Extended peptoids: a new class of oligomers based on aromatic building blocks

Article abstract of DOI:10.1016/j.tetlet.2007.02.075

Peptoids (N-substituted polyglycines) represent a class of bioinspired oligomers that have unique physical and structural properties. Here, we report the construction of 'extended peptoids' based on aromatic building blocks, in which the N-alkylaminoacetyl group of the peptoid backbone has been replaced by an N-alkylaminomethylbenzoyl spacer. Both meta- and para-bromomethylbenzoic acids were synthesized, providing access to a new class of peptoids. Further, inclusion of hydrophilic side chains confers water solubility to these compounds, showing that, like simple peptoids, extended peptoids add an extra dimension to synthetic poly-amide oligomers with potential application in a variety of biological contexts.

Full text of DOI:10.1016/j.tetlet.2007.02.075

Tetrahedron Letters 48 (2007) 2679–2682
Extended peptoids: a new class of oligomers based
on aromatic building blocks
David J. Combs and R. Scott Lokey*
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Received 28 October 2006; revised 13 February 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—Peptoids (N-substituted polyglycines) represent a class of bioinspired oligomers that have unique physical and structural
properties. Here, we report the construction of ‘extended peptoids’ based on aromatic building blocks, in which the N-alkylamino-
acetyl group of the peptoid backbone has been replaced by an N-alkylaminomethylbenzoyl spacer. Both meta- and para-bromo-
methylbenzoic acids were synthesized, providing access to a new class of peptoids. Further, inclusion of hydrophilic side chains
confers water solubility to these compounds, showing that, like simple peptoids, extended peptoids add an extra dimension to
synthetic poly-amide oligomers with potential application in a variety of biological contexts.
Ó 2007 Elsevier Ltd. All rights reserved.
Peptoids1 (N-substituted glycines) represent an interest-
O
R
N
O
ing class of biomimetic oligomers that are structurally
related to peptides but have different biological2,3 and
conformational4–6 properties. The submonomer method
of peptoid synthesis introduced by Zuckermann et al.7
allows for considerable diversity to be incorporated into
the construction of peptoid libraries due to the large
number of commercially available primary amines.
The submonomer method has been applied extensively
in the creation of peptoid libraries,8–12 and it has shown
great versatility in incorporating a diverse set of
amines13,14 and hydrazines.15 The peptoid scaffold has
been further modified to create ureapeptoids16,17 and
incorporate a variety of chemoselective functionalities.18
The bulk of these studies, however, have preserved the
haloacetic acid component while focusing on variations
in the nucleophilic displacement step. Here, we report
the solid-phase synthesis of a new class of peptoid-in-
spired biomimetics in which the haloacetic acid groups
are replaced by either meta- or para-halomethylbenzoic
acids (Fig. 1b). These extended peptoids add further
geometric diversity to oligomers based on the peptoid
concept.
H
OH
n
N
R
H
OH
n
Figure 1. (a) General peptoid structure and (b) general extended
peptoid structure.
The synthesis of meta-extended peptoids is shown in
Scheme 1. m- and p-Bromomethylbenzoic acids were
readily synthesized by bromination of the corresponding
toluic acids.19 All of the extended peptoids described
here were synthesized on Wang resin (100–200 mesh,
1.1 mmol/g).à The first bromomethylbenzoic acid sub-
monomer was coupled to the resin with diisopropyl-
carbodiimide (DIC) and 4-dimethylaminopyridine
(DMAP) in dry DCM over 1 h at room temperature.
The addition of subsequent bromomethylbenzoic acid
submonomers was performed without DMAP. Primary
amines (5 equiv) were added in dry DMF and allowed to
react at room temperature for 1 h. Elongation of the
extended peptoid chain was performed by repeating
the above steps over several cycles, followed by cleavage
Keywords: Peptoids; N-Alkyl glycines; Oligomers; Bioinspired
polymers.
*
Corresponding author. Tel.: +1 831 459 1307; fax: +1 831 459
2935; e-mail: lokey@chemistry.ucsc.edu
à Attempts to perform the synthesis on Rink amide resin resulted in
significant impurities corresponding to nucleophilic attack by the
Rink resin amine onto the bromomethyl group.
Present address: School of Medicine, University of Pennsylvania,
Philadelphia, PA 19104, USA.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.075

