Bio-Inspired Herringbone Foldamers: Strategy for Changing the

Article pubs.acs.org/joc

Bio-inspired Herringbone Foldamers: Strategy for Changing the Structure of Helices Abdulselam Adam, Gebhard Haberhauer,* and Christoph Wölper Institut für Organische Chemie, Universität Duisburg-Essen, Universitätsstr. 7, D-45117 Essen, Germany S Supporting Information *

ABSTRACT: Cyclic oligomers of azole peptides were isolated from a multitude of marine organisms and were used for a large number of molecular machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we show that a minor change, the introduction of a methyl group in the δ position, results in a significant change in the secondary structure of the corresponding oligomers. Instead of a canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the helix changes its sign at least twice per turn. This strategy allows a remarkable change of the secondary structure via a small modification. By means of enantiomerically pure amino acids, we were able to control, for the first time, both the helicity of the helix and the form of the herringbone. The investigation of the underlying herringbone basic element and its folding to a noncanonical helix were conducted by NMR and CD spectroscopy, as well as by X-ray crystallography and quantum chemical calculations.

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INTRODUCTION Peptides and proteins play a major role in living organisms. Due to their specific and highly organized structures, they are the most important molecular machines in cells.1,2 In this context, the information about the superior structure is of utmost importance: controlling the form of the structure means controlling its function.3−5 Through a specific structural change, it is possible to influence the selectivity and the effect of bioactive substances enormously.1,2,5 Therefore, a great deal of effort has been invested in manipulating the secondary structure of peptides and proteins in a highly directed and effective way. One basic structural element found in peptides and proteins is helicity.6 It has been shown that, besides the naturally occurring α-amino acids, synthetic α/β/γ-amino acids also form oligomers exhibiting helix-like structures.7−22 The incorporation of azole-containing units in these amino acids reduces the backbone flexibility and enhances the stability of the helical secondary structure.23,24 Almost all of these helical structures have a canonical form. An up-to-date, but scarcely investigated issue is the formation and control of noncanonical helices. Huc et al. were able to show that oligomers bearing aliphatic-aromatic δ-amino acids are prone to form a noncanonical helix with a herringbone form.25,26 The helicity of a noncanonical helix can be induced by incorporating a single chiral carbon of the N-terminal moiety.27 However, the control of the type of helix, the helicity and the form of the herringbone has, to the best of our knowledge, never been investigated and described. In this context, controlling the form of the helix is crucial for biological functions. © 2017 American Chemical Society

Recently, we synthesized oligomers from imidazole containing δ-amino acids, which fold into canonical helices.28 These compounds are congeners of naturally occurring marine metabolites29−32 and can be used to transfer chirality to further stereogenic elements33−35 making the design of unidirectional molecular machines possible.36−38 The helices formed by oligomers of this imidazole δ-amino acids are stabilized by both hydrogen bonds and dispersion interactions.28 It is interesting to note that in these helices hydrogen bonds are arranged almost orthogonally to the axis of the helix. In naturally occurring helices of α-amino acids, the hydrogen bonds are arranged parallel to the axis of the helix.16 Here we show that the introduction of a single methyl group in the imidazolecontaining δ-amino acid leads to a significant change in the secondary structure and its properties. Instead of a canonical helix, a noncanonical helix with a herringbone form is observed. Due to the use of enantiomerically pure amino acids, the chiral information at the stereogenic centers predetermines the helicity and the form of the herringbone.

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RESULTS AND DISCUSSION Concept for Changing the Structure and the Determination of the Herringbone Form in Noncanonical Helices. In the case of canonical helices, the building blocks are connected in such a way that the slope along the helix does not change significantly, neither in size nor in sign (see Figure 1a). In a noncanonical helix, an additional Received: January 24, 2017 Published: March 30, 2017 4203

DOI: 10.1021/acs.joc.7b00185 J. Org. Chem. 2017, 82, 4203−4215

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The Journal of Organic Chemistry

Figure 1. (a) Schematic representation of a canonical M helix as well as two noncanonical M helices showing herringbone form V and A. The blue dots at the top represent the N-termini; the red dots at the bottom represent the C-termini. (b) The dihedral angle θ(C1−N2−C3−C4) in a dimer of two achiral imidazole amino acids amounts to about 180°. The corresponding oligomer adopts a canonical M helix (left). (c) In a dimer of chiral imidazole amino acids, the absolute value of the dihedral angle θ(C1−N2−C3−C4) is significantly smaller than 180°. The corresponding oligomers should fold into noncanonical helices either with V or with A herringbone form.

In order to obtain a noncanonical helix, we used the following approach. The introduction of an alkyl group at the δ carbon atom should result in a bending of the corresponding dimer (Figure 1c). This dimer can be considered as a herringbone unit. In previous studies, we were able to show that an alkyl group (e.g., a methyl or isopropyl group) leads to a significant deviation of the dihedral angle θ(C1−N2−C3−C4) from 180°.39,40 Model studies have shown that an imidazole with a methyl group attached to the δ position have two minima: one thereof shows a dihedral angle θ(C1−N2−C3− C4) of −156°; the strongly bent one has a dihedral angle of −102°. The first conformation is stabilized by interaction * between the σ(C3−Me) orbital and the πimidazole orbital; the second one exhibits a stabilizing interaction between the σ*(C3−N2) orbital and the πimidazole orbital.41 If a couple of these dimers are formed into an oligomer, the latter should fold into a noncanonical helix with an additional herringbone form (Figure 1c). A critical point is the size of the alkyl group. On the one hand, they should be large enough to cause a bending of the dimer as previous investigations showed that the larger the alkyl groups are, the larger is the bending of the corresponding dimer.40 On the other hand, the size of the alkyl groups must not be too large: in the noncanonical helix, the alkyl groups are orientated parallel to the helix axis. If they are too bulky, the attractive interactions between the turns will probably be inhibited resulting in no helix formation. Therefore, we chose methyl groups as substituents. If the achiral imidazole amino acid is considered as equivalent to glycine (see above), the imidazole amino acid showing one methyl group at the δ carbon atom is an analogue to alanine. Furthermore, we intended to use a chiral imidazole amino acid, which should allow us to determine both the helicity and the herringbone form. Synthesis of the Oligomers. The synthesis of the oligomers is shown in Scheme 1. The first step is the synthesis of the corresponding imidazole amino acid starting from the Boc-protected alanine 1 and the amino ketone 2. The resulting diprotected imidazole amino acid can be transformed into both the free acid 4a and into the ammonium salt 5b. Starting from these two building blocks, the dimer 6a, the trimer 7, the tetramer 10a, the heptamer 11, and also the decamer 13a can be synthesized by stepwise coupling (reaction condition C),

superior structure exists; one example of this is the herringbone form (see Figure 1a). This herringbone form changes the helix in such a way that the slope along the helix changes its sign at least twice per turn. The combination of two superior structures (helix and herringbone) results in the existence of six different conformations, which are described by the following descriptors: M and P for the helicity and V and A for the herringbone form. In order to correctly use the descriptors V and A for the herringbone form, the orientation of the helix has to be specified. In the following, the discussed helices should be orientated in such a way that the N-termini are on the top and the C-termini on the bottom (Figure 1a). If we order the helices in that way, the apex of the herringbone building block is orientated downward in the herringbone form V with the opposite being true for the herringbone form A. In Figure 1a, a canonical M helix as well as two noncanonical M helices showing herringbone form V and A, respectively, are depicted schematically. The blue dots on the top represent the N-termini; the red dots at the bottom represent the C-termini. Our aim was to change the structure of a helical oligopeptide into a noncanonical herringbone helix by introduction of a small group. Whereby, we intended to govern both the helicity (M or P) and the herringbone form (V or A) of the helix by the introduction of chiral information into monomers. Recently, we were able to show that oligomers derived from imidazole peptides form canonical helices. In these δ-amino acids, the α, β, and γ centers are parts of the imidazole rings with the δ centers as aliphatic carbon atoms. With exception of the Ntermini, the foldamers consists of only achiral units; in other words, the δ carbon atoms possess two hydrogen atoms as substituents and the corresponding amino acid can be considered as being equivalent to the α-amino acid glycine. In Figure 1b, a dimer of such achiral imidazole amino acids is shown. As the δ carbon atom (C3 in Figure 1b) has two equivalent substituents (hydrogen atoms), the dihedral angle θ(C1−N2−C3−C4) should be about 180° resulting in an almost flat dimer. If a couple of these dimers are formed as an oligomer, the resulting secondary structure represents a canonical helix. The helicity of this helix can be determined by a single chiral imidazole amino acid located at the Nterminus. 4204


