A concise synthesis of (S)-γ-fluoroleucine ethyl ester

Article abstract of DOI:10.1055/s-2005-923593

We report herein a six-step, chromatography-free, through-process for the asymmetric synthesis of (S)-γ-fluoroleucine ethyl ester sulfate salt (6) that proceeds in 25% overall yield from inexpensive ethyl glyoxylate. This approach features a Ti/Zn-catalyz

Full text of DOI:10.1055/s-2005-923593

LETTER
291
A Concise Synthesis of (S)-g-Fluoroleucine Ethyl Ester
A
a
C
oncise
Synth
h
(
S
)-
g
-
r
Fluorole
i
ucine
E
s
thyl Estertian Nadeau,*a Francis Gosselin,a Paul D. O’Shea,a Ian W. Davies,b Ralph P. Volanteb
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec
H9H 3L1, Canada
Fax +1(514)4284936; E-mail: christian_nadeau@merck.com
b
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 27 September 2005
derivative into fluoroleucine that featured a DAST-medi-
ated fluorination of a tertiary alcohol.8 Our objective was
to develop a short, chromatography-free, catalytic asym-
metric synthesis that would allow us to efficiently prepare
Abstract: We report herein a six-step, chromatography-free,
through-process for the asymmetric synthesis of (S)-g-fluoroleucine
ethyl ester sulfate salt (6) that proceeds in 25% overall yield from
inexpensive ethyl glyoxylate. This approach features a Ti/Zn-cata-
lyzed glyoxylate-ene reaction–olefin hydrofluorination–amine fluoroleucine 5 (Scheme 1).
alkylation as key steps.
Me
+
Key words: (S)-g-fluoroleucine ethyl ester, asymmetric synthesis,
asymmetric
glyoxylate-ene
hydrofluorination
F
F
enantioselective glyoxylate-ene reaction, olefin hydrofluorination,
Me
Me
Me
OEt
Me
activation
alkylation
amine alkylation
Me
OEt
H2N
HO
O
O
O
Fluorine-substituted molecules are extensively used in the
preparation of biologically active agents.1 The unique
properties of fluorine induce profound changes in the
physical properties of organic molecules. For example,
fluorine substitution is commonly used in medicinal
chemistry to increase lipophilic character and metabolic
stability of drug candidates.1d,e,h Incorporation of fluorine
into molecules frequently involves fluorinated amino ac-
ids as key intermediates.2 Although a number of syntheses
of fluorinated amino acids have been reported, the effi-
cient preparation of g-fluorinated a-amino acids remains
a challenge. These amino acids have been prepared via
Claisen rearrangement3 or alkylation of N-diphenylmeth-
ylene glycine ester with fluoroalkanes electrophiles.4
Similar alkylation strategies featuring the use of chiral
auxiliaries successfully generated enantioenriched ana-
logues.5
OEt
H
5
3a
O
1
Scheme 1 Retrosynthetic analysis of (S)-g-fluoroleucine ethyl
ester 5.
We envisioned that fluoroleucine 5 could be prepared via
the displacement of activated g-fluoroleucic acid ethyl es-
ter (3a) by a nucleophilic nitrogen source. Hydroxy ester
3a could be derived from an asymmetric glyoxylate-ene
reaction between ethyl glyoxylate (1) and isobutylene fol-
lowed by a hydrofluorination reaction of the gem-disub-
stituted olefin.
