Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as dipeptide mimics and templates

Article abstract of DOI:10.1039/b908548c

A sequence of Michael addition of a primary amine onto methyl 2-chloro-2-cyclopropylidene-acetate (1), acylation of the adduct with α-bromo acid chlorides under modified Schotten-Baumann conditions and ring-closing twofold nucleophilic substitution on the

Full text of DOI:10.1039/b908548c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as
dipeptide mimics and templates†‡
Michael Limbach,a Alexander V. Lygin,a Vadim S. Korotkov,a Mazen Es-Sayedb and Armin de Meijere*a
Received 30th April 2009, Accepted 27th May 2009
First published as an Advance Article on the web 30th June 2009
DOI: 10.1039/b908548c
A sequence of Michael addition of a primary amine onto methyl 2-chloro-2-cyclopropylidene-acetate
(1), acylation of the adduct with a-bromo acid chlorides under modified Schotten-Baumann conditions
and ring-closing twofold nucleophilic substitution on the thus formed bishalides 3a–e with aliphatic or
aromatic amines according to a very simple protocol with final acid/base extraction or filtration over
silica gel for purification leads to the 3-spirocyclopropanated 5-oxopiperazine-2-carboxylates 2 or in
two cases, after intermolecular transesterification of 2, to bicyclic oxopiperazines 6, with a remarkable
variability of the substituents R1–R3 in 39–99% yields (20 examples). Starting with
a-bromophenylacetic acid chloride, the trans-configured 6-phenyl-5-oxopiperazine-2-carboxylates
are formed preferentially.
adjacent to the cyclopropyl group. Relying on exactly these
reactivities of 1, a new access to a library of spirocyclopropanated
5-oxopiperazinecarboxylates 2 has been developed and is reported
Introduction
Modern medicinal chemistry requires diverse compounds with
rigid backbones bearing pharmacophoric functionalities, since
here.
rigidity helps with the understanding of the conformational re-
quirements for biological activity. Thus, the piperazine and piper-
azinone moieties as present in the 5-oxopiperazine-2-carboxylates
Results and discussion
2 are frequently encountered in a large variety of bioactive
compounds,1 such as metalloproteinase-inhibiting antitumor
agents,2 antiarthritics,3 factor Xa4 and Xa/IIa inhibitors,5 as
well as inhibitors of a1b2 integrin-mediated cell adhesion and
osteoporosis.6 Compounds with a skeleton of type 2 can therefore
be used in the treatment of inflammatory diseases like asthma,
thrombosis, arteriosclerosis and rheumatoid arthritis. Although a
multitude of synthesis approaches to such compounds have been
reported,7 there are only a few reasonably general accesses to this
structural motif, especially few for a combinatorial synthesis.8
As has previously been demonstrated, the multifunc-
tional building block methyl 2-chloro-2-cyclopropylideneacetate
(1),9 for which a second-generation synthesis has recently
been developed,10 provides an easy access to a large vari-
ety of heterocycles11 including octahydro[2H]pyrazino[1,2-a]-
pyrazines12 with an incorporated piperazine-2,5-dione moiety in a
heterobicyclic system. Being an extremely good Michael acceptor,
1 is known to rapidly undergo addition of nucleophiles including
secondary and primary amines, and the products can further
react by nucleophilic substitution of the chlorine substituent
Five different primary amines including methyl glycinate and
two p-substituted benzylamines were added to methyl 2-chloro-
2-cyclopropylideneacetate (1) smoothly at 0 to 20 ◦C.
Since the adducts of primary amines are intrinsically un-
stable and undergo rearrangement,13 they were not isolated
in pure form, but directly acylated with a-bromoacetic and
a-bromophenylacetic acid chloride, respectively, under modi-
fied Schotten-Baumann conditions to yield the stable acyclic
bishaloesteramides 3.
Unfortunately, several attempts to condense the initial Michael
adducts obtained here with N-Boc-protected amino acids by
activation with standard carbodiimide (DCC, EDC) or even more
potent (PyBOP, HATU) peptide coupling reagents as reported
previously for certain such adducts of 1,12 were not successful.
