Catalytic enantioselective C-H functionalization of indoles with α-diazopropionates using chiral dirhodium(II) carboxylates: Asymmetric synthesis of the (+)-α-methyl-3-indolylacetic acid fragment of acremoauxin A

Article abstract of DOI:10.1016/j.tetasy.2011.05.011

An enantioselective C-H functionalization of N-methoxymethyl (MOM)-protected 2,3-unsubstituted indoles with α-diazopropionates has been effected via catalysis by dirhodium(II) tetrakis[N-phthaloyl-(S)- triethylalaninate], Rh₂((S)-PTTEA)₄, providing α-methyl-3-indolylacetates in high yields and with enantioselectivities of up to 86% ee. The effectiveness of this protocol was demonstrated by the first catalytic asymmetric synthesis of the (+)-α-methyl-3-indolylacetic acid fragment of acremoauxin A, a potent plant-growth inhibitor. Furthermore, the Fujioka protocol using a combination of TMSOTf and 2,2′-bipyridyl was shown to be superior for the removal of the N-MOM group.

Full text of DOI:10.1016/j.tetasy.2011.05.011

Tetrahedron: Asymmetry 22 (2011) 907–915
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic enantioselective C–H functionalization of indoles with
a
-diazopropionates using chiral dirhodium(II) carboxylates: asymmetric
synthesis of the (+)- -methyl-3-indolylacetic acid fragment of acremoauxin A
a
Takayuki Goto a,b, Yoshihiro Natori a, Koji Takeda a, Hisanori Nambu a, Shunichi Hashimoto a,
⇑
a Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
b Development Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective C–H functionalization of N-methoxymethyl (MOM)-protected 2,3-unsubstituted
indoles with -diazopropionates has been effected via catalysis by dirhodium(II) tetrakis[N-phthaloyl-
(S)-triethylalaninate], Rh2((S)-PTTEA)4, providing -methyl-3-indolylacetates in high yields and with
enantioselectivities of up to 86% ee. The effectiveness of this protocol was demonstrated by the first cat-
Received 25 April 2011
Accepted 17 May 2011
Available online 21 June 2011
a
a
alytic asymmetric synthesis of the (+)-a-methyl-3-indolylacetic acid fragment of acremoauxin A, a potent
plant-growth inhibitor. Furthermore, the Fujioka protocol using a combination of TMSOTf and 2,20-bipyr-
idyl was shown to be superior for the removal of the N-MOM group.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
studies have been focused on the Friedel–Crafts reaction and its
enantioselective variants using a range of electrophilic reagents.3
Functionalized indoles are prevalent structural motifs in a large
number of biologically active alkaloids and pharmaceuticals.1 It is
therefore not surprising that an enormous amount of effort has
recently been devoted to the development of efficient methods for
direct catalytic functionalization of indoles.2 The majority of these
In this context, the C–H functionalization of indoles with metal
carbenes generated from -diazocarbonyl compounds under
catalysis by metal complexes is a potentially powerful means for
installing functionalized alkyl groups on the pyrrole portion of the
indole ring system.4,5 Since the publication of the seminal work of
a
O
N
X
O
O
N
X
R
N
X
H
O
H
H
O
X
O
O
O
O
O
O
O
Rh Rh
Rh Rh
Rh Rh
R = tBu, X = H: Rh2((S)-PTTL)4 1a
R = tBu, X = F: Rh2((S)-TFPTTL)4 1b
R = tBu, X = Cl: Rh2((S)-TCPTTL)4 1c
R = Me, X = H: Rh2((S)-PTA)4 1d
R = iPr, X = H: Rh2((S)-PTV)4 1e
R = Et3C, X = H: Rh2((S)-PTTEA)4 1f
Rh2((R)-PTTEA)4
2
Rh2((S)-NTTL)4
3
O
S
N
C12H25
O
H
O
O
Rh Rh
Rh2((S)-DOSP)4
4
Figure 1. Chiral dirhodium(II) catalysts.
⇑
Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981.
E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.011

908
T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
R4
CO2Et
R2
Rh2((S)-NTTL)4
3
(0.5 mol %)
R4
CO2Et
R3
R2
+
R3
toluene, −78 °C
N
R1
N2
2 equiv
N
R1
82−96%
R1 = Me, Bn, Ar
R2 = H, Me
R4 = Et, Bu, Hex, isopentyl
84−99% ee
R3 = H, Me, MeO, F, CO2Me
Me
CO2Et
Me
Rh2((S)-NTTL)4
3
(0.5 mol %)
Me
CO2Et
Me
+
toluene, −78 °C
N
Ph
N
N2
2 equiv
Ph
79% ee
82%
Scheme 1. The enantioselective C–H functionalization of indoles with ethyl a-alkyl-a
-diazoacetates under catalysis by Rh2((S)-NTTL)4 3 reported by Fox.11
Davies and Lian on catalysis by Rh2((S)-DOSP)4 46 (Fig. 1),7 the
development of an enantioselective version of this catalytic process
has become a challenging objective. Very recently, Fox et al. made a
major breakthrough in this field when they demonstrated that the
enantioselective C–H functionalization of indoles with ethyl
Using Rh2((S)-PTTEA)4 1f as a catalyst, we next examined the ef-
fects of the N-substitution of the indole ring (Table 2). As might be
expected from precedents,4,5g,i,l,11,22 the reaction of 6a with indoles
5b and 5c with strongly electron-withdrawing Boc or Ts groups
were unsuccessful in giving the corresponding indole products
7b and 7c (entries 2 and 3); instead, an azine derived from 6a
was obtained as the major product. While the reaction of N-benzy-
lindole 5d proceeded smoothly to give 7d in 89% yield with 74% ee
(entry 4), N-methoxymethyl (MOM)-protected indole 5e provided
7e in 83% yield with a greatly improved enantioselectivity of 82%
ee (entry 5). An examination of the temperature profile demon-
strated that lowering the reaction temperature to ꢀ40 or ꢀ60 °C
had only a marginal effect on the enantioselectivity (78% and
75% ee), although a sharp drop in product yield was observed
(70% and 64%, respectively, entries 6 and 7). The effects of the ester
moiety were also evaluated. Reactions of 5e with tert-butyl and
ethyl esters 6b and 6c resulted in lower enantioselectivities than
that observed with 6a (45% and 32% ee, respectively, entries 8
and 9). These results demonstrate that the use of the 2,4-di-
methyl-3-pentyl ester moiety23 is crucial for a high degree of
enantioselection.
a-alkyl-
a
-diazoacetates via catalysis by Rh2((S)-NTTL)4 38–10 pro-
vides
a
-alkyl-substituted 3-indolylacetates in high yields and
enantioselectivities (82–96% yields, 79–99% ee, Scheme 1).11,12
While the scope of the reaction was found to accommodate a wide
array of substrates, exceptionally high performance was achieved
with diazoesters with longer-chain alkyl groups than an a-methyl
substituent when N-aryl or N-alkyl indole derivatives with small
2-substituents (R2 = H, Me) were used. We have recently been en-
gaged in the enantioselective C–H functionalization of indoles with
a
-diazopropionates catalyzed by chiral dirhodium(II) carboxylates.
Although Fox et al. described the catalytic enantioselective reaction
of 2-methyl-1-phenylindole with ethyl -diazopropionate (79% ee,
Scheme 1),11 no examples of the reaction of 2,3-unsubstituted
indoles with -diazopropionates have been reported. Herein, we
report the first example of a catalytic enantioselective C–H func-
a
a
tionalization of 2,3-unsubstituted indoles with a-diazopropionates.
