Synfacts 2018; 14(10): 1015
DOI: 10.1055/s-0037-1610969
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Trifluoromethylated Pyrrolidine and Piperidine Amino Acids

Victor Snieckus
Sara Gomes
Hao J, Milcent T. * Retailleau P, Soloshonok VA, Ongeri S, Crousse B. University of the Basque Country, San Sebastian, Spain; Université Paris-Saclay, Châtenay-Malabry and Université Paris-Sud, France
Asymmetric Synthesis of Cyclic Fluorinated Amino Acids.

Eur. J. Org. Chem. 2018; 3688-3692
Further Information

Publication History

Publication Date:
17 September 2018 (online)



The physical and chemical properties of N-heterocycles can be modified by the insertion of fluorine atoms, resulting in great advantages to medicinal chemistry and organocatalysis. In these aspects, fluorine atoms can influence the stability, conformation, basicity, and pharmacokinetic properties of N-heterocycles (see Review below).



X.-G. Hu, L. Hunter Beilstein J. Org. Chem. 2013, 9, 2696–2708.



Reported are the syntheses of the trifluoromethylated β-proline derivatives 2, 3a, and 3b through intramolecular 5-endo-trig cyclization of the N-homoallylic sulfinylamine 1, and the syntheses of tetrahydropyridines 5 through a ring-closure metathesis (RCM) approach starting from diallylic substrates 4. Because the diastereomeric mixture 2 could not be separated, the protecting group was replaced with Cbz to permit separation. The products were then separately saponified to give the N-Cbz-CF3-β-prolines 3a and 3b. The Grubbs second-generation catalyst was employed in an RCM process to synthesize the tetrahydropyridines 5. Amino acids 6, 7a, and 7b were prepared from tetrahydropyridines 5 by catalytic hydrogenation/oxidative degradation under ­Sharpless conditions for compound 6 and by catalytic hydrogenation/cleavage of the protecting group/ester hydrolysis for compounds 7a and 7b.