Synthesis of 1S,5R- and 1R,5S-glycoluriles by diastereospecific α-ureidoalkylation of (S)/(R)-N-carbamoyl-α-amino acids with 4,5-dihydroxyimidazolidin-2-one

Article abstract of DOI:10.1070/MC2004v014n06ABEH002050

A diastereospecific method for the synthesis of individual enantiomers of 1S,5R- and 1R,5S-glycoluriles has been developed based on the α-ureidoalkylation of (S)/(R)-N-carbamoyl-α-amino acids with 4,5-dihydroxyimidazolidin-2-one.

Full text of DOI:10.1070/MC2004v014n06ABEH002050

,
2004, 14(6), 253–255
Synthesis of 1S,5R- and 1R,5S-glycoluriles by diastereospecific α-ureidoalkylation
of (S)/(R)-N-carbamoyl-α-amino acids with 4,5-dihydroxyimidazolidin-2-one
a
a
a
b
Il’ya E. Chikunov,* Angelina N. Kravchenko, Pavel A. Belyakov, Konstantin A. Lyssenko,
a
a
a
Vladimir V. Baranov, Oleg V. Lebedev and Nina N. Makhova
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: kani@ioc.ac.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5085; e-mail: kostya@xrlab.ineos.ac.ru
DOI: 10.1070/MC2004v014n06ABEH002050
A diastereospecific method for the synthesis of individual enantiomers of 1S,5R- and 1R,5S-glycoluriles has been developed based
on the α-ureidoalkylation of (S)/(R)-N-carbamoyl-α-amino acids with 4,5-dihydroxyimidazolidin-2-one.
We have shown previously1–3 that glycoluriles are a new
promising class of psychotropic compounds. It was found later
that they also have other types of biological activity. In par-
H2N
HN
*
R
H
N
OH
OH
*
*
O
i
4
O
ticular, they have cancer-control activity and influence the cyto-
O
chrome P-450 dependent monooxygenase function of liver.5
The synthesis of enantiomerically pure glycoluriles as potential
pharmaceuticals is of considerable interest. One of the most
popular methods for the synthesis of glycoluriles is based on
the α-ureidoalkylation of N-mono- and N,N'-disubstituted ureas
with 4,5-dihydroxyimidazolidin-2-ones as the ureidoalkylating
N
H
OH
1
2a–f
H
N
O
*
O
NH
O
6
–10
NH
reagents.
Based on this approach, we studied the α-ureido-
HN
*
O
alkylation of achiral and enantiomerically pure N-carbamoyl-
N
*
HN
*
R
amino acids with 4,5-dihydroxyimidazolidin-2-ones. We obtained
OH
7–9
R
O
racemic glycoluriles; of these, conditions for the isolation of
enantiomers by spontaneous crystallisation from water were
3
a–f
4a–g
found for 4-[(3,7-dioxo-2-(3-carboxypropyl)-6,8-dimethyl-
7
2
,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]butanoic acid. A similar
a R = CH CH SMe (S)
2
2
reaction with enantiomerically pure N-carbamoylamino acids
occurs diastereoselectively;10 the ratio between the major and
minor products ranges from 3:1 to 15:1. Individual diastereomers
were isolated from the mixtures by fractional crystallisation.
We report here on a simple approach to the synthesis of
individual enantiomers of glycoluriles by the diastereospecific
α-ureidoalkylation of corresponding enantiomers of (S)/(R)-N-car-
bamoyl-α-amino acids 2a–f, viz., (S)/(R)-N-carbamoylmethionine
b R = CH CH SMe (R)
2 2
c R = CHMe (S)
2
d R = CHMe (R)
2
e R = CH Ph (S)
2
f R = CHEtMe (S)
g R = H
Scheme 1 Reagents and conditions: i, 1 mol 2 : 2 mol HCl, H O or
2
i
H O + Pr OH, 80 °C, 2.5 h.
