S. Du et al. / Bioorg. Med. Chem. 7 (1999) 2671±2682
2679
1
(mixture of two anomers): H NMR (CDCl3,400 MHz)
MeOH:H2O (1:3, 130 mL). The reaction progress was
monitored by TLC (silica gel, 10% MeOH:CHCl3).
After 1.5 h, the reaction was quenched by addition of
Amberlite IR-45 (OH form) resin until the pH was
neutral (pH paper). The mixture was ®ltrated and sol-
vent was removed in vacuum. Column chromatography
(2.5±7.0% MeOH:CHCl3) aorded the target triol
(2.011 g, 47.5%) as an oil: 1H NMR (CDCl3, 400 MHz)
d 1.25 (t, 3H, J=7.1 Hz, CO2CH2CH3), 1.295 (t, 3H,
J=7.1 Hz, Me of PO3Et2), 1.300 (t, 3H, J=7.1 Hz, Me
of PO3Et2), 1.33 (s, 3H, Me), 1.44 (s, 3H, Me), 3.07 (dd,
1H, J=14.3, 4.8 Hz, H-1a), 3.17 (dd, 1H, J=14.3, 6.2
Hz, H-1b), 3.20 (d, 2H, J=10.4 Hz, NCH2PO3), 3.59 (d,
1H, J=18.0 Hz, NCHHCO2), 3.68 (d, 1H, J=18.0 Hz,
NCHHCO2), 3.75 (dd, 1H, J=11.8, 2.8 Hz, H-6a), 3.85
(dd, 1H, J=11.8, 2.8 Hz, H-6b), 3.95 (m, 1H, H-4),
4.05±4.14 (m, 5H, H-5, 2CH2 of PO3Et2), 4.14 (q, 2H,
J=7.1 Hz, CH2 of CO2Et2), 4.33 (ddd, 1H, J=6.6, 6.2,
4.8 Hz, H-2), 4.38 (dd, 1H, J=6.6 and 3.4 Hz, H-3); 13C
NMR (CDCl3, 50.3 MHz) d 14.24 (CO2CH2CH3),
[16.37, 16.48 (PO3CH2CH3)], [25.12, 27.20 (C(CH3)2)],
50.81 (dd, J=162.2 Hz, NCH2P), 55.83 (d, J=6.8 Hz,
CO2CH2CH3), 55.95 (d, J=8.5 Hz, NCH2CO2), 60.51
(C1), 62.21 (d, J=6.9 Hz, POCH2CH3), 62.55 (d, J=7.0
Hz, POCH2CH3), [63.66, 69.02, 73.03, 76.06, 77.0 (C2,
C3, C4, C5, C6)], 107.99 [C(CH3)2], 170.75 (CO2); 31P
NMR (proton decoupled, CDCl3, 81.0 MHz) d 22.87
ppm; CIMS m/z 458.0 (MH+, C18H37O10NP requires
458.4).
d 1.23 (t, 3H, J=7.1 Hz, CO2CH2CH3), 1.24 (t, 3H,
J=7.1 Hz, CO2CH2CH3), [1.29, 1.30, 1.31, 1.33, 1.39,
1.41, 1.43, 1.46 (8s, 24H, Me of isopropylidene groups),
3.52 (d, 1H, J=17.2 Hz, NCHHCO2), 3.63 (d, 1H,
J=17.2 Hz, NCHHCO2), 3.90 (dd, 1H, J=7.9, 3.7 Hz,
H-3b), 3.92 (d, 1H, J=4.48, H-2a), 4.00±4.05 (m, 3H,
H-6b, H-5b, H-3a), 4.13 (q, 2H, J=7.1 Hz, CO2
CH2CH3), 4.15 (q, 2H, J=7.1 Hz, CO2CH2CH3),
4.306±4.326 (m, 3H, H-4a, H-6b, H-4b), 4.46 (d, 1H,
J=5.9 Hz, H-1b), 4.57 (dd, 1H, J=6.08, 3.54 Hz, H-
5a), 4.65 (dd, 1H, J=6.07, 3.44 Hz, H-6a), 4.67 (s, 1H,
H-1a), 4.74 (dd, 1H, J=5.96, 3.62 Hz, H-2b); 13C NMR
(CDCl3, 50.3 MHz) d 14.15 (CO2CH2CH3), [24.64,
25.24, 25.29, 25.75, 25.98, 26.85, C(CH3)2)], 46.84
(NCH2CO2), 48.05 (CO2CH2CH3), [60.72, 60.94, 66.84,
66.95, 73.21, 79.45, 79.68, 79.73, 80.31, 85.62, 91.13,
94.69 (C1, C2, C3, C4, C5, C6)], {109.01, 109.18,
112.57, 112.68 [C(CH3)2}, [171.86, 172.39 (CO2)]; CIMS
m/z 346.1 (MH+, C16H28O7N requires 346.4).
1-Deoxy-1-[(diethylphosphonomethyl)(2-ethoxy-2-oxo-
ethyl)amino]-2,3:5,6-di-O-isopropylidene-D-mannitol (8).
To a stirred mixture of compound 7 (0.9 g, 2.6 mmol)
and Na2CO3 (0.98 g) in 8 mL CH2Cl2:H2O (1:1) was
added diethylphosphonomethyltri¯ate (0.83 g, 3.11
mmol). The resulting mixture was stirred for 2 h at
45ꢁC. Additional portions of the tri¯ate (0.83g, 3.11
mmol), Na2CO3 (0.9 g), CH2Cl2 (4 mL) and H2O (4
mL) were added, and the reaction mixture was heated at
re¯ux for 2 h. After cooling to room temperature the
reaction mixture was extracted with CH2Cl2 (3Â20 mL),
dried (MgSO4) and concentrated under a vacuum.
