white foam (94% yield). HRMS found (calcd) for [M + H+]:
533.2860 (533.2857). IR (cm-1): 2902.7, 2848.7, 1716.5,
1652.9, 1456.2, 1132.1, 1099.3. [R]20D -9.0 (c 1.0, CHCl3);
) 6.6, 1H, H-1′), 5.8 (bs, 2H, CH2 Pom), 5.4 (bs, 1H, H-3′),
4.1 (s, 1H, H-4′), 3.7 (s, 6H, 2 × OMe), 3.4 (bs, 2H, H-5′),
2.7 (t, J ) 6.2, 2H, CH2 Lev), 2.5 (t, J ) 6.2, 2H, CH2
Lev), 2.4 (m, 2H, H-2′), 2.1 (s, 3H, CH3 Lev), 1.3 (s, 3H,
CH3 thymidine), 1.1 (9H, tBu Pom); 13C NMR (75 MHz,
CDCl3) δ 206.6 (CO Lev), 177.8 (CO Pom), 172.5 (COO
Lev), 162.8 (C-4), 159.0 (Cq DMTr), 150.6 (C-2), 144.5 (Cq
DMTr), 135.5 (Cq DMTr), 134.7 (C-6), 130.4, 128.4, 127.5,
113.6 (CH DMTr), 111.1 (C-5), 87.5 (Co DMTr), 85.3, 84.3
(C-1′, C-4′), 75.8 (C-3′), 65.4 (CH2 Pom), 64.0 (C-5′), 55.5
(OMe), 39.1 (Co Pom), 38.2, 38.0 (CH2 Lev, C-2′), 30.0
(CH3 Lev), 28.2 (CH2 Lev), 27.3 (CH Pom), 12.5 (C-7).
5′-O-Dimethoxytrityl-N3-benzoyl-thymidine (21). N3-
Benzoyl-thymidine12 (9.7 g, 28 mmol) was coevaporated with
and dissolved in pyridine (150 mL). Dimethoxytritylchloride
(11.2 g, 33 mmol) was added, and the mixture was stirred
for 45 min. TLC analysis (EtOAc/PE, 1/1) indicated complete
conversion of the starting compound into a higher running
product (Rf ) 0.4), and the mixture was concentrated in
vacuo. The residue was taken up in EtOAc (200 mL) and
washed with water (100 mL), 5% KHSO4 (2 × 100 mL),
water (100 mL), and finally brine (100 mL). After drying
(MgSO4), filtration, and evaporation, the crude product was
applied onto a silica gel column (prepared in the presence
of 3% Et3N) and eluted with a gradient of EtOAc in PE (1/2
f 2/1) which yielded 15.9 g, 24.5 mmol (87%) of the title
compound. HRMS found (calcd) for [M + H+]: 649.2558
(649.2544). IR (cm-1): 1747.4, 1701.1, 1651.0, 1508.2,
1442.7, 1249.8, 1176.5, 1029.9. [R]20D +5.4 (c 1.0, CHCl3);
mp 100-105 °C. 1H NMR (300 MHz, CDCl3) δ 7.9 (d, J )
7.3, 2H, H arom Bz), 7.7 (s, 1H, H-6), 7.6-7.2 (m, 12H, H
arom Bz, DMTr), 6.8 (d, J ) 8.5, 4H, H arom DMTr), 6.4
(t, J ) 7.1, 1H, H-1′), 4.5 (bs, 1H, H-3′), 4.0 (bs, 1H, H-4′),
3.8 (s, 6H, 2 × OMe), 3.40 (dd, J ) 10.6 , J ) 2.5, J ) 2.7,
1H, H-5′a), 3.3 (dd, J ) 10.6 , J ) 2.6, J ) 2.7, 1H, H-5′b),
2.5 (bs, 1H, OH), 2.3 (m, 2H, H-2′), 1.4 (s, 3H, CH3
thymidine); 13C NMR (50 MHz, CDCl3) δ 168.9 (CO Bz),
162.8 (C-4), 158.4 (Cq DMTr), 149.1 (C-2), 144.0 (Cq
DMTr), 135.8 (C-6), 135.1 (Cq DMTr), 131.1 (Cq Bz),
130.2, 129.8, 128.9, 127.8, 126.9, 113.0 (CH DMTr, Bz),
110.8 (C-5), 86.6 (Co DMTr), 86.8, 84.8 (C-1′, C-4′), 71.8
(C-3′), 63.3 (C-5′), 55.0 (OMe), 40.8 (C-2′), 11.4 (C-7).
