Synthesis and Kinetics of XylNAc-Isofagomine
allowed to rise to 23 °C, and after an additional 30 min the
reaction was quenched with 50 mL of water. Extraction with
dichloromethane (3 × 100 mL), drying with magnesium
sulfate, and then concentration gave 2.4 g (96%) of allylic
alcohol that was used directly in the next step. ESI-MS: 234
MH+.
A solution of 2.4 g (11.0 mmol) of the crude allylic alcohol
and 2.7 g (40 mmol) of imidazole in 45 mL of dry DMF was
stirred at 0 °C and treated with 3.4 g (19.2 mmol) of tert-
butyldimethylsilyl chloride. The reaction was allowed to warm
to 23 °C and after 6 h was quenched by the addition of 20 mL
of methanol and 50 mL of water. The reaction mixture was
extracted with ether (2 × 50 mL), and the combined organic
extract was washed sequentially with water (3 × 50 mL) and
brine (30 mL). Concentration followed by chromatography as
described above gave 3.5 g (96%) of rac-9 as a colorless oil with
spectroscopic properties matching those of 9 detailed above.
(pretreated as an ethanol slurry for 30 min with hydrogen gas),
0.4 mL (4.2 mmol) of acetic anhydride, and 2 mL of ethanol
was stirred for 4 h under a hydrogen atmosphere. The reaction
mixture was filtered through Celite and then concentrated.
The residue was diluted with 25 mL of ethyl acetate, which
was washed in turn with water (2 × 20 mL) and brine (10
mL). The organic layer was concentrated and then chromato-
graphed (25% ethyl acetate/petroleum ether) on silica to afford
94.8 mg (90%) of 12 as an amorphous solid, mp 112-114 °C.
1H NMR (300 MHz, CDCl3) δ: 7.42-7.25 (m, 5 H), 6.26 (d,
1H, J ) 8.7 Hz, 1 H), 5.16 (s, 2 H), 4.02 (d, J ) 2.1 Hz, 1 H),
3.93 (br d, J ) 11.1 Hz, 1 H), 3.76 (br s, 1 H), 3.22 (br t, J )
12.0 Hz, 1 H), 2.16-2.05 (m, 1 H), 1.90 (s, 3 H), 1.44 (br d, J
) 13.8 Hz, 1 H), 0.93 (s, 9 H), 0.12 (s, 6 H). 13C NMR (100
MHz, CDCl3) δ: 169.3, 155.8, 136.9, 128.5, 127.9, 127.8, 69.6,
68.9, 67.5, 61.4, 34.0, 27.5, 26.0, 23.5, 18.1, -4.8, -4.9. ESI-
MS m/z: 423 MH+.
(2S,3R,4R)-1-N-(Benzyloxycarbonyl)-4-(tert-butyldi-
methylsilyloxy)-2,3-dihydroxypiperidine (10). A solution
of 0.74 g (2.1 mmol) of 9, 0.027 g (0.1 mmol) of osmium
tetroxide, and 0.37 g (3.1 mmol) of N-methylmorpholine
N-oxide in 3.75 mL of 1:1:1 acetonitrile/acetone/water was
stirred at room temperature for 14 h. Saturated aqueous
sodium sulfite was added to quench, and after 30 min the
reaction mixture was concentrated, and the residue was
extracted with ethyl acetate. The organic layer was washed
with water and then brine, dried over anhydrous sodium
sulfate, and then concentrated. Chromatography (20% ethyl
acetate/petroleum ether) on silica afforded 0.73 g (93%) of 10
(2R,3R,4R)-2-Acetamido-4-(tert-butyldimethylsilyloxy)-
3-hydroxypiperidine (13). A solution of 0.12 g (0.28 mmol)
of 12 in 5 mL of ethanol was treated with 0.04 g of 10% Pd-C
and purged with hydrogen three times. The suspension was
allowed to stir under a hydrogen atmosphere for 18 h. The
reaction mixture was filtered through Celite, and the solid was
washed with 3 mL of ethanol. The combined organic extract
was concentrated to provide 0.08 g (98%) of 13 as an off-white
solid, mp 107-108 °C, that was directly used in the next step.
