Diastereodivergent synthesis of 2,5-diketopiperazine derivatives of β-carboline and isoquinoline from L-amino acids

Article abstract of DOI:10.1016/j.tetasy.2005.01.009

Mild Pictet-Spengler-type condensation was applied to the synthesis of several tetrahydro-β-carboline and tetrahydro-isoquinoline derivatives. l-Amino acids were promoters of 1,4-chirality transfer with up to 100% de. The stereochemistry of the final dike

Full text of DOI:10.1016/j.tetasy.2005.01.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 975–993
Diastereodivergent synthesis of 2,5-diketopiperazine derivatives
of b-carboline and isoquinoline from L-amino acids
Aleksandra Siwicka,a Krystyna Wojtasiewicz,a Beata Rosiek,a Andrzej Leniewski,a
Jan K. Maurinb,c and Zbigniew Czarnockia,*
aFaculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
bNational Institute of Public Health, Chełmska 30/34, 00-750 Warsaw, Poland
c
´
Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland
Received 4 November 2004; accepted 11 January 2005
Abstract—Mild Pictet–Spengler-type condensation was applied to the synthesis of several tetrahydro-b-carboline and tetrahydro-
isoquinoline derivatives. L-Amino acids were promoters of 1,4-chirality transfer with up to 100% de. The stereochemistry of the final
diketopiperazines strongly depended on the structure of the L-amino acids used: acyclic amino acids gave predominantly the (R)-
configuration at the newly created stereogenic centre, whereas L-proline afforded the opposite configuration, as established by X-
ray crystallography.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
in their enantiomerically pure forms. Apart from the
Pictet–Spengler reaction,3 which is probably the most
popular in this field, several other methods such as
stereoassisted Bischler–Napieralski4 or Pommeranz–
Fritsch5 condensations, asymmetric nucleophilic and
electrophilic introduction of a carbon unit at C-16 or
reductions of dihydroderivatives employing chiral or
achiral hydride reagents7 have been utilized.8 Some of
these approaches have found their applications in the
enantioselective creation of quaternary carbon centres,
a challenging target to organic chemists. In the case of
alkaloids based on isoquinoline or b-carboline skele-
tons, where the configuration at C-1 is closely related
to the bioactivity, all the above mentioned methods have
been extensively explored.
One of the most challenging topics in modern organic
chemistry is the synthesis of natural products. Despite
the considerable exploration to date within this field,
there is still a need for further development of alterna-
tive, preferably biomimetic and/or catalytic ways of
preparation for the bioactive compounds.
Among the numerous families of natural products, iso-
quinoline and b-carboline alkaloids seem to attract the
biggest attention due to their abundant presence in plant
and even in the animal kingdom, along with their often
important physiological activities.1 Their bioactivity
ranges from highly toxic, for example, strychnine to
the antihypertensive, for example, ajmalicyne and the
cytotoxic activity shown by vincoleucoblastine and vin-
cristine used for cancer chemotherapy.2 Several of them
show phenanthridine inhibiting action towards HIV 1
and 2 reverse transcriptases.2 The biodifferentiation
of enantiomers together with clinical applications and
regulatory pressure upon the pharmaceutical industry,
constitute important reasons for the preparation of
tetrahydroisoquinolines and of tetrahydro-b-carbolines
Herein the goal is the development of effective, diaste-
reoselective preparations of some diketopiperazine
derivatives of isoquinoline and indole-based systems.
The 2,5-diketopiperazine (DKP) scaffold is interesting
being a fundamental part of numerous natural products,
often formed by the cyclization of dipeptides. These
compounds exhibit a wide range of biological activities9
and, due to their rigid structure imposed by diketopiper-
azine unit, can mimic a particular peptide conforma-
tion.10 There are several examples of employing DKPꢀs
as building blocks11 or chiral auxiliaries.12 It has also
been shown that the presence of diketopiperazine
*
Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59
96; e-mail: czarnoz@chem.uw.edu.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.009

976
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
intermediates in a synthetic sequence can affect in unu-
sual ways the reaction pathway and stereochemistry of
products.13 Lazaro et al. applied the DKP scaffold to
constrain heterocycles that can act as inhibitors of plate-
let aggregation and of cell adhesion.10
Herein, we describe in detail our results concerning the
utilization of natural amino acids in the stereocontrolled
construction of diketopiperazine derivatives of some iso-
quinoline and b-carboline derivatives.25
The DKP ring is a substantial fragment of several mem-
bers of the structurally unique and potentially biologi-
cally important family of fumitremorgins.14 The
derivative formed from 6-methoxy-L-tryptophan and
L-proline causes severe tremorgenic reactions in mice
on either oral or intraperitoneal administration.15 Fur-
ther research showed that fumitremorgin C reverses
the multi-drug resistance in cells transfected with the
breast cancer resistance protein.16 Therefore, it is not
surprising that several approaches focused on total syn-
theses of those mycotoxins have recently been com-
pleted.17 The diketopiperazine skeleton could be used
as a readily available building block,18 created during
the reaction sequence in the cyclization step.19
2. Results and discussion
The approach presented is based on the idea that during
biosynthesis reactive groups along a peptide chain influ-
ence the stereochemistry created in natural alkaloids.28
Recently this hypothesis was strongly supported by the
finding that the Pictet–Spengler reaction is responsible
for the endogenous alkaloids formation in mammals
from dopa-contained enkephalins and aldehydes.29 We
have also found that effective 1,4-chirality transfer could
be realized under biomimetic conditions via Pictet–
Spengler-like reactions involving the rigid diketopiper-
azine system.
N-Blocked-N-methyl L-alanine 1, N-blocked-N-methyl
L-valine 2, N-blocked-N-methyl L-phenylalanine 3 or
N-blocked L-proline 4 served as the sources of chirality
in the reaction path outlined in Schemes 1–4. At the
beginning of the synthetic sequence, compounds 1 and
2 were subjected to a BOP-mediated coupling with
tryptamine and, after a palladium catalyzed deblocking
of the nitrogen atom under hydrogenolytic conditions
giving amides 7, and 8, respectively, with high chemical
yield (Scheme 1). In the subsequent reaction with phen-
ylpyruvic acid, again under BOP mediation, we obtained
diketoamides 9, and 11 with no observable racemiza-
tion. Unfortunately, it was impossible to isolate and
characterize either hydroxylactam 15 or 17 in this syn-
thetic sequence. In the next step, the Pictet–Spengler
cyclization was used to furnish a tetrahydro-b-carboline
system. Initially, the use of methanolic hydrogen chlo-
ride gave poor diastereoselectivity (55:45), which pre-
sumably was caused by unfavourable hydrogen
bonding with the solvent. Fortunately, the use of ethyl
acetate proved to be beneficial to stereoselectivity even
at room temperature. The tetrahydro-b-carboline deriv-
atives 23a and 23b were formed in a 93:7 diastereomeric
ratio, respectively, while the best result was obtained for
compound 9 from which 21a was obtained as a single
diastereomer (established on the basis of 1H NMR).
Such an excellent stereoselectivity together with good
chemical yields could be attributed to an intervention
of N-acylimminium ions as intermediates in the cycliza-
tion process. They play a remarkable role in a stereose-
lective carbon–carbon bond formation in nitrogen
heterocycles.30 Furthermore, intramolecular reactions
of cyclic N-acylimminium ions with p-nucleophiles pro-
ceed stereoselectively due to steric control provided by
substituents already present in the ring31 or along the
chain connecting the p-nucleophiles with the nitrogen
atom.32 These make them useful and attractive as adju-
vants in organic synthesis.33
The DKP system constitutes the key motif in a variety of
quinazolinone natural products such as fumiquinazo-
lines and fiscalins.20 An elegant and effective preparation
of certain diketopiperazine system with an unusual use
of photochemical method was presented recently by Sni-
der and Busuyek.21
The DKP skeleton prepared from natural amino acids
has also been used as an auxiliary in a general method
for the stereoselective synthesis of substituted a-amino
acids.22 The application of amino acids as stereopromo-
ters seems to be logical due to their widespread occur-
rence in living systems, accessibility in enantiomerically
pure form and well established chemical behaviour.
Moreover, amino acids could be utilized in many ways,
such as building blocks of a final molecule, chiral ligands
or parts of a catalyst applied in sub-molar amounts.
Therefore, their application in the stereoselective prepa-
ration of isoquinoline and b-carboline skeletons usually
gives effective results. A recently published successful
combination of the Pictet–Spengler condensation of
L-tryptophan with palladium catalyzed allenylation fol-
lowed by carbonylation reactions allowed a straightfor-
ward access to novel and complex indolic heterocycles.23
Another interesting approach to the synthesis of 1-
substituted tetrahydroisoquinolines was realized by
Kibayashi et al., who employed L-proline as a chiral
adjuvant.24
Recently, we proposed a general method for the con-
struction of isoquinoline and b-carboline systems, which
utilizes natural amino acids as the source of chirality.25
The obtained products are precursors of the so-called
mammalian alkaloids, endogenous compounds that are
supposed to play an important role in the pathogenesis
of Parkinsonian disease and in the generation of toxic
products under the influence of certain exogenous fac-
tors such as xenobiotics, alcohol, heroin or in an altered
metabolism in infection.26 The secondary metabolites
thus formed were even considered to be responsible
for mental illness such as schizophrenia, however this
hypothesis obviously needs further confirmation.27
The X-ray analysis of the predominant diastereomer
23a25b confirmed the same tendency as observed in the
analogous isoquinoline series25c and proven (R)-configu-
ration at the newly created stereogenic centre.

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
977
R1
Tryptamine
H2, Pd/C
HN
HN
O
BOP
HN
O
HOOC
NCbz
CH3
N
H
N
H
R1
CbzN
R1
CH3
CH3
1 R1=CH3
2 R1=CH(CH3)2
7 R1=CH3
5 R1=CH3
8 R1=CH(CH3)2
6 R1=CH(CH3)2
O
R1
OH
HO
O
N
O
HN
O
N
H
N
H
R
2
O
BOP
O
N
CH3
R1
R2
N
CH3
R1
O
15 R1=CH3 R2=Bn
9 R1=CH3 R2=Bn
16 R1=CH3 R2=CH3
17 R1=CH(CH3)2 R2=Bn
10 R1=CH3 R2=CH3
11 R1=CH(CH3)2 R2=Bn
18 R1=CH(CH3)2 R2=mClPhCH2
19 R1=CH(CH3)2 R2=CH3
20 R1=CH(CH3)2
12 R1=CH(CH3)2 R2=mClPhCH2
13 R1=CH(CH3)2 R2=CH3
14 R1=CH(CH3)2 R2=3,4(OCH2O)PhCH2
R2=3,4(OCH2O)PhCH2
7
8
6
9
solvent/HCl
12
N
H
21-26a
21-26b
N
O
R2
R2
12b
1
10
5
11
3
2
O
N
R1
R2
CH3
21 R1=CH3 R2=Bn
22 R1=CH3 R2=CH3
23 R1=CH(CH3)2 R2=Bn
24 R1=CH(CH3)2 R2=mClPhCH2
25 R1=CH(CH3)2 R2=CH3
26 R1=CH(CH3)2 R2=3,4(OCH2O)PhCH2
Scheme 1.
Tryptamine
BOP
H2, Pd/C
HN
HN
O
HN
O
N
H
N
H
HOOC
N
Cbz
CbzN
4
28
27
O
HO
R
HN
O
N
O
OH
N
N
H
O
H
R
R
O
O
BOP
N
N
O
33 R=Bn
29 R=Bn
34 R=mClPhCH2
35 R=CH3
30 R=mClPhCH2
31 R=CH3
36 R=3,4(OCH2O)PhCH2
32 R=3,4(OCH2O)PhCH2
7
8
6
9
R
R
12
N
H
37a-40a
37b-40b
12b
1
N
O
10
solvent/HCl
4
11
3
2
O
N
1'
R
3'
2'
37 R=Bn
38 R=mClPhCH2
39 R=CH3
40 R=3,4(OCH2O)PhCH2
Scheme 2.

978
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
H3CO
H3CO
H CO
1.
3
O
H3CO
H3CO
R
HN
O
R
H3C
NH2
OH
HN
HN
O
R
H3CO
O
HOOC
NCbz
CH3
H3C
O
BOP
N
CH3
BOP
O
2. H2, Pd/C
CH3
41 R=CH3
42 R=CH(CH3)2
43 R=CH2Ph
1 R=CH3
2 R=CH(CH3)2
3 R=CH2Ph
44 R=CH3
45 R=CH(CH3)2
46 R=CH2Ph
8
7
H3CO
H3CO
H3CO
H3CO
9
6
solvent/HCl
OH
N
O
R
11b
N
O
10
50a-52a
50b-52b
R
4
3
H3C
O
H3C
O
1
2
N
N
R
R
CH3
CH3
47 R=CH3
50 R=CH3
51 R=CH(CH3)2
52 R=CH2Ph
48 R=CH(CH3)2
49 R=CH2Ph
Scheme 3.
O
R
H3CO
H3CO
OH
H3CO
H3CO
O
HN
HN
O
HN
N
O
BOP
O
R
O
53
54 R=CH3
55 R=(OCH2O)PhCH2
56 R=pCH3OPhCH2
4
5
H3CO
H3CO
3
6
H3CO
H3CO
7
13a
N
O
OH
R
R
60a-62a
solvent/HCl
2
N
O
8
1
R
O
13
8a
R
O
60b-62b
N
9
N
11
10
57 R=CH3
58 R=(OCH2O)PhCH2
59 R=pCH3OPhCH2
60 R=CH3
61 R=(OCH2O)PhCH2
62 R=pCH3OPhCH2
Scheme 4.
In order to check the universality of the method we
decided to employ several derivatives of 2-oxopropanoic
acid (pyruvic acid) in analogous synthetic sequences.
The Pictet–Spengler cyclization of 12 gave compound
24 in a good chemical yield and an excellent diastereose-
lectivity (>99% as indicated by H NMR of the crude
reaction mixture). Even better results were obtained
when pyruvic acid itself was used. Treatment of keto-
amides 10 and 13 with hydrogen chloride in ethyl acetate
afforded tetrahydro-b-carboline derivatives 22 and 25,
respectively, as single diastereomers (22a and 25a,
1
according to H NMR spectroscopy).
1
Again, a final proof for the absolute stereochemistry
came from X-ray crystallography taken on the mono-
crystal of compound 25a (Fig. 1). It should be noted
N
N
O
N
H
CH3
H3C
O
CH3 CH3
25a
Figure 1. The chemical structure and the ORTEP diagram for compound 25a.

