Stereoselectivity in ring-closing olefin metathesis (RCM) of tethered dihexenoyl derivatives

Article abstract of DOI:10.1039/b111122c

Ring-closing olefin metatheses (RCM) of various tethered dihexenoyl derivatives were examined under various conditions. The E:Z ratios of the resulting double bonds of the cyclic products were determined. The stereochemistry of the resulting olefins was i

Full text of DOI:10.1039/b111122c

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Stereoselectivity in ring-closing olefin metathesis (RCM) of
tethered dihexenoyl derivatives
Mitsuhiro Arisawa, Hiroaki Kaneko, Atsushi Nishida and Masako Nakagawa*
1
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho Inage-ku,
Chiba 263-8522, Japan. E-mail: nakagawa@chiba.email.ne.jp; Fax: ϩ81-43-290-2909
Received (in Cambridge, UK) 5th December 2001, Accepted 11th February 2002
First published as an Advance Article on the web 1st March 2002
Ring-closing olefin metatheses (RCM) of various tethered dihexenoyl derivatives were examined under
various conditions. The E : Z ratios of the resulting double bonds of the cyclic products were determined.
The stereochemistry of the resulting olefins was influenced largely by the effects of the template used.
ase.6 To the best of our knowledge, the preparation of 9, which
might be used as a building block for biologically active natural
products, has not yet been reported. Although it is not yet clear
what factors control the stereoselectivity, we have now investi-
gated in detail the effects of solvents, catalysts, and/or templates
on the ratios of stereoisomers formed by RCM of various kinds
of dihexenoyl derivatives (Scheme 2). This article describes our
Introduction
Ring-closing olefin metathesis (RCM) is one of the most power-
ful methods for constructing a carbon–carbon double bond
between two olefins. Many researchers report that this method
is useful and apply it to the syntheses of natural products.1 It is
generally recognised that one of the major problems in ring-
closing ene–ene metatheses reactions is how to control/predict
the stereoselectivity in the formation of the new double bond.2,3
As part of our examination of the synthesis of nitrogen-
containing heterocycles using RCM4 and the Yb-catalysed
asymmetric Diels–Alder reaction,5 we report the syntheses of
novel axially chiral macrolactams using RCM. In the RCM
of dienes 1 and 3 to the 14-membered lactam 4 and the 18-
membered lactam 6, E-isomers are the major products.4c On the
other hand, the RCM of 2 to the 16-membered lactam 5 gave a
Z-isomer as the major product (Scheme 1).4c A stereocontrolled
Scheme 2
systematic approach to control the stereoselectivity in RCM
reactions using tethered dihexenoyl derivatives; and a dihex-
enoyl derivative with binaphthyldiamine 2, prepared by the
method we reported previously,4c was subjected to RCM reac-
tions under various conditions, and the ratio of regioisomers
formed was determined by comparison with the authentic
samples.
Results and discussion
Scheme 1
Solvent
RCM product 8 might be useful as a key intermediate for chiral
ligands, while the symmetric dicarboxylic acid 9 is a typical
metabolite of patients who lack medium acyl CoA dehydrogen-
Diene 2 was first treated in dichloromethane (3 mM) with 10
mol% of ruthenium carbene catalyst A7 at 50 ЊC for 4 h, and
DOI: 10.1039/b111122c
J. Chem. Soc., Perkin Trans. 1, 2002, 959–964
This journal is © The Royal Society of Chemistry 2002
959

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Table 1 Solvent effect in RCM: dihexenoyl derivative
Table 2 Catalyst effect in RCM: dihexenoyl derivative
Entry
Ru-complex (10 mol%)
Time/h
Yield (%)
E : Za
Entry
Solvent (3 mM)
Time/h
Yield (%)
E : Za
1
2
3
4
A
B
C
D
2.5
2.5
1.5
2.5
94
97
1 : 2.4
1 : 2.3
1 : 2.3
2.8 : 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH2Cl2
CHCl3
CCl4
ClCH2CH2Cl
Cl2CHCHCl2
CH2Br2
BrCH2CH2Br
C6H6
2.5
4.0
4.0
4.0
4.0
4.0
4.0
4.5
4.0
4.0
4.0
4.0
4.0
4.5
4.0
94
1 : 2.4
1 : 2.8
1 : 3.0
1 : 1.8
1 : 2.8
1 : 3.9
1 : 13
1 : 2.7
1 : 2.8
1 : 2.5
1 : 3.3
1 : 2.5
1 : 2.3
1 : 2.8
—
91
88
38b
88
20b
a Determined by HPLC (Chiralcel OD). b About 50% oligomers was by-
produced.
