A concise synthesis of (-)-indolmycin and (-)-5-methoxyindolmycin

Article abstract of DOI:10.1016/j.tetasy.2008.07.013

Concise syntheses of (-)-indolmycin 1 and (-)-5-methoxyindolmycin 3 were developed based on a palladium-catalyzed reaction of (2S,3R)-2-acetoxy-3-methyl-5-trimethylsilyl-4-pentynoate 6 with an o-iodoaniline derivative 10 or 11, followed by reaction with g

Full text of DOI:10.1016/j.tetasy.2008.07.013

Tetrahedron: Asymmetry 19 (2008) 1833–1838
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Tetrahedron: Asymmetry
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A concise synthesis of (ꢀ)-indolmycin and (ꢀ)-5-methoxyindolmycin
*
Noriyuki Sutou, Keisuke Kato, Hiroyuki Akita
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise syntheses of (ꢀ)-indolmycin 1 and (ꢀ)-5-methoxyindolmycin 3 were developed based on a
palladium-catalyzed reaction of (2S,3R)-2-acetoxy-3-methyl-5-trimethylsilyl-4-pentynoate 6 with an
o-iodoaniline derivative 10 or 11, followed by reaction with guanidine hydrochloride in the presence
of base. An optically active internal alkyne (2S 3R)-6 was obtained by lipase-assisted enantioselective
acetylation of (±)-(2,3)-syn-2-hydroxy-3-methyl-5-trimethylsily-4-pentynoate 4.
Received 11 June 2008
Accepted 2 July 2008
Available online 9 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
3
1
. Introduction
anti-H. pylori agent (Scheme 1). Racemic syntheses of 1 have been
4
developed by two groups. The first asymmetric synthesis of (ꢀ)-1
(ꢀ)-Indolmycin 1, an antibiotic isolated from the African strain
was achieved based on the reaction of (2R,3S)-6-alkyliden-3,4-di-
of Streptomyces albus, exhibits an antibacterial activity against
Staphylococci. Indolmycin congeners 2 and 3, which possess a
hydroxyl or methoxyl group at the 5 -position of the indole
methyl-2-phenylperhydro-1,4-oxaazepine-5,7-dione with a Grig-
nard reagent. Syntheses of optically active indolmycin 1 have
been carried out using a resolution method or based on the reac-
1
5
0
6
skeleton, have been obtained by the addition of indole precursors,
such as 5-hydroxy- and 5-methoxyindoles to growing cultures of
Streptomyces griseus ATCC 12648. These congeners show a moder-
ate increase in antimicrobial activity compared to 1. In a recent
study, 1 was reported to exhibit potent antibacterial activity
against Helicobactor pylori (H. pylori), and is thus a promising
tion of indolyl magnesium bromide with (2S,3R)-epoxy butanoate,
affording (2S,3R)-indolmycenate derivative A. Palladium-cata-
lyzed heteroannulation of internal alkynes (C) using o-iodoaniline
or its derivatives B has been reported to give indole derivatives E
via a vinylpalladium intermediate D as shown in Scheme 2,8 and
this procedure (the Larock indole synthesis) seems to be promising
7
2
Me
Me
O
Me
R
R
COOMe
2
S COOMe
N
3R
O
OH
N
H
N
H
TMS
OH
(2S,3R)-4
NHMe
A
R = H Indolmycin 1
R = OH 5-Hydroxyindolmycin 2
R = OMe
5-Methoxyindolmycin 3
(
±)-4
OMe OMe
Me
N
2
R
COOMe
3
S
MeOOC
Me
S
N
TMS
OH
2R,3S)-4
Me
(
S
Cystothiazole A (5)
Me
Scheme 1.
*
Corresponding author. Tel.: +81 047 472 1805: fax: +81 047 476 6195.
E-mail address: akita@phar.toho-u.ac.jp (H. Akita).
0
957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.013

1
834
N. Sutou et al. / Tetrahedron: Asymmetry 19 (2008) 1833–1838
R2
R2
R3
R2
R3
X
Pd(0)
+
PdX
NH
NHR1
N
R1
R3
1
R
B
C
D
E
Scheme 2. Tandem Heck reaction and cyclization.
Table 1
Lipase-assisted acetylation of (±)-4
Me
Me
lipase / acyl donor / i-Pr O
2S
COOMe
2R
COOMe
2
(
±)-4
3R
+
3S
3
3°C
TMS
OAc
2S,3R)-6
TMS
OH
(2R,3S)-4
(
Entry
Substrate
Lipase
Acyl donor
Time (days)
Products (%, % ee)
1
2
3
(±)-4 (5.012 g)
(2R,3S)-4 (44% ee) (2.980 g)
(±)-4 (5.150 g)
Amano P
Amano PS
Amano PS
Isopropenyl acetate
Vinyl acetate
Vinyl acetate
7
3
5
(2S,3R)-6 (28, 82)
(2S,3R)-6 (23, 86)
(2S,3R)-6 (48, 95)
(2R,3S)-4 (59, 44)
(2R,3S)-4 (60, 95)
(2R, 3S)-4 (50, 94)
Me
Me
Me
a
COOMe
b
COOMe
a
COOMe
(
±)-4
(±)-4
TMS
OCOPh
OH
OCOPh
(
±)-7
a) PhCOCl / DMAP / pyridine; (b) K CO / MeOH
(±)-8
(±)-9
(
2
3
for synthesis of optically active indolmycenate derivatives A
Scheme 2). Herein, we report a concise synthesis of (ꢀ)-indol-
alcohol 4 (60%, 95% ee) (Table 1, entry 2). Enzymatic acetylation
of (±)-4 using Amano PS in the presence of vinyl acetate for 5 days
(
2
7
mycin 1 and (ꢀ)-5-methoxyindolmycin 3 based on a palladium-
catalyzed reaction of o-iodoaniline congeners and (2S,3R)-2-hydro-
xy-3-methyl-5- trimethylsilyl-4-pentynoate 4 or its acetate 6 (see
Table 1). The optically active (2S,3R)-4 or (2R,3S)-4 could be
obtained based on the enantioselective acetylation of (±)-4 using
lipase. Enantiomerically pure (2R,3S)-4 obtained by an alternative
method was converted to the b-methoxyacrylate antibiotic cysto-
gave acetate (+)-6 {48%, ½
to 95% ee} and unreacted alcohol (ꢀ)-4 {50%, ½
CHCl ); corresponds to 94% ee} (Table 1, entry 3). The enantiomeric
aꢁ
¼ þ12:05 (c 1.09, CHCl
3
); corresponds
¼ ꢀ24:8 (c 1.13,
D
2
D
5
aꢁ
3
excess (ee) for each enzymatic product was calculated by HPLC
analysis after conversion of the enzymatic product to the
1
0
corresponding benzoate. The E-value of this enzymatic reaction
(entry 3) was estimated to be 139. The absolute structure of the
enzymatic reaction product (ꢀ)-4 was determined by direct com-
9
thiazole A 5.
