Microwave-assisted synthesis of tetracyclic 2,5-diketopiperazines on a soluble polymer support: A structural analogue of tadalafil

Article abstract of DOI:10.1071/CH08334

Structural analogues of tadalafil that contain two diversity points have been synthesized from a soluble polymer support employing a PictetSpengler reaction using focussed microwave irradiation. Polymer-bound deprotected tryptophan reacts with various ald

Full text of DOI:10.1071/CH08334

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 42–50
www.publish.csiro.au/journals/ajc
Microwave-Assisted Synthesis of Tetracyclic
2,5-Diketopiperazines on a Soluble Polymer
Support: A Structural Analogue of Tadalafil
Wong-Jin Chang,A Kaushik Chanda,A and Chung-Ming SunA,B
ALaboratory of Combinatorial Drug Discovery, Department of Applied Chemistry,
National Chiao Tung University, Hsinchu 300-10, Taiwan.
BCorresponding author. Email: cmsun@mail.nctu.edu.tw
Structural analogues of tadalafil that contain two diversity points have been synthesized from a soluble polymer support
employing a Pictet–Spengler reaction using focussed microwave irradiation. Polymer-bound deprotected tryptophan reacts
with various aldehydes to generate the tetrahydro-β-carbolines on the support. Subsequently immobilized tetrahydro-β-
carboline underwent a highly efficient intramolecular N-heterocyclization in a traceless fashion from various in-situ
generated α-alkyl and heteroalkyl amides in two steps to generate tetracyclic 2,5-diketopiperazines in high purity. All the
compounds were isolated as cis and trans isomers with good yields.
Manuscript received: 6 August 2008.
Final version: 30 October 2008.
Introduction
To simplify the synthetic strategy or to reduce the synthetic
steps, a cyclization–cleavage method is highly efficient and has
been developed for traceless solid phase synthesis. Advantages
associated with this method are abundant in terms of astute
choice of reactant and reaction conditions. After liberating from
the support, the desired products are easily recovered, ignoring
the requirement of post cleavage workup.[8] Moreover, the over-
all process is readily available to automated high speed parallel
synthesis and hence heterocyclic compounds of interest can be
generated free of any trace of the linker that is used to tether the
starting building blocks to the polymer support.
We have demonstrated the application of a soluble macro-
molecular support for the synthesis of diverse nitrogen hetero-
cycles like benzimidazoles,[9] quinoxalines,[10] hydantoins,[11]
and pyrimidinones.[12] Heterocycles that contain the tricyclic
indolo[3,4-b]pyridine and piperidine skeleton are known to be
part of the well known plant alkaloids like Reserpine and
Yohimibine. The β-carboline skeleton has been recognized as
a privileged structure in view of the wide range of biologi-
cal activities associated with this skeleton (Fig. 1).[13] Several
tetracyclic β-carbolines have also been isolated from natural
sources with potential applications in medicinal chemistry.[14]
The structural relevance to the present molecular library is
found in fumitremorgin C, which is a fungal metabolite[15] from
Aspergillus fumigatus BM 939 employed to overcome multidrug
resistance in cancer chemotherapy[16] and has also been reported
to interfere with the mechanism of release neurotransimitters.[17]
Interestingly this skeleton in the form of Tadalafil, is also
endowed with the property of inhibiting the cyclic guanosine
monophosphate type-5 specific phosphodiesterase (PDE 5).[18]
Because of their potent bio-properties, these tetracyclic scaf-
folds have been synthesized by classical as well as solid phase
methods.[19]
Chemogenomics is a new strategy in drug innovation that defines
the screening of the chemical universe, i.e., all possible chemical
compounds, against all proteins and other potential drug targets.
Due to the almost infinite size of the chemical universe, the sys-
tematic screening of libraries of congeneric compounds against
members of a target family offers an unprecedented chance
to search the compounds with significant activity or subtype
specificity. Over the years, natural products have been widely
utilised as small-molecule chemical probes for biological path-
ways. Many compounds that elicit specific cellular responses
havecomplex, chiral, andhighlyfunctionalizedstructures.These
properties are valuable in the search for specific binding to pro-
tein targets or to differentiate related proteins.[1] Combinatorial
chemistry is a powerful tool in the medicinal chemistry commu-
nity for the rapid synthesis of small molecules for various drug
targets. The current challenge is to develop stereo and enantio-
selective synthetic methods in solution and the solid phase to
obtain fast access to complex, functionalized, natural product-
like compounds in a high-throughput manner. The application
of solid-phase synthesis for the synthesis of heterocycles[2] and
the transformation of resin-bound peptides to heterocycles[3]
continues to be areas of great interest.
In providing a viable alternative to the solid support reac-
tion, liquid phase synthesis has been signifying the usefulness
of employing a soluble macromolecular support. Advantages
associated with this method have been enormous, in terms of
solubility, amenability for monitoring, heftiness for functional
group intercoversion, and compassion for microwave (MW)
irradiation.[4–6] MW-assisted organic synthesis has been demon-
strated to drastically accelerate organic reactions by providing
a non-conventional energy source.[7] As a result, higher yields
and shorter reaction times can often be achieved.
© CSIRO 2009
10.1071/CH08334
0004-9425/09/010042

RESEARCH FRONT
Microwave-Assisted Synthesis of Tetracyclic 2,5-Diketopiperazines
43
O
H
O
H
O
OH
N
N
N
OH
N
N
N
O
O
O
N
H
N
H
N
OCH3
OCH3
O
H
O
Fumitremorgine C
Cyclotryprostatin A
Tadalafil
Fig. 1. Structurally related biologically active compounds.
O
O
O
NHBoc
CH3O
O
DCC, cat. DMAP
n
CH3O
OH
ϩ
HO
BocHN
O
CH2Cl2
MW, 10 min
n
HN
3
NH
1
2
O
O
Cl, Et3N
Cl
1. 20% TFA/CHCl3
O
CH3O
O
O
2.
n
CH2Cl2, MW, 10 min
HN
N
H
4
H
R1
R1
MW, 30 min
cis:trans ꢀ 1:1
O
O
O
R2NH2, CH2Cl2
MW, 10 min
CH3O
O
O
n
CH3O
O
O
n
N
N
H
HN
N
N
H
5
R2
O
R1
R1
Cl
6
O
R2
N
O
H
ϩ
CH3O
O
N
n
N
H
O
R1
7
cis:trans ꢀ 1:1
Scheme 1. Synthesis of tetracyclic 2,5-diketopiperazines on PEG support.
Recently we have extended the liquid phase methodology to
generate molecular libraries with, skeletons akin to indole alka-
loids by utilizing a combination of MW irradiation, a traceless
strategy, and fluorous technology.[20] In view of our ongoing
program for the development of a novel synthetic strategy for
heterocyclic compounds, we herein report the MW-assisted syn-
thesis of diketopiperizine with two points of structural diversity
by employ the Pictet–Spengler reaction in a traceless fashion.[21]
experimental conditions in term of power and reaction time of
the MW reactor were optimized to obtain maximum yields.
