Stereocontrolled total synthesis of a polyfunctional carotenoid, peridinin

Article abstract of DOI:10.1021/jo048852v

Peridinin, which was isolated from the planktonic algae dinoflagellates causing red tides, is a highly oxidized carotenoid containing an allene and a characteristic (Z)-γ-ylidenebutenolide function in the main conjugated polyene chain in addition to funct

Full text of DOI:10.1021/jo048852v

Stereocontrolled Total Synthesis of a Polyfunctional Carotenoid,
Peridinin
Noriyuki Furuichi, Hirokazu Hara, Takashi Osaki, Masayuki Nakano, Hajime Mori, and
Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University,
Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
katsumura@ksc.kwansei.ac.jp
Received July 6, 2004
Peridinin, which was isolated from the planktonic algae dinoflagellates causing red tides, is a highly
oxidized carotenoid containing an allene and a characteristic (Z)-γ-ylidenebutenolide function in
the main conjugated polyene chain in addition to functionalized cyclohexane rings at both ends of
the molecule. We achieved a stereocontrolled total synthesis of peridinin by featuring the Sharpless
asymmetric epoxidation under precise reaction conditions, Wittig reaction with silylfuranmethylide
followed by photosensitized oxygenation, stereocontrolled Pd-catalyzed one-pot (Z)-γ-ylidenebuteno-
lide synthesis, and modified Julia-Kocienski olefination. This synthesis is the first example of
controlling the stereochemistry of polyfunctional allenic carotenoids.
Introduction
More than 600 carotenoids have been found in nature
as brilliant yellow-to-red pigments and auxiliary light-
harvesting pigments for photosynthesis. Among them,
some carotenoids possess several oxy-functional groups
in addition to the long conjugated polyene system includ-
ing allenic or acetylenic groups.1 During the past 15
years, various efforts have been made to achieve the
syntheses of optically active polyfunctional allenic caro-
2
3
tenoids, for example, peridinin (1), fucoxanthin, neox-
4
5
6
7
anthin, mimulaxanthin, and paracentrone (Figure 1).
However, satisfactory control of the stereochemistry in
the synthesis of these carotenoids has not been achieved,
and this problem has hitherto remained unsolved. We
have therefore developed a new strategy for the efficient
synthesis of polyfunctional carotenoids represented by
*
To whom correspondence should be addressed: phone 81-79-565-
314; fax 81-79-565-9077.
1) (a) Pfander, H. Key to Carotenoids, 2nd ed.; Birkhauser: Basel,
8
(
Switzerland, 1987. (b) Britton, G., Liaaen-Jensen, S., Pfander, H., Eds.
Carotenoids. Part 1A. Isolation and Analysis; Birkhauser: Basel,
Switzerland, 1995. (c) Britton, G., Liaaen-Jensen, S., Pfander, H., Eds.
Carotenoids. Part 1B. Spectroscopy; Birkhauser: Basel, Switzerland,
1
995.
2) (a) Ito, M.; Hirata, Y.; Shibata, A.; Tsukida, K. J. Chem. Soc.,
(
Perkin Trans. 1 1990, 197. (b) Yamano, Y.; Ito, M. J. Chem. Soc., Perkin
Trans. 1 1993, 1599. (c) Ito, M.; Yamano, Y.; Sumiya, S.; Wada, A.
Pure Appl. Chem. 1994, 66, 939.
(
3) (a) Yamano, Y.; Ito, M. Chem. Pharm. Bull. 1994, 42, 410. (b)
Yamano, Y.; Ito, M. J. Chem. Soc., Perkin Trans. 1 1995, 1895.
FIGURE 1. Naturally occurring allenic carotenoids.
(
(
(
4) Baumeler, A.; Eugster, C. H.Helv. Chim. Acta. 1992, 75, 773.
5) Baumeler, A.; Eugster, C. H. Helv. Chim. Acta 1991, 74, 469.
6) (a) Haugan, J. A. Tetrahedron Lett. 1996, 37, 3887. (b) Haugan,
peridinin, which is one of the most architecturally
complex molecules among the carotenoids.
J. A. J. Chem. Soc., Perkin Trans. 1 1997, 2731.
(
7) Recent reviews: (a) Britton, G., Liaaen-Jensen, S., Pfander, H.,
Eds. Carotenoids. Part 2. Synthesis; Birkhauser: Basel, Switzerland,
Peridinin was first isolated from the planktonic algae
1
6
996. (b) Pfander, H.; Traber, B.; Lanz, M. Pure Appl. Chem. 1997,
dinoflagellates causing red tides in 1890;8 later, this
9, 2047. (c) Pfander, H.; Lanz, M.; Traber, B. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: Amster-
dam, 1998; Vol. 20, p 561.
(8) Schutt, F. Ber. Deut. Bot. Ges. 1890, 8, 9.
1
0.1021/jo048852v CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
J. Org. Chem. 2004, 69, 7949-7959
7949

Furuichi et al.
FIGURE 2. Retrosynthetic analysis.
molecule was found in several marine sources as the
main carotenoid responsible for photosynthesis in the
SCHEME 1
9
sea. Its antitumor and anticarcinogenic activities have
10
been reported. The structure and absolute stereochem-
istry of peridinin was determined by Liaaen-Jensen and
co-workers by chemical derivation, the fragmentation
pattern of MS, and CD spectra in 1980.11 Peridinin (1)
is a highly oxidized C37-nor-carotenoid possessing an
allene and a characteristic (Z)-γ-ylidenebutenolide moiety
within the conjugated polyene chain, in addition to
functionalized cyclohexane rings at both ends of the
1
2
molecule. The synthesis of 1 was reported by Ito and
co-workers in 1990, 100 years after its first isolation, and2
the structure of this historic carotenoid was confirmed.
In their synthesis, however, control of the stereochem-
istry at the terminal cyclohexane rings, conjugated
polyene chain, and the (Z)-γ-ylidenebutenolide moiety
was not considered and hence the yield was very poor,
although they found an efficient one-pot procedure for
the construction of the conjugated γ-ylidenebutenolide
moiety.
Herein, we report our investigation toward the total
synthesis of peridinin, featuring stereochemical control
of the six asymmetric carbons and the geometry of the
seven double bonds in the molecule, which leads to the
development of a new synthetic strategy for polyfunc-
tional carotenoids.13
molecule at the central C-15 and C-15′ bond (Figure 1).
The molecule was divided into two advanced segments;
the C17-allenic segment 2 and the C20-ylidenebutenolide
segment 3 (Figure 2). An optically active epoxyaldehyde
derivative 4 was chosen as a common intermediate for
the synthesis of both segments.
Stereocontrolled Preparation of the Common
Intermediate, Epoxyaldehyde 4. In the carotenoid
synthesis, complete stereocontrol of the asymmetric
carbons at the C-3, C-5, and C-6 positions of the terminal
cyclohexane ring had not been achieved (Figure 1); in the
previously reported synthesis, the ratio of the diastere-
Results and Discussion
Retrosynthetic Analysis. The challenges involved in
the stereocontrolled synthesis of peridinin (1) are sum-
marized as follows: (1) the stereocontrolled construction
of the oxygen functionality at the terminal cyclohexane
rings and (2) the stereocontrolled construction of the all-
trans-conjugated polyene chain containing the asym-
metric allenic function and the (Z)-γ-ylidenebutenolide
moiety. Keeping these issues in mind, we bisected this
omers was less than 7:3, and their separation was
difficult.2
-6,14
Thus, the stereocontrol at these asymmetric
carbons has been left unsolved.
We achieved a highly stereoselective synthesis of the
epoxyaldehyde 4 by finding the precise reaction condi-
1
5
(
9) (a) Goodwin, T. W., Ed. The Biochemistry of the Carotenoids, Vol.
, Plants; Chapman & Hall: London, 1980. (b) Young, A., Britton, B.,
Eds. Carotenoids in Photosynthesis; Chapman & Hall: London, 1993.
c) Hofmann, E.; Wrench, P. M.; Sharples, F. P.; Hiller, R. G.; Welte,
W.; Diederichs, K. Science 1996, 272, 1788 and references therein.
