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A. Kato et al. / Bioorg. Med. Chem. 19 (2011) 3558–3568
6 mmol) and OxoneÒ ((2.46 g, 4.0 mmol) as a solid were added
slowly over a period of 1 h at 0 °C. After being stirred at 0 °C over-
night, the solution was quenched by adding water (25 mL), and ex-
tracted with CHCl3 (25 mL ꢁ 3). The organic extracts were
combined, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column chroma-
tography on silica gel (n-hexane/AcOEt = 11:1) to give 12 (142 mg,
3H), 3.79–3.83 (m, 2H), 4.44–4.45 (m, 0.75H), 4.75 (br s, 0.25H),
7.36–7.41 (m, 6H), 7.69–7.73 (m, 4H). 13C NMR (125 MHz, CDCl3)
d: 19.4, 25.3, 26.9, 28.4, 33.6, 51.5, 51.6, 51.9, 61.6, 80.4, 127.8,
129.8, 133.6, 135.6, 135.7, 135.8, 154.3; IR (neat) 2931.7, 1696.0,
1416.1, 1110.8, 1003.5 cmꢂ1; HRMS calcd for C27H37NO4Si (M+)
467.2422, found 467.2399. Compound 16: ½a D26
ꢃ
+57.8 (c 1.75,
CHCl3); [lit.17
½
a 2D6
ꢃ
ꢂ50.3 (c 1.42, CHCl3) for ent-16]. 1H NMR
40%) and 13 (75 mg, 21%) as colorless oils. 12: ½a D22
ꢃ
+41.3 (c 1.26,
(500 MHz, CDCl3) d: 1.06 (s, 9H), 1.40 (s, 9H), 1.88–1.93 (m, 1H),
1.99 (br s, 1H), 3.00 (br s, 1H), 3.28 (br s, 1H), 3.31 (br s, 1H),
3.40–3.88 (m, 3H), 4.50 (br s, 1H), 7.36–7.45 (m, 6H), 7.63ꢂ7.67
(m, 4H); 13C NMR (125 MHz, CDCl3) d: 19.3, 22.8, 26.9, 28.5, 50.5,
51.8, 63.8, 80.3, 127.95, 127.96, 129.9, 130.0, 133.109, 135.6,
135.7, 155.3; IR (neat) (cmꢂ1) 2932.3, 1695.4, 1421.5, 1172.1,
1109.9 ; HRMS calcd for C27H37NO4Si (M+) 467.2422, found
467.2452.
CHCl3). 1H NMR (600 MHz, CDCl3) d: 1.06 (s, 9H), 1.41 (br d,
J = 28.9 Hz, 9H), 2.33 (br d, J = 25.0 Hz, 1H), 3.06–3.28 (m, 3H),
3.37–3.77 (m, 4H), 3.93 (dd, J = 52.4, 14.5 Hz, 1H), 7.30–7.45 (m,
6H), 7.65 (d, J = 7.7 Hz, 4H). 1H NMR (400 MHz, C6D6, 60 °C) d:
1.17 (s, 9H), 1.45 (s, 9H), 2.31 (t, J = 5.9 Hz, 1H), 2.68 (t, J = 3.2 Hz,
1H), 2.96 (s, 1H), 3.10 (dd, J = 13.4, 6.8 Hz, 1H), 3.35 (br s, 1H),
3.57–3.67 (m, 3H), 3.89 (d, J = 15.1 Hz, 1H), 7.26–7.30 (m, 6H),
7.72–7.75 (m, 4H). 13C NMR (100 MHz, C6D6, 60 °C) d: 19.5, 27.1,
28.5, 37.1, 40.9, 42.9, 49.8, 52.3, 63.9, 79.2, 127.8, 128.1, 128.3,
4.1.12. (2S,3S,4S)-2-Hydroxymethylpiperidine-3,4-diol (L-
fagomine) (18)
128.5, 130.1, 133.9, 133.9, 135.9, 136.0, 155.1. IR (neat) cmꢂ1
:
2962, 2931, 2859, 1696, 1473, 1461, 1428, 1392, 1366, 1248,
1174, 1113. EI-MS (m/z): 468 (M++1). HRMS calcd for C27H37NO4Si:
467.2492, found: 467.2465.
A mixture of 16 (136 mg, 0.285 mmol), 1,4-dioxane (1.8 mL),
H2O (1.17 mL), and H2SO4 (0.12 mL) was heated at 95 °C for 3 h.
