Imprinted polymers as protecting groups for regioselective modification of polyfunctional substrates

Journal of the American Chemical Society

Volumn 121, Issue 28, 1999, Pages 6640-6651

  Alexander, Cameron ^a   Smith, Craig R ^a   Whitcombe, Michael J ^a   Vulfson, Evgeny N ^a  

^a INSTITUTE OF FOOD RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ETHYLENE GLYCOL; HYDROXYL GROUP; MONOMER; POLYMER; STEROID;

ACYLATION; ARTICLE; BINDING KINETICS; CHEMICAL MODIFICATION; EXTRACTION; INFRARED SPECTROSCOPY; STEREOCHEMISTRY; SYNTHESIS;

EID: 0033591862     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja982238h     Document Type: Article

References (131)

1. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
2. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
3. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
4. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
5. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
6. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
7. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
8. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
9. For recent reviews, see: (a) Mosbach, K.; Ramström, O. Bio/Technology 1996, 14, 163-170. (b) Shea, K. J. Trends Polym. Sci. 1994, 2, 166-173. (c) Steinke, J.; Sherrington, D. C.; Dunkin, I. R. Adv. Polym. Sci. 1995, 123, 81-125. (d) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832. (e) Vidyasankar, S.; Arnold, F. H. Curr. Opin. Biotechnol. 1995, 6, 218-224. (f) Mosbach, K. Trends Biochem. Sci. 1994, 19, 9-14. (g) Alexander, C.; Whitcombe, M. J.; Vulfson, E. N. Chem. Br. 1997, 33, 23-26. (h) Haupt, K.; Mosbach, K. J. Mol. Recogn. 1998, 11, 62-68. (i) Molecular and Ionic Recognition with Imprinted Polymers; Bartsch, R. A., Maeda, M., Eds.; ACS Symposium Series 703; American Chemical Society: Washington, DC, 1998.
10. (a) Andersson, L.; Sellergren, B.; Mosbach, K. Tetrahedron Lett. 1984, 25, 5211-5214.
11. (b) Sellergren, B.; Lepistö, M.; Mosbach, K. J. Am. Chem. Soc. 1988, 110, 5853-5860.
12. (c) Andersson, L. I.; Mosbach, K. J. Chromatogr. 1990, 516, 313-322.
13. (a) Ramström, O.; Nicholls, I. A.; Mosbach, K. Tetrahedron: Asymmetry 1994, 5, 649-656.
14. (b) Andersson, L. I.; Müller, R.; Vlatakis, G.; Mosbach, K. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 4788-4792.
15. (c) Yano, K.; Nakagiri, T.; Takeuchi, T.; Matsui, J.; Ikebukuro, K.; Karube, I. Anal. Chim. Acta 1997, 357, 91-98.
16. (a) Wulff, G.; Poll, H. G. Makromol. Chem. 1987, 188, 741-748.
17. (b) Chen, G. H.; Guan, Z. B.; Chen, C. T.; Fu, L. T.; Sundaresan, V.; Arnold, F. H. Nat. Biotechnol. 1997, 15, 354-357.
18. (c) Mayes, A. G.; Andersson, L. I.; Mosbach, K. Anal. Biochem. 1994, 222, 483-488.
19. (a) Shea, K. J.; Spivak, D. A. Macromolecules 1998, 31, 2160-2165.
20. (b) Shea, K. J.; Spivak, D. A.; Sellergren, B. J. Am. Chem. Soc. 1993, 115, 3368-3369.
21. Mathew, J.; Buchardt, O. Bioconjugate Chem. 1995, 6, 524-528.
22. Ramström, O.; Ye, L.; Mosbach, K. Chem. Biol. 1996, 3, 471-477.
23. (a) Cheong, S. H.; McNiven, S.; Rachkov, A.; Levi, R.; Yano, K.; Karube, I. Macromolecules 1997, 30, 1317-1322.
24. (b) McNiven, S.; Yokobayashi, Y.; Cheong, S. H.; Karube, I. Chem. Lett. 1997, 1297-1298.
