Synthesis of 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine as potential in vivo precursors of fluorinated norepinephrines

Article abstract of DOI:10.1021/jo010327y

The title compounds were prepared by the aldol condensation of 3,4-dibenzyloxy-2-fluorobenzaldehyde and 4,5-dibenzyloxy-2-fluorobenzaldehyde with the oxazolidinone 2, a chiral glycine equivalent. Removal of the chiral auxiliary and blocking groups produced the target amino acids 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine (1b and 1c) in >98% ee.

Full text of DOI:10.1021/jo010327y

4892
J . Org. Chem. 2001, 66, 4892-4897
Syn th esis of 2-F lu or o- a n d
6-F lu or o-(2S,3R)-(3,4-d ih yd r oxyp h en yl)ser in e
a s P oten tia l in Vivo P r ecu r sor s of F lu or in a ted Nor ep in ep h r in es
Brian Herbert, In Ho Kim, and Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892
Kennethk@bdg8.niddk.nih.gov
Received March 27, 2001
The title compounds were prepared by the aldol condensation of 3,4-dibenzyloxy-2-fluorobenzal-
dehyde and 4,5-dibenzyloxy-2-fluorobenzaldehyde with the oxazolidinone 2, a chiral glycine
equivalent. Removal of the chiral auxiliary and blocking groups produced the target amino acids
2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine (1b and 1c) in >98% ee.
Sch em e 1
In tr od u ction
The final step in the biosynthesis of norepinephrine,
an important neurotransmitter of the sympathetic and
central nervous systems, is enzymatic side-chain hy-
droxylation of dopamine (Scheme 1). Recently, much
attention has focused on (2S,3R)-(3,4-dihydroxyphenyl)-
serine (L-threo-DOPS) (1a ) as a possible alternative
biological precursor of norepinephrine that would be
independent of dopamine biosynthesis, since enzymatic
decarboxylation would produce norepinephrine directly
(Scheme 1). In addition to potential activity in the
periphery,1 there is substantial evidence that adminis-
tered L-threo-DOPS crosses the blood-brain barrier and
is subsequently decarboxylated to produce norepineph-
rine in the central nervous system.1,2 In fact, several
clinical trials suggest that L-threo-DOPS may be benefi-
cial in treating disorders of both the central and sympa-
thetic nervous systems. For example, orthostatic hy-
potension, characterized by adrenergic deficiency, has
received particular attention,3 and certain symptoms of
Parkinson’s disease can be alleviated by treatment with
L-threo-DOPS.4
For several years, we have been investigating fluori-
nated analogues of biogenic amines, including norepi-
nephrine. In this research, we discovered that ring
fluorination affects the interaction of norepinephrine with
adrenergic receptors and that this effect depends on the
site of the fluorine substituent. Thus, fluorine in the
2-position renders the analogue selective for â-adrenergic
receptors, whereas fluorine in the 6-position produces an
analogue that is selective for R-adrenergic receptors.
These selectivities of fluorinated norepinephrine and
other adrenergic agonists have made such compounds
very useful pharmacological tools.5 It follows from the
biological interest and therapeutic potential of L-threo-
DOPS that ring-fluorinated analogues of this amino acid,
as precursors of the corresponding fluorinated norepi-
nephrines, could be useful tools to study mechanistic
aspects of the biological activities of L-threo-DOPS. In
particular, such studies could give evidence as to whether
R-adrenergic or â-adrenergic receptors are involved. It
is possible that more selective medicinal agents could also
result.
We have previously reported the synthesis of racemic
dihydroxyphenylserines fluorinated in the 2- or 6-posi-
tion.6 In this paper, we describe the stereoselective
synthesis of fluorinated analogues (1b,c) of L-threo-
DOPS.
Resu lts a n d Discu ssion
The key structural feature of L-threo-DOPS is the
S-configuration of the R-amino group and the R-config-
uration of the benzylic alcohol, corresponding to the
stereochemistry of the natural amino acid and the active
enantiomer of norepinephrine formed upon enzymatic
decarboxylation. There are a variety of synthetic methods
that have been used successfully to prepare such syn-
1,2-amino alcohol subunits. The application of several of
these methods to the synthesis of ring-fluorinated L-threo-
(1) Thomas, S. A.; Marck, B. T.; Palmiter, R. D.; Matsumoto, A. M.
J . Neurochem. 1998, 70, 2468-2476.
(2) Kikuchi, K.; Nashino, K.; Ohyu, H. Brain Res. 2000, 860, 130-
135.
(3) Freeman, R.; Landsberg, L.; Young, J . Neruology 1999, 53, 2151-
2157
(4) Tohgi, H.; Abe, T.; Takahashi, S. J . Neural. Trnasm. [P. D. Sect.]
1993, 5, 27-34.
(5) Lu, S.-f.; Herbert, B.; Haufe, G.; Laue, K. W.; Padgett, W. L.;
Oshunleti, O.; Daly, J . W.; Kirk, K. L. J . Med. Chem. 2000, 43, 1611-
1619 and references cited therein.
(6) Chen, B.-H.; Nie, J .-Y.; Singh, M.; Pike, V. W.; Kirk, K. L. J .
Fluorine Chem. 1995, 75, 93-101.
10.1021/jo010327y This article not subject to U.S. Copyright. Published 2001 by the American Chemical Society
Published on Web 06/14/2001

Synthesis of 2- and 6-Fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine
J . Org. Chem., Vol. 66, No. 14, 2001 4893
Ta ble 1. Ald ol Op tim iza tion
Lewis acid
1
dr
yield
of 4c (%)
base (equiv)
(equiv)
(equiv)
T (°C)
(4c/others)a
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
LHMDS (1.4)
LHMDS (1.0)
LHMDS (1.3)
1.3
1.2
1.4
1.0
1.3
2.0
Sn(OTf)2 (1.1)
Sn(OTf)2 (1.2)
-78
-78 to -50 to 0
-78
-78
-78
-78
4:1
52
34
50
81
Sn(OTf)2 (1.0)
Sn(OTf)2 (1.3)
Sn(OTf)2 (2.0)
10:1
LHMDS (2.0)
20:1b
a
b
Determined by 1H NMR analysis of crude reaction mixtures. Estimated ratio, no other isomers detected.
