Lewis acid promoted cyclization of enyne triesters and diesters

Article abstract of DOI:10.1021/jo016159r

Reactions of enynes with three or two ester groups (1-4) in the presence of halogen-ligand Lewis acids gave cyclized products with halide incorporation (5-8) with high generality. The cyclization process was also analyzed in a theoretical study. Facile isomerization and dehydrohalogenation of five-membered products 5 and 8 by Al₂O₃ or Et₃N were also observed; this process introduces conjugated moieties into the products.

Full text of DOI:10.1021/jo016159r

J . Org. Chem. 2002, 67, 2889-2901
2889
Lew is Acid P r om oted Cycliza tion of En yn e Tr iester s a n d Diester s
Shoko Yamazaki,* Kuriko Yamada, and Shinichi Yamabe*
Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, J apan
Kagetoshi Yamamoto
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama,
Toyonaka, Osaka 560-0043, J apan
yamazaks@nara-edu.ac.jp
Received September 28, 2001
Reactions of enynes with three or two ester groups (1-4) in the presence of halogen-ligand Lewis
acids gave cyclized products with halide incorporation (5-8) with high generality. The cyclization
process was also analyzed in a theoretical study. Facile isomerization and dehydrohalogenation of
five-membered products 5 and 8 by Al2O3 or Et3N were also observed; this process introduces
conjugated moieties into the products.
I. In tr od u ction
far. Snider and Roush reported an example of cyclization
of propargylic esters of ethenetricarboxylic acid 1 in the
presence of FeCl3 as an extension of ene-ene cyclization
to give chlorinated γ-lactones (eq 1).4a Recently, we have
Lewis acid promoted reactions have been extensively
utilized for ring-forming reactions such as Diels-Alder
reactions,1 [2 + 2] cycloadditions,2 ene reactions,3 and
alkene-alkene cyclizations.4 Lewis acids play a major
role in carbon-carbon bond-forming processes by coor-
dinating to carbonyl compounds.5 Recently, transition-
metal-catalyzed cyclization reactions of enynes have been
extensively studied for the construction of ring systems.6
On the other hand, only a few examples of Lewis acid
promoted cyclizations of enynes have been reported so
(1) (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876. (b)
Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1. (c) Birney, D. M.; Houk, K. N. J . Am. Chem.
Soc. 1990, 112, 4127. (d) Carruthers, W. Cycloaddition Reactions in
Organic Synthesis; Pergamon Press: Oxford, U.K., 1991; pp 140-208.
(e) Yamabe, S.; Minato, T. J . Org. Chem. 2000, 65, 1830.
(2) (a) Takeda, T.; Fujii, T.; Morita, K.; Fujiwara, T. Chem. Lett.
1986, 1311. (b) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S.
J . Am. Chem. Soc. 1992, 114, 8869. (c) Srisiri, W.; Padias, A. B.; Hall,
H. K. J r. J . Org. Chem. 1994, 59, 5424. (d) Clark, R. D.; Untch, K. G.
J . Org. Chem. 1979, 44, 248, 253. (e) Baar, M. R.; Ballesteros, P.;
Roberts, B. W. Tetrahedron Lett. 1986, 27, 2083. (f) Okauchi, T.;
Kakiuchi, T.; Kitamura, N.; Utsunomiya, T.; Ichikawa, J .; Minami, T.
J . Org. Chem. 1997, 62, 8419.
(3) (a) Snider, B. B. Acc. Chem. Res. 1980, 13, 426. (b) Narasaka,
K.; Hayashi, Y.; Shimada, S. Chem. Lett. 1988, 1609. (c) Tietze, L. F.;
Beifuss, U.; Ruther, M.; Ru¨hlmann, A.; Antel, J .; Sheldrick, G. M.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1186. (d) Tietze, L. F.; Beifuss,
U. Synthesis 1988, 359. (e) Minami, T.; Utsunomiya, T.; Nakamura,
S.; Okubo, M.; Kitamura, N.; Okada, Y.; Ichikawa, J . J . Org. Chem.
1994, 59, 6717.
(4) (a) Snider, B. B.; Roush, D. M. J . Org. Chem. 1979, 44, 4229. (b)
Tietze, L. F.; Ruther, M. Chem. Ber. 1990, 123, 1387. (c) Tietze, L. F.;
Schu¨nke, C. Eur. J . Org. Chem. 1998, 2089.
(5) (a) Selectivities in Lewis Acid Promoted Reactions; Schinzer, D.,
Ed.; Kluwer Academic: Dordrecht, The Netherlands, 1989. (b) Sham-
bayati, S.; Crowe, W. E.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl.
1990, 29, 256.
(6) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M.; Krische, M. J .
Synlett 1998, 1. (c) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.;
Murai, S. J . Org. Chem. 2001, 66, 4433. (d) Trost, B. M.; Tanoury, G.
J .; Lautens, M.; Chan, C.; MacPherson, D. T. J . Am. Chem. Soc. 1994,
116, 4255. (e) Trost, B. M.; Romero, D, L.; Rise, F. J . Am. Chem. Soc.
1994, 116, 4268. (f) Trost, B. M.; Toste, F. D. J . Am. Chem. Soc. 2000,
122, 714. (g) Nishida, M.; Adachi, N.; Onozuka, K.; Matsumura, H.;
Mori, M. J . Org. Chem. 1998, 63, 9158.
reported ZnBr2(THF)-promoted cycloisomerizations of
enynes 1 to give exocyclic conjugated dienes 12 (eq 2).7
Since the product types are different from those
reported by Snider, we decided to explore Lewis acid
promoted reactions of triester-enyne compounds sys-
tematically. The Lewis acid promoted enyne cyclization
requires both that a highly electrophilic alkene has
coordination sites for a Lewis acid and that the alkyne
component can function as a nucleophile. Alkenes sub-
stituted with three or two carbonyl groups were designed
as very electrophilic counterparts. To this end, applica-
tion of this reaction toward the construction of oxygen-
and nitrogen-containing heterocycles and carbocycles has
been investigated.
We thus examined Lewis acid (MXn) promoted in-
tramolecular cyclizations of the designed diester- and
triester-substituted alkenes 1-4. Herein, we report a
novel and general Lewis acid promoted intramolecular
C-C bond-forming reaction to give halogenated five-
membered cyclic compounds (eq 3). The elementary
(7) Yamazaki, S.; Yamada, K.; Otsubo, T.; Haruna, M.; Kutsuwa,
E.; Tamura, H. J . Chem. Soc., Chem. Commun. 2001, 69.
10.1021/jo016159r CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/28/2002

2890 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
Ta ble 2. Tr iester -En yn e Cycliza tion (in Eq 5)a
Ta ble 1. Tr iester -En yn e Cycliza tion (in Eq 4)a
time
(h)
5
time
(h)
5 (yield 9 (yield
(%)) (%))
entry substrate R1 R2 Lewis acid
X
(yield (%))
entry substrate R3 Lewis acid
X
1
2
3
4
1a
1a
1b
1c
H
H
H
Et ZnBr2-THF 16 Br 5a -Br (52)
1
2
3
4
5
6
1d
1d
1d
1e
1e
1e
Me ZnBr2
16 Br 5d -Br (39) 9d (16)
Et FeCl3
Me FeCl3
3
3
3
Cl 5a -Cl (98)
Cl 5b-Cl (83)
Cl 5c-Cl (63b)
Me ZnBr2-THF 16 Br 5d -Br (37) 9d (30)
Me FeCl3
Et ZnBr2
Et FeCl3
Et ZnI2
3
Cl 5d -Cl (76)
Me Et FeCl3
16 Br 5e-Br (37) 9e (29)
3
16
Cl 5e-Cl (67)
5e-I (31) 9e (31)
a
Reactions were carried out using 0.4-0.8 mmol of 1a -c, 1.2
I
equiv of ZnBr2, and 1.0 equiv of THF or 1.2 equiv of FeCl3 at 0.5
M for 1a -c in CH2Cl2. Diastereomer ratio: 7:3.
b
a
Reactions were carried out using 0.4-1.0 mmol of 1d ,e, 1.2
equiv of ZnBr2, and 1.0 equiv of THF or 1.2 equiv of Lewis acid at
0.5 M for 1d ,e in CH2Cl2.
processes were also examined computationally to explore
the structural and electronic factors required for ring
closure.
The diasteroselectivity of the products is not very high
in the case of entry 4 in Table 1.
Reaction of 1d and 1e (R3 ) alkyl, see eq 5) in the
presence of ZnBr2 at room temperature for 16 h and
subsequent treatment with water gave cyclized products
5d -Br and 5e-Br along with noncyclized H2O adducts
II. Resu lts a n d Discu ssion of Cycliza tion
Rea ction
A. Cycliza tion of Tr iester -En yn es. As described in
the Introduction, ZnBr2(THF)-promoted cycloisomeriza-
tion of enynes 1 gave cyclic dienes 12 (eq 2), which are
different from the products of the FeCl3-promoted reac-
tion reported (eq 1).4a The decisive difference in the
reaction conditions employed was the workup with Et3N
instead of H2O. A workup procedure to remove Lewis acid
by addition of an amine is usually used for Lewis acid
promoted reactions in order to avoid highly acidic condi-
tions in the presence of H2O. However, the amine (Et3N)
may induce further transformation in this case. We have
examined the reaction of 1a -c with ZnBr2 (1.2 equiv)-
THF (1.0 equiv) or FeCl3 (1.2 equiv) at -40 °C in CH2Cl2
and subsequent workup with H2O (eq 4 and Table 1). The
9d and 9e, in 37-39% and 16-29% yields, respectively
(entries 1 and 4, Table 2). Reaction in the presence of
FeCl3 at room temperature for 3 h gave the cyclized
products 5d -Cl and 5e-Cl in 67-76% yields (entries 3
and 5). The olefin stereochemistry in cyclized products
5d ,e was detemined as Z by NOEs between R3 and
CHCH(CO2Et)2.
B. Diester -En yn es. Next, an alkene with only two
ester groups, the enyne 2, was examined (eq 6). Com-
isolated products were the cyclized HBr and HCl adducts
5a -c in 52-98% yield. Thus, workup with water is
appropriate to obtain halogenated cyclic compounds. The
reaction at -40 °C gave the (Z)-olefin products stereo-
selectively.8 The γ-lactone structure of 5a -c was sug-
gested by the presence of a characteristic CdO absorption
(1783-1792 cm-1) and disappearance of the 2238-2244
pound 2 was prepared by Knoevenagel condensation of
diethyl malonate with 6-phenyl-5-hexynal. Reaction with
ZnBr2 or FeCl3 in CH2Cl2 proceeded only when the
reaction temperature was raised to room temperature.
Workup with Et3N gave the cyclopentane products 6E-
Br and 6E-Cl in 64 and 56% yields, respectively (Table
3, entries 1 and 2). Other Lewis acids were also exam-
ined, and the results are shown in Table 3. In entries 3
and 5, the formation of (Z)-olefin product 6Z-Cl was
observed in low yields (note that the E and Z nomencla-
tures are opposite to those of the substrates 5 in terms
of the X-addition orientation).
1
cm-1 absorption for the CtC triple bond in 1a -c. H,
1
13C, H/13C-HSQC, HMBC, and NOESY spectra were in
agreement with the lactone structure shown in eq 4. The
stereochemistry was determined by the NOEs observed
between Ph and CHCH(CO2R2)2. Compounds 5a -c are
unstable to silica gel column chromatography and are
partially transformed to cyclic dienes 12a -c. Compounds
5a -c could be purified without dehydrohalogenation by
preparative reverse-phase column chromatography (Cos-
mosil 75C18OPN, CH3CN-H2O).
C. Diester /Am id e-En yn es. Alkenes with two ester
groups and an amide group (enynes 3a ,b) were designed
(8) Snider obtained a 55:45 Z and E olefin mixture by the reaction
of 1b at room temperature.4a

