Fluorination and the incorporation of β-amino acids into peptides represent powerful strategies to enhance their proteolytic stability and to control their conformation.^[1] These features are combined in α-fluoro-β-amino acids, which influence the conformation of β-peptides.^[2] Recently, our group developed a stereoselective method to access fluorinated aldol products using fluorinated malonic acid half thioesters (F-MAHTs) as building blocks.^[3] Herein we present highly stereoselective organocatalyzed Mannich reactions between fluorinated monothiomalonates (F-MTMs) and N-Cbz and N-Boc protected imines as well as Michael reactions between F-MTMs and nitroolefins.^[4] These reactions require only 1 mol% of organocatalyst and provide access to the corresponding α-fluoro β-amino thioesters and α-fluoro γ-nitro thioesters, respectively. α-fluoro β-amino thioesters can be directly used for peptide synthesis in solution and on solid phase, whereas α-fluoro γ-nitro thioesters can be transformed into the corresponding fluorinated lactams, as showcased in the synthesis of a fluorinated analogue of AC-264613.^[5]

[1]      D. Seebach, J. Gardiner, Acc. Chem. Res. 2008, 41, 1366–1375.
[2]      T. L. March, M. R. Johnston, P. J. Duggan, J. Gardiner, Chem. Biodiv. 2012, 9, 2410–2441.
[3]      J. Saadi, H. Wennemers, Nature Chem. 2016, 8, 276–280.
[4]    a) E. Cosimi, O. Engl, J. Saadi, M.-O. Ebert, H. Wennemers, Angew. Chem. Int. Ed. 2016, 55, 13127-13131; b) E. Cosimi, J. Saadi, H. Wennemers, Org. Lett. 2016, 18, 6014-6017.
[5]   Seitzberg, J. G.; Knapp, A. E.; Lund, B. W.; Bertozzi, S. M.; Currier, E. A.; Ma, J.-N.; Sherbukhin, V.; Burstein, E. S.; Olsson, R. J. Med. Chem. 2008, 51, 5490–5493.