Nickel-mediated cyclization of enynes under an atmosphere of carbon dioxide

Article abstract of DOI:10.1016/j.tet.2006.03.121

Nickel-mediated carboxylation of α,ω-enyne was investigated. In the presence of a stoichiometric amount of zero-valent nickel complex, enynes having an electron-withdrawing group on alkene reacted with carbon dioxide via intramolecular cyclization to affo

Full text of DOI:10.1016/j.tet.2006.03.121

Tetrahedron 62 (2006) 7589–7597
Nickel-mediated cyclization of enynes under
an atmosphere of carbon dioxide
a,
Masanori Takimoto,c Takashi Mizuno,a Miwako Morib, and Yoshihiro Sato
*
*
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
bHealth Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 061-0293, Japan
cOrganometallic Chemistry Laboratory, RIKEN (The Institute of Physical and Chemical Research),
Hirosawa 2-1, Wako, Saitama 351-0198, Japan
Received 7 December 2005; revised 3 March 2006; accepted 3 March 2006
Available online 12 June 2006
Dedicated to Professor G€unther Wilke for his contribution to the field of organonickel chemistry
Abstract—Nickel-mediated carboxylation of a,u-enyne was investigated. In the presence of a stoichiometric amount of zero-valent nickel
complex, enynes having an electron-withdrawing group on alkene reacted with carbon dioxide via intramolecular cyclization to afford cyclic
carboxylic acids in good yields. Various heterocyclic compounds were prepared by this carboxylative cyclization protocol. The reaction seems
to proceed through oxidative cycloaddition of the a,u-enyne moiety to a zero-valent nickel complex, regioselective insertion of carbon
dioxide at the Csp3-nickel bond, and hydrolysis of the resulting oxanickelacycle intermediate.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
proceeds through insertion of CO2 into a bis-allylmetal inter-
mediate.4–9
Development of the carbon dioxide (CO2) incorporation
reaction into organic molecules is regarded as an important
subject in synthetic organic chemistry. However, despite its
abundant reserve and lower toxicity, the utility in synthetic
organic chemistry has been limited because of its high
thermodynamic stability and kinetic inertness. To overcome
this disadvantage, various methods using transition metal
complexes as promoters or catalysts have been explored.1
The oxidative cycloaddition of CO2 and unsaturated hydro-
carbons to low-valent transition metal complexes is one of
the most extensively studied CO2 incorporation processes
(Scheme 1, path A) and much interest has been shown in
nickel-mediated processes.2,3 Another potentially useful
process is the insertion of CO2 into metallacycle intermedi-
ates, which are readily prepared by oxidative cycloaddition
of two unsaturated hydrocarbon components to low-valent
transition metals (Scheme 1, path B). This process is also
highly attractive because multiple carbon–carbon bond
formations are accomplished during the process; how-
ever, synthetic reactions that utilize such a process have
rarely been explored except for palladium- or nickel-
catalyzed co-oligomerization of 1,3-dienes with CO2, which
O
C
M
O
O
O
M
"M"
R1
R1
CO2
R2
path A
R2
R1
R2
R3
R2
path B
R2
O
O
alkyne
alkene
etc
R1
R3
R1
R3
"M"
CO2
R4
M
M
R4
R4
Scheme 1.
To fill this void in CO2 incorporation chemistry, a nickel-
mediated reaction using a,u-enynes as metallacycle precur-
sors have been explored. It was envisioned that a,u-enyne I
will readily react with a zero-valent nickel complex to form
oxanickelacyclopentene II (Scheme 2).10–13 There are two
possible pathways by which CO2 is inserted into II. If com-
plex II undergoes insertion of CO2 at the Csp3-nickel bond
(path a), oxanickelacycloheptene III would be formed, and
this would be hydrolyzed to provide carboxylic acid VI.
The other possible pathway, i.e., insertion of CO2 into the
Csp2–nickel bond (path b), would provide a,b-unsaturated
carboxylic acid V through the formation of oxanickelacyclo-
heptene IV. Herein, we described the results of our investiga-
tion of a nickel-mediated cyclization–carboxylation cascade
of a,u-enynes.14
* Corresponding authors. Tel.: +81 11 706 4982; fax: +81 11 706 4982
(Y.S.); tel.: +81 11 787 6045; fax: +81 11 787 6045 (M.M.); e-mail
addresses: mori@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.121

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M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
Table 1. Carboxylative cyclization of 2a under various conditionsa
R1
R1
(a)
Ni
(b)
R2
R1
O
Entry Solvent Ligand
Additive Temp Time Yields (%)
(ꢀC)
Ni(0)
CO2
O
Ni
(h)
insertion
3a
4a
R2
path a
DBUb
DBUb
DBUb
—
—
—
—
—
40 18
Reflux 13
48
9
38
77
30
15
25
9
I
R2
III
II
1
2
3
4
5
6
7
8
9
THF
THF
THF
CO2
insertion
H3O+
R1
path b
40
40
40
3
18
3
55
41
60
70
8
Toluene DBUb
Dioxane DBUb
R1
R1
Dioxane DBUb
MS 4A 40
40
MS 4A 40
3
12
4
˚
H3O+
Ni
O
b
CO2H
THF
PPh3
—
15
0
Dioxane DPPEc
Dioxane TMEDAc MS 4A 40
0
22
CO2H
˚
˚
3
0
O
R2
R2
R2
IV
Scheme 2.
V
VI
a
All reactions were carried out using 1 equiv of Ni(cod)2 under an atmo-
sphere of CO2 (1 atm). The obtained crude materials were treated with
CH2N2 before isolation.
1 equiv.
2 equiv.
b
c
2. Results and discussion
To examine the feasibility of the above-described process, a
reaction of 1,6-enyne 2a, which was readily prepared from 1
(Scheme 3), was first carried out under conditions developed
for carboxylation of unsaturated hydrocarbons.2d,3 To a
THF solution of Ni(cod)2 (1 equiv) and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU, 2 equiv to nickel) was slowly
added a solution of enyne 2a in THF at 0 ꢀC under an atmo-
sphere of CO2, and the solution was stirred at room temper-
ature for 63 h (Scheme 4). Hydrolysis of the resulting
mixture followed by treatment with diazomethane afforded
carboxylative cyclization product 3a in 25% yield along
with 45% of 4a. The configurations of each double bond
in 3a and 4a were determined to be (E) by the results of
NOE experiments for 3a and 4a. The formation of 4a
was rationalized by protonolysis of nickelacycle IIa, and
these results strongly suggested that the carboxylation pro-
ceeds through CO2 insertion into the Csp3–nickel bond of
nickelacycle IIa giving oxanickelacycle IIIa.
of 3a was obtained (entry 2). Formation of a significant
amount of 4a suggests the thermal instability of nickelacycle
IIa. In addition, it seemed that the stability of IIIa was not so
high at an elevated temperature because a shorter reaction
period resulted in better yield of 3a when the reactions were
conducted at 40 ꢀC (entry 3 vs entry 1). Although this car-
boxylative cyclization reaction could be carried out in tolu-
ene, the yield of 3a slightly decreased (entry 4). Gratifyingly,
the use of dioxane significantly improved the yield of the
carboxylation product (entry 5). Interestingly, the yield of
3a increased to 70% when the reaction was carried out in
15
˚
the presence of molecular sieves 4A (entry 6). The use
of other ligands instead of DBU reduced the yields of 3a
(entries 7–9). The low combined yields of 3a and 4a in these
reactions indicated that these ligands did not promote the
formation of nickelacycle IIa. On the basis of these results,
the reaction conditions employed in entry 6 were chosen as
the standard reaction conditions for further investigations.