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2891
Ta ble 3. Diester -En yn e Cycliza tion (in Eq 6)a
Ta ble 5. Diester /Keton e-En yn e Cycliza tion (in Eq 8)a
entry
Lewis acid
time (h)
X
6 (yield (%))
6E:6Z
sub-
Lewis temp time
8 (yield 10 (yield
(%)) (%))
entry strate R3 acid
(°C)
(h)
X
1
2
3
4
5
6
ZnBr2
FeCl3
AlCl3
ZrCl4
GaCl3
ZnCl2
13
15
16
14
15
17
Br
Cl
Cl
Cl
Cl
Cl
6E-Br (64)
6E-Cl (ca. 56)b
6E,Z-Cl (31)
6E-Cl (46)
6E,Z-Cl (23)
6E (26)
100:0
100:0
80:20
100:0
20:80
100:0
1
2
3
4a
4b
4b
Ph FeCl3 -40
3
3
Cl 8a -Cl (68)
Cl 8b-Cl (59)
Me FeCl3 -40
Me ZnBr2 room
16 Br 8b-Br (47) 10b (13)
temp
a
Reactions were carried out using 0.3 mmol of 4a ,b and 1.2
equiv of Lewis acid at 0.5 M for 4a ,b in CH2Cl2.
a
Reactions were carried out using 0.1-0.4 mmol of 2 and 1.2
b
equiv of Lewis acid at 0.5 M for 2 in CH2Cl2. A small amount of
unidentified impurity could not be separated.
tively in 59-68% yields. Reaction of 4b with ZnBr2
required room temperature and gave the brominated
cyclopentanone 8b-Br in 47% yield along with the
noncyclized H2O adduct 10b in 13% yield. Compounds
8a -Cl and 8b-Cl were also unstable to silica gel colum
chromatography and partially transform to isomeric
compounds (vide infra). The compounds 8a -Cl and 8b-
Cl could be purified by preparative reverse-phase column
chromatography (Cosmosil 75C18PREP for 8a -Cl or
Cosmosil 75C18OPN for 8b-Cl, CH3CN-H2O).
Ta ble 4. Diester /Am id e-En yn e Cycliza tion (in Eq 7)a
sub-
temp
(°C)
time
(h)
7 (yield
(%))
entry strate R3 Lewis acid
X
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3b
3b
3b
Ph ZnBr2-THF -40
16 Br 7a -Br (84)
19 Br 7a -Br (48)
Cl 7a -Cl (42)
18 Cl 7a -Cl (64)
17 7a -I (62)
Ph ZnBr2
Ph FeCl3
Ph ZnCl2
Ph ZnI2
-40
-40
-40
-40
3
I
nPr ZnBr2
nPr FeCl3
nPr ZnCl2
nPr ZnI2
room temp 16 Br 7b-Br (74)
room temp Cl 7b-Cl (69)
room temp 16 Cl 7b-Cl (60)
room temp 17 7b-I (49)
3
I
a
Reactions were carried out using 0.2-0.9 mmol of 3a ,b, 1.2
equiv of ZnBr2, and 1.0 equiv of THF or 1.2 equiv of Lewis acid at
0.5 M for 3a ,b in CH2Cl2.
for the construction of nitrogen-containing heterocycles
(eq 7). Compounds 3 were prepared by condensation of
III. Rea ction Mech a n ism for F or m a tion of
γ-La cton es
To clarify the precise features of the critical ring-
forming step, a computational study for the reaction of
the model compound M1 with ZnBr2 was carried out.10
M1 is different from 1d only in the ester substituent R2
(R2 ) Me for M1 and R2 ) Et for 1d ). Geometries were
fully optimized by the B3LYP density functional method11
together with the SCRF12 solvent effect (CH2Cl2, dielectric
constant 8.93) using GAUSSIAN 98.13 The basis set
employed was 6-31G*.14 Vibrational frequency calcula-
tions gave sole imaginary frequencies for transition
structures, which verifies that the obtained geometries
are correctly of the saddle point. All the intermediate
species were calculated to have no imaginary frequencies.
The computed energies are ∆H0 ()∆E + ZPVE).
1,1-diethyl 2-hydrogen ethenetricarboxylate with the cor-
responding propargylamines. Reaction of the phenyl-
substituted alkyne 3a with ZnBr2-THF in CH2Cl2 pro-
ceeded at -40 °C. Workup with Et3N gave the brominated
γ-lactam 7a -Br in 84% yield (Table 4, entry 1). The yield
of 7a decreased when THF was omitted from the reaction
(entry 2). Although the effect of THF is not clear, it is
presumed that coordination of THF to Zn adjusts the
strength of the Lewis acid and prevents side reactions.9
Otherwise, THF can work as a scavenger of protons
produced from trace amounts of water. Zinc chloride and
zinc iodide promoted reactions also gave the correspond-
ing halogenated γ-lactams in good yields (64% and 62%
yields in entries 4 and 5, respectively). Reaction of
n-propyl-substituted alkyne 3b with FeCl3 or zinc halides
in CH2Cl2 proceeded at room temperature (entries 6-9).
D. Diester /Keton e-En yn es. Alkenes with two ester
groups and one ketone group (enynes 4) were next
examined (eq 8, Table 5). The reaction is another example
leading to carbocycles. Starting materials 4 were pre-
pared by Wittig reaction of the corresponding carbonyl-
methylenetriphenylphosphorane with diethyl ketoma-
lonate. Reaction of enynes 4 with FeCl3 in CH2Cl2
proceeded at -40 °C. Workup with H2O gave the chlo-
rinated cyclopentanones 8a -Cl and 8b -Cl stereoselec-
(10) The structures of Lewis acid-free M1 conformers are shown in
Figure 8S (Supporting Information).
(11) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1998, 37, 785.
(12) Onsager, L. J . Am. Chem. Soc. 1938, 58, 1486.
(13) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh, PA,
1998. MO calculations using Gaussian 98 were made on the Compaq
ES40 at the Information Processing Center (Nara University of
Education).
(9) (a) Suzuki, I.; Yamamoto, Y. J . Org. Chem. 1993, 58, 4783. (b)
Barrett, D.; Sasaki, H.; Tsutsumi, H.; Murata, M.; Terasawa, T.;
Sakane, K. J . Org. Chem. 1995, 60, 3928. (c) Palazzi, C.; Colombo, L.;
Gennari, C. Tetrahedron Lett. 1986, 27, 1735. (d) Ipaktschi, J .;
Lauterbach, G. Angew. Chem., Int. Ed. Engl. 1986, 25, 354. (e) Spawn,
C.-L.; Drtina, G. J .; Wiemer, D. F. Synthesis 1986, 315.
(14) All electrons of the metals were included.

2892 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
Sch em e 1. Mech a n ism of th e Cycliza tion
Ca lcu la ted a t B3LYP /6-31G* SCRF
B3LYP/6-31G* SCRF. The energy barrier for cyclization
is +5.3 kcal/mol and indicates that the cyclization is a
facile process. The structure of the resulting zwitterionic
intermediate M4 (Figure 5S in the Supporting Informa-
tion) shows vinyl cation characteristics at C9 (atomic
charge +0.39). The alkyne group may be the key for facile
five-membered-ring formation. The two perpendicular 2pπ
orbitals of the triple bond as a nucleophile have spatial
flexibility, and one of them can be directed flexibly and
appropriately toward the electrophilic center in M2 for
the intramolecular charge transfer.
The corresponding precursors thought to give a six-
membered ring (M6) and a four-membered ring (M7)
(16) As is the case of reaction of 2 with GaCl3 and AlCl3 in entries
3 and 6 of Table 3, Cl- attack may occur intramolecularly (cis addition).
The Lewis acids consisting of the group 13 elements such as GaCl3
and AlCl3 have a tendency to form stable four-coordinated carbonyl
complexes.5a The five-coordinated anion intermediate B (see Scheme
3) is unstable for GaCl3 and AlCl3. In fact, the model calculation shows
the anion intermediate model M9 to be 9.8 kcal/mol less stable than
the neutral precursor model M8. The stability rank is opposite to that
of M2 and M4 (Scheme 1). The structures of M8 and M9 are shown in
Figure 7S (Supporting Information). As seen in structure M9, one Ga-
Cl bond length is longer than the others (2.345 Å vs 2.248 and 2.238
Å). Therefore, one Cl- anion can be released readily to compensate
the instability of M9, leading to the intramolecular Cl- cis addition.
We have made calculations to simulate the Cl- migration route. After
the tetravalent coordination of Ga pushes out a chloride ion in M9, it
would be bound to a π*CdO electrophilic carbon, C4. The smaller ion
radius of Cl- compared to that of Br- makes the internal migration of
Cl- possible. To examine the intermediacy of the Cl-fπ* CT complex,
we have made geometry optimizations with an assumed C4- - -Cl-
distance of 3.0 Å. The initial geometry has been calculated to be
converted to that of a neutral intermediate, M10, with a C9-Cl covalent
bond. Thus, the vacant orbital lobe of the vinyl cation, C9, is electro-
philic enough to attract Cl- located at the intermediate region. In
contrast to GaCl3 and AlCl3, the other Lewis acids examined form
stable two carbonyl coordinated chelate intermediates such as M4,
leading to exclusive intermolecular trans addition (Scheme 1).
The mechanism was examined for γ-lactone ring
formation and is shown in Scheme 1. Nucleophilic attack
of the alkyne moiety (C8) at the vinyl carbon (C2) of the
electrophilic olefin complexed with ZnBr2 in M2 gives the
zwitterionic intermediate M4 via the cyclization transi-
tion state (TS) M3.15 Sequential intermolecular trans
addition of halide ion (X-) of the ZnBr2 complex M4 to a
vinyl cation moiety of another M4 may lead to intermedi-
ate M5. In M4, the cis Br- addition to C9 is sterically
unfavorable, which leads to the trans-addition stereose-
lectivity in most cases.16 Protonation of C1 and removal
of ZnBrOH from the intermediate M5 yields the 5d
analogue of the bromo-γ-lactone product.
In the ZnBr2 complex M2, the ring-forming C2- - -C8
distance is only 2.860 Å, and the structure has a
conformation which is oriented properly to cyclize (Figure
1, geometry at the top).17 The ring formation transition
state M3 is shown in Figure 2. Geometry optimization
using the 6-311G* basis set was also carried out for M3.
The geometric parameters for M3 calculated using B3LYP/
6-311G* SCRF were similar to those calculated using
(15) The formation of hydrated byproducts 9 and 10b is presumed
to result from attack by trace amounts of water on the complex M2
(corresponding to A in Scheme 3). Compounds 9 and 10b were only
observed with ZnBr2 and ZnI2 and not with FeCl3. This is because the
stronger Lewis acid, FeCl, facilitates the cyclization process but the
weaker Lewis acids ZnBr2 and ZnI2 allow the alternative reaction: i.e.,
water addition to the double bond.
(17) The linear conformer M2I (Figure 4S, in the Supporting
Information) was also calculated and is 10.3 kcal/mol more stable than
M2, probably due to steric reasons. However, the energy difference is
small enough to proceed to cyclization, leading to the product M5
(-12.6 kcal/mol). In addition, M2I is only 1.2 kcal/mol more stable than
M2 in the gas phase (without SCRF and ZPVE). M2I may be
overstabilized by the SCRF solvent effect.

