Synthesis of C40-symmetrical fully conjugated carotenoids by olefin metathesis

Article abstract of DOI:10.1002/ejoc.201100935

In an effort to push olefin metathesis to the limits of conjugation in reactants and products, the C₄₀-symmetrical carotenoids β,β-carotene (1), lycopene (2), (3R,3′R)-zeaxanthin (3), and rac-isozeaxanthin (4), which are conjugated undecaenes, have been synthesized from C₂₁-terminal hexaenes by treatment with Grubbs' second-generation Ru catalyst in dichloromethane at 50 °C.

Full text of DOI:10.1002/ejoc.201100935

FULL PAPER
DOI: 10.1002/ejoc.201100935
Synthesis of C40-Symmetrical Fully Conjugated Carotenoids by Olefin
Metathesis
Noelia Fontán,[a] Marta Domínguez,[a] Rosana Álvarez,*[a] and Ángel R. de Lera*[a]
Keywords: Polyenes / Polyolefins / Terpenoids / Carotenoids / Metathesis
In an effort to push olefin metathesis to the limits of conjuga- enes, have been synthesized from C21-terminal hexaenes by
tion in reactants and products, the C40-symmetrical carot- treatment with Grubbs’ second-generation Ru catalyst in
enoids β,β-carotene (1), lycopene (2), (3R,3ЈR)-zeaxanthin (3),
and rac-isozeaxanthin (4), which are conjugated undeca-
dichloromethane at 50 °C.
Introduction
Carotenoids are a large and widely distributed group of
pigments, which are biosynthesized in large quantities by
plants, some animals and microorganisms but not by hu-
mans.[1] The role of carotenoids in the coloration of Nature,
as well as in photosynthesis and the photoprotection of
plants and animals is well established.[2] The antioxidant
properties of carotenoids have been a major focus of atten-
tion recently, with chemoprevention effects added to their
traditional use as colorants for the food and beverage in-
dustries. The enzymatic conversion of β,β-carotene (1, Fig-
ure 1) to retinol (vitamin A) via the product of central
metabolic cleavage by trans-retinal has linked carotenoid in-
take and nutrition to human health. Carotenoids also play
an important role in the prevention of certain human dis-
eases such as cardiovascular disease and cancer.[1b,1c]
Over 700 carotenoids have been described to date.[3] The
great skeletal diversity of the carotenoids originates from
enzymatic modifications of an acyclic C40 tetraterpenoid
skeleton (composed of eight isoprenoid units joined head-
to-tail except at the center, where the connection is reversed)
including cyclizations, oxidations, dehydrogenations, and
rearrangements. The carotenoid family is broadly subdi-
vided into two main classes: the carotenes, both cyclic (e.g.
1) and acyclic [e.g. lycopene (2)] hydrocarbons, and the xan-
thophylls, which incorporate at least one oxygen atom [e.g.
zeaxanthin (3) and isozeaxanthin (4)].[3]
Figure 1. Symmetrical C40 carotenoids.
Carotenoids have traditionally been synthesized[4] using
condensation methods, such as Wittig,[5] Horner–Wad-
sworth–Emmons, and Julia reactions to form Csp2=Csp2
bonds,[6] and more recently using palladium-catalyzed
cross-coupling reactions (primarily Negishi,[7,8] Stille,[9] and
Suzuki)[9a,10] to form Csp2–Csp2 bonds. Regardless of the
strategy used, functionalization of the components for the
key reaction(s) is required.[4a] This is also true for the for-
mation of C40 precursors, which generate polyenes by sul-
fone elimination[11] combined with Ramberg–Bäcklund re-
arrangement[12] and related methods.
[a] Departamento de Química Orgánica, Facultade de Química,
Universidade de Vigo,
36310 Vigo, Spain
Fax: +34-986-818622
E-mail: qolera@uvigo.es
rar@uvigo.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100935.
6704
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6704–6712

Synthesis of C40-Symmetrical Conjugated Carotenoids
In the case of C40 symmetrical carotenoids, construction from C21 hexaene precursors, which were obtained by Wit-
tactics (including those used in industrial processes) have tig olefination of all-trans-retinal and the corresponding an-
exploited the symmetry, and thus functionalized C20 retinal alogs (Figure 2).
and its derivatives (phosphonium salts and sulfones) have
been paired to afford tetraterpenoid skeletons (C40
C
=
20 + C20).[4a] In principle, dimerization reactions offer the
Results and Discussion
synthetic advantage that only one functionalized compo-
nent is required in the last step of the synthesis. In the ca-
rotenoid field, this principle has been exploited only in the
synthesis of 1[13] and isorenieratene[14] by McMurry’s low
valent titanium carbonyl coupling. An equally powerful ap-
proach would be a dimerization strategy based on olefin
metathesis,[15] which is undoubtedly one of the most general
and widely applicable synthetic methods for Csp2=Csp2
bond formation. Despite the numerous applications of ole-
fin metathesis reactions in the synthesis of a wide variety of
natural products,[16] extension of the methodology to pre-
pare conjugated polyene chains[17] has been somehow lim-
ited because of concerns about the control of site-selectivity,
stereoselectivity, and the stability of polyenes to the reaction
conditions. The cross-metathesis of 1 with ethylene or
methyl sorbate has led to complex mixtures of undesired
sideproducts in low yields.[18]
As a model system to test the applicability of the meta-
thesis protocol for the synthesis of symmetrical undecaene
carotenoids, we targeted the preparation of 1. Starting from
commercial retinol acetate 7, all-trans-hexaene 9 was syn-
thesized in good yield by a three-step sequence that in-
volved MeLi-induced acetate release to afford retinol 8,
MnO2 oxidation under basic conditions, and Wittig ole-
fination of all-trans-retinal with methyltriphenylphospho-
nium bromide using sodium bis(trimethylsilyl)amide
(NaHMDS) as base in tetrahydrofuran (THF) with hexa-
methylphosphoramide (HMPA) as cosolvent (Scheme 1).
Despite these anticipated problems, we decided to test
the scope and limitations of olefin metathesis of highly con-
jugated polyenes and explore its synthetic potential for the
preparation of symmetrical carotenoids starting from the
corresponding terminal olefins. At the outset, it was consid-
ered that the metathesis processes at the terminal double
bond would be favored over those of the tetra-, tri-, and
disubstituted double bonds in the starting polyenes given
that some olefin metathesis initiators are sensitive to steric
Scheme 1. Reagents and conditions: a) MeLi, THF, –15 °C, 45 min,
83%; b) MnO2, Na2CO3, CH2Cl2, 25 °C, 4 h, 49%; c) MePPh3Br,
NaHMDS (1 m in THF), HMPA, THF, –78 °C, 1.5 h, 85%.
With 9 in hand, we carried out an optimization study of
hindrance. After we had started this project, Katsumura the olefin metathesis using different ruthenium catalysts
and coworkers established the proof-of-principle of this ap- and solvents, taking particular care to control the reaction
proach with the total synthesis of two symmetrical C40 ca- temperature and trying to minimize reaction times to avoid
rotenoids, namely mimulaxanthin (5) and violaxanthin deterioration of the polyenes (Table 1). In all cases the all-
(6).[19]
trans isomer of 1 was obtained as the major product, but
Once we were aware of the synthesis of conjugated nona- the starting hexaene (in some cases, as a mixture of isomers
enes 5 and 6 (in the former the conjugation is interrupted ranging from 2.5:1 to 9:1) was partially recovered. In ad-
at the allene functional group), we decided to further ex- dition, 1 was accompanied by secondary products 10–12,
plore the scope of the metathesis approach by targeting presumably formed by cross-metathesis of the C9=C10,
even more conjugated carotenoids (undecaenes). We report C11=C12, and C13=C14 bonds of either the reactant, the
the application of olefin metathesis/dimerization to the syn- product or the putative chain-shortened intermediates.
thesis of representative symmetrical fully conjugated C40 ca- These secondary products were identified by comparison
rotenoids (Figure 1), namely 1, 3, 4, and acyclic 2, starting with authentic samples prepared by the Wittig reaction of
the corresponding carbonyl precursors (commercial β-
ionone, trans,trans-β-ionylideneacetaldehyde,[20] and trans-
β-apo-13-carotenone,[21] respectively). Cleavage at the β,β-
carotene double bonds has already been observed during
ethenolysis (metathesis with ethylene) of 1.[18]
Treatment of 9 with Grubbs’ second generation cata-
lyst[22] in CH2Cl2 at 40 °C for 6.5 h led to incomplete con-
version to 1 in 43% yield together with byproducts corre-
sponding to cleavage at the C9=C10 (10), C11=C12 (11),
and C13=C14 (12) bonds in Ͻ1, 6, and 5% yield, respec-
tively (Entry 1). Increasing the reaction time to 20 h led to
a higher yield of 1 without detection of 12 (Entry 2). Ex-
tending the reaction time to 70 h was detrimental (Entry 3),
Figure 2. Retrosynthetic analysis from C40 carotenoids to C20 reti-
nals.
Eur. J. Org. Chem. 2011, 6704–6712
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Table 1. Optimization of the metathesis/dimerization to 1.