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The Journal of Organic Chemistry Scheme 1. Synthesis of the Decamer 13aa

group results in a bending of the dimer (θ(C1−N2−C3−C4) ≪ 180°), should be verified. Second, cyclic peptides are known to crystallize better, allowing for an additional investigation of the conformation in solid state. In the first step, the free amino acids 14 and 21 were synthesized (Scheme 2). The one-pot cyclization of the amino acid 14 leads to the trimer 15, and the tetramer 16 in moderate yields. The macrotrimerization of the amino acid 21 result in the cyclic trimer 22; the corresponding tetramer could only be detected in traces. Investigation of the Secondary Structure. For structural investigations, the 1H NMR spectra of the linear oligomers showing different chain lengths were recorded in chloroform. A section of these spectra is depicted in Figure 2. Additionally, the 1 H NMR spectrum of decamer 23, which consists of nine achiral imidazole amino acids (the only one chiral unit is at the N-terminus and accordingly unimportant for the shape of the helix), is also given. This decamer is known to form a canonical helix in solution.28 While the amide signals are found at 7.6−8.5 ppm for the short oligomers (up to the tetramer 10a), these are shifted to lower field for the higher oligomers (heptamer 11 and decamer 13a). The NH resonances are found at values of up to 10.2 ppm. This strong shift is an unambiguous hint for the formation of hydrogen bridges. The extent of the hydrogen bond formation is comparable to that of the decamer 23 showing a canonical helix.28 The 1H NMR coupling constants of the amide protons in 13a ranges in the area from 6.9 to 8.5 Hz, which corresponds to dihedral angles θ(H−N2−C3−H) with absolute values from 140° to 153°.42 An interesting aspect in 1H NMR spectra of the linear oligomers is the broadening of the signals and thus the dynamic of the systems. In the case of the short oligomers (dimer 6a to tetramer 10a) and the decamer 13a, the peaks are sharp. Accordingly, the exchange is fast (dimer 6a to tetramer 10a) or slow (decamer 13a) with respect to the NMR time scale. In the case of heptamer 11, exchange is neither slow nor fast (Figure 2). It corresponds to an intermediate regime where different species coexist that exchange at a rate of the same order than the frequency difference of the NMR signals. The first hint for the existence of a noncanonical helix of decamer 13a can be found through a comparison to the decamer 23. Both have the same number of hydrogen bridges but show a completely different dynamic. For decamer 23, a slow dynamic with respect to the NMR time scale can be observed. Whereby, the flexibility inside the helix is slower than that at the outer sides.28 In the decamer 13a, also the monomers at the termini hardly show any dynamic indicating the whole secondary structure is equally frozen. Based on the concentration-independent 1H NMR spectra, it can be definitively excluded that these observations are caused by intermolecular processes like aggregation.28 Variable temperature 1H NMR measurements of the oligomers in CDCl3 and C2D2Cl4 show that the secondary structures collapse at higher temperatures. In the case of the heptamer 11, the hydrogen bonds are broken even at 50 °C resulting in a shift of the amide protons to the range of 7.6 ppm (Supporting Information). In the case of the decamer 13a, a temperature increase leads to only a slight high field shift of the NH signals (Supporting Information). Only from 80 °C, the amide signals become extremely broadened indicating a high dynamic of the secondary structure. At temperatures above 100 °C, the NH signals are found at about 7.6 ppm. Furthermore, NOESY experiments were performed for the decamer 13a (see Supporting Information, Figures S13−15).

a

Reaction conditions: (i) THF, NMM, ClCOOiBu, 88%; (ii) xylene, MeNH2, AcOH, Δ, 85%; (iii) MeOH, dioxane, NaOH, 83%; (iv) MeOH, H2O, Cs2CO3, PhCH2Br, DMF, 79%; general procedure A, EtOAc, HCl; general procedure B, MeOH, Pd(OH)2/C, H2; general procedure C, CH3CN, iPr2NEt, FDPP. FDPP = pentafluorophenyldiphenylphosphinate, NMM = N-methylmorpholine.

Boc-deprotection (reaction condition A), and benzyl esterdeprotection (reaction condition B) (see Scheme 1). Additionally to the linear oligomers 6a, 7, 10a, 11, and 13a, the cyclic oligomers 15, 16, and 22 were prepared (Scheme 2). These were done for the following two reasons: first, by means of these cyclic compounds, the above-mentioned thesis, that the absence of an alkyl group leads to a dihedral angle θ(C1− N2−C3−C4) of about 180° whereas the presence of a methyl Scheme 2. Synthesis of the Cyclic Trimers 15 and 22 as Well as the Cyclic Tetramer 16a

a

Reaction conditions: (i) THF, Boc2O, Pd(OH)2/C, 93%; (ii) DMF, NaH, PhCH2Br, 51%; (iii) MeOH, dioxane, NaOH, 96%; general procedure A, EtOAc, HCl; general procedure C, CH3CN, iPr2NEt, FDPP. 4205


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Figure 2. 1H NMR spectra of the oligomers dependent on their chain length in CDCl3: (a) decamer 23, (b) decamer 13a, (c) heptamer 11, (d) tetramer 10a, (e) trimer 7, (f) dimer 6a, and (g) monomer 5a.

Figure 3. (a) CD spectra (per chiral unit) of monomer 5a (red), dimer 6a (green), trimer 7 (blue), tetramer 10a (brown), heptamer 11 (light blue), and decamer 13a (yellow) in acetonitrile. (b) CD spectra (per chiral unit) of decamer 13a in acetonitrile in the range from −10 to 80 °C in steps of 10 °C.

significant decrease of the signals is found up to the trimer. At 210 nm, only the higher oligomers (heptamer and decamer) show a positive Cotton effect. Furthermore, for the higher oligomers a slight bathochromic shift for the positive Cotton effects at 235 and 260 nm are observed (Figure 3a). Our interpretation for this observation is the following: starting from a trimer, subordinate structural elements are formed that may correspond to a herringbone basic element (see Figure 1b). In higher oligomers, the herringbone basic elements arrange to an organized superordinate structure, which can be considered as a herringbone helix. This hypothesis is supported by variable temperature CD measurements of the decamer 13a (Figure 3b): increasing the temperature leads to the decrease of the organized helical structure. The positive Cotton effect at 210 nm diminishes and a hypsochromic shift of the band at 240 nm is observed. The CD spectrum of the decamer 13a at a temperature of 80 °C resembles those of the trimer 7 and the tetramer 10a at 20 °C. This means that the herringbone basic elements also remain at higher temperatures. A similar behavior is also found for the heptamer 11 (see Supporting Information). In the case of the smaller oligomers (dimer, trimer, and tetramer), only limited breakup of the herringbone basic elements is observed (see Supporting Information). CD measurements in different organic solvents and in aqueous solution show that both the herringbone basic elements and the helix remain, which is of particular importance for applications in medicinal chemistry (see Supporting Information). Furthermore, water titration experi-

Since the decamer 13a is constituted of the same monomer, the signals of the relevant nucleus appear in such narrow range that a distinction and exact assignment is not possible. This behavior is maybe a hint that folding of decamer 13a is not very compact. However, an important conclusion can be drawn when the coupling range between the amide protons and the methyl groups attached to the δ position is considered (Figure S14): some amide hydrogen atoms (e.g., at 9.16 and 9.65 ppm) are in close proximity (37 kcal/mol) that we will exclude them from a further discussion. In the case of the canonical M helix, a turn consists of about 3.5 imidazole amino acids. This was already found for the canonical helices of the achiral amino acids.28 The pitch, calculated as the distance measured between the C(3) atom of the ith imidazole unit and the carbonyl carbon atom (C1) of the (i + 3) unit, is about 4.1 Å (numbering see Figure 1b). This is in the range of typical π−π stacking interactions;56 however, it is higher than that in the helices composed of achiral imidazole amino acids (3.4 Å).28 This is due to the additional methyl groups in the M helix of decamer 13b, which are placed between the turns preventing effective π−π stacking interactions. The methyl groups at the stereogenic centers point outside the helix and are accordingly far away (>3.5 Å) from the amide hydrogen atoms. For the noncanonical M helix with herringbone form V, a full turn consists of 4.5 imidazole amino acids. The dihedral angle θ(C1−N2−C3−C4) (see Figure 1b) adopts two different values in the helix: Within the herringbone basic element (consisting of two imidazole amino acids), a value of about −105° is found (Figure 7). At the interface between two herringbone basic elements, it amounts to ca. −152°. Please note that accordingly the noncanonical M helix with herringbone form V can consist of two different conformers: The helix can start at the C-terminus either with a strongly (θ(C1−N2−C3−C4) ≈ −105°) or with a weakly bent (θ(C1− N2−C3-C4) ≈ −150°) unit. The former one is energetically more favored (Figure S19 and S21). The methyl groups (C5,

Figure 5. (a) Experimentally determined CD spectrum of the cyclic trimers 15 (red) and 25 (green) as well as the cyclic tetramer 16 (blue) in acetonitrile at 20 °C. (b) Simulated (TD-B3LYP/6-31G*) CD spectra of the cyclic trimers 15 (red) and 25 (green), as well as the cyclic tetramer 16 (blue).

obtained helical geometries and further preorientated conformations were used as starting geometries for additional quantum chemical calculations. The optimization was performed using the B3LYP functional, the empirical D3 dispersion correction, and the 6-31G* basis set. Although all possible helical structures (canonical M and P helix, noncanonical M and P helix with herringbone form V and A) were used as starting geometries for the B3LYP-D3 calculations, only four types of helical structures were verified as end structures during the optimization process. These helices are depicted in Figure 6 with their relative energies. Furthermore, the helical structures were calculated in solution using the continuum

Figure 6. Molecular structures (B3LYP-D3/6-31G*) of decamer 13b (R1 = Moc, R2 = Me) exhibiting different helicities. All hydrogen atoms were omitted for the sake of clarity. The relative energies (B3LYP-D3/6-31G*) are also given. The values in brackets stem from B3LYP-D3/6-31G*− COSMO calculations; as solvent acetonitrile was used. 4208


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Figure 7. Molecular structure of an extract of decamer 13b showing a noncanonical M helix with herringbone form V. The distances between a methyl group (C5iv) pointing inside the helix and two amide hydrogen atoms (H7″ and H7‴) as well as further characteristic data are listed.

see Figure 7) at the stereogenic centers point alternating to the inside and the outside of the helix. The methyl groups pointing inside the helix are in close proximity to two different amide hydrogen atoms, which is in agreement with the NOESY experiments of 13a (Figure 7). The methyl groups are arranged in such a pattern that repulsive interactions between methyl groups from different turns are avoided. The attractive interactions between the aromatic systems of different turns are not disturbed by them. The smallest distances between non-hydrogen atoms of neighboring turns amount to values lower than 3.3 Å. This is a possible reason for the energetic stabilization of this conformation compared to all other calculated helix structures of decamer 13b. In view of the large energy difference (>31 kcal/mol), it can be assumed that only the noncanonical M helix with herringbone form V is the dominant secondary structure in solution. Further evidence for the noncanonical M helix with herringbone form V and its dominance in solution is the comparison between the experimentally determined CD spectrum of the decamer 13a and the simulated CD spectra of the conformers of 13b (Figure 8). For the simulation, the energy of the 250 lowest singlet excitations were calculated using the TD-B3LYP/6-31G* approach. In the simulated area, the shapes of the experimentally measured and the calculated CD spectrum of the isomer showing a noncanonical M helix with herringbone form V match well: the lowest energy band is negative; it follows a positive one and the highest energy band is negative again. The calculated spectra of the other conformers match either very poorly or not at all with the experimentally determined CD spectrum. Furthermore, the CD spectra were calculated in solution using the continuum solvation model COSMO. However, the consideration of this approximation (B3LYP-D3/6-31G*− COSMO) leads to no significant changes in the simulated CD spectra (Figure S19).

