Synthesis and biological evaluation of new tetrahydro-β-carbolines as inhibitors of the mitotic kinesin Eg5

Article abstract of DOI:10.1016/j.bmc.2005.06.027

The mitotic kinesin Eg5 (or KSP) is a crucial player in the development and function of the mitotic spindle. Inhibition of this protein leads to cell cycle arrest and apoptosis without interfering with other microtubule-dependent processes. Therefore, it

Full text of DOI:10.1016/j.bmc.2005.06.027

Bioorganic & Medicinal Chemistry 13 (2005) 6094–6111
Synthesis and biological evaluation of new
tetrahydro-b-carbolines as inhibitors of the mitotic kinesin Eg5
Nils Sunder-Plassmann,a Vasiliki Sarli,a Michael Gartner,a Mathias Utz,b Jeanette Seiler,b
Stefan Huemmer,c Thomas U. Mayer,c Thomas Surreyb and Athanassios Giannisa,*
aUniversity of Leipzig, Institute for Organic Chemistry, Johannisallee 29, 04103 Leipzig, Germany
bEuropean Molecular Biology Laboratory, Cell Biology and Biophysics Programme, Meyerhofstrasse 1, 69117 Heidelberg, Germany
cMax Planck Institute for Biochemistry, Chemical Genetics, Independent Research Group,
Am Klopferspitz 18, 82152 Martinsried/Munich, Germany
Received 20 April 2005; revised 5 June 2005; accepted 10 June 2005
Available online 3 August 2005
Abstract—The mitotic kinesin Eg5 (or KSP) is a crucial player in the development and function of the mitotic spindle. Inhibition of
this protein leads to cell cycle arrest and apoptosis without interfering with other microtubule-dependent processes. Therefore, it is a
potential target in cancer therapy. Here, we report the synthesis and biological evaluation of a small library of molecules based on
the structure of the known Eg5 inhibitor HR22C16. One of these derivatives (compound trans-24) proved to be a potent and specific
Eg5 inhibitor.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The mitotic kinesin Eg5 (or KSP), a member of the kine-
sin-5 family, plays an important role in the early stages
of mitosis. It mediates centrosome separation and for-
mation of the bipolar mitotic spindle.9 It cross-links
and slides microtubules in relation to one another using
energy from ATP-hydrolysis.10 Inhibition of Eg5 leads
to cell cycle arrest during mitosis and cells with a mono-
polar spindle, so called monoasters.11 In 1999, Monas-
trol, the first small-molecule inhibitor of Eg5, was
discovered in a phenotype assay.12 Since then, more
KSP-inhibitors have been found.13–15,22
In the industrialized countries, cancer is one of the lead-
ing causes of death, claiming more than 2.5 million
victims every year. Among the various successful
approaches to treat cancer are drugs that perturb mitosis
like vinca alkaloids, taxol, and epothilone. One of their
major drawbacks is the fact that they all target the same
protein, tubulin, the subunit of microtubules that are
essential for the formation of the mitotic spindle.1,2 As
microtubules are also involved in many other cellular
processes such as maintenance of organelles, cell shape,
cell motility, synaptic vesicles, and intracellular transport
phenomena,3–5 interference with their formation or
depolymerization often leads to dose-limiting toxic side
effects like neurotoxicity, hair loss, and body weight loss.
Subsequently, after screening a compound library of
16,000 small molecules, the carboline derivative
HR22C16 was also identified as an Eg5 inhibitor
(Scheme 1).16 Recently, it was proven that HR22C16
induces mitotic arrest and cell death in taxol-resistant
cancer cells.17 This shows that Eg5 inhibitors can be
potentially used to overcome taxol-resistance in cancer
treatment. However, a systematic investigation of the
importance of the stereochemistry and the substituents
as indicated in Scheme 2 had not been performed.
The discovery of a new class of proteins, the mitotic kine-
sins, allows a novel approach to cancer treatment.6 These
proteins are exclusively involved in the formation and
function of the mitotic spindle and some of them are only
expressed in proliferating cells.7,8 Their inhibition leads
to cell cycle arrest and ultimately to apoptosis without
interfering with other microtubule-dependent processes.6
Here we describe the synthesis of a library of 60 small
molecules based on the HR22C16-structure, in order
to address the above-mentioned problem.
Keywords: Carbolines; Kinesins; KSP; Pictet–Spengler reaction.
*
Corresponding author. E-mail: giannis@chemie.uni-leipzig.de
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.06.027

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6095
cases, however, a mixture of cis- and trans-product was
formed which could easily be separated by column chro-
matography. In cases where there was no or little trans-
product, the cis-form could be obtained by simply
refluxing in acetonitrile with a small excess of potassium
carbonate. The reactions with isothiocyanates exclusive-
ly yielded the trans-adduct.
Scheme 1. The Eg5 inhibitors Monastrol and HR22C16 1.
The yields of the first two steps varied from 22 to 84%
and 8 to 100%, respectively, depending on the substitu-
ents R1, R2, and R3. To synthesize compounds 31 and
32, we first transformed L-leucine methylester into the
corresponding isocyanate 37 (Scheme 4).21 Schemes 5a
and b show the complete library.
All synthesized tetrahydro-b-carbolines were tested for
their activity against Eg5. To identify potential hits,
we first screened the library with a pyruvate kinase/lac-
tate dehydrogenase assay.22 A list of the compounds
with a relative inhibition of at least 50% at a concentra-
tion of 46 lM is shown in Figure 1. Monastrol, the first
known Eg5 inhibitor, is shown for comparison.
Scheme 2. Basic scaffold of the tetrahydro-b-carboline library.
Furthermore, we tested all compounds with the mala-
chite green assay23 for inhibition of nine different kine-
sins. Apart from Eg5, these were MKLP1, MKLP2,
MPP1, KIF4, KIF5A, KIF5B, CenpE, and MCAK.
All these kinesins were not or only weakly inhibited at
the above-mentioned concentrations. Therefore, the
synthesized tetrahydro-b-carbolines show specificity
against Eg5.
2. Results and discussion
Various ways to synthesize chiral tetrahydro-b-carbo-
lines have been published in recent years. Interesting
examples are the asymmetric Pictet–Spengler reaction18
or the usage of a chiral ruthenium complex.19 To obtain
chiral 3-substituted tetrahydro-b-carbolines we decided
to exploit the chiral pool, and used the cheap and com-
mercially available amino acid tryptophan as a starting
material.20 Depending on the desired stereochemistry
of the final product, we either used the D- or the L-form.
For the initial step, we added two equivalents of an alde-
hyde to a suspension of tryptophan in diluted sulfuric
acid (0.1 N). After refluxing for 4–5 h, the product 2
was filtered off. It was then transformed into the tetrahy-
dro-b-carbolines 3–36 by the reaction with an isocyanate
or an isothiocyanate (Scheme 3). In most cases, especial-
ly when R1 = OH, R2 = H and reaction times were short
(<4 h), the resulting product was cis-configured. In some
We found that the potent inhibitors possess certain
structural features. In most cases, the trans-isomers were
more active than the cis-isomers, with the absolute ste-
reochemistry at carbon C11a being S-configured. The
activity was also very much dependent on the substitu-
ents R1 and R2. Nearly all substitution patterns other
than R1 = OH and R2 = H lead to inactive molecules.
Thus, the meta-hydroxy function seems to be important.
However, a variety of substituents are possible for R3.
Linear alkyl chains with two to five carbon atoms
(and R1 = OH, R2 = H) all lead to comparably active
inhibitors. Benzyl-, phenyl- and o-trifluoromethoxy-
phenyl substituents also gave strong inhibitors when
C11a was S-configured. The substitution of the oxygen
at C3 with a sulfur atom did not result in an increase
in activity.
We then chose nine inhibitors to determine their IC50
values. To obtain quantitative results concerning the ef-
fect of the stereochemical configuration we included one
complete set of four diastereomers of HR22C16 (com-
pounds 9 and 10). Seven compounds were examined
with the malachite green assay,23 one with the Enz-
Checkꢁ (Molecular Probes) Phosphate Assay and one
with both tests.
The determined IC50 values are shown in Table 1. The
most potent diastereomers of HR22C16 is compound
trans-10. However trans-9 and cis-10 display significant
inhibitory activity against Eg5 whereas derivative cis-9
is almost inactive. Furthermore, derivative trans-24 with
Scheme 3. Synthesis of the tetrahydro-b-carbolines.

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Scheme 4. Synthesis of the leucine derivatives with cis-25 as example.
a N-benzyl side chain is the most active inhibitor with an
IC50 value of 0.65 0.30 lM. The other three stereoiso-
mers of trans-24 were inactive (IC50 > 45 lM). Finally,
we examined the effect of trans-24 on HeLa cells. We
examined the morphology of the cells treated with
trans-24 by immunofluorescence with an anti-tubulin
antibody (tubulin, green fluorescence) and Hoechst
33258 (DNA, blue fluorescence).22 Figure 2 shows the
normal spindle of an untreated HeLa cell and a cell
treated with trans-24. As expected a monoastral pheno-
type is induced.
in open capillaries using a Buchi Melting Point B-540
¨
1
apparatus and are uncorrected. H and 13C NMR spec-
tra were recorded on Varian VXR-200, Varian VXR-
300, and Bruker DRX-600 NMR spectrometers at room
temperature. The solvents stated were used as internal
standards. High-resolution (HR) mass spectra were ob-
tained with a 7 T APEX II mass spectrometer. Yields
are not optimized.
4.2. General procedure for the Pictet–Spengler reaction
To a suspension of L- or D-tryptophan (3 g, 14.3 mmol)
in sulfuric acid (0.1 N, 44 ml), the desired aldehyde
(2 equiv, 28.6 mmol) was added. After heating to reflux
for 4–5 h, the solid phase was filtered off, thoroughly
rinsed with diethylether, and dried in vacuo.
3. Conclusion
We synthesized a small library of 60 compounds based
on the known Eg5 inhibitor HR22C16. We identified
certain structural features that characterize the most po-
tent inhibitors of this class of molecules. All compounds
were screened for inhibition of Eg5 and eight other kine-
sins. Twenty two showed more than 50% inhibition of
Eg5 at 46 lM, 15 were more active than the first Eg5
inhibitor Monastrol. The other kinesins were not
significantly inhibited. For nine of the Eg5 inhibitors,
the IC50 values were determined. In most cases, the
trans-isomers were more active than the cis-isomers,
with the absolute stereochemistry at carbon C11a
being S-configured. The activity was also very much
dependent on the substituents R1 and R2. The meta-
hydroxyphenyl group seems to be important for activity.
4.2.1. (1S,3S)-1-Phenyl-2,3,4,9-tetrahydro-1H-b-carbo-
line-3-carboxylic acid (2a). Yield: 80%, brown solid.
1H NMR (300 MHz, DMSO-d6): d = 2.95 (m, 1H,
CHaHb), 3.18 (m, 1H, CHaHb), 3.86 (m, 1H,
CHCOOH), 5.46 (s, 1H, CHPh), 6.99–7.51 (m, 9H,
ar), 10.50 (s, 1H, CNHC).
13C NMR (75 MHz, DMSO-d6): d = 24.20 (s), 57.21 (t),
57.70 (t), 108.04 (q), 111.30 (t), 117.94 (t), 118.73 (t),
121.22 (t), 126.29 (q), 128.43 (2· t), 129.13 (t), 129.60
(2· t), 132.55 (q), 136.69 (q), 138.61 (q), 172.03 (q).
HRMS (ESI, 70 eV): C18H16N2O2: calcd: 293.1285;
found: 293.1283.
Compound trans-24 proved to be the most active inhib-
itor of Eg5-ATPase activity with an IC50 of 0.65 lM.
This novel inhibitor has the potential for being a potent
anti-cancer drug candidate.
4.2.2. (1R,3R)-1-Phenyl-2,3,4,9-tetrahydro-1H-b-carbo-
line-3-carboxylic acid (2b). Yield: 66%, brown solid.
4. Experimental
4.1. Chemistry
1H NMR (300 MHz, DMSO-d6): d = 2.95 (m, 1H,
CHaHb), 3.18 (m, 1H, CHaHb), 3.86 (m, 1H,
CHCOOH), 5.46 (s, 1H, CHPh), 6.99–7.51 (m, 9H,
ar), 10.50 (s, 1H, CNHC).
All reactions were performed with commercially avail-
able reagents and they were used without further purifi-
cation. Solvents were dried by standard methods and
stored over molecular sieves. All reactions were moni-
tored by thin-layer chromatography (TLC) carried out
on Merck silica gel 60 F254 aluminum sheets and viewed
with UV light. Flash-chromatography was performed
on Merck silica gel 60. Melting points were determined
13C NMR (75 MHz, DMSO-d6): d = 24.29 (s), 57.11 (t),
57.65 (t), 108.13 (q), 111.28 (t), 118.01 (t), 118.68 (t),
121.18 (t), 126.31 (q), 128.44 (2· t), 129.20 (t), 129.54
(2· t), 132.48 (q), 136.67 (q), 138.56 (q), 171.99 (q).
HRMS (ESI, pos.): C18H16N2O2: calcd: 293.1285;
found: 293.1283.

