36
I. Jambal et al. / Carbohydrate Research 360 (2012) 31–39
2
3.2.6. 1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-fluoro-
galactopyranose (8)
D
-
protons), 4.92 (br d, 1H, H-4, J4,F = 49.8), 4.79 (m, 4H, 2 ꢁ PhCH),
4.61–4.54 (m, 2H, PhCH), 4.47–4.30 (m, 3H, H-1, H-3, H-5), 4.28–
4.09 (m, 4H, H-2, 3 ꢁ CH3CH), 4.03 (m, 1H, CH3CH) 3.70 (dd, 1H,
J6a,6b = 10, J6a,5 = 6.6, H-6a), 3.64 (dd, 1H, J6b,5 = 10, J6b,5 = 5.8, H-
6b), 1.26 (t, 3H, J = 7.1, CH3), 1.24 (t, 3H, J = 7.1, CH3); 13C NMR
(125 MHz, CDCl3) d: 138.08, 137.90, 137.86 (C-arom. quart.),
A suspension of water (5 mL) and 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) (Selectfluor™,
1.7 g, 4.76 mmol) were added to a solution of 3,4,6-tri-O-benzylga-
lactal (1.084 g, 2.66 mmol) in CH3NO2 (25 mL) and the reaction
was allowed to proceed for 15 min at 100 °C. The reaction was
monitored by TLC (4:1, n-hexane–EtOAc) and quenched with water
(20 mL). Then the mixture was extracted with EtOAc (3 ꢁ 30 mL).
The combined organic extracts were dried with MgSO4 and con-
centrated (1.256 g, 2.78 mmol). The residue was dissolved in pyri-
dine (4 mL) and Ac2O (4 mL) was added. After 16 h, the reaction
was finished by the addition of MeOH (8 mL) and CH2Cl2 (40 mL).
After washing with 5% H2SO4 (2 ꢁ 10 mL) and satd NaHCO3 soln
(2 ꢁ 10 mL) the organic phase was dried (MgSO4). Purification on
1
128.34–127.61 (C-arom.), 87.21 (d, JC,F = 182.7, C-4), 76.31 (d,
2JC,F = 17.3, C-3), 74.62 (C-2), 73.94, 73.36, 72.63 (3 ꢁ PhCH2–),
2
1
73.57 (d, JC,F = 18.4, C-5), 71.52 (d, JC,P = 153.7, C-1), 68.15 (d,
JC,F = 4.8, C-6), 62.72 (d, JC,P = 6.4, CH3CH2), 62.14 (d, JC,P = 6.9,
CH3CH2), 16.40 (d, JC,P = 6.3, CH3), 16.33 (d, JC,P = 6.0, CH3); 19F
NMR (470 MHz, CDCl3, dec) d: ꢀ212.7 (F-4); 31P NMR
(202.5 MHz, CDCl3, dec) d: 21.6 (P-1); ESI-MS, m/z: calcd for
C31H38FNaO7P [5+Na]+: 595.22, found: 595.35. Anal. Calcd for
C
31H38FO7P: C, 65.02; H, 6.69. Found: C, 64.96; H, 6.52.
silica gel column (7:1, n-hexane–EtOAc) gave 8 (610 mg, 54%,
a/b
b-Anomer 13 (34.4 mg, 24%), syrup, ½a D20
ꢂ
+40 (c 1.0, acetone). 1H
1) as a colourless oil, ½a D20
ꢂ
+48 (c 3.0, CHCl3). 1H NMR (500 MHz,
CDCl3) d: 7.30–7.19 (m, aromatic protons), 6.32 (d, J1,2 = 3.6, H-
NMR (500 MHz, CDCl3) d: 7.39–7.27 (m, 15H, H-aromatic protons),
2
4.93 (d, 1H, J = 10.3, PhCH), 4.91 (br d, 1H, J4,F = 46.5, H-4, over-
1
a
), 5.59 (dd, J1,2 = 7.8, J1,F = 4.8, H-1b), 5.01 (ddd, J2,1 = 3.8,
lap.), 4.86 (d, 1H, J = 10.3, PhCH), 4.78 (d, 1H, J = 11.7, PhCH), 4.69
(d, 1H, J = 11.7, PhCH), 4.57–4.51 (m, 2H, 2 ꢁ PhCH), 4.25–4.2 (m,
5H, H-2, 4 ꢁ CH3CH), 3.75–3.5 (m, 5H, H-1, H-3, H-5, H-6a, H-6b),
1.27 (t, 3H, J = 7, CH3), 1.23 (t, 3H, J = 7, CH3); 13C NMR (125 MHz,
CDCl3): d 138.21, 137.63, 137.57 (C-arom. quart.), 128.49–127.58
(C-arom.), 85.63 (d, JC,F = 183.6, C-4), 81.38 (dd, JC,F = 17.6,
JC,P = 17.7, C-3), 77.46 (d, JC,P = 16.9, C-5), 75.42 (PhCH2), 74.96 (d,
1JC,P = 171.4, C-1), 74.91 (C-2), 73.67, (PhCH2), 71.84 (PhCH2),
67.64 (d, JC,F = 5.4, C-6), 63.27 (d, JC,P = 5.8, CH3CH2), 62.45 (d,
JC,P = 6.5, CH3CH2), 16.38 (d, JC,P = 5.8, CH3), 16.27 (d, JC,P = 6.4,
CH3); 19F NMR (470 MHz, CDCl3) d: ꢀ218.40 (ddd, J = 47, 27.6, F-
4); 31P NMR (202.5 MHz, CDCl3) d: 19.60 (m, P-1); TOF-ESI: m/z
calcd for C31H38FNaO7P [13+Na]+: 595.22, found: 594.93. Anal.
