Synthesis of New Diketopiperazines, Thiolation to Thiodiketopiperazines, and Examination of Their ROS-Generating Properties

Article abstract of DOI:10.1002/ejoc.201500900

A variety of new symmetrical and unsymmetrical diketopiperazines have been prepared from free amino acids by using a previously developed microwave-assisted protocol. This included the successful incorporation of L-pyroglutamic acid as an unusual building block. The diketopiperazines were then thiolated electrophilically to the corresponding bis(methylthio)- and epidithiodiketopiperazines. Initial experiments showed a promising activity towards the generation of reactive oxygen species in HeLa cells. A variety of novel symmetrical and unsymmetrical thiodiketopiperazines have been prepared by methyl dichlorophosphite assisted dimerization of free amino acids and by thiolation of the resulting cyclic dipeptides with elemental sulfur and NaHMDS. Some of the sulfur compounds showed interesting activity in the generation of reactive oxygen species in HeLa cells.

Full text of DOI:10.1002/ejoc.201500900

FULL PAPER
DOI: 10.1002/ejoc.201500900
Synthesis of New Diketopiperazines, Thiolation to Thiodiketopiperazines, and
Examination of Their ROS-Generating Properties
[a]
[a]
[b]
[c]
Sabilla Zhong, Angela E. E. Wandler, Ute Schepers, Martin Nieger, and
Stefan Bräse*[
a,b]
Keywords: Fused ring systems / Nitrogen heterocycles / Amino acids / Thiolation / Reactive oxygen species
A variety of new symmetrical and unsymmetrical diketo-
piperazines have been prepared from free amino acids by
using a previously developed microwave-assisted protocol.
were then thiolated electrophilically to the corresponding
bis(methylthio)- and epidithiodiketopiperazines. Initial ex-
periments showed a promising activity towards the genera-
tion of reactive oxygen species in HeLa cells.
This included the successful incorporation of L-pyroglutamic
acid as an unusual building block. The diketopiperazines
Introduction
Thiodiketopiperazines are a class of fungal secondary
metabolites (mycotoxins).[1] They all share a mutual struc-
tural motif: A cyclic dipeptide (diketopiperazine) bearing
sulfur units at the α positions of the peptide bonds. Thiodi-
ketopiperazine natural products generally differ by type and
connectivity of the sulfur units as well as by annulation
(cis/trans) of the peripheral rings (Figure 1). Most com-
monly, a disulfide bridge can be found in the central ring
[
2]
[
e.g., in the antiviral gliotoxin (1) or the antibacterial
[
3]
epicorazin A (2) ]. Furthermore, there are bis(methylthio)-
diketopiperazines bearing two methyl thioether moieties
[
4]
[
e.g., in the HIV-1 replication-inhibiting epicoccin G (3) ].
Sulfides containing one, three, or four sulfur atoms are also
known. The sulfur groups can furthermore be bound in dif-
ferent rings of the system as a bridging function [e.g., in the Figure 1. Examples of thiodiketopiperazines with different types
[5]
and connectivity of their sulfur units.
antimicrobial, unsymmetrical epicoccin A (4) ].
Natural products with thiodiketopiperazine units possess
toxic properties towards a variety of organisms, including
fungi, bacteria, and viruses. The mode of action of this class
of mycotoxins is presumably based on the conjugation with
proteins through thiol groups and the generation of reactive
oxygen species (ROSs), which can lead to programed cell
death (apoptosis).[1,6]
Thiolation at the α positions of the peptide bonds plays
a crucial role in the total synthesis of thiodiketopiperazine
natural products. The introduction of sulfur units at a late
stage of the synthesis is reasonable due to their sensitivity
towards redox reactions. In principle, there are two different
approaches to the thiolation of diketopiperazines: The
treatment of α,αЈ-diacylimmonium ions with nucleophilic
sulfur reagents(biomimetic approach), for example,
[
a] Karlsruhe Institute of Technology, Institute of Organic
Chemistry,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
www.ioc.kit.edu/braese
hydrogen sulfide, trithiocarbonate,[7] and thioacetate, or
[7]
[8]
the treatment of α,αЈ-dicarbanions with electrophilic sulfur
[
[
b] Institute of Toxicology and Genetics, Karlsruhe
Institute of Technology,
[
9]
reagents, for example, elementary sulfur, diphenyl disulf-
Hermann-von-Helmholtz-Platz 1,
[10]
[11]
ide,
and disulfur dichloride.
In 2012, Nicolaou et al.
76344 Eggenstein-Leopoldshafen, Germany
c] Laboratory of Inorganic Chemistry, Department of Chemistry, published a general and easily reproducible method for the
University of Helsinki,
generation of bis(methylthio)- and epidithiodiketopiper-
P. O. Box 55, Helsinki 00014, Finland
azines with elemental sulfur and NaHMDS (sodium hexa-
Supporting information for this article is available on the
[
12]
WWW under http://dx.doi.org/10.1002/ejoc.201500900.
858
methyldisilazane) as base.
We were able to transfer this
6
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Diketopiperazines and Thiodiketopiperazines
protocol to the synthesis of a selection of symmetrical and Results and Discussion
[
9a]
unsymmetrical, mostly functionalized compounds.
Herein we wish to report the synthesis of additional and,
First, we synthesized various diketopiperazines starting
furthermore, unusual diketopiperazines from unprotected from the commercially available, enantiomerically pure
amino acids and their thiolation under Nicolaou’s condi- amino acids 5a–5i (Figure 2) by using a previously reported
[
13]
tions.
one-pot protocol.
Figure 2. Overview of the amino acid starting materials 5a–5i employed for the preparation of diketopiperazines.
2
Scheme 1. Synthesis of diketopiperazines 6 with yields (including yields of isolated homodimers). Reagents and conditions: a) MeOPCl ,
3
NEt , dimethylimidazolium dimethyl phosphate, toluene, 35 °C, 2 h–overnight; then 5y (for unsymmetrical products); then microwave
irradiation, 145 °C, 1 h, or reflux, 4–6.5 h.
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FULL PAPER
In a typical procedure (Scheme 1), the first amino acid erate an activated oxazaphospholidinone.[14] To enhance the
5x was treated with the coupling reagent methyl dichloro- solubility of very polar amino acids, some ionic liquid (di-
phosphite at a slightly elevated temperature (35 °C) to gen- methylimidazolium dimethyl phosphate) can be added. In
Figure 3. Molecular structures (from top left to bottom right) of 6bb, 6cc (one of the two crystallographic independent molecules is
shown), 6dd, 6de, 6eb, 6gf, 6ge, 6hd, and 6di; displacement parameters are drawn at the 50% probability level.
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Synthesis of Diketopiperazines and Thiodiketopiperazines
the case of unsymmetrical diketopiperazines, the second Many of the dimers were crystalline and were analyzed by
amino acid 5y was then added (this step was omitted for X-ray crystallography (Figure 3), along with a diketopiper-
symmetrical products). Then the mixture was heated in a azine containing pyroglutamate as an unusual building
[
18]
closed Pyrex vial in a microwave at 145 °C (up to ca. 500 mg block (6di), an interesting and novel structural motif, al-
[
19]
scale) or at reflux (for a larger scale), to give the desired beit in only poor yields.
diketopiperazine 6xy (of course, 6xy is chemically identical With several diketopiperazines in hand, we went on to
to 6yx, however, in this manuscript the order of addition synthesize their sulfur-bearing analogues by using
reflects the nomenclature). NaHMDS and sulfur (Scheme 2). After reduction to the
A variety of symmetrical and unsymmetrical diketo- α,α-diketopiperazine-dithiolates 8 with NaBH , two dif-
4
piperazines were successfully prepared in up to 83% yield. ferent work-ups led to either bis(methylthio)diketopiper-
The low yields of diketopiperazines containing l-azetidine- azines 9 (by treatment with methyl iodide) or epidithiodi-
[
15]
2-carboxylate (6bb,
6db, 6eb, 6bg) are probably due to ketopiperazines 10 (under oxidative conditions with pot-
the low solubility of the starting material in toluene. The assium triiodide).
use of other solvents to improve solubility and yield may
The thiodiketopiperazines successfully prepared from the
be considered, however, toluene was still our solvent of symmetrical diketopiperazines are shown in Figure 4. Be-
choice as it has a sufficiently high boiling point to allow the cause starting material 6aa is sterically less hindered, we
use of high temperatures for the dimerization reaction and assume the presence of two enantiomers of the products
is easy to remove from the reaction mixture, thereby facili- 9aa and 10aa. Only one NMR signal was detected for both
tating work-up and purification. It should be noted that the methyl and methylthio groups, which confirms the pres-
only a few l-azetidine-2-carboxylate diketopiperazines are ence of only one diastereomer.
[15]
[16]
known (with annulated four, five (1 example), and six-
Because we measured a noticeable optical rotation, one
can presume a cis geometry of the sulfur functionalities,
[
16,17]
membered rings
).
Furthermore, in some cases, the corresponding homo- as the corresponding trans isomers would be achiral (meso
dimers were formed in a significant competing reaction compounds). We obtained an enantiomerically pure crystal
(e.g., along with 6db, 6df, 6hd, 6di); the products could gen- of 9aa, which was analyzed by X-ray crystallography (Fig-
erally be separated by column chromatography. All the ure 5). Diketopiperazine 6bb could neither be transformed
other products were isolated in good-to-very-good yields. into a bis(methylthio)- nor an epidithiodiketopiperazine un-
Scheme 2. General synthesis of bis(methylthio)diketopiperazines 9 and epidithiodiketopiperazines 10 by the Nicolaou protocol.[12] Rea-
gents and conditions: a) NaHMDS, S
8
, THF, room temp.; then 6; then NaHMDS, room temp., 30 min; b) NaBH
, room temp., 10 min.
4
, THF/MeOH (1:1),
0
°C to room temp., 45 min; c) MeI, room temp., overnight; d) KI
3
Figure 4. Synthesized symmetrical thiodiketopiperazines with yields.
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FULL PAPER
Figure 5. Molecular structures of 9aa (left) and rac-9dd (right); displacement parameters are drawn at the 50% probability level.
der the described reaction conditions. A reason for this recently reported by Nicolaou et al.[20] The low yield of
might be the poor solubility of 6bb in THF, making it hard 10dd can be explained by product loss during recrystalli-
to carry out the α deprotonation.
zation. The products were also obtained diastereomerically
The protected hydroxyproline dimer 6cc was also sub- pure as the cis isomers. Derivative 9dd could be crystallized
jected to the thiolation conditions. Both sulfur-function- and was analyzed by X-ray crystallography, which revealed
alized compounds 9cc and 10cc were obtained as single dia- a racemic structure (Figure 5). As both 9dd and 10dd exhi-
stereomers. Derivative 9cc is cis-configured, as only one sig- bit pronounced optical rotations, the presence of a scalemic
nal for the methyl groups was observed in the NMR spec- rather than a racemic mixture, from which a racemate crys-
tra. For epithiodiketopiperazines, such as 10cc, a cis geome- tallized, can be assumed.
try can be corroborated due to the strong steric hindrance
Bis(methylthio)diketopiperazine 9hh was obtained from
of a hypothetical trans disulfide. Furthermore, we suppose the dimer of (S)-pipecolic acid (6ff), which itself was formed
that the sulfur attack proceeds from the less-hindered con- as a side-product during the synthesis of 6df. A scalemic
vex face of the molecule with retention of configuration to mixture was also formed in this case as there is no favored
give the (5aR,10aR) configuration of 9cc/10cc, as shown. In side of attack.
support of this stereochemistry, we previously reported a
Next, we carried out experiments to synthesize novel
very similar derivative, for which the stereochemical out- thiolated compounds from a selection of the unsymmetrical
come was proven by X-ray crystallography.[
9a]
diketopiperazines shown in Scheme 1. The structures of all
(S)-Tetrahydroisoquinoline dimer 6dd was successfully the successfully synthesized bis(methylthio)- 9 and epidi-
thiolated to 9dd and 10dd, albeit in lower yields than those thiodiketopiperazines 10 are depicted in Figure 6.
Figure 6. Synthesized unsymmetrical thiodiketopiperazines with yields.
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Synthesis of Diketopiperazines and Thiodiketopiperazines
Diketopiperazine 6de is sterically highly demanding and
shows an arched structure due to the octahydroindole moi-
ety. The electrophilic attack of the sulfur unit most likely
proceeds from the more accessible convex face. Accordingly,
after thiolation, we obtained diastereo- and enantiomer-
ically pure 9de and 10de with the (6aR,14aR) configuration.
When converting unsymmetrical diketopiperazine 6db
into 9db/10db, there is probably no favored side for the sul-
fur attack because of its nearly planar structure. In accord
with the postulated mechanism for thiolation, which implies
the intermediate presence of dianions, we obtained the cor-
responding thiodiketopiperazines as cis isomers. In the case
of 10db, the product was formed as a mixture of epidithio-
and epitrithiodiketopiperazine. The latter was only detected
by mass spectrometry; the two compounds were not distin-
guishable in the NMR spectra. This implies that the geome-
try hardly changes when substituting a disulfide- for a tri-
sulfide bridge.
Figure 7. Molecular structure of 9fe, displacement parameters are
drawn at the 50% probability level.
The synthesis of the unsymmetrical bis(methylthio)di-
ketopiperazine 9eb was successful as well, however, the yield
For the cell tests, HeLa cells were incubated with thiodi-
was relatively low (17%), which may also be due to the low ketopiperazines at different concentrations for 23 h at 37 °C
solubility of the starting material 6eb. The formation of epi- and afterwards visualized with the aid of several fluores-
dithiodiketopiperazine 10eb was only observed in trace cence markers [Hoechst 33342 for staining of nuclei,
quantities. Both products were probably formed as the propidium iodide for staining apoptotic cells,[22] and 2Ј,7Ј-
(
4aR,11aR) enantiomers with cis geometry.
