Synthesis and structure investigation of stabilized aromatic oligoamides and their interaction with g quadruplex structures 4

Chapter Synthesis of Folded Circular Aromatic Pentamers with Tunable Interior Structure 4.1 Introduction Macrocyclic structures with persistent shape have unique structural features, special physical properties, and chemical behavior that differ from their acyclic counterparts.1,2 In particular, persistent-shaped aromatic macrocycles have attracted wide attention due to their defined structures and functions. Usually, the shape persistency and rigidity of these macrocyclic motifs are induced by covalent force,3 intrinsic conformational bias of the backbone4 and built-in hydrogen-bonds.5,6,7 Particularly, multiple-center H-bonding has become a top strategy for designing tailor-made macrocyclic aromatic foldmers due to its robustness and predictablity.6,7 Owning to their specific structural features, these aromatic macrocycle have enabled extensive applications in chemistry and biology. For example, their well-defined cavities may serve as species binder8 or ion transporter across cell membrane.9 Aligning rigid macrocycles into columnar assemblies should lead to organic nanotube.10 However, until now, few synthetic macrocyclic systems allow systematic fine-tuning of interior properties while maintain overall topographic feature. Herein, a series of 5-fold symmetric aromatic circular oligoamides with tunable interior functional groups were designed and synthesized. 110 4.2 Results and Discussion 4.2.1 Design and Computational Molecular Modeling of Circular Pentamer In chapters and 3, we showed that the oligoamide backbone requires five repeating units per helical turn in forming a helical structure. Accordingly, the end-to-tail cyclization of a crescent acyclic pentamer into a circular structure might not impose much angle strain on the backbone and may result in a planar conformation. To testify this speculation, ab initio calculation of the designed circular aromatic pentamer was performed with Gaussian 98 at the B3LYP/6-31G level. a) b) Figure 4.1. Structure predicted by ab intio calculation of circular pentamer 1. (a) top view and (b) side view. As shown in Figure 4.1, circular pentamers adopts almost planar structure with an appreciable cavity size. Similar to helical oligoamides, the most stable circular pentamer prefers the up-down-up-down-up fashion in terms of orientation of five interior methyl side chains. 4.2.2 Synthesis of Circular Pentamer A highly rigid and structurally well defined circular pentamer was synthesized by Dr. Bo Qin.11 This pentamer was efficiently obtained by circlizing the acyclic 111 pentamer 5a using BOP as the amide coupling reagent. Scheme 4.1. Synthesis of circular pentamer 1a O O N O O H O N H HN O 5a O O 2N N N O H H O O HN H O N O H O N O O O OH a O O a, b, c N O O a) 10% Pd/C, 40˚C, THF; b) 1M KOH, MeOH; c) BOP, DIEA, CH2Cl2, 61% (in total). 4.2.3 One-Dimensional 1H NMR Study of Circular Pentamer 1 H NMR was firstly examined to confirm the identity of circular pentamer (Firgure 4.2). The 1H NMR spectrum of revealed five sets of proton signals corresponding to the methoxy groups (4.09 ppm), aromatic (9.00 ppm, 8.02 ppm & 7.45 ppm), and amide protons (10.89 ppm) that are in excellent agreement with the symmetrical structure of 1. In particular, the amide protons of resonating at the very low field (10.88-10.89 ppm) are a diagnostic indicator of the presence of strong H-bonding interactions, leading to the rigidification of the amide linkages and a crescent aromatic backbone. Figure 4.2. 1H NMR spectrum (500 MHz, 298 K, CDCl3) of pentamer at mM. 4.2.4 Solid State Structure of Pentamer Single crystal of 1, grown by Dr Qin Bo, was obtained by slow evaporation of in 112 mixed solvents.11 Consistent to ab initio caculation, the molecules adopted an almost flat disc arrangement (Firgure 4.3). All the five methoxy oxygen atoms and amide protons point inward and contribute to the formation of a continuous intramolecularly Hydrogen-bonded network (NH•••OMe = 1.9-2.4 Å). The size of the cavity is 2.85 Å in radius. After deducting a covalent radius of 1.4 Å for oxygen atom, the actual radius is 1.45 Å, which is almost the same as K+ (~1.4 Å). The geometrical feature of circular pentamer made it a potential candidate as cation-binding medium. a) b) c) Figure 4.3. Crystal structure of pentamer 1. (a) top view with interior methoxy methyl groups omitted for clarity of view, (b) top view and (c) side view both with methoxy methyl groups in CPK representations. 