Practical synthesis of canthaxanthin

Article abstract of DOI:10.1007/s13738-019-01784-2

In this study, a novel route for the total synthesis of canthaxanthin is described. The synthesis is firstly based on an epoxidation of α-ionone with metachloroperbenzoic acid to afford the epoxide, followed by conversion of the epoxide to 3-hydroxyl-β-ionone in the presence of sodium methoxide. Next, 3-hydroxyl-C14-aldehyde was obtained by a Darzens condensation with 4-hydroxyl-β-ionone and methyl chloroacetate, which can be converted to 3-hydroxyl-C15-phophonate via a Wittig–Horner condensation with tetraethyl methylenebisphosphonate. Then, a Wittig–Horner condensation with 3-hydroxyl-C15-phosphonate and C10-trienedial resulted in 4,4′-dihydroxyl-β-carotene, followed by an oxidation afforded the target product canthaxanthin. The overall yield of this route is 37% from α-ionone. The synthetic steps are easily operated and are practical for the large-scale production.

Full text of DOI:10.1007/s13738-019-01784-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01784-2
ORIGINAL PAPER
Practical synthesis of canthaxanthin
Shiqing Pi1,2 · Meiyang Xi1 · Liping Deng1 · Huiting Xu1 · Chengjie Feng1 · Runpu Shen1,2 · Chunlei Wu1
Received: 9 April 2019 / Accepted: 24 September 2019
© Iranian Chemical Society 2019
Abstract
In this study, a novel route for the total synthesis of canthaxanthin is described. The synthesis is frstly based on an epoxida-
tion of α-ionone with metachloroperbenzoic acid to aford the epoxide, followed by conversion of the epoxide to 3-hydroxyl-
β-ionone in the presence of sodium methoxide. Next, 3-hydroxyl-C14-aldehyde was obtained by a Darzens condensation
with 4-hydroxyl-β-ionone and methyl chloroacetate, which can be converted to 3-hydroxyl-C15-phophonate via a Wit-
tig–Horner condensation with tetraethyl methylenebisphosphonate. Then, a Wittig–Horner condensation with 3-hydroxyl-
C15-phosphonate and C10-trienedial resulted in 4,4′-dihydroxyl-β-carotene, followed by an oxidation aforded the target
product canthaxanthin. The overall yield of this route is 37% from α-ionone. The synthetic steps are easily operated and are
practical for the large-scale production.
Keywords Canthaxanthin · Wittig–Horner condensation · Total synthesis · Phosphonate
Introduction
the available C15 Wittig salts and the C10-triene dialdehyde
building blocks is shown in Scheme 1, in which a major
disadvantage is the formation of triphenylphosphine oxide
during the Wittig olefnation [9–12].
Canthaxanthin, one of 10 marketed commercially carot-
enoids, is a diketo-carotenoid with nine conjugated car-
bon–carbon double bonds at the center of the molecule [1].
It appears as a red–orange lipophilic pigment [2], biosyn-
thesized in some bacteria, fungi and algae and widely used
in poultry as a feed additive [3, 4]. Furthermore, it exhibits
several potential health benefts, such as free radical scav-
enging properties, immune modulating activities and an
induction of gap junction communication [1]. These inter-
esting biological properties as well as its unique molecular
structure have stimulated a number of eforts to produce
canthaxanthin since the frst synthesis in 1958 [5], in which
the most concern is how to introduce newly conjugated car-
bon–carbon double bonds. Undoubtedly, Wittig-type con-
densation is the main shortcut for this purpose [6–8]. The
most representative disconnection of canthaxanthin based on
Barbler has frstly reported the use of the key intermedi-
ate C15 Wittig–Horner salts, instead of C15 Wittig salts to
synthesize of canthaxanthin, which can avoid the difculties
associated with the use of phosphonium salts (for example,
the separation of triphenylphosphine oxide from the prod-
ucts) [13]. But the reaction conditions for the key interme-
diate allenic phosphonate in Babler’s route are too rigorous
and its subsequent partial hydrogenation was somewhat too
difcult to fnish with high selectivity. And our team has
developed new strategies for the synthesis of β-carotene
[14], lycopene [15, 16] and ε-carotene [17] employed
C15-Wittig–Horner salts as the key intermediates.
In this paper, we report a practical approach for the syn-
thesis of canthaxanthin by an oxidation of 4,4′-dihydroxyl-
β-carotene, which was from the condensation of C15-phos-
phonate 2 and C10-trienedial 3. The key intermediate
C15-phosphonate 2 could be synthesized in four steps
employed α-ionone as the starting material (Scheme 2).
