Letter Cite This: Org. Lett. 2017, 19, 5625-5628
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Aromatic Hybrid Foldamer with a Hydrophilic Helical Cavity Capable of Encapsulating Glucose Ji Young Hwang,† Hae-Geun Jeon,† Ye Rin Choi, Junyoung Kim, Philjae Kang, Seungwon Lee, and Kyu-Sung Jeong* Department of Chemistry, Yonsei University, Seoul 03722, South Korea S Supporting Information *
ABSTRACT: An indolocarbazole−naphthyridine hybrid oligomer capable of adopting a stable helical conformation was prepared, and its folding properties were thoroughly studied in the solid state and in solution. As a result of folding, a hydrophilic cavity was generated inside the helix wherein monosaccharides were able to be encapsulated in the order of glucose (9.6 × 104 M−1) > galactose (1.0 × 104 M−1) ≫ mannose (∼0) in 10% (v/v) DMSO/CH2Cl2.
A
Scheme 1. Molecular Structures of Oligomers 1 and 2 and a Stable C-Shaped Conformation with the Dipole Direction of the Repeating Monomers in 2
romatic helical foldamers are synthetic oligomers that are comprised of aromatic repeating monomers with a strong propensity to fold into helical conformations.1 The helical folding of these oligomers gives rise to characteristic features such as the stacked array of aryl planes, the three-dimensional arrangement of functional groups, and the generation of an internal tubular cavity. Therefore, these aromatic helical foldamers have been applied to the development of synthetic receptors,2,3 transmembrane pores or channels,4 and stimuliresponsive molecules.5 In particular, the Huc group has demonstrated in recent years that aromatic oligoamide foldamers were able to discriminate closely resembling molecules with extremely high selectivity and affinity.3 The binding cavity inside the foldamer was evolved to provide optimal environments toward a target guest by sequence-specific modifications, which is a great merit of foldamer-based synthetic receptors. Recently, we prepared an indolocarbazole−pyridine (IP) hybrid foldamer 16 that adopted a helical structure with an internal cavity capable of accommodating water molecules. We envisioned that the cavity could be enlarged to encapsulate larger organic molecules by changing the monomeric units from pyridine to naphthyridine. In addition, such modification may increase the kinetic stability of a helically folded conformation because of extended aromatic stacking between the helical turns. In this context, we prepared an indolocarbazole−naphthyridine (IN) foldamer 2 that folded into a stable helical conformation with an enlarged hydrophilic cavity suitable for binding organic guests. This foldamer was found to bind monosaccharides2b,3b in the order; glucose (9.6 × 104 M−1) > galactose (1.0 × 104 M−1) ≫ mannose (∼0) in 10% (v/v) DMSO/CH2Cl2. According to computer modeling (MacroModel 9.1, MMFFs force field),7 a C-shaped planar conformation is more stable than any other possible conformation when two indolocarbazoles are linked to the 2,7-positions of 1,8-naphthyridine via ethynyl bonds (Scheme 1 and Table S3). This conformational preference is primarily attributed to local dipolar interactions between two repeating monomers. Successive connection of the two repeating © 2017 American Chemical Society
units in the same way gives rise to a helically folded structure with an internal tubular cavity in which all of the hydrogen-bonding functional groups (NH and N) in the repeating units are inwardly convergent. Given that the distance between two connecting carbons in naphthyridine is twice as long as in pyridine, the resulting IN foldamer is expected to contain a more spacious internal cavity, relative to the IP foldamer. For comparison, the internal diameter of the cavity in the energyReceived: September 5, 2017 Published: October 11, 2017 5625
DOI: 10.1021/acs.orglett.7b02768 Org. Lett. 2017, 19, 5625−5628
Letter
Organic Letters minimized structure of 2 is estimated to be approximately 6.6 (±0.2) Å, while that of 1 is 5.4 (±0.3) Å. Oligomer 2 was synthesized by repeating Sonogashira8 and protodesilylation reactions. The synthetic details are described in the Supporting Information. The 1H NMR chemical shifts of 2 were found to be very sensitive to the nature of solvents. In polar aprotic solvents such as DMSO-d6 and DMF-d7, the aromatic signals of 2 appeared in the region between 7 and 8.5 ppm, similar to the signals of monomeric units (Figure 1 and Figure
Figure 2. (a) Tube and (b) space-filling representations of the X-ray crystal structure of 2⊃4H2O. In (a), four water molecules in the cavity of 2 were shown as the space-filling view. The M helix is only shown, and tert-butyl groups and CH hydrogen atoms are all omitted for clarity.
