Â
H. Waldmann and M. Nazare
FULL PAPER
3
3
(12.6 g, 34 mmol) in propan-2-ol (200 mL). The mixture was cooled to 08C,
and NaBH4 (2.3 g, 60 mmol) was added portionwise to the solution under
vigorous stirring. After 3 h, the reaction was quenched by cautious addition
of iced water (150 mL) and was then extracted with diethyl ether (4 Â
150 mL). The combined organic layers were dried over Na2SO4, the
solvents were removed under reduced pressure, and the residue was
purified by chromatography (cyclohexane/ethyl acetate 4:1, Rf 0.24) to
give a bright yellow oil. Yield: 9.1 g (26 mmol), 77%; [a]2D0 6.5 (c 0.3
in CH2Cl2); 1H NMR (CDCl3, 400 MHz): d 7.28 (dd, 3J 15 Hz, 3J
10 Hz, 1H; H-3), 6.51 (dd, 3J 15 Hz, 3J 10 Hz, 1H; H-5), 6.17 (dd,
3J 15 Hz, 3J 10 Hz, 1H; H-4), 6.10 (dd, 3J 15 Hz, 3J 7 Hz, 1H; H-6),
5.90 (dd, 3J 15 Hz, 3J 7 Hz, 1H; H-7), 5.82 (d, 3J 15 Hz, 1H; H-2), 5.67
(m, 2H; H-11, H-10), 4.18 (m, 1H; H-9), 4.13 (d, 3J 5 Hz, 2H; H-12), 3.72
(s, 3H; OMe), 2.42 (m, 1H; H-8), 2.32 (t, 3J 7 Hz, 1H; H-8), 1.52 (brs,
1H; OH), 0.87 (s, 9H; SitBu), 0.02 (s, 6H; SiMe2); 13C NMR (CDCl3,
16 Hz, J 10 Hz, 1H , H-6'), 5.69 (m, 1H; H-10), 5.57 (q, J 8 Hz, 1H;
H-11), 5.50 (m, 1H; H-3'), 4.61 (q, 3J 3 Hz, 1H; OCHO, THP), 4.20 (t,
3J 3 Hz, 1H; H-9), 4.18 (m, 2H; H-7'), 3.98 (m, 1H; H-12), 3.85 (t, J
3
11 Hz, 1H; H-12), 3.49 (m, 1H; OCH, THP), 3.41 (quin, 3J 6 Hz, 1H;
OCH, THP), 3.11 (m, 1H; H-1'), 2.94 (m, 1H; H-1'), 2.42 (m, 1H; H-8),
2.33 (m, 1H; H-2'), 2.31 (t, 3J 7 Hz, 1H; H-8), 1.9 ± 1.5 (m, 6H; THP), 1.01
(d, 3J 7 Hz, 1H; Me-2'), 0.87 (s, 9H; SitBu), 0.02 (s, 6H; SiMe2); 13C NMR
(CDCl3, 125.5 MHz): d 166.1 (quart. C, C(1)), 141.1 (CH, C(3)), 139.7
(CH, C(7)), 137.3 (CH, C(3')), 135.5 (CH, C(5)), 135.1 (CH, C(11)), 132.2
(CH, C(4)), 131.2 (CH, C(5')), 131.1 (CH, C(6')), 130.0 (CH, C(10)), 129.4
(CH, C(6)), 126.3 (CH,C(4')), 122.8 (CH, C(2)), 97.6 (CH, THP), 72.4 (CH,
C(9)), 66.8 (CH2, THP), 63.3 (CH2, C(7')), 62.3 (CH2, C(12)), 45.2 (CH2,
C(1')), 42.0 (CH2, C(8)), 37.2 (CH, C(2')), 30.6 (CH, THP), 25.5 (CH3,
SitBu), 25.4 (CH2, THP), 19.5 (CH2, THP), 18.2 (quart. C, SitBu), 17.5
(CH3, Me-2'), 4.3 (CH3, SiMe), 4.7 (CH3, SiMe); MS (EI, 70 eV): m/z
100.5 MHz): d 167.6 (quart. C, C O, C(1)), 144.9 (CH, C(3)), 140.9 (CH,
(%): 488 (0.5) [M tBu] , 435 (0.4), 417 (0.4), 376 (1), 375 (3), 261 (2), 201
(12), 85 (100), 83 (4); HRMS-EI (70 eV) calcd for C27H42NSiO5: 488.2823,
found: 488.2855
C(7)), 136.0 (CH, C(5)), 134.0 (CH, C(11)), 132.1 (CH, C(4)), 129.0 (CH,
C(10)), 128.3 (CH, C(6)), 119.8 (CH, C(2)), 72.2 (CH, C(9)), 62.9 (CH2,
C(12)), 51.5 (CH3, OMe), 41.9 (CH2, C(8)), 25.8 (CH3, SitBu), 18.2 (quart.