2. Results and discussion
Table 1
At the outset, we explored the reaction of 2,3-unsubstituted N-
Enantioselective C–H functionalization of N-methylindole 5a with 2,4-dimethyl-3-
methylindole 5a (1.2 equiv) with 2,4-dimethyl-3-pentyl
a-diazo-
pentyl
a
-diazopropionate 6a catalyzed by chiral dirhodium(II) carboxylatesa
propionate 6a using 1 mol % of Rh2((S)-PTTL)4 1a13–15 (Table 1,
Me
CO2CHiPr2
entry 1). The reaction in dichloromethane at room temperature
Rh(II) catalyst
CO2CHiPr2
(1 mol %)
proceeded smoothly to give
a-methyl-3-indolylacetate 7a in 82%
Me
yield with no signs of ,b-unsaturated ester formation via a 1,2-hy-
a
+
dride shift.16 The enantiomeric excess of 7a was determined to be
52% by HPLC using a Daicel Chiralcel OD-H column. To further en-
hance the enantioselectivity, we evaluated the performance of
other chiral dirhodium(II) carboxylate catalysts. Although Rh2((S)-
TFPTTL)4 1b17 and Rh2((S)-TCPTTL)4 1c,18–20 fluorinated and chlori-
nated analogues of 1a, provided 7a in high yields, poor enantiose-
lectivities were obtained (43% and 22% ee, respectively, entries 2
and 3). Catalysis with Rh2((S)-PTA)4 1d and Rh2((S)-PTV)4 1e
resulted in lower product yields and enantioselectivities than those
obtained with 1a (21% and 32% ee, respectively, entries 4 and 5). We
recently developed dirhodium(II) tetrakis[N-phthaloyl-(S)-trieth-
ylalaninate], Rh2((S)-PTTEA)4 1f, characterized by an exceptionally
bulky triethylmethyl group, for the enantioselective intramolecular
C–H insertion of aryldiazoacetates.21 The use of 1f was found to in-
crease the enantioselectivity up to 67% ee (entry 6). A survey of sol-
vents with 1f revealed that dichloromethane was the optimal
solvent for this transformation in terms of both product yield and
enantioselectivity (entry 6 vs entries 7–10).
N
Me
N2
0.5 h
N
Me
5a (1.2 equiv)
6a
7a
Entry
Rh(II) catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
Rh2((S)-PTTL)4 1a
Rh2((S)-TFPTTL)4 1b
Rh2((S)-TCPTTL)4 1c
Rh2((S)-PTA)4 1d
Rh2((S)-PTV)4 1e
Rh2((S)-PTTEA)4 1f
Rh2((S)-PTTEA)4 1f
Rh2((S)-PTTEA)4 1f
Rh2((S)-PTTEA)4 1f
Rh2((S)-PTTEA)4 1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Hexane
AcOEt
82
84
90
64
72
83
87
92
76
40
52
43
22
21
32
67
59
58
65
54
Acetone
a
All reactions were carried out as follows: Rh(II) catalyst (1 mol %) was added to
a solution of 5a (0.030 mL, 0.24 mmol, 1.2 equiv) and 6a (39.7 mg, 0.20 mmol) in
the indicated solvent (1 mL) at room temperature.
b
Isolated yield.
Determined by HPLC (Daicel Chiralcel OD-H).
c

T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
909
Table 2
Enantioselective C–H functionalization of indoles 5a–e with
a
-diazopropionates 6a–c catalyzed by Rh2((S)-PTTEA)4 1f
Me
CO2R2
Rh2((S)-PTTEA)4 1f
Me
CO2R2
(1 mol %)
+
N
R1
N2
CH2Cl2
N
R1
5 (1.2 equiv)
6
7
Entry
Indole 5
Diazoester 6
T (°C)
t (h)
Product 7
R1
R2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5e
5e
5e
5e
Me
Boc
Ts
Bn
MOM
MOM
MOM
MOM
MOM
6a
6a
6a
6a
6a
6a
6a
6b
6c
iPr2CH
23
23
23
23
23
–40
–60
23
0.5
0.5
0.5
0.5
0.5
2
15
0.5
0.5
7a
83
67
–
–
74
82
78
75
45
32
iPr2CH
iPr2CH
iPr2CH
iPr2CH
iPr2CH
iPr2CH
tBu
7b
7c
7d
7e
7e
7e
7f
NDc
NDc
89
83
70
64
72
Et
23
7g
69
a
b
c
Isolated yield.
Determined by HPLC.
Not detected.
Under the optimized reaction conditions, we next explored the
age of the methyl ether linkage of the MOM protecting group to
give 8, which, upon exposure to NaOH in THF/H2O (9:1), afforded
9 in 98% yield. Reduction of 2,4-dimethyl-3-pentyl ester 9 with
scope of the reaction with respect to the indole component
(Table 3). The reaction with 2-methylindole derivative 5f resulted
in only a trace amount of product 7h (entry 1), which was mark-
LiAlH4 provided the known alcohol 10 {½a D21
¼ ꢀ23:3 (c 0.41,
ꢁ
edly different from Fox’s result with ethyl
a
-diazopropionate.24
MeOH) for 82% ee; lit.30
½
a 2D1
ꢁ
¼ ꢀ30:6 (c 0.46, MeOH) for 90% ee
The reaction with 4-methylindole 5g afforded 7i in 72% yield and
69% ee (entry 2). The reaction was also tolerant of methoxy, bromo,
and nitro groups at the 5-position of the N-MOM-protected indole
nucleus (69–83% yields, 58–72% ee, entries 3–5). The highest
enantioselectivity (86% ee) was obtained in the reaction with 7-
methylindole 5k (entry 6).
To determine the preferred absolute configuration of 7e, we ex-
plored the removal of the MOM protecting group (Scheme 2).
Hydrolysis of 7e with 2 M HCl in THF followed by treatment with
15% NaOH25 provided indole 9 in 51% yield. Treatment with
BBr3,26 aq formic acid27 or TMSI28 gave a complex mixture of prod-
ucts. After considerable experimentation, the Fujioka protocol
using a combination of TMSOTf and 2,20-bipyridyl29 proved to be
the method of choice. The treatment of 7e with TMSOTf (2 equiv)
and 2,20-bipyridyl (3 equiv) in CH2Cl2 at 0 °C led to exclusive cleav-
of (R)-10} in 87% yield. Thus, the preferred absolute configuration
of 7e was established as (R).
Using the present catalytic protocol, we conducted an asym-
metric synthesis of (+)-a
-methyl-3-indolylacetic acid 11,31 a phy-
tohormone of the auxin class32 and a constituent of a potent
plant-growth inhibitor acremoauxin A 12 (Scheme 3).33,34 Alcohol
ent-10 was prepared using Rh2((R)-PTTEA)4 2. Fortunately, Over-
man and Govek reported the chemoselective oxidation of a pri-
mary alcohol tethered to an unmasked indole substituent to a
carboxylic acid in the total synthesis of (+)-asperazine.35 Following
this precedent, the oxidation of alcohol ent-10 under standard Pari-
kh–Doering conditions36 and subsequent Lindgren–Kraus oxida-
tion37 of the crude aldehyde provided carboxylic acid 11 in 61%
yield. The spectroscopic data (1H and 13C NMR, and IR) of synthetic
material 11 were identical to those reported by Baran et al.31c The
Table 3
Enantioselective C–H functionalization of indoles 5f–k with 2,4-dimethyl-3-pentyl
a
-diazopropionate 6a catalyzed by Rh2((S)-PTTEA)4 1f
R2
Me
R2
CO2CHiPr2
R1
R3
R3
Me
CO2CHiPr2
1f (1 mol %)
R1
+
N
CH2Cl2, 0.5 h
N2
N
MOM
R4
MOM
R4
5 (1.2 equiv)
6a
7
Entry
Indole 5
Product 7
R1
R2
R3
R4
Yielda (%)
eeb (%)
1
2
3
4
5
6
5f
Me
H
H
H
H
H
Me
H
H
H
H
H
MeO
Br
NO2
H
H
H
H
H
H
Me
7h
7i
7j
7k
7l
7m
Trace
72
77
83
69
—
5g
5h
5i
5j
5k
69
58
64
72
86
H
H
83
a
Isolated yield.
