Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA

Article abstract of DOI:10.1016/S0957-4166(02)00321-X

Alkylation under phase transfer conditions of the chiral glycine synthon 2 (prepared from the commercially available Oppolzer chiral sultam) with fluorinated analogues of 3,4-dimethoxybenzyl chloride proceeded with high diastereoselectivity. Hydrolysis of

Full text of DOI:10.1016/S0957-4166(02)00321-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1135–1140
Convenient syntheses of 2-, 5- and 6-fluoro- and
2,6-difluoro- -DOPA
L
Wei-Ping Deng, Kelli A. Wong and Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD 20892, USA
Received 3 January 2002; accepted 3 June 2002
Abstract—Alkylation under phase transfer conditions of the chiral glycine synthon 2 (prepared from the commercially available
Oppolzer chiral sultam) with fluorinated analogues of 3,4-dimethoxybenzyl chloride proceeded with high diastereoselectivity.
Hydrolysis of the Schiff base, removal of the chiral auxiliary and HBr demethylation produced 2-, 5-, 6-fluoro- and 2,6-difluoro-L-
DOPA in e.e. of >99%. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The above considerations prompted us to undertake a
detailed examination of the effects of fluorine substitu-
tion on the enzymatic decarboxylation of -DOPA.
Parameters to be examined are the effects of fluorina-
tion on Km, Vmax, and the propensity to participate in a
competing Pictet–Spengler reaction. The kinetic analy-
ses and examination of any competing condensation
and decarboxylation reactions require working with the
[18F]-Radiolabeled 2-(2-Fluoro-4,5-dihydroxyphenyl)-
L
-
L
alanine (6-[18F]fluoro-
L
-DOPA), an in vivo precursor of
6-[18F]fluorodopamine, is used extensively as a PET-
scanning agent to quantify regional dopamine activity
in the central nervous system.1
Other ring-fluorinated analogues of DOPA have also
been investigated as potential PET-scanning agents, but
have not proven as useful because of problematic phar-
macodynamics.2 Although there is ample evidence for
pure L-isomers, since the unnatural D-enantiomers
could take part in the former but not the latter process.
As part of this effort, we describe in this paper the
stereoselective syntheses of 2-, 5-, 6-, and 2,6-difluoro-
the facile enzymatic conversion of 6-fluoro-
L
-DOPA to
L
-DOPA 1a–d using an efficient diastereoselective alkyl-
6-fluorodopamine,3 there appears to have been no
detailed comparative kinetic study of the isomeric
fluoro-DOPAs toward aromatic amino acid decarboxy-
lase (AADC).4 Furthermore, recent reports have pro-
vided details of possible alternative reaction paths
ation of a chiral glycine synthon.
As a reflection of the extensive biological applications
of fluoro-DOPAs, many syntheses of these compounds
have been reported. In 1957 Kaiser and Burger
available to
L
-DOPA that relate to the decarboxylase
-DOPA-induced
reported the synthesis of 2-fluoro-D,L-DOPA using an
acetamidomalonic ester synthesis.7 To study the behav-
ior of fluoro-DOPAs as substrates for catechol O-
methyl transferase, we synthesized 2-, 5-, and
mechanism or that may contribute to
L
side effects. These include a Pictet–Spengler reaction
with pyridoxal phosphate,5 the AADC cofactor, and
L-DOPA and D
-glucose.6
6-fluoro-
mal and radiofluorinated enantioselective syntheses of
D,L
-DOPA using a similar strategy.8 Both nor-
Maillard reaction between
Such reactions that involve alkylation of the electron-
rich aromatic ring could be influenced significantly by
the altered electronic properties caused by fluorine
substitution.
6-fluoro-L-DOPA, by side-chain elaboration of fluori-
nated precursors, have been reported.9 Several proce-
dures have been developed for direct electrophilic
fluorination of
L-DOPA and derivatives to prepare
[18F]fluoro-
L
-DOPAs.10 Radiofluorodestannylation has
also provided a regioselective route to 6-[18F]fluoro-
DOPA.11
L-
* Corresponding author. Fax: (301) 402-4182; e-mail: kennethk@
bdg8.niddk.nih.gov
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00321-X

1136
W.-P. Deng et al. / Tetrahedron: Asymmetry 13 (2002) 1135–1140
We report herein a new, convenient, and highly efficient
procedure for the preparative-scale syntheses of 2-, 5-
and 6-fluoro-L-DOPA, and 2,6-difluoro-L-DOPA
analogs 1a-d. We provide complete characterization of
these compounds, including, to our knowledge for the
first time, specific rotation values for these compounds.
