N-amino-imidazolin-2-one peptide mimic synthesis and conformational analysis

Article abstract of DOI:10.1021/ol302021n

Base-promoted 5-exo-dig cyclizations of aza-propargylglycinamides provided N-amino-imidazolin-2-one peptide mimics, which exhibited turn geometry in X-ray crystallographic and NMR spectroscopic analyses. Sonogashira coupling prior to cyclization afforded

Full text of DOI:10.1021/ol302021n

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4552–4555
N‑Amino-imidazolin-2-one Peptide Mimic
Synthesis and Conformational Analysis
Caroline Proulx and William D. Lubell*
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Departement de Chimie, Universite de Montreal, C.P. 6128, Succursale Centre-Ville,
Montreal, Quebec H3C 3J7, Canada
ꢀ
ꢀ
ꢀ
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william.lubell@umontreal.ca
Received July 20, 2012
ABSTRACT
Base-promoted 5-exo-dig cyclizations of aza-propargylglycinamides provided N-amino-imidazolin-2-one peptide mimics, which exhibited turn
geometry in X-ray crystallographic and NMR spectroscopic analyses. Sonogashira coupling prior to cyclization afforded N-amino-imidazolin-2-
ones with diverse 4-position aromatic substituents with potential to serve as Phe and Trp mimics.
Identification of biologically active conformers is critical
for developing therapeutics based on peptide structures,
because precise folding is essential for function. Geome-
trically restricted analogs are thus valuable tools, because
they may reduce energetic costs for folding into binding
conformations and, thereby, improve potency, selectivity,
and stability.1
To constrain backbone geometry and induce turn
conformations, R-amino-γ-lactams,2 so-called Freidingerꢀ
Veber lactams, have been commonly introduced into
peptide sequences; however, their lack of side-chain func-
tions may translate into loss of affinity and activity. Aza
analogs of amino acids possess a nitrogen atom in place of
the CHR. A variety of side chains have been installed onto
these semicarbazide structures, which when introduced into
azapeptides restrict the backbone φ and ψ dihedral angles,
due to the lone pairꢀlone pair electronic repulsion of the
adjacent nitrogen and urea planarity, respectively.3 A strat-
egy has now been devised to induce peptide turn geometry
by combining the covalent constraints of R-amino-γ-lac-
tams with the electronic restrictions and side-chain diversity
of aza-amino acids through the synthesis of substituted
N-amino-imidazolin-2-ones (Figure 1).
Imidazolin-2-ones have utility as antitumor agents,4
antibacterial MurB inhibitors,5 dopamine D4 and CGRP
(3) Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; Garcı
´
a
Ramos, Y.; Lubell, W. D. Future Med. Chem. 2011, 3, 1139–1164.
(4) (a) Congiu, C.; Cocco, M. T.; Onnis, V. Bioorg. Med. Chem. Lett.
2008, 18, 989–993. (b) Xue, N.; Yang, X.; Wu, R.; Chen, J.; He, Q.;
Yang, B.; Lu, X.; Hu, Y. Bioorg. Med. Chem. 2008, 16, 2550–2557.
(5) Bronson, J. J.; DenBleyker, F. L.; Falk, P. J.; Mate, R. A.; Ho,
H.-T.; Pucci, M. J.; Snyder, L. B. Bioorg. Med. Chem. Lett. 2003, 13,
873–875.
(6) Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones, E. A.;
Bonner, K.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Fletcher,
A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D. J. Med. Chem. 1999,
42, 2706–2715.
(1) For a selected example, see: Smith, A. B., III; Charnley, A. K.;
Hirschmann, R. Acc. Chem. Res. 2011, 44, 180–193.
(2) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.;
Saperstein, R. Science 1980, 210, 656. (b) Freidinger, R. M.; Perlow,
D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104. (c) Freidinger, R. M.
