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Design and synthesis of novel tweezer anion receptors based on deoxycholic acid
Chinese Chemical Letters 18 (2007) 287–290 www.elsevier.com/locate/cclet
Design and synthesis of novel tweezer anion receptors based on deoxycholic acid Xing Li Liu a, Zhi Gang Zhao a,*, Shu Hua Chen b a
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China b The Faculty of Chemistry, Sichuan University, Chengdu 610064, China Received 24 November 2006
Abstract A novel type of molecular tweezer receptors based on deoxycholic acid has been designed and synthesized and their binding properties were examined by UV–vis spectral titration. These molecular tweezers showed a high selectivity toward FS over ClS, BrS, IS, AcOS, H2PO4S. # 2007 Zhi Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Molecular tweezers; Deoxycholic acid; Anion; Recognition
The development of artificial receptors for the detection of biologically relevant anions is an important challenge in modern bioorganic chemistry [1,2]. So far, the exploited basic strategies for the construction of anion-binding receptors are electrostatic interaction, hydrogen bonding, hydrophobicity, coordination to a metal ion, or combination of these interactions together. Among these noncovalent interactions, we have been interested in developing hydrogen bond-based neutral anion receptors. Owing to the relatively strong hydrogen bonding ability of urea and thiourea groups, a number of molecules possessing urea or thiourea groups have been designed as neutral receptors for various anions [3–5]. For strong and selective binding, these groups should be preorganized to complement the target anion and minimize intramolecular hydrogen bonding. One way to achieve this goal is to make receptors with urea or thiourea groups connected to rigid spacers. The steroid nucleus is one of the largest rigid and chiral ubiquitous natural compounds. Based on these preorganized structural characteristics, steroid cholic acid is an ideal building block for the construction of molecular tweezers. In this paper, we report the design and synthesis of a new series of molecular tweezers and their recognition properties toward various anions. The synthetic route is shown in Scheme 1. Deoxycholic acid was converted to methyl 3a,12a-dihydroxy-5b-cholano-24-ate following a reported procedure [6]. Methyl deoxycholate 2 was reacted with p-nitrobenzoyl chloride under microwave irradiation to give 3, which was reduced with SnCl22H2O in ethyl acetate to yield intermediate 4. 4 was reacted with the phenyl isocyanate or phenyl isothiocyanate to produce molecular tweezer 5a or 5b. The reaction conditions significantly affect the yield of the intermediate 3. Only trace amount of 3 could be detected by TLC analysis, when using chloroform as solvent, TEA as base and reacting for 20 h at 41 8C, whereas the 3 was obtained in yield of 31%, when using toluene as solvent, CaH2 as base and reacting for 24 h at 90 8C. However, when reaction was carried out in chloroform under microwave irradiation for 40 min, 3 was obtained in yield of 91%. * Corresponding author. E-mail address: [email protected] (Z.G. Zhao). 1001-8417/$ – see front matter # 2007 Zhi Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.01.038
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Scheme 1. Reagents: (i) CH3OH, CH3COCl; (ii) microwave irradiation, TEA, CHCl3, p-nitrobenzoyl; (iii) SnCl22H2O, ethyl acetate; (iv) DIEA, CH2Cl2, PhNCO or PhNCS.
The recognition of molecular tweezers 5a, 5b for various anions has been investigated by UV–vis spectral titration in CHCl3 at 25 8C. The preliminary results showed that these molecular tweezers possessed the ability to form complex with anions examined. The supramolecular complexes consisted of 1:1 host and guest molecules. The association constants of molecular tweezer 5b, for example, is 23148.63, 8563.24, 2787.53, 347.29, 123.13, 58.26 mol L 1 for FS, ClS, BrS, IS, AcOS, H2PO4S anions. The main driving force is the multiple hydrogen bonds in molecular recognition. The UV–vis plot of 5a and 5b for BrS and ClS is shown in Fig. 1 and Fig. 2, respectively. The details of molecular recognition of 5a and 5b are under further studies. 1. Experimental Melting points were determined on a micro-melting point apparatus and the thermometer was uncorrected. Infrared spectra were obtained on 1700 Perkin-Elmer FTIR using KBr disks. 1H NMR spectra were recorded on a Varian INOVA 400 MHz spectrometer using CDCl3 as solvent and TMS as internal standard. Mass spectra were determined on Finnigan LCQDECA instrument. Elemental analysis was performed on a Carlo-Erba-1106 autoanalyzer. Optical rotation was measured on a Wzz-2B polarimeter. All the solvents were purified before use. 1.1. The preparation of intermediate 3 Methyl deoxycholate (1 mmol)was added to a solution of p-nitrobenzoyl (4 mmol) in 10 mL dry CHCl3 and 0.5 mL dry triethylamine (TEA) at room temperature. Then put the solution into the microwave oven, irradiated the reaction
X.L. Liu et al. / Chinese Chemical Letters 18 (2007) 287–290
Fig. 1. UV–vis spectra of molecular tweezer 5a (2.40 10 5 mol L 1) in the presence of BrS. (a) 0 mol L 1, (b) 0.64 10 (c) 1.28 10 3 mol L 1, (d) 1.92 10 3 mol L 1, (e) 2.56 10 3 mol L 1, (f) 3.84 10 3 mol L 1, (g) 5.12 10 (h) 6.40 10 3 mol L 1, (i) 7.68 10 3 mol L 1, (j) 8.96 10 3 mol L 1 with lmax at 244.0 nm.