A number of the starting fluorinated dimethoxyben-
zylchlorides have been prepared previously. 4-
(Chloromethyl)-5-fluoroveratrole 3c is readily obtained
by one-step chloromethylation of commercial 4-
fluoroveratrole,14 4-(chloromethyl)-3-fluoroveratrole 3a
is readily obtained by one-step chloromethylation of
3-fluoroveratrole, the methylation product of commer-
cial 2-fluoro-6-methoxyphenol,15 whereas 3b and 3d are
prepared from the corresponding benzaldehydes by
reduction to the alcohol and treatment with hydrochlo-
ric acid. The synthon 2 was synthesized according to
the literature.12
O
F
O
HO
HO
HO
HO
OH
OH
NH2
NH2
F
1a
1b
The preparation of 6-fluoro- -DOPA 1c illustrates the
L
O
F
O
procedure.
Using
solid–liquid
PTC
reaction
condition13d (3 eq. K2CO3, 0.1 eq. n-Bu4NBr and
CH3CN at 50°C), chiral amide 2 readily reacted with
4-(chloromethyl)-5-fluoroveratrole 3c14 to furnish alkyl-
HO
HO
HO
HO
OH
OH
NH2
NH2
F
F
1
ation product 4c in 92% yield. H NMR analysis indi-
1c
1d
cated 4c was formed with >97% diastereoisomeric
excess (d.e.). This was purified by one recrystalllization
(CH2Cl2/Hexane) to give 3c with d.e. ꢀ100%. The
absolute configuration of the newly formed carbon
center was assumed as S-configuration based on litera-
ture precedence. Compound 4c was hydrolyzed with 1
M HCl at room temperature to remove the benzophe-
none group to give an 86% yield of amine 5c. Removal
of the chiral auxiliary was readily accomplished by
treatment with 2.5 M LiOH/THF at 0°C to give amino
acid 6c (82%), isolated by precipitation from the neu-
tralized reaction mixture. Heating 6c (145°C) in 48%
HBr effected hydrolysis of the methyl ethers. After
evaporation of water and acid the residue was redis-
solved in water. Neutralization to pH 4–5 by NaHCO3
and cooling to 0°C caused precipitation of the free
amino acid. The suspension was filtered to give a 66%
2. Results and discussion
There are now many procedures available for the syn-
theses of enantiomers of a-amino acids, including both
enantioselective and diastereoselective strategies.12 We
chose a diastereoslective procedure based on the readily
available fluorinated benzyl chlorides 3a–d and the
convenience of preparation of chiral glycine synthon 2
(Scheme 1). This is prepared from the commercially
available Oppolzer chiral sultam. The ability of the
chiral amide 2, first reported by Chassaing’s group,13a
to direct highly diastereoselective alkylations has been
demonstrated in several studies.13
yield of 6-fluoro-
L
-DOPA 1c (overall yield: 43%).
O
N
R1
Ph
N
O
Ph
Ph
b)
MeO
N
Cl
R1
a)
N
SO2
Ph
+
R3
MeO
SO2
OMe
R2
R3
OMe
R2
3a, R1= F, R2= R3 = H
3b, R2 = F, R1= R3 =H
3c, R3 = F, R1 = R3= H
3d, R1 = R3 = F, R2= H
2
4a, 2-F (88%)
4b, 5-F (98%)
4c,6-F (92%)
4d, 2,6-diF (87%)
O
R1
O
R1
O
NH2
R1
N
c)
MeO
HO
d)
OH
OH
SO2
NH2
NH2
R3
MeO
R3
HO
OMe
OMe
R2
R3
R2
R2
1a, 2-F (70%)
1b, 5-F (99%)*
1c, 6-F (66%)
5a, 2-F (83%)
5b, 5-F (99%)*
5c, 6-F (86%)
6a, 2-F (80%)
6b, 5-F (77%)
6c, 6-F (82%)
1d, 2,6-diF (99%)*
5d, 2,6-diF (87%)
6d, 2,6-diF (74%)
Scheme 1. Reagents and conditions: (a) 3.0 eq. K2CO3, cat. Bu4NBr, CH3CN, 50°C; (b) 1 M HCl, CH2Cl2, rt; (c) 2.5 M LiOH,
H2O/THF, 0°C; (d) 48% HBr, 145°C, 1 h. *Yields without further purification.

W.-P. Deng et al. / Tetrahedron: Asymmetry 13 (2002) 1135–1140
1137
Although the literature gave no indication that racem-
ization occurs when this hydrolysis procedure is used,
we were concerned about the use of strong acid and
high temperature (145°C). Nonetheless, we determined
further purification, the alcohol was treated with con-
centrated HCl (11.8 mL) at 110°C for 30 min. After
standard extractive work-up, the residue was purified
with flash column chromatography (eluent: hex-
ane:ethyl acetate=6:1) to give compound 3c as a clear
by chiral HPLC that the e.e. value of 6-fluoro-
was >99% (see Section 4).
