Synthesis of the putative structure of fistulosin using the ruthenium-catalyzed cycloisomerization of diene

Article abstract of DOI:10.1021/jo0522005

Fistulosin 1, which was isolated from the root of the Welsh onion, is a novel indole alkaloid that has antifungal activity. The first total synthesis of the reported structure of fistulosin using our cycloisomerization of diene is described.

Full text of DOI:10.1021/jo0522005

Synthesis of the Putative Structure of Fistulosin
Using the Ruthenium-Catalyzed
Cycloisomerization of Diene
FIGURE 1. Reported structure of fistulosin (1).
Yukiyoshi Terada, Mitsuhiro Arisawa,*,† and
Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity,
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
arisawa@pharm.hokudai.ac.jp; nishida@p.chiba-u.ac.jp
ReceiVed October 21, 2005
FIGURE 2. Ruthenium catalysts.
(2 f 6) by a combination of Grubbs catalyst B and vinyl-
oxytrimethylsilane 3.5e,g,i These novel reactions could be applied
to the synthesis of a variety of substituted indoles 55e and
3-methylene-2,3-dihydroindoles 65g (Scheme 1). Indoles are a
major class of alkaloids of great interest and significance because
of their pharmacological activities.6 Although the selective and
catalytic cycloisomerizations7 of dienes, in which a new ring is
formed without the loss of carbon units, are highly atom-
economical reactions, the application of this reaction to the
synthesis of natural products or pharmaceutically useful com-
pounds has not been reported because of limitations regarding
the range of substrates and the tolerance of functional groups.
We report here the first synthesis of the reported structure of
fistulosin using our cycloisomerization of diene as a key step.
Initially, we planned to synthesize the key intermediate 8,
which has an octadecyl group at the 2-position of the indoline
core, from o-vinylaniline derivative 7 by ruthenium-catalyzed
cycloisomerization. Unfortunately, however, the reaction of 7
in the presence of catalyst B and 3 did not provide the desired
cyclized product 8 at all but rather gave a complex mixture of
regioisomers, which were produced by olefin migration of the
nonadecenyl side chain (Scheme 2). Therefore, we next chose
the enamide 12 as a substrate for cycloisomerization (Scheme
3). This substrate includes an olefin of an enamide group, which
Fistulosin 1, which was isolated from the root of the Welsh
onion, is a novel indole alkaloid that has antifungal activity.
The first total synthesis of the reported structure of fistulosin
using our cycloisomerization of diene is described.
The antifungal indole fistulosin 1 (Figure 1) was isolated from
the root of the Welsh onion (Allium fistulosum L.) by Tomita’s
group in 1999.1 Vegetables among Allium species are known
to be rich in flavonoids and alk(en)yl cysteine sulfoxides, which
have perceived benefits for human health.2 Since the late 1980s,
biologically active products in Allium species have been
investigated and the isolation of nematicidal and antibacterial
agents has been reported by Tada’s group.3 Furthermore,
Tomita’s group reported the isolation of the new alkaloid
fistulosin, which exhibited antifungal activities against the wilt-
producing fungi Fusarium oxysporum.1 In the field of agricul-
ture, antifungal agents isolated from natural products, such as
fistulosin, are expected to be useful as a result of their safety to
animals, humans, and ecosystems.
We have been studying the development of new methods for
the synthesis of nitrogen-containing heterocyclic compounds
using ruthenium carbene catalysts4 (A and B) (Figure 2) and
have applied them to the synthesis of biologically active natural
products.5a-i Recently, we developed the selective isomerization
of terminal olefin (2 f 4) and the cycloisomerization of dienes
(4) For reviews of metathesis, see: (a) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (b) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900-1923. (c) Deiters, A.; Martin, S. F. Chem. ReV.
2004, 104, 2199-2238. (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117-
7140. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490-4527.
(5) (a) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa,
M. Synlett 1997, 1179-1180. (b) Arisawa, M.; Kato, C.; Kaneko, H.;
Nishida, A.; Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2000, 1873-
1876. (c) Arisawa, M.; Takahashi, M.; Takezawa, E.; Yamaguchi, T.;
Torisawa, Y.; Nishida, A.; Nakagawa, M. Chem. Pharm. Bull. 2000, 48,
1593-1596. (d) Arisawa, M.; Kaneko, H.; Nishida, A.; Nakagawa, M. J.