10) For example: (a) Nishino, H. Mutat. Res. 1998, 402, 159. (b)
Maoka, T.; Tsushima, M.; Nishino, H. Chem. Pharm. Bull. 2002, 50,
630.
11) (a) Strain H.; Svec, W. A.; Aitzetmuller, K.; Grandolfo, M. C.;
tions of the Sharpless asymmetric epoxidation (AE) on
1
16
allyl alcohol 6, which was easily prepared from known
2
enantiomerically pure vinyltriflate 5 by Pd-catalyzed
(
methoxycarbonylation17 (97%) followed by LAH reduction
(
(
87%) (Scheme 1). The desired R-epoxide 7 was success-
1
fully obtained in 99% yield with 96% ds, even on a 20-g
scale, by use of freshly prepared reagents and solvents
(
Katz, J. J.; Kjosen, H.; Norgard, S.; Liaaen-Jensen, S.; Haxo, F. T.;
Wegfahrt, P.; Rapoport, H. J. Am. Chem. Soc. 1971, 93, 1823. (b)
Strain, H. H.; Svec, W. A.; Wegfahrt, P.; Rapoport, H.; Haxo, F. T.;
Norgard, S.; Kjosen, H.; Liaaen-Jensen, S. Acta Chem. Scand. B 1976,
(14) Baumeler, A.; Brade, W.; Haag, A.; Eugster, C. H. Helv. Chim.
Acta. 1990, 73, 700.
3
0, 109. (c) Johansen, J. E.; Borch, G.; Liaaen-Jensen, S. Phytochem-
istry 1980, 19, 441.
12) Quite recently, two peridinin-related nor-carotenoids were
(15) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5976. (b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(c) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(16) Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc., Perkin Trans. 1
1998, 2596.
(
isolated from the cultured dinoflagellate of the genus Symbiodinium,
a symbiont of the Okinawan soft coral Clavularia viridis; see Suzuki,
M.; Watanabe, K.; Fujiwara, S.; Kurasawa, T.; Wakabayashi, T.;
Tsuzuki, M.; Iguchi, K.; Yamori, T. Chem. Pharm. Bull. 2003, 51, 724.
(17) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Stille, J. K.; Wong, P. K. J. Org. Chem. 1975, 40, 532. (c)
Hidai, M.; Hikita, T.; Wada, Y.; Furikura, Y.; Uchida, Y. Bull. Chem.
Soc. Jpn. 1975, 48, 2075.
(
13) Preliminary communication: Furuichi, N.; Hara, H.; Osaki, T.;
Mori, H.; Katsumura, S. Angew. Chem. 2002, 114, 1065; Angew. Chem.,
Int. Ed. 2002, 41, 1023.
7950 J. Org. Chem., Vol. 69, No. 23, 2004

A Polyfunctional Carotenoid, Peridinin
and exact amounts of the reagents [(-)-D-DET (0.3 equiv),
SCHEME 2
i
Ti(O Pr)
4
(0.2 equiv), and tert-butylhydroperoxide (2.0
18
equiv)] at a constant temperature (-20 °C), while the
epoxidation under the reported conditions gave a 4:1
mixture of R-epoxide 7 and â-epoxide 8. On the other
hand, the Sharpless AE with (+)-L-DET gave the corre-
sponding â-epoxide 8 with high diastereoselection (>95%
ds) under the reported conditions by use of commercially
available reagents and solvents without further purifica-
tions. These observations led us to the conclusion that
the Sharpless AE of 6 with (-)-D-DET would be a
mismatched pair at the C-3 stereochemistry.
The R-epoxide 7 was then transformed into 4 by the
Swern oxidation,19 and sufficient quantities of the com-
mon intermediate, epoxyaldehyde 4, were prepared in
four steps and 84% overall yield from the known 5. This
is the first example achieving satisfactory control of the
stereochemistry between the C-3 hydroxy group and the
C-5,6 epoxide at the terminal cyclohexane ring in caro-
tenoid synthesis.
Stereocontrolled Synthesis of the Allenic Half-
Segment 2. The chiral allenic moiety of carotenoids is
usually attached at the terminal cyclohexane ring in an
exo manner, and at the allylic position of this ring, the
hydroxy groups that possesses syn and anti configura-
tions with respect to the allenic vinyl hydrogen and the
C-3 acetoxy group, respectively, are present. As the only
practical method for the preparation of this characteristic
steps after crystallization. Meanwhile, vinyl iodide 14,
which is a component of the allenic segment 2 (Scheme
3
), was prepared by the sequence of a tin-halogen
2
4
25
exchange of (E)-vinyl stannane 12 leading to 13,
N
allylhydroxyallenic moiety, stereospecific S 2′ reduction
oxidation, and then the Horner-Emmons reaction of the
of a conjugated ethynylepoxide such as 15 with DIBAL
resulting aldehyde.26
has been confirmed.2
-6,20
Therefore, the stereocontrolled
The Sonogashira cross-coupling reaction27 between 11
and 14 in the presence of Pd(PPh ) , cuprous iodide, and
3 4
preparation of 15 was required (Scheme 3). We applied
the Sharpless asymmetric epoxidation under our precise
reaction conditions described above and a Pd-catalyzed
triethylamine in THF afforded the desired coupling
product 15 in 60% yield, with complete stereochemical
control (Scheme 3). Furthermore, use of diisopropylamine
as a solvent improved the yield up to 84%. The conjugated
ethynylepoxide 15 obtained was transformed into allenic
triol 1628 by the stereospecific hydride reduction in 80%
yield. An acetyl group was introduced into the secondary
2
2
sp-sp cross-coupling reaction. The Pd-catalyzed sp-sp
2
-
2
and sp sp cross-coupling is an effective method for the
22
stereocontrolled construction of the conjugated polyene,2
which is the essential problem in carotenoid synthesis. 3
The carbon chain extension from 4 by the Wittig
reaction gave vinyl chloride 9 as a stereoisomeric mix-
ture, which was transformed into an acetylene derivative
2
hydroxyl group of 16 by a sequence of MnO oxidation
and acetylation28 and followed by reduction to produce
the acetate 2 in excellent yield over the three steps. In
this manner, the allenic half-segment 2 was efficiently
prepared in a stereocontrolled way in seven steps and in
30% overall yield from the common intermediate 4.
First-Generation Synthesis of the Ylidenebuteno-
lide Half-Segment 3: Retrosynthetic Analysis. The
most challenging aspect of peridinin synthesis was the
stereocontrolled preparation of a characteristic conju-
1
0 by treatment with a base in tetrahydrofuran (THF)
in a moderate yield (Scheme 2). Interestingly, under
tBuOK/dimethyl sulfoxide (DMSO) conditions, the TBS
protecting group was simultaneously removed to give the
C-3-hydroxyepoxyacetylene 1114 in 53% yield for the two
(
18) Kuba, M.; Furuichi, N.; Katsumura, S. Chem. Lett. 2002, 1248.
19) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (b) Tidwell,
(
T. T. Synthesis 1990, 857. (c) Tidwell, T. T. Org. React. 1991, 39, 297.
(
20) Alternatively, we reported the biomimetic novel synthesis of
29
gated (Z)-γ-ylidenebutenolide function. Lu et al. re-
21
the allenic moiety of carotenoids by photosensitized oxygenation; see
Nakano, M.; Furuichi, N.; Mori, H.; Katsumura, S. Tetrahedron Lett.
001, 42, 7307.
(
2
(24) (a) Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org.
Chem. 1984, 49, 3943. (b) Betzer, J.-F.; Delaloge, F.; Muller, B.;
Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62, 7768.
(25) (a) Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher, M. J.;
Danishefsky, S. J. J. Org. Chem. 1991, 56, 5834. (b) Kunishima, M.;
Hioki, K.; Kono, K.; Kato, A.; Tani, S. J. Org. Chem. 1997, 62, 7542.
(26) For the experimental procedure for preparation of vinyl iodides
13 and 14, see Supporting Information.
(27) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Takahashi, K.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627. For review: (c) Sonogashira, K. In
Comprehensive Organic Synthesis; Pergamon Press: Oxford, U.K.,
1991; Vol. 3, p 521.
