1280
V. L. Truong et al.
LETTER
Amsterdam, The Netherlands, 1993. (h) Marsh, E. N. G.
Chem. Biol. 2000, 7, R153. (i) Tsukamoto, T.;Coward, J. K.
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O
O
OH
OBn
OBn
OH
a
b
(2) (a) Ramesh, B.; Edward, K. H.; Krishma, K. J. Org. Chem.
2004, 69, 5468. (b) Anderson, J. T.; Toogood, P. L.; Marsh,
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A.; Krishna, K. Org. Lett. 2001, 3, 1285. (d) Renner, C.;
Alefelder, S.; Bae, J. H.; Budisa, N.; Huber, R.; Moroder, L.
Angew. Chem. Int. Ed. 2001, 40, 923. (e) Tang, Y.;
Ghirlanda, G.; Petka, W. A.; Nakajima, T.; Degrado, W. F.;
Tirrell, D. A. Angew. Chem. Int. Ed. 2001, 40, 1494.
(f) Tang, Y.; Tirrell, D. A. J. Am. Chem. Soc. 2001, 123,
11089. (g) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.;
DeRider, M. L.; Raines, R. T. J. Am. Chem. Soc. 2001, 123,
777. (h) Holmgren, S. K.; Taylor, K. M.; Bretscher, L. E.;
Raines, R. T. Nature 1998, 392, 666. (i) Qing, F.-L.; Peng,
S.; Hu, C.-M. J. Fluorine Chem. 1998, 88, 79. (j) Welch, J.
T. Tetrahedron 1987, 43, 3123. (k) Qiu, X. L.; Meng, W.
D.; Qing, F. L. Tetrahedron 2004, 60, 6711.
HN
O
HN
O
BocHN
O
O
2
7
8
F
c
+
(6%)
HN
O
HN
O
O
O
10
9
d, e
F
F
F
f
g
(3) Limanto, J.; Shafiee, A.; Devine, P. N.; Upadhyay, V.;
Desmond, R. A.; Foster, P. R.; Gauthier, D. R.; Reamer, R.
A.; Volante, R. P. J. Org. Chem. 2005, 70, 2372.
(4) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez,
J. Tetrahedron Lett. 1991, 32, 923.
(5) For reviews on the conversion of alcohols to alkyl fluorides:
(a) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(b) Middleton, W. J.; Bingham, E. M. Org. Synth., Coll. Vol.
VI; Wiley and Sons: New York, 1988, 835. (c) Hudlicky,
M. Org. React. 1988, 35, 513.
OH
OH
OH
TFA·H2N
BocHN
BocHN
O
O
11
13
12
Scheme 2 Reagents and conditions: a) (p-Tos)2O (1.1 equiv), pyri-
dine, dichloroethane, 0 °C, at r.t. for 1 h, then at 90 °C for 2 h, 83%;
b) MeMgBr (3 M in Et2O, 4 equiv), toluene–THF (1:1), –20 °C to
0 °C, 72%; c) DAST (1 equiv), CH2Cl2, –78 °C to r.t., 70%; d) KOH
(3 equiv), EtOH (90%)–H2O, 100 °C, 4 h; e) (Boc)2O (1.5 equiv),
Et3N, CH2Cl2, 91% (last two steps); f) H5IO6 (2.5 equiv), CrO3 (cat.),
0.75% v/v H2O/MeCN, 0 °C, 50 min, 65%; g) 20% TFA in CH2Cl2,
99%.
(6) Zhao, H.; Thurkauf, A. Synlett 1999, 1280.
(7) Experimental Procedure for the Synthesis of Compound
8.
MeMgBr (681 mL of 3 M solution in Et2O, 2.04 mol) was
added to a mixture of toluene (1 L) and THF (1 L) at –20 °C.
A solution of the benzyl ester 7 (120 g, 510 mmol) in THF
(500 mL) was added dropwise maintaining the temperature
below –10 °C and the mixture was aged at 0 °C for 2 h. The
mixture was slowly added to a mixture of H2O (3 L) and
HOAc (600 mL) and the mixture was stirred at r.t. for 2 h.
The aqueous layer was separated and the organic layer was
extracted with H2O (2 × 600 mL). The product was extracted
from the combined aqueous layers using CH2Cl2 and a
continuous extractor (2 d). The CH2Cl2 extract was
evaporated to dryness and co-evaporated with n-heptane.
The residue was purified by chromatography on silica gel
using EtOH and CH2Cl2 (1:25) to afford compound 8 (62 g,
72%). [a]D20 –7.0 (c 1.0, MeOH). 1H NMR (500 MHz,
CD3COCD3): d = 1.25 (3 H, s), 1.27 (3 H, s), 1.73 (1 H, dd,
J = 13.9, 6.1 Hz), 1.81 (1 H, dd, J = 13.9, 6.6 Hz), 3.67 (1 H,
s), 4.01 (1 H, dd, J = 8.4, 7.3 Hz), 4.12–4.18 (1 H, m), 4.49
(1 H, dd, J = 8.3, 8.3 Hz), 6.26 (1 H, s). 13C NMR (125 MHz,
CDCl3): d = 160.05, 71.14, 71.00, 50.19, 47.66, 32.14,
28.86. Anal. Calcd for C7H13NO3: C, 52.82; H, 8.23; N, 8.80.
Found: C, 52.69; H, 8.19; N, 8.76. HRMS-FAB (glycerol,
KCl): m/z [M + K]+ calcd for C7H13NO3K: 198.1878; found:
198.0532.
In conclusion, we have developed a convenient and effi-
cient procedure for the preparation of optically pure (S)-g-
fluoroleucine in multigram quantities using commercially
available N-(tert-butoxycarbonyl)-L-aspartic acid 4-
benzyl ester as a starting material. No erosion of chirality
occurred during the synthesis.
Acknowledgment
We thank Dr. Cameron W. Black and Dr. Chun-Sing Li for valuable
chemistry discussions.
References
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Synlett 2005, No. 8, 1279–1280 © Thieme Stuttgart · New York