Functionalized Helical Î²-Peptoids - The Journal of Organic Chemistry

Subscriber access provided by JAMES COOK UNIVERSITY LIBRARY

Featured Article

Functionalized Helical #-Peptoids Isabelle Wellhofer, Karla Frydenvang, Simona Kotesova, Andreas Moesgaard Christiansen, Jonas S Laursen, and Christian A. Olsen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00218 • Publication Date (Web): 13 Mar 2019 Downloaded from http://pubs.acs.org on March 19, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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

The Journal of Organic Chemistry

Functionalized Helical -Peptoids Isabelle Wellhöfer, Karla Frydenvang, Simona Kotesova, Andreas M. Christiansen, Jonas S. Laursen,# and Christian A. Olsen*

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark

Abstract: Peptidomimetic foldamers adopting well-defined three dimensional structures while being stable towards proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science. Despite their backbone flexibility, -peptoids containing N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chains can fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups onto robustly folded -peptoid helices by construction and incorporation of novel chiral building blocks. This is the first example of an X-ray crystal structure of a linear -peptoid, containing more than one type of side chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side chains protruding perpendicular to the helical axis, to provide a highly predictable display of functional groups. This work paves the way for development of -peptoid foldamers with a desired function, such as catalytic properties or as scaffolds enabling polyvalent display.

ACS Paragon Plus Environment

1

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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

Page 2 of 34

INTRODUCTION Peptoids, N-substituted peptidomimetics,1 feature desirable characteristics such as increased protease stability2 and cell permeability3 compared to peptides as well as ready access to sequence-defined oligomers containing a wide range of side chain functionalities. Peptoids have further been shown to adopt distinct three-dimensional structures such as turn mimetics,4-6 ribbons,7 sheets,8 helices,9-15 loops,16-17 bundles,18 and nanosheets19-22 and may thus be characterized as foldamers according to the definition coined by Gellman.23 Foldamers are molecules able to adopt well-defined secondary structures that either mimic or complement those exhibited by biopolymers.24-30 Peptoid secondary structures may further be combined to mimic tertiary structures18, 31 and may be decorated with functional groups to achieve metal-binding32-39 and catalysis,40-46 multivalent display4751,

recognition52-55 or biologically active ligands.56-64 However, each desired application may require an

individual fold, rendering it important to develop structures with novel folding properties as well as means to achieve control of the folding.25, 29, 65-70 We have been interested in a more sparsely investigated subcategory of the peptoids called -peptoids (N-alkyl--alanine oligomers),71-80 first described by Hamper et al.81 These peptidomimetics carry traits of both -peptoids and -peptides. Like in α-peptoids, their side chains are attached to the backbone amide bond nitrogen atom, resulting in a backbone without the capability to engage in hydrogen bonding. Due to the tertiary nature of these backbone amide bonds, they isomerize readily between the transoid and the cisoid conformation, which may be affected by the choice of side chain82-89 or introduction of thioamide bonds in the backbone.87, 90 These features are combined with an additional methylene group in the backbone as in -peptides.91-93 Although the -amino acids have additional degrees of freedom compared to -amino acids, they have been shown to complement peptide oligomers to form new secondary structures with strong folding propensities.91-97 Despite the challenges related to the lack of hydrogen bonding combined with the increased flexibility of the backbone, we have identified the N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chain to promote formation of triangular prism-shaped -peptoid helices.13, 80 However, these helices comprise exclusively hydrophobic side chains and the introduction of functional groups is necessary to improve solubility and enable applicability.98 Preliminary experiments in our laboratory indicated that various substitutions to the aromatic part of the side chains were detrimental to helical folding propensity. Instead, we here present the successful introduction of functional groups by elaborating the methyl group of the side chain, which results in retention of the helical folding while allowing for further functionalization of the foldamer surface.

RESULTS Role of Ns1npe side chains. Initially, we designed various hexamers containing side chains that had been structurally manipulated. We then relied on circular dichroism (CD) spectroscopy to evaluate folding propensity (see Figure 1, Scheme S1 and Figure S1 for details). In brief, introduction of side chains with an Rconfigured chiral center (2) furnished a mirror image CD spectrum as expected, while a stereochemically scrambled analog (3) gave rise to an entirely different CD spectrum (Figure S1). Furthermore, the positive


2

Page 3 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


maximum at 231 nm, which is believed to be indicative of helical folding,13 was significantly decreased when perturbing the structure by loss of a chiral center (4) or substitution of a single naphthyl for a phenyl group (5). Noteworthy, hexamer 4 exhibited a stronger helical signal than hexamer 5. Taken together, this might suggest that “insulation”/packing of the helical backbone from the environment is more important than having an allchiral oligomer. However, the potential importance of the strongly cis-amide inducing nature of Ns1npe is not addressed by these compounds. We therefore synthesized compounds 6–9 as outlined vide infra (Figure 2 and Scheme S2).

Figure 1. Structures of hexamers 1–5.

As a first attempt to integrate new functionalities into the helix design, we chose the highly cis-amide inducing triazolium group introduced by Taillefumier, Faure, and coworkers.85, 88 We found this strategy appealing due to the possibility of introducing a wide variety of side chains by Cu(I)-catalyzed azide–alkyne cycloaddition “click” chemistry.99-100 Applying this click reaction provided both chiral and achiral triazole-containing groups, incorporated at the peptoid trimer stage, which were coupled with an unmodified trimer to give compounds 6 and 7 (Figure 2A). Then, these oligomers were converted to their triazolium analogs (compounds 8 and 9) by alkylation using methyl iodide (Scheme S2). Unfortunately, the CD spectra of all the compounds, including 9, which contains both an -chiral and cis-inducing functionality, exhibited a lack of maximum at 231 nm (Figure 2B). Taken together with the loss of helicity for compounds 4 and 5, the results indicate, that packing of the naphthyl groups may be crucial for the robust helical folding previously reported. However, without highresolution structural information for compounds 5–9, it cannot be ruled out that the backbone remains folded while the CD signature changes due to loss of side chain interactions. Instead of attempting additional side chains recently shown to be cis-inducing,14, 101 we decided to focus on a strategy where the entire triangular prism-shaped helical core is kept intact and the protruding methyl groups are extended.


3


Page 4 of 34

Figure 2. Triazole- and triazolium-modified hexamers. (A) Structures of achiral (6, 8) and chiral (7, 9) triazole- or triazolium-containing oligomers. (B) CD spectra of compounds 6–9 compared to parent hexamer 1. Spectra were measured in MeCN (2060 M) at room temperature. The mean residue molar ellipticity [] is normalized with regards to number of residues and peptoid concentration.

Extension of side chains through the methyl group. To test the hypothesis that folding integrity might by retained by modifying the side chain methyl group, we first extended the side chain to (S)-1-(1naphthyl)pentylamine (12). We envisioned that hexamers containing the N-(S)-1-(1-naphthyl)pentyl (Ns1npp) side chain would form a helix with the alkyl chain protruding perpendicular to the helical axis. The amine building block 12 was previously prepared in racemic form102 from the corresponding ketone,103 and it was instead decided to apply the Ellman type Mannich reaction104-106 to achieve stereoselective synthesis of the Senantiomer (Scheme 1A). 1-Naphthaldehyde and tert-butanesulfinamide were condensed to give the tertbutanesulfinimine 10, which was then subjected to nBuLi to provide sulfinamide 11 with 90% d.r. determined by NMR of the crude material. After complete separation of the diastereoisomers as judged by 1H NMR, the auxiliary was cleaved with HCl to furnish building block 12 as the hydrochloride salt after precipitation from diethylether (65% yield over 3 steps). Enantiomeric purity was confirmed using Marfey’s reagent (Figure S2A). This building block was then introduced into trimer segments (14–17, Scheme 1B) by alternating azaMichael addition and acryloylation reactions as previously reported for homomers (13 and 18, Scheme 1B)13 (see Scheme S3 for details). Combination of trimer segments by HATU-mediated amide bond coupling furnished hexamers 19–22, presenting the extended hydrocarbon side chain at different positions along the helical axis (Figure 1C).


4

Page 5 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


The hexamers 19–22 were subjected to CD spectroscopy and compared to the parental structure 1. Gratifyingly, a spectrum similar to the parental helix was observed for all four variants including a strong maximum around 231 nm, suggesting helical folding (Figure 3). In addition, the cis–trans-amide bond ratios were determined using HSQC NMR experiments to provide equilibrium constants for the isomerization (Figure 3). The equilibrium constants exceeded 12 for all hexamers 19–22 containing the butyl side chain. These findings support the results from CD analysis, indicating helical folding comparable to that of the parental hexamer 1 (Kcis/trans = 11). Thus, the introduction of a longer alkyl side chain does not appear to affect the folding propensity of the -peptoid hexamers and we therefore chose this strategy to add functional groups at this position as well. Scheme 1. Synthesis of -Peptoid Hexamers with Extended Side Chains. (A) Synthesis of (S)-1-(1-Naphthyl)pentyl1-amine. (B) Structures and Combinations of Trimers. (C) Structures of Hexamers 19–22.a

aReagents

and conditions: (a) t-butanesulfinamide (1 equiv), 1-naphthaldehyde (1.1 equiv), Ti(OEt)4 (2 equiv), THF, N2, rt, 6 h; (b) n-BuLi (2 equiv), THF, N2, –78 °C, 2 h; (c) 2 M HCl in Et2O–MeOH 1:1, rt, 1 h.


5


Page 6 of 34

Figure 3. CD spectra of compounds 1 and 19–22 measured in MeCN (3070 M) at room temperature. The mean residue molar ellipticity [] is normalized with regards to number of residues and peptoid concentration. Overall Kcis/trans values for amide bond rotamers were measured by HSQC NMR in benzene-d6. aThe signals from the methine protons of side chains adopting the trans-amide conformation were below the detection limit.

X-ray diffraction crystallography. Gratifyingly, we were able to crystallize compound 21 by vapor diffusion from a mixture of toluene and acetonitrile to provide diffraction quality crystals. The X-ray diffraction crystal structure was solved to provide atomic scale insight into the three-dimensional structure (Figure S3 and Table S1). In agreement with the results from CD spectroscopy, the solid state structure of compound 21 is helical and closely resembles the crystal structure of parental compound 1 (Figure 4A). The torsion angles have similar values as the parental structure (Table 1), which is also reflected in the low RMSD = 0.228 obtained when pair-fitting all backbone atoms using the PyMol software (Figure S4). Thus, the new helix features three residues per turn and a helical pitch of 9.9 Å. The naphthyl residues align along the helical axis, covering the backbone with three highly regular faces that give rise to an overall triangular prism-shaped structure. The butyl side chain in residue 3 protrudes from the surface (Figure 4B). The top view of the helix shows an equilateral triangle with all naphthyl groups aligned along each helical face (Figure 4C). Interestingly, the crystal packing differs from the parental structure. In order to accommodate the butyl side chains, two helices face each other at an angle of approximately 110 °C (Figure 4D). Overall, this structure provides evidence supporting the conclusions drawn from the CD spectroscopy data. Together, the data shows that the elaboration of the methyl side chain does not affect the helical folding. Judging from the X-ray diffraction crystal structure, this strategy can accommodate even more sterically demanding functionalities without perturbing the folding. Table 1. Torsion Angles of Compounds 1 and 21

angle









1b

2c

1a

97.4°

166.0°

–173.9°

–13.4°

56.3°

–73.8°

21d

91.2°

163.4°

–176.2°

–4.0°

54.1°

–74.8°

aValues

were reported in reference 13. bMeasured by the naphthyl substituent. cMeasured by the methyl substituent. at residue 5 in the structure to give representative values for a residue within the helix.

dMeasured


6

Page 7 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


Figure 4. Single crystal X-ray diffraction structure of compound 21. (A) View perpendicular to the helical axis. (B) Side view in space filling representation, showing the packing of the naphthyl groups along the faces of the helix. The methyl groups are shown in tan and the protruding butyl group in green. (C) Top view down along the helical axis, showing packing of the helices. (D) Crystal packing shown perpendicular to the helical axis, demonstrating how the butyl side chains are accommodated in the solid state.

Functionalization of -peptoid helices. Encouraged by these results, we investigated the possibility of introducing functional groups into the alkyl side chain. An amino group was chosen and the respective Alloc protected building block 27 was synthesized as outlined in Scheme 2A. First, 3-bromopropylamine hydrobromide was protected to give 1-(3-bromopropyl)-2,5-dimethyl-pyrrole (23), which is stable in presence of nBuLi. Compound 23 was subjected to a lithium–halogen exchange and reacted with sulfinimine 10 in situ to give compound 24. Attempts to directly remove the auxiliary under acidic conditions at this stage led to side reactions of the pyrrole ring. In addition, the harsh conditions for pyrrole deprotection – reflux in presence of hydroxylamine – were anticipated to be problematic at a late stage in the synthesis. Therefore, we decided to change the protecting group to allyloxycarbonyl (Alloc), which can be readily removed under mild conditions. Acidic cleavage of the chiral auxiliary provided the chiral building block 27 after column chromatography in an overall yield of 20% over 6 steps.


7


Page 8 of 34

Scheme 2. Amino-Functionalized -Peptoid Oligomers. (A) Synthesis of Protected Chiral Diamine Building Block. (B) Synthesis of Oligomers 32 and 33. (C) Piperazine Modified Compound 34.a

Reagents and conditions: (a) (i) 23 (2 equiv), nBuLi (2 equiv), THF, N2, –78 °C, 45 min; then (ii) 10 (1 equiv), THF, N2, –78 °C, 45 min. (b) H2NOH•HCl (15 equiv), Et3N (10 equiv), 2-propanol–H2O 4:1, N2, reflux, 18 h. (c) Alloc-Cl (1.2 equiv), iPr2NEt (2 equiv), CH2Cl2, N2, 0 °C → rt, 1.5 h. (d) 2 M HCl in Et2O–MeOH 1:1, rt, 1 h. (e) HATU (1.2 equiv), iPr2NEt (3 equiv), CH2Cl2, rt, 18 h. (f) Pd(PPh3)4 (10 mol%), Me2NH•BH3 (15 equiv), CH2Cl2, rt, 3 h.

a

No epimerization was observed judged by conjugation of the amine with Marfey’s reagent (Figure S2B). Using the same approach as described vide supra, the building block 27 was introduced into trimers (28 and 29, Scheme S4). Peptide coupling of 13 or 28 with 29 followed by Alloc removal using Pd(PPh3)4 provided ACS Paragon Plus Environment

8

Page 9 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


hexamers 32 and 33, respectively (Scheme 2B). We envisioned that the introduction of amino groups would enhance solubility in more polar solvents than benzene and toluene significantly. However, they could be used as chemical handles in order to attach other functionalities and in this case, their contribution to the hydrophilicity of the helix would be lost. Therefore, it was also decided to test a recently reported strategy for enhancement of aqueous solubility of peptoids without affecting secondary structure by conjugation of piperazine residues107 (Scheme 2C and Scheme S5). This moiety could be attached to any peptoid and increase hydrophilicity regardless of other functional groups incorporated on the helix.

Figure 5. CD spectra of functionalized peptoids 30 and 32–34. (A) CD spectra of 30 and 32 with and without Et3N addition (10 equiv). (B) CD spectra of 33 with and without Et3N addition (20 equiv). (C) CD spectrum of 34. The spectra were measured in MeCN (35–95 M) at room temperature. The mean residue molar ellipticity [] is normalized with regards to number of residues and peptoid concentration.

Table 2. Overall Kcis/trans Values for Amide Bond Rotamers Measured by HSQC NMR in Benzene-d6

compound

1

30

32

32+Et3N

33

33+Et3N 34

Kcis/trans

11.07e

12.8

9.9

all cisa

7.3

11.0

aThe

15.5

signals from the methine protons of side chains on trans–amides were below the detection limit.

