N-Naphthyl peptoid foldamers exhibiting atropisomerism

Article abstract of DOI:10.1021/ol203452f

We introduce peptoid oligomers incorporating N-(1)-naphthyl glycine monomers. Axial chirality was established due to restricted rotation about the C - N(aryl) bond. Atropisomerism of both linear and cyclic peptoids was investigated by computational analys

Full text of DOI:10.1021/ol203452f

ORGANIC
LETTERS
2012
Vol. 14, No. 3
926–929
N-Naphthyl Peptoid Foldamers Exhibiting
Atropisomerism
Bishwajit Paul,† Glenn L. Butterfoss,† Mikki G. Boswell,‡ Mia L. Huang,†
Richard Bonneau,† Christian Wolf,‡ and Kent Kirshenbaum*,†
Department of Chemistry and Center for Genomics and Systems Biology,
New York University, New York, New York 10003, United States, and Department of
Chemistry, Georgetown University, Washington, D.C. 20057, United States
kent@nyu.edu
Received December 26, 2011
ABSTRACT
We introduce peptoid oligomers incorporating N-(1)-naphthyl glycine monomers. Axial chirality was established due to restricted rotation about the CꢀN(aryl)
bond. Atropisomerism of both linear and cyclic peptoids was investigated by computational analysis, dynamic HPLC, and X-ray crystallographic studies.
Peptoids are a family of sequence-specific oligomers
composed of diverse N-substituted glycine units.1 Peptoids
are an example of biomimetic foldamer compounds
and can recapitulate many of the structural and func-
tional attributes of polypeptides.2 Peptoids are actively
studied in the pursuit of folded oligomers that can
display desirable biomedical, materials, or catalytic
properties.3 The peptoid backbone is typically achiral
and lacks the ability to form hydrogen bond networks.
The development of functional peptoids will necessitate
an improved capability to design structural attributes,
including chirality.
of structure-inducing side chains4,5 and oligomer macro-
cyclization.6 The selection of different side chains can
guide peptoid secondary structure features in a predictable
manner.5 Noncovalent interactions play a critical role in
peptoid folding by dictating the energetically accessible dihe-
dral angles for peptoid oligomers (Scheme 1A).7 Peptoids
incorporating bulky branched N-alkyl side chains, for
example, adopt conformations featuring cis-amide bonds
that resemble polyproline I helices.8,9 Similarly, peptoids
including N-aryl side chains establish trans-amide bonds
resembling the polyproline II conformation (Scheme 1B).10,11
The lack of intrinsic backbone chirality confounds the
formation of preferred handedness in peptoid secondary
A variety of strategies have been employed to direct
ordered peptoid conformations, including the incorporation
(4) 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.
† New York Univerity
‡ Georgetown University
(5) Gorske, B. C.; Stringer, J. R.; Bastian, B. L.; Fowler, S. A.;
Blackwell, H. E. J. Am. Chem. Soc. 2009, 131, 16555.
(6) Yoo, B.; Shin, S. B. Y.; Huang, M. L.; Kirshenbaum, K. Chem.;
Eur. J. 2010, 16, 5528.
(1) (a) Zuckermann, R. N. Pept. Sci. 2011, 96, 545. (b) 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. Proc.
Natl. Acad. Sci. U.S.A. 1992, 89, 9367.
(7) Butterfoss, G. L.; Renfrew, P. D.; Kuhlman, B.; Kirshenbaum,
K.; Bonneau, R. J. Am. Chem. Soc. 2009, 131, 16798.
(8) Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack, R. L.;
Dill, K. A.; Zuckermann, R. N.; Cohen, F. E. Folding Des. 1997, 2, 369.
(9) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E.
J. Am. Chem. Soc. 2011, 133, 15559.
(10) Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau,
R.; Rabenstein, D. L.; Kirshenbaum, K. J. Am. Chem. Soc. 2008, 130,
16622.
(2) (a) Fowler, S. A.; Blackwell, H. E. Org. Biomol. Chem. 2009, 7,
1508. (b) Yoo, B.; Kirshenbaum, K. Curr. Opin. Chem. Biol. 2008, 12,
714.
