Design and synthesis of oligoamide-based double α-helix mimetics

Article abstract of DOI:10.1002/ejoc.201300363

An extensive series of bis-oligobenzamides and bis-oligopyridylamides have been efficiently prepared and studied by X-ray analysis and computational methods. A modular synthesis led to double α-helix mimics bearing between two and ten branched side-chains. The inter-helix angle and distance can be tuned by varying the length and rigidity of the spacer, thereby reproducing the recognition domains of a range of super-secondary structures.

Full text of DOI:10.1002/ejoc.201300363

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FULL PAPER
Peptidomimetics
We report the modular synthesis of bis-
oligobenzamides and bis-oligopyridyl-
amides as double-helix peptidomimetics
with a variety of spacers in which the dis-
position of strands is tuneable to mimic a
range of super-secondary structures.
O. V. Kulikov, S. Thompson, H. Xu,
C. D. Incarvito, R. T. W. Scott, I. Saraogi,
L. Nevola, A. D. Hamilton* ............ 1–14
Design and Synthesis of Oligoamide-Based
Double α-Helix Mimetics
Keywords: Synthesis design / Amides / Pep-
tidomimetics / Hydrogen bonds / Helical
structures
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A. D. Hamilton et al.
FULL PAPER
DOI: 10.1002/ejoc.201300363
Design and Synthesis of Oligoamide-Based Double α-Helix Mimetics
Oleg V. Kulikov,[a] Sam Thompson,[b] Hai Xu,[a] Christopher D. Incarvito,[a]
Richard T. W. Scott,[b] Ishu Saraogi,[c] Laura Nevola,[d] and Andrew D. Hamilton*[a,b]
Keywords: Synthesis design / Amides / Peptidomimetics / Hydrogen bonds / Helical structures
An extensive series of bis-oligobenzamides and bis-oligopyr-
idylamides have been efficiently prepared and studied by X-
ray analysis and computational methods. A modular synthe-
sis led to double α-helix mimics bearing between two and
ten branched side-chains. The inter-helix angle and distance
can be tuned by varying the length and rigidity of the spacer,
thereby reproducing the recognition domains of a range of
super-secondary structures.
Introduction
α-Helices are the most common protein secondary struc-
tural element and are found at the interface of important
domains, often as bundles of two or more helices. Two α-
helices connected by a short loop region in a specific geo-
metric arrangement constitutes an α/α-hairpin motif, which
frequently occurs in globular and trans-membrane proteins.
Different amino acid residues in the linking loop and se-
quences in the helix domains lead to a range of inter-helix
angles between the two strands. Examples of sequentially
more complex multi-helix-containing proteins include
GCN4,[1] gp-41[2] and interleukin-2,[3] which illustrate a
range of helix–helix orientations (Figure 1). A number of
different helix-packing descriptions have been proposed, in-
cluding the knob-into-hole model of Crick[4] and the ridge-
into-groove model of Chothia et al.[5,6] Both emphasise the
importance of surface shape complementarity of the two
Figure 1. Multi-helical proteins showing the folding characteristics
of (i) GCN4, (ii) gp-41 N-terminus, (iii) IL-2 and (iv) generalised
α–α-helices. D represents the inter-helical distance and ω the pack-
ing angle.
Non-peptidic small-molecule α-helix mimetics[12–18] have
attracted considerable attention because of their potential
to disrupt protein–protein interactions (PPIs) and thus pro-
vide new methods of treatment for pathologies that include
cancer, infectious diseases, Alzheimer’s, type II diabetes and
HIV. Many structural motifs[19–36] have been explored in
which the substituents on the scaffold mimic the distance
and angular orientation of the amino acid side-chains of an
α-helix. However, at present there are no examples of syn-
thetic mimics of two-helix domains in proteins.
helices leading to different packing angles
ω (Fig-
ure 1iv).[7,8] A comprehensive analysis of proteins by Chab-
bert and co-workers[9] showed that the inter-helix angle be-
tween two linked α-helices varies from 0 to 160°. Extensive
studies have been undertaken in the area of membrane pro-
tein-folding to elucidate the general principles of linking
motifs and inter-helical orientation.[10,11]
In furthering our goal of identifying synthetic molecules
that disrupt PPIs, we aimed to develop a novel series in
which two helix mimetics are linked by various spacers to
control both their relative angular orientation and side-
chain positions. We[19,37–39] and others[21,23,27,30] have shown
that oligomeric 2-alkoxy-substituted arylamides can be
readily synthesized and can mimic key helical domains at
the interface of PPIs.
We report herein the synthesis and solid-state structures
of benz- and pyridylamide-based bis-oligomers in which
each strand contains various alkyl fragments with the po-
tential to mimic side-chain residues at the i, i+4, i+7, etc.
positions on one face of an α-helix. Given the crucial im-
[a] Department of Chemistry, Yale University,
New Haven, CT 06511, USA
[b] Department of Chemistry, Chemistry Research Laboratory,
University of Oxford,
Oxford OX1 3TA, UK
Fax: +44-186-527-0085
E-mail: andrew.hamilton@admin.ox.ac.uk
Homepage: http://hamilton.chem.ox.ac.uk
[c] Department of Chemistry, Caltech,
Pasadena, CA 91125, USA
[d] IRB Barcelona – Institute for Research in Biomedicine, Parc
Científic de Barcelona,
c/ Baldiri Reixac 10, 08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300363.
2
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Oligoamide-Based Double α-Helix Mimetics
portance of the inter-helix angle and distance for protein Table 1. Results of the synthesis of the benzamide oligomers.
surface binding, we selected a range of linking groups to
n
R
RЈ
Product
Yield [%]
connect the two oligoamide α-mimics. Xanthene, phen-
anthroline, dipicolinic and isophthalic derivatives offer two
handles for oligoamide attachment to a rigid spacer,
whereas suberic and poly(ethylene glycol) derivatives offer
increased conformational flexibility. In addition to their pri-
mary function as bridging units between two rods,
xanthene- and phenanthroline-based linkers have potential
as fluorescent probes for the study of protein surface bind-
ing.
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
4
4
Me
i-Pr
Me
Me
i-Pr
i-Bu
i-Hex
i-Pr
i-Bu
i-Hex
i-Pr
i-Bu
i-Hex
i-Pr
i-Bu
i-Pr
NH2
NH2
NO2
NH2
NO2
NO2
NO2
NH2
NH2
NH2
NO2
NO2
NO2
NH2
NH2
NO2
NO2
1
2[a]
3
99
92
90
97
61
60
77
89
86
86
74
77
86
85
62
80
51
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Results and Discussion
Elongated Oligobenzamide Strands
i-Bu
[a] i-Bu ester.
In designing double-helix mimetics we sought a simple
synthetic strategy that would allow the attachment of two
strands of different lengths to a doubly activated spacer.
Oligomeric 2-alkoxy-substituted pyridylamides and benz-
amides are versatile helix mimetic scaffolds that are readily
available in different lengths.[39,40] The oligoamides are syn-
thesized by a simple (n + 1) elongation approach by hydro-
genation of the nitro group and subsequent amide coupling
with 2-chloro-1-methylpyridinium iodide (Mukaiyama’s
reagent).[41] This method allows the preparation of dimers,
trimers, tetramers and pentamers bearing between two and
five branched side-chain substituents (Scheme 1 and
Table 1).
Scheme 1. Benzamide oligomer synthesis by an iterative n + 1
elongation approach.
Scheme 2. Alternative approaches to oligomer synthesis. (a) Incor-
poration of mixed side-chains and (b) an n + 2 elongation strategy
A wide range of different side-chains can potentially be
incorporated into different positions of the strand, for ex- to provide tetramer 12.
ample, the benzyl side-chain in tetramer 19. For later-stage
convergence, an alternative to the n + 1 elongation strategy
Synthesis of Double-Helix Oligoamides
The synthesis of double-helix mimics with a rigid linker
can be employed in which two dimers are coupled to pro-
vide tetramer 12 (Scheme 2).[42] Single-crystal X-ray struc-
tures of trimers 4 and 5 demonstrate a curved backbone was accomplished by the reactions of various aryl diacids
conformation that is in close agreement with an analogous [2,7-di-tert-butyl-9,9-dimethylxanthene-4,5-dicarboxylic
trimer (CCDC: LOKYUG). This implies the nature of the acid (A), 2-methoxyisophthalic acid (B), 1,10-phen-
alkyl substituent does not significantly affect the backbone anthroline-2,9-dicarboxylic acid (C) and 2,6-pyridinedi-
curvature and thus the scaffold is able to maintain the de- carboxylic acid (D)] with amino-terminated benzamide- or
sired angular and spatial projection of a wide variety of pyridylamide oligomers (or monomers) in the presence of
side-chain groups (Figure 2 and Figures S1–S3 in the Sup- Mukaiyama’s reagent or oxalyl chloride with catalytic
porting Information).
DMF. Dimers with a high degree of flexibility were as-
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A. D. Hamilton et al.
