Synthetic studies of mycalolide B, an actin-depolymerizing marine macrolide: Construction of the tris-oxazole macrolactone using ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2010.07.046

Tris-oxazole macrolactone 2, a key intermediate of mycalolide B (1), which has 13 stereogenic centres, was synthesized through the use of ring-closing metathesis (RCM). The E/Z ratio of the RCM product 2 was reversed by the use of CH₂Cl₂ and toluene, whereas a cross-metathesis reaction yielded the C1-C35 long-chain compound 19 in a highly E-selective manner. Thus, the loss of flexibility in aliphatic carbon chains and the steric hinderance of β- and γ-substituents of the C20 olefin in the precursor 11 may affect the stereoselectivity in RCM reactions.

Full text of DOI:10.1016/j.tetlet.2010.07.046

Tetrahedron Letters 51 (2010) 4882–4885
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Tetrahedron Letters
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Synthetic studies of mycalolide B, an actin-depolymerizing marine macrolide:
construction of the tris-oxazole macrolactone using ring-closing metathesis
*
Masaki Kita, Hidekazu Watanabe, Tomoya Ishitsuka, Yuzo Mogi, Hideo Kigoshi
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Tris-oxazole macrolactone 2, a key intermediate of mycalolide B (1), which has 13 stereogenic centres,
was synthesized through the use of ring-closing metathesis (RCM). The E/Z ratio of the RCM product 2
was reversed by the use of CH2Cl2 and toluene, whereas a cross-metathesis reaction yielded the C1–
C35 long-chain compound 19 in a highly E-selective manner. Thus, the loss of flexibility in aliphatic car-
Received 9 June 2010
Revised 7 July 2010
Accepted 9 July 2010
Available online 13 July 2010
bon chains and the steric hinderance of b- and
c
-substituents of the C20 olefin in the precursor 11 may
affect the stereoselectivity in RCM reactions.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Actin-depolymerizing compound
Ring-closing metathesis
Tris-oxazole macrolide
Synthesis of marine natural products
Mycalolide B (1) is a cytotoxic and antifungal macrolide isolated
from the marine sponge Mycale sp. It bears a unique tris-oxazole
structure and has 13 stereogenic centers (Fig. 1).1 This compound
also inhibits actomyosin Mg2+–ATPase and shows potent actin-
depolymerizing activity by sequestering G-actin and forming a
1:1 complex.2 Mycalolides can be divided into two characteristic
parts: the C1–C24 macrolactone and the C25–C35 side-chain moi-
eties. Studies of the structure–activity relationship3 and photo-
affinity labeling experiments4 have established that the side-chain
part of 1 is critically important for its ability to bind to and depo-
lymerize actin. Several tris-oxazole macrolides closely related to
mycalolides have been isolated, such as ulapualides,5 halichondra-
mides,6 jaspisamides,7 and kabiramides;8 all of which exhibit po-
tent actin-depolymerizing properties. These agents may be useful
for the development of novel pharmacological tools for analyzing
actin-mediated cell functions, such as muscle contraction, cell
motility, and cytokinesis. Furthermore, it is noteworthy that aplyr-
onine A, which has an actin-binding side-chain moiety similar to
mycalolides, exhibits potent antitumor activity in vivo against
P388 leukemia and several cancers.9,10 Thus, mycalolides and re-
lated actin-targeting natural products have great potential as pre-
clinical candidates for use in cancer chemotherapy.
which Yamaguchi lactonization, cyclization of the central oxazole
ring, or intramolecular Horner–Wadsworth–Emmons olefination
OMe O
O
N
OMe
HO
N
OMe
O
O
O
MeO
O
N
OMe O
OAc
Me
N
O
CHO
Mycalolide B (1)
Nozaki–Hiyama–Kishi coupling
OMe O
11
6
7
O
N
Esterification
OMe
OMe
14
TBDPSO
N
1
Due to their extraordinary structures and important biological
activities, several synthetic studies on tris-oxazole-containing
macrolides have been reported.11 Recently, total syntheses of
mycalolide A12 and ulapualide A13 have been accomplished, in
O
O
O
O
O
OMe
N
OMe
O
35
MeO
17
20
O
24
19
RCM
2
* Corresponding author. Tel./fax: +81 29 853 4313.