The folding propensity was again investigated by CD spectroscopy (Figure 5) and determination of overall Kcis/trans values (Table 2). When measured in pure MeCN, a significant decrease in the band intensity at 231 nm was observed for the functionalized hexamer 32 (Figure 5A). Conversely, the Alloc protected hexamer 30 exhibited a similar maximum as the parental helix (1). We therefore speculated whether protonation of the amino group could affect folding propensity in MeCN. An effect of pH on folding is not unprecedented, as Shin and Kirshenbaum have described pH responsive folding of -peptoids containing carboxylic acid side chains.108 Thus, to rule out protonation of the amine as the cause of this difference in CD signature, a second CD measurement was carried out in MeCN with triethylamine (10 equiv) added. This gave rise to full recovery of the CD maximum at 231 nm of 32 (Figure 5A) and the same effect was observed for the bis-functionalized hexamer 33, which contains butylamine side chains at the 2nd and 5th position (Figure 5B). Piperazinecontaining hexamer 34 also gave rise to a CD spectrum similar to the parental hexamer (Figure 5C). The methodology of attaching piperazine residues to the termini therefore appears to be a valuable tool to increase ACS Paragon Plus Environment

9


Page 10 of 34

hydrophilicity of these -peptoids without affecting the secondary structure as reported previously for peptoids.32 Analysis of the Alloc protected -peptoid 30 and piperazine-modified 34 showed Kcis/trans values similar or higher than the parental hexamer, while the deprotected amine-containing peptoids 32 and 33 exhibited a slight decrease in Kcis/trans. Similar to the trends observed by CD spectroscopy, this could be caused by interference of the protonated amines and we therefore performed the HSQC NMR experiments in the presence of triethylamine as well. This led to an increase of the Kcis/trans, exhibiting similar or higher values then the parental hexamer (Table 2). We also tested the stability of the helical conformation of oligomer 33 towards external perturbation by heat or addition of MeOH, previously shown to denature the parent oligomer (1).13 The CD spectra showed a decrease of the signal at 231 nm when increasing temperatures (Figure 6A) and a heated sample, which was cooled down to room temperature, furnished a spectrogram similar to the original sample (Figure 6B). Changing the solvent composition by addition of varying amounts of MeOH also affected the intensity of the signal at 231 nm (Figure 6C). Taken together, these results indicate the presence of a both temperature- and solvent-dependent secondary structure of compound 33 in solution, in addition to the pH dependency discussed vide supra. Interestingly, the perturbing effect of MeOH appeared to be less pronounced than previously observed for the parent compound (1), which could simply be related to increased solubility. However, if the functionalized helices are in fact less prone to denaturing, this would be a useful feature with regard to potential future applications. Furthermore, it will be interesting to investigate the dynamics involved in the folding– unfolding processes caused by external stimuli.

Figure 6. CD spectra of functionalized peptoid 33. (A) CD spectra of 33 recorded at varying temperatures. (B) CD spectrum of 33 after cooling. (C) CD spectra of 33 in the presence of Et3N and varying amounts of MeOH. The spectra are measured in MeCN (50 M) and 20 equiv Et3N at room temperature unless otherwise noted. The mean residue molar ellipticity [] is normalized with regards to number of residues and peptoid concentration.

Finally, we analyzed hexamer 33 by CD spectroscopy in the near UV region (270–400 nm) together with a series of monomer model compounds, to investigate potential effects of folding on the CD signals arising from the naphthyl groups (Figure S5). Interestingly, the acetylated monomer gave rise to a negative maximum while the presumed folded oligomer 33 exhibited both negative and positive maxima (Figure S5B). Upon triethylamine addition, the negative maxima between 270 nm and 280 nm became more pronounced.


10

Page 11 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


In addition to achieving functionalization of the helical face as well as the N-terminus of our parent helix, without affecting its folding propensity significantly, we substantially improved upon the hydrophilicity as judged by HPLC. Thus, significant shifts in retention time were recorded when comparing to parent helix 1 132 (5.1 min), 133 (11.0 min), and 134 (6.7 min) (Figure S6).

DISCUSSION Our collective findings from CD spectroscopy, HSQC NMR spectroscopy, and X-ray diffraction crystallography provide strong evidence that preparation of the first functionalized -peptoid helices has been achieved. We report a strategy to introduce functional groups into a -peptoid helix without disrupting its three-dimensional structure. This design leaves previously discovered, helix-promoting, naphthyl groups in place while introducing functional side chains that protrude from the robustly folded triangular prism-shaped helix. Circular dichroism spectroscopy and measurement of overall Kcis/trans amide bond isomerism by HSQC NMR experiments provided preliminary evidence that extended hydrocarbon side chains would result in retained folding (compounds 19–22). In addition, single crystal X-ray diffraction crystallography provided high-resolution evidence for the envisioned helical conformation, which was in strong agreement with previously solved structures.13 Interestingly, this third X-ray diffraction crystal structure solved for a linear peptoid also revealed an alternative packing in the solid state compared to the previous two. Together with the trends observed by CD spectroscopy under various conditions in solution, this result provides further evidence that the observed structures arise from bona fide folding propensity and not merely crystal packing effects. The segment coupling strategy applied for the synthesis of the -peptoid oligomers allowed for the incorporation of variable building blocks on the desired positions in a convergent manner. To achieve the introduction of these custom synthesized side chains, we adopted the diastereoselective Mannich-type reaction developed by Ellman and co-workers.104-106 This method could also be extended beyond hydrocarbon side chains to give protected diamine building block 27. Thus, a robust strategy for introduction of further functional groups has been established for future studies. Introduction of building block 27 into hexamers furnished mono- and bis-functionalized hexamers (32 and 33), which, gratifyingly, exhibited the attributes of helical folding according to CD and HSQC NMR spectroscopy. Interestingly however, the extend of helical content as judged by these means were pH dependent, which is not unprecedented for peptoids containing side chains that engage in acid–base equilibria.108 The helical content of compounds 32 and 33 was decreased in acetonitrile (CD) and benzene-d6 (NMR) compared to parent compound (1), but the signals were rescued by addition of triethylamine. We hypothesize that this attribute could be utilized for the development of pH responsive materials; however, it will require further experiments to test this possibility. The aqueous solubility of these foldamers was also improved substantially by the N-terminal attachment of a piperazine moiety (compound 34), which did not affect the folding propensity. Potentially, this may be


11


Page 12 of 34

combined with functionalized side chains in the future to provide additive increase in the hydrophilicity of the compounds. Importantly, increased solubility achieved by either introduction of side chain functional groups and/or piperazine moieties will also enable construction of longer oligomers, as poor solubility has been the major obstacle for elongation beyond the hexamer length for Ns1npe-containing -peptoids. This may be important for designing functional molecules, although, there is also precedence for applications of shorter foldamers of 4–7 residues in length in catalysis,41-45, 109 protein surface binding ligands,110-111 or very recently as a molecular spring torsion balance.112 In summary, we have developed a strategy for preparation of functionalized -peptoid foldamers. Our design is unique among peptoids with the closest related oligomers being -peptoids containing Phe residues as side chains.108 Conversely, the aromatic part of structure-promoting side chains has mainly been the subject of functionalization previously.98,

113

The challenge associated with our strategy is that custom synthesized

building blocks are necessary to introduce the side chain functionalities. However, we provide robust synthetic methods to achieve this and envision future introduction of azide or alkyne “click” chemistry handles which will enable divergent, post-oligomerization functionalization. On the other hand, the present work provides evidence that exquisite predictability in display of functional groups can be achieved because the core surrounding the helix is untouched when applying this design. These findings are in contrast to most peptoid or -, -, and -peptide designs where mutation of residues to substitute functional groups is highly likely to affect folding. Furthermore, this is the first example of a high-resolution X-ray crystal structure solved for a linear oligomeric -peptoid, containing more than one type of side chain. The presented system is significant as it paves the way for development of -peptoid foldamers with a desired function. Efforts to introduce metalbinding groups into -peptoid helices for preparation of higher order structures such as helix bundles are currently ongoing in our laboratories, the results of which will be reported in due course.

EXPERIMENTAL SECTION General methods and materials. All chemicals and solvents were analytical grade and used without further purification. All reactions under a nitrogen atmosphere were performed in dry solvents. Dichloromethane, N,Ndimethylformamide (DMF) and tetrahydrofuran (THF) were retrieved from a solvent purification system. All reactions were monitored by thin-layer chromatography (TLC) using silica gel coated plates (analytical SiO260, F-254). Liquid column chromatography was performed on silica gel (particle size 40–63 m, or in case of vacuum liquid chromotography (VLC) 15–40 m). Ultra high-performance liquid chromatography (UPLC)mass spectrometry (MS) analyses were performed on an HPLC-system equipped with a C18 column (50 mm × 2.1 mm, 1.7 m, 100 Å) using a gradient of eluent I (0.1% HCOOH in water) and eluent II (0.1% HCOOH in acetonitrile) rising linearly from 0% to 95% of eluent II during t = 0.00–5.00 at a flow rate of 0.6 mL/min. Analytical reversed-phase HPLC was performed on a system equipped with a C8 column (250 × 4.6 mm, 5 m, 100 Å) and a diode array UV detector, using a gradient of eluent III (wateracetonitrileTFA, 95:5:0.1) and eluent IV (0.1% TFA in acetonitrile) rising linearly from 5% to 95% of eluent IV during t = 5–35 min (gradient A), from 50% to 95% of eluent IV during t = 5–40 min (gradient B) or from 50% to 95% of eluent IV during t = 5–25 min (gradient C) with a flow rate of 1.0 ml/min. Preparative HPLC purification was performed on a system equipped with a C8 column (250 × 21.2 mm, 5 m, 100 Å), a diode array UV detector ACS Paragon Plus Environment

12

Page 13 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


and an evaporative light-scattering detector (ELSD) at a flow rate of 20 mL/min. The applied gradients using eluent III (wateracetonitrileTFA, 95:5:0.1) and IV (0.1% TFA in acetonitrile) are specified for each individual compound. Fractions containing the target compound were identified using UPLC-MS and analytical HPLC. Selected fractions were pooled and lyophilized. 1H NMR and 13C NMR spectra were recorded at 298 K with a cryogenically cooled probe, at 600 MHz and 151 MHz, respectively. Chemical shifts are reported in ppm, relative to deuterated solvent as internal standard (H = CDCl3 7.26 ppm, CD3OD 3.31 ppm, CD3CN 1.94, C6D6 7.16; C = CDCl3 77.16, CD3OD 49.00, CD3CN 1.32, C6D6 128.06). Coupling constants (J) are reported in Hz. Multiplicities of NMR signals are reported as follows: s, singlet; br, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Assignments of peak identities are based on 2D NMR experiments (COSY, HSQC, HMBC). The following abbreviations are used for assignments: CHar, aromatic proton/carbon; Cq, quaternary carbon. High-resolution mass spectra (HRMS) were recorded using quadrupole time-of-flight (TOF) mass spectrometer equipped with an electrospray (ESI) source. Alternatively, they were recorded on an UHPLC equipped with a diode array detector and coupled to a QTOF mass spectrometer operated in positive electrospray or by either MALDI or ESI. Crystallization – vapor diffusion. The peptoid hexamer (5 mg) was placed in a 1.5 mL vial and dissolved in a minimum amount of toluene. The small vial was placed in a 20 mL vial and the space around it was filled with 2 mL acetonitrile. The large vial was closed tightly and left for vapour diffusion at room temperature. The crystals were formed within 23 weeks but were left in the solvent until X-ray diffraction experiments were carried out. X-ray crystallographic analysis of compound 21. Single crystals suitable for X-ray diffraction studies were grown from a solution in toluene and acetonitrile. A single crystal was mounted and immersed in a stream of nitrogen gas [T = 123(1) K]. Data were collected, using graphite-monochromated MoK radiation ( = 0.71073 Å) on a diffractometer. Data collection and cell refinement were performed using the Bruker Apex2 Suite software.114 Data reduction using SAINT115 and multi-scan correction for absorption using SADABS-2016-2116 were performed within the Apex2 Suite. The crystal data, data collection and the refinement data are given in Table S1. Structure solution and refinement of compound 21. Positions of all non-hydrogen atoms were found by direct methods (SHELXS97).117 Full-matrix least-squares refinements (SHELXL97)117 were performed on F2, minimizing w(Fo2 – kFc2)2, with anisotropic displacement parameters of the non-hydrogen atoms, except for acetonitrile. Acetonitrile was refined with isotropic displacement parameters due to partial occupancy and observed disorder. Toluene was refined with fixed geometry as a regular aromatic ring. The positions of hydrogen atoms were located in subsequent difference electron density maps and were included in calculated position with fixed isotropic displacement parameters (Uiso = 1.2Ueq for CH and CH2 and Uiso = 1.5Ueq for CH3). Refinement (space group P21: 1139 parameters, 16109 unique reflections) converged at RF = 0.061, wRF2 = 0.129 [11758 reflections with Fo > 4(Fo); w-1 = ( 2(Fo2) + (0.0562P)2 + 0.5983P), where P = (Fo2 + 2Fc2)/3; S = 1.020]. The residual electron density varied between –0.27 and 0.32 eÅ-3. Non-centrosymmetric space group is assigned. The absolute configuration could not be determined (Flack = 0(2)).118 However, the configuration was known from stereoselective synthesis of compound 21. Complex scattering factors for neutral atoms were taken from International Tables for Crystallography as incorporated in SHELXL97.117, 119 Supplementary CIF, which includes fractional atomic coordinates, a list of anisotropic displacement parameters, and a complete list of geometrical data is available free of charge from the Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif (Compound 21: CCDC 1857129).


13


Page 14 of 34

Circular dichroism (CD) spectroscopy. Spectra were acquired with a spectrophotometer equipped with a water circulating bath and a nitrogen gas flowmeter with sensor. Measurements were carried out in 1 mm quartz cuvettes and compound solutions in acetonitrile were prepared using dry weight of the lyophilized material followed by dilution to give the desired concentrations. Concentrations were verified using a NanoDrop to measure the absorbance at  = 280 nm (A280 = ·c·l). The CD data were obtained at 298 K with a bandwidth of 1.00 nm, a scanning speed of 20 nm/min, 3 accumulations and a data integration time of 4 s. The measurements were performed in triplicates. Spectra were recorded in millidegree units (m°), corrected for solvent contributions and normalized to mean residue ellipticity [] = 100·m°/l·c·n, with c being the concentration in mM, l being the path length (0.1 cm) and n being the number of peptoid amide bonds. (S)-2-Methyl-N-(naphthalen-1-ylmethylene)propane-2-sulfinamide (10). To a 0.5 M solution of Ti(OEt)4 (10.4 mL, 11.3 g, 49.5 mmol, 2.00 equiv) in anhydrous THF under nitrogen atmosphere, 1-naphthaldehyde (3.70 mL, 4.25 g, 27.2 mmol, 1.10 equiv) and (S)-t-butanesulfineamide (3.00 g, 24.8 mmol, 1.00 equiv) were added. The reaction mixture was stirred at room temperature for 6 h. It was then poured into a flask with brine (100 mL) upon rapid stirring. The suspension was filtered through a pad of Celite, and the filter cake was washed well with EtOAc. The filtrate was washed with brine (2 × 100 mL) and the aqueous layer was extracted with EtOAc (1 × 50 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified using column chromatography (short flash column as product is labile on silica, 0→1.5% MeOH in CH2Cl2) to give the sulfinimide 10 as a yellow oil that solidified upon storage at 4 °C (5.40 g, 84%). Rf = 0.18 (CH2Cl2). 1H NMR (600 MHz, CD3CN):  = 1.27 (s, 9 H, 3 × CH3), 7.59 – 7.65 (m, 2 H, 2 × CHar), 7.66 – 7.71 (m, 1 H, CHar), 8.00 (d, J = 8.2 Hz, 1 H, CHar), 8.08 (d, J = 7.2 Hz, 1 H, CHar), 8.10 (d, J = 8.2 Hz, 1 H, CHar), 9.03 (d, J = 8.6 Hz, 1 H, CHar), 9.08 (s, 1 H, N=CH). 13C{1H} NMR (151 MHz, CD3CN):  = 22.7 (3 × CCH3), 58.1 (C(CH3)3), 125.3 (CHar), 126.4 (CHar), 127.6 (CHar), 129.2 (CHar), 129.9 (CHar), 130.4 (naphthyl-Cq), 131.9 (naphthyl-Cq), 133.4 (CHar), 134.3 (CHar), 135.0 (naphthyl-Cq), 163.6 (N=CH). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C15H18NOS+, 260.1104; found 260.1110. (S)-2-Methyl-N-((S)-1-(naphthalen-1-yl)pentyl)propane-2-sulfinamide (11). A solution of sulfinimide 10 (1.00 g, 3.86 mmol, 1.00 equiv) in anhydrous THF (100 mL) was cooled to –78°C and subsequently treated with dropwise addition of n-BuLi (2.30 M in hexane) (3.35 mL, 0.49 g, 7.71 mmol, 2.00 equiv). The reaction mixture was stirred at –78°C for 2 h and then quenched by addition of sat. aq. NH4Cl (15 mL). The mixture was diluted with EtOAc (20 mL), the phases were separated and the organic phase was washed with water (50 mL). Then it was dried over MgSO4 and concentrated in vacuo. The residue was purified by VLC (5→12.5% EtOAc in heptane) to give sulfinamide 11 as a yellow oil (781 mg, 63%). Rf = 0.35 (heptane– EtOAc, 2:1). 1H NMR (600 MHz, CD3CN):  = 0.85 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.13 (s, 9 H, 3 × CCH3), 1.26 – 1.35 (m, 3 H, CH2CH2CH2/CH2CH3), 1.36 – 1.43 (m, 1 H, CH2CH2CH2), 1.96 – 2.03 (m, 2 H, NCHCH2), 4.32 (d, J = 6.8 Hz, 1 H, NH), 5.10 (q, J = 6.8 Hz, 1 H, NCH), 7.49 – 7.53 (m, 2 H, 2 × CHar), 7.56 (ddd, J = 8.5, 6.8, 1.5 Hz, 1 H, CHar), 7.64 (d, J = 6.7 Hz, 1 H, CHar), 7.82 (d, J = 8.2 Hz, 1 H, CHar), 7.91 – 7.93 (m, 1 H, CHar), 8.21 (d, J = 8.5 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3CN):  = 14.3 (CH3), 23.0 (3 × CCH3), 23.2 (CH2CH3), 29.3 (CH2CH2CH2), 38.0 (NHCHCH2), 56.2 (NCH), 56.5 (C(CH3)3), 124.1 (CHar), 125.4 (CHar), 126.4 (CHar), 126.6 (CHar), 127.1 (CHar), 128.7 (CHar), 129.8 (CHar), 131.8 (naphthyl-Cq), 134.9 (naphthyl-Cq), 140.5 (naphthyl-Cq). UPLC-MS tR = 2.20 min, m/z: calcd for [M + H]+, C19H28NOS+, 318.19; found 318.53. (S)-1-(1-Naphthyl)pentyl-1-amine·HCl (12). The sulfinamide 11 (120 mg, 0.378 mmol, 1.00 equiv) was dissolved in a 1:1 mixture of MeOH and 2.0 M HCl in diethyl ether (6.00 mL) and stirred at room temperature for 1 h. The mixture was concentrated and precipitated with diethyl ether. After cooling to 5 °C for 1 h, the precipitate was collected by filtration and washed with diethyl ether to give the amine hydrochloride 12 as a white solid (81.3 mg, 86%). Rf = 0.68 (10% MeOH, 0.25% NH3 in EtOAc). 1H NMR (600 MHz, CD3OD):  = 0.87 (t, J = 7.2 Hz, 3 H, CH3), 1.18 – 1.27 (m, 1 H, CH2CH2CH2), 1.31 – 1.42 (m, 3 H, CH2CH2CH2/CH2CH3), 2.08 – 2.20 (m, 2 H, NCHCH2), 5.25 (t, J = 7.3 Hz, 1 H, NCH), 7.57 – 7.62 (m, 2 H, 2 × CHar), 7.65 (ddd, J = 8.5, 6.8, 1.4 Hz, 1 H, CHar), 7.68 (dd, J = 7.3, 1.1 Hz, 1 H, CHar), 7.97 (m, 2 H, CHar), 8.17 (d, J = 8.5 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3OD):  = 14.1 (CH3), 23.4 (CH2CH3), 28.9 ACS Paragon Plus Environment

