Practical synthesis of ε-carotene

Article abstract of DOI:10.1055/s-0034-1378941

A novel route for the total synthesis of ε-carotene is described. The synthesis is based on a condensation between α-cyclocitral and diethyl [(2E)-3-methoxy-2-methylprop-2-en-1-yl]phosphonate to give a C₁₄ enol ether, hydrolysis of the C₁₄-enol ether to a give a C₁₄ aldehyde, and a modified Wittig-Horner reaction of the C₁₅ phosphonate from the C₁₄ aldehyde and a C₁₀ triene dialdehyde to give ε-carotene. The synthetic steps are easily performed and are practical for large-scale production.

Full text of DOI:10.1055/s-0034-1378941

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 481–484
paper
481
C. Wu et al.
Paper
Synthesis
Practical Synthesis of ε-Carotene
Chunlei Wua
Ruiwei Caob
CHO
Xiaohua Songa
Chunlei Lvb
4 steps
Weidong Yeb
Shiqing Pib
34% overall
Chaohui Chenb
Runpu Shen*a
e-carotene
a Department of Chemistry and Chemical Engineering, Shaoxing
University, Shaoxing, Zhejiang 312000, P. R. of China
srunpu@usx.edu.cn
wuchunlei2006@usx.edu.cn
b Zhejiang Medicine Co., Ltd., Xinchang, Zhejiang 312500,
P. R. of China
Received: 17.07.2014
Accepted after revision: 07.11.2014
Published online: 05.12.2014
highly efficient free-radical scavenging activities that can
be beneficial in the prevention of some of cancers and car-
diovascular disease.3 ε-Carotene is a member of the carot-
enoid family that is present in carrots and tomatoes, along-
side β-carotene and lycopene. Because ε-carotene has an α-
end group, it would be expected to possess similar func-
tional roles to β-carotene and lycopene in living systems.
For this reason, we wish to report a practical method for the
total synthesis of ε-carotene (Scheme 1).
The synthesis of carotenoids has evolved in parallel to
the development of synthetic methods for the construction
of polyenes.4 The Wittig reaction has been used as the main
shortcut for this purpose. The most classical route to ε-car-
otene was devised by Weedon and co-workers in 1965;4a
this involved the stepwise C15 + C10 + C15 double Wittig reac-
tion shown in Scheme 2. An excess of the C15 Wittig salt was
treated with (2E,4E,6E)-2,7-dimethylocta-2,4,6-trienedial
(3) to yield ε-carotene. The C15 Wittig salt was prepared
from α-ionone in three steps in an overall yield of 45%.
We recently reported syntheses of β-carotene, vitamin
A, and lycopene by a stepwise C15 + C10 + C15 Wittig–Horner
condensation5 in which C15 phosphonate building blocks,
instead of C15 triphenylphosphonium salts, were designed
and coupled with trienedial 3. Because the use of phospho-
DOI: 10.1055/s-0034-1378941; Art ID: ss-2014-h0452-op
Abstract A novel route for the total synthesis of ε-carotene is de-
scribed. The synthesis is based on a condensation between α-cyclocitral
and diethyl [(2E)-3-methoxy-2-methylprop-2-en-1-yl]phosphonate to
give a C14 enol ether, hydrolysis of the C14-enol ether to a give a C14 al-
dehyde, and a modified Wittig–Horner reaction of the C15 phosphonate
from the C14 aldehyde and a C10 triene dialdehyde to give ε-carotene.
The synthetic steps are easily performed and are practical for large-
scale production.
Key words total synthesis, Wittig reactions, carotenes, isomerizations
Carotenoids are a large group (more than 750 different
members have been described) of lipid-soluble pigments
that are biosynthesized in photosynthetic plants, bacteria,
some fungi, and algae.1 In these organisms, carotenoids are
involved in photosynthesis and in photoprotection.2 The
biological functions of some of these highly conjugated
polyenes have been elucidated, and organic syntheses have
been designed to produce these invaluable natural products
in large quantities for use as medications and nutraceuti-
cals for improving human health. Most carotenoids have a
O
O
3 steps
CHO
(EtO)2P
OMe
P(OEt)2
+
C15 phosphonate
CHO
OHC
ε-carotene
Scheme 1 Synthesis of ε-carotene
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 481–484

