Ruthenium-Catalyzed Cross-Metathesis of Allyl Acetate and Styrenes: A Practical Approach to the Synthesis of Tripolinolate A and Its Analogs

Article abstract of DOI:10.1002/ejoc.201700132

The scope of the Ru-catalyzed cross-metathesis of allyl acetates and styrenes was explored. A variety of electronically and structurally divergent styrenes were tolerated, and the resultant products were obtained in reasonable yields. The reported method was utilized in the synthesis of inhibitors of the proliferation of glioma and colorectal cancer cells, tripolinolate A and its diacetate analog.

Full text of DOI:10.1002/ejoc.201700132

A Journal of
Accepted Article
Title: Ru-catalyzed Cross-Metathesis of Allyl Acetate and Styrenes: a
Practical Approach to Synthesis of Tripolinolate A and Its Analogs
Authors: Martin Kotora, Nikola Topolovcan, and Yasuhiro Araki
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700132
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10.1002/ejoc.201700132
European Journal of Organic Chemistry
COMMUNICATION
Ru-catalyzed Cross-Metathesis of Allyl Acetate and Styrenes: a
Practical Approach to Synthesis of Tripolinolate A and Its
Analogs
Yasuhiro Araki,[a,b] Nikola Topolovčan,[a] and Martin Kotora*[a]
Abstract: The scope of Ru-catalyzed cross-metathesis of allyl
acetate and styrenes has been explored. A variety of electronically
and structurally divergent styrenes were tolerated and resultant
products were obtained in reasonable yields. The reported method
was utilized in the synthesis of inhibitors of proliferation of glioma
and colorectal cancer cells, tripolinolate A and its diacetate analog.
and styrene (and derivatives thereof) have not attracted much
attention. As a substitute to allyl acetate, electron-rich (Z)-but-2-
ene-1,4-diacetate (it can be formally considered as a dimer of
allyl acetate) has been commonly used as the coupling partner
in CM reactions. As a typical example may serve G II catalyzed
CM of cis-but-2-ene-1,4-diacetate with fluorinated styrenes,
reported by Grubbs and Chatterjee in their seminal study on
selectivity in CM reactions.[8] Another example is a reaction of
(Z)-but-2-ene-1,4-diacetate with styrene catalyzed by
a
Introduction
pyrimidine-modified NHC-ruthenium complex, which gave
preferentially E-cinnamyl acetate in a high 92% isolated yield.[9]
Furthermore, (Z)-but-2-ene-1,4-diacetate and styrene were
Olefin cross metathesis (CM) has become one of the most
synthetically useful transition-metal-catalyzed carbon-carbon
bond forming reaction and has had a large impact on modern
organic chemistry.[1] Its practicality is most evident in the
preparation of highly substituted and functionalized olefins from
simple alkene precursors and by that it can serve as an
alternative to other transition-metal catalyzed cross-coupling
transformations such as Suzuki or Stille reaction. Furthermore,
alkene CM have been used as the key step in the synthesis of
numerous compounds which exhibits biological activity.[2]
Besides highly active, but unstable Schrock type Mo-carbene
complexes,[3] the most commonly used catalysts for the olefin
metathesis are commercially available Ru-carbene complexes
tested
in
cross
metathesis
reaction
catalyzed
by
nitrochromenylmethylidene-containing ruthenium complex to test
the E/Z stereoselectivity. It yielded cinnamyl acetate in 76%
combined yield as a mixture of E/Z isomers in 34:1 ratio.[10]
A
lone example of CM of allyl benzoate with styrene catalyzed by
a cationic Ru-carbyne complex was reported by Wang and
coworkers.[11] Although it provided the desired product – E-
cinnamyl benzoate - in a nice yield of 95%, a drawback was the
use of non-commercial catalyst. Besides the aforementioned
examples, systematic exploration of cross-metathesis of allyl
acetate with styrenes have not been reported to the best of our
knowledge.