14

Page 15 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


(CH2CH2CH2), 36.0 (NCHCH2), 51.2 (NCH), 123.1 (CHar), 124.5 (CHar), 126.5 (CHar), 127.4 (CHar), 128.3 (CHar), 130.3 (CHar), 130.7 (CHar), 132.3 (naphthyl-Cq), 134.7 (naphthyl-Cq), 135.5 (naphthyl-Cq). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C15H20N+, 214.1590; found 214.1597. 1-(3-Bromopropyl)-2,5-dimethyl-1H-pyrrole (23). A solution of KOH (0.51 g, 9.14 mmol, 1.00 equiv) in MeOH (4.00 ml) and water (0.20 ml) was added over 1 h to a mixture of 3-bromopropylamine hydrobromide (2.00 g, 9.14 mmol, 1.00 equiv), hexane-2,5-dione (1.29 ml, 1.25 g, 10.9 mmol, 1.20 equiv) and MeOH (5.00 ml) which was boiling under reflux. The reaction mixture was refluxed for 2 h more, cooled and diluted with Et2O (10 mL). It was washed with brine, 2 M aq. HCl, sat. aq. NaHCO3, and brine (10 mL each). The organic phase was dried over Na2SO4 and the solvent was evaporated. The bromide 23 was obtained as a yellow oil that turned brown upon storage at 4 °C. Rf = 0.65 (heptane–EtOAc, 3:1). 1H NMR (600 MHz, CD3CN):  = 2.09 – 2.12 (m, 2 H, CH2CH2CH2), 2.18 (s, 6 H, 2 × CH3), 3.47 (t, J = 6.4 Hz, 2 H, CH2Br), 3.86 – 3.91 (m, 2 H, NCH2CH2), 5.65 (s, 2 H, pyrrole-CH). 13C{1H} NMR (151 MHz, CD3CN):  = 12.6 (2 × CH3), 31.8 (CH2Br), 34.6, (CH2CH2CH2), 42.6 (NCH2), 106.3 (2 × pyrrole-CH), 128.0 (2 × CCH3). UPLC-MS tR = 2.13 min, m/z: calcd for [M + H]+, C9H15BrN+, 216.04; found 216.05. (S)-N-((S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(naphthalen-1-yl)butyl)-2-methylpropane-2-sulfinamide (24). Bromide 23 (2.66 g, 12.3 mmol, 2.00 equiv) was dissolved in dry THF (130 mL) and cooled to –78 °C under nitrogen atmosphere. Then, n-BuLi (4.94 mL, 0.79 g, 12.3 mmol, 2.00 equiv) was added over 30 min and the mixture was stirred at –78 °C for 1 h. A solution of the aldimine 10 (1.60 g, 6.17 mmol, 1.00 equiv) in dry THF (30.0 mL) was added dropwise and the reaction mixture was stirred at –78 °C for 1.5 h. The reaction was quenched by addition of sat. aq. NH4Cl (40 mL). The mixture was diluted with EtOAc (50 mL) and the organic phase was washed with water (100 mL). The aqueous phase was extracted with EtOAc (2  100 mL) and the combined organic phases were dried with MgSO4. The solvent was evaporated and the crude residue was purified by column chromatography (heptane–EtOAc, 3:1→2:1) to give the product 24 as a yellow oil (1.27 g, 52%). Rf = 0.26 (heptane–EtOAc, 2:1). 1H NMR (600 MHz, CD3OD):  = 1.14 (s, 9 H, 3 × CH3), 1.58 – 1.68 (m, 1 H, CH2CH2CH2), 1.73 – 1.82 (m, 1 H, CH2CH2CH2), 2.02 – 2.06 (m, 2 H, CHCH2CH2), 2.07 (s, 6 H, 2 × pyrrole-CH3), 3.74 (t, J = 7.5 Hz, 2 H, CH2CH2CH2N), 5.15 (t, J = 7.0 Hz, 1 H, NCH), 5.60 (s, 2 H, pyrrole-CH), 7.45 – 7.50 (m, 2 H, 2 × CHar), 7.54 (ddd, J = 8.4, 6.7, 1.5 Hz, 1 H, CHar), 7.60 (d, J = 7.1 Hz, 1 H, CHar), 7.80 (d, J = 8.2 Hz, 1 H, CHar), 7.88 (dd, J = 8.1, 1.4 Hz, 1 H, CHar), 8.14 (d, J = 8.5 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3OD):  = 12.6 (2 × pyrrole-CH3), 23.1 (3 × C(CH3)3), 29.1 (CH2CH2CH2), 35.3 (CHCH2CH2), 44.0 (CH2CH2CH2N), 56.2 (NCH), 57.3 (C(CH3)3), 106.0 (2 × pyrrole-CH), 124.0 (CHar), 125.6 (CHar), 126.3 (CHar), 126.6 (CHar), 127.3(CHar), 128.1 (2 × pyrrole-Cq), 129.1 (CHar), 130.0 (CHar), 132.3 (naphthyl-Cq), 135.5 (naphthyl-Cq), 139.4 (naphthyl-Cq). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C24H33OSN2+, 397.2308; found 397.2308. (S)-N-((S)-4-amino-1-(naphthalen-1-yl)butyl)-2-methylpropane-2-sulfinamide (25). Under nitrogen atmosphere, the sulfinamide 24 (2.65 g, 6.68 mmol, 1.00 equiv) was dissolved in 80.0 mL 2-propanol–water 4:1. Triethylamine (9.26 mL, 6.76 g, 66.8 mmol, 10.0 equiv) and hydroxylamine hydrochloride (6.96 g, 100 mmol, 15.0 equiv) were added. The reaction mixture was stirred under reflux for 18 h. After total consumption of the starting material occurred, the mixture was cooled down to room temperature and diluted with EtOAc (50 mL). The phases were seperated and the organic phases were washed with 2 M aq. NaOH (3 × 30 mL). The aqueous phases were combined and extracted with EtOAc (3  100 mL).The combined organic phases were dried over MgSO4 and evaporated to dryness. The crude residue was purified by column chromatography (5% MeOH, 1% NH3 in CH2Cl2) to give the sulfinamide 25 as a yellow oil (1.30 g, 61%). Rf = 0.11 (5% MeOH, 1% NH3 in CH2Cl2). 1H NMR (600 MHz, CD3OD):  = 1.20 (s, 9 H, 3 × CH3), 1.48 – 1.59 (m, 1 H, CH2CH2CH2), 1.64 – 1.72 (m, 1 H, CH2CH2CH2), 2.06 – 2.14 (m, 2 H, CHCH2CH2), 2.64 – 2.74 (m, 2 H, CH2CH2CH2N), 5.21 (t, J = 7.0 Hz, 1 H, NCH), 7.50 – 7.55 (m, 2 H, 2 × CHar), 7.56 – 7.60 (m, 1 H, CHar), 7.71 (d, J = 6.9 Hz, 1 H, CHar), 7.84 (d, J = 8.2 Hz, 1 H, CHar), 7.91 – 7.93 (m, 1 H, CHar), 8.21 (d, J = 8.5 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3OD):  = 23.1 (3 × CH3), 30.7 (CH2CH2CH2), 35.8 (CHCH2CH2), 42.4 (CH2CH2CH2N), 56.4 (NCH), 57.4 (C(CH3)3), 124.0 (CHar), 125.7 (CHar), 126.4 (CHar), 126.6 (CHar), 127.3 (CHar), 129.0 (CHar), 130.0 (CHar), 132.3 (naphthyl-Cq), 135.5 (naphthyl-Cq), 139.8 (naphthyl-Cq). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C18H27OSN2+, 319.1839; found 319.1836. Allyl ((S)-4-(((S)-tert-butylsulfinyl)amino)-4-(naphthalen-1-yl)butyl)carbamate (26).Under nitrogen atmosphere, the sulfinamide 25 (1.26 g, 3.95 mmol, 1.00 equiv) was dissolved in 30.0 mL anhydrous CH2Cl2. ACS Paragon Plus Environment

15


Page 16 of 34

After cooling to 0 °C, iPr2NEt (1.38 mL, 1.02 g, 7.91 mmol, 2.00 equiv) and allyl chloroformate (0.51 mL, 572 mg, 4.74 mmol, 1.20 equiv) were added and the reaction mixture was stirred for 1 h at this temperature. After total consumption of the starting material occurred, the mixture was diluted with CH2Cl2 (10 mL) and washed with 0.1 M HCl (3 × 30 mL). The combined organic phases were dried over MgSO4 and the solvent was evaporated. The sulfinamide 26 was obtained as an orange foam (1.51 g, 92%). Rf = 0.20 (heptane–EtOAc, 1:3). 1H NMR (600 MHz, CD3OD):  = 1.17 (s, 9 H, 3 × CH3), 1.50 – 1.62 (m, 1 H, CH2CH2CH2), 1.63 – 1.74 (m, 1 H, CH2CH2CH2), 2.03 (q, J = 7.6 Hz, 2 H, CHCH2CH2), 3.13 (td, J = 6.9, 2.4 Hz, 2 H, CH2CH2CH2N), 4.49 (dt, J = 5.4, 1.6 Hz, 2 H, OCH2CH), 5.14 (dd, J =10.5, 1.5 Hz, 1 H, CH=CH2), 5.19 (t, J = 7.0 Hz, 1 H, NCHCH2), 5.26 (dd, J = 17.3, 1.9 Hz, 1 H, CH=CH2), 5.81 – 5.98 (m, 1 H, CH=CH2), 7.45 – 7.51 (m, 2 H, 2 × CHar), 7.51 – 7.56 (m, 1 H, CHar), 7.66 (dd, J = 7.3, 1.2 Hz, 1 H, CHar), 7.80 (d, J = 8.2 Hz, 1 H, CHar), 7.88 (dd, J = 8.1, 1.6 Hz, 1 H, CHar), 8.16 (d, J = 8.5 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3OD):   23.2 (3 × CH3), 28.0 (CH2CH2CH2), 35.6 (CHCH2CH2), 41.5 (CH2CH2CH2N), 56.3 (NCHCH2), 57.5 (C(CH3)3), 66.2 (OCH2CH), 117.3 (CH=CH2), 124.0 (CHar), 125.6 (CHar), 126.4 (CHar), 126.6 (CHar), 127.3 (CHar), 129.0 (CHar), 130.0 (CHar), 132.2 (naphthyl-Cq), 134.5 (CH=CH2), 135.4 (naphthyl-Cq), 139.9 (naphthyl-Cq), 158.8 (NCOO). UPLC-MS tR = 2.29 min, m/z: calcd for [M + H]+, C22H31O3SN2+, 403.20; found 403.19. Allyl (S)-(4-amino-4-(naphthalen-1-yl)butyl)carbamate (27). The sulfinamide 26 (1.49 g, 3.69 mmol, 1.00 equiv) was dissolved in 20.0 mL of a 1:1 mixture of MeOH and 2 M HCl in diethyl ether and stirred at room temperature for 1 h. The mixture was concentrated and the crude residue was purified by column chromatography (8% MeOH, 1% NH3 in EtOAc) to give the amine 27 as a yellow oil (1.02 g, 93%). Rf = 0.23 (8% MeOH, 1% NH3 in EtOAc). 1H NMR (600 MHz, CD3CN):  = 1.47 – 1.55 (m, 1 H, CH2CH2CH2), 1.57 – 1.63 (m, 1 H, CH2CH2CH2), 1.63 – 1.72 (m, 1 H, CH2CH2CH2), 1.79 – 1.88 (m, 1 H, CH2CH2CH2), 3.09 (q, J = 6.8 Hz, 2 H, CH2CH2N), 4.46 (d, J = 5.3 Hz, 2 H, OCH2CH), 4.73 (dd, J = 7.9, 5.2 Hz, 1 H, H2NCH), 5.14 (dd, J = 10.5, 1.6 Hz, 1 H, CH=CH2), 5.24 (dd, J = 17.2, 1.8 Hz, 1 H, CH=CH2), 5.63 (s, 1 H, NHCO), 5.85 – 5.93 (m, 1 H, CH=CH2), 7.47 – 7.51 (m, 2 H, 2 × CHar), 7.51 – 7.54 (m, 1 H, CHar), 7.66 (d, J = 6.8 Hz, 1 H, CHar), 7.77 (d, J = 8.2 Hz, 1 H, CHar), 7.88 – 7.91 (m, 1 H, CHar), 8.20 (d, J = 8.4 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CD3CN):  = 27.9 (CH2CH2CH2), 37.2 (CH2CH2CH2), 41.6 (CH2CH2CH2), 51.7 (H2NCH), 65.5 (OCH2CH), 117.2 (CH2=CH), 123.6 (CHar), 124.3 (CHar), 126.4 (CHar), 126.6 (CHar), 126.8 (CHar), 127.8 (CHar), 129.7 (CHar), 131.9 (naphthyl-Cq), 134.8 (CH2=CH), 134.9 (naphthyl-Cq), 144.2 (naphthyl-Cq), 157.2 (NCOO). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C18H23O2SN2+, 299.1754; found 299.1754. (Azidomethyl)benzene (S15). Benzyl bromide (500 mg, 2.90 mmol, 1.00 equiv) was dissolved in a 4:1 mixture of acetone and water (30.0 ml). Sodium azide (235 mg 3.60 mmol, 1.50 equiv) was added, and the reaction was stirred for 18 h at room temperature. The mixture was washed with water (100 ml) and extracted with diethyl ether (3 × 100 ml), then concentrated in vacuo. The azide S15 was obtained as a clear oil (233 mg 60%). 1H NMR (600 MHz, CDCl3):  = 4.35 (s, 2 H, NCH2), 7.31 – 7.37 (m, 3 H, 3 × CHar), 7.38 – 7.42 (m, 2 H, 2 × CHar). 13C{1H} NMR (151 MHz, CDCl3):  = 55.0 (CH2N), 128.4 (2 × CHar), 128.5 (CHar), 129.0 (2 × CHar), 135.6 (Cq). The data is in agreement with the literature.120 (1-Benzyl-1H-1,2,3-triazol-4-yl)methanamine (S16). Azide S15 (65.8 mg, 0.48 mmol, 1.20 equiv) and propargylamine (22.0 mg, 0.40 mmol, 1.00 equiv) were dissolved in tert-butanol (1.00 ml) and water (1.00 ml). Then CuSO4 (4.84 mg, 0.02 mmol, 0.05 equiv), sodium ascorbate (56.1 mg, 0.27 mmol, 0.68 equiv) and TBTA (10.6 mg, 0.02 mmol, 0.05 equiv) were added. After stirring for 18 h, the reaction was quenched with water (100 ml) and extracted with CH2Cl2 (3 × 100 ml), dried with MgSO4 and concentrated in vacuo. The crude residue was purified via VLC (0→10% MeOH, 1% NH3 in CH2Cl2) yielding a white solid (42.0 mg, 56%). 1H NMR (400 MHz, CDCl3):  = 1.26 (s, 2 H, NH2), 3.96 (s, 2 H, CH2NH2), 5.50 (s, 2 H, PhCH2), 7.26 – 7.30 (m, 2 H, 2 × CHar), 7.33 – 7.40 (m, 4 H, 4 × CHar). UPLC-MS tR = 0.52 min, m/z: calcd for [M + H]+, C10H13N4+, 189.1; found 189.1. The data is in agreement with the literature.121 tert-Butyl (S)-but-3-yn-2-ylcarbamate (S17). Boc-L-alanine (946 mg, 5.00 mmol, 1.00 equiv), N,Odimethylhydroxylamine·HCl (537 mg, 5.50 mmol, 1.10 equiv) and HOBt (84.0 mg, 5.50 mmol, 1.10 equiv) were dissolved in dry CH2Cl2 (20.0 mL) under nitrogen atmosphere and cooled to 0 °C. Then, iPr2NEt (1.74 mL, 10.0 mmol, 2.00 equiv) and EDC·HCl (1.43 g, 7.50 mmol, 1.50 equiv) were added and the mixture was stirred for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with 5% aq. KHSO4 (2 × 100 mL), 5% aq. NaHCO3 (2 × 100 mL), and brine (2 × 100 mL). The organic phase was dried over MgSO4 and ACS Paragon Plus Environment