2
Mendeleev Commun. 2004 253

,
2004, 14(6), 253–255
The absence of the second diastereomer after the isolation of
S(1)
C(14)
compounds 3a–f was established by the H NMR spectroscopy
1
1
of mother liquors evaporated to dryness. Analysis of the H NMR
C(12) C(13)
O(1)
spectra of the residues (in the region of signals corresponding to
the CH protons of the amino acid fragment at 3.7–4.5 ppm)
C(3)
N(4) C(7)
C(11)
O(2)
suggests that all the products give signals due to CH and CH
O(4)
2
N(2)
C(10)
protons, as well as NH protons (~8 and ~10.5 ppm) of hydantoins
N(8)
C(1)
N(6)
11
4
a–f, which are formed as a result of the self-cyclisation of
O(3)
C(5)
O(3WA)
O(2W)
O(3W)
N-carbamoyl-α-amino acids 3a–f, and hydantoin 4g, which
Ni(1)
results from a rearrangement of 4,5-dihydroxyimidazolidin-2-one
O(1W)
O(1WA)
1
1
. Furthermore, according to H NMR data, the test mixtures
contained minor amounts of target glycoluriles 3. The signals of
the second diastereomer were absent.
O(2WA)
A comparison of the results of X-ray diffraction analysis and
spectral characteristics of compound 3a10 and spectral data for
compounds 3c and 3e,f allowed us to state that the bridging
carbon atoms in these glycoluriles have the (1R,5S) configura-
tion. In the case of compounds 3b,d, it can be assumed with a
higher probability that the CH–CH moieties have an opposite
configuration, i.e., (1S,5R).
For a conclusive confirmation of the configurations of asym-
metric atoms C(1) and C(5) in glycoluriles 3b,d, we obtained
coordination compound 5 by ligand exchange between glycolurile
3b and nickel acetate in an aqueous solution with heating. An
X-ray diffraction study of single crystals grown by crystallisa-
tion from water was carried out.‡
Figure 1 The cation and anion in a crystal of compound 1.
2
a,b, (S)/(R)-N-carbamoylvaline 2c,d, (S)-N-carbamoylphenyl-
alanine 2e and (S)-N-carbamoylisoleucine 2f with 4,5-dihydroxy-
imidazolidin-2-one 1.
In order to reveal the conditions required for the reactions
of 4,5-dihydroxyimidazolidin-2-one 1 with (S)/(R)-N-carbamoyl-
amino acids 2 to occur diastereospecifically, we studied the
effect of the process parameters, such as the medium pH from 0
to 6, temperature from 40 to 90 °C and duration of the reaction
from 0.5 to 4 h, for the reaction of compound 1 with (S)/(R)-
N-carbamoylmethionines 2a,b as an example. We found that a
diastereospecific synthesis requires the following conditions:
2
mol of HCl per mole of the ureidoacid; the temperature should
It was shown that the nickel atom in compound 5 did not
participate directly in the coordination with the functional groups
of the ligand. In a crystal, the nickel atom arranged on axis 2 is
surrounded by six water molecules. In addition to the water
molecules involved in the coordination of nickel, the crystal
also contains four solvate water molecules. The ligand (L) is
in the deprotonated form [the bond lengths C(10)–O(3) and
be 80 °C; and the reaction time should be 2.5 h. (Scheme 1).
The physico-chemical characteristics of individual enantiomers
3
reported previously; the structure and absolute configuration of
compound 3a were proved by X-ray diffraction analysis.10
These conditions were used in reactions of 1 with other
a,b obtained under these conditions are consistent with data
(
S)/(R)-N-carbamoyl-α-amino acids 2c–f. In all cases, the target
†
All new compounds exhibited satisfactory elemental analyses, and
individual enantiomers of glycoluriles 3a–f were obtained in
1
13
their structures were confirmed by IR, H and C NMR spectroscopy.
preparative yields of 30–40%.†
1
13
The H and C spectra were recorded on Bruker WM-250 (250 MHz)
and Bruker AM-300 (75.5 MHz) spectrometers, respectively. Chemical
shifts were measured with reference to the residual protons of a
The diastereospecific reactions of compound 1 with (S)- and
(
R)-N-carbamoylvaline 2c and 2d give enantiomers 3c and 3d,
2
which, like compounds 3a,b, have identical melting points, as
[ H6]DMSO solvent (d 2.50 ppm).