4.2.5 Design of Circular Pentamer According to the crystal structure of 1, the methyl groups form two hydrophobic caps above and below the pentameric plane. These hydrophobic caps might prevent from binding to metal cations, such as Na+ and K+. We hypothesised that the replacement of methoxy groups with hydroxyl groups should greatly reduce the steric hindrance and hydrophobicity imparted by the interior methyl groups in 1. Furthermore, it has been well established that the fluoride atom can act as a good proton acceptor. Considering the similarity of the F•••H-N to O•••H-N motif, replacing hydroxyl groups with fluorine may form a new rigid, well-established 113 conformation. Finally, considering the bad solubility of oligoamides, the introduction of hydrophobic side chains should enhance the solubility of the pentamer. 4.2.6 Synthesis of Circular Pentamer The synthetic details for oligoamides have been discussed in Chapter 2. Herein, we focus on discussing two types of new reactions. 1) Protection of hydroxyl group with Benzyl group. To introduce hydroxyl groups into pentamers’ interior, benzyl protecting group (Bn) was used for protecting hydroxyl groups in case the coupling between amine and phenol group. Similar to alkylation, Benzyl protection was realized by reacting monomer with benzyl bromide and potassium carbonate in acetone. Since benzyl bromide was hard to remove, no more than 1.1 equiv of the benzyl bromide was used. Removal of benzyl protecting groups readily proceeded by catalytic hydrogenation, using Pd-C as the catalyst in MeOH/THF under one atmosphere of hydrogen gas. This allows us to introduce three OH groups into the resulting pentamer molecule. 2) Reduction of nitro group into amine by iron powder. Since benzyl group could be easily moved by catalytic hydrogenation, method to reduce NO2 group using Pd/C could not be used. Instead, reduction was carried out by using iron powder and glacial acetic acid, a highly efficient method for reduction of NO2 into NH2. 114 Scheme 4.2. Synthesis of circular pentamer 8a R R R a O2 N b O2N COOCH3 COOCH3 O 2N COOH OBn OBn OH 1f, 1o 8a, 8c 8b, 8d 1f, 8a, 8b: R=OC 8H 17 1o, 8c, 8d: R=CH3 OC8 H17 OC 8H 17 OC 8H 17 O O c, d O2 N COOCH3 H3 COOC OBn Bn N H O 8a 8e O OC8 H17 c, e C 8H 17 O O Bn N NO2 O O H N H O Bn F NO2 O Bn 8g OC 8H 17 OC H17 O O O O c, e C8 H17O N O O H N H O Bn O Bn c, f C 8H 17O N F H F 8h N O N O O H O O Bn O NH O O O O O OC8 H17 OC 8H 17 N H H N Bn 8m F O N N O i O N H F H N O H O H Bn Bn O O a N C 8H 17 O O c, g, h H F 8i Bn O H N C 8H 17 O N H F O 2N O 2N O H Bn H O H H N H F O F H N O a). K2CO3/ BnBr, DMF, 60 oC, h, 88~90%; b). NaOH, MeOH/H2O, reflux, h, 84~91%; c). Fe, AcOH/EtOH, reflux, 2h, 78%; d) ethyl carbonochloridate, 4-methylmorpholine, CH2Cl2, 8b, overnight, 74%; e) 8f, SOCl2, reflux, Pyridine/CH2Cl2, 56%; f) 8d, SOCl2, reflux, Pyridine/CH2Cl2, 72%; g) KOH, Dioxane/H2O, RT, overight; h) BOP, DIEA, CH2Cl2, 2h, 35%; i) H2, Pd/C, THF/MeOH, 40 oC, 3h, 40%. To study the intramolecular H-bonds in 8, 1H NMR spectra was first examined. As mentioned, amide protons typically exhibit a substantial downfield shift due to the formation of intramolecular H-bonds. Surprisingly, only three amide protons resonate 115 at chemical shifts larger than 10 ppm in CDCl3. According to previous study, these signals should be the amides adjacent to interior hydroxyl group. In comparison, two amide protons adjacent to fluorine element were less downfield (7~9 ppm). This experimental observation suggests that the three-centered F•••H-N hydrogen-bonding motif is weaker than O•••H-N hydrogen-bonding motif. This may because the small radius of fluorine make it is hard to be a hydrogen acceptor as the distance of F•••H-N and O•••H-N in our design is fixed. However, by addition of DMSO-d6 into CDCl3 (1:1), the two amide protons adjacent to fluorine also demonstrated chemical shift more than 10 ppm as a result of the H-bonding ability of DMSO. 4.2.7 Crystal