Asymmetric Synthesis of an Anticancer Agent Isolated from Marine Sources
s, 26 H, CH3(CH2)13CH2], 1.35–1.45 [m, 2 H, CH3(CH2)13CH2],
Acknowledgments
1.44 [s, 9 H, C(CH3)3], 2.09 (br. s, 1 H, OH), 3.55–3.73 (m, 2 H,
CH3CH, CHO), 4.80 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 328 K): δ = 14.0, 14.4, 22.6, 26.0, 28.4, 29.3, 29.6, 29.6,
29.6, 29.7, 31.9, 33.6, 50.7, 74.5, 79.4, 155.8 ppm. C23H47NO3
(385.62): calcd. C 71.64, H 12.28, N 3.63; found C 71.98, H 12.35,
N 3.51. HRMS (ESI+): calcd. for C23H47NO3Na [M + Na]+
408.3448; found 408.3432.
Financial support of the Spanish Ministry of Science and Innova-
tion and European Regional Development Fund (CTQ2008-00187/
BQU) and the Government of Aragón (GA E-71) is acknowledged.
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(2S,3R)-2-Amino-3-octadecanol Hydrochloride (11): A solution of
compound 9 (461 mg, 1.25 mmol) in HCl-saturated EtOAc (3 mL)
was stirred for 1 h at room temperature. After completion of the
reaction, the solvent was removed in vacuo. Filtration of an ethe-
real suspension of the residue afforded compound 11 (352 mg,
91%) as a white solid. M.p. 138–139.5 °C. [α]2D5 = +3.2 (c = 1.00,
CH3OH), IR (KBr):
ν
=
3395, 3300–2000 cm–1. 1H NMR
˜
3
(400 MHz, CD3OD): δ = 0.86 [t, JH,H = 6.4 Hz, 3 H, CH3(CH2)
3
14], 1.17 (d, JH,H = 6.8 Hz, 3 H, CH3CH), 1.19–1.54 [br. s, 26 H,
CH3(CH2)13CH2], 1.36–1.44 [m, 2 H, CH3(CH2)13CH2], 1.44–1.54
(br. s, 1 H, OH), 3.23 (qd, 3JH,H = 6.8, 2.8 Hz, 1 H, CH3CH), 3.62–
3.70 (m, 1 H, CHO), 4.60–4.73 (br. s, 3 H, NH3+) ppm. 13C NMR
(100 MHz, CD3OD): δ = 12.1, 14.5, 23.8, 27.0, 30.5, 30.7, 30.7,
30.8, 30.8, 30.8, 30.8, 33.1, 34.1, 52.7, 71.7 ppm. C18H40ClNO
(321.97): calcd. C 67.15, H 12.52, N 4.35; found C 67.30, H 12.59,
N 4.41. HRMS (ESI+): calcd. for C18H40NO [M – Cl]+ 286.3104;
found 286.3091.
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454; 1995, 72, 6–13.
(2S,3R)-2-Amino-3-octadecanol (ES-285): A solution of compound
11 (70 mg, 0.22 mmol) in CH2Cl2 (30 mL) was treated with 2
aqueous NaOH (5 mL), and the organic layer was dried with anhy-
drous MgSO4, filtered, and concentrated in vacuo to afford ES-285
in nearly quantitative yield as a white solid. M.p. 64.5–66 °C (ref.[3a]
[6] See, for example: a) C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Tetrahedron: Asymmetry 1996, 7, 529–536; b) R. Ba-
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thesis 1997, 747–749; c) R. Badorrey, C. Cativiela, M. D. Díaz-
de-Villegas, J. A. Gálvez, Tetrahedron 1997, 53, 1411–1416; d)
R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Tetrahedron 1999, 55, 14145–14160; e) R. Badorrey,
C. Cativiela, M. D. Díaz-de-Villegas, J. A. Gálvez, Tetrahedron
2002, 58, 341–354; f) R. Badorrey, C. Cativiela, M. D. Díaz-
de-Villegas, R. Díez, J. A. Gálvez, Eur. J. Org. Chem. 2002,
3763–3767; g) R. Badorrey, C. Cativiela, M. D. Díaz-de-Vil-
legas, R. Díez, J. A. Gálvez, Eur. J. Org. Chem. 2003, 2268–
2275; h) R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, R.