Calcd for C31H38FO7P: C, 65.02; H, 6.69. Found: C, 65.36; H, 6.74.
J2,3 = 9.8, J2,F = 49.5, H-2 ), 4.86 (d, J = 8.7, PhCH), 4.84 (d, J = 8.7,
a
PhCH), 4.75 (ddd, J2,1 = 8.7, J2,3 = 9.1, J2,F = 51.9, H-2b), 4.73 (d,
J = 11.9, PhCH–), 4.68 (d, J = 11.5, PhCH), 4.65–4.59 (m, 2 ꢁ PhCH),
4.53 (d, J = 11.5, PhCH), 4.49 (d, J = 11.3, PhCH), 4.41–4.30 (m,
1
2
4 ꢁ PhCH), 4.0 (br s, H-4
a
), 3.96–3.87 (m, H-5
a
, H-4b, H-3
a
),
3.64 (dd, J5,6a = J5,6b = 6.7, H-5b), 3.60 (ddd, J3,4 = 2.6,
J3,2 = J3,F = 9.6, H-3b), 3.55–3.43 (m, H-6ab, H-6bb, H-6aa, H-6ba
,),
2.06, 2.04 (2 ꢁ s, 2 ꢁ COCH3); 13C NMR (125 MHz, CDCl3) d:
169.27, 169.12 (2 ꢁ COMe), 138.2–137.58 (6 ꢁ C-quart. arom.),
2
128.44–127.45 (C-arom.); 91.99 (d, JC,F = 25.4, C-1b), 90.55 (d,
1JC,F = 183.6, C-2b), 89.73 (d, JC,F = 22.5, C-1
a
), 88.07 (d,
2
1JC,F = 188.0, C-2
a
), 79.97 (d, JC,F = 15.6, C-3b), 76.87 (d,
2
2JC,F = 15.8, C-3
), 74.27 (C-5b), 73.87 (d, JC,F = 8.4, C-4b), 73.58, 73.50, 72.86,
a
), 75.06, 74.9 (2 ꢁ PhCH2), 74.93 (d, JC,F = 8.3, C-
4a
72.80 (4 ꢁ PhCH2), 71.78 (C-5
a
), 67.93 (C-6
a
), 67.55 (C-6b),
3.3.1.2. Diethyl (3,4,6-tri-O-benzyl-2-deoxy-2-fluoro-
topyranosyl)phosphonate (6) and diethyl (3,4,6-tri-O-benzyl-2-
deoxy-2-fluoro-b- -galactopyranosyl)phosphonate
(14). From acetate 8 (550 mg, 1.11 mmol) a raw mixture of
a-D-galac-
20.93, 20.86 (2 ꢁ CH3CO–); 19F NMR (282 MHz, CDCl3) d:
a ano-
mer: ꢀ208.9 (ddd, J = 3.8, 10.0, 48.8); b anomer: ꢀ207.3 (ddd,
J = 3, 10.5, 52.5); ESI-MS, m/z: calcd for C29H35FNO6 [8+NH4]+:
512.24, found: 512.24. Anal. Calcd for C29H31FO6: C, 70.43; H,
6.32. Found: C, 69.99; H, 6.35.
D
the phosphonates 5 and 14 (743 mg) were obtained, (Rf = 0.09,
0.19; n-hexane:EtOAc 4:1). Separation on silica gel column (elution
with n-hexane:EtOAc 2:1) yielded:
