720 J . Org. Chem., Vol. 65, No. 3, 2000
Block et al.
Hz, H-5), 5.91 (dddd, 1H, J ) 10.1, 3.9, 1.7, 1.0 Hz, H-4); 13C
NMR (acetone-d6) δ 60.1 (C-2), 63.8 (C-6), 71.2 (C-1), 71.6 (C-
3), 127.5 (C-5), 131.3 (C-4); IR (KBr) 2090 cm-1 (N3). Anal.
Calcd for C6H8BrN3O2 (234.05): C, 30.79; H, 3.45; N, 17.95.
Found: C, 30.57; H, 3.47; N, 18.31. Data for racemic 11 (light
yellow crystals): mp 96-97 °C (CHCl3). Anal. Calcd for C6H8-
BrN3O2 (234.05): C, 30.79; H, 3.45; N, 17.95. Found: C, 30.75;
H, 3.53; N, 18.10.
µL, 162 mg, 1.59 mmol) dropwise at 0 °C over 10 min. The
mixture was stirred for 30 min and allowed to warm to room
temperature. Concentration under reduced pressure gave a
white solid (136 mg, 99%). Recrystallization from EtOAc/
MeOH (2:1) yielded pure (-)-15b (110 mg, 81%) as colorless
needles: mp 147-148 °C dec; R25D -97 (c 2.6, MeOH); 1H NMR
(DMSO-d6) δ 1.85 (s, 3H), 2.92 (dd, 1H, J ) 4.1, 1.4 Hz, H-7),
3.11 (dd, 1H, J ) 3.9, 1.6 Hz, H-4), 3.41 (dd, 1H, J ) 4.0, 2.8,
H-1), 3.44 (ψt, 1H, H-2), 3.49 (ddd, 1H, J ) 9.1, 6.1, 1.5 Hz,
H-6), 4.06 (m, 1H, H-5), 5.31 (d, 1H, J ) 6.0 Hz, OH), 7.85 (d,
1H, J ) 7.9 Hz, NH); 13C NMR (DMSO-d6) δ 23.2, 48.4 (C-2),
48.9 (C-1), 50.9 (C-5), 55.1 (C-7), 55.5 (C-4), 67.2 (C-6), 170.2.
Anal. Calcd for C8H11NO4 (185.17): C, 51.89; H, 5.99; N, 7.56.
Found: C, 51.70; H, 5.97; N, 7.43. Data for racemic 15b
(colorless crystals): mp 142-143 °C dec (EtOAc/MeOH (1:1)).
Anal. Calcd for C8H11NO4 (185.17): C, 51.89; H, 5.99; N, 7.56.
Found: C, 51.73; H, 5.76; N, 7.20.
LL-C10037r, (-)-3. To a solution of amide 15b (53 mg,
0.286 mmol, 6 mL of dry CH2Cl2) was added 1 equiv of Dess-
Martin periodinane at 0 °C. After being stirred for 30 min at
0 °C, the mixture was allowed to warm to room temperature
and stirred for 1 h. MeOH (200 µL) was added, and column
chromatography (silica gel, CH2Cl2/MeOH (90:10)) gave a
white solid (86 mg). A second purification by column chroma-
tography (silica gel, EtOAc) yielded fractions containing pure
(-)-3. By concentration under reduced pressure to a small
amount of solvent, pure (-)-3 (27 mg, 52%) precipitated as
colorless needles: mp 146-148 °C dec; R25D -194 (c 1.1, MeOH)
(lit.3b R25D -202 (c 0.3, MeOH)); 1H NMR (DMSO-d6) δ 2.00 (s,
3H), 3.53 (d, 1H, J ) 4.3 Hz, H-1), 3.76 (dψt, 1H, J ) 4.3 Hz,
H-6), 4.79 (dψt, 1H, J ) 6.3 Hz, H-5), 5.72 (d, 1H, J ) 6.3 Hz,
OH), 7.05 (ψt, 1H, H-4), 8.96 (s, 1H, NH); 13C NMR (DMSO-
d6) δ 23.6, 52.1 (C-1), 53.6 (C-6), 63.3 (C-5), 128.2 (C-3), 128.2
(C-4), 169.4, 189.5 (C-2). Anal. Calcd for C8H9NO4 (183.16):
C, 52.46; H, 4.95; N, 7.65. Found: C, 52.67; H, 4.99; N, 7.47.
Data for racemic 3 (colorless crystals): mp 161-163 °C dec
(lit.9 mp 167 °C dec). Anal. Calcd for C8H9NO4 (183.16): C,
52.46; H, 4.95; N, 7.65. Found: C, 52.62; H, 4.97; N, 7.42.
P r ep a r a tion of Wa ter -In solu ble Am id es 15a ,c,d . Gen -
er a l P r oced u r es. To amine 14 (1 mmol, 10 mL CH2Cl2) and
Et3N (1.5 mmol) was added a solution of acid chloride (1 mmol,
2 mL of CH2Cl2) over 5 min at 0 °C. After the mixture was
stirred for 5 h at 0 °C, water and EtOAc were added, and the
resulting precipitate was filtered off and washed with water
and EtOAc. The filtrate was diluted with 100 mL of EtOAc or
CH2Cl2, extracted with brine, and dried. Concentration gave
a white solid (80-90%, together with precipitate). Recrystal-
lization from EtOAc or mixtures of EtOAc and MeOH yielded
pure amide 15a ,c,d (70-80%).
