Practical Synthesis of Lycopene

Full text of DOI:10.1080/00304948.2016.1194133

Organic Preparations and Procedures International
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Practical Synthesis of Lycopene
Xiaohua Song, Huiting Xu, Weidong Ye, Chunlei Lv, Ruiwei Cao, Chunlei Wu &
Runpu Shen
To cite this article: Xiaohua Song, Huiting Xu, Weidong Ye, Chunlei Lv, Ruiwei Cao, Chunlei Wu
& Runpu Shen (2016) Practical Synthesis of Lycopene, Organic Preparations and Procedures
International, 48:4, 350-354, DOI: 10.1080/00304948.2016.1194133
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Date: 03 August 2016, At: 01:38

Organic Preparations and Procedures International, 48:350–354, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1194133
Practical Synthesis of Lycopene
Xiaohua Song,1 Huiting Xu,1 Weidong Ye,2 Chunlei Lv,2
Ruiwei Cao,2 Chunlei Wu,1 and Runpu Shen1
1Department of Chemistry and Chemical Engineering, Shaoxing University,
Shaoxing, Zhejiang 312000, P. R. of China
2Zhejiang Medicine Co. Ltd., Shaoxing, Zhejiang, 312000, P. R. of China
Carotenoids are a large group of lipid-soluble pigments biosynthesized in plants, in bacte-
ria, in some fungi and in algae.1,2 Lycopene is a red pigmented carotenoid found in toma-
toes. It contains thirteen double bonds and has a greater radical scavenging ability than
b-carotene. It has shown potential as protection against a variety of serious disorders such
as some cancers, cardiovascular and degenerative eye diseases.3-6 These interesting bio-
logical properties as well as its unique molecular structure have stimulated a number of
efforts to produce lycopene7-15 since its first reported synthesis in 1950,16 whose the
major goal was the design of a method to introduce newly conjugated carbon-carbon dou-
ble bonds.
We previously reported a practical route for the total synthesis of lycopene via a
stepwise C15 C C10 C C15 double Wittig-Horner reaction,17 in which C15-phosphonate 2a was
preparedasthekeybuildingblocksstartingfrom4,4-dimethoxy-3-methylbutanal(Scheme 1).
Scheme 1
More recently, we designed a new synthetic route to e-carotene from a-cyclocitral
and diethyl (3-methoxy-2-methylprop-2-en-1-yl)phosphonate 5.18 The present article
describes a three-step route to C15-phosphonate 2b from citral (4) and compound 5; com-
pound 2b was then coupled with C10-trienedial 3 to give lycopene (Scheme 2).
Received February 3, 2016; in final form May 7, 2016.
Address correspondence to Chunlei Wu, Department of Chemistry and Chemical Engineering,
Shaoxing University, Shaoxing, Zhejiang 312000, P. R. of China. E-mail: wuchunlei2006@usx.edu.cn
350

Practical Synthesis of Lycopene
351
Scheme 2
Condensation of citral (4) with diethyl (3-methoxy-2-methylallyl)phosphonate 5,
prepared according to a literature procedure 19 in the presence of potassium tert-butoxide
at ¡30 to ¡20ꢀC gave the C14-enol ether 6 in 68% yield as a colorless liquid which was
purified by distillation. The product was mainly composed of 1E, 4Z-; 1Z, 4Z-; 1E,
4E-; 1Z, 4E- four isomers in a ratio of about 1:1:1:1 according to the analysis of its NMR
spectrum. The mixture of the four isomers was used without separation in the next step.
The C14-enol ether 6 was then readily converted into the corresponding C14-aldehyde
7 in the presence of p-toluenesulfonic acid in 83% yield; during this step, the double
bonds at carbon 3 isomerized to carbon 2 to produce conjugated aldehyde 7. Then C15-
phosphonate 2b was obtained in 89% yield by condensation of 7 with tetraethyl methyle-
nebisphosphonate 8 in the presence of sodium hydride at 10 to 15ꢀC. The final step to
complete the synthesis of lycopene 1 involves a second Wittig–Horner reaction of the
C15-phosphonate 2b with the C10-trienedial 3 in the presence of sodium tert-butoxide;
However, to obtain the structure of lycopene 1, the required conversion of 1,3-diene-C15-
phosphonate 2b to the corresponding 2,4-diene-C15-phosphonate 2 prior to condensation
with the C10-trienedial 3 (Scheme 3) occurred in situ under these conditions.7
Scheme 3
The lycopene obtained in the present study was composed of at least four isomers and
the use of our previously reported procedure5 led to complete isomerization to
all-E-lycopene as indicated by stirring the crude product for 1 h at 75–80ꢀC in ethanol as
indicated by the NMR spectrum.
In summary, a new route has been developed for the total synthesis of lycopene with
an overall yield of 31% from readily available citral 4, in which a Wittig–Horner conden-
sation was used as the sole method for chain extension. 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 lycopene.
Experimental Section
1H and 13C NMR spectra were recorded on a Bruker Avance DMX II I400M spectrome-
ter. Samples were dissolved in CDCl3, which served as the deuterium lock for the