Enantiomerically pure thiodiketopiperazines 9fe, 10fe, oxidatively stressed cells]. We discovered that two of the
he, and 10he were also prepared following the general compounds, 10de and 10db, showed distinct tendencies with
dichlorodihydrofluorescein (H DCF-DA) for detection of
2
[
23]
9
thiolation protocol, as well as racemic 9hd and 10hd. Di- regard to ROS generation.
ketopiperazines 6gf, 6ge, 6df, 6db, and 6id were not sub-
Table 1 shows the confocal fluorescence microscope
jected to the thiolation conditions either because the thio- images of HeLa cells incubated with different concentra-
lated species are already known[
1,2,21]
or because there was tions (50, 20, and 10 μm) of thiodiketopiperazine 10de. The
insufficient starting material. Furthermore, the nucleophilic staining of the cells with propidium iodide reveals a large
thioacetylation of sarcosine anhydride following the pion- number of apoptotic cells (red) with a final concentration
eering work of Trown[ led to good results, and a crystal of 10de of 50 μm. Furthermore, treatment with H DCF-DA
8]
2
structure of the cis isomer could be obtained (see com- shows a significant amount of cells exhibiting oxidative
pound SI-11 in the Supporting Information).
stress (green), which is not congruent with the apoptotic
Strong evidence for the formation of enantiomerically cells. This is due to the fact that apoptosis leads to perfora-
pure thiolated products from diketopiperazines with a tion of the cell wall, which allows the fluorescein derivative
hydroindole unit was provided by the crystal structure of to leave the cell through its porous membrane. This facili-
compound 9fe (Figure 7). It is a single enantiomer with an tates the differentiation of living oxidatively stressed cells
absolute configuration of (5R,6S,10S,12R) that results from from those that have already suffered apoptosis, which indi-
sulfur attack from the less hindered convex face with reten- cates that apoptosis results from a supercritical ROS con-
tion of configuration.
centration in the cells. With a lower final concentration of
The cytotoxic properties of many thiodiketopiperazine 10de, smaller amounts of apoptotic/oxidatively stressed cells
natural products are probably due to the formation of reac- are visible. In agreement with this tendency, there are only
tive oxygen species through sulfide redox cycling. For the a few dead or ROS-containing cells with a lower substance
best-investigated representative of this class of mycotoxins, concentration of 10 μm. Therefore thiodiketopiperazine
namely gliotoxin (1), there already exist detailed studies and 10de indeed seems to enhance intracellular ROS pro-
[2,22]
hints regarding its mode of action.
However, to the best duction.
of our knowledge, there are no reports of corresponding
Accordingly, compound 10db (a mixture of epidithio-
studies on bis-annulated systems, such as the natural prod- and epitrithiodiketopiperazine) was also used for cell tests
ucts 2–4 or the synthetic derivatives shown in Figure 6. In at concentrations of 20, 10, and 5 μm (Table 2). A clear ten-
principle, the thiodiketopiperazines in Figure 5 should also dency was again observed; with an increasing thiodiketo-
be able to generate ROSs through redox cycling. To better piperazine concentration, a higher amount of oxidative
understand this process and to possibly find a connection stress and apoptosis occurs. Using a concentration of 20 μm
between structure and activity, we investigated the ability of 10db, nearly all the cells are apoptotic. Furthermore, only
these compounds to produce ROSs by visualizing this pro- a few cells per surface unit can be seen; dead cells are no
cess in a test organism (HeLa cells).
longer able to hold on to the surface. They are presumably
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FULL PAPER
Table 1. ROS generation and apoptosis induced by thiodiketopiper- tion than its disulfide analogues. Furthermore, the lower
azine 10de after incubation with HeLa cells at 37 °C for 23 h under
steric hindrance and the fact that it is a mixture of enantio-
mers probably facilitates a stronger, but also less selective
interaction with potential reaction partners within the cells.
2
a 5% CO atmosphere. Confocal microscopic images after incu-
bation with Hoechst 33342 (blue, 1 μm, 15 min incubation at 37 °C
under a 5% CO atmosphere), H DCF-DA (green, 1 μm, 15 min
incubation at 37 °C under a 5% CO
2
2
atmosphere), propidium iod- The exemplary treatment of HeLa cells with thiodiketo-
2
ide (red, 1 μm, 15 min incubation at 37 °C under a 5% CO
sphere), and merging of the images.
2
atmo- piperazines 10de and 10db and analysis with confocal mi-
croscopy (live cell imaging) has allowed a primary qualita-
tive evaluation of ROS generation by the test substances.
The results are in accordance with a redox cycling mecha-
[
2]
nism, as postulated for gliotoxin (1). The incubation tests
with the other thiodiketopiperazines did not show any reli-
able tendencies in terms of their activity and are not de-
scribed. After optimization of the cell tests, for example, by
quantification of the biological effects or by development
of automated microscopic methods for detection of highly
active thiodiketopiperazine derivatives, an important con-
tribution could be made to the understanding of modes of
action of naturally occurring toxic sulfur-containing com-
pounds.
Conclusions
We have prepared a number of novel, including unsym-
metrical, diketopiperazines by dimerization of unprotected
amino acids. These compounds were functionalized with
sulfur moieties to the corresponding bis(methylthio)- and
epidithiodiketopiperazines to give a library of new sulfur
compounds. The stereochemical outcomes of these reac-
tions have been discussed based on individual structures
and X-ray crystallographic analyses. Furthermore, the com-
pounds were analyzed with regard to their activity towards
removed from the well during the first washing step after
incubation with the fluorescence markers. When the cells
were treated with 10 μm of 10db, few dead cells but a signifi-
cant number of ROS-producing cells are observed. In con-
trast, the sample incubated with a lower concentration of
10db (5 μm) shows almost exclusively healthy cells.
Table 2. ROS generation and apoptosis induced by thiodiketopiper-
azine 10db after incubation with HeLa cells at 37 °C for 23 h under ROS generation by live cell imaging using HeLa cells as the
a 5% CO atmosphere. Confocal microscopic images after incu- model organism and confocal fluorescence microscopy. Two
bation with Hoechst 33342 (blue, 1 μm, 15 min incubation at 37 °C
under a 5% CO atmosphere), H DCF-DA (green, 1 μm, 15 min
incubation at 37 °C under a 5% CO atmosphere), propidium iod-
2
of the tested compounds showed pronounced qualitative
tendencies towards ROS generation. The experimental and
biological results presented herein could make an important
contribution to the understanding of the cytotoxicity of
naturally occurring thiodiketopiperazines.
2
2
2
2
ide (red, 1 μm, 15 min incubation at 37 °C under a 5% CO atmo-
sphere), and merging of the images.
Experimental Section
General: NMR spectra were recorded with a Bruker Avance 300,
4
00, or 600 spectrometer as solutions at room temperature. Chemi-
cal shifts (δ) are expressed in ppm downfield from tetramethylsilane
TMS) and referenced to residual solvent peaks. All the coupling
(
constants are absolute values and expressed in Hz. The spectra
were analyzed according to first order and the signals are abbrevi-
ated as follows: s = singlet, d = doublet, dd = doublet of doublets, t
=
triplet, q = quartet, and m = multiplet. Diastereotopic methylene
1
3
A B
protons are labeled as H and H . The C NMR signal patterns
were analyzed by DEPT and are described as follows: + for pri-
mary or tertiary C atom (positive signal), – for secondary C atom
(
q
negative signal), and C = quaternary C atom (no signal). EI-
MS and FAB-MS were performed by using a Finnigan MAT 90
spectrometer (70 eV). ESI-MS spectra were recorded with an
Agilent 6230 TOF LC/MS spectrometer. The molecular fragments
It can be stated that, qualitatively, 10db is more active
than 10de in ROS production. Potentially, the trithiodiketo- are quoted as the relation between mass and charge (m/z) and the
piperazine contained in 10db leads to stronger ROS genera- intensities as a percentage value relative to the intensity of the base
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Synthesis of Diketopiperazines and Thiodiketopiperazines
+
signal (100%). The abbreviation [M] refers to the molecule ion
solution of sulfur (8.00 equiv.) in dry THF at room temperature.
Then diketopiperazine 6xy (1.00 equiv.) in dry THF and more
NaHMDS (1.0 m in THF, 3.00 equiv.) were added and the mixture
was stirred for 30 min at room temp. A saturated solution of
and [M + H]+ refers to the protonated molecule ion. IR spectra
were recorded with an FTIR Bruker IFS88 spectrometer and the
data are reported as follows: frequency of absorption (cm ), inten-
sity of absorption (vs = very strong, s = strong, m = medium, w =
weak, vw = very weak, and br. = broad). Optical rotations were
determined with a Perkin–Elmer 241 polarimeter at 20 °C with a
glass cuvette and the d line of sodium. Reactions were monitored
–1
NH
CH
and the solvent was evaporated under reduced pressure. The resi-
due was dissolved in degassed THF/EtOH (1:1) and NaBH
4
Cl was added and the resulting mixture was extracted with
2
Cl , the combined organic extracts were dried with MgSO ,
2
4
4
by using silica gel coated aluminium plates (Merck, silica gel 60, (25.0 equiv.) was added. The mixture was stirred for 45 min at room
254) with detection by examination under UV light (254 nm) and temp. Then the mixture was cooled to 0 °C, quenched by the ad-
by staining with molybdatophosphate (5% phosphor molybdic acid dition of a saturated solution of NH Cl, and extracted with EtOAc.
in ethanol) or potassium permanganate (0.75% KMnO in H O). The combined organic extracts were stirred with a solution of KI
for 10 min, a solution of Na was added, and the mixture was
F
4
4
2
3
Solvents, reagents, and other chemicals were purchased from
Sigma–Aldrich, ABCR, and Fisher Scientific. THF and toluene
were distilled from sodium prior to use. EtOH was purchased from
Acros as absolute solvent. All reactions involving moisture-sensi-
tive reactants were executed under argon in oven-dried glassware.
All other solvents, reagents, and chemicals were used as purchased
unless stated otherwise. Microwave-assisted reactions were carried
out in 10 mL Pyrex vials in a CEM DISCOVER microwave reactor.
The temperature was controlled by using an IR sensor.
2 2 3
S O
stirred until the dark color disappeared. The resulting mixture was
extracted with EtOAc. The combined organic extracts were dried
with MgSO and the solvent was evaporated under reduced pres-
4
sure. Purification by column chromatography afforded the title
compounds.
(
3S,8S)-1,6-Diazatricyclo[6.2.0.03,6]decane-2,7-dione (6bb): This
compound was synthesized following GP1 from l-azetidine-2-carb-
oxylic acid (5b, 1.00 g, 9.09 mmol, 1.00 equiv.) in toluene (68 mL)
at reflux for 6.5 h. The resulting crude product was purified by
column chromatography (EtOAc). The title compound was ob-
General Procedure 1 (GP1) Ϫ Dimerization of Amino Acids to Di-
ketopiperazines 6xy
Dimerization to Symmetrical Diketopiperazines (5x = 5y): Amino
acid 5 (1.00 equiv.) was suspended in absolute toluene. Absolute
tained as a colorless solid (133 mg, 0.800 mmol, 16%). R
f
(EtOAc)
= +9.1 (c = 0.33, CHCl ).
3
): δ = 2.52–2.61, 2.75–2.84 (2 m, 4 H,
2
0
= 0.04, m.p. 191–196 °C (decomp.). [α]
D
3
1
NEt
then added and the mixture was stirred at 35 °C overnight. After NCH
irradiation under closed-vessel microwave conditions at 145 °C for
7.7 Hz, 2 H, 2 CH) ppm. C NMR (100 MHz, CDCl
h or heating at reflux for 4–6.5 h, the solution was filtered and
(–, 2 NCH CH ), 48.3 (–, 2 NCH ), 63.4 (+, 2 CH), 168.7 (C
3
(4.00 equiv.) and methyl dichlorophosphite (0.50 equiv.) were
H NMR (400 MHz, CDCl
CH ), 4.01–4.09, 4.11–4.17 (2 m, 4 H, NCH
3
2
2
2
), 4.98 (t, J =
): δ = 22.5
, 2
1
3
3
1
2
2
2
q
the precipitate was washed with hot toluene. The filtrate was evapo-
rated under reduced pressure and the resulting crude product was
purified by column chromatography.
C=O) ppm. IR (ATR): ν˜ = 2933 (vw), 2896 (vw), 1650 (m), 1447
(w), 1416 (m), 1286 (w), 1229 (w), 1114 (w), 1057 (w), 1044 (w),
972 (vw), 924 (w), 806 (vw), 767 (vw), 742 (w), 678 (w), 617 (vw),
–
1
+
5
5
1
19 (vw) cm . MS (EI, 70 eV): m/z (%) = 166 (70) [M] , 110 (42),
Dimerization to Unsymmetrical Diketopiperazines (5x ϶ 5y): The
first amino acid 5x (1.00 equiv.) was suspended in absolute toluene.
6 (100). HRMS (EI): calcd. for C
66.0741.
8 10 2 2
H N O 166.0742; found
Absolute
NEt
3
(4.00 equiv.),
methyl
dichlorophosphite
(
1.00 equiv.), and dimethylimidazolium dimethyl phosphate (3–5
(7aS,15aS)-8,13,15a,16-Tetrahydropyrazino[1,2-b:4,5-bЈ]diisoquinol-
ine-7,15(5H,7aH)-dione (6dd): This compound was synthesized fol-
lowing GP1 from (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid (5d, 1.00 g, 5.64 mmol, 1.00 equiv.) in toluene (40 mL) at re-
flux for 4 h. The resulting crude product was purified by column
chromatography (cHex/EtOAc, 1:1). The title compound was ob-
drops) were added and the mixture was stirred at 35 °C overnight.