Under conventional refluxing conditions at the same temper-
ature the reaction took 48 h to reach completion, whereas the
time has been reduced to 10 min under MW irradiation. Con-
struction of the β-carboline skeleton was perceived in terms of
a [5 + 1] approach for the six-membered heterocycles, which
needed the generation of a nucleophilic secondary amino group.
In the initial experiment, deprotection of the NHBoc group of
compound 3 needed 3 h for complete conversion, and subse-
quent cyclization with various aldehydes to form β-carboline in
20% TFA was examined, which proceeded smoothly in chloro-
form under refluxing conditions. At the end of the cyclization
reaction, the products were collected by precipitation and filtra-
tion to afford the immobilized compound 4. The initial study to
remove the Boc group was ensured by the disappearance of the
crude NMR signal of tert-butyl group at 1.4 ppm. For compari-
son, we performed the synthesis of 4 under both MW irradiation
as well as refluxing conditions, which revealed that MW irra-
diation could dramatically reduce the reaction time to 30 min
Results and Discussion
In the planning of a synthetic route to the desired compounds,
monohydric poly(ethylene glycol) (PEG)-5000 1 has been used
as a soluble polymer support (Scheme 1). The synthesis was
initiated by the generation of the PEG immobilized bis-ester 3
from the commercially available Boc-protected l-tryptophan 2.
This esterification reaction was complete within 10 min in a MW
oven under open vessel conditions by the N,Nꢀ-dicyclohexyl
carbodiimide (DCC) mediated ester in the presence of cat-
alytic quantities of N,Nꢀ-dimethylamino pyridine (DMAP). The

RESEARCH FRONT
44
W.-J. Chang, K. Chanda, and C.-M. Sun
Table 1. MW-assisted synthesis of tetracyclic 2,5-diketopiperizine libraries 7a–n
Entry
R1CHO
R2NH2
LRMSA
353
Isolated yieldB
O
7a
82% (39 + 43)
NH2
H
O
O
NH2
7b
7c
373
389
90% (50 + 40)
87% (49 + 38)
H
H
NH2
O
O
H
H
NH2
7d
418
85% (51 + 34)
O2N
O
NH2
7e
7f
416
434
84% (34 + 50)
87% (55 + 32)
O2N
O
O
NH2
H
H
O
O2N
7g
7h
456
374
83% (52 + 31)
86% (47 + 39)
NH2
O
O2N
O
NH2
H
N
O
O
O
7i
379
417
377
89% (50 + 39)
81% (43 + 38)
NH2
H
H
H
7j
7k
NH2
O
NH2
83% (35 + 48)
(Continued)

RESEARCH FRONT
Microwave-Assisted Synthesis of Tetracyclic 2,5-Diketopiperazines
45
Table 1. (Continued)
Entry
R1CHO
R2NH2
LRMSA
399
Isolated yieldB
O
O
NH2
7l
83% (34 + 49)
H
H
7m
7n
427
389
89% (50 + 39)
77% (45 + 32)
NH2
O
O
O
H3C NH2
H
ALRMS were detected with EI ionization source.
BYields were based on loading of soluble support. Parentheses denote the isolated yield of two diastereomers (trans + cis).
in a one pot manner to generate compound 4 in good yields.
The construction of polymer-bound tetrahydro-β-carboline 4
from compound 3 was achieved through the in-situ generated
aldimines, which underwent an intramolecular ring closure by
the Pictet–Spengler mechanism. The Pictet–Spengler gave rise
to free polymer-bound carboline 4, with the formation of cis and
trans diastereomers in a ratio of around 1:1.
Building up of the terminal diketo piperazine ring across the
N-2/C-3 bond on this skeleton was achieved in two steps. The
required carbonyl group with an electrophilic carbon was gener-
ated by the reaction of intermediates 4 with chloroacetyl chloride
to generate the N-chloroacetyl conjugates 5 under MW irradi-
ation in 10 min. With a view to introduce the second point of
diversity on this skeleton, it was thought pertinent to employ
various primary amines to react with the N-chloroacetyl conju-
gates 5. Initial studies were attempted at room temperature in
dichloromethane and monitoring of this step by TLC indicated
the completion of the release of compounds 7 from the support
in 10 h. However, irradiation of the same reaction mixtures by
MW afforded the title compounds 7 in 10 min, which illustrates
the remarkable ascendancy of MWs.
Treatment of the reaction mixtures with cold ether resulted in
precipitation and, surprisingly, the regeneration of PEG, instead
of the conjugate. The polymer free compounds 7 in the filtrate
were evaporated by rotary evaporation and purified by silica gel
column chromatography (Table 1). It is likely that the in-situ
generated amine conjugates 6 are stereo-electronically favoured
for an intramolecular nucleophilic attack on the PEG-ester car-
bonyl, which leads to a traceless synthesis by an acyl-polymer
oxygen bond cleavage.
The cyclization of the diketopiperizine ring and subsequent
traceless cleavage of the polymer support was performed in one
pot under mild conditions.[22] The representative library of
tertracyclic 2,5-diketopiperazine derivatives 7 and analytical
data are shown in Table 1. The present investigation for the
target molecules using the MW approach afforded the com-
pounds in the form of trans and cis isomers in various ratios with
good purity. The presently observed facile and high-yielding
ring closure using MW irradiation is in contrast to the routine
synthetic approach reported for the amino acid functionalized,
diketopiperazine fused β-carbolines, which required heating to
reflux in N,N-dimethylformamide.[23] Our approach of employ-
ing a C-3 ester conjugate seems to be better than using the
nucleophilicity of the β-carboline nitrogen for the formation
of diketopiperazine for the generation of chiral centre at C-1.
However, this cyclization would lead to mixtures of cis and
trans diastereomers. The cis/trans-stereochemistry of tetra-
cyclic 2,5-diketopiperazines derivatives 7 was identified by δH
spectroscopy and through comparison with the literature data,
using the well established method of Cook et al.[24] Normally
cis-isomer 7 is more polar in TLC than trans-isomer in all cases.
To further confirm the results obtained, we undertook the
studyofasinglecrystalX-raystudyofcompound 7a-transwhich
indicates that the diketopiperizine and carboline rings are trans
fused and the Ha and Hb protons are anti-periplanar (Fig. 2).
Conclusion
In summary, we report a successful strategy for the rapid,
efficient, and convenient protocol for the traceless synthesis
of diketopiperazine-fused β-carbolines using Pictet–Spengler
reaction under microwave irradiation. The presently reported
methodology for the parallel synthesis of target compounds can
be applied for the generation of several molecules that closely
resemble biologically active natural products.