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Figure 2. Molecular structures of trimers: (a) LOKYUG, (b) 4 and (c) 5.
Scheme 3. Synthesis of bis-benzamides and bis-pyridylamides with a range of linkers. X = CH except in starting materials 29 and 30 and
products 63 and 64 in which X = N. RЈ = Me for all compounds except 42 for which R = i-Bu.
sembled in an analogous fashion from suberic acid (E) or Conformational Analysis
a poly(ethylene glycol) diacid (F), yields ranged between
moderate and excellent with a yield of 86% for bis-mono-
Single-crystal X-ray analysis was performed on represen-
mer 35 (Scheme 3 and Table 2).
tative mimics with xanthene (35, 37, 41), isophthalic (51,
This strategy was amenable to the synthesis of mimics 52), phenanthroline (56, 57), dipicolinic acid (60, 61) and
bearing a variety of branched alkyl side-chains with strands diaminopyridine (65) linkers (Figure 3). It was not possible
between one and five aryl units in length. The bis-penta- to obtain suitable crystals of bis-oligomers with flexible lin-
mers 49 and 50 have the potential to reproduce the spatial kers E and F, presumably due to their high degree of confor-
and angular projection of 10 amino acid side-chains. Com- mational lability. The diffraction data for bis-monomer 37
pounds 63 and 64 have potential for further functionaliza- and bis-dimers 41 and 56 showed some side-chain disorder,
tion and increased aqueous solubility after removal of tert- however, the data were of sufficient quality to confirm mo-
butyl protecting groups.
lecular identity and connectivity. Although we were unable
In an alternative synthetic strategy, bis-pyridylamide 65 to obtain diffraction-quality crystals of higher-order bis-
was prepared by the coupling of two mono-acids with 2,6- oligomers, semi-empirical quantum calculations were per-
diaminopyridine (Scheme 4 and Figures S13–15 in the Sup- formed to find conformational energy minima for bis-tri-
porting Information).
mer 58, bis-tetramer 47 and bis-pentamer 49 (Figure 4 and
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Oligoamide-Based Double α-Helix Mimetics
Table 2. Results of the synthesis of bis-benzamides and bis-pyr- compounds with similar structures (see Figures S16–
S31).[43] For bis-monomers in which naphthyl or xanthene
idylamides.
units serve as the linker (44.1°, XUJRAW; 55.9°, QAWJOO,
Figures S32 and S33), the values approach those of bis-
monomers 35 and 37. Generally, the trend for bis-monomer
solid-state structures is reproduced in the bis-oligomers,
that is, the angle of inclination correlates with the linker
type in a predictable fashion. Relatively small values are
seen for oligomers derived from xanthene (47, 28.3°; 49,
24.8°; 41, 22.2°; Figure S34) and phenanthroline (56, 48.2°;
58, 43.7°; 57, 26.0°; Figures 3 and 4 as well as Figures S36
and S42), in contrast to pyridine-based analogues (61,
86.0°; 65, 111.0°; Figure S38). Figure S43 shows the super-
imposition of phenanthroline-based 57 with a two-stranded
parallel coiled-coil.[39] Although these values are taken from
the solid-state data of molecules with relatively short oligo-
mer strands and a number of computational energy minimi-
zations, we believe the angles are likely to be similar in ex-
tended systems given the well-characterized conformational
nature of the component single-strand mimetics.[40] Most of
these structures adopt a non-planar conformation except
compound 52, which has an almost planar arrangement.
We assume that out-of-plane deviations result from both
side-chain repulsive interactions and crystal-packing forces
(see Figures S34, S36, S38 and S42). Interestingly, bis-dimer
57 has a helical-like arrangement stabilized by a network of
intramolecular hydrogen bonds (NH···O 2.14 Å;
N···NH···O 2.07, 2.22 Å).
Oligoamide Linker
n
R
Yield [%] Product
22
23
24
1
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
C
C
C
C
C
D
D
E
F
0
0
0
1
1
1
1
1
2
2
2
2
3
3
4
4
0
0
1
1
0
1
1
2
3
0
1
1
0
2
i-Pr
i-Bu
Me
Me
i-Pr
i-Bu
i-Hex
i-Bu
Me
i-Pr
i-Bu
i-Hex
i-Pr
i-Bu
i-Pr
i-Bu
i-Bu
Me
Me
i-Bu
Me
Me
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
86
60
65
30
58
63
63
46
20
52
45
52
65
58
44
54
52
70
40
40
65
30
32
32
23
79
74
65
71
30
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
25
20
26
2
4
8
9
10
14
15
27[a]
28[a]
23
24
1
20
24
1
20
9
15
23
20
20
29
30
i-Bu
CH2CO2t-Bu
CH2CO2t-Bu
F
In the crystal lattice, these molecules form a supramolec-
ular spiral-shaped arrangement as a result of non-covalent
side-chain···side-chain and π–π stacking interactions (see
Figures S44–S48). Structural analogues of compound 61
previously reported by us[44–46] were designed specifically to
form a helix and as such have an ortho oligoamide arrange-
ment, unlike bis-dimers reported herein in which CONH
bonds connecting aryl rings are in para positions. Under-
standing the peculiarities of crystal lattice packing gives
valuable insight into the design, structure and potential
function of bis-α-helix mimetics as effective inhibitors of
PPIs.
[a] Carried forward without purification.
Scheme 4. Synthesis of bis-pyridylamides with a diaminopyridine
linker.
Figures S49–S51 in the Supporting Information). We define
the inter-helix angle as the convergence on the linking
group of two lines bisecting the centroids of the oligomer
strands. Values for these compounds are in the range of
Conclusions
A series of bis-oligoamides have been synthesized and
22.2° for xanthene-derived 41 and 111.0° for diaminopyr- characterized in the solid state by X-ray crystallography.
idine derivative 65, and thus have the potential to reproduce These molecules adopt non-planar conformations with in-
the broad range displayed in protein secondary structures ter-helix angles ranging from 22.2 to 111.0° depending on
(Table 3).
the nature of the linking group. The results of calculations
The angles of inclination for bis-oligomers incorporating suggest there is a similar trend for higher bis-oligoamides
a xanthene-bridging unit are considerably smaller (37.2°, of the phenanthroline and xanthene series. Given that bun-
35; 33.6°, 37) than those for analogues with a pyridyl- dles of α-helices play important roles in the structure and
(111.0°, 65; 86.0°, 61; 84.9°, 60) or isophthalic-derived function of proteins, and that a large range of inter-helix
linker (98.9°, 52; 96.1°, 51; see Figures S6, S7, S9 and S13 angles are observed, we hope this new class of peptidomi-
in the Supporting Information). These findings are in ac- metic will provide a starting point for the mimicry of
cordance with the data for a number of previously reported higher-order protein architectures.
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Figure 3. Single-crystal X-ray data showing control of the inter-helix angle with various linkers. Hydrogen atoms have been omitted for
clarity and disordered side-chains are shown as yellow spheres. See also the Supporting Information.
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Oligoamide-Based Double α-Helix Mimetics
Figure 3. (Continued)
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Figure 4. AM-1 energy minimization of elongated bis-benzamide: phenanthroline-linked bis-trimer 58, and xanthene-linked bis-tetramer
47 and bis-pentamer 49. Hydrogen atoms have been omitted for clarity. See also the Supporting Information.
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Oligoamide-Based Double α-Helix Mimetics
Molecular Modelling: Semi-empirical calculations were carried out
Table 3. Control of oligoamide inter-helix angle with various link-
ing groups.
by using the AM1 force field as integrated in Gaussian 03W.[50]
Double helix
Linker
R
Angle [°][a]
General Procedure for Amide Coupling in the Presence of Mukaiya-
ma’s Reagent. Compounds 35, 51 and 60: The dicarboxylic acid (2-
methoxyisophthalic acid, 2,6-pyridinedicarboxylic acid or
41
49
57
47
37
35
58
56
60
61
51
52
65
xanthene
xanthene
phenanthroline
xanthene
xanthene
i-Hex
i-Pr
i-Bu
i-Pr
Me
i-Pr
i-Bu
Me
i-Bu
i-Bu
i-Bu
Me
22.2
24.8
26.0
28.3
33.6
37.2
43.7
48.2
84.9
86.0
96.1
98.9
111.0
2,7-di-tert-butyl-9,9-dimethylxanthene-4,5-dicarboxylic
acid;
6.0 mmol), Mukaiyama’s reagent (2-chloro-1-methylpyridinium
iodide; 12.0 mmol) and Et3N (26 mmol) were dissolved in anhy-
drous dichloromethane (100 mL). The solution was heated at reflux
for 15 min under N2. Then a solution of the corresponding aryl-
amine (22 and 23; 15 mmol) in anhydrous dichloromethane
(50 mL) was added to the reaction mixture and resulting solution
was heated at reflux for 2 d. The solvent was concentrated in vacuo
and the residue subjected to silica gel column chromatography
(EtOAc/DCM, 1:9). In most cases, for the purification of the bis-
monomers, sonication of the crude material with a small volume
of MeCN and subsequent filtration through the glass filter could
be used instead of column chromatography.
xanthene
phenanthroline
phenanthroline
dipicolinic
dipicolinic
isophthalic
isophthalic
diaminopyridine
n/a
[a] Angles are taken from single-crystal X-ray data except for 47,
49 and 58, which were calculated.