9
b
25
D
parison with previously reported sample
(2R,3S)-4 {½
a
ꢁ
¼
ꢀ24:1 (c 1.07, CHCl
3
); corresponds to >99% ee}; thus, the absolute
2
2
. Results and discussion
configuration of acetate 6 was determined to be (2S,3R).
.1. Lipase-assisted enantioselective acetylation of (±)-4
Using a previously reported procedure,9 substrate (±)-4 was
2
.2. Synthesis of (ꢀ)-indolmycin 1 and (ꢀ)-5-
methoxyindolmycin 3
obtained by the reaction of (±)-trans-(2,3)-epoxy butanoate and
trimethylsilylacetylide. For the purpose of determining the
enantiomeric excess (ee) of the enzymatic reaction products, race-
mate (±)-4 was converted to two benzoates (±)-7 and (±)-9, which
gave two well separated peaks of the enantiomeric isomers,
respectively, in HPLC analysis (see Section 4), thus allowing the
determination of the ee of the enzymatic reaction products. A
screening experiment for finding a suitable enzyme showed that
the most effective lipase was found to be Amano P or Amano PS
from Pseudomonas sp. When (±)-4 was subjected to enantioselec-
tive acetylation using ‘Amano P’ in the presence of isopropenyl
acetate as an acylating reagent for 7 days, acetate 6 (28%, 82% ee)
and unreacted alcohol 4 (59%, 44% ee) were obtained (Table 1,
entry 1). The 44% ee of unreacted alcohol 4 was again subjected
to enzymatic acetylation using Amano PS in the presence of vinyl
acetate for 3 days, to give acetate 6 (23%, 86% ee) and unreacted
Syntheses of (ꢀ)-indolmycin 1 and (ꢀ)-5-methoxyindolmycin 3
from (2S,3R)-6 are shown in Scheme 3. At first, the reaction of
o-iodoaniline and (±)-4 in the presence of [1,1-bis(diphenylphos-
phono)-ferrocene]palladium(II) dichloride dichloromethane com-
plex, LiCl, and Na CO in DMF, followed by desilylation, did not
2 3
give the desired indolmycenate (±)-14 (Scheme 3). Then, two types
of o-iodoaniline congeners, N-(tert-butoxycarbonyl)-2-iodoaniline
1
0 and N-(tert-butoxycarbonyl)-2-iodo-4-methoxyaniline 11, were
synthesized by N-tert-butoxycarbonylation of o-iodoaniline and
1
1
the known 2-iodo-4-methoxyaniline, respectively. Reaction of
+
(
2S,3R)-6 and 10 using Pd(OAc)
and i-Pr NEt gave the indole congener 12 in 85% yield, this was
treated with CF COOH to afford 13 in 90% yield. Alcoholysis of 13
with K CO
in MeOH gave (+)-indolmycenate 14 {½
.395, CHCl ), 87% yield}, whose physical data were consistent
2 3 4
in the presence of Ph P, Et N Cl,
2
3
2
2
2
3
aꢁ
D
¼ þ3:3 (c
0
3

N. Sutou et al. / Tetrahedron: Asymmetry 19 (2008) 1833–1838
1835
Me
Me
R
COOMe
R
COOMe
c
a
b
(
2S,3R)-6
OAc
TMS
OAc
N
Boc
N
H
R = H 12 (85 %)
R = H 13 (90 %)
R = OMe 16 (88 %)
R = OMe 17 (64 %)
Me
Me
Me
O
O
R
COOMe
R
R
e
d
N
NH2
N
OH
O
O
N
N
H
N
H
H
NHMe
R = H 14 (87 %)
R = OMe 18 (99 %)
R = H 15
R = H 1 (68 % from 14)
R = OMe 19
R = OMe 3 (88 % from 18)
+
ꢀ
+
ꢀ
Scheme 3. Reagents: (a) for 12, N-Boc-2-iodoaniline 10/Pd(OAc)
CF COOH/CH Cl ; (c) K CO
2
/Ph
3
P/Et
4
N Cl /i-Pr
2
NEt; for 16 N-Boc-2-iodo-4-methoxyaniline 11/Pd(OAc)
/H O.
2
/Ph
3
P/Et
4
N Cl /i-Pr
2
NEt; (b)
3
2
2
2
3
/MeOH; (d) guanidine hydrochloride/t-BuOK/t-BuOH/molecular sieves 4 Å; (e) 40% MeNH
2
2
with those of the reported (+)-14,12 including the sign of the spe-
cific rotation. The reaction of (+)-14 with guanidine hydrochloride
in the presence of tert-BuOK using a previously reported proce-
4(5H)-oxazolone congener 19, which was reacted with 40%
methylamine to afford (ꢀ)-5-methoxyindolmycin 3 {mp 75–
2
D
2
77 °C, ½
aꢁ
¼ ꢀ161:3 (c 0.61, MeOH), 88% yield from 18}. From
7
dure gave 2-amino-4(5H)-oxazolone congener 15, which was re-
NMR studies of synthetic (ꢀ)-3, (ꢀ)-3 was also found to be a 2:1
mixture of two tautomers 3 and its tautomer.
acted with 40% methylamine to afford (ꢀ)-indolmycin 1 {mp
2
D
2
1
98–200 °C, ½
a
ꢁ
¼ ꢀ195:8 (c 0.92, MeOH), 68% yield from 14}.
The physical data of synthetic (ꢀ)-1 were consistent with those
of previously reported indolmycin {mp 204–206 °C,
¼ ꢀ198 (c 2, MeOH)}. From NMR studies of synthetic (ꢀ)-1,
2.3. Discussion
1
23
5
½
a
(
ꢁ
The formation of indole congeners 12 and 16 by a palladium(II)-
catalyzed reaction of internal alkyne (2S,3R)-6 with o-iodoaniline
derivative 10 or 11, respectively, and the corresponding catalytic
cycle may be explained as shown in Scheme 4. First, palladium(II)
is converted to palladium(0) under the specified reaction condi-
tions. Oxidative addition of o-iodoaniline congener 10 or 11 to
Pd(0) gives intermediate F, which undergoes syn insertion of the
internal alkyne (2S,3R)-6 into the arylpalladium bond to afford
intermediate G. Next, nitrogen displacement of the palladium in
D
ꢀ)-1 was found to be a 2:1 mixture of two tautomers 1 and its
tautomer. The main tautomer was the desired (ꢀ)-1. Isolation of
two tautomers was found to be difficult; this tendency was seen
7
in the previous case. Similarly, the reaction of (2S,3R)-6 and 11
+
using Pd(OAc)
2
in the presence of Ph
3
P, Et
4
N Cl, and i-Pr
2
NEt gave
the indole congener 16 (88% yield), which was treated with
CF COOH to afford 17 in 64% yield. Alcoholysis of 17 with K CO
in MeOH gave (ꢀ)-5-methoxyindolmycenate 18 {½ ¼ ꢀ11:9 (c
.84, MeOH)} in 99% yield. The reaction of (ꢀ)-18 with guanidine
hydrochloride in the presence of tert-BuOK provided 2-amino-
3
2
3
2
D
2
a
ꢁ
0
the resulting vinylpalladium intermediate
G results in the
formation of a six-membered-ring intermediate H, along with
Me
R
I
Pd(OAc)2
Ph P
R
COOMe
R = H (10) or OMe (11)
3
+
-
Et N Cl
NHBoc
4
OAc
TMS
N
i-Pr2NEt
oxidative addition
Boc
1
2 or 16
Pd(0)
reductive
elimination
COOMe
R
PdI
Me
OAc
TMS
R
NHBoc
intermediate F
Pd
N
syn insertion
Boc
intermediate H
COOMe
Me
Me
COOMe
OAc
TMS
R
TMS
OAc
2S,3R)-6
-
HI
(
PdI
NH
Boc
intermediate G
Scheme 4.

1
836
N. Sutou et al. / Tetrahedron: Asymmetry 19 (2008) 1833–1838
elimination of hydrogen iodide (HI); finally, reductive elimination
of palladium from intermediate H gives indole congener 12 or 16
and Pd(0). Annulation of unsymmetrical alkynes has proven to be
highly regioselective, providing only the appropriate regioisomer.
The more sterically bulky group is located nearer the nitrogen
atom in the indole product.8
(55 mg, 0.39 mmol) and DMAP (31 mg, 0.25 mmol), and the whole
mixture was heated with stirring for 1 h at 70 °C. The reaction mix-
ture was worked up in the same way as (±)-7 to give (±)-9 (62 mg,
50%) as a colorless oil. (±)-9: IR (CCl ): 2360, 1730 cm ; H NMR: d
4
1.36 (3H, d, J = 7.1 Hz), 2.12 (1H, d, J = 2.5 Hz), 3.18–3.25 (1H, m),
ꢀ1 1
3.77 (3H, s), 5.33 (1H, d, J = 4.5 Hz), 7.43–7.47 (2H, m), 7.55–7.60
+
(
1H, m), 8.07–8.10 (2H, m). HRMS (EI) calcd for C14
H
14
O
4
(M ):
2
(
46.0892. Found: 246.0853. HPLC {column: CHIRALPAC AD
4.6 ꢂ 250 mm), eluent: n-hexane/EtOHt = 30:1, flow rate: 0.5 ml/
min, detection: UV at 254 nm}: t = 12.0, 13.2 min.
3
. Conclusion
R
Concise syntheses of (ꢀ)-indolmycin 1 and (ꢀ)-5-methoxyin-
dolmycin 3 were achieved based on the palladium-catalyzed reac-
tion of (2S,3R)-2-acetoxy-3-methyl-5-trimethylsilyl-4-pentynoate
6
4
.1.3. Enantioselective acetylation of (±)-4
From a screening experiment using various kinds of lipase, the
with o-iodoaniline derivative 10 or 11, followed by reaction with
effective lipases were as follows: Amano P from Pseudomonas sp.
and Amano PS Pseudomonas sp. Enzymatic acetylation of (±)-4
was performed under the following condition (entries 1–3). Deter-
mination of the enantiomeric excess (ee) of the enzymatic reaction
products was carried out by the method mentioned below in this
text. The results are shown in Table 1. (1) Table 1, entry 1: A sus-
pension of (±)-4 (5.012 g, 23.8 mmol), isopropenyl acetate (10 g,
guanidine hydrochloride in the presence of tert-BuOK. The
optically active internal alkyne (2S,3R)-6 was obtained by the
lipase-assisted enantioselective acetylation of (±)-(2,3)-syn-2-hy-
droxy-3-methyl-5-trimethylsilyl-4-pentynoate 4. The formation
of indole congener 12 or 16 by a palladium(II)-catalyzed reaction
of internal alkyne (2S,3R)-6 with o-iodoaniline derivative 10 or
1
1 and the corresponding catalytic cycle are discussed.
1
00 mmol), and lipase Amano P (5 g) in diisopropyl ether (50 ml)
was stirred for 7 d at 33 °C. After the reaction mixture was filtered,
the precipitate was washed with AcOEt. The combined organic
4
4
. Experimental
layer was dried over MgSO
matographed on silica gel (200 g) to give (2S,3R)-6 (1.651 g, 28%,
2% ee) from n-hexane/AcOEt = 80:1 eluate and (2R,3S)-4
4
and evaporated. The residue was chro-
.1. Methods and results
8
1H and 13C NMR spectra were recorded on JEOL AL 400 spec-
(2.980 g, 59%, 44% ee) from n-hexane/EtOAc = 20:1 eluate, respec-
tively. (2) Table 1, entry 2: A suspension of 44% ee of (2R,3S)-4
(2.980 g), vinyl acetate (5.8 g, 67 mmol), and lipase Amano PS
(2.9 g) in diisopropyl ether (290 ml) was stirred for 3 d at 33 °C.
The reaction mixture was worked up in the same way as entry 1
to give (2S,3R)-6 (0.798 g, 23%, 86% ee) and (2R,3S)-4 (1.764 g,
60%, 95% ee). (3) Table 1, entry 3: A suspension of (±)-4 (5.150 g,
24 mmol), vinyl acetate (10 g, 116 mmol), and lipase Amano PS
trometer in CDCl
by DEPT pulse sequence. The fast atom bombardment mass spectra
FAB MS) were obtained with JEOL JMS 600H spectrometer. IR
3
. Carbon substitution degrees were established
(
spectra were recorded with a JASCO FT/IR-300 spectrometer. Opti-
cal rotations were measured with a JASCO DIP-370 digital polarim-
eter. All evaporations were performed under reduced pressure. For
column chromatography, silica gel (Kieselgel 60) was employed.
(
5 g) in diisopropyl ether (500 ml) was stirred for 5 d at 33 °C.
4
.1.1. Methyl (±)-(2ꢀ3)-syn-2-benzoyloxy-3-methyl-5-
The reaction mixture was worked up in the same way as entry 1
2
7
trimethylsilyl-4-pentynoate 7
to give (2S,3R)-6 {2.958 g, 48%, ½
responds to 95% ee} and (2R,3S)-4 {2.575 g, 50%, ½
1.13, CHCl ); corresponds to 94% ee}. (2R,3S)-4; IR (neat): 3482,
aꢁ
¼ þ12:05 (c 1.09, CHCl ); cor-
D
3
25
D
To a solution of (±)-4 (100 mg, 0.46 mmol) in pyridine (2 ml)
were added PhCOCl (130 mg, 0.92 mmol) and 4-N,N-dimethylami-
nopyridine (DMAP; 23 mg, 0.19 mmol), and the whole mixture was
heated with stirring for 1 h at 70 °C. The reaction mixture was di-
a
ꢁ
¼ ꢀ24:8 (c
3
ꢀ1 1
2168, 1741 cm
; H NMR: d 0.15 (9H, s), 1.21 (3H, d, J = 7.2 Hz),
13
2.86–2.93 (1H, m), 3.81 (3H, s), 4.21 (1H, d, J = 4.4 Hz). C NMR:
luted with H
washed with 2 M HCl, a saturated NaHCO
and dried over MgSO . Evaporation of the organic solvent gave a
2
O and extracted with AcOEt. The organic layer was
d ꢀ0.07 (3C), 15.8, 32.3, 52.4, 73.5, 86.9, 106.1, 173.1. HRMS
+
3
solution and brine,
(FAB) calcd for
C
1
0
H
19
O Si (M +1): 215.1104. Found m/z:
3
ꢀ1
1
4
215.1106. (2S,3R)-6; IR (neat): 2173, 1754, 1225 cm
; H NMR:
crude oil, which was chromatographed on silica gel (5 g, n-hex-
ane/AcOEt (80:1)) to give (±)-7 (142 mg, 95%) as a colorless oil.
d 0.13 (9H, s), 1.23 (3H, d, J = 7.0 Hz), 2.16 (3H, s), 3.05 (1H, qd,
J = 7.0, 5.2 Hz), 3.75 (3H, s), 5.08 (1H, d, J = 5.2 Hz). C NMR: d
1
3
ꢀ1 1
(
4
±)-7: IR (CCl ): 2171, 1758, 1729 cm
;
H NMR: d 0.001 (9H, s),
ꢀ0.05 (3C), 16.3, 20.5, 29.4, 52.3, 74.4, 87.2, 105.3, 169.0, 170.2.
+
1
5
8
3
.27 (3H, d, J = 7.0 Hz), 3.12 (1H, dd, J = 7.0, 5.1 Hz), 3.69 (3H, s),
HR-MS (FAB): calcd for C12
257.1187.
H
21
O
4
Si (M +1): 257.1212. Found:
.23 (1H, d, J = 5.1 Hz), 7.35–7.39 (2H, m), 7.48–7.52 (1H, m),
+
.00–8.02 (2H, m). HR-MS (FAB): calcd for C17
H
23
O
4
Si (M +1):
19.1365, found: 319.1362. HPLC {column: CHIRALPAC AD
4.1.4. Determination of ee of the enzymatic reaction products
(1) Alcohol 4 (Table 1, entries 1–3; ca. 30 mg) was converted
into the corresponding benzoate 7 in the same way as (±)-7. HPLC
(
4.6 ꢂ 250 mm), eluent: n-hexane/EtOHt = 30:1, flow rate: 0.5 ml/
min, detection: UV at 254 nm}: t = 7.8, 9.3 min.
R
R
analysis of the present 7 indicated the retention time (t = 7.8 min)
4
.1.2. Methyl (±)-(2ꢀ3)-syn-2-benzoyloxy-3-methyl-4-
pentynoate 9
1) To a solution of (±)-4 (197 mg, 0.92 mmol) in MeOH (5 ml)
was added K CO (120 mg, 0.67 mmol), and the whole mixture
for the major isomer, which is attributed to that of (2R,3S)-4. (2)
Acetate 6 (Table 1, entries 1–3; ca. 50 mg) was treated with
K CO (ca 10 mg) in MeOH (1 ml) for 10 min at rt. to give a crude
2 3
8, which was converted to the corresponding benzoate 9 in the
same way as (±)-9. HPLC analysis of the present 9 indicated the
(
2
3
was stirred for 1 h at rt. The reaction mixture was diluted with
brine and extracted with AcOEt. The organic layer was dried over
retention time (t = 13.2 min) for the major isomer, which is attrib-
R
4
MgSO . Evaporation of the organic solvent gave a crude oil, which
uted to that of (2S,3R)-6.
was chromatographed on silica gel (5 g, n-hexane/AcOEt (10:1)) to
1
give (±)-8 (71 mg, 54%) as a colorless oil. (±)-8: H NMR: d 1.14 (3H,
4.1.5. N-(tert-Butoxycarbonyl)-2-iodoaniline 10
d, J = 7.1 Hz), 2.09 (1H, d, J = 2.5 Hz), 2.89 (1H, q, d, d, J = 7.1, 3.9,
To a solution of 2-iodoaniline (1.54 g, 7.0 mmol) in anhydrous
2
.5 Hz), 3.76 (3H, s), 4.20 (1H, d, J = 3.9 Hz). (2) To a solution of
THF (15 ml) was added di-tert-butyl dicarbonate {(Boc)
2
O; 3.07 g,
(
±)-8 (71 mg, 0.5 mmol) in pyridine (2 ml) were added PhCOCl
14.1 mmol}, and the reaction mixture was stirred for 12 h at reflux.

N. Sutou et al. / Tetrahedron: Asymmetry 19 (2008) 1833–1838
1837
The reaction mixture was diluted with brine and extracted with
AcOEt. The organic layer was dried over MgSO and evaporated
to give a crude oil, which was chromatographed on silica gel
graphed on silica gel (10 g, n-hexane/AcOEt = 5:1) to give 14
2
2
4
(233 mg, 87%) as a colorless oil. Compound 14: ½
a
ꢁ
D
¼ þ3:3 (c
ꢀ1 1
3
0.395, CHCl ), IR (KBr): 3891, 1735 cm ; H NMR: d 1.35 (3H, d,
(
(
7
30 g, n-hexane) to give N-(tert-butoxycarbonyl)-2-iodoaniline
J = 7.2 Hz), 2.80 (1H, d, J = 4.4 Hz), 3.60 (1H, qd, J = 7.2, 3.2 Hz),
3.80 (3H, s), 4.53 (1H, qd, J = 4.4, 3.2 Hz), 7.09 (1H, d, J = 2.4 Hz),
7.12–7.16 (1H, m), 7.18–7.22 (1H, m), 7.34 (1H, dd, J = 7.2,
1.994 g, 89%) as a colorless oil. 1H NMR: d 1.54 (9H, s), 6.74–
.78 (1H, m), 6.82 (1H, br s), 7.29–7.33 (1H, m), 7.73–7.75 (1H,
13
13
m), 8.04–8.06 (1H, m). C NMR: d 28.3 (9C), 81.0, 124.6 (2C),
29.2 (2C), 138.8 (2C), 152.5. HRMS (EI) calcd for C11
1.2 Hz), 7.68 (1H, d, J = 8.0 Hz), 8.16 (1H, br s). C NMR: d 14.1,
1
(
H14NO
2
I
34.6, 52.5, 74.1, 111.3, 117.2, 118.7, 119.4, 121.9, 122.1, 126.5,
+
+
M ): 319.0070. Found: 319.0073.
136.2, 174.7. HRMS (EI) calcd for C13
Found: 233.1039.
H15NO
3
(M ): 233.1052.
4
.1.6. N-(tert-Butoxycarbonyl)-2-iodo-4-methoxyaniline 11
To a solution of 2-iodo-4-methoxyaniline12 (1.12 g, 4.5 mmol)
O {1.96 g, 9.0 mmol},
4.1.10. (ꢀ)-Indolmycin 1
in anhydrous THF (10 ml) was added (Boc)
2
(1) To a solution of guanidine hydrochloride (616 mg,
and the reaction mixture was stirred for 12 h at reflux. The reaction
mixture was diluted with brine and extracted with AcOEt. The or-
ganic layer was dried over MgSO and evaporated to give a crude
4
6.4 mmol) in tert-BuOH (5 ml) were added potassium tert-KOBu
(765 mg, 6.8 mmol) and molecular sieves 4 Å (600 mg) at rt, and
the reaction mixture was stirred for 3 d at rt. To the above reaction
mixture was added a solution of 14 (213 mg, 0.91 mmol) in tert-
BuOH (5 ml), and the reaction mixture was stirred for 12 h at rt.
oil, which was chromatographed on silica gel (20 g, n-hexane) to
give N-(tert-butoxycarbonyl)-2-iodo-4-methoxyaniline (1.183 g,
7
5%) as a colorless oil. 1H NMR: d 1.52 (9H, s), 3.76 (3H, s), 6.53
4
The reaction mixture was poured into saturated NH Cl solution
(
7
(
C
1H, br s), 6.89 (1H, dd, J = 8.8, 2.8 Hz), 7.29 (1H, d, J = 2.8 Hz),
.80 (1H, d, J = 8.8 Hz). 13C NMR: d 28.3 (9C), 55.7, 80.6, 114.9
2C), 123.7 (2C), 132.4, 153.1, 156.0. HRMS (EI) calcd for
(20 ml) at 0 °C and filtered. The filtrate was extracted with a mixed
solvent (AcOEt/iso-PrOH = 4:1). The organic layer was washed with
5% NaHCO solution, brine, and dried over MgSO . Evaporation of
3 4
+
12
3
H16NO I (M ): 349.0175. Found: 349.0180.
the organic solvent gave crude 15, which was used for the next
reaction without further purification. Compound 15: 1H NMR
4
.1.7. Methyl (2Sꢀ3R)-3-{1-(tert-butoxycarbonyl)-2-
6
(DMSO-d ): d 1.19 (3H, d, J = 7.2 Hz), 4.92 (1H, d, J = 2.6 Hz),
(
trimethylsilyl)-1H-indol-3-yl}-2-acetoxybutanoate 12
A mixture of 10 (141 mg, 0.44 mmol), (2S,3R)-6 (112 mg,
6.96–7.08 (2H, m), 7.13 (1H, d, J = 2.4 Hz), 7.34 (1H, d, J = 8.0 Hz),
7.57 (1H, d, J = 8.0 Hz), 8.30 (1H, br s), 8.41 (1H, br s), 10.88 (1H,
0
0
1
1
.44 mmol), Pd(OAc)
2
(10 mg, 0.044 mmol), Ph
N Cl (73 mg, 0.44 mmol), and i-Pr NEt (171 mg,
.3 mmol) in DMF (5 ml) was heated with stirring for 1.5 h at
00 °C. The reaction mixture was diluted with H O and extracted
3
P
(23 mg,
2
br s). (2) A mixture of a crude 15 and 40% MeNH solution
(15 ml) was allowed to stand in a refrigerator for 12 h, and the
reaction mixture was evaporated to a residue without heating.
+
ꢀ
.09 mmol), Et
4
2
2
The residue was chromatographed on silica gel (10 g, CHCl
MeOH = 30:1) to give the desired (ꢀ)-1, which was crystallized
from MeOH/H
O (2:1) to afford (ꢀ)-1 (159 mg, 68% yield from
14) as a colorless crystalline. (ꢀ)-1: 198–200 °C. ½
3
/
with a mixed solvent (n-hexane/AcOEt = 1:1). The organic layer
was dried over MgSO and evaporated to give a crude oil, which
was chromatographed on silica gel (10 g, n-hexane/AcOEt = 50:1)
to give 12 (168 mg, 85%) as a colorless oil. Compound 12:
4
2
2
D
2
aꢁ
1
¼ ꢀ195:8 (c
ꢀ1
0.92, MeOH); IR (KBr): 3397, 1675, 1633 cm
; H NMR (DMSO-
2
D
1
ꢀ1 1
½
a
ꢁ
¼ þ7:9 (c 0.82, CHCl
3
), IR (KBr): 1751 cm
;
H NMR: d 0.42
d
6
): d 1.19 (2H, d, J = 7.0 Hz), 1.25 (1H, d, J = 7.0 Hz), 2.77 (1H, s),
(
9H, s), 1.51 (3H, d, J = 7.2 Hz), 1.69 (9H, s), 2.13 (3H, s), 3.55 (3H,
2.80 (1H, d, J = 4.4 Hz), 3.54–3.62 (1H, m), 4.90 (1/3H, d,
J = 2.8 Hz), 4.94 (2/3H, d, J = 2.8 Hz), 6.97–7.10 (2H, m), 7.15 (2/
3H, d, J = 2.4 Hz), 7.18 (1/3H, d, J = 2.4 Hz), 7.35 (1H, d, J = 8.0 Hz),
7.58 (2/3H, d, J = 8.0 Hz), 7.59 (1/3H, d, J = 8.0 Hz), 8.63 (2/3H, br
s), 3.99 (1H, qd, J = 7.2, 6.8 Hz), 5.33 (1H, d, J = 6.8 Hz), 7.17 (1H,
ddd, J = 8.2, 7.2, 1.2 Hz), 7.25 (1H, ddd, J = 8.6, 7.2, 1.2 Hz), 7.82
(
1H, d, J = 8.2 Hz), 7.95 (1H, d, J = 8.6 Hz). 13C NMR: d 2.5 (9C),
1
3
1
1
5.6, 20.8, 28.3 (9C), 34.2, 51.9, 76.3, 83.9, 115.2, 121.7, 121.8,
24.4, 129.9, 132.0, 137.8, 138.2, 151.4, 170.0, 170.5. HRMS (EI)
6
s), 8.70 (1/3H, br s), 10.91 (1H, br s). C NMR (DMSO-d ): d
13.67 (2/3C), 13.78 (1/3C), 27.26, 28.96, 31.76 (1/3C), 31.83 (2/
3C), 85.53 (2/3C), 86.08 (1/3C), 111.62, 115.08 (1/3C), 115.45 (2/
+
calcd for C23
H33NO
6
Si (M ): 447.2077. Found: 447.2079.
3
C), 118.53 (1/3C), 118.67 (2/3C), 121.17 (1/3C), 121.21 (2/3C),
4
.1.8. Methyl (2Sꢀ3R)-3-(1H-indol-3-yl)-2-acetoxybutanoate 13
To a solution of 12 (420 mg, 0.94 mmol) in CH Cl (10 ml) was
added CF COOH {1.61 g, 14.1 mmol} at 0 °C, and the reaction mix-
122.52 (2/3C), 122.60 (1/3C), 126.21 (2/3C), 126.49 (1/3C),
136.24 (1/3C), 136.33 (2/3C), 175.50 (1/3C), 175.91 (2/3C),
2
2
3
186.89 (1/3C), 187.05 (2/3C). HR-MS (EI): calcd for C14
(M ): 257.1164. Found: 257.1154.
H
15
N
3
O
2
+
ture was stirred for 3 h at 0 °C. The reaction mixture was evapo-
rated to give a crude oil, which was chromatographed on silica
gel (10 g, n-hexane/AcOEt = 10:1) to give 13 (233 mg, 90%) as a col-
4.1.11. Methyl-(2Sꢀ3R)-3-{1-(tert-butoxycarbonyl)-5-methoxy-
2-(trimethylsilyl)-1H-indol-3-yl}-2-acetoxybutanoate 16
2
D
2
orless oil. Compound 13: ½
a
ꢁ
¼ ꢀ26:4 (c 0.605, CHCl
3
), IR (KBr):
ꢀ
1 1
1
3
7
755, 1724 cm
;
H NMR: d 1.46 (3H, d, J = 7.2 Hz), 2.10 (3H, s),
A mixture of 11 (681 mg, 1.95 mmol), (2S,3R)-6 (500 mg,
1.95 mmol), Pd(OAc) (44 mg, 0.19 mmol), Ph (102 mg,
N Cl (323 mg, 1.95 mmol), and i-Pr NEt (756 mg,
5.8 mmol) in DMF (20 ml) was heated with stirring for 1.5 h at
100 °C. The reaction mixture was diluted with H O and extracted
with a mixed solvent (n-hexane/AcOEt = 1:1). The organic layer
was dried over MgSO and evaporated to give a crude oil, which
.65 (3H, s), 3.75 (1H, qd, J = 7.2, 4.6 Hz), 5.24 (1H, d, J = 4.6 Hz),
.06 (1H, d, J = 2.4 Hz), 7.13 (1H, ddd, J = 8.0, 6.8, 1.4 Hz), 7.20
2
3
P
+
ꢀ
0.39 mmol), Et
4
2
(
1H, ddd, J = 8.0, 6.8, 1.4 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.68 (1H, d,
13
J = 8.0 Hz), 8.15 (1H, br s). C NMR: d 15.6, 20.7, 32.7, 52.2, 76.2,
2
1
1
2
11.2, 116.6, 119.0, 119.5, 121.7, 122.2, 126.5, 136.2, 170.3,
70.6. HRMS (EI) calcd for C15
75.1161.
+
H17NO
4
(M ): 275.1158. Found:
4
was chromatographed on silica gel (25 g, n-hexane/AcOEt = 50:1)
to give 16 (820 mg, 88%) as a colorless oil. Compound 16:
2
D
0
ꢀ1
1
4
.1.9. Methyl (2Sꢀ3R)-3-(1H-indol-3-yl)-2-hydroxybutanoate 14
To a solution of 13 (289 mg, 1.05 mmol) in MeOH (10 ml) was
½aꢁ
¼ þ12:5 (c 0.655, CHCl
3
), IR (KBr): 1751, 1727 cm
;
H
NMR: d 0.41 (9H, s), 1.50 (3H, d, J = 7.2 Hz), 1.68 (9H, s), 2.15
(3H, s), 3.59 (3H, s), 3.87 (3H, s), 3.97 (1H, qd, J = 7.2, 6.8 Hz),
5.34 (1H, d, J = 6.8 Hz), 6.90 (1H, dd, J = 9.2, 2.4 Hz), 7.29 (1H, d,
added K
was stirred for 20 min at rt. The reaction mixture was diluted with
O and extracted with CHCl . The organic layer was dried over
MgSO and evaporated to give a crude oil, which was chromato-
2 3
CO {145 mg, 1.05 mmol} at rt, and the reaction mixture
1
3
H
2
3
J = 2.4 Hz), 7.84 (1H, d, J = 9.2 Hz). C NMR: d 2.5 (9C), 15.3, 20.9,
4
28.2 (9C), 34.1, 51.9, 55.8, 76.2, 83.7, 104.7, 112.9, 115.8, 130.7,

1
838
N. Sutou et al. / Tetrahedron: Asymmetry 19 (2008) 1833–1838
1
C
31.7, 133.0, 138.8, 151.2, 154.9, 170.0, 170.5. HRMS (EI) calcd for
solvent (AcOEt/iso-PrOH = 4:1). The organic layer was washed with
5% NaHCO solution, brine, and dried over MgSO . Evaporation of
+
24
7
H35NO Si (M ): 477.2183. Found: 477.2155.
3
4
the organic solvent gave crude 19, which was used for the next
reaction without further purification. (2) A mixture of crude 19
4
.1.12. Methyl (2Sꢀ3R)-3-(5-methoxy-1H-indol-3-yl)-2-
acetoxybutanoate 17
2
and 40% MeNH solution (12 ml) was allowed to stand in a refrig-
To a solution of 16 (420 mg, 0.94 mmol) in CH
added CF COOH {1.61 g, 14.1 mmol} at 0 °C, and the reaction mix-
3
2
Cl
2
(10 ml) was
erator for 12 h, and the reaction mixture was evaporated to a res-
idue without heating. The residue was chromatographed on silica
ture was stirred for 3 h at 0 °C. The reaction mixture was evapo-
rated to give a crude oil, which was chromatographed on silica
gel (10 g, n-hexane/AcOEt = 5:1) to give 17 (213 mg, 87%) as a col-
gel (10 g, CHCl
was crystallized from MeOH/H
3
/MeOH = 40:1) to give the desired (ꢀ)-3, which
2
O (2:1) to afford (ꢀ)-3 (198 mg,
88% yield from 18) as colorless amorphous crystalline. (ꢀ)-3: mp
22
22
D
orless oil. Compound 17: ½
a
ꢁ
¼ ꢀ35:2 (c 0.565, CHCl
3
), IR (KBr):
H NMR: d 1.45 (3H, d, J = 7.2 Hz), 2.11 (3H, s), 3.64
3H, s), 3.68 (1H, qd, J = 7.2, 4.8 Hz), 3.87 (3H, s), 5.20 (1H, d,
J = 4.8 Hz), 6.86 (1H, dd, J = 8.8, 2.4 Hz), 7.04 (1H, dd, J = 2.4 Hz),
75–77 °C. ½
a
;
ꢁ
¼ ꢀ161:3 (c 0.61, MeOH); IR (KBr): 3292, 1733,
D
ꢀ1
1
ꢀ1
1
1
742 cm
;
1627 cm
H NMR (DMSO-d
6
): d 1.17 (2H, d, J = 7.2 Hz), 1.22
(
(1H, d, J = 7.2 Hz), 2.77 (1H, s), 2.81 (1H, d, J = 4.8 Hz), 3.50–3.59
(1H, m), 3.76 (1H, s), 3.77 (2H, s), 4.91 (1/3H, d, J = 2.8 Hz), 4.96
(2/3H, d, J = 2.8 Hz), 6.73 (1H, dd, J = 8.8, 2.4 Hz), 7.02 (2/3H, d,
J = 2.4 Hz), 7.05 (1/3H, d, J = 2.4 Hz), 7.10 (2/3H, d, J = 2.4 Hz),
7.14 (1/3H, d, J = 2.4 Hz), 7.24 (1H, d, J = 8.8 Hz), 8.61 (2/3H, br s),
6
8.73 (1/3H, br s), 10.74 (1H, br s). C NMR (DMSO-d ): d 13.57
1
3
7
.10 (1H, d, J = 2.4 Hz), 7.24 (1H, d, J = 8.8 Hz), 8.03 (1H, br s).
