Matched and Mismatched Phenomena in the Helix Orientation Bias

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Article Cite This: J. Org. Chem. 2018, 83, 5123−5131

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Matched and Mismatched Phenomena in the Helix Orientation Bias Induced by Chiral Appendages at Multiple Positions of Indolocarbazole-Pyridine Hybrid Foldamers Han Bit Jang, Ye Rin Choi, and Kyu-Sung Jeong* Department of Chemistry, Yonsei University, Seoul 03722, Korea S Supporting Information *

ABSTRACT: A series of indolocarbazole-pyridine (IP) hybrid foldamers containing chiral residues at multiple different positions were prepared to reveal the matched and mismatched phenomena of local stereocenters on the induction of helical bias. These foldamers adopted stable helical conformations, thus affording well-resolved separate sets of 1H NMR signals for right- (P) and left-handed (M) helices in water saturated organic solvents such as toluene and dichloromethane. The ratios of P- and M-helices were determined by integrating the 1 H NMR signals, in combination with the molar circular dichroism (Δε) and optical rotation ([α]D) values. The degree of helical bias was larger in the IP foldamer bearing chiral residues at the termini relative to those at the pyridine side chains, but the preferred helix orientation was opposite to each other. Foldamers 5(SS)t(SSS)py and 6(RR)t(SSS)py with chiral residues at five different positions demonstrated the matched and mismatched phenomena of local stereocenters in 6(RR)t(SSS)py and 5(SS)t(SSS)py, respectively.

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exhibited a strong negative Cotton effect at λ = 394 nm in water-saturated CH2Cl2, supporting the helical folding of 1 (Figure 2b). Moreover, 1H NMR spectroscopy exhibited two separate sets of well-resolved 1H NMR signals which corresponded to major and minor helices, and the integrations of the signals yielded the helical excess of 70% in watersaturated CH2Cl2. It should be noted that the helical folding of the IP foldamer was investigated in water-saturated organic media because the water molecules were found to play important roles in the formation and stabilization of helically folded conformations. Herein, we have prepared a series of new IP foldamers 2−6 that contain (S)- or (R)-1-phenylethanamido ((S)- or (R)PEA) moieties at up to five different positions in order to reveal the matched and mismatched phenomena of the helical excess when attached to multiple different positions of the IP foldamers (Figure 1). In all the cases, the P- and M-helices could be clearly distinguished by 1H NMR spectroscopy owing to the slow exchange between the two helical isomers in watersaturated toluene-d8 and CD2Cl2 at 25 °C. Consequently, the ratios of P- and M-helices could be estimated by the integration of 1H NMR signals. A higher degree but opposite orientation of helical bias was induced in the case of the chiral PEA units at ends of the strands, compared to those located at the pyridine side chains. As a result, helical bias was diminished in foldamer 5(SS)t(SSS)py, which contained all identical (S)-PEA units at five

INTRODUCTION Inspired by the secondary helical structures of proteins and peptides, many synthetic helical oligomers have been prepared to date using unnatural amino acids1 or aromatic monomeric units.2 Unlike natural polymers and oligomers, achiral monomers are preferably used in the synthesis of aromatic helical foldamers to avoid possible stereochemical complexity. The preferential formation of one helix over another has therefore been pursued by incorporating a chiral segment in either the side chain,3 terminal4 or backbone5 of the foldamer. Intuitively, the induction and degree of the helical bias should be sensitive to the location and sequence of the chiral unit in the foldamer strand. A more difficult but pertinent issue is that of the helical bias, which may either be augmented or diminished when chiral appendages are introduced at multiple positions in the foldamer. In other words, the chiral units at different positions can be either positively (matched) or negatively (mismatched) cooperative for the folding of the foldamer, thus affording either a higher or lower degree of helical bias. The same issue might also be applied to natural counterparts such as oligopeptides and oligonucleotides containing multiple local stereocenters. Recently, we prepared an indolocarbazole-pyridine (IP) foldamer 1 that folded to a helical structure with the biased helical excess owing to the presence of chiral moieties at ends of the strand.6 As shown in Figure 2a, the X-ray crystal analysis of 1 demonstrated a helically folded structure, in which four water molecules were trapped in the internal cavity by the formation of multiple hydrogen bonds. Also, CD spectra © 2018 American Chemical Society

Received: February 20, 2018 Published: April 25, 2018 5123

DOI: 10.1021/acs.joc.8b00482 J. Org. Chem. 2018, 83, 5123−5131

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The Journal of Organic Chemistry