1st
2nd
such as Grubbs
generation (G I)[4], Grubbs
generation (G
II)[5], Hoveyda-Grubbs
free Hoveyda-Grubbs
1).
generation (H-G I)[6], and phosphine-
generation (H-G II)[7] catalysts (Figure
1st
Our interest in a study of cross-metathesis between allyl
esters and substituted styrenes catalyzed by commercially
available Ru-carbene complexes stemmed from the fact that it
could provide an easy access to tripolinolate A 1 and its acetate
analog 2 (Figure 2), and, eventually, to its other congeners.
2nd
Mes
N
N Mes
PCy3
Mes
N
N Mes
Cl
PCy3
Cl
Ru
Cl
Cl
Ru
O
O
Cl
Ru
Ru
Cl
Cl
Cl
iPr
Ph
Ph
O
Me
O
O
Me
O
O
PCy3
O
iPr
PCy3
O
Me
O
Me
G I
G II
H-G I
H-G II
OMe
Me
OMe
1
2
Figure 1. Commonly used catalysts for olefin metathesis
Figure 2. Structures of tripolinolate A 1 and 4,9-diacetyl-coniferol 2.
Although a large number of structurally defined olefins has
been employed in various combinations,[8] CM of allyl acetate
Compound 1 is natural substance isolated from the whole
plants of Tripolium vulgare Nees and together with its synthetic
analog 2 possess inhibitory activity on proliferation of glioma
cells.[12] A retrosynthetic analysis of 1 is outlined in Scheme 1. It
was envisioned that tripolinolate A 1 could be assembled by
esterification of a substituted acetyl cinnamate, which in turn
could be obtained by CM of allyl acetate and 4-hydroxy-3-
methoxystyrene. A similar approach was envisioned also for
synthesis of 2.
[a]
Y. Araki, N. Topolovčan, Prof. Dr. Martin Kotora
Department of Organic Chemistry, Faculty of Science,
Charles University
Hlavova 8, 128 43 Praha 2, Czech Republic
E-mail: kotora@natur.cuni.cz
http://orgchem.natur.cuni.cz/kotora/
Y. Araki
[b]
A visiting student from Okayama University, Okayama, Japan
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700132
European Journal of Organic Chemistry
COMMUNICATION
O
corresponding cross-metathesis products 5ab and 5ac in
moderate yields of 56 and 45% isolated yields, respectively.
Esterification
Me
O
O
O
Me
OMe
CM
Me
O
Table 1. CM of 3a and 4a under various conditions[a]
O
Me
O
+
OH
Me
O
OH
OMe
OMe
T (°C) Yield[b]
Scheme 1. Retrosynthetic analysis of tripolinolate A
Entry
3a 4a Catalyst
Load
Time Solvent
(mol-%) (h)
(%)
1
1
1
1
1
1
1
1
1
1
1
1
1
3
2
1
1
1
1
1
1
1
3
3
3
3
3
3
3
3
3
3
1
2
1
1
3
3
3
3
3
3
3
G II
2.5
10
2.5
10
10
5
12
12
12
12
12
12
12
12
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
90
90
90
90
90
90
90
90
90
90
90
90
90
90
65
68
6
Results and Discussion
2
G II
Herein, a study to extend further applicability of CM reaction of
allyl acetate with more structurally and electronically divergent
styrenes 4 was undertaken. In order to assess the best reaction
conditions, CM of allyl acetate 3a and styrene 4a as model
substrates was carried out in the presence of Ru–based
catalysts. Initially, the reaction was carried out with 3a and 4a in
1:3 ratio using G II catalyst (2.5 mol-%) in toluene at 90 °C for 12
hours. It provided cinnamyl acetate in 65%, while increasing the
catalyst load to 10 mol-% did not have the significant impact and
5aa was formed in a comparable yield of 68% (Entries 1 and 2).