J. Org. Chem. 1985, 50, 3631. (d) Jamieson, A. G.; Boutard, N.;
Beauregard, K.; Bodas, M. S.; Ong, H.; Quiniou, C.; Chemtob, S.;
Lubell, W. D. J. Am. Chem. Soc. 2009, 131, 7917–7927. (e) Boutard, N.;
Jamieson, A. G.; Ong, H.; Lubell, W. D. Chem. Biol. Drug Des. 2010, 75,
40–50.
(7) (a) Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.;
Quigley, A. G.; Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore,
C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham,
S. L.; Williams, T. M. Bioorg. Med. Chem. Lett. 2006, 16, 5052–5056. (b)
Shaw, A.; Paone, D. V.; Nguyen, D. N.; Stump, C. A.; Burgey, C. S.;
Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan,
K. S.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Bioorg. Med. Chem.
Lett. 2007, 17, 4795–4798.
r
10.1021/ol302021n
Published on Web 08/14/2012
2012 American Chemical Society

(i.e., silver,14 palladium,15 and gold complexes).16 More-
over, cyclic amino acids, such as dehydroprolines, had
been prepared respectively by Pd- and Ag-catalyzed
5-endo-dig cyclization of N-Ts- and Boc-protected propar-
gylglycine analogs.17,18
To study the cyclization, aza-propargylglycinyl dipep-
tide 1 was used and prepared by chemoselective alkylation
of benzhydrylidene aza-glycinyl-D-phenylalanine tert-bu-
tyl ester (5) with propargyl bromide (Schemes 1 and 2).19
Attempted 5-exo-dig cyclization of azadipeptide 1 using
homogeoneous gold catalysis [(t-Bu)2(o-biphenyl)PAuCl
(5 mol %) and AgOTf (5 mol %)] failed, likely because the
urea nitrogen was insufficiently electron-deficient.
Scheme 1. N-Amino-imidazolin-2-one synthesis
Figure 1. N-Amino-imidazolin-2-one turn mimic conception.
receptor antagonists,6,7 antioxidants,8 and unnatural base
pairs.9 To the best of our knowledge, however, the synthe-
sis and biological evaluation of N-amino-imidazolin-2-
ones had not been explored.
Previously, the submonomer approach for azapeptide
synthesis surmounted issues of hydrazine chemistry to give
access to side chains inaccessible by traditional methodology,
including propargyl, allyl, and (hetero)aryl moieties.10,11 The
aza-propargylglycine side chain was later reacted in copper-
catalyzed 1,3-dipolar cycloadditions to make aza-1,2,3-
triazole-3-alaninyl peptide mimics.12 Aza-propargylglycina-
mides have now been explored in 5-exo-dig cyclizations to
access N-amino-imidazolin-2-one peptidomimetics, as well
as in Sonogashira cross-coupling reactions prior to cycliza-
tion to provide their 4-arylmethyl analogues, which may
mimic phenylalanine and tryptophan residues.
Imidazolin-2-ones and imidazolidin-2-ones have been
respectively prepared from propargylic and allylic ureas by
base-promoted 5-exo-dig cyclizations.13 Annulation has
typically necessitated an electron-deficient urea nitrogen
and activation of the π-system using transition metal salts
N-Amino-imidazolin-2-one 2 was, however, obtained in
81% yield, by adding 2.5 equiv of NaH to the mixture
containing 1 and the cationic gold complex formed in situ
in acetonitrile for 2 h. The impact of goldcatalysis was later
deemednegligible, because2 was producedin84% yield on
reaction of 1 with 2.5 equiv of NaH in acetonitrile without
a catalyst (Scheme 1). From the 5-exo-dig cyclization, an
exocyclic double bond was first produced and migrated
inside the ring to furnish the thermodynamically more
stable N-amino-imidazolin-2-one 3. Among the solvents
studied, acetonitrile proved the best (see Supporting In-
formation (SI)). Excess NaH was necessary for high yields.