C, SitBu), 4.4 (CH3, SiMe), 4.7 (CH3, SiMe).
N1-[(2R,3E,5E)-7-Hydroxy-2-methyl-3,5-heptadienyl]-(2E,4E,6E,9S,
10E)-9-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-12-hydroxy-2,4,6,10-dodeca-
tetraenamide (39c): PPTS (25 mg, 0.01 mmol) was added to a solution of
THP ether 39b (300 mg, 0.55 mmol) in propan-2-ol (50 mL), and the
reaction mixture was heated to 558C. After completion of the reaction (4 ±
5 h, TLC control), NEt3 (0.25 mL) was added, the solvent was removed
under reduced pressure, and the residue was purified by chromatography
(cyclohexane/ethyl acetate 3:7, Rf 0.45) to afford a brightly yellow oil.
Yield: 184 mg (0.40 mmol), 73%; [a]2D0 29.5 (c 0.9 in CH2Cl2);
1H NMR (CDCl3, 500 MHz): d 7.20 (dd, 3J 15 Hz, 3J 10 Hz, 1H;
Methyl(2E,4E,6E,9S,10E)-9-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-12-
(tetrahydroxy-2H-2-pyranyloxy)-2,4,6,10-dodecatetraenoate (38c): 3,5-Di-
hydro-2H-pyrane (DHP) (2.2 mL, 2.5 mmol) was added to a solution of
allylic alcohol 38b (1.7 g, 4.8 mmol) and PPTS (0.2 g, 0.8 mmol) in CH2Cl2
(100 mL), and the reaction mixture was stirred overnight. Then NEt3
(1 mL) was added, and the solvent was removed under reduced pressure.
The residue was purified by chromatography (cyclohexane/ethyl acetate
9:1, Rf 0.28) to give a yellow oil. Yield: 1.9 g (4.4 mmol), 93%; [a]D20
1.5 (c 0.5 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d 7.28 (dd, 3J
15 Hz, 3J 10 Hz, 1H; H-3), 6.49 (dd, 3J 15 Hz, 3J 10 Hz, 1H; H-5),
3
3
3
3
H-3), 6.47 (dd, J 15 Hz, J 10 Hz, 1H; H-5), 6.25 (dd, J 15 Hz, J
9 Hz, 1H; H-5'), 6.18 (dd, 3J 15 Hz, 3J 9 Hz, 1H; H-4), 6.14 (dd, 3J
15 Hz, 3J 6 Hz, 1H; H-6), 6.10 (d, 3J 15 Hz, 1H; H-6'), 6.04 (dd, 3J
15 Hz, 3J 6 Hz, 1H; H-4'), 5.87 (dd, 3J 15 Hz, 3J 7 Hz, 1H; H-7), 5.80
(d, 3J 15 Hz, 1H; H-2), 5.75 (m, 1H; H-11), 5.68 (dd, 3J 15 Hz, 3J
5 Hz, 1H; H-10), 5.50 (dd, 3J 15 Hz, 3J 4 Hz, 1H; H-3'), 4.18 (q, 3J
6 Hz, 1H; H-9), 4.15 (d, 3J 5 Hz, 2H; H-12), 4.13 (dd, 3J 6 Hz, 3J 2 Hz,
3
6.17 (dd, J 15 Hz, 3J 10 Hz, 1H; H-4), 6.13 (dd, 3J 15 Hz, 3J 7 Hz,
1H; H-6), 5.89 (d, 3J 15 Hz, 3J 7 Hz, 1H; H-7), 5.81 (dd, 3J 15 Hz,
3J 7 Hz, 1H; H-2), 5.67 (m, 2H; H-10, H-11), 4.59 (d, 3J 3 Hz, 1H;
3
OCHO, THP), 4.17 (m, 1H; H-9), 3.98 (m, 1H; H-12), 3.83 (t, J 11 Hz,
