Stereospecific interconversion of cis- and trans-γ,δ-epoxy α,β-unsaturated ester systems

Article abstract of DOI:10.1016/j.tetlet.2008.10.084

The unprecedented, stereospecific interconversion of cis- and trans-γ,δ-epoxy α,β-unsaturated ester systems has been realized, which involves the palladium-catalyzed stereospecific alkoxy or hydroxy substitution reaction with double inversion of configura

Full text of DOI:10.1016/j.tetlet.2008.10.084

Tetrahedron Letters 49 (2008) 7442–7445
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereospecific interconversion of cis- and trans-c,d-epoxy a,b-unsaturated
ester systems
*
Xiao-Qiang Yu, Fumihiko Yoshimura, Keiji Tanino, Masaaki Miyashita
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The unprecedented, stereospecific interconversion of cis- and trans-
tems has been realized, which involves the palladium-catalyzed stereospecific alkoxy or hydroxy substi-
tution reaction with double inversion of configuration at the -position as the key step. The new
methodology is not only applicable to various disubstituted and trisubstituted epoxy unsaturated esters,
but also these interconversions proceed with an extremely high degree of stereoselectivity and efficiency.
Ó 2008 Elsevier Ltd. All rights reserved.
c,d-epoxy a,b-unsaturated ester sys-
Received 18 September 2008
Revised 15 October 2008
Accepted 17 October 2008
Available online 22 October 2008
c
Keywords:
Epoxy unsaturated ester
Interconversion
Palladium-catalyzed substitution reaction
Alkoxy substitution reaction
Double inversion of configuration
Stereoselective, epoxide-opening reactions with nucleophiles
have played very important roles in organic synthesis, particularly
in the stereoselective synthesis of biologically important target
molecules in natural product and in medicinal research.1 It is well
known that the epoxide-opening reaction via an SN2 process occurs
stereospecifically, that is, the reaction of a trans-epoxide with a
nucleophile gives an anti-product stereoselectively, while that of
a cis-epoxide produces a syn-product exclusively. Therefore, if ste-
reospecific interconversion between cis-epoxides and trans-epox-
ides is realized, both anti and syn products should be available
from the same epoxide in a highly stereoselective manner. How-
ever, such transformation has been known to be methodologically
very difficult, although cis–trans isomerization of epoxides in a few
As a program of acyclic stereocontrol based on the stereospe-
cific epoxide-opening reactions, we already reported the highly
stereoselective interconversion between cis- and trans-epoxy sul-
fides.5 Our recent studies on a number of stereospecific substitu-
tion reactions of
c,d-epoxy a
,b-unsaturated esters with carbon,6
nitrogen,7 and oxygen nucleophiles8 call for an efficient and highly
stereoselective interconversion of cis- and trans-epoxy unsaturated
ester systems, which would provide very useful transformations in
organic synthesis.
We first explored an interconversion route via the palladium-
catalyzed stereospecific hydroxy substitution reaction of c,d-epoxy
a
,b-unsaturated esters with boric acid (B(OH)3) which was recently
developed by us8b (Scheme 1). Thus, the palladium-catalyzed reac-
tion of ethyl trans-4,5-epoxy-2-octenecarboxylate (1) with B(OH)3
in THF smoothly occurred giving rise to syn-diol 2 with double
particular cases such as thermal isomerization of
a-cyanostilbene
oxide,2 ruthenium-catalyzed isomerization,3 and that of
a
,b-epoxy
amides4 have been reported, most of which produced the thermo-
inversion of configuration at the c-position in excellent yield.
dynamically more stable trans-isomers predominantly.
We presumed that stereoselective interconversion of cis- and
[Pd(PPh3)4]
B(OH)3
OH
Mitsunobu
O
O
reaction
CO2Et
CO2Et
Pr
Pr
or
Pr
CO2Et
THF
96%
3
1
2
OH
RSO2Cl
then K2CO3
Scheme 1. Attempts to convert trans-epoxy unsaturated ester 1 to cis-congener 3 via vic-diol 2.
* Corresponding author at present address: Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Tokyo 192-0015, Japan. Tel./fax: +81 42 628
4870.
