A Regioselective Acylation of N-Substituted-4-Aminoindole. Its Application to the Synthesis of Indolactam V

Article abstract of DOI:10.1081/SCC-120027293

Optically active (-) Indolactam V (1) was formally synthesized with the defined stereochemistry, through an efficient procedure via bromationlithiation in the 3-position of the indole ring using 2,6-dinitrotoluene and the aminoacids: D-serine and D-valine

Full text of DOI:10.1081/SCC-120027293

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A Regioselective Acylation of
N‐Substituted‐4‐Aminoindole. Its Application to the
Synthesis of Indolactam V
Alírica I. Suárez a , María C. García b & Reinaldo S. Compagnone b
a Facultad de Farmacia , Universidad Central de Venezuela , Caracas, Venezuela
b Escuela de Química, Facultad de Ciencias , Universidad Central de Venezuela ,
Caracas, 47102, Venezuela
Published online: 16 Aug 2006.
To cite this article: Alírica I. Suárez , María C. García & Reinaldo S. Compagnone (2004) A Regioselective Acylation of
N‐Substituted‐4‐Aminoindole. Its Application to the Synthesis of Indolactam V, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:3, 523-531, DOI: 10.1081/SCC-120027293
To link to this article: http://dx.doi.org/10.1081/SCC-120027293
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 3, pp. 523–531, 2004
A Regioselective Acylation of N-Substituted-
4-Aminoindole. Its Application to the
Synthesis of Indolactam V
1
Alırica I. Suarez, Marıa C. Garcıa,
2
´
´
´
´
and Reinaldo S. Compagnone2,
*
1Facultad de Farmacia, Universidad Central de Venezuela,
Caracas, Venezuela
´
Escuela de Quımica, Facultad de Ciencias, Universidad Central
de Venezuela, Caracas, Venezuela
2
ABSTRACT
Optically active (2) Indolactam V (1) was formally synthesized with the
defined stereochemistry through an efficient procedure via bromation-
lithiation in the 3-position of the indole ring using 2,6-dinitrotoluene and
the aminoacids: D-serine and D-valine as starting materials.
Key Words: Indolactam V; Regioselective acylation; N-substituted-4-
aminoindole.
*
´
Correspondence: Reinaldo S. Compagnone, Escuela de Quımica, Facultad de
Ciencias, Universidad Central de Venezuela, 47102, Caracas, Venezuela; Fax: (58) 212
693 4677; E-mail: rcompag@strix.ciens.ucv.ve.
523
DOI: 10.1081/SCC-120027293
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Suarez, Garcıa, and Compagnone
524
Figure 1. Indolactama V.
In the past years there has been considerable interest in developing
synthetic routes to compounds that contains the naturally occurring ring of
Indolactam V (Figure 1) due mainly to their tumors promoter properties by a
mechanism which involves protein kinase C (PKC) activation.[1,2] Optically
active teleocidin, a natural product with the indolactam V ring as core,
represents an important synthetic target in medicinal chemistry because allows
to study the mentioned properties and the possible mechanisms of these
compounds. It has been proven that the indolactam V has three active
pharmacophores identified in the structure that maybe responsibles for this
biological activity.[3]
The syntheses of teleocidin, indolactam V and 4,7-disubstituted indoles
have been described previously by a number of researchers.[4–10] Recently an
indolactam library on solid phase was reported.[11,12] In some of these
methods a number of steps that include functionalization of tryptophan
derivatives present regioselectivity problems and formation of side products
from the electrophilic substitution on undesirable positions in the indole ring is
observed. Other syntheses face problems of stereochemical control, diastere-
isomers separation and low yield.[4–10]
In this work, we describe a selective method for the functionalization of
4-aminoindole on the 3-position and its application to the formal synthesis of
the indolactam V. This route entails the functionalization of the basic
molecular frame of a 4-aminoindole derivative with two aminoacids as chiral
starting materials, controlling the desired stereochemistry in the molecule
through the sequence. Our goal was to design a new synthetic method which
avoids the previously mentioned problems related to regioselectivity and
stereoselectivity.

