Design and Conformational Analysis of Peptoids
Containing N-Hydroxy Amides Reveals a Unique SheetLike Secondary Structure
J. Aaron Crapster, Joseph R. Stringer, Ilia A. Guzei, and Helen E. Blackwell*
Department of Chemistry, University of Wisconsin–Madison,
1101 University Avenue, Madison, WI 53706-1322
Supporting Information.
Characterization data and 1H NMR spectra for selected peptoid intermediates ....................... S-2
2D NOESY spectrum for peptoid intermediate Ac-NOBn-Nph-NOBn-Dma .......................... S-8
1
H NMR spectra for peptoids 1–4 ............................................................................................. S-9
X-ray crystallographic data for peptoids 2–4............................................................................ S-11
*
To whom correspondence should be addressed. blackwell@chem.wisc.edu
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Supporting Information
Characterization data and 1H NMR spectra for selected peptoid intermediates.
Intermediate in the synthesis of peptoid 1
H-NOBn-Pip. TLC: Rf = 0.29 (1:1 EtOAc/hexanes with 1% TEA); 1H NMR (CDCl3, 300 MHz):
δ 7.45-7.24 (m, 5H), 6.04 (s, 1H), 4.73 (s, 2H), 3.62 (s, 2H), 3.57 (m, 2H), 3.29 (m, 2H), 1.681.47 (m, 6H); 13C NMR (75 MHz, CDCl3, 1H broadband-decoupled): 168.0, 138.3, 128.5, 128.5,
127.9, 76.1, 52.4, 45.7, 43.2, 26.5, 25.5, 24.6; IR (ATR, cm-1): 3255, 3089, 3066, 3030, 3003,
2936, 2856, 1643, 1496, 1469, 1453, 1441, 1366, 1322, 1281, 1253, 1228, 1199, 1176, 1138,
1085, 1060, 1027, 1010, 955, 930, 913, 895, 853, 825, 798, 766, 746, 719, 699; HR-MS (ESI):
[M+H]+ calcd m/z = 249.1598, observed m/z = 249.1601.
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Supporting Information
Intermediate in the synthesis of peptoid 3
H-NOBn-NOBn-Pip. Synthesized from H-NOBn-Pip (see above) according to the general
acylation and amination procedures as described in the main text. Isolated as a white foam (34%
yield over two steps). TLC: Rf = 0.18 (3:2 EtOAc/hexanes with 1% TEA); 1H NMR (CDCl3, 300
MHz): δ 7.42-7.24 (m, 10H), 4.87 (s, 2H), 4.69 (s, 2H), 4.35 (s, 2H), 3.78 (s, 2H), 3.53 (m, 2H),
3.24 (m, 2H), 1.69-1.46 (m, 6H); 13C NMR (75 MHz, CDCl3, 1H broadband-decoupled): δ 164.0,
134.6, 129.7, 129.3, 129.0, 50.8, 46.1, 43.6, 26.4, 26.2, 25.5, 24.5; IR (ATR, cm-1): 3240, 3047,
2960, 2928, 2857, 1671, 1654, 1499, 1462, 1454, 1446, 1438, 1398, 1383, 1373, 1355, 1334,
1280, 1266, 1257, 1230, 1161, 1138, 1128, 1094, 1075, 1052, 1023, 1005, 982, 974, 946, 931,
912, 894, 854, 840, 819, 806, 777, 741, 697, 671, 651, 622, 611; HR-MS (ESI): [M+H]+ calcd
m/z = 412.2231, observed m/z = 412.2213.
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Supporting Information
Intermediates in the synthesis of peptoid 4
H-NOBn-Dma. Dimethylamine hydrochloride (7.20 g, 0.088 mol) was added to CH2Cl2 (50 mL)
under N2 and cooled to -78 °C in an acetone/dry ice bath. Bromoacetyl bromide (11.5 mL, 0.132
mol) was added to mixture under N2 via an addition funnel. TEA (30.8 mL, 0.221 mol) in
CH2Cl2 (50 mL) was added drop-wise over several hours while the reaction was kept at -78 °C.
Aqueous work-up and subsequent amination procedures were conducted according to the general
protocols described in the main text. Isolated as a clear liquid (31% yield over two steps). TLC:
Rf = 0.21 (4:1 EtOAc/hexanes with 1% TEA); 1H NMR (CDCl3, 300 MHz): δ 7.40-7.23 (m, 5H),
6.52 (brd s, 1H), 4.72 (s, 2H), 3.61 (s, 2H), 2.97 (s, 3H), 2.92 (s, 3H); 13C NMR (75 MHz,
CDCl3, 1H broadband-decoupled): δ 169.9, 138.3, 128.5, 128.5, 127.9, 76.1, 52.5, 36.3, 35.7; IR
(ATR, cm-1): 3252, 3089, 3064, 3030, 2917, 2871, 1649, 1496, 1454, 1398, 1365, 1317, 1264,
1207, 1161, 1119, 1085, 1060, 1003, 964, 939, 913, 868, 784, 746, 699, 652, 602, 589; HR-MS
(ESI): [M+H]+ calcd m/z = 231.1104, observed m/z = 231.1102.