Determined by HPLC.
b

910
T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
Me
Me
Me
CO2CHiPr2
CO2CHiPr2
b
CO2CHiPr2
a
N
MOM
7e (82% ee)
N
N
H
OH
8
9
Me
OH
c
21
[α]D
= −23.3 (c 0.41, MeOH) for 82% ee
N
21
Lit.30 [α]D = −30.6 (c 0.46, MeOH) for 90% ee
H
10
Scheme 2. Reagents and conditions: (a) TMSOTf, 2,20-bipyridyl, CH2Cl2, 0 °C, 0.5 h; (b) NaOH, THF/H2O (9:1), 24 h, 98% (two steps); (c) LiAlH4, THF, 4 h, 87%.
Me
Me
CO2CHiPr2
OH
Me
CO2CHiPr2
a
b−d
+
N2
N
N
MOM
N
H
MOM
ent-10
5e
6a
[α]D24 = +28.2 (c 0.48, MeOH)
ent-7e (83% ee)
for 83% ee
O
OH
Me
CO2H
Me
O
OH
ref. 31a,c
e,f
OH OH
N
H
NH
11
acremoauxin A 12
[α]D25 = +42.6 (c 0.12, CH2Cl2) for 83% ee
Lit.31c [α]D = +41.5 (c 0.13, CH2Cl2) for >99% ee
Scheme 3. Reagents and conditions: (a) Rh2((R)-PTTEA)4 2 (1 mol %), CH2Cl2, 0.5 h, 83%; (b) TMSOTf, 2,20-bipyridyl, CH2Cl2, 0 °C, 0.5 h; (c) NaOH, THF/H2O (9:1), 24 h, 98%
(two steps); (d) LiAlH4, THF, 4 h, 97%; (e) SO3ꢂpyridine, Et3N, DMSO; (f) NaClO2, NaH2PO4ꢂH2O, 2-methyl-2-butene, THF/H2O, 61% (two steps).
sign of the specific rotation of synthetic product 11 {½a D25
¼ þ42:6
ꢁ
4. Experimental
4.1. General
(c 0.12, CH2Cl2) for 83% ee} was the same as that reported in the
literature {lit.31c D = +41.5 (c 0.13, CH2Cl2) for >99% ee}.38 This
[a]
is the first catalytic asymmetric synthesis of the (+)-a-methyl-3-
indolylacetic acid fragment of 12.
Optical rotations were measured on a JASCO P-1030 digital
polarimeter at the sodium D line (589 nm). IR spectra were re-
corded on a JASCO FT/IR-5300 spectrometer and absorbance bands
are reported in wavenumber (cmꢀ1). 1H NMR spectra were re-
corded on a JEOL JNM-ECX 400P (400 MHz) spectrometer or
JNM-ECA 500 (500 MHz) spectrometer. Chemical shifts are re-
ported relative to internal standard (tetramethylsilane at dH 0.00
or CDCl3 at dH 7.26). Data are presented as follows: chemical shift
(d, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quar-
tet, m = multiplet, br = broad), coupling constants, integration and
assignment. 13C NMR spectra were recorded on a JEOL JNM-ECX
400P (100 MHz) spectrometer or JEOL JNM-ECA 500 (125 MHz)
spectrometer. The following internal references were used (CDCl3
at d 77.0). EI mass spectra were recorded on a JEOL JMS-FABmate
spectrometer, operating with ionization energy of 70 eV. ESI mass
spectra were recorded on a JEOL JMS-T100LCP spectrometer. Col-
umn chromatography was carried out on Kanto silica gel 60 N
(63–210 mesh). Analytical thin layer chromatography (TLC) was
carried out on Merck Kieselgel 60 F254 plates. Visualization was
accomplished with UV light, anisaldehyde stain solution or phos-
phomolybdic acid stain solution followed by heating. Analytical
high performance liquid chromatography (HPLC) was performed
3. Conclusion
We have developed a catalytic enantioselective C–H functional-
ization protocol for N-methoxymethyl (MOM)-protected 2,3-
unsubstituted indoles using 2,4-dimethyl-3-pentyl a-diazopropio-
nates. In this process, Rh2((S)-PTTEA)4, which is characterized by
an exceptionally bulky triethylmethyl group, has emerged as the
catalyst of choice for providing a-methyl-3-indolylacetates in high
yields and with enantioselectivities of up to 86% ee. This represents
the first example of a catalytic enantioselective C–H functionaliza-
tion of 2,3-unsubstituted indoles with
this methodology, we achieved the first catalytic asymmetric syn-
thesis of the (+)- -methyl-3-indolylacetic acid fragment of acre-
a-diazopropionates. Using
a
moauxin A. In our approach, the use of a MOM group as a
protecting group on the indole nitrogen was not only crucial for
high levels of enantioselection, but also synthetically advantageous
since the removal of the N-MOM group could be conducted effi-
ciently under Fujioka conditions. Further application of this meth-
odology to the catalytic asymmetric synthesis of indole alkaloids as
well as stereochemical studies are currently in progress.

T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
911
on a JASCO PU-1580 intelligent HPLC pump with JASCO UV-1575
intelligent UV/vis detector. Detection was performed at 254 nm.
Chiralcel OD-H, Chiralpak AD-H, Chiralpak IC columns
(0.46 ꢃ 25 cm) and Chiralpak IC-3 column (0.46 ꢃ 15 cm) from
Daicel were used. Retention times (tR) and peak ratios were deter-
mined with a JASCO-Borwin analysis system.
128.7 (CH), 129.6 (C), 131.5 (C), 154.5 (C); HRMS (ESI) calcd for
11H14NO2 (M+H)+ 192.10191, found 192.10193.
C
4.2.4. 5-Bromo-1-methoxymethylindole 5i
According to the procedure for the preparation of 5f, 5i was pre-
pared from 5-bromoindole (0.500 g, 2.55 mmol). The crude prod-
uct was purified by column chromatography (silica gel, 10:1
hexane/EtOAc) to provide the title compound (0.596 g, 97%) as a
All non-aqueous reactions were carried out in flame-dried
glassware under an Ar atmosphere unless otherwise noted. Re-
agents and solvents were purified by standard means. Dehydrated
CH2Cl2, THF and DMF were purchased from Kanto Chemical Co.,
Inc. Chiral dirhodium(II) carboxylates 1a–f14a,17a,18a,21 and 2,21
1-methoxymethylindole 5e,39 1-methoxymethyl-5-nitroindole
colorless oil: TLC Rf = 0.26 (10:1 hexane/EtOAc); IR (neat)
m 2936,
2360, 1452, 1328, 1183, 1089 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
3.22 (s, 3H, CH3OCH2), 5.43 (s, 2H, CH3OCH2), 6.48 (d, J = 3.2 Hz,
1H, Ar), 7.18 (d, J = 3.2 Hz, 1H, Ar), 7.32 (dd, J = 1.8, 8.6 Hz, 1H,
Ar), 7.37 (d, J = 8.6 Hz, 1H, Ar), 7.76 (d, J = 1.8 Hz, 1H, Ar); 13C
NMR (125 MHz, CDCl3) d 55.9 (CH3), 77.5 (CH2), 102.0 (CH),
111.4 (CH), 113.5 (C), 123.4 (CH), 125.0 (CH), 129.2 (CH), 130.8
5j40 and
a
-diazopropionates 6a,23c 6b41 and 6c41 were prepared
according to the literature procedures.
(C), 134.9 (C); HRMS (ESI) calcd for
240.00185, found 240.00228.
C
10H11BrNO (M+H)+
4.2. Preparation of N-MOM-protected indoles
4.2.1. 1-Methoxymethyl-2-methylindole 5f
A solution of 2-methylindole (1.00 g, 6.16 mmol) in DMF (5 mL)
was added to a solution of NaH (60% in oil, 0.34 g, 8.38 mmol) in
DMF (10 mL) at 0 °C. After stirring for 0.5 h at room temperature,
MOMCl (0.70 mL, 9.22 mmol) was added to the reaction mixture.