Experimental
General Procedure for the Synthesis of Tetracyclic
2,5-Diketopiperizine Libraries 7a–n
The soluble polymer support 1 (PEG 5000) (1.0 g, 0.2 mmol, 1.0
equiv.) was esterified in 10 mL of dichloromethane with Boc-
Trp-OH 2 (0.146 g, 0.48 mmol, 2.4 equiv.), which was treated
with DCC (0.494 g, 0.52 mmol, 2.4 equiv.) and DMAP (3 mg).
The reaction mixtures were subjected to MW irradiation for
10 min to obtain the polymer-bound Boc-Trp-OH 3.The dicyclo-
hexyl urea by-product was filtered off and the reaction mixtures
were precipitated with excess cold ether (100 mL). The pre-
cipitated polymer-bound Boc-Trp-OH 3 was filtered through a
fritted funnel and thoroughly washed with ether (100 mL) and
dried. The crude ester conjugates 3 were treated with 10 mL of

RESEARCH FRONT
46
W.-J. Chang, K. Chanda, and C.-M. Sun
IC10636 in P212121
O2
C3
C8
C9
C20
N1
C2
C19
C5
O
C4
C10
C7
N3
Hb
C6
N
4
C21
N
14
N
H
Ha
C12
C11
O
N2
C15
C13
C1
O1
C14
7a-trans
C16
C18
C17
Fig 2. Single crystal X-ray structural elucidation of compound 7a-trans.
20% trifluoroacetic acid in chloroform and a solution of alde-
hyde (3 equiv.) in chloroform, and subjected to MW irradiation
for 30 min. After completion of the reaction, ether (100 mL)
was added for precipitation to afford the polymer-immobilized
β-carbolines 4. The precipitated solid 4 was washed three
times with ether (100 mL) to remove the unreacted aldehyde
and the solid was dried for the next step. The polymer-bound
β-carbolines4werestirredwith2-chloroacetylchloride(0.052 g,
0.458 mmol, 3 equiv.), triethylamine (0.093 mL, 0.917 mmol,
6 equiv.) in dichloromethane and irradiated under MW irra-
diation for 10 min resulted in the completion of the reaction.
The solution was treated with cold ether (100 mL) to precipi-
tate the conjugates 5 in high yields. N-Chloroacetyl conjugates
5 were treated with primary amines (0.448 mmol, 3 equiv.) in
dichloromethaneunderMWirradiationfor10 minatwhichpoint
theTLC showed complete release of the desired compound from
the polymer support. The reaction mixture was then diluted with
cold ether (100 mL) to precipitate the polymer, which was then
filteredoff, andtheresiduewasagainwashedwithcoldether.The
combined extracts were subjected to rotavapor to afford crude,
polymer free compounds 7. This was subjected to silica gel col-
umn chromatography and eluted with ethyl acetate and hexane
mixture (1:1) to obtain the final compounds in high yields.
16.8, 1H), 3.61 (dd, J 15.8, 4.9, 1H), 3.05 (dd, J 15.8, 11.6, 1H),
2.31–2.13 (m, 4H), 1.88–1.83 (m, 2H), 1.24–1.17 (dd, J 14.4,
6.7, 6H), 0.81 (t, J 6.8, 3H); δC (75 MHz, CDCl3) 167.4, 166.8,
136.0, 133.7, 126.2, 122.1, 120.0, 118.3, 111.2, 107.1, 56.1,
52.6, 44.6, 44.4, 36.4, 27.0, 22.5, 22.4, 19.5, 19.4, 13.9; νmax
(neat)/cm−1 2929, 1731, 1650; m/z (EI) 353 (M+); m/z (HRMS
EI) Found: 353.2102. Calc. for C21H27N3O2: 353.2103. [α]D20
−85.91 (c 1.19, CH2Cl2).
trans-2-Isopropyl-6-phenyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7b
δH (300 MHz, CDCl3) 8.09 (br s, 1H), 7.54 (d, J 7.9, 1H), 7.33–
7.28 (m, 6H), 7.23–7.16 (m, 2H), 7.05 (s, 1H), 4.82 (m, 1H),
4.32 (dd, J 11.8, 4.2, 1H), 3.95 (s, 2H), 3.54 (dd, J 15.5, 4.2, 1H),
2.93 (ddd, J 15.5, 11.8, 1.5, 1H), 1.19–1.14 (dd, J 9.2, 6.8, 6H);
δC (75 MHz, CDCl3) 164.8, 162.4, 138.2, 136.4, 129.8, 128.9,
128.9, 126.3, 122.7, 120.1, 118.4, 111.2, 109.2, 52.9, 52.1, 44.3,
43.3, 27.5, 19.0, 18.7; νmax (neat)/cm−1 3280, 2921, 1658, 1652;
m/z (EI) 373 (M+); m/z (HRMS EI) Found: 373.1778. Calc. for
C23H23N3O2: 373.1790. [α]2D0 −143.9 (c 1.5, CH2Cl2).
cis-2-Isopropyl-6-phenyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7bꢀ
trans-6-Butyl-2-isopropyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7a
δH (300 MHz, CDCl3) 7.90 (br s, 1H), 7.60 (d, J 8.9, 1H), 7.32–
7.19 (m, 6H), 7.18–7.11 (m, 2H), 6.27 (s, 1H), 4.87 (m, 1H),
4.29 (dd, J 11.5, 4.7, 1H), 3.96 (d, J 17.3, 1H), 3.85 (d, J 17.3,
1H), 3.75 (dd, J 16.0, 4.7, 1H), 3.25 (ddd, J 16.0, 11.5, 1.3,
1H), 1.19–1.15 (dd, J 6.7, 4.6, 6H); δC (75 MHz, CDCl3) 167.6,
166.1, 141.4, 136.5, 132.8, 128.8, 127.9, 126.9, 126.3, 122.5,
120.1, 118.6, 111.2, 106.7, 56.7, 56.4, 44.5, 44.2, 23.5, 19.5,
19.3; νmax (neat)/cm−1 3316, 2921, 1659, 1412; m/z (EI) 373
(M+); m/z (HRMS EI) Found: 373.1785. Calc. for C23H23N3O2:
373.1790. [α]2D0 −44.6 (c 0.635, CH2Cl2).