Chem. Soc., Perkin Trans. 1 2002, 959-964. (e) Arisawa, M.; Terada, Y.;
Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732-4734.
(f) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron
2004, 60, 3017-3035. (g) Terada, Y.; Arisawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2004, 43, 4063-4067. (h) Theeraladanon, C.; Arisawa, M.;
Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2005, 16, 827-831.
(i) Arisawa, M.; Terada, Y.; Theeraladanon, C.; Takahashi, K.; Nakagawa,
M.; Nishida, A. J. Organomet. Chem. 2005, 690, 5398-5406.
* To whom correspondence should be addressed. Fax: +81-43-290-2909.
† Present address: Graduate School of Pharmaceutical Sciences, Hokkaido
University, Kita12, Nishi6, Kita-ku, Sapporo 060-0812, Japan. Fax: +81-11-
706-3769.
(1) Phay, N.; Higashiyama, T.; Tsuji, M.; Matsuura, H.; Fukushi, Y.;
Yokota, A.; Tomita, F. Phytochemistry 1999, 52, 271-274.
(2) For a review of biologically active compounds in onions, see:
Griffiths, G.; Trueman, L.; Crowther, T.; Thomas, B.; Smith, B. Phytother.
Res. 2002, 16, 603-615.
(3) Tada, M.; Hiroe, Y.; Kiyohara, S.; Suzuki, S. Agric. Biol. Chem.
1988, 52, 2383-2385.
(6) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73-103.
(7) For recent reviews, see: (a) Trost, B. M.; Krische, M. J. Synlett 1998,
1-16. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102,
813-834. (c) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215-236.
(d) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2004, 43, 1048-1052. Various
applications of the cycloisomerization of enynes to the synthesis of natural
products has been demonstrated by Trost and co-workers.
10.1021/jo0522005 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/27/2005
J. Org. Chem. 2006, 71, 1269-1272
1269

SCHEME 1. Synthesis of Substituted Indoles and 2,3-Dihydroindoles
SCHEME 2. Initial Approach to Fistulosin (1)
SCHEME 3. Synthesis of N-Tosyl-2-octadecyl-3-indolinone (15)a
a Reagents and conditions: (i) (E)-HO(CH2)2CHdCHCO2Me (10), DEAD, PPh3, THF, rt, 4 h, 99%; (ii) RuClH(CO)(PPh3)3, toluene, reflux, 23 h, 83%;
(iii) B (10 mol %), 3 (1 equiv), xylene, reflux, 2 h, 87%; (iv) DIBAL, toluene, -78 °C, 20 min, 87%; (v) BrMg(CH2)13Me, THF, 0 °C, 20 min, 93%; (vi)
MsCl, Et3N, DMAP, CH2Cl2, rt, 30 min, 86%; (vii) NaBH4, HMPA, 50 °C, 2 h, 71%; (viii) O3, CH2Cl2, -78 °C, 15 min, then PPh3, rt, 2 h, 70%.
SCHEME 4. Deprotection and Tautomerization
spectral analyses. However, further purifications of 16a by
column chromatography or recrystallization were unsuccessful,
even though we used the same procedure reported by Tomita,
since 16a was gradually tautomerized to more thermodynami-
cally stable 3-hydroxyindole 16b in solution.10a-c
Next, we compared the spectral data of 16a to those reported
for natural fistulosin 1 (Table in Supporting Information). The
IR spectrum of synthetic compound 16a revealed a strong band
at 1675 cm-1, which was similar to the reported data (1684
cm-1), and the reported characteristic mass peak at 133 [M -
C18H36+] was also observed in the spectrum of 16a. On the other
hand, the 1H NMR spectra showed some remarkable differences.
As for our synthetic 16a, the chemical shift of methine proton
at the 2-position was observed at 3.75 ppm, in contrast to 2.44
ppm reported by Tomita’s group. In addition, conspicuous
differences were seen in the 13C NMR spectra. For example,
the chemical shift of the carbonyl carbon of our sample was
observed at 202.7 ppm, in contrast to the reported value of 171.5
ppm. Overall, the spectral data supported the structure of 16a.