Following the procedure described above with minor modifications
(oxalyl chloride was used for the amide coupling instead of Mukai-
yama’s reagent), compounds 37, 52, 55, 63 and 65 were obtained.
Standard purification workup included silica gel chromatography
(hexanes/EtOAc, 5:1).
Experimental Section
General Methods: All starting materials were obtained from Sigma–
Aldrich, Fluka or TCI America and used without further purifica-
tion unless otherwise noted. TLC was performed on Sigma–Ald-
rich TLC Plates (silica gel on aluminium, 200 mm layer thickness,
2–25 mm particle size, 60 Å pore size). The general protocols for
the synthesis of monomeric, dimeric and trimeric arylamides have
been reported earlier.[37,39,47] Column chromatography was per-
Compounds 1, 2, 4, 8–10, 20, 21, 25, 26 and 62 were obtained
according to the general protocol for the reduction of the nitro
functionality into the corresponding amine with minor modifica-
tions.
1
formed on silica gel (230–400 mesh) from Solvent technologies. H
NMR spectra were recorded either at 400 MHz with a Bruker
Avance DPX-400 spectrometer or at 500 MHz with a DPX-500
spectrometer at room temperature. 13C NMR spectra were re-
corded with the same instruments at either 100 or 125 MHz,
respectively. 1H and 13C chemical shifts are reported in parts per
million relative to the corresponding residual solvent peak. High-
resolution Fourier-transform mass spectra (FT-ICR MS) were ob-
tained from the W. M. Keck Biotechnology Resource Laboratory
at Yale University.
Compounds 2, 3, 5–7, 11–13, 19, 34, 43–46, 53, 54, 56–58, 61, 62
and 64 were prepared by following the above general protocol for
amide coupling (either with Mukaiyama’s reagent or oxalyl chlor-
ide).
1
Compound 1: Yield 99%. H NMR (500 Hz, CDCl3): δ = 3.82 (s,
3 H, Me), 3.83 (s, 3 H, Me), 3.89 (s, 3 H, COOMe), 4.19 (s, 2 H,
NH2), 6.61–8.53 (m, 6 H, ArH), 8.55 (s, 1 H, NHCO) ppm. 13C
NMR (125 MHz, CDCl3): δ = 52.0, 55.6, 56.1, 109.9, 110.5, 113.0,
118.3, 120.0, 123.5, 123.9, 124.4, 132.6, 140.5, 146.8, 147.4, 165.3,
166.8 ppm. MS (FT-ICR, MeCN): calcd. for C17H19N2O5
[M + H]+ 331.1288; found 331.1282.
Compound Numbering: For those compounds for which structures
are not shown in the manuscript, see Figure S52 in the Supporting
Information.
1
Compound 2: Yield 92%. H NMR (500 Hz, CDCl3): δ = 0.95 (d,
Single-Crystal X-ray Diffraction Studies: X-ray crystal structures of
4, 5, 28, 35, 41, 51, 52, 56, 57, 60, 61, 65 were obtained with a
Rigaku R-AXIS RAPID imaging plate diffractometer with
multilayer mirror monochromated Cu-Kα radiation, a Rigaku
SCXmini diffractometer (Mo-Kα radiation), a Rigaku Saturn 724
CCD diffractometer (Cu-Kα radiation), a Nonius–KappaCCD dif-
fractometer (Mo-Kα radiation) and an Oxford Diffraction Super-
Nova diffractometer (Mo-Kα radiation). Structures were solved by
direct methods using Fourier techniques. Non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were refined by using
the riding model. All calculations were performed by using the
CrystalStructure crystallographic software package[48] except for re-
finement, which was performed by using SHELXL-97.[49] The crys-
tal structure of 51 has been reported previously.[39] Molecules of
the bis-oligomers 28, 41 and 56 are severely disordered, however,
their molecular identity and connectivity could be confirmed.
J = 6.8 Hz, 6 H, Mei-Bu), 0.98 (d, J = 6.4 Hz, 6 H, Mei-Bu), 1.03
(d, J = 6.7 Hz, 6 H, Mei-Bu), 1.99–2.17 (m, 3 H, OCH2CHMe2),
3.77 (d, J = 6.3 Hz, 2 H, OCH2CHMe2), 3.85 (d, J = 6.3 Hz, 2 H,
OCH2CHMe2), 4.02 (d, J = 7.0 Hz, 2 H, OCH2CHMe2), 4.16 (s, 2
H, NH2), 6.65–8.57 (m, 6 H, ArH), 8.67 (s, 1 H, NHCO) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 19.2, 19.3, 19.4, 27.9, 28.3, 70.9,
74.7, 75.0, 110.3, 111.4, 113.3, 118.1, 120.0, 123.3, 124.1, 124.8,
132.6, 140.5, 146.2, 146.8, 165.0, 166.5 ppm. MS (FT-ICR,
MeCN): calcd. For C26H37N2O5 [M + H]+ 457.2697; found
457.2693. MS (MALDI-TOF): m/z = 456.1 [M]+.
1
Compound 3: Yield 90%. H NMR (400 Hz, CDCl3): δ = 3.86 (s,
3 H, COOMe), 3.96 (s, 3 H, Me), 3.98 (s, 3 H, Me), 4.00 (s, 3 H,
Me), 7.35–8.57 (m, 9 H, ArH), 8.63 (s, 1 H, NHCO), 8.69 (s, 1 H,
NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.2, 56.2, 56.3,
56.9, 110.0, 110.7, 113.6, 117.6, 119.1, 123.6, 125.2, 126.0, 130.6,
130.7, 132.0, 139.9, 142.3, 147.6, 148.4, 153.3, 163.8, 164.6,
166.1 ppm. MS (FT-ICR, MeCN): calcd. for C25H24N3O9
[M + H]+ 510.1507; found 510.1482.
CCDC-849194 (for 52), -849195 (for 35), -849196 (for 60),
-849197 (for 65), -849441 (for 4), -849442 (for 5), -849443 (for 61)
and -849444 (for 57) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
Compound 4: Yield 97%. H NMR (500 Hz, CDCl3): δ = 3.91 (s,
3 H, COOMe), 3.93 (s, 3 H, Me), 4.01 (s, 6 H, Me), 4.37 (s, 2 H,
NH2), 6.70–8.64 (m, 9 H, ArH), 8.65 (s, 1 H, NHCO), 8.74 (s, 1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30363
/KAP1
Date: 22-05-13 19:14:52
Pages: 14
A. D. Hamilton et al.
FULL PAPER
H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 52.1, 55.7,
56.2, 60.4, 109.7, 110.0, 110.7, 113.1, 118.6, 119.3, 120.1, 123.5,
125.0, 129.1, 131.9, 132.2, 140.6, 146.9, 147.6, 148.2, 164.8, 165.3,
166.8 ppm. MS (FT-ICR, MeCN): calcd. for C25H26N3O7
[M + H]+ 480.1765; found 480.1766.
3 H, COOMe), 3.94–4.00 (m, 8 H, OCH2CHMe2), 7.40–8.70 (m,
12 H, ArH), 8.77 (s, 1 H, NHCO), 8.84 (s, 1 H, NHCO), 8.85 (s,
1 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.0, 19.4,
28.2, 28.3, 28.4, 52.1, 75.1, 75.2, 76.1, 110.3, 110.4, 111.5, 113.8,
117.3, 118.3, 118.7, 119.0, 119.1, 123.4, 125.0, 126.0, 129.8, 130.4,
130.8, 131.4, 132.3, 139.6, 141.8, 147.0, 147.7, 147.8, 152.9, 163.1,
164.3, 164.4, 166.8 ppm. MS (MALDI-TOF): m/z = 826.7 [M]+.
