Cross metathesis approach to retinoids and other β-apocarotenoids

Article abstract of DOI:10.1016/j.tet.2011.06.086

Cross metathesis (CM) reactions between polyenes, such as β-carotene, canthaxanthin or retinyl acetate, and various alkenes or dienes in the presence of second generation Hoveyda-Grubbs (H II) or Grubbs (G II) catalysts were investigated. Depending on the

Full text of DOI:10.1016/j.tet.2011.06.086

Tetrahedron 67 (2011) 6868e6875
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cross metathesis approach to retinoids and other b-apocarotenoids
*
Agnieszka Wojtkielewicz , Jadwiga Maj, Agnieszka Dzieszkowska, Jacek Witold Morzycki
Institute of Chemistry, University of Białystok, Piłsudskiego 11/4, 15-443 Białystok, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 April 2011
Received in revised form 13 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Cross metathesis (CM) reactions between polyenes, such as b-carotene, canthaxanthin or retinyl acetate,
and various alkenes or dienes in the presence of second generation HoveydaeGrubbs (H II) or Grubbs (G
II) catalysts were investigated. Depending on the cross partner different apocarotenoids were obtained.
Cross metathesis reactions of retinyl acetate proved to be fully regioselective. Carotenoid CM reactions
afforded mixtures of two products due to competing cleavage of the C11eC12 and C15eC150 double
bonds. However, regioselectivity can be controlled by choice of appropriate reaction conditions. The
reactions of polyenes with dienes worked better in respect of yields and diastereoselectivities than those
with monounsaturated cross partners.
Keywords:
Cross metathesis
Retinoids
Apocarotenoids
Carotenoids
Polyenes
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
important. Difficulties with controlling the olefin geometry and
susceptibility of some polyenes to oxidation and isomerization
Natural products containing a conjugated polyene system consti-
tute a large and structurally diverse group of compounds.1 Some of
them, including eicosanolids,2 polyene macrolides,3 carotenoids,4
apocarotenoids,5 and retinoids6 show interesting biological activity.
Particularly, retinoids (Fig. 1) play an essential role in a variety of bi-
ological processes, such as vision, reproduction, cell differentiation,
and immune response. Besides being important to normal cell func-
tion, all-trans-retinoic acid and its natural and synthetic analogues
exhibit antitumor activity.7 One of them, N-(4-hyroxyphenyl)reti-
namide (fenretinide) is currently undergoing clinical trials for the
treatment of breast, bladder, renal, and neuroblastoma malignancies.8
Due to increasing application of polyenes in medicine, nonlinear
optics, cosmetics, and the food industry, the search for efficient
synthetic routes to these compounds is becoming increasingly
make their synthesis a difficult and challenging task. Nowadays
synthetic chemists are provided with a new tool to construct
polyene compounds, i.e., olefin metathesis. Since the development
of well defined molybdenum and ruthenium catalysts (Fig. 2),
which are now commercially available, olefin metathesis has be-
come one of the most valuable methods of CeC double bond for-
mation.9 It has found application in the synthesis of a variety of
natural products.10
Although cross metathesis (CM) reactions of two alkenes, and
recently also of an alkene and a conjugated diene, have already been
studied,11 the use of CM to construct longer conjugated polyene
systems is very limited.12 In our previous paper, we reported the CM
reaction of
b-carotene with ethyl (2E,4E/Z)-3-methylhexa-2,4-
dienoate.13 In spite of the fact that there are many alternative re-
action sites in the polyene molecule, the reaction was regio- and
diastereoselective. The major product was either ethyl all-trans-
COOH
retinoate or 120- -apocaroten-120-oate, depending on reaction con-
b
OH
ditions. With this promising preliminary result in hand, we decided
vitamin A1
all-trans -retinoic acid
Mes = 2,4,6-trimethylphenyl
OH
O
Cy = cyclohexyl
Ph = phenyl
Mes N
Cl
N Mes
N
Ru
O
Mes N N Mes
H
PCy3
Ru
Cl
fenretinide
Cl
Cl
Ru
Cl
Ph
Cl
Ph
Fig. 1. Natural and synthetic retinoids.
PCy3
PCy3
G I
G II
H II
* Corresponding author. Tel.: þ48 85 7457604; fax: þ48 85 7457581; e-mail
address: jeremy@uwb.edu.pl (A. Wojtkielewicz).
Fig. 2. Examples of the commercially available metathesis catalysts.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.086

A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
6869
to define the scope and limitation of CM reactions of different
polyenes in order to develop the CM methodology of retinoid syn-
thesis, including fenretinide analogues and other apocarotenoids.
experiments were carried out under conditions elaborated in our
preliminary study on the -carotene reaction with ethyl (2E,4E/Z)-3-
b
methylhexa-2,4-dienoate (polyene concentration 0.1 M, 4 equiv of
a cross partner, second generation HoveydaeGrubbs catalyst (H II),
toluene, rt). In the case of a disappointing outcome, the reaction
conditions were optimized. Various catalysts (G II, H II), catalyst
loading (5e20 mol %), amount of a cross partner (1e4 equiv), sol-
vents (CH2Cl2, toluene, MeOH), reaction temperature (rt, 40 ꢀC, or
60 ꢀC), and time (20 mine120 h) were tested. The results are
summarized in Table 1.
2. Results and discussion
Clearly our first goal was to find out if CM of b-carotene with
different olefins can also be accomplished effectively and selectively.
As cross partners alkenoic and dienoic acid esters, amides, as well as
vinyl sulfide, sulfone, and phosphate were chosen (Scheme 1). The
11
15
G II or H II
R
+
R'
12
15'
β-carotene
R
R
+
1
2
Ph
Pr
R =
R' = H or Me
COOcholest
O
COOEt
COOEt
O
COOPh
COOEt
CNC6H4(p-OC6H13
)
CNPh
H
H
OEt
O
SMe
SPh
S Ph
O
P O
OEt
Scheme 1. CM between b-carotene and different cross partners.
Table 1
CM reactions between
b
-carotene and different cross partners
Cross partner
,
Entry
Reaction conditionsa
Yieldb c (E/Z)d
R
R'
Product 1
Product 2
113
213
3
H II, 4 equiv of olefin, toluene, 24 h, rt
H II, 4 equiv of olefin, toluene, 96 h, rt
H II, 4 equiv of olefin, toluene, 24 h, rt
H II, 4 equiv of olefin, toluene, 96 h, rt
G II, 4 equiv of olefin, toluene, 96 h, rt
9e (30:1)
38e (23:1)
R' = Me R =
R' = Me R =
R' = Me R =
R' = Me R =
R' = Me R =
COOEt
COOEt
COOPh
COOPh
COOPh
31%f (9:1)
6%e (20:1)
33%f (30:1)
4%e (30:1)
15%f (>15:1)
50%e (100:1)
57%f (60:1)
4
5
23%e (100:1)
R' = Me R =
R' = Me R =
6
7
8
H II, 4 equiv of olefin, toluene, 24 h, rt
H II, 4 equiv of olefin, toluene, 96 h, rt
H II, 3 equiv of olefin, toluene, 96 h, rt
9%e (6:1)
30%e (10:1)
8%f (8:1)
COOcholest
COOcholest
COOEt
12%f (5:1)
20%d (1.5:1)
6%d (5:1)
R' = H R =
R' = H R =
Pr
9
Various conditions
Various conditions
<1%e
<1%e
<1%e
<1%e
COOEt
Ph
10
R' = H R =
R' = Me
COOEt
O
11
H II, 2 equiv of olefin, CH2Cl2, 96 h, rt
22%f (>80:1)
32%f (20:1)
21%f (3:1)
R =
CNC6H4(p-OC6H13
)
H
O
CNPh
H
R' = Me
12
H II, 1.1 equiv of olefin, 72 h, rt, toluene/CH2Cl2
19%f (3:1)
R =
a
Catalyst (15 mol %) was used in all experiments.
b
c
d
e
f
Yields were calculated in relation to
b
-carotene and were divided by two due to the symmetry of
b-carotene molecule.