21) (a) Mori, H.; Ikoma, K.; Masui, Y.; Isoe, S.; Kitaura, K.;
Katsumura, S. Tetrahedron Lett. 1996, 37, 7771. (b) Mori, H.; Ikoma,
K.; Katsumura, S. Chem. Commun. 1997, 2243. (c) Mori, H.; Ikoma,
K.; Isoe, S.; Kitaura, K.; Katsumura, S. J. Org. Chem. 1998, 63, 8704.
(
d) Mori, H.; Matsuo, T.; Yamashita, K.; Katsumura, S. Tetrahedron
Lett. 1999, 40, 6461. (e) Mori, H.; Katsumura, S. J. Synth. Org. Chem.
Jpn. 2003, 61, 857.
(22) (a) Tsuji, J. Palladium Reagents and Catalysts, Innovations in
Organic Synthesis; John Wiley & Sons: Ltd.: Chichester, U.K., 1995.
b) Diedrich, F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, Germany, 1998.
23) For an application of the Pd-catalyzed coupling reaction to the
(
(
carotenoid synthesis, see (a) Zeng, F.; Negishi, E. Org. Lett. 2001, 3,
(28) Yamano, Y.; Sumiya, S.; Ito, M. J. Chem. Soc., Perkin Trans. 1
1995, 167.
(29) Lu, X.; Huang, X.; Ma, S. Tetrahedron Lett. 1993, 34, 5963.
7
5
19. (b) Vaz, B.; Alvarez, R.; de Lera, A. R. J. Org. Chem. 2002, 67,
040.
J. Org. Chem, Vol. 69, No. 23, 2004 7951

Furuichi et al.
SCHEME 3
SCHEME 4
ported the stereoselective construction of (Z)-γ-ylidene-
butenolide by utilizing the Pd(II)-catalyzed intramolecu-
lar 5-exo cyclization of (Z)-2-en-4-ynoic acid. This method
was further developed for the synthesis of natural
products containing the γ-ylidenebutenolide moiety by
3
0
31
Negishi’s group and that of Rossi. In our preliminary
study toward the total synthesis of peridinin, we inde-
pendently achieved the synthesis of a conjugated buteno-
lide-containing sesquiterpene, freelingyne, by utilizing
the stereocontrolled Pd(II)-catalyzed intramolecular lac-
3
2
tonization.
finally achieved this aim by utilizing the silylfuran
chemistry developed in our laboratory.3
3-35
Effective Construction of the â-Alkoxycarbonyl-
dienal System. The Wittig reaction of the common
3
4
intermediate 4 with our silylfuran-Wittig reagent 17
proceeded very smoothly to give the conjugated furan
derivative 18 as a single stereoisomer (Scheme 4).
Notably, other attempts to extend the carbon chain from
4
by alkyllithium, the Grignard reagent, and the Julia
reagent were unsuccessful.
FIGURE 3. First-generation synthetic strategy for the
ylidenebutenolide segment 3.
The silylfuran moiety of 18 was chemoselectively
1
33a
oxidized with O
2
to regiospecifically afford the corre-
On the basis of previous results, a conjugated ethy-
nylcarboxylic acid A was selected as the synthetic
precursor of ylidenebutenolide 3, which should be ob-
tained from (Z)-â-alkoxycarbonyldienal B via the Sono-
gashira coupling with 13 (Figure 3). The challenge was,
therefore, how to synthesize the dienal B from the
common intermediate 4 in a stereocontrolled manner. We
(
33) (a) Katsumura, S.; Hori, K.; Fujiwara, S.; Isoe, S. Tetrahedron
Lett. 1985, 26, 4625. (b) Katsumura, S.; Fujiwara, S.; Isoe, S.
Tetrahedron Lett. 1985, 26, 5827. (c) Katsumura, S.; Fujiwara, S.; Isoe,
S. Tetrahedron Lett. 1987, 28, 1191. (d) Katsumura, S.; Fujiwara, S.;
Isoe, S. Tetrahedron Lett. 1988, 29, 1173. (e) Katsumura, S.; Han, Q.;
Kadono, H.; Fujiwara, S.; Isoe, S.; Fujii, S.; Nishimura H.; Ikeda, K.
Bioorg. Med. Chem. Lett. 1992, 2, 1263. (f) Katsumura, S.; Ichikawa,
K.; Mori, H. Chem. Lett. 1993, 1525.
(
34) (a) Hata, T.; Tanaka, K.; Katsumura, S. Tetrahedron Lett. 1999,
4
0, 1731. (b) Furuichi, N.; Hata, T.; Soetjipto, H.; Kato, M.; Katsumura,
(
30) Review: Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707.
S. Tetrahedron 2001, 57, 8425. (c) Tanaka, K.; Hata, T.; Hara, H.;
Katsumura, S. Tetrahedron 2003, 59, 4945.
See also: (a) Kotora, M.; Negishi, E. Tetrahedron Lett. 1996, 37, 9041.
(
b) Liu, F.; Negishi, E. J. Org. Chem. 1997, 62, 8591. (c) Kotora, M.;
(35) (a) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.;
Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron Lett. 1998, 39,
1185. (b) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.;
Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron 1999, 55, 1657.
(c) Tanaka, K.; Katsumura, S. J. Synth. Org. Chem. Jpn. 1999, 57,
80.
(36) (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc.
1962, 84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972,
13, 3769. (c) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994,
35, 3529.
Negishi, E. Synthesis 1997, 121. (d) Xu, C.; Negishi, E. Tetrahedron
Lett. 1999, 40, 431. (e) Negishi, E.; Alimardanov, A.; Xu, C. Org. Lett.
2
000, 2, 65.
(
31) (a) Rossi, R.; Bellina, F.; Mannina, L. Tetrahedron Lett. 1998,
3
9, 3017. (b) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahe-
dron Lett. 1998, 39, 7799. (c) Rossi, R.; Bellina, F.; Catanese, A.;
Mannina, L.; Valensin, D. Tetrahedron 2000, 56, 479.
(
32) Mori, H.; Kubo, H.; Hara, H.; Katsumura, S. Tetrahedron Lett.
1
997, 38, 5311.
7952 J. Org. Chem., Vol. 69, No. 23, 2004

A Polyfunctional Carotenoid, Peridinin
SCHEME 5
desired carboxylic acid 24, that is, A, was obtained in
5
1% yield by treatment of 23 with 2 N aqueous KOH.
Palladium(II)-Catalyzed Intramolecular Lacton-
ization. With the conjugated ethynylcarboxylic acid 24
in hand, the key stage was set up for the synthesis of
ylidenebutenolide half-segment 25 by intramolecular
2 3 2
lactonization. The treatment of 24 with PdCl (PPh ) ,
cuprous iodide, and triethylamine in THF, which are
conditions similar to those reported by Lu and co-
workers,26 produced the desired 25 in low yield and
produced a significant amount of the dimer 26 (Scheme
37
6
). Meanwhile, the desired butenolide 25 was obtained
in 66% yield as a sole stereoisomer under our previously
reported conditions with the coexistence of a bidentate
3
2
ligand, 1,2-bis(diphenylphosphino)ethane (dppe).
The mechanism of the Pd-catalyzed lactonization could
be explained as shown in Figure 4.2
9,38
The initial Pd(0)
species is converted to Pd(II) by oxidative addition with
HX generated under the reaction conditions, and this Pd-
(
II) species coordinated with ethynylcarboxylic acid 24
sponding γ-hydroxybutenolide 19 in 77% yield in two
steps. The ring opening of the resulting γ-hydroxy-
butenolide 19 was then achieved without isomerization
of the double bond by treatment with diisopropylethyl-
amine and ethyl iodide in DMSO to furnish (Z)-â-
alkoxycarbonyldienal 20, that is, compound B, in excel-
to produce the complex i. This is followed by 5-exo
cyclization accompanied by the elimination of HX to
produce an alkenylpalladium(II) complex ii. Reductive
elimination of the intermediate ii afforded the desired
butenolide 25 and Pd(0) species. On the other hand, the
dimer 26 would be produced via iv, which was formed
from iii bearing no phosphine ligands. The Pd-catalyzed
lactonization in the absence of dppe would produce the
alkenylpalladium(II) intermediate iia; in the presence of
dppe, the alkenyl-Pd(II) intermediate iib would be
formed. It is suggested that the dissociation from ii to
iii would be prevented by a strong coordination of the
bidentate ligand with the palladium; the formation of the
dimer 26 from iii would be suppressed by the presence
of dppe.
