Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges

Article abstract of DOI:10.1002/open.202000188

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C<

Full text of DOI:10.1002/open.202000188

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Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with
Functional Groups in all three Bridges
Donglin Gao,[a] Christian Penno,[a] and Bernhard Wünsch*[a, b]
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The activity of pharmacologically active compounds can be
increased by presenting a drug in a defined conformation,
which fits exactly into the binding pocket of its target. Herein,
the piperazine scaffold was conformationally restricted by
substituted C2- or C3-bridges across the 2- and 6-position. At
first, a three-step, one-pot procedure was developed to obtain
reproducibly piperazine-2,6-diones with various substituents at
the N-atoms in high yields. Three strategies for bridging of
piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals
8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-
diazabicyclo[3.2.1]octane-2,4-diones were prepared by Die-
ckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)
acetates. 2. Stepwise allylation, hydroboration and oxidation of
piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propio-
naldehydes. Whereas reaction of such an aldehyde with base
provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-meth-
oxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10%
yield, the corresponding sulfinylimines reacted with base to
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give
N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-meth-
ylpropane-2-sulfinamides in >66% yield. 3. Transformation of a
piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-
halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-
2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a
vinyl group at the C2- or a methylene group at the C3-bridge,
respectively. Since bridging via sulfinylimines and the one-pot
bridging with 3-bromo-2-bromomethylprop-1-ene gave promis-
ing yields, these strategies will be exploited for the synthesis of
novel receptor ligands bearing various substituents in a defined
orientation at the carbon bridge
1. Introduction
The piperazine ring is a common structural element in various
pharmacologically active compounds[1] such as the antidepres-
sant trazodone (1)[2] and the histamine H1 receptor antagonist
cetirizine (2).[3,4] (Figure 1)
The piperazine ring can adopt two chair and several twist
conformations. Introduction of a bridge into the piperazine
scaffold would restrict the conformational flexibility. Presenting
a drug in an optimal but fixed conformation would increase its
free binding energy due to entropic reasons.[5] The natural
product atropine (3) represents the most prominent example
for an N-heterocycle bearing an additional two-carbon bridge.
This bridge between 2- and 6-position holds the piperidine ring
in a particular chair conformation and forces the O-acyl moiety
Figure 1. Pharmacologically active compounds containing a piperazine ring.
to adopt an axial orientation.[6] The granatane derivative
granisetron is an important 5-HT3 receptor antagonist used for
the treatment of strong emesis caused by chemotherapy and
radiotherapy. In the granatane structure, the piperidine ring is
bridged by a three-carbon bridge. As in atropine, this conforma-
tional restriction leads to an axial orientation of the acylamino
moiety.[7,8] (Figure 2)
In general, we are interested in piperidine and piperazine
rings with an additional bridge leading to conformational
restriction of the ring system. We have reported the bicyclic
KOR agonist 5 (Ki =73 nM),[9] in which the 2- and 4-positions of
the piperazine ring are connected by a three-carbon bridge
substituted with an additional amino moiety (pyrrolidine ring).
The same three-carbon bridge connects the 2- and 5-positions
of the piperazine ring in the (1S,2R,5R)-configured KOR agonist
6 (Ki =1.0 nM).[10] Although the bicyclic systems 5 and 6 contain
the same three-carbon bridge, the piperazine rings adopt
different defined conformations due to the different ring
positions, which are connected by the bridge (2,4-bridge in 5,
2,5-bridge in 6). The 6,8-diazabicyclo[3.2.2]nonane 7 with an OH
moiety at the bridge shows very high affinity towards σ1
receptors (Ki =6.5 nM).[11] Embedding the σ1 pharmacophoric
[a] D. Gao, Dr. C. Penno, Prof. B. Wünsch
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen
Wilhelms-Universität Münster
Corrensstraße 48
48149 Münster (Germany)
Tel: +49-251-8333311
Fax: +49-8332144
E-mail: wuensch@uni-muenster.de
[b] Prof. B. Wünsch
Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM)
Westfälische Wilhelms-Universität Münster
48149 Münster (Germany)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202000188
© 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution Non-Com-
mercial NoDerivs License, which permits use and distribution in any med-
ium, provided the original work is properly cited, the use is non-commercial
and no modifications or adaptations are made.
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Figure 2. Potent drugs with a bridged piperidine ring (3,4) and piperazine ring (5–7) stimulating the design of the 2,6-bridged piperazines 8.
structural elements (basic amino moiety, two lipophilic residues)
into a bicyclic framework resulted in particular high σ1 affinity.
Compared to 6, the σ1 ligand 7 contains an enantiomeric
scaffold, two benzyl moieties at the N-atoms and a hydroxy
moiety instead of the pyrrolidine ring. (Figure 2)
feature of type 8 compounds is the additional functional group
at the two- or three-carbon bridge allowing introduction of
various pharmacophoric elements in a defined 3D orientation.
In order to follow the concept of conformational restriction 2. Results and Discussion
we became interested in piperazine derivatives bearing a two-
or three-carbon bridge across the 2- and 6-positions (see
compound 8 in Figure 2). On the one hand, 2,6-bridged
piperazines 8 are regarded as aza-analogs of the tropane and
granatane scaffolds of 3 and 4, on the other hand, they are
regarded as regioisomers of 5–7 bearing a 2,6-bridge instead of
a 2,4- or 2,5-bridge across the piperazine ring.
2.1. Synthesis
In order to establish the bridge providing the desired bicyclic
compounds of type 8 key intermediate piperazine-2,6-diones
(e.g. 12, 17) should react with various dielectrophiles stepwise
or in a one-pot procedure. Piperazine-2,6-diones can be
prepared either by alkylation of α-amino acid esters with
bromoacetamide and subsequent cyclization[19,20] or by con-
densation of iminodiacetic acid derivatives with primary amines
or NH3.[21–24] As reported in literature, iminodiacetic acids 13 and
14 (structures see Scheme 2) were reacted with primary amines
under microwave irradiation. However, instead of the desired
imides only salts could be isolated.
Therefore, different strategies were pursued to synthesize
key piperazine-2,6-diones with two orthogonal protective
groups at the N-atoms. At first, piperazinediones 12a (R=Cbz)
and 12b (R=Bz) were prepared in three steps from diethyl
iminodiacetate 9. Acylation of the secondary amine 9 with
benzyl chloroformate or benzoyl chloride afforded protected
diesters 10a and 10b, respectively, which were hydrolyzed by
NaOH to give the diacids 11a and 11b. CDI coupling of the
diacids 11a and 11b with p-methoxybenzylamine led to the
imides 12a and 12b in 68% and 60% yield, respectively. The
imide formation was conducted in three steps. At first,
one equivalent CDI was added, which was supposed to form a
cyclic anhydride. The anhydride was then opened by addition
of p-methoxybenzylamine to afford an amido acid. Finally, the
second acid was activated by another equivalent of CDI to form
Some methods for the synthesis of 3,8-diazabicyclo[3.2.1]
octane (8a, n=0) and 3,9-diazabicyclo[3.3.1]nonane derivatives
(8b, n=1) have been reported in literature. Compounds with
the scaffold 8a were prepared starting from adipic acid. A four-
step reaction sequence provided pyrrolidine-2,5-dicarboxylate,
which was transformed into the bicyclic imide upon reaction
with NH3 and Ac2O. Final reduction of the imide functional
group was performed with LiAlH4.[12,13] Corresponding 3,9-
diazabicyclo[3.3.1]nonane derivatives 8b with an extended C3-
bridge were prepared by imide formation from piperidine-2,6-
dicarboxylate and subsequnt LiAlH4 reduction.[14] Another one-
pot synthesis of the bicyclic system 8a started with hexa-1,5-
diene, which was reacted with trifluoromethanesulfonamide in
the oxidation system t-BuOCl/NaI to introduce two N-atoms
oxidatively at 1,6- and 2,5-position of the diene system in 37%
yield.[15]
However, there are only few reports dealing with the
synthesis of 3,8-diazabicyclo[3.2.1]octane (8a, n=0) or 3,9-
diazabicyclo[3.3.1]nonane derivatives (8b, n=1) with additional
substituents at the two- or three-carbon bridge.[16–18] Herein, we
report various strategies to synthesize bicyclic compounds of
type 8 with different length of the carbon bridge. The particular
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Scheme 1. Preparation of piperazine-2,6-diones 12a–d. Reagents and reaction conditions: (a) Cbz-Cl, NEt3, CH2Cl2, 0 C, 18 h, 70%. (b) BzÀ Cl, NEt3, CH2Cl2, r.t.,
24 h, 90%. (c) NaOH, EtOH, H2O, r.t., 18 h, 90% (11a), 90% (11b). (d) i. CDI (1.0 eq), CH3CN, THF, reflux, 90 min; ii. PMB-NH2, THF, reflux, 90 min; iii. CDI (2.0 eq),
CH3CN, THF, reflux, 60 h, 68% (12a), 60% (12b). (e) H2, Pd/C, THF, r.t., 1 h, 95%. (f) 12d: BnBr, CH3CN, reflux, 18 h, 84%.
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with BnNH2 provided the Boc-protected imide 15. After removal
of the Boc-protective group of 15 with trifluoroacetic acid, the
resulting secondary amine 16 was alkylated with p-meth-
oxybenzyl chloride to afford piperazinedione 17 with two
orthogonal protective groups at the N-atoms. (Scheme 2)
In order to introduce a side chain with two C-atoms and a
functional group for bridging, the piperazinediones 12a–c were
Scheme 2. Preparation of piperazine-2,6-dione 17. Reagents and reaction
conditions: (a) Boc2O, NaHCO3, THF, H2O, r.t., 72 h, 74%. (b) i. CDI (1.0 eq),
CH3CN, THF, reflux, 60 min; ii. BnNH2, THF, reflux, 60 min; iii. CDI (2.0 eq),
CH3CN, THF, reflux, 18 h, 62%. (c) TFA, CH2Cl2, r.t., 24 h, 99%. (d) PMBÀ Cl,
DIPEA, CH3CN, reflux, 18 h, 88%.
deprotonated with LiHMDS or KHMDS and treated with ethyl 2-
bromoacetate. The monoalkylated piperazinediones 18a–c were
obtained in 79–84% yield. Additionally, small amounts of the
dialkylated products 19a and 19b (4–6%) could be isolated
from the reaction mixture. (Scheme 3)
The introduction of both substituents at the same position
of the piperazinediones 12a and 12b was unexpected. There-
fore, the monoalkylated piperazinedione 18b was deprotonated
the imides 12a and 12b. The N-benzyl derivative 12c was
obtained by hydrogenolytic cleavage of the Cbz protective
group of 12a followed by alkylation of secondary amine 12d
with benzyl bromide. (Scheme 1)
In the second approach leading to piperazine-2,6-dione 17
bearing the benzyl and p-methoxybenzyl protective groups at
opposite N-atoms compared to 12c, iminodiacetic acid (13) was
used as starting material. Reaction of the secondary amine 13
with Boc2O afforded 14 in 74% yield. CDI coupling of diacid 14
°
with KHMDS at À 78 C and the resulting enolate was
subsequently treated with ethyl bromoacetate. This reaction led
exclusively to the dialkylated piperazinedione 19b (73%)
bearing both acetate moieties at the same C-atom. (Scheme 3)
This experiment showed unequivocally that the CH-group (3-
CH) of N-acylated piperazinedione 18b reacted preferably with
°
Scheme 3. Synthesis of the 3,8-diazabicyclo[3.2.1]octane framework. Reagents and reaction conditions: (a) LiHMDS or KHMDS, THF, À 78 C, 1 h, then
°
°
°
BrCH2CO2Et, THF, À 78 C–r.t., 18 h, 84% (18a), 79% (18b), 84% (18c). (b) KHMDS, THF, À 78 C, 1 h, then BrCH2CO2Et, THF, À 78 C, 3 h, 73%. (c) LiHMDS, THF,
°
°
°
°
À 78 C, 15 min, then Me3SiCl, THF, À 78 C, 1 h, then r.t., 12%. (d) LiHMDS, THF, À 78 C, 15 min, then Me3SiCl, THF, À 78 C, 1 h, then r.t., 21% (21a), 10% (21b).
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electrophiles compared to the 5-CH2-moiety. Other electrophiles
such as CH3I also reacted at the 3-position of 18b. (See Scheme
SI1 in Supporting information)
For the synthesis of bicyclic systems, a Dieckmann analo-
gous cyclization making use of trapping the intermediate
addition product (anion of an hemiketal) by Me3SiCl proved
itself well.[25–27] Therefore the piperazinediones 18a–c with one
addition of piperazinediones 12a–c at methyl acrylate was
investigated. For this purpose, 12a–c were deprotonated with
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LiHMDS or KHMDS at À 78 C and after 1 h, methyl acrylate was
added. However, instead of the expected addition products 25,
the tetrahydropyridine derivatives 24 were isolated in 40–90%
yields. Several experiments were performed to avoid this
undesired reaction, including variation of the base (LiHMDS,
KHMDS, NaHMDS, LDA, KDA), the electrophile (methyl acrylate,
ethyl acrylate, ethyl 3-bromopropionate, ethyl 3-iodopropio-
nate), the temperature and reaction time. Only, after deproto-
nation of 12b with KDA or KHMDS and then reaction with ethyl
acrylate or ethyl 3-iodopropionate provided a small amount
(15% and 9%) of the propionate 25b. (Scheme 4). It is assumed
that the larger ethyl ester decreased the reactivity of the
intermediate enolate 23 to attack intramolecularely the imide
group.
°
acetate moiety were treated with LiHMDS at À 78 C and after
15 min Me3SiCl was added to the mixture. Unexpectedly, only
the benzylated piperazinedione 18c provided the mixed ethyl
silyl ketal 20c in low yield (12%) and the corresponding mixed
ethyl silyl ketals from the Cbz and Bz protected piperazine-
diones 18a and 18b could not be detected. This failure of the
bridging reaction was attributed to the preferred deprotonation
in 3-position of N-acylated piperazinediones 18a and 18b,
which could not lead to the cyclization products. (Scheme 3)
Therefore, the 3,3-dialkylated piperazinediones 19a and
19b, which could no longer be deprotonated in 3-position were
treated in the same manner with LiHMDS and Me3SiCl.
Although the yields were rather low, both compounds led to
the mixed ethyl silyl ketals 21a and 21b. This observation
supports the hypothesis of first deprotonation in 3-position of
the acylated monoacetates 18a,b as reason for the failure of the
bridging reaction. (Scheme 3)
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Formation of the tetrahydropyridines 24 was explained by
deprotonation of piperazinediones 12a–c and subsequent
addition of the enolates 22 at acrylate resulting in the new
enolates 23. Protonation of these enolates 23 can afford the
desired propionates 25. However, usually a fast attack of the
enolates 23 at one of the imide carbonyl moieties occurred
leading to cleavage of the imide and finally to the tetrahydro-
pyridines 24a–c. (Scheme 4)
In addition to the preferred deprotonation in 3-position, the
low yields of the ethano bridged piperazinediones 20 and 21
could be due to the short acetate (two C-atoms) side chain,
which could not reach the enolate at the opposite side of the
piperazine ring. In order to improve the accessibility of the
enolate, a propionate side chain leading to propano bridged
piperazinediones was envisaged. Therefore, the conjugate
The structure of the unexpected tetrahydropyridines 24a–c
1
was confirmed unequivocally by H and 13C NMR spectroscopy
and mass spectrometry. In the 1H NMR spectrum of 24c a
singlet at 11.90 ppm typical for an enol proton of a vinylogous
acid is observed. Moreover, the imide structure can no longer
be identified due to the high field shift of the signals for the
CH2 group of the p-methoxybenzyl moiety. The doublets of
°
Scheme 4. Reaction of piperazinediones 12a-c with acrylates. Reagents and reaction conditions: (a) LiHMDS or KHMDS, THF, À 78 C, 1–3 h, then methyl
°
°
°
acrylate, À 78 C, 2 h, r.t. 16 h, 90% (24a), 34% (24b), 19% (24c). (b) KDA or KHMDS, THF, À 78 C, 30 min, then ethyl acrylate, À 78 C, 2 h, r.t. 14 h, 15% (25b).
°
°
(c) KHMDS, THF, À 78 C, 90 min, then CH3I, À 78 C, 2 h, r.t. 15 h, 33%.
