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Inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5]arene subunits
Tetrahedron Letters 54 (2013) 5901–5906
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5]arene subunits Si-Zhe Li a, Ke Yang a, Hong-Bing Liu c, Yu-Xiang Xia a, Rong-Xiu Zhu b,⇑, Jun Luo a,⇑, Qian Wan a,⇑ a
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China Institute of Theoretical Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China c Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, PR China b
a r t i c l e
i n f o
Article history: Received 13 July 2013 Accepted 24 August 2013 Available online 2 September 2013 Keywords: Inherently chiral Biscalixarene Calixarene Optical resolution
a b s t r a c t Inherently chiral biscalixarenes with hetero-cavities were synthesized by a covalent assembly of p-tertbutylcalix[5]arene with a 1,3-substituted calix[4]arene via 1,3-alkylation reaction and subsequent desymmetrization. The racemates were resolved by chiral HPLC method. 1H NMR spectra, VT-NMR spectra, and theoretical calculations support that the calix[5]arene subunit of the inherently chiral calix[4][5]arene ester adopts a cone-in conformation, with the aromatic ring bearing the CH2CO2Et group tilting inward the calix[5]arene cavity. By contrast, such a cone-in structural feature of the calix[5]arene subunit disappears for the corresponding inherently chiral calix[4][5]arene carboxylic acid, due to the intramolecular hydrogen bonding between the carboxyl group and an ethereal oxygen of the glycolic chain. Ó 2013 Elsevier Ltd. All rights reserved.
Calixarenes are desirable molecular scaffolds for the construction of cavity-like functionalized molecules capable of molecular recognition and catalysis.1 Assembly of two or more calixarenes by covalent bonds leads to bis/multicalixarenes, which are expected to display intriguing properties because of their peculiar geometries and potential cooperative effects of the calixarene cavities. A variety of biscalixarenes and multicalixarenes with homo- and hetero-cavities have been synthesized.2,3 A pertinent and impressive work was the covalent linkage of a calix[5]arene with a calix[4]arene via four ethylene bridges by the base-catalyzed condensation reaction. The structural features of the resultant hetero-cavity calix[4][5]arene were investigated by X-ray crystallography and dynamic NMR studies.4 The concept of inherent chirality was first introduced by Böhmer to describe a peculiar chirality phenomenon occurring in calix[4]arenes in which chirality is not based on a chiral subunit but on the absence of a plane of symmetry or an inversion center in the molecules as a whole.5 This concept was soon accepted by researchers and further refined by Mandolini and Schiaffino.6 The most recent version of the definition was suggested by Szumna as ‘inherent chirality arises from the introduction of a curvature in an ideal planar structure that is devoid of perpendicular symmetry planes in its bidimensional representation’.7 Nowadays, a wide variety of concave molecule-based inherently chiral species, including calixarenes,8 resorcinarenes,9 heteracalixaromatics,10 ⇑ Corresponding authors. Tel.: +86 27 83650537. E-mail addresses: [email protected] (R.-X. Zhu), [email protected] (J. Luo), [email protected] (Q. Wan). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.08.091
cyclotriveratrylenes,11 and so on,7 have been prepared and in some cases have showed excellent chiral recognition and asymmetric catalytic abilities. Inherent chirality element can also be added to concave molecules consisting of repeating chiral subunits such as cyclodextrins, as was demonstrated by Sollogoub’s work.12 The endowment of inherent chirality to bis/multicalixarenes may offer more opportunities to exert their functions in fields such as chiral recognition and asymmetric catalysis.13,14 Chung’s group first designed and synthesized inherently chiral biscalix[4]arenes by covalent assembly of two calix[4]arene subunits in a 1,3-position linking with 1,2-position pattern at the narrow rims, followed by desymmetrization.13 Our group made further efforts to achieve the chemical resolution of a related inherently chiral biscalix[4]arene cone-partial cone conformer and studied its chiral recognition abilities toward chiral aminoalcohols.15 On the basis of our previous work on inherently chiral calixarenes,15–17 it is natural that we investigate the possibility of covalently assembling a calix[n P 5]arene with a calix[4]arene and endowing the resultant hetero-cavity biscalixarene with inherent chirality. Following considerations support our choice of calix[5]arene as a subunit: (1) the selective modification and conformational control of calix[5]arenes are tractable compared with calix[6]arenes and calix[8]arenes; (2) a calix[5]arene subunit, which contains a larger cavity than a calix[4]arene counterpart, may be advantageous during the recognition process.18 Herein we report on the synthesis and structural characterization of inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5] arene subunits.
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The synthetic pathway included two stages: covalent linkage of a calix[4]arene and a calix[5]arene building block to form a symmetrical calix[4][5]arene; desymmetrization of the resultant biscalixarene to generate inherently chiral species (Scheme 1). 1,3-Substituted calix[4]arene triethylene glycol ditosylate 113 (building block I) was reacted with p-tert-butylcalix[5]arene 2 (building block II) under alkaline conditions. In the presence of weak bases (CsF or K2CO3) under high dilution conditions (0.45 mmol of 2 per 100 mL of CH3CN), the desired calix[4][5]arene 3 consisting of a calix[4]arene subunit and a calix[5]arene subunit connected by two glycolic chains in the 1,3-position linking with 1,3-position pattern was efficiently produced, along with other complicated products.19 The use of CsF afforded higher yield (27%) than that of K2CO3 (12%). The calix[4][5]arene 3 was subjected to alkaline conditions for monoalkylation with ethyl bromoacetate. K2CO3 as a base did not provide the expected product (Table 1, entry 1). By contrast, CsF
Table 1 Reaction conditions and product distribution for the monoalkylation of calix[4][5]arene 3 with ethyl bromoacetate (1.2 equiv) Entry
1a 2b 3 4c 5e 6f a b c d e f
Base (equiv)
K2CO3 (10) CsF (2) CsF (4) CsF (4) CsF (4) CsF (2)
Solvent
DMF THF THF THF CH3CN CH3CN
Temperature
70 °C Reflux Reflux Reflux 70 °C Reflux
Time (d)
3 2 3 5 5 2
Isolated yield 4
5
Trace — Trace 10% 16% 20%
— 23% 33% —d 25% 51%
Very complicated products, with large amounts of 3 remained. 56% of 3 recovered. 13% of 3 recovered. Compound 6 (as hydrolysate of 5) isolated in 57% yield. 22% of 3 recovered. 8% of 3 recovered.
Scheme 1. Synthesis of inherently chiral calix[4][5]arenes. Reagents and conditions: (i) base/CH3CN, reflux, 3 d, 27% (CsF as a base) and 12% (K2CO3 as a base); (ii) BrCH2CO2Et, CsF/CH3CN, reflux, 2 d, 20% (4), 51% ((±)-5); (iii) NaOH/H2O–THF, reflux, 3 h, 99%.