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2893
F igu r e 1. B3LYP/6-31G* SCRF-optimized geometries of precursor M2 in Scheme 1 and for comparison two model
precursors, M6 and M7, to give a six-membered ring and a four-membered ring, respectively. Small white circles denote hydrogen
atoms.
were also calculated (lower half of Figure 1). The ring-
forming C2- - -C9 and C2- - -C7 distances are 3.441 and
2.911 Å, respectively. The 2pπ orbitals in M6 and M7 in
the alkyne part are not directed properly toward the vinyl
π* orbital for σ-bond formation. The six- and four-
membered-ring formations seem to be less efficient.
Experimentally, cyclization of substrate 11 (vide infra)
recovered starting material. Reaction with FeCl3 at room
temperature gave a complex mixture. Six-membered-ring
formation was not an efficient process, as suggested by
the calculation of M6. For four-membered-ring formation,
strain in the product may interfere with the cyclization;
however, this will be experimentally examined in the
future.
Intermolecular trans addition of Br- to the vinyl cation
moiety of the zwitterionic intermediate M4 was examined
by calculation of the reaction between M4 and a model,
Br2Zn(CO2Me)2CCH3-. This is because the size of a
system composed of two M4 intermediates is too large
to be calculated by B3LYP/6-31G*, owing to restricted
computer power. When the vinyl cation carbon (C9) of M4
was also examined. Reaction with ZnBr2 at -40 °C or
room temperature and with FeCl3 at -40 °C gave only
-
and Br in Br2Zn(CO2Me)2CCH3 is set to 3.5 Å as an

2894 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
F igu r e 2. B3LYP/6-31G* SCRF-optimized geometry of transition state M3 and reaction-coordinate vectors corresponding to the
sole imaginary frequency νq. The energy in brackets is relative to M2. Underlined numbers are obtained by B3LYP/6-311G*
SCRF.
Ta ble 6. Isom er iza tion a n d Deh yd r och lor in a tion of
initial structure, the vinyl cation carbon (C9) is linked
Cyclized P r od u cts
readily with the bromide ion, as shown in the optimiza-
R3
conditions
product (yield (%)) R3′
tion process (Figure 3). Thus, the intermolecular Br-
relay may occur successively, leading to the complex M5,
whose optimized structure is shown in Figure 6S (Sup-
porting Information).
compd
Y
5a -Cl
5a -Cl
5d -Cl
5e-Cl
5d -Cl
5e-Cl
8b-Cl
8b-Cl
8b-Cl
O
Ph Al2O3
Ph Et3N
Me Al2O3
12a (80)
12a (82)
12d (54)
12e (77)
17d (quant)
17e (80)
13b-Cl (99)
14b (57)
15b (26)
O
O
O
O
O
Et
Me Et3N
Et Et3N
Al2O3
H
Me
IV. Isom er iza tion a n d Deh yd r oh a logen a tion of
Cycloa d d u cts
CH2 Me SiO2 (15% H2O)
CH2 Me Al2O3
CH2 Me Et3N
H
H
H
We observed that the ZnBr2(THF)-promoted reaction
of enynes 1a -c and subsequent workup with Et3N
instead of H2O gave the dialkylidene-γ-lactones 12a -c
13b-Cl CH2 Me Al2O3(15% H2O)
14b
8a -Cl
15b (quant)
15b (quant)
13a -Cl (quant)
CH2 Me Et3N, 3 h
CH2 Ph in CDCl3

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2895
F igu r e 3. (top view) Initial structure for the geometry optimization. (bottom view) B3LYP/6-31G* SCRF-optimized structure.
(eq 2).7 In addition, partial isomerization and/or dehy-
drohalogenation of cyclized products 5 and 8 by silica gel
column chromatography leading to dienes was also
observed. After extensive examination of the reaction
conditions in this work, selective isomerization and
dehydrohalogenation of cycloadducts 5 and 8 with Al2O3
and Et3N have been established.
phase column, and subsequent Al2O3 column chromatog-
raphy in 81% total yield. The yield is better than that
Typical examples are explained in detail. Treatment
of the chlorolactone 5a -Cl with Al2O3 and Et3N gave 12a 7
in 80% and 82% yields, respectively (eq 9). Compound
12a was also obtained by the reaction of 1a with FeCl3
and workup by water, without purification by a reverse
with direct workup by Et3N (FeCl3/Et3N, 66%; ZnBr2-
THF/Et3N, 67%7). The cyclopentanone 8b-Cl isomerizes
to 13b-Cl by silica gel (containing 15% H2O) column

2896 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
Sch em e 3. Rea ction Rou tes F or m in g th e
F ive-Mem ber ed Rin gs a n d th e Con sequ en t
Isom er iza tion /Deh yd r och lor in a tion
Sch em e 2. Isom er iza tion a n d
Deh yd r och lor in a tion of Cyclized P r od u cts
Obta in ed in Eqs 4, 5, a n d 8
chromatography. Column chromatography of 8b-Cl with
Al2O3 (containing 5% H2O) gave the exomethylenic diene
14b in 57% yield. Various transformations are shown in
eq 10.
V. Con clu sion s
A novel and general Lewis acid promoted enyne
cyclization to give five-membered cyclic compounds has
been discovered. The cyclization and subsequent isomer-
ization/dehydrochlorination process is summarized in
Scheme 3. Syntheses of diverse cyclic compounds, includ-
ing heterocycles, by ring formation using transition-metal
catalysts have been relatively limited.18 Therefore, the
present method should provide an efficient alternative
to transition-metal-catalyzed cyclizations. Additionally,
the cyclized products are highly substituted and are
suitable for further elaboration (e.g. C-C bond forma-
tions). The usefulness of the combination of multiple
bonds (i.e. electrophilic carbon-carbon double bond and
the nucleophilic triple bond) in organic synthesis has been
established in this study. The design of new substrates
toward more diverse cyclic compounds and further trans-
formation of the products to useful compounds are under
investigation.
Other related reactions are included in Table 6 and
Scheme 2. As shown in Scheme 2, the reaction may
proceed through the isomerized chloro compound inter-
mediates 13 (Y ) CH2) and 16 (Y ) O), although
chlorolactones 16 (Y ) O) were not isolated. Dehydro-
chlorination of the chloro compounds gave the dialkyl-
idene-γ-lactones 12 and dialkylidenecyclopentanone 14.
In the case of R3 ) Me, Et, the vinyl unsaturated-γ-
lactones 17 and vinylcyclopentenone 15 were also ob-
tained. Dialkylidene-γ-lactones 12 and cyclopentanone 14
should be the primary products in this process. Such
isomerization of 1,2-dialkylidenecyclopentane to 1-vinyl-
cyclopentenes bytransition metals has alsobeen reported.6c,d
The diene 12a is prevented from undergoing further
isomerization due to the lack of a proton.
The cyclic diene 14a (R3 ) Ph, see Scheme 2 for
structure 14) was not isolated, probably because of
instability of the product. The structure of 12a was
confirmed by X-ray previously.7 The olefin stereochem-
istries of 12, 17, and 14 were determined by the observed
NOEs. The facile isomerization and dehydrochlorination
is probably attributable to the acidity of the R-proton of
the carbonyl group in the ring. Such isomerization and
dehydrochlorination by treatment with Et3N was not
observed for γ-lactams 7 and cyclopentanes 6.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR
1
spectra were recorded in the FT mode. H NMR spectra were
recorded at 400 MHz. 13C NMR spectra were recorded at 100.6
MHz. Chemical shifts are reported in ppm relative to Me4Si
or residual nondeuterated solvent. 13C mutiplicities were
determined by DEPT and HSQC. Mass spectra were recorded
at an ionizing voltage of 70 eV by EI. All reactions were carried
out under a nitrogen atmosphere.
P r ep a r a tion of En yn e Su bstr a tes 1a -e a n d 11. 1a ,b
were prepared by the reaction of diethyl or dimethyl ketoma-
(18) (a) Trost, B. M.; Edstrom, E. D.; Carter-Petillo, M. B. J . Org.
Chem. 1989, 54, 4489. (b) Sturla, S. J .; Kablaoui, N. M.; Buchwald, S.
L. J . Am. Chem. Soc. 1999, 121, 1976. (c) Urabe, H.; Nakajima, R.;
Sato, F. Org. Lett. 2000, 2, 3481. (d) Zhang, Q.; Lu, Z. J . Am. Chem.
Soc. 2000, 122, 7604.
Thus, the primary cycloadducts 5 and 8 may be
transformed readily with bases (Al2O3 and Et3N) to
conjugated systems, dienes 12, 17, 14, and 15.