Then the second amino acid 5y (1.20–1.50 equiv.) was added to the
mixture. After irradiation under closed-vessel microwave conditions
at 145 °C for 1 h or heating at reflux for 4–6 h, the solution was
filtered and the precipitate was washed with hot toluene. The fil-
trate was evaporated under reduced pressure and the resulting
crude product was purified by column chromatography.
tained as a colorless solid (516 mg, 1.62 mmol, 57%). R (cHex/
f
2
0
EtOAc, 1:1) = 0.28, m.p. 215–222 °C (decomp.). [α] = –422.3 (c
3
): δ = 3.02 (dd, J =
5.9, J = 12.1 Hz, 2 H, 2 NCHCHH), 3.46 (dd, J = 15.9, J =
.7 Hz, 2 H, 2 NCHCHH), 4.29 (dd, J = 12.0, J = 3.7 Hz, 2 H,
NCH), 4.35 (d, J = 17.0 Hz, 2 H, 2 NCHH), 5.40 (d, J =
7.0 Hz, 2 H, 2 NCHH), 7.18–7.28 (m, 8 H, CHAr) ppm. C NMR
): δ = 34.2 (–, 2 NCHCH ), 44.0 (–, 2 NCH ),
5.7 (+, 2 NCH), 126.3 (+, 2 CHAr), 127.07 (+, 2 CHAr), 127.09
, 2 CAr), 132.3 (C , 2
, 2 C=O) ppm. IR (ATR): ν˜ = 3007 (vw), 2956 (vw),
D
1
2
=
0.98, CHCl
3
). H NMR (400 MHz, CDCl
General Procedure 2 (GP2) Ϫ Synthesis of Bis(methylthio)diketo-
piperazines 9xy: NaHMDS (1.0 m in THF, 3.00 equiv.) was added
to a solution of sulfur (8.00 equiv.) in dry THF at room tempera-
ture. Then diketopiperazine 6xy (1.00 equiv.) in dry THF and more
NaHMDS (1.0 m in THF, 3.00 equiv.) were added and the mixture
3
2
3
1
3
2
1
(
5
3
3
2
2
1
3
100 MHz, CDCl
3
2
2
was stirred for 0.5 h at room temp. A saturated solution of NH
was added, the resulting mixture was extracted with CH Cl , the
combined organic extracts were dried with MgSO , and the solvent
was evaporated under reduced pressure. The residue was dissolved
in degassed THF/EtOH (1:1) and NaBH (25.0 equiv.) was added
and the mixture was stirred for 45 min at room temp. Then MeI
50.0 equiv.) was added and again the mixture was stirred over-
night. It was then quenched with a saturated solution of NH Cl
and then extracted with CH Cl . The combined organic extracts
were dried with MgSO and the solvent was evaporated under re-
4
Cl
2
2
(
C
+, 2 CHAr), 128.8 (+, 2 CHAr), 131.4 (C
q
q
4
Ar), 164.1 (C
q
2858 (vw), 1647 (m), 1586 (w), 1492 (vw), 1446 (w), 1347 (w), 1328
4
(
(
(
w), 1293 (w), 1250 (w), 1221 (w), 1103 (w), 989 (w), 966 (vw), 773
w), 760 (w), 750 (w), 711 (w), 689 (w), 604 (vw), 510 (vw), 476
(
–
1
w), 441 (w), 428 (w) cm . MS (EI, 70 eV): m/z (%) = 318 (22)
4
+
18 2 2
[M] , 86 (64), 84 (100). HRMS (EI): calcd. for C20H N O
2
2
318.1368; found 318.1365.
4
duced pressure. Purification by column chromatography afforded
the title compounds.
(
4aS,6aS,14aS,15aS)-1,2,3,4,4a,7,12,14a,15,15a-Decahydro-14H-
indolo[1Ј,2Ј:4,5]pyrazino[1,2-b]isoquinoline-6,14(6aH)-dione (6de):
This compound was synthesized following GP1 from (S)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid (5d, 151 mg, 0.853 mmol,
General Procedure 3 (GP3) Ϫ Synthesis of Epidithiodiketopiper-
azines 10xy: NaHMDS (1.0 m in THF, 3.00 equiv.) was added to a
Eur. J. Org. Chem. 2015, 6858–6871
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6865

S. Zhong, A. E. E. Wandler, U. Schepers, M. Nieger, S. Bräse
FULL PAPER
1
.00 equiv.), with stirring with MeOPCl
of overnight, and l-octahydroindole-2-carboxylic acid (5e, 173 mg,
.02 mmol, 1.20 equiv.) in toluene (4.0 mL) under closed-vessel mi-
crowave conditions with dimethylimidazolium dimethyl phosphate
2
at 35 °C for 2.5 h instead
lowing GP1 from l-octahydroindole-2-carboxylic acid (5e, 627 mg,
3.70 mmol, 1.00 equiv.), with stirring with MeOPCl at 35 °C for
2
2 h instead of overnight, and l-azetidine-2-carboxylic acid (5b,
449 mg, 4.44 mmol, 1.20 equiv.) in toluene (17 mL) at reflux for
1
(
4 drops). The resulting crude product was purified by column 6 h with dimethylimidazolium dimethyl phosphate (4 drops). The
chromatography (cHex/EtOAc, 2:1ǞEtOAc). The title compound
was obtained as a colorless solid (169 mg, 0.546 mmol, 64 %).
resulting crude product was purified by column chromatography
(EtOAcǞCH Cl /MeOH, 98:2). The title compound was obtained
as a colorless solid (151 mg, 0.643 mmol, 17%). R (EtOAc) = 0.18,
2
2
Furthermore, homodimers 6dd [R
f
(EtOAc) = 0.76, 27.2 mg,
(EtOAc) = 0.27, 37.0 mg, 51.2 μmol,
2%] were obtained as colorless solids. R (EtOAc) = 0.65, m.p.
f
2
0
1
7
1
1
6.8 μmol, 18%] and 6ee [R
f
m.p. 162–164 °C. [α]
D
= –1.2 (c = 0.96, CHCl
3
). H NMR
3
f
(400 MHz, CDCl ): δ = 0.99–1.09 (m, 1 H, CH
3
2
4
), 1.17 (qt, J =
52–155 °C. [α]2
0
= –61.0 (c = 0.91, CHCl
). H NMR (400 MHz,
1
12.9, J = 2.9 Hz, 1 H, CH
CH ), 1.47–1.55 (m, 1 H, CH
1.85 (m, 1 H, CH ), 1.90–1.95 (m, 1 H, CH
), 1.73 (dt, J = CH CHCH , 2 CH ), 2.61–2.67 (m, 2 H, CH
), 1.80–1.86 (m, 1 H, CH ), 2.08–2.16 2 NCH, 2 CH ), 4.83 (t, J = 7.7 Hz, 1 H, NCH) ppm. C NMR
), 2.30–2.46 (m, 3 H, CH CHCH , 2 CH ), 3.09 (dd, (100 MHz, CDCl
J = 15.5, J = 11.2 Hz, 1 H, CH ), 3.36 (dd, J = 15.5, J = 4.4 Hz,
4
), 1.32 (qt, J = 12.9, J = 3.5 Hz, 1 H,
), 1.60–1.73 (m, 2 H, CH ), 1.77–
), 2.28–2.37 (m, 3 H,
), 3.96–4.19 (m, 4 H,
3
D
3
2
3
4
CDCl
3
): δ = 1.02–1.12 (m, 1 H, CH ), 1.19 (qt, J = 12.9, J =
2
2
2
2
3
4
2
1
1
.7 Hz, 1 H, CH
.49–1.58 (m, 1 H, CH ), 1.61–1.69 (m, 1 H, CH
3.1, J = 4.7 Hz, 1 H, CH
2
), 1.34 (qt, J = 12.8, J = 3.6 Hz, 1 H, CH
2
),
2
2
2
2
2
2
2
2
2
3
3
13
2
2
2
(
m, 1 H, CH
2
2
2
2
3
3
): δ = 20.7 (–, CH
), 27.8 (–, CH ), 27.9 (–, CH
47.5 (–, NCH
.02–4.07 (m, 1 H, NCH), 4.09–4.16 (m, 1 H, NCH), 4.29 (d, J = (C , C=O), 169.8 (C
), 7.20–7.32 (w), 1661 (m), 1399 (m), 1347 (w), 1279 (w), 1263 (w), 1233 (w),
): δ = 20.7 (–, 1176 (w), 1149 (w), 1115 (w), 1057 (w), 953 (vw), 890 (w), 821 (vw),
), 29.1 (–, CH ), 772 (w), 741 (vw), 689 (w), 640 (w), 612 (w), 533 (vw), 509 (vw),
), 43.9 (–, NCH ), 55.9 (+, CH), 444 (w) cm . MS (EI, 70 eV): m/z (%) = 234 (51), 178 (69), 124
6.3 (+, CH), 59.2 (+, CH), 126.2 (+, CHAr), 127.1 (+, CHAr), (100). HRMS (EI): calcd. for C13 234.1368; found
27.5 (+, CHAr), 127.7 (+, CHAr), 133.1 (C , CAr), 134.6 (C , CAr), 234.1369.
65.6 (C , C=O), 168.6 (C , C=O) ppm. IR (ATR): ν˜ = 2926 (vw),
858 (vw), 1655 (w), 1496 (vw), 1448 (w), 1404 (w), 1360 (w), 1234
2
), 22.6 (–, CH
2
), 23.5 (–, CH
2
),
2
3
2
2
3
25.8 (–, CH
2
2
2
), 35.9 (+, CH
2
CHCH
2
),
3
4
1
4
1
H, CH
2
), 3.97 (ddd, J = 11.4, J = 4.5, J = 1.0 Hz, 1 H, NCH),
2
), 56.3 (+, CH), 59.2 (+, CH), 63.1 (+, CH), 167.6
, C=O) ppm. IR (ATR): ν˜ = 2925 (w), 2857
2
q
q
2
5.7 Hz, 1 H, CH
2
), 5.03 (d, J = 15.7 Hz, 1 H, CH
2
(
m, 4 H, CHAr) ppm. 13C NMR (100 MHz, CDCl
), 23.3 (–, CH ), 25.7 (–, CH ), 27.4 (–, CH
0.2 (–, CH ), 35.8 (+, CH CHCH
3
CH
2
2
2
2
2
–
1
3
5
1
1
2
2
2
2
2
18 2 2
H N O
q
q
q
q
(
5aS,13aS)-1,2,3,6,11,13a-Hexahydro-13H-pyrrolo[1Ј,2Ј:4,5]pyraz-
ino[1,2-b]isoquinoline-5,13(5aH)-dione (6df): This compound was
synthesized following GP1 from (S)-1,2,3,4-tetrahydroisoquinoline-
(w), 1188 (w), 1154 (vw), 1106 (vw), 1001 (vw), 930 (vw), 766 (vw),
7
4
1
43 (w), 662 (vw), 648 (vw), 604 (w), 562 (vw), 520 (vw), 505 (vw),
3-carboxylic acid (5d, 100 mg, 0.565 mmol, 1.00 equiv.) and l-prol-
–1
+
85 (w), 443 (vw) cm . MS (EI, 70 eV): m/z (%) = 310 (100) [M] ,
53 (27), 132 (50). HRMS (EI): calcd. for C19 310.1681;
ine (5f, 97.5 mg, 0.847 mmol, 1.50 equiv.) in toluene (5.0 mL) under
closed-vessel microwave conditions with addition of dimethylimid-
azolium dimethyl phosphate. The resulting crude product was puri-
22 2 2
H N O
found 310.1683.
(
4aS,12aS)-1,5,10,12a-Tetrahydroazeto[1Ј,2Ј:4,5]pyrazino[1,2-b]iso- fied by column chromatography (EtOAc). The title compound was
quinoline-4,12(2H,4aH)-dione (6db): This compound was synthe-
sized following GP1 from (S)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid (5d, 150 mg, 0.849 mmol, 1.00 equiv.), with stirring
obtained as a colorless solid (12.2 mg, 47.6 μmol, 8%). Further-
more, homodimer 6ff was obtained (25.3 mg, 0.130 mmol, 17%).
1
R
f
(EtOAc) = 0.22. H NMR (400 MHz, CDCl
3
): δ = 1.81–2.05
2
3
with MeOPCl
2
at 35 °C for 2.5 h instead of overnight, and l-azetid-
2 2
(m, 2 H, CH ), 2.09–2.24 (m, 1 H, CH ), 2.33 (dtd, J = 13.6, J
4
2
3
ine-2-carboxylic acid (5b, 103 mg, 1.02 mmol, 1.20 equiv.) in tolu-
ene (4.0 mL) under closed-vessel microwave conditions with di-
methylimidazolium dimethyl phosphate (4 drops). The resulting
crude product was purified by column chromatography (cHex/
EtOAc, 1:1). The title compound was obtained as a colorless solid
2
= 7.0, J = 3.3 Hz, 1 H, CH ), 3.03 (dd, J = 15.5, J = 11.1 Hz, 1
2
3
H, CH
(m, 2 H, CH
H, CH ), 4.86 (d, J = 16.1 Hz, 1 H, CH
CHAr) ppm. C NMR (100 MHz, CDCl
), 30.8 (–, CH ), 44.4 (–, NCH ), 45.4 (–, NCH
NCH), 59.1 (+, NCH), 126.3 (+, CHAr), 127.2 (+, CHAr), 127.7
(+, CHAr), 127.8 (+, CHAr), 132.9 (C , CAr), 134.4 (C , CAr), 165.3
, C=O), 167.8 (C , C=O) ppm. IR (ATR): ν˜ = 2976 (vw), 2862
2
), 3.34 (dd, J = 15.6, J = 4.3 Hz, 1 H, CH
2
), 3.46–3.62
2
2
), 3.97–4.11 (m, 2 H, NCH), 4.37 (d, J = 16.0 Hz, 1
2
2
2
), 7.09–7.36 (m, 4 H,
): δ = 23.0 (–, CH ), 28.4
), 56.0 (+,
1
3
3
2
(
(
(
31.2 mg, 0.129 mmol, 15 %). Furthermore, the homodimer 6dd (–, CH
2
2
2
2
51.6 mg, 0.162 mmol, 38%) was obtained as a colorless solid. R
f
20
EtOAc) = 0.19, m.p. 158–160 °C. [α]
D
= –8.6 (c = 0.60, CHCl
3
).
q
q
1
3
3
H NMR (400 MHz, CDCl
H, NCHCH ), 3.04–3.17 (m, 2 H, NCHCH
J = 5.1 Hz, 1 H, NCH ), 3.97–4.07 (m, 2 H, NCH
3
): δ = 2.66 (dt, J = 7.6, J = 7.6 Hz, (C
q
q
2
2
2
2
), 3.92 (dd, J = 10.4,
(vw), 1671 (w), 1646 (m), 1417 (w), 1365 (w), 1346 (w), 1303 (w),
3
2
2
, NCH), 4.25 1272 (w), 1227 (w), 1211 (w), 1156 (w), 1110 (w), 1029 (w), 962
2
3
(d, J = 15.8 Hz, 1 H, NCH
2
), 4.78 (t, J = 7.7 Hz, 1 H, NCH),
(w), 922 (w), 870 (vw), 747 (m), 650 (w), 627 (w), 603 (w), 568 (w),
2
–1
4
.93 (d, J = 15.8 Hz, 1 H, NCH
2
), 7.15–7.27 (m, 4 H, CHAr) ppm.
