L-Iduronic Acid-Type 1-N-Iminosugars
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 16 2631
) 10.8 and 4.9 Hz, H-5), and 5.66 (1H, d, J ) 4.9 Hz, H-6).
Anal. (C8H15N3O4‚2HCl‚2H2O) C, Cl; H: calcd, 6.49; found,
6.95.
12.7, 5.4, and 2.9 Hz, H-3), 3.46 (1H, t, J ) 12.7 Hz, Hax-2),
3.55 (1H, dd, J ) 12.7 and 5.4 Hz, Heq-2), 4.45 (1H, dd, J )
7.6 and 2.0 Hz, H-5), 4.82 (1H, dd, J ) 7.6 and 2.9 Hz, H-4),
5.08 and 5.12 (2H, AB q, J ) 12.7 Hz, PhCH2), 5.63 (1H, d, J
) 2.0 Hz, H-6), 7.27-7.38 (5H, m). Anal. (C22H30N2O8) C, H;
N; calcd, 6.22; found, 6.62.
(3R,4S,5S,6S)-6-Aceta m id o-4-[N,N′-bis(ter t-bu toxyca r -
bon yl)gu a n id in o]-1-N-(ter t-bu toxyca r bon yl)-5-h yd r oxy-
3-[(d ip h en ylm eth oxy)ca r bon yl]p ip er id in e (21). To a so-
lution of 19 (242 mg, 0.5 mmol) in DMF (5 mL) were added
triethylamine (0.28 mL, 2 mmol), N,N′-bis(tert-butoxycarbo-
nyl)thiourea (276 mg, 1 mmol), and HgCl2 (272 mg, 1 mmol)
at 0 °C, and the mixture was stirred at 0 °C for 1 h. After
dilution with a large amount of ethyl acetate, the insoluble
matters were removed by centrifugation. The insoluble mat-
ters were washed twice with ethyl acetate. The combined
solution of the supernatant and the washings was washed with
water, dried over MgSO4, and filtered. Evaporation of the
filtrate gave a solid, which was subjected to column chroma-
tography on silica gel. Elution with a mixture of toluene-
acetone (3:1) gave 21 (320 mg, 88%) as an amorphous solid:
[R]23D -2.3° (c 0.72, CHCl3); 1H NMR (CD3OD, 40 °C, 400 MHz)
δ 1.47, 1.48, and 1.49 (9H, each s), 2.01 (3H, s), 2.99 (1H, dt,
J ) 11.7 and 3.9 Hz, H-3), 3.16 (1H, br m, Hax-2), 3.73 (1H, br
m, H-5), 4.17 (1H, br m, Heq-2), 4.68 (1H, dd, J ) 11.7 and 2.5
Hz, H-4), 6.02 (1H, d, J ) 2.0 Hz, H-6), 6.81 (1H, s, Ph2CH),
and 7.24-7.34 (10H, m, Phx2). Anal. (C37H51N5O10‚1/2H2O)
C, H, N.
(3S,4S,5R,6S)-6-[(Ben zyloxyca r bon yl)a m in o]-1-N-(ter t-
bu toxyca r bon yl)-4,5-d ih yd r oxy-4,5-O-isop r op ylid en e-3-
[(d ip h en ylm eth oxy)ca r bon yl]p ip er id in e (25). Compound
25 was obtained by the similar procedures used for the
preparation of 13: yield 94% (colorless foam); [R]24 +3.6° (c
D
0.87, CH3OH); 1H NMR (CD3OD, 40 °C, 400 MHz) δ 1.33 and
1.36 (3H, each s), 1.43 (9H, s), 3.49 (1H, t, J ) 12.7 Hz, Hax-2),
3.64 (1H, dd, J ) 12.2 and 4.9 Hz, Heq-2), 4.52 (1H, dd, J )
7.8 and 2.0 Hz, H-5), 4.93 (1H, dd, J ) 7.8 and 2.4 Hz, H-4),
5.07 and 5.13 (2H, AB q, J ) 12.2 Hz, PhCH2), 5.66 (1H, d, J
) 2.0 Hz, H-6), 6.89 (1H, s, Ph2CH), 7.25-7.37 (15H, m). Anal.
(C35H40N2O8) C, H, N.
