Sulfone coupling and double-elimination strategy for carotenoid synthesis

Article abstract of DOI:10.1021/jo0516335

A highly efficient synthetic method of carotenoid compounds has been developed on the basis of the sulfone coupling and double-elimination strategy. This method highlighted the sulfone-mediated coupling with the novel C ₁₀ dialdehyde, 2,7-dimethyl-4-octenedial, which was easily prepared and efficiently utilized in the synthesis of the conjugated polyene chains.

Full text of DOI:10.1021/jo0516335

SCHEME 1. Disconnection Approach to
â-Carotene (1a) Utilizing the Double-Elimination
Strategy
Sulfone Coupling and Double-Elimination
Strategy for Carotenoid Synthesis
Samar Kumar Guha and Sangho Koo*
Department of Chemistry, Myong Ji University, Yongin,
Kyunggi-Do 449-728, Korea
sangkoo@mju.ac.kr
Received August 4, 2005
been prepared by this method.8 It was envisioned that
an efficient synthesis of â-carotene (1a) would be realized
by the sulfone-mediated coupling and double-elimination
strategy utilizing the novel C10 dialdehyde, 2,7-dimethyl-
4-octenedial (3) (Scheme 1). This sulfone chemistry is
believed to be more effective than the Wittig reaction9
for the preparation of the conjugated polyene chains of
carotenoids, especially in the production of the (E)-
configuration of CdC bonds and the treatment of
byproducts.6d We thus devised a practical synthetic
method of the C10 dialdehyde 3 and then carried out the
â-carotene synthesis by the coupling with the C15 allylic
sulfone 2a10 and the double-elimination reaction in a
highly efficient manner. The preparation of 3, details of
the double-elimination reaction exemplified for â-carotene
synthesis, and the application of this strategy to other
carotenoid syntheses are reported herein.
The synthesis of the symmetrical C10 dialdehyde 3
starting from the readily available (E)-1,4-dibromo-2-
butene (4) was delineated in Scheme 2. Diethyl methyl-
malonate (2 equiv) was used in the reaction with 4 (1
equiv) to secure the efficient coupling to give rise to the
tetraester 5 (88% yield). The standard decarboalkoxyla-
tion sequence11 of basic hydrolysis, acidification, and
thermolysis, followed by esterification in MeOH for 5,
produced the methyl diester 6 in 89% yield. Direct
reduction12 of the diester 6 to the dialdehyde 3 was not
a trivial transformation. Instead, LAH reduction all the
A highly efficient synthetic method of carotenoid compounds
has been developed on the basis of the sulfone coupling and
double-elimination strategy. This method highlighted the
sulfone-mediated coupling with the novel C10 dialdehyde,
2,7-dimethyl-4-octenedial, which was easily prepared and
efficiently utilized in the synthesis of the conjugated polyene
chains.
The sulfone-stabilized carbanion is an efficient nucleo-
phile to couple with alkyl or allyl halides in carbon-
carbon bond-forming reactions.1 A single or a double bond
can be obtained according to the sulfone elimination of
either a radical2 or a basic3 condition. When aldehydes
are used as an electrophile in the sulfone-mediated
coupling reaction, the corresponding sulfone elimination
reactions generate either a CdC bond4 or a CtC bond.5
The above CdC bond formation reactions, known as the
Julia sulfone olefination protocol, have been successfully
utilized in the synthesis of carotenoid compounds, which
have a general structure of the conjugated polyene chain.6
The above CtC bond formation reactions are, however,
limited to the case of R,â-unsaturated aldehydes, and the
conjugated dienes are generally obtained for saturated
aldehydes by the double elimination of the sulfone and
the protected hydroxyl groups under the basic condition.7
This double-elimination reaction is ideally suited for the
preparation of conjugated polyene chains, and retinol has
(6) (a) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746-750.
