Synthesis of a polyunsaturated amino ketone isolated from a Guangxi sponge of the genus Haliclona

Article abstract of DOI:10.1016/j.tetlet.2010.12.089

The first synthesis of (all-Z)-1-[(2-phenylethyl)amino]-octadeca-6,9,12,15- tetraen-3-one has been achieved in nine steps and in 13% overall yield using eicosapentaenoic acid as the starting material.

Full text of DOI:10.1016/j.tetlet.2010.12.089

Tetrahedron Letters 52 (2011) 1060–1061
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Tetrahedron Letters
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Synthesis of a polyunsaturated amino ketone isolated from a Guangxi sponge
of the genus Haliclona
⇑
Anders Vik , Trond Vidar Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of (all-Z)-1-[(2-phenylethyl)amino]-octadeca-6,9,12,15-tetraen-3-one has been
achieved in nine steps and in 13% overall yield using eicosapentaenoic acid as the starting material.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 November 2010
Revised 6 December 2010
Accepted 17 December 2010
Available online 24 December 2010
Keywords:
Polyunsaturated amino ketone
Marine natural product
Eicosapentaenoic acid
Grignard reaction
The polyunsaturated amino ketone 1 (Fig. 1) was isolated in
2010, by Xin and Guo, from a marine sponge of the genus Haliclona
off the coast of southern China.1 This unusual natural product has
so far only been evaluated for its cytotoxic effects, but was found to
2a and aldehyde 3 as the key step in the synthesis. We have used
eicosapentaenoic acid (EPA) as a starting material for the synthesis
of other polyunsaturated natural products.2–4 The polyunsaturated
bromide 2a has been obtained from EPA through aldehyde 4 by
Flock and Skattebøl.7 Aldehyde 4 was obtained over four steps
from EPA as reported by Holmeide and Skattebøl.8 Reduction of 4
with NaBH4 and subsequent treatment of the resulting alcohol 5
with triphenylphosphine and bromine in the presence of pyridine
afforded bromide 2a7 as depicted in Scheme 1.
be inactive at 10 lg/ml against three different tumor cell lines. No
total synthesis of 1 has been reported. In connection with our
interest in the synthesis and biological evaluation of polyunsatu-
rated natural products,2–6 herein an efficient first total synthesis
of (all-Z)-1-[(2-phenylethyl)amino]octadeca-6,9,12,15-tetraen-3-
one (1) is reported.
For the synthesis of aldehyde 3, Michael addition of 2-phenyl
ethylamine (6) to ethyl acrylate (7) in methanol afforded second-
ary amine 8 in high yield, essentially as reported for the corre-
According to the retrosynthetic analysis depicted in Figure 1, we
envisioned a Grignard reaction between polyunsaturated bromide
Figure 1.
⇑
Corresponding author. Tel.: +47 22857451; fax: +47 22855947.
E-mail address: anders.vik@farmasi.uio.no (A. Vik).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.089

