Solvent-free, efficient synthesis of 2,5-piperazinediones from Boc-protected dipeptide esters under microwave irradiation

Article abstract of DOI:10.1055/s-2005-865205

Microwave irradiation allows the efficient, solvent-free transformation of N-Boc dipeptide esters into 2,5-piperazinediones. The microwave-assisted conditions were found to be much better than traditional heating in terms of reaction time, yield and stere

Full text of DOI:10.1055/s-2005-865205

1158
LETTER
Solvent-Free, Efficient Synthesis of 2,5-Piperazinediones from Boc-Protected
Dipeptide Esters under Microwave Irradiation
I
mprove
d
Synthesi
l
s
of 2,5
b
-Piperazined
e
iones rto López-Cobeñas, Pilar Cledera, J. Domingo Sánchez, Rafael Pérez-Contreras, Pilar López-Alvarado,
M. Teresa Ramos, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
E-mail: josecm@farm.ucm.es
Received 20 November 2005
compared to 2–4.5 hours at 200 °C for the conventional
Abstract: Microwave irradiation allows the efficient, solvent-free
heating reactions, and yields were also normally higher
transformation of N-Boc dipeptide esters into 2,5-piperazinediones.
for the microwave assisted reactions, with the additional
The microwave-assisted conditions were found to be much better
advantage of not requiring an inert atmosphere.13 We em-
than traditional heating in terms of reaction time, yield and stereo-
center integrity.
ployed a domestic microwave oven set at 600 W, with the
reaction vessels introduced in an alumina heat sink. In our
initial experiments we irradiated the reactions in one-
minute pulses to prevent excessive heating (entry 1), how-
ever, under these conditions some N-substituted dipep-
tides reacted slowly or not at all (e.g. entry 7). In these
cases, we found that addition of 10% silica gel to the reac-
tion mixture enabled the transformation in five one-
minute pulses, normally with improved yields with regard
to the thermal reaction. The precaution of irradiating in
short pulses was subsequently proved unnecessary, since
irradiations of up to five consecutive minutes at 600 W
were tolerated without decomposition (e.g. entry 3), mak-
ing unnecessary the addition of silica gel. The microwave
reactions could be scaled-up with only slight yield loss;
for instance, the reaction in entry 12 was performed in
83% yield starting from 6 g of dipeptide.
Key words: microwave irradiation, diketopiperazines, dipeptides,
cyclizations, heterocycles
Many natural products with the 2,5-piperazinedione scaf-
fold (DKPs) have been isolated, encompassing a wide
range of biological activities.1 Unnatural DKPs are also
very common in medicinal chemistry and show a broad
spectrum of interesting pharmacological properties.2 Mo-
lecular recognition is another field of interest, since recep-
tors based on DKP backbones interact with peptidic
substrates with high specificity.3 Finally, DKPs are very
versatile synthetic intermediates.4,5
Due to their importance, the development of improved
routes to DKPs continues to be of interest.6 Diketopipera-
zines can be considered as ‘head-to-tail’ cyclic dipeptides.
As such, their simplest preparations are those that take ad-
vantage of the chirality and commercial availability of
amino acids, and normally involve the synthesis of a
suitable linear dipeptide followed by N-deprotection and
cyclization, which is normally effected under basic7 or
acidic8 conditions. Ideally, the choice of N-protecting
group should be such that deprotection takes place under
the same conditions as cyclization, leading to a one-step
preparation of the target DKP. We reasoned that, because
N-Boc deprotection has been achieved under microwave
conditions, albeit not from dipeptides,9 and cyclization of
dipeptide esters can be carried out under thermal condi-
tions, normally in refluxing toluene or xylene for 24
hours,10 the one-pot deprotection/cyclization of N-Boc
dipeptide esters would be an excellent candidate for
microwave optimization.
Stereochemical integrity is also a very important aspect of
the preparation of DKPs. A derivative of cyclo-(Gly-L-
Ala) obtained under thermal conditions has been previ-
ously shown to be enantiomerically pure by proton NMR
in the presence of Eu(hfc)3.14 Regarding valine deriva-
tives, we have found that samples of compound 3e pre-
pared using three procedures, namely thermal and
microwave cyclization of a N-Boc dipeptide ester and hy-
drogenolysis/cyclization of a N-Cbz dipeptide ester,
which is known to be safe in terms of stereochemical in-
tegrity,10 were identical in all respects, including optical
rotation. Furthermore, none of these samples showed
1
splitting of any H NMR resonances upon addition of
Eu(hfc)3, under conditions developed on a reference race-
mic sample of 3e prepared from ( )-Val. However, the re-
action in entry 5, involving (S,S)-Ile, which is known to
undergo a particularly easy epimerization,15 led to a 1:1
mixture of diastereomers under thermal conditions. In this
case, the microwave conditions afforded a (S,S/R,S) 9:1
mixture of diastereomers, showing an advantage in terms
of stereochemical integrity.
Table 1 displays the comparison between the results
obtained in the preparation of several DKPs from the cor-
responding ethyl N-aminoacyl glycinates using conven-
tional and microwave heating.11,12 The reactions were
carried out in 2–8 minutes under microwave irradiation,
In conclusion, we have developed an experimentally
simple and environmentally benign procedure for the
preparation of 2,5-piperazinediones from N-Boc-pro-
tected dipeptide esters. Because DKP ring formation is
SYNLETT 2005, No. 7, pp 1158–1160
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865205; Art ID: D34604ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
5.
2
0
0
5