(b) Bernhard, K.; Mayer, H. Pure Appl. Chem. 1991, 63, 35-44. (c)
Lee, J. S.; Jeong, Y. C.; Ji, M.; Baik, W.; Lee, S.; Koo, S. Synlett 2004,
1937-1940. (d) Jeon, H.-S.; Yeo, J. E.; Jeong, Y. C.; Koo, S. Synthesis
2004, 2813-2820. (e) Choi, H.; Ji, M.; Park, M.; Yun, I.-K.; Oh, S.-S.;
Baik, W.; Koo, S. J. Org. Chem. 1999, 64, 8051-8053. (f) Ji, M.; Choi,
H.; Park, M.; Kee, M.; Jeong, Y. C.; Koo, S. Angew. Chem., Int. Ed.
2001, 40, 3627-3629. (g) Jeong, Y. C.; Ji, M.; Lee, J. S.; Yang, J.-D.;
Jin, J.; Baik, W.; Koo, S. Tetrahedron 2004, 60, 10181-10185. (h) Chio,
S.; Koo, S. J. Org. Chem. 2005, 70, 3328-3331.
* To whom correspondence should be addressed. Phone: +82-31-
330-6185. Fax: +82-31-335-7248.
(1) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (b) Metzner P.; Thuillier, A. Sulfur Reagents in
Organic Synthesis; Academic Press: London, 1994.
(2) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477-3478.
(3) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743-746.
(4) (a) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833-4836.
(b) Julia, M.; Launay, M.; Stacino, J.-P.; Verpeaux, J.-N. Tetrahedron
Lett. 1982, 23, 2465-2468. (c) Bremner, J.; Julia, M.; Launay, M.;
Stacino, J.-P. Tetrahedron Lett. 1982, 23, 3265-3266.
(5) (a) Orita, A.; Ye, F.; Doumoto, A.; Otera, J. Chem. Lett. 2003,
32, 104-105. (b) Ye, F.; Orita, A.; Doumoto, A.; Otera, J. Tetrahedron
2003, 59, 5635-5643. (c) Ye, F.; Orita, A.; Yaruva, J.; Hamada, T.;
Otera, J. Chem. Lett. 2004, 33, 528-529.
(7) Mandai, T.; Yanagi, T.; Araki, K.; Morisaki, Y.; Kawada, M.;
Otera, J. J. Am. Chem. Soc. 1984, 106, 3670-3672.
(8) (a) Otera, J.; Misawa, H.; Mandai, T.; Ohishi, T.; Suzuki, S.;
Fujita, Y. Chem. Lett. 1985, 1883-1886. (b) Otera, J.; Misawa, H.;
Onishi, T.; Suzuki, S.; Fujita, Y. J. Org. Chem. 1986, 51, 3834-3838.
(c) Orita, A.; Yamashita, Y.; Toh, A.; Otera, J. Angew. Chem., Int. Ed.
Engl. 1997, 36, 779-780.
(9) (a) Pommer, H.; Kuhn, R. Angew. Chem. 1960, 72, 911-915. (b)
Pommer, H.; Nu¨rrenbach, A. Pure Appl. Chem. 1975, 43, 527-551. (c)
Pommer, H. Angew. Chem. 1977, 89, 437-443.
(10) Chabardes, P.; Decor, J. P.; Varagnat, J. Tetrahedron 1977, 33,
2799-2805.
(11) Heisig, G. B.; Stodola, F. H. Organic Syntheses; Wiley: New
York, 1955; Collect. Vol. III, pp 213-216.
10.1021/jo0516335 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/13/2005
9662
J. Org. Chem. 2005, 70, 9662-9665

SCHEME 2. Preparation of the Novel C10
Dialdehyde 3a
SCHEME 3. Preparation of â-Carotene (1a) by the
Double-Elimination Reactiona
a Reagents: (a) diethyl methylmalonate (1 equiv) and NaH (2
equiv) in THF and then 4 (0.5 equiv), 88%; (b) (i) 5 in aqueous
KOH solution at reflux for 2 d, (ii) H2SO4 (pH 1), heated to reflux
for 3d, (iii) H2SO4 in CH3OH at rt for 12 h, 89%; (c) LAH (2 equiv)
in THF, 100%; (d) (COCl)2 and DMSO in CH2Cl2 at -78 °C, 7,
then Et3N, and warmed to rt, 87%.
way to the diol 7, followed by the Swern oxidation13 to
the dial 3 (87% yield) was the method of choice. The
diester 6, the diol 7, and the dial 3 contained a 1:1
mixture of diastereomers14 generated from the two ste-
reocenters.
a See Table 1 for the reagents, conditions, and yields of each
reaction from 8a to 9a and from 9a to 1a.