E-mail address: bt13149@ns.kogakuin.ac.jp (M. Miyashita).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.084

X.-Q. Yu et al. / Tetrahedron Letters 49 (2008) 7442–7445
7443
trans-
c
,d-epoxy
a
,b-unsaturated esters might be possible, if the
stitution reactions of ethyl 6-benzyloxy-trans-4,5-epoxy-2-hexe-
noate (10) with these alcohols. The substitution reactions
diol 2 was to be stereoselectively converted to the corresponding
cis-epoxide 3. However, neither the Mitsunobu dehydration reac-
tion9 of 2 nor the two-step reaction sequence via mono-sulfonate
followed by treatment with a base was fruitless under various con-
ditions (Scheme 1). These results suggest that ingenuity to differ-
entiate vicinal hydroxyl groups in 2 is of critical importance for
interconversion of the trans-epoxide 1 and the cis-epoxide 3.
Very recently, we developed the novel palladium-catalyzed alk-
oxy substitution reaction by combination of a
urated ester, boron oxide, and pinacol, which proceeds with double
inversion of the configuration at the -position to afford a -alk-
oxy-d-hydroxy- ,b-unsaturated ester in a stereospecific manner
and in high yield.10 Since a variety of
-alkoxy-d-hydroxy- ,b-
smoothly occurred at room temperature to afford syn-
c-alkoxy-
d-hydroxy- ,b-unsaturated esters 11a–d, the products with reten-
a
tion of configuration, in excellent yields, as shown in Scheme 3.
After each product was treated with methanesulfonyl chloride,
the crude mesylate was subjected to the key epoxide-forming reac-
tion. Upon treatment of the mesylate derived from 11a with K2CO3
in EtOH, only tetrahydrofuran derivative 1214 was formed, and the
cis-epoxide 15 was not detected at all. On the other hand, treat-
ment of the mesylate prepared from 11b with DBU resulted in for-
mation of the elimination product 13. Next, we focused on the
reactions of 11c and 11d in expectation to generate of alkoxide
ions by treatment with a mild fluoride ion. Thus, treatment of
the mesylate derived from 11c with TBAF in THF merely resulted
in formation of diene 14. On the contrary, upon treatment of the
mesylate prepared from 11d with TBAF in THF at 50 °C, much to
our pleasure, the cis-epoxide 15 was produced as a single product
in 81% isolated yield. These outcomes demonstrate that only 4-(tri-
methylsilyl)-2-buten-1-ol serves as the alcohol counterpart for this
particular transformation that allows efficient generation of the
key alkoxide ion by elimination of 1,3-butadiene from the 4-(tri-
methylsilyl)-2-butenyl ether moiety on treatment with TBAF.
Efficient conversion of the trans-epoxide 10 to the cis-congener
15 with complete diastereoselectivity prompted us to investigate
the scope of this methodology. To our expectation, the opposite
transformation from the cis-epoxide 15 to the trans-isomer 10 also
occurred stereospecifically in three steps in 80% overall yield
(Scheme 4). Similarly, interconversion of cis- and trans-epoxy
unsaturated esters 3 and 1 that bear no ether oxygen atom on
the side chain was performed with complete stereoselectivity, as
c,d-epoxy a,b-unsat-
c
c
a
c
a
unsaturated esters 5 are easily obtainable by this method, we envi-
sioned that stereospecific interconversion between cis- and trans-
epoxy unsaturated esters might be possible, if the key alkoxide
ion 6 could effectively be generated in situ by use of a c-alkoxy
substituent after introduction of a mesyloxy group at the d-posi-
tion, as shown in Scheme 2. Based on this concept, we studied
the following three-step reaction sequence, which involves the pal-
ladium-catalyzed stereospecific alkoxy substitution reaction of a
trans-epoxy unsaturated ester 4, mesylation of the resulting alco-
hol 5 followed by the key generation of the alkoxide ion 6 leading
to a cis-epoxide 7.
