Kinetically controlled ring-closing metathesis: Synthesis of a potential scaffold for 12-membered salicylic macrolides

Article abstract of DOI:10.1002/chem.200800249

For the synthesis of a 12-membered salicylic macrolide scaffold, ringclosing metathesis (RCM) of a ω-diene compound was planned. The stereochemical outcome of the RCM reaction changed depending on the type of Ru catalyst that was used; a "first-generation

Full text of DOI:10.1002/chem.200800249

FULL PAPER
DOI: 10.1002/chem.200800249
Kinetically Controlled Ring-Closing Metathesis:
Synthesis of a Potential Scaffold for 12-Membered Salicylic Macrolides
Yuji Matsuya,* Sho-ichi Takayanagi, and Hideo Nemoto*[a]
Abstract: For the synthesis of a 12-membered salicylic macrolide scaffold, ring-
closing metathesis (RCM) of a w-diene compound was planned. The stereochemi-
cal outcome of the RCM reaction changed depending on the type of Ru catalyst
Keywords: catalysis · macrocycles ·
that was used; a “first-generation” Grubbs catalyst produced exclusively the E
metathesis · ruthenium · selectivity
isomer and “second-generation” catalysts provided a mixture of the E and Z iso-
mers under kinetic control (not thermodynamic control). Considerations for the
E/Z selectivity are described.
Introduction
Salicylic macrolide compounds constitute an important class
of bioactive natural products and have attracted the atten-
tion of a number of synthetic chemists due to their attractive
biological properties, novel mode of action, and complex
structural characteristics.[1] For example, oximidines and sali-
cylihalamides have been reported to exhibit potent cytotoxic
activity against various human cancer cell lines as a result of
selective inhibition of mammalian vacuolar-type proton ade-
nosine triphosphatase (ATPase),[2] and compounds CJ-
12950 and CJ-13357 have been shown to be potent inducers
of the low-density lipoprotein (LDL) receptor gene, which
is a major factor in the control of hypercholesterolemia.[3]
These natural compounds possess a labile enamide side
chain and a common 12-membered salicylic lactone core
and have individual unsaturation modes and oxidation
states. To date, considerable efforts have been devoted
toward the syntheses of these salicylic lactones and related
model compounds, and many of these studies rely on a ring-
closing metathesis (RCM) strategy for constructing the 12-
membered lactone core.[1,4] While RCM is a powerful meth-
odology in the field of organic synthesis and has been uti-
lized for numerous synthetic studies, including the synthesis
of cyclic natural compounds,[5] it is important to note that
the prediction of the stereochemical outcome (the E/Z se-
lectivity of the olefin product) is not always simple in cases
of large-ring formation. Although mixtures of both geomet-
rical isomers are formed with various ratios, generally ac-
cording to the thermodynamic stabilities, this drawback has
been overcome by controlling the reaction conditions, by
tuning the protecting groups affecting the conformation of
the substrates, and ultimately by chromatographic separa-
tion of the isomers. As part of our ongoing research on the
synthesis of macrolide compounds by utilizing RCM,[6] we
have grappled with the synthetic study of a 12-membered
macrolactone compound (1), a potential scaffold for a series
of salicylic macrolides with various substitution patterns;
[a] Dr. Y. Matsuya, S.-i. Takayanagi, Prof. Dr. H. Nemoto
Graduate School of Medicine and Pharmaceutical Sciemces
University of Toyama
2630 Sugitani, Toyama 930–0194 (Japan)
Fax : (+81)76-434-5047
E-mail: matsuya@pha.u-toyama.ac.jp
nemotoh@pha.u-toyama.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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5275

our aim was extensive structure–activity relationship (SAR)
research. During this investigation, we encountered a com-
pletely kinetically controlled RCM, which is an interesting
and unusual example of
a
large-ring-forming RCM.[7]
Herein, we wish to report an efficient access to the function-
alized 12-membered salicylic macrolide core skeleton 1 and
a consideration of the stereochemical outcome of the key
RCM reaction.
Results and Discussion
Our synthetic plan toward macrocycle 1 is straightforward
(Scheme 1). If the macrolide-ring formation by RCM is an-
ticipated, substrate 2 can be assembled from three simple
Scheme 2. Synthesis of the RCM substrate 11 from (+)-diethyl tartrate
(6). a) Cyclohexanone, p-TsOH; b) LiAlH4; c) NaH, TBSCl (73%,
3 steps); d) SO3–Py, DMSO, Et3N (92%); e) Ph3P=CH2, THF (76%);
f) 3, PdACTHER(UNG OAc)2, Ph3P, E t 3N, DMF (63%); g) TBAF, THF (95%);
h) (COCl)2, DMSO, CH2Cl2; then Et3N; i) CH2I2, Zn, Me3Al, THF (57%,
2 steps); j) 4, NaHMDS, THF (93%). DMSO: dimethylsulfoxide;
NaHMDS: sodium hexamethyldisilazide; p-TsOH: toluene-4-sulfonic
acid; Py: pyridine; TBAF: tetrabutylammonium fluoride.
Scheme 1. Synthetic strategy for macrolide 1. PG: protecting group;
PMB: para-methoxybenzyl; TBS: tert-butyldimethylsilyl; Tf: trifluorome-
thanesulfonyl.
parts, 3–5. T heE-olefin structure can be created by means
of the Heck coupling reaction between 3 and 5, the latter of
which can be derived from an inexpensive chiral source, di-
ethyl tartrate. The synthesis of RCM substrate 11 was per-
formed with conventional functional-group manipulations
(Scheme 2; more details are described in the Experimental
Section).
