Solid-Phase Synthesis and Combinatorial Technologies

REFERENCES 333

116.Needels, M. C., Jones, D. G., Tate, E. H., Heinkel, G. L., Kochersperger, L. M., Dower,

W.J., Barrett, R. W. and Gallop, M. A., Proc. Natl. Acad. Sci. USA 90, 10700–10704 (1993).

117.St. Hilaire, P. M., Willert, M., Juliano, M. A., Juliano, L. and Meldal, M.,J. Comb. Chem. 1, 509–523 (1999).

118.Kassarjian, A., Schellenberger, V. and Turck, C. W., Pept. Res. 6, 129–133 (1993).

119.Nestler, H. P., Wennemers, H., Sherlock, R. and Dong, D. L. Y.,Bioorg. Med. Chem. Lett. 6, 1327–1330 (1996).

120.Lam, K. S. and Wu, J., Methods 6, 401–403 (1994).

121.Meldal, M., Svendsen, L, Breddam, K. and Auzanneau, F.-I., Proc. Natl. Acad. Sci. USA 91, 3314–3318 (1994).

122.Meldal, M. and Svendsen, I., J. Chem. Soc., Perkin Trans. 1, 1591–1596 (1995).

123.Lou, Q., Leftwich, M. E. and Lam, K. S., Bioorg. Med. Chem. 4, 677–682 (1996).

124.Salmon, S. E., Lam, K. S., Lebl, M., Kandola, A., Khattri, P. S., Wade, S., Patek, M., Kocis, P., Krchnak, V. et al., Proc. Natl. Acad. Sci. USA 90, 11708–11712 (1993).

125.Berkessel, A. and Herault, D. A., Angew. Chem. Int. Ed. 38, 102–105 (1999).

126.Cho, C. Y., Liu, C. W., Wemmer, D. E. and Schultz, P. G., Bioorg. Med. Chem. 7, 1171–1179 (1999).

127.St. Hilaire, P. M., Lowary, T. L., Meldal, M. and Bock, K., J. Am. Chem. Soc. 120, 13312–13320 (1998).

128.Madden, D., Krchnak, V. and Lebl, M., Persp. Drug Disc. Design 2, 269–285 (1995).

129.Vagner, J., Barany, G., Lam, K. S., Krchnak, V., Sepetov, N. F., Ostrem, J. A., Strop, P. and Lebl, M., Proc. Natl. Acad. Sci. USA 93, 8194–8199 (1996).

130.Leon, S., Quarrell, R. and Lowe, G., Bioorg. Med. Chem. Lett. 8, 2997–3002 (1998).

131.Quarrell, R., Claridge, T. D. W., Weaver, G. W. and Lowe, G., Mol. Diversity 1, 223–232 (1996).

132.Marsh, I. R., Smith, H. K., Leblanc, C. and Bradley, M.,Mol. Diversity 2, 165–170 (1997).

133.Smith, H. K. and Bradley, M., J. Comb. Chem. 1, 326–332 (1999).

134.Kapoor, T. M., Andreotti, A. H. and Schreiber, S. L.,J. Am. Chem. Soc. 120, 23–29 (1998).

135.Morken, J. P., Kapoor, T. M., Feng, S., Shirai, F. and Schreiber, S. L., J. Am. Chem. Soc. 120, 30–36 (1998).

136.Rickles, R. J., Botfield, M. C., Zhou, X.-M., Henry, P. A., Brugge, J. S. and Zoller, M. J.,

Proc. Natl. Acad. Sci. USA 92, 10909–10913 (1995).

137.Combs, A. P., Kapoor, T. M., Feng, S., Chen, J. K., Daude-Snow, L. F. and Schreiber, S. L., J. Am. Chem. Soc. 118, 287–288 (1996).

138.Erb, E., Janda, K. D. and Brenner, S.,Proc. Natl. Acad. Sci. USA 91, 11422–11426 (1994).

139.Sutherlin, D. P. and Armstrong, R. W., J. Org. Chem. 62, 5267–5283 (1997).