The coupling reaction of the C15 allylic sulfone 2a and
the C10 dial 3 in a 2:1 molar ratio produced the C40-
coupled product 8a (Scheme 3). This coupling reaction
can be carried out efficiently (96% yield) under the kinetic
condition using n-BuLi as a base in THF at -78 °C. The
reverse aldol-type reaction of the diol 8a prevailed at
temperatures higher than -20 °C to give the starting C15
sulfone 2a again. Many diastereomers were generated
in this coupling reaction from the six chiral centers of
8a; however, these stereoisomers did not perturb the
stereoselective formation of all-(E)-â-carotene (1a) in the
double-elimination step.8 Protections of the two hydroxy
groups were required to prevent the reverse reaction of
8a under a basic condition. The base-promoted double
elimination of 9a proceeded presumably through the
initial formation of the vinyl sulfone 10, which was
isolated under the mild elimination condition at room
temperature for 3 h. The double bond migrations to the
allylic sites and the dehydrosulfonylation reactions com-
pleted the double elimination process to produce the fully
conjugated polyene chain of â-carotene (1a).6e
TABLE 1. Preparation of 9a and the
Double-Elimination Reaction To Give â-Carotene (1a)
yield of
9a (%)
elim
yield of
purified
entry
9a
Xa
condb 1ac,d (%)
1ae (%)
1
2
3
4
5
6
7
9a-1 Br
100d
A
B
A
A
C
A
A
80
84
h
100
h
98
100
38f
60g
0
9a-2 Cl
9a-3 THPO
88d
96f
29f
11f
70g
84g
9a-4 EOEO
9a-5 MOMO
91f
93f
a
Preparation conditions for X ) Br: PBr3 (1 equiv) and
pyridine (5 equiv) in CH2Cl2; X ) Cl: SOCl2 (2.2 equiv) and
pyridine (4 equiv) in CH2Cl2; X ) THPO: 3,4-dihydro-2H-pyrane
(6 equiv) and CSA (0.3 equiv) in CH2Cl2; X ) EOEO: ethyl vinyl
ether (6 equiv) and PPTS (0.3 equiv) in CH2Cl2; X ) MOMO:
CH2(OCH3)2 (20 equiv) and P2O5 (0.6 equiv × 2). b Elimination
conditions for A: KOMe (20 equiv) in cyclohexane at 80 °C for 16
h; B: t-BuOK (20 equiv) in cyclohexane at 80 °C for 16 h; C:
NaOEt (20 equiv) in EtOH at 80 °C for 16 h. c A 4:1 mixture of
all-(E)- and 13-(Z)-â-carotene was obtained. d Crude yield. e Yield
of pure all-(E)-â-carotene (1a). f Yield after SiO2 column chroma-
tography. g Yield after recrystallization from THF/MeOH. h A
complicated mixture was obtained.
Various protections of the diol 8a and the subsequent
double-elimination reactions of the protected 9a to give
rise to â-carotene (1a) are summarized in Table 1. The
bromide 9a-1 and the chloride 9a-2, which were prepared
by the reaction with PBr3 and SOCl2, respectively, in the
presence of pyridine, could not be purified because no
clear spot was seen in TLC, and the peaks of the 1H NMR
spectra were very broad. The alkyl ethers of tetrahydro-
pyranyl (THP) 9a-3, 1-ethoxyethyl (EOE) 9a-4, and
methoxymethyl (MOM) 9a-5 were prepared in high yields
(91-96%) under acidic conditions.8b Three different elimi-
nation conditions A (KOMe in cyclohexane), B (t-BuOK
in cyclohexane), and C (NaOEt in EtOH) at 80 °C were
tested for 9a. There was no significant difference accord-
ing to the base used (conditions A and B), and the similar
crude yields of 1a were obtained (entries 1 and 2). The
protic solvent (condition C) was not favorable, retarding
this double-elimination reaction to give a complicate
mixture, contrary to the case of the general dehydrosul-
fonylation reaction (entry 5).15 The alkyl ethers seemed
to be better protecting groups than bromide in providing
(12) (a) Burgstahler, A. W.; Worden, L. R.; Lewis, T. B. J. Org. Chem.