508 (w), 494 (w), 459 (w), 441 (w), 425 (w) cm . MS (EI, 70 eV):
1
3
+
C NMR (100 MHz, CDCl
NCHCH ), 43.9 (–, NCH ), 47.9 (–, NCH
+, NCH), 126.2 (+, CHAr), 127.2 (+, CHAr), 127.5 (+, CHAr),
3
): δ = 23.1 (–, NCHCH
2
), 29.5 (–,
m/z (%) = 256 (100) [M] , 257 (31). HRMS (EI): calcd. for
2
2
2
), 54.4 (+, NCH), 61.5
C
15
H
16
N
2
O
2
256.1206; found 256.1207.
4aS,11aS)-1,4a,5,11a-Tetrahydro-4H-azeto[1Ј,2Ј:4,5]pyrazino-
1,2-a]indole-4,11(2H)-dione (6bg): This compound was synthesized
following GP1 from l-azetidine-2-carboxylic acid (5b, 50.0 mg,
(
(
[
1
27.8 (+, CHAr), 132.93 (C
q
, CAr), 134.3 (C
q q
, CAr), 168.2 (C ,
C=O), 168.6 (C
q
, C=O) ppm. IR (ATR): ν˜ = 2952 (vw), 1650 (m),
1492 (w), 1438 (w), 1407 (w), 1367 (w), 1311 (w), 1231 (w), 1153
0
1
.495 mmol, 1.00 equiv.) and (S)-indoline-2-carboxylic acid (5g,
21 mg, 0.742 mmol, 1.50 equiv.) in toluene (5.0 mL) under closed-
(
(
(
[
w), 1128 (w), 1062 (w), 932 (w), 765 (w), 755 (w), 740 (w), 716
w), 665 (w), 627 (vw), 607 (w), 577 (vw), 527 (vw), 507 (w), 492
vessel microwave conditions with addition of dimethylimidazolium
dimethyl phosphate. The resulting crude product was purified by
column chromatography (cHex/EtOAc, 1:1). The title compound
–1
w), 472 (w), 442 (w) cm . MS (EI, 70 eV): m/z (%) = 242 (100)
+
M] , 214 (45), 132 (39), 104 (52). HRMS (EI): calcd. for
14 14 2 2
C H N O 242.1055; found 242.1052.
was obtained as a colorless solid (5.9 mg, 25.8 μmol, 5 %). R
f
1
(
4aS,5aS,9aS,11aS)-Decahydro-4H-azeto[1Ј,2Ј:4,5]pyrazino[1,2-a]- (cHex/EtOAc, 1:1) = 0.10. H NMR (400 MHz, CDCl
3
): δ = 2.67–
2
3
indole-4,11(2H)-dione (6eb): This compound was synthesized fol-
2.74 (m, 2 H, CH
2
), 3.21 (dd, J = 16.7, J = 10.5 Hz, 1 H, CH ),
2
6866
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6858–6871

Synthesis of Diketopiperazines and Thiodiketopiperazines
2
3
3
CH
2
.69 (dd, J = 16.7, J = 9.0 Hz, 1 H, CH ), 4.01–4.10 (m, 2 H, (w), 1288 (w), 1258 (w), 1202 (w), 1202 (w), 1135 (w), 1113 (w),
3
3
2
), 4.70 (t, J = 9.7 Hz, 1 H, NCH), 4.99 (t, J = 7.8 Hz, 1 H, 1005 (vw), 889 (vw), 865 (vw), 820 (vw), 660 (w), 633 (w), 609 (w),
NCH), 7.00–7.11 (m, 1 H, CHAr), 7.14–7.23 (m, 2 H, CHAr), 8.06 556 (vw), 466 (vw), 442 (w) cm . MS (EI, 70 eV): m/z (%) = 262
–
1
d, J = 7.8 Hz, 1 H, CHAr) ppm. 13C NMR (100 MHz, CDCl
22.8 (–, CH ), 29.3 (–, CH ), 47.9 (–, NCH ), 60.0 (+, NCH), found 262.1678.
2.9 (+, NCH), 115.9 (+, CHAr), 125.0 (+, CHAr), 125.1 (+, CHAr),
27.9 (+, CHAr), 130.9 (C , CAr), 140.6 (C , CAr), 167.8 (C , C=O),
67.9 (C , C=O) ppm. IR (ATR): ν˜ = 2920 (w), 2853 (w), 1666
3
+
(
=
6
1
1
(
1
(
(
[
3 22 2 2
): δ (100) [M] , 84 (20). HRMS (EI): calcd. for C15H N O 262.1676;
2
2
2
(
[
5aS,13aS)-1,6,11,13a-Tetrahydro-3H-pyrrolo[1Ј,2Ј:4,5]pyrazino-
1,2-b]isoquinoline-3,5,13(2H,5aH)-trione (6di): This compound was
synthesized following GP1 from (S)-1,2,3,4-tetrahydroisoquinoline-
-carboxylic acid (5d, 550 mg, 3.11 mmol, 1.00 equiv.) and l-pyro-
q
q
q
q
m), 1598 (w), 1481 (w), 1460 (w), 1405 (m), 1325 (w), 1283 (w),
245 (w), 1207 (w), 1112 (w), 1056 (w), 1023 (w), 964 (vw), 920
vw), 871 (vw), 751 (m), 712 (w), 666 (vw), 636 (vw), 550 (w), 489
w), 449 (w), 426 (w) cm . MS (EI, 70 eV): m/z (%) = 228 (100)
M] , 167 (40), 149 (100), 117 (55), 69 (51). HRMS (EI): calcd. for
3
glutamic acid (5i, 481 mg, 3.72 mmol, 1.20 equiv.) in toluene
(40 mL) at reflux for 4 h with the addition of dimethylimidazolium
dimethyl phosphate. The resulting crude product was purified by
column chromatography (cHex/EtOAc, 2:1). The title compound
was obtained as an off-white solid (15.6 mg, 57.7 μmol, 2 %).
–1
+
13 12 2 2
C H N O
228.0893; found 228.0891.
(
[
6aS,14aS)-1,3,4,7,12,14a-Hexahydropyrido[1Ј,2Ј:4,5]pyrazino-
1,2-b]isoquinoline-6,14(2H,6aH)-dione (6hd): This compound was
synthesized following GP1 from l-pipecolic acid (5h, 500 mg,
.87 mmol, 1.00 equiv.) and (S)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid (5d, 823 mg, 4.65 mmol, 1.20 equiv.) in toluene
40 mL) at reflux for 4 h with the addition of dimethylimidazolium
dimethyl phosphate. The resulting crude product was purified by
column chromatography (cHex/EtOAc, 3:1Ǟ 2:1Ǟ EtOAc). The
title compound was obtained as an off-white solid (287 mg,
.12 mmol, 24 %). Furthermore, homodimers 6hh (95.4 mg,
.353 mmol, 8%) and 6dd (236 mg, 0.874 mmol, 20%) were ob-
tained both as colorless solids. R
400 MHz, CDCl ): δ = 1.34–1.68 (m, 3 H, CH
3.2 Hz, 1 H, CH
Furthermore, homodimer 6dd was obtained as a colorless solid
1
(
(
2
3
256 mg, 0.805 mmol, 30 %). R
f
(EtOAc) = 0.24. H NMR
2
3
400 MHz, CDCl
3
): δ = 2.45 (dt, J = 8.6, J = 5.3 Hz, 2 H, CH
.62 (m, 2 H, CH ), 3.21 (dd, J = 15.5, J = 9.9 Hz, 1 H, CH
2
2
),
),
3
2
3
2
3
3
4
2
.37 (dd, J = 15.5, J = 4.9 Hz, 1 H, CH
2
), 4.17 (dd, J = 9.8, J
4.9 Hz, 1 H, NCH), 4.42 (d, J = 15.6 Hz, 1 H, NCH ), 4.49 (t,
J = 8.5 Hz, 1 H, NCH), 4.96 (d, J = 15.6 Hz, 1 H, NCH ), 7.21–
): δ = 20.6
), 55.7 (+,
NCH), 57.0 (+, NCH), 126.3 (+, CHAr), 127.6 (+, CHAr), 127.9
(
2
=
2
3
2
2
13
7
(
.34 (m, 4 H, CHAr) ppm. C NMR (100 MHz, CDCl
3
–, CH ), 29.4 (–, CH ), 31.6 (–, CH ), 43.9 (–, NCH
2
2
2
2
1
0
(
(
=
1
+, CHAr), 128.0 (+, CHAr), 133.0 (C
, C=O), 166.7 (C , C=O), 172.8 (C
3115 (w), 2923 (w), 1768 (vw), 1649 (vw), 1442 (vw), 1392 (w),
q
, CAr), 133.6 (C
q
, CAr), 165.2
1
f
(EtOAc) = 0.22. H NMR
C
, C=O) ppm. IR (ATR): ν˜
q
q
q
2
(
1
=
3
2
), 1.77 (d, J =
), 2.39 (dd, J
), 2.55 (td, J = 12.9, J = 2.9 Hz, 1
2
2
–1
2
), 2.00 (d, J = 13.9 Hz, 1 H, CH
2
112 (w), 763 (vw), 609 (vw), 493 (vw), 405 (vw) cm . MS (EI,
3
2
3
13.1, J = 2.3 Hz, 1 H, CH
), 2.97 (dd, J = 15.8, J = 12.6 Hz, 1 H, NCH
dd, J = 16.1, J = 3.6 Hz, 1 H, CH
2
+
7
0 eV): m/z (%) = 270 (100) [M] , 158 (22), 130 (39), 104 (21).
2
3
H, NCH
(
2
2
2
), 3.47
HRMS (EI): calcd. for C15
14 2 3
H N O 270.0999; found 270.0999.
2
3
2
3
2
), 3.92 (dd, J = 12.1, J =
(
2R,5aR,7R,10aR)-2,7-Di-tert-butoxy-5a,10a-bis(methylthio)octa-
.6 Hz, 1 H, CH
2
), 4.15–4.25 (m, 2 H, 2 NCH), 4.69–4.77 (m, 1 H,
2
hydro-5H,10H-dipyrrolo[1,2-a:1Ј,2Ј-d]pyrazine-5,10-dione (9cc):
Prepared according to GP2, starting from diketopiperazine 6cc
NCH
2
), 5.48 (d, J = 17.3 Hz, 1 H, NCH
2
), 7.11–7.25 (m, 4 H,
): δ = 24.5 (–, CH ), 24.8
), 43.9 (–,
CHAr) ppm. 1 C NMR (100 MHz, CDCl
3
3
2
(
102 mg, 0.300 mmol, 1.00 equiv.). Column chromatography (cHex/
(
–, CH ), 32.1 (–, CH ), 34.9 (–, CH ), 42.6 (–, NCH
NCH ), 55.6 (+, NCH), 59.4 (+, NCH), 126.3 (+, CHAr), 126.9 (+,
CHAr), 127.0 (+, CHAr), 129.0 (+, CHAr), 131.3 (C , CAr), 132.2
, CAr), 163.4 (C , C=O), 164.4 (C , C=O) ppm. IR (ATR): ν˜ =
929 (vw), 2849 (vw), 1649 (w), 1437 (w), 1346 (vw), 1320 (w), 1296
w), 1233 (w), 1143 (vw), 1100 (vw), 1019 (vw), 978 (vw), 891 (vw),
2
2
2
2
EtOAc, 5:1) afforded the title compound (49.2 mg, 0.114 mmol,
2
3
1
f
8%) as a colorless solid. R (cHex/EtOAc, 5:1) = 0.17, m.p. 142–
q
2
0
1
48 °C. [α]
D 3
= –28.6 (c = 1.12, CHCl ). H NMR (400 MHz,
(C
q
q
q
CDCl
3
): δ = 1.17 [s, 18 H, 2 C(CH
3
)
3
], 2.28 (s, 6 H, 2 SCH
3
), 2.48
2
(
8
4
[
2
3
2
(
dd, J = 14.7, J = 3.5 Hz, 2 H, 2 CHHCSMe), 2.66 (dd, J =
3
2
3
14.7, J = 3.5 Hz, 2 H, 2 CHHCSMe), 3.36 (dd, J = 12.4, J =
50 (vw), 760 (w), 648 (vw), 601 (vw), 512 (vw), 487 (vw), 473 (vw),
33 (vw), 418 (vw) cm . MS (EI, 70 eV): m/z (%) = 270 (100)
–
1
5.6 Hz, 2 H, 2 NCHH), 4.13–4.19 (m, 2 H, 2 CHOtBu), 4.29 (dd,
2
3
13
+
J = 12.4, J = 7.6 Hz, 2 H, 2 NCHH) ppm. C NMR (100 MHz,
CDCl ): δ = 15.0 (+, 2 SCH ), 28.2 [+, 2 C(CH ], 43.9 (–, 2 CH ),
2.3 (–, 2 CH ), 66.8 (+, 2 CHOtBu), 69.1 (C , 2 CSCH ), 74.2
, 2 C(CH ], 164.4 (C , 2 C=O) ppm. IR (ATR): ν˜ = 2968 (vw),
921 (vw), 1658 (w), 1404 (w), 1389 (w), 1363 (w), 1233 (vw), 1189
M] , 130 (25), 104 (33), 84 (33). HRMS (EI): calcd. for
270.1363; found 270.1364.
