Direct organocatalytic coupling of carboxylated piperazine-2,5-diones with indoles through conjugate addition of carbon nucleophiles to indolenine intermediates

Article abstract of DOI:10.1016/j.tetlet.2009.11.068

Organocatalytic conjugate addition of diketopiperazines to indoles was achieved in good to excellent yields through electrophilic indolenine intermediates generated under mild conditions. Screening of catalysts and solvents at different temperatures was p

Full text of DOI:10.1016/j.tetlet.2009.11.068

Tetrahedron Letters 51 (2010) 609–612
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct organocatalytic coupling of carboxylated piperazine-2,5-diones
with indoles through conjugate addition of carbon nucleophiles
to indolenine intermediates
*
Ramin Dubey, Bogdan Olenyuk
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic conjugate addition of diketopiperazines to indoles was achieved in good to excellent
yields through electrophilic indolenine intermediates generated under mild conditions. Screening of cat-
alysts and solvents at different temperatures was performed in order to achieve high product yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 18 September 2009
Revised 13 November 2009
Accepted 16 November 2009
Available online 20 November 2009
The indole–diketopiperazine bridge is an important structural
feature of many complex alkaloids of fungal origin that display a
spectrum of interesting biological activity. Such alkaloids contain
cyclotryptophan motifs of considerable structural diversity often
fused to N-alkylated or sulfenylated diketopiperazine rings. Ditry-
ptophenaline1 (Fig. 1), extracted from several strains of Aspergillus
flavus, incorporates 3a,3a0-bispyrrolidinoindoline core and shows
cytotoxicity in several cell lines. Alkaloid (+)-WIN 64821,2–6 also
isolated from Aspergillus sp., is a potent competitive substance P
antagonist against the human neurokinin 14–6 and cholecystokinin
type B receptors.7 Other indole alkaloids derived from tryptophan
tures bearing high sensitivity to bases and reducing agents func-
tional groups. Direct organocatalytic methods for the formation
of the indole–diketopiperazine linkage could facilitate develop-
ment of succinct routes for the efficient assembly of the key
structural blocks of dimeric ETPs and bispyrrolidinoindoline
alkaloids.
The lower reactivity of b-amido esters and diketopiperazines in
a-alkylation reactions, as compared to aldehydes and ketones,
remains the main challenge in the development of direct and effi-
units and
a-amino acids in diketopiperazine rings include (+)-
asperazine8 and (+)-gliocladin C.9 Sporidesmins, toxic secondary
metabolites produced by filamentous fungi of Chaetomium or Pith-
omyces sp., also contain cyclotryptophan motifs along with the
disulfide or polysulfide bridges spanning diketopiperazine rings.
Chaetocin and chetomin are two examples of dimeric epidithiodi-
ketopiperazine (ETP) fungal metabolites10,11 that incorporate an in-
dole system fused to the ETP core (Fig. 1). The potent biological
activity of these natural products is attributed to the redox
properties of the disulfide bridges.11,12 Apart from cytotoxic and
immunomodulatory activities, chetomin also shows promising
antiangiogenic action: it suppresses the neovascularization in solid
tumors by disrupting the transcription of the vascular endothelial
growth factor (VEGF) gene.11,13
H
N
H
N
Ph
O
O
Ph
O
O
H
H
N
N
O
O
O
O
N
HN
N
NH
N
N
N
H
N
H
H
H
Ph
Ph
Ditryptophenaline
(+)-WIN 64821
O
N
S
H
N
OH
O
H
S
N
OH
N
O
O
O
S
S
Despite their striking architecture and interesting biological
activity, many dimeric ETPs have remained elusive synthetic tar-
gets, with total synthesis of 11,110-dideoxyverticillin A, a potent
tyrosine kinase inhibitor, being the only reported example to
date.14 This highlights the challenges involved in the construction
of such stereochemically complex, densely functionalized struc-
N
N
N
S
S
N
S
S
O
N
N
N
H
N
H
H
H
O
OH
O
OH
Chetomin
Chaetocin
* Corresponding author. Tel.: +1 520 626 0754; fax: +1 520 621 8407.
E-mail address: olenyuk@email.arizona.edu (B. Olenyuk).
Figure 1. Natural products with cyclotryptophan motifs incorporating indole–
diketopiperazine linkages.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.068

