Highly Efficient Synthesis and Inclusion Properties of Star-Shaped Amphiphilic Derivatives of Cholic Acid

Abstract

New star-shaped cholic acid derivatives with different functional groups have been synthesized by the use of Cu^I-catalyzed [2+3] cyclization (click chemistry) and Curtius rearrangement of acyl azide intermediate in good yields. We have also studied the ­solution properties of these star-shaped amphiphilic compounds as host molecules to interact with nonpolar guest molecules by the use of fluorescent probes.

Key words

supermolecular chemistry - host-guest systems - oligomerization - steroids - conjugation

References and Notes

• 1 Mukhopadhyay S. Maitra U. Curr. Sci.  2004,  87:  1666 
• 2 Zhu XX. Nichifor M. Acc. Chem. Res.  2002,  35:  539 
• 3a D’Souza LJ. Maitra U. J. Org. Chem.  1996,  61:  9494 
• 3b Shim JH. Jeong IS. Lee MH. Hong HP. On JH. Kim KS. Kim H.-S. Kim BH. Cha GS. Nam H. Talanta  2004,  63:  61 
• 4a Zhao Y. Ryu E.-H. J. Org. Chem.  2005,  70:  7585 
• 4b Ryu E.-H. Zhao Y. Org. Lett.  2005,  7:  1035 
• 4c Ryu E.-H. Zhao Y. Org. Lett.  2004,  6:  3187 
• 5a Ariga K. Nakanishi T. Hill JP. Soft Matter  2006,  2:  465 
• 5b Ariga K. Nakanishi T. Hill JP. Terasaka Y. Sakai D. Kikuchi J.-i. Soft Matter  2005,  1:  132 
• 5c Ariga K. Nakanishi T. Terasaka Y. Tsuji H. Sakai D. Kikuchi J. Langmuir  2005,  21:  976 
• 6 Janout V. Lanier M. Regen SL. J. Am. Chem. Soc.  1997,  119:  640 
• 7 Janout V. Di Giorgio C. Regen SL. J. Am. Chem. Soc.  2000,  122:  2671 
• 8 Janout V. Zhang L.-h. Staina IV. Di Giorgio C. Regen SL. J. Am. Chem. Soc.  2001,  123:  5401 
• 9 Janout V. Jing B. Regen SL. Bioconjugate Chem.  2002,  13:  351 
• 10 Zhao Y. Zhong Z. J. Am. Chem. Soc.  2005,  127:  17894 
• 11a Zhao Y. Zhong Z. Org. Lett.  2006,  8:  4715 
• 11b Zhao Y. Zhong Z. J. Am. Chem. Soc.  2006,  128:  9988 
• 12a Special issue: Fibrillar Networks as Advanced Materials: Babu P. Sangeetha NM. Maitra U. Macromol. Symp.  2006,  241:  60 
• 12b Mukhopadhyay S. Maitra U. Ira I. Krishnamoorthy G. Schmidt J. Talmon Y. J. Am. Chem. Soc.  2004,  126:  15905 
• 13 Aher N. Pore V. Synlett  2005,  2155 
• 14a Bock VD. Perciaccante R. Jansen TP. Hiemstra H. Van Maarseveen JH. Org. Lett.  2006,  8:  919 
• 14b Demko ZP. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2113 
• 14c Kolb HC. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2001,  40:  2004 
• 15 Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 
• 16 Calvo-Flores FG. Isac-Garcia J. Hernandez-Mateo F. Perez-Balderas F. Calvo-Asin JA. Sanchez-Vaquero E. Santoyo-Gonzalez F. Org. Lett.  2000,  2:  2499 
• 17 Hu X. Zhang Z. Zhang X. Li Z. Zhu XX. Steroids  2005,  70:  531 
• 19 Wess G. Kramer W. Bartmann W. Enhsen A. Glombik H. Muellner S. Bock K. Dries A. Kleine H. Schmitt W. Tetrahedron Lett.  1992,  33:  195 
• 21 Rodionov VO. Fokin VV. Finn MG. Angew. Chem. Int. Ed.  2005,  44:  2210 
• 22a Scriven EFTK. Chem. Rev.  1988,  88:  297 
• 22b Curtius T. Ber. Dtsch. Chem. Ges.  1890,  23:  3023 
• 23a Okaniwa M. Takeuchi K. Asai M. Ueda M. Macromolecules  2002,  35:  6224 
• 23b Okaniwa M. Takeuchi K. Asai M. Ueda M. Macromolecules  2002,  35:  6232 
• 24 Hayes W. Osborn HMI. Osborne SD. Rastall RA. Romagnoli B. Tetrahedron  2003,  59:  7983 
• 26a Berndt DC. Faburada AL. J. Org. Chem.  1982,  47:  4167 
• 26b Ryng S. Glowiak T. Synth. Commun.  1997,  27:  1359 
• 27 Lwowski W. Chemistry of the Azido Groups   Interscience; New York: 1971.  Chap. 9.
• 28a Nakajima A. Spectrochim. Acta, Part A  1974,  30:  860 
• 28b Nakajima A. J. Mol. Spectrosc.  1976,  61:  467 