S.-Z. Li et al. / Tetrahedron Letters 54 (2013) 5901–5906
Figure 1. Resolution of inherently chiral calix[4][5]arenes by HPLC method with Chiralpak IC column: (a) (±)-5 (n-hexane/2-propanol = 90/10, v/v; 1.0 mL/min), (b) (±)-6 (n-hexane/ethanol/HOAc = 95/5/0.3, v/v/v; 0.5 mL/min).
proved to be efficient in the formation of the monoalkylation products. Using CsF (2–4 equiv) as a base and THF as a solvent, one of the two proximal hydroxyl groups of 3 could be alkylated to
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produce the inherently chiral calix[4][5]arene 5 as racemates in moderate yields of 23–33% (Table 1, entries 2 and 3). Elongation of reaction time led to higher conversion and the formation of the regioisomer 4, which was the product of 3 alkylated at the isolated hydroxyl group and is therefore achiral. However, under this condition, the inherently chiral calix[4][5]arene 5 was completely hydrolyzed to its corresponding carboxylic acid 6 due to the presence of small amounts of H2O in THF and relatively high equiv of CsF (4 equiv) (Table 1, entry 4). A change of the solvent to CH3CN enhanced the isolated yields of 4 and 5 (Table 1, entry 5). Eventually, under the optimal condition, 4 and 5 could be obtained in respective yields of 20% and 51% (Table 1, entry 6). Inherently chiral calix[4][5]arene ester 5 was hydrolyzed into its corresponding acid 6 in 99% yield. Chemical resolution of (±)- 6 was attempted using (S)-BINOL and (R)-phenylethylamine as chiral auxiliaries. However, the diastereomers formed by condensation reaction could not be separated into two isolated spots even on analytic TLC plates after several runs of developments with various development solvent systems. Alternatively, racemic calix[4][5]arene ester 5 and acid 6 could be resolved via HPLC method using DAICEL Chiralpak IC column (Fig. 1). NMR spectroscopy is very helpful to the identification of the structures and discrimination of regioisomers. The biscalix[4]arenes reported previously and the calix[4][5]arenes reported herein have a common calix[4]arene subunit.13,15 A comparison of the 1 H NMR spectra of all the biscalixarenes reported previously and
Figure 2. Partial 1H NMR spectra (8.0–6.0 ppm, 3.6–3.0 ppm, and 1.5–0.1 ppm regions) of biscalixarenes 3–6 (CDCl3, 400 MHz, 25 °C): (a) 3; (b) 4; (c) (±)-5; (d) (±)-6. Regions were plotted on different scales. In traces (a–d), structurally diagnostic resonances were marked, in which ‘a’ represents ArH resonance(s) of the calix[4]arene subunit, ‘b’ represents equatorial ArCH2Ar resonances of the calix[5]arene subunit, ‘c’ represents equatorial ArCH2Ar resonances of the calix[4]arene subunit, ‘d’ represents C(CH3)3 resonances, and ‘e’ represents the shielded ArH resonances of the calix[5]arene subunit.
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Figure 3. Partial Variable-Temperature 1H NMR spectra (d6-DMSO,1.5–0.2 ppm region) of calix[4][5]arene (±)-6 (traces (a–c): 400 MHz; traces (d–h): 600 MHz).
herein revealed that the calix[4]arene subunits in discussion adopt pinched cone conformation in all cases, as is clearly indicated by the ArH resonances at ca. 7.2 ppm (4H) and 6.5 ppm (4H). These ArH resonances, together with the equatorial ArCH2Ar resonances at ca. 3.2–3.0 ppm (4H in total) and the tert-butyl protons all at d > 0.8 ppm attributable to the pinched cone calix[4]arene subunit are quite steady and barely influenced by the presence of the other calixarene subunit. This judgment facilitates the assignment of certain diagnostic signals in the calix[5]arene subunit of the calix[4][5]arenes. All the calix[4][5]arenes 3–6 adopt cone–cone conformations, as are suggested by the ArCH2Ar carbon resonances appearing at ca. 29–31 ppm in all cases (see Supplementary data). The structural evidence of the achiral calix[4][5]arene precursor 3 includes 3 doublets (d 3.41, 3.40 and 3.39 ppm in a 1:2:2 integration ratio, J = 13.6–14.0 Hz) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 6 singlets (d 1.32, 1.31, 1.27, 1.06, 0.84 and 0.83 ppm for 9H, 18H, 18H, 18H, 9H, 9H, respectively) for the 9 tert-butyl groups, and 8 peaks (d 77.7, 77.6, 74.9, 72.1, 71.3, 71.0, 70.2, 69.8 ppm) for the OCH2CH2O and ArOCH2CH2CH3 (14 carbons in total) carbon signals, which are consistent with its symmetry. The OH signals (d 7.79 ppm, 2H; d 7.16 ppm, 1H; exchangeable with D2O) definitely corroborate the 1,3-substitution pattern of the calix[5]arene subunit (Fig. 2, trace a).20 Monoalkylation of 3 led to the formation of two regioisomers 4 and 5. The achiral isomer 4 shows a singlet (d 7.54 ppm, 2H; exchangeable with D2O) for the two hydroxyl hydrogens, 3 doublets (d 3.43, 3.38 and 3.33 ppm in a 2:1:2 integration ratio,
J = 14.0–15.2 Hz) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 6 singlets (d 1.30, 1.27, 1.22, 0.83, 0.82 and 0.45 ppm for 18H, 18H, 18H, 9H, 9H, 9H, respectively) for the 9 tert-butyl groups and these are in agreement with its symmetry and achiral structure. Noticeably, in its 1H NMR spectrum, a tertbutyl signal (d 0.45 ppm, singlet, 9H) and a ArH signal (d 6.27 ppm, singlet, 2H) appear at high fields, indicating that they suffered significant shielding effect. This tert-butyl and the two aromatic protons belong to the aromatic ring alkylated by ethyl bromoacetate according to molecular symmetry and the integration values (Fig. 2, trace b). It is plausible that this alkylated aromatic ring tilts inward the cavity formed by the other four aromatic rings of the calix[5]arene subunit due to its inability to maintain initial conformation via hydrogen bonding (formed by the phenolic hydroxyl with a proximal oxygen atom as in 3), and the steric hindrance of the newly introduced CH2CO2Et group. Therefore the calix[5]arene subunit of 4 adopts a cone-in conformation.21 The inherently chiral regioisomer 5 shows two singlets (d 7.21, 6.51 ppm; exchangeable with D2O) for the two hydroxyl hydrogens, 5 doublets (d 3.43, 3.41, 3.39, 3.36 and 3.28 ppm, 1H each, J = 14.0–16.0 Hz, slightly overlapped) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 9 singlets (d 1.34, 1.33, 1.32, 1.27, 1.23, 1.05, 0.819, 0.817 and 0.40 ppm, 9H each) for the 9 tert-butyl groups. This observation is in line with its asymmetrical structure. Likewise, the tert-butyl proton signals appearing at d 0.40 ppm (singlet, 9H), together with the ArH proton signals
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Figure 4. The calculated lowest-lying conformers of 5 and 6 at DFT-B3LYP/6-31g(d) level. Hydrogen atoms are omitted for clarity.