Thus, we achieved the completely stereocontrolled
synthesis of the ylidenebutenolide 25, but some problems
remained in terms of the low yields and the relatively
long reaction procedure (eight steps and 10% overall yield
from the common intermediate 4, for a first-generation
synthesis).
3
5
lent yield.
The next step in the synthesis of 3 was the transfor-
mation of aldehyde 20 to an acetylene derivative such
as 22, which would be prepared through vinyldibromide
2
1. The desired 21 was obtained in 93% yield under the
36c
Chuche-modified Corey-Fuchs conditions,
by treat-
ment of 20 with carbon tetrabromide and triphenylphos-
phine in the presence of triethylamine at -60 °C (Scheme
5
). The subsequent transformation from 21 into 22 was
troublesome; treatment with 2 equiv of nBuLi or LDA
according to the reported procedure3 gave the expected
product 22 in a very low yield. On the other hand,
treatment with NaHMDS3 at -100 °C cleanly produced
the intermediary bromoacetylene, which was successfully
converted into terminal acetylene 22 by reaction with 2
equiv of MeMgBr.
6a,b
6c
The Sonogashira coupling27 of the unstable acetylene
Second-Generation Synthesis: Development of a
Novel Pd-Catalyzed Domino Ylidenebutenolide For-
mation. To improve the overall efficiency, an allyl group,
which was expected to be removed by a Pd-catalyzed
reaction, was selected as a protecting group for the C-9
carboxyl moiety (Scheme 5).39 Because the Sonogashira
5,26
derivative 22 with C
4
-vinyl iodide 132
proceeded
smoothly to produce the corresponding coupling product
2
2
3 in 40% yield in two steps. Access to carboxylic acid
4 from ester 23 was not trivial due to the presence of
the labile polyene moiety. After careful examination, the
SCHEME 6
J. Org. Chem, Vol. 69, No. 23, 2004 7953

Furuichi et al.
FIGURE 4. Possible mechanism for the Pd-catalyzed intramolecular lactonization.
SCHEME 7
SCHEME 8
3
-dehydroxy congener 29a as a model compound was
examined. A mixture of 29a and vinyl iodide 13 was
stirred overnight in the presence of catalytic amounts of
3 4
Pd(PPh ) , cuprous iodide, and excess amounts of formic
acid in triethylamine at room temperature. The desired
ylidenebutenolide 30 was obtained in 43% yield as a sole
product (not optimized) (Scheme 8).
This domino reaction could be explained by considering
the successive action of Pd(0) and the π-allyl-Pd(II)
catalyst as shown in Figure 5. First, Pd(0) and the copper-
catalyzed Sonogashira coupling of 29a with 13 proceeded
to afford i (path A). The coupling product i then produced
the π-allylpalladium intermediate ii, which underwent
the π-allylpalladium(II)-assisted regio- and stereoselec-
tive intramolecular cyclization42 via iii to form the
coupling and the following lactonization also proceeded
with the aid of a Pd catalyst, we envisioned that this
three-step sequence would proceed in a domino fashion
or in a one-pot procedure under optimized reaction
conditions.
Dibromide 28 was obtained from silylfuran 18 (Scheme
1
4
) by a similar procedure through the allyl ester 27 [ O
2
(
37) (a) In the case of the 3-dehydroxy congener, the corresponding
oxygenation, allyl ester formation (70%), and then di-
bromo olefination (95%)] (Scheme 7). It is noteworthy that
this sequence was efficiently realized in a one-pot pro-
cedure; the continuous addition of the respective reagents
in three-step reactions in one flask gave the desired
dibromide 28 as a sole stereoisomer in 53% overall yield
from 4. Furthermore, the direct conversion into the C-3-
hydroxyacetylene 29 in one flask was also achieved by
treatment of intermediary 28 with excess amounts of
TBAF (81%). To the best of our knowledge, the transfor-
mation from a 1,1-dibromoethane derivative into the
terminal acetylene by TBAF has never been obtained
desired ylidenebutenolide was obtained as a single product under these
conditions; see Supporting Information. (b) Experimental conditions
and data for compounds 20-26 are described in Supporting Informa-
tion.
(
38) Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984,
25, 5323.
(
39) Review: (a) Solomon, C. J.; Mata, E. G.; Mascaretti, O. A.
Tetrahedron 1993, 49, 3714. (b) Tsuji, J.; Mandai, T. Synthesis 1996,
1
.
(40) For the transformation from 1,1-dibromoethene into bro-
moacetylene, see Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330.
(
41) For the transformation from vinylbromide into acetylene by
fluoride ion (TBAF, KF), see (a) Naso, F.; Ronzini, L. J. Chem. Soc.,
Perkin Trans. 1 1974, 340. For the transformation from haloacetylene
into the corresponding acetylene by halogen ion, see (b) Verplough,
M. C.; Donk, L.; Bos, H. J. T.; Drenth, W. Rec. Trav. Chim. 1971, 90,
765. (c) Tanaka, R.; Zheng, S. Q.; Kawaguchi, K.; Tanaka, T. J. Chem.
Soc., Perkin Trans. 2 1980, 11, 1714.
4
0,41
before,
the generality of which is now under investi-
gation in our laboratory.
Having obtained acetylene 29, we were ready for a
domino formation of the ylidenebutenolide 3. First, DL-
(
42) Mandai, T.; Ohta, K.; Baba, N.; Kawada, M.; Tsuji, J. Synlett
1992, 671.
7954 J. Org. Chem., Vol. 69, No. 23, 2004

A Polyfunctional Carotenoid, Peridinin
FIGURE 5. Possible mechanism for the Pd-catalyzed domino ylidenebutenolide formation reaction.
SCHEME 9
corresponding π-allylalkenylpalladium lactone intermedi-
ate iv. In the final step, the π-allylalkenylpalladium
moiety in iv was removed by hydrogenolysis with tri-
ethylammonium formate to produce the desired γ-ylidene-
butenolide 30.
Encouraged by this result, we attempted to carry out
the same domino procedure for the preparation of the
hydroxyl derivative 3 under identical conditions. How-
ever, the reaction of 29 with vinyl iodide 13 mainly
afforded γ-methylene-γ-butenolide 31 (Scheme 9). This
result was probably because the π-allyl-Pd(II)-catalyzed
lactonization (path B) was more favorable than the Pd-
ation brought about the successful one-pot procedure for
3. Thus, a mixture of 29 and 13 was stirred in the
presence of catalytic amounts of Pd(PPh and cuprous
iodide in triethylamine at room temperature for 1 h. After
the complete consumption of 29 was ascertained by TLC,
formic acid was added to the reaction mixture at room
temperature, and then the resulting mixture was stirred
for a further 20 h. By this procedure, we obtained the
desired ylidenebutenolide 3 in 49% yield as a single
stereoisomer.
3 4
)
The efficient and stereocontrolled elaboration of the
ylidenebutenolide segment 3 was thus achieved from the
common intermediate 4 in only four steps in 21% overall
yield, focusing on the sequential three one-pot reactions.
This is a so-called second-generation synthesis.
Completion of the Total Synthesis by Utilizing
the Modified Julia-Kocienski Olefination. With the
(
0)-catalyzed Sonogashira coupling (path A) in this case,
and path B produced γ-methylene-γ-butenolide 31, as
shown in Figure 5. Interestingly, the presence of the
hydroxy group at the C-3 position affected the reaction
pathway. In the case of the 3-hydroxy derivative 29, the
presence of formic acid led to the formation of undesired
advanced C17-allenic segment 2 (Scheme 3) and the C20
-
3
1. We envisaged that the desired Sonogashira-coupling
ylidenebutenolide segment 3 in hand, the final elabora-
tion was conducted toward the total synthesis of peridinin
(1) via the connection of both segments. After several
trials, we noticed that the allyl halides derived from the
would be preferred in the absence of formic acid and that
the later addition of the hydride source would afford the
desired ylidenebutenolide 3. Fortunately, this consider-
J. Org. Chem, Vol. 69, No. 23, 2004 7955

Furuichi et al.