δH (300 MHz, CDCl3) 8.42 (br s, 1H), 7.43 (d, J 7.6, 1H), 7.30
(d, J 7.6, 1H), 7.19–7.07 (m, 2H), 5.82 (dd, J 9.1, 5.2, 1H), 4.92
(m, 1H), 4.41 (dd, J 11.8, 4.2, 1H), 4.04 (d, J 17.6, 1H), 3.93 (d, J
17.6, 1H), 3.41 (dd, J 15.3, 4.2, 1H), 2.82 (dd, J 15.3, 11.8, 1H),
1.92–1.77 (m, 2H), 1.52–1.29 (m, 4H), 1.24–1.21 (dd, J 9.0, 6.9,
6H), 0.90 (t, J 7.1, 3H); δC (75 MHz, CDCl3) 166.8, 165.2, 135.9,
132.9, 126.4, 122.4, 120.0, 118.2, 110.9, 106.8, 53.7, 49.6, 44.3,
43.3, 34.0, 28.4, 27.4, 22.7, 19.0, 18.8, 13.9; νmax (neat)/cm−1
3307, 1710, 1651; m/z (EI) 353 (M+); m/z (HRMS EI) Found:
353.2119. Calc. for C21H27N3O2: 353.2103. [α]2D0 −124.0 (c
1.63, CH2Cl2).
trans-2-(2-Methoxyethyl)-6-phenyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7c
cis-6-Butyl-2-isopropyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7aꢀ
δH (300 MHz, CDCl3) 8.18 (br s, 1H), 7.54 (d, J 7.0, 1H), 7.32–
7.27 (m, 5H), 7.23–7.12 (m, 2H), 7.07 (s, 1H), 4.32 (dd, J 11.7,
4.1, 1H), 4.28 (d, J 16.9, 1H), 4.14 (d, J 16.9, 1H), 3.69 (m,
1H), 3.60–3.56 (m, 3H), 3.48–3.35 (m, 2H), 3.33 (s, 3H), 2.96
(ddd, J 15.4, 11.7, 1.4, 1H); δC (75 MHz, CDCl3) 165.5, 162.2,
138.3, 136.4, 129.8, 128.9, 128.9, 128.8, 126.3, 122.7, 120.0,
δH (300 MHz, CDCl3) 8.43 (br s, 1H), 7.59 (d, J 7.2, 1H), 7.39
(d, J 7.3, 1H), 7.23–7.13 (m, 2H), 5.42 (t, J 6.5, 1H), 4.98 (m,
1H), 4.01 (dd, J 15.8, 4.9, 1H), 4.00 (d, J 16.8, 1H), 3.80 (d, J

RESEARCH FRONT
Microwave-Assisted Synthesis of Tetracyclic 2,5-Diketopiperazines
47
118.4, 111.2, 109.0, 70.6, 58.8, 52.6, 52.0, 51.3, 46.3, 27.7; νmax
(neat)/cm−1 3407, 2921, 1650, 1613; m/z (EI) 389 (M+); m/z
(HRMS EI) Found: 389.1746. Calc. for C23H23N3O3: 389.1739.
[α]2D0 −111.8 (c 0.526, CH2Cl2).
EI) Found: 416.1497. Calc. for C23H20N4O4: 416.1485. [α]D20
−129.2 (c 1.065, CH2Cl2).
cis-2-Cyclopropyl-6-(4-nitrophenyl)-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7eꢀ
cis-2-(2-Methoxyethyl)-6-phenyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7cꢀ
δH (300 MHz, (D6)acetone) 10.21 (br s, 1H), 8.19 (d, J 8.8, 2H),
7.56 (d, J 8.8, 2H), 7.10 (d, J 6.4, 1H) 7.29 (d, J 6.3, 1H), 7.11–
7.02 (m, 2H), 6.36 (s, 1H), 4.44 (dd, J 11.5, 4.4, 1H), 4.17 (d, J
17.1, 1H), 3.88 (d, J 17.1, 1H), 3.68 (dd, J 16.0, 4.4, 1H), 3.15
(ddd, J 16.0, 11.5, 1.4, 1H), 2.79 (m, 1H), 0.88–0.72 (m, 4H); δC
(75 MHz, (D6)acetone) 167.8, 167.3, 150.6, 147.0, 137.2, 132.5,
127.9, 126.3, 123.5, 121.9, 119.4, 118.4, 111.3, 106.5, 56.4, 56.3,
50.1, 23.8, 6.4, 5.1; νmax (neat)/cm−1 3299, 2921, 1659, 1516,
1349; m/z (EI) 416 (M+); m/z (HRMS EI) Found: 416.1475.
Calc. for C23H20N4O4: 416.1485. [α]2D0 −40.4 (c 0.82, CH2Cl2).
δH (300 MHz, CDCl3) 8.01 (br s, 1H), 7.60 (d, J 6.3, 1H), 7.33–
7.27 (m, 6H), 7.21–7.16 (m, 2H), 6.27 (s, 1H), 4.33 (dd, J 11.7,
4.5, 1H), 4.24 (d, J 17.7, 1H), 4.06 (d, J 17.7, 1H), 3.90 (m,
1H), 3.76 (dd, J 16.0, 4.5, 1H), 3.66–3.52 (m, 2H), 3.40 (m,
1H), 3.32 (s, 3H), 3.25 (ddd, J 16.0, 11.7, 0.9, 1H); δC (75 MHz,
CDCl3) 167.4, 166.7, 141.4, 136.6, 132.9, 128.7, 127.8, 127.1,
126.2, 122.5, 120.1, 118.6, 111.3, 106.6, 70.7, 58.9, 56.7, 56.2,
52.1, 46.5, 23.5; νmax (neat)/cm−1 3334, 2911, 1632, 1610; m/z
(EI) 389 (M+); m/z (HRMS EI) Found: 389.1735. Calc. for
C23H23N3O3: 389.1739. [α]2D0 −44.8 (c 0.88, CH2Cl2).
trans-2-(2-Methoxyethyl)-6-(4-nitrophenyl)-2,3,6,7,
12,12a-hexahydro-pyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7f
trans-2-Isopropyl-6-(4-nitrophenyl)-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7d
δH (300 MHz, CDCl3) 8.20 (br s, 1H), 8.12 (d, J 11.1, 2H), 7.55
(d, J 7.6, 1H), 7.48–7.45 (m, 2H), 7.34 (d, J 7.7, 1H), 7.27–
7.06 (m, 2H), 7.13 (s, 1H), 4.33 (d, J 17.9, 1H), 4.23 (dd, J
11.7, 4.0, 1H), 4.20 (d, J 17.9, 1H), 3.72 (m, 1H), 3.61–3.53
(m, 3H), 3.45 (m, 1H), 3.33 (s, 3H), 3.00 (dd, J 15.5, 11.7, 1H);
δC (75 MHz, CDCl3) 165.0, 162.6, 148.0, 145.2, 136.5, 129.7,
128.1, 126.1, 124.0, 123.2, 121.7, 120.4, 118.6, 111.4, 109.7,
70.6, 58.9, 52.9, 51.3, 51.3, 46.4, 27.5; νmax (neat)/cm−1 3271,
2929, 1660, 1645, 1519, 1452; m/z (EI) 434 (M+); m/z (HRMS
EI) Found: 434.1589. Calc. for C23H22N4O4: 434.1590. [α]D20
−134.6 (c 0.735, CH2Cl2).