140.Gordeev, M. F., Patel, D. V. and Gordon, E. M., J. Org. Chem. 61, 924–928 (1996).

141.Gordeev, M. F., Patel, D. V., England, B. P., Jonnalagadda, S., Combs, J. D. and Gordon,

E.M., Bioorg. Med. Chem. 6, 883–889 (1998).

142.Bellemann, P., Schade, A. and Towart, R., Proc. Natl. Acad. Sci. USA 80, 2356–2360 (1983).

143.Baldwin, J. J. and Dolle, R. E., Annu. Rep. Combi. Chem. Mol. Div. 1, 287–297 (1997).

334SYNTHETIC ORGANIC LIBRARIES: SOLID-PHASE POOL LIBRARIES

144.Schriemer, D. C. and Hindsgaul, O., Combi. Chem. High Throughput Screen . 1, 155–170 (1998).

145.Seneci, P., in Combinatorial Chemistry and Combinatorial Technologies: Methods and Applications, S. Miertus and G. Fassina (Eds.). Marvel Dekker, New York, 1999, 91–125.

146.Rohrer, S. P., Birzin, E. T., Mosley, R. T., Berk, S. C., Hutchins, S. M., Shen, D.-M., Xiong, Y., Hayes, E. C., Parmar, R. M. and Foor, F., Science 282, 737–740 (1998).

147.Rohrer, S. P. and Berk, S. C., Curr. Opin. Drug Discovery Dev . 2, 293–303 (1999).

148.Berk, S. C., Rohrer, S. P., Degrado, S. J., Birzin, E. T., Mosley, R. T., Hutchins, S. M., Pasternak, A., Schaeffer, J. M., Underwood, D. J. and Chapman, K. T., J. Comb. Chem. 1, 388–396 (1999).

149.Heizmann, G., Hildebrand, P., Tanner, H., Ketterer, S., Pansky, A., Froidevaux, S., Beglinger, C. and Eberle, A. N., J. Recept. Signal Transduction Res. 19, 449–466 (1999).

150.Lohse, A., Jensen, K. B. and Bols, M., Tetrahedron Lett. 40, 3033–3036 (1999).

151.Lohse, A., Jensen, K. B., Lundgren, K. and Bols, M., Bioorg. Med. Chem. 7, 1965–1971 (1999).

152.Roussel, P., Bradley, M., Kane, P., Bailey, C., Arnold, R. and Cross, A., Tetrahedron 55, 6219–6230 (1999).

153.Szardenings, A. K., Antonenko, V., Campbell, D. A., DeFrancisco, N., Ida, S., Shi, L., Sharkov, N., Tien, D., Wang, Y. and Navre, M., J. Med. Chem. 42, 1348–1357 (1999).

154.Ng, S., Goodson, B., Ehrhardt, A., Moos, W. H., Siam, M. and Winter, J., Bioorg. Med. Chem. 7, 1781–1785 (1999).

155.Martin, E. J., Blaney, J. M., Siani, M. A., Spellmeyer, D. C., Wong, A. K. and Moos, W. H., J. Med Chem. 38, 1431–1436 (1995).

156.Abato, P., Conroy, J. L. and Seto, C. T., J. Med. Chem. 42, 4001–4009 (1999).

157.Pinilla, C., Appel, J. R., Blanc, P. and Houghten, R. A.,BioTechniques 13, 901–905 (1992).

158.Pinilla, C., Buencamino, J., Appel, J. R., Hopp, T. P. and Houghten, R. A.,Mol. Diversity 1, 21–28 (1995).

159.Dooley, C. T., Ny, P., Bidlack, J. M. and Houghten, R. A.,J. Biol. Chem. 273, 18848–18856 (1998).

160.Pinilla, C., Appel, J. R., Campbell, G. D., Buencamino, J., Benkirane, N., Muller, S. and Greenspan, N. S., J. Mol. Biol. 283, 1013–1025 (1998).

161.Apletalina, E., Appel, J., Lamango, N. S., Houghten, R. A. and Lindberg, I.,J. Biol. Chem. 273, 26589–26595 (1998).