16

Page 17 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


concentrated in vacuo yielding the crude Weinreb amide as a colorless oil. Under nitrogen atmosphere, LiAlH4 (228 mg, 6.00 mmol, 1.20 equiv) was added at 0°C to a solution of the Weinreb amide in dry THF (25.0 mL). After stirring for 1 h, the reaction was quenched by slow addition of 5% aq. KHSO4 (50 ml). The mixture was diluted with EtOAc (60 mL), and washed with 5% aq. KHSO4 (2 × 100ml), 5% aq. NaHCO3 (2 × 100 ml) and brine (2 × 100 ml). The organic phase was dried with MgSO4 and concentrated in vacuo yielding the crude aldehyde. K2CO3 (2.07 g, 15.0 mmol, 3.00 equiv) and p-toluenesulfonylazide (1.18 g, 6.00 mmol, 1.20 equiv) were suspended in dry MeCN (14.0 mL) under nitrogen atmosphere. Dimethyl-(2-oxopropyl)-phosphonate (1.00 g, 6.00 mmol, 1.20 equiv) was added and the mixture was stirred for 2 h at room temperature. The aldehyde was dissolved in dry MeOH (4.00 mL) and added to the reaction mixture, which was left stirring 18 h before being concentrated in vacuo. The resulting residue was redissolved in EtOAc (30 mL), washed with water (2 × 100 ml) and brine (2 × 100 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was purified via VLC (0→2% MeOH in CH2Cl2) yielding alkyne S17 as a white solid (113 mg, 13% over three steps). 1H NMR (600 MHz, CDCl3):  = 1.39 (d, J = 6.9 Hz, 3 H, CHCH3), 1.45 (s, 9 H, 3 × CCH3), 2.25 (d, J = 2.3 Hz, 1 H, CHCCHNH), 4.48 (br, 1 H, CHCCHNH), 4.70 (br, 1 H, NH). 13C{1H} NMR (151 MHz, CDCl3):  = 22.7 (CH3), 28.5 (3 × CCH3), 38.5 (CHNH), 70.3 (CHCCHNH), 80.1 (C(CH3)3), 84.7 (CHCCHNH), 154.8 (COO). The data is in agreement with the literature.122 (S)-1-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethan-1-amine (S18). Azide S15 (32.9 mg, 0.24 mmol, 1.20 equiv) and alkyne S17 (33.0 mg, 0.20 mmol, 1.00 equiv) were dissolved in tert-butanol (1.00 ml) and water (1.00 ml). Subsequently, CuSO4 (1.60 mg, 0.01 mmol, 0.05 equiv), sodium ascorbate (19.8 mg, 0.10 mmol, 0.50 equiv) and TBTA (5.30 mg, 0.01 mmol, 0.05 equiv) were added. After stirring for 18 h the reaction was quenched with water (100 ml), extracted with CH2Cl2 (3 × 100 ml), dried over MgSO4 and concentrated in vacuo. The crude residue was purified via VLC (0→2% MeOH, 0.5% NH3 in CH2Cl2) yielding the Bocprotected product as a white solid (51.0 mg, 84%). The carbamate (51.0 mg, 0.17 mmol, 1.00 equiv) was dissolved in CH2Cl2 (4.00 ml). TFA (1.00 ml) was added and the mixture was stirred for 2 h at room temperature. The mixture was concentrated in vacuo (coevaporation with toluene and CH2Cl2). The amine S18 was obtained as the TFA salt in form of a yellow solid (45.0 mg, 84%). 1H NMR (600 MHz, CD3CN):  = 1.62 (d, J = 6.7 Hz, 3 H, CH3), 4.67 (q, J = 6.9 Hz, 1 H, CHCH3), 5.53 (s, 2 H, CH2), 7.27 – 7.31 (m, 2 H, 2 × CHar), 7.32 – 7.39 (m, 3 H, 3 × CHar), 7.93 (s, 1 H, triazole-CH), 8.17 (br, 2 H, NH2). 13C{1H} NMR (151 MHz, CD3CN):  = 19.2 (CH3), 44.8 (CHCH3), 54.7 (CH2), 123.9 (triazole-CH), 129.0 (2 × CHar), 129.4 (CHar), 129.9 (2 × CHar), 136.5 (Car), 146.4 (triazole-Car). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C11H15N4+, 203.1291; found 203.1290. tert-Butyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (S30). Methyl-3-bromopropionate (2.69 g, 16.1 mmol, 1.50 equiv) was dissolved in 100 mL MeCN. Then, iPr2NEt (2.81 mL, 2.08 g, 16.1 mmol, 1.50 equiv) and Boc-piperazine (2.00 g, 10.7 mmol, 1.00 equiv) were added and the reaction mixture was stirred at 50 °C for 18 h. The solvent was removed in vacuo and the residue resuspended in acetone. The remaining insoluble solids were filtered off and the filtrate was concentrated. The crude was purified via column chromatography (5% MeOH in CH2Cl2) to give the piperazine derivative S30 as a yellow oil (2.47 g, 85%). Rf = 0.45 (5% MeOH in CH2Cl2). 1H NMR (600 MHz, CDCl3):  = 1.44 (s, 9 H, 3 × CCH3), 2.59 (br, 4 H, 2 × OOCNCH2CH2N), 2.68 (br, 2 H, CH2COOCH3), 2.87 (br, 2 H, NCH2CH2COO), 3.55 (br, 4 H, 2 × OOCNCH2CH2N), 3.67 (s, 3 H, OCH3). 13C{1H} NMR (151 MHz, CDCl3):  = 28.5 (3 × CCH3), 31.4 (CH2COOCH3), 42.4 (OOCNCH2CH2N), 43.3 (OOCNCH2CH2N), 52.0 (OCH3), 52.7 (2 × OOCNCH2CH2N), 53.4 (NCH2CH2COO), 80.2 (C(CH3)3), 154.6 (COOCH3), 172.4 (COOC(CH3)3). UPLC-MS tR = 0.68 min, m/z: calcd for [M + H]+, C13H25O4N2+, 273.18; found 273.18. The data is in agreement with the literature.123 Allyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (S31). The Boc-protected building block S30 (2.45 g, 9.00 mmol, 1.00 equiv) was dissolved in 25% TFA in CH2Cl2 (20.0 mL) and stirred at room temperature for 2 h. After reaction completion the solvent was removed in vacuo. The residual brown liquid crystallized during solvent-removal. The crystals were washed with CH2Cl2 to give the crude product as TFAsalt, which was used for the next reaction without further purification. Under nitrogen atmosphere, the crude (2.55 g, 8.90 mmol, 1.00 equiv) was dissolved in 70.0 mL anhydrous THF. At 0 °C, iPr2NEt (6.22 mL, 4.60 g, 35.6 mmol, 2.00 equiv) and allyl chloroformate (1.42 mL, 1.61 g, 13.4 mmol, 1.50 equiv) were added and the reaction mixture was stirred for 1 h while it was allowed to reach room temperature. After total consumption of the starting material occurred, the mixture was diluted with EtOAc (30 mL) and washed with ACS Paragon Plus Environment

17


Page 18 of 34

water (50 mL), 0.1 M aq. HCl (50 mL) and sat. aq. NaHCO3. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude residue was purified by column chromatography (2% MeOH in CH2Cl2) to give the piperazine derivative S31 as a white oil (1.87 g, 81%). Rf = 0.58 (2% MeOH in CH2Cl2). 1H NMR (600 MHz, CDCl ): δ = 2.42 (t, J = 5.1 Hz, 4 H, 2 × OOCNCH CH N), 2.50 (t, J = 7.3 Hz, 2 H, 3 2 2 NCH2CH2COO), 2.70 (t, J = 7.3 Hz, 2 H, NCH2CH2COO), 3.48 (t, J = 5.1 Hz, 4 H, 2 × OOCNCH2CH2N), 3.67 (s, 3 H, OCH3), 4.58 (dt, J = 5.6, 1.5 Hz, 2 H, OCH2CH), 5.19 (dq, J = 10.5, 1.5 Hz, 1 H, CH=CH2), 5.28 (dq, J = 17.2, 1.5 Hz, 1 H, CH=CH2), 5.87 – 5.97 (m, 1 H, CH=CH2). 13C{1H} NMR (151 MHz, CDCl3): δ = 32.2 (NCH2CH2COO), 43.8 (2 × OOCNCH2CH2N), 51.8 (OCH3), 52.7 (2 × OOCNCH2CH2N), 53.6 (NCH2CH2COO), 66.2 (OCH2CH), 117.5 (CH=CH2), 133.2 (CH=CH2), 155.1 (NCOO), 172.8 (CH2COO). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C12H21O4N2+, 257.1496; found 257.1494. 3-(4-((Allyloxy)carbonyl)piperazin-1-yl)propanoic acid (S32). The protected piperazine building block S31 (1.80 g, 7.02 mmol, 1.00 equiv) was dissolved in MeOH (100 mL) and 1 M aq. LiOH (100 mL) was added. The solution was stirred at room temperature for 2 h. After dilution with water (20 mL) the aqueous solution was acidified to pH 1 using aq. conc. HCl. It was then extracted with EtOAc (10 × 100 mL), whereas some product stayed in the aqueous phase. The organic phase was dried over Na2SO4 and the solvent was evaporated, yielding crude product. The solid was washed with EtOAc to give the product S32 as a white solid (837 mg, 3.47 mmol). The remaining aqueous phase was lyophilized and the resulting mixture of product and salt was resuspended in pyridine. The suspension was filtered and the solvent removed in vacuo to give the second batch of product S32 as a white pyridine salt (814 mg, 2.53 mmol, 86% overall). 1H NMR (600 MHz, CD3OD):  = 2.83 (t, J = 7.2 Hz, 2 H, CH2COOH), 3.16 (t, J = 5.3 Hz, 4 H, 2 × OOCNCH2CH2N), 3.29 (t, J = 7.2 Hz, 2 H, NCH2CH2COO), 3.79 (br, 4 H, 2 × OOCNCH2CH2N), 4.64 (dt, J = 5.6, 1.5 Hz, 2 H, OCH2CH), 5.25 (dq, J = 10.5, 1.5 Hz, 1 H, CH=CH2), 5.35 (dq, J = 17.2, 1.5 Hz, 1 H, CH=CH2), 5.95 – 6.05 (m, 1 H, CH=CH2), [7.44 – 7.50 (m, 2 H, 2 × pyridine-NCHCH), 7.90 (tt, J = 7.7, 1.8 Hz, 1 H, pyridine-NCHCHCH), 8.54 – 8.57 (m, 2 H, 2 × pyridine-NCH)]. 13C{1H} NMR (151 MHz, CD3OD):  = 30.1 (CH2COOH), 42.5 (2 × OOCNCH2CH2N), 52.9 (2 × OOCNCH2CH2N), 54.2 (NCH2CH2COO), 67.8 (OCH2CH), 118.3 (CH=CH2), [125.8 (2 × pyridine-NCHCH)], 133.9 (CH=CH2), [139.0 (pyridine-NCHCHCH), 149.7 (2 × pyridine-NCH),] 156.2 (COO), 174.2 (COO). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C11H19O4N2+, 243.1339; found 243.1338.

General procedure for synthesis of -peptoid oligomers General procedure A: Aza-Michael addition. The respective amine (2.00 equiv) was added to a solution of the acrylated -peptoid (0.1 M) in MeOH. When amine·HCl-salts were used, iPr2NEt (2.00 equiv) was added to the reaction mixture additionally. The reaction mixture was stirred at 50 °C for 18 h. After completion, the solvent was evaporated. In case of the dimeric and trimeric peptoids, the residue was redissolved in EtOAc (10 mL) and washed with 2 M aq. HCl (2 × 10 mL) and sat. aq. NaHCO3 (10 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (1→2% MeOH, 0.25% NH3 in CH2Cl2). General procedure B: Acryloylation reaction. Under nitrogen atmosphere, the peptoid (1.00 equiv) and Et3N (1.20 equiv) were dissolved in anhydrous THF (0.05 M) and the mixture was cooled to 0 °C. Acryloyl chloride (1.40 equiv) was added and the solution was stirred for 1 h at this temperature. The reaction mixture was filtered and the filter cake was washed with cold EtOAc. The combined filtrates were concentrated in vacuo to give the crude acrylamide, which was used without further purification. General procedure C: N-terminal acylation. To a solution of the peptoid (1.00 equiv) in anhydrous CH2Cl2 (0.02 M) at 0 °C, Et3N (1.40 equiv) and acetyl chloride (1.20 equiv) were added. The reaction mixture was slowly allowed to reach room temperature and stirred for 1 h. The solvent was evaporated and the crude product was used without further purification. General procedure D: C-terminal deprotection. A solution of the peptoid (6.00 mM) in 1 M aq. LiOH– MeOH 1:1 was stirred at room temperature for 25 h (methylester deprotection) or 48 h (t-butylester deprotection)a, respectively. After dilution with water (1), the solution was acidified (pH 1) with aq. conc. HCl. This caused precipitation and the suspension was extracted with EtOAc (3). The combined organic ACS Paragon Plus Environment

18

Page 19 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


layers were dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by column chromatography (1→2% MeOH, 0.25% AcOH in CH2Cl2). a t-butylester deprotection can also be achieved by conventional acidic deprotection (15% TFA in CH Cl ). 2 2 However, the reaction has to be monitored closely, as cleavage of a naphthylethyl group was be observed after 2 h under these conditions.

-Peptoid trimer 13. The peptoid trimer was synthesized from trimer S6 (1.91 g, 2.69 mmol, 1.00 equiv) according to procedures C and D. The peptoid trimer 13 was obtained as a white foam after column chromatography (1.47 g, 74%). Rf = 0.13 (3% MeOH, 0.25% AcOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+,C47H50N3O5+, 736.3765; found 736.3740. Purity according to analytical HPLC (gradient A): 90%.

