Enantioselective synthesis and antimicrobial activities of tetrahydro-β-carboline diketopiperazines

Article abstract of DOI:10.1002/chir.22193

A series of single isomers tetrahydro-β-carboline diketopiperazines were stereoselectively synthesized starting from l-tryptophan methyl ester hydrochloride and six aldehydes through a four-step reaction including Pictet-Spengler reaction, crystallization-induced asymmetric transformations (CIAT), Schotten-Baumann reaction, and intramolecular ester amidation. The chemical structures were characterized by nuclear magnetic resonance (NMR) and elemental analysis, among which two compounds were determined by x-ray single crystal diffraction. Moreover, antimicrobial activities of all the compounds were also tested. Chirality 25:656-662, 2013. 2013 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22193

CHIRALITY (2013)
Enantioselective Synthesis and Antimicrobial Activities of Tetrahydro-
Β-Carboline Diketopiperazines
1
1
1
YANGMIN MA, HAO WU, JIN ZHANG, AND YANCHAO LI2
*
1Key Laboratory of Auxiliary Chemistry and Technology for Chemical Industry, Ministry of Education, Shaanxi University of Science & Technology,
Xi’an, China
2Northwest Institute of Nonferrous Metals, Xi0an, China
ABSTRACT
A series of single isomers tetrahydro-b-carboline diketopiperazines were
stereoselectively synthesized starting from L-tryptophan methyl ester hydrochloride and six
aldehydes through a four-step reaction including Pictet-Spengler reaction, crystallization-
induced asymmetric transformations (CIAT), Schotten-Baumann reaction, and intramolecular
ester amidation. The chemical structures were characterized by nuclear magnetic resonance
(NMR) and elemental analysis, among which two compounds were determined by x-ray single
crystal diffraction. Moreover, antimicrobial activities of all the compounds were also tested.
Chirality 00:000–000, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: antimicrobial activity; configuration; crystallization-induced asymmetric transformations;
tetrahydro-b-carboline diketopiperazine; x-ray single crystal diffraction
INTRODUCTION
mixtures of tetrahydro-b-carboline (cis- and trans-) which are
difficult to separate25–28 and may accordingly make the reac-
tion hard to scale up. What’s more, crystallization-induced
asymmetric transformation (CIAT) has been reported in the
purification of chiral compounds29–31 in in recent years. The
combination of an asymmetric Pictet-Spengler reaction and
CIAT was a very important and useful tool for constructing
synthons containing tetrahydro-b-carbolines structural
moieties and able to obtain single enantiomers.32–37
A series of indole alkaloids have been used on the treat-
ment of many diseases such as cancer and AIDS.1
Diketopiperazines as the smallest cyclopeptides have two
hydrogen-bond donors and two receptors; the hydrogen bonds
are the main way for coactions with receptors.2 Tetrahydro-b-
carboline diketopiperazines, which block cell cycle progres-
sion, are attracting much attention as potential therapeutic
agents.3,4 Tetrahydro-b-carboline diketopiperazines are of wide
interest because they exhibit a wide range of biological activi-
ties.5–7 Verruculogen TR-2A and fumitremorgin C, for example,
are selective inhibitors of the breast cancer resistance protein
(BCRP/ABCG2).3,8,9 In addition, fumitremorgin C can also
induce sustained tremors in animals.10–16 We have found that
they have a tetrahydro-b-carboline diketopiperazines skeleton
by comparing the structures, as shown in Fig. 1.
Mostly, a series of tetrahydro-b-carboline diketopiperazines
were extracted as secondary metabolites of fungi.17 For
example, fumitremorgin C was isolated from metabolites of
Alternaria sp. FL25.4 Because of the unique structures and
important activities, a lot of natural tetrahydro-b-carboline
diketopiperazines have been prepared through total synthe-
sis. However, the traditional methods gave lower yield and
cis and trans diastereomeric mixtures. The tetrahydro-b-
carboline skeleton is the basic structure unit of tetrahydro-b-
carboline diketopiperazines. The first problem to be
addressed was the construction of the 1,3-disubstituted-
1,2,3,4-tetrahydro-b- carboline framework (shown in Fig. 2)
with establishment of the C-1 stereocenter. In 1997, Wang
and Ganesan and Hino18 and Nakagawa19 used a two-step
reaction to synthesize demethoxyfumitremorgin C. In 2001,
Bailey et al.20 reported a three-step method of total synthesis
of fumitremorgins with yields between 21% and 38% to get
diastereomeric mixtures. Both methods were of low yield.
One of the most straightforward ways for the construction
of the key skeleton was based on the Pictet-Spengler
reaction,21–24 of which the main advantage was the formation
of a product with a stable C–C bond in a single step. However,
almost all the approaches inevitably led to the diastereomeric
In this study,
a
series of tetrahydro-b-carboline
diketopiperazines were synthesized starting from L-tryptophan
methyl ester hydrochloride and a series of aldehydes. Instead
of the low-productive reaction by preparing Schiff base from
L–tryptophan methyl ester first and then ring-closing via
protonic acid,38 L-tryptophan methyl ester hydrochloride and
aldehydes were directly refluxed in isopropanol. The new
one-step reaction had much higher yields. In order to obtain
the single chiral isomers, CIAT was used after Pictet-Spengler
reaction with high enantiomeric excess (ee) values. We synthe-
sized six new tetrahydro–b–carboline diketopiperazines for the
first time, and two of them were confirmed by single-crystal
x-ray diffraction analysis. Moreover, the antibacterial and anti-
fungal activities of all six final compounds were also determined.