Bis(oxazoline)copper-catalyzed glyoxylate-ene reactions
have been reported for the highly enantioselective prepa-
ration of a-hydroxyester 2.9 A drawback associated with
the Cu-based ene reaction is that it requires the use of ex-
pensive and not readily available bis(oxazoline) chiral
ligands. Consequently, we decided to investigate the Ti-
catalyzed glyoxylate-ene reaction which uses readily
available and inexpensive BINOL as chiral ligand.10
As part of a drug development program, we were required
to prepare multi-gram quantities of (S)-g-fluoroleucine
ethyl ester sulfate salt (6). The synthesis of fluoroleucine
5 has been previously reported for the preparation of cy-
closporine A derivatives.6 Schöllkopf’s bis-lactim ether
alkylation methodology was used as a key step towards
the synthesis of these immunosuppressive analogues. This
approach suffered from low-yielding alkylation–hydroly-
sis step and required distillative separation from the ex-
pensive valine chiral auxiliary. Our research laboratories
recently reported two synthetic approaches towards fluo-
roleucine 5. One approach featured an enzyme-catalyzed
dynamic kinetic ring-opening of an azalactone that effi-
ciently generated fluoroleucine.7 The second route in-
volved the multi-step transformation of an L-aspartic acid
As illustrated in Table 1, the Ti-catalyzed reaction re-
quires distillative depolymerization of ethyl glyoxylate
(1) immediately prior to the reaction (Table 1, entries 1
and 2).10c This can be problematic for large scale applica-
tions since distilled ethyl glyoxylate was found to repoly-
merize at a rate of approximately 10%/h at room
1
temperature (40% after 4 h) as determined by H NMR
spectroscopy. Therefore, we sought a way to promote the
depolymerization of glyoxylate in situ without mediating
a racemic glyoxylate-ene reaction. We investigated the
depolymerization of ethyl glyoxylate using Lewis acid co-
catalysts and found that CuSO4 and Zn(OTf)2 promoted
the depolymerization of 1 but also catalyzed the ene
reaction (Table 1, entries 3 and 4). After an extensive
SYNLETT 2006, No. 2, pp 0291–0295
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923593; Art ID: S09505ST
© Georg Thieme Verlag Stuttgart · New York

292
C. Nadeau et al.
LETTER
F
investigation we were pleased to find that addition of
MgCl2 led to depolymerization of ethyl glyoxylate with-
out adverse effects on the ene reaction (Table 1, entry 5).
Ultimately, we identified ZnCl2 as the additive of choice
(Table 1, entry 6). Addition of 5 mol% ZnCl2 proved to be
the optimal amount. These conditions afforded the best
yield (60%) and enantioselectivity (>95% ee). By com-
parison, addition of 1 mol% ZnCl2 led to lower yield
(55%) and addition of 10 mol% ZnCl2 led to erosion of
enantioselectivity (92%ee).
Me
O
Me
Me
OEt
a
b
H
OEt
OEt
HO
HO
O
O
O
1
2
3a
Scheme 2 Reagents and conditions: (a) TiCl2(Oi-Pr)2 (5 mol%, 0.3
M toluene), (R)-BINOL (7 mol%), isobutylene (4 equiv), 4 Å MS (2.9
g/g), ZnCl2 (5 mol%), toluene, –78 °C then 4 °C, 16 h. Darco KB-B
(1 g/g), heptane, 57%, >95% ee; (b) HF·pyridine (20 equiv), heptane,
0 °C, 2 h, 71%, >95% ee.
Table 1 Enantioselective Ti-Catalyzed Glyoxylate-Ene Reaction
TiCl2(Oi-Pr)2 (5 mol%)
(R)-BINOL (7 mol%)
isobutylene (4 equiv), 4Å MS (2.9 g/g)
We converted hydroxy ester 3a to triflate 3b by reaction
with Tf2O and 2,6-lutidine in heptane (≥99% conversion
by GC analysis, Scheme 3). The crude triflate 3b was used
without purification in the subsequent nucleophilic dis-
placement reaction. We also prepared the corresponding
tosylate, brosylate and nosylate but these electrophiles
afforded lower conversion or generated more impurities
in the following nucleophilic displacement.
O
Me
OEt
H
OEt
additive (5 mol%)
toluene, −78 °C then 4 °C, 16 h
HO
O
O
1
2
undistilled
57 wt% in toluene
Entry
Additive
None
Yield (%)a
ee (%)b
Nd
F
F
1
2c
3
4
5
6
27
67
43
59
47
60
Me
Me
OEt
Me
Me
OEt
c
b
None
>95
90
d
RO
BnHN
CuSO4
O
O
d
Zn(OTf)2
86
3a: R = H
a
4
3b: R = OTf
MgCl2
>95
>95
F
F
ZnCl2
Me
Me
OEt
Me
Me
OEt
d
a Determined by HPLC analysis.
b Determined by chiral GC analysis (Cyclodex-B column).
c Freshly distilled ethyl glyoxylate was used.
d 1 mol% of additive was used.