Figure 8. (a) Experimentally determined CD spectrum of 13a in acetonitrile at 20 °C. (b) Simulated (TD-B3LYP/6-31G*) CD spectra of different conformations of 13b. Only the simulated CD spectrum of the isomer showing a noncanonical M helix with herringbone form V matches with the experimentally determined CD spectrum of 13a. Due to the different width of the spectra, the experimentally determined and simulated spectra are depicted in different areas.

oligomers derived from achiral imidazole amino acids fold into canonical helices, the oligomers derived from chiral imidazole amino acids form noncanonical helices. These helices exhibit an additional structural element: a herringbone form, which enlarged the family of helices. By the use of enantiomeric pure amino acids, we were able to predetermine both the helicity of the helix and the form of the herringbone. The investigation of the underlying herringbone basic element and their folding to a noncanonical helix were conducted by NMR and CD spectroscopy in different solvents and temperatures. Quantum chemical calculations support both the formation of the herringbone basic element and the folding into a superior noncanonical helix. The formation of the herringbone basic

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CONCLUSION In sum, we were able to synthesize novel noncyclic oligomers derived from imidazole amino acids. Whereas achiral imidazole amino acids were utilized in previous work, here the corresponding chiral congeners were used. They differ only in the formal introduction of a methyl group in the δ position. However, the thus caused impact is remarkable: Whereas 4209


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temperature. The solvent was evaporated, the residue was dissolved in DCM and then washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography with silica gel (DCM/EtOAc 90:10 → 75:25) to yield 3a (23.834 g, 78.834 mmol, 88.1%) as a white solid. 1 H NMR (600 MHz, CDCl3): δ = 7.33−7.19 (m, 2 H), 5.23 (d, J = 6.6 Hz, 1 H), 5.23 (d, J = 6.6 Hz, 1 H), 4.99 (brs, 2 H), 4.33−4.19 (m, 2 H), 3.81 (s, 6 H), 2.37 (s, 3 H), 2.37 (s, 3 H), 1.45 (s, 9 H), 1.45 (s, 9 H), 1.38 (d, J = 7.1 Hz, 3 H), 1.38 ppm (d, J = 7.1 Hz, 3 H). 13C NMR (151 MHz, CDCl3): δ = 198.4, 198.2, 172.7, 166.5, 166.4, 155.6, 155.5, 80.5, 63.0, 53.5, 50.1, 50.0, 28.4, 28.1, 28.0, 18.2, 18.1 ppm. Imidazole 4b (R1 = Boc, R2 = Me). To a solution of amido ketone 3a (18.0 g, 59.538 mmol) in xylenes (390 mL), acetic acid (43.5 mL) and methylamine (8 M in EtOH, 35.0 mL, 279.829 mmol) were added at room temperature. The mixture was stirred at 170 °C with azeotropic removal of water for 3.5 h and then cooled to room temperature. The solvent was concentrated in vacuo; the residue was dissolved in DCM and washed with saturated NaHCO3 solution. The aqueous solution was extracted with DCM, the combined organic layers were dried over MgSO4 and concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:0 → 75:25:3) to yield imidazole 4b (15.122 g, 50.856 mmol, 85.4%) as a white solid. Mp: 65−66 °C. 1H NMR (600 MHz, CDCl3): δ = 5.34 (d, J = 7.7 Hz, 1 H), 4.99−4.89 (m, 1 H), 3.86 (s, 3 H), 3.54 (s, 3 H), 2.51 (s, 3 H), 1.55 (d, J = 7.0 Hz, 3 H), 1.40 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3): δ = 164.2, 155.2, 148.8, 136.9, 127.2, 79.9, 51.7, 42.6, 30.4, 28.4, 20.6, 10.2 ppm. IR (ATR): ν̃ = 3348, 2966, 2975, 2936, 1694, 1678, 1570, 1516, 1438, 1366, 1325, 1246, 1221, 1201, 1157, 1074, 1061, 1030 cm−1. UV/vis (MeOH): λmax (log ε) = 244 nm (4.03). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H24N3O4+ 298.1761, found 298.1772; [M + Na]+ calcd for C14H23N3O4Na+ 320.1581, found 320.1584. Imidazole 4a (R1 = Boc, R2 = H). Imidazole 4b (5.579 mg, 18.7624 mmol) was dissolved in a mixture of methanol (208 mL) and dioxane (145 mL) followed by slow addition of NaOH solution (2 M, 94 mL, 187.6240 mmol) at 0 °C. The ice bath was removed and stirring was continued until TLC showed consumption of all starting material (24 h). Then, the solution was poured onto an ice/DCM mixture and acidified with 2 M HCl to pH = 1. The layers were separated, the aqueous layer was saturated with NaCl and then repeatedly extracted with DCM. The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give 4.407 g (15.5543 mmol, 82.9%) of the free acid 4a as a white solid, which was used in the next step without further purification. Mp: 107−108 °C. 1H NMR (600 MHz, CDCl3): δ = 10.11 (brs, 1 H), 7.24−7.05 (m, 1 H), 5.15−5.04 (m, 1 H), 3.78 (s, 3 H), 2.57 (s, 3 H), 1.75 (d, J = 6.4 Hz, 3 H), 1.36 ppm (s, 9 H). 13 C NMR (151 MHz, CDCl3): δ = 161.5, 155.8, 149.5, 136.1, 123.0, 80.4, 42.5, 31.8, 28.4, 19.5, 10.0 ppm. IR (ATR): ν̃ = 3384, 2976, 2931, 2877, 1698, 1636, 1509, 1449, 1367, 1248, 1161, 1067 cm−1. UV/vis (MeOH): λmax (log ε) = 228 nm (4.05). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H22N3O4+ 284.1605, found 284.1611; [M + Na]+ calcd for C13H21N3O4Na+ 306.1424, found 306.1431; [M − H]− calcd for C13H20N3O4− 282.1448, found 282.1542. Imidazole 5a (R1 = Boc, R2 = Bn). Imidazole 4a (500 mg, 1.7647 mmol) was dissolved in a mixture of methanol (7.4 mL) and water (1 mL) followed by the addition of Cs2CO3 (604 mg, 1.8529 mmol). The solution was evaporated to dryness, and the residue was reevaporated twice from DMF (65 °C). The solid was dissolved in DMF, and benzyl bromide (315 μL, 2.6471 mmol) was added. The solvent was evaporated after stirring at room temperature for 24 h. The crude product was taken up in water, extracted several times with DCM, dried over MgSO4, and concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (DCM/ EtOAc/MeOH 75:25:0 → 75:25:10) to yield imidazole 5a (519 mg, 1.3906 mmol, 78.8%) as a white solid. Mp: 106−107 °C. 1H NMR (600 MHz, CDCl3): δ = 7.47−7.41 (m, 2 H), 7.37−7.32 (m, 2 H), 7.32−7.27 (m, 1 H), 5.44−5.32 (m, 3 H), 4.98−4.89 (m, 1 H), 3.53 (s, 3 H), 2.48 (s, 3 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.42 ppm (s, 9 H). 13 C NMR (151 MHz, CDCl3): δ = 163.7, 155.3, 149.0, 136.74, 136.71, 128.6, 128.4, 128.0, 127.4, 79.9, 66.0, 42.7, 30.4, 28.5, 20.8), 10.5 ppm.

element was further supported by the X-ray analysis of the cyclic oligomer. Furthermore, we demonstrate that the foldamers show a high stability in organic as well as in aqueous media, which is of particular importance for applications in medicinal chemistry. As the corresponding imidazole amino acids are easy accessible and modifiable, this approach allows access to a wide diversity of enantiopure secondary structures showing completely different forms. Moreover, as short cyclic oligomers from azole-containing pseudopeptides are also present in marine organisms,29,31,32 the question arises, if noncanonical helices could be found in nature and if they are biologically active intermediates.