289
3 3
mol L 1, mol L 1,
Fig. 2. UV–vis spectra of molecular tweezer 5b (4.71 10 5 mol L 1) in the presence of ClS. (a) 0 mol L 1, (b) 0.67 10 3 mol L 1, (c) 1.23 10 3 mol L 1, (d) 2.11 10 3 mol L 1, (e) 2.63 10 3 mol L 1, (f) 3.46 10 3 mol L 1, (g) 4.15 10 3 mol L 1, (h) 4.72 10 3 mol L 1, (i) 5.28 10 3 mol L 1, (j) 6.38 10 3 mol L 1 with lmax at 243.0 nm.
mixture for 40 min at 300 W. The solvent was removed and the residue was diluted with 10 mL ethyl acetate and washed with 10% NaHCO3 (15 mL 3), brine (15 mL 3), and finally dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate/cyclohexane as eluant. Yellow pale solid, yield 91%, m.p. 108–109 8C, [a]D20 + 97.2 (c 0.32, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 8.46–8.07 (m, 8H, ArH), 5.44 (s, 1H, 12b-H), 4.96–4.86 (m, 1H, 3b-H), 3.67 (s, 3H, COOCH3), 0.97 (s, 3H, 19-CH3), 0.88 (d, 3H, J = 6.4 Hz, 21-CH3), 0.76 (s, 3H, 18-CH3). IR (KBr, cm 1): 2955, 2868, 1721, 1618, 1536, 1445, 1176. ESI–MS m/z (%): 727 [(M + Na)+, 100]. 1.2. The preparation of intermediate 4 The intermediate 3 (1 mmol)was reacted with SnCl22H2O (8 mmol)in ethyl acetate at 60 8C with stirring under N2 atmosphere for 3 h. The mixture was then poured into 10% NaHCO3 solution and extracted with ethyl acetate (10 mL 3). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed to yield the crude product, which was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate as eluant. White solid, yield 89%, m.p. 105–106 8C, [a]D20 + 83.2 (c 0.20, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 7.89–6.63 (m, 8H, ArH), 5.31 (s, 1H, 12b-H), 4.90–4.84 (m, 1H, 3b-H), 3.64 (s, 3H, COOCH3),
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3.43 (s, 4H, ArNH2), 0.93 (s, 3H, 19-CH3), 0.84 (d, 3H, J = 6.4 Hz, 21-CH3), 0.79 (s, 3H, 18-CH3). IR (KBr, cm 1): 3423, 3363, 2936, 2876, 1723, 1614, 1576, 1481, 1178. ESI–MS m/z (%): 667 [(M + Na)+, 100]. 1.3. General procedure for preparation of molecular tweezers 5a and 5b Phenyl isocyanate or phenyl isothiocyanate (2 mmol) was added to the solution of intermediate 4 (0.5 mmol) in 10 mL anhydrous CH2Cl2 and 0.2 mL diisopropylethyl-amine (DIEA). The mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was diluted with 20 mL ethyl acetate and washed with 10% NaHCO3 (10 mL 3), brine (10 mL 3) and finally dried over anhydrous Na2SO4. The crude product was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate as eluant. 5a: White solid, yield 52%, m.p. 140–141 8C, [a]D20 + 117.0 (c 0.12, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 8.07–7.80 (d, 4H, J = 8.8 Hz, CONH), 7.57–6.93 (m, 18H, ArH), 5.35 (s, 1H, 12b-H), 4.87–4.76 (m, 1H, 3b-H), 3.62 (s, 3H, COOCH3), 0.93 (s, 3H, 19-CH3), 0.86 (d, 3H, J = 6.4 Hz, 21-CH3), 0.81 (s, 3H, 18-CH3). IR (KBr, cm 1): 3412, 2945, 2864, 1714, 1598, 1520, 1442, 1172. ESI–MS m/z (%): 882 (M+, 100). Anal. calcd. for C53H62N4O8: C 72.08, H 7.08, N 6.34; found: C 71.96, H 7.12, N 6.37. 5b: White solid, yield 45%, m.p. 136–137 8C, [a]D20 + 96.3 (c 0.15, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 12.31 (d, 4H, J = 8.9 Hz, CSNH), 7.76–6.62 (m, 18H, ArH), 5.37 (s, 1H, 12b-H), 4.91–4.84 (m, 1H, 3b-H), 3.65 (s, 3H, COOCH3), 0.98 (s, 3H, 19-CH3), 0.93 (d, 3H, J = 6.4 Hz, 21-CH3), 0.82 (s, 3H, 18-CH3). IR (KBr, cm 1): 3353, 2978, 2864, 1623, 1578, 1506, 1476, 1214. ESI–MS m/z (%): 938 [(M + Na)+, 100]. Anal. calcd. for C53H62N4S2O6: C 69.55, H 6.83, N 6.12; found: C 69.39, H 6.90, N 6.19. Acknowledgment We are very grateful to the National Natural Science Foundation of China (No. 20272038) for the financial support. References [1] [2] [3] [4] [5] [6]
