Stereocontrolled total synthesis of fucoxanthin and its polyene chain-modified derivative

Article abstract of DOI:10.1021/ol203344c

Fucoxanthin exhibits high energy transfer efficiencies to Chlorophyll a (Chl a) in photosynthesis in the sea. In order to reveal how each characteristic functional group, such as the length of the polyene chain, allene, and conjugated carbonyl groups, of

Full text of DOI:10.1021/ol203344c

ORGANIC
LETTERS
2012
Vol. 14, No. 3
808–811
Stereocontrolled Total Synthesis
of Fucoxanthin and Its Polyene
Chain-Modified Derivative
Takayuki Kajikawa,† Satoshi Okumura,† Takashi Iwashita,‡ Daisuke Kosumi,§
Hideki Hashimoto,§ and Shigeo Katsumura*,†
Department of Chemistry, School of Science and Tchnology, Kwansei Gakuin
University, Gakuen, Sanda, Hyogo 669-1337, Japan, Suntory Institute For Bioorganic
Research, Wakayamadai, Shimamoto, Mishimagun, Osaka 618-8503, Japan, and
Department of Physics and CREST/JST, Graduate School of Science, Osaka City
University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
katsumura@kwansei.ac.jp
Received December 15, 2011
ABSTRACT
Fucoxanthin exhibits high energy transfer efficiencies to Chlorophyll a (Chl a) in photosynthesis in the sea. In order to reveal how each
characteristic functional group, such as the length of the polyene chain, allene, and conjugated carbonyl groups, of this marine natural product are
responsible for its remarkably efficient ability, the total synthesis of fucoxanthin by controlling the stereochemistry was achieved. The method
established for fucoxanthin synthesis was successfully applied to the synthesis of the C42 longer chain analogue.
The allenic carotenoids possessing a conjugated carbo-
nyl group, such as peridinin (1) and fucoxanthin (2), have
been paid much attention as the main light-harvesting
pigments in photosynthesis in the sea, because they exhibit
high energy transfer efficiencies to Chlorophyll a (Chl a),
reported as >95% in peridinin and >80% in fucoxanthin,
and inthe complexes constructedbythese carotenoids with
chlorophylls and a protein, the so-called PCP and FCP.1,2
These energy transfer efficiencies are thought to be related
tothe intricate structures of these attractive carotenoids. In
order to examine the relationship between their unique
structures and excellent energy transfer ability, our atten-
tion first focused on peridinin. We achieved the highly
efficient stereocontrolled synthesis of peridinin and then
successfully carried out the syntheses of a series of allene-
modified,3 ylidenebutenolide-modified,4 and π-electron
chain length-modified5 derivatives of peridinin. The mea-
surements of the ultrafast time-resolved optical absorption
and the Stark spectroscopy performed on these peridinin-
modified derivatives have clearly revealed that an intra-
molecular charge transfer (ICT) state behaves indepen-
dently from the S1 state, and furthermore, the striking
observation in the data is that the lifetime of the ICT state
converges to a value of 10 ( 1 ps in methanol for all
the peridinin analogues regardless of the extent of the
(3) Kajikawa, T.; Aoki, K.; Singh, R. S.; Iwashita, T.; Kusumoto, T.;
Frank, H. A.; Hashimoto, H.; Katsumura, S. Org. Biomol. Chem. 2009,
7, 3723.
(4) Kajikawa, T.; Aoki, K.; Iwashita, T.; Niedzwiedzki, D. M.;
Frank, H. A.; Katsumura, S. Org. Biomol. Chem. 2010, 8, 2513.
(5) Kajikawa, T.; Hasegawa, S.; Iwashita, T.; Kusumoto, T.; Hashimoto,
H.; Niedzwiedzki, D. M.; Frank, H. A.; Katsumura, S. Org. Lett. 2009,
11, 5006.
