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S1
– Supporting Information (SI) –
Ring-Closing Metathesis Approaches for the Solid-Phase Synthesis of Cyclic Peptoids
Sharaf Nawaz Khan,† Arim Kim,† Robert H. Grubbs,‡ and Yong-Uk Kwon*,†
† Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, South Korea;
E-mail: [email protected]
‡ The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Table of contents
General methods ------------------------------------------------------------------------ S2
Peptoid synthesis ---------------------------------------------------------------------- S2
General procedure for RCM of peptoids under microwave conditions ---------- S2
General procedure for RCM of peptoids at 40oC ----------------------------------- S3
General TFA cleavage procedure and reverse-phase HPLC ------------------------ S3
Ozonolysis of cyclic peptoid --------------------------------------------------------- S3
Abbreviations ---------------------------------------------------------------------------- S3
References ------------------------------------------------------------------------------- S3
Table S1. MALDI-MS data of synthesized peptoids ------------------------------- S4
Figure S1. Amines and RCM catalysts employed in this study --------------------- S5
Table S2. RCM of peptoids (1-4) containing allylamines ------------------------ S5
Figure S2-S22. Schemes, HPLC chromatograms and MALDI-TOF spectra ----- S6-S26
S2
General methods
Chemical reagents were purchased from commercial sources and were used without further purification
unless noted otherwise. Methylamine was used as 2 M solution in THF and glycine tert-butyl ester acetic
acid was neutralized with aq. Na2CO3 and extracted with DCM prior to use. Moisture sensitive reactions
were performed under nitrogen or argon atmosphere. CH2Cl2 was dried over calcium hydride. Grubbs
Catalyst 1st generation (G1), Grubbs catalyst 2nd generation (G2) and Hoveyda-Grubbs Catalyst 2nd
Generation (HG2) were purchased from Aldrich. Rink Amide AM resin LL (0.4 mmol/g) and TentaGel
MB RAM (0.4 mmol/g) were purchased from Novabiochem. Reverse-phase HPLC experiments were
conducted through an ACE 5 C18-HL (250 x 4.6mm) reverse phase column on a Shimadzu binary HPLC
system equipped with a UV-visible detector at 220 nm. The typical flow rate for analytical HPLC was 1
mL/min. In all cases, a gradient elution of water/acetonitrile with 0.05% TFA was used. MALDI-TOF
MS was performed on a Voyager-DE STR biospectrometry workstation (Applied Biosystems) with α-
hydroxy cinnamic acid as a matrix. The peptoids were synthesized in an incubator shaker (JEIO TECH,
model SI-600R) or in a microwave oven (Daewoo, model KR-B200R). The microwave reactions were
performed at a power of 100 W for peptoid synthesis and at a power of 300 W for RCM reactions.
Peptoid synthesis
Peptoids were synthesized on Rink amide (1-5, 7-10, 15-16 and 19-23) and TentaGel (24-29) resins by
the conventional submonomer strategy.1 Peptoid syntheses were performed in 25 mL standard glass
peptide synthesis vessels. The resins were swelled in DMF at 25 oC for 1-2 h. Then DMF was drained,
and the beads were incubated 20% piperidine in DMF for 1 h and washed thoroughly with DMF (8 x 3
mL). The beads were treated with 2 M bromoacetic acid (1.0-1.5 mL) and 3.2 M DIC (1-1.5 mL) and
irradiated in a microwave oven (100 W) for 3 x 12 sec with shaking for 30 sec after each pulse. The beads
were thoroughly washed with DMF (8 x 3 mL) and then treated with primary amines (1-2 M, 2 mL) in
DMF in a microwave oven (100 W) for 3 x 12 sec with shaking for 30 sec after each pulse. Both acylation
and displacement were successively repeated to form the desired peptoid sequences. To prevent
inactivation of RCM catalyst from free amines, the peptoids were capped with Boc-anhydride (10 eq.)
and triethylamine (1 mL) in DCM (5 mL) and the beads were shaken for 2 h before being washed with
MeOH (8 x 3 mL) and DCM (8 x 3 mL), and left to dry under vacuum for 2 h before RCM.
General procedure for RCM of peptoids under microwave conditions
The beads (15 mg) containing linear peptoids were swelled in DCB (1 mL) in reaction vessel for 30 min.
Then 2 mol% RCM catalysts were added and irradiated under microwave (300 W) for 4 x 30 sec (total 2
min) with shaking for 30 sec after each pulse. The resin was thoroughly washed with DCM (8 x 3 mL).