Compound 13: Yield 86%. 1H NMR (500 Hz, CDCl3): δ = 0.87–
0.95 (m, 24 H, Me), 1.40–1.53 (m, 16 H, CHCH2Me), 1.67–1.77
(m, 4 H, OCH2CHEt2), 3.85 (s, 3 H, COOMe), 4.01–4.07 (m, 8 H,
OCH2CHEt2), 7.30–8.63 (m, 12 H, ArH), 8.72 (s, 1 H, NHCO),
8.79 (s, 2 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 11.1,
11.2, 11.3, 23.2, 23.8, 40.8, 40.9, 41.0, 52.1, 70.7, 70.8, 70.9, 71.8,
110.3, 110.4, 111.4, 113.8, 117.1, 118.3, 118.5, 118.8, 118.9, 123.4,
125.0, 125.8, 129.8, 130.4, 130.9, 131.5, 132.3, 139.6, 141.7, 147.1,
147.8, 147.9, 153.0, 163.2, 164.4, 164.5, 166.8 ppm. MS (FT-ICR,
MeCN): calcd. for C53H71N4O11 [M + H]+ 939.5114; found
939.5141. MS (MALDI-TOF): m/z = 938.6 [M]+.
Compounds 11, 14, 17 and those for which experimental data is
not provided were synthesised according to previously described
methods.[39,40]
Compound 6 (Methyl Ester): Yield 60%. 1H NMR (400 Hz,
CDCl3): δ = 1.07–1.14 (m, 18 H, Mei-Bu), 2.16–2.28 (m, 3 H,
OCH2CHMe2), 3.91 (s, 3 H, COOMe), 3.94–3.99 (m, 6 H,
OCH2CHMe2), 7.40–8.66 (m, 9 H, ArH), 8.78 (s, 1 H, NHCO),
8.84 (s, 1 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.0,
19.4, 28.2, 28.3, 28.4, 52.1, 75.1, 75.2, 76.1, 110.4, 111.5, 113.7,
117.4, 118.4, 118.9, 119.0, 123.4, 125.1, 126.0, 130.5, 130.8, 132.1,
139.6, 141.7, 147.0, 147.8, 152.8, 163.1, 164.2, 166.7 ppm. MS (FT-
ICR, MeCN): calcd. for C34H40N3O9 [M – H]+ 634.2770; found
634.2767. MS (MALDI-TOF): m/z = 634.7 [M – H]+.
1
Compound 6 (Isobutyl Ester): Yield 5%. 1H NMR (400 Hz,
CDCl3): δ = 1.03–1.14 (m, 24 H, Mei-Bu), 2.06–2.28 (m, 4 H,
OCH2CHMe2), 3.95–3.99 (m, 6 H, OCH2CHMe2), 4.11 (d, J =
5.7 Hz, 2 H, COOCH2CHMe2), 7.41–8.68 (m, 9 H, ArH), 8.79 (s,
1 H, NHCO), 8.87 (s, 1 H, NHCO) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.0, 19.3, 19.4, 28.0, 28.2, 71.1, 75.1, 75.2, 76.1, 110.5,
111.6, 113.8, 117.3, 118.4, 119.0, 123.3, 125.5, 126.0, 130.8, 132.1,
139.7, 141.7, 147.0, 147.8, 152.9, 163.2, 164.4, 166.4 ppm. MS
(MALDI-TOF): m/z = 678.2 [M + H]+.
Compound 7: Yield 77%. 1H NMR (500 Hz, CDCl3): δ = 0.86–0.94
(m, 18 H, Me), 1.42–1.50 (m, 12 H, CHCH2Me), 1.66–1.74 (m,
3 H, OCH2CHEt2), 3.86 (s, 3 H, COOMe), 4.01–4.06 (m, 6 H,
OCH2CHEt2), 7.30–8.60 (m, 9 H, ArH), 8.71 (s, 1 H, NHCO), 8.78
(s, 1 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.1, 10.2,
10.3, 22.2, 22.8, 39.8, 40.0, 40.1, 51.1, 69.7, 69.9, 70.9, 109.5, 110.4,
112.8, 116.1, 117.4, 117.8, 122.4, 124.1, 124.9, 129.6, 129.8, 131.2,
138.6, 140.8, 146.1, 146.9, 152.0, 162.2, 163.3, 165.8 ppm. MS (FT-
ICR, MeCN): calcd. for = C40H54N3O9 [M + H]+ 720.3855; found
720.3856. MS (MALDI-TOF): m/z = 719.1 [M]+.
Compound 15: Yield 62%. H NMR (400 Hz, CDCl3): δ = 1.06 (d,
J = 7.6 Hz, 6 H, Mei-Bu), 1.13 (d, J = 6.9 Hz, 18 H, Mei-Bu), 2.12–
2.30 (m,
4 H, OCH2CHMe2), 3.86 (d, J = 6.7 Hz, 2 H,
OCH2CHMe2), 3.92 (s, 3 H, COOMe), 3.94–3.99 (m, 6 H,
OCH2CHMe2), 4.25 (s, 2 H, NH2), 6.74–8.73 (m, 12 H, ArH), 8.74
(s, 1 H, NHCO), 8.86 (s, 2 H, NHCO) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.4, 28.3, 28.4, 52.1, 74.7, 75.0, 75.1, 110.1, 110.2,
111.4, 113.4, 118.3, 118.4, 118.5, 119.1, 120.1, 123.4, 123.8, 124.9,
128.9, 129.4, 131.6, 132.1, 132.3, 140.7, 146.2, 147.0, 147.5, 147.6,
164.4, 164.5, 165.1, 166.8 ppm. MS (FT-ICR, MeCN): calcd. for
C45H57N4O9 [M + H]+ 797.4120; found 797.4119. MS (MALDI-
TOF): m/z = 796.1 [M]+.
Compound 17: Yield 51%. 1H NMR (400 Hz, CDCl3): δ = 1.07–
1.16 (m, 30 H, Mei-Bu), 2.15–2.29 (m, 5 H, OCH2CHMe2), 3.91 (s,
3 H, COOMe), 3.94–4.01 (m, 10 H, OCH2CHMe2), 7.40–8.72 (m,
15 H, ArH), 8.78 (s, 1 H, NHCO), 8.85 (s, 3 H, NHCO) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.0, 19.4, 28.2, 28.3, 28.4, 52.1,
75.1, 75.2, 110.3, 110.4, 111.5, 113.8, 117.3, 118.3, 118.6, 118.7,
119.0, 119.1, 123.4, 125.0, 126.0, 129.7, 130.4, 130.8, 131.5, 131.6,
132.3, 139.6, 141.8, 147.0, 147.7, 147.8, 152.9, 163.2, 164.3, 164.5,
166.8 ppm. MS (FT-ICR, MeCN): calcd. for C56H68N5O13 [M +
H]+ 1018.4804; found 1018.4796. MS (MALDI-TOF): m/z =
1017.2 [M]+.
Compound 19: Yield 60%. 1H NMR (500 Hz, [D6]DMSO): δ = 0.96
(d, J = 6.2 Hz, 6 H, Mei-Bu), 0.99 (d, J = 6.5 Hz, 12 H, Mei-Bu),
2.03–2.15 (m, 3 H, OCH2CHMe2), 3.82 (s, 3 H, COOMe), 3.88–
3.91 (m, 6 H, OCH2CHMe2), 5.37 (s, 2 H, OCH2Ph), 7.40–8.12
(m, 17 H, ArH), 9.41 (s, 1 H, NHCO), 9.48 (s, 1 H, NHCO), 9.83
(s, 1 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.4, 27.3,
51.1, 70.3, 74.1, 109.2, 109.4, 110.5, 113.7, 116.7, 117.3, 117.6,
118.0, 122.4, 124.0, 125.0, 126.1, 127.5, 127.8, 128.8, 129.5, 129.8,
130.4, 131.2, 133.9, 138.6, 141.1, 146.0, 146.7, 146.8, 151.2, 161.9,
163.3, 163.4, 165.7 ppm. MS (FT-ICR, MeCN): calcd. for
C48H53N4O11 [M + H]+ 861.3705; found 861.3708. MS (MALDI-
TOF): m/z = 861.2 [M + H]+.
1
Compound 9: Yield 86%. H NMR (400 Hz, CDCl3): δ = 1.06 (d,
J = 6.8 Hz, 6 H, Mei-Bu), 1.11–1.13 (m, 12 H, Mei-Bu), 2.10–2.28
(m, 3 H, OCH2CHMe2), 3.85 (d, J = 6.4 Hz, 2 H, OCH2CHMe2),
3.92 (s, 3 H, COOMe), 3.93–3.97 (m, 4 H, OCH2CHMe2), 4.24 (s,
2 H, NH2), 6.73–8.71 (m, 9 H, ArH), 8.74 (s, 1 H, NHCO), 8.87
(s, 1 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3, 19.4,
28.3, 28.4, 52.1, 74.8, 75.1, 110.2, 110.3, 111.5, 113.4, 118.3, 118.4,
119.1, 120.1, 123.4, 124.0, 124.9, 129.1, 132.1, 132.4, 140.6, 146.2,
147.0, 147.6, 164.6, 165.2, 166.8 ppm. MS (FT-ICR, MeCN): calcd.
for C34H42N3O7 [M – H]+ 604.3028; found 604.3035. MS (MALDI-
TOF): m/z = 605.2 [M]+.
Compound 10: Yield 86%. 1H NMR (500 Hz, CDCl3): δ = 0.88–
0.94 (m, 18 H, Me), 1.42–1.52 (m, 12 H, CHCH2Me), 1.66–1.75
(m, 3 H, OCH2CHEt2), 3.85 (s, 3 H, COOMe), 3.92 (d, J = 6.0 Hz,
2 H, OCH2CHEt2), 4.00 (d, J = 5.3 Hz, 2 H, OCH2CHEt2), 4.03
(d, J = 5.6 Hz, 2 H, OCH2CHEt2), 4.15 (s, 2 H, NH2), 6.66–8.64
(m, 9 H, ArH), 8.66 (s, 1 H, NHCO), 8.79 (s, 1 H, NHCO) ppm.