Employing H-G I catalyst in the 2.5 and 10 mol-% loads
decreased the yield of 5aa to 6 and 30%, respectively (Entries 3
and 4). A higher yield of the product (75%) was obtained by
using 10 mol-% of H-G II catalyst; however, decreasing the
catalyst load to 5, 2.5, and 1 mol-% was again followed by
decrease of 5aa yields (Entries 5-8). Gratifyingly, higher yields of
5aa were obtained already after 3 and 6 hours (Entries 9 and
10). Changing the molar ratio of 3a and 4a in favor of the former
resulted in diminished yields of 5aa (Entries 11-14), and it is
evident that styrene needs to be used in excess. Since it was
shown that perfluorinated solvents have a positive effect on the
course of the CM reactions,[13] the reaction was run in
octafluorotoluene in the presence of 2.5 and 10 mol-% of G II
catalysts providing 5aa in 76 and 75% yields, respectively
(Entries 15 and 16). Carrying the same reaction with H-G II
catalyst gave 5aa in satisfactory yield of 75% after 3 hours and
92% yields after 12 hours (Entries 17 and 18). The reaction
catalyzed by G I resulted in the formation of 5aa in only 30%
yield (Entry 19). Further screening of the CM reaction in
dichloromethane showed superiority of G II catalyst (77% yield)
over H-G II catalyst (63% yield) (Entries 20 and 21).
3
H-G I
H-G I
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
G II
4
30
75
42
39
34
75
65
48
56
55
46
76
75
75
92
30
77
63
5
6
7
2.5
1
8
9
10
10
10
10
10
10
2.5
10
10
10
10
10
10
10
11
12
13
14
15
16
17
18
19
20
21
6
12
12
12
12
12
12
3
C6F5CF3 90
C6F5CF3 90
C6F5CF3 90
C6F5CF3 90
C6F5CF3 90
G II
H-G II
H-G II
G I
12
3
G II
12
12
DCM
DCM
40
40
H-G II
In summary, the obtained results indicate that the best
reaction conditions for the CM of 3a with 4a are met when the
reaction is catalyzed by H-G II catalyst in octafluorotoluene for
12 hours (Entry 18). From point of view of cost-effectiveness, the
reaction conditions using toluene as the solvent and 2.5 mol-%
load of the G-II catalysts are also worth of mentioning.
[a] Reaction conditions: 3a (0.5 mmol), 4a (1.5 mmol), solvent 1.5 mL, unless
otherwise noted. [b] Determined by 1H NMR analysis of the crude mixture,
using mesitylene as an internal standard.
In a similar fashion proceeded also the reactions with
styrenes possessing electron-withdrawing groups such as 4-
acetoxystyrene 4d, 4-bromostyrene 4e, 4-chlorostyrene 4f, 4-
fluorostyrene 4g, 4-trifluoromethyl styrene 4h, and 4-
cyanostyrene 4i providing the corresponding cinnamyl acetates
in the range of 40-56% (isolated yields). Attempt to carry out the
reaction with 4-nitrostyrene 4j resulted in the formation of a
complex reaction mixture in which the expected product was not
With the optimized reaction conditions on hand, we explored
the scope of cross-metathesis of allyl esters 3 with respect to
substituted styrenes 4 bearing various functional groups (Table
2). Reactions of styrenes bearing electron-donating methyl and
methoxy groups in the para position of 4b and 4c gave the
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10.1002/ejoc.201700132
European Journal of Organic Chemistry
COMMUNICATION
detected. Then our attention turned to styrenes with a higher
degree of substitution. CM of allyl acetate 3a with 3,4
dimethoxystyrene 4k and 3,4,5-trifluorostyrene 4l furnished the
corresponding products 5ak and 5al in 50% isolated yields. We
then extended our protocol to the reaction with 2-methoxy-4-
vinylphenol 4m. Although 1H NMR analysis indicated that the
desired product 5am was formed in 86% yield, it was isolated in
20% yield only. A rather big discrepancy between the conversion
and the isolated yield could be attributed to the problems
encountered during the isolation of 5am from side products,
namely homodimerization product of 2-methoxy-4-vinylphenol. A
similar phenomenon was observed also in other cases, see
rather big difference in 1H NMR and isolated yields for 5ab, 5ad,
5ah, 5ai, and 5ak. CM with TBDMS protected vinylphenol 4n
gave 5an in 45% isolated yield. Its structure was unequivocally
confirmed by a single crystal X-ray analysis (Figure 3). Similarly,
from NOE experiments of 5ag (see Supporting Information) we
confirmed its E-selectivity. It should be noted that in all cases
were detected E-isomers only.
