Synthesis of 3-hydroxyindolin-2-one alkaloids, (±)-donaxaridine and (±)-convolutamydines A and E, through enolization-Claisen rearrangement of 2-allyloxyindolin-3-ones

Article abstract of DOI:10.1016/j.tet.2004.02.031

Claisen rearrangement triggered by enolization of 2-allyloxyindolin-3-ones with DBU was performed in order to prepare 3-allyl-3-hydroxyindolin-2-ones. Total synthesis of 3-hydroxyindolin-2-one alkaloids, (±)-donaxaridine, as well as (±)-convolutamydines A

Full text of DOI:10.1016/j.tet.2004.02.031

Tetrahedron 60 (2004) 3493–3503
Synthesis of 3-hydroxyindolin-2-one alkaloids, (6)-donaxaridine
and (6)-convolutamydines A and E, through enolization–Claisen
rearrangement of 2-allyloxyindolin-3-ones
*
Tomomi Kawasaki, Miyuki Nagaoka, Tomoko Satoh, Ayako Okamoto, Rie Ukon
and Atsuyo Ogawa
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Received 26 November 2003; accepted 9 February 2004
Abstract—Claisen rearrangement triggered by enolization of 2-allyloxyindolin-3-ones with DBU was performed in order to prepare 3-allyl-
3-hydroxyindolin-2-ones. Total synthesis of 3-hydroxyindolin-2-one alkaloids, (^)-donaxaridine, as well as (^)-convolutamydines A and E,
was achieved by transformation of the allyl moiety of 3-allyl-3-hydroxyindolin-2-ones.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
for synthesis of the 3-hydroxyindolin-2-one alkaloids, (^)-
donaxaridine (1) as well as (^)-convolutamydines A (2a) and
E (2b), using Claisen rearrangement triggered by enolization
of 2-allyloxyindolin-3-ones 3 to 3-allyl-3-hydroxyindolin-2-
ones 4 (Scheme 1).
3-Substituted 3-hydroxyindolin-2-ones are useful synthetic
intermediates for alkaloids and biologically active com-
pounds such as donaxaridine (1),1 convolutamydines (2),2
dioxibrassinine,3 welwitindolinone C,4 30-hydroxygluco-
isatisin,5 and TMC-95s,6 in addition to several others
(Fig. 1) .7 In particular, 3-allyl-3-hydroxyindolin-2-ones are
attractive intermediates for synthesis of biologically active
compounds. Although a number of routes to 3-substituted
3-hydroxyindolin-2-ones are known,8–17 there are relatively
few synthetic methods for 3-allyl-3-hydroxyindolin-2-ones.
The known examples are addition of allylmetallic
(indium,18 gallium19 and boran20) reagents to isatin, but
there are difficulties in obtaining the desired 3-allyl-3-
hydroxyindolin-2-one owing to the low regioselectivity of
the allylic reaction site.18,19 Reaction of allylmagnesium
2. Results and discussion
2.1. Preparation of 3-allyl-3-hydroxyindolin-2-ones
The starting 2-allyloxyindolin-3-ones 3 were readily
available using our synthetic method.23 Initially, we
examined the enolization of 2-allyloxyindolin-3-one 3a
with DBU and DBN as a base under several reaction
conditions and the results are summarized in Table 1. When
3a was treated with DBU at 40 8C in acetonitrile, the desired
enolization readily took place through Claisen rearrange-
ment of an intermediary indole to afford 3-allyl-3-hydro-
xyindolin-2-one 4a, its deacetyl derivative 5a, and
carboxylic acid 6 in 9, 12, and 36% yields, respectively
(Scheme 2 and Table 1, entry 1). It is known that Claisen
rearrangement of the enolate of a-allyloxy carbonyl
compounds competes with [2,3]-Wittig rearrangement.25
However, comparison of the 13C NMR spectrum of 5a with
those of 3-hydroxyindolin-2-one 7 and 2-hydroxyindolin-3-
one 826 shows that the product in the reaction of 4a is not the
[2,3]-Wittig rearrangement product 5a0 but the Claisen
rearrangement product 5a (Fig. 2). Formation of 5a and 6 is
effected by hydrolysis of 4a under basic reaction conditions,
and thus 4a was smoothly hydrolyzed with lithium
hydroxide at room temperature to give 5a in 85% yield.
When the reaction was performed in methylene chloride
chloride with isatin resulted in diallylation to give only 2,2-
21
diallylindolin-3-one.21 Recently, Merour et al. reported
´
alkaline hydrolysis of 2-ethoxycarbonyl-2-allyloxyindolin-
3-ones followed by decarboxylation and Claisen rearrange-
ment to give 3-allyl-3-hydroxyindolin-2-one. We have
previously shown a synthetic methodology for regio-
selective introduction of an allyl moiety to an indole
nucleus using Claisen rearrangement, converting 3-allyl-
oxyindole to 2-allylindolin-3-one,22 3-alkyl-2-allyloxyin-
dole to 3-alkyl-3-allylindolin-2-one23 and 3-vinyloxyindoline
to 4-carbamoylmethylindoles.24 We herein report a method
Keywords: DBU; Allylalcohol; Osmium tetraoxide; Wacker oxidation;
Molybdenum peroxide.
*
Corresponding author. Fax: þ81-424-95-8763;
e-mail address: kawasaki@my-pharm.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.031

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T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
Figure 1. 3-Hydroxy-indolin-2-one alkaloids.
Scheme 1. Enolization–Claisen rearrangement.
Scheme 2. Enolization–Claisen rearrangement of 2-allyloxyindolin-3-one 3a.
Table 1. Reaction conditions in enolization–Claisen rearrangement of 2-allyloxyin, rdolin-3-one 3a
Entry
Base
Solvent
Reaction temperature (8C)
Reaction time (min)
Yield (%)
4a
5a
6
1
2
3
4
5
6
7
DBU
DBU
DBU
DBU
DBU
DBN
DBN
MeCN
40
40
40
rt
110
40
rt
30
10
20
80
5
9
12
16
16
13
55
70
63
36
30
—
—
3
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
12
70
56
—
2
10
60
2
6
—
instead of acetonitrile, the reaction was completed in a
shorter time, though by-product 6 was still formed (entry 2).
Using toluene as the reaction solvent resulted in reduced
formation of 6, thus improving the total yields of 4a and 5a
(entry 3). Further attempts to carry out the reaction at
various temperatures (entries 4 and 5) confirmed that the
reaction conditions shown in entry 3 were the most suitable.
When DBN was used instead of DBU, the reaction
proceeded more smoothly to give the desired 5a as the
chief product in good yield; however, small amounts of by-
product 6 were formed (entries 6 and 7).
Next, we investigated the DBU-promoted reaction of
various 2-allyloxyindolin-3-ones 3b-f. The results are
summarized in Scheme 3 and Table 2. When 3b was treated
with DBU in toluene at 40 8C for 10 min, 3-(2-methyl-2-
buten-2-yl)-3-hydroxyindolin-2-one 4b and the deacety-
lated 5b were obtained in 70 and 9% yields (entry 1). The

T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
3495
reaction of 3c under the same conditions required prolonged
heating (120 min) to give the Claisen products 4c and 5c in
moderate yields (entry 2). A similar reaction of (E)-
cinnamyl derivative 3d for 20 min afforded a mixture of
the diastereoisomers of 4d (50%, 1.5:1) together with 5d
(20%) (entry 3). As examples of secondary rather than
primary ethers, reactions of 2-buten-2-yl and cyclo-2-
hexenyl derivatives 3e and 3f were performed. The reaction
of 3e proceeded through stereoselective Claisen rearrange-
ment to give (E)-buten-2-ylindolin-3-ones 4e (54%) and 5e
(8%) (entry 4). The (E)-product 4e is predominantly
produced via chair-like transition state A which is more
favorable than boat-like transition state B (Fig. 3).25 For the
reaction of 3f, 4f and 5f were obtained as respective
mixtures of their diastereoisomers (4:1) in 59% and 18%
yields (entry 5).