accommodated by chainlike multiple hydrogen bonds (Figure S22 and Table S6). Each helix consists of approximately 2.5 turns, and all of the aryl planes are tightly stacked with an interplanar distance of ∼3.4 Å (Figure 2b).10 In addition, two monomeric units with the opposite dipolar direction, indolocarbazoles and naphthyridines, are stacked on top of each other in the helix (Figure 2a), which may further stabilize the folding conformation.11 In oligomer 2, there are two methyl groups at the end of the strand which appear as one singlet in the 1H NMR spectrum when unfolded in DMSO-d6 (Figure S4). However, this signal is split into two separate singlets upon folding owing to the intrinsic chirality of the helix. These diastereotopic signals can be exchanged via the interconversion of P and M helices. Consequently, the exchange rate of the two signals is a good indicator of the kinetic stability of the helices because interconversion between the two helical enantiomers takes place either via an unfolded or a partially folded conformation. Using two-dimensional exchange spectroscopy (2D-EXSY) (Figure S5),12 the exchange rate (kex) was calculated to be 4.8 (±0.4) s−1 at 25 °C in 9% (v/v) CD3OD/water-saturated CD2Cl2, corresponding to the free energy barrier (ΔG‡) of 16.6 (±0.3) kcalmol−1. For comparison, the exchange rate of oligomer 1 containing pyridine monomers was too fast to be measured in the same solvent system, displaying a time-averaged singlet for both the methyl groups without splitting even at −60 °C (Figure S6). Therefore, the folding structure of 2 is kinetically more stable than that of 1, possibly because of the expanded surface for more effective aromatic stacking, naphthyridine vs pyridine. Compared with 1, foldamer 2 contains an enlarged internal cavity and therefore may encapsulate organic molecules such as monosaccharides containing multiple hydroxyl groups.2b,3b,13 The chirality of the monosaccharides may be transmitted to the binding, thus displaying induced circular dichroism (CD) signals as a result of the preferential formation of one helical complex.2b,3b As shown in Figure 3, strong induced CD signals were observed when monosaccharides (10 equiv) were added to a solution of 2 (5 × 10−5 M) in 10% (v/v) DMSO/CH2Cl2 containing water (v/v 0.02−0.03%). It should be noted that 2 adopts a helical conformation under these conditions (Figure S2c). More specifically, D-glucose gave rise to strong negative CD signals (Δε = −88 M−1 cm−1 at λmax = 384 nm and −134 M−1 cm−1 at λmax = 456 nm) and its enantiomer, L-glucose, induced an inverted symmetrical CD spectrum. D-Galactose also afforded an identical but slightly less intense CD spectrum compared to Dglucose. Surprisingly, no induced CD signal was observed by Dmannose under the same conditions, which is consistent with the 1 H NMR observation that binding of D-mannose to 2 was negligible (Figure S7). The CD titration experiments were conducted by gradually increasing the amount of each saccharide at a constant concentration (5.0 × 10−5 M) of 2 in 10% (v/v)
Figure 1. Helically folded structure of 2 with NOE cross signals and its partial 1H NMR spectra (400 MHz, 25 °C) in water-saturated CD2Cl2 and DMSO-d6.
