Tetrahedron Letters
Stereoselective synthesis of zooxanthellactone
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Martin Gjerde Jakobsen, Anders Vik, Trond Vidar Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, POB 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 marine polyunsaturated natural product zooxanthellactone was synthesized in six steps and in 11%
overall yield from eicosapentaenoic acid. The key synthetic steps were a Sonogashira cross-coupling
reaction and a stereoselective semi-reduction. These efforts, together with NMR and optical rotation data,
confirmed the reported structure of zooxanthellactone.
Received 27 January 2014
Revised 27 February 2014
Accepted 18 March 2014
Available online 27 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Oxylipin
Zooxanthellactone
Stereoselective synthesis
Polyunsaturated fatty acid
Marine natural products
Polyunsaturated fatty acids (PUFAs), and in particular their oxy-
genated derivatives, display a wide variety of interesting biological
activities.1 Several marine natural products derived from eicosa-
pentaenoic (EPA, 1) and docosahexaenoic acid (DHA, 2) have been
reported (Fig. 1).2,3 One such example is zooxanthellactone (3),
that was reported isolated from several strains of microalgae of
the genus Symbiodinium.4 The biosynthesis mostly likely involves
DHA (2) as the substrate for a lipoxygenase-catalyzed formation
of the 4S-hydroxyl functional group, via the corresponding hydro-
(S)-Vinylic iodide 9 was then prepared in a three-step sequence
as depicted in Scheme 1. The acid chloride 7, obtained from 6, was
directly converted via a Rosenmund reduction into aldehyde 8.12
This unstable aldehyde was immediately submitted to a Takai olef-
ination reaction.13 After purification by column chromatography,
the vinylic iodide 9 was obtained in 20% yield in three steps. In
addition, the Z-isomer of 9 was also isolated in 5% yield.
The Sonogashira cross-coupling reaction14 between 5 and io-
dide 9 was conducted at ambient temperature using Pd(PPh3)2Cl2,
CuI, and Et3N in THF. This afforded a 71% yield of alkyne 10. The
final step of the synthesis of zooxanthellactone (3) was the Z-selec-
tive semi-reduction of the internal triple bond in 10. The first
experiments were conducted with Lindlar’s catalyst.15 In all our at-
tempts, no conversion of alkyne 10 was observed. A modification of
the Lindlar protocol, adding pyridine and 1-octene, was also unsuc-
peroxide, followed by the formation of the c-lactone in 3. This nat-
ural compound exhibits mild cytotoxic activity toward several
human cancer cell lines.4
Two groups have reported the synthesis of racemic 3.5 In con-
nection with the preparation of polyunsaturated fatty acids6 and
their derivatives,7 all-Z skipped PUFAs such as EPA (1) and DHA
(2), have been used as starting materials. Hence, we decided on a
synthetic strategy where alkyne 5 was to be prepared from EPA
(1). The vinylic halide 9 should be accessible from commercially
available acid 6. A Sonogashira reaction between these two frag-
ments, followed by a Z-stereoselective reduction of the triple bond,
would yield the natural product 3 (Fig. 1 and Scheme 1).
The alkyne 5 was prepared in 56% yield from the aldehyde 4 as
outlined in Scheme 1 following a literature protocol.8 The Ohira–
Bestmann9 and the Colvin reactions10 were also attempted for
the conversion of aldehyde 4 into alkyne 5, but the Corey–Fuchs
reaction11 provided the best result producing alkyne 5 (56% yield
from aldehyde 4).
cessful.16 Next, an effort to use pure 10% Pd/CaCO3 was made.17 1
H
NMR analysis of the crude reaction product showed a significant
amount of over-reduced products. When 10% of Pd/CaCO3 in
EtOAc/pyridine/1-octene (10:1:1) was tried, only a minor amount
of the desired natural product 3 was isolated. In addition, experi-
ments with the Zn(Cu/Ag) protocol reported by Boland et al.18 were
unsuccessful. Finally, Pd/BaSO419 with pyridine as the solvent gave
the desired natural product 3, albeit in 29% yield due to problems
with over-reduction of the product (Scheme 1).20
The MS and NMR data of 3 were in agreement with the litera-
ture.4 However, the specific optical rotation value was lower
25
([
a
]
+40.3 (c 0.30, CH3Cl)) than that reported by Ojika and co-
D
25
workers ([
a]
+64.6, (c 0.24, CH3Cl)). HPLC analysis of the final
D
product with a chiral stationary phase column revealed the pres-
ence of 12% of impurity (see Supporting information). Synthesis
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.