To avoid hydrolysis of the a-bromo acid chlorides under the
usual biphasic Schotten-Baumann conditions, 2 –3 equivalents of
the acid chloride and solid sodium bicarbonate were added to a
solution of the respective amine adduct of 2 in 1,2-dichloroethane,
and water was added very slowly drop by drop under vigorous
stirring, to furnish 3a–e in high yields (Table 1). In this way, the
liberated hydrogen chloride was trapped by sodium bicarbonate
in a very small volume of an aqueous phase without the danger
of letting the acid chloride in the organic phase be quenched by
a large excess of water. Even with the sterically more encumbered
a-bromophenacetyl chloride, this method furnished respectable
yields (80–86%) of the acylation products 3c and 3e.
aInstitut fu¨r Organische und Biomolekulare Chemie, Georg-August-
Universita¨t Go¨ttingen, Tammannstrasse 2, 37077 Go¨ttingen, Germany.
E-mail: ameijer1@gwdg.de; Fax: +49(0)551 399475
bBayer CropScience AG, Alfred-Nobel-Strasse 50, 40789 Monheim,
Germany
† Cyclopropyl Building Blocks for Organic Synthesis, 153. Part 152: V. A.
Rassadin, A. A. Tomashevskiy, V. V. Sokolov, A. Ringe, J. Magull, A. de
Meijere, Eur. J. Org. Chem., 2009, 2635–2641. Part 151: M. W. No¨tzel, D.
Frank, T. Labahn, A. de Meijere, Eur. J. Org. Chem. 2009, 1683–1686.
An intermolecular nucleophilic substitution of the bromide in
3a–e with a second set of nitrogen nucleophiles and a subsequent
ring-closing intramolecular nucleophilic substitution of the chlo-
ride adjacent to the methoxycarbonyl group (Scheme 2, reaction
mode A) yielded the substituted oxopiperazincarboxylates 2. From
‡ Electronic supplementary information (ESI) available: Experimental
details for compounds not included in Experimental Section, 1H and 13
spectra. See DOI: 10.1039/b908548c
C
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Table 1 Michael addition of primary amines to methyl 2-chloro-2-
cyclopropylideneacetate (1) and direct acylation of the adducts with
a-bromo acid chlorides (see Scheme 1)
Table 2 Ring-closing twofold nucleophilic substitution on dihaloami-
doesters 3 with various nitrogen nucleophiles (see Scheme 2)
Yield
R1
R2
Product
Yield (%)a
R1
R2 R3
Product T/◦C Time/h (%)
BnO(CH2)3
H
H
Ph
H
Ph
3a
3b
3c
3d
3e
91
66
86
72
80
BnO(CH2)3
MeO(CH2)2
MeO(CH2)2
MeO(CH2)2
MeO(CH2)2
H
H
H
H
H
Bn
Bn
3-MeC6H4
4-PhC6H4
2-MeC6H4
2af
20
20
120
50
120
20 120
50
20
20
50
80
80
40
40
20
20
20
80
40
50
48
24
48
36
48
75
81
80
87
76
68
73
87
MeO(CH2)2
MeO2CCH2
4-ClC6H4CH2
4-F3CC6H4CH2
2bf
2bg
2bh
2bi
2cj-Ph
2dk
2dl
MeO2CCH2 Ph 4-MeOC6H4
a Yield of isolated product over two steps.
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-F3CC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
4-MeC6H4
16
72
72
48
24
24
36
36
48
48
48
72
16
12
2-F3CC6H4CH2
Me2CHCH2
MeO2CCH2
(S)-PhCHCO2Me 2dn
(S)-iPrCHCO2Me 2do
(R)-HOCH2CHPh 6dp
(S)-HOCH2CHPh 6dq
4-O2NC6H4CH2
2-NaphthCH2
3,4-Me2C6H3
4-ClC6H4
2dm
2dd
90
64
70a
70a
70a,b
65a,b
84
2dr
2ds
85
72
39
99
2dt
2du
2dv
3-indolyl-(CH2)2
Ph 4-MeOC6H4
2ej-Ph
62
a Total yield of isolated diastereomers, which were separated. b The product
of subsequent intramolecular transesterification of initially formed 2.
Scheme 1 Michael addition of primary amines to methyl 2-chloro-2-
cyclopropylideneacetate (1) and direct acylation of the adducts with
a-bromo acid chlorides. For details see Table 1.
