A Short and Efficient Synthesis of Crocetin-dimethylester and Crocetindial

Article abstract of DOI:10.1021/jo034545y

In this paper we describe an efficient six-step synthesis of crocetin-dimethylester that could be further reduced to a "four-step" synthesis through the use of in situ procedures. The simplicity of the whole process, the ready availability of starting materials, and the high overall yield render this strategy a very attractive synthesis of this very important compound, which is the key intermediate for the synthesis of several carotenoids and other polyene natural products.

Full text of DOI:10.1021/jo034545y

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A Sh or t a n d Efficien t Syn th esis of
Cr ocetin -d im eth ylester a n d Cr ocetin d ia l
Daniel Frederico, Paulo Marcos Donate,*
Mauricio Gomes Constantino, Erika Soares Bronze, and
Mirela I. Sairre
Departamento de Qu´ımica, Faculdade de Filosofia,
Cieˆncias e Letras de Ribeira˜o Preto, Universidade de
Sa˜o Paulo, 14040-901 Ribeira˜o Preto, SP, Brazil
pmdonate@usp.br
Received April 28, 2003
Abstr a ct: In this paper we describe an efficient six-step
synthesis of crocetin-dimethylester that could be further
reduced to a “four-step” synthesis through the use of in situ
procedures. The simplicity of the whole process, the ready
availability of starting materials, and the high overall yield
render this strategy a very attractive synthesis of this very
important compound, which is the key intermediate for the
synthesis of several carotenoids and other polyene natural
products.
F IGURE 1. Structure of polyene chains.
derivatives,5 and can be used as starting material for the
syntheses of carotenoids and many other natural pro-
ducts.1,4a,5
The traditional synthetic approaches for compounds
1-4 involve the bismetal acetylide coupling/partial hy-
drogenation1,6 or the Wittig and related reactions.1,7
However, these procedures invariably produce a mixture
of isomers, requiring careful, tedious, and unproductive
isolation-purification processes.1,2c The highly efficient
J ulia’s sulfone olefination protocol8 has found wide use
in the preparation of simple double bonds and conjugated
polyenes, but the presumed instability of some interme-
diates has limited the general utilization of this method.9
For this reason, the search continues for new, selective,
The polyene chains 1-2 (Figure 1) are the starting
materials for the syntheses of carotenoids, which are
compounds widely distributed among plants, animals,
and certain bacteria, that are used as natural pigments
for foodstuffs.1 It is well-known that certain carotenoids
have important biochemical and biological functions, and
have nutritional importance as provitamin A in man.2
Recently, the use of carotenoids as chemoprevention
agents against certain types of cancer has been reported.3
The usage of carotenoids as food additives has been
dramatically increased.
Crocin (3) and crocetin (4) esters are the coloring
principles of saffron, which find uses in medicine as well
as flavoring and coloring agents.4 The crocetin-dimeth-
ylester (1) is a very useful compound because it can be
easily converted to crocetindial (2) and crocin or crocetin
(4) (a) Pfander, H.; Wittwer, F. Helv. Chim. Acta 1975, 58, 1608.
(b) Gainer, J . L.; J ones, J . R. Experientia 1975, 31, 548. (c) Gainer, J .
L.; Wallis, D. A.; J ones, J . R. Oncology 1976, 33, 222. (d) Nair, S. C.;
Pannikar, B.; Panikkar, K. R. Cancer Lett. 1991, 57, 109. (e) Salomi,
M. J .; Nair, S. C.; Panikkar, K. R. Nutr. Cancer 1991, 16, 67. (f)
Morimoto, S.; Umezaki, Y.; Shoyama, Y.; Saito, H.; Nishi, K.; Irino,
N. Planta Med. 1994, 60, 438. (g) Escribano, J .; Alonso, G. L.; Coca-
Prados, M.; Fernandes, J . A. Cancer Lett. 1996, 100, 23. (h) Konashima,
T.; Takasaki, M.; Tokuda, H.; Morimoto, S.; Tanaka, H.; Kawata, E.;
Xuan, L. J .; Saito, H.; Sugiura, M.; Molnar, J .; Shoyama, Y. Phytother.
Res. 1998, 12, 400.
(5) Pfander, H.; Wittwer, F. Helv. Chim. Acta 1979, 62, 1944.
(6) (a) Inhoffen, H. H.; Isler, O.; Bey, G. V. D.; Raspe´, G.; Zeller, P.;
Ahrens, R. Liebigs Ann. Chem. 1953, 580, 7. (b) Mildner, P.; Weedon,
B. C. L. J . Chem. Soc. 1953, 3294. (c) Ahmad, R.; Weedon, B. C. L. J .
Chem. Soc. 1953, 3299. (d) Isler, O.; Lindlar, H.; Montavon, M.; Ru¨egg,
R.; Zeller, P. Helv. Chim. Acta 1956, 39, 249. (e) Manchand, P. S.;
Ru¨egg, R.; Schwieter, U.; Siddons, P. T.; Weedon, B. C. L. J . Chem.