Carboxylative cyclizations of enynes having various sub-
stituents on the alkene or alkyne moiety were examined
(Table 2). First, enynes 2b–2e, whose alkene moieties were
NaH, NaI
MeO2C
MeO2C
E
E
CO2Me
Me
Methy 4-bromocrotonate
Me
DMF, rt
81%
1
2a
(E = CO2Me)
Table 2. Substituent effects of enynes
Scheme 3.
R1
R1
R2
1) CO2 (1 atm)
E
E
E
E
E
E
R1
R2
CO2Me
NOE
CO2Me
Ni(cod)2, DBU
Hb
1) Ni(cod)2 (1 equiv)
DBU (2 equiv)
+
E
E
E
dioxane, MS 4A
40 °C, 3 h
CO2Me
Me
CO2Me
Ha
2b-i
R2
3b-i
2) CH2N2
CO2 (1 atm)
THF, rt, 63 h
(E = CO2Me)
E
4b-i
3+4
(after workup)
2a
Me
3a (25%)
then H3O+
(E = CO2Me)
R1
R2
Yields (%)
2) CH2N2 (after workup)
Entry
Enyne
+
3
4
NOE
CO2Me
MeO2C
CO2Me
CO2
Hb
O
E
E
E
E
E
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
H
Me
COMe
CN
CO2Me
CO2Me
CO2Me
CO2Me
Me
Me
Me
Me
CH2OMe
Ph
0
0
0
44
56
51
27
0
0
0
54
2
16
24
61
61
0
0
Ni
O
Ha
Me
E
54
46
72
75
88
61
Ni
4a
(45%)
Me
IIa
IIIa
Me
Scheme 4.
CO2Me
SiMe3
To improve the yield of carboxylation product 3a, enyne 2a
was submitted to various reaction conditions (Table 1).
When the reaction was carried out in THF at 40 ꢀC, the yield
of 3a was improved to 48% (entry 1). However, when the
reaction was carried out under reflux conditions, only 9%
H
MeO2C
MeO2C
OH
5

M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
7591
Table 3. Carboxylative cyclizations of various 1,6-enynes
modified from enyne 2a, were submitted to the carboxylation
CO2Me
reaction. Reaction of enyne 2b, which had no substituent at
the terminus of alkyne, provided neither carboxylation prod-
uct 3b nor simply cyclized compound 4b (entry 1). The re-
action of 2c having a methyl group on its alkene moiety
also gave the same result. The fact that cyclized compounds
3 and 4 were not obtained in these two reactions indicated
that oxidative cycloaddition of 2b and 2c did not proceed
under these conditions. The reaction of enyne 2d having an
electron-withdrawing keto-carbonyl group on alkene af-
forded no carboxylation product (entry 3). However, in this
reaction, cyclized product 4d and bicyclic alcohol 5 were
obtained in 54 and 39% yields, respectively. It was specu-
lated that 5 was formed via the formal [3+2] cycloaddition
pathway proposed by Montgomery.12i,k,m The reaction in-
volves tautomerization of oxanickelacycle IId to nickel
enolate VII and selective mono-protonation of VII followed
by carbonyl insertion into the nickel–carbon bond of VIII to
give 5 (Scheme 5). Thus, the formation 5 also indicated that
oxidative cycloaddition of 2d took place. In contrast to these
results (entries 1–3), enyne 2e, having a cyano group on
alkene as an electron-withdrawing group, underwent
carboxylative cyclization to give 3e in 44% yield (entry 4).
CO2Me
1) CO2 (1 atm)
Ni(cod)2, DBU
CO2Me
CO2Me
R2
X
X
+
X
dioxane, MS 4A
40 °C, 3 h
R2
R2
2j-m
2) CH2N2
(after workup)
3j-m
4j-m
Entry Enyne
X
R2
Yields (%)
Recovery of 2 (%)
3
4
1
2
3
4
2j
CH2 Me
TsN Me
31
54
22
25
34
12
39
0
0
2k
2l
2m
TsN CH2OMe 55
Me 68
O
0
tethers, proceeded smoothly to afforded desired heterocyclic
products 3 in good yields (entries 2–4).
Carboxylative cyclizations of 1,7-enynes 6 were then exam-
ined to apply this method for construction of a six-membered
ring skeleton (Table 4). When reaction of 6a was carried out
under standard conditions for 8 h, the desired compound 7a
was obtained in 47% yield. Carboxylative cyclization of
6b, which had a nitrogen atom in the tether chain, proceeded
smoothly to afford compound 7b with a piperidine skeleton
in 80% yield. It was noteworthy that substrates 6c and 6d,
in which a pre-existing five-membered ring was present in
the tether chain, also underwent carboxylative cyclization
to provide 7c and 7d, which have a bicyclic skeletal frame-
work, in 55 and 75% yields, respectively, in a stereospecific
manner.
COMe
H+X-
Ni(0)
E
E
E
E
2d
Ni
O
Ni
IId Me
VII
E = CO2Me
+
H
H
O
H+X-
E
E
E
ONiX
5
Ni
E
X-
IX
VIII
Table 4. Carboxylative cyclizations of various 1,7-enynes
Scheme 5.
Enyne
Product
CO2Me
CO2Me
Yield (%)
47
Next, the effects of substituents on the alkyne moiety were
investigated using enynes 2f–2i. Reaction of enynes 2f or
2g having an alkyl or aryl group on alkyne provided car-
boxylative cyclization product 3f or 3g in 56 or 51% yields,
respectively (entries 5 and 6). In contrast to these results,
the reaction of 2h having a methoxycarbonyl group on
alkyne gave 3h in only 27% yield (entry 7) and that of 2i
afforded no carboxylation product. However, since the com-
bined yields of 3 and 4 were relatively high in these reactions
(entries 5–8), oxidative cycloaddition of enyne to Ni(0)
might proceed. From the results shown in Table 2, the effects
of substituents on alkene or alkyne are summarized as fol-
lows: (i) an electron-withdrawing substituent on alkene is
necessary for oxidative cycloaddition of enynes to a Ni(0)
complex and (ii) the carboxylation step, which would pro-
ceed through insertion of CO2 into the nickelacyclopentenes,
is greatly affected by substituents on both alkene and alkyne
moieties (entries 3–8).
MeO2C
MeO2C
MeO2C
MeO2C
CO2Me
6a
7a
CO2Me
CO2Me
CO2Me
80
55
TsN
TsN
6b
7b
MeO2C
H
CO2Me
CO2Me
H
N
N
H
Ts
H
Ts
6c
7c
MeO2C
H
CO2Me
CO2Me
H
H
To explore the utility of this novel method for synthesis of
cyclic compounds, reactions of enynes with various tethers
were next examined (Table 3). In cyclization of enyne 2j
having no substituent on its tether, the desired carboxylation
product 3j was obtained in only 31% yield (Table 3, entry 1).
In contrast to this result, carboxylative cyclizations of
enynes 2k, 2l, and 2m, which had a heteroatom in those
75
N
N
H
Ts
Ts
6d
7d
All reactions were carried out in dioxane at 40 ꢀC for 8 h in the presence of
˚
MS 4A under an atmosphere of CO2 (1 atm). All products were isolated as
methyl esters by treating crude products with diazomethane.

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M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
3. Conclusion
(s, 3H), 2.81 (d, J¼7.6 Hz, 0.5H), 2.73–2.69 (m, 3.5H),
1.75 (t, J¼2.3 Hz, 3H), 1.65 (d, J¼6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.4, 170.4, 130.1, 124.1, 78.6,
73.3, 57.4, 52.5, 52.5, 35.3, 22.9, 18.0, 3.5; LRMS (EI,
m/z) 239 (M+), 207, 178, 147; HRMS (EI, m/z) calcd for
C12H15O3 (M+ꢁOMe): 207.1021. Found: 207.1027.
