Synthesis of juniperonic acid

Article abstract of DOI:10.1016/j.tetlet.2010.03.085

Synthesis of juniperonic acid [(all-Z)-5,11,14,17-eicosatetraenoic acid], has been achieved in eight steps and in 19% overall yield starting from eicosapentaenoic acid.

Full text of DOI:10.1016/j.tetlet.2010.03.085

Tetrahedron Letters 51 (2010) 2852–2854
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Synthesis of juniperonic acid
a
b
b
Anders Vik a, , Trond Vidar Hansen , Anne Kristin Holmeide , Lars Skattebøl
*
a School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1185 Blindern, N-0316, Oslo, Norway
b Department of Chemistry, University of Oslo, PO Box 1185 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:
Synthesis of juniperonic acid [(all-Z)-5,11,14,17-eicosatetraenoic acid], has been achieved in eight steps
and in 19% overall yield starting from eicosapentaenoic acid.
Received 20 January 2010
Revised 11 March 2010
Accepted 19 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Polyunsaturated fatty acids
Eicosapentaenoic acid
Wittig
Z-selectivity
Juniperonic acid (1, Fig. 1), (all-Z)-5,11,14,17-eicosatetraenoic
acid, belongs to a group of naturally occurring methylene-inter-
rupted polyunsaturated fatty acids (PUFA). The seeds of the conifer
Juniperus communis has a high content of this acid, hence the name
juniperonic acid.1 It was first found in the leaves and nuts of the
conifer Ginkgo biloba.2,3 It has since been found in other conifers,4,5
flowering plants,6,7 joint pine8 and also in some marine inverte-
brates.9–11 It is present in the seeds of the conifer Biota orientalis4
which is used in traditional Chinese medicines.12 This PUFA exhib-
in 79% overall yield. Oxidative cleavage of 6 with periodic acid in
diethyl ether and subsequent selective double bond migration in
7 by treatment with DBU in diethyl ether furnished the
urated aldehyde 4 in 49% yield over the two steps. The
a
,b-unsat-
a
,b-double
bond of this aldehyde was then selectively reduced with DIBAL/CuI
in THF/HMPA at À20 °C, essentially as reported by Hamberg
et al.,21 to give aldehyde 2 in 74% yield.
A Wittig reaction between aldehyde 2 and the phosphonium
bromide 3 using NaHMDS as base in dry THF at À100 °C provided
juniperonic acid in a Z:E ratio of 93:7 and a moderate yield of 46%
(Table 1, entry 3). This was not entirely satisfactory. Others have
reported that the presence of anionic groups such as carboxyl in
triphenylphosphonium ylides causes a shift in stereoselectivity to-
wards the E-isomer. Although this effect is significantly stronger
for aromatic aldehydes and seems more trivial for aliphatic alde-
hydes,23 we decided to protect the carboxyl group. We were unable
to obtain the methyl ester of 3 as a solid, and its use in a Wittig
reaction with aldehyde 2 under conditions identical to those de-
scribed above was not successful. We therefore prepared the phos-
phonium iodide 9 (Scheme 2). Finkelstein reaction of 8 followed by
reaction with triphenylphosphine in refluxing acetonitrile afforded
9 as a colorless solid after recrystallisation from acetonitrile/ethyl
acetate. The yield was only 42% because a substantial amount of
the acetal was cleaved under these reaction conditions.
The Wittig reaction between aldehyde 2 and triphenylphospho-
nium iodide 9 was performed under identical conditions to those
described above to provide acetal 10 in 87% yield with a Z:E ratio
of 98:2 as determined by GLC analysis. We also investigated if
addition of HMPA would improve the stereoselectivity as HMPA
has provided very good Z-selectivity in similar reactions.24,25
Changing the solvent to THF/HMPA (4:1) gave 10 with excellent
its interesting biological activity13,14 and it is converted into
a-lin-
oleic acid in animal models.15 No synthesis has been reported;
however, the synthesis of a tetradeuterated derivative of the
methyl ester has been described.16
Juniperonic acid is actually a 8,9-dihydroderivative of EPA.
Although there is no way we can selectively hydrogenate that par-
ticular double bond of EPA, this fatty acid seemed a good starting
material. We have used EPA as a starting material for the synthesis
of other natural products.17–19 EPA is readily converted into the
C-15 aldehyde 4 (Fig. 1).20 Selective saturation of the
a,b-double
bond in 4 should then provide aldehyde 221 which can participate
in a Wittig reaction with 4-carboxybutyltriphenylphosphorane (3)
to afford juniperonic acid. We anticipated the stereoselectivity of
the Wittig reaction to be the crucial point in our synthesis.
However, under appropriate conditions, a high Z:E ratio has been
observed with non-stabilized Wittig reagents such as 3.22
Aldehyde 4 was obtained as depicted in Scheme 1.20 Iodolacton-
ization of EPA and subsequent treatment of the resulting iodolac-
tone 5 with potassium carbonate in methanol provided epoxide 6
* 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.2010.03.085

