Total synthesis of prolycopene, a novel 7,9,7′,9′-tetra-cis(Z) carotenoid and main pigment of the tangerine tomato Lycopersicon esculentum

Article abstract of DOI:10.1016/j.tet.2006.05.023

A total synthesis of the 7,9,7′,9′-tetra-cis(Z) isomer of lycopene, also known as 'prolycopene', produced as the major carotenoid pigment in fruits of the tangerine tomato Lycopersicon esculentum ('Tangella') is described. The synthesis is based on: (i) a

Full text of DOI:10.1016/j.tet.2006.05.023

Tetrahedron 62 (2006) 7477–7483
Total synthesis of prolycopene, a novel 7,9,70,90-tetra-cis(Z)
carotenoid and main pigment of the tangerine tomato
Lycopersicon esculentum
*
Gerald Pattenden and David C. Robson
School of Chemistry, The University of Nottingham, Nottingham, NG7 2RD, UK
Received 6 March 2006; revised 21 April 2006; accepted 4 May 2006
Available online 9 June 2006
This paper is dedicated to the memory of Basil C. L. Weedon, 1923–2003
Abstract—A total synthesis of the 7,9,70,90-tetra-cis(Z) isomer of lycopene, also known as ‘prolycopene’, produced as the major carotenoid
pigment in fruits of the tangerine tomato Lycopersicon esculentum (‘Tangella’) is described. The synthesis is based on: (i) a modified
Sonogashira coupling reaction between the E-alkenyl bromide 6 and the Z-enynol 7, leading to the 2Z-trienynol 8, followed by (ii) a Wittig
reaction between the phosphonium salt 4 and the C10-triene dialdehyde 5 producing the symmetrical 9,90-Z isomer of the bis-acetylene 3 and
(iii) semi-hydrogenation of 3 in the presence of Lindlar’s catalyst, and chromatography.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
1
Prolycopene 2 is the tetra-cis(Z) isomer of the more familiar
carotenoid, all-E-lycopene 1, found in commercial toma-
toes. It was first isolated by Zechmeister et al. in 19411
from the tangerine tomato Lycopersicon esculentum var,
known as ‘Tangella’. Although the stereochemistry of proly-
copene was investigated extensively by Zechmeister et al.
over two decades, it was not until NMR spectroscopy, and
particularly carbon NMR spectroscopy, became routinely
2
available that the intriguing tetra-Z geometry of the pigment
was established independently by Englert et al.2 and our-
The synthesis of conjugated polyisopenoids with one or
selves3 in 1979. In contemporaneous studies we also sepa-
rated and characterised the Z-isomers of the carotenoid
more Z-double bonds has been a formidable challenge since
the early beginnings of carotenoid chemistry.7 Without
doubt, the Wittig reaction and its variants have been the cor-
nerstone of polyene synthesis in recent years.8 This is in
spite of the fact that the stereochemical outcomes of these
reactions are less predictable, and often lead to mixtures of
Z- and E-isomers at the newly introduced double bonds. Pro-
lycopene 2 has a symmetrical structure and accommodates
two Z-disubstituted and two Z-trisubstituted double bonds.
This led us to design a synthesis of the compound based
on semi-hydrogenation of the bis-acetylenic precursor 3,
which we planned to elaborate from the Z-allylphosphonium
salt 4 and the known C10-triene dialdehyde 5. There is con-
siderable precedent for the formation of Z-disubstituted
bonds from semi-hydrogenations of acetylene precursors
in the carotenoid field, since the early work of Lindlar in
pigments phytoene, phytofluene, z-carotene and neurospor-
ene, congeners to prolycopene, in L. esculentum.4 Later
we described the total synthesis of prolycopene,5 Hengart-
ner, Englert and co-workers, in 1992, presented the synthe-
ses of six bis- and three tris-Z-isomers of lycopene.6 In this
paper we describe full details of our synthesis of natural
(tetra-Z) prolycopene 2.
* Corresponding author. Tel.: +44 115 951 3530; fax: +44 115 951 3535;
e-mail: gp@nottingham.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.023

7478
G. Pattenden, D. C. Robson / Tetrahedron 62 (2006) 7477–7483
1952, i.e., Pd on CaCO3 deactivated by quinoline.9 Further-
more, the Z-pentenynol 7 is readily available, and we
planned to use this precursor in a palladium-catalysed
coupling reaction with the E-vinyl bromide 6, to produce
the C15-2Z,6E-trienynol intermediate 8, en route to the
corresponding phosphonium salt 4.