-carotene, although its stereochemical purity was not analyzed.
The remaining material was mainly the unreacted
b
Diastereomeric ratio determined by NMR or HPLC analysis.
Yield obtained by quantitative HPLC analysis.
Isolated yield.

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A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
It appeared that both second generation catalysts (G II, H II)
reactions with unsaturated esters, the amide substrates provided
CM products in slightly lower yields but with similar selectivities.
O-n-Hexylfenretinide (Table 1, entry 11) was obtained in 22% yield
along with its analogue possessing a longer polyenic chain. Both
products showed high E-diastereoselectivity (E/Z better than 20:1).
Also fenretinide analogues were synthesized according to this
strategy, using N-phenylcrotonamide as a cross partner (Table 1,
entry 12). However, the E/Z ratio of products was less satisfactory
(3:1). Interestingly, the same products were obtained in the re-
effectively promote the examined reactions. In most experiments
slightly better product yields were achieved in the presence of H II.
All reactions promoted with these catalysts proceeded with similar
regioselectivity with respect to
b-carotene. Two double bonds
C11eC12 and C15eC150 in the polyene molecule were cleaved
during CM reactions. Analyzing the results obtained in the series of
-carotene reactions with unsaturated esters (Table 1, entries 1e8),
b
a conclusion can be drawn that shorter reaction time, less active
catalyst, and more demanding substrates favor formation of prod-
uct 2. However, compounds 2 can undergo secondary CM reactions
to give products 1. Therefore the more forcing conditions (longer
reaction time, more active catalyst, and higher catalyst loading)
give higher yields of products 1. In most cases, the regio- and
stereoselectivity can be, to some extent, controlled by selection of
the reaction conditions. All ester products in optimized experi-
ments were obtained in rather moderate yields. Interestingly,
higher conversion and better diastereoselectivity was achieved in
reactions with 3-methylhexa-2,4-dienoates (Table 1, entries 1e5)
than those with monounsaturated esters (ethyl pent-4-enoate or
cholesteryl crotonate, Table 1, entries 6e8). The higher conversion
action between b-carotene and N-phenylsorbamide (Scheme 2) but
with better E-diastereoselectivity (at least 10:1).
In contrast to the previously reported CM reactions of sorba-
mide,11b N-phenylsorbamide exhibited different regioselectivity in
reactions with
b-carotenedthe internal C2eC3 double bond
proved to be more reactive than the C4eC5 double bond.
Although many examples of successful CM reactions of vinyl
sulfides, sulfones, and phosphates are known in the literature,16 the
reactions of b-carotene with such olefins failed, ever under harsh
reaction conditions.
Generally, various
b
-apocarotenoids (including retinoids, 13-
-apocarotenoids, and 140-
-apocarotenoids)
-carotene, albeit
b-
apocarotenoids, 120-
b
b
b
and better diastereoselectivity attained in reactions of
b
-carotene
may be obtained in one-step by CM reactions of
in moderate yields.
with 3-methylhexa-2,4-dienoates than in those with mono-
unsaturated cross partners can be explained by the likely formation
of chelate intermediates in the latter case. We assume that during
reactions with ethyl pent-4-enoate a new alkylidene ruthenium
complex is formed with the oxygen atom of the carbonyl group
coordinated to the metallic center (Fig. 3). Such six-membered
chelate intermediates were proposed earlier by Taylor for homo-
In our further study, the CM reactions of other poly-
enesdcanthaxanthin and retinyl acetate were also examined.
Canthaxanthin is the oxygenated analogue of
b-carotene, pos-
sessing two carbonyl groups in positions 4 and 40. It was of in-
terest to check if the reactivity of the polyene system conjugated
with carbonyl groups remains the same, as in the case of b-car-
allylic alcohol CM14 and by Grubbs for
reactions.15 As chelation decreases catalyst turnover it would result
in lower product yields. In the case of reaction of -carotene with
g-
d
unsaturated amide CM
otene, and also what is the regio- and diastereoselectivity of CM
reactions of such system. The reaction of canthaxanthin with
ethyl (2E,4E/Z)-3-methylhexa-2,4-dienoate was carried out under
standard conditions (Scheme 3). After 96 h ethyl 4-oxoretinoate
b
cholesteryl crotonate formation of a four-membered chelate in-
termediate could be considered.15
(3, 13%) and ethyl 4-oxo-120-apo- -caroten-120-oate (4, 21%)
b
were isolated from the reaction mixture.17 All trans isomers of
these products predominated. The obtained result shows that
both carotenoids behave similarly in CM reactions, however
conversion was much lower for cantaxanthin (60% of unreacted
substrate was recovered).
N
N
Mes
Cl
Cl
Mes
Ru
O
EtO
O
COOEt
Fig. 3. Proposed structure of chelation in CM reaction with ethyl pent-4-enoate.
11
12
15
15'
H II catalyst (15 mol%),
toluene, RT, 96 h, Ar
We also examined reactions of b-carotene with ethyl penta-2,4-
dienoates substituted at C-3 by a substituent larger than a methyl
group (n-propyl or phenyl, Table 1, entries 9 and 10). However, to
our surprise the reactions with these substrates failed. Despite
testing various reaction conditions (type and amount of catalyst,
amount of cross partner, solvent, temperature, and additives, e.g.,
chlorocatecholborane) only trace amounts (<1%) of products were
obtained.
O
COOEt
COOEt
+
4
3
O
O
13% (11E/11Z = 15/1)
21% (15E/15Z = 5/1)
Scheme 3. CM between cantaxanthin and ethyl (2E,4E/Z)-3-methylhexa-2,4-dienoate.
Having in mind the synthesis of fenretinide analogues, we also
In the case of cantaxanthin reaction with (2E,4E/Z)-N-
(4-hexyloxyphenyl)-3-methylhexa-2,4-dienamide after 24 h the
investigated
b-carotene reactions with amide cross partners (Table
1, entries 11, 12 and Scheme 2). In comparison with the results of
O
15
15'
β-carotene
11
12
15 mol% HII
+
NHPh
toulene/CH2Cl2, r.t.
O
O
NHPh
NHPh
+
after 24 h: 20%
after 24 h: 4%
after 72 h: 13% (11E/11Z = >50/1)
after 72 h: 22% (15E/15Z = >10/1)
Scheme 2. CM between b-carotene and N-phenylsorbamide.

