2,5-Imidazolidinedione formation from seven membered cyclodipeptide rearrangement

Article abstract of DOI:10.1081/SCC-100103990

Cyclization of the linear peptide 5 prepared by coupling a suitably β-amino acid 1 with N-protected L-Ala yielded 2,5-imidazolidinedione 6.

Full text of DOI:10.1081/SCC-100103990

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2,5-IMIDAZOLIDINEDIONE
FORMATION FROM SEVEN
MEMBERED CYCLODIPEPTIDE
REARRANGEMENT
A. Jenhi a , J.-P. Lavergne b , M. Rolland b , J.
Martinez b & A. Hasnaoui a
a Université Cadi Ayyad , Laboratoire de Chimie
des Substances Naturelles et des, Hétérocycles,
Marrakech, BP S15, Maroc
b Université s Montpellier, I et II , Laboratoire des
Aminoacides, des Peptides et des Protéïnes CNRS-
UMR 5810, Montpellier, Cédex 5, 34095, France
Published online: 09 Nov 2006.
To cite this article: A. Jenhi , J.-P. Lavergne , M. Rolland , J. Martinez & A.
Hasnaoui (2001) 2,5-IMIDAZOLIDINEDIONE FORMATION FROM SEVEN MEMBERED
CYCLODIPEPTIDE REARRANGEMENT, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:11, 1707-1714,
DOI: 10.1081/SCC-100103990
To link to this article: http://dx.doi.org/10.1081/SCC-100103990
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SYNTHETIC COMMUNICATIONS, 31(11), 1707–1714 (2001)
2,5-IMIDAZOLIDINEDIONE FORMATION
FROM SEVEN MEMBERED
CYCLODIPEPTIDE REARRANGEMENT
A. Jenhi,1 J.-P. Lavergne,2, M. Rolland,2 J. Martinez,2
*
and A. Hasnaoui1
1Laboratoire de Chimie des Substances Naturelles et des
Heterocycles, Universite Cadi Ayyad, BP S15,
Marrakech, Maroc
2Laboratoire des Aminoacides, des Peptides et des
Proteınes, CNRS-UMR 5810, Universites Montpellier
I et II, 34095 Montpellier Cedex 5, France
ABSTRACT
Cyclization of the linear peptide 5 prepared by coupling a
suitably b-amino acid 1 with N-protected L-Ala yielded
2,5-imidazolidinedione 6.
Cyclopeptides constitute an important class of compounds in view
of their wide spectrum of biological activity.1 Several cyclic dipeptides of
different sizes including diketopiperazines have been prepared.2
The synthesis of seven-membered cyclopeptides of type A was
envisioned by two ways from the linear precursors B (Scheme 1). We have
previously described the results using the first strategy (pathway a).3 The
cyclic diazepinedione, presenting two carbomethoxy groups in position trans,
was obtained in good yields but without control of chirality at C-2 carbon.
* Corresponding author. E-mail: lavergne@univ-montp2.fr
1707
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1708
JENHI ET AL.
Scheme 1.
We report here the synthesis and the cyclization of peptide 5 (type B),
following the second strategy (pathway b) which includes activation of the
C-terminal of the b-amino acid. This compound was prepared in three steps
(Scheme 2) from the b-amino acid 1 and diBoc-L-Ala.4 Compound 1 was
obtained in 65% yield through alkylation of N-benzyloxycarbonyl-2-chloro-
glycine methyl ester5 by the anion derived from t-butyl methylmalonate
followed by hydrogenolysis of the benzyloxycarbonyl groups.
Coupling of the two amino acids using BOP/DIEA in dichloro-
methane,6 afforded peptide 3 in 70% yield. In the following step the amide
bond was benzylated with benzyl bromide using phase transfer catalysis. It
was shown that alkylation of the amide nitrogen was essential to allow
cyclization.7 Compound 4 was deprotected by 30% TFA to afford the
linear peptide 5 (Scheme 2). Cyclization of this peptide was achieved
using the method previously described3 in the presence of BOP/DIEA in
DMF. The isolated compound (in 50% yield) was not the expected diaze-
pinedione but the imidazolidinedione 6 (mixture of four diastereomers:
6a1/6a2, 6b1/6b2), (Scheme 3).
The structure of compound 6 was established from the spectral data
and from X-ray crystallographic analysis (Figure 1). Formation of 6 can be
explained by a transannular reaction of the initially formed, but not iso-
lated, seven-membered cyclodipeptide, followed by migration of the benzyl
group like in the Stevens rearrangement (Scheme 3).
EXPERIMENTAL
General
Reagents and solvents were purified in the usual way. Thin layer
chromatography was performed on Merck precoated silica gel 60F254