(5S,6S)-6-[(Ben zyloxyca r b on yl)a m in o]-1-N-(ter t-b u -
toxyca r bon yl)-3,4-d id eh yd r o-3-[(d ip h en ylm eth oxy)ca r -
bon yl]p ip er id in e (26). To a solution of 25 (799 mg, 1.3
mmol) in THF (16 mL) was added potassium tert-butoxide (15
mg, 0.13 mmol) at 0 °C under atmosphere of argon gas, and
the mixture was stirred for 2 h under the same condition. After
dilution with CHCl3, the solution was washed with NH4Cl-
saturated aqueous solution and water, dried over MgSO4, and
filtered. Evaporation of the filtrate gave an oil, which was
subjected to column chromatography on silica gel. Elution in
the toluene-acetone (7:1) gave 26 (508 mg, 70%) as a colorless
(3R,4S,5S,6R)-6-Aceta m id o-4-gu a n id in o-5-h yd r oxyp i-
p er id in e-3-ca r boxylic Acid (8). Compound 8 was obtained
by the similar procedures used for the preparation of 6: yield
1
94%: [R]26 +16.8° (c 0.26, H2O); H NMR (D2O, 400 MHz) δ
D
foam: [R]24 +62.9° (c 0.89, CHCl3); 1H NMR (CD3OD, 40 °C,
2.31 (3H, s), 3.35 (1H, br dt, J ) 11.0 and 4.4 Hz, H-3), 3.54
(1H, t, J ) 12.0 Hz, Hax-2), 3.69 (1H, dd, J ) 12.0 and 4.4 Hz,
Heq-2), 4.38 (1H, t, J ) 3.2 Hz, H-5), 4.45 (1H, dd, J ) 11.0
and 3.2 Hz, H-4), and 5.52 (1H, d, J ) 3.2 Hz, H-6). Anal.
(C9H17N5O4‚2HCl‚2/3H2O) C, N, Cl; H: calcd, 6.17; found, 6.59.
(2S,3R,4S,5R)-2-[(Ben zyloxyca r bon yl)a m in o]-1-N-(ter t-
bu toxycar bon yl)-5-(h ydr oxym eth yl)-3,4-O-isopr opyliden e-
p ip er id in e-3,4-d iol (23). To a solution of 2223 (3.24 g, 10.7
mmol) in CH3OH (65 mL) were added N,N-diisopropylethy-
lamine (7.46 mL, 42.8 mmol) and benzyloxycarbonyl chloride
(4.58 mL, 32.1 mmol) at 0 °C, and the mixture was stirred at
0 °C for 1 h. Another portion of benzyloxycarbonyl chloride
(0.76 mL, 5.35 mmol) was added to the mixture, and the
mixture was further stirred at 0 °C for 30 min. Addition of
water (1.5 mL) and evaporation of the solvent gave an oil,
which was dissolved in CHCl3. The solution was washed with
NaHCO3-saturated aqueous solution and water, dried over
MgSO4, and filtered. Evaporation of the filtrate gave an oil,
which was subjected to column chromatography on silica gel.
D
400 MHz) δ 1.47 (9H, s), 3.81 (1H, d, J ) 19.0 Hz, Ha-2), 4.19
(1H, d, J ) 5.4 Hz, H-5), 4.53 (1H, d, J ) 19.0 Hz, Hb-2), 5.06
and 5.10 (2H, ABq, J ) 12.7 Hz, PhCH2), 5.92 (1H, d, J ) 1.0
Hz, H-6), 6.95 (1H, s, Ph2CH), 7.70 (1H, m, H-4), and 7.26-
7.40 (15H, m). Anal. (C32H34N2O7) C, H, N.
(3a S,4R,7S,7a S)-7-[(Ben zyloxyca r b on yl)a m in o]-6-N-
(ter t-bu toxyca r bon yl)-2-(tr ich lor om eth yl)-4-[(d ip h en yl-
m et h oxy)ca r b on yl]-3a ,7a -d ih yd r ooxa zolo[5,4-c]p ip er i-
d in e (27) a n d (3a S,4S,7S,7a S)-Isom er 28. Compounds 27
and 28 were obtained by the similar procedures used for
preparation of 15 and 16 in 70 and 23% yields, respectively.
27: colorless foam; [R]26 +2.0° (c 0.89, CHCl3); 1H NMR
D
(CD3OD, 40 °C, 400 MHz) δ 1.42 (9H, s), 3.39 (1H, br t, J )
11.7 Hz, Hax-2), 3.54 (1H, ddd, J ) 12.7, 4.9 and 4.4 Hz, H-3),
3.64 (1H, dd, J ) 11.7 and 4.9 Hz, Heq-2), 5.09 and 5.14 (2H,
AB q, J ) 11.7 Hz, PhCH2), 5.18 (1H, dd, J ) 9.8 and 4.4 Hz,
H-4), 5.27 (1H, br d, J ) 9.8 Hz, H-5), 5.82 (1H, d, J ) 2.0 Hz,
H-6), 6.92 (1H, s, Ph2CH), and 7.23-7.41 (15H, m). Anal.
(C34H34Cl3N3O7) C, H, N.