A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
6871
all-trans-amide 5 (Fig. 4) was selectively obtained in 17% yield. Only
a trace amount (<1%) of 4-oxoretinamide was formed. This result
and the previous one demonstrated that the presence of additional
carbonyl groups in the molecule slightly diminished the reactivity
of the C11eC12 double bond in cantaxanthin when compared with
In the next stage, CM reactions of retinyl acetate with different
dienes and alkenes (Scheme 4) were investigated. The results are
shown in Table 2.
As could be expected, in all cases the C11eC12 double
bond of retinyl acetate was selectively cleaved. The reactions
with (2E,4E/Z)-3-methylhexa-2,4-dienoic acid esters proceeded
smoothly under promotion of the HoveydaeGrubbs second
generation catalyst (H II) as well as Grubbs second generation
catalyst (G II) to afford the desired retinoates in satisfactory
yields and with high diastereoselectivities (Table 2, entries 1e3).
The product yield of reaction with the less reactive analogous
dienoic amide proved to be a bit lower (Table 2, entry 8). O-n-
Hexylfenretinide was obtained in 26% yield with an excellent
diastereoselectivity (Table 2, entry 8). Surprisingly, once again,
reactions with alkenoic acid esters (Table 2, entries 4 and 5)
proceeded much less effectively and less diastereoselectively.
For example, the reaction with ethyl pent-4-enoate afforded the
desired product only in 10% yield as a mixture of 11E/11Z iso-
mers in the 5:1 ratio (Table 2, entry 5). As the main product
tetraene 6 (33%, Fig. 5) was obtained through the undesirable
b
-carotene. The isolated pure amide 5 upon standing in chloroform
solution spontaneously underwent partial transformation to its
isomer (presumably rotamer), the structure of which was not un-
equivocally established. The mixture of isomers could be separated
by preparative HPLC, but within a few hours both pure isomers
afforded again the same equilibrium mixture of isomers.
OC6H13
O
N
H
5
O
Fig. 4. Product of cantaxanthin CM reaction with (2E,4E/Z)-N-(4-hexyloxyphenyl)-3-
methylhexa-2,4-dienamide.
11
H II or G II
R
R
+
OAc
R'
12
R' = H or Me
Pr
Ph
COOcholest
R =
COOEt
COOPh
O
COOEt
COOEt
O
S Ph
O
OEt
P O
OEt
COOEt
CNC6H4(p-OC6H13
)
SPh
SMe
H
Scheme 4. CM reactions between retinyl acetate and different cross partners.
Table 2
CM reactions between retinyl acetate and different cross partners
,c
Entry
Cross partner
Reaction conditionsa
Yield (E/Z)b
Product
R
R'
R' = Me
1
2
3
R =
R =
H II, 4 equiv of olefin, toluene, 96 h, rt
G II, 4 equiv of olefin, toluene, 96 h, rt
H II, 4 equiv of olefin, toluene, 96 h, rt
55%e (40:1)
35%e (80:1)
40%e (50:1)
COOEt
COOEt
COOPh
R' = Me
R' = Me R =
R' = Me
4
5
6
H II, 4 equiv of olefin, toluene, 96 h, rt
H II, 2 equiv of olefin, toluene, 96 h, rt
H II, 4 equiv of olefin, toluene, 96 h, rt
31%e (1.8:1)
R = COOcholest
,
10%e f (5:1)
COOEt
R' = H
R =
Pr
<1%e
<1%e
R' = H R =
COOEt
COOEt
Ph
7
H II, 4 equiv of olefin, toluene, 96 h, rt
R' = H
R =
R' = Me
O
8
H II, 1.2 equiv of olefin, toluene/CH2Cl2, 96 h, rt
26%d (95:1)
R =
CNC6H4(p-OC6H13
)
H
a
Catalyst (15 mol %) was used in all experiments.
b
c
d
e
f
Diastereomeric ratio determined by NMR or HPLC analysis.
The remaining material was mainly the unreacted retinyl acetate.
Isolated yield.
Yield obtained by quantitative HPLC analysis.
Tetraene 6 was the major reaction product (33%).

6872
A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
metathesis reaction. The derivatives of sorbic acid (Scheme 5)
were regioselectively cleaved at the C2eC3 double bond, yield-
In our opinion, CM reactions of different retinoids and carot-
enoids provide an alternative, one-step route to apocarotenoids,
including retinoids. The cross metathesis seems to be a fast and
useful approach to the synthesis of small samples of various
apocarotenoids for biological and structural studies.
ing mainly 13
retinyl acetate. Ethyl 13-apo-
b
-apocarotenoid products of CM reactions with
-carotenoate as well as 13-apo-b-
b
carotenamides were obtained in low yields (10%e15%).
4. Experimental
4.1. General information
6
Fig. 5. Main product of retinyl acetate CM with ethyl pent-4-enoate.
All manipulations of retinoids, such as isolation, purification,
etc. were performed in argon atmosphere. All retinoids were stored
O
R
O
11
+
OAc
R
12
R = OEt, NHPh, NHC6H4(p-OH)
R = OEt: 15% (E/Z = 6/1)
R = NHPh: 10% (E/Z = 6/1)
R = NHC6H4(p-OH): 13% (E/Z = 90/1)
Scheme 5. CM reactions between retinyl acetate and sorbic acid derivatives.
Analogously, as in the case of
of retinyl acetate with vinyl sulfone, sulfide or phosphate.
b
-carotene, there was no reactions
in argon atmosphere at ꢁ20 ꢀC. Toluene and dichloromethane for
CM reactions were distilled over calcium hydride under argon just
prior to use.
NMR spectra were recorded with a Bruker Avance II 400 spec-
trometer using CDCl3 solutions with TMS as the internal standard
(only selected signals in the 1H NMR spectra are reported). Infrared
spectra were recorded on a Nicolet series II Magna-IR 550 FT-IR
spectrometer in chloroform solutions. Mass spectra were
obtained at 70 eV with AMD-604 spectrometer. UV/vis spectra were
recorded in dichloromethane. The reactions were analyzed by TLC
or HPLC method. The products were isolated by column chroma-
tography performed on 70e230 mesh silica gel (J. T. Baker) or by
semipreparative HPLC.
3. Conclusions
In summary, CM reactions between polyenes (b-carotene, can-
thaxanthin, retinyl acetate) and various alkenes and dienes were
investigated. Only reaction of retinyl acetate was fully regioselective
and yielded, depending on the structure of a cross partner, different
apocarotenoids (i.e., retinoids, 13-apocarotenoids). In the case of
carotenoid reactions, mixtures of two products 1 and 2 were formed.
However, appropriate choice of conditions improved the reaction
regio- and diastereoselectivity. Surprisingly, higher yields were
obtained in polyene CM reactions with dienes than in those with
monounsaturated substrates. This can be rationalized taking into
account higher electron density at the terminal double bonds in
dienes. The reactivity of dienes in CM reactions depends both on
electronic and steric factors. Indeed, the more electron-withdrawing
the substituent (ArNHe, EtOe, PhOe) at the carbonyl group, the
better the yield of CM reactions. A very important role plays sub-
stituent at C-3 in dienes. A bulky substituent (n-propyl, phenyl) at
this position suppresses completely the reaction, probably due to
steric hindrance in the intermediate ruthenium complex (Fig. 6),
which prevents the partner olefin from approaching the reaction
site. The methyl group allows CM reactions to occur but at the same
time it discriminates between different approaches of the partner
olefin and favors intermediates leading to E-configurated products
(reactions are highly E-diastereoselective). When there is no sub-
stituent at C-3, a different mode of CM reactions was observed. The
reactions occurred with C2eC3 double bond cleavage. The lower
yields observed for reactions of polyenes with alkenoic esters may
result from carbonyl chelation to the ruthenium center (Fig. 3) and
in consequence, diminished catalyst activity.