With RCM substrate 11 in hand, the stage was set to ex-
plore the reactivity of these compounds for macrocycliza-
tion. We used three types of ruthenium-based catalyst,
Grubbs “first-generation” (A),[8] Grubbs “second-genera-
tion” (B),[9] and Hoveyda–Grubbs “second-generation” (C)
catalysts.[10] When substrate 11 was subjected to the RCM
reaction with 5 mol% of catalyst A in dichloromethane for
24 h, macrocyclic product 15-E was obtained as the only ste-
reoisomer in 64% yield after isolation (Scheme 3; Table 1,
entry 1). Increased amounts of the catalyst gave rise to im-
proved yields (up to 78%) of the E isomer, 15-E, whereas
the Z isomer, 15-Z, could not be detected in any case
(Table 1, entries 2 and 3). On the other hand, the same sub-
strate, 11, provided a mixture of 15-E and 15-Z with an ap-
proximately 1:1 ratio when catalysts B or C were used
Scheme 3. RCM reaction of substrates 11–14. Cy: cyclohexyl; Mes: mesi-
tyl; MOM: methoxymethyl.
(Table 1, entries 4 and 5), and an optimal total yield was re-
corded under reflux conditions in 1,2-dichloroethane
(Table 1, entry 6). Thus, the results of the RCM of com-
pound 11 were of great interest because the stereochemical
course could be controlled by choice of the RCM catalyst.
These findings prompted us to investigate the generality of
the reaction, and the analogous substrates 12–14 (Scheme 3)
were prepared from 11 by simple functional-group manipu-
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Chem. Eur. J. 2008, 14, 5275 – 5281

Ring-Closing Metathesis
FULL PAPER
Table 1. Yields after isolation of the RCM products 15–18.
formed as a kinetic product in each case (catalysts A–C)
and catalysts B and C established the thermodynamic equi-
librium (E/Zꢀ1:1 for 15-E/15-Z, E/Zꢀ5:1 for 16-E/16-Z,
etc.) by secondary isomerization, but catalyst A could not
do that due to its relatively low reactivity and stability. This
interpretation was ruled out, however, because 1) the reac-
tions of 11 with catalyst A or B under the same conditions
as those depicted in Scheme 3 were traced by 1H NMR spec-
troscopy and it was revealed that the E/Z ratios remained
constant throughout the reaction from the beginning for
24 h (only E isomer for catalyst A, E/Zꢀ1:1 for catalyst B),
and 2) pure isolated E isomer (15-E) and Z isomer (15-Z)
were allowed to react with catalysts A and B under the
same conditions but the substrates were recovered un-
changed in all four cases (even under an ethylene atmos-
phere). These experimental findings clearly indicate that re-
verse ring opening cannot proceed once macrocyclization
occurs and interconversion between the E and Z isomers is
impossible under the above reaction conditions. Therefore,
it is most likely that the RCM in this study is a purely kinet-
ically controlled reaction and the stereochemical results do
not depend on the relative stabilities of the E and Z iso-
mers.
A question is raised as to why the stereochemical course
of the present RCM is changed by the catalysts under the
kinetic control. Recent advances in the understanding of the
function of various ligands on RCM catalysts have provided
insight into the factors controlling E/Z selectivity for macro-
cyclic-olefin formation.[11–15] In particular, DFT-calculation
studies have suggested the energy levels of intermediates in
olefin-metathesis catalytic cycles, including those with first-
and second-generation ruthenium complexes.[16] To explain
our experimental results, we would like to set forth a hy-
pothesis that the energy level of the intermediate ruthenacy-
clobutane is higher than that of olefin–ruthenium p complex
in the case of bisphosphane-type catalysts, but lower in the
case of NHC-containing catalysts.[17] This idea is consistent
with the fact that NHCs, being stronger two-electron s
donors, can better stabilize the Ru4+ center of the metalla-
cyclobutane than a phosphine group.[14] This implies that the
rate-determining step is likely to be ruthenacycle formation
in the former case (that is, with catalyst A) and ruthenacycle
cleavage in the latter case (that is, with catalysts B and
C).[18]
Entry
Substrate
Catalyst
(amount used [mol%])
Yield of
Yield of
E [%][a]
Z [%][a]
1
2
3
4
11
A (5)
A (10)
A (20)
B (5)
C (5)
C (5)
A (5)
B (5)
C (5)
A (5)
B (5)
A (5)
B (5)
64 (85)
72 (79)
78 (88)
21 (42)
10 (20)
44 (47)
47 (94)
35 (85)
30 (56)
38 (62)
51 (51)
77 (77)
51 (51)
0
0
0
16 (32)
11 (22)
39 (42)
0
6 (15)
6 (11)
0
24 (24)
0
29 (29)
5
6[b]
7
12
8
9
10
11
12
13
13
14
[a] Yields in parentheses are based on the recovered starting material.
[b]The reaction was carried out in 1,2-dichloroethane under reflux condi-
tions.
lations (see the Experimental Section). As shown in Table 1,
similar results were obtained for TBS ether 12, methyl ether
13, and methoxymethyl ether 14; that is, exclusive formation
of the E isomer was observed when catalyst A was used,
whereas both isomers were formed when catalysts B or C
were used (Table 1, entries 7–13).
The reaction mechanism of RCM has been well estab-
lished by both theoretical and experimental studies;[11] it in-
volves a sequence of phosphane-ligand dissociation from the
alkylidene metal complex, olefin coordination (p-complex
formation), formal [2+2] cycloaddition (metallacyclobutane
formation), cycloreversion (another p-complex formation),
and release of the product olefin. Generally, the reversible
nature of this sequential process is responsible for the ther-
modynamic control of the metathesis product.[12] Thus, in
principle, the stereochemical outcome of the RCM reaction
to form macrocycles will be governed by the thermal stabili-
ties of the corresponding E and Z isomers, and a thermody-
namic distribution of the products will be achieved after suf-
ficient reaction time. Although this may imply that the same
substrate will always produce a settled ratio of the E/Z mix-
ture regardless of the class of RCM initiator, there have
been a number of examples in which the structure of the
RCM initiator affected the E/Z selectivity of the macrocy-
clic products. This fact has been reasonably explained on the
basis of different degrees of catalytic activity and thermal
stability among RCM initiators with different ligands.[13] It
has been well recognized that first-generation catalysts, with
two phosphane ligands, show much less activity and stability
than second-generation catalysts, with one N-heterocyclic
carbene (NHC) ligand.[11e,14] As sufficient activity and stabil-
ity of the catalysts is needed to establish thermodynamic
equilibrium, first-generation catalysts are, in general, prone
to produce macrocyclic compounds with a relatively kinetic
E/Z ratio, whereas second-generation catalysts are likely to
afford products under thermodynamic control.[15]
Based on this hypothesis, a rationale for the observed ste-
reochemical outcome of the present RCM could be reached.