Figure 2. 13C NMR spectra of hydroxyindolin-2-ones and 2-hydroxy-
indolin-3-one.
Scheme 3. Enolization–Claisen rearrangement of 2 allyloxyindolin 3-one 3b-f.
Table 2. Preparation of 3-allyl-3-hydroxyindolin-2-ones 4 and 5
Entry
Indolin-3-one 3
Reaction time (min)
Product (yield)
1
3b
10
4b (70%)
5b (9%)
2
3
3c
120
4c (45%)
5c (10%)
3d
20
4d (50%)a
5d (20%)a
4
3e
3f
10
80
4e (54%)
5e (8%)
5
4f (59%)a
5f (18%)a
a
The ratio of diastereomers measured by HPLC; 4d (1:1.4), 5d (1.1:1), 4f (2:1), 5f (4:1).

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T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
yield from 5a (Scheme 4). All spectral data are identical to
those of the natural and synthetic samples.1
For transformation of the allyl group to the acetonyl group,
we utilized Wacker oxidation because Wacker oxidation of
olefins containing b-oxygenated functional groups with
O2–PdCl2–CuCl2 or –CuCl in DMF–H2O regioselectively
afforded the corresponding ketones.27 However, Wacker
oxidation of 5a and its O-TBDMS derivative 9 under these
conditions was very slow (Scheme 5 and Table 3, entries
1–5). When 9 was allowed to react with O2–PdCl2–CuCl
in 1,4-dioxane-H2O, the desired Wacker oxidation readily
took place to afford 10 in high yield (entry 6). In addition,
the reaction using other Pd catalysts was attempted to give
moderate results (entries 7 and 8). Deprotection of 10 with
tetrabutylammonium fluoride (TBAF) and acetic acid gave
the 3-acetonyl-3-hydroxyindolin-2-one 11 in moderate
yield.28
Figure 3. Transition states A and B in Claisen rearrangement of 3e.
2.2. Synthesis of (6)-donaxaridine and (6)-
convolutamydines A and E
For the synthesis of 3-hydroxyindolin-2-one alkaloids,
donaxaridine (1) and convolutamydines A (2a) and E
(2b), we attempted transformation of the allyl group of
3-allyl-3-hydroxyindolin-2-one 5a to aldehyde and acetonyl
groups. When 5a was treated with OsO4 and N-methyl-
morpholine N-oxide (NMO) followed by NaIO4, the
unstable aldehyde was obtained and used in the following
reaction without purification. Reductive amination of the
aldehyde with NaBH3CN in the presence of methyl-
ammonium chloride gave the 3-methylaminoethyl-3-
hydroxyindolin-2-one (^)-donaxaridine (1) in 41% overall
Finally, we applied these preparative methods to the
total synthesis of (^)-convolutamydines A (2a) and E
(2b). 4,6-Dibromoindolin-3-one 14 was readily obtained
from 4,6-dibromoindole 1229 by molybdenum peroxide
oxidation followed by demethoxylation30 in 50% overall
Scheme 4. Reagents: (a) OsO4, NMO, MeCN, rt, 2 h and then NalO4, dioxane–H2O (2:1), rt, 10 min. (b) MeNH2·HCl, MeOH, rt, 3 h and then NaBH3CN, rt,
36 h, 41% (overall yield from 5a).
Scheme 5. Reagents: (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 8C to rt, 3 days, 73%. (b) See Table 3. (c) TBAF, AcOH, 0 8C to rt, 50%.
Table 3. Wacker oxidation of 3-allylindolin-2-ones 5a and 9 with O2
Entry
Olefin
Reagents (equiv.)
Solvents
Temperature (8C)
Time
Yield (%)
1
2
3
4
5
6
7
8
5a
9
9
9
9
9
9
9
PdCl2–CuCl2 (0.1:1)
PdCl2–CuCl2 (0.1:1)
PdCl2–CuCl2 (1:10)
PdCl2–CuCl2 (1:10)
PdCl2–CuCl (0.1:1)
DMF–H2Oa
DMF–H2Oa
DMF–H2Oa
DMF–H2Oa
DMF–H2Oa
dioxane–H2Oa
DMF–H2Oa
AcOH–H2Ob
rt
rt
rt
50
50
50
50
50
1 week
1 week
1 week
1 week
4 days
5 h
—
8
10
11
5
88
25
71
PdCl2–CuCl (0.1:1)
PdCl2(PhCN)2–CuCl2 (0.1:1)
Na2PdCl2–t-BuO2H (0.2:1.5)
1 day
5 h
a
The ratio of solvents (7:1).
The ratio of solvents (1:1).
b

T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
3497
yield. Successive bromination of 14, substitution with allyl
alcohol, DBU-promoted enolization–Claisen rearrange-
ment of 15 and hydrolysis with LiOH gave the desired
4,6-dibromo-3-hydroxyindolin-2-one 16 in 84% yield
(Scheme 6). The OsO4–NaIO4 oxidation of 16 followed
by NaBH4 reduction yielded (^)-convolutamydine E (2b)
in 65% yield (Scheme 7).
synthesis of (^)-donaxaridine (1) as well as (^)-con-
volutamydines A (2a) and E (2b).
4. Experimental
4.1. General
Synthesis of (^)-convolutamydine A (2a) was achieved by
TBDMS protection of 16 followed by Wacker oxidation of
1731 and deprotection of 18 with tris(dimethylamino)sulfur
(trimethylsilyl)difluoride (TAS-F) (Scheme 7).32 All spec-
tral data of 2a and 2b are identical to those of the natural and
synthetic samples.2
1H NMR spectra were obtained using a JEOL JNM-EX-300,
JNM-EX-400, or JNM-LA-500 spectrometer with tetra-
methylsilane as an internal standard. J-Values are given in
Hz. Mass spectra were obtained using a JEOL JMS-DX302
or JMS-700 instrument with a direct inlet system operating
at 70 eV. IR spectra were recorded with a Shimadzu FTIR-
8100 spectrophotometer. All mp values are uncorrected, and
were measured on a Yanagimoto micromelting point
apparatus. HPLC was performed on a JASCO PU-1580
with a JASCO Finepak SIL-5 column. Elemental analyses
were obtained using a Yanaco CHN Corder MT-6 elemental
analyzer. Column chromatography was carried out on
silica gel (Kanto Chemical Co. Inc., Silica Gel 60N,
100–200 mesh and Merck, Silica Gel 60, 230–400 mesh).
Preparative TLC was undertaken using Merck Silica Gel 60
3. Conclusion
In conclusion, we have presented a general and useful
method for synthesis of 3-allyl-3-hydroxyindolin-2-ones 5
using Claisen rearrangement triggered by DBU-promoted
enolization of 2-allyloxyindolin-3-ones 3. As examples of
the synthetic utility of 5, we performed transformation of the
allyl group in 5a to aldehyde and acetonyl groups, and
respectively applied these methodologies to achieve total
F254
.
Scheme 6. Reagents: (a) MoO5·HMPA, MeOH, rt, 1 week, 90%. (b) CSA, MeCN, reflux, 56%. (c) Br2, CH2Cl2, 0 8C, for 2h, and then allyl alcohol, MS 4A,
DMF, rt, for 2 days. (d) DBU, toluene, 40 8C, 3 h, and then LiOH, MeOH, rt, 3 days, 84% (overall yield from 14).