Díez, J. A. Gálvez, Tetrahedron Lett. 2004, 45, 719–722; i) R.
Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, R. Díez, J. A.
Gálvez, Synlett 2005, 1734–1735.
[7] See, for example: a) J. Branalt, I. Kvarnstrom, B. Classon, B.
Samuelsson, U. Nillroth, U. H. Danielson, A. Karlen, A.
Hallberg, Tetrahedron Lett. 1997, 38, 3483–3486; b) P.
Castejón, M. Pastó, A. Moyano, M. A. Pericàs, A. Riera, Tet-
rahedron Lett. 1995, 36, 3019–3022; c) P. Castejón, A. Moyano,
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Lett. 1999, 40, 3913–3916.
m.p. 66–67 °C). [α]2D5 = +24.0 (c = 1.00, CHCl3) {ref.[3a] [α]2D6
=
+24.9 (c = 1.00, CHCl3)}. 1H NMR (300 MHz, CD3OD): δ = 0.89
[t, 3JH,H = 6.9 Hz, 3 H, CH3(CH2)14], 1.03 (d, 3JH,H = 6.6 Hz, 3 H,
CH3CH), 1.20–1.58 [br. s, 31 H, CH3(CH2)14, OH, NH2], 2.77 (qd,
3
3JH,H = 6.6, 4.2 Hz, 1 H, CH3CH), 3.40 (ddd, JH,H = 8.4, 4.2,
4.2 Hz, 1 H, CHO) ppm. 13C NMR (75 MHz, CD3OD): δ = 14.5,
17.3, 23.8, 27.4, 30.6, 30.8, 30.9, 30.9, 30.9, 30.9, 30.9, 33.2, 34.0,
52.2, 76.6 ppm. C18H39NO (285.51): calcd. C 75.72, H 13.77, N
4.91; found C 75.77, H 13.69, N 5.02. HRMS (ESI+): calcd. for
C18H40NO [M + H]+ 286.3104; found 286.3112.
Crystal Structure Determination of 5: Data for crystal structure
analysis were collected at 150 K with a Xcalibur diffractometer by
using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å).
The structure was solved by direct methods by using SHELXS
97[18] and refinement was performed by using SHELXL 97[19] by
the full-matrix least-squares technique with anisotropic thermal
factors for heavy atoms. Hydrogen atoms were calculated at ideal-
ized positions, and during refinement they were allowed to ride on
their carrying atom with an isotropic thermal factor fixed to 1.2
times the Ueq value of the carrier atom (1.5 for the methyl protons).
Colorless needles of 5 were obtained by slow evaporation from an
[8] R. Díez, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez,
Eur. J. Org. Chem. 2007, 2114–2120.
[9] O. Mitsunobu, Synlett 1981, 1–28.
ethanol
solution.
Crystallographic
data:
crystal
size
0.29ϫ0.12ϫ0.06 mm3. M = 245.31, crystal system orthorhombic,
space group P212121, unit cell dimensions a = 9.4735(3) Å, b =
16.6944(4) Å, c = 18.0222(6) Å, V = 2850.29(15) Å3, Z = 8, absorp-
tion coefficient µ (Mo-Kα) = 0.085 mm–1, 18486 reflections col-
lected 6428 unique [R(int) = 0.0526] which were used in all calcula-
tions. Final R indices [IϾ2σ(I)] R1 = 0.0417, wR2 = 0.0476, R
indices (all data) R1 = 0.1062, wR2 = 0.0536. CCDC-747000 (for
5) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[10] P. Merino, E. Castillo, S. Franco, F. L. Merchán, T. Tejero,
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7549–7552.
[12] C. Hertweck, P. Sebek, A. Svatos, Synlett 2001, 1965–1967.
ˇ
ˇ
[13]
H. Imogaï, M. Larchevêque, Tetrahedron: Asymmetry 1997, 8,
965–972.
[14]
Compound 6 showed physical and spectroscopic data that fully
agree with those previously described,[4] but the specific rota-
tion value was not coincident; nevertheless, ES-285 obtained
from this compound showed almost identical physical and
spectroscopic data and exhibited, within the limits of experi-
Eur. J. Org. Chem. 2009, 6172–6178
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6177