610
R. Dubey, B. Olenyuk / Tetrahedron Letters 51 (2010) 609–612
cient procedures of their alkylation. Although many examples of
organocatalytic alkylations of aldehydes and ketones can be found
in the recent literature,15 none have been reported so far for substi-
tuted b-amido esters and diketopiperazines. Organocatalytic trans-
formations of the piperazine-2,5-dione ring system are known to
be more challenging as compared to those of aldehydes, ketones,
and esters due to its lower reactivity toward electrophiles and
greater steric bulk.16 In this Letter, we report the first direct, organ-
ocatalytic coupling of substituted diketopiperazines and indoles.
Only a few strategies for the direct construction of the indole–
diketopiperazine bridge are known to date. The most commonly
used is the method pioneered by the groups of Kametani and
Somei (Fig. 2).17,18 This remarkable reaction involves coupling of
the nucleophilic substrate with gramine in refluxing acetonitrile
in the presence of trialkylphosphine. This reaction has received a
number of applications, for example, in the synthesis of paraher-
quamides A19 and B,20,21 by Williams and co-workers as well as
in the mechanistic study of the Morin rearrangement,22 although
it uses toxic trialkylphosphine and generally gives the product in
moderate yields (40–70%). An interesting modification of this reac-
tion has been reported by Hart and Magomedov, where treatment
of substituted diketopiperazine with Li2CuCl4 followed by the addi-
tion of gramine methosulfate gave coupling product in 54% yield.23
Our first goal was to improve the efficiency and increase prod-
uct yields in the coupling of gramine with substituted diketopiper-
azines. Hence, we directed our initial efforts to exploration of the
feasibility of the reaction between gramine 1a and ethyl ester 2a
using inexpensive, readily available quinine as a Lewis base
(Fig. 2). The results were encouraging as higher yields were ob-
tained when quinine was used in place of tributylphosphine. To
further explore the scope of this transformation, three substrates
2a–c were tested at temperatures ranging from ambient to the re-
flux of acetonitrile (Table 1). No reaction was taking place at room
temperature, and low yields were obtained at 50 °C (Table 1, En-
tries 1–4), presumably due to the low rate of formation of 3-meth-
ylene indolenine intermediate from gramine. However, further
increase of the temperature to 82 °C dramatically improved the
reaction. The products 3a–3c formed in good to excellent yields,
although as expected, the reaction showed decrease in yields with
the increase in the steric bulk of the ester groups in substrates 2a–
2c (Table 1, Entries 5–7). To compensate for such a decrease, longer
reaction time and larger excess of 1a were used. The use of chiral
quinine opened a possibility for an asymmetric induction during
the catalytic cycle. Unfortunately, the observed enantioselectivity
was rather low, with ee ranging from 10 to 25%. The use of gra-
mine-N-oxide 1b24 or 1-Boc-gramine 1c25 (Fig. 3) did not improve
product yield or enantioselectivity.
In a search for donors that generate indolenine intermediates at
ambient temperature and tolerating indole ring and methylene
bridge substituents, we turned to arylsulfonyl indoles that have
been recently reported to promote proline-catalyzed
a-alkylation
of aldehydes.15,26,27 Two types of arylsulfonyl indoles were chosen:
one with the phenyl group at the indolyl position, which could
facilitate determination of the diastereomeric ratio of the products,
and the substrate 5c with unsubstituted methylene bridge28 (vide
infra). The sulfonyl group at the benzylic position of 3-substituted
NMe2
Tributylphosphine
(0.5 eq.)
O
O
N
H
EtO
CH3CN, reflux
42%
1a
N
HN
N
O
O
O
O
H
Quinine (1.0 eq.)
EtO
N
3a
HN
CH3CN, reflux
92%
2a
Figure 2. Alkylation of piperazine-2,5-dione 2a with gramine 1a.
Table 1
Effect of substrate and temperature on the quinine-promoted alkylation of substituted diketopiperazines with gramine
O
O
O
R1O
O
O
NMe2
Quinine (1.0 eq.)
CH3CN
N
R1O
N
N
N
R2
N
H
R2
N
H
O
2a: R1=Et, R2=H
2b: R1=Et, R2=Me
1a
3
2c: R1=t-Bu, R2=Me
Entry
Substrate
Equiv of 1a
Time (h)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
7
2a
2b
2a
2b
2a
2b
2c
2.0
2.0
2.0
2.0
2.0
3.5
4.0
24
24
24
24
24
48
48
rt
rt
NR
NR
10
<5
92
81
72
50
50
82
82
82
a
Yield of purified product after chromatographic separation.

