 13C NMR (150 MHz, CDCl3) δ
0
3751
dx.doi.org/10.1021/jo200033p |J. Org. Chem. 2011, 76, 3742–3753