L-DOPA
1
oil (1.22 g, 78%, two steps). H NMR: 6.77 (1H, dd,
2.1, 10.8), 6.73 (1H, br. s), 4.51 (2H, s), 3.93 (3H, s),
3.90 (3H, s). HRMS calcd. For C9H10ClFO2: 204.0353.
Found: 204.0355.
Essentially the same results were obtained when the
sequence was initiated with 3a, 3b, and 3d. The corre-
sponding amino acids, 2-, 5-fluoro and 2,6-difluoro-L-
DOPA 1a, 1b, 1d, were obtained in similar overall yield
using the same sequence (Scheme 1). Following removal
of the chiral auxiliary of 5a, the free amino acid 6a was
not precipitated by simple neutralization, so an ion
exchange column was used (see Section 4).
4.1.2.
2-Chloromethyl-1,3-difluoro-4,5-dimethoxy-ben-
zene, 3d. Using the procedure described for the prepa-
ration of 3c, 2,6-difluoroveratraldehyde17 (800 mg, 3.97
mmol) gave 3d (617 mg, 70%). H NMR: 6.50 (1H, dd,
2.1, 11.1), 4.63 (1H, s), 3.89 (3H, s), 3.87 (3H, s).
HRMS calcd. For C9H9F2ClO2: 202.0259. Found:
202.0252.
1
3. Conclusion
4.1.3. (2R)-N-[(2S)-2-((Diphenylmethylidene)amino)-2-
(2%-fluoro-4%,5%-dimethoxybenzyl)-ethan-1-oyl]bornane-
10,2-sultam, 4c. To a stirred mixture of potassium
carbonate (1.65 g, 12.0 mmol) and tetra-
butylammonium bromide (132 mg, 0.4 mmol) in anhy-
drous acetonitrile (50 mL) was added synthon 2 (1.75 g,
4.0 mmol) and 4-(chloromethyl)-5-fluoroveratrole 3c
(1.64 g, 8.0 mmol). The resulting mixture was stirred
for 10 h at 50°C (TLC monitoring), then filtered, and
the filtrate evaporated under vacuum. The residue was
chromatographed on silica gel under pressure, eluting
with hexane:ethyl acetate mixtures of increasing polar-
ity, from 9:1 to 2:1. The product 4c was further purified
by recrystallization from dichloromethane and hexane
(2.22 g, 92%). Mp 196.5–198.5°C [h]2D0=−106.5 (c 0.68,
CHCl3). 1H NMR: 7.65 (2H, d, 7.2), 7.26–7.45 (6H, m),
6.94–6.96 (2H, m), 6.44–6.50 (2H, m), 5.08 (1H, t, 7.2),
3.90 (1H, dd, 4.8, 7.5), 3.78 (3H, s), 3.62 (3H, s), 3.34
(2H, s), 3.23 (1H, dd, 6.6, 12.9), 3.06 (1H, dd, 7.8, 12.9),
2.05 (1H, dd, 7.8, 13.2), 1.77–1.92 (4H, m), 1.29–1.41
(2H, m), 0.88 (3H, s), 0.78 (3H, s). 13C NMR: 171.9,
170.9, 155.4 (d, 240.6, C-F), 148.5 (d, 9.8), 144.9, 139.8,
135.8 (d, 13.6), 135.8, 130.4, 129.1, 128.6, 128.4, 128.2,
128.0, 114.1 (d, 9.6), 113.5 (d, 5.4), 99.7 (d, 28.1), 66.4,
65.2, 56.2, 56.0, 53.3, 48.5, 47.8, 44.7, 38.4, 33.9, 32.9,
26.6, 20.4, 20.0. 19F NMR: −48.81 (t, 11.0). HRMS
calcd. For C34H38FN2O5S: 605.2485 (M+1). Found:
605.2498.
In conclusion, the synthetic pathway described in this
paper is an excellent practical method for the synthesis
of the 2-, 5-, 6-fluoro- and 2,6-difluoro-L-DOPAs. The
amino acids are obtained in high overall yield (43% for
1c and similar yields for other three fluorinated 1a,b,d)
and with excellent enantiomeric purity (>99%). These
analogues are now being investigated as substrates for
aromatic amino acid decarboxylase.
4. Experimental section
4.1. General
1
Melting points are uncorrected. H, 13C and 19F NMR
spectra were recorded at 300.1, 75.5 and 282.2 MHz.
Chemical shifts (l) of protons and carbons are relative
to TMS (0 ppm), and the fluorine shifts are relative to
trifluoroacetic acid (0 ppm), all in ppm. Coupling con-
stants are presented in Hz. The solvent is CDCl3 unless
otherwise noted. Low resolution MS (LRMS) was per-
formed with chemical ionization under ammonia gas.
High resolution MS (HRMS) was done with FAB
ionization under xenon gas. Silica gel Merck 60 (0.040–
0.063 mm) was used for column chromatography, Uni-
plate™ GF (Analteck) was used for preparative TLC.
