Advances towards aromatic oligoamide foldamers: Synthesis and X-ray structures of dimeric arylopeptoids with conformation-directing side chains

Article abstract of DOI:10.1002/ejoc.201402040

We have efficiently synthesized 36 arylopeptoid dimers with ortho-, meta-, and para-substituted aromatic backbones and tert-butyl or phenyl side chains. The dimers were synthesized by using a submonomer method on solid phase, by applying a simplified common set of reaction conditions. X-ray crystallographic analysis of two of these dimers disclosed that the tert-butyl side chain invokes a cis amide conformation with a comparatively more closely packed structure of the surrounding aromatic backbone while the phenyl side chain results in a trans amide conformation with a more open, extended structure of the surrounding aromatic backbone. Investigation of the X-ray structures of two arylopeptoid dimers disclosed that the tert-butyl side chain invokes a cis amide conformation with a closely packed structure of the surrounding aromatic backbone while the phenyl side chain results in a trans amide conformation with a more open, extended structure of the surrounding aromatic backbone. Copyright

Full text of DOI:10.1002/ejoc.201402040

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402040
Advances towards Aromatic Oligoamide Foldamers: Synthesis and X-ray
Structures of Dimeric Arylopeptoids with Conformation-Directing Side Chains
Thomas Hjelmgaard,*[a][‡] Malene Plesner,[b] Mette Marie Dissing,[b]
Jeanette Marker Andersen,[b] Karla Frydenvang,[b] and John Nielsen*[b]
Keywords: Amides / Solid-phase synthesis / Structure elucidation / Foldamers
We have efficiently synthesized 36 arylopeptoid dimers with
ortho-, meta-, and para-substituted aromatic backbones and
tert-butyl or phenyl side chains. The dimers were synthe-
sized by using a “submonomer method” on solid phase, by
applying a simplified common set of reaction conditions. X-
ray crystallographic analysis of two of these dimers disclosed
that the tert-butyl side chain invokes a cis amide conforma-
tion with a comparatively more closely packed structure of
the surrounding aromatic backbone while the phenyl side
chain results in a trans amide conformation with a more
open, extended structure of the surrounding aromatic back-
bone.
Introduction
Aromatic oligoamides assembled from aromatic amino
acid building blocks in a “one-way sequence” fashion repre-
sent an intriguing subgroup of aryl-based foldamers.[1] Sec-
ondary structures have been reported for N-alkylated ben-
zanilides,[2] benzanilides,[3] pyridylamides,[3f,3k,4] and oligo-
amides of quinolines,[5] naphthyridines,[6] aminophenoxy
acetic acid,[7] and aminomethylphenyl acetic acid (Fig-
ure 1).[8] Depending on their nature, these aromatic oligo-
amides fold into spherand or crown ether-like struc-
tures,[3m,3o] crescent or helical structures,[2c,3j,3p–3r,4a–4e,5–8]
or rod-like structures,[3h,3n] and they have furthermore been
used as α-helix mimetics.[2a,2b,3a–3g,3i,3k,3l,4f,4g]
Figure 1. “One-way sequence” aromatic oligoamide foldamers.
strategy for greatly increasing the structural diversity of
aromatic oligoamides as exemplified by N-alkylated amino-
methylbenzamides[9] termed arylopeptoids (Figure 2).[10]
Amongst these foldamers, only the N-alkylated benzanil-
ides carry side chains at the backbone amide nitrogen
atoms. This may be a result of the often less straightforward
synthetic pathways to N-alkylated aromatic oligoamides
and because folding promoted by intramolecular hydrogen
bonding involving backbone amide protons is not possible.
Nevertheless, N-alkylation represents a conceptually simple
Figure 2. Arylopeptoids: N-alkylated aminomethylbenzamides.