After evaporation of the reaction mixture, the residue was treated
Compound 13: ½a 2D2
ꢃ
+30.5 (c 1.33, CHCl3). 1H NMR (400 MHz,
with ion-exchange resin (Amberlite IRA-410) to yield
L
-fagomine
CDCl3) d: 1.07 (s, 9H), 1.44 (s, 9H), 2.27–2.32 (m, 1H), 2.70–2.72
(m, 1H), 3.25 (br s, 1H), 3.25–3.30 (m, 2H), 3.43–3.51 (m, 1H),
3.64–3.80 (m, 3H), 3.92–4.06 (m, 1H), 7.38–7.45 (m, 6H), 7.66–
7.69 (m, 4H). 13C NMR (150 MHz, CDCl3) d: 19.2, 26.8, 28.4, 38.2,
40.1, 40.7, 41.7, 50.7, 51.9, 63.7, 79.8, 127.7, 129.7, 133.4, 133.4,
135.5, 135.6, 154.7. IR (neat) cmꢂ1: 2962, 2932, 2859, 1695,
1473, 1462, 1428, 1392, 1366, 1247, 1174, 1152, 1113, 1083. EI-
MS (m/z): 468 (M++1). HRMS calcd for C27H37NO4Si: 467.2492,
found: 467.2580.
(18) (34 mg, 80%) as a solid. MP 184–185 °C; ½a D26
ꢃ
ꢂ20.8 (c 1.13,
H2O). [lit.17
½
a 2D4 +18.0 (c 0.92, H2O) for ent-18]. 1H NMR
ꢃ
(500 MHz, D2O) d: 1.31 (ddd, J = 20.0, 12.8, 4.2 Hz, 1H), 1.83–1.87
(m, 1H), 2.36–2.40 (m, 1H), 2.46 (td, J = 12.8, 2.56 Hz, 1H), 2.84–
2.88 (m, 1H), 3.02 (t, J = 9.4 Hz, 1H), 3.47–3.43 (m, 1H), 3.50 (dd,
J = 11.5, 6.4 Hz, 1H), 3.72 (dd, J = 11.5, 2.9 Hz, 1H). 13C NMR
(125 MHz, D2O) d: 33.5, 43.4, 61.7, 62.5, 74.0, 74.0.
4.1.13. (2S,3R,4R)-2-Hydroxymethylpiperidine-3,4-diol (
L-3,4-di-
epi-fagomine) (19)
4.1.10. (3R,4R,5S)-3,4-Dihydroxy-5-hydroxymethylpiperidine
A mixture of 17 (200 mg, 0.42 mmol), 1,4-dioxane (10.7 mL),
and 0.3 M KOH (21.5 mL) was refluxed overnight. After evapora-
tion, MeOH (4.1 mL) and 6 N HCl (11.7 mL) were added to the res-
idue. The mixture was heated at 60 °C for 1 h and then evaporated
to give an oil. The residue was separated by ion-exchange resin
(L
-3,4-di-epi-isofagomine) (14)
A mixture of 1212 (140 mg, 0.30 mmol), 1,4-dioxane (7.6 mL),
and 3 M KOH (15.3 mL) was refluxed overnight. After evaporation,
methanol (3 mL) and 6 N HCl (9.1 mL) were added to the residue.
The mixture was heated at 60 °C for 1 h and evaporated. The resi-
due was treated with 28% NH4OH and evaporated. The residue was
chromatographed on silica gel (MeOH/10% NH4OH = 10:1) to give 6
chromatography to give
L-fagomine (18) (10.5 mg, 17%) and
L
-3,4-di-epi-fagomine (19) (51.2 mg, 81%). For 19. ½a D25
ꢂ14.0
ꢃ
(c 1.96, H2O). [lit.17
½
a 2D5 +13.4 (c 0.32, H2O) for ent-19]. 1H NMR
ꢃ
(12 mg, 28%) and 14 (28 mg, 64%). ½a D24
ꢃ
ꢂ18.7 (c 1.28, EtOH). [lit.12
(500 MHz, D2O) d: 1.43–1.50 (m, 1H), 1.86 (m, 1H), 2.78 (m, 2H),
3.02–3.06 (m, 1H), 3.56–3.57 (m, 2H), 3.61 (br s, 1H), 3.80 (br s,
1H). 13C NMR (125 MHz, D2O) d: 28.2, 39.3, 56.0, 61.3, 68.2, 69.1.