H2N
H2SO4⋅H2N
O
O
5
6
Scheme 3 Reagents and conditions: (a) Tf2O (1.5 equiv), 2,6-luti-
dine (2.0 equiv), heptane, 0 °C, 1 h, ≥99% conv.; (b) BnNH2 (1.2
equiv), K2CO3 (2.0 equiv), MeCN, 0 °C, 1.5 h, 80% (two steps),
>95% ee; (c) H2 (54 psi), Pd(OH)2/C (4 wt%, 20 wt% on C), EtOH,
r.t., 18 h, 95%, 95% ee; (d) H2SO4 (1.1 equiv), i-PrOAc, 0 °C, 1 h,
83%, 96% ee.
The desired hydroxy ester 2 was readily isolated by pre-
cipitation of the titanium salts by controlled addition of
heptane in the presence of Darco KB-B activated carbon
(Scheme 2). Alternatively, the crude hydroxy ester could
be distilled under high vacuum to yield the desired prod-
uct 2 in 52% yield. The purification of the hydroxy ester
was critical in order to reach complete conversion in the
following hydrofluorination step.
We performed the subsequent alkylation of benzylamine
with triflate 3b by using MeCN as solvent and powdered
K2CO3 as base (Scheme 3).13 A slight excess of benzyl-
amine was used and the reaction afforded complete con-
version after 1.5 hours at 0 °C to afford N-benzyl
fluoroleucine 4 in 83% yield over two steps. We also in-
vestigated solutions of ammonia (in MeOH, i-PrOH, di-
oxane) and hexamethyldisilazane as nitrogen sources but
we observed lower conversions as well as significant
amounts (20–40%) of dialkylation at nitrogen. Acid/base
work-up led to significant removal of color and complete
rejection of BINOL-related impurities that were carried
through from the glyoxylate-ene step. We observed less
than 1% epimerization at the reacting triflate chiral center
as determined by chiral HPLC analysis. Unfortunately,
this material behaved erratically in the subsequent hydro-
genolysis step, presumably because of residual amine-in-
We found that hydrofluorination of hydroxy ester 2 pro-
ceeded smoothly using HF·pyridine at 0 °C in heptane as
solvent to afford (R)-g-fluoroleucic acid ethyl ester (3a) in
71% yield.11 Heptane was superior to a broad variety of
solvents in terms of yield and impurity generation. HF·py-
ridine also afforded the best conversion and yield among
several HF sources.12 We observed that longer reaction
time (≥2.5 h) led to decreased yields of 3a and significant
impurity generation. Work up involved neutralization of
excess HF·pyridine with a pH 7 Na2HPO4/NaH2PO4 aque-
ous buffer solution directly in the reaction vessel. This
procedure obviated the use of a Teflon-lined separatory
funnel for subsequent extractions. We used the crude
isolated (R)-g-fluoroleucic acid ethyl ester 3a directly
without purification.
Synlett 2006, No. 2, 291–295 © Thieme Stuttgart · New York