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6097
(a)
Scheme 5. (a): Tetrahydro-b-carboline library (1) (b): Tetrahydro-b-carboline library (2).
4.2.3. (1S,3S)-1-(3-Hydroxyphenyl)-2,3,4,9-tetrahydro-
1H-b-carboline-3-carboxylic acid (2c). Yield: 84%,
brown solid.
CHCOOH), 5.39 (s, 1H, CHPh), 6.81–7.50 (m, 8H,
ar), 10.51 (s, 1H, CNHC).
13C NMR (75 MHz, DMSO-d6): d = 24.03 (s), 57.37 (t),
57.66 (t), 108.02 (q), 111.51 (t), 115.90 (t), 116.51 (t),
117.98 (t), 118.77 (t), 120.16 (t), 121.28 (t), 126.26 (t),
1H NMR (300 MHz, DMSO-d6): d = 2.92 (m, 1H,
CHaHb), 3.21 (m, 1H, CHaHb), 3.82 (m, 1H,

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N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
(b)
Scheme 5. (continued)
Figure 1. Eg5 inhibitors and their relative inhibition of Eg5-ATPase activity.
129.44 (q), 132.25 (q), 136.72 (q), 139.37 (q), 157.65 (q),
171.81 (q).
4.2.4. (1R,3R)-1-(3-Hydroxyphenyl)-2,3,4,9-tetrahydro-1H-
b-carboline-3-carboxylic acid (2d). Yield: 71%, brown solid.
HRMS (ESI, 70 eV): C18H16N2O3: calcd: 309.1234;
found: 309.1232.
1H NMR (200 MHz, DMSO-d6): d = 2.86 (m, 1H,
CHaHb), 3.16 (m, 1H, CHaHb), 3.76 (m, 1H,

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6099
13C NMR (75 MHz, DMSO-d6): d = 24.34 (s), 57.05 (t),
57.62 (t), 107.78 (q), 111.36 (t), 115.52 (t), 116.08 (t), 117.77
(t), 118.59 (t), 119.93 (t), 121.05 (t), 126.27 (q), 129.34 (t),
132.98 (q), 136.57 (q), 140.34 (q), 157.45 (q), 172.05 (q).
Table 1. IC50 values of selected Eg5 inhibitors
Compound
IC50 value (lM)
cis-9a
36 9.9
14 5.8
trans-9a
cis-10a
21 16.4
4.3 1.18
0.65 0.30
18 2.5
13 0.6a
15 1.1b
11 5.9
trans-10a (HR22C16)
HRMS (ESI, 70 eV): C18H16N2O3: calcd: 338.1135;
found: 338.1142.
trans-24b
29a
30
4.2.7. (1S,3S)-1-(3-Bromophenyl)-2,3,4,9-tetrahydro-1H-
b-carboline-3-carboxylic acid (2g). Yield: 12%, auburn
solid.
33a
34a
17 2.8
a EnzChek-Assay.
b Malachite green assay.
1H NMR (300 MHz, DMSO-d6): d = 2.92–4.32 (m, 3H,
CHaHb, CHCOOH), 5.39 (s, 1H, CHPh), 6.91–7.95 (m,
8H, ar), 10.41 (s, 1H, CNHC).
13C NMR (75 MHz, DMSO-d6): d = 24.34 (s), 59.94 (t),
60.62 (t), 105.68 (q), 112.13 (t), 112.63 (t), 118.74 (t),
119.52 (t), 119.84 (t), 120.03 (t), 122.08 (t), 127.52 (q),
129.42 (t), 132.79 (q), 136.11 (q), 138.17 (q), 146.85
(q), 192.80 (q).
HRMS (ESI, 70 eV): C18H15BrN2O2: calcd: 369.0244;
found: 369.0232.
4.2.8.
(1R,3R)-1-(3-Bromophenyl)-2,3,4,9-tetrahydro-
1H-b-carboline-3-carboxylic acid (2h). Yield: 22%, au-
burn solid.
Figure 2. HeLa cells with normal spindle (left) and with monoasters
after treatment with trans-24 (20 lM) (right).
1H NMR (300 MHz, DMSO-d6): d = 2.92–4.32 (m, 3H,
CHaHb, CHCOOH), 5.39 (s, 1H, CHPh), 6.91–7.95 (m,
8H, ar), 10.41 (s, 1H, CNHC).
CHCOOH), 5.33 (s, 1H, CHPh), 6.76–7.46 (m, 8H, ar),
10.45 (s, 1H, CNHC).
13C NMR (75 MHz, DMSO-d6): d = 24.25 (s), 57.19 (t),
57.65 (t), 107.86 (q), 111.40 (t), 115.65 (t), 116.24 (t), 117.82
(t), 118.62 (t), 119.95 (t), 121.09 (t), 126.26 (q), 129.33 (t),
132.70 (q), 136.61 (q), 139.99 (q), 157.53 (q), 172.02 (q).
13C NMR (75 MHz, DMSO-d6): d = 24.26 (s), 60.45 (t),
61.32 (t), 105.97 (q), 111.23 (t), 112.63 (t), 118.11 (t), 118.33
(t), 118.44 (t), 119.89 (t), 122.37 (t), 127.73 (q), 129.22 (t),
132.83 (q), 136.33 (q), 138.12 (q), 146.95 (q), 191.91 (q).
HRMS (ESI, 70 eV): C18H16N2O3: calcd: 309.1234;
found: 309.1230.
HRMS (ESI, 70 eV): C18H16N2O3: 369.0244; found:
369.0237.
4.2.5. (1S,3S)-1-(3-Nitrophenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylic acid (2e). Yield: 71%, auburn solid.
4.2.9.
(1S,3S)-1-(3,4-Dihydroxyphenyl)-2,3,4,9-tetra-
hydro-1H-b-carboline-3-carboxylic acid (2i). Yield: 46%,
brown solid.
1H NMR (200 MHz, DMSO-d6): d = 2.95–3.91 (m, 2H,
CHaHb), 4.13 (m, 1H, CHCOOH), 5.55 (s, 1H, CHPh),
7.00–8.34 (m, 8H, ar), 10.43 (s, 1H, CNHC).
1H NMR (200 MHz, DMSO-d6): d = 3.02 (m, 1H,
CHaHb), 3.32 (m, 1H, CHaHb), 3.89 (m, 1H,
CHCOOH), 5.53 (s, 1H, CHPh), 6.62–7.53 (m, 7H,
ar), 10.53 (s, 1H, CNHC).
13C NMR (75 MHz, DMSO-d6): d = 22.39 (s), 57.02 (t),
59.03 (t), 107.13 (q), 111.40 (t), 117.94 (t), 118.63 (t),
118.95 (t), 121.25 (t), 122.08 (t), 123.08 (t), 124.05
(t), 125.93 (q), 134.16 (q), 136.30 (q), 136.95 (q), 147.75
(q), 171.67 (q).
13C NMR (50 MHz, DMSO-d6): d = 23.94 (s), 55.00 (t),
58.08 (t), 107.82 (q), 112.21 (t), 116.34 (t), 117.90 (t),
118.11 (t), 118.81 (t), 119.51 (t), 121.70 (t), 126.73 (q),
131.88 (q), 137.24 (q), 137.42 (q), 145.96 (q), 146.10
(q), 171.71 (q).
HRMS (ESI, 70 eV): C18H16N2O3: calcd: 338.1135;
found: 338.1140.
HRMS (ESI, 70 eV): C18H16N2O4: calcd: 323.1037
4.2.6. (1R,3R)-1-(3-Nitrophenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylic acid (2f). Yield: 50%, auburn solid.
[MÀH]À; found: 323.1035.
1H NMR (200 MHz, DMSO-d6): d = 2.92–3.89 (m, 2H,
CHaHb), 4.07 (m, 1H, CHCOOH), 5.50 (s, 1H, CHPh),
7.00–8.20 (m, 8H, ar), 10.43 (s, 1H, CNHC).
4.2.10. (1R,3R)-1-(3,4-Dihydroxyphenyl)-2,3,4,9-tetra-
hydro-1H-b-carboline-3-carboxylic acid (2j). Yield: 39%,
brown solid.

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1H NMR (200 MHz, DMSO-d6): d = 3.02 (m, 1H,
CHaHb), 3.27 (m, 1H, CHaHb), 3.84 (m, 1H,
CHCOOH), 5.55 (s, 1H, CHPh), 6.62–7.53 (m, 7H,
ar), 10.58 (s, 1H, CNHC).
126.38 (q), 127.90 (2· t), 128.75 (t), 128.99 (2· t),
133.68 (q), 136.94 (q), 138.89 (q), 154.93 (q), 171.81 (q).
HRMS (ESI): C23H23N3O2: calcd: 374.1863 [M+H]+;
found: 374.1865.
13C NMR (50 MHz, DMSO-d6): d = 22.82 (s), 56.02 (t),
57.59 (t), 104.66 (q), 111.24 (t), 114.66 (t), 115.09 (t),
117.98 (t), 118.69 (t), 118.78 (t), 121.22 (t), 125.88 (q),
131.37 (q), 135.36 (q), 136.58 (q), 144.25 (q), 144.87 (q),
171.66 (q).
4.3.2.
(5S,11aR)-2-Butyl-5-phenyl-6H-1,2,3,5,11,11a-
hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione trans-3.
Yield: 30%, brown solid.
TM = 111 ꢂC.
HRMS (ESI, 70 eV): C18H16N2O4: calcd: 323.1037
[MÀH]À; found: 323.1033.
1H NMR (600 MHz, DMSO-d6): d = 0.87 (t, J = 7.5 Hz,
3H, CH3), 1.25 (m, 2H, CH2CH3), 1.51 (m, 2H,
CH2CH2CH3), 2.81 (m, 1H, CHaHb), 3.39 (m, 1H,
CHaHb), 3.41 (m, 2H, NCH2), 4.59 (dd, J1 = 5.6 Hz,
J2 = 11.1 Hz, 1H, CHC(O)N), 6.23 (s, 1H, CHPh),
7.03–7.54 (m, 9H, ar), 10.87 (s, 1H, NH).
4.3. General procedure for the synthesis of the tetrahydro-
b-carbolines
To a solution of the desired tetrahydro-b-carboline-3-
carboxylic acid 2 (12 mmol) in a mixture of acetone
(40 ml) and DMSO (17 ml), the corresponding isocya-
nate or isothiocyanate (12 mmol, 1 equiv) was added
and heated to reflux. After 2 h, the progress of the reac-
tion was monitored by TLC and prolonged for another
2 h if necessary. Finally, the mixture is hydrolyzed with
water and extracted three times with dichloromethane.
The combined organic layers were washed with water,
dried, and concentrated in vacuo.
13C NMR (151 MHz, DMSO-d6): d = 13.46 (p), 19.36
(s), 22.72 (s), 29.64 (s), 37.67 (s), 51.53 (t), 52.88 (t),
105.98 (q), 111.37 (t), 118.20 (t), 118.84 (t), 121.68 (t),
125.77 (q), 127.78 (2· t), 128.11 (t), 128.72 (2· t),
131.23 (q), 136.70 (q), 140.13 (q), 154.38 (q), 172.65 (q).
HRMS (ESI): C23H23N3O2: calcd: 374.1863 [M+H]+;
found: 374.1860.
In case of the isothiocyanates, the product is trans.
When using isocyanates, the result is either exclusively
cis-product or a mixture of cis and trans. In the latter
case, purification by column chromatography (silica
gel, hexane/ethyl acetate 1:2) is necessary.
4.3.3.
hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
Yield: 73%, brown solid.
(5R,11aR)-2-Butyl-5-phenyl-6H-1,2,3,5,11,11a-
cis-4.
Overall yield for both enantiomers: 93%.
In case the sole product is cis-configured, the trans-prod-
uct may be obtained as follows.
TM = 201 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.3 Hz,
3H, CH3), 1.29 (m, 2H, CH2CH3), 1.50 (m, 2H,
CH2CH2CH3), 3.03 (m, 1H, CHaHb), 3.30–3.38 (m,
3H, NCH2, CHaHb), 4.58 (dd, J1 = 4.3 Hz,
J2 = 11.3 Hz, 1H, CHC(O)N), 5.89 (s, 1H, CHPh),
6.97–7.59 (m, 9H, ar), 10.77 (s, 1H, NH).
To a solution of cis-product (10.8 mmol) in acetonitrile
(150 ml), potassium carbonate (14 mmol, 1.3 equiv)
was added and stirred under reflux for 2 h. When the
reaction was finished (monitored by TLC), the reaction
mixture was filtered, the filtrate was concentrated
in vacuo.
13C NMR (75 MHz, DMSO-d6): d = 14.22 (p), 20.07 (s),
22.56 (s), 30.40 (s), 38.14 (s), 56.42 (t), 58.26 (t), 105.74
(q), 112.02 (t), 118.90 (t), 119.54 (t), 122.13 (t), 126.62
(q), 128.08 (2· t), 128.73 (t), 128.94 (2· t), 135.51 (q),
137.42 (q), 141.58 (q), 154.91 (q), 172.44 (q).
The Rf-values for the trans-products are generally lower
than for the cis-products.
4.3.1. (5S,11aS)-2-Butyl-5-phenyl-6H-1,2,3,5,11,11a-hexa-
hydro-imidazo[1,5-b]-b-carboline-1,3-dione cis-3. Yield:
63%, brown solid.
HRMS (ESI): C23H23N3O2: calcd: 396.1683 [M+Na]+;
found: 374.1685.
TM = 195 ꢂC.
4.3.4.
(5S,11aR)-2-Butyl-5-phenyl-6H-1,2,3,5,11,11a-
1H NMR (600 MHz, DMSO-d6): d = 0.92 (t, J = 7.5 Hz,
3H, CH3), 1.33 (m, 2H, CH2CH3), 1.60 (m, 2H,
CH2CH2CH3), 3.07 (m, 1H, CHaHb), 3.48 (m, 2H,
NCH2), 3.53 (m, 1H, CHaHb), 4.39 (dd, J1 = 4.6 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.80 (s, 1H, CHPh),
7.17–7.59 (m, 9H, ar), 10.77 (s, 1H, NH).
hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione trans-4.
Yield: 30%, brown solid.
Overall yield for both enantiomers: 93%.
TM = 95 ꢂC.
13C NMR (151 MHz, DMSO-d6): d = 13.72 (p), 20.12
(s), 22.69 (s), 30.23 (s), 38.63 (s), 56.89 (t), 58.06 (t),
107.13 (q), 111.35 (t), 118.61 (t), 120.30 (t), 122.88 (t),
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.5 Hz,
3H, CH3), 1.24 (m, 2H, CH2CH3), 1.52 (m, 2H,
CH2CH2CH3), 2.83 (m, 1H, CHaHb), 3.37–3.47 (m,