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
979
here, that for unknown reasons compounds 11, 12 and
14 were obtained only in quite low chemical yields due
to an extensive decomposition of the mixture and for-
mation of tar-like products.
acid–TFA or HClaq). As compound 37b appears to be
thermodynamically less stable, we presumed that under
an influence of the acid (TFA, room temperature; 10%
HCl, reflux) it will be transformed into the more stable
(3S,12bS) 37a. Even after 10 days we observed no reac-
tion. Therefore, it seems that the final b-carbolines and
isoquinolines were formed in a nonreversible Pictet–
Spengler reaction.
In order to avoid a somewhat troublesome N-methyl-
ation procedure for N-blocked-N-methyl L-alanine 1
and N-blocked-N-methyl L-valine 2 we employed a sim-
ilar synthetic path with N-nor-analogues of compounds
1 and 2. Although the initial steps were extremely effi-
cient and no racemization was observed, we were unable
to promote formation of the desired cyclic derivatives.
Presumably, the presence of a methyl group is crucial,
as it prevents the enolization process that disabled the
Pictet–Spengler reaction.
Despite many efforts, we were unable to obtain
well-formed crystals of compound 37a suitable for the
X-ray analysis. In a search for a better crystallising
derivative we decided to employ m-chlorophenylpyruvic
acid in the synthesis. The diketopiperazine derivative 38
was obtained with 41% chemical yield and very high dia-
stereoselectivity (98%, 38a:38b). The X-ray diffraction
measurements revealed the (S)-configuration at the C-1
quaternary carbon atom.25b
The high stereoselectivity observed in the predominant
formation of diastereomer 26a as well as 21a–25a clearly
follows our previous findings in the isoquinoline ser-
ies.25c Furthermore, we observed the opposite diastereo-
meric preference in the case of b-carbolines when
N-Cbz-L-proline 4 was used as the chiral adjuvant as it
was the case for isoquinolines.
Two further sets of experiments with L-proline as the chi-
rality source indicated the greater stability of selected
hydroxylactams over the corresponding ketoamide forms.
The amount of compound 36 after the coupling with
3-benzo[1,3]dioxyol-5-yl-pyruvic acid was undoubtedly
bigger than its diketoamide analogue 32, whereas the
reaction with 2-oxopropanoic acid (pyruvic acid) gave
only the cyclic tautomer 35. Consequently, 35 and 32 to-
gether with 36 were transformed in the Pictet–Spengler
cyclization into the desired b-carbolines 39 and 40,
respectively. The results of the X-ray analysis of the
minor diastereomer of 39 (39b) correlated with our prior
findings and confirmed (S)-configuration at the created
stereogenic centre in the predominant diastereomer
(Fig. 2). Here, as previously for 38a, also two independent
molecules are present in the asymmetric part of the crystal
lattice. Interestingly, the crystal packing, in spite of the
same crystal symmetry was dramatically different.
Amide 28 was conveniently prepared in two steps with
84% chemical yield. Subsequent coupling of 28 with
phenylpyruvic acid gave a mixture of ketoamide 29
and hydroxylactam 33, with the latter being the more
stable tautomeric form. The results of optimization of
the Pictet–Spengler cyclization made for the L-proline
series are presented below in Table 1. Temperature vari-
ations had only a slight effect, whereas the solvent
played the crucial role (Table 1).
Table 1. The solvent and temperature effect on the Pictet–Spengler
reaction of 37
Entry
Solvent
Temperature (ꢁC)
37a:37ba
The cyclization of 35 suffered from low diastereoselectiv-
ity. The use of trifluoroacetic or formic acid as the pro-
moters of cyclization process gave no observable
improvement. Finally, the utilization of Lewis acid
(BF3) gave a reasonable diastereoselectivity (75%, see
Table 2).
1
2
3
4
5
6
MeOH, HCl
THF, HCl
THF, HCl
THF, HCl
THF, HCl
AcOEt, HCl
5
55.5:44.5
80:20
83:17
71:29
78:22
93:7
5
25
40
66
25
a As established on the basis of 1H NMR.
The generality of the presented approach was further
demonstrated by the synthesis of two series of isoquino-
line derivatives with pyruvic acid. In one of them, acyclic
L-amino acids (Ala, Val and Phe) were used to give 41,
42 and 43, respectively.25c
In order to check if kinetic or thermodynamic factors
affect the cyclization process we treated the (3S,12bR)
diastereomer 37b with a strong acid (trifluoroacetic
N
N
O
N
H
H3C
O
39b
Figure 2. The chemical structure and the ORTEP diagram for compound 39b.

980
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
Table 2. The solvent influence on diastereomeric ratio of 39a:39b
ture. The strong preference for the formation of the
(R)-configuration at the quaternary carbon centre was
also observed in the case of ketoamides 45 (>99% de
of 51a) and 46 (65% de of 52a). The final proof for this
observation came from the X-ray analysis for the minor
diastereomer 52b in which the chirality was generated by
L-Phe (Fig. 4).
Entry
Solvent, rt
39a:39ba
De
% Yield
1
2
3
4
5
6
7
8
9
10
Ethyl acetate, HCl
Dichloromethane, HCl
Acetone, HCl
Ether, HCl
67:33
60:40
33
20
20
33
10
24
20
24
24
75
85
79
64
81
67
54
48
38
41
75
60:40
67:33
THF, HCl
DMF, HCl
55.5:44.5
62:38
60:40
DMSO, HCl
TFA, neat
When L-Pro was used as the stereochemistry promoter,
compounds 54–56 were obtained efficiently from the
amide 5324 and the appropriate (aryl)pyruvic acids.
72:28
62:38
87.5:12.5
Formic acid, neat
5% BF3ÆEt2O in Et2O
a Established on the basis of 1H NMR spectroscopy.
The application of hydrogen chloride in anhydrous ethyl
acetate brought about the formation of hydroxylactam
derivatives that underwent a mild Pictet–Spengler cycli-
zation via N-acylimminium ion stage. The hydroxylac-
tam 57a was stable enough to allow its X-ray analysis
(Fig. 5).
The coupling with pyruvic acid under an influence of
BOP gave ketoamides 45, 46 and hydroxylactam 47,
respectively, in good chemical yields. Noteworthy, in
the case of compound 47 both diastereomers 47a and
47b could be isolated and characterized spectroscopi-
cally and, after a careful experimentation, the X-ray
structure for 47b could also be solved (Fig. 3).
A diastereoselectivity of 56% was observed in the forma-
tion of the final diketopiperazine derivatives with isomer
60a being predominant. The result of the X-ray struc-
tural analysis of 60b is presented in Figure 6.
As could be expected, there was no observable difference
in the behaviour of diastereomers 47a and 47b towards
the acidic reagents. Both hydroxylactams smoothly
formed 50a and 50b in the same ratios in a good yield
upon the treatment with EtOAc/HCl at room tempera-
The versatility and efficiency of the above approach
could be observed for other derivatives obtained from
substituted arylpyruvic acids. Thus, the final diastereo-
H3CO
H3CO
H3CO
H3CO
OH
OH
N
O
N
O
H3C
O
H3C
O
N
CH3
CH3
N
CH3
CH3
47a
47b
Figure 3. The structures of diastereomers 47a and 47b and ORTEP diagram for 47b.
H3CO
N
O
H3CO
H3C
O
N
CH3
52b
Figure 4. The structure and ORTEP diagram for compound 52b.
H3CO
OH
N
O
H3CO
H3C
O
N
57a
Figure 5. The structure and independent part of the unit cell for compound 57a.

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
981
H3CO
H3CO
N
N
O
H3C
O
60b
Figure 6. The structure and ORTEP diagram for compound 60b.
mers 61 and 62 were obtained in 98% or better
diastereoselectivities.
4.2. Preparation of (2S)-{1-[2-(1H-indol-3-yl)-ethyl-
carbamoyl]-ethyl}-methyl-carbamic acid benzyl ester 5
A sample of 5.00 g (21 mmol) of Cbz-N-methyl alanine
1 was dissolved in 100 mL of dry THF, cooled in ice
bath and to the resultant mixture tryptamine (3.37 g,
21 mmol), triethylamine (3.75 g, 42 mmol) and BOP
(10.25 g, 23 mmol) were introduced. Cooling and stir-
ring were continued for 2 h and afterwards the reaction
was left at room temperature overnight. After evapora-
tion of the volatile components the crude mixture was
dissolved in ethyl acetate (150 mL) and washed with
brine (2 · 100 mL). The organic phase was dried with
magnesium sulfate and the residue was purified with col-
umn chromatography on silica gel with 0.5% (v/v) meth-
3. Conclusions
In summary, several tetrahydroisoquinoline and b-carb-
oline derivatives bearing a quaternary carbon atom were
prepared in a stereoselective way under the chiral influ-
ence of L-amino acids. The biomimetic type Pictet–Spen-
gler condensation was accompanied by 1,4-chirality
transfer which in several cases proceeded in surprisingly
high efficiency approaching 100% de with good to excel-
lent chemical yield. Selected intermediate hydroxylac-
tams were isolated and subjected to X-ray analyses.
The stereochemistry of the final diketopiperazines
strongly depended on the structure of L-amino acids
used: acyclic amino acids gave predominantly the (R)-
configuration at the newly created stereogenic centre,
whereas L-proline afforded the formation of the opposite
configuration. This interesting feature allows the diaste-
reodivergent creation of chirality within these reactions.
Again, the X-ray analysis proved to be indispensable
tool for the stereochemical assignments.
anol in dichloromethane as eluent to afford yellow oil of
23
D
5 (7.64 g, 95%); ½aꢀ ¼ ꢁ33:3 (c 1.05, CHCl3); IR (film)
1
3320, 2930, 1680, 1660, 1450, 1300, 1150; H NMR (se-
vere broadening of selected signals was observed due to
the presence of amide rotamers) (CDCl3, 500 MHz): d
7.99 (br s, 1H, NH, indole), 7.58 (d, J = 8 Hz, 1H, H-4in-
dole), 7.33 (m, 3H, Harom), 7.32–7.21 (m, 3H, Harom), 7.18
(t, J = 7.5 Hz, 1H, H-6indole), 7.11 (t, J = 7.5 Hz, 1H,
H-7indole), 6.90 (s, 1H, H-2indole), 6.13 (br s, 1H,
NHCH2CH2), 5.08 (br s, 2H, CH2Ph), 4.67 (br m, 1H,
H-2), 3.55 (m, 2H, NHCH2CH2), 2.91 (br t, 2H,
NHCH2CH2), 2.73 (s, 3H, NCH3), 1.33 (d, J = 7 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz): d 170.97,
156.89, 136.36, 128.61, 128.24, 127.96, 127.17, 122.16,
122.04, 119.45, 118.63, 112.64, 111.24, 67.53, 54.39,
39.55, 29.46, 25.17, 13.64; ESI (+) m/z (%): 402
[M+Na]+ (100).
4. Experimental
4.1. General
The NMR spectra were recorded on a Varian Unity Plus
spectrometer operating at 500 and 200 MHz for 1H
NMR and at 125 and 50 MHz for 13C NMR. Tetra-
methylsilane (TMS) or solvents were used as internal
standards. Chemical shifts were reported in ppm. Mass
spectra were collected on AMD 604 apparatus and
Micromass LCT apparatus; high-resolution mass spec-
tra were acquired using LSIMS (positive ion mode).
Optical rotations were measured on a Perkin–Elmer
247 MC polarimeter. TLC analyses were performed on
Merck 60 silica gel glass plates and visualized using an
UV hand lamp and iodine vapour. Column chromato-
graphy was carried out at atmospheric pressure using Sil-
ica Gel 60 (230–400 or under 400 mesh, Merck). Melting
points were determined on a Boetius hot-plate micro-
scope. The X-ray intensity data for 25a, 39b, 47b, 52b,
57a, 60b were measured at T = 293 K on Kuma KM4
4.3. Preparation of (2S)-{1-[2-(1H-indol-3-yl)-ethyl-
carbamoyl]-2-methyl-propyl}-methyl-carbamic acid
benzyl ester 6
Compound 2 (5.80 g, 21.88 mmol) was converted into 6
according to the procedure described for 5 as a yellow
23
oil (8.68 g, 97%); ½aꢀ ¼ ꢁ42 (c 1.07, CHCl3); IR (film):
D
3320, 2960, 2930, 1660, 1450; 1H NMR (CDCl3,
500 MHz): d 8.10 (s, 1H, NH, indole), 7.57 (d,
J = 7.5 Hz, 1H, H-4indole), 7.38–7.27 (m, 5H, 5 · Harom),
7.19–7.08 (m, 3H, 3 · Hindole), 6.89 (d, J = 1.5 Hz, 1H,
H-2indole), 6.13 (br t, 1H, NHCH2CH2), 5.11 and 5.08
(qAB, J = 12.5 Hz, 2H, CH2Ph), 4.00 (d, J = 16.5 Hz,
1H, H-2), 3.55 (m, 2H, NHCH2CH2), 2.90 (m, 2H,
NHCH2CH2), 2.88 (s, 3H, NCH3), 2.28 (m, 1H,
CH(CH3)2), 0.90 and 0.85 (2d, J = 7 Hz, J = 7.5 Hz,
2 · 3H, CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d
˚
diffractometer with Mo Ka radiation (k = 0.71073 A).
The structures were solved by direct methods from
SHELXS97 and refined using SHELXL97 software.35
34