CMR spectroscopic data with those of its 2Z,6Z-, 2E,6Z-
and 2E,6E-isomers, which were prepared from correspond-
ing sp2–sp coupling reactions involving 6 and the Z-vinyl
bromide 10, and 7 and the E-allyl alcohol 11. The relevant
diagnostic 13C NMR chemical shift data for each of these
isomers are collected on structures 12, 13, 14 and 15 (Fig. 1).
Bromination of the 2Z-trienynol 8, using dibromotetra-
chloroethane in the presence of triphenylphosphine,12 next
gave the 2Z-allyl bromide 9, which was immediately reacted
with triphenylphosphine leading to the corresponding phos-
phonium salt 4. The salt 4 was obtained as colourless crys-
tals, which were very hygroscopic (Scheme 1). A Wittig
reaction between molar equivalents of the phosphonium
salt 4 and the C10 triene dial 5,13 using aq NaOH as base
3
22.9
O
35.0
23.4
23.6
19.7
61.5
PPh3Br
OH
OH
39.0
61.7
4
5
O
12, 2Z, 6E-isomer
13, 2Z, 6Z-isomer
2. Results and discussion
22.8
Thus, a Wittig reaction between 6-methyl-5-hepten-2-one
and bromomethyltriphenylphosphonium bromide, in the
presence of KOBut at ꢀ60 ꢁC to 25 ꢁC gave a 3:1 mixture
of E- and Z-isomers of the vinyl bromide 6,10 from which
the E-isomer was easily separated by gas chromatography
(Scheme 1). An sp2–sp coupling reaction between the vinyl
bromide 6 and the enynol 7 under modified Sonogashira
conditions, i.e., Ph4Pd–CuI–PrNH2,11 next gave the 2Z-
trienynol 8 in 72% yield. The stereochemistry assigned to
8 followed from analysis and comparison of its PMR and
35.0
19.4
19.4
54.1
OH
17.7
59.2
38.8
OH
14, 2E, 6Z-isomer
15, 2E, 6E-isomer
Figure 1. Pertinent 13C NMR chemical shift data for the four isomers of the
substituted 2,4,10-trien-4-yn-1-ol (8).
i
ii
Br
O
OH
6
8
OH
7
iii
iv
4
Br
9
OH
Br
10
11
þ
ꢀ
Scheme 1. Reagents and conditions: (i) BrCH2 PPh3Br, KOBut, THF, ꢀ60 ꢁC, 81%, 3:1 E/Z mixture; (ii) (PPh3)4Pd, PrNH2, then 7, CuI, 70%;
(iii) BrCl2CCCl2Br, PPh3, Et2O, 0 ꢁC, 98% and (iv) PPh3, C6H6, 25 ꢁC, 85%.

G. Pattenden, D. C. Robson / Tetrahedron 62 (2006) 7477–7483
17.8
7479
12.9
in ClCH2CH2Cl, followed by chromatography, led cleanly to
the 9Z-heptenynal 16 (Scheme 2). The geometry of 16 fol-
lowed from analysis of its CMR spectroscopic data14 and
comparison with similar data recorded for the related 9Z-
and 9E-polyenynals 18 and 19,15 respectively (Fig. 2).y A
second Wittig reaction between the salt 4 and the 9Z-hepte-
nynal 16, using aq NaOH in ClCH2CH2Cl, then gave the
symmetrical 9,90-Z isomer of the bis-acetylene 3, which
was obtained as a deep red solid. HPLC analysis demon-
strated that the bis-acetylene 3 was produced as a mixture
of two 110Z,E-isomers in the ratio 2:1, identified as the re-
quired 9Z,11E,90Z,110E-isomer 3 (major product) and the
isomeric 9Z,11E,90Z,110Z compound 17.
O
9.6
HO
18
O
23.0
24.3
HO
12.9
13.0
O
9.5
O
9.6
i
(4) + (5)
19
16
O
Figure 2. Pertinent 13C NMR chemical shift data for the C-9Z polyenal 16
and the related C-9E- and C-9Z-analogues 18 and 19, respectively.
16
23.6
1.98
O
ii, iii
17.8
19.7
1.61
1.98
1.69
25.8
39.0
12.8
1.55
+ 3
20, 13C-NMR data
21, 1H-NMR data
17
11'
Figure 3. Pertinent 13C and 1H NMR chemical shift data for the 9Z- and
90Z-bis-acetylene 3.
All that now remained to complete our synthesis of natural
prolycopene 2 was to carry out a semi-hydrogenation of the
bis-acetylene 3 in the presence of Lindlar’s catalyst. This
was no trivial task especially in view of the limited amounts
of 3 that were available. After considerable experimentation,
using alternative polyenyne substrates as models, different
microhydrogenator designs and various Lindlar catalyst
cocktails, we successfully hydrogenated the bis-acetylene
3 on 10 mg scale to produce prolycopene 2, which was puri-
fied by HPLC and obtained in ca. 15% yield. The synthetic
material did not separate from naturally derived prolycopene
in HPLC analysis and their PMR spectroscopic and mass
spectrometric data were closely identical. Hengartner et al.6
later carried out the same semi-hydrogenation of the bis-
acetylene 3 on 10 times the scale we had been able to use,
but also in the presence of Lindlar’s catalyst, and secured
a 44% yield of crystalline prolycopene.