162.Pirrung, M. C. and Chen, J., J. Am. Chem. Soc. 117, 1240–1245 (1995).

163.Pirrung, M. C., Chau, J. H. L. and Chen, J., Chem. Biol. 2, 621–626 (1995).

164.Smith, P. W., Lai, J. Y. Q., Whittington, A. R., Cox, B., Houston, J. G., Stylli, C. H., Banks, M. N. and Tiller, P. R., Bioorg. Med. Chem. Lett. 4, 2821–2824 (1994).

165.Appel, J. R., Johnson, J., Narayanan, V. L. and Houghten, R. A.,Mol. Diversity 4, 91–102 (1999).

166.Blondelle, S. E., Crooks, E., Ostresh, J. M. and Houghten, R. A., Antimicrob. Ag. Chemother. 43, 106–114 (1999).

167.Berk, S. C. and Chapman, K. T., Bioorg. Med. Chem. Lett. 7, 837–842 (1997).

168.Deprez, B., Williard, X., Bourel, L., Coste, H., Hyafil, F. and Tartar, A.,J. Am. Chem. Soc. 117, 5405–5406 (1995).

REFERENCES 335

169.Carell, T., Wintner, E. A, Sutherland, A. J, Rebek, J. Jr, Dunayevskiy, Y. M and Vouros, P., Chem. Biol. 2, 171–183 (1995).

170.Campian, E., Peterson, M. L., Saneii, H. H. and Furka, A., Bioorg. Med. Chem. Lett. 8, 2357–2362 (1998).

171.Blake, J. and Litzi-Davis, L., Bioconjug. Chem. 3, 510–513 (1992).

172.Boger, D. L., Chai, W. and Jing, Q., J. Am. Chem. Soc. 120, 7220–7225 (1998).

173.Freier, S. M., Konings, D. A. M., Wyatt, J. R. and Ecker, D. J., Bioorg. Med. Chem. 4, 717–725 (1996).

174.Stankova, M., Strop, P., Chen, C. and Lebl, M., inMolecular Diversity and Combinatorial Chemistry, Chaiken, I. M. and Janda, K. D. (Eds.). ACS, Washington, DC, 1996, pp. 137–141.

175.Konings, D. A. M., Wyatt, J. R., Ecker, D. J. and Freier, S. M., J. Med. Chem. 39, 2710–2719 (1996).

176.Konings, D. A. M., Wyatt, J. R., Ecker, D. J. and Freier, S. M., J. Med. Chem. 40, 4386–4395 (1997).

177.Brenner, S. and Lerner, R. A., Proc. Natl. Acad. Sci. USA 89, 5381–5383 (1992).

178.Kerr, J. M., Banville, S. C. and Zuckermann, R. N., J. Am. Chem. Soc. 115, 2529–2531 (1993).

179.Nielsen, J. and Janda, K. D., Methods: Meth. Enzymol. 6, 361–371 (1994).

180.Nielsen, J., Brenner, S. and Janda, K. D., J. Am. Chem. Soc. 115, 9812–9813 (1993).

181.Needels, M. C., Jones, D. G., Tate, E. H., Heinkel, G. L., Kochersperger, L. M., Dower, W. J., Barrett, R. W. and Gallop, M. A., Proc. Natl. Acad. Sci. USA 90, 10700–10704 (1993).

182.Jones, D. G., Polym. Prepr. 35, 981–982 (1994).

183.Fenniri, H., Janda, K. D. and Lerner, R. A., Proc. Natl. Acad. Sci. USA 92, 2278–2282 (1995).

184.Fenniri, H., CHEMTECH 26, 15–25 (1996).

185.Nikolaiev, V., Stierandova, A., Krchnak, V., Seligmann, B., Lam, K. S., Salmon, S. E. and Lebl, M., Pept. Res. 6, 161–170 (1993).

186.Hornik, V. and Hadas, E., React. Polym. 22, 213–220 (1994).