982
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
170.10, 157.43, 136.70, 136.39, 128.58, 128.13, 127.65,
127.23, 122.25, 121.93, 119.37, 118.69, 112.65, 111.23,
67.40, 65.43, 39.36, 29.74, 26.10, 25.41, 19.67, 18.64;
ESI (+) m/z (%): 430 [M+Na]+ (100).
0 ꢁC for 2 h. Stirring was continued at room tempera-
ture overnight. The solvent was evaporated and the res-
idue was dissolved in dichloromethane (100 mL),
washed with brine (2 · 60 mL) and dried. The product
was purified with column chromatography on silica
4.4. Preparation of (2S)-N-[2-(1H-indol-3-yl)-ethyl]-2-
methylamino-propionamide 7
gel using cyclohexane–ethyl acetate 1:1 (v/v) to afford
23
compound 7 (3.06 g, 57%) as an oil; ½aꢀ ¼ ꢁ77:2 (c
D
0.99, CHCl3); IR (film): 3330, 2938, 1620, 1425; 1H
NMR (CDCl3, 500 MHz) (two conformers I and II,
I:II 4:3): d 8.16 (br s, 1H, NH, indole) (I), 8.11 (br s,
1H, NH, indole) (II), 7.59 (t, J = 8.5 Hz, 2H, 2 ·
H-4indole) (I), 7.36–7.35 (m, 2H, 2 · H-4indole) (II),
7.31–7.25 (m, 6H, 6 · Harom), 7.22–7.19 (m, 4H,
4 · Hindole), 7.18–7.15 (m, 2H, 2 · Harom) (I), 7.14–
7.10 (m, 2H, 2 · Harom) (II), 7.01 (d, J = 2.5 Hz, 1H,
H-2indole) (II), 6.99 (d, J = 2.5 Hz, 1H, H-2indole) (I),
6.30 (br s, 1H, NHCH2CH2) (I), 5.84 (br s, 1H,
NHCH2CH2) (II), 4.91 (q, J = 7 Hz, 1H, H-2) (II),
4.24 and 3.89 (qAB, J = 14 Hz, 2H, CH2Ph) (I), 3.97
(s, 2H, CH2Ph) (II), 3.61–3.54 (m, 1H, NHCH2CH2),
3.51–3.41 (m, 3H, NHCH2CH2), 3.79 (q, J = 7 Hz,
1H, H-2) (I), 2.94–2.90 (m, 4H, NHCH2CH2), 2.59
(s, 3H, NCH3) (I), 2.48 (s, 3H, NCH3) (II), 1.21
(d, J = 7 Hz, 3H, CH3) (II), 0.82 (d, J = 7 Hz, 3H,
CH3) (I); 13C NMR (CDCl3, 125 MHz): d 198.32,
196.92, 169.31, 168.66, 167.15, 166.80, 136.41, 136.38,
131.04, 130.52, 129.94, 129.84, 129.34, 129.00, 127.99,
127.83, 127.17, 127.16, 122.25, 122.21, 122.15, 119.48,
119.45, 118.63, 112.53, 55.60, 51.73, 47.14, 47.01,
39.87, 39.66, 30.17, 27.43, 25.18, 25.17, 13.61, 12.79;
ESI (+) m/z (%): 414 [M+Na]+; ESI (ꢁ) m/z (%): 390
[MꢁH]ꢁ.
A mixture of 5 (5.40 g, 14.2 mmol) and concd HCl
(4 mL) in absolute ethanol (100 mL) was hydrogenated
over palladium on charcoal catalyst (10% Pd, 0.3 g) at
50 ꢁC with vigorous stirring for 2 h. The mixture was
than filtrated through Celite, evaporated and the residue
was dissolved in chloroform, washed with saturated
sodium bicarbonate solution and dried to afford yellow
23
viscous oil of 7 (3.30 g, 95%); ½aꢀ ¼ ꢁ4:2 (c 1.03,
D
CHCl3); IR (KBr): 3300, 2950, 1650, 153; 1H NMR
(CDCl3, 500 MHz): d 8.36 (br s, 1H, exchangeable with
D2O, NH, indole), 7.62 (d, J = 8 Hz, 1H, H-4indole), 7.36
(m, 1H, H-7indole), 7.24 (br s, 1H, exchangeable with
D2O, NHCH2CH2), 7.19 (m, 1H, H-6indole), 7.12 (m,
1H, H-5indole), 7.01 (d, J = 2.5 Hz, 1H, H-2indole), 3.61
(m, 2H, NHCH2CH2), 2.98 (m, 2H, 2 · H-6), 2.98 (m,
1H, H-2), 2.27 (s, 3H, NCH3), 1.34 (br s, 1H, exchange-
able with D2O, H-1), 1.24 (d, J = 7 Hz, 3H, CH3);
13C NMR (CDCl3, 125 MHz): 174.88, 136.39, 127.37,
122.02, 121.99, 119.29, 118.74, 113.00, 111.23, 60.36,
39.14, 35.13, 25.47, 19.63; ESI (+) m/z (%): 246
[M+H]+ (87), 268 [M+Na]+ (50); ESI (ꢁ) m/z (%): 244
[MꢁH]ꢁ (100).
4.5. Preparation of (2S)-N-[2-(1H-indol-3-yl)ethyl]-3-
methyl-2-(methylamino)butanamide 8
4.7. Preparation of (2S)-N-{1-[2-(1H-indol-3-yl)-ethyl-
carbamoyl]-ethyl}-N-methyl-2-oxo-propionamide 10
Compound 6 (8.60 g, 21.1 mmol) was subjected to the
same procedure as described for the preparation of 7 to
afford compound 8 as pink coloured product (5.20 g,
The reaction was performed in the same manner as for
compound 9. Amide 7 (600 mg, 2.45 mmol) was sub-
jected to a coupling with pyruvic acid (215 mg,
2.45 mmol) diluted with dry THF (30 mL) in the pres-
ence of triethylamine (436 mg, 4.90 mmol) with the
23
90%); ½aꢀ ¼ ꢁ19:2 (c 0.98, CHCl3); IR (KBr): 3280,
D
1
2950, 1630, 750; H NMR (CDCl3, 500 MHz): d 8.61
(br s, 1H, exchangeable with D2O, NH, indole), 7.62
(d, J = 8 Hz, 1H, H-4indole), 7.35 (d, J = 8.5 Hz, 1H,
H-7indole), 7.27 (br t, 1H, exchangeable with D2O,
NHCH2CH2), 7.18 (td, J = 7 Hz, J = 2 Hz, 1H,
H-6indole), 7.10 (td, J = 8.5, J = 1 Hz, 1H, H-5indole),
6.99 (d, J = 2 Hz, 1H, H-2indole), 3.64 (m, 2H,
NHCH2CH2), 2.98 (m, 2H, NHCH2CH2), 2.72 (d,
J = 5 Hz, 1H, H-2), 2.24 (s, 3H, NCH3), 2.05 (m, 1H,
CH(CH3)2), 1.55 (very br s, 1H, exchangeable with
D2O, H-1), 0.94 and 0.87 (2d, J = 7 Hz, 2 · 3H,
CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d 173.53,
136.41, 127.30, 122.00, 121.86, 119.16, 118.65, 112.79,
111.24, 70.80, 39.07, 36.07, 31.27, 25.64, 19.58, 17.77;
ESI (+) m/z (%): 274 [M+H]+ (100), 296 [M+Na]+
(40), 569 [2M+Na]+ (10).
use of BOP (1.14 g, 2.69 mmol) to afford ketoamide
23
10 (556 mg, 72%); ½aꢀ ¼ ꢁ57 (c 1.04, CHCl3); IR
D
(film): 3350, 2930, 1630, 1450; 1H NMR (CDCl3,
500 MHz) (two conformers I and II, I:II 4:3): d 8.20
(br s, 1H, NH, indole) (I), 8.17 (br s, 1H, NH, indole)
(II), 7.59 (m, 2H, 2 · H-4indole), 7.36 (s, 1H, H-7indole
)
(II), 7.34 (s, 1H, H-7indole) (I), 7.19 (m, 2H, 2 ·
H-5indole), 7.14 (m, 2H, 2 · H-6indole), 7.02 (d,
J = 2 Hz, 1H, H-2indole) (I), 7.01 (d, J = 2 Hz, 1H,
H-2indole) (II), 6.60 (br t, 1H, NHCH2CH2) (II), 6.08
(br t, 1H, NHCH2CH2) (I), 4.94 (q, J = 7 Hz, 1H, H-
2) (II), 4.28 (q, J = 7 Hz, 1H, H-2) (I), 3.64 (m, 2H,
NHCH2CH2), 3.59–3.49 (m, 2H, NHCH2CH2), 2.97
(m, 4H, NHCH2CH2), 2.83 (s, 3H, NCH3) (I), 2.73 (s,
3H, NCH3) (II), 2.43 (s, 3H, 3 · H-30) (II), 2.30 (s,
3H, 3 · H-30) (I), 1.35 (d, J = 7 Hz, 3H, CH3) (I), 1.34
(d, J = 7 Hz, 3H, CH3) (II); 13C NMR (CDCl3,
125 MHz): d 198.89, 198.11, 169.61, 168.88, 167.08,
166.69, 136.40, 127.21, 127.15, 122.24, 122.18, 119.48,
119.47, 118.61, 112.49, 112.48, 55.37, 51.84, 39.88,
39.61, 30.57, 25.14, 14.54, 14.14, 13.07; ESI (+) m/z
(%): 338 [M+Na]+ (100).
4.6. Preparation of (2S)-N-{1-[2-(1H-indol-3-yl)-ethyl-
carbamoyl]-ethyl}-N-methyl-2-oxo-3-phenyl-propionamide
9
Phenylpyruvic acid (2.42 g, 14.7 mmol) was added to a
solution of 7 (3.30 g, 13.4 mmol), triethylamine (2.38 g,
26.8 mmol) and BOP (6.52 g, 14.7 mmol) in dry THF
(100 mL) and the mixture was stirred vigorously at

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
983
4.8. Preparation of (2S)-N-{1-[2-(1H-indol-3-yl)-ethyl]-3-
methyl}-2-[methyl-(2-oxo-2-phenyl-propionyl)-amino]-
butyramide 11
165.83, 136.41, 136.38, 135.25, 134.83, 133.20, 133.19,
130.25, 130.16, 130.05, 129.99, 128.36, 128.25, 128.00,
127.96, 127.21, 127.15, 122.26, 122.20, 122.15, 122.12,
119.47, 119.45, 118.69, 118.65, 112.59, 112.49, 111.25,
111.18, 66.32, 62.78, 46.49, 46.20, 39.55, 39.34, 30.68,
30.17, 25.54, 25.37, 25.31, 25.27, 19.48, 19.41, 18.09,
17.86; ESI (+) m/z (%): 476 [M+Na]+ (100); ESI (ꢁ)
m/z (%): 452 [MꢁH]ꢁ.
The same procedure as for 9 was applied for the forma-
tion of compound 11. The BOP (6.23 g, 14.08 mmol)-
mediated coupling of amide 8 (3.50 g, 12.8 mmol) with
phenylpyruvic acid (2.30 g, 14.08 mmol) in the presence
of triethylamine (2.27 g, 15.6 mmol) gave, after chro-
matographic purification (silica gel, 30% CHCl3 in
4.10. Preparation of (2S)-N-{1-[2-(1H-indol-3-yl)-ethyl-
carbamoyl]-ethyl}-N-methyl-2-oxo-propionamide 13
cyclohexane v/v), product 11 as an oil (846 mg, 16%);
23
D
½aꢀ ¼ ꢁ52:3 (c 1.01, CHCl3); IR (film): 3350, 3000,
1
2950,1630; H NMR (CDCl3, 500 MHz) (two conform-
ers I and II, I:II ꢂ1:1): d 8.13 (br s, 1H, NH, indole),
8.04 (br s, 1H NH, indole), 7.46 (d, J = 2 Hz, 1H,
H-4indole), 7.45 (d, J = 2 Hz, 1H, H-4indole), 7.36–7.27
(m, 10H, 10 · Harom), 7.22–7.15 (m, 6H, 6 · Hindole),
7.00 (d, J = 2 Hz, 1H, H-2indole), 6.95 (d, J = 2 Hz, 1H,
H-2indole), 6.75 (br t, 1H, NHCH2CH2), 5.95 (br t, 1H,
NHCH2CH2), 4.23 and 4.01 (qAB, J = 14.5 Hz, 2H,
CH2Ph), 4.23 (d, J = 11.5 Hz, 1H, H-2), 4.03 and 3.92
(qAB, J = 15 Hz, 2H, CH2Ph), 3.57–3.46 (m, 4H,
NHCH2CH2), 3.31 (d, J = 11 Hz, 1H, H-2), 2.92 (m,
4H, NHCH2CH2), 2.78 (s, 3H, NCH3), 2.64 (s, 3H,
NCH3), 2.30–2.14 (m, 2H, CH(CH3)2), 0.87 and 0.59
(2d, J = 6.5 Hz, 6H, CH(CH3)2), 0.70 and 0.25 (2d,
J = 6.5 Hz, 6H, CH(CH3)2); 13C NMR (CDCl3,
125 MHz): d 198.59, 197.02, 168.38, 167.94, 167.50,
166.27, 136.46, 134.11, 131.71, 131.04, 130.14, 129.90,
129.07, 124.89, 124.66, 122.52, 122.36, 122.18, 122.02,
119.62, 119.36, 118.76, 118.66, 112.66, 112.51, 111.22,
66.25, 62.68, 47.03, 46.99, 39.64, 39.41, 30.60, 29.74,
28.37, 28.16, 25.51, 25.35, 19.46, 18.15; ESI (+) m/z
(%): 442 [M+Na]+ (100).
Analogously to the previously mentioned procedure for
the preparation of 9, amide 8 (685 mg, 2.51 mmol) was
coupled with pyruvic acid (220 mg, 2.51 mmol) diluted
with dry THF (30 mL) to yield derivative 13 (620 mg,
23
D
72%) as a yellow oil; ½aꢀ ¼ ꢁ84:1 (c 1.01, CHCl3); IR
1
(KBr): 3320, 2970, 2930, 1640, 1450; H NMR (CDCl3,
500 MHz) (two conformers I and II, I:II ꢂ1:1): d 8.18
(br s, 1H, NH, indole), 8.12 (br s, 1H, NH, indole),
7.61 (d, J = 8.5 Hz, 1H, H-4indole), 7.59 (d, J = 8.5 Hz,
1H, H-4indole), 7.35 (d, J = 8 Hz, 1H, H-7indole), 7.35
(d, J = 8 Hz, 1H, H-7indole), 7.19 (t, J = 8 Hz, 1H, H-
6indole), 7.19 (t, J = 8 Hz, 1H, H-6indole), 7.11 (t, J = 8 Hz,
1H, H-5indole), 7.11 (t, J = 8 Hz, 1H, H-5indole), 7.01 (d,
J = 2.5 Hz, 1H, H-2indole), 6.99 (d, J = 2.5 Hz, 1H,
H-2indole), 6.69 (br t, 1H, NHCH2CH2), 6.04 (br t, 1H,
NHCH2CH2), 4.28 (d, J = 11 Hz, 1H, H-2), 3.66 (m,
2H, NHCH2CH2), 3.54 (m, 2H, NHCH2CH2), 3.46 (d,
J = 11 Hz, 1H, H-2), 2.97 (m, 2H, NHCH2CH2), 2.97
(m, 2H, NHCH2CH2), 2.92 (s, 3H, NCH3), 2.81 (s,
3H, NCH3), 2.44 (s, 3H, CH3), 2.35 (m, 1H, CH(CH3)2),
2.32 (s, 3H, CH3), 0.93 (d, J = 6.5 Hz, 3H, CH(CH3)2),
0.86 (d, J = 6.5 Hz, 3H, CH(CH3)2), 0.85 (d,
J = 6.5 Hz, 3H, CH(CH3)2), 0.77 (d, J = 6.5 Hz, 3H,
CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d 200.35,
198.21, 168.59, 167.78, 167.63, 166.75, 136.40, 127.16,
122.23, 122.20, 122.16, 122.09, 119.43, 119.41, 118.68,
118.62, 112.57, 112.43, 111.24, 111.19, 66.58, 62.69,
39.50, 39.30, 30.87, 29.70, 28.10, 27.59, 25.61, 25.52,
25.31, 19.55, 19.46, 18.73, 18.32; ESI (+) m/z (%): 366
[M+Na]+ (100).
4.9. Preparation of (2S)-2-{[3-(3-chloro-phenyl)-2-oxo-
propionyl]-methyl-amino}-N-[2-(1H-indol-3-yl)-ethyl]-3-
methyl-butyramide 12
Following the procedure described for the synthesis of 9,
compound 8 (340 mg, 1.24 mmol) underwent a reaction
with m-chlorophenylpyruvic acid (270 mg, 1.36 mmol)
upon addition of triethylamine (220 mg, 2.48 mmol)
and BOP (600 mg, 1.36 mmol) in dry CH2Cl2 affording
4.11. Preparation of (2S)-2[(3-benzo[1,3]dioxol-5-yl-2-
oxo-propionyl)-methyl-amino]-N-[2-(1H-indol-3-yl)-
ethyl]-3-methyl-butyramide 14
23
D
1
ketoamide 12 (50 mg, 9%); ½aꢀ ¼ ꢁ39:4 (c 0.97,
CHCl3); IR (film): 3330, 2970, 1640; H NMR (CDCl3,
500 MHz) (two conformers I and II, I:II ꢂ1:1) d: 8.10
(br s, 1H, NH, indole), 8.04 (br s, 1H, NH, indole),
7.60 (m, 1H, H-4indole), 7.59 (m, 1H, H-4indole), 7.37–
7.16 (m, 8H, 8 · Harom), 7.13–7.10 (m, 4H, 4 · Harom),
7.07 (m, 1H, Harom), 7.06 (m, 1H, Harom), 7.01 (d,
J = 2 Hz, 1H, H-2indole), 6.96 (d, J = 2 Hz, 1H,
H-2indole), 6.72 (br t, 1H, NHCH2CH2), 5.99 (br t, 1H,
NHCH2CH2), 4.24 (d, J = 11 Hz, 1H, H-2), 4.15 and
The procedure applied to the synthesis of 14 was the same
as used in the preparation of 9. Compound 8 (657 mg,
2.4 mmol) underwent
2.6 mmol) coupling with 3-benzo[1,3]dioxol-5-yl-2-oxo-
a
BOP-mediated (1.17 g,
propionic acid (500 mg, 2.4 mmol) to give ketoamide
23
14 (130 mg, 12%); ½aꢀ ¼ ꢁ36 (c 1.02, MeOH); IR (film):
D
3350, 2960, 2920, 1640, 1590, 1250, 1050; 1H NMR
(CDCl3, 500 MHz) (two conformers I and II, I:II 3:2):
d 8.17 (br s, 1H, NH, indole) (I), 8.11 (br s, 1H, NH, in-
dole) (II), 7.60 (m, 1H, H-4indole) (I), 7.59 (m, 1H, H-
4indole) (II), 7.36 (m, 2H, 2 · H-7indole), 7.19 (t, J = 7 Hz,
2H, 2 · H-5indole), 7.12 (m, 2H, 2 · H-6indole), 7.01 (s, 1H,
H-2indole) (I), 6.96 (s, 1H, H-2indole) (II), 6.76 (d, J =
7 Hz, 1H, Harom) (II), 6.72 (d, J = 8 Hz, 1H, Harom) (I),
6.70 (d, J = 1.5 Hz, 1H, Harom) (II), 6.68 (d, J = 2 Hz,
4.03 (qAB, J = 15 Hz, 2H, CH2Ph), 4.01 and 3.85 (qAB
,
J = 15 Hz, 2H, CH2Ph), 3.61–3.48 (m, 4H,
NHCH2CH2), 3.34 (d, J = 11 Hz, 1H, H-2), 2.96 (t,
J = 7 Hz, 2H, NHCH2CH2), 2.94 (t, J = 6.5 Hz, 2H,
NHCH2CH2), 2.80 (s, 3H, NCH3), 2.73 (s, 3H,
NCH3), 2.25 (m, 2H, CH(CH3)2), 0.89 and 0.64 (2d,
J = 6.5 Hz, 6H, CH(CH3)2), 0.74 and 0.36 (2d,
J = 6.5 Hz, 6H, CH(CH3)2); 13C NMR (CDCl3,
125 MHz): d 197.89, 196.25, 168.33, 167.79, 166.98,
1H, Harom) (I), 6.65 (dd, J = 8, J = 1 Hz, 1H, Harom
)