appearing at d 6.32 (d, 1H, J = 2.0 Hz) and 6.24 (d, 1H, J = 2.0 Hz) indicates that the calix[5]arene subunit of 5 also adopts a cone-in conformation (Fig. 2, trace c). Interestingly, the corresponding signals in discussion concomitantly downfield shift to d > 0.8 ppm (for tert-butyl) and d >7.0 ppm (for ArH) in acid 6, indicating that hydrolysis causes a common cone conformation (Fig. 2, trace d). We speculate that this conformational adjustment is induced by the formation of an intramolecular hydrogen bond between the carboxyl group and an oxygen atom of the glycolic chain in 6. To verify the relationship between intramolecular hydrogen bonding and the conformational change, we conducted a VT-NMR experiment (in DMSO-d6) for inherently chiral calix[4][5]arene acid (±)-6. As is shown in Figure 3, accompanied with the rising of temperature, the resonance of a tert-butyl (9H) has a definite tendency to shift to high field (from d 0.99 ppm at 308 K to d 0.76 ppm at 413 K). Since the hydrogen bond is weakened by heat, this observation is consistent with our speculation that in the presence of such an intramolecular hydrogen bonding, the calix[5]arene subunittends to adopt a commoncone conformation, otherwise cone-in conformation is favored. We also turn to theoretical calculations for corroboration of the structural features of the inherently chiral calix[4][5]arenes 5 and 6.22Figure 4 shows the calculated lowest-lying conformers of 5 and 6 at DFT-B3LYP/6-31g(d) level. In the optimized geometry of 5, the aromatic ring bearing the ester group (ring A) slightly tilts inward the calix[5]arene cavity to avoid steric hindrance, the dihedral
angle between the ring A and the reference plane J (the mean plane containing the five methylene bridge carbons of the calix[5]arene subunit) being 83.98°. The dihedral angles between each of the other four aromatic rings of the calix[5]arene subunit (ring B–E) and plane J are all larger than 90° (Fig. 4, Table 2). There are two hydrogen bondings between O2 O3 (2.856 Å) and O4 O5 (2.784 Å), which contribute to maintaining such a cone-in conformation of the calix[5]arene subunit of 5. In the optimized geometry of 6, the ring A, which bears the carboxyl group, tilts outward the calix[5]arene cavity (dihedral angle of A/J = 118.60°). This is obviously facilitated by the hydrogen bonding between the carboxyl group and the glycolic chain (O15 O7 = 2.860 Å). There are also two hydrogen bondings between O2 O3 (2.757 Å) and O4 O5 (2.817 Å), which contribute to maintaining the cone conformation of the calix[5]arene subunit of 6. In addition, in the optimized geometry of 5 and 6, the calix[4]arene subunits adopt pinched cone conformation (Fig. 4, Table 2). In conclusion, we successfully synthesized inherently chiral biscalixarenes consisting of a calix[4]arene and a calix[5]arene subunits. The racemates were resolved via HPLC with Chiralpak IC column. 1H NMR, VT-NMR, and theoretical calculations verify that the calix[5]arene subunit of the inherently chiral biscalixarene ester adopts a cone-in conformation. However, after hydrolysis into corresponding carboxylic acid, the calix[5]arene subunit adopts a common cone conformation, owing to the formation of an intramolecular hydrogen bond between the carboxyl group
Table 2 Theoretical calculation results of the optimized geometries of 5 and 6 at DFT-B3LYP/6-31g(d) level Dihedral anglea
Structure
5 6
A/J
B/J
C/J
D/J
E/J
F/K
G/K
H/K
I/K
J/K
83.98 118.60
148.37 135.79
97.81 93.28
139.45 148.00
131.97 95.25
93.41 93.04
137.76 138.52
88.33 95.86
142.54 136.33
49.03 20.13
a A, B, C, D, and E represent the aromatic rings consisting of the calix[5]arene subunit. F, G, H, and I represent the aromatic rings consisting of the calix[4]arene subunit. J represents the mean plane containing the five methylene bridge carbons of the calix[5]arene subunit. K represents the mean plane containing the four methylene bridge carbons of the calix[4]arene subunit.
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and a glycolic oxygen atom. Much more effort has to be made for better understanding of the structures and properties of such geometrically interesting inherently chiral biscalixarenes. 9.
Acknowledgments We are grateful to the National Natural Science Foundation of China (No. 20902029) and the Fundamental Research Funds for the Central Universities (HUST: No. 2012QN009) for financial support. We also thank the Analytical and Testing Center of Huazhong University of Science and Technology for measurement service.
10.