MATERIALS AND METHODS
L-Tryptophan, benzaldehyde, vanillin, 4-hydroxy- benzaldehyde, i-butyral-
dehyde, 4-nitrobenzaldehyde, anisaldehyde, and Fmoc-L-proline were
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Scientific Research Project Item for Key Laboratory
of Shaanxi Province Education Department, China; Contract grant number:
No. 2010JS056.
Contract grant sponsor: Xianyang City Science and Technology Project,
China; Contract grant number: No. 2010 K10-06.
*Correspondence to: Y. Ma, Key Laboratory of Auxiliary Chemistry and 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 21 April 2013; Accepted 07 May 2013
DOI: 10.1002/chir.22193
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2013 Wiley Periodicals, Inc.

MA ET AL.
(5:1, v/v) to give 3.55 g (yield 93%) of 1. White solid, mp.
217–218 ꢀC. 1H NMR (400 MHz, DMSO-d6) (ppm,
from TMS): 11.15 (s, 1H, NH on the indole ring), 8.65
(s, 3H, -NH+3), 7.51 (d, J = 7.96 Hz, 1H, 4-H), 7.38 (d, J = 8.04
Hz, 1H, 7-H), 7.26 (s, 1H, 2-H), 7.10 (m, 1H, 6-H), 7.01 (m,
1H, 5-H), 4.22 (t, J = 4.06 Hz, 1H, -CH2-CH-COOCH3), 3.65
(s, 3H, -COOCH3), 3.30 (m, 2H, -CH2-CHCOOCH3); 13C
NMR (100 MHz, DMSO-d6) (ppm, from TMS): 170.23,
136.67, 127.35, 122.45, 121.62, 119.07, 118.45, 112.03, 106.77,
53.10, 26.55. IR (KBr) n/cm-1: 3256, 2955, 1746, 1230. Anal.
Calcd. for C12H15N2O2Cl: C, 56.59; H, 6.00; N, 11.07. Found:
C, 56.58; H, 5.98; N, 11.10%.
Fmoc-L-prolyl chloride (Fmoc-L-Pro-Cl, 6). Fifty mL of CH2Cl2
in a dried 3-neck flask with a condenser added and a dry pipe
with anhydrous CaCl2 solid, an isobarical dropping funnel,
and a stirrer. Five mL SOCl2 was slowly dropped in the flask
at the rate of 10–15 drops per minute from the isobarical
dropping funnel. After that, the solvent was heated and
refluxed for about 4 h, tracked by TLC, and reduced pressure
distillation to obtain the orange liquid 6. 6 was dissolved in 50
mL CH2Cl2 and sealed to preserve.
Fig. 1. Skeleton of tetrahydro-¦Â-carboline diketopiperazines and
their analogues.
One of the six aldehydes (10 mmol) was added with 1 (2.62 g,
12 mmol) into isopropanol (50 mL). The reaction was refluxed
for 4 h and then the solvent was removed, washed with toluene,
and dried. This was pushed into a toluene-nitromethane
mixture, refluxed for 10–22 h, and then filtered with decom-
pression, washed by the mixed solvent, and dried, to afford
products 3a–3f. 3 was added into saturated sodium carbonate
aqueous solution (50 mL), stirred for full reaction, extracted by
ethyl acetate (30 mLꢁ 3), dried by anhydrous MgSO4, solvent
removed, and recrystallized from methanol to afford crystals
3a–3f. (The yields for reaction are shown in Table 1.)
Fig. 2. Basic skeleton of 1,3-disubstituted-1,2,3,4-tetrahydro-¦Â-carboline
framework.
purchased from Aladdin Chemical (Shanghai, China). Sodium carbonate,
anhydrous calcium chloride and anhydrous magnesium sulfate were
purchased from Tianjin Baishi Chemical Engineering(China). Morpholine,
dichlorosulfane, and all the solvents were purchased from Tianjin Hongyan
Chemical Reagents Factory (China). Silica gel for column chromatography
(200–300 mesh) was purchased from Tsingtao Haiyang Silica Gel Desiccant
Factory (China). The IR chromatography was recorded with a Bruker
VECTOR–22 FT-IR Spectrometer (Billerica, MA). The optical rotations
were measured through Wuhan Gelai WZZ-1S polarimeters. 1D and 2D
nuclear magnetic resonance (NMR) spectra were recorded on Bruker
AVANCE 400 MHz spectrometer with tetramethylsilane (TMS) as internal
standard. Deuterated chloroform and deuterated dimethylsulfoxide were
purchased from Beijing Boya Dabei Technological Development (China).
The elemental analysis was carried out with an Elemeraor Vario EL III
elemental analyzer. The x-ray single crystal diffraction analysis was carried
out with a Bruker BRUKERSMARTAPEXIICCD diffractometer; the data
were restored by TEXSAN program, analyzed on an Lx97 system. The bac-
teria E. coli, P. aeruginosa, S. aureus, B. subtilis, and fungi C. gloeosporioides,
V. mali, A. alternata, A. brassicae were provided from the College of Life
Science & Engineering, Shaanxi University of Science & Technology (Xi’an,
P.R. China). Both the antibacterial and antifungal activities were determined
by the minimum inhibitory concentration (MIC) method on 96-well cell
culture cluster, which was made by Costar (Cambridge, MA).