F.P. Schmidtchen, M. Berger, Chem. Rev. 97. (1997) 1609. P.D. Beer, P.A. Gale, Angew. Chem. Int. Ed. 40 (2001) 486. J. Scheerder, J.F. Engbersen, A. Casnati, et al. J. Org. Chem. 60 (1995) 6448. S.O. Kang, K.C. Nam, Bull. Korean Chem. Soc. 23 (2002) 640. S.Y. Liu, Y.B. He, J.L. Wu, et al. Org. Biomol. Chem. 2 (2004) 1582. R. Hu, Z.M. Zhao, Z.X. Yang, et al. J. Sichuan University 36 (1999) 800 (Natural Science Edition, in Chinese).
Design and synthesis of novel tweezer anion receptors based on deoxycholic acid Xing Li Liu a, Zhi Gang Zhao a,*, Shu Hua Chen b a
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China b The Faculty of Chemistry, Sichuan University, Chengdu 610064, China Received 24 November 2006
Abstract A novel type of molecular tweezer receptors based on deoxycholic acid has been designed and synthesized and their binding properties were examined by UV–vis spectral titration. These molecular tweezers showed a high selectivity toward FS over ClS, BrS, IS, AcOS, H2PO4S. # 2007 Zhi Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Molecular tweezers; Deoxycholic acid; Anion; Recognition
The development of artificial receptors for the detection of biologically relevant anions is an important challenge in modern bioorganic chemistry [1,2]. So far, the exploited basic strategies for the construction of anion-binding receptors are electrostatic interaction, hydrogen bonding, hydrophobicity, coordination to a metal ion, or combination of these interactions together. Among these noncovalent interactions, we have been interested in developing hydrogen bond-based neutral anion receptors. Owing to the relatively strong hydrogen bonding ability of urea and thiourea groups, a number of molecules possessing urea or thiourea groups have been designed as neutral receptors for various anions [3–5]. For strong and selective binding, these groups should be preorganized to complement the target anion and minimize intramolecular hydrogen bonding. One way to achieve this goal is to make receptors with urea or thiourea groups connected to rigid spacers. The steroid nucleus is one of the largest rigid and chiral ubiquitous natural compounds. Based on these preorganized structural characteristics, steroid cholic acid is an ideal building block for the construction of molecular tweezers. In this paper, we report the design and synthesis of a new series of molecular tweezers and their recognition properties toward various anions. The synthetic route is shown in Scheme 1. Deoxycholic acid was converted to methyl 3a,12a-dihydroxy-5b-cholano-24-ate following a reported procedure [6]. Methyl deoxycholate 2 was reacted with p-nitrobenzoyl chloride under microwave irradiation to give 3, which was reduced with SnCl22H2O in ethyl acetate to yield intermediate 4. 4 was reacted with the phenyl isocyanate or phenyl isothiocyanate to produce molecular tweezer 5a or 5b. The reaction conditions significantly affect the yield of the intermediate 3. Only trace amount of 3 could be detected by TLC analysis, when using chloroform as solvent, TEA as base and reacting for 20 h at 41 8C, whereas the 3 was obtained in yield of 31%, when using toluene as solvent, CaH2 as base and reacting for 24 h at 90 8C. However, when reaction was carried out in chloroform under microwave irradiation for 40 min, 3 was obtained in yield of 91%. * Corresponding author. E-mail address: [email protected] (Z.G. Zhao). 1001-8417/$ – see front matter # 2007 Zhi Gang Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.01.038
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Scheme 1. Reagents: (i) CH3OH, CH3COCl; (ii) microwave irradiation, TEA, CHCl3, p-nitrobenzoyl; (iii) SnCl22H2O, ethyl acetate; (iv) DIEA, CH2Cl2, PhNCO or PhNCS.