Scheme 7. Reagents: (a) OsO4, NMO, MeCN, rt 1 h, and then NaIO4, dioxane–H2O, rt, 1 h. (b) NaBH4 MeOH, 0 8C, 30 min., 65% (c) TBDMSOTf, 2,6-
lutidine, 0 8C to rt, 3 days, and then AcOH, H2O, THF, 80 8C, 2 h, 69%. (d) PdCl2, CuCl, dioxane–H2O (7:1), 50 8C, 24 h, 12%, (e) TAS–F, 0–15 8C, 2.5 h,
75%.

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T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
4.2. General procedure for the preparation of 3-allyl-3-
hydroxyindolin-2-ones 4-5
J¼10.8, 1.2 Hz, –CHvCH2), 6.19 (1H, dd, J¼17.4,
10.8 Hz, –CHvCH2), 6.81 (1H, d, J¼7.6 Hz, Ar-H), 7.02
(1H, td, J¼7.6, 0.9 Hz, Ar-H), 7.25 (1H, td, J¼7.6 1.3 Hz,
Ar-H), 7.37 (1H, dd, J¼7.6, 0.7 Hz, Ar-H). MS m/z (%): 217
(Mþ, 2), 149 (100), 119 (3), 69 (15), 41 (7). HRMS m/z
calcd for C13H15NO2: 217.1103. Found: 217.1098. Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
72.05; H, 6.99; N, 6.17.
A solution of 2-allyloxyindolin-3-ones 3 (1.0 mmol) and
DBU or DBN (1.0 mmol) in dry solvent (13 ml) as shown in
Table 1 was stirred at a designated temperature (rt ,110 8C)
under nitrogen atmosphere for a designated period
(10–120 min), as shown in Tables 1 and 2. The reaction
mixture was neutralized with AcOH at 0 8C and extracted
with EtOAc. The extract was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure to give a
residue. The residue was subjected to chromatography on a
silica gel column with EtOAc–hexane (1:1–2) as an eluent
to give 3-allyl-3-hydroxyindolin-2-ones 4, deacetyl deriva-
tives 5, and carboxylic acid 6.
4.2.5. 1-Acetyl-3-(2-methyl-2-propenyl)-3-hydroxyindo-
lin-2-one (4c). Viscous oil. IR (CHCl3) cm21: 3559, 1765,
1713. 1H NMR (CDCl3, 300 MHz) d: 1.40 (3H, s,
–CMevCH2), 2.60 (3H, s, –Ac), 2.66 (1H, d,
J¼12.9 Hz, –CH2–), 2.75 (1H, dd, J¼12.9, 0.7 Hz,
–CH2–), 2.98 (1H, br, –OH), 4.63 (1H, d, J¼0.9 Hz,
–CMevCH2), 4.80 (1H, t, J¼1.7 Hz, –CMevCH2), 7.24
(1H, td, J¼7.4, 1.1 Hz, Ar-H), 7.37 (1H, td, J¼7.4, 1.5 Hz,
Ar-H), 7.42 (1H, ddd, J¼7.4, 1.5, 0.6 Hz, Ar-H), 8.18 (1H,
d, J¼7.7 Hz, Ar-H). 13C NMR (CDCl3, 100 MHz) d: 23.8,
26.5, 47.2, 76.4, 116.5, 116.6, 123.9, 125.4, 128.8, 130.1,
138.3, 139.6, 170.3, 178.5. MS m/z (%): 245 (Mþ, 22), 190
(42), 162 (31), 148 (100), 130 (3), 102 (3), 90 (4), 43 (10).
HRMS m/z calcd for C14H15NO3: 245.1052. Found:
245.1052.
4.2.1. 1-Acetyl-3-allyl-3-hydroxyindolin-2-one (4a). Mp
98–101 8C (EtOAc–hexane). IR (CHCl3) cm21: 3559,
1
1763, 1717. H NMR (CDCl3, 300 MHz) d: 2.59 (3H, s,
–Ac), 2.60 (1H, dd, J¼13.1, 8.8 Hz, –CH2–), 2.68 (1H, dd,
J¼13.1, 6.2 Hz, –CH2–), 2.80 (1H, br, –OH), 5.07 (1H, d,
J¼11.2 Hz, –CHvCH2), 5.08 (1H, d, J¼16.0 Hz,
–CHvCH2), 5.49 (1H, m, –CHvCH2), 7.19 (1H, td,
J¼7.5, 1.0 Hz, Ar-H), 7.32 (1H, td, J¼7.5, 1.5 Hz, Ar-H),
7.37 (1H, ddd, J¼7.5, 1.5, 0.6 Hz, Ar-H), 8.15 (1H, d,
J¼7.5 Hz, Ar-H). MS m/z (%): 231 (Mþ, 11), 190 (47), 162
(22), 148 (100), 43 (11). HRMS m/z calcd for C13H13NO3:
231.0895. Found: 231.0896. Anal. Calcd for C13H13NO3: C,
67.52; H, 5.67; N, 6.06. Found: C, 67.39; H, 5.72; N, 5.82.
4.2.6. 3-(2-Methyl-2-propenyl)-3-hydroxyindolin-2-one
(5c). Mp 163 8C (EtOAc–hexane). IR (CHCl3) cm21
:
1
3435, 1736. H NMR (CDCl3, 300 MHz) d: 1.54 (3H, s,
–CMevCH2), 1.60 (1H, br, –OH), 2.68 (2H, s, –CH2–),
4.65 (1H, d, J¼1.1 Hz, –CMevCH2), 4.78 (1H, t,
J¼1.7 Hz, –CMevCH2), 6.83 (1H, d, J¼7.5 Hz, Ar-H),
7.05 (1H, td, J¼7.5, 0.9 Hz, Ar-H), 7.24 (1H, td, J¼7.5,
1.3 Hz, Ar-H), 7.35 (1H, d, J¼7.5 Hz, Ar-H), 7.76 (1H, br,
–NH). MS m/z (%): 203 (Mþ, 11), 185 (4), 148 (100), 119
(5), 92 (3), 65 (3). HRMS m/z calcd for C12H13NO2:
203.0946. Found: 203.0945. Anal. Calcd for C12H13NO2: C,
70.92; H, 6.45; N, 6.89. Found: C, 70.74; H, 6.54; N, 6.55.
4.2.2. 3-Allyl-3-hydroxyindolin-2-one (5a). Mp 112–
115 8C (EtOAc–hexane); [lit.20 123–124 8C]. IR (CHCl3)
cm21: 1728, 1624. 1H NMR (CDCl3, 400 MHz) d: 2.61 (1H,
dd, J¼13.2, 8.5 Hz, –CH2–), 2.75 (1H, dd, J¼13.2, 6.3 Hz,
–CH2–), 3.65 (1H, brs, –OH), 5.10 (1H, d, J¼18.1 Hz,
–CHvCH2), 5.11 (1H, d, J¼8.8 Hz, –CHvCH2), 5.65 (1H,
m, –CHvCH2), 6.88 (1H, d, J¼7.6 Hz, Ar-H), 7.07 (1H, t,
J¼7.6 Hz, Ar-H), 7.25 (1H, t, J¼7.3 Hz, Ar-H), 7.36 (1H, d,
J¼7.3 Hz, Ar-H). 13C NMR (CDCl3, 100 MHz) d: 42.9, 76.3,
110.3, 120.4, 122.9, 124.3, 129.5, 130.06, 130.14, 140.1,
180.0. MS m/z (%): 189 (Mþ, 9), 148 (100), 120 (3), 92 (3), 65
(3), 39 (2). HRMS m/z calcd for C11H11NO2: 189.0790.
Found: 189.0788.