1H NMR (400 MHz, CD3OD) δ: 4.31 (d, J ) 8.0 Hz, 1 H), 3.58
(ddd, J ) 4.8, 8.0, 10.0 Hz, 1 H), 3.17 (t, J ) 8.0 Hz, 1 H), 2.92
(dt, J ) 4.0, 12.4 Hz, 1 H), 2.64 (dt, J ) 2.4, 12.0 Hz, 1 H),
1.98 (s, 3 H), 1.90 (qd, 4.0, 14.0 Hz, 1 H), 1.50 (dddd, 4.4, 10.4,
11.6, 14.0 Hz, 1 H), 0.92 (s, 9 H), 0.12 (s, 3 H), 0.11 (s, 3 H).
13C NMR (100 MHz, CD3OD) δ: 173.9, 75.9, 75.3, 67.6, 41.5,
34.7, 26.5, 22.9, 19.1, -4.1, -4.4. ESI-MS m/z: 289 MH+.
(2R,3R,4R)-2-Acetamido-3,4-dihydroxypiperidine (Xyl-
NAc-isofagomine, 3). A solution of 0.08 g (0.27 mmol) of 12
in 5 mL of ethanol was treated with 5 mL of 3 N hydrochloric
acid at 0 °C. After 5 h, the reaction mixture was concentrated
and water was removed by azeotropic codistillation with
toluene. The residue was dissolved in several µL of methanol
(containing 1% concentrated aq ammonia) and applied to a
small silica column. Elution with 10% methanol/dichlo-
romethane containing 1% ammonia afforded 3 as the free base,
0.035 g (73%). Rf 0.2 (20% methanol/dichloromethane). 1H
NMR (400 MHz, CD3OD) δ: 4.54 (d, J ) 8.4 Hz, 1 H), 3.65-
3.55 (ddd, J ) 4.4, 8.4, 10.0 Hz, 1 H), 3.40 (t, J ) 8.4 Hz, 1 H),
3.13 (dt, J ) 4.4, 12.8 Hz, 1 H), 2.87 (ddd, J ) 3.0, 11.4, 12.8
Hz, 1 H), 2.10-2.05 (obsc d, 2 H), 2.01 (s, 3 H),1.62 (dddd, J )
4.4, 10.4, 11.6, 14.4 Hz, 1 H). 13CNMR (100 MHz, CD3OD) δ:
167.5, 74.3, 72.4, 66.7, 41.3, 31.8, 22.8. ESI-MS m/z: 175 MH+.
[R]D 12.5° (c ) 0.01, MeOH).
1
as a white solid, mp 99-101 °C. H NMR (400 MHz, CDCl3)
δ: 7.35 (br s, 5 H), 5.85 (br, s, 1 H), 5.14 (s, 2 H), 3.98-3.89
(m, 1 H), 3.87 (ddd, J ) 4.8, 8.8, 11.2, 2 H), 3.40 (dd, J ) 3.6,
9.2 Hz, 1 H), 3.19 (br app t, J ) 12.8 Hz, 1 H), 2.49 (br s, 1 H),
1.85 (br d, J ) 12.8 Hz, 1 H), 1.62 (br s, 1 H), 1.53 (tdd, J )
13.2, 11.2, 4.8 Hz, 1 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3
H). 13C NMR (100 MHz, CDCl3) δ: 156.1, 136.3, 128.8, 128.4,
128.2, 74.7, 70.2, 69.7, 67.9, 37.9, 32.9, 26.0, 18.2, -4.1, -4.4.
ESI-MS m/z: 380 (M-H)+.
(2R,3R,4R)-2-Azido-1-N-(benzyloxycarbonyl)-4-(tert-
butyldimethylsilyloxy)-3-hydroxypiperidine (11). A solu-
tion of 1.59 g (23.3 mmol) of imidazole in 34 mL of dry THF
was cooled to 0 °C. Thionyl chloride (0.43 mL, 5.9 mmol) was
added over a 5 min period. The reaction mixture was stirred
at 0 °C for 30 min and then filtered to remove the imidazole
hydrochloride precipitate. The filtrate was slowly added to a
stirred suspension of 800 mg (2.1 mmol) of 10 in 10 mL of dry
DMF at -60 °C. The reaction mixture was allowed to stir at
-30 °C for 1 h, and then a solution of 420 mg (8.5 mmol) of
lithium azide in 35 mL of DMF was added over a 30 min
period. The reaction mixture was allowed to warm to 0 °C over
2 h and then was quenched by the addition of 10 mL of water.
