Synthesis of Indolyldiketopiperazines with NBS

Article abstract of DOI:10.1002/chir.22346

Two series of indolyldiketopiperazines were synthesized starting from methyl 1-substituted-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochlorides via N-bromo-succinimide (NBS) as an important reagent. All eight compounds were characterized by nuclear

Full text of DOI:10.1002/chir.22346

CHIRALITY 26:790–792 (2014)
Synthesis of Indolyldiketopiperazines with NBS
YANGMIN MA, * DECHENG REN, HAO WU, JIN ZHANG, TINGTING FENG, AND YANCHAO LI
1
1
2
1
3
4
1
Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry, Ministry of Education, Shaanxi University of Science & Technology,
Xi’an, China
2
WuXiAppTec (Tianjin) Co., Ltd., TEDA, Tianjin, China
3
Pharmaron (Xi’an) Co., Ltd., Xi’an, China
4
Northwest Institute of Nonferrous Metals, Xi’an, China
ABSTRACT
-substituted-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochlorides via N-bromo-succinimide
NBS) as an important reagent. All eight compounds were characterized by nuclear magnetic
Two series of indolyldiketopiperazines were synthesized starting from methyl
1
(
resonance (NMR) and elemental analysis. Furthermore, the mechanisms of NBS-reacted
rearrangements are also discussed. Chirality 26:790–792, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: N-bromosuccinimide; conjugative effect; indolyldiketopiperazine; rearrangement
INTRODUCTION
NBS Reacted Rearrangement and Further Treatments
Over the past decades, indolyldiketopiperazines have
2
Compound 4 was dissolved in THF-H O (30 mL, 1:1, v/v) and then
AcOH (5 mL) was added. After cooling the mixture to 0–5°C using an
ice bath, ice-bathed NBS (3 mmol) was added dropwise. After a 5-min
ice bath, it was stirred for 30 min at room temperature (reaction
progression was monitored by TLC). After the completion of the reaction,
attracted increasing attention due to the awareness of their
1
,2
3
bioactivities such as antitumor, antimicrobial, and anti-HIV
4
agents. There are three skeletons of indolyldiketopiperazines
according to their structural features: the open-ring
indolyldiketopiperazines (i) in which the indolyl and
diketopiperazine units were linked by a chemical bond, the
close-ring ones (ii) which consist of a closed ring between the
two units, and the spiro-ones (iii) which have spiro-carbons in
the structures. The basic skeleton of all three structures are
shown in Figure 1.
it was quenched by solid Na
was vacuum-filtered and distilled to wipe THF, then extracted with
CH Cl (3 × 15 mL). The combined organic extracts were dried over
anhydrous MgSO and concentrated to yield the crude product, which
2 3 2 3
SO , and neutralized with Na CO (aq.). It
2
2
4
was also used without further purification.
Morpholine (5 mL) was added to a solution of the crude product above
2 2
in CH Cl (30 mL) and the mixture was heated to 40°C for 40 min
(
reaction progression was monitored by TLC), and concentrated to yield
There are many methods for the synthesis of the spiro-
compounds. For example, 1,3-cyclic addition was used to
the crude product, which was further purified by column chromatography
(silica gel, petroleum ether: ethyl acetate = 2:1, v/v) to give 1 or 2.
The structures of the isolated products 1a–1d and 2e–2h were
5
establish a spiro-carbon and then obtain the spiro-indolyldiket-
opiperazines.6 In addition, the N-bromosuccinimide (NBS)
