The Journal of Organic Chemistry
Article
1454, 1345, 1160, 1090, 930, 736, 698 cm−1; H NMR (400 MHz,
CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.35−7.23 (m, 15H), 7.20 (d, J =
8.1 Hz, 2H), 5.84 (ddd, J = 17.3, 10.4, 7.7 Hz, 1H), 5.45 (m, 1H), 5.27
(dd, J = 10.4, 1.6 Hz, 1H), 5.22 (ddd, J = 17.3, 1.6, 0.9 Hz, 1H), 4.99
(dd, J = 3.8, 1.4 Hz, 1H), 4.96 (dd, J = 10.4, 1.4 Hz, 1H), 4.76 (d, J =
11.6 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H),
4.59 (d, J = 11.7 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H), 4.36 (d, J = 11.7
Hz, 1H), 4.14 (dd, J = 7.7, 5.3 Hz, 1H), 3.99 (dt, J = 7.7, 4.3 Hz, 1H),
3.81(dd, J = 6.4, 1.3 Hz, 2H), 3.56 (t, J = 4.9 Hz, 1H), 3.43 (dd, J =
14.9, 4.2 Hz, 1H), 3.22 (dd, J = 14.9, 7.6 Hz, 1H), 2.40 (s, 3H)); 13C
NMR (100 MHz, CDCl3) δ 143.1, 138.5, 138.3, 136.8,135.5, 132.9,
129.6, 128.3, 128.2, 128.0, 127.9, 127.6, 127.5, 127.4, 118.8, 80.7, 80.5,
78.5, 74.1, 73.3, 70.6, 52.5, 48.4, 21.5; HRMS (ESI) calcd for
[C37H41NO5S + Na]+ 634.2598, found 634.2600.
138.9, 138.6, 133.0, 132.8, 128.4, 128.3, 128.2, 127.7, 127.6, 127.5,
127.4, 127.3, 83.6, 80.7, 80.5, 77.5, 75.4, 72.9, 71.9, 46.6, 46.5, 28.5;
HRMS (ESI) calcd for [C33H39NO5 + Na]+ 552.2720, found
552.2711.
1
(3S,4S,5R,Z)-3,4,5-Tris(benzyloxy)-1,2,3,4,5,8-hexahydroazocine
(16). A solution of Na metal (405 mg, 17.6 mmol) and naphthalene
(2.48 g, 19.4 mmol) in 1,2-dimethoxyethane (18 mL) was stirred at
room temperature for 2 h. To a solution of 7a (664 mg, 1.14 mmol) in
1,2-dimethoxyethane (13 mL) at −78 °C was added the Na-
naphthalene solution (11.4 mL) dropwise for 30 min. The reaction
mixture was stirred at −78 °C for 5 min and then H2O (2.1 mL) was
slowly added to the mixture at −78 °C to quench the reaction. The
reaction mixture was diluted with Et2O (120 mL), dried over
anhydrous MgSO4 and concentrated under reduced pressure. The
residue was purified by silica column chromatography
(MeOH:CH2Cl2 1: 9) to furnish 16 as a yellowish oil (366 mg,
(3S,4S,5R,Z)-3,4,5-Tris(benzyloxy)-1-tosyl-1,2,3,4,5,8-hexahydroa-
zocine (7a). A solution of 8a (3.9 g, 6.3 mmol) and Grubbs catalyst II
(0.53 g, 0.63 mmol, 10 mol %) in CH2Cl2 (1600 mL) was refluxed for
1 h. The reaction mixture was concentrated under reduced pressure,
and the resulting crude product was purified by silica column
chromatography (EtOAc/hexanes 1:5) to afford 7a as a viscous
semisolid (3.1 g, 84%): [α]24D +86.5 (c 1.00 CHCl3); IR (neat) 3063,
75%): [α]24 −13.6 (c 1.00 CHCl3); IR (neat) 3364, 3063, 3029,
D
1
2863, 1496, 1454, 1355, 1207, 1090, 1069, 735, 697 cm−1; H NMR
(400 MHz, CDCl3) δ 7.37−7.22 (m, 15H), 5.76 (m, 1H), 5.69 (dd, J
= 11.7, 6.7 Hz, 1H), 4.77 (m, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.65 (d, J
= 11.5 Hz, 1H), 4.63 (d, J = 11.8 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H),
4.53 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 3.71 (dd, J = 7.4,
5.4 Hz, 1H), 3.57 (m, 1H), 3.44 (dd, J = 16.8, 4.8 Hz, 1H), 3.29 (ddd,
J = 16.8, 5.2, 1.5 Hz, 1H), 3.06 (m, 2H)); 13C NMR (100 MHz,
CDCl3) δ 138.7,138.6, 138.5, 132.9, 130.0, 128.4, 128.3, 128.1, 127.7,
127.6, 127.5, 84.0, 79.9, 78.2, 74.2, 72.3, 71.7, 48.1, 47.8; HRMS (ESI)
calcd for [C28H31NO3 + Na]+ 452.2196, found 452.2209. Compound
16 was also obtained from 7b. Compound 7b (20 mg, 0.038 mmol)
was dissolved with 4 N HCl in dioxane (118 μL, 0.47 mmol). The
solution was stirred at room temperature for 1 h. Excess HCl and
dioxane were removed by evaporation. Concentrated NH4OH (60 μL)
and H2O (300 μL) were added to the concentrated mixture. The
mixture was extracted with CH2Cl2 (3 × 2 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure. The crude product
was purified by silica column chromatography (MeOH/CH2Cl2 1:9)
to give 16 as a yellowish oil (14 mg, 85%). All the spectra are identical
with the ones of compound 16 obtained from compound 7a.
3029, 2865, 1453, 1347, 1162, 1092, 1070, 738, 698 cm−1; H NMR
1
(400 MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.35−7.22 (m, 17H),
5.67 (ddd, J = 11.8, 6.5, 1.7 Hz, 1H), 5.45 (br d, J = 11.8 Hz, 1H), 5.00
(t, J = 7.6 Hz, 1H), 4.91 (d, J = 11.1 Hz, 1H), 4.70 (d, J = 11.7 Hz,
1H), 4.66 (d, J = 11.1 Hz, 1H), 4.62 (s, 2H), 4.58 (d, J = 11.7 Hz, 1H),
4.22 (br d, J = 16.4 Hz, 1H), 3,96 (ddd, J = 8.5, 6.8, 3.3 Hz, 1H), 3.60
(dd, J = 14.5, 3.3 Hz, 1H), 3.57 (dd, J = 9.1, 6.8 Hz, 1H), 3.24 (dd, J =
16.4, 4.9 Hz, 1H), 2.87 (dd, J = 14.5, 8.5 Hz, 1H), 2.4 (s, 3H)); 13C
NMR (100 MHz, CDCl3) δ 143.7, 138.9, 138.7, 138.6, 134.2, 134.0,
129.8, 128.4, 128.3, 128.0, 127.8, 127.6, 127.5, 127.4, 125.0, 83.5, 81.4,
77.6, 75.3, 73.2, 72.5, 48.9, 48.0, 21.6; HRMS (ESI) calcd for
[C35H37NO5S + Na]+ 606.2285, found 606.2277.
tert-Butyl Allyl ((2S,3S,4R)-2,3,4-tris(benzyloxy)hex-5-en-1-yl)-
carbamate (8b). To a solution of 15 (1.6 g, 3.5 mmol) and Boc
anhydride (916 mg, 4.20 mmol) in CH2Cl2 (14 mL) was added
DMAP (43 mg, 0.35 mmol). The mixture was stirred at room
temperature for 16 h and then concentrated under reduced pressure.
The residue was purified by column chromatography (EtOAc/hexanes
(3S,4S,5R,Z)-3,4,5-Tris(benzyloxy)-1-butyl-1,2,3,4,5,8-hexahy-
droazocine (17a). To a solution of 16 (200 mg, 0.47 mmol) and
butyraldehyde (40 μL, 0.45 mmol) in 1,2-dichloroethane (2 mL) at
room temperature was added NaBH(OAc)3 (140 mg, 0.65 mmol).
The reaction mixture was stirred at room temperature for 16 h, diluted
with EtOAc (16 mL), washed with saturated NaHCO3 (2 × 4 mL),
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was purified by silica column
chromatography (EtOAc/hexanes 1:3) to give 17a as a yellowish oil
1:8) to give 8b (1.56 g, 80%) as a colorless oil: [α]22 −29.1 (c 1.00
D
CHCl3); IR (neat) 3065, 3031, 2977, 1694, 1644, 1455, 1405, 1247,
925, 735 cm−1; H NMR (400 MHz, CDCl3) δ 7.35−7.22 (m, 15H),
1
5.81 (m, 1H), 5.68 (br s, 1H), 5.27 (d, J = 10.8 Hz, 1H), 5.22 (d, J =
17.8 Hz, 1H), 5.04 (d, J = 9.6 Hz, 1H), 4.96 (d, J = 17.1 Hz, 1H), 4.82
(d, J = 11.5 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.60 (m, 2H), 4.38 (d,
J = 11.8 Hz, 1H), 4.14 (t, J = 6.9 Hz, 1H), 3.91 (dd, J = 9.4, 5.2 Hz,
1H), 3.71 (br s, 2H), 3.48 (dd, J = 6.0, 4.3 Hz, 1H), 3.37 (br s, 2H),
1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.6, 138.5, 135.5,
134.0, 128.3, 128.2, 128.0, 127.5, 118.9, 115.9, 81.2, 79.6, 74.2, 73.3,
70.7, 50.9, 47.8, 28.5; HRMS (ESI) calcd for [C35H43NO5 + H]+
558.3219, found 558.3229.
(170 mg, 75%): [α]24 +1.8 (c 1.0 CHCl3); IR (neat) 3063, 3029,
D
1
2930, 2861, 1496, 1454, 1358, 1207, 1091, 1068, 734, 697 cm−1; H
NMR (400 MHz, CDCl3) δ 7.36−7.22 (m, 15H), 5.57 (ddd, J = 11.9,
5.7, 1.6 Hz, 1H), 5.50 (br d, J = 11.7 Hz, 1H), 5.18 (br s, 1H), 4.94 (d,
J = 10.7 Hz, 1H), 4.69 (d, J = 11.3 Hz, 1H), 4.68 (d, J = 10.7 Hz, 1H),
4.66 (d, J = 11.3 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.58 (d, J = 11.6
Hz, 1H), 3.54 (m, 2H), 3.25 (br d, J = 16.4 Hz, 1H), 2.97 (dd, J =
16.4, 3.6 Hz, 1H), 2.76 (dd, J = 13.8, 8.9 Hz, 1H), 2.57 (d, J = 13.8 Hz,
1H), 2.37 (m, 2H), 1.35 (m, 2H), 1.24 (sex, J = 7.2 Hz, 2H), 0.86 (t, J
= 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.3, 139.2, 138.9,
133.1, 128.8, 128.3, 128.2, 127.9, 127.7, 127.5, 127.4, 127.2, 85.1, 81.4,
78.2, 75.7, 72.9, 71.9, 57.7, 55.1, 55.0, 30.0, 20.5, 14.0; HRMS (ESI)
calcd for [C32H39NO3 + H]+ 486.3003, found 486.3020.
(5R,6S,7S)-tert-Butyl 5,6,7-Tris(benzyloxy)-5,6,7,8-tetrahydroazo-
cine-1(2H)-carboxylate (7b). A solution of 8b (100 mg, 0.179 mmol)
and Grubbs catalyst II (15 mg, 0.018 mmol, 10 mol %) in CH2Cl2 (45
mL) was refluxed for 4 h. The reaction mixture was concentrated
under reduced pressure, and the resulting crude product was purified
by silica column chromatography (EtOAc/hexaness 1:8) affording 88
mg (92%) of a rotameric mixture of 7b (1:1.4) as a colorless oil.
Rotamer A: 1H NMR (400 MHz, CDCl3) δ 7.36−7.23 (m, 15H), 5.66
(m, 2H), 4.84 (d, J = 12.0 Hz, 1H), 4.71−4.50 (m, 5H), 4.47 (m, 1H),
4.17 (d, J = 16.1 Hz, 1H), 3.90 (dd, J = 14.6, 3.0 Hz, 1H), 3.80 (m,
1H), 3.66 (dd, J = 16.6, 4.0 Hz, 1H), 3.60 (dd, J = 9.0, 6.5 Hz, 1H),
3.25 (dd, J = 14.3, 8.3 Hz, 1H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 155.3, 138.7, 138.5, 133.0, 132.8, 128.4, 128.3, 128.2, 127.7,
127.6, 127.5, 127.4, 127.3, 83.8, 79.9, 79.8, 77.5, 75.1, 72.7, 71.9, 46.6,
(3S,4S,5R,Z)-3,4,5-Tris(benzyloxy)-1-nonyl-1,2,3,4,5,8-hexahy-
droazocine (17b). To a solution of 16 (220 mg, 0.51 mmol) and
nonyl aldehyde (85 μL, 0.49 mmol) in 1,2-dichloroethane (2 mL) at
room temperature was added NaBH(OAc)3 (152 mg, 0.717 mmol).
The reaction mixture was stirred at room temperature for 16 h, diluted
with EtOAc (18 mL), washed with saturated NaHCO3 (2 × 5 mL),
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was purified by silica column
chromatography (EtOAc/hexanes 1:4) to give 17b as a yellowish oil
1
45.8, 28.4. Rotamer B: H NMR (400 MHz, CDCl3) δ 7.36−7.23
(m, 15H), 5.66 (m, 2H), 4.89 (d, J = 11.0 Hz, 1H), 4.71−4.50 (m, 5H),
4.47 (m, 2H), 3.90 (dd, J = 14.6, 3.0 Hz, 1H), 3.80 (m, 1H), 3.60 (dd,
J = 9.0, 6.5 Hz, 1H), 3.57 (dd, J = 18.7, 2.6 Hz, 1H), 3.16 (dd, J = 14.7,
8.4 Hz, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.5,
(217 mg, 76%). [α]24 −3.5 (c 1.0 CHCl3); IR (neat) 3063, 3030,
D
2926, 2855, 1496, 1454, 1357, 1207, 1092, 1068, 733, 697 cm−1;
3090
dx.doi.org/10.1021/jo202054g | J. Org. Chem. 2012, 77, 3082−3098