New syntheses of retinal and its acyclic analog γ-retinal by an extended aldol reaction with a C6 building block that incorporates a C5 unit after decarboxylation. A formal route to lycopene and β-carotene

Article abstract of DOI:10.1002/hlca.200790053

Since the C₁₅ β-end-group aldehyde 10 ((β-ionylidene) acetaldehyde), an excellent intermediate in the syntheses of retinoids, can be synthesized in many ways from β-ionone, and since the corresponding acyclic C₁₅ ψ-end-group aldehyde 5 can easily be synthesized from citral (1) (Scheme 3), we applied the C₁₅ + C₅ route to the syntheses of γ-retinal ((all-E)-8) (Scheme 3) and retinal ((all-E)-13) (Scheme 4), and therefore, by coupling (2 x C₂₀ → C ₄₀), to the preparation of lycopene (14) and β-carotene (15) (Scheme 5). Our new syntheses of retinal ((all-E)-13) and γ-retinal ((all-E)-8 use an extended aldol reaction with a C₆ building block that incorporates a C₅ unit after decarboxylation.

Full text of DOI:10.1002/hlca.200790053

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Helvetica Chimica Acta – Vol. 90 (2007)
New Syntheses of Retinal and Its Acyclic Analog g-Retinal by an Extended
Aldol Reaction with a C6 Building Block That Incorporates a C5 Unit after
Decarboxylation. A Formal Route to Lycopene and b-Carotene
by Alain Valla*a), Benoist Vallaa), Re´gis Le Guilloua), Dominique Cartiera), Laurent Dufosse´ b), and
Roger Labiaa)
a
´
) FRE 2125 CNRS, Chimie et Biologie des Substances Naturelles, 6, rue de lꢀUniversite,
F-29000 Quimper (e-mail: alain.valla@neuf.fr)
b) Laboratoire de Chimie des Substances Naturelles et des Sciences des Aliments,
´
´
´
Universite de La Reunion, Faculte des Sciences et Technologies, E.S.I.D.A.I., 15,
´
´
avenue Rene Cassin, BP 7151, F-97715 Saint-Denis Cedex 9, La Reunion
Since the C15 b-end-group aldehyde 10 ((b-ionylidene)acetaldehyde), an excellent intermediate in
the syntheses of retinoids, can be synthesized in many ways from b-ionone, and since the corresponding
acyclic C15 y-end-group aldehyde 5 can easily be synthesized from citral (1) (Scheme 3), we applied the
C15 þ C5 route to the syntheses of g-retinal ((all-E)-8) (Scheme 3) and retinal ((all-E)-13) (Scheme 4),
and therefore, by coupling (2 Â C20 ! C40), to the preparation of lycopene (14) and b-carotene (15)
(Scheme 5). Our new syntheses of retinal ((all-E)-13) and g-retinal ((all-E)-8 use an extended aldol
reaction with a C6 building block that incorporates a C5 unit after decarboxylation.
Introduction. – Fruits and vegetables of the human diet contain a lot of the over 600
carotenoid pigments described to occur in Nature. Among these, two major carotenoids
are b-carotene (¼ b,b-carotene) and lycopene (¼ y,y-carotene). b-Carotene is a very
potent antioxidant which protects the cell against singlet oxygen, and lycopene acts also
as an effective singlet-oxygen quencher in human plasma and exhibits a quenching rate
constant with singlet oxygen almost twice as high as that of b-carotene. The remarkable
role of b-carotene as an ꢁunusual antioxidantꢀ in reactions under various oxygen
pressures becomes clearer. The so-called ꢁpro-oxidant effectsꢀ concern primarily the
antioxidant itself and its degradation, since no or very little damage to the substrate
occurs in this type of experience. The role of lycopene has been of particular interest
recently as regards its role in treatment of prostate cancer. b-Carotene is a provitamin-
A carotenoid, and this is a fundamental role because vitamin A and other natural
retinoids are present in all living organisms and are known as fundamental mediators
for many biological processes, e.g., vision, cellular growth, differentiation of epithelial
tissue, reproduction, etc. Retinal occupies an intermediate position in this respect, with
the ability to convert to both retinol and retinoic acid. Considering the interplay
between the configuration of retinoids and carotenoids and their biological activities,
any synthetic approach to these compounds must meet the requirement of stereo-
chemical control, in order to obtain the desired isomer in a highly regioselective
manner. Despite the recent achievements in the preparation of conjugated (E/Z)-
ꢂ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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513
dienes and trienes by a variety of synthetic procedures, there is still a need for versatile
and efficient approaches to synthesize higher unsaturated (E/Z)-polyolefins with
convenient configuration. The emphasis for the past twenty years has been the
stereoselective/regioselective syntheses of economically important retinoids and
carotenoids, such as retinol, retinal, retinoic acid, b-carotene, and lycopene.
