Angewandte
Chemie
in a biphasic system with 50 mL of water and 10 mL of ethyl
acetate, the lactone was not obtained even after a prolonged
reaction period (24 h, entry 4). Using the water-soluble ligand
4,[9] prepared by sulfonation of tri(o-tolyl)phosphine with
oleum, instead of tppts greatly enhanced the yield and
selectivity (2:3, entry 6). Obviously, ligand 4 can suppress
the isomerization of the p-allylpalladium intermediate, an
isomerization that results in the formation of the more stable
cis-configured nine-membered ring structure 3. The reaction
in THF also provided lactones 2 and 3, but yield and
selectivity were far less than those observed in the biphasic
system (entry 7).[10] Since we have recently reported that p-
allylpalladium species can be prepared from allylic alcohols in
an aqueous system,[11] we attempted the direct use of an allylic
alcohol as the substrate. Disappointingly, the desired lactone
was not obtained (entry 5).[12]
biphasic conditions with ligand 4. As shown in Scheme 3, the
substrate 11 that has a Z olefin moiety afforded the Z-
configured lactone 12 in excellent yield and with high
selectivity.
Scheme 3. Cyclization of a cis isomer in the biphasic system.
In conclusion, we have succeeded in synthesizing medium-
and large-sized lactones in high yields in an aqueous–ethyl
acetate biphasic system without the use of large amounts of
solvent. These lactones retain the original configuration of the
olefin moiety in their rings. We propose that the biphasic
cyclization protocol is a useful tool for the preparation of
medium- and large-sized ring compounds.
Under the optimized reaction conditions, we conducted
the synthesis of medium- and large-sized lactones with the
substrates that have longer methylene chains, 1c–f
(Scheme 2). These substrates afforded the desired lactones
Experimental Section
Representative standard procedure: [PdCl(h3-C3H5)]2 (4.6 mg,
0.0125 mmol) and 4 (67.5 mg, 0.11 mmol) were placed in a 20-mL
flask under an argon atmosphere. Degassed water (5 mL) was
introduced, and the mixture was stirred vigorously at 758C for
15 min. Na2CO3 (127.2 mg, 1.2 mmol) and ethyl acetate (3 mL) were
added to the homogeneous clear yellow solution at room temper-
ature. A solution of 1c (128.1 mg, 0.5 mmol) in ethyl acetate (2 mL)
was added to the ethyl acetate phase. After stirring for 12 h, the
mixture was extracted with ethyl acetate. The organic extracts were
dried and concentrated. Purification of the residual oil afforded 3-
acetyl-3,4,7,8,9,10-hexahydrooxecin-2-one (5, 85.7 mg, 0.44 mmol) in
87% yield.
Received: November 20, 2004
Published online: March 16, 2005
Scheme 2. Synthesis of medium- and large-sized lactones in the bipha-
sic system. The product formed by 1b (n=3) is shown in Table 1.
Keywords: allylation · biphasic catalysis · lactones · palladium ·
solvent effects
.
in high yields without any byproducts, as in the case with 1b,
R = OAc. In contrast, the reaction of 1e in N,N-dimethyl-
formamide (DMF, 0.05m) provided the 12-membered lactone
7 in only 28% yield. Formation of the 13-membered lactone
from 1 f proceeded slowly to provide the product 8 in 17%
yield (with 51% recovered starting material) under the
biphasic conditions at room temperature for 12 h. However,
the yield of 8 was improved to 57% when an elevated reaction
temperature was used (608C for 12 h), although the stereo-
selectivity was decreased (E/Z = 3:1). Substrate 1a afforded
only 9 in 51% yield by 6-exo cyclization. The eight-membered
lactone 10 was not detected.
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To elucidate the configuration of the olefin moiety in the
lactones, we conducted methanolysis of the products. The
configuration of the double bond was assigned as E in all cases
1
on the basis of H NMR spectroscopy analysis and compar-
ison with authentic samples. Interestingly, the configuration
of the substrates is retained in the products under the aqueous
Angew. Chem. Int. Ed. 2005, 44, 2397 –2400
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