Stereoselective Synthesis of Chiral IBR2 Analogues Xiao-Long Qiu,* ,† Jiewen Zhu, † Guikai Wu, † Wen-Hwa Lee,* ,† and A. Richard Chamberlin ‡,§ Department of Biological Chemistry, School of Medicine, Department of Chemistry, and Department of Pharmaceutical Sciences, UniVersity of California, IrVine, IrVine, California 92697 qiux@uci.edu; whlee@uci.edu ReceiVed NoVember 24, 2008 Two stereoselective routes were developed to synthesize optically pure IBR2 analogues 1-16. The first features addition of N-Boc-3-bromoindole 26 to the sulfinamide 25, providing a 1:1 ratio of the separable diasteroisomers 27 and 28 in good yield. In a straightforward fashion, the sulfinamides 27 and 28 were conveniently converted into the key amines 39 and 47 over 8 steps, respectively, from which a series of 3,4-dihydroisoquinolinyl IBR2 analogues 1-14 containing fluorinated and trifluoromethylated benzyl groups were prepared. Another route highlights the highly enantioselective addition of indole to the sulfonyl amide 50 with bifunctional aminothioureas 57 and 58 as catalysts. After the reaction conditions were optimized, the desired sulfonyl amides (R)-55 and (S)-55 were obtained in 99% ee and 98% ee, respectively. Acylation of (R)-55 and (S)-55 separately and subsequent allylation gave compounds 60 and 63, respectively, which were further subjected to RCM to furnish compounds 61 and 64 and, after removal of the Boc groups, the desired IBR2 analogues 15 and 16. It is well-known that Rad51 plays an essential role in DNA damage repair and cell proliferation. For example, it has been demonstrated that inactivation of mouse Rad51 gene would result in embryonic lethality 1 and depletion of Rad51 in DT40 chicken B lymphocytes clearly leads to cell cycle arrest and subsequent cell death. 2 Expression of Rad51 protein and the rate of Rad51-mediated homologous recombination (HR) are both elevated in various types of rapidly proliferating cancer cells, including breast cancer, pancreatic cancer, nonsmall-cell lung carcinoma, glioblastoma, acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), compared to normal cells. 3-6 It is also well-known that Rad51 overex- pression may contribute to tumor progression 7 and is positively correlated with the resistance to DNA damage inducing radio- or chemotherapies, 8 whereas its depletion with siRNA or antisense increases radiosensitivity. 9,10 Moreover, Rad51 inter- * To whom correspondence should be addressed. † Department of Biological Chemistry, School of Medicine. ‡ Department of Chemistry. § Department of Pharmaceutical Sciences. (1) Tsuzuki, T.; Fujii, Y.; Sakumi, K.; Tominaga, Y.; Nakao, K.; Sekiguchi, M.; Matsushiro, A.; Yashimura, Y.; Morita, T. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 6236. (2) Sonoda, E.; Sasaki, M. S.; Buerstedde, J.-M.; Bezzubova, O.; Shinohara, A.; Ogawa, H.; Takata, M.; Yamaguchi-Iwai, Y.; Takeda, S. EMBO J. 1998, 17, 598. (3) Qiao, G.-B.; Wu, Y.-L.; Yang, X.-N.; Zhong, W.-Z.; Xie, D.; Guan, X.- Y.; Fischer, D.; Kolberg, H.-C.; Kruger, S.; Stuerzbecher, H.-W. Br. J. Cancer 2005, 93, 137. (4) Slupianek, A.; Hoser, G.; Majsterek, I.; Bronisz, A.; Malecki, M.; Blasiak, J.; Fishel, R.; Skorski, T. Mol. Cell. Biol. 2002, 22, 4189. (5) Han, H.; Bearss, D. J.; Browne, L. W.; Calaluce, R.; Nagle, R. B.; Von Hoff, D. D. Cancer Res. 2002, 62, 2890. (6) Raderschall, E.; Stout, K.; Freier, S.; Suckow, V.; Schweiger, S.; Haaf, T. Cancer Res. 2002, 62, 219. (7) Flygare, J.; Falt, S.; Ottervald, J.; Castro, J.; Dackland, A.-L.; Hellgren, D.; Wennborg, A. Exp. Cell Res. 2001, 268, 61. (8) Vispe, S.; Cazaux, C.; Lesca, C.; Defais, M. Nucleic Acids Res. 1998, 26, 2859. 10.1021/jo802607f CCC: $40.75  2009 American Chemical Society 2018 J. Org. Chem. 2009, 74, 2018–2027 Published on Web 02/03/2009