DOPS was unsuccessful but provided significant insight.7
For example, the addition of nucleophiles to aldehydes
3b and 3c8 was made difficult by low reactivity of the
carbonyl groups. The ready racemization of the benzylic
position of key intermediates under acidic conditions
ruled out approaches requiring strong acid, and unpro-
tected catechol rings are easily oxidized under basic
conditions. In part because of these problems, most of
our early approaches to the title compounds provided
intermediates exhibiting low diastereo- and enantiomeric
ratios. Clearly, we needed a method that would enable
us to overcome these difficulties.
Evans and co-workers have developed the isothiocy-
anate 2 as a chiral glycine equivalent and have used this
for the synthesis of â-hydroxy-R-amino acids.9 Outstand-
ing selectivities and yields have been documented using
this approach, and we anticipated achieving similar
results. Oxazolidinone 2 was expected to drive the
reaction to completion by providing an internal trap in
the isothiocyanate. Furthermore, the synthesis could be
adjusted to allow for protecting groups that could be
removed without affecting the catechol or the integrity
of the benzylic stereocenter.
We began our endeavor by studying the aldol conden-
sation between oxazolidinone 2 and aldehyde 3c. Genera-
tion of the tin enolate of oxazolidinone 2 in the presence
of tin(II) triflate with N-ethylpiperidine followed by the
addition of aldehyde 3c provided a trace amount of the
product carbamate 4c (Table 1). Adjustment of all
variables for this standard protocol failed to provide
meaningful quantities of the aldol product. The use of
1.4 equiv of a lithium enolate, generated with lithium
hexamethyldisilazane (LHMDS), resulted in the partial
consumption of the starting aldehyde. A separable pair
of diastereomeric thiocarbamates 4c were obtained in a
4:1 ratio (1H NMR), the major isomer being isolated in
52% yield. Deprotonation of the acyloxazolidinone 2 with
LHMDS (1.3 equiv) in the presence of Sn(OTf)2 (1.3 equiv)
followed by the addition of the aldehyde 3c provided a
10:1 ratio of diastereomers. The major diastereomer was
identical to the major diastereomer formed using the
lithium enolate and was isolated in 50% yield. The use
of stoichiometric quantities of substrate and enolate
resulted in diminished yield (34%). Our final optimization
entailed the use of 2 equiv of the tin/lithium enolate at
-78 °C for 1.5 h, a procedure that routinely provided a
20:1 ratio of diastereomeric thiocarbamates 4c. The
isomers were readily separable by chromatography, and
the major diastereomer was obtained in 81% yield. A
slight erosion of selectivity and yield (8.5:1 dr, 72% yield)
was observed for the 2-fluoro isomer 4b using the same
protocol (Scheme 2).
The use of the isothiocyanate derived oxazolidinone 2
enabled us to overcome the diminished reactivity of
aldehyde 3 and provided the aldol products in good yield.
The amino alcohols were obtained in their protected form,
as thiocarbamates. However, the extreme conditions
required to remove the thiocarbamate are incompatible
with our substrate. The Evans strategy circumvents this
difficulty by transforming the thiocarbamate to an oxo-
carbamate. To prepare for this transformation, the chiral
auxiliary was removed with methoxymagnesium bromide
to provide methyl esters 5b (88%) and 5c (93%). The
thiocarbamate nitrogen was protected as a tert-butyl
carbamate (6b,c) in good yield.
We began with the sulfur to oxygen protocol described9
for related systems. Thus, thiocarbamate 6c was allowed
to react with a mixture of formic acid and hydrogen
peroxide to provide cyclic carbamate 7c. The yield of the
reaction was highly variable, ranging between 10% and
63%, and the relative product distribution changed
frequently. 1H NMR studies revealed that neither hy-
drogen peroxide nor formic acid alone was the source of
difficulty. Substitution of trifluoroacetic acid or acetic acid
in the reaction met with limited success. Only a trace of
product was observed using m-CPBA10 to effect the
conversion.
We also examined a variety of exotic reagent combina-
tions in an effort to overcome the difficulties. The use of
yeast in a pH 7 buffer11 and the use of manganese oxide12
both failed to provide any conversion to the product.
Nitrosonium tetrafluoroborate13 and the combination of
iodine and potassium tert-butoxide14 resulted in the
destruction of the molecule. We were delighted to discover
that using merury(II) acetate15 in dichloromethane re-
sulted in the smooth conversion of thiocarbamate 6c to
the oxygen analogue 7c. The product was routinely
obtained in 85-90% yield, independent of the scale of
(7) For a review of the methods examined in the context of DOPS
and fluorinated norepinephrine analogues, see: Kirk, K. L.; Herbert,
B.; Lu, S.-F.; J ayachandran, Padgett, W. L.; Olufunke, O.; Daly, J . W.;
Haufe, G.; Laue, K. W. In Asymmetric Synthesis of Fluoro-Organic
Compounds; Ramachandran, P. V., Ed.; ACS Symposium Series 746;
American Chemical Society: Washington, DC, 2000; pp 194-209.
(8) Preparation of 2-fluoroveratraldehyde: Adejare, A.; Gusovsky,
F.; Padgett, W.; Creveling, C. R.; Daly, J . W.; Kirk, K. L. J . Med. Chem.