Initially, a number of alcohol nucleophiles were examined to
find out which type of an alkoxy substituent in 5 is most suitable
for in situ generation of the alkoxide ion 6. For this purpose, we
selected 2-nitroethanol, 2-(phenylsulfonyl)ethanol, 2-trimethylsi-
lylethanol, and 4-(trimethylsilyl)-2-buten-1-ol11,12 as alcohol
counterparts, and carried out the palladium-catalyzed alkoxy sub-
[Pd(PPh3)4]
B2O3, pinacol
OH
OMs
1) MsCl
O
CO2Et
CO2Et
R'
CO2Et
R
R
R
2) base
—
R'
O
O
HO
5
6
4
trans-epoxide
R'
OH
[Pd(PPh3)4]
B2O3, pinacol
OMs
O
1) MsCl
2) base
CO2Et
R'
R
CO2Et
R
R
CO2Et
O
R'
O
HO
9
8
7 cis-epoxide
R'
—
Scheme 2. Strategy for stereospecific interconversion of cis- and trans-epoxy unsaturated esters.
OH
MsO
CO2Et
NO2
O2N
BnO
BnO
BnO
CO2Et
NO2
1) MsCl, pyridine
BnO
BnO
BnO
OH
2) K2CO3, EtOH
60%
O
88%
O
O
O
11a
12
OH
PhO2S
1) MsCl, pyridine
OH
CO2Et
SO2Ph
CO2Et
SO2Ph
2) DBU, CH2Cl2
54%
[Pd(PPh3)4]
93%
O
11b
13
14
B2O3, pinacol
O
BnO
CO2Et
OH
THF
TMS
10
CO2Et
TMS
CO2Et
TMS
OH
1) MsCl, pyridine
2) TBAF, THF
87%
91%
O
11c
OH
OH
TMS
1) MsCl, Et3N
CH2Cl2
O
BnO
CO2Et
(E/Z = 6:1)
91%
BnO
CO2Et
2) TBAF, THF
50 °C
O
11d
15
TMS
81%
Scheme 3. Pd(0)-catalyzed substitution reactions of 10 with various alcohols and subsequent epoxide-forming reactions.

7444
X.-Q. Yu et al. / Tetrahedron Letters 49 (2008) 7442–7445
[Pd(PPh3)4]
[Pd(PPh3)4]
B2O3, pinacol
B2O3, pinacol
OH
OH
OH
OH
TMS
(E/Z = 6:1)
TMS
(E/Z = 6:1)
CO2Et
TMS
BnO
CO2Et
TMS
O
O
Pr
CO2Et
BnO
CO2Et
Pr
O
O
THF
THF
10
80% from 15
1
syn-11d
77% from 3
syn-isomer
1) MsCl, Et3N
CH2Cl2
1) MsCl, Et3N
CH2Cl2
1) MsCl, Et3N
CH2Cl2
1) MsCl, Et3N
CH2Cl2
2) TBAF,THF
50 °C
2) TBAF,THF
50 °C
2) TBAF,THF
50 °C
2) TBAF,THF
50 °C
[Pd(PPh3)4]
B2O3, pinacol
[Pd(PPh3)4]
B2O3, pinacol
OH
OH
OH
OH
TMS
(E/Z = 6:1)
TMS
(E/Z = 6:1)
O
O
BnO
CO2Et
CO2Et
BnO
Pr
CO2Et
Pr
CO2Et
THF
THF
O
O
15
3
TMS
TMS
anti-11d
73% from 1
74% from 10
anti-isomer
Scheme 4. Stereospecific interconversion cycle of 10 and 15 and that of 1 and 3.
shown in Scheme 4. In this way, the stereospecific interconversion
lyzed alkoxy substitution reaction of trans-epoxide 16 with 4-(tri-
methylsilyl)-2-buten-1-ol smoothly occurred to furnish alcohol 17,
the corresponding mesylate could not be isolated because of the
concomitant elimination reactions that are yielding a mixture of
dienes 18 and 19 (Scheme 5). These preliminary results suggest
of the disubstituted
established.
c,d-epoxy
a,b-unsaturated ester systems was
We next focused on interconversion of trisubstituted
c,d-epoxy
a,b-unsaturated esters. As a result, although the palladium-cata-
[Pd(PPh3)4]
B2O3, pinacol
MsCl, Et3N
CH2Cl2
Me OH
R
Me
Me
Me
Me
R
OH
O
CO2Et
TMS
TMS
CO2Et
TMS
CO2Et
TMS
CO2Et
R
Me
+
70%
THF
70%
O
O
O
16
17
18
19
R = Me2C=CH(CH2)2-
Scheme 5. Application to trisubstituted epoxy ester 16.