Structure of a Tetramer and Computational Molecular Modeling of Circular Pentamer To demonstrate the existence of intramolecular hydrogen-bonds that restrict the rotational freedom of the aryl-amide bonds to enforce a crescent structure, X-ray crystallography of tetramer 8h was obtained by slow evaporation of 8h in mixed solvents of 1:1 dichloromethane and methanol. The X-ray results showed that the presence of the bulky benzyloxy group does not disrupt the crescent-shaped conformation. In addition, the H-bond distances of F•••NH and OH•••NH are no more than 2.3 Å, indicating the formation of intramolecular hydrogen bonds. However, numerous attempts to obtain single crystal structure of pentamer were unsuccessful. 116 Figure 4.4. X-ray crystal structure of tetramer 8h. Since our previous study showed that ab initio molecular calculation has consistently allowed us to reliably predict the 3D topography of helical and circular oligomers, modeling with the B3LYP/6-31G basis set of circular pentamer was performed. The modeling result showed that the interior cavity dimension of cyclic pentamer is about 5.64 Å (Figure 4.5), suggesting that the replacement of interior methoxy groups with hydroxyl or fluorine groups increasingly opened the interior cavity. Moreover, pentamer still folds into a roughly planar disk arrangement akin to pentamer 1. a) b) Figure 4.5. Structure predicted by ab intio calculation of circular pentamer 8. (a) top view and (b) side view. 117 4.3 Conclusion X-ray diffraction results of illustrated that the pentamer was almost planar with intramolecular hydrogen-bonding between the amide protons and methoxy oxygen atoms to rigidify the amide linkage. A new generation of circular pentamer was successfully synthesized that folds based on intromolecular F•••N-H H-bonds. The planar structure and the interior cavity of these macrocycles may give arise to their potential applications in chemical and biological settings. 4.4 Experimental Section Compound 1: Compound 5a (0.442 g, 0.559 mmol) was reduced by catalytic hydrogenation in THF (50 mL) at 50 oC, using Pd-C (0.75 g, 20%) as the catalyst for hours. The reaction mixture was then filtered and the solvent removed in vacuo to give a brown liquid 1x. Yield: 0.425 g, quantitative. Compound 1x (0.425 g, 0.558 mmol) was dissolved in hot methanol (5 mL) to which 1M KOH (1.20 mL, 1.20 mmol) was added. The mixture was heated under reflux for hours and then quenched with water (20 mL). The aqueous layer was neutralized with 1M KHSO4 (1.2 mL). The precipitated crude product 1y was collected by filtration. Compound 1y (0.763 g, 1.0 mmol) and BOP (0.88 g, 2.0 mmol) were dissolved in CH2Cl2 (3.2 ml) at oC. DIEA (0.5 ml, 3.0 mmol) was added and the reaction mixture was stirred continuously for hr at oC, then stirred at room temperature for hours. Removal of solvent in vacuo gave the crude product, which was purified by flash column chromatography on silica gel 118 using CH2Cl2/CH3CN (1:10) as the eluent to give a pure white product 1. Yield: 0.465 g, 62%; Decomposition in 340-345 oC; 1H NMR (500 MHz, CDCl3) δ 10.88 (s, 5H), 9.00 (d, 5H, J = 8.2, 1.5), 8.02 (d, 5H, J = 8.0, 1.5), 7.44 (t, 5H, J = 8.1), 4.09 (s, 15H). 13 C NMR (125 MHz, CDCl3) δ 162.3, 146.5, 132.9, 126.6, 126.2, 125.6, 124.3, 63.3. HRMS-EI: exact mass calculated for [M]+ (C40H35N5O10): m/z 745.2384, found: m/z 745.2387. Compound 8a: Methyl 2-hydroxy-3-nitro-5-(octyloxy)benzoate (8.12 g, 25.0 mmol) was dissolved in anhydrous DMF (100 mL), to which anhydrous K2CO3 (14.00 g, 0.1 mol) and benzene bromide (3.1 mL, 26.0 mmol) was added. The mixture was heated under reflux for 60 oC hours. CH2Cl2 (200 mL) was then added and the reaction mixture was filtered. The solvent was removed in vacuo and the concentrate was dissolved in CH2Cl2 (200 mL), washed with water (2 x 100 mL) and dried over anhydrous Na2SO4. Removal of CH2Cl2 gave the pure product 8a as a red liqid. Yield: 9.40 g, 90%. Yield: 1.76 g, 85%. 1H NMR (500 MHz, CDCl3): δ 7.56 (d, 1H, J = 3.2 Hz), 7.47 (d, 2H, J = 6.9 Hz), 7.44 (d, 1H, J = 3.8 Hz), 5.11 (s, 2H), 3.99 (t, 2H, J = 6.3 Hz), 3.88 (s, 3H), 1.29 (m, 12H), 0.91 (t, 3H, J = 13.5 Hz). 