1H; H-12), 3.71 (s, 3H; OMe), 3.46 (m, 2H; OCH, THP), 2.43 (m, 1H;
H-8), 2.31 (t, 3J 7 Hz, 1H; H-8), 1.80 (m, 1H; THP), 1.72 (m, 1H; THP),
1.57 (m, 4H; THP), 0.85 (s, 9H; SitBu), 0.02 (s, 6H; SiMe2); 13C NMR
3
2H; H-7'), 3.09 (q, J 6 Hz, 1H; H-1'), 2.94 (m, 1H; H-1'), 2.42 (m, 1H;
3
H-8), 2.33 (m, 1H; H-2'), 2.30 (t, J 7 Hz, 1H; H-8), 1.8 ± 1.5 (brm, 2H;
OH), 1.02 (d, 3J 7 Hz, 3H; Me-2'), 0.87 (s, 9H; SitBu), 0.02 (s, 6H;
SiMe2); 13C NMR (CDCl3, 125.5 MHz): d 166.3 (quart. C, C(1)), 141.0
(CH, C(3)), 139.6 (CH, C(7)), 137.1 (CH, C(3')), 134.9 (CH, C(5)), 134.8
(CH, C(11)), 132.2 (CH, C(4)), 131.2 (CH, C(5')), 129.9 (CH, C(4')), 129.0
(CH, C(6)), 128.4 (CH, C(6')), 127.3 (CH, C(10)), 123.0 (CH, C(2)), 72.3
(CH, C(9)), 63.0 (CH2, C(7')), 62.8 (CH2, C(12)), 44.9 (CH2, C(1')), 42.0
(CH2, C(8)), 37.1 (CH, C(2')), 25.8, (CH3, SitBu), 18.2 (quart. C, SitBu), 17.9
(CH3, Me-2'), 4.4 (CH3, SiMe), 4.8 (CH3, SiMe); MS (EI, 70 eV): m/z
(CDCl3, 100.5 MHz): d 167.5 (quart. C, C O, C(1)), 144.9 (CH, C(3)),
141.0 (CH, C(7)), 136.1 (CH, C(5)), 135.4 (CH, C(11)), 132.0 (CH, C(4)),
129.6 (CH, C(10)), 128.2 (CH, C(6)), 119.8 (CH, C(2)), 97.5 (CH, THP),
72.4 (CH, C(9)), 66.7 (CH2, THP), 62.2 (CH2, C(12)), 51.3 (CH3, OMe),
41.9 (CH2, C(8)), 30.6 (CH2, THP), 25.8 (CH3, SitBu), 25.4 (CH2, THP),
19.5 (CH2, THP), 18.2 (quart. C, SitBu ), 4.4 (CH3, SiMe), 4.7 (CH3,
SiMe).
(2E,4E,6E,9S,10E)-9-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-12-(tetrahy-
droxy-2H-2-pyranyloxy)-2,4,6,10-dodecatetraenic acid (39): LiOH mono-
hydrate (143 mg, 3 mmol) was added to a solution of ester 38c (532 mg,
1.2 mmol) in THF/MeOH/water (1:2:2, 10 mL), and the reaction mixture
was stirred overnight. The pH of the solution was then adjusted to 4 by
addition of 10% NaH2PO4 solution, and the solution was extracted with
CH2Cl2 (3 Â 50 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure, and the residue was filtered with
diethyl ether through a short plug of silica. Yield: 368 g (0.87 mmol), 72%.
The crude acid was directly subjected to the following amide coupling.
(%): 404 (3) [M tBu] , 376 (3), 375 (11), 315 (14), 243 (7), 202 (14), 201
(100), 120 (15), 115 (8), 91 (14), 85 (15), 75 (47), 73 (63), 57 (6); HRMS-EI
(70 eV) calcd for C22H37NO4Si: 404.2257, found: 404.2231.