(1S,3S)-methyl 1-phenyl-2,3,4,9-tetrahydro-1H–pyrido [3,4–b]indole–
3–carboxylate (cis-3a). Yield 86.5%, white solid, mp. 223–224 ꢀC,
20
[a]D + 14.2ꢀ (c 1.5, CHCl3), 1H NMR (400 MHz, CDCl3)
(ppm, from TMS): 7.56–7.52 (m, 1H, Ar-H), 7.45 (s, 1H, NH
on the indole ring), 7.40–7.34 (m, 5H, Ar-H), 7.22–7.18 (m,
1H, Ar-H), 7.17–7.10 (m, 2H, Ar-H), 5.23 (s, 1H, 1-H), 3.98
(dd, J = 11.2, 4.2 Hz, 1H, 3-H), 3.81 (s, 3H, -COOCH3), 3.23
(m, 1H, 4-Hb), 3.05–2.97 (m, 1H, 4-Ha), 2.45 (br s, 1H, 2-H).
13C NMR (100 MHz, CDCl3) (ppm, from TMS): 173.23,
140.72, 136.14, 134.70, 129.01, 128.66, 127.11, 121.99, 119.66,
118.24, 110.96, 108.93, 58.71, 56.91, 52.32, 25.73. IR(KBr) n/cm-1:
3394, 3332, 2952, 2785, 1740, 1452, 1437, 1357, 1325, 1205,
746, 690. Anal. calcd. for C19H18N2O2: C, 74.56; H, 6.03; N,
9.15. Found: C, 74.49; H, 6.02; N, 9.15%.
EXPERIMENTAL
Preparation of Basic Materials
(1S,3S)-methyl 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9- tetrahydro-1
H-pyrido[3,4-b]indole-3-carboxylate (cis-3b). Yield 95.7%,
20
ꢀ
L-Tryptophan methyl ester hydrochlorid. Fifty mL of methanol
in a dried 3-neck flask with a condenser added and a dry pipe
with anhydrous CaCl2 solid, an isobarical ꢀdropping funnel,
and a stirrer. An ice bath no more than 5 C, 15 mL SOCl2
was slowly dropped in the flask at the rate of 10–15 drops per
minute from the isobarical dropping funnel. After droppimg, it
was stirred for 30 minutes and then withdrawn in an ice-bath
and heated to reflux. TLC (ethyl acetate as the developer)
should be used to track the reaction process. After that, the
solvent was cooled to room temperature, L-tryptophan added
(3.06 g, 15 mmol), and then refluxed for 4 h, tracked by TLC
(ethyl acetate as the developer), after the reaction, the solvents
were removed, recrystallized from methanol-ethyl ether
Chirality DOI 10.1002/chir
white solid, mp. 177–178 C, [a]D - 41.0ꢀ (c 1.0, CHCl3),
1H NMR (400 MHz, CDCl3) (ppm, from TMS): 7.58 (s, 1H,
20-H), 7.56 (s, 1H, NH on the indole ring), 7.28–7.22 (m, 1H,
Ar-H), 7.20–7.12 (m, 2H, Ar-H), 6.92–6.87 (m, 3H, Ar-H), 5.18
(s, 1H, 1-H), 3.99 (dd, J =11.1, 4.1 Hz, 1H, H-3), 3.84 (s, 3H,
-COOCH3), 3.80 (s, 3H, Ar-OCH3), 3.25 (dd, J =15.1, 2.5 Hz,
1H, 4-Hb), 3.08–2.97 (m, 1H, 4-Ha). 13C NMR (100 MHz,
CDCl3) (ppm, from TMS): 173.27, 147.07, 145.96, 136.09,
135.02, 132.52, 127.19, 121.91, 121.55, 119.62, 118.20,
114.31, 110.99, 110.64, 108.69, 58.69, 56.98, 56.02, 52.30,
25.63. IR(KBr) n/cm-1: 3405, 3263, 2931, 1741, 1518, 1449 ,
1269, 1223, 744. Anal. calcd. for C20H20N2O4: C, 68.17; H,
5.72; N, 7.95. Found: C, 68.43; H, 5.74; N, 7.94%.

SYNTHESIS AND BIOACTIVITIES OF TETRAHYDRO-Β-CARBOLINE DIKETOPIPERAZINES
TABLE 1. Preparation of single enantiomer tetrahydro-b-carboline diketopiperazines from L-tryptophan methyl ester hydrochloride
and aldehydes by a four-step synthesis
Step 2 (CIAT)
Step 1
time (h)
Solvent CH3NO2 /
Toluenea
Timeb
(h)
Configuration
(cis-/trans-)c
Yield
(%)
Step 3
time (h) time (min)
Step 4
Yieldd
(%)
Entry
R
ee (%)
5a
5b
5c
5d
5e
5f
Ph
4
4
4
4
4
4
1:10
1:1
2:3
1:1
2:3
4:5
22
10
10
20
20
12
cis-3a
98
98
99
98
99
99
86.5
95.7
97.2
94.6
93.5
87.4
3
3
3
3
3
3
30
30
30
30
30
30
92.1
97.7
96.5
95.6
91.4
93.8
3-OMe-4-OH-C6H3
4-OH-C6H4
i-Pr
4-NO2-C6H4
4-OCH3-C6H4
cis-3b
cis-3c
trans-3d
cis-3e
trans-3f
aVolume ratio.
bUnder reflux.
cDetermined by 1H-1H NOESY.
dTotal yield of Steps 3 and 4.