E-mail address: kigoshi@chem.tsukuba.ac.jp (H. Kigoshi).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.046

M. Kita et al. / Tetrahedron Letters 51 (2010) 4882–4885
4883
were used to construct macrocycles. Subsequent studies have
shown that olefin metathesis is a useful method for connecting
the C19–C20 double bonds in mycalolide analogs.14 Here we de-
scribe the synthesis of tris-oxazole macrolactone 2, a key synthetic
intermediate of mycalolides, through the use of ring-closing
metathesis (RCM). We expected that the convergent assembly of
three fragments via Ni/Cr-mediated Nozaki–Hiyama–Kishi cou-
pling15 at C6–C7, esterification, and RCM at the C19–C20 olefin
could efficiently afford 2.
The synthesis started with removal of the Boc and acetonide
groups of the previously reported oxazole (ꢀ)-314 under acidic
conditions, and subsequent condensation with 2-chloroxazole-4-
carboxylic acid16 afforded amide 4 (77%, two steps) (Scheme 1).
Due to the considerable instability of the 2-vinyloxazole moieties
under basic and dehydration conditions, we planned to introduce
the vinyl group into the oxazole ring after construction of the
tris-oxazole structure. Dehydrating cyclization of 4 by diethylami-
nosulfur trifluoride (DAST)17 gave an oxazoline intermediate (85%),
which was oxidized with a combination of bromotrichloromethane
and 1,8-diazabicycloundec-7-ene (DBU)18 at room temperature to
give tris-oxazole 5 (98% based on recovered starting material).19
We found that acetonitrile is a better solvent than the conventional
CH2Cl2 in this reaction. Catalytic dihydroxylation of 5 with OsO4–
NMO and Migita–Stille coupling with tri-n-butylvinyltin furnished
a vinyloxazole intermediate, and this was transformed into alde-
hyde 6 via oxidative cleavage of the 1,2-diol with NaIO4 (73%, three
steps).
Fragment coupling between 6 and vinyl iodide 712 by a Ni/Cr-
mediated coupling reaction was followed by oxidation of the C7
allylic alcohol with Dess–Martin periodinane (DMP)20 to afford a
ketone (71%, two steps), the tert-butyl group of which was re-
moved to give carboxylic acid 8 (90%). Removal of the tert-butyldi-
methylsilyl (TBS) group in 914,3b,21 by tetra-n-butylammonium
fluoride (TBAF) gave C20–C35 fragment 10 (97%), which was con-
densed with 8 by the Shiina procedure22 to afford the RCM precur-
sor 11 in 55% yield.
With the key intermediate 11 in hand, RCM reactions were exam-
ined(Table1). First, treatmentof11with30 mol %of2nd-generation
Grubbs catalyst (12)23 in degassed refluxing toluene led to the
decomposition of the starting material and gave a complex mixture
(entry1). Weassumedthatthelowreactivityof 11towardRCMreac-
tions would be due to the electron-deficient C19 olefin. To overcome
this problem, a more thermally-stable and highly-active catalyst
was considered. Treatment of 11 with 30 mol % of 2nd-generation
Hoveyda–Grubbs catalyst (13)24 in refluxing CH2Cl2 (0.8 mM)
yielded tris-oxazole lactone 2 as a separable 2:1 mixture of stereo-
isomers in 30% yield (entry 2).25–27 With the use of toluene as a sol-
vent (0.9 mM), the yield of 2 was improved to 76%, but the E/Z-
product ratio was changed to 1:1.2 (entry 3).