N1-[(2R,3E,5E)-2-Methyl-7-oxo-3,5-heptadienyl]-(2E,4E,6E,9S,10E)-9-
{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-12-oxo-2,4,6,10-dodecatetraenamide
(40): nPr4RuO4 (10 mg, 0.03 mmol) was added to a suspension of diol 39c
(200 mg, 0.44 mmol) in 4-methylmorpholine N-oxide (150 mg, 1.2 mmol)
freshly activated 3 molecular sieves (60 mg) in CH2Cl2 (5 mL), and the
reaction mixture was stirred at room temperature. After 1 h, the aldehyde
was directly purified by chromatography (cyclohexane/ethyl acetate 1:1,
Rf 0.53) to afford a lucent yellow oil. Yield: 157 mg (0.34 mmol), 78%;
[a]2D0 34.1 (c 0.2 in CH2Cl2); 1H NMR (CDCl3, 400 MHz): d 9.59 (d,
3J 8 Hz, 1H; H-7'), 9.53 (d, 3J 8 Hz, 1H; H-12), 7.28 (dd, 3J 15 Hz,
N1-[(2R,3E,5E)-7-Hydroxy-2-methyl-3,5-heptadienyl]-
(2E,4E,6E,9S,10E)-9-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-12-(tetrahy-
dro-2H-2-pyranyloxy)-2,4,6,10-dodecatetraene amide (39b): BOP-Cl
(446 mg, 1.8 mmol) and iPr2NEt (0.35 mL, 2 mmol) were added to a
solution of acid 39 (500 mg, 1.2 mmol)Ðwhich had been dried by repeated
codistillation with tolueneÐin THF (10 mL), and the reaction mixture was
stirred at room temperature. After 1.5 h, a solution of amine 33 (211 mg,
1.5 mmol) and DMAP (20 mg) in THF (3 mL) was added dropwise, and the
reaction mixture was stirred overnight. Finally, the solvent was removed
under reduced pressure, and the residue was directly purified by
chromatography (cyclohexane/ethyl acetate 1:1, Rf 0.35) to afford a
yellow oil. Yield: 491 mg (0.9 mmol), 75%; [a]2D0 16.3 (c 0.9 in
CH2Cl2); 1H NMR (CDCl3, 500 MHz): d 7.21 (dd, 3J 16 Hz, 3J
10 Hz, 1H; H-3), 6.47 (dd, 3J 16 Hz, 3J 10 Hz, 1H; H-5), 6.21 (dd,
3J 10 Hz, 1H; H-3), 7.06 (dd, J 16 Hz, J 10 Hz, 1H; H-5'), 6.78 (dd,
3
3
3J 15 Hz, 3J 4 Hz, 1H; H-10), 6.46 (dd, 3J 15 Hz, 3J 7 Hz, 1H; H-5),
3
3
6.26 (dd, J 16 Hz, J 10 Hz, 1H; H-3'), 6.23 ± 6.07 (m, 5H; H-11, H-6,
H-4, H-6', H-4'), 5.87 (dd, 3J 15 Hz, 3J 7 Hz, 1H; H-2), 5.80 (d, 3J
15 Hz, 1H; H-2), 5.60 (brs 1H; NH), 4.47 (m, 1H; H-9), 3.42 (q, 3J 6 Hz,
3
1H; H-1'), 3.28 (q, J 6 Hz, 1H; H-1'), 2.55 (m, 1H; H-8), 2.43 (m, 1H;
H-8), 2.31 (m, 1H; H-2'), 1.09 (d, 3J 7 Hz, 3H; Me-2), 0.89 (s, 9H; SitBu),
0.04 (s, 3H; SiMe), 0.02 (s, 3H; SiMe); 13C NMR (CDCl3, 100.5 MHz): d
193.8 (CH, C(7')), 193.4 (CH, C(12)), 166.1 (quart. C, C(1)), 152.0 (CH,
C(5')), 148.6 (CH, C(4')), 141.1 (CH, C(3)), 139.2 (CH, C(7)), 137.5 (CH,
C(3')), 133.9 (CH, C(11)), 132.5 (CH, C(4)), 130.9 (CH, C(5)), 129.0 (CH,
C(10)), 128.7 (CH, C(6)), 123.0 (CH, C(2)), 120.2 (CH, C(6')), 71.2 (CH,
C(9)), 44.5 (CH2, C(1')), 40.9 (CH2, C(8)), 37.9 (CH, C(2')), 25.7 (CH3,
3
3
3
3J 16 Hz, J 9 Hz, 1H; H-5'), 6.17 (dd, J 16 Hz, J 9 Hz, 1H; H-4),
6.12 (d, 3J 15 Hz, 1H; H-6), 6.09 (d, 3J 15 Hz, 1H; H-4'), 5.85 (dd, 3J
3
3
3
15 Hz, J 10 Hz, 1H; H-7), 5.80 (d, J 16 Hz, 1H; H-2), 5.76 (dd, J
3374
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0715-3374 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 15