[a] Department of Chemistry, Section for Chemical Biology and
Nanobioscience, Faculty of Science, University of Copenhagen,
Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark
The backbone structure of arylopeptoids allow for syn-
thesis by using highly convenient “submonomer” ap-
[b] Department of Drug Design and Pharmacology, Faculty of proaches wherein the arylopeptoid residues are created in
Health and Medical Sciences, University of Copenhagen,
an iterative manner directly on the growing oligoamide
Universitetsparken 2, 2100 Copenhagen Ø, Denmark
chains with a unique acylation–substitution cycle (Fig-
ure 2). As a result of our recent efforts, arylopeptoids with
ortho-,[10a] meta-,[10b–10d] or para-substitution pattern[10b–10d]
in the backbone may now be synthesized efficiently both on
solid phase, by use of either COMU-activated chlorometh-
ylbenzoic acids[10c] or chloromethylbenzoyl chlorides[10a,10b]
in the coupling steps, as well as in solution.[10a,10d] These
E-mail: john.nielsen@sund.ku.dk
www.sund.ku.dk
[‡] Current address: Rockwool International A/S, Group Research
and Development,
Hovedgaden 584, Entrance C, 2640 Hedehusene, Denmark
E-mail: thomas.hjelmgaard@rockwool.com
www.rockwool.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402040.
Eur. J. Org. Chem. 2014, 3971–3975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3971

T. Hjelmgaard, J. Nielsen et al.
SHORT COMMUNICATION
methods have enabled our recent discovery of the first bio- (20 equiv., 2 m in DMSO) at 50 °C for 1 h. Acylation or
logically active arylopeptoids.[11]
capping after substitution with aniline was carried out by
NMR spectroscopic studies have furthermore enabled us using 2-, 3-, or 4-(chloromethyl)benzoyl chloride or benzoyl
to establish that most side chains give rise to the presence chloride (3 equiv., 0.5 m in CH2Cl2) in the presence of DI-
of cis/trans amide mixtures resulting in flexible structures PEA (6 equiv.) at room temp. for 1 h. Acylation or capping
and complex spectra.[10a,10b,10d] However, homooligomers after substitution with tert-butylamine was carried out by
carrying tert-butyl or phenyl side chains represent intri- using 2-, 3-, or 4-(chloromethyl)benzoyl chloride or benzoyl
guing exceptions, because they produce simple NMR spec- chloride (6 equiv., 1.0 m in CH2Cl2) in the presence of DI-
tra. Extensive overlap in the aromatic region of the NMR PEA (12 equiv.) at room temp. for 1 h, except when the acy-
spectra unfortunately hinders the extraction of conforma- lating reagent or the residue to be acylated was an ortho-
tional data, and we have hitherto not been successful in substituted aromatic group, in which case the reaction time
obtaining single crystals of any of these homooligomers. was extended to 3 h. The dimers were cleaved from the res-
However, some limited conformational data can be ob- ins by using CH2Cl2/HFIP (4:1) for 1 h and purified by pre-
tained by performing NOESY studies on model arylopep- parative HPLC as described previously.[10a,10b] With these
toid monomers,[10a,10b,10d] for which we have established methods, the 12 dimers of the p-series were obtained in 34–
that the tert-butyl side chain invokes a 100% cis conforma- 58% purified yield (Ն 94% purity) and the 12 dimers of the
tion about the amide bond (Figure 3, left), while the phenyl m-series were obtained in 51–69% purified yield (Ն 95%
side chain results in a 100% trans amide conformation (Fig- purity). The 12 dimers of the o-series were obtained in a
ure 3, right).
more varied 15–48% purified yield (Ն 83% purity; 11 of
Figure 3. cis and trans amide conformations found in model arylo-
peptoid monomers.
Obtaining single crystals for X-ray analysis of arylopep-
toid fragments with tert-butyl or phenyl side chains would
represent a substantial advance towards the possible future
design of foldamers based on arylopeptoids. During our
previous work we have observed that monomers with free
acids at the C-terminus often display a high level of crystal-
linity, which therefore prompted us to investigate the pos-
sibility for crystallizing the corresponding dimeric arylo-
peptoids.
