From cyclic dehydrodipeptides to uncommon acyclic peptide mimetics

Article abstract of DOI:10.1016/j.tetlet.2006.07.095

1-Acetyl-3-arylmethylene-2,5-piperazinediones gave N-3-arylpyruvylamino esters by acid-promoted alcoholysis under thermal conditions or microwave irradiation. Compounds obtained from 1-acetyl-3-(o-nitro)arylmethylene-2,5-piperazinediones gave, after reduc

Full text of DOI:10.1016/j.tetlet.2006.07.095

Tetrahedron Letters 47 (2006) 6711–6714
From cyclic dehydrodipeptides to uncommon
acyclic peptide mimetics
*
´
Juan Francisco Gonzalez, Elena de la Cuesta and Carmen Avendano
˜
Departamento de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 29 June 2006; revised 18 July 2006; accepted 20 July 2006
Available online 8 August 2006
Abstract—1-Acetyl-3-arylmethylene-2,5-piperazinediones gave N-3-arylpyruvylamino esters by acid-promoted alcoholysis under
thermal conditions or microwave irradiation. Compounds obtained from 1-acetyl-3-(o-nitro)arylmethylene-2,5-piperazinediones
gave, after reduction of the nitro group and spontaneous cyclization, N-2-indolylcarbonylamino acid derivatives. A similar alcoho-
lysis/reduction sequence applied to dehydrodipeptides bearing a 3(4)-nitroaryl substituent gave N-3(4)-aminophenyl-a-ketopropion-
ylamino acid derivatives. Coupling of the free amino group with Boc-protected amino acids gave tripeptide mimetics with a
6-aminoindole-2-carboxylic or a 3(4)-aminophenyl-a-ketopropionic acid as the second residue.
Ó 2006 Elsevier Ltd. All rights reserved.
Cyclic dehydrodipeptides have been employed as chiral
templates in the synthesis of a-amino acids,1–3 but very
little is known about their interest as intermediates for
other synthetic objectives. We here report the acid-pro-
moted alcoholysis of 1-acetyl-3-arylmethylene-2,5-piper-
azinediones to give N-3-arylpyruvylamino esters. The
method was extended to nitroaryl derivatives taking
part in the synthesis of tripeptide mimetics with an
aminoindole-2-carboxylic acid or an aminophenyl-a-
ketopropionic acid as the second residue.
an important goal for the pharmaceutical industry
where the search for novel peptide mimetic inhibitors
is a very active field. Several of these inhibitors are based
on the a-ketoamide linkage in which the affinity towards
proteases is related to the nonplanarity of the dicarbonyl
group.18,19 From the synthetic point of view, a-keto-
amides are usually prepared by Dess–Martin periodinane
oxidation of the corresponding a-hydroxyamides,15,16
oxidation of a-cyanoketones20 and amidation of
a-ketoacids.21
Indoles are privileged structures in drug discovery4 and,
probably, represent the most relevant of all structural
classes.5 Indole-2-carboxamides, in particular, are
important moieties of biologically active compounds
such as the reverse transcriptase inhibitors, delaviridine
and ateviridine6,7 or antitumour agents.8,9 Several syn-
thetic procedures among the great number of alterna-
tives leading to the indole ring system,10 involve a
cyclizative condensation between an amino and a car-
bonyl or an imine group.11,12
In the course of a project directed to the synthesis of
tetrahydroisoquinoline antitumour antibiotics where
compounds 1 are starting materials,22 we observed that
compounds 2 were N-deacetylated at room temperature
upon standing in chlorohydric acid–methanol. In a
detailed study of this process we isolated N-3-aryl-
pyruvylamino esters 3 and methanol-adducts 4. Forma-
tion of these minor products indicated that the enamine
portion of compounds 2, after protonation to give the
corresponding N-acyliminium cations (I), can be
attacked by nucleophiles at the iminium carbon atom
to give adducts 4, or at the N-carbonyl group leading
to ring-opening and production of imine intermediates
which hydrolyze to a-ketoamides 3 (Scheme 1). The last
pathway represents the reversal of a protocol that
has been applied for the synthesis of cyclic
dehydrodipeptides.23
On the other hand, the a-ketoamide moiety is an impor-
tant building block in neuroregenerative or immunosup-
pressive macrocyclic polyketides such as FK506 and
rapamycin,13 in the antitumour antibiotic lankacidin,14
and in many transition-state protease inhibitors.15–17
The development of the last compounds has become
*
Given the significant yields of 3 that could be obtained
Corresponding author. Tel./fax: +34 913941821; e-mail: ecuestae@
when the acid-promoted alcoholysis was performed
farm.ucm.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.095

6712
J. F. Gonza´lez et al. / Tetrahedron Letters 47 (2006) 6711–6714
O
O
O
O
Ac
NH
N
NH
MeOH, HCl
AcOMe
H
HN
HN
N
H
R
R
MeOH
OMe
R
O
O
1
2
I
O
O
MeO
HN
NH
O
O
H
N
+
R
R
O
4
3
Scheme 1.