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2897
lonate with propargyl (triphenylphosphoranylidene)acetate
and subsequent Sonogashira coupling19 with iodobenzene.7 1c
was prepared by the reaction of diethyl ketomalonate with
2-but-3-ynyl (triphenylphosphoranylidene)acetate and subse-
quent Sonogashira coupling with iodobenzene.7 1d ,e were
prepared by the reaction of diethyl ketomalonate with 1-but-
2-ynyl and 1-pent-2-ynyl (triphenylphosphoranylidene)ace-
tates. 11 was prepared by the reaction of diethyl ketomalonate
with 1-but-3-ynyl (triphenylphosphoranylidene)acetate and
subsequent Sonogashira coupling with iodobenzene.7 These
(triphenylphosphoranylidene)acetate esters were prepared by
the reaction of the corresponding chloroacetates and tri-
phenylphosphine in benzene and subsequent treatment with
NaOH.20 The chloroacetates were prepared by the reaction of
the corresponding alcohols (1 equiv) and chloroacetyl chloride
(1 equiv) in the presence of pyridine (1 equiv) in ether at 0
°C.7
1,1-Diet h yl 2-P r op a r gyl E t h en e-1,1,2-t r ica r b oxyla t e.
To an ice-water-cooled solution of diethyl ketomalonate (0.79
mL, 0.902 g, 5.18 mmol) in benzene (10.3 mL) was added
propargyl (triphenylphosphoranylidene)acetate (1.856 g, 5.18
mmol). The mixture was warmed to room temperature and
stirred for 5 h. The benzene was evaporated, and ether was
added. The precipitate was removed by filtration. The filtrate
was concentrated, and the residue was purified by column
chromatography over silica gel with hexane-ether (1:2) as
eluent to give the title compound (860 mg, 65%; Rf ) 0.7):
colorless crystals; mp 55-56 °C; 1H NMR (400 MHz, CDCl3) δ
(ppm) 1.32 (t, J ) 7.1 Hz, 3H), 1.36 (t, J ) 7.1 Hz, 3H), 2.52
(t, J ) 2.4 Hz, 1H), 4.31 (q, J ) 7.1 Hz, 2H), 4.39 (q, J ) 7.1
Hz, 2H), 4.79 (d, J ) 2.4, 2H), 6.89 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.99 (q), 14.04 (q), 53.14 (t), 62.34 (t),
62.72 (t), 75.85 (d), 76.64 (s), 128.80 (d), 140.02 (s), 162.12 (s),
162.83 (s), 164.03 (s); IR (KBr) 3272, 3084, 2992, 2968, 2948,
2136, 1730 cm-1; MS (EI) m/z 254. Anal. Calcd for C12H14O6:
C, 56.69; H, 5.55. Found: C, 56.60; H, 5.51.
7.1 Hz, 2H), 4.39 (q, J ) 7.1 Hz, 2H), 5.02 (s, 2H), 6.93 (s,
1H), 7.30-7.35 (m, 3H), 7.44-7.46 (m, 2H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.98 (q), 14.03 (q), 54.08 (t), 62.31 (t),
62.68 (t), 81.87 (s), 87.39 (s), 121.92 (s), 128.42 (d), 129.04 (d),
129.07 (d), 131.97 (d), 139.83 (s), 162.17 (s), 162.99 (s), 164.10
(s); IR (neat) 2986, 2244, 1734, 1653 cm-1; MS (EI) m/z 330;
exact mass M+ 330.1084 (calcd for C18H18O6 330.1103).
1
1b: yield 72%; Rf ) 0.6 (hexane-ether 1:2); yellow oil; H
NMR (400 MHz, CDCl3) δ (ppm) 3.87 (s, 3H), 3.91 (s, 3H), 5.02
(s, 2H), 6.97 (s, 1H), 7.30-7.38 (m, 3H), 7.44-7.47 (m, 2H);
13C NMR (100.6 MHz, CDCl3) δ (ppm) 53.18 (q), 53.48 (q), 54.22
(t), 81.79 (s), 87.48 (s), 121.86 (s), 128.46 (d), 129.08 (d), 129.84
(d), 131.97 (d), 139.13 (s), 162.54 (s), 162.90 (s), 164.57 (s); IR
(neat) 2958, 2238, 1734, 1653 cm-1; MS (EI) m/z 302; exact
mass M+ 302.0798 (calcd for C16H14O6 302.0790).
1
1c: yield 53%; Rf ) 0.7 (hexane-ether 1:2); yellow oil; H
NMR (400 MHz, CDCl3) δ (ppm) 1.32 (t, J ) 7.1 Hz, 3H), 1.34
(t, J ) 7.1 Hz, 3H), 1.62 (d, J ) 6.6 Hz, 3H), 4.30 (q, J ) 7.1
Hz, 2H), 4.38 (qd, J ) 7.1, 0.7 Hz, 2H), 5.76 (q, J ) 6.6 Hz,
1H), 6.91 (s, 1H), 7.28-7.34 (m, 3H), 7.42-7.45 (m, 2H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 13.94 (q), 14.00 (q), 21.42
(q), 62.21 (t), 62.49 (d), 62.58 (t), 85.44 (s), 86.37 (s), 121.99
(s), 128.33 (d), 128.84 (d), 129.65 (d), 131.89 (d), 139.42 (s),
162.21 (s), 162.53 (s), 164.13 (s); IR (neat) 2988, 2238, 1729,
1647 cm-1; MS (EI) m/z 344; exact mass M+ 344.1272 (calcd
for C19H20O6 344.1260).
1
11: yield 68%; Rf ) 0.6 (hexane-ether 1:2); yellow oil; H
NMR (400 MHz, CDCl3) δ (ppm) 1.32 (t, J ) 7.1 Hz, 3H), 1.35
(t, J ) 7.1 Hz, 3H), 2.79 (t, J ) 6.9 Hz, 2H), 4.31 (q, J ) 7.1
Hz, 2H), 4.37 (t, J ) 6.9 Hz, 2H), 4.38 (q, J ) 7.1 Hz, 2H),
6.91 (s, 1H), 7.27-7.31 (m, 3H), 7.38-7.42 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 14.01 (q), 14.04 (q), 19.85 (t), 62.25
(t), 62.63 (t), 63.68 (t), 82.39 (s), 84.84 (s), 123.21 (s), 128.13
(d), 128.33 (d), 129.55 (d), 131.75 (d), 139.54 (s), 162.27 (s),
163.46 (s), 164.23 (s); IR (neat) 2986, 2362, 1729, 1653 cm-1
;
MS (EI) m/z 344; exact mass M+ 344.1285 (calcd for C19H20O6
344.1260). Anal. Calcd for C19H20O6: C, 66.27; H, 5.85.
Found: C, 66.12; H, 5.89.
1d : yield 71%; Rf ) 0.6 (hexane-ether 1:2); colorless
1
crystals; mp 34-35 °C; H NMR (400 MHz, CDCl3) δ (ppm)
1.32 (t, J ) 7.1 Hz, 3H), 1.36 (t, J ) 7.1 Hz, 3H), 1.86 (t, J )
2.4 Hz, 3H), 4.30 (q, J ) 7.1 Hz, 2H), 4.39 (q, J ) 7.1 Hz, 2H),
4.75 (q, J ) 2.4 Hz, 2H), 6.90 (s, 1H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 3.73 (q), 13.97 (q), 14.03 (q), 54.08 (t), 62.28
(t), 62.66 (t), 72.20 (s), 84.26 (s), 129.19 (d), 139.68 (s), 162.18
(s), 163.02 (s), 164.16 (s); IR (KBr) 2986, 2254, 1735, 1725,
1657 cm-1; MS (EI) m/z 268; exact mass M+ 268.0995 (calcd
for C13H16O6 268.0947). Anal. Calcd for C13H16O6: C, 58.20;
H, 6.01. Found: C, 58.24; H, 5.98.
1e: yield 61%; Rf ) 0.6 (hexane-ether 1:2); colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.14 (t, J ) 7.5 Hz, 3H),
1.32 (t, J ) 7.1 Hz, 3H), 1.36 (t, J ) 7.1 Hz, 3H), 2.23 (qt, J )
7.5, 2.2 Hz, 2H), 4.30 (q, J ) 7.1 Hz, 2H), 4.38 (q, J ) 7.1 Hz,
2H), 4.78 (t, J ) 2.2 Hz, 2H), 6.90 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 12.49 (t), 13.50 (q), 13.95 (q), 14.00 (q),
54.09 (t), 62.24 (t), 62.62 (t), 72.35 (s), 89.93 (s), 129.25 (d),
139.63 (s), 162.18 (s), 163.00 (s), 164.13 (s); IR (neat) 2984,
2944, 2244, 1734, 1653 cm-1; MS (EI) m/z 282; exact mass M+
282.1136 (calcd for C14H18O6 282.1103).
Typ ica l P r oced u r e for P r ep a r a tion of 1a -c a n d 11. A
mixture of 1,1-diethyl 2-propargyl ethene-1,1,2-tricarboxylate
(763 mg, 3.0 mmol), iodobenzene (0.34 mL, 612 mg, 3.0 mmol),
PdCl2(PPh3)2 (42 mg, 0.06 mmol), and CuI (23 mg, 0.12 mmol)
in Et2NH (8.2 mL) was stirred at room temperature for 21 h.
After removal of diethylamine under reduced pressure, water
was added to the residue. The mixture was extracted with
ether. The organic phase was washed with saturated aqueous
NaCl, dried (MgSO4), and evaporated in vacuo. The residue
was purified by column chromatography over silica gel with
hexane-ether (1:2) as eluent to give 1a (615 mg, 62%).
1a : Rf ) 0.6; yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm)
1.32 (t, J ) 7.1 Hz, 3H), 1.35 (t, J ) 7.1 Hz, 3H), 4.31 (q, J )
P r ep a r a tion of En yn e Su bstr a te 2. A solution of ClTi-
(OEt)3 (3.8 mL of 2 M solution in THF, 7.7 mmol)21 and diethyl
malonate (1.23 g, 7.7 mmol) was added to a solution of
6-phenyl-5-hexynal6g (1.3 g, 7.7 mmol) in THF (46 mL). To the
mixture was added Et3N (1.1 mL, 0.779 g, 7.7 mmol) at 0 °C,
and the mixture was stirred for 1.5 h at room temperature.
The reaction mixture was poured onto 4% aqueous HCl and
extracted with ether and the extract washed with brine and
dried over Na2SO4. After evaporation of the solvent, the residue
was chromatographed on silica gel (hexane-ether 2:1) to afford
2 (808 mg, 34%).
2: Rf ) 0.3 (hexane-ether 1:1); pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.29 (t, J ) 7.1 Hz, 3H), 1.30 (t, J
) 7.1 Hz, 3H), 1.77-1.84 (m, 2H), 2.45-2.52 (m, 4H), 4.23 (q,
J ) 7.1 Hz, 2H), 4.28 (q, J ) 7.1 Hz, 2H), 7.04 (t, J ) 7.9 Hz,
1H), 7.26-7.30 (m, 3H), 7.37-7.40 (m, 2H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 14.18 (q), 14.22 (q), 19.16 (t), 27.47 (t),
28.96 (t), 61.39 (t), 81.54 (s), 88.99 (s), 123.75 (s), 127.76 (d),
128.27 (d), 129.41 (s), 131.60 (d), 148.25 (d), 163.98 (s), 165.51
(s); IR (neat) 2980, 1730, 1647 cm-1; MS (EI) m/z 314 (17),
285 (43), 269 (30), 241 (100); exact mass M+ 314.1541 (calcd
for C19H22O4 314.1518).
P r ep a r a tion of En yn e Su bstr a tes 3. To a solution of 1,1-
diethyl 2-hydrogen ethenetricarboxylate (499 mg, 2.3 mmol)
(prepared from 1,1-diethyl 2-tert-butyl ethenetricarboxylate
upon treatment with CF3CO2H)22 in THF (3.3 mL) were added
N-methyl-N-(phenylpropargyl)amine23 (670 mg, 4.6 mmol),
HOBt (707 mg, 4.6 mmol), and WSC (1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride; 460 mg, 2.4 mmol)
at 0 °C. The reaction mixture was stirred for 1 h at 0 °C,
warmed to room temperature, and stirred for 16 h. After
(21) Reetz, M. T.; Westermann, J .; Steinbach, R.; Wenderoth, B.;
Peter, R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421.
(22) Kelly, T. R. Tetrahedron Lett. 1973, 437.
(23) Labrecque, D.; Nwe, K. T.; Chan, T. H. Organometallics 1994,
13, 332.
(19) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(20) (a) Maercker, A. Org. React. 1965, 14, 270. (b) Considine, W. J .
J . Org. Chem. 1962, 27, 647.

