Palladium(II)-catalyzed asymmetric cyclization of (Z)-4′-acetoxy-2′-butenyl 2-alkynoates. Role of nitrogen-containing ligands in palladium(II)-mediated reactions

Article abstract of DOI:10.1021/jo0105181

Pd(OAc)₂ combined with nitrogen-containing ligands (e.g., 2,2′-bipyridine) catalyzed the cyclization of (Z)-4′-acetoxy-2′-butenyl 2-alkynoates (1) in acetic acid to afford the α-(Z)-acetoxyalkylidene-β-vinyl-γ-butyrolactones (2) with high efficiency and high stereoselectivity. The nitrogen-containing ligands, like halides, served to favor β-heteroatom elimination over β-hydride elimination in Pd(II)-mediated reactions. The generality of this ligand effect was probed in both stoichiometric and catalytic reactions. With these results in hand, the catalytic asymmetric protocol was achieved with high enantioselectivity (up to 92% ee) when pymox (pyridyl monooxazoline) or bisoxazoline was used. The absolute configuration of the products and the synthetic utility of this asymmetric transformation were established through the convenient synthesis of (3S)-(+)-A-factor.

Full text of DOI:10.1021/jo0105181

7676
J . Org. Chem. 2001, 66, 7676-7684
P a lla d iu m (II)-Ca ta lyzed Asym m etr ic Cycliza tion of
(Z)-4′-Acetoxy-2′-bu ten yl 2-Alk yn oa tes. Role of
Nitr ogen -Con ta in in g Liga n d s in P a lla d iu m (II)-Med ia ted Rea ction s
Qinghai Zhang, Xiyan Lu,* and Xiuling Han
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@pub.sioc.ac.cn
Received May 22, 2001
Pd(OAc)2 combined with nitrogen-containing ligands (e.g., 2,2′-bipyridine) catalyzed the cyclization
of (Z)-4′-acetoxy-2′-butenyl 2-alkynoates (1) in acetic acid to afford the R-(Z)-acetoxyalkylidene-â-
vinyl-γ-butyrolactones (2) with high efficiency and high stereoselectivity. The nitrogen-containing
ligands, like halides, served to favor â-heteroatom elimination over â-hydride elimination in
Pd(II)-mediated reactions. The generality of this ligand effect was probed in both stoichiometric
and catalytic reactions. With these results in hand, the catalytic asymmetric protocol was achieved
with high enantioselectivity (up to 92% ee) when pymox (pyridyl monooxazoline) or bisoxazoline
was used. The absolute configuration of the products and the synthetic utility of this asymmetric
transformation were established through the convenient synthesis of (3S)-(+)-A-factor.
In tr od u ction
low induction,5 which was improved moderately by the
use of chiral amide-diphosphine ligands (about 50% ee).6
When a derivative of trans-coordinating (S,S)-(R,R)-
TRAP ligand was utilized for cyclization of a series of
substituted sulfonamido enynes, good to excellent (95%
ee, one example) enantioselectivity was obtained.7 More
recently, Rh-diphosphine complexes catalyzed cyclo-
isomerization of enyne ethers and amines generated the
five-membered heterocycles with high enantioselectiv-
ity.8,9 For other types of enyne cyclizations, Ti,10 Co,11
Rh,12 and Ir13 catalyzed cyclocarbonylation of enynes were
reported.
A Pd(II)-catalyzed cyclization of 4′-X (X ) leaving
groups)-2′-butenyl 2-alkynoates has been developed for
the synthesis of γ-butyrolactones in this group.14 Differ-
ent from the known methods for the cyclization of
enynes,15 the current system employs halide ions as
Carbon-carbon bond formation reaction is fundamen-
tally important in organic chemistry. Recent years wit-
nessed tremendous growth in a number of reactions and
reagents for carbon-carbon bond formation. Among
them, carbocyclizations of alkenes and alkynes catalyzed
by transition metals and their complexes are emerging
as one of the most important and useful reactions.1 The
method offers the unique tool to construct a variety of
synthetically important carbo- and heterocycles with high
efficiency not normally accessible with traditional meth-
ods. Due to the existence of the wealth of biologically
active and naturally occurring chiral cyclic compounds,
development of catalytic asymmetric annulation protocols
is of great interest in organic synthesis.2 However, highly
enantioselective transition metal-catalyzed cyclizations
are rare in contrast with the extensively studied racemic
variants.3 A powerful and well-studied reaction is the
transition metal-catalyzed cycloisomerization of 1,6-
enynes.4 The early contribution of Pd-catalyzed asym-
metric cyclization with chiral carboxylic acids gave fairly
(4) Pd: (a) Trost, B. M.; Lautens, M.; Chan, C.; J ebaratnam, D. J .;
Mueller, T. J . Am. Chem. Soc. 1991, 113, 636. (b) Trost, B. M.; Tanoury,
G. J .; Lautens, M.; Chan, C.; MacPherson, D. T. J . Am. Chem. Soc.
1994, 116, 4255. Ru: (c) Trost, B. M.; Mu¨eller, T. J . J . J . Am. Chem.
Soc. 1994, 116, 4985. (d) Trost, B. M.; Indolese, A. F.; Mu¨eller, T. J .
J .; Treptow, B. J . Am. Chem. Soc. 1995, 117, 615. (e) Trost, B. M.;
Toste, F. D. J . Am. Chem. Soc. 1999, 121, 9728. (f) Trost, B. M.; Toste,
F. D. J . Am. Chem. Soc. 2000, 122, 714. Ti: (g) Sturla, S. J .; Kablaoui,
N. M.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 1976. Rh: (h)
Cao, P.; Wang, B.; Zhang, X. J . Am. Chem. Soc. 2000, 122, 6490.
(5) Trost, B. M.; Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651.
(6) Trost, B. M.; Czeskis, B. A. Tetrahedron Lett. 1994, 35, 211.
(7) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 662.
(1) For reviews, see: (a) Trost, B. M.; Krische, M. J . Synlett 1998,
1. (b) Fru¨hauf, H.-W. Chem. Rev. 1997, 97, 523. (c) Ojima, I.;
Tzamarioudaki, M.; Li, Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635.
(d) Negishi, E.-I.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev.
1996, 96, 365. (e) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996,
96, 49.
(2) (a) Hudlicky, T.; Price, J . D. Chem. Rev. 1989, 89, 1467. (b) Trost,
B. M. Chem. Soc. Rev. 1982, 11, 141.
(3) For key examples, see: (a) Heck reaction: Shibasaki, M.; Boden,
C. D. J .; Kojima, A. Tetrahedron 1997, 53, 7371. (b) Overman, L. E.
Pure Appl. Chem. 1994, 66, 1423. (c) [4 + 2] Cycloisomerization:
Gilbertson, S. R.; Hoge, G. S.; Genov, D. G. J . Org. Chem. 1998, 63,
10077. (d) Lautens, M.; Lautens, J . C.; Smith, A. C. J . Am. Chem. Soc.
1990, 112, 5627. (e) Brunner, H.; Muschiol, M.; Prester, F. Angew.
Chem., Int. Ed. Engl. 1990, 29, 652. (f) Hydroacylation: Barnhart, R.
W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J .; Bosnich, B. J .
Am. Chem. Soc. 1994, 116, 1821. (g) C-H insertion: Doyle, M. P.;
Dyatkin, A. B.; Roos, G. H. P.; Can˜as, F.; Pierson, D. A.; van Basten,
A.; Mu¨ller, P.; Polleux, P. J . Am. Chem. Soc. 1994, 116, 4507. (h)
Cyclocarbonylation: Yu, W.-Y.; Bensimon, C.; Alper, H. Chem. Eur.
J . 1997, 3, 417. (i) Cao, P.; Zhang, X. J . Am. Chem. Soc. 1999, 121,
7708. (j) Murakami, M.; Itami, K.; Ito, Y.; J . Am. Chem. Soc. 1997,
119, 2950. (k) Hydrosilylation: Perch, N. S.; Widenhoefer, R. A. J . Am.
Chem. Soc. 1999, 121, 6960.
(8) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104.
(9) During the preparation of this manuscript, a palladium-catalyzed
asymmetric enyne cycloisomerization was reported: Hatano, M.;
Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249.
(10) (a) Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118,
8, 11688. (b) Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1999,
121, 7026. (c) Sturla, S. J .; Buchwald, S. L. J . Org. Chem. 1999, 64,
5547.
(11) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron Lett.
2000, 41, 891.
(12) J eong, N.; Sung, B. K.; Choi, Y. K. J . Am. Chem. Soc. 2000,
122, 6771.
(13) Shibata, T.; Takagi, K. J . Am. Chem. Soc. 2000, 122, 9852.