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6101
3H, CHaHb, NCH2), 4.62 (dd, J1 = 5.8 Hz, J2 = 11.0 Hz,
1H, CHC(O)N), 6.25 (s, 1H, CHPh), 7.02–7.59 (m, 9H,
ar), 10.93 (s, 1H, NH).
3.39 (m, 2H, NCH2), 4.49 (dd, J1 = 4.0 Hz, J2 = 11.2 Hz,
1H, CHC(O)N), 5.73 (s, 1H, CHPh), 6.59–7.54 (m, 8H,
ar), 9.27 (s, 1H, OH), 10.70 (br, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.21 (p), 20.11 (s),
23.47 (s), 30.39 (s), 38.41 (s), 52.27 (t), 53.61 (t), 106.73
(q), 112.12 (t), 118.95 (t), 119.58 (t), 122.41 (t), 126.51
(q), 128.54 (2· t), 128.85 (t), 129.46 (2· t), 131.96 (q),
137.44 (q), 140.89 (q), 155.11 (q), 173.38 (q).
13C NMR (75 MHz, DMSO-d6): d = 13.34 (p), 21.81
(s), 32.73 (s), 55.69 (t), 57.61 (t), 104.89 (q), 111.29
(t), 114.17 (t), 114.42 (t), 118.07 (t), 118.18 (t), 118.78
(t), 121.35 (t), 125.85 (q), 129.11 (t), 134.82 (q),
136.64 (q), 142.07 (q), 153.91 (q), 157.15 (q), 171.40
(q).
HRMS (ESI): C23H23N3O2: calcd: 396.1683 [M+Na]+;
found: 396.1681.
HRMS (ESI): C21H19N3O3: calcd: 362.1499 [M+H]+;
found: 362.1502.
4.3.5. (5S,11aS)-2-Ethyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione cis-
5. Yield: 84%, brown solid.
4.3.8. (5R,11aS)-2-Ethyl-5-(3-hydroxyphenyl)-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-6. Yield: 90%, brown solid.
TM = 142 ꢂC.
TM = 170 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.11 (t, J = 7.2 Hz,
3H, CH3), 3.01 (m, 1H, CHaHb), 3.36 (m, 1H, CHaHb),
3.40 (m, 2H, NCH2), 4.52 (dd, J1 = 4.5 Hz, J2 = 11.7 Hz,
1H, CHC(O)N), 5.78 (s, 1H, CHPh), 6.62–7.58 (m, 8H,
ar), 9.32 (s, 1H, OH), 10.75 (s, 1H, NH).
1H NMR (200 MHz, DMSO-d6): d = 1.13 (t, J = 7.2 Hz,
3H, CH3), 2.83 (m, 1H, CHaHb), 3.34 (m, 1H, CHaHb),
3.45 (m, 2H, NCH2), 4.47 (dd, J1 = 5.9 Hz, J2 = 10.9 Hz,
1H, CHC(O)N), 6.10 (s, 1H, CHPh), 6.58–7.56 (m, 8H,
ar), 10.96 (br, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.37 (p), 21.80 (s),
32.75 (s), 55.69 (t), 57.63 (t), 104.90 (q), 111.32 (t),
114.20 (t), 114.45 (t), 118.13 (t), 118.21 (t), 118.82 (t),
121.39 (t), 125.88 (q), 129.18 (t), 134.85 (q), 136.66 (q),
142.14 (q), 153.96 (q), 157.20 (q), 171.47 (q).
13C NMR (50 MHz, DMSO-d6): d = 14.00 (p), 23.33 (s),
33.68 (s), 52.29 (t), 53.47 (t), 106.37 (q), 112.07 (t),
116.22 (t), 116.57 (t), 116.68 (t), 118.77 (t), 119.43 (t),
122.22 (t), 126.48 (q), 130.05 (t), 132.31 (q), 137.34 (q),
141.71 (q), 154.70 (q), 161.49 (q), 173.16 (q).
HRMS (ESI): C21H19N3O3: calcd: 362.1499 [M+H]+;
found: 362.1500.
HRMS (ESI): C21H19N3O3: calcd: 400.1058 [M+K]+;
found: 400.1060.
4.3.6. (5S,11aR)-2-Ethyl-5-(3-hydroxyphenyl)-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-5. Yield: 84%, brown solid.
4.3.9. (5S,11aS)-5-(3-Hydroxyphenyl)-2-propyl-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-7. Yield: 89%, yellow solid.
TM = 165 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.13 (t, J = 7.2 Hz,
3H, CH3), 2.83 (m, 1H, CHaHb), 3.35 (m, 1H, CHaHb),
3.45 (m, 2H, NCH2), 4.47 (dd, J1 = 5.6 Hz, J2 = 10.9 Hz,
1H, CHC(O)N), 6.10 (s, 1H, CHPh), 6.62–7.56 (m, 8H,
ar), 10.96 (s, 1H, NH).
TM = 92 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 0.81 (t, J = 7.8 Hz,
3H, CH3), 1,49 (m, 2H, CH2CH3), 2.89 (m, 1H,
CHaHb), 3.27 (m, 1H, CHaHb), 3.30 (m, 2H, NCH2),
4.51 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CHC(O)N),
5.74 (s, 1H, CHPh), 6.59–7.54 (m, 8H, ar), 9.27 (s, 1H,
OH), 10.72 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.27 (p), 22.62 (s),
35.73 (s), 51.52 (t), 52.74 (t), 105.70 (q), 111.32 (t),
115.32 (t), 115.67 (t), 118.04 (t), 118.69 (t), 121.51 (t),
125.75 (t), 129.38 (t), 131.48 (q), 136.61 (q), 141.03 (q),
153.97 (q), 160.09 (q), 162.24 (q), 172.37 (q).
13C NMR (50 MHz, DMSO-d6): d = 11.12 (p), 21.04 (s),
23.30 (s), 39.38 (s), 55.69 (t), 57.54 (t), 104.87 (q), 111.35
(t), 114.17 (t), 114.45 (t), 118.15 (2· t), 118.85 (t), 121.42
(t), 125.91 (q), 129.20 (t), 134.90 (q), 136.68 (q), 142.20
(q), 154.16 (q), 157.23 (q), 171.80 (q).
HRMS (ESI): C21H19N3O3: calcd: 400.1058 [M+K]+;
found: 400.1063.
HRMS (ESI): C22H21N3O3: calcd: 398.1475 [M+Na]+;
found: 398.1478.
4.3.7. (5R,11aR)-2-Ethyl-5-(3-hydroxyphenyl)-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-6. Yield: 87%, pale yellow solid.
4.3.10. (5S,11aR)-5-(3-Hydroxyphenyl)-2-propyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-7. Yield: 87%, brown solid.
TM = 234 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 1.06 (t, J = 7.2 Hz,
3H, CH3), 2.95 (m, 1H, CHaHb), 3.28 (m, 1H, CHaHb),
TM = 120 ꢂC.