OH
[Pd(PPh3)4]
B
Me
OH
O
Me
R
B(OH)3, THF
O
CO2Et
CO2Et
Me
R
R
CO2Et
OH
20 syn-diol
16 R = Me2C=CH(CH2)2-
82% from 21 (cis trans = 2:98)
O
/
1) MsCl, pyridine
CH2Cl2
1) MsCl, pyridine
CH2Cl2
2) K2CO3, EtOH
2) K2CO3, EtOH
OH
B
[Pd(PPh3)4]
B(OH)3, THF
OH
O
Me
R
Me
R
O
Me
R
CO2Et
CO2Et
CO2Et
OH
21 R = Me2C=CH(CH2)2-
87% from 16 (cis trans = 98:2)
O
22 anti-diol
/
OH
B
[Pd(PPh3)4]
B(OH)3, THF
OH
O
CO2Et
CO2Et
O
R
R
CO2Et
HO Me
syn-diol
Me
R
Me
O
23 R = Ph(CH2)2-
72% from 24 (cis trans = 5:95)
/
1) MsCl, pyridine
CH2Cl2
1) MsCl, pyridine
CH2Cl2
2) K2CO3, EtOH
2) K2CO3, EtOH
OH
B
[Pd(PPh3)4]
B(OH)3, THF
OH
O
Me
O
CO2Et
Me
R
CO2Et
R
CO2Et
R
HO
24 R = Ph(CH2)2-
86% from 23 (cis trans = 99:1)
Me
O
anti-diol
/
Scheme 6. Stereospecific interconversion cycle of trisubstituted epoxides 16 and 21, and that of 23 and 24 with the different substitution patterns.

X.-Q. Yu et al. / Tetrahedron Letters 49 (2008) 7442–7445
7445
that the successful methodology for disubstituted epoxides is not
applicable to trisubstituted epoxides.
University) for their mass spectrometric analyses. Financial sup-
port from the Ministry of Education, Culture, Sports, Science and
Technology, Japan (a Grant-in-Aid for Scientific Research (B) (No.
16350049)) is gratefully acknowledged.
Although the first strategy for interconversion of 1 and 3 via
mono-sulfonate was unsuccessful as described in Scheme 1, we
hopefully anticipated that this methodology should be applicable
to interconversion of trisubstituted epoxy esters, because of differ-
ent steric hindrance and reactivity of the secondary and the ter-
tiary hydroxyl groups in the products. Indeed, the palladium-
catalyzed substitution reaction of 16 with B(OH)3 yielded syn-diol
20 quantitatively, and subsequent mesylation of the secondary hy-
droxyl group followed by treatment of the resulting mesylate with
K2CO3 in EtOH produced cis-epoxide 21 with remarkably high ste-
reoselectivity (cis/trans = 98:2) in three steps in 87% yield (Scheme
6). As well, the opposite conversion from the cis-epoxide 21 to the
trans-isomer 16 was performed in an efficient and highly stereose-
lective manner (cis/trans = 2:98).
Supplementary data
Typical experimental procedures and characterization data are
available. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.10.084.
References and notes
1. (a) Klunder, J. M.; Posner, G. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 207–239; (b) Knight, D. W.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 3, pp 241–270; (c) Garratt, P. J. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp
271–292; (d) Posner, G. H. Org. React. 1975, 22, 253–400; (e) Gorzynski-Smith,
J. Synthesis 1984, 629–656; (f) Hanson, R. M. Chem. Rev. 1991, 91, 437–475; (g)
Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–635; (h) Bonini, C.; Righi,
G. Synthesis 1994, 225–238.
Furthermore, we found that this methodology was also applica-
ble to alternative trisubstituted epoxy unsaturated ester 23 with
the different substitution pattern (Scheme 6). Namely, the trans-
epoxide 23 bearing a methyl group at the c-position was success-
2. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1977, 16, 572–585; (b) MacDonald, H.