Results and Discussion
We synthesized a library comprising all 36 possible com-
binations of dimers with an ortho-aromatic (o-series), meta-
aromatic (m-series), or para-aromatic (p-series) substitution
at the C-terminus, ortho-, meta-, or para-aromatic substitu-
tion at the N-terminus, and tert-butyl or phenyl side chains
(Scheme 1, see Supporting Information for details). This is
the first time arylopeptoids with mixed ortho-, meta-, and
Scheme 1. Solid-phase submonomer synthesis of arylopeptoid di-
para-substituted backbones have been synthesized and mers. Reagents and conditions: (a) o-series: Rink acid polystyrene
resin, ClCH2ArCOCl (3.0 equiv., 0.5 m), DMAP (3.0 equiv.),
studied. The o-series was synthesized by using a Rink acid
DIPEA (3.0 equiv.), CH2Cl2, room temp., 20 min; m-/p-series: 2-
polystyrene resin,[10a] while the m- and p-series were synthe-
chlorotrityl chloride polystyrene resin, ClCH2ArCOOH (1.2 equiv.,
0.14 m), DIPEA (6.0 equiv.), CH2Cl2, room temp., 1 h. (b) R = Ph:
PhNH2 (20 equiv., 4.0 m), DMSO, 50 °C, 3 h; R = tBu: tBuNH2
(20 equiv., 2.0 m), DMSO, 50 °C, 1 h. (c) ClCH2ArCOCl
(3.0 equiv., 0.5 m or 6.0 equiv., 1.0 m), DIPEA (6.0 or 12.0 equiv.),
CH2Cl2, room temp., 1 h or 3 h. (d) BzCl (3.0 equiv., 0.5 m or
6.0 equiv., 1.0 m), DIPEA (6.0 or 12.0 equiv.), CH2Cl2, room temp.,
sized by using a 2-chlorotrityl chloride (2-ctc) polystyrene
resin.[10b] Loading onto these resins was performed as we
have previously described.[10a,10b] In order to facilitate the
library synthesis, we applied a set of simplified chain elong-
ation conditions (Scheme 1). Thus, the substitution reac-
tions were all performed by using either aniline (20 equiv.,
1 h or 3 h. (e) HFIP/CH2Cl2 (1:4), room temp., 1 h. See Supporting
4 m in DMSO) at 50 °C for 3 h or tert-butylamine Information for yields and purities.
3972
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3971–3975

Dimeric Arylopeptoids with Conformation-Directing Side Chains
the 12 dimers were isolated in Ն 96% purity), and although and 3.644(4) Å (between ring II and III). We propose that
optimization might increase these yields and purities, we steric effects of the bulky tert-butyl side chain cause the
did not investigate these options, as we obtained sufficient amide to adopt the observed cis conformation, which en-
material for full characterization and crystallization.
ables the tert-butyl side chains to point outwards from the
As expected, NMR spectra of all dimers showed the twist created by the two surrounding backbone aromatic
presence of a single conformer only (see Supporting Infor- rings. The carboxylic acid moiety is slightly bent out of the
mation). However, overlap of signals in the aromatic region plane of the aromatic ring [6.3(4)°]. Dimer o-4 (Figure 4,
unfortunately hinders conformational analysis. Crystalli- bottom right) crystallizes in the monoclinic space group
zation of the 36 dimers was then investigated from a range P21/n. The observed amide conformations likewise confirm
of different solvents and solvent compositions. We suc- and extend our previous findings from NMR spectroscopic
ceeded in obtaining suitable crystals of two of the dimers: studies on model arylopeptoid monomers:[10a,10b,10d] A cis
m-2 of the meta-series (Figure 4, top left), which is con- conformation is observed at the first amide moiety that car-
structed of two meta-residues both carrying tert-butyl side ries a tert-butyl side chain [torsion angle: –6.4(2)°], while
chains, and o-4 of the ortho-series (Figure 4, top right), the second amide moiety, which carries a phenyl side chain,
which is constructed of two ortho-residues carrying a tert- adopts a trans conformation [torsion angle: –179.9(1)°].
butyl side chain on the first residue and a phenyl side chain Analogous to m-2, the tert-butyl side chain leads to a com-
on the second. Crystals of dimer m-2 were obtained by slow pact structure about the amide moiety where the two sur-
concentration from a solution of approximately 10 mg of rounding backbone aromatic rings are close to perpendicu-
the compound in 1 mL of CDCl3 containing a few drops of lar [the dihedral angle between rings I and II is 76.75(4)°],
MeOD, while crystals of o-4 were isolated by slow concen- and the distance between the branching points of the aro-
tration from a solution of approximately 10 mg of the com- matic rings is 3.696(2) Å. The phenyl side chain, on the
pound in 1 mL of CH2Cl2/CHCl3 (2:1) containing a few other hand, leads to a more open, extended conformation
drops of MeOH.