13C NMR (125 MHz, CDCl3): δ = 10.2, 10.3, 22.5, 22.8, 40.0, 40.1,
51.1, 69.4, 69.6, 69.7, 109.2, 109.3, 110.4, 112.2, 117.3, 117.9, 118.9,
122.4, 123.0, 123.9, 128.1, 131.1, 131.4, 139.6, 145.4, 146.1, 146.7,
163.6, 164.2, 165.8 ppm. MS (FT-ICR, MeCN): calcd. for
C40H56N3O7 [M + H]+ 690.4113; found 690.4103. MS (MALDI-
TOF): m/z = 689.1 [M]+.
1
Compound 35: Yield 86%. H NMR (400 Hz, CDCl3): δ = 1.24 (d,
J = 6.0 Hz, 12 H, Mei-Pr), 1.41 (s, 18 H, t-Bu), 1.77 (s, 6 H, Mex-
anth), 3.93 (s, 6 H, COOMe), 4.58–4.64 (m, 2 H, OCHMe2), 7.22–
8.14 (m, 10 H, ArH), 9.14 (s, 2 H, NHCO) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.8, 31.4, 34.7, 35.1, 51.9, 71.1, 112.6,
118.8, 122.5, 123.3, 124.7, 125.6, 126.7, 131.0, 132.3, 145.6, 147.0,
163.5, 166.7 ppm. MS (FT-ICR, MeCN): calcd. for C47H57N2O9
Compound 12: Yield 77%. 1H NMR (400 Hz, CDCl3): δ = 1.08– [M + H]+ 793.4059; found 793.4028. MS (MALDI-TOF): m/z =
1.15 (m, 24 H, Mei-Bu), 2.15–2.29 (m, 4 H, OCH2CHMe2), 3.91 (s, 791.7 [M – H]+.
10
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Job/Unit: O30363
/KAP1
Date: 22-05-13 19:14:52
Pages: 14
Oligoamide-Based Double α-Helix Mimetics
1
Compound 36: Yield 60%. H NMR (400 Hz, CDCl3): δ = 0.71 (d,
Compound 42: Yield 46%. 1H NMR (500 Hz, CDCl3): δ = 0.72 (d,
J = 7.2 Hz, 12 H, Mei-Bu), 0.97 (d, J = 6.7 Hz, 12 H, Mei-Bu), 1.02
(d, J = 7.2 Hz, 12 H, Mei-Bu), 1.33 (s, 18 H, t-Bu), 1.66 (s, 6 H,
Mexanth), 1.79–1.87 (m, 2 H, OCH2CHMe2), 2.00–2.15 (m, 4 H,
J = 6.6 Hz, 12 H, Mei-Bu), 1.31 (s, 18 H, t-Bu), 1.65 (s, 6 H, Mex-
anth), 1.75–1.85 (m, 2 H, OCH2CHMe2), 3.66 (d, J = 6.7 Hz, 4 H,
OCH2CHMe2), 3.83 (s, 6 H, COOMe), 7.13–8.03 (m, 10 H, ArH),
9.09 (s, 2 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.0, OCH2CHMe2), 3.59 (d, J = 6.4 Hz, 4 H, OCH2CHMe2), 3.73 (d,
27.9, 31.4, 31.6, 34.8, 35.1, 52.0, 74.8, 111.1, 118.3, 122.8, 123.4,
J = 7.1 Hz, 4 H, OCH2CHMe2), 4.01 (d, J = 6.4 Hz, 4 H,
124.6, 125.7, 126.7, 130.8, 131.7, 145.3, 146.8, 147.0, 163.5, OCH2CHMe2), 6.83–8.39 (m, 16 H, ArH), 8.62 (s, 2 H, NHCO),
166.7 ppm. MS (FT-ICR, MeCN): calcd. for C49H61N2O9
[M + H]+ 821.4372; found 821.4362. MS (MALDI-TOF): m/z =
820.5 [M]+.
9.14 (s, 2 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.0,
18.3, 26.8, 26.9, 27.2, 30.3, 30.6, 33.8, 34.1, 69.8, 73.7, 73.9, 109.2,
109.9, 117.0, 117.3, 121.6, 122.3, 124.1, 124.7, 125.8, 127.8, 129.8,
130.1, 130.8, 144.2, 145.8, 146.1, 146.5, 162.5, 162.8, 165.0 ppm.
1
Compound 37: Yield 65%. H NMR (500 Hz, CDCl3): δ = 1.31 (s,
MS (FT-ICR, MeCN): calcd. for C77H99N4O13 [M
+
H]+
18 H, t-Bu), 1.69 (s, 6 H, Mexanth), 3.71 (s, 6 H, Me), 3.80 (s, 6 H,
COOMe), 7.08–8.28 (m, 10 H, ArH), 9.04 (s, 2 H, NHCO) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.6, 31.7, 33.2, 35.1, 52.3, 56.5,
110.6, 118.3, 123.2, 127.6, 130.6, 132.0, 145.0, 147.4, 164.5,
166.9 ppm. MS (FT-ICR, MeCN): calcd. for C43H49N2O9
[M + H]+ 737.3433; found 737.3408.
1287.7203; found 1287.7222. MS (MALDI-TOF): m/z = 1287.8
[M + H]+.
1
Compound 43: Yield 20%. H NMR (400 Hz, CDCl3): δ = 1.40 (s,
18 H, t-Bu), 1.79 (s, 6 H, Mexanth), 3.88 (s, 6 H, COOMe), 3.91 (s,
6 H, Me), 3.97 (s, 6 H, Me), 4.03 (s, 6 H, Me), 7.08–8.53 (m, 22
H, ArH), 8.55 (s, 2 H, NHCO), 8.60 (s, 2 H, NHCO), 9.13 (s, 2 H,
NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.4, 33.0, 34.6,
34.7, 52.0, 56.2, 56.3, 109.1, 109.5, 110.3, 118.0, 118.3, 123.1, 124.6,
126.7, 127.3, 128.8, 131.2, 144.5, 147.1, 147.2, 147.7, 148.0, 164.0,
164.4, 166.6 ppm. MS (FT-ICR, MeCN): calcd. for C75H77N6O17
[M + H]+ 1333.2706; found 1333.2702.
1
Compound 38: Yield 30%. H NMR (400 Hz, CDCl3): δ = 1.40 (s,
18 H, t-Bu), 1.79 (s, 6 H, Mexanth), 3.83 (s, 6 H, Me), 3.88 (s, 6 H,
Me), 3.91 (s, 6 H, COOMe), 6.97–8.54 (m, 16 H, ArH), 9.18 (s, 2
H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 30.3, 31.9,
33.7, 51.0, 54.9, 55.3, 108.6, 109.0, 116.8, 116.9, 121.7, 122.1, 123.6,
125.6, 126.3, 130.7, 143.5, 146.1, 146.8, 162.9, 163.1, 165.5 ppm.
+
H]+
Compound 44: Yield 52%. 1H NMR (500 Hz, CDCl3): δ = 1.20 (d,
J = 5.5 Hz, 12 H, Mei-Pr), 1.33 (s, 18 H, t-Bu), 1.38 (d, J = 5.9 Hz,
12 H, Mei-Pr), 1.41 (d, J = 5.5 Hz, 12 H, Mei-Pr), 1.68 (s, 6 H,
Mexanth), 3.83 (s, 6 H, COOMe), 4.57–4.65 (m, 6 H, OCHMe2),
6.88–8.34 (m, 22 H, ArH), 8.60 (s, 2 H, NHCO), 8.61 (s, 2 H,
NHCO), 9.05 (s, 2 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3):
δ = 20.9, 21.2, 30.4, 33.8, 34.1, 50.9, 70.3, 70.6, 110.1, 110.7, 111.7,
117.0, 117.3, 117.4, 117.7, 118.1, 122.0, 122.3, 123.5, 124.7, 125.7,
128.0, 128.1, 130.0, 130.7, 130.9, 131.8, 144.5, 144.6, 145.2, 145.4,
146.1, 162.7, 162.8, 162.9, 165.7 ppm. MS (FT-ICR, MeCN): calcd.
for C87H101N6O17 [M + H]+ 1501.7218; found 1501.7252. MS
(MALDI-TOF): m/z = 1500.2 [M]+.
MS (FT-ICR, MeCN): calcd. for C59H63N4O13 [M
1035.4386; found 1035.4410.
1
Compound 39: Yield 58%. H NMR (400 Hz, CDCl3): δ = 1.18 (d,
J = 5.5 Hz, 12 H, Mei-Pr), 1.32 (s, 18 H, t-Bu), 1.35 (d, J = 6.0 Hz,
12 H, Mei-Pr), 1.68 (s, 6 H, Mexanth), 3.82 (s, 6 H, COOMe), 4.47–
4.53 (m, 2 H, OCHMe2), 4.57–4.63 (m, 2 H, OCHMe2), 6.79–8.33
(m, 16 H, ArH), 8.62 (s, 2 H, NHCO), 9.06 (s, 2 H, NHCO) ppm.