25. (a) Fischer, L.; Müller, R.; Ekberg, B.; Mosbach, K. J. Am. Chem. Soc. 1991, 113, 9358-9360.
26. (b) Vlatakis, G.; Andersson, L. I.; Müller, R.; Mosbach, K. Nature 1993, 361, 645-647.
27. (c) Ramström, O.; Yu, C.; Mosbach, K. J. Mol. Recognit. 1996, 9, 691-696.
28. (d) Senholdt, M.; Siemann, M.; Mosbach, K.; Andersson, L. I. Anal. Lett. 1997, 30, 1809-1821.
29. (e) Siemann, M.; Andersson, L. I.; Mosbach, K. J. Antibiot. 1997, 50, 89-91.
30. (f) Tomioka, Y.; Kudo, Y.; Hayashi, T.; Nakamura, H.; Niizeki, M.; Hishinuma, T.; Mizugaki, M. Biol. Pharm. Bull. 1997, 20, 397-400.
31. (g) Matsui, J.; Takeuchi, T. Anal. Commun. 1997, 34, 199-200.
32. (a) Muldoon, M. T.; Stanker, L. H. J. Agric. Food Chem. 1995, 43, 1424-1427.
33. (b) Haupt, K.; Dzgoev, A.; Mosbach, K. Anal. Chem. 1998, 70, 628-631.
34. (c) Dickert, F. L.; Besenböck, H.; Tortschanoff, M. Adv. Mater. 1998, 10, 149-151.
35. (d) Lübke, M.; Whitcombe, M. J.; Vulfson, E. N. J. Am. Chem. Soc. 1998, 120, 13342-13348.
36. (a) Ramström, O.; Ansell, R. J. Chirality 1998, 10, 195-209.
37. (b) Sellergren, B. Trends Anal. Chem. 1997, 16, 310-320.
38. (c) Kempe, M.; Mosbach, K. J. Chromatogr. A 1995, 694, 3-13.
39. (d) Kempe, M.; Mosbach, K. J. Chromatogr. A 1994, 664, 276-279.
40. (a) Sellergren, B. Anal. Chem. 1994, 66, 1578-1582.
41. (b) Muldoon, M. T.; Stanker, L. H. Anal. Chem. 1997, 69, 803-808.
42. (c) Andersson, L. I.; Paprica, A.; Arvidsson, T. Chromatographia 1997, 46, 57-62.
43. (d) Rashid, B. A.; Briggs, R. J.; Hay, J. N.; Stevenson, D. Anal. Commun. 1997, 34, 303-305.
44. (e) Walshe, M.; Howarth, J.; Kelly, M. T.; O'Kennedy, R.; Smyth, M. R. J. Pharm. Biomed. Anal. 1997, 16, 319-325.
45. (f) Martin, P.; Wilson, I. D.; Morgan, D. E.; Jones, G. R.; Jones, K. Anal. Commun. 1997, 34, 45-47.
46. (g) Mullett, W. M.; Lai, E. P. C. Anal. Chem. 1998, 70, 3636-3641.
47. (h) Zander, A.; Findlay, P.; Renner, T.; Sellergren, B.; Swietlow, A. Anal. Chem. 1998, 70, 3304-3314.
48. Byström, S. E.; Borje, A.; Akermark, B. J. Am. Chem. Soc. 1993, 115, 2081-2083.
49. (a) Beach, J. V.; Shea, K. J. J. Am. Chem. Soc. 1994, 116, 379-380.
50. (b) Muller, R.; Andersson, L. I.; Mosbach, K. Makromol. Chem. Rapid Commun. 1993, 14, 637-641.
51. (c) Wulff, G.; Gross, T.; Schönfeld, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1962-1964.
52. (d) Matsui, J.; Nicholls, I. A.; Karube, I.; Mosbach, K. J. Org. Chem. 1996, 61, 5414-5417.
53. (e) Liu, X.-C.; Mosbach, K. Macromol. Rapid Commun. 1997, 18, 609-615.
