F. Stolz, A. Blume, S. Hinderlich, W. Reutter, R. R. Schmidt
FULL PAPER
to a cooled (0 °C) solution of 11 (500 mg, 0.8 mmol) in abs. di-
chloromethane (20 mL) and dry ethanol (10 mL) and the stirred
solution was allowed to warm to room temperature over a period
of 3 h. After complete conversion (TLC: toluene/acetone, 2:1, Rf ϭ
0.40) the reaction mixture was poured into an aqueous ammonium
chloride solution (50 mL). The aqueous layer was extracted with
dichloromethane; the pooled organic layer was washed with water
and dried over Na2SO4. After concentration under reduced press-
ure the remaining residue was purified by flash chromatography
(toluene/acetone, 6:1) to afford compound 12 (375 mg, 0.74 mmol,
93%) as a white solid. The physical data are in good agreement
with the reported data.[12] Additional data: 1H NMR: J2,3 Ͻ 1,
J3,4 ϭ 1, J5,6 Ͻ 1, J4,5 ϭ 2.9 Hz.
Triethylammonium [3-Acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-
deoxy-1-(di-O-benzyl phosphoryl)-D-erythro-L-ido/L-gulo-heptitol-1-
O-yl] (2Ј,3Ј-Di-O-acetyluridin-5Ј-yl) Phosphate (15): 1H-Tetrazole
(28 mg, 0.40 mmol) and 14 (160 mg, 0.30 mmol) was added to a
solution of 13 (210 mg, 0.27 mmol) in abs. CH2Cl2 (5 mL) under
argon. After stirring at room temperature for 2 h, the reaction mix-
ture was cooled to 0 °C and a 5.5 solution of tBuOOH in decane
(55 µL, 0.30 mmol) was added slowly. After stirring at room tem-
perature for 40 min, triethylamine (0.5 mL) was added and the mix-
ture was stirred for 16 h. After concentration under reduced press-
ure, the remaining residue was purified by flash chromatography
(ethyl acetate/MeOH, 4:1, ϩ 1% Et3N) to afford compound 15
(240 mg, 0.19 mmol, 71%) as a colourless oil. TLC (ethyl acetate/
MeOH, 3:1, ϩ 1% Et3N): Rf ϭ 0.30. 1H NMR (250 MHz,
[D4]MeOH): δ ϭ 1.21 (t, 9 H, NCH2CH3), 1.91, 1.96, 2.05 (3 s, 9
H, Ac), 3.02 (q, 6 H, NCH2CH3), 3.58Ϫ3.62, 3.89, 4.05Ϫ4.30 [3
m, (3 H, 1 H, 7 H), 4Ј-H, 5Јa,b-H, 1ЈЈ-H, 2ЈЈ-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-
H, 6ЈЈ-H, 7a,bЈЈ-H], 4.43 (m, 4 H, CH2Ph), 4.54, 4.66 (2 d, J ϭ
11.7 Hz, 2 H, CH2Ph), 5.05Ϫ5.12 (m, 4 H, POCH2Ph), 5.37Ϫ5.45
(m, 2 H, 2Ј-H, 3Ј-H), 5.75 (d, J5,6 ϭ 8.1 Hz, 1 H, 5-H), 6.05 (d,
J1Ј,2Ј ϭ 6.2 Hz, 1 H, 1Ј-H), 7.18Ϫ7.27 (m, 25 H, Ph), 7.90 (d,
J6,5 ϭ 8.1 Hz, 1 H, 6-H), 8.12 (br. d, NH) ppm. MALDI-MS
(3-Acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-
D-erythro-L-
ido/ -gulo-heptitol-1-C-yl) Dibenzyl Phosphonate (13): A solution
L
of 12 (130 mg, 0.26 mmol) in abs. dichloromethane (5 mL) was
treated with DessϪMartin periodinane (150 mg, 0.35 mmol). After
stirring at room temperature for 2 h, the reaction was quenched
by adding saturated aqueous solutions of NaHCO3 (10 mL) and
Na2S2O3 (10 mL). The mixture was then diluted with diethyl ether
(50 mL) and stirred at room temperature for 30 min. The aqueous
layer was extracted with diethyl ether; the pooled organic layer was
dried over Na2SO4 and concentrated under reduced pressure. The
remaining residue was dissolved in dichloromethane (3 mL) and
treated with triethylamine (0.1 mL) and diallyl phosphonate (250
µL, 1.6 mmol). After stirring for 2 h at room temperature under
argon, the reaction mixture was concentrated under reduced press-
ure. Purification by flash chromatography (toluene/acetone, 4:1) af-
forded compound 13 (375 mg, 1.15 mmol, 94%) as a colourless oil.