18

Preparation of Trimer 6 (Similar for Tetramer 7)
A solution of cholic acid 2-azidoethyl ester (5, 1 mmol, 476 mg), trialkyne (0.33 mmol, 83 mg), DIPEA (0.5 mL), PPh₃ (0.1 mmol, 26 mg), and CuBr (15 mg, 0.1 equiv) in 10 mL DMF was stirred at r.t. for 48 h. Then 50 mL of H₂O was added to precipitate out the sticky crude product which was dried under vacuum at 40 °C. Column chromatography of the crude product on silica gel with an eluent of 4:1 EtOAc-MeOH gave 240 mg of a light yellow solid 6 in 44% yield. ¹H NMR (400 MHz, CD₃OD): δ = 8.06 (3 H, s), 4.71 (6 H, t, J = 4.5 Hz), 4.57 (6 H, s), 4.51 (6 H, t, J = 4.0 Hz), 3.95 (3 H, s), 3.81 (3 H, s), 3.48 (8 H, s), 3.59 (2 H, s), 3.50 (6 H, s), 3.39 (3 H, m), 2.18-2.41 (12 H, m), 1.20-2.00 (69 H, m), 1.20-2.37 (63 H, m), 0.97 (9 H, d, J = 6.4 Hz), 0.93 (9 H, s), 0.70 (9 H, s). ¹³C NMR (100 MHz, CD₃OD): δ = 12.1, 16.7, 22.2, 23.3, 26.9, 27.7, 28.6, 30.2, 30.8, 31.1, 34.9 (2 C), 35.5, 35.7, 39.5, 40.0, 42.0, 42.3, 45.8, 46.5, 46.9, 49.5, 61.4, 62.5, 64.4, 68.0, 69.2, 71.9, 72.9, 124.4, 174.2. HRMS: m/z calcd for C₉₂H₁₄₈N₉O₁₉ [M + H]⁺: 1683.0886; found [M + H]⁺: 1683.0877.
Tetramer 7: 23% yield; mp 140 °C. ¹H NMR (400 MHz, CD₃OD): δ = 8.01 (4 H, s), 4.71 (8 H, t, J = 5.1 Hz), 4.55 (8 H, s), 4.51 (8 H, t, J = 5.0 Hz), 3.95 (4 H, m), 3.81 (4 H, m), 3.48 (8 H, s), 2.18-2.41 (16 H, m), 1.12-2.41 (80 H, m), 0.97 (12 H, s), 0.93 (12 H, s), 0.70 (12 H, s). ¹³C NMR (100 MHz, CD₃OD): δ = 12.1, 16.7, 22.2, 23.3, 26.9, 27.7, 28.6, 30.2, 30.9, 31.1, 34.9 (2 C), 35.6, 35.7, 39.5, 40.0, 42.0, 42.2, 46.5, 47.0, 49.4, 62.5, 64.5, 68.0, 68.7, 69.0, 71.9, 72.9, 124.7, 174.2. HRMS: m/z calcd for C₁₂₁H₁₉₃N₁₂O₂₄ [M + H]⁺: 2198.4245; found [M + H]⁺: 2198.4170.