(80 ◦C) and gave a poor yield (39%) of 2du with a number of
by-products.
Surprisingly, in no case was the seven-membered chlorolactam
5 formed by an intramolecular attack of the terminal amino group
in the intermediate 4 on the ester moiety (Scheme 2, reaction mode
B), as evidenced by LC-MS of the crude products. Chlorolactams
of type 5, however, have previously been obtained as the main
products, when free aminoacyl derivatives of type 4 were cyclized
under biphasic basic conditions.15
To demonstrate the possible diversity of substituents R3 in the
5-oxopiperazinecarboxylates 2, the substitution of the bromide
in 3 was performed with methyl glycinate as well as with
enantiomerically pure a-amino acid esters and enantiomerically
pure b-amino alcohols, to yield the oxopiperazinecarboxylates
2dn, 2do and bicyclic oxopiperazines 6dp, 6dq, respectively, as 1:1
mixtures of diastereomers, which could be separated by column
chromatography. Apparently, the latter two products (Fig. 1) were
obtained by intramolecular transesterification of initially formed
products of type 2.
Scheme 2 Ring-closing twofold nucleophilic substitution on compounds
3a–e to yield methyl 5-oxo-4,7-diazaspiro[2.5]octane-8-carboxylates 2. For
details see Table 2.
precursors with R2 = Ph, the trans-configured products 2cj-Ph and
2ej-Ph were formed diastereoselectively.
This intramolecular substitution is apparently particularly
efficient because of the 1,1-disubstituted cyclopropane motif in the
precursors 3a–e which, due to its Thorpe-Ingold effect,14 favors the
ring closure. The yields strongly depended on the nucleophilicity
of the amine. While alkyl- and benzylamines cleanly gave the corre-
spondingly substituted oxopiperazinecarboxylates 2 (see Table 2)
at ambient temperature, the less nucleophilic anilines in some
cases required higher temperatures (up to 120 ◦C) and longer
reaction times (up to 120 h). While donor-substituted anilines
such as p-toluidine and 3,4-dimethylaniline reacted smoothly at
40 ◦C, p-chloroaniline only reacted under more drastic conditions
Fig. 1 Bicyclic oxopiperazines 6dp, 6dq, obtained from 3d and (R)- or
(S)-phenylglycinol, respectively.
The achievable substitution pattern on this scaffold was
extended by acylation of the free secondary amino group
in the previously reported15 4-(3-benzyloxypropyl)-5-oxopi-
perazinecarboxylate 7, and subsequent cyclization following the
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Dr Tottoli (Bu¨chi); values are uncorrected. Elemental analyses:
Mikroanalytisches Laboratorium des Instituts fu¨r Organische und
Biomolekulare Chemie der Universita¨t Go¨ttingen.
Methyl
2-(1-(N-(3-(benzyloxy)propyl)-2-bromoacetamido)-
solution of methyl
cyclopropyl)-2-chloroacetate (3a). To
a
2-chloro-2-cyclopropylideneacetate (1) (2.00 g, 13.7 mmol) in
THF (100 mL) was added 3-benzyloxypropylamine (2.48 g,
15.0 mmol) at 0 ◦C, and the solution was stirred at this
temperature for 8 h. (Michael adduct, ninhydrine, hexane/EtOAc
2 : 1, Rf = 0.37). Volatiles were removed under reduced pressure,
the residue was taken up in 1,2-dichloroethane (100 mL),
bromoacetyl chloride (6.45 g, 41.0 mmol) and solid NaHCO3
(3.44 g, 41.0 mmol) were added with stirring at 20 ◦C and slowly
water (10 mL). The suspension was vigorously stirred for 5 h,
a saturated NaHCO3 solution (10 mL) was added, the phases
were separated, the aqueous phase was extracted with CH2Cl2
(1 ¥ 50 mL), the combined organic phases were dried over
Na2SO4, and the solvent was removed under reduced pressure.
Chromatographic purification of the residue on silica (50 g, 4 ¥
40 cm, pentane/Et2O 1 : 1, ninhydrine, Rf = 0.41) yielded 5.39 g
(91%) of 3a as a colorless solid, m.p. 60 - 61 ◦C. IR (film):
Scheme 3 Synthesis of the bicyclic tripeptide mimic 9.
protocol described above for the preparation of oxopiperazinecar-
boxylates 2.