A stepwise transformation for macrocyclization, which ulti-
mately determines the E/Z selectivity, is illustrated in
Scheme 4. Formation of olefin–ruthenium p complex 19 is
the initial step for macrocyclization, if it is assumed that the
first interaction of the Ru catalyst with the w-diene sub-
strate occurs at the less-hindered double bond. Two possible
pathways exist for ruthenacycle formation and lead to trans-
ruthenacycle 20 and cis-ruthenacycle 21; the latter is proba-
bly less stable due to repulsion of the substituents on the
four-membered ring. These ruthenacycles can return to the
initial p complex 19 or go on to one of two other p com-
In light of this, one possible explanation for the selectivity
of the present study is as follows: the E isomer was initially
Chem. Eur. J. 2008, 14, 5275 – 5281
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5277

Y. Matsuya, H. Nemoto, and S. Takayanagi
course of the RCM reaction in
this study may bring forward
some new ideas for macrocycle-
forming RCM reactions.[19]
Experimental Section
General remarks: All nonaqueous re-
actions were carried out under an Ar
atmosphere. Reagents were purchased
from commercial sources and used as
received. Anhydrous solvents were
prepared by distillation over CaH2 or
purchased from commercial sources.
1H and 13C NMR spectra were ob-
Scheme 4. RCM catalytic cycle for the formation of the E and Z isomers. L: ligand; RDS: rate-determining
step.
tained on a Varian Gemini 300 instru-
ment by using the chloroform peak as
an internal reference (brs refers to
broad singlet). Mass spectra were mea-
sured on a JEOL D-200 or a JEOL
plexes, 22 or 23, which provide the E-macrocyclic-olefin
product or the Z isomer, respectively, after dissociation of
the p complex. If the formation of the ruthenacycles 20 and
21 is indeed the rate-determining step when catalyst A is
used, production of the E-macrocyclic-olefin product will
prevail over that of the Z isomer because of the lower
energy barrier for the formation of the more stable trans-
ruthenacycle 20 than that for the formation of 21. This con-
curs with our experimental results in which exclusive forma-
tion of the E isomer was observed. On the other hand, rela-
tively unstable cis-ruthenacycle 21 should have a lower
energy barrier for ruthenacycle cleavage, that is, conversion
of 21 into 23, than the equivalent barrier for 20 (to form
22). If the ruthenacycle cleavage is the rate-determining
step when the ligand (L) is NHC (that is, with catalysts B or
C), it is expected that ruthenacycles 20 and 21 will undergo
fast equilibrium with a predominance of the more stable 20,
which conversely has a higher energy barrier for this rate-
determining step. Therefore, competitive formation of the E
macrocyclic olefin and the Z isomer will arise, as was ob-
served in the present study. Once the macrocyclic-olefin
products are released, these compounds cannot participate
in the reaction in a reversible manner, probably because p-
complex formation with the Ru catalyst is impeded due to
steric congestion of the spiro-bicyclic acetal moiety.
AX 505 mass spectrometer, and the ionization method was electron
impact (EI, 70 eV). IR spectra were recorded on a JASCO FT/IR-
460Plus spectrometer. Column chromatography was carried out by em-
ploying Cica silica gel 60N (spherical, neutral, 40–50 mm or 63–210 mm).
Compound 7 was prepared according to reported methods from (+)-di-
ethyl l-tartrate (6).[20]
Compound 5: Sulfur trioxide/pyridine complex (5.87 g, 36.1 mmol) in
DMSO (21 mL) was added to a stirred solution of the alcohol 7 (2.37 g,
7.5 mmol) in DMSO (15 mL) and Et3N (15 mL) at room temperature
under an Ar atmosphere. After the mixture had been continuously
stirred for 6 h at room temperature, it was diluted with water and extract-
ed with Et2O. The organic layer was washed with brine and dried over
MgSO4, and the solvent was evaporated to leave a residue, which was pu-
rified by chromatography on silica gel to afford the corresponding alde-
hyde (2.18 g, 92%) as a pale-yellow oil.
nBuLi (1.6m in hexane, 8.65 mL, 13.85 mmol) was added to a suspension
of methyltriphenylphosphonium iodide (5.60 g, 13.85 mmol) in anhydrous
THF (25 mL) at 08C. After the mixture had been stirred for 30 min at
room temperature, the aldehyde (2.18 g, 6.92 mmol) in THF was added
and the resulting mixture was stirred for 10 h. The reaction mixture was
diluted with saturated NH4Cl and the aqueous mixture was extracted
with Et2O. The organic layer was dried over MgSO4 and then evaporated.
The residue was purified by silica gel column chromatography to afford
olefin 5 (1.64 g, 76%) as a pale-yellow oil. [a]1D9 =À3.35 (c=1.00 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=5.91–5.80 (m, 1H), 5.35 (d, J=
17 Hz, 1H), 5.21 (d, J=10 Hz, 1H), 4.33–4.28 (m, 1H), 3.78–3.72 (m,
3H), 1.63 (brs, 8H), 1.38 (brs, 2H), 0.89 (s, 9H), 0.07 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=136.2, 118.0, 109.8, 81.0, 79.2, 62.9, 36.83,
36.75, 26.2, 25.4, 24.2, 24.1, 18.6, À5.0 ppm; IR (neat): n˜ =2934, 2858,
1254, 1143, 1097 cmÀ1; MS (EI): m/z: 312 [M+]; HRMS (EI): m/z: calcd
for C17H32O3Si: 312.2121 [M+]; found: 312.2145.