(14) (a) Ma, S.; Lu, X. J . Chem. Soc., Chem. Commun. 1990, 733.
(b) Ma, S.; Lu, X. J . Org. Chem. 1991, 56, 5120. (c) Lu, X.; Zhu, G.;
Wang, Z. Synlett 1998, 115.
10.1021/jo0105181 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

Palladium(II)-Catalyzed Asymmetric Cyclization
J . Org. Chem., Vol. 66, No. 23, 2001 7677
Ta ble 1. P d (II)-Ca ta lyzed Cycliza tion of
nuclephile to attack the Pd(II)-coordinated alkynes as the
initial step and â-heteroatom elimination as the final
step. It should be noted here that halide ions acts not
only as a nucleophile but also as a ligand which plays
the key role in inhibiting the usual â-hydride elimination
and promoting the â-heteroatom elimination, making the
catalytic cycle of the Pd(II) species possible.16,17 Thus,
halide ion is necessary in the halopalladation initiated
reaction as a ligand.
(Z)-4′-Acetoxy-2′-bu ten yl 2-Alk yn oa tes (1)a
entry
1
R1
R2
R2 time (h)
2
yield (%)b,c
Our long-standing goal is to develop the enantioselec-
tive process of this Pd(II)-catalyzed reaction. Compared
to the impressive development of the asymmetric reac-
tions with chiral Pd(0) catalyst,18 asymmetric reactions
with Pd(II) species have received much less attention.19,20
Moreover, most of the Pd(II)-catalyzed asymmetric reac-
tions quench the carbon-palladium bond using excess
amounts of oxidants to recycle the Pd(II) species from
Pd(0) species produced by â-hydride abstraction,20 while
our reaction system employs â-heteroatom elimination
to regenerate the Pd(II) species instead of using an
oxidant.
1
2
3
4
5
6
7
8
1a CH3
1b n-Pr
1c Ph
1d i-C7H15
1e CH3OCH2
1f CH3
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
10
10.5
34
18
10.5
24
2a
2b
2c
2d
2e
2f
87
90
90
83
83
76
89d
92d
1g CH3
1h CH3
i-Pr
n-C5H11
12
11
2g
2h
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (0.027 mmol), and
bpy (0.032 mmol) in HOAc (2.0 mL) at 60 °C. Isolated yield. c Z:
E > 95:5. â,γ-Relative stereochemistry is cis, determined by NOE
experiments.
b
d
palladium catalyst via trans-acetoxypalladation followed
by protonolysis (eq 2),22 which implied that acetate might
be a good nucleophile to replace halide ion in the Pd(II)-
catalyzed cyclization of enyne esters. From our previous
work, however, it was shown that acetate as the ligand,
unlike halides, could not inhibit the usual â-hydride
elimination.16 Thus, we would have to find another ligand
to play this role of halides. Herein we report a highly
efficient Pd(II)-catalyzed cyclization of enyne esters initi-
ated by acetoxypalladation as well as its asymmetric
version employing nitrogen-containing ligands.23
However, much effort devoted toward realizing the
halopalladation-initiated asymmetric cyclization failed.21
The reaction rate decreased dramatically in the presence
of the commonly used chiral nitrogen or phosphine
ligands, and no chiral induction was observed. These
results indicated that the extra chiral ligand drastically
altered the reactivity of the catalyst; hence, it affected
the reaction significantly. On the other hand, the inevi-
table disturbance of the excess of requisite halide ions
to the coordination of chiral ligands with palladium
species might also contribute to the difficulty of develop-
ing the catalytic asymmetric cyclizations.
To solve the problems, it seems that the halide ions
must be excluded from the reaction. A new type of
reaction should be developed where a weakly coordinated
nucleophile will replace halide ions to act as the nucleo-
phile (eq 1).
Resu lts a n d Discu ssion
Develop in g of Rea ction Con d ition s a n d Syn th etic
Scop e. We initially examined the reaction of (Z)-4′-
acetoxy-2′-butenyl 2-butynoate (1a ) in the presence of
LiOAc with HOAc as solvent under different catalyst
systems. The reaction of 1a catalyzed by Pd(OAc)2 with
no extra ligand afforded only the hydroacetoxylation
product 3 in 82% yield. Other catalyst systems such as
Pd(OAc)2/PPh3, Pd(OAc)2/AsPh3, Pd(OAc)2/PhSMe, PdCl2-
(PPh3)2, and Pd2(dba)3‚CHCl3 as well as common solvents
such as DMF, CH3CN, THF, benzene, and dioxane were
also tested, but no desired cyclization product was
produced. Finally, subjecting 1a to 5 mol % Pd(OAc)2, 6
mol % bpy (2,2′-bipyridine), and 1.2 equiv of LiOAc at
60 °C led to a 53% yield of the cyclization product R-(Z)-
acetoxymethylidene-â-vinyl-γ-butyrolactone (2a ) and a
37% yield of 3 (eq 3). Further experiments revealed that
LiOAc could be omitted, and the yield was raised to 87%
without the detection of 3 (Table 1, entry 1). The
stereochemistry of the exocyclic double bond in 2a was
Hydroacetoxylation of alkynoates was developed in
early work where acetate attacked the triple bond under
(15) Ferna´ndez-Rivas, C.; Me´ndez, M.; Echavarren, A. M. J . Am.
Chem. Soc. 2000, 122, 1221 and references therein.
(16) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19, 775.
(17) Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organometallics
2001, 20, 3724.
(18) Notable examples include allylic substitution and Heck reac-
tion: (a) Tenaglia, A.; Heumann, A. Angew. Chem., Int. Ed. 1999, 38,
2180 and references therein. (b) Hayashi, T. J . Organomet. Chem. 1999,
576, 195. (c) Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96,
395. (d) Tsuji, J . Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; J ohn Wiley & Sons: Chichester, 1995.
(19) (a) Hao, J .; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059.
(b) Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998, 120,
2474. (c) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J . Org. Chem. 1995,
60, 2648.
1
assigned (Z)-configuration based on H NMR and NOESY
analysis.
(20) (a) Hollis, T. K.; Overman, L. E. J . Organomet. Chem. 1999,
576, 290. (b) Mikami, K.; Hatano, M.; Terada, M. Chem. Lett. 1999,
55. (c) El-Qisairi, A.; Hamed, O.; Henry, P. M. J . Org. Chem. 1998,
63, 2790. (d) Itami, K.; Palmgren, A.; Thorarensen, A.; Ba¨ckvall, J . E.
J . Org. Chem. 1998, 63, 6466. (e) Uozumi, Y.; Kato, K.; Hayashi, T. J .
Am. Chem. Soc. 1997, 119, 5063. (f) Hosokawa, T.; Murahashi, S.-I.
Acc. Chem. Res. 1990, 23, 49.
(21) Chiral ligands such as bisoxazolines, (S)-MOP, [(3,2,10-η3-
pinene)PdCl]2, and BINOL have been tested.

7678 J . Org. Chem., Vol. 66, No. 23, 2001
Zhang et al.
Ta ble 2. Effect of Bip yr id yl/P yr id yl Su bstitu en t on th e
Cycliza tion a
Other substituted alkynyl esters, e.g., phenyl, n-alkyl,
or methoxymethyl, reacted smoothly to furnish the
γ-butyrolactones in high yields (Table 1, entries 2-5).
The substrate containing the 4′-phenyl group (1f) pro-
duced the cyclization product in 76% yield (Table 1, entry
6). The enyne esters possessing the 1′-substitent, e.g., i-Pr
or n-C5H11, afforded the â,γ-cis-disubstituted γ-butyro-
lactones in high yields (Table 1, entries 7 and 8).24 It is
noteworthy that all the reactions are stereoselective to
afford the γ-butyrolactones with the exocyclic double bond
in (Z)-configuration.