(6) (a) Chatterjee, N.; Niedzwiedzki, D. M.; Kajikawa, T.; Hasegawa,
S.; Katsumura, S.; Frank, H. A. Chem. Phys. Lett. 2008, 463, 219. (b)
Niedzwiedzki, D. M.; Chatterjee, N.; Enriquez, M. M.; Kajikawa, T.;
Hasegawa, S.; Katsumura, S.; Frank, H. A. J. Phys. Chem. B 2009, 113,
13604.
† Kwansei Gakuin University.
‡ Suntory Institute For Bioorganic Research.
§ Osaka City University.
(1) (a) Song, P. S.; Koba, P.; Prezelin, B. B.; Haxo, F. T. Biochemistry
1976, 15, 4422. (b) Koba, P.; Song, P. S. Biochim. Biophys. Acta 1977,
495, 220. (c) Bautista, J. A.; Hiller, R. G.; Sharples, F. P.; Gosztola, D.;
Wasielewski, M. R.; Frank, H. A. J. Phys. Chem. A 1999, 103, 2267.
(2) Papagiannakis, E.; van Stokkum, I. H. M.; Fey, H.; Buchel, C.;
van Grondelle, R. Photosynth. Res. 2005, 86, 241.
r
10.1021/ol203344c
Published on Web 01/18/2012
2012 American Chemical Society

π-electron conjugation.6 This unique and noticeable ob-
servation can be regarded as an inherent characteristic of
the ICT state. Moreover, the allene and unique C37 carbon
skeleton of peridinin (1) contribute to the generation of a
large dipole moment in the excited state of the molecule.7
These unexpected findings are the first in particular in the
field ofmolecularspectroscopy. Therefore, the nextstage is
to verify the generality and specificity of the remarkable
results obtained in peridinin.
For the efficient synthesis of polyfunctional carotenoids,
the stereocontrolled construction of the terminal oxidized
cyclohexane moiety is very important along with the poly-
olefin chain construction (Figure 1). In the case of the
peridinin synthesis reported by four groups,8 all of them
applicable for the syntheses of various kinds of fuco-
xanthin modified derivatives. We now report the stereo-
controlled total syntheses of fucoxanthin and the longer
chain C42 derivative 3 based on the successful stereocon-
trolled construction of the terminal cyclohexane moiety.
In our retrosynthetic analysis (Figure 2), the labile β,γ-
epoxyketo moiety of fucoxanthin (2) would be formed
in the final step. We bisected an allenic segment and a hydroxy
sulfone segment to form a library of each half-segment in
order to synthesize the various designed fucoxanthin deriva-
tives. The allenic segment 4 would be synthesized from the
optically homogeneous epoxyaldehyde derivative 6,12 which
had been prepared from (À)-actinol 7.9 Therefore, the subject
is how to synthesize the hydroxyl sulfone segment 5 under
satisfactorily stereocontrolled conditions, in particular, the
cyclohexane moiety possessing the hydroxyl and epoxy func-
tions. We planned to construct 5 introducing the C8 oxygen
function from the β,γ-unsaturated aldehyde 8, which would
be prepared from 3-epi actinol 913 possessing an unnatural
stereochemistry (carotenoid numbering). We thoroughly in-
vestigated the satisfactorily stereocontrolled introduction of
the cis-epoxide to the C3-R-homoallylic alcohol by utilizing
the Sharpless epoxidation, then followed by inversion of the
resulting unnatural stereochemistry at the C3 hydroxyl group
to the corrected one by the Mitsunobu reaction.
Figure 1. Structure of target molecules.
used the Sharpless asymmetric epoxidation of the corre-
sponding allyl alcohol as a key step for the construction of
the oxidized cyclohexane moiety.9 However, for the stereo-
controlled synthesis of fucoxanthin, the method estab-
lished in the synthesis of peridinin cannot be applied,
because this carotenoid possesses a β,γ-epoxyketo moiety,
which is known to be extremely labile to alkali.10 Although
the synthesis of fucoxanthin was only reported by Ito’s
group, the stereochemical control of both the epoxidation
and polyene chain formation were not achieved due to this
labile moiety.11 Therefore, the second synthesis of fuco-
xanthin must be a stereocontrolled one and should be
Figure 2. Retrosynthesis.
