A cross-metathesis approach to the synthesis of new etretinate type retinoids, ethyl retinoate and its 9Z-isomer

Article abstract of DOI:10.1016/j.tetlet.2012.07.122

Two aromatic retinoids were synthesized from styrene derivatives using a novel strategy with a cross-metathesis reaction as a key step. The biological activity of the new etretinate analogues was tested. Cross-metathesis reactions were also employed for the preparation of ethyl retinoate and its 9Z-isomer via the C₁₅ + C₅ route.

Full text of DOI:10.1016/j.tetlet.2012.07.122

Tetrahedron Letters 53 (2012) 5430–5433
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A cross-metathesis approach to the synthesis of new etretinate type
retinoids, ethyl retinoate and its 9Z-isomer
Jadwiga Maj a, Jacek W. Morzycki a, Lucie Rárová b, Grzegorz Wasilewski a, Agnieszka Wojtkielewicz a,
⇑
a Institute of Chemistry, University of Białystok, Piłsudskiego 11/4, Białystok 15-443, Poland
b Faculty of Science, Palacky´ University, Šlechtitelu 11, Olomouc 783 71, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Two aromatic retinoids were synthesized from styrene derivatives using a novel strategy with a cross-
metathesis reaction as a key step. The biological activity of the new etretinate analogues was tested.
Cross-metathesis reactions were also employed for the preparation of ethyl retinoate and its 9Z-isomer
via the C15 + C5 route.
Received 31 May 2012
Revised 15 July 2012
Accepted 27 July 2012
Available online 4 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cross-metathesis
Retinoids
Etretinate analogues
Polyenes
Retinoids are natural and synthetic analogues of retinoic acid.
They play an essential role in a variety of biological processes such
as vision, reproduction, cell differentiation, and immune re-
sponses.1 The scope of natural retinoid therapy is limited by their
susceptibility to double bond isomerization and oxidation by cyto-
chrome P450 enzymes, which affects their activity and selectivity
of action. Modification of the structure of natural retinoids to over-
come these problems has resulted in the synthesis of atypical sec-
ond generation retinoids, in which the trimethylcyclohexenyl unit
was replaced by a functionalized benzene ring, and third genera-
tion retinoids with robust polyaromatic systems (Fig. 1).2 These
aromatic derivatives are more stable as well as more active and
selective. Several such synthetic retinoids (etretinate, acitretin, tez-
arotene, bexarotene, adapalene) along with all-E-retinoic acid are
used clinically. Numerous synthetic methods were elaborated to
prepare natural and atypical second generation aromatic retinoids.
Traditionally, polyene chain construction was accomplished using
Wittig, Horner-Wadsworth-Emmons (HWE), Julia, and Stobbe
reactions; more recently palladium-catalyzed cross-coupling reac-
tions were applied.3
The arsenal of polyene synthesis methods has been extended to
include olefin metathesis, which after the discovery of active and
stable second generation catalysts has become a powerful syn-
thetic tool in the hands of organic chemists.4
In our previous studies,5 we proved that cross-metathesis (CM)
may be applied to the synthesis of different apocarotenoids,
including retinoids from b-carotene or retinyl acetate. However,
in the case of these polyene substrates the reaction course depends
atypical retinoids
2nd generation retinoid
natural retinoid
3rd generation retinoid
COOC2H5
COOH
COOH
bexarotene
H3CO
all-trans-retinoic acid
etretinate
Figure 1. Natural and atypical retinoids.
⇑
Corresponding author. Tel.: +48 85 7457604; fax: +48 85 7457581.
E-mail address: jeremy@uwb.edu.pl (A. Wojtkielewicz).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.122