-Peptoid trimer 14. The peptoid trimer was synthesized from trimer S26 (600 mg, 0.80 mmol, 1.00 equiv) according to general procedures C and D. The peptoid trimer 14 was obtained as a white foam after column chromatography (597 mg, 97%). Rf = 0.26 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C50H56N3O5+, 778.4214; found 778.4207. Purity according to analytical HPLC (gradient A): 84%.

-Peptoid trimer 15. The peptoid trimer was synthesized from trimer S23 (130 mg, 1.70 mmol, 1.00 equiv) according to general procedures C and D. The peptoid trimer 15 was obtained as a white foam after column chromatography (102 mg, 77%). Rf = 0.25 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C50H56N3O5+, 778.4214; found 778.4203. Purity according to analytical HPLC (gradient A): 92%.

-Peptoid trimer 16. The peptoid trimer was synthesized from dimer S21 (0.24 g, 0.38 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.12 mL, 0.13 g, 0.76 mmol, 2.00 equiv). The peptoid trimer 16 was obtained as a white foam after column chromatography (183 mg, 61%). Rf = 0.22 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C52H62N3O4+, 792.4735; found 792.4751. Purity according to analytical HPLC (gradient A): 86%.

-Peptoid trimer 17. The peptoid trimer was synthesized from dimer S4 (535 mg, 1.02 mmol, 3.20 equiv) according to general procedure B, followed by general procedure A using the (S)-1-(1naphthyl)pentylamine·HCl (12) (80 mg, 0.32 mmol, 1.00 equiv). The peptoid trimer 17 was obtained as a white foam after column chromatography (117 mg, 46%). Rf = 0.21 (3% MeOH in CH2Cl2). HRMS (MALDITOF) m/z: calcd for [M + H]+, C52H62N3O4+, 792.4735; found 792.4730. Purity according to analytical HPLC (gradient A): 79%.

-Peptoid trimer 18. The peptoid trimer was synthesized from dimer S4 (5.30 g, 9.16 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (2.94 mL, 3.14 g, 18.3 mmol, 2.00 equiv). The peptoid trimer 18 was obtained as light yellow foam after column chromatography (4.74 g, 69%). Rf = 0.20 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C49H56N3O4+, 750.4265; found 750.4279. Purity according to analytical HPLC (gradient A): 91%.

-Peptoid trimer 28. The peptoid trimer was synthesized from trimer S29 (225 mg, 0.27 mmol, 1.00 equiv) according to general procedures C and D. The peptoid trimer 28 was obtained as a white foam after column chromatography (154 mg, 66%). Rf = 0.27 (2% MeOH, 0.2% AcOH in CH2Cl2). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C53H59N4O7+, 863.4378; found 863.4364. Purity according to analytical HPLC (gradient A): 90%.

-Peptoid trimer 29. The peptoid trimer was synthesized from dimer S27 (250 mg, 0.38 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.10 mL, 0.10 g, 0.60 mmol, 2.00 equiv). The peptoid trimer 29 was obtained as a white foam after column chromatography (174 mg, 52%). Rf = 0.20 (3% MeOH in CH2Cl2). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C55H65N4O6+, 877.4899; found 877.4927. Purity according to analytical HPLC (gradient A): 86%.


19


Page 20 of 34

-Peptoid monomer S1. The peptoid monomer was synthesized according to general procedure A from tbutyl acrylate (2.62 g, 20.4 mmol, 1.00 equiv) and (S)-1-(1-naphthyl)ethylamine (6.56 mL, 7.00 g, 40.8 mmol, 2.00 equiv). The peptoid monomer S1 was obtained as a yellow oil after column chromatography (5.70 g, 93%). Rf = 0.26 (heptane–EtOAc, 3:1). 1H NMR (600 MHz, CDCl3):  = 1.45 (s, 9 H, 3 × CCH3), 1.53 (d, J = 6.6 Hz, 3 H, CH3), 2.43 – 2.52 (m, 2 H, COCH2), 2.77 – 2.87 (m, 2 H, NCH2), 4.69 (q, J = 6.6 Hz, 1 H, NCH), 7.53 – 7.46 (m, 3 H, 3 × CHar), 7.71 (d, J = 7.2 Hz, 1 H, CHar), 7.75 (d, J = 8.2 Hz, 1 H, CHar), 7.87 (dd, J = 8.3, 1.3 Hz, 1 H, CHar), 8.18 (d, J = 8.4 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CDCl3):  = 23.7 (CH3), 28.3 (3 × CCH3), 36.0 (COCH2), 43.4 (NCH2), 53.7 (NCH), 80.7 (C(CH3)3), 122.9 (CHar), 123.1 (CHar), 125.5 (CHar), 125.9 (CHar), 126.1 (CHar), 127.6 (CHar), 129.1 (CHar), 131.4 (naphthyl-Cq), 134.1 (naphthylCq), 140.5 (naphthyl-Cq), 172.2 (COO). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C19H26NO2+, 300.1958; found 300.1961. The data is in agreement with literature.76

-Peptoid monomer S2. The peptoid monomer was synthesized according to general procedure A from methyl acrylate (1.32 mL, 1.26 g, 14.6 mmol, 1.00 equiv) and (S)-1-(1-naphthyl)ethylamine (4.69 mL, 5.00 g, 29.2 mmol, 2.00 equiv). The peptoid monomer S2 was obtained as a yellow oil after column chromatography (3.55 g, 95%). Rf = 0.34 (3% MeOH in CH2Cl2). 1H NMR (600 MHz, CDCl3):  = 1.52 (d, J = 6.7 Hz, 3 H, CH3), 2.48 – 2.60 (m, 2 H, CH2CH2), 2.79 – 2.91 (m, 2 H, NHCH2), 3.68 (s, 3 H, OCH3), 4.63 – 4.75 (m, 1 H, NCH), 7.46 – 7.53 (m, 3 H, 3 × CHar), 7.69 (d, J = 7.1 Hz, 1 H, CHar), 7.76 (d, J = 8.0 Hz, 1 H, CHar), 7.88 (dd, J = 8.0, 1.5 Hz, 1 H, CHar), 8.19 (d, J = 8.4 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CDCl3):  = 23.8 (CHCH3), 34.8 (CH2CH2), 43.1 (NHCH2), 51.7 (OCH3), 53.8 (NCH), 122.9 (CH), 123.0 (CH), 125.5 (CHar), 125.9 (CHar), 125.9 (CHar), 127.4 (CHar), 129.1 (CHar), 131.4 (naphthyl-Cq), 134.1 (naphthyl-Cq), 140.7 (naphthyl-Cq), 173.4 (COOMe). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C16H20NO2+, 258.1489; found 258.1484.

-Peptoid monomer S3. The peptoid monomer was synthesized according to general procedure A from tbutyl acrylate (2.25 g, 17.5 mmol, 1.00 equiv) and (R)-1-(1-naphthyl)ethylamine (5.62 mL, 6.00 g, 35.0 mmol, 2.00 equiv). The peptoid monomer S3 was obtained as a yellow oil after column chromatography (4.60 g, 88%). Rf = 0.53 (3% MeOH in CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 1.44 (s, 9 H, 3 × CCH3), 1.56 (d, J = 6.4 Hz ,3 H, CH3), 2.46  2.51 (m, 2 H, COCH2), 2.79 – 2.87 (m, 2 H, NCH2), 4.73 (q, J = 6.5 Hz, 1 H, NCH), 7.47 – 7.53 (m, 3 H, 3 × CHar ), 7.73 (d, J = 7.1 Hz , 1 H, CHar), 7.76 (d, J = 8.2 Hz, 1 H, CHar), 7.88 (dd, J = 8.0, 1.3 Hz , 1 H, CHar), 8.17 (d, J = 8.4, 1 H, CHar). 13C{1H} NMR (151 MHz, CDCl3): δ = 23.6 (CH3), 28.3 (3 × CCH3), 35.6 (COCH2), 43.3 (NCH2), 53.8 (NCH), 80.9 (C(CH3)3), 122.9 (CHar), 123.1 (CHar), 125.6 (CHar), 125.9 (CHar), 126.1 (CHar), 127.6 (CHar), 129.1 (CHar), 131.4 (naphthyl-Cq), 134.1 (naphthylCq), 140.5 (naphthyl-Cq), 172.2 (COO). UPLC-MS tR = 1.62 min, m/z: calcd for [M + H]+, C19H26NO2+, 300.20; found 300.86.

-Peptoid dimer S4. The peptoid dimer was synthesized from monomer S1 (6.73 g, 19.0 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (6.11 mL, 6.52 g, 38.1 mmol, 2.00 equiv). The peptoid dimer S4 was obtained as a yellow foam after column chromatography (7.84 g, 99%). Rf = 0.28 (3 % MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C34H41N2O3+, 525.3112; found 525.3119. -Peptoid dimer S5. The peptoid dimer was synthesized from monomer S2 (2.00 g, 6.42 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (2.06 mL, 2.20 g, 12.8 mmol, 2.00 equiv). The peptoid dimer S5 was obtained as a light yellow foam after column chromatography (2.08 g, 67%). Rf = 0.17 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C31H35N2O3+, 483.2642; found 483.2631.

-Peptoid trimer S6. The peptoid trimer was synthesized from dimer S5 (2.25 g, 4.19 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (1.35 mL, 1.44 g, 8.39 mmol, 2.00 equiv). The peptoid trimer S6 was obtained as a light yellow foam after column


20

Page 21 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


chromatography (2.14 g, 72%). Rf = 0.27 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.27 min, m/z: calcd for [M + H]+, C46H50N3O4+, 708.38; found 708.51.

-Peptoid trimer S7. The peptoid trimer was synthesized from dimer S4 (273 mg, 0.52 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using 1-naphthylmethylamine (0.15 mL, 0.16 g, 1.04 mmol, 2.00 equiv). The peptoid trimer S7 was obtained as a white foam after column chromatography (212 mg, 55%). Rf = 0.15 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C48H54N3O4+, 736.4109; found 763.4105. Purity according to analytical HPLC (gradient A): 82%. -Peptoid trimer S8. The peptoid trimer was synthesized from peptoid dimer S4 (116 mg, 0.20 mmol, 1.00 equiv) and (S)-1-phenylethylamine (29.0 mg, 0.24 mmol, 1.20 equiv) according to general procedure A. The peptoid trimer S8 was obtained as a white solid after column chromatography (106 mg, 68%). UPLC-MS tR = 2.90 min, m/z: calcd for [M + H]+, C45H54N3O4+, 700.4; found 700.3.

-Peptoid dimer S9. The peptoid dimer was synthesized from monomer S3 (4.60 g, 15.4 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (4.79 mL, 5.11 g, 29.9 mmol, 2.00 equiv). The peptoid dimer S9 was obtained as a white foam after column chromatography (7.18 g, 92%). Rf = 0.42 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.20 min, m/z: calcd for [M + H]+, C34H41N2O3+, 525.31; found 525.29.

-Peptoid dimer S10. The peptoid dimer was synthesized from monomer S3 (424 mg, 1.41 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.45 mL, 0.48 mg, 2.83 mmol, 2.00 equiv). The peptoid dimer S10 was obtained as a dark yellow oil after column chromatography (553 mg, 74%). Rf = 0.32 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.42 min, m/z: calcd for [M + H]+, C34H41N2O3+, 525.31; found 525.34. -Peptoid trimer S11. The peptoid trimer was synthesized from dimer S10 (0.55 g, 1.05 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (R)-1-(1-naphthyl)ethylamine (0.23 mL, 0.24 g, 1.43 mmol, 2.00 equiv). The peptoid trimer S11 was obtained as a white foam after column chromatography (363 mg, 68%). Rf = 0.21 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C49H56N3O4+, 750.4265; found 750.4276. Purity according to analytical HPLC (gradient C): 95%.

-Peptoid trimer S12. The peptoid trimer was synthesized from trimer S11 (182 mg, 0.24 mmol, 1.00 equiv) according to procedures C and D. The peptoid trimer S12 was obtained as a white foam after column chromatography (109 mg, 72%). Rf = 0.67 (3% MeOH, 0.25% AcOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C47H50N3O5+, 736.3745; found 736.3737. – Purity according to analytical HPLC (gradient C): 61%. -Peptoid dimer S13. The peptoid dimer was synthesized from dimer S9 (2.33 g, 4.45 mmol, 1.00 equiv) according to general procedures C and D. The product S13 was obtained as a light yellow foam after column chromatography (1.81 g, 80%). Rf = 0.41 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.38 min, m/z: calcd for [M + H]+, C32H35N2O4+, 511.26; found 511.26.

-Peptoid tetramer S14. Under nitrogen atmosphere, the peptoid dimers S9 (514 mg, 0.980 mmol, 1.00 equiv), S13 (500 mg, 0.98 mmol, 1.00 equiv) and HATU (447 mg, 1.18 mmol, 1.20 equiv) were dissolved in anhydrous CH2Cl2 (2.00 mL). Subsequently, iPr2NEt (0.41 mL, 0.30 mg, 2.35 mmol, 2.00 equiv) was added. The reaction was stirred for 18 h at room temperature. After completion, the solution was washed with 2 M aq. HCl (2 × 10 mL) and sat. aq. NaHCO3 (10 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (1.5→3.0% MeOH in CH2Cl2) yielding peptoid tetramer S14 as a white foam (470 mg, 47%). Rf = 0.44 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C66H73N4O6+, 1017.5525; found 1017.5523. Purity according to analytical HPLC (gradient C): 59%. ACS Paragon Plus Environment

21


Page 22 of 34

-Peptoid trimer S19. The peptoid trimer was synthesized from peptoid dimer S4 (180 mg, 0.31 mmol, 1.20 equiv) according to general procedure B, followed by general procedure A using amine S16 (48.2 mg, 0.26 mmol, 1.00 equiv). The peptoid trimer S19 was obtained as a white solid after column chromatography (97.0 mg, 41%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C47H55N6O4+, 767.4279; found 767.4291.

-Peptoid trimer S20. The peptoid trimer was synthesized from peptoid dimer S4 (231 mg, 0.90 mmol, 2.00 equiv) according to general procedure B, followed by general procedure A using amine S18 (26.0 mg, 0.20 mmol, 1.00 equiv). The peptoid trimer S20 was obtained as a white solid after column chromatography (91.0 mg, 83%). UPLC-MS tR = 2.05 min, m/z: calcd for [M + H]+, C48H57N6O4+, 781.4; found 781.4.

-Peptoid dimer S21. The peptoid dimer was synthesized from monomer S1 (706 mg, 2.00 mmol, 2.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)pentylamine·HCl (12) (250 mg, 1.00 mmol, 1.00 equiv). The peptoid dimer S21 was obtained as a yellow oil after column chromatography (403 mg, 71%). Rf = 0.27 (3% MeOH in CH2Cl2). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C37H47N2O3+, 567.3581; found 567.3594. -Peptoid dimer S22. The peptoid dimer was synthesized from monomer S2 (412 mg, 1.60 mmol, 2.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)pentylamine·HCl (12) (200 mg, 0.80 mmol, 1.00 equiv). The peptoid dimer S22 was obtained as a yellow oil after column chromatography (157 mg, 37%). Rf = 0.32 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.35 min, m/z: calcd for [M + H]+, C34H41N2O3+, 525.31; found 525.45.

-Peptoid trimer S23. The peptoid trimer was synthesized from dimer S22 (150 mg, 0.29 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.09 mL, 0.09 g, 0.55 mmol, 2.00 equiv). The peptoid trimer S23 was obtained as a light yellow foam after column chromatography (131 mg, 31%). Rf = 0.14 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.72 min, m/z: calcd for [M + H]+, C49H56N3O4+, 750.43; found 750.68.

-Peptoid monomer S24. The peptoid monomer was synthesized according to general procedure A from methyl acrylate (0.32 mL, 304 mg, 3.54 mmol, 2.00 equiv) and (S)-1-(1-naphthyl)-pentylamine·HCl (12) (441 mg, 1.77 mmol, 1.00 equiv). The peptoid monomer S24 was obtained as a clear oil after column chromatography (457 mg, 86%). Rf = 0.27 (heptane–EtOAc, 3:1). 1H NMR (600 MHz, CDCl3):  = 0.84 (t, J = 7.1 Hz, 3 H, CH3), 1.19 – 1.41 (m, 4 H, CH2CH3/CH2CH2CH2), 1.77 – 1.92 (m, 2 H, NCHCH2), 2.44 – 2.57 (m, 2 H, COCH2), 2.71 – 2.84 (m, 2 H, NCH2CH2), 3.66 (s, 3 H, OCH3), 4.51 (t, J = 6.6 Hz, 1 H, NCH), 7.45 – 7.53 (m, 3 H, 3 × CHar), 7.65 (d, J = 7.1 Hz, 1 H, CHar), 7.76 (d, J = 8.1 Hz, 1 H, CHar), 7.85 – 7.91 (m, 1 H, CHar), 8.23 (d, J = 8.4 Hz, 1 H, CHar). 13C{1H} NMR (151 MHz, CDCl3):  = 14.0 (CH3), 22.8 (CH2CH3), 28.7 (CH2CH2CH2), 34.6 (COCH2), 37.5 (NCHCH2), 43.0 (NCH2CH2), 51.6 (OCH3), 58.7 (NCH), 123.1 (CHar), 123.8 (CHar), 125.3 (CHar), 125.6 (CHar), 125.7 (CHar), 127.3 (CHar), 129.0 (CHar), 131.9 (naphthylCq), 134.0 (naphthyl-Cq), 139.6 (naphthyl-Cq), 173.3 (COO). UPLC-MS tR = 1.22 min, m/z: calcd for [M + H]+, C19H26NO2+, 300.20; found 300.29.

