Synthesis of Differentially Protected Azatryptophan Analogs via Pd(dba)/XPhos Catalyzed Negishi Coupling of -Ts Azaindole Halides with Zinc Derivative from Fmoc-Protected -Butyl ()-2-Amino-3-iodopropanoate.

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from -tosyl-3-haloazaindoles and Fmoc-protected -butyl iodoalanine via a Negishi coupling. Through ligand screening, Pd(dba)/XPhos was found to be a superior catalyst for the coupling of with the zinc derivative of to give -butyl ()-2-((((9-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1-pyrrolo[2,3-]pyridin-3-yl)propanoate derivatives in 69-91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and Bu, can be easily removed selectively.