Iminocyclitols as Inhibitors of Glycosidases
J . Org. Chem., Vol. 64, No. 14, 1999 5287
purified by column chromatography (2:1 hexane-EtOAc) to
give 20a (157 mg, 82%) as a colorless oil.
3.50 (1H, dd, J ) 6.2, 11.8 Hz), 3.47 (1H, dd, J ) 6.9, 11.8
Hz), 2.92 (1H, ddd, J ) 5.8, 6.2, 7.5 Hz), and 2.89 (1H, dd, J
) 5.8, 7.3 Hz). 13C NMR (D2O): δ 78.27, 78.09, 73.14, 63.77,
62.35, 61.97, and 61.93. MALDITOF MS, m/z: 194 [M + H]+,
216 [M + Na]+.
(1′′R,2R,3R,4R,5R)-N-Bu tyloxyca r bon yl-3,4-bis(ben zyl-
oxy)-5-[(ben zyloxy)m eth yl]-2-(1,2-dih ydr oxyeth yl)pyr r oli-
d in e (22). To a solution of 21 (336 mg, 0.73 mmol) in CH2Cl2
(7 mL) and Et3N (121 µL, 0.87 mmol) was added (Boc)2O (412
µL, 1.74 mmol) at 0 °C, and the mixture was stirred at rt for
20 h. The reaction mixture was diluted with CH2Cl2 and
washed with 10% citric acid, saturated NaHCO3, and water,
dried over MgSO4, and concentrated. The resulting material
was purified on a column of silica gel eluted with hexane-
EtOAc (3:1) to afford 22 (374 mg, 91%); [R]D ) -31.3° (c 1.0,
CHCl3).
IR 2200 cm-1. 1H NMR (CDCl3): δ 7.40-7.20 (15H, m), 4.70-
4.40 (6H, m), 3.80 (2H, m), 3.70 (3H, m), 3.60 (1H, m), 3.46
(1H, dd, J ) 2.6, 6.3 Hz), 3.08 (1H, dd, J ) 2.0, 6.3 Hz), and
2.97 (1H, m). 13C NMR (CDCl3): δ 78.20, 77.61, 74.79, 73.46,
73.33, 69.54, 61.10, 60.79, 58.58, and 54.20.
(1′R,2S,3R,4R,5R)-3,4-Bis(b en zyloxy)-5-[(b en zyloxy)-
m eth yl]-2-[1′,2′-d ih yd r oxyeth yl]p yr r olid in e (21a ). A solu-
tion of compound 20a (175 mg, 0.36 mmol) and triphenylphos-
phine (113 mg, 0.43 mmol) in THF (5 mL) containing ca. 0.5%
H2O was stirred at rt for 48 h. After removal of the solvent,
the residual mixture was purified by column chromatography
(20:1 CHCl3-MeOH) to give 21a (137 mg, 82%).
1H NMR (CDCl3): δ 7.35-7.20 (15H, m), 4.65-4.30 (6H, m),
4.10 (1H, bd, J ) 4.6 Hz), 3.90 (1H, m), 3.90 (1H, m), 3.70
(2H, m), 3.50 (2H, m), 3.30 (1H, m), 3.26 (1H, dd, J ) 4.6, 6.9
Hz). 13C NMR (CDCl3): δ 84.33, 83.94, 73.14, 71.63, 71.25,
70.82, 70.80, 65.34, 63.87, and 62.86.
1H NMR (CDCl3): δ 7.25-7.31 (15H), 4.54 (2H, s), 4.49 (2H,
s), 4.76 (1H, AB, J ) 10.2 Hz), 4.26 (1H, s), 4.21 (1H, s), 4.18
(1H, AB, J ) 10.2 Hz), 4.03 (1H, dd, J ) 4.10, 10.6 Hz), 3.96
(1H, d, J ) 7.9 Hz), 3.83 (1H, dd, J ) 4.0, 8.6 Hz), 3.78-3.86
(1H, m), 3.74 (1H, dd, J ) 5.9, 8.2 Hz), 3.54-3.60 (2H, m),
3.51 (1H, dd, J ) 8.6, 10.6 Hz), 3.25 (1H, d, J ) 9.6 Hz), and
1.41 (9H, s). 13C NMR (CDCl3): δ 156.08, 83.25, 83.02, 81.47,
73.37, 71.59, 71.47, 71.59, 68.36, 65.73, 63.92, 62.89, and 28.59.
Anal. Calcd for C33H41NO7: C, 70.32; H, 7.33; N, 2.48. Found:
C, 70.36; H, 7.36; N, 2.48.
(2R,3S,4R,5R,1′R)-5-(Hyd r oxym eth yl)-3,4-d ih yd r oxy-2-
(1,2-d ih yd r oxyeth yl)p yr r olid in e (1). A solution of 21a (58
mg, 0.13 mmol) in MeOH (1 mL) was stirred with Pd/C under
a H2 atmosphere at rt for 48 h. The crude material, obtained
after removal of the catalyt and solvent, was purified by
column chromatography (6:4:1 CHCl3-MeOH-H2O) to afford
1 (17 mg, 70%); [R]D +11° (c 0.1, D2O).