Supplementary data Supplementary data (experimental procedures, NMR spectra of new compounds, resolution facts of (±)-5 and (±)-6 by chiral HPLC, and theoretical calculations) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.091. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Gutsche, C. D. Calixarenes—an Introduction In Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cambridge, 2008; Vol. 6,. 2nd ed.. 2. Zheng, Q.; Gong, S.; Zhang, C.; Wang, W.; Chen, Y. Prog. Chem. 2007, 19, 722. 3. (a) Saadioui, M.; Böhmer, V. In Calixarenes 2001; Asfari, Z., Böhmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001; Vol. 3, p 130. 2nd ed. Chapter 7; (b) Cheriaa, N.; Mahouachi, M.; Othman, A. B.; Baklouti, L.; Abidi, R.; Kim, J. S.; Kim, Y.; Harrowfield, J.; Vicens, J. In Calixarenes in the Nanoworld; Vicens, J., Harrowfield, J., Eds.; Springer, 2007; p 89. Chapter 5. 4. Notti, A.; Occhipinti, S.; Pappalardo, S.; Parisi, M. F.; Pisagatti, I.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2002, 67, 7569. 5. Böhmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion Phenom. Mol. Recognit. Chem. 1994, 19, 17. 6. Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. New. New J. Chem. 2004, 28, 1198. 7. Szumna, A. Chem. Soc. Rev. 2010, 39, 4274. 8. (a) Xu, Z.-X.; Zhang, C.; Huang, Z.-T.; Chen, C.-F. Chin. Sci. Bull. 2010, 55, 2859; (b) Xu, Z.-X.; Huang, Z.-T.; Chen, C.-F. Tetrahedron Lett. 2009, 50, 5430; (c) Xu, Z.-X.; Li, G.-K.; Chen, C.-F.; Huang, Z.-T. Tetrahedron 2008, 64, 8668; (d) Xu, Z.X.; Zhang, C.; Yang, Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2008, 10, 477; (e) Xu, Z.-X.; Zhang, C.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2007, 9, 4447; (f) Li, S.-Y.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron: Asymmetry 2005, 16, 641; (g) Karpus, A. O.; Yesypenko, O. A.; Andronov, L. P.; Boyko, V. I.; Garasevich, S. G.; Voitenko, Z. V.; Chernega, A. N.; Kalchenko, V. I. Tetrahedron: Asymmetry 2012, 23, 1243; (h) Slavik, P.; Dudic, M.; Flidrova, K.; Sykora, J.; Cisarova, I.; Böhm, S.; Lhotak, P. Org. Lett. 2012, 14, 3628; (i) Troisi, F.; Pierro, T.; Gaeta, C.; Carratù, M.; Neri, P. Tetrahedron Lett. 2009, 50, 4416; (j) Shirakawa, S.; Shimizu, S. New J. Chem. 2010, 12, 1916; (k) Ciaccia, M.; Tosi, I.; Cacciapaglia, R.; Casnati, A.; Baldini, L.; Di Stefano, S. Org. Biomol. Chem. 2013, 11, 3642; (l)
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Kundrat, O.; Kroupa, J.; Böhm, S.; Budka, J.; Eigner, V.; Lhotak, P. J. Org. Chem. 2010, 75, 8372; (m) Herbert, S. A.; Arnott, G. E. Org. Lett. 2010, 12, 4600; (n) Herbert, S. A.; Arnott, G. E. Org. Lett. 2009, 11, 4986; (o) Colasson, B.; Reinaud, O. J. Am. Chem. Soc. 2008, 130, 15226. (a) Vachon, J.; Harthong, S.; Dubessy, B.; Dutasta, J.-P.; Vanthuyne, N.; Roussel, C.; Naubron, J.-V. Tetrahedron: Asymmetry 2010, 21, 1534; (b) Kuberski, B.; Pecul, M.; Szumna, A. Eur. J. Org. Chem. 2008, 3069; (c) Wiegmann, S.; Neumann, B.; Stammler, H.-G.; Mattay, J. Eur. J. Org. Chem. 2012, 3955; (d) Wiegmann, S.; Mattay, J. Org. Lett. 2011, 13, 3226; (e) Paletta, M.; Klaes, M.; Neumann, B.; Stammler, H.-G.; Grimme, S.; Mattay, J. Eur. J. Org. Chem. 2008, 555; (f) Vachon, J.; Harthong, S.; Jeanneau, E.; Aronica, C.; Vanthuyne, N.; Roussel, C.; Dutasta, J.-P. Org. Biomol. Chem. 2011, 9, 5086; (g) Wiegmann, S.; Fukuhara, G.; Neumann, B.; Stammler, H.-G.; Inoue, Y.; Mattay, J. Eur. J. Org. Chem. 2013, 1240. (a) Pan, S.; Wang, D.-X.; Zhao, L.; Wang, M.-X. Org. Lett. 2012, 14, 6254; (b) Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Wang, M.-X. Tetrahedron 2007, 63, 10801; (c) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2009, 74, 5361; (d) Katz, J. L.; Tschaen, B. A. Org. Lett. 2010, 12, 4300; (e) Bizier, N. P.; Vernamonti, J. P.; Katz, J. L. Eur. J. Org. Chem. 2012, 2303; (f) Raimundo, J.-M.; Chen, Z.; Siri, O. Chem. Commun. 2011, 10410; (g) Ishibashi, K.; Tsue, H.; Takahashi, H.; Tamura, R. Tetrahedron: Asymmetry 2009, 20, 375. (a) Yu, J.-T.; Huang, Z.-T.; Zheng, Q.-Y. Org. Biomol. Chem. 2012, 10, 1359; (b) Perraud, O.; Martinez, A.; Dutasta, J.-P. Chem. Commun. 2011, 5861; (c) Perraud, O.; Raytchev, P. D.; Martinez, A.; Dutasta, J.-P. Chirality 2010, 22, 885; (d) Payet, E.; Dimitrov-Raytchev, P.; Chatelet, B.; Guy, L.; Grass, S.; Lacour, J.; Dutasta, J.P.; Martinez, A. Chirality 2012, 24, 1077; (e) Bouchet, A.; Brotin, T.; Linares, M.; Ågren, H.; Cavagnat, D.; Buffeteau, T. J. Org. Chem. 2011, 76, 4178. Guieu, S.; Zaborova, E.; Blériot, Y.; Poli, G.; Jutand, A.; Madec, D.; Prestat, G.; Sollogoub, M. Angew. Chem., Int. Ed. 2010, 49, 2314. Luo, J.; Shen, L.-C.; Chung, W.-S. J. Org. Chem. 2010, 75, 464. Zheng, Y.-S.; Luo, J. J. Inclusion Phenom. Macrocycl. Chem. 2011, 71, 35. Li, S.-Z.; Shi, J.; Yang, K.; Luo, J. Tetrahedron 2012, 68, 8557. Xia, Y.-X.; Zhou, H.-H.; Shi, J.; Li, S.-Z.; Zhang, M.; Luo, J.; Xiang, G.-Y. J. Incl. Phenom. Macrocycl. Chem. 2012, 74, 277. Shi, J.; Li, S.-Z.; Xia, Y.-X.; Wang, X.-G.; Luo, J.; Wan, Q. J. Incl. Phenom. Macrocycl. Chem. doi: http://dx.doi.org/10.1007/s10847-012-0250-5. Notti, A.; Parisi, M. F.; Pappalardo, S. In Calixarenes 2001; Asfari, Z., Böhmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001; p 54. Chapter 3. Analytic TLC indicates that the products are rather complicated. After careful chromatography, we could also isolate another product (ca. 25% yield). However, we could not unambiguously determine its structure at present, though partial evidence supported it is probably the 1,2-substitution isomer. In the 1,2-substitution pattern of the calix[5]arene subunit, the resonances of the three contiguous OH groups are expected to appear at lower field than the 1,3-substitution pattern, as a broad singlet with d >8.0 ppm, or two broad singlets in a 1:2 ratio with the central 1 OH resonance appearing at lower field than the two flanking OHs due to the strong intramolecular hydrogen bonding. By contrast, in the 1,3-substitution pattern of the calix[5]arene subunit, the resonances of the two proximal OHs are expected to appear at lower field than that of the ‘isolated’ 1 OH. This argument has been commonly applied to the assignment of the substitution patterns of calix[5]crowns, see : (a) Ref. 4; (b) Kraft, D.; Arnecke, R.; Böhmer, V.; Vogt, W. Tetrahedron 1993, 49, 6019; (c) Pappalardo, S.; Ferguson, G. J. Org. Chem. 1996, 61, 2407. Gattuso, G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Pilati, T.; Terraneo, G. CrystEngComm 2012, 14, 2621. For details, see Supplementary data.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5]arene subunits Si-Zhe Li a, Ke Yang a, Hong-Bing Liu c, Yu-Xiang Xia a, Rong-Xiu Zhu b,⇑, Jun Luo a,⇑, Qian Wan a,⇑ a
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China Institute of Theoretical Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China c Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, PR China b
a r t i c l e
i n f o
Article history: Received 13 July 2013 Accepted 24 August 2013 Available online 2 September 2013 Keywords: Inherently chiral Biscalixarene Calixarene Optical resolution
a b s t r a c t Inherently chiral biscalixarenes with hetero-cavities were synthesized by a covalent assembly of p-tertbutylcalix[5]arene with a 1,3-substituted calix[4]arene via 1,3-alkylation reaction and subsequent desymmetrization. The racemates were resolved by chiral HPLC method. 1H NMR spectra, VT-NMR spectra, and theoretical calculations support that the calix[5]arene subunit of the inherently chiral calix[4][5]arene ester adopts a cone-in conformation, with the aromatic ring bearing the CH2CO2Et group tilting inward the calix[5]arene cavity. By contrast, such a cone-in structural feature of the calix[5]arene subunit disappears for the corresponding inherently chiral calix[4][5]arene carboxylic acid, due to the intramolecular hydrogen bonding between the carboxyl group and an ethereal oxygen of the glycolic chain. Ó 2013 Elsevier Ltd. All rights reserved.