352
Shen et al.
spectrometers. TMS and residual CHCl3 were used as an internal standard. GC-MS meas-
urements were performed 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. Citral 4, methylene-bisphosphonic acid tetraethyl
ester 8, and C10-trienedial 3 were supplied by Zhejiang Medicine Co. Ltd..
1-Methoxy-2,6,10-Trimethylundeca-1,3,5,9-tetraene (6)
To a solution of KOt-Bu (12.3 g, 0.11 mol) in 8:1 (v/v) mixture of dry THF and DMSO
(50 mL), phosphonate 5 (22.2 g, 0.1 mol) was added dropwise over 30 minutes at ¡30 to
¡20ꢀC under N2 and the mixture was stirred at that temperature for 1 h. Then a solution of
citral 4 (15.2 g, 0.1 mol) in 8:1 (v/v) mixture of dry THF and DMSO (10 mL) was added
dropwise over 1 h. The mixture was stirred for another 30 min until the reaction was complete
(GC). Water (50 mL) and diethyl ether (100 mL) were added, and the mixture was stirred for
another 10 min. The organic layer was separated, washed with 5% aqueous NaCl (5%, 3 £
25 mL), dried (MgSO4), and evaporated in vacuo to leave 16.1 g (68%) of crude C14-enol
ether 6 as a colorless liquid (composed of four isomers) (GC content 93.5%)
1
IR (film): 3120, 1683, 1657, 1250 cm¡1. H NMR (400 MHz, CDCl3): d 1.61 (s, 3H,
CH3C D CHOCH3), 1.68 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.78 (s, 3H, CH D CCH3), 2.05-
2.17 (m, 4H, CH2CH2), 3.62 (s, 3H, OCH3), 5.06–5.16 (m, 1H, CH), 5.87 (s, 1H, C D
CHOCH3), 5.94 (dd, J D 11.2 Hz, 5.6 Hz, 1H, CH D CH), 6.29 (dd, J D 15.2 Hz, 11.2 Hz,
1H, C D CH), 6.63 (dd, J D 15.2 Hz, 12.4Hz, 1H, CH D CH). 13C NMR (100 MHz, CDCl3):
d 14.5, 17.7, 24.0, 25.7, 26.6, 26.8, 32.7, 40.1, 59.8, 112.8, 123.2, 126.7, 129.0, 138.0, 144.8.
13C DEPT135 (100 MHz, CDCl3): d 14.5, 17.7, 24.0, 25.7, 26.6 (¡), 26.8 (¡), 32.7 (¡), 40.1
(¡), 59.8, 123.2, 126.7, 144.8. HRMS (ESI): m/z [M C H]C Calcd for C15H24O: 220.1827.
Found: 220.1823.
2,6,10-Trimethylundeca-2,5,9-trienal (7)
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 to 25ꢀC for 24 h. When hydrolysis was complete (GC), 9% aqueous NaHCO3
(20 mL) was added and the THF was removed under reduced pressure. Cyclohexane
(100 mL) was added and the organic layer was separated, washed with H2O
(30 mL), dried, and concentrated in vacuo to give 9.1 g (88%) of crude product (GC
content 93.1%) as a pale yellow liquid.
1H NMR (400 MHz, CDCl3): d 1.11 (t, J D 7.6 Hz, 3H, CH3CCHO), 1.51 (s, 3H, CH3C
D CH), 1.63 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.85–1.89 (m, 2H, CH2CH2), 2.18–2.29 (m, 2H,
CH2CH2), 2.24–2.33 (m, 2H, CH2), 5.11–5.12 (m, 1H, CH), 5.67 (s, 1H, CH3C D CH), 6.51
(t, J D 7.2 Hz, 1H, CH D CCHO), 9.44 (s, 1H, CHO). 13C NMR (100 MHz, CDCl3): d 12.7,
17.6, 18.3, 23.4, 25.6, 26.4, 39.4, 115.5, 123.9, 131.6, 140.7, 143.0, 156.8, 194.4. 13C
DEPT135 (100 MHz, CDCl3): d 12.7, 17.6, 18.3, 23.4 (¡), 25.6, 26.4 (¡), 39.4 (¡), 115.5,
123.9, 156.8, 194.4. GC-MS: m/z (%) D 206, 191, 177, 163, 109, 91, 77, 69(100%), 53, 41,
27. HRMS (ESI): m/z [M C H]C Calcd for C14H22O: 206.1671; Found:206.1673.
Diethyl (3,7,11-trimethyldodeca-1,3,6,10-Tetraenyl)phosphonate (2b)
A solution of tetraethyl methylenebis-phosphonate (8, 8.6 g, 0.03 mol) in toluene
(20 mL) was added dropwise over 30 min to a solution of 1.1 g of NaH (60% in oil,

