S1 Topologically diverse shapes accessible by modular design of arylopeptoid macrocycles. Thomas Hjelmgaard, §† Lionel Nauton, ‡ Francesco De Riccardis, || Laurent Jouffret, ‡ Sophie Faure* ‡ § Department of Chemistry, Section for Chemical Biology and Nanobioscience, Faculty of Science, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark, || Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II n. 132, I-84084 Fisciano (SA) ITALY ‡ Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, 63000 Clermont-Ferrand, France and CNRS, UMR 6296, ICCF, F-63178 Aubière Cedex, France. * [email protected]Contents S2-S12: Experimental section S13: Macrocyclization Optimization study S14-S17: HPLC and LC-MS profiles S18-S40: NMR spectra S41-S45: NMR study S46: X-Ray crystallography S47: Molecular modelling S48-S50: Complexation study S51: References
51
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S1
Topologically diverse shapes accessible by modular design of arylopeptoid macrocycles.
Thomas Hjelmgaard,§† Lionel Nauton,‡ Francesco De Riccardis,|| Laurent Jouffret,‡ Sophie Faure*‡
§ Department of Chemistry, Section for Chemical Biology and Nanobioscience, Faculty of Science, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark, || Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II n. 132, I-84084 Fisciano (SA) ITALY ‡ Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, 63000 Clermont-Ferrand, France and CNRS, UMR 6296, ICCF, F-63178 Aubière Cedex, France.
42.9 (12CH2, 6×CH2CH2OCH3 and 6×CONCH2Ar) ppm. HRMS (TOF MS ES+) calcd for
C66H79N6O12 [M + H]+ m/z 1147.5751, found 1147.5731.
S13
Macrocyclization Optimization study
The optimization of the macrocyclization process was carried out using the following four linear arylopeptoids as model systems: pppp-1 (the tetramer with the highest number of atoms between the C- and N-termini), pppppp-2 (the hexamer with the highest number of atoms between the C- and N-termini), momo-9 (the tetramer with the lowest number of atoms between the C- and N-termini), momomo-10 (the hexamer with the lowest number of atoms between the C- and N-termini). After Boc-removal with TFA, HATU, COMU and PyBOP showed similar efficiency for the macrocyclization of linear precursors 2, 9 and 10. However, PyBOP generally proved to be the least convenient reagent due to the formation of tripyrrolidinophosphine oxide which was difficult to separate from the macrocyclic products using column chromatography. While the cyclization of the linear precursors 2, 9 and 10 provided the derived macrocycles in 61-82% yield, the cyclization of tetramer 1 proved more challenging. Thus, 3:2 mixtures of the derived macrocyclic tetramer and octamer were obtained in approximately 50% yield regardless of the coupling reagent used. Fortunately the two macrocycles were easily separable by flash chromatography. A higher proportion of the cyclotetramer was obtained by increasing the dilution to 2.5 mM, however, the cyclooctamer remained present in ~20% yield. Table S1. Macrocyclization of linear arylopeptoids. Key: (a) CH2Cl2/TFA 1:1, 0 ºC, 3 h. (b) coupling reagent (1.2 equiv), DIPEA (5.0 equiv), CH2Cl2, 2.5-5.0 mM, 0 ºC to rt.