4.2.7. 1-Acetyl-3-(1-phenyl-2-propenyl)-3-hydroxyindo-
lin-2-one (4d). Viscous oil. IR (CHCl3) cm21: 3550,
1
1765, 1715. H NMR (CDCl3, 300 MHz) d: 2.31 (3H£0.6,
s, –Ac), 2.55 (3H£0.4, s, –Ac), 2.97 (1H£0.6, br, –OH),
3.18 (1H£0.4, br, –OH), 3.82 (1H£0.4, d, J¼10.5 Hz,
–CH-Ph), 3.86 (1H£0.6, d, J¼8.3 Hz, –CH-Ph), 5.26
(1H£0.6, dt, J¼16.9, 1.3 Hz, –CHvCH2), 5.39 (1H, ddd,
J¼10.5, 2.4, 1.3 Hz, –CHvCH2), 5.43 (1H£0.4, dd,
J¼16.9, 1.3 Hz, –CHvCH2), 6.30 (1H£0.4, m,
–CHvCH2), 6.37 (1H£0.6, m, –CHvCH2), 6.70 (1H, m,
Ar-H), 6.9–7.5 (7H, m, Ph, Ar-H), 7.97 (1H£0.4, d,
J¼8.1 Hz, Ar-H), 7.99 (1H£0.6, d, J¼7.9 Hz, Ar-H). MS
m/z (%): 307 (Mþ, 0.3), 289 (0.5), 247 (0.6), 148 (12), 117
(100), 91 (4). HRMS m/z calcd for C19H17NO3: 307.1208.
Found: 307.1205.
4.2.3. 1-Acetyl-3-(2-methyl-3-buten-2-yl)-3-hydroxyin-
dolin-2-one (4b). Mp 73–75 8C (EtOAc–hexane). IR
(CHCl3) cm21: 3565, 1765, 1713. 1H NMR (CDCl3,
300 MHz) d: 1.06 (3H, s, C–Me), 1.17 (3H, s, C–Me),
2.61 (3H, s, –Ac), 2.84 (1H, brs, –OH), 5.14 (1H, dd,
J¼17.6, 1.1 Hz, –CHvCH2), 5.22 (1H, dd, J¼10.8,
1.1 Hz, –CHvCH2), 5.94 (1H, dd, J¼17.6, 10.8 Hz,
–CHvCH2), 7.21 (1H, td, J¼7.5, 1.1 Hz, Ar-H), 7.36
(1H, td, J¼7.7, 1.5 Hz, Ar-H), 7.42 (1H, dd, J¼7.5, 1.5 Hz,
Ar-H), 8.21 (1H, dt, J¼8.4, 0.6 Hz, Ar-H). MS m/z (%): 259
(Mþ, 0.2), 217 (0.2), 191 (100), 162 (9), 149 (80), 69 (55),
41 (14). HRMS m/z calcd for C15H17NO3: 259.1208. Found:
259.1208.
The ratio (1:1.4) of two diastereoisomers was determined by
HPLC.
4.2.8. 3-(1-Phenyl-2-propenyl)-3-hydroxyindolin-2-one
(5d). Mp 179–181 8C (EtOAc–hexane) [lit.18 mp 160–
162 8C; 1:1 diastereomer mixture]. IR (CHCl3) cm21: 3420,
1736. 1H NMR (CDCl3, 300 MHz) d: 2.79 (1H, brs, –OH),
3.85 (1H£0.4, d, J¼9.7 Hz, –CH-Ph), 3.88 (1H£0.6, d,
J¼8.1 Hz, –CH-Ph), 5.25 (1H£0.4, dt, J¼17.0, 1.4 Hz,
4.2.4. 3-(2-Methyl-3-buten-2-yl)-3-hydroxyindolin-2-one
(5b). Mp 188–190 8C (EtOAc–hexane). IR (CHCl3) cm21
3431, 1732. H NMR (CDCl3, 300 MHz) d: 1.12 (3H, s,
C–Me), 1.18 (3H, s, C–Me), 2.84 (1H, brs, –OH), 5.15
(1H, dd, J¼17.4, 1.2 Hz, –CHvCH2), 5.24 (1H, dd,
:
1

T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
3499
–CHvCH2), 5.3–5.4 (1H, m, –CHvCH2), 5.44 (1H£0.6,
dd, J¼17.0, 1.4 Hz, –CHvCH2), 6.3–6.55 (1H, m,
–CHvCH2), 6.63 (1H, m, Ar-H), 6.8–7.55 (7H, m, Ar-
H). MS m/z (%): 265 (Mþ, 2), 247 (2), 148 (38), 117 (100),
91 (7). HRMS m/z calcd for C17H15NO2: 265.1103. Found:
265.1095.
The ratio (4:1) of two diastereoisomers was determined by
HPLC.
4.2.13. 2-[2-(Acetylamino)phenyl]-2-hydroxypent-4-
enoic acid (6). Viscous oil. IR (CHCl3) cm21: 3437,
3368, 1740, 1624. 1H NMR (CDCl3, 300MHz) d: 2.07
(3H, s, –COMe), 2.61 (1H, dd, J¼13.6, 7.9 Hz, –CH2–
CHv), 2.81 (1H, ddt, J¼13.6, 6.4, 1.2 Hz, –CH2–CHv),
5.09 (1H, dq, J¼17.2, 1.0 Hz, –CHvCH2), 5.10 (1H, dq,
J¼9.5, 1.0 Hz, –CHvCH2), 5.62 (1H, dddd, J¼16.3, 11.0,
8.3, 6.6 Hz, –CHvCH2), 6.85 (1H, d, J¼7.7 Hz, Ar-H),
7.03 (1H, td, J¼7.5, 0.9 Hz, Ar-H), 7.21 (1H, d, J¼7.7 Hz,
Ar-H), 7.26 (1H, td, J¼7.7, 1.3 Hz, Ar-H). 13C NMR
(CDCl3, 75 MHz) d: 22.6, 40.9, 79.4, 110. 0, 120.7, 122.6,
123.3, 127.6, 129.2, 129.7, 140.6, 169.0, 171.2, 175.6. MS
m/z (%): 213 (Mþ2H2O, 23), 190 (13), 148 (100). HRMS
(Mþ2H2O) m/z calcd for C13H13NO3: 231.0896. Found:
231.0900.
The ratio (1.1:1) of two diastereoisomers was determined by
HPLC.
4.2.9. (E)-1-Acetyl-3-(2-butenyl)-3-hydroxyindolin-2-one
(4e). Mp 50–55 8C (EtOAc–hexane). IR (CHCl3) cm21
:
3561, 1765, 1713. 1H NMR (CDCl3, 300 MHz) d: 1.60 (3H,
d, J¼6.3 Hz, –CHvCHMe), 2.61 (3H, s, –Ac), 2.5–2.69
(2H, m, –CH2–CHvCH), 2.97 (1H, br, –OH), 5.19 (1H,
dddd, J¼15.2, 8.7, 6.3, 1.7 Hz, –CHvCHMe), 5.56 (1H,
dq, J¼15.2, 6.3 Hz, –CHvCHMe), 7.23 (1H, td, J¼7.5,
1.1 Hz, Ar-H), 7.36 (1H, td, J¼7.5, 1.8 Hz, Ar-H), 7.42
(1H, ddd, J¼7.5, 1.5, 0.6 Hz, Ar-H), 8.18 (1H, d, J¼8.2 Hz,
Ar-H). MS m/z (%): 245 (Mþ, 12), 203 (3), 191 (43),
162 (32), 148 (100), 130 (3), 102 (3), 90 (4), 43(11).
HRMS m/z calcd for C14H15NO3: 245.1051. Found:
245.1053.
4.3. Synthesis of (6)-donaxaridine (1)
4.3.1. Hydrolysis of 1-acetyl-3-allyl-3-hydroxyindolin-2-
one (4a) to 3-allyl-3-hydroxyindolin-2-one (5a). A
solution of 4a (51 mg, 0.2 mmol) and LiOH (10%, 0.1 ml)
in MeOH (2 ml) was stirred at room temperature for 75 min.