LETTER
Improved Synthesis of 2,5-Piperazinediones
1159
Table 1 Comparison of the Results Obtained in the Synthesis of 2,5-Piperazinediones from N-Boc Dipeptide Esters under Conventional Ther-
mal and Microwave-Assisted Conditions
Entry
Compound
R1
R2
Conf. at *
Heating (200 °C)
Microwave (600 W)
Time (h)
2
Yield (%)
Time (min)
Yield (%)
1
2
3
4
5
3a
3a
3b
3c
3d
H
H
H
H
H
Me
S
S
S
S
S
84
5a
6b
5c
2c
65
98
87
82
Me
i-Pr
3.5
4.5
4.5
56
72
Bn
(S)-s-Bu
81 (1:1 diast. 5c
mixture)
92 (9:1 diast.
mixture)
6
7
3e
3f
3f
3f
3g
3g
3h
3i
3-Indolylmethyl i-Pr
S
–
–
–
S
S
–
–
–
–
2
2
85
81
3c
5a
5d
3c
5d
3c
8b
3c
5d
5d
90
0
Bn
H
8
Bn
H
64
84
65
90
95
72
99
99
9
Bn
H
10
11
12
13
14
15
Ph(CH2)2
Ph(CH2)2
Me
i-Pr
i-Pr
H
2
81
3 (220 °C)
84
–
(4-MeO)Bn
(3,4-MeO)2Bn
Ph(CH2)2
H
–
2
2
3j
3k
H
79
80
H
a Cycles of 1-min irradiation followed by 1-min cooling periods.
b Two irradiations, with intermediate 2-min cooling periods.
c Irradiation without intermediate cooling periods.
d The starting dipeptide was mixed with 10% silica gel prior to irradiation using conditions c.
J.; Huang, L. H.; Sutcliffe, J.; Kojima, N. J. Antibiot. 2001,
54, 911. (b) Kanoh, K.; Kohno, S.; Katada, J.; Takahashi, J.;
Uno, I.; Hayashi, Y. Bioorg. Med. Chem. 1999, 7, 1451.
(2) See, for instance: (a) Boger, D. L.; Fink, B. E.; Hedrick, M.
P. Bioorg. Med. Chem. Lett. 2000, 10, 1019. (b) Carbonell,
T.; Masip, I.; Sánchez-Baeza, F. M.; Delgado, M.; Araya, E.;
Llorens, O.; Corcho, F.; Pérez, J. J.; Pérez-Payá, E.;
Messeguer, A. Mol. Diversity 2002, 5, 131.
(3) Wennemers, H.; Conza, M.; Nold, M.; Krattiger, P. Chem.–
Eur. J. 2001, 7, 3342.
(4) For a recent example of their role in the preparation of
unnatural aminoacids, see: Bull, S. D.; Davies, S. G.; Garner,
A. C.; O’Shea, M. D.; Savory, E. D.; Snow, E. J. J. Chem.
Soc., Perkin Trans. 1 2002, 2442.
sequence-dependent, being particularly favored for Pro or
Gly residues but more difficult when hindered amino
acids like Phe, Trp, Tyr, Val, Ile, etc. are involved, future
work will be focused on the study of these cases, with
special attention to stereochemical issues.
Acknowledgment
We thank CICYT for financial support of this research through
grant SAF 2003-03141. Studentships from Ministerio de Educación
y Ciencia to ALC (Beca FPU) and RPC (Beca de Colaboración) are
also gratefully acknowledged.
(5) For examples of their use as starting materials in natural
product synthesis, see: (a) Williams, R. M.; Cox, R. J. Acc.
Chem. Res. 2003, 36, 127. (b) Scott, J. D.; Williams, R. M.
Chem. Rev. 2002, 102, 1669.
References
(1) See, for instance: (a) Sugie, Y.; Hirai, H.; Inagaki, T.;
Ishiguro, M.; Kim, Y.-J.; Kojima, Y.; Sakakibara, T.;
Sakemi, S.; Sugiura, A.; Suzuki, Y.; Brennan, L.; Duignan,
Synlett 2005, No. 7, 1158–1160 © Thieme Stuttgart · New York