20

Preparation of Trimer 9
3β-Azido-cholic acid (8, 0.6 mmol, 270 mg), trialkyne (0.2 mmol, 51.8 mg), CuSO₄ (0.03 mmol, 7.5 mg) and sodium ascorbate (0.12 mmol, 24 mg) were suspended in a 2:1 mixture (20 mL) of H₂O and t-BuOH, and the mixture was stirred at 90 °C for 48 h. The crude product precipitated at r.t. by adding 50 mL of H₂O, and was collected by centrifuga-tion. The residue was purified by column chromatography on silica gel with a 5:1:1 mixture of EtOAc-MeOH-AcOH as eluent to give a light yellow solid (175 mg, 54%). ¹H NMR (400 MHz, CD₃OD): δ = 8.14 (3 H, s), 4.70 (6 H, s), 4.59 (6 H, s), 4.00 (3 H, s), 3.85 (3 H, s), 3.56 (2 H, s), 3.48 (6 H, s), 3.50 (6 H, s), 3.07 (3 H, t, J = 13.1 Hz), 1.20-2.00 (69 H, m), 1.20-2.42 (69 H, m), 1.04 (9 H, d, J = 6.6 Hz), 0.89 (9 H, s), 0.74 (9 H, s). ¹³C NMR (100 MHz, CD₃OD): δ = 12.0, 16.6, 19.5, 22.5, 23.2, 24.8, 27.0, 27.7, 28.7, 30.8, 30.9, 31.2, 32.6, 34.1, 35.1, 35.8, 37.5, 40.0, 42.0, 46.6, 47.0, 57.6, 64.3, 67.9, 69.2, 72.9, 113.6, 116.4, 175.0. HRMS: m/z calcd for C₈₆H₁₃₆N₉O₁₆ [M + H]⁺: 1551.0099; found [M + H]⁺: 1551.0133.

25

Curtius Reaction to Prepare Trimer 14
A pressure-resistant vessel equipped with a Teflon screw cap was used as the reactor. A solution of choloyl azide 10 (2.3 mmol, 1 g) in 20 mL THF was tightly sealed and stirred at 140 °C for 30 min and cooled down to r.t. Triaminoethylamine (0.77 mmol, 0.11 g) was added into the solution and then stirred at 120 °C overnight. Then THF was evaporated under vacuum. The residue was purified by column chromatography on silica gel with a 1:1 mixture of EtOAc-MeOH as eluent to yield 900 mg (80%) of a white solid product 14. ¹H NMR (400 MHz, CD₃OD): δ = 3.98 (3 H, s), 3.81 (3 H, s), 3.39 (3 H, m), 3.23 (3 H, m), 3.17 (6 H, t, J = 5.5 Hz), 3.10 (3 H, m), 2.58 (6 H, t, J = 5.6 Hz), 2.18-2.41 (6 H, m), 1.12-2.41 (63 H, m), 1.06 (9 H, d, J = 6.6 Hz), 0.94 (9 H, s), 0.74 (9 H, s). ¹³C NMR (100 MHz, CD₃OD): δ = 12.1, 17.1, 22.2, 23.3, 26.9, 27.9, 28.6, 30.2, 34.1, 34.1, 34.9, 35.5, 36.5, 37.8, 38.4, 39.5, 40.0, 42.0, 42.2, 46.6, 47.5, 55.2, 68.1, 71.9, 73.0, 160.4. HRMS: m/z calcd for C₇₈H₁₃₃N₁₆O₉ [M + H]⁺: 1438.0435; found [M + H]⁺: 1438.0453.
Tetramer 15: 54% yield. ¹H NMR (400 MHz, CD₃OD): δ = 3.99 (4 H, s), 3.81 (4 H, s), 3.39 (4 H, m), 3.19 (8 H, t, J = 7.3 Hz), 2.33 (8 H, s), 2.23-2.37 (8 H, m), 1.12-2.30 (88 H, m), 1.08 (12 H, d, J = 6.3 Hz), 0.94 (12 H, s), 0.74 (12 H, s). ¹³C NMR (100 MHz, CD₃OD): δ = 12.1, 17.1, 22.3, 23.3, 25.5, 26.9, 28.0, 28.6, 30.2, 34.0, 34.9 (2 C), 35.5, 36.6, 37.8, 39.0, 39.5, 40.0, 42.0, 42.2, 46.6, 47.5, 68.1, 71.9, 73.0, 160.2. HRMS: m/z calcd for C₁₀₁H₁₇₃N₈O₁₆ [M + H]⁺: 1754.2964; found [M + H]⁺: 1754.2938.