2680
D. J. Combs, R. S. Lokey / Tetrahedron Letters 48 (2007) 2679–2682
In order to establish the generality of the synthesis
CO2H
O
Br
(1)
toward different primary amines, extended peptoid
dimers were synthesized using amines 2–9. Amine
coupling and acylation efficiencies were assessed using
model compounds with the test amine at the first mono-
mer position and amine 9 in the second position
(Scheme 2). Amines with a primary substituent coupled
efficiently, whereas those with a secondary substituent
(e.g., 5 and 6) showed little to no reaction with the
resin-bound bromomethyl benzoate ester (Table 1).
Relatively electron deficient amines such as 2 and 8 also
showed diminished coupling efficiencies at the amine
addition step. This observation contrasts with reports
in the literature on the efficient synthesis of similarly
substituted peptoids. LC/MS analysis showed that the
principal impurity among the poorly coupled amines
was an end-capped deletion sequence, consistent with
a failure at the nucleophilic displacement step. Despite
these limitations, however, the high coupling efficiencies
for amines 3, 4, 7, and 9 show that a range of function-
alities can be tolerated during the amine addition step
and that extended peptoids can be generated from a
diverse collection of building blocks.
Br
HO
O
DIC, DMAP
CH2Cl2
O
R-NH2
HN
R
O
DMF, 1 h
O
1. 1, DIC
H
N
R
O
2. R-NH2
(repeat n times)
n
O
O
1. Ac2O, TEA, DMF
H3C
N
R
OH
2. TFA, 5% i-Pr3SiH
n
To demonstrate the viability of synthesizing larger
extended peptoids, pentamers using both para- and
meta-bromotoluic acids and amines 7 and 9 were made.
Product purities after each monomer addition were as-
sessed by HPLC and yields were determined by weighing
the final cleaved products. Excellent purities and moder-
Scheme 1. General scheme for the solid-phase synthesis of meta-
extended peptoids.
from the resin with trifluoroacetic acid (TFA) contain-
ing triisopropylsilane.
O
O
2 - 9
O
O
Br
HN
R
O
O
H
N
N
R
OH
Ph
10 -17
N
N
N
NH2
H2N
H2N
O
N
O2N
3
2
4
7
O
O
NH2
N
t-BuO
NH2
NH2
5
6
H
N
H2N
N
H2N
8
9
Scheme 2. Monomer assessment studies using amines 2–9 on model extended peptoid backbone.

D. J. Combs, R. S. Lokey / Tetrahedron Letters 48 (2007) 2679–2682
Table 1. Coupling efficiencies of amines 2–9
2681
polycyclic spacer elements that contain reactive allylic
and benzylic halides, further increasing the potential
diversity of this class of compounds. These compounds
represent a new type of oligomer based on a simple elab-
oration of standard peptoid chemistry, providing access
to a large variety of new compounds with potentially
interesting properties. Among these properties, the
inherent hydrophobicity and rigidity of these extended
peptoids, in particular, may be well suited as macro-
molecule ligands for proteomics and drug discovery
applications.
Amine
Compound
% Puritya
% Crude yieldc
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
9
87
54
>99
>99
0b
79
0b
0b
0b
>99
46
>99
>99
55
>99
a Determined by % area of light scattering signal in LC/MS analysis of
crude product after cleavage from resin.
b No product was detected by mass.
c TFA removed by evaporation; crude product washed several times
with Et2O, resuspended in 1:1 H2O ACN and lyophilized.
Acknowledgments
We are grateful to the following agencies for financial
support of this work: The California Institute for Bio-
engineering, Biotechnology and Quantitative Biomedical
Research (QB3) opportunity fund; the National Cancer
Institute (1R01CA104569-01); California Cancer Re-
search Coordinating Committee (Award SC-04-76).
We thank Mr. J. Loo for assistance with the NMR
experiments. We are also grateful to Roche Palo Alto
for the donation of the mass spectrometer used for this
work.
Table 2. Yields and purities of extended peptoid oligomers
Spacer
Sequencea
% Purityb
% Purified yieldc
18
19
20
21
m
m
p
Ac-7-7-7-7
Ac-9-9-9-9-9
Ac-7-7-7-7
Ac-9-9-9-9-9
94
99
95
99
37
12
20
12
p
a Ac = N-acyl.
b Determined by % area of light scattering signal in LC/MS analysis of
crude product after cleavage from resin.
c Compounds purified by preparative HPLC and lyophilized.
Supplementary data
ate isolated, purified yields were obtained (see Table 2).
NMR spectra taken at room temperature for all four
synthesized pentamers were highly complex, most likely
due to the presence of multiple amide bond rotamers.
Supplementary data (general experimental procedures;
LC/MS traces for compounds 10–21 and NMR spectra
for compounds 18–21) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.075.
When NMR spectra were obtained at 100 °C in DMSO-
d6, the spectra for pentamers based on amine 9 were
greatly simplified and amenable to straightforward
interpretation; however, pentamers based on amine 7
degraded (in both DMSO-d6 and D2O) at the high tem-
peratures required to coalesce the amide rotamers.§ Pen-
tamers incorporating amine 7 were found to be highly
water soluble (80 mg/ml), suggesting that the back-
bone’s intrinsic hydrophobicity can be overcome with
appropriate hydrophilic side chains to generate water-
soluble extended peptoids.
References and notes
1. Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner,
V. D.; Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.;
Rosenberg, S.; Marlowe, C. K.; Spellmeyer, D. C.; Tan,
R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P.
A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367–9371.
2. Nguyen, J. T.; Porter, M.; Amoui, M.; Miller, W. T.;
Zuckermann, R. N.; Lim, W. A. Chem. Biol. 2000, 7, 463–
473.
3. Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.;
Stauber, G. B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi,
G. M.; Goff, D. A.; Siani, M. A.; Simon, R. J.; Banville, S.
C.; Brown, E. G.; Wang, L.; Richter, L. S.; Moos, W. H.
J. Med. Chem. 1994, 37, 2678–2685.
The discrepancy between the high purity of the crude
product and moderate isolated yield is likely due to ami-
nolysis of the peptide from the Wang linker. Future
studies will be aimed at optimizing conditions on the
Rink resin or attempting syntheses on the more steri-
cally hindered 2-chlorotrityl resin. Microwave-based
synthesis of these compounds was explored but showed
no significant improvement for either impurities or
yields (data not shown).
4. Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.;
Armand, P.; Bradley, E. K.; Truong, K. T.; Dill, K. A.;
Cohen, F. E.; Zuckermann, R. N. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4303–4308.
5. Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack, R.
L., Jr.; Dill, K. A.; Zuckermann, R. N.; Cohen, F. E. Fold.
Des. 1997, 2, 369–375.
In principle, the extended peptoid concept could be fur-
ther elaborated to include vinylogous, heterocyclic, and
6. Sanborn, T. J.; Wu, C. W.; Zuckermann, R. N.; Barron,
A. E. Biopolymers 2002, 63, 12–20.
7. Figliozzi, G. M.; Goldsmith, R.; Ng, S. C.; Banville, S. C.;
Zuckermann, R. N. Methods Enzymol. 1996, 267, 437–
447.
§ It should be noted that the aromatic resonances due to the side chain
of 7 were not distinguishable from those of the extended peptoid
backbone in the NMR spectrum.