3
3
3
)
3
2
16 18 2 2
C H N O
5
2
q
3
(
[
4aS,6aS,12aS,13aS)-Dodecahydro-12H-pyrido[1Ј,2Ј:4,5]pyrazino-
1,2-a]indole-6,12(6aH)-dione (6he): This compound was synthe-
sized following GP1 from l-pipecolic acid (5h, 250 mg, 1.94 mmol,
.00 equiv.) and l-octahydroindole-2-carboxylic acid (5e, 393 mg,
.32 mmol, 1.20 equiv.) in toluene (20 mL) at reflux for 4 h with
the addition of dimethylimidazolium dimethyl phosphate. The re-
sulting crude product was purified by column chromatography
cHex/EtOAc, 3:1Ǟ2:1Ǟ1:1). The title compound was obtained
[C
q
3
)
3
q
2
(
7
w), 1131 (vw), 1092 (w), 1015 (w), 901 (vw), 884 (vw), 770 (vw),
1
2
–1
16 (vw), 688 (vw), 672 (vw), 660 (vw), 611 (vw), 484 (vw) cm .
+
MS (EI, 70 eV): m/z (%) = 430 (2) [M] , 381 (44), 336 (100) [M –
2
+
SMe] , 280 (58), 225 (88). HRMS (EI): calcd. for C20
34 2 2 4
H S N O
430.1960; found. 430.1957.
(
as an off-white solid (273 mg, 1.04 mmol, 53%). R
f
(EtOAc) = 0.21. (2R,5aR,7R,10aR)-2,7-Di-tert-butoxytetrahydro-1H,5H,6H,10H-
), 1.39– 5a,10a-epidithiodipyrrolo[1,2-a:1Ј,2Ј-d]pyrazine-5,10-dione (10cc):
CHCH ), 2.67 Prepared according to GP3, starting from diketopiperazine 6cc
), 3.68–3.78 (m, 1 H, NCH ), (109 mg, 0.323 mmol, 1.00 equiv.). Column chromatography (cHex/
1
H NMR (600 MHz, CDCl
.58 (m, 5 H, CH ), 2.34–2.00 (m, 5 H, 4 CH
td, J = 12.9, J = 3.5 Hz, 1 H, CH
.02–4.10 (m, 2 H, 2 NCH), 4.10–4.16 (m, 1 H, NCH), 4.43 (d, J
13.7 Hz, 1 H, NCH ): δ =
) ppm. 13C NMR (150 MHz, CDCl
0.7 (–, CH ), 21.0 (–, CH ), 22.7 (–, CH ), 23.2 (–, CH ), 23.4 0.53, m.p. 174–179 °C. [α]
–, CH ), 25.9 (–, CH ), 28.5 (–, CH ), 30.3 (–, CH ), 35.4 (+, (400 MHz, CDCl ): δ = 1.19 [s, 18 H, 2 C(CH
CHCH ), 42.3 (–, NCH ), 56.6 (+, CH), 57.5 (+, CH), 60.6 14.4, J = 6.1 Hz, 2 H, 2 CHHCSMe), 3.31 (dd, J = 14.4, J =
, C=O), 169.3 (C
923 (w), 2854 (w), 1652 (m), 1448 (w), 1409 (m), 1370 (w), 1334 2 NCHH), 3.89 (dd, J = 11.7, J = 6.6 Hz, 2 H, 2 NCHH), 4.33
3
): δ = 1.03–1.36 (m, 6 H, CH
2
1
2
2
,1 CH
2
2
3
4
(
2
2
2
4
EtOAc, 5:1 Ǟ 3:1) afforded the title compound (40.4 mg,
0.101 mmol, 31 %) as a colorless solid. R (cHex/EtOAc, 5:1) =
=
2
3
f
2
0
1
2
2
2
2
2
D
= –195.8 (c = 1.34, CHCl
3
). H NMR
2
(
2
2
2
2
3
3 3
) ], 2.18 (dd, J =
3
2
3
CH
2
2
2
2
3
(
+, CH), 165.6 (C
q
q
, C=O) ppm. IR (ATR): ν˜ = 7.3 Hz, 2 H, 2 CHHCSMe), 3.52 (dd, J = 11.7, J = 6.7 Hz, 2 H,
2
3
2
Eur. J. Org. Chem. 2015, 6858–6871
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6867

S. Zhong, A. E. E. Wandler, U. Schepers, M. Nieger, S. Bräse
FULL PAPER
(
quint., J = 6.6 Hz, 2 H, 2 CHOtBu) ppm. 13C NMR (100 MHz,
3
3.05–3.12 (m, 1 H, CH
), 3.85 (d, J = 16.4 Hz, 1 H, CH
2
CHCH
2
), 3.37 (d, J = 16.4 Hz, 1 H, CH
2
2
),
2
CDCl
8.6 (+, 2 CHOtBu), 74.3, 74.7 [2 C
, 2 C=O) ppm. IR (ATR): ν˜ = 3370 (vw), 2923 (w), 2852 (w), 7.27–7.35 (m, 4 H, CHAr) ppm. 13C NMR (100 MHz, CDCl
692 (m), 1463 (w), 1435 (w), 1388 (w), 1364 (w), 1302 (vw), 1257 20.7 (–, CH ), 22.8 (–, CH ), 25.1 (–, CH ), 27.8 (–, CH ), 33.5
(–, CH ), 34.9 (–, CH ), 35.3 (+, CH CHCH ), 43.2 (–, CH ), 58.2
61 (vw), 937 (vw), 890 (w), 850 (vw), 685 (vw), 638 (w), 547 (vw), (+, NCH), 73.1, 75.3 (2 C , CSSC), 126.3 (+, CHAr), 127.8 (+,
CHAr), 128.1 (+, CHAr), 128.2 (+, CHAr), 131.9 (C , CAr), 132.0
(C , CAr), 162.4 (C , C=O), 165.1 (C , C=O) ppm. IR (ATR): ν˜ =
3
): δ = 28.1 [+, 2 C(CH
3
)
3
], 39.7 (–, 2 CH
2
), 51.4 (–, 2 CH
2
2
), 4.18–4.26 (m, 1 H, NCH), 4.45
2
2
6
q
, CSSC, 2 C(CH
3
)
3
], 163.5
(d, J = 15.6 Hz, 1 H, CH
2
), 4.92 (d, J = 15.6 Hz, 1 H, CH
2
),
(C
q
3
): δ =
1
2
2
2
2
(w), 1213 (w), 1192 (w), 1158 (w), 1105 (w), 1090 (w), 1044 (w),
2
2
2
2
2
9
5
q
–1
04 (vw), 486 (w), 428 (vw), 402 (vw) cm . MS (EI, 70 eV): m/z
q
+
+
(
%) = 400 (4) [M] , 385 (8), 336 (100) [M – S
06 (40), 57 (49). HRMS (EI): calcd. for C18
found 400.1493.
2
] , 280 (88), 224 (85),
q
q
q
2
H
28
S
2
N
2
O
4
400.1491; 2928 (m), 2860 (w), 1670 (s), 1461 (w), 1367 (m), 1298 (m), 1242
(m), 1199 (m), 1181 (m), 1093 (m), 1027 (w), 966 (w), 881 (w), 838
(
5
w), 816 (w), 747 (m), 723 (w), 697 (w), 665 (w), 631 (w), 613 (w),
6
6
a,12a-Bis(methylthio)octahydrodipyrido[1,2-a:1Ј,2Ј-d]pyrazine-
,12(2H,6aH)-dione (9hh): Prepared according to GP2, starting
–1
82 (w), 543 (m), 520 (w), 508 (w), 497 (w), 456 (w), 413 (w) cm .
+
2
MS (EI, 70 eV): m/z (%) = 308 (77) [M – S ] , 279 (22), 149 (57),
8
3
from diketopiperazine 6hh (43.3 mg, 0.195 mmol, 1.00 equiv.). Col-
umn chromatography (cHex/EtOAc, 3:1 Ǟ EtOAc) afforded the
title compound (22.1 mg, 63.9 μmol, 33%, scalemic mixture) as a
+
20 2 2 2
5 (59), 43 (100). HRMS (EI): calcd. for C19H N O [M – S ]
08.1525; found 308.1523.
1
4a,12a-Bis(methylthio)-1,5,10,12a-tetrahydroazeto[1Ј,2Ј:4,5]pyr-
azino[1,2-b]isoquinoline-4,12(2H,4aH)-dione (9db): Prepared ac-
cording to GP2, starting from diketopiperazine 6db (20.3 mg,
83.8 μmol, 1.00 equiv.). Column chromatography (cHex/EtOAc,
3:1) afforded the title compound (12.3 mg, 36.8 μmol, 44%, sca-
colorless solid. R
CDCl ): δ = 1.34–1.49 (m, 2 H, CH
), 1.91 (tt, 3J = 13.4, J = 3.5 Hz, 2 H,
.72–1.84 (m, 4 H, CH
CH SC CH ), 2.18 (s, 6 H, 2 SCH
J = 3.1 Hz, 2 H, CH SC CH ), 3.16 (td, J = 15.6, J = 3.1 Hz, 2
H, NCH ), 4.48–4.55 (m, 2 H, NCH
) ppm. 13C NMR (100 MHz,
CDCl ): δ = 14.2 (+, 2 SCH ), 19.7 (–, 2 CH ), 24.2 (–, 2 CH ),
2.6 (–, 2 CH ), 38.4 (–, 2 CH ), 66.2 (C , 2 CSCH ), 165.5 (C , 2
C=O) ppm. IR (ATR): ν˜ = 2937 (m), 2857 (w), 1645 (s), 1434 (m),
386 (s), 1278 (s), 1264 (m), 1246 (m), 1189 (m), 1154 (m), 1138
f
(cHex/EtOAc, 3:1) = 0.37. H NMR (400 MHz,
3
2 2
), 1.59–1.69 (m, 2 H, CH ),
4
1
2
2
3
3
q
2
3
), 2.49 (ddd, J = 14.6, J = 4.9,
4
3
4
3
q
2
lemic mixture) as a yellow solid. R (cHex/EtOAc, 3:1) = 0.15, m.p.
1
f
2
2
2
0
1
36–140 °C. [α]
D
= –2.7 (c = 0.38, CHCl
), 2.37 (s, 3 H, SCH
J = 11.9, J = 7.8, J = 4.0 Hz, 1 H, CH ), 3.09–3.16 (m, 1 H,
3
). H NMR (400 MHz,
3
3
2
2
CDCl ): δ = 2.02 (s, 3 H, SCH
3
3
3
), 2.72 (ddd,
3
2
2
q
3
q
2
3
3
2
2
2
CH
H, CH
s, 2 H, CH
(100 MHz, CDCl ): δ = 13.7 (+, SCH ), 13.9 (+, SCH ), 32.0 (–,
2
), 3.28 (d, J = 16.2 Hz, 1 H, CH
), 4.10–4.15 (m, 1 H, CH ), 4.21–4.28 (m, 1 H, CH
), 7.23–7.32 (m, 4 H, CHAr) ppm. C NMR
2
), 3.49 (d, J = 16.2 Hz, 1
1
), 4.68
(m), 1107 (m), 1070 (m), 991 (w), 962 (m), 928 (m), 860 (w), 833
2
2
2
1
3
(
2
(
m), 780 (w), 752 (w), 721 (w), 669 (m), 526 (w), 488 (w), 406
–1
+
(m) cm . MS (EI, 70 eV): m/z (%) = 314 (1) [M] , 267 (100) [M –
3
3
3
+
CH ), 35.9 (–, CH ), 45.4 (–, CH ), 47.3 (–, CH ), 65.5 (C ,
CSCH
SCH
3
3
] , 220 (85), 192 (33). HRMS (EI): calcd. for C14
H
22
N
2
O
2
S
2
2
2
2
2
q
), 72.3 (C
q
, CSCH
3
), 126.1 (+, CHAr), 127.4 (+, CHAr),
, CAr), 131.8 (C , CAr),
, C=O) ppm. IR (ATR): ν˜ = 2919 (w),
14.1117; found 314.1116.
3
1
1
2
1
(
(
(
(
27.6 (+, CHAr), 128.2 (+, CHAr), 131.7 (C
q
q
(
4aS,6aR,14aR,15aS)-6a,14a-Bis(methylthio)-1,2,3,4,4a,7,12,14a,
67.0 (C
q
, C=O), 167.7 (C
q
1
6
5,15a-decahydro-14H-indolo[1Ј,2Ј:4,5]pyrazino[1,2-b]isoquinoline-
,14(6aH)-dione (9de): Prepared according to GP2, starting from
853 (vw), 1671 (w), 1650 (m), 1499 (vw), 1455 (vw), 1379 (m),
282 (w), 1219 (w), 1184 (w), 1152 (w), 1112 (w), 1094 (w), 1019
w), 991 (w), 951 (w), 917 (vw), 825 (vw), 800 (vw), 768 (w), 747
diketopiperazine 6de (35.8 mg, 0.115 mmol, 1.00 equiv.). Column
chromatography (cHex/EtOAc, 10:1) afforded the title compound
w), 725 (w), 685 (w), 644 (vw), 603 (w), 562 (w), 507 (w), 407
(13.0 mg, 32.3 μmol, 28%) as a yellow oil. R
f
(cHex/EtOAc, 10:1)
–1
+
w) cm . MS (EI, 70 eV): m/z (%) = 334 (3) [M] , 300 (8), 287
0.23. [α]2
): δ = 0.88–0.96 (m, 1 H, CH
.46–1.54 (m, 1 H, CH ), 1.57–1.63 (m, 1 H, CH
H, CH ), 2.04 (s, 3 H, SCH ), 2.16 (s, 3 H, SCH
H, CH ), 2.28–2.36 (m, 1 H, CH ), 2.49–2.58 (m, 1 H, CH
.91–2.98 (m, 1 H, CH CHCH ), 3.01 (d, J = 16.7 Hz, 1 H, CH
.58 (d, J = 16.7 Hz, 1 H, CH
0
= –26.5 (c = 0.42, CHCl
), 1.11–1.28 (m, 2 H, CH
), 1.69–1.76 (m,
), 2.19–2.24 (m,
). H NMR (400 MHz,
1
=
CDCl
D
3
+
100) [M – SCH
3
] , 279 (39), 259 (31), 239 (30), 167 (33), 149 (84),
30 (32). HRMS (EI): calcd. for C16 334.0810; found
34.0808.