1988, 31, 1972-1977. Preparation of 6-fluoroveratraldehyde: Furlano,
D. C.; Kirk, K. L. J . Org. Chem. 1986, 51, 4073-4075. Conversion to
3b,c: Kirk, K. L.; Cantacuzene, D.; Collins, B.; Chen, G. T.; Nimit, Y.;
Creveling, C. R. J . Med. Chem. 1982, 25, 680-684.
(10) Kochhar, K. S.; Cottrell, D. A.; Pinnick, H. W. Tetrahedron Lett.
1983, 24, 1323-1326.
(11) Kamal, A.; Rao, M. V.; Rao, A. B. Chem. Lett. 1990, 655-656.
(12) Radha Rani, B.; Rahman, M. F.; Bhalerao, U. T. Tetrahedron
1992, 48, 1953-1958.
(13) Olah, G. A.; Arvanaghi, M.; Ohannesian, L.; Prakash, G. K. S.
Synthesis 1984, 785-786.
(14) Singh, H.; Singh, P.; Malhotra, N. J . Chem. Soc., Perkin Trans.
1 1981, 2647-2649.
(9) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6757-
6761.
(15) Davies, S. G.; Mortlock, A. A. Tetrahedron Lett. 1991, 32, 4791-
4794.

4894 J . Org. Chem., Vol. 66, No. 14, 2001
Herbert et al.
Sch em e 2
the reaction. The 2-fluoro analogue 6b was similarly
converted to the corresponding carbamate 7b in 96%
yield.
6FDOPS, 1c).17 Although 1c is only slightly soluble in
methanol and is insoluble in water, it readily dissolved
in 1 N HCl. However, 1H NMR analysis revealed that 1c
undergoes epimerization at the benzylic position under
these acidic conditions to give the erythro diastereomer
as a contaminant. For this reason, direct comparison of
the sign of the optical rotations of L-threo-DOPS (1a )18
and L-threo-6FDOPS (1c) in 1 N HCl could not be made.
In contrast to the above results, (2S,3R)-3-(3,4-dihy-
droxy-2-fluorophenyl)serine (L-threo-2FDOPS, 1b), pre-
pared from 10b under the conditions we used to prepare
pure 1c, consistently was contaminated with unknown
byproducts. Furthermore, repeated attempts to purify 1b
by recrystallization, using many solvent systems, met
with failure. Fortunately, we discovered that the use of
methanol and 3 N HCl (4/1) as hydrogenation solvent
suppressed the side reaction, and we obtained relatively
clean 1b. Unlike the behavior of 1c, there was no
The remaining tasks to complete the synthesis of the
fluorinated L-threo-DOPS entailed the removal of the
protecting groups. The cyclic carbamates 7b and 7c were
cleaved (Cs2CO3 in MeOH), and the Boc group was
cleaved with gaseous HCl in ethyl acetate16 to furnish
the amino acid methyl ester 9b,c in good yields. Chiral
HPLC analysis of amino alcohols 9b and 9c revealed that
each compound was essentially a single enantiomer
(g98% ee). The methyl esters were readily saponified to
provide (2S,3R)-3-(3,4-dibenzyloxy-2-fluorophenyl)serine
(10b ) and (2S,3R)-3-(4,5-dibenzyloxy-2-fluorophenyl)-
serine (10c).
The low solubility of the saponified zwitterionic amino
acids 10b,c presented difficulties in the final step. For
example, hydrogenolysis of 10c with 10% Pd-C was
performed using 60 mg of substrate partially dissolved
in 24 mL of methanol. This procedure cleanly produced
(2S,3R)-3-(4,5-dihydroxy-2-fluorophenyl)serine (L-threo-
(17) 1H NMR analysis showed no evidence of diastereomer formation
during the final manipulations, confirming that no loss of stereochem-
ical integrity had occurred.
(18) L-threo-DOPS: [R]20 ) -42.6 (c ) 1, 1 M HCl). Tanaka, C.;
D
(16) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J . Org. Chem.
1994, 39, 3216-3218.
Fujiwara, H.; Nakamura, M.; Ohmura, I. J . Pharm. Pharmacol. 1981,
33, 772-777.

Synthesis of 2- and 6-Fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine
J . Org. Chem., Vol. 66, No. 14, 2001 4895
(81%) of 4c: white solid; mp 92-93 °C (from EtOAc/hexanes);
1H NMR (CDCl3) δ 7.61 (br s, 1H), 7.47-7.29 (m, 13H), 7.18
(dd, J ) 6.6, 1.5 Hz, 2H), 6.98 (d, J ) 7.2 Hz, 1H), 6.68 (d, J
) 12.0 Hz, 1H), 6.60 (d, J ) 4.8 Hz, 1H), 5.14 (d, J ) 11.0 Hz,
2 H), 5.10 (d, J ) 11.0 Hz, 2H), 4.96 (dd, J ) 4.2, 1.2 Hz, 1H),
4.74 (ddd, J ) 12.0, 7.5, 3.6 Hz, 1H), 4.35 (dd, J ) 14.0, 9.3
Hz, 1H), 4.33 (dd, J ) 11.0, 1.5 Hz, 1H), 3.25 (dd, J ) 14.0,
3.3 Hz, 1H), 2.96 (dd, J ) 14.0, 8.7 Hz, 1H); 13C NMR (CDCl3)
δ 188.0, 165.4, 154.2 (d, J ) 241.3 Hz), 153.7, 150.9 (d, J )
10.2 Hz), 145.4 (d, J ) 2.9 Hz), 136.5, 136.0, 133.9, 129.4 (2C),
129.2 (2C), 128.6 (2C), 128.5 (2C), 128.12, 128.06, 127.8, 127.7
(2C), 127.2 (2C), 115.2 (d, J ) 14.3 Hz), 113.6 (d, J ) 4.6 Hz),
102.9 (d, J ) 25.6 Hz), 78.7 (d, J ) 2.3 Hz), 72.2, 71.2, 67.6,
64.2 (d, J ) 1.7 Hz), 55.1, 37.4; MS m/z (M+) calcd 612.1726,
epimerization of the benzylic position, as determined by
1H NMR. After removal of Pd-C (Celite filtration), the
product was further purified using a Dowex ion-exchange
column to give pure L-threo-2FDOPS (1b).