S3
General procedure for RCM of peptoids at 40oC
The beads (15 mg) containing linear peptoids were charged in reaction flask and allowed to swell in
anhydrous DCM (1 mL) for 30 min. Then 2 mol% RCM catalysts were added and refluxed at 40 oC under
nitrogen atmosphere for 2 h. The resin was thoroughly washed with DCM (8 x 3 mL).
General TFA cleavage procedure and reverse-phase HPLC
Peptoid-tethered resin was suspended in a cleavage cocktail (92% TFA/5% H2O/3% TIS) for 1-2 h. After
cleavage solution was removed by blowing N2 gas, 50% aq. acetonitrile containing 0.1% TFA was added
and mixed uniformly. The mixture was filtered through 0.2 µm PTFE filter tip and the obtained solution
was directly used for HPLC and MALDI-TOF analyses. Reverse-phase HPLC experiments were
conducted through a C18 reverse phase column on a Shimadzu binary HPLC system by using a gradient
elution of water/acetonitrile with 0.1% TFA. RCM products were produced as a mixture of E/Z isomers.
Ozonolysis of cyclic peptoid
The requisite cyclic peptoid was cleaved from resin by a cleavage cocktail, concentrated and dried. Then
cyclic peptoid was dissolved in DCM and cooled to -78 oC. Ozone gas was purged through the cooled
solution, which turned blue after a few minutes. Then ozone was bubbled further for 10 min.
Dimethylsulfide was added to the reaction mixture which turned it into clear solution. The reaction
mixture was warmed slowly to room temperature and the solvent was removed in vacuo.
Abbreviations
DMF: N,N-dimethylformamide, DCB: 1,2-dichlorobenzene, DCE: 1,2-dichloroethane, DCM: methylene
chloride, TFA: trifluoroacetic acid, TIS: triisopropylsilane, DIC: N,N′-diisopropylcarbodiimide, G1:
Grubbs Catalyst 1st generation [bis(tricyclohexylphosphine) benzylidine ruthenium(IV) chloride], G2:
Grubbs catalyst 2nd generation [1,3-bis-(2,4,6-trimethylphenyl)-2-
(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine) ruthenium], HG2: Hoveyda-
Grubbs Catalyst 2nd Generation [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-
isopropoxyphenylmethylene)ruthenium], RCM: ring-closing metathesis, HPLC: high-performance liquid
chromatography, MALDI-TOF: matrix-assisted laser desorption/ionization-time of flight.
References 1. (a) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am. Chem. Soc. 1992, 114,
10646-10647. (b) Olivos, H. J.; Alluri, P. G.; Reddy, M. M.; Salony, D.; Kodadek, T. Org. Lett. 2002, 4, 4057-4509.
S4
Table S1 MALDI-MS data of synthesized peptoids
Entry Peptoid MS (calcd.) MS (obs.) [M+H]+ [M+Na]+
1 3a 647.36 - 670.41 2 3b 619.33 - 642.37 3 3c 1266.70 - 1290.01 4 4a 875.51 - 898.84 5 4b 847.48 - 870.79 6 4c 1722.99 - 1746.65 7 5a 682.40 - 705.34 8 6 654.37 655.32 677.33 9 6a 1308.74 1309.78 1331.80 10 7a 381.24 382.09 404.06 11 8a 452.27 453.13 475.12 12 9a 523.31 524.27 546.26 13 10a 594.35 595.22 617.20 14 11 353.21 354.18 376.24 15 12 424.24 425.41 447.41 16 13 495.28 496.18 518.16 17 14 566.32 567.43 589.44 18 15a 438.26 439.09 461.07 19 16a 509.30 510.20 532.18 20 17 410.22 411.26 433.23 21 18 481.26 482.40 504.40 22 19a 491.27 492.20 514.22 23 20a 604.36 605.48 627.50 24 21a 719.42 720.09 742.08 25 22a 734.40 735.20 757.21 26 23a 832.51 833.36 855.36 27 24a 504.31 505.34 527.31 28 25a 682.33 683.34 705.36 29 26a 682.30 683.38 705.37 30 31 32 33 34 35 36 37 38 39 40 41 42 43
27a 28a 29a 30 31 32 33 34 35 36 37 38 39 40
795.42 734.40 847.40 463.24 576.33 691.39 706.36 804.47 476.27 654.30 654.26 767.38 706.36 819.45
- 735.21 848.75 464.40 577.53 692.39 707.41 805.69 477.39 655.15 655.35
- 707.51 820.68
818.60 757.21 870.74 486.41 599.55 714.38 729.39 827.64 499.40 677.12 677.32 790.62 729.51 842.69
44 41 723.38 724.17 746.17
S5
Figure S1. Amines and RCM catalysts employed in this study
NH2 NH2NH2O
NH2O
NH2
Methylamine (Nala)
Furfurylamine (Nffa)
Isobutylamine (Nleu)
2-Methoxyethylamine (Nmea)
Allylamine (Nall)
NH2
3-Buten-1-amine(Nbte)
H2NHN
BocH2N
O
O
O
O
NH2
Piperonylamine(Npip)
Glycine tert-butyl ester(Nasp)*
N-Boc-1,4-diaminobutane(Nlys)*
* Nlys and Nasp: protecting groups (Boc and tert-butyl) were removed with the treatment of 92% TFA at the cleavage step.