482
C. Wu et al.
Paper
Synthesis
+
3 steps
CH2PPh3
C10 trienedial 3
O
ε-carotene
Hal–
C15 Wittig salt
Scheme 2 Weedon’s method for the synthesis of ε-carotene
nate should avoid some of the difficulties associated with
the use of phosphonium salts (for example, the separation
of triphenylphosphine oxide from the products), our strate-
gy for synthesizing ε-carotene involved using the corre-
sponding phosphonate to couple with trienedial 3. The en-
tire synthesis is shown in Scheme 3. In this route, the key
intermediate C15 phosphonate can be prepared from α-cyc-
locitral and diethyl [(2E)-3-methoxy-2-methylprop-2-en-
1-yl]phosphonate (5) in three steps. The starting material 5
can be synthesized according to the literature.6 α-Cycloci-
tral (4), tetraethyl methylenebisphosphonate (8) and
trienedial 3 of technical grade were purchased.
The condensation of α-cyclocitral (4) with phosphonate
5 in the presence of potassium tert-butoxide at –20 °C gave
the C14 enol ether 6 in 70% yield. The product was a color-
less liquid that could be purified by distillation. In this step,
the key substrate 5 was initially converted into its corre-
sponding carbanion by the base. This carbanion was stabi-
lized by the presence of the double bond and the phospho-
nate group, permitting the condensation to occur smoothly.
We have previously used phosphonate 5, with its interest-
ing structure, in our synthesis of another carotenoid, lyco-
pene.7
Next, the vinyl C15 phosphonate 2v was obtained in 90%
yield by condensation of the C14 aldehyde 7 with tetraethyl
methylenebisphosphonate (8) in the presence of sodium
hydride at 10–15 °C; again, the product could be purified by
distillation.
All that now remained to complete our synthesis of ε-
carotene (1) was to carry out a second Wittig–Horner reac-
tion of the C15 phosphonate 2v and the C10 triene aldehyde 3
in the presence of sodium tert-butoxide. However, to obtain
the structure of ε-carotene (1), the vinyl C15 phosphonate
2v needed to be converted into the corresponding allyl C15
phosphonate 2a before condensation with the C10 trienedial
3 (Scheme 4). Babler and Schlidt8 reported that an analo-
gous vinyl phosphonate readily isomerized to give the cor-
responding allyl phosphonate in the presence of a base cat-
alyst, so we surmised that this process might also proceed
smoothly with vinyl C15 phosphonate 2v. To confirm this
conjecture, a mixture of vinyl C15 phosphonate 2v and sodi-
um tert-butoxide in dimethyl sulfoxide was stirred at
–15 °C for three hours and then the mixture was hydro-
lyzed. We were amazed to find that isomerization of vinyl
C15 phosphonate 2v into allyl C15 phosphonate 2a occurred
smoothly, as shown by 1H NMR and 13C NMR spectroscopy.
ε-Carotene 1 was subsequently obtained in 75% yield by
adding trienedial 3 to the isomerized mixture at –15 °C.
In summary, a new route has been developed for the to-
tal synthesis of ε-carotene (1) with a total yield of 34%, in
which a Wittig–Horner condensation is used as the sole
method for chain extension. The synthesis starts from α-cy-
clocitral (4); neither the intermediate C14 enol ether 6 nor
the C15 phosphonates 2 have been reported before. Because
all the synthetic steps are readily performed and all the key
The C14 enol ether 6 was then readily converted into the
corresponding C14 aldehyde 7 in 72% yield. The hydrolysis
proceeded under mild conditions with 4-toluenesulfonic
acid as the catalyst, so that the original double bond system
remained in balance and the nonconjugated C14 aldehyde 7
was obtained.
O
CHO
OMe
CHO
i
ii
(EtO)2P
OMe
+
5
4
7
6
O
iv
iii
P(OEt)2
ε-carotene
CH2[PO(OEt)2]2
CHO
1
OHC
8
2
3
Scheme 3 Reagents and conditions: (i) KOt-Bu, THF–DMSO, –20 °C, 70%; (ii) PTSA, acetone–H2O, 20–25 °C, 72%; (iii) NaH, toluene, 10–15 °C, 90%; (iv)
NaOt-Bu, THF–DMSO, –20 to 10 °C, 75%.
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C. Wu et al.
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Synthesis
O
O
NaOt-Bu, DMSO
P(OEt)2
P(OEt)2
vinyl C15 phosphonate 2v
Scheme 4 The isomerization of vinyl C15 phosphonate 2 to allylic C15 phosphonate 2
allyl C15 phosphonate 2a
building blocks can be prepared on a large scale, the syn-
thetic route discussed here might be useful as a practical
route for the synthesis of ε-carotene.