pairs of 9a (2.2 equiv) and 13b, 9b (2.0 equiv) and 13a, and 9b (2.2 equiv) and 13b gave the desired chiral foldamers 2 (63%), 3 (71%), and 4 (83%), respectively. Foldamers 2, 3 and 4 were found to adopt compact helical conformations in water-saturated toluene-d8 and CD2Cl2, but they existed in an unfolded extended conformation in DMSOd6. As a representative example, the 1H NMR spectra of 2 in these three different solvents are shown and compared in Figure 3. It is noted that 1H NMR spectra of the foldamers are concentration-independent in water-saturated toluene-d8 (0.2− 8 mM) and CD2Cl2 (0.2−10 mM) (Figure S2−S6), indicative of negligible aggregation under the conditions. The aromatic CH signals were noticeably upfield-shifted in water-saturated toluene-d8 and CD2Cl2, as compared with the signals in DMSO-d6. In particular, the CHp signal of the middle pyridine was the most upfield-shifted with Δδ = 2.36 ppm, whereas the CH signals of the two outer pyridines were shifted by Δδ = 1.70 ppm (Hi), 1.37 ppm (Hg) and 1.26 ppm (Hh) in watersaturated toluene-d8. A similar trend of upfield shifts was also observed in water-saturated CD2Cl2 (Figure 3, S1 and Table S1). It should be emphasized that the magnitudes of the upfield shifts for the middle pyridine were approximately twice than those in the two outer pyridines, implying that the former experienced much stronger ring current effects by the adjacent aromatic rings than the latter. This characteristic upfield shift provides direct evidence for the helical folding of 2. The middle pyridine was sandwiched between two indolocarbazole planes in the helical structure, but the two outer pyridines were stacked only with one indolocarbazole plane. The 1H NMR spectral observations provide clear evidence for helical folding of 2 in water-saturated toluene-d8 and CD2Cl2 but not in DMSO-d6. In addition, 2D-ROESY spectra showed characteristic NOE cross peaks between aromatic signals, strongly supporting the helical folding of 2 (Figure S7−S8). Another important evidence for helical folding is that the 1H NMR spectrum of 2 was split into two sets of signals in watersaturated toluene-d8 and CD2Cl2 but only one set of the signals appeared in DMSO-d6 (Figure 3 and 4). This phenomenon is attributed to the intrinsic chirality of helix. Upon helical folding, the resulting P- and M-helices became diastereomers of each other if any stereogenic center existed in the foldamer like 2. As a result, these two helices could be distinguished in the 1H NMR spectrum unless their exchange was too fast on the NMR time scale.4,6,9 Foldamers 3 and 4 contained two and three (S)PAC groups in the strands, respectively. The 1H NMR spectra of 3 and 4 were practically identical to that of 2 in the aspect of the splitting patterns and chemical shifts. However, there was a difference in the ratios of major and minor helices, as summarized in Table 1 (Figure S9−S13). In water-saturated toluene-d8, the populations of major helices increased in the order of 2 (60%) < 3 (69%) < 4 (77%) with increasing the number of the chiral residues. The free energy differences (ΔΔG°) between the major and minor helices of 2, 3 and 4 were 0.24, 0.47, and 0.72 kcal/mol, respectively. It is worthwhile noting that each increment of the chiral residues increased the helical bias by ∼0.24 kcal/mol in toluene-d8. In CD2Cl2, however, the degree of helical bias was slightly larger when the chiral residue was located at the outer pyridines (0.32/2 = 0.16 kcal/mol in 3) than in the middle (0.09 kcal in 2). Nevertheless, these results imply that the chiral residues work independently to induce the same helical orientation regardless of the relative positions of pyridine units in the strand.

Figure 1. Molecular structures of foldamers 1−6 containing chiral residues at different positions.

Figure 2. (a) X-ray crystal structure of 1 ⊃ 4H2O. t-Butyl groups and CH protons except that in the stereocenters were all omitted for clarity. (b) CD spectra (10 μM, 25 °C) of 1 in water-saturated CH2Cl2 and DMSO.

different positions, i.e., two at the terminal ends and three at pyridines, as compared with foldamer 1 containing the chiral units only at both ends. In contrast, foldamer 6(RR)t(SSS)py, which had (R)-PEAs at both ends and (S)-PEAs at the three pyridines, showed increased helical bias.

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RESULTS AND DISCUSSION Foldamers 2, 3 and 4 which possess (S)-N-(phenylethyl)amidocarbonyl ((S)-PAC) groups at the 4-positions of the existing pyridine rings were prepared by repeating Sonogashira7 and protodesilylation (Scheme 1). The coupling reaction of 7a8 with 8a or 8b in the presence of Cul and Pd(PPh3)2Cl2 yielded 9a8a (56%) or 9b (65%), respectively. Similarly, the coupling reaction of 11a or 11b with 108a (2.1 equiv) afforded 12a8a (91%) or 12b (96%), respectively, which were treated with tetrabutylammonium fluoride (TBAF) to give 13a8a (95%) or 13b (97%). Finally, the coupling reactions between the right 5124

DOI: 10.1021/acs.joc.8b00482 J. Org. Chem. 2018, 83, 5123−5131

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The Journal of Organic Chemistry Scheme 1. Syntheses of Foldamers 2−6a

a Reagents and conditions: (a) CuI, Pd(PPh3)2Cl2, THF/Et3N, 55 °C, 56% (9a), 65% (9b), 51% (9c), 57% (9d); (b) CuI, Pd(PPh3)2Cl2, THF/ Et3N, 55 °C, 91% (12a), 96% (12b); (c) TBAF, THF, rt, 95% (13a), 97% (13b); (d) CuI, Pd(PPh3)2Cl2, THF/Et3N, 55 °C, 63% (2), 71% (3), 83% (4), 34% (5(SS)t(SSS)py), 25% (6(RR)t(SSS)py).

All the foldamers were strongly CD-active and their [α]D values were very large, implying the preferred formation of one specific helical isomer over another. It is known that the specific rotations of helices are typically very high.10 The molar circular dichroism (Δε) and specific rotation ([α]D) values of all the foldamers studied here are summarized in Table 2. Several trends were apparent. First, the magnitudes of Δε and [α]D values increased in the order of 2 < 3 < 4. This was in good agreement with the trend of the relative ratios of P- and Mhelices, as calculated by 1H NMR spectroscopy. Second, the chiral foldamers 2−4 showed CD spectra with two maxima in the region between 350 and 450 nm but foldamer 1 had a single maximum band. This was attributed to additional conjugation of pyridine units with the carbonyl groups that connect chiral residues to the foldamers. Third, the sign of Δε and [α]D for 2, 3 and 4 were opposite to that of foldamer 1 containing the chiral unit at terminal ends, indicating that the orientation of the preferred helices may be opposite to each other. Previously, it was proven by X-ray crystal structure (Figure 2a) that foldamer 1 folded into a left-handed (M) helix. Therefore, the formation of right-handed (P) helices may be preferred in the folding of 2, 3 and 4. Computer modeling studies (MacroModel 9.1, MMFFs force field, gas phase)11 also demonstrated that the P-helix of 2 was more stable than the Mhelix by 1.1 kJ/mol (Figure 6 and S14). In the M-helix, steric collision between the phenyl group of a chiral residue and a tbutyl group in the indolocarbazole is suggested by the calculations to be important (Figure 6b). As described above, the opposite trend of the preferred helical bias led us to prepare foldamers 5(SS)t(SSS)py and 6(RR)t(SSS)py, using which we investigated matched and

