Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (-)-tert-butyl 6-cyano-3[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (-)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (-)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (-)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (-)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (-)-3 showed a higher binding affinity compared to (+)-3. (C) 2011 Elsevier Ltd. All rights reserved.