(1S,3S)-methyl 1-(4-hydroxyphenyl)-2,3,4,9-tetrahydro- 1H-pyrido
[3,4-b]indole-3-carboxylate (cis-3c). Yield 97.2%, white solid,
132.98, 129.62, 126.87, 124.16, 122.47, 119.98, 118.43, 111.06,
109.53, 58.07, 56.58, 52.46, 25.49. IR(KBr) n/cm-1: 3397,
3338, 2950, 2789, 1452, 1440, 1357, 650. Anal. calcd. for
C19H17N3O4: C, 64.95; H, 4.88; N, 11.96. Found: C, 64.86; H,
4.87; N, 12.00%.
mp. 227–228 ꢀC, [a]D - 33.2ꢀ (c 1.2, acetone), 1H NMR
20
(400 MHz, DMSO-d6) (ppm, from TMS): 10.31 (s, 1H, NH
on the indole ring), 9.42 (s, 1H, ArOH), 7.42 (d, J = 7.6 Hz,
1H, Ar-H), 7.21 (d, J = 7.9 Hz, 1H, Ar-H), 7.14 (d, J = 8.4 Hz,
2H, Ar-H), 6.97 (dt, J = 14.7, 7.1 Hz, 2H, Ar-H), 6.75
(d, J = 8.3 Hz, 2H, Ar-H), 5.11 (s, 1H, 1-H), 3.86 (dd, J = 11.0,
4.0 Hz, 1H, 3-H), 3.71 (s, 3H, -OCH3), 3.02 (dd, J = 14.6, 3.1
Hz, 1H, 4-Hb), 2.81 (t, J = 13.8 Hz, 1H, 4-Ha). 13C NMR (100
MHz, DMSO-d6) (ppm, from TMS): 173.45, 157.53, 136.74,
136.36, 132.70, 130.17, 127.03, 121.06, 118.80, 117.97, 115.51,
111.66, 107.20, 57.70, 56.74, 52.24, 25.93. IR(KBr) n/cm-1:
3365, 3300, 3269, 2981, 1730, 1615, 1522, 1458, 1437, 1325,
1278, 1219, 1178, 835, 752, 740. Anal. calcd. for C19H18N2O3:
C, 70.70; H, 5.62; N, 8.70. Found: C, 70.79; H, 5.63; N, 8.69%.
(1R,3S)-methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro- 1H-pyrido
[3,4-b]indole-3-carboxylate (trans-3f).. Yield 87.4%, white solid,
20
mp. 195–197 ꢀC, [a]D - 44.0ꢀ (c 2.5, CHCl3), 1H NMR
(400 MHz, CDCl3) (ppm, from TMS): 7.73 (br s, 1H, on the
indole ring NH), 7.54 (d, J = 6.96 Hz, 1H, Ar-H), 7.22–7.18
(m, 1H, Ar-H), 7.17–7.09 (m, 4H, Ar-H), 6.82 (d, J = 8.52 Hz.
2H, Ar-H), 5.30 (s, 1H, 1-H), 3.93 (t, J = 6.10 Hz, 1H, 3-H), 3.76
(s, 3H, -COOCH3), 3.69 (s, 3H, -ArOCH3), 3.24 (dd, J= 15.36 Hz,
5.24 Hz, 1H, 4-Ha), 3.09 (dd, J= 15.28 Hz, 6.88 Hz, 1H, 4-Hb),
2.46 (br s, 1H, 2-H) 13C NMR (100 MHz, CDCl3) (ppm, from
TMS): 174.22, 159.43, 136.13, 134.14, 133.63, 129.60, 127.02(2),
121.91, 119.49, 118.24, 114.05(2), 110.93, 108.34, 55.35, 54.31,
52.52, 52.16, 24.68. IR(KBr) n/cm-1: 3400, 3343, 2791, 1740,
1442, 1205, 710. Anal. calcd. for C20H20N2O3: C, 71.41; H, 5.99;
N, 8.33. Found: C, 71.35; H, 5.98; N, 8.35%.
(1R,3S)-methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]
indole-3-carboxylate (trans-3d). Yield 94.6%, white solid, mp.
146–147 ꢀC, [a]D + 53.4ꢀ (c 1.0, CHCl3), 1H NMR
20
(400 MHz, DMSO-d6) (ppm, from TMS): 10.65 (s, 1H, NH
on the indole ring), 7.38 (d, J = 7.7 Hz, 1H, Ar-H), 7.28
(d, J = 8.0 Hz, 1H, Ar-H), 7.01 (t, J = 7.3 Hz, 1H, Ar-H), 6.94
(t, J = 7.3 Hz, 1H, Ar-H), 4.12 (d, J = 2.7 Hz, 1H, 1-H), 3.97
(t, J = 5.0 Hz, 1H, 3-H), 3.59 (s, 3H, -OCH3), 2.91 (d, J = 4.8
Hz, 2H, 4-H), 2.70 (br s, 1H, 2-H), 2.33–2.11 (m, 1H, -CH
(CH3)2), 1.05 (d, J = 6.9 Hz, 3H, -CH-CH3), 0.73 (d, J = 6.7 Hz,
3H, -CH-CH3). 13C NMR (100 MHz, DMSO-d6) (ppm, from
TMS): 175.03, 136.40, 136.06, 127.13, 120.78, 118.62, 117.79,
111.30, 106.40, 54.48, 53.67, 51.99, 32.19, 24.76, 20.04, 17.24.