Con clu sion
We have developed routes to fluorinated analogues of
L-threo-DOPS. We expect these compounds to prove
useful for examination of the mechanisms of actions of
the parent compound. However, for this to be true, 1b,c
must (1) cross the blood-brain barrier and (2) be decar-
boxylated to give the corresponding fluorinated nor-
epinephrines. Accordingly, experiments are underway to
determine the efficiency of blood-brain barrier transport
as well as the behavior of 1b,c as substrates for aromatic
obsd 612.1730; [R]23 +148 (c 1.0, CHCl3). Anal. Calcd for
D
C
34H29FN2O6S: C, 66.65; H, 4.77; N, 4.57. Found: C, 66.44;
H, 4.77; N, 4.63.
(4S,5R)-5-[3,4-Bis(b en zyloxy)-2-flu or op h en yl]-2-t h i-
oxooxa zolid in e-4-ca r boxylic Acid Meth yl Ester (5b). To
a cooled (0 °C) solution of 3 M methylmagnesium bromide (0.68
mL, 2.04 mmol) in anhydrous THF (6.5 mL) was added
dropwise 13 mL of anhydrous MeOH, and the mixture was
stirred for 5 min. To this was added compound 4b (834 mg,
1.36 mmol) in anhydrous THF (6.5 mL). After the resulting
solution was stirred for 20 min at 0 °C, the reaction was
quenched with 1 M NaHSO4. The mixture was concentrated
under vacuum to remove methanol and THF, and the aqueous
solution was diluted with water and extracted three times with
CH2Cl2. The combined organic layer was dried with anhydrous
MgSO4, filtered, and concentrated. The residue was purified
by flash column chromatography (2:1 hexane/ethyl acetate) to
give 562 mg (88%) of compound 5b: colorless oil; 1H NMR
(CDCl3) δ 7.43-7.31 (m, 11H), 7.04 (t, J ) 8.4 Hz, 1H), 6.79
(dd, J ) 8.9, 1.8 Hz, 1H), 6.09 (d, J ) 6.0 Hz, 1H), 5.15 (s,
2H), 5.12 (s, 2H), 4.50 (d, J ) 5.7 Hz, 1 H), 3.86 (s, 3H); 13C
NMR (CDCl3) δ 188.5, 168.3, 154.3 (d, J ) 4.8 Hz), 154.1 (d, J
) 247.7 Hz), 136.6, 136.5 (d, J ) 12.8 Hz), 135.9, 128.5 (2C),
128.3 (2C), 128.2 (2C), 128.11, 128.07, 127.3 (2C), 121.9 (d, J
) 4.3 Hz), 117.0 (d, J ) 11.6 Hz), 109.3 (d, J ) 2.9 Hz), 80.9
(d, J ) 2.6 Hz), 75.6 (d, J ) 2.3 Hz), 71.0, 63.2, 53.3; MS (FAB+)
amino acid decarboxylase.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H and
13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively, with CDCl3, CD3OD, and DMSO-d6 as solvents. Ele-
mental analyses were performed at Atlantic Microlab, Inc.
HPLC was performed on a chiral-phase column Chiralpak AD
(Diacel Ltd., 250 × 4 mm, equipped with a precolumn 80 × 4
mm, n-hexane/EtOH ) 1:1 + 0.2% diethylamine, flow rate 1
mL/min). THF and ether were distilled from sodium benzophe-
none ketyl under nitrogen prior to use. Methylene chloride was
distilled from CaH2, and ethyl acetate was distilled from P2O5.
All reactions were performed under a dry N2 atmosphere.
Analytical TLC was performed on Kisegel 60 GF254 (Merck),
and flash column chromatography was performed with silica
gel 60 (230-400 mesh, Merck).