First, the synthesis of the hydroxyl sulfone segment 5 is
described (Scheme 1). The β,γ-unsaturated aldehyde 8 was
synthesized by the known method.11,14 To extend the
carbon chain of 8 accompanied by introducing the C8
hydroxyl group, the vinyl anion preparedfrom vinyl iodide
10 and tert-butyllithium was reacted with the aldehyde 8 to
produce the desired alcohol in high yield. Acetylation of
the resulting alcohol and then chemoselective removal of
the TES group led to the R-homoallylic alcohol 11. Next,
(7) Kusumoto, T.; Horibe, T.; Kajikawa, T.; Hasegawa, S.; Iwashita, T.;
Cogdell, R. J.; Birge, R. R.; Frank, H. A.; Katsumura, S.; Hashimoto, H.
Chem. Phys. 2010, 373, 71.
(8) (a) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S.
€
Angew. Chem., Int. Ed. 2002, 41, 1023. (b) Olpp, T.; Bruckner, R. Angew.
Chem., Int. Ed. 2006, 45, 4023. (c) Vaz, B.; Dominguez, M.; Alvarez, R.; de
Lera, A. R. Chem.;Eur. J. 2007, 13, 1273. (d) Woerly, E. M.; Cherney,
A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941.
(9) Kuba, M.; Furuichi, N.; Katsumura, S. Chem. Lett. 2002, 1248.
(10) (a) Bonnett, R.; Mallams, A. K.; Spark, A. A.; Tee, J. L.;
Weedon, B. C. L. J. Chem. Soc. C 1969, 429. (b) Bernhard, K.; Moss,
G. P.; Toth, Gy.; Weedon, B. C. L. Tetrahedron Lett. 1974, 3899. (c)
Bernhard, K.; Moss, G. P.; Toth, Gy.; Weedon, B. C. L. Tetrahedron
Lett. 1976, 115. (d) Liaaen-Jensen, S. Pure Appl. Chem. 1991, 63, 1. (e)
Haugan, J. A.; Englert, G.; Gliz, E.; Liaaen-Jensen, S. Acta Chem.
Scand. 1992, 46, 389.
(12) Murakami, Y.; Nakano, M.; Shimofusa, T.; Furuichi, N.;
Katsumura, S. Org. Biomol. Chem. 2005, 3, 1372.
(13) Leuenberger, H. G. W.; Boguth, W.; Widmer, E.; Zell, R. Helv.
Chim. Acta 1976, 59, 1832.
(14) (a) Pauling, H.; Andrews, D. A.; Hindley, N. C. Helv. Chem.
Acta 1976, 59, 1233. (b) Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc.
Perkin Trans. 1 1998, 2569. (c) Tode, C.; Yamano, Y.; Ito, M. J. Chem.
Soc., Perkin Trans. 1 2001, 3338.
(11) Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc., Perkin Trans. 1
1995, 1895.