67b
62b
19b
69b
77b
61b
38b
50b
51b
43b
0
C6H5Cl
C6H5CH3
C6H5CF3
AcOEt
Acetone
THF
DME
a Determined by HPLC (Chiralcel OD). b Determined by 1H-NMR.
macrolactam 5 was obtained in 94% yield as a mixture of E and
Z isomers. These stereoisomers were readily separated by col-
umn chromatography to give an E : Z ratio of 1 : 2.4.4c Based on
these findings, we studied the stereochemical outcome of this
reaction in various solvents. These results are summarised in
Table 1. In other halocarbon solvents such as chloroform or
1,2-dichloroethane (entries 2 and 4), 5 was obtained in almost
the same yield, although the ratio of stereoisomers was
increased in chloroform and decreased in 1,2-dichloroethane.
In tetrachloromethane, 1,1,2,2-tetrachloroethane, and dibromo-
methane (entries 3, 5, and 6), the diastereoselectivity was
increased but the yields were decreased. The reaction in 1,2-
dibromoethane (entry 7) gave the best diastereoselectivity,
although the yield decreased to 19%. In aromatic solvents
(entries 8–11), 5 was obtained in good to moderate yields,
and the diastereoselectivity was almost the same as it was in
dichloromethane. Reactions in ethyl acetate, acetone, and tetra-
hydrofuran also gave 5, but the polar solvent 1,2-dimethoxy-
ethane (DME) gave no product (entries 12–15). Due to the
poor conversion, tetrachloromethane, 1,2-dibromoethane and
α,α,α-trifluorotoluene gave 5 in lower yields, and it is known
that Grubb’s catalyst can react with halogenated solvent.8 Some
solvents showed enhanced E–Z selectivity compared to dichloro-
methane, but only to a small extent.
the stereoselectivity of these cyclised compounds efficiently, we
developed an analytical method that involves the conversion of
(E)-5 or (Z)-5 to the corresponding 11 (Scheme 3). Since (E)-11
and (Z)-11 exhibit strong UV absorbances, the ratio of (E)-11
to (Z)-11 could be easily determined by HPLC (tR-(E)11 = 45.92
min, tR-(Z)11 = 33.98 min. Chiralpak AD, i-PrOH : n-hexane =
5 : 95, 1.0 ml minϪ1). Scheme 4 shows our four-step procedure
starting with the preparation of dihexenoyl derivatives 7 from a
template 12 and hexenoic acid, RCM to give 8, and conversion
of 8 to 11. The experimental details are summarised in Table
3. Each of the following was used as a template: catechol,
cyclohexane-1,2-diol 12d,e, cyclopentane-1,2-diol 12f,g, or
butane-1,4-diol 12h. The reactions using each template gave
Z-isomers as with binaphthyl-2,2Ј-diamine, and 12g gave the
highest Z-selectivity. On the other hand, 2,2’-bi-2-napthol 12a
and biphenyl-2,2Ј-diol 12b gave predominantly E-isomers.
These results suggest that some strict chelation or steric effect
may affect the stereoselectivity in a newly formed double
bond.11
Conclusions
In conclusion, we studied the RCM reactions of tethered dihex-
enoyl derivatives under various conditions (i.e. with various
solvents, catalysts, and templates) and examined the stereo-
selectivity of the reaction leading to the new double bond. Of
the conditions investigated, the selection of a template was
found to be the most effective way to influence stereoselectivity
and that the desired isomer could be obtained as a major prod-
uct. Further studies to control the stereoselectivity in RCM are
underway in our laboratory.
Catalyst
Next, we examined the effects of catalysts B–D9 in the RCM
reaction of diene 2 (Table 2). With catalysts B and C, 2 gave 5 in
excellent yields, with almost the same selectivity as in the reac-
tion with catalyst A. On the other hand, with the 4th-generation
catalyst D, 2 gave 5 in only 20% yield and undesired oligomeric
compounds were formed. However, the stereoselectivity of 5
was dramatically changed, and the E-isomer became the major
isomer.10 Thus, none of the catalysts A–D was particularly
effective in influencing the stereochemical outcome of the
reaction.