under reflux conditions and the accessibility of com-
pounds 1,24 we explored this reaction with compounds
bearing nitro groups at o-, m- or p-positions of the aryl
substituent. The starting materials were obtained in very
good yields by condensation of the corresponding
nitrobenzaldehyde and N,N0-diacetyl-2,5-piperazinedi-
one in the presence of potassium tert-butoxide. Conden-
sation of aromatic aldehydes bearing an o-nitro group
was performed in dichloromethane,25 while tetrahydro-
furan was a better solvent for m- and p-nitro derivatives.
in 3g to give 5d (Table 2). The chiral compound 3h
gave indolecarboxamide 5e without detection of
epimerization.
Catalytic hydrogenation of the nitro group in com-
pound 3i and 3l gave the corresponding aminophenyl-
a-ketopropionylamino acid derivatives (6i,l). These
products, as well as compound 5d, were N-acylated29
through standard procedures in peptide chemistry to
give compounds 8, 9 and 7, respectively.
O
O
O
N
CO2Bn
BocHN
H
N
CO2Me
N
N
H
H
H
O
H2N
Ph
7
6
O
Ph
O
H
O
N
CO2Me
N
BocHN
N
CO2Me
H
BocHN
O
H
N
O
O
H
Ph
8
9
The
success
of
the
ring-opening
reaction
Table 1. Synthesis of N-3-arylpyruvylamino esters 3
(1 to 3) in the first studied o-nitrophenyl compounds
was highly dependent on the type of the alcohol em-
ployed (methanol, isopropanol or benzylic alcohol).
Thus, while isopropanol or methanol gave the corre-
sponding N-3-arylpyruvylamino esters in very low or
moderate yields, benzylic alcohol gave these products
in good to excellent yields (see compounds 3a–h in Table
1).26 Although these differences could be explained by
steric reasons they are mainly due to the greater solubil-
ity in benzylic alcohol of N-deacetyl intermediates 2.
Application of this protocol to m- and p-nitrophenylm-
ethylene derivatives, which were less soluble than the o-
nitro compounds in the tested alcohols, gave very low
yields for alcoholysis products under thermal condi-
tions. Fortunately, the process worked better by apply-
ing microwave irradiation.27
O
NO
HCl,
2
O N
2
Ac
ROH
O
O
N
x
H
R
N
N
1
OR
R
H
x
R
1
O
O
R
3
1
Product Yield (%) Rx
R1
R
Nitro group
position
3a
3b
3c
3d
3e
3f
3g
3h
3i
59a
93a
95a
66a
98a
11a
50a
80a
8a
12a
16a
41b
61b
H
H
H
H
H
H
H
H
H
Me 20
Bn
Bn
Bn
Bn
iPr
Bn
20
20
20
20
20
20
20
6-Cl
3,6-(MeO)2
4,5-(MeO)2
4,5-(MeO)2
4-NO2
H
Me Bn
H
H
H
H
H
H
H
H
H
Me 30
Et
3j
30
30
Catalytic hydrogenation of the o-nitro group in com-
pounds 3a–h afforded in good yields, as it was planned,
the corresponding N-indole-2-carbonylamino acid
derivatives 5.28 Under these reaction conditions hydro-
genolysis of the benzyl ester and aryl halide groups took
place, although the benzyl ester group was maintained
3k
3i
Bn
Me 30
Me 40
3l
H
a Reflux time: 2.5 h.
b Microwave irradiation time: 5 min.

J. F. Gonza´lez et al. / Tetrahedron Letters 47 (2006) 6711–6714
6713
Table 2. Synthesis of N-(indole-2-carbonyl)amino acids 5
W. A.; Theoharides, A. D.; Anderson, P. S. J. Med. Chem.
1993, 36, 1291–1294.
7. Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.;
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May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. V.;
Busso, M.; Tan, Ch.-K.; Voorman, R. L.; Reusser, F.;
Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.;
Tarpley, W. G.; Aristoff, P. A. J. Med. Chem. 1994, 37,
999–1014.
Starting
compound (yield %)
Product
R4
R5
R6
R7
R
R1
8. Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.;
Kawamoto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H.
J. Antibiot. 1990, 43, 1037–1038.
9. Kobayashi, E.; Okamoto, A.; Asada, N.; Okabe, M.;
Nagamura, S.; Asai, A.; Saito, H.; Gosni, K.; Hirata, T.
Cancer Res. 1994, 54, 2404–2410.
10. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045–
1075.
11. Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin 1
1990, 673–679.
3a
3b
3c
3d
3e
3g
3h
5a (76)
5a (83)
5a (94)
5b (79)
5c (94)
5d (60)
5e (92)
H
H
H
MeO
H
H
H
H
H
H
H
H
H
H
H
H
MeO
H
H
H
H
H
H
H
Me
H
H
H
H
H
Bn
H
MeO MeO
H
H
H
H
NH2
H
H
H
12. Tsuji, Y.; Kotachi, S.; Huhm, K.-T.; Watanabe, Y. J. Org.
Chem. 1990, 55, 580–584.
13. Schreiber, S. L. Science 1991, 251, 283–287.
14. Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J.
Am. Chem. Soc. 1995, 117, 8258–8270.
15. Han, W.; Hu, Z.; Jiang, X.; Decicco, C. P. Bioorg. Med.
Chem. 2000, 10, 711–713.
16. Sun, D. X.; Liu, L.; Heinz, B.; Kolykhalov, A.; Lamar, J.;
Johnson, R. B.; Wang, Q. M.; Yip, Y.; Chen, S. Bioorg.
Med. Chem. 2004, 14, 4333–4338.
17. Chen, K. X.; Njoroge, F. G.; Arasappan, A.; Venkat-
raman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.;
Pichardo, J.; Prongay, A.; Cheng, K.; Butkiewicz, N.;
Yao, N.; Madison, V.; Girijavallabhan, V. J. Med. Chem.
2006, 49, 995–1005.
In conclusion, the regioselective ring opening of the read-
ily available compounds 1 is the key-step in the synthesis
of N-3-arylpyruvylamino esters. These compounds may
be subsequently derived to tripeptide mimetics bearing
an aminoindole-2-carboxylic acid or an aminophenyl-
a-ketopropionic acid as the intermediate residue. Fur-
ther research on the application of this protocol to the
synthesis of more complex peptide mimetics are in
progress in our laboratories.
Acknowledgements
18. Bach, R. D.; Mintcheva, I.; Kronenberg, W. J.; Schlegel,
H. B. J. Org. Chem. 1993, 58, 6135–6138.
19. Kahn, K.; Bruice, T. C. Bioorg. Med. Chem. 2000, 8,
1881–1891.
We thank CICYT (project SAF 2003-03141) and
´
Comunidad Autonoma de Madrid (Group 920234) for
financial support of this research.
20. Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. Org. Lett. 2002, 4, 1103–1105.
21. Nakamura, M.; Inoue, J.; Yamada, T. Bioorg. Med.
Chem. Lett. 2000, 10, 2807–2910.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.095.
´
22. Gonzalez, J. F.; Salazar, L.; de la Cuesta, E.; Avendano,
˜
C. Tetrahedron 2005, 61, 7447–7455.
23. Li, W.; Peng, S. Tetrahedron Lett. 1998, 39, 7373–7376.
´
24. Gonzalez, J. F.; de la Cuesta, E.; Avendano, C. Synth.
˜
Commun. 2004, 34, 1589–1597.
25. Condensation procedure. Synthesis of 1a: To a solution of
N,N0-diacetyl-2,5-piperazinedione (2 g, 10 mmol) in anhy-
drous CH2Cl2 (10 mL), under Ar atmosphere, were added
o-nitrobenzaldehyde (1.66 g, 11 mmol) and 1 equiv of a
1 M solution of potassium tert-butoxide in tert-butyl
alcohol. The reaction was stirred at room temperature for
5 h. After addition of hexane (10 mL), the condensation
product precipitated. The filtrate was first washed with
water and then with hexane giving 1a (2.83 g, 98%):
mp 173–174 °C, IR (NaCl, film): 1693, 1640 and
References and notes
1. Hashimoto, Y.; Aoyagi, H.; Waki, M.; Kato, T.; Izumiya,
N. Int. J. Protein Res. 1983, 21, 11–15.
2. Oba, M.; Terauchi, T.; Owari, Y.; Imai, Y.; Motoyama, I.;
Nishiyama, K. J. Chem. Soc., Perkin Trans. 1 1998, 1275–
1281.