Table 2. The scope of cross metathesis reaction of 3 and 4.
O
O
H-G II (10 mol%)
R2
+
R1
O
R2
R1
O
octafluorotoluene
90 °C, 12 h
3
4
5
O
O
O
O
O
Me
Me
O
Me
Me
O
Me
O
Me
O
Me
O
Me
F
OMe
CF3
OAc
Br
Cl
5ab, 56% (77%)a
5ac, 45% (70%)
5ad, 40% (68%)
5ae, 55% (78%)
5af, 56% (76%)
O
O
O
O
O
O
Me
O
Me
O
O
Me
O
NO2
OMe
CN
5ag
, 43% (68%)
5ah
5ai
, 43% (66%)
5aj
, -
5ak
, 41% (73%)
,50% (90%)
OMe
O
O
O
O
O
F
F
Me
O
Me
O
Me
O
tBu
O
Me
O
OH
OTBS
Me
5ca
F
OMe
, 20% (86%)
OMe
, 45%
5al
5am
5an
5ba
, 63%
, 50% (54%)
, -
O
O
5da
, 48% (75%)
[a] 1H NMR yields are in parentheses
homometathesis) was isolated from the reaction mixture. CM of
allyl benzoate 3d and styrene 4a again proceeded uneventfully
furnishing cinnamyl benzoate 5da in 48% isolated yield. With
5am on hand we proceeded with synthesis of tripolinolate A 1
(Scheme 2). Its esterification with (S)-(+)-2-methylbutyric acid
yielded the desired natural tripolinolate A 1 in 36% isolated yield.
CM of allyl acetate 3a with 4o under standard conditions gave
diacetyl-coniferol 2 in 38% isolated yield (40% 1H NMR yield).
Figure 3. PLATON drawing of 5an showing displacement ellipsoids on the
50% probability level.
In the next stage, CM of other allyl acetate derivatives 3b-3d
with styrene 4a was tested. Thus allyl pivalate 3b reacted with
4a uneventfully giving rise to cinnamyl pivalate 5ba in good yield
of 63%. On the other hand, the reaction with a more sterically
hindered double bond in 2-methylallyl acetate 3c did not give us
the desired product 5ca and only stilbene (product of styrene
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COMMUNICATION
O
Keywords: Cross-metathesis • Allyl acetate • Styrenes •
Cinnamyl esters
(S)-(+)-2-methylbutyric acid
(2.5 eq), SOCl2 (3.5 eq)
Me
O
O
5am
pyridine (1.2 eq)
50 °C, 2 h, CH2Cl2
O
Me
[1]
a) J. S. Connon, S. Blechert, Angew. Chem. Int. Ed. 2003, 42, 1900–
OMe
Me
tripolinolate A 1, 36%
1923. b) C. Dearaedt; M. d’Halluin, M. Astruc, Eur. J. Inorg. Chem.
2013, 4881–4908. c) V. Paradiso, C. Costabile, F. Grisi, Molecules
2016, 21, 117-137.
O
H-G II (10 mol%)
Me
O
[2]
a) K. C. Nicolau, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005,
44, 4490–4527. b) D. L. Hughes, Org. Process Res. Dev. 2016, 20,
1008−1015.
3a +
OAc
90 °C, 12 h
octafluorotoluene
OAc
OMe
4o
OMe
2
, 38%
[3]
[4]
R. R. Schrock, Acc. Chem. Res. 1986, 19, 342-348.
a) P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew. Chem.
Int. Ed. 1995, 34, 2039-2041. b) P. Schwab, R. H. Grubbs, J. W. Ziller,
J. Am. Chem. Soc. 1996, 118, 100-110.
Scheme 2. Synthesis of tripolinolate A 1 and its analog 2
[5]
[6]
[7]
M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953-
956.
