Radical Cyclization in Heterocycle Synthesis. 11. A Novel Synthesis of α,β-Disubstituted γ-Lactones via Sulfanyl Radical Addition-Cyclization Using Hydroximates as a Tether

Article abstract of DOI:10.1021/jo000472w

A combination of sulfanyl radical addition-cyclization of dienes connected with hydroximates and subsequent conversion of the resulting cyclic hydroximate to the lactones provides a novel method for the construction of α,β-disubstituted γ-lactones. Upon treatment with thiophenol in the presence of AIBN, dienes connected with hydroximates smoothly underwent sulfanyl radical addition-cyclization to give cyclic cis- and trans-hydroximates. Hydrolysis of cyclic hydroximates gave the desired cis- and trans-lactones in high yield. This method was successfully applied to the practical synthesis of (±)-oxo-parabenzlactone.

Full text of DOI:10.1021/jo000472w

6922
J . Org. Chem. 2000, 65, 6922-6931
Ra d ica l Cycliza tion in Heter ocycle Syn th esis. 11.1 A Novel
Syn th esis of r,â-Disu bstitu ted γ-La cton es via Su lfa n yl Ra d ica l
Ad d ition -Cycliza tion Usin g Hyd r oxim a tes a s a Teth er
Okiko Miyata,† Atsuko Nishiguchi,† Ichiya Ninomiya,† Keiichi Aoe,‡ Kimio Okamura,‡ and
Takeaki Naito*,†
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, J apan, and Analytical
Research Laboratory, Tanabe Seiyaku, Co. Ltd., Kashima, Yodogawa, Osaka 532-0031, J apan
taknaito@kobepharma-u.ac.jp
Received March 28, 2000
A combination of sulfanyl radical addition-cyclization of dienes connected with hydroximates and
subsequent conversion of the resulting cyclic hydroximate to the lactones provides a novel method
for the construction of R,â-disubstituted γ-lactones. Upon treatment with thiophenol in the presence
of AIBN, dienes connected with hydroximates smoothly underwent sulfanyl radical addition-
cyclization to give cyclic cis- and trans-hydroximates. Hydrolysis of cyclic hydroximates gave the
desired cis- and trans-lactones in high yield. This method was successfully applied to the practical
synthesis of (()-oxo-parabenzlactone.
In tr od u ction
based on sulfanyl radical addition-cyclization, which
proceeds by the formation of a carbon-centered radical
species generated by the addition of a sulfanyl radical to
a multiple bond and then intramolecular addition of the
resulting carbon-centered radical to a multiple bond.3 The
synthetic potentiality was demonstrated by the syntheses
of anantine,3a,g oxo-parabenzlactone,3d R-kainic acid,3e,f
and cispentacin.3h
Free radical reactions are of paramount importance in
organic synthesis.2 In particular, free-radical-mediated
cyclization has developed as a potential method for
preparing various types of cyclic compounds via intramo-
lecular carbon-carbon bond-forming processes. Most of
the radical cyclizations are carried out using tributyltin
hydride. However, because of the toxicity of tributyltin
hydride, an area of continuing and important research
is to develop new methods of radical generation that
avoid the use of this reagent. We have recently explored
a new efficient carbon-carbon bond-forming reaction
We disclose herein the full details of the sulfanyl
radical addition-cyclization3c of dienes connected with
hydroximates, which are indispensable in cyclization and
lactone synthesis, and application of this method to
synthesis of a lignan of dibenzylbutyrolactone type, (()-
oxo-parabenzlactone.3d The lactone structures not only
are found in many biologically active compounds4 but also
are known to be important intermediates for the synthe-
sis of stereo-defined acyclic and other natural products.
Among many known methods, construction of γ-lactones
* Tel: +81(78)-441-7554. Fax: +81(78)-441-7556.
† Kobe Pharmaceutical University.
‡ Tanabe Seiyaku, Co. Ltd.
(1) Part 10: Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetra-
hedron 2000, 56, 6199-6207.
(2) For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Baldwin, J . E., Ed.; Pergamon
Press: Oxford, 1986. (b) Ramaiah, M. Tetrahedron 1987, 43, 3541-
3676. (c) Curran, D. P. Synthesis 1988, 417-439 and 489-513. (d)
J asperse, C. P.; Curran, D. P.; Fervig, T. Chem. Rev. 1991, 1237-1286.
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B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach, F. Organic
Reactions; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1996;
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1996, 96, 177-194. (h) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997,
53, 17543-17594. (i) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2562-2579. (j) Chatgilialoglu, C.; Bertrand, M. P.;
Ferreri, C. The Chemistry of Free Radicals: S-Centered Radicals;
Alfassi, Z. B., Ed.; J ohn Wiley & Sons: Chichester, 1999; pp 311-
348. (k) Naito, T. Heterocycles 1999, 50, 505-541. (l) Bowman, W. R.;
Bridge, C. F.; Brookes, P. J . Chem. Soc., Perkin Trans. 1 2000, 1-14.
(3) (a) Naito, T.; Honda, Y.; Miyata, O.; Ninomiya, I. Chem. Pharm.
Bull. 1993, 41, 217-219. (b) Naito, T.; Honda, Y.; Miyata, O.;
Ninomiya, I. J . Chem. Soc., Perkin Trans. 1 1995, 19-26. (c) Miyata,
O.; Nishiguchi, A.; Ninomiya, I.; Naito, T.; Aoe, K.; Okamura, K.
Tetrahedron Lett. 1996, 37, 229-232. (d) Miyata, O.; Nishiguchi, A.;
Ninomiya, I.; Naito, T. Chem. Pharm. Bull. 1996, 44, 1285-1287. (e)
Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Synlett 1997, 275-276.
(f) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Aoe, K.; Hiramatsu, H.; Naito,
T. Heterocycles 1997, 46, 321-333. (g) Naito, T.; Honda, Y.; Bhavakul,
V.; Yamaguchi, S.; Fujiwara, A.; Miyata, O.; Ninomiya, I. Chem.
Pharm. Bull. 1997, 45, 1932-1939. (h) Miyata, O.; Muroya, K.; Koide,
J .; Naito, T. Synlett 1998, 275-276. (i) Miyabe, H.; Tanaka, H.; Naito,
T. Tetrahedron Lett. 1999, 40, 8387-8390.
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Whiting, D. A. Nat. Prod. Rep. 1987, 499-525. (d) Ward, R. S. Nat.
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Pure Appl. Chem. 1988, 60, 1659-1668. (c) Belletire, J . L.; Mahmoodi,
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H.; Moustrou, C.; Surzur, J .-M. P. J . Org. Chem. 1989, 54, 5689-5688.
(e) Lee, E.; Ko, S. B.; J ung, K. W. Tetrahedron Lett. 1989, 30, 827-
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1989, 30, 7469-7472. (g) Barth, F.; Yang, C. Tetrahedron Lett. 1990,
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10.1021/jo000472w CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/15/2000

Radical Cyclization in Heterocycle Synthesis. 11.
J . Org. Chem., Vol. 65, No. 21, 2000 6923
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. Allyla tion of Hyd r oxa m a te 6a
reagent
addi-
tive
sol-
temp time yield
ratio
1 by formation of the CR-Câ bond has recently drawn
the attention of synthetic chemists.
entry
11
vent
(°C) (h) (%) Z-8a :E-9a :10a
1
2
3
4
5
X ) Br
X ) OTs K2CO3 Me2CO
X ) Br
X ) OTs K2CO3 DMF
X ) Br AgNO3 Et2O
K2CO3 Me2CO
rt
rt
60
60
rt
24
24
2
2
24
86
59
98
87
28
1:---:2.7
1:---:0.8
1:---:1.2
1:---:0.4
1:7.6:2
Radical cyclization methodology has been explored in
this field.5 The use of halogeno or dienyl esters 2 or 3 as
precursors for the preparation of functionalized lactones
seems to be a promising route (Scheme 1). However, the
desired lactones 1 are obtained in low yield because the
cyclization of the R-carbonyl radical takes place slowly.
This is partially because ester 3 exists primarily in an
s-trans conformer 3A, while the cyclization process
requires an s-cis conformer 3B (Scheme 2).5j Therefore,
Stork6b and Ueno6a have developed an indirect bromo-
acetal method for the preparation of lactones (4 f 1).
Expecting that, contrary to the esters, the Z-O-alkyl-
hydroximates 5 would exist in conformer 5B, preferable
for intramolecular cyclization over the less favored
conformer 5A as a result of the steric repulsion between
the substituents on nitrogen and oxygen atoms in the
conformer 5A, we started systematic study of sulfanyl
radical addition-cyclization of the hydroximates 5.