RuPh
Cl
Cl
PCy3
NMesMesN
G2
RuPh
Cl
Cl
PCy3
PCy3
HG2
RuCl
O
Cl
NMesMesN
G1
Ring-closing metathesis catalysts
Table S2. RCM of peptoids (1-4) containing allylamines
NH
NN
ON
BocO R
O
n
1: n = 2, Nall-Nleu-Nffa-Nall 2: n = 3, Nall-Nleu-Nmea-Nala-Nall3: n = 4, Nall-Nleu-Nffa-Nleu-Nmea-Nall4: n = 6, Nall-Nmea-Nleu-Nffa-Nala-Nmea-Nleu-Nall
Entry Peptoid Catalyst Solvent Temp. Time (h) Remarks 1 4-mer (1) G1 DCM 25 12 No RCM 2 4-mer (1) G2 DCM 25 12 No RCM 3 5-mer (2) G1 DCM 25 12 No RCM 4 5-mer (2) G2 DCM 25 12 No RCM 5 5-mer (2) G2 DCB 80 12-24 No RCM 6 5-mer (2) G2 DCE 80 12-24 No RCM 7 5-mer (2) G2 DCM MW 3 min No RCM 8 6-mer (3) G2 DCM 25 24 No RCM 9 6-mer (3) G2 DCM 40 48 No RCM 10 6-mer (3) G2 DCB 80 24 No RCM 11 6-mer (3) G2 DCE 80 24 No RCM 12 6-mer (3) HG2 DCB MW 2 min 10-20% 12 8-mer (4) G1 DCM 25 12 No RCM 13 8-mer (4) G2 DCM 25 12 No RCM 14 8-mer (4) G2 DCM MW 3 min No RCM 15 8-mer (4) HG2 DCB MW 2 min 10-20%
S6
33a (after cleavage)
NH
NN
NN
NO
O
O
O
O
O
O
O
NBoc
1. HG2, DCB300W µwave, 2min
2. 92% TFA
NH N
N
NN
NH2N
O O
OO
O
O
O
O
NH2N
NN
NN
O
O
O
O
O
O
O
O
HN
3c
H2NN
NN
NN
O
O
O
O
O
O
O
O
NH
3b
+
(a)
(b)
Figure S2. RCM of peptoid 3 using HG2 under microwave: (a) HPLC chromatogram and (b) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
1.4E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 670.4, 13743]
670.4100
642.3662
620.3910
672.4173644.3889172.0596 419.2865
1048.0 1181.4 1314.8 1448.2 1581.6 1715.0Mass (m /z)
0
8737.2
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 234.1, 12544]
1290.0130
1249.97311291.0129
1267.9830
1268.9640
1320.03721227.94051321.04691228.9159
1299.00241269.9889
1279.98391192.9449 1535.2141 1645.26731099.8646
3a
3c
3b
3a + 3b 3c
S7
1. HG2, DCB300W µwave, 2min
2. 92% TFA
NH
NN
NN
NO
O
O
O
O
O
O
O
N
O
NO
ON
Boc
H2NN
NN
NN
O
O
O
O
O
O
O
O
N
O
NO
ONH
N N
NN
NN
N NH
H2N
O
O
OO
OO
O
O
OO
O
H2NN
NN
NN
O
O
O
O
O
O
O
O
N
O
NO
ONH
+4b
4c
44a (after cleavage)
(a)
(b)
Figure S3. RCM of peptoid 4 using HG2 under microwave: (a) HPLC chromatogram and (b) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
732 784 836 888 940 992Mass (m /z)
0
2374
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 870.8, 2374]
870.7882 898.8437
871.7966 899.8431
900.8637872.8037
848.8011876.8268
849.8045 873.8117 901.8471
1303.0 1442.6 1582.2 1721.8 1861.4 2001.0Mass (m /z)
0
7629.9
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 1093.0, 9274]
1746.65461747.6631
1748.6643
1706.6095
1749.66971708.6305
1732.64261776.7041
4b
4c
4a
4a + 4b 4c
S8
49.0 339.4 629.8 920.2 1210.6 1501.0Mass (m /z)
0
3099
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 705.4, 3099]
705.3876
233.9947
212.0060
656.0564445.0191 679.3817
622.3172379.0903172.0173 707.4293384.2448 861.1063683.4246
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
3.0E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 677.3, 30413]
677.3287
655.3178
234.0008
172.0247190.0358
679.3351445.0074
657.3364294.0552
92% TFA
1. HG2, DCB300W mwave, 2min2. 92% TFA
H2N
N
N
N
N
O
O
O
ON
N
NH
O
O
O
O
O
NH
NN
NN
O
O
O
O
NN
NO
O
O
O O
5
Boc H2NN
NN
N
O
O
O
O
NN
NHO
O
O
O O
H2NN
NN
N
O
OO
O
NN
NHO
OO
OO
NH2NNN
N
O
OO
O
NN
HNO
OO
O O
5a
6 6a (a)
(b)
(c)