1H NMR (D2O): δ 4.03 (1H, dd, J ) 1.2, 3.9 Hz), 3.80 (1H,
dd, J ) 1.2, 3.5 Hz), 3.77 (1H, ddd, J ) 3.0, 6.5, 9.3 Hz), 3.65
(1H, dd, J ) 3.0, 12.1 Hz), 3.61 (1H, dd, J ) 5.5, 11.6 Hz),
3.56 (1H, dd, J ) 6.4, 11.6 Hz), 3.49 (1H, dd, J ) 6.5, 12.1
Hz), 3.09 (1H, dd, J ) 3.9, 9.3 Hz), and 2.97 (1H, ddd, J ) 3.5,
5.5, 6.4 Hz). 13C NMR (D2O): δ 79.24, 77.47, 69.84, 67.10,
64.36, 62.44, and 62.07. MALDITOF MS, m/z: 194 [M + H]+,
216 [M + Na]+.
(2R,3S,4S,5R,6S)-6-[((Ch lor om eth yl)su lfon yl)oxy]-2,3-
ep oxy-4,5,7-tr is(ben zyloxy)-2(E)-h ep ten -1-ol (19b). Com-
pound 19b was synthesized using 18 (250 mg, 0.43 mmol), a
solution of Ti(O-i-Pr)4 (260 µL, 0.86 mmol), D-(-)-diethyltar-
trate (150 µL, 0.86 mmol), a solution of t-BuOOH (5 M, 260
µL, 1.29 mmol), a solution of 10% tartaric acid, MS 4A, and
CH2Cl2 (4 mL, total volume) as described for the synthesis of
compound 19a . Yield of 19b: 235 mg, 91%, a colorless oil.
1H NMR (CDCl3): δ 7.40-7.20 (15H, m), 5.09 (1H, ddd, J )
2.3, 6.3, 6.3,Hz), 4.80-4.30 (8H, m), 3.78 (1H, dd, J ) 3.3, 6.3
Hz), 3.50 (4H, m), 3.30 (2H, m), and 2.98 (1H, m).
(2R,3S,4S,5R,6R)-6-Azido-2,3-epoxy-4,5,7-tr is(ben zyloxy)-
2(E)-h ep ten -1-ol (20b). Compound 20b was synthesized
using 19b (195 mg, 0.34 mmol), NaN3 (44 mg, 0.68 mmol) and
DMF (3 mL) as described for the synthesis of 20a . Yield of
20b: 144 mg, 87%, a colorless oil; [R]D -29.3° (c 1, CHCl3).
IR 2170 cm-1. 1H NMR (CDCl3): δ 7.40-7.20 (15H, m), 4.80-
4.40 (6H, m), 3.80 (1H, m), 3.70 (3H, m), 3.66 (1H, dd, J )
2.6, 7.3 Hz), 3.50 (1H, m), 3.29 (2H, m), and 2.92 (1H, m). 13C
NMR (CDCl3): δ 79.46, 78.74, 74.18, 73.35, 72.27, 69.20, 61.06,
60.94, 56.50, and 54.22. FAB MS, m/z: 490 [M + H]+.
(2R,3S,4R,5R,1′R)-5-[(Ben zyloxy)m et h yl]-3,4-b is(b en -
zyloxy)-2-(1,2-d ih yd r oxyet h yl)p yr r olid in e (21b ). Com-
pound 21b was synthesized using 20b (3.44 g, 7.03 mmol),
triphenylphosphine (2.21 g, 8.44 mmol) and THF (36 mL), as
described for the synthesis of 21a . Yield of 21b: 2.98 g, 91%.
1H NMR (CDCl3): δ 7.36-7.25 (15H, m), 4.59-4.43 (6H, m),
4.10 (1H, dd, J ) 3.6, 4.6 Hz), 3.93 (1H, dd, J ) 3.6, 4.0 Hz),
3.70 (1H, 2H, m), 3.37 (1H, m), 3.49 (2H, m), and 3.26 (1H,
dd, J ) 4.6, 5.0 Hz). 13C NMR (CDCl3): δ 85.50, 85.39, 73.17,
71.88, 71.77, 70.44, 69.47, 65.28, 64.93, and 61.78. MALDITOF
MS, m/z: 464 [M + H]+. Anal. Calcd for C28H33NO5: C, 72.55;
H, 7.17; N, 3.02. Found: C, 72.48; H, 7.17; N, 3.03.
(2S,3R,4R,5R)-N-Bu tyloxyca r bon yl-3,4-bis(ben zyloxy)-
5-[(ben zyloxy)m eth yl]p yr r olid in e-2-ca r ba ld eh yd e (23).
To a solution of compound 22 (740 mg, 1.3 mmol) in toluene
(13 mL) was added Pb(OAc)4 (959 mg, 2.0 mmol). The reaction
mixture was stirred for 1.5 h at rt, then diluted with Et2O,
filtered through a Celite pad, and concentrated. The resulting
residue was purified on a column of silica gel eluted with 8:1
hexane-EtOAc to afford 23 (684.8 mg, ∼quantitative); [R]D
-56.6° (c 1.0, CHCl3).