Entry
Conditions
1
10
11
12
9
1
2
3
4
5
6
7
8
9
Grubbs 2nd generation, CH2Cl2, 40 °C, 6.5 h
Grubbs 2nd generation, CH2Cl2, 40 °C, 20 h
Grubbs 2nd generation, CH2Cl2, 40 °C, 70 h
Grubbs 2nd generation, toluene, 40 °C, 20 h
Grubbs 2nd generation, CH2Cl2, 50 °C, 6.5 h
Grubbs 2nd generation, CH2Cl2, 50 °C, 25 h
Hoveyda–Grubbs, CH2Cl2, 50 °C, 44 h
Grubbs 2nd generation, CuI, Et2O, 40 °C, 3 h
NeolystTM M1, CH2Cl2, 50 °C, 44 h
43%
50%
31%
50%
traces
1%
–
2%
traces
2%
2%
–
6%
8%
17%
7%
3%
9%
9%
3%
–
5%
–
–
14%
25%
16%
11%
15%
–
–
57%
5%
19%
–
2%
–
45%
49%[a]
53%
1%
16%
32%
19%
21%[b]
13%[a]
–
10
Nitro Grela, CH2Cl2, 50 °C, 6.5 h
traces
6%
4%
[a] The final product (as a mixture of isomers) is contaminated with the catalyst and/or ruthenium byproducts. [b] The final isolated
product contained impurities.
scavenging reagent, led to faster metathesis rates and avo-
ided the need for chlorinated solvents, the yield of the final
product could not be improved. Further attempts to in-
crease the reaction selectivity and yield by changing the cat-
alyst to more reactive and thermally robust ruthenium carb-
enes, such as recyclable Hoveyda–Grubbs,[23] NeolystTM
M1,[25] and Nitro Grela[26] catalysts, had a detrimental ef-
fect on the reaction (Entries 8–10).
Once optimized, we extended this methodology to the
synthesis of different C40 carotenoids starting from the ter-
minal C21 hexaenes. The terminal alkenes were prepared by
Wittig olefination of the corresponding retinal analogs
(Figure 2), which were synthesized by palladium-catalyzed
cross-coupling reactions.
A new stereoselective synthesis of the acyclic retinal (γ-
retinal) 19,[27] shown in Scheme 2, was developed, which
used the Stille cross-coupling reaction between the pre-
viously described stannane 17[28] and iodide 16. Iodide 16
was prepared in good yield from commercial (E)-geraniol
as the yield of 1 decreased, whereas that of 11 originating
from metathesis at the sterically less hindered disubstituted
C11=C12 double bond increased. This finding is consistent
with previous results from the cross-metathesis reaction of
1 and ethylene (12, 6%; 11, 8%; 10, Ͻ1%) at ambient tem-
perature using Hoveyda–Grubbs second generation cata-
lyst[23] in toluene with prolonged reactions times (48–96 h).
The effect of the solvent on the metathesis reaction was
briefly examined (Entry 4), but the replacement of CH2Cl2
by toluene did not lead to an improvement. Regarding the
optimal temperature, an increase from 40 to 50 °C afforded
1 in 57% yield (Entry 5), whereas longer reaction times
proved detrimental, with 12 isolated in 19% yield after 25 h
(Entry 6). Treatment of 9 with Grubbs’ second-generation
catalyst using CuI as cocatalyst in ether at 40 °C, as re-
ported by Lipshutz and coworkers,[24] led to 1 in 53% yield
together with the byproducts (Entry 7) in just 3 h. Although
the use of a copper(I) salt, which is considered to play a
Scheme 2. Reagents and conditions: a) TPAP/NMO, CH2Cl2,
25 °C, 4 h, 83%; b) iPr2NH, nBuLi, TMSCHN2, THF, –78 to
25 °C, 1.5 h, 84%; c) i. Cp2ZrCl2, DIBAL-H, THF, 25 °C, 1 h. ii.
I2, THF, –78 °C, 30 min, 73%; d) Compound 17 (1.3 equiv.), 16
(1.0 equiv.), [NBu4][Ph2PO2] (1.1 equiv.), CuTC (1.5 equiv.),
Pd(PPh3)4 (10 mol-%), 58%; e) MnO2, Na2CO3, THF, 25 °C,
beneficial role both as a catalyst stabilizer and phosphane- 30 min, 96%.
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Eur. J. Org. Chem. 2011, 6704–6712

Synthesis of C40-Symmetrical Conjugated Carotenoids
13 by a three-step sequence. The oxidation of 13 with tetra-
n-propylammonium perruthenate (TPAP) and N-methyl-
morpholine N-oxide (NMO) in CH2Cl2, was followed by
chain extension of aldehyde 14 to terminal alkyne 15 (83%
yield) using the Colvin rearrangement.[29] Hydrozir-
conation/iodination of 15 using the Schwartz reagent[30]
[generated in situ from Cp2ZrCl2 and diisobutylaluminium
hydride (DIBAL-H)][31] and trapping with iodine afforded
iodide 16 in 73% yield. Stille cross-coupling between 16
(1.0 equiv.) and 17 (1.0 equiv.) under Fürstner conditions
{Pd(PPh3)4, copper thiophenecarboxylate (CuTC), and
[NBu4][Ph2PO2] as tin scavenger}[32] afforded hexaenol 18
in 35% yield. The product of the destannylation of 17 was
also isolated on using an excess of stannane,
[NBu4][Ph2PO2] or CuTC. When 1.3 equiv. of stannane
were used, the yield of 18 increased to 58%. Subsequent
MnO2 oxidation of 18 under basic conditions afforded 19
in excellent yield.
Scheme 5. Reagents and conditions: a) MePPh3Br, NaHMDS or
nBuLi, HMPA, THF, –78 °C, 2 h (26, 86%; 27, 57%; 28, 97%); b)
Grubbs 2nd generation catalyst, CH2Cl2, 50 °C, 6.5 h (2, 59%); c)
tetrabutylammonium fluoride (TBAF), THF, 25 °C (3, 67%; 4,
44% combined yields).
The terminal polyenes 26–28 were subjected to the opti-
mized conditions for metathesis described for the prepara-
tion of 1. Surprisingly, the cleavage of other double bonds
was minimized in contrast to the results obtained with 1
(and its hexaene precursor). Thus, 2 was produced in 59%
yield, whereas 3 (for other syntheses, see ref.[4a]) and 4 (for
other syntheses, see ref.[35,36]) were acquired in 67 and 44%
yield, respectively, following the deprotection of the
TBDMS group with TBAF in THF at 25 °C and purifica-
tion of the reaction mixtures by column chromatography
(C18 silica gel, from 90:10 CH3CN/CH2Cl2 to 80:20
CH3CN/CH2Cl2).
(R)-all-trans-3-(tert-Butyldimethylsilyloxy)retinal
(21)
was obtained from (R)-3-(tert-butyldimethylsilyloxy)retinol
(20)[33] in quantitative yield by oxidation with MnO2 under
basic conditions (Scheme 3).
Scheme 3. Reagents and conditions: a) MnO2, Na2CO3, CH2Cl2,
5 h, 99% (TBDMSO = tert-butyldimethylsilyloxy).
Conclusions
The positional isomer at C4 [4-(tert-butyldimethylsilyl-
oxy)retinol, 24] was prepared in 80% yield by C8–C9 Stille
cross-coupling of dienyliodide 23 easily obtained from 22[34]
and 17[28] using Fürstner conditions (Scheme 4).[32] Oxi-
dation of 24 with Dess–Martin periodinane in CH2Cl2/pyr-
idine afforded protected 4-hydroxyretinal 25 in good yield
(65%).
We have developed a new stereoselective synthesis for
four representative C40-symmetrical carotenoids [cyclic β,β-
carotene (1), acyclic lycopene (2), and two xanthophylls,
zeaxanthin (3) and rac-isozeaxanthin (4)] and demonstrated
that the olefin metathesis protocol can be extended to the
synthesis of conjugated polyenes with up to eleven double
bonds.[4a] The release of ethylene upon metathesis opens a
new construction strategy for these natural products in ca-
rotenoid synthetic terminology,[4a] namely C40 = C21
+
C21 – C2.[4a] These carotenoids represent the longest conju-
gated polyenic compounds prepared to date using a metath-
esis reaction.
Experimental Section
Scheme 4. Reagents and conditions: a) TBDMSCl, imidazole, N,N-
dimethylformamide (DMF), 25 °C, 4.5 h, 89%; b) [NBu4][Ph2PO2],
CuTC, Pd(PPh3)4, DMF, 25 °C, 2 h, 80%, c) Dess–Martin
periodinane, pyridine, CH2Cl2, 0 °C, 4 h, 65%.
General: Solvents were dried according to published methods and
distilled before use. All other reagents were commercial compounds
of the highest purity available. All reactions were carried out under
an argon atmosphere and those not involving aqueous reagents
were carried out in oven-dried glassware. All solvents and anhy-
drous solutions were transferred through syringes and cannulae
previously dried in the oven for at least 12 h and kept in a dessic-
ator with KOH. THF, CH2Cl2, and DMF were dried using a Pure-
solvTM solvent purification system. Et3N and pyridine were dried
by distillation with CaH2. For reactions at low temperature, ice-
water or CO2/acetone systems were used. For different tempera-
tures, a HaaKe EK90 Immersion Cooler (–90 °C to –15 °C) was
Wittig olefination of 19, 21, and 25 with methyltri-
phenylphosphonium bromide using NaHMDS or nBuLi as
base in THF with HMPA or 1,3-dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone
(DMPU)
as
cosolvent
(Scheme 5) gave good yields of the terminal hexaenes 26–
28, which were required as starting materials for the dimer-
ization metathesis reactions.
