Heterocyclic amines for the construction of peptoid oligomers bearing multi-dentate ligands

Article abstract of DOI:10.1016/j.tetlet.2007.11.047

Peptoids are oligomers of N-substituted glycine that can be readily assembled using haloacetic acids and primary amines as synthons. Here, we report the synthesis and characterization of three new heterocyclic amines, 2-(2,2′:6′,2″-terpyridine-4′-yloxy)ethylamine, 2-(1,10-phenanthroline-5-yloxy)ethylamine and 8-hydroxy-2-quinolinemethylamine, and their incorporation into a series of different peptoid oligomer sequences. Since the heterocycles are all known to coordinate metal ions, the peptidomimetic products are designed to bind metal species with the potential for applications in catalysis and materials science.

Full text of DOI:10.1016/j.tetlet.2007.11.047

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 335–338
Heterocyclic amines for the construction of peptoid
oligomers bearing multi-dentate ligands
Galia Maayan,a,b Barney Yooa and Kent Kirshenbauma,*
aDepartment of Chemistry, New York University, 100 Washington Square East, New York, NY 10003-6688, USA
bMolecular Design Institute, New York University, 100 Washington Square East, New York, NY 10003-6688, USA
Received 7 September 2007; revised 5 November 2007; accepted 7 November 2007
Available online 13 November 2007
Abstract—Peptoids are oligomers of N-substituted glycine that can be readily assembled using haloacetic acids and primary amines
as synthons. Here, we report the synthesis and characterization of three new heterocyclic amines, 2-(2,20:60,200-terpyridine-40-
yloxy)ethylamine, 2-(1,10-phenanthroline-5-yloxy)ethylamine and 8-hydroxy-2-quinolinemethylamine, and their incorporation into
a series of different peptoid oligomer sequences. Since the heterocycles are all known to coordinate metal ions, the peptidomimetic
products are designed to bind metal species with the potential for applications in catalysis and materials science.
ꢀ 2007 Elsevier Ltd. All rights reserved.
N-Substituted glycine peptoid oligomers, or ‘peptoids’,
are abiotic polypeptide mimics that are capable of
adopting stable secondary structures.1 By employing a
solid-phase synthesis protocol,2 a wide variety of side
chains can be incorporated into peptoid sequences, as
shown in Scheme 1. This ‘submonomer’ protocol
enables the generation of peptoid oligomers possessing
a wide range of chemical and structural diversity.3 For
example, the incorporation of nitrogen-containing
heterocyclic side chains (imidazole, pyridine, etc.) in
peptoid oligomers has been reported previously.4 Multi-
dentate ligands for metal coordination such as terpyr-
idine, phenanthroline, and hydroxyquinoline,5 however,
have not yet been explored in the context of peptoid syn-
thesis. Such ligands, especially bipyridine and terpyr-
idine, have been incorporated into other oligomeric
scaffolds (e.g., PNA) and utilized for metal binding.6
Hence, the incorporation of such ligands as side chains
in peptoids will enable their use for metal coordination
and may further expand the functional diversity of pep-
toids for applications in catalysis and materials science.
We report here, for the first time, the synthesis of three
primary amines: 2-(2,20:60,200-terpyridine-40-yloxy)ethyl-
amine, 2-(1,10-phenanthroline-5-yloxy)ethylamine and
8-hydroxy-2-quinolinemethylamine, and their utilization
as reagents in the solid-phase synthesis of peptoid
oligomers.
Primary amines 1–3 were synthesized in simple one-step
reactions from commercially available starting materials.
Compound 1, 2-(2,20:60,200-terpyridine-40-yloxy)ethyl-
amine, was synthesized similarly to a known procedure,7
by adding 40-chloro-2,20:60,200-terpyridine and ethanol-
amine to a suspension of powdered KOH in DMSO,
and stirring at 40 ꢁC for 2 h.8 Compound 2, 2-(1,10-phe-
O
O
H
DIC
DMF
X
+
R2 NH2
N
X
N
HO
R1
R1
nanthroline-5-yloxy)ethylamine,
was
synthesized
R2
N
R2
HN
accordingly, but because 5-chloro-1,10-phenanthroline
is much less reactive than 40-chloro-2,20:60,200-terpyr-
idine, a higher temperature (80 ꢁC) and a longer reaction
time (6 h) were required.9 Compound 3, 8-hydroxy-2-
quinolinemethylamine, was synthesized by reduction
of 8-hydroxy-2-quinolinecarbonitrile with molecular
hydrogen using palladium on carbon as a catalyst.10
Conversion of the nitrile to the amine was confirmed
by the 1H NMR spectrum, showing a characteristic
O
O
H
N
R
N
N
iterate
O
R1
R1
n
X = Br or Cl; R= peptoid side chain
Scheme 1. Solid-phase ‘submonomer’ peptoid synthesis.