LETTER
A Concise Synthesis of (S)-g-Fluoroleucine Ethyl Ester
293
(br, 1 H), 2.52 (dd, J = 4.2, 14.2 Hz, 1 H), 2.36 (dd, J = 8.2, 14.2 Hz,
1 H), 1.78 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 174.8, 141.0, 114.0, 69.1, 61.7, 42.7, 22.5, 14.2.
HRMS (ES): m/z calcd for [C8H14O3 + Na]+: 181.0841; found:
181.0838. Enantiomeric excess was determined by GC with a Cy-
clodex-B column (60 °C for 1 min, 20 °C/min to 100 °C, hold to
100 °C for 15 min, injector 180 °C, detector 250 °C, split 10:1, 13.5
psi helium); R enantiomer tR = 10.9 min; S enantiomer tR = 11.2
min; >95% ee. Conversion was determined by GC with a HP-1 col-
umn (50 °C for 1 min, 20 °C/min to 90 °C, 3 °C/min to 105 °C,
30 °C/min to 230 °C, injector 180 °C, detector 250 °C, split 5:1,
15.3 psi helium); ethyl glyoxylate tR = 2.1 min; hydroxy ester 2
tR = 5.5 min. Yield was determined by HPLC with a 4.6 mm × 25.0
cm Zorbax Rx-C8 column (0.1% H3PO4–MeCN 70:30 to 55:95
over 25 min, 2 mL/min, 220 nm, 35 °C); hydroxy ester 2 tR = 4.01
min. The hydroxy ester 2 was directly used for the subsequent hy-
drofluorination reaction.
duced catalyst poisoning. We ultimately found that a
CuSO4 wash (10% aqueous) of the organic layer was re-
quired in order to obtain reproducible conversion in the
following hydrogenolysis step.
We proceeded to the hydrogenolysis of N-benzyl fluoro-
leucine 4 in EtOH with Pearlman’s catalyst under 54 psi
of H2 at room temperature and obtained g-fluoroleucine
ethyl ester 5 in 95% yield.14 The use of lower pressure of
H2 led to incomplete conversion (0–50%). After filtration
to remove the catalyst and concentration, crude fluoroleu-
cine 5 (95% ee HPLC) was isolated as its sulfate salt ac-
cording to published procedure.7,16 (S)-g-Fluoroleucine
ethyl ester sulfate salt (6) was obtained in 83% yield and
96% ee according to chiral HPLC analysis.
In conclusion, we have reported a chromatography-free,
through-process for the multigram synthesis of (S)-g-fluo-
roleucine ethyl ester sulfate salt that proceeds in 6 steps
and 25% overall yield from inexpensive ethyl glyoxylate.
This approach features an unprecedented Ti/Zn-catalyzed
asymmetric glyoxylate-ene reaction.
Ethyl (2R)-4-fluoro-2-hydroxy-4-methylpentanoate (3a)
A solution of hydroxy ester 2 (17.5 g at 70.0 wt%, 12.25 g, 77.4
mmol) in heptane (123 mL) was added to a solution of HF·pyridine
(40.2 mL, 1.55 mol) in a Teflon-lined flask over 10 min while main-
taining the temperature at 0–4 °C. The mixture was stirred at 0 °C
for 2 h (GC analysis showed 93% conversion). Then, MTBE (123
mL) and an aq Na2HPO4/NaH2PO4 buffer solution (550 mL, 2 M,
pH = 7) were added. Afterwards, aq 2 M NaOH (approximately 490
mL) was added until the aqueous layer reached pH = 7. The layers
were separated and the aqueous layer was extracted with MTBE
(123 mL). The combined organic layers were washed with aq 1 N
HCl (123 mL), H2O (123 mL), dried with MgSO4, filtered and con-
centrated under vacuum to afford g-fluoroleucic acid ethyl ester 3
as a yellow oil. GC analysis showed 17.71 g at 55.5 wt% (9.83 g,
71% yield) of desired product that was directly used for the next
General Methods
All reactions were conducted under N2 atmosphere. Commercial re-
agents and solvents were used without further purification. Concen-
tration under vacuum refers to removal of the solvents using a rotary
evaporator at reduced pressure (10–20 torr). 1H NMR and 13C NMR
spectra were measured on either a 400 MHz or 500 MHz Bruker in-
strument and the chemical shifts were measured relative to solvent
residual peak (CHCl3 or DMSO). 19F NMR spectra were measured
on a 400 MHz Bruker instrument and the chemical shifts were mea-
sured relative to a,a,a-trifluorotoluene as an internal reference (d =
–62.7 ppm). Infrared spectra were reported in wave numbers and
measured on a Nexus 470 FT-IR spectrometer or an ASI React IR
instrument. Optical rotations were measured on a Perkin-Elmer 241
polarimeter. Melting points were measured on a Büchi B-540 in-
strument and are uncorrected. High-resolution mass spectrometry
(HRMS) measurements were performed at Merck Research Labo-
ratories, Rahway, NJ.