Figure 3. Partial 1H NMR spectra (400 MHz, 25 °C) of 2 (2 mM) in DMSO-d6, water-saturated toluene-d8 and CD2Cl2. Blue- and redcolored signals correspond to the CH signals of the two outer pyridines and one middle pyridine, respectively.

The helical folding and bias of foldamers 2, 3 and 4 containing up to three (S)-PAC groups at the pyridines were also investigated by circular dichroism (CD) spectroscopy and polarimetry in water-saturated toluene and CH2Cl2 (Figure 5). 5125

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Figure 4. Partial 1H NMR spectra (400 MHz, 25 °C) showing the major and minor helices of 2, 3, and 4 (2 mM) in (a) water-saturated toluene-d8 and (b) water-saturated CD2Cl2. Peaks used to calculate the ratio are marked with red circles (major) and blue triangles (minor).

Table 1. Ratios of (+)- and (−)-Helices of 1−6 and Their Free Energy Differences (ΔΔG° kcal/mol) in Water-Saturated Toluene-d8 and CD2Cl2 at 25 °Ca toluene-d8

CD2Cl2

foldamer

Helix ratio (+):(−)

ΔΔG° (kcal/mol)

Helix ratio (+):(−)

ΔΔG° (kcal/mol)

1 2 3 4 5(SS)t(SSS)py 6(RR)t(SSS)py

19:81 60:40 69:31 77:23 43:57 88:12

0.86 0.24 0.47 0.72 0.17 1.13

15:85 54:46 62:38 65:35 25:75 89:11

1.03 0.09 0.32 0.37 0.65 1.24

a

(+)- and (−)-Helices were assigned based on the CD and specific rotation values in Table 2. The ratios were calculated and averaged by the integration of well-resolved 1H NMR signals, with errors of individual signals in percentages being within 1%.

but enhanced in 6(RR)t(SSS)py as compared with that of foldamer 1 with the chiral residues only at both ends of the strand. The ratio of (+)- and (−)-helices was changed from 19:81 for 1 to 43:57 for 5(SS)t(SSS)py and 88:12 for 6(RR)t(SSS)py in watersaturated toluene-d8 (Table 1). A similar trend was also seen in water-saturated CH2Cl2 (Table 1 and Figure S12−S13). In addition, the magnitudes of specific rotations ([α]D) nicely corresponded to the degree of helical bias, determined by 1H NMR spectroscopy (Figure 7b, S15 and Table 2). These results clearly indicated that the (S)-configuration of the chiral residue

mismatched phenomena in the helical bias induced by the chiral residues introduced at multiple different positions. Foldamers 5(SS)t(SSS)py and 6(RR)t(SSS)py were synthesized following the same procedures for the preparation of 2−4. These two foldamers had the same (S)-PAC residues at all the existing three pyridines, but they had opposite configurations, (S) and (R), of the chiral residues at terminal ends. The 1H NMR and CD spectra of these foldamers are shown in Figure 6 and the spectral data are summarized in Table 1 and 2. Apparently, the degree of helical bias was reduced in 5(SS)t(SSS)py 5126

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Figure 5. CD spectra (10 μM, 25 °C) of 1−4 in water-saturated (a) toluene and (b) CH2Cl2.

Table 2. Molar CD Values (Δε) at λmax and Specific Rotations ([α]D) of 1−6 in Water-Saturated Toluene and CH2Cl2 (24 ± 1 °C)a toluene

a

CH2Cl2

foldamer

Δε (M−1 cm−1) (λmax (nm))

[α]D

Δε (M−1 cm−1) (λmax (nm))

[α]D

1 2 3 4 5(SS)t(SSS)py 6(RR)t(SSS)py

−201 (394) +35 (374), +47 (407) +44 (374), +64 (403) +53 (374), +82 (417) −40 (398), −31 (417) +131 (398), +118 (417)

−1507° +567° +965° +1333° −167° +1702°

−196 (394) +14 (379), +20 (405) +29 (379), +43 (405) +32 (379), +54 (415) −88 (396), −92 (419) +121 (396), +120 (419)

−1771° +290° +667° +867° −1308° +1930°

All measurements were duplicated, and the errors of Δε and [α]D values were within 1%.

Figure 6. (a) Energy-minimized P-helix (Macromodel 9.1, MMFFs, gas phase) of 2. t-Butyl groups and CH protons except that in the stereocenter were all omitted for clarity. (b) Schematic comparison of the chiral residue in P- and M-helices. On the basis of calculations, the P-helix was more stable by 1.1 kJ/mol than the M-helix because of the steric collision between phenyl and t-butyl groups in the M-helix.

at the pyridine units was matched with the opposite (R)configuration but mismatched with the same (S)-configuration at the terminal ends.