OMe
OMe
For comparison, we also used a cross-metathesis reaction
(Scheme 2). Acidic treatment of cyanide 15 in aqueous MeOH,
which was prepared from (S)-epichlorohydrin (14),28 and protec-
tion of the hydroxyl group gave 16 (60% in two steps). Ozonolysis
of the terminal olefin (80%) and Takai olefination29 gave vinyl io-
dide 17 (66%, E/Z = 11:1). Nozaki–Hiyama–Kishi coupling between
compounds 6 and 17 gave an allylic alcohol (87%), which was oxi-
dized with DMP to afford the C1–C19 ketone 18 in 84% yield. In
contrast to the RCM reactions, treatment of the C1–C19 segment
18 (1.2 equiv) and the C20–C35 segment 9 with 50 mol % of cata-
lyst 13 in refluxing CH2Cl2 (7 mM for 9) for 25 h yielded the C1–
C35 long-chain compound 19 in a highly E-selective manner
(66%, E/Z = 5:1).25,30–32
OMe
O
O
O
O
N
N
HO
O
N
a,b
c,d
NH
N
O
O
NBoc
O
N
N
e-g
3
Cl
Cl
4
5
OMe
OMe O
CHO
7
O
O
O
N
N
N
h-j
I
6
Our work demonstrated that the RCM reaction of 11 proceeded
with low stereoselectivity, unlike the cross-metathesis reaction of
+
N
TBDPSO
O
O
1 COOH
TBDPSO
N
N
1
t
CO2 Bu
Table 1
Ring-closing metathesis of 11
O
8
7
6
19
19
l
DMPMOM
OMe
N
N
Mes
OMe O
Mes
MeO
OR OMe
O
O
N
N
Mes
Ph
Mes
OMe O
Cl
Cl
Ru
O
Cl
Cl
Ru
O
O
N
PCy3
N
N
9 (R = TBS)
10 (R = H)
12
13
k
TBDPSO
N
N
11
TBDPSO
O
O
DMPMOM
1
OMe
O
O
DMPMOM
OMe
O
O
O
O
OMe
MeO
20
N
OMe
O
O
MeO
35
20
O
19
O
19
2
11
Entry
Catalyst (30 mol %)
Reaction conditions
Yields (%)
Scheme 1. Synthesis of the RCM precursor 11. Reagents and conditions: (a) 3 M
HCl, EtOAc, rt; (b) 2-chlorooxazole-4-carboxylic acid, EDCIꢁHCl, HOBt, Et3N, CH2Cl2,
0 °C to rt, 77% in two steps; (c) DAST, CH2Cl2, ꢀ78 to 0 °C, 85%; (d) DBU, BrCCl3,
Product
19Z-isomer
a
1
2
3
12
13
13
Toluene, reflux, 4 h
CH2Cl2, reflux, 24 h
Toluene, reflux, 3 h
Trace
20
34
Trace
10
s
m); (e) OsO4, NMO, THF–tBuOH–H2O, rt; (f) tri-n-
b
MeCN, rt, 54% (98% br
butylvinyltin, PdCl2(PPh3)2, 1,4-dioxane, reflux; (g) NaIO4, EtOH–H2O, rt, 73% in
three steps; (h) 7, CrCl2–NiCl2, THF–DMF, rt; (i) DMP, pyridine, CH2Cl2, rt, 71% in
two steps; (j) TFA, CH2Cl2, 0 °C, 90%; (k) TBAF, THF, 40 °C, 97%; (l) 10, MNBA, Et3N,
DMAP, CH2Cl2, rt, 55%.
42
a
S.m. was decomposed and not recovered.
S.m. was recovered (50%).
b

4884
M. Kita et al. / Tetrahedron Letters 51 (2010) 4882–4885
T.; Matsui, K.; Miya, S.; Kuribayashi, S.; Sakakura, A.; Kigoshi, H. Tetrahedron
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Faulkner, D. J. J. Org. Chem. 1988, 53, 5014.