20
step. [a]D +10.6 (c 1.43, EtOH). IR (neat): n = 3474 (br), 2983,
1
1733, 1471, 1374, 1204, 1142, 1092 cm–1. H NMR (400 MHz,
CDCl3): d = 4.34 (ddd, J = 2.8, 5.3, 9.0 Hz, 1 H), 4.21 (q, J = 7.1
Hz, 2 H), 3.01 (d, J = 5.1 Hz, 1 H), 2.14 (ddd, J = 2.6, 14.8, 17.9 Hz,
1 H), 1.88 (ddd, J = 9.1, 14.7, 20.2 Hz, 1 H), 1.43 (d, J = 21.8 Hz, 3
H), 1.42 (d, J = 21.8 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 175.0, 95.1 (d, J = 165.9 Hz), 67.7 (d,
J = 5.5 Hz), 61.9, 45.1 (d, J = 22.6 Hz), 27.7 (d, J = 24.3 Hz), 26.9
(d, J = 24.5 Hz), 14.1. 19F NMR (375 MHz, CDCl3): d = –136.1.
HRMS (ES): m/z calcd for [C8H15FO3 + Na]+: 201.0903; found:
201.0896. Enantiomeric excess was determined by GC with a Cy-
clodex-B column (60 °C for 1 min, 20 °C/min to 100 °C, hold to
100 °C for 15 min, injector 180 °C, detector 250 °C, split 10:1, 13.5
psi helium); R enantiomer tR = 12.4 min; S enantiomer tR = 12.9
min; >95% ee. Conversion and yield were determined by GC with
a HP-1 column (50 °C for 1 min, 20 °C/min to 90 °C, 3 °C/min to
105 °C, 30 °C/min to 230 °C, injector 180 °C, detector 250 °C, split
5:1, 15.3 psi helium); g-fluoroleucic acid ethyl ester 3a tR = 5.6 min.
g-Fluoroleucic acid ethyl ester 3a must be kept at –20 °C since it
forms the corresponding lactone upon standing at r.t.
Ethyl (2R)-2-hydroxy-4-methylpent-4-enoate (2)
Powdered (R)-BINOL (6.01 g, 21.0 mmol) and 4 Å activated mo-
lecular sieves (88.80 g) were suspended in toluene (257 mL).
10c,15
TiCl2(Oi-Pr)2
(50.0 mL of 0.3 M solution in toluene, 15.0
mmol) was added and the reaction mixture was stirred at r.t. for 1 h.
Then, ZnCl2 (2.04 g, 15.0 mmol) was added and the reaction mix-
ture was cooled to –78 °C. Isobutylene was bubbled in the solution
until a weight increase of 67.33 g (1.20 mol) was measured. Ethyl
1
glyoxylate (53.73 g of 57 wt% in toluene by H NMR, 30.63 g,
300.0 mmol) was added and the reaction was let stir at 4 °C for 16
h (GC analysis showed 90% conversion). The solution was filtered
on Solka-Floc® and concentrated under vacuum. HPLC analysis
showed 68.60 g of a-hydroxy-ester 2 at 41.5 wt% (28.47 g, 60%
yield) isolated as a dark red oil. To a portion of hydroxy ester 2
(36.14 g at 41.5 wt%, 15.00 g, 94.8 mmol) was added Darco KB-B
activated carbon (15.00 g) and heptane (150 mL) was added to the
stirred mixture over 1 h. The resulting suspension was stirred for 16
h at r.t., filtered on Solka-Floc® and concentrated under vacuum to
afford hydroxy ester 2 (20.36 g at 70.0 wt%, 14.25 g, 57% yield
overall). [a]D20 +8.8 (c 3.83, Et2O) {lit.9b [a]D20 +9.5 (c 5.3, Et2O)}.