Calixarenes are desirable molecular scaffolds for the construction of cavity-like functionalized molecules capable of molecular recognition and catalysis.1 Assembly of two or more calixarenes by covalent bonds leads to bis/multicalixarenes, which are expected to display intriguing properties because of their peculiar geometries and potential cooperative effects of the calixarene cavities. A variety of biscalixarenes and multicalixarenes with homo- and hetero-cavities have been synthesized.2,3 A pertinent and impressive work was the covalent linkage of a calix[5]arene with a calix[4]arene via four ethylene bridges by the base-catalyzed condensation reaction. The structural features of the resultant hetero-cavity calix[4][5]arene were investigated by X-ray crystallography and dynamic NMR studies.4 The concept of inherent chirality was first introduced by Böhmer to describe a peculiar chirality phenomenon occurring in calix[4]arenes in which chirality is not based on a chiral subunit but on the absence of a plane of symmetry or an inversion center in the molecules as a whole.5 This concept was soon accepted by researchers and further refined by Mandolini and Schiaffino.6 The most recent version of the definition was suggested by Szumna as ‘inherent chirality arises from the introduction of a curvature in an ideal planar structure that is devoid of perpendicular symmetry planes in its bidimensional representation’.7 Nowadays, a wide variety of concave molecule-based inherently chiral species, including calixarenes,8 resorcinarenes,9 heteracalixaromatics,10 ⇑ Corresponding authors. Tel.: +86 27 83650537. E-mail addresses: [email protected] (R.-X. Zhu), [email protected] (J. Luo), [email protected] (Q. Wan). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.08.091
cyclotriveratrylenes,11 and so on,7 have been prepared and in some cases have showed excellent chiral recognition and asymmetric catalytic abilities. Inherent chirality element can also be added to concave molecules consisting of repeating chiral subunits such as cyclodextrins, as was demonstrated by Sollogoub’s work.12 The endowment of inherent chirality to bis/multicalixarenes may offer more opportunities to exert their functions in fields such as chiral recognition and asymmetric catalysis.13,14 Chung’s group first designed and synthesized inherently chiral biscalix[4]arenes by covalent assembly of two calix[4]arene subunits in a 1,3-position linking with 1,2-position pattern at the narrow rims, followed by desymmetrization.13 Our group made further efforts to achieve the chemical resolution of a related inherently chiral biscalix[4]arene cone-partial cone conformer and studied its chiral recognition abilities toward chiral aminoalcohols.15 On the basis of our previous work on inherently chiral calixarenes,15–17 it is natural that we investigate the possibility of covalently assembling a calix[n P 5]arene with a calix[4]arene and endowing the resultant hetero-cavity biscalixarene with inherent chirality. Following considerations support our choice of calix[5]arene as a subunit: (1) the selective modification and conformational control of calix[5]arenes are tractable compared with calix[6]arenes and calix[8]arenes; (2) a calix[5]arene subunit, which contains a larger cavity than a calix[4]arene counterpart, may be advantageous during the recognition process.18 Herein we report on the synthesis and structural characterization of inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5] arene subunits.
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The synthetic pathway included two stages: covalent linkage of a calix[4]arene and a calix[5]arene building block to form a symmetrical calix[4][5]arene; desymmetrization of the resultant biscalixarene to generate inherently chiral species (Scheme 1). 1,3-Substituted calix[4]arene triethylene glycol ditosylate 113 (building block I) was reacted with p-tert-butylcalix[5]arene 2 (building block II) under alkaline conditions. In the presence of weak bases (CsF or K2CO3) under high dilution conditions (0.45 mmol of 2 per 100 mL of CH3CN), the desired calix[4][5]arene 3 consisting of a calix[4]arene subunit and a calix[5]arene subunit connected by two glycolic chains in the 1,3-position linking with 1,3-position pattern was efficiently produced, along with other complicated products.19 The use of CsF afforded higher yield (27%) than that of K2CO3 (12%). The calix[4][5]arene 3 was subjected to alkaline conditions for monoalkylation with ethyl bromoacetate. K2CO3 as a base did not provide the expected product (Table 1, entry 1). By contrast, CsF
Table 1 Reaction conditions and product distribution for the monoalkylation of calix[4][5]arene 3 with ethyl bromoacetate (1.2 equiv) Entry
1a 2b 3 4c 5e 6f a b c d e f
Base (equiv)
K2CO3 (10) CsF (2) CsF (4) CsF (4) CsF (4) CsF (2)
Solvent
DMF THF THF THF CH3CN CH3CN
Temperature
70 °C Reflux Reflux Reflux 70 °C Reflux
Time (d)
3 2 3 5 5 2
Isolated yield 4
5
Trace — Trace 10% 16% 20%
— 23% 33% —d 25% 51%
Very complicated products, with large amounts of 3 remained. 56% of 3 recovered. 13% of 3 recovered. Compound 6 (as hydrolysate of 5) isolated in 57% yield. 22% of 3 recovered. 8% of 3 recovered.
Scheme 1. Synthesis of inherently chiral calix[4][5]arenes. Reagents and conditions: (i) base/CH3CN, reflux, 3 d, 27% (CsF as a base) and 12% (K2CO3 as a base); (ii) BrCH2CO2Et, CsF/CH3CN, reflux, 2 d, 20% (4), 51% ((±)-5); (iii) NaOH/H2O–THF, reflux, 3 h, 99%.
