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

• DOI: 10.1021/acs.joc.0c00973
• Publication Date: 2020-08-10T17:01:30Z
• Authors: Roshan Y Nimje; Devaiah Vytla; Prakasam Kuppusamy; Rajeswari Velayut...; Lokesh Babu Jarugu; China Anki Reddy; Nanjundaswamy Kan...; Richard A. Rampulla; Cullen L. Cavallaro; Jianqing Li; Arvind Mathur; Anuradha Gupta; Amrita Roy
• Keywords: 01 natural sciences; 0104 chemical sciences; 3. Good health

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.