Chemoenzymatic route to Tyrphostins involving lipase-catalyzed kinetic resolution of 1-phenylethanamine with alkyl cyanoacetates as novel acylating agents

Ethyl and isopropyl cyanoacetates were tested as acylating agents in the kinetic resolution of racemic 1-phenylethanamine rac-1 catalyzed by lipase B from Candida antarctica. The best conversion combined with high enantioselectivity was achieved with ethyl cyanoacetate 2a as the acylating agent and immobilized lipase B from Candida antarctica (CaLB N435) as the biocatalyst. Enantiomers of the amides (R)-3 and (S)-3 were obtained with high enantiopurity (ee >98%) by lipase-catalyzed kinetic resolution and by chemical conversion of the residual (S)-1, respectively. The amides were reacted with various aromatic aldehydes 4a–c,e in Knoevenagel condensation to yield Tyrphostins rac-5a–c,e, (R)-5a–c,e and (S)-5a–c,e, which were tested as protein tyrosine kinase inhibitors on human cancer cell lines HCT 116, A549, PC9, PC9ER, Jurkat, and MV4-11. Although some of the novel Tyrphostins exhibited weak biological activities (EC50 ∼6–60 μM), none of them proved to have a significant effect on the growth of the investigated cell lines.

Figure optionsDownload as PowerPoint slide

(R)-2-Cyano-N-(1-phenylethyl)acetamideC11H12N2OEe = 99.9% (HPLC on Chiralpak IB column)[α]D28 = +80.1 (c 1.0, CH2Cl2)Source of chirality: lipase-catalyzed kinetic resolutionAbsolute configuration: (R)

(R,E)-2-Cyano-3-phenyl-N-(1-phenylethyl)acrylamideC18H16N2OEe = 99.9% (HPLC on Chiralpak IB column, for the precursor)[α]D28 = −4.1 (c 1.0, CH2Cl2)Source of chirality: lipase-catalyzed kinetic resolution of a precursorAbsolute configuration: (R)

(R,E)-3-(1-Benzyl-1H-indol-3-yl)-2-cyano-N-(1-phenylethyl)acrylamideC27H23N3OEe = 99.9% (HPLC on Chiralpak IB column, for the precursor)[α]D28 = −15.0 (c 1.0, CH2Cl2)Source of chirality: lipase-catalyzed kinetic resolution of a precursorAbsolute configuration: (R)

(2E,4E)-2-Cyano-5-phenyl-N-[(R)-1-phenylethyl]penta-2,4-dienamideC20H18N2OEe = 99.9% (HPLC on Chiralpak IB column, for the precursor)[α]D28 = +28.7 (c 1.0, CH2Cl2)Source of chirality: lipase-catalyzed kinetic resolution of a precursorAbsolute configuration: (R)

(S,E)-2-Cyano-N-(1-phenylethyl)-3-(pyridin-3-yl)acrylamideC17H15N3OEe = 99.3% (HPLC on Chiralpak IB column, for the precursor)[α]D28 = −5.9 (c 1.0, CH2Cl2)Source of chirality: lipase-catalyzed kinetic resolution of a precursorAbsolute configuration: (S)