* Chunlei Wu
wuchunlei2006@usx.edu.cn
1
Department of Chemistry and Chemical Engineering,
Shaoxing University, Shaoxing 312000, Zhejiang,
People’s Republic of China
2
Zhejiang Medicine Co. Ltd, Xinchang
Pharmaceutical Factory, Xinchang 312500, Zhejiang,
People’s Republic of China
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Scheme 1 C15+C10+C15
disconnection of canthaxanthin
via Wittig reaction or Wittig–
Horner reaction
O
1
O
C15 -Wittig salts X=PPh3Br
CHO
3
OHC
X
C10-trienedial
C15-Wittig-Horner phosphonate X=PO(OEt)2
O
Scheme 2 Reagents and conditions: (i) MCPBA, CH2Cl2, 0–5 °C,
95%; (ii) sodium methoxide, CH3OH, refuxing, 85%; (iii) sodium
methoxide, toluene, −20 to10 °C, 83%; (iv) NaOEt, ethanol, 25 °C,
93%; (v) KOt-Bu, THF and HMPT, −25 to −15 °C, 68%; (vi) alu-
minum isopropoxide, acetone, refuxing, 88%
impurities according to the literature [18], which is not
suitable for large-scale production. Here, we found a new
methodology to purify the crude 4-hydroxyl-β-ionone.
It was reacted with succinic anhydride to aford the cor-
responding ester, which then was dissolved in a basic
aqueous solution and the impurities can be separated by
extraction with water insoluble solvent. The ester was then
alcoholysis by methanol in the presence of sodium meth-
oxide to aford pure 4-hydroxyl-β-ionone 6 in 85% yield
with 98% content (GC).
Results and discussion
Firstly, according to the literature [18], α-ionone 4 was
epoxidated with MCPBA to aford a mixture of epoxides
5, in which one isomer predominates about 92%. The
reaction should be quenched when the material α-ionone
disappeared by GC, or a by-product will be formed. The
structure of this impurity is a Baeyer–Villiger reaction
substance 9 according to its GC–MS (Scheme 3).
Then, the above epoxide was converted to 4-hydroxyl-
β-ionone 6 via isomerization in the presence of sodium
methoxide. The by-product diketone was about 6% (GC),
which is consistent with the literature [18], and the other
by-product dehydrate was also verified according to
GC–MS with about 1–2% ratio (GC). The crude prod-
uct can be chromatographed on silica gel to remove the
Next, a Darzens reaction was carried out with 4-hydroxyl-
β-ionone 6 and methyl chloroacetate. During the process,
40% sodium methoxide was added dropwise into the reac-
tion mixture of 4-hydroxyl-β-ionone and methyl chloroace-
tate at −20 °C, and then, another 3-h stirring at −10 °C was
needed until the spot of 4-hydroxyl-β-ionone disappeared
by TLC. Then, decarboxylation was carried out at 40 °C for
30–40 min. But the TLC showed no mainly product formed.
We then found the product 3-hydroxyl-C14-aldehyde 7
is very sensitive to base. In fact, the decarboxylation has
been fnished after 3-h stirring at − 10 °C and 3-hydroxyl-
C14-aldehyde 7 will be destroyed by the base at 40 °C. So
when 4-hydroxyl-β-ionone disappeared, tenfold water was
added to quench the reaction, and then, toluene was added
to extract the crude product 4-hydroxyl-C14-aldehyde 7 to
Scheme 3 Over-oxidation of α-ionone
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Journal of the Iranian Chemical Society
avoid hydrolysis. The yield of the crude product was 85%
with 90% content (GC), which can be raised to 94% by dis-
tillation in vacuo.
5973N-GC6890N. GC analysis was carried out on a Shang-
hai Tianmei 7890F instrument
A Wittig condensation between 3-hydroxyl-C14-aldehyde
7 and tetraethyl methylenebisphosphonate was carried out
in the presence of a base to aford 3-hydroxyl-C15-phos-
phonate 2. During the process, NaH was used to promote
the reaction, but the result 3-hydroxyl-C15-phosphonate 2
was presented as a pasty and difcult to handle. Then, we
found that sodium ethoxide used as the base catalyst can
resolve the above problem. After the condition optimization,
3-hydroxyl-C15-phosphonate 2 can be obtained as a pale
yellow solid in 93% yield.