S1). This indicates that oligomer 2 exists in an extended conformation without stacking between the aromatic components. Both DMSO-d6 and DMF-d7 contain a strong hydrogen bond acceptor with a β value of 0.76.9 Therefore, they strongly solvate the indolocarbazole NH protons, which possibly interferes with the helical folding. In sharp contrast, the aromatic signals showed significant upfield shifts in relatively nonpolar solvents such as CD2Cl2, CDCl3, and THF-d8 (Figure 1 and Figure S2). For example, the indolocarbazole CH signals were shifted upfield in wet CD2Cl2 by Δδ = 0.1−0.6 ppm compared to the shifts in DMSO-d6 (Table S1). The naphthyridine CH signals showed much more pronounced upfield shifts, Δδ = δ (DMSO-d6) − δ (CD2Cl2) = 0.6−2.8 ppm. More specifically, the CH signals in the central naphthyridine were dramatically shifted upfield (Δδ = 2.8 and 2.5 ppm), and these shifts are much larger than the shifts observed in the other two naphthyridines (Δδ = 1.38, 0.91, 0.87, and 0.64 ppm). This can be rationalized by the folding of 2 into a helical conformation wherein the central naphthyridine plane was sandwiched by upper and lower aryl planes but the other naphthyridines were stacked with a single aryl plane. The helical folding of 2 was proven by the 1H−1H ROESY experiment in 5% (v/v) CD3OD/water-saturated CDCl3. There were clearly observed NOE cross peaks between the remote aromatic protons, which could be located in close proximity only in a helical conformation (Figure 1 and Figure S3). The helical folding of 2 was further confirmed by the X-ray crystal structure (Figure 2). Slow evaporation of a methanol (v/v ∼5%)/ethyl acetate solution containing 2 yielded single crystals suitable for X-ray crystal diffraction. As anticipated, 2 folded to give a racemic mixture of P and M helices (Figure S21). All of the indolocarbazole NH protons and naphthyridine nitrogen atoms in 2 are present inside the cavity. As a result, the cavity provides a hydrophilic environment for four water molecules to be 5626
DOI: 10.1021/acs.orglett.7b02768 Org. Lett. 2017, 19, 5625−5628
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Organic Letters
glucose must be encapsulated in the cavity. Furthermore, the CH signals of D-glucose showed large downfield shifts (Δδ = 1−3 ppm) possibly owing to the formation of CH···N (naphthyridine) hydrogen bonds.17 These observations are in agreement with the energy-minimized structure7 for complex between 2 and α-D-glucose (Figure 5, Figures S18 and S20, and Table S4). Upon
Figure 3. (a) CD spectra of 2 (5 × 10−5 M) and monosaccharides (10 equiv) in 10% (v/v) DMSO/CH2Cl2 at 25 ± 1 °C, (b) CD spectral changes of 2 with increasing D-glucose, and (c) experimental and theoretical (Ka = 9.6(±0.1) × 104 M−1, Δεmax= −134 M −1 cm−1) curves of CD titration data at 456 nm. Figure 5. (a) Energy-minimized structure of 2⊃H2O·α-D-glucose through Monte Carlo conformational search using the MacroModel 9.1 program (MMFFs force field, gas phase) and (b) a schematic representation for the hydrogen-bonding network observed in the energy-minimized structure. Three molecules of water were replaced by α-D-glucose, and one molecule remained in the cavity of the complex.
DMSO/CH2Cl2 at 25 ± 1 °C. The binding constants were determined to be 9.6 (±0.1) × 104 for D-glucose and 1.0 (±0.1) × 104 M−1 for D-galactose by nonlinear regression analyses14 of a 1:1 binding isotherm (Figure 3 and Figures S16 and S17). More details on binding between foldamer 2 and D-glucose were revealed by NMR spectroscopic techniques (Figure 4 and
