A straightforward synthesis and partial hydrolysis of cysteine-derived 2,5-diketopiperazines

Article abstract of DOI:10.1016/j.tetlet.2010.06.108

A mild and straightforward preparation of cysteine-derived 2,5-diketopiperazines (DKPs) is reported, by cyclization of (R)-2,2- dimethyltetrahydrothiazole-4-carboxylic acid hydrochloride or of (R)-tetrahydrothiazole-4-carboxylic acid hydrochloride, mediated by HBTU and DIEA. One DKP has been characterized by X-ray analysis, while the other has been hydrolyzed to cyclo-Cys-Cys. The preparation of this latter compound has been previously reported to be troublesome and low yielding.

Full text of DOI:10.1016/j.tetlet.2010.06.108

Tetrahedron Letters 51 (2010) 4558–4559
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A straightforward synthesis and partial hydrolysis of cysteine-derived
2,5-diketopiperazines
Daniela Iannotta, Nicola Castellucci, Magda Monari, Claudia Tomasini *
Dipartimento di Chimica ‘G: Ciamician’, Alma Mater Studiorum Università di Bologna, Via Selmi, 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and straightforward preparation of cysteine-derived 2,5-diketopiperazines (DKPs) is reported, by
cyclization of (R)-2,2-dimethyltetrahydrothiazole-4-carboxylic acid hydrochloride or of (R)-tetrahydro-
thiazole-4-carboxylic acid hydrochloride, mediated by HBTU and DIEA. One DKP has been characterized
by X-ray analysis, while the other has been hydrolyzed to cyclo-Cys-Cys. The preparation of this latter
compound has been previously reported to be troublesome and low yielding.
Received 10 May 2010
Revised 21 June 2010
Accepted 22 June 2010
Available online 25 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
2
,5-Diketopiperazines (DKPs) are a class of compounds useful in
tion fused with two outer thiazolidine rings in a half-chair confor-
mation (Fig. 1).
The crystal packing of 2a, shown in Figure 2, is characterized by
the presence of intermolecular hydrophobic interactions and
C–Hꢀ ꢀ ꢀO hydrogen bonds. All carbonylic oxygens of the DKP ring
participate in the weak intermolecular non classic H-bonds with
medicinal chemistry, combinatorial chemistry, and targeted organ-
ic synthesis. A variety of DKPs have been found to possess inter-
esting biological properties such as antitumor, antimicrobial,
and antiviral activities.
DKPs are usually prepared by cyclization of deprotected dipep-
tides. This reaction takes place easily with aliphatic or aromatic
1
2
3
4
5
amino acids, such as alanine, valine, or phenylalanine, while sev-
eral problems occur when derivatized amino acids are used. More
recently, some methods for the preparation of DKPs in one step
O
O
R
R
from unprotected
a-amino acids have been reported, but they
are not mild and cannot be applied for the preparation of DKPs de-
OH
Cl-
HBTU, DIEA
3
6
CH CN
N
rived from cysteine.
+
S
NH
2
S
S
On the contrary, a couple of synthesis of some DKPs derived
r. t., 2 h
N
from protected
L-cysteine has been reported by a three-step
7
R
R
procedure, starting from thiazoline-4-carboxylic acid derivatives.
1a-b
a: R = CH
3
, yield = 78%
R
R
2a-b
b: R = H, yield = 70%
O
Herein we report a one-step synthesis of (R)-2,2-dimethyltetrahy-
8
drothiazole-4-carboxylic acid hydrochloride 1a or (R)-thiazole-
Scheme 1. Synthesis of DKPs 2a and 2b.
9
4
-carboxylic acid hydrochloride 1b (Scheme 1).
The 2,5-diketopiperazines 2a and 2b were obtained by the
simultaneous formation of the two amide bonds, by reaction with
HBTU in the presence of diisopropylethyl amine (DIEA) in acetoni-
trile. In both cases the reaction takes place for 2 h and with high
yields. A similar result has been obtained if DIEA is replaced with
1
,8-diazabicyclo[5.4.0]undec-7-ene (DBU). An inert atmosphere is
1
0
not necessary.
While compound 2b has previously been fully characterized,7
a has never been characterized and has been reported only as a
2
1
1,12
by-product.
Therefore, we grew crystals from methanol and
13
carried out a single crystal X-ray diffraction study. The molecular
structure of 2a consists of a central DKP ring in a boat conforma-
*
Corresponding author. Tel.: +39 0512099596; fax: +39 0512099456.
E-mail address: claudia.tomasini@unibo.it (C. Tomasini).
Figure 1. ORTEP drawing of 2a.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.108