(4S)-4-Ben zyl-3-[(4S,5R)-1-[5-[3,4-bis(ben zyloxy)-2-flu o-
r oph en yl]-2-th ioxooxazolidin -4-yl]m eth an oyl]oxazolidin -
2-on e (4b). Freshly generated lithium hexamethyldisilazane
was prepared by addition of 1.0 mL of a 2.5 M (2.5 mmol)
solution of n-butyllithium to a cooled (0 °C) solution of
1,1,1,3,3,3-hexamethyldisilazane (0.54 mL, 2.56 mmol) in dry
THF (2 mL). After the mixture was stirred for 30 min at 0 °C,
the reagent was transferred to a cooled (-78 °C) solution of
oxazolidinone 2 (704 mg, 2.55 mmol) and stannous triflate
(1.06 g, 2.54 mmol) in dry THF (5.2 mL). After the mixture
was stirred for 30 min at -78 °C, the aldehyde 3b (434 mg,
1.29 mmol) was added in one portion. The reaction mixture
was stirred for 1.5 h at -78 °C and then was quenched with
10 mL of a 1:1 mixture of pH 7 phosphate buffer and saturated
aqueous NH4Cl. The mixture was poured into CH2Cl2, and the
organic layer was washed with 1 M NaHSO4 and brine. The
organic layer was dried with anhydrous Na2SO4, filtered, and
concentrated. The solid residue was purified by flash column
chromatography (2:1 hexane/ethyl acetate) to give 566 mg
(72%) of compound 4b: colorless solid; mp 89-90 °C (from
EtOAc/hexanes); 1H NMR (CDCl3) δ 7.56 (br s, 1H), 7.45-7.31
(m, 14H), 7.20 (d, J ) 6.9 Hz, 1H), 7.09 (t, J ) 8.4 Hz, 1H),
6.80 (dd, J ) 8.7, 1.8 Hz, 1H), 6.67 (d, J ) 4.5 Hz, 1H), 5.15
(s, 2H), 5.10 (s, 2H), 4.95 (d, J ) 4.5 Hz, 1H), 4.82-4.75 (m,
1H), 4.44-4.34 (m, 2H), 3.23 (dd, J ) 13.5, 3.3 Hz, 1H), 3.00
(dd, J ) 13.5, 8.7 Hz, 1H); 13C NMR (CDCl3) δ 188.0, 165.3,
154.1 (d, J ) 4.9 Hz), 153.65 (d, J ) 245.9 Hz), 153.6, 136.7,
136.44 (d, J ) 11.4 Hz), 136.0, 134.0, 129.3 (2C), 129.0 (2C),
128.5 (2C), 128.3 (2C), 128.2 (2C), 128.13, 128.12, 127.6, 127.3
(2C), 121.5 (d, J ) 4.6 Hz), 117.6 (d, J ) 11.9 Hz), 109.4 (d, J
) 2.9 Hz), 78.9 (d, J ) 2.9 Hz), 75.7 (d, J ) 2.3 Hz), 71.0, 67.5,
64.0, 55.1, 37.3; MS (FAB+) m/z (M + H+) calcd 613.1808, obsd
m/z (M + H+) calcd 468.1281, obsd 468.1281; [R]23 +42.6 (c
D
2.41, CHCl3). Anal. Calcd for C25H22FNO5S: C, 64.23; H, 4.74;
N, 3.00. Found: C, 64.25; H, 4.88; N, 2.99.
(4S,5R)-5-[4,5-Bis(b en zyloxy)-2-flu or op h en yl]-2-t h i-
oxooxa zolid in e-4-ca r boxylic Acid Meth yl Ester (5c). A
similar procedure was used as described for 5b. To a cooled (0
°C) solution of 1 M methylmagnesium bromide (2.7 mL, 2.7
mmol) in anhydrous THF (5 mL) was added anhydrous MeOH
(23 mL) dropwise. After 5 min, compound 4c (1.41 g, 2.3 mmol)
in anhydrous THF (6 mL) was added, and the solution was
stirred for 35 min at the same temperature. The reaction
mixture was quenched with pH 7 phosphate buffer (10 mL),
and CH2Cl2 was added. Isolation and purification as with 5b
gave 1.0 g (93%) of compound 5c: colorless oil; 1H NMR
(CDCl3) δ 7.45-7.33 (m, 11H), 6.92 (d, J ) 6.9 Hz, 1H), 6.71
(d, J ) 11.7 Hz, 1H), 6.05 (d, J ) 5.7 Hz, 1H), 5.15 (s, 2H),
5.14 (d, J ) 12.0 Hz, 1 H), 5.09 (d, J ) 12.0 Hz, 1H), 4.45 (d,
J ) 5.7 Hz, 1H), 3.83 (s, 3H); 13C NMR (CDCl3) δ 188.7, 168.3,
154.7 (d, J ) 242.5 Hz), 151.2 (d, J ) 9.7 Hz), 145.2 (d, J )
2.3 Hz), 136.5, 135.9, 128.6 (2C), 128.5 (2C), 128.1, 128.0, 127.7
(2C), 127.1 (2C), 114.5 (d, J ) 13.7 Hz), 113.9 (d, J ) 4.5 Hz),
102.9 (d, J ) 26.2 Hz), 80.7 (d, J ) 2.3 Hz), 72.2, 71.1, 63.4 (d,
J ) 1.1 Hz), 53.4; MS m/z (M+) calcd 467.1203, obsd 467.1215;
[R]23 +51.0 (c 1.1, CHCl3). Anal. Calcd for C25H22FNO5S: C,
D
64.23; H, 4.74; N, 3.00. Found: C, 64.47; H, 4.85; N, 2.95.
(4S,5R)-5-[3,4-Bis(b en zyloxy)-2-flu or op h en yl]-2-t h i-
oxooxa zolid in e-3,4-d ica r boxylic Acid 3-ter t-Bu tyl Ester
4-Meth yl Ester (6b). To a solution of compound 5b (271 mg,
0.58 mmol) in anhydrous CH2Cl2 (5 mL) were added di-tert-
butyl dicarbonate (253 mg, 1.16 mmol) and DMAP (7 mg, 0.06
mmol). The reaction mixture was stirred for 40 min at room
temperature, cooled to 0 °C, quenched with 1 M NaHSO4, and
extracted three times with CH2Cl2. The combined organic layer
was dried with anhydrous MgSO4, filtered, and concentrated.
The residue was purified by flash column chromatography (3:1
613.1818; [R]23D +121.7 (c 2.30, CHCl3). Anal. Calcd for C34H29
FN2O6S: C, 66.65; H, 4.77; N, 4.57. Found: C, 66.48; H, 4.77;
N, 4.56.