Figure S4. RCM of peptoid 5 using HG2 under microwave: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000mAU
Detector A:220nm
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
2.0E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 234.0, 20388]
234.0089212.0291
172.0402
190.0442
656.07441331.7976
707.4269 1309.7842445.0375
379.0941413.2733
1333.8063659.2934294.0851 861.1131 1388.82581106.6345650.0793192.0473 467.0775
6
6a
5a
6 6a
Common impurity
5a
Common impurity
S9
7
NH
NN
NN
O
O
O
O Boc
92% TFA
N
HNN
N
H2N
OO
OO
H2NN
NN
NH
O
O
O
O
7a
11
1. HG2, DCM 40oC, 2h2. 92% TFA
(a)
(b)
(c)
Figure S5. RCM of peptoid 7 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
49.0 339.4 629.8 920.2 1210.6 1501.0Mass (m /z)
0
6509
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 404.1, 6509]
404.0638
382.0870
150.0452
714.1162189.9759 406.0809 532.0865152.0440
384.0993233.9231 716.1320420.0401
110.0 198.6 287.2 375.8 464.4 553.0Mass (m /z)
0
3.0E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 376.2, 30059]
376.2361212.0435
234.0339
172.0497
190.0608
377.2280
362.2087173.0543191.0659
445.0782355.2390235.0411
202.1670 294.1068146.0702 340.2210 413.3026217.1185 380.1212 446.0859326.2599174.0609 256.0423
7a
11
7a
11
Common impurity
Common impurity
S10
92% TFANH
NN
NN
O
O
O
O
NO
Boc
8
HN
N
N
N
N
H2N
OO
O
O
O
8a
12
H2NN
NN
N
O
O
O
O
NHO
1. HG2, DCM40oC, 2h2. 92% TFA
(a)
(b)
(c)
Figure S6. RCM of peptoid 8 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
250
500
750
1000
1250
1500
1750
mAUDetector A:220nm
127.0 289.8 452.6 615.4 778.2 941.0Mass (m /z)
0
2.2E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 475.1, 21631]
475.1151
453.1273
476.1133
171.9816 674.1450
189.9850150.0540 532.1169
454.1292324.2379 675.1416233.9341152.0512 413.2699 856.1992342.1023 533.1227254.0713
79.0 259.2 439.4 619.6 799.8 980.0Mass (m /z)
0
3.6E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 447.4, 36001]
447.4097212.0962
425.4051
172.0970
234.0966
448.4108
656.3061379.2329
173.1014
445.2030191.1179235.1021
825.4122657.3217449.4039294.1829146.1083446.2106 861.4017192.1284 658.3137414.4293335.2271 747.8961193.5525
8a
12
12
8a
S11
92% TFANH
NN
NN
O
O
O
O
NO
9
NO Boc
H2NN
NN
N
O
O
O O
N
O
NHO
9a
13
H2NN
NN
N
O
O
O
O
NO
NHO
1. HG2, DCM 40oC, 2h2. 92% TFA
(a)
(b)
(c)
Figure S7. RCM of peptoid 9 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
mAUDetector A:220nm
49.0 339.4 629.8 920.2 1210.6 1501.0Mass (m /z)
0
1.2E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 546.2, 12481]
546.2619
150.0897 524.2683 674.3035172.0205 548.2640 816.3746
152.0870 532.2467324.3172998.4919457.4032 617.3020
49.0 319.6 590.2 860.8 1131.4 1402.0Mass (m /z)
0
1.9E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 518.2, 19176]
518.1627
496.1803
211.9776
190.0018646.1848520.1622379.0064 655.9183
9a
13
9a
13
S12
92% TFA
10a
H2N
N
N
N
N
O
O
O
ON
N
NH
O
O
O
NH
NN
NN
O
O
O
O
NN
NO
O
O
10
Boc
14
H2NN
NN
N
O
O
O
O
NN
NHO
O
O
1. HG2, DCM40oC, 2h2. 92% TFA
(a)
(b)
(c)
Figure S8. RCM of peptoid 10 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000mAU
Detector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
mAUDetector A:220nm
49.0 298.8 548.6 798.4 1048.2 1298.0Mass (m /z)
0
2382