Compound 8: A mixture of olefin 5 (90 mg, 0.288 mmol), triflate 3[4c,21]
(94 mg, 0.288 mmol), PdACHTRE(UGN OAc)2 (3.2 mg, 0.0144 mmol), PPh3 (7.6 mg,
Conclusion
0.0288 mmol), and Et3N (120 mL, 0.864 mmol) in DMF (2.5 mL) was
heated at 808C on an oil bath for 12 h. The mixture was diluted with
Et2O and filtered through a Celite pad. The filtrate was washed with
water and brine, then dried over MgSO4. The solvent was evaporated to
leave a residue, which was purified by chromatography on silica gel to
afford compound 8 (89 mg, 63%) as a pale-yellow oil. [a]1D8 =À9.95 (c=
1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.75 (d, J=16 Hz, 1H),
7.44 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H),
6.17 (dd, J=16, 7.4 Hz, 1H), 4.54 (dd, J=8.3, 7.4 Hz, 1H), 3.89–3.81 (m,
3H), 1.75–1.43 (m, 14H), 1.40 (brs, 2H), 0.88 (s, 9H), 0.09 (s, 3H),
0.07 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=160.1, 156.8, 141.1,
135.2, 131.6, 131.1, 121.7, 116.7, 111.0, 110.1, 105.4, 81.4, 78.7, 63.0, 36.9,
36.8, 26.2, 26.0, 25.8, 25.5, 24.2, 24.1, 18.6, À4.96, À5.01 ppm; IR (neat):
In this paper, we have described a novel kinetically con-
trolled RCM reaction as a part of an efficient access to a po-
tential scaffold for 12-membered salicylic macrolide com-
pounds. The synthesized macrocyclic compounds 15–18 are
fully functionalized for further transformations and are good
starting points for SAR investigation of bioactive salicylic
macrolides. We have proposed that the change in the E/Z
selectivity depending on the type of RCM initiator may be
attributed to alteration of the rate-determining step in the
RCM catalytic cycle. Consideration of the stereochemical
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Chem. Eur. J. 2008, 14, 5275 – 5281

Ring-Closing Metathesis
FULL PAPER
n˜ =2997, 2993, 1739, 1578, 1476, 1317, 1272 cmÀ1; MS (EI): m/z: 488 [M+
]; HRMS (EI): m/z: calcd for C27H40O6Si: 488.2594 [M+]; found:
488.2557.
(75 MHz, CDCl3): d=170.4, 162.3, 159.2, 140.4, 134.9, 134.7, 134.2, 133.2,
130.2, 129.4, 127.0, 120.3, 119.0, 118.7, 117.5, 113.8, 111.2, 110.0, 82.3,
81.5, 73.4, 72.9, 66.1, 55.4, 39.0, 37.0, 36.8, 34.0, 25.4, 24.1 ppm; IR (neat):
n˜ =2936, 2861, 1734, 1658, 1514, 1449 cmÀ1; MS (EI): m/z: 548 [M+];
HRMS (EI): m/z: calcd for C33H40O7: 548.2774 [M+]; found: 548.2785.
Compound 9: A 1m solution of tetra-n-butylammonium fluoride in THF
(3.17 mL, 3.17 mmol) was added to
a stirred solution of 8 (1.55 g,
3.17 mmol) in THF (15 mL) at room temperature, and the mixture was
stirred for 2.5 h at room temperature. The solvent was evaporated off to
leave a residue, which was dissolved in AcOEt; the resulting organic
layer was washed with water and brine, then dried over MgSO4. Evapora-
tion of the solvent left a residue, which was purified by chromatography
on silica gel to give the alcohol 9 (1.13 g, 95%) as a pale-yellow oil.
[a]1D9 =+7.55 (c=1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68
(d, J=16 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.86
(d, J=8.0 Hz, 1H), 6.11 (dd, J=16, 7.4 Hz, 1H), 4.52 (dd, J=8.2, 7.4 Hz,
1H), 3.92–3.85 (m, 2H), 3.74–3.69 (m, 1H), 2.29 (brs, 1H), 1.73–1.64 (m,
14H), 1.40 ppm (brs, 2H); 13C NMR (75 MHz, CDCl3): d=160.2, 156.7,
140.8, 135.3, 132.0, 130.7, 121.8, 116.8, 111.0, 110.2, 105.5, 81.0, 78.1, 61.4,
36.8, 36.7, 26.1, 25.6, 25.3, 24.1, 24.0 ppm; IR (neat): n˜ =3461, 3005, 2937,
2861, 1730 cmÀ1; MS (EI): m/z: 374 [M+]; HRMS (EI): m/z: calcd for
C21H26O6: 374.1729 [M+]; found: 374.1723.
Compound 12: TBSOTf (0.32 mL, 1.37 mmol) was added dropwise to a
stirred solution of compound 11 (500 mg, 0.911 mmol) and 2,6-lutidine
(0.16 mL, 1.37 mmol) in CH2Cl2 (10 mL) at 08C under an Ar atmosphere.
After the mixture had been continuously stirred for 2 h at 08C, it was di-
luted with CH2Cl2, washed successively with 5% HCl, saturated
NaHCO3, and brine, and dried over MgSO4. Evaporation of the solvent
afforded a residue, which was purified by chromatography on silica gel to
give compound 12 (602 mg, 99%) as a colorless oil. [a]2D5 =À14.58 (c=
1
1.00 in CHCl3); H NMR (300 MHz, CDCl3): d=7.25 (d, J=8.7 Hz, 2H),
7.23–7.13 (m, 2H), 6.86 (d, J=8.7 Hz, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.64
(d, J=16 Hz, 1H), 6.12 (dd, J=16, 6.6 Hz, 1H), 5.87–5.73 (m, 2H), 5.35
(d, J=17 Hz, 1H), 5.25–5.21 (m, 2H), 5.14–5.07 (m, 2H), 4.45 (d, J=
11 Hz, 1H), 4.39 (d, J=11 Hz, 1H), 4.18–4.13 (m, 2H), 3.80 (s, 3H),
3.58–3.53 (m, 2H), 2.54–2.47 (m, 2H), 2.01–1.95 (m, 2H), 1.57 (brs, 8H),
1.40 (brs, 2H), 0.97 (s, 9H), 0.23 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3): d=167.3, 159.1, 152.5, 135.1, 134.4, 133.5, 130.5, 130.1, 129.9,
129.3, 128.5, 119.1, 118.4, 118.3, 113.9, 110.1, 82.1, 81.7, 72.9, 72.7, 66.6,
55.5, 38.6, 36.9, 36.8, 33.4, 26.0, 25.4, 24.1, 18.6, À3.8 ppm; IR (neat): n˜ =
2934, 2859, 1731, 1514, 1467 cmÀ1; MS (EI): m/z: 662 [M+]; HRMS (EI):
m/z: calcd for C39H54O7Si: 662.3639 [M+]; found: 662.3643.