984
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
(I), 6.62 (dd, J = 7 Hz, J = 1.5 Hz, 1H, Harom) (II), 5.94 (m,
2H, OCH2O) (II), 5.92 (br s, 2H, NHCH2CH2), 5.90 (s,
2H, OCH2O) (I), 4.24 (d, J = 11 Hz, 1H, H-2) (II), 4.13
and 3.90 (qAB, J = 15 Hz, 2H, CH2Ph(OCH2)) (II), 3.92
and 3.82 (qAB, J = 15 Hz, 2H, CH2Ph(OCH2)) (I), 3.73
(m, 1H, NHCH2CH2) (II), 3.68 (m, 1H, NHCH2CH2)
(I), 3.63–3.58 (m, 2H, NHCH2CH2), 3.33 (d, J = 11 Hz,
1H, H-2) (I), 2.95 (t, J = 6.5 Hz, 2H, NHCH2CH2) (I),
2.93 (t, J = 6.5 Hz, 2H, NHCH2CH2) (II), 2.78 (s, 3H,
NCH3) (I), 2.68 (s, 3H, NCH3) (II), 2.25 (m, 2H,
CH(CH3)2), 0.88 and 0.35 (2d, J = 6.5 Hz, CH(CH3)2)
(II), 0.73 and 0.65 (2d, J = 6.5 Hz, CH(CH3)2) (I);
13C NMR (CDCl3, 125 MHz): d 198.84, 198.48, 168.38,
167.91, 167.51, 166.22, 148.24, 148.19, 147.35, 147.25,
136.42, 136.38, 130.91, 127.23, 127.14, 123.37, 123.15,
122.31, 122.15, 122.07, 119.42, 118.69, 118.64, 112.60,
112.47, 110.29, 110.11, 108.80, 108.71, 101.22, 66.25,
61.85, 46.67, 46.28, 39.58, 39.37, 31.64, 30.63, 25.49,
25.36, 25.30, 19.44, 19.25, 18.10, 17.72; ESI (+) m/z
(%): 486 [M+Na]+ (100).
4.13. Preparation of (3S,12bR)-2,3,12b-trimethyl-
2,3,6,7,12,12b-hexahydro-pyrazino[10,20:1,2]pyrido[3,4-
b]indole-1,4-dione 22a
Compound 10 (116 mg, 0.4 mmol) was dissolved in ethyl
acetate (50 mL) saturated with hydrogen chloride and
was left at room temperature overnight. The solvent
was evaporated in vacuo and the residue was taken up
into CHCl3, washed with sodium bicarbonate solution
(30 mL), water (30 mL), dried (MgSO4) and chromato-
graphed (silica gel, CHCl3) to give 22a as a single diast-
¼
23
D
ereomer (based on 1H NMR) (61 mg, 56%); ½aꢀ
ꢁ35:2 (c 0.99, CHCl3); IR (KBr): 3400, 2930, 2830,
1
1660, 1450; H NMR (CDCl3, 500 MHz): d 9.39 (br s,
1H, H-12), 7.48 (d, J = 8 Hz, 1H, H-8), 7.36 (d,
J = 8.5 Hz, 1H, H-11), 7.19 (td, J = 7.5 Hz, J = 1.5 Hz,
1H, H-9), 7.06 (td, J = 6.5 Hz, J = 1 Hz, 1H, H-10),
5.04 (m, 1H, H-3), 3.74–3.58 (m, 1H, H-6), 3.18 (m,
1H, H-6), 3.00 (s, 3H, NCH3), 2.91 (m, 1H, H-7),
2.82–2.79 (m, 1H, H-7), 1.94 (s, 3H, 3 · H-10), 1.61 (d,
J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz): d
167.60, 165.50, 136.35, 132.68, 126.18, 122.55, 119.59,
118.41, 111.51, 109.74, 59.92, 58.20, 37.25, 32.52,
26.91, 20.58, 19.16; ESI (+) m/z (%): 320 [M+Na]+.
4.12. Preparation of (3S,12bR) and (3S,12bS)-12b-
benzyl-2,3-dimethyl-2,3,6,7,12,12b-hexahydro-pyraz-
ino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione, 21a and 21b
(a) Ketoamide 7 (50 mg, 0.1 mmol) was dissolved in dry
THF (50 mL) saturated with HClgas and left at room
temperature overnight. After evaporation of the solvent,
the reaction mixture was taken up into a sodium bicar-
bonate solution (20 mL) and extracted with toluene
(50 mL) and water (20 mL). The organic layer was then
dried with MgSO4 and evaporated leaving a mixture of
21a and 21b (33.2 mg, 70%, total yield; 91:9 ratio based
4.14. Preparation of (3S,12bR) and (3S,12bS)-12b-benz-
yl-3-isopropyl-2-methyl-2,3,6,7,12,12b-hexahydro-pyr-
azino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione, 23a and 23b
Following the procedure described for the preparation
of 22a, ketoamide 11 (50 mg, 0.1 mmol) was converted
into diastereomeric mixture of 23a and 23b. In toluene
(50 mL) saturated with hydrogen chloride the diastereo-
meric ratio was 72:28 (38 mg, 79%), whereas when ethyl
acetate (50 mL) was used the ratio improved to 97:3
1
on H NMR spectroscopy). A column chromatography
on Al2O3 using 10% ethyl acetate in cyclohexane (v/v)
afforded the pure diastereomers 21a and 21b.
1
(according to H NMR spectroscopy) (40 mg, 84%).
(b) Ketoamide 7 (50 mg, 0.01 mmol) was dissolved in
dry THF (50 mL) saturated with HClgas and left at
5 ꢁC for 10 days. The solvent was evaporated, the resi-
due was dissolved in CHCl3, washed with a sodium
bicarbonate solution (20 mL), water (20 mL) and dried.
After a chromatographic purification (Al2O3, 10% ethyl
acetate in cyclohexane [v/v]) the compound 21a was ob-
tained (26 mg, 55%, the compound 21b was undetectable
The major diastereomer (3S,12bR)-23a: mp 220–227 ꢁC;
23
½aꢀ ¼ ꢁ53:2 (c 0.97, CHCl3); IR (KBr): 3410, 2910,
D
1
1660, 1400; H NMR (CDCl3, 500 MHz): d 9.27 (br s,
1H, H-12), 7.49 (d, J = 8 Hz, 1H, Harom), 7.38 (d,
J = 8 Hz, 1H, Harom), 7.28–7.18 (m, 4H, 4 · Harom),
7.15–7.08 (m, 3H, 3 · Harom), 4.90 (dd, J = 13 Hz,
J = 5 Hz, 1H, H-6), 3.81 and 3.48 (qAB, J = 14.5 Hz,
2H, CH2Ph), 3.49 (d, J = 6.5 Hz, 1H, H-3), 3.25 (td,
J = 12.5 Hz, J = 4.5 Hz, 1H, H-6 or H-7), 3.03 (m, 1H,
H-6 or H-7), 2.93 (s, 3H, NCH3), 2.74 (dd, J = 16,
J = 4 Hz, 1H, H-6 or H-7), 1.08 (octet, J = 6.5 Hz, 1H,
CH(CH3)2), 0.79 and 0.50 (2d, J = 7.0 Hz, J = 6.5 Hz,
6H, CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d
166.69, 165.34, 136.02, 135.38, 132.76, 130.55, 128.77,
127.63, 126.51, 122.72, 119.69, 118.58, 109.53, 68.22,
66.04, 45.54, 38.48, 35.90, 29.76, 20.68, 20.20, 18.47;
ESI (+) m/z (%): 402 [M+H]+ (27), 424 [M+Na]+ (100).
1
with H NMR spectra).
23
D
The major diastereomer (3S,12bR)-21a: ½aꢀ ¼ ꢁ24:6 (c
1.06, CHCl3); IR (KBr): 3410, 3350, 2930, 1660, 1440;
1H NMR (CDCl3, 500 MHz): d 9.47 (s, 1H, H-12), 7.52
(d, J = 8 Hz, 1H, H-8), 7.39 (d, J = 8 Hz, 1H, H-9 or H-
10), 7.33 (m, 2H, 2 · Harom), 7.27 (m, 1H, H-9 or H-10),
7.21 (m, 1H, H-11), 7.17 (td, J = 7 Hz, J = 1 Hz, 1H,
Harom), 7.16 (m, 2H, 2 · Harom), 5.18–5.14 (m, 1H, H-6),
3.74 and 3.39 (qAB, J = 12.5 Hz, 2H, CH2Ph), 3.73 (d,
J = 7 Hz, 1H, H-3), 3.44 (td, J = 13 Hz J = 5 Hz, 1H,
H-6), 3.03–2.97 (m, 1H, H-7), 2.88 (dd, J = 15.5 Hz,
J = 3.5 Hz, 1H, H-7), 2.79 (s, 3H, NCH3), 0.38 (d,
J = 7 Hz, 3H, CH3); 13C NMR (CDCl3, 125 MHz): d
165.61, 165.49, 136.04, 134.91, 132.38, 130.49, 128.83,
127.80, 126.30, 122.65, 119.65, 118.47, 111.52, 109.05,
65.17, 57.56, 45.60, 37.24, 32.03, 20.67, 17.51; ESI (+)
m/z (%): 374 [M+H]+ (4), 396 [M+Na]+ (100).
4.15. Preparation of (3S,12bR)-12b-(3-chloro-benzyl)-
3-isopropyl-2-methyl-2,3,6,7,12,12b-hexahydro-pyr-
azino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione 24a
Compound 12 (38 mg, 0.08 mmol) underwent a Pictet–
Spengler-type condensation in an ethyl acetate/hydrogen
chloride solution (50 mL) in the manner described for
22a to afford the diastereomer 24a almost quantitatively.

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
985
23
D
The major diastereomer (3S,12bR): ½aꢀ ¼ ꢁ41:8 (c 0.96,
ꢁ38:7 (c 1.07, CHCl3); IR (film): 3350, 2900, 1730,
1
1
CHCl3); IR (film): 2960, 2930, 1650, 1400; H NMR
(CDCl3, 500 MHz): d 9.20 (br s, 1H, H-12), 7.49 (d,
J = 7.5 Hz, 1H, H-9), 7.38 (d, J = 8 Hz, 1H, H-10),
7.25–7.16 (m, 4H, 4 · Harom), 7.11 (t, J = 7.5 Hz, 1H,
H-11), 7.02 (d, J = 7.5 Hz, 1H, H-8), 4.92 (dd,
1650, 1500, 1450, 1250; H NMR (CDCl3, 500 MHz): d
9.22 (br s, 1H, H-12), 7.48 (d, J = 7.5 Hz, 1H, H-11),
7.37 (d, J = 8 Hz, 1H, H-8), 7.21 (m, 1H, H-9), 7.11
(m, 1H, H-10), 6.71 (d, J = 8.5 Hz, 1H, Harom), 6.62 (d,
J = 1.5 Hz, 1H, Harom), 6.59 (dd, J = 8 Hz, J = 1.5 Hz,
1H, Harom), 5.91 (d, J = 3 Hz, 2H, OCH2O), 4.91 (dd,
J = 13.5 Hz, J = 5 Hz, 1H, H-6), 3.81 and 3.42 (qAB
,
J = 14.5 Hz, 2H, CH2PhCl), 3.51 (d, J = 6 Hz, 1H, H-
3), 3.29 (td, J = 12.5 Hz, J = 4 Hz, 1H, H-7), 3.06 (m,
1H, H-6), 2.94 (s, 3H, NCH3), 2.76 (dd, J = 15.5 Hz,
J = 4 Hz, 1H, H-7), 1.15 (m, 1H, CH(CH3)2), 0.84 (d,
J = 7.0 Hz, 3H, CH(CH3)2), 0.50 (d, J = 6.5 Hz, 3H,
CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d 166.24,
165.26, 137.36, 135.91, 134.64, 132.46, 130.56, 129.93,
128.73, 127.77, 126.44, 122.81, 119.74, 118.55, 111.50,
109.46, 68.06, 65.84, 44.77, 38.50, 35.70, 33.26, 20.50,
19.98, 18.08; ESI (+) m/z (%): 458 [M+Na]+ (8).
J = 13 Hz, J = 5.5 Hz, 1H, H-6), 3.73 and 3.37 (qAB,
J = 14.5 Hz, 2H, CH2Ph(OCH2O)), 3.52 (d, J = 6 Hz,
1H, H-3), 3.23 (td, J = 13 Hz, J = 4 Hz, 1H, H-7), 3.03
(m, 1H, H-6), 2.94 (s, 3H, NCH3), 2.73 (m, 1H, H-7),
1.37 (m, 1H, CH(CH3)2), 0.88 (d, J = 7 Hz, 3H,
CH(CH3)2), 0.60 (d, J = 7.5 Hz, 3H, CH(CH3)2); 13C
NMR (CDCl3, 125 MHz): d 166.58, 165.23, 147.87,
147.13, 135.93, 132.63, 128.94, 126.46, 123.75, 122.67,
119.65, 118.50, 111.47, 110.79, 109.43, 108.49, 100.99,
68.12, 66.02, 45.06, 38.39, 33.22, 20.53, 20.04, 18.44,
18.31; ESI (+) m/z (%): 468.2 [M+Na]+ (35).
4.16. Preparation of (3S,12bR)-3-isopropyl-2,12b-
dimethyl-2,3,6,7,12,12b-hexahydro-pyrazino[10,20:1,2]-
pyrido[3,4-b]indole-1,4-dione 25a
4.18. Preparation of (2S)-{1-[2-(1H-indol-3-yl)-ethylcar-
bamoyl]-ethyl}-methyl-carbamic acid benzyl ester 27
The procedure described for 22a was applied for the for-
mation of 25a (>99% according to 1H NMR, 70% chem-
ical yield) from ketoamide 13 (120 mg, 0.3 mmol);
(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carboxylic acid
4 (6.92 g, 27.8 mmol) was converted into 27 (6.69 g,
79.2%) analogously to the procedure described for 5;
23
23
½aꢀ ¼ ꢁ93:9 (c 1.03, CHCl3); IR (film): 3400, 3000,
½aꢀ ¼ ꢁ48:6 (c 1.02, CHCl3); IR (film): 3450, 3200,
D
D
1
1650, 1410, 1300, 1200; H NMR (CDCl3, 500 MHz): d
9.24 (br s, 1H, H-12), 7.47 (dd, J = 7.5 Hz, J = 1 Hz,
1H, H-11), 7.35 (dt, J = 13 Hz, J = 1 Hz, 1H, H-8),
7.18 (m, 1H, H-9), 7.09 (m, 1H, H-10), 4.97 (ddd,
J = 13.0 Hz, J = 5.5 Hz, J = 1.0 Hz, 1H, H-6), 3.87 (d,
J = 3.5 Hz, 1H, H-3), 3.19 (td, J = 13 Hz, J = 4.5 Hz,
1H, H-7), 2.99 (s, 3H, NCH3), 2.95 (m, 1H, H-6), 2.74
(ddd, J = 15 Hz, J = 4 Hz, J = 1 Hz, 1H, H-7), 2.33 (m,
1H, CH(CH3)2), 2.00 (s, 3H, 3 · H-10), 1.21 (d,
J = 7 Hz, 3H, CH(CH3)2), 1.06 (d, J = 7 Hz, 3H,
CH(CH3)2); 13C NMR (CDCl3, 125 MHz): d 167.97,
163.17, 135.97, 133.96, 126.33, 122.51, 119.56, 118.38,
108.80, 67.87, 60.30, 37.53, 34.40, 31.76, 28.56, 20.35,
19.80, 18.26; ESI (+) m/z (%): 326 [M+H]+ (5), 348
[M+Na]+ (100); X-ray data: C19H23N3O2, Mr = 325.40,
3000, 2500, 1700, 1450, 1200; 1H NMR (a severe
broadening of selected signals was observed due to
amide rotamers) (CDCl3, 500 MHz): d 8.17 (br s, 1H,
exchan- geable with D2O, NH, indole), 7.55 (m, 1H,
H-7indole), 7.36–7.26 (m, 5H, 5 · Harom), 7.18 (t, J =
7.5 Hz, 1H, H-6indole), 7.10 (t, J = 7.5 Hz, 1H, H-5indole),
6.95 (br s, 1H, H-4indole), 6.74 (m, 1H, H-2indole), 6.03 (br
s, 1H, NHCH2CH2), 5.07 (br m, 2H, CH2Ph), 4.27 (br d,
J = 12.5 Hz, 1H, H-2), 3.51 (m, 2H, NHCH2CH2), 3.38
(s, 2H, NCH2CH2 CH2), 2.90 (m, 2H, NHCH2- CH2),
2.27–2.07 (m, 2H, NCH2CH2CH2), 1.83 (m, 2H,
NCH2CH2CH2); 13C NMR (CDCl3, 125 MHz): d
171.67, 155.52, 136.43, 128.56, 128.18, 127.93, 127.27,
122.33, 121.97, 119.97, 118.58, 112.56, 111.22, 67.19,
60.91, 47.23, 39.59, 30.95, 25.10, 23.46; HR ESI: calcd
for C23H25N3O3Na 414.1794. Found 414.1797.
monoclinic P21, a = 7.1980(14), b = 9.950(2), c =
3
˚
˚
24.047(5) A, b = 94.82(3)ꢁ, V = 1716.2(6) A , Z = 4,
qx = 1.259 g cmꢁ3, F(000) = 696; data collection: Kuma
KM4CCD j-axis diffractometer, 33 reflections with
11.4 > 2h > 23.7ꢁ were used in a least squares procedure
4.19. Preparation of (2S)-N-[2-(1H-indol-3-yl)ethyl]pyr-
rolidine-2-carboxamide 28
to determine
a
crystal lattice, colourless crystal
The compound 27 (5.20 g, 13.2 mmol) underwent a
hydrogenolysis over palladium-on-charcoal catalyst
(10% Pd, 0.3 g) following the procedure described for
0.2 · 0.5 · 0.7 mm, 5683 intensities were measured,
5292 independent (Rint = 0.0255); 2218 with I > 2r(I);
structure solution and refinement: direct methods,34
refined using SHELXL,35 least squares on F2 (all reflec-
tions), R = 0.0509, wR2 = 0.1478 (observed). There are
two independent molecules in asymmetric part of
the unit cell differing only slightly in molecular geometry.
7
to give 28 as dark-orange oil (2.85 g, 84%);
23
½aꢀ ¼ ꢁ32:5 (c 1.08, CHCl3); IR (film): 3300,
D
2950, 1650, 1520, 1450, 1100; 1H NMR (CDCl3,
500 MHz): d 8.46 (br s, 1H, exchangeable with D2O,
NH, indole), 7.61 (d, J = 7.5 Hz, 1H, H-4indole),
7.28 (br t, 1H, exchangeable with D2O, NHCH2CH2),
7.16 (dt, J = 8 Hz, J = 1 Hz, 1H, H-5indole), 7.11 (m,
1H, H-6indole), 7.02 (d, J = 2.5 Hz, 1H, H-2indole),
3.56 (q, J = 6.5 Hz, 2H, NHCH2CH2CH2), 3.34 (m,
2H, NHCH2CH2), 2.97 (t, J = 7 Hz, 2H, NHCH2CH2),
2.45 (very br s, 1H, exchangeable with D2O,
NHCH2CH2CH2), 2.01 (m, 1H, H-2), 1.88 (m, 2H,
NHCH2CH2CH2), 1.69 (td, J = 7 Hz, J = 2 Hz,
1H, NHCH2CH2CH2), 1.64 (qt, J = 7 Hz, 1H,
4.17. Preparation of (3S,12bR)-12b-benzo[1,3]dioxol-5-
ylmethyl-3-isopropyl-2-methyl-2,3,6,7,12,12b-hexahydro-
pyrazino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione 26a
Analogously to the procedure applied to the synthesis of
22a compound 14 (30 mg, 0.06 mmol) was transformed
into the diketopiperazine derivative 26a (>99% de) in
¼
23
D
an ethyl acetate/hydrogen chloride solution; ½aꢀ

