Cross metathesis of β-carotene with electron-deficient dienes. A direct route to retinoids

Article abstract of DOI:10.1016/j.tetlet.2009.06.032

Cross metathesis (CM) reactions of β-carotene and alkenes occur regioselectively in the presence of the Hoveyda second generation catalyst. Scission of the C15-C15′ and C11-C12 bonds of β-carotene in all CM reactions predominates. The reaction with ethyl

Full text of DOI:10.1016/j.tetlet.2009.06.032

Tetrahedron Letters 50 (2009) 4734–4737
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Cross metathesis of b-carotene with electron-deficient dienes.
A direct route to retinoids
*
Agnieszka Wojtkielewicz , Jadwiga Maj, Jacek W. 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:
Cross metathesis (CM) reactions of b-carotene and alkenes occur regioselectively in the presence of the
Hoveyda second generation catalyst. Scission of the C15–C150 and C11–C12 bonds of b-carotene in all
CM reactions predominates. The reaction with ethyl (2E,4E/Z)-3-methylhexa-2,4-dienoate is both regio-
and diastereoselective, and affords ethyl all-trans-retinoate as the major product, if suitable CM condi-
tions are applied.
Received 16 April 2009
Revised 28 May 2009
Accepted 5 June 2009
Available online 11 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cross metathesis
Retinoids
b-Carotene
Polyenes
Retinol (vitamin A1) along with its metabolites such as 11-cis-
retinal, all-trans-retinoic acid and 9-cis-retinoic acid are involved
in regulating many biological processes including vision, reproduc-
tion, cell differentiation and growth.1 Besides being essential to
normal cell function, all-trans-retinoic acid and its natural and syn-
thetic analogues show antitumour activity.2 One of them, N-(4-
hydroxyphenyl)retinamide (fenretinide), is currently undergoing
clinical trials for treatment of breast, bladder, renal and neuroblas-
toma malignancies (Fig. 1).3
Despite the long history of these compounds, there is still a
need for effective and fast methods for the preparation of retinoids
for biological and structural studies.4 Retrosynthetic analysis re-
vealed that the synthesis of all-trans-retinoids could be achieved
in one simple step by regioselective cross metathesis of b-carotene
with an appropriate olefinic partner. Olefin metathesis5 provides a
useful synthetic tool for such transformations, since this method
enables the formation of new carbon–carbon bonds under mild
conditions and in relatively short times, which is especially impor-
tant for unstable compounds such as b-carotene and retinoids.
CM reactions of b-carotene, a symmetric polyene containing
eleven conjugated double bonds, may produce a complex mixture
of products. However, our preliminary studies on b-carotene
ethenolysis proved that only three double bonds of the polyene
system are cleaved under CM conditions, with scission of the
C11–C12 double bond predominating (Scheme 1).6 Assuming the
same regioselectivity for CM between b-carotene and other olefins,
the synthesis of retinoids would require suitably functionalized
1,3-diene cross partners showing preference for terminal double
bond cleavage in CM reactions.
Ethyl (2E,4E)-3-methylhexa-2,4-dienoate7 was chosen as a suit-
able substrate for the b-carotene CM reaction. The reaction was
carried out with the second generation Hoveyda catalyst (Hoveyda
II, 15 mol %) in toluene at room temperature for 24 h. The reaction
appeared to be relatively clean, but unexpectedly, ester 2 (Scheme
2) was formed as the major product by cleavage of the b-carotene
C15–C150 double bond (38%).8 The all-trans isomer 2 predominated
(>92%) as was determined by 1H NMR analysis. The desired ethyl
retinoate (1) was obtained in 9% yield as the all-trans isomer
(ꢀ89%).
The main reaction products were accompanied by a number of
by-products, such as tetraene 3 (3%; a mixture of E/Z isomers in the
ratio 3:1), triene 4 (5%; a mixture of E/Z isomers in the ratio 2:1)
and ester 5 (less than 1%, a mixture of isomers with one of them,
probably the all-trans, predominating). The amounts of these by-
products varied with time. The hydrocarbon products 3 and 4 were
formed by cleavage of the C11–C12 or C9–C10 double bond,
respectively. Compound 5 was apparently formed by double scis-
sion of b-carotene. The products obtained were detected and ana-
lyzed by GC–MS method,9 esters 1, 2 and 5 were additionally
isolated by preparative HPLC or column chromatography. Increas-
ing the reaction time resulted in a decrease in yield of ester 2 in fa-
vour of ethyl retinoate (1). Most likely, the initially formed
products (including 2) underwent consecutive CM reactions pro-
ducing 1 (this was proved in a separate experiment). After 96 h,
a 31% yield of the desired retinoate 1 (isolated by HPLC) was
achieved, whereas the yield of ester 2 decreased to 15%. The influ-
ence of the reaction time on the product distribution is shown in
* 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 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.032

