Synthesis of new calcineurin inhibitors via Pd-catalyzed cross-coupling reactionsLunxiang Yin111.11.1.18#71.1.22602#5983499#1401.1.3565#1514507#127595#1655540#1481.21.2.1316#21461.2.2593#5901.2.37514#2501.381.3.11.3.1.19491#375497#11510563#99499#18711538#103538#1031.3.1.212448#388508#2131.3.1.313435#275495#1861.3.1.414403#273437#1691.3.2151.3.2.116514#1001.3.2.217555#157467#20018516#2121.3.31.3.3.1410#2111.3.3.219544#195570#16320410#151516#115531#1972212.1158#10122559#273491#307232.22.2.1482#3102425497#3942.2.226540#265403#31527333#11928444#251427#26129444#1202.3302.3.1555#36731529#252322.3.2605#3172.42.4.133516#11034518#13435604#301474#19836531#3112.4.237382#1362.538553#52039508#264527#3592.640358#11341459#4592.72.7.142489#205489#1212.7.2582#1243433.13.1.1192#893.1.244352#256350#36645420#334546#25546348#266363#38647363#259471#37648328#122476#36249605#505453#132503.1.3279#126543#27051520#27452404#256353#134549#13053476#1593.1.4516#31054453#113451#108482#3103.255353#105493#92563.2.1531#2263.2.257567#2923.2.3518#2293.2.458525#145527#2513.3593.3.1353#111469#18660433#199558#158440#1283.3.261545#2063.3.362525#289482#24063518#2814644.14.1.14.1.1.165493#222511#26366480#110558#107509#1904.1.1.267487#25768592#117554#26869493#1394.1.2585#120538#11270514#144601#1474.1.34.1.3.171563#254485#26372527#3224.1.3.273467#365513#2994.2744.2.1493#187476#8575453#112478#98520#104460#18376489#97451#57498#82422#18277547#205489#90476#984.2.278556#5594.379563#115540#209505#18480507#175476#9581549#2644.465#7082471#205491#189471#18983509#193514#195382#10384482#255487#141500#1344.58565#64482#35386520#237440#24187514#3024.688429#90447#94589#184493#14789536#98456#120433#98511#10890464#301438#10291422#203552#2845925.15.293181#162565#14694109#61116#93109#93123#91130#90127#72130#5585#71137#86107#91116#89112#929594#90112#105109#105118#105121#91118#105121#91109#105123#75132#5996126#116113#101128#96120#64122#63122#64122#39126#59149#4198#66156#3997134#54134#52107#51115#51115#65115#53122#68117#54508#31798141#58134#61143#48134#55130#53134#55143#48126#51141#58145#59139#5999117#56128#56149#89137#69132#54132#4792#76122#55124#59109#73109#73100143#45145#4696#4883#55134#43134#43587#383101529#136518#293102555#254350#153103501#3276104273#170316#120105369#188531#231106538#391107538#187568#250108478#91602#161109514#14971107.1111540#233486#106467#323112538#1837.27.2.17.2.1.1211#851131141157.2.1.2192#951167.2.1.3152#87117147#92149#86118164#837.2.27.2.2.1527#132119538#1331207.2.2.2467#1261217.2.2.3122169#92173#831237.2.2.4186#102216#1021241251267.2.2.5194#991277.2.3256#122128129130243#119131152#99132243#122218#127133224#1347.2.4134324#1545#115#11135136326#142337#165137138344#163171#134139260#97250#1481405#115#11186#148141169#1357.2.5142115#877.2.6143177#97239#97144241#927.2.7145184#57235#961467.37.3.1602#1171477.3.2467#119148452#1151497.3.3171#106150175#83152#106151152#1067.3.4173#101152262#99241#1061537.3.5267#106154271#103248#1067.41557.4.1192#587.4.2284#58156316#58157260#587.4.3248#91158277#797.4.4269#82159243#58277#931607.4.5190#58161235#1037.57.5.1162190#637.5.2277#63163273#637.5.3164224#91250#91165273#637.67.6.1184#721667.6.2273#767.6.3167273#727.77.7.17.7.1.1175#82139#82168143#82152#82169137#82137#821707.7.1.298#79171137#90100#78172162#116162#1111737.7.27.7.2.1192#102174250#144190#821757.7.2.2184#107190#96176226#106186#821777.7.37.7.3.1203#957.7.3.2178186#837.7.3.3186#83179213#867.7.3.4196#87180220#907.87.8.1181113#617.8.2105#58182105#827.8.3190#857.8.4183179#58137#581847.97.9.1109#59102#611857.9.2186#807.9.3186181#587.107.10.1105#651877.10.2166#96188198#64205#757.10.3189124#1017.117.11.177#8919077#897.11.2191147#1287.11.3132#891927.127.12.1273#97193186#737.12.2141#80194149#80198#93195190#90 