Reaction of 7 with bromoacetyl chloride under the established
conditions, subsequent nucleophilic substitution of the bromine
in the bromoacetyl moiety on the dipeptide scaffold 8 with
tryptamine and thermally induced ring closure gave the bicyclic
tripeptide mimic 9 with further potentially addressable variation
points (the benzyloxy group, two C,H-acidic methylene groups a
to carbonyls, one NH in the indol moiety) for increased diversity
and the possible build-up of tetrapeptide isosteres.
=
=
˜
n = 2953, 2860, 1752 (C O), 1662 (C O), 1453, 1435, 1404,
1
1369, 1290, 1203, 1167, 1102, 911, 734 cm-1. H NMR (CDCl3,
300 MHz, mixture of two rotamers): d = 1.04–1.12 (m, 1 H,
Cpr-H), 1.24–1.46 (m, 2 H, Cpr-H), 1.52–1.64 (m, 1 H, Cpr-H),
1.78–2.08 (m, 2 H, CH2), 3.43–3.50 (m, 3 H, CH2, CH), 3.57–3.71
(m, 2 H), 3.76 (s, 1 H, CH3), 3.77 (s, 2 H, CH3), 3.85–3.98 (m, 1
H, CH2), 4.20–4.36 (m, 1 H, CH2), 4.49 (dd, J = 5.6, 5.6 Hz, 2 H,
CH2), 7.28–7.36 (m, 5 H, aryl-H). 13C NMR (CDCl3, 75.5 MHz,
APT): d = 13.2 (-, Cpr-C), 13.6 (-, Cpr-C), 17.0 (-, Cpr-C), 19.2
(-, Cpr-C), 26.9 (-, CH2), 27.0 (-, CH2), 27.2 (-, CH2), 28.3 (-,
CH2), 43.3 (Cquat, Cpr-C), 43.6 (Cquat, Cpr-C), 47.8 (-, NCH2),
48.1 (-, NCH2), 53.1 (+, CH), 53.3 (+, CH), 61.1 (+, OCH3),
63.7 (OCH3), 67.0 (-, CH2), 67.8 (-, CH2), 72.8 (-, CH2), 73.1
(-, CH2), 127.4 (+, aryl-C), 127.5 (+, aryl-C), 127.6 (+, aryl-C),
Experimental section
General remarks
All reagents were used as purchased from commercial suppliers
without further purification. Solvents were purified and dried
according to conventional methods prior to use. 1H- and 13C-NMR
spectra were recorded at ambient temperature with a Bruker AM
250 (250 MHz for 1H and 62.9 MHz for 13C) or a Varian UNITY-
300 (300 MHz for 1H and 75.5 MHz for 13C) instrument. Chemical
shifts d are presented in ppm relative to residual resonances of
solvents (1H: 7.26 ppm for CHCl3; 13C: 77.0 ppm for CDCl3),
coupling constants J are given in Hertz. Characterization of the
multiplicities of signals: s = singlet, br s = broad singlet, d =
doublet, t = triplet, m = multiplet. The multiplicities of 13C
signals were determined by the DEPT or the APT technique:
DEPT: + = primary or tertiary (positive DEPT signal), - =
secondary (negative DEPT signal), Cquat = quaternary C-atom;
APT: + = primary or tertiary (positive APT signal), - = secondary
or quaternary C-atom (negative APT signal). IR: Bruker IFS 66.
EI-MS: Finnigan MAT 95, 70 eV; ESI-MS: Finnigan LCQ. High
resolution mass spectrometry (HRMS): APEX IV 7T FTICR,
Bruker Daltonic. Chromatography: Separations were carried out
on Merck Silica 60 (0.063–0.200 mm, 70–230 mesh ASTM).
The dimensions of the columns are given as “diameter ¥ height
of the silica gel column”. TLC: Macherey-Nagel, TLC plates
127.7 (+, aryl-C), 128.3 (+, aryl-C), 128.4 (+, aryl-C), 137.9 (Cquat
,
aryl-C), 138.2 (Cquat, aryl-C), 167.4 (Cquat), 167.5 (Cquat), 169.3
(Cquat), 169.4 (Cquat). MS (ESI), m/z (%): 456.1/458.1 (76/100)
[M + Na]+, 888.6/886.6 (66/78) [2M + Na]+.–C18H23BrClNO4
(432.7): calcd. C 49.96, H 5.36, N 3.24; found C 50.21, H 5.08, N
3.11.