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N-Substituted-4-Aminoindole
525
Figure 2.
The indolactam V was disconnected in the three fragments as shown in
Figure 1.
Figure 2 depicts in a retrosynthetic scheme, which details the overall
strategy of this formal synthesis.
The required 4-aminoindole which represents fragment A was synthes-
ized from 2,6-dinitrotoluene (8) by a modified Leingruber–Batcho pro-
cedure,[13,14] without solvent and at high temperature. Reductive cyclization
of compound 7 using a Pd/C 10% furnished the 4-aminoindole (5) in 95%
overall yield.
The synthesis of the fragment B moiety began with the N-alkylation of 5
using the D-valine-CBZ triflate, according to the method reported by
Kogan[15] afford 3 with the desired stereochemistry in 79% yield. Attempts to
prepare 3 from the bromoester instead of the triflate were unsuccessful.[16,17]
The protection of N-1 in 5 was necessary to avoid byproducts in the next step
and to enhance the nucleophilicity of C-3 in the indole ring.[18] This protection
was carried out using BuLi and trimethylsilyl chloride in THF (Scheme 1).
N-methylation of the 4-amino group was achieved employing the
conditions developed by Endo.[19] The use of methyl iodide with NaHCO3 in
methanol gave 10 in 64% overall yield.

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Suarez, Garcıa, and Compagnone
526
Scheme 1.
Once 10 was prepared, we decided to explore the key step in this
approach, that is the acylation of the 3-position in the indole ring using
protected D-serine aminoacid derivative. Friedel–Crafts reaction under
several different conditions using the acid chloride of N–CBZ–O-serine was
examined. The best result was obtained when the reaction was carried out with
SnCl2 in THF to give only 12% yield of the desired adduct 12; therefore, this
route was abandoned.
It was also found that an attempted Grignard mediated acylation[20] of 10
in ethyl ether led to a complex mixture of products. Another approach using a
peptide coupling procedure which transformed the benzyl ester 3 into the
corresponding acid by hydrogenolysis reaction followed by treatment with
D-serine benzyl ester in presence of dicyclohexylcarbodiimide (DCC) gave
only decomposition products.
The most efficient strategy for the preparation of 12 found was based on a
reported procedure for functionalization of C-3 in unsubstituted indoles.[21]