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D. J. Combs, R. S. Lokey / Tetrahedron Letters 48 (2007) 2679–2682
8. Murphy, J. E.; Uno, T.; Hamer, J. D.; Cohen, F. E.;
13. Uno, T.; Beausoleil, E.; Goldsmith, R. A.; Levine, B. H.;
Zuckermann, R. N. Tetrahedron Lett. 1999, 40, 1475–
1478.
Dwarki, V.; Zuckermann, R. N. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 1517–1522.
9. Boden, P.; Eden, J. M.; Hodgson, J.; Horwell, D. C.;
Hughes, J.; McKnight, A. T.; Lewthwaite, R. A.; Prit-
chard, M. C.; Raphy, J.; Meecham, K.; Ratcliffe, G. S. J.
Med. Chem. 1996, 39, 1664–1675.
10. Linusson, A.; Wold, S.; Norden, B. Mol. Divers. 1998, 4,
103–114.
11. Humet, M.; Carbonell, T.; Masip, I.; Sanchez-Baeza, F.;
Mora, P.; Canton, E.; Gobernado, M.; Abad, C.; Perez-
Paya, E.; Messeguer, A. J. Comb. Chem. 2003, 5, 597–
605.
12. Alluri, P. G.; Reddy, M. M.; Bachhawat-Sikder, K.;
Olivos, H. J.; Kodadek, T. J. Am. Chem. Soc. 2003, 125,
13995–14004.
14. Burkoth, T. S.; Fafarman, A. T.; Charych, D. H.;
Connolly, M. D.; Zuckermann, R. N. J. Am. Chem. Soc.
2003, 125, 8841–8845.
15. Cheguillaume, A.; Lehardy, F.; Bouget, K.; Baudy-Floc’h,
M.; Le Grel, P. J. Org. Chem. 1999, 64, 2924–2927.
16. Wilson, M. E.; Nowick, J. S. Tetrahedron Lett. 1998, 39,
6613–6616.
17. Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J.
Tetrahedron Lett. 1997, 38, 5335–5338.
18. Horn, T.; Lee, B. C.; Dill, K. A.; Zuckermann, R. N.
Bioconjugate Chem. 2004, 15, 428–435.
19. Kikuchi, D.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998,
63, 6023–6026.