SCHEME 10
allenic segment 2 were unstable under the reaction
conditions required for the preparation of the correspond-
ing Wittig salt, although a very similar C15-Wittig salt
a benzene solution at room temperature in the dark.
Thus, after 3 days, the thermodynamic isomerization
from the 15-cis isomer to the all-trans isomer reached
more than a 5:1 ratio. This phenomenon was followed
by the H NMR and HPLC analyses as shown in Figure
6.
3
was reported. We then turned our attention to the
43
1
modified Julia-Kocienski olefination. This olefination
reaction seemed to be attractive for the preparation of
the unstable conjugated polyene chains, because it can
be carried out at low temperature. Recently, this coupling
reaction has been shown to be effective for polyene
macrolide synthesis.44 On the other hand, the coupling
between conjugated sulfone derivatives and the conju-
gated aldehydes has been less studied.45
Allene 2 was transformed into benzothiazolyl sulfone
2 by the Mitsunobu reaction with 2-mercaptobenzothia-
3
zole, followed by the molybdenum(VI)-catalyzed oxidation
Scheme 10). The conjunction between sulfone 32 and
aldehyde 33, which was derived from ylidenebutenolide
by manganese dioxide oxidation, successfully proceeded
within 5 min by use of 2 equiv of NaHMDS as a base at
78 °C in the dark. The crude product obtained as a red
(
3
-
film was a mixture of the desired all-trans-peridinin (1)
FIGURE 6. HPLC analysis after the thermal isomerization.
Conditions: column, Develosil CN-UG (0.6 × 25 cm); UV
detection, 450 nm; mobile phase, acetone/n-hexane ) 1/10; flow
rate, 1.54 mL/min.
1
and its 15-cis congener (34) in a 1:3 ratio based on H
NMR analysis (see Supporting Information). Fortunately,
we found that the cis isomer (34) was isomerized into
the thermodynamically more stable trans isomer (1) in
The desired optically active peridinin (1) was obtained
after purification by preparative HPLC in the dark. The
(43) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
1
13
Lett. 1991, 32, 1175. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel,
O. Bull. Soc. Chim. Fr. 1993, 130, 336. (c) Baudin, J. B.; Hareau, G.;
Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856.
spectral data for the synthesized peridinin ( H and
C
NMR, IR, MS, and CD spectra) were in good agreement
with those for the natural product.2 Thus, we completed
the convergent and stereocontrolled total synthesis of the
polyfunctional C37 nor-carotenoid, peridinin.
,11
(
d) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1
998, 26. (d) Recent review: Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563.
44) For recent application to the natural product synthesis, see (a)
(
Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002,
1
24, 11102. (b) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124,
263. (c) Kang, S. H.; Jeong, J. W.; Hwang, Y. S.; Lee, S. B. Angew.
Summary
2
Chem., Int. Ed. 2002, 41, 5411. (d) Lee, E.; Song, H. Y.; Kang, J. W.;
Kim, D. S.; Jung, C. K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384.
In summary, we achieved an efficient and convergent
total synthesis of the polyfunctional carotenoid peridinin
by controlling the stereochemistry of all six asymmetric
carbons and the geometry of the seven double bonds in
this molecule. Our synthesis focuses on the stereocon-
trolled preparation of the common intermediate 4 by
(e) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508.
(f) Compostella, F.; Franchini, L.; Panza, L.; Prosperi, D.; Ronchetti,
F. Tetrahedron 2002, 58, 4425. (g) Lausten, M.; Colucci, J. T.; Hiebert,
S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879.
(45) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Syn-
thesis 1996, 285.
7956 J. Org. Chem., Vol. 69, No. 23, 2004

A Polyfunctional Carotenoid, Peridinin
utilizing Sharpless asymmetric epoxidation under re-
strictedly optimized conditions, the stereocontrolled con-
struction of the conjugated polyene moiety including (Z)-
γ-ylidenebutenolide by Pd-catalyzed reactions, and a
modified Julia-Kocienski olefination. In particular, the
construction of the characteristic conjugated (Z)-γ-
ylidenebutenolide moiety was achieved in a one-pot
procedure utilizing Pd(0)- and Pd(II)-catalyzed reactions.
We believe that this is the first example of controlling
the stereochemistry of polyfunctional allenic carotenoids
and that the methodology developed here will be ap-
plicable to other carotenoid synthesis.
4
combined, washed with brine, dried over MgSO , filtered, and
concentrated in vacuo to afford the crude silylfuran 18, which
was used in the next reaction without further purification.
A solution of the crude 18 and tetraphenylporphine (5 mg)
in dichloromethane (50 mL) was irradiated with a halogen-
tungsten lamp under oxygen atmosphere for 30 min at -78
°
C. After the mixture was allowed to warm to room temper-
ature, the solvents were removed in vacuo. Purification by
silica gel column chromatography (from 2% to 50% ethyl
acetate in hexane) afforded γ-hydroxybutenolide 19 (2.01 g,
21
7
7% for two steps) as a yellow oil: [R]
D
-47.49 (c 0.34,
-
1
CHCl ); IR (NaCl, cm ) 3376, 2957 2932, 2859, 1769, 1659;
3
1
3
H NMR (400 MHz, CDCl ) δ 7.22 (d, 1H, J ) 15.6 Hz), 6.93
(
s, 1H), 6.27 (d, 1H, J ) 15 Hz), 5.95 (s, 1H), 4.97 (br s, 1H),
3
.83 (m, 1H), 2.23 (ddd, 1H, J ) 14.6, 5.1, 1.5 Hz), 1.65 (dd,
H, J ) 14.6, 8.3 Hz), 1.49 (ddd, 1H, J ) 12.9, 3.4, 1.7 Hz),
Experimental Section
1
Methyl (2E,4E)-7-[(1′R,2′R,4′S)-1′,2′-Epoxy-4′-hydroxy-
1.26 (dd, 1H, J ) 12.9, 10.0 Hz), 1.16 (s, 3H), 0.92 (s, 3H),
1
3
2
′,6′,6′-trimethylcyclohexyl]-5-methylhepta-2,4-dien-6-
3
0.86 (s, 9H), 0.04 (s, 6H); C NMR (100 MHz, CDCl ) δ 169.8,
14
26
ynoate (15). To a solution of 11 (2.15 g, 11.9 mmol) and 14
3.00 g, 11.9 mmol) in diisopropylamine (60 mL) were added
143.0, 135.6, 131.3, 120.7, 96.2, 70.6, 67.5, 64.6, 46.8, 41.1, 35.0,
+
(
29.3, 25.8, 24.9, 19.9, 18.1, -4.78, -4.81; EI HRMS found
+
tetrakis(triphenylphosphine)palladium (138 mg, 0.12 mmol)
and cuprous iodide (22.5 mg, 0.12 mmol) at room temperature.
After being stirred for 1 h at the same temperature, the
m/z 394.2175, calcd for C24
H
38
O
5
Si M 394.2173.
(
3Z,5E)-4-Allyloxycarbonyl-6-[(1′S,2′R,4′S)-4′-tert-bu-
tyldimethylsiloxy-1′,2′ -epoxy-2′,6′,6′-trimethylcyclohex-
′-yl]-1,1-dibromohexa-1,3,5-triene (28). A solution of the
reaction mixture was poured into a saturated aqueous NH
solution and then extracted with diethyl ether. The organic
layers were combined, washed with brine, dried over MgSO
4
Cl
1
crude 18 and 5,10,15,20-tetraphenyl-21H,23H-porphine (5 mg)
in dichloromethane (30 mL) was irradiated with a halogen-
tungsten lamp under oxygen atmosphere for 30 min at -78
4
,
filtered, and concentrated in vacuo. Purification by silica gel
column chromatography (from 20% to 50% ethyl acetate in
hexane) afforded the coupling product 15 (3.04 g, 84%) as a
°C (γ-hydroxybutenolide 19 was formed in situ). After the
reaction mixture was allowed to warm to room temperature,
diisopropylethylamine (1.75 mL, 10.05 mmol) was added. After
the resulting mixture was stirred for 3 h at room temperature,
allyl bromide (0.43 mL, 5.03 mmol) was added dropwise, and
then the mixture was stirred for 1 h [(Z)-â-alkoxycarbonyl-
dienal 27 was formed in situ]. To a solution of carbon
tetrachloride (4.44 g, 13.40 mmol) and triphenylphosphine
(7.00 g, 26.80 mmol) in dichloromethane (20 mL) was added
dropwise the reaction mixture at -60 °C. After the mixture
was stirred for 1 h at the same temperature, hexane was
added, the precipitate was removed by filtration through a pad
of Celite, and then the solvents were removed in vacuo.