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EXPERIMENTAL SECTION

General Remarks. All chemicals were reagent grade and were used as purchased. Reactions were monitored by TLC analysis with silica gel 60 F254 thin-layer plates. Flash chromatography was carried out on silica gel 60 (230−400 mesh). 1H and 13C NMR spectra were measured with Bruker Avance DRX 300, Avance DRX 500, and Avance HD 600 spectrometers. All chemical shifts (δ) are given in ppm. The spectra were referenced to the peak for the protium impurity in the deuterated solvents indicated in brackets in the analytical data. HR-MS spectra were recorded with a Bruker BioTOF III Instrument. UV/vis absorption spectra were obtained with Jasco J815 and V-550 spectrophotometers. CD absorption spectra were recorded with a Jasco J-815 spectrophotometer. IR absorption spectra were recorded with a Varian 3100 FT-IR spectrophotometer. Melting points were measured using a Büchi B-540 melting point apparatus. General Procedure A for the Cleavage of the Boc Group. The Boc-protected compound (1 equiv) was dissolved in ethyl acetate (7 mL/mmol starting material), and the solution was cooled to 0 °C. HCl in EtOAc (4 M; 2.5 mL/mmol starting material) was added at that temperature. The ice bath was removed after 30 min and stirring was continued at room temperature until all starting material was consumed, which was detected by thin layer chromatography. The mixture was concentrated in vacuo to provide a quantitative yield of the hydrochloride, which was used in the next step without further purification. General Procedure B for the Cleavage of the Benzyl Ester Group. Palladium hydroxide (80 mg/mmol starting material) was added at room temperature to a solution of the protected compound (1 equiv) in methanol (40 mL/mmol starting material). The mixture was stirred under H2 atmosphere until all starting material was consumed, which was detected by thin layer chromatography. Then, the mixture was filtered and concentrated in vacuo to give the acid compound, which was used in the next step without further purification. General Procedure C for the Peptide Coupling. To a solution of the acid (1 equiv) and the aminohydrochloride (1.2 mmol/mmol starting material) in acetonitrile (40 mL/mmol starting material), N,Ndiisopropylethylamine (7.3 mmol/mmol starting material) was added dropwise at room temperature. After 30 min, pentafluorophenyldiphenylphosphinate (FDPP; 1.2 mmol/mmol starting material) was added, and the solution was stirred at room temperature until all starting material was consumed, which was detected by thin layer chromatography (several days). Afterward, the solvent was evaporated, and the residue was purified by chromatography on silica gel to provide the peptide. Experimental Procedures and Analytical Data. Amido Ketone 3a (R1 = Boc, R2 = Me, R3 = Me).57 Boc-L-alanine-OH (1, 16.934 g, 89.50 mmol) was dissolved under argon in absolute tetrahydrofuran (THF) (250 mL), and then 1 equiv of N-methylmorpholine (NMM) (9.85 mL, 89.50 mmol) was added. The solution was cooled to −25 °C, and isobutyl chloroformate (11.6 mL, 89.50 mmol) was added, while the reaction mixture was maintained at −25 °C. After 2 h, aminoketone 2 (15.000 g, 89.50 mmol) and the second equivalent of NMM (9.85 mL, 89.50 mmol) were added at −25 °C. Stirring was continued for 15 h while the solution was allowed to warm to room 4210


Article

The Journal of Organic Chemistry IR (ATR): ν̃ = 3359, 2980, 2933, 2867, 1680, 1566, 1514, 1447, 1393, 1328, 1224, 1202, 1159, 1064, 1047, 1036, 727, 692 cm−1. UV/vis (CH3CN): λmax (log ε) = 198 (4.18), 248 nm (4.05). HRMS (ESITOF) m/z: [M + H]+ calcd for C20H28N3O4+ 374.2074, found 374.2077; [M + Na]+ calcd for C20H27N3O4Na+ 396.1894, found 396.1898. Imidazole 5b (R1 = HCl*H, R2 = Bn). This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 5a (729 mg, 1.9521 mmol) to yield 5b (605 mg, 1.9521 mmol, quantitative) as a white solid. Mp: 171−172 °C. 1H NMR (600 MHz, MeOD): δ = 7.51−7.45 (m, 2 H), 7.42−7.32 (m, 3 H), 5.40 (s, 2 H), 5.04 (q, J = 7.0 Hz, 1 H), 3.79 (s, 3 H), 2.60 (s, 3 H), 1.77 ppm (d, J = 7.0 Hz, 3 H). 13C NMR (151 MHz, MeOD): δ = 161.6, 145.5, 140.2, 137.1, 130.0, 129.9, 129.8, 125.0, 68.4, 43.7, 32.7, 18.2, 10.3 ppm. IR (ATR): ν̃ = 3445, 3357, 3050, 2841, 2787, 2647, 2590, 1743, 1723, 1623, 1435, 1377, 1284, 1224, 1188, 1085, 757, 702 cm−1. UV/vis (MeOH): λmax (log ε) = 211 (4.05), 242 nm (4.02). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H20N3O2+ 274.1550, found 274.1566; [M + Na]+ calcd for C15H19N3O2Na+ 296.1369, found 296.1372. Dimer 6a (R1 = Boc, R2 = Me, R3 = Bn). This compound was synthesized according to the general procedure C for the peptide coupling from 4a (503 g, 1.7753 mmol) and 5b. After flash column chromatography with silica gel (DCM/MeOH 99:1 → 93:7) 6a was obtained as a white solid (528 mg, 0.9800 mmol, 55.2%). Mp: 87−88 °C. 1H NMR (600 MHz, CDCl3): δ = 7.61 (brs, 1 H), 7.46−7.41 (m, 2 H), 7.36−7.31 (m, 2 H), 7.31−7.27 (m, 1 H), 5.51−5.43 (m, 1 H), 5.39 (d, J = 12.5 Hz, 1 H), 5.32 (d, J = 12.5 Hz, 1 H), 5.17 (brs, 1 H), 4.93−4.84 (m, 1 H), 3.58 (s, 3 H), 3.48 (s, 3 H), 2.52 (s, 3 H), 2.48 (s, 3 H), 1.70 (d, J = 7.0 Hz, 3 H), 1.49 (d, J = 7.0 Hz, 3 H), 1.42 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3): δ = 163.7, 162.9, 155.2, 148.8, 147.3, 136.9, 136.7, 133.5, 128.9, 128.5, 128.4, 128.1, 127.4, 80.0, 66.0, 42.7, 39.9, 30.5, 30.1, 28.5, 20.8, 19.9, 10.5, 9.9 ppm. IR (ATR): ν̃ = 3304, 2978, 2934, 1698, 1647, 1589, 1506, 1497, 1456, 1366, 1190, 1157, 1061, 737, 698 cm−1. UV/vis (CH3CN): λmax (log ε) = 196 (4.40), 246 nm (4.35). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H39N6O5+ 539.2976, found 539.2937; [M + Na]+ calcd for C28H38N6O5Na+ 561.2796, found 561.2750. Dimer 6b (R1 = HCl*H, R2 = Me, R3 = Bn). This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 6a (959 mg, 1.7804 mmol) to yield 6b (846 mg, 1.7804 mmol, quantitative) as a white solid. Mp: 198−199 °C. 1H NMR (600 MHz, MeOD): δ = 7.51−7.45 (m, 2 H), 7.42−7.32 (m, 3 H), 5.45 (q, J = 7.3 Hz, 1 H), 5.42 (s, 2 H), 4.86 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 3.65 (s, 3 H), 2.61 (s, 3 H), 2.49 (s, 3 H), 1.79 (d, J = 7.3 Hz, 3 H), 1.71 ppm (d, J = 6.8 Hz, 3 H). 13C NMR (151 MHz, MeOD): δ = 164.6, 159.6, 151.1, 145.1, 139.6, 137.6, 136.7, 130.1, 130.0, 129.9, 128.6, 120.9, 68.9, 44.5, 42.9, 32.9, 31.4, 19.0, 18.1, 10.1, 9.9 ppm. IR (ATR): ν̃ = 3362, 2812, 2717, 1723, 1662, 1654, 1636, 1542, 1516, 1456, 1338, 1318, 1294, 1191, 1168, 1076, 755, 700 cm−1. UV/vis (MeOH): λmax (log ε) = 209 (4.23), 243 nm (4.31). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H31N6O3+ 439.2452, found 439.2460; [M + Na]+ calcd for C23H30N6O3Na+ 461.2272, found 461.2269. Trimer 7. This compound was synthesized according to the general procedure C for the peptide coupling from 4a (472 g, 1.6649 mmol) and 6b. After flash column chromatography with silica gel (DCM/ MeOH 98:2 → 95:5), 7 was obtained as a white solid (518 mg, 0.7360 mmol, 44.2%). Mp: 94−95 °C. 1H NMR (600 MHz, CDCl3): δ = 7.74−7.61 (m, 1 H), 7.47−7.40 (m, 2 H), 7.38−7.30 (m, 3 H), 7.29− 7.23 (m, 1 H), 5.53−5.44 (m, 1 H), 5.44−5.36 (m, 2 H), 5.32 (d, J = 12.5 Hz, 1 H), 5.15 (brs, 1 H), 4.93−4.81 (m, 1 H), 3.58 (s, 3 H), 3.48 (s, 3 H), 3.48 (s, 3 H), 2.52 (s, 3 H), 2.51 (s, 3 H), 2.47 (s, 3 H), 1.70 (d, J = 7.0 Hz, 3 H), 1.61 (d, J = 7.0 Hz, 3 H), 1.47 (d, J = 7.0 Hz, 3 H), 1.38 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3): δ = 163.8, 163.1, 162.8, 155.1, 148.8, 147.3, 147.0, 136.9, 136.7, 133.8, 133.6, 129.0, 128.5, 128.4, 128.3, 128.0, 127.4, 79.9, 65.9, 42.6, 40.0, 39.8, 30.5, 30.2, 30.1, 28.4, 20.6, 19.9, 19.7, 10.5, 9.88, 9.85 ppm. IR (ATR): ν̃ = 3253, 2980, 2935, 1699, 1645, 1587, 1497, 1367, 1158, 1061, 737, 698 cm−1. UV/vis (CH3CN): λmax (log ε) = 194 (4.63), 245 nm