13 C NMR (75 MHz, CDCl3): δ 190.36, 164.85, 154.52, 145.97, 144.65, 136.04, 128.65, 128.57, 128.48, 128.42, 121.57, 114.06, 78.56, 69.22, 52.72, 50.74, 31.73, 29.19, 29.14, 28.91, 25.85, 22.60, 14.02. HRMS-ESI: calculated for [M+Na] + (C23H29NO6Na): m/z 438.1887 found: m/z 438.1868. 119 Compound 8b: 8a (1.25 g, 3.0 mmol) was dissolved in hot MeOH (20 mL), to which 1N NaOH (6 mL, 6.0 mmol) was added. The mixture was heated under reflux for h and then quenched with water (20 mL). The aqueous layer was neutralized by addition of 1M HCl (8 mL). The precipitated crude product was collected by filtration, which was recrystallized from MeOH to give a yellow solid 8b. Yield: 0.90 g, 91%. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, 1H, J = 3.2 Hz), 7.60 (d, 1H, J = 3.2 Hz), 7.47 (m, 2H), 7.41 (m, 3H), 5.14 (s, 2H), 4.93 (t, 2H, J = 6.4 Hz), 1.81 (m, 3H), 1.46 (m, 3H), 1.30(m, 6H), 0.90 (t, 3H, J = 6.9 Hz). 13 C NMR (75 MHz, DMSO-d6): δ 165.62, 154.01, 145.53, 144.01, 135.89, 129.12, 127.90, 121.11, 113.20, 68.68, 31.25, 28.72, 28.66, 28.45, 25.38, 22.12, 13.62. HRMS-ESI: calculated for [M] + (C23H29NO6): m/z 400.1887 found: m/z 400.1868. Compound 8c: Methyl 2-hydroxy-3-nitro-5-(octyloxy)benzoate (1.05 g, 5.0 mmol) was dissolved in anhydrous DMF (20 mL), to which anhydrous K2CO3 (3.0 g, 21.7 mol) and benzene bromide (0.7 mL, 5.8 mmol) was added. The mixture was heated under reflux for 60 o C hours. CH2Cl2 (50 mL) was then added and the reaction mixture was filtered. The solvent was removed in vacuo and the concentrate was dissolved in CH2Cl2 (50 mL), washed with water (2 x 50 mL) and dried over anhydrous Na2SO4. Removal of CH2Cl2 gave the pure product 8c as a red liquid. Yield: 1.32 g, 88%. 1H NMR (300 MHz, CDCl3): δ 7.73 (d, 1H, J = 2.0 Hz), 2.2 (d, 1H, J = 2.2 Hz), 7.36 (m, 2H), 7.23 120 (m, 3H), 5.00 (s, 2H), 3.75 (s, 3H), 2.27 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ 164.86, 149.06, 145.36, 135.94, 135.85, 134.39, 128.57, 128.52, 128.34, 127.49, 78.33, 52.50, 20.35. MS-ESI: calculated for [M+Na]+ (C16H15NO5Na): m/z 324.0950, found: m/z 324.0952. Compound 8d: 8c (1.2 g, 4.0 mmol) was dissolved in hot MeOH (20 mL), to which 1N NaOH (8 mL, 8.0 mmol) was added. The mixture was heated under reflux for h and then quenched with water (20 mL). The aqueous layer was neutralized by addition of 1M HCl (10 mL). The precipitated crude product was collected by filtration, which was recrystallized from MeOH to give a yellow solid 8d. Yield: 0.97 g, 84%.1H NMR (500 MHz, CDCl3): δ 8.15 (d, 1H, J = 1.9 Hz), 7.91 (d, 1H, J = 1.9 Hz), 7.49 (m, 2H), 7.43 (m, 3H), 5.19 (s, 2H), 2.49 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ 165.88, 148.53, 145.04, 135.89, 135.74, 133.87, 128.37, 127.97, 77.71, 20.06. MS-ESI: calculated for [M-H]+ (C15H13NO5): m/z 286.0794 found: m/z 286.0742. Compound 8e: 8a (1.0 g, 2.4 mmol) was first dissolved in ethanol (20 mL), to which acetic acid (5.0 mL), and iron powder (0.6 g, 10.7 mmol) was added. The reaction was stirred and heated under reflux for hours. The reaction mixture was then filtered and the filtrate solvent was removed in vacuo. The residue after solvent removal was dissolved in CH2Cl2 (30 mL), washed with water (2 x 30 mL), and dried over anhydrous Na2SO4. Removal of CH2Cl2 solvent gave pure amine which was immediately used for the next coupling. Acid 8b (1.0 g, 2.5 mmol) was dissolved in CH2Cl2 (20 mL) to which 121 4-methylmorpholine, NMM (0.43 mL, 3.5 mmol) and ethyl chloroformate (0.36 mL, 3.0 mmol) was added at oC. The reaction mixture was stirred for at least 15 then a solution of above amine (0.85 g, 2.2 mmol) dissolved in CH2Cl2 (20 mL) was added. The reaction mixture was allowed to stir continuously overnight at room temperature. The reaction mixture was washed with 1M KHSO4 (30 mL), followed by saturated NaHCO3 (30 mL) and saturated NaCl (30 mL). Drying over Na2SO4 and removal of solvent in vacuo gave the crude product, which was recrystallized from methanol to give the pure product 8e as a white solid. Yield: 1.32 g, 78%. 