(3) (a) Zuckermann, R. N.; Kodadek, T. Curr. Opin. Mol. Ther. 2009,
11, 299. (b) Nam, K. T.; Shelby, S. A.; Choi, P. H.; Marciel, A. B.; Chen,
R.; Tan, L.; Chu, T. K.; Mesch, R. A.; Lee, B.-C.; Connolly, M. D.;
Kisielowski, C.; Zuckermann, R. N. Nat. Mater. 2010, 9, 454. (c)
Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 13679.
r
10.1021/ol203452f
Published on Web 01/24/2012
2012 American Chemical Society

structures. Nevertheless, a suitable choice of side chain
features can surmount this limitation. Bulky chiral N-alkyl
side chains promote conformational ordering and can
induce chirality in the peptoid backbone.12 Handedness
of the secondary structure may thus be dictated by the
choice of side chain stereochemistry.13
Control of chirality has been demonstrated in a variety
of folded oligomeric systems and does not necessarily
require stereocenters in each of the monomer units.14
One approach is to incorporate a chiral “sergeant”, a
specific chiral center capable of directing chirality through-
out the oligomeric molecule.15 Alternatively, handedness
in folded oligomers can arise from the presence of other
chiral elements, such as a chiral axis.16
We now evaluate whether the inclusion of N-(1)-naphthyl
glycine monomers in peptoids may similarly provide re-
stricted rotation due to peri interactions. The peri hydrogen
atom (H8) in the naphthyl ring could engender a CꢀN(aryl)
rotational barrier of sufficient magnitude to generate atro-
pisomerism (Scheme 2C). Additionally, the use of naphthyl
amines to generate N-(1)-naphthyl peptoids may enable
convenient solid phase synthesis using an established
“submonomer” method.19
Scheme 2. Biaryl and Nonbiaryl Atropisomers: (A) Biphenyl,
(B) Tertiary Anilide, and (C) N,N-Disubstituted N-Naphthyl-
amide
Atropisomerism is a stereochemical phenomenon in
which the molecular chirality is established by virtue
of restricted rotation around one or more bonds
(Scheme 2A).17 For congested tertiary anilides, electronic
factors and steric hindrance can give rise to restricted
rotation around the CꢀN(aryl) bond, promoting atrop-
isomerism (Scheme 2B).16,18 We have previously demon-
strated that certain N-aryl peptoid oligomers incorporating
bulky ortho-substituted anilide groups display chiral attri-
butes due to atropisomerism.16 N-aryl peptoids including
ortho-iodo or ortho-tert-butyl anilide groups exhibit signifi-
cant energy barriers to rotation about the stereogenic
CꢀN(aryl) bond, allowing isolation of stable atropisomeric
forms. Unfortunately, the synthesis of ortho-substituted
N-aryl peptoids necessitates laborious solution phase
chemistry and purification of intermediates.
Quantum mechanical modeling of the N-(1)-naphthyl
peptoid minimal unit (Mono-1) indicates that conforma-
tional preferences are similar to those previously seen in
ortho-substituted anilides.16,20 In the low energy con-
formations, the naphthyl plane is oriented perpendi-
cular to the plane of the backbone amide (χ1 ≈ (100°;
Scheme 1A). The naphthyl group projects away from the
following backbone carbonyl oxygen. This side chain
rotamer is preferred by ∼1.6 kcal/mol at the B3LYP/6-
311þG** level of theory. Transition state energy calcu-
lations for rotation around the χ1 dihedral angle of
Mono-1 yielded barriers of ∼24ꢀ26 kcal/mol (see Sup-
porting Information, SI). The calculated rotational barrier
height is comparable to that previously observed in ortho-
substituted N-aryl peptoid atropisomers16 and indicates the
potential for axial chirality in N-(1)-naphthyl peptoids.