2898 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
removal of the solvent under reduced pressure, the residue
was dissolved in CH2Cl2 and the organic phase was washed
with saturated aqueous NaHCO3 solution, 2 M aqueous citric
acid, saturated aqueous NaHCO3, and water, dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column
chromatography over silica gel with hexane-ether (1:2) as
eluent to give 3a (434 mg, 55%).
Typ ica l Cycliza tion P r oced u r e (Ta ble 1, En tr y 1). To
a solution of 1a (122 mg, 0.37 mmol) in dichloromethane (0.8
mL) was added ZnBr2 (96 mg, 0.43 mmol), followed by THF
(30 µL, 27 mg, 0.37 mmol) at -78 °C. The mixture was warmed
to -40 °C and stirred for 16 h. The reaction mixture was
quenched by water and then saturated aqueous NaHCO3. The
mixture was extracted with dichloromethane, and the organic
phase was washed with water, dried (Na2SO4), and evaporated
in vacuo. The residue was purified by reverse-phase column
chromatography over Cosmosil 75C18-OPN with CH3CN-H2O
(8:2) as eluent to give 5a -Br (79 mg, 52%).
1
3a : Rf ) 0.3 (hexane-ether 1:2); pale yellow oil; H NMR
(400 MHz, CDCl3) (2 rotamers, ratio 6:4) δ (ppm) 1.32 (t, J )
7.1 Hz, 3H), 1.33 (t, J ) 7.1 Hz, 3H), 3.13 (s, 3 × 0.4H, minor
rotamer), 3.19 (s, 3 × 0.6H, major rotamer), 4.28-4.36 (m, 4H
+ 2 × 0.4H), 4.51 (s, 2 × 0.6H), 7.29-7.35 and 7.41-7.44 (m,
6H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.99 (q), 14.08
(q), 32.99 (q), 34.82 (q), 36.80 (t), 40.81 (t), 61.95 (t), 61.99 (t),
62.31 (t), 82.29 (s), 82.95 (s), 84.40 (s), 85.56 (s), 121.99 (s),
122.46 (s), 126.88 (d), 128.38 (d), 128.46 (d), 128.61 (d), 128.74
(d), 128.89 (d), 131.82 (d), 134.18 (d), 134.56 (d), 134.71 (d),
162.97 (s), 163.00 (s), 163.81 (s), 164.07 (s), 164.24 (s), 164.29
(s); IR (neat) 2984, 2938, 1734, 1655 cm-1; MS (EI) m/z 343;
exact mass M+ 343.1397 (calcd for C18H21NO5 343.1420).
Methyl(2-hexynyl)amine was prepared according to the
procedure for methyl(phenylpropargyl)amine:24 colorless oil;
5a -Br : Rf ) 0.5 (hexane-ether 1:2); colorless crystals; mp
1
126-127 °C (hexane-ether 1:2); H NMR (400 MHz, CDCl3)
δ (ppm) 1.23 (t, J ) 7.1 Hz, 3H), 1.25 (t, J ) 7.1 Hz, 3H), 3.17
(d, J ) 4.5 Hz, 1H), 4.05 (ddd, J ) 4.5, 2.2, 2.2 Hz, 1H), 4.12-
4.27 (m, 4H), 4.90-4.91 (m, 2H), 7.34-7.37 (m, 2H), 7.38-
7.46 (m, 3H) (selected NOEs are between δ 3.17 and 7.34-
7.37 and δ 4.05 and 7.34-7.37); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 13.92 (q), 14.09 (q), 43.76 (d), 51.06 (d), 62.07 (t), 62.37
(t), 73.05 (t), 117.65 (s), 128.01 (d), 129.25 (d), 130.03 (d), 133.53
(s), 137.47 (s), 166.40 (s), 166.93 (s), 174.60 (s); IR (neat) 2980,
2936, 1789, 1744, 1721 cm-1; MS (EI) m/z 412, 410; exact mass
M+ 412.0343 (calcd for C18H19O681Br 412.0344), M+ 410.0334
(calcd for C18H19O679Br 410.0365).
1
bp 30-40 °C/15 mmHg; H NMR (400 MHz, CDCl3) δ (ppm)
0.982 (t, J ) 7.4 Hz, 3H), 1.53 (qt, J ) 7.2, 7.1 Hz, 2H), 1.60
(bs, 1H), 2.17 (tt, J ) 7.1, 2.2 Hz, 2H), 2.46 (s, 3H), 3.36 (t, J
) 2.2 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.54
(q), 20.76 (t), 22.35 (t), 35.30 (q), 40.44 (t), 78.02 (s), 83.71 (s);
IR (neat) 3320, 2968, 2936, 2876, 2362 cm-1; MS (EI) m/z 111.
3b: yield 48%; Rf ) 0.3 (hexane-ether 1:2); colorless oil;
1H NMR (400 MHz, CDCl3) (2 rotamers, ratio 5.5:4.5) δ (ppm)
0.970 (t, J ) 7.3 Hz, 3 × 0.55H, major rotamer), 0.973 (t, J )
7.3 Hz, 3 × 0.45H, minor rotamer), 1.32-1.34 (m, 6H), 1.47-
1.57 (m, 2H), 2.13-2.19 (m, 2H), 3.04 (s, 3 × 0.45H), 3.11 (s,
3 × 0.55H), 4.07 (t, J ) 2.3 Hz, 2 × 0.45H), 4.25 (t, J ) 2.3
Hz, 2 × 0.55H), 4.27-4.36 (m, 4H), 7.32 (s, 1 × 0.55H), 7.36
(s, 1 × 0.45H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.53
(q), 13.56 (q), 13.99 (q), 14.10 (q), 20.67 (t), 20.73 (t), 21.97 (t),
22.08 (t), 32.85 (q), 34.56 (q), 36.42 (t), 40.43 (t), 61.88 (t), 61,
93 (t), 62.27 (t), 73.47 (s), 73.73 (s), 85.00 (s), 86.27 (s), 134.42
(t), 134.50 (t), 134.59 (s), 163.04 (s), 163.65 (s), 163.93 (s); IR
(neat) 2974, 1734 cm-1; MS (EI) m/z 309; exact mass M+
309.1554 (calcd for C16H23NO5 309.1576).
P r ep a r a tion of En yn e Su bstr a tes 4a ,b. 4a ,b were pre-
pared by the reaction of diethyl ketomalonate with carbonyl-
methylenetriphenylphosphoranes in the same manner as the
preparation of 1,1-diethyl 2-propargyl ethene-1,1,2-tricarboxy-
late described above. The corresponding carbonylmethylene-
triphenylphosphoranes were prepared from the reaction of
acetomethylenetriphenylphosphorane, n-BuLi, and phenyl-
propargyl bromide24 or 1-bromo-2-butyne, according to the
literature procedure.25
5a -Cl: yield 98%, Table 1, entry 2; Rf ) 0.6 (hexane-ether
1:2)); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.23
(t, J ) 7.1 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H), 3.25 (d, J ) 4.4
Hz, 1H), 4.11-4.53 (m, 5H), 4.99 (dd, J ) 14.6, 2.4 Hz, 1H),
5.02 (dd, J ) 14.6, 2.0 Hz, 1H), 7.39-7.48 (m, 5H) (selected
NOEs are between δ 3.25 and 7.39-7.48 and δ 4.11-4.53 and
7.39-7.48); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.91 (q),
14.03 (q), 42.93 (d), 50.95 (d), 62.03 (t), 62.36 (t), 71.04 (t),
127.13 (s), 127.76 (d), 129.20 (d), 130.10 (d), 130.55 (s), 135.76
(s), 166.48 (s), 166.89 (s), 174.55 (s); IR (neat) 2986, 2942, 1792,
1740, 1734 cm-1; MS (EI) m/z 368, 366; exact mass M+
366.0855 (calcd for C18H19ClO6 366.0870).
5b-Cl: yield 83%, Table 1, entry 3; Rf ) 0.3 (hexane-ether
1:1)); colorless crystals (hexane-EtOAc 1:1); mp 133-135 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 3.29 (d, J ) 4.4 Hz, 1H),
3.71 (s, 3H), 3.73 (s, 3H), 4.15 (ddd, J ) 4.4, 2.3, 2.1 Hz, 1H),
5.00 (dd, J ) 14.6, 2.3 Hz, 1H), 5.03 (dd, J ) 14.6, 2.1 Hz,
1H), 7.38-7.48 (m, 5H) (selected NOEs are between δ 3.29
and 7.38-7.48 and δ 4.15 and 7.38-7.48); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 42.99 (d), 50.74 (d), 53.05 (q), 53.24 (q),
71.12 (t), 127.40 (s), 127.77 (d), 129.29 (d), 130.16 (d), 130.38
(s), 135.78 (s), 166.92 (s), 167.41 (s), 174.52 (s); IR (neat) 2956,
1787, 1750, 1729 cm-1; MS (EI) m/z 338; exact mass M+
338.0519 (calcd for C16H15ClO6 338.0557). Anal. Calcd for
C
16H15ClO6: C, 56.73; H, 4.46; Cl, 10.47. Found: C, 56.49; H,
4.33; Cl, 10.23. The NMR spectra were identical with those
reported for a major isomer reported by Snider.4a
5c-Cl: yield 63%; diastereomer ratio 7:3, Table 1, entry 4;
recrystallization of the diastereomer mixture with EtOAc gave
a 9:1 diastereomer mixture (43% yield); Rf ) 0.5 (hexane-
ether 1:2); colorless crystals; mp 125-126 °C (EtOAc); 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.22 (t, J ) 7.1 Hz, 3H), 1.23 (t, J
) 7.1 Hz, 3H), 1.69 (d, J ) 6.4 Hz, 3 × 0.9H, major
diastereomer), 1.74 (d, J ) 6.6 Hz, 3 × 0.1H, minor diastere-
omer), 3.07 (d, J ) 4.2 Hz, 1 × 0.1H, minor), 3.15 (d, J ) 4.4
Hz, 1 × 0.9H, major), 4.08-4.23 (m, 5H), 5.38 (qd, J ) 6.4,
2.1 Hz, 1H), 7.35-7.38 (m, 2H), 7.42-7.45 (m, 3H) (selected
NOEs are between δ 3.15 and 7.35-7.38 and δ 4.08-4.23 and
7.35-7.38); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.92 (q),
14.07 (q), 19.13 (major) (q), 18.63 (minor) (q), 43.29 (major)
(d), 44.01 (minor) (d), 50.58 (major) (d), 51.09 (minor) (d), 61.82
(t), 62.32 (t), 79.02 (major) (d), 79.24 (minor) (d), 127.10 (s),
128.18 (major) (d), 127.77 (minor) (d), 129.12 (major) (d), 129.30
(minor) (d), 130.25 (major) (d), 129.93 (minor) (d), 135.32 (s),
136.41 (s), 166.67 (s), 166.85 (s), 173.53 (s); IR (neat) 2990,
2940, 1783, 1744, 1721 cm-1; MS (EI) m/z 380; exact mass M+
380.1013 (calcd for C19H21ClO6 380.1027). Anal. Calcd for
4a : yield 41%; Rf ) 0.6 (hexane-ether 1:2); pale yellow oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.32 (t, J ) 7.1 Hz, 3H),
1.34 (t, J ) 7.1 Hz, 3H), 2.73 (t-like, J ) 7.3 Hz, 2H), 2,96
(t-like, J ) 7.0 Hz, 2H), 4.30 (q, J ) 7.1 Hz, 2H), 4.37 (q, J )
7.1 Hz, 2H), 7.18 (s, 1H), 7.27-7.29 (m, 3H), 7.37-7.39 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.80 (t), 13.92
(q), 14.02 (q), 42.73 (t), 62.19 (t), 62.60 (t), 81.47 (s), 87.72 (s),
123.40 (s), 127.93 (d), 128.27 (d), 131.63 (d), 134.81 (d), 135.88
(s), 162.69 (s), 164.63 (s), 196.57 (s); IR (neat) 2986, 1734, 1707,
1630 cm-1; MS (EI) m/z 328.
4b: yield 53%; Rf ) 0.6 (hexane-ether 1:2); pale yellow
1
crystals; mp 28-29 °C; H NMR (400 MHz, CDCl3) δ (ppm)
1.32 (t, J ) 7.1 Hz, 3H), 1.34 (t, J ) 7.1 Hz, 3H), 1.75 (t, J )
2.6 Hz, 2H), 2.42-2.47 (m, 2H), 2.80-2.84 (m, 2H), 4.30 (q, J
) 7.1 Hz, 2H), 4.45 (q, J ) 7.1 Hz, 2H), 7.15 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 3.44 (q), 13.07 (t), 13.85 (q), 13.97
(q), 42.99 (t), 62.06 (t), 62.49 (t), 76.67 (s), 76.91 (s), 134.92
(d), 135.62 (s), 162.68 (s), 164.58 (s), 196.84 (s); IR (neat) 2986,
2924, 1736, 1700, 1630 cm-1; MS (EI) m/z 266.
C
19H21ClO6: C, 59.92; H, 5.56; Cl, 9.31. Found: C, 59.57; H,
(24) Yi, X.-H.; Meng, Y.; Hua, X.-G.; Li, C.-J . J . Org. Chem. 1998,
63, 7472.
(25) (a) Taylor, J . D.; Wolf, J . F.; J . Chem. Soc., Chem. Commun.
1972, 876. (b) Cooke, M. P., J r. J . Org. Chem. 1973, 38, 4082.
5.47; Cl, 9.10.
Typ ica l P r oced u r e (Ta ble 2, En tr y 3). To a solution of
1d (109 mg, 0.41 mmol) in dichloromethane (0.7 mL) was