6102
N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
1H NMR (200 MHz, DMSO-d6): d = 0.85 (t, J = 8.2 Hz,
3H, CH3), 1,55 (m, 2H, CH2CH3), 2.90 (m, 1H,
CHaHb), 3.27 (m, 1H, CHaHb), 3.43 (m, 2H, NCH2),
4.51 (dd, J1 = 5.6 Hz, J2 = 10.9 Hz, 1H, CHC(O)N),
6.16 (s, 1H, CHPh), 6.73–7.59 (m, 8H, ar), 9.50 (s, 1H,
OH), 10.97 (s, 1H, NH).
TM = 225 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.5 Hz,
3H, CH3), 1.28 (m, 2H, CH2CH3), 1.52 (m, 2H,
CH2CH2CH3), 3.00 (m, 1H, CHaHb), 3.39 (m, 1H,
CHaHb), 3.41 (m, 2H, NCH2), 4.58 (dd, J1 = 4.5 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.76 (s, 1H, CHPh),
6.70–7.58 (m, 8H, ar), 9.33 (s, 1H, OH), 10.87 (s, 1H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 11.05 (p), 20.96 (s),
22.78 (s), 51.34 (s), 52.70 (t), 54.86 (t), 105.96 (q), 111.35
(t), 114.71 (t), 115.05 (t), 118.13 (t), 118.38 (t), 118.78 (t),
121.62 (t), 125.75 (q), 129.71 (t), 131.16 (q), 136.64 (q),
141.34 (q), 154.25 (q), 157.58 (q), 172.59 (q).
13C NMR (75 MHz, DMSO-d6): d = 13.46 (p), 19.36 (s),
22.78 (s), 29.64 (s), 37.49 (s), 56.42 (t), 58.06 (t), 107.98
(q), 111.37 (t), 115.26 (t), 115.35 (t), 118.20 (t), 118.84
(t), 118.86 (t), 121.72 (t), 125.54 (q), 129.54 (t), 131.11
(q), 136.68 (q), 139.98 (q), 154.08 (q), 157.65 (q),
172.62 (q).
HRMS (ESI): C22H21N3O3: calcd: 376.1656 [M+H]+;
found: 376.1660.
4.3.11. (5R,11aR)-5-(3-Hydroxyphenyl)-2-propyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-8. Yield: 85%, yellow solid.
HRMS (ESI): C23H23N3O3: calcd: 412.1632 [M+Na]+;
found: 412.1635.
4.3.14. (5S,11aR)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-9. Yield: 84%, brown solid.
TM = 110 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 0.81 (t, J = 7.8 Hz,
3H, CH3), 1,50 (m, 2H, CH2CH3), 2.92 (m, 1H,
CHaHb), 3.30 (m, 1H, CHaHb), 3.33 (m, 2H, NCH2),
4.51 (dd, J1 = 4.4 Hz, J2 = 11.4 Hz, 1H, CHC(O)N),
5.74 (s, 1H, CHPh), 6.58–7.54 (m, 8H, ar), 9.27 (s, 1H,
OH), 10.71 (s, 1H, NH).
TM = 118 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.84 (t, J = 6.8 Hz,
3H, CH3), 1.25 (m, 2H, CH2CH3), 1.49 (m, 2H,
CH2CH2CH3), 2.75 (m, 1H, CHaHb), 3.30 (m, 1H,
CHaHb), 3.42 (m, 2H, NCH2), 4.41 (dd, J1 = 5.7 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.04 (s, 1H, CHPh),
6.50–7.51 (m, 8H, ar), 9.33 (s, 1H, OH), 10.91 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 11.12 (p), 21.04 (s),
23.30 (s), 38.95 (s), 55.68 (t), 57.53 (t), 104.86 (q), 111.34
(t), 114.16 (t), 114.45 (t), 118.15 (2· t), 118.84 (t), 121.42
(t), 125.90 (q), 129.20 (t), 134.89 (q), 136.67 (q), 142.21
(q), 154.15 (q), 157.23 (q), 171.80 (q).
13C NMR (75 MHz, DMSO-d6): d = 13.46 (p), 19.36 (s),
22.78 (s), 29.64 (s), 37.49 (s), 51.42 (t), 52.06 (t), 105.98
(q), 111.37 (t), 115.26 (t), 115.35 (t), 118.20 (t), 118.84
(t), 118.86 (t), 121.72 (t), 125.54 (q), 129.54 (t), 131.11
(q), 136.68 (q), 139.98 (q), 154.08 (q), 157.65 (q),
172.62 (q).
HRMS (ESI): C22H21N3O3: calcd: 398.1475 [M+Na]+;
found: 398.1479.
4.3.12. (5R,11aS)-5-(3-Hydroxyphenyl)-2-propyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-8. Yield: 78%, brown solid.
HRMS (ESI): C23H23N3O3: calcd: 412.1632 [M+Na]+;
found: 412.1628.
TM = 103 ꢂC.
4.3.15. (5R,11aR)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-10. Yield: 88%, yellow solid.
1H NMR (200 MHz, DMSO-d6): d = 0.85 (t, J = 8.2 Hz,
3H, CH3), 1.59 (m, 2H, CH2CH3), 2.89 (m, 1H,
CHaHb), 3.30–3.45 (m, 3H, CHaHb, NCH2), 4.51 (dd,
J1 = 5.5 Hz, J2 = 10.6 Hz, 1H, CHC(O)N), 6.15 (s, 1H,
CHPh), 6.70–7.58 (m, 8H, ar), 10.96 (br, 1H, NH).
TM = 134 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.90 (t, J = 7.5 Hz,
3H, CH3), 1.30 (m, 2H, CH2CH3), 1.52 (m, 2H,
CH2CH2CH3), 2.99 (m, 1H, CHaHb), 3.39 (m, 1H,
CHaHb), 3.41 (t, J = 6.9 Hz, 2H, NCH2), 4.53 (dd,
J1 = 4.2 Hz, J2 = 10.6 Hz, 1H, CHC(O)N), 5.79 (s, 1H,
CHPh), 6.64–7.59 (m, 8H, ar), 9.33 (s, 1H, OH), 10.77
(s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 11.75 (p), 21.66 (s),
23.94 (s), 52.10 (s), 53.42 (t), 106.60 (q), 112.08 (t),
115.61 (t), 115.96 (t), 118.53 (t), 118.84 (t), 119.50 (t),
122.32 (t), 126.47 (q), 130.36 (t), 131.99 (q), 137.35 (q),
141.99 (q), 154.97 (q), 159.04 (q), 173.37 (q).
HRMS (ESI): C22H21N3O3: calcd: 376.1656 [M+H]+;
found: 376.1649.
13C NMR (75 MHz, DMSO-d6): d = 13.50 (p), 19.35 (s),
21.89 (s), 29.70 (s), 32.22 (t), 37.42 (s), 55.67 (t), 57.52
(t), 104.85 (q), 111.33 (t), 114.17 (t), 114.43 (t), 118.14
(t), 118.82 (t), 121.39 (t), 125.88 (q), 129.16 (t), 134.87
(q), 136.65 (q), 142.17 (q), 154.11 (q), 157.22 (q),
171.73 (q).
4.3.13. (5S,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,
5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-9. Yield: 86%, brown solid.

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6103
HRMS (ESI): C23H23N3O3: calcd: 412.1632 [M+Na]+;
found: 412.1629.
13C NMR (50 MHz, DMSO-d6): d = 13.79 (p), 21.64 (s),
21.92 (s), 22.78 (s), 37.95 (s), 51.36 (t), 52.71 (t), 106.00
(q), 111.40 (t), 114.75 (t), 115.08 (t), 118.18 (t), 118.42
(t), 118.82 (t), 121.66 (t), 125.78 (q), 129.75 (t), 131.20
(q), 136.68 (q), 141.38 (q), 154.26 (q), 157.63 (q),
172.58 (q).
4.3.16. (5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-10. Yield: quant., brown solid.
HRMS (ESI): C24H25N3O3: calcd: 404.1969 [M+H]+;
found: 404.1972.
TM = 107 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.9 Hz,
3H, CH3), 1.22 (m, 2H, CH2CH3), 1.51 (m, 2H,
CH2CH2CH3), 2.83 (m, 1H, CHaHb), 3.30 (m, 1H,
CHaHb), 3.42 (m, 2H, NCH2), 4.41 (dd, J1 = 5.8 Hz,
J2 = 10.9 Hz, 1H, CHC(O)N), 6.04 (s, 1H, CHPh),
6.50–7.51 (m, 8H, ar), 9.33 (s, 1H, OH), 10.91 (s, 1H,
NH).
4.3.19. (5R,11aR)-5-(3-Hydroxyphenyl)-2-pentyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-12. Yield: 83%, pale yellow solid.
TM = 200 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.85 (m, 3H, CH3),
1.23–1.37 (m, 4H, CH2CH2CH3), 1.53 (m, 2H, CH2),
2.99 (m, 1H, CHaHb), 3.35 (m, 3H, NCH2, CHaHb),
4.55 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CHC(O)N),
5.78 (s, 1H, CHPh), 6.63–7.59 (m, 8H, ar), 9.31 (s, 1H,
OH), 10.76 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.21 (p), 20.13 (s),
23.51 (s), 32.94 (s), 38.42 (s), 52.13 (t), 53.45 (t), 106.66
(q), 112.12 (t), 115.62 (t), 115.96 (t), 118.74 (t), 118.89
(t), 119.53 (t), 122.36 (t), 126.51 (q), 130.41 (t), 132.01
(q), 137.40 (q), 142.06 (q), 154.99 (q), 158.92 (q),
173.35 (q).
13C NMR (75 MHz, DMSO-d6): d = 13.86 (p), 21.68 (s),
21.96 (s), 27.26 (s), 28.28 (s), 37.68 (s), 55.66 (t), 57.52
(t), 104.83 (q), 111.34 (t), 114.17 (t), 114.43 (t), 118.15
(2· t), 118.83 (t), 121.40 (t), 125.89 (q), 129.17 (t),
134.88 (q), 136.66 (q), 142.20 (q), 154.11 (q), 157.23
(q), 171.73 (q).
HRMS (ESI): C23H23N3O3: calcd: 412.1632 [M+Na]+;
found: 412.1632.
4.3.17. (5S,11aS)-5-(3-Hydroxyphenyl)-2-pentyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-11. Yield: 87%, pale yellow solid.
HRMS (ESI): C24H25N3O3: calcd: 426.1788 [M+Na]+;
found: 426.1784.
TM = 201 ꢂC.
4.3.20. (5R,11aS)-5-(3-Hydroxyphenyl)-2-pentyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-12. Yield: 93%, pale yellow solid.
1H NMR (300 MHz, DMSO-d6): d = 0.87 (m, 3H, CH3),
1.22–1.38 (m, 4H, CH2CH2CH3), 1.53 (m, 2H, CH2),
2.99 (m, 1H, CHaHb), 3.35 (m, 3H, NCH2, CHaHb),
4.55 (dd, J1 = 4.5 Hz, J2 = 11.4 Hz, 1H, CHC(O)N),
5.79 (s, 1H, CHPh), 6.64–7.58 (m, 8H, ar), 9.32 (s, 1H,
OH), 10.77 (s, 1H, NH).
TM = 81 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.86 (m, 3H, CH3),
1.22–1.40 (m, 4H, CH2CH2CH3), 1.58 (m, 2H, CH2), 2.83
(m, 1H, CHaHb), 3.40 (m, 3H, CHaHb, NCH2), 4.51 (dd,
J1 = 5.7 Hz, J2 = 10.8 Hz, 1H, CHC(O)N), 6.17 (s, 1H,
CHPh), 6.74–7.58 (m, 8H, ar), 10.98 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.83 (p), 21.66 (s),
21.93 (s), 27.24 (s), 28.27 (s), 37.49 (s), 55.65 (t), 57.50
(t), 104.82 (q), 111.32 (t), 114.17 (t), 114.42 (t), 118.11
(2· t), 118.81 (t), 121.38 (t), 125.38 (q), 129.14 (t),
134.87 (q), 136.66 (q), 142.18 (q), 154.09 (q), 157.22
(q), 171.71 (q).
13C NMR (75 MHz, DMSO-d6): d = 13.80 (p), 21.67 (s),
22.80 (s), 27.25 (s), 28.31 (s), 37.97 (s), 51.40 (t), 52.74
(t), 105.99 (q), 111.41 (t), 114.84 (t), 115.17 (t), 118.19
(t), 118.27 (t), 118.83 (t), 121.67 (t), 125.80 (q), 129.75
(t), 131.25 (q), 136.70 (q), 141.38 (q), 154.27 (q),
157.89 (q), 172.61 (q).
HRMS (ESI): C24H25N3O3: calcd: 404.1969 [M+H]+;
found: 404.1973.
4.3.18. (5S,11aR)-5-(3-Hydroxyphenyl)-2-pentyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-11. Yield: 93%, brown solid.
HRMS (ESI): C24H25N3O3: calcd: 426.1788 [M+Na]+;
found: 426.1784.
TM = 83 ꢂC.
4.3.21. (5R,11aS)-2-Ethyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-13. Yield: 21%, yellow solid.
1H NMR (300 MHz, DMSO-d6): d = 0.81 (m, 3H, CH3),
1.22–1.36 (m, 4H, CH2CH2CH3), 1.51 (m, 2H, CH2),
2.78 (m, 1H, CHaHb), 2.95 (m, 1H, CHaHb), 3.39 (m,
2H, NCH2), 4.46 (dd, J1 = 5.8 Hz, J2 = 11.0 Hz, 1H,
CHC(O)N), 6.13 (s, 1H, CHPh), 6.70–7.54 (m, 8H,
ar), 9.46 (s, 1H, OH), 10.93 (s, 1H, NH).
TM = 91 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, J = 7.2 Hz,
3H, CH3), 3.17 (m, 1H, CHaHb), 3.45 (m, 1H, CHaHb),