Experimental
All melting points are uncorrected. Infrared (IR) absorption
spectra (cmϪ1) were recorded using a KBr pellet. Specific optical
rotations were measured on a JASCO DIP-140 and are given in
units of 10Ϫ1 deg cm2 gϪ1.1H NMR (and 13C NMR) spectra
were recorded in CDCl3 unless otherwise noted, at 400, 500 or
Template
Finally, we examined the effects of various templates. The
binaphthyldiamine moiety in 2 was replaced by other templates,
such as binaphthol, biphenol, catechol, and diols. To determine
960
J. Chem. Soc., Perkin Trans. 1, 2002, 959–964

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Table 3 Template effect in RCM: dihexenoyl derivative
E : Za
Yield (%)
1 : 2.4
94
1.3 : 1
28
1.6 : 1
54
1 : 2.5
96
1 : 4.6
71
1 : 3.1
67
1 : 3.6
84
1 : 4.8
50
1 : 1.3
75
a Determined by HPLC (ChiralPak AD).
Scheme 3 General procedure for common ester synthesis.
Scheme 4 Experimental cycle.
600 MHz, with TMS as an internal standard. E. Merck silica
gel 60 was used for column chromatography, and E. Merck
precoated TLC plates, silica gel F254, were used for prepar-
ative thin layer chromatography. The organic layers were dried
The reaction was quenched by adding 1 M aq. NaOH (10.0
mL), and organic products were extracted with CH2Cl2. The
combined organic layers were washed with 1 M HCl and brine.
The solvent was removed by an evaporator, and the residue was
subjected to column chromatography (AcOEt–n-hexane = 1 : 5)
to give 2 (712 mg, 75%) as colorless rods.
with anhydrous MgSO or Na SO . Cl (PCy ) Ru᎐CHPh was
᎐
4
2
4
2
3 2
obtained commercially.
2: colorless rods (AcOEt–n-hexane); mp 148–149; [α]2D4
=
1
ϩ83.0 (c 1.00, CHCl3). H-NMR (400 MHz, CDCl3): δ 8.34
(2H, d, J = 9.0 Hz), 8.04 (2H, d, J = 9.0 Hz), 7.94 (2H, d, J =
8.3 Hz), 7.45 (2H, dd, J = 6.9, 1.0 Hz), 7.28 (2H, dd, J = 8.3,
7.8 Hz), 7.06 (2H, d, J = 8.5 Hz), 6.96 (2H, br s), 5.56–5.47 (2H,
m), 4.80 (2H, dd, J = 22.4, 1.0 Hz), 4.76 (2H, dd, J = 29.2,
1.0 Hz), 1.99 (4H, td, J = 7.7, 3.4 Hz), 1.76 (4H, dd, J = 14.2,
7.3 Hz), 1.42–1.36 (4H, m); 13C-NMR (100 MHz, CDCl3):
δ 171.99, 137.42, 134.80, 132.36, 131.43, 129.74, 128.30, 127.24,
125.64, 125.10, 122.56, 122.19, 115.14, 36.32, 32.50, 24.21; IR
(KBr) cmϪ1: 3208, 3004, 2917, 2849, 1652, 1592, 1572, 1493,
Synthesis of (R)-N,NЈ-dihex-5-enoyl-1,1Ј-binaphthyl-2,2Ј-
diamine (2)
To a stirring solution of N-methylmorpholine (0.550 mL,
2.5 eq.) in CH2Cl2 (10.0 mL), were added hex-5-enoic acid
(0.550 mL, 2.3 eq.) and isobutyl chloroformate (0.550 mL, 2.1
eq.) at Ϫ15 ЊC under an Ar atmosphere. To this mixture was
added a solution of (R)-1,1Ј-binaphthyl-2,2Ј-diamine (569 mg,
2.0 mmol) in CH2Cl2 (10.0 mL) at Ϫ15 ЊC, and stirring was
continued at the same temperature for 30 min and at rt for 3 h.
J. Chem. Soc., Perkin Trans. 1, 2002, 959–964
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1427, 1252, 1025, 992, 907, 863, 818, 778, 748; LRMS (EI):
m/z 476 (Mϩ); HRMS (FAB): calcd for C32H33O2N2 (Mϩ ϩ H):
477.2534, found 477.2521.
pounds were extracted with ether. Organic layers were dried
over MgSO4 and filtered, and the solvents were removed under
vacuum. To the crude residue obtained were added CH2Cl2,
DMAP (0.1 eq.), DCC (2.2 eq.) and β-naphthol (2.05 eq.), and
stirring was continued at rt for 12 h. The reaction mixture was
filtered and subjected to column chromatography (SiO2,
AcOEt–n-hexane = 1 : 20) to give 11.