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2899
added FeCl3 (75.8 mg, 0.47 mmol) at -78 °C. The mixture was
warmed to room temperature and stirred for 16 h. The reaction
mixture was quenched by water and then saturated aqueous
NaHCO3. The mixture was extracted with dichloromethane,
and the organic phase was washed with water, dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column
chromatography over silica gel with hexane-ether (1:2) as
eluent to give 5d -Cl (94 mg, 76%).
53.65 (d), 62.34 (t), 62.61 (t), 70.79 (t), 127.15 (s), 133.15 (s),
166.36 (s), 166.96 (s), 174.72 (s); IR (neat) 2982, 2942, 1785,
1736 cm-1; MS (EI) m/z 318, 320; exact mass M+ 318.0898
(calcd for C14H19ClO6 318.0870). Anal. Calcd for C14H19ClO6:
C, 52.75; H, 6.01; Cl, 11.12. Found: C, 53.06; H 5.98; Cl, 10.99.
5e-I: yield 31%, Table 2, entry 6; Rf ) 0.5 (hexane-ether
1
1:2); colorless crystals; mp 74-75 °C (EtOAc); H NMR (400
MHz, CDCl3) δ (ppm) 1.21 (t, J ) 7.4 Hz, 3H), 1.28 (t, J ) 7.0
Hz, 3H), 1.32 (d, J ) 7.1 Hz, 3H), 2.41-2.51 (m, 2H), 2.55-
2.64 (m, 2H), 3.91-3.92 (m, 1H), 3.93 (d, J ) 4.6 Hz, 1H),
4.16-4.38 (m, 4H), 4.60-4.62 (m, 2H) (selected NOEs are
between δ 2.41-2.51 and 3.91-3.92, δ 2.55-2.64 and 3.91-
3.92, δ 2.41-2.51 and 3.93, and δ 2.55-2.64 and 3.93); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 13.94 (q), 13.98 (q), 14.67
(q), 34.50 (t), 43.65 (d), 53.52 (d), 62.23 (t), 62.49 (t), 77.18 (t),
105.28 (s), 135.04 (s), 166.14 (s), 166.84 (s), 175.01 (s); IR (KBr)
2987, 2936, 1783, 1738 cm-1; MS (EI) m/z 410; exact mass M+
5d -Cl: Rf ) 0.5 (hexane-ether 1:2); pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.29 (t, J ) 7.1 Hz, 3H), 1.31 (t, J
) 7.1 Hz, 3H), 2.19 (dd, J ) 1.9, 1.9 Hz, 3H), 3.89-3.92 (m,
1H), 3.95 (d, J ) 4.4, 1H), 4.17-4.35 (m, 4H), 4.79 (ddq, J )
13.6, 2.3, 1.9 Hz, 1H), 4.87 (ddq, J ) 13.6, 1.9, 1.7 Hz, 1H)
(selected NOEs are between δ 2.19 and 3.89-3.92 and δ 2.19
and 3.95.; 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.96 (q),
13.99 (q), 22.96 (q), 42.38 (d), 53.01 (d), 62.36 (t), 62.53 (t),
70.84 (t), 126.79 (s), 127.91 (s), 166.38 (s), 166.96 (S), 174.78
(S); IR (neat) 2986, 2944, 1783, 1734, 1653 cm-1; MS (EI) m/z
306, 304; exact mass M+ 304.0762 (calcd for C13H17ClO6
304.0714).
410.0259 (calcd for C14H19IO6 410.0226). Anal. Calcd for C14H19
IO6: C 40.99; H, 4.67. Found: C, 40.76; H, 4.52.
-
Typ ica l Cycliza tion P r oced u r e (Ta ble 4, En tr y 1). To
a solution of 3a (294 mg, 0.86 mmol) in dichloromethane (1.9
mL) was added ZnBr2 (223 mg, 0.99 mmol), followed by THF
(70 µL, 62 mg, 0.86 mmol), at -78 °C. The mixture was
warmed to -40 °C and stirred for 16 h. The reaction mixture
was quenched by triethylamine (0.21 mL, 154 mg, 1.52 mmol)
and then saturated aqueous NaHCO3. The mixture was
extracted with dichloromethane, and the organic phase was
washed with water, dried (Na2SO4), and evaporated in vacuo.
The residue was purified by column chromatography over silica
gel with hexane-ether as eluent to give 7a -Br (264 mg, 84%).
7a -Br : Rf ) 0.3 (ether); pale yellow crystals; mp 108-110
°C (EtOAc); 1H NMR (400 MHz, CDCl3) δ (ppm) 1.226 (t, J )
7.1 Hz, 3H), 1.228 (t, J ) 7.1 Hz, 3H), 2.98 (d, J ) 0.7 Hz,
3H), 3.08 (d, J ) 4.6 Hz, 1H), 3.96-3.97 (m, 1H), 4.04 (dd, J
) 15.3, 1.9 Hz, 1H), 4.09 (dd, J ) 15.3, 1.9 Hz, 1H), 4.10-4.25
(m, 4H), 7.34-7.45 (m, 5H) (selected NOEs are between δ 3.08
and 7.34-7.45 and δ 3.96-3.97 and 7.34-7.45); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 13.96 (q), 14.19 (q), 29.56 (q), 45.75
(d), 50.77 (d), 56.81 (t), 61.43 (t), 61.93 (t), 118.33 (s), 128.15
(d), 129.07 (d), 129.65 (d), 132.70 (s), 138.25 (s), 167.36 (s),
5d -Br : yield 39%, Table 2, entry 1; Rf ) 0.6 (hexane-ether
1:2)): Pale yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.30
(t, J ) 7.1 Hz, 3H), 1.31 (t, J ) 7.1 Hz, 3H), 2.38 (ddd, J )
2.0, 2.0, 2.0 Hz, 3H), 3.87-3.90 (m, 1H), 3.97 (d, J ) 4.4 Hz,
1H), 4.17-4.35 (m, 4H), 4.71 (dq, J ) 13.7, 12.2, 2.0 Hz, 1H),
4.78 (dq, J ) 13.7, 2.0, 1.8 Hz, 1H) (selected NOEs are between
δ 2.38 and 3.87-3.90 and δ 2.38 and 3.97); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.96 (q), 13.97 (q), 25.39 (q), 43.03 (d),
52.87 (d), 54.39 (s), 62.28 (t), 62.36 (t), 62.53 (s), 62.62 (s), 72.90
(t), 117.57 (s), 130.71 (s), 166.30 (s), 166.92 (s), 174.85 (s); IR
(neat) 2986, 2942, 1787, 1734 cm-1; MS (EI) m/z 350, 348; exact
mass M+ 348.0205 (calcd for C13H17O6Br 348.0209).
9d : yield 16%, Table 2, entry 1; Rf ) 0.4, hexane-ether (1:
2); colorless crystals; mp 29-30 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.296 (t, J ) 7.1 Hz, 3H), 1.302 (t, J ) 7.1 Hz, 3H),
1.85 (t, J ) 2.4 Hz, 3H), 3.54 (d, J ) 7.1 Hz, 1H), 3.98 (d, J )
4.0 Hz, 1H), 4.21-4.33 (4H, m), 4.69-4.82 (3H, m); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 3.72 (q), 14.00 (q), 14.06 (q), 54.45
(t), 55.04 (d), 62.15 (t), 62.17 (t), 69.77 (d), 72.27 (s), 84.18 (s),
166.98 (s), 167.16 (s), 171.13 (s); IR (KBr) 3432, 2978, 2248,
1750-1709 cm-1; MS (EI) m/z 286; exact mass M+ 286.1012
(calcd for C13H18O7 286.1053).
171.61 (s); IR (neat) 2988, 2942, 2920, 1750, 1727, 1707 cm-1
;
MS (EI) m/z 425, 423. Anal. Calcd for C19H22BrNO5: C, 53.79;
H, 5.23; N, 3.30; Br, 18.85. Found: C, 53.74; H, 5.15; N, 3.34;
Br, 18.83.
5e-Br : yield 37%, Table 2, entry 4; Rf ) 0.6 (hexane-ether
1
1:2); colorless crystals (hexane-ether 1:2); mp 60-61 °C; H
NMR (400 MHz, CDCl3) δ (ppm) 1.17 (t, J ) 7.4 Hz, 3H), 1.29
(t, J ) 7.1 Hz, 3H), 1.32 (t, J ) 7.1 Hz, 3H), 2.42-2.61 (m,
2H), 3.89 (m, 1H), 3.91 (d, J ) 4.4 Hz, 1H), 4.19-4.34 (m, 4H),
4.70 (dd, J ) 13.6, 1.3 Hz, 1H), 4.77 (d, J ) 13.6 Hz, 1H)
(selected NOEs are between δ 2.42-2.61 and 3.89 and δ 2.42-
2.61 and 3.91); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.26
(q), 14.00 (q), 14.03 (q), 31.34 (t), 43.06 (d), 53.55 (d), 62.33 (t),
62.59 (t), 72.84 (t), 125.80 (s), 129.90 (s), 166.27 (s), 166.93
(s), 174.75 (s); IR (neat) 2982, 2940, 1783, 1736 cm-1; MS (EI)
m/z 364, 362; exact mass M+ 364.0388 (calcd for C14H19O681Br
364.0344), M+ 362.0327 (calcd for C14H19O679Br 362.0365).
9e: yield, 29%, Table 2, entry 4; Rf ) 0.4 (hexane-ether
1:2); colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.14 (t,
J ) 7.5 Hz, 3H), 1.295 (t, J ) 7.1 Hz, 3H), 1.300 (t, J ) 7.1
Hz, 3H), 2.22 (qt, J ) 7.5, 2.2 Hz, 2H), 3.59 (d, J ) 7.1 Hz,
1H), 3.97 (d, J ) 4.0 Hz, 1H), 4.22-4.31 (m, 4H), 4.74 (dt, J )
15.0, 2.2 Hz), 4.77 (dd, J ) 7.1, 4.0 Hz, 1H), 4.82 (dt, J ) 15.0
2.2 Hz); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 12.42 (t), 13.44
(q), 13.95 (q), 13.99 (q), 54.39 (t), 55.04 (d), 62.04 (t), 62.06 (t),
69.70 (d), 72.38 (s), 89.79 (s), 166.89 (s), 167.07 (s), 171.06 (s);
IR (neat) 3478, 2984, 2944, 2244, 1740, 1734 cm-1; MS (EI)
m/z 300; exact mass M+ 300.1240 (calcd for C14H20O7 300.1209).
5e-Cl: yield 67%, Table 2, entry 5; Rf ) 0.6 (hexane-ether
1:2); colorless crystals (hexane-ether 1:2); mp 164-165 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.17 (t, J ) 7.4 Hz, 3H),
1.29 (t, J ) 7.1 Hz, 3H), 1.32 (t, J ) 7.2 Hz, 3H), 2.32-2.50
(m, 2H), 3.89 (d, J ) 4.6 Hz, 1H), 3.90-3.92 (m, 1H), 4.19-
4.64 (m, 4H), 4.79 (ddt, J ) 13.7, 1.6, 1.6 Hz, 1H), 4.87 (ddt, J
) 13.7, 1.1, 1.1 Hz, 1H) (selected NOEs are between δ 2.32-
2.50 and 3.89 and δ 2.32-2.50 and 3.90-3.92); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 12.31 (q), 14.04 (q), 29.43 (t), 42.31 (d),
6E-Br : yield 64%, Table 3, entry 1; Rf ) 0.6 (hexane-ether
1:1); colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.14 (t,
J ) 7.1 Hz, 3H), 1.26 (t, J ) 7.1 Hz, 3H), 1.60-1.72 (m, 1H),
1.82-1.91 (m, 5H), 2.01-2.15 (m, 2H), 2.53 (dddd, J ) 17.3,
9.9, 7.6, 2.3 Hz, 1H), 2.69 (ddd, J ) 17.3, 7.9, 3.7 Hz, 1H),
3.06 (d, J ) 5.7 Hz, 1H), 3.42 (dddd, J ) 7.7, 7.7, 5.7, 2.3 Hz,
1H), 3.92-4.08 (m, 2H), 4.09-4.17 (m, 2H), 7.27-7.37 (m, 5H)
(selected NOEs are between δ 3.06 and 7.27-7.37 and δ 3.42
and 7.27-7.37); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.04
(q), 14.21 (q), 23.87 (t), 30.88 (t), 38.01 (t), 42.70 (d), 52.20 (d),
60.99 (t), 61.31 (t), 115.21 (s), 128.53 (d), 128.62 (d), 128.87
(d), 140.32 (s), 145.79 (s), 168.15 (s), 168.59 (s); IR (neat) 2968,
1734 cm-1; MS (EI) m/z 394; exact mass 394.0806 (calcd for
C
19H23O4Br 394.0780).
6E-Cl: yield 46%, Table 3, entry 4; Rf ) 0.6 (hexane-ether
1
1:1); pale yellow oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.14
(t, J ) 7.1 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H), 1.60-1.71 (m,
1H), 1.82-1.91 (m, 1H), 1.97-2.12 (m, 2H), 2.54 (dddd, J )
17.2, 9.3, 8.3, 2.3 Hz, 1H), 2.73 (ddd, J ) 17.2, 7.7, 3.5 Hz,
1H), 3.10 (d, J ) 5.7 Hz, 1H), 3.50 (dddd, J ) 7.2, 7.2, 5.7, 2.3
Hz, 1H), 3.91-4.15 (m, 4H), 7.30-7.38 (m, 5H) (selected NOEs
are between δ 3.10 and 7.30-7.38 and δ 3.50 and 7.30-7.38);
13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.02 (q), 14.16 (q), 23.87
(t), 30.60 (t), 34.96 (t), 42.32 (d), 52.28 (d), 60.96 (t), 61.30 (t),
124.44 (s), 128.59 (d), 128.68 (d), 138.70 (s), 142.79 (s), 168.16
(s), 168.65 (s); IR (neat) 2982, 1734 cm-1; MS (EI) m/z 350;
exact mass M+ 350.1311 (calcd for C19H23ClO4 350.1285).
6Z-Cl (as a 8:2 mixture with 6E-Cl): yield 23%, Table 3,
entry 5; Rf ) 0.6 (hexane-ether 1:1); pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.28 (t, J ) 7.1 Hz, 3H), 1.29 (t, J
) 7.1 Hz, 3H), 1.41-1.53 (m, 1H), 1.79-1.88 (m, 1H), 1.97-