3. Kukula, P.; Prins, R. Diastereoselective hydrogenation in
the preparation of Fine Chemicals. In Topics in Catalysis;
Springer-Science+Business media B., 2003; Vol. 25, pp
29–42.
1524 cmꢀ1 1H (250 MHz, CDCl3): d, ppm 8.24 (d, 1H,
;
J = 8.2 Hz), 7.95 (ws, 1H), 7.73 (dd, 1H, J = 8.0 and
7.8 Hz), 7.62 (dd, 1H, J = 8.0 and 7.8 Hz), 7.46 (d, 1H,
J = 8.2 Hz), 7.44 (s, 1H), 4.48 (s, 2H), 2.69 (s, 3H); 13C
(63 MHz, CDCl3): d, ppm 172.5, 162.7, 158.9, 147.9,
134.4, 130.6, 128.1, 127.0, 126.0, 116.4, 46.1, 27.3. Anal.
Calcd for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53.
Found: C, 53.63; H, 3.87; N, 14.18.
4. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893–930.
5. For summary of the applications of indoles, see: Gribble,
G. W. Five-membered rings with one heteroatom and
fused carbocyclic derivatives. In Comprehensive Heterocy-
clic Chemistry; 2nd ed. Bird, C. W., Katrizky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1995; Vol. 2, pp 207–257.
6. Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
MacTough, S. C.; Rooney, C. S.; Balani, S. K.; Condra,
J. H.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.;
Kauffman, L. R.; O’Brien, J. A.; Sardana, V. V.; Schleif,
26. Acid-promoted alcoholysis under thermal conditions. Syn-
thesis of 3b: To a solution of 1a (500 mg, 1.75 mmol) in
benzyl alcohol (50 mL), was added 5 N HCl (5 mL). The
reaction was refluxed for 2.5 h, the solvent was distilled in
vacuo to dryness, and the solid residue was purified by

6714
J. F. Gonza´lez et al. / Tetrahedron Letters 47 (2006) 6711–6714
flash chromatography (CH2Cl2 as eluant) to give 3b
(EtOAc as eluant) to give 5a (82 mg, 83%): mp 158–
159 °C, IR (NaCl, film): 3371, 3275, 1738, 1642 and
(580 mg, 93%): mp 92–93 °C, IR (NaCl, film): 3382, 1750,
1
1689 and 1524 cmꢀ1; H (250 MHz, CDCl3): d, ppm 8.17
1552 cmꢀ1 1H (250 MHz, DMSO-d6): d, ppm 11.63 (s,
;
(dd, 1H, J = 8.1 and 1.2 Hz), 7.63 (dt, 1H, J = 7.5 and
1.3 Hz), 7.50 (dt, 1H, J = 8.1 and 1.5 Hz), 7.44 (ws, 1H),
7.37 (s, 5H), 7.32 (dd, 1H, J = 7.5 and 1.2 Hz), 5.22 (s,
2H), 4.64 (s, 2H); 4.16 (d, 2H, J = 5.7 Hz). 13C (63 MHz,
CDCl3): d, ppm 193.2, 168.5, 159.7, 148.6, 134.9, 133.8,
133.7, 129.4, 128.7, 128.6, 128.4, 125.4, 67.5, 42.5, 41.2.
Anal. Calcd for C18H16N2O6: C, 60.67; H, 4.53; N, 7.85.
Found: 60.82; H, 4.70; N, 7.65.
1H), 8.96 (t, 1H, J = 5.7 Hz), 7.62 (d, 1H, J = 7.9 Hz),
7.42 (d, 1H, J = 8.1 Hz), 7.18 (dd, 1H, J = 8.1 and
7.5 Hz), 7.03 (dd, 1H, J = 7.9 and 7.5 Hz), 7.11 (s, 1H),
2.02 (d, 2H, J = 5.7 Hz). 13C (63 MHz, DMSO-d6): d, ppm
170.7, 161.7, 136.7, 131.2, 127.2, 123.7, 121.8, 120.0, 112.6,
103.2, 41.0. Anal. Calcd for C11H10N2O3: C, 60.55; H,
4.62; N, 12.84. Found: C, 60.34; H, 4.23; N, 12.60.