References196197198199200201202203204205206AbbreviationsZusammenfassung294#140LebenslaufSelbständigkeitserklärung64#21Publications from the thesisenTable of contentsHelp References 1. Wang, J. H.; Desai, R. Biochem. Biophys. Res. Commun. 1976, 72, 926-932. 2. Watterson, D. M.; Vanaman, T. C. Biochem. Biophys. Res. Commun. 1976, 73, 40-46. 3. Rusnak, F.; Mertz, P. Physiolog. Rev. 2000, 80, 1483-1521. 4. Loh, C.; Shaw, K. T. Y.; Carew, J.; Viola, J. P. B. J. Biol. Chem. 1996, 271, 10884-10891. 5. Perrino, B. A.; Fong, Y. L.; Brickey, D. A. J. Biol. Chem. 1992, 267, 15965-15969. 6. Lai, M. M.; Burnett, P. E.; Woloker, H.; Blackshaw, S.; Snyder, S. H. J. Biol. Chem. 1998, 273, 18325-18331. 7. Kashishian, A.; Howard, M.; Loh, C. J. Biol. Chem. 1996, 271, 10884-10891. 8 Sussman, M. A.; Lim, H. W.; Gude, N.; Taigen, T. Science 1998, 281, 1690-1693. 9. Glynne, R.; Akkaraju, S.; Healy, J. I.; Bayner, J.; Coodnoow, C. C.; Mack, D. H. Nature 2000, 403, 672-676. 10. Matin B. L.; Spannaus-Matin, D. J. Bio Chem. Pharmacol. 2000, 60, 803-888. 11. Fischer, G.; Bang, H.; Mech, C. Biomed. Biochim. Acta 1984, 43, 1101-1111. 12. Fischer, G.; Grabley, S.; Thiericke, R. Drug Discovery from Nature, Springer-Verlag 1999, 257-280. 13. Liebscher, J.; Pätzel, M. Synlett 1994, 471-478. 14. Pätzel, M.; Liebscher, J. Synthesis 1995, 879-894. 15. Pätzel, M.; Knoll, A.; Steinke, T.; Löwis, M.; Liebscher, J. J. Prakt. Chem. 1993, 335, 639-643. 16. (a) Karanik, M.; Pätzel, M.; Liebscher, J. Synthesis 2003, 1201-1208. (b) Karanik, M. Ph. D. Thesis, 2004, Humboldt University. 17. Brown, D. J.; Cowden, W. B.; Lan, S. B.; Mori, K. Aust. J. Chem. 1984, 37, 155-163. 18. Diederich, F.; Stang. J. Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH,

Weihein, Germany,

1998. 19. Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis, Wiley,

Chichester, UK,

1995. 20. Malleron, J. L.; Fiaud, J. C.; Legros, J. Y. Handbook of Palladium-Catalyzed Organic Reactions, Academic Press, 1997. 21. Tsuji, J. Perspectives in Organo Palladium Chemistry for the 21st Century, Elsevier, 1999. 22. Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875-1916. 23. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd Ed., University Science Books,

Mill Valley, USA,

1999. 24. Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596-597. 25. Negishi, E. Acc. Chem. Res. 1982, 15, 340-348 26. Erdric, E. Tetrahedron 1992, 48, 9577-9648. 27. Sakamoto, T.; Nishimura, S.; Kondo, Y.; Yamanaka, H. Synthesis 1988, 485-486. 28. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636-8; 1979, 101, 4992-4998. 29. Stile, J. K. Angew. Chem., Int. Ed. 1986, 25, 508-524. 30. Farina, V.; Krishnamurphy, V.; Scott, W. Organic Reactions 1997, 50, 1-652. 31. Sandosham, J.; Undheim, K. Acta Chem. Scand. 1989, 43, 684-689. 32. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. 33. Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. 34. Chemler, S. R.; Trauner, D. Angew. Chem. Int. Ed. 2001, 40, 4544-4568. 35. Thompson, W. J.; Gaudino, J. J. Org.Chem. 1984, 49, 5237-5243. 36. Kamatatant, A.; Overman, L. E. J. Org.Chem. 1999, 64, 8743-8744 37. Tamao, K.; Sumitani, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958-1969. 38. Amatore, C.; Jutand, A.; Fauvarque, J. F. J. Organomet. Chem. 1990, 390, 389-398. 39. Minato, A; Suzuki, K; Tamao, K; Kumada, M. Tetrahedron Lett. 1981, 22, 5319-5322. 40. Minato, A.; Suzuki, K.; Kumada, M. J. Chem. Soc., Chem. Commun. 1984, 511-513 41. Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303-306. 42. Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471-1478. 43. Schibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309-1310. 44. Sonagashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 17, 4467-4470. 45. Rossi, R.; Carpita, A.; Belina, F. Org.Prep. Proc. Int. 1995, 27, 129-160. 46. Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979-2017. 47. Edo, kiyoto.; Yamanaka, H.; Sakamoto, T. Heterocycles 1978, 9, 271-274. 48. Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A. J. Org.Chem. 1998, 63, 1109-1118. 49. Mizoroki, J. F.; Mori, K.; Ozaki, A.; Bull. Chem. Soc. Jpn. 1971, 44, 581-584. 50. Heck, R. F.; Nolley, J. P. J. Org.Chem. 1972, 37, 2320-2322. 51. Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 7449-7476. 52. Sakamoto, T.; Arakida, H.; Edo, Kiyota; Yamanaka, H. Heterocycles 1981, 16, 965-968. 53. Busacca, C. A.; Dong, Y. Tetrahedron Lett. 1996, 37, 3947-3950. 54. Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969-5970. 55. Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901-7902. 56. A Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org.Chem. 2003, 68, 2861-2873. 57. Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Nolan, S. Org.Lett. 2003, 5, 1479-1482. 58. Kalinin, V. N. Synthesis 1992, 413-432. 59. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry, Pergamon Press, 2000. 60. Undheim, K.; Benneche, T. Adv. Heterocycl. Chem. 1995, 62, 305-418. 61. Stanforth, S. P. Tetrahedron 1998, 54, 263-303. 62. Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27, 2225-2249. 63. Aoyaki, Y.; Inoue, A.; Koizumi, I.; Ohta, A. Heterocycles 1992, 33, 257-272. 64 Sandosham, J.; Undheim, K. Acta. Chem. Scand. 1989, 43, 62-68. 65. Cruskie, M. P.; Zoltewicz, J. A.; Abboud, K. A. J. Org.Chem. 1995, 60, 7491-7495. 66. Wu, G. G.; Wong, Y. W.; Poirier, M. Org.Lett. 1999, 1, 745-747. 67. Meyers, C.; Maes, B. U. W.; Loones, K. T. J. J. Org.Chem. 2004, 69, 6010-6017. 68. Malpass, J. R.; Cox, C. D. Tetrahedron Lett. 1999, 40, 1419-1422. 69. Cox, C. D.; Malpass, J. R. Tetrahedron 1999, 55, 11879-11888. 70. Bracher, F.; Daab, J. Eur. J. Org.Chem. 2002, 14, 2288-2291. 71. Havelková, M.; Hocek, M.; Česnek, M.; Dvoák, D. Synlett 1999, 1145-1147. 72. Novinson, T.; Bhooshan, B.; Okabe, T.; Revankar, G. R.; Wilson, H. R. J. Med. Chem. 1976, 19, 512-516. 73. Senga, K.; Novinson, T.; Wilson, H. R. J. Med. Chem. 1981, 24, 610-613. 74. Suzuki, M.; Iwasaki, H.; Fujikawa, Y.; Sakashita, M.; Kitahara, M.; Sakoda, R. Bio Org.Med. Chem. Lett. 2001, 11, 1285-1288. 75. Al-mansa, C.; Arriba, A. F.; Cavalcanti, F. L.; Gomez, L. A.; Miralles, A.; Forn J. J. Med. Chem. 2001, 44, 350-361. 