Eur. J. Org. Chem. 2011, 6704–6712
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N. Fontán, M. Domínguez, R. Álvarez, Á. R. de Lera
FULL PAPER
used. Analytical TLC was performed on aluminium plates with
Merck Kieselgel 60F254 and visualized by UV irradiation (254 nm)
or by staining with a solution of phosphomolibdic acid or anisal-
dehyde. Flash column chromatography was carried out using
Merck Kieselgel 60 (230–400 mesh) under pressure. UV/Vis spectra
were recorded with a Cary 100 Bio spectrophotometer in MeOH.
IR spectra were obtained with a JASCO FTIR 4200 spectropho-
tometer, from a thin film deposited onto NaCl glass. EI-MS were
recorded with a GC-TOF instrument (Waters Micromass). HRMS
(ESI+) were measured with an Apex III FT ICR mass spectrometer
(Bruker Daltonics). 1H NMR spectra were recorded in CDCl3,
C6D6, and (CD3)2CO at ambient temperature with a Bruker AMX-
400 spectrometer operating at 400.16 MHz with residual protic sol-
vent as the internal reference [CDCl3, δ = 7.26 ppm; C6D6, δ =
7.16 ppm; (CD3)2CO, δ = 2.05 ppm]; chemical shifts (δ) are given
in parts per million (ppm) and coupling constants (J) are given in
Hertz (Hz). The proton spectra are reported as follows: δ (multi-
plicity, coupling constant J, number of protons). 13C NMR spectra
were recorded in CDCl3, C6D6, and (CD3)2CO at ambient tempera-
ture with the same spectrometer operating at 101.62 MHz with the
central peak of CDCl3 (δC = 77.2 ppm), C6D6 (δC = 128.0 ppm),
and (CD3)2CO (δC = 29.84 ppm) as the internal reference. A
DEPT-135 pulse sequence was used to aid the assignment of signals
in the 13C NMR spectra.
(1E,3E)-2-(3-methylhexa-1,3,5-trienyl)-1,3,3-trimethylcyclohex-1-
ene (11, C11–C12 cleavage), 1.0 mg (5%) of an oil identified as
(1E,3E,5E)-2-(3,7-dimethylocta-1,3,5,7-tetraenyl)-1,3,3-trimethyl-
cyclohex-1-ene (12, C13–C14 cleavage), 2.9 mg of 9 (15% recovery),
and 11 mg (57%) of a red solid identified as 1.
1
Data for 1: H NMR (400.13 MHz, C6D6): δ = 6.79 (dd, J = 14.8,
11.4 Hz, 2 H), 6.7–6.6 (m, 2 H), 6.49 (d, J = 14.9 Hz, 2 H), 6.4–
6.3 (m, 8 H), 1.99 (t, J = 5.6 Hz, 4 H), 1.94 (s, 6 H), 1.88 (s, 6 H),
1.82 (s, 6 H), 1.7–1.6 (m, 4 H), 1.5–1.4 (m, 4 H), 1.16 (s, 12 H)
ppm. MS (EI): m/z (%) = 536 (51) [M]+, 209 (31), 171 (40), 169
(35), 159 (60), 157 (62), 145 (71), 143 (54), 133 (57), 131 (43), 121
(53), 119 (99), 107 (56), 105 (100), 95 (57), 93 (53), 91 (62). HRMS
(EI): calcd. for C40H56 [M]+ 536.4382; found 536.4387. UV
(MeOH): λmax = 449, 280, 241 nm.
Data for 10: 1H NMR (400 MHz, C6D6): δ = 6.28 (d, J = 16.1 Hz,
1 H), 6.19 (d, J = 16.1 Hz, 1 H), 5.00 (s, 1 H), 4.95 (s, 1 H), 1.93
(t, J = 6.2 Hz, 2 H), 1.84 (s, 3 H), 1.73 (s, 3 H), 1.6–1.5 (m, 2 H),
1.5–1.4 (m, 2 H), 1.08 (s, 6 H) ppm. 13C NMR (100.62 MHz,
C6D6): δ = 142.5 (s), 138.0 (s), 136.7 (d), 129.0 (s), 127.8 (d), 115.5
(t), 40.0 (t), 34.5 (s), 33.2 (t), 29.1 (q, 2ϫ), 21.8 (q), 19.8 (t), 18.7
(q) ppm. MS (EI): m/z (%) = 190 (20) [M]+, 175 (27), 133 (29), 120
(28), 119 (28), 105 (100), 91 (47), 77 (20). HRMS (EI): calcd. for
C14H22 [M]+ 190.1722; found 190.1731. IR (NaCl): ν = 2962 (s, C–
˜
H), 2928 (s, C–H), 2865 (m, C–H), 1452 (s), 968 (s) cm–1. UV
(1E,3E,5E,7E)-2-(3,7-Dimethyldeca-1,3,5,7,9-pentaenyl)-1,3,3-tri-
methylcyclohex-1-ene (9): General procedure for the Wittig ole-
fination. To a suspension of methyltriphenylphosphonium bromide
(1.13 g, 3.16 mmol) in THF (2.8 mL) was added dropwise sodium
bis(trimethylsilyl)amide (2.81 mL, 1 m in hexanes, 2.81 mmol), and
the resulting mixture was stirred for 30 min at room temp. The
mixture was cooled to –60 °C and HMPA (0.42 mL, 2.64 mmol)
was added. After stirring for 10 min, the mixture was cooled to
–78 °C and a solution of retinal (0.5 g, 1.76 mmol) in THF (22 mL)
was added. After being stirred for 1.5 h at the same temperature,
hexane was added, and the combined organic layers were washed
(MeOH): λmax = 261, 227 nm.
1
Data for 11: H NMR (400 MHz, C6D6): δ = 6.70 (ddd, J = 16.7,
11.1, 10.2 Hz, 1 H), 6.26 (d, J = 15.8 Hz, 1 H), 6.25 (d, J = 15.8 Hz,
1 H), 6.13 (d, J = 11.1 Hz, 1 H), 5.18 (d, J = 16.7 Hz, 1 H), 5.07
(d, J = 10.2 Hz, 1 H), 1.95 (t, J = 6.3 Hz, 2 H), 1.79 (s, 3 H), 1.75
(s, 3 H), 1.6–1.5 (m, 2 H), 1.5–1.4 (m, 2 H), 1.10 (s, 6 H) ppm. 13
C
NMR (100.62 MHz, C6D6): δ = 138.4 (s), 138.2 (d), 136.1 (s), 133.7
(s), 131.2 (d), 129.2 (s), 127.3 (d), 117.0 (t), 39.9 (t), 34.5 (s), 33.2
(t), 29.2 (q, 2ϫ), 21.9 (q), 19.7 (t), 12.6 (q) ppm. MS (EI): m/z (%)
= 216 (31) [M]+, 201 (32), 145 (72), 133 (47), 131 (60), 119 (80),
with brine (3ϫ) and water (3ϫ), dried (Na2SO4), and the solvent 105 (83), 95 (53), 91 (100). HRMS (EI): calcd. for C16H24 [M]+
was evaporated. The residue was purified by column chromatog-
raphy (silica gel, from 97:3 hexane/Et3N to 90:10 hexane/EtOAc)
to afford 0.413 g (85%) of a yellow solid identified as 9. H NMR
216.1878; found 216.1875. IR (NaCl): ν = 2927 (s, C–H), 2864 (m,
˜
C–H), 1453 (m), 1360 (m), 969 (m) cm–1. UV (MeOH): λmax
=
1
281 nm.
(400.13 MHz, C6D6): δ = 6.8–6.7 (m, 2 H), 6.4–6.3 (m, 3 H), 6.27
(d, J = 11.0 Hz, 1 H), 6.15 (d, J = 11.4 Hz, 1 H), 5.21 (d, J =
16.5 Hz, 1 H), 5.08 (d, J = 10.0 Hz, 1 H), 1.97 (t, J = 6.1 Hz, 2 H),
1.89 (s, 3 H), 1.80 (s, 3 H), 1.77 (s, 3 H), 1.7–1.6 (m, 2 H), 1.5–1.4
(m, 2 H), 1.14 (s, 6 H) ppm. 13C NMR (100.62 MHz, C6D6): δ =
138.7 (s), 138.4 (s), 137.7 (d), 136.5 (s), 135.9 (s), 133.8 (d), 132.5
(d), 131.6 (d), 129.3 (s), 126.9 (d), 125.7 (d), 117.5 (t), 40.0 (t), 34.6
(s), 33.4 (t), 29.2 (q, 2ϫ), 22.0 (q), 19.8 (t), 12.8 (q), 12.7 (q) ppm.
MS (EI): m/z (%) = 282 (100) [M]+, 267 (27), 197 (27), 161 (26),
159 (38), 157 (37), 145 (77), 143 (53), 133 (46), 131 (59), 129 (41),
119 (84), 107 (44), 105 (93), 93 (42), 91 (80). HRMS (EI): calcd.