986
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
NHCH2CH2CH2); 13C NMR (CDCl3, 125 MHz): d
175.03, 136.36, 127.54, 123.89, 121.97, 119.21, 118.70,
113.09, 111.22, 60.56, 47.20, 36.95, 30.74, 26.18, 25.45;
ESI (+) m/z (%): 258 [M+H]+ (100).
procedure described for 9 to give products 30 (140 mg,
13%) and 34 (120 mg, 12%).
23
Analytical data for 30: ½aꢀ ¼ ꢁ43:3 (c 1.05, CHCl3); IR
D
(KBr): 3330, 2950, 1650, 1400; 1H NMR (CDCl3,
500 MHz) (two conformers I and II, I:II ꢂ1:1): d 8.09
(br s, 2H, 2 · NH, indole), 7.78 (d, J = 7.5 Hz, 1H, H-
4indole), 7.56 (d, J = 8 Hz, 1H, H-4indole), 7.37 (m,
1H, H-7indole), 7.34 (m, 1H, H-7indole), 7.25–7.17 (m,
6H, 6 · Harom), 7.14–7.09 (m, 2H, 2 · Harom), 6.96 (s,
1H, H-2indole), 6.95 (s, 1H, H-2indole), 6.51 (br t, 1H,
NHCH2CH2), 5.52 (br t, J = 2 Hz, 1H, NHCH2CH2),
4.25 (m, 2H, 2 · H-2), 3.65 (m, 2H, NCH2CH2CH2),
3.59 (m, 2H, NHCH2CH2), 3.45 (m, 2H,
NCH2CH2CH2), 3.12 (m, 1H, NHCH2CH2), 3.10 (d,
J = 4 Hz, 2H, NHCH2CH2), 3.06 (d, J = 4 Hz, 4H,
CH2PhCl), 3.01 (m, 1H, NHCH2CH2), 2.97 (m, 1H,
NHCH2CH2), 2.90 (m, 1H, NHCH2CH2), 2.08 (m,
2H, NCH2CH2CH2), 1.97 (m, 2H, NCH2CH2CH2),
1.80 (m, 4H, NCH2CH2CH2); 13C NMR (CDCl3,
125 MHz): d 198.88, 195.82, 171.27, 169.98, 163.76,
163.44, 136.37, 136.36, 135.33, 134.18, 134.15, 129.99,
129.89, 129.74, 129.65, 128.53, 128.41, 127.66, 127.60,
127.23, 127.15, 122.27, 122.18, 122.14, 122.08, 119.52,
119.44, 118.56, 112.79, 112.34, 111.31, 111.23, 61.02,
60.81, 48.10, 47.40, 44.94, 44.68, 39.84, 39.77, 29.70,
29.56, 25.68, 25.07, 22.69, 22.43; ESI (+) m/z (%): 438
[M+H]+ (5), 460 [M+Na]+ (100).
4.20. Preparation of (2S)-1-(2-oxo-3-phenyl-propionyl)-
pyrrolidine-2-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-
amide 29 and (8aS)-3-benzyl-3-hydroxy-2-[2-(1H-indol-3-
yl)-ethyl]-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione 33
Following the preparation scheme applied for 9, phenyl-
pyruvic acid (1.54 g, 9.35 mmol) was added to a stirring
solution of 28 (2.20 g, 8.5 mmol) in dry THF (150 mL),
with triethylamine (1.51 g, 17 mmol) and BOP (4.16 g,
9.35 mmol). A purification with column chromatogra-
phy (silica gel, cyclohexane–ethyl acetate 1:1 [v/v],
increasing polarity) gave compound 29 (0.75 g, 22%)
and 33 (0.81 g, 23%).
23
Analytical data for 29: ½aꢀ ¼ ꢁ37:9 (c 1.06, CHCl3); IR
D
(KBr): 3310, 1640, 1450; 1H NMR (CDCl3, 500
MHz) (two conformers I and II, I:II 3:2): d 8.07 (br s,
2H, exchangeable with D2O, 2 · NH, indole), 7.60 (d,
J = 7.5 Hz, 1H, H-4indole) (I), 7.55 (d, J = 8 Hz, 1H, H-
4indole) (II), 7.36–7.18 (m, 10H, 10 · Harom), 7.15–7.12
(m, 4H, 4 · Hindole), 7.08 (m, 2H, 2 · H-7indole), 7.02
(s, 1H, H-2indole) (I), 6.88 (s, 1H, H-2indole) (II), 6.52
(br t, 1H, NHCH2CH2) (I), 5.68 (br t, 1H, NHCH2CH2)
(II), 4.44 (dd, J = 6 Hz, J = 2 Hz, 1H, H-2) (I), 4.40 (t,
1
J = 6.5 Hz, 1H, H-2) (II), 4.32 and 4.05 (qAB
,
Analytical data for 34: H NMR (CDCl3, 500 MHz): d
J = 17 Hz, 4H, CH2Ph), 3.64–3.45 (m, 8H), 2.96
(m, 4H, NHCH2CH2), 2.53 (m, 2H, NCH2CH2CH2),
2.23 (m, 2H, NCH2CH2CH2), 2.00–1.63 (m, 4H,
NCH2CH2CH2); 13C NMR (CDCl3, 125 MHz): d
197.46, 196.56, 171.25, 170.00, 164.05, 163.96, 136.22,
132.99, 131.87, 130.13, 129.82, 128.89, 128.56, 127.62,
127.57, 127.26, 122.49, 122.32, 122.06, 122.11, 119.49,
119.42, 118.66, 118.56, 112.74, 112.32, 111.28, 111.23,
61.16, 60.51, 47.26, 46.15, 45.45, 45.31, 39.82, 39.70,
29.48, 29.37, 25.08, 24.91, 22.70, 22.23; ESI (+) m/z
(%): 404 [M+H]+ (6), 426 [M+Na]+ (100).
8.10 (br s, 1H, NH, indole), 7.56 (d, J = 7.5 Hz, 1H,
H-4indole), 7.36 (m, 1H, H-7indole), 7.25–7.17 (m, 3H,
3 · Harom), 7.14–7.09 (m, 2H, 2 · Hindole), 7.06 (m, 1H,
Harom), 6.91 (s, 1H, H-2indole), 4.70 (br s, 1H, OH),
4.29 and 4.06 (qAB, J = 18 Hz, 2H, CH2PhCl), 4.02 (m,
1H, H-8a), 3.59 (m, 2H, NCH2CH2), 3.45 (m, 2H,
2 · H-6), 2.97 (m, 2H, NCH2CH2), 1.97 (m, 2H, H-8),
1.80 (m, 2H, 2 · H-7); 13C NMR (CDCl3, 125 MHz): d
166.12, 165.63, 136.21, 135.59, 134.27, 130.40, 130.22,
128.02, 127.88, 127.33, 122.46, 121.97, 119.36, 118.68,
113.45, 111.08, 86.11, 59.40, 45.40, 43.21, 36.82, 32.21,
27.38, 22.11.
1
Analytical data for 33: H NMR (CDCl3, 500 MHz): d
8.07 (br s, 1H, exchangeable with D2O, NH, indole),
7.82 (d, J = 8 Hz, 1H, H-4indole), 7.36–7.18 (m, 5H,
5 · Harom), 7.08 (m, 3H, 3 · Hindole), 7.07 (s, 1H,
H-2indole), 4.10 (m, 1H, H-8a), 4.07 (br s, 1H, OH),
3.64–3.45 (m, 4H), 3.16 and 3.09 (qAB, J = 13.5 Hz,
2H, CH2Ph), 2.96 (m, 2H, NCH2CH2), 2.15 (m, 2H,
2 · H-8), 2.00–1.63 (m, 2H, 2 · H-7); 13C NMR (CDCl3,
125 MHz): d 166.34, 165.78, 136.34, 133.60, 130.37,
128.50, 127.78, 127.14, 122.18, 121.96, 119.45, 119.37,
113.59, 111.06, 86.63, 59.07, 47.86, 45.56, 43.30, 29.70,
25.73, 21.95.
4.22. Preparation of (8aS)-3-hydroxy-2-[2-(1H-indol-3-
yl)-ethyl]-3-methyl-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-
dione 35
The coupling of 28 (2.20 g, 0.8 mmol) with pyruvic acid
(0.82 g, 9.4 mmol) proceeded analogously to the proce-
dure described for 9 but afforded the product in a form
of hydroxylactam 35 (2.4 g, 78%) as the predomi-
23
D
nant form; ½aꢀ ¼ ꢁ50:9 (c 1.03, CHCl3); IR (film):
1
3300, 2930, 2870, 1660, 1450, 1200; H NMR (CDCl3,
500 MHz): d 8.06 (br s, 1H, exchangeable with D2O,
NH, indole), 7.76 (d, J = 7.5 Hz, 1H, H-4indole), 7.34
(d, J = 8 Hz, 1H, H-7indole), 7.18 (td, J = 8 Hz, J =
7.5 Hz, 1H, H-5indole), 7.12 (t, J = 7 Hz, 1H. H-6indole),
7.06 (s, 1H, H-2indole), 4.70 (br s, 1H, exchangeable with
D2O, OH), 4.11 (m, 1H, H-8a), 3.97 (m, 1H,
NCH2CH2), 3.67 (m, 1H, NCH2CH2), 3.57 (m, 2H,
2 · H-6), 3.12–3.00 (m, 2H, NCH2CH2), 2.46 (m, 1H,
H-8), 2.07 (m, 1H, H-8), 1.96 (m, 2H, 2 · H-7), 1.52
(s, 3H, CH3); 13C NMR (CDCl3, 125 MHz): d 167.44,
4.21. Preparation of (2S)-1-[3-(3-chloro-phenyl)-(2-oxo-
propionyl)-pyrrolidine-2-carboxylic acid [2-(1H-indol-3-
yl)-ethyl]-amide 30 and (8aS)-3-(3-chloro-benzyl)-3-
hydroxy-2-[2-(1H-indol-3-yl)-ethyl]-hexahydro-pyrrolo-
[1,2-a]pyrazine-1,4-dione 34
Amide 28 (600 mg, 2.3 mmol) was coupled with m-chloro-
phenylpyruvic acid (500 mg, 2.6 mmol) following the