After stirring for 1 h, the reaction was quenched by the addition
of water (30 mL). The mixture was extracted with EtOAc
(2 ꢃ 20 mL) and the combined organic layers were washed with
water (30 mL) and brine (30 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (1.65 g), which was purified by column chromatography
(silica gel, 20:1 hexane/EtOAc) to provide 5f (1.20 g, 90%) as a col-
4.2.5. 1-Methoxymethyl-7-methylindole 5k
According to the procedure for the preparation of 5f, 5k was
prepared from 7-methylindole (0.500 g, 3.08 mmol). The crude
product was purified by column chromatography (silica gel, 20:1
hexane/EtOAc) to provide the title compound (0.658 g, 99%) as a
colorless oil: TLC Rf = 0.25 (20:1 hexane/EtOAc); IR (neat)
m 2930,
1462, 1305 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.74 (s, 3H, CH3Ar),
;
3.23 (s, 3H, CH3OCH2), 5.53 (s, 2H, CH3OCH2), 6.49 (d, J = 3.2 Hz, 1H,
Ar), 6.98 (d, J = 7.2 Hz, 1H, Ar), 7.04 (dd, J = 7.2, 7.7 Hz, 1H, Ar), 7.10
(d, J = 3.2 Hz, 1H, Ar), 7.47 (d, J = 7.2 Hz, 1H, Ar); 13C NMR
(100 MHz, CDCl3) d 19.2 (CH3), 55.2 (CH3), 79.3 (CH2), 102.3 (CH),
118.9 (CH), 120.5 (CH), 121.9 (C), 124.9 (CH), 130.1 (CH), 130.4
(C); HRMS (ESI) calcd for C11H14NO (M+H)+ 176.10699, found
176.10714.
orless oil: TLC Rf = 0.38 (20:1 hexane/EtOAc); IR (neat)
m 2948,
2252, 1460, 1308 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.48 (s, 3H,
;
CH3Ar), 3.24 (s, 3H, CH3OCH2), 5.43 (s, 2H, CH3OCH2), 6.29 (s, 1H,
Ar), 7.09 (ddd, J = 0.9, 7.7, 8.2 Hz, 1H, Ar), 7.16 (ddd, J = 1.4, 7.2,
8.2 Hz, 1H, Ar), 7.40 (d, J = 8.2 Hz, 1H, Ar), 7.51 (d, J = 7.2 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3) d 12.4 (CH3), 55.5 (CH3), 73.6
(CH2), 101.7 (CH), 109.0 (CH), 119.7 (CH), 120.0 (CH), 121.1 (CH),
128.2 (C), 136.7 (CH), 137.5 (C); HRMS (ESI) calcd for C11H14NO
(M+H)+ 176.10699, found 176.10708.
4.3. Enantioselective C–H functionalization of indoles with
diazopropionates
a-
4.3.1. Typical procedure for the C–H functionalization of
indoles: (R⁄)-2,4-dimethyl-3-pentyl 2-[(1-methyl)-1H-indol-3-
yl]propionate 7a (Table 1, entry 6)
4.2.2. 1-Methoxymethyl-4-methylindole 5g
At first, Rh2((S)-PTTEA)4ꢂ2EtOAc 1f (3.18 mg, 0.002 mmol,
According to the procedure for the preparation of 5f, 5g was
prepared from 4-methylindole (0.500 g, 3.08 mmol). The crude
product was purified by column chromatography (silica gel, 20:1
hexane/EtOAc) to provide the title compound (0.639 g, 96%) as a
1 mol %) was added in one portion to a solution of 2,4-dimethyl-
3-pentyl
a-diazopropionate 6a (39.7 mg, 0.200 mmol) and 1-
methylindole 5a (0.030 mL, 0.24 mmol) in CH2Cl2 (1.0 mL) at room
temperature. After stirring for 0.5 h at room temperature, the reac-
tion mixture was concentrated in vacuo, and the residue was puri-
fied by column chromatography (silica gel, 20:1 hexane/EtOAc) to
provide 7a (50.2 mg, 83%) as a colorless oil: TLC Rf = 0.43 (10:1 hex-
colorless oil: TLC Rf = 0.31 (20:1 hexane/EtOAc); IR (neat)
m 2928,
2251, 1519, 1493, 1303, 1236 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
2.56 (s, 3H, CH3Ar), 3.23 (s, 3H, CH3OCH2), 5.45 (s, 2H, CH3OCH2),
6.56 (dd, J = 0.9, 3.2 Hz, 1H, Ar), 6.95 (ddd, J = 0.9, 0.9, 8.2 Hz, 1H,
Ar), 7.15 (d, J = 8.2 Hz, 1H, Ar), 7.17 (d, J = 3.2 Hz, 1H, Ar), 7.33 (d,
J = 8.2 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) d 18.7 (CH3), 55.9
(CH3), 77.5 (CH2), 101.1 (CH), 107.5 (CH), 120.5 (CH), 122.3 (CH),
127.5 (CH), 129.0 (C), 130.5 (CH), 136.1 (C); HRMS (ESI) calcd for
ane/EtOAc); ½a 2D4
ꢁ
¼ ꢀ24:0 (c 0.99, CHCl3) for 67% ee; IR (neat)
m
2966, 1730, 1471, 1371, 1330, 1242, 1177 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 0.68 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.72 (d,
J = 6.8 Hz, 3H, CH(CH3)2), 0.82 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.84
(d, J = 7.2 Hz, 3H, CH(CH3)2), 1.63 (d, J = 7.2 Hz, 3H, CH3CHAr),
1.77–1.92 (m, 2H, CH(CH3)2), 3.76 (s, 3H, CH3N), 4.06 (q,
J = 7.2 Hz, 1H, CH3CHAr), 4.58 (t, J = 6.3 Hz, 1H, CO2CH), 7.03 (s,
1H, Ar), 7.10 (m, 1H, Ar), 7.21 (m, 1H, Ar), 7.28 (d, J = 8.2 Hz, 1H,
Ar), 7.68 (d, J = 8.2 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) d 17.0
(CH3), 17.2 (CH3), 18.3 (CH3), 19.4 (CH3), 19.5 (CH3), 29.4 (CH),
32.7 (CH3), 37.2 (CH), 82.6 (CH), 109.1 (CH), 114.3 (C), 118.9
(CH), 119.4 (CH), 121.6 (CH), 126.3 (CH), 127.0 (C), 136.9 (C),
175.3 (CO); HRMS (EI+) calcd for C19H27NO2 (M)+ 301.20418, found
301.20346. The enantiomeric excess of 7a was determined to be
67% by HPLC with a Daicel Chiralpak OD-H column (eluent:
100:1 hexane/2-propanol; flow: 1.0 mL/min): tR = 8.5 min for min-
or enantiomer; tR = 9.5 min for major enantiomer. The preferred
absolute configuration of 7a was not determined.
C
11H14NO (M+H)+ 176.10699, found 176.10704.
4.2.3. 5-Methoxy-1-methoxymethylindole 5h
According to the procedure for the preparation of 5f, 5h was
prepared from 5-methoxyindole (0.500 g, 3.40 mmol). The crude
product was purified by column chromatography (silica gel, 10:1
hexane/EtOAc) to provide the title compound (0.583 g, 90%) as a
colorless oil: TLC Rf = 0.29 (10:1 hexane/EtOAc); IR (neat)
m 2938,
1486, 1239, 1151, 1101 cmꢀ1 1H NMR (400 MHz, CDCl3) d 3.23
;
(s, 3H, CH3OCH2), 3.86 (s, 3H, CH3OAr), 5.42 (s, 2H, CH3OCH2),
6.46 (d, J = 2.7 Hz, 1H, Ar), 6.90 (dd, J = 2.3, 9.1 Hz, 1H, Ar), 7.10
(d, J = 2.3 Hz, 1H, Ar), 7.15 (d, J = 3.2 Hz, 1H, Ar), 7.38 (d,
J = 8.6 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) d 55.7 (CH3), 55.8
(CH3), 77.6 (CH2), 102.1 (CH), 102.6 (CH), 110.6 (CH), 112.3 (CH),

912
T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
4.3.2. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(1-benzyl)-1H-indol-3-
yl]propionate 7d (Table 2, entry 4)
According to the typical procedure for the C–H functionalization
of indole, 7d was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 1-benzylindole 5d (49.7 mg,
0.24 mmol). The crude product was purified by column chroma-
tography (silica gel, 30:1 hexane/EtOAc) to provide 7d (67.4 mg,
CH3OCH2), 3.90 (q, J = 7.2 Hz, 1H, CH3CHAr), 5.42 (s, 2H, CH3OCH2),
7.11 (s, 1H, Ar), 7.15 (dd, J = 7.2, 8.0 Hz, 1H, Ar), 7.24 (dd, J = 8.0,
8.0 Hz, 1H, Ar), 7.45 (d, J = 8.4 Hz, 1H, Ar), 7.69 (d, J = 7.6 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3) d 17.8 (CH3), 28.0 (CH3), 37.8
(CH), 55.8 (CH3), 77.3 (CH2), 80.4 (C), 109.8 (CH), 116.0 (C), 119.6
(CH), 119.8 (CH), 122.3 (CH), 125.3 (CH), 127.8 (C), 136.6 (C),
174.3 (CO); HRMS (ESI) calcd for
C
17H23NO3Na (M+Na)+
89%) as
¼ ꢀ16:4 (c 1.00, CHCl3) for 74% ee; IR (neat)
1468, 1173 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.64 (d, J = 6.8 Hz,
a
colorless oil: TLC Rf = 0.43 (10:1 hexane/EtOAc);
312.15701, found 312.15655. The enantiomeric excess of 7f was
determined to be 45% by HPLC with a Daicel Chiralpak OD-H col-
umn (eluent: 100:1 hexane/2-propanol; flow: 1.0 mL/min):
tR = 10.6 min for major enantiomer; tR = 11.4 min for minor enan-
tiomer. The preferred absolute configuration of 7f was not
determined.
½
a 2D1
ꢁ
m
2966, 1728,
;
3H, CH(CH3)2), 0.70 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.78 (d,
J = 6.8 Hz, 3H, CH(CH3)2), 0.81 (d, J = 6.8 Hz, 3H, CH(CH3)2), 1.63
(d, J = 7.2 Hz, 3H, CH3CHAr), 1.76–1.87 (m, 2H, CH(CH3)2), 4.07 (q,
J = 7.2 Hz, 1H, CH3CHAr), 4.57 (t, J = 6.3 Hz, 1H, CO2CH), 5.27 (d,
J = 16.3 Hz, 1H, ArCHH), 5.32 (d, J = 16.3 Hz, 1H, ArCHH), 7.06–
7.17 (m, 5H, Ar), 7.22–7.29 (m, 4H, Ar), 7.72 (d, J = 7.7 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3) d 16.9 (CH3), 17.2 (CH3), 18.1
(CH3), 19.4 (CH3), 19.4 (CH3), 29.4 (CH), 29.4 (CH), 37.2 (CH), 49.9
(CH2), 82.5 (CH), 109.6 (CH), 115.0 (C), 119.1 (CH), 119.6 (CH),
121.8 (CH), 125.6 (CH), 126.6 (CH), 127.3 (C), 127.5 (CH), 128.6
(CH), 136.4 (C), 137.5 (C), 175.0 (CO); HRMS (ESI) calcd for
4.3.5. (R⁄)-Ethyl 2-[(1-methoxymethyl)-1H-indol-3-
yl]propionate 7g (Table 2, entry 9)
According to the typical procedure for the C–H functionalization
of indole, 7g was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
ethyl
a-diazopropionate 6c (25.6 mg, 0.200 mmol) and 5e
(38.7 mg, 0.24 mmol). The crude product was purified by column
chromatography (silica gel, 10:1?5:1 hexane/EtOAc) to provide
7g (36.0 mg, 69%) as a colorless oil: TLC Rf = 0.10 (10:1 hexane/
C
25H31NO2Na (M+Na)+ 400.22470, found 400.22451. The enantio-
meric excess of 7d was determined to be 74% by HPLC with a Dai-
cel Chiralpak OD-H column (eluent: 100:1 hexane/2-propanol;
flow: 1.0 mL/min): tR = 16.0 min for minor enantiomer;
tR = 17.7 min for major enantiomer. The preferred absolute config-
uration of 7d was not determined.
EtOAc); ½a 2D2
ꢁ
¼ ꢀ19:5 (c 1.00, CHCl3) for 32% ee; IR (neat)
m 2980,
1731, 1466, 1330, 1181, 1089 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d
1.22 (t, J = 6.8 Hz, 3H, CH3CH2O), 1.60 (d, J = 7.2 Hz, 3H, CH3CHAr),
3.25 (s, 3H, CH3OCH2), 4.00 (q, J = 7.2 Hz, 1H, CH3CHAr), 4.07–4.20
(m, 2H, CH3CH2O), 5.42 (s, 2H, CH3OCH2), 7.13 (s, 1H, Ar), 7.16 (dd,
J = 7.2, 7.7 Hz, 1H, Ar), 7.25 (d, J = 7.2, 8.2 Hz, 1H, Ar), 7.46 (d,
J = 8.2 Hz, 1H, Ar), 7.69 (d, J = 7.7 Hz, 1H, Ar); 13C NMR (100 MHz,
CDCl3) d 14.2 (CH3), 17.9 (CH3), 36.9 (CH), 55.9 (CH3), 60.7 (CH2),
77.4 (CH2), 109.9 (CH), 115.7 (C), 119.5 (CH), 120.0 (CH), 122.4
(CH), 125.4 (CH), 127.7 (C), 136.7 (C), 175.0 (CO); HRMS (ESI) calcd
for C15H19NO3Na (M+Na)+ 284.12571, found 284.12538. The enan-
tiomeric excess of 7g was determined to be 32% by HPLC with a
Daicel Chiralpak OD-H column (eluent: 9:1 hexane/2-propanol;
flow: 1.0 mL/min): tR = 8.0 min for major enantiomer; tR = 10.7 min
for minor enantiomer. The preferred absolute configuration of 7g
was not determined.
4.3.3. (R)-2,4-Dimethyl-3-pentyl 2-[(1-methoxymethyl)-1H-
indol-3-yl]propionate 7e (Table 2, entry 5)
According to the typical procedure for the C–H functionalization
of indole, 7e was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (79.3 mg, 0.400 mmol) and 1-methoxymethylindole 5e
(77.4 mg, 0.480 mmol). The crude product was purified by column
chromatography (silica gel, 5:1 hexane/Et2O) to provide 7e
(111 mg, 83%) as a colorless oil: TLC Rf = 0.30 (10:1 hexane/EtOAc);
½
a 2D0
ꢁ
¼ ꢀ20:3 (c 1.04, CHCl3) for 82% ee; IR (neat)
m 2966, 1730,
1466, 1181, 1090 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.65 (d,
;
J = 6.8 Hz, 3H, CH(CH3)2), 0.71 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.80
(d, J = 6.3 Hz, 3H, CH(CH3)2), 0.82 (d, J = 6.8 Hz, 3H, CH(CH3)2),
1.64 (d, J = 7.2 Hz, 3H, CH3CHAr), 1.75–1.90 (m, 2H, CH(CH3)2),
3.19 (s, 3H, CH3OCH2), 4.05 (q, J = 7.2 Hz, 1H, CH3CHAr), 4.58 (t,
J = 6.3 Hz, 1H, CO2CH), 5.39 (d, J = 10.9 Hz, 1H, CH3OCHH), 5.44
(d, J = 11.3 Hz, 1H, CH3OCHH), 7.15 (m, 1H, Ar), 7.15 (s, 1H, Ar),
7.23 (m, 1H, Ar), 7.45 (d, J = 8.2 Hz, 1H, Ar), 7.70 (d, J = 7.7 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3) d 16.9 (CH3), 17.2 (CH3), 18.0
(CH3), 19.3 (CH3), 19.5 (CH3), 29.4 (CH), 37.1 (CH), 55.7 (CH3),
77.3 (CH2), 82.6 (CH), 109.8 (CH), 115.9 (C), 119.6 (CH), 119.9
(CH), 122.3 (CH), 125.4 (CH), 127.8 (C), 136.5 (C), 174.9 (CO); HRMS
(ESI) calcd for C20H29NO3Na (M+Na)+ 354.20451, found 354.20480.
The enantiomeric excess of 7e was determined to be 82% by HPLC
analysis with a Daicel Chiralpak IC column (eluent: 100:1 hexane/
2-propanol; flow: 1.0 mL/min): tR (minor) = 9.8 min for (S)-7e; tR
(major) = 11.0 min for (R)-7e.
4.3.6. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(1-methoxymethyl-4-
methyl)-1H-indol-3-yl]propionate 7i (Table 3, entry 2)
According to the typical procedure for the C–H functionalization
of indole, 7i was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 1-methoxymethyl-4-methylindole
5g (42.1 mg, 0.24 mmol). The crude product was purified by column
chromatography (silica gel, 5:1 hexane/Et2O) to provide 7i (49.5 mg,
72%) as a colorless oil: TLC Rf = 0.18 (5:1 hexane/Et2O); ½a D22
¼ ꢀ28:1
ꢁ
(c 0.89, CHCl3) for 69% ee; IR (neat)
m 2966, 1730, 1465, 1181,
1096 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.64 (d, J = 6.8 Hz, 3H,
;
CH(CH3)2), 0.72 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.81 (d, J = 7.2 Hz, 3H,
CH(CH3)2), 0.83 (d, J = 7.7 Hz, 3H, CH(CH3)2), 1.61 (d, J = 6.8 Hz, 3H,
CH3CHAr), 1.76–1.90 (m, 2H, CH(CH3)2), 2.76 (s, 3H, CH3Ar), 3.18
(s, 3H, CH3OCH2), 4.40 (q, J = 6.8 Hz, 1H, CH3CHAr), 4.58 (t,
J = 6.3 Hz, 1H, CO2CH), 5.36 (d, J = 11.3 Hz, 1H, CH3OCHH), 5.44 (d,
J = 11.3 Hz, 1H, CH3OCHH), 6.89 (d, J = 7.2 Hz, 1H, Ar), 7.11 (dd,
J = 7.7, 7.7 Hz, 1H, Ar), 7.18 (s, 1H, Ar), 7.31 (d, J = 8.2 Hz, 1H, Ar);
13C NMR (100 MHz, CDCl3) d 16.9 (CH3), 17.2 (CH3), 19.4 (CH3),
19.5 (CH3), 19.8 (CH3), 20.5 (CH3), 29.4 (CH), 29.4 (CH), 37.5 (CH),
55.7 (CH3), 77.4 (CH2), 82.6 (CH), 107.9 (CH), 116.9 (C), 122.2 (CH),
125.8 (CH), 126.4 (C), 130.8 (C), 136.6 (C), 175.5 (CO); HRMS (ESI)
calcd for C21H31NO3Na (M+Na)+ 368.21962, found 368.21912. The
enantiomeric excess of 7i was determined to be 69% by HPLC with
a Daicel Chiralpak OD-H column (eluent: 200:1 hexane/2-propanol;
flow: 1.0 mL/min): tR = 15.5 min for minor enantiomer; tR =
17.9 min for major enantiomer. The preferred absolute configura-
tion of 7i was not determined.
4.3.4. (R⁄)-tert-Butyl 2-[(1-methoxymethyl)-1H-indol-3-
yl]propionate 7f (Table 2, entry 8)
According to the typical procedure for the C–H functionalization
of indole, 7f was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
tert-butyl
a-diazopropionate 6b (31.2 mg, 0.200 mmol) and 5e
(38.7 mg, 0.24 mmol). The crude product was purified by column
chromatography (silica gel, 10:1 hexane/EtOAc) to provide 7f
(41.6 mg, 72%) as a colorless oil: TLC Rf = 0.13 (10:1 hexane/EtOAc);
½
a 2D2
ꢁ
¼ ꢀ24:4 (c 1.06, CHCl3) for 45% ee; IR (neat)
1466, 1367, 1149, 1089 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.41
(s, 9H, (CH3)3C), 1.56 (d, J = 7.2 Hz, 3H, CH3CHAr), 3.23 (s, 3H,
m 2978, 1726,
;

T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
913
4.3.7. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(5-methoxy-1-
1519, 1336, 1179, 1102 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 0.63
methoxymethyl)-1H-indol-3-yl]propionate 7j (Table 3, entry 3)
According to the typical procedure for the C–H functionalization
of indole, 7j was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 5-methoxy-1-methoxymethylindole
5h (45.9 mg, 0.24 mmol). The crude product was purified by col-
umn chromatography (silica gel, 5:1 hexane/Et2O) to provide 7j
(55.6 mg, 77%) as a colorless oil: TLC Rf = 0.13 (10:1 hexane/EtOAc);
(d, J = 6.8 Hz, 3H, CH(CH3)2), 0.71 (d, J = 6.8 Hz, 3H, CH(CH3)2),
0.83 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.85 (d, J = 6.8 Hz, 3H, CH(CH3)2),
1.67 (d, J = 7.2 Hz, 3H, CH3CHAr), 1.77–1.94 (m, 2H, CH(CH3)2), 3.23
(s, 3H, CH3OCH2), 4.09 (q, J = 7.2 Hz, 1H, CH3CHAr), 4.59 (t,
J = 6.3 Hz, 1H, CO2CH), 5.43 (d, J = 10.9 Hz, 1H, CH3OCHH), 5.47
(d, J = 10.9 Hz, 1H, CH3OCHH), 7.31 (s, 1H, Ar), 7.50 (d, J = 9.1 Hz,
1H, Ar), 8.16 (d, J = 1.8, 9.1 Hz, 1H, Ar), 8.70 (d, J = 2.3 Hz, 1H, Ar);
13C NMR (100 MHz, CDCl3) d 16.9 (CH3), 17.1 (CH3), 17.8 (CH3),
19.3 (CH3), 19.5 (CH3), 29.3 (CH), 36.8 (CH), 56.1 (CH3), 77.8
(CH2), 83.3 (CH), 110.1 (CH), 117.1 (CH), 118.1 (C), 118.3 (CH),
127.3 (C), 128.4 (CH), 139.4 (C), 142.0 (C), 174.2 (CO); HRMS
½
a 2D2
ꢁ
¼ ꢀ24:7 (c 1.12, CHCl3) for 58% ee; IR (neat)
m 2966, 1730,
1488, 1222, 1172, 1088 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.66
;
(d, J = 6.3 Hz, 3H, CH(CH3)2), 0.72 (d, J = 6.8 Hz, 3H, CH(CH3)2),
0.81 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.83 (d, J = 6.8 Hz, 3H, CH(CH3)2),
1.63 (d, J = 7.2 Hz, 3H, CH3CHAr), 1.76–1.91 (m, 2H, CH(CH3)2), 3.18
(s, 3H, CH3OCH2), 3.86 (s, 3H, CH3OAr), 4.00 (q, J = 7.2 Hz, 1H,
CH3CHAr), 4.58 (t, J = 6.3 Hz, 1H, CO2CH), 5.35 (d, J = 11.3 Hz, 1H,
CH3OCHH), 5.40 (d, J = 11.3 Hz, 1H, CH3OCHH), 6.89 (dd, J = 2.3,
8.6 Hz, 1H, Ar), 7.12 (s, 1H, Ar), 7.13 (d, J = 2.3 Hz, 1H, Ar), 7.34 (d,
J = 8.6 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) d 17.0 (CH3), 17.2
(CH3), 17.8 (CH3), 19.4 (CH3), 19.5 (CH3), 29.4 (CH), 29.4 (CH),
37.1 (CH), 55.6 (CH3), 55.8 (CH3), 77.5 (CH2), 82.6 (CH), 101.3
(CH), 110.7 (CH), 112.6 (CH), 115.4 (C), 126.0 (CH), 128.3 (C),
131.7 (C), 154.3 (C), 174.9 (CO); HRMS (ESI) calcd for C21H31NO4Na
(M+Na)+ 384.21453, found 384.21465. The enantiomeric excess of
7j was determined to be 58% by HPLC with a Daicel Chiralpak AD-H
column (eluent: 9:1 hexane/2-propanol; flow: 1.0 mL/min):
tR = 5.3 min for minor enantiomer; tR = 6.2 min for major enantio-
mer. The preferred absolute configuration of 7j was not
determined.
(ESI) calcd for
C
20H28N2O5Na (M+Na)+ 399.18904, found
399.18926. The enantiomeric excess of 7l was determined to be
72% by HPLC with a Daicel Chiralpak AD-H column (eluent: 9:1
hexane/2-propanol; flow: 1.0 mL/min): tR = 7.2 min for minor
enantiomer; tR = 11.6 min for major enantiomer. The preferred
absolute configuration of 7l was not determined.
4.3.10. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(1-methoxymethyl-7-
methyl)-1H-indol-3-yl]propionate 7m (Table 3, entry 6)
According to the typical procedure for the C–H functionalization
of indole, 7m was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 1-methoxymethyl-7-methylindole
5k (42.1 mg, 0.24 mmol). The crude product was purified by col-
umn chromatography (silica gel, 5:1 hexane/Et2O) to provide 7m
(57.3 mg, 83%) as a colorless oil: TLC Rf = 0.17 (5:1 hexane/Et2O);
½
a 2D2
ꢁ
¼ ꢀ9:7 (c 0.95, CHCl3) for 86% ee; IR (neat)
m 2968, 1725,
1463, 1183, 1106 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.67 (d,
;
4.3.8. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(5-bromo-1-
J = 6.8 Hz, 3H, CH(CH3)2), 0.72 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.82
(d, J = 6.8 Hz, 3H, CH(CH3)2), 0.84 (d, J = 6.8 Hz, 3H, CH(CH3)2),
1.61 (d, J = 7.2 Hz, 3H, CH3CHAr), 1.76–1.91 (m, 2H, CH(CH3)2),
2.72 (s, 3H, CH3Ar), 3.19 (s, 3H, CH3OCH2), 4.03 (q, J = 7.2 Hz, 1H,
CH3CHAr), 4.58 (t, J = 6.3 Hz, 1H, CO2CH), 5.46 (d, J = 10.9 Hz, 1H,
CH3OCHH), 5.54 (d, J = 11.3 Hz, 1H, CH3OCHH), 6.98 (d, J = 7.2 Hz,
1H, Ar), 7.05 (dd, J = 7.2, 7.7 Hz, 1H, Ar), 7.09 (s, 1H, Ar), 7.52 (d,
J = 7.7 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) d 17.0 (CH3), 17.2
(CH3), 18.3 (CH3), 19.2 (CH3), 19.4 (CH3), 19.5 (CH3), 29.4 (CH),
36.9 (CH), 55.1 (CH3), 79.2 (CH2), 82.6 (CH), 115.3 (C), 117.2 (CH),
120.2 (CH), 121.9 (C), 125.1 (CH), 127.5 (CH), 129.1 (C), 134.8 (C),
methoxymethyl)-1H-indol-3-yl]propionate 7k (Table 3, entry 4)
According to the typical procedure for the C–H functionalization
of indole, 7k was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 5-bromo-1-methoxymethylindole
5i (57.6 mg, 0.24 mmol). The crude product was purified by col-
umn chromatography (silica gel, 5:1 hexane/Et2O) to provide 7k
(67.9 mg, 83%) as a colorless oil: TLC Rf = 0.11 (10:1 hexane/EtOAc);
½
a 2D2
ꢁ
¼ ꢀ36:0 (c 1.12, CHCl3) for 64% ee; IR (neat)
m 2966, 1731,
1469, 1353, 1177, 1097 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.66
;
(d, J = 6.8 Hz, 3H, CH(CH3)2), 0.71 (d, J = 6.8 Hz, 3H, CH(CH3)2),
0.82 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.84 (d, J = 6.8 Hz, 3H, CH(CH3)2),
1.62 (d, J = 7.2 Hz, 3H, CH3CHAr), 1.78–1.90 (m, 2H, CH(CH3)2), 3.18
(s, 3H, CH3OCH2), 3.98 (q, J = 7.2 Hz, 1H, CH3CHAr), 4.58 (t,
J = 6.3 Hz, 1H, CO2CH), 5.36 (d, J = 10.9 Hz, 1H, CH3OCHH), 5.41
(d, J = 10.9 Hz, 1H, CH3OCHH), 7.75 (s, 1H, Ar), 7.32 (d, J = 0.9 Hz,
1H, Ar), 7.32 (s, 1H, Ar), 7.85 (d, J = 0.9 Hz, 1H, Ar); 13C NMR
(100 MHz, CDCl3) d 16.9 (CH3), 17.2 (CH3), 17.8 (CH3), 19.3 (CH3),
19.5 (CH3), 29.4 (CH), 37.0 (CH), 55.8 (CH3), 77.5 (CH2), 82.9 (CH),
111.4 (CH), 113.4 (C), 115.5 (C), 122.4 (CH), 125.2 (CH), 126.5
(CH), 129.5 (C), 135.2 (C), 174.5 (CO); HRMS (ESI) calcd for
175.0 (CO); HRMS (ESI) calcd for
C
21H31NO3Na (M+Na)+
368.21962, found 368.21957. The enantiomeric excess of 7m was
determined to be 86% by HPLC with a Daicel Chiralpak IC column
(eluent: 200:1 hexane/2-propanol; flow: 1.0 mL/min): tR = 17.5 min
for minor enantiomer; tR = 18.9 min for major enantiomer. The pre-
ferred absolute configuration of 7m was not determined.
4.4. Determination of absolute configuration of (R)-2,4-
dimethyl-3-pentyl 2-[(1-methoxymethyl)-1H-indol-3-
yl]propionate 7e (Scheme 2)
C
20H28BrNO3Na (M+Na)+ 432.11448, found 432.11508. The enan-
tiomeric excess of 7k was determined to be 64% by HPLC with a
Daicel Chiralpak AD-H column (eluent: 9:1 hexane/2-propanol;
flow: 1.0 mL/min): tR = 4.5 min for minor enantiomer; tR = 5.8 min
for major enantiomer. The preferred absolute configuration of 7k
was not determined.
4.4.1. (R)-2,4-Dimethyl-3-pentyl 2-(1H-indol-3-yl)propionate 9
At first, TMSOTf (0.061 mL, 0.33 mmol) was added to a solution
of 7e (55.0 mg, 0.166 mmol) and 2,20-bipyridyl (77.8 mg,
0.498 mmol) in CH2Cl2 (1.0 mL) at 0 °C. After stirring for 0.5 h at
0 °C, the reaction was quenched by the addition of water
(3 mL). The mixture was extracted with EtOAc (2 ꢃ 5 mL), and
the combined organic layers were washed with 1 M aq HCl
(2 ꢃ 3 mL), saturated aq NaHCO3 (3 mL) and brine (3 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished (R)-2,4-dimethyl-3-pentyl 2-[(1-hydroxymethyl)-1H-in-
dol-3-yl]propionate 8 (60.5 mg), which was used without further
purification. Next, NaOH (66.4 mg, 1.66 mmol) was added to the
solution of 8 (60.5 mg) in THF (3.6 mL) and water (0.4 mL). After
stirring for 24 h at room temperature, the reaction was quenched
with addition of saturated NH4Cl (10 mL). The mixture was
4.3.9. (R⁄)-2,4-Dimethyl-3-pentyl 2-[(1-methoxymethyl-5-
nitro)-1H-indol-3-yl]propionate 7l (Table 3, entry 5)
According to the typical procedure for the C–H functionalization
of indole, 7l was prepared from 1f (3.18 mg, 0.002 mmol, 1 mol %),
6a (39.7 mg, 0.200 mmol) and 1-methoxymethyl-5-nitroindole 5j
(45.9 mg, 0.24 mmol). The crude product was purified by column
chromatography (silica gel, 3:1 hexane/EtOAc) to provide 7l
(52.1 mg, 69%) as a colorless oil: TLC Rf = 0.50 (5:1 hexane/EtOAc);
½
a 2D2
ꢁ
¼ ꢀ71:0 (c 0.50, CHCl3) for 72% ee; IR (neat)
m 2967, 1731,

914
T. Goto et al. / Tetrahedron: Asymmetry 22 (2011) 907–915
extracted with EtOAc (2 ꢃ 10 mL), and the combined organic lay-
ers were washed with brine (10 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (62.0 mg), which was purified by column chromatogra-
phy (silica gel, 6:1 hexane/EtOAc) to provide 9 (47.3 mg, 98%) as
colorless oil: ½a D24
ꢁ
¼ þ28:2 (c 0.48, MeOH) for 83% ee {lit.,30
½
a 2D5
ꢁ
¼ þ30:6 (c 0.46, MeOH) for 90% ee}.