54. (f) Gamez, P.; Dunjic, B.; Pinel, C.; Lemaire, M. Tetrahedron Lett. 1995, 36, 8779-8782.
55. (a) Yamamura, K.; Hatakeyama, H.; Naka, K.; Tabushi, I.; Kurihara, K. J. Chem. Soc., Chem. Commun. 1988, 79-81.
56. (b) Starodub, S.; Piletsky, S. A.; Lavryk, N. V.; Elskaya, A. V. Sens. Actuators B 1994, 18-19, 629-632.
57. (c) Hedborg, E.; Winquist, F.; Lundström, I.; Andersson, L. I.; Mosbach, K. Sens. Actuators A 1993, 37-38, 796-799.
58. (d) Kriz, D.; Ramström, O.; Mosbach, K. Anal. Chem, 1997, 69, A345-A349.
59. (a) Whitcombe, M. J.; Alexander, C.; Vulfson, E. N. Trends Food Sci. Technol. 1997, 8, 140-145.
60. (b) Joshi, V. P.; Karode, S. K.; Kulkarni, M. G.; Mashelkar, R. A. Chem. Eng. Sci. 1998, 53, 2271-2284.
61. D'Souza, S. M.; Alexander, C.; Carr, S. W.; Waller, A. M.; Whitcombe, M. J.; Vulfson, E. N. Nature 1999, 398, 312-316.
62. (a) Mallik, S.; Plunkett, S. D.; Dhal, P. K.; Johnson, R. D.; Pack, D.; Shnek, D.; Arnold, F. H. New J. Chem. 1994, 18, 299-304.
63. (b) Shnek, D. R.; Pack, D. W.; Sasaki, D. Y.; Arnold, F. H. Langmuir 1994, 10, 2382-2388.
64. (c) Hjerten, S.; Liao, J. L.; Nakazato, K.; Wang, Y.; Zamaratskaia, G.; Zhang, H. X. Chromatographia 1997, 44, 227-234.
65. (a) Aherne, A.; Alexander, C.; Perez, N.; Payne, M. J.; Vulfson, E. N. J. Am. Chem. Soc. 1996, 118, 8771-8772.
66. (b) Alexander, C.; Vulfson, E. N. Adv. Mater. 1997, 9, 751-755.
67. Shea, K. J.; Sasaki, D. Y.; Stoddard, G. J. Macromolecules 1989, 22, 1722-1730.
68. Wulff, G.; Kemmerer, R.; Vietmeier, J.; Poll, H.-G. Nouv. J. Chim. 1982, 6, 681-687.
69. (a) Wulff, G.; Vesper, W.; Grobe-Einsler, R.; Sarhan, A. Makromol. Chem. 1977, 178, 2799-2816.
70. (b) Wulff, G.; Grobe-Einsler, R.; Vesper, W.; Sarhan, A. Makromol. Chem. 1977, 178, 2817-2825.
71. (c) Wulff, G.; Vesper, W. J. Chromatogr. 1978, 167, 171-186.
72. (d) Wulff, G.; Oberkobusch, D.; Minarik, M. React. Polym. Ion Exch. Sorbents 1985, 3, 261-275.
73. (a) Wulff, G.; Sarhan, A.; Zabrocki, K. Tetrahedron Lett. 1973, 4329-4332.
74. (b) Wulff, G.; Schulze, I.; Zabrocki, K.; Vesper, W. Makromol. Chem. 1980, 181, 531-544.
75. Wulff, G.; Minarik, M. J. Liquid Chromatogr. 1990 13 (15), 2987-3000. See also ref 4a above for the effect of flexibility in the polymerizable boronic acid on the resolution of phenyl-α-D-mannopyranoside.
76. Sasaki, D. Y.; Shea, K. J. J. Am. Chem. Soc. 1991, 113, 4109-4120.
77. (a) Wulff, G. Polymeric Reagents and Catalysts; Ford, W. T., Ed.; ACS Symposium Series 308; American Chemical Society: Washington, DC, 1986; pp 186-230.
78. (b) Wulff, G.; Vieitmeier, J. Makromol. Chem. 1989, 190, 1717-1726.