Synthesis of (R)-N,NЈ-(dec-5-ene-1,10-dioyl)-1,1Ј-binaphthyl-
2,2Ј-diamine (5)
To a stirring solution of 2 (812 mg, 1.70 mmol) in CH2Cl2
(500 mL) was added ruthenium catalyst A (141 mg, 0.170
mmol). The solvent was degassed three times by the FPT
(freeze–pump–thaw cycles) method, and the reaction mixture
was stirred at 50 ЊC for 2.5 h. The solvent was removed under
reduced pressure to give a residue, which was purified by silica
gel column chromatography (n-hexane : AcOEt = 15 : 1). (E)-5
(235 mg, 28%) and (Z)-5 (563 mg, 66%) were isolated as color-
less rods, respectively.
1
(Z)-11: white solid; mp. 115–117 ЊC; H-NMR (400 MHz,
CDCl3): δ 7.2 (4H, d, J = 8.5 Hz), 7.78–7.76 (2H, m), 7.53
(2H, br d), 7.48–7.42 (4H, m), 7.21 (2H, dd, J = 8.7, 2.2 Hz),
5.51 (2H, t, J = 4.7 Hz), 2.63 (4H, t, J = 7.5 Hz), 2.25 (4H, dd,
J = 12.6, 7.0 Hz), 1.92–1.85 (4H, m); 13C-NMR (100 MHz,
CDCl3): δ 172.24, 148.32, 133.73, 131.38, 129.73, 129.35,
127.72, 127.59, 126.49, 125.62, 121.11, 118.44, 33.76, 26.56,
24.79; LRMS (FAB) m/z 453 (Mϩ ϩ H); HPLC (Chiralpak AD,
i-PrOH–n-hexane = 5 : 95, 1.0 ml minϪ1) tR = 33.98 min.
(E)-5: colorless rods (AcOEt–n-hexane); mp 262–263; [α]2D0
=
1
(E)-11: white solid; mp. 109–111 ЊC; H-NMR (600 MHz,
1
ϩ59.7 (c 1.00, CHCl3). H-NMR (400 MHz, CDCl3): δ 8.77
(2H, d, J = 8.3 Hz), 8.07 (2H, d, J = 9.1 Hz), 7.94 (2H, d, J =
8.2 Hz), 7.43 (2H, dd, J = 7.3, 7.6 Hz), 7.24 (2H, dd, J = 7.3,
7.6 Hz), 6.94 (2H, d, J = 8.5 Hz), 6.84 (2H, br s), 5.35 (2H, br s),
2.24–2.19 (4H, m), 2.05–1.80 (6H, m), 1.40–1.30 (2H, m);
13C-NMR (100 MHz, CDCl3): δ 171.65, 135.17, 132.61, 130.91,
130.28, 128.28, 127.24, 125.31, 120.12, 36.01, 31.52, 22.94;
IR (KBr) cmϪ1: 3401, 2923, 1700, 1598, 1500, 1427, 1334,
1274, 1174, 971, 821, 752; LRMS (FAB): m/z 449 (Mϩ ϩ H);
HRMS (FAB): calcd for C30H29O2N2 (Mϩ ϩ H): 449.2229,
found 449.2225; HPLC (Chiralcel OD, i-PrOH–n-hexane =
5 : 95, 1.0 ml minϪ1) tR = 15.12 min.
CDCl3): δ 7.2 (4H, d, J = 8.5 Hz), 7.78–7.76 (2H, m), 7.53 (2H,
br d), 7.48–7.42 (4H, m), 7.21 (2H, dd, J = 8.7, 2.2 Hz), 5.53
(2H, t, J = 3.8 Hz), 2.63 (4H, t, J = 7.4 Hz), 2.19 (4H, dd, J =
12.3, 7.1 Hz), 1.87–2.05 (4H, m); LRMS (FAB) m/z 453 (Mϩ ϩ
H); HPLC (Chiralpak AD, i-PrOH–n-hexane = 5 : 95, 1.0 ml
min1) tR = 45.92 min.
Synthesis of dihexenoate (7a–7h) (condensation of acid with
templates)
To a stirring solution of template 12 (2.00 mmol) in CH2Cl2
(10.0 mL) was added DMAP (0.100 eq.), DCC (2.20 eq.) and
hex-5-enoic acid (2.1 eq.). This was stirred for 1–3 h until all
of 12 was consumed. The mixture was filtered through Celite
545 and subjected to column chromatography (SiO2, AcOEt–n-
hexane) to give 7.