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CONCLUSION In this study, we prepared a series of indolocarbarzole-pyridine hybrid foldamers 2−6 that contained chiral residues either at the strand termini or at the pyridine side chains. As demonstrated by 1H NMR, CD spectroscopy and polarimetry, these chiral foldamers adopted stable helical conformations in different ratios of P- and M-helices, which allowed us to analyze matched or mismatched phenomena in the helical bias of the foldamer when the chiral residues were located at multiple different positions. Despite an identical chiral segment, the

Figure 7. (a) Partial 1H NMR spectra (2 mM, 400 MHz, 25 °C) showing the two helical isomers of 1, 5(SS)t(SSS)py and 6(RR)t(SSS)py in water-saturated toluene-d8. (b) CD spectra (10 μM, 25 °C) of 1, 5(SS)t(SSS)py and 6(RR)t(SSS)py in water-saturated toluene.

degree and orientation of helical bias were found to be sensitive to the relative positions in the strand. The degree of helical bias was larger in the foldamer bearing chiral residues at the termini as compared to those at the pyridines, whereas their preferred 5127

DOI: 10.1021/acs.joc.8b00482 J. Org. Chem. 2018, 83, 5123−5131

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2155.0972, found 2155.0975; IR (KBr pellet) ν 3362 (N−H), 2205 (CC), 1676 (CO), 1227 (C−O) cm−1. 3: Compound 3 was synthesized according to the general procedure using 13a8a (150 mg, 0.17 mmol), 9b (260 mg, 0.34 mmol), CuI (2.3 mg, 0.01 mmol), Pd(PPh3)2Cl2 (6.5 mg, 0.01 mmol), THF (1 mL) and Et3N (0.8 mL). Reaction time 1 h; eluent: EtOAc/hexane = 1:5 (v/v); yellow solid; 71% yield (270 mg); mp >231 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 2H), 11.35 (s, 2H), 11.25 (s, 2H), 10.96 (s, 2H), 9.32 (d, J = 7.5 Hz, 2H), 8.39 (s, 2H), 8.34 (d, J = 1.8 Hz, 2H), 8.34 (d, J = 2.4 Hz, 2H), 8.29 (s, 2H), 8.28 (s, 2H), 8.20 (s, 2H), 8.06 (s, 4H), 8.00 (s, 4H), 7.76 (s, 2H), 7.70 (s, 2H), 7.65 (s, 2H), 7.43 (s, 2H), 7.39−7.36 (m, 6H), 7.29−7.25 (m, 5H), 7.18 (t, J = 6.8 Hz, 2H), 5.52 (s, 2H), 5.20−5.13 (m, 2H), 1.48 (s, 18H), 1.45 (s, 18H), 1.40 (s, 36H), 1.38 (s, 18H); 13C NMR (400 MHz, DMSO-d6) δ 165.5, 144.1, 143.8, 143.7, 142.9, 142.8, 142.3, 142.1, 142.1, 141.9, 137.8, 137.8, 137.7, 137.3, 137.0, 128.3, 128.3, 126.8, 126.7, 126.2, 126.2, 126.1, 126.1, 126.1, 126.0, 126.0, 125.9, 125.8, 125.7, 124.8, 124.7, 124.3, 124.2, 124.1, 123.7, 120.9, 120.8, 120.7, 120.5, 119.0, 118.8, 118.6, 116.9, 112.6, 112.5, 112.5, 112.2, 104.9, 103.2, 103.0, 102.9, 99.7, 91.8, 91.8, 91.7, 87.9, 87.7, 86.7, 77.4, 63.9, 49.0, 34.6, 34.5, 34.5, 34.4, 31.8, 31.8, 31.8, 31.7, 31.7, 22.0; HRMS (ESI-TOF) m/z [M+2Na] 2+ calcd for C 159 H145 N13 O4 1173.5686, found 1173.5687; IR (KBr pellet) ν 3401 (N−H), 2204 (CC), 1658 (CO), 1227 (C−O) cm−1. 