The recognition of molecular tweezers 5a, 5b for various anions has been investigated by UV–vis spectral titration in CHCl3 at 25 8C. The preliminary results showed that these molecular tweezers possessed the ability to form complex with anions examined. The supramolecular complexes consisted of 1:1 host and guest molecules. The association constants of molecular tweezer 5b, for example, is 23148.63, 8563.24, 2787.53, 347.29, 123.13, 58.26 mol L 1 for FS, ClS, BrS, IS, AcOS, H2PO4S anions. The main driving force is the multiple hydrogen bonds in molecular recognition. The UV–vis plot of 5a and 5b for BrS and ClS is shown in Fig. 1 and Fig. 2, respectively. The details of molecular recognition of 5a and 5b are under further studies. 1. Experimental Melting points were determined on a micro-melting point apparatus and the thermometer was uncorrected. Infrared spectra were obtained on 1700 Perkin-Elmer FTIR using KBr disks. 1H NMR spectra were recorded on a Varian INOVA 400 MHz spectrometer using CDCl3 as solvent and TMS as internal standard. Mass spectra were determined on Finnigan LCQDECA instrument. Elemental analysis was performed on a Carlo-Erba-1106 autoanalyzer. Optical rotation was measured on a Wzz-2B polarimeter. All the solvents were purified before use. 1.1. The preparation of intermediate 3 Methyl deoxycholate (1 mmol)was added to a solution of p-nitrobenzoyl (4 mmol) in 10 mL dry CHCl3 and 0.5 mL dry triethylamine (TEA) at room temperature. Then put the solution into the microwave oven, irradiated the reaction
X.L. Liu et al. / Chinese Chemical Letters 18 (2007) 287–290
Fig. 1. UV–vis spectra of molecular tweezer 5a (2.40 10 5 mol L 1) in the presence of BrS. (a) 0 mol L 1, (b) 0.64 10 (c) 1.28 10 3 mol L 1, (d) 1.92 10 3 mol L 1, (e) 2.56 10 3 mol L 1, (f) 3.84 10 3 mol L 1, (g) 5.12 10 (h) 6.40 10 3 mol L 1, (i) 7.68 10 3 mol L 1, (j) 8.96 10 3 mol L 1 with lmax at 244.0 nm.
289
3 3
mol L 1, mol L 1,
Fig. 2. UV–vis spectra of molecular tweezer 5b (4.71 10 5 mol L 1) in the presence of ClS. (a) 0 mol L 1, (b) 0.67 10 3 mol L 1, (c) 1.23 10 3 mol L 1, (d) 2.11 10 3 mol L 1, (e) 2.63 10 3 mol L 1, (f) 3.46 10 3 mol L 1, (g) 4.15 10 3 mol L 1, (h) 4.72 10 3 mol L 1, (i) 5.28 10 3 mol L 1, (j) 6.38 10 3 mol L 1 with lmax at 243.0 nm.