1
20
Initial 4,5-dihydroxyimidazolin-2-one 2 was synthesised according to
well as IR and H NMR spectra, whereas their [a] have the
D
1
2
2
0
the known method from urea and glyoxal; N-carbamoyl-α-amino acids
same absolute values but opposite signs: [a] +1.21° for 3c;
D
2
0
3a–d were synthesised by analogy to published methods from α-amino
[
a] –1.21° for 3d. The ureidoalkylation of (S)-N-carbamoyl-
D
13,14
acids and KOCN.
phenylalanine 2e and (S)-N-carbamoylisoleucine 2f also occurs
diastereoselectively to give enantiomerically pure glycoluriles
(+)-2-[(1R,5S)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(S)-
4
-methylthiobutanoic acid 3a: yield 37%, mp 256–258 °C (decomp.),
D
3
e,f.
20
[
a] +18.50° (c 2, 1 N NaOH), see ref. 10.
(–)-2-[(1S,5R)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(R)-
4
-methylthiobutanoic acid 3b: yield 37%, mp 256–258°C (decomp.),
2
0
1
2
[
a] –18.50° (c 2, 1 N NaOH). H NMR ([ H ]DMSO) d: 2.05–2.17 (m,
D
6
3
5
H, Me + CH ), 2.36–2.64 (m, 2H, CH ), 4.47 (dd, 1H, CH, J 9.4 Hz,
2 2
3
3
3
J 6.3 Hz), 5.29 [dd, 1H, C(1)H, J 8.44±0.04 Hz, J 1.7 Hz], 5.41 [dd,
3
3
1
H, C(5)H, J 8.44±0.04 Hz, J 2.4 Hz], 7.25 (br. s, 2H, 2NH), 7.48
1
3
2
(
br. s, 1H, NH), 12.81 (br. s, 1H, OH). C NMR ([ H ]DMSO) d: 14.64
6
(
1
Me), 28.79 (CH ), 30.28 (CH ), 53.18 (CH), 62.99 (CH), 67.48 (CH),
2
2
Ni
Ni
Ni
60.02 (CO), 161.53 (CO), 173.01 (COOH).
+)-2-[(1R,5S)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(S)-
(S)-3-methylbutanoic acid 3c: yield 30.5%, mp 158–159 °C (decomp.),
(
3
[
2
0
1
2
a]
+1.21°. H NMR ([ H ]DMSO) d: 0.9 (m, 2Me), 2.19 (m, CH),
D
6
3
3
3
.9 (d, 1H, CH, J 10.7 Hz), 5.27 [br. dd, 1H, C(1)H, J 8.4 Hz], 5.51
3
3
[dd, 1H, C(5)H, J 2.3 Hz, J 8.4 Hz], 7.32 (s, NH), 7.40 (s, NH), 7.55
(
s, NH), 12,79 (br. s, COOH).
(–)-2-[(1R,5S)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(S)-
3
[
(S)-3-methylbutanoic acid 3d: yield 30.5%, mp 158–159 °C (decomp.),
2
0
1
2
a] –1.21°. H NMR ([ H ]DMSO) d: (see 3c).
D
6
(
+)-2-[(1R,5S)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(S)-
2
0
3
-phenylpropanoic acid 3e: yield 35%, mp 170–172 °C (decomp.), [a]
19.34°. H NMR ([ H ]DMSO) d: 3.07–3.23 (m, 2H, CH ), 4.47–4.55
D
1
2
+
6
2
(m, 1H, CH), 5.20 (br. s, 2H, CH–CH), 7.15–7.27 (m, 6H, Ph + NH),
7
.35 (s, 1H, NH), 7.44 (s, 1H, NH).