A. Wojtkielewicz et al. / Tetrahedron Letters 50 (2009) 4734–4737
4735
COOH
-retinoic acid
OH
all-trans
vitamin A1
OH
O
N
H
fenretinide
Figure 1. Structures of vitamin A1, all-trans-retinoic acid and fenretinide as examples of natural or synthetic retinoids.
11
9
15
Mes N N Mes
12
10
15'
Cl
Ru
Cl
O
β-carotene
ethene
Hoveyda II catalyst (15 mol%),
toluene, rt, 48 h
Hoveyda II catalyst
+
+
6%
8%
<1%
Scheme 1. Ethenolysis of b-carotene.
11
15
9
12
10
15'
β-carotene
Hoveyda II catalyst (15 mol%),
toluene, rt, 96 h, Ar
COOEt
COOEt
COOEt
COOEt
+
1 (31%)
2 (15%)
+
+
+
3 (2%)
5 (<1%)
4 (11%)
Scheme 2. CM of b-carotene with (2E,4E)-3-methylhexa-2,4-dienoate.
Table 1. The optimal reaction time was 96 h; at least 80% of b-car-
otene was consumed in four days. Further extension of the reaction
time led to a diminished yield of ethyl retinoate (1), probably due
to secondary CM reactions of this compound.
Table 1
Influence of the reaction time on the product distribution of the CM between b-
carotene and ethyl (2E,4E)-3-methylhexa-2,4-dienoate (4 equiv) in the presence of
the second generation Hoveyda catalyst (15 mol %) in dry toluene at room
temperature
Similar results were obtained when a stereoisomeric mixture of
ethyl 3-methylhexa-2,4-dienoate (2E,4Z and 2E,4E in the ratio 5:3)
was used instead of a single stereoisomer (2E,4E) as the cross part-
ner for metathesis reactions. This is not surprising since blank
experiments revealed that the mixture of stereoisomeric esters
undergoes fast isomerization to the more stable (2E,4E)-3-methyl-
Time (h)
24
48
72
96
120
Ester 1 yield (%)*
Ester 2 yield (%)*
9
38
13
17
23
12
31a
15a
21
10
*
Yields obtained by quantitative HPLC analysis.
Isolated yield following HPLC.
a