2900 J . Org. Chem., Vol. 67, No. 9, 2002
Yamazaki et al.
2.11 (m, 2H), 2.33 (ddd, J ) 15.3, 7.3, 2.2 Hz, 1H),. 2.48-2.57
(m, 1H), 3.55 (dddd, J ) 7.7, 7.7, 5.7, 2.2 Hz, 1H), 4.17-4.27
(m, 4H), 4.35 (d, J ) 5.7 Hz, 1H), 7.27-7.40 (m, 5H) (selected
NOEs are between δ 2.33 and 7.27-7.40 and δ 2.48-2.55 and
7.27-7.40); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.20 (q),
14.25 (q), 25.51 (t), 28.86 (t), 34.33 (t), 43.87 (d), 52.39 (d), 61.15
(t), 61.49 (t), 124.34 (s), 128.04 (d), 128.16 (d), 128.67 (d), 139.12
cm-1; MS (EI) m/z 437; exact mass M+ 437.0705 (calcd for
C
16H24INO5 437.0699). Anal. Calcd for C16H24INO5: C, 43.95;
H, 5.53; N, 3.20. Found: C, 43.72; H, 5.59; N, 3.20.
8a -Cl: yield 68%, Table 5, entry 1; purified by Cosmosil
75C18PREP (CH3CN-H2O ) 7:3); Rf ) 0.6 (SiO2, hexane-
ether 1:2); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm)
1.217 (t, J ) 7.1 Hz, 3H), 1.221 (t, J ) 7.1 Hz, 3H), 2.51-2.59
(m, 1H), 2.70-2.78 (m, 1H), 2.84-3.02 (m, 2H), 3.12 (d, J )
4.6 Hz, 1H), 3.80 (bs, 1H), 7.33-7.43 (m, 5H) (selected NOEs
are between δ 3.80 and 7.33-7.43); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 13.91 (q), 14.10 (q), 28.90 (t), 36.88 (t), 50.16
(d), 53.09 (d), 61.73 (t), 61.88 (t), 128.12 (d), 129.03 (d), 129.33
(d), 136.72 (s), 137.67 (s), 167.69 (s), 167.74 (s), 215.14 (s).
8a -Cl in CDCl3 solution isomerized to 13a -Cl (R3 ) Ph in
Scheme 2) after 1 day, in quantitative yield.26
13a -Cl: Rf ) 0.6 (SiO2, hexane-ether 1:2); pale yellow oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.26 (t, J ) 7.0 Hz, 3H),
1.30 (t, J ) 7.1 Hz, 3H), 2.38-2.57 (m, 3H), 2.92-3.01 (m, 1H),
4.07-4.33 (m, 4H), 4.84 (s, 1H), 6.40 (s, 1H), 7.32-7.41 (m,
3H), 7.56-7.59 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
14.05 (q), 25.38 (t), 33.37 (t), 47.02 (d), 57.81 (d), 62.36 (t), 62.56
(t), 127.68 (d), 128.68 (d), 128.69 (d), 132.75 (s), 136.76 (s),
167.19 (s), 172.48 (s), 206.81 (s); IR (neat) 2986, 1940, 1745,
1734, 1715, 1644 cm-1; MS (EI) m/z 364, 366; exact mass
364.1094 (calcd for C19H21ClO5 364.1078).
8b-Cl: yield 59%, Table 5, entry 2; purified by Cosmosil
75C18OPN (CH3CN-H2O ) 3:2); Rf ) 0.2 (silica gel, hexane-
ether 1:2); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm)
1.27 (t, J ) 7.1 Hz, 3H), 1.31 (t, J ) 7.1 Hz, 3H), 2.16 (bs, 3H),
2.35-2.46 (m, 1H), 2.59-2.73 (m, 2H), 2.85-2.94 (m, 1H),
3.57-3.59 (m, 1H), 3.84 (d, J ) 4.4 Hz, 1H), 4.12-4.33 (m,
4H) (selected NOEs are between δ 2.16 and 3.57-3.59 and δ
2.16 and 3.84); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.02
(q), 23.22 (q), 28.25 (t), 37.98 (t), 49.35 (d), 54.84 (d), 62.05 (t),
62.17 (t), 127.20 (s), 133.68 (s), 167.55 (s), 7.73 (s), 215.65 (s);
IR (neat) 2986, 2938, 1745, 1734, 1715, 1647 cm-1; MS (EI)
m/z 302, 304; exact mass 302.0948 (calcd for C14H19O5Cl
302.0921).
(s), 143.10 (s), 168.78 (s), 169.13 (s); IR (neat) 2966, 1734 cm-1
;
-
MS (EI) m/z 350; exact mass M+ 350.1262 (calcd for C19H23
ClO4 350.1285).
7a -Cl: yield 64%, Table 4, entry 4; Rf ) 0.3 (ether); pale
yellow crystals; mp 94-95 °C (EtOAc); 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.21 (t, J ) 7.1 Hz, 3H), 1.24 (t, J ) 7.2 Hz,
3H), 2.99 (d, J ) 0.7 Hz, 3H), 3.15 (d, J ) 4.6 Hz, 1H), 4.04-
4.06 (m, 1H), 4.07-4.26 (m, 6H), 7.38-7.46 (m, 5H) (selected
NOEs are between δ 3.15 and 7.38-7.46 and δ 4.04-4.06 and
7.38-7.46); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.00 (q),
14.17 (q), 29.60 (q), 45.09 (d), 50.76 (d), 54.48 (t), 61.42 (t),
61.96 (t), 127.51 (s), 127.99 (d), 129.08 (d), 129.72 (d), 129.72
(d), 129.75 (s), 136.63 (s), 167.37 (s), 171.54 (s); IR (neat) 2988,
1752, 1725, 1709 cm-1; MS (EI) m/z 379; exact mass M+
379.1207 (calcd for C19H22ClNO5). Anal. Calcd for C19H22
-
ClNO5: C, 60.08; H, 5.84; N, 3.69; Cl, 9.33. Found: C, 59.81;
H, 5.74; N, 3.68; Cl, 9.51.
7a -I: yield 62%, Table 4, entry 5; Rf ) 0.3 (ether); pale
yellow crystals; mp 91-92 °C (EtOAc); 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.21 (t, J ) 7.1 Hz, 3H), 1.25 (t, J ) 7.1 Hz,
3H), 2.99 (d, J ) 0.5 Hz, 3H), 3.03 (d, J ) 4.6 Hz, 1H), 3.95-
3.96 (m, 3H), 4.07-4.23 (m, 4H), 7.28-7.41 (m, 5H) (selected
NOEs are between δ 3.03 and 7.28-7.41 and δ 3.95-3.96 and
7.28-7.41); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.95 (q),
14.26 (q), 29.52 (q), 46.22 (d), 50.92 (d), 61.43 (t), 61.52 (t),
61.90 (t), 95.21 (s), 127.77 (d), 129.06 (d), 129.24 (d), 138.58
(s), 141.61 (s), 167.30 (s), 167.40 (s), 172.01 (s); IR (neat) 2986,
2918, 1748, 1725, 1705 cm-1; MS (EI) m/z 471; exact mass M+
471.0508 (calcd for C19H22INO5 471.0543). Anal. Calcd for
C
19H22INO5: C 48.42; H, 4.71; N, 2.97; I, 26.93. Found: C,
48.50; H, 4.58; N, 3.01; I, 26.49.
7b-Br : yield 74%, Table 4, entry 6; Rf ) 0.4 (ether); pale
yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.95 (t, J ) 7.3
Hz, 3H), 1.26 (t, J ) 7.1 Hz, 3H), 1.31 (t, J ) 7.2 Hz, 3H),
1.47-1.62 (m, 1H), 1.64-1.76 (m, 1H), 2.38-2.53 (m, 2H), 2.93
(d, J ) 0.5 Hz, 3H), 3.79 (bd, J ) 4.5 Hz, 1H), 3.85 (d, J ) 4.5
Hz, 1H), 3.85 (dd. J ) 14.3, 1.5 Hz, 1H), 3.95 (dd. J ) 14.3,
1.1 Hz, 1H), 4.13-4.36 (m, 4H) (selected NOEs are between δ
2.38-2.53 and 3.79 and δ 2.38-2.53 and 3.85); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.16 (q), 14.02 (q), 14.06 (q), 21.70 (t),
29.51 (q), 39.27 (t), 45.16 (d), 53.26 (d), 56.48 (t), 61.66 (t), 62.09
(t), 125.17 (s), 129.51 (s), 167.18 (s), 167.32 (s), 171.67 (s); IR
(KBr) 2968, 1745, 1734, 1715 cm-1; MS (EI) m/z 391, 389; exact
mass M+ 389.0859 (calcd for C16H24BrNO5 389.0838).
7b-Cl: yield 69%, Table 4, entry 7; Rf ) 0.5 (ether); pale
yellow oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.95 (t, J ) 7.4
Hz, 3H), 1.26 (t, J ) 7.1 Hz, 3H), 1.31 (t, J ) 7.1 Hz, 3H),
1.47-1.75 (m, 2H), 2.29-2.42 (m, 2H), 2.93 (s, 3H), 3.81 (bd,
J ) 4.5 Hz, 1H), 3.84 (d, J ) 4.5 Hz, 1H), 3.91 (dd, J ) 14.3,
1.4 Hz, 1H), 4.01 (dd. J ) 14.3, 0.9 Hz, 1H), 4.13-4.36 (m,
4H) (selected NOEs are between δ 2.29-2.42 and 3.81); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 13.30 (q), 14.04 (q), 14.07
(q), 20.69 (t), 29.57 (q), 37.42 (t), 44.52 (d), 53.36 (d), 53.98 (t),
61.66 (t), 62.08 (t), 126.68 (s), 132.06 (s), 167.25 (s), 167.38
(s), 171.64 (s); IR (neat) 2920, 1740, 1734, 1710 cm-1; MS (EI)
m/z 345; exact mass M+ 345.1329 (calcd for C16H24ClNO5
345.1343).
7b-I: yield 49%, Table 4, entry 9; Rf ) 0.5 (ether); colorless
crystals; mp 65-66 °C (hexane-ether 1:1); 1H NMR (400 MHz,
CDCl3) δ (ppm) 0.96 (t, J ) 7.3 Hz, 3H), 1.26 (t, J ) 7.1 Hz,
3H), 1.32 (t, J ) 7.1 Hz, 3H), 1.43-1.57 (m, 1H), 1.61-1.74
(m, 1H), 2.37-2.53 (m, 2H), 2.93 (s, 3H), 3.76-3.84 (m, 3H),
3.88 (d, J ) 4.6 Hz, 1H), 4.13-4.36 (m, 4H) (selected NOEs
are between δ 2.37-2.53 and 3.76-3.84 and δ 2.37-2.53 and
3.88); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 12.93 (q), 14.02
(q), 14.09 (q), 23.34 (t), 29.46 (q), 42.32 (t), 45.64 (d), 53.28 (d),
61.46 (t), 61.65 (t), 62.09 (t), 105.48 (s), 134.94 (s), 167.10 (s),
167.27 (s), 172.01 (s); IR (KBr) 2980, 1731, 1705
8b-Br : yield 47%, Table 5, entry 3); purified by silica gel
(hexane-ether 1:2); Rf ) 0.2 (hexane-ether 1:2); pale yellow
1
oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.27 (t, J ) 7.1 Hz,
3H), 1.31 (t, J ) 7.1 Hz, 3H), 2.36 (ddd, J ) 1.3, 1.3, 1.3 Hz,
3H), 2.36-2.47 (m, 1H), 2.56-2.73 (m, 2H), 2.79-2.86 (m, 1H),
3.55-3.58 (m, 1H), 3.85 (d, J ) 4.6 Hz, 1H), 4.12-4.33 (m,
4H) (selected NOEs are between δ 2.36 and 3.55-3.58 and δ
2.36 and 3.85); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.00
(q), 25.77 (q), 31.28 (t), 38.19 (t), 49.83 (d), 54.72 (d), 62.05 (t),
62.17 (t), 118.96 (s), 136.62 (s), 167.45 (s), 167.68 (s), 215.65
(s); IR (neat) 2984, 2938, 1750, 1734, 1640 cm-1; MS (EI) m/z
346, 348; exact mass 346.0453 (calcd for C14H19BrO5 346.0416).
10b: yield 13%, Table 5, entry 3; Rf ) 0.5 (hexane-ether
1:2); colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.28 (t,
J ) 7.1 Hz, 3H), 1.30 (t, J ) 7.1 Hz, 3H), 2.71 (t, J ) 7.4 Hz,
3H), 2.97-3.11 (m, 2H), 3.99 (d, J ) 7.7 Hz, 1H), 4.07 (d, J )
3.5 Hz, 1H), 4.18-4.32 (m, 4H), 4.58 (dd, J ) 7.7, 3.5 Hz, 1H),
7.26-7.29 (m, 3H), 7.37-7.39 (m, 2H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 13.71 (t), 14.01 (q), 14.08 (q), 38.08 (t), 54.26
(d), 62.25 (t), 62.31 (t), 76.17 (d), 81.08 (s), 88.36 (s), 123.61
(s), 127.83 (d), 128.26 (d), 131.64 (d), 167.91 (s); IR (neat) 3480,
2984, 2238, 1735, 1601 cm-1; MS (EI) m/z 346; exact mass
346.1386 (calcd for C19H22O6 346.1416).
Con ver sion of 5a to 12a (in Eq 9). (A) Filtration of 5a
(132 mg, 0.36 mmol) on 35 g of Al2O3 containing 5% H2O by
column (2.3 × 10 cm) with hexane-ether (1:1) as eluent
yielded 12a (94 mg, 80%).
(B) To a solution of 5a (128 mg, 0.35 mmol) in dichlo-
romethane (2.4 mL) was added triethylamine (86 µL, 63 mg,
0.62 mmol) at room temperature. The mixture was stirred for
1 h. The reaction mixture was concentrated in vacuo. The
(26) Compounds 12e, 14b, and 13b-Cl could not be completely
purified due to the lability to column packing. NMR spectra of pure
compounds 8a -Cl and 3a could not be obtained due to the lability in
CDCl3 solution. Nevertherless, the major peaks in the NMR spectra
agree with the structures.