(4.57). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H50N9O6+ 704.3879, found 704.3879; [M + Na]+ calcd for C36H49N9O6Na+ 726.3638, found 726.3694; [M − H]− calcd for C36H48N9O6− 702.3722, found 702.3712. Trimer 8. This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 7 (216 mg, 0.3069 mmol) to yield 8 (197 mg, 0.3096 mmol, quantitative) as a white solid. Mp: 212−213 °C. 1H NMR (600 MHz, MeOD): δ = 7.48−7.44 (m, 2 H), 7.42−7.33 (m, 3 H), 5.49−5.38 (m, 4 H), 4.78 (q, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.61 (s, 3 H), 2.61 (s, 3 H), 2.57 (s, 3 H), 2.48 (s, 3 H), 1.81 (d, J = 7.2 Hz, 3 H), 1.78 (d, J = 7.2 Hz, 3 H), 1.65 ppm (d, J = 6.8 Hz, 3 H). 13C NMR (151 MHz, MeOD): δ = 165.7, 160.2, 159.8, 150.6, 150.4, 145.6, 139.8, 138.6, 137.4, 136.8, 130.2, 130.14, 130.07, 129.9, 122.4, 121.3, 69.1, 45.0, 43.8, 42.6, 33.1, 32.7, 31.1, 19.4, 18.8, 17.9, 10.2, 10.0, 9.9 ppm. IR (ATR): ν̃ = 3361, 3219, 2922, 2850, 1724, 1660, 1542, 1515, 1455, 1325, 1295, 1195, 1168, 1077, 738, 700 cm−1. UV/vis (MeOH): λmax (log ε) = 243 nm (4.73). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H42N9O4+ 604.3354, found 604.3342; [M + Na]+ calcd for C31H41N9O4Na+ 626.3174, found 626.3143; [M + Cl]− calcd for C31H41ClN9O4− 638.2965, found 638.2963. Trimer 9. This compound was synthesized according to the general procedure B for the cleavage of the benzyl ester group from imidazole 7 (290 mg, 0.4120 mmol) to yield 9 (212 mg, 0.3454 mmol, 83.8%) as a white solid. Mp: 310−312 °C. 1H NMR (600 MHz, MeOD): δ = 5.74−5.24 (m, 2 H), 4.86−4.65 (m, 1 H), 3.65 (s, 3 H), 3.54 (s, 6 H), 2.71−2.28 (m, 9 H), 1.72−1.25 ppm (m, 18 H). 13C NMR (151 MHz, MeOD): δ = 165.5, 165.1, 165.0, 157.3, 149.3, 149.1, 148.9, 136.0, 135.9, 135.8, 129.7, 129.4, 129.3, 80.5, 44.0, 41.9, 41.6, 31.0, 30.6, 30.5, 28.7, 19.8, 19.42, 19.36, 9.8, 9.6 ppm. IR (ATR): ν̃ = 3385, 3308, 2980, 2935, 1698, 1635, 1588, 1506, 1471, 1367, 1235, 1163, 1054 cm−1. UV/vis (MeOH): λmax (log ε) = 261 nm (4.83). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H44N9O6+ 614.3409, found 614.3401; [M − H]− calcd for C29H42N9O6− 612.3253, found 612.3249. Tetramer 10a (R1 = Boc, R2 = Bn). This compound was synthesized according to the general procedure C for the peptide coupling from 4a (82 mg, 0.2890 mmol) and 8. After flash column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:9), 10a was obtained as a white solid (169 mg, 0.1945 mmol, 67.3%). Mp: 150−151 °C. 1H NMR (600 MHz, CDCl3): δ = 8.53−7.26 (m, 8 H), 5.54−5.06 (m, 6 H), 4.89 (brs, 1 H), 3.58 (s, 3 H), 3.57−3.44 (m, 9 H), 2.58−2.50 (m, 9 H), 2.48 (s, 3 H), 1.73 (d, J = 7.0 Hz, 3 H), 1.69−1.56 (m, 6 H), 1.54−1.35 ppm (m, 12 H). 13C NMR (151 MHz, CDCl3): δ = 164.0, 163.3, 163.20, 163.16, 155.3, 148.9, 147.6, 147.2, 147.0, 137.3, 137.0, 134.4, 134.11, 134.07, 128.8, 128.6, 128.5, 128.2, 127.7, 127.62, 127.58, 80.4, 66.1, 42.8, 42.3, 40.20, 40.17, 30.8, 30.6, 30.3, 30.0, 28.7, 20.7, 20.0, 19.8, 19.8, 10.8, 10.2, 10.12, 10.09 ppm. IR (ATR): ν̃ = 3252, 2980, 2934, 1699, 1636, 1587, 1506, 1497, 1465, 1456, 1367, 1160, 1053, 738, 699 cm−1. UV/vis (CH3CN): λmax (log ε) = 196 (4.67), 244 nm (4.66). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C44H61N12O7+ 869.4781, found 869.4767; [M + Na]+ calcd for C44H60N12O7Na+ 891.4600, found 891.4587. Tetramer 10b (R1 = HCl*H, R2 = Bn). This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 10a (159 mg, 0.1830 mmol) to yield 10b (147 mg, 0.1830 mmol, quantitative) as a white solid. Mp: 234− 235 °C. 1H NMR (500 MHz, MeOD): δ = 7.49−7.44 (m, 2 H), 7.42− 7.34 (m, 3 H), 5.54−5.38 (m, 5 H), 4.81−4.75 (m, 1 H), 3.93−3.80 (m, 9 H), 3.60 (s, 3 H), 2.65−2.53 (m, 9 H), 2.49 (s, 3 H), 1.86−1.73 (m, 9 H), 1.66 ppm (d, J = 5.5 Hz, 3 H). 13C NMR (126 MHz, MeOD): δ = 165.4, 160.2, 160.0, 159.7, 150.5, 150.1, 149.4, 145.4, 139.7, 138.5, 138.0, 137.2, 136.7, 130.04, 129.99, 129.95, 129.8, 122.64, 122.58, 121.2, 69.0, 45.0, 43.8, 43.7, 42.6, 33.3, 32.91, 32.86, 31.2, 19.3, 18.8, 18.4, 18.0, 10.3, 10.11, 10.06, 10.0 ppm. IR (ATR): ν̃ = 3384, 3226, 2922, 2826, 2718, 1727, 1653, 1542, 1515, 1456, 1328, 1197, 1170, 739, 701 cm−1. UV/vis (MeOH): λmax (log ε) = 212 (4.40), 250 nm (4.68). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H53N12O5+ 769.4256, found 769.4256. Heptamer 11. This compound was synthesized according to the general procedure C for the peptide coupling from 9 (106 mg, 0.1729 4211


Article


Cyclic Trimer 15. This compound was synthesized according to the general procedure C for the peptide coupling from 14 (184 mg, 0.8376 mmol). After flash column chromatography with silica gel (DCM/ MeOH 92:8), 15 was obtained as a white solid (73 mg, 0.1473 mmol, 52.8%). Mp: >350 °C. 1H NMR (600 MHz, CDCl3): δ = 8.90 (d, J = 7.0 Hz, 1 H), 5.23−5.14 (m, 1 H), 3.48 (s, 3 H), 2.55 (s, 3 H), 1.53 ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz, CDCl3): δ = 162.7, 147.2, 132.9, 129.0, 41.8, 29.8, 21.8, 9.4 ppm. IR (ATR): ν̃ = 3376, 2980, 2926, 1644, 1591, 1526, 1505, 1464, 1366, 1221, 1205, 1050, 916 cm−1. UV/vis (CH3CN): λmax (log ε) = 192 (4.76), 237 nm (4.62). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H34N9O3+ 496.2779, found 496.2799; [M + Na]+ calcd for C24H33N9O3Na+ 518.2599, found 518.2604. Cyclic Tetramer 16. This compound was synthesized according to the general procedure C for the peptide coupling from 14 (184 mg, 0.8376 mmol). After flash column chromatography with silica gel (DCM/MeOH 92:8), 16 was obtained as a white solid (30 mg, 0.0454 mmol, 21.7%). Mp: >350 °C. 1H NMR (600 MHz, CDCl3): δ = 7.70 (brs, 1 H), 5.42−5.33 (m, 1 H), 3.59 (s, 3 H), 2.49 (s, 3 H), 1.66 ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz, CDCl3): δ = 162.9, 147.8, 132.9, 128.9, 39.7, 30.1, 20.2, 9.7 ppm. IR (ATR): ν̃ = 3385, 2981, 2933, 1645, 1636, 1588, 1506, 1497, 1466, 1368, 1226, 1123, 1030 cm−1. UV/vis (CH3CN): λmax (log ε) = 195 (5.26), 274 nm (4.99). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C32H45N12O4+ 661.3681, found 661.3707; [M + Na]+ calcd for C32H44N12O4Na+ 683.3501, found 683.3586. Amido Ketone 3b (R1 = Z, R2 = H, R3 = Me).58 Z-Glycine-OH (14.040 g, 67.13 mmol) was dissolved under argon in absolute tetrahydrofuran (THF) (410 mL), and 1 equiv of N-methylmorpholine (NMM) (7.38 mL, 67.13 mmol) was added. The solution was cooled to −25 °C, and isobutyl chloroformate (8.73 mL, 67.13 mmol) was added, while the reaction mixture was maintained at −25 °C. After 2 h, aminoketone 2 (11.250 g, 67.13 mmol) and the second equivalent of NMM (7.38 mL, 67.13 mmol) were added at −25 °C. Stirring was continued for 14 h while the solution was allowed to warm to room temperature. The solvent was evaporated, and the residue was dissolved in EtOAc and then washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography with silica gel (nHexane/EtOAc 1:1) to yield 3b (16.980 g, 52.68 mmol, 78.5%) as a white solid. Mp: 78 °C. 1H NMR (500 MHz, CDCl3): δ = 7.40−7.29 (m, 5 H), 7.27−7.14 (m, 1 H), 5.61−5.50 (m, 1 H), 5.27 (d, J = 6.5 Hz, 1 H), 5.13 (s, 2 H), 3.96 (d, J = 5.4 Hz, 2 H), 3.80 (s, 3 H), 2.36 ppm (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 198.2, 169.1, 166.5, 156.7, 136.3, 128.7, 128.3, 128.2, 67.4, 63.0, 53.5, 44.3, 28.1 ppm. IR (ATR): ν̃ = 3396, 3315, 3034, 2957, 1741, 1725, 1652, 1522, 1438, 1361, 1282, 1253, 1153, 1044, 749, 698 cm−1. UV/vis (MeOH): λmax (log ε) = 216 (3.28), 274 nm (3.08). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H18N2O6Na+ 345.1068, found 345.1063. Imidazole 17. To a solution of amido ketone 3b (7.091 g, 22.0 mmol) in xylenes (300 mL), trifluoroacetic acid (3.3 mL, 44.0 mmol) and ammonia (7 M in MeOH, 6.3 mL, 44.0 mmol) were added at room temperature. The mixture was stirred at 175 °C with azeotropic removal of water for 20 h and then cooled to room temperature. The solvent was concentrated in vacuo; the residue was dissolved in EtOAc, washed with brine and saturated NaHCO3 solution, and dried over MgSO4. The solution was concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (nhexane/EtOAc 2:3 → 1:10) to yield imidazole 17 (4.838 g, 16.0 mmol, 73.0%) as a white solid. Mp: 140 °C. 1H NMR (500 MHz, CDCl3): δ = 7.35−7.27 (m, 5 H), 6.03 (t, J = 6.0 Hz, 1 H), 5.09 (s, 2 H), 4.34 (d, J = 6.0 Hz, 2 H), 3.83 (s, 3 H), 2.48 ppm (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 163.2, 157.8, 145.5, 139.0, 136.1, 128.7, 128.4, 128.1, 124.5, 67.5, 51.6, 38.6, 12.2 ppm. IR (ATR): ν̃ = 3392, 3304, 3250, 3021, 2960, 1715, 1692, 1650, 1522, 1439, 1408, 1356, 1282, 1250, 1213, 1115, 1042, 748, 691 cm−1. UV/vis (MeOH): λmax (log ε) = 214 (3.80), 245 nm (3.89). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H18N3O4+ 304.1292, found 304.1298; [M + Na]+ calcd for C15H17N3O4Na+ 326.1111, found 326.1115.

