Synthesis and structure investigation of stabilized aromatic oligoamides and their interaction with g quadruplex structures 3

Chapter Helical Organization in Foldable Aromatic Oligoamides 3.1 Introduction Largely driven by a strong desire to build biopolymer-like functions into much simpler yet completely abiotic systems, there have been many recent advances in elegantly devised folding systems geared toward designing unnatural folding helices.(for recent reviews)1 . In particular, the helical organization emanating from multiply centered hydrogen bonds (H-bonds) has attracted special interest in recent years. 1a-j Despite substantial exceptions2, the exact helical dimensions and properties for a large portion of the hitherto known molecular helices have always remained as eminently intriguing in the absence of crystal structures.1j,3 Obtaining such quantitative descriptions of molecular properties in solid state is critically important as this very often leads to insightful, testable hypotheses,2i and novel utilities in such as functional foldamer design1j, 1l,4 as well as reveals gaps in our current understanding that must be filled. 89 3.2 Result and Discussion 3.2.1 Helical Conformation in Pentamer and Hexamer R1 O O N H N O 11 H 10 O O O 25 R2 O O N R3 19 23R4 O R1 6b: R1=O(CH2)7CH3, R2=OCH(CH3)2 6c: R1=CH3, R2 =OCH(CH3)2 O 22 N O2N 6a: R1=R2=H 18 H O O 17 21 O2 N 24 O O H 20 O O H 14 16 N H N R2 N H O 13 12 O 15 O O 5a: R1=R2=R3 =R4=H 5b: R1 =O(CH2)7CH3, R2=R4 =OCH(CH3 )2 , R3=CH3 5c: R1=O(CH2)7CH3, R2=OCH(CH3)2, R3=R4=CH3 Early investigations3c,5 have established a crescent folding backbone in solid state for internally H-bonded oligomers of up to trimer with repeating units represented by oligomers and 6. Although the corresponding helical conformation for longer oligomers in solution has not been investigated, early molecular modeling5a on a hexamer like 6a using the MM3 force field suggested it to adopt a crescent, two-dimensional conformation that encloses an acyclic, open-ended cavity of ~ 4.3 in radius defined by six interior methoxy oxygen atoms (or 2.9 covalent radius of 1.4 binding mode was after deducting a for oxygen atom); on this basis, a hexameric, head to tail proposed to account for the helicity induction in porphyrin-modified hexamer by six chiral C60-incorporating histidines.3c The existence of such a large cavity of 2.9 , however, may seem uncertain as amide linkages are known to possess a great degree of plasticity in bond angles, instructing 90 the H-bond rigidified backbone to curve toward the H-bonded side.1f,2c Our computational molecular modeling at the level of B3LYP/6-31G* on 5a showed that oligomers of higher than tetramer should take up a helical backbone rather than the planar conformation as proposed previously.3c,5a Consequently, a helical cavity of ~1.4 in radius that is much smaller than 2.9 should result. Consistent with these modeling results, we now provide here the solid state evidences involving helical organizations in 5a and 6a by a continuous H-bonding network and the convincing 2D NOESY studies that support the helically folded conformations adopted by 5b and 6b and 6c, respectively, in solution. These distinct helically folded conformations may better explain the helicity induction observed previously.3c Figure 3.1. Side and top views of oligoamides and 6: (a) crystal structure of pentamer 5a, (b) ab initio calculated structure of 5a and (c) crystal structure of hexamer 6a. Interior methoxy methyl groups are omitted for clarity. As mentioned in chapter 2, Oligomers and were synthesized from commercially available