3
2
2
),
1
3
18 2 2 2
H S N O
1
2
1
2
3
2
2
2
3
3
1
,2,5,10-Tetrahydro-4H,12H-4a,12a-epidithioazeto[1Ј,2Ј:4,5]pyr-
2
2
2
),
),
2
azino[1,2-b]isoquinoline-4,12-dione and 1,2,5,10-Tetrahydro-
4H,12H-4a,12a-epitrithioazeto[1Ј,2Ј:4,5]pyrazino[1,2-b]isoquinoline-
4,12-dione (10db): Prepared according to GP3, starting from di-
ketopiperazine 6db (28.6 mg, 0.118 mmol, 1.00 equiv.). Column
chromatography (cHex/EtOAc, 2:1) afforded the title compound as
an inseparable mixture (10.5 mg, 34.5 μmol, 29%, scalemic mix-
ture) as a colorless solid. R (cHex/EtOAc, 2:1) = 0.36, m.p. 193–
f
1
(
1
2
2
2
2
2
), 4.11–4.17 (m, 1 H, NCH), 4.50
2
2
(d, J = 17.7 Hz, 1 H, CH
2
), 4.97 (d, J = 17.7 Hz, 1 H, CH
2
),
.12–7.25 (m, 4 H, CHAr) ppm. 1 C NMR (100 MHz, CDCl
3
7
1
3
): δ =
4.4 (+, SCH
), 27.0 (–, CH
), 44.5 (–, CH
3
), 15.3 (+, SCH
), 31.8 (+, CH
), 58.2 (+, NCH), 64.8 (C
), 125.7 (+, CHAr), 127.0 (+, CHAr), 127.3 (+, CHAr),
, CAr), 131.3 (C , CAr), 165.4 (C , C=O),
3
), 21.2 (–, CH
2
), 22.9 (–, CH
), 35.9 (–, CH
, CSCH
2
), 25.3
(
(
(
–, CH
–, CH
, CSCH
2
2
2
CHCH
2
2
), 37.5
2
2
q
3
), 69.6
2
0
1
95 °C (decomp.). [α]
D 3
= –236.2 (c = 0.28, CHCl ). H NMR
C
q
3
2
3
3
400 MHz, CDCl ): δ = 2.53 (ddd, J = 13.4, J = 8.5, J = 5.2 Hz,
3
1
1
28.5 (+, CHAr), 130.4 (C
q
q
q
2
H, CH
2 2
), 3.27 (d, J = 16.7 Hz, 1 H, CH ), 3.27–3.34 (m, 1 H,
), 3.61 (d, J = 16.7 Hz, 1 H, CH ), 4.03 (td, J = 9.3, J =
65.8 (C
q
, C=O) ppm.
2
2
3
CH
2
2
2
3
(
6
4aS,6aR,14aR,15aS)-2,3,4,4a,7,12,15,15a-Octahydro-1H,6H,14H- 5.2 Hz, 1 H, CH
a,14a-epidithioindolo[1Ј,2Ј:4,5]pyrazino[1,2-b]isoquinoline-6,14-di-
(d, 2J = 16.2 Hz, 1 H, CH
7.21–7.31 (m, 4 H, CHAr) ppm. 13C NMR (100 MHz, CDCl
29.9 (–, CH ), 35.3 (–, CH ), 45.3 (–, CH ), 46.1 (–, CH ), 71.7 (C
CS), 80.0 (C , CS), 126.1 (+, CHAr), 127.8 (+, CHAr), 128.1 (+,
CHAr), 128.4 (+, CHAr), 130.8 (C , CAr), 130.9 (C , CAr), 167.6
(C , C=O), 167.7 (C , C=O) ppm. IR (ATR): ν˜ = 2919 (vw), 1685
), (vw), 1451 (vw), 1411 (vw), 1356 (vw), 1274 (vw), 1230 (vw), 1194
(vw), 1160 (vw), 1101 (vw), 1005 (vw), 969 (vw), 761 (vw), 722
2
), 4.14 (td, J = 8.8, J = 7.1 Hz, 1 H, CH
2
), 4.64
), 5.26 (d, J = 16.2 Hz, 1 H, CH ),
): δ =
2
2
2
one (10de): Prepared according to GP2, starting from diketopiper-
azine 6de (44.4 mg, 0.143 mmol, 1.00 equiv.). Column chromatog-
raphy (cHex/EtOAc, 5:1) afforded the title compound (9.0 mg,
3
2
2
2
2
q
,
q
24 μmol, 17%) as a yellow solid. R
f
(cHex/EtOAc, 5:1) = 0.20, m.p.
q
q
71–172 °C. [α]2
): δ = 1.18–1.43 (m, 3 H, CH
.63–1.69 (m, 1 H, CH ), 1.72–1.80 (m, 1 H, CH
0
= –88.1 (c = 0.19, CHCl
), 1.54–1.62 (m, 1 H, CH
). H NMR (400 MHz,
1
1
D
3
q
q
CDCl
1
1
3
2
2
2
2
), 1.81–1.89 (m,
–
1
H, CH
2
), 2.12–2.23 (m, 2 H, CH
2
), 2.86–2.94 (m, 1 H, CH
2
), (vw), 674 (vw), 624 (vw), 542 (vw), 500 (vw) cm . MS (EI, 70 eV):
6868
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6858–6871

Synthesis of Diketopiperazines and Thiodiketopiperazines
+
+
m/z (%) = 336 (0.6) [M] (trithio), 304 (0.4) [M] (dithio), 272 (1)
(–, CH
NCH ), 43.2 (–, NCH
CHAr), 127.9 (+, CHAr), 128.2 (+, CHAr), 128.3 (+, CHAr), 130.7
(C , CAr), 131.0 (C , CAr), 162.9 (C , C=O), 165.1 (C , C=O) ppm.
IR (ATR): ν˜ = 2925 (vw), 2849 (vw), 1673 (w), 1494 (vw), 1444
2
), 22.3 (–, CH
2
), 29.1 (–, CH
2
), 33.4 (–, CH
2
), 40.8 (–,
+
+
+
[
[
M – S
M – S
2
] (trithio), [M – S] (dithio), 240 (100) [M – S
] (dithio). HRMS [EI]: calcd. for , C14H S N O (dithio)
04.0340; found 304.0338.
3
] (trithio),
2
2
), 69.8 (C
q
, C
q
S
2
), 71.9 (C . C
q
q 2
S ), 126.3 (+,
+
2
12 2 2 2
3
q
q
q
q
(
[
4aR,5aS,9aS,11aR)-4a,11a-Bis(methylthio)decahydro-4H-azeto-
1Ј,2Ј:4,5]pyrazino[1,2-a]indole-4,11(2H)-dione (9eb): Prepared ac-
cording to GP2, starting from diketopiperazine 6eb (21.2 mg,
0.5 μmol, 1.00 equiv.). Column chromatography (cHex/EtOAc,
(
(
vw), 1354 (vw), 1255 (vw), 1238 (vw), 1168 (vw), 1146 (vw), 1115
vw), 1050 (vw), 962 (vw), 896 (vw), 853 (vw), 749 (vw), 712 (vw),
6
60 (vw), 645 (vw), 619 (vw), 548 (vw), 525 (vw), 490 (vw), 435
9
1
–1
+
(
vw) cm . MS (EI, 70 eV): m/z (%) = 332 (1) [M] , 270 (100) [M –
:1) afforded the title compound (4.9 mg, 15 μmol, 17%) as a yel-
+
S
2
] . HRMS (EI): calcd. for C16
16 2 2 2
H N O S 332.0648; found
1
low oil. R
δ = 0.88–0.99 (m, 1 H, CH
m, 1 H, CH ), 1.52–1.86 (m, 4 H, CH
H, CH ), 2.12 (s, 3 H, SCH
f
(cHex/EtOAc, 1:1) = 0.28. H NMR (400 MHz, CDCl
3
):
332.0649.
2
), 1.11–1.22 (m, 1 H, CH
2
), 1.24–1.34
2
(
2
2
), 2.04 (dd, J = 13.1 Hz, 1 (4aS,6aR,12aR,13aS)-6a,12a-Bis(methylthio)dodecahydro-12H-
), 2.35 (s, 3 H, SCH ), 2.48–2.57 (m, pyrido[1Ј,2Ј:4,5]pyrazino[1,2-a]indole-6,12(6aH)-dione (9he): Pre-
2
3
3
2
3
3
2
3
H), 2.68 (ddd, J = 12.1, J = 7.8, J = 4.2 Hz, 1 H, CH
.03 (m, 2 H), 4.00–4.07 (m, 2 H), 4.11–4.17 (m, 1 H) ppm.
): δ = 13.5 (+, SCH ), 14.7 (+, SCH
), 23.3 (–, CH ), 25.3 (–, CH ), 27.1 (–, CH ), 31.9 75.1 μmol, 29%) as an off-white solid. R
), 32.2 (+, CH CHCH ), 35.5 (–, CH ), 46.4 (–, CH
+, NCH), 71.4 (C , CSCH , CSCH ), 167.2 (C , C=O),
69.8 (C
vw), 1383 (vw), 1168 (vw), 1102 (vw), 956 (vw), 841 (vw), 819
2
), 2.85–
pared according to GP2, starting from diketopiperazine 6he
(43.5 mg, 0.166 mmol, 1.00 equiv.). Column chromatography
1
3
C
NMR (100 MHz, CDCl
1.1 (–, CH
–, CH
3
3
3
), (cHex/EtOAc, 10:1Ǟ5:1) afforded the title compound (17.0 mg,
(cHex/EtOAc, 5:1) = 0.27.
2
2
2
2
2
f
1
2
3
(
(
2
2
2
2
2
), 58.1
H NMR (400 MHz, CDCl
3
): δ = 0.96 (ddd, J = 14.0, J = 10.5,
), 1.14–1.31 (m, 3 H, CH ), 1.49–1.58 (m, 2
), 1.62 (dd, J = 13.1, J = 3.3 Hz, 1 H, CH ), 1.70–1.83
), 1.91 (tt, J = 13.4, J = 3.3 Hz, 1 H, CH ), 2.16 (s,
), 2.18–2.26 (m, 4 H, SCH , CH CHCH ), 2.32 (t, J =
13.1 Hz, 1 H, CH ), 2.45–2.59 (m, 2 H, CH ), 2.97 (ddd, J = 18.6,
4
q
3
), 74.2 (C
q
3
q
J = 3.7 Hz, 1 H, CH
2
2
2
3
1
q
, C=O) ppm. IR (ATR): ν˜ = 2921 (vw), 2854 (vw), 1664
H, CH
(m, 4 H, CH
3 H, SCH
2
2
2
3
(
(
2
2
–
1
3
vw), 793 (vw), 727 (vw), 621 (vw), 464 (vw) cm . MS (EI, 70 eV):
3
3
2
2
+
+
2
m/z (%) = 326 (0.3) [M] , 279 (3) [M – SCH
3
] , 232 (0.6) [M –
] , 86 (61), 84 (100). HRMS (EI): calcd. for C15
26.1123; found 326.1121.
2
2
2
+
3
4
3
2
3
SCH
3
H
22
S
2
N
2
O
2
J = 10.4, J = 5.4 Hz, 1 H, CH
2
), 3.08 (td, J = 13.4, J = 3.1 Hz,
), 4.45–5.56 (m, 1 H,
): δ = 13.9 (+, CH ), 15.4
),23.0(–,CH ),24.3(–,CH
), 31.6 (+, CH CHCH ), 32.5 (–, CH
), 38.4 (–, NCH ), 58.1 (+, CH), 65.4 (C , C SCH
SCH ), 164.4 (C , C=O), 164.8 (C , C=O) ppm. IR (ATR):
1 H, NCH ), 4.10–4.20 (m, 1 H, NCH
2
2
1
3
NCH) ppm. C NMR (100 MHz, CDCl
3
3
6
a,14a-Bis(methylthio)-1,3,4,7,12,14a-hexahydropyrido[1Ј,2Ј:4,5]-
pyrazino[1,2-b]isoquinoline-6,14(2H,6aH)-dione (9hd): Prepared ac-
cording to GP2, starting from diketopiperazine 6hd (52.8 mg,
.195 mmol, 1.00 equiv.). Column chromatography (cHex/EtOAc,
0:1) afforded the title compound (27.1 mg, 75.1 μmol, 39 %,
(
(
(
(
+,CH
–, CH
–, CH
, C
3
),19.5(–,CH
2
),21.2(–,CH
2
2
2
),25.3
2
), 36.1
3
), 68.4
2
), 26.9 (–, CH
2
2
2
2
2
q
q
0
1
C
q
q
3
q
q
ν˜ = 2920 (m), 2854 (w), 1726 (w), 1650 (s), 1386 (s), 1287 (m), 1263
m), 1199 (m), 1158 (m), 1135 (m), 1103 (w), 1070 (w), 1024 (w),
39 (w), 891 (w), 834 (w), 813 (w), 780 (w), 747 (w), 702 (w), 670
scalemic mixture) as a colorless solid. R
f
(cHex/EtOAc, 5:1) = 0.24.