binding to foldamer 2, α-D-glucose is inserted inside the cavity as a result of the formation of multiple hydrogen bonds. The C1, C2, and C3 atoms of α-D-glucose are oriented in the deeper cavity, while the C5 and C6 atoms are positioned around the periphery of the cavity. This geometry may be responsible for selective binding of glucose over mannose. A change in the stereochemistry of C2, like in mannose, seems to disturb the hydrogen-bonding network in the energy-minimized structure between 2 and glucose (Figure 5b and Figure S18). The complexation-induced shifts (CISs) are consistent with the energy-minimized structure. For example, the OH1, OH2, and OH3 hydrogen atoms, showing large downfield shifts (Δδ = 3.6, 7.8, and 4.8 ppm), participate in cooperative chain hydrogen bonds18 with the NH protons (indolocarbazoles) and the nitrogen atoms (naphthyridines). Moreover, the CH2, CH3, and CH4 hydrogen atoms (Δδ = 2.9, 1.1, and 1.7 ppm) appear to participate in CH···N (naphthyridine) hydrogen bonds. On the other hand, the CH1 hydrogen atom also showed a large downfield shift (Δδ = 2.1 ppm), but it does not participate in hydrogen bonding in the minimized structure. Instead, the CH1 hydrogen is located close to the center of an ethynyl bond, and therefore its downfield shift is possibly attributed to the deshielding effect19 of the carbon−carbon triple bond. The ROESY experiment also supported the energy-minimized structure of the complex (Figures S15 and S20). In order to obtain direct evidence for the binding geometry, we attempted to obtain single crystals suitable for X-ray diffraction but failed. There are two possible diastereomeric complexes of the P and M helices that can be formed between 2 and D-glucose. The 1H NMR spectrum exhibited one set of well-resolved signals for a major isomer, indicative of the predominant formation of one helical complex. In contrast, D-galactose, featuring weaker CD intensity and lower binding affinity than D-glucose, afforded broad 1H NMR spectrum upon binding to 2 at 25 °C (Figure S7). At −20 °C, the spectrum became sharpened but was complicated owing to the presence of unidentified minor components (Figure S8). For the complex of 2 with α-D-glucose which exhibited strong negative Cotton effects at λmax = 384 and 456 nm (Figure 3), computer modeling showed that the lefthanded helix (M) was energetically more stable by 25 kJ mol−1 in
Figure 4. Molecular structure of D-glucose, its complexation-induced shifts (ppm, Δδ = δcomplex − δfree), and 1H NMR spectra (400 MHz, 10% (v/v) DMSO-d6/CD2Cl2 containing water (v/v 0.02−0.03%), 25 °C) of 2 (1.0 mM) (top), a mixture of 2 and D-glucose (1.1 equiv) (middle), and D-glucose (α/β = 89:11) (bottom).
Figures S9−S15).15 The 1H NMR spectra of both 2 and Dglucose were noticeably changed when these were mixed together in 10% (v/v) DMSO-d6/CD2Cl2 (v/v 0.02−0.03% water). It should be noted that the anomeric ratio (α/β) of Dglucose was estimated to be 89:11 by the 1H NMR integrations under the given conditions.3b,16 Owing to the symmetrical nature of 2, the eight indolocarbazole NH protons appeared as four singlet peaks. However, these proton signals were split into eight singlets in the presence of D-glucose. This is evidence for the tight binding of the chiral guest D-glucose to 2. In addition, the OH signals of D-glucose were shifted significantly downfield (Δδ = 1.5−7.8 ppm) with the exception of OH6 (Figure 4 and Table S2), indicating the formation of strong hydrogen bonds with the naphthyridine nitrogen atoms which function as hydrogen acceptors in 2. Given that the nitrogen atoms are all located inside the helical cavity, these results clearly indicate that D5627
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(4) (a) Yamato, K.; Kline, M.; Gong, B. Chem. Commun. 2012, 48, 12142. (b) Zhao, H.; Sheng, S.; Hong, Y.; Zeng, H. J. Am. Chem. Soc. 2014, 136, 14270. (c) Xin, P.; Zhu, P.; Su, P.; Hou, J.-L.; Li, Z.-T. J. Am. Chem. Soc. 2014, 136, 13078. (d) Lang, C.; Li, W.; Dong, Z.; Zhang, X.; Yang, F.; Yang, B.; Deng, X.; Zhang, C.; Xu, J.; Liu, J. Angew. Chem., Int. Ed. 2016, 55, 9723. (5) (a) Stadler, A.-M.; Kyritsakas, N.; Lehn, J.-M. Chem. Commun. 2004, 2024. (b) Hu, H.-Y.; Xiang, J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10, 1275. (c) Hua, Y.; Flood, A. H. J. Am. Chem. Soc. 2010, 132, 12838. (d) Suk, J.