mmol) and 10b. After flash column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:12), 11 was obtained as a white solid (197 mg, 0.1444 mmol, 83.5%). Mp: 217−218 °C. 1H NMR (500 MHz, CDCl3): δ = 10.02−6.05 (m, 12 H), 5.60−4.37 (m, 9 H), 3.67− 2.89 (m, 21 H), 2.62−2.11 (m, 21 H) 1.70−0.99 ppm (m, 30 H). 13C NMR (126 MHz, CDCl3): δ = 164.2, 163.6, 163.2, 163.0, 162.9, 154.9, 146.7, 146.3, 145.8, 145.1, 144.8, 144.5, 137.3, 136.9, 136.5, 134.8, 134.2, 133.7, 128.8, 128.6, 128.4, 128.1, 127.9, 127.5, 126.7, 126.2, 78.7, 65.5, 43.1, 41.5, 41.1, 40.5, 39.8, 30.4, 30.2, 30.0, 29.9, 29.6, 28.3, 28.0, 19.3, 19.2, 18.6, 10.3, 10.1, 9.7, 9.5, 9.3 ppm. IR (ATR): ν̃ = 3391, 3201, 2982, 2934, 1703, 1633, 1584, 1494, 1464, 1368, 1227, 1158, 1115, 1068, 1051, 739, 698 cm−1. UV/vis (CH3CN): λmax (log ε) = 194 (4.79), 247 nm (4.86). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C68H94N21O10+ 1364.7487, found 1364.7463; [M + Na]+ calcd for C68H93N21O10Na+ 1386.7306, found 1386.7285. Heptamer 12. This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 11 (178 mg, 0.1304 mmol) to yield 12 (170 mg, 0.1304 mmol, quantitative) as a white solid. Mp: 245−247 °C. 1H NMR (600 MHz, MeOD): δ = 7.50−7.44 (m, 2 H), 7.43−7.33 (m, 3 H), 5.56−5.38 (m, 8 H), 4.80 (q, J = 6.6 Hz, 1 H), 3.97−3.77 (m, 18 H), 3.61 (s, 3 H), 2.72−2.53 (m, 18 H), 2.49 (s, 3 H), 1.90−1.69 (m, 18 H), 1.66 ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz, MeOD): δ = 165.4, 160.2, 160.1, 160.0, 159.7, 150.5, 150.0, 149.4, 149.3, 149.18, 149.16, 145.4, 139.7, 138.6, 138.14, 138.05, 138.00, 137.97, 137.2, 136.7, 130.02, 129.99, 129.9, 129.7, 123.0, 122.9, 122.8, 122.6, 122.5, 121.1, 68.9, 44.9, 43.72, 43.67, 43.65, 43.6, 42.5, 33.1, 32.83, 32.75, 32.7, 31.1, 19.3, 18.7, 18.34, 18.31, 18.26, 17.9, 10.22, 10.18, 10.13, 10.08, 10.0, 9.9 ppm. IR (ATR): ν̃ = 3362, 3219, 3030, 2921, 2850, 1732, 1717, 1660, 1653, 1541, 1519, 1508, 1456, 1328, 1201, 736, 701 cm−1. UV/vis (MeOH): λmax (log ε) = 207 (4.59), 258 nm (4.97). HRMS (ESITOF) m/z: [M + H]+ calcd for C63H86N21O8+ 1264.6963, found 1264.6934; [M + Na]+ calcd for C63H85N21O8Na+ 1286.6782, found 1286.6759; [M + Cl]− calcd for C63H85ClN21O8− 1298.6573, found 1298.6558. Decamer 13a. This compound was synthesized according to the general procedure C for the peptide coupling from 9 (41 mg, 0.0662 mmol) and 12. After flash column chromatography with silica gel (DCM/MeOH 9:1), 13a was obtained as a white solid (90 mg, 0.0484 mmol, 73.1%). Mp: 222−223 °C. 1H NMR (600 MHz, CDCl3): δ = 9.85 (d, J = 7.8 Hz, 1 H), 9.82 (d, J = 7.8 Hz, 2 H), 9.80 (d, J = 7.9 Hz, 2 H), 9.76 (d, J = 7.7 Hz, 1 H), 9.67 (d, J = 7.9 Hz, 1 H), 9.65 (d, J = 8.5 Hz, 1 H), 9.16 (d, J = 6.9 Hz, 1 H), 7.43−7.31 (m, 5 H), 5.43− 5.05 (m, 12 H), 4.98−4.89 (m, 1 H), 3.58−3.29 (m, 27 H), 2.97 (s, 3 H), 2.57−2.40 (m, 24 H), 2.21 (s, 3 H), 2.08 (s, 3 H), 1.62−1.11 ppm (s, 39 H). 13C NMR (151 MHz, CDCl3): δ = 170.4, 164.21, 164.17, 164.1, 162.7, 154.8, 146.7, 146.4, 145.2, 144.6, 144.5, 144.44, 144.40 137.4, 135.7, 135.0, 134.81, 134.76, 134.6, 134.2, 128.9, 128.8, 128.7, 128.6, 128.44, 128.35, 128.3, 128.1, 125.8, 78.6, 65.8, 41.5, 41.4, 40.9, 39.9, 31.8, 30.3, 30.1, 30.0, 29.8, 29.6, 29.2, 29.0, 28.3, 27.9, 27.8, 22.8, 22.6 19.3, 19.22, 19.15, 19.1 18.7, 18.3 10.2, 9.8, 9.67, 9.66, 9.2 ppm. IR (ATR): ν̃ = 3396, 3237, 2984, 2933, 1716, 1705, 1630, 1627, 1583, 1506, 1497, 1456, 1406, 1370, 1158, 1117, 1069, 751, 699 cm−1. UV/ vis (CH3CN): λmax (log ε) = 193 (4.99), 249 nm (5.00). HRMS (ESITOF) m/z: [M + H]+ calcd for C92H127N30O13+ 1860.0193, found 1860.0220; [M + Na]+ calcd for C92H126N30O13Na+ 1882.0013, found 1882.0062. Imidazole 14. This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 4a (250 mg, 0.8824 mmol) to yield 14 (194 mg, 0.8824 mmol, quantitative) as a white solid. Mp: 234−235 °C. 1H NMR (600 MHz, MeOD): δ = 5.09 (q, J = 7.0 Hz, 1 H), 3.83 (s, 3 H), 2.64 (s, 3 H), 1.81 ppm (d, J = 7.0 Hz, 3 H). 13C NMR (151 MHz, MeOD): δ = 162.2, 144.9, 139.8, 125.0, 43.4, 32.9, 17.9, 10.1 ppm. IR (ATR): ν̃ = 3566, 3348, 2801, 2710, 1716, 1705, 1567, 1397, 1386, 1252, 1235, 1183, 1136, 1097, 889 cm−1. UV/vis (MeOH): λmax (log ε) = 245 (4.06), 270 nm (4.01). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H14N3O2+ 184.1081, found 184.1089; [M + Na]+ calcd for C8H13N3O2Na+ 206.0900, found 206.0896. 4212