K2CO3 DMF
Then, we investigated the allylation of 6a as shown in
Table 1. Alkylation of 6a with allyl bromide in the
presence of potassium carbonate gave a 1:2.7 mixture of
the Z-hydroximate 8a and the amide 10a in 86% com-
bined yield (entry 1). On alkylation using allyl tosylate,
a mixture of 8a and 10a was obtained in lower yield and
with a ratio of 1:0.8 (entry 2). When DMF and allyl
tosylate were used as the solvent and reagent, respec-
tively, the desired Z-hydroximate 8a was obtained as the
major product (entry 4). Interestingly, reaction of 6a with
allyl bromide in the presence of silver nitrate afforded
the E-hydroximate 9a as the major product but in low
yield (entry 5).7 According to route B, chlorination of
hydroxamate 6a with phosphorus pentachloride followed
by treatment of the resulting imidoyl chloride 7a with
sodium allylate gave the Z-hydroximate 8a as the sole
product in 76% yield. The E/Z-geometries of hydroxi-
Resu lts a n d Discu ssion
P r ep a r a tion a n d Su lfa n yl Ra d ica l Ad d ition -Cy-
cliza tion of Hyd r oxim a tes. To investigate the general-
ity of the sulfanyl radical addition-cyclization, we chose
the Z- and E-cinnamylhydroximate 8a and 9a as the
substrate (Scheme 3). According to the known procedure,7
8a and 9a were prepared via two different routes (routes
A and B). Acylation of methoxyamine with cinnamoyl
chloride gave the hydroxamate 6a in a quantitative yield.
1
mates 9a and 8a were determined by H NMR spectros-
copy (Figure 1).7 The 1H NMR spectra of the Z- and
E-isomers are known to differ mainly in the chemical
shifts of the methylene hydrogens (Ha and Hb) attached
to the nitrogen and oxygen atoms of these molecules. It
is known7 that the hydroximates 12 exhibiting signals
for the hydrogen Ha and Hb at lower field have Z-
(6) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J . Am. Chem. Soc. 1982, 104, 5564-5566. (b) Stork, G.; Mook, R., J r.;
Biller, S. A.; Rychnovsky, S. D. J . Am. Chem. Soc. 1983, 105, 3741-
3742. (c) Fukuzawa, S.; Tsuchimoto, T. Synlett 1993, 803-804.
(7) (a) J ohnson, J . E.; Springfield, J . R.; Hwang, J . S.; Hayes, L. J .;
Cunningham, W. C.; McClaugherty, D. L. J . Org. Chem. 1971, 36, 284-
294. (b) J ohnson, J . E.; Ghafouripour, A.; Haug, Y. K.; Cordes, A. W.;
Pennington, W. T. J . Org. Chem. 1985, 50, 993-997. (c) J ohnson, J .
E.; Nalley, E. A.; Kunz, Y. K.; Springfield, J . R. J . Org. Chem. 1976,
41, 252-259.
F igu r e 1. Z/E-Hydroximates.

6924 J . Org. Chem., Vol. 65, No. 21, 2000
Miyata et al.
Ta ble 2. 1H NMR Da ta of 8a a n d 9a
Sch em e 4
δ (ppm)
8a
9a
3.83 (s)
4.62 (dt, 5.5, 1.5)
7.09 (d, 16.5)
7.26 (d, 16.5)
OMe
1′-H2
2-H
3.89 (s)
4.76 (dt, 6, 1)
6.50 (d, 16)
7.13 (d, 16)
3-H
Sch em e 5
F igu r e 2. Crystal structure of 13a .
geometries, while the hydroximates 12 showing those at
higher field have E-geometries (Figure 1). Signals due
to methoxy and allylic hydrogens of Z-isomer 8a (OMe:
δ 3.89, 1′-H2: δ 4.76) appeared downfield compared with
those of E-isomer 9a (OMe: δ 3.83, 1′-H2: δ 4.62) (Table
2).
Next, we investigated the sulfanyl radical addition-
cyclization of Z- and E-hydroximates 8a and 9a (Table
3). A solution containing thiophenol and AIBN in benzene
was added dropwise (5 mL/h) to a solution of Z-8a in
boiling benzene with stirring under nitrogen. The solu-
tion was then refluxed for further 2 h and concentrated
to give a 1.8:1 mixture of cyclized cis- and trans-products
13a and 14a in 82% combined yield, both of which
possess a phenylsulfanylmethyl group at the 4-position
(entry 1). When triethylborane was used as a radical
initiator, yield of cyclized product 13a and 14a decreased
(entries 2 and 3).3i
On the other hand, the sulfanyl radical addition-
cyclization of E-hydroximate 9a gave only adduct 16 in
3% yield, with no formation of the cyclized product 17.
To compare the reactivity of Z-hydroximate 8a with that
of the corresponding ester 18, we investigated sulfanyl
radical addition-cyclization of ester 18. However, under
the same reaction conditions, 18 did not give the cyclized
product 19 and the substrate 18 was mostly recovered
(Scheme 4).
The stereostructures of cyclized products cis-13a and
trans-14a were firmly established by single-crystal X-ray
analysis of cis-13a (Figure 2) and irreversible isomeriza-
tion of cis-hydroximate 13a to trans-isomer 14a by
treatment with sodium ethoxide (Scheme 5). Previously,
Ikeda8 and we3b have reported that, upon treatment with
sodium ethoxide in ethanol, cis-3,4-dimethylpyrrolidin-
2-ones were readily isomerized into the correponding
stable trans-isomers. When the cyclic hydroximate 14a
was treated with sodium ethoxide in refluxing ethanol,
it was recovered unchanged, while the cyclic hydroximate
13a was converted into a 1:2 mixture of the two cyclic
hydroximates 13a and 14a .
The sulfanyl radical addition-cyclization of cinnamyl-
hydroximate can be summarized as follows. (a) The
sulfanyl radical prefers to attack the allyl group. (b) The
radical cyclization takes place exclusively in a 5-exo-trig-
manner. (c) The cis-hydroximate 13a is formed in prefer-
ence to the trans-isomer 14a . Beckwith9a,b has explained
that the preferential formation of the cis-product from
the 1-substituted hexenyl radical is ascribed to the effects
of orbital symmetry. (d) The corresponding E-isomer 9a
and ester 18 did not give the cyclized products. We
propose a plausible explanation for the non-cyclization
of 9a and 18 as follows. The E-isomer 9 would exist in a
stable conformer 9C, which is unfavorable for intramo-
lecular cyclization. Another conformer 9B is favorable for
cyclization but has steric repulsion between the methoxy
group and olefinic hydrogen. Furthermore, the zigzag
conformation of 9A has also steric repusion between the
methoxy group and olefinic hydrogen. On the other hand,
Z-isomer 8a would exist in a conformer 8B, which is
preferable for the intramolecular cyclization to the less
favored conformer 8A as a result of steric repulsion
between the substituents on the nitrogen and oxygen
atoms in the conformer 8A (Scheme 6). Examination of
molecular models of the ground state provides some
indication of the different reactivity between Z-8a and
E-9a . The PM3-optimized ground state conformations 8C
and 9D (R ) H), which correspond to Z-8a and E-9a , are
shown in Scheme 6.9c The PM3-optimized conformation
8C (R ) H) of Z-8a would be favorable for cyclization
while the PM3-optimized conformation 9D (R ) H) of in
E-9a would be unfavorable for intramolecular cyclization.
Scop e a n d Lim ita tion s. To establish the generality
of the sulfanyl radical addition-cyclization, we also
investigated the reactions of the Z-hydroximates 8b-d
(9) (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073-3100. (b)
Curran, D. P.; Poter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines and Synthetic Application; VCH:
Weinheim, 1995. (c) Optimized ground state conformations were
calculated with a semiempirical MOPAC method utilizing a PM3
Hamiltonian and CAChe system (SONY Tektronix).
(8) Sato, T.; Wada, Y.; Nishimoto, M.; Ishibashi, H.; Ikeda, M. J .
Chem. Soc., Perkin Trans. 1 1989, 879-886.

Radical Cyclization in Heterocycle Synthesis. 11.
J . Org. Chem., Vol. 65, No. 21, 2000 6925
Ta ble 3. Su lfa n yl Ra d ica l Ad d ition -Cycliza tion of Z-8a
entry
solvent
radical initiator
temp (°C)
yield (%)
cis-13a :trans-14a :15
1
2
3
benzene
toluene
toluene
AIBN (method A)
Et3B (method B)
Et3B (method B)
80
rt
60
82
30
47
1.8:1:---
2.4:1:1
1.8:1:0.9
Sch em e 6
Ta ble 4. Su lfa n yl Ra d ica l Ad d ition -Cycliza tion of 8b-d
and 14c in slightly better yield (entry 2). The cyclization
of hydroximate 8d having an ethoxycarbonyl group also
afforded the cyclized products 13d and 14d (entry 3).
Absence of the substituents at the â-position in the
unsaturated hydroximates 20a -e influenced markedly
the regioselectivity of the addition of the phenylsulfanyl
radical, resulting in the exclusive formation of the
3-phenylsulfanylmethyl products cis-21a -e and trans-
22a -e as shown in Table 5. The sulfanyl radical addi-
tion-cyclization of hydroximates 20a -d having phenyl,
dimethyl, and ethoxycarbonyl groups gave a mixture of
cis-21a -d and trans-22a -d . In the case of hydroximate
20e with no substituent at the terminal olefins, the
sulfanyl radical attacked the olefin to give cis-21e and
trans-22e. These results suggest that the dienes con-
nected with Z-hydroximates undergo a smooth 5-exo-trig
type of radical cyclization though its regiochemistry
depends on the substituents attached to the dienes.
yield
(%)
ratio
cis-13:trans-14
entry substrate
R1
Me
Ph
COOEt
R2
R3
1
2
3
8b
8c
8d
Me Me
H
H
80
94
78
1.7:1.0
1.8:1.0
0.8:1.0
Bn
Bn
and 20a -e, which were prepared from the corresponding
hydroxamates via route A. The results of the sulfanyl
radical addition-cyclization of Z-hydroximates 8b-d
with substituents at the â-position of the unsaturated
hydroximate group are summarized in Table 4. Sulfanyl
radical addition-cyclization of hydroximate 8b having
a dimethyl group proceeded smoothly to give a 1.7:1.0
mixture of cis-13b and trans-14b in 80% combined yield
(entry 1). The hydroximate 8c, including a benzyloxy
group on the nitrogen atom, gave cyclized products 13c
Next, we also investigated the reactions of the ω-al-
kenylhydroximates 23a -c with a longer carbon chain
(Table 6). However, 23a -c underwent no cyclization, and
instead, addition of thiophenol to the allyl group and
partial isomerization of the oxime ether group took place
to give adducts 25b,c and E-hydroximates 24a -c both
in low yields, along with recovered Z-hydroximates
(entries 1-3).