1963, 28, 2918-2919. (b) Muraki, M.; Mukaiyama, T. Chem. Lett. 1975,
215-218. (c) Brown, H. C.; Cha, J. S.; Yoon, N. M.; Nazer, B. J. Org.
Chem. 1987, 52, 5400-5406. (d) Cha, J. S.; Kwon, S. S. J. Org. Chem.
1987, 52, 5487-5489. (e) Chandrsekhar, S.; Kumar, M. S.; Muralidhar,
B. Tetrahedron Lett. 1998, 39, 909-910. (f) Abe, T.; Haga, T.; Negi,
S.; Morita, Y.; Takayanagi, K.; Hamamura, K. Tetrahedron 2001, 57,
2701-2710. (g) Goossen, L. J.; Ghosh, K. Chem. Commun. 2002, 836-
837.
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480-2482.
(14) The 1:1 ratios of diastereomers were estimated on the basis of
their 13C NMR spectra, which were included in the Supporting
Information.
J. Org. Chem, Vol. 70, No. 23, 2005 9663

SCHEME 4. Application to the Synthesis of Other
Carotenoidsa
syntheses of organic conducting materials based on the
conjugated polyene chain structure are currently under-
way.
Experimental Section
General Procedure of the Carotenoid Synthesis by the
Doubl-Elimination Process Exemplified for â-Carotene
(1a). (1) Coupling. 5,14-Bis(benzenesulfonyl)-3,7,12,16-tet-
ramethyl-1,18-bis(2,6,6-trimethyl-1-cyclohexenyl)octadeca-
1,3,9,15,17-pentaene-6,13-diol (8a). To a stirred solution of
1-benzenesulfonyl-3-methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-
2,4-pentadiene (2a) (3.09 g, 8.97 mmol) in THF (40 mL) was
added a 1.6 M solution of n-BuLi in hexane (6.6 mL, 10.61 mmol)
at -78 °C. The mixture was stirred at that temperature for 20
min, and a solution of 2,7-dimethyl-4-octenedial (3) (686 mg, 4.08
mmol) in THF (10 mL) was added. The resulting mixture was
stirred at -78 °C for 1 h and quenched with 1 M HCl solution
(20 mL). The mixture was diluted with ether, washed with 1 M
HCl solution, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by SiO2
flash column chromatography (hexanes/EtOAc ) 4:1-3:2) to give
the diol 8a (3.35 g, 3.91 mmol) in 96% yield as a white solid,
which contained many stereoisomers due to the presence of six
chiral centers. The major stereoisomer, which was presumed to
be the all-(E)-isomer, was carefully purified again by preparative
TLC for spectroscopic analysis.
a Reagents: (a) 2 (1.1 equiv) and n-BuLi (1.2 equiv) in THF at
-78 °C, then 3 (0.5 equiv), 91% for 8b, 79% for 8c, 88% for 8d; (b)
P2O5 (0.6 equiv × 2), CH2(OCH3)2 (20 equiv), and 8 (1 equiv) at
rt, 92% for 9b, 90% for 9c, 67% for 9d; (c) KOMe (20 equiv) and
9 (1 equiv) in cyclohexane at 80 °C for 16 h, 49% (recrystallization)
for 1b, 77% (SiO2) for 1c, 28% (recrystallization) for 1d.
a little higher crude yields of 1a, while no double
elimination has been observed in the case of chloride
under condition A. The crude double elimination product
1a contained two major stereoisomers of all-(E) and 13-
(Z) in a 4:1 ratio.16 Purification by careful SiO2 column
chromatography provided all-(E)-1a only in 29-38% yield
presumably due to the abstraction by silica gel. Recrys-
tallization from MeOH and THF, on the other hand, gave
all-(E)-1a in 60-84% yields as a dark-red crystal.
