3838
C.-S. Yu et al.
PAPER
1
3
a
H NMR (500 MHz, CDCl ): d = 2.05 (s, 3 H, H ), 2.13 (s, 3 H,
3
Ac
Rf = 0.70 (n-hexane–EtOAc, 1:1); colorless oil.
HAc), 2.13 (s, 3 H, H ), 4.19 (ddd, J
= 4.0, J
= 4.0,
Ac
4¢–5¢a
4¢–3¢
1
J4¢–5¢b = 6.0 Hz, 1 H, H4¢), 4.36 (dd, J5¢a–4¢ = 4.0, J5¢a–5¢b = 12.0 Hz,
H NMR (500 MHz, C D ): d = 0.27–0.40 (m, 9 H, SnMe ), 1.41 (s,
6
6
3
1
H, H ), 4.43 (dd, J
= 6.0, J5¢b–5¢a = 12.0 Hz, 1 H, H ), 5.09
5
¢a
5¢b–4¢ 5¢b
3
3
(
H, H ), 1.49 (s, 3 H, H ), 1.71 (s, 3 H, H ), 1.77 (s, 9 H, H ),
Ac Ac Ac Boc
(
dd, J3¢–4¢ = 4.0, J3¢–2¢ = 2.0 Hz, 1 H, H ), 5.42 (dd, J
= 2.0,
2¢–3¢
3¢
.82 (ddd, J4¢–3¢ = 3.0, J4¢–5¢a = 4.0, J4¢–5¢b = 7.5 Hz, 1 H, H ), 4.24
4¢
J2¢–1¢ = 4.0 Hz, 1 H, H ), 6.23 (dd, J
= 4.0, J1¢–F¢ = 1.0 Hz, 1 H,
2¢
1¢–2¢
dd, J5¢a–4¢ = 4.0, J5¢a–5¢b = 12.0 Hz, 1 H, H ), 4.35 (dd, J
= 7.5,
5¢a
5¢b–4¢
H ), 7.63 (d, J = 7.0 Hz, 1 H, H ), 8.26 (d, J = 7.0 Hz, 1 H,
1¢
6–F
6
NH–F
J5¢b–5¢a = 12.0 Hz, 1 H, H5¢b), 5.02 (br s, 1 H, H ), 5.53 (dd,
J2¢–1¢ = 3.5, J
(
1
3¢
NH).
= 1.5 Hz, 1 H, H ), 6.35 (br s, 1 H, H ), 7.26–7.36
2¢–3¢
2¢ 1¢
1
3
19
m, 1 H, H6). C NMR (125 MHz, C D ): d = –9.22 (CH , SnMe ),
F NMR (470.7 MHz, CDCl ): d = –165.21 (dd, J = 7.0,
3 F–6
6
6
3
3
9.83 (CH , Ac), 19.87(CH , Ac), 20.32 (CH , Ac), 29.62 (CH ,
JF–NH = 7.0 Hz, 1 F).
3
3
3
3
Boc), 61.69 (CCH , Boc), 62.52 (CH , C-5¢), 75.04 (CH), 76.73
+
+
+
3
2
ESI-QTOF: m/z =388.1 [M ], 389.0 [M + H] , 411.0 [M + Na] ,
(
CH), 80.86 (CH), 85.67 (CH), 112.93 (C-5), 140.63 (CH, C-6),
51.99 (C=O, C-2), 164.80 (C=O, Boc), 167.92 (C=O, C-4), 168.06
CH CO), 169.19 (CH CO), 169.75 (CH CO).
+
7
99.2 [2 × M + Na] .
1
(
3
3
3
5
-Fluoro Arabinosyl Uridine (6)
To a solution of 5 (25 mg) in MeOH (1 mL), NaOMe in MeOH (0.2
M, 1 mL) was added and the reaction was stirred for 30 min [mon-
itored by TLC (MeOH–CHCl , 1:3)]. The resulting solution was
+
+
ESI-QTOF: m/z = 634.1 [M ], 534.9 [M – Boc + 2H] . Clustering
of the peaks corresponding to isotope distribution of Sn was ob-
served.
3
+
treated with Dowex 500 (500 mg, WX8-400, H form) and filtered.
3
b
After evaporation under reduced pressure at 40 °C, the crude prod-
uct 6 was obtained as a colorless solid (16 mg, 95%). Further puri-
fication was performed by RP-HPLC (Agilent 1100), sample loop
Rf = 0.59 (n-hexane–EtOAc, 1:1); colorless oil.