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doubles for these protons indicate an additional coupling with
the NH-proton of the amide in 24c. Deprotonation of the β-
oxoester 24b and subsequent methylation with CH3I, afforded
the methylated β-oxoester 26b providing an additional proof
for the tetrahydropyridine structure of 24a–c.
bridged piperazinediones 35 (66%) and 36 (69%). The main
isomer of the mixture of diastereomers could be isolated in
22% and 27% yields, respectively. (Scheme 5)
Since the sulfinylimines 33 and 34 provided the bridged
systems 35 and 36 in high yields, the same reaction was tried
with the corresponding aldehyde 31. In fact, deprotonation of
the aldehyde 31 with LiHMDS led to the endo-oriented bicyclic
alcohol 37. However, the yield of 37 did not exceed 10% even
after careful optimization. (Scheme 5)
As the reaction of the enolates of piperazinediones 12c and
17 with allyl bromide gave high yields of substitution products
27 and 28, a dihalide presenting the allyl halide moiety twice
should be reacted with the enolate of 17 to establish the bridge
in only one reaction step. The linear dibromide 38 was
frequently used in the literature to form systems with a vinyl
moiety.[28] The branched dihalides 40 were employed to prepare
compounds with large rings,[29–32] in particular, 1,5-diazacyclooc-
tanes and tricyclic fused tetrazole derivatives. 3,7-Dimethylene-
1,5-diazacyclooctanes were obtained by reaction of two equiva-
lents of p-toluenesulfonamide or methanesulfonamide with
two equivalents of dichloride 40a.[31,32] Tricyclic fused tetrazole
derivatives were achieved in two steps. At first, diazotizative
allylation of 2-aminobenzonitrile derivatives with dibromide
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Since the direct introduction of a propionate side chain was
not successful, the stepwise introduction of a C3-fragment with
an electrophilic functional group at the end was envisaged. For
this purpose, the piperazinediones 12c and 17 were deproto-
nated and reacted with allyl bromide to afford racemic allyl
substituted piperazinediones 27 and 28, respectively. After
hydroboration with 9-BBN and then oxidation with H2O2, the
alcohols 29 and 30 were oxidized with Dess-Martin Periodinane
(DMP) and the resulting aldehydes 31 and 32 were condensed
with (S)-configured Ellman’s sulfinamide (S)-2-methylpropane-2-
sulfinamide in the presence of Ti(OC2H5)4 to give the sulfinyl-
imines 33 and 34 in 82% and 90% yield, respectively. Due to
the high electrophilicity of the sulfinylimines 33 and 34, the
bridge could be established by deprotonation with LiHMDS.
The resulting enolates were able to attack intramolecularly the
electrophilic C-atom of the sulfinylimine group of 33 and 34
leading to the bicyclic sulfinamides 35 and 36. Both trans-
formations led to high yields of mixtures of diastereomeric
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°
°
Scheme 5. Synthesis of 3,9-diazabicyclo[3.2.1]nonanes. Reagents and reaction conditions: (a) LiHMDS, THF, À 78 C, 30 min, then BrCH2CH=CH2, THF, À 78 C,
°
2 h, r.t., 18 h, 61% (27), 67% (28). (b) i. 9-BBN, r.t. 16 h; ii. H2O2, NaOH, THF, À 25 C, 45 min, r.t., 60 min, 94% (29), 55% (30) (c) DMP, CH2Cl2, 3 h, r.t., 87% (31),
°
94% (32). (d) (S)-2-methylpropane-2-sulfinamide, Ti(OC2H5)4, THF, r.t., 3 h, 82% (33), 90% (34). (e) LiHMDS, THF, À 78 C-r.t., 6 h, 66% (35), 69% (36). (f) LiHMDS,
°
THF, À 78 C, 30 min, then r.t. 2.5 h, 10%.
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40b was performed and then a tandem reaction comprised of a
cycloaddition between the nitrile and (TMS)N3 followed by an
intramolecular N-allylation gave the desired products.[29]
Two one-step syntheses of the bicyclic compounds 39 and
41 employed the linear and branched allylic dihalides 38 and
40. The bicyclic system 39 with an additional vinyl group at the
C2-bridge and 41 with a methylene moiety at the C3-bridge
were obtained in 22% (39) and 52% (41) yield, respectively. The
vinyl and methylene moiety at the carbon bridge will allow the
introduction of various substituents and functional groups at
the carbon bridge.
Altogether, bridged piperazines with a mixed ketal (20,21),
an OH moiety (37) and a vinyl group (39) at the carbon bridge
were obtained in low yields, whereas piperazines with a three-
carbon bridge bearing a sulfinamido group (35,36) and a
methylene moiety (41) were obtained in high yields. The 3,9-
diazabicyclo[3.3.1]nonanes 35, 36 and 41 will be exploited for
synthesis of pharmacologically active compounds.
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For this purpose, piperazinedione 17 was deprotonated
with 1.2 equivalents of LiHMDS. Subsequently, trans-1,4-dibro-
mobut-2-ene (38) was added and after 16 h, another 1.2 equiv-
alents of LiHMDS were added. Thus, the 2,6-bridged piperazine-
dione 39 was obtained by subsequent SN2 and SN2’ reactions at
1,4-dibromobut-2-ene 38 in 22% yield. As for the alcohol 37,
only the endo-oriented vinyl derivative 39 was formed. The
reaction of piperazinedione 17 with allylic dihalides 40 was
performed in the same manner. Among the three allylic
dihalides, the highest yield of 52% was obtained by reacting 17
with 3-bromo-2-(bromomethyl)prop-1-ene (40b). This one-step
procedure will allow to prepare large amounts of 41 and exploit
the additional double bond in the bridge to introduce further
substituents as pharmacophoric elements. (Scheme 6)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Experimental Section
3. Conclusions
Chemistry, General Methods
Oxygen and moisture sensitive reactions were carried out under
nitrogen, dried with silica gel with moisture indicator (orange gel,
VWR, Darmstadt, Germany) and in dry glassware (Schlenk flask or
Schlenk tube). Temperature was controlled with dry ice/acetone
Different strategies were investigated to obtain 2,6-bridged
piperazine derivatives 8 with various functional groups in the
third carbon bridge. For this purpose, at first a method was
developed to prepare piperazine-2,6-diones 12 and 17 in high
and reproducible yields. These piperazine-2,6-diones 12 and 17
contain different orthogonal protective groups at the N-atoms.
The first approach made use of a Dieckmann analogous
cyclization of piperazinediones 18 and 19 with an acetate side
chain leading to bicyclic ethyl silyl ketals 20 and 21, although in
low yields.
Cyclization of sulfinylimines 33 and 34 afforded the 3,9-
diazabicyclo[3.3.1]nonanes 35 and 36 bearing a sulfinamido
group in the C3-bridge in 66% (35) and 69% (36) yields. Both
compounds were obtained as mixtures of four diastereomers. It
has to be noted that the sulfinylimino group is an ideal
functional group to initiate this cyclization, since the intra-
molecular aldol reaction of aldehyde 31 led to the bicyclic
alcohol 37 in only 10% yield.
°
°
°
(À 78 C/À 25 C), ice/water (0 C), Cryostat (Julabo TC100E-F, Seel-
bach, Germany), magnetic stirrer MR 3001K (Heidolph, Schwalbach,
Germany) or RCT CL (IKA, Staufen, Germany), together with temper-
ature controller EKT HeiCon (Heidolph) or VT-5 (VWR) and PEG or
silicone bath. All solvents were of analytical or technical grade
quality. Demineralized water was used. CH2Cl2 was distilled from
CaH2; THF was distilled from sodium/benzophenone; MeOH was
distilled from magnesium methanolate. Thin layer chromatography
(tlc): tlc silica gel 60 F254 on aluminum sheets (VWR). Flash
chromatography (fc): Silica gel 60, 40–63 μm (VWR); parentheses
include: diameter of the column (∅), length of the stationary phase
(l), fraction size (v) and eluent. Automated flash chromatography:
Isolera™ Spektra One (Biotage®); parentheses include: cartridge
size, flow rate, eluent, fractions size was always 20 mL. Melting
point: Melting point system MP50 (Mettler Toledo, Gießen,
Germany), open capillary, uncorrected. MS: MicroTOFQII mass
spectrometer (Bruker Daltonics, Bremen, Germany); deviations of
the found exact masses from the calculated exact masses were
°
Scheme 6. Reaction of piperazinedione 17 with dielectrophiles 38 and 40. Reagents and reaction conditions: (a) i. LiHMDS, THF, À 78 C, 90 min; ii. trans-1,4-
°
°
°
dibromobut-2-ene (38), THF, À 78 C; 90 min, then r.t., 16 h; iii. LiHMDS, THF, À 78 C, 2 h, r.t., 18 h, 22%. (b) i. LiHMDS, THF, À 78 C, 30 min; ii. 3-halo-2-
°
°
(halomethyl)prop-1-enes 40a-c, THF, À 78 C; 90 min; iii. LiHMDS, THF, À 78 C, 2 h, r.t., 18 h, 26–52%.
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5 ppm or less; the data were analyzed with DataAnalysis® (Bruker
Daltonics). NMR: NMR spectra were recorded in deuterated solvents
on a AV300 (Bruker), DPX (Bruker), AV400 (Bruker), AS400 mercury
plus NMR spectrometer (Varian), a 600 MHz unity plus NMR
spectrometer (Varian), Agilent DD2 400 MHz and 600 MHz spec-
trometers (Agilent, Santa Clara CA, USA); chemical shifts (δ) are
reported in parts per million (ppm) against the reference substance
tetramethylsilane and calculated using the solvent residual peak of
the undeuterated solvent; coupling constants are given with 0.5 Hz
resolution; assignment of 1H and 13C NMR signals was supported by
2-D NMR techniques where necessary.IR: FT/IR IR Affinity®-1
spectrometer (Shimadzu, Düsseldorf, Germany) using ATR techni-
que. Optical rotation: UniPol L1000 (Schmidt+Haensch); 1.0 dm
chloride (817 mg, 5.81 mmol) was added. The reaction mixture was
stirred at rt for 24 h. The solution was washed with H2O (4×), the
combined organic layers were dried (Na2SO4) and the solvent was
removed in vacuo. The remaining residue was purified by fc (∅=
4.5 cm, h=23 cm, V=20 mL, cyclohexane:ethyl acetate=3:1, Rf
0.18) to obtain a pale yellow oil. Yield 1.39 g (90%). C15H19NO5
1
2
3
4
5
6
7
8
9
1
(293.3). H NMR (400 MHz, CDCl3): δ (ppm)=1.26 (t, J=7.1 Hz, 3H,
OCH2CH3), 1.31 (t, J=7.1 Hz, 3H, OCH2CH3), 4.11 (s, 2H, NCH2CO2),
4.21 (q, J=7.1 Hz, 2H, OCH2CH3), 4.26 (q, J=7.1 Hz, 2H, OCH2CH3),
4.32 (s, 2H, NCH2CO2), 7.37–7.47 (m, 5H, Harom.). FT-IR: v˜ (cmÀ 1)=
2983 (w, v, CÀ H, alkyl), 1739 (s, v, C=O, ester), 1650 (s, v, C=O,
amide), 701 (m, δ, CÀ H, arom.). MS (ESI): 609 [(2×M+Na)+, 100],
587 [(2×M+H)+, 14].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
tube; concentration c in g/100 mL; T=20 C; wavelength 589 nm
T
(D-line of Na light); the unit of the specific rotation ([α]D
grad.mLdmÀ 1 gÀ 1) is omitted for clarity.
2,2’-(N-Benzyloxycarbonylimino)diacetic acid (11a)
The diester 10a (14.68 g, 45.46 mmol) was dissolved in a mixture of
2 M NaOH (200 mL) and EtOH (200 mL). The mixture was stirred for
18 h at rt. Then this mixture was extracted with Et20 (300 mL) once.
Conc. HCl was added to the aqueous layer until pH 1 and the
aqueous layer was extracted with Et20 (8×). The organic layers were
dried (Na2SO4) and the solvent was removed in vacuum. The
obtained oil was dried in high vacuum over night to yield a
HPLC
Equipment 1: Pump: L-7100, degasser: L-7614, autosampler: L-7200,
UV detector: L-7400, interface: D-7000, data transfer: D-line, data
acquisition: HSM-Software (all from Merck Hitachi, Darmstadt,
Germany); Equipment 2: Pump: LPG-3400SD, degasser: DG-1210,
autosampler: ACC-3000T, UV-detector: VWD-3400RS, interface: DIO-
NEX UltiMate 3000, data acquisition: Chromeleon 7 (equipment and
software from Thermo Fisher Scientific, Lauenstadt, Germany);
column: LiChrospher® 60 RP-select B (5 μm), LiChroCART® 250–
4 mm cartridge; flow rate: 1.0 mL/min; injection volume: 5.0 μL;
detection at λ=210 nm; solvents: A: demineralized water with
0.05% (V/V) trifluoroacetic acid, B: CH3CN with 0.05% (V/V) trifluoro-
acetic acid; gradient elution (% A): 0–4 min: 90%; 4–29 min:
gradient from 90% to 0%; 29–31 min: 0%; 31–31.5 min: gradient
from 0% to 90%; 31.5–40 min: 90%. Unless otherwise mentioned,
the purity of all test compounds is greater than 95%.
1
colorless viscous oil. Yield 10.97 g (90%). C12H13NO6 (267.0). H NMR
(300 MHz, DMSO): δ (ppm)=3.99 (s, 2H, NCH2CO2), 4.02 (s, 2H,
NCH2CO2), 5.08 (s, 2H, PhCH2O), 7.27–7.41 (m, 5H, Hphenyl), 12.75 (s,
2H, CO2H). 13C NMR (300 MHz, DMSO): δ (ppm)=49.2 (1C, NCH2CO2),
49.6 (1C, NCH2CO2), 66.6 (1C, OCH2Ph), 127.2 (2C, C-2phenyl, C-6phenyl),
127.8 (1C, C-4phenyl), 128.4 (2C, C-3phenyl, C-5phenyl), 136.7 (1C. C-1phenyl),
155.6 (1C, OCO2N), 170.9 (1C, NCH2CO2), 171.0 (1C, NCH2CO2). FT-IR:
v˜ (cmÀ 1)=3600–2300 (s, v, OÀ H, acid), 3037 (w, v, CÀ H, arom.),
2987 (m, v, CÀ H, alkyl), 1693 (s, v, C=O, acid), 737, 696 (m, δ, CÀ H,
mono-substituted arom.). A signal for the C=O moiety of the
carbamate cannot be detected. MS (APCI): calcd. for C12H13NO6H+
268.0821, found 268.0847. HPLC: purity 99.1%, tR =12.21 min.
Synthetic Procedures
2,2‘-(N-Benzoylimino)diacetic acid (11b)
Diethyl 2,2‘-(N-benzyloxycarbonylimino)diacetate (10a)
The diester 10b (839 mg, 2.86 mmol) was dissolved in a mixture of
2 M NaOH (25 mL) and EtOH (25 mL). The mixture was stirred for
6 h at rt. Then this mixture was acidified with 1 M HCl until pH 1.
The aqueous layer was extracted with Et2O (6×). The combined
organic layers were dried (Na2SO4) and the solvent was removed in
vacuo to obtain a colorless viscous oil. Yield 608 mg (90%).
Under ice-cooling, benzyl chloroformate (10.8 mL, 75.68 mmol) was
added slowly to a solution of diethyl iminodiacetate 9 (13.0 g,
68.80 mmol) and NEt3 (10.6 mL, 75.68 mmol) in CH2Cl2. The mixture
was warmed to rt and stirred for 18 h. Then the solvent was
evaporated in vacuum. The residue was purified by fc (cyclohexane:
ethyl acetate=3:1, ∅=8.0 cm, l=8.0 cm, V=100 mL, Rf 0.17) to
1
C15H19NO5 (237.2). H NMR (400 MHz, CDCl3): δ (ppm)=3.97 (s, 2H,
1
NCH2CO2), 4.13 (s, 2H, NCH2CO2), 7.29–7.33 (m, 2H, 3-Hphenyl, 5-
yield a colorless oil. Yield 15.6 g (70%). C16H21NO6 (323.1). H NMR
H
phenyl), 7.43–7.50 (m, 3H, 2-Hphenyl, 4-Hphenyl, 6-Hphenyl). FT-IR: v˜ (cmÀ 1
)
(300 MHz, CDCl3): δ (ppm)=1.21 (t, J=7.1 Hz, 3H, OCH2CH3), 1.27 (t,
J=7.1 Hz, 3H, OCH2CH3), 4.10 (s, 2H, NCH2CO2), 4.14 (q, J=7.1 Hz,
2H, OCH2CH3), 4.17 (s, 2H, NCH2CO2), 4.20 (q, J=7.1 Hz, 2H,
OCH2CH3), 5.15 (s, 2H, PhCH2O), 7.27–7.39 (m, 5H, Harom.). 13C NMR
(300 MHz, CDCl3): δ (ppm)=14.2 (1C, OCH2CH3), 14.3 (1C, OCH2CH3),
49.3 (1C, NCH2CO2), 49.5 (1C, NCH2CO2), 61.4 (1C, OCH2CH3), 61.5
(1C, OCH2CH3), 68.0 (1C, OCH2Ph), 127.9 (2C, C-2phenyl, C-6phenyl), 128.2
(1C, C-4phenyl), 128.6 (2C, C-3phenyl, C-5phenyl), 136.2 (1C, C-1phenyl), 156.1
(1C, OCO2N), 169.5 (1C, NCH2CO2), 169.6 (1C, NCH2CO2). FT-IR: v˜
(cmÀ 1)=3062 (w, v, CÀ H, arom.), 2982 (m, v, CÀ H, alkyl), 1744 (s, v,
C=O, ester), 1708 (s, v, C=O, carbamate), 737, 698 (m, δ, CÀ H,
arom.). MS (APCI): calcd. for C16H21NO6H+ 324.1442, found 324.1377.
HPLC: purity 98.4%, tR =19.44 min.
=3600–2300 (s, v, OÀ H, acid), 2925 (s, v, CÀ H, alkyl), 1719, (s, v,
C=O, acid), 1596 (s, v, C=O, amide), 700 (m, δ, CÀ H, arom.). MS (ESI,
negative mode): 473 [(2×MÀ H)À , 100], 236 [(MÀ H)À , 89].
Benzyl 4-(4-methoxybenzyl)-3,5-dioxopiperazine-1-carboxylate
(12a)
A solution of the diacid 11a (11.06 g, 41.40 mmol) in THF (250 mL)
was heated to reflux in a three-neck-flask (Two necks sealed with
rubber septa.). Then a solution of carbonyldiimidazole (6.71 g,
41.40 mmol) in acetonitrile (20 mL) was added slowly over 30 min.