We synthesized an N-aryl peptoid monomer (Mono-2)
using 1-naphthyl amine as a synthon (Scheme 3A). Ad-
ditionally, an N-aryl peptoid monomer incorporating the
2-naphthyl group was synthesized as a control (Mono-3). For
the synthesis of the peptoid monomers, we used a solution
phase synthesis protocol as previously described.5,16
Scheme 1. (A) Dihedral Angles (ω, j, ψ, and χ1) for Peptoids and
(B) Amide Bond Isomerization in N-Alkyl and N-Aryl Peptoids
(15) (a) Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.;
Cook, R.; Lifson, S. Science 1995, 268, 1860. (b) Kamer, P. C. J.; Cleij,
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J. Am. Chem. Soc. 1988, 110, 1581.
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Yeung, F. G.; Shah, N. H.; Wolf, C.; Bonneau, R.; Kirshenbaum, K.
J. Am. Chem. Soc. 2011, 133, 10910.
(11) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E.
J. Org. Chem. 2010, 75, 6068.
(12) 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.
(17) (a) Eliel, E.L.; ; Wilen, S. H. Stereochemistry of Organic Com-
pounds; Wiley Interscience: New York, 1994. (b) Wolf, C. Dynamic
Stereochemistry of Chiral Compounds; RSC Publishing: Cambridge,
2008. (c) Clayden, J. Angew. Chem., Int. Ed. 1997, 36, 949.
(18) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am.
Chem. Soc. 1994, 116, 3131. (b) Clayden, J.; Vallverdu, L.; Helliwell, M.
Org. Biomol. Chem. 2006, 4, 2106.
(13) Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.; Barron, A. E.
J. Am. Chem. Soc. 2001, 123, 2958.
(19) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H.
J. Am. Chem. Soc. 1992, 114, 10646.
(20) (a) Adler, T.;Bonjoch, J.;Clayden, J.;Font-Bardia, M.;Pickworth,
M.; Solans, X.; Sole, D.; Vallverdu, L. Org. Biomol. Chem. 2005, 3, 3173. (b)
Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani,
A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry
1997, 8, 3955.
(14) (a) Kendhale, A. M.; Poniman, L.; Dong, Z.; Laxmi-Reddy, K.;
Kauffmann, B.; Ferrand, Y.; Huc, I. J. Org. Chem. 2010, 76, 195. (b)
Sola, J.; Morris, G. A.; Clayden, J. J. Am. Chem. Soc. 2011, 133, 3712. (c)
Ko, E.; Liu, J.; Perez, L. M.; Lu, G.; Schaefer, A.; Burgess, K. J. Am.
Chem. Soc. 2010, 133, 462. (d) Gaucher, A.; Dutot, L.; Barbeau, O.;
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F.; Crisma, M.; Toniolo, C. Tetrahedron: Asymmetry 2006, 17, 30.
Org. Lett., Vol. 14, No. 3, 2012
927

Scheme 3. Chemical Structures of Peptoid (A) Monomers, (B)
Dimers, and (C) Macrocyclesa
Figure 1. Dynamic HPLC studies of peptoid Mono-2. (A) En-
antiomerization of Mono-2 atropisomeric forms. (B) Variable
temperature HPLC profiles of Mono-2.
The results from the study of the peptoid monomers
allowed us to pursue atropisomeric features in peptoid
dimers incorporating the N-(1)-naphthyl side chain. We
synthesized a hybrid N-alkyl/N-aryl peptoid (Dimer-1,
Scheme 3B) and two N-aryl peptoids (Dimer-2 and Di-
mer-3). Thelinear peptoidsweresynthesizedon solid phase
using “submonomer” methods, as described previously,
and then purified by HPLC (SI).10,19
a N-1-Naphthyl groups are in red.
In the absence of a chiral controlling influence, the ratio
of P and M conformers of peptoid Mono-2 are equally
populated at room temperature (Figure 1A). However, it is
possible to alter the relative population of interconverting
atropisomers.24 To this end, we obtained Dimer-1 featur-
ing the chiral (S)-N-(1-naphthylethyl) side chain at the C-
terminusand the axially chiralN-(1)-naphthyl side chain at
the N-terminus. This would presumably bias the N-aryl
atropisomers of Dimer-1 such that one conformer might
predominate (Figure 2A). Below 15 °C, baseline separa-
tion of Dimer-1 was observed. Upon further increase of
temperature, on-column diastereomerization was observed.