Linear precursor Conditionsa Macrocycle Macrocyclic dimer
Number Backbone Reagent Solvent Conc. (mM) Temp. Number Yieldb Purityc Yieldb Purityc
1 p-p-p-p HATU (1.2) CH2Cl2 5.0 0 °C to rt 13/14 32 >95 20 >90
1 p-p-p-p PyBOP (1.2) CH2Cl2 5.0 0 °C to rt 13/14 32d >91e 21 >91
1 p-p-p-p COMU (1.2) CH2Cl2 5.0 0 °C to rt 13/14 30 >99 16 >97
1 p-p-p-p COMU (1.2) CH2Cl2 2.5 0 °C to rt 13/14 47 >99 19 >98
2 p-p-p-p-p-p HATU (1.2) CH2Cl2 5.0 0 °C to rt 15 61 >99 - -
2 p-p-p-p-p-p PyBOP (1.2) CH2Cl2 5.0 0 °C to rt 15 65 >98 - -
2 p-p-p-p-p-p COMU (1.2) CH2Cl2 5.0 0 °C to rt 15 62 >97 - -
9 m-o-m-o HATU (1.2) CH2Cl2 5.0 0 °C to rt 20 78 >98 - -
9 m-o-m-o PyBOP (1.2) CH2Cl2 5.0 0 °C to rt 20 82 >98 - -
9 m-o-m-o COMU (1.2) CH2Cl2 5.0 0 °C to rt 20 79 >98 - -
10 m-o-m-o-m-o HATU (1.2) CH2Cl2 5.0 0 °C to rt 21 69 >97 - -
10 m-o-m-o-m-o PyBOP (1.2) CH2Cl2 5.0 0 °C to rt 21 65d >97e - -
10 m-o-m-o-m-o COMU (1.2) CH2Cl2 5.0 0 °C to rt 21 71 >97 - -
aTetramers on 0.045 mmol scale and hexamers on 0.030 mmol scale. bIsolated yield of pure product after purification by flash chromatography unless otherwise stated. cMeasured by analytical LC-MS. dCalculated yield since the product was isolated as a 1:1 mixture with tripyrrolidinophosphine oxide as judged by NMR. eTripyrrolidinophosphine oxide not detected on LC-MS.
S14
HPLC and LC-MS profiles of synthesised arylopeptoids
Linear arylopeptoid pppp-1 Linear arylopeptoid pppppp-2
Linear arylopeptoid mmmm-3 Linear arylopeptoid mmmmmm-4
Linear arylopeptoid mpmp-5 Linear arylopeptoid mpmpmp-6
Linear arylopeptoid pmpm-7 Linear arylopeptoid pmpmpm-8
S15
Linear arylopeptoid momo-9 Linear arylopeptoid momomo-10
Linear arylopeptoid popo-11 Linear arylopeptoid popopo-12
NMR spectra of linear arylopeptoid pppppp-2 (CDCl3)
ppm (t1)
050100150
172.067
168.888
168.720
155.732
155.507
142.966
142.513
142.352
140.255
139.015
138.701
135.180
134.616
131.445
130.310
129.234
128.954
127.839
127.455
127.020
126.907
126.279
79.966
71.097
70.691
70.271
70.172
58.745
58.622
54.330
53.672
51.400
50.564
48.270
48.072
46.376
46.185
44.649
28.261
OH
O
6
NBoc
OMe
S20
NMR spectra of linear arylopeptoid mmmm-3 (CDCl3)
ppm (t1)
050100150
172.120
169.019
168.661
155.783
155.473
139.223
138.889
138.844
137.729
137.589
137.455
136.633
136.489
136.139
132.666
132.535
131.301
130.565
130.292
129.376
128.995
128.750
128.508
128.163
127.762
126.262
125.893
125.547
125.085
79.980
71.056
70.652
70.260
58.735
58.623
53.685
51.385
50.540
48.096
47.984
46.266
46.150
44.757
44.502
28.280
OH
O
4
NBoc
OMe
S21
NMR spectra of linear arylopeptoid mmmmmm-4 (CDCl3)
ppm (t1)
050100150200
172.112
168.634
168.231
155.831
155.457
139.255
138.899
137.744
137.460
136.474
136.213
132.540
131.191
130.734
130.473
128.800
128.507
128.184
127.781
126.341
125.927
125.513
125.047
79.932
71.073
70.634
70.244
69.793
58.744
58.638
53.649
51.394
50.529
47.977
46.301
46.088
44.506
28.288
OH
O
6
NBoc
OMe
S22
NMR spectra of linear arylopeptoid mpmp-5 (CDCl3)
ppm (t1)
050100150
172.197
169.237
168.966