Soc. 1965, 2019.
(7) (a) Buchta, E.; Andree, F. Chem. Ber. 1960, 93, 1349. (b) Pommer,
H.; Kuhn, R. Angew. Chem. 1960, 72, 911. (c) Pommer, H.; Nu¨rrenbach,
A. Pure Appl. Chem. 1975, 43, 527. (d) Pommer, H. Angew. Chem. 1977,
89, 437. (e) Zumbrunn, A.; Uebelhart, P.; Eugster, C. H. Helv. Chim.
Acta 1985, 68, 1519.
(8) (a) J ulia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743. (b) J ulia,
M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746. (c) Olson, G. L.; Cheung,
H.-C.; Morgan, K. D.; Neukom, C.; Saucy, G. J . Org. Chem. 1976, 41,
3287. (d) Fischli, A.; Mayer, H.; Simon, W.; Stoller, H.-J . Helv. Chim.
Acta 1976, 59, 397. (e) Otera, J .; Misawa, H.; Onishi, T.; Suzuki, S.;
Fujita, Y. J . Org. Chem. 1986, 51, 3834. (f) Hagen, J .; Klaus, K.;
Manfred, H. Eur. Patent 523 534, 1992.
(9) (a) Buchta, E.; Andree, F. Ann. 1961, 640, 29. (b) Surmatis, J .
D.; Ofner, A. J . Org. Chem. 1961, 26, 1171. (c) Okukado, N.; Uchikawa,
O.; Nakamura, Y. Chem. Lett. 1988, 1449. (d) Choi, H.; J i, M.; Park,
M.; Yun, I.-K.; Oh, S.-S.; Baik, W.; Koo, S. J . Org. Chem. 1999, 64,
8051 and references therein.
(1) (a) Isler, O., Ed. Carotenoids; Birkha¨user Verlag: Basel, Swit-
zerland, 1971. (b) Isler, O. Pure Appl. Chem. 1979, 51, 447. (c) Widmer,
E. Pure Appl. Chem. 1985, 57, 741. (d) Pfander, H., Ed. Key to
Carotenoids, 2nd ed.; Birkha¨user Verlag: Basel, Switzerland, 1987.
(e) Bernhardt, K.; Mayer, H. Pure Appl. Chem. 1991, 63, 35. (f) Paust,
J . Pure Appl. Chem. 1991, 63, 45. (g) Britton, G.; Liaaen-J ensen, S.;
Pfander, H., Eds. Carotenoids; Vol. 2, Synthesis; Birkha¨user: Neward,
Switzerland, 1996.
(2) (a) Goodwin, T. W., Ed. Chemistry and Biochemistry of Plant
Pigments; Academic Press: London, UK, 1976. (b) Bauernfeind, J . C.
Carotenoids as Colorants and Vitamin A Precursors; Academic Press:
New York, 1981. (c) Britton, G.; Goodwin, T. W., Eds. Carotenoid:
Chemistry and Biochemistry; Pergamon Press: Oxford, UK, 1982. (d)
Bendich, A.; Olson, J . A. FASEB J . 1989, 3, 1927. (e) Olson, J . A. J .
Nutr. 1989, 119, 94. (f) Krinsky, N. I. Carotenoids: Chemistry and
Biology; Plenum: New York, 1990. (g) Miki, W. Pure Appl. Chem. 1991,
63, 141. (h) Britton, G. FASEB J . 1995, 9, 1551.
(3) (a) Ames, B. N. Science 1983, 221, 1256. (b) Krinsky, N. I. Clin.
Nutr. 1988, 7, 107. (c) Bendich, A. J . Nutr. 1989, 119, 112. (d) Ziegler,
R. G. J . Nutr. 1989, 119, 116. (e) Ziegler, R. G. Am. J . Clin. Nutr. 1991,
53, 2515. (f) Malone, W. F. Am. J . Clin. Nutr. 1991, 53, S305. (g)
Sengupta, A.; Das, S. Eur. J . Cancer Prevent. 1999, 8, 325. (h) Pe´rez-
Ga´lvez, A.; M´ınguez-Mosquera, M. I. J . Agric. Food Chem. 2001, 49,
4864 and references therein.