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 617.2, 2382]
617.2024
595.2177
633.1839150.0650
332.2440
360.2789379.0082171.9893
958.3281211.9731 816.3099510.2001 674.2330283.1209 467.2117 652.2258 832.2457 1141.3926974.3255227.944555.4289
49.0 220.8 392.6 564.4 736.2 908.0Mass (m /z)
0
3437
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 589.4, 3437]
589.4371
567.4339360.4391
332.3939
605.4122590.4440
172.0615
212.0602 550.8026551.7762190.0786 361.4406
646.4711568.4439234.0530102.1320 523.7584 607.4033 794.4898228.0515 312.4248 495.7476417.1429 593.4164
10a
14
10a
14
S13
92% TFA
1. HG2, DCM 40oC, 4h2. 92% TFA
NH
NN
NN
O
O
O
O
NO
Boc
NH
NN
NN
H2N
O
O
O
O
O
H2NN
NN
N
O
O
O
O
NHO
15 15a
17 (a)
(b)
(c)
Figure S9. RCM of peptoid 15 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500mAU
Detector A:220nm
49.0 231.6 414.2 596.8 779.4 962.0Mass (m/z )
0
2.2E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 439.1, 21596]
439.0882
461.0719171.9768189.9838
440.0895378.9451
271.0816510.0866169.0344
368.0903283.0917188.9741 532.0916379.9448 674.1143293.9805100.0009 479.0481 842.1667214.0696
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
3602.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 433.2, 3602]
433.2256
411.2530
656.0971234.0163212.0288
445.0643
482.2778150.1023 659.3195 861.1547
17
15a
15a
17
S14
92% TFA
1. HG2, DCM 40oC, 4h2. 92% TFA
NH
NN
NN
O
O
O
O
NO
NO Boc
HN
N
N N
N N
H2N
O
O
OO
O
O
H2NN
NN
N
O
O
O
O
NO
NHO
16 16a
18 (a)
(b)
(c)
Figure S10. RCM of peptoid 16 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
mAUDetector A:220nm
57.0 266.6 476.2 685.8 895.4 1105.0Mass (m/z )
0
1.6E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 185.1, 15895]
185.0883
510.1964
171.9939
532.1849190.0038
202.1087 511.1913379.0166186.0924
342.1465191.0074 548.1561383.2655143.0554 240.0939 368.1532 512.2072 816.3097674.2400100.0182 230.2010 984.3814414.1885
3.0 252.8 502.6 752.4 1002.2 1252.0Mass (m /z)
0
2.1E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 482.4, 20701]
482.4007
234.0732
212.0887
172.0828
656.2527379.1867294.1628
506.3990143.1222 342.3093 861.3511534.4197 659.5060
16a
18
16a
18
S15
19
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
NH
NN
NN
O
O
O
O
O
O
Boc
N
HNN
N
H2N
OO
OO
OO
19a
30
H2NN
NN
NH
O
O
O
O
O
O
(a)
(b)
(c)
Figure S11. RCM of peptoid 19 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
250
500
750
1000
1250
1500
mAUDetector A:220nm
0 242.4 484.8 727.2 969.6 1212.0Mass (m /z)
0
2591.9
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 514.2, 2592]
514.2171
488.2017
185.0911
550.5698934.3843
233.9962
492.1946171.9926 304.2701610.1386379.023881.0227 912.3303227.1111 708.2416349.9945 552.6079214.1277 886.3416
49.0 236.2 423.4 610.6 797.8 985.0Mass (m /z)
0
7762.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 464.4, 7762]
464.3914486.3798
502.3496190.0997
465.3931
379.1998294.1638212.0892242.3443
437.6567234.074981.0496 488.3598230.3032 321.2999 504.3587102.1489 691.4464 825.3395192.1149 409.5342322.2960
19a
30
19a
30
S16
92% TFA
1. HG2, DCM40oC, 2h2. 92% TFA
20
NH
NN
NN
NO
O
O
O
O
O
BocO
HN
N
N
N
N
H2N
OO
O O
O
OO
31
H2NN
NN
NNH
O
O
O
O
O
O
O
20a
(a)
(b)
(c)