δH (300 MHz, CDCl3) 8.16 (br s, 1H), 8.11 (d, J 5.0, 2H), 7.54
(d, J 7.5, 1H), 7.46 (d, J 7.4, 2H), 7.34 (d, J 7.9, 1H), 7.27–7.16
(m, 2H), 7.04 (s, 1H), 4.81 (m, 1H), 4.20 (dd, J 11.8, 4.1, 1H),
3.99 (s, 2H), 3.55 (dd, J 15.6, 4.1, 1H), 2.96 (ddd, J 15.6, 11.8,
1.4, 1H), 1.20–1.15 (dd, J 9.6, 6.9, 6H); δC (75 MHz, CDCl3)
164.3, 162.8, 148.0, 145.1, 136.5, 129.7, 128.1, 126.1, 124.0,
123.2, 120.4, 118.6, 111.4, 109.8, 53.1, 51.3, 44.5, 43.3, 27.4,
19.0, 18.7; νmax (neat)/cm−1 3280, 1659, 1605, 1520, 1457;
m/z (EI) 418 (M+); m/z (HRMS EI) Found: 418.1646. Calc.
for C23H22N4O4: 418.1641. [α]2D0 −158.9 (c 0.80, CH2Cl2).
cis-2-(2-Methoxyethyl)-6-(4-nitrophenyl)-2,3,6,7,
12,12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7fꢀ
cis-2-Isopropyl-6-(4-nitrophenyl)-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7dꢀ
δH (300 MHz, CDCl3) 8.35 (br s, 1H), 8.05 (d, J 8.3, 2H), 7.59 (d,
J 6.5, 1H), 7.46 (d, J 8.5, 2H), 7.26 (d, J 6.6, 1H), 7.19–7.13 (m,
2H), 6.28 (s, 1H), 4.35 (dd, J 11.3, 4.3, 1H), 4.29 (d, J 18.9, 1H),
4.05(d, J18.9, 1H), 3.90(m, 1H), 3.80(dd, J16.1, 4.3, 1H), 3.65–
3.56 (m, 2H), 3.40 (m, 1H), 3.26 (s, 3H), 3.22 (dd, J 16.1, 11.3,
1H); δC (75 MHz, CDCl3) 167.5, 166.2, 148.7, 147.2, 136.8,
131.1, 127.8, 127.7, 126.0, 124.1, 123.0, 120.4, 118.8, 111.4,
107.2, 70.6, 59.0, 56.4, 56.1, 52.0, 46.7, 23.9; νmax (neat)/cm−1
3343, 2921, 1668, 15161335; m/z (EI) 434 (M+); m/z (HRMS
EI) Found: 434.1577. Calc. for C23H22N4O4: 434.1590. [α]D20
−44.6 (c 0.635, CH2Cl2).
δH (300 MHz, CDCl3) 8.11 (br s, 1H), 8.09 (d, J 8.5, 2H), 7.61
(d, J 6.4, 1H), 7.47 (d, J 8.8, 2H), 7.28 (d, J 6.5, 1H), 7.22–
7.14 (m, 2H), 6.25 (s, 1H), 4.88 (m, 1H), 4.30 (dd, J 11.4,
4.5, 1H), 3.96 (d, J 17.4, 1H), 3.88 (d, J 17.4, 1H), 3.81 (dd,
J 16.2, 4.5, 1H), 3.25 (dd, J 16.2, 11.4, 1H), 1.20–1.16 (dd, J
6.7, 3.9, 6H); δC (75 MHz, CDCl3) 167.7, 165.6, 148.6, 147.3,
136.7, 131.0, 127.9, 126.0, 124.2, 123.1, 120.5, 118.9, 111.4,
107.4, 56.4, 56.3, 44.6, 44.1, 23.8, 19.3, 19.2; νmax (neat)/cm−1
3298, 1651, 1520, 1452; m/z (EI) 418 (M+); m/z (HRMS EI)
Found: 418.1642. Calc. for C23H22N4O4: 418.1641. [α]2D0 −36.0
(c 0.685, CH2Cl2).
trans-2-Furan-2-ylmethyl-6-(4-nitrophenyl)-2,3,6,7,
12,12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7g
trans-2-Cyclopropyl-6-(4-nitrophenyl)-2,3,6,7,12,
12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7e
δH (300 MHz, CDCl3) 8.30 (br s, 1H), 8.10 (d, J 8.5, 2H), 7.54
(d, J 7.6, 1H), 7.44 (d, J 8.5, 2H), 7.38 (s, 1H), 7.33 (d, J 7.6, 1H),
7.26–7.15 (m, 2H), 7.10 (s, 1H), 6.35 (s, 2H), 4.71 (d, J 15.2, 1H),
4.49 (d, J 15.2, 1H), 4.25 (dd, J 11.8, 4.1, 1H), 4.12 (d, J 17.8,
1H), 4.05 (d, J 17.8, 1H), 3.59 (dd, J 15.6, 4.1, 1H), 2.99 (dd, J
15.6, 11.8, 1H); δC (75 MHz, CDCl3) 164.8, 162.2, 148.3, 148.0,
145.1, 142.3, 136.5, 129.8, 128.0, 126.1, 124.0, 123.2, 120.4,
118.6, 111.4, 110.7, 110.1, 109.6, 53.0, 51.3, 49.0, 42.0, 27.5;
νmax (neat)/cm−1 3307, 2911, 1664, 1520, 1457; m/z (EI) 456
(M+); m/z (HRMS EI) Found: 456.1437. Calc. for C25H20N4O5:
456.1434. [α]2D0 −143 (c 0.65, CH2Cl2).
δH (300 MHz, (D6)acetone) 10.20 (br s, 1H), 8.20 (d, J 8.8, 2H),
7.56 (d, J 8.7, 2H), 7.55 (d, J 8.0, 1H), 7.38 (d, J 8.0, 1H),
7.18–7.06 (m, 2H), 7.14 (s, 1H), 4.22 (d, J 17.4, 1H), 4.15 (dd,
J 12.0, 4.3, 1H), 4.00 (d, J 17.4, 1H), 3.37 (dd, J 15.5, 4.3,
1H), 2.99 (ddd, J 15.5, 12.0, 1.5, 1H), 2.70 (m, 1H), 0.79–0.66
(m, 4H); δC (75 MHz, (D6)acetone) 166.3, 162.9, 147.9, 146.4,
137.0, 129.8, 129.3, 126.5, 123.6, 122.3, 119.5, 118.3, 111.4,
109.0, 53.3, 51.0, 49.3, 30.1, 26.8, 5.7, 5.5; νmax (neat)/cm−1
3280, 2921, 1660, 1520, 1453; m/z (EI) 416 (M+); m/z (HRMS

RESEARCH FRONT
48
W.-J. Chang, K. Chanda, and C.-M. Sun
cis-2-Furan-2-ylmethyl-6-(4-nitrophenyl)-2,3,6,7,
12,12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7gꢀ
cis-6-Cyclohexyl-2-isopropyl-2,3,6,7,12,12a-
hexahydro-pyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7iꢀ
δH (300 MHz, CDCl3) 8.10 (br s, 1H), 8.08 (d, J 8.7, 2H), 7.61
(d, J 6.3, 1H), 7.47 (d, J 8.7, 2H), 7.38 (s, 1H), 7.26 (d, J 7.5, 1H),
7.21–7.13 (m, 2H), 6.35 (s, 2H), 6.26 (s, 1H), 4.89 (d, J 15.2, 1H),
4.45 (d, J 15.2, 1H), 4.34 (dd, J 11.3, 4.4, 1H), 4.07 (d, J 17.6,
1H), 3.99 (d, J 17.6, 1H), 3.84 (dd, J 16.1, 4.4, 1H), 3.25 (dd, J
16.1, 11.3, 1H); δC (75 MHz, CDCl3) 167.0, 165.9, 148.6, 147.2,
143.2, 136.7, 131.0, 127.8, 126.0, 124.2, 123.1, 120.5, 118.8,
111.4, 110.7, 109.9, 107.3, 56.6, 56.2, 49.8, 42.6, 42.3, 24.1;
νmax (neat)/cm−1 3316, 2929, 1661, 1520, 1421; m/z (EI) 456
(M+): m/z (HRMS EI) Found: 456.1422. Calc. for C25H20N4O5:
456.1434. [α]2D0 −53.3 (c 0.635, CH2Cl2).
