Stereoselective synthesis of chiral IBR2 analogues.
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.
Qiu
Xiao-Long
XL
Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, California 92697, USA. qiux@uci.edu
Zhu
Jiewen
J
Wu
Guikai
G
Lee
Wen-Hwa
WH
Chamberlin
A Richard
AR
D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry
C551678:(R)-1-(1H-indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroisoquinoline; D000577:Amides; D000588:Amines; D007211:Indoles; D044005:Tetrahydroisoquinolines