2 steps
ref. 26
a,b
c,d
O
HO
15
TBDPSO
16
TBDPSO
CN
e,f
CO2Me
OMe O
1 CO2Me
Cl
(S)-14
17
7. Kobayashi, J.; Murata, O.; Shigemori, H. J. Nat. Prod. 1993, 56, 787.
8. (a) Matsunaga, S.; Fusetani, N.; Hashimoto, K. J. Am. Chem. Soc. 1986, 108, 847;
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T.; Ogawa, T.; Yamada, K. J. Am. Chem. Soc. 1994, 116, 7441; (c) Kigoshi, H.;
Suenaga, K.; Mutou, T.; Ishigaki, T.; Atsumi, T.; Ishiwata, H.; Sakakura, A.;
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10. Reviews: (a) Ojika, M.; Kigoshi, H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.;
Tsukada, I.; Arakawa, M.; Ekimoto, H.; Yamada, K. Tetrahedron 2007, 63, 3138;
(b) Yamada, K.; Ojika, M.; Kigoshi, H.; Suenaga, K. Nat. Prod. Rep. 2009, 26, 27.
11. Reviews: (a) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41, 4632; (b)
Chattopadhyay, S. K.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 2000, 2429. and
references are therein.
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K. Angew. Chem., Int. Ed. 2007, 46, 4359; (b) Chattopadhyay, S. K.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 6095.
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Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am.
Chem. Soc. 1986, 108, 6048; (c) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J.
Am. Chem. Soc. 1977, 99, 3179.
O
O
N
6
N
TBDPSO
O
1 CO2Me
N
OMe O
18
19
O
g
N
N
1
CO2Me
N
TBDPSO
O
TBS
O
DMPMOM
OMe
35
MeO
OMe
O
O
20
O
19
19
Scheme 2. Cross-metathesis reaction. Reagents and conditions: (a) concd H2SO4,
MeOH–H2O, reflux; (b) TBDPSCl, imidazole, DMF, rt, 60% in two steps; (c) O3,
CH2Cl2, ꢀ78 °C, then Me2S, ꢀ78 °C to rt, 80%; (d) CrCl2, CHI3, 1,4-dioxane–THF, rt,
65%; (e) 17, CrCl2–NiCl2, THF–DMF, rt, 87%; (f) DMP, pyridine, CH2Cl2, rt, 84%; (g) 9,
13 (50 mol %), CH2Cl2, reflux, 55% with 11% of 19Z-isomer.
16. (a) Young, G. L.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 3797; (b)
Grank, G.; Fouris, M. J. J. Med. Chem. 1971, 14, 1075.
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1165.
18. Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38,
331.
18. The E/Z ratios did not significantly change during the course of
the metathesis reactions, and thus the formation of C@C bonds in 2
and 19 would take place under kinetic control. In the ruthenocyc-
lobutane intermediate for the desired 19E-isomer of 2, the oxazole
rings and the C21–C35 alkyl chain are located in an anti-orienta-
19. NiO2 oxidation of oxazoline intermediate also afforded 8, but a low yield
(ꢂ30%) and significant loss of starting material recovery, probably due to the
strong coordination of bis- or tris-oxazole nitrogen atoms to nickel atom.
20. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
21. Although configuration of the C35 acetal carbon in 9 has not been determined,
9 is a single stereoisomer. See Ref. 3b.
22. (a) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535; (b) Shiina,
I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822.
23. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
tion. Due to the rigidness of the tris-oxazole and
a,b-unsaturated
ketone moieties, the anti-ruthenocyclobutane intermediate would
be more strained than the syn-intermediate, which may affect the
stereoselectivity in RCM reactions.
24. (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem.
Soc. 1999, 121, 791; (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
In conclusion, we achieved the synthesis of tris-oxazole macro-
lactone 2 through the use of RCM reactions as a key step, which in-
cludes all of the 13 stereogenic centers and the whole carbon
framework of mycalolide B (1). Also, this key intermediate pos-
sesses a common framework for mycalolides and related actin-
depolymerizing tris-oxazole macrolides. Studies on the total syn-
thesis of mycalolide B (1) as well as on the stereoselectivity of
RCM reactions, especially solvent effects, are currently underway.