(Z)-5: colorless rods mp >300 ЊC (from AcOEt–n-hexane);
[α]2D0 = ϩ39.0 (c 1.00, CHCl3). H-NMR (400 MHz, CDCl3):
1
δ (ppm) 8.74 (2H, d, J = 9.0 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.94
(2H, d, J = 8.1 Hz), 7.43 (2H, ddd, J = 8.1, 6.9, 1.2 Hz), 7.24
(2H, ddd, J = 8.5, 6.9, 1.2 Hz), 6.93 (2H, d, J = 8.5 Hz), 6.88
(2H, br s), 5.32 (2H, dd, J = 4.2, 4.2 Hz), 2.27–2.21 (2H, m),
2.18–2.13 (2H, m), 2.01–1.83 (6H, m), 1.42–1.36 (2H, m);
13C-NMR (100 MHz, CDCl3): δ (ppm) 171.6, 135.0, 132.6,
130.9, 130.1, 129.7, 128.2, 127.1, 125.3, 125.3, 120.5, 118.4,
36.7, 26.3, 24.2; IR (KBr) cmϪ1 3221, 2921, 1686, 1499; LRMS
(FAB) m/z 449 (Mϩ ϩ H); HRMS (FAB) calcd for C30H29N2O2
(Mϩ ϩ H): 449.2229, found 449.2225; HPLC (Chiralcel OD,
i-PrOH–n-hexane = 5 : 95, 1.0 ml minϪ1) tR = 21.74 min.
Hex-5-enoic acid 2Ј-hex-5-enoyloxy-1,1Ј-binaphthalenyl-2-yl
ester (7a). Pale yellow oil; 98% yield; Rf = 0.54 (AcOEt–n-
hexane = 1 : 4);. 1H-NMR (400 MHz, CDCl3): δ 7.98–7.90 (4H,
m), 7.46–7.39 (4H, m), 7.31–7.21 (4H, m), 5.55–5.48 (2H, m),
4.86–4.76 (4H, m), 2.09 (4H, td, J = 7.3, 3.9 Hz), 1.66–1.63 (4H,
m), 1.27–1.21 (4H, m); LRMS (FAB) m/z 479 (Mϩ ϩ H);
HRMS (FAB) calcd for C32H31O4 (Mϩ ϩ H): 479.2214, found
479.2192.
Conversion of 5 to dec-5-enedioic acid dimethyl ester (10)
Hex-5-enoic acid 2Ј-hex-5-enoyloxybiphenyl-2-yl ester (7b).
Colorless oil; 88% yield; Rf = 0.61 (AcOEt–n-hexane = 1 : 4);
1H-NMR (400 MHz, CDCl3): δ 7.40–7.35 (2H, m, Ar), 7.29–
7.24 (5H, m), 7.14–7.11 (2H, m), 5.72–5.65 (2H, m), 4.97–4.92
(4H, m), 2.29 (4H, t, J = 7.3 Hz), 1.96–1.91 (4H, m), 1.59–1.52
(4H, m); LRMS (FAB) m/z 379 (Mϩ ϩ H); HRMS (FAB) calcd
for C24H27O4 (Mϩ ϩ H): 379.1902, found 379.1912.
To a stirring solution of (E)-5 or (Z)-5 in MeOH was added
c. H2SO4 (3.00 eq.), and the mixture was refluxed until all of the
starting material was consumed on TLC. To the reaction
mixture was added sat. aq. NaHCO3, and organic compounds
were extracted with AcOEt. The combined organic layers were
washed in brine and dried over Na2SO4. The solvent was
removed using a rotary evaporator, and the remaining residue
was subjected to column chromatography (SiO2, n-hexane–
AcOEt = 10 : 1) to give (E)-10 or (Z)-10, respectively, together
with (R)-1,1Ј-binaphthyl-2,2Ј-diamine.
Hex-5-enoic acid 2-hex-5-enoyloxyphenyl ester (7c). Colorless
1
oil; 56% yield; Rf = 0.57 (AcOEt–n-hexane = 1 : 4); H-NMR
(400 MHz, CDCl3): δ 7.24–7.15 (4H, m), 5.85–5.75 (2H, m),
5.08–5.01 (4H, m), 2.53 (4H, t, J = 7.4 Hz), 2.16 (4H, dd, J =
14.0, 7.4 Hz), 1.86–1.79 (4H, m); LRMS (FAB) m/z 379 (Mϩ ϩ
H); HRMS (FAB) calcd for C18H23O4 (Mϩ ϩ H): 303.1590,
found 303.1587.