HPLC analysis: HPLC was performed with LabAlliance apparatus
comprised of pumps (III Pump series), UV/vis detector (525 Dual-
wavelength) and injection valve (Rheodyne Model 7725i). Analyt-
ical HPLC was carried out with a Supelco-Si column (5
m
m
m),
m),
0.46ꢂ25 cm, and semipreparative HPLC with SMTeSilica (5
1.0ꢂ25 cm, eluting solvent was 98.5:1.5 n-hexane/ethyl acetate,
isocratic, the flow rate: 3.4 ml/min. The elution pattern of retinoids
was monitored continuously by UV at 340 or 365 nm.
4.2. General procedure for CM reactions
To the solution of a polyene (c¼9.7ꢂ10ꢁ2 or 4.9ꢂ10ꢁ2 M) and of
Hoveyda (Grubbs) second generation catalyst (15 mol %) in dry
toluene (or dichloromethane or methanol) olefin (1e4 equiv) was
added dropwise. The reaction mixture was stirred at rt under argon
atmosphere. Then the mixture was analyzed by HPLC and purified
by semipreparative HPLC or column chromatography.
4.3. Synthesis
4.3.1. Phenyl retinoate. UV/vis (dichloromethane) lmax
(43,650); IR (CHCl3) nmax 1723, 1579, 1493, 1220, 1127, 968 cmꢁ1; 1H
NMR (400 MHz; CDCl3) 1.05 (s, 6H), 1.49 (m, 2H), 1.64 (m, 2H), 1.74
(s, 3H), 2.037 (s, 3H), 2.040 (m, 2H), 2.42 (s, 3H), 6.01 (s, 1H), 6.17 (d,
J¼16.1 Hz, 1H), 6.20 (d, J¼11.4 Hz, 1H), 6.29 (d, J¼15.0 Hz, 1H), 6.32
(d, J¼16.1 Hz, 1H), 6.39 (d, J¼12.0 Hz, 1H), 7.09 (dd, J¼11.4, 15.0 Hz,
1H), 7.13 (m, 2H), 7.23 (m, 1H), 7.39 (m, 2H); 13C NMR (100 MHz;
(
3
)¼370 nm
N
Cl
Cl
N
Mes
d
Mes
Ru
R
O
X
R = H, Me, n-Pr, Ph
X = OPh, OEt, NHAr
CDCl3) d 13.0 (CH3), 14.1 (CH3), 19.2 (CH2), 12.9 (CH3)21.7 (CH3), 29.0
(2ꢂ CH3), 33.1 (CH2), 34.3 (C), 39.6 (CH2), 117.2 (CH), 121.8 (2ꢂ CH),
Fig. 6. Ruthenium complex formed in CM reaction with (2E,4E/Z)-3-methylhexa-2,4-
dienoic acid derivatives.
129.1 (CH), 125.5 (CH), 130.2 (C), 129.3 (2ꢂ CH), 129.4 (CH), 137.2

A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
6873
(CH), 131.9 (CH), 134.8 (CH), 140.4 (C), 137.7 (C), 150.8 (C), 155.5 (C),
165.5 (C); LRMS (EI): m/z (%): 376 (Mþ, 41), 283 (124), 267 (12);
HRMS (ESI): m/z calcd for C26H32O2Na (MNaþ): 399.2300, found:
399.2303.
(CH2), 21.7 (CH3), 22.6 (CH3), 22.8 (CH3), 23.8 (CH2), 24.3 (CH2), 27.9
(CH2), 28.0 (CH), 28.2 (CH2), 29.0 (2ꢂ CH3), 31.91 (CH2), 31.94 (CH),
33.1 (CH2), 34.3 (C), 35.8 (CH), 36.2 (CH2), 36.7 (C), 37.1 (CH2), 38.3
(CH2), 39.5 (CH2), 39.7 (CH2), 39.8 (CH2), 42.3 (C), 50.1 (CH), 56.2 (CH),
56.7 (CH), 73.8 (CH), 120.8 (CH), 122.6 (CH), 128.0 (CH), 128.3 (CH),
128.5 (CH), 129.8 (C), 130.1 (CH), 136.0 (CH), 137.5 (CH), 138.3 (C), 139.8
(C), 140.2 (CH), 142.9 (C), 144.2 (C), 166.9 (C); LRMS (ESI): m/z 717
(MNaþ); HRMS (ESI): m/z calcd for C49H74O2Na (MNaþ): 717.5586,
found: 717.5599.
4.3.2. Phenyl 120-apo-
lmax
)¼414 (26,220); IR (CHCl3) nmax 1722, 1590, 1552, 1493, 1126,
967 cmꢁ1; 1H NMR (400 MHz; CDCl3)
1.05 (s, 6H); 1.48 (m, 2H),1.63
b
-caroten-120-oate. UV/vis (dichloromethane)
(3
d
(m, 2H), 1.73 (s, 3H), 2.00 (s, 3H), 2.03 (m, 2H), 2.06 (s, 3H), 2.42 (s,
3H), 6.02 (s, 1H), 6.15 (m, 2H), 6.20 (d, J¼12.4 Hz, 1H), 6.27 (d,
J¼11.4 Hz, 1H), 6.38 (d, J¼15.0 Hz, 1H), 6.41 (d, J¼15.0 Hz, 1H), 6.78
(dd, J¼11.4, 15.0 Hz 1H), 7.08 (dd, J¼11.6, 15.0 Hz, 1H), 7.13 (m, 2H),
4.3.6. Ethyl (11E/Z) 13-nor-13,14-dihydroretinoate. UV/vis (dichloro-
methane) lmax
(
3
)¼290 (14,200); IR (CHCl3) nmax 1727, 1604,
7.23 (m, 1H), 7.39 (m, 2H); 13C NMR (100 MHz; CDCl3)
d
13.1 (CH3),
1265 cmꢁ1; 1H NMR (400 MHz; CDCl3)
d
1.02 (s, 6H),1.27 (t, J¼7.1 Hz,
14.1 (CH3), 12.8 (CH3), 19.2 (CH2), 29.0 (2ꢂ CH3), 21.8 (CH3), 33.1
(CH2), 34.3 (C), 39.6 (CH2), 117.4 (CH), 127.0 (CH), 121.8 (2ꢂ CH),125.5
(CH), 129.3 (2ꢂ CH), 127.5 (CH), 130.4 (CH), 129.7 (C), 135.2 (CH),
130.8 (CH), 131.9 (CH), 137.4 (C), 136.5 (CH), 137.6 (CH), 140.5 (C),
137.8 (C), 150.8 (C), 155.4 (C) and 165.4 (C); LRMS (ESI): m/z 465
(MNaþ); HRMS (ESI): m/z calcd for C31H38O2Na (MNaþ): 465.2770,
found: 465.2785.