NMR (CDCl3) analysis showed that 23 existed as two
conformational isomers designated to be “major” and “minor”.
Major/minor ) 10/7. 1H NMR: (for a major component) δ 9.39
(1H, d, J ) 2.6 Hz), 7.19-7.31 (15H, m), 4.42-4.65 (6H, m),
4.34 (1H, t, J ) 4.6 Hz), 4.20 (1H, d, J ) 2.6 Hz), 4.18 (1H, s),
4.03 (1H, s), 3.94 (1H, dd, J ) 4.6, 8.9 Hz), 3.62 (1H, dd, J )
4.6, 8.9 Hz), and 1.42 (9H, s); (for a minor component) δ 9.45
(1H, d, J ) 2.0 Hz), 7.19-7.31 (15H, m), 4.42-4.65 (6H, m),
4.34 (1H, d, J ) 2.0 Hz), 4.19 (1H, s), 4.12-4.18 (1H, m), 4.07
(1H, s), 3.77 (1H, dd, J ) 4.3, 8.9 Hz), 3.58 (1H, dd, J ) 4.6,
8.9 Hz), and 1.44 (9H, s). 13C NMR (CDCl3): (for a major
component) δ 200.75, 153.74, 84.65, 81.15, 81.02, 73.06, 71.72,
71.64, 71.09, and 70.87, 70.42, 67.69, 62.84, and 28.26; (for a
minor component) δ 201.07, 153.74, 83.20, 81.33, 79.75, 73.06,
71.72, 71.64, 71.09, 70.87, 71.01, 68.16, 63.13, and 28.30.
(2R,3R,4R,5R)-N-Bu tyloxyca r bon yl-3,4-bis(ben zyloxy)-
5-[(ben zyloxy)m eth yl]-2-(h ydr oxym eth yl)pyr r olidin e (24).
To a solution of 23 (1.17 g, 2.2 mmol) in CH2Cl2 (15 mL) cooled
to 0 °C was added 0.98 M diisobutylaluminum hydride
(DIBAL) in hexane (2.7 mL, 2.6 mmol), and the resulting
mixture was stirred for 0.5 h until completion. MeOH (1 mL)
was added to the mixture and was stirred at rt for 0.5 h. The
mixture was diluted with Et2O, washed with brine, dried over
MgSO4, and concentrated to give a syrup, which was purified
by flash column chromatography using 4:1 hexane-EtOAc as
the eluent to give 24 (1.14 g, 97%); [R]D -42° (c 1.0, CHCl3).
Major/minor ) 20/7.
1H NMR (CDCl3): (for a major component) δ 7.19-7.35
(15H, m), 4.38-4.67 (6H, m), 4.14 (1H, s), 4.11 (1H, dd, J )
3.3, 4.6 Hz), 4.04-4.08 (1H, m), 4.07 (1H, dd, J ) 4.0, 10.6
Hz), 3.82 (1H, s), 3.79-3.83 (2H, m), 3.75 (1H, dd, J ) 8.9, 4.0
Hz), 3.51 (1H, dd, J ) 8.9, 10.56 Hz), and 1.42 (9H, s); (for a
minor component) δ 7.19-7.35 (15H, m), 4.38-4.67 (6H, m),
4.28 (1H, dd, J ) 4.0, 10.6 Hz), 4.17 (1H, s), 3.99-4.04 (1H,
m), 3.96 (1H, s), 3.87-3.93 (1H, m), 3.79-3.83 (2H, m), 3.43-
3.51 (1H, m), 2.78 (1H, broad dd, J ) 3.3, 4.93 Hz), and 1.47
(9H, s). 13C NMR (CDCl3): (for a major component) δ 155.49,
84.15, 81.65, 80.72, 73.03,71.27, 68.30, 66.45, 64.58, 63.36, and
28.34; (for a minor component) δ 155.49, 85.68, 80.72, 80.20,
73.03, 71.27, 67.76, 65.41, 63.02, 62.23, and 28.34. Anal. Calcd
(1′R,2S,3R,4R,5R)-3,4-Dih ydr oxy-2-(1,2-dih ydr oxyeth yl)-
5-(h yd r oxym eth yl)p yr r olid in e (2). Compound 2 was ob-
tained by hydrogenolysis of 21b (100 mg, 0.22 mmol), which
was carried out as described for the synthesis of 1 in MeOH
(1 mL), to afford 2 (30 mg, 72%); [R]D +25.6° (c 0.3, D2O).
1H NMR (D2O): δ 3.94 (1H, dd, J ) 6.5, 7.3 Hz), 3.73 (1H,
dd, J ) 6.5, 7.5 Hz), 3.64 (1H, ddd, J ) 3.3, 5.8, 6.9 Hz), 3.58
[(1H, dd, J ) 3.3, 11.8 Hz), 3.55 (1H, dd, J ) 5.8, 11.8 Hz)],