): δ = 1.46 (m, 2 H, CH ), 1.68 (ddd,
J = 14.6, J = 13.4, J = 3.7 Hz, 1 H, CH ), 1.82 (dd, J = 18.6,
J = 16.4 Hz, 2 H, CH ), 1.90–2.01 (m, 1 H, NCH ), 2.13 (s, 3 H,
), 2.24 (s, 3 H, CH ), 2.50–2.59 (m, 1 H, NCH ), 3.18–3.29 (m,
), 4.52–4.62 (m, 1 H,
), 7.16–7.31 (m, 4 H,
(
1
H NMR (400 MHz, CDCl
3
2
9
2
3
3
3
2
2
–1
(
m), 605 (w), 585 (w), 517 (w), 451 (w), 435 (w) cm . MS (EI,
2
2
+
+
7
0 eV): m/z (%) = 354 (2) [M] , 307 (100) [M – SCH
3
] , 260 (87)
CH
H, CH
NCH ), 5.16 (d, J = 17.8 Hz, 1 H, NCH
CHAr) ppm. 13C NMR (100 MHz, CDCl
+, CH ), 19.5 (–, CH ), 24.2 (–, CH
8.6 (–, NCH ), 43.9 (–, NCH ), 68.0 (C
SCH ), 125.8 (+, CHAr), 126.9 (+, CHAr), 127.3 (+, CHAr), 128.6
+, CHAr), 130.0 (C , CAr), 131.0 (C , CAr), 165.2 (C
, C=O) ppm. IR (ATR): ν˜ = 2918 (w), 1652 (m), 1499 (vw),
383 (m), 1281 (w), 1243 (w), 1179 (w), 1141 (w), 1113 (w), 1071 (400 MHz, CDCl
w), 980 (w), 858 (w), 749 (m), 731 (w), 707 (w), 680 (w), 603 (vw), 1.69–1.96 (m, 6 H, CH
3
3
2
+
[
M – (SCH
3
)
2
] , 232 (22), 179 (17). HRMS (EI): calcd. for
2
2
2 2
), 3.63 (d, J = 16.9 Hz, 1 H, CH
C
17 26 2 2 2
H N O S 354.1430; found 354.1432.
2
2
2
3
): δ = 14.2 (+, CH
), 32.5 (–, CH
3
), 14.8 (4aS,6aR,12aR,13aS)-Decahydro-1H,6H,12H-6a,12a-epidithio-
), pyrido[1Ј,2Ј:4,5]pyrazino[1,2-a]indole-6,12-dione (10he): Prepared
(
3
3
2
2
2
), 37.5 (–, CH
), 64.3 (C
2
2
2
q
, C SCH
q
3
q
,
according to GP3, starting from diketopiperazine 6he (43.2 mg,
0.165 mmol, 1.00 equiv.). Column chromatography (cHex/EtOAc,
C
q
3
(
(
q
q
q
, C=O), 165.7 10:1Ǟ5:1) afforded the title compound (10.7 mg, 33.0 μmol, 20%)
1
C
q
as an off-white solid. R
f
(cHex/EtOAc, 5:1) = 0.25. H NMR
2
3
1
3
): δ = 1.26 (dd, J = 8.4, J = 5.8 Hz, 4 H, CH ),
2
2
(
5
=
2
), 2.11–2.25 (m, 3 H, CH
2
), 2.44 (ddd, J
–
1
3
3
2
3
55 (w), 530 (vw), 508 (w), 430 (vw) cm . MS (EI, 70 eV): m/z (%)
362 (1) [M] , 315 (68) [M – SCH
40 (95), 130 (42), 103 (20). HRMS (EI): calcd. for C18
62.1117; found 362.1119.
= 15.9, J = 13.2, J = 4.1 Hz, 1 H, CH ), 2.87 (ddd, J = 13.1, J
2
+
+
+
3
2
3
3
] , 268 (100) [M – 2SCH
3
] , = 6.4, J = 2.5 Hz, 1 H, CH
3.8 Hz, 1 H, CH ), 3.01–3.09 (m, 1 H, NCH), 4.12 (q, J = 7.1 Hz,
2 H, 1 CH , 1 NCH
2 2
CHCH ), 2.96 (td, J = 13.2, J =
3
2
3
H
22
N
2
O
2
S
2
2
2
3
2
2
), 4.23 (dt, J = 12.8, J = 6.4 Hz, 1 H,
) ppm. C NMR (100 MHz, CDCl ): δ = 19.4 (–, CH ), 20.8
–, CH ), 22.3 (–, CH ), 22.8 (–, CH ), 25.1 (–, CH ), 27.8 (–, CH
8.6 (–, CH ), 34.6 (–, CH ), 35.0 (+, CH CHCH ) 41.0 (–, NCH
8.3 (+, CH), 71.3 (+, C ), 71.4 (+, C ), 160.0 (C
65.0 (C , C=O) ppm. IR (ATR): ν˜ = 2923 (w), 2854 (w), 1684
1
3
NCH
(
2
5
1
2
3
2
1
,2,3,4,7,12-Hexahydro-6H,14H-6a,14a-epidithiopyrido[1Ј,2Ј:4,5]-
pyrazino[1,2-b]isoquinoline-6,14-dione (10hd): Prepared according
to GP3, starting from diketopiperazine 6hd (52.8 mg, 0.195 mmol,
.00 equiv.). Column chromatography (cHex/EtOAc, 5:1) afforded
the title compound (12.5 mg, 37.6 μmol, 22%, scalemic mixture) as
2
2
2
2
2
),
),
2
2
2
2
2
q
S
2
q
S
2
q
, C=O),
1
q
(
m), 1446 (w), 1358 (w), 1263 (w), 1205 (w), 1166 (w), 1147 (w),
1
a colorless solid. R
CDCl ): δ = 1.42–1.58 (m, 2 H, CH
.95 (m, 2 H, CH
f
(cHex/EtOAc, 5:1) = 0.27. H NMR (400 MHz,
), 1.71 (m, 1 H, CH ), 1.82–
), 2.43 (ddd, J = 15.8, J = 13.2, J = 4.1 Hz, 1
1
5
107 (w), 1058 (w), 845 (w), 739 (vw), 687 (vw), 654 (w), 599 (vw),
3
2
2
–1
+
04 (w), 454 (w) cm . MS (EI, 70 eV): m/z (%) = 324 (1) [M] , 260
2
3
3
1
2
+
(
100) [M – S
2
] , 179 (19). HRMS (EI): calcd. for C15
20 2 2 2
H N O S
3
3
2
H, CH
=
(
2
), 2.92 (td, J = 13.2, J = 3.9 Hz, 1 H, NCH
2
), 3.33 (d, J
324.0961; found 324.0962.
2
16.4 Hz, 1 H, NCH
2
), 3.82 (d, J = 16.4 Hz, 1 H, CH ), 4.06
2
2
3
3
2
ddt, J = 15.6, J = 4.9, J = 2.1 Hz, 1 H, CH
2
), 4.47 (d, J =
), 4.85 (d, J = 15.6 Hz, 1 H, NCH ), 7.18– 6ge, 6hd, 6di, 9aa, 9dd, 9fe, and SI-11: Single-crystal X-ray diffrac-
.32 (m, 4 H, CHAr) ppm. 13C NMR (100 MHz, CDCl
): δ = 19.5 tion studies were carried out with a Bruker–Nonius Kappa CCD
Crystal Structure Determinations of 6bb, 6cc, 6dd, 6de, 6eb, 6gf,
2
15.5 Hz, 1 H, NCH
2
2
7
3
Eur. J. Org. Chem. 2015, 6858–6871
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6869

S. Zhong, A. E. E. Wandler, U. Schepers, M. Nieger, S. Bräse
FULL PAPER
diffractometer at 123(2) K using Mo-K
α
radiation (λ = 0.71073 Å; = 0.207/–0.135 e Å–3, Flack’s x = 0.0(8), Parsons’ x = –0.3(3),
6bb, 6cc, 6dd, 6eb, 6gf, 6ge, 9dd, SI-11), a Bruker ApexDuo dif- Hooft’s y = –0.2(3).
α
fractometer at 120(2) K using Mo-K radiation (λ = 0.71073 Å;
6
0
9
5
eb: Colorless crystals, C13
.16ϫ0.12ϫ0.04 mm, monoclinic, space group P2
.128(2), b = 5.978(1), c = 10.924(2) Å, β = 99.15(1)°, V =
H
18
N
2
O
2
, M
r
= 234.29, crystal size
6
de), a Bruker–Nonius ApexII diffractometer at 123(2) K using
1
(No. 4), a =
α
Mo-K radiation (λ = 0.71073 Å; 9aa, 9fe), and a Bruker D8 Ven-
ture diffractometer equipped with a Photon100 detector at
23(2) K using Cu-K radiation (λ = 1.54178 Å; 6hd, 6di). Direct
3
–3
–1
α
88.51(19) Å , Z = 2, ρ = 1.322 Mgm , μ(Mo-K ) = 0.090 mm ,
1
α
F(000) = 252, 2θmax = 52°, 8164 reflections, of which 2313 were
independent (Rint = 0.037), 154 parameters, 1 restraint, R = 0.040
for 1994 IϾ2σ(I)], wR = 0.090 (all data), S = 1.08, largest diff.
peak/hole = 0.160/–0.217 eÅ , Flack’s x = –1.0(14), Parsons’ x =
[24]
Methods (SHELXS-97) were used for structure solution and re-
finement was carried out by using SHELXL97 or SHELXL-2013/
1
[
2
[
24]
2
2014 (full-matrix least-squares on F ). Hydrogen atoms were lo-
–3
calized by difference electron density determination and refined by
using a riding model. For 6hd an extinction correction was applied.
Semi-empirical absorption corrections were applied for 6de, 6eb,
–1.0(7), Hooft’s y = 0.2(9).
6
gf: Colorless crystals, C14
H
14
N
2
O
2
, M
r
= 242.27, crystal size
0.50ϫ0.25ϫ0.15 mm, tetragonal, space group P4 2 2 (No. 92), a
1 1
3
6hd, 6di, and 9dd. SI-11 is a non-merohedral twin with three do-
=
8.445(1), c = 32.226(6) Å, V = 2298.3(6) Å , Z = 8, ρ =
mains.
–
3
–1
1.400 Mgm , μ(Mo-K
55°, 27245 reflections, of which 2570 were independent (Rint
0.033), 163 parameters, R = 0.036 [for 2448 IϾ2σ(I)], wR
α
) = 0.095 mm , F(000) = 1024, 2θmax
=
=
The absolute configurations of 6bb, 6cc, 6dd, 6de, 6eb, 6gf, and
6ge were not been established by anomalous dispersion effects in
1
2
= 0.081
diffraction measurement of the crystals. The enantiomers were as-
signed by reference to an unchanging stereogenic center in the syn-
thetic procedure. The absolute structures could not be determined
–3
(
all data), S = 1.14, largest diff. peak/hole = 0.233/–0.177 eÅ ,
Flack’s x = –0.4(12), Parsons’ x = –0.1(3), Hooft’s y = 0.0(3).
[25]
2 2 r
6ge: Colorless crystals, C18H20N O , M = 296.36, crystal size
0.40 ϫ 0.12 ϫ0.08 mm, orthorhombic, space group P2 2 2 (No.
1 1 1
19), a = 8.3378(6), b = 8.8511(6), c = 19.6570(11) Å, V =
reliably by refinement of Flack’s x parameter, Parsons’ x param-
eter,[
26]
or by using Bayesian statistics on Bijvoet differences
[
27]
(Hooft’s y parameter ).
3
–3
–1
1
450.66(16) Å , Z = 4, ρ = 1.357 Mgm , μ(Mo-K
F(000) = 632, 2θmax = 55°, 16807 reflections, of which 3323 were
independent (Rint = 0.034), 199 parameters, R = 0.037 [for 2960
IϾ2σ(I)], wR = 0.087 (all data), S = 1.07, largest diff. peak/hole
0.226/–0.242 eÅ , Flack’s x = –1.4(11), Parsons’ x = –0.5(4),
Hooft’s y = –0.3(4).
α
) = 0.089 mm ,
The absolute configurations of 6hd, 6di, 9aa, and 9fe were estab-
lished by anomalous dispersion effects in diffraction measurements
of the crystals. In addition, the enantiomers were assigned by refer-
ence to an unchanging chiral center in the synthetic procedure for
1
2
–3
=
6hd, 6di, and 9fe.
6
0
1
7
bb: Colorless crystals, C
.40ϫ0.20 ϫ0.12 mm, orthorhombic, space group P2 2 2
1 1 1
8
H
10
N
2
O
2
, M
r
= 166.18, crystal size
(No.
9), a = 6.5974(2), b = 8.1688(4), c = 14.1310(5) Å, V =
6
0
8
6
hd: Colorless crystals, C16
.36ϫ0.18ϫ0.04 mm, monoclinic, space group P2
.0622(4), b = 10.2212(5), c = 8.2711(4) Å, β = 94.022(1)°, V =
H
18
N
2
O
2
, M
r
= 270.32, crystal size
1
(No. 4), a =
3
–3
–1
61.56(5) Å , Z = 4, ρ = 1.449 Mgm , μ(Mo-K
α
) = 0.106 mm ,
3
–3
–1
α
79.90(6) Å , Z = 2, ρ = 1.320 Mgm , μ(Cu-K ) = 0.707 mm ,
F(000) = 352, 2θmax = 55°, 7622 reflections, of which 1746 were
independent (Rint = 0.024), 109 parameters, R = 0.029 [for 1678
IϾ2σ(I)], wR = 0.076 (all data), S = 1.07, largest diff. peak/hole
0.281/–0.136 e Å , Flack’s x = 0.2(10), Parsons’ x = 0.0(3),
Hooft’s y = 0.7(4).
F(000) = 288, 2θmax = 144.2°, 8180 reflections, of which 2614 were
independent (Rint = 0.019), 182 parameters, 1 restraint, R = 0.026
for 2602 IϾ2σ(I)], wR = 0.071 (all data), S = 1.04, largest diff.
peak/hole = 0.220/–0.130 eÅ , Flack’s x = 0.00(21), Parsons’ x =
.02(6), Hooft’s y = 0.02(4).