13C NMR (100 MHz, CDCl3): δ = 20.8, 21.1, 30.4, 33.8, 34.1, 50.9,
70.2, 70.4, 110.6, 111.4, 116.7, 116.9, 117.9, 121.7, 122.3, 123.4,
124.6, 125.8, 127.9, 130.0, 130.6,131.6, 144.4, 144.6, 145.3, 146.1,
162.6, 162.8, 165.6 ppm. MS (FT-ICR, MeCN): calcd. for
C67H79N4O13 [M
+
H]+ 1147.5638; found 1147.5612. MS
(MALDI-TOF): m/z = 1146.6 [M]+.
Compound 45: Yield 45%. 1H NMR (500 Hz, CDCl3): δ = 0.76 (d,
J = 6.9 Hz, 12 H, Mei-Bu), 1.06–1.09 (m, 24 H, Mei-Bu), 1.33 (s, 18
H, t-Bu), 1.67 (s, 6 H, Mexanth), 1.83–1.91 (m, 2 H, OCH2CHMe2),
2.13–2.23 (m, 4 H, OCH2CHMe2), 3.69 (d, J = 6.7 Hz, 4 H,
OCH2CHMe2), 3.73 (d, J = 6.5 Hz, 4 H, OCH2CHMe2), 3.77 (d,
J = 6.5 Hz, 4 H, OCH2CHMe2), 3.84 (s, 6 H, COOMe), 6.89–8.40
(m, 22 H, ArH), 8.57 (s, 2 H, NHCO), 8.61 (s, 2 H, NHCO), 9.12
(s, 2 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.0, 18.4,
18.5, 26.8, 27.3, 27.4, 30.3, 30.5, 33.8, 34.1, 51.0, 73.9, 108.1, 109.3,
110.1, 117.1, 117.2, 117.5, 118.2, 122.1, 122.2, 123.5, 124.7, 125.7,
127.7, 127.8, 130.0, 130.2, 131.0, 144.4, 145.7, 146.3, 146.5, 162.6,
162.7, 165.7 ppm. MS (FT-ICR, MeCN): calcd. for C93H114N6O17
[M + 2H]2+ 1586.8189; found 1586.8146. MS (MALDI-TOF): m/z
= 1584.8 [M]+.
1
Compound 40: Yield 63%. H NMR (400 Hz, CDCl3): δ = 0.73 (d,
J = 6.7 Hz, 12 H, Mei-Bu), 1.04 (d, J = 6.6 Hz, 12 H, Mei-Bu), 1.33
(s, 18 H, t-Bu), 1.66 (s, 6 H, Mexanth), 1.78–1.87 (m, 2 H,
OCH2CHMe2), 2.10–2.18 (m, 2 H, OCH2CHMe2), 3.58 (d, J =
6.5 Hz,
4 H, OCH2CHMe2), 3.73 (d, J = 6.7 Hz, 4 H,
OCH2CHMe2), 3.84 (s, 6 H, COOMe), 6.81–8.38 (m, 16 H, ArH),
8.61 (s, 2 H, NHCO), 9.13 (s, 2 H, NHCO) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.0, 19.4, 27.9, 28.2, 31.4, 31.6, 34.8, 35.1,
52.0, 74.8, 74.9, 110.3, 110.9, 117.8, 117.9, 118.4, 122.7, 123.3,
124.6, 125.8, 126.8, 128.8, 130.9, 131.1,131.9, 145.3, 146.7, 147.2,
147.5, 163.6, 163.7, 166.6 ppm. MS (FT-ICR, MeCN): calcd. for
C71H87N4O13 [M
+
H]+ 1203.6264; found 1203.6215. MS
(MALDI-TOF): m/z = 1203.9 [M + H]+.
1
1
Compound 41: Yield 63%. H NMR (400 Hz, CDCl3): δ = 0.57 (t, Compound 46: Yield 52%. H NMR (500 Hz, CDCl3): δ = 0.60 (t,
J = 7.4 Hz, 12 H, Me), 0.95 (t, J = 7.4 Hz, 12 H, Me), 1.08–1.22 J = 6.4 Hz, 12 H, Me), 0.92–0.99 (m, 24 H, Me), 1.13–1.25 (m, 10
(m, 8 H, CHCH2Me),1.33 (s, 18 H, t-Bu), 1.41–1.52 (m, 10 H,
CHCH2Me + OCH2CHEt2),1.69 (s, 6 H, Mexanth), 1.72–1.78 (m, 2 CHCH2Me + OCH2CHEt2), 1.69 (s, 6 H, Mexanth), 1.72–1.80 (m,
H, OCH2CHEt2), 3.73 (d, J = 5.8 Hz, 4 H, OCH2CHEt2), 3.84– 4 H, OCH2CHEt2), 3.85–3.88 (m, 14 H, OCH2CHEt2 + COOMe),
3.86 (m, 10 H, OCH2CHEt2 + COOMe), 6.76–8.39 (m, 16 H, 3.94 (d, J = 5.7 Hz, 4 H, OCH2CHEt2), 6.86–8.36 (m, 22 H, ArH),
H, CHCH2Me),1.33 (s, 18 H, t-Bu), 1.45–1.53 (m, 16 H,
ArH), 8.58 (s, 2 H, NHCO), 9.17 (s, 2 H, NHCO) ppm. 13C NMR
(100 MHz, CDCl3): δ = 9.9, 10.3, 22.0, 22.6, 30.3, 32.1, 33.7, 39.4,
39.8, 51.0, 69.6, 70.6, 109.2, 109.8, 116.7, 116.8, 117.1, 121.6, 122.0,
123.5, 125.6, 126.4, 127.7, 128.9, 130.0, 130.9, 143.3, 145.7, 146.0,
146.6, 162.6, 165.5 ppm. MS (FT-ICR, MeCN): calcd. for
C79H103N4O13 [M + H]+; found 1315.7495. MS (MALDI-TOF):
m/z = 1313.8 [M – H]+.
8.59 (s, 2 H, NHCO), 8.62 (s, 2 H, NHCO), 9.16 (s, 2 H,
NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.0, 11.3, 11.4,
23.1, 23.7, 31.4, 32.8, 34.8, 40.5, 41.0, 52.0, 70.6, 70.8, 71.6, 109.5,
110.2, 111.1, 118.1, 118.2, 118.4, 118.8, 123.0, 123.1, 124.6, 126.5,
127.3, 128.9, 129.1, 130.2, 131.2, 131.3, 132.2, 144.6, 147.0, 147.1,
147.5, 147.7, 163.5, 163.8, 163.9, 166.8. ppm. MS (MALDI-TOF):
m/z = 1755.7 [M + H]+.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O30363
/KAP1
Date: 22-05-13 19:14:52
Pages: 14
A. D. Hamilton et al.
FULL PAPER
Compound 47: Yield 65%. H NMR (500 Hz, CDCl3): δ = 1.21 (d,
J = 5.5 Hz, 12 H, Mei-Pr), 1.33 (s, 18 H, t-Bu), 1.37 (d, J = 4.7 Hz,
1
2.19 (m, 4 H, OCH2CHMe2), 3.85 (s, 6 H, COOMe), 3.88–3.90 (m,
8 H, OCH2CHMe2), 4.01 (s, 3 H, OMeanisole), 7.38–8.68 (m, 15 H,
12 H, Mei-Pr), 1.44–1.45 (m, 24 H, Mei-Pr), 1.68 (s, 6 H, Mexanth), ArH), 8.81 (s, 2 H, NHCO), 9.78 (s, 2 H, NHCO) ppm. 13C NMR
3.81 (s, 6 H, COOMe), 4.57–4.66 (m, 6 H, OCHMe2), 4.70–4.75 (125 MHz, CDCl3): δ = 19.2, 19.4, 28.1, 28.4, 52.1, 64.6, 75.2, 75.4,
(m, 2 H, OCHMe2), 6.87–8.34 (m, 28 H, ArH), 8.57 (s, 2 H,
110.8, 111.5, 118.3, 118.8, 120.0, 123.4, 125.1, 125.6, 128.3, 130.3,
NHCO), 8.61 (s, 2 H, NHCO), 8.62 (s, 2 H, NHCO), 9.04 (s, 2 H, 131.3, 132.2, 135.1, 147.0, 148.1, 163.1, 164.4, 166.9 ppm. MS
NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.9, 22.0, 22.2,
31.4, 32.2, 34.8, 35.2, 52.0, 71.3, 71.6, 71.7, 111.0, 111.5, 111.8,
112.7, 117.9, 118.2, 118.3, 118.4, 118.8, 119.1, 123.0, 123.3, 124.5,
125.8, 126.8, 128.8, 128.9, 129.0, 131.1, 131.7, 132.0, 132.3, 132.8,
145.5, 145.7, 146.2, 146.3, 146.4, 147.1,163.8, 163.9, 166.7 ppm. MS
(MALDI-TOF): m/z = 1857.2 [M + H]+.