6926 J . Org. Chem., Vol. 65, No. 21, 2000
Miyata et al.
Ta ble 5. Su lfa n yl Ra d ica l Ad d ition -Cycliza tion of
20a -e
Ta ble 7. Con ver sion of Hyd r oxim a tes in to La cton es
u n d er Acid ic a n d Ba sic Con d ition s
yield (%)
entry substrate method
conditions
(CH2O)n,
Amberlyst 15
acetone/H2O (10:1)
80 °C, 24 h
cis-26 trans-27
1
2
cis-13a
A
50
---
---
60
trans-14a
yield
(%)
3
4
cis-13a
trans-14a
B
C
10% HCl/THF
rt, 0.5 h
93
--
--
95
entry
substrate
R1
Ph
Me
Me
COOEt
H
R2
cis-21:trans-22
1
2
3
4
5
20a
20b
20c
20d
20e
H
H
Me
H
H
78
56
58
49
31
1.7:1.0
1.4:1.0
1.1:1.0
1.3:1.0
1.5:1.0
5
6
cis-13a
trans-14a
10% KOH/MeOH
50 °C, 8 h
--
--
--
79
[bis(trifluoroacetoxy)iodo]benzene (BTIB) (Table 8). Treat-
ment of cis-13a with 1 equiv of HTIB gave cis-sulfinyl-
lactone 28 and cis-sulfinylhydroximate 30 in 47% and
52% yield, respectively (entry 1). Under the same condi-
tions, 30 was converted into 28 in good yield. When 3
equiv of HTIB was used, cis-28 was obtained in 79% yield
as the sole product (entry 3). Similarly, trans-sulfinyl-
lactone 29 was obtained from trans-14a in 77% yield
(entry 4). Although oxidation of cis-13a with BTIB gave
cis-30, lactone 28 could not be detected in the reaction
mixture (entry 5). Thus, we succeed in a generation of
the lactones from the corresponding cyclic hydroximates
under both hydrolytic and oxidative conditions. The
sulfoxides 28-31 were obtained as 1:1 diastereomeric
mixture based on the phenylsulfinyl group.
Syn th esis of (()-Oxo-p a r a ben zla cton e. We then
applied this methodology to the synthesis of (()-oxo-
parabenzlactone 40 (Scheme 7). (+)-Oxo-parabenzlac-
tone11 was recently isolated from the wood of Protium
tenuifolium (Burseraceae). Previously, the enantiomer of
40 was obtained as an oxidation product of a lignan, (-)-
parabenzlactone, which had been isolated from Paraben-
zoin trilobum Nakai.12 The lignans of the dibenzylbu-
tyrolactone type exhibit various biological activities such
as antitumor and platelet-activating factor (PAF) an-
tagonistic activities in addition to inhibitory effects on
microsomal monooxygenase in insects.4 Sulfanyl radical
addition-cyclization of the allyl hydroximate 33, pre-
pared from the hydroxamate 32, in the presence of
thiophenol (1 equiv) and AIBN (0.5 equiv) proceeded
smoothly to give a ca. 1:2 mixture of the cyclic products
34 and 35 in 73% combined yield, which was readily
separated. The unstable cis-35 was readily isomerized
into the trans-34 upon treatment with sodium ethoxide
in ethanol. Hydrolytic conversion of the cyclic hydroxi-
mate 34 into the lactone 36 was readily achieved in 96%
yield by treatment with 10% HCl in methanol. Oxidation
of the trans-sulfide 36 with m-chloroperbenzoic acid
(mCPBA) at 0 °C gave the corresponding sulfoxide 37 in
81% yield. However, oxidative conversion of the cyclic
hydroximate 34 into the desired sulfinyl lactone 37
proceeded ineffectively to give the lactone 37 in only 19%
yield under the conditions using HTIB as an oxidant.
Ta ble 6. Rea ction of 23a -c w ith Th iop h en ol
yield (%)
entry
substrate
n
24
25
1
2
3
23a
23b
23c
1
2
3
24
37
15
---
3
5
Con ver sion of Cyclic Hyd r oxim a tes to La cton es.
We next investigated conversion of the cyclic hydroxi-
mates to the lactones. To our knowledge, there are few
examples of the transformation of the hydroximates to
the esters or lactones, though several groups reported
both the conversion10a of the imidates into the esters or
lactones and the regeneration10b-f of the carbonyl com-
pounds from the oximes, oxime ethers, and hydrazones.10
To convert cyclic hydroximates into the lactones, we
investigated four different sets of conditions (methods
A-D) as shown in Tables 7 and 8. The results employing
hydrolysis are summarized in Table 7. The cis-hydroxi-
mate 13a was treated with Amberlyst 15 in the presence
of paraformaldehyde at 80 °C for 24 h to give the cis-
lactone 26 in 50% yield (entry 1). Similarly, trans-14a
was converted into trans-lactone 27 (entry 2). Reaction
of cis-13a and trans-14a with hydrochloric acid proceeded
smoothly even at room temperature and for a short time
to afford 26 and 27 in excellent yield, respectively (entries
3 and 4). Hydrolysis of trans-14a under the basic condi-
tions (10% NaOH/MeOH) gave the desired lactone 27 in
79% yield (entry 6), while cis-13a gave not the lactone
26 but a complex mixture under the same conditions
(entry 5).
We next examined the oxidative method (method D)
using commercially available hypervalent organoiodo
reagents, [hydroxy(tosyloxy)iodo]benzene (HTIB) and
(10) (a) Perrin, C. L. The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; J ohn Wiley and Sons: Chichester, 1991; Vol.
2, pp 147-229. (b) Corey, E. J .; Pynes, G. Tetrahedron Lett. 1983, 24,
2821-2824. (c) Ballini, R.; Petrini, M. J . Chem. Soc., Perkin Trans. 1
1988, 2563-2565. (d) Sakamoto, T.; Kikugawa, Y. Synthesis 1993,
563-564. (e) Moriarty, R. M.; Varid, R. K.; Koser, G. F. Synlett 1990,
365-383. (f) Barton, D. H.; J aszberenyi, J . Cs.; Shinada, T. Tetrahedron
Lett. 1993, 34, 7191-7194.
(11) Siqueira, J . B. G.; Zoghbi, M. d. G. B.; Cabral, J . A.; Filho, W.
W. J . Nat. Prod. 1995, 58, 730-732.
(12) (a) Wada, K.; Munakata, K. Tetrahedron Lett. 1970, 2017-2019.
(b) Niwa, M.; Iguchi, M.; Yamamura, S.; Nishibe, S. Bull. Chem. Soc.
J pn. 1976, 49, 3359-3360.

Radical Cyclization in Heterocycle Synthesis. 11.
J . Org. Chem., Vol. 65, No. 21, 2000 6927
Ta ble 8. Con ver sion of Hyd r oxim a tes in to La cton es u n d er Oxid a tive Con d ition s
yield (%)
entry
substrate
conditions
cis-28
trans-29
cis-30
trans-31
1
2
3
4
5
cis-13a
trans-14a
cis-13a
trans-14a
cis-13a
1 equiv PhI(OH)OTs, 0 °C
1 equiv PhI(OH)OTs, 0 °C
3 equiv PhI(OH)OTs, 0 °C
3 equiv PhI(OH)OTs, 0 °C
3 equiv PhI(OCOCF3)2, 0 °C
47
---
79
---
---
---
48
---
77
---
52
---
---
---
80
---
38
---
---
---
the hydroxamate 6. The compound 6a had the following
properties. The properties for compounds 6b-e are provided
in the Supporting Information.
Introduction of an aryl group into the 1′′-position in 37
was readily achieved according to a conventional route
involving Pummerer rearrangement and subsequent
Grignard reaction. The trans-sulfoxide 37 was subjected
to the Pummerer reaction and subsequent hydrolysis to
obtain the desired trans-aldehyde 38 in 84% yield.
Treatment of the aldehyde 38 with a Grignard reagent
gave a diastereomeric mixture of the adducts 39, which
without separation was converted into the ketone 40 (mp.
138-139 °C (lit.11 (+)-40 105-106 °C) by oxidation with
pyridinium chlorochromate (PCC) in 45% yield. The
ketone 40 obtained was identical with oxo-patabenzlac-
tone11 upon comparison of the spectral data with those
of the authentic sample.