*
Corresponding author. E-mail: kent@nyu.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.047

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G. Maayan et al. / Tetrahedron Letters 49 (2008) 335–338
Table 1. Peptoid oligomer sequences
Peptoid
Oligomer sequence
Oligomer length
Molecular weight
Puritya (%)
Calcd:found
4
5
Netp–Npm–Nme
3mer
4mer
5mer
5mer
5mer
3mer
3mer
3mer
611.7:612.4
758.9:759.5
874.0:874.5
820.9:821.5
755.9:756.4
671.8:672.3
618.7:619.3
553.6:554.3
>95
>95
>95
>90
87
95
87
56
Npm–Netp–Npm–Nme
Nme–Npm–Netp–Npm–Nme
Nme–Npm–Neph–Npm–Nme
Nme–Npm–Nhq–Npm–Nme
Nspe–Netp–Nspe
6
7
8
9
10
11
Nspe–Neph–Nspe
Nspe–Nhq–Nspe
a As determined by analytical HPLC of crude product. Compounds 9–11 were subsequently purified by preparative HPLC to >95%. Nme = 2-
methoxyethylamine; Npm = benzylamine; Netp = 2-(2,20:60,200-terpyridine-40-yloxy)ethylamine; Neph = 2-(1,10-phenanthroline-5-yloxy)ethyl-
amine and Nhq = 8-hydroxy-2-quinolinemethylamine.
singlet signal for the methylene amine hydrogen mole-
cules (CH2–NH2) at d 4.03 ppm.
N
N
O
N
N
OH
N
O
N
NH2
NH2
2.0 2.5
3.0
3.5
4.0 4.5
5.0
5.5
6.0
6.5
7.0 7.5
8.0
NH2
1
2
3
Retention time [Minutes]
Figure 1. HPLC traces of crude peptoid oligomers 4–6 prior to
purification (offset in y-dimension only). Top: Netp–Npm–Nme trimer
(4); middle: Npm–Netp–Npm–Nme tetramer (5); bottom: Nme–Npm–
Netp–Npm–Nme pentamer (6).
N-Substituted glycine oligomers 4–11 (Table 1) were
synthesized as C-terminal amides in good yields and
high purities by using haloacetic acids and the following
primary amines: 1 (Netp); 2 (Neph); 3 (Nhq); (S)-(ꢀ)-1-
phenylethylamine (Nspe); 2-methoxyethylamine (Nme);
and benzylamine (Npm).11 The test sequence, Nme–
Npm–Netp–Npm–Nme was evaluated at various stages
of the synthesis to ensure compatibility of the hetero-
cycles with oligomer synthesis. Figure 1 shows high
performance liquid chromatographic (HPLC) character-
ization following incorporation of Netp (trimer 4), Npm
(tetramer 5), and Nme (pentamer 6).
ondary structures,1a,d we were interested in evaluating
amines 1–3 in the synthesis of peptoids incorporating
structure-inducing (S)-(ꢀ)-1-phenylethyl glycine (Nspe)
monomers. Therefore, we further synthesized peptoids
9–11, with the sequences Nspe–Netp–Nspe, Nspe–
Neph–Nspe, and Nspe–Nhq–Nspe, respectively.
As shown in Figure 1, 2-(2,20:60,200-terpyridine-40-
yloxy)ethylamine was incorporated successfully into
the peptoid sequence, resulting in peptoid 6, with high
purity. Accordingly, amines 2 and 3 were incorporated
in similar sequences to form the peptoids Nme–Npm–
Neph–Npm–Nme (7) and Nme–Npm–Nhq–Npm–Nme
(8).