A. Vik et al. / Tetrahedron Letters 51 (2010) 2852–2854
2853
Figure 1. Retrosynthetic analysis of juniperonic acid.
Scheme 1.
Table 1
Wittig reactions with 2
Entry
Phosphonium halide
Solvent
Tempa (°C)
% Yieldb
Z:E ratioc
1
2
3
4
5
6
3
3
3
9
9
9
Toluene/THF (10:1)
THF
THF
THF
THF:HMPA (4:1)
THF
À100
À78
82
47
46
85:15
90:10
93:7
À100
À78
60
94:6
À100
À100
74d
87
99:1d
98:2
NaHMDS was used as the base in all experiments.
a
Temperature during addition of the aldehyde. The cooling bath was removed after complete addition and the mixture was allowed to reach rt and stirred until full
conversion of 2 as judged by TLC.
b
Isolated yield.
c
Determined by GLC analysis of the resulting methyl ester in entries 1–3 and the acetal in entries 4–6.
Contained 10% of an unidentified inseparable by-product containing a conjugated double bond.
d
Scheme 2.
Z-selectivity (Z:E ratio 99:1), but unfortunately some of the product
had isomerized to form an inseparable unidentified by-product
containing a conjugated double bond. We therefore avoided the
use of HMPA.
Acetal 10 was cleaved with 80% aqueous formic acid in 1,4-
dioxane to give aldehyde 11 in 89% yield. The conversion was very
slow at room temperature, but when the mixture was heated at
60 °C, full conversion was achieved in one hour. Oxidation of 11