E-10: colorless oil; 1H-NMR (400 MHz, CDCl3): δ 5.32 (2H,
t, J = 3.7 Hz), 3.59 (6H, s), 2.23 (4H, t, J = 7.5 Hz), 1.97–1.93
(4H, m), 1.65–1.58 (4H, m); 13C-NMR (100 MHz, CDCl3):
δ 174.12, 130.14, 51.44, 33.35, 31.84, 24.62.
Z-10: colorless oil; 1H-NMR (400 MHz, CDCl3): δ 5.31 (2H,
t, J = 4.6 Hz), 3.60 (6H, s), 2.24 (4H, t, J = 7.2 Hz), 2.01–1.96
(4H, m), 1.65–1.57 (4H, m); 13C-NMR (100 MHz, CDCl3):
δ 174.05, 129.59, 51.45, 33.42, 26.51, 24.79.
Hex-5-enoic acid cis-2-hex-5-enoyloxycyclohexyl ester (7d).
Colorless oil; 73% yield; Rf = 0.43 (AcOEt–n-hexane = 1 : 4);
1H-NMR (400 MHz, CDCl3): δ 5.83–5.72 (2H, m), 5.05–4.96
(4H, m), 2.30 (4H, t, J = 7.5 Hz), 2.09 (4H, dd, J = 14.0, 7.3 Hz),
1.86–1.79 (2H, m), 1.74 (2H, t, J = 7.5 Hz), 1.70 (2H, t, J =
7.3 Hz), 1.64–1.62 (4H, m), 1.45–1.42 (2H, m); 13C-NMR
(100 MHz, CDCl3): δ 172.56, 137.52, 115.14, 70.59, 33.56,
32.82, 27.53, 23.95, 21.53; LRMS (FAB) m/z 309 (Mϩ ϩ H);
HRMS (FAB) calcd for C18H29O4 (Mϩ ϩ H): 309.2058, found
309.2057.
Conversion of 10 to dec-5-enedioic acid di-2-naphthyl ester (11)
To a stirring solution of (E)-10 or (Z)-10 in THF–H2O (6 : 4)
was added KOH (3.00 eq.), and the mixture was refluxed until
all of the starting material was consumed (as shown by TLC).
The reaction mixture was then washed with ether. To the
reaction mixture was added 1 M HCl, and the organic com-
962
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Hex-5-enoic acid trans-2-hex-5-enoyloxycyclohexyl ester (7e).
Colorless oil; 65% yield; Rf = 0.53 (AcOEt–n-hexane = 1 : 4);
1H-NMR (400 MHz, CDCl3): δ 5.81–5.71 (2H, m), 5.04–4.95
(4H, m), 4.82–4.80 (2H, m), 2.27 (4H, td, J = 7.5, 0.9 Hz), 2.09–
2.02 (6H, m), 1.73–1.65 (6H, m), 1.40–1.31 (4H, m); 13C-NMR
(100 MHz, CDCl3): δ 172.72, 137.42, 115.25, 73.30, 33.61,
32.85, 30.02, 24.00, 23.26; LRMS (FAB) m/z 309 (Mϩ ϩ H);
HRMS (FAB) calcd for C18H29O4 (Mϩ ϩ H): 309.2058, found
309.2057.
23.49, 21.557; LRMS (FAB) m/z 281 (Mϩ ϩ H); HRMS (FAB)
calcd for C16H25O4 (Mϩ ϩ H): 281.1746, found 281.1765.
threo-1,2,3,4,4a,7,8,9,12,13,14,16a-Dodecahydro-5,16-dioxa-
benzocyclotetradecene-6,15-dione (8e). Brown oil; 67% yield; Rf
= 0.57 (AcOEt–n-hexane = 1 : 4); 1H-NMR (400 MHz, CDCl3,
E–Z mixture): δ 5.41–5.33 (2H, m), 4.86–4.84 & 4.81–4.78 (2H,
m), 2.35–2.26 (4H, m), 2.10–2.03 (6H, m), 1.86–1.54 (6H, m),
1.34 (4H, br d, J = 4.9 Hz); 13C-NMR (100 MHz, CDCl3, E–Z
mixture): δ 173.17, 129.88, 129.80, 74.03, 33.18, 31.85, 30.73,
30.64, 25.95, 24.33, 23.74, 22.29; LRMS (FAB) m/z 281 (Mϩ ϩ
H); HRMS (FAB) calcd for C16H25O4 (Mϩ ϩ H): 281.1746,
found 281.1753.