Figure S12. RCM of peptoid 20 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
1.1E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 627.5, 10799]
627.5010
1160.9213
605.4821150.1310
1162.9214912.760981.0484 251.1958 607.4758 1140.9074914.7657
49.0 439.4 829.8 1220.2 1610.6 2001.0Mass (m /z)
0
1.1E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 577.6, 10509]
577.5284172.0964
190.1032599.5454
615.5327
379.2192
251.2342550.7699
81.0512 601.5199299.330686.1161 617.5396412.4503 804.6040242.3748 585.5240
20a
31
20a
31
S17
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
21
NH
NN
NN
NO
O
O
O
O
O
O
O
NBoc
O
H2NN
NN
NN
O
O
O
O
O
O
O
O
NH
O
H2NN
NN
N
O
O
O O
N
O
NHO
O
O
O
21a
32 (a)
(b)
(c)
Figure S13. RCM of peptoid 21 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
mAUDetector A:220nm
5 9 .0 3 5 5 .2 6 5 1 .4 9 4 7 .6 1 2 4 3 .8 1 5 4 0 .0M a s s (m /z )
0
5 0 3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
% I
nte
ns
ity
Voyager Spec #1[BP = 742.0, 503]
742.0845
211.9306720.0935
233.9032378.9201
189.9499 494.1029 758.0743 971.1704357.0728
57.0 264.8 472.6 680.4 888.2 1096.0Mass (m /z)
0
2241
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 714.4, 2241]
714.3818
692.3948
715.3890
212.0156
693.3993233.9943
716.3947379.0829213.0199 656.0425
294.0982 730.3876 884.5115
21a
32
21a
32
S18
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
22
NH
NN
NN
NO
O
O
O
O
ON
Boc
O
HN
Boc
O
O
O H2NN
NN
NN
O
O
O
O
O
ONH
O
H2N
O
OH
O
22a
H2N
N
N
NN
O
O
OO
N
O
NH
O
O
OH
H2N
O
O
33 (a)
(b)
(c)
Figure S14 RCM of peptoid 22 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min-2000
-1000
0
1000
2000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
1000
2000
3000
4000
5000
mAUDetector A:220nm
288.0 404.4 520.8 637.2 753.6 870.0Mass (m /z)
0
3802.1
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 212.0, 5085]
757.2138
779.2020
378.9747
758.2274
780.2065655.8904735.2037444.9251
379.9831 478.8641 736.2257656.9279293.9866 413.1567360.2111 781.2208480.8844400.9268 773.1519472.9136
140.0 286.6 433.2 579.8 726.4 873.0Mass (m /z)
0
997
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 234.0, 997]
234.0270
212.0477
729.3941
656.0934
707.4111730.4017445.0705190.0628
213.0465 752.3738379.1215 657.1144
413.2671 708.4252235.0286731.4100467.0393294.1151 659.3775401.0886 747.6564167.0463 573.4932 680.7986
22a
33
22a
33
S19
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
NH
NN
NN
NO
O
O
O
O
O
O
O
NN
O
Boc
23
O
H2N
N
N
N
N
O
O
O
ON
N
NH
O
O
O
34
H2NN
NN
NN
O
O
O
O
O
O
O
O
NNH
O
O
23a
(a)
(b)
(c)
Figure S15. RCM of peptoid 22 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000mAU
Detector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
mAUDetector A:220nm
49.0 539.4 1029.8 1520.2 2010.6 2501.0Mass (m /z)
0
1158
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 855.3, 1158]
855.3629
833.35911616.6684
211.9812171.9890
846.4156631.1870 1392.5768369.3533
49.0 539.4 1029.8 1520.2 2010.6 2501.0Mass (m /z)
0
3944.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 827.6, 3944]
827.6380
805.6854212.0875
813.6438234.0716843.6446323.2789
34
23a
34
23a
S20
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
24
H2NN
NN
NH
O
O
O
O
H2N
N
N N