Thus, we concluded that the spectral data of 16a did not agree
with those reported for fistulosin.
is expected to efficiently undergo our cycloisomerization, and
an ester group for subsequent extension of the alkyl chain. The
preparation of 12 was commenced with the Mitsunobu reaction
of readily available 9 with alcohol 10, and treatment of 11 with
8
RuClH(CO)(PPh3)3 (10 mol %) provided enamide 12 in 83%
yield. With substrate 12 in hand, cycloisomerization of 12 in
the presence of Grubbs catalyst B (10 mol %) and 3 (1 equiv)
gave cyclized product 13 as a stable colorless crystal in 87%
yield. Installation of a tetradecyl group was achieved through a
four-step procedure. Cyclized product 13 was reduced with
DIBAL to give aldehyde 14, and then treatment of 14 with
Grignard reagent gave the secondary alcohol in 93% yield.
Mesylation of the hydroxy group followed by the reduction of
mesylate with NaBH4 gave indoline 8, which was converted to
3-indolinone 15 by ozonolysis. Finally, treatment of 15 with
concentrated H2SO4 at 0 °C9 gave the deprotected product 16a
quantitatively in crude form (Scheme 4). 3-Indolinone 16a was
pure and stable enough for the structure to be characterized by
(8) (a) Wakamatsu, H.; Nishida, M.; Adachi, N.; Mori, M. J. Org. Chem.
2000, 65, 3966-3970. (b) van Otterlo, W. A. L.; Ngidi, E. L.; de Koning,
C. B. Tetrahedron Lett. 2003, 44, 6483-6486. (c) van Otterlo, W. A. L.;
Pathak, R.; de Koning, C. B. Synlett 2003, 12, 1859-1861. (d) van Otterlo,
W. A. L.; Morgans, G. L.; Khanye, S. D.; Aderibigbe, B. A. A.; Michael,
J. P.; Billing, D. G. Tetrahedron Lett. 2004, 45, 9171-9175.
FIGURE 3. Structure of oxindole 17.
We next compared the spectral data of the more stable
tautomer 16b and oxindole 17, which are other candidates of
the natural product “fistulosin”. Tautomerization of 16a occurred
smoothly in an acidic medium, such as aqueous HCl or H2SO4,
(9) Hirokawa, Y.; Harada, H.; Yoshikawa, T.; Yoshida, N.; Kato, S.
Chem. Pharm. Bull. 2002, 50, 941-959.
1270 J. Org. Chem., Vol. 71, No. 3, 2006

N-p-Toluenesulfonyl-2-octadecyl-3-methylene-2,3-dihydroin-
dole (8). To a cooled (-78 °C) solution of 14 (106 mg, 0.30 mmol)
in THF (3.0 mL) was slowly dropped C14H29MgBr (0.5 M, THF
solution, 1.80 mL, 0.90 mmol). The mixture was stirred at 0 °C
for 20 min, and the reaction was quenched by saturated aqueous
NH4Cl. The organic compounds were extracted with AcOEt, and
the combined organic layers were washed with brine and dried over
Na2SO4. After removal of the solvent, the residue was subjected to
column chromatography (n-hexane/AcOEt ) 6:1) to give the
alcohol (153 mg, 93%) as a colorless oil.
To a solution of alcohol (209 mg, 0.38 mmol), DMAP (46.1
mg, 0.38 mmol), and Et3N (0.26 mL, 1.89 mmol) in CH2Cl2 (9.0
mL) was added methanesulfonyl chloride (0.09 mL, 1.13 mmol)
dropwise, and the mixture was stirred for 30 min at room
temperature. After addition of saturated aqueous NH4Cl, the organic
compounds were extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was subjected to column
chromatography (n-hexane/AcOEt ) 5:1) to give the mesylate (204
mg, 86%) as a colorless oil.
to give 16b, which could be purified by recrystallization from
n-hexane/AcOEt. Although the crystals of 16b were not suitable
for X-ray analysis, other spectra including 2D-NMR spectra
(1H-1H COSY, HMBC, and HMQC) unambiguously confirmed
the structure of 16b. Oxindole 17 was synthesized by the
procedures reported by Overman and co-workers.11 However,
the spectral data of both 16b and 17 were also not consistent
with the reported data of fistulosin (Table in Supporting
Information). Further investigations are necessary to elucidate
the structure of fistulosin.