+)-2-[(1R,5S)-(3,7-Dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-2(S)-
(S)-3-methylpentanoic acid 3f: yield 35.5%, mp 244–246 °C (decomp.),
(
3
[
2
0
1
2
a] +7.12°. H NMR ([ H ]DMSO) d: 0.80–0.88 (m, 6H, 2Me), 1.02–
D
6
1
.19 (m, 1H, CH), 1.43–1.62 (m, 2H, CH ), 1.94–2.12 (m, 2H, CH ),
2 2
3
3
4
.01 (d, 1H, CH, J 10.3 Hz), 5.26 [br. d, 1H, C(1)H, J 8.1 Hz], 5.51
[dd, 1H, C(5)H, J 2.2 Hz, J 8.1 Hz], 7.32 (s, 1H, NH), 7.37 (s, 1H,
3
3
Figure 2 A projection of crystal packing that demonstrates alternating
cationic layers and anionic chains.
NH), 7.55 (s, 1H, NH).
2
54 Mendeleev Commun. 2004

,
2004, 14(6), 253–255
acids with 4,5-dihydroxyimidazolidin-2-one as a ureidoalkylating
reagent. The absolute configurations of the resulting compounds
were established by X-ray diffraction analysis.
O(1)
O(3) O(4)
N(2)
C(3)
N(4)
S(1)
C(5)
C(1)
C(7) N(8)
This work was supported by the Russian Foundation for
Basic Research (grant no. 02-03-33257) and Russian Academy
of Sciences (program ‘Fundamental Sciences for Medicine’).
N(6)
O(2)
References
1
S. S. Novikov, Izv. Akad. Nauk. SSSR, Ser. Khim, 1979, 2261 (Bull.
Acad. Sci. USSR, Div. Chem. Sci., 1979, 28, 2247).
Figure 3 Double chains combined through the N–H···O bonds in a crystal
of compound 5.
2
O. V. Lebedev, L. I. Khmel’nitskii, L. V. Epishina, L. I. Suvorova,
I. V. Zaikonnikova, I. E. Zimakova, S. V. Kirshin, A. M. Karpov, V. S.
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Moscow, 2000, vol. 1, p. 86 (in Russian).
C(10)–O(4) equal 1.247(3) and 1.255(4) Å, respectively]; hence,
the overall composition of the crystal can be represented as
Ni(H O) L (H O) (Figure 1).
3
4
2
6
2
2
4
The existence of a large number of proton donors and
acceptors in a crystal of compound 5 results in a complex
supramolecular organisation. Alternating inorganic (cationic)
and organic (anionic) parts can be distinguished in a crystal
(a) K. Kim, Y. J. Jeon, S.-Y. Kim, Y. H. Ko, WO Pat. 0324978
(
Chem. Abstr., 2003, 138, 264767); (b) H. Herbert, C. Hase and
M. Budnowski, Ger. Offen. 3003356 (Chem. Abstr., 1981, 95, 187252).
(a) A. I. Khlebnikov, R. R. Akhmedzhanov, O. I. Naboka, T. P.
Novozheeva and A. S. Saratikov, Pharm. Chem. J., 1999, 33, 644;
(b) R. R. Akhmedzhanov, A. I. Khlebnikov, O. I. Naboka, T. P.
Novozheeva, A. S. Saratikov and K. A. Krasnov, Pharm. Chem. J.,
5
(
Figure 2).
The cationic part is a hexaaqua nickel complex. The cations
are combined into layers parallel to the ac crystallographic plane
through hydrogen bonds with solvate water molecules.
The anions are combined through the N–H···O bonds to form
double chains (Figure 3).
1
999, 33, 499; (c) A. I. Khlebnikov, A. A. Bakibaev, R. R. Akhmedzhanov,
T. P. Novozheeva and A. S. Saratikov, Khim.-Farm. Zh., 1997, 31 (6),
4 (in Russian).
4
6
(a) H. Petersen, Synthesis, 1973, 5, 273; (b) F. B. Slezak and
H. Bluestone, US Patent 3187004 (Chem. Abstr., 1965, 63, 13273);
Note that the previous10 X-ray diffraction study of glycolurile
a showed that molecules in the crystal were combined through
3
(c) A. N. Kravchenko, O. V. Lebedev and E. Yu. Maksareva, Mendeleev
hydrogen bonds into a three-dimensional H-bonded framework.