The resulting mixture was evaporated under reduced
pressure to give a residue, which was extracted with
EtOAc. The extract was washed with water, dried over
MgSO4, and concentrated under reduced pressure to give a
residue. The residue was purified by column chromato-
graphy on silica gel with EtOAc–hexane (2:1) as an eluent
to give 5a (45 mg, 85%).
4.2.10. (E)-3-(2-Butenyl)-3-hydroxyindolin-2-one (5e).
Mp 115–120 8C (EtOAc–hexane). IR (CHCl3) cm21
:
1
3435, 1726. H NMR (CDCl3, 300 MHz) d: 1.61 (3H, d,
J¼6.4 Hz, –CHvCHMe), 2.52 (1H, dd, J¼13.5, 8.5 Hz,
–CH2–CHvCH), 2.63 (1H, dd, J¼13.5, 6.4 Hz, –CH2–
CHvCH), 5.31 (1H, ddd, J¼15.0, 8.4, 6.4 Hz,
–CHvCHMe), 5.63 (1H, dq, J¼15.0, 6.4 Hz,
–CHvCHMe), 6.84 (1H, d, J¼7.6 Hz, Ar-H), 7.06 (1H,
td, J¼7.6, 0.9 Hz, Ar-H), 7.25 (1H, td, J¼7.6, 1.3 Hz,
Ar-H), 7.34 (1H, d, J¼7.6 Hz, Ar-H), 7.67 (1H, br, –NH).
MS m/z (%): 203 (Mþ, 12), 185 (7), 170 (8), 148 (100), 119
(3), 92 (4), 65 (3). HRMS m/z calcd for C12H13NO2:
203.0946. Found: 203.0943.
4.3.2. 3-(2-Methylaminoethyl)-3-hydroxyindolin-2-one
[(6)-donaxaridine, 1].
A solution of 5a (89 mg,
0.47 mmol), OsO4 (4% in water, 182 ml, d¼4.9,
0.14 mmol), and NMO (50% in water, 194 ml, d¼1.13,
0.94 mmol) in MeCN (3.5 ml) was stirred at room
temperature for 2 h. The reaction mixture was filtered
through Celitew 545. The filtrate was concentrated under
reduced pressure to give a residue containing 1,2-diol. A
solution of the residue and NaIO4 (100 mg, 0.78 mmol) in
1,4-dioxane–H2O (1.5 ml, 2:1) was stirred at room
temperature for 10 min. After diluting the resulting mixture
with diethyl ether, the organic layer was washed with H2O,
and the aqueous layer was extracted with EtOAc. The
combined organic solution was dried over MgSO4, and
concentrated under reduced pressure to give the crude
aldehyde 7 [IR (CHCl3) cm21; 3435, 1738, 1728. 1H NMR
(CDCl3, 300 MHz) d: 2.95 (1H, dd, J¼16.6, 1.7 Hz,
–CH2CHO), 3.02 (1H, dd, J¼16.6, 1.7 Hz, –CH2CHO),
4.24 (1H, br, OH), 6.89 (1H, d, J¼7.7 Hz, Ar-H), 7.05 (1H,
t, J¼7.7 Hz, Ar-H), 7.25 (1H, t, J¼7.7 Hz, Ar-H), 7.32 (1H,
d, J¼7.7 Hz, Ar-H), 8.54 (1H, br, NH), 9.80 (1H, t,
J¼1.7 Hz, –CH2CHO)], which was used without further
purification because of its instability.
4.2.11. 1-Acetyl-3-(2-cyclohexenyl)-3-hydroxyindolin-2-
one (4f). Mp 158–160 8C (EtOAc–hexane). IR (CHCl3)
cm21: 3550, 1738. 1H NMR (CDCl3, 300 MHz) d: 0.7–2.0
(6H, m, –(CH2)3–), 2.58 and 2.59 (3H, s, –COMe), 2.77
(1H, m, –CH–CH2–), 5.6–5.9 (2H, m, –CHvCH–), 7.1–
7.2 (1H, m, Ar-H), 7.25–7.4 (2H, m, Ar-H), 8.17 (1H, d,
J¼8.3 Hz, Ar-H). MS m/z (%): 271 (Mþ, 1), 253 (9), 211
(12), 191 (100), 149 (69), 81 (73), 43 (8). HRMS m/z calcd
for C16H17NO3: 271.1208. Found: 271.1210.
The ratio (2:1) of two diastereoisomers was determined by
HPLC.
4.2.12. 3-(2-Cyclohexenyl)-3-hydroxyindolin-2-one (5f).
Mp 158–163 8C (EtOAc–hexane). IR (CHCl3) cm21
:
1
3440, 1728. H NMR (CDCl3, 300 MHz) d: 0.87 (1H, m,
–CH), 1.4–2.0 (5H, m, –(CH2)3–), 2.80 (1H, m, –CH–
CH2–), 5.6–5.8 (2H£0.2, m, –CHvCH–), 5.95 (1H£0.8,
m, –CHvCH–), 6.07 (1H£0.8, m, –CHvCH–), 6.85 (1H,
d, J¼7.5 Hz, Ar-H), 7.04 (1H£0.8, td, J¼7.5, 0.9 Hz,
Ar-H), 7.07 (1H£0.2, td, J¼7.5, 0.9 Hz, Ar-H), 7.3–7.45
(2H, m, Ar-H). MS m/z (%): 229 (Mþ, 3), 149 (100), 119
(3), 92 (3), 81 (23), 65 (3). HRMS m/z calcd for C14H15NO2:
229.1103. Found: 229.1094. Anal. Calcd for C14H15NO2: C,
73.34; H, 6.59; N, 6.11. Found: C, 73.04; H, 6.34; N, 5.88.
A solution of 7 and MeNH2·HCl (56 mg, 0.85 mmol) in
MeOH (2.7 ml) was stirred at room temperature. After
disappearance of 7 was confirmed by TLC (3 h), NaBH3CN
(82 mg, 1.3 mmol) was added to the reaction mixture at
room temperature. The mixture was stirred for 36 h and
extracted with CH2Cl2. The extract was washed with H2O,

3500
T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
dried over MgSO4, and concentrated under reduced pressure
to give a residue. The residue was subjected to chromato-
graphy on a silica gel column with EtOAc–hexane (2: 1) as
an eluent to give (^)-donaxaridine (1, 40 mg, 41%). Mp
175 8C; [lit.1a 175–176 8C]. IR (KBr) cm21; 3404, 3236,
(1H, d, J¼15.9 Hz, –CH2CO–), 3.25 (1H, d, J¼15.9 Hz,
–CH2CO–), 6.83 (1H, d, J¼7.8 Hz, Ar-H), 7.02 (1H, t,
J¼7.8 Hz, Ar-H), 7.21–7.29 (2H, m, Ar-H), 7.46 (1H, brs,
–NH). MS (FAB) m/z (%): 320 (MHþ, 54), 262 (37), 188
(38), 146 (100), 73 (44). HRMS (FAB, MHþ) m/z calcd for
C17H25NO3Si: 320.1682. Found: 320.1671.