(E)-N-Meth oxy-3-ph en yl-2-pr open am ide (6a): 23 g (yield
87%) from cinnamoyl chloride (25 g); colorless crystals; mp 93-
95 °C; IR (CHCl3) 3449 (NH), 1686 (CON) cm-1; 1H NMR (200
MHz, CDCl3) δ 8.65 (1H, br s), 7.76 (1H, d, J ) 16 Hz), 7.60-
7.28 (5H, m), 6.49 (1H, d, J ) 16 Hz), 3.85 (3H, s); HRMS (EI,
m/z) calcd for C10H11NO2 (M+) 177.0791, found 177.0766. Anal.
Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.91. Found: C,
67.75; H, 6.26; N, 7.78.
P r ep a r a tion of Hyd r oxim a te 8a -d , 20a -e, a n d 23a -
c. Rou te A (Ta ble 1, en tr ies 1 a n d 2). To a solution of 6a
(1.77 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in acetone (50
mL) was added dropwise a solution of either allyl bromide (1.21
g, 10 mmol) or allyl tosylate13 (1.98 g, 10 mmol) in acetone (5
mL) under a nitrogen atmosphere at room temperature. After
being stirred at room temperature for 24 h, the reaction
mixture was diluted with H2O and extracted with CH2Cl2. The
organic phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (hexane/AcOEt
3:1) afforded 8a (521 mg, 23% in entry 1) (716 mg, 33% in entry
2) and 10a (1.35 g, 63% in entry 1) (564 mg, 26% in entry 2).
Rou te A (Ta ble 1, en tr ies 3 a n d 4). To a solution of 6a
(35 mg, 0.2 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (2
mL) was added a solution of either allyl bromide (24 mg, 0.4
mmol) or allyl tosylate (79 mg, 0.4 mmol) in DMF (0.2 mL)
under a nitrogen atmosphere at 60 °C. After being stirred at
the same temperature for 2 h, the reaction mixture was diluted
with H2O and extracted with CH2Cl2. The organic phase was
washed with H2O, dried over Na2SO4, and concentrated at
reduced pressure. Purification of the residue by medium-
pressure column chromatography (hexane/AcOEt 3:1) afforded
8a (20 mg, 45% in entry 3) (27 mg, 62% in entry 4) and 10a
(23 mg, 53% in entry 3) (11 mg, 25% in entry 4). 8b-d and
20a -e were prepared by the same procedure.
Rou te A (Ta ble 1, en tr y 5). According to the literature
procedure,7a to a solution of 6a (1.77 g, 10 mmol) in 95% EtOH
(7.1 mL) and 29% NH3 (0.65 mL) was added a solution of
AgNO3 (1.8 g, 10 mmol) in H2O (2.5 mL) under a nitrogen
atmosphere at room temperature. The precipitated silver salt
was separated from the solution by filtration, washed with
acetone, and dried. To a suspension of the silver salt in Et2O
(3 mL) was added a solution of allyl bromide (6.0 mmol) in
Et2O (0.3 mL) under a nitrogen atmosphere at room temper-
ature. After being stirred at the same temperature for 24 h,
the reaction mixture was filtered to remove AgBr. The filtrate
was concentrated at reduced pressure and the residue was
purified by medium-pressure column chromatography (hexane/
AcOEt 3:1) to afford 8a (59 mg, 2.7%), 9a (434 mg, 20%), and
10a (118 mg, 5.3%).
Con clu sion
We have developed for the first time radical cyclization
of the dienes connected with the hydroximates. The
feasibility of sulfanyl radical addition-cyclization is
dependent upon the structure of substrates. The radical
cyclization of Z-hydroximates proceeded smoothly to give
the cyclized product in good yield, while the correspond-
ing E-isomer did not undergo the radical cyclization. The
newly found radical cyclization of the hydroximates
provides a novel method for the construction of the
substituted lactones, which were effectively derived by
either hydrolysis or oxidation. This method was success-
fully applied to the practical synthesis of (()-oxo-
patabenzlactone.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded at 200, 300, or 500 MHz and at 50 MHz,
respectively. IR spectra were recorded using FTIR apparatus.
Mass spectra were obtained by EI method. Flash column
chromatography was preformed using E. Merck Kieselgel 60
(230-400 mesh). Medium-pressure column chromatography
was performed using Lober Gro¨sse B (E. Merck 310-25,
Lichroprep Si60).
P r ep a r a tion of th e Hyd r oxa m a tes 6a -b. To a stirred
solution of the corresponding acid chloride (0.15 mol) in CH2-
Cl2 (600 mL) was added N-methoxyamine hydrochloride (13.8
g, 0.165 mol) under a nitrogen atmosphere at room tempera-
ture. After the solution was stirred at the same temperature
for 15 min, pyridine (28 mL, 0.351 mol) was added dropwise
to the reaction mixture at 0 °C. After being stirred at room
temperature for 2 h, the reaction mixture was diluted with
CH2Cl2 and washed with water. The organic phase was dried
over Na2SO4 and concentrated at reduced pressure. Purifica-
tion of the residue by recrystallization (hexane/CHCl3) afforded
Rou te B. To a solution of 6a (87 mg, 0.5 mmol) in benzene
(1 mL) was added phosphorus pentachloride (156 mg, 0.75
(13) Fo¨ldi, Z. Chem. Ber. 1920, 53, 1836-1839.

6928 J . Org. Chem., Vol. 65, No. 21, 2000
Miyata et al.
(hexane/CH2Cl2 1:1) afforded 8a (82 mg, 76%) as colorless oil.
23a -c were prepared by the same procedure.
Sch em e 7
The compound 8a , 9a , and 10a had the following properties.
The properties for compounds 8b-d , 20a -e, and 23a -c are
provided in the Supporting Information.
2-P r op en yl (Z,E)-N-m et h oxy-3-p h en yl-2-p r op en im i-
d a te (8a ): colorless oil; IR (CHCl3) 1634 (CdN) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.52-7.24 (5H, m), 7.13 (1H, d, J ) 16
Hz), 6.50 (1H, d, J ) 16 Hz), 6.04 (1H, ddt, J ) 17, 10, 6 Hz),
5.40 (1H, dq, J ) 17, 1 Hz), 5.28 (1H, dq, J ) 10, 1 Hz), 4.76
(2H, dt, J ) 6, 1 Hz), 3.89 (3H, s); 13H NMR (CDCl3) δ 154.7,
135.6, 134.7, 133.1, 128.7, 128.5, 126.9, 118.8, 118.1, 72.2, 62.1;
HRMS (EI, m/z) calcd for C13H15NO2 (M+) 217.1104, found
217.1100.
2-P r op en yl (E,E)-N-m et h oxy-3-p h en yl-2-p r op en im i-
d a te (9a ): colorless oil; IR (CHCl3) 1636 (CdN) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.54-7.29 (5H, m), 7.26 (1H, d, J ) 16.5
Hz), 7.09 (1H, d, J ) 16.5 Hz), 6.09 (1H, ddt, J ) 17, 10.5, 5.5
Hz), 5.41 (1H, dq, J ) 17, 1.5 Hz), 5.27 (1H, dq, J ) 10.5, 1.5
Hz), 4.62 (2H, dt, J ) 5.5, 1.5 Hz), 3.83 (3H, s). NOE was
observed between the methoxyl group (δ 3.83) and 2-H (δ 7.09)
in NOESY spectroscopy. 13H NMR (CDCl3) δ 158.5, 136.3,
135.7, 133.1, 129.0, 128.5, 127.5, 117.4, 111.6, 67.2, 61.8;
HRMS (EI, m/z) calcd for C13H15NO2 (M+) 217.1104, found
217.1100.
(E )-N -Me t h oxy-3-p h e n yl-N -(2-p r op e n yl)-2-p r op e n -
1
a m id e (10a ): colorless oil; IR (CHCl3) 1651 (CON) cm-1; H
NMR (200 MHz, CDCl3) δ 7.77 (1H, d, J ) 16 Hz), 7.62-7.26
(5H, m), 7.04 (1H, d, J ) 16 Hz), 5.93 (1H, ddt, J ) 16, 10, 6
Hz), 5.30 (1H, dq, J ) 16, 1 Hz), 5.24 (1H, dq, J ) 10, 1 Hz),
4.36 (2H, dt, J ) 6, 1 Hz), 3.78 (3H, s); HRMS (EI, m/z) calcd
for C13H15NO2 (M+) 217.1104, found 217.1105.
Gen er a l P r oced u r e for Ra d ica l Cycliza tion . Meth od
A. To a boiling solution of the hydroximate 8a (109 mg, 0.5
mmol) in benzene (5 mL) under nitrogen atmosphere was
added (5 mL/h) by a syringe pump over 2 h a solution
containing thiophenol (0.05 mL, 0.5 mmol) and AIBN (41 mg,
0.25 mmol) in benzene (10 mL). After the reaction mixture
was heated at reflux for a further 2 h, the solvent was
evaporated at reduced pressure. Purification of the residue by
medium-pressure column chromatography (hexane/AcOEt 3:1)
afforded the cis-13a (173 mg, 53%) and trans-14a (95 mg, 29%)
as shown in Table 3. 8b-d , 20a -e, and 23a -c underwent
the radical reaction by the same procedure.