However, attempts to cyclize the (Z)-4′-acetoxy-2′-
butenyl propiolate (1i) failed, which was in accord with
Pd(OAc)2-catalyzed hydroacetoxylation of 2-alkynoates22a
and might be attributed to the possible formation of
(alkynyl)palladium species.25 Additionally, the reaction
of (E)-4′-acetoxy-2′-butenyl 2-butynoate (1j)26 was in-
effective under the same reaction condition, and the
starting material remained intact after 24 h even at
elevated temperature. The stronger coordinating ability
of (Z)-olefins compared to (E)-olefins may account for the
discrepancy.27
In flu en ce of Bip yr id yl/P yr id yl Su bstitu en t. As
shown above, bpy ligand is crucial for the success of the
cycloisomerization of the enyne esters. Employment of
1,10-phenanthroline (phen) as the ligand gave similar
result with that of bpy (Table 2, entries 1 and 2). For
further insight into the scope of the reaction, we also
examined the influence of pyridyl/bipyridyl substituent
with different electronic or steric character on the model
reaction of 1a in the presence of 5 mol % Pd(OAc)2 in
HOAc at 60 °C (Table 2). Generally, increasing steric
hindrance adjacent to the nitrogen atom of the bipyridine
decreases its coordinating ability to palladium,28 and its
effect on the reaction is significant. Employment of the
6-substituted bipyridine as the ligands led to a lower yield
of 2a than bpy or phen did and gave predominately 3
(Table 2, entries 3 and 4). While the use of the 6,6′-
disubstituted bipyridine as the ligands totally suppressed
the cyclization of 1a and only hydroacetoxylation oc-
curred (Table 2, entries 5 and 6). These results indicated
that excessive steric crowding of the coordinating plane
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (0.027 mmol), and
b
L (0.032 mmol) in HOAc (2.0 mL) at 60 °C. Isolated yield.
c L/Pd ) 2/1.
(22) (a) Lu, X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205. (b)
Wakabayashi, T.; Ishii, Y.; Murata, T.; Mizobe, Y.; Hidai, M. Tetra-
hedron Lett. 1995, 36, 5585.
(23) A preliminary report has been published: Zhang, Q.; Lu, X. J .
Am. Chem. Soc. 2000, 122, 7604.
(24) The stereochemical result is similar to that of the reactions
initiated by halopalladation, see: Ma, S.; Zhu, G.; Lu, X. J . Org. Chem.
1993, 58, 3692.
(25) (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter,
G. J . Am. Chem. Soc. 1997, 119, 698. (b) Melikyan, G. G.; Nicholas, K.
M. In Mordern Acetylene Chemistry; Stang, P. J .; Diederich, F., Eds.;
VCH: New York, 1995; p 79.
(26) Zhu, G.; Ma, S.; Lu, X. J . Chem. Res, (S) 1993, 366.
(27) Hartley F. R. The Chemistry of Platinum and Palladium: with
Particular Reference to Complexes of the Elements; Applied Science
Publication Ltd: London, 1973; p 377.
(28) (a) Mckenzie, E. D. Coord. Chem. Rev. 1971, 6, 187. (b) Reedijk,
J . In Comprehensive Coordination Chemistry; Wilkinson, G.; Gillard,
R. D.; McCleverty, J . A., Eds.; Pergamon: Oxford, 1987; Vol. 2, p 73.
(c) Chieh, P. C. J . Chem. Soc., Dalton Trans. 1972, 1643.
around palladium was detrimental to the efficiency of
cyclization. Pyridine could also serve as the ligand in the
reaction to furnish a 36% yield of 2a as well as a 30%
yield of 3 (Table 2, entry 7). The effect of the electronic
and steric factor of the pyridyl substituent on the reaction
was also evident. For example, employment of the
electron-donating group substituted 2-isopropyloxy py-
ridine as the ligand afforded a 13% yield of 2a in addition
to a 55% yield of 3 (Table 2, entry 8), while utilizing
2-methyl or 2-chloro pyridine as the ligands, 3 was
isolated as the sole product in 75% and 70% yield,
respectively (Table 2, entries 9 and 10). Only 3 was
obtained in 77% yield with DMAP as the ligand (Table
2, entry 11), which might be due to the protonation of

Palladium(II)-Catalyzed Asymmetric Cyclization
J . Org. Chem., Vol. 66, No. 23, 2001 7679
Ta ble 3. In ter m olecu la r Cou p lin g of Meth yl 2-Bu tyn oa te
w ith Allyl Com p ou n d sa
Sch em e 1
entry
Y
4, yield (%)b
1
2
3
4
OAc
Cl
OEt
OH
57 (55)c
9d
<2d
<2d
a
Reaction conditions: methyl 2-butynoate (1 mmol), allyl
compounds (4 mmol), Pd(OAc)2 (0.049 mmol), and bpy (0.058
b
mmol) in HOAc (5.0 mL) at 60 °C. 1H NMR yield with CH2Br2
d
as internal standard. c Isolated yield in parentheses. Most of the
starting materials remained intact.
the pyridyl nitrogen in acetic acid making its coordination
ability decreased.
acid and the rate of intramolecular olefinic insertion is
much faster than that of protonolysis.
Apparently, there existed competency between the
cyclization and hydroacetoxylation in the reaction. The
current results indicated that the strong coordinating
ability of bipyridine/pyridine ligand with palladium was
beneficial to the cycloisomerization of the enyne esters.
Effect of Lea vin g Gr ou p s. In the above reactions,
acetate played the roles as a nucleophile as well as a
leaving group. We have demonstrated previously in the
Pd(II)-catalyzed cyclization of 4′-heteroatom-2′-butenyl
2-alkynoates initiated by halopalladation that the leaving
ability of â-elimination follows the order Cl- > OAc >
OMe > OH ∼ H in HOAc.29 To investigate the possibility
of other leaving groups in the enyne couplings initiated
by acetoxypalladation, we examined the reaction of
methyl 2-butynoate and allyl compounds in the presence
of 5 mol % Pd(OAc)2, 6 mol % bpy in HOAc at 60 °C (Table
3). Similar to the intramolecular cylizations, the inter-
molecular coupling with allyl acetate gave a 57% yield
of the coupling product 4 (Table 3, entry 1). However,
with allyl chloride as a partner only 9% of 4 was obtained
according to the NMR analysis (Table 3, entry 2). It was
proposed that the chloride dissociated at the beginning
of the reaction would replace the acetate around the
palladium coordination sphere, and then the chloride ion
coordinated palladium complex deactivated the coupling.
Additionally, only trace amounts of 4 were observed with
OEt or OH as the leaving group, and most of the starting
materials remained intact (Table 3, entries 3 and 4).
Thus, acetate is still the most appropriate leaving group
of those tested.
Mech a n ism . The mechanism for this transformation
is believed to be analogous to that of the halopalladation
initiated cyclization of enyne esters.14b This will involve
insertion of the pendant olefin into the vinyl-palladium
intermediate II formed by trans-acetoxypalladation of the
carbon-carbon triple bond, followed by â-deacetoxy-
palladation to give the γ-butyrolactone and the catalyti-
cally active Pd(II) species (Scheme 1). Additionally, the
intermediate II may also be intercepted by acid to
produce the hydroacetoxylation product. Which route
(cyclization or protonolysis) predominates depends on the
kinetics of the reaction. As shown above, no detectable 3
was formed with bpy as ligand (Table 1, entry1), which
means that the intermediate II is stable enough in acetic
The stereospecific (Z)-configuration of the exocyclic
double bond in the γ-butyrolactones supports the mech-
anism of the trans-acetoxypalladation of alkynes. This
point is different from the halopalladation of alkynes
where cis-halopalladation is manifested especially in the
event of low concentration of halide ions.14b,30
Role of Nitr ogen -Con ta in in g Liga n d s. â-Hydride
elimination usually occurs with an alkyl palladium
species with a â-hydrogen atom to carbon-palladium
bond (Heck-type reaction). Our previous work has shown
that excess of halide ions can block the usual â-hydride
elimination.16,17 In the above catalytic cycle, the normal
â-hydride elimination is also inhibited and â-acetoxy
elimination takes place instead for the alkylpalladium
intermediate III (Scheme 1). Evidently, nitrogen-contain-
ing ligands play a key role here.
To probe the role of nitrogen-containing ligands, we
investigated the stoichiometric reaction of the palladium
complex 5 with allyl acetate by providing different
coordinating ligands in HOAc at room temperature
(Table 4). We postulate an intermediate IV formed by
intermolecular olefinic insertion into the aromatic carbon-
palladium bond. From the intermediate, â-hydride elimi-
nation leads to 6, while â-acetoxy elimination gives 7.
As shown in Table 4, reaction with no extra ligand gave
6 as the only product in 66% yield together with precipi-
tated palladium black (Table 4, entry 1), while reaction
in the presence of Cl- afforded 7 in 75% yield (Table 4,
entry 2). Significantly, all the reactions with pyridine,
bpy, or phen as the ligands also produced exclusively 7
in 69%, 81%, and 77% yield, respectively (Table 4, entries
3-5).
The generality of this ligand effect was further exam-
ined in a catalytic process incorporating Pd(II)-mediated
transmetalation.18d The reaction of phenylmercuric ac-
etate with allyl acetate in the presence of 5 mol %
Pd(OAc)2 in HOAc was conducted with different ligands.17
As shown in Table 5, reaction with no extra ligand gave,
(30) (a) Dietl, H.; Reinheimer, H.; Moffat, J .; Maitlis, P. M. J . Am.