IR(KBr) n/cm-1: 3330, 2965, 2880, 1730, 1459, 1457, 1425,
1338, 1271, 1225, 1196, 1135, 1003, 836, 742, 630. Anal. calcd
for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.47;
H, 7.42; N, 10.32%.
Synthesis of Tetrahydro-b-carboline Diketopiperazines
(cis- or trans-5a–5f)
Compound 6 (1.01 g, 2.84 mmol) was dissolved in CH2Cl2, then
compound 3 added (2.4 mmol), which was also dissolved in CH2Cl2
under stirring. After that, it was put into saturated sodium carbonate
aqueous solution (50 mL) to make a biphasic system. It was stirred for
4 h and then stilled, separated from the CH2Cl2 phase, the water phase
extracted by CH2Cl2 (30 mLꢁ 3), the organic phases gathered and dried
by anhydrous magnesium sulfate, and the solvent removed to give 4. 4
was resolved in CH2Cl2, morpholine added (5 mL), and after stirring for
40 min at room temperature, the solvent removed to obtain the final
product. The product was purified by column chromatography with the
eluents of petroleum ether, ethyl acetate, and methanol to afford
compounds 5a–5f. (The yields for reaction were shown in Table 1.)
(1S,3S)-methyl 1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H- pyrido
[3,4-b]indole-3-carboxylate (cis-3e). Yield 93.5%, yellow solid,
(5aS,12S,14aS)-12-phenyl-1,2,3,5a,6,14a-hexahydropyrrolo
[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b]indole-5,14 (11H,12H)-
20
mp. 171–172 ꢀC, [a]D - 5.4ꢀ (c 2.5, CHCl3), 1H NMR
1
ꢀ
(400 MHz, CDCl3) (ppm, from TMS): 8.21 (d, J = 8.6 Hz, 2H,
Ar-H), 7.59 (d, J = 8.5 Hz, 2H, Ar-H), 7.56 (d, J = 7.2 Hz, 1H,
Ar-H), 7.46 (s, 1H, NH on the indole ring), 7.22 (t, J = 6.2 Hz,
1H, Ar-H), 7.19–7.11 (m, 2H, Ar-H), 5.38 (s, 1H, 1-H), 3.98
(dd, J = 11.1, 4.1 Hz, 1H, 3-H), 3.83 (s, 3H, -OCH3), 3.26 (dd,
J = 14.7, 3.1 Hz, 1H, 4-Hb), 3.03 (ddd, J = 15.12, 11.24, 2.16
Hz, 1H, 4-Ha), 2.60 (br s, 1H, 2-H). 13C NMR (100 MHz,
CDCl3) (ppm, from TMS): 172.92, 148.24, 148.05, 136.36,
dione (cis-5a). Yield 92.1%, white solid, mp. 329–330 C, H
NMR (400 MHz, DMSO-d6) (ppm, from TMS): 11.25 (s, 1H,
NH on the indole ring), 7.58 (d, J = 7.7 Hz, 1H, Ar-H), 7.35
(d, J = 8.0 Hz, 1H, Ar-H), 7.29 (m, 4H, Ar-H), 7.17 (t, J = 7.0
Hz, 1H, Ar-H), 7.08 (t, J = 7.4 Hz, 1H, Ar-H), 7.02 (t, J = 7.4
Hz, 1H, Ar-H), 6.36 (s, 1H, 12-H), 4.56 (dd, J = 11.5, 5.0 Hz,
1H, 5a-H), 4.36 (t, J = 7.8 Hz, 1H, 14a-H), 3.59–3.48 (m, 2H,
3-H), 3.46 (d, J = 5.4 Hz, 1H, 6-Hb), 3.03 (dd, J =15.7,
Chirality DOI 10.1002/chir

MA ET AL.
11.8 Hz, 1H ,6-Ha), 2.26–2.14 (m, 1H, 1-H), 2.00–1.90 (m, 1H,
26.73, 21.84, 20.14, 20.07. Anal. calcd. for C20H23N3O2: C,
71.19; H, 6.87; N, 12.45. Found: C, 71.28; H, 6.85; N, 12.11%.
1-H), 1.90–1.79 (m, 2H, 2-H). 13C NMR (100 MHz, DMSO-d6)
(ppm, from TMS): 170.40, 165.86, 143.25, 136.52, 134.51,
128.94, 127.41, 126.22, 126.19, 121.72, 119.40, 118.62,
111.85, 104.96, 58.88, 56.74, 55.46, 45.35, 28.50, 23.11,
22.04. IR(KBr) n/cm-1: 3285, 1663,1456, 1396. Anal. calcd.
for C23H21N3O2: C, 74.37; H, 5.70; N, 11.31. Found: C,
74.44; H, 5.69; N, 11.28%.
(5aS,12S,14aS)-12-(4-nitrophenyl)-1,2,3,5a,6,14a-hexa-hydro-
pyrrolo[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b]
indole-5,14
(11H,12H)-dione (cis-5e). Yield 91.4%, yellow solid, mp.
