Ouchi et al.
MHz, CDCl3) δ 21.1, 28.4, 42.8, 44.9, 65.7, 79.9, 123.7, 130.4,
154.5, 170.3. IR (neat) (cm-1) 1740, 1700. EI-MS (m/z) 242 (M+
+ 1). HRMS calcd for C12H19NO4 241.1314, found 241.1321.
added to a solution of tetravinyltin (1.14 g, 5 mmol) in Et2O
(7 mL) at room temperature and the mixture was stirred for
1 h at the same temperature. The solution was added to a
suspension of CuCN (224 mg, 2.5 mmol) in dry Et2O (20 mL)
at -78 °C and the mixture was stirred under argon atmo-
sphere at -78 °C for 10 min. The resulting solution was
warmed to -10 °C and stirred for 30 min. The reaction mixture
was cooled to -78 °C and a solution of 9 (454 mg, 1 mmol) in
dry Et2O (20 mL) was added to the reaction mixture dropwise
via syringe at -78 °C. The mixture was stirred at -78 °C for
10 min. BF3‚OEt2 (4 mol/L in Et2O, 5 mL, 2 mmol) was added
to the reaction mixture at -78 °C and the solution was stirred
for 2 h. The reaction mixture was quenched with 28% NH4-
OH/sat. NH4Cl (1:9) solution (50 mL) and stirred overnight at
room temperature. The organic layer was separated and the
aqueous layer was extracted with Et2O (2 × 20 mL). The
combined organic phases were washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel (n-hexane:AcOEt ) 8:1) to give 11 (357
(R)-N-tert-Butoxycarbonyl-5-hydroxy-3-piperidene
((-)-3). A mixture of acetate (-)-7 (1.1 g, 4.5 mmol) and
acetone (3.14 mL) in phosphate buffer (0.1 mol/L, pH 7.0, 51
mL) was stirred with lipase (0.46 g, immobilized on Ceramic
particles from Psedomonas cepacia) at 40 °C for 18 h. After
filtration, the filtrate was extracted with AcOEt (3 × 50 mL).
The combined organic extracts were washed with brine (50
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel (n-hexane:AcOEt ) 1:1) to give (-)-3 (0.88 g, 98%)
as colorless needles; mp 71-72 °C (n-hexane). [R]30 -83.3 (c
D
1.10, CHCl3).
(S)-N-tert-Butoxycarbonyl-5-(tert-butyldiphenylsil-
yloxy)-3-piperidene (8). To a solution of (+)-3 (996 mg, 5
mmol) in CH2Cl2 (10 mL) was added imidazole (511 mg, 7.5
mmol), DMAP (122 mg, 1 mmol), and tert-butylchlorodiphe-
nylsilane (1.512 g, 5.5 mmol). The mixture was stirred at room
temperature for 3 h. The reaction mixture was filtered through
a Celite pad. The filtrate was washed with brine (10 mL), dried
over MgSO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (n-hexane:AcOEt ) 8:1) to give 8 (2.35 g, 99%) as a colorless
oil; [R]27D +22.6 (c 1.80, CHCl3). 1H NMR (600 MHz, CDCl3) δ
1.08 (s, 9H), 1.40 (s, 9H), 3.21 (br s, 1H), 3.62-3.96 (m, 3H),
4.25 (br s, 1H), 5.58-5.72 (m, 2H), 7.36-7.44 (m, 6H), 7.67-
7.70 (m, 4H). 13C NMR (67.8 MHz, CDCl3) δ 19.2, 26.9, 28.4,
42.7, 47.9, 65.1, 79.5, 126.0, 127.4, 129.2, 129.5, 133.7, 135.5,
154.4. IR (neat) (cm-1) 1703. EI-MS (m/z) 438 (M+ + 1). HRMS
calcd for C26H35NO3Si 437.2386, found 437.2448. Anal. Calcd
for C26H35NO3Si: C, 71.35; H, 8.06; N, 3.20. Found: C, 71.16;
H, 7.96; N, 3.23.