HPLC was performed on a chiral phase column
Crownpak® CR (Diacel Ltd., 250×4 mm, equipped with
a precolumn 80×4 mm, aq. HClO4 pH=1.6, flow rate
1.0 mL/min). All reagents and dry solvents were pur-
chased from Aldrich if not otherwise indicated and used
without further purification or drying.
4.1.4. (2R)-N-[(2S)-2-((Diphenylmethylidene)amino)-2-
(2%-fluoro-3%,4%-dimethoxybenzyl)-ethan-1-oyl]bornane-
10,2-sultam (4a). Prepared as for 4c, the product 4a was
obtained in 88% yield as a single diastereoisomer. Mp
185–187°C [h]2D0=−107.3 (c 0.24, CHCl3). 1H NMR:
7.65 (2H, d, 6.6), 7.26–7.50 (6H, m), 6.96–7.10 (2H, m),
6.70 (1H, t, 8.4), 6.49 (1H, d, 9.0), 5.06 (1H, t, 7.2),
3.89 (1H, dd, 4.5, 7.2), 3.78 (3H, s), 3.77 (3H, s), 3.31
(2H, s), 3.27 (1H, dd, 7.2, 13.2), 3.02 (1H, dd, 6.6,
13.2), 2.04 (1H, dd, 7.5, 13.5), 1.75–1.84 (4H, m),
1.26–1.39 (2H, m), 0.87 (3H, s), 0.72 (3H, s). 13C NMR:
171.9, 171.0, 155.1 (d, 248.1, C-F), 152.7 (d, 4.6),
139.8, 137.1 (d, 13.7), 135.8, 130.4, 129.1, 128.7, 128.3,
128.2, 128.0, 125.3 (d, 5.7), 117.4 (d, 15.1), 107.1 (d,
2.9), 66.0, 65.2, 61.5 (d, 4.0), 56.4, 53.2, 48.4, 47.7,
4.1.1.
1-Fluoro-2,3-dimethoxy-5-chloromethylbenzene,
3b. A solution of 5-fluoroveratraldehyde16 (1.64 g, 8.91
mmol) in THF (15 mL) was added dropwise to a
suspension of NaBH4 (0.674 g, 17.8 mmol) in THF (30
mL) and the mixture was stirred for 1 h at 40°C. Excess
NaBH4 was decomposed by the addition of water and a
few crystals of NaH2PO4. THF and water were
removed by rotary evaporation, and the residue was
extracted three times with ether. The ether layer was
dried over CaCl2 and evaporated yielding the crude
alcohol of sufficient purity for the next step. Without

1138
W.-P. Deng et al. / Tetrahedron: Asymmetry 13 (2002) 1135–1140
44.7, 38.4, 34.3, 33.0, 26.6, 20.6, 20.0. 19F NMR: −49.05
(t, 11.0). HRMS calcd. For C34H38FN2O5S: 605.2485
(M+1). Found: 605.2493.
47.8, 44.9, 38.3, 34.5, 33.0, 26.6, 20.5, 20.0. 19F NMR:
−48.93 (t, 11.0). HRMS calcd. For C21H30FN2O5S:
441.1859 (M+1). Found: 441.1847.
4.1.8. (2R)-N-[(2S)-2-Amino-2-(2%-fluoro-3%,4%-dimethoxy-
benzyl)-ethan-1-oyl]bornane-10,2-sultam, 5a. Prepared as
described for the preparation of 5c, the product 5a was
obtained in 83% yield as a colorless solid. Mp 152–
4.1.5. (2R)-N-[(2S)-2-((Diphenylmethylidene)amino)-2-
(5%-fluoro-3%,4%-dimethoxybenzyl)-ethan-1-oyl]bornane-
10,2-sultam (4b). Prepared as for 4c, the product 4b was
obtained in 98% yield as a single diastereoisomer. Mp
1
1
153°C [h]2D0=−10.6 (c 0.5, CHCl3). H NMR: 6.87 (1H,
217°C dec. [h]2D0=−121.5 (c 0.59, CHCl3). H NMR:
t, 9.1), 6.59 (1H, d, 9.4), 4.32 (1H, t, 7.2), 3.78–3.90
(7H, m,) 3.42 (2H, d, 3.9), 2.96 (2H, d, 6.0), 1.79–2.05
(5H, m), 1.29–1.42 (2H, m), 0.92 (3H, s), 0.81 (3H, s).
13C NMR: 175.7, 155.2 (d, 246.4, C-F), 152.8, 137.3 (d,
14.3), 124.9 (d, 5.7), 117.5 (d, 15.1), 107.3 (d, 3.4), 65.2,
61.7, 56.4, 55.1, 53.2, 48.7, 47.8, 44.9, 38.3, 34.8, 33.1,
26.6, 20.7, 20.0. 19F NMR: −57.85 (d, 5.4). HRMS
calcd. For C21H30FN2O5S: 441.1859 (M+1). Found:
441.1868.