Crude oligomer purities ranging from 56% to 95% were
obtained, as determined by HPLC. Low peptoid yields
were observed with the incorporation of 8-hydroxy-2-
quinolinemethylamine. Diminished yields may arise
due to the variations in the length of the spacer between
the heterocycle and the reactive amine functionality. In
the case of 8-hydroxy-2-quinolinemethylamine, the
heterocycle is positioned closer to the peptoid backbone,
which may enhance side reactions such as acylation of
the heterocyclic nitrogen center. Molecular weights were
Due to the fact that only peptoid oligomers containing
bulky a-chiral side chains are known to form stable sec-
O
O
O
O
O
O
O
O
N
NH2
N
N
NH2
HN
N
HN
N
HN
N
N
N
NH2
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
6
9
4
Netp-Npm-Nme
Nme-Npm-Netp-Npm-Nme
Nspe-Netp-Nspe

G. Maayan et al. / Tetrahedron Letters 49 (2008) 335–338
337
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confirmed by electrospray mass spectrometry and were
in agreement with the expected values (Table 1).
The study presented here establishes the compatibility of
terpyridine, phenanthroline and hydroxyquinoline
groups with the solid-phase synthesis of peptoid oligo-
mers. Furthermore, we demonstrate the feasibility of
incorporating these heterocyclic ligands in peptoids of
various lengths and sequences. The results establish
the opportunity for realizing peptoid metal complexes,
using late transition metal ions (e.g., Co and Cu) as a
starting point. The ability to place one or two monomers
incorporating metal coordinating centers at specific
positions in the context of a peptidomimetic scaffold will
be exploited to direct the formation of intermolecular or
intramolecular metal complexes. This may enable the
control of peptoid structure and will point the way to
the formation of peptoid podands, as well as foldamers
with unique secondary, tertiary, or quaternary struc-
tures. We have recently obtained metal complexes of
peptoids bearing such ligands, which are currently under
investigation in our laboratory.
6. For example: (a) Gilmartin, B. P.; Ohr, K.; McLaughlin,
R. L.; Koerner, R.; Williams, M. E. J. Am. Chem. Soc.
2005, 127, 9546–9555; (b) Nicoll, A. J.; Miller, D. J.;
Futterer, K.; Ravelli, R.; Allemann, R. K. J. Am. Chem.
Soc. 2006, 128, 9187–9193.
7. Andres, P. A.; Lunkwitz, R.; Pabst, G. R.; Bohn, K.;
Wouters, D.; Scmatloch, S.; Schubert, U. S. Eur. J. Org.
Chem. 2003, 3769–3776.
8. 40-Chloro-2,20:60,200-terpyridine (286 mg, 1 mmol) and
ethanolamine (100 ll, 1.1 mmol) were added to a stirred
suspension of powdered KOH (280 mg, 5 mmol) in
DMSO (5 ml) and stirred at 40 ꢁC for 2 h. The reaction
mixture was then added to 40 ml of methylene chloride
and washed with water (3·). The methylene chloride
solution was dried over Na2SO4 and the solvent was
removed. 2-(2,20:60,200-Terpyridine-40-yloxy) ethylamine
(286 mg, 0.97 mmol) was obtained as a light yellow solid
in 97% yield and used subsequently without further
purification. 1H NMR (400 MHz, CDCl3): d = 3.9 (t,
Acknowledgments
00
This work was supported by a National Science Foun-
dation CAREER Award (#0645361). We thank the
NCRR/NIH for a Research Facilities Improvement
Grant (C06RR-165720) at NYU. We gratefully
acknowledge Professor Michael Ward for his helpful
comments and for the support of this study through
the Molecular Design Institute.
2H, Ha), 4.8 (t, 2H, Hb), 7.25 (t, 2H, H5;5 ), 7.75 (t, 2H,
00
0
0
00
H4;4 ), 8.05 (s, 2H, H3 ;5 ), 8.55 (d, 2H, H3;3 ), 8.65 (d, 2H,
H6;6 ) ppm. 13C NMR (400 MHz, CDCl3): d = 40.9 (Ca),
00
00
00
00
77.1 (Cb), 107.4 (C5,5 ), 121.3 ðC4;4 Þ, 123.8 ðC3;3 Þ, 136.7
0
0
00
00
0
0
ðC3 ;5 Þ, 149.0 ðC6;6 Þ, 155.87 ðC2;2 Þ, 156.5 ðC2 ;6 Þ, 166.8
+
+
0
(C4 ) ppm. ESI-MS: m/z = 293.1 (M ), 315.2 (M+Na ).