mixture for 40 min at 300 W. The solvent was removed and the residue was diluted with 10 mL ethyl acetate and washed with 10% NaHCO3 (15 mL 3), brine (15 mL 3), and finally dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate/cyclohexane as eluant. Yellow pale solid, yield 91%, m.p. 108–109 8C, [a]D20 + 97.2 (c 0.32, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 8.46–8.07 (m, 8H, ArH), 5.44 (s, 1H, 12b-H), 4.96–4.86 (m, 1H, 3b-H), 3.67 (s, 3H, COOCH3), 0.97 (s, 3H, 19-CH3), 0.88 (d, 3H, J = 6.4 Hz, 21-CH3), 0.76 (s, 3H, 18-CH3). IR (KBr, cm 1): 2955, 2868, 1721, 1618, 1536, 1445, 1176. ESI–MS m/z (%): 727 [(M + Na)+, 100]. 1.2. The preparation of intermediate 4 The intermediate 3 (1 mmol)was reacted with SnCl22H2O (8 mmol)in ethyl acetate at 60 8C with stirring under N2 atmosphere for 3 h. The mixture was then poured into 10% NaHCO3 solution and extracted with ethyl acetate (10 mL 3). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed to yield the crude product, which was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate as eluant. White solid, yield 89%, m.p. 105–106 8C, [a]D20 + 83.2 (c 0.20, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 7.89–6.63 (m, 8H, ArH), 5.31 (s, 1H, 12b-H), 4.90–4.84 (m, 1H, 3b-H), 3.64 (s, 3H, COOCH3),
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3.43 (s, 4H, ArNH2), 0.93 (s, 3H, 19-CH3), 0.84 (d, 3H, J = 6.4 Hz, 21-CH3), 0.79 (s, 3H, 18-CH3). IR (KBr, cm 1): 3423, 3363, 2936, 2876, 1723, 1614, 1576, 1481, 1178. ESI–MS m/z (%): 667 [(M + Na)+, 100]. 1.3. General procedure for preparation of molecular tweezers 5a and 5b Phenyl isocyanate or phenyl isothiocyanate (2 mmol) was added to the solution of intermediate 4 (0.5 mmol) in 10 mL anhydrous CH2Cl2 and 0.2 mL diisopropylethyl-amine (DIEA). The mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was diluted with 20 mL ethyl acetate and washed with 10% NaHCO3 (10 mL 3), brine (10 mL 3) and finally dried over anhydrous Na2SO4. The crude product was purified by column chromatography on silica gel H with dichloromethane/ethyl acetate as eluant. 5a: White solid, yield 52%, m.p. 140–141 8C, [a]D20 + 117.0 (c 0.12, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 8.07–7.80 (d, 4H, J = 8.8 Hz, CONH), 7.57–6.93 (m, 18H, ArH), 5.35 (s, 1H, 12b-H), 4.87–4.76 (m, 1H, 3b-H), 3.62 (s, 3H, COOCH3), 0.93 (s, 3H, 19-CH3), 0.86 (d, 3H, J = 6.4 Hz, 21-CH3), 0.81 (s, 3H, 18-CH3). IR (KBr, cm 1): 3412, 2945, 2864, 1714, 1598, 1520, 1442, 1172. ESI–MS m/z (%): 882 (M+, 100). Anal. calcd. for C53H62N4O8: C 72.08, H 7.08, N 6.34; found: C 71.96, H 7.12, N 6.37. 5b: White solid, yield 45%, m.p. 136–137 8C, [a]D20 + 96.3 (c 0.15, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d ppm): 12.31 (d, 4H, J = 8.9 Hz, CSNH), 7.76–6.62 (m, 18H, ArH), 5.37 (s, 1H, 12b-H), 4.91–4.84 (m, 1H, 3b-H), 3.65 (s, 3H, COOCH3), 0.98 (s, 3H, 19-CH3), 0.93 (d, 3H, J = 6.4 Hz, 21-CH3), 0.82 (s, 3H, 18-CH3). IR (KBr, cm 1): 3353, 2978, 2864, 1623, 1578, 1506, 1476, 1214. ESI–MS m/z (%): 938 [(M + Na)+, 100]. Anal. calcd. for C53H62N4S2O6: C 69.55, H 6.83, N 6.12; found: C 69.39, H 6.90, N 6.19. Acknowledgment We are very grateful to the National Natural Science Foundation of China (No. 20272038) for the financial support. References [1] [2] [3] [4] [5] [6]
F.P. Schmidtchen, M. Berger, Chem. Rev. 97. (1997) 1609. P.D. Beer, P.A. Gale, Angew. Chem. Int. Ed. 40 (2001) 486. J. Scheerder, J.F. Engbersen, A. Casnati, et al. J. Org. Chem. 60 (1995) 6448. S.O. Kang, K.C. Nam, Bull. Korean Chem. Soc. 23 (2002) 640. S.Y. Liu, Y.B. He, J.L. Wu, et al. Org. Biomol. Chem. 2 (2004) 1582. R. Hu, Z.M. Zhao, Z.X. Yang, et al. J. Sichuan University 36 (1999) 800 (Natural Science Edition, in Chinese).