Preparation of (E)‑4‑(1,3,3‑trimethyl‑7‑oxa‑bicy‑
clo[4.1.0]heptan‑2‑yl)but‑3‑en‑2‑one 5
MCPBA (22.8 g, 0.116 mol) dissolved in CH2Cl2 (60 mL)
was added dropwise over 30 min to a solution of α-ionone
(22.2 g, 0.116 mol) in CH2Cl2 (85 mL) at 0 °C. The mix-
ture was stirred for 1 h at 10 °C to complete the reaction
according to TLC and GC. Then, the reaction mixture was
fltered and the residue was washed with CH2Cl2 (50 mL).
The above combined CH2Cl2 was then washed with 10%
aq Na2SO3, 5% aq NaOH and water successively and dried
(MgSO4). The crude product epoxide 5 was aforded by con-
centration in vacuo in 95% yield (21.1 g) with a content of
92.6% (GC). GC–MS: m/z (%)=208, 193, 109.
Then, 4,4′-dihydroxyl-β-carotene 8 was obtained in 68%
yield by condensation of 3-hydroxyl-C15-phosphonate 2 and
C10-trienedial 3 in the presence of potassium tert-butox-
ide. However, to obtain the structure of canthaxanthin, the
required conversion of 1,3-diene-3-hydroxyl-C15-phospho-
nate to the corresponding 2,4-diene-3-hydroxyl-C15-phos-
phonate prior to condensation with C10-trienedial occurred
in situ under these conditions (Scheme 4).
Preparation of (E)‑4‑(3‑hydroxy‑2,6,6‑trimethylcy‑
clohex‑1‑enyl)but‑3‑en‑2‑one 6
All that now remained to complete our strategy for can-
thaxanthin was to carry out an Oppennauer reaction of the
4,4′-dihydroxyl-β-carotene 8 catalyzed by aluminum isopro-
poxide. The oxidation proceeded almost quantitatively. The
resulted crude canthaxanthin 1 was composed of 15–20%
cis-isomer according to HPLC. Accordingly, an isomeriza-
tion of the crude product was carried out by refuxing in
isobutanol for 10 h, and then, the aubergine all-E-canthax-
anthin was obtained in 88% yield with 97% content (GC).
30% sodium methoxide was added to the above epoxide 5
(20.9 g, 0.1 mol) in 80 mL CH3OH, and the mixture was
stirred for 3 h in refuxing. Then, 0.5 mL glacial acetic acid
was added at rt and the methanol was evaporated in vacuo.
Twenty milliliters of H2O was added to the above residue,
which was then extracted by ethyl acetate (15 mL×2). Suc-
cinic anhydride (11 g, 0.11 mol) was added into the above
extract and refuxing for 5 h. After cooling to rt, saturated aq
Na2CO3 (30 mL) was added for extraction and the organic
layer was discarded. Then, the extract was acidifed to PH
1–2 with 10% aq HCl, which was then extracted with ethyl
acetate (30 mL×2), followed by drying (MgSO4) and dis-
tillation in vacuo to aford the corresponding ester. Then,
30% sodium methoxide (25 mL) was added and refuxing for
1 h. After cooling to rt, methanol was evaporated in vacuo
and 25 mL water was added to the residue. Then, extrac-
tion with ethyl acetate (20 mL × 2), drying (MgSO4) and
evaporation in vacuo, a purifed 4-hydroxyl-β-ionone 6 in
85% yield with 98% content (GC), was aforded. GC–MS:
m/z (%)=208, 109.
Experimental
Materials and method
1H NMR spectra were determined on a Bruker AVANCE
DMX III 400M spectrometer and, 13C NMR spectra were
obtained on the same instrument, respectively. Samples were
dissolved in deuterated chloroform (CDCl3), which provided
the deuterium lock for the spectrometers. Tetramethylsilane
or residual chloroform was used as an internal standard.
GC–MS measurements were determined on Agilent MS
Preparation of (E)‑4‑(3‑hydroxy‑2,6,6‑trimethylcy‑
clohex‑1‑enyl)‑2‑methylbut‑2‑enal 7
A mixture of 4-hydroxyl-β-ionone 6 (20 g, 0.096 mol),
methyl chloroacetate (10.5 g, 0.096 mol) and 50 mL tolu-
ene was cooled to − 20 °C, and 30% sodium methoxide
(25 g) was added dropwise in 30 min. The reaction mix-
ture was stirred for 3 h at − 10 °C. Then, 200 mL water
was added and separated. The water layer was extracted
with toluene (100 mL × 2). The combined organic layer
was washed with water (50 mL), dried with MgSO4 and
Scheme 4 Isomerization of 1,3-diene -C15-phosphonate to
2,4-diene-C15-phosphonate
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Journal of the Iranian Chemical Society
evaporated in vacuo to aford crude 4-hydroxyl-C14-alde-
hyde 7 (17.6 g) in 83% yield with content of 91% (GC).