mg, 74%) as a colorless oil; [R]24 -10.5 (c 1.16, CHCl3). 1H
D
NMR (600 MHz, CDCl3) δ 1.09 (s, 9H), 1.31 (s, 9H), 2.12 (br s,
1H), 2.23 (br s, 1H), 2.50 (br s, 1H), 2.65 (dd, J ) 11.0, 12.5
Hz, 1H), 3.42 (t, J ) 9.0 Hz, 1H), 3.51-3.55 (m, 1H), 3.82-
4.23 (m, 2H), 5.16-5.20 (m, 2H), 5.66-5.72 (m, 1H), 7.38-
7.45 (m, 6H), 7.68-7.71 (m, 4H). 13C NMR (67.8 MHz, CDCl3)
δ 19.4, 27.0, 28.3, 45.8, 46.5, 48.7, 73.6, 77.7, 79.8, 117.7, 127.7,
129.8, 133.3, 135.7, 135.9, 154.0. IR (neat) (cm-1) 3472, 1698.
EI-MS (m/z) 482 (M+ + 1). HRMS calcd for C28H39NO4Si
481.2649, found 481.2686. Anal. Calcd for C28H39NO4Si: C,
69.82; H, 8.16; N, 2.91. Found: C, 70.10; H, 8.07; N, 2.77.
(3R,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)piperi-
dine (2, isofagomine). To a solution of 11 (193 mg, 0.4 mmol)
in EtOH (4 mL) and H2O (4 mL) was added an aqueous
solution of 4% OsO4 (131 µL, 0.02 mmol) and the solution was
stirred at room temperature for 10 min. NaIO4 (190 mg, 0.88
mmol) as a powder was added slowly over a period of 30 min,
and the mixture was stirred at room temperature for 24 h.
NaBH4 (76 mg, 2 mmol) as a powder was added, and the
reaction mixture was stirred at room temperature for 1 h. The
solvent was removed in vacuo. The residue was diluted with
CHCl3 (80 mL) and successively washed with 10% Na2S2O3
(20 mL), sat. NaHCO3 (20 mL), and brine (10 mL). The organic
solution was dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (n-hexane:AcOEt ) 1:1)
to give (3R,4R,5R)-N-tert-butoxycarbonyl-3-(tert-butyldiphe-
(3R,4R,5R)-N-tert-Butoxycarbonyl-3-(tert-butyldi-
phenylsilyloxy)-4,5-epoxypiperidine (9) and (3R,4S,5S)-
N-tert-Butoxycarbonyl-3-(tert-butyldiphenylsilyloxy)-
4,5-epoxypiperidine (10). To a cooled (0 °C) solution of 8
(945 mg, 2.16 mmol) in CH3CN (20 mL) was added 4 mmol/L
of aq Na2EDTA (10 mL, 0.04 mmol) and 1,1,1-trifluoroacetone
(2 mL). The mixture of NaHCO3 (1.26 g, 15 mmol) and Oxone
(6.13 g, 10 mmol) as a solid was added slowly over a period of
1 h at 0 °C. After being stirred at 0 °C overnight, the solution
was quenched by adding water (60 mL) and extracted with
CHCl3 (3 × 60 mL). The organic extracts were combined, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatogra-
phy on silica gel (n-hexane:AcOEt ) 8:1) to give 9 (706 mg,
72%) as colorless prisms and 10 (170 mg, 17%) as colorless
needles.
nylsilyloxy)-4-hydroxy-5-(hydroxymethyl)piperidine (167 mg,
1
86%) as a colorless oil; [R]25 -15.9 (c 1.35, CHCl3). H NMR
D
9: mp 70-72 °C (n-pentane); [R]30 +29.2 (c 1.11, CHCl3).