5′-O-Dimethoxytrityl-N3-pivaloyloxymethyl-thymi-
dine (22). 5′-O-Dimethoxytrityl-3-O-levulinoyl-N3-pivaloyl-
oxymethyl-thymidine (20, 30.2 g, 40 mmol) was dissolved
in a mixture of pyridine and acetic acid (4/1, 400 mL), and
hydrazine monohydrate (1.9 mL, 60 mmol) was added. TLC
analysis (EtOAc) after 30 min showed the formation of a
more hydrophilic compound. Acetylacetone (8.3 mL, 80
mmol) was added to quench the hydrazine, and the mixture
was stirred for 5 min. The solvents were removed by
evaporation, and the residue was taken up in diethylether
(350 mL) and extracted with water (350 mL), 10% KHSO4
(2 × 350 mL), 10% NaHCO3 (2 × 350 mL), and finally
brine (350 mL). After drying (MgSO4) and filtration the
solvents were removed by evaporation, and the crude product
1
mp 63-68 °C. H NMR (300 MHz, CDCl3) δ 7.7 (s, 1H,
H-6), 6.3 (t, J ) 6.8, H-1′), 6.0 (s, 2H, CH2 Pom), 5.3 (bs,
1H, H-3′), 4.1 (s, 1H, H-4′), 3.9 (s, 2H, H-5′), 2.9 (bs, 1H,
OH), 2.4 (bs, 2H, H-2′), 2.1 (s, 2H, CH2CO, Ada), 1.9 (m,
3H, 3 × CH Ada), 1.7 (m, 12H, 6 × CH2 Ada), 1.2 (s, 9H,
tBu Pom); 13C NMR (75 MHz, CDCl3) δ 177.0 (CO Pom),
170.7 (CO Ada), 162.2 (C-4), 149.8 (C-2), 135.1 (C-6), 109.5
(C-5), 85.4, 84.9 (C-1′, C-4′), 74.1 (C-3′), 64.4 (C-5′), 61.8
(CH2 Pom), 47.9 (CH2CO Ada), 41.8 (CH2 Ada), 38.2 (Co
Pom), 37.2 (C-2′), 37.2 (CH2 Ada), 32.3 (Co Ada), 27.9 (tBu
Pom), 26.3 (CH Ada), 12.5 (C-7).
5′-O-Dimethoxytrityl-3′-O-levulinoyl-thymidine (19).
5′-O-Dimethoxytritylthymidine (7.59 g, 14.0 mmol) was
coevaporated with dioxane and dissolved in dioxane (100
mL). To this solution were added levulinic acid (2.87 mL,
28.0 mmol), EDC (5.4 g, 28 mmol), and DMAP (171 mg,
0.1 mmol). After stirring for 2.5 h TLC analysis (5% MeOH/
DCM) indicated complete conversion of the starting material.
The solvent was removed by evaporation in vacuo, and the
residue was dissolved in DCM (100 mL). After washing of
the organic phase with water, 10% KHSO4, and 10%
NaHCO3 (3×), the organic phase was dried (MgSO4),
filtered, and concentrated to give a foam (19), which was
used directly in the next reaction.
Although 19 is a known compound, no analytical data
were reported. MS found (calcd) for [M + H+]: 643.4
(643.3). IR (cm-1): 2360.7, 2341.4, 1693.4, 1508.2, 1249.8.
1
[R]20 +8.0 (c 1.0, CHCl3); mp 88-92 °C. H NMR (300
D
MHz, CDCl3) δ 8.7 (s, 1H, H-3), 7.6 (s, 1H, H-6), 7.4-7.2
(m, 9H, H arom DMTr), 6.9 (d, J ) 8.9, 4H, H arom DMTr),
6.4 (t, J ) 7.0, 1H, H-1′), 5.5 (bs, 1H, H-3′), 4.1 (s, 1H,
H-4′), 3.8 (s, 6H, 2 × OMe), 3.5 (bs, 2H, H-5′), 2.8 (t, J )
6.8, 2H, CH2 Lev), 2.6 (t, J ) 6.3, 2H, CH2 Lev), 2.5 (m,
2H, H-2′), 2.2 (s, 3H, CH3 Lev), 1.4 (CH3 thymidine).
5′-O-Dimethoxytrityl-3′-O-levulinoyl-N3-pivaloyloxy-
methyl-thymidine (20). The foam obtained in the previous
reaction (19, 12.1 g) was dissolved in DMF (70 mL);
chloromethylpivalate (6.1 mL, 42 mmol) and K2CO3 (7.73
g, 56 mmol) were added, and the mixture was stirred
overnight. TLC analysis (diethylether) indicated the forma-
tion of a more lipophilic product. Diethylether (250 mL) was
added, and the resulting mixture was extracted with water
(150 mL). The aqueous layer was back-extracted with
diethylether (100 mL). The combined organic phases were
concentrated in vacuo to give an oil. A silica gel column
was prepared using 1% Et3N in didiethylether. After ap-
plication of the crude product onto the column, diethylether
was used as the eluent. Concentration of the appropriate
fractions gave 10.2 g, 13.5 mmol (96% yield) of the title
compound. HRMS found (calcd) for [M + Na+]: 779.3150
(779.3150). IR (cm-1): 1716.5, 1666.4, 1508.2, 1461.9,
1249.8. [R]20D +7.0 (c 1.0, CHCl3); mp 59-64 °C. 1H NMR
(300 MHz, CDCl3) δ 7.7 (s, 1H, H-6), 7.4-7.2 (m, 9H, H
arom DMTr), 6.8 (d, J ) 8.7, 4H, H arom DMTr), 6.3 (t, J
1244
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Vol. 10, No. 6, 2006 / Organic Process Research & Development