-Peptoid dimer S25. The peptoid dimer was synthesized from monomer S24 (440 mg, 1.46 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1naphthyl)ethylamine (0.47 mL, 500 mg, 2.92 mmol, 2.00 equiv). The peptoid dimer S25 was obtained as a yellow oil after column chromatography (631 mg, 82%). Rf = 0.28 (3% MeOH in CH2Cl2). UPLC-MS tR = 1.84 min, m/z: calcd for [M + H]+, C34H41N2O3+, 525.31; found 525.34. -Peptoid trimer S26. The peptoid trimer was synthesized from dimer S25 (620 mg, 1.18 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.38 mL, 404 mg, 2.36 mmol, 2.00 equiv) The peptoid trimer S26 was obtained as a white foam after column chromatography (626 mg, 71%). Rf = 0.29 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.06 min, m/z: calcd for [M + H]+, C49H56N3O4+, 750.43; found 750.57. ACS Paragon Plus Environment

22

Page 23 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


-Peptoid dimer S27. The peptoid dimer was synthesized from S1 (325 mg, 0.92 mmol, 2.00 equiv) according to general procedure B, followed by general procedure A using the amine 27 (155 mg, 0.46 mmol, 1.00 equiv) and iPr2NEt (0.16 mL, 120 mg, 0.92 mmol, 2.00 equiv). The peptoid dimer S27 was obtained as a yellow oil after column chromatography (265 mg, 66%). Rf = 0.15 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.03 min, m/z: calcd for [M + H]+, C40H50N3O5+, 652.37; 652.32 found.

-Peptoid dimer S28. The peptoid dimer was synthesized from monomer S2 (345 mg, 1.34 mmol, 2.00 equiv) according to general procedure B, followed by general procedure A using the amine 27 (200 mg, 0.67 mmol, 1.00 equiv) and iPr2NEt (0.23 mL, 173 mg, 1.34 mmol, 2.00 equiv). The peptoid dimer S28 was obtained as a white foam after column chromatography (269 mg, 66%). Rf = 0.09 (3% MeOH in CH2Cl2). UPLC-MS tR = 1.81 min, m/z: calcd for [M + H]+, C37H44N3O5+, 610.33; 610.29 found.

-Peptoid trimer S29. The peptoid trimer was synthesized from dimer S28 (250 mg, 0.41 mmol, 1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.12 mL, 0.13 g, 0.75 mmol, 2.00 equiv). The peptoid trimer S29 was obtained as a white foam after column chromatography (230 mg, 66%). Rf = 0.23 (3% MeOH in CH2Cl2). UPLC-MS tR = 1.89 min, m/z: calcd for [M + H]+, C52H54N4O6+, 835.44; 835.48 found.

-Peptoid trimer S33. 3-(4-((Allyloxy)carbonyl)piperazin-1-yl)propanoic acid (S32) (171 mg, 0.71 mmol, 2.50 equiv) was placed in a vial and dissolved in anhydrous DMF (2.00 mL). Subsequently, HATU (161 mg, 0.42 mmol, 1.50 equiv) and iPr2NEt (0.15 mL, 110 mg, 0.85 mmol, 3.00 equiv) were added. After shaking at room temperature for 10 min, the peptoid trimer S6 (200 mg, 0.28 mmol, 1.00 equiv) was added to the vial and the reaction was left on a shaker for 2 h. The crude was purified by column chromatography (2→2.5% MeOH, 0.25% NH3 in CH2Cl2) to give the peptoid trimer S33 as a white foam (133 mg, 51%). Rf = 0.28 (3% MeOH in CH2Cl2). UPLC-MS tR = 2.65 min, m/z: calcd for [M + H]+, C57H66N5O7+, 932.50; 932.36 found.

-Peptoid trimer S34. The peptoid trimer was synthesized from peptoid S33 (133 mg, 0.17 mmol, 1.00 equiv) according to general procedure D. Due to the zwitterionic character, the crude was not purified by column chromatography and instead used without any further purification. The product S34 was obtained as a white foam (crude 120 mg, 93%). Rf = 0.06 (3% MeOH in CH2Cl2). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C56H64N4O7+, 918.4800; found 918.4869. Purity according to analytical HPLC (gradient A): 65%.

-Peptoid hexamer 1. The peptoid trimers 13 (20.0 mg, 270 mol, 1.00 equiv) and 18 (19.6 mg, 270 mol, 1.00 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (120 L). Subsequently, iPr2NEt (13.9 L, 10.3 mg, 0.08 mmol, 3.00 equiv) and HATU (12.2 mg, 320 mol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 30 min, tR = 41.3–45.5). The peptoid hexamer 1 was obtained as a white solid (17.0 mg, 96%). UPLC-MS, tR = 3.30 min, m/z: calcd for [M + H]+, C96H103N6O8+, 1467.78; found 1467.73. Purity according to analytical HPLC (gradient C): 99%. The data is in agreement with the previously described synthesis by sequential addition of monomers.13

-Peptoid hexamer 2. Under nitrogen atmosphere, the peptoid trimers S11 (98.0 mg, 0.13 mmol, 1.00 equiv) and S12 (80.0 mg, 0.01 mmol, 1.00 equiv) and HATU (24.3 mg, 0.06 mmol, 1.20 equiv) were dissolved in anhydrous CH2Cl2 (200 L). Subsequently, iPr2NEt (26.0 L, 19.0 mg, 0.33 mmol, 3.00 equiv) was added. The reaction was left to stir for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (2.00 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 20 min, tR = 31.8–33.5). The peptoid hexamer 2 was obtained as a white solid (21.6 ACS Paragon Plus Environment

23


Page 24 of 34

mg, 13%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C96H103N6O8+, 1467.7832; found 1467.7843. Purity according to analytical HPLC (gradient C): 99%.

-Peptoid hexamer 3. Peptoid tetramer S14 (470 mg, 0.46 mmol, 1.00 equiv) was subjected to C-terminal deprotection according to general procedure D. The crude was purified by column chromatography to give the deprotected peptoid tetramer as a white solid (368 mg, 84 %). Under nitrogen atmosphere, the tetramer (80.0 mg, 0.08 mmol, 1.00 equiv), dimer S9 (44.0 mg, 0.08 mmol, 1.00 equiv) and HATU (38.0 mg, 0.10 mmol, 1.20 equiv) were dissolved in anhydrous CH2Cl2 (170 L). Subsequently, iPr2NEt (30.0 L, 22.0 mg, 0.17 mmol, 2.00 equiv) was added. The reaction was stirred for 18 h at room temperature. After completion, the reaction mixture was transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (2.00 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 20 min, tR = 31.2–32.5). The peptoid hexamer 3 was obtained as a white solid (56.0 mg, 46%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C96H103N6O8+, 1467.7832; found 1467.7786. Purity according to analytical HPLC (gradient C): 99%.

-Peptoid hexamer 4. The peptoid trimers S7 (80.0 mg, 0.11 mmol, 1.00 equiv) and 13 (96.0 mg, 0.13 mmol, 1.20 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (500 L). Subsequently, iPr2NEt (56.8 L, 42.2 mg, 0.33 mmol, 3.00 equiv) and HATU (49.6 mg, 0.13 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, tR = 30.6–32.5 min). The peptoid hexamer 4 was obtained as a white solid (73.5 mg, 47%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C95H101N6O8+, 1453.7675; found 1453.7618. Purity according to analytical HPLC (gradient B): 99%. -Peptoid hexamer 5. The peptoid trimers 13 (52.2 mg, 0.07 mmol, 1.00 equiv) and S8 (50.0 mg, 0.07 mmol, 1.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (32.3 mg, 0.09 mmol, 1.20 equiv) and iPr2NEt (10.9 mg, 0.19 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room temperature. The reaction was then washed with 2 M aq. HCl and extracted with CH2Cl2 (3×). The resulting organic phase was then washed with water before being concentrated in vacuo. The crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 45→95% in eluent III over 35 min, tR = 52.7– 54.7 min). The peptoid hexamer 5 was obtained as a white solid (40.0 mg, 39%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C92H101N6O8+, 1417.7675; found 1417.7631. Purity according to analytical HPLC (gradient C): 90%.

-Peptoid hexamer 6. The peptoid trimers 13 (19.0 mg, 0.03 mmol,1.00 equiv) and S19 (20.0 mg, 0.03 mmol, 1.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (11.9 mg, 0.03 mmol, 1.20 equiv) and iPr2NEt (6.74 mg, 0.05 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room temperature. The reaction was then washed with 2 M aq. HCl and extracted with CH2Cl2 (3×). The resulting organic phase was then washed with water before being concentrated in vacuo. The crude residue was purified via VLC (0→2% MeOH in CH2Cl2) yielding peptoid hexamer 6 as a white solid (5.40 mg, 5%). HRMS (MALDI-TOF) m/z: calcd for [M + Na]+, C94H101N9O8Na+, 1507.7699; found 1507.7769. Purity according to analytical HPLC (gradient C): 98%.

-Peptoid hexamer 7. The peptoid trimers 13 (110 mg, 0.13 mmol, 1.20 equiv) and S20 (81.0 mg, 0.12 mmol, 1.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (45.0 mg, 0.19 mmol, 1.20 equiv) and iPr2NEt (28.0 mg, 0.24 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room temperature. The mixture was then washed with 2 M aq. HCl and extracted with CH2Cl2 (3×). The resulting organic phase was washed with water before being concentrated in vacuo. The crude residue was purified via VLC (0→3% MeOH in CH2Cl2). The crude residue was further purified by preparative HPLC (gradient of eluent IV rising linearly from 45→95% in eluent III over 25 min, tR = 47.9–50.3 min). The peptoid hexamer 7 was obtained as ACS Paragon Plus Environment

24

Page 25 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


a white solid (13.0 mg, 48%). HRMS (MALDI-TOF) m/z: calcd for [M + Na]+, C95H103N9O8Na+, 1520.7822; found 1520.7759. Purity according to analytical HPLC (gradient C): 96%.

-Peptoid hexamer 8. The peptoid hexamer 6 (27.1 mg, 0.02 mmol, 1.00 equiv) was dissolved in MeCN (0.1 M). Subsequently, methyl iodide (38.9 mg, 0.27 mmol, 15.0 equiv) was added and the mixture was stirred at 70 °C for 18 h. The crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 45→95% in eluent III over 35 min, tR = 34.9–36.4). The peptoid hexamer 8 was obtained as a white solid (7.00 mg, 25%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C95H104N9O8+, 1498.8002; found 1498.7958. Purity according to analytical HPLC (gradient C): 94%.

-Peptoid hexamer 9. The peptoid hexamer 7 (55.0 mg, 0.04 mmol, 1.00 equiv) was dissolved in MeCN (0.1 M). Subsequently, methyl iodide (85.0 mg, 0.60 mmol, 15.0 equiv) was added and the mixture was stirred at 70 °C for 18 h. The crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 45→95% in eluent III over 35 min, tR = 34.737.3). The peptoid hexamer 9 was obtained as a white solid (21.0 mg, 38%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C96H106N9O8+, 1512.8159; found 1512.8098. Purity according to analytical HPLC (gradient C): 90%.

-Peptoid hexamer 19. The peptoid trimers 16 (50.0 mg, 0.06 mmol, 1.00 equiv) and 13 (46.5 mg, 0.06 mmol, 1.00 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (300 L). Subsequently, iPr2NEt (33.0 L, 24.5 mg, 0.19 mmol, 3.00 equiv) and HATU (28.8 mg, 0.08 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 20 min, tR = 41.6–47.5 min). The peptoid hexamer 19 was obtained as a white solid (24.5 mg, 26%). HRMS (MALDI-TOF) m/z: calcd for [M + Na]+, C99H108N6O8Na+, 1532.8154; found 1532.8152. Purity according to analytical HPLC (gradient C): 95%.

-Peptoid hexamer 20. The peptoid trimers 17 (63.0 mg, 0.08 mmol, 1.00 equiv) and 13 (58.5 mg, 0.08 mmol, 1.00 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (500 L). Subsequently, iPr2NEt (41.6 L, 30.8 mg, 0.24 mmol, 3.00 equiv) and HATU (36.3 mg, 0.10 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 35 min, tR = 43.1–48.5 min). The peptoid hexamer 20 was obtained as a white solid (23.7 mg, 28%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C99H108N6O8+, 1509.8301; found 1509.8237. Purity according to analytical HPLC (gradient B): 99%. -Peptoid hexamer 21. The peptoid trimers 18 (40.0 mg, 0.05 mmol, 1.00 equiv) and 14 (41.5 mg, 0.05 mmol, 1.00 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (300 L). Subsequently, iPr2NEt (28.0 L, 20.7 mg, 0.16 mmol, 3.00 equiv) and HATU (24.3 mg, 0.06 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 70→95% in eluent III over 30 min, tR = 38.2–40.5 min). The peptoid hexamer 21 was obtained as a white solid (10.4 mg, 13%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C99H108N6O8+, 1509.8301; found 1509.8294. Purity according to analytical HPLC (gradient C): 99%.

-Peptoid hexamer 22. The peptoid trimers 18 (29.0 mg, 0.04 mmol, 1.00 equiv) and 15 (30.1 mg, 0.04 mmol, 1.00 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (300 L). Subsequently, iPr2NEt (20.2 L, 15.0 mg, 0.12 mmol, 3.00 equiv) and HATU (17.6 mg, 0.05 mmol, 1.20 equiv) were added. The reaction ACS Paragon Plus Environment

25


Page 26 of 34

was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 70→95% in eluent III over 25 min, tR = 33.2–39.0 min). The peptoid hexamer 22 was obtained as a white solid (9.00 mg, 15%). HRMS (MALDI-TOF) m/z: calcd for [M + H]+, C99H108N6O8+, 1509.8301; found 1509.8309. Purity according to analytical HPLC (gradient C): 73%.

-Peptoid hexamer 30. The peptoid trimers 29 (50.0 mg, 0.06 mmol, 1.00 equiv) and 13 (45.0 mg, 0.07 mmol, 1.10 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (500 L). Subsequently, iPr2NEt (30.0 L, 22.1 mg, 0.17 mmol, 3.00 equiv) and HATU (26.0 mg, 0.068 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 30 min, tR = 40.6–42.5 min). The peptoid hexamer 30 was obtained as a white solid (36.2 mg, 40%). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C102H112N7O10+, 1594.8465; found 1594.8414. Purity according to analytical HPLC (gradient C): 99%. -Peptoid hexamer 32. Under nitrogen atmosphere, the peptoid hexamer 30 (20.0 mg, 13.0 mol, 1.00 equiv) was dissolved in 600 L anhydrous CH2Cl2. Dimethylamine borane complex (11.7 mg, 200 mol, 15.0 equiv) and tetrakis palladium (1.53 mg, 1.30 mol, 10 mol%) were added and the mixture was stirred for 3 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, tR = 25.3–26.2 min). The peptoid hexamer 32 was obtained as a white solid (9.40 mg, 48%). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C98H108N7O8+, 1510.8254; found 1510.8243. Purity according to analytical HPLC (gradient C): 95%.

-Peptoid hexamer 33. The peptoid trimers 28 (50.0 mg, 0.06 mmol, 1.00 equiv) and 29 (60.9 mg, 0.07 mmol, 1.20 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (500 L). Subsequently, iPr2NEt (30.3 L, 22.5 mg, 0.17 mmol, 3.00 equiv) and HATU (26.4 mg, 0.07 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product (36.0 mg, 21.0 mol, 1.00 equiv) was redissolved in anhydrous CH2Cl2 (1.00 mL) under nitrogen atmosphere. Dimethylamine borane complex (25.0 mg, 0.42 mmol, 20.0 equiv) and subsequently tetrakis palladium (4.83 mg, 4.20 mol, 20 mol%) were added and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, tR = 16.1–17.8 min). The peptoid hexamer 33 was obtained as a white solid (15.7 mg, 24%). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C100H113N8O8+, 1553.8676; found 1553.8657. Purity according to analytical HPLC (gradient C): 99%.