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3.49 (m, 2H, NCH2), 4.60 (dd, J1 = 5.2 Hz, J2 = 11.0 Hz,
1H, CHC(O)N), 6.13 (s, 1H, CHPh), 7.03–8.12 (m, 8H,
ar), 10.86 (s, 1H, NH).
3.48 (m, 2H, NCH2), 4.70 (dd, J1 = 5.4 Hz, J2 = 10.8 Hz,
1H, CHC(O)N), 6.45 (s, 1H, CHPh), 7.07–8.26 (m, 8H,
ar), 10.93 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.31 (p), 21.59 (s),
32.83 (s), 54.87 (t), 57.47 (t), 105.76 (q), 111.37 (t),
118.42 (t), 119.00 (t), 121.74 (t), 122.60 (t), 122.73 (t),
125.82 (q), 129.93 (t), 133.58 (t), 134.17 (q), 136.83 (q),
142.86 (q), 147.62 (q), 154.35 (q), 171.43 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.25 (p), 22.42 (s),
33.08 (s), 50.95 (t), 53.23 (t), 106.55 (q), 111.46 (t),
118.37 (t), 118.99 (t), 121.92 (t), 122.73 (t), 123.14 (t),
125.73 (t), 130.29 (t), 130.40 (q), 134.52 (q), 136.81 (q),
142.14 (q), 147.92 (q), 154.50 (q), 172.35 (q).
HRMS (ESI): C21H18N4O4: calcd: 391.1401 [M+H]+;
found: 391.1399.
HRMS (ESI): C21H18N4O4: calcd: 413.1220 [M+Na]+;
found: 413.1219.
4.3.22. (5S,11aR)-2-Ethyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-13. Yield: 21%, dark yellow solid.
4.3.25. (5S,11aS)-5-(3-Bromophenyl)-2-ethyl-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-15. Yield: 22%, brown solid.
TM = 109 ꢂC.
TM = 137 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.13 (t, J = 7.3 Hz,
3H, CH3), 2.86 (m, 1H, CHaHb), 3.35 (m, 1H, CHaHb),
3.48 (m, 2H, NCH2), 4.47 (dd, J1 = 5.4 Hz, J2 = 10.8 Hz,
1H, CHC(O)N), 6.44 (s, 1H, CHPh), 7.04–7.96 (m, 8H,
ar), 10.94 (s, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, J = 7.3 Hz,
3H, CH3), 3.05 (m, 1H, CHaHb), 3.30–4.51 (m, 3H,
CHaHb, NCH2), 4.55 (m, 1H, CHC(O)N), 5.90 (s, 1H,
CHPh), 6.90–7.61 (m, 8H, ar), 10.81 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.46 (p), 22.59 (s),
37.49 (s), 56.42 (t), 58.06 (t), 107.13 (q), 111.27 (t),
115.36 (t), 115.35 (t), 118.17 (t), 118.84 (t), 118.68 (t),
121.72 (t), 125.54 (q), 129.54 (t), 131.11 (q), 136.68 (q),
141.88 (q), 154.08 (q), 154.57 (q), 172.62 (q).
13C NMR (600 MHz, DMSO-d6): d = 13.18 (p), 22.36
(s), 33.00 (s), 50.87 (t), 53.14 (t), 106.47 (q), 111.38 (t),
118.31 (t), 118.93 (t), 121.86 (t), 122.63 (t), 123.08 (t),
125.66 (q), 130.22 (t), 130.34 (t), 134.44 (q), 136.73 (q),
142.05 (q), 147.85 (q), 154.42 (q), 172.27 (q).
HRMS (ESI): C21H18BrN3O2: calcd: 424.0655 [M+H]+;
found: 424.0663.
HRMS (ESI): C21H18N4O4: calcd: 391.1401 [M+H]+;
found: 391.1404.
4.3.26. (5S,11aR)-5-(3-Bromophenyl)-2-ethyl-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-15. Yield: 35%, brown solid.
4.3.23. (5R,11aR)-2-Ethyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-14. Yield: 21%, yellow solid.
TM = 116 ꢂC.
TM = 92 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.13 (t, J = 7.3 Hz,
3H, CH3), 2.81 (m, 1H, CHaHb), 3.24 (m, 1H, CHaHb),
3.50 (m, 2H, NCH2), 4.67 (dd, J1 = 4.4 Hz, J2 = 11.4 Hz,
1H, CHC(O)N), 6.24 (s, 1H, CHPh), 7.01–7.96 (m, 8H,
ar), 10.91 (s, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 1.11 (t, J = 7.3 Hz,
3H, CH3), 3.12 (m, 1H, CHaHb), 3.38 (m, 1H, CHaHb),
3.43 (m, 2H, NCH2), 4.60 (dd, J1 = 5.4 Hz, J2 = 10.8 Hz,
1H, CHC(O)N), 6.12 (s, 1H, CHPh), 7.03–8.34 (m, 8H,
ar), 10.84 (s, 1H, NH).
13C NMR (600 MHz, DMSO-d6): d = 13.46 (p), 22.59
(s), 37.49 (s), 51.42 (t), 52.06 (t), 105.98 (q), 111.27 (t),
115.36 (t), 115.35 (t), 118.17 (t), 118.84 (t), 118.68 (t),
121.72 (t), 125.54 (q), 129.54 (t), 131.11 (q), 136.68 (q),
139.98 (q), 154.08 (q), 157.47 (q), 172.62 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.26 (p), 21.62 (s),
32.81 (s), 54.89 (t), 57.45 (t), 105.74 (q), 111.33 (t),
114.58 (t), 118.35 (t), 118.95 (t), 121.70 (t), 122.53 (t),
122.70 (t), 125.79 (t), 129.84 (t), 130.87 (q), 133.53 (q),
136.82 (q), 142.81 (q), 147.60 (q), 154.30 (q), 171.34 (q).
HRMS (ESI): C21H18BrN3O2 H+: calcd: 424.0655
[M+H]+; found: 424.0663.
HRMS (ESI): C21H18N4O4: calcd: 413.1220 [M+Na]+;
found: 413.1218.
4.3.27. (5R,11aR)-5-(3-Bromophenyl)-2-ethyl-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-16. Yield: 8%, brown solid.
4.3.24. (5R,11aS)-2-Ethyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-14. Yield: 21%, yellow solid.
TM = 120 ꢂC.
TM = 86 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.11 (t, J = 7.3 Hz,
3H, CH3), 3.05 (m, 1H, CHaHb), 3.30–3.44 (m, 3H,
CHaHb, NCH2), 4.57 (dd, J1 = 4.0 Hz, J2 = 10.8 Hz,
1H NMR (300 MHz, DMSO-d6): d = 1.14 (t, J = 7.3 Hz,
3H, CH3), 2.86 (m, 1H, CHaHb), 3.35 (m, 1H, CHaHb),

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6105
1H, CHC(O)N), 5.91 (s, 1H, CHPh), 6.97–7.62 (m, 8H,
ar), 10.81 (s, 1H, NH).
CH2CH2CH3), 2.85 (m, 1H, CHaHb), 3.40–3.46 (m,
3H, CHaHb, NCH2), 4.73 (dd, J1 = 5.4 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.45 (s, 1H, CHPh),
7.04–8.25 (m, 8H, ar), 10.95 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.30 (p), 21.60 (s),
32.78 (s), 55.04 (t), 57.54 (t), 105.45 (q), 111.32 (t),
118.26 (t), 118.88 (t), 121.34 (t), 121.56 (t), 125.80 (t),
126.39 (t), 130.30 (q), 130.35 (t), 130.43 (q), 133.97 (q),
136.73 (q), 143.28 (q), 154.12 (q), 171.36 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.42 (p), 19.31 (s),
22.53 (s), 29.57 (s), 37.69 (s), 50.89 (t), 53.15 (t), 106.50
(q), 111.43 (t), 118.37 (t), 118.97 (t), 121.91 (t), 122.66
(t), 123.12 (t), 125.70 (t), 130.28 (t), 134.44 (q), 134.85
(q), 136.77 (q), 142.10 (q), 147.89 (q), 154.65 (q), 172.57 (q).
HRMS (ESI): C21H18BrN3O2: calcd: 424.0655 [M+H]+;
found: 424.0661.
HRMS (ESI): C23H22N4O4: calcd: 419.4602 [M+H]+;
found: 419.4597.
4.3.28. (5R,11aS)-5-(3-Bromophenyl)-2-ethyl-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-16. Yield: 95%, brown solid.
4.3.31. (5R,11aR)-2-Butyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-18. Yield: 23%, yellow solid.
TM = 225 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 1.08 (t, J = 7.0 Hz,
3H, CH3), 2.79 (m, 1H, CHaHb), 3.38–3.48 (m, 3H,
CHaHb, NCH2), 4.63 (dd, J1 = 5.6 Hz, J2 = 10.6 Hz,
1H, CHC(O)N), 6.20 (s, 1H, CHPh), 6.97–7.55 (m,
8H, ar), 10.87 (br, 1H, NH).
TM = 79 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 0.83 (t, J = 7 Hz,
3H, CH3), 1.24 (m, 2H, CH2CH3), 1.46 (m, 2H,
CH2CH2CH3), 3.07 (m, 1H, CHaHb), 3.20–3.41 (m,
3H, CHaHb, NCH2), 4.58 (dd, J1 = 4.2 Hz, J2 =
11.2 Hz, 1H, CHC(O)N), 6.09 (s, 1H, CHPh), 6.97–
8.28 (m, 8H, ar), 10.82 (br, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.00 (p), 23.19 (s),
33.77 (s), 51.80 (t), 53.82 (t), 107.01 (q), 112.19 (t),
119.03 (t), 119.65 (t), 122.55 (t), 122.71 (t), 126.47 (t),
127.71 (t), 131.32 (q), 131.38 (t), 131.69 (q), 131.81 (q),
137.50 (q), 143.44 (q), 155.11 (q), 173.15 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.42 (p), 19.28 (s),
21.68 (s), 29.58 (s), 37.46 (s), 54.82 (t), 57.32 (t), 105.68 (q),
111.33 (t), 118.38 (t), 118.96 (t), 121.71 (t), 122.53 (t),
122.61 (t), 125.79 (t), 129.87 (t), 133.53 (q), 134.08 (q),
136.81 (q), 142.84 (q), 147.60 (q), 154.46 (q), 171.63 (q).
HRMS (ESI): C21H18BrN3O2: calcd: 446.0475
[M+Na]+; found: 446.0480.
4.3.29. (5S,11aS)-2-Butyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-17. Yield: 23%, dark yellow solid.
HRMS (ESI): C23H22N4O4: calcd: 419.4602 [M+H]+;
found: 419.4598.
4.3.32. (5R,11aS)-2-Butyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-18. Yield: 20%, pale brown solid.
TM = 97 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 0.83 (t, J = 7 Hz,
3H, CH3), 1.24 (m, 2H, CH2CH3), 1.49 (m, 2H,
CH2CH2CH3), 3.09 (m, 1H, CHaHb), 3.32 (m, 1H,
CHaHb), 3.41 (t, J = 6.9 Hz, 2H, NCH2), 4.56 (dd,
J1 = 4.4 Hz, J2 = 11.4 Hz, 1H, CHC(O)N), 6.08 (s, 1H,
CHPh), 6.98–8.13 (m, 8H, ar), 10.82 (s, 1H, NH).
TM = 67 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.2 Hz,
3H, CH3), 1.28 (m, 2H, CH2CH3), 1.54 (m, 2H,
CH2CH2CH3), 2.80 (m, 1H, CHaHb), 3.40–3.46 (m,
3H, CHaHb, NCH2), 4.72 (dd, J1 = 5.4 Hz,
J2 = 10.5 Hz, 1H, CHC(O)N), 6.45 (s, 1H, CHPh),
7.04–8.58 (m, 8H, ar), 10.94 (br, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.46 (p), 19.30 (s),
21.68 (s), 29.60 (s), 37.48 (s), 54.82 (t), 57.33 (t), 105.67
(q), 111.36 (t), 118.41 (t), 118.97 (t), 121.72 (t), 122.56 (t),
122.64 (t), 125.80 (t), 129.90 (t), 133.56 (q), 134.10 (q),
136.81 (q), 142.87 (q), 147.59 (q), 154.48 (q), 171.66 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.42 (p), 19.31 (s),
22.53 (s), 29.57 (s), 37.69 (s), 50.89 (t), 53.15 (t), 106.50
(q), 111.43 (t), 118.37 (t), 118.97 (t), 121.91 (t), 122.66
(t), 123.12 (t), 125.70 (t), 130.28 (t), 134.44 (q), 134.85
(q), 136.77 (q), 142.10 (q), 147.89 (q), 154.65 (q), 172.57 (q).
HRMS (ESI): C23H22N4O4: calcd: 419.4602 [M+H]+;
found: 419.4598.
4.3.30. (5S,11aR)-2-Butyl-5-(3-nitrophenyl)-6H-1,2,3,5,
11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-17. Yield: 13%, yellow solid.
HRMS (ESI): C23H22N4O4: calcd: 441.1533 [M+Na]+;
found: 441.1530.
4.3.33. (5S,11aS)-2-Butyl-5-(2,3-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione cis-19. Yield: 25%, purple solid.
TM = 51 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.88 (t, J = 7 Hz,
3H, CH3), 1.28 (m, 2H, CH2CH3), 1.54 (m, 2H,
TM = 176 ꢂC.