In summary, nickel-mediated carboxylative cyclization of
enynes was investigated. The effects of substituents on
alkene and alkyne were investigated, and it was revealed
that an electron-withdrawing group on alkene is necessary
for this process. The utility of this novel method was demon-
strated by application to the synthesis of various carboxylic
acid derivatives having five- to six-membered ring skeletons,
involving bicyclic skeletal frameworks.
4.2.3. Dimethyl 2-(but-2-ynyl)-2-{(E)-4-oxopent-2-enyl}-
malonate (2d). IR (neat) 2955, 1738, 1677, 1267 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 6.64 (dt, J¼7.5, 14.5 Hz,
1H), 6.14 (d, J¼14.5 Hz, 1H), 3.75 (s, 6H), 2.93 (d,
J¼7.5 Hz, 2H), 2.76 (q, J¼2.5 Hz, 2H), 2.36 (s, 3H), 1.77
(t, J¼2.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 198.8,
170.6, 170.6, 141.9, 135.3, 80.1, 73.0, 57.3, 53.1, 53.1,
35.7, 27.0, 23.9, 3.5; LRMS (EI, m/z) 266 (M+), 251, 235,
207, 175, 147; HRMS (EI, m/z) calcd for C14H17O5
(M+ꢁH): 265.1076. Found: 265.1079.
4. Experimental
4.1. General
All manipulations were performed under an argon atmo-
sphere unless otherwise stated. Ni(cod)2 was prepared
according to the previously reported procedure.16 DMF
and DBU were distilled from CaH2. THF (dehydrated, stabi-
lizer-free) was purchased from Kanto Kagaku Co. and used
as received. Toluene and dioxane were distilled from sodium
benzophenone ketyl. CO2 (UHP grade, >99.995%) was pur-
chased from Sumitomo Seika Chemicals Co., Ltd and used
without further purification. All other reagents were purified
when necessary using standard procedures. Column chroma-
tography was performed on silica gel 60 (70–230 mesh or
230–400 mesh). Enyne 2b was prepared by the procedure
reported in the literature.17 Methods for preparing enynes
2c–2m and 6a–6d are described in the electronic Supple-
mentary data.
4.2.4. Dimethyl 2-(but-2-ynyl)-2-(3-cyanoallyl)malonate
1
(2e). IR (neat) 2956, 2225, 1733, 1207 cmꢁ1; H NMR
(400 MHz, CDCl3) d 6.63 (dt, J¼7.7, 15.4 Hz, 0.83H),
6.48 (dt, J¼7.9, 10.9 Hz, 0.17H), 5.48 (d, J¼15.4 Hz,
0.83H), 5.47 (d, J¼10.9 Hz, 0.17H), 3.76 (s, 6H), 3.14 (d,
J¼7.9 Hz, 0.34H), 2.92 (d, J¼7.7 Hz, 1.66H), 2.76–2.73
(m, 2H), 1.77 (t, J¼2.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 169.5, 169.4, 149.5, 148.4, 116.6, 115.1, 103.5,
102.7, 80.2, 80.0, 72.3, 72.2, 56.7, 56.7, 53.0, 53.0, 53.0,
53.0, 36.4, 34.8, 24.0, 23.9, 3.5, 3.4; LRMS (EI, m/z)
249 (M+), 218, 189, 158; HRMS (EI, m/z) calcd for
C13H15NO4: 249.1001. Found: 240.1002.
4.2.5. Trimethyl (E)-8-methoxyoct-1-en-6-yne-1,4,4-tri-
carboxylate (2f). IR (neat) 2954, 1737, 1268 cmꢁ1 1H
;
4.2. Preparation of enynes
NMR (400 MHz, CDCl3) d 6.77 (dt, J¼7.6, 15.5 Hz, 1H),
5.93 (d, J¼15.5 Hz, 1H), 4.06 (t, J¼2.1 Hz, 2H), 3.75 (s,
6H), 3.72 (s, 3H), 3.34 (s, 3H), 2.94 (d, J¼7.6 Hz, 2H),
2.86 (t, J¼2.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 169.5, 169.5, 166.0, 141.9, 125.2, 80.5, 79.7, 59.8, 57.4,
56.7, 53.0, 53.0, 51.6, 35.1, 23.5; LRMS (EI, m/z) 311
(M+), 280, 253, 221, 193, 161; HRMS (EI, m/z) calcd for
C15H20O7: 311.1131. Found: 311.1128.
4.2.1. Trimethyl (E)-Oct-1-en-6-yne-1,4,4,-tricarboxylate
(2a). To a suspension of NaH (60% dispersion in oil,
240 mg, 6.0 mmol) in DMF (15 mL) was added 118 (1.1 g,
6.6 mmol) in DMF (10 mL) at 0 ꢀC, and then the mixture
had been stirred at room temperature for 1 h. The resulting
mixture was cooled to 0 ꢀC, and then methyl 4-bromocroto-
nate (1.1 mL, 9.0 mmol) and NaI (90 mg, 0.6 mmol) were
added. After the mixture had been stirred at room tempera-
ture for 3 h, saturated aqueous solution of NH4Cl was added
at 0 ꢀC. The aqueous layer was extracted with AcOEt. The
combined organic layers were washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
EtOAc ¼ 8/1) to afford 1a (1.4 g, 81%) as a colorless crystal.
4.2.6. Trimethyl (E)-7-phenylhept-1-en-6-yne-1,4,4-tri-
1
carboxylate (2g). IR (neat) 2954, 1737, 1278 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.38–7.36 (m, 2H), 7.31–7.29
(m, 3H), 6.83 (dt, J¼7.8, 15.5 Hz, 1H), 5.97 (d,
J¼15.5 Hz, 1H), 3.78 (s, 6H), 3.72 (s, 3H), 3.03 (s, 2H),
3.01 (d, J¼7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 169.4, 169.4, 165.9, 141.9, 131.4, 131.4, 128.0, 128.0,
127.9, 125.0, 122.7, 84.0, 83.4, 56.8, 53.4, 52.9, 51.4,
35.2, 24.0; LRMS (EI, m/z) 344 (M+), 329, 312, 285, 253,
225; HRMS (EI, m/z) calcd for C19H20O6: 344.1260. Found:
344.1259.
Mp 53.0–55.0 ꢀC; IR (neat) 2954, 1738, 1279 cmꢁ1; H
1
NMR (500 MHz, CDCl3) d 6.78 (dt, J¼8.0, 15.6 Hz, 1H),
5.93 (d, J¼15.6 Hz, 1H), 3.75 (s, 6H), 3.72 (s, 3H), 2.93
(dd, J¼1.5, 8.0 Hz, 2H), 2.75 (q, J¼2.6 Hz, 1H), 1.76
(t, J¼2.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 169.7,
169.7, 166.1, 142.2, 124.9, 79.5, 72.7, 56.9, 52.9, 52.9,
51.5, 35.1, 23.5, 3.5; LRMS (EI, m/z) 281 (M+ꢁH), 251,
223, 191, 163; HRMS (EI, m/z) calcd for C14H18O6:
282.1103. Found: 282.1107; Anal. Calcd for C14H18O6:
C, 59.57; H, 6.43. Found: C, 59.44; H, 6.38.
4.2.7. Tetramethyl (E)-hept-1-en-6-yne-1,4,4,7-tetracar-
1
boxylate (2h). IR (neat) 2955, 1723, 1267 cmꢁ1; H NMR
(400 MHz, CDCl3) d 6.74 (dt, J¼7.6, 15.2 Hz, 1H), 5.97
(d, J¼15.2 Hz, 1H), 3.78 (s, 6H), 3.76 (s, 3H), 3.73 (s,
3H), 2.96 (s, 2H), 2.95 (d, J¼7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 169.7, 169.7, 166.6, 154.0, 141.7,
126.2, 83.0, 76.1, 56.4, 53.3, 53.3, 52.9, 51.8, 35.3, 23.4;
LRMS (EI, m/z) 326 (M+), 311, 295, 267, 235; HRMS (EI,
m/z) calcd for C15H18O8: 326.1001. Found: 326.1005.