Compound 10: DMSO (34 mL, 0.48 mmol) was dissolved in anhydrous
CH2Cl2 (1 mL) and cooled to À788C. Oxalyl chloride (28 mm, 0.32 mmol)
was added dropwise to the solution, and the resulting mixture was stirred
for 15 min at À788C. A solution of alcohol 9 (60 mg, 0.16 mmol) in
CH2Cl2 (0.5 mL) was added to the reaction mixture and stirred at À788C.
After 1 h, Et3N (0.11 mL, 0.80 mmol) was added, and the resulting mix-
ture was warmed to room temperature for 0.5 h. The mixture was diluted
with CH2Cl2, washed with 5% HCl, saturated NaHCO3, and brine, then
dried over MgSO4. The solvent was evaporated and the residue obtained
was purified by chromatography on silica gel to afford the corresponding
aldehyde (55 mg) as a colorless oil, which was used immediately for the
next reaction.
Compound 13: MeI (0.5 mL) was added to a mixture of compound 11
(110 mg, 0.2 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (3 mL), and
the resulting mixture was stirred at room temperature for 1.5 h. The reac-
tion mixture was diluted with H2O and the aqueous mixture was extract-
ed with Et2O. The organic layer was washed with brine and then dried.
Evaporation of the solvent gave a residue, which was purified by chroma-
tography on silica gel to afford the methyl ether 13 (79 mg, 70%) as a
colorless oil. [a]2D5 =À17.45 (c=1.68 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.30–7.25 (m, 3H), 7.18 (d, J=8.1 Hz, 1H), 6.87 (d, J=
8.5 Hz, 2H), 6.82 (d, J=8.1 Hz, 1H), 6.69 (d, J=16 Hz, 1H), 6.17 (dd,
J=16, 6.8 Hz, 1H), 5.90–5.75 (m, 2H), 5.45–5.40 (m, 1H), 5.35 (d, J=
17 Hz, 1H), 5.23 (d, J=11 Hz, 1H), 5.15–5.07 (m, 2H), 4.48 (d, J=11 Hz,
1H), 4.42 (d, J=11 Hz, 1H), 4.20–4.13 (m, 2H), 3.80 (s, 3H), 3.76 (s,
3H), 3.62–3.55 (m, 2H), 2.53–2.47 (m, 2H), 2.00–1.93 (m, 2H), 1.62 (brs,
8H), 1.40 ppm (brs, 2H); 13C NMR (75 MHz, CDCl3): d=167.2, 159.1,
156.2, 134.7, 134.2, 133.4, 130.4, 130.1, 129.7, 129.2, 129.1, 128.6, 123.4,
118.8, 118.0, 117.7, 113.7, 113.6, 110.1, 109.9, 81.9, 81.4, 72.7, 72.0, 66.2,
55.6, 55.2, 38.7, 36.5, 36.4, 33.7, 25.0, 23.8, 23.7 ppm; IR (neat): n˜ =2936,
2860, 1731, 1577, 1514, 1472 cmÀ1; MS (EI): m/z: 562 [M+]; HRMS (EI):
m/z: calcd for C34H42O7: 562.2931 [M+]; found: 562.2958.
Me3Al (2.0m in hexane, 0.15 mL, 0.3 mmol) was added to a suspension of
zinc powder (290 mg, 4.43 mmol) and diiodomethane (396 mg,
1.48 mmol) in anhydrous THF (1 mL) at 08C. After 15 min, a solution of
the aldehyde (55 mg) in THF (0.5 mL) was added dropwise, and the reac-
tion mixture was stirred for 3.5 h at 08C and for an additional 0.5 h at
room temperature. The reaction mixture was diluted with Et2O, washed
successively with 5% HCl and brine, then dried over MgSO4. Evapora-
tion of the solvent gave a residue, which was purified by column chroma-
tography to afford the compound 10 (34 mg, 57% over 2 steps) as a pale-
1
yellow oil. [a]1D4 =À1.38 (c=1.00 in CHCl3); H NMR (300 MHz, CDCl3):
d=7.75 (d, J=16 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz,
1H), 6.88 (d, J=8.0 Hz, 1H), 6.13 (dd, J=16, 7.1 Hz, 1H), 5.95–5.84 (m,
1H), 5.40 (dd, J=17, 2.5 Hz, 1H), 5.27 (dd, J=10, 2.5 Hz, 1H), 4.35 (dd,
J=7.4, 7.1 Hz, 1H), 4.21 (dd, J=7.4, 6.6 Hz, 1H), 1.70 (brs, 14H),
1.41 ppm (brs, 2H); 13C NMR (75 MHz, CDCl3): d=160.2, 156.8, 140.9,
135.3, 134.4, 131.9, 129.9, 121.8, 118.9, 116.8, 111.1, 110.2, 105.4, 82.1,
81.6, 36.83, 36.77, 26.0, 25.8, 25.4, 24.1 ppm; IR (neat): n˜ =2937, 2861,
1732, 1600, 1578, 1477 cmÀ1; MS (EI): m/z: 370 [M+]; HRMS (EI): m/z:
calcd for C22H26O5: 370.1780 [M+]; found: 370.1757.