The reaction mixture was concentrated and then partitioned
between 50 mL of ether and 30 mL of additional water. The
organic layer was dried with anhydrous sodium sulfate,
concentrated, and then chromatographed (15% ethyl acetate/
petroleum ether) on silica to afford 819 mg (96%) of 11 as an
amorphous solid, mp 98-100 °C. A sample crystallized from
ether had a mp of 99-101 °C and had an ee measured at 99+%
with a Chiralcel OD-H column (250 × 4.6 mm), isocratic 6%
methanol/carbon dioxide at 1.5 mL/min, 200 bar, 35 °C, 215
nm detection, 15 min run time. 1H NMR (400 MHz, CDCl3) δ:
7.36 (br s, 5 H), 5.67 (br s, 1 H), 5.19 and 5.15 (ABq, J ) 12.0
Hz, 2 H), 3.91 (br d, J ) 12.8, 1 H), 3.87 (app q, J ) 4.0 Hz, 1
H), 3.72 (br s, 1 H), 3.39 (dt, J ) 3.2, 12.9 Hz, 1 H), 2.01 (dddd,
J ) 3.5, 5.6, 12.8, 14.0 Hz, 1 H), 1.56 (dq, J ) 14.0, 3.2 Hz, 1
H), 0.91 (s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3 H). 13C NMR (100
MHz, CDCl3) δ: 165.3, 136.0, 128.8, 128.5, 128.3, 71.7, 70.2,
68.3, 67.8, 35.3, 27.7, 25.8, 18.2, -4.7, -4.8. ESI-MS m/z: 407
MH+.
(2R*,3R*,4R*)-2-Acetamido-4-(tert-butyldimethylsilyl-
oxy)-3-hydroxy-1-N-(p-methoxybenzyl)-piperidine (rac-
14). A mixture of 0.15 g (0.52 mmol) of 3, 0.14 g (1.03 mmol)
of potassium carbonate, 0.15 g (1.0 mmol) of sodium iodide,
98 µL (0.61 mmol) of p-methoxybenzyl chloride, and 4 mL of
acetone was stirred for 1 h. The reaction mixture was
concentrated, and then the residue was partitioned between
10 mL of ethyl acetate and 10 mL of water. The organic layer
was washed sequentially with water (2 × 10 mL) and brine
(10 mL) and then concentrated. Chromatography on silica
1
afforded 0.16 g (70%) of rac-14 as a light yellow oil. H NMR
(300 MHz, CDCl3) δ: 7.44 (d, J ) 9.3 Hz, 1 H), 7.20 (d, J )
8.4 Hz, 2 H), 6.83 (d, J ) 8.4 Hz, 2 H), 5.07 (dd, J ) 3.0, 9.0
Hz, 1 H), 3.93 (d, J ) 3.0 Hz, 1 H), 3.83 (d, J ) 13.5 Hz, 1 H),
3.78 (s, 3 H), 3.53 (br s 1 H), 3.27 (d, J ) 13.5 Hz, 1 H), 2.82
(br d, J ) 8 Hz, 1 H), 2.60 (dt, J ) 2.7, 12 Hz, 1 H), 2.31 (qd,
J ) 2.8, 7.2 Hz, 1 H), 2.02 (s, 3 H), 1.97-1.92 (m, 1 H), 1.46
(dd, J ) 2.1, 14.4 Hz, 1 H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.10 (s,
3 H). 13C NMR (100 MHz, CDCl3) δ: 170.3, 158.8, 130.1, 113.8,
70.0, 69.6, 67.9, 58.1, 55.4, 39.4, 28.6, 25.9, 23.7, 18.1, -4.8,
-4.9. ESI-MS m/z: 409 MH+.
(2S,3R,4R)-2-Acetamido-1-N-(benzyloxycarbonyl)-4-
(tert-butyldimethylsilyloxy)-3-hydroxypiperidine (12). A
mixture of 100 mg (0.25 mmol) of 11, 80 mg of Raney nickel
J. Org. Chem, Vol. 70, No. 19, 2005 7719