CYCLODIPEPTIDE REARRANGEMENT
1709
Scheme 2.
Scheme 3.
plates and spots were visualized by ultraviolet light or by iodine vapour.
Column chromatography was performed on silica gel Merck 60. Spectra
were recorded with the following instruments: IR spectra: Perkin-Elmer
FT-IR Parangon 1000, 1H NMR spectra: Brucker AC-250, 13C NMR spec-
tra: Brucker WP-200, Mass spectra: Jeol JMS DX 300. Melting points are
reported uncorrected and were obtained on a Buchi 510 apparatus. Routine
analyse agreed with calculated values within þ/À 0.3%.
Synthesis of the b-Amino Ester 1
NaH (0.19 g, 8 mmoles, 1.1 equiv.) was added to a stirred solution of
t-butyl methylmalonate (1.39 g, 8 mmoles, 1.1 equiv.) in dry THF (20 ml), at
À10ꢀC. The mixture was stirred at À10ꢀC (15 mn) and then a solution of

1710
JENHI ET AL.
Figure 1. X-Ray structure of 6a1 (S,S,S,), 6a2 (R,R,S).
N-benzyloxycarbonyl-2-chloroglycine methyl ester (1.85 g, 7,2 mmoles,
1 equiv.) in THF (3 ml) was added using a syringe at À78ꢀC. After the
mixture had been stirred at À78ꢀC for 2 h, it was washed with a saturated
solution of NH4Cl and the aqueous phase was then extracted with ethyl
acetate (3 Â 20 ml). The organic layer was dried (MgSO4) and then concen-
trated under reduced pressure and purified by chromatography on silica gel
(EtOAc/hexane: 1/9). Yield: 1.66 g (69%), colourless oil. Rf ¼ 0.70 (hexane/
EtOAc: 7/3).
1H-NMR (CDCl3), d ppm: 7.29 (s, 5H, Ar), 5.94 (d, 1H, NH,
J ¼ 9.5 Hz), 5.11 (s, 2H, CH2Ph), 5.02 (dd, 1H, CHa, J ¼ 9.5 Hz,
J ¼ 4.2 Hz), 4.07 (d, 1H, CHb, J ¼ 4.2 Hz), 3.73 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 1.43 (s, 9H, t-Bu). [MþHþ] ¼ 396 (FABþ/GT). IR (NaCl,
film): ꢀNH ¼ 3390 cmÀ1, ꢀCO ¼ 1750, 1728, 1716, 1688 cmÀ1
.
Hydrogenolysis
20% palladium hydroxyde (0.05 g) was added to a solution of the
protected b-aminoester (1 g, 2.53 mmoles) in EtOH/HCl 0.03 N (50 ml).
The mixture was stirred at room temperature under H2. After stirring
(2 h), the mixture was filtered on celite and the solvent was concentrated
in vacuo to yield 1. Yield: 0.43 g (85%).
1H-NMR (CDCl3), d ppm: 4.68 (d, 1H, CHa, J ¼ 5.6 Hz), 4.32 (d, 1H,
CHb, J ¼ 5.6 Hz), 3.78 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 1.41 (s, 9H,

