Subscribe to RSS
DOI: 10.1055/s-2007-977420
Stereocontrolled Synthesis of (S)-γ-Fluoroleucine
Publication History
Publication Date:
13 April 2007 (online)
![](https://www.thieme-connect.de/media/synlett/200707/lookinside/thumbnails/10.1055-s-2007-977420-1.jpg)
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
- For reviews, see:
-
1a
Neil E.Marsh G. Chem. Biol. 2000, 7: 153 -
1b
Yoder NC.Kumar K. Chem. Soc. Rev. 2002, 31: 335 - 2 For a review, see:
Jäckel C.Koksch B. Eur. J. Org. Chem. 2005, 4483 - 3 For a review, see:
Walsh CT. Annu. Rev. Biochem. 1984, 53: 493 - 4 For a review, see:
Ojima I. New Developments in the Synthesis and Medicinal Applications of Fluoroamino Acids and Peptides, In Organofluorine Compounds in Medicinal Chemistry and Biomedical ApplicationsFiller R.Kobayashi Y.Yagupolskii LM. Elsevier; Amsterdam: 1993. p.241-273 - See, for example:
-
5a
Tolman V. Amino Acids 1996, 11: 15 -
5b
Kröger S.Haufe G. Amino Acids 1997, 12: 363 -
5c
Sutherland A.Willis CL. Nat. Prod. Rep. 2000, 17: 621 -
5d
Qiu X.-L.Meng W.-D.Qing F.-L. Tetrahedron 2004, 60: 6711 - 6
Ozawa K.Dixon NE.Otting G. IUBMB Life 2005, 57: 615 - 7
Feeney J.McCormick JE.Bauer CJ.Birdsall B.Moody CM.Starkmann BA.Young DW.Francis P.Havlin RH.Arnold WD.Oldfield E. J. Am. Chem. Soc. 1996, 118: 8700 - 8
Papageorgiou C.Borer X.French RR. Bioorg. Med. Chem. Lett. 1994, 4: 267 - 9
Limanto J.Shafiee A.Devine PN.Upadhyay V.Desmond RA.Foster BR.Gauthier DR.Reamer RA.Volante RP. J. Org. Chem. 2005, 70: 2372 - 10
Truong VL.Gauthier JY.Boyd M.Roy B.Scheigetz J. Synlett 2005, 1279 -
11a
Easton CJ.Hutton CA.Rositano G.Tan EW. J. Org. Chem. 1991, 56: 5614 -
11b
Easton CJ.Hutton CA.Roselt PD.Tiekink ERT. Tetrahedron 1994, 50: 7327 -
11c
Easton CJ.Hutton CA.Merrett MC.Tiekink ERT. Tetrahedron 1996, 52: 7025 -
11d
Easton CJ. Chem. Rev. 1997, 97: 53 -
11e
Easton CJ.Hutton CA. Synlett 1998, 457 -
12a
Ogawa A.Curran DP. J. Org. Chem. 1997, 62: 450 -
12b
O’Connell JL.Simpson JS.Dumanski PG.Simpson GW.Easton CJ. Org. Biomol. Chem. 2006, 4: 2716 -
13a
Wolman Y.Gallop PM.Patchornik A.Berger A. J. Am. Chem. Soc. 1962, 84: 1889 -
13b
Cheung HT.Blout ER. J. Org. Chem. 1965, 30: 315
References and Notes
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).