D. Iannotta et al. / Tetrahedron Letters 51 (2010) 4558–4559
4559
References and notes
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Acids 2004, 23, 1815–1824.
(a) Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297–3312; (b) Campo,
V. L.; Martins, M. B.; da Silva, C. H. T. P.; Carvalho, I. Tetrahedron 2009, 65, 5343–
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1
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349; (c) Zeng, Y.; Li, Q.; Hanzlika, R. P.; Aube, J. Bioorg. Med. Chem. Lett. 2005,
1, 3034–3038; (d) Tullberg, M.; Grøtli, M.; Luthman, K. Tetrahedron 2006, 62,
484–7491; (e) Fischer, P. M. J. Pept. Sci. 2003, 9, 9–35; (f) Martins, M. B.;
Carvalho, I. Tetrahedron 2007, 63, 9923–9932; (g) Thajudeen, H.; Park, K.;
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(a) Jainta, M.; Nieger, M.; Bräse, S. Eur. J. Org. Chem. 2008, 5418–5424; (b) Zadel,
G.; Breitmaier, E. Chem. Ber. 1994, 127, 1323–1326; (c) Tang, H.; Zhao, G.; Zhou,
Z.; Zhou, Q.; Tang, C. Tetrahedron Lett. 2006, 47, 5717–5721; (d) Basiuk, V. A.;
Gromovoy, T. Y.; Chuiko, A. A.; Soloshonok, V. A.; Kukhar, V. P. Synthesis 1992,
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6
49–451; (e) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett. 2006, 8,
139–6142.
7
.
.
(a) Gonzàles, A.; Vorob’eva, S. L.; Linares, A. Tetrahedron: Asymmetry 1995, 6,
Figure 2. View down the c axis of the crystal packing of 2a. Dotted lines indicate
the weak intermolecular H-bonds.
1
1
357–1366; (b) Gy o} rgydeák, Z.; Dinya, Z.; Bognár, R. Chem. Heterocycl. Compd.
979, 15, 983–988.
8
Suaifan, G. A. R.; Mahon, M. F.; Arafat, T.; Threadgill, M. D. Tetrahedron 2006, 62,
1245–11266.
9. Ratner, S.; Clarke, H. T. J. Am. Chem. Soc. 1937, 59, 200–206.
0. Experimental procedure for the formation of 2,5-diketopiperazines 2a and 2b: A
solution of (R)-2,2-dimethyltetrahydrothiazole-4-carboxylic acid
1
O
O
O
1
0
.2 M HCl
hydrochloride 1a (0.2 g, 1 mmol) or of (R)-2,2-dimethyltetrahydrothiazole-4-
carboxylic acid hydrochloride 1b (0.17 g, 1 mmol) and HBTU (0.4 g, 1.00 mmol)
in dry acetonitrile (15 mL) was stirred under inert atmosphere for 10 min at
room temperature. Then DIEA (3.2 mmol, 0.56 mL) in dry acetonitrile (10 mL)
was added dropwise at room temperature. The solution was stirred for 3 h
under inert atmosphere, then acetonitrile was removed under reduced
pressure and replaced with ethyl acetate. The mixture was washed with
N
in MeOH
NH
S
S
HS
SH
N
88%
HN
2b
3
O
brine, 1 N aqueous HCl (3 ꢁ 30 mL), and with 5% aqueous NaHCO (1 ꢁ 30 mL),
3
Scheme 2. Synthesis of cyclo-Cys-Cys 3.
dried over sodium sulfate, and concentrated in vacuo. The product 2a was
obtained pure after recrystallization from methanol, while the product 2b was
obtained pure after silica gel chromatography (DCM 100%?DCM/ethyl acetate
8
0:20 as the eluant).
the methyne and methyl hydrogens of neighboring molecules thus
generating layers perpendicular to the c axis. Hydrophobic contacts
between methyl and methylene groups of different layers further
stabilize the packing of 2a giving a 3D network.
1
1
1. (a) Vorbr u} ggen, H. Synthesis 2008, 23, 3739–3741; (b) Goldfarb, D. S. U.S. Pat.
Appl. Publ., 2009, US 2009163545 A1 20090625.
2
0
2. Characterization data for 2a: mp = 218 °C; ½
aꢂ
¼ ꢃ96:8 (c 1.0, CHCl
3
); IR
, 400 MHz): d 1.84 (s,
H, Me), 1.8 (s, 3H, Me), 3.28 (ABX, 2H, J = 6.2, 10.4, 12.4 Hz, CH S), 4.60 (dd,
, 100 MHz): d 27.7, 29.6, 30.0, 66.2, 73.0,
D
ꢃ1
1
(
2 2 3
CH Cl , 3 mM): m 1685, 1675, 1671 cm ; H NMR (CDCl
3
2
13
Finally DKP 2b was hydrolyzed to obtain cyclo-
L-cysteine-L-cys-
J = 6.2, 10.2 Hz, CHN); C NMR (CDCl
63.7.
3. Crystal data for 2a: C12
), a = 17.576(4),