187.Felder, E. R., Heizmann, G., Matthews, I. T., Rink, H. and Spieser, E., Mol. Diversity 1, 109–112 (1996).

188.Dawson, P. E., Fitzgerald, M. C., Muir, T. W. and Kent, S. B. H., J. Am. Chem. Soc. 119, 7917–7927 (1997).

189.Nestler, H. P., Bartlett, P. A. and Still, W. Clark, J. Org. Chem. 59, 4723–4724 (1994).

190.Burger, M. T. and Clark Still, W., J. Org. Chem. 60, 7382–7383 (1995).

191.Cheng, Y., Suenaga, T. and Still, W. Clark, J. Am. Chem. Soc. 118, 1813–1814 (1996).

192.Clark Still, W., Acc. Chem. Res. 29, 155–163 (1996).

193.Liang, R., Yan, L, Loebach, J., Ge, M., Uozumi, Y., Sekanina, K., Horan, N., Gildersleeve, J., Thompson, C. et al., Science 274, 1520–1522 (1996).

194.Baldwin, J. J., Mol. Diversity 2, 81–88 (1996).

336SYNTHETIC ORGANIC LIBRARIES: SOLID-PHASE POOL LIBRARIES

195.Dilanni Carroll, C., Patel, H., Johnson, T. O., Guo, T., Orlowski, M., He, Z.-M., Cavallaro,

C.L., Guo, J., Oksman, A., Gluzman, I. Y., Connelly, J., Chelsky, D., Goldberg, D. E. and Dolle, R. E., Bioorg. Med. Chem. Lett. 8, 2315–2320 (1998).

196.Tan, D. S., Foley, M. A., Shair, M. D. and Schreiber, S. L., J. Am. Chem. Soc. 120, 8565–8566 (1998).

197.Ni, Z.-J., Maclean, D., Holmes, C. P., Murphy, M. M., Ruhland, B., Jacobs, J. W., Gordon,

E.M. and Gallop, M. A., J. Med. Chem. 39, 1601–1608 (1996).

198.Fitch, W. L., Baer, T. A., Chen, W., Holden, F., Holmes, C. P., Maclean, D., Shah, N., Sullivan, E., Tang, M., Waybourn, P., Fischer, S. M., Miller, C. A., Snyder, L. R.,J. Comb. Chem. 1, 188–194 (1999).

199.Lane, S. J. and Pipe, A., Rapid Commun. Mass Spectrom. 12, 667–674 (1998).

200.Lane, S. J. and Pipe, A., Rapid Commun. Mass Spectrom. 13, 798–814 (1999).

201.Atuegbu, A., Maclean, D., Nguyen, C., Gordon, E. M. and Jacobs, J. W., Bioorg. Med. Chem. 4, 1097–1106 (1996).

202.Ni, Z.-J., Maclean, D., Holmes, C. P. and Gallop, M. A., Meth. Enzymol. 267, 261–272 (1996).

203.MacLean, D., Schullek, J. R., Murphy, M. M., Ni, Z.-J., Gordon, E. M. and Gallop, M. A., Proc. Natl. Acad. Sci. USA 94, 2805–2810 (1997).

204.Silen, J. L., Lu, A. T., Solas, D. W., Gore, M. A., Maclean, D., Shah, N. H., Coffin, J. M., Bhinderwala, N. S., Wang, Y., Tsutsui, K. T., Look, G. C., Campbell, D. A., Hale, R. L., Navre, M. and DeLuca-Flaherty, C. R., Antimicrob. Ag. Chemother. 42, 1447–1453 (1998).

205.Garigipati, R. S. and Adams, J. L., WO Patent 9630337 A1, 961003, 32 pp.

206.Geysen, H. M., Wagner, C. D., Bodnar, W. M., Markworth, C. J., Parke, G. J., Schoenen,

F.J., Wagner, D. S. and Kinder, D. S., Chem. Biol. 3, 679–688 (1996).

207.Wagner, D. S., Markworth, C. J., Wagner, C. D., Schoenen, F. J., Rewerts, C. E., Kay, B.