Chromatography of the crude residue (EtOAc:hexane,
3:2) furnished 8 (0.84 g, 65%), along with unreacted 7
The above triol (50 mg, 0.11 mmol) was dissolved in dry
pyridine (5 mL), to which dimethyl-tert-butyl-chloro-
silane (50 mg, 0.33 mmol) and catalytic amount 4-
dimethylaminopyridine were added at 0ꢁC. The reaction
mixture was stirred at room temperature for 2 h, then
diluted with EtOAc and washed with saturated
NaHCO3. The organic fraction was dried (MgSO4) and
concentrated to give the corresponding silylated pro-
duct. This crude product, without further puri®cation,
was dissolved in dry pyridine (2 mL) and acetic anhy-
dride (0.5 mL) was added. The reaction mixture was
stirred at room temperature for 1.5 h, then diluted with
EtOAc, washed with saturated NaHCO3, dried
(MgSO4), and evaporated to dryness. Puri®cation by
chromatography on silica gel (EtOAc:hexane, 3:2) gave
1
(20.6 mg, 2.3%). Data for 8: H NMR (CDCl3, 400
MHz) d 1.22 (t, 3H, J=7.1 Hz, CO2CH2CH3), 1.28 (t,
3H, J=7.1 Hz, Me of PO3Et2), 1.28 (t, 3H, J=7.1 Hz,
Me of PO3Et2), 1.30 (s, 3H, Me), 1.31 (s, 3H, Me), 1.35
(s, 3H, Me), 1.43 (s, 3H, Me), 3.14-3.16 (m, 2H, 2H-1),
3.19 (dd, 1H, J=15.9, 9.6 Hz, NCHHPO3), 3.24 (dd,
1H, J=15.9, 10.6 Hz, NCHHPO3), 3.48 (dd, 1H,
J=7.0, 0.7 Hz, H-4), 3.64 (d, 1H, J=18.0 Hz,
NCHHCO2), 3.69 (d, 1H, J=18.0 Hz, NCHHCO2),
3.95 (dd, 1H, J=6.2, 3.2 Hz, H-6a), 3.98±4.04 (m, 1H,
H-5), 4.04±4.156 (m, 7H, H-6b and OCH2CH3),
4.28(dd, J=7.2, 0.7 Hz, H-3), 4.35 (ddd, 1H, J=7.2,
5.5, 5.0 Hz, H-2); 13C NMR (CDCl3, 50.3 MHz) d 14.19
(CO2CH2CH3), {16.37, 16.48 [PO3(CH2CH3)2]}, {24.72,
25.24, 26.65, 26.81 [C(CH3)2]}, 50.27 (d, J=159.8 Hz,
NCH2P), 55.21 (d, J=9.2 Hz, NCH2CO2), 56.20 (d,
J=4.9 Hz, CO2CH2CH3), 60.37 (C1), 61.95 (d, J=5.8
Hz, PO3CH2CH3), 62.10 (d, J=6.5 Hz, PO3CH2CH3),
[67.28, 70.47, 76.06 (bs), 76.20 (C2, C3, C4, C5, C6)],
{108.13, 109.17 [C(CH3)2]}, 170.89 (CO2); 31P NMR
(proton decoupled, CDCl3, 81.0 MHz) d 22.86; CIMS
m/z 497.9 (MH+, C21H41O10NP requires 498.5).
1
pure product 9 (67 mg, 93%): H NMR (CDCl3, 400
MHz) d 0.02 (s, 6H, SiMe2), 0.85 (s, 9H, SiCt-Bu), 1.24
(t, 3H, J=7.1 Hz, CO2CH2CH3), 1.297 (t, 3H, J=7.1
Hz, Me of PO3Et2) 1.301 (t, 3H, J=7.1 Hz, Me of
PO3Et2), 1.30 (s, 3H, Me), 1.43 (s, 3H, Me), 2.02 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 2.78 (ddd, 1H, J=13.7, 3.6,
2.8 Hz, H-1a), 2.99 (dd, 1H, H-1b, J=13.7, 8.1 Hz),
3.19 (dd, 1H, J=16.0, 8.0 Hz, NCHHP), 3.26 (dd, 1H,
J=16.0, 11.8 Hz, NCHHP), 3.61 (dd, 1H, J=11.3, 6.8
Hz, H-6a), 3.62 (d, 1H, J=18.0 Hz, NCHHCO2), 3.73
(d, 1H, J=18.0 Hz, NCHHCO2), 3.93 (dd, 1H, J=11.3,
4.0 Hz, H-6b), 4.067±4.158 (m, 6H, 3CH2CH3), 4.29 (dd,
1H, J=6.4, 2.9 Hz, H-3), 4.35 (ddd, 1H, J=8.0, 6.4, 3.6
Hz, H-2), 4.97 (ddd, 1H, J=6.8, 4.7, 4.0 Hz, H-5), 5.09
(dd, 1H, J=4.7, 2.9 Hz, H-4); 13C NMR (CDCl3, 50.3
1-Deoxy-1-[(diethylphosphonomethyl)(2-ethoxy-2-oxo-
ethyl)amino]-2,3-O-isopropylidene-4,5-di-O-acetate-6-
[(tert-butyl)dimethylsilyl]-D-mannitol (9). To a stirred
solution of 8 (4.6 g, 9.24 mmol) in methanol (130 mL)
was added 0.33 M solution of tri¯uoroacetic acid in
MHz)
(CO2CH2CH3), [16.42, 16.54 (PO3CH2CH3)], [20.92,
d
5.46 (SiMe3), 14.17 (SiCMe3), 14.23
21.04 (CH3CO)], 25.66 [C(CH3)2], 25.76 (SiCMe3), 26.74