4: Compound 4 was synthesized according to the general procedure using 13b (100 mg, 0.09 mmol), 9b (150 mg, 0.15 mmol), CuI (1.9 mg, 0.01 mmol), Pd(PPh3)2Cl2 (5.4 mg, 0.007 mmol), THF (0.5 mL) and Et3N (0.6 mL). Reaction time 1 h; eluent: EtOAc/hexane = 1:3 (v/v); yellow solid; 83% yield (190 mg); mp >232 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 2H), 11.33 (s, 2H), 11.30 (s, 2H), 10.89 (s, 2H), 9.26 (d, J = 7.8 Hz, 2H), 9.18 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 1.5 Hz, 2H), 8.35 (d, J = 1.5 Hz, 2H), 8.33 (d, J = 1.4 Hz, 2H), 8.23 (s, 2H), 8.22 (s, 4H), 8.19 (d, J = 1.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 4.1 Hz, 2H), 8.00 (d, J = 4.3 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 1.7 Hz, 2H), 7.34−7.32 (m, 4H), 7.26− 7.21 (m, 6H), 7.17−7.13 (m, 4H), 7.11−7.07 (m, 1H), 5.50 (s, 2H), 5.14−5.07 (m, 2H), 5.02−4.97 (m, 1H), 1.48 (s, 18H), 1.44 (s, 12H), 1.41−1.40 (m, 24H), 1.39 (s, 18H), 1.38 (s, 18H), 1.28 (d, J = 6.8 Hz, 3H); 13C NMR (400 MHz, acetone-d6) δ 162.8, 162.4, 145.2, 145.1, 143.6, 143.4, 143.1, 142.9, 142.8, 142.7, 142.6, 142.0, 141.6, 140.5, 139.6, 138.8, 138.6, 129.5, 129.4, 129.4, 129.4, 128.3, 128.1, 127.9, 127.7, 127.6, 127.6, 127.3, 127.0, 126.9, 126.9, 126.8, 126.3, 125.4, 125.1, 125.0, 125.0, 124.9, 124.1, 122.7, 122.6, 122.3, 122.3, 122.2, 119.5, 119.3, 119.0, 117.3, 113.2, 113.1, 113.1, 112.8, 106.2, 104.8, 104.6, 104.3, 99.1, 93.3, 92.8, 92.3, 89.0, 88.7, 87.9, 78.3, 65.1, 50.5, 35.4, 35.3, 35.2, 32.6, 32.5, 32.3, 31.7, 31.6, 22.2, 22.0; HRMS (ESITOF) m/z [M+2Na]2+ calcd for C168H154N14O5 1247.1028, found 1247.1025; IR (KBr pellet) ν 3392 (N−H), 2206 (CC), 1666 (C O), 1227 (C−O) cm−1. 5(SS)t(SSS)py: Compound 5(SS)t(SSS)py was synthesized according to the general procedure using 13b (67 mg, 0.06 mmol), 9c (120 mg, 0.12 mmol), CuI (2.0 mg, 0.006 mmol), Pd(PPh3)2Cl2 (3.4 mg, 0.005 mmol), THF (0.4 mL) and Et3N (0.4 mL). Reaction time 1 h; eluent: EtOAc/hexane = 1:5 (v/v); yellow solid; 34% yield (60 mg); mp >238 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 2H), 11.36 (s, 2H), 11.21 (s, 4H), 9.30 (d, J = 7.4 Hz, 2H), 9.23 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 8.1 Hz, 2H), 8.35 (d, J = 1.3 Hz, 2H), 8.33 (d, J = 1.4 Hz, 4H), 8.27 (d, J = 1.3 Hz, 2H), 8.22 (s, 4H), 8.21 (s, 2H), 8.18 (s, 2H), 8.04−7.98 (m, 8H), 7.75 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 1.5 Hz, 3H), 7.69 (s, 1H), 7.66 (d, J = 1.7 Hz, 2H), 7.65 (d, J = 1.7 Hz, 2H), 7.64 (d, J = 1.9 Hz, 2H), 7.33−7.30 (m, 8H), 7.25−7.20 (m, 12H), 7.16− 7.12 (m, 6H), 7.07 (t, J = 7.1 Hz, 1H), 5.14−5.05 (m, 4H), 5.01−4.94 (m, 1H), 1.44 (s, 36H), 1.38 (d, J = 5.1 Hz, 12H), 1.37 (s, 18H), 1.36 (s, 1.36), 1.26 (d, J = 7.1 Hz, 3H); 13C NMR (400 MHz, acetone-d6) δ 165.5, 162.8, 162.3, 145.6, 145.4, 145.2, 142.5, 142.4, 142.4, 142.3, 142.0, 142.0, 141.9, 141.0, 140.6, 140.0, 139.8, 139.3, 139.1, 134.4, 133.3, 129.5, 129.5, 129.5, 129.1, 129.1, 128.3, 128.2, 128.1, 127.8, 127.6, 127.6, 127.6, 127.6, 127.3, 127.1, 127.1, 126.8, 126.8, 126.7, 126.6, 126.5, 125.7, 125.6, 125.5, 125.0, 124.8, 124.6, 124.5, 124.0, 123.0, 122.5, 122.4, 122.4, 122.0, 121.9, 121.8, 119.3, 118.8, 118.8,