1
Data for 12: H NMR (400 MHz, C6D6): δ = 6.66 (dd, J = 15.2,
11.2 Hz, 1 H), 6.39 (d, J = 15.2 Hz, 1 H), 6.34 (d, J = 16.1 Hz, 1
H), 6.28 (d, J = 16.1 Hz, 1 H), 6.22 (d, J = 11.2 Hz, 1 H), 5.02 (s,
1 H), 4.96 (s, 1 H), 1.97 (t, J = 6.3 Hz, 2 H), 1.87 (s, 3 H), 1.81 (s,
3 H), 1.79 (s, 3 H), 1.7–1.6 (m, 2 H), 1.5–1.4 (m, 2 H), 1.13 (s, 6
H) ppm. MS (EI): m/z (%) = 256 (63) [M]+, 185 (32), 171 (56), 159
(55), 157 (50), 145 (68), 120 (51), 107 (70), 105 (92), 93 (44), 91
(100). HRMS (EI): calcd. for C19H28 [M]+ 256.2191; found
256.2196. IR (NaCl): ν = 2958 (s, C–H), 2926 (s, C–H), 2864 (m,
˜
C–H), 1452 (m), 1378 (m), 966 (s) cm–1. UV (MeOH): λmax = 319,
305 nm.
for C21H30 [M]+ 282.2348; found 282.2342. IR (NaCl): ν = 2926 (s,
˜
C–H), 2863 (s, C–H), 1448 (m), 963 (s) cm–1. UV (MeOH): λmax
=
β,β-Carotene (1) by Metathesis with CuI in Diethyl Ether: To a de-
gassed solution of 9 (25 mg, 0.090 mmol) in diethyl ether (0.9 mL)
were added Grubbs 2nd generation catalyst (3 mg, 0.0036 mmol)
and CuI (1 mg, 0.005 mmol). After stirring at 40 °C for 3 h, the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, from hexane to 90:10 hexane/acetone)
to afford 0.64 mg (3%) of 11, 0.46 mg (2%) of 12, and 13 mg (53%)
of 1.
348 nm.
β,β-Carotene (1): General procedure for the metathesis reaction
(largest scale). To a degassed solution of 9 (20 mg, 0.071 mmol) in
CH2Cl2 (1.3 mL) was added Grubbs 2nd generation catalyst (3 mg,
0.0035 mmol). After stirring at 50 °C for 6.5 h, the reaction mixture
was filtered through Celite®, which was washed with acetone and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, from hexane to 90:10 hexane/acetone)
to afford, in order of elution, 0.2 mg (0.1%) of an oil identified as
(E)-2-(3-methylbuta-1,3-dienyl)-1,3,3-trimethylcyclohex-1-ene (10,
C9–C10 cleavage), 0.5 mg (3%) of a yellow oil identified as
(E)-Geranial (14): To a cooled (0 °C), stirring solution of (E)-gera-
niol 13 (2.0 g, 2.25 mL, 12.97 mmol) in CH2Cl2 (156 mL), contain-
ing molecular sieves (4 Å), were added NMO (2.28 g, 19.45 mmol)
and TPAP (0.19 g, 0.54 mmol), and the mixture was stirred at room
6708
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6704–6712

Synthesis of C40-Symmetrical Conjugated Carotenoids
temp. for 4 h. The mixture was washed with a saturated aqueous
(2E,4E,6E,8E,10E)-3,7,11,15-Tetramethylhexadeca-2,4,6,8,10,14-
Na2SO3 solution (3ϫ). The organic layer was dried (Na2SO4), and hexaen-1-ol (18): General procedure for the Stille reaction. A de-
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, 90:10 hexane/EtOAc) to afford 1.63 g
(83%) of a colourless oil identified as 14. H NMR (400.13 MHz,
gassed solution of (2E,4E,6E)-7-(tributylstannyl)-3-methylocta-
2,4,6-trien-1-ol (17, 0.14 g, 0.328 mmol) and 16 (0.07 g,
0.253 mmol) in DMF (1.5 mL) was added to flamed-dried
[NBu4][Ph2PO2] (0.127 g, 0.278 mmol) at room temp. CuTC
(0.072 g, 0.379 mmol) was introduced followed by Pd(PPh3)4
1
CDCl3): δ = 9.99 (d, J = 8.1 Hz, 1 H, CHO), 5.88 (dt, J = 8.1,
1.2 Hz, 1 H) 5.1–5.0 (m, 1 H), 2.3–2.2 (m, 4 H), 2.16 (s, 3 H), 1.68
(s, 3 H), 1.60 (s, 3 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ = (0.039 g, 0.025 mmol). After stirring the reaction mixture for
190.3 (d), 162.9 (s), 132.1 (s), 126.9 (d), 122.3 (d), 40.1 (t), 25.3 (t),
25.1 (q), 17.2 (q), 16.9 (q) ppm. MS (EI): m/z (%) = 152 (4) [M]+,
123 (12), 109 (18), 84 (20), 69 (100). HRMS (EI): calcd. for
45 min, water was added and the aqueous phase was extracted with
Et2O (3ϫ). The combined organic layers were washed with water
(3ϫ), dried (Na2SO4), and the solvent was evaporated. The residue
was purified by column chromatography (silica gel, from 85:12:3
hexane/AcOEt/Et3N to 80:20 hexane/AcOEt) to afford 0.042 g
(58%) of a yellow solid identified as 18. 1H NMR (400.13 MHz,
C6D6): δ = 6.7–6.6 (m, 2 H), 6.39 (d, J = 15.2 Hz, 1 H), 6.31 (d, J
= 15.1 Hz, 1 H), 6.25 (d, J = 11.3 Hz, 1 H), 6.13 (d, J = 10.6 Hz,
1 H), 5.61 (t, J = 6.7 Hz, 1 H), 5.23 (t, J = 5.8 Hz, 1 H), 4.01 (t, J
= 5.8 Hz, 2 H), 2.2–2.1 (m, 4 H), 1.89 (s, 3 H), 1.74 (s, 3 H), 1.67
(s, 3 H), 1.63 (s, 3 H), 1.56 (s, 3 H, CH3) ppm. HRMS (ESI+):
calcd. for C20H30ONa [M + Na]+ 309.2189; found 309.2190. IR
C10H16O [M]+ 152.1201; found 152.1203. IR (NaCl): ν = 2968 (m,
˜
C–H), 2922 (m, C–H), 2857 (m, C–H), 1675 (s, C=O), 1442 (m),
1191 (m), 1120 (m) cm–1. UV (MeOH): λmax = 238 nm.
(E)-4,8-Dimethylnona-3,7-dien-1-yne (15): A cooled (0 °C) solution
of iPr2NH (0.2 g, 0.27 mL, 1.93 mmol) in THF (13.9 mL) was
treated with nBuLi (1.81 mL, 1.55 m in hexane, 2.80 mmol) and
stirred for 30 min. The mixture was cooled to –78 °C and (trimeth-
ylsilyl)diazomethane (1.23 mL, 2 m in hexane, 2.45 mmol) was
added. After stirring for 30 min,
a solution of 14 (0.27 g,
(NaCl): ν = 3600–3100 (br., O–H), 2964 (s, C–H), 2926 (s, C–H),
˜
1.75 mmol) in THF (8.8 mL) was added, and the resulting mixture
was stirred for 1 h at –78 °C and for 30 min at room temp. The
mixture was poured over ice-water and extracted with Et2O (3ϫ).
The combined organic layers were dried (Na2SO4), and the solvent
was evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, 99:1 hexane/EtOAc) to af-
1447 (m), 1380 (m) cm–1. UV (MeOH): λmax = 277, 238 nm.
(2E,4E,6E,8E,10E)-3,7,11,15-Tetramethylhexadeca-2,4,6,8,10,14-
hexaenal (19): General procedure for MnO2 oxidation. To a cooled
(0 °C) solution of 18 (0.035 g, 0.123 mmol) in THF (2.4 mL) were
added manganese dioxide (0.2 g, 2.22 mmol) and sodium carbonate
(0.235 g, 2.22 mmol). The reaction mixture was stirred at room
temp. for 30 min and then filtered through a pad of Celite®. The
solvent was evaporated to afford 0.034 g (96%) of a yellow solid
1
ford 0.219 g (84%) of a colourless volatile oil identified as 15. H
NMR (400.13 MHz, C6D6): δ = 5.3–5.2 (m, 1 H), 5.1–5.0 (m, 1 H),
2.81 (d, J = 2.2 Hz, 1 H), 2.0–1.9 (m, 2 H), 1.9–1.8 (m, 2 H), 1.86
(s, 3 H), 1.60 (s, 3 H), 1.45 (s, 3 H) ppm. 13C NMR (100.62 MHz,
C6D6): δ = 153.4 (s), 132.0 (s), 123.9 (d), 104.9 (d), 82.0 (s), 80.4
(d), 38.8 (t), 26.6 (t), 25.8 (q), 19.3 (q), 17.7 (q) ppm. MS (EI): m/z
(%) = 133 (47), 105 (9), 91 (10), 77 (14), 69 (100). HRMS (EI):
1
identified as 19. H NMR (400.13 MHz, C6D6): δ = 10.02 (d, J =
7.8 Hz, 1 H), 6.80 (dd, J = 15.0, 11.5 Hz, 1 H), 6.68 (dd, J = 15.1,
11.0 Hz, 1 H), 6.29 (d, J = 15.1 Hz, 1 H), 6.11 (d, J = 11.1 Hz, 1
H), 6.04 (d, J = 11.1 Hz, 1 H), 6.02 (d, J = 15.1 Hz, 1 H), 5.97 (d,
J = 7.8 Hz, 1 H), 5.3–5.2 (m, 1 H), 2.2–2.1 (m, 4 H), 1.76 (s, 3 H),
1.72 (s, 6 H), 1.68 (s, 3 H), 1.56 (s, 3 H) ppm. MS (EI): m/z (%) =
284 (30) [M]+, 215 (44), 145 (100), 119 (80), 105 (68), 95 (64), 91
(91). HRMS (EI): calcd. for C20H28O [M]+ 284.2140; found
calcd. for C11H16 [M]+ 148.1252; found 148.1249. IR (NaCl): ν =
˜
3307 (s, CϵC–H), 2968 (s, C–H), 2921 (s, C–H), 2857 (m, C–H),
2045 (s, CϵC), 1444 (s), 1380 (m) cm–1. UV (MeOH): λmax
=
228 nm.