1H NMR (400 MHz, CDCl3): δ = 0.82 (s, 3 H, CH3), 0.89 (s, 3 H, CH3),
1.20 (d, J = 3.4 Hz, 3 H, CHCH3), 1.38–1.45 (m, 2 H, CH2CH2C), 1.58 (s, 3
H, CCH3), 2.0 (m, 2 H, CH2CH2C), 2.13 (d, J = 4.4 Hz, 1 H, CCHC), 3.06–
3.11 (m, 1 H, CHCHO), 5.32–5.34 (m, 1 H, CH2CHC), 5.36–5.47 (m, 2 H,
CH=CH), 9.56 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): δ = 13.6, 22.7, 23.0 (–), 26.8, 27.5, 31.5 (–),
50.0, 54.5, 121.2, 127.3, 135.5, 201.7.
13C DEPT135 (100 MHz, CDCl3): δ = 14.7, 23.0 (D), 23.1, 27.1, 27.6,
31.9 (D), 55.1, 59.6, 120.4, 126.1, 129.1, 143.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H22O: 206.1671; found:
206.1669.
1H and 13C NMR spectra were recorded on a Bruker AVANCE DMX II
I400M spectrometer. Samples were dissolved in CDCl3, which provid-
ed the deuterium lock for the spectrometers. TMS or residual CHCl3
was used as an internal standard. GC-MS measurements were per-
formed on an Agilent MS 5973N-GC6890N. HRMS measurements
were performed on a Waters Micromass GCT Premier. GC analysis
was carried out on a Shanghai Tianmei 7890F instrument.
Diethyl [(1E,4E)-3-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-
yl)penta-1,4-dien-1-yl]phosphonate (2v)
6-[(1E,3E)-4-Methoxy-3-methylbuta-1,3-dien-1-yl]-1,5,5-trimeth-
ylcyclohexene (6)
A solution of tetraethyl methylenebisphosphonate (8; 31.5 g, 0.11
mol) in toluene (80 mL) was added dropwise over 30 min to a solution
of NaH (60% content, 4 g, 0.1 mol) in toluene (20 mL) at 10–15 °C un-
der N2, and the mixture was stirred for 30 min. A solution of aldehyde
7 (18.5 g, 0.09 mol) in toluene (30 mL) was added dropwise over 30
min at 10–15 °C, and the mixture was stirred for a further 30 min.
H2O (80 mL) was added and the mixture was stirred for 10 min. The
organic layer was washed with 10% aq NaCl (80 mL), dried (MgSO4),
and concentrated in vacuo to give the crude product (GC content
94.3%) as a pale-brown liquid; yield: 32.3 g (90%). This was purified
by distillation in vacuo (~130 °C, 1 mmHg).
Phosphonate 5 (24.4 g, 0.11 mol) was added dropwise over 30 min to
a solution of KOt-Bu (12.3 g, 0.11 mol) in 8:1 anhyd THF–DMSO (50
mL) at –20 °C min under N2. The mixture was stirred at –20 °C for 1 h
and then a solution of α-cyclocitral (4; 15.2 g, 0.1 mol) in 8:1 THF–
DMSO (10 mL) was added dropwise over 30 min. The mixture was
stirred for another 30 min until the reaction was complete (GC). H2O
(50 mL) and Et2O (100 mL) were added, and the mixture was stirred
for another 10 min. The organic layer was separated, washed with 5%
aq NaCl (3 × 25 mL), dried (MgSO4), and concentrated in vacuo to give
the crude product (GC content 98.6%) as a colorless liquid; yield: 15.4
g (70%); bp 93–95 °C (1 mmHg).
IR (film): 1626, 1596, 1247, 1026, 961 cm–1
.
IR (film): 3120, 1683, 1657, 1250 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.80 (s, 3 H, CH3), 0.88 (s, 3 H, CH3),
1.15 (d, J = 6.8 Hz, 3 H, CHCHCH3), 1.33 (t, J = 6.8 Hz, 6 H, 2 ×
OCH2CH3), 1.56 (s, 3 H, CHCCH3), 1.41–1.43, 1.73–1.74 (m, 2 H, 2 ×
CHCH2CH2), 1.99–2.04 (m, 2 H, CHCH2CH2), 2.07 (d, J = 8.8 Hz, 1 H,
CCHCH), 2.99–3.03 (m, 1 H, CHCH3), 4.03–4.10 (m, 4 H, 2 × OCH2),
5.29–5.30, 5.31–5.32 (m, 2 H, CHCH=CHCH), 5.38–5.39 (m, 1 H,
CH2CH), 5.62 (m, 1 H, CH=CHP), 6.70–6.77 (m, 1 H, CH=CHP).