Compound 14: Chloromethyl methyl ether (30 mL, 0.4 mmol) was added
to a mixture of compound 11 (110 mg, 0.2 mmol) and diisopropylethyl-
amine (105 mL, 0.6 mmol) in dry CH2Cl2 (3 mL), and the resulting mix-
ture was stirred at room temperature for 2.5 h. The reaction mixture was
diluted with CH2Cl2 and washed successively with 10% HCl, saturated
NaHCO3, and brine. The organic layer was dried and evaporated to give
a residue, which was purified by chromatography on silica gel to afford
the MOM ether 14 (84 mg, 71%) as a pale-yellow oil. [a]2D5 =À13.72 (c=
1.97 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35–7.21 (m, 4H), 7.08
(d, J=8.1 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 6.67 (d, J=16 Hz, 1H), 6.19
(dd, J=16, 6.6 Hz, 1H), 5.95–5.78 (m, 2H), 5.50–5.35 (m, 2H), 5.29–5.05
(m, 5H), 4.49 (d, J=11 Hz, 1H), 4.45 (d, J=11 Hz, 1H), 4.25–4.12 (m,
2H), 3.82 (s, 3H), 3.65–3.60 (m, 2H), 3.45 (s, 3H), 2.51 (t, J=6.3 Hz,
2H), 2.02–1.95 (m, 2H), 1.65 (brs, 8H), 1.42 ppm (brs, 2H); 13C NMR
(75 MHz, CDCl3): d=166.9, 159.0, 153.6, 134.7, 134.1, 133.3, 130.3, 130.0,
129.5, 129.2, 129.1, 128.7, 124.1, 118.8, 118.0, 113.7, 113.6, 109.9, 94.4,
81.9, 81.4, 72.7, 72.1, 66.3, 56.1, 55.3, 36.6, 33.8, 25.2, 23.9 ppm; IR (neat):
n˜ =2936, 2860, 1732, 1646, 1615, 1577, 1514, 1471 cmÀ1; MS (EI): m/z:
592 [M+]; HRMS (EI): m/z: calcd for C35H44O8: 592.3036 [M+]; found:
592.2990.
Compound 11: NaHMDS (1.0m in THF, 4.49 mL, 4.49 mmol) was added
dropwise to a stirred solution of alcohol 4[22] (848 mg, 3.59 mmol) in an-
hydrous THF (20 mL) at 08C, and the mixture was stirred for 1 h. A so-
lution of compound 10 (1.10 g, 2.99 mmol) in THF (10 mL) was added to
the reaction mixture, which was stirred for 0.5 h at 08C and for an addi-
tional 2 h at room temperature. The reaction was quenched with 5%
HCl, the aqueous solution was extracted with AcOEt, and the combined
organic layer was dried over MgSO4. Evaporation of the solvent left a
residue, which was purified by chromatography on silica gel to give com-
pound 11 (1.53 g, 93%) as a colorless oil. [a]2D4 =À16.85 (c=1.00 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=11.26 (s, 1H), 7.34 (t, J=
8.0 Hz, 1H), 7.27 (d, J=15 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.94–6.90
(m, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.91–5.75 (m, 3H), 5.49–5.38 (m, 1H),
5.40 (d, J=17 Hz, 1H), 5.27 (d, J=10 Hz, 1H), 5.13 (d, J=9.9 Hz, 1H),
5.12 (d, J=18 Hz, 1H), 4.41 (d, J=11 Hz, 1H), 4.36 (d, J=11 Hz, 1H),
4.23–4.13 (m, 2H), 3.76 (s, 3H), 3.52–3.46 (m, 2H), 2.52–2.46 (m, 2H),
2.03–1.95 (m, 2H), 1.65 (brs, 8H), 1.42 ppm (brs, 2H); 13C NMR
General procedure for the RCMreaction of compounds 11–14 : Ru cata-
lyst (A–C, 5–20 mol%) was added to a solution of substrate (11–14,
0.1 mmol) in CH2Cl2 (100 mL), and the mixture was stirred at room tem-
Chem. Eur. J. 2008, 14, 5275 – 5281
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5279

Y. Matsuya, H. Nemoto, and S. Takayanagi
perature for 24 h under an Ar atmosphere. In the case described in
entry 6 of Table 1, the reaction was performed in 1,2-dichloroethane
under reflux at the same concentration for 24 h. The reaction mixture
was concentrated in vacuo and subjected to column chromatography. The
starting material, E isomer, and Z isomer could be easily separated. The
yields of isolated product are indicated in Table 1.
Compound 15-E: Pale-yellow oil; [a]2D7 =+146.02 (c=0.4 in CHCl3);
1H NMR (300 MHz, CDCl3): d=10.91 (s, 1H), 7.34 (t, J=8.0 Hz, 1H),
7.24 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H),
6.87 (d, J=8.8 Hz, 2H), 6.64 (d, J=16 Hz, 1H), 5.94 (dd, J=16, 6.6 Hz,
1H), 5.84–5.74 (m, 1H), 5.54–5.42 (m, 2H), 4.46 (d, J=12 Hz, 1H), 4.39
(d, J=12 Hz, 1H), 4.16 (dd, J=8.7, 6.6 Hz, 1H), 4.04 (t, J=8.7 Hz, 1H),
3.81 (s, 3H), 3.51 (dd, J=6.9, 5.8 Hz, 2H), 2.70–2.65 (m, 2H), 2.18–2.05
(m, 1H), 1.96–1.85 (m, 1H), 1.69 (brs, 8H), 1.26 ppm (brs, 2H);
13C NMR (75 MHz, CDCl3): d=170.5, 161.8, 159.2, 139.9, 135.7, 134.4,
131.8, 130.1, 129.4, 128.0, 125.1, 119.8, 117.0, 113.9, 112.1, 110.6, 83.4,
82.3, 73.3, 72.9, 66.6, 55.5, 37.0, 36.9, 35.0, 33.5, 25.4, 24.12, 24.07 ppm; IR
(neat): n˜ =2936, 2861, 1731, 1654, 1603, 1514, 1450 cmÀ1; MS (EI): m/z:
520 [M+]; HRMS: m/z: calcd for C31H36O7: 520.2461 [M+]; found:
520.2504.
