Stereocontrolled synthesis of (S)-γ-fluoroleucine

Article abstract of DOI:10.1055/s-2007-977420

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 silven(I) fluoride as the fluorinating reagent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977420

LETTER
1083
Stereocontrolled Synthesis of (S)-g-Fluoroleucine
S
a
tereocontrolledS
h
ynthesis of
(
S
)-
g
-Fluoro
r
leucine shana Padmakshan,a Simon A. Bennett,a Gottfried Otting,*a Christopher J. Easton*a,b
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
Received 26 June 2006
Treatment of (S)-leucine (1) with phthalic anhydride and
Et3N in refluxing toluene, and then reaction of the corre-
sponding phthalimide with SOCl2-pretreated methanol,
afforded the amino acid derivative 2, which reacted with
NBS to give the bromide 3.11 The amino acid protecting
groups and the brominating reagent were carefully select-
ed to control the regioselectivity of the halogenation. The
solvent reported for the latter reaction is CCl4 but trifluo-
romethylbenzene is generally more acceptable12 and
proved to be a suitable alternative for this purpose. Reac-
tion of the bromide 3 with AgF gave the fluoride 6, which
had to be separated from the byproducts, the lactone 4 and
the alkene 5, through chromatography. Despite a com-
prehensive investigation of all the reaction variables, in-
cluding temperature and time, and relative and absolute
concentrations of the reagent and the substrate 3, forma-
tion of the byproducts was unavoidable. All attempts to
remove both of the protecting groups from the fluoride 6
in a single procedure failed to afford the free analogue 8,
with most protocols instead producing the lactones 4 and
9. However, treatment of the fluoride 6 with hydrazine
gave the hydrazide 7, from which the hydrobromide salt
of (S)-g-fluoroleucine (8) was obtained, in >95% ee, by
treatment with NBS.13 The yield of the crude product was
virtually quantitative, but isolation and purification of the
free amino acid 8 by treatment with propylene oxide in
ethanol was accompanied by decomposition to the lactone
9, such that the pure zwitterion 8 was obtained in only
45% yield. We have included full details of our experi-
mental protocols and spectral data for the synthesis and
characterization of the fluoride 8,14 since neither of the
previous reports8,10 provided that information.
Abstract: Starting with (S)-leucine, the corresponding g-fluoride 8
has been prepared in a stereocontrolled fashion, by exploiting
methods for the direct side-chain bromination of amino acid deriv-
atives and silver(I) fluoride as the fluorinating reagent.
Key words: (S)-g-fluoroleucine, stereoselective synthesis, silver
fluoride, amino acids, halogenation
Fluorinated amino acids and their derivatives are of
interest as mechanistic1 and spectroscopic probes,2 and as
enzyme inhibitors3 and in the development of pharmaceu-
ticals.4 Consequently they have attracted considerable
attention as synthetic targets, with particular emphasis on
asymmetric syntheses and methods to introduce the fluo-
rine under straightforward conditions.4,5 We are exploring
the incorporation of aliphatic fluorinated amino acids into
proteins by cell-free protein synthesis.6 In this context,
(S)-g-fluoroleucine (8) presents a particularly attractive
probe because of the simplicity of its spin system and be-
cause leucine 1 is an abundant amino acid in proteins,
both at positions inside the protein structure and on the
protein surface. (2S,4S)-5-Fluoroleucine has already been
shown to be incorporated into proteins made by E. coli.7
In 1994, Papageorgiou et al.,8 reported the synthesis of the
ethyl ester of (S)-g-fluoroleucine (8), using Schöllkopf’s
bislactim ether methodology and starting by treating
isobutylene oxide with HF·pyridine. They noted briefly
that saponification of the ester with Ba(OH)2 afforded the
free amino acid 8. Another synthesis of the ester, also
starting with isobutylene and HF·pyridine, and with li-
pase-catalyzed resolution of a racemic intermediate, was
reported in 2005.9 A complementary approach is to begin
with a chiral amino acid, where the stereochemical center
of the starting material is retained in the product. In that
context, Truong et al.10 recently reported the synthesis of
the trifluoroacetate salt of the amino acid 8 in eight steps
from N-(tert-butoxycarbonyl)-(S)-aspartic acid 4-benzyl
ester, using DAST in a key step to introduce the fluorine.
This publication prompts us to report our stereocontrolled
synthesis of the amino acid 8 from (S)-leucine (1), by
exploiting methods for the direct side-chain bromination
of amino acid derivatives11 and AgF as the fluorinating
reagent.
In summary, the synthesis outlined in Scheme 1 provides
ready access to gram quantities of (S)-g-fluoroleucine (8),
in only five steps, using convenient protocols and the
cheap and readily available starting material 1, while
avoiding the use of toxic and corrosive reagents such as
HF·pyridine and DAST, and the need to resolve stereo-
isomers. It further illustrates the utility of side-chain func-
tionalization and manipulation of amino acid derivatives
in stereocontrolled synthesis. Our preliminary experi-
ments have shown that both the hydrazide 7 and the free
amino acid 8 are incorporated in place of leucine 1 during
cell-free protein synthesis, an intriguing result that is the
subject of on-going investigations.
SYNLETT 2007, No. 7, pp 1083–1084
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977420; Art ID: S13706ST
© Georg Thieme Verlag Stuttgart · New York