76. Fraley, M. E.; Rubino R. S.; Hoffman, W. F.; Hambaugh S. R.; Thomas K. A. Bio Org.Med. Chem. Lett. 2002, 12, 3537-3541. 77. Novinson, T.; Hanson, R.; Dimmitt, M. K.; Simmon , L. N.; Robins, R. K.; O’Brien, D. E. J. Med. Chem. 1974, 17, 645-648. 78. Selleri , S.; Bruni , F.; Costagli, C.; Costanzo, A.; Guerrini, G.; Ciciani, G.; Costa, B.; Martini, C. Bio Org.Med. Chem. 2001, 9, 2661-2671. 79. Kirkpatrick, W. E.; Okabe, T.; Hillyard, I. W.; Robin, R. K.; Dren, A. T. J. Med. Chem. 1977, 20, 386-393. 80. Shioto, T.; Yamamori, T. J. Org.Chem. 1999, 64, 453-457. 81. Vattoly J. M.; Jaya P. J.; John M. J. S.; Dileep, K. Adv. Synth. Catal. 2003, 345, 620-624. 82. Fraley, M. E.; Hoffman, W. F.; Rubino, R. S.; Hungate, R.W.; Thomas, K. A. Bio Org.Med. Chem. Lett. 2002, 12, 2767-2770. 83. Bellec, C.; Lhommet, G. J. Heterocycl. Chem. 1995, 32, 1793-1800. 84. Danagulyan, G. G.; Pannosyan, G. A.; Boyakhchyan, A. P. Chem. Heterocycl. Comp. 2002, 38, 581-585. 85. Petrov, A. A.; Emelina, E. E.; Firsov, A. V. Russ. J. Org.Chem. 2000, 36, 1027-1032. 86. Emelina, E. E.; Petrov, A. A.; Firsov, A. V. Russ. J. Org.Chem. 2001, 37, 852-8 87. Springer, R. H. J. Med. Chem. 1976, 19, 291-296. 88. Hori, I. Bull. Chem. Soc. Jpn. 1970, 43, 849-855. 89. Brindley, J. C.; Caldwell, J. M.; Meakins, G. D.; Plackett, S. J.; Price, S. J. J. Chem. Soc. , Perkin Trans, 1 1987, 1153-1158. 90. Caldwell, J. M.; Meakins, G. D; Jones, R. H.; Kidd, T. R.; Prout, K. J. Chem. Soc. Perkin Trans, 1 1987, 2305-2310. 91. Robins, R. K.; Revankar, G. R.; O'Brien, D. E.; Springer, R. H. J. Heterocycl. Chem. 1985, 22, 601-634. 92. Novinson,T. J. Med. Chem. 1977, 20, 296-299, J. Med. Chem. 1976, 19, 517-519. 93. Allen, W. E.; Fowler, C. J.; Lynch, V. M.; Sessler, J. L. Chem. Eur. J. 2001, 7, 721-729. 94. Whitcombe, N. J.; Hii, K. K.; Gibson; S. E. Tetrahedron 2001, 57, 7449-7476. 95. Kundu, N. G.; Nandi, B. J. Org.Chem. 2001, 66, 4563-4575. 96. Heidenreich, R. G.; Köhler, K.; Krauter, J. K.; Pietsch, J. Synlett 2002, 1118-1122. 97. (a) Gala, D.; Jenkins, S. J.; Kugelman, M. Organic Progress Research & Development 1997, 1, 163-164. (b) Dyer, U. C.; Shapland, P. D.; Tiffin, P. D. Tetrahadron Lett. 2002, 42, 1765-1767. (c) McClure, M. S.; Roschangar, F.; Hodson, S. J.; Millar, a.; Osterhout, M. H. Synthesis 2001, 1681-1685. (d) Sakurai, H.; Tsukuda, T.; Hirao, T. J. Org.Chem. 2002, 67, 2721-2722. (e) Tagata, T.; Nishida, M. J. Org.Chem. 2003, 68, 9412-9415. (f) LeBlond, C. R.; Andrews, A. T.; Sun, Y. K.; Sowa, Jr. J. R. Org.Lett. 2001, 3, 1555-1557. (g) Organ, M. G.; Mayer, S. J. Comb. Chem. 2003, 5, 118-124. (h) Accadi, A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur. J. Org.Chem. 2003, 4080-4086. 98. (a) Reardon, P.; Metts, S.; Crittendon, C.; Dangherity, P.; Parson, E. J. Organometallics 1995, 14, 3810-3816. (b) Hagiwara, H.; Shimizu, Y.; Hoshi, T.; Suzuki, T. etal. Tetrahedron Lett. 2001, 42, 4349-4351. (c) Xie, X. F.; Lu, J. P.; Chen, B.; Han, J. J.; She, X. G.; Pan, X. F. Tetrahedron Lett. 2004, 45, 809-811. (d) Mehnert, C. P.; Weaver, D. W.; Ying, J. Y. J. Am. Chem. Soc. 1998, 120, 12289-12296. (e) Khan, S. I.; Grinstaff, M. W. J. Org.Chem. 1999, 64, 1077-1078. 