Development of a Safe and Practical Synthesis of Enantiomerically Pure (S)- and (R)‑N‑Boc-3-(Trifluoromethyl)piperazines Enabled by Aza-Michael Addition of Optically Pure 4‑Phenyl-2-Oxazolidinone to 3,3,3-Trifluoro-1-Nitropropene

• Published in: Organic process research & development Vol. 28; no. 8; pp. 3423 - 3435
• Main Authors: Darne, Chetan Padmakar, Li, Ning, Smith, Daniel, Zhang, Shasha, Neithnadka, Premsai Rai, Silamkoti, Arundutt, Arumugam, Arunachalam, Gupta, Anuradha, Hong, Zhenqiu, Krishnananthan, Subramaniam, Wang, Bei, Zhao, Rulin, Yip, Shiuhang, Wu, Dauh-Rurng, Kempson, James, Mortensen, Deborah S., Mathur, Arvind, Li, Jianqing
• Format: Journal Article
• Language: English
• Published: American Chemical Society 16.08.2024
• Subjects: diastereoselective synthesis; 3,3,3-trifluoropropane-1,2-diamines; (S)- and (R)-N-Boc-3-(trifluoromethyl)piperazines; aza-Michael addition
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00289

(S)- and (R)-N-Boc-3-(trifluoromethyl)­piperazines are attractive building blocks for the rational design of drugs. Until now, their chiral syntheses were unknown. Exploration of three synthetic approaches via chiral 3,3,3-trifluoropropane-1,2-diamines yielded a scalable route that has been used for multigram synthesis. Two routes were not amendable for scale-up due to low yielding, tedious purification, limited availability of reagents, and safety issues. The successful and practical route relied on a modified process to mitigate the safety issues for the synthesis of (E)-3,3,3-trifluoro-1-nitroprop-1-ene, which was used as a stock solution for the highly diastereoselective aza-Michael addition of optically pure 4-phenyl-2-oxazolidinone. Boc protection of an amino group allowed subsequent transformations to chiral N-Boc-protected 3,3,3-trifluoropropane-1,2-diamine under mild conditions, without the need for chiral chromatography. The amidation of chiral N-Boc-protected 3,3,3-trifluoropropane-1,2-diamine with 2-chloroacetyl chloride, followed by intramolecular cyclization and subsequent reduction afforded enantiomerically pure N-Boc-3-(trifluoromethyl)­piperazines.