δH (300 MHz, CDCl3) 8.76 (br s, 1H), 7.57 (d, J 7.5, 1H), 7.38 (d,
J 8.0, 1H), 7.22–7.14 (m, 2H), 5.37 (d, J 5.3, 1H), 4.89 (m, 1H),
4.02 (d, J 16.9, 1H), 3.78 (d, J 16.9, 1H), 3.95 (dd, J 11.6, 8.5,
1H), 3.51 (dd, J 15.7, 8.5, 1H), 3.12 (dd, J 15.7, 11.6, 1H), 2.00–
1.55 (m, 5H), 1.28–0.83 (m, 6H), 1.25–1.17 (dd, J 15.8, 6.8, 6H);
δC (75 MHz, CDCl3) 168.2, 167.1, 135.8, 132.1, 126.0, 122.0,
119.9, 118.2, 111.2, 107.5, 57.1, 56.0, 44.8, 44.4, 43.7, 30.1,
27.6, 26.3, 26.0, 25.8, 22.1, 19.7, 19.6; νmax (neat)/cm−1 3289,
2928, 1666, 1646; m/z (EI) 379 (M+); m/z (HRMS EI) Found:
379.2271. Calc. for C23H29N3O2: 379.2260. [α]2D0 −93.84 (c
1.44, CH2Cl2).
trans-2-Isopropyl-6-pyridin-3-yl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7h
trans-6-Cyclohexyl-2-furan-2-ylmethyl-2,3,6,7,12,
12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7j
δH (300 MHz, CDCl3) 9.24 (br s, 1H), 8.56 (s, 1H), 8.42 (d,
J 3.8, 1H), 7.54 (d, J 7.2, 1H), 7.46 (d, J 7.9, 1H), 7.33 (d, J
6.3, 1H), 7.24–7.13 (m, 3H), 6.99 (s, 1H), 4.84 (m, 1H), 4.22
(dd, J 11.8, 4.2, 1H), 3.97 (s, 2H), 3.55 (dd, J 15.4, 4.2, 1H),
2.95 (ddd, J 15.4, 11.8, 1.4, 1H), 1.20–1.15 (dd, J 8.1, 7.0, 6H);
δC (75 MHz, CDCl3) 164.5, 162.6, 150.0, 149.7, 136.6, 136.2,
134.4, 128.4, 126.2, 123.8, 122.9, 120.1, 118.5, 111.4, 109.4,
53.1, 50.1, 44.6, 43.3, 27.4, 19.0, 18.7; νmax (neat)/cm−1 3289,
2992, 1662, 1650; m/z (EI) 374 (M+); m/z (HRMS EI) Found:
374.1740. Calc. for C22H22N4O2: 374.1743. [α]2D0 −204.43
(c 1.35, CH2Cl2).
δH (300 MHz, CDCl3) 8.36 (br s, 1H), 7.43 (d, J 7.6, 1H), 7.41
(s, 1H), 7.34 (s, 1H), 7.29 (d, J 7.9, 1H), 7.18–7.08 (m, 2H),
6.37 (s, 1H), 5.51 (d, J 8.6, 1H), 4.86 (d, J 15.2, 1H), 4.55 (dd,
J 11.8, 4.6, 1H), 4.50 (d, J 15.2, 1H), 4.09 (d, J 17.7, 1H), 4.00
(d, J 17.7, 1H), 3.43 (dd, J 15.5, 4.6, 1H), 2.85 (dd, J 15.5,
11.8, 1H), 1.96–1.67 (m, 5H), 1.26–1.15 (m, 6H); δC (75 MHz,
CDCl3) 165.9, 162.9, 148.6, 143.2, 141.7, 135.9, 126.2, 122.3,
119.8, 118.1, 111.0, 110.6, 106.8, 105.3, 54.3, 53.9, 49.0, 42.0,
41.9, 39.2, 30.3, 29.8, 27.5, 26.0, 25.9; νmax (neat)/cm−1 3307,
2929, 1660, 1462; m/z (EI) 417 (M+); m/z (HRMS EI) Found:
417.2036. Calc. for C25H27N3O3: 417.2052. [α]2D0 −137.60 (c
1.00, CH2Cl2).
cis-2-Isopropyl-6-pyridin-3-yl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7hꢀ
cis-6-Cyclohexyl-2-furan-2-ylmethyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7jꢀ
δH (300 MHz, CDCl3) 9.83 (br s, 1H), 8.71 (d, J 2.0, 1H), 8.30
(dd, J 4.8, 1.4, 1H), 7.62 (dd, J 8.4, 1.6, 1H), 7.39 (dd, J 9.8,
1.7, 1H), 7.31 (dd, J 6.9, 1.8, 1H), 7.16 (m, 2H), 7.05 (dd, J
7.9, 4.8, 1H), 6.24 (s, 1H), 4.87 (m, 1H), 4.17 (dd, J 11.5, 4.6,
1H), 3.88 (d, J 17.4, 1H), 3.76 (d, J 17.4, 1H), 3.79 (dd, J 15.5,
4.6, 1H), 3.20 (dd, J 15.5, 11.5, 1H), 1.17–1.13 (dd, J 12.9, 6.9,
6H); δC (75 MHz, CDCl3) 167.6, 165.7, 149.4, 148.4, 137.5,
137.1, 134.8, 132.0, 126.1, 123.9, 122.6, 120.0, 118.6, 111.6,
106.7, 56.2, 54.7, 44.5, 43.9, 23.9, 19.2; νmax (neat)/cm−1 3263,
2921, 1668, 1646; m/z (EI) 374 (M+); m/z (HRMS EI) Found:
374.1758. Calc. for C22H22N4O2: 374.1743. [α]2D0 −71.11 (c
0.45, CH2Cl2).