IR (neat): n = 3462 (br), 3080, 2984, 1733, 1648, 1447, 1374, 1200,
1096 cm–1. 1H NMR (400 MHz, CDCl3): d = 4.88 (s, 1 H), 4.81 (s,
1 H), 4.31 (dd, J = 4.3, 8.2 Hz, 1 H), 4.24 (q, J = 7.1 Hz, 2 H), 2.57
Ethyl 4-fluoro-4-methyl-2-{[(trifluoromethyl)sulfonyl]oxy}pen-
tanoate (3b)
(R)-g-Fluoroleucic acid ethyl ester (3b, 11.44 g at 70.0 wt%, 8.01 g,
44.95 mmol) and 2,6-lutidine (10.46 mL, 89.90 mmol) were dis-
solved in heptane (80 mL) and cooled to 0–5 °C. Trifluoromethane-
sulfonic anhydride (11.34 mL, 67.43 mmol) was added dropwise
over 10 min. The solution was let stir at 0–5 °C for 1 h and then di-
luted with heptane (80 mL) and H2O (80 mL). The layers were sep-
arated and the organic layer was washed with 10% aq CuSO4
(2 × 80 mL), H2O (80 mL), brine (80 mL), dried with MgSO4 fil-
tered and concentrated at r.t. under vacuum to afford triflate 3b that
1
was directly used for the next step. H NMR (500 MHz, CDCl3):
d = 5.31 (dd, J = 3.9, 7.4 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 2.41–
Synlett 2006, No. 2, 291–295 © Thieme Stuttgart · New York

294
C. Nadeau et al.
LETTER
2.26 (m, 2 H), 1.47 (d, J = 21.3 Hz, 3 H), 1.46 (d, J = 21.2 Hz, 3 H),
1.33 (t, J = 7.1 Hz, 3 H). 19F NMR (375 MHz, CDCl3): d = –74.8,
–140.5. Conversion was determined by GC with a HP-1 column
(50 °C for 1 min, 20 °C/min to 90 °C, 3 °C/min to 105 °C, 30 °C/
min to 230 °C, injector 180 °C, detector 250 °C, split 5:1, 15.3 psi
helium); triflate 3b tR = 8.0 min.
cine ethyl ester 5 at 74.0 wt% (2.81 g, 95% yield) isolated as a pale
yellow oil. [a]D +15.3 (c 0.56, EtOH) {lit.7 [a]D +15.9 (c 0.54,
EtOH)}. IR (neat): n = 3388, 3360, 2984, 1733, 1467, 1374, 1282,
20
25
1
1185, 1031, 861 cm–1. H NMR (400 MHz, CDCl3): d = 4.15 (q,
J = 7.1 Hz, 2 H), 3.64 (dd, J = 5.0, 7.8 Hz, 1 H), 2.11 (ddd, J = 4.9,
14.6, 23.6 Hz, 1 H), 1.81 (ddd, J = 7.9, 14.6, 18.9 Hz, 1 H), 1.60 (br,
2 H), 1.41 (d, J = 21.5 Hz, 3 H), 1.39 (d, J = 21.5 Hz, 3 H), 1.25 (t,
J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 175.6, 95.1 (d,
J = 165.7 Hz), 61.0, 51.5 (d, J = 2.7 Hz), 45.5 (d, J = 21.5 Hz), 27.4
(d, J = 24.7 Hz), 26.8 (d, J = 24.8 Hz), 14.1. 19F NMR (375 MHz,
CDCl3): d = –137.7. HRMS (ES): m/z calcd for [C8H16FNO2 + Na]+:
200.1063; found: 200.1065. Enantiomeric excess was determined
by HPLC with a 4.6 mm × 15.0 cm Crownpack CR(+) column
(0.3% HClO4 in H2O pH = 1.5–1.6, hold 20 min, 1 mL/min, 205 nm,
25 °C); R enantiomer tR = 5.6 min; S enantiomer tR = 7.6 min; 95%
ee. Yield was determined by HPLC with a 3.0 mm × 15.0 cm Zor-
bax Extend-C18 column (14.4 mM NH4Cl, pH = 9.0–MeCN 90:10
to 10:90 over 25 min, 0.75 mL/min, 205 nm, 25 °C); g-fluoroleu-
cine ethyl ester 5 tR = 6.59 min.