To study the effect of N-amino-imidazolin-2-one on
peptide conformation, model 10 was synthesized and
examined by X-ray crystallography and NMR spectro-
scopy (Scheme 2). Benzhydrylidene aza-glycinyl-D-pheny-
lalanine isopropyl amide 7 was made from 5 by tert-butyl
ester cleavage in a 1:1 v/v mixture of TFA/DCM
and coupling to isopropylamine by way of a mixed
anhydride.20 Alkylation of semicarbazone 7 with
propargylbromide19,20 gave aza-propargylglycinamide 8
in 71% yield without detectable racemization; however,
(8) (a) Smith, R. C.; Reeves, J. C. Biochem. Pharmacol. 1987, 36,
1457. (b) Watanabe, K.; Morinaka, Y.; Hayashi, Y.; Shinoda, M.; Nishi,
H.; Fukushima, N.; Watanabe, T.; Ishibashi, A.; Yuki, S.; Tanaka, M.
Bioorg. Med. Chem. Lett. 2008, 18, 1478–1483.
(9) (a) Hirao, I.; Kimoto, M.; Harada, Y.; Fujiwara, T.; Sato, A.;
Yokoyama, S. Nucleic Acids Res. Suppl. 2002, 2, 37–38. (b) Hirao, I.;
Harada, Y.; Kimoto, M.; Mitsui, T.; Fujiwara, T.; Yokoyama, S. J. Am.
Chem. Soc. 2004, 126, 13298–13305.
(10) (a) Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.;
Boeglin, D.; Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650. (b)
Sabatino, D.; Proulx, C.; Pohankova, P.; Ong, H.; Lubell, W. D. J. Am.
Chem. Soc. 2011, 133, 12493–12506.
(11) Proulx, C.; Lubell, W. D. Org. Lett. 2010, 12, 2916–2919.
(12) Proulx, C.; Lubell, W. D. J. Org. Chem. 2010, 75, 5385–5387.
(13) (a) Chiu, S.-K.; Keifer, L.; Timberlake, J. W. J. Med. Chem.
1979, 22, 746–748. (b) Easton, N. R.; Cassady, D. R.; Dillard, R. D.
J. Org. Chem. 1964, 29, 1851–1855.
(17) Wolf, L. B.; Tjen, K. C. M. F.; ten Brick, H. T.; Blaauw, R. H.;
Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal.
2002, 344, 70–83.
(18) Van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.;
Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791–1795.
´
(19) Garcıa-Ramos, Y.; Proulx, C.; Lubell, W. D. Can. J. Chem.
(14) Peshkov, V. A.; Pereshivko, O. P.; Sharma, S.; Meganathan, T.;
Parmar, V. S.; Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem.
2011, 76, 5867–5872.
(15) (a) Lei, A.; Lu, X. Org. Lett. 2000, 2 (17), 2699–2702. (b) Fritz,
J. A.; Wolfe, J. P. Tetrahedron. 2008, 64, 6838–6852.
(16) (a) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed.
2012, 90, in press.
(20) Bourguet, C. B.; Proulx, C.; Klocek, S.; Sabatino, D.; Lubell,
2011, 50, 1–6. (b) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379–4382.
W. D. J. Pept. Sci. 2010, 16, 284–296.
Org. Lett., Vol. 14, No. 17, 2012
4553

subsequent NaH-promoted 5-exo-dig cyclization gave imi-
dazolin-2-one 9 in 78% yield with 10% racemization
(see SI). Olefin migration occurred upon hydrazone
removal, using hydroxylamine hydrochloride in pyridine,9
to afford N-amino-imidazolone hydrochloride which, with-
out further purification, was treated with 4-methoxybenzoyl
chloride to provide N-acyl dipeptide amide 10 in 56%
overall yield.