J. Maj et al. / Tetrahedron Letters 53 (2012) 5430–5433
5431
dimerization (self-metathesis) is slow. Additionally, the ester
functionality present in this compound allows for convenient elon-
gation of the unsaturated chain by a sequence of simple transfor-
mations. At first we investigated the CM reactions of styrene (1a)
and cinnamaldehyde (1b) with ethyl (2E,4E/Z)-3-methylhexa-2,4-
dienoate (2) promoted by second generation catalysts (Scheme 2).
In all the experiments, apart from the major reaction product — the
aromatic ester (3), side products: E-stilbene (4) and the non-
aromatic ester (5) were formed. The desired CM product 3 was
obtained in a better yield by coupling with cinnamaldehyde than
with styrene. Probably, competitive self-metathesis of styrene is
faster than that of cinnamaldehyde, and for this reason a signifi-
cant lowering of the CM product yield was observed in the former
case. Both second generation catalysts (Grubbs and Grubbs–Hov-
eyda complexes) efficiently promoted the reaction of cinnamalde-
hyde with the dienoate affording the desired CM product with
complete diastereoselectivity — the all-E-isomer6 was obtained in
yields above 90% (Scheme 2).
15
COOEt
11
7
9
13
10
14
12
8
R
CM
CM
COOEt
5
3
2
4
R1
R
R3
R2
R
R
Scheme 1. Retrosynthesis of etretinate analogue.
largely on the structure of the cross-metathesis partner and the
reaction conditions. Herein, we present a novel protocol for
the synthesis of aromatic retinoids using a CM reaction to extend
the polyene chain. We have also synthesized ethyl retinoate and
its 9Z-isomer employing the C15 + C5 route, that is, the CM reaction
between a substrate donating a fifteen-carbon atom fragment
(C15-synthon) and the other one being a donor of a five-carbon
atom fragment (C5-synthon).
The retrosynthetic analysis of etretinate analogues is shown in
Scheme 1. Assuming that the disubstituted double bonds of the
retinoid chain are more accessible than the trisubstituted ones
by the CM approach, in order to build a polyene chain of aromatic
retinoids from a styrene derivative, a CM coupling with partners
bearing a 2-methylbuta-1,3-diene moiety was considered. Based
on our previous experience,5 we chose readily available ethyl
3-methylhexa-2,4-dienoate, as it has been proved that its CM
reactions occur regioselectively at the terminal C4–C5, while its
In the next step the ester group of the CM product 3 was
transformed into the corresponding aldehyde 66b,7 by a known
reduction–oxidation procedure (DIBAL-H, toluene, 0 °C, 2 h, then
MnO2, CH2Cl2, 16 h, rt.,).8 The aldehyde was subjected to Wittig
methylenation (MePPh3Br, NaH, DMSO)9 affording the all-E-triene
7. The consecutive CM reaction of the triene with ethyl (2E,4E/Z)-3-
methylhexa-2,4-dienoate (2) provided the etretinate analogue 810
in 90% yield under optimized conditions (10 mol % of the 2nd
generation Grubbs–Hoveyda catalyst, slow addition of 3 equiv of
the diene partner at rt., 16 h) with high stereoselectivity
(11E/11Z = 35/1). The aromatic retinoid 8 was synthesized in 55%
total yield from cinnamaldehyde (Scheme 3). Using the same
strategy, its analogue with a substituted phenyl ring (12) was syn-
thesized from 5-but-10-enyl-1,2,3-trimethoxybenzene (9)11
(Scheme 4). As in the previous case, both CM steps were efficient
and highly E-stereoselective. Both synthesized etretinate
analogues 8 and 12 were screened against various tumor cells
R
Mes
Cl
Cl
N
N
Mes
Ph
COOEt
(3 eq)
+
Ru
PCy3
2
1a (R = H)
1b (R =CHO)
2nd generation catalyst (10 mol%),
50 oC, toluene
Grubbs 2nd generation catalyst
(Mes = 2,4,6-trimethylphenyl, Cy = cyclohexyl
Ph = phenyl)
Mes
Cl
N
N Mes
COOEt
COOEt
+
+
R
Ru
O
Cl
5a (R = H)
5b (R = CHO)
4
3
from 1b, Grubbs catalyst: 95%, all E;
from 1b, Grubbs-Hoveyda catalyst: 92%, all E;
from 1a, Grubbs catalyst: 56%, all E
Grubbs-Hoveyda
2
nd generation catalyst
Scheme 2. CM reaction between styrene or cinnamaldehyde and ethyl (2E,4E/Z)-3-methylhexa-2,4-dienoate.
COOEt
CHO
1. DIBAL-H, toluene, 0 oC (95%)
2. MnO2, CH2Cl2, r.t. (82%)
3
6
(78%)
COOEt
(3 eq)
COOEt
CH3PPh3Br
NaH, DMSO
Grubbs-Hoveyda 2nd generation
(10 mol%), r.t., toluene
8 (90%;11E/11Z =35/1)
7 (82%)
Scheme 3. Synthesis of the phenyl analogue of etretinate.