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
987
166.23, 136.15, 127.59, 121.98, 121.90, 119.31, 119.29,
113.50, 111.01, 83.05, 59.74, 46.16, 42.31, 29.42, 25.67,
25.11, 22.59; EI 70 eV m/z (%): 70 (14), 130 (38), 143
(100), 144 (19), 327 [M] (8); LSIMS (+) (%): 135 (54),
143 (17), 180 (100), 328 [M+H]+ (8), 350 [M+Na]+ (5);
EI HR: calcd for C18H21N3O3 327.15829. Found
327.15874.
122.09, 121.94, 119.41, 119.35, 113.53, 110.53, 108.32,
101.11, 86.42, 59.36, 45.63, 45.01, 43.01, 29.57, 25.73,
22.11.
4.24. Preparation of (3S,12bS) and (3S,12bR)-12b-benz-
yl-2,3,6,7,12,12b-hexahydropyrrolo-pyrazino[10,20:1,2]-
pyrido[3,4-b]indole-1,4-dione, 37a and 37b
4.23. Preparation of (2S)-1-(3-benzo[1,3]dioxol-5-yl-2-
oxo-propionyl)-pyrrolidine-2-carboxylic acid [2-(1H-
indol-3-yl)-ethyl]-amide 32 and (8aS)-3-benzo[1,3]dioxol-
5-ylmethyl-3-hydroxy-2-[2-(1H-indol-3-yl)-ethyl]-3-
methyl-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione 36
Compounds 29 and 33 (50 mg, 0.12 mmol) underwent a
facile Pictet–Spengler-type condensation in AcOEt,
THF or MeOH (50 mL each) saturated with hydrogen
chloride affording diastereomeric mixture of 37a and
37b in different proportions depending on the solvent
used: 93:7, 83:17, 55.5:44.5, respectively (25 mg, 53%).
All the operations followed the procedure described
for 22. Diastereomers 37a and 37b were separated chro-
matographically (silica gel, ethyl acetate–cyclohexane
1:1 [v/v]).
Following the preparation of 9, the product was ob-
tained as a mixture of 32 (177 mg, 16%) and 36
(355 mg, 32%) from amide 28 (640 mg, 2.5 mmol) and
3-benzo[1,3]dioxyol-5-yl-pyruvic acid (520 mg, 2.5
mmol) in the presence of triethylamine (440 mg,
4.9 mmol) and BOP (1.20 g, 2.7 mmol).
23
The major diastereomer (3S,12bS)-37a: ½aꢀ ¼ þ68:6 (c
D
0.97, CHCl3); IR (film): 3410, 2930, 1650, 1450, 1300; 1H
NMR (CDCl3, 500 MHz): d 9.66 (s, 1H, H-12), 7.51 (d,
J = 8 Hz, 1H, H-8), 7.40 (d, J = 8 Hz, 1H, H-11), 7.32
(m, 3H, 3 · Harom), 7.19 (m, 3H, 3 · Harom), 7.12 (td,
J = 8 Hz, J = 1 Hz), 5.19 (ddd, J = 12 Hz, J = 5 Hz,
J = 3 Hz, 1H, H-6), 3.62 and 3.39 (qAB, J = 14 Hz, 2H,
CH2Ph), 3.53 (dt, J = 12 Hz, J = 8.5 Hz, 1H, H-30),
3.31 (m, 2H), 2.89 (m, 2H), 2.19 (dd, J = 11 Hz, J =
6 Hz, 1H, H-3), 2.08 (dtd, J = 11.5 Hz, J = 5 Hz,
J = 1.5 Hz, 1H, H-10), 1.82 (m, 1H, H-10), 1.66 (dq,
J = 11.5 Hz, J = 8 Hz, 1H), 1.55 (m, 1H); 13C NMR
(CDCl3, 125 MHz): d 166.08, 164.96, 136.64, 134.52,
132.22, 130.16, 128.60, 128.07, 126.16, 122.62, 119.63,
118.47, 111.65, 109.77, 66.43, 57.67, 45.47, 44.80,
36.89, 29.42, 20.79, 20.99; ESI (+) m/z (%): 386
[M+H]+ (5), 408 [M+Na]+ (100).
23
Analytical data for 32: ½aꢀ ¼ ꢁ49:2 (c 0.96, MeOH); IR
D
(film): 3320, 2950, 1660, 1450, 1250, 1050; 1H NMR
(CDCl3, 500 MHz) (two conformers
I
and II,
I:II ꢂ1:1): d 8.15 (br s, 2H, 2 · NH, indole), 7.60 (d,
J = 7.5 Hz, 1H, H-4indole), 7.56 (d, J = 7.5 Hz, 1H, H-
4indole), 7.35 (m, 2H, 2 · H-7indole), 7.18 (m, 2H, 2 · H-
5indole), 7.13 (m, 2H, 2 · H-6indole), 7.05 (d, J = 1.5 Hz,
1H, H-2indole), 7.03 (d, J = 2 Hz, 1H, H-2indole), 6.70
(d, J = 1.5 Hz, 1H, Harom), 6.68 (d, J = 2 Hz, 1H,
Harom), 6.73 (d, J = 7.5 Hz, 1H, Harom), 6.65 (dd,
J = 8 Hz, J = 2 Hz, 1H, Harom), 6.61 (dd, J = 8 Hz,
J = 2 Hz, 1H, Harom), 6.54 (br t, 1H, NHCH2CH2),
5.92 (m, 2H, OCH2O), 5.88 and 5.86 (qAB, J = 1.5 Hz,
2H, OCH2O), 5.71 (br t, J = 5.5 Hz, 1H, NHCH2CH2),
4.43 (m, 2H, 2 · H-2), 4.22 and 3.96 (qAB, J = 17 Hz,
2H, CH2 CH2Ph(OCH2O)), 3.98 and 3.88 (qAB
,
23
D
J = 15 Hz, 2H, CH2Ph(OCH2O)), 3.72 (m, 2H),
3.63–3.55 (m, 2H), 3.63–3.55 (m, 4H), 2.95 (m, 2H),
2.87 (m, 2H), 2.05–1.90 (m, 4H), 1.56 (m, 2H,
NCH2CH2CH2), 1.36 (m, 2H, NCH2CH2CH2); 13C
NMR (CDCl3, 125 MHz): d 197.59, 196.50, 171.25,
170.01, 163.98, 163.91, 148.01, 147.69, 147.02, 146.67,
136.37, 135.35, 127.31, 127.18, 127.11, 126.53, 123.22,
123.01, 122.43, 122.30, 122.19, 122.10, 121.94, 121.10,
118.68, 18.56, 112.76, 112.40, 111.30, 111.22, 110.44,
110.09, 108.33, 108.31, 101.16, 100.97, 61.81, 61.12,
47.93, 47.26, 45.01, 44.85, 39.84, 39.77, 32.05, 31.61,
25.10, 24.99, 22.28, 22.10; ESI (+) m/z (%): 470
[M+Na]+ (82).
The minor diastereomer (3S,12bR)-37b: ½aꢀ ¼ ꢁ79:5
1
(c 1.02, CHCl3); H NMR (CDCl3, 500 MHz): d 9.40
(s, 1H, H-12), 7.52 (m, 1H, H-8), 7.39 (dd, J = 5.5 Hz,
J = 1.5 Hz, 1H, H-11), 7.33 (m, 2H, 2 · Harom),
7.28 (m, 1H, H-9), 7.22 (m, 1H, H-10), 7.15 (m, 2H,
2 · Harom), 7.12 (m, 1H, Harom), 5.25 (ddd,
J = 13.5 Hz, J = 5.5 Hz, J = 1.2 Hz, 1H, H-6), 3.77
(dd, J = 12 Hz, J = 6 Hz, 1H, H-3), 3.69 and 3.42
(qAB, J = 13.5 Hz, 2H, CH2Ph), 3.48 (m, 1H), 3.14 (m,
1H), 2.98 (m, 1H), 2.92 (m, 1H), 1.91 (m, 1H), 1.58
(m, 3H), 1.50 (m, 1H); 13C NMR (CDCl3, 125 MHz):
d 164.42, 164.29, 136.03, 134.71, 131.66, 130.38,
128.57, 127.77, 126.35, 122.60, 119.69, 118.43, 111.50,
108.51, 65.85, 59.29, 46.33, 44.30, 36.43, 28.57, 21.02,
20.81.
1
Analytical data for 36: H NMR (CDCl3, 500 MHz): d
8.11 (br s, 1H, NH, indole), 7.80 (d, J = 7.5 Hz, 1H,
H-4indole), 7.35 (d, J = 8 Hz, 1H, H-7indole), 7.18 (dt,
J = 7,5 Hz, J = 1 Hz, 1H, H-5indole), 7.13 (t, J = 7.5 Hz,
1H, H-6indole), 7.05 (s, 1H, H-2indole), 6.68 (d, J = 8 Hz,
1H, Harom), 6.58 (d, J = 2 Hz, 1H, Harom), 6.51 (dd,
J = 8 Hz, J = 1.5 Hz, 1H, Harom), 4.03 (m, 1H, H-8a),
3.64 (m, 1H), 3.45 (m, 2H, 2 · H-6), 3.10 (d,
J = 4.5 Hz, 2H, CH2Ph(OCH2O)), 3.03 (m, 2H,
NCH2CH2), 2.26 (m, 1H), 1.97 (m, 1H), 1.75 (m, 2H,
2 · H-7); 13C NMR (CDCl3, 125 MHz): d 166.28,
165.96, 147.68, 147.15, 136.23, 127.62, 127.12, 123.52,
4.25. Preparation of (3S,12bS) and (3S,12bR)-12b-(3-
chloro-benzyl)-2,3,6,7,12,12b-hexahydropyrrolo-pyraz-
ino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione, 38a and 38b
Both ketoamide 30 and hydroxylactam 34 (50 mg,
0.11 mmol) were converted directly into 38 (19.6 mg,
41%) analogously to 22a. Several different solvents were
applied (toluene, THF, ethyl acetate, 50 mL each), and
again ethyl acetate/hydrogen chloride solution was
found optimal (>99% 38a).

988
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
The major diastereomer (3S,12bS)-38a: mp 205–208 ꢁC;
measured; 5432 independent (Rint = 0.0223); 2073 with
I > 2r(I); structure solution and refinement: direct meth-
ods from SHELXS9734 and then refined on F2 by applica-
tion of SHELXL97 software,35 final R and wR were 0.0334
and 0.0925, respectively. There are two independent
molecules in asymmetric part of the unit cell differing
only slightly in molecular geometry.
23
½aꢀ ¼ þ61:4 (c 1.08, CHCl3); IR (KBr): 3410, 2950,
D
1660, 1430; 1H NMR (CDCl3, 500 MHz): d 9.62 (s,
1H, H-12), 7.51 (d, J = 7 Hz, 1H, H-8), 7.41 (d,
J = 7.5 Hz, 1H, H-11), 7.32 (m, 1H, Harom), 7.24 (m,
3H, 3 · Harom), 7.12 (m, 1H, H-9), 7.05 (m, 1H, H-10),
5.18 (ddd, J = 13 Hz, J = 5 Hz, J = 2 Hz, 1H, H-6),
3.61 and 3.37 (qAB, J = 14 Hz, 2H, CH2PhCl), 3.56 (m,
1H, H-30), 3.30 (m, 2H), 2.90 (m, 2H, 2 · H-7), 2.37
(dd, J = 11 Hz, J = 6 Hz, 1H, H-3), 2.15 (m, 1H, H-
10), 1.86 (m, 1H, H-10), 1.65 (m, 2H, 2 · H-20); 13C
NMR (CDCl3, 125 MHz): d 165.71, 164.71, 136.66,
136.58, 134.52, 131.84, 130.66, 129.88, 128.41, 128.19,
126.13, 122.77, 119.73, 118.51, 111.69, 109.96, 66.25,
57.84, 45.04, 44.94, 36.97, 29.53, 21.03, 20.74; ESI (+)
m/z (%): 442 [M+Na]+ (100); LSIMS (+) (%): 136 (38),
294 (42), 420 [M+H]+ (13), 442 [M+Na]+ (9).
4.27. Preparation of (3S,12bS) and (3S,12bR)-12b-
benzo[1,3]dioxol-2,3,6,7,12,12b-hexahydropyrrolo-pyraz-
ino[10,20:1,2]pyrido[3,4-b]indole-1,4-dione, 40a and 40b
The cyclization step of 32 and 36 (74 mg, 0.16 mmol)
proceeded in ethyl acetate/hydrogen chloride solution
following the procedure described for 22a to give 40a
as a single diastereomer (36 mg, 49%), while when diethyl
ether saturated with HClgas was applied, the ratio be-
tween 40a and 40b was estimated at the level of 80:20.
4.26. Preparation of (3S,12bS) and (3S,12bR)-12b-
methyl-2,3,6,7,12,12b-hexahydropyrrolo-pyrazino-
[10,20:1,2]pyrido[3,4-b]indole-1,4-dione, 39a and 39b
23
Data for (3S,12bS)-40a: ½aꢀ ¼ þ33:0 (c 1.09, CHCl3);
D
IR (film): 3400, 2930, 1660, 1500, 1250, 1050; 1H
NMR (CDCl3, 500 MHz): d 9.60 (s, 1H, H-12), 7.50
(d, J = 8.0 Hz, 1H, H-8), 7.40 (d, J = 8 Hz, 1H, H-
11), 7.21 (td, J = 8.5 Hz, J = 1 Hz, 1H, H-9),
7.11 (m, 1H, H-10), 6.75 (d, J = 8.5 Hz, 1H, Harom),
6.68 (d, J = 2 Hz, 1H, Harom), 6.64 (dd, J = 8 Hz,
J = 2 Hz, 1H, Harom), 5.96 (s, 2H, OCH2O), 5.17
(ddd, J = 13.5 Hz, J = 5.5 Hz, J = 1.5 Hz, 1H, H-6),
The same protocol as for 22a was applied for 35 (50 mg,
0.15 mmol) to give a mixture of 39a and 39b (with the
diastereomeric ratio given in Table 2).
23
D
The major diastereomer (3S,12bS)-39a: ½aꢀ ¼ þ147:2
1
(c 0.97, CHCl3); IR (film): 3360, 3020, 1650, 1430; H
NMR (CDCl3, 500 MHz): d 9.40 (s, 1H, H-12), 7.48
(d, J = 8 Hz, 1H, H-8), 7.37 (d, J = 7.5 Hz, 1H, H-11),
7.18 (td, J = 7.5 Hz, J = 1 Hz, 1H, H-9), 7.09 (t,
J = 7.5 Hz, 1H, H-10), 5.04 (ddd, J = 13.5 Hz,
J = 4 Hz, J = 2 Hz, 1H, H-6), 4.14 (m, 1H), 3.62 (m,
2H), 3.12 (m, 1H, H-10), 2.82 (m, 2H, 2 · H-7), 2.51
(m, 1H, H-3), 2.04 (m, 2H), 1.94 (m, 1H), 1.86 (s, 3H,
CH3); 13C NMR (CDCl3, 125 MHz): d 166.49, 165.88,
136.88, 132.73, 126.13, 122.48, 119.56, 118.40, 111.60,
109.69, 61.31, 58.59, 45.82, 37.04, 29.88, 26.09,
21.80, 20.57; ESI (+) m/z (%): 310 [M+H]+ (5), 332
[M+Na]+ (30); ESI (ꢁ) m/z (%): 308 [MꢁH]ꢁ (8).
3.71 (m, 1H), 3.65 (m, 2H), 3.54 and 3.30 (qAB
,
J = 13.5 Hz, 2H, CH2Ph(OCH2O)), 2.90 (m, 2H,
2 · H-7), 2.60 (dd, J = 6 Hz, J = 5.5 Hz, 1H, H-3), 2.20
(m, 1H, H-10), 1.90 (m, 1H, H-10), 1.57 (m, 2H, 2 · H-
20); 13C NMR (CDCl3, 125 MHz): d 165.98, 165.07,
147.83, 147.39, 136.60, 132.15, 130.17, 126.15, 123.36,
122.63, 119.65, 118.47, 111.64, 110.27, 109.75, 108.44,
101.20, 66.46, 57.93, 45.12, 44.92, 36.88, 29.55, 21.08,
20.77; ESI (+) m/z (%): 452 [M+Na]+ (100); ESI (ꢁ)
m/z: 428 [MꢁH]ꢁ.
4.28. Preparation of (6S)-4-[2-(3,4-dimethoxy-phenyl)-
ethyl]-3-hydroxy-1,3,6-trimethyl-piperazine-2,5-dione 47
The minor diastereomer (3S,12bR)-39b: mp 196–198 ꢁC;
23
½aꢀ ¼ ꢁ168:5 (c 1.06, CHCl3); 1H NMR (CDCl3,
D
The BOP-mediated (1.95 g, 4.6 mmol) coupling of amide
41 (1.07 g, 4.0 mmol) with pyruvic acid (390 mg,
4.4 mmol) proceeded analogously as described for 9 to
give the mixture of diastereomeric hydroxylactams 47a
and 47b (1.00 g, 74%, total yield). No contamination
of other tautomeric forms was detected. Both diastereo-
mers could be isolated with column chromatography on
silica gel (ethyl acetate–cyclohexane 1:1 [v/v]).
500 MHz): d 9.06 (s, 1H, H-12), 7.47 (d, J = 8.5 Hz,
1H, H-8), 7.34 (d, J = 8.5 Hz, 1H, H-11), 7.19 (td,
J = 7.5 Hz, J = 1 Hz, 1H, H-9), 7.10 (td, J = 8 Hz,
J = 1 Hz, 1H, H-10), 5.06 (ddd, J = 13.5 Hz,
J = 7.5 Hz, J = 1.0 Hz, 1H, H-6), 4.00 (m, 2H, H-30),
3.37 (m, 1H, H-6), 3.28 (m, 1H, H-7), 2.94 (m, 1H, H-
7), 2.77 (ddd, J = 16 Hz, J = 4.5 Hz, J = 1 Hz, 1H,
H-3), 2.52 (m, 1H, H-10), 2.06 (m, 1H, H-10), 1.97 (s,
3H, CH3), 1.90 (m, 2H, 2 · H-20); 13C NMR (CDCl3,
125 MHz): d 165.84, 164.36, 135.84, 132.20, 126.46,
122.50, 119.67, 118.34, 111.40, 108.05, 61.46, 59.43,
44.96, 37.06, 30.17, 30.07, 21.34, 20.73; X-ray data:
C18H19N3O2, Mr = 309.36, monoclinic P21, a =
23
Diastereomer (3R,6S)-47a: ½aꢀ ¼ þ2:6 (c 0.99, CHCl3);
D
1H NMR (CDCl3, 500 MHz): d 6.81 (s, 3H, 3 · Harom),
4.76 (very br s, 1H, OH), 4.01 (q, J = 7 Hz, 1H, H-6),
3.88 and 3.86 (2 · s, 2 · 3H, 2 · OCH3), 3.85 (m, 1H,
NCH2CH2), 3.43 (m, 1H, NCH2CH2), 3.05 (s, 3H,
NCH3), 2.95 (m, 1H, NCH2CH2), 2.84 (m, 1H,
NCH2CH2), 1.58 (s, 3H, 3 · H-10), 1.54 (d, J = 7 Hz,
3H, CH3); 13C NMR (CDCl3, 125 MHz): d 168.07,
165.68, 148.86, 147.54, 131.85, 120.84, 112.10, 111.21,
82.23, 58.45, 55.91, 55.87, 44.14, 35.18, 32.40, 28.21,
18.00.
˚
9.100(10), b = 14.092(11), c = 12.476(17) A, b =
3
ꢁ3
˚
103.04(10)ꢁ, V = 1559(3) A , Z = 4, qx = 1.318 g cm
,
F(000)=656; data collection: Kuma KM4 j-axis diffrac-
tometer, 32 reflections with 11.5 > 2h > 21.5ꢁ were used
in a least squares procedure to determine a crystal
lattice, colourless fragment of dimensions 0.2 ·
0.5 · 0.7 mm, cut from the larger crystal, 5647 intensities

