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.

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(+)-Ethyl 2-(6-cyano-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoateC14H11F3N2O3Ee = 81%[α]D25=+1.2 (c 1.98, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(−)-tert-Butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylateC19H19F3N2O5Ee = >99%[α]D25=-1.7 (c 2.05, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(−)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)-1H-indole-1-carboxylateC17H17F3N2O4[α]D25=-13.3 (c 2.06, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(−)-tert-Butyl 6-cyano-3-(1,1,1-trifluoro-2-hydroxy-3-{[(4-methylphenyl)sulfonyl]oxy}-propan-2-yl)-1H-indole-1-carboxylateC24H23F3N2O6S[α]D25=-16.5 (c 2.07, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(−)-tert-Butyl 6-cyano-3-[2-(trifluoromethyl)oxiran-2-yl]-1H-indole-1-carboxylateC17H15F3N2O3[α]D25=-14.6 (c 2.03, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(+)-Ethyl [4-({1-[2-(6-cyano-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropyl]piperidin-4-yl}oxy)-3-methoxyphenyl]acetateC28H30F3N3O5[α]D25=+6.7 (c 2.01, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(−)-{4-[(1-{2-[6-Cyano-1-(cyclohexylmethyl)-1H-indol-3-yl]-3,3,3-trifluoro-2-hydroxy-propyl}piperidin-4-yl)oxy]-3-methoxyphenyl}acetic acidC33H38F3N3O5Ee = >99%ee[α]D25=-6.2 (c 2.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown

(+)-{4-[(1-{2-[6-Cyano-1-(cyclohexylmethyl)-1H-indol-3-yl]-3,3,3-trifluoro-2-hydroxy-propyl}piperidin-4-yl)oxy]-3-methoxyphenyl}acetic acidC33H38F3N3O5Ee = >99%ee[α]D25=+6.1 (c 2.01, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: unknown