K.and Geysen, H. M., Combi. Chem. High Throughput Screen . 1, 143–153 (1998).

208.Rahman, S. S., Busby, D. J. and Lee, D. C., J. Org. Chem. 63, 6196–6199 (1998).

209.Hochlowski, J. E., Whittern, D. N. and Sowin, T. J., J. Comb. Chem. 1, 291–293 (1999).

210.Scott, R. H., Barnes, C., Gerhard, U. and Balasubramanian, S., Chem. Commun., 1331– 1332 (1999).

211.Guo, J., Wu, J., Siuzdak, G. and Gary, F. M. G., Angew. Chem. Int. Ed. 38, 1755–1758 (1999).

212.Czarnik, A. W., Curr. Opin. Chem. Biol. 1, 60–66 (1997).

213.Jacobs, J. W. and Ni, Z.-J., in Combinatorial Chemistry and Molecular Diversity in Drug Discovery, E. M. Gordon and J. Kerwin (Eds.). Wiley-Liss, New York, 1998, pp. 271–290.

214.Seneci, P., in Combinatorial Chemistry and Combinatorial Technologies: Methods and Applications, S. Miertus and G. Fassina (Eds.). Marcel Dekker, New York, 1999, pp. 127–167.

215.Terrett, N., Combinatorial Chemistry. Oxford University Press, Oxford, UK, 1999, pp. 77–94.

216.Baldwin, J. J. and Dolle, R., in A Practical Guide to Combinatorial Chemistry , A. W. Czarnik and S. H. DeWitt (Eds.). ACS, Washington DC, 1997, pp. 153–174.

REFERENCES 337

217.Barnes, C,. Scott, R. H. and Balasubramanian, S.,Recent Res. Dev. Org. Chem. 2, 367–379 (1998).

218.Scott, R. H. and Balasubramanian, S., Bioorg. Med. Chem. 7, 1567–1572 (1997).

219.Egner, B. J., Rana, S., Smith, H., Bouloc, N., Frey, J. G., Brocklesby, W. S. and Bradley, M., Chem. Commun. 735–736 (1997)

220.Main, B. G. and Shute, R. E., WO Patent 9703931 A1, June 2nd, 1997.

221.Hughes, I., J. Med. Chem. 41, 3804–3811 (1998).

222.Guiles, J. W., Lanter, C. L. and Rivero, R. A.,Angew. Chem. Int. Ed. 37, 926–932 (1998).

223.Xiao, X., Zhao, C., Potash, H. and Nova, M. P., Angew. Chem. Int. Ed. Engl. 36, 780–782 (1997).

224.Gercken, B., Felder, E., Rink, H. and Vetter, D., Spec. Publ - R. Soc. Chem 241, 222–234 (1999).

225.Nicolaou, K. C., Xiao, X.-Y., Parandoosh, Z., Senyei, A. and Nova, M. P.,Angew. Chem. Int. Ed. Engl. 34, 2289–2291 (1995).

226.Moran, E. J., Sarshar, S., Cargill, J. F., Shahbaz, M. M., Lio, A., Mjalli, A. M. M. and Armstrong, R. W., J. Am. Chem. Soc. 117, 10787–10788 (1995).

227.Mendonca, A. J., Am. Laboratory 30, 46–47 (1998).

228.Li, R., Xiao, X.-Y. and Czarnik, A. W., Tetrahedron Lett. 39, 8581–8584 (1998).

229.Zhao, C., Shi, S., Mir, D., Hurst, D., Li, R., Xiao, X.-Y., Lillig, J. and Czarnik, A. W., J. Comb. Chem. 1, 91–95 (1999).

230.TranSort and TranStems, Chiron Technologies Pty Ltd. http://www.chirontechnologies.com.au/product/frame2.htm

231.Xiao, X.-Y., Parandoosh, Z. and Nova, M. P., J. Org. Chem. 62, 6029–6033 (1997).