The above double-elimination strategy has been ap-
plied to the synthesis of other carotenoid compounds
1b-d (Scheme 4). Allylic sulfones 2b, 2c,17 and 2d18
coupled with the dialdehyde 3 to produce the diols 8b-d
in 79-91% yields. Protections of the diols to MOM ethers
9b and 9c proceeded in 92% and 90% yields, respectively.
A much lower 67% yield was obtained for 9d, presumably
due to the instability of the conjugated triene moiety. The
KOMe-mediated double-elimination reactions of 9b-d in
cyclohexane at 80 °C for 16 h (condition A) produced all-
(E)-carotenoids 1b19 (49% yield), 1c20 (77% yield), and 1d6f
(28% yield) after purifications. The lower yields of the
carotenoids 1b and 1d may be ascribed to the intrinsic
instability of the acyclic conjugated polyene chains.
In conclusion, we have developed a highly efficient
synthetic method of carotenoid compounds by the sulfone
coupling and double elimination strategy. This method
highlighted the sulfone-mediated coupling with the novel
2,7-dimethyl-4-octenedial (3), which was easily prepared
and efficiently utilized in the synthesis of the conjugated
polyene chains. Applications of this method to the
Data for 8a: Rf ) 0.15-0.23 (hexanes/EtOAc ) 4:1); 1H NMR
(major) δ 0.75 (d, J ) 6.8 Hz, 6H), 0.96 (s, 6H), 0.99 (s, 6H),
1.22 (s, 6H), 1.40-1.50 (m, 4H), 1.50-1.70 (m, 6H), 1.67 (s, 6H),
1.90-2.25 (m, 8H), 2.65 (br s, 2H), 4.04 (dd, J ) 11.0, 9.3 Hz,
2H), 4.37 (dd, J ) 9.2, 1.8 Hz, 2H), 4.98 (d, J ) 11.0 Hz, 2H),
5.32-5.50 (m, 2H), 5.96 (s, 4H), 7.44-7.55 (m, 4H), 7.58-7.68
(m, 2H), 7.75-7.85 (m, 4H); 13C NMR (major) δ 11.5, 12.2, 19.2,
21.6, 28.8, 28.9, 32.9, 34.1, 36.3, 37.3, 39.4, 70.0, 71.0, 117.7,
128.7, 128.8, 129.4, 129.8, 130.5, 133.8, 135.7, 137.1, 137.3, 141.9;
IR (KBr) 3524, 2928, 1446, 1298, 1143 cm-1; HRMS (FAB+) calcd
for C40H61O2 (C52H73O6S2 - 2C6H6O2S) 573.4672, found 573.4681.
(2) MOM Protection. 5,14-Bis(benzenesulfonyl)-3,7,12,
16-tetramethyl-1,18-bis(2,6,6-trimethyl-1-cyclohexenyl)oc-
tadeca-1,3,9,15,17-pentaene-6,13-diol, Bis(methoxymethyl)
Ether (9a-5). To a stirred solution of the diol 8a (1.183 g, 1.38
mmol) in dimethoxymethane (2.45 mL, 27.6 mmol) was added
P2O5 (0.12 g, 0.83 mmol) at room temperature. After the mixture
was stirred for 5 h, an additional portion of P2O5 (0.12 g, 0.83
mmol) was added again to the mixture. After being stirred for
20 h at room temperature, the mixture was extracted with
toluene, and 10% NaHCO3 solution was added. The organic layer
was washed again with 10% NaHCO3 solution, dried over Na2-
SO4, filtered, and concentrated under reduced pressure. The
crude product (1.42 g) was purified by SiO2 flash column
chromatography (hexanes/EtOAc ) 8:1-2:1) to give the MOM
diether 9a-5 (1.212 g, 1.282 mmol) in 93% yield as a white solid,
which contained many stereoisomers due to the presence of six
chiral centers. The major stereoisomer, which was presumed to
be all-(E)-isomer, was carefully purified again by preparative
TLC for spectroscopic analysis.