99. (a) Potts, K. T.; Horwitz, C. P.; Fessak, A.; Keshavarz-K, M.; Nash, K. E.; Toscano, P. J. J. Am. Chem. Soc. 1993, 115, 10444-10445. (b) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115-1116. (c) Cosford, N. D. P.; Bleicher, C. L.; Herbaut, A. J. Med. Chem. 1996, 39, 3235-3237. (d) Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.; McDonald, I. A. J. Org.Chem. 1998, 63, 1109-1118. (e) Novak, Z.; Szabo, A.; Kotschy, A. J. Org. Chem. 2003, 68, 3327-3329. (f) Lopez-Deber; M.P., Castedo, L.; Granja, J.R. Org.Lett. 2001, 3, 2823-2826. (g) Pal, M.; Subramanian, V.; Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221-8225 (h) Novak, Z.; Szabo, A.; Repasi, J. J. Org.Chem. 2003, 68, 3327-3329. 100. Fairlamb, I. J. S.; Bäuerlein, P. S.; Marrison, L. R. M. Chem. Commun. 2003, 632-633 101. Hyun Oh, C.; Lee, S. C.; Lee, K. S.; Woo, E. R.; Hong, C. Y.; Cho, J. H. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 187-190. 102. Detty, M. R. J. Org.Chem. 1979, 44, 2073-2077. 103. (a) Kelley, J. L.; Krochmal, M. P.; Linn, J. A.; Mclean, E. W.; Sooko, F. E. J. Med. Chem. 1988, 31, 606-612. (b) Kelley, J. L.; Linn, J. A.; Krochmal, M. P. J. Med. Chem. 1988, 31, 2001-2004. 104. Imbach, P.; Carpraro, H. G.; Furet, P.; Mett, H.; Meyer, T.; Zimermann, J. Bio Org.Med. Chem. Lett. 1999, 9, 91-96. 105. Bakkestuen, A. K.; Gundersen, L. L.; Langli, G.; Liu, F. Nolsǿe, J. M. J. Bio Org.Med. Chem. Lett. 2000, 10, 1207-1210. 106. Brathe, A.; Gundersen, L. L.; Meyer, J. N.; Rise, F.; Spilsberg, B. Bio Org.Med. Chem. Lett. 2003, 13, 877-880. 107. Hocek, M.; Vortruba, I. Bio Org.Med. Chem. Lett. 2002, 12, 1055-1058. 108. Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H, Nomoto, R. J. Med. Chem. 1992, 35, 241-252. 109. Cristalli, G.; Volpini, R.; Vittori, S.; Campioni, E.; Monopoli, A.; Conti, A. J. Med. Chem. 1994, 37, 1720-1726. 110. LaMontagne, M. P.; Smith, D. C.; Wu, G. S. J. Heterocycl. Chem. 1983, 20, 295-299. 111. Chapman, E.; Ding, S.; Schultz, P. G.; Wong, C. H. J. Am. Chem. Soc. 2002, 124, 14524-14525. 112. Marasco, Jr.C. J.; Kramer, D. L.; Miller, J.; Porter, C. W.; Bacchi, C. J.; Rattendi, D. J. Med. Chem. 2002, 45, 5112-5122. 113. Havelková, M.; Dvořák, D.; Hocek, M. Synthesis 2001, 1704-1710. 114. Hocek, M.; Hocková, D.; Dvořáková, H. Synthesis 2004, 889-894. 115. Gunderson, L. L.; Rise, F. Tetrahedron 1994, 50, 9743-9756. 116. Gunderson, L. L. Tetrahedron Lett. 1994, 35, 3155-3158. 117. Liu, F. S.; Dalhaus, B.; Gunderson, L. L.; Rise, F. Acta Chem. Scand. 1999, 53, 269-279. 118. Langli, G.; Gunderson, L. L.; Rise, F. Tetrahedron Lett. 1995, 36, 1945-1948. 119. Langli, G.; Gunderson, L. L.; Rise, F. Tetrahedron Lett. 1996, 52, 5625-5638. 120. Nolsøe, J. M.; Gunderson, L. L.; Rise, F. Acta Chem. Scand. 1999, 53, 366-72. 121. Bergstrom, D. E.; Reday, P. A. Tetrahedron Lett. 1982, 23, 4191-4194. 122. Cong-Danh, N.; Beaucourt, J. P.; Pichat, L. Tetrahedron Lett. 1979, 20, 3159-3162. 123. Hirota, K.; Kitade, Y.; Kanbe, Y. J. Org.Chem. 1992, 57, 5268-6270. 124. Hocek, M.; Stará, I. G.; Dvořáková, H. Collect. Czech. Chem. Commun. 2002, 67, 1223-1235. 125. Harada, H.; Asano, O.; Hoshiro, Y.; Yoschikawa, S.; Matskura, M.; Abe, S. J. Med. Chem. 2001, 44, 170-179. 126. Oh, C. H.; Lee, S. C.; Lee, K. S.; Woo, E. R.; Cho, J. H. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 187-190. 127. Geir, L.; Lise-Lotte, G.; Frode, R. Tetrahedron 1996, 52, 5625-5638. 