At 31.3 °C, the ratio of the diastereomers was estimated as
1.4:1 (Figure 2B). Based on DHPLC analysis of the elution
profile obtained at this temperature, the activation energy
and the rate for the diastereomerization of the major to the
minor atropisomer were calculated as 23.0 kcal/mol and
0.0104 minꢀ1, respectively (SI). Thus, the relative energies
of the axially chiral anilide rotamers can be influenced by an
adjacent stable stereogenic center.25
Two N-aryl dimers (Dimer-2 and Dimer-3, Scheme 3B)
were prepared to further explore axial chirality in peptoid
oligomers. Dimer-2 and Dimer-3 were synthesized incor-
porating the N-(1)-naphthyl side chain at the C-terminus
or N-terminus, respectively. Dimer-2 atropisomers could
be resolved by chiral HPLC. The activation energy for
isomerization of the atropisomers was comparable to the
energy barrier for Dimer-1 (ΔGq = 21.9 kcal/mol at 25 °C, SI).
In contrast to Dimer-1, the ratio of enantiomers (P and
M forms) of Dimer-2 was 1:1 at ambient temperature,
indicative of an equal population of interconverting atro-
pisomers. Dimer-3 atropisomers could similarly be sepa-
rated by chiral HPLC. These results establish that peptoid
The presence of restricted rotation around the χ1 dihe-
dral angle was evaluated by NMR. For Mono-2, we
observed that the backbone geminal methylene protons
(Scheme 3A) were magnetically nonequivalent at 25 °C
and appeared as doublet of a doublets (SI).21 For Mono-3
including the 2-naphthyl side chain, the geminal methylene
protons were observed as a singlet.22 This result indicates
the importance of peri interactions in the N-(1)-naphthyl
system to establish atropisomerism.
A significant energy barrier about a stereogenic CꢀN-
(aryl) bond can permit the separation of atropisomeric
conformers.16,23 We observed that Mono-2 can be resolved
by chiral HPLC allowing enantioseparation into (M)-
Mono-2 and (P)-Mono-2, on Chiralpak AD stationary
phase (Figure 1). Dynamic HPLC (DHPLC) can be
performed at variable temperatures, providing a means
to determine enantioconversion barriers. At 20.0 °C, base-
line separation of (M)-Mono-2 and (P)-Mono-2 was ob-
served. Upon increase of the temperature, characteristic
changes in the HPLC elution profiles were observed due to
on-column racemization (Figure 1). Computational fitting of
the experimentally obtained DHPLC elution profiles23 gave
an activation energy for the atropisomerization (ΔGq) of
23.0 kcal/mol at 25.0 °C, consistent with the computational
evaluation of Mono-1 (vide supra). This activation energy is
comparable to the energy barriers determined previously for
ortho-substituted N-aryl peptoid atropisomers.16 A van’t
Hoff plot of the DHPLC data obtained for Mono-2 gave
ΔHq = 18.7 kcal/mol and ΔSq = ꢀ14.5 cal/K mol, indicat-
ing a highly organized transition state.
(21) Stewart, W. E.; Siddall, T. H. Chem. Rev. 1970, 70, 517.
(22) Siddall, T. H. J. Phys. Chem. 1966, 70, 2249.
(23) Wolf, C. Chem. Soc. Rev. 2005, 34, 595.
(24) Clayden, J.; Moran, W.; Edwards, P.; LaPlante, S. Angew.
Chem., Int. Ed. 2009, 48, 6398.
(25) Clayden, J. Chem. Soc. Rev. 2009, 38, 817.
928
Org. Lett., Vol. 14, No. 3, 2012

dimers incorporating the N-(1)-naphthyl side chain at
either the N-terminus or C-terminus can form stable
atropisomers.
Figure 3. X-ray structure depicting a conformer of Cyclo-3.