TLC (toluene/acetone, 3:2): Rf ϭ 0.52. [α]D ϭ Ϫ9.0 (c ϭ 1, CDCl3).
1H NMR (600 MHz, CDCl3): δ ϭ 1.89 (s, 3 H, Ac), 3.68 (m, 1 H,
1-H), 3.74 (m, 2 H, 4-H, 5-H), 3.76 (dd, J7a,b ϭ 9.0, J7a,6 ϭ 6.0 Hz,
1 H, 7a-H), 3.94 (dd, J7b,6 ϭ J7b,a ϭ 9.0 Hz, 1 H, 7b-H), 4.28 (m,
2 H, 6-H, 3-H), 4.35Ϫ4.65 (m, 7 H, 2-H, CH2Ph), 5.05Ϫ5.15 (m,
4 H, POCH2Ph), 5.25 (br. d, 1 H, OH), 7.22Ϫ7.37 (m, 26 H, Ph,
NH) ppm. 13C NMR (151 MHz, CDCl3): δ ϭ 23.1 (1 C, Ac), 45.9
(d, J3,P ϭ 13 Hz, 1 C, 3-C), 66.7 (d, J1,P ϭ 173 Hz, 1 C, 1-C), 67.6,
68.3 (2 d, J ϭ 6.5 Hz, 2 C, POCH2Ph), 68.0 (1 C, 7-C), 68.7 (1 C,
2-C), 71.8, 71.9, 73.3 (3 C, CH2Ph), 72.7, 73.3 (2 C, 4-C, 5-C), 74.6
(1 C, 6-C), 127.5Ϫ138.2 (30 C, Ph), 172.1 (1 C, Ac) ppm. 31P NMR
(243 MHz, CDCl3): δ ϭ 26.8 (1 P) ppm. MALDI-MS (positive
mode, DHB): m/z ϭ 787.9 [M ϩ Na]ϩ, 804.0 [M ϩ K]ϩ.
C44H48NO9P (765.86): calcd. C 69.01, H 6.32, N 1.83; found C
68.89, H 6.33, N 1.77.
(ATT, negative mode): m/z
C57H62N3O19P2·C6H16N (1257.3).
ϭ 1154.3 [M Ϫ
HNEt3ϩ]Ϫ.
Bis(triethylammonium)
(3-Acetamido-2,6-anhydro-3-deoxy-D-er-
ythro- -ido/ -gulo-heptitol-1-C-yl) Phosphonate (16): A mixture of
L
L
13 (100 mg, 130 µmol) and Pd/C (10%, 40 mg) in methanol (16 mL)
and water (0.5 mL) was stirred at room temperature for 1 day under
a positive pressure of hydrogen. The catalyst was removed by fil-
tration and the resulting solution was treated with Et3N (0.1 mL),
stirred at room temperature for 5 min and concentrated in vacuo
to afford compound 16 in quantitative yield, which was used in the
next step without purification. 1H NMR (250 MHz, D2O): δ ϭ
1.34 (t, 18 H, Et3N), 2.02 (s, 3 H, Ac), 3.21 (q, 12 H, Et3N), 3.43
(dd, J5,4 ϭ J5,6 ϭ 4.5 Hz, 1 H, 5-H), 3.52 (dd, J7a,b ϭ 9.1, J7a,6
ϭ
4.1 Hz, 1 H, 7a-H), 3.77 (dd, J7b,a ϭ J7b,6 ϭ 9.1 Hz, 1 H, 7b-H),
3.92 (m, 2 H, 4-H, 6-H), 4.12 (m, 2 H, 1-H, 3-H), 4.28 (m, 1 H, 2-
H) ppm. MALDI-MS (negative mode, ATT): m/z ϭ 315.0 [M Ϫ 2
HNEt3 ϩ Hϩ]Ϫ. C9H16NO9P·2C6H16N (517.6).