Chem. Soc. 1970, 92, 2276. (b) Mann, B. E.; Bailey, P. M.; Maitlis, P.
M. J . Am. Chem. Soc. 1975, 97, 1275. (c) Maitlis, P. M. Acc. Chem.
Res. 1976, 9, 93. (d) Kaneda, K.; Uchiyama, T.; Kobayashi, H.;
Fujiwara, Y.; Imanaka, T.; Teranishi, S. Tetrahedron Lett. 1977, 23,
2008. (e) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.;
Teranishi, S. J . Org. Chem. 1979, 44, 55. (f) Imanaka, T.; Kimura, T.;
Kaneda, K.; Teranishi, S. J . Mol. Catal. 1980, 9, 103. (g) Ba¨ckvall, J .
E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organometallics 1995, 14, 4242.
(29) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.

7680 J . Org. Chem., Vol. 66, No. 23, 2001
Zhang et al.
Ta ble 4. Stoich iom etr ic Rea ction s of P a lla d iu m
Com p lex (5) w ith Allyl Aceta tea
Ta ble 6. Asym m etr ic Cycliza tion of 1a Em p loyin g
Oxa zolin e Liga n d sa
yield (%)b
entry
L*
T (°C)
2a
3
16
ee % of 2a c
1d
2
(S,S)-11a
(S,S)-11b
(R,R)-11c
(R,R)-11c
(R,R)-11c
(R,R)-11c
(R,R)-12
(S)-13a
60
60
60
60
60
60
60
60
60
40
60
24
34
29
36
50
67
78
15
82
88
89
82
18
40
33
0
91
88
89
92
68
34h
81
83
64h
3e
4f
5
yield (%)b
6g
7e
8
9
10
11
entry
L
L/Pd
observation
6
7
44
1
2
3
4
5
none
Cl-c
py
bpy
phen
Pd V
66
(R)-13b
(R)-13b
13c
10/1
2/1
1/1
clear solution
clear solution
clear solution
clear solution
75
69
81
77
1/1
a
Unless otherwise noted, the reaction was carried out under
a
the following conditions. 1a (0.5 mmol), Pd(OAc)2 (0.027 mmol),
Reaction conditions: complex 5 (0.13 mmol) and allyl acetate
b
and L* (0.054 mmol) in HOAc (5 mL). Isolated yield. c Deter-
b
(1.3 mmol) in HOAc (2.0 mL) at room temperature. Isolated yield
based on Pd. c LiCl.
mined by chiral HPLC using the chiralcel OJ column eluting with
d
hexane:2-propanol (8:2, v:v) (λ ) 214 nm). 43% of 1a was
g
recovered. e HOAc (0.5 mL). f HOAc (2.0 mL). 1a (0.5 mmmol),
Ta ble 5. Ca ta lytic Rea ction s of P h en ylp a lla d iu m
Com p lexes w ith Allyl Aceta te th r ou gh Tr a n sm eta la tion a
h
Pd(OAc)2 (0.049 mmol), and (R,R)-11c (0.099 mmol). Reversed
configuration compared with other ligands.
hydrine was formed effectively at [Cl-] as low as 0.2 M.
While at this low [Cl-] in the absence of pyridine, PdCl4
-
gave only acetaldehyde at any [CuCl2].32 The work
implied that there existed some relationship between the
catalysts with pyridine or chloride as ligand.33
Asym m etr ic Cycliza tion . The racemic variant of the
acetoxypalladation initiated cyclization of enyne esters
has been realized under the catalysis of nitrogen-coordin-
tated Pd(II) complexes. With these results in hand,
further effort to the development of an asymmetric
catalysis was made using the homochiral nitrogen-
containing ligands. We initially employed oxazoline
ligands34 due to their availability and the wealth of
asymmetric transformations which utilized these ligands.35
Generally the reaction of 1a was carried out with 5 mol
% Pd(OAc)2 and 10 mol % chiral ligand in HOAc at 60
°C (Table 6). First we targeted the C2-symmetric bis-
oxazoline ligands 11 and found that the different sub-
stituent on the oxazoline ring significantly affected the
entry
L
observation
8:9:10b
yield (%)c
1
none
Cl-e
bpy
Pd V
clear solution
clear solution
-
3d
76
65
2
trace:5:2
trace:6:1
3f
a
Reaction conditions: PhHgOAc (3 mmol), allyl acetate (9
mmol), and Pd(OAc)2 (5 mol %) in HOAc (15 mL) at room
temperature. b 1H NMR ratio. c Isolated yield. Only 8 was ob-
d
tained. e LiCl/Pd ) 200/1. f 80 °C and bpy/Pd ) 1/1.
via â-hydride elimination of the intermediate V, cinnamyl
acetate (8) in 3% yield (60% based on Pd) (Table 5, entry
1). Reactions with bpy and excess amounts of Cl- as the
ligands gave very similar results where allylbenzene (9)
and 1,3-diphenylpropene (10) were isolated as the main
products (Table 5, entries 2 and 3). Allybenzene was
produced via â-acetoxy elimination from the intermediate
V. Presumably, 1,3-diphenylpropene was formed by the
consecutive reaction of allylbenzene with phenylmercuric
acetate in the presence of Pd(II) complexes while the
Hg(II) salts formed through transmetalation served as
reoxidant.31
The above two experiments strongly demonstrate that
the nitrogen-containing ligands, like halides, serve to
favor â-heteroatom elimination over â-hydride elimina-
tion.
Henry et al. ever reported that when adding pyridine
to the PdCl2-CuCl2 Wacker oxidation system chloro-
(32) Francis, J . W.; Henry, P. M. J . Mol. Catal. A: Chem. 1995, 99,
77.
(33) This phenomenon may be explained from our suggestion that
pyridine, like chlorides, can inhibit the â-H abstraction, and the
oxidative cleavage occurs in the presence of CuCl2.
(34) Employing 4,5-dihydro-2-phenyloxazole as the extra ligand in
the stoichiometric reaction similar to that shown in Table 4, a 18%
yield of 7 was formed and no detectable 6 was observed by NMR spectra
after 1 h. However, further reaction occurred affording N-acetoxy-2-
methylindole as a major product on lengthening the reaction time (24
h: 21% yield of 7 and 67% yield of N-acetoxy-2-methylindole). 7 was
reported to be converted to N-acetoxy-2-methylindole with palladium
dichloride: Hegedus, L. S.; Allen, G. F.; Bozell, J . J .; Waterman, E. L.
J . Am. Chem. Soc. 1978, 100, 5800. These results shows that the
reaction did favor â-heteroatom elimination in the presence of the
oxazoline ligand.
(35) For reviews, see: (a) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339.
(b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron: Asym-
metry 1998, 9, 1. (c) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed.
Engl. 1994, 33, 497. (d) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. Rev. 2000, 100, 2159.
(31) Heck, F. R. J . Am. Chem. Soc. 1968, 90, 5526.

Palladium(II)-Catalyzed Asymmetric Cyclization
J . Org. Chem., Vol. 66, No. 23, 2001 7681
Ta ble 7. Asym m etr ic Cycliza tion of 1 Em p loyin g
reactivity and enantioselectivity of the reaction. For
example, no cyclization product 2a was obtained with the
benzyl-substituted bisoxazoline ligand (S,S)-11a (Table
6, entry 1) and only a 29% yield of 2a with disappointing
zero enantiomeric excess employing the isopropyl sub-
stituted bisoxazoline (S,S)-11b as the ligand (Table 6,
entry 2). Luckily, employment of the phenyl-substituted
bisoxazoline (R,R)-11c as the ligand led to remarkable
improvement in enantioselectivity (91% ee). However, a
two-component adduct 16 emerged as a major byproduct
at high substrate concentration (1.0 M) (Table 6, entry
3). It was expected that the intermolecular reaction
should be suppressed by diluting the reaction system. As
expected, when the concentration of 1a was reduced to
0.1 M, no detectable 16 was formed and the yield of 2a
was raised to 67% and without great loss of enantio-
selectivity (89% ee) (Table 6, entry 5). Increasing the
catalyst loading to 10 mol % Pd(OAc)2 and 20 mol %
(R,R)-11c gave 2a in 78% yield (92% ee) (Table 6, entry
6). While the use of another kind of bisoxazoline ligand
(R,R)-12 afforded lower yield and enantioselectivity than
did (R,R)-11c (15% yield and 68% ee) (Table 6, entry 7).