CYCLODIPEPTIDE REARRANGEMENT
1711
t-Bu). [MþHþ] ¼ 262 (FABþ/GT). IR (NaCl, film):ꢀCO ¼ 1745, 1730, 1710,
1694 cmÀ1
.
Coupling Reaction, Synthesis of Compound 3
To a stirred and cooled solution of 1 (1.04 g, 4 mmoles) in DCM
(10 ml), were added (Boc)2-Gly-OH (0.88 g, 4 mmoles), BOP reagent
(1.94 g, 4.4 mmoles) and DIEA (1.53 ml, 8 mmoles). The mixture was stirred
for 16 h at À10ꢀC. The solvent was evaporated and ethyl acetate (20 ml) was
added. The organic fraction was washed with KHSO4, water, NaHCO3 and
saturated brine. The organic phase was dried over anhydrous MgSO4, fil-
tered and concentrated in vacuo. The residue was then purified by chroma-
tography on silica gel (hexane/EtOAc : 4/1) to give 3. Yield: 1.45 g (68%).
Rf ¼ 0.36 (hexane/EtOAc: 4/1).
1H-NMR (CDCl3), d ppm: 6.96 (br, 1H, NH), 5.17 (m, 1H, C5-H), 4.76
(m, 1H, C2-H), 3.98 (m, 1H, C6-H), 3.69 (s, 3H, OCH3), 3.67 (s, 3H, OCH3),
1.43 (s, 27H, 2Boc, tBu), 1.38 (d, 3H, CH3, J ¼ 7.0 Hz). [MþHþ] ¼ 533 (ES).
IR (NaCl, film): ꢀNH ¼ 3438 cmÀ1 , ꢀCO ¼ 1746, 1731, 1698 cmÀ1
.
N-Benzylation of Compound 3
To a solution of 3 (2.13 g, 4 mmoles) in dry toluene (80 ml) were added
pulverized K2CO3, tetrabutylammonium bromide (0.8 g) and benzyl
bromide (0.64 ml). The mixture was stirred at room temperature for 48 h.
The reaction mixture was then filtered, concentrated in vacuo, purified on
silica gel (hexane/EtOAc: 4/1) to give 4. Yield: 1.12 g (45%). Rf ¼ 0.36
(hexane/EtOAc: 4/1).
1H-NMR (CDCl3), d ppm: 7.12 (m, 5H, Ar), 5.16 (m, 1H, C5-H), 4.75
(m, 1H, C6-H), 3.98 (m, 1H, C6-H), 3.69 (s, 3H, OCH3), 3.67 (s, 3H, OCH3),
3.41 (q, 1H, C2-H, J ¼ 7.0 Hz), 3.21 (m, 2H, CH2Ph), 1.43 (s, 27H, 2Boc,
tBu), 1.13 (d, 3H, CH3, J ¼ 7.0 Hz). [MþHþ] ¼ 533 (ES). IR (NaCl, film):
ꢀNH ¼ 3438 cmÀ1, ꢀCO ¼ 1746, 1731, 1698 cmÀ1
.
Cleavage of the Boc and tBu Groups, Synthesis of Compound 5
Compound 4 (1 g, 1.88 mmole), was treated with trifluoroacetic acid
(30%) in DCMfor 4 h at room temperature. The mixture was concentrated
in vacuo and the corresponding trifluoroacetic salt 5, was dried under high
vacuum to constant weight. Yield: 0.90 g (100%).