General procedure for the preparation of di- and trisubstituted
methyl 4,7-diazaspiro[2.5]octane-8-carboxylates (2). To a solu-
tion of the respective bishalo ester amide 3a–e (1.00 g, 2.44 mmol)
in MeOH (20 mL) was added at 20 ◦C the respective amine
(288 mg, 2.69 mmol) as well as triethylamine (764 mg, 5.91 mmol),
and the solution was stirred at the stated temperature for the stated
time. The solvent was removed under reduced pressure, the residue
taken up in CH2Cl2 (100 mL), the solution extracted with aq. 1 N
HCl (20 mL), the organic phase dried over MgSO4, and the solvent
removed under reduced pressure. Chromatographic purification of
the residue on silica gel or recrystallization from the stated solvent
yielded the respective compound.
Methyl 7-benzyl-4-(3-benzyloxypropyl)-5-oxo-4,7-diazaspiro-
[2.5]octane-8-carboxylate (2af). The crude product from 3a
(4.11 g, 9.80 mmol) in MeOH (50 mL), benzylamine (1.16 g,
10.8 mmol), triethylamine (2.98 mL, 29.4 mmol) at 20 ◦C within
R
Alugramꢀ Sil G/UV254. Detection under UV light at 254 nm,
development with MOPS reagent (10% molybdophosphoric acid,
solution in ethanol). Melting points: apparatus according to
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48 h was purified by chromatography on 50 g of silica gel (3 ¥
(19), 125 (100), 105 (100), 77 (62).–C22H21ClN2O3 (396.9): calcd.
C 66.58, H 5.33, N 7.06; found C 66.73, H 5.55, N 7.26.
20 cm, MOPS, pentane/Et2O 1 : 3; Rf = 0.43 [Et2O]) to yield
-1
˜
2.98 g (75%) of 2af as a colorless oil. IR (film): n = 3448 cm ,
Methyl 4-(3-benzyloxypropyl)-7-(2-bromacetyl)-5-oxo-4,7-di-
azaspiro[2.5]octane-8-carboxylate (8). To a solution of 715
(3.76 g, 11.3 mmol) in 1,2-dichloroethane (100 mL) was added at
=
=
3005, 2953, 1749 (C O), 1684 (C O), 1436, 1365, 1336, 1277,
1198, 1167, 1014, 947, 876, 807, 762, 691, 657. 1H NMR (CDCl3,
250 MHz): d = 0.67–0.96 (m, 4 H, Cpr-H), 1.36–1.43 (m, 1 H,
CH2), 1.69–1.74 (m, 2 H, CH2), 2.54–2.59 (m, 1 H, CH2), 2.72
(s, 1 H, CH), 3.41–3.50 (m, 2 H, CH2), 3.59–3.84 (m, 7 H, 2
◦
20 C bromoacetyl chloride (2.13 g, 13.6 mmol), solid NaHCO3
(1.14 g, 13.6 mmol), and then water (5 mL) was slowly added
dropwise with vigorous stirring. The mixture was extracted
with NaHCO3 solution (50 mL) and the organic phase dried
over Na2SO4. Purification of the residue after concentration, by
chromatography on 100 g silica gel (3 ¥ 35 cm, CH2Cl2/MeOH
40 : 1, Rf = 0.21, MOPS) gave 3.57 g (87%) of 8 as a colorless oil.