79. (c) Wulff, G.; Vieitmeier, J. Makromol. Chem. 1989, 190, 1727-1735.
80. (a) Shea, K. J.; Thompson, E. A. J. Org. Chem. 1978, 43, 4253-4255.
81. (b) Shea, K. J.; Thompson, E. A.; Pandey, S. D.; Beauchamp, P. S. J. Am. Chem. Soc. 1980, 102, 3149-3151.
82. (c) Damen, J.; Neckers, D. C. Tetrahedron Lett. 1980, 21, 1913-1916.
83. (d) Damen, J.; Neckers, D. C. J. Am. Chem. Soc. 1980, 102, 3265-3267.
84. Hoberman, J. M.; Yesalis, C. E. Sci. Am. 1995, 272, 76-81.
85. The noncovalent strategy has been used successfully for imprinting steroids (see refs 7 and 8). However, it was not suitable for our investigation owing to the necessity of working with an excess of functional monomer, which would inevitably lead to the incorporation of some functional groups "outside" the imprints, thus complicating any investigation of cooperative interactions in the recognition sites.
86. Wulff, G.; Haarer, J. Makromol. Chem. 1991, 192, 1329.
87. Whitcombe, M. J.; Rodriguez, M. E.; Villar, P.; Vulfson, E. N. J. Am. Chem. Soc. 1995, 117, 7105-7111.
88. Lennarz, W. J.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 2172-2175.
89. This compound was first reported in a Ph.D. Thesis (Dederichs, W. Ph.D. Dissertation, University of Dusseldorf, Germany, 1983), and its potential as a binding group for monoalcohols was alluded to in reviews (see: Wulff, G. Pure Appl. Chem. 1982, 11, 2093-2102. Wulff, G.; Dederichs, W.; Grotstollen, R.; Jupe, C. In Affinity Chromatography and Related Techniques; Gibnau, T. C. J., Visser, J., Nivard, R. J. F., Eds.; Elsevier: Amsterdam, 1982; pp 207-216).
90. This compound was first reported in a Ph.D. Thesis (Dederichs, W. Ph.D. Dissertation, University of Dusseldorf, Germany, 1983), and its potential as a binding group for monoalcohols was alluded to in reviews (see: Wulff, G. Pure Appl. Chem. 1982, 11, 2093-2102. Wulff, G.; Dederichs, W.; Grotstollen, R.; Jupe, C. In Affinity Chromatography and Related Techniques; Gibnau, T. C. J., Visser, J., Nivard, R. J. F., Eds.; Elsevier: Amsterdam, 1982; pp 207-216).
91. 1H NMR assignment of these complexes has been published (Smith, C. R.; Whitcombe, M. J.; Vulfson, E. N. In Separations for Biotechnology 3; Pyle, D. L., Ed.: Royal Society of Chemistry: Cambridge, UK, 1994; pp 482-488).
92. 3, monitoring the 3α and 17α protons at 4.2 and 4.3 ppm, respectively, indicated that the complexes remained intact up to the point of gelation, when signal broadening rendered spectra difficult to interpret. IR spectra of the polymers prior to washing did not display free hydroxyl bands, further suggesting that the boronophthalide esters were not decomposed under the polymerization conditions.
93. Ground polymers were not subject to any particle sizing. In view of the slow kinetics of binding and the fact that polymers were used at equilibrium, it was not considered necessary.
94. 2, uptake of templates was exceedingly slow. No binding of sterol to drying agent alone was observed.
95. Previous reports (Wulff, G.; Vietmeier, J.; Poll, H. G. Makromol. Chem. 1987, 188, 731-740) have suggested that EGDMA-based imprinted polymers were superior in performance to those made with DVB, due possibly to the greater flexibility of the polymer chains, thus allowing facile removal and rebinding of templates. However, in this work, no problems were encountered in template removal with DVB polymers, which was essentially quantitative in all cases, and in uptake experiments these polymers performed as well as those prepared with EGDMA.
96. The improvement in selectivity engendered by the introduction of a second binding group in the imprinted site has been well-documented by Wulff, (see ref 1d, pp 1819 and references therein).