4736
A. Wojtkielewicz et al. / Tetrahedron Letters 50 (2009) 4734–4737
11
9
15
12
10
15'
β-carotene
Hoveyda II catalyst (15 mol%),
toluene, rt, 72 h, Ar
COOEt
COOEt
COOEt
+
+
6 (32%)
7 (5%)
COOEt
+
+
8 (5%)
3 (3%)
4 (5%)
Scheme 3. CM of b-carotene with ethyl sorbate.
Table 2
Influence of the reaction conditions on the CM of b-carotene and ethyl (2E,4E/Z)-3-methylhexa-2,4-dienoate, analyzed after 72 h
Conditions
Yield* (%)
Ethyl retinoate (1)
b-Carotene concentration (M)
Catalyst
Cross partner (equiv)
Solvent
Ester 2
4.9 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
9.7 ꢁ 10ꢂ2
Hoveyda II (15 mol %)
Hoveyda II (15 mol %)
Hoveyda II (7.5 mol %)
Hoveyda II (4 mol %)
Hoveyda II (15 mol %)
Hoveyda II (15 mol %)
Grubbs II (15 mol %)
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
2 equiv
4 equiv
4 equiv
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Toluene
Toluene
Toluene
14
23
7
1
1
12
3
<1
34
12
18
8
4
9
11
5
Modified Hoveyda II (15 mol %)
*
Yields obtained by quantitative HPLC analysis.
hexa-2,4-dienoate stereoisomer under CM conditions. It should be
noted that during CM reactions with dienic esters highly regiose-
A dramatic change was observed when toluene was replaced by
dichloromethane; conversion was much lower and the yield of
retinoate 1 amounted to only 1%. A drop in yield was also noticed
when the catalyst loading or amount of the cross partner was de-
creased. These results are summarized in Table 2.
lective cleavage of the c–d double bond occurred, as was expected
from earlier studies on CM of substituted 1,3-dienes.10 Only a trace
amount of a CM product originating from scission of the C11–C12
bond in b-carotene and the
a
–b bond of the dienic ester was
This is the first report on CM reactions of b-carotene with elec-
tron-deficient dienes. In spite of the fact that there are many alter-
native reaction sites in the polyene system a reasonable yield of
the desired product can be achieved by appropriate selection of
the CM conditions. Although there are two double bonds in b-car-
otene (C15–C150 and C11–C12), which are preferably cleaved dur-
ing CM reactions, the reaction course can be controlled to some
extent. Short reaction times, low catalyst loading, a less active cat-
alyst or lower concentration of reagents favour formation of ester 2
as the kinetic product. This product may react further with an ex-
cess of a dienic ester in consecutive CM reactions. Therefore, more
forcing conditions are advantageous for formation of retinoate 1.
However, compound 1 cannot be considered as a thermodynamic
product, since CM processes may progress even further, for exam-
ple, with scission of the C9–C10 double bond. Nevertheless, the
studies performed allowed determination of the optimal condi-
tions for preparation of ethyl all-trans-retinoate 1. The methodol-
ogy developed will be applied to the synthesis of other retinoids,
including fenretinide and other retinoic acid derivatives.
detected by GC–MS analysis. CM reactions of b-carotene with ethyl
sorbate [ethyl (2E,4E)-hexa-2,4-dienoate], carried out under
the same conditions, showed opposite regioselectivity with
respect to the dienic partner (Scheme 3). In this case, CM products
formed by cleavage of the C11–C12 double bond of b-carotene and
the
c–d (compound 7) or a–b (compound 6) double bond of
sorbate were isolated from the reaction mixture (reaction time
72 h) in 5% or 32% yields. In addition to these two products, a
hexadienic ester 8 was also formed in 5% yield by cleavage of the
C15–C150 double bond of b-carotene and the
a–b double bond of
ethyl sorbate. This example emphasizes the importance of the
detailed structure of the dienic partner for obtaining regioselectivity
in the reaction.
Other commercially available second generation catalysts were
also tested for their ability to promote the CM reactions of b-caro-
tene. The second generation Grubbs’ catalyst (Grubbs II) proved to
be much less efficient than the Hoveyda II catalyst. The yield of
retinoate 1 decreased from 23% to 3%, while the yield of ester 2 re-
mained roughly the same. The recently introduced modified Hov-
eyda catalyst with toluyl groups in place of mesityl substituents
on the NHC ligand was even less active. Only a 5% yield of ester
2 and below 1% of retinoate 1 were achieved under similar condi-
tions. The solvent effect on the reaction course was also examined.
Acknowledgements
We thank Mr. Lech Szczepaniak for skilful technical assistance
with GC–MS analysis. Financial support from the Ministry of Sci-

A. Wojtkielewicz et al. / Tetrahedron Letters 50 (2009) 4734–4737
4737
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Supplementary data
Supplementary data associated with this article can be found, in
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