1712
JENHI ET AL.
1H-NMR (CD3COCD3), d ppm: 7.35 (m, 5H, Ar), 4.42–5.35 (m, 4H,
C5-H, CH2Ph, C6-H), 3.70 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.60 (m, 1H,
C2-H), 1.58 (d, 3H, CH3, J ¼ 7.0 Hz). [MþHþ] ¼ 366 (ES).
Cyclisation Reaction Synthesis of Compound 6
The linear precursor 5 (0.5 g, 1.4 mmole) was added over 5 h from a
syringe pump to a stirred and cooled solution (À30ꢀC) of BOP reagent
(0.63 g, 1.43 mmole) and DIEA (0.68 ml, 3.9 mmoles) in DMF (10 ml). The
mixture was stirred 24 h at room temperature. The solvent was removed
under reduced pressure and the residue was dissolved in ethyl acetate
(10 ml) and washed with KHSO4, water, NaHCO3 and saturated brine.
The organic phase was dried over anhydrous MgSO4, filtered and con-
centrated in vacuo. The residue was purified by chromatography on silica
gel (hexane/EtOAc: 1/1). Yield: 0.23 g (49%).
Dimethyl 3-Benzyl-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)
butanedioate: 6
Mixture of Four Diastereoisomers
6a1/a2 (16%): mp ¼ 134ꢀC (EtOAc). Rf ¼ 0.25 (hexane/EtOAc: 1/4),
HPLC (CH3CN/H2O: 70/30), Rt: 20.42 mn. Anal. Calcd. for C17H20N2O6:
C, 58,61; H, 5,78; N, 7,82. Found: C, 58,68; H, 5,75; N, 7,85.
Crystal Structure of 6a1/6a2: C17H20N2O6, MW ¼ 348.355, Monoclinic,
space group P 21, Z ¼ 4, a ¼ 11.0323(7), b ¼ 11.7742(4), c ¼ 14.1121(9) A,
b ¼ 99.380(2)ꢀ V ¼ 1808.6(2)A3, d calc ¼ 1.23 g cmÀ3, ꢁ(MoKa) ¼ 1.5418 A,
m ¼ 0.88 mmÀ1
. Intensity data were measured on a Enraf-Nonius
KappaCCD diffractometer using graphite-monochromated Mo Ka radia-
tion and the f-scan technique. 12894 collected reflexions, 3708 unique
(Rint ¼ 0.055) of which 2890 were considered as observed having I>3
ꢂ(I). Hydrogen are in theoretical position. Refinement of F2, R[F2>3ꢂ
(F2)] ¼ 0.059 and wR(F2) ¼ 0.059 w ¼ 1/[ꢂ2(Fo2)þ0.030þFo2] goodness
of fit >1.51. The residual electron density in the final difference map was
located between À0.20 and 0.311 e A3. Two independent molecules form a
dimer. Computer-programs: MaXus.
6b1/b2 (33%) : mp ¼ 141ꢀC (EtOAc). Rf ¼ 0.28 (hexane/EtOAc: 1/4),
HPLC (CH3CN/H2O: 70/30), Rt: 20.31 mn. [MþHþ] ¼ 349 (FABþ/GT).
Anal. Calcd. for C17H20N2O6: C, 58,61; H, 5,78; N, 7,82. Found:C, 58,65;
H, 5,77; N, 7,87.

CYCLODIPEPTIDE REARRANGEMENT
1H-NMR (CD3COCD3): d ppm
1713
6a1/a2: 7.02 (m, 5H, Ar), 4.88 (d, 1H, J ¼ 10.6 Hz, CH-COOMe), 3.92
(qd, 1H, C4-H, J ¼ 6.9, 1.3 Hz), 3.54 (s, 3H, OCH3), 3.46 (m, 1H, CH-
COOMe), 3.35 (s, 3H, OCH3), 2.68 (m, 1H, CH2Ph), 2.55 (m, 1H,
CH2Ph), 1.21 (d, 3H, CH3, J ¼ 7.2 Hz).
6b1/6b2: 7.11 (m, 5H, Ar), 4.69 (d, 1H, J ¼ 9.6 Hz, CH-COOMe), 4.03
(qd, 1H, C4-H, J ¼ 6.5, 1.3 Hz), 3.60 (s, 3H, OCH3), 3.56 (m, 1H, CH-
COOMe), 3.35 (s, 3H, OCH3), 3.01 (m, 1H, CH2Ph), 2.85 (m, 1H,
CH2Ph), 1.20 (d, 3H, CH3, J ¼ 7.2 Hz).
13C-NMR (CD3COCD3): d ppm
6a1/6a2: 174.8, 173.3, 168.6, 155.9 (C ¼ O), 138.3, 129.0, 128.7, 128.6,
126.9, 126.8 (C-Ar), 53.4, 53.3, 53.1, 52.7, 52.6, 51.6, 51.4, 46.5 (OCH3, CH-
2, CH-3, CH-CH3), 36.1 (CH2Ph), 17.2 (CH3).
6b1/6b2: 174.3, 174.2, 171.9, 168.5, 155.6 (C ¼ O), 139.3, 129.1, 128.8,
128.4, 126.9, 126.8 (C-Ar), 54.4, 52.9, 52.8, 52.7, 52.6, 52.5, 51.5, 48.1
(OCH3, CH-2, CH-3, CH-CH3), 36.2, 36.1 (CH2Ph), 17.3, 17.2 (CH3).
ABBREVIATIONS
Boc : tert-butyloxycarbonyl
BOP : benzotriazol-1-yloxy-tris (dimethylamino)phosphonium hexafluoro-
phosphate
DMF : dimethylformamide
DCM : dichloromethane
DIEA : diisopropylethylamine
TFA : trifluoroacetic acid
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Accepted in the Netherlands August 3, 2000