Synthesis of Differentially Protected Azatryptophan Analogs via Pd2(dba)3/XPhos Catalyzed Negishi Coupling of N-Ts Azaindole Halides with Zinc Derivative from Fmoc-protected tert-Butyl (R)-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 N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Negishi coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for the coupling of 1 with the zinc derivative of 2 to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate derivatives 3 in 69-91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and tBu, can be easily removed selectively.