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Cyclic Trimer 22. This compound was synthesized according to the general procedure C for the peptide coupling from 21 (451 g, 1.601 mmol). After flash column chromatography with silica gel (cyclohexane/EtOAc/MeOH 1:2:0 → 1:9:1), 22 was obtained as a white solid (36 mg, 0.053 mmol, 9.9%). Mp: >350 °C. 1H NMR (500 MHz, CDCl3): δ = 8.87 (t, J = 3.3 Hz, 1 H), 7.32−7.23 (m, 3 H), 6.96−6.89 (m, 2 H), 5.07 (s, 2 H), 4.45 (d, J = 3.3 Hz, 2 H), 2.54 ppm (s, 3 H). 13 C NMR (126 MHz, CDCl3): δ = 163.8, 142.8, 134.8, 133.7, 129.7, 129.3, 128.3, 125.8, 46.5, 36.8, 9.6 ppm. IR (ATR): ν̃ = 3376, 3061, 2943, 1651, 1596, 1539, 1504, 1467, 1455, 1434, 1372, 1345, 1219, 1115, 1028, 931, 756, 731, 696 cm−1. UV/vis (DCM): λmax (log ε) = 244 (4.28), 289 nm (3.64). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H40N9O3+ 682.3245, found 682.3249; [M + Na]+ calcd for C39H39N9O3Na+ 704.3069, found 704.3068. 1,10-Phenanthroline 1-Oxide.59,60 1,10-Phenanthroline (1.000 g, 5.5491 mmol) was dissolved in glacial acetic acid (5.0 mL) followed by slow addition of hydrogen peroxide (30%, 0.6 mL). The mixture was heated to 75 °C for 3 h and cooled to rt, and again hydrogen peroxide (30%, 0.6 mL) was added. After 3 h, the reaction mixture was cooled to rt and basified to pH = 10 with a saturated potassium hydroxide solution. The solids were dissolved with water and extracted repeatedly with chloroform. The organic layers were combined, dried over MgSO4 and concentrated in vacuo to give 0.675 g (3.4404 mmol, 61.7%) of 1,10-phenanthroline 1-oxide as a pale yellow solid, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ = 9.29 (dd, J = 1.9 Hz, 4.4 Hz, 1 H), 8.72 (dd, J = 1.1 Hz, 6.4 Hz, 1 H), 8.22 (dd, J = 1.9 Hz, 8.1 Hz, 1 H), 7.80−7.67 (m, 3 H), 7.63 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 7.43 ppm (dd, J = 6.4 Hz, 8.3 Hz, 1 H). 2-Chloro-1,10-phenanthroline.60,61 1,10-Phenanthroline 1-oxide (1.200 g, 6.1162 mmol) and NaCl (7.280 g, 123.7802 mmol) were dissolved under argon in absolute DMF (21.8 mL). The mixture was cooled to 0 °C, POCl3 (1.7 mL, 18.2758 mmol) was slowly added, and the reaction mixture was heated to 100 °C for 20 h. After the mixture was cooled to rt, water (49 mL) was added, and the solution was basified with aqueous ammonia to pH = 10. The aqueous layer was saturated with NaCl, the solids were filtered, and the solution was repeatedly extracted with chloroform. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (DCM/cyclohexane/EtOAc 7:3:1 → 7:3:3) to yield 2chloro-1,10-phenanthroline (0.750 g, 3.3776 mmol, 55.2%) as a white solid. 1H NMR (300 MHz, CDCl3): δ = 9.23 (dd, J = 1.7 Hz, 4.3 Hz, 1 H), 8.26 (dd, J = 1.7 Hz, 8.1 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 4.3 Hz, 8.1 Hz, 1 H), 7.63 ppm (d, J = 8.4 Hz,1 H). N-(1,10-Phenanthroline-2-yl)acetamide.62 Sodium hydride (60%, 1.082 g, 27.0721 mmol) was slowly added to a solution of acetamide (1.631 g, 27.5566 mmol) in xylene (50 mL) at 100 °C. After 1 h, 2Chloro-1,10-phenanthroline (0.650 g, 3.0282 mmol) was added, and the solution was heated to 140 °C. After 16 h, the mixture was cooled to rt, and the solids were filtered and dissolved in methanol. The solvent was removed in vacuo, and the residue was purified by flash column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:5 → 75:25:10). After separation of the acetamide by sublimation, N-(1,10-phenanthroline-2-yl)acetamide (0.465 g, 1.9592 mmol, 64.7%) was obtained as a white solid, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ = 9.20−9.01 (m, 2 H), 8.62 (d, J = 8.8 Hz, 1 H), 8.25 (d, J = 8.8 Hz, 1 H), 8.23 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.61 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 2.27 ppm (s, 3 H). 2-Amino-1,10-phenanthroline.60 Sodium hydroxide (835 mg, 20.8845 mmol) was added to a solution of N-(1,10-phenanthroline2-yl)acetamide (398 mg, 1.6775 mmol) in methanol (11.9 mL) and water (4.0 mL), and the mixture was refluxed for 1 h. Then, methanol was evaporated in vacuo, solids were filtered and washed with water, and the crude product was purified by flash column chromatography with silica gel (DCM/MeOH 95:5 → 85:15) to yield 2-amino-1,10phenanthroline (295 mg, 1.5111 mmol, 90.1%) as a white solid. 1H

Imidazole 18. To a solution of imidazole 17 (2.832 g, 9.34 mmol) in absolute tetrahydrofuran (THF, 100 mL), di-tert-butyl dicarbonate (2.24 mL, 10.27 mmol) and palladium hydroxide (0.330 g) were added at room temperature. The mixture was stirred under H2 atmosphere overnight. Then, the mixture was filtered and concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (n-hexane/EtOAc 1:1 → 1:4) to yield imidazole 18 (2.342 g, 8.73 mmol, 93.2%) as a white solid. Mp: 176 °C. 1H NMR (500 MHz, CDCl3): δ = 5.71−5.61 (m, 1 H), 4.31 (d, J = 6.1 Hz, 2 H), 3.85 (s, 3 H), 2.51 (s, 3 H), 1.43 ppm (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 163.0, 157.4, 146.1, 138.7, 124.3, 80.8, 51.6, 38.2, 28.5, 12.2 ppm. IR (ATR): ν̃ = 3351, 3053, 2978, 2933, 1710, 1687, 1598, 1513, 1435, 1367, 1320, 1280, 1251, 1211, 1163, 1100, 1040, 1025 cm−1. UV/vis (MeOH): λmax (log ε) = 245 nm (4.05). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H20N3O4+ 270.1448, found 270.1453; [M + Na]+ calcd for C12H19N3O4Na+ 292.1268, found 292.1272. Imidazole 19. To a solution of imidazole 18 (2.279 g, 8.46 mmol) in dimethylformamide (DMF) (85 mL), sodium hydride (60 wt %, 0.440 g, 11.00 mmol) was added at 0 °C. After 1 h, benzyl bromide (1.33 mL, 11.00 mmol) was added, and the mixture was stirred at that temperature for 2 h and at room temperature overnight. The mixture was poured into water, the precipitated white solid was washed with water, and the crude product was dissolved in DCM. The aqueous solution was extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo, and the residue was purified by flash column chromatography with silica gel (cyclohexane/ EtOAc 1:1 → 1:2) to yield imidazole 19 (1.544 g, 4.30 mmol, 50.8%) as a white solid. Mp: 141 °C. 1H NMR (500 MHz, CDCl3): δ = 7.33− 7.24 (m, 3 H), 6.93−6.88 (m, 2 H), 5.33−5.18 (m, 3 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.90 (s, 3 H), 2.43 (s, 3 H), 1.32 ppm (s, 9 H). 13C NMR (126 MHz, CDCl3): δ = 163.8, 155.6, 145.6, 137.4, 135.3, 129.3, 128.1, 127.6, 125.8, 80.1, 51.8, 47.3, 37.0, 28.3, 10.3 ppm. IR (ATR): ν̃ = 3361, 2957, 2939, 1698, 1681, 1570, 1525, 1455, 1436, 1389, 1362, 1340, 1250, 1222, 1164, 1082, 729, 694 cm−1. UV/vis (MeOH): λmax (log ε) = 243 nm (4.01). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H26N3O4+ 360.1918, found 360.1924; [M + Na]+ calcd for C19H25N3O4Na+ 382.1737, found 382.1742. Imidazole 20. Imidazole 19 (2.157 mg, 6.00 mmol) was dissolved in a mixture of methanol (73 mL) and dioxane (54 mL) followed by slow addition of NaOH solution (2 M, 30 mL, 60.00 mmol) at 0 °C. The ice bath was removed, and stirring was continued until TLC showed consumption of all starting materials (24 h). Then, the solution was poured onto an ice/DCM mixture and acidified with 2 M HCl to pH = 1. The layers were separated; the aqueous layer was then repeatedly extracted with DCM. The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give 1.988 g (5.80 mmol, 95.9%) of the free acid 20. Mp: 240 °C. 1H NMR (500 MHz, [D6]-DMSO): δ = 7.40−7.23 (m, 4 H), 7.06−6.93 (m, 2 H), 5.26 (s, 2 H), 4.20 (d, J = 5.7 Hz, 2 H), 2.27 (s, 3 H), 1.26 ppm (s, 9 H). 13C NMR (126 MHz, [D6]-DMSO): δ = 164.7, 155.4, 145.2, 136.5, 136.4, 128.8, 127.5, 127.4, 126.0, 78.2, 46.4, 36.8, 28.1, 10.0 ppm. IR (ATR): ν̃ = 3430, 2978, 2930, 2857, 1708, 1524, 1488, 1452, 1391, 1364, 1277, 1247, 1164, 1011, 747, 694 cm−1. UV/vis (MeOH): λmax (log ε) = 233 nm (3.96). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H24N3O4+ 346.1761, found 346.1770; [M + Na]+ calcd for C18H23N3O4Na+ 368.1581, found 368.1593. Imidazole 21. This compound was synthesized according to the general procedure A for the cleavage of the Boc group from imidazole 20 (1.250 g, 3.62 mmol) to yield 21 (1.020 g, 3.62 mmol, quantitative) as a white solid. Mp: 178 °C. 1H NMR (500 MHz, [D6]-DMSO): δ = 8.60 (brs, 3 H), 7.42−7.37 (m, 2 H), 7.36−7.31 (m, 1 H), 7.08−7.04 (m, 2 H), 5.34 (s, 2 H), 4.10 (s, 2 H), 2.40 ppm (s, 3 H). 13C NMR (126 MHz, [D6]-DMSO): δ = 164.0, 141.2, 137.1, 135.7, 129.0, 127.9, 127.6, 126.3, 46.5, 34.8, 10.0 ppm. IR (ATR): ν̃ = 3419, 2930, 2786, 2700, 1712, 1614, 1548, 1499, 1467, 1383, 1335, 1262, 1225, 1180, 1039, 732, 714, 696 cm−1. UV/vis (MeOH): λmax (log ε) = 235 nm (3.95). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H16N3O2+ 246.1237, found 246.1241; [M + Na]+ calcd for C13H15N3O2Na+ 268.1056, found 268.1060. 4213