(4S)-4-Ben zyl-3-[(4S,5R)-1-[5-[4,5-bis(ben zyloxy)-2-flu o-
r oph en yl]-2-th ioxooxazolidin -4-yl]m eth an oyl]oxazolidin -
2-on e (4c). Using the same procedure, from 3.49 g (12.6 mmol)
of 2 and 2.12 g (6.3 mmol) of 3c there was obtained 3.12 g
-

4896 J . Org. Chem., Vol. 66, No. 14, 2001
Herbert et al.
hexane/ethyl acetate) to give 283 mg (86%) of compound 6b:
white solid; mp 107-108 °C; 1H NMR (CDCl3) δ 7.42-7.32 (m,
10H), 7.00 (t, J ) 8.4 Hz, 1H), 6.78 (dd, J ) 8.7, 1.2 Hz, 1H),
5.68 (d, J ) 4.8 Hz, 1H), 5.15 (s, 2H), 5.13 (s, 2H), 4.83 (d, J
) 4.8 Hz, 1 H), 3.87 (s, 3H), 1.53 (s, 9H); 13C NMR (CDCl3) δ
182.3, 168.2, 154.5 (d, J ) 4.6 Hz), 153.9 (d, J ) 246.4 Hz),
148.4, 136.6, 136.5 (d, J ) 12.5 Hz), 135.9, 128.5 (2C), 128.3
(2C), 128.2 (2C), 128.18, 128.15, 127.3 (2C), 121.4 (d, J ) 4.5
Hz), 116.7 (d, J ) 11.9 Hz), 109.3 (d, J ) 3.5 Hz), 85.6, 77.1,
75.6 (d, J ) 2.3 Hz), 71.0, 66.1 (d, J ) 1.1 Hz), 53.2, 27.7 (3C);
53.2, 27.8 (3C); MS m/z (M+) calcd 551.1955, obsd 551.1963;
[R]23 +69.3 (c 1.2, CHCl3). Anal. Calcd for C30H30FNO8: C,
D
65.33; H, 5.48; N, 2.54. Found: C, 65.52; H, 5.55; N, 2.53.
(2S,3R)-3-[3,4-b is(b en zyloxy)-2-flu or op h en yl]-2-ter t-
bu toxyca r bon yla m in o-3-h yd r oxyp r op ion ic Acid Meth yl
Ester (8b). Solid Cs2CO3 (25 mg, 0.08 mmol) was added to a
solution of compound 7b (208 mg, 0.38 mmol) in anhydrous
MeOH (9.5 mL), and the mixture was stirred for 3.5 h at room
temperature. The reaction mixture was then cooled to 0 °C,
quenched with 1 M HCl (2 mL), and concentrated in vacuo to
remove MeOH. The mixture was extracted three times with
CH2Cl2, dried with anhydrous MgSO4, filtered, and concen-
trated. The residue was purified by flash column chromatog-
raphy (2:1 hexane/ethyl acetate) to give 165 mg (83%) of
compound 8b: colorless oil; 1H NMR (CDCl3) δ 7.45-7.30 (m,
10H), 7.07 (t, J ) 8.1 Hz, 1H), 6.73 (dd, J ) 8.4 Hz, 1H), 5.44
(t, J ) 3.8 Hz), 5.25 (d, J ) 8.7 Hz, 1H), 5.10 (s, 2H), 5.09 (s,
2H), 4.58 (d, J ) 7.2 Hz, 1 H), 3.78 (s, 3H), 2.92 (brs, 1H), 1.33
(s, 9H); 13C NMR (CDCl3) δ 171.0, 155.7, 153.5 (d, J ) 244.1
Hz), 152.7 (d, J ) 4.6 Hz), 137.1, 136.5, 136.0 (d, J ) 13.1
Hz), 128.5 (2C), 128.4 (2C), 128.2 (2C), 128.03, 127.96, 127.3
(2C), 121.3 (d, J ) 5.2 Hz), 121.0 (d, J ) 11.9 Hz), 109.1 (d, J
) 2.9 Hz), 80.0, 75.7 (d, J ) 2.3 Hz), 71.1, 68.2, 58.2, 52.5,
28.1 (3C); MS (FAB+) m/z (M + H+) calcd 526.2241, obsd
MS (FAB+) m/z (M + H+) calcd 568.1805, obsd 568.1802; [R]23
D
+7.8 (c 1.88, CHCl3). Anal. Calcd for C30H30FNO7S: C, 63.48;
H, 5.33; N, 2.47. Found: C, 63.50; H, 5.34; N, 2.49.
(4S ,5R )-5-[4,5-b is(b e n zyloxy)-2-flu or op h e n yl]-2-t h i-
oxooxa zolid in e-3,4-d ica r boxylic Acid 3-ter t-Bu tyl Ester
4-Met h yl E st er (6c). A similar procedure as described for
6b was used. Compound 5c (3.12 g, 6.67 mmol) in anhydrous
CH2Cl2 (33 mL) was stirred with di-tert-butyl dicarbonate (1.7
mL, 7.4 mmol) and DMAP (10 mg, 0.08 mmol) for 1 h at room
temperature. The reaction mixture was poured onto water and
separated, and the CH2Cl2 solution was washed with saturated
brine. Isolation and purification as for 6b gave 3.61 g (95%) of
compound 6c: colorless oil; 1H NMR (CDCl3) δ 7.43-7.29 (m,
10H), 6.88 (d, J ) 7.2 Hz, 1H), 6.72 (d, J ) 11.0 Hz, 1H), 5.66
(d, J ) 5.1 Hz, 1H), 5.14 (s, 2H), 5.13 (d, J ) 12.0 Hz, 1 H),
5.08 (d, J ) 12.0 Hz, 1 H), 4.79 (d, J ) 5.1 Hz, 1H), 3.84 (s,
3H), 1.52 (s, 9H); 13C NMR (CDCl3) δ 182.3, 168.2, 154.5 (d, J
) 241.9 Hz), 151.2 (d, J ) 9.7 Hz), 148.4, 145.3 (d, J ) 2.9
Hz), 136.4, 135.9, 128.7 (2C), 128.5 (2C), 128.2, 128.1, 127.7
(2C), 127.1 (2C), 114.4 (d, J ) 13.7 Hz), 113.4 (d, J ) 4.5 Hz),
102.9 (d, J ) 25.6 Hz), 85.7, 76.7 (d, J ) 2.9 Hz), 72.2, 71.2,
66.3 (d, J ) 1.1 Hz), 53.3, 27.7 (3C); MS m/z (M+) calcd
526.2228; [R]23D -20.2 (c 1.52, CHCl3). Anal. Calcd for C29H32
-
FNO7: C, 66.27; H, 6.14; N, 2.67. Found: C, 66.30; H, 6.24;
N, 2.65.