(MALDI-TOF): m/z = 987.9 [M – H]+, 973.8 [M – Me]+.
1
Compound 55: Yield 65%. H NMR (500 Hz, CDCl3): δ = 3.49 (s,
6 H, Me), 3.94 (s, 6 H, COOMe), 7.44–8.77 (m, 12 H, ArH), 11.48
(s, 2 H, NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 52.2, 55.8,
110.3, 119.0, 121.5, 125.7, 128.0, 130.7, 131.7, 138.0, 144.3, 148.7,
149.7, 162.6, 166.7 ppm. MS (FT-ICR, MeCN): calcd. for
C32H27N4O8 [M + H]+ 595.1823; found 595.1813.
1
Compound 48: Yield 58%. H NMR (500 Hz, CDCl3): δ = 0.81 (d,
J = 6.2 Hz, 12 H, Mei-Bu), 1.10 (d, J = 7.8 Hz, 12 H, Mei-Bu), 1.15–
1.17 (m, 24 H, Mei-Bu), 1.38 (s, 18 H, t-Bu), 1.72 (s, 6 H, Mexanth),
1
Compound 56: Yield 30%. H NMR (400 Hz, CDCl3): δ = 3.57 (s,
6 H, Me), 3.92 (s, 6 H, Me), 4.02 (s, 6 H, COOMe), 7.46–8.81 (m,
1.90–1.96 (m,
2 H, OCH2CHMe2), 2.18–2.31 (m, 6 H,
18 H, ArH), 8.84 (s, 2 H, NHCO), 11.50 (s, 2 H, NHCO) ppm. 13
C
OCH2CHMe2), 3.77–3.80 (m, 12 H, OCH2CHMe2), 3.86 (s, 6 H,
COOMe), 3.90 (d, J = 6.5 Hz, 4 H, OCH2CHMe2), 6.93–8.45 (m,
28 H, ArH), 8.59 (s, 2 H, NHCO), 8.61 (s, 2 H, NHCO), 8.66 (s,
2 H, NHCO), 9.16 (s, 2 H, NHCO) ppm. 13C NMR (125 MHz,
CDCl3): δ = 18.9, 19.4, 19.5, 27.8, 28.3, 28.4, 31.3, 31.4, 34.8, 35.1,
51.9, 74.9, 108.9, 110.0, 110.4, 111.1, 117.9, 118.1, 118.4, 118.5,
119.3, 123.0, 123.2, 124.5, 125.7, 126.8, 128.6, 128.7, 128.8, 131.0,
131.2, 131.3, 131.9, 145.4, 146.7, 147.1, 147.2, 147.4, 147.5, 163.5,
163.6, 163.7, 166.6 ppm. MS (MALDI-TOF): m/z = 1968.9 [M]+.
NMR (100 MHz, CDCl3): δ = 51.7, 52.1, 53.5, 55.9, 56.2, 109.3,
110.6, 118.7, 119.2, 119.3, 120.4, 123.5, 128.0, 130.5, 134.9, 138.1,
144.3, 147.6, 149.3, 149.7, 162.7, 164.6, 166.8 ppm. MS (FT-ICR,
MeCN): calcd. for C48H41N6O12 [M + H]+ 893.2777; found
893.2792.
1
Compound 57: Yield 32%. H NMR (500 Hz, CDCl3): δ = 0.61 (d,
J = 7.4 Hz, 12 H, Mei-Bu), 1.00 (d, J = 6.9 Hz, 12 H, Mei-Bu), 1.83–
1.91 (m, 2 H, OCH2CHMe2), 2.05–2.13 (m, 2 H, OCH2CHMe2),
3.31 (d, J = 6.8 Hz, 4 H, OCH2CHMe2), 3.81 (d, J = 6.0 Hz, 4 H,
OCH2CHMe2), 3.85 (s, 6 H, COOMe), 7.31–8.74 (m, 18 H, ArH),
8.81 (s, 2 H, NHCO), 11.21 (s, 2 H, NHCO) ppm. 13C NMR
(125 MHz, CDCl3): δ = 17.9, 18.4, 27.1, 27.4, 51.1, 74.0, 74.6,
109.1, 110.4, 117.4, 118.4, 120.5, 122.4, 124.0, 127.0, 127.8, 129.3,
129.7, 130.3, 131.2, 136.9, 143.6, 146.0, 148.0, 148.9, 161.8, 163.1,
165.8 ppm. MS (FT-ICR, MeCN): calcd. for C60H65N6O12 [M +
H]+ 1061.4655; found 1061.4618. MS (MALDI-TOF): m/z =
1060.9 [M]+.
1
Compound 49: Yield 44%. H NMR (500 Hz, CDCl3): δ = 1.26 (d,
J = 5.4 Hz, 12 H, Mei-Pr), 1.37 (s, 18 H, t-Bu), 1.44 (d, J = 6.2 Hz,
12 H, Mei-Pr), 1.48–1.52 (m, 36 H, Mei-Pr), 1.73 (s, 6 H, Mexanth),
3.86 (s, 6 H, COOMe), 4.63–4.80 (m, 10 H, OCHMe2), 6.91–8.41
(m, 34 H, ArH), 8.61–8.66 (m, 8 H, NHCO), 9.07 (s, 2 H,
NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.9, 22.2, 31.4,
34.7, 35.1, 51.9, 71.3, 71.6, 110.9, 111.4, 111.5, 111.8, 112.8, 117.9,
118.2, 118.3, 118.4, 118.5, 118.8, 119.1, 123.0, 123.3, 124.5, 125.7,
126.7, 128.7, 128.8, 128.9, 129.0, 131.0, 131.7, 131.9, 132.0, 132.8,
145.5, 145.6, 146.1, 146.2, 146.3, 146.4, 147.1, 163.7, 163.8,
166.7 ppm. MS (MALDI-TOF): m/z = 2209.9 [M]+.
1
Compound 58: Yield 32%. H NMR (500 Hz, CDCl3): δ = 0.62 (d,
J = 7.0 Hz, 12 H, Mei-Bu), 1.01–1.04 (m, 24 H, Mei-Bu), 1.83–1.91
(m, 2 H, OCH2CHMe2), 2.06–2.17 (m, 4 H, OCH2CHMe2), 3.26
1
Compound 50: Yield 54%. H NMR (500 Hz, CDCl3): δ = 0.77 (d,
(d,
J = 6.2 Hz, 4 H, OCH2CHMe2), 3.81–3.83 (m, 8 H,
J = 6.7 Hz, 12 H, Mei-Bu), 1.08–1.14 (m, 48 H, Mei-Bu), 1.33 (s, 18
H, t-Bu), 1.67 (s, 6 H, Mexanth), 1.84–1.90 (m, 2 H, OCH2CHMe2),
2.14–2.26 (m, 8 H, OCH2CHMe2), 3.70 (d, J = 6.1 Hz, 4 H,
OCH2CHMe2), 3.74–3.87 (m, 22 H, COOMe + OCH2CHMe2),
6.82–8.36 (m, 34 H, ArH), 8.38–8.41 (m, 6 H, NHCO), 8.49 (s, 2
H, NHCO), 9.08 (s, 2 H, NHCO) ppm. MS (MALDI-TOF): m/z
= 2351.5 [M + H]+.
OCH2CHMe2), 3.84 (s, 6 H, COOMe), 7.26–8.73 (m, 24 H, ArH),
8.76 (s, 2 H, NHCO), 8.80 (s, 2 H, NHCO), 11.3 (s, 2 H,
NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.9, 19.4, 28.1,
28.3, 52.0, 75.0, 75.6, 109.9, 110.2, 111.4, 118.3, 118.7, 118.9, 119.3,
119.7, 121.4, 123.2, 124.8, 128.0, 129.6, 129.9, 130.7, 131.3, 131.4,
132.1, 137.9, 144.4, 146.9, 147.7, 148.9, 149.8, 162.7, 164.0, 164.2,
166.7 ppm. MS (MALDI-TOF): m/z = 1444.7 [M + 2H]2+
.
1
Compound 52: Yield 70%. H NMR (500 Hz, CDCl3): δ = 3.93 (s,
1
Compound 59: Yield 23%. H NMR (500 Hz, CDCl3): δ = 0.62 (d,
J = 6.7 Hz, 12 H, Mei-Bu), 1.00 (d, J = 6.5 Hz, 12 H, Mei-Bu), 1.03–
1.06 (m, 24 H, Mei-Bu), 1.80–1.88 (m, 2 H, OCH2CHMe2), 2.03–
6 H, Me), 4.03 (s, 3 H, OMeanisole), 4.06 (s, 6 H, COOMe), 7.44–
8.69 (m, 9 H, ArH), 10.26 (s, 2 H, NHCO) ppm. 13C NMR
(125 MHz, CDCl3): δ = 52.2, 56.1, 64.5, 110.9, 119.4, 123.6, 125.5,
125.7, 127.8, 132.1, 135.7, 147.9, 156.0, 162.6, 166.7 ppm. MS (FT-
ICR, MeCN): calcd. for C27H27N3O9 [M + H]+ 523.1711; found
523.1686.