Citral (¼ 3,7-dimethylocta-2,6-dienal) is the main constituent of lemon-grass oil [1],
as a mixture of two geometric isomers (i.e., geranial (6E)1) and neral (6Z)1)). It is also
present in various natural products such as citrus fruits [2] and flowers and trees [3].
Citral has been extensively produced by synthesis for a long time [4], and we have
recently reported alternative syntheses of this terpene aldehyde [5]. It is commonly
used for the preparation of y-ionone [6], which is an important compound for the
production of b-ionone, a key-step intermediate in retinoid and carotenoid chemistry
[7] (Scheme 1).
Scheme 1
A lot of natural (and synthetic) terpenes exhibit important properties such as
cytotoxicity [8], antitumor [9], antiviral [10], anti-inflammatory [11], or immunosup-
pressive [12] activities.
Syntheses of g-retinal (¼(2E,4E,6E,8E,10E)-3,7,11,15-tetramethylhexadeca-
2,4,6,8,10,14-hexaenal; (all-E)-8) have been poorly documented [13], comparatively
to its isomer retinal ((all-E)-13) (for recent ref., see [14]).
The latter is a chromophore in the visual system of the retina which binds with a
lysine residue of opsin through a Schiff base [15]. The obtained rhodopsin is moved on
to an excited state by photons, which induces a bleaching process by an enzymatic
cascade, and signals are transferred to the brain through synapses [16].
Retinal has been found to be active in the regulation and differentiation of
epithelium, and, therefore, been tested to fight skin diseases [17]. The decrease in
vascular endothelial growth factor (VEGF) expression by keratinocytes on contact
with retinal has been recently published, and the conclusions showed that the decrease
in VEGF expression may prevent skin neoangiogenesis in certain skin diseases [18]. We
recently reported on the syntheses of 9-methylene- and 13-methyleneretinals1) [19].
Since 1990, more than forty references have reported (b-ionylidene)acetaldehyde
(¼ 3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienal; 10) as an excep-
tional intermediate in the syntheses of retinoids [20]. This could be attributed to the
fact that C15 aldehyde 10 can be synthesized in many ways from b-ionone, a relatively
inexpensive C13 product. Thus, we have selected the C15 þ C5 route for the syntheses of
1
)
Carotenoid numbering.

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Helvetica Chimica Acta – Vol. 90 (2007)
g-retinal and retinal, and therefore, by coupling (2 Â C20 ! C40), for the preparation of
lycopene and b-carotene, as illustrated in Scheme 2.
Scheme 2
Results. – To synthesize g-retinal ((all-E)-8), the required C15 aldehyde 5 was
synthesized by condensation of citral (1) with methyl 2-cyano-3-methylbut-2-enoate (2)
under Stobbeꢀs conditions (MeOK, MeOH, 08, then 48 h at room temp.). Under these
experimental conditions, isomerization of the C¼C bond of the starting citral takes
place, and the obtained a-cyano acid 3 (as a (9E)/(9Z)1) mixture of 80 :20) was further
decarboxylated in pyridine/piperidine (reflux, 2 – 4 h) to provide nitrile 4 ((9E)/(9Z)
80 :20). After reduction with diisobutylaluminium hydride (DIBAL-H; 08, 30 min),
aldehyde 5 ((9E)/(9Z) 80 :20) was condensed in an iterative way with methyl
cyanobutenoate 2 to provide a mixture 6 of a-cyano acids. Further decarboxylation in
piperidine/pyridine led to the g-retinonitrile 7 ((13E)/(13Z) 80 :20) which was reduced
with DIBAL-H into g-retinal 8 ((13E)/(13Z) 80 :20) (Scheme 3).
