C
F. Stauffert et al.
Paper
Synthesis
cautiously added under stirring. Aq 10% NaOH solution (7.2 mL) and
H2O (10.8 mL) were then successively added and the mixture was
stirred until the grey color of the heterogeneous solution was dis-
charged. The insoluble material was filtered off and the filtrate was
concentrated under reduced pressure. The crude residue was diluted
with CH2Cl2 and washed with H2O. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford 7
(5.02 g, 99%) as a white solid; mp 58–59 °C; Rf = 0.20 (CH2Cl2/MeOH,
96:4); [α]D20 +63 (c 1.0, CHCl3).
Selectride solution in THF (15.3 mL, 15.3 mmol) was added dropwise
at –78 °C. The reaction mixture was stirred at –78 °C for 3 h. MeOH (3
mL) and aq 1 M NaOH solution (100 mL) were then successively add-
ed and the resulting mixture was extracted with CH2Cl2 (2 × 100 mL).
The combined organic extracts were washed successively with sat. aq
NH4Cl and brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography (EtOAc/PE, 20:80 to 30:70) to afford 10 (3.73 g, 74%)
20
as a pale yellow oil; Rf = 0.33 (EtOAc/PE, 30:70); [α]D –25 (c 1.0,
CHCl3).
IR (neat): 3444 cm–1
IR (neat): 3315 cm–1
.
.
1H NMR (CDCl3, 400 MHz): δ = 2.18 (br s, 2 H, OH, NH), 2.49 (dd, J =
12.3, 10.5 Hz, 1 H, HA-1), 2.74 (m, 1 H, H-5), 3.16 (dd, J = 12.3, 5.2 Hz, 1
H, HB-1), 3.30–3.44 (m, 2 H, H-3, H-4), 3.49–3.62 (m, 2 H, H-2, HA-6),
3.67 (dd, J = 8.9, 2.1 Hz, 1 H, HB-6), 4.45 (d, J = 11.9 Hz, 1 H, OCH2Ph),
4.50 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.53 (d, J = 11.0 Hz, 1 H, OCH2Ph),
4.75 (d, J = 11.5 Hz, 1 H, OCH2Ph), 4.83 (d, J = 11.0 Hz, 1 H, OCH2Ph),
4.97 (d, J = 11.5 Hz, 1 H, OCH2Ph), 7.17–7.42 (m, 15 H, HAr).
13C NMR (CDCl3, 100 MHz): δ = 49.6, 60.1, 70.1, 72.2, 73.6, 75.1, 75.4,
80.4, 88.1, 127.9, 128.0, 128.1, 128.6, 128.8, 138.1, 138.3, 138.8.
HRMS (ESI): m/z [M + H]+ calcd for C27H32NO4: 434.2326; found:
434.2330.
1H NMR (CDCl3, 400 MHz): δ = 2.10 (d, J = 12.4 Hz, 1 H, HA-1), 2.36–
2.46 (m, 1 H, H-5), 2.51 (br s, 1 H, OH), 2.82 (dd, J = 12.3, 4.5 Hz, 1 H,
HB-1), 3.32 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.38 (dd, J = 8.4, 3.1 Hz, 1 H,
H-3), 3.67–3.76 (m, 2 H, H-6), 3.78–3.86 (m, 2 H, H-2, H-4), 4.07 (d, J =
13.5 Hz, 1 H, NCH2Ph), 4.32–4.39 (m, 2 H, OCH2Ph), 4.44 (d, J = 11.0
Hz, 1 H, OCH2Ph), 4.55 (d, J = 11.8 Hz, 1 H, OCH2Ph), 4.61 (d, J = 11.8
Hz, 1 H, OCH2Ph), 4.82 (d, J = 11.0 Hz, 1 H, OCH2Ph), 7.11–7.29 (m, 20
H, HAr).
13C NMR (CDCl3, 100 MHz): δ = 54.3, 57.1, 64.7, 65.2, 67.1, 71.6, 73.2,
75.0, 75.9, 83.4, 127.2, 127.7, 127.76, 127.82, 127.9, 128.0, 128.1,
128.46, 128.52, 129.1, 138.2, 138.3, 138.7.
HRMS (ESI): m/z [M + H]+ calcd for C34H38NO4: 524.2795; found:
524.2823.
N-Benzyl-3,4,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (8)
K2CO3 (1.12 g, 8.10 mmol) and BnBr (1.6 mL, 13.38 mmol) were added
to a solution of 7 (5.02 g, 11.58 mmol) in dry DMF (120 mL) and the
resulting mixture was stirred at 60 °C for 3 h. The solvent was then
evaporated under reduced pressure and the residue was dissolved in
EtOAc and washed with H2O (3 ×). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography (CH2Cl2/MeOH,
99:1) to afford 8 (5.06 g, 83%) as a pale yellow oil; Rf = 0.29
(CH2Cl2/MeOH, 99:1); [α]D20 +4 (c 1.0, CHCl3).