Crystalswere grown by slow diffusion of hexanes intoan
ethyl acetate/chloroform solution of 10. X-ray diffraction
revealed two turn conformations in the solid state
(Figure 2): 10a exhibiting a type II0 β-turn with an intra-
molecular ten-membered hydrogen bond between residues
i and i þ 3, and 10b showing a seven-membered hydrogen
bonded conformer in an inverse γ turn. The X-ray struc-
tures for 10 deviate primarily by rotation of the ψiþ2
dihedral angle, as shown by comparison of their j and ψ
dihedral angles with an ideal turn geometry and crystal
structures of azapeptide and R-amino-γ-lactams, which
adopted a turn geometry (Table 1).21ꢀ23 In contrast to
amino lactams, the planar geometry of the N-amino-
imidazalone causes the ψiþ1 dihedral angle to deviate by
33°ꢀ46° from that of an ideal type II0 β-turn, the geometry
of which is contingent on the stereochemistry of the
C-terminal residue (i.e., Phe).
Figure 2. X-ray structures of N-(amido)imidazolin-2-one amide
10. Broken lines represent inferred hydrogen bonds.
Table 1. Structures 10ꢀ13 and Their φ and ψ Dihedral Angles
(in degrees) from Crystal Analyses Compared with Ideal Turns
Scheme 2. Synthesis of N-(p-Methoxybenzamido)imidazolin-2-
one Isopropyl Amide (10)
type of turn
jiþ1
60
ψiþ1
jiþ2
ψiþ2
β-II0
inverse γ
10a
10b
β-II
11
ꢀ120
n/a
ꢀ80
ꢀ70
ꢀ69.1
ꢀ71.7
80
0
n/a
60
58.9
62.1
ꢀ60
ꢀ55.4
ꢀ42
ꢀ40
ꢀ153.3
ꢀ166.1
120
ꢀ4.6
65.7
0
120.9
133
89.3
89
17.8
ꢀ6.9
ꢀ97
12
13
116
96
(hydrogen-bonded) and exposed hydrogens,24 as found
in the X-ray structure.
To access constrained Phe, Trp, and His mimics, Sono-
gashira couplings were performed on dipeptide 1, using
various aryl iodides, Pd(PPh3)2Cl2, and CuI in a 1:1
DMF/Et2NH mixture (Scheme 3, Table 2). Electron-rich
and -poor aryl iodides as well as N-protected indole and
imidazole iodides all reacted in the coupling reaction to
furnish aza-arylpropargylglycines 14 in 50ꢀ93% yields.
Exposure of 14 to the NaH-promoted 5-exo-dig cycliza-
tion produced mixtures possessing endo- and exocyclic
double bonds. For example, imidazolin-2-ones 15a and
16a were isolated as isomeric mixtures in 69% yield.
Although either Z or E geometry were possible for 15, a
Measurement of the amide chemical shift values of 10 as
a function of DMSO-d6 % (1 to 100%) in CDCl3 indicated
relatively little variation (0.45 ppm) for the isopropylamide
NH signal compared to the benzamide chemical shift
(1.21 ppm; see SI), consistent with solvent-shielded
ꢀ
(21) (a) Andre, F.; Boussard, G.; Bayeul, D.; Didierjean, C.; Aubry,
ꢀ
A.; Marraud, M. J. Pept. Res. 1997, 49, 556–562. (b) Andre, F.; Vicherat,
A.; Boussard, G.; Aubry, A.; Marraud, M. J. Pept. Res. 1997, 50, 372–
381. (c) Lecoq, A.; Boussard, G.; Marraud, M.; Aubry, A. Biopolymers
1993, 33, 1051–1059. (d) Marraud, M.; Aubry, A. Pept. Sci 1996, 40, 45–
83. (e) Benatalah, Z.; Aubry, A.; Boussard, G.; Marraud, M. Int. J. Pept.
Protein Res. 1991, 38, 603–605.
(22) Baures, P. W.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.;
Johnson, R. L. J. Med. Chem. 1994, 37, 3677–3683.
(23) St-Cyr, D. J.; Maris, T.; Lubell, W. D. Heterocycles 2010, 82,
729–737.