-M.; Naidu, V. R.; Liu, X.; Lah, M. S.; Jeong, K.-S. J. Am. Chem. Soc. 2011, 133, 13938. (e) Ghosh, K.; Moore, J. S. J. Am. Chem. Soc. 2011, 133, 19650. (f) Yu, Z.; Hecht, S. Angew. Chem., Int. Ed. 2011, 50, 1640. (6) (a) Jeon, H.-G.; Jung, J. Y.; Kang, P.; Choi, M.-G.; Jeong, K.-S. J. Am. Chem. Soc. 2016, 138, 92. (b) Kim, J. S.; Jeon, H.-G.; Jeong, K.-S. Chem. Commun. 2016, 52, 3406. (c) Jeon, H.-G.; Jang, H. B.; Kang, P.; Choi, Y. R.; Kim, J.; Lee, J. H.; Choi, M.-G.; Jeong, K.-S. Org. Lett. 2016, 18, 4404. (d) Kim, J.; Jeon, H.-G.; Kang, P.; Jeong, K.-S. Chem. Commun. 2017, 53, 6508. (7) (a) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440. (b) MacroModel, version 9.1; Schrödinger, LLC: New York, 2005. (8) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874. (9) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, 2005. (10) (a) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc. Perkin Trans2 2001, 651. (b) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (11) (a) Li, Y.; Pink, M.; Karty, J. A.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 17293. (b) Abe, H.; Machiguchi, H.; Matsumoto, S.; Inouye, M. J. Org. Chem. 2008, 73, 4650. (c) Abe, H.; Ohtani, K.; Suzuki, D.; Chida, Y.; Shimada, Y.; Matsumoto, S.; Inouye, M. Org. Lett. 2014, 16, 828. (12) Perrin, C. L.; Dwyer, T. J. Chem. Rev. 1990, 90, 935. (13) (a) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38, 2978. (b) Mazik, M. Chem. Soc. Rev. 2009, 38, 935. (c) Sun, X.; James, T. D. Chem. Rev. 2015, 115, 8001. (d) Abe, H.; Chida, Y.; Kurokawa, H.; Inouye, M. J. Org. Chem. 2011, 76, 3366. (e) Mandal, P. K.; Kauffmann, B.; Destecroix, H.; Ferrand, Y.; Davis, A. P.; Huc, I. Chem. Commun. 2016, 52, 9355. (14) (a) Bindfit; www.supramolecular.org (accessed Jun 20, 2017). (b) Thordarson, P. Chem. Soc. Rev. 2011, 40, 1305. (15) The association constant could not be determined by 1H NMR titrations owing to the slow exchange between free species and complexes and to the overlapped complicated signals. (16) Gurst, J. E. J. Chem. Educ. 1991, 68, 1003. The ratio of two anomers was measured after the solution was allowed to stand for 12 h at room temperature. (17) (a) Gessler, K.; Krauss, N.; Steiner, T.; Betzel, C.; Sarko, A.; Saenger, W. J. Am. Chem. Soc. 1995, 117, 11397. (b) Yates, J. R.; Pham, T. N.; Pickard, C. J.; Mauri, F.; Amado, A. M.; Gil, A. M.; Brown, S. P. J. Am. Chem. Soc. 2005, 127, 10216. (18) Mahadevi, A. S.; Sastry, G. N. Chem. Rev. 2016, 116, 2775. (19) (a) Mallory, F. B.; Baker, M. B. J. Org. Chem. 1984, 49, 1323. (b) Kleinpeter, E.; Klod, S. J. Am. Chem. Soc. 2004, 126, 2231.
the gas phase in comparison with the corresponding righthanded one (P) (Figure S19). In conclusion, we have demonstrated that an indolocarbazole−naphthyridine oligomer folds into a stable helical conformation. This new hybrid IN foldamer contains an internal hydrophilic cavity in which D-glucose is encapsulated with high affinity and selectivity compared to D-galactose and D-mannose. Thanks to the modularity and addressability of monomeric units in the foldamer strand, it is possible to develop foldamers that can encapsulate some saccharides selectively while affording characteristic optical signals in a more hydrophilic medium.
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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.orglett.7b02768. Syntheses and characterizations of new compounds, NMR, CD spectroscopy, computer modeling and X-ray crystallographic data for 2⊃4H2O (PDF) Crystallographic data for 2⊃4H2O (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hae-Geun Jeon: 0000-0002-0797-5148 Kyu-Sung Jeong: 0000-0003-1023-1796 Author Contributions †
J.Y.H. and H.-G.J. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2015R1A2A1A10053607). We acknowledge Pohang Accelerator Laboratory (PAL) for beamline use (2016-3rd-2D-020).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02768 Org. Lett. 2017, 19, 5625−5628