Cyclization of Enyne Triesters and Diesters
J . Org. Chem., Vol. 67, No. 9, 2002 2901
residue was extracted with dichloromethane, and the organic
phase was washed with saturated aqueous NaHCO3, dried
(Na2SO4), and evaporated in vacuo. The residue was purified
by column chromatography over silica gel with hexane-ether
as eluent to give 12a (95 mg, 82%).
17d : quantitative yield; Rf ) 0.4 hexane-ether (1:2);
1
colorless oil; H NMR (400 MHz, CDCl3) 1.29 (t, J ) 7.1 Hz,
6H), 4.20-4.28 (m, 4H), 4.73 (s, 1H), 5.03 (s, 2H), 5.63 (d, J )
17.8 Hz, 1H), 5.65 (d, J ) 11.0 Hz, 1H), 6.90 (dd, J ) 17.8,
11.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) 14.08 (q), 48.21
(d), 62.55 (t), 69.56 (t), 119.60 (s), 123.55 (t), 127.55 (d), 158.01
(s), 166.55 (s), 173.39 (s); IR (neat) 2986, 1765-1734, 1659,
1601 cm-1; MS (EI) m/z 268; exact mass M+ 268.0954 (calcd
for C13H16O6 268.0947).
12a :7 Rf ) 0.4, hexane-ether (1:1); yellow crystals; mp 98-
1
99 °C (EtOAc); H NMR (400 MHz, CDCl3) δ (ppm) 1.34 (t, J
) 7.1 Hz, 3H), 1.37 (t, J ) 7.1 Hz, 3H), 4.35 (q, J ) 7.1 Hz,
2H), 4.41 (q, J ) 7.1 Hz, 2H), 5.18 (d, J ) 2.4 Hz, 2H), 7.25-
7.28 (m, 2H), 7.39-7.46 (m, 3H) and 8.15 (t, J ) 2.4 Hz, 1H)
(selected NOEs in the 2D-NOESY spectra were between δ 8.15
and 7.25-7.28 and δ 5.18 and 7.25-7.28); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.90 (q), 14.00 (q), 62.47 (t), 62.48 (t),
69.89 (t), 128.27 (s), 129.12 (d), 129.78 (s), 129.84 (d), 132.20
(s), 134.93 (s), 136.88 (d), 163.03 (s), 164.75 (s) and 167.85 (s);
IR (KBr) 2984, 1775, 1738, 1700 cm-1; MS (EI) m/z 330; exact
mass M+ 330.1090 (calcd for C18H18O6 330.1103). Anal. Calcd
for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.27; H, 5.38.
Filtration of 8b-Cl (70 mg, 0.23 mmol) on SiO2 containing
15% H2O by column chromatography (2.3 × 10 cm) with
hexane-ether (1:1) as eluent yielded 13b-Cl (in eq 10) (69 mg,
ca. 99%).26
17e: yield 80%; Rf ) 0.4 (hexane-ether 1:2); pale yellow
1
oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (t, J ) 7.0 Hz,
6H), 1.94 (dd, J ) 6.8, 1.6 Hz, 3H), 4.18-4.30 (m, 4H), 4.69 (s,
1H), 4.98 (s, 2H), 6.19 (dq. J ) 16.1, 6.8 Hz, 1H), 6.58 (bd, J
) 16.1 Hz, 1H) (selected NOEs are between δ 1.94 and 6.58
and δ 4.98 and 6.19); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
14.03 (q), 19.32 (q), 48.08 (d), 62.34 (t), 69.65 (t), 116.70 (s),
122.39 (d), 137.42 (d), 158.32 (s), 166.71 (s) 173.65 (s); IR (neat)
2988, 2942, 1750, 1657 cm-1; MS (EI) m/z 282; exact mass
282.1111 (calcd for C14H18O6 282.1103).
Column chromatography of 8b-Cl with Al2O3 (containing 5%
H2O) gave 14b (in eq 10) in 57% yield.
14b: Rf ) 0.5 (hexane-ether 1:2); colorless oil; 1H NMR (400
MHz, CDCl3) δ (ppm) 1.31 (t, J ) 7.1 Hz, 3H), 1.34 (t, J ) 7.1
Hz, 3H), 1.88 (dt, J ) 7.2, 1.5 Hz, 3H), 2.49-2.53 (m, 2H),
2.66-2.70 (m, 2H), 4.29 (q, J ) 7.1 Hz, 2H), 4.35 (q, J ) 7,1
Hz, 2H), 6.38 (qt, J ) 7.2, 2.5 Hz, 1H) (selected NOEs are
between δ 1.88 and 2.66-2.70); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 13.91 (q), 13.99 (q), 15.36 (q), 23.69 (t), 35.95 (t), 62.06
(t), 125.20 (s), 133.58 (d), 134.62 (s), 140.23 (s), 164.15 (s),
166.07 (s), 205.71 (s); IR (neat) 2986, 2940, 1734 cm-1; MS (EI)
m/z 266; exact mass M+ 266.1155 (calcd for C14H18O5 266.1154).
Column chromatography of 13b-Cl with Al2O3 (containing
5% H2O) gave 15b (in eq 10) quantitatively. Treatment of 8b-
Cl with Et3N in CH2Cl2 for 1 h and purification with column
chromatography (SiO2) gave 15b in 26% yield. Treatment of
8b-Cl with Et3N in CDCl3 for 3 days gave 15b quantitatively.
15b: Rf ) 0.2 (hexane-ether 1:2; colorless oil; 1H NMR (400
MHz, CDCl3) δ (ppm) 1.26 (t, J ) 7.1 Hz, 6H), 2.50-2.53 (m,
2H), 2.81-2.83 (m, 2H), 4.15-4.27 (m, 4H), 4.76 (s, 1H), 5.62
(dd, J ) 10.7, 0.9 Hz, 1H), 5.87 (dd, J ) 17.4, 0.9 Hz, 1H),
7.03 (dd, J ) 17.4, 10.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 14.10 (q), 25.72 (t), 33.14 (t), 47.13 (d), 62.09 (t), 123.48
(t), 131.60 (d), 132.75 (s), 167.53 (s), 168.09 (s), 206.73 (s); IR
(neat) 2986, 2940, 1745, 1734, 1700, 1634 cm-1; MS (EI) m/z
266; exact mass M+ 266.1154 (calcd for C14H18O5 266.1154).
13b-Cl: Rf ) 0.6 (hexane-ether 1:2); pale yellow oil; 1H
NMR (400 MHz, CDCl3) δ (ppm) 1.26 (t, J ) 7.0 Hz, 3H), 1.28
(t, J ) 7.1 Hz, 3H), 1.73 (d, J ) 6.7 Hz, 3H), 2.15-2.54 (m,
2H), 2.70 (ddd, J ) 18.6, 6.1, 3.7 Hz, 1H), 2.98 (ddd, J ) 18.6,
6.0, 3.8 Hz, 1H), 4.15-4.31 (m, 4H), 4.75 (s, 1H), 5.32 (s, 1H),
5.32 (q, J ) 6.7 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
14.03 (q), 14.08 (q), 22.69 (q), 24.22 (t), 33.29 (t), 46.74 (d),
52.80 (d), 62.34 (t), 62.52 (t), 131.79 (s), 167.21 (s), 167.24 (s),
174.74 (s), 206.82 (s); IR (neat) 2986, 2938, 1734, 1715, 1647
cm-1; MS (EI) m/z 302; exact mass 302.0893 (calcd for C14H19
-
ClO5 302.0921).
Column chromatography of 5d -Cl and 5e-Cl by Al2O3 gave
12d (R3 ) Me, Scheme 2) and 12e (R3 ) Et), respectively.
12d : yield 50%; Rf ) 0.4 (hexane-ether 1:2); yellow oil; 1H
NMR (400 MHz, CDCl3) δ (ppm) 1.32 (t, J ) 7.1 Hz, 3H), 1.35
(t, J ) 7.1 Hz, 3H), 1.86 (dt, J ) 7.6, 1.4 Hz, 3H), 4.30 (q, J )
7.1 Hz, 2H), 4.38 (q, J ) 7.1 Hz, 2H), 4.91 (dq, J ) 2.6, 1.4 Hz,
2H), 7.52 (qt, J ) 7.6, 2.6 Hz, 1H) (selected NOEs are between
δ 1.86 and 4.91); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.90
(q), 13.97 (q), 15.42 (q), 62.32 (t), 62.34 (t), 68.83 (t), 128.87
(s), 129.47 (s), 131.01 (s), 135.81 (d), 163.03 (s), 164.98 (s),
168.87 (s); IR (neat) 2988, 1765, 1748 cm-1; MS (EI) m/z 268;
exact mass 268.0974 (calcd for C13H16O6 268.0947).
12e: yield 77%; Rf ) 0.4 (hexane-ether 1:2)); yellow oil; 1H
NMR (400 MHz, CDCl3) δ (ppm) 1.12 (t, J ) 7.5 Hz, 3H), 1.33
(t, J ) 7.1 Hz, 3H), 1.35 (t, J ) 7.1 Hz, 3H), 2.13-2.21 (m,
2H), 4.31 (q, J ) 7.1 Hz, 2H), 4.38 (q, J ) 7.1 Hz, 2H), 4.90
(ddd, J ) 2.5, 1.2, 1.2 Hz, 2H), 7.39 (ddt, J ) 7.7, 5.1, 2.5 Hz,
1H) (selected NOEs are between δ 2.13-2.21 and 4.90; 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 12.94 (q), 13.88 (q), 13.97
(q), 23.25 (t), 62.30 (t), 62.32 (t), 68.67 (t), 127.36 (s), 129.50
(s), 130.99 (s), 142.29 (d), 162.99 (s), 164.94 (s), 168.78 (s); IR
(neat) 2984, 2944, 1770, 1750, 1734 cm-1; MS (EI) m/z 282.
Treatment of 5d -Cl and 5e-Cl with Et3N in CH2Cl2 gave
17d (R3 ) Me, Scheme 2)7 and 17e (R3 ) Et), respectively.
Ack n ow led gm en t. This work was supported by the
Ministry of Education, Culture, Sports, Science, and
Technology of the J apanese Government.
Su p p or t in g In for m a t ion Ava ila b le: Figures giving
B3LYP/6-31G* SCRF-optimized geometries of M2I, M4, M5,
M8, M9, M10 and M1 and 1H and 13C NMR spectra for
compounds 5a -Br , 5d -Cl, 6E-Cl, 6E-Br and 7b-Br . This
information is available free of charge via the Internet at
http://pubs.acs.org.
J O016159R