7.64–7.68 (2H, m), 7.27–7.41 (6H, m), 6.85–6.88 (2H,
m), 6.43 (1H, dd, 2.1, 11.1), 6.30 (1H, t, 1.8), 4.99 (1H,
dd, 6.0, 7.8), 3.92 (1H, dd, 4.8, 7.8), 3.86 (3H, d, 1.2),
3.62 (3H, s), 3.36 (2H, s), 3.29 (1H, dd, 5.4, 12.6), 2.30
(1H, dd, 8.1, 12.6), 2.07 (1H, dd, 7.8, 14.1), 1.79–1.93
(4H, m), 1.31–1.43 (2H, m), 0.91 (3H, s), 0.87 (3H, s).
13C NMR: 171.3, 170.7, 155.2 (d, 241.6, C–F), 152.8 (d,
5.7), 139.1, 135.4, 132.3 (d, 9.1), 130.1, 128.6, 128.2,
127.8 (d, 5.7), 127.7, 110.0, 109.7, 108.9, 66.9, 64.9, 61.2
(d, 3.5), 55.6, 52.9, 48.1, 47.4, 44.3, 40.8, 38.0, 32.5,
26.1, 20.1, 19.5. 19F NMR: -56.07 (d, 10.7). HRMS
calcd. For C34H38FN2O5S: 605.2485 (M+1). Found:
605.2508.
4.1.9. (2R)-N-[(2S)-2-Amino-2-(5%-fluoro-3%,4%-dimethoxy-
benzyl)-ethan-1-oyl]bornane-10,2-sultam, 5b. Using the
same procedure described for 5b, the product 5c was
obtained in 99% yield as a colorless solid. Mp 138–
1
140°C [h]2D0=+4.9 (c 0.44, CHCl3). H NMR: 6.64 (1H,
4.1.6. (2R)-N-[(2S)-2-((Diphenylmethylidene)amino)-2-
(2%,6% - difluoro - 3%,4% - dimethoxybenzyl) - ethan - 1 - oyl]-
bornane-10,2-sultam (4d). Prepared as for 4a, the
product 4d was obtained in 87% yield as a single
diastereoisomer. Mp 187–189 °C [a]2D0=−90.6 (c 0.40,
t, 1.8), 6.59 (1H, dd, 1.5, 11.1), 4.31 (1H, t, 7.5),
3.83–3.89 (7H, m) 3.44 (2H, d, 4.2), 2.97 (1H, dd, 7.8,
13.2), 2.78 (1H, dd, 7.2, 13.2), 2.00 (1H, dd, 7.5, 13.2),
1.69–1.92 (4H, m), 1.28–1.42 (2H, m), 0.92 (3H, s), 0.83
(3H, s). 13C NMR: 175.2, 155.7 (d, 245.2, C-F), 153.5
(d, 5.7), 135.8 (d, 13.8), 132.7 (d, 8.6), 110.1 (d, 20.6),
109.0 (d, 2.3), 65.1, 61.5 (d, 3.4), 56.2, 56.0, 53.1, 48.6,
47.7, 44.7, 41.7, 38.2, 32.9, 26.5, 20.4, 19.8. 19F NMR:
-55.70 (d, 11.0). HRMS calcd. For C21H30FN2O5S:
441.1859 (M+1). Found: 441.1863.
1
CHCl3). H NMR: 7.61–7.66 (2H, m), 7.24–7.45 (6H,
m), 7.12–7.15 (2H, m), 6.33 (1H, dd, 1.8, 10.8), 5.12
(1H, t, 7.2), 3.90 (1H, dd, 4.8, 7.8), 3.78 (3H, s), 3.74
(3H, s), 3.32 (2H, s), 3.36 (1H, dd, 7.8, 13.2), 2.92 (1H,
dd, 6.6, 13.2), 2.06 (1H, dd, 7.8, 13.5), 1.76–1.94 (4H,
m), 1.28–1.40 (2H, m), 0.88 (3H, s), 0.78 (3H, s). 13C
NMR: 171.7, 171.0, 157.0 (d, 242.5, C-F), 155.2 (d,
245.9, C-F), 152.7 (dd, 6.8, 11.9), 139.7, 135.6, 134.0
(dd, 5.2, 14.3), 130.3, 129.0, 128.7, 128.3, 128.2,127.9,
105.0 (t, 19.9), 95.6 (d, 25.1), 65.3, 64.2, 61.6, 56.3, 53.2,
48.3, 47.7, 44.7, 38.2, 32.9, 28.0, 26.5, 20.4, 19.9. 19F
NMR: −41.65 (d, 12.4), –54.14. HRMS calcd. For
C34H37F2N2O5S: 623.2391(M+1). Found: 623.2405.
4.1.10.