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N-Substituted-4-Aminoindole
527
The substituted indole 10 was subjected to regioselective bromination using
N-bromosuccinimide in THF at 2788C. In a “one pot reaction,” the 3-
bromoindole 11 was treated with t-BuLi and acylated using as electrophilic
agent the acid chloride of N–CBZ-O-benzylserine to afford the adduct 12
which constitute a precursor of Indolactam V. Selective reduction of the
ketone, deprotection under hydrogenolysis conditions and formation of the
amide bond will give the nine-membered ring of (2) Indolactam V with
defined stereochemistry as it has been reported previously.[15] The procedure
described here would allow the preparation of libraries of compounds using
different aminoacids triflates derivatives and alkylating agents on the nitrogen
in the 4-position of the indole ring.[22]
EXPERIMENTAL SECTION
Melting points were determined on a Electrothermal Digital Melting
Points Apparatus and are uncorrected. IR spectra were recorded on a Perkin–
Elmer 1600 Series FTIR. NMR spectra were obtained on a Bruker ACP-400
and JEOL Eclipse 270; values are given in d (ppm). The MS spectra were
recorded in a VG ZAB-2SEQ. Unless otherwise specified, materials were
purchased from commercial suppliers and used without further purification.
THF and ether were distilled from sodium/benzophenone immediately prior
to use. Moisture-sensitive reactions were conducted in oven-dried glassware
under argon atmosphere. Analytical thin-layer chromatography was per-
formed on Merck precoated silica gel (60 F254) plates and flash column
chromatography was accomplished on Merk Kiesegel 60 (230–400 mesh).
trans-[2-(2,6-Dinitrophenyl)-vinyl]-dimethylamine (7). A mixture of
2,6-dinitrotoluene (9.1 g, 50 mmol), N,N-dimethyformamide (20 mL,
150 mmol) and propionic acid (1.18 g, 15.9 mmol) was heated at 1058C in a
3 neck 100 mL flask equipped with a condenser for 2 h, After this time the
methanol produced as a by-product was completely distilled and the red
residue was recrystallized in a chloroform hexane mixture to give 9.93 g
1
(84%) of 7 as a red solid, m.p. 99–1018C. H NMR (CDCl3) d 2.87 (6H, s
NCH3), 5.36 (1H, d, J ¼ 13.7 Hz, CH55CHN), 6.47 (1H, d, J ¼ 13.7 Hz,
CH55CHN), 7.11 (1H, dd, J ¼ 7.9 Hz, 5-CH), 7.73 (2H, d, J ¼ 8 Hz, 4-CH,
6CH).
4-Aminoindole (5). To a suspension of Pd/C (2.52 g) in dry methanol in
a Parr reactor was added a solution of 7 (5 g, 21.1 mmol) in MeOH (160 mL).
The reactor was charged with hydrogen (200 psi) and shaken by 2 h. The
mixture was filtered using celite pad and the solvent evaporated under vacuo.
The oily residue was purified by flash column chromatography on silica gel
eluting with EtOAc/CHCl3 1 : 9 to afford 2.20 g (95%) of the indole 5 as a