13
CH2, CH3), 4.47 (s, 2 H, CH2), 7.23–7.38 (m, 10 H, aryl-H).- C
NMR (CDCl3, 62.9 MHz): d = 9.5 (-, Cpr-C), 12.8 (-, Cpr-C),
37.4 (-, CH2), 41.2 (Cquat, Cpr-C), 41.4 (-, NCH2), 51.5 (+,
OCH3), 53.8 (-, NCH2Ph), 59.0 (-, CH2), 66.2 (+, CHN), 68.0
(-, OCH2Ph), 73.1 (-, OCH2), 127.5 (+, 2 C, aryl-C), 127.6 (+,
2 C, aryl-C), 128.3 (+, 2 C, aryl-C), 128.5 (+, 2 C, aryl-C), 128.9
(+, 2 C, aryl-C), 137.0 (Cipso, aryl-C), 138.1 (Cipso, aryl-C), 169.6
=
=
˜
IR (film): n = 3489, 2954, 2861, 2248, 1748 (C O), 1661 (C O),
1
1409, 1347, 1209, 1102, 1028, 910, 733 cm-1. H NMR (CDCl3,
300 MHz): d = 0.79–0.87 (m, 1 H, Cpr-H), 0.94–1.01 (m, 1 H,
Cpr-H), 1.32–1.41 (m, 1 H, Cpr-H), 1.47–1.55 (m, 1 H, Cpr-H),
1.55–1.77 (m, 2 H, CH2), 2.88–2.98 (m, 1 H, CH2), 3.37–3.46 (m,
2 H, CH2), 3.61–3.68 (m, 1 H, CH2), 3.72 (s, 3 H, CH3), 3.91 (dd,
J = 31.3, 11.3 Hz, 2 H, CH2), 4.09 (s, 1 H, CH), 4.38 (dd, J = 27.5,
15.5 Hz, 2 H, CH2), 4.46 (s, 2 H, CH2), 7.27–7.36 (m, 5 H, aryl-H).
13C NMR (CDCl3, 75.5 MHz, APT): d = 9.6 (-, Cpr-C), 13.1
(-, Cpr-C), 25.4 (-, CH2), 28.5 (-, Cquat, Cpr-C), 39.3 (-, CH2),
39.4 (-, CH2), 49.0 (-, CH2), 52.4 (+, CH), 61.4 (+, CH3), 67.2
(-, CH2), 72.7 (-, CH2), 125.2 (+, aryl-C), 127.3 (+, 2C, aryl-C),
128.1 (+, 2C, aryl-C), 138.0 (Cquat, aryl-C), 165.7 (-, Cquat), 166.4
(-, Cquat), 168.8 (-, Cquat). MS (ESI), m/z (%): 475.1/477.1 (100)
[M + Na]+, 927.2/929.2 (73) [M + Na]+–HRMS (ESI): calcd. for
C20H25BrN2O5Na [M + Na+] 475.0839; found 475.0846.
=
=
(Cquat, CN O), 171.0 (Cquat, C O). MS (ESI), m/z: 445.2 (100)
[M + Na]+, 867.4 (95) [2M + Na]+. C25H30N2O4 (422.5): calcd. C
71.07, H 7.16, N 6.63; found C 71.38, H 6.95, N 6.76.
Methyl 4-(4-chlorobenzyl)-7-(methoxyphenylmethyl)-5-oxo-4,7-
diazaspiro[2.5]octane-8-carboxylate (6dp). The crude product
obtained from 3d (1.12 g, 2.73 mmol) in MeOH (20 mL), (R)-a-
phenylglycinol (412 mg, 3.00 mmol) and triethylamine (1.50 mL,
10.9 mmol) at 20 ◦C in 24 h, was purified by chromatography on
50 g of silica gel (3 ¥ 20 cm, MOPS, Et2O; Rf = 0.32) to yield 707 mg
(70%) of 6dp as a colorless oil (1:1 mixture of diastereomers,
which were separated by column chromatography on silica gel).