5432
J. Maj et al. / Tetrahedron Letters 53 (2012) 5430–5433
COOEt
H3CO
H3CO
C2H5
1. DIBAL-H, toluene, 0 oC (70%)
COOEt
H3CO
H3CO
(3 eq)
Grubbs 2nd generation
(10 mol%), 50 oC, toluene
2. MnO2, CH2Cl2, r.t. (95%)
3. CH3PPh3Br, NaH, DMSO (81%)
OCH3
OCH3
9
10 (64%)
H3CO
H3CO
COOEt
H3CO
H3CO
COOEt
(3 eq)
Grubbs 2nd generation
(10 mol%), r.t., toluene
OCH3
OCH3
11 (54%)
12 (74%;11E/11Z =10/1)
Scheme 4. Synthesis of an etretinate trimethoxyphenyl analogue.
Table 1
was used for the further study of CM reactions with dienes. How-
ever, these attempted CM reactions with ethyl 3-methylhexa-2,4-
dienoate (2) failed, as in the previous experiments with b-ionone
or b-ionol. In contrast, the CM reaction with ethyl sorbate
[(2E,4E)-hexa-2,4-dienoate, (14)] afforded a difficult to separate
mixture of ester products, 15 and 16, albeit in a very low yield.
The mixture consisted of products resulting from the CM cleavage
of sorbate either at the C2–C3 or C4–C5 double bond in the ratio
1:3 (Scheme 5). Due to the lack of selectivity and low conversion,
the synthetic strategy had to be changed.
Thus the C15 + C5 route for retinoid synthesis using CM reactions
was explored. The C15-synthon (Scheme 6) was prepared from b-
ionone by known methods. HWE reaction of b-ionone with diethyl
cyanomethylphosphonate in the presence of NaH led to a mixture
of unsaturated 2E,4E and 2Z,4E nitriles 17 in the ratio 1.7:1.3b This
mixture was reduced with DIBAL-H to give the corresponding alde-
hydes 18.13 After separation of the isomers, each was subjected to
Wittig methylenation9 affording two C15-synthons (all E-tetraene
19a and 9Z-tetraene 19b) that were next coupled to ethyl (2E,4E/
Z)-3-methylhexa-2,4-dienoate (C5-synthon) using the CM
approach. The coupling of all E-tetraene 19a with ethyl 3-methyl-
hexa-2,4-dienoate promoted by the 2nd generation Grubbs–
Hoveyda catalyst under optimized conditions provided ethyl all
E-retinoate 20a3b,3d,14 in 88% yield and with high diastereoselectiv-
ity (11E/11Z = 33:1; Scheme 7). Use of the Grubbs’ catalyst instead
resulted in a lower product yield (79%) and reaction selectivity
(11E/11Z = 10:1). The CM reaction of the isomeric 9Z-tetraene
Cytotoxic activity of the etretinate analogues
Analogue
Cell line IC50 (lM)
CEM
MCF7
HeLa
BJ
8
12
>50
27.2 0.7
>50
>50
>50
14.6 3.5
34.2 6.2
17.3 0.3
(Table 1). The unsubstituted aromatic retinoid 8 proved inactive
against three malicious cancer cell lines. In contrast, the trimeth-
oxy analogue 12 showed moderate antiproliferative activity. The
cytotoxicity (IC50) value of this compound varied between 17.3–
34.2 lM depending on the cancer cell line. However, tests have
shown that it was also toxic (IC50 = 14.6
lM) toward normal
human fibroblasts (BJ).
Further study concerned the synthesis of ethyl retinoate from b-
ionone by a similar protocol. Despite testing various catalysts, dif-
ferent cross partners and reaction conditions, the CM reactions of
b-ionone failed. The double bond of b-ionone was found to be resis-
tant to metathetic transformations due to electronic and steric fac-
tors. Therefore the electron density of the double bond was
changed by the reduction of b-ionone to b-ionol. However, also
in the case of this allylic alcohol and its acetate, no CM reactions
occurred. These results may suggest that the double bond in these
systems is too hindered to form ruthenacyclobutane metathesis
intermediates. As CM reactions of a b-ionone methylene derivative
13 with various alkenes have been recently described,12 this triene
COOEt
2 (3 eq)
2nd generation catalyst
(10 mol%), 50 oC, toluene
no reaction
COOEt
COOEt
COOEt
14 (3 eq)
+
13
2nd generation catalyst
(10 mol%), 50 oC, toluene
16 (11E/11Z = 1.1/1)
15 (7E/7Z = 4.4/1)
conversion ~5%
Scheme 5. CM reactions of b-ionone methylene derivative 13 with dienes.
CN
CHO
Wittig
O
NaH
CNCH2P(O)(OEt)2
DIBAL-H
19a (9E)
19b (9Z)
β-ionone
18 (9E/9Z = 1.7/1)
17
Scheme 6. Synthesis of C15 synthons (all E- and 9Z-tetraenes).