155.804
155.532
140.411
138.936
138.461
137.593
136.492
135.279
134.639
132.645
131.542
130.478
129.006
128.732
128.319
127.878
127.472
126.949
126.107
125.497
79.990
71.080
70.665
70.325
58.739
58.620
53.671
51.358
50.521
48.025
46.330
46.137
44.614
28.263
OH
O
2
N
OMe
O
NBoc
OMe
S23
NMR spectra of linear arylopeptoid mpmpmp-6 (CDCl3)
ppm (t1)
050100150
172.153
168.751
168.530
155.753
155.494
140.526
138.921
138.508
137.812
137.577
136.432
135.258
134.695
132.524
131.487
130.601
130.405
129.478
128.918
128.786
128.699
128.282
127.879
127.498
126.942
126.276
125.902
125.564
125.417
79.953
71.082
70.637
70.221
58.731
58.618
53.661
51.388
50.523
48.039
46.321
46.155
44.532
28.256
OH
O
3
N
OMe
O
NBoc
OMe
S24
NMR spectra of linear arylopeptoid pmpm-7 (CDCl3)
ppm (t1)
050100150
172.128
168.859
155.774
155.455
143.088
142.474
139.307
138.911
137.618
136.485
136.134
135.127
130.347
129.469
129.223
129.073
128.827
128.529
127.886
127.666
127.374
127.155
126.871
126.464
125.811
125.477
125.105
79.980
71.078
70.762
70.350
58.747
58.633
53.735
51.380
50.596
48.003
46.293
44.442
28.285
OH
O
2
N
OMe
O
NBoc
OMe
S25
NMR spectra of linear arylopeptoid pmpmpm-8 (CDCl3)
ppm (t1)
050100150
172.270
168.821
168.593
155.912
155.676
142.525
139.289
139.087
137.916
137.597
136.622
136.276
135.315
130.427
129.480
128.946
128.632
128.063
127.537
127.327
126.997
126.574
126.416
125.988
125.659
125.187
80.055
71.200
70.801
70.533
70.289
58.867
58.752
53.789
51.533
50.720
48.131
46.451
46.269
44.591
28.402
OH
O
3
N
OMe
O
NBoc
OMe
S26
NMR spectra of linear arylopeptoid momo-9 (CDCl3)
ppm (t1)050100150
172.560
172.408
172.287
171.892
171.743
171.613
171.258
171.201
170.786
170.735
170.542
168.914
168.689
155.936
137.776
137.675
137.076
137.024
136.885
136.724
136.453
135.634
135.580
135.445
135.223
135.012
134.875
134.280
134.057
132.774
132.617
131.905
130.613
130.568
129.470
129.220
129.107
129.008
128.844
128.743
128.606
128.148
127.713
127.541
127.439
127.266
127.098
126.920
126.724
126.683
126.281
126.017
125.922
125.504
125.248
125.114
80.046
79.928
70.476
70.234
69.866
69.532
69.402
58.701
58.644
58.604
58.552
58.519
53.097
52.961
52.811
51.038
50.746
49.221
49.090
48.528
48.097
47.947
47.806
47.549
46.674
46.393
45.411
45.068
44.196
44.012
43.551
28.316
S27
NMR spectra of linear arylopeptoid momomo-10 (CDCl3)
ppm (t1)050100150
172.540
172.289
171.585
171.426
171.174
170.776
170.497
168.520
168.360
156.019
155.912
137.734
137.629
136.808
136.698
136.437
136.209
135.404
135.232
134.877
134.258
134.028
133.798
133.637
132.646
132.547
130.674
129.427
129.320
129.154
129.043
128.853
128.732
128.554
127.812
127.513
127.446
127.178
127.069
126.681
126.541
126.432
126.253
125.927
125.718
125.530
125.344
125.068
79.959
70.492
70.453
70.212
69.952
69.850
69.392
69.170
58.631
58.537
52.967
50.884
48.544
48.453
48.050
47.884
47.767
47.551
46.768
46.569
46.281
45.274
45.071
44.818
43.970
43.798
43.563
28.293
S28
NMR spectra of linear arylopeptoid popo-11 (CDCl3)
ppm (t1)
050100150
172.503