Dodecan oic Acid (6-Hydr oxy-3,8-dioxatr icyclo[5.1.0.02,4]-
oct-5-yl)a m id e, 15c: white solid (77%); mp 169-171 °C
(EtOAc); 1H NMR (DMSO-d6) δ 0.82 (t, 3H, J ) 6.8 Hz, H-12),
1.21-1.26 (m, 16H, H-4 to H-11), 1.46 (m, 2H, H-3), 2.08 (t,
2H, J ) 7.4 Hz, H-2), 2.89 (dd, 1H, J ) 4.0, 1.3 Hz H-7′), 3.06
(dd, 1H, J ) 3.9, 1.6 Hz, H-4′), 3.38 (ψt, 1H, H-1′), 3.41 (ψt,
1H, H-2′), 3.47 (ψt, 1H, H-6′), 4.05 (m, 1H, H-5′), 5.25 (d, 1H,
J ) 5.5 Hz, OH), 7.70 (d, 1H, J ) 8.0 Hz, NH); 13C NMR
(DMSO-d6) δ 13.8 (C-12), 22.0, 25.1, 28.5, 28.6, 28.7, 28.8, 28.9,
28.9, 31.2, 35.2, 47.7 (C-2′), 48.2 (C-1′), 50.0 (C-5′), 54.4 (C-7′),
54.7 (C-4′), 66.4 (C-6′), 172.5 (C-1); MS (EI) m/z 325 (M+; 4),
57 (C4H9+; 100). Anal. Calcd for C18H31NO4 (325.44): C, 66.43;
H, 9.60; N, 4.30. Found: C, 66.35; H, 9.44; N, 4.24.
(1S,2S,3S,4S,5R,6S)-5-Azid o-3-br om o-7-oxa bicylo[4.1.0]-
h ep ta n e-2,4-d iol, (-)-12. To alkene (-)-11 (2.0 g, 8.55 mmol,
50 mL of CH2Cl2) was added a freshly prepared solution of
trifluoroperacetic acid23 (from TFAA (4.3 mL, 6.5 g, 30.9 mmol)
and H2O2 (85%, 1.0 mL, 30 mmol) in 15 mL of CH2Cl2)
dropwise at 0 °C over 2 h. Then the solution was allowed to
warm to room temperature. After the end was determined by
TLC (ca. 1 h), the reaction mixture was slowly added to a
cooled and stirred solution of 7 g of NaHCO3 in 100 mL of brine
and 150 mL of EtOAc. After addition of Na2S2O3 the organic
layer was washed with NaHCO3, NH4Cl, and brine and then
dried. Evaporation of the solvent gave a yellow solid (2.10 g,
99%). Recrystallization from CHCl3 yielded colorless needles
(1.72 g, 81%): mp 95-96 °C; R25 -115 (c 1.1, acetone); 1H
D
NMR (acetone-d6) δ 3.45 (ψt, 1H, J ) 3-4 Hz, H-1), 3.58 (ψt,
1H, J ) 3-4 Hz, H-6), 3.95 (dψt, 1H, H-4), 4.03 (dd, 1H, J )
6.5, 2.9 Hz, H-5), 4.11 (dd, 1H, J ) 4.5, 2.2 Hz, H-3), 4.41 (m,
1H, H-2), 4.58 (d, 1H, J ) 7.5 Hz, OH-2), 4.86 (d, 1H, J ) 5.4
Hz, OH-4); 13C NMR (acetone-d6) δ 55.7 (C-1), 56.5 (C-6), 59.8
(C-3), 63.4 (C-5), 70.4 (C-4), 71.2 (C-2); IR (KBr) 2090 cm-1
(N3). Anal. Calcd for C6H8BrN3O3 (250.05): C, 28.82; H, 3.22;
N, 16.80. Found: C, 28.65; H, 3.16; N, 17.12. Data for racemic
12 (colorless crystals): mp 83-84 °C (CHCl3). Anal. Calcd for
C6H8BrN3O3 (250.05): C, 28.82; H, 3.22; N, 16.80. Found: C,
28.68; H, 3.23; N, 17.11.