97. The best uptake of templates was shown in the solvent used for polymerization, chloroform, which accords well with previous observations (Spivak, D.; Gilmore, M. A.; Shea, K. J. J. Am. Chem. Soc. 1997, 119, 4388-4393), suggesting that the imprinted site returns to its original conformation only if swollen by the correct solvent. Nevertheless, some binding of templates was observed in tetrahydrofuran and ethyl acetate, with the pattern of sterol binding being rather similar to that seen in chloroform.
98. The increase in levels of template loading from 2.5 and 5 mol % for DVB polymers (and for 2-5 mol % imprinted polymers prepared from EGDMA and TRIM) did not lead to a difference in the selectivity of ligand binding, as might be anticipated if the sites became less isolated. Clearly, if the sites were not sufficiently isolated, the difunctional template 3 might "bridge" boronophthalide residues from adjacent sites, and the level of uptake would have decreased relative to that of 1 and 2. In addition, if the sites were "poorly defined", reaction of excess monoalcohol 1 and diol 3, respectively, with androst-5-ene-3β,17β-diol-imprinted polymer should lead to substantially higher level of binding of 1 as compared to 3 (i.e., two one-point bindings of the mono-alcohol as opposed to one two-point binding of the diol). In fact, only 1 mol of androst-5-ene-3β-ol bound per bifunctional site, suggesting that binding of androst-5-ene-3β-ol in the cavity rendered the second residue of boronophthalide completely unreactive, presumably due to steric shielding: once one molecule was bound, a second could not enter the site.
99. The formation of the boronophthalide-sterol esters was followed by IR and NMR: representative spectra for starting materials and the product of reaction between 3 and I are appended as Supporting Information.
100. Shea and Sasaki, in their detailed study (ref 25) of acetal-forming reaction between benzylic alcohols and diketones, also observed that, despite extensive one-point binding taking place after 24 h in the imprinting sites, even after a further 24 h reaction time only 60% of the difunctional template was bound covalently at both positions. The authors suggested that this was largely due to a rate-limiting segmented chain motion of the polymer backbone supporting the binding groups: this reasoning should apply in our case, too.
101. -1, even after 36 h reflux, may indicate that a number of sterol hydroxyl groups were attached to the polymer via hydrogen bonds rather than as esters: however, the low intensity of this band suggests that this number was small.
102. 3 at reflux), both the 3β and 17β hydroxyl groups were rapidly acylated in solution in the absence of polymer. The same acylation procedure carried out on polymer P3 prior to hydrolysis (i.e., with androst-5-ene-3β,17β-diol remaining bound to the polymer) yielded only the unmodified diol in the protic wash fraction.
103. Although the two isomeric mono-acetates were resolvable by TLC, GC analysis under a range of conditions failed to effect baseline separation.
104. 1H NMR (monitoring the 3α and 17α protons at 4.2 and 4.3 ppm, respectively) indicated that the complexes did not break down under these conditions, and no acetylation of the steroid hydroxyl groups took place while esterified with boronophthalide.
105. This provided further evidence for site isolation: reaction of androst-5-ene-3β,17β-diol (added in excess) with P3 (250 mg, theoretical boronophthalide content 366 μmol/g) led to the binding of 46 ± 2 μmol (188 ± 8 μmol/g) of sterol, corresponding to 100-104% occupation of available binding sites (based on theoretical content and template removal, respectively) or 0.51-0.52 mol of sterol/mol of available boronophthalide group rather than the theoretical value of 0.5. If this was a "coincidence" with the ligand forming "random" covalent bonds in bridging sites, acylation of the polymer bound diol should have yielded a significant amount of monoacetates, rather than the 3% observed.
106. For a discussion of polymeric supports used as protecting groups, see: Hodge, P. In Syntheses and Separations Using Functional Polymers; Sherrington, D. C., Hodge, P., Eds.; John Wiley & Sons: Chichester, 1988; pp 43-122.