(2S,3R)-3-[4,5-Bis(b en zyloxy)-2-flu or op h en yl]-2-ter t-
bu toxyca r bon yla m in o-3-h yd r oxyp r op ion ic Acid Meth yl
Ester (8c). Using a similar procedure (quenching with 1 M
NaHSO4), compound 7c (2.66 g, 4.82 mmol) in anhydrous
MeOH (60 mL) and Cs2CO3 (318 mg, 0.98 mmol) gave 1.92 g
567.1727, obsd 567.1719; [R]23 +23.6 (c 0.98, CHCl3). Anal.
D
1
(76%) of 8c: colorless oil; H NMR (CDCl3) δ 7.45-7.28 (m,
Calcd for C30H30FNO7S: C, 63.48; H, 5.33; N, 2.47. Found: C,
63.85; H, 5.42; N, 2.44.
10H), 7.08 (d, J ) 7.2 Hz, 1H), 6.66 (d, J ) 11.4 Hz, 1H), 5.43
(t, J ) 3.6 Hz, 1H), 5.30 (d, J ) 8.4 Hz, 1H), 5.12-5.04 (m,
4H), 4.57 (d, J ) 7.5 Hz, 1H), 3.75 (s, 3H), 2.86 (d, J ) 15.6
Hz, 1H), 1.34 (s, 9H); 13C NMR (CDCl3) δ 171.0, 155.7, 154.1
(d, J ) 245.9 Hz), 149.5 (d, J ) 10.3 Hz), 145.1, 137.1, 136.5,
128.55 (2C), 128.46 (2C), 128.0, 127.9, 127.5 (2C), 127.2 (2C),
118.6 (d, J ) 14.9 Hz), 114.2 (d, J ) 5.2 Hz), 102.6 (d, J )
26.8 Hz), 80.2, 72.3, 71.3, 68.1, 58.2, 52.6, 28.1 (3C); MS m/z
(M+) calcd 525.2163, obsd 525.2154; [R]23D -3.27 (c 1.0, CHCl3).
Anal. Calcd for C29H32FNO7: C, 66.27; H, 6.14; N, 2.67.
Found: C, 66.35; H, 6.20; N, 2.66.
(4S,5R)-5-[3,4-b is(b en zyloxy)-2-flu or op h en yl]-2-oxo-
oxa zolid in e-3,4-d ica r boxylic Acid 3-ter t-Bu tyl Ester 4-
Meth yl Ester (7b). Solid Hg(OAc)2 (302 mg, 0.95 mmol) was
added in one portion to a cooled (0 °C) solution of compound
6b (358 mg, 0.63 mmol) in CH2Cl2 (13 mL). The mixture was
stirred for 1 h at 0 °C, was allowed to come to room
temperature, and was stirred for an additional 2.5 h. The
resulting white suspension was recooled to 0 °C, quenched with
10 mL of 1 M K2CO3, and extracted three times with CH2Cl2.
The combined organic layer was washed with brine, dried with
anhydrous MgSO4, filtered, and concentrated. The residue was
purified by flash column chromatography (5:2 hexane/ethyl
acetate) to give 334 mg (96%) of compound 7b: colorless oil;
1H NMR (CDCl3) δ 7.41-7.31 (m, 10H), 7.00 (t, J ) 8.3 Hz,
1H), 6.78 (dd, J ) 8.9, 1.5 Hz, 1H), 5.46 (d, J ) 4.2 Hz, 1H),
5.14 (s, 2H), 5.12 (s, 2H), 4.61 (d, J ) 4.5 Hz, 1 H), 3.86 (s,
3H), 1.51 (s, 9H); 13C NMR (CDCl3) δ 168.8, 154.3 (d, J ) 4.9
Hz), 153.9 (d, J ) 246.8 Hz), 150.5, 148.3, 136.59, 136.57 (d, J
) 12.8 Hz), 135.9, 128.6 (2C), 128.3 (2C), 128.24 (2C), 128.19,
128.15, 127.3 (2C), 121.0 (d, J ) 4.5 Hz), 117.4 (d, J ) 11.6
Hz), 109.2 (d, J ) 2.9 Hz), 84.8, 75.7 (d, J ) 2.3 Hz), 71.9 (d,
J ) 3.2 Hz), 71.0, 62.7, 53.1, 27.7 (3C); MS (FAB+) m/z (M +
H+) calcd 551.2034, obsd 551.2040; [R]23D +54.4 (c 2.15, CHCl3).
Anal. Calcd for C30H30FNO8: C, 65.33; H, 5.48; N, 2.54.
Found: C, 65.44; H, 5.54; N, 2.59.