Data for 9a-5: Rf ) 0.17-0.25 (hexanes/EtOAc ) 4:1); 1H
NMR (major) δ 0.93 (s, 6H), 0.95 (s, 6H), 0.98 (d, J ) 5.9 Hz,
6H), 1.16 (s, 6H), 1.35-1.50 (m, 4H), 1.50-1.70 (m, 6H), 1.62
(s, 6H), 1.70-1.87 (m, 2H), 1.92-2.13 (m, 6H), 3.41 (s, 6H), 4.16
(d, J ) 7.7 Hz, 2H), 4.29 (dd, J ) 11.4, 7.7 Hz, 2H), 4.77 (d, J )
7.2 Hz, 2H), 4.94 (d, J ) 7.2 Hz, 2H), 5.16 (d, J ) 11.4 Hz, 2H),
5.20 (br s, 2H), 5.88 (s, 4H), 7.38-7.48 (m, 4H), 7.50-7.60 (m,
2H), 7.72-7.84 (m, 4H); 13C NMR (major) δ 12.3, 16.7, 19.1, 21.6,
28.0, 28.0, 32.8, 34.0, 34.2, 37.0, 39.3, 56.2, 68.7, 82.4, 99.0, 119.5,
128.5, 128.6, 129.0, 129.6, 130.2, 133.1, 135.8, 137.2, 139.2, 141.6;
IR (KBr) 2928, 1454, 1306, 1146, 1033 cm-1; HRMS (FAB+) calcd
for C42H65O3 (C56H81O8S2 - 2C6H6O2S - C2H4O) 617.4928, found
617.4951.
(15) Manchand, P. S.; Rosenberger, M.; Saucy, G.; Wehrli, P. A.;
Wong, H.; Chambers, L.; Ferro, M. P.; Jackson, W. Helv. Chim. Acta
1976, 59, 387-396.
(16) The 13-(Z)-â-carotene shows the characteristic peak of C(12)-H
at 6.87 ppm in 1H NMR spectrum. See: Carotenoids, Vol. 1B:
Spectroscopy; Britton, G., Ed.; Birkha¨user: Basel, 1995; Chapter 6.
(17) Torii, S.; Uneyama, K.; Isihara, M. Chem. Lett. 1975, 479-482.
(18) Ji, M.; Choi, H.; Jeong, Y. C.; Jin, J.; Baik, W.; Lee, S.; Kim, J.
S.; Park, M.; Koo, S. Helv. Chim. Acta 2003, 86, 2620-2628.
(19) Schurtenberger, H.; Vo¨geli, U.; Pfander, H. Helv. Chim. Acta
1983, 66, 2346-2357.
(3) Double-Elimination Reaction. â-Carotene (1a). Con-
dition D. To a stirred solution of the MOM diether 9a-5 (0.945
g, 1.0 mmol) in cyclohexane (25 mL) was added KOMe (1.403 g,
(20) Robeson, C. D. US Pat. 2,932,674, 1960; Chem. Abstr. 1960,
54, 129318.
9664 J. Org. Chem., Vol. 70, No. 23, 2005

20.0 mmol). The mixture was heated to 80 °C for 16 h and cooled
to room temperature. The mixture was then diluted with
hexanes, washed three times with H2O, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product (0.548 g), which consisted of a 4:1 mixture of all-(E) and
13-(Z) stereoisomers, was purified by recrystallization (THF/
MeOH ) 1:5) to give all-(E)-1a (0.453 g, 0.84 mmol) in 84% yield
as a red solid.
Acknowledgment. This work was supported by the
Regional Research Center Program of MOCIE (Ministry
of Commerce, Industry and Energy) and Kyunggi-Do.
Supporting Information Available: Experimental pro-
cedures and analytical data for 5-7, 3, 9a-1, 9a-3, 9a-4, 10,
1a-d; 1H NMR spectra of 1a-d, 3, 5-7, 8a, 9a-1, 9a-3, 9a-5,
and 10; and 13C NMR spectra of 6, 7, and 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
The 1H NMR data of 1a were identical with those of the
authentic sample.
JO0516335
J. Org. Chem, Vol. 70, No. 23, 2005 9665