10.1021/jo034545y CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003
9126
J . Org. Chem. 2003, 68, 9126-9128

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SCHEME 1. Syn th esis of Cr ocetin -d im eth ylester (1) a n d Cr ocetin d ia l (2)a
a
Reagents: (a) (i) Br2, CH3OH, (ii) Na2CO3, 75%; (b) Amberlyst-15, CH2Cl2, H2O (2 equiv), 6 (2 equiv), 73%; (c) LiAlH4, THF, 93%;
(d) MnO2, CH2Cl2, 9 (2 equiv), 75%; (e) (i) DIBALH, CH2Cl2, (ii) H2O, (iii) MnO2, 55-63%.
and efficient routes for the synthesis of polyene chains,
carotenoids, and related natural products.10
32% overall yield from the commercially available tiglic
acid).6a,7a,13,17,19 The all-E isomer of compound 1 was thus
obtained in 75% yield from 8 as a brick-red solid after
purification through silica gel column chromatography.
This reaction also supplied (∼15% yield) the geometric
isomer of compound 1 with the double bond in carbons 4
and/or 12 with Z stereochemistry. The reaction of 1 with
diisobutylaluminum hydride in methylene chloride at
-20 °C afforded the corresponding diol, which was
submitted to oxidation with manganese dioxide without
further purification to give compound 2 in 55-63% yield
as a red solid.
In summary, the crocetin-dimethylester (1) was ob-
tained from furan by a short and efficient six-step
synthesis (or four isolation-purification operations) with
an overall yield of 38%. This compound was then con-
verted in crocetindial (2) in two steps (or one isolation-
purification operation) in 55-63% overall yield. The
careful, tedious, and yield-lowering isomer separation
and product purification steps associated with the con-
ventional syntheses of the polyene chain of carotenoids
can be circumvented by the methodology reported here.
This strategy can possibly be applied to the synthesis of
several kinds of related natural products.
In this paper, we describe a short and efficient syn-
thetic route to obtain crocetin-dimethylester (1) using in
situ procedures, involving one-pot hydrolysis of ketals or
oxidation of alcohols followed by Wittig reactions. Com-
pound 1 was later converted in crocetindial (2) in a two-
step process.
The synthesis starts by treatment of furan with a
solution of bromine in methyl alcohol followed by sodium
carbonate, according to the procedure described by Gre´e
et al.,11 to give the fumaraldehyde dimethylacetal 5 as a
colorless oil with a 75% yield (Scheme 1). Compound 5
was submitted to an in situ hydrolysis-Wittig reaction
sequence by treatment with Amberlyst-15 in a two-phase
solvent system consisting of a mixture of methylene
chloride and water,12 and 2 equiv of 2-(triphenyl-λ5-phos-
phanylidene)propionic acid methyl ester (phosphorane 6)
(prepared in two steps from methyl 2-bromopropionate
in 41% overall yield13 or alternatively in four steps from
ethyl bromoacetate in 87% overall yield14) to give only
the all-E isomer of compound 7, in 73% yield from
dimethyl acetal 5, as a white solid.15
Reduction of 7 with lithium aluminum hydride pro-
duced diol 8, which was purified by recrystallization from
n-hexane to give a white solid in 93% yield.18 Compound
8 was submitted to an in situ oxidation-Wittig reaction16
sequence with manganese dioxide and 2 equiv of the
2-methyl-4-(triphenyl-λ5-phosphanylidene)but-2-enoic acid
methyl ester (phosphorane 9) (prepared in four steps in
Exp er im en ta l Section
(2E)-1,1,4,4-Tetr a m eth oxybu t-2-en e (5). Freshly distilled
furan (9.40 mL, 129 mmol) and anhydrous methyl alcohol (65
mL) were placed in a 250-mL three-necked flask and cooled to
-45 °C under a nitrogen atmosphere. A solution of bromine (6.80
mL; 133 mmol) in methyl alcohol (65 mL) was added dropwise
at such a rate that the temperature did not exceeded -25 °C.
At the end of the addition, the reaction mixture was stirred for
2 h at -10 °C. Powdered anhydrous sodium carbonate (40 g)
was added portionwise over a period of about 30 min and the
(10) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719 and references
therein.
(11) Gre´e, R.; Tourbah, H.; Carrie´, R. Tetrahedron Lett. 1986, 27,
4983.
(12) Coppola, G. M. Synthesis 1984, 1021.
(13) Isler, O.; Gutmann, H.; Montavon, M. Helv. Chim. Acta 1957,
40, 1242.
(14) J ansen, F. J . H. M.; Lugtenburg, J . Pure Appl. Chem. 1994,
66, 963.
(17) Ingold, K. V.; Roberts, B. P. Free Radical Substitution Reactions;
J ohn Wiley & Sons: New York, 1971; p 22.
(18) (a) Inhoffen, H. H.; Bey, G. V. D. Liebigs Ann. Chem. 1953, 583,
100. (b) Inhoffen, H. H.; Krause, H. J .; Bork, S. Liebigs Ann. Chem.
1954, 585, 132.
(15) Fischetti, W.; Mak, K. T.; Stakem, F. G.; Kim, J .-I.; Rheingold,
A. L.; Heck, R. F. J . Org. Chem. 1983, 48, 948.
(16) Wei, W.; Taylor, R. K. J . Org. Chem. 2000, 65, 616.