[the dihedral angle between rings II and III is 53.35(5)°,
and the distance between the branching points of the aro-
matic rings is 4.671(2) Å (between ring II and III)]. The
trans amide conformation causes the phenyl side chain to
point inwards into the twist created by the two surrounding
backbone aromatic rings. We speculate that the trans amide
preference may be because the N-phenyl side chain is less
bulky than the N-methylbenzyl group and because of the
electronic repulsion between the carbonyl lone pair and the
phenyl π-electrons.[13] The carboxylic acid moiety of o-4 is
bent out of the plane of the aromatic ring [–35.2(2)°], pre-
sumably because of the ortho-substitution. See Supporting
Information for details regarding the crystal packing of the
two dimers.
Conclusions
Figure 4. X-ray structures of dimers m-2 and o-4.
The three-dimensional structures of the two dimers were
We have used a common set of simplified reaction condi-
then determined by X-ray crystallography (see Supporting tions for efficient submonomer solid-phase synthesis of a
Information for details).[12] Dimer m-2 (Figure 4, bottom library of 36 dimeric arylopeptoids with ortho-, meta-, and
¯
left), crystallizes in the triclinic space group P1. The confor- para-substituted aromatic backbones and tert-butyl and
mations of both amide moieties are cis [torsion angles: phenyl side chains. Arylopeptoids with mixed ortho-, meta-,
–3.6(4)°, 14.0(4)°], which confirms our previous findings and para-substituted backbones have been synthesized and
from NMR spectroscopic studies on model monomers re- studied for the first time. Also for the first time, we suc-
garding the tert-butyl side chain.[10a,10b,10d] Importantly, ceeded in obtaining single crystals suitable for X-ray crys-
these findings allow us for the first time to establish that tallographic studies of two of the dimers: Amides with a
the cis-amide-directing action of the tert-butyl side chain in tert-butyl side chain were found to adopt a cis amide con-
model arylopeptoid monomers is likewise extended to an formation, while an amide with phenyl side chain was found
arylopeptoid dimer. The tert-butyl side chain leads to a rel- to adopt a trans amide conformation. These results thus
atively compact structure about the amide moiety where the confirm and extend our previous findings from NMR spec-
two surrounding backbone aromatic rings are nearly per- troscopic studies on model arylopeptoid monomers. We
pendicular to one another [the dihedral angle between rings furthermore found that the phenyl side chain in the crys-
I and II is 89.86(9)° and that between rings II and III is tallized dimers results in a comparatively more open, ex-
86.81(10)°], and the distances between the branching points tended backbone structure where the phenyl side chain
of the aromatic rings are 3.666(4) Å (between ring I and II) points inwards into the twist created by the surrounding
Eur. J. Org. Chem. 2014, 3971–3975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3973

T. Hjelmgaard, J. Nielsen et al.
SHORT COMMUNICATION
72, 870–877; n) R. Abbel, H. Frey, D. Schollmeyer, A. F. M.
Kilbinger, Chem. Eur. J. 2005, 11, 2170–2176; o) H.-P. Yi, C.
Li, J.-L. Hou, X.-K. Jiang, Z.-T. Li, Tetrahedron 2005, 61,
7974–7980; p) L. Yuan, H. Zeng, K. Yamato, A. R. Sanford,
W. Feng, H. S. Atreya, D. K. Sukumaran, T. Szyperski, B.
Gong, J. Am. Chem. Soc. 2004, 126, 16528–16537; q) B. Gong,
H. Zeng, J. Zhu, L. Yuan, Y. Han, S. Cheng, M. Furukawa,
R. D. Parra, A. Y. Kovalevsky, J. L. Mills, E. Skrzypczak-Jan-
kun, S. Martinovic, R. D. Smith, C. Zheng, T. Szyperski, X. C.