Compound 15-Z: Pale-yellow oil; [a]2D8 =+84.59 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=10.12 (s, 1H), 7.33 (t, J=8.0 Hz, 1H),
7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H),
6.85 (d, J=8.0 Hz, 1H), 6.73 (d, J=17 Hz, 1H), 6.03 (dd, J=17, 4.4 Hz,
1H), 5.81 (dt, J=12, 4.5 Hz, 1H), 5.60 (dd, J=12, 9.1 Hz, 1H), 5.03 (m,
1H), 4.53 (t, J=9.1 Hz, 1H), 4.46 (d, J=12 Hz, 1H), 4.37 (d, J=12 Hz,
1H), 4.38–4.34 (m, 1H), 3.81 (s, 3H), 3.54 (dd, J=6.9, 5.8 Hz, 2H), 2.85–
2.73 (m, 1H), 2.42–2.37 (m, 1H), 2.29–2.18 (m, 1H), 1.94–1.83 (m, 1H),
1.68 (brs, 8H), 1.22 ppm (brs, 2H); 13C NMR (75 MHz, CDCl3): d=
170.5, 160.5, 159.2, 140.0, 134.2, 132.7, 132.6, 130.2, 129.6, 129.3, 126.7,
119.4, 116.5, 113.9, 112.5, 110.1, 79.6, 76.5, 76.1, 72.8, 66.1, 55.5, 36.9, 34.4,
33.3, 25.3, 24.12, 24.07 ppm; IR (neat): n˜ =3218, 2934, 2857, 1733, 1669,
1605, 1571, 1514, 1455 cmÀ1; MS (EI): m/z: 520 [M+]; HRMS: m/z calcd
for C31H36O7: 520.2461 [M+]; found: 520.2484.
Compound 16-E: Pale-yellow oil; [a]2D5 =+132.64 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.28 (d, J=8.8 Hz, 2H), 7.21 (t, J=
8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.74 (d, J=
8.0 Hz, 1H), 6.23 (d, J=16 Hz, 1H), 5.90 (dd, J=16, 7.4 Hz, 1H), 5.67–
5.57 (m, 1H), 5.47 (dd, J=16, 7.4 Hz, 1H), 5.04–4.97 (m, 1H), 4.50 (d,
J=11 Hz, 1H), 4.41 (d, J=11 Hz, 1H), 4.05 (dd, J=8.6, 7.4 Hz, 1H),
3.93 (dd, J=8.6, 7.4 Hz, 1H), 3.81 (s, 3H), 3.59 (t, J=6.3 Hz, 2H), 2.61–
2.52 (m, 1H), 2.43–2.24 (m, 2H), 1.96–1.87 (m, 1H), 1.67 (brs, 8H), 1.43
(brs, 2H), 0.98 (s, 9H), 0.24 ppm (s, 6H); 13C NMR (75 MHz, CDCl3):
d=168.3, 159.2, 151.6, 135.8, 133.1, 131.7, 130.4, 130.2, 129.4, 128.2, 126.8,
126.4, 117.84, 117.81, 113.9, 110.6, 83.1, 82.7, 77.1, 72.3, 66.4, 55.5, 36.9,
36.8, 35.4, 35.3, 25.9, 25.3, 24.1, 18.5, À3.7, À4.1 ppm; IR (neat): n˜ =2933,
2859, 1728, 1574, 1514, 1468 cmÀ1; MS (EI): m/z: 634 [M+]; HRMS: m/z:
calcd for C37H50O7Si: 634.3326 [M+]; found: 634.3322.
(s, 3H), 3.79 (s, 3H), 3.61–3.57 (m, 2H), 2.70–2.62 (m, 1H), 2.42–2.35 (m,
1H), 2.25–2.16 (m, 1H), 1.98–1.91 (m, 1H), 1.65 (brs, 8H), 1.40 ppm
(brs, 2H); 13C NMR (75 MHz, CDCl3): d=167.9, 155.3, 147.8, 135.5,
132.9, 131.4, 130.5, 130.4, 129.3, 128.6, 126.9, 123.3, 117.5, 113.8, 110.5,
109.8, 108.2, 82.9, 82.4, 75.3, 72.8, 66.2, 55.8, 55.3, 36.61, 36.56, 35.4, 35.3,
25.0, 23.80, 23.77 ppm; IR (neat): n˜ =2936, 2860, 1731, 1576, 1514,
1472 cmÀ1; MS (EI): m/z: 534 [M+]; HRMS: m/z: calcd for C32H38O7:
534.2618 [M+]; found: 534.2611.
Compound 17-Z: Colorless oil; [a]2D5 =+29.63 (c=0.46 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.33–7.26 (m, 3H), 6.93 (d, J=7.3 Hz,
1H), 6.88 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.53 (d, J=16 Hz,
1H), 5.97 (dd, J=16, 5.5 Hz, 1H), 5.89 (td, J=12, 4.3 Hz, 1H), 5.52–5.45
(m, 2H), 4.50 (d, J=11 Hz, 1H), 4.43–4.36 (m, 2H), 4.26 (td, J=6.0,
0.9 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.58 (t, J=6.4 Hz, 2H), 2.70–2.63
(m, 1H), 2.29–2.22 (m, 1H), 1.97–1.91 (m, 2H), 1.65 (brs, 8H), 1.40 ppm
(brs, 2H); 13C NMR (75 MHz, CDCl3): d=166.4, 159.1, 155.7, 137.0,
133.5, 130.8, 130.7, 130.4, 129.9, 129.3, 129.2, 127.5, 122.5, 118.9, 113.74,
113.70, 110.2, 109.9, 80.1, 76.6, 72.8, 66.0, 55.7, 55.2, 36.6, 36.5, 36.3, 34.2,
25.0, 23.8, 23.7 ppm; IR (neat): n˜ =2936, 2860, 1732, 1576, 1514,
1470 cmÀ1; MS (EI): m/z: 534 [M+]; HRMS: m/z: calcd for C32H38O7:
534.2618 [M+]; found: 534.2642.