S.-Z. Li et al. / Tetrahedron Letters 54 (2013) 5901–5906
Figure 1. Resolution of inherently chiral calix[4][5]arenes by HPLC method with Chiralpak IC column: (a) (±)-5 (n-hexane/2-propanol = 90/10, v/v; 1.0 mL/min), (b) (±)-6 (n-hexane/ethanol/HOAc = 95/5/0.3, v/v/v; 0.5 mL/min).
proved to be efficient in the formation of the monoalkylation products. Using CsF (2–4 equiv) as a base and THF as a solvent, one of the two proximal hydroxyl groups of 3 could be alkylated to
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produce the inherently chiral calix[4][5]arene 5 as racemates in moderate yields of 23–33% (Table 1, entries 2 and 3). Elongation of reaction time led to higher conversion and the formation of the regioisomer 4, which was the product of 3 alkylated at the isolated hydroxyl group and is therefore achiral. However, under this condition, the inherently chiral calix[4][5]arene 5 was completely hydrolyzed to its corresponding carboxylic acid 6 due to the presence of small amounts of H2O in THF and relatively high equiv of CsF (4 equiv) (Table 1, entry 4). A change of the solvent to CH3CN enhanced the isolated yields of 4 and 5 (Table 1, entry 5). Eventually, under the optimal condition, 4 and 5 could be obtained in respective yields of 20% and 51% (Table 1, entry 6). Inherently chiral calix[4][5]arene ester 5 was hydrolyzed into its corresponding acid 6 in 99% yield. Chemical resolution of (±)- 6 was attempted using (S)-BINOL and (R)-phenylethylamine as chiral auxiliaries. However, the diastereomers formed by condensation reaction could not be separated into two isolated spots even on analytic TLC plates after several runs of developments with various development solvent systems. Alternatively, racemic calix[4][5]arene ester 5 and acid 6 could be resolved via HPLC method using DAICEL Chiralpak IC column (Fig. 1). NMR spectroscopy is very helpful to the identification of the structures and discrimination of regioisomers. The biscalix[4]arenes reported previously and the calix[4][5]arenes reported herein have a common calix[4]arene subunit.13,15 A comparison of the 1 H NMR spectra of all the biscalixarenes reported previously and
Figure 2. Partial 1H NMR spectra (8.0–6.0 ppm, 3.6–3.0 ppm, and 1.5–0.1 ppm regions) of biscalixarenes 3–6 (CDCl3, 400 MHz, 25 °C): (a) 3; (b) 4; (c) (±)-5; (d) (±)-6. Regions were plotted on different scales. In traces (a–d), structurally diagnostic resonances were marked, in which ‘a’ represents ArH resonance(s) of the calix[4]arene subunit, ‘b’ represents equatorial ArCH2Ar resonances of the calix[5]arene subunit, ‘c’ represents equatorial ArCH2Ar resonances of the calix[4]arene subunit, ‘d’ represents C(CH3)3 resonances, and ‘e’ represents the shielded ArH resonances of the calix[5]arene subunit.
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Figure 3. Partial Variable-Temperature 1H NMR spectra (d6-DMSO,1.5–0.2 ppm region) of calix[4][5]arene (±)-6 (traces (a–c): 400 MHz; traces (d–h): 600 MHz).
herein revealed that the calix[4]arene subunits in discussion adopt pinched cone conformation in all cases, as is clearly indicated by the ArH resonances at ca. 7.2 ppm (4H) and 6.5 ppm (4H). These ArH resonances, together with the equatorial ArCH2Ar resonances at ca. 3.2–3.0 ppm (4H in total) and the tert-butyl protons all at d > 0.8 ppm attributable to the pinched cone calix[4]arene subunit are quite steady and barely influenced by the presence of the other calixarene subunit. This judgment facilitates the assignment of certain diagnostic signals in the calix[5]arene subunit of the calix[4][5]arenes. All the calix[4][5]arenes 3–6 adopt cone–cone conformations, as are suggested by the ArCH2Ar carbon resonances appearing at ca. 29–31 ppm in all cases (see Supplementary data). The structural evidence of the achiral calix[4][5]arene precursor 3 includes 3 doublets (d 3.41, 3.40 and 3.39 ppm in a 1:2:2 integration ratio, J = 13.6–14.0 Hz) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 6 singlets (d 1.32, 1.31, 1.27, 1.06, 0.84 and 0.83 ppm for 9H, 18H, 18H, 18H, 9H, 9H, respectively) for the 9 tert-butyl groups, and 8 peaks (d 77.7, 77.6, 74.9, 72.1, 71.3, 71.0, 70.2, 69.8 ppm) for the OCH2CH2O and ArOCH2CH2CH3 (14 carbons in total) carbon signals, which are consistent with its symmetry. The OH signals (d 7.79 ppm, 2H; d 7.16 ppm, 1H; exchangeable with D2O) definitely corroborate the 1,3-substitution pattern of the calix[5]arene subunit (Fig. 2, trace a).20 Monoalkylation of 3 led to the formation of two regioisomers 4 and 5. The achiral isomer 4 shows a singlet (d 7.54 ppm, 2H; exchangeable with D2O) for the two hydroxyl hydrogens, 3 doublets (d 3.43, 3.38 and 3.33 ppm in a 2:1:2 integration ratio,
J = 14.0–15.2 Hz) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 6 singlets (d 1.30, 1.27, 1.22, 0.83, 0.82 and 0.45 ppm for 18H, 18H, 18H, 9H, 9H, 9H, respectively) for the 9 tert-butyl groups and these are in agreement with its symmetry and achiral structure. Noticeably, in its 1H NMR spectrum, a tertbutyl signal (d 0.45 ppm, singlet, 9H) and a ArH signal (d 6.27 ppm, singlet, 2H) appear at high fields, indicating that they suffered significant shielding effect. This tert-butyl and the two aromatic protons belong to the aromatic ring alkylated by ethyl bromoacetate according to molecular symmetry and the integration values (Fig. 2, trace b). It is plausible that this alkylated aromatic ring tilts inward the cavity formed by the other four aromatic rings of the calix[5]arene subunit due to its inability to maintain initial conformation via hydrogen bonding (formed by the phenolic hydroxyl with a proximal oxygen atom as in 3), and the steric hindrance of the newly introduced CH2CO2Et group. Therefore the calix[5]arene subunit of 4 adopts a cone-in conformation.21 The inherently chiral regioisomer 5 shows two singlets (d 7.21, 6.51 ppm; exchangeable with D2O) for the two hydroxyl hydrogens, 5 doublets (d 3.43, 3.41, 3.39, 3.36 and 3.28 ppm, 1H each, J = 14.0–16.0 Hz, slightly overlapped) for the 5 equatorial ArCH2Ar hydrogens of the calix[5]arene subunit, 9 singlets (d 1.34, 1.33, 1.32, 1.27, 1.23, 1.05, 0.819, 0.817 and 0.40 ppm, 9H each) for the 9 tert-butyl groups. This observation is in line with its asymmetrical structure. Likewise, the tert-butyl proton signals appearing at d 0.40 ppm (singlet, 9H), together with the ArH proton signals
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Figure 4. The calculated lowest-lying conformers of 5 and 6 at DFT-B3LYP/6-31g(d) level. Hydrogen atoms are omitted for clarity.