4.2.2. Dimethyl non-2-en-7-yne-5,5-dicarboxylate (2c).
IR (neat) 2954, 1736, 1284 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 5.63–5.53 (m, 1H), 5.26–5.19 (m, 1H), 3.72

M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
7593
4.2.8. Trimethyl (E)-7-(trimethylsilyl)hept-1-en-6-yne-
1,4,4-tricarboxylate (2i). IR (neat) 2956, 1736, 1279 cmꢁ1
4.2.14. Methyl (E)-5-{N-(but-2-ynyl)-N-tosylamino}pent-
2-enoate (6b). IR (neat) 2951, 1722, 1273 cmꢁ1; H NMR
1
;
1H NMR (500 MHz, CDCl3) d 6.77 (dt, J¼7.9, 15.5 Hz,
1H), 5.93 (d, J¼15.5 Hz, 1H), 3.74 (s, 6H), 3.72 (s, 3H),
2.93 (dd, J¼0.8, 8.0 Hz, 2H), 2.81 (s, 2H), 0.13 (s, 9H);
13C NMR (100 MHz, CDCl3) d 169.5, 169.5, 166.0, 142.0,
125.2, 100.5, 89.0, 56.8, 53.0, 53.0, 51.6, 35.1, 24.6, 0.0,
0.0, 0.0; LRMS (EI, m/z) 340 (M+), 325, 309, 281; HRMS
(EI, m/z) calcd for C16H24O6Si: 340.1342. Found: 340.1345.
(500 MHz, CDCl3) d 7.73–7.71 (m, 2H), 7.30–7.29 (m,
2H), 6.90 (dt, J¼6.9, 15.5 Hz, 1H), 5.89 (d, J¼15.5 Hz,
1H), 4.05 (q, J¼1.9 Hz, 2H), 3.73 (s, 3H), 3.29 (t,
J¼7.4 Hz, 2H), 2.50 (dt, J¼6.9, 7.4 Hz, 2H), 2.42 (s, 3H),
1.58 (t, J¼1.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.2, 144.6, 143.2, 135.3, 129.1, 129.0, 127.5, 127.4,
122.7, 81.7, 71.3, 51.3, 44.8, 37.1, 30.7, 21.4, 3.1; LRMS
(EI, m/z) 335 (M+), 304, 236, 184, 155, 91; HRMS (EI,
m/z) calcd for C17H21O4NS: 335.1191. Found: 335.196.
4.2.9. Methyl (E)-non-2-en-7-ynoate (2j). IR (neat) 2950,
1
1724, 1268 cmꢁ1; H NMR (500 MHz, CDCl3) d 6.97 (dt,
J¼7.0, 14.0 Hz, 1H), 5.86 (d, J¼14.0 Hz, 1H), 3.73 (s,
3H), 2.31 (dt, J¼8.5, 8.5 Hz, 2H), 2.19–2.15 (m, 2H), 1.78
(t, J¼2.5 Hz, 3H), 1.64 (tt, J¼7.1, 7.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 166.9, 148.6, 121.3, 78.1, 76.3, 51.4,
31.2, 27.3, 18.2, 3.5; LRMS (EI, m/z) 165 (M+ꢁH), 151,
134, 107; HRMS (EI, m/z) calcd for C10H13O2 (M+ꢁH):
165.0915. Found: 165.0915.
4.2.15. Methyl (E)-3-[(1R*,2R*)-2-{N-(but-2-ynyl)-N-
tosylamino}cyclopentyl]acrylate (6c). IR (neat) 2954,
1720, 1653, 1261 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 7.79–7.77 (m, 2H), 7.28–7.26 (m, 2H), 6.97 (dd, J¼8.3,
15.6 Hz, 1H), 5.77 (d, J¼15.6 Hz, 1H), 4.19 (dq, J¼2.1,
18.4 Hz, 1H), 4.11 (dt, J¼8.5, 8.5 Hz, 1H), 3.75 (dq,
J¼2.3, 18.4 Hz, 1H), 3.72 (s, 3H), 2.99–2.92 (m, 1H), 2.42
(s, 3H), 1.93–1.81 (m, 4H), 1.65–1.48 (m, 2H), 1.64 (t,
J¼2.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.5,
148.0, 143.0, 137.2, 129.1, 129.1, 127.6, 127.7, 121.8,
80.8, 74.6, 61.5, 51.5, 45.4, 36.2, 29.0, 27.7, 21.7, 21.5,
3.4; LRMS (EI, m/z) 375 (M+), 344, 290, 220; HRMS (EI,
m/z) calcd for C20H25O4NS: 375.1504. Found: 375.1503.
4.2.10. Methyl (E)-4-{N-(but-2-ynyl)-N-tosylamino}but-
1
2-enoate (2k). IR (neat) 3055, 1724, 1266 cmꢁ1; H NMR
(500 MHz, CDCl3) d 7.73 (d, J¼8.3 Hz, 2H), 7.31 (d,
J¼8.3 Hz, 2H), 6.82 (dt, J¼5.8, 15.7 Hz, 1H), 6.03 (d, J¼
15.7 Hz, 1H), 4.02 (q, J¼2.3 Hz, 2H), 3.96 (d, J¼5.8 Hz,
2H), 3.74 (s, 3H), 2.43 (s, 3H), 1.55 (t, J¼2.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 165.8, 143.5, 141.9, 135.5,
129.2, 129.2, 127.6, 127.6, 123.6, 82.2, 71.0, 51.6, 47.0,
37.2, 21.4, 3.2; LRMS (EI, m/z) 321 (M+), 290, 262, 166;
HRMS (EI, m/z) calcd for C16H19NO4S: 321.1035. Found:
321.1039.
4.2.16. Methyl (E)-3-[(1R*,2S*)-2-{N-(but-2-ynyl)-N-
tosylamino}cyclopentyl]acrylate (6d). IR (neat) 2952,
1722, 1656, 1273 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 7.74–7.73 (m, 2H), 7.24–7.22 (m, 2H), 6.64 (dd, J¼8.5,
16.0 Hz, 1H), 5.71 (d, J¼16.0 Hz, 1H), 4.15 (dq, J¼1.9,
18.1 Hz, 1 H), 4.02 (dt, J¼8.1, 8.1 Hz, 1H), 3.93 (dq,
J¼2.5, 18.1 Hz, 1H), 3.70 (s, 3H), 2.84 (ddt, J¼8.7, 8.7,
8.7 Hz, 1H), 2.40 (s, 3H), 1.90–1.83 (m, 2H), 1.77–1.65
(m, 3H), 1.71 (t, J¼2.5 Hz, 3H), 1.48–1.40 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 166.3, 149.3, 143.0, 137.5,
129.0, 129.0, 127.4, 127.4, 121.5, 80.6, 75.1, 63.8, 51.3,
44.9, 33.1, 30.1, 28.7, 22.0, 21.5, 3.4; LRMS (EI, m/z) 375
(M+), 344, 316, 220; HRMS (EI, m/z) calcd for
C20H25O4NS: 375.1504. Found: 375.1504.