δH (300 MHz, CDCl3) 8.12 (br s, 1H), 7.57 (d, J 7.3, 1H)
7.38 (s, 1H), 7.37 (d, J 6.8, 1H), 7.23–7.13 (m, 2H), 6.35 (s,
2H), 5.30 (d, J 4.8, 1H), 4.92 (d, J 15.3, 1H), 4.45 (d, J 15.3,
1H), 4.07 (d, J 17.1, 1H), 4.03 (dd, J 11.8, 4.7, 1H), 3.99
(d, J 17.1, 1H), 3.54 (dd, J 15.8, 4.7, 1H), 3.10 (dd, J 15.8,
11.8, 1H), 2.10–1.50 (m, 5H), 1.38–0.65 (m, 6H); δC (75 MHz,
CDCl3) 167.5, 167.4, 149.1, 143.0, 135.8, 131.8, 126.0, 122.1,
120.0, 118.2, 111.1, 110.6, 109.4, 107.8, 57.3, 55.7, 50.6, 43.5,
42.3, 30.1, 27.3, 26.3, 26.0, 25.8, 22.3; νmax (neat)/cm−1 3316,
2920, 1672, 1659; m/z (EI) 417 (M+); m/z (HRMS EI) Found:
417.2033. Calc. for C25H27N3O3: 417.2052. [α]2D0 −76.45
(c 0.48, CH2Cl2).
trans-6-Cyclohexyl-2-isopropyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7i
trans-6-Cyclohexyl-2-cyclopropyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7k
δH (300 MHz, CDCl3) 8.35 (br s, 1H), 7.43 (d, J 7.5, 1H), 7.31
(d, J 7.9, 1H), 7.19–7.07 (m, 2H), 5.52 (d, J 8.8, 1H), 4.90 (m,
1H), 4.50 (dd, J 11.8, 4.5, 1H), 4.03 (d, J 17.6, 1H), 3.88 (d, J
17.6, 1H), 3.40 (dd, J 15.3, 4.5, 1H), 2.85 (dd, J 15.3, 11.8, 1H),
2.05–1.68 (m, 5H), 1.31–1.09 (m, 6H), 1.26–1.19 (dd, J 13.0,
6.8, 6H); δC (75 MHz, CDCl3) 165.5, 163.5, 135.9, 132.0, 126.3,
122.3, 119.8, 118.1, 111.0, 106.8, 54.3, 54.0, 44.5, 43.2, 41.8,
30.3, 29.9, 27.3, 26.0, 25.9, 19.0, 18.9; νmax (neat)/cm−1 3316,
2929, 1659, 1651; m/z (EI) 379 (M+); m/z (HRMS EI) Found:
379.2263. Calc. for C23H29N3O2: 379.2260. [α]2D0 −76.77 (c
1.39, CH2Cl2).
δH (300 MHz, CDCl3) 8.35 (br s, 1H), 7.44 (d, J 7.6, 1H), 7.32
(d, J 7.8, 1H), 7.20–7.04 (m, 2H), 5.50 (d, J 8.7, 1H), 4.48 (dd,
J 18.0, 4.6, 1H), 4.04 (d, J 17.6, 1H), 3.97 (d, J 17.6, 1H), 3.40
(dd, J 15.4, 4.6, 1H), 2.88–2.76 (m, 2H), 1.97–1.55 (m, 7H),
1.28–1.16 (m, 4H), 0.98–0.71 (m, 4H); δC (75 MHz, CDCl3)
167.9, 163.3, 135.9, 132.0, 126.2, 122.4, 119.9, 118.1, 110.9,
107.0, 54.3, 54.3, 49.7, 42.5, 41.9, 30.4, 29.8, 29.0, 27.3, 26.0,
25.9. 6.8, 6.1; νmax (neat)/cm−1 3307, 2921, 1664, 1651, 1318;
m/z (EI) 377 (M+); m/z (HRMS EI) Found: 377.2104. Calc. for
C23H27N3O2: 377.2103. [α]2D0 −32.11 (c 0.48, CH2Cl2).

RESEARCH FRONT
Microwave-Assisted Synthesis of Tetracyclic 2,5-Diketopiperazines
49
cis-6-Cyclohexyl-2-cyclopropyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7kꢀ
J 7.3, 4.0, 1H), 4.96 (m, 1H), 4.00 (dd, J 11.6, 4.7, 1H), 3.95
(d, J 16.6, 1H), 3.85 (d, J 16.6, 1H), 3.62 (dd, J 15.8, 4.7, 1H),
3.09 (dd, J 15.8, 11.6, 1H), 2.65–2.49 (m, 2H), 2.31–2.15 (m,
2H), 1.95–1.85 (m, 2H), 1.78–1.71 (m, 2H), 1.68–1.57 (m, 2H),
1.53–1.29 (m, 2H); δC (75 MHz, CDCl3) 167.5, 167.0, 140.9,
136.0, 133.1, 128.5, 128.3, 126.1, 122.2, 120.0, 118.4, 111.3,
107.3, 56.0, 54.1, 52.4, 45.8, 37.9, 31.3, 28.8, 28.4, 24.5, 24.3,
22.6;νmax (neat)/cm−1 3299, 1664, 1641;m/z(EI)427(M+);m/z
(HRMS EI) Found: 427.2257. Calc. for C27H29N3O2: 427.2260.
[α]2D0 −43.72 (c 2.175, CH2Cl2).
δH (300 MHz, CDCl3) 8.42 (br s, 1H), 7.57 (d, J 7.3, 1H), 7.37 (d,
J 7.3, 1H), 7.22–7.12 (m, 2H), 5.31(d, J 4.8, 1H), 4.05(dd, J 11.7,
5.1, 1H), 4.03(d, J17.2, 1H), 3.99(d, J17.2, 1H), 3.49(dd, J15.7,
5.1, 1H), 3.06 (dd, J 15.7, 11.7, 1H), 2.78 (m, 1H), 2.04–1.55
(m, 7H), 1.25–1.04 (m, 4H), 0.88–0.78 (m, 4H); δC (75 MHz,
CDCl3) 169.0, 167.9, 135.8, 131.9, 126.0, 122.0, 119.9, 118.2,
111.2, 107.6, 57.3, 56.3, 51.5, 43.5, 30.1, 29.2, 27.3, 26.3, 26.0,
25.8, 22.1, 7.2, 6.3; νmax (neat)/cm−1 3307, 2911, 1667, 1412;
m/z (EI) 377 (M+); m/z (HRMS EI) Found: 377.2105. Calc. for
C23H27N3O2: 377.2103. [α]2D0 −52.92 (c 0.92, CH2Cl2).