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1H NMR (200 MHz, DMSO-d6): d = 0.85 (t, J = 7.0 Hz,
3H, CH3), 1.24 (m, 2H, CH2CH3), 1.46 (m, 2H,
CH2CH2CH3), 2.88 (m, 1H, CHaHb), 3.28 (m, 1H,
CHaHb), 3.33 (m, 2H, NCH2), 4.48 (dd, J1 = 4.4 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.66 (s, 1H, CHPh),
6.62–7.53 (m, 7H, ar), 8.72 (br, 1H, OH), 8.78 (br, 1H,
OH), 10.67 (br, 1H, NH).
4.3.36. (5R,11aS)-2-Butyl-5-(2,3-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione trans-20. Yield: 45%, purple solid.
TM = 134 ꢂC.
1H NMR (200 MHz, DMSO-d6): d = 0.85 (t, J = 7.3 Hz,
3H, CH3), 1.19 (m, 2H, CH2CH3), 1.52 (m, 2H,
CH2CH2CH3), 2.82 (m, 1H, CHaHb), 3.40 (m, 1H,
CHaHb), 3.42 (m, 2H, NCH2), 4.46 (dd, J1 = 5.5 Hz,
J2 = 10.7 Hz, 1H, CHC(O)N), 6.08 (s, 1H, CHPh),
6.57–7.57 (m, 7H, ar), 10.94 (br, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.45 (p), 19.32 (s),
21.94 (s), 29.65 (s), 37.34 (s), 55.51 (t), 57.59 (t), 104.65
(q), 111.25 (t), 114.67 (t), 115.10 (t), 118.00 (t), 118.70
(t), 118.79 (t), 121.23 (t), 125.89 (q), 131.39 (q), 135.38
(q), 136.60 (q), 144.78 (q), 144.89 (q), 154.00 (q),
171.69 (q).
13C NMR (50 MHz, DMSO-d6): d = 13.47 (p), 19.37 (s),
22.82 (s), 29.82 (s), 37.64 (s), 51.07 (t), 52.44 (t), 105.87
(q), 111.33 (t), 115.26 (t), 115.55 (t), 118.12 (t), 118.74
(t), 118.90 (t), 121.56 (t), 125.80 (q), 130.98 (q), 131.71
(q), 136.60 (q), 145.25 (q), 145.40 (q), 154.08 (q),
172.62 (q).
HRMS (ESI): C23H23N3O4: calcd: 406.1761 [M+H]+;
found: 406.1763.
4.3.34. (5S,11aR)-2-Butyl-5-(2,3-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione trans-19. Yield: 40%, purple solid.
HRMS (ESI): C23H23N3O4: calcd: 406.1761 [M+H]+;
found: 406.1758.
TM = 128 ꢂC.
4.3.37. (5S,11aS)-5-(3-Hydroxyphenyl)-2-phenyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-21. Yield: 35%, brown solid.
1H NMR (200 MHz, DMSO-d6): d = 0.89 (t, J = 7.2 Hz,
3H, CH3), 1.25 (m, 2H, CH2CH3), 1.53 (m, 2H,
CH2CH2CH3), 2.80 (m, 1H, CHaHb), 3.40 (m, 1H,
CHaHb), 3.42 (m, 2H, NCH2), 4.45 (dd, J1 = 5.8 Hz,
J2 = 10.9 Hz, 1H, CHC(O)N), 6.10 (s, 1H, CHPh),
6.62–7.54 (m, 7H, ar), 8.99 (br, 2H, OH), 10.94 (br,
1H, NH).
TM = 170 ꢂC (decomp.).
1H NMR (200 MHz, DMSO-d6): d = 3.15 (m, 1H,
CHaHb), 3.34 (m, 1H, CHaHb), 4.69 (dd, J1 = 4.4 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.81 (s, 1H, CHPh),
6.59–7.57 (m, 13H, ar), 9.29 (s, 1H, OH), 10.75 (s, 1H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 13.44 (p), 19.36 (s),
22.80 (s), 29.66 (s), 37.63 (s), 51.05 (t), 52.42 (t), 105.84
(q), 111.29 (t), 115.23 (t), 115.52 (t), 118.06 (t), 118.70 (t),
118.86 (t), 121.51 (t), 125.76 (q), 130.94 (q), 131.67 (q),
136.56 (q), 145.21 (q), 145.35 (q), 154.03 (q), 172.55 (q).
13C NMR (75 MHz, DMSO-d6): d = 21.84 (s), 55.90 (t),
57.63 (t), 104.89 (q), 111.28 (t), 114.19 (t), 114.38 (t),
114.44 (t), 118.11 (t), 118.78 (t), 121.37 (t), 121.80 (t),
125.83 (q), 126.44 (t), 127.69 (t), 128.64 (t), 129.10 (t),
131.89 (q), 134.60 (q), 136.64 (t), 139.70 (q), 141.92
(q), 153.03 (q), 157.13 (q), 170.58 (q).
HRMS (ESI): C23H23N3O4: calcd: 406.1761 [M+H]+;
found: 406.1764.
4.3.35. (5R,11aR)-2-Butyl-5-(2,3-dihydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione cis-20. Yield: 45%, purple solid.
HRMS (ESI): C25H19N3O3: calcd: 410.1499 [M+H]+;
found: 410.1500.
TM = 154 ꢂC.
4.3.38. (5S,11aR)-5-(3-Hydroxyphenyl)-2-phenyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-21. Yield: 35%, pale yellow solid.
1H NMR (200 MHz, DMSO-d6): d = 0.90 (t, J = 7.2 Hz,
3H, CH3), 1.26 (m, 2H, CH2CH3), 1.49 (m, 2H,
CH2CH2CH3), 2.93 (m, 1H, CHaHb), 3.33 (m, 1H,
CHaHb), 3.42 (m, 2H, NCH2), 4.52 (dd, J1 = 4.5 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.70 (s, 1H, CHPh),
6.64–7.57 (m, 7H, ar), 8.80 (br, 2H, 2· OH), 10.67 (br,
1H, NH).
TM = 161 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 3.10 (m, 1H,
CHaHb), 3.48 (m, 1H, CHaHb), 4.70 (dd, J1 = 5.4 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.24 (s, 1H, CHPh),
6.78–7.61 (m, 13H, ar), 11.12 (br, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.47 (p), 19.34 (s),
21.97 (s), 29.67 (s), 37.35 (s), 55.53 (t), 57.59 (t), 104.66
(q), 111.24 (t), 114.66 (t), 115.09 (t), 117.98 (t), 118.69 (t),
118.78 (t), 121.22 (t), 125.88 (q), 131.37 (q), 135.36 (q),
136.58 (q), 144.77 (q), 144.87 (q), 153.97 (q), 171.66 (q).
13C NMR (75 MHz, DMSO-d6): d = 22.65 (s), 51.66 (t),
52.80 (t), 106.09 (q), 111.42 (t), 114.99 (t), 115.25 (t),
118.15 (t), 118.23 (t), 118.39 (t), 118.86 (t), 121.71 (t),
125.82 (q), 126.93 (t), 127.95 (t), 128.74 (t), 129.77 (t),
131.11 (q), 131.95 (q), 136.69 (t), 141.17 (2· q), 153.27
(q), 157.96 (q), 171.61 (q).
HRMS (ESI): C23H23N3O4: calcd: 406.1761 [M+H]+;
found: 406.1759.

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6107
HRMS (ESI): C25H19N3O3: calcd: 410.1499 [M+H]+;
found: 410.1496.
HRMS (ESI): C26H21N3O3: calcd: 424.1656 [M+H]+;
found: 424.1656.
4.3.39.
(5R,11aR)-5-(3-Hydroxyphenyl)-2-phenyl-6H-
4.3.42.
(5S,11aR)-2-Benzyl-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione cis-22. Yield: 61%, yellow solid.
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione trans-23. Yield: 79%, brown solid.
TM = 171 ꢂC (decomp.).
TM = 151 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 3.09 (m, 1H,
CHaHb), 3.45 (m, 1H, CHaHb), 4.73 (dd, J1 = 4.2 Hz,
J2 = 11.4 Hz, 1H, CHC(O)N), 5.87 (s, 1H, CHPh),
6.65–7.61 (m, 13H, ar), 9.35 (s, 1H, OH), 10.81 (br,
1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.82 (m, 1H,
CHaHb), 3.38 (m, 1H, CHaHb), 4.55–4.62 (m, 3H,
CHC(O)N, CH2Ph), 6.16 (s, 1H, CHPh), 6.70–7.56 (m,
13H, ar), 9.47 (s, 1H, OH), 10.93 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 23.51 (s), 42.16 (s),
52.24 (t), 53.68 (t), 106.68 (q), 112.15 (t), 115.55 (t),
115.89 (t), 118.95 (t), 119.21 (t), 119.56 (t), 122.44 (t),
126.51 (q), 128.11 (2· t), 128.18 (t), 129.31 (2· t),
130.54 (q), 131.87 (q), 137.32 (q), 137.42 (t), 142.05
(q), 154.81 (q), 158.38 (q), 173.22 (q).
13C NMR (50 MHz, DMSO-d6): d = 21.86 (s), 55.93 (t),
57.66 (t), 104.93 (q), 111.34 (t), 113.86 (t), 114.22 (t),
114.44 (t), 118.18 (t), 118.85 (t), 121.45 (t), 121.80 (t),
125.89 (q), 126.51 (t), 127.77 (t), 128.77 (t), 129.19 (t),
131.93 (q), 134.66 (q), 136.69 (t), 139.70 (q), 142.00
(q), 153.10 (q), 157.19 (q), 170.67 (q).
HRMS (ESI): C26H21N3O3: calcd: 424.1656 [M+H]+;
found: 424.1647.
HRMS (ESI): C25H19N3O3: calcd: 410.1499 [M+H]+;
found: 410.1501.
4.3.43.
(5R,11aR)-2-Benzyl-5-(3-hydroxyphenyl)-6H-
4.3.40. (5R,11aS)-5-(3-Hydroxyphenyl)-2-phenyl-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
trans-22. Yield: 97%, dark brown solid.
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione cis-24. Yield: 86%, yellow solid.
TM = 204 ꢂC.
TM = 168 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 3.04 (m, 1H,
CHaHb), 3.38 (m, 1H, CHaHb), 4.58–4.68 (m, 3H,
CHC(O)N, CH2Ph), 5.82 (s, 1H, CHPh), 6.64–7.59 (m,
13H, ar), 9.34 (s, 1 H, OH), 10.78 (s, 1 H, NH).
1H NMR (200 MHz, DMSO-d6): d = 3.08 (m, 1H,
CHaHb), 3.44 (m, 1H, CHaHb), 4.70 (dd, J1 = 5.4 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.24 (s, 1H, CHPh), 6.75–
7.62 (m, 13H, ar), 9.52 (s, 1H, OH), 11.00 (br, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 22.62 (s), 41.88 (s),
56.49 (t), 58.45 (t), 105.55 (q), 112.06 (t), 114.96 (t),
115.21 (t), 118.87 (t), 118.94 (t), 119.57 (t), 122.13 (t),
126.59 (q), 128.14 (2· t), 129.23 (2· t), 129.90 (q),
128.89 (t), 135.52 (q), 137.34 (t), 137.38 (q), 142.76 (q),
154.61 (q), 157.94 (q), 172.36 (q).
13C NMR (75 MHz, DMSO-d6): d = 22.65 (s), 51.63 (t),
52.80 (t), 106.12 (q), 111.43 (t), 114.91 (t), 115.18 (t),
118.17 (t), 118.64 (t), 118.88 (t), 121.73 (t), 121.81 (t),
125.82 (q), 126.93 (t), 127.96 (t), 128.75 (t), 128.80 (t),
129.81 (q), 131.07 (q), 131.95 (t), 136.70 (q), 141.21
(q), 153.29 (q), 157.66 (q), 171.61 (q).
HRMS (ESI): C26H21N3O3: calcd: 424.1656 [M+H]+;
found: 424.1653.
HRMS (ESI): C25H19N3O3: calcd: 410.1499 [M+H]+;
found: 410.1494.
4.3.44.
(5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-
4.3.41. (5S,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,
3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione
cis-23. Yield: 94%, pale yellow solid.
1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione trans-24. Yield: 79%, brown solid.
TM = 148 ꢂC.
TM = 131 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 2.86 (m, 1H,
CHaHb), 3.40 (m, 1H, CHaHb), 4.59–4.65 (m, 3H,
CHC(O)N, CH2Ph), 6.19 (s, 1H, CHPh), 6.74–7.59 (m,
13H, ar), 9.51 (s, 1H, OH), 10.98 (s, 1H, NH).
1H NMR (200 MHz, DMSO-d6): d = 3.00 (m, 1H,
CHaHb), 3.35 (m, 1H, CHaHb), 4.53–4.65 (m, 3H,
CHC(O)N, CH2Ph), 5.76 (s, 1H, CHPh), 6.59–7.55 (m,
13H, ar), 9.27 (s, 1H, OH), 10.71 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 23.50 (s), 42.14 (s),
52.23 (t), 53.66 (t), 106.65 (q), 112.11 (t), 115.52 (t),
115.87 (t), 118.93 (t), 119.19 (t), 119.57 (t), 122.42 (t),
126.49 (q), 128.08 (t), 128.17 (2· t), 129.30 (2· t),
130.52 (q), 131.86 (t), 137.29 (q), 137.38 (q), 142.02
(q), 154.79 (q), 158.34 (q), 173.21 (q).
13C NMR (50 MHz, DMSO-d6): d = 22.58 (s), 41.81 (s),
56.45 (t), 58.41 (t), 105.49 (q), 112.01 (t), 114.92 (t),
115.16 (t), 118.82 (t), 118.88 (t), 119.51 (t), 122.09 (t),
126.55 (q), 127.23 (q), 127.68 (t), 128.06 (t), 128.89 (t),
129.19 (t), 129.84 (t), 135.47 (q), 137.28 (t), 137.33 (q),
142.71 (q), 154.57 (q), 157.88 (q), 172.27 (q).

6108
N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
HRMS (ESI): C26H21N3O3: calcd: 424.1656 [M+H]+;
found: 424.1656.
1H, CCHaHb), 3.38 (m, 1H, CCHaHb), 3.63 (m, 3H,
OCH3), 4.69 (m, 2H, CHC(O)N, NCHC(O)OMe),
5.79 (s, 1H, CHPh), 6.63–7.60 (m, 8H, ar), 9.31 (s, 1H,
OH), 10.82 (br, 1H, NH).
4.3.45. Methyl(2S)-4-methyl-2-(5S,11aS)-5-(3-hydroxy-
phenyl)-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydro-imidazo-
[1,5-b]-b-carboline-pentanoate cis-25. Yield: 13%, brown
solid.
13C NMR (600 MHz, DMSO-d6): d = 20.82 (p), 22.08
(s), 23.09 (p), 24.31 (t), 36.43 (s), 49.89 (t), 52.37 (p),
55.47 (t), 57.14 (t), 104.18 (q), 111.32 (t), 113.77 (t),
114.38 (t), 117.67 (t), 118.14 (t), 118.83 (t), 121.43 (t),
125.85 (q), 129.10 (t), 134.72 (q), 136.61 (q), 142.09
(q), 153.05 (q), 157.25 (q), 169.66 (q), 171.52 (q).
TM = 123 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.90 (m, 6H,
CH(CH3)2), 1.56 (m, 1H, CH(CH3)2), 1.77 (m, 1H,
CHCHaHbCH), 2.06 (m, 1H, CHCHaHbCH), 2.92 (m,
1H, CCHaHb), 3.41 (m, 1H, CCHaHb), 3.63 (m, 3H,
OCH3), 4.69 (m, 2H, CHC(O)N, NCHC(O)OMe),
5.85 (s, 1H, CHPh), 6.61–7.59 (m, 8H, ar), 9.34 (s, 1H,
OH), 10.80 (br, 1H, NH).
HRMS (ESI): C26H27N3O5: calcd: 462.2024 [M+H]+;
found: 462.2012.
4.3.48. Methyl(2S)-4-methyl-2-(5R,11aS)-5-(3-hydroxyphe-
nyl)-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-
b-carboline-pentanoate trans-26. Yield: 61%, brown
solid.
13C NMR (75 MHz, DMSO-d6): d = 20.88 (p), 22.22 (s),
23.03 (p), 24.33 (t), 36.23 (s), 50.12 (t), 52.57 (p), 55.71
(t), 57.16 (t), 104.40 (q), 111.31 (t), 114.04 (t), 114.44
(t), 117.90 (t), 118.07 (t), 118.81 (t), 121.40 (t), 125.84
(q), 129.11 (t), 134.68 (q), 136.61 (q), 141.85 (q),
153.02 (q), 157.21 (q), 169.58 (q), 171.47 (q).
TM = 70 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.82–0.90 (m, 6H,
CH(CH3)2), 1.47 (m, 1H, CH(CH3)2), 1.81 (m, 1H,
CHCHaHbCH), 2.09 (m, 1H, CHCHaHbCH), 2.77 (m,
1H, CCHaHb), 3.49 (m, 1H, CCHaHb), 3.66 (m, 3H,
OCH3), 4.63–4.78 (m, 2H, CHC(O)N, NCHC(O)OMe),
6.20 (s, 1H, CHPh), 6.75–7.61 (m, 8H, ar), 9.59 (s, 1H,
OH), 11.02 (br, 1H, NH).
HRMS (ESI): C26H27N3O5: calcd: 462.2024 [M+H]+;
found: 462.2026.
4.3.46. Methyl(2S)-4-methyl-2-(5S,11aR)-5-(3-hydroxy-
phenyl)-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydro-imidazo-
[1,5-b]-b-carboline-pentanoate trans-25. Yield: 65%,
brown solid.
13C NMR (75 MHz, DMSO-d6): d = 20.63 (p), 22.76 (s),
23.02 (p), 24.67 (t), 36.29 (s), 50.20 (t), 51.81 (p), 52.78
(t), 53.04 (t), 105.72 (q), 111.43 (t), 114.50 (t), 114.87
(t), 117.93 (t), 118.36 (t), 118.99 (t), 121.71 (t), 125.55
(q), 129.67 (t), 130.86 (q), 136.69 (q), 141.22 (q),
153.67 (q), 157.22 (q), 169.43 (q), 171.96 (q).
TM = 102 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.84 (m, 6H,
CH(CH3)2), 1.39 (m, 1H, CH(CH3)2), 1.76 (m, 1H,
CHCHaHbCH), 2.05 (m, 1H, CHCHaHbCH), 2.71 (m,
1H, CCHaHb), 3.43 (m, 1H, CCHaHb), 3.61 (m, 3H,
OCH3), 4.57–4.72 (m, 2H, CHC(O)N, NCHC(O)OMe),
6.14 (s, 1H, CHPh), 6.70–7.56 (m, 8H, ar), 9.49 (s, 1H,
OH), 10.95 (br, 1H, NH).
HRMS (ESI): C26H27N3O5: calcd: 462.2024 [M+H]+;
found: 462.2021.
4.3.49. (5S, 11aR)-2-Butyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 27. Yield: 84%, yellow-greenish solid.
13C NMR (75 MHz, DMSO-d6): d = 20.83 (p), 22.96 (s),
23.10 (p), 24.45 (t), 36.42 (s), 50.36 (t), 51.39 (p), 52.57
(t), 52.64 (t), 105.68 (q), 111.41 (t), 114.56 (t), 114.67
(t), 118.24 (t), 118.35 (t), 118.89 (t), 121.77 (t), 125.68
(q), 129.81 (t), 130.96 (q), 136.62 (q), 141.12 (q),
153.49 (q), 157.62 (q), 169.63 (q), 172.39 (q).
TM = 52 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.90 (t, J = 6.8 Hz,
3H, CH3), 1.28 (m, 2H, CH2CH3), 1.61 (m, 2H,
CH2CH2CH3), 2.93 (m, 1H, CHaHb), 3.49 (m, 1H,
CHaHb), 3.76 (m, 2H, NCH2), 4.79 (dd, J1 = 6.2 Hz,
J2 = 10.9 Hz, 1H, CHC(O)N), 6.73–6.78 (m, 1H, ar),
6.84 (s, 1H, CHPh), 6.89–7.59 (m, 7H, ar), 9.51 (s, 1H,
OH), 11.05 (s, 1H, NH).
HRMS (ESI): C26H27N3O5: calcd: 484.1843 [M+Na]+;
found: 484.1843.
4.3.47.
Methyl(2S)-4-methyl-2-(5R,11aR)-5-(3-hydroxy-
phenyl)-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydro-imidazo-
[1,5-b]- b-carboline-pentanoate cis-26. Yield: 15%, yellow
solid.
13C NMR (75 MHz, DMSO-d6): d = 13.62 (p), 19.47 (s),
23.05 (s), 29.35 (s), 40.41 (s), 54.94 (t), 55.32 (t), 105.61
(q), 111.44 (t), 115.36 (t), 115.45 (t), 118.30 (t), 118.96
( 2· t), 121.84 (t), 125.62 (q), 129.69 (t), 131.22 (q),
136.76 (q), 140.10 (q), 157.54 (q), 173.19 (q), 179.78
(q).
TM = 127 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (m, 6H,
CH(CH3)2), 1.55 (m, 1H, CH(CH3)2), 1.76 (m, 1H,
CHCHaHbCH), 2.08 (m, 1H, CHCHaHbCH), 2.95 (m,
HRMS (ESI): C23H23N3O2S: calcd: 406.1584 [M+H]+;
found: 406.1587.