Zeng, Proc. Natl. Acad. Sci. USA 2002, 99, 11583–11588; r) J.
Zhu, R. D. Parra, H. Zeng, E. Skrzypczak-Jankun, X. C. Zeng,
B. Gong, J. Am. Chem. Soc. 2000, 122, 4219–4220.
a) W. Q. Ong, H. Zhao, C. Sun, J. Wu, Z. Wong, S. F. Y. Li, Y.
Hong, H. Zeng, Chem. Commun. 2012, 48, 6343–6345; b) H.
Zhao, W. Q. Ong, F. Zhou, X. Fang, X. Chen, S. F. Y. Li, H.
Su, N.-J. Cho, H. Zeng, Chem. Sci. 2012, 3, 2042–2046; c) H.
Zhao, W. Q. Ong, X. Fang, F. Zhou, M. N. Hii, S. F. Y. Li, H.
Su, H. Zeng, Org. Biomol. Chem. 2012, 10, 1172–1180; d) W. Q.
Ong, H. Zhao, Z. Du, J. Z. Y. Yeh, C. Ren, L. Z. W. Tan, K.
Zhang, H. Zeng, Chem. Commun. 2011, 47, 6416–6418; e)
W. Q. Ong, H. Zhao, X. Fang, S. Woen, F. Zhou, W. Yap, H.
Su, S. F. Y. Li, H. Zeng, Org. Lett. 2011, 13, 3194–3197; f) L. A.
Estroff, C. D. Incarvito, A. D. Hamilton, J. Am. Chem. Soc.
2004, 126, 2–3; g) J. T. Ernst, J. Becerril, H. S. Park, H. Yin,
A. D. Hamilton, Angew. Chem. Int. Ed. 2003, 42, 535–539; An-
gew. Chem. 2003, 115, 553.
See for example: a) Y. Qi, V. Maurizot, H. Noguchi, T. Charo-
enraks, B. Kauffmann, M. Takafuji, H. Ihara, I. Huc, Chem.
Commun. 2012, 48, 6337–6339; b) M. Shravani, S. Balaiah, K.
Srinivas, K. Bhanuprakash, I. Huc, ChemPhysChem 2012, 13,
3526–3534; c) A. M. Kendhale, L. Poniman, Z. Dong, K.
Laxmi-Reddy, B. Kauffmann, Y. Ferrand, I. Huc, J. Org.
Chem. 2011, 76, 195–200; d) Q. Gan, F. Li, G. Li, B.
Kauffmann, J. Xiang, I. Huc, H. Jiang, Chem. Commun. 2010,
46, 297–299; e) N. Delsuc, T. Kawanami, J. Lefeuvre, A.
Shundo, H. Ihara, M. Takafuji, I. Huc, ChemPhysChem 2008,
9, 1882–1890; f) Q. Gan, C. Bao, B. Kauffmann, A. Grélard,
J. Xiang, S. Liu, I. Huc, H. Jiang, Angew. Chem. Int. Ed. 2008,
47, 1715–1718; Angew. Chem. 2008, 120, 1739; g) P. S. Shirude,
E. R. Gilles, S. Ladame, F. Godde, K. Shin-ya, I. Huc, S. Balas-
ubramanian, J. Am. Chem. Soc. 2007, 129, 11890–11891; h)
E. R. Gillies, F. Deiss, C. Staedel, J.-M. Schmitter, I. Huc, An-
gew. Chem. Int. Ed. 2007, 46, 4081–4084; Angew. Chem. 2007,
119, 4159; i) E. R. Gillies, C. Dolain, J.-M. Léger, I. Huc, J.
Org. Chem. 2006, 71, 7931–7939; j) C. Dolain, A. Grélard, M.
Laguerre, H. Jiang, V. Maurizot, I. Huc, Chem. Eur. J. 2005,
11, 6135–6144; k) C. Dolain, H. Jiang, J.-M. Léger, P. Guion-
neau, I. Huc, J. Am. Chem. Soc. 2005, 127, 12943–12951; l) H.