1
13
corroborated by H NMR and C NMR spectroscopy, elemental analysis,
7
method was often found in the literature. NBS, which can
1
1
and/or H- H NOESY.
provide the Br + or Br·, is a very common reagent used in
Selected data: (2S,3S,5aS,10aS)-3-ethyl-5a,6,7,8-tetrahydro-1H-spiro
8
many reactions such as selectrophilic substitutions and
[
dipyrrolo[1,2-a:1’,2’-d]pyrazine-2,3’-indoline]-2’,5,10(3H,10aH)-trione
9
1
radical reactions. In the present work, NBS was used as
(1a). Yield 57.44%. White solid; mp133–134 °C; H NMR (400 MHz,
DMSO-d ) δ: 10.59 (s, 1H), 7.36 (d, J = 7.08 Hz, 1H), 7.26 (t, J = 7.62 Hz,
1H), 6.99 (t, J = 7.48 Hz, 1H), 6.87 (d, J = 7.64 Hz, 1H), 4.81 (t, J = 8.34 Hz,
H), 4.40 (t, J = 7.86, 1H), 3.78 (dd, J = 8.56, 3.08 Hz, 1H), 2.51
m, 3H), 2.29-2.16 (m, 2H), 2.05-1.95 (m, 1H), 1.92-1.80 (m, 3H), 1.72-
the reagent of spiro-rearrangement and our study obtained
6
the compounds successfully. However,
a
series of
1
(
1
compounds with another skeleton were obtained in the same
surroundings (Scheme 1).
1
3
6
.63 (m, 1H), 0.44 (t, J = 7.32 Hz, 3H); C NMR (101 MHz, DMSO-d )
δ: 180.75, 168.34, 166.54, 142.64, 129.18, 127.81, 125.78, 122.10,
10.10, 63.66, 60.99, 58.45, 54.95 (spiro-C), 45.02, 34.13, 27.90, 23.70,
EXPERIMENTAL
1
The substrates (methyl 1-substituted-1,2,3,4-tetrahydro-β-carboline-3-
carboxylate hydrochlorides 3) were asymmetrically synthesized through
23.65, 11.21; NOE data: 1-Hα (1-Hβ), 1-Hβ (1-Hα, 10a-H, 3-H), 10a-H
(1-Hβ, 3-H), 3-H (1-Hβ, 10a-H), 3a-H (4’-H), 4’-H (3a-H); Elemental
1
0
a reference method. All reagents were commercially available. Melting
points were measured on an X-6micro-melting point apparatus and were
uncorrected. The nuclear magnetic resonance (NMR) spectra were
analysis, calcd. for C19
21 3 3
H N O : C 67.24, H 6.24, N 12.38; found: C
67.25, H 6.25, N 12.37%.
(3S,8aS)-3-((2-(4-Methoxybenzoyl)-1H-indol-3-yl)methyl)hexahydropyrrolo
[1,2-a]pyrazine-1,4-dione (2e). Yield 55.24%. Faint yellow solid; mp181–183 °C;
1
13
obtained on an AVANCE-400 instrument ( H NMR at 400 MHz,
C
NMR at 101 MHz) using CDCl or DMSO-d as the solvent with
3
6
tetramethylsilane (TMS) as an internal standard. Elemental analysis
was carried out with Vario EL III elemental analyzer.
Contract grant sponsor: Scientific Research Project Item for Key Laboratory of
Shaanxi Province Education Department, China; Contract grant number:
2
010JS056.
N-protected
Contract grant sponsor: Xianyang City Science and Technology Project, China
Contract grant number: 2010 K10-06.
To a mixture of one of the substrates (3, 1.5 mmol) and Fmoc-L-Pro-Cl
*Correspondence to: Y. Ma, Key Laboratory of Auxiliary Chemistry & Tech-
nology for Chemical Industry, Ministry of Education, Shaanxi University of
Science & Technology, Xi’an 710021, China. E-mail: mym63@sina.com
Received for publication 19 December 2013; Accepted 22 April 2014
DOI: 10.1002/chir.22346
Published online 18 July 2014 in Wiley Online Library
(wileyonlinelibrary.com).
(
2 2
prepared by Fmoc-L-Pro, 1.8 mmol) in CH Cl (15 mL) was added
Na CO (aq.) (15 mL) to be a double phase system and the mixture was
2
3
stirred for1 h (reaction progression was monitored by thin-layer chroma-
tography [TLC]). After the completion of the reaction, the N-protected
compound 4 was obtained and could be used without purification.
©
2014 Wiley Periodicals, Inc.