In conclusion, we have achieved the first synthesis of the
reported structure of fistulosin featuring our ruthenium-catalyzed
cycloisomerization of diene. Further applications of our meth-
odology to the syntheses of pharmacologically active products
are currently in progress.
Experimental Section
N-p-Toluenesulfonyl-2-(3-methoxycarbonylpropyl)-3-methyl-
ene-2,3-dihydroindole (13). To a stirred solution of 12 (262 mg,
0.68 mmol) and vinyloxytrimethylsilane 3 (79.0 mg, 0.68 mmol)
in xylene (54.4 mL) was added ruthenium carbene catalyst B (57.7
mg, 0.068 mmol) under an Ar atmosphere, and the mixture was
refluxed for 2 h. After the removal of solvent, the residue was
purified by column chromatography (n-hexane/Et2O ) 5:1) to give
13 (229 mg, 87%) as a colorless prism. Mp 140-141 °C (n-hexane/
AcOEt); 1H NMR δ 7.75 (d, 1H, J ) 8.1 Hz), 7.52 (d, 2H, J ) 8.4
Hz), 7.26-7.31 (m, 2H), 7.14 (d, 2H, J ) 8.6 Hz), 7.05 (dd, 1H,
J ) 7.7, 7.7 Hz), 5.37 (d,1H, J ) 2.6 Hz), 4.88 (d, 1H, J ) 2.0
Hz), 4.60-4.63 (m, 1H), 3.63 (s, 3H), 2.25-2.44 (m, 2H), 2.33 (s,
3H), 2.09-2.17 (m, 1H), 1.71-1.86 (m, 2H), 1.61-1.68 (m, 1H);
13C NMR δ 173.8, 144.6, 144.0, 143.8, 134.1, 130.1, 130.0, 129.5,
127.2, 124.5, 120.9, 117.0, 103.0, 66.1, 51.5, 36.4, 33.8, 21.5, 18.6;
IR (neat) cm-1 2947, 1732, 1460, 1352, 1163, 662; LRMS (EI)
m/z 385 (M+, 41%), 230 (100%, base peak); HRMS (FAB) calcd
for C21H24NO4S (M+ + H) 386.1426, found 386.1420. Anal. Calcd
for C21H23NO4S: C 65.43 H 6.01 N 3.63. Found: C 65.48 H 6.09
N 3.62.
4-(N-p-Toluenesulfonyl-3-methylene-2,3-dihydroindolyl)bu-
tanal (14). To a cooled (-78 °C) solution of 13 (159 mg, 0.41
mmol) in toluene (25.0 mL) under Ar atmosphere was added
DIBAL (1.01 M, toluene solution, 0.49 mL, 0.49 mmol). The
mixture was stirred at -78 °C for 20 min, and the reaction was
quenched by the addition of MeOH and saturated aqueous Roch-
elle’s salt. Then the solution was allowed to stir at room temperature
until separation of organic and water layers. The mixture was
extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. After removal of the
solvent, the residue was subjected to column chromatography (n-
hexane/AcOEt ) 4:1) to give 14 (126 mg, 87%) as a colorless oil.
1H NMR δ 9.72 (t, 1H, J ) 1.5 Hz), 7.75 (d, 1H, J ) 8.1 Hz),
7.52 (d, 2H, J ) 8.3 Hz), 7.26-7.31 (m, 2H), 7.14 (d, 2H, J ) 8.5
Hz), 7.05 (dd, 1H, J ) 7.6, 7.6 Hz), 5.38 (d, 1H, J ) 2.4 Hz), 4.89
(d, 1H, J ) 2.0 Hz), 4.60-4.62 (m, 1H), 2.40-2.48 (m, 2H), 2.33
(s, 3H), 2.10-2.16 (m, 1H), 1.75-1.85 (m, 2H), 1.60-1.70 (m,
1H); 13C NMR δ 202.4, 144.6, 144.1, 143.8, 134.0, 130.13, 130.10,
129.6, 127.2, 124.6, 120.9, 117.1, 103.0, 66.1, 43.6, 36.5, 21.5,
15.8; IR (neat) cm-1 1720, 1460, 1351, 1163, 661; LRMS (EI)
m/z 355 (M+, 36%), 200 (100%, base peak); HRMS (FAB) calcd
for C20H22NO3S (M+ + H) 356.1320, found 356.1309.