helix orientation was opposite to each other. The matched and mismatched principle of local stereocenters observed in this study may be applied not only to the degree of helical bias but also to the stabilities of synthetic or natural helical secondary structures.

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EXPERIMENTAL SECTION

General Methods. All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. Dichloromethane (CH2Cl2) was purified by drying over calcium hydride (CaH2), followed by distillation. Hexane, ethyl acetate (EtOAc), and acetone were distilled. Water-saturated toluene-d8 and CD2Cl2 were prepared by sonicating the organic solvent containing a few drops of distilled water for 30 min. After 1 h standing, the organic layer was carefully separated out for use. Thin layer chromatography (TLC) was performed on Merck (silica gel 60, F-254, 0.25 mm). Silica gel 60 (230−400 mesh, Merck) was used for column chromatography. Melting points were determined with a Barnstead Electrothermal (IA9100) apparatus. FT-IR spectra were measured by using a Vertex70 FT-IR spectrometer. The ESI-HRMS spectrometric measurements were performed at the Organic Chemistry Research Center at Sogang University. 1D and 2D NMR spectra were measured by using Bruker DRX 400, Avance instruments. Chemical shifts were reported in reference to residual solvent peaks (for 1H NMR spectra, acetone-d6 2.05 ppm; CD2Cl2 5.32 ppm; toluene-d8 2.08 ppm; DMSO-d6 2.50 ppm and for 13C NMR spectra, acetone-d6 206.26 ppm; DMSO-d6 39.52 ppm). 2D NMR (ROESY) of 2 (10 mM) was measured in water-saturated toluene-d8 and CD2Cl2 at 25 °C (Figure S7−S8) (mixing time: 400 ms). Circular dichroism (CD) spectra were obtained on a JASCO (J810). Each solution of foldamers 1−6 (10 μM) was prepared in watersaturated toluene and CH2Cl2. The CD spectra were recorded under the following conditions: Scanning rate: 500 nm min−1, bandwidth: 1.0 nm, response time: 1.0 s, accumulations: 3 scans, temperature: 25 °C. Optical rotation values of foldamers 1−6 were measured with the concentration (c, mg/mL) of 1.0 at 24 ± 1 °C using the RUDOLPH (III-589). General Procedure of Sonogashira Coupling Reaction.7 A Schlenk flask containing two coupling compounds, CuI and Pd(PPh3)2Cl2 was evacuated under vacuum and backfilled with nitrogen. Anhydrous, degassed tetrahydrofuran (THF) and triethylamine (Et3N) were added sequentially and the solution was stirred at 50− 55 °C in an oil bath for a given time period. The mixture was filtered through Celite and concentrated, and the residue was dissolved in CH2Cl2. The solution was washed with NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel). 2: Compound 2 was synthesized according to the general procedure using 13b (170 mg, 0.16 mmol), 9a8a (220 mg, 0.35 mmol), CuI (3.8 mg, 0.016 mmol), Pd(PPh3)2Cl2 (7.4 mg, 0.01 mmol), THF (1 mL) and Et3N (1 mL). Reaction time 1.5 h; eluent: EtOAc/hexane = 1:5 (v/v); yellow solid; 63% yield (210 mg); mp >245 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 6H), 10.93 (s, 2H), 9.30 (d, J = 7.5 Hz, 1H), 8.39 (d, J = 0.8 Hz, 2H), 8.36 (d, J = 0.8 Hz, 2H), 8.33 (d, J = 1.1 Hz, 2H), 8.30 (s, 2H), 8.20 (d, J = 1.1 Hz, 2H), 8.11 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 7.4 Hz, 2H), 7.74 (d, J = 1.6 Hz, 2H), 7.70 (d, J = 1.8 Hz, 2H), 7.69 (d, J = 1.8 Hz, 2H), 7.64 (t, J = 7.6 Hz, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 1.6 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 5.56 (s, 2H), 5.56−5.09 (m, 1H), 1.49 (s, 12H), 1.46 (s, 18H), 1.43 (s, 37H), 1.40 (s, 19H); 13C NMR (400 MHz, DMSO-d6) δ 162.5, 144.0, 143.7, 143.0, 142.9, 142.7, 142.2, 142.2, 142.0, 141.8, 137.8, 137.8, 137.6, 137.3, 137.2, 128.2, 126.9, 126.8, 126.3, 126.1, 126.0, 126.0, 125.9, 125.9, 125.9, 125.7, 125.7, 125.6, 124.7, 124.2, 124.1, 124.0, 123.6, 120.8, 120.8, 120.7, 120.4, 118.8, 118.5, 118.5, 116.8, 112.6, 112.5, 112.3, 112.2, 104.8, 103.2, 103.0, 102.9, 99.7, 91.8, 91.8, 91.7, 87.7, 87.0, 86.6, 77.4, 63.9, 63.9, 49.0, 34.5, 34.5, 34.5, 34.4, 31.7, 31.7, 31.7, 31.7, 21.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C150H136N12O3 5128