Meth od B. To a solution of the hydroximate 8a (109 mg,
0.5 mmol) and thiophenol (0.06 mL, 0.6 mmol) in toluene (4
mL) was added Et3B (1.0 M in hexane) (0.1 mL, 0.1 mmol)
under nitrogen atmosphere at either room temperature or 60
°C. After being stirred at the same temperature for 2 h, the
reaction mixture was neutralized with 5% KOH and extracted
with AcOEt. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated at reduced pressure. Purifica-
tion of the residue by medium-pressure column chromatogra-
phy (hexane/AcOEt 3:1) afforded the cis-13a (26.8 mg, 16.4%
in entry 2) (37.4 mg, 22.9% in entry 3), trans-14a (11 mg, 6.8%
in entry 2) (20.8 mg, 12.7% in entry 3), and 15 (11 mg, 6.8%
in entry 2) (18.5 mg, 11.4% in entry 3) as shown in Table 3.
The compounds 13a , 14a , and 15 had the following proper-
ties. The properties for compounds 13b-d , 14b-d , 21a -e,
22a -e, 24a -c, and 25b,c are provided in the Supporting
Information.
[Z(cis)]-N-[Tet r a h yd r o-3-p h en ylm et h yl-4-(p h en ylsu l-
fa n yl)-m et h ylfu r a n -2-ylid en e]-O-m et h ylh yd r oxya m in e
(13a ): colorless crystals, mp 103-105 °C (hexanes/Et2O); IR
(CHCl3) 1672 (CdN) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.36-
6.86 (10H, m), 4.51 (1H, dd, J ) 9.5, 1.5 Hz), 4.16 (1H, ddd, J
) 9.5, 5, 1.5 Hz), 3.83 (3H, s), 3.39 (1H, ddd, J ) 12, 7.5, 5
Hz), 3.28 (1H, dd, J ) 15, 5 Hz), 3.21 (1H, ddd, J ) 13.5, 3.5,
1.5 Hz), 2.72 (1H, dd, J ) 15, 12 Hz), 2.60 (1H, dd, J ) 13.5,
12 Hz), 2.44 (1H, m); 13H NMR (CDCl3) δ 158.6, 138.0, 134.3,
128.7, 128.5, 128.2, 126.3, 125.7, 72.9, 62.0, 43.0, 38.3, 31.3,
29.8; HRMS (EI, m/z) calcd for C19H21NO2S (M+) 327.1294,
found 327.1303. Crystal data of 13a : C19H21NO2S, space group
Pbca with a ) 18.131(3), b ) 26.611 (2), c ) 14.575 (1) Å, V )
7032.4 (1.5) Å3, final R value 0.060 for 5980 reflections.
mmol) by small portions under a nitrogen atmosphere at 0 °C.
After being stirred at the same temperature for 2 h, H2O was
added to the reaction mixture. The resulting solution was
extracted with CH2Cl2, and the organic phase was washed with
H2O, dried over Na2SO4, and concentrated at reduced pressure
to afford the crude hydroximoyl chloride 7a . After being
characterized by NMR spectra, 7a was immediately subjected
to the following reaction. To a suspension of NaH (60% oil
suspension) (100 mg, 2.5 mmol) in THF was added allyl alcohol
(145 mg, 2.5 mmol) under a nitrogen atmosphere at 0 °C. After
being stirred at room temperature for 20 min, a solution of
the crude hydroximoyl chloride in THF (5 mL) was added at
reflux. The reaction mixture was heated at reflux for a further
2 h, then cooled at 0 °C, diluted with H2O, and extracted with
CH2Cl2. The organic phase was washed with H2O, dried over
Na2SO4, and concentrated at reduced pressure. Purification
of the residue by medium-pressure column chromatography

Radical Cyclization in Heterocycle Synthesis. 11.
J . Org. Chem., Vol. 65, No. 21, 2000 6929
[Z(tr a n s)]-N-[Tet r a h yd r o-3-p h en ylm et h yl-4-(p h en yl-
s u lfa n y l)m e t h y lfu r a n -2-y lid e n e ]-O -m e t h y lh y d r o x y -
Na2SO4, and concentrated at reduced pressure. Purification
of the residue by medium-pressure column chromatography
(AcOEt) afforded 28 (15 mg, 47%) and 30 (19 mg, 52%) or 29
(15 mg, 48%) and 31 (13 mg, 38%).
(Ta ble 8, en tr ies 3 a n d 4). To a solution of 13a or 14a (33
mg, 0.1 mmol) in CH2Cl2 (10 mL) was added HTIB (118 mg,
0.3 mmol) under a nitrogen atmosphere at 0 °C. After being
stirred at the same temperature for 4 h, the reaction mixture
was diluted with H2O and extracted with CH2Cl2. The organic
phase was washed with H2O, dried over Na2SO4, and concen-
trated at reduced pressure. Purification of the residue by
medium-pressure column chromatography (AcOEt) afforded
28 (25 mg, 79%) or 29 (24 mg, 77%).
1
a m in e (14a ): colorless oil; IR (CHCl3) 1670 (CdN) cm-1; H
NMR (500 MHz, CDCl3) δ 7.30-7.06 (10H, m), 4.32 (1H, dd,
J ) 9.5, 7 Hz), 4.07 (1H, dd, J ) 9.5, 6 Hz), 3.84 (3H, s), 3.15
(1H, dd, J ) 14, 5 Hz), 2.96 (1H, ddd, J ) 10, 6, 4 Hz), 2.71
(2H, m), 2.59 (1H, dd, J ) 14, 9.5 Hz), 2.36 (1H, m); 13H NMR
(CDCl3) δ 159.6, 137.6, 134.2, 129.7, 128.7, 128.6, 128.2, 126.4,
126.2, 74.0, 61.8, 45.2, 40.6, 37.3, 36.0; HRMS (EI, m/z) calcd
for C19H21NO2S (M+) 327.1294, found 327.1295.
3-(P h en ylsu lfa n yl)p r op yl (Z,E)-N-Meth oxy-3-p h en yl-
2-p r op en im id a te (15): colorless oil; IR (CHCl3) 1637 (CdN)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.50-7.15 (10H, m), 7.09
(1H, d, J ) 16 Hz), 6.48 (1H, d, J ) 16 Hz), 4.37 (2H, t, J ) 6
Hz), 3.86 (3H, s), 3.13 (2H, t, J ) 7 Hz), 2.08 (2H, tt, J ) 7, 6
Hz); HRMS (EI, m/z) calcd for C19H21NO2S (M+) 327.1294,
found 327.1314.
cis-Dih ydr o-3-ph en ylm eth yl-4-(ph en ylsu lfan yl)m eth yl-
2(3H)-fu r a n on e (26): colorless crystals, mp 116-117 °C
1
(Et2O); IR (CHCl3) 1773 (lactone) cm-1; H NMR (200 MHz,
CDCl3) δ 7.40-6.90 (10H, m), 4.47 (1H, dd, J ) 9, 1 Hz), 4.19
3-(P h en ylsu lfa n yl)p r op yl (E,E)-N-Meth oxy-3-p h en yl-
2-p r op en im id a te (16). 9a (109 mg, 0.5 mmol) was subjected
to sulfanyl radical addition-cyclization using thiophenol (0.05
mL, 0.5 mmol) and AIBN (41 mg, 0.25 mmol) to afford the
adduct 16 (10 mg, 3%) as colorless oil: IR (CHCl3) 1637 (Cd
(1H, dd, J ) 9, 5 Hz), 3.36 (1H, dd, J ) 15, 5 Hz), 3.27-3.10
(2H, m), 2.75 (1H, dd, J ) 15, 12 Hz), 2.64-2.48 (2H, m); 13
H
NMR (CDCl3) δ 177.2, 137.8, 134.2, 128.9, 128.7, 128.6, 128.1,
126.6, 126.0, 69.5, 43.9, 37.3, 30.8, 30.7; HRMS (EI, m/z) calcd
for C18H18O2S (M+) 298.1027, found 298.1027. Anal. Calcd for
N) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.55-7.15 (10H, m),
C18H18O2S: C, 72.45; H, 6.08; S, 10.74. Found: C, 72.19; H,
6.09; S, 10.87.
7.20 (1H, d, J ) 16.5 Hz), 7.05 (1H, d, J ) 16.5 Hz), 4.20 (2H,
t, J ) 6 Hz), 3.81 (3H, s), 3.10 (2H, t, J ) 7 Hz), 2.10 (2H, tt,
J ) 7, 6 Hz); HRMS (EI, m/z) calcd for C19H21NO2S (M+)
327.1294, found 327.1304.
t r a n s-Dih yd r o-3-p h e n ylm e t h yl-4-(p h e n ylsu lfa n yl)-
m eth yl-2(3H)-fu r a n on e (27): colorless oil; IR (CHCl3) 1771
(lactone) cm-1; 1H NMR (200 MHz, CDCl3) δ 7.35-7.05 (10H,
m), 4.29 (1H, dd, J ) 9.5, 7.5 Hz), 3.91 (1H, dd, J ) 9.5, 7.5
Hz), 3.18 (1H, dd, J ) 13.5, 4.5 Hz), 2.90-2.40 (5H, m); 13H
NMR (CDCl3) δ 177.6, 137.3, 134.2, 130.1, 128.9, 128.6, 126.8,
126.7, 70.4, 46.0, 39.3, 36.4, 35.1; HRMS (EI, m/z) calcd for
Isom er iza t ion of Tw o Cyclic H yd r oxim a t es cis-13a
a n d tr a n s-14a . According to the literature procedure,3b,8
sodium (19.1 mg, 0.675 mmol) was dissolved in anhydrous
ethanol (30 mL), and an aliquot of the resulting solution (1
mL) was diluted to 2 mL by the addition of further ethanol (1
mL). To this solution was added cis-13a (10 mg, 0.03 mmol).
