499
moiety occurred to yield 1,4-benzodioxene derivative 10,14
which is an important precursor of potential drug candidates
for asthma and arthritis therapy15 (Entry 3). The ¡-(2-propynyl)-
substituted amino acids such as Boc-¡-(2-propynyl)-L-glycine
11 and Boc-¡-(2-propynyl)-L-proline 13 underwent 5-exo cy-
clization to form 3-substituted-5-methylene-£-butyrolactone
1216 and 14, respectively (Entries 4 and 5). Di(2-propynyl)
substrate, 2-(methoxycarbonyl)-2-(2-propynyl)-4-pentynoic acid
(15) was cyclized to yield the corresponding acetylene lactone,
Table 1. Supramolecular xerogel 1-catalyzed cyclization reac-
tion of alkynoic acid derivativesa
Entry
Substrate
Product
Yield/%b(Time/h)
Ph
CH2 CH2 COOH
1
O
O
72 (6)
O
6
Ph
5
C5H11
CH2 COOH
2
>99c (3)
82 (10)
>99c (3)
C5H11
O
8
7
methyl
tetrahydro-5-methylene-2-oxo-3-(2-propynyl)furan-3-
O
O
carboxylate (16) along with a hydrolysis product of methyl
tetrahydro-5-methylene-2-oxo-3-(2-oxopropyl)furan-3-carboxyl-
ate (17) (Entry 6). Although notable chiral induction was not
observed in the reaction, we are currently studying the
application of the supramolecular gel catalysts to asymmetric
synthesis.
3
4
O
OH
9
10
Boc
O
Boc
N
N
COOH
H
H
O
1H NMR time-course-dependent analysis was performed on
the cyclization of 3 in order to compare the catalytic activity of
the xerogel of 1 with that of the parent complex of [PdCl(dpb)].
The catalytic activities were estimated by the initial NMR yield
of the cyclization product 4 from 0 to 0.5 h. The yield 4 of 88%
for the gel catalyst 1 and 55% for [PdCl(dpb)] indicated slightly
yet apparently enhanced activity of the supramolecular gel
catalysts. It can be attributed to the amphiphilicity of alkynoic
acid, which presumably facilitates substrate transportation from
the aqueous phase to the organic gel phase. Unfortunately, the
heterogeneous gel-phase reaction and the homogeneous solu-
tion-phase reaction could not be accurately compared. Because
this cyclization-addition reaction was quite sluggish under the
homogeneous conditions in aprotic solvents such as toluene,
THF, and CHCl3 in which the xerogel of 1 showed excellent
solubility, affording a solution of 1 instantly, the observed
solvent effect demonstrates that poor solvents for 1 are essential
for the success of the present reaction. Protonolysis would be
crucial to complete the catalytic cycle, and hence, the reaction
was accelerated in water (vide infra).
11
12
[α]2D5 = –4.3
(c 0.030, CHCl3)
[α]2D5 = +7.0
(c 0.11, CHCl3)
84 (3)
5
N
O
O
N
COOH
Boc
Boc
13
[α]2D5 = +5.8
(c 0.15, CHCl3)
14
[
α
]
25 = +1.6
D
(c 0.18, CHCl3)
O
O
O
O
O
O
O
OH
O
O
+
6
O
O
O
15
16
14 (6)
17
20 (6)
aReactions were carried out with substrate (0.5 mmol), xerogel
1 (0.5 mol % Pd content), and NEt3 (3 mol %) in H2O at 70 °C.
c
bIsolated yield. NMR yield.
shows the change in the xerogel catalyst 1 upon the occurrence
of the reaction. When substrate 3 was added to the xerogel
particle in D2O, the lemon yellow xerogel (Figure 1a) promptly
swelled through the absorption of 3 to afford an orange gel
(Figure 1b). Upon heating the reaction mixture, the correspond-
ing five-membered ring-cyclization product (E)-5-(2-deuterium-
methylene)-£-butyrolactone (4) was obtained in 82% yield. The
water-insoluble gel catalyst can be recovered by filtration and
reused at least three times, without significant loss of catalytic
activity; this catalyst afforded 4 in 69% and 70% yields when it
was reused the second and the third time, respectively. The
residual palladium catalyst in the product 4 was found to be very
low content (23 ppm), which was determined by ICP-MS
analysis. Table 1 summarizes the supramolecular gel-catalyzed
cyclization with various substrates. 5-Phenyl-4-pentynoic acid
(5), having an internal C-C triple bond also underwent 5-exo
cyclization to give (Z)-£-benzylidene-£-butyrolactone (6) ex-
clusively (Entry 1). The stereochemistry of 6 was confirmed by
1H NMR analysis in comparison with the literature data.12 In the
case of the cyclization of 3-alkynoic acid 7, 5-endo cyclization
proceeded to afford 5-n-pentyl-2,3-dihydro-2-furanone (8)13
with an excellent yield (Entry 2). Upon treatment of the 2-
propynyl ether of catechol 9 with the xerogel catalyst 1, 6-exo
cyclization of the phenolic hydroxy group onto the alkyne
The proposed catalytic cycle of the NCN-pincer Pd-
complex-bound norvaline-catalyzed cyclization of alkynoic
acids is illustrated in Figure 2. This reaction can be rationalized
by assuming the carbophilic Pd(II) cationic intermediate B,
which was formed via Cl ligand exchange on catalyst A by the
substrate alkyne. The intramolecular addition of carboxylate
oxygen to the activated C-C triple bond proceeded to afford the
vinyl Pd(II) species C. The observed 5-exo cyclization as shown
in Table 1 supports the formation of C. Subsequent protonolysis
of C in conjunction with ligand recombination afford the
cyclization product and the catalyst A to complete the catalytic
cycle. The formation of deuterio product in the cyclization of 4-
pentynoic acid definitely corroborates the proposed protonolysis
step. The Pd(II) catalytic cycle was confirmed by Pd K-edge
XANES spectra of gel catalyst 1.17,18 The spectra showed no
significant change between the states before and after the
cyclization of 4-pentynoic acid in water with the divalent
[PdCl(dpb)] complex.
In summary, the efficiency of an amino-acid-based supra-
molecular gel catalyst was shown by using NCN-pincer Pd-
complex-bound norvaline 1. The incorporated, highly assembled
Pd-complex array in the supramolecular gel of 1 catalyzed the
cyclization reaction of alkynoic acids to yield the corresponding
lactones. The robustness of the hydrogen-bonding-based supra-
Chem. Lett. 2012, 41, 498-500
© 2012 The Chemical Society of Japan
Ogata, Kazuki