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Supporting Information
H-Nph-NOBn-Dma. Synthesized from H-NOBn-Dma following the general acylation and
amination procedures described in the main text with the following modifications. During the
amination step, aniline was coupled for 60 min at rt. Following the aqueous work-up, a major
fraction of the pure product precipitated out as the EtOAc was removed in vacuo. The remaining
product could be isolated from the brownish crude oil by flash silica gel column
chromatography. Isolated as a white solid (72% yield over two steps). TLC: Rf = 0.29 (EtOAc
with 1% TEA); 1H NMR (CDCl3, 300 MHz): δ 7.50-7.35 (m, 5H), 7.16 (m, 2H), 6.70 (m, 1H),
6.53 (m, 2H), 4.95 (s, 1H), 4.48 (brd. s, 1H), 4.37 (s, 2H), 4.04 (s, 2H), 2.96 (s, 3H), 2.92 (s, 3H);
13
C NMR (75 MHz, CDCl3, 1H broadband-decoupled): δ 166.1, 147.6, 134.9, 129.8, 129.4,
129.4, 129.0, 117.8, 113.2, 50.9, 45.4, 36.5, 36.0; IR (ATR, cm-1): 3370, 3053, 3037, 2938, 1667,
1659, 1604, 1582, 1507, 1499, 1445, 1421, 1402, 1395, 1387, 1342, 1271, 1249, 1236, 1217,
1179, 1147, 1077, 1061, 1039, 993, 971, 912, 871, 846, 814, 796, 744, 699, 693, 669, 693, 669,
642, 619, 599, 583; HR-MS (ESI): [M+H]+ calcd m/z = 342.1813, observed m/z = 342.1808.
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Supporting Information
H-NOBn-Nph-NOBn-Dma. Synthesized from H-Nph-NOBn-Dma following the general
acylation and amination procedures described in the main text. Isolated as a white foam (73%
yield over two steps). TLC: Rf = 0.15 (4:1 EtOAc/hexanes with 1% TEA); 1H NMR (CDCl3, 300
MHz): δ 7.44-7.21 (m, 15H), 6.45 (brd. s, 1H), 5.30 (s, 2H), 5.01 (s, 2H), 4.65 (s, 2H), 4.63 (s,
2H), 4.30 (s, 2H), 3.41 (s, 2H), 2.91 (s, 3H), 2.86 (s,3H); 13C NMR (75 MHz, CDCl3, 1H
broadband-decoupled): δ 170.9, 166.2, 141.9, 138.3, 134.9, 129.9, 129.7, 129.1, 128.8, 128.6,
128.6, 128.5, 128.5, 128.4, 127.8, 76.1, 53.1, 51.67, 50.8, 36.6, 36.0; IR (ATR, cm-1): 3089,
3063, 3032, 2938, 2870, 1659, 1596, 1495, 1454, 1406, 1388, 1329, 1262, 1214, 1148, 1072,
1018, 994, 964, 944, 911, 847, 805, 732, 699, 646, 607; HR-MS (ESI): [M+H]+ calcd m/z =
505.2446, observed m/z = 505.2451.
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Supporting Information
Ac-NOBn-Nph-NOBn-Dma. Synthesized from H-NOBn-Nph-NOBn-Dma following the
general acetylation procedure described in the main text. Isolated as a white powder (76%
isolated yield); TLC: Rf = 0.18 (5% MeOH in EtOAc); 1H NMR (10 mM CDCl3, 600 MHz): δ
7.42-7.29 (m, 15H), 4.98 (s, 2H), 4.85 (s, 2H), 4.64 (s, 2H), 4.31 (s, 2H), 4.14 (s, 2H), 2.91 (s,
3H), 2.86 (s, 3H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCl3, 1H broadband-decoupled): δ 172.2,
167.4, 166.2, 141.8, 135.1, 134.9, 129.97, 129.68, 129.60, 129.07, 128.9, 128.80, 128.78, 128.60,
128.33, 51.9, 50.8, 50.5, 36.6, 36.0, 20.5; IR (ATR, cm-1): 3089, 3066, 3033, 2942, 2877, 1664,
1596, 1495, 1455, 1420, 1387, 1338, 1295, 1260, 1214, 1149, 1072, 1033, 1018, 973, 911, 846,
805, 730, 700, 646, 631, 605; HR-MS (ESI): [M+Na]+ calcd m/z = 569.2371, observed m/z =
569.2379.
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Supporting Information
2D NOESY spectrum for peptoid intermediate Ac-NOBn-Nph-NOBn-Dma.