J. Maj et al. / Tetrahedron Letters 53 (2012) 5430–5433
5433
COOEt
(3 eq)
COOEt
20a (88%; 11E/11Z = 33/1)
Grubbs-Hoveyda 2nd generation
(10 mol%), r.t., toluene
19a
19b
COOEt
(3 eq)
Grubbs-Hoveyda 2nd generation
(10 mol%), r.t., toluene
20b (37%)
COOEt
Scheme 7. Synthesis of ethyl all-E-retinoate and ethyl 9Z-retinoate via the C15 + C5 route.
(e) Frencz, R. R.; Holzer, P.; Leuenberger, M. G.; Woggon, W.-D. Angew. Chem.,
Int. Ed. 2000, 39, 1267; (f) Otero, P. M.; Torrado, A.; Pazos, Y.; Sussman, F.; de
Lera, A. R. J. Org. Chem. 2000, 65, 5917; (g) Lopez, S.; Montenegro, J.; Saa, C. J.
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19b with the same diene promoted by the Grubbs–Hoveyda cata-
lyst afforded ethyl 9Z-retinoate 20b,15 diastereoselectively, in 37%
yield (Scheme 7).
In summary, we have developed a novel method for the synthe-
sis of aromatic retinoids from styrene derivatives which employs
alternately, dienoate CM and Wittig reactions to build polyene
chains. Using this strategy, several retinoids were obtained in high
yields and with satisfactory stereoselectivities. The CM approach
was successfully applied to the synthesis of ethyl all-E-retinoate
and ethyl 9Z-retinoate via the C15 + C5 route.
4. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (b) Deiters, A.; Martin, S. F. Chem.
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(b) Wojtkielewicz, A.; Maj, J.; Dzieszkowska, A.; Morzycki, J. W. Tetrahedron
2011, 67, 6868.
6. The spectral data of this compound agreed with literature values: (a)
Mannathan, S.; Cheng, C.-H. Chem. Comunn. 2010, 46, 1923; (b) Wang, X.-F.;
Koyama, Y.; Nagae, H.; Yamano, Y.; Ito, M.; Wada, Y. Chem. Phys. Lett. 2006, 420,
309.
7. The spectral data of this compound agreed with literature values: Kann, N.;
Rein, T.; Akermark, B.; Helquist, P. J. Org. Chem. 1990, 55, 5312.
8. Moses, J. E.; Baldwin, J. E.; Bruckner, S.; Eade, S.; Adlington, R. M. Org. Biomol.
Chem. 2003, 1, 3670.
Acknowledgements
We thank Dr. Alina Dubis for providing 5-but-10-enyl-1,2,3-tri-
methoxybenzene and Professor Miroslav Strnad’s group from the
´
Palacky University (Olomouc, Czech Republic) for biological tests.
Financial support from the Ministry of Science and Higher Educa-
tion (Grant No. N N204 154936) and the National Science Centre
(DEC 2011/02/A/ST5/00459) is gratefully acknowledged.
9. Pohnert, G.; Boland, W. Tetrahedron 1997, 53, 13681.
10. The spectral data of this compound agreed with literature values: Trost, B. M.;
Fortunak, J. M. D. Tetrahedron Lett. 1981, 22, 3459.
Supplementary data
Supplementary data (experimental data and 1H and 13C NMR
spectra) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.07.122.
11. (a) Poplawski, J.; Lozowicka, B.; Dubis, A. T.; Lachowska, B.; Witkowski, S.;
Siluk, D.; Petrusewicz, J.; Kaliszan, R.; Cybulski, J.; Strzalkowska, M.;
Chilmonczyk, Z. J. Med. Chem. 2000, 43, 3671; (b) Grabowski, S. J.; Pfitzner,
A.; Zabel, M.; Dubis, A. T.; Palusiak, M. J. Phys. Chem. B 2004, 108, 1831.
12. Lopez-Sanchez, C.; Hernandez-Cervantes, C.; Rosales, A.; Alvarez-Corrol, M.;
Munoz-Dorado, M.; Rodriguez-Garcia, I. Tetrahedron 2009, 65, 9542.
13. The spectral data of this compound agreed with the literature values: (a)
Dugger, R. W.; Heathcock, C. H. Synth. Commun. 1980, 10, 509; (b) Becker, R. S.;
Berger, S.; Dalling, D. K. J. Am. Chem. Soc. 1974, 96, 700; (c) Boehm, M. F.;
McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.; White, S. K.; Herbert, J.; Winn,
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14. The spectral data obtained for this compound were consistent with those given
in the literature: (a) Domingez, B.; Iglesisas, B.; De Lera, A. R. Tetrahedron 1999,
55, 15071; (b) Andriamialisoa, Z.; Valla, A.; Zennache, S.; Giraud, M.; Potier, P.
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