-Peptoid hexamer 34. The peptoid trimers S34 (36.7 mg, 0.04 mmol, 1.00 equiv) and 18 (36.0 mg, 0.05 mmol, 1.20 equiv) were placed in a vial and dissolved in anhydrous CH2Cl2 (300 L). Subsequently, iPr2NEt (20.9 L, 15.5 mg, 0.12 mmol, 3.00 equiv) and HATU (18.2 mg, 0.05 mmol, 1.20 equiv) were added. The reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the residual crude product (33.0 mg, 0.02 mmol, 1.00 equiv) was redissolved in anhydrous CH2Cl2 (1.00 mL) under nitrogen atmosphere. Dimethylamine borane complex (17.7 mg, 0.30 mmol, 15.0 equiv) and subsequently tetrakis palladium (2.31 mg, 2.00 mol, 10 mol%) were added and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, tR = 21.9–23.5 min). The


26

Page 27 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


peptoid hexamer 34 was obtained as a white solid (16.4 mg, 30%). HRMS (ESI-TOF) m/z: calcd for [M + H]+, C101H113N8O8+, 1565.8676; found 1565.8644. Purity according to analytical HPLC (gradient C): 98%.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website. Supporting schemes, figures, and tables, experimental procedures, HPLC traces, and copies of UV and NMR spectra (PDF). Data for compound 21 (CCDC 1857129) (CIF) AUTHOR INFORMATION Corresponding Author *Email: [email protected] ORCID Christian A. Olsen: 0000-0002-2953-8942 Isabelle Wellhöfer: 0000-0002-3311-2856 Present address #J.S.L.

is research and development chemist at NCK A/S, Rugmarken 28, DK-3520, Farum, Denmark

Notes The authors declare no competing financial interests ACKNOWLEDGMENT This work was supported by the Carlsberg Foundation (2013-01-0333; C.A.O.), the Danish Independent Research Council  Technical and Production Sciences (Grant No. 6111-00170), and The University of Copenhagen (Center for Biopharmaceuticals grant). Mr. Niels Vissing Holst (Department of Chemistry, University of Copenhagen) is gratefully acknowledged for technical assistance with X-ray diffraction data collecting and reduction.

REFERENCES 1. Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.; Marlowe, C. K.; Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P. A., Peptoids: A Modular Approach to Drug Discovery. Proc. Natl. Acad. Sci. U. S. A. 1992, 89 (20), 9367-9371. 2. Miller, S. M.; Simon, R. J.; Ng, S.; Zuckermann, R. N.; Kerr, J. M.; Moos, W. H., Proteolytic Studies of Homologous Peptide and N-Substituted Glycine Peptoid Oligomers. Bioorg. Med. Chem. Lett. 1994, 4 (22), 2657-2662. ACS Paragon Plus Environment

27


Page 28 of 34

3. Kwon, Y.-U.; Kodadek, T., Quantitative Evaluation of the Relative Cell Permeability of Peptoids and Peptides. J. Am. Chem. Soc. 2007, 129 (6), 1508-1509. 4. Shin, S. B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K., Cyclic Peptoids. J. Am. Chem. Soc. 2007, 129 (11), 3218-3225. 5. Pokorski, J. K.; Miller Jenkins, L. M.; Feng, H.; Durell, S. R.; Bai, Y.; Appella, D. H., Introduction of a Triazole Amino Acid into a Peptoid Oligomer Induces Turn Formation in Aqueous Solution. Org. Lett. 2007, 9 (12), 2381-2383. 6. Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E., Construction of Peptoids with All trans-Amide Backbones and Peptoid Reverse Turns via the Tactical Incorporation of N-Aryl Side Chains Capable of Hydrogen Bonding. J. Org. Chem. 2010, 75 (18), 6068-6078. 7. Crapster, J. A.; Guzei, I. A.; Blackwell, H. E., A Peptoid Ribbon Secondary Structure. Angew. Chem., Int. Ed. 2013, 52 (19), 5079-5084. 8. Crapster, J. A.; Stringer, J. R.; Guzei, I. A.; Blackwell, H. E., Design and Conformational Analysis of Peptoids Containing N‐Hydroxy Amides Reveals a Unique Sheet‐Like Secondary Structure. Peptide Science 2011, 96 (5), 604-616. 9. Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand, P.; Bradley, E. K.; Truong, K. T. V.; Dill, K. A.; Cohen, F. E.; Zuckermann, R. N., Sequence-Specific Polypeptoids: A Diverse Family of Heteropolymers with Stable Secondary Structure. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (8), 4303-4308. 10. Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.; Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E., Structural and Spectroscopic Studies of Peptoid Oligomers with α-Chiral Aliphatic Side Chains. J. Am. Chem. Soc. 2003, 125 (44), 13525-13530. 11. Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E., Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains. J. Am. Chem. Soc. 2011, 133 (39), 15559-15567. 12. Fuller, A. A.; Yurash, B. A.; Schaumann, E. N.; Seidl, F. J., Self-Association of Water-Soluble Peptoids Comprising (S)-N-1-(Naphthylethyl)glycine Residues. Org. Lett. 2013, 15 (19), 5118-5121. 13. Laursen, J. S.; Harris, P.; Fristrup, P.; Olsen, C. A., Triangular Prism-Shaped β-Peptoid Helices as Unique Biomimetic Scaffolds. Nat. Commun. 2015, 6, 7013. 14. Roy, O.; Dumonteil, G.; Faure, S.; Jouffret, L.; Kriznik, A.; Taillefumier, C., Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains. J. Am. Chem. Soc. 2017, 139 (38), 13533-13540. 15. Zborovsky, L.; Smolyakova, A.; Baskin, M.; Maayan, G., A Pure Polyproline Type I-like Peptoid Helix by Metal Coordination. Chem. Eur. J. 2018, 24 (5), 1159-1167. 16. Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum, K.; Zuckermann, R. N.; Barron, A. E.; Radhakrishnan, I., A Threaded Loop Conformation Adopted by a Family of Peptoid Nonamers. J. Am. Chem. Soc. 2006, 128 (5), 1733-1738. 17. Fowler, S. A.; Luechapanichkul, R.; Blackwell, H. E., Synthesis and Characterization of Nitroaromatic Peptoids: Fine Tuning Peptoid Secondary Structure through Monomer Position and Functionality. J. Org. Chem. 2009, 74 (4), 1440-1449. 18. Lee, B.-C.; Zuckermann, R. N.; Dill, K. A., Folding a Nonbiological Polymer into a Compact Multihelical Structure. J. Am. Chem. Soc. 2005, 127 (31), 10999-11009. 19. Nam, K. T.; Shelby, S. A.; Choi, P. H.; Marciel, A. B.; Chen, R.; Tan, L.; Chu, T. K.; Mesch, R. A.; Lee, B.-C.; Connolly, M. D.; Kisielowski, C.; Zuckermann, R. N., Free-Floating Ultrathin TwoDimensional Crystals from Sequence-Specific Peptoid Polymers. Nat. Mater. 2010, 9, 454-460. 20. Sanii, B.; Kudirka, R.; Cho, A.; Venkateswaran, N.; Olivier, G. K.; Olson, A. M.; Tran, H.; Harada, R. M.; Tan, L.; Zuckermann, R. N., Shaken, Not Stirred: Collapsing a Peptoid Monolayer To Produce Free-Floating, Stable Nanosheets. J. Am. Chem. Soc. 2011, 133 (51), 20808-20815. 21. Mannige, R. V.; Haxton, T. K.; Proulx, C.; Robertson, E. J.; Battigelli, A.; Butterfoss, G. L.; Zuckermann, R. N.; Whitelam, S., Peptoid Nanosheets Exhibit a New Secondary-Structure Motif. Nature 2015, 526 (7573), 415-420. 22. Robertson, E. J.; Battigelli, A.; Proulx, C.; Mannige, R. V.; Haxton, T. K.; Yun, L.; Whitelam, S.; Zuckermann, R. N., Design, Synthesis, Assembly, and Engineering of Peptoid Nanosheets. Acc. Chem. Res. 2016, 49 (3), 379-389. 23. Gellman, S. H., Foldamers: A Manifesto. Acc. Chem. Res. 1998, 31 (4), 173-180. 24. Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S., A Field Guide to Foldamers. Chem. Rev. 2001, 101 (12), 3893-4012.


28

Page 29 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


25. Hecht, S.; Huc, I., Foldamers: Structure, Properties, and Applications. Wiley-VCH GmbH & Co. KGaA: Weinheim, 2007. 26. Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F., Foldamers as Versatile Frameworks for the Design and Evolution of Function. Nat. Chem. Biol. 2007, 3 (5), 252-262. 27. Guichard, G.; Huc, I., Synthetic Foldamers. Chem. Commun. 2011, 47 (21), 5933-5941. 28. Zhang, D.-W.; Zhao, X.; Hou, J.-L.; Li, Z.-T., Aromatic Amide Foldamers: Structures, Properties, and Functions. Chem. Rev. 2012, 112 (10), 5271-5316. 29. Martinek, T. A.; Fülöp, F., Peptidic Foldamers: Ramping Up Diversity. Chem. Soc. Rev. 2012, 41 (2), 687-702. 30. Gopalakrishnan, R.; Frolov, A. I.; Knerr, L.; Drury, W. J.; Valeur, E., Therapeutic Potential of Foldamers: from Chemical Biology Tools to Drug Candidates? J. Med. Chem. 2016, 59 (21), 9599-9621. 31. Craven, T. W.; Bonneau, R.; Kirshenbaum, K., PPII Helical Peptidomimetics Templated by Cation–π Interactions. ChemBioChem 2016, 17 (19), 1824-1828. 32. Lee, B.-C.; Chu, T. K.; Dill, K. A.; Zuckermann, R. N., Biomimetic Nanostructures: Creating a High-Affinity Zinc-Binding Site in a Folded Nonbiological Polymer. J. Am. Chem. Soc. 2008, 130 (27), 8847-8855. 33. Maayan, G.; Ward, M. D.; Kirshenbaum, K., Metallopeptoids. Chem. Commun. 2009, 0 (1), 5658. 34. Maayan, G.; Liu, L.-K., Silver Nanoparticles Assemblies Mediated by Functionalized Biomimetic Oligomers. Biopolymers 2011, 96 (5), 679-687. 35. Izzo, I.; Ianniello, G.; De Cola, C.; Nardone, B.; Erra, L.; Vaughan, G.; Tedesco, C.; De Riccardis, F., Structural Effects of Proline Substitution and Metal Binding on Hexameric Cyclic Peptoids. Org. Lett. 2013, 15 (3), 598-601. 36. De Cola, C.; Fiorillo, G.; Meli, A.; Aime, S.; Gianolio, E.; Izzo, I.; De Riccardis, F., Gadolinium-Binding Cyclic Hexapeptoids: Synthesis and Relaxometric Properties. Org. Biomol. Chem. 2014, 12 (3), 424-431. 37. Baskin, M.; Maayan, G., Water-Soluble Chiral Metallopeptoids. Biopolymers 2015, 104 (5), 577-584. 38. De Santis, E.; Edwards, A. A.; Alexander, B. D.; Holder, S. J.; Biesse-Martin, A. S.; Nielsen, B. V.; Mistry, D.; Waters, L.; Siligardi, G.; Hussain, R.; Faure, S.; Taillefumier, C., Selective Complexation of Divalent Cations by a Cyclic ,-Peptoid Hexamer: A Spectroscopic and Computational Study. Org. Biomol. Chem. 2016, 14 (48), 11371-11380. 39. Baskin, M.; Panz, L.; Maayan, G., Versatile Ruthenium Complexes Based on 2,2’-Bipyridine Modified Peptoids. Chem. Commun. 2016, 52 (68), 10350-3. 40. Pirrung, M. C.; Park, K.; Tumey, L. N., 19F-Encoded Combinatorial Libraries: Discovery of Selective Metal Binding and Catalytic Peptoids. J. Comb. Chem. 2002, 4 (4), 329-344. 41. Maayan, G.; Ward, M. D.; Kirshenbaum, K., Folded Biomimetic Oligomers for Enantioselective Catalysis. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (33), 13679-13684. 42. Della Sala, G.; Nardone, B.; De Riccardis, F.; Izzo, I., Cyclopeptoids: A Novel Class of PhaseTransfer Catalysts. Org. Biomol. Chem. 2013, 11 (5), 726-731. 43. Schettini, R.; Nardone, B.; De Riccardis, F.; Della Sala, G.; Izzo, I., Cyclopeptoids as PhaseTransfer Catalysts for the Enantioselective Synthesis of α-Amino Acids. Eur. J. Org. Chem. 2014, 2014 (35), 7793-7797. 44. Prathap, K. J.; Maayan, G., Metallopeptoids as Efficient Biomimetic Catalysts. Chem. Commun. 2015, 51 (55), 11096-11099. 45. Schettini, R.; De Riccardis, F.; Della Sala, G.; Izzo, I., Enantioselective Alkylation of Amino Acid Derivatives Promoted by Cyclic Peptoids under Phase-Transfer Conditions. J. Org. Chem. 2016, 81 (6), 2494-2505. 46. Mohan, D. C.; Sadhukha, A.; Maayan, G., A Metallopeptoid as an Efficient Bioinspired Cooperative Catalyst for the Aerobic Oxidative Synthesis of Imines. J. Catal. 2017, 355, 139-144. 47. Jang, H.; Fafarman, A.; Holub, J. M.; Kirshenbaum, K., Click to Fit: Versatile Polyvalent Display on a Peptidomimetic Scaffold. Org. Lett. 2005, 7 (10), 1951-1954. 48. Kang, B.; Chung, S.; Ahn, Y. D.; Lee, J.; Seo, J., Porphyrin–Peptoid Conjugates: Face-to-Face Display of Porphyrins on Peptoid Helices. Org. Lett. 2013, 15 (7), 1670-1673. 49. Wang, Y.; Dehigaspitiya, D. C.; Levine, P. M.; Profit, A. A.; Haugbro, M.; Imberg-Kazdan, K.; Logan, S. K.; Kirshenbaum, K.; Garabedian, M. J., Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells. Cancer Res. 2016, 76 (17), 5124-5132. ACS Paragon Plus Environment