The resulting solution was refluxed for 2.5 h, then diluted with
aqueous ammonium chloride, and finally extracted with CH2-
Cl2. The organic phase was washed with H2O, dried over Na2-
SO4, and concentrated at reduced pressure. The1H NMR
spectrum of the residue showed that the product consisted of
a 1:2 mixture of the cis-13a and trans-14a . Under the same
conditions, the trans-14a was recovered quantitatively.
Con ver sion of th e Cyclic Hyd r oxim a tes in to La cton es.
Meth od A. (Ta ble 7, en tr ies 1 a n d 2). To a stirred solution
of the cyclic hydroximate 13a or 14a (17 mg, 0.05 mmol) in
acetone (4.5 mL) and H2O (0.5 mL) was added paraformalde-
hyde (15 mg) and Amberlyst 15E (10 mg) under a nitrogen
atmosphere at room temperature. After the solution was
stirred at 80 °C for 24 h, the reaction mixture was filtered to
remove Amberlyst 15E. The filtrate was diluted with CH2Cl2
and washed with water. The organic phase was dried over Na2-
SO4 and concentrated at reduced pressure. Purification of the
residue by medium-pressure column chromatography (hexane/
AcOEt 3:1) afforded 26 (8 mg, 50%) or 27 (12 mg, 60%).
Meth od B. (Ta ble 7, en tr ies 3 a n d 4). A solution of 13a
or 14a (33 mg, 0.1 mmol) in concentrated HCl (1.5 mL) and
THF (3.5 mL) was stirred at room temperature for 30 min,
and H2O was added to the reaction mixture. The resulting
solution was extracted with CH2Cl2, and the organic phase was
washed with H2O, dried over Na2SO4, and concentrated at
reduced pressure. Purification of the residue by medium-
pressure column chromatography (hexane/AcOEt 3:1) afforded
26 (28 mg, 93%) or 27 (28.3 mg, 95%).
Meth od C. (Ta ble 7, en tr ies 5 a n d 6). A solution of 14a
(33 mg, 0.1 mmol) in a methanolic solution of KOH (10%, 5
mL) was stirred at 50 °C for 8 h. The reaction mixture was
made acidic with 5% HCl and then extracted with CH2Cl2. The
organic phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (hexane/AcOEt
3:1) afforded 27 (24 mg, 79%).
Meth od D. (Ta ble 8, en tr ies 1 a n d 2). To a solution of
13a or 14a (33 mg, 0.1 mmol) in CH2Cl2 (10 mL) was added
HTIB (118 mg, 0.1 mmol) under a nitrogen atmosphere at 0
°C. After being stirred at the same temperature for 4 h, the
reaction mixture was diluted with H2O and extracted with
CH2Cl2. The organic phase was washed with H2O, dried over
C
18H18O2S (M+) 298.1027, found 298.1035.
cis-Dih yd r o-3-p h en ylm eth yl-4-(p h en ylsu lfin yl)m eth yl-
2(3H)-fu r a n on e (28): the sulfoxide 28 was obtained as a 1:1
diastereomeric mixture based on the phenylsulfinyl group,
which was separated by medium-pressure column chromatog-
raphy (AcOEt).
Less p ola r isom er : colorless oil; IR (CHCl3) 1776 (lactone)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.54-7.05 (10H, m), 4.61
(1H, dd, J ) 10, 1.5 Hz), 4.23 (1H, dd, J ) 10, 5.5 Hz), 3.18
(1H, dd, J ) 15, 4.5 Hz), 3.13-2.96 (2H, m), 2.92-2.74 (2H,
m), 2.60 (1H, dd, J ) 15, 9.5 Hz); HRMS (EI, m/z) calcd for
C
18H18O3S (M+) 314.0976, found 314.0980.
P ola r isom er : colorless oil; IR (CHCl3) 1777 (lactone) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.55-7.15 (10H, m), 4.32 (1H,
dd, J ) 9, 3 Hz), 4.23 (1H, dd, J ) 9, 5.5 Hz), 3.28-2.98 (3H,
m), 2.93-2.78 (2H, m), 2.73 (1H, dd, J ) 14.5, 9 Hz); HRMS
(EI, m/z) calcd for C18H18O3S (M+) 314.0976, found 314.0982.
t r a n s-Dih yd r o-3-p h e n ylm e t h yl-4-(p h e n ylsu lfin yl)-
m eth yl-2(3H)-fu r a n on e (29): the sulfoxide 29 was obtained
as a 1:1 diastereomeric mixture based on the phenylsulfinyl
group, which was separated by medium-pressure column
chromatography (AcOEt).
Less p ola r isom er : colorless oil; IR (CHCl3) 1771 (lactone)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.54-7.15 (10H, m), 4.21
(1H, dd, J ) 9.5, 7.5 Hz), 3.89 (1H, dd, J ) 9.5, 8.5 Hz), 3.29
(1H, dd, J ) 14, 4.5 Hz), 2.86 (1H, dd, J ) 14, 9 Hz), 2.84 (1H,
m), 2.67 (1H, m), 2.65 (1H, dd, J ) 13, 9 Hz), 2.45 (1H, dd, J
) 13, 4 Hz); HRMS (EI, m/z) calcd for C18H18O3S (M+)
314.0976, found 314.0983.
P ola r isom er : colorless oil; IR (CHCl3) 1772 (lactone) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.58-7.17 (10H, m), 4.56 (1H,
dd, J ) 10, 7 Hz), 4.09 (1H, br dd, J ) 10, 8.5 Hz), 3.18 (1H,
m), 2.81 (1H, dd, J ) 13.5, 10 Hz), 2.73-2.52 (3H, m), 2.40
(1H, dd, J ) 13.5, 3 Hz); HRMS (EI, m/z) calcd for C18H18O3S
(M+) 314.0976, found 314.0981.
[Z(cis)]-N-[Tetr a h yd r o-3-p h en ylm eth yl-4-(p h en ylsu lfi-
n yl)m e t h yl-fu r a n -2-ylid e n e ]-O-m e t h ylh yd r oxya m in e
(30): the sulfoxide 30 was obtained as a 1:1 diastereomeric
mixture based on the phenylsulfinyl group, which was sepa-
rated by medium-pressure column chromatography (AcOEt).
Less p ola r isom er : colorless oil; IR (CHCl3) 1673 (CdN)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.60-7.18 (10H, m), 4.60
(1H, br d, J ) 9.5 Hz), 4.33 (1H, dd, J ) 9.5, 4 Hz), 3.79 (3H,
s), 3.30 (1H, m), 3.11 (1H, dd, J ) 15, 5.5 Hz), 2.90-2.76 (3H,

6930 J . Org. Chem., Vol. 65, No. 21, 2000
Miyata et al.
m), 2.57 (1H, dd, J ) 15, 10 Hz); HRMS (EI, m/z) calcd for
cyclization of the hydroximate 33 (131 mg, 0.5 mmol) using
thiophenol (0.05 mL, 0.5 mmol) and AIBN (41 mg, 0.25 mmol)
followed by purification of the crude product by medium-
pressure column chromatography (hexane/AcOEt 10:1) af-
forded cis-35 (92 mg, 49%) as colorless crystals and trans-34
(44 mg, 24%) as colorless oil.
C
19H21NO3S (M+) 343.1241, found 343.1226.
P ola r isom er : colorless oil; IR (CHCl3) 1674 (CdN) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.54-7.14 (10H, m), 4.30 (1H,
dm, J ) 9 Hz), 4.21 (1H, dm, J ) 9 Hz), 3.78 (3H, s), 3.33 (1H,
m), 3.14 (1H, br dd, J ) 15, 5 Hz), 2.96-2.79 (3H, m), 2.69
(1H, dd, J ) 15, 10 Hz); HRMS (EI, m/z) calcd for C19H21NO3S
(M+) 343.1241, found 343.1228.
[Z(cis)]-N-[3-[(1,3-Ben zod ioxol-5-yl)m eth yl]tetr a h yd r o-
4-(p h en ylsu lfa n yl)m et h ylfu r a n -2-ylid en e]-O-m et h ylh y-
d r oxya m in e (35): mp 112-114 °C (Et2O); IR (CHCl3) 1671
(CdN) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.18-6.97 (5H, m),
6.77 (1H, d, J ) 8 Hz), 6.73 (1H, d, J ) 1.5 Hz), 6.69 (1H, dd,
J ) 8, 1.5 Hz), 5.97 (2H, m), 4.50 (1H, dd, J ) 9.5, 2 Hz), 4.17
(1H, ddd, J ) 9.5, 5, 1.5 Hz), 3.82 (3H, s), 3.29 (1H, ddd, J )
11, 6.5, 5.5 Hz), 3.20 (1H, ddd, J ) 13.5, 3.5, 1.5 Hz), 3.17
(1H, dd, J ) 15, 5.5 Hz), 2.64 (1H, dd, J ) 15, 11 Hz), 2.61
(1H, dd, J ) 13.5, 12 Hz), 2.46 (1H, m); 13H NMR (CDCl3) δ
158.6, 147.7, 146.1, 134.4, 131.8, 128.7, 128.6, 121.3, 108.6,
108.2, 100.8, 73.0, 62.1, 43.2, 38.5, 31.1, 30.1; HRMS (EI, m/z)
calcd for C20H21NO4S (M+) 371.1191, found 371.1190. Anal.