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
989
Diastereomer
(3S,6S)-47b:
mp
165–170 ꢁC;
(172 mg, 1.9 mmol) diluted in dry THF (50 mL) gave
23
D
23
D
½aꢀ ¼ þ18:5 (c 0.97, CHCl3); IR (film): 3330, 2940,
46 (845 mg, 92%) as a yellow oil; ½aꢀ ¼ ꢁ72:5 (c
1
1660, 1500, 1250, 1100; H NMR (CDCl3, 500 MHz):
d 6.81 (s, 3H, 3 · Harom), 4.39 (s, 1H, exchangeable with
D2O, OH), 4.00 (q, J = 7 Hz, 1H, H-6), 3.88 and 3.86
(2 · s, 2 · 3H, 2 · OCH3), 3.81 (m, 1H, NCH2CH2),
3.57 (m, 1H, NCH2CH2), 3.01 (s, 3H, NCH3), 2.93
(m, 1H, NCH2CH2), 2.84 (m, 1H, NCH2CH2), 1.73 (s,
3H, 3 · H-10), 1.61 (d, J = 6.5 Hz, 3H, CH3); 13C
NMR (CDCl3, 125 MHz): 166.49, 166.32, 147.84,
146.54, 130.60, 119.69, 111.00, 110.17, 81.98, 56.26,
54.85, 54.81, 43.32, 33.99, 31.15, 24.87, 17.37; HR
ESI: calcd for C17H24N2O5Na 359.1583. Found
1.06, CHCl3); IR (film): 2950, 1730, 1640, 1510,
1260; 1H NMR (CDCl3, 500 MHz) (two conformers
I and II, I:II 3:1): d 7.32–7.20 (m, 8H, 4 · Harom I,
4 · Harom II), 7.05 (m, 2H, 2 · Harom), 6.79 (m, 2H,
2 · Harom), 6.72 (m, 2H, 2 · Harom), 6.70 (d,
J = 2 Hz, 1H, Harom
)
(II), 6.62 (dd, J = 8 Hz,
J = 2 Hz, 1H, Harom) (II), 6.51 (br t, J = 5 Hz, 1H,
NHCH2CH2) (I), 5.98 (br t, 1H, NHCH2CH2) (II),
5.14 (dd, J = 9 Hz, J = 7 Hz, 1H, H-2) (II), 4.29 (dd,
J = 11 Hz, J = 3.5 Hz, 1H, H-2) (I), 3.87 and 3.86
(2 · s, 2 · 6H, 4 · OCH3 I and II), 3.62 (m, 2H,
NHCH2CH2) (II), 3.48 (m, 2H, NHCH2CH2) (I),
3.13 and 2.99 (qAB, J = 14.5 Hz, 2H, CH2Ph) (I),
3.12 and 2.96 (qAB, J = 14.5 Hz, 2H, CH2Ph) (II),
2.87 (s, 3H, NCH3) (II), 2.81 (s, 3H, NCH3) (I), 2.78
(m, 4H, NHCH2CH2), 2.20 (s, 3H, 3 · H-30) (II),
1.74 (s, 3H, 3 · H-30) (I); 13C NMR (CDCl3,
125 MHz): d 200.13 (I), 197.84 (II), 168.55 (II),
168.22 (I), 167.35 (II), 167.19 (I), 149.03 (I and II),
147.72 (I and II), 137.33 (I), 136.41 (II), 132.44 (I
and II), 130.89 (I), 130.87 (II), 129.11 (I), 129.11 (I),
128.94 (I), 128.94 (I), 128.80 (II), 128.80 (II), 128.64
(II), 128.64 (II), 111.69 (I and II), 111.36 (I), 111.31
(II), 62.74 (I and II), 55.91 (I and II), 55.82 (I and
II), 40.98 (I), 40.73 (II), 35.28 (I), 35.15 (II), 33.51
(II), 33.37 (I), 28.14 (I and II), 27.39 (II), 26.66 (I);
ESI (+) m/z (%): 413 [M+H]+ (56), 435 [M+Na]+
(100).
359.1567; X-ray data: C17H24N2O5, monoclinic P1,
a = 10.79(3),
˚
c = 11.79(4) A,
b = 7.006(17),
b =
106.5(3)ꢁ; data collection: Kuma KM4 j-axis dif-
fractometer, colourless crystal of dimensions 0.2 ·
0.35 · 0.65 mm, 2822 reflection measured (2691
independent, Rint = 0.1496), 1609 of them had intensities
larger than 2r; structure solution and refinement: direct
methods34 and then refined on F2 by application of
SHELXL97 software.35 Although there were no trouble
in either solving or refining the structure the respective
R and wR factors were unacceptably high (0.1770 and
0.3609, respectively), probably due to low quality of
the crystal and data collection (as suggested by high Rint
value). Nevertheless there was no ambiguity in structure
determination and hence we decided not to redetermine
this structure.
4.29. Preparation of (2S)-N-[2-(3,4-dimethoxy-phenyl)-
ethyl]-3-methyl-2-[methyl-(2-oxo-propionyl)-amino]-
butyramide 45
4.31. Preparation of (3S,11bR) and (3S,11bS)-9,10-
dimethoxy-2,3,11b-trimethyl-2,3,7,11b-tetrahydro-6H-
pyrazino[2,1-a]isoquinoline-1,4-dione, 50a and 50b
Amide 42 (1.02 g, 3.7 mmol) was converted into 45
(945 mg, 72%) following the operation scheme applied
Hydroxylactam 47 (150 mg, 0.4 mmol) underwent the
Pictet–Spengler-type cyclization in ethyl acetate
(50 mL), dichloromethane (50 mL) and methanol
(50 mL) saturated with hydrogen chloride (gas) as de-
scribed for 22a affording the diketopiperazines 50a and
50b (114 mg, 80%, total yield) in the ratio 75:25,
71.5:28.5, 75:25, respectively, according to 1H NMR
spectroscopy.
23
for 9; ½aꢀ ¼ ꢁ75:3 (c 0.98, CHCl3); IR (film): 3350,
D
2960, 1640, 1510, 1260, 1030; 1H NMR (CDCl3,
500 MHz) (two conformers I and II, I:II ꢂ4:3): d 6.79
(m, 2H, 2 · Harom), 6.71 (m, 4H, 4 · Harom), 6.06 (br t,
2H, NHCH2CH2), 4.28 (d, J = 11 Hz, 1H, H-2) (II),
3.87 and 3.86 (2 · s, 2 · 6H, 4 · OCH3 I and II), 3.57
(m, 2H, NCH2CH2) (I), 3.49 (m, 2H, NCH2CH2) (I),
3.47 (d, J = 10.5 Hz, 1H, H-2) (I), 2.95 (s, 3H, NCH3)
(II), 2.82 (s, 3H, NCH3) (I), 2.75 (m, 6H), 2.48 (s, 3H,
3 · H-30) (II), 2.38 (s, 3H, 3 · H-30) (I), 0.93 (d,
J = 6.5 Hz, 3H, CH(CH3)2) (II), 0.87 (d, J = 6.5 Hz,
3H, CH(CH3)2) (I), 0.86 (d, J = 6.5 Hz, 3H, CH(CH3)2)
(II), 0.78 (d, J = 6.5 Hz, 3H, CH(CH3)2) (II); 13C NMR
(CDCl3, 125 MHz): d 200.54, 197.91, 168.70, 167.83,
167.56, 166.62, 149.01, 148.95, 147.71, 147.62,
130.99, 130.96, 120.72, 120.64, 111.76, 111.71, 111.31,
66.54, 62.81, 55.92, 55.91, 55.85, 55.80, 40.69, 40.49,
35.30, 35.27, 30.97, 28.15, 27.81, 27.61, 25.58, 25.55,
19.55, 19.47, 18.72, 18.35; ESI (+) m/z (%): 387
[M+Na]+ (100).
23
D
The major diastereomer (3S,11bR)-50a: ½aꢀ ¼ ꢁ128:2
(c 1.02, CHCl3); IR (film): 3400, 2940, 1660, 1510,
1450, 1260; 1H NMR (CDCl3, 500 MHz): d 7.76 (s,
1H, H-11), 6.53 (s, 1H, H-8), 4.89 (m, 1H, H-6), 4.04
(q, J = 7 Hz, 1H, H-3), 3.94 and 3.85 (2 · s, 6H,
2 · OCH3), 3.85 (m, 1H, H-6), 2.96 (s, 3H, NCH3),
2.95 (m, 1H, H-7), 2.60 (m, 1H, H-7), 1.90 (s, 3H,
3 · H-100), 1.56 (d, J = 7 Hz, 3H, CH3); 13C NMR
(CDCl3, 125 MHz): d 168.04, 166.06, 148.26, 146.94,
128.24, 127.23, 112.76, 110.73, 61.96, 58.03, 56.05,
55.81, 37.17, 33.15, 30.80, 28.93, 18.92; ESI (+) m/z
(%): 341 [M+Na]+ (80).
4.30. Preparation of (2S)-N-{1-[2-(3,4-dimethoxy-phen-
yl)-ethylcarbamoyl]-2-phenyl-ethyl}-N-methyl-2-oxo-
propionamide 46
4.32. Preparation of (3S,11bR)-3-isopropyl-9,10-dime-
thoxy-2,11b-dimethyl-2,3,7,11b-tetrahydro-6H-pyraz-
ino[2,1-a]isoquinoline-1,4-dione 51a
According to the same procedure as described for 9, a
coupling of 43 (672 mg, 1.9 mmol) with pyruvic acid
Dissolving 45 (145 mg, 0.4 mmol) in ethyl acetate/
hydrogen chloride solution promoted the Pictet–Spengler

990
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
condensation analogously to the formation of 22a
and after purification with column chromatography
(silica gel, chloroform), gave compound 51 (130 mg,
4.34. Preparation of (2S)-1-(2-oxo-propionyl)-pyrrol-
idine-2-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-
amide 54 and (8aS)-2-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-
hydroxy-3-methyl-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-
dione 57
94%) as
a
single diastereomer (3S,11bR)-51a:
23
½aꢀ ¼ ꢁ62:0 (c 1.08, CHCl3); IR (film): 2960, 2930,
D
1650, 1250; 1H NMR (CDCl3, 500 MHz): d 7.87 (s,
1H, H-11), 6.53 (s, 1H, H-8), 4.80 (m, 1H, H-6),
3.91 and 3.85 (2 · s, 6H, 2 · OCH3), 3.85 (m, 1H, H-
6), 3.06 (m, 2H, 2 · H-7), 2.93 (s, 3H. NCH3), 2.57
(d, J = 13 Hz, 1H, H-3), 2.32 (m, 1H, CH(CH3)2),
1.96 (s, 3H, 3 · H-10) 1.19 (d, J = 7 Hz, 3H,
CH(CH3)2), 1.01 (d, J = 6.5 Hz, 3H, CH(CH3)2); 13C
NMR (CDCl3, 125 MHz): d 168.72, 163.42, 148.23,
147.06, 129.76, 126.77, 111.15, 111.10, 67.59, 62.53,
56.01, 55.79, 37.31, 34.80, 31.48, 30.46, 28.08, 19.74,
17.81; ESI (+) m/z (%): 347 [M+H]+ (20), 369
[M+Na]+ (100).
The same operation scheme as for 9 was applied to the
synthesis of 54 (20 mg, 4%) and 57 (diastereomeric mix-
ture of 57a and 57b) (1.5 g, 80% yield).
23
Analytical data for 54: ½aꢀ ¼ þ11:2 (c 1.05, CHCl3);
D
1H NMR (CDCl3, 500 MHz): d 6.74 (m, 3H, 3 ·
Harom), 6.60 (br t, 1H, NHCH2CH2), 4.59 (dd,
J = 8 Hz, J = 5 Hz, 1H, H-2), 3.89 and 3.87
(2 · s, 6H, 2 · OCH3), 3.67–3.42 (m, 4H), 2.76 (m,
2H, NHCH2CH2), 2.17 (m, 2H, NCH2CH2CH2),
1.96 (m, 2H, NCH2CH2CH2), 1.52 (s, 3H, CH3);
13C NMR (CDCl3, 125 MHz): d 198.30, 163.60,
163.33, 148.81, 147.51, 131.79, 120.87, 112.13,
111.18, 61.18, 55.90, 55.90, 47.41, 40.94, 35.25,
27.06, 25.10, 22.64; ESI (+) m/z (%): 371 [M+Na]+
(100).
4.33. Preparation of (3S,11bR) and (3S,11bS)-3-benzyl-
9,10-dimethoxy-2,11b-dimethyl-2,3,7,11b-tetrahydro-6H-
pyrazino[2,1-a]isoquinoline-1,4-dione, 52a and 52b
Operating on the same scheme as described for 22a the
condensation of 46 (140 mg, 0.3 mmol) in CH2Cl2/
HClgas (50 mL), AcOEt/HClgas (50 mL), MeOH/HClgas
(50 mL) afforded a diastereomeric mixture of 52a and
52b (60 mg, 45%, total yield) in the ratio 83.3:16.7,
75:25, 83.3:16.7, respectively.
Analytical data for the enolic form of 54: IR (film):
3300, 2950, 1670, 1510, 1250, 750; 13C NMR (CDCl3,
50 MHz): d 165.11 (NHCO), 157.79 (NHCO), 149.00
(C–OCH3), 147.86 (C–OCH3), 137.91 (Carom), 130.48
(C–OH), 120.79 (Carom), 112.04 (Carom), 111.38 (Carom),
102.70 (C-30), 58.84 (C-2), 55.95 (OCH3), 55.92 (OCH3),
45.52 (NHCH2CH2), 44.57 (NCH2CH2CH2), 31.92
23
D
The major diastereomer (3S,11bR)-52a: oil; ½aꢀ
¼
ꢁ50:1 (c 1.04, CHCl3); IR (film): 3000, 2940, 1650,
(NHCH2CH2),
(NCH2CH2CH2).
29.35
(NCH2CH2CH2),
21.84
1
1520, 1450, 1250, 1100; H NMR (CDCl3, 500 MHz):
d 7.77 (s, 1H, H-11), 7.31 (m, 2H, 2 · Harom), 7.15 (m,
2H, 2 · Harom), 6.81 (m, 1H, Harom), 6.47 (s, 1H, H-8),
4.81 (ddd, J = 12.5, J = 5.5 Hz, J = 1.5 Hz, 1H, H-3),
4.29 (m, 1H, H-6), 3.85 and 3.81 (2 · s, 6H,
2 · OCH3), 3.36 and 3.23 (qAB, J = 4.0 Hz, 2H, CH2Ph),
3.05 (s, 3H, NCH3), 2.98 (m, 1H, H-6), 2.81 (td,
J = 12.5 Hz, J = 3.5 Hz, 1H, H-7), 2.53 (dd,
J = 16 Hz, J = 2 Hz, 1H, H-7), 0.88 (s, 3H, 3 · H-10);
13C NMR (CDCl3, 125 MHz): d 168.41, 163.41,
148.07, 146.95, 135.01, 130.20, 129.28, 128.77, 127.53,
126.59, 111.28, 110.91, 63.28, 62.14, 55.87, 55.76,
37.23, 36.75, 33.78, 29.53, 28.51; ESI (+) m/z (%): 417
[M+Na]+ (100).
Analytical data for diastereomer (8aS,3R)-57a: mp
23
150–155 ꢁC; ½aꢀ ¼ ꢁ87:9 (c 0.96, CHCl3); IR (KBr):
D
3490, 2950, 1660, 1640, 1520, 1250, 1150, 1030; 1H
NMR (CDCl3, 500 MHz): 6.78 (m, 3H, 3 · Harom),
4.35 (m, 1H, H-8a), 4.30 (br s, 1H, exchangeable with
D2O, OH), 3.88 and 3.86 (2 · s, 6H, 2 · OCH3), 3.81
(m, 1H, NCH2CH2), 3.61–3.48 (m, 3H), 2.87 (m,
1H, NCH2CH2), 2.82 (m, 1H, NCH2CH2), 2.01 (m,
2H, 2 · H-8), 1.86 (m, 2H, 2 · H-7), 1.82 (s, 3H,
CH3); 13C NMR (CDCl3, 125 MHz):
d 170.23,
165.16, 149.01, 147.74, 131.47, 120.67, 112.03,
111.30, 85.08, 58.64, 55.91, 55.91, 45.76, 44.44, 34.97,
29.18, 23.28, 22.33; X-ray data: C18H24N2O5,
The minor diastereomer (3S,11bS)-52b was obtained in
a very tiny amount in a form of single monocrystal,
which unfortunately was destroyed during the X-ray
measurements: mp 224–226 ꢁC; X-ray data: C22H26-
orthorhombic P212121, a = 10.272(8), b = 14.404(12),
˚
3
˚
c = 23.39(2) A, a = b = c = 90ꢁ, V = 3460(5) A , Z = 8,
qx = 1.338 g cmꢁ3
,
F(000) = 1488; data collection:
Kuma KM4 j-axis diffractometer, 32 reflections
with 12.5 > 2h > 23.3ꢁ, colourless crystal 0.2 · 0.25 ·
0.7 mm, Mo Ka radiation, 5849 intensities mea-
sured; 5811 independent (Rint = 0.0131), 1986 with
I > 2r(I); structure solution and refinement: direct
methods,34 refined using SHELXL,35 final R and wR
0.0395 and 0.1086, respectively. There are two inde-
pendent molecules in the asymmetric unit with mole-
cular geometric parameters differing only slightly.
The planar fragments of the two molecules are inclined
to each other by 19.7(2)ꢁ. Molecules A and B are
interlinked by series of O–Hꢃ ꢃ ꢃO hydrogen bonds.
Additionally some C–Hꢃ ꢃ ꢃO contacts are observed
(Table 3).
N2O4, orthorhombic unit cell with a = 8.473(3), b =
˚
13.963(3),
c = 16.480(5) A,
a = b = c = 90ꢁ,
V =
3
1949.7(11) A , Z = 4, qx = 1.344 g cmꢁ3, F(000) = 840,
space group P212121; data collection: Kuma KM4 j-axis
diffractometer, 42 reflections with 12.6 > 2h > 21.8ꢁ were
used in a least squares procedure to determine a crystal
lattice, colourless crystal 0.4 · 0.4 · 0.7 mm, Mo Ka
radiation, 3549 intensities measured, 3475 independent
(Rint = 0.0157); 2188 with I > 2r(I); structure solution
and refinement: direct methods,34 refined using
SHELXL,35 final R and wR 0.0376 and 0.1031, respec-
tively. There was no observable hydrogen bonding in
the structure.
˚