1,5-Dideoxy-1,5-imino-D-mannitol Hydrochloride (2·HCl)
Aq 1 M HCl (56 mL) and Pd(OH)2/C (1 g, 20% Pd on C) were added to
compound 10 (3.72 g, 7.10 mmol) dissolved in THF (80 mL) and i-
PrOH (80 mL). The flask was evacuated under vacuum and backfilled
with argon (4 cycles) and then evacuated under vacuum and back-
filled with H2 (4 cycles). The reaction mixture was stirred under an
atmosphere of H2 (balloon) at r.t. for 23 h. The resulting mixture was
filtered through a pad of Celite, previously rinsed first with aq 1 M
HCl (at least 250 mL) and then with H2O. The catalyst was rinsed with
MeOH and H2O, and the filtrate was concentrated under reduced
IR (neat): 3431 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.23 (dd, J = 11.5, 8.3 Hz, 1 H, HA-1),
2.64 (br s, 1 H, OH), 2.74 (ddd, J = 7.4, 3.8, 3.4 Hz, 1 H, H-5), 3.05 (dd,
J = 11.5, 4.0 Hz, 1 H, HB-1), 3.49 (t, J = 7.4 Hz, 1 H, H-3), 3.57 (d, J = 13.6
Hz, 1 H, NCH2Ph), 3.70–3.78 (m, 1 H, H-2), 3.78 (t, J = 7.4 Hz, 1 H, H-4),
3.88 (m, 2 H, H-6), 4.07 (d, J = 13.6 Hz, 1 H, NCH2Ph), 4.50–4.57 (m, 2
H, OCH2Ph), 4.60 (d, J = 11.2 Hz, 1 H, OCH2Ph), 4.74 (d, J = 11.7 Hz, 1 H,
OCH2Ph), 4.84 (d, J = 11.2 Hz, 1 H, OCH2Ph), 4.88 (d, J = 11.7 Hz, 1 H,
OCH2Ph), 7.27–7.42 (m, 20 H, HAr).
13C NMR (CDCl3, 100 MHz): δ = 54.1, 57.5, 63.7, 66.2, 69.2, 73.4, 74.1,
74.3, 78.0, 84.7, 127.2, 127.77, 127.80, 127.85, 127.90, 128.1, 128.4,
128.52, 128.54, 128.7, 129.2, 138.2, 138.4, 138.7.
HRMS (ESI): m/z [M + H]+ calcd for C34H38NO4: 524.2795; found:
524.2745.
20
pressure to afford 2·HCl (1.41 g, 99%) as a colorless glassy solid; [α]D
–35.5 (c 0.25, H2O) (measured for 2).
The analytical data of 2·HCl were consistent with those reported in
the literature.18
1H NMR (D2O, 400 MHz): δ = 3.18 (ddd, J = 10.6, 6.7, 3.2 Hz, 1 H, H-5),
3.27 (dd, J = 13.6, 1.2 Hz, 1 H, HA-1), 3.44 (dd, J = 13.6, 3.1 Hz, 1 H, HB-
1), 3.71 (dd, J = 9.5, 3.0 Hz, 1 H, H-3), 3.87 (dd, J = 12.7, 6.7 Hz, 1 H, HA-
6), 3.89 (dd, J = 10.6, 9.5 Hz, 1 H, H-4), 4.02 (dd, J = 12.7, 3.2 Hz, 1 H,
HB-6), 4.27 (ddd, J = 3.1, 3.0, 1.2 Hz, 1 H, H-2).
13C NMR (D2O, 100 MHz): δ = 47.5, 58.1, 60.4, 65.7, 65.9, 72.4.
HRMS (ESI): m/z [M + H]+ calcd for C6H14NO4: 164.0917; found:
164.0920.
N-Benzyl-3,4,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-mannitol
(10)
Acknowledgment
Under an argon atmosphere, DMSO (3.2 mL, 45.05 mmol) was added
to a solution of (COCl)2 (2.1 mL, 24.45 mmol) in dry CH2Cl2 (100 mL)
at –78 °C. The solution was stirred at –78 °C for 45 min, then a solu-
tion of 8 (5.05 g, 9.64 mmol) in dry CH2Cl2 (200 mL) was added. After
3 h 30 at –78 °C, Et3N (13.4 mL, 96.44 mmol) was added and the reac-
tion mixture was kept stirring at –78 °C for 2 h. The mixture was then
washed with H2O (2 × 50 mL) and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
oxidized product was then dissolved in dry THF (200 mL) and a 1 M L-
This work was supported by the Institut Universitaire de France (IUF),
the CNRS, the University of Strasbourg, the Centre International de
Recherche aux Frontières de la Chimie (FRC), and doctoral fellowships
from the French Department of Research to F.S., M.M.P., and M.L.L.
The authors express their gratitude to Julien Garnier, Marie Plociniak,
and Najet El Harmouchi for assistance with synthetic work.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–D