1H NMR (400 MHz, CDCl3): δ = 0.89 (s, 3 H, CH3), 0.81 (s, 3 H, CH3),
1.15–1.21, 1.42–1.49 (m, 2 H, CCH2CH2), 1.59 (s, 3 H, CHCCH3), 1.62 (s,
3 H, OCHCCH3), 2.00–2.02 (m, 2 H, CH2CH), 2.18 (d, J = 9.6 Hz, 1 H,
CCHCH), 3.61 (s, 3 H, OCH3), 5.38 (dd, J = 9.6, 15.6 Hz, 1 H, CHCH=CH),
5.38–5.39 (m, 1 H, CH2CH), 5.81 (s, 1 H, C=CHO), 6.50 (d, J = 15.6 Hz, 1
H, CH=CHC).
13C NMR (100 MHz, CDCl3): δ = 14.7, 23.1, 23.0, 27.1, 27.6, 31.9, 32.2,
55.1, 59.6, 112.0, 120.4, 126.1, 129.1, 134.9, 143.8.
13C DEPT135 (100 MHz, CDCl3): δ = 14.7, 23.0 (–), 23.1, 27.1, 27.6, 31.9
13C NMR (100 MHz, CDCl3): δ = 16.3, 16.4, 19.4, 22.8, 23.1, 27.0, 27.5,
31.6, 31.9, 41.0, 54.4, 61.6, 61.7, 115.1 (d, J = 187.3 Hz, CP), 120.9,
132.0, 133.0, 134.1, 157.3.
13C DEPT135 (100 MHz, CDCl3): δ = 16.3, 16.4, 19.4, 22.8, 23.1 (–),
27.0, 27.5, 31.6 (–), 41.0, 54.4, 61.6 (–), 61.7 (–), 115.1 (d, J = 187.3 Hz,
CP), 120.9, 132.0, 133.0, 157.3.
(–), 55.1, 59.6, 120.4, 126.1, 129.1, 143.8.
GC-MS: m/z (%) = 220, 177 (100), 121, 109, 93, 77, 69, 65, 55, 43.
HRMS (ESI): m/z [M + H]+ calcd for C15H24O: 220.1827; found:
220.1824.
GC-MS: m/z (%) = 340, 325, 284, 219, 146 (100), 131, 119, 105, 91, 81,
55, 41.
HRMS (ESI): m/z [M + H]+ calcd for C19H33O3P: 340.2167; found:
340.2163.
(3E)-2-Methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-enal
(7)9
A three-necked flask was charged with enol ether 6 (11.0 g, 0.05 mol),
THF (100 mL), PTSA (1.5 g), and H2O (22 g) under N2, and the mixture
was stirred at 20–25 °C for 24 h. When hydrolysis was complete (GC),
9% aq NaHCO3 (20 mL) was added and the THF was removed under
reduced pressure. Cyclohexane (100 mL) was added and the organic
layer was washed with H2O (30 mL), dried, and concentrated in vacuo
to give a crude product (GC content 73.1%); yield: 10.1 g (72%).
Diethyl [(2E,4E)-3-Methyl-5-(2,6,6-trimethylcyclohex-2-en-1-
yl)penta-2,4-dien-1-yl]phosphonate (2a)10
A sample was taken during the next step, the synthesis of ε-carotene
(1), to show that the vinyl C15 phosphonate 2v rearranged completely
into the allyl C15 phosphonate 2a.