4.2.11. Methyl (E)-4-{N-(4-methoxybut-2-ynyl)-N-tosyl-
amino}but-2-enoate (2l). IR (neat) 2951, 2255, 1725,
1
1279 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.74–7.72 (m,
2H), 7.32–7.30 (m, 2H), 6.82 (dt, J¼5.6, 15.6 Hz, 1H),
6.04 (d, J¼15.6 Hz, 1H), 4.13 (s, 2H), 3.98 (d, J¼5.6 Hz,
2H), 3.85 (s, 2H), 3.74 (s, 3H), 3.20 (s, 3H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) d 166.5, 144.4, 142.2, 136.2,
130.0, 130.0, 128.1, 128.1, 124.4, 82.3, 78.8, 59.6, 57.5,
51.8, 47.4, 37.1, 21.5; LRMS (EI, m/z) 351 (M+), 335,
196, 155; HRMS (EI, m/z) calcd for C17H21NO5S:
351.1140. Found: 351.1128.
4.3. Typical procedurefornickel-mediated carboxylative
cyclization (Table 1, entry 4)
4.2.12. Methyl (E)-4-(but-2-ynyloxy)but-2-enoate (2m).
IR (neat) 2952, 1724, 1267 cmꢁ1
A flame-dried round bottom flask was charged with Ni(cod)2
˚
(49 mg, 0.18 mmol), MS 4A (500 mg), and degassed
;
1H NMR (400 MHz,
CDCl3) d 6.96 (dt, J¼4.0, 15.6 Hz, 1H), 6.09 (d, J¼
15.6 Hz, 1H), 4.21 (dd, J¼2.4, 4.0 Hz, 2H), 4.15 (q,
J¼2.4 Hz, 2H), 3.74 (s, 3H), 1.86 (t, J¼2.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 166.5, 143.9, 121.1, 83.1, 74.5,
67.9, 58.5, 51.6, 3.6; LRMS (EI, m/z) 167 (M+ꢁH), 153,
138, 109; HRMS (EI, m/z) calcd for C9H11O3 (M+ꢁH):
167.0708. Found: 167.0706.
dioxane (1.5 mL). To this was added DBU (0.055 mL,
0.35 mmol), and the flask was immersed in a liquid nitrogen
bath. After the mixture had been frozen, the flask was evac-
uated to 0.05 mmHg. The flask was backfilled with CO2 in
a plastic balloon and the frozen mixture was slowly thawed
at ambient temperature. To this suspension was slowly added
2a (50 mg, 0.18 mmol) in degassed dioxane (2 mL) over
a period of 1 h. The resulting mixture was stirred at 40 ꢀC
for 3 h and then quenched with 10% aqueous HCl at 0 ꢀC.
The mixture was extracted with AcOEt and the combined
organic layers were extracted with saturated aqueous
NaHCO3 (base extraction). The basic aqueous layers were
acidified with 10% HCl and then extracted with AcOEt.
The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was
treated with diazomethane according to the standard proce-
dure. The obtained crude material was purified by silica gel
4.2.13. Trimethyl (E)-non-1-en-7-yne-1,4,4-tricarboxy-
late (6a). IR (neat) 3054, 1734, 1266 cmꢁ1 1H NMR
;
(500 MHz, CDCl3) d 6.78 (dt, J¼7.8, 15.5 Hz, 1H), 5.89
(d, J¼15.5 Hz, 1H), 3.74 (s, 6H), 3.72 (s, 3H), 2.81 (d,
J¼7.8 Hz, 2H), 2.12 (s, 4H), 1.75 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 170.8, 170.8, 166.3, 142.7, 125.2,
77.6, 76.8, 57.1, 52.9, 52.9, 51.7, 35.8, 32.4, 14.4, 3.6;
LRMS (EI, m/z) 295 (M+ꢁH), 281, 264, 230, 198; HRMS
(EI, m/z) calcd for C15H20O6: 296.1260. Found: 296.1256.

7594
M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
column chromatography (hexane/AcOEt ¼ 5/1) to afford 3a
(42.4 mg, 70%) as a colorless oil. From the residual organic
layer of the base extraction, 4a (4.5 mg, 9%) was obtained as
a colorless oil after standard workup and purification by a
silica gel column chromatography (hexane/AcOEt ¼ 5/1).
3H), 3.74 (s, 3H), 3.63 (d, J¼6.0 Hz, 0.33H), 3.30–3.25
(m, 1H), 3.05 (d, J¼17.2 Hz, 1H), 2.90 (d, J¼17.2 Hz,
1H), 2.65 (dd, J¼3.6, 11.2 Hz, 0.33H), 2.61 (dd, J¼6.8,
11.6 Hz, 0.66H), 2.17 (dd, J¼11.6, 13.2 Hz, 0.66H), 2.14
(dd, J¼3.6, 9.6 Hz, 0.33H), 1.68 (d, J¼6.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 172.5, 172.1, 148.1, 145.2,
132.7, 127.9, 127.9, 126.4, 125.5, 125.5, 93.9, 63.3, 53.0,
52.9, 49.8, 46.6, 40.0, 32.1, 10.4; LRMS (EI, m/z) 330
(M+), 312, 299, 280, 253; HRMS (EI, m/z) calcd for
C19H22O5: 330.1467. Found: 330.1470.
4.3.1. Dimethyl (E)-3-{di(methoxycarbonyl)methyl}-4-
ethylidenecyclopentane-1,1-dicarboxylate (3a). IR (neat)
2955, 1736, 1257 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 5.27–5.21 (m, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.73 (s,
3H), 3.72 (s, 3H), 3.58 (d, J¼8.0 Hz, 1H), 3.32–3.25 (m,
1H), 3.02 (d, J¼16.8 Hz, 1H), 2.84 (d, J¼16.8 Hz, 1H),
2.57 (dd, J¼7.6, 13.1 Hz, 1H), 2.27 (dd, J¼9.5, 13.1 Hz,
1H), 1.59 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 171.8, 171.8, 168.7, 168.3, 139.3, 118.0, 58.3, 54.9,
52.9, 52.8, 52.5, 52.4, 41.9, 36.9, 36.8, 14.8; LRMS (EI,
m/z) 342 (M+), 311, 282, 250, 222, 191; HRMS (EI, m/z)
calcd for C16H22O8: 342.1315. Found: 342.1308.
4.3.6. Dimethyl (E)-3-{di(methoxycarbonyl)methyl}-4-
(2-methoxyethylidene)cyclopentane-1,1-dicarboxylate
(3f). IR (neat) 2955, 1735, 1266 cmꢁ1; 1H NMR (500 MHz,
CDCl3) d 5.36–5.33 (m, 1H), 3.91 (dq, J¼6.6, 13.1 Hz, 2H),
3.75 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.65 (d,
J¼7.5 Hz, 1H), 3.36–3.30 (m, 1H), 3.28 (t, J¼11.5 Hz, 3H),
3.07 (d, J¼16.9 Hz, 1H), 2.92 (d, J¼16.9 Hz, 1H), 2.59 (dd,
J¼8.2, 13.1 Hz, 1H), 2.32 (dd, J¼9.9, 13.1 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 171.6, 171.5, 168.5, 168.1,
143.0, 120.3, 69.6, 58.4, 57.7, 54.4, 53.0, 52.9, 52.6, 52.4,
42.1, 37.1, 36.3; LRMS (EI, m/z) 341 (M+ꢁOMe), 309,
280, 249, 240, 221, 180; HRMS (EI, m/z) calcd for
C16H21O8 (M+ꢁOMe): 341.1236. Found: 341.1234.
4.3.2. Dimethyl (E)-3-{(methoxycarbonyl)methyl}-4-
ethylidenecyclopentane-1,1-dicarboxylate (4a). IR (neat)
2954, 1736, 1258 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 5.26–5.20 (m, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.68 (s,
3H), 3.02 (d, J¼17.4 Hz, 1H), 2.94–2.92 (m, 1H), 2.84 (d,
J¼17.4 Hz, 1H), 2.63 (dd, J¼7.4, 13.0 Hz, 1H), 2.59 (dd,
J¼5.4, 15.5 Hz, 1H), 2.28 (dd, J¼8.7, 15.5 Hz, 1H), 1.89
(dd, J¼10.6, 13.0 Hz, 1H), 1.60 (d, J¼6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 173.6, 172.9, 172.8, 141.9,
117.0, 58.5, 53.1, 53.0, 51.8, 40.2, 38.9, 38.7, 37.2, 14.7;
LRMS (EI, m/z) 284 (M+), 253, 224, 192; HRMS (EI, m/z)
calcd for C14H20O6: 284.1260. Found: 284.1267.