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6109
4.3.50. (5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 28. Yield: 92%, yellow solid.
HRMS (ESI): C22H20N3O2S: calcd: 390.1271[M+H]+;
found: 390.1272.
4.3.53. (5S,11aS)-5-(3-Hydroxyphenyl)-2-[2-(trifluormeth-
oxy)phenyl]-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1,3-dione cis-31. Yield: 44%, pale yellow solid.
TM = 78 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 0.91 (t, J = 6.8 Hz,
3H, CH3), 1.28 (m, 2H, CH2CH3), 1.61 (m, 2H,
CH2CH2CH3), 2.93 (m, 1H, CHaHb), 3.49 (m, 1H,
CHaHb), 3.76 (m, 2H, NCH2), 4.79 (dd, J1 = 6.2 Hz,
J2 = 10.9 Hz, 1H, CHC(O)N), 6.73–6.78 (m, 1H, ar),
6.84 (s, 1H, CHPh), 6.89–7.59 (m, 7H, ar), 9.51 (s, 1H,
OH), 11.05 (s, 1H, NH).
TM = 159 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 2.99 (m, 1H, CHa
Hb), 3.52 (m, 1H, CHaHb), 4.82 (dd, J1 = 3.9 Hz, J2 =
11.4 Hz, 1H, CHC(O)N), 5.89 (s, 1H, CHPh), 6.67–
7.64 (m, 12H, ar), 9.36 (s, 1H, OH), 10.86 (s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 13.62 (p), 19.47 (s),
23.05 (s), 29.35 (s), 40.41 (s), 54.94 (t), 55.32 (t), 105.61
(q), 111.44 (t), 115.36 (t), 115.45 (t), 118.30 (t), 118.96
( 2· t), 121.84 (t), 125.62 (q), 129.69 (t), 131.22 (q),
136.76 (q), 140.11 (q), 157.54 (q), 173.20 (q), 179.79 (q).
13C NMR (50 MHz, DMSO-d6): d = 22.40 (s), 55.97 (t),
57.75 (t), 104.50 (q), 111.38 (t), 114.38 (t), 114.51 (t),
117.65 (t), 118.19 (t), 118.91 (t), 121.51 (t), 121,84 (t),
124.61 (q), 125.88 (t), 127.83 (t), 128.10 (q), 129.10 (t),
130.94 (t), 134.69 (q), 136.75 (q), 141.78 (q), 144.46
(q), 152.13 (q), 157.28 (q), 165.02 (q), 170.23 (q).
HRMS (ESI): C23H23N3O2S: calcd: 406.1584 [M+H]+;
found: 406.1585.
HRMS (ESI): C26H18F3N3O4: calcd: 494.1322 [M+H]+;
found: 494.1319.
4.3.51. (5S,11aR)-2-Allyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 29. Yield: 98%, yellow solid.
4.3.54. (5S,11aR)-5-(3-Hydroxyphenyl)-2-[2-(trifluormeth-
oxy)phenyl]-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1,3-dione trans-31. Yield: 90%, brown solid.
TM = 116 ꢂC.
TM = 158 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 2.97 (m, 1H,
CHaHb), 3.49 (m, 1H, CHaHb), 4.38 (m, 2H, NCH2),
4.84 (dd, J1 = 6.1 Hz, J2 = 10.7 Hz, 1H, CHC(O)N),
5.13 (m, 2H, CHCH2), 5.85 (m, 1H, CHCH2), 6.73–
6.78 (m, 1H, ar), 6.85 (s, 1H, CHPh), 6.90–7.60 (m,
7H, ar), 9.52 (s, 1H, OH), 11.06 (br, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.79 (m, 1H,
CHaHb), 3.54 (m, 1H, CHaHb), 4.78 (dd, J1 = 5.1 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.29 (s, 1H, CHPh),
6.77–7.67 (m, 12H, ar), 9.54 (s, 1H, OH), 11.04 (s, 1H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 23.03 (s), 42.88 (s),
55.04 (t), 55.40 (t), 105.57 (q), 111.41 (t), 115.38 (t),
116.76 (t), 116.97 (t), 118.25 (s), 118.89 (t), 121.81 (t),
125.59 (q), 129.63 (t), 131.13 (t), 131.39 (q), 131.65 (t),
136.72 (q), 140.01 (q), 157.49 (q), 172.71 (q), 179.46 (q).
13C NMR (75 MHz, DMSO-d6): d = 22.52 (s), 51.80 (t),
53.26 (t), 105.62 (q), 111.46 (t), 115.08 (t), 115.19 (t),
115.28 (t), 118.29 (t), 118.60 (t), 118.92 (t), 121.84 (t),
124.43 (q), 125.79 (t), 125.79 (t), 128.42 (q), 129.78 (t),
131.04 (q), 131.23 (q), 136.69 (t), 140.95 (q), 144.55
(q), 152.42 (q), 157.65 (q), 171.02 (q).
HRMS (ESI): C22H20N3O2S: calcd: 390.1271[M+H]+;
found: 390.1273.
HRMS (ESI): C26H18F3N3O4: calcd: 494.1322 [M+H]+;
found: 494.1312.
4.3.52. (5R,11aS)-2-Allyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 30. Yield: 98%, yellow solid.
4.3.55. (5R,11aR)-5-(3-Hydroxyphenyl)-2-[2-(trifluormeth-
oxy)phenyl]-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1,3-dione cis-32. Yield: 44%, yellow solid.
TM = 70 ꢂC.
TM = 175 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 2.96 (m, 1H,
CHaHb), 3.50 (m, 1H, CHaHb), 4.35 (m, 2H, NCH2),
4.84 (dd, J1 = 6.2 Hz, J2 = 10.8 Hz, 1H, CHC(O)N),
5.07 (m, 2H, CHCH2), 5.82 (m, 1H, CHCH2), 6.75–
6.78 (m, 1H, ar), 6.85 (s, 1H, CHPh), 6.91–7.60 (m,
7H, ar), 9.53 (s, 1H, OH), 11.01 (br, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.93 (m, 1H,
CHaHb), 3.45 (m, 1H, CHaHb), 4.80 (dd, J1 = 3.9 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 5.87 (s, 1H, CHPh), 6.65–
7.63 (m, 12H, ar), 9.35 (s, 1H, OH), 10.84 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d = 23.09 (s), 56.67 (t),
58.67 (t), 105.18 (q), 112.10 (t), 115.06 (t), 115.19 (t),
118.33 (t), 118.96 (t), 119.64 (t), 122.25 (t), 122.67 (t),
125.33 (q), 126.58 (q), 128.58 (q), 128.92 (t), 129.84 (t),
131.61 (t), 131.73 (t), 135.42 (q), 136.43 (q), 142.50 (q),
145.14 (q), 152.86 (q), 158.01 (q), 171.00 (q).
13C NMR (75 MHz, DMSO-d6): d = 23.74 (s), 43.61 (s),
55.77 (t), 56.15 (t), 106.32 (q), 112.16 (t), 116.01 (t),
116.14 (t), 117.70 (s), 119.05 (t), 119.65 (t), 119.70 (t),
122.58 (t), 126.32 (q), 130.41 (t), 131.89 (q), 132.42 (t),
137.46 (q), 140.77 (q), 158.24 (q), 173.50 (q), 180.21 (q).

6110
N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
HRMS (ESI): C26H18F3N3O4: calcd: 494.1322 [M+H]+;
found: 494.1313.
HRMS (ESI): C21H19N3O2S H+: calcd: 378.1271
[M+H]+; found: 378.1270.
4.3.56. (5R,11aS)-5-(3-Hydroxyphenyl)-2-[2-(trifluormeth-
oxy)phenyl]-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1,3-dione trans-32. Yield: 44%, brown solid.
4.3.59. (5S,11aR)-5-(3-Hydroxyphenyl)-2-phenyl-3-thi-
oxo-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carbo-
line-1-on 35. Yield: quant., auburn solid.
TM = 160 ꢂC.
TM = 118 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 2.80 (m, 1H,
CHaHb), 3.55 (m, 1H, CHaHb), 4.79 (m, 1H,
CHC(O)N), 6.30 (s, 1H, CHPh), 6.79–7.68 (m, 12H,
ar), 9.57 (s, 1H, OH), 11.08 (s, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 3.19– 3.59 (m, 2H,
CHaHb), 4.98 (dd, J1 = 6.2 Hz, J2 = 10.8 Hz, 1H, CHC
(O)N), 6.78 (m, 1H, ar), 6.94 (s, 1H, CHPh), 6.96–7.63
(m, 12H, ar), 9.57 (s, 1H, OH), 11.10 (br, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 22.62 (s), 51.80 (t),
53.26 (t), 105.62 (q), 111.45 (t), 114.98 (t), 115.13 (t),
115.26 (t), 118.09 (t), 118.40 (t), 118.92 (t), 121.78 (t),
124.22 (q), 125.71 (q), 125.79 (q), 128.14 (t), 129.70 (t),
129.77 (t), 131.07 (t), 131.23 (q), 136.67 (q), 140.94 (q),
144.51 (q), 152.41 (q), 157.62 (q), 171.01 (q).
13C NMR (75 MHz, DMSO-d6): d = 23.04 (s), 55.18 (t),
55.77 (t), 105.73 (q), 111.49 (t), 115.46 (t), 115.64 (t),
118.33 (t), 119.03 (t), 119.21 (t), 121.89 (t), 125.69 (q),
125.97 (t), 128.01 (t), 128.76 (t), 129.07 (t), 129.74 (t),
129.93 (t), 131.24 (q), 133.56 (q), 136.79 (q), 140.04
(q), 157.60 (q), 172.67 (q), 179.82 (q).
HRMS (ESI): C26H18F3N3O4: calcd: 494.1322 [M+H]+;
found: 494.1324.
HRMS (ESI): C25H19N3O2S: calcd: 426.1271 [M+H]+;
found: 426.1266.
4.3.57. (5S,11aR)-2-Ethyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 33. Yield: 24%, brown solid.
4.3.60.
(5R,11aS)-5-(3-Hydroxyphenyl)-2-phenyl-3-
thioxo-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-
carboline-1-on 36. Yield: quant., auburn solid.
TM = 118 ꢂC.
TM = 107 ꢂC.
1H NMR (300 MHz, DMSO-d6): d = 1.17 (t, J = 7.0 Hz,
3H, CH3), 2.94 (m, 1H, CHaHb), 3.48 (m, 1H, CHaHb),
3.80 (m, 2H, NCH2), 4.79 (dd, J1 = 6.2 Hz, J2 = 10.6 Hz,
1H, CHC(O)N), 6.84 (s, 1H, CHPh), 6.69–7.54 (m, 8H,
ar), 9.46 (s, 1H, OH), 11.00 (br, 1H, NH).
1H NMR (300 MHz, DMSO-d6): d = 3.23 (m, 1H,
CHaHb), 3.56 (m, 1H, CHaHb), 4.99 (dd, J1 = 6.3 Hz,
J2 = 10.8 Hz, 1H, CHC(O)N), 6.78 (m, 1H, ar), 6.95
(s, 1H, CHPh), 6.97–7.63 (m, 12H, ar), 9.58 (s, 1H,
OH), 11.11 (br, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 12.73 (p), 22.83 (s),
35.88 (s), 54.81 (t), 56.26 (t), 105.52 (q), 111.33 (t),
115.26 (t), 115.35 (t), 118.16 (t), 118.86 (2· t), 121.73
(t), 125.54 (q), 129.54 (t), 131.11 (q), 136.68 (q), 139.98
(q), 157.43 (q), 172.76 (q), 179.43 (q).
13C NMR (50 MHz, DMSO-d6): d = 23.03 (s), 55.13 (t),
55.71 (t), 105.67 (q), 111.41 (t), 115.40 (t), 115.58 (t),
118.24 (t), 118.95 (t), 119.13 (t), 121.81 (t), 125.63 (q),
125.85 (t), 127.90 (t), 128.66 (t), 128.97 (t), 129.64 (t),
129.83 (q), 131.16 (q), 133.48 (t), 136.73 (q), 139.67
(q), 157.53 (q), 172.55 (q), 179.74 (q).
HRMS (ESI): C21H19N3O2S H+: calcd: 378.1271
[M+H]+; found: 378.1266.
HRMS (ESI): C25H19N3O2S: calcd: 426.1271 [M+H]+;
found: 426.1267.
4.3.58. (5R,11aS)-2-Ethyl-5-(3-hydroxyphenyl)-3-thioxo-
6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-b-carboline-
1-on 34. Yield: quant., pale yellow solid.
4.3.61. Methyl N-(oxomethylen)-L-leucinate 37. Caution!
The evolving phosgene is a very toxic gas!.
TM = 132 ꢂC.
To a solution of L-leucine methylester (1.18 g, 6.5 mmol)
in a mixture of dichloromethane (25 ml) and sat. NaH-
CO3-solution (25 ml), triphosgen (0.65 g, 2.2 mmol,
0.34 equiv) was added at 0 ꢂC under vigorous stirring.
After 15 min, the reaction was warmed to rt and extracted
three times with ethylacetate. The combined organic lay-
ers were dried over Na2SO4 and concentrated in vacuo.
1H NMR (200 MHz, DMSO-d6): d = 1.16 (t, J = 7.3
Hz, 3H, CH3), 2.97 (m, 1H, CHaHb), 3.46 (m, 1H,
CHaHb), 3.75 (m, 2H, NCH2), 4.78 (dd, J1 = 6.2 Hz,
J2 = 10.7 Hz, 1H, CHC(O)N), 6.84 (s, 1H, CHPh),
6.77–7.55 (m, 8H, ar), 9.51 (s, 1H, OH), 11.05 (br, 1H,
NH).
Yield: 945 mg, 5.5 mmol, 85%, colorless oil.
13C NMR (75 MHz, DMSO-d6): d = 12.78 (p), 22.84 (s),
35.90 (s), 54.83 (t), 55.30 (t), 105.57 (q), 111.38 (t),
115.31 (t), 115.40 (t), 118.23 (t), 118.92 (2· t), 121.79
(t), 125.58 (q), 129.62 (t), 131.15 (q), 136.72 (q), 140.05
(q), 157.48 (q), 172.84 (q), 179.47 (q).
1H NMR (300 MHz, DMSO-d6): d = 0.91 (d, 6H,
2· CH3), 1.50–1.74 (m, 3H, CH2CH(CH3)2), 3.77 (s,
3H, OCH3), 4.40 (dd, J1 = 3.6 Hz, J2 = 5.8 Hz, 1H,
NCH).

N. Sunder-Plassmann et al. / Bioorg. Med. Chem. 13 (2005) 6094–6111
6111
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