ϩ
(3-Acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-D-glycero-D-
ido-heptitol-1-yl) Dibenzyl Phosphate (18): 1H-Tetrazole (63 mg,
0.90 mmol) was added to a solution of 12 (230 mg, 0.45 mmol) in
abs. CH2Cl2 (10 mL) under argon. Then, bis(benzyloxy)(diisoprop-
ylamino)phosphane (222 µL, 0.68 mmol) was added slowly to the
reaction mixture. After stirring at room temperature for 3 h, the
2Ј,3Ј-Di-O-acetyluridine-5Ј-O-yl(2-cyanethoxy)(diisopropylamino)- solution was cooled to 0 °C and a solution of 5.5 tBuOOH in
phosphane (14): Compound 14 was prepared similarly to the re- nonane (120 µL, 0.68 mmol) was added slowly to the reaction mix-
ported procedure.[23Ϫ25]
solution of 2,3-di-O-acetyluridine ture. After stirring at room temperature for 1 h the reaction mixture
(700 mg, 2.1 mmol) in abs. dichloromethane (18 mL) was treated was poured into an aqueous solution of Na2S2O3 (50 mL). The
with diisopropylammonium tetrazolide (180 mg, 1.1 mmol) and organic layer was washed with a NaCl solution, a NaHCO3 solu-
bis(diisopropylamido)phosphoric acid 2-cyanoethyl ester (1.2 mL, tion and water (each 50 mL). The aqueous layer was extracted
4 mmol) and stirred at room temperature under argon for 16 h. The again with CH2Cl2 (2 ϫ 25 mL). The pooled organic layer was
A
mixture was concentrated under reduced pressure and the remain-
ing residue was purified by flash chromatography (toluene/ethyl
acetate, 2:1) to afford the diastereomeric mixture of 14 (1.1 g,
2.0 mmol, 95%) as a colourless foam. Additional physical data:
TLC (toluene/acetone, 3:2): Rf ϭ 0.59. 1H NMR (250 MHz,
dried over Na2SO4 and concentrated under reduced pressure. The
remaining residue was purified by flash chromatography (toluene/
acetone, 2:1) to afford compound 18 (300 mg, 0.39 mmol, 87%) as
a colourless oil. TLC (toluene/acetone, 2:1): Rf ϭ 0.38. [α]D ϭ Ϫ7.1
1
(c ϭ 1, dioxane). H NMR (600 MHz, CDCl3): δ ϭ 1.79 (s, 3 H,
CDCl3): δ ϭ 1.10Ϫ1.23 (m, 12 H, iPr), 2.02Ϫ2.14 (4 s, 6 H, Ac), Ac), 3.63, 3.68 (2 m, 2 H, 4-H, 5-H), 3.77 (m, 2 H, 7a,b-H), 4.05
2.62 (m, 2 H, CH2CH2CN), 3.49Ϫ3.93 (m, 7 H, 4Ј-H, 5a,bЈ-H, (m, 2 H, 1a,b-H), 4.18 (ddd, J2,3 ϭ J2,1a ϭ 5.6, J2,1b ϭ 2 Hz, 1 H,
CH2CH2CN, iPr), 5.22Ϫ5.42 (m, 2 H, 2Ј-H, 3Ј-H), 5.73 (2 d, J ϭ 2-H), 4.26 (m, 2 H, 3-H, 6-H), 4.44Ϫ4.51 (m, 4 H, CH2Ph), 4.59
4.0 Hz, 1 H, 1Ј-H), 6.25 (2 d, J ϭ 7.9 Hz, 1 H, 5-H), 7.76 (2 d, J ϭ (d, J ϭ 11.7 Hz, 1 H, CH2Ph), 4.61 (d, J ϭ 11.7 Hz, 1 H CH2Ph),
7.9 Hz, 1 H, 6-H), 9.5 (br. s, 1 H, NH).
5.02Ϫ5.05 (m, 4 H, POCH2Ph), 6.54 (d, J ϭ 9.9 Hz, 1 H, NH),
3310
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 3304Ϫ3312