1
H NMR (500 MHz, C D ): d = 0.23–0.37 (m, 9 H, SnMe ), 1.43 (s,
6
6
3
(
500 mL), semipreparative column (C-18, 10 × 250 mm, 5 mm;
3
H, H ), 1.48 (s, 9 H, H ), 1.50 (br d, 3 H, H ), 1.70 (s, 3 H,
Ac Boc Ac
MeOH–H O, 3:7; 3 mL/min) with UV detection at 260 nm.
2
H ), 3.90–3.95 (m, 2 H), 4.15 (dd, J
1
= 4.0, J5¢a–5¢b = 12.0 Hz,
5¢a–4¢
= 6.5, J5¢b–5¢a = 12.0 Hz, 1 H, H ), 4.73
= 3.5 Hz, 1 H, H ), 7.35–7.44 (m, 1 H,
Ac
1
H, H ), 4.36 (dd, J
H NMR (500 MHz, CD OD): d = 3.78 (dd, J
= 5.0,
5¢a–4¢
= 3.5, J5¢b–5¢a = 12.0 Hz,
5
¢a
5¢b–4¢
5¢b
3
(br s, 1 H, H ), 6.09 (d, J
J5¢a–5¢b = 12.0 Hz, 1 H, H ), 3.82 (dd, J
3
1¢–2¢
1¢
5¢a
5¢b–4¢
H6).
1 H, H ), 3.90 (ddd, J
= 3.5, J4¢–5¢a = 5.0, J4¢–5¢b = 3.5 Hz, 1 H,
5¢b
4¢–3¢
1
3
H4¢), 4.06 (dd, J3¢–2¢ = 3.0, J3¢–4¢ = 3.5 Hz, 1 H, H3¢), 4.16 (dd,
C NMR (125 MHz, C D ): d = –9.34 (CH , SnMe ), 19.95 (CH ,
6
6
3
3
3
J2¢–1¢ = 3.0, J2¢–3¢ = 3.0 Hz, 1 H, H ), 6.09 (dd, J
= 3.0, J1¢–F = 4.0
2¢
1¢–2¢
Ac), 20.30 (CH , Ac), 27.42 (CH , Boc), 62.87 (CH , C-5¢), 73.93
(
1
3
3
2
Hz, 1 H, H ), 8.03 (d, J = 7.0 Hz, 1 H, H6).
1¢
6–F
CH), 79.05 (CH), 81.82 (CH), 86.02 (CCH , Boc), 87.05 (CH),
10.30 (C-5), 144.60 (CH, C-6), 149.09 (C=O, C-2), 149.55 (C=O,
3
1
9
F NMR (470.7 MHz, CD OD): d = –171.10 (br d, J = 7.0 Hz,
3 F–6
C-4), 163.66 (C=O, Boc), 169.37 (CH CO), 169.77 (CH CO). The
1 F).
3
3
corresponding signals for one set of CH CO were not found.
+
+
+
3
ESI-QTOF: m/z = 262.1 [M ], 263.0 [M + H] , 285.0 [M + Na] ,
547.1 [2 × M + Na] .
+
+
+
ESI-QTOF: m/z = 634.1 [M ], 535.0 [M – Boc + 2H] , 635.0
+
[M+H] . Clustering of the peaks corresponding to isotope distribu-
tion of Sn was observed.
3-N-Boc-5-fluoro-2¢,3¢,5¢-tri-O-acetyl Arabinosyl Uridine (7)
Following the procedure for the preparation of 5 above, 3a (10 mg,
0.02 mmol), MeCN (1.5 mL) and Selectfluor (8 mg, 0.02 mmol)
were stirred at 50 °C for 5 h to give the crude product 7, which was
purified by column chromatography (n-hexane–EtOAc, 3:1) and
normal-phase HPLC (EtOAc–n-hexane, 1:3).
3c
Rf = 0.55 (n-hexane–EtOAc, 1:1); colorless oil.
1
H NMR (500 MHz, C D ): d = 0.20–0.33 (m, 9 H, SnMe ), 1.40 (s,
6
6
3
3
3
H, H ), 1.43 (s, 9 H, H ), 1.44 (s, 3 H, H ), 1.69 (s, 3 H, H ),
Ac Boc Ac Ac
.73 (ddd, J4¢–3¢ = 4.0, J4¢–5¢a = 3.0, J4¢–5¢b = 6.0 Hz, 1 H, H ), 4.19
Yield: 4 mg (50%); colorless oil.
4¢
(
dd, J5¢a–4¢ = 3.0, J5¢a–5¢b = 12.0 Hz, 1 H, H ), 4.35 (dd, J
= 6.0,
1
5¢a
5¢b–4¢
H NMR (600 MHz, C D ): d = 1.38 (s, 3 H, H ), 1.40 (s, 3 H, H ),
6
6
Ac
Ac
J5¢b–5¢a = 12.0 Hz, 1 H, H5¢b), 5.02 (br s, 1 H, H ), 5.43 (dd,
J2¢–1¢ = 4.0, J2¢–3¢ = 1.5 Hz, 1 H, H ), 6.26 (d, J
H ), 7.24–7.33 (m, 1 H, H ).