29. N-Acylation. Synthesis of compound 8: To a solution of 6i
(17 mg, 0.66 mmol), N-Boc-L-phenylalanine (175 mg,
27. Acid-promoted alcoholysis under microwave irradiation.
Synthesis of 3l: The microwave instrument used in this
experiment was the CEM, Discover. To 1l (100 mg,
0.35 mmol) in methanol (5 mL), was added 5 N HCl
(1 mL) and the mixture was placed in a MW test tube
(10 mL) containing a magnetic stirring bar. The tube was
sealed and irradiated at 130 °C for 5 min. After cooling to
room temperature, the solution was filtered and the
solvent evaporated in vacuo. To the residue was added
EtOAc (50 mL). The organic solution was washed with
brine (50 mL), dried over sodium sulfate, filtered and
concentrated. The crude product was purified by flash
chromatography (hexane–EtOAc, 7:3 as eluant), to give 3l
(60 mg, 61%): mp 80–81 °C, IR (NaCl, film): 3397, 1750,
0.66 mmol),
(103 mg, 0.73 mmol), and 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide (EDC) hydrochloride (152 mg,
1-hydroxy-7-azabenzotriazole
(HOAt)
0.79 mmol), in anhydrous DMF (10 mL) under Ar atmo-
sphere at 0 °C, was added 4-methylmorpholine (NMM)
(0.22 mL, 1.98 mmol). After being stirred at 0 °C for 2 h,
the reaction mixture was kept in a freezer overnight (16 h)
and it was then warmed at room temperature. EtOAc
(300 mL), brine (50 mL) and 5% H3PO4 (50 mL) were
added and the layers were separated. The organic solution
was washed consecutively with a 1 N solution of sodium
bicarbonate (50 mL) and water (50 mL), dried with
sodium sulfate, filtered and concentrated to afford 8
(195 mg, 63%) as a white solid. An analytical sample was
obtained through flash chromatography (hexane–EtOAc,
7:3 as eluant): mp 64–65 °C, IR (NaCl, film): 3312, 2977,
1
1688 and 1519 cmꢀ1; H (250 MHz, CDCl3): d, ppm 8.22
(d, 2H, J = 8.8 Hz), 7.45 (d, 2H, J = 8.8 Hz), 4.37 (s, 2H),
4.12 (d, 2H, J = 5.7 Hz), 3.81 (s, 3H). 13C (63 MHz,
CDCl3): d, ppm 193.7, 167.0, 159.5, 147.2, 139.9, 130.8,
123.8, 52.6, 42.9, 41.0. Anal. Calcd for C12H12N2O6: C,
51.43; H, 4.32; N, 10.00. Found: C, 51.29; H, 4.15; N, 9.82.
28. Reductive cyclization of compounds 3. Synthesis of 5a: A
mixture of 3b (160 mg, 0.45 mmol), in a suspension of Pd–
C (20 mg) in EtOAc (30 mL), was hydrogenated at room
temperature for 5 h. After filtration over celite and
evaporation of the solvent under reduced pressure, the
solid residue was purified by flash chromatography
1
1752 and 1682 cmꢀ1; H (250 MHz, CDCl3): d, ppm 7.39
(t, 1H, J = 7.5 Hz), 6.89 (d, 1H, J = 7.5 Hz), 5.01 (m, 1H),
4.49 (m, 1H), 4.08 (s, 2H), 4.01 (d, 2H, J = 5.7 Hz), 3.70 (s,
3H), 3.05 (m, 2H), 1.33 (s, 9H). 13C (63 MHz, CDCl3): d,
ppm 194.6, 169.6, 169.2, 162.4, 159.9, 137.5, 136.5, 133.2,
129.2, 129.1, 128.7, 127.0, 125.9, 121.3, 118.9, 80.8, 56.6,
52.6, 42.9, 40.9, 38.3, 28.3. Anal. Calcd for C26H31N3O7:
C, 62.76; H, 6.28; N, 8.45. Found: C, 62.48; H, 6.15; N,
8.32.