2.19 (m,
6 H, OCH2CHMe2), 3.18 (d, J = 6.6 Hz, 4 H,
OCH2CHMe2), 3.78 (d, J = 6.6 Hz, 8 H, OCH2CHMe2), 3.83–3.84
(m, 10 H, OCH2CHMe2 + COOMe), 7.17–8.63 (m, 30 H, ArH),
8.70 (s, 4 H, NHCO), 8.75 (s, 2 H, NHCO), 11.30 (s, 2 H,
NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.0, 28.2, 28.4,
52.0, 75.0, 109.7, 110.1, 111.3, 118.2, 118.5, 118.8, 119.0, 119.3,
1
Compound 53: Yield 40%. H NMR (400 Hz, CDCl3): δ = 3.93 (s,
6 H, Me), 4.03 (s, 6 H, Me), 4.06 (s, 3 H, OMeanisole), 4.11 (s, 6 H,
COOMe), 7.46–8.77 (m, 15 H, ArH), 8.78 (s, 2 H, NHCO), 10.30 120.0, 121.4, 123.2, 124.8, 128.0, 129.2, 129.4, 129.7, 130.6, 131.4,
(s, 2 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.2, 56.2,
64.5, 110.0, 110.7, 118.6, 119.3, 119.6, 123.5, 125.1, 127.7, 130.2,
135.8, 147.6, 148.6, 156.0, 162.6, 164.7, 166.8 ppm. MS (FT-ICR,
MeCN): calcd. for C43H41N4O13 [M + H]+ 821.2665; found
821.2631.
131.6, 132.1, 137.9, 144.4, 146.8, 147.7, 149.0, 149.7, 162.7, 163.9,
164.0, 164.1, 166.7 ppm. MS (MALDI-TOF): m/z = 1828.9 [M +
2H]2+
.
1
Compound 60: Yield 79%. H NMR (400 Hz, CDCl3): δ = 0.71 (d,
J = 6.7 Hz, 12 H, Mei-Bu), 1.80–1.90 (m, 2 H, OCH2CHMe2), 3.73
(d, J = 6.6 Hz, 4 H, OCH2CHMe2), 3.87 (s, 6 H, COOMe), 7.50–
1
Compound 54: Yield 40%. H NMR (500 Hz, CDCl3): δ = 0.95 (d,
J = 6.6 Hz, 12 H, Mei-Bu), 1.06 (d, J = 6.6 Hz, 12 H, Mei-Bu), 2.07– 8.55 (m, 9 H, ArH), 10.21 (s, 2 H, NHCO) ppm. 13C NMR
12
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30363
/KAP1
Date: 22-05-13 19:14:52
Pages: 14
Oligoamide-Based Double α-Helix Mimetics
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(100 MHz, CDCl3): δ = 18.9, 28.2, 52.2, 75.1, 111.6, 119.1, 123.3,
125.7, 125.9, 131.3, 139.8, 147.8, 149.6, 161.5, 166.8 ppm. MS (FT-
ICR, MeCN): calcd. for C31H36N3O8 [M + H]+ 578.2497; found
578.2503. MS (MALDI-TOF): m/z = 577.6 [M]+.
1
Compound 61: Yield 74%. H NMR (400 Hz, CDCl3): δ = 0.74 (d,
J = 6.7 Hz, 12 H, Mei-Bu), 1.06 (d, J = 6.7 Hz, 12 H, Mei-Bu), 1.84– [11] R. F. S. Walters, W. F. DeGrado, Proc. Natl. Acad. Sci. USA
2006, 103, 13658.
1.92 (m, 2 H, OCH2CHMe2), 2.12–2.22 (m, 2 H, OCH2CHMe2),
3.78 (d, J = 6.5 Hz, 4 H, OCH2CHMe2), 3.85 (s, 6 H, COOMe),
3.88 (d, J = 6.4 Hz, 4 H, OCH2CHMe2), 7.42–8.62 (m, 15 H, ArH),
8.82 (s, 2 H, NHCO), 10.22 (s, 2 H, NHCO) ppm. 13C NMR
(125 MHz, CDCl3): δ = 18.9, 19.2, 28.1, 28.4, 52.1, 75.1, 75.2,
110.4, 111.5, 118.4, 118.9, 119.4, 123.4, 125.1, 125.7, 130.5, 132.2,
139.8, 146.9, 148.4, 149.5, 161.6, 164.4, 166.8 ppm. MS (MALDI-
TOF): m/z = 958.6 [M – H]+.
[12] S. Hecht, I. Huc (Eds.), Foldamers: Structure, Properties, and
Applications, Wiley-VCH, Weinheim, Germany, 2007.
[13] J. Iriondo-Alberdi, K. Laxmi-Reddy, B. Bouguerne, C. Staedel,
I. Huc, ChemBioChem 2010, 11, 1679.
[14] B. Baptiste, C. Douat-Casassus, K. Laxmi-Reddy, F. Godde, I.
Huc, J. Org. Chem. 2010, 75, 7175.
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Jiang, I. Huc, Science 2011, 331, 1172.
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Am. Chem. Soc. 2011, 133, 3165.
1
Compound 62: Yield 65%. H NMR (500 Hz, CDCl3): δ = 0.99 (d,
J = 6.3 Hz, 12 H, Mei-Bu), 1.03 (d, J = 6.3 Hz, 12 H, Mei-Bu), 1.39–
1.41 (m, 4 H, CH2CH2), 1.70–1.73 (m, 4 H, CH2CH2), 2.09–2.16
(m, 4 H, OCH2CHMe2), 2.36 (t, 4 H, NHCOCH2CH2), 3.83–3.86
(m, 14 H, COOMe + OCH2CHMe2), 7.30–8.47 (m, 12 H, ArH),
8.54 (s, 1 H, NHCO), 8.55 (s, 1 H, NHCO), 8.76 (s, 2 H,
NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.2, 19.3, 25.2,
28.1, 28.3, 28.9, 37.9, 52.0, 75.1, 110.4, 111.5, 118.3, 118.8, 118.9,
123.4, 124.9, 129.5, 131.3, 132.2, 147.0, 147.3, 164.4, 166.8,
171.2 ppm. MS (FT-ICR, MeCN): calcd. for C54H71N4O12 [M +
H]+ 967.5063; found 967.5097. MS (MALDI-TOF): m/z = 966.98
[M]+.
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1
Compound 63: Yield 71%. H NMR (500 Hz, CDCl3): δ = 1.47 (s,
11, 4418.
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18 H, t-Bu), 3.76–3.79 (m, 8 H, OCH2CH2OCH2CH2O), 3.90 (s, 6
H, COOMe), 4.16 (s, 4 H, COCH2O), 4.91 (s, 4 H, OCH2COOt-
Bu), 7.77–8.75 (m, 4 H, ArH), 9.10 (s, 2 H, NHCO) ppm. MS-ESI:
m/z = 773.52 [M + Na]+.
Compound 64: Yield 30%. 1H NMR (500 Hz, CDCl3): δ = 1.35–
1.47 (m, 54 H, t-Bu), 3.78–3.82 (m, 8 H, OCH2CH2OCH2CH2O),
3.89 (s, 6 H, COOMe), 4.18 (s, 4 H, NHCOCH2O), 4.99–5.12 (m,
12 H, OCH2COOt-Bu), 7.81–8.99 (m, 12 H, ArH), 9.04 (s, 2 H,
NHCO), 10.20 (s, 2 H, NHCO), 10.30 (s, 2 H, NHCO) ppm. MS
(ESI): m/z = 1774.76 [M + Na]+.
1
Compound 65: Yield 37%. H NMR (500 Hz, CDCl3): δ = 4.05 (s,
6 H, COOMe), 7.32–8.53 (m, 9 H, ArH), 10.36 (s, 2 H,
NHCO) ppm. 13C NMR (125 MHz, CDCl3): δ = 53.0, 110.3, 125.7,
127.8, 138.8, 140.7, 146.9, 149.4, 149.6, 161.8, 164.9 ppm. MS
(ESI): m/z = 436.15 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, crystallographic data and details
of the structures, additional colour figures of the crystal structures
and calculated structures.
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Acknowledgments
The authors thank the National Science Foundation (NSF) (CHE-
0750357), National Institutes of Health (NIH) (CA67771) and the
University of Oxford, UK for funding.
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In some cases coupling was accompanied by transesterification,
for example, the isobutyl ester analogue of 12 was isolated as
a minor product (see the Supporting Information).
CCDC: 103.8°, JEVDEU; 123.8°, ATIQAV; 146.8°, NIQBOF;
97.3°, PULHUZ; 95.3°, UDEDEN; 119.6°, VEBSUQ; 137.8°,
[43]
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13

Job/Unit: O30363
/KAP1
Date: 22-05-13 19:14:52
Pages: 14
A. D. Hamilton et al.
FULL PAPER
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Received: March 10, 2013
Published Online: ᭿
14
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