Scheme 2. Reagents and conditions: (i) aq NaOH, ClCH2CH2Cl, 25 ꢁC,
36%; (ii) 4, aq NaOH, ClCH2CH2Cl, 25 ꢁC, then 16, 61%, 2:1 mixture of
3 and 17 and (iii) I2, C6H6, 90%.
Ratherthanseparating thetwoisomersatthisstage, asolution
containing a mixture of the isomers in hexane was treated
with a very dilute solution of iodine in benzene, and the
progress of the isomerisation of the 9Z,11E,90Z,110Z-isomer
17 to the isomer 3 was monitored by HPLC analysis. After
washing with aqueous sodium thiosulfate solution, work up
and crystallisation gave the symmetrical 9,90-Z isomer of
the bis-acetylene 3 as minute orange crystals, mp 110 ꢁC.
Consistent with its symmetrical structure only 20 carbon sig-
nals were observed in the CMR spectrum of 3, which also
showed diagnostic resonances at d 39.0 and d 19.7 (5E and
50E double bonds), d 23.6 (9Z and 90Z double bonds) and at
3. Experimental
1
d 12.8 (11E and 110E double bonds). Pertinent 13C and H
NMR data are collected on structures 20 and 21 (Fig. 3). Sev-
eral years after we had published a preliminary communica-
tion,5 Hengartner et al.6 published an identical synthetic
approach to the same 9,90-Z isomer of the bis-acetylene 3,
on large scale.
3.1. General details
Melting points of polyenes were determined in evacuated
capillary tubes using a Gallenkamp melting point apparatus.
Infrared spectra were recorded as liquid films, unless stated
otherwise, on a Phillips P.U. 9706 spectrophotometer. H
NMR spectra were determined on a Bruker WM 250 PFT
or AM 400 PFT spectrometer and 13C NMR spectra were
obtained on the same instruments at 63.0 and 100.0 MHz,
y
1
The system of numbering carotenoids recommended by I.U.P.A.C. is used
throughout this paper, i.e., lycopene.
15' 13' 11' 9' 7' 5' 3' 1'
1
3
5
7
9
13 15
11

7480
G. Pattenden, D. C. Robson / Tetrahedron 62 (2006) 7477–7483
respectively. Samples were dissolved in deuterated chloro-
form (CDCl3), which provided the deuterium lock for the
spectrometers. Tetramethylsilane or residual chloroform
was used as an internal standard. Mass measurements were
determined on either an AEI MS 902 or a VG 707E spec-
trometer. Elemental analyses were carried out on a Perkin
Elmer 240B elemental analyser.
2.07–2.37 (4H, m), 1.79 (3H, d, J¼1.5, ]CMe), 1.70 (3H,
d, J¼1.1, ]CMe), 1.63 (3H, s, Me) ppm; dC 141.5 (s,
]C), 132.3 (s, ]C), 123.6 (d, ]C), 100.9 (d, ]C), 34.6
(t, CH2), 25.6 (q, CH3), 22.3 (q, CH3), 17.7 (q, CH3) ppm.
3.1.2. (2Z,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-4-yn-
1-ol (8). E-1-Bromo-2,6-dimethyl-1,5-heptadiene (6) (0.54 g,
2.7 mmol) was added to a stirred suspension of tetrakistri-
phenylphosphine palladium(0) (0.20 g, 0.17 mmol) in freshly
distilled, degassed propylamine (5.0 ml) under a nitrogen
atmosphere in the dark, and the resulting mixture was then
stirred at room temperature for 20 min. Z-2-Methylpent-2-
en-4-yn-1-ol (0.26 g, 2.7 mmol) followed by freshly purified
copper (I) iodide (0.14 g, 0.74 mmol) were added, and the
resulting deep brown viscous mixture was then stirred at room
temperature for a further 17 h. The mixture was evaporated in
vacuo to leave a brown oil, which was dissolved in ether
(50 ml). The ether solution was washed with saturated ammo-
nium chloride solution (4ꢂ100 ml) and water (2ꢂ100 ml),
then dried and evaporated in vacuo to leave the crude trienynol
as a brown oil. Chromatography [silica G, ether/petrol ether
(bp 40–60 ꢁC), 1:2], followed by bulb-to-bulb distillation
gave the 2Z,6E alcohol (0.41 g, 70%) as a colourless liquid,
bp 150 ꢁC at 0.3 mmHg. Found: C, 82.5; H, 10.9%.
