H. Wang, H. Luo, X. Ma, W. Zou, H. Shao
FULL PAPER
(2R,3aR,6R,7R,7aS)-2,6,7-Trihydroxy-2-methyl-4-octyltetra-
hydrofuro[3,2-b]piperidine (9e): Yield 68%, over two steps. Yellow
oil. [α]2D0 = –57.4 (c = 0.4, CHCl3). 1H NMR (CDCl3): δ = 4.12 (br.
s, 1 H), 3.94 (br. s, 1 H), 3.62 (t, J = 7.3 Hz, 1 H), 3.54 (br. s, 1 H),
3.30 (dd, J = 3.6, 12.8 Hz, 1 H), 2.93 (pt, J = 6.2 Hz, 1 H), 2.82–
2.77 (m, 1 H), 2.36 (d, J = 13.2 Hz, 1 H), 2.24–2.20 (m, 2 H), 1.90
(dd, J = 3.6, 13.2 Hz, 1 H), 1.59–1.51 (m, 1 H), 1.48–1.43 (m, 1
mixture was poured into cold water (30 mL) and extracted with
EtOAc (3ϫ 40 mL). The organic layer was successively washed
with water (2ϫ 50 mL) and brine (3ϫ 100 mL), then dried with
anhydrous Na2SO4. The filtrate was concentrated to give a colorless
oil, which was subsequently heated with 6 n HCl/THF (1:1; 20 mL)
at 50 °C. After 18 h, the aqueous mixture was neutralized with
NaHCO3 powder and extracted with EtOAc (3 ϫ 60 mL). The
H), 1.48 (s, 3 H), 1.29–1.26 (m, 12 H), 0.88 (t, J = 13.9 Hz, 3 H) combined organic phases were dried with anhydrous Na2SO4 and
ppm. 13C NMR (CDCl3): δ = 106.0, 80.3, 69.6, 68.8, 63.0, 55.2,
54.0, 42.9, 31.7, 29.4, 29.1, 27.2, 26.4, 25.5, 22.5, 14.0 ppm. ESI-
concentrated to give a brown oil. Without further purification, the
obtained oil was dissolved in Ac2O (6 mL) at 0 °C and treated with
HRMS: calcd. for C16H32NO4 [M + H]+ 302.2326; found 302.2330. DMAP (8 mg). The ice bath was removed, and the solution was
stirred at room temperature for 5 h. The mixture was poured into
(2R,3aR,6R,7R,7aS)-2,6,7-Trihydroxy-2-methyl-4-nonyltetrahydro-
cold water (30 mL), washed with 1 n HCl, brine, and water, and
furo[3,2-b]piperidine (9f): Yield 68 %, over two steps. Yellow oil.
dried with Na2SO4. The filtrate was concentrated in vacuo and
purified by silica gel flash column chromatography (petroleum
[α]2D0 = –47.8 (c = 0.3, CHCl3). H NMR (CDCl3): δ = 4.12 (br. s,
1
1 H), 3.94 (br. s, 1 H), 3.62 (br. s, 1 H), 3.30 (dd, J = 2.9, 12.4 Hz,
ether/ethyl acetate, 5:1) to afford compound 10a as a colorless oil
1 H), 2.93 (t, J = 5.8 Hz, 1 H), 2.82–2.77 (m, 1 H), 2.36 (d, J =
(0.6 g, 2.1 mmol, 78%, over three steps). [α]2D0 = +70.0 (c = 0.1,
13.2 Hz, 1 H), 2.24–2.16 (m, 2 H), 1.90 (dd, J = 5.8, 13.3 Hz, 1 H),
CHCl3). 1H NMR (CDCl3): δ = 5.74–5.68 (m, 1 H), 5.41 (t, J =
1.58–1.53 (m, 1 H), 1.48–1.37 (m, 1 H), 1.48 (s, 3 H), 1.29–1.26 (m,
7.9 Hz, 1 H), 5.25 (dd, J = 4.6, 7.8 Hz, 1 H), 5.07 (dd, J = 1.5,
17.2 Hz, 1 H), 5.05 (dd, J = 0.9, 9.8 Hz, 1 H), 4.22 (td, J = 3.4,
6.9, 14.1 Hz, 1 H), 4.15–4.12 (m, 1 H), 3.55 (dd, J = 3.2, 13.2 Hz,
12 H), 0.88 (t, J = 13.9 Hz, 3 H) ppm. 13C NMR (CDCl3): δ =
106.0, 80.3, 69.6, 68.8, 63.0, 55.3, 54.1, 42.9, 31.8, 29.48, 29.42,
29.2, 27.2, 26.4, 25.5, 22.6, 14.0 ppm. ESI-HRMS: calcd. for
1 H), 3.27 (dd, J = 4.2, 13.2 Hz, 1 H), 2.42–2.37 (m, 1 H), 2.34–
C17H34NO4 [M + H]+ 316.2484; found 316.2494.