H. J.; Crawford, R. J. Can. J. Chem. 1972, 50, 428–433.
fully transformed into cis-congener 24 (cis/trans = 99:1) in 86%
overall yield as shown in Scheme 6, while 24 could be converted
to 23 (cis/trans = 5:95) in 72% isolated yield. Thus, stereospecific
3. Lo, C.-Y.; Pal, S.; Odedra, A.; Liu, R.-S. Tetrahedron Lett. 2003, 44, 3143–3146.
4. Martín-Ortiz, L.; Chammaa, S.; Pino-González, M. S.; Sánchez-Ruiz, A.; García-
Castro, M.; Assiego, C.; Sarabia, F. Tetrahedron Lett. 2004, 45, 9069–09072.
5. Hirai, A.; Tonooka, T.; Wakatsuki, K.; Tanino, K.; Miyashita, M. Angew. Chem.,
Int. Ed. 2002, 41, 819–821.
interconversion cycle of cis- and trans-trisubstituted
c,d-epoxy
a,b-unsaturated ester systems with the different substitution pat-
terns has been established. To the best of our knowledge, this is the
first case in interconversion between trisubstituted epoxides.
In conclusion, we developed the new methodologies for inter-
6. (a) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991, 56, 6483–
6485; (b) Shanmugam, P.; Miyashita, M. Org. Lett. 2003, 5, 3265–3268; (c) Hirai,
A.; Matsui, A.; Komatsu, K.; Tanino, K.; Miyashita, M. Chem. Commun. 2002,
1970–1971.
7. Miyashita, M.; Mizutani, T.; Tadano, G.; Iwata, Y.; Miyazawa, M.; Tanino, K.
Angew. Chem., Int. Ed. 2005, 44, 5094–5097.
conversion of cis- and trans-c,d-epoxy a,b-unsaturated ester sys-
tems. Interconversion of disubstituted cis- and trans-epoxy
unsaturated esters was achieved by the three-step reaction se-
quence involving the palladium-catalyzed stereospecific alkoxy
substitution reaction with 4-(trimethylsilyl)-2-buten-1-ol, mesyla-
tion of the resulting alcohol followed by treatment with TBAF. On
the other hand, interconversion of trisubstituted epoxy unsatu-
rated esters was performed by the different three-step reaction se-
quence that involves the palladium-catalyzed hydroxy substitution
reaction with B(OH)3, selective mesylation of the secondary hydro-
xyl group followed by treatment with K2CO3. Since these intercon-
versions proceed with remarkably high diastereoselectivity and
efficiency, the present methodologies should provide very useful
transformations in organic synthesis, particularly in natural prod-
uct synthesis and in medicinal research. Application of these meth-
odologies to the synthesis of complex natural products is in
progress in our laboratory.
8. (a) Hirai, A.; Yu, X.-Q.; Tonooka, T.; Miyashita, M. Chem. Commun. 2003, 2482–
2483; (b) Yu, X.-Q.; Hirai, A.; Miyashita, M. Chem. Lett. 2004, 33, 764–765.
9. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L. Org. React. 1992, 42,
335–656.
10. Yu, X.-Q.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.; Tanino, K.; Miyashita, M.
Angew. Chem., Int. Ed. 2008, 47, 750–754.
11. Mastalerz, H. J. Org. Chem. 1984, 49, 4092–4094.
12. 4-(Trimethylsilyl)-2-buten-1-ol was prepared by the cross metathesis
reaction13 of allyltrimethylsilane with 2-butene-1,4-diol. The product
consisting of an E/Z 6:1 mixture was directly used for the palladium-
catalyzed alkoxy substitution reaction.
PCy3
Cl
Cl
Ru
Ph
OH
PCy3
OH
+
TMS
TMS
CH2Cl2
reflux
HO
E/Z = 6:1
38%
13. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
14. The stereochemistry of 12 has not been determined.
Acknowledgments
The authors thank Dr. Eri Fukushi and Mr. Kenji Watanabe (GC–
MS and NMR Laboratory, Graduate School of Agriculture, Hokkaido