284.2149. IR (NaCl): ν = 2963 (w, C–H), 2918 (w, C–H), 2852 (w,
˜
(1E,3E)-4,8-Dimethyl-1-iodonona-1,3,7-triene (16): To a suspension
of Cp2ZrCl2 (0.465 g, 1.590 mmol) in THF (3.6 mL) was added
dropwise a solution of DIBAL-H (1.59 mL, 1 m in hexanes,
1.59 mmol) in THF (0. 58 mL) at 0 °C. The resultant suspension
was stirred for 30 min at 0 °C, followed by addition of a solution
of 15 (0.157 g, 1.060 mmol) in THF (0.55 mL). The mixture was
warmed to 25 °C and stirred until a homogeneous solution resulted
(1 h), which was cooled to –78 °C. A solution of I2 (0.35 g,
1.378 mmol) in THF (1.7 mL) was added and the resulting mixture
was stirred for 30 min at –78 °C. The reaction was quenched with
citric acid, extracted with Et2O (3ϫ) and washed successively with
aqueous saturated solutions of Na2S2O3 (3ϫ), NaHCO3 (3ϫ), and
brine (3ϫ). The combined organic layers were dried (Na2SO4), and
the solvent evaporated. The residue was purified by column
chromatography (C18 silica gel, CH3CN) to afford 0.214 g (73%)
C–H), 1657 (s, C=O), 1561 (s), 1164 (m), 961 (m) cm–1. UV
(MeOH): λmax = 400 nm.
(R)-all-trans-3-(tert-Butyldimethylsilyloxy)retinal (21): Following
the general procedure for the MnO2 oxidation, the reaction of (R)-
all-trans-3-(tert-butyldimethylsilyloxy)retinol 20 (0.152 g,
0.365 mmol), manganese dioxide (0.591 g, 6.570 mmol) and so-
dium carbonate (0.696 g, 6.570 mmol) in THF (7.1 mL) at room
1
temp. for 2 h afforded 0.151 g (99%) of an oil identified as 21. H
NMR (400.13 MHz, C6D6): δ = 10.01 (d, J = 7.8 Hz, 1 H), 6.82
(dd, J = 15.0, 11.5 Hz, 1 H), 6.29 (d, J = 16.2 Hz, 1 H), 6.23 (d, J
= 16.2 Hz, 1 H), 6.02 (d, J = 15.0 Hz, 1 H), 6.01 (d, J = 11.7 Hz,
1 H), 5.96 (d, J = 7.8 Hz, 1 H), 4.1–4.0 (m, 1 H, 1 H), 2.4–2.2 (m,
2 H), 1.81 (ddq, J = 12.4, 3.6, 0.9 Hz, 1 H), 1.76 (s, 3 H), 1.74 (s,
3 H), 1.71 (d, J = 0.9 Hz, 3 H), 1.7–1.6 (m, 1 H), 1.14 (s, 3 H),
1.10 (s, 3 H), 1.06 (s, 9 H), 0.16 (s, 3 H), 0.15 (s, 3 H) ppm. 13C
NMR (100.62 MHz, C6D6): δ = 189.8 (d), 153.0 (s), 140.0 (s), 138.3
(d), 137.6 (s), 135.7 (d), 131.5 (d), 130.6 (d), 129.9 (d), 128.6 (d),
128.0 (s), 65.9 (d), 49.3 (t), 43.6 (t), 37.2 (s), 30.4 (s), 28.9 (q), 26.2
(q, 3ϫ), 21.8 (q), 18.4 (s), 12.8 (q), 12.5 (q), –4.3 (q, 2ϫ) ppm.
HRMS (ESI+): calcd. for C26H42O2SiNa [M + Na]+ 437.28463;
1
of a colourless oil identified as 16. H NMR (400.13 MHz, C6D6):
δ = 7.23 (dd, J = 14.1, 11.1 Hz, 1 H), 5.87 (d, J = 14.1 Hz, 1 H),
5.57 (d, J = 11.1 Hz, 1 H), 5.1 (t, J = 7.0 Hz, 1 H), 2.1–2.0 (m, 2
H), 1.86 (m, 2 H), 1.64 (s, 3 H), 1.50 (s, 3 H), 1.34 (s, 3 H) ppm.
13C NMR (100.62 MHz, C6D6): δ = 142.3 (d), 139.9 (s), 131.7 (s),
125.5 (d), 124.3 (d), 77.1 (d), 39.9 (t), 26.6 (t), 25.9 (q), 17.8 (q),
16.7 (q) ppm. MS (EI): m/z (%) = 276 (18) [M]+, 183 (23), 107 (17),
93 (18), 80 (45), 79 (34), 77 (16), 69 (100). HRMS (EI): calcd. for
found 437.28471. IR (NaCl): ν = 2954 (s, C–H), 2828 (s, C–H),
˜
2857 (m, C–H), 1660 (s, C=O), 1576 (m), 1082 (s) cm–1. UV
C11H17I [M]+ 276.0375; found 276.0380. IR (NaCl): ν = 2966 (m,
(MeOH): λmax = 378 nm.
˜
C–H), 2924 (s, C–H), 2854 (w, C–H), 1638 (w), 1560 (w), 1442 (m), rac-(E)-tert-Butyl-[3-(2-iodovinyl)-2,4,4-trimethylcyclohex-2-enyl-
1378 (m), 942 (s) cm–1. UV (MeOH): λmax = 258 nm.
oxy]dimethylsilane (23): To a cold (0 °C) solution of rac-(E)-3-
Eur. J. Org. Chem. 2011, 6704–6712
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6709

N. Fontán, M. Domínguez, R. Álvarez, Á. R. de Lera
FULL PAPER
(2-iodovinyl)-2,4,4-trimethylcyclohex-2-en-1-ol
(22,
0.132 g,
H), 2930 (m, C–H), 2855 (m, C–H), 1660 (s, C=O), 1577 (m) cm–1.
0.452 mmol) in DMF (1.5 mL) were added sequentially imidazole
(0.077 g, 1.13 mmol) and a solution of tert-butylchlorodimethylsil-
ane (0.102 g, 0.68 mmol) in DMF (0.6 mL). After stirring for 4.5 h
at 25 °C, the reaction was quenched with H2O, and extracted with
hexane (2ϫ) and EtOAc (2ϫ). The combined organic layers were
washed with H2O (3ϫ), dried (Na2SO4), filtered, and the solvents
evaporated. The residue was purified by column chromatography
(silica gel, 90:10 hexane/EtOAc) to afford 0.164 g (89%) of a prod-
UV (MeOH): λmax = 377 nm.
(3E,5E,7E,9E,11E)-4,8,12,16-Tetramethylheptadeca-1,3,5,7,9,
11,15-heptaene (26): Following the general procedure for the Wittig
reaction, the reaction of methyltriphenylphosphonium bromide
(0.30 g, 0.846 mmol), sodium bis(trimethylsilyl)amide (0.75 mL,
1 m in THF, 0.752 mmol), HMPA (0.41 mL, 2.35 mmol), and 19
(0.067 g, 0.235 mmol) in THF (3.8 mL) at –78 °C for 2 h, afforded,
after purification by column chromatography (silica gel, from 98:2
hexane/Et3N to 95:5 hexane/EtOAc), 0.057 g (86%) of a yellow so-
lid identified as 26. 1H NMR (400.13 MHz, C6D6): δ = 6.8–6.6 (m,
3 H), 6.4–6.3 (m, 2 H), 6.28 (d, J = 11.4 Hz, 1 H), 6.2–6.1 (m, 2
H), 5.3–5.2 (m, 2 H), 5.08 (d, J = 10.2 Hz, 1 H), 2.3–2.1 (m, 4 H),
1.88 (s, 3 H), 1.77 (s, 3 H), 1.74 (s, 3 H), 1.67 (s, 3 H), 1.56 (s, 3
H) ppm. 13C NMR [100.62 MHz, (CD3)2CO]: δ = 139.8 (s), 138.0
(d), 137.2 (s), 137.0 (s), 136.2 (d), 134.3 (d), 132.8 (d), 132.1 (d),
132.0 (s), 126.8 (d), 126.4 (d), 125.9 (d), 124.8 (d), 117.9 (t), 40.8
(t), 27.3 (t), 25.8 (q), 17.7 (q), 16.9 (q), 12.9 (q), 12.7 (q) ppm. MS
(EI): m/z (%) = 282 (82) [M]+, 213 (77), 171 (48), 157 (76), 145
(79), 143 (66), 133 (61), 119 (62), 107 (45), 105 (83), 93 (83), 91
(100). HRMS (EI): calcd. for C21H30 [M]+ 282.2348; found
1
uct identified as 23. H NMR [400.13 MHz, (CD3)2CO]: δ = 6.99
(d, J = 14.8 Hz, 1 H), 6.16 (d, J = 14.8 Hz, 1 H), 4.05 (s, 1 H),
1.9–1.8 (m, 1 H), 1.71 (s, 3 H), 1.65 (t, J = 10.6 Hz, 2 H), 1.41 (app
t, J = 10.6 Hz, 1 H), 1.02 (s, 3 H), 0.98 (s, 3 H), 0.91 (s, 9 H), 0.12
(s, 6 H) ppm. 13C NMR [100.62 MHz, (CD3)2CO]: δ = 144.4 (d),
141.7 (s), 133.4 (s), 80.2 (d), 71.3 (d), 35.4 (t), 34.7 (s), 29.7 (t), 28.3
(q), 26.3 (q, 3ϫ), 18.8 (q), 16.2 (s), –3.9 (q), –4.4 (q) ppm. HRMS
(ESI+): calcd. for C17H31IOSiNa [M + Na]+ 429.1081; found
429.1097. IR (NaCl): ν = 2955 (s, C–H), 2929 (s, C–H), 2856 (m,
˜
C–H), 1582 (w), 1471 (m), 1254 (s) cm–1.