128. Cavier, R. Chim. Ther. 1966, 66, 327-330. 129. Haley, T. J.; Flesher A. M.; Vcomelt, R. Proc. Soc. Biol. Med. 1957, 96, 579-584. 130. Cavallini, G.; Massarani, E.; Nardi, D.; Magrassi, F.; Altucci, P. J. Med. Pharm. Chem. 1959, 1, 327-332. 131. Kumari, S.; Ghai, P.; Sexsena, A. Indian J. Chem. B, 1992, 31, 92-97. 132. Vinot, M. Bull. Soc. Chim. Fr. 1976, 251-253. 133. Armand, J.; Chekir, K.; Pinson, J. Can. J. Chem. 1978, 56, 1804-1816. 134. Sanfilippo, P. J.; Urbanski, M.; Press, J. B. J. Med. Chem. 1988, 31, 2221-2217. 135. Kaminiski, J: J.; Puchalski, C.; Solomon, D. L. J. Med. Chem. 1989, 32, 1686-1700. 136. Gyoten, M.; Nagaya, H.; Fukuda, S.; Ashida, Y. Chem. Pharm. Bull. 2003, 51, 122-133. 137. Ishikawa, T.; Lizawa, Y.; Okonogi, K.; Miyake, A. J. Antibiot. 2000, 53, 1053-1070. 138. Enguehard, C.; Renou, J. L.; Collot, V. J. Org.Chem. 2000, 65, 6572-6575. 139. Enguehard, C.; Hervet, M.; Théry, I. Helv. Chim. Acta, 2001, 84, 3610-3615. 140. Thomas, A. P.; Allott, C. P.; Gibson, K. H. J. Med. Chem. 1992; 35, 877-885. 141. Enguehard, C.; Allouchi, H.; Gueiffier, A. Buchwald, S. L. J. Org.Chem. 2003, 68, 4367-4370. 142. Gudmundsson, K. S.; Williams, J. D.; Duach, J. C.; Townsend, L. B. J. Med. Chem. 2003, 46, 1449-1455. 143. (a) Enguehard, C.; Hervet, M.; Thery, I.; Renou, J. L. Fauvelle, F.; Gueiffier, A. Helv. Chim. Acta 2001, 84, 3610-3615. (b) Yananaka, M.; Miyake, S.; Suda, S.; Ohhara, H.; Ogawa, T. Chem. Pharm. Bull. 1991, 39, 1556-1567. 144. Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma, D.; Caliari, S.; Subissi, A. J. Med. Chem. 1995, 38, 4806-4820 145. Ban, M.; Taguchi, H.; Katsushima, T.; Aoki, S.; Watanabe, A. BioOrg.Med. Chem. 1998, 6, 1057-1067. 146. Dinan, F. J.; Bardos, T. J. J. Med. Chem. 1980, 23, 569-572. 147. Wright, G. E.; Brown, N, C. J. Med. Chem. 1980, 23, 34-38. 148. Hendry, J. A.; Homer R. F. J. Chem. Soc. 1952, 328-333. 149. Koga, M.; Schneller, S. W. J. Heterocycl. Chem. 1992, 29, 1741-1747. 150. Borowski, T.; Krol, M.; Broclwwic, E, Baranowski, T. C.; Mokrosz, M. J. J. Med. Chem. 2000, 43, 1901-1909. 152. Wellmar, U.; Hörnfeld, A. B.; Gronowitz, S. J. Heterocycl. Chem. 1995, 32, 1159-63. 153. Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R.A.; Walbank, P. J. Tetrahedron 1992, 48, 8117-8126. 153. Edo, K.; Sakamoto, T. Heterocycles 1978, 9, 271-274. 154. Bleicher, L.S.; Cosford, N.D.; Herbaut, A.; McCallum, J. S.; McDonald, I.A. J. Org.Chem. 1998, 63, 1109-1118. 155. Varlhac, J. B.; Pereyre, M.; Shin, H. Organomatallics 1991, 10, 3007-3009. 156. Sakamoto, T.; Nishimura, S.; Kondo, Y.; Yamanka, H. Synthesis 1988, 485-486. 157. Miller, W. H.; Seefeld, M. A.; Newlander, K. A. J. Med. Chem. 2002, 45, 3246-3256. 158. Sakamoto, T.; Arakida, H.; Edo, K.; Yamanaka, H. Heterocycles 1981, 16, 965-968. 159. Majeed, A. J.; Antonsen, Ø.; Benneche, T. Tetrahedron 1989, 45, 993-1006. 160. Schomaker, J. M.; Delia, T. J. J. Org.Chem. 2001, 66, 7125-7128. 161. Mangalagiu, I, Benneche, T, Undheim, K. Acta Chem. Scand. 1996, 50, 914-917. 162. Shibata, T.; Yonebubo, S.; Soai, K. Angew. Chem. Int. Ed. 1999, 38, 659-661. 163. Edo, K.; Sakamoto, T.; Yamanaka, H. Heterocycles 1979, 12, 383-386. 164. Brown, D. J.; Cowden, W. B.; Lan, S. B.; Mori, K. Aust. J. Chem. 1984, 37, 155-163. 