Jiang, C. Dolain, J.-M. Léger, H. Gornitzka, I. Huc, J. Am.
Chem. Soc. 2004, 126, 1034–1035; m) H. Jiang, J.-M. Léger, I.
Huc, J. Am. Chem. Soc. 2003, 125, 3448–3449; n) H. Jiang, J.-
M. Léger, C. Dolain, P. Guionneau, I. Huc, Tetrahedron 2003,
59, 8365–8374.
aromatic backbone, while the tert-butyl side chain results in
a more closely packed structure that enables the tert-butyl
side chains to point outwards from the twist created by the
two surrounding backbone aromatic rings. We believe that
these findings represent an important advance for future
development and design of arylopeptoid-based foldamers,
and we will report our progress in due time.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods, experimental procedures and
characterization data, methods used for analytical and preparative
HPLC, HPLC profiles and NMR spectra of synthesized arylopep-
toid dimers, detailed X-ray crystallographic analysis of dimers m-2
and o-4.
[4]
Acknowledgments
We are grateful to Dr. Sophie Faure and Prof. Claude Taillefumier
[Institut de Chimie de Clermont-Ferrand (ICCF), Université Blaise
Pascal, Clermont-Ferrand, France] for inspirational and helpful
discussions. The technical assistance of Ms. L. Berring and Dr. K.
Ståhl (Department of Chemistry, Technical University of Den-
mark) with the collection of X-ray data and data reduction is grate-
fully acknowledged. We likewise thank the Carlsberg Foundation
(grant 2011_01_0432 to T. H.), as well as the Lundbeck Founda-
tion, the Aase and Ejnar Danielsens Foundation, and the Augus-
tinus Foundation for financial support.
[5]
[1] a) D.-W. Zhang, X. Zhao, J.-L. Hou, Z.-T. Li, Chem. Rev. 2012,
112, 5271–5316; b) K. Yamato, M. Kline, B. Gong, Chem.
Commun. 2012, 48, 12142–12158; c) G. Guichard, I. Huc,
Chem. Commun. 2011, 47, 5933–5941; d) I. Saraogi, A. D.
Hamilton, Chem. Soc. Rev. 2009, 38, 1726–1743; e) I. Huc, Eur.
J. Org. Chem. 2004, 17–19.
[2] a) K. Long, T. A. Edwards, A. J. Wilson, Bioorg. Med. Chem.
2013, 21, 4034–4040; b) F. Campbell, J. P. Plante, T. A. Ed-
wards, S. L. Warriner, A. J. Wilson, Org. Biomol. Chem. 2010,
8, 2344–2351; c) A. Tanatani, A. Yokoyama, I. Azumaya, Y.
Takakura, C. Mitsui, M. Shiro, M. Uchiyama, A. Muranaka,
N. Kobayashi, T. Yokozawa, J. Am. Chem. Soc. 2005, 127,
8553–8561.
[3] a) N. S. Murphy, P. Prabhakaran, V. Azzarito, J. P. Plante, M. J.
Hardie, C. A. Kilner, S. L. Warriner, A. J. Wilson, Chem. Eur.
J. 2013, 19, 5546–5550; b) O. V. Kulikov, S. Thompson, H. Xu,
C. D. Incarvito, R. T. W. Scott, I. Saraogi, L. Nevola, A. D.
Hamilton, Eur. J. Org. Chem. 2013, 3433–3445; c) P. Prabhaka-
ran, A. Barnard, N. S. Murphy, C. A. Kilner, T. A. Edwards,
A. J. Wilson, Eur. J. Org. Chem. 2013, 3504–3512; d) V. Azzar-
ito, P. Prabhakaran, A. I. Bartlett, N. S. Murphy, M. J. Hardie,
C. A. Kilner, T. A. Edwards, S. L. Warriner, A. J. Wilson, Org.
Biomol. Chem. 2012, 10, 6469–6472; e) O. V. Kulikov, A. D.
Hamilton, RSC Adv. 2012, 2, 2454–2461; f) I. Saraogi, J. A.
Hebda, J. Becerril, L. A. Estroff, A. D. Miranker, A. D. Hamil-
ton, Angew. Chem. Int. Ed. 2010, 49, 736–739; Angew. Chem.