1160
A. López-Cobeñas et al.
LETTER
(6) For reviews, see: (a) Rajappa, S.; Natekar, M. V. Adv.
Heterocycl. Chem. 1993, 57, 187. (b) Dinsmore, C. J.;
Beshore, D. C. Tetrahedron 2002, 58, 3297. (c) Fisher, P.
M. J. Pept. Sci. 2003, 9, 9.
(7) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc.
1999, 121, 11953.
(8) Suzuki, K.; Sasaki, Y.; Endo, N.; Mihara, Y. Chem. Pharm.
Bull. 1981, 29, 233.
(9) Siro, J. G.; Martín, J.; García-Navío, J. L.; Remuiñán, M. J.;
Vaquero, J. J. Synlett 1998, 147.
(13) Representative Procedure.
A glass vial containing N¢-Boc-Val-(N-3-indolylmethyl)-
Gly-OEt (170 mg, 0.39 mmol) was submerged in alumina,
contained in a beaker, and irradiated for 5 min at 600 W in a
domestic microwave oven. Recrystallization from acetone
gave diketopiperazine 3e (91 mg, 90%) as a white solid; mp
228–229 °C; [a]D23 6.0 (c 0.4 g/100 mL in MeOH). IR
(KBr): 3403, 3559, 1682, 1647, 742 cm–1. 1H NMR (250
MHz, CDCl3): d = 8.23 (br s, 1 H, NHindole), 7.71 (d, 1 H,
J = 7.5 Hz, H-4¢), 7.37 (d, 1 H, J = 8.0 Hz, H-7¢), 7.20–7.09
(m, 3 H, H-2¢,5¢,6¢), 6.15 (br s, 1 H, H-4), 4.90 and 4.71 (AB
system, 2 H, J = 14.5 Hz, N-CH2), 3.92–3.89 (m, 1 H, H-3),
3.85 (s, 2 H, H-6), 2.51–2.41 [m, 1 H, CH(CH3)2], 1.00 and
0.82 [2 d, 3 H, J = 7.0 Hz, CH(CH3)2] ppm. 13C NMR (63
MHz, CDCl3): d = 166.3, 165.2, 136.2, 127.7, 124.7, 122.8,
120.3, 119.2, 111.4, 110.1, 61.0, 48.3, 40.8, 33.0, 19.0, 16.1
ppm. Anal. Calcd for C16H19N3O2 (M = 285): C, 67.36; H,
6.66; N, 14.73. Found: C, 66.92; H, 6.33; N, 14.53.
(14) Cledera, P.; Avendaño, C.; Menéndez, J. C. Tetrahedron
1998, 54, 12349.
(10) See, for instance: Bull, S. D.; Davies, S. G.; Moss, W. O.
Tetrahedron: Asymmetry 1998, 9, 321.
(11) For representative reviews and books on microwave-assisted
organic synthesis, see: (a) Lidstrom, P.; Tierney, J.; Wathey,
B.; Westman, J. Tetrahedron 2001, 57, 9225.
(b) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med.
Chem. 2002, 9, 1251. (c) Tierney, J.; Lindstrom, P.
Microwave Assisted Organic Synthesis; Blackwell: London,
2004.
(12) Although not related to our work, two recent reports have
been published where preparation of 2,5-piperazinediones
was assisted by microwave irradiation: (a) Santagada, V.;
Fiorino, F.; Perissutti, E.; Severino, B.; Terracciano, S.;
Cirini, G.; Caliendo, G. Tetrahedron Lett. 2003, 44, 1145.
(b) Cho, S.; Keum, G.; Kang, S. B.; Kim, Y. Mol. Diversity
2003, 6, 283.
(15) Smith, G. G.; Evans, R. C.; Baum, R. J. Am. Chem. Soc.
1986, 108, 7327.
Synlett 2005, No. 7, 1158–1160 © Thieme Stuttgart · New York