232.Nicolaou, K. C., Vourloumis, D., Li, T., Pastor, J., Winssinger, N., He, Y., Ninkovic, S., Sarabia, F., Vallberg, H., Roschangar, F., King, N. P., Finlay, M. R. V., Giannakakou, P., Verdier-Pinard, P. and Hamel, E., Angew. Chem. Int. Ed. Engl. 36, 2097–2103 (1997).

233.Zhu, Z. and McKittrick, B., Tetrahedron Lett. 39, 7479–7482 (1998).

234.Brown, A. R., J. Comb. Chem. 1, 283–285 (1999).

235.Sofia, M. J., Allanson, N., Hatzenbuhler, N. T., Jain, R., Kakarla, R., Kogan, N., Liang, R., Liu, D., Silva, D. J., Wang, H., Gange, D., Anderson, J., Chen, A., Chi, F., Dulina, R., Huang, B., Kamau, M., Wang, C., Baizman, E., Branstrom, A., Bristol, N., Goldman, R., Han, K., Longley, C., Midha, S. and Axelrod, H. R.,J. Med. Chem. 42, 3193–3198 (1999).

236.Andres, C. J., Swann, R. T., Severino, J., Grant-Young, K., Edinger, K., Mongillo, J. and Deshpande, M. S., Biotechnol. Bioeng. 61, 93–94 (1998).

237.Andres, C. J., Swann, R. T., Grant-Young, K., D’Andrea, S. V. and Deshpande, M. S.,

Comb. Chem. High Throughput Screening 2, 29–32 (1999).

238.Parandoosh, Z., Knowles, S. K., Xiao, X-Y., Zhao, C., David, G. S. and Nova, M. P.,

Combi. Chem. High Throughput Screen. 1, 135–142 (1998).

239.Shi, S., Xiao, X.-Y. and Czarnik, A. W., Biotechnol. Bioeng. 61, 6–12 (1998).

240.Tan, D. S., Foley, M. A., Stockwell, B. R., Shair, M. D. and Schreiber, S. L.,J. Am. Chem. Soc. 121, 9073–9087 (1999).

241.Borchardt, A., Liberles, S. D., Biggar, S. R., Crabtree, G. R. and Schreiber, S. L.,Chem. Biol. 4, 961–968 (1997).

338SYNTHETIC ORGANIC LIBRARIES: SOLID-PHASE POOL LIBRARIES

242.You, A. J., Jackman, R. J., Whitesides, G. M. and Schreiber, S. L.,Chem. Biol. 4, 969–975 (1997).

243.Stockwell, B. R., Haggarty, S. J. and Schreiber, S. L., Chem. Biol. 6, 71–83 (1999).

244.MacBeath, G., Koehler, A. N. and Schreiber, S. L., J. Am. Chem. Soc. 121, 7967–7968 (1999).

245.Brown, B. B., Wagner, D. S. and Geysen, H. M., Mol. Diversity 1, 4–12 (1995).

246.Tamura, O., Okabe, T., Yamaguchi, T., Gotanda, K., Noe, K. and Sakamoto, M.,Tetrahedron 51, 107–118 (1995).

247.Tamura, O., Okabe, T., Yamaguchi, T., Kotani, J., Gotanda, K., and Sakamoto, M., Tetrahedron 51, 119–128 (1995).

248.McGowan, D. A. and Berchtold, G. A., J. Org. Chem. 46, 2381–2383 (1981).

249.Wood, H. B. and Ganem, B., J. Am. Chem. Soc. 112, 8907–8909 (1990).

250.Keirs, D. and Overton, K., Heterocycles 28, 841–848 (1989).

251.Acheson, R. M. and Lee, G. C. M., J. Chem. Soc., Perkin Trans. 1, 2321–2332 (1987).

252.Schena, M., Shalon, D., Davis, R. W. and Brown, P. O., Science 270, 467–470 (1995).

253.Oldenburg, K. R., Vo, K. T., Ruhland, B., Schatz, P. J. and Yuan, Z.,J. Biomol. Screening 1, 123–130 (1996).

254.Schullek, J. R., Butler, J. H., Ni, Z.-J., Chen, D. and Yuan, Z.,Anal. Biochem. 246, 20–29 (1997).