Hex-5-enoic acid cis-2-hex-5-enoyloxycyclopentyl ester (7f ).
Colorless oil; quant.; Rf = 0.53 (AcOEt–n-hexane = 1 : 4);
1H-NMR (400 MHz, CDCl3): δ 5.82–5.72 (2H, m), 5.15–4.97
(6H, m), 2.31–2.27 (4H, m), 2.10–1.59 (16H, m). 13C-NMR
(100 MHz, CDCl3): δ 172.69, 137.52, 115.18, 73.84, 33.42,
32.87, 28.07, 23.91, 18.99; LRMS (FAB) m/z 295 (Mϩ ϩ H).
erythro-2,3,3a,6,7,8,11,12,13,15a-Decahydro-1H-4,15-dioxa-
cyclopentacyclotetradecene-5,14-dione (8f ). White solid; 84%
yield; Rf = 0.47 (AcOEt–n-hexane = 1 : 4); 1H-NMR (400 MHz,
CDCl3, E–Z mixture): δ 5.35–5.30 (2H, m), 5.16–5.12 (2H, m),
2.44 & 2.40 (2H, dd, J = 9.7, 2.9 Hz), 2.35–2.23 (2H, m), 2.20–
2.11 (2H, m), 2.02–1.99 (4H, m), 1.87–1.79 (4H, m), 1.62–1.50
(4H, m); 13C-NMR (100 MHz, CDCl3, E–Z mixture): δ 173.12,
172.81, 130.39, 129.97, 73.89, 73.68, 32.77, 32.38, 31.47, 28.98,
25.81, 24.36, 22.68, 19.20, 19.06; LRMS (FAB) m/z 267 (Mϩ ϩ
H).
Hex-5-enoic acid trans-2-hex-5-enoyloxycyclopentyl ester
(7g). Colorless oil; 71% yield; Rf = 0.68 (AcOEt–n-hexane =
1 : 4); 1H-NMR (400 MHz, CDCl3): δ 5.81–5.71 (2H, m), 5.07–
4.96 (6H, m), 2.31–2.27 (4H, m), 2.12–2.05 (6H, m), 1.80–1.60
(8H, m); 13C-NMR (100 MHz, CDCl3): δ 172.69, 137.51,
115.29, 76.67, 33.48, 32.90, 30.25, 23.91, 21.36; LRMS (FAB)
m/z 295 (Mϩ ϩ H).
Hex-5-enoic acid 4-hex-5-enoyloxybutyl ester (7h). Colorless
oil; 90% yield; Rf = 0.55 (AcOEt–n-hexane = 1 : 4); H-NMR
(400 MHz, CDCl3): δ 5.83–5.72 (2H, m), 5.05–4.97 (4H, m),
4.09 (4H, t, J = 5.5 Hz), 2.31 (4H, t, J = 7.5 Hz), 2.09 (4H, dd,
J = 14.1, 7.4 Hz), 1.76–1.69 (8H, m); 13C-NMR (100 MHz,
CDCl3): δ 173.50, 137.60, 115.30, 63.68, 33.47, 33.00, 25.29,
24.00; LRMS (FAB) m/z 283 (Mϩ ϩ H).
threo-2,3,3a,6,7,8,11,12,13,15a-Decahydro-1H-4,15-dioxa-
cyclopentacyclotetradecene-5,14-dione (8g). Brown oil; 50%
yield; Rf = 0.50 (AcOEt–n-hexane = 1 : 4); 1H-NMR (400 MHz,
CDCl3, E–Z mixture): δ 5.41–5.36 (2H, m), 5.16–5.09 (2H, m),
2.40–2.28 (4H, m), 2.25–2.19 (2H, m), 2.12–1.97 (4H, m), 1.84–
1.74 (2H, m), 1.71–1.62 (4H, m), 1.54–1.48 (2H, m); 13C-NMR
(100 MHz, CDCl3, E–Z mixture): δ 173.61, 129.65, 129.52,
77.00, 76.68, 34.08, 33.06, 31.24, 27.23, 26.79, 26.02, 25.05,
22.79, 18.51; LRMS (FAB) m/z 267 (Mϩ ϩ H).