salicylic acid and 2,5-dihydroxybenzoic acid in 12-18 steps. Crystals of 5a and 6a suitable for X-ray structure determination were obtained by slow evaporation of 5a and 6a in mixed solvents containing hexane and chloroform 91 (1:1 v/v) for 5a and hexane and dichloromethane (1:1 v/v) for 6a at room temperature. Their crystal structures viewed along or perpendicular to helical axis are presented in Fig. 3.1a and 3.1c. The common structural features shared between 5a and 6a are the following: (1) both unit cells contain two enantiomeric helices of opposite helical senses (e.g., right/left handed) that tightly stack on each other with no inclusion of solvent molecules; (2) both structures possess a helical periodicity of ~five repeating units per turn; (3) the interior methoxy groups, pointing up and down alternatively, fill the helix hollow of ~1.4 in radius and completely prevent them from the encapsulation of guest molecules; and (4) as expected, all the inward-pointing amide protons and methoxy oxygen atoms participate in the formation of a continuous internally located H-bonding network that comprises up to ten intramolecular H-bonds (NH…OMe = 1.933-2.306 Å). One disparity between 5a and 6a involves the helical pitch. While hexamer 6a has a pitch of ~ 3.4 Å typically observed in aromatic foldamers,2a-f an appreciably larger helical pitch of Å is observed in 5a. Such a large pitch may stem, in part, from the steric crowdedness involving the two end methoxy groups in the absence of favorable π-π stacking interactions and was also found in an aliphatic peptoid foldamer in solid state.2g The solid state structures of 5a and 6a (1) provide the most conclusive evidence for the adoption of a helical conformation by the foldable molecular strands 5a and 6a, (2) validate our conceptual reasoning and others’ observations1f,2c detailing a significant effect the H-bonding forces may have on the backbone curvature of aromatic folamers and 92 (3) corroborate the power of ab initio molecular modeling at the B3LYP/6-31G* level in the satisfactory prediction of 3D topologies of aromatic foldamers.2f,6. Figure 3.2. 1H NMR spectra of pentamers. (a) pentamer 5a (500 MHz, mM, 298 K, CDCl3) and (b) pentamer 5b (800 MHz, 25 mM, 298 K, CDCl3). The highly repetitive nature of 5a (Figure 3.2a) and 6a6 led to the extensive 1H NMR signal overlaps among aromatic protons, hampering the elucidation of their folded structures in solution. To overcome this difficulty, linear and branched alkoxyl side chains as well as a methyl group para to the interior methoxy groups are deliberately introduced into 5b. At 25 mM, the 1H NMR spectrum of 5b recorded in CDCl3 displays highly dispersed proton resonances for most of its protons (Figure 3.2b). The amide protons resonating at low fields (9.87-10.36 ppm) are in line with the existence of strong intramolecular H-bonds in 5b.2c,2d Since the inter-atomic distances between amide and methoxy protons from the crystal structure of 5a range from 2.279 to 3.690 Å, two NOE contacts between every amide proton and its adjacent methoxy methyl groups should be seen in the 2D NOESY spectrum if a folded conformation does prevail for 5b in solution. The well-resolved amide protons and internal methoxy groups of 5b indeed permit us to observe the expected eight NOE 93 cross peaks, two for each amide protons. Presumably owing to its unusually large helical pitch (5 Å), the NOEs between the end residues that are indicative of the helical conformation of 5b was not detected (Figure 3.3). Figure 3.3. NOE contacts (NOESY, 800 MHz, 25 mM, 298 K, 500 ms, CDCl3) seen between amide protons and their adjacent interior methoxy protons of 5b. Figure 3.4 demonstrated full spectrum of NOESY and partial spectrum of TOCSY. The TOCSY sequence is a homonuclear experiment which produces a COSY-like plot. COSY gives correlations between protons that are coupled to one another, while TOCSY gives correlations between all protons in a given spin system. In our experiment, TOCSY turns out to be the most efficient method to determine aromatic protons that are adjacent to each other. The contacts between amide protons and aromatic protons could also be observed easily by TOCSY (Figure 3.4c). 94 a) b) c) Figure 3.4. 2D NOESY (25 mM, 800 MHz, 298 K, 500 ms) & TOCSY (80ms) studies of pentamer 5b in CDCl3. (a) Full spectrum (2D NOESY), (b) Partial spectrum (2D NOESY) showing contacts observed between external side chain protons and aromatic protons), (c) Partial spectrum (2D TOCSY) showing contacts observed between amide protons and aromatic protons. Such a helical conformation, however, can be confirmed by 2D NOESY study for longer oligomers such as where the favorable π-π stacking interactions between the first and sixth aromatic rings bring the two end residues closer to each other, leading to a typically observed helical pitch of ~ 3.4 Å for aromatic foldamers. 95 Correspondingly, a strong NOE cross peak between the end ester methyl protons and the aromatic proton 24, serving as an indicator for helical formation, was observed for 6c at 10 mM in CDCl3. The existence of this helical conformation can be nicely supported by the ab initio molecular modeling at the level of B3LYP/6-31G* and the determined crystal structure of 6a (Figure 3.1c), both of which point to an energetically optimized configuration for 6c where the six interior methoxy methyl groups point up and down alternatively along the aromatic backbone helically biased by a continuous H-bonding network. Before pentamer 5b and hexamer 6b were designed, pentamer 5c and hexamer 6c modified with various side chains were actually made first to probe the helical conformation that may be adopted by these longer oligomers. However, the side chains introduced into 5c not give rise to a complete resolution of amide protons and internal methoxy methyl groups. As to 6c, although good end-to-end NOE contacts between either proton or proton and aromatic proton 24 can be detected in CDCl3 at 283 K but not 298K, the signal overlap between protons and makes the accurate assignment of 1H NMR signals difficult. This issue can be solved by addition of up to 25% DMSO-d6 into CDCl3, leading to a good separation between protons and in both 6b and 6c (Figure 3.6). However, 2D NOESY collected for hrs at 10 mM in 3:1 CDCl3/DMSO-d6 at either 283 K or 298 K failed to yield detectable NOE contact between protons and 24 in 6c. Consequently, either crescent or helical conformation concerning oligomers 5c and 6c can not be confidently deduced. 96 a) b) c) 24 24 15 24 1,5 e) d) 24 f) 24 24 6c Figure 3.5. 2D NOESY (500 MHz, 10 mM, 500 ms) & ROESY (500 MHz 10 mM, 200 ms) studies of 6c, showing end-to-end contact between protons and 24 that is indicative of helical conformation. (a) 2D NOESY (283 K, CDCl3, hrs), (b) 2D NOESY (298 K, CDCl3, hrs), (c) 2D NOESY (283 K, CDCl3/DMSO-d6 (3:1 v/v), hrs), (d) 2D NOESY (283 K, CDCl3/DMSO-d6 (3:1 v/v), hrs), (e) 2D NOESY (298 K, CDCl3/DMSO-d6 (3:1 v/v), hrs) and (f) 2D ROESY (298 K, CDCl3/DMSO-d6 (3:1 v/v), hrs). Compared to (d), NOE peak intensity in (e) is much weaker. 97 a) 25% 25% 20% 20% 15% 15% 10% 10% 5% 5% b) 51 25% 25% 20% 20% 15% 15% 10% 10% 5% 5% Figure 3.6. Effect of DMSO-d6 percentage in CDCl3 on the 1H NMR signal dispersion involving protons and in hexamers: (a) hexamer 6b and (b) hexamer 6c. Before it was realized that lengthening the total acquisition time of 2D NOESY from hrs to about hrs in 3:1 CDCl3/DMSO-d6 allows us to detect an end-to-end contact between proton and proton 24 in 6c (Figures 3.5d and 3.5e), we decided to replace the methyl side chain at the nitro end with an isopropyloxy side chain to generate 5b and with an octyloxy side chain to generate 6b. Such a minute difference in structure pleasingly leads to completely resolved 1H NMR signals for critically important protons that allow us to unambiguously confirm a crescent conformation 98 for 5b in pure CDCl3 and a helical structure for 6b in 3:1 CDCl3/DMSO-d6 at room temperature. 6c was also confirmed to assume a helical conformation in solution by 2D NOESY experiment with a longer acquisition time (Figures 3.5d and 3.5e) or by 2D ROESY study (Figure 3.5f). As mentioned above, the incorporation of two different side chains into 6b at only one end differentiates the aromatic proton signals of the modified end units from all the other remaining units in the same molecule in CDCl3. Addition of 25% DMSO-d6 into CDCl3 further separates ester methyl protons from the interior methoxy methyl protons 5. As such, the ROE cross peak between the end units (methyl protons and aromatic proton 24, Figure 3.7) is clearly identifiable. This end-to-end ROE, along with the observation of numerous ROE contacts among amide protons and their adjacent interior methoxy protons, evidently support the presence of the H-bond enforced helical ordering in 6b in solution that leads to the stacking of one end over the other. Observation of these end-to-end NOE or ROE contacts in 6b (Figure 3.7) fully accords with the shortest inter-atomic distance (2.748 Å) found between protons and 24 in the crystal structure of 6a. 99 O O NH O CH3 O N H O O O O NO2 OMe NH O HN O H 24 HN 6b O O R 1O OR2 Figure 3.7. End-to-end NOE (top, 500 MHz, 20 mM, 283 K, 500 ms, CDCl3) and ROE (bottom, ROESY, 500 MHz, 15 mM, 298 K, 200 ms, CDCl3/25%DMSO-d6) contacts seen between the end units of 6b. a) b) (24,1) (24,1) 100 c) d) e) f) O N O O O2N 13 14 O H 10 11 O O O 6b O 15 N 16 H O 20 O 26 25 21 H H N 29 27 12 N H O 24 O CH 2(CH 2) 6CH O 17 18 N 19 O 22 O 23 28 Figure 3.8. 2D NOESY (500 MHz, 20 mM, 283 K, CDCl3, 500 ms) and ROESY (500 MHz, 15 mM, 298 K, CDCl3/DMSO-d6 (3:1 v/v), 200 ms) studies of hexamer 6b. (a) Full spectrum (2D NOESY) showing end-to-end contacts, (b) Full spectrum (2D ROESY) showing end-to-end contacts, (c) Partial spectrum (2D NOESY) showing contacts observed between aromatic protons and their adjacent alkoxyl protons, (d) Partial spectrum (2D ROESY) showing contacts observed between aromatic protons and their adjacent alkoxyl protons, (e) Partial spectrum (2D NOESY) showing contact observed between amide protons and their adjacent interior methoxy protons, (f) Chemical structure of 6b. More NOESY, ROESY and TOXSY studies of 6b were demonstrated in Figure 3.8 and Figure 3.9. Figure 3.8c and 3.8d show the contacts between aromatic protons and their adjacent alkoxyl protons, observed by NOESY and ROESY, respectively. 101 Contacts between amide protons and their adjacent interior methoxy protons in 6b were shown in Figure 3.7e. The well-resolved amide protons and internal methoxy groups of 6b permit us to observe the expected ten NOE cross peaks, two for each amide protons. a) b) Figure 3.9. 2D TOCXY (500 MHz, 20 mM, 298 K, CDCl3, mixing time: 80 ms) study of hexamer 6b. (a) Full spectrum, (b) Partial spectrum showing contact observed between aromatic protons and aromatic protons. 3.2.2 Helical Conformation of Heptamer Scheme 3.1. Synthesis of heptamer 7a OC 8H 17 O O NO2 N O O N H O O O 3g O H N + H O N O OH O O O N H O O 4a H O N H O a, b O N H3 O O O O NO2 H O O H N N O2 N O O O O OC8 H 17 a o a) 3g, (COCl)2, DMF, CH2Cl2; b) H2, Pd/C, THF, 40 C, 4a, then TEA/CH2Cl2. Heptamer was obatained by a convergent route with relatively high yield 15%. For high-level oligomers, convergent coupling was used more frequently than 102 stepwise fashion in order to saving time. However, the reaction yield was usually low due to the steric hindrance imposed by helical conformation of oligoamides. Figure 3.10. H NMR spectra of heptamer (500 MHz, mM, 298 K, CDCl3). One dimensional 1H NMR of heptamer was presented in Figure 3.10. Similar to pentamer and hexamer, the amide protons resonate at low fields (9.71-10.15 ppm), suggesting the existence of strong intramolecular H-bonds in 7. Furthermore, the crescent and helical structure in was probed by 2D NOESY study (Figure 3.11). NOE contacts between amide proton and its adjacent methoxy methyl groups could be observed in the 2D NOESY spectrum, suggesting a folded conformation of in solution. However, the aromatic protons in were too overlapping, making it hard to assign them. Accordingly, amide protons and methoxy methyl group could not be determined. The only aromatic protons (27, 29, 32, 34) that could be assigned are the ones at the last two benzyl units adjacent to nitro group end, due to their interaction with exterior side chains (Figure 3.11c). Although the position of each aromatic proton is unclear, a strong NOE cross between methyl proton and aromatic proton was observed, which is similar to end-to-end contact in 6b and 6c. Obviously, the aromatic proton was not belongs to monomeric units at the nitro end (27, 29, 32, 34). Thus, it was assumed be the NOE between the end ester methyl protons and the aromatic 103 proton 24. a) O 22 23 N 24 N O H3 H O 25 26 N O O H 30 O 27 O O 31 28 H 35 O N O 29 O2 N O 32 34 O 33 OC8 H 17 b) c) Figure 3.11. 2D NOESY (500 MHz, 20 mM, 298 K, CDCl3, 500 ms) study of heptamer 7. (a) Full spectrum, (b) Partial spectrum showing contact observed between amide protons and their adjacent interior methoxy protons, (c) Partial spectrum showing contact observed between aromatic protons and their adjacent interior methoxy protons. To validate this assumption, single crystal was tried to be grown by our traditional slow evaporation method. Unfortunately, solid state structure of heptamer could not be obtained despite of various solvent pairs. To predict the structure of 7, ab initio molecular modeling was performed. As seen in Figure 3.12, heptamer possess a 104 helical periodicity of about five repeating units per turn and has a typical pitch of ~ 3.4 Å. All these results were in agreement with previous studies of pentamer and hexamer. Hereto, the similarity of helical conformation in hexamer and heptamer again prove the structural predictability of those designed oligoamides. Moreover, the close distance between ester methyl group and aromatic proton 24 corresponds well with the end-to-end NOE contact found in 2D NOESY spectrum (Figure 3.12b). a) b) c) Figure 3.12. Ab initio calculated structure of heptamer 7. (a) top views, (b) side views, (c) side views. 3.3 Conclusion To summarize, the helical propagation over several internally rigidified, lengthened oligoaromatic backbones as in 5, and in solution and solid states has been established experimentally and substantiated theoretically by the computational molecular modeling at the B3LYP/6-31G* level. The detailed elucidation of such structural information contained within the helically folded framework should guide the design of supramolecular (bio)nanoarchitectures of increasing complexity via 105 peripheral functionalizations, which may find important utilities in a variety of materials science,3c medicinal1l, and biological settings.1l, 4a-c. 3.4 Experimental Section Compound 7: Compound 4a (0.20 g, 0.32 mmol) was reduced by catalytic hydrogenation in THF (15 mL) at 50 oC, using Pd-C (0.040 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 3g (0.38 g, 0.5 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (5 mL) and DMF (27 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (67 μL, 0.53 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.17 g, 0.36 mmol) was dissolved in 10 mL dry CH2Cl2 and triethylamine (0.10 mL, 0.69 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 oC for hrs 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 recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using Hexane/EA (2:1 v/v) as the eluent to give pure product as a white solid. Yield: 50 mg, 15%. 1H NMR (500 MHz, CDCl3) δ 10.15 (s, H), 10.12 (s, 1H), 10.07 (s, 1H), 10.00 (s, 1H), 9.81 (s, 1H), 9.71 (s, 1H), 106 8.78 (m, 5H), 8.34 (d, 1H, J = 3.2), 7.91 (d, 1H, J = 6.7), 7.86 (m, 3H), 7.81 (d, 1H, J = 6.8), 7.40 (d, 1H, J = 3.2), 7.37 (m, 5H), 7.31 (t, 1H), 7.17 (t, 1H), 4.63 (m, 1H), 4.05 (s, 3H), 4.04 (s, 3H), 4.02 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.90 (s, 6H), 3.83 (s, 3H), 3.82 (s, 3H), 1.67 (m, 2H), 1.48 (s, 6H), 1.27 (m, 8H), 1.15 (m, 2H), 0.66 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 165.43, 163.43, 163.01, 162.81, 162.67, 161.13, 155.38, 155.08, 149.09, 147.43, 147.39, 147.19, 147.09, 144.42, 143.95, 140.53, 132.91, 132.53, 132.36, 132.28, 132.21, 132.13, 129.39, 126.91, 126.83, 126.69, 126.52, 126.45, 125.63, 125.45, 125.36, 124.94, 124.80, 124.63, 124.42, 123.11, 121.23, 115.01, 112.60, 112.49, 70.68, 69.29, 67.05, 64.49, 63.31, 63.10, 63.00, 62.97, 62.91, 62.32, 53.23, 31.74, 29.66, 29.21, 29.16, 28.90, 25.86, 22.61, 21.96, 14.07. 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T., Tetrahedron 2005, 61, 7974. (b) Kanamori, D.; Okamura, T. A.; Yamamoto, H.; Ueyama, N., Angew. Chem. Int. Ed. 2005, 44, 969. 6. Buffeteau, T.; Ducasse, L.; Poniman, L.; Delsucb, N.; Huc, I., Chem. Commun. 2006, 2714. 109 [...]... 4. 63 (m, 1H), 4.05 (s, 3H), 4.04 (s, 3H), 4.02 (s, 2H), 4.00 (s, 3H), 3. 94 (s, 3H), 3. 90 (s, 6H), 3. 83 (s, 3H), 3. 82 (s, 3H), 1.67 (m, 2H), 1.48 (s, 6H), 1.27 (m, 8H), 1.15 (m, 2H), 0.66 (m, 3H) 13C NMR (125 MHz, CDCl3) δ 165. 43, 1 63. 43, 1 63. 01, 162.81, 162.67, 161. 13, 155 .38 , 155.08, 149.09, 147. 43, 147 .39 , 147.19, 147.09, 144.42, 1 43. 95, 140. 53, 132 .91, 132 . 53, 132 .36 , 132 .28, 132 .21, 132 . 13, 129 .39 ,... NOESY) showing contact observed between amide protons and their adjacent interior methoxy protons, (f) Chemical structure of 6b More NOESY, ROESY and TOXSY studies of 6b were demonstrated in Figure 3. 8 and Figure 3. 9 Figure 3. 8c and 3. 8d show the contacts between aromatic protons and their adjacent alkoxyl protons, observed by NOESY and ROESY, respectively 101 Contacts between amide protons and their adjacent... 1998, 31 , 1 73 (b) Gong, B., Chem Eur J 2001, 7, 433 6 (c) Hill, D J.; Mio, M J.; Prince, R B.; Hughes, T S.; Moore, J S., Chem Rev 2001, 101, 38 93 (d) Sanford, A R.; Gong, B., Curr Org Chem 20 03, 7, 1649 (e) Schmuck, C., Angew Chem Int Ed 20 03, 42, 2448 (f) Huc, I., Eur J Org Chem 2004, 17 (g) Sanford, A R.; Yamato, K.; Yang, X.; Yuan, L.; Han, Y.; Gong, B., Eur J Biochem 2004, 271, 1416 (h) Cheng, R... 129 .39 , 126.91, 126. 83, 126.69, 126.52, 126.45, 125. 63, 125.45, 125 .36 , 124.94, 124.80, 124. 63, 124.42, 1 23. 11, 121. 23, 115.01, 112.60, 112.49, 70.68, 69.29, 67.05, 64.49, 63. 31, 63. 10, 63. 00, 62.97, 62.91, 62 .32 , 53. 23, 31 .74, 29.66, 29.21, 29.16, 28.90, 25.86, 22.61, 21.96, 14.07 HRMS-ESI: calculated for [M+Na]+ (C41H37N3O13Na): m/z 131 4.4881 found: m/z 131 4.4877 107 Reference: 1 (a) Gellman, S H., Acc... aromatic proton was not belongs to monomeric units at the nitro end (27, 29, 32 , 34 ) Thus, it was assumed be the NOE between the end ester methyl protons 1 and the aromatic 1 03 proton 24 a) O 22 23 N 4 24 N O H3 3 H O 6 25 26 N 2 O O H 5 7 30 O 27 O O 31 28 1 H 35 O N O 29 O2 N O 32 34 O 33 OC8 H 17 b) c) Figure 3. 11 2D NOESY (500 MHz, 20 mM, 298 K, CDCl3, 500 ms) study of heptamer 7 (a) Full spectrum,... only aromatic protons (27, 29, 32 , 34 ) that could be assigned are the ones at the last two benzyl units adjacent to nitro group end, due to their interaction with exterior side chains (Figure 3. 11c) Although the position of each aromatic proton is unclear, a strong NOE cross between methyl proton and aromatic proton was observed, which is similar to end-to-end contact in 6b and 6c Obviously, the aromatic. .. the structure of 7, ab initio molecular modeling was performed As seen in Figure 3. 12, heptamer 7 possess a 104 helical periodicity of about five repeating units per turn and has a typical pitch of ~ 3. 4 Å All these results were in agreement with previous studies of pentamer and hexamer Hereto, the similarity of helical conformation in hexamer and heptamer again prove the structural predictability of. .. designed oligoamides Moreover, the close distance between ester methyl group 1 and aromatic proton 24 corresponds well with the end-to-end NOE contact found in 2D NOESY spectrum (Figure 3. 12b) a) b) c) Figure 3. 12 Ab initio calculated structure of heptamer 7 (a) top views, (b) side views, (c) side views 3. 3 Conclusion To summarize, the helical propagation over several internally rigidified, lengthened... to saving time However, the reaction yield was usually low due to the steric hindrance imposed by helical conformation of oligoamides Figure 3. 10 1 H NMR spectra of heptamer 7 (500 MHz, 5 mM, 298 K, CDCl3) One dimensional 1H NMR of heptamer 7 was presented in Figure 3. 10 Similar to pentamer and hexamer, the amide protons resonate at low fields (9.71-10.15 ppm), suggesting the existence of strong intramolecular... Furthermore, the crescent and helical structure in 7 was probed by 2D NOESY study (Figure 3. 11) NOE contacts between amide proton and its adjacent methoxy methyl groups could be observed in the 2D NOESY spectrum, suggesting a folded conformation of 7 in solution However, the aromatic protons in 7 were too overlapping, making it hard to assign them Accordingly, amide protons and methoxy methyl group could not . 161. 13, 155 .38 , 155.08, 149.09, 147. 43, 147 .39 , 147.19, 147.09, 144.42, 1 43. 95, 140. 53, 132 .91, 132 . 53, 132 .36 , 132 .28, 132 .21, 132 . 13, 129 .39 , 126.91, 126. 83, 126.69, 126.52, 126.45, 125. 63, . (s, 3H), 3. 94 (s, 3H), 3. 90 (s, 6H), 3. 83 (s, 3H), 3. 82 (s, 3H), 1.67 (m, 2H), 1.48 (s, 6H), 1.27 (m, 8H), 1.15 (m, 2H), 0.66 (m, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 165. 43, 1 63. 43, 1 63. 01,. Chemical structure of 6b. More NOESY, ROESY and TOXSY studies of 6b were demonstrated in Figure 3. 8 and Figure 3. 9. Figure 3. 8c and 3. 8d show the contacts between aromatic protons and their