3H), 1.47 (m, 2H), 1.62 (m, 2H), 1.70 (s, 3H), 1.90 (s, 3H), 2.01 (t,
J¼6.2 Hz, 2H), 2.36 (s, 3H), 2.43 (m, 2H), 2.47 (m, 2H), 4.15 (q,
J¼7.1 Hz, 2H), 5.71 (dt, J¼6.7, 15.0 Hz, 1H), 5.99 (d, J¼11.2 Hz, 1H),
6.03e6.15 (m, 2H), 6.46 (m, 1H); 13C NMR (100 MHz; CDCl3)
d 12.5
(CH3), 14.2 (CH3), 14.3 (CH3), 19.3 (CH2), 21.4 (CH3), 21.7 (CH3), 28.4
(CH2), 28.9 (2ꢂ CH3), 33.0 (CH2), 34.2 (C, CH2), 39.6 (CH2), 60.3 (CH2),
126.3 (CH), 128.0 (CH), 128.9 (C), 129.4 (CH), 132.1 (CH), 134.5 (C),
137.7 (CH), 137.9 (C), 173.0 (C), LRMS (EI): m/z (%) 316 (Mþ, 72), 301
(3), 157 (39), 145 (64), 91 (100); HRMS (EI): m/z calcd for C21H32O2
(Mþ): 316.2402, found: 316.2411.
4.3.3. Cholesteryl (all E) 13-apo-
methane) lmax
)¼336 (47,013); IR (CHCl3) nmax 1693, 1598, 1272,
1148 cmꢁ1 1H NMR (400 MHz; CDCl3)
0.69 (s, 3H), 0.876 (d,
b-caroten-13-oate. UV/vis (dichloro-
(3
;
d
J¼6.6 Hz, 3H), 0.881 (d, J¼6.6 Hz, 3H), 0.93 (d, J¼6.5 Hz, 3H), 1.04 (s,
6H), 1.05 (s, 3H), 1.74 (s, 3H), 2.01 (m, 2H), 2.05 (s, 3H), 2.38 (m, 2H),
4.70 (m, 1H), 5.40 (d, J¼5.0 Hz, 1H), 5.86 (d, J¼5.0 Hz, 1H), 6.16 (m,
2H), 6.39 (d, J¼15.4 Hz, 1H), 7.71 (dd, J¼12.0, 15.0 Hz, 1H); 13C NMR
4.3.7. Ethyl (15E/Z) 120-apo-130-nor-130,140-dihydro-
b
-caroten-120-
1.03 (s, 6H), 1.27 (t, J¼7.1 Hz,
oate. 1H NMR (400 MHz; CDCl3)
d
3H), 1.49 (m, 2H), 1.62 (m, 2H), 1.72 (s, 3H), 1.92 (s, 3H), 1.97 (s, 3H),
2.03 (t, J¼6.2 Hz, 2H), 2.36 (s, 3H), 2.44 (m, 2H), 2.48 (m, 2H), 4.15
(q, J¼7.1 Hz, 2H), 5.74 (dt, J¼6.6, 14.3 Hz, 1H), 6.05e6.15 (m, 4H),
6.30 (d, J¼15.0 Hz, 1H), 6.44 (m, 1H), 6.61 (dd, J¼11.3, 14.9 Hz, 1H).
A very unstable compounddit decomposed during 13C NMR
analysis.
(100 MHz; CDCl3) d 11.9 (CH3), 13.0 (CH3), 19.2 (CH2), 18.7 (CH3), 19.4
(CH3), 21.0 (CH2), 21.7 (CH3), 22.6 (CH3), 22.8 (CH3), 23.8 (CH2), 24.3
(CH2), 27.9 (CH2), 28.0 (CH), 28.2 (CH2), 28.9 (2ꢂ CH3), 31.87 (CH),
31.92 (CH2), 33.1 (CH2), 34.2 (C), 35.8 (CH), 36.2 (CH2), 36.6 (C), 37.0
(CH2), 38.2 (CH2), 39.6 (CH2), 39.7 (CH2), 42.3 (C), 50.0 (CH), 56.1 (CH),
56.7 (CH), 73.7 (CH), 120.5 (CH), 122.6 (CH), 127.3 (CH), 130.65 (C),
130.73 (CH),136.7 (CH),137.5 (C),139.8 (C),140.5 (CH),144.2 (C),167.0
(C); LRMS (ESI): m/z 1280 (2MNaþ), 683 (MNaþþMeOH), 651
(MNaþ); HRMS (ESI): m/z calcd for C44H68O2Na (MNaþ): 651.5117,
found: 651.5131.
4.3.8. N-(4-Hexyloxyphenyl)retinamide. UV/vis (dichloromethane)
lmax
(
3
)¼370 (63,700); IR (CHCl3) nmax 3434, 1663, 1580, 1511, 1242,
1156 cmꢁ1; 1H NMR (400 MHz; CDCl3)
d
0.92 (t, J¼6.9 Hz, 3H), 1.04
(s, 6H), 1.35 (m, 4H), 1.46 (m, 4H), 1.63 (m, 2H), 1.73 (s, 3H), 1.77 (m,
2H), 2.01 (s, 3H), 2.03 (m, 2H), 2.43 (s, 3H), 3.94 (t, J¼6.6 Hz, 2H),
5.79 (s, 1H), 6.15 (m, 2H), 6.29 (m, 2H), 6.86 (m, 2H), 6.99 (dd,
J¼11.5, 14.8 Hz, 1H), 7.07 (br s, 1H), 7.45 (d, J¼8.4 Hz, 2H); 13C NMR
4.3.4. Cholesteryl (11Z) 13-apo-
methane) lmax
)¼334 (23,900); IR (CHCl3) nmax 1698, 1598,
1273 cmꢁ1 1H NMR (400 MHz; CDCl3)
0.69 (s, 3H), 0.87 (d,
b-caroten-13-oate. UV/vis (dichloro-
(3
(100 MHz; CDCl3) d 12.9 (CH3), 13.6 (CH3), 14.0 (CH3), 19.2 (CH2),
;
d
21.7 (CH3), 22.6 (CH2), 25.7 (CH2), 29.0 (2ꢂ CH3), 29.2 (CH2), 31.6
(CH2), 33.1 (CH2), 34.3 (C), 39.6 (CH2), 68.3 (CH2), 114.9 (2ꢂ CH),
121.36 (CH), 121.42 (CH), 121.5 (C), 128.4 (CH), 129.5 (2ꢂ CH), 129.9
(C), 130.2 (CH), 131.2 (C), 135.4 (CH), 137.3 (CH), 137.7 (C), 139.1 (C),
150.2 (C), 155.9 (C); LRMS (ESI): m/z 973 (2MNaþ), 498 (MNaþ);
HRMS (ESI): m/z calcd for C32H45NO2Na (MNaþ): 498.3348, found:
498.3358.
J¼6.6 Hz, 3H), 0.88 (d, J¼6.6 Hz, 3H), 0.93 (d, J¼6.5 Hz, 3H), 1.04 (s,
6H), 1.05 (s, 3H), 1.72 (s, 3H), 2.02 (m, 2H), 2.08 (s, 3H), 2.38 (m, 2H),
4.70 (m, 1H), 5.40 (d, J¼4.3 Hz, 1H), 5.86 (d, J¼15.0 Hz, 1H), 6.16 (m,
2H), 6.39 (d, J¼15.6 Hz, 1H), 7.71 (dd, J¼11.9, 15.0 Hz, 1H); 13C NMR
(100 MHz; CDCl3) d 11.9 (CH3), 13.0 (CH3), 18.7 (CH3), 19.2 (CH2), 19.4
(CH3), 21.0 (CH2), 21.7 (CH3), 22.6 (CH3), 22.8 (CH3), 23.8 (CH2), 24.3
(CH2), 27.9 (CH2), 28.0 (CH), 28.2 (CH2), 28.9 (2ꢂ CH3), 31.90 (CH),
31.93 (CH2), 33.1 (CH2), 34.3 (C), 35.8 (CH), 36.2 (CH2), 36.6 (C), 37.1
(CH2), 38.3 (CH2), 39.5 (CH2), 39.6 (CH2), 39.8 (CH2), 42.3 (C), 50.1
(CH), 56.2 (CH), 56.7 (CH), 73.8 (CH), 120.5 (CH), 122.6 (CH), 127.3
(CH), 130.6 (C), 130.7 (CH), 136.8 (CH), 137.5 (C), 139.8 (C), 140.5 (CH),
144.2 (C), 166.9 (C); LRMS (ESI): m/z 1280 (2MNaþ), 683
(MNaþþMeOH), 651 (MNaþ); HRMS (ESI): m/z calcd for C44H68O2Na
(MNaþ): 651.5117, found: 651.5131.
4.3.9. N-(4-Hexyloxyphenyl)-120-apo-
(dichloromethane) lmax
)¼480 (16,300); IR (CHCl3) nmax 3433,
1663, 1596, 1511, 1241, 1157 cmꢁ1 1H NMR (400 MHz; CDCl3)
b
-caroten-120-amide. UV/vis
(
3
;
d
0.92 (t, J¼6.9 Hz, 3H), 1.04 (s, 6H), 1.35 (m, 4H), 1.48 (m, 4H), 1.63
(m, 2H), 1.73 (s, 3H), 1.78 (m, 2H), 2.00 (s, 3H), 2.04 (s, m, 5H), 2.43
(s, 3H), 3.94 (t, J¼6.6 Hz, 2H), 5.80 (s, 1H), 6.12e6.24 (m, 4H), 6.31
(d, J¼15.0 Hz, 1H), 6.37 (d, J¼15.0 Hz, 1H), 6.74 (dd, J¼11.4, 14.5 Hz,
1H), 6.86 (m, 2H), 6.98 (dd, J¼10.9, 14.0 Hz, 1H), 7.06 (br s, 1H),
4.3.5. Cholesteryl (all E) 140-apo-
methane) lmax
)¼390 (19,200); IR (CHCl3) nmax 1693, 1615, 1563,
1305, 1155 cmꢁ1 1H NMR (400 MHz; CDCl3)
0.69 (s, 3H), 0.87 (d,
b
-caroten-140-oate. UV/vis (dichloro-
7.45 (d, J¼8.2 Hz, 2H); 13C NMR (100 MHz; CDCl3)
d 12.8 (CH3),
(3
13.0 (CH3), 13.6 (CH3), 14.0 (CH3), 19.3 (CH2), 21.8 (CH3), 22.6 (CH2),
25.7 (CH2), 29.0 (2ꢂ CH3), 29.2 (CH2), 31.6 (CH2), 33.1 (CH2), 34.3
(C), 39.6 (CH2), 68.3 (CH2), 114.8 (2ꢂ CH), 121.4 (CH), 121.6 (CH),
126.4 (CH), 127.3 (2ꢂ CH), 129.6 (2ꢂ C), 130.2 (CH), 130.5 (CH),
131.0 (CH), 135.9 (CH), 136.7 (CH), 137.0 (C), 137.6 (CH), 137.9 (C),
139.2 (C), 150.1 (C), 155.9 (C), 164.8 (C); LRMS (ESI): m/z 564
(MNaþ); HRMS (ESI): m/z calcd for C37H51NO2Na (MNaþ):
564.3817, found: 564.3826.
;
d
J¼6.6 Hz, 3H), 0.88 (d, J¼6.6 Hz, 3H), 0.93 (d, J¼6.5 Hz, 3H),1.04 (s, 6H),
1.05 (s, 3H), 1.73 (s, 3H), 2.00 (s, 3H), 2.04 (m, 2H), 2.07 (s, 3H), 2.38 (m,
2H), 4.71 (m, 1H), 5.40 (d, J¼4.6 Hz, 1H), 5.88 (d, J¼15.0 Hz, 1H),
6.10e6.28 (m, 4H), 6.36 (d, J¼14.7 Hz, 1H), 6.83 (dd, J¼11.4, 15.0 Hz,
1H), 7.69 (dd, J¼12.0, 15.0 Hz, 1H); 13C NMR (100 MHz; CDCl3)
d 11.9
(CH3), 12.8 (CH3), 13.2 (CH3), 18.7 (CH3), 19.3 (CH2), 19.4 (CH3), 21.1

6874
A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
4.3.10. N-Phenyl-13-apo-
b
-caroten-13-amide. UV/vis (dichloro-
(ESI): m/z calcd for C
27H36O3Na (MNaþ): 431.2562, found:
methane) lmax
(
3
)¼342 (13,500); IR (CHCl3) nmax 3431, 1674, 1597,
431.2580.
1522, 1438 cmꢁ1; 1H NMR (400 MHz; CDCl3)
d
1.05 (s, 6H), 1.49 (m,
2H), 1.63 (m, 2H), 1.73 (s, 3H), 2.03 (m 2H), 2.08 (s, 3H), 5.99 (d,
J¼14.5 Hz, 1H), 6.15e6.20 (m, 2H), 6.40 (d, J¼16.2 Hz, 1H), 7.12 (m,
2H), 7.35 (m, 2H), 7.59 (br s, 2H), 7.82 (dd, J¼12.0, 14.5 Hz, 1H); 13C
4.3.15. N-(4-Hexyloxyphenyl)-4-oxo-120-apo-
(5, 17%). UV/vis (dichloromethane) lmax
(CHCl3) nmax 3434, 1653, 1595, 1511, 1470, 1354, 1240, 1157,
969 cmꢁ1; 1H NMR (400 MHz; CDCl3)
b
-caroten-120-amide
(
3
)¼420 (42,670); IR
NMR (100 MHz; CDCl3)
d
13.0 (CH3), 19.2 (CH2), 21.7 (CH3), 28.9
d
0.92 (t, J¼6.9 Hz, 3H), 1.21
(2ꢂ CH3), 33.1 (CH2), 34.3 (C), 39.6 (CH2), 119.7 (CH), 124.3 (CH),
127.1 (2ꢂ CH), 129.0 (3ꢂ CH), 129.1 (C), 130.6 (C), 130.7 (CH), 136.8
(2ꢂ CH), 137.6 (C), 138.4 (C), 144.2 (C); LRMS (ESI): m/z 358
(MNaþ); HRMS (ESI): m/z calcd for C23H29NONa (MNaþ):
358.2147, found: 358.2145.
(s, 6H), 1.35 (m, 3H), 1.46 (m, 2H), 1.78 (m, 3H), 1.86 (m, 2H), 1.88
(s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.43 (s, 3H), 2.52 (t, J¼6.7 Hz,
2H), 3.95 (t, J¼6.6 Hz, 2H), 5.82 (s, 1H), 6.27 (m, 2H), 6.35 (m, 2H),
6.44 (d, J¼15.1 Hz, 1H), 6.73 (dd, J¼11.6, 15.2 Hz, 1H), 6.87 (d,
J¼8.9 Hz, 2H), 7.00 (dd, J¼11.9, 14.9 Hz, 1H), 7.07 (br s, 1H), 7.46 (d,
J¼8.9 Hz, 2H); 13C NMR (100 MHz; CDCl3)
d 12.6 (CH3), 13.0 (CH3),
4.3.11. N-Phenyl-140-apo-
methane) lmax
)¼382 (52,100); IR (CHCl3) nmax 3430, 1671, 1599,
1522, 1438 cmꢁ1; 1H NMR (400 MHz; CDCl3)
1.05 (s, 6H), 1.48 (m,
b
-caroten-140-amide. UV/vis (dichloro-
13.6 (CH3), 13.8 (CH3), 14.0 (CH3), 22.6 (CH2), 25.7 (CH2), 27.7 (2ꢂ
CH3), 29.2 (CH2), 31.6 (CH2), 34.3 (CH2), 35.7 (C), 37.4 (CH2), 68.3
(CH2), 114.8 (2ꢂ CH), 121.4 (CH), 122.1 (CH), 124.5 (CH), 125.7 (CH),
129.9 (2ꢂ C), 131.1 (CH), 132.3 (CH), 134.0 (CH), 134.2 (CH), 135.5
(C), 136.8 (CH), 138.78 (C), 138.84 (CH), 141.1 (CH, C), 149.9 (C),
155.9 (C), 161.1 (C), 199.3 (C); LRMS (ESI): m/z 1134 (2MNaþ), 578
(MNaþ); HRMS (ESI): m/z calcd for C37H49NO3Na (MNaþ):
578.3610, found: 578.3618.
(
3
d
2H), 1.63 (m, 2H), 1.73 (s, 3H), 2.01 (s, 3H), 2.04 (m, 2H), 2.10 (s,
3H), 6.00 (d, J¼14.4 Hz, 1H), 6.13e6.28 (m, 4H), 6.37 (d, J¼15.0 Hz,
1H), 6.84 (dd, J¼11.5, 15.0 Hz, 1H), 7.11e7.21 (m, 2H), 7.35 (m, 2H),
7.59 (m, 2H), 7.81 (dd, J¼12.0, 14.4 Hz, 1H); 13C NMR (100 MHz;
CDCl3)
d
12.9 (CH3), 13.2 (CH3), 19.2 (CH2), 21.7 (CH3), 29.0 (2ꢂ
CH3), 33.1 (CH2), 34.3 (C), 39.6 (CH2), 119.8 (CH), 124.2 (CH), 128.0
(CH), 128.3 (CH), 129.0 (4ꢂ CH), 129.8 (C), 130.1 (2ꢂ CH), 136.0
(CH), 137.5 (2ꢂ CH), 137.8 (C), 138.2 (C), 138.56 (C), 138.59 (C),
144.2 (C); LRMS (ESI): m/z 424 (MNaþ); HRMS (ESI): m/z calcd for
C28H35NONa (MNaþ): 424.2616, found: 424.2617.
4.3.16. 12-Apo-b-carotene (6, 33%). UV/vis (dichloromethane) lmax
(
3
)¼304 (19,600); 1H NMR (200 MHz; CDCl3)
d 1.03 (s, 6H), 1.48 (m,
2H),1.63 (m, 2H),1.71 (s, 3H), 1.93 (s, 3H), 2.02 (m, 2H), 5.18 (m, 2H),
6.03e6.15 (m, 2H), 6.65e6.84 (m, 1H); 13C NMR (50 MHz; CDCl3)
d
12.6 (CH3), 19.3 (CH2), 21.7 (CH3), 28.9 (2ꢂ CH3), 33.0 (CH2), 34.2
4.3.12. N-(4-Hydroxyphenyl)-13-apo-
(dichloromethane) lmax
)¼348 (13,300); IR (CHCl3) nmax 3432,
3313, 1663, 1592, 1514. 1265 cmꢁ1 1H NMR (400 MHz; CDCl3)
1.03 (s, 6H), 1.47 (m, 2H), 1.61 (m, 2H), 1.71 (s, 3H), 2.02 (m, 2H),
b
-caroten-13-amide. UV/vis
(C), 39.6 (CH2), 116.7 (CH2), 127.2 (CH), 129.1 (C), 130.2 (CH), 133.3
(CH),136.2 (C), 137.5 (CH),137.8 (C); LRMS (EI): m/z (%) 216 (Mþ, 74),
201 (45),173 (18), 159 (32),145 (99) 131 (100); HRMS (EI): m/z calcd
for C16H24 (Mþ): 216.1878, found: 216.1886.
(
3
;
d
2.06 (s, 3H), 4.90 (br s, 1H), 5.94 (d, J¼14.5 Hz, 1H), 6.15 (m, 2H),
6.37 (d, J¼15.8 Hz, 1H), 6.80 (d, J¼8.8 Hz, 2H), 7.04 (br s, 1H), 7.43
(m, 2H), 7.78 (dd, J¼12.0, 14.5 Hz, 1H); 13C NMR (100 MHz; CDCl3)
Acknowledgements
d
13.0 (CH3), 19.2 (CH2), 21.7 (CH3), 28.9 (2ꢂ CH3), 33.1 (CH2), 34.3
Financial support from the Ministry of Science and Higher Ed-
ucation (Grant No. N N204 154936) is gratefully acknowledged.
(C), 39.6 (CH2), 115.7 (2ꢂ CH), 127.1 (CH), 128.3 (4ꢂ CH), 130.53
(2ꢂ C), 130.54 (CH), 136.8 (C, CH), 137.6 (C), 144.0 (C), 146.0 (C);
LRMS (ESI): m/z 374 (MNaþ); HRMS (ESI): m/z calcd for
C23H29NO2Na (MNaþ): 374.2096, found: 374.2102.
Supplementary data
IR, 1H NMR, 13C NMR, and MS spectra for all compounds. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2011.06.086.
4.3.13. Ethyl 4-oxoretinoate (3, 13%). UV/vis (dichloromethane)
lmax
(3
)¼360 (44,545); IR (CHCl3) nmax 1702, 1652, 1610, 1590, 1353,
1242, 1156, 970 cmꢁ1; 1H NMR (400 MHz; CDCl3)
d
1.20 (s, 6H), 1.31
(t, J¼7.1 Hz, 3H), 1.865 (s, 3H), 1.870 (m, 2H), 2.04 (s, 3H), 2.37 (s,
3H), 2.51 (m, 2H), 4.20 (q, J¼7.1 Hz, 2H), 5.82 (s, 1H), 6.27 (d,
J¼11.0 Hz, 1H), 6.34e6.39 (m, 3H), 6.99 (dd, J¼11.3, 15.0 Hz, 1H); 13C
References and notes
1. Thirsk, C.; Wihting, A. J. Chem. Soc., Perkin Trans. 1 2002, 999.
2. (a) Leukotrienes and Lipoxygenase; Rockack, J., Ed.; Elsevier: New York, NY, 1989;
(b) Green, R. H.; Lambeth, P. F. Tetrahedron 1983, 39, 1687.
3. (a) Omura, S.; Tanaka, H. In Macrolide antibiotics: Chemistry, Biology and Pratice;
Omura, S., Ed.; Academic: New York, NY, 1984; pp 351e552; (b) Rychnovsky, S.
D. Chem. Rev. 1995, 95, 2021.
4. (a) Carotenoids; Isler, O., Ed.; Birkhauser: Basel, 1971; p 932; (b) Carotenoid
Chemistry and Biochemistry; Britton, G., Goodwin, T. W., Eds.; Pergamon:
Oxford, 1982; p 224.
NMR (100 MHz; CDCl3)
d 12.8 (CH3), 13.76 (CH3), 13.81 (CH3), 14.3
(CH3), 27.6 (2ꢂ CH3), 34.3 (CH2), 35.7 (C), 37.4 (CH2), 59.8 (CH2),
119.8 (CH), 125.9 (CH), 130.1 (CH), 132.8 (CH), 137.2 (CH), 137.9 (C),
140.5 (CH), 145.0 (C), 152.1 (C), 160.8 (C), 167.0 (C), 199.2 (C); LRMS
(ESI): m/z 365 (MNaþ); HRMS (ESI): m/z calcd for C22H30O3Na
(MNaþ): 365.2093, found: 365.2105.
4.3.14. Ethyl 4-oxo-120-apo-
(dichloromethane) lmax
)¼410 (73,073); IR (CHCl3) nmax 1701,
1651, 1595, 1242, 1156, 969 cmꢁ1 1H NMR (400 MHz; CDCl3)
b
-caroten-120-oate (4, 21%). UV/vis
5. Walter, M. H.; Floks, D. S.; Strack, D. Planta 2010, 232, 1.
6. (a) Fishkin, N.; Berova, N.; Nakanishi, K. Chem. Rec. 2004, 4, 120; (b) Gudas, L. J. J.
Biol. Chem. 1994, 269, 15399; (c) Mark, M.; Ghyselinck, N. B.; Chambon, P. Annu.
Rev. Pharmacol. Toxicol. 2006, 46, 451; (d) Chambon, P. FASEB J. 1996, 10, 940; (e)
Heyman, R. A.; Mangelsdorf, D. J.; Dyck, J. A.; Stein, R. B.; Eichele, G.; Evans, R.
M.; Thaller, C. Cell 1992, 68, 397.
7. (a) Chomienne, C.; Ballerini, P.; Balitrand, N.; Amar, M.; Bernard, J. F.; Boivin, P.;
Daniel, M. T.; Berger, R.; Castaigne, S.; Degos, L. Lancet 1989, 2, 746; (b) Hong,
W. K.; Sporn, M. B. Science 1997, 278, 1073; (c) Simeone, A. M.; Tari, A. M. Cell.
Mol. Life Sci. 2004, 61, 1475.
8. (a) Moon, R. C.; Metha, R. G.; Rao, K. V. N. In The Retinoids: Biology, Chemistry and
Medicine; Sporn, M. B., Roberts, A. B., Goodmans, D. S., Eds.; Raven: New York, NY,
1994; Vol. 2, pp 573e595; (b) Deccensi, A.; Bruno, S.; Constantini, M.; Torrisi, R.;
Curotto, A.; Gatteschi, B.; Nicolo, G.; Polizzi, A.; Perloff, M.; Malone, W. F.; Bruzzi, P.
J. Natl. Cancer Inst.1994, 86,138; (c) Reynolds, C. P. Curr. Oncol. Rep. 2000, 2, 511; (d)
Vaishampayan, U.; Heilbrun, L. K.; Parchment, R. E.; Jain, V.; Zwiebel, J.; Boinpally,
R. R.; LoRusso, P.; Hussain, M. Invest. New Drugs 2005, 23, 179.
(
3
;
d
1.20 (s, 6H), 1.30 (t, J¼7.1 Hz, 3H), 1.86 (m, 2H), 1.89 (s, 3H), 2.02
(s, 3H), 2.04 (s, 3H), 2.37 (s, 3H), 2.52 (m, 2H), 4.19 (q, J¼7.1 Hz,
2H), 5.81 (s, 1H), 6.26e6.29 (m, 2H), 6.33e6.37 (m, 2H), 6.37 (d,
J¼16.0 Hz, 1H), 6.44 (d, J¼15.0 Hz, 1H), 6.73 (dd, J¼11.4, 15.0 Hz,
1H), 6.99 (dd, J¼11.5, 15.0 Hz, 1H); 13C NMR (100 MHz; CDCl3)
d
12.6 (CH3), 13.0 (CH3), 13.8 (CH3), 14.3 (CH3), 21.1 (CH3), 27.7 (2ꢂ
CH3), 34.3 (CH2), 35.7 (C), 37.4 (CH2), 59.7 (CH2), 119.4 (CH), 124.6
(CH), 125.8 (CH), 129.9 (C), 130.6 (CH), 132.1 (CH), 134.0 (CH),
135.6 (C), 136.5 (CH), 138.8 (CH), 139.2 (C), 141.0 (CH), 152.3 (C),
161.1 (C), 167.1 (C), 199.3 (C); LRMS (ESI): m/z 431 (MNaþ); HRMS

A. Wojtkielewicz et al. / Tetrahedron 67 (2011) 6868e6875
6875
9. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (b) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199; (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900.
10. (a) Nicolaou, K. C.; Bulger, P. G. Angew. Chem., Int. Ed. 2005, 44, 4490; (b)
Morzycki, J. W. Steroids 2011, 76, 949.
11. (a) Funk, W. T.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187; (b) Ferrie, L.;
Amans, D.; Reymont, S.; Bellosta, V.; Capdevielle, P.; Cossy, J. J. Organomet. Chem.
2006, 61, 5456; (c) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5; (d) Dewi,
P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577; (e) Morita, A.; Kuwa-
hara, S. Tetrahedron Lett. 2007, 48, 3163; (f) Krishna, C. V.; Bhonde, V. R.; De-
vendar, A.; Maitra, S.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2008, 12, 2013; (g)
Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96; (h) Lee,
H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855; (i) Royer, F.; Vilain, C.;
Elkaim, L.; Grimaud, L. Org. Lett. 2003, 5, 2007.
12. (a) Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem., Int. Ed. 2007, 46,
1066; (b) Kajikawa, T.; Iguchi, N.; Katsumura, S. Org. Biomol. Chem. 2009, 7,
4586; (c) Lopez-Sanchez, C.; Hernandez-Cervantes, C.; Rosales, A.; Alvarez-
Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I. Tetrahedron 2009, 65, 9542;
(d) Jermacz, I.; Maj, J.; Morzycki, J. W.; Wojtkielewicz, A. Toxicol. Mech. Methods
2008, 18, 469.
13. Wojtkielewicz, A.; Maj, J.; Morzycki, J. W. Tetrahedron Lett. 2009, 50, 4734.
14. Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209.
15. Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40,
1277.
16. de Weghe, P. V.; Bisserte, P.; Blanchard, N.; Eustache, J. J. Organomet. Chem.
2006, 691, 5078.
17. Yields were calculated in relation to cantaxanthin and were divided by two due
to the symmetry of cantaxanthin molecule.