Palladium-pymox (pyridyl monooxazoline) complexes are
relatively uncrowded in comparison with those of bis-
oxazoline ligands. As a result, these complexes catalyzed
the cyclization more efficiently and led to higher cycliza-
tion yield (Table 6, entries 8-11). Again, employment of
the phenyl-substituted ligand (R)-13b gave the highest
enantioselectivity (81% ee) of the kind (Table 6, entry 9).
Lowing the temperature (40 °C) only raised the enantio-
selectivity slightly (Table 6, entry 10). Other types of
ligands such as the quinolinyl-oxazoline (S)-14 and the
tridentate ligand (S,R)-Indan-Ambox 15 were also tested,
but no detectable cyclization product was formed.
(R,R)-11c or (R)-13b a s Liga n d
entry
1
conditionsa (time)
2
yield (%)b % eec (config)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
A (18 h)
B (35 h)
A (34 h)
B (42 h)
A (48 h)
B (72 h)
A (23 h)
B (48 h)
A (41 h)
B (48 h)
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
88
78
83
80
70
58
86
77
72
67
81 ((+)-R)
92 ((+)-R)
81 ((+)-R)
80 ((+)-R)
81 ((+)-R)
79 ((+)-R)
84 ((+)-R)
85 ((+)-R)
79 ((+)-R)
87 ((+)-R)
10
a
Conditions A: 1 (0.5 mmol), Pd(OAc)2 (0.027 mmol), and (R)-
13b (0.054 mmol) in HOAc (5 mL) at 60 °C. Conditions B: 1 (0.5
mmol), Pd(OAc)2 (0.049 mmol), and (R,R)-11c (0.099 mmol) in
b
HOAc (5 mL) at 60 °C. Isolated yield. c Determined by chiral
HPLC using the chiralcel OJ column eluting with hexane:2-
propanol (8:2, v:v) (λ ) 214 nm).
Sch em e 2a
a
Reagents and conditions: (a) cat. K2OsO4, NMO, acetone-
H2O, rt; (b) NaIO4/SiO2, CH2Cl2, rt; (c) NaBH4, MeOH, -2 °C; (d)
cat. 4-(dimethylamino)pyridine, MeOH, 9 °C.
the asymmetric protocol, we chose A-factor as our target
molecule.36 A-factor is an inducer of the biosynthesis of
Streptomycin in inactive mutants of Streptomycis gri-
seus.37 Mori et al. determined the absolute configuration
of its two enantiomers by synthesizing them from chiral
paraconic acid.36b,38 The retrosynthetic analysis of A-
factor could easily identify γ-butyrolactone 2d as the key
intermediate. Thus, selective cleavage of the terminal
alkene of (+)-2d was performed with potassium osmate-
(VI) (1 mol %) and NMO (1.1 equiv) followed by sodium
periodate cleavage of the resulting diol. The aldehyde was
used without purification in a subsequent reduction with
sodium borohydride in methanol at -2 °C to give (+)-17
in 82% overall yield from (+)-2d . Finally, transformation
of the vinyl acetate in (+)-17 to ketone (either existing
as enol form) under the catalysis of DMAP in methanol
at 9 °C furnished the enantiomerically enriched (3S)-(+)-
A-factor (86% ee39) in 70% yield (Scheme 2). Hence, the
starting material (+)-2d was assigned 3R configuration.
Thus, by comparing the signs of the specific rotation of
the other γ-butyrolactones with (+)-2d and based on their
On the basis of these results, (R,R)-11c and (R)-13b
were selected as the preferred ligands for the Pd(II)-
catalyzed cyclization of the enyne esters. Some repre-
sentative results employing the two ligands were sum-
marized in Table 7. High enantioseclectivity (79-92% ee)
was achieved. In general, the catalyst system with (R,R)-
11c as the ligand showed relatively lower reactivity but
higher enantioselectivity than that with (R)-13b (Table
7, compare entries 1 with 2 and 9 with 10). But in some
cases, the two catalyst systems showed similar enantio-
selectivity (Table 7, compare entries 3 with 4 and 7 with
8).
(36) (a) Kleiner, E. M.; Onoprienko, V. V.; Pliner, S. A.; Soifer, V.
S.; Khokhlov, A. S. Bioorg. Khim. 1977, 3, 424. (b) Mori, K.; Yamane,
K. Tetrahedron 1982, 38, 2919. (c) Mori, K.; Chiba, N. Liebigs Ann.
Chem. 1990, 31. (d) Kinoshita, T.; Hirano, M. J . Heterocycl. Chem.
1992, 29, 1025. (e) J i, J .; Zhang, C.; Lu, X. J . Org. Chem. 1995, 60,
1160.
(37) (a) Khokhlov, A. S.; Anisova, L. N.; Tovarova, I. I.; Kleiner, E.
M.; Kovalenko, I. V.; Krasilnikova, O. I.; Kornitskaya, E. Y.; Pliner, S.
A. Z. Allg. Mikrobiol. 1973, 13, 67. (b) Kleiner, E. M.; Pliner, S. A.;
Soifer, V. S.; Onoprienko, V. V.; Balasheva, T. A.; Rozynov, B. V.;
Khokhlov, A. S. Bioorg. Khim. 1976, 2, 1142.
Absolu te Con figu r a tion . To establish the absolute
configuration of the optically active γ-butyrolactones
obtained above and demonstrate the synthetic utility of
(38) Mori, K. Tetrahedron 1983, 39, 3107.
(39) The 86% ee of our synthesized (3S)-(+)-A-factor is calculated
according to the specific rotation ([R]22 +10.9°, lit.36b [R]22 +12.7°).
D
D

7682 J . Org. Chem., Vol. 66, No. 23, 2001
Zhang et al.
employing 300-400 mesh silica gel. 1H NMR yield was
determined with CH2Br2 as internal standard. Acetic acid was
purified by heating with acetic acid and CrO3 and then
fractionally distilling.40
Sch em e 3
The substituted 2,2′-bipyridines were prepared according to
the literature methods.41 The oxazoline ligands 11a -c,42a-b
12,42c and 13a -c42d-e were pepared by known methods. Pal-
ladium complex 5 was prepared by the literature procedure.43
Typ ica l P r oced u r e for th e Syn th esis of (Z)-4′-Acetoxy-
2′-bu ten yl 2-Alk yn oa tes (1). Syn th esis of (Z)-4′-Acetoxy-
2′-bu ten yl 2-Bu tyn oa te (1a ). To a solution of 2-butynoic acid
(1.68 g, 20 mmol) and (Z)-1-acetoxy-2-buten-4-ol (2.86 g, 22
mmol) in CH2Cl2 (20 mL) was added dropwise at -20 °C a
solution of 1,3-dicyclohexylcarbodiimide (4.13 g, 20 mmol) and
4-(dimethylamino)pyridine (224 mg, 2 mmol) in CH2Cl2 (20
mL) with stirring. Then the reaction mixture was stirred at
room temperature for 10 h. After the reaction was complete,
the white solid was filtered off and the solvent was removed
in vacuo. The residue was then submitted to column chroma-
tography on silica gel (petroleum ether:ethyl acetate 5:1),
affording 1a as an oil: yield 91%. IR (neat) 2960, 2243, 1741,
similarity in the order of retention time in the HPLC
analysis (Table 6), all other γ-butyrolactones in Table 6
were identified to be in 3R configuration.
1712, 1442, 1377, 1253 cm-1 1H NMR (300 MHz, CDCl3) δ
.
5.80-5.76 (m, 2H), 4.76 (d, J ) 5.4 Hz, 2H), 4.68 (d, J ) 5.3
Hz, 2H), 2.08 (s, 3H), 2.00 (s, 3H). MS (m/z) 197 (M+ + 1),
163, 137, 113, 67 (100), 43. Anal. Calcd for C10H12O4 C, 61.22;
H, 6.16. Found C, 60.98; H, 6.33.
(Z)-4′-Acetoxy-2′-bu ten yl 2-Hexyn oa te (1b). Oil: yield
89%. IR (neat) 2965, 2235, 1743, 1714. 1H NMR (300 MHz,
CDCl3) δ 5.88-5.70 (m, 2H), 4.77 (d, J ) 5.3 Hz, 2H), 4.68 (d,
J ) 5.1 Hz, 2H), 2.32 (t, J ) 7.1 Hz, 2H), 2.07 (s, 3H), 1.62 (m,
2H), 1.02 (t, J ) 7.4 Hz, 3H). MS (m/z) 225 (M+ + 1), 165, 113,
95 (100), 43. Anal. Calcd for C12H16O4 C, 64.27; H, 7.19. Found
C, 64.42; H, 7.16.
(Z)-4′-Acetoxy-2′-bu ten yl 3-P h en yl-2-p r op yn oa te (1c).