NH
O
O
O
O
O
NH2
NH
NN
NN
O
O
O
O BocO
24a
OH2N
35
NH
Boc
(a)
(b)
(c)
Figure S16. RCM of peptoid 24 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500mAU
Detector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000mAU
Detector A:220nm
99.0 479.4 859.8 1240.2 1620.6 2001.0Mass (m /z)
0
2153
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 527.3, 2153]
527.3146
234.0296505.3416212.0496
656.0890 861.1089379.1118529.3450 825.2214172.0564
112 249 386 523 660 797Mass (m /z)
0
189
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 499.4, 189]
499.3956
656.2065477.3921
234.0671
657.2514
445.1489212.0825413.3750 479.4006
173.1011 446.1458379.1852238.2268582.3571384.1998 679.9945501.3657305.0819152.1836
596.4554 721.8569658.2436417.1032213.0468 522.5560315.6186114.1412 449.0981
24a
35
24a
35
S21
92% TFA
1. HG2, DCM 40oC, 4h2. 92% TFA
25
H2NN
NN
NNH
O
O
O
O
O
O
OO
O
NH
NN
NN
NBoc
O
O
O
O
O
O
OO
O
25a
H2NN
N N
N
NHO
O
O
O
O
O
OOO
36 (a)
(b)
(c)
Figure S17. RCM of peptoid 25 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000
3500
mAUDetector A:220nm
49.0 264.4 479.8 695.2 910.6 1126.0Mass (m /z)
0
1.7E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 705.4, 16870]
705.3555
706.3561
212.0231
234.0174
172.0402
190.0465 683.3437656.0822135.0464
379.0829684.3468173.0449
294.071581.0241 435.2419 657.0855 825.1555
138.0 316.2 494.4 672.6 850.8 1029.0Mass (m /z)
0
877
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 677.5, 877]
677.5090
655.5122
678.5206
594.4417656.5414212.0972
234.0735 380.1961 693.5289610.4440 825.3647726.6063
25a
36
25a
36
S22
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
26
H2NN
NN
NNH
O
O
O
O
O
OH
H2NN
N N
N
NHO
O
O
O
O
O
OO
O
NH
NN
NN
NBoc
O
O
O
O
O
O
O
OO
O
26a
OOH
O
O
O
37 (a)
(b)
(c)
Figure S18. RCM of peptoid 26 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500mAU
Detector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
mAUDetector A:220nm
99.0 479.4 859.8 1240.2 1620.6 2001.0Mass (m /z)
0
963.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 705.4, 963]
705.3711
727.3699
683.3815
707.40421432.7236135.0681 721.3735 939.3519
128 292 456 620 784 948Mass (m /z)
0
1372
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 234.0, 1372]
234.0305
212.0498
677.3238
656.1547
699.3071445.0848
657.1227379.1305172.0601 655.3586413.3207 825.2135190.0527 700.3437294.1168 380.1420 628.5200495.3181 826.2196193.3511
26a
37
26a
37
S23
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
27
H2NN
NN
NN
O
O
O
O
O
O
O
O
NH
H2N
N
N
N
N
O
O
OO
N
O
NHO
OO
OO
NH
NN
NN
NO
O
O
O
O
O
O
O
NBoc
OO
27a
OO
38 (a)
(b)
(c)
Figure S19. RCM of peptoid 27 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
250
500
750
1000
1250
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
3000mAU
Detector A:220nm
99.0 579.4 1059.8 1540.2 2020.6 2501.0Mass (m /z)
0
961.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 818.6, 961]
818.6049
656.2267445.1163234.0724
821.5742
99.0 379.4 659.8 940.2 1220.6 1501.0Mass (m /z)
0
1.8E+4
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 790.6, 18326]
790.6245
234.0753
212.0905
707.5521172.0904
792.6264
656.2670379.1906 776.5809445.1710 825.3458592.4500135.0767 294.1654 861.3465709.5760