(1S,2R,4R,5S,6S,7S)-6-Azid o-3,8-d ioxa tr icylo[5.1.0.02,4]-
octa n -5-ol, (+)-13. A solution of (-)-12 (2.20 g, 8.80 mmol)
and KOH (5% in MeOH, 15 mL) was stirred for 2 h at 0 °C,
then further KOH (10% in MeOH, 7 mL) was added, and the
reaction mixture was stirred for another 1 h at 0 °C. Solid NH4-
Cl, brine, and EtOAc were added, and the mixture was
extracted three times with EtOAc. Drying and concentration
gave a white solid (1.46 g, 100%). Recrystallization from CHCl3
yielded pure (+)-13 (1.29 g, 84%) as colorless needles: mp
1
119-120 °C; R25 +8.6 (c 1.3, acetone); H NMR (acetone-d6)
D
δ 2.97 (dd, 1H, J ) 4.0, 1.2 Hz, H-4), 3.27 (d, 1H, J ) 3.8 Hz,
H-7), 3.38 (dd, 1H, J ) 4.0, 2.6 Hz, H-2), 3.45 (ψt, 1H, H-1),
3.73 (m, 1H, H-5), 3.86 (d, 1H, J ) 9.6 Hz, H-6), 5.05 (d, 1H,
J ) 5.8 Hz, OH); 13C NMR (acetone-d6) δ 49.2 (C-1), 50.1 (C-
2), 56.3 (C-4), 56.7 (C-7), 65.2 (C-6), 70.9 (C-5); IR (KBr) 2100,
2080 cm-1 (N3). Anal. Calcd for C6H7N3O3 (169.13): C, 42.61;
H, 4.17; N, 24.84. Found: C, 42.70; H, 4.28; N, 24.74. Data
for racemic 13 (light yellow needles): mp 92-93 °C (CHCl3).
Anal. Calcd for C6H7N3O3 (169.13): C, 42.61; H, 4.17; N, 24.84.
Found: C, 42.99; H, 4.17; N, 25.14.
(1S,2R,4R,5S,6S,7S)-6-Am in o-3,8-d ioxa tr icylo[5.1.0.02,4]-
octa n -5-ol, (-)-14. Azide (-)-13 (1.10 g, 6.50 mmol, 100 mL
of dry EtOH) was stirred with Lindlar catalyst (250 mg, Pd/
CaCO3, Pd 5%) in an atmosphere of H2 for 6-8 h at room
temperature. The solution was filtered two times (folded filters)
and the residue washed with EtOH (200 mL). Concentration
to a small amount of EtOH caused crystallization of (-)-14 as
colorless needles (870 mg, 79%): mp 130 °C dec; R25 -44 (c
D
1.50, MeOH); 1H NMR (DMSO-d6) δ 1.63 (br s, 2 H, NH2), 2.86
(dd, 1H, J ) 3.9, 1.4 Hz, H-4), 2.92 (dd, 1H, J ) 8.6, 1.5 Hz,
H-6), 3.08 (dd, 1H, J ) 3.7, 1.3, H-7), 3.27 (dd, 1H, J ) 8.6,
1.3 Hz, H-5), 3.36 (dd, 1H, J ) 3.8, 2.8 Hz, H-2), 3.38 (m, 1H,
H-1), 5.28 (br s, 1H, OH); 13C NMR (DMSO-d6) δ 47.4 (C-1),
48.5 (C-2), 52.5 (C-6), 54.4 (C-4), 56.4 (C-7), 70.0 (C-5). Anal.
Calcd for C6H9NO3 (143.14): C, 50.35; H, 6.34; N, 9.79.
Found: C, 50.31; H, 6.37; N, 9.76. Data for racemic 14
(colorless crystals): mp 134-135 °C dec. Anal. Calcd for C6H9-
NO3 (143.14): C, 50.35; H, 6.34; N, 9.79. Found: C, 50.28; H,
6.33; N, 9.71.
N-(6-Hyd r oxy-3,8-d ioxa tr icyclo[5.1.0.02,4]oct-5-yl)ben -
za m id e, 15d : white solid (73%); mp 167-171 °C (EtOAc/
MeOH (1:1)); 1H NMR (DMSO-d6) δ 2.96 (dd, 1H, J ) 4.0, 1.4
Hz H-7), 3.21 (dd, 1H, J ) 4.0, 1.5 Hz, H-4), 3.42 (dd, 1H, J )
4.0, 2.7 Hz H-1), 3.47 (ψt, 1H, H-2), 3.75 (ddd, 1H, J ) 9.3,
6.1, 1.4 Hz H-6), 4.31 (dψt, 1H, H-5), 5.35 (d, 1H, J ) 6.1 Hz,
OH), 7.41-7.52 (m, 3H, ArH), 7.82-7.88 (m, 2H, ArH), 8.27
(d, 1H, J ) 8.0 Hz, NH); 13C NMR (DMSO-d6) δ 47.7 (C-2),
48.3 (C-1), 51.1 (C-5), 54.7 (C-7), 55.0 (C-4), 66.0 (C-6), 127.3,
128.1, 131.2, 134.2, 166.5; MS (EI) m/z 247 (M+; 1), 105 (C6H5-
CO+; 100). Anal. Calcd for C13H13NO4 (247.26): C, 63.15; H,
5.30; N, 5.66. Found: C, 62.89; H, 5.25; N, 5.82.
(1S ,2R ,4R ,5S ,6S ,7S )-N -(6-H yd r oxy-3,8-d ioxa t r icylo-
[5.1.0.02,4]oct-5-yl)a ceta m id e, (-)-15b. To amino alcohol (-)-
14 (105 mg, 0.73 mmol, 4 mL of MeOH) was added Ac2O (150