appearing at d 6.32 (d, 1H, J = 2.0 Hz) and 6.24 (d, 1H, J = 2.0 Hz) indicates that the calix[5]arene subunit of 5 also adopts a cone-in conformation (Fig. 2, trace c). Interestingly, the corresponding signals in discussion concomitantly downfield shift to d > 0.8 ppm (for tert-butyl) and d >7.0 ppm (for ArH) in acid 6, indicating that hydrolysis causes a common cone conformation (Fig. 2, trace d). We speculate that this conformational adjustment is induced by the formation of an intramolecular hydrogen bond between the carboxyl group and an oxygen atom of the glycolic chain in 6. To verify the relationship between intramolecular hydrogen bonding and the conformational change, we conducted a VT-NMR experiment (in DMSO-d6) for inherently chiral calix[4][5]arene acid (±)-6. As is shown in Figure 3, accompanied with the rising of temperature, the resonance of a tert-butyl (9H) has a definite tendency to shift to high field (from d 0.99 ppm at 308 K to d 0.76 ppm at 413 K). Since the hydrogen bond is weakened by heat, this observation is consistent with our speculation that in the presence of such an intramolecular hydrogen bonding, the calix[5]arene subunittends to adopt a commoncone conformation, otherwise cone-in conformation is favored. We also turn to theoretical calculations for corroboration of the structural features of the inherently chiral calix[4][5]arenes 5 and 6.22Figure 4 shows the calculated lowest-lying conformers of 5 and 6 at DFT-B3LYP/6-31g(d) level. In the optimized geometry of 5, the aromatic ring bearing the ester group (ring A) slightly tilts inward the calix[5]arene cavity to avoid steric hindrance, the dihedral
angle between the ring A and the reference plane J (the mean plane containing the five methylene bridge carbons of the calix[5]arene subunit) being 83.98°. The dihedral angles between each of the other four aromatic rings of the calix[5]arene subunit (ring B–E) and plane J are all larger than 90° (Fig. 4, Table 2). There are two hydrogen bondings between O2 O3 (2.856 Å) and O4 O5 (2.784 Å), which contribute to maintaining such a cone-in conformation of the calix[5]arene subunit of 5. In the optimized geometry of 6, the ring A, which bears the carboxyl group, tilts outward the calix[5]arene cavity (dihedral angle of A/J = 118.60°). This is obviously facilitated by the hydrogen bonding between the carboxyl group and the glycolic chain (O15 O7 = 2.860 Å). There are also two hydrogen bondings between O2 O3 (2.757 Å) and O4 O5 (2.817 Å), which contribute to maintaining the cone conformation of the calix[5]arene subunit of 6. In addition, in the optimized geometry of 5 and 6, the calix[4]arene subunits adopt pinched cone conformation (Fig. 4, Table 2). In conclusion, we successfully synthesized inherently chiral biscalixarenes consisting of a calix[4]arene and a calix[5]arene subunits. The racemates were resolved via HPLC with Chiralpak IC column. 1H NMR, VT-NMR, and theoretical calculations verify that the calix[5]arene subunit of the inherently chiral biscalixarene ester adopts a cone-in conformation. However, after hydrolysis into corresponding carboxylic acid, the calix[5]arene subunit adopts a common cone conformation, owing to the formation of an intramolecular hydrogen bond between the carboxyl group
Table 2 Theoretical calculation results of the optimized geometries of 5 and 6 at DFT-B3LYP/6-31g(d) level Dihedral anglea
Structure
5 6
A/J
B/J
C/J
D/J
E/J
F/K
G/K
H/K
I/K
J/K
83.98 118.60
148.37 135.79
97.81 93.28
139.45 148.00
131.97 95.25
93.41 93.04
137.76 138.52
88.33 95.86
142.54 136.33
49.03 20.13
a A, B, C, D, and E represent the aromatic rings consisting of the calix[5]arene subunit. F, G, H, and I represent the aromatic rings consisting of the calix[4]arene subunit. J represents the mean plane containing the five methylene bridge carbons of the calix[5]arene subunit. K represents the mean plane containing the four methylene bridge carbons of the calix[4]arene subunit.
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and a glycolic oxygen atom. Much more effort has to be made for better understanding of the structures and properties of such geometrically interesting inherently chiral biscalixarenes. 9.
Acknowledgments We are grateful to the National Natural Science Foundation of China (No. 20902029) and the Fundamental Research Funds for the Central Universities (HUST: No. 2012QN009) for financial support. We also thank the Analytical and Testing Center of Huazhong University of Science and Technology for measurement service.
10.