29


Page 30 of 34

50. Lepage, M. L.; Schneider, J. P.; Bodlenner, A.; Meli, A.; De Riccardis, F.; Schmitt, M.; Tarnus, C.; Nguyen-Huynh, N.-T.; Francois, Y.-N.; Leize-Wagner, E.; Birck, C.; Cousido-Siah, A.; Podjarny, A.; Izzo, I.; Compain, P., Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels. Chem. Eur. J. 2016, 22 (15), 5151-5155. 51. Battigelli, A.; Kim, J. H.; Dehigaspitiya, D. C.; Proulx, C.; Robertson, E. J.; Murray, D. J.; Rad, B.; Kirshenbaum, K.; Zuckermann, R. N., Glycosylated Peptoid Nanosheets as a Multivalent Scaffold for Protein Recognition. ACS Nano 2018, 12 (3), 2455-2465. 52. Reddy, M. M.; Kodadek, T., Protein “Fingerprinting” in Complex Mixtures with Peptoid Microarrays. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (36), 12672-12677. 53. Knight, A. S.; Zhou, E. Y.; Pelton, J. G.; Francis, M. B., Selective Chromium(VI) Ligands Identified Using Combinatorial Peptoid Libraries. J. Am. Chem. Soc. 2013, 135 (46), 17488-17493. 54. Olivier, G. K.; Cho, A.; Sanii, B.; Connolly, M. D.; Tran, H.; Zuckermann, R. N., AntibodyMimetic Peptoid Nanosheets for Molecular Recognition. ACS Nano 2013, 7 (10), 9276-9286. 55. Baskin, M.; Maayan, G., A Rationally Designed Metal-Binding Helical Peptoid for Selective Recognition Processes. Chem. Sci. 2016, 7 (4), 2809-2820. 56. Nguyen, J. T.; Turck, C. W.; Cohen, F. E.; Zuckermann, R. N.; Lim, W. A., Exploiting the Basis of Proline Recognition by SH3 and WW Domains: Design of N-Substituted Inhibitors. Science 1998, 282 (5396), 2088-2092. 57. Patch, J. A.; Barron, A. E., Helical Peptoid Mimics of Magainin-2 Amide. J. Am. Chem. Soc. 2003, 125 (40), 12092-12093. 58. Hara, T.; Durell, S. R.; Myers, M. C.; Appella, D. H., Probing the Structural Requirements of Peptoids That Inhibit HDM2−p53 Interactions. J. Am. Chem. Soc. 2006, 128 (6), 1995-2004. 59. Chongsiriwatana, N. P.; Patch, J. A.; Czyzewski, A. M.; Dohm, M. T.; Ivankin, A.; Gidalevitz, D.; Zuckermann, R. N.; Barron, A. E., Peptoids that Mimic the Structure, Function, and Mechanism of Helical Antimicrobial Peptides. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (8), 2794-2799. 60. Brown, N. J.; Wu, C. W.; Seurynck-Servoss, S. L.; Barron, A. E., Effects of Hydrophobic Helix Length and Side Chain Chemistry on Biomimicry in Peptoid Analogues of SP-C. Biochemistry 2008, 47 (6), 1808-1818. 61. Huang, M. L.; Benson, M. A.; Shin, S. B. Y.; Torres, V. J.; Kirshenbaum, K., Amphiphilic Cyclic Peptoids That Exhibit Antimicrobial Activity by Disrupting Staphylococcus aureus Membranes. Eur. J. Org. Chem. 2013, 2013 (17), 3560-3566. 62. D’Amato, A.; Volpe, R.; Vaccaro, M. C.; Terracciano, S.; Bruno, I.; Tosolini, M.; Tedesco, C.; Pierri, G.; Tecilla, P.; Costabile, C.; Della Sala, G.; Izzo, I.; De Riccardis, F., Cyclic Peptoids as Mycotoxin Mimics: An Exploration of Their Structural and Biological Properties. J. Org. Chem. 2017, 82 (17), 88488863. 63. Czyzewski, A. M.; McCaig, L. M.; Dohm, M. T.; Broering, L. A.; Yao, L.-J.; Brown, N. J.; Didwania, M. K.; Lin, J. S.; Lewis, J. F.; Veldhuizen, R.; Barron, A. E., Effective In Vivo Treatment of Acute Lung Injury with Helical, Amphipathic Peptoid Mimics of Pulmonary Surfactant Proteins. Sci. Rep. 2018, 8 (1), 6795. 64. Shyam, R.; Charbonnel, N.; Job, A.; Blavignac, C.; Forestier, C.; Taillefumier, C.; Faure, S., 1,2,3-Triazolium-Based Cationic Amphipathic Peptoid Oligomers Mimicking Antimicrobial Helical Peptides. ChemMedChem 2018, 13 (15), 1513-1516. 65. Bautista, A. D.; Craig, C. J.; Harker, E. A.; Schepartz, A., Sophistication of Foldamer Form and Function In Vitro and In Vivo. Curr. Opin. Chem. Biol. 2007, 11 (6), 685-692. 66. Yoo, B.; Kirshenbaum, K., Peptoid Architectures: Elaboration, Actuation, and Application. Curr. Opin. Chem. Biol. 2008, 12 (6), 714-721. 67. Fowler, S. A.; Blackwell, H. E., Structure-Function Relationships in Peptoids: Recent Advances toward Deciphering the Structural Requirements for Biological Function. Org. Biomol. Chem. 2009, 7 (8), 1508-1524. 68. Horne, W. S., Peptide and Peptoid Foldamers in Medicinal Chemistry. Expert Opin. Drug Discovery 2011, 6 (12), 1247-1262. 69. Sun, J.; Zuckermann, R. N., Peptoid Polymers: A Highly Designable Bioinspired Material. ACS Nano 2013, 7 (6), 4715-4732. 70. Gangloff, N.; Ulbricht, J.; Lorson, T.; Schlaad, H.; Luxenhofer, R., Peptoids and Polypeptoids at the Frontier of Supra- and Macromolecular Engineering. Chem. Rev. 2016, 116 (4), 1753-1802. 71. Norgren, A. S.; Zhang, S.; Arvidsson, P. I., Synthesis and Circular Dichroism Spectroscopic Investigations of Oligomeric β-Peptoids with α-Chiral Side Chains. Org. Lett. 2006, 8 (20), 4533-4536. ACS Paragon Plus Environment

30

Page 31 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


72. Mejías, X.; Feliu, L.; Planas, M.; Bardají, E., Synthesis of Nucleobase-Functionalized βPeptoids and β-Peptoid Hybrids. Tetrahedron Lett. 2006, 47 (46), 8069-8071. 73. Baldauf, C.; Günther, R.; Hofmann, H.-J., Helices in Peptoids of - and -Peptides. Phys. Biol. 2006, 3 (1), S1-S9. 74. Olsen, C. A.; Bonke, G.; Vedel, L.; Adsersen, A.; Witt, M.; Franzyk, H.; Jaroszewski, J. W., αPeptide/β-Peptoid Chimeras. Org. Lett. 2007, 9 (8), 1549-1552. 75. Vedel, L.; Bonke, G.; Foged, C.; Ziegler, H.; Franzyk, H.; Jaroszewski, J. W.; Olsen, C. A., Antiplasmodial and Prehemolytic Activities of α-Peptide–β-Peptoid Chimeras. ChemBioChem 2007, 8 (15), 1781-4. 76. Bonke, G.; Vedel, L.; Witt, M.; Jaroszewski, J. W.; Olsen, C. A.; Franzyk, H., Dimeric Building Blocks for Solid-Phase Synthesis of α-Peptide-β-Peptoid Chimeras. Synthesis 2008, 2008 (15), 2381-2390. 77. Roy, O.; Faure, S.; Thery, V.; Didierjean, C.; Taillefumier, C., Cyclic β-Peptoids. Org. Lett. 2008, 10 (5), 921-924. 78. Olsen, C. A.; Lambert, M.; Witt, M.; Franzyk, H.; Jaroszewski, J. W., Solid-Phase Peptide Synthesis and Circular Dichroism Study of Chiral β-Peptoid Homooligomers. Amino Acids 2008, 34 (3), 465471. 79. Olsen, C. A., β-Peptoid “Foldamers”—Why the Additional Methylene Unit? Biopolymers 2011, 96 (5), 561-566. 80. Laursen, J. S.; Engel-Andreasen, J.; Olsen, C. A., β-Peptoid Foldamers at Last. Acc. Chem. Res. 2015, 48 (10), 2696-2704. 81. Hamper, B. C.; Kolodziej, S. A.; Scates, A. M.; Smith, R. G.; Cortez, E., Solid Phase Synthesis of β-Peptoids: N-Substituted β-Aminopropionic Acid Oligomers. J. Org. Chem. 1998, 63 (3), 708-718. 82. Gorske, B. C.; Bastian, B. L.; Geske, G. D.; Blackwell, H. E., Local and Tunable n→π* Interactions Regulate Amide Isomerism in the Peptoid Backbone. J. Am. Chem. Soc. 2007, 129 (29), 89288929. 83. Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau, R.; Rabenstein, D. L.; Kirshenbaum, K., Oligo(N-aryl glycines): A New Twist on Structured Peptoids. J. Am. Chem. Soc. 2008, 130 (49), 16622-16632. 84. Gorske, B. C.; Stringer, J. R.; Bastian, B. L.; Fowler, S. A.; Blackwell, H. E., New Strategies for the Design of Folded Peptoids Revealed by a Survey of Noncovalent Interactions in Model Systems. J. Am. Chem. Soc. 2009, 131 (45), 16555-16567. 85. Caumes, C.; Roy, O.; Faure, S.; Taillefumier, C., The Click Triazolium Peptoid Side Chain: A Strong cis-Amide Inducer Enabling Chemical Diversity. J. Am. Chem. Soc. 2012, 134 (23), 9553-9556. 86. Roy, O.; Caumes, C.; Esvan, Y.; Didierjean, C.; Faure, S.; Taillefumier, C., The tert-Butyl Side Chain: A Powerful Means to Lock Peptoid Amide Bonds in the cis Conformation. Org. Lett. 2013, 15 (9), 2246-2249. 87. Laursen, J. S.; Engel-Andreasen, J.; Fristrup, P.; Harris, P.; Olsen, C. A., Cis–trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains. J. Am. Chem. Soc. 2013, 135 (7), 2835-2844. 88. Aliouat, H.; Caumes, C.; Roy, O.; Zouikri, M.; Taillefumier, C.; Faure, S., 1,2,3-TriazoliumBased Peptoid Oligomers. J. Org. Chem. 2017, 82 (5), 2386-2398. 89. Dumonteil, G.; Bhattacharjee, N.; Angelici, G.; Roy, O.; Faure, S.; Jouffret, L.; Jolibois, F.; Perrin, L.; Taillefumier, C., Exploring the Conformation of Mixed cis–trans α,β-Oligopeptoids: A Joint Experimental and Computational Study. J. Org. Chem. 2018, 83 (12), 6382-6396. 90. Engel-Andreasen, J.; Wich, K.; Laursen, J. S.; Harris, P.; Olsen, C. A., Effects of Thionation and Fluorination on cis–trans Isomerization in Tertiary Amides: An Investigation of N-Alkylglycine (Peptoid) Rotamers. J. Org. Chem. 2015, 80 (11), 5415-5427. 91. Cheng, R. P.; Gellman, S.; DeGrado, W. F., β-Peptides: From Structure to Function. Chem. Rev. 2001, 101 (10), 3219-3232. 92. Seebach, D.; Beck, A. K.; Bierbaum, D. J., The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components. Chem. Biodiv. 2004, 1 (8), 1111-1239. 93. Horne, W. S.; Gellman, S. H., Foldamers with Heterogeneous Backbones. Acc. Chem. Res. 2008, 41 (10), 1399-1408. 94. Dado, G. P.; Gellman, S. H., Intramolecular Hydrogen Bonding in Derivatives of -Alanine and -Amino Butyric Acid; Model Studies for the Folding of Unnatural Polypeptide Backbones. J. Am. Chem. Soc. 1994, 116 (3), 1054-1062.


31


Page 32 of 34

95. Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H., β-Peptides: Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a β-Hexapeptide in Solution and its Stability towards Pepsin. Helv. Chim. Acta 1996, 79 (4), 913-941. 96. Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.; Barchi Jr, J. J.; Gellman, S. H., Residue-Based Control of Helix Shape in β-Peptide Oligomers. Nature 1997, 387, 381-384. 97. Seebach, D.; Gardiner, J., β-Peptidic Peptidomimetics. Acc. Chem. Res. 2008, 41 (10), 13661375. 98. Seo, J.; Barron, A. E.; Zuckermann, R. N., Novel Peptoid Building Blocks: Synthesis of Functionalized Aromatic Helix-Inducing Submonomers. Org. Lett. 2010, 12 (3), 492-495. 99. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem., Int. Ed. 2002, 41 (14), 2596-2599. 100. Tornøe, C. W.; Christensen, C.; Meldal, M., Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67 (9), 3057-3064. 101. Gimenez, D.; Aguilar, J. A.; Bromley, E. H. C.; Cobb, S. L., Stabilising Peptoid Helices Using Non-Chiral Fluoroalkyl Monomers. Angew. Chem., Int. Ed. 2018, 57 (33), 10549-10553. 102. Schultz, E. M.; Bolhofer, W. A.; Augenblick, A.; Bicking, J. B.; Habecker, C. N.; Horner, J. K.; Kwong, S. F.; Pietruszkiewicz, A. M., Maleamic Acids That Affect Plasma Cholesterol and Penicillin Excretion. J. Med. Chem. 1967, 10 (4), 717-724. 103. Nunn, L. G.; Henze, H. R., Certain 1-Naphthyl Ketones. J. Org. Chem. 1947, 12 (4), 540-542. 104. Liu, G.; Cogan, D. A.; Ellman, J. A., Catalytic Asymmetric Synthesis of tertButanesulfinamide. Application to the Asymmetric Synthesis of Amines. J. Am. Chem. Soc. 1997, 119 (41), 9913-9914. 105. Cogan, D. A.; Liu, G.; Ellman, J., Asymmetric Synthesis of Chiral Amines by Highly Diastereoselective 1,2-Additions of Organometallic Reagents to N-tert-Butanesulfinyl Imines. Tetrahedron 1999, 55 (29), 8883-8904. 106. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A., Synthesis of Enantiomerically Pure N-tert-Butanesulfinyl Imines (tert-Butanesulfinimines) by the Direct Condensation of tertButanesulfinamide with Aldehydes and Ketones. J. Org. Chem. 1999, 64 (4), 1278-1284. 107. Darapaneni, C. M.; Kaniraj, P. J.; Maayan, G., Water Soluble Hydrophobic Peptoids via a Minor Backbone Modification. Org. Biomol. Chem. 2018, 16 (9), 1480-1488. 108. Shin, S. B. Y.; Kirshenbaum, K., Conformational Rearrangements by Water-Soluble Peptoid Foldamers. Org. Lett. 2007, 9 (24), 5003-5006. 109. Bécart, D.; Diemer, V.; Salaün, A.; Oiarbide, M.; Nelli, Y. R.; Kauffmann, B.; Fischer, L.; Palomo, C.; Guichard, G., Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C–C Bond-Forming Reactions. J. Am. Chem. Soc. 2017, 139 (36), 12524-12532. 110. Buratto, J.; Colombo, C.; Stupfel, M.; Dawson, S. J.; Dolain, C.; Langlois d'Estaintot, B.; Fischer, L.; Granier, T.; Laguerre, M.; Gallois, B.; Huc, I., Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution. Angew. Chem., Int. Ed. 2014, 53 (3), 883-887. 111. Lao, B. B.; Grishagin, I.; Mesallati, H.; Brewer, T. F.; Olenyuk, B. Z.; Arora, P. S., In Vivo Modulation of Hypoxia-Inducible Signaling by Topographical Helix Mimetics. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (21), 7531-7536. 112. Wechsel, R.; Žabka, M.; Ward, J. W.; Clayden, J., Competing Hydrogen-Bond Polarities in a Dynamic Oligourea Foldamer: A Molecular Spring Torsion Balance. J. Am. Chem. Soc. 2018, 140 (10), 35283531. 113. Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.; Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann, R. N.; Bradley, E. K., NMR Determination of the Major Solution Conformation of a Peptoid Pentamer with Chiral Side Chains. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (8), 4309-4314. 114. Bruker Apex2 Suite, Bruker AXS: Madison, Wisconsin, USA, 2016. 115. Bruker SAINT Version 8.37A. Data reduction and correction program., Bruker AXS: Madison, Wisconsin, USA, 2016. 116. Bruker SADABS-2016/2. Bruker/Siemens Area Detector Absorption Correction program. , Bruker AXS: Madison, Wisconsin, USA, 2016. 117. Sheldrick, G. M., A short history of SHELX. Acta Crystallogr., Sect. A 2008, 64 (1), 112-122. ACS Paragon Plus Environment

32

Page 33 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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


118. Flack, H. D., On enantiomorph-polarity estimation. Acta Crystallogr., Sect. A 1983, 39 (6), 876881. 119. International Tables for Chrystallography. In International Tables for Chrystallography, Wilson, A. J. C., Ed. Kluwer Academic Publishers: Dordrecht, The Netherlands, 1995; Vol. C. 120. Alvarez, S. G.; Alvarez, M. T., A Practical Procedure for the Synthesis of Alkyl Azides at Ambient Temperature in Dimethyl Sulfoxide in High Purity and Yield. Synthesis 1997, 1997 (04), 413-414. 121. Campbell-Verduyn, L. S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.; Feringa, B. L., Phosphoramidite Accelerated Copper(i)-Catalyzed [3 + 2] Cycloadditions of Azides and Alkynes. Chem. Commun. 2009, 0 (16), 2139-2141. 122. Reginato, G.; Mordini, A.; Messina, F.; Degl'Innocenti, A.; Poli, G., A New Stereoselective Synthesis of Chiral γ-Functionalized (E)-Allylic Amines. Tetrahedron 1996, 52 (33), 10985-10996. 123. Fincham, C. I.; Bressan, A.; D’Andrea, P.; Ettorre, A.; Giuliani, S.; Mauro, S.; Meini, S.; Paris, M.; Quartara, L.; Rossi, C.; Squarcia, A.; Valenti, C.; Daniela, F.; Maggi, C. A., Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. Synthesis and structure-relationships of α,αtetrahydropyranylglycine. Bioorg. Med. Chem. 2012, 20 (6), 2091-2100.


33


Page 34 of 34

TOC Graphic


34

Functionalized Helical Î²-Peptoids - The Journal of Organic Chemistry

Recommend Documents