Concise syntheses of three ω-3 polyunsaturated fatty acids

Article abstract of DOI:10.1016/j.tetlet.2012.08.009

The synthesis of the three ω-3 polyunsaturated fatty acids, eicosatetraenoic acid (3), docosapentaenoic acid (4), and stearidonic acid (5) has been achieved using eicosapentaenoic acid or docosahexaenoic acid as the starting materials.

Full text of DOI:10.1016/j.tetlet.2012.08.009

Tetrahedron Letters 53 (2012) 5837–5839
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Tetrahedron Letters
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Concise syntheses of three
x-3 polyunsaturated fatty acids
⇑
Martin Gjerde Jakobsen, 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 synthesis of the three x-3 polyunsaturated fatty acids, eicosatetraenoic acid (3), docosapentaenoic
Received 25 June 2012
Revised 24 July 2012
Accepted 2 August 2012
Available online 29 August 2012
acid (4), and stearidonic acid (5) has been achieved using eicosapentaenoic acid or docosahexaenoic acid
as the starting materials.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Polyunsaturated fatty acids
Docosapentaenoic acid
Eicosatetraenoic acid
Stereadonic acid
Stereoselective synthesis
The mechanism of action behind the beneficial health effects of
-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic
rated natural products.15–20 This approach also seemed attractive
for making multi-milligram quantities of 3–5, and these efforts
are reported herein.
x
acid (EPA, 1) and docosahexaenoic acid (DHA, 2), remains a topic of
interest and discussion. These -3 PUFAs exhibit positive effects
x
The synthesis of eicosatetraenoic acid (3) started from DHA (2),
which was converted into epoxy ester 6 according to a slightly
1
2
3,4
against cancer, diabetes, cardiovascular diseases, and rheuma-
toid arthritis. The mechanisms behind these effects are still under
5
21
modified three-step literature procedure. Subsequently, 6 was
2
1
investigation, but it seems likely that endogenous oxygenated
metabolites derived from EPA (1) and DHA (2) play an important
part. Recently, Serhan and co-workers isolated and structurally
elucidated several new classes of hydroxylated metabolites of both
transformed into the C-18 aldehyde 7 using the protocol pub-
2
2
lished by Holmeide and Skattebøl. Treatment of 7 with DBU in
diethyl ether resulted in the formation of ,b-unsaturated alde-
a
2
1
hyde 8, which was reduced immediately to the more stable alde-
6
,7
8,9
1
and 2, such as the resolvins, the protectins, and the mare-
hyde 9. The aldehyde obtained in this manner was subjected to a
1
0
sins. These compounds exhibit a plethora of interesting biological
activities, and have attracted significant interest as lead com-
pounds toward several maladies. So far, only EPA (1) and DHA
2) have been employed as enzymatic substrates for the biosynthe-
Wittig reaction to afford
and Skattebøl have investigated the chemo-selective reduction of
several PUFA derived ,b-unsaturated esters with variable re-
sults. In our hands, reduction of the ,b-unsaturated bond with
a,b-unsaturated ester 10, Scheme 1. Flock
1
1
11
a
1
5
(
a
1
7,18
sis of the aforementioned novel oxygenated metabolites. In this
context, multi-milligram quantities were needed of the following
three PUFAs; eicosatetraenoic acid, (ETA, 3), docosapentaenoic acid
DIBAL-H/CuI in the presence of HMPA,
followed by aqueous
hydrolysis with LiOH, yielded the desired PUFA 3 in 22% yield over
eleven steps.
(
DPA, 4), and stearidonic acid (SDA, 5), Figure 1.
The synthesis of docosapentaenoic acid (4) commenced with
In the metabolic pathway leading to DHA (2), SDA (5) is trans-
LiAlH
primary alcohol which was then oxidized to the C-20 aldehyde 12.
This aldehyde was converted into the ,b-unsaturated ester 13,
according to Scheme 2. For the regioselective reduction of the
a,b-double bond in 13, the DIBAL-H/CuI method afforded the best
yield for this particular compound. Among the methods attempted
for the hydrolysis of 14, aqueous KOH in MeOH gave the highest
yield of acid 4. This concluded our five step synthesis of docosapen-
taenoic acid (4) in 30% overall yield.
4
reduction of the ethyl ester of EPA (11) to its corresponding
formed into DPA (4) via the sequential conversion into ETA (3) and
EPA (1). Moreover, these three PUFAs exhibit interesting biological
a
1
2,13
activities.
All three PUFAs are commercially available, but their
14
costs are prohibitively high. Eicosatetraenoic acid (3) and docosa-
pentaenoic acid (4) are actually dihydroderivatives of EPA (1) and
DHA (2), respectively. We and other research groups have used 1
and 2 as starting materials for the synthesis of several polyunsatu-
The synthesis of stearidonic acid (5) started with the same
chemistry as depicted in Scheme 1, except that EPA (1) was used
as the starting material. The C-15 aldehyde 16 was obtained in four
⇑
Corresponding author. Tel.: +47 22857450; fax: +47 22855947.
E-mail address: t.v.hansen@farmasi.uio.no (T.V. Hansen).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.009