2.29 (m, 1 H), 2.10 (s, 3 H), 2.00 (s, 3 H) ppm. 13C NMR (CDCl3):
δ = 169.8, 159.5, 133.0, 117.7, 79.0, 78.2, 72.7, 72.4, 52.0, 33.8,
20.5, 20.4 ppm. ESI-HRMS: calcd. for C12H17N3O5Na [M + Na]+
306.1060; found 306.1063. A solution of Jones reagent (2 m, 6 mL)
was added dropwise to a solution of 10a (0.6 g, 2.1 mmol) and
Hg(OAc)2 (200 mg, 0.6 mmol) in acetone/water (4:1, 20 mL) at
0 °C. The dark greenish-brown mixture was stirred at 0 °C to room
temperature overnight and then poured into cold water (40 mL).
The aqueous mixture was extracted with EtOAc (3ϫ 60 mL). The
organic layer was successively washed with water (2ϫ 50 mL) and
brine (5ϫ 100 mL) and dried with anhydrous Na2SO4. The filtrate
was concentrated in vacuo, and the residue was purified by silica
gel flash column chromatography (petroleum ether/ethyl acetate,
2:1) to afford compound 10 as a colorless oil (0.47 g, 1.6 mmol,
76%). [α]2D0 = +66.0 (c = 0.1, CHCl3). 1H NMR (CDCl3): δ = 5.51
(t, J = 8.7 Hz, 1 H), 5.29 (dd, J = 4.8, 7.3 Hz, 1 H), 4.70–4.67 (m,
1 H), 4.14–4.12 (m, 1 H), 3.54 (dd, J = 6.3, 13.1 Hz, 1 H), 3.33
(dd, J = 4.6, 13.1 Hz, 1 H), 2.82 (dd, J = 7.3, 16.9 Hz, 1 H), 2.69
(dd, J = 5.9, 16.9 Hz, 1 H), 2.19 (s, 3 H), 2.11 (s, 3 H), 3.11 (s, 3
H) ppm. 13C NMR (CDCl3): δ = 204.9, 169.6, 169.5, 78.4, 75.2,
72.7, 72.4, 52.1, 43.5, 30.3, 20.4, 20.4 ppm. ESI-HRMS: calcd. for
C12H17N3O6Na [M + Na]+ 322.1010; found 322.1016.
(2R,3aR,6R,7R,7aS)-4-Cyclohexyl-2,6,7-trihydroxy-2-methyltetra-
hydrofuro[3,2-b]piperidine (9g): Yield 71%, over two steps. White
powder. [α]2D0 = –93.5 (c = 0.1, CHCl3). 1H NMR (CDCl3): δ = 4.13
(br. s, 1 H), 3.94 (br. s, 1 H), 3.58 (t, J = 7.3 Hz, 1 H), 3.45 (br. s,
1 H), 3.32 (t, J = 5.8 Hz, 1 H), 3.14 (dd, J = 3.6, 12.4 Hz, 1 H),
2.80–2.76 (tt, J = 6.2, 11.5, 21.4 Hz, 1 H), 2.45 (d, J = 13.6 Hz, 1
H), 2.40 (d, J = 12.4 Hz, 1 H), 1.85 (dd, J = 3.3, 13.5 Hz, 2 H),
1.82–1.78 (m, 2 H), 1.68–1.66 (m, 1 H), 1.61–1.60 (m, 1 H), 1.52–
1.49 (m, 1 H), 1.48 (s, 3 H), 1.37–1.05 (m, 6 H) ppm. 13C NMR
(CDCl3): δ = 105.8, 80.6, 69.7, 68.8, 59.0, 57.5, 49.0, 42.7, 31.1,
26.3, 26.0, 25.9, 25.4, 24.5 ppm. ESI-HRMS: calcd. for C14H26NO4
[M + H]+ 272.1856; found 272.1863.
