structures;6 (2) a threaded loop structure was formed by
intramolecular hydrogen bonds in peptoid nonamers;7 and
(3) head-to-tail macrocyclizations provided conformationally
restricted cyclic peptoids.8
diverse monomer units and (2) precise control of secondary
structures to expand applications of peptoid helices.
To form secondary and tertiary structures, natural proteins
utilize noncovalent interactions (i.e., hydrophobic, electro-
static, and hydrogen bonds) and covalent bonds (i.e., disul-
fides). Inspired by the natural system, our goal is to build
higher-order structures by modulating monomer functionality
and sequence.2,21 In this study, we present the synthesis of
several novel peptoid submonomers that are capable of
displaying functional groups as well as inducing a helical
conformation. A sophisticated decoration of the peptoid helix
can promote interactions between helices and can therefore
be used to create novel peptoid-based ordered constructs.
Understanding the factors that influence peptoid conforma-
tion has been a central theme of peptoid research. Previously,
we elucidated the dependence of oligomer sequence,9 chain
length,10 and solvent composition7,11 on the formation of
the helical or threaded loop conformations. More recently,
Blackwell and co-workers demonstrated the ability to control
peptoid secondary structure using electron-deficient sub-
monomers such as (S)-1-(pentafluorophenyl)ethylamine12 or
(S)-1-(2-nitro-phenyl)ethylamine.13 In particular, they pro-
vided strong evidence that an electronic nfπ* interaction
at the monomer level was essential to the backbone cis/trans
isomerism14 and, potentially, to the global peptoid conforma-
tion. The role of monomer units on peptoid folding was also
investigated by Kirshenbaum et al. They introduced novel
submonomers such as (1) (S)-N-(1-carboxy-2-phenylethyl)g-
lycine15 that provided pH dependent conformational change
in peptoid secondary structure and (2) N-aryl glycines16 that
could control the backbone cis/trans isomerism.
Utilizing the relationship between peptoid monomer
sequence and adopted secondary structure, functional peptoid
foldamers have been developed including antimicrobial
peptoids,17 pulmonary surfactant protein mimics,18 asym-
metric catalysts,19 and zinc binding peptoids.20 These studies
demonstrate the importance of (1) access to chemically
Figure 1. Peptoid submonomer design.
As shown in Figure 1, three new peptoid submonomers
were designed.22 These new submonomers are derivatives
of (S)-1-phenylethylamine, or Nspe, which can be readily
incorporated into a peptoid and induces a stable helical fold.6a
Functionalized peptoids containing the new submonomers
can form noncovalent bonds (i.e., hydrogen bonds) as well
as covalent bonds (i.e., disulfide bonds, metal-ligand
interactions). In addition, they can modulate the hydropho-
bicity and water solubility11,15 of the peptoid helix.
Thiol submonomer 6 was synthesized as shown in Scheme
1. For the asymmetric synthesis of the R-branched amine,
we employed Ellman’s N-tert-butanesulfinyl imine as a key
intermediate.23 A condensation of commercially available
(+)-tert-butanesulfinamide (1) and 4-(methylthio)benzalde-
hyde with Ti(OEt)4 as a Lewis acid catalyst24 provided
sulfinimine 2 in a 94% yield. S-Methyl thioether protecting
group was well-tolerated in the Grignard reaction conditions,
and the addition of methylmagnesium bromide to sulfinimine
(6) (a) Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand, P.;
Bradley, E. K.; Truong, K. T. V.; Dill, K. A.; Cohen, F. E.; Zuckermann,
R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4303–4308. (b) Armand, P.;
Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.; Barron, A. E.; Truong,
K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann, R. N.;
Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4309–4314. (c) Wu,
C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.; Huang, K.; Dill, K. A.;
Zuckermann, R. N.; Barron, A. E. J. Am. Chem. Soc. 2003, 125, 13525–
13530.
(7) Hunag, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum,
K.; Zuckermann, R. N.; Barron, A. E.; Radhakrishnan, I. J. Am. Chem.
Soc. 2006, 128, 1733–1738.
(8) Shin, S. -B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. J. Am.
Chem. Soc. 2007, 129, 3218–3225.
(9) Wu, C. W.; Sanborn, T. J.; Kai, H.; Zuckermann, R. N.; Barron,
A. E. J. Am. Chem. Soc. 2001, 123, 6778–6784.
(10) Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.; Barron, A. E. J. Am.
Chem. Soc. 2001, 123, 2958–2963.
(11) Sanborn, T. J.; Wu, C. W.; Zuckermann, R. N.; Barron, A. E.
Biopolymers 2002, 63, 12–20
.
(12) Gorske, B. C.; Blackwell, H. E. J. Am. Chem. Soc. 2006, 128,
14378–14387.
(13) Fowler, S. A.; Luechapanichkul, R.; Blackwell, H. E. J. Org. Chem.
2009, 74, 1440–1449.
(14) Gorske, B. C.; Bastian, B. L.; Gaske, G. D.; Blackwell, H. E. J. Am.
Chem. Soc. 2007, 129, 8928–8929.
(21) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180.
(22) A guanidine functionalized submonomer was also designed and
synthesized, but sidechain cleavage was observed after incorporation into
peptoid. See Supporting Information S13-S16 for detailed discussion.
(23) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913–9914. (b) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278–1284. (c) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995. (d) Higashibayashi,
S.; Tohmiya, H.; Mori, T.; Hashimoto, K.; Nakata, M. Synlett 2004, 3, 457–
460.
(15) Shin, S. B. Y.; Kirshenbaum, K. Org. Lett. 2007, 9, 5003–5006.
(16) Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau, R.;
Rabenstein, D. L.; Kirshenbaum, K. J. Am. Chem. Soc. 2008, 130, 16622–
16632.
(17) (a) Patch, J. A.; Barron, A. E. J. Am. Chem. Soc. 2003, 125, 12092–
12093. (b) Chongsiriwatana, N. P.; Patch, J. A.; Czyzewski, A. M.; Dohm,
M. T.; Ivankin, A.; Gidalevitz, D.; Zuckermann, R. N.; Barron, A. E. Proc.
Natl. Acad. Sci. U.S.A. 2008, 105, 2794–2799.
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(24) Initially, we used anhydrous CuSO4 as a catalyst; however, the
reaction proceeded sluggishly. After 5 days at room temperature, only 64%
isolated yield was obtained. Alternatively, Cs2CO3 is known to be an
effective catalyst and water scavenger (ref 23d). Cs2CO3 is especially
amenable for large scale reactions due to the ease of reaction workup and
catalyst removal.
(19) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 13679–13684.
(20) Lee, B.-C.; Chu, T. K.; Dill, K. A.; Zuckermann, R. N. J. Am.
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