4.5.4. (S)-(+)-a
-Methyl-3-indolylacetic acid 1131
At first, an SO3ꢂpyridine complex (114 mg, 0.718 mmol) was
added to a solution of ent-10 (30.0 mg, 0.171 mmol) and Et3N
(0.11 mL, 0.789 mmol) in DMSO (1.0 mL) at room temperature.
After stirring for 0.5 h at room temperature, the reaction mixture
was poured into a mixture of saturated aq NH4Cl (5 mL) and sat-
urated aq NaHCO3 (5 mL). The mixture was extracted with EtOAc
(2 ꢃ 5 mL) and the combined organic layers were washed with
brine (5 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo gave the crude aldehyde, which was used
without further purification. Next, NaH2PO4ꢂH2O (534 mg,
3.42 mmol) and NaClO2 (70.0 mg, 0.619 mmol) were added to
the solution of the crude aldehyde in THF (1.0 mL), tBuOH
(0.3 mL), 2-methyl-2-butene (0.3 mL) and water (1.0 mL). After
stirring for 0.5 h, the reaction mixture was poured into saturated
aq NH4Cl (5 mL), and whole was extracted with EtOAc (2 ꢃ 5 mL).
The combined organic layers were washed with brine (5 mL) and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (109 mg), which was purified by col-
umn chromatography (silica gel, 1:1 hexane/EtOAc) to provide 11
a yellow oil: ½a 2D2
ꢁ
¼ ꢀ40:4 (c 0.71, CHCl3) for 82% ee; IR (neat)
m
3412, 2968, 1716, 1459, 1186 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
0.66 (d, J = 6.9 Hz, 3H, CH(CH3)2), 0.71 (d, J = 6.9 Hz, 3H,
CH(CH3)2), 0.80 (d, J = 6.9 Hz, 3H, CH(CH3)2), 0.83 (d, J = 6.9 Hz,
3H, CH(CH3)2), 1.64 (d, J = 6.9 Hz, 3H, CH3CHAr), 1.77–1.90 (m,
2H, CH(CH3)2), 4.07 (q, J = 6.8 Hz, 1H, CH3CHAr), 4.58 (t,
J = 6.3 Hz, 1H, CO2CH), 7.10–7.13 (m, 1H, Ar), 7.17 (s, 1H, Ar),
7.19 (m, 1H, Ar), 7.35 (d, J = 8.0 Hz, 1H, Ar), 7.71 (d, J = 8.0 Hz,
1H, Ar), 8.03 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) d 16.9
(CH3), 17.2 (CH3), 18.0 (CH3), 19.3 (CH3), 19.5 (CH3), 29.4 (CH),
29.4 (CH), 37.2 (CH), 77.2 (CH), 82.6 (CH), 111.1 (CH), 115.7 (C),
119.3 (CH), 121.5 (CH), 122.0 (CH), 126.5 (C), 136.1 (C), 175.2
(CO); HRMS (ESI) calcd for C18H25NO2Na (M+Na)+ 310.17775,
found 310.17797.
4.4.2. (R)-2-(1H-Indol-3-yl)propane-1-ol 1030
At first, LiAlH4 (22.7 mg, 0.598 mmol) was added to a solution of
9 (43.0 mg, 0.150 mmol) in THF (1.0 mL) at 0 °C. After stirring for
4 h at room temperature, the reaction was quenched with addition
of water (0.023 mL). Next, 15% aq NaOH (0.023 mL) and water
(0.069 mL) were added to the reaction mixture. After stirring for
0.5 h at room temperature, filtration and evaporation in vacuo fur-
nished the crude product (34.8 mg), which was purified by column
chromatography (silica gel, 1:1 hexane/EtOAc) to provide 10
(19.8 mg, 61%) as a dark yellow oil: ½a D25
¼ þ42:6 (c 0.12, CH2Cl2)
ꢁ
for 83% ee {lit.,31c
[a]D = +41.5 (c 0.13, CH2Cl2) for >99% ee}; IR
(neat)
m ;
3415, 2983, 1709, 1458, 1248 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 1.63 (d, J = 7.3 Hz, 3H, CH3CHAr), 4.05 (q, J = 7.3 Hz, 1H,
CH3CHAr), 7.13 (dd, J = 7.3, 8.0 Hz, 1H, Ar), 7.15 (s, 1H, Ar), 7.20
(dd, J = 7.3, 7.3 Hz, 1H, Ar), 7.36 (d, J = 8.0 Hz, 1H, Ar), 7.69 (d,
J = 7.6 Hz, 1H, Ar), 8.07 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 17.5 (CH3), 36.7 (CH), 111.2 (CH), 114.9 (C), 119.3 (CH), 119.7
(CH), 121.7 (CH), 122.4 (CH), 126.3 (C), 136.2 (C), 180.0 (CO).
The enantiomeric excess of 11 was determined to be 83% by
HPLC analysis with a Daicel Chiralpak IC-3 column [eluent: 9:1
hexane/2-propanol (contained 0.1% AcOH); flow: 0.5 mL/min;
40 °C]: tR (major) = 12.2 min for (S)-11; tR (minor) = 18.2 min for
(R)-11.
(22.7 mg, 87%) as a colorless oil: ½a D24
¼ ꢀ23:3 (c 0.41, MeOH) for
ꢁ
82% ee {lit.,30
½
a 2D5
ꢁ
¼ þ30:6 (c 0.46, MeOH) for (S)-10 (90% ee)};
1H NMR (500 MHz, CDCl3) d 1.41 (d, J = 7.3 Hz, 3H, CH3CHAr),
3.30–3.34 (m, 1H CH3CHAr), 3.80–3.86 (m, 2H, CH2OH), 7.07 (s,
1H, Ar), 7.10 (m, 1H, Ar), 7.22 (m, 1H, Ar), 7.38 (d, J = 8.0 Hz, 1H,
Ar), 7.67 (d, J = 8.0 Hz, 1H, Ar), 8.07 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 17.2 (CH3), 33.9 (CH), 67.8 (CH2), 111.3 (CH),
117.9 (C), 119.2 (CH), 119.3 (CH), 121.2 (CH), 122.1 (CH), 126.7
(C), 136.5 (C).
Acknowledgments
4.5. Synthesis of (S)-(+)-a-methyl-3-indolylacetic acid 11, a
constituent of acremoauxin A 12 (Scheme 3)
This research was supported, in part, by a Grant-in-Aid for
Scientific Research on Innovative Areas (Project No. 2105: Organic
Synthesis Based on Reaction Integration) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. We
thank Ms. S. Oka, and M. Kiuchi of the Center for Instrumental
Analysis at Hokkaido University for technical assistance in mass
spectra.
4.5.1. (S)-2,4-Dimethyl-3-pentyl 2-[(1-methoxymethyl)-1H-
indol-3-yl]propionate ent-7e
According to the typical procedure for the C–H functionalization
of indole, ent-7e was prepared from Rh2((R)-PTTEA)4ꢂ2EtOAc 2
(3.18 mg, 0.002 mmol, 1 mol %), 6a (79.3 mg, 0.400 mmol) and 5e
(77.4 mg, 0.48 mmol). The crude product was purified by column
chromatography (silica gel, 5:1 hexane/Et2O) to provide ent-7e
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