172.293
172.078
171.502
171.412
171.186
170.707
170.466
169.569
169.292
156.027
155.913
155.824
143.222
142.785
142.077
139.108
138.852
138.265
137.804
135.467
135.202
135.147
134.983
134.851
134.600
134.386
134.102
134.021
133.915
130.287
129.951
129.470
129.332
129.192
129.044
128.913
127.976
127.788
127.668
127.587
127.397
127.205
126.930
126.603
126.474
126.207
125.777
125.559
79.996
70.505
70.264
70.114
69.962
69.758
69.393
69.282
58.711
58.665
58.608
58.546
53.124
48.373
47.714
46.764
46.621
46.221
45.226
44.998
44.154
43.775
28.289
OH
O
2
N
OMe
ON
Boc
OMe
S29
NMR spectra of linear arylopeptoid popopo-12 (CDCl3)
ppm (t1)
050100150
172.432
172.260
172.076
171.440
171.216
170.706
170.481
169.096
168.886
155.882
143.120
142.010
138.918
138.288
137.831
135.546
135.307
135.210
134.770
134.086
133.890
130.259
129.929
129.473
129.315
129.193
129.023
127.995
127.930
127.820
127.642
127.405
127.196
126.983
126.494
126.216
126.019
125.837
125.571
79.980
70.528
70.289
70.147
70.027
69.336
58.665
58.609
58.542
53.131
53.016
51.222
48.405
47.751
46.287
45.271
44.217
43.837
28.296
OH
O
3
N
OMe
ON
Boc
OMe
S30
NMR spectra of macrocyclic arylopeptoid cyclo-pppp-13 (CDCl3)
ppm (t1)050100150
171.502
138.367
135.701
127.022
126.776
71.026
58.810
53.482
44.817
S31
NMR spectra of macrocyclic arylopeptoid cyclo-pppppppp-14 (CDCl3)
ppm (t1)050100150
171.979
139.021
138.810
135.443
127.887
127.177
126.764
70.836
70.337
58.857
53.755
48.052
44.762
S32
NMR spectra of macrocyclic arylopeptoid cyclo-pppppp-15 (CDCl3)
ppm (t1)050100150
171.883
138.905
135.193
127.184
126.632
70.723
70.224
58.764
53.618
48.004
44.683
S33
NMR spectra of macrocyclic arylopeptoid cyclo-mmmm-16 (CDCl3)
S34
NMR spectra of macrocyclic arylopeptoid cyclo-mmmmmm-17 (CDCl3)
NO
O
O
N
O
N
OO
N
OO
N
O
N
O
O
O
S35
NMR spectra of macrocyclic arylopeptoid cyclo-pmpm-18 (CDCl3)
S36
NMR spectra of macrocyclic arylopeptoid cyclo-pmpmpm-19 (CDCl3)
S37
NMR spectra of macrocyclic arylopeptoid cyclo-momo-20 (CDCl3)
ppm (t1)050100150
172.363
171.767
171.312
170.324
169.691
138.167
137.170
136.591
135.325
134.535
133.855
133.601
133.090
129.540
129.276
129.028
128.802
128.566
128.372
127.954
127.689
127.270
126.991
126.556
126.250
125.954
125.743
125.268
124.885
124.746
124.561
70.706
70.378
70.171
70.047
69.903
69.375
58.800
58.729
58.656
58.464
51.620
51.326
50.691
48.244
47.413
46.424
46.179
43.978
42.951
S38
NMR spectra of macrocyclic arylopeptoid cyclo-momomo-21 (CDCl3)
ppm (t1)050100150
172.185
171.257
170.435
137.926
136.996
136.800
134.959
134.269
133.829
129.317
129.122
128.731
127.505
127.118
126.500
126.249
126.126
70.149
69.831
58.703
58.591
50.712
48.392
47.264
46.169
45.968
45.309
45.154
43.724
43.556
S39
NMR spectra of macrocyclic arylopeptoid cyclo-popo-22 (CDCl3)
N
N
O
O
O
O
N
O
O
N
OO
S40
NMR spectra of macrocyclic arylopeptoid cyclo-popopo-23 (CDCl3)
S41
NMR study
Figure S1: 1H NMR spectra of pppp-13 at different concentrations in CDCl3 at 298K (black curve 0.2
mM, blue curve 1 mM, purple curve 5 mM).