1084
D. Padmakshan et al.
LETTER
(7) Feeney, J.; McCormick, J. E.; Bauer, C. J.; Birdsall, B.;
Br
Moody, C. M.; Starkmann, B. A.; Young, D. W.; Francis, P.;
Havlin, R. H.; Arnold, W. D.; Oldfield, E. J. Am. Chem. Soc.
1996, 118, 8700.
a,b
c
+
ref. 11
ref. 11
–
H3N
CO2
Phth
CO2Me
Phth
CO2Me
(8) Papageorgiou, C.; Borer, X.; French, R. R. Bioorg. Med.
Chem. Lett. 1994, 4, 267.
1
2
3
(9) Limanto, J.; Shafiee, A.; Devine, P. N.; Upadhyay, V.;
Desmond, R. A.; Foster, B. R.; Gauthier, D. R. Jr.; Reamer,
R. A.; Volante, R. P. J. Org. Chem. 2005, 70, 2372.
(10) Truong, V. L.; Gauthier, J. Y.; Boyd, M.; Roy, B.; Scheigetz,
J. Synlett 2005, 1279.
(11) (a) Easton, C. J.; Hutton, C. A.; Rositano, G.; Tan, E. W.
J. Org. Chem. 1991, 56, 5614. (b) Easton, C. J.; Hutton, C.
A.; Roselt, P. D.; Tiekink, E. R. T. Tetrahedron 1994, 50,
7327. (c) Easton, C. J.; Hutton, C. A.; Merrett, M. C.;
Tiekink, E. R. T. Tetrahedron 1996, 52, 7025. (d) Easton,
C. J. Chem. Rev. 1997, 97, 53. (e) Easton, C. J.; Hutton, C.
A. Synlett 1998, 457.
d
F
+
+
O
Phth
CO2Me
Phth
Phth
CO2Me
O
4
5
6
e
(12) (a) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(b) O’Connell, J. L.; Simpson, J. S.; Dumanski, P. G.;
Simpson, G. W.; Easton, C. J. Org. Biomol. Chem. 2006, 4,
2716.
(13) (a) Wolman, Y.; Gallop, P. M.; Patchornik, A.; Berger, A.
J. Am. Chem. Soc. 1962, 84, 1889. (b) Cheung, H. T.; Blout,
E. R. J. Org. Chem. 1965, 30, 315.
F
F
f
O
+
–
NH2
H3N
CO2
NH2
CONHNH2
O
8
7
9
O
(14) Preparation of the Fluoride 6
A mixture of the bromide 311 (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): d = 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): d = 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).
Phth =
N
O
Scheme 1 Reagents and conditions: a) phthalic anhydride, toluene
at reflux, 25 min; b) SOCl2–MeOH, 25 °C, 12 h; c) NBS, CCl4 or
CF3Ph, hn, reflux, 5 h; d) AgF, MeCN, 25 °C, 22 h; e) N2H4·H2O,
EtOH, reflux, 1 h; f) NBS, H2O, 25 °C, 0.5 h.
Acknowledgment
Preparation of the Hydrazide 7
The authors gratefully acknowledge the support received for this
work from the Australian Research Council, including a Federation
Fellowship for G.O.
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): d = 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):
d = 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).
References and Notes
(1) For reviews, see: (a) Neil, E.; Marsh, G. Chem. Biol. 2000,
7, 153. (b) Yoder, N. C.; 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, C. T. Annu. Rev. Biochem. 1984,
53, 493.
Preparation of (S)-g-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 tR = 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 tR = 9.2 min], mp
200–202 °C. [a]D –19.2° (c 0.040, MeOH). 1H NMR (D2O):
d = 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): d 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).
(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 Applications; Filler, R.;
Kobayashi, Y.; Yagupolskii, L. M., Eds.; Elsevier:
Amsterdam, 1993, 241–273.
(5) See, for example: (a) Tolman, V. Amino Acids 1996, 11, 15.
(b) Kröger, S.; Haufe, G. Amino Acids 1997, 12, 363.
(c) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17,
621. (d) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron
2004, 60, 6711.
(6) Ozawa, K.; Dixon, N. E.; Otting, G. IUBMB Life 2005, 57,
615.
Synlett 2007, No. 7, 1083–1084 © Thieme Stuttgart · New York

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