(24) For a selected example, see: Lee, H.-J.; Ahn, I.-A.; Ro, S.; Choi,
K.-H.; Choi, Y.-S.; Lee, K.-B. J. Pept. Res. 2000, 56, 35–46.
4554
Org. Lett., Vol. 14, No. 17, 2012

lower yields due to decomposition. In contrast, electron-
rich aza-p-methoxyphenylpropargylglycinamide 14b
afforded N-amino-imidazolin-2-one 15b in only 10% yield
with recovered starting material. Imidazolyl alkyne 14g
failed to react and was exclusively recouped. In contrast,
N-Boc-3-indolyl alkyne 14f underwent base-promoted
cyclization to afford constrained tryptophan mimic imi-
dazolin-2-one 15f in 40% yield with recovered starting
material.
Scheme 3. Sonogashira/Cyclization Reaction Sequence for the
Synthesis of 4-Substituted N-Amino-imidazolin-2-ones
4-Substituted N-amino-imidazolin-2-ones have been
prepared as hybrids of the covalent and electronic con-
straints of R-amino-γ-lactams and aza-amino acids.
Opportunity for adding side-chain functionality was
demonstrated by using a Sonogashira arylation prior to
NaH-promoted 5-exo-dig cyclization of aza-propargylgly-
cinamide to afford 4-substituted N-amino-imidazolin-2-
one mimics. The propensity of the N-amino-imidazolin-2-
one subunit to induce turn conformations was confirmed
using X-ray crystallography and NMR spectroscopy of
model peptide 10. Considering their conformational pre-
ferences and potential for their diversification, N-amino-
imidazolinones represent a promising class of geometri-
cally restrained mimics for studying peptide structure.
Incorporation of N-amino-imidazolinones into a biologi-
cally active peptide sequence is currently under investiga-
tion and will be reported in due time
Table 2. Sonogashira/Cyclization Reaction Sequence Yields
Acknowledgment. This research was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC) and the Canadian Institutes of Health
Research (CIHR) Grant No. TGC-114046. C.P. is grateful
to NSERC and Boehringer Ingelheim for graduate student
€ €
fellowships. The authors thank Dr. A. Furtos, K. Venne,
a Starting material was recovered.
ꢀ
and M.-C. Tang (Universite de Montreal) for assistance
with mass spectrometry. We also thank F. Belanger-
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ꢀ
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Gariepy (Universite de Montreal) and CYLview for X-ray
analysis, G. Beaudry-Dubois and S. Bilodeau for NMR
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through-space interaction between the vinyl proton and
the methylene of imidazolidinone 15c in a 2D NOESY
experiment revealed an exclusive exocyclic Z double bond
geometry. Acid cleavage of the tert-butyl ester promoted
double bond migration inside the five-membered ring to
furnish 17a (Scheme 3).25
In the NaH-promoted 5-exo-dig cyclization, the fluorine
p-substituent was well tolerated and gave 15c in 64%
yield (Table 2). Substrates 14 with electron-withdrawing
substituents (i.e., trifluoromethyl) reacted rapidly giving
complete consumption of the starting material, albeit with
ꢀ
analysis (Universite de Montreal), and C. Camy and V. N.
G. Lindsay for SFC analysis (Universite de Montreal).
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ꢀ
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NoteAddedafterASAPPublication. The Table 1 graphic
contained an error in the version published ASAP August
14, 2012. The correct version reposted August 22, 2012.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and NMR
spectra for new compounds. Crystallographic informa-
tion files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Partial epimerization (er 74:26) was observed for 15a, likely due
to the alkaline cyclization conditions (see SI). The extent of racemization
is consistent with that (er 88:12ꢀ85:15) observed during the NaH-
promoted cyclization of phenylalanine-containing methionine-sulfo-
nium dipeptides, to provide R-amino-γ-lactams in ref 1b.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4555