C15H22O requires: C, 82.5; H, 10.2%; lmax (EtOH) 264 inf
(14,000), 272 (16,700), 286 inf (11,600) nm; nmax 3320,
2920, 2190, 1615, 835 cmꢀ1, dH 5.83 (1H, tq, J¼6.5 and
1.4, ]CHCH2OH), 5.43 (1H, ]CHC), 5.08 (1H, br,
Me2C]CH), 4.35 (2H, d, J¼6.5, CH2OH), 3.20 (1H, br,
–OH), 2.12–2.17 (4H, m), 1.92 (6H, 2ꢂ]CMe), 1.69 (3H,
]CMe), 1.61 (3H, ]CMe) ppm; dC 152.8 (s, ]C), 134.2
(d, ]CH), 132.4 (s, ]C), 123.5 (d, ]CH), 121.7 (s, ]C),
104.9 (t, ]CH), 93.1 (s, ^C), 90.2 (s, ^C), 61.7 (t, CH2),
39.0 (t, CH2), 26.5 (t, CH2), 25.9 (q, CH3), 23.6 (q, CH3),
19.9 (q, CH3), 17.9 (q, CH3) ppm; m/z 218.1667; C15H22O
requires M 218.1671.
Due to their sensitivity, strict methods of handling polyenes
were adhered to throughout the experimental work. Thus, all
solutions of polyenes were handled under a nitrogen blanket
in subdued light or in darkness, and all columns and TLC
chambers used in chromatographic separations were wrap-
ped in aluminium foil. Transfers of polyenes were carried out
rapidly under a blanket of nitrogen and at no time were
solutions containing polyenes heated above room tempera-
ture; all polyenes were stored under nitrogen at ꢀ12 ꢁC.
All solvents were distilled before use. Solutions were dried
over anhydrous MgSO4 and concentrated under reduced
pressure.
Analytical HPLC analyses were carried out on a Zorbax, Sil-
ica, 250ꢂ4.6 mm column using a Waters 6000 or 6000A
pump connected to a Cecil C212 variable wavelength mon-
itor or a Waters Model 440 absorbance detector. Preparative
HPLC work was carried out on a C-18 column using a Waters
Prep LC/System 500 pump fitted with an integral refractive
index detector.
Capillary GLC analysis was performed on a Perkin Elmer
Sigma 2 instrument using a Carbowax 50 m column. Prepar-
ative GLC was carried out on a 76 cmꢂ8 mm silicone oil
(15%) on diatomite column using an Aerograph Auroprep
Model A-700 instrument.
3.1.1. (E,Z)-1-Bromo-2,6-dimethyl-1,5-heptadiene (6).
Freshly prepared potassium tertiary butoxide (7.2 g, 6.4
mmol) was added, all at once, to a stirred suspension of bro-
momethyltriphenylphosphonium bromide (31 g, 7.1 mmol)
in dry THF (500 ml) at room temperature under a nitrogen
atmosphere, and the resulting mixture was then stirred at
room temperature for 30 min. The deep yellow solution of
the corresponding ylide was cooled to ꢀ60 ꢁC and then
6-methylhept-5-en-2-one (3.0 g, 2.4 mmol) in dry THF
(20 ml) was added over 10 min. The mixture was stirred
at ꢀ60 ꢁC for 1 h, and then allowed to warm to room tem-
perature where it was stirred for a further 24 h. The mixture
was evaporated to dryness in vacuo and the residue was then
triturated with petrol (bp 40–60 ꢁC) (4ꢂ100 ml). The com-
bined organic extracts were evaporated to leave a brown
oil. Chromatography followed by distillation gave a 3:1 mix-
ture of E- and Z-isomers of the vinyl bromide (3.9 g, 81%)
as a colourless oil, bp 56 ꢁC at 0.6 mmHg. The E- and
Z-isomers were separated by preparative GC to give: (i)