Calcd for C20H21NO4S: C, 64.67; H, 5.70; N, 3.77; S, 8.63.
Found: C, 64.63; H, 5.55; N, 3.74; S, 8.80.
[Z(tr a n s)]-N-[Tet r a h yd r o-3-p h en ylm et h yl-4-(p h en yl-
su lfin yl)m e t h yl-fu r a n -2-ylid e n e ]-O-m e t h ylh yd r oxy-
a m in e (31): the sulfoxide 31 was obtained as a 1:1 diastereo-
meric mixture based on the phenylsulfinyl group, which was
separated by medium-pressure column chromatography (AcO-
Et).
Less p ola r isom er : colorless oil; IR (CHCl3) 1671 (CdN)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.55-7.15 (10H, m), 4.42
(1H, dd, J ) 9.5, 7.5 Hz), 3.93 (1H, dd, J ) 9.5, 7 Hz), 3.84
(3H, s), 3.27 (1H, dd, J ) 13.5, 4 Hz), 2.98-2.49 (4H, m), 2.30
(1H, dd, J ) 13.5, 4.5 Hz); HRMS (EI, m/z) calcd for C19H21
-
NO3S (M+) 343.1241, found 343.1221.
P ola r isom er : colorless oil; IR (CHCl3) 1672 (CdN) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.55-6.99 (10H, m), 4.56 (1H,
dd, J ) 9.5, 7 Hz), 4.13 (1H, dd, J ) 9.5, 7 Hz), 3.82 (3H, s),
3.17 (1H, dd, J ) 13.5, 4.5 Hz), 2.94-2.31 (5H, m); HRMS (EI,
m/z) calcd for C19H21NO3S (M+) 343.1241, found 343.1223.
(E )-3-(1,3-B e n zo d io x o l-5-y l)-N -m e t h o x y -2-p r o p e n -
a m id e (32). According to the procedure described in the
preparation of 6a , acylation of methoxyamine hydrochloride
(9.2 g, 0.11 mol) with 3,4-methylenedioxycinnamoyl chloride
(21 g, 0.1 mol) gave the hydroxamate 32 (9.2 g, 96%) as
colorless crystals: mp 145-147 °C (hexane/CHCl3); IR (CHCl3)
[Z(tr a n s)]-N-[3-[(1,3-Ben zod ioxol-5-yl)m eth yl]tetr a h y-
d r o-4-(p h en ylsu lfa n yl)m eth ylfu r a n -2-ylid en e]-O-m eth yl-
h yd r oxya m in e (34): IR (CHCl3) 1670 (CdN) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.27-7.12 (5H, m), 6.69 (1H, d, J ) 8 Hz),
6.66 (1H, d, J ) 1.5 Hz), 6.56 (1H, dd, J ) 8, 1.5 Hz), 5.95
(2H, m), 4.34 (1H, dd, J ) 9.5, 7 Hz), 4.07 (1H, dd, J ) 9.5, 6
Hz), 3.83 (3H, s), 3.05 (1H, dd, J ) 14, 4.5 Hz), 2.90 (1H, ddd,
J ) 9.5, 6, 4.5 Hz), 2.78 (1H, dd, J ) 13.5, 5.5 Hz), 2.65 (1H,
dd, J ) 14, 9.5 Hz), 2.62 (1H, dd, J ) 13.5, 9.5 Hz), 2.36 (1H,
m); 13H NMR (CDCl3) δ 159.8, 147.6, 146.2, 134.3, 131.4, 130.0,
128.8, 126.5, 121.9, 109.2, 108.1, 100.7, 74.3, 62.1, 45.5, 40.7,
37.3, 36.3; HRMS (EI, m/z) calcd for C20H21NO4S (M+) 371.1191,
found 371.1176.
Isom er iza tion of cis-35 to tr a n s-34. According to the
procedure described in the isomerization of cis-13a , a solution
of cis-35 (37 mg, 0.1 mmol) and NaOEt (153 mg, 2.25 mmol)
in EtOH (10 mL) was refluxed for 10 h. After usual workup,
crude product was purified by medium-pressure column chro-
matography (hexane/AcOEt 10:1) to afford trans-34 (27 mg,
73%) as colorless oil, which was identical with trans-34
obtained by the radical cyclization of 33.
tr a n s-3-[(1,3-Ben zodioxol-5-yl)m eth yl]dih ydr o-4-(ph en -
ylsu lfa n yl)-m eth yl-2(3H)-fu r a n on e (36). A solution of 34
(501 mg, 1.35 mmol) in concentrated HCl (19 mL) and MeOH
(49 mL) was stirred at room temperature for 1 h, and H2O
was added to the reaction mixture. The resulting solution was
extracted with CH2Cl2, and the organic phase was washed with
H2O, dried over Na2SO4, and concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography (hexane/AcOEt 3:1) afforded the lactone 36 (443
mg, 96%) as colorless oil: IR (CHCl3) 1770 (lactone) cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.36-7.16 (5H, m), 6.70 (1H, d, J )
8 Hz), 6.62 (1H, d, J ) 1.5 Hz), 6.53 (1H, dd, J ) 8, 1.5 Hz,
ArH), 5.95 (2H, m), 4.31 (1H, dd, J ) 9.5, 7.5 Hz), 3.92 (1H,
dd, J ) 9.5, 8 Hz), 3.13-2.38 (6H, m); 13H NMR (CDCl3) δ
177.6, 147.8, 146.4, 134.3, 130.9, 130.3, 129.0, 126.9, 122.1,
109.3, 108.3, 100.9, 70.6, 46.3, 39.3, 36.6, 34.9; HRMS (EI, m/z)
calcd for C19H18O4S (M+) 342.0919, found 342.0913.
tr a n s-3-[(1,3-Ben zodioxol-5-yl)m eth yl]dih ydr o-4-(ph en -
ylsu lfin yl)-m eth yl-2(3H)-fu r a n on e (37). By Oxid a tion of
36. To a solution of the lactone 36 (443 mg, 1.3 mmol) in CH2-
Cl2 (50 mL) was added dropwise a solution mCPBA (70%
assay) (319 mg, 1.3 mmol) in CH2Cl2 (50 mL) under a nitrogen
atmosphere at 0 °C. The reaction mixture was made alkaline
with saturated aqueous NaHCO3 and then extracted with CH2-
Cl2. The organic phase was washed with H2O, dried over Na2-
SO4, and concentrated at reduced pressure. Purification of the
residue by medium-pressure column chromatography (hexane/
AcOEt 1:1) afforded the sulfoxide 37 (376 mg, 81%) as a 1:1
diastereomeric mixture based on a sulfinyl group, which was
separated by medium-pressure column chromatography (AcO-
Et).
1
3392 (NH), 1676 (CON) cm-1; H NMR (200 MHz, CDCl3) δ
8.55 (1H, br s), 7.66 (1H, d, J ) 15.5 Hz), 7.03 (1H, br s), 7.01
(1H, br d, J ) 8.5 Hz), 6.79 (1H, br d, J ) 8 Hz), 6.30 (1H,
very br), 6.00 (2H, s), 3.83 (3H, s); HRMS (EI, m/z) calcd for
C
11H11NO4 (M+) 221.0688, found 221.0700. Anal. Calcd for
C11H11NO4: C, 59.72; H, 5.01; N, 6.33. Found: C, 59.44; H, 4.98;
N, 6.27.
2-P r op en yl (Z,E)-3-(1,3-Ben zod ioxol-5-yl)-N-m eth oxy-
2-p r op en im id a te (33). To a solution of 32 (221 mg, 1 mmol)
and triphenylphosphine (524 mg, 2 mmol) in acetonitrile (15
mL) was added carbon tetrabromide (664 mg, 2 mmol) under
a nitrogen atmosphere at room temperature. The reaction
mixture was heated at reflux for 5 h. After the solvent was
evaporated at reduced pressure, purification of the residue by
medium-pressure column chromatography (hexane/AcOEt 7:1)
afforded the corresponding hydroximoyl bromide (283 mg,
quant) as colorless crystals. After being characterized by NMR
spectra, the hydroximoyl bromide was immediately subject to
the following reaction. To a suspension of NaH (60% oil
suspension) (22 mg, 0.54 mmol) in THF was added the allyl
alcohol (0.05 mL, 0.72 mmol) under a nitrogen atmosphere at
0 °C. After being stirred at room temperature for 20 min, a
solution of the hydroximoyl bromide (40 mg, 0.18 mmol) in
THF (5 mL) was added to the reaction mixture. After being
refluxed at 60 °C for 8 h, the reaction mixture was diluted
with saturated aqueous NH4Cl and extracted with CH2Cl2. The
organic phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (hexane/AcOEt
5:1) afforded 33 (22 mg, 61%) as colorless crystals: mp 43-46
1
°C (Et2O); IR (CHCl3) 1636 (CdN) cm-1; H NMR (200 MHz,
CDCl3) δ 7.40 (1H, d, J ) 16 Hz), 6.96 (1H, d, J ) 1.5 Hz),
6.90 (1H, dd, J ) 8, 1.5 Hz), 6.77 (1H, d, J ) 8 Hz), 6.32 (1H,
d, J ) 16 Hz), 6.03 (1H, ddt, J ) 17, 10, 6 Hz), 5.97 (2H, s),
5.38 (1H, dq, J ) 17, 1.5 Hz), 5.27 (1H, dq, J ) 10, 1.5 Hz),
4.74 (2H, dt, J ) 6, 1.5 Hz), 3.87 (3H, s); 13H NMR (CDCl3) δ
158.6, 148.5, 148.1, 136.0, 133.1, 130.2, 123.3, 117.4, 109.8,
108.3, 106.2, 101.2, 67.2, 61.8; HRMS (EI, m/z) calcd for C14H15
-
-
NO4 (M+) 261.1000, found 261.1006. Anal. Calcd for C14H15
NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.33; H, 5.73; N,
5.22.