Purification by silica gel column chromatography (from 2% to
5% ethyl acetate in hexane) afforded dibromide 28 (1.05 g, 53%
from 4) as a yellow oil.
2
2
-1
pale yellow oil: [R]
439, 2963, 2930, 2872, 2211, 1719, 1618; H NMR (400 MHz,
CDCl ) δ 7.54 (dd, 1H, J ) 15.1, 12.0 Hz), 6.47 (ddd, 1H, J )
2.0, 1.5, 0.98 Hz), 5.91 (d, 1H, J ) 15.1 Hz), 3.84 (m, 1H),
.76 (s, 3H), 2.37 (ddd, 1H, J ) 14.4, 5.1, 1.7 Hz), 2.03 (d, 3H,
D
3
5.28 (c 0.63, CHCl ); IR (NaCl, cm )
1
3
3
1
3
J ) 0.98 Hz), 1.66 (dd, 1H, J ) 14.4, 8.8 Hz), 1.62 (ddd, 1H, J
)
)
13.0, 3.4, 1.7 Hz), 1.51 (s, 3H), 1.27 (s, 3H), 1.24 (dd, 1H, J
1
3
3
13.0, 10.5 Hz), 1.13 (s, 3H); C NMR (100 MHz, CDCl ) δ
1
4
3
67.3, 138.9, 133.2, 127.1, 121.7, 89.8, 88.5, 67.3, 63.6, 51.6,
+
5.7, 39.8, 34.4, 29.8, 25.6, 21.6, 18.1; EI HRMS found m/z
+
04.1679, calcd for C18
H
24
O
4
M
304.1675.
(
2E,4E)-7-[(1′R,2′R,4′S)-4′-Acetoxy-2′-hydroxy-2′,6′,6′-
trimethylcyclohexylidene]-5-methylhepta-2,4,6-trien-1-
2
8
ol (2). To a solution of 3-acetoxy allenic aldehyde (1.96 g,
.21 mmol) in methanol (60 mL) was added sodium borohy-
6
Data for 27: [R]D -77.47 (c 0.97, CHCl ); IR (NaCl, cm-1)
22
dride (707 mg, 18.7 mmol) at 0 °C. The reaction mixture was
stirred for 15 min at room temperature, and water was added
dropwise, and then the resulting mixture was extracted with
ethyl acetate. The organic layers were combined, washed with
3
2959, 2930, 2857, 1734, 1680, 1626, 1589, 1472, 1381, 1345;
1
H NMR (400 MHz, CDCl ) δ 9.83 (d, 1H, J ) 7.6 Hz), 6.50 (d,
3
1H, J ) 15.6 Hz), 6.36 (d, 1H, J ) 15.6 Hz), 6.10 (d, 1H, J )
brine, dried over MgSO
4
, filtered, and concentrated in vacuo
7
)
.6 Hz), 5.98 (ddt, 1H, J ) 17.1, 10.5, 6.1 Hz), 5.42 (dd, 1H, J
2
1
to afford alcohol 2 (1.95 g, 98%) as a pale yellow solid: [R]
D
17.1, 1.2 Hz), 5.34 (dd, 1H, J ) 10.3, 1.2 Hz), 4.83 (m, 2H),
-
1
-
6.91 (c 0.45, CHCl
3
); IR (KBr, cm ) 3397, 2969, 2926, 2861,
3
1
1
.84 (m, 1H), 2.24 (ddd, 1H, J ) 14.6, 4.9, 1.5 Hz), 1.65 (dd,
1
1
935, 1734, 1657, 1640, 1456, 1368; H NMR (400 MHz, CDCl )
3
H, J ) 14.4, 8.1 Hz), 1.50 (ddd, 1H, J ) 13.2, 3.4, 1.5 Hz),
δ 6.55 (ddt, 1H, J ) 15.1, 11.2, 1.5 Hz), 6.02 (d, 1H, J ) 11.2
Hz), 6.00 (s, 1H), 5.85 (dt, 1H, J ) 15.1, 6.0 Hz), 5.37 (tt, 1H,
J ) 11.5, 4.2 Hz), 4.24 (br m, 2H), 2.28 (ddd, 1H, J ) 12.9,
.25 (dd, 1H, J ) 13.2, 9.8 Hz), 1.17 (s, 3H), 1.13 (s, 3H), 0.95
13
(
s, 3H), 0.87 (s, 9H), 0.05 (s, 6H); C NMR (100 MHz, CDCl
3
)
δ 190.8, 165.5, 147.9, 138.5, 129.8, 128.9, 120.3, 70.2, 67.6, 66.6,
4
.1, 2.2 Hz), 2.04 (s, 3H), 1.99 (ddd, 1H, J ) 12.44, 4.2, 2.2
6
4.5, 46.6, 41.1, 35.1, 29.2, 25.8, 25.1, 20.0, 15.3, -4.75, -4.79;
Hz), 1.76 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.30-1.50 (m, 2H),
+
+
EI HRMS found m/z 434.2487, calcd for C24
H
38
5
O Si M
13
1
1
3
3
3
.07 (s, 3H); C NMR (100 MHz, CDCl ) δ 202.0, 170.4, 132.4,
4
34.2488.
Data for 28: [R]
31.8, 127.8, 126.6, 117.4, 102.8, 72.6, 68.0, 63.6, 45.4, 45.2,
2
1
); IR (NaCl, cm-1
+
D
-45.81 (c 1.19, CHCl
3
)
5.6, 32.0, 31.2, 29.2, 21.4, 13.8; EI HRMS found m/z
1
+
2957, 2930, 2858, 1721, 1462, 1383, 1364; H NMR (400 MHz,
20.1997, calcd for C19
H
28
O
4
M
320.1987.
CDCl
3
) δ 7.56 (d, 1H, J ) 11.2 Hz), 6.44 (d, 1H, J ) 11.2 Hz),
.30 (d, 1H, J ) 15.6 Hz), 6.26 (d, 1H, J ) 15.6 Hz), 5.98 (ddt,
H, J ) 17.1, 10.2, 5.9 Hz), 5.39 (dd, 1H, J ) 17.1, 1.2 Hz),
(
5RS)-Hydroxy-3-[(1′E)-2′-(1′′S,2′′R,4′′S)-4′′-tert-butyldi-
6
1
methylsiloxy-1′′,2′′-epoxy-2′′,6′′,6′′-trimethylcyclohex-1′′-
ylethen-1′-yl]-2-(5H)furanone (19). To a suspension of
3
4
5.30 (dd, 1H, J ) 10.5, 1.2 Hz), 4.75 (m, 2H), 3.85 (m, 1H),
2.24 (ddd, 1H, J ) 14.4, 5.1, 1.5 Hz), 1.64 (dd, 1H, J ) 14.4,
8.3 Hz), 1.50 (ddd, 1H, J ) 13.2, 3.4, 1.5 Hz), 1.24 (dd, 1H, J
) 13.2, 10.0 Hz), 1.18 (s, 3H), 1.12 (s, 3H), 0.96 (s, 3H), 0.87
silylfuran-Wittig reagent 17 (2.16 g, 4.02 mmol) in diethyl
n
ether (20 mL) was added dropwise BuLi (1.6 M in hexane,
.52 mL, 4.02 mmol) at 0 °C. After the mixture was stirred
2
for 10 min at 0 °C, a solution of 4 (1.0 g, 3.35 mmol) in diethyl
ether (5 mL) was added, and the reaction mixture was stirred
for 3 h at room temperature. It was filtered through a pad of
Celite. Water was added to the filtrate, and the resulting
mixture was extracted with ether. The organic layers were
1
3
3
(s, 9H), 0.05 (s, 3H), 0.04 (s, 6H); C NMR (100 MHz, CDCl )
δ 166.2, 133.4, 131.5, 131.4, 130.0, 98.2, 70.3, 67.2, 65.8, 64.6,
+
47.0, 41.3, 35.1, 29.3, 25.9, 25.0, 20.0-4.7, -4.8; EI HRMS
7
9
+
found m/z 588.0916, calcd for C25
38 4 2
H O Br Si M 588.0907.