R. Dubey, B. Olenyuk / Tetrahedron Letters 51 (2010) 609–612
611
indoles constitutes a good leaving group, which under basic or
acidic conditions allows for a facile generation of an electrophilic
indolenine intermediate. To generate such intermediates from
the arylsulfonyl indoles, a method that involves treatment with
KF on basic alumina29 is often used. Because b-amido esters are
usually compatible with such bases, we sought to develop a simple
and general protocol for the alkylation of substituted diketopiper-
azines with arylsulfonyl indoles using cinchona alkaloids as
catalysts.
O
NMe2
NMe2
N
N
H
1b
Boc 1c
Figure 3. Gramine-N-oxide 1b and 1-Boc-protected gramine 1c as substrates for
organocatalytic
a
-alkylation of diketopiperazines.
We first performed the reaction with substrates 2c and 5a in
dichloromethane as the solvent. The presence of a phenyl group
at the indolyl position produces diastereomeric products whose
dr could be readily determined by 1H NMR spectroscopy. This
would provide an opportunity to study the effect of different
organocatalysts (Fig. 4) on the diastereoselectivity of the reac-
tion. Gratifyingly, the reaction proceeded in moderate to high
yields with moderate amounts of cinchona alkaloids (Table 2,
Entries 1–11). After the successful reaction of the arylsulfonyl
indole 5a with the diketopiperazine 2a we focused on optimiz-
ing the reaction conditions by varying solvents, temperatures,
and substituents on aryl indoles and diketopiperazine. Substitu-
ents at the indole ring (C-2 position) and at the bridging carbon
are well tolerated, suggesting wide scope of the reaction
(Table 2, Entries 10-11). We found that 80 mg of KF/alumina
per 0.1 mmol of sulfone was needed to obtain good yields. Next,
the effects of catalyst loading, temperature, and solvents were
studied in the reactions with substrate 2c. The catalyst 4b gave
the best yields with good diastereomeric ratios at room temper-
ature. Lowering the reaction temperature to 0 °C resulted in a
decrease of product yield but did not improve stereoselectivity
of the reaction. Even with the relatively bulky substrate 2c, high
yields were obtained after increasing its stoichiometric amount
from three to five equivalents (Table 2, Entry 7). Finally, aryl-
sulfonyl indole 5c, with methylene group at the indolyl position
in the reactions with substrate 2c, gave product in 90% yield
(Table 2, Entry 12), illustrating that this transformation could
be readily used in the synthesis of natural products containing
cyclotryptophan motifs.
H
H
Et
Et
Ph
N
N
H
O
O
H
H
H
MeO
N
N
OMe
Ph
N
N
4a: (DHQD)2PYR
H
H
Et
Et
N
N
O
H
O
H
H
H
N
N
MeO
OMe
N
N
4b: (DHQD)2PHAL
H
HO
N
MeO
N
4c: Quinine
Figure 4. Cinchona alkaloid Lewis bases used in this study.
Table 2
Scope of a-alkylation of diketopiperazines 2b–2c with arylsulfonyl indoles 5a–5c catalyzed by cinchona alkaloids 4a–4c
O
O
R3O
R2
O
O
R2
SO2
R1
Me
KF/alumina
NMe
R3O
Me
N
+
MeN
N
Catalyst
Me
R1
(15 mol %)
O
N
H
N
H
O
1.0 eq.
6
3.0 eq.
5a: R1 = Me, R2 = Ph
5b: R1 = H, R2 = Ph
5c: R1 = H, R2 = H
2b: R3 = Et
2c: R3 = t-Bu
Entry
Indole
DKP
Solvent
Catalyst
Temp. (°C)
Time (h)
Yielda (%)
dr
1
2
3
4
5
6
7
8
9
5a
5b
5a
5a
5a
5b
5a
5a
5a
5a
5b
5c
2c
2c
2c
2c
2c
2c
2c
2b
2b
2c
2c
2c
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4b
rt
rt
rt
0
rt
rt
rt
rt
rt
rt
rt
rt
48
72
48
120
120
72
72
48
48
48
55
70
72
NR
46
75
89b
71
54
70
70
90
5:1
2.6:1
4.5:1
—
3.8:1
3:1
4.5:1
1:1
1:1
10
11
12
2.7:1
2.5:1
N/A
72
48
a
Yield of purified product after chromatographic separation.
5 equiv of 2c was used.
b

612
R. Dubey, B. Olenyuk / Tetrahedron Letters 51 (2010) 609–612
4. Oleynek, J. J.; Sedlock, D. M.; Barrow, C. J.; Appell, K. C.; Casiano, F.; Haycock, D.;
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yields were obtained when the arylsulfonyl indole, as opposed to
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coupling of substituted diketopiperazines with indoles has been
developed through the use of 3-(-1-arylsulfonylalkyl)indoles as con-
venient precursors to indolenine intermediates and cinchona alka-
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means for rapid construction of bispyrrolidinoindoline scaffolds of
alkaloids and epidithiodiketopiperazine fungal metabolites. Further
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Acknowledgments
We thank the National Science Foundation (CHE-0748838) and
the National Institutes of Health (R21 CA129388) for funding.
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Supplementary data
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Supplementary data (synthetic procedures, characterization,
and NMR spectra of compounds 3a–c and 6a–c) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.068.
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