Ethyl (2S)-2-(benzylamino)-4-fluoro-4-methylpentanoate (4)
Triflate 3b (44.95 mmol) was dissolved in MeCN (80 mL). Then,
K2CO3 (12.43 g, 89.90 mmol) was added and the slurry was cooled
to 0–5 °C. Benzylamine (5.89 mL, 53.94 mmol) was added over 10
min and the slurry was stirred at 0–5 °C for 1.5 h (GC analysis
showed complete conversion). The batch was diluted with MTBE
(160 mL) and H2O (80 mL). The layers were separated and the or-
ganic layer was washed with brine (80 mL). The organic layer was
washed with aq 1 N HCl (2 × 80 mL). MTBE (80 mL) was added to
the combined acidic aqueous layers which were neutralized with aq
2 M Na2CO3 (approximately 80 mL) until pH = 9. The layers were
separated and the aqueous layer was extracted with MTBE (80 mL).
The combined organic layers were washed with H2O (80 mL), fil-
tered on Solka-Floc®, concentrated under reduced pressure and
flushed with toluene (80 mL). HPLC analysis showed 12.71 g of N-
benzyl fluoroleucine ethyl ester 4 at 76.4 wt% (9.71 g, 81% yield)
isolated as a pale yellow oil. A portion of crude N-benzyl fluoroleu-
cine 4 (5.93 g at 76.4 wt%, 4.53 g, 16.96 mmol) was dissolved in
MTBE (45 mL), 10% aq CuSO4 (27 mL) was added and the bipha-
sic mixture was stirred vigorously for 1 h at r.t. The layers were sep-
arated and the organic layer was washed with H2O (2 × 27 mL),
filtered on Solka-Floc® and concentrated under reduced pressure.
HPLC analysis showed 5.80 g of N-benzyl fluoroleucine ethyl ester
4 at 76.7 wt% (4.45 g, 80% yield) isolated as a pale yellow oil.
[a]D20 –43.5 (c 1.24, EtOH). IR (neat): n = 3330, 3030, 2984, 1733,
1459, 1374, 1185, 1026 cm–1. 1H NMR (500 MHz, CDCl3):
d = 7.36–7.34 (m, 4 H), 7.30–7.26 (m, 1 H), 4.23 (q, J = 7.1 Hz, 2
H), 3.83 (d, J = 12.8 Hz, 1 H), 3.67 (d, J = 12.8 Hz, 1 H), 3.49 (app
t, J = 6.6 Hz, 1 H), 2.23 (br, 1 H), 2.10 (ddd, J = 6.4, 14.5, 17.9 Hz,
1 H), 1.95 (ddd, J = 6.8, 14.6, 23.0 Hz, 1 H), 1.44 (d, J = 21.5 Hz, 3
H), 1.40 (d, J = 21.6 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): d = 175.0, 139.4, 128.4, 127.2, 94.9 (d,
J = 165.6 Hz), 60.9, 57.5 (d, J = 3.7 Hz), 52.0, 44.5 (d, J = 22.4 Hz),
27.7 (d, J = 24.5 Hz), 26.5 (d, J = 24.7 Hz), 14.3. 19F NMR (375
MHz, CDCl3): d = –135.7. HRMS (ES): m/z calcd for [C15H22FNO2
+ H]+: 268.1713; found: 268.1711. Enantiomeric excess was deter-
mined by HPLC with a 4.6 mm × 25.0 cm Chiralcel OD column
[1:1 n-PrOH/MeOH–hexane (0.8:99.2), hold 8 min, to 4:96 over 2
min, 1 mL/min, 224 nm, 25 °C]; S enantiomer tR = 5.8 min; R enan-
tiomer tR = 6.3 min; >95% ee. Conversion was determined by GC
with a HP-1 column (50 °C for 1 min, 20 °C/min to 90 °C, 3 °C/min
to 120 °C, 20 °C/min to 250 °C, injector 180 °C, detector 250 °C,
split 5:1, 15.3 psi helium); N-benzyl fluoroleucine ethyl ester 4
tR = 17.8 min. Yield was determined by HPLC with a 4.6
mm × 25.0 cm Zorbax Rx-C8 column (0.1% H3PO4–MeCN 70:30
to 55:95 over 25 min, 2 mL/min, 220 nm, 35 °C); N-benzyl fluoro-
leucine ethyl ester 4 tR = 2.72 min.