25. The stereochemistry of the C19 olefins in 2 and 19 was established based on
3JH19,H20 values (15.8 and 15.9 Hz). In contrast, the 3JH19,H20 values of 19Z-2 and
19Z-19 were 11.4 and 11.3 Hz, respectively.
26. Spectral data for 2: Rf 0.12 (hexane/EtOAc = 1:1); ½a D24
ꢀ26.2 (c 0.030, CHCl3);
ꢃ
1H NMR (500 MHz, CDCl3) d 8.11 (s, 1H, H-14), 8.06 (s 1H, H-17), 7.71–7.67 (m,
4H, –Si(tBu)Ph2), 7.66 (s, 1H, H-11), 7.42–7.34 (m, 6H, –Si(tBu)Ph2), 7.15–7.06
(m, 2H, H-5, H-20), 6.90–6.80 (m, 3H, –C6H3(OMe)2), 6.32 (d, J = 15.8 Hz, 1H, H-
19), 5.90 (d, J = 16.2 Hz, 1H, H-6), 5.12 (m, 1H, H-24), 4.86 (d, J = 4.7 Hz, 1H, H-
35), 4.81–4.79 (AB quart, J = 11.2 Hz, 2H, –OCH2O–), 4.56 (s, 2H, –OCH2Ar), 4.43
(m, 1H, H-22), 4.37 (d, J = 9.5 Hz, 1H, H-9), 4.28 (m, 1H, H-3), 4.19 (m, 1H, H-
26), 4.02 (m, 1H, H-30), 3.87 (s, 3H, –OMe), 3.86 (s, 3H, –OMe), 3.54 (m, 1H, H-
32), 3.26 (s, 3H, –OMe), 3.24 (s, 3H, –OMe), 3.22 (s, 3H, –OMe), 3.10 (s, 3H,
–OMe), 2.98 (m, 1H), 2.74–2.70 (m, 2H), 2.45–2.28 (m, 2H), 1.80 (m, 4H), 1.66–
1.40 (m, 10H), 1.08 (d, J = 6.6 Hz, 3H), 1.03 (s, 9H, –Si(tBu)Ph2), 0.88–0.77 (m,
12H); IR (CHCl3) 2930, 1733, 1654, 1516, 1458, 1381, 1262, 1106, 1027, 755,
Acknowledgments
Support was provided by JSPS via Grants-in-Aids for Scientific
Research (21681028 and 21651091 for M.K., and 20310129 for
H.K.), by the Kato Memorial Bioscience Foundation, and by the
Uehara Memorial Foundation.
704 cmꢀ1; HRMS (ESI) m/z 1282.6232 (calcd for C70H93N3NaO18Si [M+Na]+,
+1.0 mmu).
D
27. The dimer of 11 was not formed.
28. Hanazawa, T.; Okamoto, T.; Sato, F. Tetrahedron Lett. 2001, 42, 5455.
References and notes
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5281.
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1989, 30, 2809; (b) Matsunaga, S.; Liu, P.; Celatka, C. A.; Panek, J. S.; Fusetani, N.
J. Am. Chem. Soc. 1999, 121, 5605.
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322, 151; (b) Saito, S.; Watabe, S.; Ozaki, H.; Fusetani, N.; Karaki, H. J. Biol. Chem.
1994, 269, 29710.
30. Spectral data for 19: Rf 0.10 (hexane/EtOAc = 1:1); ½a D25
ꢀ15.5 (c 0.415, CHCl3);
ꢃ
1H NMR (270 MHz, CDCl3) d 8.33 (s, 1H, H-14), 8.28 (s, 1H, H-17), 7.69 (s, 1H, H-
11), 7.69–7.64 (m, 4H, –Si(tBu)Ph2), 7.42–7.36 (m, 6H, –Si(tBu)Ph2), 6.93–6.75
(m, 5H, H-5, H-20, –C6H3(OMe)2), 6.44 (d, J = 15.9 Hz, 1H, H-19), 6.11 (d,
J = 15.7 Hz, 1H, H-6), 4.89 (d, J = 4.9 Hz, 1H, H-35), 4.83 (s, 2H, –OCH2O–), 4.59
(s, 2H, –OCH2Ar), 4.39 (d, J = 10.0 Hz, 1H, H-9), 4.32 (m, 1H, H-3), 4.07 (m, 1H,
H-30), 3.92 (m, 1H, H-24), 3.89 (s, 3H, –OMe), 3.87 (s, 3H, –OMe), 3.58 (dd,
3. (a) Suenaga, K.; Miya, S.; Kuroda, T.; Handa, T.; Kanematsu, K.; Sakakura, A.;
Kigoshi, H. Tetrahedron Lett. 2004, 45, 5383; (b) Suenaga, K.; Kimura, T.; Kuroda,

M. Kita et al. / Tetrahedron Letters 51 (2010) 4882–4885
4885
J = 6.8, 9.5 Hz, 1H, H-22), 3.56 (s, 3H, –OMe), 3.44 (m, 1H, H-32), 3.36 (s, 3H,
–OMe), 3.33 (s, 3H, –OMe), 3.29 (s, 3H, –OMe), 3.20 (m, 1H, H-26), 3.17 (s, 3H,
–OMe), 3.03 (m, 1H), 2.60 (m, 1H), 2.53–2.39 (m, 5H), 2.30–2.05 (m, 3H), 1.87
–1.73 (m, 2H), 1.69–1.12 (m, 7H), 1.11 (d, J = 6.5 Hz, 3H), 1.04 (s, 9H,
–Si(tBu)Ph2), 0.95 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 7.6 Hz, 3H), 0.87–0.82 (m,
6H), 0.84 (s, 9H, –Si(tBu)Me2), 0.00 (s, 3H, –Si(tBu)Me2), ꢀ0.06 (s, 3H,
–Si(tBu)Me2); 13C NMR (150 MHz, CDCl3) d 201.8, 171.4, 161.9, 156.1, 155.5,
148.9, 148.5, 142.7, 139.8, 138.6 (2C), 138.5, 137.2, 135.9 (2C), 135.8 (2C),
133.4 (2C), 132.9, 131.5, 130.7, 130.5, 129.9, 129.8, 127.7 (2C), 127.6 (2C),
120.5, 118.0, 111.3, 110.8, 104.6, 94.4, 87.1, 82.5, 82.1, 78.4, 77.5, 69.6, 69.4,
69.2, 57.6, 57.2, 56.9, 55.9, 55.8, 54.5, 51.5, 46.9, 43.4, 43.1, 42.5, 41.5, 40.2,
35.9, 34.6, 33.7, 32.6, 30.6, 26.9, 26.9, 26.9, 26.8, 25.8, 25.8, 25.8, 20.1, 19.2,
18.0, 15.8, 14.1, 9.2, 8.8, ꢀ4.1, ꢀ4.7; IR (CHCl3) 1733, 1664, 1517, 1464, 1380,
1260, 1096, 1029, 919, 823 cmꢀ1
;
HRMS (ESI) m/z 725.8638 (calcd for
+1.4 mmu).
(C77H111N3Na2O17Si2)/2 [M+2Na]2+
,
D
31. The C20–C35 dimer was afforded in 15% yield, and the dimer of 18 was not
formed.
32. Model reactions for the cross-metathesis of 2-vinyloxazole derivatives using
catalyst 13 in toluene at 40 °C also preferentially yielded E-isomer, but the
selectivity was lower than in the case of CH2Cl2 (E/Z = 2.0–1.5:1). Thus, the
difference of solvent (CH2Cl2 and toluene) rather than reaction temperature
may affect the stereoselectivity in the RCM reactions of 11.