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Suarez, Garcıa, and Compagnone
528
white solid, mp 103–1078C. 1H NMR (CDCl3) d: 3.92 (2H, s, NH2), 6.40 (1H,
d, J ¼ 7.4 Hz, 7-CH), 6.47 (1H, m, 3-CH), 6.86 (1H, d, J ¼ 7.7 Hz, 5-CH),
7.02 (1H, dd, J ¼ 7.7 Hz, 6-CH), 7.11(1H, dd, J ¼ 2.7 Hz, 2-CH), 8.13 (1H, s,
ArNH). 13C NMR (CDCl3) d: 99.2, 103.7, 105.3, 119.5, 123.3, 123.5.
(S)-2-(1-H-Indol-4-ylamino)-3-methyl-butyric acid benzyl ester (3).
To a solution of 4-aminoindole (200 mg, 1.5 mmol) in 1,2 dichloroethane
(6 mL) was added benzyl-D-2-trifluoromethylsulphonyloxy-3-methylbutano-
ate (306 mg, 1.6 mmol) and colidine (115 mL) and the mixture refluxed for
18 h. The mixture was cooled to room temperature and the solvent distilled off
under reduced pressure. The residue was purified by flash column chroma-
tography eluting with EtOAc/hexane 2 : 3 to furnish 129 mg (52%) of a
substituted indole 3 as a green oil. 1H NMR (CDCl3) d: 1.07 (3H, d,
J ¼ 6.3 Hz, CHCH3), 1.12 (3H, d, J ¼ 6.3 Hz, CHCH3), 2.28 (1H, m,
CHCH3), 4.21 (1H, d, J ¼ 6.3 Hz, CHN), 5.23 (2H, s, OCH2Ph), 6.32 (1H, d,
J ¼ 7.6 Hz, 7-CH), 6.54 (1H, s (br), 3-CH), 6.86 (1H, d, J ¼ 7.6 Hz, 5-CH),
7.04 (2H, m, 2-CH, 6-CH), 7.34 (5H, s (br), H-Ar), 8.20 (1H, s (br), ArNH).
13C (CDCl3) d: 18.6, 18.8, 31.5, 62.5, 66.6, 98.7, 100.5, 102.4, 117.6, 122.5,
123.5, 128.5, 128.6, 135.9, 136.9, 140.73, 174.5.
(S)-2-[1-(tert-Butyl-dimethylsilyl)-1H-indol-4-ylamino]-3-methyl-
butyric acid benzyl ester (9). A solution of the indole 3 in THF (5 mL) was
cooled to 2788C and n-BuLi (1,4 mL, 1.73 mmol) was added dropwise. After
stirring for 1 h, a solution of terbutyldimethylsilyl chloride (260 mg,
1.73 mmol) dissolved in THF (5 ml) was added and the resulting mixture
was stirred at 2788C by 1 h. The solution was treated with H2O and extracted
with ether. The organic phase was dried with MgSO4 and evaporated under
reduced pressure. The crude product was purified by flash chromatography
with silica gel eluting with chloroform/hexane 1 : 3 to give 347 mg (57%) of
1
the indole 9 as a yellow oil. H NMR (CDCl3) d: 0.60 (6H, s, CH3Si), 0.96
(9H, s, CH3C), 1.07 (3H, d, J ¼ 6.7 Hz, CH3CH), 4.11 (1H, d, J ¼ 5.9 Hz,
CHN), 5.18 (2H, s, OCH2Ph), 6.30 (1H, dd, J ¼ 5.7, 2.5 Hz, 7-CH), 6.62 (1H,
d, J ¼ 3.2 Hz, 2-CH), 7.33 (5H, s (br), H-Ar). 13C NMR (CDCl3) d: 24.3,
18.5, 18.8, 19.1, 31.5, 62.4, 66.5, 100.6, 100.9, 105.4, 120.8, 122.8, 128.5,
128.6, 128.7, 129.2, 135.9, 140.6, 142.0, 174.4.
(S)-2-f[1-(tert-Butyl-dimethylsilyl)-1H-indol-4-yl]-methylaminog-3-
methyl butyric acid benzyl ester (10). To a mixture of NaHCO3, (346 mg,
4.12 mmol) and the indole 9 (328 mg, 0.88 mmol) in methanol (30 mL), was
added methyl iodide (30 mL). The mixture was heated to reflux for 48 h, the
solvent evaporated under vacuum and the residue purified by flash
chromatography eluting with chloroformo/hexane 1 : 1 to afford the title
compound 10 as a green oil (216.8 mg, 64%). 1H NMR (CDCl3) d: 0.60 (6H,
s, CH3Si), 0.94 (9H, s, CH3CH), 1.00 (3H, m, CH3CH), 1.13 (3H, d,
J ¼ 6.7 Hz, CH3CH), 2.40 (1H, m, CHCH3), 3.01 (3H, s, CH3N), 4.14 (1H,

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N-Substituted-4-Aminoindole
529
d, J ¼ 10.8 Hz, CHN), 5.09 (2H, m, OCH2Ph), 6.63 (1H, d, J ¼ 7.4 Hz,
7-CH), 6.80 (1H, d, J ¼ 3.0 Hz, 3-CH), 7.02 (1H, m, 6-CH), 7.10 (1H, d,
J ¼ 3 Hz, 2-CH), 7.17 (1H, d, J ¼ 7.4 Hz, 5-CH), 7.26 (5H, m, HAr). 13C
NMR (CDCl3) d: 24.3, 13.7, 19.0, 19.1, 25.7, 26.1, 33.7, 65.6, 70.7, 103.8,
108.2, 108.6, 122.1, 124-3, 128.2, 128.3, 128.6, 128.8, 129.5, 136.2, 142.8,
145.8, 172.2.
(S)-2-f[3-Bromo-1-(tert-butyl-dimethylsilyl)-1H-indol-4-yl]-methyl-
aminog-3-methyl butyric acid benzyl ester (11). To a solution of 10
(200 mg, 0.44 mmol) in THF (15 mL) was added N-bromosuccinimide (79 mg,
0.44 mmol). The resulting solution was stirred at 2788C for 2 h. After 1 h at
08C, pyridine (0.1 mL) was added. The mixture was filtered through a celite
pad and the residue purified by flash chromatography with silica gel eluting
with chloroform to yield 192 mg (96%) of the bromocompound 11 as a
colorless solid. 1H NMR (CDCl3) d: 0.56 (6H, s, CH3Si), 0.88 (9H, s, CH3C),
0.90 (3H, m, CH3CH), 1.30 (3H, d, J ¼ 6.7 Hz, CH3CH), 2.34 (1H, m,
CHCH3), 3.11 (3H, s, CH3N), 3.60 (1H, d, J ¼ 10.4 Hz, CHN), 5.14 (2H, m,
OCH2Ph), 6.65 (1H, d, J ¼ 3.2 Hz, 5-CH), 6.87 (1H, s, 2-CH), 7.03 (1H, d,
J ¼ 3.2 Hz, 7-CH), 7-10–7.40 (6H, m, 6-CH and Har). 13C NMR (CDCl3) d:
24.4, 19.0, 19.2, 19.5, 25.9, 29.4, 34.5, 66.1, 70.4, 104.4, 112,3, 113.0, 125.0,
126.5, 127.9, 128.3, 128.4, 128.6, 130.9, 135,9, 141.9, 173.0 Anal. Calcd. for
C27H37BrN2O2Si: C, 61.37; H, 7.04; Br, 15.09; N, 5.29; O, 6.04; Si, 5.30.
Found: C, 61.29; H, 7.06; N, 5.29.
(S,R)-2-f[3-(3-Benzyloxy-(2R)-benzyloxycarbonylamino-propionyl)-
1-(tert-butyl-dimethyl silyl)-1H-indol-4-yl]-methylaminog-3-methyl-buty-
ric acid benzyl ester (12). In a flame-dried flask, a solution of the
bromoindole 11 (100 mg, 0.19 mmol) in dry THF (10 mL) was cooled under
Ar to 2788C. tBuLi (1.6 M in hexane, 216 mL) was added dropwise. After
15 min at 2788C, this mixture was treated with a solution of acid chloride of
N-carbobenzoxy-O-benzylserine (84 mg, 2.55 mmol) in THF (5 mL) and then
set aside to reach room temperature over 30 min. The reaction mixture was
poured into a cool (25 mL, 5%) sodium bicarbonate solution and was extracted
with methylene chloride and dried with Na2SO4. The solvent was evaporated
under vacuum, and the residue purified by flash chromatography with silica
gel eluting with chloroform/hexane 3 : 2 to give 68 m (46%) of the acylated
1
product 2. H NMR (CDCl3) d: 0.56 (6H, s, CH3Si), 0.98 (15H, m, CH3C,
CH3CH), 2.39 (1H, m, CHCH3), 3.12 (3H, s, CH3N), 4.15 (1H, m, CH2CH),
4.98 (1H, d, J ¼ 3.7 Hz, CHCH2), 5.11 (1H, d, J ¼ 5.5 Hz, CHCH2), 5.17
(2H, s, CH2CH2Ph), 5.19 (2H, s, CHCOOCH2Ph), 5.25 (2H, m,
NHCOOCH2Ph), 5.72 (1H, s, NH), 6.67 (1H, m, 5-CH), 6.87 (1H, m,
2-CH), 7.05 (1H, m, 7-CH), 7.10–7.45 (16H, m, 6-CH and Har). 13C NMR
(CDCl3) d: 17.9, 19.2, 19.7, 27.5, 30.8, 54.4, 67.2, 67.3, 68.0, 87.9, 105,2,
107.7, 108.4, 114.3, 128.00, 128.8, 128.9, 134.7, 135.5, 167.0, 169.8 Anal.

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Suarez, Garcıa, and Compagnone
530
Calcd. for: C45H55N3O6Si: C, 70.92; H, 7.27; N, 5.51; O, 12.59; Si, 3.68.
Found: C, 71.04; H, 7.23; N, 5.48.
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Received in the USA August 14, 2003

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