1
1673, 1613, 1470, 1308. H NMR (CDCl3, 300 MHz) d:
2.42 (1H, td, J¼12.8, 9.0 Hz, –C–CH2–CH2–), 2.77 (1H,
ddd, J¼12.8, 6.2, 1.7 Hz, –C–CH2–CH2–), 2.97 (3H, s,
–NMe), 3.26 (1H, td, J¼9.5, 6.2 Hz, –CH2–N–), 3.34 (1H,
ddd, J¼9.5, 9.5, 1.7 Hz, –CH2–N–), 4.31 (1H, brs, –OH),
4.71 (1H, br, –NH), 6.69 (1H, td, J¼7.6, 1.3 Hz, Ar-H),
6.72 (1H, dd, J¼7.9, 0.7 Hz, Ar-H), 6.88 (1H, dd, J¼7.6,
1.5 Hz, Ar-H), 7.11 (1H, td, J¼7.6, 1.5 Hz, Ar-H). MS m/z
(%): 206 (Mþ, 100), 188 (9), 177 (8), 173 (7), 159 (6), 149
(42), 148 (11), 147 (29), 146 (37), 135 (24), 130 (19), 120
(58), 93 (13), 92 (18), 77 (6), 65 (15), 58 (43). HRMS m/z
calcd for C11H14N2O2:206.1055. Found: 206.1050.
4.4.3. 3-(2-Oxopropyl)-3-hydroxyindolin-2-one (11). A
solution of TBDMS derivative 10 (8.4 mg, 0.026 mmol),
TBAF (1.0 M, 22 ml, 22 mmol), and AcOH (15 ml) in THF
(1 ml) was stirred at room temperature for 3 days. After
addition of EtOAc, the organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by preparative TLC
with EtOAc as a developing solvent to give 3-hydroxy-
indolin-2-one 11 (2.5 mg, 50%). Mp 165–168 8C [lit.9a mp
166–168 8C]. IR (CHCl3) cm21: 3445, 1740, 1624. 1H
NMR (300 MHz, CDCl3) d: 2.20 (3H, s, –COMe), 2.97
(1H, d, J¼17.0 Hz, –CH2CO–), 3.19 (1H, d, J¼17.0 Hz,
–CH2CO–), 4.37 (1H, br, –OH), 6.87 (1H, d, J¼7.5 Hz,
Ar-H), 7.05 (1H, td, J¼7.5, 0.9 Hz, Ar-H), 7.27 (1H, td,
J¼7.5, 1.2 Hz, Ar-H), 7.35 (1H, d, J¼7.5 Hz, Ar-H), 7.65
(1H, br, –NH). MS m/z (%): 205 (Mþ, 88), 187 (24), 172
(27), 162 (98), 148 (100), 120 (72), 92 (41), 43 (36). HRMS
m/z calcd for C11H11NO3: 205.0739. Found: 205.0742.
4.4. Synthesis of 3-acetonyl-3-hydroxyindolin-2-one (11)
4.4.1. 3-Allyl-3-tert-butyldimethylsilyloxyindolin-2-one
(9). A solution of 3-hydroxyindolin-2-one 5a (57 mg,
0.3 mmol), 2,6-lutidine (128 mg, 1.2 mmol), and tert-
butyldimethylsilyl triflate (317 mg, 1.2 mmol) in dry
CH2Cl2 (4 ml) was stirred at 0 8C to room temperature for
1 h. The reaction mixture was diluted with CH2Cl2. The
organic layer was washed with brine, dried over MgSO4,
and evaporated to give a residue, of which a solution in
THF–AcOH–H2O (1:1:1, l ml) was stirred at 80 8C for 5 h.
The resulting mixture was diluted with CH2Cl2. The organic
layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure to give a residue,
which was purified by silica gel column chromatography
with EtOAc–hexane (1:3) as an eluent to give TBDMS
ether 9 (67 mg, 73%). viscous oil. IR (CHCl3) cm21: 1720.
1H NMR (300 MHz, CDCl3) d: 20.26 (3H, s, –SiMe), 0.06
(3H, s, –SiMe), 0.87 (9H, s, –SitBu), 2.53 (1H, dd, J¼13.4,
8.2 Hz, –CH2CHv), 2.74 (1H, dd, J¼13.4, 6.4 Hz,
–CH2CHv), 5.02 (2H, m, –CHvCH2), 5.66 (1H, m,
–CHvCH2), 6.86 (1H, d, J¼7.7 Hz, Ar-H), 7.03 (1H, dd,
J¼7.7, 8.3 Hz, Ar-H), 7.25 (2H, m, Ar-H), 8.74 (1H, brs,
–NH). 13C NMR (CDCl3, 100 MHz) d: 23.9, 23.5, 18.2,
25.8, 44.3, 78.0, 110.2, 119.1, 122.2, 124.6, 129.2, 130.9,
131.0, 140.0, 180.0. MS (FAB) m/z (%): 304 (MHþ, 11),
246 (18), 205 (19), 172 (100). HRMS (FAB, MHþ) m/z
calcd for C17H26NO2Si: 304.1733. Found: 304.1739.
4.5. Syntheses of (6)-convolutamydines A (2a) and E
(2b)
4.5.1. 1-Acetyl-4,6-dibromo-3-hydroxy-2-methoxy-
indoline (13). A solution of 1-acetyl-4,6-dibromoindole29
(12, 7.0 g, 22.0 mmol) and hexamethylphosphoramide-
oxodiperoxomolybdenum (VI) (MoO5·HMPA) (17.2 g
46.3 mmol) in MeOH (450 ml) was stirred at room
temperature for a week. The resulting mixture was
concentrated under reduced pressure, treated with sat.
Na2SO3, and extracted with CH2Cl2. The extract was
washed with H2O, dried over MgSO4, and concentrated
under reduced pressure. The obtained residue was purified
by silica gel column chromatography with EtOAc–hexane
(1:1) as an eluent to give 3-hydroxy-2-methoxyindoline 13
(7.2 g, 90%). Mp 165–168 8C (CH2Cl2). IR (CHCl3) cm21
:
1
3600, 1686. H NMR ?300 MHz, CDCl3) d: 2.32 (3H, s,
N–COMe), 2.37 (1H, brs, OH), 3.43 (3H, s, –OMe), 4.89
(1H, brs, –CH–OH), 5.28 (1H, brs, –CH–OMe), 7.46 (1H,
d, J¼1.7 Hz, Ar-H), 8.27 (1H, br, Ar-H). MS m/z (%): 367
(Mþ4, 25), 365 (Mþ2, 53), 363 (Mþ, 26), 324 (47), 322
(89), 320 (43), 292 (62), 290 (100), 288 (46), 280 (26), 278
(21), 263 (16), 213 (10), 211 (16), 149 (13), 43 (59). HRMS
m/z calcd for C11H11Br2NO3: 362.9106. Found: 362.9106.
4.4.2. Typical procedure for Wacker oxidation of 3-
allylindolin-2-one 9 to 3-(2-oxopropyl)-3-TBDMS-oxy-
indolin-2-one (10). A suspension of palladium (II) chloride
(8 mg, 0.0043 mmol) and copper (I) chloride (4.3 mg,
0.043 mmol) in dioxane–H2O (7:1, 1 ml) was vigorously
stirred with bubbling oxygen gas at room temperature for
1 h. The indolin-2-one 9 (13 mg, 0.043 mmol) was added to
the mixture. After heating at 50 8C for 5 h, the reaction
mixture was cooled to room temperature and diluted with
CH2Cl2. The precipitate was filtered off, and the filtrate was
dried over MgSO4, and evaporated off. The obtained residue
was purified by flash silica gel column chromatography with
EtOAc–hexane (2:3) as an eluent to give 3-(2-oxopropyl)-
indolin-2-one 10 (12 mg, 88%). viscous oil. 1H NMR
(300 MHz, CDCl3) d: 20.19 (3H, s, –SiMe), 0.08 (3H, s,
–SiMe), 0.95 (9H, s, –SitBu), 2.14 (3H, s, –COMe), 3.07
4.5.2. 1-Acetyl-4,6-dibromoindolin-3-one (14). A solution
of 13 (364 mg, 1.0 mmol) and 10-camphorsulfonic acid
(715 mg, 3.08 mmol) in MeCN was heated under reflux for
30 min. The reaction mixture was evaporated under reduced
pressure and extracted with EtOAc. The extract was washed
with sat. NaHCO3 and brine, dried over MgSO4, and
concentrated under reduce pressure. The residue was
purified by silica gel column chromatography with
EtOAc–hexane (1:1) as an eluent to give indolin-3-one 14
(186 mg, 56%). Mp 160–164 8C (EtOAc–hexane). IR
1
(CHCl3) cm21: 1727, 1693. H NMR (300 MHz, CDCl3)
d: 2.33 (3H, s, N–COMe), 4.32 (2H, s, COCH2N–), 7.49

T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
3501
(1H, d, J¼1.5 Hz, Ar-H), 8.76 (1H, brs, Ar-H). 13C NMR
(CDCl3, 100 MHz) d: 24.5, 56.7, 119.5, 120.4, 121.5, 131.5,
132.1, 155.0, 167.8, 190.7. MS m/z (%): 335 (Mþ4, 23), 333
(Mþ2, 47), 331 (Mþ, 24), 293 (48), 291 (100), 289 (51), 263
(23), 43 (25). HRMS m/z calcd for C10H7Br2NO2: 330.8844.