A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
991
˚
Table 3. The hydrogen bonds distances (A) and angles (ꢁ) for 57a
147.71, 147.54, 147.19, 131.85, 127.03, 123.51, 120.91,
112.19, 111.20, 110.50, 108.34, 101.14, 86.34, 59.35,
55.84, 45.65, 45.03, 44.07, 36.68, 29.64, 22.13.
D–H
Hꢃ ꢃ ꢃA
Dꢃ ꢃ ꢃA
<(DHA)
Bond
0.80(5)
0.78(5)
0.97
1.98(5)
1.97(5)
2.55
2.780(4)
2.744(4)
3.368(5)
3.413(5)
173(5)
171(5)
142.2
147.2
O5A–H5Aꢃ ꢃ ꢃO1Ba
O5B–H5Bꢃ ꢃ ꢃO1Aa
C7A–H7A2ꢃ ꢃ ꢃO1Ba
C7B–H7B2ꢃ ꢃ ꢃO1Aa
4.36. Preparation of (8aS)-2-[2-(3,4-dimethoxy-phenyl)-
ethyl]-3-hydroxy-3-(4-methoxy-benzyl)-hexahydro-pyr-
rolo[1,2-a]pyrazine-1,4-dione 59
0.97
2.56
Symmetry operations to generate equivalent atoms:
a
ꢁ0.5 + x, 1.5 ꢁ y, ꢁz.
In the same preparation scheme as presented for 9 amide
53 underwent a reaction with (40-methoxy)-phenylpyru-
vic acid (270 mg, 1.4 mmol) affording predominantly
compound 59 (66 mg, 11%; only a slight amount of 56
was present in the crude reaction mixture and therefore
Analytical data for diastereomer (8aS,3S)-57b:
23
D
½aꢀ ¼ ꢁ60:6 (c 0.95, CHCl3); 1H NMR (CDCl3,
500 MHz): d 6.79 (m, 3H, 3 · Harom), 4.75 (s, 1H,
OH), 4.13 (m, 1H, H-8a), 3.88 and 3.86 (2 · s, 6H,
2 · OCH3, 3.87 (m, 1H, NCH2CH2), 3.68 (m, 1H, H-
6), 3.59 (m, 1H, H-6), 3.45 (m, 1H, NCH2CH2), 2.83
(m, 2H, NCH2CH2), 2.48 (m, 1H, H-8), 2.08 (m, 2H),
1.95 (m, 1H), 1.52 (s, 3H, CH3); 13C NMR (CDCl3,
125 MHz): d 167.42, 166.17, 148.79, 147.50, 131.80,
120.86, 112.12, 111.17, 83.08, 59.72, 55.90, 55.85,
46.20, 43.16, 35.66, 29.49, 25.09, 22.62.
it was impossible to isolate it for characterization);
23
D
½aꢀ ¼ ꢁ61:1 (c 0.96, CHCl3); IR (film): 3400, 3000,
1
1650, 1520, 1250; H NMR (CDCl3, 500 MHz): d 6.99
(m, 2H, 2 · Harom), 6.87–6.73 (m, 5H, 5 · Harom), 4.61
(very br s, 1H, OH), 3.95 (m, 2H), 3.89 and 3.87 and
3.78 (3 · s, 9H, 3 · OCH3), 3.65 (m, 1H, H-6), 3.39
(m, 2H), 3.10 and 3.03 (qAB
,
J = 14 Hz, 2H,
CH2PhOCH3), 2.91 (td, J = 12.0 Hz, J = 5.5 Hz, 1H,
NCH2CH2), 2.81 (td, J = 11.5 Hz, J = 5.5 Hz, 1H,
NCH2CH2), 2.20 (m, 1H, H-8), 1.96 (m, 1H, H-8),
1.75 (m, 2H, 2 · H-7); 13C NMR (CDCl3, 125 MHz): d
166.26, 165.84, 159.22, 148.85, 147.53, 131.93, 131.36,
125.45, 120.90, 113.88, 112.18, 111.21, 86.64, 59.11,
55.88, 55.87, 55.26, 45.46, 44.66, 44.14, 35.69, 29.59,
21.94; ESI (+) m/z (%): 455 [M+H]+ (38), 477
[M+Na]+ (20); ESI (ꢁ) m/z (%): 453 [MꢁH]ꢁ (100).
4.35. Preparation of (2S)-1-(3-benzo[1,3]dioxol-5-yl-2-
oxo-propionyl)-pyrrolidine-2-carboxylic acid [2-(3,4-
dimethoxy-phenyl)-ethyl]-amide 55 and (8aS)-3-benzo-
[1,3]dioxol-5-ylmethyl-2-[2-(3,4-dimethoxy-phenyl)-
ethyl]-3-hydroxy-hexahydro-pyrrolo[1,2-a]pyrazine-1,4-
dione 58
A conversion of amide 53 (372 mg, 1.3 mmol) into prod-
uct 55 (126 mg, 21%) and 58 (379 mg, 62%) proceeded
analogously to the formation of 9.
4.37. Preparation of (8aS,13aS) and (8aS,13aR)-13a-
methyl-2,3-dimethoxy-5,8a,9,10,11,13a-hexahydro-8H-
pyrrolo[10,20:4,5]pyrazino[2,1-a]isoquinoline-8,13(6H)-
dione, 60a and 60b
1
Analytical data for 55: H NMR (CDCl3, 500 MHz): d
6.75 (m, 4H, 4 · Harom), 6.67 (d, J = 1 Hz, 1H, Harom),
6.50 (dd, J = 8 Hz, J = 1 Hz, 1H, Harom), 5.89 (m, 2H,
OCH2O), 5.61 (br t, 1H, exchangeable with D2O, 1H,
NHCH2CH2), 4.98 and 4.23 (qAB, J = 16.0 Hz, 2H,
CH2Ph(OCH2O)), 4.46 (m, 1H, H-2), 3.89 and 3.85
(2 · s, 6H, 2 · OCH3), 3.61 (t, J = 7 Hz, 1H,
NHCH2CH2), 3.55–3.30 (m, 3H), 2.88 (m, 1H,
NHCH2CH2), 2.75 (m, 1H, NHCH2CH2), 2.01 (m,
2H, NCH2CH2CH2), 1.81 (m, 2H, NCH2CH2CH2);
13C NMR (CDCl3, 125 MHz): d 197.59, 171.22,
163.91, 149.04, 148.05, 147.63, 147.05, 131.28, 126.42,
123.19, 112.07, 111.31, 110.40, 110.04, 108.07, 101.18,
61.16, 55.87, 47.27, 44.92, 40.95, 35.18, 27.15, 22.27;
ESI (+) m/z (%): 491 [M+Na]+ (100).
The compounds 54 and 57 (100 mg, 0.3 mmol) were con-
verted into a diastereomeric mixture of diketopiper-
azines 60a and 60b (50 mg, 53%, dr of 78:22, 67:33,
75:25, respectively) under acidic conditions (ethyl ace-
tate/HCl, dichloromethane/HCl, methanol/HCl, 50 mL
each) accordingly to the procedure described for 22a.
23
D
The major diastereomer (8aS,13aS)-60a: ½aꢀ ¼ þ106:9
1
(c 1.06, CHCl3); IR (film): 2990, 1650, 1500, 1250; H
NMR (CDCl3, 500 MHz): d 7.28 (s, 1H, H-1), 6.57 (s,
1H, H-4), 4.83 (m, 1H, H-8a), 3.87 (m, 1H, H-6), 3.86
and 3.84 (2 · s, 6H, 2 · OCH3), 3.54 (m, 1H, H-6),
3.40 (m, 1H, H-11), 3.14 (m, 1H, H-11), 2.64 (dd,
J = 17 Hz, J = 5.5 Hz, 2H, 2 · H-5), 2.46 (m, 1H, H-9),
2.04 (m, 1H, H-9), 1.96 (m, 1H, H-10), 1.94 (s, 3H,
CH3), 1.86 (m, 1H, H-10); 13C NMR (CDCl3,
125 MHz): d 167.90, 165.63, 148.57, 147.42, 129.51,
125.24, 112.14, 107.94, 64.40, 58.71, 56.13, 56.02,
46.19, 37.29, 30.40, 29.91, 26.67, 21.78; ESI (+) m/z
(%): 353 [M+Na]+ (100).
23
D
Analytical data for 58: ½aꢀ ¼ ꢁ78:6 (c 1.07, CHCl3); 1H
NMR (CDCl3, 500 MHz): d 6.80 (s, 3H, 3 · Harom), 6.71
(d, J = 8 Hz, 1H, Harom), 6.59 (d, J = 1 Hz, 1H, Harom),
6.53 (dd, J = 8 Hz, J = 1 Hz, 1H, Harom), 5.94 (s, 2H,
OCH2O), 4.75 (br s, 1H, exchangeable with D2O,
OH), 4.12 (q, J = 7.5 Hz, 1H, H-8a), 3.89 and 3.86
(2 · s, 6H, 2 · OCH3), 3.67 (m, 1H, NCH2CH2), 3.47
and 3.45 (qAB, J = 7 Hz, 2H, CH2Ph(OCH2O)), 3.46
(m, 1H, H-6), 3.33 (td, J = 11.0 Hz, J = 5.0 Hz, 1H,
NCH2CH2), 3.01 (m, 1H, H-6), 2.89 (m, 1H,
NCH2CH2), 2.78 (m, 1H, NCH2CH2), 2.29 (m, 1H, H-
8), 2.00 (m, 1H, H-8), 1.83 (m, 2H, 2 · H-7); 13C
NMR (CDCl3, 125 MHz): d 166.20, 165.89, 148.84,
The minor diastereomer (8aS,13aR)-60b: mp 194–
23
D
195 ꢁC; ½aꢀ ¼ ꢁ86:6 (c 1.03, CHCl3); 1H NMR (CDCl3,
500 MHz): d 7.25 (s, 1H, H-1), 6.55 (s, 1H, H-4), 4.88 (m,
1H, H-8a), 4.22 (dd, J = 9.5 Hz, J = 6.5 Hz, 1H, H-6),
3.94 and 3.86 (2 · s, 6H, 2 · OCH3), 3.61 (m, 1H, H-6),
2.86 (m, 2H, 2 · H-11), 2.66 (m, 1H, H-5), 2.52 (m, 1H,
H-5), 2.04 (m, 2H, 2 · H-9), 1.93 (m, 2 · H-10), 1.82

992
A. Siwicka et al. / Tetrahedron: Asymmetry 16 (2005) 975–993
(s, 3H, CH3); 13C NMR (CDCl3, 125 MHz): d 167.40,
166.57, 148.29, 146.70, 127.31, 126.55, 114.09, 110.41,
63.05, 58.74, 56.16, 55.83, 46.43, 36.87, 30.00, 29.09,
26.50, 22.14; X-ray data: C18H22N2O4, orthorhombic
J = 15.5 Hz, 2H, CH2PhOCH3), 2.85 (m, 2H, 2 · H-
11), 2.62 (m, 1H, H-5), 2.47 (dd, J = 11 Hz, J = 6 Hz,
1H, H-5), 2.17 (m, 1H, H-9), 1.86 (m, 1H, H-9), 1.70
(m, 1H, H-10), 1.60 (m, 1H, H-10); 13C NMR (CDCl3,
125 MHz): d 166.77, 165.38, 159.35, 149.70, 148.30,
131.52, 128.01, 126.86, 126.69, 113.92, 113.82, 110.65,
68.19, 57.77, 56.18, 55.82, 55.29, 46.10, 45.42, 36.87,
29.78, 29.34, 21.13; ESI (+) m/z (%): 437 [M+H]+
(100); ESI (+) (+NaOAc) m/z (%): 459 [M+Na]+ (100).
˚
P212121, a = 10.142(4), b = 12.484(3), c = 13.041(6) A,
3
˚
a = b = c = 90ꢁ, V = 1651.2(10) A , Z = 4, qx =
1.329 g cmꢁ3, F(000) = 704; data collection: Kuma
KM4 j-axis diffractometer, 54 reflections with
12.0 > 2h > 26.3ꢁ, colourless crystal of dimensions
0.6 · 0.6 · 0.4 mm, 5488 intensities measured, 4848 inde-
pendent (Rint = 0.0756), 3518 with I > 2r(I); structure
solution and refinement: direct methods,34 refined using
SHELXL,35 final R and wR 0.0376 and 0.1098, respec-
tively. There was no observable hydrogen bonding in
the structure.
CCDC-251687 25a, CCDC-251689 39b, CCDC-251690
52b, CCDC-251691 57a and CCDC-252557 60b, contain
the supplementary crystallographic data. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/
const/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; Fax: (internat.) +44 1223/336 033; e-mail:
deposit@ccdc.cam.ac.uk].
4.38. Preparation of (8aS,13aS) and (8aS,13aR)-13a-
([1,3]dioxol-benzyl)-2,3-dimethoxy-5,8a,9,10,11,13a-
hexahydro-8H-pyrrolo[10,20:4,5]pyrazino[2,1-a]isoquino-
line-8,13(6H)-dione 61a and 61b
References
The same as above Pictet–Spengler reaction was applied
to compounds 55 and 58 (42 mg, 0.09 mmol) in order to
obtain the diketopiperazines 61a and 61b (16 mg, 40%).
Depending on the solvent used, the diastereomeric ratio
was of 75:25 (50 mL of MeOH/HCl), 75:25 (50 mL of
AcOEt/HCl) and 99.9:0.1 (5.0 mL of 5% BF3ÆEt2O in
Et2O).
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J = 8 Hz, J = 1.5 Hz, 1H, Harom), 6.55 (s, 1H, H-4),
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23
D
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