White solid: mp 27-28 °C. yield 87%. IR (neat) 2225, 1741,
1711, 1286, 1232. 1H NMR (300 MHz, CDCl3) δ 7.57-7.54 (m,
2H), 7.43-7.32 (m, 3H), 5.84-5.74 (m, 2H), 4.82 (d, J ) 4.5
Hz, 2H), 4.68 (d, J ) 4.5 Hz, 2H), 2.05 (s, 3H). MS (m/z) 259
(M+ + 1), 149, 57 (100), 43. Anal. Calcd for C15H14O4 C, 69.76;
H, 5.46. Found C, 69.51; H, 5.60.
(Z)-4′-Acet oxy-2′-b u t en yl 5-Met h yl-2-n on yn oa t e (1d ).
Oil: yield 93%. IR (neat) 2956, 2236, 1744, 1714, 1232. 1H
NMR (300 MHz, CDCl3) δ 5.80-5.76 (m, 2H), 4.76 (d, J ) 5.2
Hz, 2H), 4.68 (d, J ) 5.1 Hz, 2H), 2.33 (t, J ) 7.1 Hz, 2H),
2.07 (s, 3H), 1.59-1.37 (m, 5H), 1.21-1.16 (m, 2H), 0.88 (d, J
) 6.6 Hz, 6H). MS (m/z) 281 (M+ + 1), 221, 197, 113 (100), 43.
Anal. Calcd for C16H24O4 C, 68.55; H, 8.63. Found C, 68.62; H,
8.77.
Mech a n ism of Asym m etr ic In d u ction . It has been
noted that distortion of the normal square planar struc-
ture of Pd(II) complexes toward a tetrahedral arrange-
ment due to steric interactions, especially in the event
that bulky substitution occurred in adjacent to coordina-
tion atoms, such as the nitrogen of bipyridine and
phenanthroline ligands.28b,c In the above asymmetric
cyclizations, the large steric effect around the Pd(II)
sphere may be significant in determining the preference
for a rarely precedented tetrahedral species. According
to this tetrahedral model, we speculated that the steric
interaction between the allylic ester and the proximal
phenyl substituent of oxazoline (with (R,R)-11c as ex-
ample) would prefer the intermediate VI (with the Pd
atom situated in front of the olefinic double bond) to VII
(Scheme 3). From the favored transition state, the
cyclization would give the γ-butyrolactones in 3R con-
figuration. This speculation is in accord with those
observed experimentally.
Con clu sion
We developed a new type of carbocyclization of enyne
esters for the synthesis of γ-butyrolactones initiated by
acetoxypalladation under Pd(II) catalysis with high ef-
ficiency and stereoselectivity. The nitrogen-containing
ligands, e.g., bpy and phen, are crucial to realize the
cyclization and like halides, serve to favor â-heteroatom
elimination over â-hydride elimination. This important
finding is expected to have a broad impact on the studies
of Pd(II)-catalyzed reactions and lead to rational design
of efficient catalytic systems. In addition, employing
bisoxazoline (R,R)-11c or pymox (R)-13b as the ligands,
the catalytic asymmetric protocol was established with
high enantioselectivity (up to 92% ee). While the asym-
metric cyclization of enyne is usually catalyzed with
Pd(0) catalyst,5-7 this work is the first example of
realizing the efficient asymmetric synthesis of the opti-
cally active γ-butyrolactones from the cyclization of enyne
esters catalyzed by Pd(II) species.
(Z)-4′-Acetoxy-2′-bu ten yl 4-Meth oxy-2-bu tyn oa te (1e).
Oil: yield 90%. IR (neat) 2940, 2237, 1741, 1416, 1452, 1248,
1230. 1H NMR (300 MHz, CDCl3) δ 5.85-5.72 (m, 2H), 4.80
(d, J ) 5.6 Hz, 2H), 4.68 (d, J ) 5.5 Hz, 2H), 4.24 (s, 2H), 3.42
(s, 3H), 2.07 (s, 3H). MS (m/z) 227 (M+ + 1), 167, 113 (100),
97, 43. Anal. Calcd for C11H14O5 C, 58.40; H, 6.24. Found C,
58.61; H, 6.32.
(Z)-4′-Acet oxy-4′-p h en yl-2′-b u t en yl 2-Bu t yn oa t e (1f).
Oil: yield 62%. IR (neat) 3035, 2243, 1739, 1712, 1495, 1454,
1371, 1257, 1233 cm-1 1H NMR (300 MHz, CDCl3) δ 7.37-
.
7.26 (m, 5H), 6.52 (d, J ) 8.3 Hz, 1H), 5.86-5.72 (m, 2H),
4.98-4.85 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H). MS (m/z) 230
(M+ - CH2CO), 213, 146 (100), 128, 117, 67. Anal. Calcd for
C
16H16O4 C, 70.57; H, 5.92. Found C, 70.78; H, 6.20.
(Z)-4′-Acetoxy-1′-isopr opyl-2′-bu ten yl 2-Bu tyn oate (1g).26
Oil: yield 75%. 1H NMR (300 MHz, CDCl3) δ 5.81-5.72 (m,
(40) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals; Butterworth Heinemann: Oxford, 1996.
(41) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber.
1992, 125, 1169.
(42) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul M. M.
J . Am. Chem. Soc. 1991, 113, 726. (b) Corey, E. J .; Imai, N.; Zhang, H.
J . Am. Chem. Soc. 1991, 113, 728. (c) Mu¨ller, D.; Umbricht, G.; Weber,
B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232. (d) Brunner, H.;
Obermann, U. Chem. Ber. 1989, 122, 499. (e) Cheng, J .; Deming, T. J .
Macromolecules 1999, 32, 4745.
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR spectra were obtained at 300
MHz. Optical rotations were measured with a Perkin-Elmer
model 341 polarimeter. HPLC was conducted on a Waters 515
pump/2487 instrument. Flash chromatography was performed
(43) Horino, H.; Inoue, N. J . Org. Chem. 1981, 46, 4416.

Palladium(II)-Catalyzed Asymmetric Cyclization
J . Org. Chem., Vol. 66, No. 23, 2001 7683
1H), 5.57-5.49 (m, 1H), 5.29 (dd, J ) 9.5, 7.0 Hz, 1H), 4.77-
4.71 (m, 2H), 2.06 (s, 3H), 1.99 (s, 3H), 1.95-1.81 (m, 1H), 0.96
(d, J ) 6.7 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H).
1H), 6.17 (dd, J ) 15.8, 7.9 Hz, 1H), 4.45 (dd, J ) 9.1, 8.4 Hz,
1H), 4.08 (dd, J ) 9.1, 3.7 Hz, 1H), 3.95-3.89 (m, 1H), 2.26 (s,
3H), 2.03 (s, 3H). MS (m/z) 272 (M+), 230, 212 (100), 184,
141, 128, 43. HRMS Calcd for C16H16O4 272.1049, Found
272.1041.
r-(Z)-(1′-Acetoxyeth ylid en e)-cis-â-vin yl-γ-isop r op yl-γ-
bu tyr ola cton e (2 g). Oil: IR (neat) 2965, 1759, 1687, 1369,
1213, 1191, 1168, 1142, 1001 cm-1. 1H NMR (300 MHz, CDCl3)
δ 5.84-5.72 (m, 1H), 5.28-5.22 (m, 2H), 3.95 (dd, J ) 10.3,
5.9 Hz, 1H), 3.63-3.59 (m, 1H), 2.24 (s, 3H), 1.99 (s, 3H), 1.98-
1.78 (m, 1H), 1.07 (d, J ) 6.5 Hz, 3H), 0.91 (d, J ) 6.6 Hz,
3H). MS (m/z) 239 (M+ + 1), 197, 179, 155, 124, 95, 43(100).
Anal. Calcd for C13H18O4 C, 65.53; H, 7.61. Found C, 65.25; H,
7.71.
(Z)-4′-Acetoxy-1′-p en tyl-2′-bu ten yl 2-Bu tyn oa te (1h ).
Oil: yield 70%. IR (neat) 3030, 2958, 2935, 2243, 1743, 1710,
1
1255, 1232 cm-1. H NMR (300 MHz, CDCl3) δ 5.75-5.64 (m,
1H), 5.58-5.45 (m, 2H), 4.84-4.65 (m, 2H), 2.06 (s, 3H), 1.98
(s, 3H), 1.80-1.45 (m, 2H), 1.32-1.28 (m, 6H), 0.89 (t, J ) 6.7
Hz, 3H). MS (m/z) 223 (M+ - CH3CO), 207, 183, 140, 67 (100),
43. Anal. Calcd for C15H22O4 C, 67.64; H, 8.33. Found C, 67.84;
H, 8.42.