The mixture was heated to reflux for 90 min. Subsequently a
solution of p-methoxybenzylamine (5.37 mL, 41.40 mmol) in THF
(20 mL) was added slowly over 30 min and the mixture was heated
to reflux for 90 min. Subsequently a solution of carbonyldiimidazole
(13.42 g, 82.80 mmol) in acetonitrile (50 mL) was added slowly to
the reaction mixture over 30 min. The mixture was heated to reflux
for 60 h. Then most of the solvent was removed in vacuum. The
Diethyl 2,2‘-(N-benzoylimino)diacetate (10b)
Diethyl iminodiacetate 9 (1.0 g, 5.29 mmol) was dissolved in CH2Cl2
(30 mL) and NEt3 (535 mg, 5.29 mmol) was added. Then benzoyl
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residue was dissolved in Et2O and 2 M HCl was added. The mixture
was extracted with Et2O (2×), then 5 M NaOH was added to the
aqueous layer until pH 12. The aqueous layer was extracted with
CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and
the solvent was evaporated in vacuum. The residue was purified by
fc (cyclohexane:ethyl acetate=7:3, ∅=8.0 cm, l=8.0 cm, V=
100 mL) to obtain a pale yellow solid. (Rf 0.48, cyclohexane:ethyl
was dissolved in CH2Cl2 and saturated NaHCO3 solution and mixture
was washed with CH2Cl2 (4×). The combined organic layers were
dried (Na2SO4) and the solvent was removed in vacuum. The
residue was purified by fc (cyclohexane:ethyl acetate=1:1, ∅=
5.0 cm, l=8.5 cm, V=30 mL) to obtain a pale yellow solid. (Rf 0.63,
cyclohexane:ethyl acetate=1:1): Yellow solid. Yield 2.99 g (84%).
1
2
3
4
5
6
7
8
9
1
C19H20N2O3 (324.2). H NMR (300 MHz, CDCl3): δ (ppm)=3.39 (s, 4H,
°
acetate=1:1): Pale yellow solid, mp. 71 C. Yield 10.37 g (68%).
NCH2CO), 3.59 (s, 2H, NCH2Ph), 3.78 (s, 3H, OCH3), 4.86 (s, 2H,
NCH2Ar), 6.82 (d, J=8.7 Hz, 2H, 3-HPMB, 5-HPMB), 7.24 (dd, J=6.1/
4.4 Hz, 2H, 2-Hbenzyl, 6-Hbenzyl), 7.28–7.39 (m, 3H, 3-Hbenzyl, 4-Hbenzyl, 5-
Hbenzyl), 7.34 (d, J=8.7 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR (300 MHz,
CDCl3): δ (ppm)=41.9 (1C, NCH2Ar), 55.4 (2C, NCH2CO), 56.5 (1C,
OCH3), 60.9 (1C, NCH2Ph), 113.9 (2C, C-3PMB, C-5PMB), 128.2 (1C, C-
1
C20H20N2O5 (368.1). H NMR (300 MHz, CDCl3): δ (ppm)=3.78 (s, 3H,
OCH3), 4.39 (s, 4H, 2-CH2, 6-CH2), 4.88 (s, 2H, NCH2Ph), 5.15 (s, 2H,
PhCH2O), 6.82 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.31–7.41 (m, 5H,
H
phenyl), 7.34 (d, J=8.8 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR (300 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
CDCl3): δ (ppm)=42.4 (1C, NCH2Ar), 47.3 (2C, C-2, C-6), 55.4 (1C,
OCH3), 68.5 (1C, OCH2Ph), 114.0 (2C, C-3PMB, C-5PMB), 128.4 (1C, C-
1PMB), 128.5 (2C, C-2phenyl, C-6phenyl), 128.8 (2C, C-3phenyl, C-5phenyl), 128.8
(1C, C-4phenyl), 131.0 (2C, C-2PMB, C-6PMB), 135.5 (1C, C-1phenyl), 154.0
1
PMB), 128.8 (2C, C-2benzyl, C-6benzyl), 129.0 (2C, C-3benzyl, C-5benzyl), 129.3
(1C, C-4benzyl), 130.7 (2C, C-2PMB, C-6PMB), 135.4 (1C, C-1benzyl), 159.2
(1C, C-4PMB), 170.0 (2C, NCH2CO). FT-IR: v˜ (cmÀ 1)=3062 (w, v, CÀ H,
arom.), 2958 (m, v, CÀ H, alkyl), 1736 (s, v, C=O, imide), 1679 (s, v,
C=O, imide), 822 (m, δ, CÀ H, para-substituted arom.), 742, 700 (m,
δ, CÀ H, mono-substituted arom.). MS (APCI): calcd. for C19H20N2O3H+
325.1547, found 325.1582. HPLC: purity 95.1%, tR =20.19 min.
(1C, OC(=O)N), 159.4 (1C, C-4PMB), 167.8 (2C, COimide). FT-IR: v˜ (cmÀ 1
)
=3067 (w, v, CÀ H, arom.), 2961 (w, v, CÀ H, alkyl), 1738 (w, v, C=O,
imide), 1676 (s, v, C=O, imide), 820 (w, δ, CÀ H, para-substituted
arom.), 747, 694 (m, δ, CÀ H, mono-substituted arom.). A signal for
the C=O of the carbamate group cannot be detected. MS (APCI):
calcd. for C20H20N2O5 368.1372, found 368.1362. HPLC: purity 98.9%,
tR =20.22 min.
1-(4-Methoxybenzyl)piperazine-2,6-dione (12d)
The imide 12a (1.01 g, 2.73 mmol) was dissolved in THF (50 mL)
and Pd/C (10%, 0.11 mg) was added. The mixture was stirred under
H2 atmosphere (1 atm) at rt for 1 h. The mixture was filtered
through Celite® with THF and the solvent was evaporated in
vacuum. The residue was purified by fc (cyclohexane:ethyl
acetate=1:1!100% ethyl acetate, ∅=3.0 cm, l=4.5 cm, V=
30 mL) to obtain a pale yellow solid. (Rf 0.01, cyclohexane:ethyl
4-Benzoyl-1-(4-methoxybenzyl)piperazine-2,6-dione (12b)
A solution of the diacid 11b (2.75 g, 11.60 mmol) in THF (150 mL)
was heated to reflux in a three-neck-flask (Two necks sealed with
rubber septa.). Then a solution of carbonyldiimidazole (1.88 g,
11.60 mmol) in acetonitrile (30 mL) was added slowly over 30 min.
The mixture was stirred for 60 min. Subsequently a solution of p-
methoxybenzylamine (1.51 mL, 11.60 mmol) in THF (10 mL) was
added slowly over 30 min and the mixture was stirred for 60 min. A
solution of carbonyldiimidazole (3.76 g, 23.20 mmol) in acetonitrile
(50 mL) was added slowly to the reaction mixture over 30 min. The
mixture was refluxed for 18 h. Then most of the solvent was
removed in vacuum. The remaining residue was dissolved in CH2Cl2
and 1 M HCl was added. The mixture was extracted with CH2Cl2
(3×). The combined CH2Cl2 layers were alkalized with 2 M NaOH
and washed with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4) and the solvent was evaporated in vacuum. The
residue was purified by fc (cyclohexane:ethyl acetate=7:3, ∅=
8.0 cm, l=10.0 cm, V=100 mL) to obtain a pale yellow oil. (Rf 0.35,
cyclohexane:ethyl acetate=1:1): Pale yellow oil. Yield 2.36 g (60%).
°
acetate=1:1). mp: 131–132 C. Yield 0.61 g (95%). C12H14N2O3
(234.1). H NMR (300 MHz, CDCl3): δ (ppm)=3.70 (s, 4H, NCH2CO),
1
3.78 (s, 3H, OCH3), 4.88 (s, 2H, NCH2Ar), 6.82 (d, J=8.7 Hz, 2H, 3-
HPMB, 5-HPMB), 7.35 (d, J=8.7 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR
(300 MHz, CDCl3): δ (ppm)=41.5 (1C, NCH2Ar), 50.0 (2C, NCH2CO),
55.4 (1C, OCH3), 113.9 (2C, C-3PMB, C-5PMB), 129.2 (1C, C-1PMB), 130.9
(2C, C-2PMB, C-6PMB), 159.2 (1C, C-4PMB), 171.1 (2C, NCH2CO). FT-IR: v˜
(cmÀ 1)=3335 (s, v, NÀ H, amine), 3075 (w, v, CÀ H, arom.), 2962 (m, v,
CÀ H, alkyl), 1714 (s, v, C=O, imide), 1665 (s, v, C=O, imide), 832 (m,
δ, CÀ H, para-substituted arom.). MS (APCI): calcd. for C12H14N2O3H+
235.1077, found 235.1103. HPLC: purity 99.7%, tR =11.52 min.
N-(tert-Butoxycarbonyl)iminodiacetic acid (14)
1
C19H18N2O4 (338.4). H NMR (400 MHz, CDCl3): δ (ppm)=3.78 (s, 3H,
A mixture of iminodiacetic acid (11.0 g, 83 mmol, 1 eq) and NaHCO3
(27.8 g, 331 mmol, 4 eq) were dissolved in H2O (100 mL) of water.
After bubbling finished, THF (100 mL) was added followed by
Boc2O (18.0 g, 83 mmol, 1 eq). The mixture was stirred at ambient
temperature for 3 d. THF was removed in vacuo and the aqueous
layer was washed with Et2O (2×). The pH of the aqueous layer was
then adjusted to pH 1 using 6 M HCl. The aqueous layer was
extracted with ethyl acetate (4×). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated in vacuo to
OCH3), 4.51 (s, broad, 4H, 2×NCH2CO), 4.89 (s, 2H, NCH2Ar), 6.83 (d,
J=8.7 Hz, 2H, 3-HPMB, 5-HPMB), 7.34 (d, J=8.6 Hz, 2H, 2-HPMB, 6-HPMB),
7.37–7.41 (m, 2H, 3-Hbenzoyl, 5-Hbenzoyl), 7.41–7.53 (m, 3H, 2-Hbenzoyl, 4-
H
benzoyl, 6-Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=42.6 (1C,
NCH2Ar), 48.7 (s, broad, 2C, NCH2CO), 55.4 (1C, OCH3), 114.0 (2C, C-
PMB, C-5PMB), 127.6 (2C, C-2benzoyl, C-6benzoyl), 128.4 (1C, C-1PMB), 129.1
(2C, C-3benzoyl, C-5benzoyl), 130.9 (1C, C-4benzoyl), 131.3 (2C, C-2PMB, C-
3
6
PMB), 133.1 (1C, C-1benzoyl), 159.4 (1C, C-4PMB), 167.5 (1C, NCH2CO),
170.2 (1C, NCH2CO). FT-IR: v˜ (cmÀ 1)=3060 (w, v, CÀ H, arom.), 2927
(m, v, CÀ H, alkyl), 1737 (m, v, C=O, imide), 1683 (s, v, C=O, imide),
810 (m, δ, CÀ H, para-substituted arom.), 721, 701 (m, δ, CÀ H, mono-
substituted arom.). MS (EI): 338 [M+, 100].
°
provide the product. Colorless solid, mp 127–131 C, (decomposi-
tion), yield 14.2 g (74%). C9H15NO6 (233.2). 1H NMR (400 MHz,
CDCl3): δ (ppm)=1.35 (s, 9H, C(CH3)3), 3.87 (s, 2H, NCH2COOH), 3.91
(s, 2H, NCH2COOH), 12.63 (s, 2H, 2×COOH). 13C NMR (101 MHz,
CDCl3): δ (ppm)=27.8 (3C, C(CH3)3), 49.1 (1C, NCH2CO), 49.7 (1C,
NCH2CO), 79.5 (1C, C(CH3)3), 154.8 (1C, NCOO), 171.18 (1C, COOH),
171.21 (1C, COOH). IR (neat): v˜ (cmÀ 1)=3113 (OÀ H), 2978 and 2943
(C-Haliph), 1724 (C=O, acid), 1651 (C=O, carbamate). MS (APCI): m/z=
234.0966 (calcd. 234.0972 for C9H16NO6 [M+H]+).
51 4-Benzyl-1-(4-methoxybenzyl)piperazine-2,6-dione (12c)
52
53
N-Ethyl-N,N-diisopropylamine (15.8 mL, 88.1 mmol) and benzyl
bromide (1.58 mL, 13.2 mmol) were added to a solution of the
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secondary amine 12d (2.58 g, 11.01 mmol) in acetonitrile (60 mL).
The mixture was heated to reflux and stirred for 18 h. The solvent
was removed in vacuum almost completely. The remaining solution
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0.38, cyclohexane:ethyl acetate= 75:25). Pale yellow solid, mp. 51–
tert-Butyl 4-benzyl-3,5-dioxopiperazine-1-carboxylate (15)
1
2
3
4
5
6
7
8
9
52 C, yield 14.0 g (88%). C19H20N2O3 (324.4). 1H NMR (600 MHz,
°
A solution of the diacid 14 (15.0 g, 64 mmol, 1 eq) in THF (250 mL)
was heated to reflux in a three-necked-flask. Two necks were sealed
with rubber septum. Then, a solution of carbonyldiimidazole
(10.0 g, 64 mmol, 1 eq) in CH3CN (60 mL) was added slowly over
30 min. The mixture was stirred for 60 min. Subsequently, a solution
of benzylamine (7.03 mL, 64 mmol, 1 eq) in THF (20 mL) was added
slowly over 30 min and the mixture was stirred for 60 min. A
solution of carbonyldiimidazole (21.0 g, 129 mmol, 2 eq) in CH3CN
(100 mL) was added slowly to the reaction mixture over 30 min.
The mixture was heated to reflux for 18 h. Then, most of the solvent
was removed in vacuo. The remaining residue was dissolved in
ethyl acetate and 1 M HCl was added. The mixture was extracted
with ethyl acetate (3×). 2 M NaOH was added to the combined
ethyl acetate layers and the mixture was extracted with ethyl
acetate (3×). The combined organic layers were dried (Na2SO4) and
the solvent was evaporated in vacuo. The residue was purified by fc
(cyclohexane: ethyl acetate=91:9!83:17, ø=5 cm, l=12 cm, V=
100 mL). (Rf 0.66, cyclohexane:ethyl acetate=67:33). Colorless solid,
DMSO-d6): δ (ppm)=3.46 (s, 4H, NCH2CO), 3.58 (s, 2H, NCH2PhOMe),
3.74 (s, 3H, OCH3), 4.80 (s, 2H, NCH2Ph), 6.91 (d, J=8.6 Hz, 2H, 3-
CHPMB, 5-CHPMB), 7.20 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.21–7.23
(m, 2H, 2-CHbenzyl, 6-CHbenzyl), 7.23–7.26 (m, 1H, 4-CHbenzyl), 7.28–7.34
(m, 2H, 3-CHbenzyl, 5-CHbenzyl). 13C NMR (151 MHz, DMSO-d6): δ (ppm)
=41.3 (1C, NCH2Ph), 55.0 (1C, CH3O), 55.1 (2C, NCH2CO), 58.3 (1C,
NCH2PhOMe), 113.8 (2C, C-3PMB, C-5PMB), 127.1 (1C, C-4benzyl), 127.5
(2C, C-2benzyl, C-6benzyl), 127.8 (1C, C-1PMB), 128.4 (2C, C-3benzyl, C-5benzyl),
130.4 (2C, C-2PMB, C-6PMB), 136.9 (1C, C-1benzyl), 158.7 (1C, C-4PMB),
170.3 (2C, NCH2CO). IR (neat): v˜ (cmÀ 1)=2955 and 2931 (C-Haliph),
1735 and 1682 (C=O), 821 (C-Harom). MS (APCI): m/z=325.1553
(calcd. 325.1547 for C19H21N2O3 [M+H]+). Purity (HPLC): 97.2% (tR =
21.2 min).
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Benzyl
2-(ethoxycarbonylmethyl)-4-(4-meth-
oxybenzyl)-3,5-dioxopiperazine-1-carboxylate (18a) and diethyl
2,2‘-[1-(benzyloxycarbonyl)-4-(4-meth-
oxybenzyl)-3,5-dioxopiperazine-2,2-diyl]diacetate (19a)
mp 147–149 C, yield 12.1 g (62%). C16H20N2O4 (304.3). 1H NMR
°
(400 MHz, CDCl3): δ (ppm)=1.45 (s, 9H, C(CH3)3), 4.32 (s, 4H,
NCH2CO), 4.95 (s, 2H, NCH2Ph), 7.25–7.32 (m, 3H, 3-CHbenzyl, 4-CHbenzyl
,
5-CHbenzyl), 7.35–7.39 (m, 2H, 2-CHbenzyl, 6-CHbenzyl). 13C NMR (101 MHz,
A solution of the imide 12a (1.02 g, 2.76 mmol) in THF (30 mL) was
CDCl3): δ (ppm)=28.3 (3C, C(CH3)3), 42.9 (1C, NCH2Ph), 47.3 (2C,
NCH2CO), 82.4 (1C, C(CH3)3), 128.0 (1C, C-4benzyl), 128.7 (2C, C-3benzyl
C-5benzyl), 129.2 (2C, C-2benzyl, C-6benzyl), 136.3(1C, C-1benzyl), 153.2 (1C,
NCOO), 168.2 (2C, NCOCH2).IR (neat): v˜ (cmÀ 1)=2982 (C-Haliph), 1678
(C=O), 856 (C-Harom). MS (APCI): m/z=305.1408 (calcd. 305.1496 for
C16H21N2O4 [M+H]+). Purity (HPLC): 99.8% (tR =20.9 and 21.1 min).
