Asymmetric Alkylation of 2-Monosubstituted Indolin-3-ones

Article abstract of DOI:10.3987/COM-07-S(U)42

The asymmetric alkylation of 2-monosubstituted indolin-3-ones with optically active phase transfer catalysts (PTCs) has been studied. The prenylation of 2-benzyl indolin-3-one gave 2,2-dialkylated indolin-3-one 9a in 99% yield and 65% enantioselectivity.

Full text of DOI:10.3987/COM-07-S(U)42

HETEROCYCLES, Vol. 73, 2007
641
HETEROCYCLES, Vol. 73, 2007, pp. 641 - 650. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2007, Accepted, 10th August, 2007, Published online, 17th August, 2007. COM-07-S(U)42
ASYMMETRIC ALKYLATION OF 2-MONOSUBSTITUTED
INDOLIN-3-ONES
Kazuhiro Higuchi, Kouhei Masuda, Tamami Koseki, Masahiro Hatori,
Masanori Sakamoto, and Tomomi Kawasaki*
Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose, Tokyo 204-8588,
Japan; E-mail: kawasaki@my-pharm.ac.jp
Abstract – The asymmetric alkylation of 2-monosubstituted indolin-3-ones with
optically active phase transfer catalysts (PTCs) has been studied. The
prenylation of 2-benzyl indolin-3-one gave 2,2-dialkylated indolin-3-one 9a in
99% yield and 65% enantioselectivity. The alkylation was investigated with
various 2-monosubstituted indolin-3-ones 5a-e and alkyl halides. The absolute
configuration of 5d was determined by derivatization to the known amino acid.
INTRODUCTION
2,2-Dialkylsubstituted indolin-3-ones 1 are key intermediates in the synthesis of biologically active
alkaloids such as brevianamide A (2),1 austamide (3)2 and hinckdentine A (4).3 There are a few
examples of the construction of quaternary carbon center for 1, and it therefore remains a challenging
theme.4
We previously developed efficient synthetic methodology for 2-monoalkylsubstituted
indolin-3-ones 5, and investigated the chemistry.5 In this study, we have described the asymmetric
alkylation of 5 with optically active phase transfer catalysts (PTCs).
O
O
O
Br
H
O
O
H
H
N
NH
R1
R2
O
N
H
N
H
N
N
N
N
N
Br
O
Br
H
H
O
1
N
2
austamide (3)
4
hinckdentine A ( )
brevianamide A ( )
Figure 1

642
HETEROCYCLES, Vol. 73, 2007
RESULTS AND DISCUSSION
Synthetic application of PTCs has various advantages, for example ease of procedure, large-scale
synthesis, easy tuning of the PTC substituent and so on.6 Because of these advantages, PTCs have been
used for the synthesis of indacrinone7 and physostigmine in pharmaceutical laboratories.8 We started the
asymmetric alkylation of 2-monosubstituted indolin-3-ones 5 with optically active cinchoninium and
cinchonidinium salts 7a-c, 8.
6a
O
O
Br
*
Ph
Catalyst, Temp.
Solvent, NaOH
Ph
N
N
Ac
Ac
9a
5a
Catalyst Temp. (oC)
%eea)
48
[α]D
NaOH
Solvent
Yield (%)
Entry
1
2
3
4
5
6
7
7a
7a
7a
7a
7b
7c
8
rt
0
0
0
0
0
0
50% aq. toluene
50% aq. toluene
89
99
65
80
95
96
91
65 -4.9
powder
toluene
CH2Cl2
26
31
63
55
50% aq.
50% aq. toluene
50% aq. toluene
50% aq. toluene
39 +1.8
a) determined by 1H-NMR with Eu(hfc)3
H
H
OH
H
N
N
H
HO
X
Cl
N
N
R
8
7a; R = H, X = Cl
7b; R = CF3, X = Br
7c; R = OMe, X = Br
Table 1 Prenylation of 5a with optically active PTCs
To find out the optimized reaction conditions, prenylation of 2-benzyl indolin-3-one 5a5e was carried out
(Table 1). Higher enantioselectivity was observed by using cinchoninium salt 7a and 50% NaOH at
lower temperature (entry 1 vs. 2). Powder-NaOH applied to the PTC reaction at low temperature gave
unsatisfactory results (entry 3). As a solvent, toluene gave better selectivity than dichloromethane (entry
2 vs. 4). These results support the tight ion pair hypothesis that enantioselectivity between the catalysts
and enolates is important in the alkylation of indolin-3-one 5a.9 We also investigated the electrostatic
effect of benzyl groups in PTCs 7a-c, 8, but there were no remarkable differences in enantioselectivity
(entry 2 vs. 5, 6). The use of cinchonidinium salt 8 gave rise to (+)-9a (entry 7).

HETEROCYCLES, Vol. 73, 2007
643
O
O
R2-Br (6)
R1
R2
Catalyst (7a)
50% aq. NaOH, toluene
0 oC
R1
N
N
Ac
9
Ac
5a-e
Yield (%)
Entry
5
R1
R2
9
%ee
33
1
2
3
4
5
6
5a
5a
5b
5c
5d
5e
CH2Ph
CH2Ph
CH2-C6H4-NO2-p
CH2CH=CH2 9b
86
39
94
68
77
88
Mea)
9c
CH2CH=CMe2 9d
50
CH2Ph
CH2CH=CMe2
CH2CH=CMe2
9a
9e
9f
13
CH2CH=CMe2
12b)
37b)
Me
Ph
a) MeI b) determined by MTPA esters
Table 2 PTC-Alkylation of 5a-e with alkylhalides 6
Next, we examined the reactivity and enantioselectivity between various indolin-3-ones 5a-e and
alkylhalides 6 with the above optimized conditions (Table 2). The methylation of 5a was slower than
both the allylation and benzylation (entry 2). Enantioselectivity was better with benzyl substituted
indolin-3-one 5a than with the p-nitrobenzyl substituted conpound 5b (Table 1, entry 2 vs. Table 2, entry
3). Interestingly, better enantioselectivity of 9a was observed in the prenylation of 2-benzyl
indolin-3-one 5a than in the benzylation of 2-prenyl indolin-3-one 5c (Table 1, entry 2 vs. Table 2, entry
4). This indicates that the interaction between PTC 7a and the enolate of 5a was much better than that
of 5c.
NOE
H
H
O
OH
R
(R)- or (S)-MTPA-Cl
O-MTPA-(R) or -(S)
R
NaBH4
R
DMAP, Et3N
N
N
N
Ac
Ac
Ac
11a; R = Me
11b; R = Ph
9e; R = Me
9f; R = Ph
10a; R = Me
10b; R = Ph
Scheme 1 Determination of enantioselectivity for 9e and 9f
The determination of enantioselectivity for 9e and 9f was not available by 1H-NMR experiments with the
chiral shift reagents. So, these compounds were introduced to MTPA esters 11 and the ratio of
1
diastereomers was determined by H-NMR.
The reduction of 9e with NaBH4 gave 10a as a single
diastereomer and the stereochemistries were determined by NOE measurement (Scheme 1). Then 10a
was acylated with MTPA-Cl to afford 11a.

644
HETEROCYCLES, Vol. 73, 2007
O
O
EtO2C Me
1. O3, then Me2S
1. RuCl3, NaIO4
2. EtI, K2CO3
Me
CO2Me
N
Me
CO2Me
2. m-CPBA
3. CH2N2
AcHN
N
Ac
Ac
9e
13
[α]D -4.3o
12
[α]D -16.5o (70%ee)
lit.,10
Scheme 2 Transformation of 9e to amino acid ester 13
The absolute stereochemistry of 9e was confirmed by introduction to the known amino acid ester R-(-)-13
(Scheme 2).10 The ozonolysis of 9e followed by oxidation and methylation afforded ester 12.
RuO4-oxidation and esterification of 12 provided the desired compound (-)-13. The R configuration of
13 indicates that the transition state in the alkylation of indolin-3-one is similar to that of indanone, as
suggested by Dolling.11
In this study, we have developed the asymmetric alkylation of indolin-3-ones by optically active phase
transfer catalyst. Further applications of this methodology to the synthesis of biologically active
alkaloids are in progress.
EXPERIMENTAL
All melting points are uncorrected, and were measured on a Yanagimoto micromelting point apparatus.
Optical rotations were obtained on a JASCO DIP-140 digital polarimater. IR spectra were recorded on a
Shimadzu FTIR-8400s spectrophotometer. 1H and 13C NMR spectra were measured on a JEOL
JMN-PMX270 (270 MHz) or JEOL JMN-GSX 400 (400 MHz) spectrometer with tetramethylsilane as an
internal standard. J-Values are given in Hertz. Mass spectra were recorded on a JEOL JMS-DX 302 or
JEOL JMS 700 instrument with a direct inlet system. Elemental analyses were obtained using a
Perkin-Elmer Model 240B elemental analyzer. [α]D were measured on a JEOL DIP-140. Column
chromatography was carried out on a silica gel (Kanto Chemical Co. Inc., 230-400 mesh and Merck,
230-400 mesh).
1-Acetyl-2-(p-nitrobenzyl)indolin-3-one (5b)
To a solution of 1-acetyl-2-methoxyindolin-3-one5e (1.2g, 6.0 mmol) in benzene (60 mL) was added
p-nitrobenzyl bromide (6.5 g, 30 mmol), triethylbenzylammonium bromide (30 mg) and 33% aqueous
NaOH (15 mL) and then stirred at rt for 4 h. The mixture was added AcOEt (60 mL) and washed with
H2O (10 mLx3). The organic layer was dried over MgSO4 and concentrated. The residue was purified
by column chromatography (CH2Cl2) gave 1-acetyl-2-methoxy-2-(p-nitrobenzyl)indolin-3-one (1.2 g,
60%) as an yellow oil.

HETEROCYCLES, Vol. 73, 2007
645
o
Mp 133-134 C. 1H NMR (CDCl3, 270 MHz): δ 2.63 (3H, s), 3.21 (3H, s), 3.54 (2H, d, J = 3.6 Hz),
7.05-7.58 (6H, m), 7.93 (2H, d, J = 8.6 Hz). MS (EI) m/z (%): 251 (M+, 4), 204 (55), 162 (100).
HRMS (EI): m/z calcd for C18H16N2O5: 340.1065. Found: 340.1059.
To a solution of 1-acetyl-2-methoxy-2-(p-nitrobenzyl)indolin-3-one (1.5 g, 4.4 mmol) in MeOH (35 mL)
o
was added NaBH4 (1.7 g, 44 mmol) at 0 C and stirred for 20 min. The reaction mixture was
concentrated and added H2O (30 mL). The mixture was extracted by AcOEt (20 mLx3) and the extract
was dried over MgSO4. The organic layer was concentrated to give crude alcohol (1.5 g, 4.4 mmol).
To a solution of above crude alcohol in CH2Cl2 (80 mL) was added SnCl4 (2.0 g, 5.7 mmol) and stirred at
o
0 C for 20 min. The reaction mixture was washed by H2O (10 mLx3) and dried over MgSO4. The
concentrated residue was purified by column chromatography (AcOEt:hexane=1:1) gave 5b (0.73 g,
54%) as white crystals.
o
Mp 151-152 C. 1H NMR (CDCl3, 270 MHz): δ 2.50 (3H, s), 3.54 (2H, d, J = 2.6 Hz), 4.68 (1H, brs),
7.11 (2H, t, J = 7.9 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.54 (1H, m), 7.62 (1H, brd, J = 7.6 Hz), 7.96 (2H, d, J
= 8.6 Hz). IR (CHCl3); 1723, 1670 cm-1. Anal. Calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03.
Found: C, 65.72; H, 4.61; N, 8.80. MS (EI) m/z (%): 310 (M+, 41), 268 (13), 174 (12), 137 (13), 132
(100), 43 (24).
1-Acetyl-2-phenylindolin-3-one (5e)
To a solution of 1-acetyl-2-methoxy-2-phenylindolin-3-one5f (0.57g, 2.0 mmol) in MeOH (20 mL) was
added NaBH4 (0.76 g, 20 mmol) at 0 oC and stirred for 50 min. The reaction mixture was concentrated
and added H2O (10 mL). The mixture was extracted by AcOEt (10 mLx3) and the extract was dried
over MgSO4. The organic layer was concentrated to give a crude alcohol (0.52 g). To a solution of
o
alcohol in CH2Cl2 (40 mL) was added SnCl4 (0.62 g, 2.4 mmol) and stirred at 0 C for 30 min. The
reaction mixture was washed by H2O (10 mLx3) and dried over MgSO4. The concentrated residue was
purified by column chromatography (CH2Cl2:hexane=1:1) gave 5b (0.28 g, 61%) as white crystals.
Mp 128-129 oC. 1H NMR (CDCl3, 270 MHz): δ 2.07 (3H, s), 5.20 (1H, s), 7.20-7.30 (4H, m), 7.34-7.41
(2H, m), 7.71-7.76 (2H, m), 8.69 (1H, d, J = 7.6 Hz). IR (CHCl3); 1727, 1682 cm-1. Anal. Calcd for
C16H13NO2: C, 76.47; H, 5.22; N, 5.57. Found: C, 76.19; H, 5.29; N, 5.61. MS (EI) m/z (%): 251 (M+,
80), 209 (56), 208 (44), 181 (57), 180 (100), 152 (21), 104 (12), 77 (17).
Representative procedure for alkylation of 5a with PTC
1-Acetyl-2-benzyl-2-(3-methylbut-2-enyl)indolin-3-one (9a)
To a solution of 5a (53 mg, 0.20 mmol), 50% NaOH (1.0 mL) and 7a (4.5 mg, 0.01 mmol) in toluene (5.0
mL) was added 1-bromo-3-methyl-2-butene (0.12 mL, 1.0 mmol) and the reaction mixture was stirred at

646
HETEROCYCLES, Vol. 73, 2007
0 oC under Ar atmosphere for 3 h. The mixture was added AcOEt (5.0 mL) and washed by H2O (2.0 mL
x 4). The organic layer was dried over MgSO4 and concentrated. The residue was purified by column
chromatography (AcOEt:hexane=1:4) gave 9a (66 mg, 99%) as a pale yellow oil.
25
[α]D -4.9o (c 1.62, CHCl3). 1H NMR (CDCl3, 270 MHz): δ 1.45 (3H, s), 1.59 (3H, s), 2.45 (3H, s),
2.82 (1H, brs), 3.27 (2H, br), 3.77 (1H, br), 4.63 (1H, t, J = 7.3 Hz), 6.95-7.14 (6H, m), 7.14 (1H, br),
7.42 (1H, t, J = 7.3 Hz), 7.62 (1H, d, J = 7.3 Hz). IR (CHCl3); 1716, 1668 cm-1. Anal. Calcd for
C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C, 78.85; H, 6.93; N, 4.08. HRMS (EI): m/z calcd for
C22H23NO2: 333.1729. Found: 333.1754.
1-Acethyl-2-allyl-2-benzylindolin-3-one (9b)
The mixture of 5a (53 mg, 0.20 mmol), allyl bromide (87 µL, 1.0 mmol), 7a (4.5 mg), 50% aqueous
NaOH (1.0 mL) and toluene (5.0 mL) stirring at 0 oC for 20 h gave 9b (53 mg, 86%) as a white solid.
Mp 86-87 oC. [α]D25 -1.25 o (c 0.8, CHCl3). 1H NMR (CDCl3, 270 MHz): δ 2.47 (3H, s), 2.86 (1H, br),
3.25 (1H, d, J = 13.2 Hz), 3.38 (1H, br), 3.77 (3H, d, J = 12.9 Hz), 4.87 (1H, d, J = 10.2 Hz), 5.07 (1H, d,
J = 16.7 Hz), 5.26-5.41 (1H, m), 6.93-7.05 (6H, m), 7.16 (1H, br), 7.40-7.47 (1H, m), 7.63 (1H, d, J = 7.5
Hz). IR (CHCl3); 1719, 1667 cm-1. MS (EI) m/z (%): 305 (M+, 42), 264 (12), 222 (47), 214 (17), 172
(100), 91 (12), 43 (16). HRMS (EI): m/z Calcd for C20H19NO2: 305.1416. Found: 305.1416.
1-Acethyl-2-benzyl-2-methylindolin-3-one (9c)
The mixture of 5a (53 mg, 0.20 mmol), methyl iodide (67 µL, 1.0 mmol), 7a (4.5 mg), 50% aqueous
NaOH (1.0 mL) and toluene (5.0 mL) stirring at rt for 3 days gave 9c (22 mg, 39%) as a viscous oil.
1H NMR (CDCl3, 270 MHz): δ 1.74 (3H, s), 2.49 (3H, s), 3.28 (1H, d, J = 13.2 Hz), 3.73 (1H, brs),
6.92-7.08 (5H, m), 7.47 (2H, t, J = 8.0 Hz), 7.67 (2H, d, J = 7.6 Hz). IR (CHCl3); 1718, 1670 cm-1.
MS (EI) m/z (%): 279 (M+, 32), 188 (19), 147 (12), 146 (100), 43 (10). HRMS (EI): m/z Calcd for
C18H17NO2: 279.1259. Found: 279.1267.
1-Acethyl-2-(3-methylbut-2-enyl)-2-p-nitrobenzylindolin-3-one (9d)
The mixture of 5b (62 mg, 0.20 mmol), 1-bromo-3-methyl-2-butene (0.12 mL, 1.0 mmol), 7a (4.5 mg),
50% aqueous NaOH (1.0 mL), and toluene (5.0 mL) stirring at 0 oC for 2.5 h gave 9d (71 mg, 94%) as an
yellow oil.
25
[α]D -23 o (c 1.31, CHCl3). 1H NMR (CDCl3, 270 MHz): δ 1.45 (3H, s), 1.59 (3H, s), 2.47 (3H, s),
2.82 (1H, brs), 3.34 (1H, brs), 3.37 (1H, d, J = 12.9 Hz), 3.90 (1H, d, J = 13.2 Hz), 4.62 (1H, t, J = 6.9
Hz), 7.04-7.15 (2H, m), 7.13, (2H, d, J = 8.9 Hz), 7.47 (1H, t, J = 7.3 Hz), 7.65 (1H, t, J = 7.3 Hz), 7.87
(2H, d, J = 8.9 Hz). IR (CHCl3); 1722, 1675 cm-1. MS (EI) m/z (%): 378 (M+, 13), 311 (20), 310 (98),

HETEROCYCLES, Vol. 73, 2007
647
268 (100), 242 (12), 221 (14), 200 (26), 149 (15), 69 (21), 43 (23). HRMS (EI): m/z Calcd for
C22H22N2O4: 378.1579. Found: 378.1575.
1-Acetyl-2-benzyl-2-(3-methylbut-2-enyl)indolin-3-one (9a): benzylation of 5c
The mixture of 5c5e (50 mg, 0.20 mmol), benzyl bromide (0.12 mL, 1.0 mmol), 7a (4.5 mg), 50% NaOH
o
(1.0 mL) and toluene (5.0 mL) stirring at 0 C for 20 h gave 9a (46 mg, 68%) as a pale yellow oil.
[α]D25 -4.9o (c 1.22, CHCl3).
1-Acetyl-2-methyl-2-(3-methylbut-2-enyl)indolin-3-one (9e)
The mixture of 5d5e (38 mg, 0.20 mmol), 1-bromo-3-methyl-2-butene (0.12 mL, 1.0 mmol), 7a (4.5 mg),
50% aqueous NaOH (1.0 mL) and toluene (5.0 mL) stirring at 0 oC for 3.5 h gave 9e (40 mg, 77%) as an
yellow oil.
25
[α]D -4.3 o (c 0.70, CHCl3). 1H NMR (CDCl3, 270 MHz): δ 1.45 (3H, s), 1.56 (3H, s), 1.61 (3H, s),
2.49 (3H, s), 2.76 (1H, brs), 3.00 (1H, brs), 4.60 (1H, t, J = 7.3 Hz), 7.20 (1H, t, J = 7.9 Hz), 7.62-7.70
(1H, m), 7.77 (1H, d, J = 7.6 Hz). IR (CHCl3); 1726, 1670 cm-1. MS (EI) m/z (%): 257 (M+, 10), 189
(50), 147 (49), 146 (100), 43 (13). HRMS (EI): m/z Calcd for C16H19NO2: 257.1416. Found: 257.1413.
1-Acetyl-2-(3-methylbut-2-enyl)-2-phenylindolin-3-one (9f)
The mixture of 5e (50 mg, 0.20 mmol), 1-bromo-3-methyl-2-butene (0.12 mL, 1.0 mmol), 7a (4.5 mg),
50% aqueous NaOH (1.0 mL) and toluene (5.0 mL) stirring at 0 oC for 4.5 h gave 9f (57 mg, 88%) as an
yellow oil.
[α]D25 -150 o (c = 1.02, CHCl3). 1H NMR (CDCl3, 270 MHz): δ 1.50 (3H, s), 1.64 (3H, s), 1.97 (3H, s),
3.10 (1H, brs), 3.64 (1H, brs), 4.73 (1H, t, J = 6.9 Hz), 7.21-7.38 (6H, m), 7.74 (2H, m), 8.82 (1H, br).
IR (CHCl3); 1722, 1666 cm-1. MS (EI) m/z (%): 319 (M+, 5), 251 (39), 250 (11), 209 (41), 208 (100).
HRMS (EI): m/z Calcd for C21H21NO2: 319.1572. Found: 319.1573.
1-Acetyl-3-hydroxy-2-methyl-2-(3-methylbut-2-enyl)indoline (10a)
To a solution of 9e (30 mg, 0.12 mmol) in MeOH (3.0 mL) was added NaBH4 (44 mg, 1.2 mmol) at 0 oC
and the reaction mixture was stirred for 15 min. The mixture was concentrated and added H2O (5.0 mL).
The mixture was extracted with AcOEt (5.0 mLx3) and the extract was dried over MgSO4. The residue
was purified by column chromatography (AcOEt:hexane=1:2) gave 10a (24 mg, 79%) as a colorless oil.
1H NMR (CDCl3, 270 MHz): δ 1.52 (3H, s), 1.60 (3H, s), 1.65 (3H, s), 2.33 (1H, d, J = 6.1 Hz), 2.43 (3H,
s), 2.82 (1H, br), 2.97 (1H, br), 4.77 (1H, d, J = 7.6 Hz), 5.09 (1H, t, J = 6.4 Hz), 7.08 (1H, t, J = 7.5 Hz),
7.29 (1H, t, J = 7.5 Hz), 7.41 (1H, d, J = 7.2 Hz). IR (CHCl3); 3504, 1645 cm-1. MS (EI) m/z (%): 259

648
HETEROCYCLES, Vol. 73, 2007
(M+, 11), 241 (16), 190 (50), 184 (23), 149 (13), 148 (100), 131 (15), 130 (10). HRMS (EI): m/z Calcd
for C16H21NO2: 259.1572. Found: 259.1570.
1-Acetyl-3-[(2-methoxy-2-phenyl-3,3,3-trifluoro)propioxy]-2-methyl-2-(3-methylbut-2-enyl)indoline
(11a)
To a solution of 10a (13 mg, 0.050 mmol) in CH2Cl2 (1.0 mL) was added dry Et3N (14 µL, 1.0 mmol),
DMAP (12 mg, 1.0 mmol) and (S)-MTPA chloride (56 µL, 0.30 mmol) at 0 oC and then stirred for 1.5 h.
The reaction mixture was concentrated and the residue was purified by preparative TLC
(AcOEt:hexane=1:3) gave (S)-MTPA ester 11a (15 mg, 61%) as an yellow oil. (R)-MTPA ester was
obtained by similar procedure as above.
1H NMR (CDCl3, 270 MHz): δ 1.41 (1.68H, s), 1.47 (1.32H, s), 1.52 (3H, s), 1.55 (1.32H, s), 1.58 (1.68H,
s), 2.37 (1.32H, s), 2.40 (1.68H, s), 2.51 (0.56H, dd, J = 6.6, 14.8 Hz), 2.68 (0.44H, dd, J = 7.3, 15.5 Hz),
2.96 (0.56H, d, J = 14.5 Hz), 2.98 (0.44H, d, J = 14.5 Hz), 3.41 (1.68H, s), 3.43 (1.32 H, s), 4.75 (0.56H, t,
J = 6.6 Hz), 4.87 (0.44H, t, J = 6.9 Hz), 6.03 (0.56H, s), 6.06 (0.44H, s), 6.98-7.09 (1H, m), 7.10-7.50
(8H, m). IR (CHCl3); 1747, 1655 cm-1. MS (EI) m/z (%): 475 (M+, 2), 406 (18), 364 (14), 241 (35),
199 (16), 198 (13), 190 (19), 189 (100), 184 (47), 175 (11), 148 (47), 146 (13), 144 (15), 131 (34), 130
(16), 105 (17), 91 (17), 77 (13), 43 (11). HRMS (EI): m/z Calcd for C26H28NO4F3: 475.1970. Found:
475.1971.
1-Acetyl-3-hydroxy -2-(3-methylbut-2-enyl) -2-phenylindoline (10b)
As a similar procedure of the preparation of 10a, to a solution of 9f (56 mg, 0.18 mmol) in MeOH (1.4
mL) was added NaBH4 (166 mg, 4.4 mmol) at 0 oC and the reaction mixture was stirred for 25 h to afford
10b (32 mg, 57%).
1H NMR (CDCl3, 270 MHz): δ 1.56 (3H, s), 1.71 (3H, s), 1.86 (3H, br), 2.33 (1H, d, J = 10.2 Hz), 2.96
(1H, br), 3.56 (1H, br), 5.05 (1H, t, J = 5.9 Hz), 5.12 (1H, d, J = 10.6 Hz), 7.13 (1H, t, J = 7.6 Hz),
7.26-7.40 (7H, m), 8.47 (1H, br).
1-Acetyl-3-[(2-methoxy-2-phenyl-3,3,3-trifluoro)propioxy]-2-(3-methylbut-2-enyl)-2-phenylindoline
(11b)
As a similar procedure of the preparation of 11a, to a solution of major alcohol 10b (8.0 mg, 0.025mmol)
in dry CH2Cl2 (0.3 mL) was added dry Et3N (21 µL, 0.15 mmol), DMAP (24 mg, 0.20 mmol) and
(R)-MTPA chloride (21 µL, 0.15 mmol) at rt and stirred for 23 h to give (R)-MTPA ester 11b (5.8 mg,
43%) as an yellow oil. (S)-MTPA ester was prepared by similar procedure as above.

HETEROCYCLES, Vol. 73, 2007
649
1H NMR (CDCl3, 270 MHz): δ 1.26 (2.04H, s), 1.37 (0.96H, s), 1.46 (3H, s), 1.91 (3H, brs), 2.75-3.25
(2H, m), 3.46 (2.04H, s), 3.49 (0.96H, s), 4.90 (1H, s), 6.39 (0.32H, s), 6.42 (0.68H, s), 7.00-7.49 (13H,
m), 8.30 (1H, brs). IR (CHCl3); 1750, 1662 cm-1.
1-Acethyl-2-methyl-2-(2-methoxy-2-oxoethyl)indolin-3-one (12)
o
A solution of 9e (200 mg, 0.78 mmol) in CH2Cl2-MeOH (25 mL, 10:1) was bubbled with O3 at -78 C.
After the starting material consumption on TLC, Me2S (53 mg) was added and stirred at rt for 1 day.
The reaction mixture was concentrated and dissolved in CH2Cl2 (20 mL). m-CPBA (380 mg, 80%, 1.8
mmol) was added to the solution at rt and stirred for 2 h. The reaction mixture was concentrated and
dissolved in Et2O (20 mL). CH2N2 in Et2O was added to the solution and stirred at rt for 1 day. The
reaction mixture was concentrated and the residue was purified by column chromatography
(AcOEt:hexane=1:2) gave 12 (185 mg, 91%) as a white solid.
1H NMR (CDCl3, 270 MHz): δ 1.56 (3H, s), 2.54 (3H, s), 3.15 (1H, d, J = 16.8 Hz), 3.47 (3H, s), 3.74
(1H, brs), 7.24 (2H, t, J = 7.9 Hz), 7.67 (1H, t, J = 7.3 Hz), 7.86 (1H, d, J = 7.6 Hz). IR (CHCl3); 1714,
1609 cm-1. MS (EI) m/z (%): 261 (M+, 33), 230 (12), 220 (13), 219 (100), 191 (42), 190 (39), 188 (18),
176 (17), 160 (11), 159 (16), 146 (42), 144 (13), 132 (11), 130 (19), 118 (27), 117 (14), 43 (21).
Amino acid (13)
To a solution of 12 (90 mg, 0.35mmol) in MeCN (1.4 mL) was added NaIO4 (1.3g 6.2 mmol) and a
solution of RuCl3 (1.6 mg, 0.076 mmol) in CCl4-H2O (4.2 mL, 1:2). The reaction mixture was stirred at
rt for 3 days. The mixture was filtrated and extracted by AcOEt (10 mLx3) and dried over MgSO4.
After the extract was concentrated, the residue was dissolved in acetone (3.0 mL), K2CO3 (0.20 g) and EtI
(1.3 mL) were added to the solution and stirred at rt for 3 h. The reaction mixture was concentrated and
the residue was purified by column chromatography (AcOEt:hexane=1:1) gave 13 (6.0 mg, 8%) as a
white solid.
o
25
Mp 72-73 C. [α]D -4.3o (c 0.6, CHCl3). [lit.,10 [α]D = -16.5o (c 1, CHCl3), 70%ee]. 1H NMR
(CDCl3, 270 MHz): δ 1.28 (3H, t, J = 6.9 Hz), 1.64 (3H, s), 1.98 (3H, s), 2.93 (1H, d, J = 16.8 Hz), 3.56
(1H, d, J = 16.5 Hz), 3.65 (3H, s), 4.18-4.30 (2H, m), 6.65 (1H, brs). IR (CHCl3); 1719, 1667 cm-1.
MS (EI) m/z (%): 231 (M+, 1.2), 158 (69), 116 (100), 84 (25), 43 (38), 42 (29). HRMS (EI): m/z Calcd
for C10H17NO5: 231.1107. Found: 231.1109.
ACKNOWLEDGEMENTS
We thank N. Eguchi, T. Koseki, and S. Kubota of the Analytical Center at our University for
microanalysis and mass spectral measurements.

650
HETEROCYCLES, Vol. 73, 2007
REFERENCES
1. L. A. Adams, M. W. N. Valente, and R. M. Williams, Tetrahedron, 2006, 62, 5195, and references
were cited therein.
2. P. S. Baran and E. J. Corey, J. Am. Chem. Soc., 2002, 124, 7904.
3. Y. Liu and W. W. McWhorter Jr., J. Am. Chem. Soc., 2003, 125, 4240.
4. X. Zhang and C. S. Foote, J. Am. Chem. Soc., 1993, 115, 8867.
5. a) T. Kawasaki, Y. Nonaka, K. Watanabe, A. Ogawa, K. Higuchi, R. Terashima, K. Masuda, and M.
Sakamoto, J. Org., Chem., 2001, 66, 1200. b) T. Kawasaki, K. Masuda, Y. Baba, R. Terashima, K.
Takada, and M. Sakamoto, J. Chem. Soc., Perkin Trans. 1, 1996, 729. c) T. Kawasaki, K. Watanabe,
K. Masuda, and M. Sakamoto, J. Chem. Soc., Chem. Commun., 1995, 381. d) T. Kawasaki, K.
Masuda, Y. Baba, R. Terashima, K. Takada, and M. Sakamoto, Chem. Pharm. Bull., 1994, 42, 1974.
e) T. Kawasaki, Y. Nonaka, M. Kobayashi, and M. Sakamoto, J. Chem. Soc., Perkin Trans. 1, 1991,
2445. f) C.-S. Chien, T. Takanami, T. Kawasaki, and M. Sakamoto, Chem. Pharm. Bull., 1985, 33,
1843.
6. Reviews: a) B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518. b) K. Maruoka and T. Ooi,
Chem. Rev., 2003, 103, 3013.
7. U.-H. Dolling, P. Davis, and E. J. J. Grabowski, J. Am. Chem. Soc., 1984, 106, 446.
8. B. K. Thomas and G. S. K. Wong, J. Org. Chem., 1991, 56, 872.
9. D. L. Hughes, U.-H. Dolling, K. M. Ryan, E. F. Schoenewaldt, and E. J. J. Grabowski, J. Org.
Chem., 1987, 52, 4545.
10. G. I. Georg, X. Guand, and J. Kant, Tetrahedron Lett., 1988, 29, 403.
11. A. Bhattacharya, U.-H. Dolling, E. J. J. Grabowski, S. Karady, K. M. Ryan, and L. M. Weinstock,
Angew. Chem., Int. Ed. Engl., 1986, 25, 476.