A purifed product was obtained as a pale yellow liquid
after a distillation under a vacuo of 8 Pa with the content
of 94.2%. b.p. 105–108 °C (2 mmHg). 1H NMR (400 Hz,
CDCl3): δ = 0.99 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.68
(s, 6H, 2 × CH3), 1.82 (s, 4H, CH2CH2), 2.18 (s, 1H,
OH), 3.05–3.06 (d, 2H, CH2), 3.97 (s, 1H, OCH), 6.33
(s, 1H, = CH), 9.38 (s, 1H, CHO) [18]. ESI–MS: 205
(M + 1-H2O, 100).
Preparation of canthaxanthin 1
Aluminum isopropoxide (5 g, 0.0245 mol) was added to the
solution of 4,4′-dihydroxyl-β-carotene (10.5 g, 0.0185 mol)
and acetone (100 mL), and the mixture was stirred for 5 h
at refux temperature under N2. Then, the solvent acetone
was evaporated and 10% aq H2SO4 was added, followed by
extracting with CH2Cl2 (120 mL), washing with aqueous
NaCl (5%, 3 × 10 mL), dried (MgSO4) and evaporated to
leave crude canthaxanthin, in which 50 mL isobutanol was
added and stirred at 80 °C for 10 h under N2 for isomeriza-
tion to aford all-E-canthaxanthin in 88% yield with the con-
tent of 97% (HPLC). 1H NMR (400 Hz, CDCl3): δ=1.19 (s,
12H, 4×CH3), .84 (d, 4H, 2×CH2), 1.87 (s, 6H, 2×CH3),
1.99 (d, 12H, 4 × CH3), 2.51 (t, 4H, 2 × CH2–C = O),
6.22–6.67 (m, 14H, = CH). 13C NMR (100 Hz, CDCl3):
δ = 12.7, 13.4, 27.6, 34.2, 35.6, 37.2, 124.0-141.3, 161.2,
199.3 [19, 20]. ESI–MS: 565.3 (M+1).
Preparation of diethyl [(1E,3E)‑3‑methyl‑5‑(3‑hydroxyl‑
2,6,6‑trimethylcyclohex‑2‑en‑2‑yl)penta‑1,3‑dien‑1‑yl]
phosphonate 2
Sodium (2.0 g) was dissolved in anhydrous alcohol (100 mL)
under N2. Then, tetraethyl methylenebisphosphonate (25.0 g,
0.087 mol) was added dropwise to the above sodium eth-
oxide solvent at 25 °C under N2. A solution of 4-hydroxyl-
C14-aldehyde 7 (17.5 g, 0.079 mol) in ethanol (30 mL) was
added dropwise over 30 min at 25 °C, and the mixture was
stirred for a further 2 h. After the reaction was completed
according to GC, the pH value of the reaction mixture was
adjusted to about 7 with acetic acid. Then, H2O (100 mL)
and acetyl acetate (100 mL) were added. The organic layer
was separated, washed with 10% aq NaCl (100 mL), dried
with anhydrous MgSO4 and concentrated in vacuo to give
the crude product as a pale yellow powder in 93% yield
Conclusions
In summary, a new route has been developed for the total
synthesis of canthaxanthin with an overall yield of 37% from
α-ionone. Because all the steps are readily performed and
all the key building blocks can be prepared on a large scale,
the route described here should be useful as a practical route
for the synthesis of canthaxanthin.
1
(25.6 g). M.p.: 115–117 °C. H NMR (400 Hz, CDCl3):
Acknowledgements This study was supported by the Public Projects
δ = 0.85 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.32–1.39 (6H,
CH3), 1.59–1.71 (m, 7H, CH2CH2, CH3), 2.89–2.92 (d, 2H,
CH2), 3.04 (s, 1H, OCH), 4.04–4.13 (m, 4H, OCH2 × 2),
5.51–5.60 (t, 1H,=CH), 5.66–5.69 (t, 1H,=CH), 7.04–7.27
(m, 1H,=CH) [18]. ESI–MS m/z (%): 713.7 (2 M+H, 100),
735.3 (2 M+Na, 85).
of Zhejiang Province of China (No. LGG19B020002).
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