NMR: d 15.7, 20.7, 32.7, 52.2, 56.0, 76.2, 101.0, 111.9, 112.4,
16.3, 122.4, 126.9, 131.3, 154.1, 170.3, 170.5. HRMS (EI) calcd
C
1
+
13
for C16
H19NO
5
(M ): 305.1263. Found: 305.1265.
(
2/3C), 13.67 (1/3C), 27.09, 28.85, 31.57, 55.38 (2/3C), 55.41 (1/
4
.1.13. Methyl (2Sꢀ3R)-3-(5-methoxy-1H-indol-3-yl)-2-
3C), 85.28 (1/3C), 85.88 (1/3C), 100.22 (2/3C), 100.38 (1/3C),
111.18 (1/3C), 111.27 (2/3C), 112.13, 114.83 (1/3C), 115.10 (2/
3C), 123.03 (2/3C), 123.15 (1/3C), 126.39 (2/3C), 126.64 (1/3C),
131.25 (1/3C), 131.28 (2/3C), 153.02 (1/3C), 153.08 (2/3C),
hydroxybutanoate 18
To a solution of 17 (270 mg, 0.88 mmol) in MeOH (10 ml) was
added K
was stirred for 20 min at rt. The reaction mixture was diluted with
O and extracted with CHCl . The organic layer was dried over
MgSO and evaporated to give a crude oil, which was chromato-
graphed on silica gel (10 g, n-hexane/AcOEt = 3:1) to give 18
2 3
CO {122 mg, 0.88 mmol} at rt, and the reaction mixture
175.83, 186.72 (1/3C), 186.88 (2/3C). HR-MS (EI): calcd for
+
H
2
3
C H
15 17
N
3
O
3
(M ): 287.1270. Found: 287.1277.
4
2
D
2
(
0
231 mg, 99%) as a colorless oil. Compound 18: ½
aꢁ
¼ ꢀ11:9 (c
References
ꢀ1
1
.84, MeOH), IR (KBr): 3391, 1747 cm ; H NMR: d 1.33 (3H, d,
1
.
(a) Rao, K. V. Antibiot. Chemother. 1960, 10, 312–315; (b) Marsh, W. S.;
Garretson, A. L.; Wesel, E. M. Chemotherapy 1960, 10, 316–320.
Werner, R. G.; Demain, A. J. Antibiot. 1981, 34, 551–554.
J = 7.2 Hz), 2.72 (1H, d, J = 4.8 Hz), 3.58 (1H, qd, J = 7.2, 3.2 Hz),
.80 (3H, s), 3.88 (3H, s), 4.50 (1H, dd, J = 3.2, 4.8 Hz), 6.87 (1H,
3
2
.
dd, J = 8.8, 2.4 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.12 (1H, d, J = 2.4 Hz),
3. Kanamaru, T.; Nakano, Y.; Toyoda, Y.; Miyagawa, K.; Tada, M.; Kaisho, T.;
.24 (1H, d, J = 8.8 Hz), 7.98 (1H, br s). 1 C NMR: d 14.3, 34.7,
3
Nakao, M. Antimicrob. Agents Chemother. 2001, 45, 2455–2459.
7
5
1
4.
(a) Dirlam, J. P.; Clark, D. A.; Hecker, S. J. J. Org. Chem. 1986, 51, 4920–4924; (b)
Shue, Y.-K. Tetrahedron Lett. 1996, 37, 6447–6448.
2.5, 56.0, 74.2, 101.0, 111.9, 112.2, 117.2, 122.7, 127.1, 131.4,
+
54.1, 174.7. HRMS (EI) calcd for C14
H
17NO
4
(M ): 263.1158.
5. Takeda, T.; Mukaiyama, T. Chem. Lett. 1980, 163–166.
6.
Preobrazhenskaya, M. N.; Balashova, E. G.; Turchin, K. F.; Padeiskaya, E. N.;
Found: 263.1173.
Yvarova, N. V.; Pershin, G. N.; Suvorov, M. N. Tetrahedron Lett. 1968, 24, 6131–
6
143.
4
.1.14. (ꢀ)-5-Methoxyindolmycin 3
1) To solution of guanidine hydrochloride (635 mg,
.6 mmol) in tert-BuOH (5 ml) were added potassium tert-KOBu
7. Hasuoka, A.; Nakayama, Y.; Adachi, M.; Kamiguchi, H.; Kamiyama, K. Chem.
Pharm. Bull. 2001, 49, 1604–1608.
(
a
8
9
.
.
Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–6690.
(a) Kato, K.; Sasaki, T.; Takayama, H.; Akita, H. Tetrahedron 2003, 59, 2679–
2685; (b) Akita, H.; Sutou, N.; Sasaki, T.; Kato, K. Tetrahedron 2006, 62, 11592–
11598.
0. Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28, 695–707.
1. Deborah, L. M.; Marcin, D.; Teresa, K.-C.; Nadya, I. T.; Christopher, J. M. Bioorg.
Med. Chem. Lett. 2007, 17, 2380–2384.
6
(
791 mg, 7.0 mmol) and molecular sieves 4 Å (600 mg) at rt, and
the reaction mixture was stirred for 3 d at rt. To the above reaction
mixture was added a solution of 18 (206 mg, 0.78 mmol) in tert-
BuOH (5 ml), and the reaction mixture was stirred for 12 h at rt.
1
1
The reaction mixture was poured into saturated NH
4
Cl solution
12. (a) Akita, H.; Kawaguchi, T.; Enoki, Y.; Oishi, T. Chem. Pharm. Bull. 1990, 38,
23–328; (b) Bando, T.; Shishido, K. Heterocycles 1997, 46, 111–114.
3
(
20 ml) at 0 °C and filtered. The filtrate was extracted with a mixed