Figure S2: Variable temperature study of pppp-13 in CDCl3 (5 mM): 278 K (black curve), 288K (blue
curve), 298 K (purple curve).
Figure S3: 1H NMR spectra of pppp-13 in different solvents at 298K (black curve CDCl3, blue curve CD3CN, purple curve CD3OD).
S42
Figure S4: Variable temperature study of pppp-13 in CD3CN (5 mM): 278 K (black curve), 288K
(blue curve), 298 K (purple curve), 308 K (green curve), 318 K (red curve), 328 K (orange curve), 338
K (pale green curve) and 343 K (pink curve).
Figure S5: Variable temperature study of momo-20 in CD3CN (2 mM): 268 K (black curve), 278 K
(blue curve),288K (purple curve), 298 K (green curve), 308 K (red curve), 318 K (orange curve), 328
K (pale green curve).
S43
Figure S6: Variable temperature study of popo-22 in CD3CN (5 mM): 278 K (black curve), 288 K (blue curve), 298K (purple curve), 308 K (green curve), 318 K (red curve), 328 K (orange curve), 338 K (pale green curve) and 343 K (pink curve).
Figure S7: 4-6 ppm region of the variable temperature study of popo-22 in CD3CN (5 mM): 278 K (black curve), 288 K (blue curve), 298K (purple curve), 308 K (green curve), 318 K (red curve), 328 K (orange curve), 338 K (pale green curve) and 343 K (pink curve).
S44
Figure S8: 1H NMR spectra of the macrocycle popo-22 in CDCl3 at 298K.
Figure S9: NOESY experiments of the macrocycle popo-22 in CDCl3 at 298K and zoom region.
S45
Figure S10: Variable temperature study of mmmm-16 in CD3CN (5 mM): 298 K (black curve), 288 K (blue curve), 278K (purple curve), 268 K (green curve).
S46
X-Ray cristallography
Figure S11: Crystal packing of X-ray crystal structure of mmmm-16 in CDCl3 at 298K and zoom
region.
S47
Molecular modelling2
On the basis of the different crystallographic structures obtained for the macrocycles pppp-13,
mmmm-16, momo-20 and popo-22, we propose by molecular modeling two models for the pmpm
system build as a centrosymmetric form for the first one and as a C2 symmetric form for the second
one, both with a cis-trans-cis-trans conformation of the backbone amides (Figure S12). Each model
was constructed using the chimera software.3 Molecular dynamics was performed using NAMD4 and
the charmm225 force field parameters. From each dynamics, the lowest energy structures have been
optimized at the DFT//B3LYP/6-31g(d,p) level of theory using the Gaussian G09 software.6
The observation of the variation of two dihedral angles ψ and θ of each monomer (Figure S13) over
each dynamics as well as the comparison of the energies calculated by DFT, suggest that the most
likely structure may be the second model (Figure S12b).
Figure S12. Computational models for cyclotetramer pmpm-18 (a) model build as a centrosymmetric form and (b) model build as a C2 symmetric form.
(a)
(b)
Figure S13. Dihedral angles: For ortho series: ψ [Caa; Cab; C(i); N(i+1)], θ [Cab; Caa; Ca(i); N(i)]; For meta series: ψ [Cab; Cac; C(i); N(i+1)], θ [Cab; Caa; Ca(i); N(i)], For para series: ψ [Cac or ae;
Cad; C(i); N(i+1)], θ [Cab or af; Caa; Ca(i); N(i)].