Supplementary data Supplementary data (experimental procedures, NMR spectra of new compounds, resolution facts of (±)-5 and (±)-6 by chiral HPLC, and theoretical calculations) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.091. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Gutsche, C. D. Calixarenes—an Introduction In Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cambridge, 2008; Vol. 6,. 2nd ed.. 2. Zheng, Q.; Gong, S.; Zhang, C.; Wang, W.; Chen, Y. Prog. Chem. 2007, 19, 722. 3. (a) Saadioui, M.; Böhmer, V. In Calixarenes 2001; Asfari, Z., Böhmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001; Vol. 3, p 130. 2nd ed. Chapter 7; (b) Cheriaa, N.; Mahouachi, M.; Othman, A. B.; Baklouti, L.; Abidi, R.; Kim, J. S.; Kim, Y.; Harrowfield, J.; Vicens, J. In Calixarenes in the Nanoworld; Vicens, J., Harrowfield, J., Eds.; Springer, 2007; p 89. Chapter 5. 4. Notti, A.; Occhipinti, S.; Pappalardo, S.; Parisi, M. F.; Pisagatti, I.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2002, 67, 7569. 5. Böhmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion Phenom. Mol. Recognit. Chem. 1994, 19, 17. 6. Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. New. New J. Chem. 2004, 28, 1198. 7. Szumna, A. Chem. Soc. Rev. 2010, 39, 4274. 8. (a) Xu, Z.-X.; Zhang, C.; Huang, Z.-T.; Chen, C.-F. Chin. Sci. Bull. 2010, 55, 2859; (b) Xu, Z.-X.; Huang, Z.-T.; Chen, C.-F. Tetrahedron Lett. 2009, 50, 5430; (c) Xu, Z.-X.; Li, G.-K.; Chen, C.-F.; Huang, Z.-T. Tetrahedron 2008, 64, 8668; (d) Xu, Z.X.; Zhang, C.; Yang, Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2008, 10, 477; (e) Xu, Z.-X.; Zhang, C.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2007, 9, 4447; (f) Li, S.-Y.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron: Asymmetry 2005, 16, 641; (g) Karpus, A. O.; Yesypenko, O. A.; Andronov, L. P.; Boyko, V. I.; Garasevich, S. G.; Voitenko, Z. V.; Chernega, A. N.; Kalchenko, V. I. Tetrahedron: Asymmetry 2012, 23, 1243; (h) Slavik, P.; Dudic, M.; Flidrova, K.; Sykora, J.; Cisarova, I.; Böhm, S.; Lhotak, P. Org. Lett. 2012, 14, 3628; (i) Troisi, F.; Pierro, T.; Gaeta, C.; Carratù, M.; Neri, P. Tetrahedron Lett. 2009, 50, 4416; (j) Shirakawa, S.; Shimizu, S. New J. Chem. 2010, 12, 1916; (k) Ciaccia, M.; Tosi, I.; Cacciapaglia, R.; Casnati, A.; Baldini, L.; Di Stefano, S. Org. Biomol. Chem. 2013, 11, 3642; (l)
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Kundrat, O.; Kroupa, J.; Böhm, S.; Budka, J.; Eigner, V.; Lhotak, P. J. Org. Chem. 2010, 75, 8372; (m) Herbert, S. A.; Arnott, G. E. Org. Lett. 2010, 12, 4600; (n) Herbert, S. A.; Arnott, G. E. Org. Lett. 2009, 11, 4986; (o) Colasson, B.; Reinaud, O. J. Am. Chem. Soc. 2008, 130, 15226. (a) Vachon, J.; Harthong, S.; Dubessy, B.; Dutasta, J.-P.; Vanthuyne, N.; Roussel, C.; Naubron, J.-V. Tetrahedron: Asymmetry 2010, 21, 1534; (b) Kuberski, B.; Pecul, M.; Szumna, A. Eur. J. Org. Chem. 2008, 3069; (c) Wiegmann, S.; Neumann, B.; Stammler, H.-G.; Mattay, J. Eur. J. Org. Chem. 2012, 3955; (d) Wiegmann, S.; Mattay, J. Org. Lett. 2011, 13, 3226; (e) Paletta, M.; Klaes, M.; Neumann, B.; Stammler, H.-G.; Grimme, S.; Mattay, J. Eur. J. Org. Chem. 2008, 555; (f) Vachon, J.; Harthong, S.; Jeanneau, E.; Aronica, C.; Vanthuyne, N.; Roussel, C.; Dutasta, J.-P. Org. Biomol. Chem. 2011, 9, 5086; (g) Wiegmann, S.; Fukuhara, G.; Neumann, B.; Stammler, H.-G.; Inoue, Y.; Mattay, J. Eur. J. Org. Chem. 2013, 1240. (a) Pan, S.; Wang, D.-X.; Zhao, L.; Wang, M.-X. Org. Lett. 2012, 14, 6254; (b) Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Wang, M.-X. Tetrahedron 2007, 63, 10801; (c) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2009, 74, 5361; (d) Katz, J. L.; Tschaen, B. A. Org. Lett. 2010, 12, 4300; (e) Bizier, N. P.; Vernamonti, J. P.; Katz, J. L. Eur. J. Org. Chem. 2012, 2303; (f) Raimundo, J.-M.; Chen, Z.; Siri, O. Chem. Commun. 2011, 10410; (g) Ishibashi, K.; Tsue, H.; Takahashi, H.; Tamura, R. Tetrahedron: Asymmetry 2009, 20, 375. (a) Yu, J.-T.; Huang, Z.-T.; Zheng, Q.-Y. Org. Biomol. Chem. 2012, 10, 1359; (b) Perraud, O.; Martinez, A.; Dutasta, J.-P. Chem. Commun. 2011, 5861; (c) Perraud, O.; Raytchev, P. D.; Martinez, A.; Dutasta, J.-P. Chirality 2010, 22, 885; (d) Payet, E.; Dimitrov-Raytchev, P.; Chatelet, B.; Guy, L.; Grass, S.; Lacour, J.; Dutasta, J.P.; Martinez, A. Chirality 2012, 24, 1077; (e) Bouchet, A.; Brotin, T.; Linares, M.; Ågren, H.; Cavagnat, D.; Buffeteau, T. J. Org. Chem. 2011, 76, 4178. Guieu, S.; Zaborova, E.; Blériot, Y.; Poli, G.; Jutand, A.; Madec, D.; Prestat, G.; Sollogoub, M. Angew. Chem., Int. Ed. 2010, 49, 2314. Luo, J.; Shen, L.-C.; Chung, W.-S. J. Org. Chem. 2010, 75, 464. Zheng, Y.-S.; Luo, J. J. Inclusion Phenom. Macrocycl. Chem. 2011, 71, 35. Li, S.-Z.; Shi, J.; Yang, K.; Luo, J. Tetrahedron 2012, 68, 8557. Xia, Y.-X.; Zhou, H.-H.; Shi, J.; Li, S.-Z.; Zhang, M.; Luo, J.; Xiang, G.-Y. J. Incl. Phenom. Macrocycl. Chem. 2012, 74, 277. Shi, J.; Li, S.-Z.; Xia, Y.-X.; Wang, X.-G.; Luo, J.; Wan, Q. J. Incl. Phenom. Macrocycl. Chem. doi: http://dx.doi.org/10.1007/s10847-012-0250-5. Notti, A.; Parisi, M. F.; Pappalardo, S. In Calixarenes 2001; Asfari, Z., Böhmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001; p 54. Chapter 3. Analytic TLC indicates that the products are rather complicated. After careful chromatography, we could also isolate another product (ca. 25% yield). However, we could not unambiguously determine its structure at present, though partial evidence supported it is probably the 1,2-substitution isomer. In the 1,2-substitution pattern of the calix[5]arene subunit, the resonances of the three contiguous OH groups are expected to appear at lower field than the 1,3-substitution pattern, as a broad singlet with d >8.0 ppm, or two broad singlets in a 1:2 ratio with the central 1 OH resonance appearing at lower field than the two flanking OHs due to the strong intramolecular hydrogen bonding. By contrast, in the 1,3-substitution pattern of the calix[5]arene subunit, the resonances of the two proximal OHs are expected to appear at lower field than that of the ‘isolated’ 1 OH. This argument has been commonly applied to the assignment of the substitution patterns of calix[5]crowns, see : (a) Ref. 4; (b) Kraft, D.; Arnecke, R.; Böhmer, V.; Vogt, W. Tetrahedron 1993, 49, 6019; (c) Pappalardo, S.; Ferguson, G. J. Org. Chem. 1996, 61, 2407. Gattuso, G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Pilati, T.; Terraneo, G. CrystEngComm 2012, 14, 2621. For details, see Supplementary data.