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Synlett 2007(7): 1083-1084  
DOI: 10.1055/s-2007-977420
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereocontrolled Synthesis of (S)-γ-Fluoroleucine

Dharshana Padmakshana, Simon A. Bennetta, Gottfried Otting*a, Christopher J. Easton*a,b
a Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia
Fax: +61(2)61258114; e-Mail: easton@rsc.anu.edu.au;
b ARC Centre of Excellence in Free Radical Chemistry and Biotechnology
Further Information

Publication History

Received 26 June 2006
Publication Date:
13 April 2007 (online)

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Abstract

Starting with (S)-leucine, the corresponding γ-fluoride 8 has been prepared in a stereocontrolled fashion, by exploiting ­methods for the direct side-chain bromination of amino acid derivatives and silver(I) fluoride as the fluorinating reagent.

Key words

(S)-γ-fluoroleucine - stereoselective synthesis - silver fluoride - amino acids - halogenation

14

Preparation of the Fluoride 6 A mixture of the bromide 3 [11] (15 g, 42 mmol) and AgF (53 g, 0.42 mol) in dry MeCN (0.25 L) was stirred at 25 °C for 22 h, before it was filtered through silica. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica, eluting with Et2O-hexane (1:1, v/v), to give the fluoride 6 (3.7 g, 30%) as a colorless oil. 1H NMR (CDCl3): δ = 1.36 (3 H, d, J = 25 Hz), 1.43 (3 H, d, J = 25 Hz), 2.62 (2 H, m), 3.73 (3 H, s), 5.15 (1 H, m), 7.72-7.79 (4 H, m). 13C NMR (CDCl3): δ = 170.1 (s), 167.9 (s), 134.5 (s), 132.2 (s), 123.9 (s), 94.8 (d, J = 167 Hz), 53.4 (s), 48.6 (s), 38.9 (d, J = 21 Hz), 28.3 (d, J = 24 Hz), 25.8 (d, J = 25 Hz). Preparation of the Hydrazide 7
A mixture of the fluoride 6 (2 g, 6.8 mmol)and N2H4·H2O (2.9 mL, 59 mmol) in EtOH (30 mL) was heated at reflux for 1 h, before it was cooled and filtered. The filtrate was concentrated under reduced pressure to give the hydrazide 7 (0.96 g, 86%) as a colorless solid, mp 78-80 °C. 1H NMR (TFA-D2O): δ = 1.46 (3H, d, J = 23 Hz), 1.48 (3 H, d, J = 22 Hz), 2.29 (2 H, m), 4.40 (1 H, m). 13C NMR (TFA-D2O): δ = 171.0 (s), 99.2 (d, J = 162 Hz), 51.7 (s), 43.6 (d, J = 21 Hz), 29.5 (d, J = 23 Hz), 27.3 (d, J = 23 Hz). Preparation of ( S )-γ-Fluoroleucine 8
A solution of the hydrazide (0.89 g, 5.5 mmol) in H2O (3 mL) was added dropwise over 0.5 h to a vigorously stirred solution of NBS (1.9 g, 11 mmol) in H2O (2 mL) at 25 °C, then the mixture was concentrated under reduced pressure. The residue was dissolved in dry EtOH (14 mL) and propylene oxide (1.8 mL) was added, before the mixture was let stand at 5 °C for 24 h. The resultant precipitate was separated by filtration to give the fluoride 8 (0.37 g, 45%) as colorless granules, in >95% ee [HPLC t R = 10.9 min, using a Daicel Chemical Industries Ltd. Crownpak® CR(+) column, 150 mm × 4 mm I.D., eluting at 0.2 mL min-1 with 10 mM aq HClO4, compared to a racemic sample under which conditions the R-enantiomer had t R = 9.2 min], mp 200-202 °C. [α]D -19.2° (c 0.040, MeOH). 1H NMR (D2O): δ = 1.30 (3 H, d, J = 23 Hz), 1.32 (3 H, d, J = 23 Hz), 2.09 (2 H, m), 3.81 (1 H, m). 13C NMR (D2O): δ 177.3 (s), 100.4 (d, J = 160 Hz), 54.6 (s), 43.7 (d, J = 21 Hz), 30.2 (d, J = 24 Hz), 27.0 (d, J = 24 Hz).