1H NMR (500 MHz, CDCl3) δ 9.73 (s, 1H), 8.32 (d, 1H, J = 2.0), 7.62 (d, 1H, J = 0.9), 7.42 (d, 1H, J = 3.0), 7.30 (d, 1H, J = 6.9), 7.10~7.20 (m, 10H), 4.91 (s, 2H), 3.92 (s, 2H), 4.00 (m, 4H), 3.92 (s, 3H), 1.80 (m, 2H), 1.46 (m, 2H), 1.27 (m, 8H), 0.88 (m, 3H).13C NMR (125 MHz, CDCl3) δ 165.81, 161.64，155.11, 155.08, 145.26, 142.11, 141.79, 136.19, 133.87, 133.48, 131.50, 129.70，128.96, 128.85, 128.56, 128.42, 128.34, 128.30, 124.22, 120.38, 114.35, 111.80, 110.88, 79.59, 77.7, 69.24, 68.61, 52.29, 31.80, 31.76, 29.33, 29.23, 29.17, 28.93, 26.02, 25.86, 22.65, 22.62, 14.07, 14.06. HRMS-ESI: calculated for [M+Na] + (C45H56N2O9Na): m/z 791.3878 found: m/z 791.3906. Compound 8g: 8e (0.32 g, 0.42 mmol) was first dissolved in ethanol (5 mL), to which acetic acid (1 mL), and iron powder (0.1 g, 2.1 mmol) was added. The reaction was stirred and heated under reflux for hours. The reaction mixture was then filtered and the filtrate solvent was removed in vacuo. The residue after solvent removal was dissolved in CH2Cl2 (10 mL), washed with water (2 x 10 mL), and dried over anhydrous Na2SO4. 122 Removal of CH2Cl2 solvent gave pure amine which was immediately used for the next coupling. Acid 8f (0.15 g, 0.6 mmol) was dissolved in thionyl chloride (1 mL) and the mixture was heated under reflux for h. The solvent was removed in vacuo and anhydrous ether (2 x 15 mL) was added and removed again. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of mL dry CH2Cl2. The above amine (0.27 g, 0.36 mmol) was dissolved in mL dry CH2Cl2 and pyridine (0.1 mL, 1.2 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 oC for hours and then was washed with aq NaHCO3 (50 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (4:1) as the eluent to give pure 8g as yellow solid. Yield: 0.18 g, 74%. 1H NMR (300 MHz, CDCl3) δ 10.26 (s, 1H), 8.80 (d, 1H, J = 3.2), 8.67 (d, 1H, J = 11.1), 8.44~8.55 (m, 4H), 7.69~7.72 (m, 4H), 7.61 (d, 1H, J = 3.2), 7.47~7.56 (m, 6H), 5.23 (s, 2H), 5.11 (s, 2H), 4.33 (m, 1H), 4.24 (s, 3H), 2.10 (m, 2H), 1.19 (m, 8H), 1.68 (m, 2H), 1.62 (m, 8H), 1.18 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 165.84, 162.98, 158.88， 156.07, 155.31, 155.23, 141.73, 139.79, 137.04, 136.89, 136.42, 134.63, 133.93, 133.12, 132.48, 129.23, 129.06, 128.77, 128.68, 128.60, 128.56, 128.42, 127.57, 124.77, 124.73, 124.28, 124.19, 124.14, 112.23, 111.71, 111.49, 111.29, 111.21, 110.82, 79.44, 78.51, 77.80, 68.68, 68.63, 60.37, 52.42, 52.34, 31.81, 29.33, 29.23, 22.65, 14.08. HRMS-ESI: calculated for [M+Na] + (C52H60FN3O10Na): m/z 928.4155 found: m/z 928.4148. Compound 8h: 123 8g (1.20 g, 1.32 mmol) was first dissolved in ethanol (20 mL), to which acetic acid (4 mL), and iron powder (0.4 g, 7.0 mmol) was added. The reaction was stirred and heated under reflux for hours. The reaction mixture was then filtered and the filtrate solvent was removed in vacuo. The residue after solvent removal was dissolved in CH2Cl2 (30 mL), washed with water (2 x 30 mL), and dried over anhydrous Na2SO4. Removal of CH2Cl2 solvent gave pure amine which was immediately used for the next coupling. Acid 8b (0.37 g, 2.0 mmol) was dissolved in thionyl chloride (1.5 mL) and the mixture was heated under reflux for h. The solvent was removed in vacuo and anhydrous ether (2 x 30 mL) was added and removed again. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (1.06 g, 1.21 mmol) was dissolved in 10 mL dry CH2Cl2 and pyridine (0.32 mL, mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 oC for hours and then was washed with aq NaHCO3 (30 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1) as the eluent to give pure 8h as white solid. Yield: 0.91 g, 72%. 1H NMR (300 MHz, CDCl3) δ 10.04 (s, 1H), 8.71~8.83 (m, 2H), 8.66 (d, 2H, J = 3.0), 8.52 (d, 2H, J = 3.0), 7.97 (m, 1H), 7.77 (m, 1H), 7.55~7.61 (m, 4H), 7.37~7.48 (m, 5H), 7.04~7.34 (m, 5H), 5.12 (m, 2H), 5.03 (m, 2H), 4.25 (m, 2H), 4.17 (s, 3H), 2.03 (m, 2H), 1.71 (m, 2H), 1.50 (m, 8H), 1.11 (m, 3H). 13 C NMR (125 MHz, CDCl3) δ 165.83, 163.13, 160.41, 159.44, 156.14, 155.30, 154.23, 152.13, 151.56, 149.60, 141.79, 139.47, 138.29, 137.54, 124 136.47, 134.80, 133.90, 132.79, 129.91, 129.00, 128.94, 128.66, 128.41, 128.22, 128.15, 127.70, 127.23, 126.25, 126.01, 125.91, 125.25, 125.31, 125.16, 125.11, 124.13, 123.78, 123.69, 121.66, 121.58, 111.66, 111.25, 110.82, 110.73, 78.92, 77.86, 68.68, 68.63, 52.33, 31.82, 29.34, 29.25, 29.22, 26.02, 22.66, 14.09. HRMS-FAB: calculated for [M]- (C16H23NO6): m/z 1041.4545 found: m/z 1041.4461. Compound 8i: 8h (0.18 g, 0.15 mmol) was first dissolved in ethanol (2 mL), to which acetic acid (0.4 mL), and iron powder (0.1 g, 1.78 mmol) was added. The reaction was stirred and heated under reflux for hours. The reaction mixture was then filtered and the filtrate solvent was removed in vacuo. The residue after solvent removal was dissolved in CH2Cl2 (5 mL), washed with water (2 x mL), and dried over anhydrous Na2SO4. Removal of CH2Cl2 solvent gave pure amine which was immediately used for the next coupling. Acid 8b (0.1 g, 0.35 mmol) was dissolved in thionyl chloride (0.5 mL) and the mixture was heated under reflux for h. The solvent was removed in vacuo and anhydrous ether (2 x mL) was added and removed again. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of mL dry CH2Cl2. The above amine (0.14 g, 0.14 mmol) was dissolved in mL dry CH2Cl2 and 3ml DMF and pyridine (0.05 mL, 0.7 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 60 0C for hours and then was washed with aq NaHCO3 (10 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1) as the eluent to 125 give pure 8i as white solid. Yield: 0.1 g, 56%. 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.55 (s, 1H), 8.55~8.67 (m, 2H), 8.42 (d, 2H, J = 3.2), 8.30 (d, 1H, 2H, J = 3.2), 8.28 (m, 2H), 7.85~7.93 (m, 2H), 7.65 (m, 1H), 7.32~7.39 (m, 2H), 7.28 (d, 1H, 2H, J = 1.9), 7.24 (d, 1H, 2H, J = 5.3), 7.17~7.22 (m, 3H), 7.05 (m, 2H), 6.93~7.02 (m, 5H), 5.11 (s, 1H), 4.83 (s, 1H), 4.80 (s, 1H), 4.02 (m, 4H), 3.89 (m, 3H), 2.49 (s, 3H), 1.82 (m, 2H), 1.48 (m, 2H), 1.30 (m, 8H), 0.88 (m, 3H). 13 C NMR (125 MHz, CDCl3) δ 165.69, 163.10，161.19, 161.00, 160.73, 156.09, 155.24, 152.19, 148.92, 147.57, 144.17, 141.74, 139.32, 136.80, 136.41, 135.75, 134.60. 133.87, 132.81, 129.91, 129.38, 129.25, 129.10, 128.89, 128.72, 128.62, 128.36, 128.15, 127.73, 127.30, 126.56, 126.44, 126.29, 126.03, 125.32, 125.03, 123.97, 121.88, 121.74, 120.76, 120.61, 120.23, 116.27, 111.69, 111.12, 110.78, 110.68, 80.12, 78.99, 78.61, 77.76, 77.18, 68.59, 52.20, 31.80, 29.66, 29.32, 29.22, 25.99, 22.64, 20.69, 14.07. HRMS-FAB: calculated for [M] - (C74H76F2N5O13): m/z 1280.5408 found: m/z 1280.4984. Compound 8m: 8i (0.1 g, 0.08 mmol) was first dissolved in ethanol (1 mL), to which acetic acid (0.1 mL), and iron powder (0.04 g, 0.7 mmol) was added. The reaction was stirred and heated under reflux for hours. The reaction mixture was then filtered and the filtrate solvent was removed in vacuo. The residue after solvent removal was dissolved in CH2Cl2 (2 mL), washed with water (2 x mL). Removal of CH2Cl2 solvent gave pure amine 8j. Compound 8j was dissolved in dioxane (2 ml) to which 1M KOH (0.4 ml, 0.4 mmol) was added. The mixture was heated at 50 0C overnight and then quenched 126 with water (4 ml). The aqueous layer was neutralized with 1M KHSO4 (0.4ml) and extracted with DCM (2 x mL). Removal of CH2Cl2 solvent gave pure compound 8k. Compound 8k (0.073 g, 0.06 mmol) and BOP (0.066 g, 0.15 mmol) were dissolved in CH2Cl2 (2 ml) and stirred for 30min, DIEA (0.05 ml, 0.3 mmol) was added and the reaction mixture was stirred at room temperature for hours. Removal of solvent in vacuo gave the crude product, which was purified by flash column chromatography on silica gel using DCM/MeOH (50:1) as the eluent to give a pure white product 8m. Yield: 34 mg, 35%. 1H NMR (500 MHz, CDCl3) δ 10.50 (s, 1H), 10.44 (s, 1H), 9.77 (s, 1H), 8.98~9.12 (m, 2H), 8.91 (m, 1H), 8.84 (m, 1H), 8.70 (d, 1H, J = 1.4), 8.50 (d, 1H, J = 1.4), 8.35 (d, 1H, J = 1.4), 7.97 (m, 1H), 7.85 (m, 1H), 7.65 (d, 1H, J = 1.4), 7.40~7.48 (m, 3H), 7.37 (d, 1H, J = 1.4), 7.23 (d, 2H, J = 6.9), 5.18 (m, 2H), 4.87 (m, 2H), 4.83 (m, 2H), 4.09 (m, 4H), 2.49 (s, 3H), 1.87 (m, 2H), 1.50 (m, 2H), 1.35 (m, 8H), 0.89 (m, 3H). 13 C NMR (125 MHz, CDCl3) δ 165.77, 164.04, 163.15, 161.20, 160.74, 156.12, 155.25, 151.99, 148.77, 141.73, 139.37, 136.32, 135.47, 134.60, 133.90, 132.83, 129.00, 128.84, 128.76, 128.56, 128.36, 128.18, 127.64, 127.44, 126.41, 126.22, 125.97, 125.56, 126.22, 125.06, 124.01, 121.45, 121.04, 120.35, 111.65, 111.21, 110.88, 110.71, 78.94, 77.72, 68.62, 52.25, 31.79, 29.67, 29.32, 29.22, 25.99, 22.64, 20.98, 14.07. HRMS-FAB: calculated for [M]- (C74H76F2N5O13): m/z 1218.5404 found: m/z 1218.4984. Compound 8: 8m (20 mg, 0.016 mmol) was reduced by catalytic hydrogenation in THF/MeOH (2 ml/2 ml) at 40 0C, using Pd/C (10 mg, 50%) as the catalyst for h. The reaction 127 mixture was then filtered and the solvent removed in vacuo to give the pure yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 10.48 (s, 1H), 9.97 (s, 1H), 8.11(m, 1H), 8.01 (m, 1H), 7.88 (m, 1H), 7.75 (m, 2H), 7.60 (m, 1H), 7.37 (m, 4H), 7.11 (m, 1H), 7.03 (m, 1H), 6.69 (m, 1H), 3.92 (m, 4H), 2.20 (s, 3H), 1.75 (m, 2H), 1.70 (m, 2H), 1.25 (m, 8H), 0.88 (m, 3H). 