trans-6-Benzo[1,3]dioxol-4-yl-2-methyl-2,3,6,7,12,
12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7n
δH (300 MHz, CDCl3) 8.40 (br s, 1H), 7.52 (d, J 7.2, 1H), 7.31–
7.17 (m, 3H), 6.95 (s, 1H), 6.77 (s, 1H), 6.66 (d, J 0.9, 2H), 5.89
(dd, J 13.8, 1.2, 2H), 4.33 (dd, J 13.8, 4.2, 1H), 4.11 (d, J 17.7,
1H), 3.95 (d, J 17.7, 1H), 3.52 (dd, J 15.6, 4.2, 1H), 2.97 (s, 3H),
2.94 (m, 1H); δC (75 MHz, CDCl3) 165.5, 161.6, 148.1, 148.0,
136.4, 132.1, 129.7, 126.2, 122.7, 122.5, 120.0, 118.4, 111.2,
109.1, 108.9, 108.3, 101.4, 52.4, 51.9, 51.5, 33.4, 27.6; νmax
(neat)/cm−1 3316, 2911, 1641, 1488; m/z (EI) 389 (M+); m/z
(HRMS EI) Found: 389.1373. Calc. for C22H19N3O4: 389.1376.
[α]2D0 −281.87 (c 1.21, CHCl3).
trans-2-Cyclopropyl-6-phenethyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7l
δH (300 MHz, CDCl3) 8.26 (br s, 1H), 7.43 (d, J 7.5, 1H), 7.28–
7.24 (m, 3H), 7.20–7.07 (m, 5H), 5.90 (t, J 7.5, 1H), 4.27 (dd, J
11.7, 4.2, 1H), 3.93 (d, J 17.7, 1H), 3.85 (d, J 17.7, 1H), 3.36 (dd,
J 15.5, 4.2, 1H), 2.91–2.65 (m, 4H), 2.21–2.13 (m, 2H), 0.95–
0.84 (m, 2H), 0.78 (m, 1H), 0.64 (m, 1H); δC (75 MHz, CDCl3)
167.3, 163.3, 140.9, 136.1, 132.6, 128.5, 128.1, 126.3, 126.3,
122.3, 119.9, 118.2, 111.1, 106.5, 53.7, 49.7, 49.6, 34.9, 32.6,
28.8, 27.4, 6.7, 6.0; νmax (neat)/cm−1 3288, 2920, 1659, 1646;
m/z (EI) 399 (M+); m/z (HRMS EI) Found: 399.1936. Calc. for
C25H25N3O2: 399.1947. [α]2D0 −112.15 (c 1.45, CH2Cl2).
cis-6-Benzo[1,3]dioxol-4-yl-2-methyl-2,3,6,7,12,
12a-hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7nꢀ
δH (300 MHz, CDCl3) 8.21 (br s, 1H), 7.60 (m, 1H), 7.25 (m,
1H), 7.23 (d, J 1.8, 1H), 7.20–7.12 (m, 2H), 6.81 (dd, J 7.8,
1.8, 1H), 6.66 (d, J 8.1, 1H), 6.12 (s, 1H), 5.82 (dd, J 6.2, 1.2,
2H), 4.28 (dd, J 11.5, 4.5, 1H), 4.08 (d, J 17.6, 1H), 3.95 (d,
J 17.6, 1H), 3.78 (dd, J 16.0, 4.5, 1H), 3.20 (dd, J 16.0, 11.5,
1H), 3.02 (s, 3H); δC (75 MHz, CDCl3) 166.9, 166.5, 147.8,
147.1, 136.6, 135.4, 132.9, 126.2, 122.5, 120.7, 120.1, 118.6,
111.3, 108.3, 107.5, 106.4, 101.2, 56.7, 56.2, 52.1, 33.7, 23.9;
νmax (neat)/cm−1 3326, 2921, 2848, 1651, 1483; m/z (EI) 389
(M+); m/z (HRMS EI) Found: 389.1367. Calc. for C22H19N3O4:
389.1376. [α]2D0 −99.41 (c 1.03, CHCl3).
cis-2-Cyclopropyl-6-phenethyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7lꢀ
δH (300 MHz, CDCl3) 8.50 (br s, 1H), 7.59 (d, J 7.2, 1H), 7.36 (d,
J 7.2, 1H), 7.23–7.14 (m, 5H), 7.11–7.05 (m, 2H), 5.47 (t, J 5.4,
1H), 3.99 (m, 1H), 3.97 (s, 2H), 3.62 (dd, J 15.8, 5.1, 1H), 3.03
(dd, J 15.8, 12.0, 1H), 2.73 (m, 1H), 2.59–2.46 (m, 2H), 2.28–
2.17 (m, 2H), 1.00–0.61 (m, 4H); δC (75 MHz, CDCl3) 168.6,
167.2, 140.9, 136.1, 133.0, 128.4, 128.2, 126.1, 126.0, 122.1,
119.9, 118.3, 107.2, 56.4, 52.5, 51.3, 37.5, 31.0, 29.1, 22.7, 7.4,
6.1; νmax (neat)/cm−1 3283, 2911, 1659, 1651; m/z (EI) 399
(M+); m/z (HRMS EI) Found: 399.1932. Calc. for C25H25N3O2:
399.1947. [α]2D0 −112.15 (c 1.45, CH2Cl2).
Accessory Publication
Supporting information containing the general methods, crystal
trans-2-Cyclopentyl-6-phenethyl-2,3,6,7,12,12a-
hexahydropyrazino[1ꢀ,2ꢀ:1,6]pyrido[3,4-b]
indole-1,4-dione 7m
1
data, and H and 13C NMR spectra of compounds 7a–n are
available from the journal’s website.
δH (300 MHz, CDCl3) 8.23 (br s, 1H), 7.44 (d, J 7.5, 1H), 7.29–
7.24 (m, 4H), 7.20–7.17 (m, 4H), 5.90 (t, J 7.0, 1H), 4.95 (m,
1H), 4.34 (dd, J 11.8, 4.2, 1H), 3.90 (s, 2H), 3.39 (dd, J 15.4, 4.2,
1H), 2.88–2.72 (m, 3H), 2.21–2.13 (m, 2H), 1.90–1.75 (m, 2H),
1.73–1.43 (m, 6H); δC (75 MHz, CDCl3) 165.5, 163.5, 140.8,
136.1, 132.6, 128.6, 128.2, 126.4, 126.3, 122.4, 119.9, 118.3,
111.1, 106.0, 54.2, 53.6, 49.6, 44.5, 35.1, 32.6, 27.9, 27.4, 24.2,
24.2;νmax (neat)/cm−1 3362, 1664, 1646;m/z(EI)427(M+);m/z
(HRMS EI) Found: 427.2263. Calc. for C27H29N3O2: 427.2260.
[α]2D0 −112.15 (c 3.47, CH2Cl2).
Acknowledgement
The authors thank the National Science Council of Taiwan for the financial
assistance and the authorities of the National Chiao Tung University for
providing the laboratory facilities. We are grateful to the National Center for
High-performance computing for computer time and facilities.
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