(Scheme 3C).26 The tetramer sequence Cyclo-1 and two
hexamer sequences Cyclo-2 and Cyclo-3 were synthesized
incorporating a N-(1)-naphthyl side chain. For both Cy-
clo-1 and Cyclo-2, chiral HPLC resolved the atropisomeric
forms at room temperature (SI). Crystals were obtained
for the cyclic hexamer Cyclo-3 by slow evaporation in
ethanol. Cyclo-3 was monoclinic and crystallized in space
group P21/n. The crystal structure of Cyclo-3 displays two
trans-amides atN-aryl positions 3 and 6, (Figure 3) and cis-
amide bonds at the N-alkyl positions (1, 2, 4 and 5). The ω,
j, and ψ dihedral angles conform to the previously
determined X-ray structure of a cyclic hexamer N-alkyl/
N-aryl peptoid (SI).10 Substantial disorder was observed in
the side chains of Cyclo-3. The disorder prohibited a
complete analysis of the (χ1) side chain dihedral angles,
which were investigated further by computational model-
ing (SI). The chiral features that may be established by
atropisomeric peptoid macrocycles remain an intriguing
topic for future studies.27
Peptoids provide an attractive platform to evaluate the
relationship between the sequence and structure of folded
oligomeric molecules. We demonstrate that chirality can be
established in peptoids in the absence of formal stereocen-
ters. Peptoids incorporating the N-(1)-naphthyl side chain
can exhibit axial chirality. We observed significant barriers
to rotation around the CꢀN(aryl) bond. The slow isomer-
ization rates allowed separation of linear and cyclic peptoid
atropisomers by chiral HPLC. These advances will provide
new strategies to define peptoid conformations and facilitate
the development of more elaborate peptoid architectures.
Figure 2. Dynamic HPLC and X-ray studies of peptoid Dimer-1.
(A) Diastereomerization of Dimer-1. (B) Variable temperature
HPLC profiles of Dimer-1. (C) X-ray structure of (P,S)-Dimer-1
(red dashed line indicates hydrogen bond).
The peptoid Dimer-1 was crystallized from ethanol by
slow evaporation. The Dimer-1 crystal was monoclinic and
corresponded to the chiral space group P21. We observed
one exclusive diastereomeric form (P,S) of Dimer-1 in the
solid state (Figure 2C, SI). To our knowledge, this is
the first crystal structure for a linear N-aryl/N-alkyl
hybrid peptoid. As observed for other N-aryl peptoid
monomers,10 the N-(1)-naphthyl monomer unit features a
trans-amide bond with ω = 176.3°. Correspondingly, the
N-alkyl peptoid unit (S)-N-(1-naphthylethyl) monomer in-
cludes a cis-amide bond with ω = ꢀ1.9°. Dimer-1 features
an intramolecular hydrogen bond between the carbonyl
oxygen at the N-terminus and the NH2 group of the
amidated C-terminus, suggestive of a reverse turn motif
(Figure 2C). Both the N-terminal (N)-1-naphthyl and
C-terminal (S)-N-(1-naphthylethyl) monomer positions
include predictable dihedral angles as evaluated previously
by X-ray studies and molecular modeling (SI).7,9ꢀ11 In
addition, the overall conformationofDimer-1 corresponds
to the low energy structure as modeled by calculation per-
formed at the M052X/6-311þG** level of theory (SI).
We sought to establish atropisomerism in large pep-
toid macrocycles. We prepared three macrocycles from
corresponding linear peptoids as previously described
Acknowledgment. ThisworkwassupportedbytheNSF
(CHE-0645361 to K.K. and CHE-0910604 to C.W.). We
thank the NCRR/NIH for a Research Facilities Im-
provement Grant (C06RR-165720). We thank Chunhua
(Tony) Hu of the NYU Dept. of Chemistry for technical
assistance.
Supporting Information Available. Additional informa-
tion regarding characterization of peptoids by HPLC,
DHPLC, ESIꢀMS, NMR and computational studies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Shin, S. B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. J. Am.
Chem. Soc. 2007, 129, 3218.
(27) Szumna, A. Chem. Soc. Rev. 2010, 39, 4274.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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