E-1-bromo-2,6-dimethyl-1,5-heptadiene,10 nmax 2920, 1630,
825, 720 cmꢀ1, dH 5.9 (1H, q, J¼1, ]CHBr), 5.06 (1H,
br, ]CH), 2.08–2.16 (4H, m), 1.8 (3H, d, J¼1, ]CMe),
1.68 (3H, s, Me), 1.60 (3H, s, Me) ppm; dC 141.5 (s, ]C),
132.2 (s, ]C), 123.3 (d, ]CH), 101.4 (d, ]CH), 38.5 (t,
CH2), 26.4 (t, CH2), 25.7 (q, CH3), 19.2 (q, CH3), 17.7 (q,
CH3) ppm and (ii) Z-1-bromo-2,6-dimethyl-1,5-heptadiene,
nmax 2980, 2920, 1635, 780, 730 cmꢀ1, dH 5.86 (1H, q,
J¼1.5, ]CHBr), 5.14 (1H, tqn, J¼7 and 1.5, ]CH),
3.1.3. (2Z,6Z)-3,7,11-Trimethyldodeca-2,6,10-trien-4-yn-
1-ol (13). Z-1-Bromo-2,6-dimethyl-1,5-heptadiene (0.19 g,
0.94 mmol) and Z-2-methylpent-2-en-4-yn-1-ol (0.09 g,
0.95 mmol) were reacted together in an identical manner
to that described for the preparation of the corresponding
2Z,6E alcohol. The product (0.13 g, 63%) was obtained as
a colourless oil. Found: C, 82.6; H, 10.6%. C15H22O re-
quires: C, 82.5; H, 10.2%; lmax (EtOH) 263 inf (11,700),
272 (13,900), 285 inf (9750) nm; nmax 3320, 2920, 2190,
1615, 830 cmꢀ1, dH 5.82 (1H, tq, J¼6.6 and 1.4,
]CHCH2OH), 5.42 (1H, d, J¼1.4 ]CHC), 5.14 (1H, tqn,
J¼6.3 and 1.4, Me2C]CH), 4.32 (2H, d, J¼6.6, CH2OH),
2.73 (1H, br, –OH), 2.33 (2H, t, J¼7.6, CH2C]CH2), 2.13
(2H, q, J¼7.6, CH2CH2), 1.91 (3H, d, J¼1.2, ]CMe),
1.83 (3H, d, J¼1.4, ]CMe), 1.69 (3H, d, J¼0.8, ]CMe),
1.62 (3H, Me) ppm; dC 152.9 (s, ]C), 134.0 (d, ]CH),
132.2 (s, ]C), 123.7 (d, ]CH), 121.8 (s, ]C), 105.4 (d,
]CH), 92.8 (s, ^C), 89.7 (s, ^C), 61.5 (t, CH2), 35.2 (t,
CH2), 26.4 (t, CH2), 25.8 (q, CH3), 23.4 (q, CH3), 22.9 (q,
CH3), 17.8 (q, CH3) ppm; m/z 218.1673; C15H22O requires
M 218.1671.
3.1.4. (2E,6Z)-3,7,11-Trimethyldodeca-2,6,10-trien-
4-yn-1-ol (14) and (2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trien-4-yn-1-ol (15). A 3:1 mixture of E- and Z- iso-
mers of 1-bromo-2,6-dimethyl-1,5-heptadiene (6) (0.54 g,

G. Pattenden, D. C. Robson / Tetrahedron 62 (2006) 7477–7483
7481
2.7 mmol) was added to a stirred suspension of tetrakis-
triphenylphosphine palladium(0) (0.20 g, 0.17 mmol) in
freshly distilled, degassed n-propylamine (5.0 ml) under a
nitrogen atmosphere in the dark, and the resulting mixture
was then stirred at room temperature for 20 min. E-2-
Methylpent-2-en-4-yn-1-ol (0.26 g, 2.7 mmol) followed by
freshly purified copper (I) iodide (0.14 g, 0.74 mmol) were
added, and the resulting deep brown viscous mixture was
then stirred at room temperature for a further 17 h. The mix-
ture was evaporated in vacuo to leave the crude mixture of
trienynol isomers as a brown oil. Chromatography [silica
G, ether/petrol ether (bp 40–60 ꢁC), 1:2], followed by bulb-
to-bulb distillation gave a 3:1 mixture of the E-2 and the E-6
isomers (0.27 g, 46%) as a colourless oil (bp 150 ꢁC at
0.3 mmHg). The two isomers were separated by preparative
reverse phase HPLC to give: (i) the (2E,6E)-isomer (15),
Found: C, 82.5; H, 10.4%. C15H22O requires: C, 82.5; H,
10.2%; lmax (EtOH) 262 inf (13,300), 271 (16,000), 284