(19) Duffield, J . J .; Pettit, G. R. J . Nat. Prod. 2001, 64, 472.
J . Org. Chem, Vol. 68, No. 23, 2003 9127

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reaction mixture was stirred for 18 h at room temperature. The
mixture was then filtered and the solvent was removed under
vacuum. The residue was purified by distillation (65-70 °C, 1
mmHg) and compound 5 (17.1 g; 97 mmol) was obtained in 75%
yield.
Dim et h yl (2E,4E,6E)-2,7-Dim et h yloct a -2,4,6-t r ien e-1,8-
d ioa te (7). A solution of compound 5 (0.636 g; 3.6 mmol) in
methylene cloride (15 mL) was added to a solution of phospho-
rane 6 (2.54 g; 7.3 mmol) in methylene cloride (40 mL).
Amberlyst-15 (0.420 g) and water (0.13 mL; 7.2 mmol) were
added and the suspension was stirred for 1 h at room temper-
ature. The solvent was removed under vacuum and the residue
was purified by column chromatography through silica gel, using
a mixture of n-hexane and ethyl acetate (8.5:1.5) as eluent. After
evaporation of the solvent, compound 7 was obtained in 73%
yield (0.589 g; 2.6 mmol).
(2E,4E,6E)-2,6-Dim eth ylocta -2,4,6-tr ien e-1,8-d iol (8). A
solution of compound 7 (0.180 g; 0.8 mmol) in dry THF (6 mL)
was added to lithium aluminum hydride (0.075 g; 1.98 mmol)
in dry THF (30 mL) at 0 °C. The mixture was stirred at this
temperature for 10 min. The reaction was quenched by succes-
sive addition of water (0.12 mL), 15% aqueous sodium hydroxide
(0.12 mL), and again water (0.24 mL). The solid was removed
by filtration and the solvent was evaporated. The residue was
recrystallized from n-hexane to give compound 8 in 93% yield
(0.125 g; 0.74 mmol).
(8.5:1.5) as eluent. After evaporation of the solvent, compound
1 was obtained in 75% yield (0.064 g; 0.18 mmol).
(2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-Tet r a m et h ylh exa -
d eca -2,4,6,8,10,12,14-h ep ta en e-1,16-d ia l (2). To a solution of
compound 1 (0.030 g; 0.084 mmol) in dry methylene chloride (5
mL) was added a solution (0.5 M) of diisobutylaluminum hydride
in dry methylene chloride (0.50 mL; 0.252 mmol) at -20 °C. The
mixture was stirred at this temperature for 30 min in the dark.
Subsequently, water (0.2 mL) was added and the suspension was
strongly stirred for 5 h at room temperature. Manganese dioxide
(0.120 g; 1.26 mmol) was then added and the reaction mixture
was stirred at room temperature for an additional 12-h period.
The solid was removed by filtration through a pad of magnesium
sulfate and washed several times with methylene chloride. The
solvent was removed under vacuum and the residue was purified
by column chromatography through silica gel, using a mixture
of n-hexane and ethyl acetate (1:1) as eluting solvent. After
evaporation of the solvent, compound 2 was obtained in 55-
63% yield (0.013-0.015 g; 0.046-0.53 mmol).
Ack n ow led gm en t. The authors wish to thank the
Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo
(FAPESP), the Conselho Nacional de Desenvolvimento
Cient´ıfico e Tecnolo´gico (CNPq), and the Coordenadoria
de Aperfeic¸oamento de Pessoal do Ensino Superior
(CAPES) for financial support. Useful discussions with
Prof. Dr. Gil Valdo J ose´ da Silva (FFCLRP-USP) and
Prof. Dr. Norberto Peporini Lopes (FCFRP-USP) are
also acknowledged.
Dim eth yl
(2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-Tetr a -
m eth ylh exa d eca -2,4,6,8,10,12,14-h ep ta en e-1,16-d ioa te (1).
A mixture of compound 8 (0.040 g; 0.24 mmol), phosphorane 9
(0.195 g; 0.52 mmol), and manganese dioxide (0.310 g; 3.56
mmol) in dry methylene chloride (15 mL) was stirred at room
temperature for 24 h. The reaction was monitored by TLC (8.5:
1.5 n-hexane:ethyl acetate) until the starting material was no
longer detectable. The solid was removed by filtration through
a pad of magnesium sulfate, which was then washed with
additional methylene chloride. The solvent was removed under
vacuum and the residue was purified by column chromatography
through silica gel, using a mixture of n-hexane and ethyl acetate
Su p p or tin g In for m a tion Ava ila ble: General methods
and characterization data for compounds 1, 2, 5, 7, and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O034545Y
9128 J . Org. Chem., Vol. 68, No. 23, 2003