Practical Synthesis of Lycopene
353
0.028 mol) in toluene (10 mL) at 10 to 15ꢀC under nitrogen, and the mixture was stirred
for 30 min. Then a solution of aldehyde 7 (5.1 g, 0.025 mol) in toluene (20 mL) was
added dropwise over 30 min at 10 to15ꢀC, and the mixture was stirred for a further
30 min. Water (20 mL) was added and the mixture was stirred for 10 min. The organic
layer was separated, washed with 10% aq NaCl (80 mL), dried (MgSO4), and concen-
trated in vacuo to give the crude product (GC content 93.2%) as a pale-brown liquid;
yield: 7.5 g (89%).
1H NMR (400 MHz, CDCl3): d 0.98 (t, J D 7.6 Hz, 3H, CH3), 1.32 (t, J D 6.8 Hz,
6H, 2 £ OCH2CH3), 1.46 (s, 3H, CH3), 1.63 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.96-2.04
(m, 2H, CH2CH2), 2.04-2.14 (m, 2H, CH2CH2), 2.15–2.20 (m, 2H, CH2), 4.03-4.10 (m,
4H, 2 £ OCH2CH3), 5.10-5.11 (m, 1H, CH), 5.55–5.56 (m, 1H, CH), 5.51 (dd, J D
16.8 Hz, 20.0 Hz, 1H, CH D CHP), 5.86 (t, J D 7.2 Hz, 1H, CH), 7.08 (dd, J D 17.6 Hz,
21.6 Hz, 1H, CH D CH). 13C NMR (100 MHz, CDCl3): d 12.8, 15.9, 16.0, 17.0, 17.3,
22.7, 25.3, 25.9, 38.6, 61.0, 60.9, 112.4 (d, J D 189.4 Hz), 118.2, 123.7, 131.2, 135.5 (d,
J D 24.1 Hz), 141.0, 142.7, 151.3. 13C DEPT135 (100 MHz, CDCl3): d 12.8, 15.9, 16.0,
17.0, 17.3, 22.7 (¡), 25.3, 25.9 (¡), 38.6 (¡), 61.0 (¡), 60.9 (¡), 112.4 (d, J D 189.4
Hz), 118.2, 123.7, 142.7, 151.3. GC-MS: m/z (%) D 340, 325, 284, 271, 243, 217(100%),
205, 192, 159, 105, 79. HRMS (ESI): m/z [M C H]C Calcd for C19H33O3P: 340.2167;
Found: 340.2170.
All-E-Lycopene (1)
To a solution of KOt-Bu (2.3 g, 0.021 mol) in 8:1 (v/v) mixture of dry THF and DMSO
(30 mL), C15-phosphonate 2b (6.8 g, 0.02 mol) was added dropwise at ¡30 to ¡25ꢀC
over 30 min under N2, and the resulting mixture was stirred for further 5 h at that tempera-
ture. Then, C10-trienedial 3 (1.6 g, 0.0098 mol) in 8:1 (v/v) THF and DMSO (10 mL) was
added dropwise over 20 min. The mixture was stirred for 15 min at ¡30 to ¡25ꢀC, and
then stirred for further 1 h at 20 to 25ꢀC. Chloroform (100 mL) was added and the organic
layer was separated, washed with aqueous 5% NaCl (3 £ 75 mL), dried (MgSO4), and
evaporated in vacuo to leave crude product as a red solid, which was recrystallized from
CH2Cl2 (30 mL) and then the solid product stirred for 1 h at 75 to 80ꢀC in 30 mL ethanol
to complete the isomerization to afford pure product (3.1 g, 59%), as a red solid, mp. 170–
171ꢀC, lit.20 mp. 171ꢀC. Its identity was confirmed by IR and NMR analysis.
1
IR (film): 1627, 968 cm¡1. H NMR (400 MHz, CDCl3): d 1.61 (s, 6H, 2 £ CH3),
1.69 (s, 6H, 2 £ CH3), 1.82 (s, 6H, 2 £ CH3), 1.97 (s, 12H, 4 £ CH3), 2.20-2.23 (m, 8H, 4
£ CH2), 5.11 (t, 2H, 2 £ CHCH2), 5.95 (d, 2H, 2 £ CHCH), 6.19 (d, 2H, 2 £ CHCH),
6.27 (d, 4H, 4 £ CHCH), 6.35 (d, 2H, 2 £ CHCH), 6.52 (t, 2H, 2 £ CHCH), 6.63 (m,
4H, CHCHCH). 13C NMR (100 MHz, CDCl3): d 12.8, 12.9, 17.0, 17.7, 25.7, 26.7, 40.2,
124.0, 124.8, 125.2, 125.7, 130.1, 131.6, 131.7, 132.6, 135.4, 136.2, 136.5, 137.4, 139.5.
13C DEPT135 (100 MHz, CDCl3): d 12.8, 12.9, 17.0, 17.7, 25.7, 26.7 (¡), 40.2 (¡),
124.0, 124.8, 125.2, 125.7, 130.1, 131.6, 132.7, 135.4, 137.4. HRMS (ESI): m/z [M C
H]C Calcd for C40H56: 536.8726; Found: 536.8724.
Acknowledgments
We acknowledge the National Natural Science Foundation of China (No. 21176156),
Public Projects of Zhejiang Province of China (No. 2016C31032) and Research Fund of
Zhejiang Educational Committee of China (Y 201431839).

354
Shen et al.
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