Org. Lett., Vol. 14, No. 3, 2012
809

Scheme 1. Synthesis of Hydroxy Sulfone 5
we surveyed the diastereoselective epoxidation of the tetra-
substitutedolefin inthe cyclohexene ring with the aid of the
C3 homoallylic hydroxyl group.15 For the combination of
the rather general Mo and V catalysts with TBHP, an
unknown compound was produced along with a small
amount of the desired product. After a thorough investiga-
tion of the substrates and conditions, we found that the
reaction of organoaluminum peroxide prepared in situ
from TBHP and (t-BuO)3Al16 to the acetate 11 resulted
in the complete stereocontrol and gave the desired com-
pound in 74% yield as a single diastereomer. The inversion
of the resulting secondary hydroxyl group under the
Mitsunobu reaction conditions using p-nitrobenzoic acid
afforded the diester 12 in 70% yield in a completely
stereocontrolled manner. This satisfactorily stereocon-
trolled introduction of the oxygen function to the terminal
cyclohexene ring of carotenoids is the second example in
addition to the natural peridinin synthesis.8a The obtained
diester 12 was followed by the sequence of TBAF treat-
ment, MnO2 oxidation, and the HornerÀEmmons reac-
tion to produce 13 (13E/13Z= 15/1). Selective hydrolysis
ofthe p-nitrobenzoylgroup and then TES protection ofthe
resulting alcohol afforded the triene ester 14 in excellent
yield. The ester group of 14 was transformed into the
sulfide 15 by DIBAL reduction followed by the Mitsunobu
reaction. The successful oxidation of the sulfide 15 to the
sulfone 16 to employ the modified-Julia olefination for
coupling with the allenic segment proceeded in the limited
substrate under restricted conditions. After an extensive
investigation, we found that oxidation was successful only
to the C8 carbonyl derivative; meanwhile the correspond-
ing hydroxyl derivatives such as acetate and silyl ether gave
no desired product. The reaction smoothly proceeded and
afforded 16 in 65% yield. Reprotection of the C3 hydroxyl
group with TES followed by the Luche reduction afforded
the desired hydroxyl sulfone 5. The corresponding Wittig
salt and HornerÀEmmons reagents could not be prepared.
The next step of the fucoxanthin synthesis was the
coupling between segment 4 prepared from aldehyde 6
through 1712 and segment 5 (Scheme 2). The crucial reac-
tion conditions of the modified Julia olefination were
explored in detail, and the appropriate reaction conditions
were found. At 0 °C, 4 equiv of NaHMDS was added to a
mixture of the aldehyde 4 and sulfone 5 in THF. The
reaction immediately proceeded in the dark to produce the
desired couplingproduct 18in56% amount asa mixture of
diastereomers. On the other hand, other bases (LHMDS,
KHMDS), solvents (DMF), and temperature (À78 °C)
did not give good results. On the basis of the previous
experiments,3À5,17 it is anticipated that the modified Julia
olefination of 4 and 5 mainly produced the Z-isomer at the
connected double bond, although we could not estimate
the ratio of isomers for compound 18 because of the mix-
ture with the C8-epimer on HPLC analysis. We then tried
to estimate the ratio at the next step. For the coupling
product 18, oxidation of the secondary hydroxyl group
Scheme 2. Synthesis of C40 Fucoxanthin (2)
and removal of the TES group under mild acidic condi-
tions produced the crude fucoxanthin. After DessÀMartin
oxidation, we observed that the initially generated major
peak is 45% (peak 1) based on HPLC as shown in Figure
3A.18 Another oxidation (MnO2 and TPAP) did not give
the expected results. After deprotection of the TES group
(15) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136. (b) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.;
Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254.
(16) Takai, K.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1983,
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€
(17) (a) Bruckner, R.; Song, A. Synlett 2005, 2, 289. (b) Vaz, B.;
Alvarez, R.; Souto, J. A.; de Lera, A. R. Synlett 2005, 2, 294.
810
Org. Lett., Vol. 14, No. 3, 2012

with PPTS, the isomerization to the desired all-trans 2 was
then attempted in benzene at room temperature under
fluorescent light in an argon atmosphere. After 3 days, the
major peak 1 grew to 76% as shown in Figure 3C. We then
isolated this peak and confirmed the structure to be the all-
Scheme 3. Synthesis of C42 Fucoxanthin Derivative 3
1
trans 2. The H and 13C NMR spectra of the synthesized
fucoxanthin were directly compared to those of the natural
one, which were completely identical.10a,10e We thus achieved
the stereocontrolled total synthesis of fucoxanthin.