13 C NMR (75 MHz, DMSO) δ 170.50, 169.90, 166.71, 163.94, 162.01, 155.52, 155.01, 152.10, 151.65, 147.06, 146.80, 138.67, 130.69, 130.21, 129.65, 128.59, 127.98, 127.76, 127.27, 127.09, 126.84, 126.68, 125.40, 124.45, 124.49, 119.78, 117.13, 116.18, 115.04, 113.09, 110.83, 110.45, 108.62, 69.27, 69.16, 54.62, 53.79, 32.29, 30.04, 29.81, 29.71, 26.59, 26.52, 26.16, 23.13, 21.65, 14.99, 13.50. HRMS-FAB: calculated for [M] - (C74H76F2N5O13): m/z 948.4073 found: m/z 948.3992. 128 Reference: 1. (a) Meng, Q.; Hesse, M. Top. Curr. Chem. 1992, 161, 107. (b) Sessler, J.; Burrell, A. Top. Curr. Chem. 1992, 161, 177. (c) Bernhardt, P. V.; Moore, E. G. Aust. J. Chem. 2003, 56, 239. 2. (a) Grave, C.; Schlu¨ter, A. D. Eur. J. Org. Chem. 2002, 3075. (b) Ho¨ger, S. Chem. Eur. J. 2004, 10, 1320. (c) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416. 3. Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416. 4. Holub, J. M.; Jang, H. J.; Kirshenbaum, K. Org. Lett. 2007, 9, 3275. 5. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore. J. S. Chem. Rev. 2001, 101, 3893. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101, 3219. (d) Huc, I. Eur. J. Org. Chem. 2004, 17. (e) Li, Z. T.; Hou, J. L.; Li, C.; Yi, H. P. Chem. Asian J. 2006, 1, 766. (f) Gong, B. Acc. Chem. Res. 2008, 41, 1376. (g) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399. (h) Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428. For some selected H-bonded macrocyles, see: (i) Srinivasan, A.; Ishizuka, T.; Osuka, A.; Furuta, H. J. Am. Chem. Soc. 2003, 125, 878. (j) Jiang, H.; Leger, J. M.; Guionneau, P.; Huc, I. Org. Lett. 2004, 6, 2985. 6. (a) Yuan, L.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu, D.; Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126, 11120. (b) Xing, L. Y.; Ziener, U.; Sutherland, T. C.; Cuccia, L. A. Chem. Commun. 2005, 5751. (c) Zhang, A. M.; Han, Y. H.; Yamato, K.; Zeng, X. C.; Gong, B. Org. Lett. 2006, 8, 803. (d) Qin, B.; Chen, X. Y.; Fang, X.; Shu, Y. Y.; Yip, Y. K.; Yan, Y.; Pan, S. Y.; Ong, W. Q.; Ren, C. L.; Su, H. B.; Zeng, H. Q. Org. Lett. 2008, 10, 5127. (e) Berni, E.; Dolain, C.; Kauffmann, B.; Lger, J.-M.; Zhan, C.; Huc, I. J. Org. Chem. 2008, 73, 2687. (f) Zhu, Y. Y.; Li, C.; Li, G. Y.; Jiang, X. K.; Li, Z. T. J. Org. Chem. 2008, 73, 1745. (g) Ahn, H. C.; Yun, S. M.; Choi, K. Chem. Lett. 2008, 37, 10. 7. (a) Feng, W.; Yamato, K.; Yang, L. Q.; Ferguson, J. S.; Zhong, L. J.; Zou, S. L.; Yuan, L. H.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc. 2009, 131, 2629. (b) Ferguson, J. S.; Yamato, K.; Liu, R.; He, L.; Zeng, X. C.; Gong, B. Angew. Chem., Int. Ed. 2009, 48, 3150. (c) Yang, L. Q.; Zhong, L. J.; Yamato, K.; Zhang, X. H.; Feng, W.; Deng, P. C.; Yuan, L. H.; Zeng, X. C.; Gong, B. New J. Chem. 2009, 33, 729. (d) Li, F.; Gan, Q.; Xue, L.; Wang, Z.-M.; Jiang, H. Tetrahedron Lett. 2009, 50, 2367. 8. Zhu, Y. Y.; Li, C.; Li, G. Y.; Jiang, X. K.; Li, Z. T. J. Org. Chem. 2008, 73, 1745. 9. Helsel, A. J.; Brown, A. L.; Yamato, K.; Feng, W.; Yuan, L. H.; Clements, A. J.; Harding, S. V.; Szabo, G.; Shao, Z. F.; Gong, B. J. Am. Chem. Soc. 2008, 130, 15784. 10. Bing Gong, Chem. Eur. J. 2001,7, 4337. 11. Qin, B.; Chen, X. Y.; Fang, X.; Shu, Y. Y.; Yip, Y. K.; Yan, Y.; Pan, S. Y.; Ong, W. Q.; Ren, C. L.; Su, H. B.; Zeng, H. Q. Org. Lett. 2008, 10, 5127. 12. Babb, D. A., ARKIVOC 2004, 2003, 164. 129 [...]... Li, C.; Li, G Y.; Jiang, X K.; Li, Z T J Org Chem 2008, 73, 1 745 (g) Ahn, H C.; Yun, S M.; Choi, K Chem Lett 2008, 37, 10 7 (a) Feng, W.; Yamato, K.; Yang, L Q.; Ferguson, J S.; Zhong, L J.; Zou, S L.; Yuan, L H.; Zeng, X C.; Gong, B J Am Chem Soc 2009, 131, 2629 (b) Ferguson, J S.; Yamato, K.; Liu, R.; He, L.; Zeng, X C.; Gong, B Angew Chem., Int Ed 2009, 48 , 3150 (c) Yang, L Q.; Zhong, L J.; Yamato,... 127. 64, 127 .44 , 126 .41 , 126.22, 125.97, 125.56, 126.22, 125.06, 1 24. 