Compound 18-E: Colorless oil; [a]2D5 =+117.60 (c=1.09 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.32–7.27 (m, 3H), 7.11 (d, J=7.7 Hz,
1H), 7.04 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 6.30 (d, J=16 Hz,
1H), 5.91 (dd, J=16, 8.5 Hz, 1H), 5.61 (ddd, J=16, 9.8, 5.1 Hz, 1H), 5.47
(dd, J=16, 8.1 Hz, 1H), 5.20–5.15 (m, 1H), 5.12 (s, 2H), 4.49 (d, J=
12 Hz, 1H), 4.42 (d, J=12 Hz, 1H), 4.07 (t, J=8.5 Hz, 1H), 3.92 (t, J=
8.1 Hz, 1H), 3.80 (s, 3H), 3.60 (t, J=6.8 Hz, 2H), 3.43 (s, 3H), 2.68–2.60
(m, 1H), 2.40–2.32 (m, 1H), 2.23–2.15 (m, 1H), 1.99–1.93 (m, 1H), 1.65
(brs, 8H), 1.41 ppm (brs, 2H); 13C NMR (75 MHz, CDCl3): d=167.7,
159.2, 152.8, 135.5, 132.8, 131.3, 130.4, 130.3, 129.2, 128.6, 126.9, 123.4,
118.6, 113.8, 113.5, 110.5, 94.5, 82.9, 82.3, 75.3, 72.8, 66.2, 56.1, 55.2, 36.6,
36.5, 35.4, 35.2, 25.0, 23.8 ppm; IR (neat): n˜ =2936, 2861, 1731, 1575,
1514, 1469 cmÀ1 MS (EI): m/z: 564 [M+]; HRMS: m/z: calcd for
;
C33H40O8: 564.2723 [M+]; found: 564.2709.
Compound 18-Z: Colorless oil; [a]2D5 =+41.31 (c=2.87 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.31–7.26 (m, 3H), 7.07 (d, J=8.6 Hz,
1H), 6.99 (d, J=7.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.52 (d, J=16 Hz,
1H), 5.98 (dd, J=16, 5.5 Hz, 1H), 5.89 (td, J=12, 4.3 Hz, 1H), 5.53–5.47
(m, 2H), 5.15 (d, J=6.8 Hz, 1H), 5.12 (d, J=6.8 Hz, 1H), 4.50 (d, J=
11 Hz, 1H), 4.42–4.38 (m, 2H), 4.26 (ddd, J=7.3, 6.0, 1.3 Hz, 1H), 3.80
(s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.42 (s, 3H), 2.72–2.65 (m, 1H), 2.28–
2.23 (m, 1H), 1.97–1.93 (m, 2H), 1.65 (brs, 8H), 1.41 ppm (brs, 2H);
13C NMR (75 MHz, CDCl3): d=166.2, 159.1, 153.3, 137.0, 133.5, 130.8,
130.6, 130.3, 129.8, 129.3, 129.2, 127.6, 123.4, 120.0, 113.8, 113.6, 110.2,
94.5, 80.0, 76.6, 72.8, 66.0, 56.1, 55.2, 36.6, 36.5, 36.3, 34.1, 25.0, 23.7 ppm;
IR (neat): n˜ =2936, 2860, 1732, 1575, 1514, 1466 cmÀ1; MS (EI): m/z: 564
[M+]; HRMS: m/z: calcd for C33H40O8: 564.2723 [M+]; found: 564.2740.
Compound 16-Z: Pale-yellow oil; [a]2D5 =+60.97 (c=0.48 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.30–7.22 (m, 3H), 6.97 (d, J=7.7 Hz,
1H), 6.89 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 6.52 (d, J=17 Hz,
1H), 6.03 (dd, J=17, 5.1 Hz, 1H), 5.86 (td, J=12, 4.3 Hz, 1H), 5.51 (t,
J=12 Hz, 1H), 5.39–5.32 (m, 1H), 4.48 (d, J=11 Hz, 1H), 4.45–4.40 (m,
2H), 4.30 (td, J=7.2, 1.3 Hz, 1H), 3.83 (s, 3H), 3.60 (t, J=6.4 Hz, 2H),
2.72–2.65 (m, 1H), 2.38–2.33 (m, 1H), 2.09–2.01 (m, 1H), 1.98–1.92 (m,
1H), 1.67 (brs, 8H), 1.43 (brs, 2H), 1.01 (s, 9H), 0.27 (s, 3H), 0.25 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=166.2, 159.1, 152.7, 137.6, 133.6,
130.5, 130.3, 130.2, 129.7, 129.2, 127.8, 124.5, 119.2, 118.3, 113.7, 110.1,
79.9, 76.7, 72.9, 72.4, 66.3, 60.4, 55.2, 36.6, 36.5, 35.9, 33.5, 25.7, 25.0, 23.8,
21.0, 18.3, 14.2, À4.1, À4.3 ppm; IR (neat): n˜ =2932, 2857, 1731, 1574,
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1514, 1464 cmÀ1 MS (EI): m/z: 634 [M+]; HRMS: m/z calcd for
;
C37H50O7Si: 634.3326 [M+]; found: 634.3334.
Compound 17-E: Colorless oil; [a]2D5 =+121.97 (c=0.6 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.32–7.26 (m, 3H), 7.06 (d, J=7.7 Hz,
1H), 6.88 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.1 Hz, 1H), 6.30 (d, J=16 Hz,
1H), 5.91 (dd, J=16, 7.7 Hz, 1H), 5.61 (ddd, J=16, 8.5, 5.1 Hz, 1H), 5.47
(dd, J=16, 8.1 Hz, 1H), 5.20–5.13 (m, 1H), 4.50 (d, J=12 Hz, 1H), 4.42
(d, J=12 Hz, 1H), 4.06 (t, J=8.5 Hz, 1H), 3.92 (t, J=8.1 Hz, 1H), 3.81
5280
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Chem. Eur. J. 2008, 14, 5275 – 5281

Ring-Closing Metathesis
FULL PAPER
[5] For recent reviews, see: a) A. Gradillas, J. Perez-Castells, Angew.
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[17] This proposal is not necessarily in agreement with the past theoreti-
cal studies but most likely rationalizes the experimental results ob-
tained here. We would like to emphasize that this hypothesis is not
applied in general but is limited to our present reaction system be-
cause the relative energy levels of RCM intermediates can be sub-
strate dependent.
[18] In the overall RCM process, a rate-determining step for the second-
generation catalysts has been reported to be a phosphine-dissocia-
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which determines the E/Z selectivity.
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Received: February 9, 2008
Published online: April 28, 2008
Chem. Eur. J. 2008, 14, 5275 – 5281
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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