½
a 1D9 +18.4 (c 0.96, EtOH) for ent-14]. 1H NMR (270 MHz, D2O) d:
ꢃ
1.90–2.02 (m, 1H), 2.47–2.65 (m, 3H), 2.84 (dd, J = 13.8, 2.9 Hz,
1H), 3.42 (dd, J = 11.1, 8.0 Hz, 1H), 3.48–3.68 (m, 2H), 3.69 (dd,
J = 5.6, 3.6 Hz, 1H). 13C NMR (67.8 MHz, D2O) d: 38.2, 41.4, 45.7,
59.3, 66.8, 68.7. EI-MS (m/z): 147 (M+).
4.1.14. (R)-6-Hydroxymethyl-3,6-dihydro-2H-pyridine-1-
carboxylic acid tert-butyl ester (20)
A solution of TBAF (1.59 mL, 1.59 mmol) was added to a solu-
tion of 15 (597 mg, 1.32 mmol) in THF (15 mL) with ice cooling
and the mixture was stirred at room temperature for 2.5 h. After
being diluted with H2O, the mixture was extracted with AcOEt
three times. The extracts were washed with brine, dried, and evap-
orated. The residue was purified by chromatography (hexane/
4.1.11. (2S,6R,7S)-2-(tert-Butyldiphenylsilanyloxymethyl)-7-
oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl
ester (17) and (2S,6S,7R)-2-(tert-
butyldiphenylsilanyloxymethyl)-7-oxa-3-
azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (16)
To
a
solution of (R)-1517 (377 mg, 0.83 mmol) in CH3CN
AcOEt = 3:1) to yield 20 (274 mg, 97%) as an oil. ½a D24
ꢃ
+230.7 (c
(6.4 mL) was successively added 4 ꢁ 10ꢂ4 M Na2ꢀEDTA (4.2 mL)
and CF3COCH3 (0.78 mL) at 0 °C. A mixture of NaHCO3 (545 mg)
and Oxone (2.56 g) was added to the reaction mixture over 1 h at
0 °C and the whole mixture was stirred at the same temperature
for 30 min. H2O (7 mL) was added to the reaction mixture and
the mixture was extracted with CH2Cl2. The extract was dried
and evaporated. The residue was purified by chromatography (hex-
ane/AcOEt = 5:1) to yield a diastereomeric mixture. The mixture
was purified by medium-pressure chromatography (hexane/
AcOEt = 15:1) to yield 17 (115 mg, 29%) and 16 (231 mg, 59%) as
1.75, CHCl3). [lit.17
½
a 2D4
ꢃ
ꢂ227.5 (c 1.02, CHCl3) for ent-20]. 1H
NMR (300 MHz, CDCl3) d: 1.42 (s, 9H), 1.91–1.99 (m, 1H), 2.12–
2.21 (m, 1H), 2.52 (br s, 0.5H), 2.83–2.90 (m, 1H), 3.17 (br s,
0.5H), 3.57–3.63 (m, 2H), 4.05 (br s, 1H), 4.49 (br s, 1H), 5.57–
5.63 (m, 1H), 5.88–5.93 (1H, m). 13C NMR (75 MHz, CDCl3) d:
25.0, 26.7, 28.6, 39.3, 54.2, 64.8, 80.2, 124.7, 127.5, 134.7; IR (neat)
(cmꢂ1) 3440.0, 2975.8, 2930.1, 1693.0, 1674.3, 1423.6 . HRMS calcd
for C11H19NO3 (M+) 213.1652, found 213.1638.
4.1.15. (2S,3S,4R)-2-Hydroxymethylpiperidine-3,4-diol (L-3-epi-
fagomine) (21)
oils. 17: ½a 2D4
ꢃ
+79.8 (c 2.41, CHCl3). [lit.17
½
a 2D4
ꢃ
ꢂ71.2 (c 1.27, CHCl3)
for ent-17]. 1H NMR (500 MHz, CDCl3) d: 1.07 (s, 9H), 1.38 (s, 6H),
A solution of NMO (559 mg, 2.39 mmol) and a solution of
K2OsO4ꢀ2H2O (14.7 mg, 39.7 mol) in water (0.7 mL) were succes-
1.44 (s, 3H), 1.86–2.01 (m, 2H), 2.63–2.67 (m, 1H), 3.34–3.71 (m,
l