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A. Vik et al. / Tetrahedron Letters 51 (2010) 2852–2854
18. Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2004, 45, 2809–2811.
19. Anwar, H. F.; Hansen, T. V. Org. Lett. 2009, 11, 587–588.
20. Flock, S.; Lundquist, M.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 436–445.
21. Hamberg, M.; Chechetkin, I. R.; Grechkin, A. N.; Ponce de Leon, I.; Castresana,
C.; Bannenberg, G. Lipids 2006, 41, 499–506.
22. Viala, J.; Santelli, M. J. Org. Chem. 1988, 53, 6121–6123.
23. Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J. Am. Chem. Soc. 1985, 107,
217–226.
using sodium chlorite in aqueous acetonitrile at room temperature
with 2-methyl-2-butene as scavenger afforded juniperonic acid (1)
in 86% yield.
In conclusion, juniperonic acid was obtained from EPA in 19%
overall yield over eight steps.26 The particular advantage of our
method is the conservation of the all-Z-configuration of the meth-
ylene-interrupted double bonds. We believe this strategy com-
petes well with other procedures for synthesizing an assembly of
methylene-interrupted double bonds.
24. Viala, J.; Santelli, M. Synthesis 1988, 395–397.
25. Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron 2000, 56, 8083–8094.
26. Spectroscopic data of selected compounds: Juniperonic acid (1): 1H NMR
(300 MHz, CDCl3) d 11.55 (br s, 1H), 5.48–5.25 (m, 8H), 2.81 (t, J = 5.7 Hz,
4H), 2.36 (t, J = 7.5 Hz, 2H), 2.15–1.98 (m, 8H), 1.70 (p, J = 7.5 Hz, 2H), 1.45–1.30
(m, 4H), 0.98 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 179.86 (CO2H),
132.11 (CH), 131.26 (CH), 130.29 (CH), 128.44 (2 Â CH), 128.38 (CH), 127.96
(CH), 127.26 (CH), 33.51 (CH2), 29.45 (CH2), 29.42 (CH2), 27.28 (2 Â CH2), 26.59
(CH2), 25.78 (CH2), 25.68 (CH2), 24.75 (CH2), 20.71 (CH2), 14.42 (CH3). MS (EI)
m/z: 304 (M+, 7), 121 (34), 108 (61), 95 (57), 79 (100) and 67 (84). HRMS (EI)
C20H32O2 requires 304.2402, found 304.2396. Compound 2:21 1H NMR (CDCl3,
300 MHz): d 9.75 (t, J = 1.8 Hz, 1H), 5.46–5.15 (m, 6H), 2.86–2.74 (m, 4H), 2.42
(td, J = 7.3 and 1.8 Hz, 2H), 2.20–1.92 (m, 4H), 1.65 (dt, J = 15.2 and 7.3 Hz, 2H),
1.52–1.28 (m, 2H) and 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d
202.63 (CHO), 132.11 (CH), 129.54 (CH), 128.54 (CH), 128.48 (CH), 128.13 (CH),
127.15 (CH), 43.88 (CH2), 29.44 (CH2), 27.04 (CH2), 25.74 (CH2), 25.65 (CH2),
21.80 (CH2), 20.67 (CH2), 14.38 (CH3). MS (EI) m/z: 220 (M+, 9), 108 (39), 95
(63), 79 (100) and 67 (79). HRMS (EI) C15H24O requires 220.1827, found
220.1821. Compound 10: 1H NMR (300 MHz, CDCl3) d 5.46–5.20 (m, 8H), 4.85
(t, J = 4.7 Hz, 1H), 4.01–3.76 (m, 4H), 2.88–2.70 (m, 4H), 2.17–1.92 (m, 8H),
1.72–1.56 (m, 2H), 1.55–1.28 (m, 6H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 132.07 (CH), 130.37 (CH), 130.31 (CH), 129.43 (CH), 128.41 (CH),
128.37 (CH), 127.89 (CH), 127.24 (CH), 104.70 (CH), 64.97 (2ÂCH2), 33.59
(CH2), 29.48 (CH2), 29.41 (CH2), 27.26 (2ÂCH2), 27.17 (CH2), 25.76 (CH2), 25.66
(CH2), 24.23 (CH2), 20.68 (CH2), 14.41 (CH3). MS (EI) m/z: 332 (M+, 9), 108 (43),
99 (72), 79 (58) and 73 (100). HRMS (EI) C22H36O2 requires 332.2715, found
332.2709. Compound 11: 1H NMR (300 MHz, CDCl3) d 9.76 (t, J = 1.7 Hz, 1H),
5.57–5.15 (m, 8H), 2.90–2.68 (m, 4H), 2.43 (td, J = 7.3, 1.7 Hz, 2H), 2.16–1.94
(m, 8H), 1.69 (p, J = 7.4 Hz, 2H), 1.44–1.28 (m, 4H), 0.97 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 202.66 (CHO), 132.09 (CH), 131.26 (CH), 130.23 (CH),
128.50 (CH), 128.44 (CH), 128.34 (CH), 127.97 (CH), 127.23 (CH), 43.42 (CH2),
29.40 (CH2), 29.39 (CH2), 27.26 (CH2), 27.24 (CH2), 26.60 (CH2), 25.75 (CH2),
25.66 (CH2), 22.19 (CH2), 20.68 (CH2), 14.40 (CH3). MS (EI) m/z: 288 (M+, 5), 108
(61), 95 (63), 79 (100) and 67 (88). HRMS (EI) C20H32O requires 288.2453,
found 288.2446.
Acknowledgements
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.
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