SYNTHESIS OF INDOLYLDIKETOPIPERAZINES
791
Fig. 1. Basic structures of three indolyl diketopiperazines.
1
H NMR (400 MHz, CDCl
d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H),
.47-7.38 (m, 1H), 7.27-7.21 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.30 (dd,
J = 8.3, 2.9 Hz, 1H), 3.96 (t, J = 7.5 Hz, 1H), 3.89 (s, 3H), 3.72 (d, J = 5.3 Hz,
H), 3.58 (dd, J = 8.3, 5.3 Hz, 2H), 3.44 (dd, J = 14.5, 8.6 Hz, 1H), 2.26
3
) δ: 9.22 (s, 1H, indole-NH), 8.15 (s, 1H), 7.90
RESULTS AND DISCUSSION
(
7
As shown in Scheme 1, the R- of the starting material
appeared to be the important influencing factor whether the
endproducts were spiro-cyclic or open-cyclic compounds.
While the R was aliphatic, the spiro-product would be given;
while aromatic, it would be an open-cyclic compound.
It is possible that there were two paths for the reaction of
NBS according to the effects between conjunctive and
electrophile: one was the 1-C in 4, the other was the 4a,9a-
double bond, which was on the unit of indolyl. First, HO-Br,
which deviated the OH part, was given by NBS and AcOH
2
13
(
ddd, J = 12.2, 10.5, 7.7 Hz, 1H), 2.01-1.84 (m, 3H); C NMR (101 MHz,
CDCl ) δ: 187.58, 169.79, 165.93, 163.63, 136.49, 132.91, 132.40, 130.31,
27.50, 126.30, 121.15, 121.04, 119.56, 113.96, 112.44, 59.07, 56.55, 55.61,
3
1
4
6
5.38, 27.94, 24.83, 22.79; Elemental analysis, calcd. forC24
9.05, H 5.55, N 10.07; found: C 69.07, H 5.52, N 10.06%.
23 3 4
H N O : C
Characterization data of other compounds (1b–1d, 2f–2h) are shown
in the Supporting Information.
Scheme 1. Synthesis of two series of indolyl diketopiperazines through three-step procedures including NBS rearrangements.
Scheme 2. Plausible mechanisms of NBS rearrangements.
Chirality DOI 10.1002/chir

7
92
MA ET AL.
(
see Scheme 2(I)). When the R was an aromatic group,1-C
ACKNOWLEDGMENTS
was neighbored by three conjugated units (an indolyl
group, a phenyl or its diverse, and an amido group), which3
made the carbon easy to change from the hybridization sp
to sp and obtain a C = N , the conjunctive effect showing
the main effect. H-1 was dropped with a HO-Br and the
We thank the Scientific Research Project Item for Key
Laboratory of Shaanxi Province Education Department,
China (Grant No. 2010JS056) and the Xianyang City Science
and Technology Project, China (Grant No. 2010 K10-06) for
financial support.
2
+
1
-C was made a double-bond with N, and then the carbon
was attacked by OH duplet. After electron transfers, the
open-cyclic structure was obtained (see Scheme 2(III)).
When the R was an aliphatic group, 1-C was neighbored
by two conjugated units (an indolyl group and an amido
group), and a more electrophile effect was obtained. It
was more possible that the 4a,9a-double bond would be
more active for reacting than the 1-C. The 4a,9a-double
bond was attacked by HO-Br to give a trans-4a-bromo-9a-
hydroxy intermediate, and then rearranged like a pinacol-
rearrangement to get the spiro- compound (see Scheme 2
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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Chirality DOI 10.1002/chir