3¢
1
.65 (s, 3 H, H ), 1.71 (s, 9 H, H ), 3.74 (ddd, J
= 4.2,
Ac
Boc
4¢–5¢a
= 4.0 Hz, 1 H,
2¢
2¢–1¢
J4¢–3¢ = 7.8, J4¢–5¢b = 6.0 Hz, 1 H, H ), 4.08 (dd, J
J5¢a–5¢b = 12.0 Hz, 1 H, H ), 4.23 (dd, J = 6.0, J5¢b–5¢a = 12.0 Hz,
1 H, H ), 4.95 (br s, 1 H, H ), 5.46 (dd, J = 4.2, J2¢–1¢ = 3.0, 1 H,
5¢b 3¢ 2¢–3¢
= 4.2,
4¢
5¢a–4¢
1¢
6
5¢a
5¢b–4¢
13
C NMR (125 MHz, C D ): d = –9.35 (CH , SnMe ), 19.75 (CH ,
6
6
3
3
3
Ac), 19.78 (CH , Ac), 20.28 (CH , Ac), 27.35 (CH , Boc), 62.33
H ), 6.18 (d, J
= 3.0 Hz, 1 H, H ), 7.44 (s, J = 5.4 Hz, 1 H,
3
3
3
2¢
1¢–2¢ 1¢ 6–F
(
CH , C-5¢), 75.01 (CH), 76.29 (CH), 80.87 (CH), 84.94 (CCH ,
H6).
13
2
3
Boc), 86.06 (CH), 111.06 (C-5), 143.41 (C-H, C-6), 148.58 (C=O,
C NMR (150.77 MHz, C D ): d = 19.62 (CH , Ac), 19.80 (CH ,
6
6
3
3
C-2), 149.21 (C=O, C-4), 162.80* (C=O, Boc), 168.03 (CH CO),
3
Ac), 20.14 (CH , Ac), 29.61 (CH , Boc), 62.27 (CH , C-5¢), 63.64
3
3
2
1
69.17 (CH CO), 169.72 (CH CO). * = very weak signal.
3
3
(
CCH , Boc), 74.64 (CH), 76.07 (CH), 80.56 (CH), 85.19 (CH),
3
+
+
ESI-QTOF: m/z = 634.1 [M ], 535.0 [M – Boc + 2H] , 635.0 [M +
120.68 (d, JC6–F = 35.1 Hz, C-6, CH), 140.12 (d, JC6–F = 231.6 Hz,
C-5), 149.98 (C=O, C-2), 158.26 (C=O, C-4), 158.42 (C=O, Boc),
168.31 (CH CO), 169.10 (CH CO), 169.82 (CH CO).
+
+
+
H] , 652.1 [M + NH ] , 673.0 [M + K] . Clustering of the peaks cor-
4
responding to isotope distribution of Sn was observed.
3
3
3
19
F NMR (564.2 MHz, C D ): d = –163.60 (br s, 1 F).
6
6
5
-Fluoro-2¢,3¢,5¢-tri-O-acetyl Arabinosyl Uridine (5)
To a dried round-bottomed flask (25 mL), compound 4 (100mg,
.19 mmol), MeCN (15 mL) and Selectfluor (69 mg, 0.20 mmol)
+
+
ESI+Q–TOF: m/z = 488.1 [M ], 371.0 [M – Boc + 2H] , 511.1 [M
+
+
Na] .
0
were added. The mixture was stirred at 55 °C for 10 h, during which
the progress of the reaction was followed by TLC, until the starting
3
-N-Boc-5-ethynyl-2¢,3¢,5¢-tri-O-acetyl Arabinosyl Uridine (9)
Compound 8 (569 mg, 1.4 mmol), (Boc) O (1.1 mL, 4.9 mmol) and
material 4 [R = 0.78 (n-hexane–acetone, 1:1)] had been consumed
2
f
THF (30 mL) were stirred at 80 °C for 5 min. The solution was al-
lowed to come to r.t. then DMAP (176 mg, 1.44 mmol) was added
and the mixture was stirred for 4 h [reaction monitored by TLC ( n-
(~10 h). The solvent was removed and the crude mixture was puri-
fied by column chromatography (n-hexane–EtOAc, 3:2).
Yield: 25 mg (30%); white foam; R = 0.50 (n-hexane–acetone, 1:1).
f
Synthesis 2006, No. 22, 3835–3840 © Thieme Stuttgart · New York