rac-all-trans-4-(tert-Butyldimethylsilyloxy)retinol (24): Following
the general procedure for the Stille reaction, the reaction of 17
(0.179 g, 0.419 mmol), 23 (0.177 g, 0.436 mmol), [NBu4][Ph2PO2]
(0.212 g, 0.461 mmol), CuTC (0.12 g, 0.628 mmol), and Pd(PPh3)4
(0.042 g, 0.042 mmol) in DMF (2.5 mL) at room temp. for 2 h af-
forded, after purification by column chromatography (silica gel,
90:7:3 hexane/EtOAc/Et3N), 0.146 g (80%) of a product identified
282.2347. IR (NaCl): ν = 2923 (s, C–H), 2857 (s, C–H), 1447 (m),
˜
1382 (m), 966 (s) cm–1. UV (MeOH): λmax = 381, 361, 343 nm.
Lycopene (2): Following the general procedure for the metathesis
reaction, the reaction of 26 (13 mg, 0.046 mmol) and Grubbs 2nd
generation catalyst (2 mg, 0.0023 mmol) in CH2Cl2 (0.9 mL) at
50 °C for 6.5 h, afforded, after purification by column chromatog-
raphy (C18 silica gel, from 90:10 CH3CN/CH2Cl2 to 80:20 CH3CN/
CH2Cl2), 7.2 mg (58%) of a red solid identified as 2. 1H NMR
(400.13 MHz, C6D6): δ = 6.77 (dd, J = 14.8, 11.3 Hz, 2 H), 6.7–6.6
(m, 4 H), 6.49 (d, J = 14.8 Hz, 2 H), 6.44 (d, J = 15.2 Hz, 2 H),
6.4–6.3 (m, 4 H), 6.16 (d, J = 11.1 Hz, 2 H), 5.24 (t, J = 6.3 Hz, 2
H), 2.4–2.0 (m, 8 H), 1.93 (s, 6 H), 1.88 (s, 6 H), 1.75 (s, 6 H), 1.68
(s, 6 H), 1.57 (s, 6 H) ppm. MS (EI): m/z (%) = 536 (10) [M]+, 171
(27), 169 (25), 157 (42), 145 (51), 119 (45), 105 (64), 93 (40), 91
(63), 81 (39), 69 (100). HRMS (EI): calcd. for C40H56 [M]+
536.4382; found 536.4374. UV (MeOH): λmax = 360, 327, 282,
241 nm.
1
as 24. H NMR [400.13 MHz, (CD3)2CO]: δ = 6.65 (dd, J = 15.1,
11.2 Hz, 1 H), 6.35 (d, J = 15.1 Hz, 1 H), 6.19 (d, J = 11.2 Hz, 1
H), 6.2–6.1 (m, 2 H), 5.68 (app t, J = 6.5 Hz, 1 H), 4.24 (t, J =
6.4 Hz, 2 H), 4.10 (t, J = 5.3 Hz, 1 H), 1.97 (s, 3 H), 1.9–1.8 (m, 1
H), 1.82 (s, 3 H), 1.76 (s, 3 H), 1.7–1.6 (m, 2 H), 1.5–1.4 (m, 1 H),
1.04 (s, 3 H), 1.01 (s, 3 H), 0.92 (s, 9 H), 0.12 (s, 6 H) ppm. 13C
NMR [100.62 MHz, (CD3)2CO]: δ = 141.0 (s), 139.5 (d), 138.3 (d),
135.6 (s), 135.4 (s), 133.8 (d), 132.1 (d), 131.6 (s), 126.4 (d), 124.9
(d), 71.8 (d), 59.3 (t), 35.8 (t), 35.3 (s), 29.9 (t), 29.1 (q), 28.5 (q),
26.3 (q, 3ϫ), 19.1 (q), 18.6 (s), 12.8 (q), 12.7 (q), –4.0 (q), –4.5 (q)
ppm. HRMS (ESI+): calcd. for C26H44O2SiNa [M
+
Na]+
439.3003; found 439.3008. IR (NaCl): ν = 3500–3000 (br., O–H),
˜
2954 (s, C–H), 2929 (s, C–H), 2856 (m, C–H), 1472 (w), 1457 (w),
1252 (m) cm–1. UV (MeOH): λmax = 324 nm.
tert-Butyl-{4-[(1E,3E,5E,7E)-3,7-dimethyldeca-1,3,5,7,9-pentaenyl]-
3,5,5-trimethylcyclohex-3-enyloxy}dimethylsilane (27): Following
the general procedure for the Wittig reaction, the reaction of meth-
yltriphenylphosphonium bromide (0.216 g, 0.606 mmol), nBuLi
(0.387 mL, 1.39 m in hexane, 0.538 mmol), DMPU (0.061 mL,
0.505 mmol), and 21 (0.139 g, 0.336 mmol) in THF (5 mL) at
–78 °C for 2 h afforded, after purification by column chromatog-
raphy (silica gel, from 98:2 hexane/Et3N to 97.5:2.5 hexane/EtOAc),
rac-all-trans-4-(tert-Butyldimethylsilyloxy)retinal (25): To a cold
(0 °C) solution of 24 (0.116 g, 0.278 mmol) in CH2Cl2 (12.8 mL)
were sequentially added pyridine (0.25 mL) and Dess–Martin
periodinane (0.153 g, 0.362 mmol), and the mixture was stirred for
4 h at 0 °C. A saturated aqueous solution of NaHCO3 was added,
and the resulting mixture was extracted with CH2Cl2 (3ϫ). The
combined organic layers were washed with saturated aqueous solu-
tions of NaHCO3 (3ϫ) and Na2S2O3 (3ϫ), dried (Na2SO4), and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, 90:7:3 hexane/EtOAc/Et3N) to afford
0.079 g (57%) of
a
yellow oil identified as 27. 1H NMR
(400.13 MHz, C6D6): δ = 6.8–6.6 (m, 2 H), 6.4–6.3 (m, 2 H), 6.26
(d, J = 11.6 Hz, 1 H), 6.21 (d, J = 16.2 Hz, 1 H), 6.15 (d, J =
11.2 Hz, 1 H), 5.21 (d, J = 17.3 Hz, 1 H), 5.08 (d, J = 10.7 Hz, 1
H), 4.2–4.1 (m, 1 H), 2.4–2.3 (m, 2 H), 1.88 (s, 3 H), 1.77 (s, 6 H),
1.7–1.6 (m, 2 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.05 (s, 9 H), 0.16 (s,
3 H), 0.15 (s, 3 H) ppm. 13C NMR (100.62 MHz, C6D6): δ = 139.0
(d), 137.9 (d), 136.4 (s), 135.7 (s), 133.7 (d), 132.6 (d), 131.8 (d),
127.9 (s), 127.1 (s), 126.1 (d), 125.6 (d), 117.7 (t), 66.0 (d), 49.4 (t),
43.6 (t), 37.3 (s), 30.5 (q), 28.9 (q), 26.2 (q, 3ϫ), 21.9 (q), 18.4 (s),
12.8 (q), 12.7 (q), –4.3 (q, 2ϫ) ppm. HRMS (ESI+): calcd. for
0.075 g (65%) of
a
yellow oil identified as 25. 1H NMR
[400.13 MHz, (CD3)2CO]: δ = 10.10 (d, J = 8.0 Hz, 1 H), 7.27 (dd,
J = 15.1, 11.5 Hz, 1 H), 6.47 (d, J = 15.1 Hz, 1 H), 6.32 (d, J =
16.1 Hz, 1 H), 6.29 (d, J = 11.7 Hz, 1 H), 6.20 (d, J = 16.1 Hz, 1
H), 5.88 (d, J = 8.0 Hz, 1 H), 4.07 (t, J = 4.9 Hz, 1 H), 2.34 (s, 3
H), 2.03 (s, 3 H), 1.9–1.8 (m, 1 H), 1.74 (s, 3 H), 1.7–1.6 (m, 2 H),
1.4–1.3 (m, 1 H), 1.01 (s, 3 H), 0.99 (s, 3 H), 0.88 (s, 9 H), 0.09 (s,
6 H) ppm. 13C NMR [100.62 MHz, (CD3)2CO]: δ = 191.2 (d), 155.1
(s), 141.1 (s), 140.8 (s), 139.0 (d), 136.1 (d), 133.1 (d), 132.4 (s),
131.3 (d), 129.9 (d), 129.4 (d), 71.7 (d), 35.8 (t), 35.3 (s), 29.8 (q),
29.1 (t), 28.5 (q), 26.3 (q, 3ϫ), 19.1 (q), 18.6 (s), 13.0 (q), 12.9 (q),
–4.0 (q), –4.5 (q) ppm. HRMS (ESI+): calcd. for C26H42O2SiNa
C27H45OSi [M + H]+ 413.3234; found 413.3231. IR (NaCl): ν =
˜
2955 (s, C–H), 2928 (s, C–H), 2857 (m, C–H), 1461 (m), 1254 (m),
1082 (s) cm–1. UV (MeOH): λmax = 282, 242 nm.