J. Org. Chem, Vol. 69, No. 23, 2004 7957

Furuichi et al.
(
3Z,5E)-4-Allyloxycarbonyl-6-[(1′S,2′R,4′S)-4′-hydroxy-
Hz), 2.03 (s, 3H), 1.98 (ddd, 1H, J ) 12.4, 4.4, 2.2 Hz), 1.74 (s,
3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.30-1.50 (m, 2H), 1.05 (s, 3H);
1
′,2′-epoxy-2′,6′,6′-trimethylcyclohex-1′-yl]hexa-3,5-dien-
-yne (29). To a solution of 28 (1.50 g, 2.54 mmol) in THF (25
13
1
3
C NMR (100 MHz, CDCl ) δ 202.1, 170.4, 166.2, 153.2, 135.3,
mL) was added tetra-n-butylammonium fluoride (4.00 g, 15.2
132.8, 131.0, 126.4, 126.3, 126.0, 124.2, 121.5, 121.0, 117.5,
mmol) at room temperature. After being stirred for 20 h at 45
102.7, 72.5, 68.0, 45.4, 45.2, 36.2, 35.6, 32.0, 31.2, 29.1, 21.4,
+
°
C, the reaction mixture was poured into a saturated aqueous
13.8; EI HRMS found m/z 469.1748, calcd for C26
H
31
O
3
NS
2
+
NH
4
Cl solution and then extracted with diethyl ether. The
M
469.1743.
To a solution of the thioether (500 mg, 1.07 mmol) in ethanol
organic layers were combined, washed with brine, dried over
MgSO
4
, filtered, and concentrated in vacuo. Purification by
(10 mL) was added dropwise a solution of ammonium hepta-
molybdate tetrahydrate (132 mg, 0.11 mmol) in hydrogen
peroxide (30 wt % in water, 2.0 mL) at 0 °C. After being stirred
for 1 h at the same temperature, the reaction mixture was
poured into brine and then extracted with diethyl ether. The
short silica gel column chromatography (from 10% to 30% ethyl
acetate in hexane) afforded terminal acetylene 29 (652 mg,
8
1%) as an orange oil, which was immediately used in the next
-
1
reaction: IR (NaCl, cm ) 3412, 3293, 3086, 2963, 2930, 2874,
097, 1725, 1649, 1582, 1453, 1383, 1366, 1223, 1163, 1049;
2
organic layers were combined, dried over MgSO , filtered, and
4
1
H NMR (400 MHz, CDCl
7.1, 10.5, 5.9 Hz), 5.84 (d, 1H, J ) 2.7 Hz), 5.42 (dd, 1H, J )
7.1, 1.2 Hz), 5.29 (dd, 1H, J ) 10.5, 1.2 Hz), 4.80 (m, 2H),
.88 (m, 1H), 3.42 (d, 1H, J ) 2.7 Hz), 2.37 (ddd, 1H, J ) 14.2,
.1, 1.7 Hz), 1.50-1.70 (m, 2H), 1.23 (dd, 1H, J ) 13.2, 10.5
3
) δ 6.25 (s, 2H), 5.99 (ddt, 1H, J )
concentrated in vacuo. Purification by short alumina column
chromatography (from 30% to 50% ethyl acetate in hexane)
1
1
3
5
2
1
afforded sulfone 32 (474 mg, 89%) as a pale yellow solid: [R]
D
-
1
-6.15 (c 0.77, CDCl ); IR (KBr, cm ) 3356, 2976, 2928, 1935,
3
1725, 1630, 1472, 1426, 1375, 1331, 1248, 1148, 1109, 1073;
13
1
Hz), 1.19 (s, 3H), 1.12 (s, 3H), 0.97 (s, 3H); C NMR (100 MHz,
CDCl ) δ 165.6, 142.9, 131.8, 131.5, 128.8, 119.0, 113.1, 87.1,
0.0, 69.9, 67.3, 65.8, 64.0, 46.9, 40.8, 35.2, 29.3, 24.8, 19.8;
H NMR (400 MHz, CDCl ) δ 8.24 (dd, 1H, J ) 7.8, 1.2 Hz),
3
3
8.01 (dd, 1H, J ) 7.8, 1.2 Hz), 7.65 (ddd, 1H, J ) 7.8, 7.8, 1.2
Hz), 7.59 (ddd, 1H, J ) 7.8, 7.8, 1.2 Hz), 6.53 (dd, 1H, J )
15.1, 11.7 Hz), 5.95 (d, 1H, J ) 11.7 Hz), 5.93 (s, 1H), 5.61 (dt,
1H, J ) 15.1, 7.8 Hz), 5.36 (tt, 1H, J ) 11.7, 4.4 Hz), 4.32 (d,
2H, J ) 7.8 Hz), 2.27 (ddd, 1H, J ) 12.7, 4.4, 2.0 Hz), 2.03 (s,
3H), 1.97 (ddd, 1H, J ) 12.7, 4.4, 2.0 Hz), 1.57 (s, 3H), 1.36 (s,
8
+
+
EI HRMS found m/z 316.1684, calcd for C19
5Z)-[(2′E)-4′-Hydroxy-2′-methyl-1′-butenylidene]-3-
(1′′E)-2′′-(1′′′S,2′′′R,4′ ′′S)-4′′′-hydroxy-1′′′,2′′′-epoxy-2′′′,6′′′,6′′′-
24 4
H O M 316.1673.
(
[
trimethylcyclohex-1′′′-ylethen-1′′-yl]-2-(5H)furanone (3).
To a solution of 29 (650 mg, 2.04 mmol) and 13 (450 mg, 2.28
mmol) in triethylamine (20 mL) were added tetrakis(tri-
phenylphosphine)palladium (236 mg, 0.20 mmol) and cuprous
iodide (40 mg, 0.20 mmol) at room temperature. The reaction
mixture was stirred at room temperature until 29 was
completely consumed by monitoring with TLC (ca. 1 h), and
formic acid (0.30 mL, 6.52 mmol) was added dropwise. After
being stirred for the additional 20 h, the resulting mixture
was poured into a saturated aqueous NH
extracted with diethyl ether. The organic layers were com-
bined, washed with brine, dried over MgSO , filtered, and
concentrated in vacuo. Purification by short silica gel column
chromatography (from 70% ethyl acetate in hexane) afforded
ylidenebutenolide 3 (345 mg, 49%) as an orange solid: [R]
1
3
3
H), 1.30 (s, 3H), 1.30-1.50 (m, 2H), 1.02 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 202.5, 170.4, 165.6, 152.6, 137.0, 136.8,
3
1
7
35.3, 127.9, 127.6, 125.5, 125.4, 122.3, 117.6, 115.1, 102.4,
2.4, 67.9, 59.0, 45.3, 45.2, 35.6, 31.9, 31.0, 29.0, 21.3, 13.6;
+
+
EI HRMS found m/z 501.1637, calcd for C26
01.1642.
(5Z)-[(2′E)-2′-Methyl-4′-oxo-2′-butenylidene]-3-[(1′′E)-
31 5 2
H O NS M
5
2′′-(1′′′S,2′′′R,4′′′S)-4 ′′′-hydroxy-1′′′,2′′′-epoxy-2′′′,6′′′,6′′′-tri-
methylcyclohex-1′′′-ylethen-1′′-yl]-2-(5H)furanone (33).