Acknowledgment
We thank Dr. Thomas F. Hooker for chiral HPLC analysis of
fluoroleucine samples 5 and 6, Dr. Thomas J. Novak for HRMS data
and Dr. Gregory Hughes for helpful discussions.
References and Notes
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Yagupolskii, L. M. In Organofluorine Compounds in
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Eswarakrishan, S. In Fluorine in Bioorganic Chemistry;
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Chemistry; Filler, R.; Kobayashi, Y., Eds.; Elsevier
Biomedical Press: Amsterdam, 1982.
(2) (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004,
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2000, 17, 621.
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2005, 126, 557. (b) For a review on g-fluoro-a-amino acids
synthesis see: Haufe, G.; Kröger, S. Amino Acids 1996, 11,
409.
(4) (a) Kröger, S.; Haufe, G. Amino Acids 1997, 12, 363.
(b) Haufe, G.; Laue, K. W.; Triller, M. U. Tetrahedron 1998,
54, 5929.
(5) (a) Shendage, D. M.; Fröhlich, R.; Bergander, K.; Haufe, G.
Eur. J. Org. Chem. 2005, 719. (b) Laue, K. W.; Kröger, S.;
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Ethyl (2S)-2-amino-4-fluoro-4-methylpentanoate (5)
N-benzyl fluoroleucine ethyl ester 4 (5.80 g at 76.7 wt%, 4.45 g,
16.66 mmol) was dissolved in EtOH (42 mL) and Pd(OH)2/C (890
mg at 20 wt%, 178 mg, 4 wt%) was added. The pressure bottle was
filled, vented, and refilled 5 times with H2 (54 psi). The suspension
was then stirred at r.t. for 16 h under 54 psi of H2. The suspension
was then filtered on Solka-Floc® and the filtrate was concentrated
under reduced pressure. HPLC analysis showed 3.79 g of fluoroleu-
Synlett 2006, No. 2, 291–295 © Thieme Stuttgart · New York

LETTER
A Concise Synthesis of (S)-g-Fluoroleucine Ethyl Ester
295
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(12) Poly-4-vinylpyridinium poly(hydrogen fluoride) (PVPHF),
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(16) Spectral data for compound 6: [a]D20 +9.9 (c 0.52, EtOH)
{lit.7: [a]D25 +9.8 (c 0.52, EtOH)}; mp 104–105 °C. IR
(NaCl, thin film): n = 3419 (br), 2986, 2942, 1742, 1520,
1377, 1291, 1204, 1171, 1050 cm–1. 1H NMR (500 MHz,
DMSO-d6): d = 8.34 (br, 3 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.17
(app t, J = 6.7 Hz, 1 H), 2.21 (ddd, J = 6.6, 15.0, 22.9 Hz, 1
H), 2.09 (ddd, J = 6.6, 15.0, 20.8 Hz, 1 H), 1.41 (d, J = 21.6
Hz, 3 H), 1.41 (d, J = 21.6 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 170.0, 95.1 (d,
J = 165.5 Hz), 62.5, 49.5 (d, J = 1.1 Hz), 41.4 (d, J = 21.8
Hz), 26.9 (d, J = 23.6 Hz), 26.8 (d, J = 23.7 Hz), 14.3. 19
F
NMR (375 MHz, DMSO-d6): d = –138.3. HRMS (ES): m/z
calcd for [C8H16FNO2 + Na]+: 200.1063; found: 200.1067.
Enantiomeric excess was determined by HPLC with a 4.6
mm × 15.0 cm Crownpack CR(+) column (0.3% HClO4 in
H2O pH = 1.5–1.6, hold 20 min, 1 mL/min, 205 nm, 25 °C;
R enantiomer tR = 5.6 min; S enantiomer tR = 7.6 min; 96%
ee.
(k) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K.
Chem. Commun. 1997, 281.
(11) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.;
Kerekes, I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872.
Synlett 2006, No. 2, 291–295 © Thieme Stuttgart · New York