4.3.7. Dimethyl (E)-3-{(methoxycarbonyl)methyl}-4-(2-
methoxyethylidene)cyclopentane-1,1-dicarboxylate (4f).
IR (neat) 2953, 1734, 1266 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 5.37–5.33 (m, 1H), 3.93 (d, J¼6.3 Hz, 2H), 3.74
(s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 3.31(s, 3H), 3.08 (d,
J¼17.3 Hz, 1H), 3.02–2.95 (m, 1H), 2.92 (d, J¼17.3 Hz,
1H), 2.68–2.62 (m, 2H), 2.34 (dd, J¼8.7, 15.7 Hz, 1H),
1.92 (dd, J¼10.7, 13.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 172.5, 171.7, 171.7, 145.0, 118.7, 69.8, 58.4,
57.9, 53.0, 52.9, 51.7, 39.5, 39.1, 38.2, 37.1; LRMS (EI,
m/z) 314 (M+), 282, 250, 222, 191; HRMS (EI, m/z) calcd
for C15H22O7: 314.1365. Found: 314.1361.
4.3.3. Dimethyl (E)-3-ethylidene-4-(2-oxopropyl)cyclo-
pentane-1,1-dicarboxylate (4d). IR (neat) 2955, 1733,
1267 cmꢁ1 1H NMR (500 MHz, CDCl3) d 5.20–5.15
;
(m, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.01 (d, J¼17.0 Hz,
1H), 2.99–2.93 (m, 1H), 2.82 (d, J¼17.0 Hz, 1H), 2.70
(dd, J¼5.3, 17.0 Hz, 1H), 2.62 (dd, J¼7.4, 12.6 Hz, 1H),
2.45 (dd, J¼8.3, 17.0 Hz, 1H), 2.15 (s, 3H), 1.78 (dd,
J¼10.5, 12.9 Hz, 1H), 1.59 (d, J¼6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 207.5, 172.2, 172.0, 141.7, 116.1,
58.3, 52.8, 52.8, 48.3, 40.1, 37.8, 37.0, 30.3, 14.6; LRMS
(EI, m/z) 268 (M+), 237, 208, 176, 151; HRMS (EI, m/z)
calcd for C14H20O5: 268.1310. Found: 268.1313.
4.3.8. Dimethyl (E)-3-{di(methoxycarbonyl)methyl}-4-
benzylidenecyclopentane-1,1-dicarboxylate (3g). IR (neat)
2955, 1732, 1266 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 7.34–7.20 (m, 5H), 6.29 (s, 0.77H), 3.82–3.68 (m, 1H),
3.75 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 3.56–
3.51 (m, 1H), 3.29 (d, J¼17.5 Hz, 1H), 3.25 (d, J¼17.5 Hz,
1H), 2.65 (dd, J¼8.0, 13.0 Hz, 1H), 2.37 (dd, J¼9.5,
13.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 172.5, 172.5,
169.5, 169.1, 142.1, 142.0, 137.9, 137.8, 129.1, 128.9,
127.3, 124.8, 59.5, 55.3, 53.2, 53.2, 52.9, 52.8, 44.0, 38.9,
36.1; LRMS (EI, m/z) 404 (M+), 373, 344, 312, 284, 253,
225; HRMS (EI, m/z) calcd for C21H24O8: 404.1471. Found:
404.1477.
4.3.4. (3aR*,5R*)-Dimethyl 2-(methyl)bicyclo[3,3,0]oct-
1-en-3-ol-7,7-dicarboxylate (5). IR (neat) 3507, 2952,
1
1732, 1262 cmꢁ1; H NMR (500 MHz, CDCl3) d 3.77 (s,
3H), 3.69 (s, 3H), 2.67 (dd, J¼1.7, 13.1 Hz, 1H), 2.65 (dd,
J¼1.7, 13.2 Hz, 1H), 2.51 (d, J¼14.0 Hz, 1H), 2.44 (br s,
1H), 2.43–2.37 (m, 1H), 2.25 (d, J¼14.0 Hz, 1H), 1.89 (d,
J¼13.1 Hz, 1H), 1.86 (dd, J¼9.0, 13.2 Hz, 1H), 1.62 (s,
3H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3) d 173.3,
171.3, 134.0, 133.2, 96.4, 60.9, 53.0, 52.6, 47.8, 45.4,
42.1, 42.0, 14.3, 9.3; LRMS (EI, m/z) 268 (M+), 250, 237,
190, 131; HRMS (EI, m/z) calcd for C14H20O5: 268.1310.
Found: 268.1313.
4.3.9. Dimethyl (E)-3-{(methoxycarbonyl)methyl}-4-
benzylidenecyclopentane-1,1-dicarboxylate (4g). IR (neat)
2954, 1732, 1266 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 7.38–7.19 (m, 5H), 6.25 (s, 0.86H), 3.73 (s, 3H), 3.72 (s,
3H), 3.71 (s, 3H), 3.36 (d, J¼17.5 Hz, 1H), 3.23–3.19 (m,
1H), 3.21 (d, J¼17.5 Hz, 1H), 2.75 (dd, J¼5.3, 15.6 Hz,
1H), 2.71 (dd, J¼8.5, 13.0 Hz, 1H), 2.45 (dd, J¼9.0,
15.6 Hz, 0.76H), 1.98 (dd, J¼10.5, 13.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 172.5, 171.8, 171.7, 143.3,
143.2, 137.2, 131.6, 128.3, 128.2, 126.5, 122.7, 59.1, 52.9,
52.9, 51.7, 40.6, 40.5, 39.1, 39.0; LRMS (EI, m/z) 346
4.3.5. Dimethyl (E)-3-{(methoxycarbonyl)(cyano)-
methyl}-4-ethylidenecyclopentane-1,1-dicarboxylate
1
(3e). IR (neat) 3520, 2954, 1731, 1265 cmꢁ1; H NMR
(400 MHz, CDCl3) d 5.50–5.43 (m, 0.33H), 5.41–5.34 (m,
0.67H), 3.83 (s, 3H), 3.80 (d, J¼4.8 Hz, 0.67H), 3.76 (s,

M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
7595
(M+), 315, 286, 256, 226; HRMS (EI, m/z) calcd for
C19H22O6: 345.1416. Found: 346.1417.
4.3.15. Dimethyl 2-{(Z)-4-ethylidene-1-tosylpyrrolidin-3-
yl}malonate (3k). IR (neat) 2953, 1737, 1347, 1162 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 7.75–7.70 (m, 2H), 7.38–
7.32 (m, 2H), 7.35–7.31 (m, 1H), 3.88 (d, J¼15.2 Hz, 1H),
3.72 (s, 3H), 3.69 (s, 3H), 3.61 (d, J¼15.2 Hz, 1H), 3.52
(d, J¼9.0 Hz, 1H), 3.42 (dd, J¼2.7, 9.7 Hz, 1H), 3.29–
3.24 (m, 1H), 3.18 (dd, J¼6.5, 9.7 Hz, 1H), 2.44 (s, 3H),
1.51 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.2, 168.0, 143.7, 135.3, 132.0, 129.6, 129.6, 127.8,
127.8, 120.2, 54.5, 52.7, 52.5, 51.7, 49.0, 42.7, 21.6, 14.7;
LRMS (EI, m/z) 381 (M+), 350, 250, 226; HRMS (EI, m/z)
calcd for C18H23NO6S: 381.1246. Found: 381.1266.