DOI: 10.1021/acs.joc.8b00482 J. Org. Chem. 2018, 83, 5123−5131

Article

The Journal of Organic Chemistry

CuI (2.1 mg, 0.009 mmol), Pd(PPh3)2Cl2 (6.6 mg, 0.009 mmol), THF (1 mL) and Et3N (1 mL). Reaction time 1 h; eluent: EtOAc/hexane = 1:3 (v/v); yellow solid; 51% yield (150 mg); mp >211 °C (dec); 1H NMR (400 MHz, acetone-d6) δ 10.69 (s, 1H), 10.57 (s, 1H), 8.57 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 8.00−7.98 (m, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.46−7.44 (m, 4H), 7.32−7.26 (m, 4H), 7.22−7.15 (m, 2H), 5.39−5.28 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H), 1.50 (s, 9H), 1.50 (s, 9H); 13C NMR (400 MHz, DMSO-d6) δ 165.1, 162.2, 145.1, 144.9, 144.9, 144.2, 143.8, 142.7, 142.6, 142.0, 137.9, 135.2, 134.5, 130.5, 129.4, 129.3, 128.7, 128.7, 128.6, 128.6, 128.3, 127.2, 127.0, 126.8, 126.4, 126.3, 126.3, 126.2, 126.1, 125.9, 125.8, 125.2, 124.4, 124.1, 122.8, 121.1, 120.8, 119.4, 118.2, 113.0, 112.7, 104.5, 102.8, 92.7, 91.2, 89.1, 87.3, 49.5, 49.0, 34.9, 34.8, 32.0, 32.0, 22.4, 22.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C59H52BrN5O2 964.3202, found 964.3199; IR (KBr pellet) ν 3331 (N−H), 2204 (CC), 1648 (CO) cm−1. 9d: Compound 9d was synthesized according to the general procedure using 7c13 (190 mg, 0.29 mmol), 8b (110 mg, 0.29 mmol), CuI (2.4 mg, 0.009 mmol), Pd(PPh3)2Cl2 (7.1 mg, 0.009 mmol), THF (1 mL) and Et3N (1 mL). reaction time 1 h; eluent: EtOAc/hexane = 1:3 (v/v); yellow solid; 57% yield (160 mg); mp >213 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 11.26 (s, 1H), 9.29 (d, J = 7.7 Hz, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.30 (s, 1H), 8.29 (d, J = 1.2 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 8.01 (s, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 4H), 7.35−7.29 (m, 4H), 7.25−7.19 (m, 2H), 5.24−5.14 (m, 2H), 1.51 (d, J = 2.8 Hz, 3H), 1.49 (d, J = 2.9 Hz, 3H), 1.46 (s, 18H); 13C NMR (400 MHz, DMSO-d6) δ 164.6, 161.8, 144.9, 144.8, 144.8, 144.0, 143.5, 142.3, 142.2, 141.8, 137.7, 135.0, 134.2, 130.2, 129.1, 128.8, 128.4, 128.4, 128.3, 128.3, 128.1, 126.9, 126.7, 126.6, 126.2, 126.2, 126.1, 126.0, 125.9, 125.6, 125.5, 125.0, 124.2, 123.8, 122.6, 120.9, 120.6, 119.1, 117.9, 112.6, 112.4, 104.2, 102.6, 92.4, 91.0, 88.9, 87.1, 49.1, 48.7, 34.6, 34.6, 31.8, 31.8, 22.2, 22.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C59H52BrN5O2 964.3202, found 964.3200; IR (KBr pellet) ν 3319 (N−H), 2202 (CC), 1647 (CO) cm−1. 12b: Compound 12b was synthesized according to the general procedure using 11b (= 8b) (275 mg, 0.72 mmol), 108a (880 mg, 1.51 mmol), CuI (3.3 mg, 0.021 mmol), Pd(PPh3)2Cl2 (15.2 mg, 0.021 mmol), THF (3 mL) and Et3N (5 mL). Reaction time 1.5 h; eluent: EtOAc/hexane = 1:4 (v/v); orange solid; 96% yield (950 mg); mp >208 °C (dec); 1H NMR (400 MHz, acetone-d6) δ 10.52 (s, 2H), 10.22 (s, 2H), 8.62 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, 2H), 8.31 (d, J = 1.6 Hz, 2H), 8.23 (s, 2H), 8.06 (s, 2H), 8.06 (s, 2H), 7.81 (d, J = 1.1 Hz, 2H), 7.61 (d, J = 1.7 Hz, 2H), 7.51 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 5.47−5.39 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.51 (s, 18H), 1.44 (s, 18H), 0.99 (S, 42H); 13C NMR (400 MHz, acetone-d6) δ 163.8, 145.2, 144.8, 144.1, 143.4, 143.3, 139.3, 138.7, 129.3, 128.0, 127.8, 127.3, 127.1, 127.0, 127.0, 125.6, 125.4, 125.1, 122.7, 122.5, 119.5, 118.4, 113.3, 113.3, 106.3, 105.2, 104.3, 94.7, 92.6, 88.4, 50.6, 35.3, 35.2, 32.2, 32.2, 22.4, 18.9, 11.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C92H106N6OSi2 1389.7865, found 1389.7862; IR (KBr pellet) ν 3382 (N−H), 2201 (CC), 1650 (CO) cm−1. 13b: 12b (310 mg, 0.23 mmol) was dissolved in THF (2.3 mL) and tetrabutylammonium fluoride (TBAF) (0.57 mL, 1.0 M solution in THF, 0.58 mmol) was added at 0 °C. The reaction mixture was stirred for 50 min at room temperature and after concentrating the solution, the residue was purified by flash column chromatography (silica gel, EtOAc/hexane = 1:5 (v/v)). orange solid; 97% yield (230 mg); mp >182 °C (dec); 1H NMR (400 MHz, acetone-d6) δ 10.91 (s, 2H), 10.33 (s, 2H), 8.70 (d, J = 7.9 Hz, 1H), 8.42 (d, J = 1.5 Hz, 2H), 8.33 (d, J = 1.5 Hz, 2H), 8.21 (s, 2H), 8.07 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 1.7 Hz, 2H), 7.64 (d, J = 1.7 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 5.51−5.44 (m, 1H), 3.90 (s, 2H), 1.68 (d, J = 6.9 Hz, 3H), 1.51 (s, 18H), 1.47 (s, 18H); 13C NMR (400 MHz, acetone-d6) δ 164.2, 145.3,