inf (11,500) nm; nmax 3320, 2925, 2200, 1615, 740,
700 cmꢀ1, dH 5.97 (1H, tq, J¼6.8 and 1.4, ]CHCH2OH),
5.38 (1H, ]CHC), 5.08 (1H, br, Me2C]CH), 4.21 (2H, d,
J¼6.8, CH2OH), 2.24 (1H, br, –OH), 2.11–2.12 (4H, m),
1.9 (3H, d, J¼1, ]CMe), 1.86 (3H, d, J¼0.7, ]CMe),
1.68 (3H, ]CMe), 1.60 (3H, ]CMe) ppm; dC 152.1 (s,
]C), 134.1 (d, ]CH), 132.1 (s, ]C), 123.5 (d, ]CH),
121.4 (s, ]C), 104.8 (d, ]CH), 94.3 (s, ^C), 86.1 (s,
^C), 59.1 (t, CH2), 38.8 (t, CH2), 26.3 (t, CH2), 25.7 (q,
CH3), 19.4 (q, CH3), 17.7 (q, CH3) ppm and (ii) the
(2E,6Z)-isomer (14), Found: C, 82.5; H, 10.4%. C15H22O re-
quires: C, 82.5; H, 10.2%; lmax (EtOH) 262 inf (11,000), 271
(13,000), 286 (9820) nm; nmax 3320, 2925, 2195, 1615,
1005, 833 cmꢀ1, dH 5.96 (1H, tq, J¼6.9 and 1.3,
]CHCH2OH), 5.38 (1H, ]CHC), 5.15 (1H, tt, J¼7.1 and
1.3, Me2C]CH), 4.23 (2H, d, J¼6.9, CH2OH), 2.32 (2H,
t, J¼7.5, CH2CH2), 2.14 (2H, q, J¼7.5, CH2CH2), 1.86
(3H, d, J¼0.6, ]CMe), 1.86 (3H, d, J¼1.4, ]CMe), 1.70
(3H, Me), 1.63 (3H, Me) ppm; dC 152.5 (s, ]C), 133.8 (d,
]CH), 132.1 (s, ]C), 123.8 (d, ]CH), 121.6 (s, ]C),
105.3 (d, ]CH), 93.7 (s, ^C), 86.0 (s, ^C), 59.2 (t,
CH2), 35.0 (t, CH2), 26.4 (t, CH2), 25.7 (q, CH3), 17.7 (q,
CH3), 17.4 (q, CH3) ppm; m/z 218.1663; C15H22O requires
M 218.1671.
132.2 (s, ]C), 130.12 (d, ]CH), 124.7 (s, ]C), 123.3 (d,
]CH), 104.8 (d, ]CH), 95.1 (s, ^C), 89.3 (s, ^C), 38.9
(t, CH2), 30.8 (t, CH2), 25.7 (q, CH3), 23.3 (q, CH3), 19.6
(q, CH3), 17.7 (q, CH3) ppm; m/z 280.0836; C15H2179Br
requires M 280.0826.
3.1.6. (2Z,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-4-
ynyl-triphenylphosphonium bromide (4). Triphenylphos-
phine (0.26 g, 0.99 mmol) was added to a solution of freshly
prepared (2Z,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-
trien-4-yne (9) (0.279 g, 0.99 mmol) in dry benzene
(15 ml) and the mixture was then stirred in the dark, over-
night under a nitrogen atmosphere. The benzene was evapo-
rated leaving a sticky pale brown solid, which was triturated
with dry ether (6ꢂ10 ml). The ether was evaporated leaving
the phosphonium salt (0.46 g, 85%) as an extremely hygro-
scopic, flaky colourless solid, which showed lmax (CHCl3)
230 (36,300), 277 (18,640), 268 (17,830), 303 (13,500) nm;
nmax (CHCl3 solution) 3380, 2900, 2480, 2200, 1615,
1010 cmꢀ1
, dH 7.70–7.90 (15H, m), 5.65 (1H, br,
]CHCH2), 5.21 (1H, ]CHC]), 5.04 (1H, br, Me2C]CH),
4.94 (2H, dd, J¼6 and 12, CH2PPh3), 2.07–2.12 (4H, m),
1.83 (3H, d, J¼6, ]CMe), 1.72 (3H, ]CMe), 1.69 (3H,
]CMe), 1.60 (3H, ]CMe) ppm; dC 153.4 (s, ]C), 135.0
(d, ]CH), 133.8 (d, J¼9.5, ]CH), 132.3 (s, ]C), 130.3
(d, J¼12.2, ]CH), 128.9 (d, J¼13.8, ]CH), 123.2 (d,
]CH), 118.5 (d, J¼10.5, ]CH), 118.1 (d, J¼85.5,
]CH), 104.3 (d, ]CH), 94.8 (s, ^C), 89.3 (s, ^C), 38.6
(t, CH2), 27.0 (t, J¼50.1, CH2), 26.1 (t, CH2), 25.6 (q,
CH3), 23.5 (q, CH3), 19.5 (q, CH3), 17.7 (q, CH3) ppm;
FAB mass spectrum m/z 463 (MꢀBr) (73%), 262 (53%),
183 (57%), 69 (94%), 55 (100%).