4.3.10. Dimethyl (E)-3-{di(methoxycarbonyl)methyl}-
4-{(methoxycarbonyl)methylene}cyclopentane-1,1-
dicarboxylate (3h). IR (neat) 2955, 1735, 1265 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 5.68–5.66 (m, 1H), 3.76 (s,
3H), 3.75 (s, 3H), 3.74–3.66 (m, 2H), 3.73 (s, 3H), 3.73 (s,
3H), 3.70 (s, 3H), 3.48–3.42 (m, 1H), 3.34 (d, J¼19.2 Hz,
1H), 2.59 (dd, J¼8.4, 13.2 Hz, 1H), 2.40 (dd, J¼10.8,
13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 171.5,
171.0, 168.0, 167.5, 166.2, 162.4, 113.4, 58.4, 53.3, 52.9,
52.9, 52.8, 52.6, 51.2, 43.5, 40.3, 35.6; LRMS (EI, m/z)
386 (M+), 354, 322, 294, 262, 235, 207; HRMS (EI, m/z)
calcd for C17H22O10: 386.1212. Found: 386.1203.
4.3.16. Methyl 2-{(Z)-4-ethylidene-1-tosylpyrrolidin-3-
yl}acetate (4k). IR (neat) 2953, 1736, 1346, 1161 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 7.75–7.70 (m, 2H), 7.38–
7.32 (m, 2H), 5.31–5.26 (m, 1H), 3.81 (d, J¼14.2 Hz, 1H),
3.74 (d, J¼14.2 Hz, 1H), 3.67 (s, 3H), 3.47–3.43 (m, 1H),
2.98 (d, J¼6.0 Hz, 2H), 2.49 (dd, J¼9.3, 16.1 Hz, 1H),
2.44 (s, 3H), 2.32 (dd, J¼8.7, 16.1 Hz, 1H), 1.61 (d,
J¼5.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 172.1,
143.6, 137.8, 132.3, 129.6, 129.6, 127.8, 127.8, 117.8,
53.3, 51.8, 49.4, 39.0, 37.6, 21.6, 14.6; LRMS (EI, m/z)
323 (M+), 292, 250, 168; HRMS (EI, m/z) calcd for
C16H21NO4S: 323.1191. Found: 323.1188.
4.3.11. Dimethyl (E)-3-{(methoxycarbonyl)methyl}-4-
{(methoxycarbonyl)methylene}cyclopentane-1,1-di-
1
carboxylate (4h). IR (neat) 2954, 1735, 1266 cmꢁ1; H
NMR (400 MHz, CDCl3) d 5.68 (br s, 1H), 3.74 (s, 6H),
3.71 (s, 3H), 3.70 (s, 3H), 3.72–3.67 (m, 1H), 3.36 (d,
J¼19.6 Hz, 1H), 3.19–3.11 (m, 1H), 2.70–2.65 (m, 1H),
2.65 (dd, J¼5.2, 16.4 Hz, 1H), 2.41 (dd, J¼8.4, 16.4 Hz,
1H), 2.00 (dd, J¼11.2, 12.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 171.7, 171.5, 171.3, 166.5, 164.5, 112.7, 58.4,
53.0, 52.9, 51.8, 51.2, 40.8, 40.4, 38.8, 37.5; LRMS (EI,
m/z) 328 (M+), 296, 268, 236, 209; HRMS (EI, m/z) calcd
for C15H20O8: 328.1158. Found: 328.1165.
4.3.17. Dimethyl 2-{(Z)-4-(2-methoxyethylidene)-1-tosyl-
pyrrolidin-3-yl}malonate (3l). IR (neat) 2953, 1736, 1347,
1
1162 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.71–7.69 (m,
4.3.12. Dimethyl (E)-3-{(methoxycarbonyl)methyl}-4-
{(trimethylsilyl)methylene}cyclopentane-1,1-dicarboxy-
2H), 7.35–7.34 (m, 2H), 5.44–5.42 (m, 1H), 3.93 (d,
J¼14.3 Hz, 1H), 3.80–3.77 (m, 2H), 3.72 (s, 3H), 3.71 (s,
3H), 3.68 (d, J¼14.3 Hz, 1H), 3.56 (d, J¼8.8 Hz, 1H),
3.43 (dd, J¼3.2, 9.9 Hz, 1H), 3.33–3.29 (m, 1H), 3.26 (s,
3H), 3.21 (dd, J¼6.4, 9.9 Hz, 1H), 2.44 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 167.7, 167.6, 143.7, 138.0, 131.8,
129.6, 129.6, 127.6, 121.8, 121.8, 69.3, 58.2, 54.3, 52.9,
52.7, 51.2, 49.0, 43.0, 21.7; LRMS (EI, m/z) 411 (M+),
379, 366, 348; HRMS (EI, m/z) calcd for C19H25NO7S:
411.1352. Found: 411.1345.
late (4i). IR (neat) 2985, 1741, 1243 cmꢁ1 1H NMR
;
(500 MHz, CDCl3) d 5.31 (s, 0.16H), 3.74 (s, 3H), 3.73 (s,
3H), 3.68 (s, 3H), 3.08 (d, J¼16.5 Hz, 1H), 2.94–2.89 (m,
1H), 2.91 (d, J¼16.5 Hz, 1H), 2.68–2.61 (m, 2H), 2.29
(dd, J¼9.2, 15.9 Hz, 0.34H), 1.92 (dd, J¼10.4, 13.2 Hz,
1H), 0.11 (s, 9H); 13C NMR (100 MHz, CDCl3) d 173.2,
172.3, 172.2, 159.0, 120.9, 59.0, 53.3, 53.2, 52.0,
41.6, 40.8, 39.4, 39.1, 0.0, 0.0, 0.0; LRMS (EI, m/z) 342
(M+), 327, 311, 283, 251; HRMS (EI, m/z) calcd for
C16H26O6Si: 342.1498. Found: 342.1496.
4.3.18. Methyl 2-{(Z)-4-(2-methoxyethylidene)-1-tosylpyr-
rolidin-3-yl}acetate (4l). IR (neat) 2927, 1735, 1266 cmꢁ1
;
4.3.13. Dimethyl 2-{(E)-2-ethylidenecyclopentyl}malo-
nate (3j). IR (neat) 2962, 1735, 1263 cmꢁ1 1H NMR
;
1H NMR (500 MHz, CDCl3) d 7.71–7.70 (m, 2H), 7.35–
7.33 (m, 2H), 5.40–5.39 (m, 1H), 3.86 (d, J¼15.0 Hz, 1H),
3.81 (d, J¼7.1 Hz, 2H), 3.67 (s, 3H), 3.48 (dd, J¼7.1,
9.3 Hz, 1H), 3.33 (d, J¼15.0 Hz, 1H), 3.28 (s, 3H), 3.07–
3.05 (m, 1H), 2.98 (dd, J¼6.2, 9.3 Hz, 1H), 2.53 (dd,
J¼5.2, 16.3 Hz, 1H), 2.44 (s, 3H), 2.38 (dd, J¼8.7,
16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 171.8, 143.8,
141.0, 132.4, 129.7, 129.7, 127.8, 127.8, 119.6, 69.5, 58.2,
52.8, 51.8, 49.4, 39.4, 37.3, 21.6; LRMS (EI, m/z) 353
(M+), 321, 308, 248, 198, 155; HRMS (EI, m/z) calcd for
C17H23NO5S: 353.1297. Found: 353.1291.
(500 MHz, CDCl3) d 5.23–5.21 (m, 1H), 3.72 (s, 3H),
3.72 (s, 3H), 3.45 (d, J¼9.0 Hz, 1H), 3.12–3.09 (m, 1H),
2.35–2.16 (m, 2H), 1.84–1.71 (m, 2H), 1.65–1.54 (m, 2H),
1.56 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 169.1, 168.8, 143.2, 116.3, 55.3, 52.2, 44.0, 30.5, 28.3,
23.4, 14.8, 1.0; LRMS (EI, m/z) 226 (M+), 195, 166;
HRMS (EI, m/z) calcd for C12H18O4: 226.1205. Found:
226.1204.