(2R)-N-[(2S)-2-Amino-2-(2,6%-difluoro-3%,4%-
dimethoxybenzyl)-ethan-1-oyl]bornane-10,2-sultam, 5d.
Using the procedure describe for the preparation of 5c,
800 mg of alkylation product 4d gave 512 mg of 5d
(87%) as a colorless solid. Mp 114–115°C [h]2D0=−22.5
(c 0.25, CHCl3). 1H NMR: 6.43 (1H, dd, 2.1, 10.8), 4.35
(1H, t, 6.9), 3.78–3.90 (7H, m,) 3.43 (2H, d, 3.6), 3.10
(1H, dd, 7.8, 13.5), 2.90 (1H, dd, 6.6, 13.5), 2.05 (1H,
dd, 7.8, 13.8), 1.80–1.96 (4H, m), 1.26–1.42 (2H, m),
0.93 (3H, s), 0.89 (3H, s). 13C NMR: 175.6, 157.1 (d,
241.3, C-F), 155.3 (d, 244.7, C-F), 152.8 (dd, 6.8, 12.5),
133.9 (d, 14.8), 105.3 (t, 19.4), 95.9 (dd, 3.4, 28.4), 65.3,
61.8, 56.5, 54.1, 53.2, 48.7, 47.8, 44.9, 38.3, 33.1, 28.6,
26.6, 20.7, 20.1. 19F NMR: -42.74 (d, 9.0), −55.22.
HRMS calcd. For C21H29F2N2O5S: 459.1765 (M+1).
Found: 459.1776.
4.1.7. (2R)-N-[(2S)-2-Amino-2-(2%-fluoro-4%,5%-dimethoxy-
benzyl)-ethan-1-oyl]bornane-10,2-sultam, 5c. A vigor-
ously stirred mixture of 4c (604 mg, 1.0 mmol) in 10
mL of dichloromethane and 10 mL of 1 M hydrochlo-
ric acid was left at room temperature for 5 h (TLC
monitoring). After adding 50 mL of hexane, the two
phases were separated, the aqueous layer was washed
with 30 mL of diethyl ether, then was basified with
sodium bicarbonate and extracted with ethyl acetate.
The combined organic solvent was dried with magne-
sium sulfate and evaporated to dryness. After flash
column chromatography (eluent: hexane:ethyl acetate=
1:2), 509 mg of product 5c was obtained (86% of yield)
as a colorless solid. Mp 65–67°C [h]2D0=−15.3 (c 0.27,
4.1.11.
6-Fluoro-
L
-3,4-dimethoxyphenylalanine,
6c.
Aqueous lithium hydroxide solution (2.5 M, 0.6 mL,
1.5 mmol) was added at 0°C to a magnetically stirred
solution of 5c (220 mg, 0.5 mmol) in THF (1 mL). The
resulting mixture was stirred at this temperature for an
additional 1 h. THF was evaporated, the aqueous
solution was acidified with 1 M hydrochloric acid until
pH=2 and the mixture was extracted with ethyl acetate
(3×5 mL). The aqueous phase was neutralized with 1 M
sodium bicarbonate solution until pH=5–6. At this
point, precipitation of a colorless solid occurred. The
1
CHCl3). H NMR: 6.76 (1H, d, 7.2), 6.58 (1H, d, 10.8),
4.32 (1H, t, 7.2), 3.79–3.87 (7H, m), 3.43 (2H, d, 3.6),
2.95 (2H, d, 7.2), 1.79–2.03 (5H, m), 1.29–1.41 (2H, m),
0.92 (3H, s), 0.82 (3H, s). 13C NMR: 175.6, 155.5 (d,
239.5, C-F), 148.8 (d, 9.7), 145.2, 114.3 (d, 17.2), 113.5
(d, 5.7), 100.0 (d, 28.7), 65.2, 56.4, 56.2, 55.4, 53.2, 48.7,

W.-P. Deng et al. / Tetrahedron: Asymmetry 13 (2002) 1135–1140
1139
precipitate was filtered and dried under vacuum to
afford product 6c (100 mg, 82%). Mp 210–212°C dec.
ized with 1 M aqueous sodium bicarbonate solution
until pH=4–5. The neutralized solution was placed in a
refrigerator and the off-white solid that precipitated
was filtered and washed with cold water and acetone.
This solid was dried under vacuum to afford off-white
solid 1c (51 mg, 66%). Chiral HPLC analysis of this
sample showed that the product e.e. was >99.5%, reten-
tion times of racemate:8 7.02 min (S), 4.96 min (R). Mp
234–238°C dec. [h]2D0=−5.5 (c 0.50, 1 M HCl). 1H
NMR (CD3OD): 6.70 (1H, d, 7.5), 6.54 (1H, d, 10.8),
3.71 (1H, dd, 4.5, 9.0), 3.23 (1H, dd, 3.9, 14.7), 2.86
(1H, dd, 9.0, 14.7). 13C NMR (CD3OD): 173.8, 156.2
(d, 234.9, C-F), 147.1 (d, 11.5), 143.1, 118.1, 113.5 (d,
17.1), 104.2 (d, 27.0), 57.1, 31.3. 19F NMR (CD3OD):
−52.76 (t, 8.2). HRMS calcd. For C9H11FNO4:
216.0672 (M+1). Found: 216.0670.