V = 2132.7(8) Å , F(0 0 0) = 912,
3
1
teine 3. The preparation of 3 has been reported in the past, follow-
1
18 2 2 2
H N O S , M = 286.40, monoclinic. space group C2 (No.
ing a different pathway, that is troublesome and requires several
5
b = 11.309(3),
(Mo
c = 10.749(2) Å,
b = 93.442(3)°,
1
4
15
3
ꢃ1
ꢃ3
steps. Furthermore 3 has never been fully characterized.
l
K
a
) = 0.371 cm
,
D = 1.338 g cm
,
c
T = 296 K. Intensity data were collected on a SMART Apex II diffractometer
with graphite-monochromated radiation (k = 0.71073 Å). total of 4169
independent reflections were collected of which 3901 were considered
observed [I > 2 (I)]. The structure was solved by direct methods (SIR97) [see:
In our approach, compound 2b was stirred with 0.2 M HCl in
methanol at room temperature for 24 h. Compound 3 was obtained
as a white solid simply by filtration of the reaction mixture in 88%
yield (Scheme 2).
In contrast, DKP 2a does not react at all under several reaction
conditions. After prolonged reaction times at high temperature,
the molecule decomposes with the formation of a complex
mixture. The remarkable stability of 2a is probably due to the high
steric hindrance of the four methyl groups present on the tetrahy-
drothiazole rings.
In conclusion, we have reported a very mild and straightfor-
ward synthesis of cysteine-derived 2,5-diketopiperazines that af-
fords the desired compounds in short times and high yields.
Furthermore, cyclo-L-Cys-L-Cys was easily prepared; in the past this
compound had been obtained only by a troublesome and low
yielding method.
A
r
Altomare, A.; Burla, M.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Moliterni,
A.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115–118] and2
subsequent Fourier syntheses and refined by full-matrix least-squares on F
(SHELXTL) [see: Sheldrick, G.M. SHELXTLplus Version 5.1 (Windows NT version)-
Structure Determination Package; Bruker Analytical X-ray Instruments Inc.:
Madison, WI, 1998], using anisotropic thermal parameters for all non-
hydrogen atoms. Hydrogen atoms were added in geometrically idealized
positions and treated as riding atoms. The structure was eventually refined to
2
R = 0.0673 (wR = 0.1924). Crystallographic data for this structure have been
deposited with the Cambridge Crystallographic Data Centre as Supplementary
publication number CCDC 776236. Copies of the data can be obtained, free of
charge, via www.ccdc.cam.ac.uk (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax. +44 1223 336 033; or e-
mail: deposit@ccdc.cam.ac.uk).
1
4. (a) Gockel, P.; Vogler, R.; Gelinsky, M.; Meißner, A.; Albrich, H.; Vahrenkamp, H.
Inorg. Chim. Acta 2001, 323, 16–22; (b) Greenstein, J. P. J. Biol. Chem. 1937, 118,
321–329; (c) Cook, J. M.; Baker, D. A.; Yin, W.; Johnson, E. M. II PTC Int. Appl.,
WO2009100431 A1 20090813, 2009.; (d) Yang, C.-H.; Brown, J. N.; Kopple, K. D.
Int. J. Pept. Protein Res. 1979, 14, 12–20; Some quantum chemical calculations
on the boat-like conformation of cyclo-Cys-Cys have been reported: (e) Zhu, Y.;
Tang, M.; Shi, X.; Zhao, Y. J. Quantum Chem. 2007, 107, 745–753; (f) Kolaskar, A.
S.; Sarathy, K. P. Biopolymers 1980, 19, 1345–1355.
Acknowledgments
We are grateful to Ministero dell’Università e della Ricerca Sci-
entifica (PRIN 2008) and Università di Bologna (Funds for selected
topics) for financial support. C.T. is grateful to Fondazione del
Monte di Bologna e di Ravenna for financial support.
2
0
1
5. Characterization data for 3: mp = 172 °C; ½
a
ꢂ
¼ ꢃ44:3 (c 0.7, H
2
O); IR (nujol):
, 400 MHz): d 3.26 (d, 2H, J = 6.8 Hz,
S), 4.57 (t, J = 6.8 Hz, CHN); C NMR (DMSO-d , 100 MHz): d 33.6, 64.1,
m
D
ꢃ1
1
3
379, 1650 cm ; H NMR (DMSO-d
6
13
CH
2
6
169.6.