(2R,3aR,6R,7R,7aS)-2,6,7-Trihydroxy-2-methyl-4-phenethyltetra-
hydrofuro[3,2-b]piperidine (9h): Yield 68%, over two steps. Yellow
oil. [α]2D0 = –59.0 (c = 0.3, CHCl3). H NMR (CDCl3): δ = 7.32–
1
7.29 (t, J = 15.0 Hz, 2 H), 7.23 (t, J = 14.7 Hz, 1 H), 7.19 (d, J =
7.6 Hz, 1 H), 4.09 (br. s, 1 H), 3.96 (br. s, 1 H), 3.62 (br. s, 1 H),
3.44 (dd, J = 3.3, 12.4 Hz, 2 H), 3.07–3.02 (m, 2 H), 2.95 (br. s, 1
H), 2.89–2.85 (m, 1 H), 2.79–2.72 (m, 1 H), 2.55–2.50 (m, 1 H),
2.29 (dd, J = 12.4, 26.5 Hz, 2 H), 2.16 (d, J = 5.4 Hz, 1 H), 1.89
(dd, J = 3.7, 13.5 Hz, 1 H), 1.43 (s, 3 H) ppm. 13C NMR (CDCl3):
δ = 139.0, 128.7, 128.7, 128.6, 128.6, 126.6, 105.7, 80.1, 69.5, 68.8,
62.9, 55.8, 55.7, 43.1, 32.9, 25.7 ppm. ESI-HRMS: calcd. for
C16H24NO4 [M + H]+ 294.1700; found 294.1695.
1-C-Acetylmethyl 2,3-Di-O-acetyl-5-deoxy-5-amino-β-D-ribopyrano-
side (11a): A solution of compound 10 (0.4 g, 1.3 mmol) in meth-
anol (8 mL) was bubbled with hydrogen in the presence Pd/C cata-
lyst (200 mg) and stirred at room temperature for 8 h. Then, the
solution was filtered and concentrated to give a yellow oil, which
was immediately treated with 1% MeONa in methanol at room
temperature for 8 h. The reaction mixture was concentrated to give
a yellow crude product. The crude product was purified by silica
gel flash column chromatography (ethyl acetate/methanol, 10:1) to
give the final product 11a as a yellow oil (0.27 g, 1.0 mmol, 75%).
(2R,3aR,6R,7R,7aS)-4-(p-Fluorophenethyl)-2,6,7-trihydroxy-2-
methyltetrahydrofuro[3,2-b]piperidine (9i): Yield 69 %, over two
steps. Yellow oil. [α]2D0 = –64.2 (c = 0.4, CHCl3). 1H NMR (CDCl3):
δ = 7.16–7.13 (m, 2 H), 7.00–6.97 (m, 2 H), 4.11 (br. s, 1 H), 3.97
(m, 1 H), 3.63 (t, J = 7.3 Hz, 1 H), 3.50 (br. s, 1 H), 3.41 (dd, J =
3.6, 12.4 Hz, 1 H), 3.07–2.99 (m, 1 H), 2.95 (t, J = 6.2 Hz, 1 H),
2.87–2.84 (m, 1 H), 2.77–2.70 (m, 1 H), 2.52–2.47 (m, 1 H), 2.28
(dd, J = 12.4, 24.1 Hz, 2 H), 2.16 (s, 1 H), 1.90 (dd, J = 3.6,
13.5 Hz, 1 H), 1.44 (s, 3 H), 1.23 (d, J = 17.9 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = 162.4, 160.8, 134.6, 130.0, 129.9, 115.5, 105.8,
80.1, 69.5, 68.7, 62.9, 55.9, 43.1, 43.1, 32.2, 25.6 ppm. ESI-HRMS:
calcd. for C16H23NFO4 [M + H]+ 312.1606; found 312.1607.
1
[α]2D0 = –28.2 (c = 0.3, CHCl3). H NMR (CDCl3): δ = 5.43 (d, J
= 2.2 Hz, 1 H), 4.50 (br. dd, J = 2.9, 10.3 Hz, 1 H), 3.79–3.77 (m,
1 H), 3.28–3.25 (m, 1 H), 2.92–2.89 (m, 1 H), 2.81 (dd, J = 2.6,
11.7 Hz, 1 H), 2.78 (d, J = 2.9 Hz, 1 H), 2.73 (br. s, 1 H), 2.61 (br.
dd, J = 2.6, 17.6 Hz, 1 H), 2.35 (m, 1 H), 2.12 (s, 3 H), 2.11 (s, 3
H), 1.96 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 207.7, 171.0, 169.9,
71.8, 71.2, 67.5, 49.5, 46.3, 44.8, 30.8, 30.5, 20.8, 20.7 ppm. ESI-
1-C-Acetylmethyl 2,3-Di-O-acetyl-5-azido-5-deoxy-α-D-ribfurano-
side (10): A solution of 5 (0.8 g, 2.7 mmol) in DMF (10 mL) was HRMS: calcd. for C12H20NO6Na [M + H]+ 274.1285; found
treated with NaN3 (0.5 g, 8.2 mmol) at 80 °C for 8 h. Then, the 274.1286.
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Eur. J. Org. Chem. 2011, 4834–4840