Figure S-1. Partial 1H and NOESY spectra (600 MHz, CDCl3, 10 mM, 24 °C) of Ac-NOBn-Nph-NOBnDma. NOESY data were recorded as described in the main text, with the following specific parameters:
spectral width = 5200, mix time = 1.4 s, d1 = 9.0 s, ni = 340, nt = 8. Red boxes highlight the absence of
NOEs between the three main chain (ac1-3-Hα) methylenes (left box) and the absence of NOEs between
the NT-H methyl and the ac1-Hα methylene protons (right box). These data indicate that all of the amides
in this intermediate are trans.
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Supporting Information
1H
NMR spectra for peptoids 1–4.
Peptoid 1: Ac-NOBn-Pip.
Peptoid 2: Ac-NOH-Pip.
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Peptoid 3: Ac-(NOH)2-Pip.
Peptoid 4: Ac-NOH-Nph-NOH-Dma.
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Supporting Information
X-ray crystallographic data for peptoids 2–4.
Peptoids (~40 mg) were dissolved in appropriate solvents (~1 mL). Slow evaporation afforded
crystals suitable for X-ray analysis after several days (2 and 3) to two weeks (4). Table S-1
summarizes key crystal and diffraction parameters for these compounds.
Table S-1. Crystal data and structure refinement of peptoids 2–4
Peptoid 2
Peptoid 3
Peptoid 4
Empirical formula
C9H16N2O3
C11H19N3O5
C16H22N4O6 • H2O
Formula weight
200.24
273.29
384.39
Crystallizing solvent
CHCl3/n-hexanes
MeOH/CH3CN
1-propanol
Cocrystallized solvent
None
None
water
Crystal size (mm3)
0.36 x 0.27 x 0.17
0.51 x 0.11 x 0.09
0.35 x 0.18 x 0.13
Crystal system
Triclinic
Monoclinic
Monoclinic
Radiation
CuKα (λ = 1.54178 Å)
Cu Kα (λ = 1.54178 Å)
Mo Kα (λ = 0.71073 Å)
Temperature (K)
100(1)
100(1)
100(1)
θ range (°)
5.49 - 69.60
4.72 - 69.21
1.77 - 30.01
Space group
P 1�
P21/c
P21/c
a (Å)
7.889(3)
9.467(3)
11.9868(3)
b (Å)
8.001(7)
9.588(2)
9.8042(2)
c (Å)
9.198(4)
14.370(4)
16.9239(4)
α (deg)
100.35(5)
90
90
β (deg)
114.12(3)
98.463(19)
106.541(1)
γ (deg)
100.49(4)
90
90
499.7(5)
1290.1(7)
1906.60(8)
2
4
4
Density (g cm ) (calc.)
1.331
1.407
1.339
F (000)
216
584
816
Reflections collected
7937
18526
45322
Independent reflections
1803 [R(int) = 0.0181]
2393 [R(int) = 0.0220]
5499 [R(int) = 0.0.0236]
Completeness to θ = 69.60°
95.60%
99.50%
98.60%
Absorption correction
Empirical w/ SADABS
Empirical w/ SADABS
Analytical w/ SADABS
Data/restraints/parameters
1803/0/192
2393/0/248
5499/1/257
Maximum transmission
0.8716
0.9233
0.9864
Minimum transmission
0.754
0.6419
0.9639
1.014
1.043
0.916
R1 = 0.0308
R1 = 0.0310
R1 = 0.0340
wR2 = 0.0890
wR2 = 0.0786
wR2 = 0.0890
R1 = 0.0314
R1 = 0.0335
R1 = 0.0378
Unit cell dimensions
3
Volume (Å )
Z
-3
Goodness-of-fit on F
2
Final R indices [I > 2 σ (I)]
R indices (all data)
wR2 = 0.0898
Largest diff. peak and hole
wR2 = 0.0805
-3
0.243 and -0.147 e.Å
wR2 = 0.0925
-3
0.212 and -0.172 e.Å
0.442 and -0.254 e.Å-3
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Supporting Information
Figure S-2. Molecular diagrams (drawn with 50% probability ellipsoids) of the X-ray crystal structures of
peptoids 2 (A), 3 (B), and 4 (C).1
Table S-2. Hydrogen bonds observed in the X-ray crystal structures of peptoids 2 and 3 [distances
(Å) and angles (°)].
Peptoid
2
3
D-H...A
d (D-H)
d (H...A)
d (D...A)
< (DHA)
O(2)-H(13)...O(1)#1 [intermolecular]
0.889(17)
1.885(17)
2.701(3)
151.7(15)
O(2)-H(13)...O(1)
[intramolecular]
0.889(17)
2.540(17)
3.029(3)
115.3(12)
O(2)-H(2)...O(5)#1
[intermolecular]
0.96(2)
1.65(2)
2.605(1)
177.4(18)
O(4)-H(4)...O(3)#2
[intermolecular]
0.84(2)
1.99(2)
2.755(1)
150.7(17)
Symmetry transformations used to generate equivalent atoms:
2
#1 -x,-y+1,-z
3
#1 -x+1,y+1/2,-z+3/2
#2 -x+1,y-1/2,-z+3/2
1
Pennington, W. T. J. Appl. Cryst. 1999, 32, 1028-1029.
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