The corresponding 2E,6E-triphenylphosphonium salt was
prepared in a similar manner from the 2E,6E-alcohol (15),
and was obtained as a very hygroscopic flaky colourless
solid, which showed lmax (EtOH) 200 (31,000), 231 inf
(10,800), 267 (5560), 275 (6180), 287 inf (4940), 303 inf
(4630) nm; nmax 2920, 2440, 2200, 1610, 920 cmꢀ1, dH
7.69–7.91 (15H, m), 5.66 (1H, q, J¼7.4 ]CHCH2), 5.21
(1H, ]CHC]), 5.04 (1H, br, Me2C]CH), 4.79 (2H, dd,
J¼16 and 8, CH2PPh3), 2.10 (4H, m), 1.84 (3H, ]CMe),
1.67 (3H, ]CMe), 1.59 (3H, ]CMe), 1.54 (3H, d, J¼4.0,
]CMe) ppm; dC 153.5 (s, ]C), 135.2 (d, ]CH), 133.9
(d, J¼9.6, ]CH), 132.2 (s, ]C), 130.4 (d, J¼12.4,
]CH), 128.9 (d, J¼13.8, ]CH), 123.2 (d, J¼10.9,
]CH), 117.8 (d, J¼85.5, ]CH), 104.3 (d, ]CH), 93.2
(s, ^C), 88.3 (s, ^C), 38.7 (t, CH2), 26.2 (t, CH2), 25.7
(q, CH3), 25.4 (t, J¼47.8, CH2), 19.5 (q, CH3), 18.7 (q,
CH3), 17.8 (q, CH3) ppm.
3.1.5. (2Z,6E)-1-Bromo-3,7,11-trimethyldodeca-2,6,10-
trien-4-yne (9). A solution of 1,2-dibromotetrachlorethane
(0.21 g, 0.64 mmol) in dry ether (5 ml) was added over
5 min to a stirred solution of (2Z,6E)-3,7,11-trimethyldo-
deca-2,6,10-trien-4-yn-1-ol (8) (0.82 g, 3.8 mmol) and tri-
phenylphosphine (0.17 g, 0.65 mmol) in dry ether (5 ml) at
0 ꢁC under a nitrogen atmosphere in the dark, and the mix-
ture was then stirred at this temperature for 10 min. The mix-
ture was warmed to room temperature and the stirring was
then continued for a further 20 min, by which time a colour-
less precipitate of triphenylphosphine oxide had formed.
The precipitate was filtered off, and the ether was then evap-
orated to leave a brown oil. Chromatography [silica G, ether/
petrol ether (bp 40–60 ꢁC), 1:3] gave the 2Z,6E-alkyl bro-
mide (0.12 g, 98%) as a colourless oil, which showed lmax
(EtOH) 283 (13,000) nm; nmax 2920, 2190, 1610, 835, 780,
755 cmꢀ1, dH 5.87 (1H, tq, J¼8.0 and 1.3, ]CHCH2Br),
5.47 (1H, ]CHC]), 5.09 (1H, br, Me2C]CH), 4.25 (2H,
d, J¼8.0, CH2Br), 2.15 (4H, m), 1.94 (6H, 2ꢂ]CMe),
1.69 (3H, Me), 1.61 (3H, Me) ppm; dC 153.3 (s, ]C),
3.1.7. (10Z)-2,7,11,15,19-Pentamethyleicosa-2,4,6,8,10,14,18-
hepten-12-yn-1-al (16). Aqueous 2 M sodium hydroxide
(2 ml, 4 mmol) was added to a stirred solution of (2Z,6E)-
3,7,11-trimethyldodeca-2,6,10-trien-4-ynyl-triphenylphospho-
nium bromide (4) (0.4 g, 0.74 mmol) in 1,2-dichloroethane
(200 ml) and the mixture was then stirred under an argon
atmosphere, at room temperature, in the dark for 10 min.
A solution of the C10-triene dialdehyde (5) (0.483 g,
2.9 mmol) in 1,2-dichloroethane (40 ml) was added to the
stirred deep red coloured solution of the ylide over a period
of 10 min and stirring was then continued at room tempera-
ture for a further 2 h. Glacial acetic acid (2 ml, 35 mmol)

7482
G. Pattenden, D. C. Robson / Tetrahedron 62 (2006) 7477–7483
was added, followed by ether (200 ml) and the mixture was
then washed with water (4ꢂ100 ml). The combined aqueous
washings were re-extracted with ether (2ꢂ100 ml), and the
combined ether solutions were then dried and evaporated
leaving a viscous orange oil. Purification by preparative
thin layer chromatography [silica G, ether/petrol ether (bp
40–60 ꢁC), 1:2] gave the (Z-10) C25 aldehyde (0.092 g,
36%) as a bright orange-red oil. lmax (hexane) 391 inf
(26,800), 411 (32,000), 434 (24,300) nm; nmax (CHCl3 solu-
tion) 2920, 1660, 1560, 985 cmꢀ1, dH 9.45 (1H, CHO), 6.29–
6.72 (7H, m, ]CH), 5.53 (1H, ]CH), 5.10 (1H, br, ]CH),
2.17 (4H, m), 2.02 (3H, Me), 2.00 (3H, Me), 1.99 (3H, Me),
1.70 (3H, Me), 1.62 (3H, Me) ppm; dC 39.0 (t, CH2), 26.6
(t, CH2), 25.7 (q, CH3), 23.8 (q, CH3), 19.7 (q, CH3), 17.8
(q, CH3), 13.1 (s), 9.7 (q, CH3) ppm; m/z 348.2454;
C25H32O requires M 348.2453.