(Z)-4′-Acetoxy-2′-bu ten yl P r op iola te (1i). Oil: yield 82%.
IR (neat) 3261, 2956, 2122, 1739, 1718, 1450, 1378, 1222 cm-1
.
1H NMR (300 MHz, CDCl3) δ 5.87-5.73 (m, 2H), 4.81 (d, J )
6.0 Hz, 2H), 4.68 (d, J ) 5.6 Hz, 2H), 2.96 (s, 1H), 2.08 (s,
3H). MS (m/z) 183 (M+ + 1), 123, 113, 70, 53, 43 (100). Anal.
Calcd for C9H10O4 C, 59.74; H, 5.53. Found C, 59.35; H, 5.69.
Typ ica l P r oced u r e for th e Cycliza tion of (Z)-4′-Ac-
etoxy-2′-bu ten yl 2-Alk yn oa tes (1). Syn th esis of r-(Z)-(1′-
Acetoxyeth ylid en e)-â-vin yl-γ-bu tyr ola cton e (2a ). To a
solution of Pd(OAc)2 (6 mg, 0.027 mmol) and 2,2′-bipyridine
(5 mg, 0.032 mmol) in HOAc (2 mL) at 60 °C was added 1a
(98 mg, 0.5 mmol) with stirring. The reaction mixture was
monitored by TLC. After the reaction was complete, ethyl ether
(80 mL) was added. The mixture was washed with saturated
NaHCO3 solution (2 × 20 mL) and brine (20 mL). The ether
layer was dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was submitted to column chromatography on silica
gel (petroleum ether:ethyl acetate 4:1), affording pure 2a as
r-(Z)-(1′-Acetoxyeth ylid en e)-cis-â-vin yl-γ-p en tyl-γ-bu -
tyr ola cton e (2h ). Oil: IR (neat) 3084, 2956, 2935, 1760, 1688,
1637, 1213, 1170 cm-1 1H NMR (300 MHz, CDCl3) δ 5.83-
.
5.69 (m, 1H), 5.28-5.22 (m, 2H), 4.47-4.39 (m, 1H), 3.63 (t, J
) 7.4 Hz, 1H), 2.25 (s, 3H), 1.99 (s, 3H), 1.57-1.29 (m, 8H),
0.89 (t, J ) 6.7 Hz, 3H). MS (m/z) 266 (M+), 225 (100), 206,
181, 124, 43. Anal. Calcd for C15H22O4 C, 67.64; H, 8.33. Found
C, 67.99; H, 8.38.
Th e P r oced u r e for th e Cycliza tion of (Z)-4′-Acetoxy-
2′-bu ten yl 2-Bu tyn oa te (1a ) Em p loyin g Su bstitu ted P y-
r id in e or 2,2′-Bip yr id in e a s th e Liga n d s Wa s Sim ila r a s
Above in th e P r ep a r a tion of 2a .
(Z)-4′-Acetoxy-2′-bu ten yl (Z)-3-Acetoxy-2-bu ten oate (3).
Oil: IR (neat) 2958, 1768, 1743, 1729, 1674, 1441, 1370, 1276,
1231, 1175, 1140 cm-1 1H NMR (300 MHz, CDCl3) δ 5.75-
.
1
an oil: yield 87%. IR (neat) 1756, 1684, 1638, 1212, 1162. H
5.71 (m, 2H), 5.60 (s,1H), 4.68-4.64 (m, 4H), 2.22 (s, 3H), 2.05
(s, 3H), 2.01 (s, 3H). MS (m/z) 257 (M+ + 1), 215, 155, 139,
113, 85, 43 (100). HRMS Calcd for C12H16O6 256.0947, Found
256.0940.
NMR (300 MHz, CDCl3) δ 5.90-5.79 (m, 1H), 5.30-5.21 (m,
2H), 4.42 (dd, J ) 9.0, 8.3 Hz, 1H), 4.04 (dd, J ) 9.0, 3.5 Hz,
1H), 3.80-3.74 (m, 1H), 2.25 (s, 3H), 2.02 (d, J ) 1.2 Hz, 3H).
MS (m/z) 196 (M+), 155, 136, 111, 43 (100). Anal. Calcd for
Gen er a l P r oced u r e for th e Cou p lin g Rea ction s of
Meth yl 2-Bu tyn oa te w ith Allyl Com p ou n d s. To a solution
of Pd(OAc)2 (11 mg, 0.049 mmol) and 2,2′-bipyridine (9 mg,
0.058 mmol) in HOAc (5 mL) at room temperature was added
allyl compounds (4 mmol) and methyl 2-butynoate (98 mg, 1
mmol) with stirring. The reaction mixture was heated at 60
°C and monitored by TLC. After the reaction was complete,
ethyl ether (80 mL) was added. The mixture was washed with
saturated NaHCO3 solution (2 × 20 mL) and brine (20 mL).
The ether layer was dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was submitted to column chromatogra-
phy on silica gel (petroleum ether:ethyl acetate 10:1), affording
4 as the product as shown in Table 3.
C
10H12O4 C, 61.22; H, 6.16. Found C, 61.19; H, 6.11.
r-(Z)-(1′-Acet oxyb u t ylid en e)-â-vin yl-γ-b u t yr ola ct on e
(2b). Oil: yield 90%. IR (neat) 2967, 1759, 1675, 1637, 1368,
1
1208, 1156. H NMR (300 MHz, CDCl3) δ 5.89-5.81 (m, 1H),
5.28 (dt, J ) 17.0, 1.0 Hz, 1H), 5.22 (dt, J ) 10.0, 0.9 Hz, 1H),
4.42 (dd, J ) 9.0, 8.1 Hz, 1H), 4.05 (dd, J ) 9.0, 3.4 Hz, 1H),
3.82-3.75 (m, 1H), 2.31-2.26 (m, 5H), 1.60 (m, 2H), 0.95 (t, J
) 7.4 Hz, 3H). MS (m/z) 225 (M+ + 1), 183 (100), 164, 136.
Anal. Calcd for C12H16O4 C, 64.27; H, 7.19. Found C, 64.36; H,
7.33.
r-(Z)-(1′-Ace t oxy-1′-p h e n ylm e t h ylid e n e )-â-vin yl-γ-
bu tyr ola cton e (2c). White solid: mp 77-79 °C. IR (KBr)
1763, 1741, 1654, 1218, 1199. 1H NMR (300 MHz, CDCl3) δ
7.59-7.55 (m, 2H), 7.43-7.30 (m, 3H), 5.93-5.81 (m, 1H), 5.27
(dt, J ) 17.2, 0.7 Hz, 1H), 5.21 (dt, J ) 10.1, 1.0 Hz, 1H), 4.38
(dd, J ) 8.7, 7.3 Hz, 1H), 4.10 (dd, J ) 8.7, 2.6 Hz, 1H), 3.96-
3.90 (m, 1H), 2.35 (s, 3H). MS (m/z) 258 (M+), 216, 198, 111,
105 (100), 77, 43. Anal. Calcd for C15H14O4 C, 69.76; H, 5.46.
Found C, 69.42; H, 5.17.
Meth yl (Z)-3-Acetoxy-2-a llyl-2-bu ten oa te (4). Oil: IR
(neat) 3082, 3009, 1763, 1723, 1657, 1641, 1230, 1175 cm-1
.
1H NMR (300 MHz, CDCl3) δ 5.80-5.69 (m, 1H), 5.04 (dd, J
) 17.2, 1.6 Hz, 1H), 4.97 (dd, J ) 10.2, 1.6 Hz, 1H), 3.63 (s,
3H), 3.00 (d, J ) 6.2 Hz, 2H), 2.11 (s, 3H), 1.93 (s, 3H). MS
(m/z) 198 (M+), 156, 141, 124, 109, 96, 43 (100). HRMS Calcd
for C10H14O4 198.0892, Found 198.0887.
r-(Z)-(1′-Acetoxy-6′-m eth ylh ep tylid en e)-â-vin yl-γ-bu ty-
r ola cton e (2d ). Oil: yield 83%. IR (neat) 2957, 1761, 1723,
1675, 1368, 1226, 1209, 1157. 1H NMR (300 MHz, CDCl3) δ
5.93-5.81 (m, 1H), 5.28 (dt, J ) 17.0, 0.9 Hz, 1H), 5.22 (dd, J
) 10.0, 0.9 Hz, 1H), 4.42 (dd, J ) 9.0, 8.2 Hz, 1H), 4.04 (dd, J
) 9.0, 3.4 Hz, 1H), 3.81-3.75 (m, 1H), 2.30 (t, J ) 8.6 Hz,
2H), 2.27 (s, 3H), 1.55-1.47 (m, 3H), 1.34-1.14 (m, 4H), 0.87
(d, J ) 6.6 Hz, 6H). MS (m/z) 281 (M+ + 1), 239 (100), 220,
113, 43. Anal. Calcd for C16H24O4 C, 68.55; H, 8.63. Found C,
68.09, H, 8.66.