(3R,3ЈR)-Zeaxanthin (3): Following the general procedure for the
metathesis reaction, the reaction of 27 (9.2 mg, 0.0223 mmol) and
[M + Na]+ 437.2846; found 437.2846. IR (NaCl): ν = 2954 (m, C–
˜
6710
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6704–6712

Synthesis of C40-Symmetrical Conjugated Carotenoids
Grubbs 2nd generation catalyst (0.9 mg, 0.0011 mmol) in CH2Cl2
(0.5 mL) at 50 °C for 6.5 h afforded, after purification by column
chromatography (silica gel, from hexane to 99.5:0.5 hexane/ace-
tion
of
methyltriphenylphosphonium
bromide
(1.67 g,
4.680 mmol), sodium bis(trimethylsilyl)amide (4.16 mL, 1 m in
THF, 4.16 mmol), HMPA (0.60 mL, 3.90 mmol), and β-ionone
tone), 6.2 mg of a product, which was used in the next step without (0.529 mL, 2.60 mmol) in THF (36.2 mL) at –78 °C for 2 h, af-
further purification.
forded, after purification by column chromatography (silica gel,
from 98:2 hexane/Et3N to 95:5 hexane/EtOAc), 0.318 g (64%) of a
yellow oil identified as 10.
General Procedure for Deprotection: A cooled (0 °C) solution of
protected 3 (9.2 mg, 0.0115 mmol) in THF (0.36 mL) was treated
with nBu4NF (0.033 mL, 1 m in THF, 0.033 mmol) and stirred for
1 h at 0 °C and then for 6 h at room temp. The reaction mixture
was poured into an aqueous solution of NaHCO3. The aqueous
layer was extracted with Et2O (3ϫ), dried (Na2SO4), and the sol-
vent was evaporated under reduced pressure. The residue was puri-
fied by column chromatography (C18 silica gel, from 90:10 CH3CN/
CH2Cl2 to 80:20 CH3CN/CH2Cl2) to afford 4.4 mg (67%, two
(1E,3E)-2-(3-Methylhexa-1,3,5-trienyl)1,3,3-trimethylcyclohex-1-
ene (11): Following the general procedure for the Wittig reaction,
the reaction of methyltriphenylphosphonium bromide (0.77 g,
2.061 mmol), sodium bis(trimethylsilyl)amide (1.83 mL, 1 m in
THF, 1.832 mmol), HMPA (0.30 mL, 1.718 mmol), and (2E,4E)-3-
methyl-5-(2,6,6-trimethylcyclohex-1-enyl)penta-2,4-dienal[20]
(0.25 g, 1.145 mmol) in THF (16.2 mL) at –78 °C for 8 h, afforded,
after purification by column chromatography (silica gel, from 98:2
hexane/Et3N to 95:5 hexane/EtOAc), 0.146 g (59%) of a yellow oil
identified as 11.
1
steps) of a solid identified as 3. H NMR (400.13 MHz, CDCl3): δ
= 6.7–6.6 (m, 4 H), 6.36 (d, J = 14.9 Hz, 2 H), 6.3–6.2 (m, 2 H),
6.15 (d, J = 11.5 Hz, 2 H), 6.1–6.0 (m, 4 H), 4.0–3.9 (m, 2 H), 2.39
(dd, J = 17.6, 5.1 Hz, 2 H), 2.04 (dd, J = 16.9, 9.9 Hz, 2 H), 1.87
(s, 6 H), 1.7–1.6 (m, 2 H), 1.64 (s, 6 H), 1.38 (t, J = 12.0 Hz, 2 H),
0.97 (s, 12 H) ppm. MS (ESI+): m/z (%) = 569 (70) [M + H]+, 568
(37) [M]+ 567 (34). HRMS (ESI+): calcd. for C40H57O2 [M + H]+
569.4353; found 569.4354. UV (MeOH): λmax = 476, 449, 276 nm.
(1E,3E,5E)-2-(3,7-Dimethylocta-1,3,5,7-tetraenyl)-1,3,3-trimethyl-
cyclohex-1-ene (12): Following the general procedure for the Wittig
reaction, the reaction of methyltriphenylphosphonium bromide
(0.13 g, 0.365 mmol), nBuLi (0.237 mL, 1.37 m in hexane,
0.324 mmol), DMPU (0.037 mL, 0.304 mmol), and (3E,5E,7E)-6-
methyl-8-(2,6,6-trimethylcyclohex-1-enyl)octa-3,5,7-trien-2-one[21]
(0.052 g, 0.203 mmol) in THF (3 mL) at –78 °C for 1 h and at room
temp. for 1.5 h afforded, after purification by column chromatog-
raphy (silica gel, from 98:2 hexane/Et3N to 97.5:2.5 hexane/EtOAc),
0.014 g (28%) of a yellow solid identified as 12.
rac-tert-Butyl-{(S)-3-[(1E,3E,5E,7E)-3,7-dimethyldeca-1,3,5,7,9-pen-
taenyl]-2,4,4-trimethylcyclohex-2-enyloxy}dimethylsilylane (28): Fol-
lowing the general procedure for the Wittig reaction, the reaction
of methyltriphenylphosphonium bromide (0.155 g, 0.434 mmol),
nBuLi (0.257 mL, 1.5 m in hexane, 0.385 mmol), HMPA (0.210 mL,
1.204 mmol), and 25 (0.050 g, 0.120 mmol) in THF (2 mL) at
–78 °C for 1 h afforded, after purification by column chromatog-
raphy (silica gel, from 98:2 hexane/Et3N to 95:5 hexane/EtOAc),
0.048 g (97%) of an oil identified as 28. 1H NMR (400.13 MHz,
C6D6): δ = 6.7–6.6 (m, 2 H), 6.4–6.3 (m, 2 H), 6.3–6.2 (m, 2 H),
6.16 (d, J = 11.4 Hz, 1 H), 5.21 (d, J = 16.3 Hz, 1 H), 5.08 (d, J =
10.1 Hz, 1 H), 4.04 (t, J = 5.0 Hz, 1 H), 2.00 (s, 3 H), 1.86 (s, 3 H),
1.8–1.7 (m, 4 H), 1.65 (s, 3 H), 1.11 (s, 3 H), 1.08 (s, 3 H), 1.03 (s,
9 H), 0.14 (s, 3 H), 0.13 (s, 3 H) ppm. 13C NMR (100.62 MHz,
C6D6): δ = 140.9 (s), 139.4 (d), 138.0 (d), 136.5 (s), 135.7 (s), 133.7
(d), 132.6 (d), 132.1 (d), 131.4 (s), 126.4 (d), 125.6 (d), 117.6 (t),
71.6 (d), 35.6 (t), 35.0 (s), 29.8 (t), 28.9 (q), 28.5 (q), 26.2 (q, 3ϫ),
19.2 (q), 18.4 (s), 12.8 (q), 12.7 (q), –4.0 (q), –4.4 (q) ppm. HRMS
(ESI+): calcd. for C27H44OSiNa [M + Na]+ 435.3054; found
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of the compounds
described in the text.
Acknowledgments
The authors are grateful to the Spanish Ministerio de Ciencia e
Innovación (MICINN) (grant number SAF2010-17935, Fondos
Europeos para el Desarrollo Regional (FEDER), FPU Fellowship
to N. F.), Xunta de Galicia (grant number 08CSA052383PR from
DXI + D + i; Consolidación 2006/15 from DXPCTSUG; INBI-
OMED; Parga Pondal Contract to M. D.) for financial support.
We thank Dr. Thomas Netscher (DSM Nutritional Products) for
generously donating (–)-actinol for our synthetic carotenoid pro-
gram and Prof. Joaquín Plumet (UCM) for his early suggestion to
undertake this project.