°
cooled to À 78 C. Then a 1 M solution of lithium hexameth-
,
yldisilazide (LiHMDS, 2.76 mL, 2.76 mmol) was added and the
mixture was stirred for 1 h. Ethyl 2-bromoacetate (0.61 mL,
°
5.51 mmol) was added and the mixture was stirred at À 78 C for
2 h. The mixture was warmed to rt overnight. The solvent was
removed in vacuum and the remaining residue was purified by fc
(n-hexane:ethyl acetate=8/2, ∅=4.0 cm, l=8.5 cm, V=30 mL) to
obtain two pale yellow oils. 18a (Rf 0.57, cyclohexane:ethyl
acetate=1:1): Pale yellow oil. Yield 1.06 g (84%). C24H26N2O7
1-Benzylpiperazine-2,6-dione (16)
1
(454.1). H NMR (300 MHz, CDCl3): δ (ppm)=1.18 (t, J=7.2 Hz, 3H,
A solution of 15 (70 mg, 0.23 mmol, 1 eq) in CH2Cl2 (5 mL) was
OCH2CH3), 2.92 (s, broad, 1H, CHCH2CO2Et), 3.14 (dd, broad, J=17.3/
4.8 Hz, 1H, CHCH2CO2Et), 3.77 (s, 3H, OCH3), 3.99–4.15 (m, 3H,
OCH2CH3, 2-CH), 4.90 (d, J=13.8 Hz, 1H, NCH2Ph), 4.91 (s, broad, 2H,
6-CH2), 4.97 (d, J=13.8 Hz, 1H, NCH2Ph), 5.15 (s, 2H, PhCH2O), 6.81
(d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.29–7.41 (m, 5H, Hphenyl), 7.32 (d,
J=8.8 Hz, 2H, 2-HPMB, 6-HPMB). FT-IR: v˜ (cmÀ 1)=3067 (w, v, CÀ H,
arom.), 2962 (m, v, CÀ H, alkyl), 1726 (s, v, C=O, ester),1712 (s, v,
C=O, carbamate), 1681 (s, v, C=O, imide), 815 (m, δ, CÀ H, para-
substituted arom.), 735, 698 (m, δ, CÀ H, mono-substituted arom.). A
second signal for the imide-C=O group cannot be detected. MS
(APCI): calcd. for C24H26N2O7H+ 455.1813, found 455.1969. HPLC:
purity 82.6%, tR =21.24 min. 19a (Rf 0.65, cyclohexane:ethyl
acetate=1:1): Pale yellow oil. Yield 0.06 g (4%). C28H32N2O9 (540.2).
°
cooled to 0 C. CF3COOH (2 mL) was added slowly to the mixture.
The mixture was stirred overnight at rt. The solvent was removed in
vacuo. The residue was dissolved in CH2Cl2 (20 mL) and the mixture
was washed with saturated NaHCO3 solution (20 mL). The aqueous
layer was extracted with CH2Cl2 (4×). The organic layers were
combined and dried (Na2SO4). The solvent was evaporated in vacuo
and the residue was purified by fc (cyclohexane:ethyl acetate:
dimethylethylamine=50:50:1!25:75:1, ø=1 cm, l=10 cm, V=
7 mL). (Rf 0.24, cyclohexane:ethyl acetate:dimethylethylamine=
°
20:80:1): Colorless solid, mp 149–151 C, yield 12.1 g (99%).
C11H12N2O2 (204.2). H NMR (600 MHz, DMSO-d6): δ (ppm)=3.59 (s,
4H, NCH2CO), 4.82 (s, 2H, NCH2Ph), 7.20–7.27 (m, 3H, 2-CHbenzyl, 4-
1
CHbenzyl, 6-CHbenzyl), 7.27–7.33 (m, 2H, 3-CHbenzyl, 5-CHbenzyl). 13C NMR
1H NMR (300 MHz, CDCl3):
δ (ppm)=1.09 (t, J=7.1 Hz, 6H,
(151 MHz, DMSO-d6):
δ (ppm)=40.8 (1C, NCH2Ph), 49.1 (2C,
OCH2CH3), 3.01 (d, J=17.2 Hz, 2H, 2×CH2CO2), 3.76 (s, 3H, OCH3),
3.82–4.10 (m, 6H, OCH2CH3, 2×CH2CO2), 4.45 (s, 2H, 6-Hdioxopiperazine),
4.97 (s, 2H, NCH2Ph), 5.14 (s, 2H, PhCH2O), 6.79 (d, J=8.8 Hz, 2H, 3-
NCH2CO), 126.9 (1C, C-4benzyl), 127.4 (2C, C-2benzyl, C-6benzyl), 128.2 (2C,
C-3benzyl, C-5benzyl), 137.2 (1C, C-1benzyl), 172.1 (2C, C=O). IR (neat): v˜
(cmÀ 1)=3321 (NÀ H), 2954, 2924 and 2854 (C-Haliph), 1724 and 1662
(C=O), 840 (C-Harom). MS (APCI): m/z=205.0973 (calcd. 205.0972 for
C11H13N2O2 [M+H]+). Purity (HPLC): 95.9% (tR =12.2 min).
H
PMB, 5-HPMB), 7.27–7.42 (m, 5H, Hphenyl), 7.32 (d, J=8.8 Hz, 2H, 2-HPMB,
6-HPMB). FT-IR: v˜ (cmÀ 1)=3062 (w, v, CÀ H, arom.), 2958 (m, v, CÀ H,
alkyl), 1728 (s, v, C=O, ester), 1706 (s, v, C=O, carbamate), 1675 (s, v,
C=O, imide), 819 (m, δ, CÀ H, para-substituted arom.), 736, 698 (m,
δ, CÀ H, mono-substituted arom.). A second signal for the imide-
C=O group cannot be detected. MS (ESI, negative mode): m/z (%)=
1103 [(2×M+Na)À , 97], 563 [(M+Na)À , 100].
1-Benzyl-4-(4-methoxybenzyl)piperazine-2,6-dione (17)
N-Ethyl-N,N-diisopropylamine (24.3 mL, 147 mmol, 3 eq) and 4-
methoxybenzyl chloride (7.0 mL, 52 mmol, 1.05 eq) were added to
a solution of the secondary amine 16 (10.0 g, 49 mmol, 1 eq) in
CH3CN (100 mL). The mixture was heated to reflux for 18 h. The
solvent was removed in vacuo almost completely. The remaining
residue was dissolved in CH2Cl2 (100 mL) and saturated NaHCO3
solution (100 mL). The mixture was extracted with CH2Cl2 (4×). The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuo. The residue was purified by fc (cyclohexane:
ethyl acetate=91:9!75:25, ø=6 cm, l=18 cm, V=65 mL). (Rf
Ethyl 2-(1-benzoyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl)
acetate (18b) and diethyl
2,2‘-(1-benzoyl-4-(4-meth-
oxybenzyl)-3,5-dioxopiperazine-2,2-diyl)diacetate (19b)
A solution of the imide 12b (257 mg, 0.76 mmol) in THF (15 mL)
°
was cooled to À 78 C and 0.5 M KHMDS-solution in THF (1.59 mL,
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0.76 mmol) was added. After 30 min ethyl 2-bromoacetate (168 μL,
1.52 mmol) was added. The reaction mixture was stirred for 1.5 h at
1H, 6-Hdioxopiperazine), 3.68 (d, J=12.9 Hz, 1H, NCH2Ar), 3.79 (s, 3H,
OCH3), 4.04 (t, J=6.8 Hz, 1 H, 2-Hdioxopiperazine), 4.14 (q, J=7.1 Hz, 2H,
OCH2CH3), 4.84 (d, J=13.8 Hz, 1H, NCH2Ph), 4.90 (d, J=13.8 Hz, 1H,
NCH2Ph), 6.83 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.27–7.38 (m, 5H,
1
2
3
4
5
6
7
8
9
°
À 78 C and then warmed to rt. An excess of 1 M HCl solution was
added and the mixture was concentrated in vacuum. The residue
was dissolved in CH2Cl2 and washed with water (4×). The combined
organic layers were dried (Na2SO4) and the solvent was removed in
vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=
8:2, ∅=3.0 cm, l=12.0 cm, V=20 mL) to obtain two pale yellow
oils 18b and 19b. 18b (Rf 0.42, cyclohexane:ethyl acetate=1:1):
Pale yellow oil. Yield 254 mg (79%). C23H24N2O6 (424.5). 1H NMR
(400 MHz, CDCl3): δ (ppm)=1.26 (t, J=7.1 Hz, 3H, OCH2CH3), 3.00
(d, broad, J=16.9 Hz, 1H, CH2CO2Et), 3.20 (d, broad, J=16.3 Hz, 1H,
CH2CO2Et), 3.79 (s, 3H, OCH3), 4.12 (q, J=7.1 Hz, 2H, OCH2CH3), 4.38
(d, J=16.3 Hz, 1H, NCH2CO), 4.61 (s, broad, 1H, NCH2CO), 4.94 (s,
2H, NCH2Ar), 5.48 (s, broad, 1H, NCHCO), 6.83 (d, J=8.7 Hz, 2H, 3-
H
benzyl) 7.34 (d, J=8.8 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR (300 MHz,
CDCl3): δ (ppm)=14.3 (1C, OCH2CH3), 34.9 (1C, CH2CO2Et), 42.2 (1C,
NCH2Ar), 52.4 (1C, NCH2CO), 55.4 (1C, OCH3), 57.7 (1C, NCHCO), 61.1
(1C, OCH2CH3), 61.3 (1C, PhCH2N), 114.0 (2C, C-3PMB, C-5PMB), 128.3
(1C, C-1PMB), 128.8 (1C, C-4benzyl), 129.2 (2C, C-2benzyl, C-6benzyl), 129.7
(2C, C-3benzyl, C-5benzyl), 130.7 (2C, C-2PMB, C-6PMB), 135.7 (1C, C-1benzyl),
159.2 (1C, C-4PMB), 169.6 (1C, NCH2CO), 170.3 (COester), 171.1 (1C,
NCHCO). FT-IR: v˜ (cmÀ 1)=3062 (w, v, CÀ H, arom.), 2982 (m, v, CÀ H,
alkyl), 1732 (s, v, C=O, ester), 1679 (s, v, C=O, imide), 819 (m, δ, CÀ H,
para-substituted arom.), 744, 700 (m, δ, CÀ H, mono-substituted
arom.). A second signal for the imide-C=O cannot be detected. MS
(APCI): calcd. for C23H26N2O5H+ 411.1914, found 411.1944. HPLC:
purity 92.8%, tR =21.05 min.
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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50
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H
PMB, 5-HPMB), 7.32 (d, J=8.6 Hz, 2H, 2-HPMB, 6-HPMB), 7.36 (dd, J=8.0/
1.3 Hz, 2H, 3-Hbenzoyl, 5-Hbenzoyl), 7.40–7.53 (m, 3H, 2-Hbenzoyl, 4-Hbenzoyl
,
6-Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=14.2 (1C, OCH2CH3),
36.5 (1C, C-2), 42.9 (1C, NCH2Ar), 51.1 (1C, NCH2CO), 55.4 (1C, OCH3),
60.5 (1C, NCHCO), 61.8 (1C, OCH2CH3), 114.0 (2C, C-3PMB, C-5PMB),
(1RS,5SR,6RS)-8-Benzyl-6-ethoxy-3-(4-meth-
oxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]
octane-2,4-dione (20c)
127.4 (2C, C-2benzoyl, C-6benzoyl), 128.4 (1C, C-1PMB), 129.0 (2C, C-3benzoyl
,
C-5benzoyl), 130.5 (1C, C-4benzoyl), 131.1 (2C, C-2PMB, C-6PMB), 133.6 (1C,
C-1benzoyl), 159.3 (1C, C-4PMB), 167.4 (1C, CObenzoyl), 167.4 (1C, NCH2CO),
170.0 (1C, NCH2CO), 171.3 (1C, CH2CO2Et). FT-IR: v˜ (cmÀ 1)=3062 (w,
v, CÀ H, arom.), 2940 (w, v, CÀ H, alkyl), 1731 (m, v, C=O, imide), 1683
(s, v, C=O, imide), 1652 (s, v, C=O, amide), 811 (m, δ, CÀ H, para-
substituted arom.), 722, 702 (m, δ, CÀ H, mono-substituted arom.).
MS (EI): 424 [M+, 100], 319 [(M–C6H5CO)+, 70], 303 [(M-
H3COC6H4CH2)+, 98]. 19b (Rf 0.52, cyclohexane:ethyl acetate=1:1):
Pale yellow oil. Yield 22 mg (6%). C27H30N2O8 (510.5). 1H NMR
(400 MHz, CDCl3): δ (ppm)=1.17 (t, J=7.1 Hz, 6H, 2×OCH2CH3),
3.09 (d, J=17.4 Hz, 2H, 2× CH2CO2Et), 3.76 (s, 3H, OCH3), 4.00 (q, J=
7.2 Hz, 4H, 2× OCH2CH3), 4.16 (d, J=17.4 Hz, 2H, 2× CH2CO2Et), 4.36
A solution of the acetate 18c (145 mg, 0.35 mmol) in THF (15 mL)
°
was cooled to À 78 C and 1.0 M LiHMDS-solution (531 μL,
0.53 mmol) was added. After 15 min TMSÀ Cl (157 μL, 1.24 mmol)
°
was added. The reaction mixture was stirred for 1.0 h at À 78 C and
then warmed to rt. The solvent was removed in vacuum, the
residue dissolved in CH2Cl2 was poured into CH2Cl2/saturated
NaHCO3 and extracted four time with CH2Cl2. The combined organic
layers were dried (Na2SO4) and the solvent was evaporated in
vacuum. The residue was purified by fc (cyclohexane:ethyl
acetate=9:1, ∅=2.0 cm, l=8.5 cm, V=20 mL) to obtain a pale
yellow oil. (Rf 0.72, cyclohexane:ethyl acetate=1:1). Yield 20 mg
(12%). C26H34N2O5Si (482.6). 1H NMR (300 MHz, CDCl3): δ (ppm)=
0.02 (s, 9H, Si(CH3)3), 1.16 (t, J=7.1 Hz, 3H, OCH2CH3), 2.56 (d, J=
11.0 Hz, 1H, 7-CH2), 2.63 (d, J=13.0 Hz, 1H, 7-CH2), 3.41 (dq, J=9.4/
7.0 Hz, 1H, OCH2CH3), 3.49 (s, 1H, 5-CH), 3.57 (dq, J=9.4/7.1 Hz, 1H,
OCH2CH3), 3.62 (d, J=12.9 Hz, 1H, NCH2Ph), 3.70 (d, J=13.0 Hz, 1H,
NCH2Ph), 3.78 (s, 3H, OCH3), 3.80–3.84 (m, 1H, 1-CH), 4.79 (d, J=
13.6 Hz, 1H, NCH2Ar), 4.85 (d, J=13.7 Hz, 1H, NCH2Ar), 6.84 (d, J=
8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.14 (dd, J=7.5/2.0 Hz, 2H, 2-Hbenzyl, 6-
(s, 2H, NCH2CO), 4.94 (s, 2H, NCH2Ar), 6.80 (d, J=8.6 Hz, 2H, 3-HPMB
,
5-HPMB), 7.22–7.25 (m, 2H, 3-Hbenzoyl, 5-Hbenzoyl), 7.31 (d, J=8.6 Hz, 2H,
2-HPMB, 6-HPMB), 7.37–7.47 (m, 3H, 2-Hbenzoyl, 4-Hbenzoyl, 6-Hbenzoyl). 13C
NMR (400 MHz, CDCl3): δ (ppm)=14.2 (2C, OCH2CH3), 31.1 (1C,
CH2CO2Et), 41.1 (1C, CH2CO2Et), 43.8 (1C, NCH2Ar), 51.7 (1C,
NCH2CO), 55.3 (1C, OCH3), 60.6 (1C, NCCO), 61.2 (1C, OCH2CH3), 62.5
(1C, OCH2CH3), 113.7 (2C, C-3PMB, C-5PMB), 126.2 (2C, C-2benzoyl, C-
6
benzoyl), 128.3 (1C, C-1PMB), 129.1 (2C, C-3benzoyl, C-5benzoyl), 130.3 (1C,
C-4benzoyl), 130.5 (2C, C-2PMB, C-6PMB), 136.2 (1C, C-1benzoyl), 159.1 (1C,
C-4PMB), 166.4 (1C, CObenzoyl), 170.5 (1C, NCH2CO), 171.6 (1C, NCH2CO),
172.9 (1C, CH2CO2). FT-IR: v˜ (cmÀ 1)=3062 (w, v, CÀ H, arom.), 2936
(w, v, CÀ H, alkyl), 1727 (s, v, C=O, imide), 1676 (s, v, C=O, imide),
1651 (s, v, C=O, amide), 818 (m, δ, CÀ H, para-substituted arom.),
728, 702 (m, δ, CÀ H, mono-substituted arom.). MS (EI): 510 [M+,
100], 465 [(M-OCH2CH3)+, 16], 405 [(M–C6H5CO)+, 15].
H
benzyl), 7.27–7.34 (m, 3H, 3-Hbenzyl, 4-Hbenzyl, 5-Hbenzyl), 7.41 (d, J=
8.8 Hz, 2H, 2-HPMB, 6-HPMB). FT-IR: v˜ (cmÀ 1)=3067 (w, v, CÀ H, arom.),
2925 (m, v, CÀ H, alkyl), 1736 (m, v, C=O, imide), 1685 (s, v, C=O,
imide), 843 (m, δ, CÀ H, para-substituted arom.), 739, 697 (m, δ, CÀ H,
mono-substituted arom.). MS (APCI): calcd. for C26H34N2O5SiH+
483.2315, found 483.2386. HPLC: purity 83.1%, tR =23.87 min.
Benzyl
Ethyl 2-(1-benzyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl)
acetate (18c)
(1RS,5RS,7SR)-6-ethoxy-1-(ethoxycarbonylmethyl)-3-(4-meth-
oxybenzyl)-2,4-dioxo-6-(trimethylsilyloxy)-3,8-diazabicyclo
[3.2.1]octane-8-carboxylate (21a)
A solution of the imide 12c (21 mg, 0.07 mmol) in THF (5 mL) was
°
cooled to À 78 C. Then a 1 M solution of lithium hexameth-
A solution of the diacetate 19a (158 mg, 0.29 mmol) in THF (15 mL)
yldisilazide (LiHMDS, 0.07 mL, 0.07 mmol) was added and the
°
was cooled to À 78 C and 1.0 M LiHMDS-solution (438 μL,
mixture was stirred for 1 h. Ethyl 2-bromoacetate (15 μL,
0.44 mmol) was added. After 15 min TMSÀ Cl (129 μL, 1.02 mmol)
°
0.13 mmol) was added and the mixture was stirred at À 78 C for
°
was added. The reaction mixture was stirred for 1.0 h at À 78 C and
1 h. The mixture was warmed to rt. The solvent was removed in
vacuum and the remaining residue was purified by fc (n-hexane:
ethyl acetate=8/2, ∅=1.0 cm, l=4.0 cm, V=5 mL) to obtain a
yellow oil. (Rf 0.62, cyclohexane:ethyl acetate=1:1): Yellow oil.
Method A: Yield 0.32 g (85%). Method B; Yield 24 mg (89%).
then warmed to rt. The solvent was removed in vacuum, the
remaining residue was purified by fc (cyclohexane:ethyl acetate=
8:2, ∅=3.0 cm, l=8.0 cm, V=20 mL) to obtain a pale yellow oil. (Rf
0.55, cyclohexane:ethyl acetate=1:1). Pale yellow oil. Yield 38 mg
(21%). C31H40N2O9Si (612.7). 1H NMR (400 MHz, CDCl3): δ (ppm)=
0.01 (s, 9H, Si(CH3)3), 1.13 (t, J=7.0 Hz, 3H, OCH2CH3), 1.20 (t, J=
7.1 Hz, 3H, CO2CH2CH3), 2.27 (d, J=13.3 Hz, 1H, 7-CH2), 2.75 (dd, J=
13.9/0.9 Hz, 1H, 7-CH2), 3.31 (d, J=16.9 Hz, 1H, CH2CO2Et), 3.44 (d,
1
C23H26N2O5 (410.1). H NMR (300 MHz, CDCl3): δ (ppm)=1.23 (t, J=
7.1 Hz, 3H, OCH2CH3), 2.87 (dd, J=15.6/7.5 Hz, 1H, CHCH2CO2Et),
2.96 (dd, J=15.6/5.7 Hz, 1H, CHCH2CO2Et), 3.40 (d, J=17.6 Hz, 1H,
6-Hdioxoperazine), 3.62 (d, J=12.9 Hz, 1H, NCH2Ar), 3.67 (d, J=17.6 Hz,
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J=16.6 Hz, 1H, CH2CO2Et), 3.43–3-54 (m, 1H, OCH2CH3), 3.54–3.63
(m, 1H, OCH2CH3), 3.74 (s, 3H, OCH3), 4.05–4.16 (m, 2H, CO2CH2CH3),
4.68 (d, J=13.9 Hz, 1H, NCH2Ar), 4.81 (d, J=13.9 Hz, 1H, NCH2Ar),
4.96 (s, 1H, 5-CH), 4.96 (d, J=12.2 Hz, 1H, PhCH2O), 5.04 (d, J=
12.2 Hz, 1H, PhCH2O), 6.77 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.19–
arom.). MS (APCI): calcd. for C24H26N2O7H+ 455.1813, found
455.1858.
1
2
3
4
5
Methyl 1-benzoyl-5-hydroxy-2-[N-(4-methoxybenzyl)
carbamoyl]-1,2,3,6-tetrahydropyridine-4-carboxylate (24b)
7.25 (m, 2H, 3-Hphenyl, 5-Hphenyl), 7.28–7.38 (m, 5H, 2-Hphenyl, 4-Hphenyl
,
6-Hphenyl, 2-HPMB, 6-HPMB).
6
A solution of the imide 12b (49 mg, 0.15 mmol) in THF (5 mL) was
°
cooled to À 78 C and 0.5 M KHMDS-solution in THF (290 μL,
7
8
9
0.15 mmol) was added. After 180 min methyl acrylate (39 μL,
Ethyl
0.44 mmol) was added. The reaction mixture was stirred for 2.0 h at
2-[(1RS,5RS,6SR)-8-benzoyl-6-ethoxy-3-(4-meth-
oxybenzyl)-2,4-dioxo-6-(trimethylsilyloxy)-3,8-diazabicyclo
[3.2.1]octan-1-yl]acetate (21b)
°
À 78 C and then at rt for 16 h. The solvent was removed in vacuum
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
and the residue was purified by fc (cyclohexane:ethyl acetate=7:3,
∅=1.5 cm, l=7.5 cm, V=10 mL) to obtain a colorless solid. (Rf
0.21, cyclohexane:ethyl acetate=1:1): Colorless solid. Yield 21 mg
A solution of the diacetate 19b (42 mg, 0.08 mmol) in THF (10 mL)
1
(34%). C23H24N2O6 (424.5). The H NMR spectrum shows only broad
°
was cooled to À 78 C and 1.0 M LiHMDS-solution in THF (123 μL,
signals. The structure of 24b was identified by subsequent trans-
formation. FT-IR: v˜ (cmÀ 1)=3316 (m, v, NÀ H, amide), 3059 (w, v,
CÀ H, arom.), 2953 (m, v, CÀ H, alkyl), 1733 (s, v, C=O, ester), 1667 (s,
v, C=O, amide), 810 (m, δ, CÀ H, para-substituted arom.), 730, 702
(m, δ, CÀ H, mono-substituted arom.). MS (EI): 424 [M+, 15], 392 [(M-
HOCH3)+, 50], 287 [(M-H3OC6H4CH2NH2)+, 100].
0.12 mmol) was added. After 15 min TMSÀ Cl (36 μL, 0.29 mmol) was
°
added. The reaction mixture was stirred for 1.0 h at À 78 C and
then warmed to rt. The solvent was removed in vacuum, the
residue was purified by fc (cyclohexane:ethyl acetate=8:2, ∅=
1.5 cm, l=8.0 cm, V=20 mL) to obtain a pale yellow oil. Yield 5 mg
(10%). C30H38N2O8Si (582.7). 1H NMR (400 MHz, CDCl3): δ (ppm)=
0.00 (s, 9H, Si(CH3)3), 1.19 (t, J=7.1 Hz, 3H, COCH2CH3), 1.20 (t, J=
6.9 Hz, 3H, CO2CH2CH3), 2.32 (d, J=14.0 Hz, 1H, 7-CH2), 2.87 (d, J=
14.1 Hz, 1H, 7-CH2), 3.28 (dq, J=8.8/6.8 Hz, 1H, OCH2CH3), 3.50 (d,
J=16.4 Hz, 1H, CH2CO2Et), 3.53–3.62 (m, 1H, OCH2CH3), 3.60 (d, J=
16.4 Hz, 1H, CH2CO2Et), 3.78 (s, 3H, OCH3), 4.06–4.17 (m, 2H,
CO2CH2CH3), 4.61 (s, 1H, 5-CH), 4.73 (d, J=14.0 Hz, 1H, NCH2Ar), 4.90
(d, J=13.9 Hz, 1H, NCH2Ar), 6.83 (d, J=8.6 Hz, 2H, 3-HPMB, 5-HPMB),
7.31 (d, J=8.6 Hz, 2H, 2-HPMB, 6-HPMB), 7.35–7.51 (m, 5H, Hbenzoyl).
Methyl 1-benzyl-5-hydroxy-2-[(4-methoxybenzyl)
carbamoyl]-1,2,3,6-tetrahydro-pyridine (24c)
A solution of the imide 12c (210 mg, 0.65 mmol) in THF (30 mL)
°
was cooled to À 78 C and 1.0 M LiHMDS-solution in THF (646 μL,
0.65 mmol) was added. After 180 min methyl acrylate (70 μL,
0.78 mmol) was added. The reaction mixture was stirred for 2.0 h at
À 78 C and then at rt for 16 h. The solvent was removed in vacuum
°
and the residue was purified by fc (cyclohexane:ethyl acetate=
19:1, ∅=2.0 cm, l=9.0 cm, V=10 mL) to obtain a colorless solid.
(Rf: 0.38, cyclohexane:ethyl acetate=1:1). Yield 50 mg (19%).
C23H26N2O5 (410.5). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.61 (dd,
J=16.5/6.0 Hz, 1H, 3-H), 2.85 (dd, J=16.5/6.3 Hz, 1H, 3-H), 3.17 (d,
J=18.4 Hz, 1H, 6-H), 3.37 (d, J=18.5 Hz, 1H, 6-H), 3.48 (t, J=6.1 Hz,
1H, 2-H), 3.62 (d, J=13.4 Hz, 1H, NCH2Ph), 3.71 (d, J=13.2 Hz, 1H,
NCH2Ph), 3.79 (s, 6H, ArOCH3, CO2CH3), 4.36 (dd, J=14.4/5.6 Hz, 1H,
NHCH2Ar), 4.45 (dd, J=14.3/6.3 Hz, 1H, NHCH2Ar), 6.84 (d, J=8.7 Hz,
2H, 3-HPMB, 5-HPMB), 7.07–7.23 (m, 4H, 2-HPMB, 6-HPMB, 2-Hbenzyl, 6-
1-Benzyl 4-methyl 5-hydroxy-2-[(4-methoxybenzyl)
carbamoyl]-1,2,3,6-tetrahydro-pyridine-1,4-dicarboxylate (24a)
A solution of the imide 12a (0.51 g, 1.38 mmol) in THF (20 mL) was
°
cooled to À 78 C. Then a 1 M solution of lithium hexameth-
yldisilazide (LiHMDS, 1.38 mL, 1.38 mmol) was added and the
°
mixture was stirred for À 78 C for 1 h. Methyl acrylate (0.37 mL,
4.13 mmol) was added and the reaction mixture was stirred at
°
À 78 C for 2 h and then warmed to rt overnight. The reaction was
stopped with a few drops of a solution of saturated NaHCO3. The
solvent was almost completely evaporated in vacuum and CH2Cl2
and water were added to the residue. The mixture was extracted
with CH2Cl2 (4×) and the combined organic layers were dried
(Na2SO4). The solvent was removed in vacuum and the residue was
purified by fc (cyclohexane:ethyl acetate=7:3!1:1!100% ethyl
acetate, ∅=3.0 cm, l=8.5 cm, V=30 mL) to obtain a pale yellow
solid. (Rf: 0.34, cyclohexane:ethyl acetate=1:1). Yield 0.56 g (90%).
C24H26N2O7 (454.5). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.26 (dd,
broad, J=15.6/5.9 Hz, 1H, 3-H), 3.09 (dd, broad, J=27.8/15.9 Hz, 1H,
5-H), 3.78 (s, 3H, CO2CH3), 3.79 (s, 3H, ArOCH3), 3.85 (d, broad, J=
22.0 Hz, 1H, 6-H), 4.24–4.48 (s, broad, 3H, NHCH2Ar, 2-H), 4.96 (d,
broad, J=22.8 Hz, 1H, 6-H), 5.14 (d, J=13.0 Hz, 1H, PhCH2O), 5.19
(d, J=13.0 Hz, 1H, PhCH2O), 6.06 (d, broad, J=32.9 Hz, 1H, NH),
H
benzyl) 7.27–7.39 (m, 3H, 3-Hbenzyl, 4-Hbenzyl, 5-Hbenzyl), 11.90 (s, 1H,
OH). A signal for the NÀ H of the amide cannot be detected. 13C
NMR (300 MHz, CDCl3): δ (ppm)=19.1 (1C, C-3), 43.1 (1C, NHCH2Ar),
50.0 (1C, C-6), 51.8 (1C, CO2CH3), 55.4 (1C, ArOCH3), 57.0 (1C, C-2),
60.2 (1C, PhCH2N), 95.2 (1C, C-4), 114.3 (2C, C-3PMB, C-5PMB), 127.1
(2C, C-2phenyl, C-6phenyl), 127.8 (1C, C-1PMB), 128.75 (1C, C-4phenyl),
128.76 (2C, C-3phenyl, C-5phenyl), 129.3 (2C, C-2PMB, C-6PMB), 137.5 (1C, C-
1
phenyl), 159.2 (1C, C-4PMB), 167.6 (1C, CO2CH3), 171.1 (1C, C-5), 172.1
(1C, CONH). FT-IR: v˜ (cmÀ 1)=3378 (m, v, OÀ H), 3285 (m, v, NÀ H,
amide), 3062 (w, v, CÀ H, arom.), 2952 (m, v, CÀ H, alkyl), 1732 (s, v,
C=O, ester), 1666 (s, v, C=O, imide), 817 (m, δ, CÀ H, para-substituted
arom.), 735, 699 (m, δ, CÀ H, mono-substituted arom.). MS (APCI):
calcd. for C23H26N2O5H+ 411.1914, found 411.1949.
6.83 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.12 (d, J=8.8 Hz, 2H, 2-HPMB
,
6-HPMB), 7.27–7.41 (m, 5H, Hphenyl), 11.96 (s, 1H, OH). 13C NMR
(300 MHz, CDCl3): δ (ppm)=22.6 (1C, C-3), 43.2 (1C, C-6), 43.4 (1C,
NHCH2Ar), 52.0 (1C, CO2CH3), 52.8 (1C, C-2), 55.4 (1C, ArOCH3), 68.4
(1C, PhCH2O), 95.1 (1C, C-4), 110.1 (1C, C-5), 114.3 (2C, C-3PMB, C-
Ethyl 3-(1-benzoyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl)
propanoate (25b)
A solution of the imide 12b (155 mg, 0.46 mmol) in THF (10 mL)
5
4
PMB), 128.2 (2C, C-2phenyl, C-6phenyl), 128.6 (1C, C-1PMB), 128.7 (1C, C-
phenyl), 128.8 (2C, C-3phenyl, C-5phenyl), 129.0 (2C, C-2PMB, C-6PMB), 135.8
°
was cooled to À 78 C and a freshly prepared potassium diisopropy-
lamide solution (KDA, 1 M in THF, 0.46 mL, 0.46 mmol) was added.
(1C, C-1phenyl), 159.2 (1C, C-4PMB), 165.2 (1C, OCON), 169.7 (1C,
CO2CH3), 171.7 (1C, CONH). FT-IR: v˜ (cmÀ 1)=3331 (m, v, OÀ H), 3067
(w, v, CÀ H, arom.), 2954 (m, v, CÀ H, alkyl), 1747 (s, v, C=O, ester),
1704 (s, v, C=O, carbamate), 1665 (s, v, C=O, imide), 808 (m, δ, CÀ H,
para-substituted arom.), 734, 698 (m, δ, CÀ H, mono-substituted
After 30 min ethyl acrylate (100 μL, 0.92 mmol) was added. The
°
reaction mixture was stirred for 2 h at À 78 C, then warmed to rt
and stirred for additional 14 h. Then an excess of 1 M HCl solution
was added. The solvent of the mixture was removed in vacuum, the
residue was dissolved in CH2Cl2 and washed with water (4×). The
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combined organic layers were dried (Na2SO4) and the solvent was
removed in vacuo. The residue was purified by fc (cyclohexane:
ethyl acetate=3:1, ∅=2.5 cm, l=12.0 cm, V=20 mL) to obtain a
pale yellow oil. (Rf 0.40, cyclohexane:ethyl acetate=1:1). Yield
30 mg (15%). C24H26N2O6 (438.5). 1H NMR (400 MHz, CDCl3): δ (ppm)
=1.27 (t, J=7.1 Hz, 3H, OCH2CH3), 2.20 (s, broad, 2H, 3-CH2), 2.47 (s,
broad, 2H, 2-CH2), 3.79 (s, 3H, OCH3), 4.04–4.15 (m, 2H, OCH2CH3),
4.25 (s, broad, 1H, NCHCO), 4.86 (d, J=13.7 Hz, 1H, NCH2Ph), 4.91
(d, J=13.8 Hz, 1H, NCH2Ph), 6.83 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB),
7.31 (d, J=8.8 Hz, 2H, 2-HPMB, 6-HPMB), 7.35 (dd, J=8.1/1.4 Hz, 2H, 3-
Hbenzoyl, 5-Hbenzoyl), 7.40–7.52 (m, 3H, 2-Hbenzoyl, 4-Hbenzoyl, 6-Hbenzoyl).
The signals for the CH2 protons of the piperazine ring appear as
very broad signals and are therefore not given. 13C NMR (400 MHz,
CDCl3): δ (ppm)=14.3 (1C, OCH2CH3), 29.9 (1C, C-1), 32.1 (1C, C-2),
42.6 (1C, NCH2Ar), 52.8 (1C, NCH2CO), 55.4 (1C, OCH3), 60.6 (1C,
NCHCO), 61.1 (1C, OCH2CH3), 114.0 (2C, C-3PMB, C-5PMB), 127.4 (2C, C-
organic layers were dried (Na2SO4) and the solvent was evaporated
in vacuum. The residue was purified by fc (cyclohexane:ethyl
acetate=19:1, ∅=4.0 cm, l=9.5 cm, V=20 mL) to obtain two pale
yellow oils. (Rf 0.58, cyclohexane:ethyl acetate=1:1): Pale yellow
oil. Yield 0.97 g (61%). C22H24N2O3 (364.4). 1H NMR (300 MHz, CDCl3):
δ (ppm)=2.62 (m, 2H, CHCH2CH=CH2), 3.38 (d, 17.9 Hz, 1H, 5-H),
3.54 (t, J=6.9 Hz, 1H, 3-Hpiperazine-2,6-dione), 3.63 (d, J=13.1 Hz, 1H,
NCH2Ph), 3.72 (d, J=13.5 Hz, 1H, NCH2Ph), 3.72 (d, J=17.8 Hz, 1H,
5-H), 3.79 (s, 3H, OCH3), 4.83 (d, J=13.7 Hz, 1H, NCH2Ar), 4.91 (d, J=
13.7 Hz, 1H, NCH2Ar), 5.08–5.12 (m, 2H, CHCH2CH=CH2), 5.70–5.87
(m, 1H, CHCH2CH=CH2), 6.83 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB),
7.18–7.25 (m, 2H, 2-Hbenzyl, 6-Hbenzyl), 7.27–7.36 (m, 3H, 3-Hbenzyl, 4-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
H
benzyl, 5-Hbenzyl), 7.33 (d, J=8.7 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR
(400 MHz, CDCl3): δ (ppm)=33.2 (1C, CHCH2CH=CH2), 41.8 (1C,
NCH2Ar), 51.7 (1C, NCH2CO), 55.4 (1C, OCH3), 58.2 (1C, NCH2Ph), 63.3
(1C, NCHCO), 113.9 (2C, C-3PMB, C-5PMB), 118.1 (1C, CHCH2CH=CH2),
128.1 (1C, C-1PMB), 128.8 (2C, C-2benzyl, C-6benzyl), 129.1 (2C, C-3benzyl, C-
2
benzoyl, C-6benzoyl), 128.5 (1C, C-1PMB), 129.1 (2C, C-3benzoyl, C-5benzoyl),
130.6 (1C, C-4benzoyl), 131.1 (2C, C-2PMB, C-6PMB), 133.4 (1C, C-1benzoyl),
159.4 (1C, C-4PMB), 166.5 (1C, CObenzoyl), 167.4 (1C, NCH2CO), 170.6
(1C, NCH2CO), 177.4 (1C, CH2CO2). MS (EI): 438 [M+, 20], 333 [(M–
C6H5CO)+, 64], 121 [H3COC6H4CH2+, 100].
5benzyl), 129.4 (1C, C-4benzyl), 130.6 (2C, C-2PMB, C-6PMB), 133.5 (1C,
CHCH2CH=CH2), 136.4 (1C, C-1benzyl), 159.1 (1C, C-4PMB), 170.1 (1C,
NCH2CO), 172.0 (1C, NCHCO). FT-IR: v˜ (cmÀ 1)=3064 (w, v, CÀ H,
arom.), 2933 (w, v, CÀ H, alkyl), 1729 (m, v, C=O, imide), 1677 (s, v,
C=O, imide), 821 (m, δ, CÀ H, para-substituted arom.), 737, 700 (m,
δ, CÀ H, mono-substituted arom.). MS (EI): m/z=365 [(M+H)+, 100].
HPLC: purity 98.2%, tR =22.17 min.
Methyl
1-benzoyl-2-(4-methoxybenzylcarbamoyl)-4-meth-
yl-5-oxopiperidine-4-carboxylate (26b)
3-Allyl-1-benzyl-4-(4-methoxybenzyl)piperazine-2,6-dione (28)
A solution of the amide 24b (312 mg, 0.73 mmol) in THF (20 mL)
A solution of imide 17 (22.1 g, 68 mmol, 1 eq) in dry THF (500 mL)
°
was cooled to À 78 C and 0.5 M KHMDS-solution in THF (1.47 mL,
°
was cooled down to À 78 C and a 1 M LiHMDS-solution in THF
0.73 mmol) was added. After 60 min CH3I (181 μL, 2.57 mmol) was
(72 mL, 72 mmol, 1.05 eq) was added. After 1 h, allyl bromide
(7.1 mL, 82 mmol, 1.2 eq) was added. The reaction mixture was
°
added. The reaction mixture was stirred for 2 h at À 78 C and then
warmed to rt over 15 h. The solvent was removed in vacuum and
the residue was purified by fc (cyclohexane:ethyl acetate=8:2, ∅=
3.0 cm, l=8.5 cm, V=20 mL) to obtain a colorless oil. (Rf 0.48,
cyclohexane:ethyl acetate=3:7): Colorless oil. Yield 107 mg (33%).
°
stirred at À 78 C for 2 h and then warmed up to rt overnight. The
reaction was stopped with an excess of saturated NaHCO3 solution.
The solvent was removed in vacuo and the residue was dissolved in
CH2Cl2. The CH2Cl2 solution was washed with saturated NaHCO3
solution (4×) and the organic solvent was evaporated in vacuo. The
residue was purified by fc (cyclohexane:ethyl acetate=95:5!
83:17). (Rf 0.62, cyclohexane:ethyl acetate=2:1). Pale yellow solid,
1
C24H26N2O6 (438.5). H NMR (400 MHz, CDCl3): δ (ppm)=1.42 (s, 3H,
CCH3), 2.46 (dd, J=14.7/10.3 Hz, 1H, 3-CH2), 2.64 (dd, J=14.7/
8.6 Hz, 1H, 3-CH2), 3.75 (s, 3H, CO2CH3), 3.80 (s, 3H, ArOCH3), 4.00 (d,
J=19.0 Hz, 1H, 6-CH2), 4.33 (d, J=18.7 Hz, 1H, 6-CH2), 4.36 (dd,
14.4/5.9 Hz, 1H, NHCH2Ar), 4.44 (dd, J=14.6/6.0 Hz, 1H, NHCH2Ar),
5.24 (t, J=9.4 Hz, 1H, 2-CH), 6.86 (d, J=8.6 Hz, 2H, 3-HPMB, 5-HPMB),
6.99 (s, broad, 1H, NH), 7.19 (d, J=8.5 Hz, 2H, 2-HPMB, 6-HPMB), 7.24–
mp 58–60 C, yield 16.62 g (67%). C22H24N2O3 (364.4). 1H NMR
°
(400 MHz, CDCl3): δ (ppm)=2.56–2.75 (m, 2H, CHCH2CH=CH2), 3.44
(d, J=17.9 Hz, 1H, NCH2CO), 3.59 (t, J=6.9 Hz, 1H, CHCH2CH=CH2),
3.65 (d, J=12.9 Hz, 1H, NCH2PhOMe), 3.70 (d, J=12.9 Hz, 1H,
NCH2PhOMe), 3.76 (d, J=17.9 Hz, 1H, NCH2CO), 3.80 (s, 3H, OCH3),
4.91 (d, J=13.9 Hz, 1H, NCH2Ph), 4.96 (d, J=13.9 Hz, 1H, NCH2Ph),
5.09 (d, J=11.5 Hz, 1H, CHCH2CH=CH2), 5.10 (d, J=15.5 Hz, 1H,
CHCH2CH=CH2), 5.70–5.85 (m, 1H, CHCH2CH=CH2), 6.85 (d, J=
8.6 Hz, 2H, 3-CHPMB, 5-CHPMB), 7.14 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-
CHPMB), 7.24–7.28 (m, 1H, 4-CHbenzyl), 7.28–7.33 (m, 2H, 3-CHbenzyl, 5-
CHbenzyl), 7.34–7.39 (m, 2H, 2-CHbenzyl, 6-CHbenzyl). 13C NMR (101 MHz,
CDCl3): δ (ppm)=33.1 (1C, CHCH2CH=CH2), 42.5 (1C, NCH2Ph), 51.3
(1C, NCH2CO), 55.5 (1C, OCH3), 57.7 (1C, NCH2PhOMe), 62.9 (1C,
CHCH2CH=CH2), 114.3 (2C, C-3PMB, C-5PMB), 118.4 (1C, CHCH2CH=
CH2), 127.2 (1C, C-1PMB), 127.8 (1C, C-4benzyl), 128.6 (2C, C-3benzyl, C-
5benzyl), 129.0 (2C, C-2benzyl, C-6benzyl), 130.6 (2C, C-2PMB, C-6PMB), 133.1
(1C, CHCH2CH=CH2), 136.9 (1C, C-1benzyl), 159.7 (1C, C-4PMB), 169.4
(1C, NCH2CO), 171.3 (1C, NCHCO). IR (neat): v˜ (cmÀ 1)=3066 (C-
7.28 (m, 2H, 3-Hbenzoyl, 5-Hbenzoyl), 7.38–7.47 (m, 3H, 2-Hbenzoyl, 4-Hbenzoyl
,
6-Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=21.2 (1C, CCH3), 31.2
(1C, C-3), 43.3 (1C, NCH2Ar), 51.6 (1C, C-5), 53.1 (1C, CO2CH3), 53.5
(1C, C-4), 53.7 (1C, C-2), 55.5 (1C, ArOCH3), 114.3 (2C, C-3PMB, C-5PMB),
127.1 (2C, C-2benzoyl, C-6benzoyl), 128.9 (1C, C-1PMB), 129.0 (2C, C-3benzoyl
,
C-5benzoyl), 130.2 (1C, C-4benzoyl), 130.8 (2C, C-2PMB, C-6PMB), 133.1 (1C,
C-1benzoyl), 159.2 (1C, C-4PMB), 169.3 (1C, CObenzoyl), 171.5 (1C, CO2CH3),
171.8 (1C, CONH), 202.3 (1C, COketone). FT-IR: v˜ (cmÀ 1)=3309 (m, v,
NÀ H, amide), 3062 (w, v, CÀ H, arom.), 2936 (m, v, CÀ H, alkyl), 1726
(s, v, C=O, ester), 1644 (s, v, C=O, amide), 819 (m, δ, CÀ H, para-
substituted arom.), 728, 701 (m, δ, CÀ H, mono-substituted arom.).
MS (EI): 438 [M+, 12], 302 [(M-H3COC6H4CH2NH)+, 100]. HPLC:
purity 82.3%, tR =18.65 min.
3-Allyl-4-benzyl-1-(4-methoxybenzyl)piperazine-2,6-dione (27)
H
arom), 2951 (C-Haliph), 1732 and 1670 (C=O), 721 (C-Harom). MS (APCI):
m/z=365.1882 (calcd. 365.1860 for C22H25N2O3 [M+H]+). Purity
(HPLC): 97.6% (tR =23.5 min).
A solution of the imide 12c (1.42 g, 4.38 mmol) in THF (30 mL) was
°
cooled down to À 78 C and a 1 M LiHMDS-solution in THF (4.38 mL,
5.26 mmol) was added. After 30 min, allyl bromide (0.46 mL,
°
0.40 mmol) was added. The reaction mixture was stirred at À 78 C
4-Benzyl-3-(3-hydroxypropyl)-1-(4-methoxybenzyl)
piperazine-2,6-dione (29)
for 2 h and then warmed up to rt overnight. The reaction was
stopped with an excess of saturated NaHCO3 solution. The solvent
was removed in vacuum and the residue was dissolved in CH2Cl2
and washed with saturated NaHCO3 solution (4×). The combined
The allyl compound 27 (0.89 g, 2.45 mmol) was dissolved in THF
(100 mL). Under N2 atmosphere, 9-borabicyclo[3.3.1]nonane (0.5 M
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solution, 9.81 mL, 4.91 mmol) was slowly added. The solution was
stirred overnight. On the next morning again 9-borabicyclo[3.3.1]
nonane (0.5 M solution, 3.68 mL, 1.84 mmol) was slowly added to
transform 27 completely. 90 min later the solution was cooled to
NMR (101 MHz, DMSO-d6): δ (ppm)=24.6 (1C, CH2CH2CH2OH), 28.7
(1C, CH2CH2CH2OH), 41.3 (1C, NCH2Ph), 50.4 (1C, NCH2CO), 55.0 (1C,
OCH3), 56.5 (1C, NCH2PhOMe), 60.01 (1C, CH2CH2CH2OH), 61.9 (1C,
NCHCO), 113.8 (2C, C-3PMB, C-5PMB), 127.1 (1C, C-4benzyl), 127.3 (2C, C-
1
2
3
4
5
6
7
8
9
°
À 25 C and then NaOH (2 M solution, 3.68 mL, 7.36 mmol) was
2benzyl, C-6benzyl), 128.3 (2C, C-3benzyl, C-5benzyl), 128.9 (1C, C-1PMB), 130.0
added while vigorously stirring. After 15 min H2O2 (30% solution,
2.79 mL, 24.5 mmol) was added. The mixture was stirred for further
(2C, C-2PMB, C-6PMB), 137.2 (1C, C-1benzyl), 158.7 (1C, C-4PMB), 170.1(1C,
NCH2CO), 172.7 (1C, NCHCO). IR (neat): v˜ (cmÀ 1)=3390 (OH), 2935
(C-Haliph), 1728 and 1674 (C=O), 817 and 698 (C-Harom). MS (APCI):
m/z=383.1957 (calcd. 365.1965 for C22H27N2O4 [M+H]+). Purity
(HPLC): 99.7% (tR =19.8 min).
°
45 min at À 25 C and subsequently for 60 min at rt. Then it was
°
warmed to 40 C to destroy the excess of H2O2. When the formation
of gas while cooling to rt was finished, the solution was poured
into H2O/CH2Cl2 and extracted with CH2Cl2 (4×). The combined
organic layers were dried (Na2SO4) and the solvent was evaporated
in vacuum. The residue was purified by fc (cyclohexane:ethyl
acetate=8:2!1:1, ∅=3.0 cm, l=10.0 cm, V=20 mL) to obtain a
colorless oil. (Rf 0.16, cyclohexane:ethyl acetate=1:1). Yield 0.88 g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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49
50
51
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55
56
57
3-[1-Benzyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl]
propanal (31)
The primary alcohol 29 (0.77 g, 2.0 mmol) was dissolved in CH2Cl2
(50 mL) and Dess-Martin-Periodinane (1.02 g, 2.4 mmol) was added.
The mixture was stirred at rt for 2 h. Then NaOH (2 M solution,
30 mL) was added. When the mixture was clear again the mixture
was poured into CH2Cl2/saturated NaHCO3 solution and extracted
with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4)
and the solvent was removed in vacuum. The residue was purified
by fc (cyclohexane:ethyl acetate=9:1!8:2, ∅=3.0 cm, l=9.5 cm,
V=20 mL) to obtain a colorless oil. (Rf 0.42, cyclohexane:ethyl
acetate=1:1). Yield 0.66 g (87%). C22H24N2O4 (380.4). 1H NMR
(300 MHz, CDCl3): δ (ppm)=2.02–2.27 (m, 2H, CH2CH2CHO), 2.55 (t,
J=6.8 Hz, 2H, CH2CH2CHO), 3.38 (d, J=17.6 Hz, 1H, NCH2Ph), 3.41
(dd, J=6.8/2.4 Hz, 1H, 2-H), 3.64 (s, 2H, 5-H), 3.71 (d, J=18.0 Hz, 1H,
NCH2Ph), 3.79 (s, 3H, OCH3), 4.84 (d, J=13.7 Hz, 1H, NCH2Ar), 4.90
(d, J=13.8 Hz, 1H, NCH2Ar), 6.84 (d, J=8.6 Hz, 2H, 3-HPMB, 5-HPMB),
1
(94%). C22H26N2O4 (382.5). H NMR (400 MHz, CDCl3): δ (ppm)=1.72
(q, J=13.1/6.6 Hz, 2H, CH2CH2CH2OH), 1.91–1.99 (m, 2H,
CH2CH2CH2OH), 3.44 (d, J=18.0 Hz, 1H, NCH2Ph), 3.52 (t, J=7.0 Hz,
1H, 3-Hpiperazine-2,6-dione), 3.53–3.69 (m, 2H, CH2OH), 3.69 (s, 2H,
NCH2CO2), 3.75 (d, J=18.0 Hz, 1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.85
(d, J=13.7 Hz, 1H, NCH2Ar), 4.90 (d, J=13.7 Hz, 1H, NCH2Ar), 6.84
(d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.20 (dd, J=7.7/1.6 Hz, 2H, 2-
Hbenzyl, 6-Hbenzyl), 7.28–7.36 (m, 3H, 3-Hbenzyl, 4-Hbenzyl, 5-Hbenzyl), 7.33 (d,
J=8.7 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=
26.0 (1C, CH2CH2CH2OH), 29.4 (1C, CH2CH2CH2OH), 41.7 (1C, NCH2Ar),
50.9 (1C, NCH2CO), 55.4 (1C, OCH3), 58.7 (1C, NCH2Ph), 62.4 (1C,
NCHCO), 63.4 (1C, CH2CH2CH2OH), 114.0 (2C, C-3PMB, C-5PMB), 128.2
(1C, C-1PMB), 128.9 (2C, C-2benzyl, C-6benzyl), 129.3 (2C, C-3benzyl, C-5benzyl),
129.3 (1C, C-4benzyl), 130.6 (2C, C-2PMB, C-6PMB), 136.0 (1C, C-1benzyl),
159.2 (1C, C-4PMB), 169.7 (1C, NCH2CO), 172.7 (1C, NCHCO). FT-IR: v˜
(cmÀ 1)=3454 (m, v, OÀ H, alcohol), 3062 (w, v, CÀ H, arom.), 2931 (m,
v, CÀ H, alkyl), 1727 (s, v, C=O, imide), 1674 (s, v, C=O, imide), 822
7.17 (d, J=7.7 Hz, 2H, 2-Hbenzyl, 6-Hbenzyl), 7.27–7.37 (m, 3H, 3-Hbenzyl
,
4-Hbenzyl, 5-Hbenzyll), 7.32 (d, J=8.7 Hz, 2H, 2-HPMB, 6-HPMB), 9.77 (s, 1H,
CHO). 13C NMR (400 MHz, CDCl3): δ (ppm)=21.6 (1C, CH2CH2CHO),
40.0 (1C, CH2CH2CHO), 41.7 (1C, NCH2Ar), 50.9 (1C, NCH2CO), 55.3
(m, δ, CÀ H, para-substituted arom.), 736, 700 (m, δ, CÀ H, mono-
+
substituted arom.). MS (EI): m/z (%)=382 [M+, 40], 91 [PhCH2
100]. HPLC: purity 99.1%, tR =19.19 min.
,
(1C, OCH3), 58.8 (1C, NCH2Ph), 62.4 (1C, NCHCO), 113.9 (2C, C-3PMB
,
C-5PMB), 128.1 (1C, C-1PMB), 128.8 (2C, C-2benzyl, C-6benzyl), 129.1 (2C, C-
3benzyll, C-5benzyl), 129.2 (1C, C-4benzyl), 130.5 (2C, C-2PMB, C-6PMB), 136.2
(1C, C-1benzyl), 159.1 (1C, C-4PMB), 169.9 (1C, NCH2CO), 172.1 (1C,
NCHCO), 200.7 (1C, CHO). FT-IR: v˜ (cmÀ 1)=3067 (w, v, CÀ H, arom.),
2929 (m, v, CÀ H, alkyl), 1731 (s, v, C=O, aldehyde), 1677 (s, v, C=O,
imide), 819 (m, δ, CÀ H, para-substituted arom.), 745, 701 (m, δ, CÀ H,
mono-substituted arom.). MS (APCI): calcd. for C22H24N2O4H+
381.1809, found 381.1813. HPLC: purity 91.2%, tR =19.87 min.
1-Benzyl-3-(3-hydroxypropyl)-4-(4-methoxybenzyl)
piperazine-2,6-dione (30)
The allyl derivative 28 (9.1 g, 25 mmol, 1 eq) was dissolved in THF
(400 mL). Under N2 atmosphere, a 0.5 M solution of 9-borabicyclo
[3,3,1]nonane in THF (0.5 M, 100 mL, 50 mmol) was slowly added.
The solution was stirred overnight. After 20 h, again 9-BBN in THF
(0.5 M, 38 mL, 19 mmol) was slowly added to transform 28
3-[4-Benzyl-1-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl]
propanal (32)
°
completely. 90 min later the solution was cooled to À 25 C and
then 2 M NaOH (37 mL, 75 mmol) was added while vigorously
stirring. After 15 min H2O2 (30%, 26 mL, 250 mmol) was added. The
The primary alcohol 30 (5.15 g, 13.5 mmol, 1 eq) was dissolved in
CH2Cl2 (250 mL) and Dess Martin Periodinane (6.85 g, 16.2 mmol,
1.2 eq) was added. The mixture was stirred at rt for 3 h. Then 2 M
NaOH (300 mL) was added. When the mixture became clear again,
it was poured into CH2Cl2/saturated NaHCO3 solution and extracted
with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4)
and the solvent was evaporated in vacuo. The residue was purified
by fc (cyclohexane: ethyl acetate=91:9!75:25, ∅=4 cm, I=
10 cm, V=25 mL). (Rf 0.34, cyclohexane:ethyl acetate =2:1): Color-
less oil, yield 4.8 g (94%). C22H24N2O4 (380.4). 1H NMR (600 MHz,
DMSO-d6): δ (ppm)=1.96–2.03 (m, 1H, CHCH2CH2CHO), 2.15–2.22
(m, 1H, CHCH2CH2CHO), 2.51 (t, J=6.8 Hz, 2H, CHCH2CH2CHO), 3.39
(d, J=17.8 Hz, 1H, NCH2CO), 3.53 (dd, J=9.8, 5.2 Hz, 1H, NCHCO),
3.62 (d, J=13.1 Hz, 1H, NCH2PhOMe), 3.66 (d, J=13.1 Hz, 1H,
NCH2PhOMe), 3.74 (s, 3H, OCH3), 3.84 (d, J=17.8 Hz, 1H, NCH2CO),
4.79 (s, 2H, NCH2Ph), 6.89 (d, J=8.6 Hz, 2H, 3-CHPMB, 5-CHPMB), 7.13
°
mixture was stirred for further 45 min at À 25 C and subsequently
for 60 min at rt. Then Na2S2O3 was added to destroy the excess of
H2O2. After the mixture was stirred for 30 min, most of the solvent
was removed in vacuo. The residue was poured into CH2Cl2/
saturated NaHCO3 solution and the mixture was extracted with
CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and
the solvent was evaporated in vacuo. The residue was purified by fc
(cyclohexane:ethyl acetate=91:9!50:50, ∅=5 cm, I=14 cm, V=
35 mL). (Rf 0.34, cyclohexane:ethyl acetate=50:50): Colorless oil,
1
yield 5.2 g (55%). 22H26N2O4 (382.5). H NMR (400 MHz, DMSO-d6): δ
(ppm)=1.40–1.60 (m, 2H, CH2CH2CH2OH), 1.93–1.70 (m, 2H,
CH2CH2CH2OH), 3.37 (q, J=6.1 Hz, 2H, CH2CH2CH2OH), 3.43 (d, J=
18.0 Hz, 1H, NCH2CO), 3.48 (dd, J=8.9/6.0 Hz, 1H, NCHCO), 3.62 (d,
J=13.1 Hz, 1H, NCH2PhOMe), 3.67 (d, J=13.0 Hz, 1H, NCH2PhOMe),
3.74 (s, 3H, OCH3), 3.81 (d, J=17.8 Hz, 1H, NCH2CO), 4.40 (t, J=
5.2 Hz, 1H, CH2CH2CH2OH), 4.80 (d, J=15.1 Hz, 1H, NCH2Ph), 4.81 (d,
J=15.1 Hz, 1H, NCH2Ph), 6.90 (d, J=8.7 Hz, 2H, 3-CHPMB, 5-CHPMB),
(d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.22 (d, J=6.9 Hz, 2H, 2-CHbenzyl
,
6-CHbenzyl), 7.25 (t, J=7.4 Hz, 1H, 4-CHbenzyl), 7.32 (t, J=7.6 Hz, 2H, 3-
CHbenzyl, 5-CHbenzyl), 9.65–9.63 (t, J=1.4 Hz, 1H, CHCH2CH2CHO). The
7.15 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.21–7.26 (m, 3H, 2-CHbenzyl
,
4-CHbenzyl, 6-CHbenzyl), 7.32 (t, J=7.2 Hz, 2H, 3-CHbenzyl, 5-CHbenzyl). 13C
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peak at 2.51 ppm is partly overlapping with the signal for DMSO.
13C NMR (151 MHz, DMSO-d6): δ (ppm)=21.2 (1C, CHCH2CH2CHO),
39.5 (1C, CHCH2 CH2CHO), 41.3 (1C, NCH2Ph), 49.9 (1C, NCH2CO),
55.0 (1C, OCH3), 56.9(1C, NCH2PhOMe), 61.6 (1C, NCHCO), 113.9 (2C,
C-3PMB, C-5PMB), 127.1 (1C, C-4benzyl), 127.4 (2C, C-2benzyl, C-6benzyl),
128.4 (2C, C-3benzyl, C-5benzyl), 128.7 (1C, C-1PMB), 130.1 (2C, C-2PMB, C-
Colorless oil of both diastereomers, yield 3.6 g (90%). C26H33N3O4S
(483.6). 1H NMR (600 MHz, DMSO-d6): δ (ppm)=1.07 (s, 9×0.5H,
(CH3)3C),1.08 (s, 9×0.5H, (CH3)3C), 2.01–2.10 (m, 1H,
CHCH2CH2CH=N), 2.17–2.26 (m, 1H, CHCH2CH2CH=N), 2.58–2.65 (m,
2H, CHCH2CH2CH=N), 3.44 (d, J=17.7 Hz, 1H, NCH2CO), 3.55 (dd, J=
9.6/5.3 Hz, 0.5H, NCHCO), 3.60–3.65 (m, 1.5H, NCHCO (0.5H),
NCH2PhOMe (1H)), 3.68 (d, J=13.0 Hz, 0.5H, NCH2PhOMe), 3.69 (d,
J=13.1 Hz, 0.5H, NCH2PhOMe), 3.735 (s, 3×0.5H, OCH3), 3.737 (s, 3×
0.5H, OCH3), 3.898 (d, J=17.8 Hz, 0.5H, NCH2CO), 3.901 (d, J=
17.8 Hz, 0.5H, NCH2CO), 4.80 (s, 2H, NCH2Ph), 6.88 (d, J=8.7 Hz, 2×
0.5H, 3-CHPMB, 5-CHPMB), 6.89 (d, J=8.7 Hz, 2×0.5H, 3-CHPMB, 5-
CHPMB), 7.14 (d, J=8.6 Hz, 2×0.5H, 2-CHPMB, 6-CHPMB), 7.15 (d, J=
8.5 Hz, 2×0.5H, 2-CHPMB, 6-CHPMB), 7.20–7.26 (m, 3H, 2-CHbenzyl, 4-
CHbenzyl, 6-CHbenzyl), 7.32 (t, J=7.4 Hz, 2H, 3-CHbenzyl, 5-CHbenzyl), 7.96
(t, J=3.9 Hz, 0.5H, CHCH2CH2CH=N), 7.98 (t, J=3.9 Hz, 0.5H,
CHCH2CH2CH=N). Ratio of diastereomers 1:1. 13C NMR (151 MHz,
1
2
3
4
5
6
7
8
9
6
PMB), 137.1 (1C, C-1benzyl), 158.7 (1C, C-4PMB), 170.1 (1C, NCH2CO),
172.2(1C, NCHCO), 202.4 (CH=O). IR (neat): v˜ (cmÀ 1)=2835 (C-Haliph),
1720 and 1674 (C=O), 821and 698 (C-Harom). MS (APCI): m/z=
383.1768 (calcd. 381.1809 for C22H25N2O4 [M+H]+). Purity (HPLC):
98.3% (tR =20.7 min).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
(S)-N-{(E)-3-[(S)- and
(R)-1-Benzyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl]
propylidene}- 2-methylpropane-2-sulfinamide (33)
DMSO-d6):
δ
(ppm)=21.8 (3C, (CH3)3C), 23.7/23.8 (1C,
The aldehyde 31 (0.16 g, 0.42 mmol) was dissolved in THF
(10 mL).(S)-2-methylpropane-2-sulfinamide (0.06 g, 0.49 mmol) and
titanium(IV) ethanolate (0.20 mL) were added to this mixture, which
was stirred for 3 h at rt. Then the mixture was poured into CH2Cl2/
saturated NaHCO3 solution and was extracted with CH2Cl2 (4×). The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuum. The residue was purified by fc (cyclohexane:
ethyl acetate=8:2!1:1, ∅=3.0 cm, l=9.5 cm, V=20 mL) to obtain
a colorless oil of both diastereomers. (Rf 0.36, cyclohexane:ethyl
acetate=1:1). Yield 0.17 g (82%). C26H33N3O4S (483.6). 1H NMR
(400 MHz, CDCl3): δ (ppm)=1.166 (s, 9×0.5H, C(CH3)3), 1.169 (s, 9×
0.5H, C(CH3)3), 2.04–2.30 (m, 2H, CH2CH2CH=N), 2.50–2.75 (m, 2H,
CH2CH2CH=N), 3.42 (d, J=18.0 Hz, 1H, PhCH2N), 3.50 (dd, J=8.2/
6.0 Hz, 0.5H, NCHCO), 3.57 (dd, J=8.2/6.0 Hz, 0.5H, NCHCO), 3.65 (s,
2H, NCH2CO), 3.72 (d, J=17.9 Hz, 0.5 H, PhCH2N), 3.73 (d, J=
18.0 Hz, 0.5H, PhCH2N), 3.79 (s, 3H, OCH3), 4.85 (d, J=13.7 Hz, 0.5H,
NCH2Ar), 4.86 (d, J=13.8 Hz, 0.5H, NCH2Ar), 4.90 (d, J=13.7 Hz, 1H,
NCH2Ar), 6.84 (d, J=8.7 Hz, 2H, 3-HPMB, 5-HPMB), 7.15–7.24 (m, 2H, 2-
CHCH2CH2CH=N), 31.75/31.76 (1C, CHCH2CH2CH=N), 41.3 (1C,
NCH2Ph), 50.27/50.31 (1C, NCH2CO), 55.0 (1C, OCH3), 55.9/56.0 (1C,
(CH3)3C), 56.8 /56.9 (1C, NCH2PhOMe), 61.3/61.5 (1C, NCHCO), 113.8/
113.9 (2C, C-3PMB, C-5PMB), 127.1 (1C, C-4benzyl), 127.33/127.35 (2C, C-
2
benzyl, C-6benzyl), 128.4 (2C, C-3benzyl, C-5benzyl), 128.7 (1C, C-1PMB),
129.97/130.01 (2C, C-2PMB, C-6PMB), 137.1 (1C, C-1benzyl), 158.7 (1C, C-
PMB), 169.10 /169.14 (1C, CHCH2CH2CH=N), 170.05/170.07 (1C,
NCH2CO), 172.28 /172.31 (1C, NCHCO). IR (neat): v˜ (cmÀ 1)=2958 (C-
aliph), 1728, 1674 and 1620 (C=O), 1342 (S=O), 817and 698 (C-Harom).
4
H
MS (APCI): m/z=484.2347 (calcd. 484.2265 for C26H34N3O4S [M+
H]+). Purity (HPLC): 83.2% (tR =22.9 min).
9-Benzyl-3-(4-methoxybenzyl)-2,4-dioxo-3,9-diazabicyclo[3.3.1]
nonan- 6-yl]-2-methylpropane-2-sulfinamide (35)
A solution of (S)-sulfinylimine 33 (ratio of diastereomers 1:1,
589 mg, 1.22 mmol) in THF (30 mL) was cooled under N2 atmos-
°
phere to À 78 C. Then LiHMDS (1 M solution in THF, 1.82 mL,
H
benzyl, 6-Hbenzyl), 7.27–7.35 (m, 5H, 3-Hbenzyl, 4-Hbenzyl, 5-Hbenzyl, 2-HPMB,
1.82 mmol) was added. After 3 h, the mixture was warmed to rt,
poured into CH2Cl2/saturated NaHCO3 solution and extracted with
CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and
the solvent was removed in vacuum. The residue was purified by fc
(cyclohexane:ethyl acetate=19:1!1:1!100% ethyl acetate, ∅=
3.0 cm, l=9.5 cm, V=20 mL) to obtain two pale oils of the main
diastereomer of 35 and a mixture of the other three diastereomers
of 35. Total yield 386 mg (66%). Main stereoisomer 35a (Rf 0.32,
cyclohexane:ethyl acetate=1:1): Pale yellow oil. Yield 127 mg
(22%). C26H33N3O4S (483.6). 1H NMR (300 MHz, CDCl3): δ (ppm)=
1.24 (s, 9H, C(CH3)3), 1.39–1.48 (m, 1H, 7-CH2),1.63–1.68 (m, 1H, 7-
CH2), 1.70–1.78 (m, 1H, 8-CH2), 1.89–1.99 (m, 1H, 8-CH2), 3.52–3.54
(m, 1H, 1-CH), 3.53 (d, J=13.0 Hz, 1H, NCH2Ph), 3.69 (d, J=13.1 Hz,
1H, NCH2Ph), 3.71–3.75 (m, 1H, 6-CH), 3.79 (s, 3H, OCH3), 3.93 (m,
1H, 5-CH), 4.44 (d, J=9.1 Hz, 1H, NH), 4.88 (s, 2H, NCH2Ar), 6.83 (d,
J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.13–7.20 (m, 2H, 2-Hphenyl, 6-Hphenyl),
7.27–7.34 (m, 3H, 3-Hphenyl, 4-Hphenyl, 5-Hphenyl), 7.36 (d, J=8.7 Hz, 2H,
2-HPMB, 6-HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=22.7 (3C, C
(CH3)3), 23.0 (1C, C-8), 25.3 (1C, C-7), 41.6 (1C, NCH2Ar), 51.9 (1C, C-
6), 55.4 (1C, OCH3), 56.0 (1C, C(CH3)3), 58.3 (1C, C-1), 59.4 (1C,
PhCH2N), 65.9 (1C, C-5), 114.0 (2C, C-3PMB, C-5PMB), 128.2 (1C, C-1PMB),
128.9 (2C, C-2benzyl, C-6benzyl), 129.2 (2C, C-3benzyl, C-5benzyl), 129.3 (1C,
C-4benzyl), 130.8 (2C, C-2PMB, C-6PMB), 136.2 (1C, C-1benzyl), 159.2 (1C, C-
6-HPMB), 8.07 (t, J=3.8 Hz, 0.5H, NH), 8.10 (t, J=3.8 Hz, 0.5H, NH).
Ratio of diastereomers 1:1. 13C NMR (400 MHz, CDCl3): δ (ppm)=
22.5 (0.5 C, CH2CH2CH=N), 22.4 (0.5 C, CH2CH2CH=N), 22.5 (9 C, C
(CH3)3), 24.3 (0.5 C, CH2CH2CH=N), 24.5 (0.5 C, CH2CH2CH=N), 41.7
(1C, NCH2Ar), 51.1 (0.5 C, NCH2CO), 51.3 (0.5 C, NCH2CO), 55.4 (1C,
OCH3), 56.78 (0.5 C, C(CH3)3), 56.82 (0.5 C, C(CH3)3), 58.7 (0.5 C,
NCH2Ph), 58.8 (0.5 C, NCH2Ph), 62.4 (0.5 C, NCHCO), 62.6 (0.5 C,
NCHCO), 114.0 (2C, C-3PMB, C-5PMB), 128.2 (1C, C-1PMB), 128.9 (2C, C-
2
benzyl, C-6benzyl), 129.1 (2C, C-3benzyl, C-5benzyl), 129.3 (1C, C-4benzyl),
130.5 (2C, C-2PMB, C-6PMB), 136.3 (1C, C-1benzyl), 159.2 (1C, C-4PMB),
168.1 (1C, C=N), 169.9 (1C, NCH2CO), 172.2 (2C, NCHCO). FT-IR: v˜
(cmÀ 1)=3063 (w, v, CÀ H, arom.), 2928 (m, v, CÀ H, alkyl), 1724 (m, v,
C=O, imide), 1678 (s, v, C=O, imide), 822 (m, δ, CÀ H, para-
substituted arom.), 745, 702 (m, δ, CÀ H, mono-substituted arom.).
MS (APCI): calcd. for C26H33N3O4H+ 484.2265, found 484.2347. HPLC:
purity 79.2%, tR =21.66 min.
(S)-N-{(E)-3-[(S)- and
(R)-4-Benzyl-1-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl]
propylidene}-2-methylpropane-2-sulfinamide (34)
The aldehyde 32 (3.13 g, 8.2 mmol, 1.0 eq) was dissolved in THF
(200 mL). (S)-2-Methylpropane-2-sulfinamide (1.00 g, 8.2 mmol,
1.0 eq) and titanium(IV) ethanolate (4 mL) were added to this
mixture, which was stirred for 4 h at rt. Then the mixture was
poured into CH2Cl2/saturated NaHCO3 solution and was extracted
with CH2Cl2 for four times. The combined organic layers were dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue was
purified by fc (cyclohexane:ethyl acetate=90:10!67:33, ∅=4 cm,
I=16 cm, V=35 mL). (Rf 0.19, cyclohexane:ethyl acetate=67:33).
4
PMB), 170.5 (1C, NCH2CO), 172.1 (1C, NCHCO). FT-IR: v˜ (cmÀ 1)=3267
(w, v, NÀ H, sulfinamide), 2932 (m, v, CÀ H, alkyl), 1728 (m, v, C=O,
imide), 1674 (s, v, C=O, imide), 818 (m, δ, CÀ H, para-substituted
arom.), 733, 698 (m, δ, CÀ H, mono-substituted arom.). MS (APCI):
calcd. for C26H33N3O4SH+ 484.2265, found 484.2282. HPLC: purity
97.9%, tR =21.74 min. specific rotation: [α]20D = +53.0 (c=0.80;
CH2Cl2).
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N-[-3-Benzyl-9-(4-methoxybenzyl)-2,4-dioxo-3,9-diazabicyclo
[3.3.1]nonan-6-yl]-2-methylpropane-2-sulfinamide (36)
(1RS,5SR,6SR)-3-Benzyl-8-(4-meth-
oxybenzyl)-6-vinyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (39)
1
2
3
4
5
6
7
8
9
A solution of the (S)-sulfinylimine 34 (ratio of diastereomers 1:1,
3.37 g, 7.0 mmol, 1 eq) in THF (150 mL) was cooled down to À 78 C
A solution of 17 (120 mg, 0.37 mmol) in dry THF (4 mL) was cooled
°
°
down to À 78 C and LiHMDS (0.44 mL, 0.44 mmol) was added
under N2 atmosphere. Then LiHMDS (1 M solution in THF, 10.4 mL,
10.4 mmol, 1.5 eq) was added dropwise. After 3 h, the mixture was
warmed to rt. Saturated NaHCO3 was added and the mixture was
extracted with CH2Cl2 (4×). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo. The residue was
purified by fc (cyclohexane : ethyl acetate=90:10!50:50, ∅=
4 cm, I=15 cm, V=35 mL) to obtain a pale yellow oil of the main
diastereomer of 36 and a mixture of the other three diastereomers
of 36. Total yield 2.34 g (69%). Main stereoisomer 36a (Rf 0.47,
cyclohexane:ethyl acetate=50:50): pale yellow oil, yield 0.91 g
slowly. After 90 min, trans-1,4-dibromobut-2-ene (38, 95 mg,
°
0.44 mmol) was added. The reaction was stirred at À 78 C for
90 min and then warmed up to rt for 16 h. Another portion of
°
LiHMDS (0.44 mL, 0.44 mmol) was added at À 78 C and the mixture
was stirred for another 2 h and then warmed up to room temper-
ature overnight. Saturated NaHCO3 solution was added to the
reaction mixture, which was then extracted with CH2Cl2 (4×). The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuo. The residue was purified by column
chromatography (cyclohexane: ethyl acetate=98:2!94:6, ∅=
1.5 cm, l=20 cm, V=10 mL). Rf 0.24, cyclohexane:ethyl acetate=
80:20. Pale yellow oil, yield 30 mg (22%). C23H24N2O3 (376.5). 1H
NMR (600 MHz, CDCl3): δ (ppm)=1.73 (dd, J=13.7/5.5 Hz, 1H, 7-
CH2), 2.64 (ddd, J=13.7/10.6/7.8 Hz, 1H, 7-CH2), 3.30–3.39 (m, 1H, 6-
CH), 3.63 (d, J=12.7 Hz, 1H, NCH2PhOMe), 3.66 (d, J=12.1 Hz, 1H,
NCH2PhOMe), 3.79 (s, 3H, OCH3), 3.82 (d, J=6.9 Hz, 1H, 5-CH), 3.85
(d, J=7.7 Hz, 1H, 1-CH), 4.91 (s, 2H, NCH2Ph), 5.02 (dt, J=10.4/
1.3 Hz, 1H, CH=CH2), 5.05 (dt, J=16.9/1.2 Hz, 1H, CH=CH2), 5.41
(ddd, J=17.1/10.3/7.7 Hz, 1H, CH=CH2), 6.83 (d, J=8.7 Hz, 2H, 3-
CHPMB, 5-CHPMB), 7.06 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.26–7.29
(m, 1H, 4-CHbenzyl), 7.32 (t, J=7.3 Hz, 2H, 3-CHbenzyl, 5-CHbenzyl), 7.44
(d, J=6.9 Hz, 2H, 2-CHbenzyl, 6-CHbenzyl). 13C NMR (151 MHz, CDCl3): δ
(ppm)=31.9 (1C, C-7), 41.8 (1C, NCH2Ph), 43.2 (1C, C-6), 52.8 (1C,
NCH2PhOMe), 55.4 (1C, OCH3), 63.7 (1C, C-1), 68.1 (1C, C-5), 114.2
(2C, C-3PMB, C-5PMB), 118.4 (1C, CH=CH2), 127.6 (1C, C-1PMB), 128.0
(1C, C-4benzyl), 128.6 (2C, C-3benzyl, C-5benzyl), 129.6 (2C, C-2benzyl, C-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
(27%). C26H33N3O4S (483.6). H NMR (400 MHz, DMSO-d6): δ (ppm)=
1.14 (s, 9H, C(CH3)3), 1.47 (tt, J=14.0/4.5 Hz, 1H, 7-CH2), 1.57–1.71
(m, 2H, 7-CH2, 8-CH2), 2.07–2.20 (m, 1H, 8-CH2), 3.50–3.57 (m, 2H, 1-
CH, 6-CH), 3.62 (s, 2H, NCH2PhOMe), 3.73 (s, 4H, 5-CH, OCH3), 4.85 (s,
2H, NCH2Ph), 5.12 (d, J=7.6 Hz, 1H, NH), 6.87 (d, J=8.6 Hz, 2H, 3-
CHPMB, 5-CHPMB), 7.13 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.24–7.31
(m, 3H, 2-CHbenzyl, 4-CHbenzyl, 6-CHbenzyl), 7.38–7.32 (m, 2H, 3-CHbenzyl
,
5-CHbenzyl). 13C NMR (101 MHz, DMSO-d6): δ (ppm)=22.0 (1C, C-8),
22.4 (3C, C(CH3)3), 24.3 (1C, C-7), 41.6 (1C, NCH2Ph), 49.7 (1C, C-6),
55.0 (1C, OCH3), 55.3 (1C, C(CH3)3), 57.5 (1C, NCH2PhOMe)„ 58.2 (1C,
C-1), 64.3 (1C, C-5), 113.8 (2C, C-3PMB, C-5PMB), 127.3 (1C, C-4benzyl),
128.1 (2C, C-2benzyl, C-6benzyl), 128.3 (1C, C-1PMB), 128.4 (2C, C-3benzyl, C-
5
benzyl), 129.8 (2C, C-2PMB, C-6PMB), 137.1 (1C, C-1benzyl), 158.7 (1C, C-
4PMB), 170.7 (1C, C-4), 171.9 (1C, C-2). IR (neat): v˜ (cmÀ 1)=3275
(NÀ H), 2951 (C-Haliph), 1732 and 1678 (C=O), 1346 and 1330 (S=O),
806 and 698 (C-Harom). MS (APCI): m/z=484.2275 (calcd. 484.2265
for C26H34N3O4S [M+H]+). Purity (HPLC): 98.3% (tR =22.8 min).
Specific rotation: [α]20D = +57.1 (c=0.18; CH3CN).
6
1
benzyl), 130.4 (2C, C-2PMB, C-6PMB), 134.3 (1C, CH=CH2), 136.9 (1C, C-
benzyl), 159.6 (1C, C-4PMB), 170.4 (1C, C-4), 172.9 (1C, C-2). IR (neat): v˜
(cmÀ 1)=2959 (C-Haliph), 1732 and 1678 (C=O), 822 and 698 (C-Harom).
MS (APCI): m/z=377.1869 (calcd. 377.1860 for C23H25N2O3 [M+H]+).
Purity (HPLC): 98.7% (tR =23.3 min).
(1RS,5SR,6RS)-9-Benzyl-6-hydroxy-3-(4-meth-
oxybenzyl)-3,9-diazabicyclo[3.3.1]no-nane-2,4-dione (37)
A solution of the aldehyde 31 (100 mg, 0.26 mmol) in THF (10 mL)
3-Benzyl-9-(4-methoxybenzyl)-7-methylene-3,9-diazabicyclo
[3.3.1]nonane-2,4-dione (41)
°
was cooled under N2 atmosphere to À 78 C. Then LiHMDS (1 M
solution in THF, 0.39 mL, 0.39 mmol) was added. After 30 min at
°
À 78 C, the mixture was warmed to rt and stirred at rt for 3 h. The
A solution of 17 (214 mg, 0.66 mmol) in dry THF (5 mL) was cooled
°
mixture was poured into CH2Cl2/saturated NaHCO3 solution and
extracted with CH2Cl2 (4×). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuum. The residue was
purified by fc (cyclohexane:ethyl acetate=9:1, ∅=2.0 cm, l=
9.5 cm, V=20 mL) to obtain a pale yellow oil. (Rf 0.26, cyclohexane:
down to À 78 C and LiHMDS (0.73 mL, 0.73 mmol) was added
slowly. After 30 min, 3-bromo-2-bromomethylprop-1-ene (40b,
°
0.83 μL, 0.73 mmol) was added. The reaction was stirred at À 78 C
for 90 min and then LiHMDS (0.73 mL, 0.73 mmol) was added again.
°
The mixture was stirred at À 78 C for another 2 h and then warmed
1
ethyl acetate=1:1). Yield 10 mg (10%). C22H24N2O4 (380.4). H NMR
up to room temperature overnight. Saturated NaHCO3 solution was
added and THF was removed almost completely in vacuo. The
residue was extracted with ethyl acetate (4×). The combined
organic layers were dried (Na2SO4) and the solvent was evaporated
in vacuo. The residue was purified by column chromatography
(cyclohexane: ethyl acetate=20:1, ∅=1 cm, l=12 cm, V=8 mL). Rf
0.62, cyclohexane:ethyl acetate=2:1. Pale yellow solid, mp 58–
(400 MHz, CDCl3): δ (ppm)=1.07–1.22 (m, 1H, 8-CH2), 1.92–1.99 (m,
2H, 7-CH2), 2.00–2.08 (m, 1H, 8-CH2), 3.53 (t, J=2.8 Hz, 1H, 1-CH),
3.61 (d, J=13.2 Hz, 1H, NCH2Ph), 3.63–3.70 (m, 1H, 5-CH), 3.67 (d,
J=13.0 Hz, 1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.00 (dt, J=14.2/4.0 Hz,
1H, 6-CH), 4.93 (d, J=13.7 Hz, 1H, NCH2Ar), 4.97 (d, J=13.7 Hz, 1H,
NCH2Ar), 6.85 (d, J=8.8 Hz, 2H, 3-HPMB, 5-HPMB), 7.13–7.17 (m, 2H, 2-
60 C, yield 129 mg (52%). C23H24N2O3 (376.5). 1H NMR (600 MHz,
°
H
benzyl, 6-Hbenzyl), 7.27–7.35 (m, 3H, 3-Hbenzyl, 4-Hbenzyl, 5-Hbenzyl), 7.38 (d,
J=8.7 Hz, 2H, 2-HPMB, 6-HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=
26.9 (1C, C-8), 27.8 (1C, C-7), 41.6 (1C, NCH2Ar), 55.4 (1C, OCH3), 59.0
(1C, C-1), 59.1 (1C, PhCH2N), 64.6 (1C, C-5), 68.1 (1C, 6-C), 114.0 (2C,
C-3PMB, C-5PMB), 128.1 (1C, C-1PMB), 128.8 (2C, C-2benzyl, C-6benzyl), 128.9
(2C, C-3benzyl, C-5benzyl), 129.5 (1C, C-4benzyl), 130.8 (2C, C-2PMB, C-6PMB),
136.2 (1C, C-1benzyl), 159.2 (1C, C-4PMB), 171.1 (1C, NCH2CO), 172.5 (1C,
NCHCO). FT-IR: v˜ (cmÀ 1)=3434 (m, v, OÀ H, alcohol), 3062 (w, v,
CÀ H, arom.), 2932 (m, v, CÀ H, alkyl), 1726 (m, v, C=O, imide), 1671
(s, v, C=O, imide), 823 (m, δ, CÀ H, para-substituted arom.), 730, 698
(m, δ, CÀ H, mono-substituted arom.). MS (EI): 380 [M+, 7], 121
[H3COC6H4CH2+, 88], 91 [C6H5CH2+, 100].
CDCl3): δ (ppm)=2.48 (dm, J=13.8 Hz, 2H, 6-CH2, 8-CH2), 2.69 (dm,
J=12.0 Hz, 2H, 6-CH2, 8-CH2), 3.65 (s, 2H, NCH2PhOMe), 3.68–3.71
(m, 2H, 1-CH, 5-CH), 3.80 (s, 3H, OCH3), 4.70 (t, J=2.0 Hz, 2H,
C=CH2), 4.93 (s, 2H, NCH2Ph), 6.84 (d, J=8.6 Hz, 2H, 3-CHPMB, 5-
CHPMB), 7.11 (d, J=8.6 Hz, 2H, 2-CHPMB, 6-CHPMB), 7.24 (t, J=7.3 Hz,
1H, 4-CHbenzyl), 7.29 (t, J=7.3 Hz, 2H, 3-CHbenzyl, 5-CHbenzyl), 7.37 (d,
J=6.9 Hz, 2H, 2-CHbenzyl, 6-CHbenzyl). 13C NMR (151 MHz, CDCl3): δ
(ppm)=36.7 (2C, C-6, C-8), 42.1 (1C, NCH2Ph), 55.4 (1C, OCH3), 58.3
(1C, NCH2PhOMe), 60.3 (2C, C-1, C-5), 114.2 (2C, C-3PMB, C-5PMB),
114.6 (1C, C=CH2), 127.7 (2C, C-1PMB, C-4benzyl), 128.4 (2C, C-3benzyl, C-
5
benzyl), 129.2 (2C, C-2benzyl, C-6benzyl), 130.4 (2C, C-2PMB, C-6PMB), 137.1
(1C, C-1benzyl), 137.7 (1C, C=CH2), 159.6 (1C, C-4PMB), 172.2 (2C, 2×
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C=O). IR (neat): v˜ (cmÀ 1)=2959 and 2936 (C-Haliph), 1670 (C=O), 733
and 694 (C-Harom). MS (APCI): m/z=377.1852 (calcd. 377.1860 for
C23H25N2O3 [M+H]+). Purity (HPLC): 97.9% (tR =22.4 min).
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Open access funding enabled and organized by Projekt DEAL.
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The authors declare no conflict of interest.
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Keywords: bridged piperazines · rigid scaffolds · Dieckmann
cyclization · aldol reactions · medicinal chemistry
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Manuscript received: June 29, 2020
Revised manuscript received: July 6, 2020
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