3.3. Diethyl galactosyl phosphonates 5, 13, 6 and 14.
Debenzylated diethyl galactosyl phosphonates 18 and 20
a
-Anomer 6 (128 mg, 20%), syrup, ½a D20
ꢂ
+26 (c 1.1, CHCl3). 1H
NMR (500 MHz, CDCl3) d: 7.26–7.17 (m, 15H, aromatic protons),
4.99 (dddd, 1H, J2,F = 48.0, J2,P = 12.8, J2,3 = 6.0, J2,1 = 3.8, H-2),
2
3.3.1. General procedure for phosphonylation of galactosyl
acetates 7 and 8
4.64–4.62 (m, 3H, 3 ꢁ PhCH), 4.49–4.39 (m, 3H, 3 ꢁ PhCH), 4.34–
2
4.31 (m, 1H, H-5), 4.29 (ddd, J1,2 = 3.7, J1,P = 14.3, J1,F = 23.3, H-1),
To a solution of anomeric acetates 7 or 8 (0.2–1.2 mmol) in
CH2Cl2 (4 mL/mmol of substrate), (EtO)3P (2.6 mol equiv) was
added under Ar. After cooling to ꢀ1 °C, TMSOTf (2 mol equiv)
was added dropwise for 1 h and the mixture stirred at room tem-
perature for 1 day and monitored by TLC until all the starting
material was consumed and two products had been formed. The
reaction was finished by the addition of a mixture of water and
EtOAc (1:10, 25 mL/mmol of substrate). After washing two times
with a satd soln of NaHCO3 and two times with a satd soln of NaCl,
the organic phase was dried (MgSO4), evaporated and the residue
was separated on a silica gel column.
4.15–4.03 (m, 5H, H-3, 4 ꢁ CH3CH), 3.93 (ddd, 1H, J = 3.5, H-4),
3.79 (dd, 1H, J6a,6b = 11.1, J6a,5 = 8.1, H-6a), 3.55 (dd, 1H,
J6b,6a = 11.1, J6b,5 = 4.0, H-6b), 1.2 (m, 6H, 2 ꢁ CH3); 13C NMR
(125 MHz, CDCl3) d: 138.19, 137.96, 137.87 (C-arom. quart.),
1
2
128.41–127.59 (C-arom.), 88.67 (dd, JC,F = 182.4, JC,P = 2.5, C-2),
2
75.56 (d, JC,P = 8.6, C-5), 75.35 (br d, JC,F = 24.4, C-3), 73.92 (br d,
1
JC,F = 3.4, C-4), 73.42, 73.21 (3 ꢁ PhCH2), 67.52 (dd, JC,P = 166.6,
2JC,F = 22.9, C-1), 66.51 (C-6), 63.24 (d, JC,P = 6.2, CH3CH2), 62.63
(d, JC,P = 6.7, CH3CH2), 16.41 (d, JC,P = 8.19, CH3), 16.34 (d, JC,P = 8.6,
CH3); 19F NMR (282 MHz, CDCl3) d: ꢀ200.2 (m, F-2); 31P NMR
(202.5 MHz) d: 19.01 (m, P-1); ESI-MS, m/z: calcd for C31H42FNO7P
[6+NH4]+: 590.27, found: 590.23. Anal. Calcd for C31H38FO7P: C,
65.02; H, 6.69. Found: C, 65.01; H, 6.61.
3.3.1.1. Diethyl (2,3,6-tri-O-benzyl-4-deoxy-4-fluoro-
topyranosyl)phosphonate (5) and diethyl (2,3,6-tri-O-benzyl-4-
deoxy-4-fluoro-b- -galactopyranosyl)phosphonate
(13). From acetate 7 (128 mg, 0.25 mmol) a crude mixture of
a-D-galac-
b-Anomer 14 (218 mg, 34%), syrup, ½a D20
ꢂ
+9 (c 1.2, CHCl3). 1H
NMR (500 MHz, CDCl3) d: 7.28–7.17 (m, 15H, aromatic protons),
D
-
D
2
5.05 (dddd, 1H, J2,F = 50.7, J2,P = J2,1 = J2,3 = 9.8, H-2), 4.85, 4.74,
the phosphonates 5 and 13 (198 mg) was obtained, (Rf = 0.15, 0.45;
3:1, n-hexane–EtOAc). Separation on silica gel column (elution
with n-hexane: EtOAc 3:1) yielded:
4.61, 4.48 (4 ꢁ d, 4H, 4 ꢁ PhCH), 4.37–4.31 (m, 2H, 2 ꢁ PhCH),
4.14–4.06 (m, 4H, 4 ꢁ CH3CH), 3.90 (dd, 1H, J4,3 = J4,5 = 2.7, H-4),
2
3.60 (ddd, 1H, J1,2 = J1,F = 9.8, J1,P = 4.5, H-1), 3.57–3.45 (m, 4H, H-
a
-Anomer 5 (75.6 mg, 53%), mp 103–105 °C; ½a D20
ꢂ
+53 (c 1.0,
3, H-5, H-6a, H-6b), 1.22 (t, 3H, J = 7.07, CH3), 1.18 (t, 3H, J = 7.08,
CHCl3). 1H NMR (500 MHz, CDCl3) d: 7.4–7.28 (m, 15H, aromatic
CH3); 13C NMR (125 MHz, CDCl3) d: 138.5, 138.06, 137.76 (C-arom.