The main geometric parameters in compounds 3a and 3b are
similar. In all the molecules, the bridging hydrogen atoms are
characterised by the cis configuration. It was found that the
C(1) and C(5) atoms in compound 5 have the (1S,5R) absolute
configuration, which suggests that compound 3b has a similar
configuration of the bridging carbon atoms. This fact confirms
our assumption on the opposite configuration of the C(1)–C(5)
atoms in the enantiomer pairs.
Commun., 2000, 27.
K. Yu. Chegaev, A. N. Kravchenko, O. V. Lebedev and Yu. A. Strelenko,
Mendeleev Commun., 2001, 32.
A. N. Kravchenko, E. Yu. Maksareva, P. A. Belyakov, A. S. Sigachev,
K. Yu. Chegaev, K. A. Lyssenko, O. V. Lebedev and N. N. Makhova,
Izv. Akad. Nauk, Ser. Khim., 2003, 180 (Russ. Chem. Bull, Int. Ed.,
7
8
2
003, 52, 192).
9
K. A. Lyssenko, D. G. Golovanov, A. N. Kravchenko, I. E. Chikunov,
O. V. Lebedev and N. N. Makhova, Mendeleev Commun., 2004, 105.
0 A. N. Kravchenko, K. Yu. Chegaev, I. E. Chikunov, P. A. Belyakov,
E. Yu. Maksareva, K. A. Lyssenko, O. V. Lebedev and N. N. Makhova,
Mendeleev Commun., 2003, 269.
1
Thus, we were the first to develop diastereospecific syntheses
of (1S,5R)- and (1R,5S)-glycoluriles, including enantiomeric
pairs, by the α-ureidoalkylation of (S)/(R)-N-carbamoyl-α-amino
11 T. Suzuki, T. Tomioka and K. Tuzimura, Can. J. Biochem., 1977, 55,
21.
12 H. Petersen, Liebigs Ann. Chem., 1969, 726, 89.
5
‡
X-ray diffraction analysis: at 120 K, the crystals of 5 (C H N NiO S )
18
46
8
18 2
1
3 J. Taillades, L. Boiteau, I. Beuzelin, O. Lagrille, J.-P. Biron, W. Vayaboury,
O. Vandenabeele-Trambouze, O. Giani and A. Commeyras, J. Chem.
Soc., Perkin Trans. 2, 2001, 1247.
4 A. G. Pechenkin, A. V. Evseeva, A. P. Gilev and T. V. Mikhailova, Izv.
Tomsk. Politekh. Inst., 1974, 233, 73 (in Russian).
are orthorhombic, space group P2 2 2, a = 7.664(1), b = 32.849(5) and
1
1
3
c = 6.722(1) Å, V = 1692.3(5) Å , Z = 2 (Z' = 0.5), M = 785.46, d
=
calc
–
3
–1
=
1.541 g cm , (MoKα) = 7.81 cm , F(000) = 828. The intensities of
1
1
1714 reflections were measured with a Smart 1000 CCD diffractometer
at 120 K [l(MoKα) = 0.71072 Å, 2q < 58°], and 4025 independent
1
5 H. D. Flack, Acta Crystallogr., 1983, A39, 876.
reflections (R = 0.0409) were used in the further refinement. The
int
structure was solved by the direct method and refined by the full-matrix
2
least-squares technique against F in the anisotropic–isotropic approxi-
mation. Analysis of the Fourier density synthesis revealed that one of
solvate water molecules is disordered by centre of symmetry and the
other one is disordered by two positions with occupancies of 0.4 and 0.6.
The hydrogen atoms were located from the Fourier density synthesis
with the only exception of disordered water molecules for which the
positions of hydrogen atoms were not found. The absolute configuration
was determined by means of the Flack parameter,15 the value of which
in the case of the 1S,5R configuration of the C(1) and C(5) atoms was
0
.00(2). The refinement converged to wR = 0.1052 and GOF = 1.084
2
for all independent reflections [R = 0.0480 was calculated against F
1
for 29658 observed reflections with I > 2s(I)]. All calculations were
performed using SHELXTL PLUS 5.0.
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(
CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference number 257433. For details, see ‘Notice to Authors’,
Mendeleev Commun., Issue 1, 2004.
Received: 29th September 2004; Com. 04/2375
Mendeleev Commun. 2004 255