435.3050. IR (NaCl): ν = 2954 (s, C–H), 2931 (s, C–H), 2857 (m,
˜
C–H), 1462 (m), 1360 (w), 1253 (m), 1082 (m), 1049 (m) cm–1. UV
(MeOH): λmax = 334, 285, 243 nm.
rac-Isozeaxanthin (4): Following the general procedure for metathe-
sis, the reaction of 28 (12.5 mg, 0.0303 mmol) and Grubbs 2nd gen-
eration catalyst (1.3 mg, 0.0015 mmol) in CH2Cl2 (0.6 mL) at 50 °C
for 6.5 h, afforded, after purification by chromatography (silica gel,
from hexane to 99.5:0.5 hexane/acetone) a product that was used
in the next step without further purification. Following the general
procedure for deprotection, the reaction of protected 4 (12.1 mg,
0.0152 mmol) and nBu4NF (0.044 mL, 1 m in THF, 0.044 mmol) in
THF (0.48 mL) at 0 °C for 7 h afforded, after purification by col-
umn chromatography (C18 silica gel, from 90:10 CH3CN/CH2Cl2
to 80:20 CH3CN/CH2Cl2), 3.8 mg (44%, two steps) of a solid iden-
[1] a) G. Britton, S. Liaaen-Jensen, H. Pfander (Eds.), Carotenoids,
Part 1A, Isolation and Analysis, Birkhäuser, Basel, 1995; b)
A. V. Rao, L. G. Rao, Pharmacol. Res. 2007, 55, 207–216; c)
J. T. Laudrum, Carotenoids: Physical, Chemical and Biological
Functions and Properties, CRC Press, Boca Raton, Fl, 2010.
[2] G. Britton, S. Liaaen-Jensen, H. Pfander (Eds.), Carotenoids,
Part 1B, Spectroscopy, Birkhäuser, Basel, 1995.
[3] G. Britton, S. Liaaen-Jensen, H. Pfander (Eds.), Carotenoids
Handbook, Birkhäuser, Basel, 2004.
[4] a) G. Britton, S. Liaaen-Jensen, H. Pfander (Eds.), Carotenoids,
Part 2, Synthesis, Birkhäuser, Basel, 1996; b) M. Ito, Y. Yam-
ano, C. Tode, A. Wada, Arch. Biochem. Biophys. 2009, 483,
224–228.
1
tified as 4. H NMR (400.13 MHz, CDCl3): δ = 6.7–6.6 (m, 4 H),
6.37 (d, J = 14.9 Hz, 2 H), 6.3–6.2 (m, 8 H), 4.2–4.0 (m, 2 H), 1.97
(s, 12 H), 1.9–1.8 (m, 8 H), 1.7–1.6 (m, 4 H), 1.5–1.4 (m, 4 H), 1.06
(s, 6 H), 1.02 (s, 6 H) ppm. HRMS (EI): calcd. for C40H56O2 [M]+
568.4275; found 568.4275. UV (MeOH): λmax = 475, 449, 276 nm.
[5] F. Khachik, A.-N. Chang, J. Org. Chem. 2009, 74, 3875–3885.
[6] a) C. Tode, Y. Yamano, M. Ito, J. Chem. Soc. Perkin Trans. 1
2002, 1581–1587; b) T. Olpp, R. Brückner, Angew. Chem. 2006,
118, 4128; Angew. Chem. Int. Ed. 2006, 45, 4023–4027; c) N.
Furuichi, H. Hara, T. Osaki, H. Mori, S. Katsumura, Angew.
Chem. 2002, 114, 1065; Angew. Chem. Int. Ed. 2002, 41, 1023–
1026.
(E)-2-(3-Methylbuta-1,3-dienyl)-1,3,3-trimethyl-cyclohex-1-ene (10):
Following the general procedure for the Wittig reaction, the reac-
Eur. J. Org. Chem. 2011, 6704–6712
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6711

N. Fontán, M. Domínguez, R. Álvarez, Á. R. de Lera
FULL PAPER
[7] F. Zeng, E.-i. Negishi, Org. Lett. 2001, 3, 719–722.
[8] E.-i. Negishi, G. Wang, H. Rao, Z. Xu, J. Org. Chem. 2010,
75, 3151–3182.
[19]
[20]
[21]
[22]
T. Kajikawa, N. Iguchi, S. Katsumura, Org. Biomol. Chem.
2009, 7, 4586–4589.
R. W. Dugger, C. H. Heatchcock, Synth. Commun. 1980, 10,
509–515.
J. A. Pardoen, E. M. M. van den Berg, C. Winkel, J. Lugten-
burg, Recl. Trav. Chim. Pays-Bas 1986, 105, 92–98.
a) J. P. Morgan, R. H. Grubbs, Org. Lett. 2000, 2, 3153–3155;
b) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett.
1999, 1, 953–956.
S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179.
K. Voigtritter, S. Ghorai, B. H. Lipshutz, J. Org. Chem. 2011,
76, 4697–4702.
A. Fürstner, O. Guth, A. Düffels, G. Seidel, M. Liebl, B.
Gabor, R. Mynott, Chem. Eur. J. 2001, 7, 4811–4820.
A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G. Dol-
gonos, K. Grela, J. Am. Chem. Soc. 2004, 126, 9318–9325.
A. Valla, B. Valla, R. Le Guillou, D. Cartier, L. Dufossé, R.
[9] a) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005,
117, 4516; Angew. Chem. Int. Ed. 2005, 44, 4442–4489; b) B.
Vaz, R. Alvarez, A. R. de Lera, J. Org. Chem. 2002, 67, 5040–
5043; c) B. Vaz, R. Alvarez, R. Brückner, A. R. de Lera, Org.
Lett. 2005, 7, 545–548; d) B. Vaz, M. Domínguez, R. Álvarez,
A. R. de Lera, J. Org. Chem. 2006, 71, 5914–5920; e) B. Vaz,
M. Domínguez, A. Álvarez, A. R. de Lera, Chem. Eur. J. 2007,
13, 1273–1290; f) J. Burghart, R. Brückner, Angew. Chem. 2008,
120, 7777; Angew. Chem. Int. Ed. 2008, 47, 7664–7668.
[10] E. M. Woerly, A. H. Cherney, E. K. Davis, M. D. Burke, J. Am.
Chem. Soc. 2009, 131, 6941–6943.
[11] M. Ji, H. Choi, M. Park, M. Kee, Y. C. Jeong, S. Koo, Angew.
Chem. 2001, 113, 3739; Angew. Chem. Int. Ed. 2001, 40, 3627–
3629.
[12] S. Choi, S. Koo, J. Org. Chem. 2005, 70, 3328–3331.
[13] J. E. McMurry, M. P. Fleming, J. Am. Chem. Soc. 1974, 96,
4708–4709.
[23]
[24]
[25]
[26]
[27]
Labia, Helv. Chim. Acta 2007, 90, 512–520.
[14] S. Akiyama, S. Nakatsuji, S. Eda, M. Kataoka, M. Nakagawa,
Tetrahedron Lett. 1979, 20, 2813–2816.
[28] B. Domínguez, B. Iglesias, A. R. de Lera, Tetrahedron 1999, 55,
[15] a) R. H. Grubbs, in: Handbook of Metathesis, Wiley-VCH,
Weinheim, Germany, 2003; b) A. H. Hoveyda, A. R. Zhugra-
lin, Nature 2007, 450, 243–251; c) G. C. Vougioukalakis, R. H.
Grubbs, Chem. Rev. 2009, 110, 1746–1787; d) C. Samojtowicz,
M. Bieniek, K. Grela, Chem. Rev. 2009, 109, 3708–3742.
[16] a) S. J. Connon, S. Blechert, Angew. Chem. 2003, 115, 1944;
Angew. Chem. Int. Ed. 2003, 42, 1900–1923; b) K. C. Nicolaou,
P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4564; Angew.
Chem. Int. Ed. 2005, 44, 4490–4527; c) A. Fürstner, Chem.
Commun. 2011, 47, 6505–6511.
15071–15098.
[29] E. W. Colvin, B. J. Hamill, J. Chem. Soc., Chem. Commun.
1973, 151–152.
[30] a) D. W. Hart, J. Schwartz, J. Am. Chem. Soc. 1974, 96, 8115–
8116; b) D. W. Hart, T. F. Blackburn, J. Schwartz, J. Am. Chem.
Soc. 1975, 97, 679–680.
[31] Z. Huang, E.-i. Negishi, Org. Lett. 2006, 8, 3675–3678.
[32] A. Fürstner, J.-A. Funel, M. Tremblay, L. C. Bouchez, C. Nev-
ado, M. Waser, J. Ackerstaff, C. C. Stimson, Chem. Commun.
2008, 2873–2875.
[17] T. W. Funk, J. Efskind, R. H. Grubbs, Org. Lett. 2005, 7, 187–
190.
[33] M. Domínguez, R. Alvarez, E. Borrás, J. Farrés, X. Parés,
A. R. de Lera, Org. Biomol. Chem. 2006, 4, 155–164.
[34] M. Domínguez, R. Alvarez, S. Martras, J. Farrés, X. Parés,
A. R. de Lera, Org. Biomol. Chem. 2004, 2, 3368–3373.
[35] O. Isler, H. Lindlar, M. Montavon, R. Rüegg, P. Zeller, Helv.
Chim. Acta 1956, 39, 449–454.
[18] a) I. Jermacz, J. Maj, J. W. Morzycki, A. Wojtkielewicz, Tox-
icol. Mech. Methods 2008, 18, 469–471; b) A. Wojtkielewicz, J.
Maj, J. W. Morzycki, Tetrahedron Lett. 2009, 50, 4734–4737.
The authors describe the cross-metathesis of β,β-carotene and
ethyl 3-methylhexa-2,4-dienoate after 96 h under the same re-
action conditions to afford the more stable methylretinoate in
31% yield.
[36] A. Haag, C. H. Eugster, Helv. Chim. Acta 1982, 65, 1795–1803.
Received: June 28, 2011
Published Online: September 21, 2011
6712
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6704–6712