4.3.14. Methyl 2-{(E)-2-ethylidenecyclopentyl}acetate
(4j). IR (neat) 2954, 1733, 1265 cmꢁ1
;
1H NMR
4.3.19. Dimethyl 2-{(Z)-4-ethylidene-tetrahydrofuran-
3-yl}malonate (3m). IR (neat) 2954, 1737, 1273 cmꢁ1; 1H
NMR (500 MHz, CDCl3) d 5.41–5.38 (m, 1H), 4.36 (d,
J¼13.5 Hz, 1H), 4.28 (d, J¼13.5 Hz, 1H), 3.90 (dd,
J¼5.6, 9.3 Hz, 1H), 3.85 (dd, J¼3.0, 9.3 Hz, 1H), 3.74 (s,
3H), 3.73 (s, 3H), 3.55 (dd, J¼9.6 Hz, 1H), 3.32–3.29 (m,
1H), 1.56 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.4, 168.4, 139.1, 117.3, 71.8, 68.7, 54.5, 52.6,
52.3, 43.7, 14.8; LRMS (EI, m/z) 228 (M+), 197, 132,
(400 MHz, CDCl3) d 5.24–5.18 (m, 1H), 3.67 (s, 3H),
2.79–2.69 (m, 1H), 2.52 (dd, J¼5.2, 14.8 Hz, 1H), 2.31–
2.12 (m, 3H), 2.22 (dd, J¼8.8, 14.8 Hz, 1H), 1.91 (dt,
J¼7.2, 19.2 Hz, 1H), 1.79–1.70 (m, 1H), 1.61–1.54 (m,
1H), 1.58 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 173.5, 145.6, 114.4, 51.3, 40.6, 39.2, 33.1, 28.7, 23.8,
14.6; LRMS (EI, m/z) 168 (M+), 108, 95, 79; HRMS (EI,
m/z) calcd for C10H16O2: 168.1150. Found: 168.1156.

7596
M. Takimoto et al. / Tetrahedron 62 (2006) 7589–7597
97; HRMS (EI, m/z) calcd for C11H16O5: 228.0998. Found:
228.0997.
3.64 (s, 3H), 3.60 (s, 3H), 3.57 (d, J¼13.5 Hz, 1H), 3.56
(d, J¼6.9 Hz, 1H), 2.66 (dd, J¼6.9, 10.9 Hz, 1H), 2.48
(ddd, J¼6.9, 10.9, 10.9 Hz, 1H), 2.43 (s, 3H), 2.30–2.25
(m, 1H), 2.02–1.99 (m, 1H), 1.85–1.62 (m, 4H), 1.60 (d,
J¼7.0 Hz, 3H), 1.16–1.07 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 168.6, 168.6, 143.3, 134.3, 132.5, 129.5,
129.4, 127.6, 127.6, 122.6, 62.8, 54.7, 52.5, 47.2, 46.7,
46.1, 31.1, 26.5, 21.5, 20.8, 13.9, 13.9; LRMS (EI, m/z)
435 (M+), 404, 304, 280; HRMS (EI, m/z) calcd for
C22H29O6NS: 435.1715. Found: 435.1707.
4.3.20. Methyl 2-{(Z)-4-ethylidene-tetrahydrofuran-
3-yl}acetate (4m). IR (neat) 2952, 1735, 1266 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 5.35–5.32 (m, 1H), 4.35 (d,
J¼15.8 Hz, 1H), 4.32 (d, J¼15.8 Hz, 1H), 4.05 (dd,
J¼6.6, 8.6 Hz, 1H), 3.69 (s, 3H), 3.56 (dd, J¼5.9, 8.6 Hz,
1H), 3.06–2.99 (m, 1H), 2.54 (dd, J¼5.6, 16.1 Hz, 1H),
2.39 (dd, J¼9.2, 16.1 Hz, 1H), 1.57 (d, J¼6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 172.6, 141.7, 114.9, 73.7,
69.1, 51.6, 40.0, 37.5, 14.7; LRMS (EI, m/z) 170 (M+),
139, 110, 97; HRMS (EI, m/z) calcd for C9H14O3:
170.0943. Found: 170.0939.
Acknowledgements
This work was supported by Grant-in-Aids for Scientific
Research (No. 14771235) and Scientific Research on Prior-
ity Area (A): ‘Creation of Biologically Functional Mole-
cules’ (No. 17035003) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan,
which are gratefully acknowledged.
4.3.21. Dimethyl (E)-3-{di(methoxycarbonyl)methyl}-4-
ethylidenecyclohexane-1,1-dicarboxylate (7a). IR (neat)
2955, 1734, 1240 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d 5.07 (q, J¼6.7 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.71
(s, 3H), 3.67 (s, 3H), 3.56 (d, J¼10.8 Hz, 1H), 2.97–2.93
(m, 1H), 2.45–2.40 (m, 1H), 2.28 (dd, J¼4.6, 13.6 Hz,
1H), 2.17–1.98 (m, 4H), 1.57 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 172.0, 171.3, 168.4, 168.3,
136.9, 116.8, 54.5, 54.3, 52.7, 52.7, 52.5, 52.4, 41.3, 35.0,
32.0, 23.6, 12.9; LRMS (EI, m/z) 356 (M+), 325, 264, 237,
205; HRMS (EI, m/z) calcd for C17H24O8: 356.1471. Found:
356.1475.
Supplementary data
Information on procedures for preparation of enynes 2c–2n
and 6a–6d, spectral data for all synthetic intermediates of
those enynes, and determination of the stereochemistry of
7c and 7d are described. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2006.03.121.
4.3.22. Dimethyl 2-{(Z)-3-ethylidene-1-tosylpiperidin-4-
1
yl}malonate (7b). IR (neat) 2954, 1736, 1268 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.67–7.66 (m, 2H), 7.34–7.33
(m, 2H), 5.38 (q, J¼6.8 Hz, 1H), 3.88 (d, J¼13.0 Hz, 1H),
3.71 (s, 3H), 3.63 (s, 3H), 3.55 (d, J¼11.2 Hz, 1H), 3.39
(d, J¼13.0 Hz, 1H), 3.31–3.27 (m, 1H), 3.00–2.91 (m,
2H), 2.45 (s, 3H), 1.88–1.81 (m, 1H), 1.66 (d, J¼6.8 Hz,
3H), 1.64–1.58 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 167.8, 167.8, 143.4, 133.1, 130.7, 129.5, 129.5, 127.5,
127.4, 122.8, 52.9, 52.7, 52.5, 43.9, 43.3, 41.4, 28.8, 21.7,
13.2; LRMS (EI, m/z) 395 (M+), 364, 304, 264, 240;
HRMS (EI, m/z) calcd for C19H25O6NS: 395.1395. Found:
395.1399.
References and notes
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octahydro-1-tosyl-1H-cyclopenta[b]pyridin-4-yl}malo-
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;
´
´
(500 MHz, CDCl3) d 7.75–7.74 (m, 2H), 7.32–7.31 (m,
2H), 5.42–5.40 (m, 1H), 4.31 (dd, J¼8.1, 18.7 Hz, 1H),
4.21 (d, J¼15.6 Hz, 1H), 3.82 (d, J¼11.8 Hz, 1H), 3.72 (s,
3H), 3.66 (d, J¼15.6 Hz, 1H), 3.60 (s, 3H), 2.76 (d,
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168.7, 143.2, 136.2, 129.6, 129.6, 129.4, 129.4, 127.3,
124.4, 55.2, 54.7, 52.5, 52.1, 46.3, 40.7, 39.1, 31.6, 28.0,
24.2, 21.6, 12.9; LRMS (EI, m/z) 435 (M+), 404, 304, 280;
HRMS (EI, m/z) calcd for C22H29O6NS: 435.1715. Found:
435.1707.
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˚
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˚
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