To a solution of 3 (180 mg, 0.51 mmol) in diethyl ether (6.0
mL) was added manganese dioxide (3.0 g) at room tempera-
ture. After being stirred at the same temperature for 5 min,
the reaction mixture was filtered through a pad of Celite. The
solvents were removed in vacuo to afford the crude aldehyde
33, which was used to the next reaction without further
purification.
4
Cl solution and then
4
2
1
D
-1
-
1
38.52 (c 0.83, CHCl
640, 1440, 1381, 1248, 1154, 1121, 1047; H NMR (400 MHz,
CDCl ) δ 7.19 (d, 1H, J ) 15.6 Hz), 7.04 (s, 1H), 6.37 (d, 1H,
J ) 15.6 Hz), 5.97 (t, 1H, J ) 6.6 Hz), 5.65 (s, 1H), 4.36 (d,
H, J ) 6.6 Hz), 3.90 (m, 1H), 2.40 (ddd, 1H, J ) 14.4, 5.1, 1.7
Hz), 1.50-1.70 (m, 2H), 1,25 (m, 1H), 1.21 (s, 6H), 0.97 (s, 3H);
3
); IR (KBr, cm ) 3420, 2965, 2928, 1755,
1
3
Peridinin (1). To a solution of 32 (261 mg, 0.51 mmol) and
the crude 33 in THF (10 mL) was added dropwise sodium bis-
(trimethylsilyl)amide (1.0 M in THF, 1.00 mL, 1.00 mmol) at
-78 °C in the dark. After being stirred for 5 min at the same
temperature, the reaction mixture was poured into brine and
then extracted with diethyl ether. The organic layers were
2
13
3
C NMR (100 MHz, CDCl ) δ 168.6, 146.6, 136.9, 134.3, 133.9,
1
25.9, 121.5, 117.6, 70.4, 67.5, 64.1, 59.5, 47.0, 40.9, 35.3, 29.4,
+
2
4.9, 19.8, 15.5; EI HRMS found m/z 346.1788, calcd for
combined, washed with brine, dried over MgSO , filtered, and
4
+
C
20
H
26
O
5
M
346.1779.
concentrated in vacuo. Purification by short silica gel column
chromatography (from 50% ethyl acetate in hexane) in the
dark afforded a mixture of all-trans-peridinin (1) and its 15-
2
-[(((2′E,4′E)-7′-(1′′R,2′′R,4′′S)-4′′-Acetoxy-2′′-hydroxy-
2
′′,6′′,6′′-trimethylcyclohexylidene)-5′-methylhepta-2′,4′,6′-
1
trienyl)sulfonyl]benzothiazole (32). To a solution of 2 (465
mg, 1.45 mmol), 2-mercaptobenzothiazole (291 mg, 1.74 mmol),
and triphenylphosphine (456 mg, 1.74 mmol) in THF (15 mL)
was added dropwise diisopropyl azodicarboxylate (0.27 mL,
cis isomer (34) (168 mg, 50%, ca. 1:3 based on H NMR
analysis) as a red film.
A solution of a mixture of all-trans-peridinin and its 15-cis
isomer in benzene (2.0 mL) was left at room temperature in
the dark. After 3 days, a thermodynamic equilibrium was
reached, E:Z ) >5:1, and then purification and partial
separation by preparative HPLC [column, Develosil CN-UG
(0.6 × 25 cm); mobile phase, acetone/n-hexane ) 1/10; flow
rate, 1.54 mL/min; UV detection, 450 nm; retention time, (all-
trans isomer) 50 min., (15-cis isomer) 53 min] in the dark
afforded the desired optically active peridinin (1) as a red
1
.88 mmol) at 0 °C. The reaction mixture was stirred for 1.5
h at room temperature, and then all solvents were removed
in vacuo. To the residue was added diethyl ether, and the
precipitate was removed by filtration through a pad of Celite
to give the crude products as a solution, which was concen-
trated in vacuo. Purification by short silica gel column chro-
matography (from 20% to 50% ethyl acetate in hexane)
2
1
-1
afforded thioether (529 mg, 78%) as a pale yellow solid: [R]
D
powder: IR (KBr, cm ) 3418, 2963, 2926, 2857, 1929, 1738,
-
1
1
-
2
1
7.02 (c 0.89, CDCl
3
); IR (KBr, cm ) 3426, 3061, 3029, 2965,
1657, 1524, 1456, 1439, 1365, 1250, 1161, 1121, 1030; H NMR
926, 1933, 1719, 1632, 1458, 1427, 1372, 1250, 1182, 1163,
3
(400 MHz, CDCl ) δ 7.17 (d, 1H, J ) 15.6 Hz), 7.02 (s, 1H),
1
109, 1073, 1030; H NMR (400 MHz, CDCl
3
) δ 7.88 (dd, 1H,
6.61 (dd, 2H, J ) 14.2, 11.7 Hz), 6.51 (dd, 1H, J ) 14.2, 10.5
Hz), 6.45 (d, 1H, J ) 11.5 Hz), 6.384 (dd, 1H, J ) 14.4, 10.5
Hz), 6.377 (d, 1H, J ) 15.6 Hz), 6.11 (d, 1H, J ) 11.2 Hz),
6.06 (s, 1H), 5.73 (s, 1H), 5.38 (tt, 1H, J ) 11.7, 4.4 Hz), 3.90
(m, 1H), 2.40 (ddd, 1H, J ) 14.2, 5.0, 1.5 Hz), 2.28 (ddd, 1H,
J ) 13.0, 4.2, 2.0 Hz), 2.23 (s, 3H), 2.04 (s, 3H), 1.99 (ddd, 1H,
J ) 7.8, 1.2 Hz), 7.76 (dd, 1H, J ) 7.8, 1.2 Hz), 7.42 (ddd, 1H,
J ) 7.8, 7.8, 1.2 Hz), 7.30 (ddd, 1H, J ) 7.8, 7.8, 1.2 Hz), 6.65
(
1
dd, 1H, J ) 14.6, 11.0 Hz), 5.98 (d, 1H, J ) 11.0 Hz), 5.96 (s,
H), 5.86 (dt, 1H, J ) 14.6, 7.6 Hz), 5.37 (tt, 1H, J ) 11.5, 4.2
Hz), 4.10 (d, 2H, J ) 7.8 Hz), 2.27 (ddd, 1H, J ) 12.7, 3.9, 2.2
7958 J. Org. Chem., Vol. 69, No. 23, 2004

A Polyfunctional Carotenoid, Peridinin
J ) 12.4, 4.0, 2.0 Hz), 1.80 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H),
for their high-resolution mass spectra measurements.
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan. N.F. is grateful
for the research fellowships of the Japan Society for the
Promotion of Science for Young Scientists, and also for
the Sasagawa science research grant from The Japan
Science Society (2001).
1
3
1
.21 (s, 3H), 1.20 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H); C NMR
(
3
100 MHz, CDCl ) δ 202.6, 170.4, 168.8, 146.8, 138.0, 137.2,
1
1
4
1
M
36.3, 134.0, 133.9, 133.6, 133.0, 131.5, 128.9, 128.1, 124.8,
21.8, 119.2, 117.6, 103.3, 72.7, 70.4, 67.9, 67.5, 64.2, 47.1, 45.4,
5.2, 40.9, 35.8, 35.3, 32.1, 31.3, 29.5, 29.2, 24.9, 21.4, 19.9,
+
5.4, 14.0; EI HRMS found m/z 630.3544, calcd for C39
50 7
H O
+
630.3554. For CD spectra, see Supporting Information.
Acknowledgment. We are grateful to Professor
Masayoshi Ito and Dr. Yumiko Yamano at Kobe Phar-
maceutical University for providing natural and their
synthesized peridinin. We also thank Dr. Kayoko Saiki
at Kobe Pharmaceutical University and Mr. Tamotsu
Yamamoto and co-workers of the Institute for Life
Science Research at Asahi Chemical Industry Co. Ltd.
Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 4-14, 16-
1
13
2
6, and model studies (29a and 30) and copies of H and
C
NMR spectra (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO048852V
J. Org. Chem, Vol. 69, No. 23, 2004 7959