To a solution of mesylate (104 mg, 0.17 mmol) in HMPA (2.2
mL) was added NaBH4 (24.9 mg, 0.66 mmol), and the mixture
was stirred at 50 °C for 2 h. After addition of saturated aqueous
NaHCO3, the organic compounds were extracted with AcOEt. The
combined organic layers were washed with brine and dried over
Na2SO4. After removal of the solvent, the residue was subjected to
column chromatography (n-hexane/AcOEt ) 40:1) to give 8 (62.6
mg, 71%) as a colorless oil. 1H NMR δ 7.74 (d, 1H, J ) 8.1 Hz),
7.53 (d, 2H, J ) 8.1 Hz), 7.29 (d, 1H, J ) 7.1 Hz), 7.27 (dd, 1H,
J ) 7.5, 7.5 Hz), 7.13 (d, 2H, J ) 8.2 Hz), 7.04 (dd, 1H, J ) 7.5,
7.5 Hz), 5.34 (d, 1H, J ) 2.4 Hz), 4.85 (d, 1H, J ) 1.8 Hz), 4.60-
4.62 (m, 1H), 2.32 (s, 3H), 2.03-2.09 (m, 1H), 1.73-1.79 (m,
1H), 1.22-1.43 (m, 32H), 0.88 (t, 3H, J ) 6.4 Hz); 13C NMR δ
145.2, 144.0, 143.8, 134.4, 130.3, 129.9, 129.5, 127.1, 124.4, 120.7,
117.0, 102.6, 66.7, 37.2, 31.9, 29.4-29.7 (m), 22.8, 22.7, 21.5,
14.1; IR (neat) cm-1 2920, 2850, 1457, 1353, 1167; LRMS (EI)
m/z 537 (M+, 100%, base peak), 382 (44%); HRMS (FAB) calcd
for C34H52NO2S (M+ + H) 538.3719, found 538.3732.
N-p-Toluenesulfonyl-2-octadecyl-3-indolinone (15). To a cooled
(-78 °C) solution of 8 (137 mg, 0.25 mmol) in CH2Cl2 (25.0 mL)
was bubbled O3 gas until the color of the solution turned to blue.
After the addition of PPh3 (200 mg, 0.76 mmol), the mixture was
stirred at room temperature for 2 h. The solvent was removed under
reduced pressure, and the residue was subjected to column
chromatography (n-hexane/AcOEt ) 30:1 to 8:1) to give 15 (94.0
1
mg, 70%) as a red oil. H NMR δ 8.08 (d, 1H, J ) 8.3 Hz), 7.67
(ddd, 1H, J ) 7.3, 7.3, 1.5 Hz), 7.61 (d, 2H, J ) 8.5 Hz), 7.61 (d,
1H, J ) 8.5 Hz), 7.20 (d, 2H, J ) 8.1 Hz), 7.19 (ddd, 1H, J ) 7.1,
7.1, 0.7 Hz), 3.98 (dd, 1H, J ) 6.1, 3.7 Hz), 2.35 (s, 3H), 2.08-
2.27 (m, 2H), 1.06-1.44 (m, 32H), 0.88 (t, 3H, J ) 6.6 Hz); 13C
NMR δ 198.8, 153.5, 144.9, 137.1, 133.5, 129.9, 127.2, 125.2,
124.5, 124.2, 117.1, 67.4, 32.0, 31.9, 29.3-29.7 (m), 23.0, 22.7,
21.5, 14.1; IR (neat) cm-1 2915, 2848, 1733, 1604, 1355, 1151;
LRMS (EI) m/z 539 (M+, 12%), 433 (42%), 91 (100%, base peak);
HRMS (FAB) calcd for C33H50NO3S (M+ + H) 540.3511, found
540.3535.
2-Octadecyl-3-indolinone (16a). A mixture of 15 (90.0 mg, 0.17
mmol) and concentrated H2SO4 (2.0 mL) was stirred at 0 °C for
1.5 h. To the solution was slowly poured cooled water at 0 °C, and
the aqueous layer was neutralized with saturated aqueous NaHCO3.