165. (a) Vlad, G.; Horvath, I. T. J. Org.Chem. 2002, 67, 6550-6552. (b) Lepretre, A.; Turck, A.; Ple, N.; Knochel, P.; Queguiner, G. Tetrahedro, 2000, 56, 265-273. (c) Ple. N.; Turck, A. Heynderickx, A.; Queguiner, G. Tetrahedron 1998, 54, 9701-9710. (d) Maes, B. U. W.; Lemiere, G. L. F. Tetrahedron 2000, 56, 1777-1781. 166. Hendry, H. J. Chem. Soc. 1952, 328-333. 167. (a) Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett. 2002, 43, 7247-7250. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009-4091. (c) Hassan, J.; Gozzi, C.; Schulz, E.; Lemaire, M. J. Organomet. Chem. 2003, 687, 280-283. (d) Cortese, N. A.; Heck, F. R. J. Org.Chem. 1977, 42, 3491-3494. 168. Delia, T.J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem. 1995, 32, 1177-1780. 169. Lednicer, D. In Strategies for Organic Drug Synthesis and Design, John Wiley & Sons:

New York,

1988, 242-257. 170. (a) Barbera, J.; Melendez, E.; Remero, P. Mol. Cryst. Liq. Cryst. 1985, 126, 259-264. (b) Seto, K.; Shimojitosyo, H.; Matsubara, H.; Takahashi, S. Chem. Lett. 1990, 323-3. 171. Lee, A. W. M.; Chan, W. H.; Wong, M. S. J. Chem. Soc., Chem. Commun. 1988, 1585-1586. 172. (a) Meyer, T. Acc. Chem. Res. 1989, 22, 163-170. (b) Pyle, A. M.; Barton, J. K. Prog. In Org.Chem. 1990, 38, 413-416. (c) Gittins, D. I.; Bethell, D.; Nichols, R. J.; Schiffrin, D. J. Adv. Mater. 1999, 737-740. 173. Brandao, M. A.; Oliveria, A. B.; Snieckus, V. Tetrahedron Lett. 1993, 34, 2437-2440. 174. Prim, D.; Kirsch, G. J. Chem. Soc., Perkin Trans. 1, 1994, 2603-2606. 175. Cross, P. E.; Dickinson, R. P.; Parry, M. J. J. Med. Chem. 1986, 29, 1637-1643. 176. Sandosham, J.; Undlheim, K. Acta Chem. Scand. 1989, 43, 684-689. 177. Tiley, J. W.; Levitan, P.; Lind, J.; Welton, A. F. J. Med. Chem. 1987, 30, 185-193. 178. Wagaw, S.; Buchwald, S. L. J. Org.Chem. 1996, 61, 7240-7241. 179. Niu, C.; Li, J.; Doyle, T. W.; Chen, S. H. Tetrahedron 1998, 54, 6311-6318. 180. Minato, A.; Suzuki, K.; Tamao, K. J. Chem. Soc., Chem. Commun. 1984, 511-513. 181. Tilley, J.; Zawoiski, S. J. Org.Chem. 1988, 53, 386-390. 182. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959-62. 183. Chapman, G. M.; Stanforth, S. P.; Tarbit, B.; Watson, M. D. J. Chem. Soc., Perkin Trans. 1, 2002, 581-582. 184. Cruskie, M. P.; Zoltewicz, J. A.; Abboud, K. A. J. Org.Chem. 1995, 60, 7491-7495. 185. Bargar, T. M.; Wilson, T.; Daniel, J. K. J. Heterocycl. Chem. 1985, 22, 1583-1592. 186. Cox, C. D.; Malpass, J. R. Tetrahedron 1999, 55, 11879-11888. 187. Bessard, Y.; Roduit, J. P. Tetrahedron 1999, 55, 393-404. 188. Meyers, C.; Maes, B. U. W.; Loones, K. T. J. J. Org.Chem. 2004, 69, 6010-6017 189. (a) Johnstone, R. A. W.; Wilby, A. H. Chem. Rev. 1985, 85, 129-170. (b) Weil, J. R.; Pater, B. A.; Heck, F. R. J. Org.Chem. 1980, 45, 4926-4931. 190. Robertson, D. W.; Beedle, E. E.; Jones, N. D. J. Med. Chem. 1986, 29, 635-640. (b) Colucci, W. S.; Wright, R. F.; Braunwald, E. New Eng. J. Med. 1986, 314, 349-355. 191. Watanabe, T.; Hayashi, K.; Sakurada, J.; Ohki, M. Heterocycle, 1989, 29, 123-131. 192. Jones, K.; Keenan, M.; Hibbert, F. Synlett 1996, 509-510. 193. Yang, Y.; Martin, A. R. Heterocycles 1992, 34, 1395-1398 194. Akita, Y.; Kanekawa, H.; Kawasaki, T. J. Heterocycl. Chem. 1988, 25, 975-977. 195. Turck, A.; Plé, N.; Dognon, D.; Harmoy, C, Quéguiner, G. J. Heterocycl. Chem. 1994, 31, 1449-1453. 