Stereocontrolled Synthesis of (S)-γ-Fluoroleucine

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.

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

References and Notes

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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).