340 SYNTHETIC ORGANIC LIBRARIES: SOLUTION-PHASE LIBRARIES

Figure 8.1 Solution phase versus solid phase: relative strengths.

and catalyst that are suited to the selected synthetic route. The use of a solid support limits the choice of reagents (interactions with the support itself must be avoided), solvents (a good swelling is needed), temperature (extremely low and high temperatures must be avoided), concentrations (diluted reagent solutions will not yield complete coupling with the support), and catalysts (heterogeneous catalysts cannot be used).

•A knowledge of the theoretical and experimental notions of solution-phase chemistry is possessed by any good chemist; however, a deep understanding of the implications of carrying out a reaction on a support, such as the choice of reaction vessels or SP synthesizer and of equipment needed for the handling and/or purification of samples, is acquired mostly by direct experience and is not yet widely spread among synthetic chemists in general.

•When the target molecule is similar to known structures, or when a sound synthetic scheme is drawn, the assessment of the best experimental conditions in solution is straightforward, while the transfer of a reaction sequence onto SP requires more theoretical (selection of the best support and linker) and experimental work to find appropriate reaction conditions.

•Homogeneous reactions are monitored by simple and effective methods, such as TLC, and characterized using a wide variety of analytical techniques, whereas the synthesis of supported intermediates and/or final products can only be monitored by sophisticated on-bead methods or after cleavage from the support.

•The use of a support and a linker requires at least two additional chemical steps, the anchoring to the support at the beginning of the synthesis and the final cleavage of the target compound.

The only advantages of SPS techniques for the preparation of single compounds are the purification/work-up procedures, which usually involve filtering off the solvents and washing the resin beads with fresh solvents and the use of a large excess of reagents in solution to drive the reactions to completion. Reactions in solution usually require work-up procedures including extractions, concentrations, drying, and often chromatographic purification. Nevertheless, the advantages of the synthesis of single compounds in solution override these inconveniences and generally render this the preferred format for single-compound synthesis. Solid-phase chemistry has some niche applications, for example when the support is used as a protecting group in a

8.1 SOLUTIONVERSUS SOLID-PHASE SYNTHETIC LIBRARIES: WHICH ONES TO USE? 341

synthetic scheme and the loading/cleavage steps are equivalent to a protection/deprotection protocol.

The comparison is different when dealing with combinatorial libraries:

•Simultaneous handling of multiple reactions make simple automated purification protocols extremely important when large libraries are being considered.

•Resin beads, which can be considered as individual microreactors, allow the use of mix-and-split techniques, which are not applicable when using homogeneous reaction conditions.

•Miniaturization of reaction scale-down to the level of a single bead in SP reduces the amount of precious reagents and solvents used.

•Solid-phase is more suited to partially or totally automated synthetic procedures, freeing the chemist from having to perform the more repetitive operations.

Having said this, the synthesis of solution-phase libraries is possible, and indeed is more appropriate, than the corresponding SP chemistry under certain circumstances. The value of such libraries is discussed in the following sections, but it is appropriate to stress the concept of complementarity, rather than mutual exclusivity of the solution and SP library formats. The goal for a combinatorial chemist is always to select the best library format according to the needs of the project without exclusion of individual options due to personal preference.

8.1.2 Pool Libraries: Solution Versus Solid Phase

SP pool libraries benefit greatly from the mix-and-split technique, which can produce high-quality libraries when a fully validated and rehearsed synthetic scheme is used. The loading of a single compound on each bead, the roughly equimolar quantity of each library component in a pool, and the ease of handling and purification of resin aliquots are not matched by any library synthesis method in solution. Only the postsynthesis mix of solutions would provide comparable pools, but such a method is only useful for the pooling of large, preexisting compound collections for screening. This is a serious limitation for solution-phase pool libraries; nevertheless, several interesting approaches to the synthesis of pools in solution have been reported and will be discussed here.