92.4 (s, ^C), 39.0 (t, CH2), 26.4 (t, CH2), 25.8 (q, CH3),
23.6 (q, CH3), 19.6 (q, CH3), 17.8 (q, CH3), 12.8 (q,
CH3) ppm; m/z 532.4058; C40H52 requires M 532.4069.
3.1.9. Prolycopene (2). Lindlar’s catalyst (10 mg) was
added to freshly distilled, degassed ethyl acetate (5 ml) in
a microhydrogenator in the dark, and the system was then
flushed out three times with hydrogen. A solution of the tet-
rahydrolycopene (3) (10 mg, 0.019 mmol) in ethyl acetate
(2 ml) was added and hydrogen uptake started immediately.
After 30 s hydrogen uptake had ceased! The catalyst was fil-
tered off and the ethyl acetate was then evaporated in vacuo
to leave a bright orange oil. Analysis by HPLC showed that
the oil was a mixture of compounds, the major one of which
was isoretentive with authentic prolycopene. The prolyco-
pene was separated by HPLC to give a red solid (<1 mg),
which showed lmax (n-hexane) 417, 438, 468 nm; dH 6.62–
5.95 (16H, m), 5.07 (2H, br), 2.05–2.07 (8H, m), 1.98 (6H,
2ꢂCH3), 1.87 (6H, 2ꢂCH3), 1.78 (6H, 2ꢂCH3), 1.65 (6H,
2ꢂCH3), 1.56 (6H, 2ꢂCH3) ppm; m/z 536.4388; C40H56
requires M 536.4382. The synthetic prolycopene did not
separate from authentic, naturally derived prolycopene in
chromatographic analysis and their visible absorption, PMR
spectroscopic data, together with mass spectrometry data
were closely identical.
3.1.8. (9Z,90Z)-7,8,70,80-Tetradehydrolycopene (3). Aque-
ous 2 M sodium hydroxide (1 ml, 2 mmol) was added to a
stirred solution of (2Z,6E)-3,7,11-trimethyldodeca-2,6,10-
trien-4-ynyl-triphenylphosphonium bromide (4) (0.286 g,
0.53 mmol) in 1,2-dichloroethane (20 ml), and the mixture
was then stirred under an argon atmosphere, at room temper-
ature, in the dark for 10 min. A solution of the (10Z) C25-
aldehyde (16) (0.092 g, 0.026 mmol) in 1,2-dichloroethane
(30 ml) was added and the mixture was stirred at room
temperature for a further 2 h. Glacial acetic acid (1 ml,
17.5 mmol) was added, followed by ether (200 ml) and
the mixture was then washed with water (4ꢂ50 ml). The
combined aqueous washings were re-extracted with ether
(2ꢂ100 ml), and the ether solutions were then dried and
evaporated leaving a deep red solid. The solid was purified
by preparative thin layer chromatography [silica G, 10%
acetone in n-hexane] to give the tetradehydro C40 com-
pound (0.05 g, 61%) as a deep red solid. HPLC analysis
showed that the solid consisted of a 2:1 mixture of the de-
sired 9Z,11E,90Z,110E-isomer (3) and the 9Z,11E,90Z,110Z-
isomer (17).
Acknowledgements
We thank Imperial Tobacco Ltd, Nottingham for support of
this work (studentship to D.C.R). We also thank Dr. (now
Professor) J. A. Murphy for his interest in this study.
References and notes
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A very dilute solution of iodine in benzene (0.5 ml) was
added to a solution of the tetrahydrolycopene isomers
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atmosphere. The solution was stirred under a nitrogen atmo-
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419 (37,000), 443 (55,600), 472 (49,100) nm; nmax (CHCl3
solution) 1600, 980, 930, 880 cmꢀ1, dH 6.80 (2H, dd,
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(2H, d, J¼11, C10, C100-H), 6.25 (BB0 of AA0BB0 spin
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