1
[h]2D0=−15.6 (c 0.55, 1 M HCl) H NMR (D2O, DCl):
6.86 (1H, d, 3.0), 6.83 (1H, d, 7.5), 4.28 (1H, t, 6.3),
3.77 (3H, s), 3.76 (3H, s), 3.28 (1H, dd, 5.6, 14.7), 3.15
(1H, dd, 7.5, 14.7). 13C NMR (D2O, DCl): 173.8, 156.2
(d, 234.9, C-F), 147.1 (d, 11.5), 143.1, 118.1, 113.5 (d,
17.1), 104.2 (d, 27.0), 57.1, 56.1, 54.3, 31.3. 19F NMR
(D2O, DCl): −48.76 (d, 11.0). HRMS calcd. For
C11H15FNO4: 244.0985 (M+1). Found: 244.0986.
4.1.12.
2-Fluoro-
L
-3,4-dimethoxyphenylalanine,
6a.
Aqueous lithium hydroxide solution (2.5 M, 1.5 mL,
3.88 mmol) was added at 0°C to a stirred solution of 5a
(400 mg, 0.91 mmol) in THF (2 mL). The resulting
mixture was stirred at this temperature for an addi-
tional 2 h. The THF solvent was evaporated, and the
aqueous solution was acidified with 1 M hydrochloric
acid until pH=2. The solution was extracted with ethyl
acetate (3×5 mL). The aqueous phase was neutralized
with 1 M sodium bicarbonate solution until pH=5–6,
then evaporated to dryness. This residue was purified
using a Dowex (50w×8-200) ion-exchange resin column
to give 6a as a colorless solid (177 mg, 80%). Mp
170–172°C dec. [h]2D0=−16.3 (c 0.77 1 M HCl) 1H
NMR (D2O, DCl): 6.91 (1H, t, 8.4), 6.75 (1H, d, 8.7),
4.19 (t, 6.6), 3.73 (6H, s), 3.21 (1H, dd, 6.3, 15.0), 3.08
(1H, dd, 6.9, 15.0). 13C NMR (D2O, DCl): 171.3, 154.7
(d, 243.1, C-F), 153.3, 136.3 (d, 13.7), 126.3, 114.6 (d,
13.7), 108.9, 62.0, 56.5, 53.3, 29.4. 19F NMR (D2O,
DCl): -59.35 (d, 8.2). HRMS calcd. For C11H15FNO4:
244.0985 (M+1). Found: 244.0987.
4.1.16. 2-Fluoro-L-3,4-dihydroxyphenylalanine, 1a. Pre-
pared as for 1c, the product 1a was obtained in 70%
yield as an off-white solid. Chiral HPLC analysis of this
sample showed that the product e.e. was >99.5%, reten-
tion times of racemate:8 5.74 min (S), 4.20 min (R). Mp
259–262 °C dec. [h]2D0=−4.6 (c 0.48, 1 M HCl). 1H
NMR (D2O, DCl): 6.50–6.60 (2H, m), 4.14 (1H, t, 6.6),
3.16 (1H, dd, 6.0, 15.0), 3.00 (1H, dd, 7.5, 15.0). 13C
NMR (D2O, DCl): 171.4, 151.4 (d, 238.3, C-F), 146.2
(d, 4.8), 132.7 (d, 15.4), 121.8, 113.3 (d, 14.1), 112.0,
53.5, 29.4. 19F NMR (D2O, DCl): −63.89 (d, 5.6).
HRMS calcd. For C9H11FNO4: 216.0672 (M+1).
Found: 216.0678.
4.1.17. 5-Fluoro-L-3,4-dihydroxyphenylalanine·HBr, 1b.
Under nitrogen, compound 6b (115 mg, 0.47 mmol)
was suspended in 48% aqueous HBr (2 mL). This
reaction mixture was stirred for 1.5 h at 145°C, then
evaporated under vacuum to dryness. The resulting
residue 1c was obtained in >99% yield. (NMR indicated
>97% purity without further purification). [h]2D0=−5.4
(c 0.93, 1 M HCl). Chiral HPLC analysis of this sample
showed that the product e.e. was >99.4%, retention
times of racemate:8 8.68 min (S), 5.98 min (R). 1H
NMR (D2O, DCl): 6.83–6.87 (2H, m), 4.54 (1H, dd,
6.0,7.8), 3.39 (1H, dd, 6.0, 15.0), 3.26 (1H, dd, 7.8,
14.7). 13C NMR (D2O, DCl): 171.6, 152.6 (d, 238.4,
C-F), 146.6 (d, 5.6), 132.0 (d, 15.8), 126.1 (d, 8.8),
113.2, 109.4 (d, 19.5), 54.4, 32.2. 19F NMR (D2O, DCl):
-59.72 (d, 12.4). HRMS calcd. For C9H11FNO4:
216.0672 (M+1). Found: 216.0672.