107. No previous NMR data were available for this compound; however, the 11α-proton in a structurally similar 11-acetoxyandrost-5-ene sterol was reported with a chemical shift of 5.2-5.3 ppm (Moon, S.; Stuhmiller, L. M.; Chadha, R. K.; McMorris, T. C. Tetrahedron 1990, 46, 2287-2306).
108. 3 at reflux for 4 h.
109. Androst-5-ene-3β,11β,17β-triol was formerly obtainable in milligram quantities from Sigma, but production was discontinued before the end of the project.
110. 1H NMR spectroscopy, following proton resonances at C3β (4.5 ppm) and C7β (4.8 ppm) or C12β (4.7 ppm), verified the complete formation of the complexes.
111. The removal of adsorbed template in this way ensured that the product distribution reflected only modifications of templates bound at or in the sites.
112. 3 at reflux), in solution in the absence of polymer all the steroid hydroxyl groups were acylated. Thus, any difference in the pattern of acetate products was due to the effect of the polymer imprint site, rather than that of the intrinsic reactivity of the sterols.
113. The differences in the reactivity of the various hydroxyl groups on the cholic acid framework have been considered thoroughly elsewhere (Baker, J. F.; Blickenstaff, R. T. J. Org. Chem. 1975, 40, 1579) (and by Bonar-Law et al. in ref 57); however, in this case, binding of the sterol to the polymer was more likely to occur via the reactive primary hydroxyl at C24 rather than the secondary hydroxyl groups at C3, C7, and C12.
114. The formation of diesters might also be expected for "unmatched" template-polymer complexes, but none were observed, due possibly to the difficulties in fitting two acetate groups into the sites.
115. Characterization of reaction products was based on NMR assignments. See: (a) Bonar-Law, R. P.; Davis, A. P. Tetrahedron 1993, 49, 9845-9854.
116. (b) Bonar-Law, R. P.; Davis, A. P.; Dorgan, B. J. Tetrahedron 1993, 49, 9855-9866 and references therein.
117. 4 introduced into imprinted sites after template removal. This is, however, different from carrying out regioselective modifications with added reagents using imprinted polymers as "self-assembled" protecting groups.
118. Khmelnitsky, Y. L.; Budde, C.; Arnold, J. M.; Usyatinsky, A.; Clark, D. S.; Dordick, J. S. J. Am. Chem. Soc. 1997, 119, 11554-11555.
119. Perrin, D. D.; Armanego, W. F.; Perrin, D. R. Purification of Laboratory Chemicals, 2nd ed.; Pergamon: Oxford 1980.
120. Halsall, T. G.; Jones, E. R. H.; Tan, E. L.; Chaudhry, G. R. J. Chem. Soc. C. 1966, 1374-1383.
121. Crabb, T. A.; Dawson, P. J.; Williams, R. O. J. Chem. Soc., Perkin Trans. 1 1980, 2535-2541.
122. Shoppee, C. W.; Killick, R. W. J. Chem. Soc. C 1970, 1513.
123. Suginome, H.; Nakayama, Y. J. Chem. Soc., Perkin Trans. 1 1992, 1843-1847.
124. Johns, W. F.; Salomon, K. W. J. Org. Chem. 1971, 36, 1952-1960.
125. Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 3415-3417.
126. Bonar-Law, R. P.; Davis, A. P.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1 1990, 2245-2250.
127. Kihira, K.; Mikami, T.; Ikawa, S.; Okamoto, A.; Yoshii, M.; Miki, S.; Mosbach, E. H.; Hoshita, T. Steroids 1992, 57, 193-198.
128. Ahmed, S.; Alauddin, M.; Caddy, B.; Martin-Smith, M.; Sidwell, W. T. L.; Watson, T. R. Aust. J. Chem. 1971, 24, 521-547.
129. Spero, G. B.; McIntosh, A. V.; Levin, R. H. J. Am. Chem. Soc. 1948, 70, 1907-1910.
130. Hammann, P. E.; Habermehl, G. G. Z. Naturforsch. B 1987, 42, 781-782.
131. Posner, G. H.; Oda, M. Tetrahedron Lett. 1981, 22, 5003-5006.