262–264 ꢀC, 1H NMR (400 MHz, DMSO-d6) (ppm, from
TMS): 11.21 (s, 1H, NH on the indole ring), 8.14 (d, J = 8.7
Hz, 2H, Ar-H), 7.59 (d, J = 8.8 Hz, 3H, Ar-H), 7.33 (d, J = 8.0
Hz, 1H, Ar-H), 7.08 (t, J = 7.3 Hz, 1H, Ar-H), 7.01 (t, J = 7.3
Hz, 1H, Ar-H), 6.35 (s, 1H, 12-H), 4.58 (dd, J = 11.5, 4.7 Hz,
1H, 5a-H), 4.37 (t, J = 7.3 Hz, 1H, 14a-H), 3.60–3.44 (m, 3H,
6-Hb, 3-H), 3.05 (dd, J = 15.9, 11.7 Hz, 1H, 6-Ha), 2.25–2.14
(m, 1H, 1-H), 1.94–1.82 (m, 3H, 1-H, 2-H). 13C NMR
(100 MHz, DMSO-d6) (ppm, from TMS): 170.73, 165.40,
150.82, 146.88, 136.79, 132.98, 127.64, 126.13, 124.31,
122.05, 119.52, 118.81, 111.92, 105.65, 58.76, 56.80, 55.82,
45.40, 28.56, 22.90, 22.48. Anal. calcd. for C23H20N4O4: C,
66.34; H, 4.84; N, 13.45. Found: C, 66.42; H, 4.85; N, 13.40%.
(5aS,12S,14aS)-12-(4-hydroxy-3-methoxyphenyl)-1,2,3,5a,6,14a-
hexahydropyrrolo[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b]
indole-5,14 (11H,12H)-dione (cis-5b). Yield 97.7%, white solid,
mp. 254–255 ꢀC, 1H NMR (400 MHz, DMSO-d6) (ppm,
from TMS): 11.22 (s, 1H, NH on the indole ring), 8.90 (s, 1H,
Ar-OH), 7.55 (d, J = 7.8 Hz, 1H, Ar-H), 7.33 (d, J = 8.0 Hz,
1H, Ar-H), 7.06 (t, J = 7.5 Hz, 1H, Ar-H), 7.00 (t, J = 7.4 Hz,
1H, Ar-H), 6.89 (s, 1H, Ar-H), 6.62 (d, J = 8.2 Hz, 1H, Ar-H),
6.55 (d, J = 8.1 Hz, 1H, Ar-H), 6.29 (s, 1H, 12-H), 4.52 (dd,
J = 11.6, 5.3 Hz, 1H, 5a-H), 4.36 (t, J = 7.9 Hz, 1H, 14a-H), 3.70
(s, 3H, Ar-OCH3), 3.55-3.44 (m, 2H, 3-H), 3.41 (dd, J = 15.8,
5.4 Hz, 1H, 6-Hb), 2.97 (dd, J = 15.6, 11.8 Hz, 1H, 6-Ha), 2.21
(td, J = 12.0, 5.2 Hz, 1H, 1-H), 1.97 (dt, J = 11.7, 8.7 Hz, 1H, 1-H),
1.87 (dd, J = 12.5, 6.1 Hz, 2H, 2-H). 13C NMR (100 MHz,
DMSO-d6) (ppm, from TMS): 170.20, 166.13, 147.73, 145.95,
136.33, 134.93, 134.01, 126.18, 121.56, 119.32, 118.54, 117.93,
115.77, 111.82, 110.79, 104.61, 58.93, 56.60, 55.95, 54.56, 45.37,
28.33, 23.27, 21.68. Anal. calcd. for C24H23N3O4: C, 69.05; H,
5.55; N, 10.07. Found: C, 69.10; H, 5.54; N, 10.04%.
(5aS,12R,14aS)-12-(4-methoxyphenyl)-1,2,3,5a,6,14a-
hexahydropyrrolo[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b]
indole-5,14(11H,12H)-dione (trans-5f). Yield 93.8%, white
solid, mp. 262–264 ꢀC, 1H NMR (400 MHz, DMSO-d6)
(ppm, from TMS): 10.96 (s, 1H, NH on the indole ring),
7.52 (d, J =7.7 Hz, 1H, Ar-H), 7.30 (d, J =8.0 Hz, 1H, Ar-H), 7.19
(d, J = 8.6 Hz, 2H, Ar-H), 7.09 (t, J = 7.5 Hz, 1H, Ar-H), 7.02
(t, J = 7.4 Hz, 1H, Ar-H), 6.90 (d, J = 8.6 Hz, 2H, Ar-H), 6.85
(s, 1H, 12-H), 4.35 (dd, J = 10.6, 4.5 Hz, 1H, 5a-H), 4.15
(dd, J = 8.5, 6.6 Hz, 1H, 14a-H), 3.72 (s, 3H, Ar-OCH3), 3.67
(dd, J= 13.6, 6.2 Hz, 1H, 3-H), 3.45 (dd, J= 15.8, 4.8 Hz, 1H, 2-H),
3.32–3.22 (m, 1H, 3-H), 2.89 (dd, J= 15.6, 10.9 Hz, 1H, 2-H), 2.24
(dd, J= 9.4, 6.1 Hz, 1H, 1-H), 1.89 (dd, J= 11.1, 7.4 Hz, 1H, 1-H),
1.85–1.72 (m, 2H, 6-H). 13C NMR (100 MHz, DMSO-d6)
(ppm, from TMS): 165.30, 164.00, 159.53, 136.87, 132.38,
131.38, 129.76, 126.33, 121.95, 119.25, 118.52, 114.32, 111.71,
107.11, 59.10, 55.60, 53.25, 51.62, 45.04, 29.77, 27.68, 21.53.