5
838
M. G. Jakobsen et al. / Tetrahedron Letters 53 (2012) 5837–5839
Figure 1.
Scheme 1.
steps and in 35% yield as previously reported.22 Aldehyde 16 was
subjected to a Wittig reaction with (methoxymethyl)triphenyl-
phosphonium chloride and n-butyl-lithium as base which afforded
the C-16 aldehyde 17 in 19% yield after hydrolysis.15 This aldehyde
In conclusion, the three x-3 polyunsaturated fatty acids eicosa-
tetraenoic acid (3), docosapentaenoic acid (4), and stearidonic acid
(5) have been prepared using well established chemistry from
eicosapentaenoic acid (1) and docosahexaenoic acid (2). All spec-
tral data were in accord with the structures and no significant
isomerization of the sensitive skipped Z-olefins was observed.
Our synthesis of 4 compares favorably with that reported in the lit-
was then converted into the a,b-unsaturated ester 18. Again, regio-
selective reduction (CuI/DIBAL-H) and hydrolysis (KOH in aqueous
MeOH) afforded stearidonic acid (5) in 3% overall yield over the
nine steps (Scheme 3). Stearidonic acid (SDA, 5) was also obtained
in 56% yield from aldehyde 9 using Pinnick oxidation23 (Scheme 1).
This protocol afforded the acid 5 in 13% yield over eight steps.
2
4
erature, and the two PUFAs 3 and 5 are now available by simple
operational procedures. Enzymatic studies of the three -3 poly-
unsaturated fatty acids 3–5 will be reported in due time elsewhere.
x
Scheme 2.

M. G. Jakobsen et al. / Tetrahedron Letters 53 (2012) 5837–5839
5839
Scheme 3.
8.
Marcheselli, V. L.; Hong, S.; Lukiw, W. J.; Tian, X. H.; Gronert, K.; Musto, A.;
Hardy, M.; Gimenez, J. M.; Chiang, N.; Serhan, C. N.; Bazan, N. G. J. Biol. Chem.
Acknowledgements
2
003, 278, 43807.
M.G.J. is thankful for a scholarship from The School of Phar-
macy, University of Oslo. The Norwegian Research Council (KOSK
II) is gratefully acknowledged for a scholarship to A.V. We also
would like to thank Pronova Biopharma AS for a generous gift of
the ethyl esters of EPA and DHA.
9. Serhan, C. N.; Gotlinger, K.; Hong, S.; Lu, Y.; Siegelman, J.; Baer, T.; Yang, R.;
Colgan, S. P.; Petasis, N. A. J. Immunol. 1848, 2006, 176.
0. Serhan, C. N.; Yang, R.; Martinod, K.; Kasuga, K.; Pillai, P. S.; Porter, T. F.; Oh, S.
F.; Spite, M. J. Exp. Med. 2009, 206, 15.
1. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922.
12. Kaur, G.; Cameron-Smith, D.; Garg, M.; Sinclair, A. J. Prog. Lipid Res. 2011, 50, 28.
3. Guil-Guerrero, J. L. Eur. J. Lipid Sci. Technol. 2007, 109, 1226.
1
1
1
1
4. 3B Scientific (www.3bsc.com): $750 for 5 mg of eicosatetraenoic acid (3);
Supplementary data
Cayman
(http://www.caymanchem.com):
$1250
for
10 mg
of
docosapentaenoic acid (4) and $1000 for 10 mg of stearidonic acid (5),
respectively.
Supplementary data associated with this article can be found, in
1
5. Flock, S.; Skattebøl, L. J. Chem. Soc., Perkin Trans. 1 2000, 3071.
the
online
version,
at
http://dx.doi.org/10.1016/
16. Holmeide, A. K.; Skattebøl, L.; Sydnes, M. J. Chem. Soc., Perkin Trans. 1 2001,
942.
7. (a) Vik, A.; Hansen, T. V.; Holmeide, A. K.; Skattebøl, L. Tetrahedron Lett. 2010,
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