LETTER
Lipophilic Amino Acids
245
(15) (a) Koszinowski, K.; Bohrer, P. Organometallics 2009, 28,
100. (b) Koszinowski, K.; Bohrer, P. Organometallics 2009,
28, 771.
NHBoc
CO2Me
(16) Hardick, D.; Tozer, M.; Canfield, J.; Wilson, M.; Rae, A.;
Fallon, P.; Classon, B.; Lindquist, C.; Ayesa, S. (Medivir
UK Ltd. / UK; Peptimmune, Inc) WO Patent
WO2006064286 (A1), 2006.
(17) Grimes, R. M.; Hartley, C. D.; Mordaunt, J. E.; Shah, P.;
Slater, M. J.; White, G. V. (Smithkline Beecham
13
F
NHBoc
CO2Me
ent-12a
NHBoc
CO2Me
5 (44% brsm)
•
i) HF py, toluene
ii) Boc2O,
NaHCO3
dioxane
LiOH (0.5 M)
THF–MeCN
Corporation, USA) WO Patent 2008059042 (A1), 2008.
(18) General Method for the Preparation of Alkynes 4:
The organozinc reagent 1 was prepared from protected
iodoalanine 9 (329 mg, 1 mmol) as a ca. 1 M solution in
DMF according to our previously reported method.11
CuBr·DMS (20.6 mg, 0.1 mmol) was gently heated under
vacuum in a dry flask until the powder turned light green,
and was then allowed to cool under nitrogen. DMF (0.6 mL)
and the bromoallene 8 (1.1 mmol) were added. The reaction
mixture was cooled to –10 °C. After 2 min stirring at –10 °C,
a solution of the organozinc reagent 1 (1 mL of a 1 M
solution in DMF, 1 mmol) was added dropwise via syringe
over 10 min. The reaction mixture was stirred for the time
indicated at either –10 °C or 0 °C. The reaction mixture was
applied directly to a silica gel column, which was eluted (5%
Et2O in toluene) to give the alkynes 419–21 and the allenes 10
as light yellow oils.
F
NHBoc
CO2H
14 (93%)
Scheme 4 Addition of HF to cyclopentenylalanine derivative ent-12a
In conclusion, we have reported simple methods18 for the
synthesis of a range of new a-amino acids with lipophilic
side chains.
Acknowledgment
We thank Dr Salem Abuhanak for preliminary experiments.
General Method for the Preparation of Alkenes 12: The
cycloalken-1-yl triflate 3 (1.3 mmol, 1.3 equiv), Pd2(dba)3
(22 mg, 2.5 mol%), SPhos (21 mg, 5 mol%) and LiCl (1.8
mmol, 1.8 equiv), if required, were added at r.t. to the
organozinc reagent 1 (1 mL of a ca. 1 M solution in DMF).
The reaction mixture was stirred at r.t. overnight under a
positive pressure of nitrogen, and then applied directly to a
silica gel column, which was eluted (10% EtOAc in
petroleum ether) to give the cross-coupled product 12.
(R)-2-Amino-3-(1-fluorocyclopentyl)propionic Acid
Methyl Ester (5): Alkene ent-12a (492 mg, 1.83 mmol) was
dissolved in toluene (4 mL) in a Teflon bottle, cooled to 0 °C
and stirred vigorously. HF–pyridine (70% HF, 3.2 mL,
CAUTION: very toxic) was added and the bottle was
sealed. After 2 h, the reaction mixture was carefully
transferred into a slurry of CaCO3 (12.8 g) in H2O (50 mL)
and CH2Cl2 (35 mL) cooled to 0 °C. The mixture was stirred
while the pH was adjusted to ca. 10 by addition of sat. aq
Na2CO3, followed by stirring for a further 30 min. Celite (6.4
g) was washed with Na2CO3 solution, H2O, EtOH, EtOAc
and CH2Cl2 in sequence and added to the slurry. The
suspension was filtered and the filter cake was washed with
CH2Cl2 (50 mL in portions) and H2O (25 mL). The phases
were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic phases were
washed with sat. aq NaHCO3 (20 mL) and evaporated. The
crude mixture of amino esters (0.253 g) was dissolved in 1,4-
dioxane (4 mL), aq sat. NaHCO3 (6 mL) was added and the
mixture was cooled to 0 °C with stirring. Boc2O (0.323 g,
1.48 mmol) in 1,4-dioxane (4 mL) was added to the reaction
mixture. The reaction mixture was allowed to reach r.t. and
stirred for 1 h. The reaction mixture was diluted with Et2O
(10 mL) and H2O (10 mL) and the layers were separated. The
aqueous phase was extracted with Et2O (2 × 10 mL). The
combined organic phases were washed with H2O and brine
(10 mL each) and evaporated. The product was purified by
gradient column chromatography [Column 40 mm i.d. × 82
mm, loaded with 50 g Biotage KP-Sil (silica gel) 2–17%
EtOAc in iso-hexane] to give 522 (158 mg, 30% over two
steps) and recovered ent-12a (160 mg, 32%).
References and Notes
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© Thieme Stuttgart · New York
Synlett 2012, 23, 243–246