Synthesis of a novel tricyclic peptidomimetic scaffold

Article abstract of DOI:10.1021/ol801506y

(Chemical Equation Presented) An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones has been discovered. The scaffold can function as a peptide backbone mimetic (highlighted) with two substituents independently variable to fine-tune biological response. Halogenation of the pyrazolo ring followed by Suzuki couplings made it possible to introduce substituents with variable electronic properties late in the synthetic route, which is preferable in library synthesis.

Full text of DOI:10.1021/ol801506y

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4005-4007
Synthesis of a Novel Tricyclic
Peptidomimetic Scaffold
Magnus Sellstedt and Fredrik Almqvist*
Department of Chemistry, Umeå UniVersity, SE-901 87 Umeå, Sweden
fredrik.almqVist@chem.umu.se
Received July 3, 2008
ABSTRACT
An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones
has been discovered. The scaffold can function as a peptide backbone mimetic (highlighted) with two substituents independently variable to
fine-tune biological response. Halogenation of the pyrazolo ring followed by Suzuki couplings made it possible to introduce substituents with
variable electronic properties late in the synthetic route, which is preferable in library synthesis.
Small molecules designed to mimic the behavior of peptides,
i.e., peptidomimetics, are interesting as drug candidates.
Peptidomimetics can offer improved pharmacological prop-
erties compared to peptides by introduction of conformational
restrains and replacement of metabolically sensitive groups.1
We have previously described bicyclic 2-pyridone 1 (Figure
1) that is active as a novel type of antibacterial agent,
targeting virulence.2 Similar heterocyclic systems have been
used as peptidomimetics active, as e.g., human rhinovirus
(HRV) 3C protease inhibitors3 (compound 2) and hepatitis
C virus (HCV) NS3 protease inhibitors.4
Here, we report the synthesis of a novel ring-fused
pyrazole-2-pyridone-thiazoline scaffold. Biologically active
ring-fused pyrazole-2-pyridones have previously been re-
Figure 1. Examples of biologically active ring-fused 2-pyridones.
(1) Pauletti, G. M.; Gangwar, S.; Siahaan, T. J.; Aube, J.; Borchard,
R. T. AdV. Drug DeliV. ReV. 1997, 27, 235–256.
ported. For instance, 3 (Figure 1) intercalates DNA5 and
inhibits proliferation of human pulmonary carcinoma cells
and 4 functions as a benzodiazepine receptor inhibitor.6 Our
new scaffold constitutes a rigid peptide backbone mimetic.
(2) (a) Pinkner, J. S.; Remaut, H.; Buelens, F.; Miller, E.; Åberg, V.;
Pemberton, N.; Hedenstro¨m, M.; Larsson, A.; Seed, P.; Waksman, G.;
Hultgren, S. J.; Almqvist, F. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 17897–
17902. (b) Åberg, V.; Almqvist, F. Org. Biomol. Chem. 2007, 5, 1827–
1834.
(3) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Brown,
E. L.; Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.;
Matthews, D. A., III; Ferre, R. A.; Worlandy, S. T. Bioorg. Med. Chem.
Lett. 2002, 12, 733–738.
(5) Maggio, B.; Daidone, G.; Raffa, D.; Plescia, S.; Bombieri, G.;
Meneghetti, F. HelV. Chim. Acta 2005, 88, 2272–2281.
(4) Zhang, X. J.; Schmitt, A. C.; Decicco, C. P. Tetrahedron Lett. 2002,
43, 9663–9666.
(6) Palazzino, G.; Cecchi, L.; Melani, F.; Colotta, V.; Filacchioni, G.;
Martini, C.; Lucacchini, A. J. Med. Chem. 1987, 30, 1737–1742.
10.1021/ol801506y CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