In summary, we achieved the stereocontrolled total syn-
thesis of fucoxanthin (2), which possesses an allene and a
labile β,γ-epoxyketo moiety, by utilizing the stereocon-
trolled Sharpless epoxidation of a homoallyllic alcohol as
the key step. This synthesis includes a second example to
have satisfactorily controlled the stereochemistry at the
terminal cyclohexane moiety of polyfunctional carot-
enoids that is essentially important for the highly oxygen-
ated carotenoid synthesis. The ultrafast time-resolved
optical absorption measurements of the synthesized fuco-
xanthin derivative have revealed very interesting informa-
tion on the relationship between the ICT energy level and
the polyene chain length.20 In addition, the syntheses of
allene and the β,γ-epoxyketo moiety modified derivatives
are currently in progress in our laboratory.
Figure 3. HPLC analysis of fucoxanthin (2).
Our next objective was the synthesis of the C42 fuco-
xanthin derivative 3 (Scheme 3). If the C42 derivative
having a polyene chain longer than the natural product
would stably exist, the expected modified Julia olefination
between the sulfone 5 and aldehyde 20 would yield the
desired coupling product according to the same synthetic
strategy used for the fucoxanthin synthesis. The C22
allenic tetraenal 20 was prepared by the MnO2 oxidation
of 17 followed by the HornerÀEmmons reaction and then
DIBAL reduction without any isomerization of the double
bond. Oxidation and acetylation of the resulting triol
afforded the unstable allenic tetraenal segment 20 accom-
panied by a slight isomerization (13E/13Z = 6/ 1) in good
yield. The modified Julia olefination between 5 and 20
fortunately proceeded under the same conditions as that of
the fucoxanthin synthesis at 0 °C to produce the expected
coupling compound 21 in 45% amount as a mixture of
stereoisomers. The oxidation of the C8 secondary hydroxyl
group, however, was problematic. Under the DessÀMartin
oxidation condition, the product gradually decomposed.
Another oxidation (TPAP, Swern, SO3-pyr, and Pfitzner-
Moffatt oxidation) did not give the expected results. How-
ever, we obtained the desired product by the successful IBX
oxidation in 38% yield along with the deprotected C42-
fucoxanthin derivative 3 in 31% yield. Removal of the TES
group with PPTS achieved the synthesis of the C42 derivative
3. It was estimated to be 62% based on the HPLC analysis
after the isomerization under the same conditions as those of
the fucoxanthin synthesis.19 We then isolated the major peak
and confirmed the structure by NMR (750 MHz).
Acknowledgment. We thank Dr. Thomas Netscher of
DSM Nutritional Products, Ltd., for the donation of (À)-
actinol. This work was supported by a Grant-in-Aid for
Scientific Research (C) 22550160 from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan. This work was also supported by a Matching Fund
Subsidy for a Private University. T.K. is also grateful for
receiving a Grant-in-Aid for JSPS Fellows.
Supporting Information Available. Experimental de-
tails and characterization data of 2À5, 8, 11À16, and 20.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) The C35-fucoxanthin (fx) derivative 22 and C37-fx 23 were also
synthesized by the similar synthetic method. Ultrafast time-resolved
optical absorption measurements were performed on C42-fx 3, C40-fx
(2), C37-fx 23, and C35-fx 22, which possess 5À8 conjugated olefins. The
obtained results showed that the S1 lifetimes for fucoxanthin and its
derivatives were similar to that of peridinin. Although the shorter
polyene chain derivatives had the longer lifetime in hexane, the S1
lifetime in methanol converged to a value of 15À22 ps. These results
strongly support the unique characteristics of the ICT state that we have
observed in peridinin. The detailed results will be reported in another
specific journal.
(18) Peak 2 consists of two peaks; we presumed them to be the 15Z-
isomer and 13Z-isomer based on a peak at around a 310 nm absorption
of carotenoids, the cis-peak, in the UV spectra. For the cis-peak, see: Hu,
Y.; Hashimoto, H.; Moine, G.; Hengartner, U.; Koyama, Y. J. Chem.
Soc., Perkin Trans. 2 1997, 2699.
(19) The data of the HPLC analysis of the fucoxanthin derivatives are
provided in the Supporting Information.
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