Gen er a l P r oced u r e for th e Rea ction s of Di-µ-a ceta to-
b is(2-a cet a m in op h en yl-2C,O)d ip a lla d iu m (II) (5) w it h
Allyl Aceta te. To a suspension of complex 5 (80 mg, 0.13
mmol) and ligand in HOAc (1 mL) was added allyl acetate (135
mg, 1.35 mmol). The mixture was stirred at room temperature
for 1.5 h. After separation of the palladium by filtration
through a short column of silica gel with the aid of ethyl
acetate, the filtrate was concentrated under vacuum and the
residue was submitted to column chromatography on silica gel
(petroleum ether:ethyl acetate 2:1) to afford products 6 and 7
as shown in Table 4.
r-(Z)-(1′-Ace t oxy-2′-m e t h oxye t h ylid e n e )-â-vin yl-γ-
bu t yr ola ct on e (2e). Oil: yield 83%. IR (neat) 1762, 1683,
N-[2-(3-Acetoxy-1-pr open yl)ph en yl]acetam ide (6). White
solid: mp 97-98 °C. IR (KBr) 3240, 1736, 1652, 1579, 1542,
1
1370, 1205, 1161, 1116. H NMR (300 MHz, CDCl3) δ 5.94-
5.83 (m, 1H), 5.28 (dd, J ) 17.0, 1.0 Hz, 1H), 5.25 (dd, J )
10.0, 1.0 Hz, 1H), 4.44 (td, J ) 8.4, 0.3 Hz, 1H), 4.14-4.01 (m,
3H), 3.95-3.89 (m, 1H), 3.37 (s, 3H), 2.30 (s, 3H). MS (m/z)
227 (M+ + 1), 185, 152, 139, 121, 43 (100). Anal. Calcd for
1455, 1301, 1239, 1025 cm-1 1H NMR (300 MHz, CDCl3) δ
.
7.64-7.07 (m, 5H), 6.66 (dd, J ) 15.8, 1.4 Hz, 1H), 6.11 (dt, J
) 15.8, 6.3 Hz, 1H), 4.65 (dd, J ) 6.3, 1.4 Hz, 2H), 2.11 (s,
3H), 2.03 (s, 3H). MS (m/z) 233 (M+), 191, 173, 130(100), 118,
77, 43. Anal. Calcd for C13H15NO3 C, 66.94; H, 6.48; N, 6.00.
Found C, 66.73; H, 6.45; N, 5.82.
C
11H14O5 C, 58.40; H, 6.24. Found C, 58.36; H, 6.32.
r-(Z)-(1′-Acetoxyeth ylid en e)-â-(E)-styr yl-γ-bu tyr ola c-
t on e (2f). Oil: IR(neat) 3028, 2974, 1756, 1682, 1600,
N-[2-(2-P r op en yl)p h en yl]a ceta m id e (7).44 White solid:
mp 87-89 °C. IR (KBr): 3286, 1657, 1587, 1536, 1482, 1371,
1578, 1494, 1479, 1450, 1370, 1210, 1162 cm-1
.
1H NMR
1
(300 MHz, CDCl3) δ 7.39-7.25 (m, 5H), 6.58 (d, J ) 15.8 Hz,
1298, 994, 970, 916, 753 cm-1. H NMR (300 MHz, CDCl3) δ

7684 J . Org. Chem., Vol. 66, No. 23, 2001
Zhang et al.
7.75 (d, J ) 8.0 Hz, 1H), 7.22-7.02 (m, 4H), 5.95-5.84 (m,
1H), 5.11 (dd, J ) 10.1, 1.4 Hz, 1H), 5.03 (dd, J ) 17.1, 1.6
Hz, 1H), 3.31 (dt, J ) 6.1, 1.6 Hz, 2H), 2.21 (s, 3H). MS (m/z)
176 (M+ + 1), 175 (M+), 160, 132 (100), 118, 91, 77.
Above in th e P r ep a r a tion of 2a . Enantiomers were sepa-
rated by HPLC using the chiralcel OJ column eluting with
hexane:2-propanol (8:2, v:v) (λ ) 214 nm).
16. Oil: IR(neat) 2916, 1752, 1724, 1660, 1644, 1433, 1373,
Gen er a l P r oced u r e for th e P a lla d iu m Ca ta lyzed Re-
a ction s of P h en ylm er cu r ic Aceta te w ith Allyl Aceta te.
To a mixture of phenylmercuric acetate (1.14 g, 3 mmol) and
ligand in HOAc (15 mL) was added allyl acetate (9 mmol) and
Pd(OAc)2 (34 mg, 5 mol %). After stirring at room temperature
(80 °C in the case of bpy as the ligand) for 24 h, the mixture
was poured into water (50 mL) and extracted with pentane
(200 mL). The organic layer was washed with saturated
NaHCO3 solution and brine and dried (Na2SO4). After remov-
ing the solvent, the residue was purified by column chroma-
tography on silica gel (pentane) to obtain products 8, 9, and
10 (pentane:ethyl acetate 19:1) as shown in Table 5.
Cin n a m yl Aceta te (8). 1H NMR (300 MHz, CDCl3) δ 7.43-
7.28 (m, 5H), 6.67 (d, J ) 15.8 Hz, 1H), 6.31 (dt, J ) 15.8, 6.4
Hz, 1H), 4.75 (d, J ) 6.4 Hz, 2H), 2.12 (s, 3H).
1226, 1193, 1170 cm-1 1H NMR (300 MHz, CDCl3) δ 5.68-
.
5.56 (m, 3H), 5.05 (dt, J ) 17.0, 1.0 Hz, 1H), 4.96 (d, J ) 10.4
Hz, 1H), 4.66-4.53 (m, 4H), 4.28 (dd, J ) 9.1, 7.5 Hz, 1H),
4.00 (dd, J ) 9.1, 2.8 Hz, 1H), 3.58 (m, 1H), 2.33 (s, 3H), 2.16
(s, 3H), 2.00 (s, 3H), 1.87 (s, 3H). MS (m/z) 393 (M+ + 1), 351,
291, 221, 113, 43(100). HRMS Calcd for C20H24O8 392.1472,
Found 392.1494.
Ack n ow led gm en t. The Major State Basic Research
Program (Grant No. G2000077502-A). We thank the
National Natural Sciences Foundation of China and
Chinese Academy of Sciences for the financial support.
We also thank Professor Xumu Zhang for providing
(S,R)-Indan-Ambox 15 and Professor Qilin Zhou for
providing Quinolinyl-oxazoline (S)-14.
Allylben zen e (9). 1H NMR (300 MHz, CDCl3) δ 7.38-7.33
(m, 2H), 7.29-7.24 (m, 3H), 6.10-5.97 (m, 1H), 5.17-5.11 (m,
2H), 3.45 (d, J ) 6.6 Hz, 2H).
Su p p or tin g In for m a tion Ava ila ble: 1HMR spectra for
2f, 3, 4, 16, and 17, and the NOE spectra for 4, 2a , 2g, and
2h . Spectroscopic and analytical data for 6-(1-methoxy-2,2′-
dimethylpropyl)-2,2′-bipyridine (entry 4 in Table 2). The
specific rotation of the optically active γ-butyrolactones 2.
Retention time for 2 in the HPLC analysis. Experimental
details for the synthesis of (3S)-(+)-A-factor. This material is
available free of charge via the Internet at http://pubs.acs.org.
(E)-1,3-Dip h en ylp r op en e (10). 1H NMR (300 MHz, CDCl3)
δ 7.58-7.26 (m, 10 H), 6.54 (d, J ) 15.8 Hz, 1H), 6.41 (dt, J )
15.8, 6.4 Hz, 1H), 3.60 (d, J ) 6.4 Hz, 2H).
Th e P r oced u r e for th e Asym m etr ic Cycliza tion of (Z)-
4′-Acetoxy-2′-bu ten yl 2-Alk yn oa tes (1) Wa s Sim ila r a s
(44) Ikeda, M.; Obata, K.; Oka, J .; Ishibashi, H.; Sato, T. Heterocycles
1997, 44, 203-212.
(45) Zhang, Y.-L.; Shing, T. K. M. J . Org. Chem. 1997, 62, 2622.
J O0105181