Anal. calcd. for C24H23N3O3: C, 71.80; H, 5.77; N, 10.47.
Found: C, 71.85; H, 5.76; N, 10.45%.
(5aS,12S,14aS)-12-(4-hydroxyphenyl)-1,2,3,5a,6,14a-hexa-
hydropyrrolo[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b] indole-5,14
(11H,12H)-dione (cis-5c). Yield 96.5%, white solid, mp.
278–279 ꢀC, 1H NMR (400 MHz, DMSO-d6) (ppm, from
TMS): 11.13 (s, 1H, NH on the indole ring), 9.30 (s, 1H,
Ar-OH), 7.56 (d, J = 7.7 Hz, 1H, Ar-H), 7.31 (d, J = 8.0 Hz,
1H, Ar-H), 7.08–6.97 (m, 4H, Ar-H), 6.62 (d, J = 8.5 Hz, 2H,
Ar-H), 6.25 (s, 1H, 12-H), 4.50 (dd, J = 11.6, 5.3 Hz, 1H, 5a-H),
4.33 (t, J = 7.8 Hz, 1H, 14a-H), 3.54–3.44 (m, 2H, 3-H), 3.41
(dd, J = 16.0, 5.3 Hz, 1H, 6-Hb), 2.97 (dd, J = 15.6, J = 11.8 Hz,
1H, 6-Ha), 2.25–2.16 (m, 1H, 1-H), 1.95 (dd, J = 17.3, 9.1Hz,
1H, 1-H), 1.86 (dt, J = 15.1, 7.6 Hz, 2H, 2-H). 13C NMR
(100 MHz, DMSO-d6) (ppm, from TMS): 170.33, 165.95,
156.81, 136.43, 135.14, 133.39, 127.73, 126.23, 121.56,
119.30, 118.53, 115.48, 111.79, 104.77, 58.91, 56.75,
54.70, 45.29, 28.41, 23.15, 21.88. Anal. calcd. for
C23H21N3O3: C, 71.30; H, 5.46; N, 10.85. Found: C, 71.39;
H, 5.43; N, 10.82%.
Biological Assay
Both antibacterial and antifungal activities were assayed by the
minimum inhibitory concentrations (MICs) method. Each compound
was set at 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, and 0.39 mg/mL by the
continuous dilution method44 while the tested strains were incubated in
the liquid mediums at the set temperatures. For bacteria, the beef extract
peptone medium was made up of beef extract 3.0 g/L, peptone 10 g/L,
NaCl 5 g/L, pH 7.2–7.4. The culture temperature was 37 ꢀC. For fungi,
the potato-glucose medium was made up of percolate of 200 g potato
under boiling for 30 min, glucose 20 g, constant volume to be 1 L by
water. The culture temperature was 28 ꢀC. The positive control of
Gram-positive bacteria (S. aureus and B. subtilis) was penicillin sodium,
while Gram-negative bacteria (E. coli and P. aeruginosa) streptomycin sul-
fate, and fungi ketoconazole. The minimum inhibitory concentrations
were defined as the lowest concentration at which no microbial growth
could be observed.
(5aS,12R,14aS)-12-isopropyl-1,2,3,5a,6,14a-hexahydro-pyrrolo
[1’’,2’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4-b]indole-5,14(11H,12H)-
dione (tras-5d). Yield 95.6%, white solid, mp. 254–255 ꢀC, 1H
NMR (400 MHz, DMSO-d6) (ppm, from TMS): 10.93 (s, 1H,
NH on the indole ring), 7.43 (d, J = 7.8 Hz, 1H, Ar-H), 7.34
(d, J = 8.0 Hz, 1H, Ar-H), 7.07 (t, J = 7.3 Hz, 1H, Ar-H), 6.98
(t, J = 7.3 Hz, 1H, Ar-H), 5.45 (d, J = 8.0 Hz, 1H, 12-H), 4.59
(dd, J = 8.7, 6.2 Hz, 1H, 5a-H), 4.37–4.30 (m, 1H, 14a-H),
3.65 (dt, J = 11.5, 7.8 Hz, 1H, 3-H), 3.33–3.23 (m, 2H, 3-H,
6-Ha), 2.97 (dd, J = 15.7, 9.2 Hz, 1H, 6-Hb), 2.25–2.14 (m,
2H, 1-H, -CH(CH3)2), 1.93–1.74 (m, 3H, 1-H, 2-H), 1.03 (d,
J = 6.7 Hz, 3H, -CH-CH3), 0.94 (d, J = 6.8 Hz, 3H, -CH-CH3).
13C NMR (100 MHz, DMSO-d6) (ppm, from TMS): 165.96,
164.80, 136.37, 133.24, 126.44, 121.57, 119.14, 118.19,
111.62, 105.91, 58.77, 54.35, 54.17, 45.17, 33.53, 29.46,
RESULTS AND DISCUSSION
Synthesis and Characterization
The four-step synthetic route for tetrahydro-b-carboline
diketopiperazines 5 including Pictet-Spengler, CIAT, Schotten-
Baumann reactions, and intramolecular ester amidation,
starting with L-tryptophan methyl ester hydrochloride and
aldehydes, as shown in Scheme 1.
Chirality DOI 10.1002/chir

SYNTHESIS AND BIOACTIVITIES OF TETRAHYDRO-Β-CARBOLINE DIKETOPIPERAZINES
the proton at C-1 position in the 1H-1H NOESY (nuclear
Overhauser enhancement spectroscopy) spectra of the
cis-isomers, while the proton at C-3 position correlates with
the neighboring protons but does not correlate with the
proton at C-1 position in the trans-isomers. The NMR signals
of protons for C-1 and C-3 were assigned by 1H-1H COSY and
HSQC experiments.
According to Table 1, there were four cis- and two
trans-compounds (3a ~ 3f) after CIAT. The product,
whether cis- or trans-, depended on the solubility between the
two configurations in the nitromethane-toluene solvent. The
precipitation of the isomer with lower solubility destroyed
the balance between the cis- and trans-isomers, leading to the
higher solubility of one transfer into the other. In the end, a
single one was acquired as a solid, but the specific of the isomer
was uncertain.
Single-crystal structures of compounds 5c and 5e were
obtained by recrystallizing from methanol, and the further
structural information of 5c and 5e was confirmed by
single-crystal x-ray diffraction analysis (Fig. 3). The structures
were solved by direct methods and refined by full-matrix least
squares analysis on F2 using SHELXL.39–43 Hydrogen atoms
were refined on the riding model with isotropic thermal param-
eters set 20% greater than those of their bonding partners. All
other atoms were refined anisotropically.
Antimicrobial Activities
The in vitro antimicrobial activities were tested against two
Gram-positive (G+) bacteria (Staphylococcus aureus, Bacillus
subtilis), two Gram-negative (G-) bacteria (Escherichia coli,
Pseudomonas aeruginosa), and four plant pathogenic fungi
(Colletotirchum gloeosporioides, Valsa mali, Alternaria alternata,
Alternaria brassicae). The activities were determined at differ-
ent concentrations of the compounds 5a–5f (0.39–50 mg/mL)
in DMSO and the results were compared with lower concentra-
tions of known antibiotics including penicillin sodium against
G+ bacteria, streptomycin sulfate against G- bacteria, and
ketoconazole against fungi. The microdilution method for
estimation of minimum inhibitory concentration (MIC) values
was carried out to evaluate the antimicrobial activity. The
MIC values were determined on 96-well microdilution plates.
The screening data of the antifungal activity of these series
of compounds showed a wide range of antifungal activity
with MIC values 6.25–12.5 mg/mL (ketoconazole showed
MIC 12.5 mg/mL). It is interesting that 5b and 5c exhibited
the most potent in vitro antifungal activity with MIC
6.25 mg/mL against A. brassicae, while 5e and 5f exhibited
the same MIC value against C. gloeosporioides (6.25 mg/mL).
Scheme 1. Synthesis of tetrahydro-¦Â-carboline diketopiperazines.
In this work, we have reported a concise and efficient
synthetic route to generate a series of single enantiomers.
Six tetrahydro-b-carboline diketopiperazines (5a–5f) were
synthesized in this way for the first time. Starting from
optically pure L-tryptophan methyl ester hydrochloride with
various aldehydes in isopropanol, a mixture of the hydrochlo-
ride salts of cis- and trans-tetrahydro-b-carbolines were
obtained, and then a process of CIAT was performed in a
mixed solvent with different ratios of nitromethane and
1
toluene (Table 1). After dehydrochlorination, the H NMR
analysis showed the rings were formed (a single-peak with
C-1 proton at between d 5.11–5.38 ppm except 3d showed a
double-peak at d 4.12 ppm). The assignment of cis-/trans-
stereochemistry in these tetrahydro-b-carbolines relied on
the NMR methods established by Cook and colleagues.38
The proton at C-3 position has an obvious correlation with
Fig. 3. ORTEP Drawing of Compounds 5c and 5e.
Chirality DOI 10.1002/chir

MA ET AL.
TABLE 2. Results of antibacterial and antifungal test of compounds 5a-5f
MIC (mg/mL)
Compound
S. aureus
B. subtilis
P. aeruginosa
E. coli
C. gloeosporioides
V. mali
A. alternata
A. brassicae
5a
0.78
0.78
0.78
0.39
0.78
0.78
0.78
—
1.56
1.56
1.56
1.56
1.56
1.56
1.56
—
1.56
1.56
1.56
1.56
1.56
1.56
—
0.78
0.78
0.78
0.78
0.78
0.78
—
12.5
12.5
12.5
12.5
6.25
6.25
—
12.5
6.25
12.5
12.5
12.5
12.5
—
12.5
12.5
12.5
12.5
12.5
6.25
—
12.5
6.25
6.25
12.5
12.5
12.5
—
5b
5c
5d
5e
5f
Penicillin sodium
Streptomycin sulfate
Ketoconazole
1.56
—
0.78
—
—
12.5
—
12.5
—
12.5
—
12.5
—
—
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Six novel tetrahydro-b-carboline diketopiperazines were
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Their antibacterial and antifungal activities were tested. Par-
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pounds were similar or a little better than the traditional
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antibacterial activities. In a further study the present route
will be employed to synthesize the derivatives of tetrahydro-
b-carboline diketopiperazines.
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ACKNOWLEDGMENTS
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