4.1.13.
5-Fluoro-
L
-3,4-dimethoxyphenylalanine,
6b.
Treatment of compound 5b (433 mg) as for preparation
of 6c gave 6b as a colorless solid (177 mg, 74%). Mp
175°C dec. [h]2D0=+2.5 (c 0.32, 1 M HCl) 1H NMR
(D2O, DCl): 6.75–6.85 (2H, m) 4.00 (1H, dd, 5.7, 8.1),
3.92 (3H, s), 3.25 (1H, dd, 5.4, 14.7), 3.11 (1H, dd, 7.8,
14.7). 13C NMR (D2O, DCl): 174.9, 155.9 (d, 244.2,
C-F), 153.4 (d, 5.7), 135.5 (d, 13.4), 132.4 (d, 9.4), 110.3
(d, 20.1), 109.7 (d, 2.6), 62.0 (d, 3.4), 56.6, 56.3, 37.0.
19F NMR (D2O, DCl): −55.76 (d, 9.0). HRMS calcd.
For C11H15FNO4: 244.0985 (M+1). Found: 244.0978.
4.1.14. 2,6-Difluoro-L-3,4-dimethoxyphenylalanine, 6d.
Treatment of compound 5d (400 mg) as for preparation
of 6c, gave 6d as a colorless solid (168 mg, 74%). Mp
1
242–244°C [h]2D0=+16.9 (c 0.40, 1 M HCl) H NMR
(D2O, DCl): 6.75 (1H, dd, 2.4, 12.0), 4.23 (t, 6.9), 3.81
(3H, s), 3.79 (3H, s), 3.17–3.32 (2H, m). 13C NMR
(D2O, DCl): 171.3, 157.5 (dd, 10.6, 241.9, C–F), 154.8
(dd, 11.5, 244.5, C-F), 153.5 (dd, 7.2, 13.1), 133.1 (dd,
4.6, 14.6), 102.7 (dd, 19.2, 21.6), 97.0 (dd, 2.6, 28.1),
62.1 (d, 2.6), 56.7, 52.7, 23.4. 19F NMR (D2O, DCl):
−43.18 (d, 12.1), −57.42. HRMS calcd. For
C11H14F2NO4: 262.0891 (M+1). Found: 262.0898.
4.1.18. 2,6-Difluoro-L-3,4-dihydroxyphenylalanine·HBr,
1d. Using the same procedure, 6d (80 mg, 0.31 mmol)
gave 1d in >99% yield (>97% pure by NMR). Chiral
HPLC analysis of this sample on a CROWNPAK
CR-(+) column eluted with aqueous HClO4 (pH 1.6) at
a flow rate of 0.5 mL/min showed that it is >99.9% e.e.,
retention times of racemate:18 11.28 min (S), 8.44 min
1
(R). Mp 145–147°C H NMR (D2O, DCl): 6.52 (1H, d,
10.8), 4.23 (1H, t, 6.9), 3.26 (1H, dd, 6.0, 15.0), 3.16
(1H, dd, 7.5, 15.0). 13C NMR (D2O, DCl): 171.5, 154.6
(dd, 9.7, 235.7, C-F), 151.0 (dd, 11.4, 236.8), 146.5 (dd,
8.0, 14.3), 129.2 (d, 15.4), 101.5 (dd, 18.8, 21.7), 99.5 (d,
26.2), 53.0, 23.4. 19F NMR (D2O, DCl): −50.25 (t, 6.2),
−62.01. HRMS calcd. For C9H10F2NO4: 234.0578 (M+
4.1.15.
6-Fluoro-
L
-3,4-dihydroxyphenylalanine,
1c.
Under nitrogen, compound 6c (87 mg, 0.34 mmol) was
suspended in 48% aqueous HBr (2 mL). This reaction
mixture was stirred at 145°C for 1 h, then evaporated
under vacuum to dryness. The dry mixture was neutral-

1140
W.-P. Deng et al. / Tetrahedron: Asymmetry 13 (2002) 1135–1140
1). Found: 234.0579. HRMS calcd. for C9H11FNO4:
216.0672 (M+1). Found: 216.0672.
Aerts, J.; Luxen, A. J. Labelled Cpd. Radiopharm. 1998,
42. Suppl. 1, S113-S115.
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Chirakal, R.; Vasdev, N.; Schobilgen, G. J.; Nahmias, C.
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