Elution with CHCl3-CH3OH (40:1) gave 23 (4 g, 86%) as a
colorless foam: [R]24 +12.8° (c 1.09, CHCl3); H NMR (CD3-
28: colorless foam; [R]26 -18.5° (c 0.92, CHCl3); H NMR
1
1
D
D
OD, 40 °C, 400 MHz) δ 1.34 (3H, s), 1.44 (12H, s), 1.94 (1H, t,
J ) 5.9 Hz, OH), 2.04 (1H, br m, H-5), 3.17 (1H, t, J ) 12.2
Hz, Hax-6), 3.45 (1H, dd, J ) 12.2 and 4.4 Hz, Heq-6), 3.75 (2H,
t, J ) 5.9 Hz, CH2OH), 4.53 (1H, dd, J ) 7.8 and 2.4 Hz, H-3),
4.57 (1H, br d, J ) 7.8 Hz, H-4), 4.87 (1H, br s, NHCO), 5.08
and 5.13 (2H, AB q, J ) 12.0 Hz, PhCH2), 5.65 (1H, dd, J )
(CD3OD, 40 °C, 400 MHz) δ 1.44 (9H, s), 2.73 (1H, m, H-3),
3.45 (1H, br dd, J ) 12.2 and 8.8 Hz, Hax-2), 3.86 (1H, dd, J )
13.4 and 5.1 Hz, Heq-2), 4.98-5.06 (4H, m, PhCH2, H-4 and
H-5), 6.06 (1H, s , H-6), 6.89 (1H, s, Ph2CH), and 7.24-7.39
(15H, m). Anal. (C34H34Cl3N3O7) C, H, N.
(3R,4S,5S,6S)-6-[(Ben zyloxyca r bon yl)a m in o]-1-N-(ter t-
b u t oxyca r b on yl)-4-(t r ich lor oa cet a m id o)-5-h yd r oxy-3-
[(d ip h en ylm eth oxy)ca r bon yl]p ip er id in e (29). Compound
29 was obtained by the similar procedures used for preparation
6.1 and 2.4 Hz, H-2), and 7.29-7.35 (5H, m). Anal. (C22H32
-
N2O7) C, H, N.
(3S,4S,5R,6S)-6-[(Ben zyloxyca r bon yl)a m in o]-1-N-(ter t-
bu toxyca r bon yl)-4,5-d ih yd r oxy-4,5-O-isop r op ylid en ep i-
p er id in e-3-ca r boxylic Acid (24). To a solution of 23 (2.18
g, 5 mmol) in a mixture of CCl4 (30 mL) and CH3CN (30 mL)
were added a solution of NaIO4 (3.21 g, 15 mmol) in water (9
mL) and RuO2 (8.0 mg, 0.06 mmol), and the mixture was
vigorously stirred at room temperature for 40 min. The phases
were separated. The aqueous phase was extracted twice with
ethyl acetate. To the combined organic extracts was added
2-propanol (5 mL), and the mixture was stirred at room
temperature for 2 h. After removal of inorganic salts by
filtration, the mixture was washed with water, dried over
MgSO4, and filtered. Evaporation of the filtrate gave a solid,
which was subjected to column chromatography on silica gel.
Elution with CHCl3-CH3OH-concentrated aqueous ammonia
of 17: yield 95% (colorless foam); [R]26 -5.7° (c 0.92, CHCl3);
D
1H NMR (CD3OD, 40 °C, 400 MHz) δ 1.45 (9H, s), 3.14 (1H, br
t, J ) 12.4 Hz, Hax-2), 3.23 (1H, dt, J ) 11.7 and 4.1 Hz, H-3),
3.84 (1H, br s, H-5), 4.24 (1H, br d, J ) 12.2 Hz, Heq-2), 4.52
(1H, dd, J ) 11.5 and 2.7 Hz, H-4), 5.10 and 5.14 (2H, AB q,
J ) 12.7 Hz, PhCH2), 5.87 (1H, d, J ) 2.0 Hz, H-6), 6.83 (1H,
s, Ph2CH), and 7.24-7.38 (15H, m). Anal. (C34H36Cl3N3O8)
C, H, N.
(3R,4S,5S,6S)-4-Am in o-6-[(ben zyloxyca r bon yl)a m in o-
1-N-(ter t-b u t oxyca r b on yl)-5-h yd r oxy-3-[(d ip h en ylm e-
th oxy)ca r bon yl]p ip er id in e (30). Compound 30 was ob-
tained by the similar procedures used for preparation of 19:
1
yield 68%; [R]26 +6.3° (c 1.90, CHCl3); H NMR (CD3OD, 40
D
°C, 400 MHz) δ 1.44 (9H, s), 2.84 (1H, dt, J ) 11.4 and 4.1 Hz,
H-3), 2.99 (1H, t, J ) 12.5 Hz, Hax-2), 3.22 (1H, dd, J ) 10.7
and 2.9 Hz, H-4), 3.74 (1H, br s, H-5), 4.22 (1H, dd, J ) 13.4
and 4.6 Hz, Heq-2), 5.09 (2H, s, PhCH2), 5.86 (1H, d, J ) 1.5
(60:10:1) gave 24 (1.79 g, 80%) as an amorphous solid: [R]23
D
1
+5.7° (c 0.96, CHCl3); H NMR (CD3OD, 40 °C, 400 MHz) δ
1.32 and 1.37 (3H, each s), 1.44 (9H, s), 2.96 (1H, ddd, J )