1
RCM reaction of dihexenoate (general procedure)
Ru catalyst was added to a stirring solution of coupling precur-
sor in CH2Cl2, and the mixture was stirred under the conditions
described in the text. The solvent was removed to leave a crude
residue, which was subjected to silica gel column chrom-
atography. The cyclised product was obtained in good yield.
1,6-Dioxacyclohexadec-11-ene-7,16-dione (8h). Brown oil;
75% yield; Rf = 0.31 (AcOEt–n-hexane = 1 : 4); H-NMR (400
MHz, CDCl3, E–Z mixture): δ 5.38–5.35 (2H, m), 4.19–4.12
(4H, m), 2.35–2.30 (4H, m), 2.09–2.04 (4H, m), 1.78–1.64 (8H,
m); LRMS (FAB) m/z 255 (Mϩ ϩ H).
1
O,OЈ-(Dec-5-ene-1,10-dioyl)-1,1Ј-bi-2,2Ј-naphthol
(8a).
Brown amorphous solid; 28% yield; Rf = 0.51 (AcOEt–n-hexane
= 1 : 4); H-NMR (400 MHz, CDCl3, E–Z mixture): δ 7.99 &
Acknowledgements
1
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) “Exploitation of Multi-
Element Cyclic Molecules” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
7.98 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.52–7.41 (4H,
m), 7.27–7.22 (2H, m), 7.11 (2H, t, J = 8.1 Hz), 5.50–5.43 (2H,
m), 2.28–2.04 (8H, m), 1.67–1.65 (4H, m); LRMS (FAB)
m/z 451 (Mϩ ϩ H).
7,8,9,12,13,14-Hexahydro-5,16-dioxadibenzo[a,c]cyclohexa-
decene-6,15-dione (8b). Brown amorphous solid; 54% yield; Rf =
0.57 (AcOEt–n-hexane = 1 : 4); H-NMR (400 MHz, CDCl3,
References
1
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E–Z mixture): δ 7.41–7.20 (10H, m), 5.53 (2H, t, J = 2.4 Hz),
2.46–2.22 (8H, m), 2.05–1.93 (2H, m), 1.78–1.76 (2H, m);
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6,15-dione (8c). Brown oil; 96% yield; Rf = 0.42 (AcOEt–n-
1
hexane = 1 : 2); H-NMR (400 MHz, CDCl3, E–Z mixture):
δ 7.25–7.22 (2H, m), 7.19–7.16 (2H, m), 5.40 (2H, t, J = 4.8 Hz),
2.61 & 2.60 (4H, t, J = 5.8 Hz), 2.26–2.21 (4H, m), 1.86–1.77
(4H, m); LRMS (FAB) m/z 275 (Mϩ ϩ H).
erythro-1,2,3,4,4a,7,8,9,12,13,14,16a-Dodecahydro-5,16-
dioxabenzocyclotetradecene-6,15-dione (8d). Brown oil; 71%
yield; Rf = 0.63 (AcOEt–n-hexane = 1 : 4); 1H-NMR (400 MHz,
CDCl3, E–Z mixture): δ 5.31–5.28 (2H, m), 4.95 & 4.90 (2H, d,
J = 6.5 Hz), 2.38–2.18 (4H, m), 2.04–1.98 (4H, m), 1.90–1.82
(2H, m), 1.72–1.52 (8H, m), 1.35 (2H, br s); 13C-NMR (100
MHz, CDCl3, E–Z mixture): δ 173.23, 172.74, 130.09, 129.82,
71.29, 70.98, 33.42, 33.06, 31.39, 27.62, 27.50, 26.01, 24.71,
3 Alkyne metathesis: (a) A. Fürstner, C. Mathes and C. W. Lehmann,
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and G. Seidel, J. Am. Chem. Soc., 1999, 121, 11108; (c) A. Fürstner
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9 Catalyst B: (a) S. T. Nguyen, R. H. Grubbs and J. W. Ziller, J. Am.
Chem. Soc., 1993, 115, 9858; (b) S. T. Nguyen, R. H. Grubbs and
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10 It is reported that catalysts C and D result in improved selectivity in
the (E)-cycloalkene.2c,2d
11 In the RCM reactions of other substrates, it was also reported that
minor changes at remote sites of the substrate can have a daramatic
effect on the E : Z ratio.2a,2e,2i,4b
964
J. Chem. Soc., Perkin Trans. 1, 2002, 959–964