A. Vik, T. V. Hansen / Tetrahedron Letters 52 (2011) 1060–1061
1061
Scheme 1.
Scheme 2.
sponding methyl ester9 (Scheme 2). An attempt to obtain amine 8
in a reductive amination reaction between 2-phenylacetaldehyde
and b-alanine ethyl ester using sodium cyanoborohydride was less
successful. Boc-protection of 8 followed by reduction of the result-
ing ester with DIBAL-H gave poor results. We, therefore, avoided
the use of DIBAL-H and reduced ester 8 to alcohol 9 with lithium
aluminum hydride and then protected the secondary amine in 9
as its Boc-amide. Oxidation of alcohol 10 using pyridinium chloro-
chromate (PCC) gave poor results, but Swern oxidation provided
aldehyde 3 in a total yield of 51% over the four steps.
tone 1 in 83% yield. The spectral data were in agreement with those
published.1,11
In conclusion, the polyunsaturated amino ketone 1 was ob-
tained in 13% yield over nine steps from EPA. The particular advan-
tage of our method is the conservation of the all-Z-configuration of
the methylene-interrupted double bonds. Biological evaluation of
this polyunsaturated amino ketone is in progress and will be re-
ported elsewhere.
Acknowledgments
The Grignard reagent of bromide 2a reacted with aldehyde 3 to
give alcohol 11 in 41% yield when using one equivalent of the bro-
mide (Scheme 3); using 1.5 equiv of the bromide increased the
yield to 58%. We also tried to use the lithium compound derived
from iodide 2b prepared in 95% yield by Finkelstein reaction of bro-
mide 2a. The metal-halogen exchange on 2b was performed using
two equivalents of t-BuLi in diethyl ether.10 However, significant
isomerization of the double bonds in 11 was observed under these
conditions. Alcohol 11 was oxidized with Dess–Martin periodinane
(DMP) to afford ketone 12 in 78% yield. Finally, removal of the Boc-
group with trifluoroacetic acid (TFA) in dichloromethane followed
by aqueous basic work-up provided the polyunsaturated amino ke-
The Norwegian Research Council (KOSK II) is gratefully
acknowledged for a scholarship to A.V. We thank Pronova Biophar-
ma for a generous gift of the ethyl ester of EPA.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.089.
References and notes
1. Sun, J.-Z.; Yao, L.-G.; Chen, K.-S.; Liu, H.-L.; Xin, G.-R.; Guo, Y.-W. Helv. Chim.
Acta 2010, 93, 1199.
2. Vik, A.; Hansen, T. V.; Holmeide, A. K.; Skattebøl, L. Tetrahedron Lett. 2010, 51,
2852.
3. Anwar, H. F.; Hansen, T. V. Org. Lett. 2009, 11, 587.
4. Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2004, 45, 2809.
5. Hansen, T. V.; Stenstrøm, Y. Tetrahedron: Asymmetry 2001, 12, 1407.
6. Hansen, T. V.; Stenstrøm, Y. Synth. Commun. 2000, 30, 2549.
7. Flock, S.; Lindquist, M.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 436.
8. Holmeide, A. K.; Skattebøl, L. J. Chem. Soc., Perkin Trans. 1 2000, 2271.
9. Fakhraian, H.; Riseh, M. B. P. Org. Prep. Proced. Int. 2005, 37, 579.
10. Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406.
11. Spectroscopic data of 1: 1H NMR (300 MHz, CDCl3) d 7.34–7.26 (m, 2H), 7.21 (m,
3H), 5.47–5.28 (m, 8H), 2.92–2.76 (m, 12H), 2.61 (t, J = 6.4 Hz, 2H), 2.48 (m,
2H), 2.39–2.29 (m, 2H), 2.15–2.03 (m, 2H), 1.60 (br s, 1H, NH), 0.99 (t,
J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 209.68 (q), 139.98 (q), 132.04 (CH),
129.04 (CH), 128.69 (2 Â CH), 128.61 (CH), 128.47 (2 Â CH), 128.33 (CH),
128.26 (CH), 128.06 (CH), 127.87 (CH), 127.05 (CH), 126.17 (CH), 51.39 (CH2),
44.22 (CH2), 43.00 (CH2), 42.77 (CH2), 36.43 (CH2), 25.66 (CH2), 25.61 (CH2),
25.58 (CH2), 21.58 (CH2), 20.60 (CH2), 14.32 (CH3). Rf = 0.32 (CH2Cl2/MeOH,
90:10). IR (CH2Cl2); mmax 3322, 3054, 3014, 2966, 2933, 1711, 1454, 1422, 1265,
896, 746, 704. MS EI m/z (rel.%) 379 (3, M+), 289 (27), 288 (100), 134 (14), 105
(28). HRMS (EI) C26H37NO requires 379.2875, found 379.2865.
Scheme 3.