117.6, 112.9, 112.8, 112.6, 112.6, 105.8, 105.4, 104.8, 103.8, 92.8, 92.5, 92.3, 92.0, 89.1, 88.3, 88.2, 86.7, 50.4, 50.2, 49.9, 35.4, 35.2, 35.2, 35.2, 32.8, 32.7, 32.5, 32.4, 22.3, 22.1, 21.8; HRMS (ESI-TOF) m/z [M +2Na]2+ calcd for C192H168N16O5 1412.6623, found 1412.6625; IR (KBr pellet) ν 3357 (N−H), 2204 (CC), 1670 (CO) cm−1. 6(RR)t(SSS)py: Compound 6(RR)t(SSS)py was synthesized according to the general procedure using 13b (75 mg, 0.07 mmol), 9d (140 mg, 0.14 mmol), CuI (2.1 mg, 0.007 mmol), Pd(PPh3)2Cl2 (5.2 mg, 0.007 mmol), THF (0.5 mL) and Et3N (0.5 mL). Reaction time 1 h; eluent: EtOAc/hexane = 1:3 (v/v); yellow solid; 25% yield (50 mg); mp >226 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 2H), 11.35 (s, 2H), 11.21 (s, 2H), 11.20 (s, 2H), 9.27 (d, J = 7.9 Hz, 2H), 9.21 (d, J = 7.3 Hz, 1H), 8.87 (s, 1H), 8.85 (s, 1H), 8.35 (d, J = 1.3 Hz, 2H), 8.33 (s, 4H), 8.27 (d, J = 1.5 Hz, 2H), 8.22 (s, 4H), 8.21 (s, 2H), 8.19 (s, 2H), 8.07−7.98 (m, 8H), 7.75 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 1.7 Hz, 3H), 7.70 (s, 1H), 7.66 (d, J = 1.7 Hz, 2H), 7.65 (d, J = 1.7 Hz, 2H), 7.64 (d, J = 1.7 Hz, 2H), 7.33−7.30 (m, 8H), 7.25−7.20 (m, 12H), 7.16−7.12 (m, 6H), 7.07 (t, J = 7.3 Hz, 1H), 5.12−5.05 (m, 4H), 5.00−4.94 (m, 1H), 1.44 (s, 36H), 1.39 (d, J = 6.8 Hz, 12H), 1.37 (s, 18H), 1.36 (s, 18H), 1.27 (d, J = 7.0 Hz, 3H); 13C NMR (400 MHz, acetone-d6) δ 145.6, 145.4, 145.2, 142.5, 142.4, 142.4, 124.3, 142.0, 142.0, 141.9, 141.0, 140.6, 140.0, 139.8, 139.3, 139.1, 134.4, 133.3, 129.5, 129.5, 129.5, 129.1, 129.1, 128.3, 128.2, 128.1, 127.8, 127.6, 127.6, 127.6, 127.6, 127.3, 127.1, 127.1, 126.8, 126.8, 126.7, 126.6, 126.5, 125.7, 125.6, 125.5, 125.0, 124.8, 124.6, 124.5, 124.0, 123.0, 122.5, 122.4, 122.4, 122.0, 121.9, 121.8, 119.3, 118.8, 118.8, 117.6, 112.9, 112.8, 112.6, 112.6, 105.8, 105.4, 104.8, 103.8, 92.8, 92.5, 92.3, 92.0, 89.1, 88.3, 88.2, 86.7, 50.4, 50.2, 49.9, 35.4, 35.2, 35.2, 35.2, 32.8, 32.7, 32.5, 32.4, 22.3, 22.1, 21.8; HRMS (ESI-TOF) m/z [M +2Na]2+ calcd for C192H168N16O5 1412.6623, found 1412.6625; IR (KBr pellet) ν 3347 (N−H), 2205 (CC), 1656 (CO) cm−1. 8b: To a solution of 2,6-dibromopyridn-4-ol12 (4.90 g, 17.4 mmol) in CH2Cl2 (80 mL), oxalyl chloride (3.06 mL, 34.8 mmol) and a catalytic amount of DMF at 0 °C were carefully added under Ar. The solution was stirred at room temperature for 1.5 h and the concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and placed at 0 °C. Triethylamine (Et3N) (3.72 mL, 26.1 mmol) and (S)-1-phenylethanamine (2.29 mL, 17.4 mmol) were added slowly to the reaction mixture, and the resulting solution was stirred for 1.5 h at room temperature. After concentration, the mixture was washed with brine and sodium bicarbonate and dried over anhydrous Na2SO4. The crude mixture was purified by flash column chromatography (silica gel, DCM). white solid; 76% yield (5.12 g); mp >138 °C; 1H NMR (400 MHz, acetone-d6) δ 8.44 (s, 1H), 8.01 (s, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 5.29−5.22 (m, 1H), 1.56 (d, J = 7.0 Hz, 3H); 13C NMR (400 MHz, acetone-d6) δ 162.2, 147.9, 144.6, 141.5, 129.2, 127.9, 127.1, 126.2, 50.5, 22.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H12Br2N2O 406.9194, found 406.9190; IR (KBr pellet) ν 3314 (N−H), 1644 (CO) cm−1. 9b: Compound 9b was synthesized according to the general procedure using 7a8 (750 mg, 1.58 mmol), 8b (1.29 g, 3.32 mmol), CuI (12.5 mg, 0.063 mmol), Pd(PPh3)2Cl2 (52.3 mg, 0.063 mmol), THF (8 mL) and Et3N (8 mL). reaction time 2.5 h; eluent: EtOAc/ hexane = 1:2 (v/v); yellow solid; 65% yield (810 mg); mp >210 °C (dec); 1H NMR (400 MHz, acetone-d6) δ 10.64 (s, 1H), 10.24 (s, 1H), 8.50 (d, J = 7.1 Hz, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.05 (s, 2H), 8.03 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 5.37−5.30 (m, 1H), 4.58 (s, 1H), 1.67 (s, 6H), 1.62 (d, J = 1.2 Hz, 3H), 1.50 (s, 9H), 1.47 (s, 9H); 13C NMR (400 MHz, acetone-d6) δ 163.0, 146.1, 145.1, 144.8, 143.5, 143.3, 142.7, 139.4, 139.0, 129.3, 129.3, 127.9, 127.3, 127.1, 127.1, 126.9, 126.7, 126.0, 125.5, 125.0, 122.7, 122.2, 119.7, 117.7, 113.4, 113.1, 106.3, 104.0, 100.0, 91.9, 89.4, 78.5, 65.5, 50.5, 35.4, 35.2, 32.3, 32.2, 32.2, 22.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C47H45BrN4O2 799.2624, found 799.2622; IR (KBr pellet) ν 3549 (N−H), 2204 (CC), 1655 (CO) cm−1. 9c: Compound 9c was synthesized according to the general procedure using 7b13 (200 mg, 0.31 mmol), 8b (120 mg, 0.31 mmol), 5129

DOI: 10.1021/acs.joc.8b00482 J. Org. Chem. 2018, 83, 5123−5131

Article

The Journal of Organic Chemistry

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144.6, 144.0, 143.5, 143.2, 139.6, 139.4, 129.3, 127.9, 127.2, 127.2, 127.1, 127.0, 126.9, 125.5, 125.0, 125.0, 122.6, 122.3, 119.5, 118.4, 113.4, 113.2, 105.1, 104.3, 92.8, 88.5, 83.0, 81.5, 50.6, 35.3, 35.2, 32.3, 32.2, 22.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C74H66N6O 1077.5196, found 1077.5194; IR (KBr pellet) ν 3361 (N−H), 3299 (C(sp)-H), 2202 (CC), 1651 (CO) cm−1.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00482. 1 H and 13C NMR spectra of compounds, 1H NMR studies, modeling studies, CD studies (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kyu-Sung Jeong: 0000-0003-1023-1796 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2015R1A2A1A10053607).

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REFERENCES

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