The organic compounds were extracted with AcOEt, and the
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo
to give 16a (66.0 mg, 100%) as an orange solid. Mp 100-102 °C;
1H NMR δ 7.61 (d, 1H, J ) 7.9 Hz), 7.44 (dd, 1H, J ) 8.2, 7.1
Hz), 6.88 (d, 1H, J ) 8.6 Hz), 6.82 (dd, 1H, J ) 7.3, 7.3 Hz), 4.70
(brs, 1H), 3.75 (dd, 1H, J ) 8.4, 4.2 Hz), 1.83-1.96 (m, 1H), 1.55-
1.64 (m, 1H), 1.25-1.40 (m, 32H), 0.88 (t, 3H, J ) 6.8 Hz); 13C
(10) For 3-hydroxyindoles, see: (a) Capon, B.; Kwok, F.-C. J. Am. Chem.
Soc. 1989, 111, 5346-5356. (b) Hickman, Z. L.; Sturino, C. F.; Lachance,
N. Tetrahedron Lett. 2000, 41, 8217-8220. (c) Kirby, G. W.; Shah, S. W.
Chem. Commun. 1965, 381.
(11) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043-14053.
J. Org. Chem, Vol. 71, No. 3, 2006 1271

NMR δ 202.7, 161.3, 136.9, 124.5, 121.5, 118.9, 112.6, 64.3, 32.0,
31.9, 29.3-29.7 (m), 25.8, 22.7, 14.1; IR (neat) cm-1 3394, 2914,
2848, 1675, 1469, 1321, 734; LRMS (EI) m/z 385 (M+, 18%), 161
(15%), 133 (10%), 84 (34%), 18 (100%, base peak).
22.7, 14.1, IR (neat) cm-1 2915, 2848, 1674, 1613, 1484, 1327,
740; LRMS (EI) m/z 385 (M+, 20%), 383 (100%, base peak), 172
(45%), 146 (53%). Anal. Calcd for C26H43NO: C 80.98 H 11.24
N 3.63. Found: C 80.97 H 10.93 N 3.49.
2-Octadecyl-3-hydroxyindole (16b). A mixture of 15 (20.7 mg,
38.3 µmol) and concentrated H2SO4 (1.0 mL) was stirred at 0 °C
for 1.5 h. To the solution was added cooled water (3.0 mL) and
AcOEt (4.0 mL) at 0 °C slowly, and the mixture was stirred at
room temperature for 1 h. After the aqueous layer was neutralized
with saturated aqueous NaHCO3, the organic compounds were
extracted with AcOEt, and the combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried over Na2-
SO4 and concentrated in vacuo to give 16b (13.3 mg, 91%,
Acknowledgment. This research was supported by Grants-
in-Aid for the Encouragement of Young Scientists (A), for
Scientific Research (B), for Priority Area (17035014), and for
Exploratory Research from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. We also thank
the Naito Foundation and the Fujisawa Foundation for financial
support.
1
estimated by H NMR) as yellow needles. Mp 107-108 °C (n-
1
hexane/AcOEt); H NMR δ 7.56 (d, 1H, J ) 7.7 Hz), 7.49 (dd,
Supporting Information Available: Experimental procedures
of the synthesis of 11, 12, and 17, and 1H and 13C NMR spectra of
8, 11, 13-15, 16a, and 16b. This material is available free of charge
via the Internet at http://pubs.acs.org.
1H, J ) 8.1, 8.1 Hz), 6.95 (d, 1H, J ) 8.2 Hz), 6.78 (dd, 1H, J )
7.1, 7.1 Hz), 6.08 (brs, 1H), 1.84-1.90 (m, 1H), 0.99-1.31 (m,
34H), 0.88 (t, 3H, J ) 6.4 Hz), The peak at 6.08 ppm was
disappeared in CDCl3/D2O (10/1); 13C NMR δ 204.6, 162.0, 138.1,
124.2, 121.5, 118.3, 112.0, 72.5, 32.0, 31.9, 29.3-29.8 (m), 23.0,
JO0522005
1272 J. Org. Chem., Vol. 71, No. 3, 2006