IR (film): 1615, 1587, 1252, 1026, 964 cm–1
.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.80 (s, 3 H, CH3), 0.90 (s, 3 H, CH3),
1.15–1.19, 1.40–1.47 (m, 2 H, CCH2CH2), 1.31 (t, J = 7.0 Hz, 6 H, 2 ×
CH2CH3), 1.57 (s, 3 H, CH3), 1.77 (d, J = 4.0 Hz, 3 H, CH3), 1.98–2.01 (m,
2 H, CCH2CH2), 2.14 [d, J = 9.6 Hz, 1 H, CCHCH(C)], 2.70 (dd, J = 8.0,
22.8 Hz, 2 H, CHCH2P), 4.05–4.15 (m, 4 H, 2 × OCH2CH3), 5.40–5.47 (m,
3 H, 3 × =CH), 6.06 (d, J = 15.2 Hz, 1 H, CH=CHC).
Acknowledgment
We acknowledge the National Natural Science Foundation of China
(No. 21176156 and No. 81202411) and Research Fund
of Zhejiang Educational Committee of China (Y 201431839).
13C NMR (100 MHz, CDCl3): δ = 12.8, 16.4, 16.5, 23.0, 23.1, 26.8 (d, J =
139.4 Hz, CH2P), 27.0, 27.6, 31.7, 32.3, 54.6, 61.9, 62.0, 117.5, 120.8,
130.1, 134.4, 135.2, 137.8.
13C DEPT135 (100 MHz, CDCl3): δ = 12.8, 16.4, 16.5, 23.0, 23.1 (–), 26.8
(–; d, J = 139.4 Hz, CH2P), 27.0, 27.6, 31.7 (–), 54.6, 61.9 (–), 62.0 (–),
117.5, 120.8, 130.1, 135.2.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378941.
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References
GC-MS: m/z (%) = 340, 218 (100), 189, 161, 138, 123, 91, 81, 55, 41.
HRMS (ESI): m/z [M + H]+ calcd for C19H33O3P: 340.2167; found:
340.2169.
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A solution of NaOt-Bu (24 g, 0.25 mol) in DMSO (50 mL) was added
dropwise over 30 min to a solution of vinyl C15 phosphonate 2v (94 g,
0.275 mol) in toluene (250 mL) at –15 °C under N2. The mixture was
stirred for a further 3 h to ensure that the vinyl phosphonate 2v was
converted into the carbanion of the corresponding allyl C15 phospho-
nate 2a. A solution of dial 3 (20.5 g, 0.125 mol) in THF (50 mL) was
added dropwise over 20 min, and the mixture was stirred for another
12 h at 10 °C. When the reaction was complete, H2O (500 mL) was
added. A first fraction of a crude red solid product precipitated and
was collected by filtration. The filtrate was separated and the inor-
ganic layer was extracted with toluene (2 × 100 mL). The organic lay-
ers were combined, washed with H2O (2 × 100 mL) and sat. aq NaCl
(3 × 75 mL), dried (MgSO4), and evaporated in vacuo to obtain a resi-
due. The residue was treated with EtOH (100 mL) to precipitate a sec-
ond fraction of the crude product. The first and second fractions of
the crude product were combined and recrystallized from EtOH–
CH2Cl2 (1:5) to give the pure product (HPLC content 96.8%); yield:
51.2 g (75%).
1H NMR (400 MHz, CDCl3): δ = 0.82 (s, 6 H, 2 × CH3), 0.90 (s, 6 H, 2 ×
CH3), 1.15–1.21, 1.42–1.49 (m, 4 H, 2 × CH2), 1.59 (s, 6 H, 2 × CH3), 1.91
(s, 6 H, 2 × CH3), 1.96 (s, 6 H, 2 × CH3), 2.01–2.05 (m, 4 H, 2 × CH2), 2.18
(dd, J = 1.2, 4.0 Hz, 2 H, 2 × CH), 5.41 (s, 2 H, 2 × =CH), 5.50–5.56 (m, 2
H, 2 × =CH), 6.09–6.11 (m, 2 H, 2 × =CH), 6.13–6.16 (m, 2 H, 2 × =CH),
6.23–6.27 (m, 2 H, 2 × =CH), 6.32–6.36 (m, 2 H, 2 × =CH), 6.58–6.64
(m, 4 H, 4 × =CH).
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13C NMR (100 MHz, CDCl3): δ = 12.8, 13.2, 23.1, 23.2, 27.1, 27.7, 31.7,
32.6, 54.9, 120.8, 125.0, 130.0, 130.3, 131.0, 132.4, 134.5, 135.6, 136.2,
136.4, 137.2.
13C DEPT135 (100 MHz, CDCl3): δ = 12.8, 13.2, 23.1, 23.2 (–), 27.1,
27.7, 31.7 (–), 54.9, 120.8, 125.0, 130.0, 130.3, 131.0, 132.4, 136.2,
137.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 481–484