(600 MHz, CDCl3) δ 1.09 (s, 9H), 1.31 (s, 9H), 1.66 (br s, 1H),
2.48 (br s, 3H), 2.63 (t, J ) 11.0 Hz, 1H), 3.48-3.56 (m, 2H),
3.67 (s, 2H), 3.85-4.16 (m, 2H), 7.39-7.46 (m, 6H), 7.67-7.69
(m, 4H). 13C NMR (67.8 MHz, CDCl3) δ 19.4, 27.0, 28.3, 42.8,
43.9, 48.5, 63.2, 73.6, 77.7, 79.9, 127.8, 129.9, 133.3, 135.5,
154.2. IR (neat) (cm-1) 3420, 1696, 1674. EI-MS (m/z) 486 (M
+ H+). HRMS calcd for C27H39NO5Si 485.2598, found 485.2585.
To a solution of the prepared diol (160 mg, 0.33 mmol) in
dioxane (2.5 mL) was added a solution of 10% HCl (10 mL),
and the solution was refluxed for 1 h. After the reaction
mixture was cooled to room temperature and diluted with H2O
(50 mL), the resulting dilute solution was washed with Et2O
(2 × 20 mL). The aqueous layer was concentrated under
reduced pressure. The residue was dissolved in 28% NH4OH
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (28% NH4OH:EtOH )
1:10) to give 2 (48.5 mg, 99%) as a white powder; [R]25D +25.4
(c 1.30, EtOH). 1H NMR (600 MHz, D2O) δ 1.61-1.68 (m, 1H),
2.33-2.38 (m, 2H), 3.05 (dd, J ) 13.0, 3.5 Hz, 1H), 3.10 (dd, J
) 12.1, 4.8 Hz, 1H), 3.27 (t, J ) 9.9 Hz, 1H), 3.43-3.48 (m,
1H), 3.59 (dd, J ) 11.4, 7.0 Hz, 1H), 3.78 (dd, J ) 11.4, 3.3
Hz, 1H).13C NMR (67.8 MHz, D2O) δ 43.9, 45.7, 48.8, 59.8, 71.4,
D
1H NMR (400 MHz, CDCl3) δ 1.10 (s, 9H), 1.37 and 1.46 (2 s,
9H), 3.07-3.41 (m, 4H), 3.07-3.88 (m, 2H), 4.09-4.15 (m, 1H),
7.36-7.45 (m, 6H), 7.63-7.69 (m, 4H). 13C NMR (67.8 MHz,
CDCl3) δ 19.3, 27.0, 28.4, 41.4, 45.3, 50.6, 53.7, 65.2, 79.8,
127.7, 129.8, 133.1, 135.5, 154.9. IR (KBr) (cm-1) 1701. EI-
MS (m/z) 453 (M+). HRMS calcd for C26H35NO4Si 453.2336,
found 453.2343. Anal. Calcd for C26H35NO4Si: C, 68.84; H,
7.78; N, 3.09. Found: C, 69.03; H, 7.64; N, 2.93.
10: mp 110-111 °C (n-pentane); [R]26D -6.2 (c 0.80, CHCl3).
1H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H), 1.35 (s, 9H), 2.87
(br t, J ) 10.7 Hz, 1H), 3.09 (br s, 1H), 3.20-3.40 (m, 2H),
3.75 (br s, 1H), 3.99-4.03 (m, 2H), 7.37-7.46 (m, 6H), 7.67-
7.74 (m, 4H). 13C NMR (67.8 MHz, CDCl3) δ 19.3, 27.0, 28.3,
40.6, 43.1, 53.3, 54.6, 67.5, 79.9, 127.7, 129.8, 133.1, 135.6,
154.0. IR (KBr) (cm-1) 1698. EI-MS (m/z) 454 (M+ + 1). HRMS
calcd for C26H35NO4Si 453.2336, found 453.2351. Anal. Calcd
for C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found: C, 68.96;
H, 7.88; N, 3.12.
(3R,4R,5S)-N-tert-Butoxycarbonyl-3-(tert-butyldi-
phenylsilyloxy)-4-hydroxy-5-vinylpiperidine (11). A solu-
tion of n-BuLi (3.125 mL, 1.6 M in n-hexane, 5 mmol) was
5212 J. Org. Chem., Vol. 70, No. 13, 2005