196. Akita, Y.; Inoue, A.; Mori, Y.; Ohta, A. Heterocycles 1986, 24, 2093-2097. 197. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R. Heterocycles 1992, 33, 257-272. 198. Karmas, G.; Spoerrt, P. E. J. Am. Chem. Soc. 1952, 74, 1580-1584. 199. Hodgetts, K. J.; Kershaw, M. T. Org.Lett. 2002, 4, 2905-2907. 200. Sakamoto, T.; Nagata, H.; Kondo, Y. Chem. Pharm. Bull. 1987, 35, 823-828. 201. Gilchrist, T. L.; Pearson, D. P. J. J. Chem. Soc., Perkin Trans. 1, 1976, 989-993. 202. Genin, M. J.; Biles, C.; Kaiser, B. J.; Poppe, S, M. J. Med. Chem. 2000, 43, 1034-1040. 203. (a) Penning, T. D.; Talley, J. J. Bertenshaw, S. R. J. Med. Chem. 1997, 40, 1347-65. (b) Almansa, C.; Alfon, J. Arriba, A. F.; Cavalcanti, F. L. J. Med. Chem. 2003, 46, 3463-3475. 204. Siskovic, D. R.; Roth, B. D.; Wilson, M. W. J. Med. Chem. 1990, 33, 31-38. 205. (a) Regan, J.; Breitifelder, S.; Cirillo, P.; J. Med. Chem. 2002, 45, 2994-3008. (b) Dumas, J.; Mokdad, H. H.; Silbley, R. Bio Org.Med. Chem. Lett. 2000, 10, 2051-2054. 206. Stauffer, S. R.; Huang, Y.; Cooletta, C. J.; Tedesco, R.; Katzenebogen, J. A. Bio Org.Med. Chem. 2001, 9, 141-150. 207. Chupp, J. P. J. Heterocycl . Chem. 1994, 1377-1380. 208. Organ, M. G.; Mayer, S. J. Comb. Chem. 2003, 118-124. 209. Huang, Y. R.; Katzenllenbogen, J. A. Org.Lett. 2000, 2, 2833-2336. 210. Tolf, B. R.; Dahlbom, R.; Theorellel, H. Acta Chem. Scand. B, 1982, 36, 101-1077. 211. Higley, C. A.; Wilde, R. G.; Maduskuie, T. P. J. Med. Chem. 1994, 37, 3511-3522. 212. Khanna, I. K.; Weier, R. M.; Xiang, Y. Y. J. Med. Chem. 1997, 40, 1634-1647. 213. Wadsworth, S. A.; Cavender, D. E. Pharm. Experi. Ther. 1999, 291, 680-687 214. Elz, S.; Krammer, K.; Pertz, H. H. Detert, H. J. Med. Chem. 2000, 43, 1071-1084. 215. Wang, D. M.; Haseltine, J. J. Heterocycl. Chem. 1994, 31, 1637-1639. 216. Ali, N, M.; Mckillop, A.; Mitchell, M. B. Tetrahedron 1992, 48, 8117-8126 217. Dobler, M. R. Tetrahedron Lett. 2003, 44, 7115-7117. 218. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M. Heterocyles 1990, 31, 1951-1957. 219. Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H. Yuwsa, K. Heterocycles 1989, 29, 939-945. 220. Evans, D. A.; Bach, T. Angew. Chem. Int. Ed. 1993, 32, 1326-1327. 221. Milgrom, L. R.; Dempsey, P. J. F.; Yahioglu, G. Tetrahedron 1996, 52, 9877-9890. 222. Cheng, Y. X.; Dukat, M, Dowd, M.; Fiedler, W. Glennon, R. A. Eur. J. Med. Chem. 1999, 34, 177-190. 223. Liebscher, J.; Neumann, B.; Hartmann, H. J. Prakt. Chem. 1983, 325, 915-918. 224. Hartmann, H.; Liebscher, J. Synthesis 1984, 276-277. 225. Jourdan, F.; Ladurée, D.; Robba, M. J. Heterocycl. Chem. 1994, 31, 305-312. 226. Joshi, K. C.; Pathak, V. N.; Garg, U. J. Indian Chem. Soc. 1983, 60, 1074-1076 227. Chen, L. S.; Cummings, S. C. In Org.Chem. 1978, 17, 2358-2361. 228. Arthur A. V; Piet, H.; Hubert, V. Nucleosides Nucleotides 1988, 7, 75-90. 229. (a) Janine, C.; Samir, B.; Claude, C. J. Tetrahedron-Asymmetry 1999, 10, 3859-3862. (b) Chaudhary, S. K.; Hernardez, O. Tetrahedron, Lett. 1979, 20, 95-98. 230. Palucki, M.; Hughes, D. L.; Yasuda, N. Tetrahedron Lett. 2001, 42, 6811-6814. 231. Paul, M.; Hassan, I. Tetrahedron-Asymmetry 1998, 9, 4419-4428. 232. Kankare, J.; Haenninen, E. Acta Chem. Scand. Ser. B, 1988, 42, 448-454.