2010, 122, 748; g) Y. Yan, B. Qin, C. Ren, X. Chen, Y. K. Yip,
R. Ye, D. Zhang, H. Su, H. Zeng, J. Am. Chem. Soc. 2010,
132, 5869–5879; h) H. Seyler, C. Storz, R. Abbel, A. F. M.
Kilbinger, Soft Matter 2009, 5, 2543–2545; i) J. P. Plante, T.
Burnley, B. Malkova, M. E. Webb, S. L. Warriner, T. A. Ed-
wards, A. J. Wilson, Chem. Commun. 2009, 5091–5093; j) Y.
Yan, B. Qin, Y. Shu, X. Chen, Y. K. Yip, D. Zhang, H. Su,
H. Zeng, Org. Lett. 2009, 11, 1201–1204; k) I. Saraogi, C. D.
Incarvito, A. D. Hamilton, Angew. Chem. Int. Ed. 2008, 47,
9691–9694; Angew. Chem. 2008, 120, 9837; l) J.-M. Ahn, S.-Y.
Han, Tetrahedron Lett. 2007, 48, 3543–3547; m) H.-P. Yi, J.
Wu, K.-L. Ding, X.-K. Jiang, Z.-T. Li, J. Org. Chem. 2007,
[6]
Y. Ferrand, A. M. Kendale, J. Garric, B. Kauffmann, I. Huc,
Angew. Chem. Int. Ed. 2010, 49, 1778–1781; Angew. Chem.
2010, 122, 1822.
M. Akazome, Y. Ishii, T. Nireki, K. Ogura, Tetrahedron Lett.
2008, 49, 4430–4433.
N. Raynal, M.-C. Averlant-Petit, G. Bergé, C. Didierjean, M.
Marraud, C. Duru, J. Martinez, M. Amblard, Tetrahedron
Lett. 2007, 48, 1787–1790.
a) R. N. Zuckermann, D. A. Goff, S. Ng, K. Spear, B. O. Scott,
A. C. Sigmund, R. A. Goldsmith, C. K. Marlowe, Y. Pei, L.
Richter, R. Simon, US005877278A, 1999; b) R. N. Zuckerm-
ann, D. A. Goff, S. Ng, K. Spear, B. O. Scott, A. C. Sigmund,
R. A. Goldsmith, C. K. Marlowe, Y. Pei, L. Richter, R. Simon,
WO9640202A1, 1996; c) R. N. Zuckermann, J. M. Kerr, S.
Kent, W. H. Moos, R. J. Simon, D. A. Goff, WO9406451A1,
1994; d) D. J. Combs, R. S. Lokey, Tetrahedron Lett. 2007, 48,
2679–2682.
[7]
[8]
[9]
3974
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3971–3975

Dimeric Arylopeptoids with Conformation-Directing Side Chains
[10] a) T. Hjelmgaard, J. Nielsen, Eur. J. Org. Chem. 2013, 3574–
3589; b) T. Hjelmgaard, S. Faure, E. De Santis, D. Staerk, B. D.
Alexander, A. A. Edwards, C. Taillefumier, J. Nielsen, Tetrahe-
dron 2012, 68, 4444–4454; c) T. Hjelmgaard, S. Faure, D. Sta-
erk, C. Taillefumier, J. Nielsen, Org. Biomol. Chem. 2011, 9,
6832–6843; d) T. Hjelmgaard, S. Faure, D. Staerk, C.
Taillefumier, J. Nielsen, Eur. J. Org. Chem. 2011, 4121–4132.
[11] K. Worm-Leonhard, T. Hjelmgaard, R. K. Petersen, K. Kristi-
ansen, J. Nielsen, Bioorg. Med. Chem. Lett. 2013, 23, 4162–
4165.
[12]
CCDC-957928 (for m-2) and -957925 (for o-4)] contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] S. Saito, Y. Toriumi, N. Tomioka, A. Itai, J. Org. Chem. 1995,
60, 4715–4720.
Received: February 8, 2014
Published Online: May 11, 2014
Eur. J. Org. Chem. 2014, 3971–3975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3975