27a
38
27a
38
S24
92% TFA
1. HG2, DCM 40oC, 2h2. 92% TFA
28
NH
NN
NN
NO
O
O
O
O
ON
Boc
O
HN
Boc
O
O
O H2NN
NN
NN
O
O
O
O
O
ONH
O
H2N
O
OH
O
28a
H2N
N
N
NN
O
O
OO
N
O
NH
O
O
OH
H2N
O
O
39 (a)
(b)
(c)
Figure S20. RCM of peptoid 28 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
250
500
750
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500
mAUDetector A:220nm
284.0 404.4 524.8 645.2 765.6 886.0Mass (m /z)
0
3802.1
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 212.0, 5085]
757.2138
779.2020
378.9747
758.2274
780.2065655.8904735.2037444.9251
379.9831 478.8641 736.2257656.9279293.9866 413.1567360.2111 781.2208480.8844400.9268 773.1519472.9136
99.0 479.4 859.8 1240.2 1620.6 2001.0Mass (m /z)
0
5711
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 707.5, 5711]
707.5121
729.5093
751.5044
212.0528
656.2036234.0539445.1179 709.5157
413.3258773.5193172.0618
28a
39
28a
39
S25
92% TFA
1. HG2, DCM 40oC, 4h2. 92% TFA
29
NH
NN
NN
NO
O
O
O
O
O
O
N
O
H2NN
NN
N
O
O
O O
N
O
N
O
O
OH
H2N
NBoc
O
NH
Boc
29a
O
HN O
40
O
O
O
H2NN
NN
NN
O
O
O
O
O
O
O
N
OH
NHO
NH2
O
O
(a)
(b)
(c)
Figure S21. RCM of peptoid 29 using HG2 at 40 oC: HPLC chromatograms (a) before RCM and (b) after RCM, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
1000
2000
3000
4000
5000
mAUDetector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0
500
1000
1500
2000
2500mAUDetector A:220nm
99.0 579.4 1059.8 1540.2 2020.6 2501.0Mass (m /z)
0
831.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 892.7, 831]
892.7612
870.7437234.0802
212.0889
656.2713
848.7526445.1753
1734.5166172.0961 906.8028 1669.5093379.2087 674.5363 909.8647 1459.8564 1750.49221119.8789142.1555 372.4090
176 388 600 812 1024 1236Mass (m /z)
0
1146
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 842.7, 1146]
842.6901
820.6867
821.6681234.0714
843.6786
865.6817
656.2494212.0907445.1715
822.6769657.2509759.6526379.1855 866.6841
252.2975 834.6991371.3535 495.3786 679.2644
29a
40
40
29a
S26
H2NN
NN
N
O
O
O O
N
O
NHO
O
O
OH2N
NN
NN
NO
O
O
O
O
O
CHO
O
O
NH
CHO
O1) O3, CH2Cl2, 10min, -78oC
32 41
2) Me2S
(a)
(b)
(c)
Figure S22. Ozonolysis of cyclic peptoid 32: HPLC chromatograms (a) before ozonolysis and (b) after ozonolysis, and (c) MALDI-TOF spectra.
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0.0
0.5
1.0
1.5
2.0
mAU(x1,000)Detector A:220nm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 min
0.00
0.25
0.50
0.75
1.00
mAU(x1,000)Detector A:220nm
57.0 264.8 472.6 680.4 888.2 1096.0Mass (m /z)
0
2241
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 714.4, 2241]
714.3818
692.3948
715.3890
212.0156
693.3993233.9943
716.3947379.0829213.0199 656.0425
294.0982 730.3876 884.5115
99.0 579.4 1059.8 1540.2 2020.6 2501.0Mass (m /z)
0
378.0
0
10
20
30
40
50
60
70
80
90
100
% In
tens
ity
Voyager Spec #1[BP = 746.2, 378]
746.1662
211.9804
750.2259
229.0842
724.1721413.2020
736.2211655.9166
762.1436172.0021 659.1556
379.0520144.0446 702.1759666.1952190.0067
460.3304 782.1250 1419.4740186.0965 792.1578432.2406 1445.5151 2053.83531169.2840200.0610 826.1285573.6818 1692.19881440.4930 2057.17661182.2471849.3450238.4825 616.2788
32
41
32
41
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