Found: 330.8836.
an eluent to give (^)-convolutamydine E (2b, 6.6 mg,
65%). Mp 204–206 8C (CHCl3) [lit.2c oil]. IR (KBr) cm21
:
1
3350, 1736, 1605, 1261, 1088, 801. H NMR (300 MHz,
C5D5N) d: 3.10 (2H, t, J¼7.3 Hz, –C–CH2CH2O–), 3.96
(2H, m, –C–CH2CH2O–), 7.02 (1H, d, J¼1.6 Hz, Ar-H),
7.41 (1H, d, J¼1.6 Hz, Ar-H), 8.31 (1H, s, –NH). 13C NMR
(C5D5N, 125 MHz) d: 39.3, 58.1, 77.4, 112.6, 112.6, 120.9,
128.2, 130.2, 146.7, 180.6. MS (FAB) m/z (%): 354
(MHþþ4, 50), 352 (MHþþ2, 99), 350 (MHþ, 53), 336
(20), 334 (32), 332 (16), 306 (57), 304 (100), 302 (50).
HRMS (FAB, MHþ) m/z calcd for C10H9Br2NO3: 349.9027.
Found: 349.9031.
4.5.3. 3-Allyl-4,6-dibromo-3-hydroxyindolin-2-one (16).
A solution of bromine (1.0 M in CH2Cl2, 78 ml) was added
to a solution of 14 (7.8 mg, 23.5 mmol) in CH2Cl2 at 0 8C for
2 h. The reaction mixture was extracted with EtOAc, and the
extract was then washed with sat. NaHCO3 and brine, dried
over MgSO4, and concentrated under reduce pressure to
give a residue. A mixture of the residue (9.7 mg), allyl
alcohol (d¼0.85, 6.2 ml, 91 mmol) and MS 4A (22 mg) in
DMF (1 ml) was stirred at room temperature for 2 days. The
reaction mixture was diluted with diethyl ether and filtrated
through Celitew 545. The filtrate was evaporated under
reduced pressure to give a residue, which was extracted with
EtOAc and 5% NH4OH. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The obtained residue (9.1 mg) and DBU (3.6 mg,
23.5 mmol) in toluene (1 ml) was stirred at 40 8C for 3 h.
The mixture was neutralized with AcOH, diluted in H2O,
and extracted with EtOAc. The extract was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. A mixture of the residue and 10% LiOH (25 ml) in
MeOH was stirred at room temperature for 3 days. After
evaporation, an EtOAc solution of the residue was washed
with H2O and brine, dried over MgSO4, and concentrated.
The residue was purified by silica gel column chromato-
graphy with EtOAc–hexane (1:1) as an eluent to give
indolin-2-one 16 (6.9 mg, 84%). Mp 220–222 8C (EtOAc–
hexane). IR (KBr) cm21: 3378, 1733, 1641. 1H NMR
(300 MHz, acetone-d6) d: 2.59 (1H, dd, J¼12.8, 7.4 Hz,
–CH2–), 3.08 (1H, dd, J¼12.8, 7.4 Hz, –CH2–), 4.77 (1H,
ddt, J¼10.1, 2.2, 1.3 Hz, vCH2), 4.91 (1H, ddt, J¼17.3,
2.2, 1.3 Hz, vCH2), 5.09 (1H, s, –OH), 5.22 (1H, ddt,
J¼17.3, 10.1, 7.4 Hz, –CHvCH2), 6.94 (1H, d, J¼1.7 Hz,
Ar-H), 7.22 (1H, d, J¼1.7 Hz, Ar-H). MS m/z (%): 349
(Mþ4, 2), 347 (Mþ2, 4), 345 (Mþ, 2), 308 (49), 306 (100),
304 (51). HRMS m/z calcd for C11H9Br2NO2: 344.9000.
Found: 344.9003.
4.5.5. 3-Allyl-4,6-dibromo-3-(tert-butyldimethylsilyl-
oxy)indolin-2-one (17). A solution of 3-hydroxyindolin-2-
one 16 (59 mg, 0.17 mmol), TBDMSOTf (235 mg,
0.89 mmol), and 2,6-lutidin (95 mg, 0.89 mmol) in
CH2Cl2 was stirred at 0 8C to room temperature. After 3
days, the reaction mixture was quenched with brine and
extracted with CH2Cl2. The extract was dried over MgSO4
and concentrated under reduced pressure. A solution of the
residue in AcOH–THF–H2O (1:1:1, 1 ml) was stirred at
80 8C for 2 h. After cooling, the reaction mixture was
extracted with EtOAc. The extract was washed with H2O
and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to chromato-
graphy on a silica gel column with EtOAc–hexane (1:4) as
an eluent to give 3-silyloxy-indolin-2-one 17 (56 mg, 69%).
Viscous oil. IR (CHCl3) cm21: 3427, 1732, 1641. 1H NMR
(300 MHz, CDCl3) d: 20.13 (3H, s, –SiMe), 0.06 (3H, s,
–SiMe), 0.90 (9H, s, –SitBu), 2.78 (1H, dd, J¼12.8, 7.5 Hz,
vCH–CH–), 3.24 (1H, dd, J¼12.8, 7.0 Hz, vCH–CH–),
4.92 (1H, d, J¼9.9 Hz, CvCH2), 5.17 (1H, d, J¼16.5 Hz,
CvCH2), 5.29 (1H, m, –CHvCH2), 6.97 (1H, d,
J¼1.4 Hz, Ar-H), 7.34 (1H, d, J¼1.4 Hz, Ar-H), 8.25 (1H,
br, NH). 13C NMR (CDCl3, 100 MHz) d: 23.5, 23.4, 18.4,
25.8, 40.7, 79.3, 112.3, 120.0, 120.5, 123.2, 127.8, 129.4,
129.7, 142.6, 177.3. MS (FAB) m/z (%): 464 (MHþþ4, 4),
462 (MHþþ2, 7), 460 (MHþ, 5), 4221 (7), 420 (10), 4187
(6), 4065 (15), 404 (24), 402 (12), 365 (12), 363 23), 361
12), 332 (51), 330 (100), 328 (52). HRMS (FAB, MHþ) m/z
calcd for C17H23Br2NO2Si: 459.9943. Found: 459.9920.