˜
Diastereomer 1: IR (KBr): n = 3319, 3213, 3090, 3068, 2961, 2928,
=
1682 (C O), 1495, 1462, 1443, 1325, 1229, 1092, 1016, 819, 813,
804, 735, 604, 553, 433 cm-1. H NMR (CDCl3, 250 MHz): d =
7¢-Indolylmethyl-1¢,3¢,4¢,6¢,7¢,8¢,9¢,9a¢-octahydro-2¢-(3-benzylo-
xypropyl)spiro(cyclopropane-1,1¢-[2H]pyrazino[1, 2-a]-pyrazin)-
3¢,6¢,9¢-trione (9). To a solution of 7 (1.50 g, 3.31 mmol) in
MeOH (30 mL) were added tryptamine (583 mg, 3.64 mmol)
and triethylamine (402 mg, 3.97 mmol), and the mixture was
stirred at 20 ◦C for 12 h. The volatile material was removed
under reduced pressure, the residue taken up in THF (50 mL),
triethylamine (402 mg, 3.97 mmol) was added again and the
mixture heated under reflux for 18 h. The solvents were removed
under reduced pressure, the residue taken up in CH2Cl2 (100 mL),
the solution washed with 1 N HCl (30 mL), and the organic phase
dried (MgSO4). Chromatographic purification of the residue
after evaporation of the solvent, on 50 g of silica gel (3 ¥ 40 cm,
CH2Cl2/MeOH 40 : 1 → 20 : 1, Rf = 0.37 (CH2Cl2/MeOH 20 : 1),
MOPS) gave 1.40 g (85%) of 9 as a colorless foam. IR (KBr): n =
1
0.26–0.35 (m, 1 H, Cpr-H), 0.55–0.64 (m, 1 H, Cpr-H), 0.95–1.04
(m, 1 H, Cpr-H), 1.12–1.23 (m, 1 H, Cpr-H), 2.38–2.61 (br s, 1 H,
OH), 3.08 (s, 1 H, CH), 3.54 (s, 3 H, OCH3), 3.68–3.81 (m, 4 H,
3
2 ¥ CH, CH2), 3.83–3.91 (m, 1 H, CH), 3.92 (d, J = 7.90 Hz, 1
H, A-part of an AB-system), 4.68 (d, 3J = 7.90 Hz, 1 H, B-part of
an AB-system), 7.06 (d, 3J = 4.16 Hz, 2 H, aryl-H), 7.22–7.41 (m,
7 H, aryl-H). 13C NMR (CDCl3, 62.9 MHz): d = 9.67 (-, Cpr-C),
12.6 (-, Cpr-C), 42.6 (Cquat, Cpr-C), 44.3 (-, CH2), 52.0 (+, OCH3),
53.1 (-, CH2), 62.8 (-, CH2), 63.7 (+, CH), 67.9 (+, CH), 128.1 (+,
2 C, aryl-C), 128.3 (+, aryl-C), 128.4 (+, 2 C, aryl-C), 128.6 (+, 2 C,
aryl-C), 128.8 (+, 2 C, aryl-C), 128.9 (+, 2 C, aryl-C), 132.9 (Cquat
Cipso), 136.4 (Cquat, Cipso), 136.8 (Cquat, Cipso), 170.5 (Cquat, C O),
172.4 (Cquat, C O). MS (EI, 70 eV), m/z (%): 397 (100) [M] , 369
(19), 236 (15), 125 (50). C22H21ClN2O3 (396.9): calcd. C 66.58, H
,
=
+
=
=
=
=
5.33, N 7.06; found C 66.72, H 5.55, N 7.16. Diastereomer 2: IR
3330 (NH), 3033, 2929, 1692 (C O), 1662 (C O), 1646 (C O),
1456, 1399, 1363, 1325, 1288, 1228, 1190, 987, 813, 738 cm-1.