1
1
2
[
2
–
3
=
–3
0
6
0
1
1
cc: Colorless crystals, C18
.45ϫ0.25ϫ0.15 mm, monoclinic, space group P2
6.036(2), b = 6.047(1), c = 19.709(2) Å, β = 99.60(1)°, V =
H
30
N
2
O
4
, M
r
= 338.44, crystal size
2 3 r
6di: Colorless crystals, C15H14N O , M = 270.28, crystal size
1
(No. 4), a = 0.10 ϫ 0.06 ϫ0.02 mm, orthorhombic, space group P2 2 2 (No.
1
1 1
19), a = 5.9558(3), b = 9.9182(4), c = 21.0431(9) Å, V =
3
–3
–1
3
–3
–1
884.4(4) Å , Z = 4, ρ = 1.193 Mgm , μ(Mo-K ) = 0.084 mm , 1243.03(10) Å , Z = 4, ρ = 1.444 Mgm , μ(Cu-K ) = 0.842 mm ,
α
α
F(000) = 736, 2θmax = 50°, 25564 reflections, of which 6639 were F(000) = 568, 2θmax = 144.8°, 14649 reflections, of which 2443 were
independent (Rint = 0.045), 433 parameters, 1 restraint, R
for 5547 IϾ2σ(I)], wR = 0.079 (all data), S = 1.09, largest diff.
peak/hole = 0.134/–0.152 eÅ , Flack’s x = 0.4(7), Parsons’ x =
1
= 0.039
independent (Rint = 0.047), 181 parameters, R = 0.040 [for 2349
1
[
2
IϾ2σ(I)], wR = 0.102 (all data), S = 1.09, largest diff. peak/hole
2
–3
–3
= 0.220/–0.197 eÅ , Flack’s x = –0.08(35), Parsons’ x = –0.03(12),
0
.6(4), Hooft’s y = 0.7(5).
Hooft’s y = –0.02(11).
6
0
1
1
1
1
0
0
dd: Colorless crystals, C20
.20ϫ0.12ϫ0.04 mm, hexagonal, space group P6
H
18
N
2
O
2
, M
r
= 318.36, crystal size
(No. 172), a =
9aa: Colorless crystals, C H N O S , M = 262.38, crystal size
0.24ϫ0.12ϫ0.06 mm, monoclinic, space group P2 (No. 4), a =
1
1
0
18
2
2
2
r
4
3
3.148(2), c = 7.823(1) Å, V = 1171.2(3) Å , Z = 3, ρ = 6.1450(1), b = 6.8961(3), c = 15.1630(6) Å, β = 95.074(2)°, V =
–3
–1
3
–3
–1
.354 Mgm , μ(Mo-K
5941 reflections, of which 1780 were independent (Rint = 0.061),
09 parameters, 1 restraint, R = 0.048 [for 1497 IϾ2σ(I)], wR
α
α
) = 0.088 mm , F(000) = 504, 2θmax = 55°, 640.04(4) Å , Z = 2, ρ = 1.361 Mgm , μ(Mo-K ) = 0.404 mm ,
F(000) = 280, 2θmax = 55°, 7703 reflections, of which 2886 were
1
2
=
independent (Rint = 0.023), 151 parameters, 1 restraint, R = 0.024
1
.109 (all data), S = 1.05, largest diff. peak/hole = 0.191/– [for 2819 IϾ2σ(I)], wR = 0.058 (all data), S = 1.08, largest diff.
2
–3
–3
.266 eÅ , Flack’s x = 2(2), Parsons’ x = 1.8(7), Hooft’s y = 0.7(9). peak/hole = 0.222/–0.179 eÅ , Flack’s x = 0.02(5), Parsons’ x =
.03(2), Hooft’s y = 0.03(2).
9dd: Colorless crystals, C22
0.50ϫ0.15ϫ0.10 mm, monoclinic, space group P2
) = 0.086 mm , = 12.8773(13), b = 7.9822(7), c = 19.5887(12) Å, β = 107.621(5)°,
0
6
0
1
1
de: Colorless crystals, C19
.15ϫ0.10 ϫ0.05 mm, orthorhombic, space group P2
9), a = 10.3629(3), b = 10.5958(4), c = 14.2711(5) Å, V =
H
22
N
2
O
2
, M
r
= 310.39, crystal size
1
2
1
2
1
(No.
H
22
N
2
O
2
S
2
, M
r
= 410.54, crystal size
/c (No. 14), a
1
3
–3
–1
567.01(9) Å , Z = 4, ρ = 1.316 Mgm , μ(Mo-K
α
3
–3
F(000) = 664, 2θmax = 55°, 19869 reflections, of which 3598 were V = 1919.0(3) Å , Z = 4, ρ = 1.421 Mg m , μ(Mo-K
independent (Rint = 0.026), 208 parameters, R
IϾ2σ(I)], wR = 0.075 (all data), S = 1.04, largest diff. peak/hole
α
) =
0.299 mm , F(000) = 864, 2θmax = 55°, 34821 reflections, of which
4390 were independent (Rint = 0.027), 255 parameters, R = 0.028
–
1
1
= 0.029 [for 3436
2
1
6870
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6858–6871

Synthesis of Diketopiperazines and Thiodiketopiperazines
[
for 4025 IϾ2σ(I)], wR
2
= 0.076 (all data), S = 1.05, largest diff.
[8] P. W. Trown, Biochem. Biophys. Res. Commun. 1968, 33, 402–
–3
407.
peak/hole = 0.394/–0.215 eÅ .
[
9] a) B. M. Ruff, S. Zhong, M. Nieger, S. Brase, Org. Biomol.
Chem. 2012, 10, 935–940; b) K. C. Nicolaou, S. Totokotso-
poulos, D. Giguere, Y.-P. Sun, D. Sarlah, J. Am. Chem. Soc.
9
0
1
1
fe: Colorless crystals, C16
.28ϫ0.20 ϫ0.04 mm, orthorhombic, space group P2
9), a = 11.0962(9), b = 11.2692(6), c = 13.3747(11) Å, V =
H
24
N
2
O
2
S
2
, M
r
= 340.49, crystal size
1 1 1
2 2
(No.
2
011, 133, 8150–8153; c) G. W. Kirby, D. J. Robins, W. M.
3
–3
–1
Stark, J. Chem. Soc., Chem. Commun. 1983, 812–813; d) H.
Poisel, U. Schmidt, Chem. Ber. 1972, 105, 625–634; e) E.
Oehler, H. Poisel, F. Tataruch, U. Schmidt, Chem. Ber. 1972,
α
672.4(2) Å , Z = 4, ρ = 1.352 Mgm , μ(Mo-K ) = 0.327 mm ,
F(000) = 728, 2θmax = 55°, 14845 reflections, of which 3813 were
independent (Rint = 0.065), 201 parameters, R = 0.042 [for 3473
IϾ2σ(I)], wR = 0.090 (all data), S = 1.09, largest diff. peak/hole
0.294/–0.249 eÅ–3, Flack’s x = 0.04(8), Parsons’ x = 0.01(4),
1
1
05, 635–641.
2
[
10] M. Pichowicz, N. S. Simpkins, A. J. Blake, C. Wilson, Tetrahe-
dron 2008, 64, 3713–3735.
=
Hooft’s y = 0.03(4).
[11] T. Hino, T. Sato, Tetrahedron Lett. 1971, 12, 3127–3129.
[12] K. C. Nicolaou, D. Giguere, S. Totokotsopoulos, Y.-P. Sun, An-
14 2 4 2 r
SI-11: Colorless crystals, C10H N O S , M = 290.35, crystal size
0
8
gew. Chem. Int. Ed. 2012, 51, 728–732.
¯
.40 ϫ 0.25 ϫ 0.15 mm, triclinic, space group P1 (No. 2), a = [13] a) A. Friedrich, M. Jainta, M. Nieger, S. Bräse, Synlett 2007,
.143(1), b = 9.334(1), c = 9.444(1) Å, α = 73.17(1), β = 75.35(1),
2127–2129; b) M. Jainta, M. Nieger, S. Braese, Eur. J. Org.
Chem. 2008, 5418–5424; c) U. Gross, M. Nieger, S. Bräse,
Chem. Eur. J. 2010, 16, 11624–11631.
3
–3
γ = 75.96(1)°, V = 653.51(13) Å , Z = 2, ρ = 1.476 Mgm , μ(Mo-
–1
K
α
) = 0.415 mm , F(000) = 304, 2θmax = 55°, 2938 reflections, of
which 2938 were independent (Rint = 0.000, non-merohedral twin
with three domains), 169 parameters, R = 0.110 [for 2413
IϾ2σ(I)], wR = 0.367 (all data), S = 1.19, largest diff. peak/hole
1.565/–0.885 eÅ .
[
[
14] X. Ma, Y. Zhao, J. Org. Chem. 1989, 54, 4005–4008.
15] K. Blaha, M. Budesinsky, I. Fric, J. Smolikova, J. Vicar, Tetra-
hedron Lett. 1972, 1437–1440.
16] a) J. Vicar, M. Budesinsky, K. Blaha, Collect. Czech. Chem.
Commun. 1973, 38, 1940–1956; b) J. Vicar, J. Smolikova, K.
Blaha, Collect. Czech. Chem. Commun. 1973, 38, 1957–1970.
17] a) H. He, S. G. Rabindran, L. M. Greenberger, G. T. Carter,
Med. Chem. Res. 1999, 9, 424–437; b) R. Petersen, S. T.
Le Quement, T. E. Nielsen, Angew. Chem. Int. Ed. 2014, 53,
11778–11782; c) S. K. Rabindran, H. He, L. M. Greenberger
1
2
[
–3
=
CCDC-1407307 (for 6bb), -1407308 (for 6cc), -1407309 (for 6dd),
-
(
9
1
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[
1407310 (for 6de), -140731 (for 6eb), -1407312 (for 6gf), -1407313
for 6ge), -1407314 (for 6hd), -1407315 (for 6di), -1407316 (for
aa), -1407317 (for 9dd), -1407318 (for 9ef), and -1407319 (for SI-
1) contain the supplementary crystallographic data for this paper.
(
American Cyanamid Company, USA), US patent, 2002, 19 p.
18] a) F. Belaj, Phosphorus Sulfur Silicon Relat. Elem. 2008, 183,
71–672; b) C. Claverie, A. Ghinet, P. Gautret, C.-T. Vuong,
[
6
B. Rigo, Tetrahedron 2013, 69, 6821–6825; c) C. Malavasic, B.
Brulc, P. Cebasek, G. Dahmann, N. Heine, D. Bevk, U. Groselj,
A. Meden, B. Stanovnik, J. Svete, J. Comb. Chem. 2007, 9, 219–
2
29; d) B. Rigo, S. El Ghammarti, P. Gautret, D. Couturier,
Acknowledgments
Synth. Commun. 1994, 24, 2597–2607; e) R. K. Sharma, W. G.
Chan, J. Wang, B. E. Waymack, J. B. Wooten, J. I. Seeman,
M. R. Hajaligol, J. Anal. Appl. Pyrolysis 2004, 72, 153–163.
19] D. Fabbri, A. Adamiano, G. Falini, R. De Marco, I. Mancini,
J. Anal. Appl. Pyrolysis 2012, 95, 145–155.
This work was supported by Deutsche Telekom Stiftung as well by
the “Concept for the Future” of the Karlsruhe Institute of Technol-
ogy within the framework of the German Excellence Initiative. The
authors thank Anne Friedrich, Manuel Jainta, and Bettina Ruff for
directing the experiments and starting materials/building blocks, as
well as Maxim Schlegel, Thomas Kauz, Thomas Hurrle, and Ju-
dith E. Seltenreich for dedicated laboratory assistance.
[
[
20] K. C. Nicolaou, M. Lu, S. Totokotsopoulos, P. Heretsch, D.
Giguere, Y.-P. Sun, D. Sarlah, T. H. Nguyen, I. C. Wolf, D. F.
Smee, C. W. Day, S. Bopp, E. A. Winzeler, J. Am. Chem. Soc.
2012, 134, 17320–17332.
[21] a) J. P. Silva, K. H. Winterhalter, C. Richter, Redox Rep. 1997,
3, 331–341; b) M. C. Golden, S. J. Hahm, R. E. Elessar, S. Sak-
sonov, J. J. Steinberg, Mycoses 1998, 41, 97–104; c) D. Dixit, R.
Ghildiyal, N. P. Anto, E. Sen, Cell Death Dis. 2014, 5, e1212.
[22] L. E. Munoz, C. Maueröder, R. Chaurio, C. Berens, M.
Herrmann, C. Janko, Autoimmunity 2013, 46, 336–341.
[23] C. P. LeBel, H. Ischiropoulos, S. C. Bondy, Chem. Res. Toxicol.
1992, 5, 227–231.
[24] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[25] H. Flack, Acta Crystallogr., Sect. A 1983, 39, 876–881.
[26] S. Parsons, H. Flack, Acta Crystallogr., Sect. A 2004, 60, 61–
61.
[
[
[
[
[
1] D. M. Gardiner, P. Waring, B. J. Howlett, Microbiology (Read-
ing, U.K.) 2005, 151, 1021–1032.
2] P. Waring, J. Beaver, Gen. Pharmacol. - Vascs 1996, 27, 1311–
1316.
3] M.-A. B. M.-A. Baute, G. Deffieux, R. Baute, A. Neveu, J.
Antibiot. 1978, 31, 1099–1101.
4] H. Guo, B. Sun, H. Gao, X. Chen, S. Liu, X. Yao, X. Liu, Y.
Che, J. Nat. Prod. 2009, 72, 2115–2119.
5] Y. Zhang, S. Liu, Y. Che, X. Liu, J. Nat. Prod. 2007, 70, 1522–
1525.
[27] R. W. Hooft, L. H. Straver, A. L. Spek, J. Appl. Crystallogr.
2008, 41, 96–103.
[
6] E. M. Fox, B. J. Howlett, Mycol. Res. 2008, 112, 162–169.
[
7] J. Kim, J. A. Ashenhurst, M. Movassaghi, Science 2009, 324,
Received: July 7, 2015
238–241.
Published Online:
Eur. J. Org. Chem. 2015, 6858–6871
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6871