Su lfa n yl Ra d ica l Ad d ition -Cycliza tion of th e Hy-
d r oxim a te 33. According to the procedure described in the
preparation of 13a (method A), sulfanyl radical addition-
Less p ola r isom er : colorless oil; IR (CHCl3) 1772 (lactone)
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.58-7.46 (5H, m), 6.76

Radical Cyclization in Heterocycle Synthesis. 11.
J . Org. Chem., Vol. 65, No. 21, 2000 6931
(1H, d, J ) 8 Hz), 6.69 (1H, d, J ) 1.5 Hz), 6.64 (1H, dd, J )
8, 1.5 Hz), 5.99-5.92 (2H, m), 4.35 (1H, dd, J ) 9.5, 7.5 Hz),
3.90 (1H, dd, J ) 9.5, 8 Hz), 3.17 (1H, J ) 13.5, 5 Hz), 2.92-
2.58 (5H, m); HRMS (EI, m/z) calcd for C19H18O5S (M+)
358.0854, found 358.0856.
organic phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (hexane/AcOEt
1:1) afforded the alcohol 39 (47 mg, 45%) as a 1:1 diastereo-
meric mixture based on 1′′-position: colorless oil; IR (CHCl3)
3589 (OH), 1765 (lactone) cm-1; 1H NMR (200 MHz, CDCl3) δ
6.90-6.45 (6H, m), 6.00-5.85 (4H, m), 4.61 (1/3H, dd, J ) 6.5,
2.5 Hz), 4.38 (2/3H, dd, J ) 6, 2.5 Hz), 4.16-4.06 (5/3H, m),
3.93 (1/3H, d, J ) 7.5 Hz), 2.99-2.46 (4H, m), 2.04 (1/3H, d, J
) 2.5 Hz), 2.01 (2/3H, d, J ) 2.5 Hz); HRMS (EI, m/z) calcd
for C20H18O7 (M+) 370.1052, found 370.1059.
P ola r isom er : colorless oil; IR (CHCl3) 1773 (lactone) cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.60-7.42 (5H, m), 6.65 (1H, d,
J ) 8 Hz), 6.47 (1H, d, J ) 1.5 Hz), 6.36 (1H, dd, J ) 8, 1.5
Hz), 5.99-5.92 (2H, m), 4.59 (1H, br dd, J ) 10, 7 Hz), 4.10
(1H, br dd, J ) 10, 8.5 Hz), 3.14-2.44 (6H, m); HRMS (EI,
m/z) calcd for C19H18O5S (M+) 358.0854, found 358.0854.
By Oxid a tion of 34. According to the procedure described
in the preparation of 28, oxidation of 34 (341 mg, 0.1 mmol)
with HTIB (118 mg, 0.3 mmol) followed by purification of the
crude product by medium-pressure column chromatography
(hexane/AcOEt 1:1) afforded the sulfoxide 37 (7 mg, 19%). This
compound was identical with 37 obtained by oxidation of 36.
tr a n s-3-[(1,3-Ben zodioxol-5-yl)m eth yl]-4-for m yldih ydr o-
2(3H)-fu r a n on e (38). To a solution of the sulfoxide 37 (119
mg, 0.33 mmol) and 2,6-lutidine (0.15 mL, 1.33 mmol) in dry
MeCN (3.3 mL) was added a solution of TFAA (0.19 mL, 1.33
mmol) in dry MeCN (1.5 mL) under a nitrogen atmosphere at
0 °C. After being stirred at same temperature for 1 h, once
again 2,6-lutidine (0.15 mL, 1.33 mmol) and TFAA (0.19 mL,
1.33 mmol) were added to the reaction mixture. After being
stirred at same temperature for 1 h, a solution of NaHCO3
(672 mg, 8 mmol) in H2O (10 mL) was added to the reaction
mixture. The resulting solution was stirred at same temper-
ature for 2 h. The reaction mixture was diluted with H2O and
extracted with CH2Cl2. The organic phase was washed with
5% HCl, saturated aqueous NaHCO3, and H2O, dried over Na2-
SO4, and concentrated at reduce pressure. Purification of the
residue by medium-pressure column chromatography (hexane/
AcOEt 1:1) afforded the aldehyde 38 (69 mg, 84%) as colorless
oil. After being characterized by NMR spectra, unstable 38
was immediately subjected to the following reaction. IR
(CHCl3) 1772 (lactone) cm-1; 1H NMR (300 MHz, CDCl3) δ 9.37
(1H, d, J ) 1.5 Hz), 6.70 (3H, m), 5.95 (2H, d, J ) 4.5 Hz),
4.37 (1H, dd, J ) 9.5, 7.5 Hz), 4.25 (1H, dd, J ) 9.5, 8.5 Hz),
3.40-2.75 (4H, m).
(()-Oxo-p a r a ben zla cton e (40). To a solution of the alcohol
39 (23 mg, 0.06 mmol) in CH2Cl2 (2 mL) was added PCC (32
mg, 0.15 mmol) under a nitrogen atmosphere at room tem-
perature. After being stirred at same temperature for 4 h, the
reaction mixture was diluted with Et2O and filtered through
a pad of Celite, and the filtrate was concentrated at reduced
pressure. Purification of the residue by medium-pressure
column chromatography (hexane/AcOEt 3:1) afforded the
ketone 40 (12 mg, 52%) as colorless crystals. This compound
was identical with authentic sample upon comparison of their
spectral data: mp 138-139 °C (Et2O/benzene) (lit.11 (+)-40 mp
1
105-106 °C); IR (CHCl3) 1772 (lactone) cm-1; H NMR (200
MHz, CDCl3) δ 7.27 (1H, dd, J ) 8, 2 Hz), 7.21 (1H, d, J ) 2
Hz), 6.81 (1H, dd, J ) 8, 2 Hz), 6.62 (1H, d, J ) 8 Hz), 6.61
(1H, d, J ) 2 Hz), 6.53 (1H, dd, J ) 8, 2 Hz), 6.07 (2H, s), 5.90
(1H, d, J ) 1 Hz), 5.89 (1H, d, J ) 1 Hz), 4.40 (1H, t, J ) 8.5
Hz), 4.14 (1H, t, J ) 8.5 Hz), 4.01 (1H, q, J ) 8.5 Hz), 3.47
(1H, br td, J ) 9, 6 Hz), 3.06 (1H, dd, J ) 14, 5.5 Hz), 2.92
(1H, dd, J ) 14, 7.5 Hz); HRMS (EI, m/z) calcd for C20H16O7
(M+) 368.0895, found 368.0898.
Ack n ow led gm en t. We are grateful to Dr. M. G. B.
Zoghbi (Instututo Nacional de Pesquisas da Amazoˆnia,
Manaus, Brazil) for providing us the spectral data of
the authentic sample of (-)-oxo-parabenzlactone. This
work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture, J apan and a research grant
from the Science Research Promotion Fund of the J apan
Private School Promotion Foundation.
tr a n s-4-[(1,3-Ben zod ioxol-5-yl)h yd r oxym eth yl]-3-[(1,3-
ben zod ioxol-5-yl)m eth yl]d ih yd r o-2(3H)-fu r a n on e (39). To
a suspension of Mg (34 mg, 1.39 mmol) in dry Et2O (2 mL)
was added 4-bromo-1,2-methylenedioxybenzene (0.27 mL, 2.22
mmol) under a nitrogen atmosphere at room temperature.
After being heated under reflux for 1 h, the reaction mixture
was cooled to 0 °C in an ice bath. A solution of the aldehyde
38 (69 mg, 0.28 mmol) in dry THF (2 mL) was added dropwise
to the reaction mixture. After being stirred at same temper-
ature for 1.5 h, the reaction mixture was diluted with
saturated aqueous NH4Cl and extracted with CH2Cl2. The
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and materials, as well as complete experimental
procedures and characterization data for compounds 6b-e,
8b-d , 20a -e, 23a -c, 13b-d , 14b-d , 21a -e, 22a -e, 24 a -c,
and 25b,c and X-ray crystallographic data for compound 13a .
These materials are available free of charge via the Internet
at http://pubs.acs/org.
J O000472W