9. 5-Chloro-1,10-phenanthroline (560 mg, 2.6 mmol) and
ethanolamine (175 ll, 2.9 mmol) were added to powder
KOH (730 mg, 13 mmol) in DMSO (10 ml) and stirred at
80 ꢁC for 6 h. The reaction mixture was then added to
100 ml of methylene chloride and washed with water (4·).
The methylene chloride solution was dried over Na2SO4
and the solvent was removed. The brown solid was
purified from warm methylene chloride (2·) and 2-(1,10-
phenanthroline-5-yloxy) ethylamine (442 mg, 1.85 mmol)
was obtained as a light brown solid in 71% yield and used
subsequently without further purification. 1H NMR d
(400 MHz, DMSO): d = 9.03 (dd, 2H, H2,9), 8.42 (dd, 2H,
References and notes
1. (a) Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.;
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3225.
2. Patch, J. A.; Kirshenbaum, K.; Seurynck, S. L.; Zucker-
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Discovery 2004, 1–31.
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H
4,7), 7.9 (s, 1H, H6), 7.7 (dd, 2H, H3,8) ppm. 13C NMR
(400 MHz, CDCl3): d = 40.0 (Ca), 79.5 (Cb), 123.3 (C3,8),
126.6 (C6), 129.1 (C6a), 130.8 (C4a), 136.2 (C4,7), 145.8 and
147.3 (C10a,b), 150.1 (C2,9) 151.4 (C5) ppm. ESI-MS:
m/z = 240.0 (M+), 262.1 (M+Na+).
10. 8-Hydroxy-2-quinolinecarbonitrile (1 g, 5.9 mmol) was
dissolved in acetic acid (43 ml). Pd/C (10%, 220 mg) was
added and the solution was treated with H2 (1 atm) for
14 h. The catalyst was filtered and the solvent was
removed. The crude product was re-crystallized from a
mixture of CHCl3 and Et2O. The light brown solid was
filtered, dissolved in CHCl3 (160 ml), and treated with a
1 M potassium bicarbonate solution (4 ml). The product
was extracted with CHCl3, dried over Na2SO4, and the
solvent was removed. 8-Hydroxy-2-quinolinemethylamine
(66 mg, 3.8 mmol) was obtained as a light brown solid in
65% yield and used subsequently without further purifi-
cation. 1H NMR (400 MHz, DMSO): d = 8.2 (d, 1H, H7),
7.5 (d, 1H, H2), 7.35 (dt, 2H, H5,6), 7.08 (dd, 1H, H3), 5.2
(br s, 2H, NH2), 4.03 (s, 2H, Ha) ppm. 13C NMR
(400 MHz, DMSO): d = 46.35 (Ca), 110.0 (C7), 116.4 (C5),
119.5 (C3), 125.7 (C6), 126.5 (C4a), 135.1 (C4), 136.4 (C8a),
4. Burkoth, T. S.; Fafarman, A. T.; Charych, D. H.;
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2003, 125, 8841–8845.
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338
G. Maayan et al. / Tetrahedron Letters 49 (2008) 335–338
151.9 (C8) 159.6 (C2) ppm. ESI-MS: m/z = 174.9
(M+).
diisopropylcarbodiimide (DIC) were added to the resin
and mixed at room temperature for 20 min. For the
displacement steps, a 1.0 M solution of the desired amine
was prepared in DMF. From this solution, 1 ml was added
to the resin and mixed for 20 min at room temperature.
This two-step addition cycle was modified as follows: after
incorporation of heterocyclic amines 1–3, chloroacetic acid
was used in place of bromoacetic acid, and for the next
displacement steps, 2.0 M solutions of the desired amine
were used and the displacement was done in 35 ꢁC for 1 h.4
11. Peptoid oligomers were synthesized manually on Rink
amide resin using the submonomer approach.2 Typically,
100 mg of resin was deprotected with 2 ml of 20%
piperidine in N,N-dimethylformamide (DMF) for 20 min.
This was followed by a two-step monomer addition cycle
for each residue—acylation and nucleophilic amine dis-
placement. For the haloacylation step, 0.85 ml of a 0.4 M
solution of bromoacetic acid and 0.2 ml of neat N,N0-