H NMR (250 MHz, CDCl3): d = 0.89–1.11 (m, 3 H, Cpr-H),
1.32–1.38 (m, 1 H, Cpr-H), 2.80 (dd, 3J = 9.6, 2J = 17.5 Hz, 1 H,
CH at C-7¢), 3.07 (dd, 3J = 2.8, 2J = 17.5 Hz, 1 H, CH at C-7¢),
=
=
˜
(KBr): n = 3304, 3055, 2950, 1736 (C O), 1659 (C O), 1457,
1436, 1419, 1341, 1213, 745 cm-1.- H NMR (CDCl3, 250 MHz):
1
d = 0.44–0.48 (m, 1 H, Cpr-H), 0.63–0.67 (m, 1 H, Cpr-H), 0.86–
0.93 (m, 1 H, Cpr-H), 1.12–1.25 (m, 1 H, Cpr-H), 2.76 (s, 1 H,
OH), 3.08 (s, 1 H, CH), 3.52 (s, 3 H, OCH3), 3.69–4.02 (m, 6 H,
2 ¥ CH, 2 ¥ CH2), 4.72 (d, 3J = 7.85 Hz, 1 H, A-part of an AB-
2
4.01 (d, J = 17.1 Hz, 1 H), 4.05 (s, 1 H, CH at 9a¢-H), 4.22 (d,
2J = 15.9 Hz, 1 H), 4.39 (dt, J = 2.8, J = 9.6 Hz, 1 H, 7¢-H),
3
2
3
2
2
system), 7.05 (d, J = 4.13 Hz, 2 H, aryl-H), 7.21–7.36 (m, 7 H,
4.85 (d, J = 15.9 Hz, 1 H), 5.02 (d, J = 17.1 Hz, 1 H), 5.15 (s,
2 H, OCH2), 6.58 (d, 3J = 2.7 Hz, 1 H, NH), 7.12 (d, 3J = 8.5 Hz,
2 H, Ar-H), 7.28 (d, 3J = 8.5 Hz, 2 H, Ar-H), 7.25–7.41 (m, 5 H,
Ar-H). 13C NMR (75.5 MHz, CDCl3, APT): d = 8.8 (-, Cpr-C),
12.0 (-, Cpr-C), 37.4 (-, CH2 at C-7¢), 41.2 (Cquat, Cpr-C), 46.2 (-,
C-4¢ and NCH2), 52.2 (+, C-7¢), 61.1 (+, C-9a¢), 67.3 (-, OCH2),
128.1 (+, 2 Ar-C), 128.4 (+, 2 Ar-C), 128.7 (+, Ar-C), 128.8 (+, 2
Ar-C), 128.9 (+, 2 Ar-C), 133.2 (Cquat, Ar-C), 134.8 (Cquat, Ar-C),
13
aryl-H).- C NMR (CDCl3, 62.9 MHz): d = 9.53 (-, Cpr-C), 13.3
(-, Cpr-C), 41.3 (Cquat, Cpr-C), 44.4 (-, CH2), 50.0 (+, CH), 52.0
(+, OCH3), 62.0 (-, CH2), 65.6 (-, CH2), 67.8 (+, CH), 128.45 (+,
2 C, aryl-C), 128.52 (+, 3 C, aryl-C), 128.6 (+, 2 C, aryl-C), 128.9
(+, 2 C, aryl-C), 132.9 (Cquat, Cipso), 136.3 (Cquat, Cipso), 136.6 (Cquat
Cipso), 170.4 (Cquat, C O), 171.6 (Cquat, C O). MS (EI, 70 eV),
m/z (%): 399/397 (32/100) [M]+, 369 (21), 249 (16), 236 (24), 139
,
=
=
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View Article Online
=
=
135.9 (Cquat, Ar-C), 163.4 (Cquat, C O), 167.9 (Cquat, C O), 169.9
7 (a) C. J. Dinsmore and C. B. Aartman, Tetrahedron Lett., 2000, 6309–
6312; (b) A. Pohlmann, V. Schanen, D. Guillaume, J.-C. Quiron and
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and A. Giannis, Angew. Chem., 1992, 104, 1394–1395; Angew. Chem.,
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T. E. Rawson, Tetrahedron Lett., 1992, 33, 7089–7092; (i) F. van Hove,
S. Vanwetswinkel, S. J. Marchand-Brynaert and J. Fastrez, Tetrahedron
Lett., 1995, 36, 9313–9316; (j) S. Maignan, J. P. Guilloteau, Y. M. Choi-
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Mikol, J. Med. Chem., 2003, 46, 685–690.
+
=
(Cquat, C O).–MS (EI, 70 eV), m/z (%): 483/481 (14/42) [M ],
392/390 (25/72), 330 (10), 288 (19), 281 (11), 127/125 (14/45), 91
(76). C35H36N4O4 (576.7): calcd. C 72.90, H 6.29, N 9.72; found C
72.68, H 6.32, N 9.56.
Acknowledgements
This work was supported by Bayer CropScience AG and the Fonds
der Chemischen Industrie. The authors are grateful to Celanese
and Degussa AG for generous gifts of chemicals. M. L. is indebted
to the German Merit Foundation (Studienstiftung des deutschen
Volkes) for a student and a doctoral student fellowship. A. V. L.
and V. S. K. are indebted to the Degussa Foundation (Evonik
Industries AG) for doctoral student fellowships.
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3342 | Org. Biomol. Chem., 2009, 7, 3338–3342
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