4.5.6. 4,6-Dibromo-3-(tert-butyldimethylsilyloxy)-3-(2-
oxopropyl)indolin-2-one (18). A suspension of palladium
(II) chloride (3.2 mg, 0. 019 mmol) and copper (I) chloride
(18.8 mg, 0.19 mmol) in dioxane–H2O (7:1, 3 ml) was
vigorously stirred with bubbling oxygen gas at room
temperature for 1 h under oxygen atmosphere. The
indolin-2-one 17 (87 mg, 0.19 mmol) was added to the
mixture. After heating at 50 8C for 24 h, the reaction
mixture was cooled to room temperature and diluted with
CH2Cl2. The precipitate was filtered off, and the filtrate was
dried over MgSO4, and evaporated off. The obtained residue
was purified by flash silica gel column chromatography with
EtOAc–hexane (1:1) as an eluent to give 3-(tert-butyl-
dimethylsilyloxy)-3-(2-oxopropyl)indolin-2-one (18, 11 mg,
12%). Viscous oil. IR (CHCl3) cm21: 3431, 1747, 1718. 1H
NMR (300 MHz, CDCl3) d: 20.21 (3H, s, –SiMe), 0.04 (3H,
s, –SiMe), 0.87 (9H, s, –SitBu), 2.08 (3H, s, –COMe), 3.31
(1H, d, J¼18.2 Hz, –CHCO–), 3.99 (1H, d, J¼18.2 Hz,
–CHCO–), 6.97 (1H, d, J¼1.4 Hz, Ar-H), 7.27 (1H, d,
J¼1.4 Hz, Ar-H), 7.56(1H,br, –NH).MS(FAB)m/z(%):480
4.5.4. (6)-Convolutamydine E (2b). A solution of 3-
allylindolin-2-one 16 (10 mg, 29 mmol), OsO4 (4% aqueous
solution, d¼1.04, 53 ml, 8.7 mmol), and NMO (50%
aqueous solution, d¼1.13, 13 ml, 63 mmol) in MeCN
(3 ml) was stirred at room temperature for 1 h. The reaction
mixture was evaporated under reduced pressure. A solution
of the residue and NaIO4 (7.5 mg, 30 mmol) in aqueous 1,4-
dioxan (3 ml) was stirred at room temperature for 1 h. The
reaction mixture was extracted with EtOAc, and the extract
was then washed with H2O and brine, dried over MgSO4,
and concentrated under reduced pressure. To a solution of
the residue in MeOH (2 ml), NaBH4 (11 mg, 0.3 mmol) was
gradually added at 0 8C, and the mixture was then stirred at
0 8C for 30 min. After adding aqueous NH4Cl followed by
evaporating the MeOH under reduced pressure, the residue
was extracted with EtOAc. The organic layer was washed
with H2O and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography with EtOAc–hexane (3:1) as

3502
T. Kawasaki et al. / Tetrahedron 60 (2004) 3493–3503
(MHþþ4, 14), 478 (MHþþ2, 26), 476 (MHþ, 13), 422 (12),
420 (23), 418 12), 348 (16), 346 (30), 344 (16), 306 (50), 34
(100), 302 (34). HRMS (FAB, MHþ) m/z calcd for C17H23-
Br2NO3Si: 475.9892. Found: 475.9879.
M.; Dzurilla, M.; Balentova, E. J. Org. Chem. 2001, 66,
3940–3947.
4. Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L.
J. Nat. Prod. 1999, 62, 569–572.
´ ´
5. Frechard, A.; Fabre, N.; Pean, C.; Montaut, S.; Fauvel, M.-T.;
´
Rollin, P.; Fouraste, I. Tetrahedron Lett. 2001, 42,
9015–9017.
4.5.7. (6)-Convolutamydine A (2a). Tris(dimethylamino)-
sulfur (trimethylsilyl)difluoride (TAS-F) (6.4 mg, 23 mmol)
was gradually added to a stirred solution of indolin-2-one 17
(11 mg, 23 mmol) in dry DMF (1 ml) at 0 8C. The mixture
was stirred at 15 8C for 2.5 h, diluted with EtOAc, washed
with sat. KHSO4, and extracted with EtOAc. The extract
was dried over MgSO4 and evaporated. The obtained
residue was purified by silica gel column chromatography
with EtOAc–hexane (3:2) as an eluent to give (^)-
convolutamydine A (2a, 6.3 mg, 75%). Mp 192–195 8C
(EtOAc–hexane) [lit.2b mp 190–195 8C]. IR (CHCl3)
6. Isolation: (a) Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi,
K.; Okuda, T.; Ohnuki, T.; Komatsubara, S. J. Antibiot. 2000,
53, 105–109. Structure: (b) Khono, J.; Koguchi, Y.; Nishio,
M.; Nakao, K.; Juroda, M.; Shimizu, R.; Ohnuki, T.;
Komatsubara, S. J. Org. Chem. 2000, 65, 990–995. Synthesis:
(c) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
512–515. (d) Albrecht, B. K.; Williams, R. M. Org. Lett.
2003, 5, 197–200.
7. Others: (a) Pedras, M. S.; Montaut, S.; Xu, Y.; Khan, A. Q.;
Loukaci, A. Chem. Commun. 2001, 1572–1573.
(b) Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.;
Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.;
Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem.
2002, 45, 1487–1499. (c) Codding, P. W.; Lee, T. A.;
Richardson, J. F. J. Med. Chem. 1984, 27, 649–654. (d) Popp,
F. D.; Pajouhesh, H. J. Pharm. Sci. 1982, 71, 1052–1054.
8. Sundberg, R. J. The chemistry of indoles; Academic: New
York, 1970; pp 341–392.
1
cm21: 3430, 1747, 1610. H NMR (300 MHz, CDCl3) d:
2.16 (3H, s, –COMe), 3.34 (1H, d, J¼17.3 Hz, –CHCO–),
3.73 (1H, d, J¼17.3 Hz, –CHCO–), 5.12 (1H, br, –OH),
7.00 (1H, d, J¼1.6 Hz, Ar-H), 7.32 (1H, d, J¼1.7 Hz,
Ar-H), 7.74 (1H, s, –NH). MS m/z (%): 365 (Mþ4, 20), 363
(Mþ2, 42), 361 (Mþ, 21), 322 (8), 320 (16), 318 (10), 308
(47), 306 (100), 304 (59), 279 (44), 277 (91), 275 (48), 252
(14), 250 (31), 248 (18), 170 (18), 168 (18), 88 (12). HRMS
m/z calcd for C11H9Br2NO3: 360.8949. Found: 360.8947.
9. Aldol condensation of isatins with methylketones: (a) Garden,
S. J.; da Silva, R. B.; Pinto, A. C. Tetrahedron 2002, 58,
8399–8412. (b) Beccalli, E. M.; Marchesini, A.; Pilati, T.
J. Chem. Soc., Perkin Trans. 1 1994, 579–587. (c) Pajouhesh,
H.; Parson, R.; Popp, F. D. J. Pharm. Sci. 1983, 72, 318–321.
(d) Popp, F. D. J. Heterocycl. Chem. 1982, 19, 589–592.
10. Addition of Grignard reagent to isatins: (a) Sharma, V. M.;
Prasanna, P.; Seshu, K. V. A.; Renuka, B.; Rao, C. V. L.;
Kumar, G. S.; Narasimhulu, C. P.; Babu, P. A.; Puranik, R. C.;
Subramanyam, D.; Venkateswarlu, A.; Rajagopal, S.; Kumar,
K. B. S.; Rao, C. S.; Mamidi, N. V. S. R.; Deevi, D. S.;
Ajaykumar, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett.
2002, 12, 2303–2307. (b) Hewawasam, P.; Gribkoff, V. K.;
Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez, E.;
Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.;
Yeleswaram, K.; Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone,
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Acknowledgements
We wish to thank N. Eguchi and T. Koseki, S. Kubota, and
T. Suzuki in the Analytical Center of our University for
conducting microanalysis and obtaining mass spectra. This
work was financially supported by a Grant-in-Aid (No.
14572018) for Scientific Research (C) from the Ministry of
Education, Science, Sports, and Culture, Japan.
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