Conclusions
J. S. Kingsbury, J. P. A. Harrity, P. J. Jr. Bonitatebus, A. H. Hoveyda,
J. Am. Chem. Soc. 1999, 121, 791-799.
In summary, we have explored the Ru-catalyzed cross-
metathesis reaction between the allyl esters and various
substituted styrenes. The cross-metathesis was efficiently
catalyzed by Hoveyda-Grubbs second-generation catalyst
furnishing the corresponding cinnamyl esters in moderate yields
with the exclusive E-selectivity. The developed protocol was
applied to the synthesis of inhibitors of proliferation of glioma
and colorectal cancer cells tripolinolate A and its diacetate
analog.
a) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168-8179. b) S. Gessler, S. Randl, S.
Blechert, Tetrahedron Lett. 2000, 41, 9973-9976.
A. K. Chatterjee, T-L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2003, 125, 11360-11370.
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[11] a) M. Shao, L. Zheng, W. Qiao, J. Wang, J. Wang, Adv. Synth. Catal.
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Experimental Section
[12] L. Chen, Y. Liang, T. Song, K. Anjum, W. Wang, S. Yu, H. Huang, X-Y.
Lian, Z. Zhang, Bioorg. Med. Chem. Lett. 2015, 25, 2629–2633.
[13] a) C. Samojłowicz, E. Borré, M. Mauduit, K. Grela, Adv. Synth. Catal.
2011, 353, 1993−2002. b) C. Samojłowicz, M. Bieniek, A. Pazio, A.
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General procedure for cross-metathesis of allyl esters
3 and
styrenes 4. Under argon atomosphere, Hoveyda-Grubbs second-
generation catalyst (0.05 mmol) was dissolved in octafluorotoluene (1.5
mL). Allyl ester (0.5 mmol) and styrene (1.5 mmol) were added and the
resulting mixture was stirred at 90 °C. After 12 h, solvent was evaporated
under reduced pressure and under argon atmosphere. Without
purification, 1H NMR analysis of the residue was conducted in order to
obtain the 1H NMR yields. (Mesitylene, 0.5 mmol was used as internal
standard). Column chromatography of the residue on silica gel (4/1
hexanes/EtOAc) provided the cross-metathesis products.
(E)-3-(4-Hydroxy-3-methoxyphenyl)allyl acetate (5am). Column
chromatography of the residue on silica gel (4/1 hexanes/EtOAc) yielded
0.022
g (20%) of the title compound as a yellow liquid. Rf (4/1
hexanes/EtOAc) = 0.13; 1H NMR (400 MHz, CDCl3) δ 6.92-6.85 (m, 3H),
6.58 (d, J = 15.8 Hz, 1H), 6.14 (dt, J = 15.8 Hz, 6.6 Hz, 1H), 5.68 (s, 1H),
4.71 (dd, J = 6.6 Hz, 1.2 Hz, 2H), 3.90 (s, 3H), 2.09 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 170.9, 146.6, 145.9, 134.5, 128.7, 120.7, 120.6,
114.4, 108.3, 65.3, 55.87, 21.0; IR (KBr)
3408, 2942, 1734, 1235,
νmax
1031 cm-1; HRMS (TOF-MS-EI) m/z: calcd for C12H14O4 222.0892; found
222.0891.
Acknowledgements
This work was supported by the Czech Science Foundation
(Grant No. 13-15915S) and the Charles University Grant Agency
(Grant No. 1132/2015). The authors would like to thank Dr.
Ivana Císařová for the X-ray analysis.
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10.1002/ejoc.201700132
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Metathesis, catalysis
Yasuhiro Araki, Nikola Topolovčan, and
Martin Kotora*
Page No. – Page No.
Ru-catalyzed Cross-Metathesis of
Allyl Acetate and Styrenes: a
Practical Approach to Synthesis of
Tripolinolate A and its Analogs
Cross-metathesis between allyl esters and variously substituted styrenes is
discussed. The reaction is efficiently catalysed by Hoveyda-Grubbs second-
generation catalyst in perfluorinated toluene providing cinnamyl acetates in
reasonable yields. The presented method was utilized in the synthesis of natural
products which exhibits anticancer activity.
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