01, 121 .45 , 121. 04, 120.35, 111.65, 111.21, 110.88, 110.71, 78. 94, 77.72, 68.62, 52.25, 31.79, 29.67, 29.32, 29.22, 25.99, 22. 64, 20.98, 14. 07 HRMS-FAB: calculated for [M]- (C74H76F2N5O13): m/z 1218. 540 4 found: m/z 1218 .49 84 Compound 8: 8m (20 mg, 0.016 mmol) was reduced by catalytic hydrogenation in THF/MeOH (2 ml/2 ml) at 40 0C, using... (125 MHz, CDCl3) δ 165. 84, 162.98, 158.88， 156.07, 155.31, 155.23, 141 .73, 139.79, 137. 04, 136.89, 136 .42 , 1 34. 63, 133.93, 133.12, 132 .48 , 129.23, 129.06, 128.77, 128.68, 128.60, 128.56, 128 .42 , 127.57, 1 24. 77, 1 24. 73, 1 24. 28, 1 24. 19, 1 24. 14, 112.23, 111.71, 111 .49 , 111.29, 111.21, 110.82, 79 .44 , 78.51, 77.80, 68.68, 68.63, 60.37, 52 .42 , 52. 34, 31.81, 29.33, 29.23, 22.65, 14. 08 HRMS-ESI: calculated... Yamato, K.; Zhang, X H.; Feng, W.; Deng, P C.; Yuan, L H.; Zeng, X C.; Gong, B New J Chem 2009, 33, 729 (d) Li, F.; Gan, Q.; Xue, L.; Wang, Z.-M.; Jiang, H Tetrahedron Lett 2009, 50, 2367 8 Zhu, Y Y.; Li, C.; Li, G Y.; Jiang, X K.; Li, Z T J Org Chem 2008, 73, 1 745 9 Helsel, A J.; Brown, A L.; Yamato, K.; Feng, W.; Yuan, L H.; Clements, A J.; Harding, S V.; Szabo, G. ; Shao, Z F.; Gong, B J Am Chem Soc... 163. 94, 162.01, 155.52, 155.01, 152.10, 151.65, 147 .06, 146 .80, 138.67, 130.69, 130.21, 129.65, 128.59, 127.98, 127.76, 127.27, 127.09, 126. 84, 126.68, 125 .40 , 1 24. 45, 1 24. 49, 119.78, 117.13, 116.18, 115. 04, 113.09, 110.83, 110 .45 , 108.62, 69.27, 69.16, 54. 62, 53.79, 32.29, 30. 04, 29.81, 29.71, 26.59, 26.52, 26.16, 23.13, 21.65, 14. 99, 13.50 HRMS-FAB: calculated for [M] - (C74H76F2N5O13): m/z 948 .40 73... 7.65 (d, 1H, J = 1 .4) , 7 .40 ~7 .48 (m, 3H), 7.37 (d, 1H, J = 1 .4) , 7.23 (d, 2H, J = 6.9), 5.18 (m, 2H), 4. 87 (m, 2H), 4. 83 (m, 2H), 4. 09 (m, 4H), 2 .49 (s, 3H), 1.87 (m, 2H), 1.50 (m, 2H), 1.35 (m, 8H), 0.89 (m, 3H) 13 C NMR (125 MHz, CDCl3) δ 165.77, 1 64. 04, 163.15, 161.20, 160. 74, 156.12, 155.25, 151.99, 148 .77, 141 .73, 139.37, 136.32, 135 .47 , 1 34. 60, 133.90, 132.83, 129.00, 128. 84, 128.76, 128.56,... ml, 0 .4 mmol) was added The mixture was heated at 50 0C overnight and then quenched 126 with water (4 ml) The aqueous layer was neutralized with 1M KHSO4 (0.4ml) and extracted with DCM (2 x 5 mL) Removal of CH2Cl2 solvent gave pure compound 8k Compound 8k (0.073 g, 0.06 mmol) and BOP (0.066 g, 0.15 mmol) were dissolved in CH2Cl2 (2 ml) and stirred for 30min, DIEA (0.05 ml, 0.3 mmol) was added and the... by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (4: 1) as the eluent to give pure 8g as yellow solid Yield: 0.18 g, 74% 1H NMR (300 MHz, CDCl3) δ 10.26 (s, 1H), 8.80 (d, 1H, J = 3.2), 8.67 (d, 1H, J = 11.1), 8 .44 ~8.55 (m, 4H), 7.69~7.72 (m, 4H), 7.61 (d, 1H, J = 3.2), 7 .47 ~7.56 (m, 6H), 5.23 (s, 2H), 5.11 (s, 2H), 4. 33 (m, 1H), 4. 24 (s, 3H), 2.10 (m, 2H),... 41 , 1376 (g) Horne, W S.; Gellman, S H Acc Chem Res 2008, 41 , 1399 (h) Li, X.; Wu, Y.-D.; Yang, D Acc Chem Res 2008, 41 , 142 8 For some selected H-bonded macrocyles, see: (i) Srinivasan, A.; Ishizuka, T.; Osuka, A.; Furuta, H J Am Chem Soc 2003, 125, 878 (j) Jiang, H.; Leger, J M.; Guionneau, P.; Huc, I Org Lett 20 04, 6, 2985 6 (a) Yuan, L.; Feng, W.; Yamato, K.; Sanford, A R.; Xu, D.; Guo, H.; Gong,... 165.83, 163.13, 160 .41 , 159 .44 , 156. 14, 155.30, 1 54. 23, 152.13, 151.56, 149 .60, 141 .79, 139 .47 , 138.29, 137. 54, 1 24 136 .47 , 1 34. 80, 133.90, 132.79, 129.91, 129.00, 128. 94, 128.66, 128 .41 , 128.22, 128.15, 127.70, 127.23, 126.25, 126.01, 125.91, 125.25, 125.31, 125.16, 125.11, 1 24. 13, 123.78, 123.69, 121.66, 121.58, 111.66, 111.25, 110.82, 110.73, 78.92, 77.86, 68.68, 68.63, 52.33, 31.82, 29. 34, 29.25, 29.22, . symmetric aromatic circular oligoamides with tunable interior functional groups were designed and synthesized. 111 4. 2 Results and Discussion 4. 2.1 Design and Computational Molecular Modeling of. 163.13, 160 .41 , 159 .44 , 156. 14, 155.30, 1 54. 23, 152.13, 151.56, 149 .60, 141 .79, 139 .47 , 138.29, 137. 54, 125 136 .47 , 1 34. 80, 133.90, 132.79, 129.91, 129.00, 128. 94, 128.66, 128 .41 , 128.22,. CDCl 3 ): δ 190.36, 1 64. 85, 1 54. 52, 145 .97, 144 .65, 136. 04, 128.65, 128.57, 128 .48 , 128 .42 , 121.57, 1 14. 06, 78.56, 69.22, 52.72, 50. 74, 31.73, 29.19, 29. 14, 28.91, 25.85, 22.60, 14. 02. HRMS-ESI: