The Journal of Organic Chemistry
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To a solution of phosphonate ent-17 (451 mg, 1.32 mmol) in THF
(4.4 mL) was added NaHMDS (0.99 M in THF, 1.33 mL, 1.32 mmol)
at 0 °C under Ar atmosphere. After 30 min, a solution of crude
aldehyde in THF (4.4 mL) was added to the mixture. The mixture was
warmed to room temperature, stirred for 12 h, quenched with
saturated NaHCO3, extracted with AcOEt (×3), washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
α,β-unsaturated imide 29 was employed directly in the next reaction.
To a solution of CuBr·Me2S complex (452 mg, 2.20 mmol) in THF
(4.4 mL) was added dropwise MeMgBr (0.96 M in THF, 3.07 mL,
2.95 mmol) at −78 °C under Ar atmosphere. After 20 min, a solu-
tion of crude α,β-unsaturated imide (249 mg, 0.581 mmol) in THF
(4.4 mL) was added to the mixture. The mixture was warmed to
−40 °C, stirred for 1 h, quenched with saturated NaHCO 3, extracted
with AcOEt (×3), washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (AcOEt/hexane = 20:80) to give imide 30 (255 mg,
0.573 mmol, 65%) as a colorless oil: [α]25D −55.5 ( c 1.54, CHCl3), 1
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (AcOEt/
hexane = 30:70) to give 7-epi-kalkitoxin 3 (13.6 mg, 0.0371 mmol,
47%) as a colorless oil: [α]26 +17.7 (c 0.79, CHCl3), 1H NMR
D
(benzene-d6) δ 0.65−1.32 (21H, m), 1.46−1.53 (1H, m), 1.79−1.90
(1H, m), 1.98 (1H, m), 2.25 (1H, m), 2.31 (1H, m), 2.41 (3H, s), 2.48
(1H, m), 2.65 (1H, dd, J = 8.3, 15.6 Hz), 2.89 (1H, dd, J = 8.8, 15.6
Hz), 3.30 (2H, m), 4.73 (1H, m), 4.96 (1H, d, J = 10.5 Hz), 5.19 (1H,
d, J = 17.3 Hz), 5.78 (1H, ddd, J = 6.3, 10.5, 17.3 Hz); 13C NMR
(benzene-d6) δ 175.2, 174.9, 169.7, 169.4, 138.2, 138.1, 115.3, 115.2,
79.3, 71.7, 56.1, 47.8, 46.0, 42.5, 40.0, 38.9, 37.6, 37.0, 36.8, 36.4, 35.5,
34.7, 33.7, 33.6, 33.6, 28.4, 28.1, 27.7, 19.8, 19.6, 18.4, 17.7, 14.8, 14.7,
14.5, 14.5, 12.6, 12.4; IR (neat) 2954, 2918, 2868, 1640, 1460, 1410,
1377, 1260, 1193, 1084, 1026, 921, 802, 701; MS FAB-MS m/z FAB-
MS m/z 367 (M+ + H); high-resolution FAB-MS m/z 367.2802 (M+ +
H, calcd for C21H39N2OS 367.2783).
(R)-3-((R,E)-6-((tert-Butyldiphenylsilyl)oxy)-5-methylhex-2-
enoyl)-4-phenyloxazolidin-2-one (32). To a solution of phospho-
nate 17 (104.0 mg, 0.304 mmol) in THF (1.3 mL) was added
NaHMDS (1.06 M in THF, 0.287 mL) at 0 °C under Ar atmosphere.
After 30 min, a solution of ent-16 (93.9 mg, 0.276 mmol) in THF
(1.3 mL) was added to the mixture. The mixture was warmed to room
temperature, stirred for 2.5 h, quenched with saturated NaHCO3,
extracted with AcOEt (×3), washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by silica
gel column chromatography (AcOEt/hexane = 10:90) to give α,β-
H NMR (CDCl ), δ 0.63−0.97 (12H, m), 1.04 (3H, d, J = 6.9 Hz,
3
1 rotamer), 1.09 (3H, d, J = 6.9 Hz, 1 rotamer), 1.12−1.19 (2H, m),
1.24−1.75 (6H, m), 1.92−2.08 (1H, m), 2.50−2.62 (1H, m), 2.74−
2.83 (2H, m), 2.85−2.95 (1H, m), 2.89, 2.97 (total 3H, each s), 3.14−
3.47 (2H, m), 4.23−4.29 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 5.38−5.47
13
(1H, m), 7.25−7.55 (5H, m) ; C NMR (CDCl ), 176.3, 176.0,
3
172.5, 172.4, 153.6, 139.1, 139.0, 129.1, 129.05, 129.02, 128.8, 128.6,
125.9, 125.85, 125.79, 125.77, 72.5, 69.8, 57.7, 56.3, 48.1, 48.0, 46.1,
45.8, 39.9, 39.8, 39.0, 38.3, 37.4, 37.24, 37.21, 37.18, 35.4, 35.2, 34.8,
34.7, 34.38, 34.35, 34.06, 34.04, 33.7, 33.3, 29.7, 28.2, 27.4, 27.1, 20.5,
18.9, 17.8, 17.2, 16.7, 16.4, 16.31, 16.27, 14.1, 12.2, 12.1; IR (neat)
2961, 2926, 2874, 1780, 1703, 1637, 1456, 1384, 1321, 1196, 1135,
1080, 1043, 963, 916, 762, 704; MS ESI-MS m/z 467 (M + Na+);
high-resolution ESI-MS m/z 467.2875 (M+ + Na, calcd for
C26H40N2O4Na 467.2880)
unsaturated imide 32 (80.9 mg, 0.153 mmol, 55%) as a colorless oil:
1
[α]23 −12.2 (c 1.78, CHCl3); H NMR (CDCl3) δ 0.88 (3H, d,
D
6.8 Hz), 1.05 (9H, s), 1.83−1.88 (1H, m), 2.07−2.16 (1H, m), 2.47−
2.53 (1H, m), 3.43−3.53 (2H, m), 4.28 (1H, dd, J = 3.9, 8.8 Hz), 4.70
(1H, t, J = 8.8 Hz), 5.48 (1H, dd, J = 3.9, 8.8 Hz), 7.03−7.11 (1H, m),
7.30−7.43 (12H, m), 7.62−7.66 (4H, m); 13C NMR (CDCl3) δ 164.3,
153.5, 150.7, 139.1, 135.5, 133.6, 129.5, 129.1, 128.6, 127.6, 125.9,
121.2, 69.9, 68.3, 57.7, 36.6, 35.5, 26.9, 19.3, 16.5; IR (neat) 3064,
2950, 2924, 2852, 1776, 1685, 1630, 1425, 1382, 1358, 1336, 1193,
1109, 1005, 896, 823, 703; FAB-MS m/z 550 (M+ + Na); high-resolu-
tion FAB-MS m/z 550.2374 (M+ + Na, calcd for C32H37NO4SiNa
550.2390).
(3S,4S,6S)-8-((R)-N,2-Dimethylbutanamido)-3,4,6-trimethyl-
N-((R)-1-(tritylthio)but-3-en-2-yl)octanamide (31). To a solution
of imide 30 (255 mg, 0.574 mmol) in THF/H2O (2.4 mL, 4: 1) was
added 30% H2O2 (328 μL) and 0.5 M LiOH (3.4 mL) at room
temperature. The mixture was stirred for 12 h, 1 N NaOH was added,
and the mixture was washed with AcOEt. The aqueous layer was
acidified with 1 N HCl, extracted with AcOEt (×3), washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude carboxylic acid was employed directly in the next reaction.
To a solution of amine 10 (47.5 mg, 0.138 mmol) and caroboxlic
acid (27.4 mg, 0.0920 mmol) in CH2Cl2 (0.9 mL) were added EDCI
(26.5 mg, 0.138 mmol) and DMAP (1.0 mg, 8.1 μmol) at room
temperature under Ar atmosphere. The mixture was stirred for 5 h,
quenched with 1 N HCl, extracted with AcOEt (×3), washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (AcOEt/
hexane = 30:70) to give amide 31 (49.2 mg, 0.0577 mmol, 85%) as a
pale oil: [α]26D +45.8 (c 0.70, CHCl3), 1H NMR (CDCl3) δ 0.80−0.89
(12H, m), 1.08 (3H, t, J = 6.7 Hz), 1.23−1.50 (8H, m), 1.65−1.70
(1H, m), 1.90−1.95 (1H, m), 2.13−2.20 (1H, m), 2.37−2.39 (1H, m),
2.41−2.59 (2H, m), 2.90, 3.00 (total 3H, each s), 3.28−3.40 (2H, m),
4.54 (1H, s), 5.04−5.08 (2H, d, J = 14.9 Hz), 5.62−5.66 (1H, m),
7.20−7.41 (15H, m); 13C NMR (CDCl3) δ 176.3, 176.0, 171.8, 171.5,
144.5, 136.8, 136.7, 129.4, 127.9, 127.8, 126.7, 126.7, 126.0, 115.4,
66.7, 66.7, 56.4, 49.9, 49.9, 48.0, 46.2, 42.2, 42.2, 41.9, 37.4, 37.2, 36.9,
36.6, 35.3, 34.9, 34.9, 34.9, 33.9, 33.8, 33.7, 33.7, 29.7, 29,7, 28.2, 27.5,
27.2, 27.1, 19.5, 19.3, 17.8, 17.2, 14,6, 14.6, 14.4, 12.2, 12.1; IR (neat)
3288, 3052, 2956, 2919, 2868, 1625, 1535, 1489, 1457, 1443, 1413,
1378, 1294, 1081, 1033, 988, 922, 700; MS EI-MS m/z 626 (M+);
high-resolution EI-MS m/z 626.3906 (M+, calcd for C40H54N2O2S
626.3900).
(R)-3-((3S,5R)-6-((tert-Butyldiphenylsilyl)oxy)-3,5-dimethyl-
hexanoyl)-4-phenyloxazolidin-2-one (33). To a solution of
CuBr·Me2S complex (1.12 g, 5.45 mmol) in THF (30 mL) was
added dropwise MeMgBr (0.96 M in THF, 9.54 mL, 9.16 mmol) at
−78 °C under Ar atmosphere. After 10 min, a solution of α,β-unsaturated
imide 32 (1.15 g, 2.18 mmol) in THF (30 mL) was added to the mixture.
The mixture was stirred for 30 min, warmed to −40 °C, stirred for 2 h,
quenched with saturated NaHCO3, extracted with AcOEt (×3), washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (AcOEt/hexane =
20:80) to give imide 33 (1.16 mg, 2.13 mmol, 98%) as a colorless oil:
[α]23D +19.4 (c 1.52, CHCl3); 1H NMR (CDCl3) δ 0.82 (3H, d, 6.6 Hz),
0.91 (3H, d, 6.6 Hz), 1.04 (9H, s), 1.31−1.35 (2H, m), 1.70−1.71
(1H, m), 2.00−2.08 (1H, m), 2.77−2.81 (2H, m), 3.34 (1H, dd, J = 6.8,
10.0 Hz), 3.49 (1H, dd, J = 5.4, 10.0 Hz), 4.24 (1H, dd, J = 3.9, 9.0 Hz),
4.65 (1H, t, J = 8.8 Hz), 5.39 (1H, dd, J = 3.9, 8.8 Hz), 7.29−7.42 (11H,
m), 7.62−7.66 (4H, m); 13C NMR (CDCl3) δ 172.1, 153.5, 139.1, 135.5,
133.9, 129.4, 129.0, 128.5, 127.5, 125.8, 69.8, 68.8, 57.6, 42.4, 40.9, 33.2,
27.4, 26.9, 20.4, 19.4, 17.7; IR (neat) 3064, 2950, 2922, 2850, 1780, 1704,
1456, 1425, 1382, 1322, 1195, 1109, 1003, 823, 703; EI-MS m/z 544
(M+ + H); high-resolution ESI-MS m/z 544.2863 (M+ + H, calcd for
C33H42NO4Si 544.2883).
(3S,5R)-6-((tert-Butyldiphenylsilyl)oxy)-3,5-dimethylhexan-1-ol
(34). To a solution of imide 33 (964 mg, 1.78 mmol) in THF (18
mL) were added MeOH (162 μL, 3.56 mmol) and LiBH4 (155 mg,
7.12 mmol) at room temperature under Ar atmosphere. The mixture
was stirred for 30 min, quenched with saturated NaHCO3, extracted
with AcOEt (×3), washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (AcOEt/hexane = 20:80) to give alcohol
34 (487 mg, 1.26 mmol, 71%) as a colorless oil: [α]23D +5.95 (c 1.60,
(R)-N,2-Dimethyl-N-((3S,5S,6S)-3,5,6-trimethyl-7-((R)-4-vinyl-
4,5-dihydrothiazol-2-yl)heptyl)butanamide (3). To a solution of
amide 31 (49.2 mg, 0.0785 mmol) in CH2Cl2 (1.5 mL) was added
TiCl4 (25.3 μL, 0.230 mmol) at room temperature under Ar atmo-
sphere. The mixture was stirred for 12 h, quenched with saturated
Rochelle salt, stirred for 1 h, extracted with AcOEt (×3), washed with
1
CHCl3); H NMR (CDCl3) δ 0.82 (3H, d, J = 6.6 Hz), 0.93 (3H, d,
364
dx.doi.org/10.1021/jo201951s | J. Org. Chem. 2012, 77, 357−370