Analogously, retinal ((all-E)-13) was synthesized via the C15 (b-ionylidene)acetal-
dehyde 10 which has been prepared previously (for recent ref., see [21]). We now
report a new improved synthesis which allowed to produce aldehyde 10 in only two
steps, with excellent yield (82%) and good regioselectivity. Thus, a Knoevenagel
condensation of b-ionone with cyanoacetic acid in piperidine/benzene (Dean – Stark,
reflux) led to nitrile 9 in nearly quantitative yield ((9E)/(9Z)1) 95 :5 – 98 :2; Scheme 4).
Piperidine (8 equiv.) and benzene (as solvent) seemed to be indispensable because
other bases and solvents led to a mixture of nitriles. Under the chosen experimental
conditions, the a-cyano acids initially formed ((9E)/(9Z)1) 95 :5 – 98 :2) were
concomitantly decarboxylated in the reaction mixture. The C15 nitrile 9 was then
reduced by DIBAL-H in toluene (08, 30 min) into (b-ionylidene)acetaldehyde 10
(82%; (9E)/(9Z) 95 :5 – 98 :2), and the latter condensed with methyl cyanobutenoate 2
to give the C20 a-cyano acid 11 ((13E)/(13Z) 70 :30) in 75% yield. Subsequent
decarboxylation in piperidine/pyridine (reflux, 2 – 4 h) gave the retinonitrile 12 ((13E)/
(13Z) 70 :30; 90%) which was reduced with DIBAL-H (08, 30 min) to retinal (13;
(13E)/(13Z) 70 :30) in 75% yield.
McMurry coupling (low-valent titanium coupling) of g-retinal ((all-E)-8) and
retinal ((all-E)-13) led to lycopene (14) and b-carotene (15; Scheme 5). The synthesis
of b-carotene (15) by this process has been previously reported [22].

Helvetica Chimica Acta – Vol. 90 (2007)
515
Scheme 3
Experimental Part
Methyl 2-Cyano-3-methylbutanoate (2). In a flask equipped with a Soxhlet extractor containing
CaCl2, methyl cyanoacetate (177 ml, 1.986 mol), b-alanine (0.88 g, 9.9 mmol, 0.005 equiv.), acetone
(294 ml, 3.972 mol, 2 equiv.), and AcOH (37.5 ml, 655.4 mmol, 0.33 equiv.) were refluxed for 19 h. After
cooling to r.t., the crude mixture was neutralized with sat. NaHCO3 soln. The solvent was removed under
reduced pressure, and the crude product was rectified at 88 – 908/2 Torr: 133 g (49%) of 2. Colorless oil.
IR: 2259, 1734. 1H-NMR (CDCl3, 400 MHz): 3.82 (s, CO2Me); 2.41 (s, Me); 2.32 (s, Me).
(2E,4E,6E,)/(2Z,4E,6E)-2-Cyano-3,7,11-trimethyldodeca-2,4,6,10-tetraenoic Acid (3). At 08, a mix-
ture of citral (1; 1.52 g, 10ꢀ2 mol) and 2 (2.325 g, 1.5 · 10ꢀ2 mol) was added to tBuOK (1.12 g, 10ꢀ2 mol) in
MeOH (25 ml). The soln. was then stirred at r.t. for 48 h. The MeOH was evaporated and ice (100 g) was
added. The mixture was extracted with Et2O, the aq. layer acidified and extracted with Et2O, and the
extract washed with H2O, dried (MgSO4), and concentrated: 3.
(2E,4E,6E)/(2Z,4E,6E)-3,7,11-Trimethyldodeca-2,4,6,10-tetraenenitrile (4). A soln. of crude 3
(1.06 g, 0.4 · 10ꢀ2 mol) in piperidine/pyridine 1:1 (100 ml) was refluxed until the release of CO2 was
completed (2 – 3 h). The bases were evaporated and the crude product was extracted with Et2O and the
extract washed successively with 1m HCl and H2O, dried (MgSO4), and concentrated: 4 (85%), (E)/(Z)
80 :20. The isomers were separated by column chromatography (CC; silica gel, CH2Cl2).

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 4
Scheme 5
1
Data of (all-E)-41): IR: 2213 (CN). H-NMR (CDCl3): 1.60 (s, Me(1a)); 1.68 (s, Me(1b)); 1.87 (s,
MeꢀC(5)); 2.17 (m, CH2(3), CH2C(4)); 2.21 (s, MeꢀC(9)); 5.17 (m, HꢀC(2)); 5.29 (s, HꢀC(10)); 5.93
(d, J ¼ 11.0, HꢀC(6)); 6.19 (d, J ¼ 15.2, HꢀC(8)); 6.76 (dd, J ¼ 15.2, 11.0, HꢀC(7)). 13C-NMR (CDCl3,
75 MHz): 133.0 (CH); 130.2 (CH); 127.6 (CH); 123.8 (CH); 96.4 (CH) 40.7 (CH2); 26.8; (CH2); 26.1
(Me); 18.1 (Me); 17.0 (Me).
1
Data of (9Z)-41): H-NMR (CDCl3): 1.56 (s, Me(1a)); 1.64 (s, Me(1b)), 3 H); 1.86 (s, MeꢀC(5));
2.10 (m, CH2(3), CH2(4)); 2.18 (s, Meꢀ(9)); 5.11 (m, HꢀC(2), HꢀC(10)); 6.04 (d, J ¼ 11.0, HꢀC(6));
6.70 (d, J ¼ 15.0, HꢀC(8)); 6.76 (dd, J ¼ 15.0, 11.0, HꢀC(7)). 13C-NMR (CDCl3, 75 MHz): 133.5 (CH);
129.9 (CH); 125.7 (CH); 124.8 (CH); 95.0 (CH); 33.3 (CH2); 27.2 (CH2); 24.8 (Me); 19.8 (Me); 18.1
(Me).
(2E,4E,6E)/(2Z,4E,6E)-3,7,11-Trimethyldodeca-2,4,6,10-tetraenal (5). Nitrile
4 (0.645 g, 0.3 ·
10ꢀ2 mol) in toluene was reduced at 08 by DIBAL-H (1.1 equiv.) in toluene. After 30 min, the reaction
was quenched with 1m H2SO4. After filtration of the salts and usual workup, the org. layer was rapidly
filtered over Al2O3: 5 (65%), (9E)/(9Z)1) 80 :20. The isomers were separated by CC (silica gel, CH2Cl2).
1
Data of (all-E)-51): IR: 1661 (CO). H-NMR (CDCl3): 1.60 (s, Me(1a)); 1.70 (s, Me(1b)); 1.89 (s,
MeꢀC(5)); 2.05 (m, CH2(3), CH2(4)); 2.36 (s, MeꢀC(9)); 5.11 (m, HꢀC(2)); 5.96 (d, J ¼ 8.1,
HꢀC(10)); 6.03 (m, HꢀC(8)); 6.24 (m, HꢀC(6), HꢀC(7)); 10.09 (d, J ¼ 8.0, HꢀC(11)). 13C-NMR
(CDCl3, 75 MHz): 191.6 (CO); 133.1 (CH); 129.1 (CH); 126.3 (CH); 125.3 (CH); 123.8 (CH); 40.7
(CH2); 26.8 (CH2); 26.1 (Me); 17.7 (Me); 13.5 (Me).

Helvetica Chimica Acta – Vol. 90 (2007)
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Data of (9Z)-51): 1H-NMR (CDCl3): 1.61 (s, Me(1a)); 1.68 (s, Me(1b)); 1.87 (s, MeꢀC(5)); 2.15 (m,
CH2(3), CH2(4)); 2.3 (s, MeꢀC(9)); 5.08 (m, HꢀC(2)); 5.85 (d, J ¼ 8.0, HꢀC(10)); 5.95 (d, J ¼ 15.0,
HꢀC(6)); 6.98 (d, J ¼ 15.0, HꢀC(8)); 7.37 (m, HꢀC(7)); 10.18 (d, J ¼ 7.5, HꢀC(11)). 13C-NMR (CDCl3,
75 MHz): 190.4 (CO); 134.0 (CH); 133.3 (CH); 127.9 (CH); 125.4 (CH); 125.1 (CH); 33.4 (CH2); 27.2
(CH2); 24.9 (Me); 21.6 (Me); 18.1 (Me).
(2E,4E,6E,8E,10E)/(2Z,4E,6E,10E)-2-Cyano-3,7,11,15-tetramethylhexadeca-2,4,6,8,10,14-hexadi-
enoic Acid (6). As described for 3: 6 (80%) as a mixture of isomers.
(2E,4E,6E,8E,10E)/(2Z,4E,6E,10E)-3,7,11,15-Tetramethylhexadeca-2,4,6,8,10,14-hexadienenitrile
(7). As described for 4: 7 (90%), (all-E)/(13Z)1) 80 :20. The isomers were separated by CC (silica gel,
CH2Cl2).
1
Data of (all-E)-71): IR: 2215 (CN). H-NMR (CDCl3): 1.62 (s, Me(1a)); 1.69 (s, Me(1b)); 1.84 (s,
MeꢀC(5)); 2.02 (s, MeꢀC(9)); 2.17 (m, CH2(3), CH2(4)); 2.22 (s, MeꢀC(13)); 5.1 (m, HꢀC(2)); 5.17 (s,
HꢀC(14)); 5.97 (m, HꢀC(6)); 6.15 (m, HꢀC(10)); 6.28 (m, HꢀC(8)); 6.61 (m, HꢀC(12)); 6.65 (m,
HꢀC(7)); 6.92 (m, HꢀC(11)).
Data of (13Z)-71): 1H-NMR (CDCl3): 1.62 (s, Me(1a)); 1.69 (s, Me(1b)); 1.84 (s, MeꢀC(5)); 2.02 (s,
MeꢀC(9)); 2.13 (s, MeꢀC(13)); 2.17 (m, CH2(3), CH2(4)); 5.07 (s, HꢀC(14)); 5.1 (m, HꢀC(2)); 5.97
(m, HꢀC(6)); 6.15 (m, HꢀC(10)); 6.28 (m, HꢀC(8)); 6.65 (m, HꢀC(7)); 6.82 (m, HꢀC(12)); 6.92 (m,
HꢀC(11)).
(2E,4E,6E,8E,10E)/(2Z,4E,6E,8E,10E)-3,7,11,15-Tetramethylhexadeca-2,4,6,8,10,14-hexadienal (8).
As described for 5: 8 (55%), (all-E)/(13Z)1) 80 :20. The isomers were separated by CC (silica gel,
CH2Cl2).
Data of g-Retinal (all-E)-81)2): IR: 1659 (CO). 1H-NMR (CDCl3): 1.56 (s, Me(1a)); 1.62 (s, Me(1b));
1.72 (s, MeꢀC(5)); 1.87 (s, MeꢀC(9)); 2.07 (m, CH2(3), CH2(4)); 2.14 (s, MeꢀC(13)); 5.14 (m,
HꢀC(2)); 5.97 – 6.32 (m, HꢀC(6), HꢀC(8), HꢀC(10), HꢀC(14)); 6.77 (m, HꢀC(12)); 7.05 (m,
HꢀC(7)); 7.5 (m, HꢀC(11)); 9.60 (d, J ¼ 8.05, HꢀC(15)).
Data of (13Z)-81): 1H-NMR (CDCl3): 1.56 (s, Me(1a)); 1.62 (s, Me(1b)); 1.69 (s, MeꢀC(5)); 1.87 (s,
MeꢀC(9)); 2.02 (s, MeꢀC(13)); 2.29 – 2.32 (2m, CH2(3), CH2(4)); 5.12 (m, HꢀC(2)); 5.97 – 6.39 (m,
HꢀC(6), HꢀC(7), HꢀC(8), HꢀC(10), HꢀC(14)); 6.63 (m, HꢀC(11)); 7.10 (m, HꢀC(12)); 10.10 (d,
J ¼ 8.3, HꢀC(15)).
(2E,4E)/(2Z,4E)-3-Methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienenitrile (9). In a
Dean – Stark apparatus, at 08, piperidine (60 ml, 2 equiv.) was slowly added to b-ionone (58.27 g) and
cyanoacetic acid (51.85 g, 2 equiv.) in benzene (100 ml). The heterogeneous mixture was refluxed for
6.30 h (removal of formed H2O). After cooling, the mixture was washed twice with H2O (50 ml) the org.
layer dried (MgSO4), the benzene evaporated and the oily product dissolved in CH2Cl2 (150 ml). This
soln. was rapidly filtered over basic alumina (20 g): 9 (ca. 100%) (9E)/(9Z)1) 95 :5 – 98 :2. A pure sample
1
of the (all-E)-9 was obtained by CC (SiO2, CH2Cl2). IR: 2206. H-NMR1) (CDCl3, 400 MHz): 6.55 (d,
J ¼ 16.1, HꢀC(7)); 6.13 (d, J ¼ 16.1, HꢀC(8)); 5.15 (s, HꢀC(10)); 2.44 (s, MeꢀC(9)); 2.02 (t, CH2(4));
1.74 (s, MeꢀC(5)); 1.61 (m, CH2(3)); 1.46 (m, CH2(2)); 1.01 (s, 2 MeꢀC(1)). 13C-NMR (CDCl3,
75 MHz): 132.5 (CH); 128.1 (CH); 39.3 (CH2); 33.0 (CH2); 26.7 (Me); 21.5 (Me); 16.9 (CH2); 16.3 (Me).
(2E4E)/(2Z,4E)-3-Methyl-5-(2,6,6-trimethylcyclohexa-1-en-1-yl)penta-2,4-dienal (10). Under Ar, at
08, 1.2m DIBAL-H in toluene (23.5 ml, 28.2 mmol, 1.1 equiv.) was added slowly to 9 (5.06 g, 23.5 mmol)
in toluene (20 ml). After 30 min, the reaction was quenched with 1m H2SO4. The salts were filtered off,
and Et2O (40 ml) and H2O (20 ml) were added. The org. layer was decanted, washed twice with brine,
dried (MgSO4), and concentrated. The crude 10 ((9E)/(9Z) 95 :5 – 98 :2) was purified by CC (SiO2,
CH2Cl2): 4.21 g (82%) of 10, (all-E). Yellow oil. IR: 1668. 1H-NMR1) (CDCl3, 400 MHz): 10.11 (d, J ¼
8.16, HꢀC(11)); 6.73 (d, J ¼ 16.2, HꢀC(7)); 6.20 (d, J ¼ 16.2, HꢀC(8)); 5.92 (d, J ¼ 8.16, HꢀC(10));
2.3 (s, MeꢀC(9)); 2.03 (m, CH2(4)); 1.71 (s, MeꢀC(5)); 1.6 (m, CH2(3)); 1.47 (m, CH2(2)); 1.03 (s,
2 MeꢀC(1)). 13C-NMR (CDCl3, 75 MHz): 135.7 (CH); 135.4 (CH); 128.7 (CH); 39.7 (CH2); 33.4 (CH2);
28.9 (Me); 21.6 (Me); 19.4 (CH2); 12.9 (Me).
2
)
The NMR data are identical to these described in [13][23].

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(2E,4E,6E,8E)/(2Z,4E,6E,8E)-2-Cyano-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-
2,4,6,8-tetraenoic Acid (11). As described for 3, from the (all-E) aldehyde 10: 11 (75%), mixture of
isomers.
(2E,4E,6E,8E)/(2Z,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tet-
raenenitrile (12). As described for 4: 12 (90%), (all-E)/(13Z)1) 70 :30. The isomers were separated by CC
(silica gel, CH2Cl2).
Data of (all-E)-121): IR: 2213 (CN). 1H-NMR (CDCl3): 1.00 (s, 2 MeꢀC(1)); 1.40 (m, CH2(2)); 1.60
(m, CH2(3)); 1.70 (s, MeꢀC(5)); 2.00 (m, CH2(4)); 2.00 (s, MeꢀC(9)); 2.20 (s, MeꢀC(13)); 5.20 (s,
HꢀC(14)); 6.10 (d, J ¼ 16.0, HꢀC(7)); 6.10 (d, J ¼ 11.0, HꢀC(10)); 6.30 (d, J ¼ 16.0, HꢀC(8)); 6.30 (d,
J ¼ 15.0, HꢀC(12)); 6.90 (dd, J ¼ 15.0, 11.0, HꢀC(11)). 13C-NMR (CDCl3, 75 MHz): 137.6 (CH); 132.5
(CH); 131.2 (CH); 130.4 (CH); 129.6 (CH); 39.5 (CH2); 33.1 (CH2); 28.9 (Me); 21.7 (Me); 19.1 (CH2);
16.5 (Me); 12.9 (Me).
Data of (13Z)-121): IR: 2209 (CN). 1H-NMR (CDCl3): 1.05 (s, 2 MeꢀC(1)); 1.49 (m, CH2(2)); 1.63
(m, CH2(3)); 1.74 (s, MeꢀC(5)); 1.97 (s, MeꢀC(9)); 2.06 (m, CH2(4)); 2.09 (s, MeꢀC(13)); 5.10 (s,
HꢀC(14)); 6.18 (d, J ¼ 16.0, HꢀC(8)); 6.10 (d, J ¼ 11.0, HꢀC(10)); 6.30 (d, J ¼ 16.0, HꢀC(7)); 6.30 (d,
J ¼ 15.0, HꢀC(11)); 6.90 (dd, J ¼ 15.0, 11.0, HꢀC(12)). 13C-NMR (CDCl3, 75 MHz): 136.9 (CH); 132.9
(CH); 129.6 (CH); 128.9 (CH); 128.5 (CH); 39.5 (CH2); 33.0 (CH2); 28.9 (Me); 21.7 (Me); 19.3 (Me);
19.1 (CH2); 12.9 (Me).
(2E,4E,6E,8E)/(2Z,4E,6E8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona2,4,6,8-tetra-
enal (13). As described for 5: 13 (75%), (all-E)/(13Z)1) 70 :30. The isomers were separated by CC (silica
gel, CH2Cl2).
Data of Retinal (all-E-13)1): IR: 1671 (CO). 1H-NMR (CDCl3): 1.03 (s, 2 MeꢀC(1)); 1.47 (m,
CH2(2)); 1.61 (m, CH2(3)); 1.72 (s, MeꢀC(5)); 2.03 (s, MeꢀC(9)); 2.04 (m, CH2(4)); 2.32 (s,
MeꢀC(13)); 5.97 (d, J ¼ 8.2, HꢀC(14)); 6.16 (d, J ¼ 16.0, HꢀC(8)); 6.18 (d, J ¼ 11.7, HꢀC(10)); 6.33
(d, J ¼ 16.0, HꢀC(7)); 6.35 (d, J ¼ 16.0, HꢀC(12)); 7.14 (dd, J ¼ 16.0, 11.7, HꢀC(11)); 10.10 (d, J ¼ 8.2,
HꢀC(15)). 13C-NMR: (CDCl3, 75 MHz): 139.0 (CH); 137.1 (CH); 134.4 (CH); 132.7 (CH); 129.6 (CH);
129.4 (CH); 129.2 (CH); 39.2 (CH2); 33.0 (CH2); 28.9 (Me); 22.0 (Me); 21.2 (Me); 19.0 (CH2); 13.1
(Me).
Data of (13Z)-131): IR: 1668 (CO). 1H-NMR (CDCl3): 1.01 (s, 2 MeꢀC(1)); 1.44 (m, CH2(2)); 1.59
(m, CH2(3)); 1.71 (s, MeꢀC(5)); 2.02 (s, MeꢀC(9)); 2.00 (m, CH2(4)); 2.15 (s, MeꢀC(13)); 5.83 (d, J ¼
8.3, HꢀC(13)); 6.16 (d, J ¼ 16.0, HꢀC(8)); 6.22 (d, J ¼ 11.6, HꢀC(10)); 6.32 (d, J ¼ 16.0, HꢀC(7));
7.04 (dd, J ¼ 16.0, 11.6, HꢀC(11)); 10.22 (d, J ¼ 8.3, HꢀC(15)). 13C-NMR (CDCl3, 75 MHz): 134.4
(CH); 133.5 (CH); 129.6 (CH); 129.4 (CH); 129.3 (CH); 127.6 (CH); 125.8 (CH); 39.2 (CH2); 33.0
(CH2); 28.9 (Me); 21.9 (Me); 21.4 (Me); 19.0 (CH2); 13.1 (Me).
Lycopene (14) and b-Carotene (15): General Procedure (the McMurry reaction has not been used
previously for the synthesis of lycopene from g-retinal): Under Ar, LiAlH4 (1.1 equiv.) was slowly added
to a stirred soln. of of TiCl3 (2.2 equiv.) in anh. THF (10 ml). The soln. was stirred at r.t. for 2 h. Then, a
soln. of 500 mg (1 equiv.) of g-retinal ((all-E)-8) or of retinal ((all-E)-13) in anh. THF (5 ml) was slowly
added, and the mixture was left overnight at r.t. The mixture was cooled at 08 and hydrolyzed by 2m HCl
(30 ml). The crude mixture was extracted with Et2O, the org. layer washed with H2O, dried (MgSO4),
and concentrated: crude 14 (75%) or crude 15 (84%), resp. 1H- and 13C-NMR: identical to those
reported in [22][24] for the (all-E) compounds.
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Received September 19, 2006