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The Journal of Organic Chemistry NMR (300 MHz, CDCl3): δ = 9.11 (dd, J = 1.7 Hz, 4.4 Hz, 1 H), 8.19 (dd, J = 1.7 Hz, 8.1 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.55 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 5.17 ppm (brs, 2 H). 1,10-Phenanthroline Dimer 24. To a solution of dimer 6c (R1 = Boc, R2 = H, R3 = H)28 (50 mg, 0.1189 mmol) in acetonitrile (20 mL), N,N-diisopropylethylamine (147 μL, 0.8644 mmol) was added dropwise under argon at room temperature. After 1 h, pentafluorophenyldiphenylphosphinate (FDPP; 69 mg, 0.1796 mmol) was added, and the solution was stirred at room temperature until all starting material was consumed, which was detected by thin layer chromatography (7 days). Afterward, the solvent was evaporated, the residue was dissolved in absolute toluene (12 mL), and 2-amino-1,10phenanthroline (27 mg, 0.1383 mmol) was added to the solution. The mixture was stirred at 110 °C for 2 days, then the solvent was removed in vacuo, and the residue was purified by flash column chromatography with silica gel (DCM/MeOH/triethylamine 85:15:0 → 85:15:10) to yield 24 (49 mg, 0.0820 mmol, 69.0%) as a white solid. Mp: 141−142 °C. 1H NMR (600 MHz, CDCl3): δ = 10.29 (brs, 1 H), 9.17−9.10 (m, 1 H), 8.79 (d, J = 8.1 Hz, 1 H), 8.27−8.18 (m, 2 H), 7.77−7.71 (m, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.59 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 5.53 (brs, 1 H), 4.64 (d, J = 5.7 Hz, 2 H), 4.40 (d, J = 5.7 Hz, 2 H), 3.56 (s, 3 H), 3.51 (s, 3 H), 2.58 (s, 3 H), 2.54 (s, 3 H), 1.37 ppm (s, 9 H). 13 C NMR (151 MHz, CDCl3): δ = 163.5, 162.6, 155.6, 151.8, 149.6, 145.2, 144.6, 143.5, 138.2, 136.2, 135.2, 133.8, 129.3, 129.1, 129.0, 126.3, 125.8, 124.2, 122.8, 115.5, 79.7, 37.0, 34.9, 30.2, 20.0, 28.2, 9.9, 9.7 ppm. IR (ATR): ν̃ = 3498, 3376, 3254, 3044, 2957, 2924, 2852, 1703, 1641, 1584, 1504, 1476, 1386, 1268, 1163, 848, 734, 718 cm−1. UV/vis (CH3CN): λmax (log ε) = 193 (4.50), 232 (4.50), 290 (4.42), 338 (3.77), 354 nm (3.54). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H36N9O4+ 598.2885, found 598.2885; [M + Na]+ calcd for C31H35N9O4Na+ 620.2704, found 620.2691; [M − H]− calcd for C31H34N9O4− 596.2728, found 596.27418.

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(2) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; WileyVCH: Weinheim, 2015. (3) Milburn, M. V.; Tong, L.; DeVos, A. M.; Brunger, A.; Yamaizumi, Z.; Nishimura, S.; Kim, S.-H. Science 1990, 247, 939−945. (4) Browne, W. R.; Feringa, B. L. Nat. Nanotechnol. 2006, 1, 25−35. (5) Lerch, M. M.; Hansen, M. J.; van Dam, G. M.; Szymanski, W.; Feringa, B. L. Angew. Chem., Int. Ed. 2016, 55, 10978−10999. (6) Martinek, T. A.; Fülöp, F. Chem. Soc. Rev. 2012, 41, 687−702. (7) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071−13072. (8) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913− 941. (9) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173−180. (10) Hanessian, S.; Luo, X.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569−8570. (11) Hintermann, T.; Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998, 81, 983−1002. (12) Pengo, B.; Formaggio, F.; Crisma, M.; Toniolo, C.; Bonora, G. M.; Kamphuis, J.; Saviano, M.; Iacovino, R.; Rossi, F.; Benedetti, E.; Broxterman, Q. B. J. Chem. Soc., Perkin Trans. 2 1998, 1651−1658. (13) Inai, Y.; Kurokawa, Y.; Hirabayashi, T. Biopolymers 1999, 49, 551−564. (14) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893−4012. (15) Inai, Y.; Kurokawa, Y.; Kojima, N. J. Chem. Soc., Perkin Trans. 2 2002, 1850−1857. (16) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252−262. (17) Hecht, S.; Huc, I. Foldamers: Structure, Properties and Applications; Wiley-VCH: Weinheim, 2007. (18) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399− 1408. (19) Clayden, J.; Castellanos, A.; Solà, J.; Morris, G. A. Angew. Chem., Int. Ed. 2009, 48, 5962−5965. (20) Sola, J.; Helliwell, M.; Clayden, J. J. Am. Chem. Soc. 2010, 132, 4548−4549. (21) Grison, C. M.; Miles, J. A.; Robin, S.; Wilson, A. J.; Aitken, D. J. Angew. Chem., Int. Ed. 2016, 55, 11096−11100. (22) Grison, C. M.; Robin, S.; Aitken, D. J. Chem. Commun. 2016, 52, 7802−7805. (23) Mathieu, L.; Legrand, B.; Deng, C.; Vezenkov, L.; Wenger, E.; Didierjean, C.; Amblard, M.; AverlantPetit, M. C.; Masurier, N.; Lisowski, V.; Martinez, J.; Maillard, L. T. Angew. Chem., Int. Ed. 2013, 52, 6006−6010. (24) Zhao, W.; Wang, Y.; Shang, J.; Che, Y.; Jiang, H. Chem. - Eur. J. 2015, 21, 7731−7735. (25) Delsuc, N.; Godde, F.; Kauffmann, B.; Léger, J.-M.; Huc, I. J. Am. Chem. Soc. 2007, 129, 11348−11349. (26) Kudo, M.; Carbajo López, D.; Maurizot, V.; Masu, H.; Tanatani, A.; Huc, I. Eur. J. Org. Chem. 2016, 2016, 2457−2466. (27) Akazome, M.; Ishii, Y.; Nireki, T.; Ogura, K. Tetrahedron Lett. 2008, 49, 4430−4433. (28) Adam, A.; Haberhauer, G. Chem. - Eur. J. 2015, 21, 4333−4339. (29) Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1−23. (30) Wipf, P. Chem. Rev. 1995, 95, 2115−2134. (31) Wipf, P. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Elsevier: Amsterdam, 1998. (32) Comba, P.; Dovalil, N.; Gahan, L. R.; Hanson, G. R.; Westphal, M. Dalton Trans. 2014, 43, 1935−1956. (33) Haberhauer, G.; Oeser, T.; Rominger, F. Chem. Commun. 2005, 2799−2801. (34) Pintér, Á .; Haberhauer, G.; Hyla-Kryspin, I.; Grimme, S. Chem. Commun. 2007, 3711−3713. (35) Haberhauer, G.; Kallweit, C. Angew. Chem., Int. Ed. 2010, 49, 2418−2421. (36) Haberhauer, G. Angew. Chem., Int. Ed. 2008, 47, 3635−3638. (37) Haberhauer, G. Angew. Chem., Int. Ed. 2010, 49, 9286−9289.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00185. NMR and CD spectra, calculated molecular structures and crystal structure data of 15, 16, 22, and 24, 1H NMR and 13C NMR spectra of the new compounds, Cartesian coordinates, and absolute energies of all calculated compounds (PDF) Crystallographic information for 15, 16, 22, and 24 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Abdulselam Adam: 0000-0003-3588-5737 Gebhard Haberhauer: 0000-0002-5427-7510 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was generously supported by the Professor Werdelmann-Stiftung (T167/23664/2013). The authors thank Dr. Felix Niemeyer, Dr. Torsten Schaller, and Udo Kranz for helpful support.

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REFERENCES

(1) Whitford, D. Proteins: Structure and Function; John Wiley & Sons: Chichester, 2013. 4214


Article

The Journal of Organic Chemistry (38) Haberhauer, G. Angew. Chem., Int. Ed. 2011, 50, 6415−6418. (39) Haberhauer, G.; Pintér, Á .; Oeser, T.; Rominger, F. Eur. J. Org. Chem. 2007, 2007, 1779−1792. (40) Haberhauer, G.; Drosdow, E.; Oeser, T.; Rominger, F. Tetrahedron 2008, 64, 1853−1859. (41) Pintér, Á .; Haberhauer, G. In Modeling of Molecular Properties; Comba, P., Ed.; Wiley-VCH: Weinheim, 2011. (42) Karplus, M. J. Chem. Phys. 1959, 30, 11−15. (43) Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002, 43, 6335−6338. (44) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098− 3100. (45) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (46) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200−206. (47) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (48) Grimme, S. Chem. - Eur. J. 2012, 18, 9955−9964. (49) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724−728. (50) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257−2261. (51) Bauernschmitt, R.; Ahlrichs, R. Chem. Phys. Lett. 1996, 256, 454−464. (52) Casida, M. E.; Jamorski, C.; Casida, K. C.; Salahub, D. R. J. Chem. Phys. 1998, 108, 4439−4449. (53) Furche, F.; Ahlrichs, R. J. Chem. Phys. 2002, 117, 7433−7447. (54) Maestro, version 9.5, Schrödinger, LLC, 2013. (55) Klamt, A.; Schüürmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 2, 799−805. (56) Sebaoun, L.; Maurizot, V.; Granier, T.; Kauffmann, B.; Huc, I. J. Am. Chem. Soc. 2014, 136, 2168−2174. (57) Moody, C. J.; Bagley, M. C. Chem. Commun. 1998, 2049−2050. (58) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin, A. M. Z. Synlett 1996, 1996, 825−826. (59) Corey, E. J.; Borror, A. L.; Foglia, T. J. Org. Chem. 1965, 30, 288−290. (60) Engel, Y.; Dahan, A.; Rozenshine-Kemelmakher, E.; Gozin, M. J. Org. Chem. 2007, 72, 2318−2328. (61) Halcrow, B. E.; Kermack, W. O. J. Chem. Soc. 1946, 0, 155−157. (62) Kumar, P.; Madyal, R. S.; Joshi, U.; Gaikar, V. G. Ind. Eng. Chem. Res. 2011, 50, 8195−8203.

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