Most of the early work was restricted to a few high-yielding chemical transformations typically leading to amide libraries and employing monomer sets as equimolar mixtures of all their representatives. For example, Smith et al. (1) reported a 1600-member library of amides as two 40-pool sublibraries suitable for structure determination by positional scanning (see Section 7.3.3) and Storer (2) and Bailey et al. (3) described the preparation of a 160,000-member library of diamides made by capping an acid function with a mixture of amines and obtaining 4000 pools that were subsequently deconvoluted using iterative deconvolution. The synthesis and deconvolution by positional scanning of five small pool libraries was reported recently; namely, carbamates were obtained from the reaction of alcohols with isocyanates (54 members divided into two sublibraries) (4); tetrahydroacrid-

342 SYNTHETIC ORGANIC LIBRARIES: SOLUTION-PHASE LIBRARIES

ines from the reaction of cyclohexanones with aromatic aminonitriles (72 members, two sublibraries) (5); diamide analogues of a human neurokinin 3 receptorantagonist from the reaction of highly functionalized amines with acylating agents (49 members, two sub-libraries) (6); polyenes from the Sonogashira coupling reaction of vinyl iodides with alkynes (42 members, two sublibraries) (7); chalcones from aldolic condensation of naphthyl ketones with benzaldehydes (20 members, two sublibraries) (8). A 700-member pool library of functionalized thiazoles prepared from a-haloketones, aromatic nitroaldehydes, and cyclic anhydrides aimed at finding leukotriene D4 antagonists by iterative deconvolution has been described (9). Vendeville et al. (10) reported the synthesis of a 2560-member tetrahydroisoquinoline carboxylic acid (Tic)-based library as 32 pools of 80 compounds that was iteratively deconvoluted to give a low-nanomolar positive against a parasitic prolyl endopeptidase target. Decoration of orthogonally protected piperazine with aryl nitrofluorides and acyl chlorides to give a 48-member arylpiperazine pool library was described by Neuville and Zhu (11). Epoxide opening with amines to give a library of over 6000 β-aminoalcohols made as four-member pools was described by Chng and Ganesan (12). Epoxide opening was also used by van Niel et al. (13) to prepare a large pool library of 3-aryloxy- 2-propanolamines which was iteratively deconvoluated to give a dual affinity ligand for 5-HT1A and serotonin re-uptake receptors. Yu et al. (14) prepared 13 large β-cyclodextrin libraries (>28,000 individuals) using a common scaffold and decorating it with mixtures of amines; the libraries were tested for their phosphataselike hydrolytic activity and iterative deconvolution was planned for the active pools.

A few other reports merit more attention. The decoration of a number of symmetrical carboxylic acid scaffolds (8.1–8.3, Fig. 8.2) with amines to give large amide or urea libraries that were characterized and deconvoluted using subtractive deconvolution (see section 7.3.3) has been reported by Rebek and co-workers (15–22). Solution-phase pool libraries of polyazapyridinocyclophane scaffolds containing macrocycles of various sizes (8.4–8.6) and the synthesis of linear pyridinopolyamine, oxyamine, and piperazine scaffolds (8.7–8.9) made by the simultaneous addition of functionalities via selective deprotection/coupling protocols followed by iterative deconvolution have also been described (23–29); the same group has also carefully monitored the synthesis of some pool libraries via capillary electrophoresis (30), and has deconvoluted some other libraries via HPLC fractionation (31). Large solution-phase pool libraries have been prepared from iminodiacetic acid–based (8.10, 8.11) and tricyclic scaffolds (8.12, Fig. 8.2) by acylation, olefin metathesis, and reduction, with deconvolution either by positional scanning or by deletion synthesis (32–34).

The above reports have produced valuable, large solution-phase libraries taking advantage of specific structural features, such as the symmetry of common scaffolds, the wide knowledge accumulated on the reactions used, or the extreme similarity of reactivities of the monomers. Thus, these approaches cannot be generally applied to a wide diversity of scaffolds, monomers with significantly different reactivities, or difficult reaction steps that produce incomplete reactions or side-products. Consequently, the general synthesis of solution-phase pool libraries is not possible, and for