Rigidity is often beneficial for drug potency, as long as the
bioactive conformation is still adaptable.7 A recent study
possibly due both to nitrosation and dimerization of the
pyrazole as indicated by LC-MS. Dimerization has previ-
ously been reported during formation of other ring-fused
pyrazoles by reaction of the pyrazole derivative with
intermediate diazonium salt.13 Fortunately, performing the
reaction in aqueous sulfuric acid instead of acetic acid
significantly increased the yield of the desired product. To
achieve high yields of 7a, addition of THF to improve
solubility was necessary. The methyl esters 7 were subse-
quently hydrolyzed to reveal the peptidomimetic scaffold 8
in excellent yields (94-97%).
Table 1. Synthesis of Amino-Functionalized Pyridones
With the improved synthesis of 7b in hand, a way of
introducing new substitiuents in the pyrazole ring by bro-
mination followed by Suzuki couplings was in sight. This
allows introduction of new R2 substitiuents, including
electron-rich substituents incompatible with the nitration step
in synthesis of 6 (Table 1). It also introduces a late
diversification point in the synthetic route, which is important
in library synthesis. Bromination was accomplished by
treatment of 7b with bromine in the presence of potassium
acetate as acid scavenger (Scheme 1).
entry
R1
R2
product
yielda (%)
1
2
3
cyclopropyl
1-naphthyl
H
isobutyl
6a
6b
6c
75
71
67
Ph
Ph
a Isolated yields (%).
indicates that rigidity might be important for activity also
for our antibacterial compounds.8
Ring-fused 2-pyridones 5 (Table 1) are easily prepared
from acyl Meldrum’s acid derivatives and thiazolines,9 and
we have previously described the synthesis of amino-
functionalized bicyclic 2-pyridone 6a.10
Scheme 1. Bromination of the Ring-Fused Pyrazole 7b
We found that attempted Sandmeyer reactions on 6
resulted in ring-closure to form pyrazoles. Diazomethyl
quinolinones have previously been thermally converted to
ring-fused pyrazole-quinolinones. It is noteworthy, however,
that attempted ring-closure of 1-methyl-4-diazomethyl-2-
pyridone failed under the same conditions.11 Electron-
deficient 2-methylaniline derivatives efficiently form inda-
zoles when treated with aqueous NaNO2 in acetic acid.12
Under similar conditions, we successfully converted ami-
nopyridones 6 into a novel heterocyclic scaffold (Table 2).
Suzuki couplings of ring-fused thiazolo-2-pyridones have
proven difficult, but the use of S-Phos14 and Pd(OAc)2 in
THF have previously been successful.15 Unfortunately,
applying these conditions did not result in any conversion
of 9.
Unprotected ring-fused pyrazoles have been subjected to
Suzuki couplings using Pd(dppf)Cl2·CH2Cl2 in dioxane with
phosphate base and microwave heating.16 Utilizing these
conditions, coupling of 9 with phenylboronic acid was
observed. However, the coupling was sluggish with signifi-
cant precipitation of palladium black. When 10 mol % of
Table 2. Formation of Ring-Fused Pyrazoles
(7) Kubinyi, H. Persp. Drug Disc. Design. 1998, 9/10/11, 225–252.
(8) Åberg, V.; Das, P.; Chorell, E.; Hedenstro¨m, M.; Pinkner, J. S.;
Hultgren, S. J.; Almqvist, F. Bioorg. Med. Chem. Lett. 2008, 18, 3536–
3540.
yielda
method
(9) Emtena¨s, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, 6756–
6761.
(10) Åberg, V.; Sellstedt, M.; Hedenstro¨m, M.; Pinkner, J. S.; Hultgren,
S. J.; Almqvist, F. Bioorg. Med. Chem. 2006, 14, 7563–7581.
(11) Ito, K.; Maruyama, J. J. Heterocycl. Chem. 1988, 25, 1681–1687.
(12) Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.; Vasudevan,
A.; Judd, A. S.; Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.;
Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R.
J. Med. Chem. 2005, 48, 1318–1321.
yielda
product (%)
entry
R1
R2
product
A
B
1
2
3
cyclopropyl 1-naphthyl
7a
7b
7c
61 46/82b
8a
8b
8c
94
95
97
Ph
Ph
H
31
54
85
61
isobutyl
a Isolated yields (%). b THF used as cosolvent.
(13) Chapman, D.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1980, 11,
2398–2404.
(14) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
(15) Seger, H.; Geyer, A. Synthesis 2006, 19, 3224–3230.
(16) Wu, T. Y. H.; Schultz, P. G.; Ding, S. Org. Lett. 2003, 5, 3587–
3590.
Both aliphatic and aromatic R2 groups were well tolerated,
but for R2 ) H the yield dropped significantly (31%),
4006
Org. Lett., Vol. 10, No. 18, 2008

palladium was used, only 25% coupling product was isolated.
The use of 20 mol % of palladium resulted in approximately
60% conversion according to crude H NMR. Pd(dppf)-
Table 3. Suzuki Couplingsa
1
Cl2·CH2Cl2 could be exchanged for Pd(OAc)2 and BINAP
with similar results. Turning to the more heat-stable Her-
rmann catalyst17 did not give any conversion of starting
material. Instead, a range of different solvents was tested
together with Pd(OAc)2 and BINAP as catalysts. The use of
DMF and acetonitrile resulted in mixtures of methylated
products as indicated by LC-MS, presumably via deproto-
nation and nucleofilic attack of the pyrazole on the solvent.
In acetone very low conversion was detected, and in
formamide almost exclusive dehalogenation of 9 to give 7b
was observed. Methanol proved to be a good choice of
solvent with good conversion of starting material. Competing
dehalogenation was detected as well as hydrolysis of the
methyl ester. The latter was avoided by the use of potassium
fluoride as a boronic acid activator18 rather than phosphate,
carbonate, or hydroxide bases. Using these conditions,
electron-rich, electron-poor, and heteroaromatic boronic acids
were coupled (Table 3). Even the sterically demanding ortho-
tolylboronic acid could be coupled; however, prolonged
reaction time was needed for full conversion. The coupled
products were directly hydrolyzed before reversed-phase
HPLC purification.
entry
R
product
yieldb (%)
1
2
3
4
5
Ph
10a
10b
10c
10d
10e
61
55
37
4-MeOPh
3-NO2Ph
3-furyl
53
2-MePh
32c
a 2.0 equiv of boronic acid, 10 mol % of Pd(OAc)2, heated for 3 min
at 50 °C and then 20 min at 140 °C. b Isolated yields (%) over two steps.
c Heated for 3 min at 50 °C and 60 min at 140 °C.
functionalized through Suzuki couplings with both heteroar-
yls and aryls with different electronic and steric properties.
The resulting molecules are rigid, substituted heterocyclic
structures with potential to function as peptidomimetics. By
changing the substitution pattern this scaffold has potential
to target a variety of biological systems.
Acknowledgment. We thank the Swedish Natural Re-
search Council, the Knut and Alice Wallenberg Foundation,
and JC Kempe Foundation (SJCKMS) for financial support.
In conclusion, we have shown that ring-fused pyrazole-
2-pyridone scaffolds can be made by diazotation of amino-
functionalized 2-pyridones, resulting in a novel rigid pepti-
domimetic scaffold. This new scaffold could be further
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
¨
(17) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. 1995, 34,
1844–1848.
(18) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095–6097.
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