(4S,5R)-5-[4,5-Bis(b en zyloxy)-2-flu or op h en yl]-2-oxo-
oxa zolid in e-3,4-d ica r boxylic Acid 3-ter t-Bu tyl Ester 4-
Met h yl E st er (7c). Compound 6c (601 mg, 1.06 mmol) in
CH2Cl2 (10 mL) was treated as above with 405 mg (1.27 mmol)
of Hg(OAc)2 for 1 h, then at room temperature for 4 h. Isolation
and purification by column chromatography (5:2 hexane/ethyl
acetate) gave 509 mg (87%) of compound 7c: colorless oil; 1H
NMR (CDCl3) δ 7.43-7.30 (m, 10H), 6.90 (d, J ) 7.2 Hz, 1H),
6.73 (d, J ) 11.4 Hz, 1H), 5.45 (d, J ) 4.8 Hz, 1H), 5.14 (s,
2H), 5.10 (s, 2H), 4.58 (d, J ) 4.5 Hz, 1H), 3.84 (s, 3H), 1.51
(s, 9H); 13C NMR (CDCl3) δ 168.8, 154.5 (d, J ) 241.4 Hz),
151.1 (d, J ) 10.3 Hz), 150.6, 148.3, 145.3 (d, J ) 2.3 Hz),
136.5, 136.0, 128.7 (2C), 128.5 (2C), 128.2, 128.1, 127.6 (2C),
127.2 (2C), 115.0 (d, J ) 13.7 Hz), 113.2 (d, J ) 4.6 Hz), 103.0
(d, J ) 25.7 Hz), 84.9, 72.3, 71.5 (d, J ) 2.9 Hz), 71.2, 63.0,
(2S,3R)-2-Am in o-3-[3,4-bis(ben zyloxy)-2-flu or op h en yl]-
3-h yd r oxyp r op ion ic Acid Meth yl Ester (9b). To a solution
of compound 8b (200 mg, 0.38 mmol) in 8.0 mL of ethyl acetate
was added 4.0 mL of ethyl acetate that had been saturated
with HCl gas. The solution was stirred for 5 h at room
temperature. The resulting white heterogeneous reaction
mixture was then cooled to 0 °C, filtered, and washed with
hexane. The white solid was purified by recrystallization
from methanol, ethyl acetate, and ether to give 127 mg
(72%) of compound 9b: white solid; mp 152-153 °C; 1H NMR
(CD3OD) δ 7.48-7.24 (m, 11H), 7.00 (d, J ) 9.0 Hz, 1H), 5.38
(d, J ) 4.8 Hz, 1H), 5.18 (s, 2H), 5.08 (s, 2H), 4.16 (d, J ) 4.8
Hz, 1 H), 3.80 (s, 3H); 13C NMR (CD3OD) δ 169.0, 155.1 (d, J
) 243.0 Hz), 155.0 (d, J ) 4.6 Hz), 138.6, 137.5, 137.4 (d, J )
13.7 Hz), 129.74 (2C), 129.69 (2C), 129.45 (2C), 129.38, 129.32,
129.0 (2C), 123.2 (d, J ) 5.2 Hz), 121.1 (d, J ) 11.9 Hz), 111.0
(d, J ) 2.9 Hz), 76.9 (d, J ) 2.3 Hz), 72.3, 66.7 (d, J ) 2.3 Hz),
59.3, 53.9; MS (FAB+) m/z (M + H+) calcd 426.1717, obsd
426.1722; [R]23D +3.18 (c 1.56, MeOH). Anal. Calcd for C24H25
-
ClFNO5: C, 62.41; H, 5.46; N, 3.03. Found: C, 62.43; H, 5.55;
N, 3.03. HPLC: ee g99% (Chiralpak AD; 1:1 n-hexane/EtOH
+ 0.2% diethylamine; flow rate 1 mL/min; retention time
(2S,3R)-enantiomer ) 16.22 min, (2R,3S)-enantiomer ) 10.02
min).
(2S,3R)-2-Am in o-3-[4,5-bis(ben zyloxy)-2-flu or op h en yl]-
3-h yd r oxyp r op ion ic Acid Meth yl Ester (9c). In the same
manner, compound 8c (620 mg, 1.18 mmol) in 4.0 mL ethyl
acetate was treated with 2.0 mL of ethyl acetate saturated
with HCl gas. Workup as before and purification by recrys-
tallization from methanol, ethyl acetate, and ether gave 502

Synthesis of 2- and 6-Fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine
J . Org. Chem., Vol. 66, No. 14, 2001 4897
mg (92%) of 9c as a white solid: mp 147-148 °C; 1H NMR
(CD3OD) δ 7.47-7.44 (m, 4H), 7.38-7.30 (m, 6H), 7.28 (d, J
) 7.5 Hz, 1H), 6.91 (d, J ) 12.0 Hz, 1H), 5.39 (d, J ) 4.8 Hz,
1H), 5.15 (s, 2H), 5.12 (s, 2H), 4.15 (d, J ) 4.8 Hz, 1H), 3.78
(s, 3H); 13C NMR (CD3OD) δ 169.0, 155.7 (d, J ) 237.9 Hz),
151.8 (d, J ) 10.3 Hz), 147.0 (d, J ) 2.9 Hz), 138.7, 138.2,
129.7 (2C), 129.6 (2C), 129.3, 129.2, 129.0 (2C), 128.8 (2C),
118.9 (d, J ) 14.9 Hz), 115.6 (d, J ) 5.1 Hz), 104.0 (d, J )
27.3 Hz), 73.4, 72.4, 66.4, 59.4, 53.9; MS m/z (M+) calcd
J ) 10.2 Hz), 146.8 (d, J ) 2.9 Hz), 138.9, 138.4, 129.7 (2C),
129.6 (2C), 129.2, 129.1, 129.0 (2C), 128.8 (2C), 121.0 (d, J )
15.3 Hz), 115.8 (d, J ) 5.6 Hz), 104.2 (d, J ) 26.7 Hz), 73.4,
72.4, 66.7, 61.0; MS (FAB-) m/z (M+ - H) calcd 410.1404, obsd
410.1402; [R]23 -15.3 (c 0.15, MeOH).
D
(2S ,3R )-3-(3,4-D ih y d r o x y p h e n y l-2-flu o r o p h e n y l)-
ser in e (2-F -L-th r eo-DOP S) (1b). Compound 10b (50 mg, 0.12
mmol) was dissolved in a 4:1 mixture of MeOH and 3 N HCl
(20 mL), and 50 mg of 10% Pd/C was added. The heterogeneous
solution was put under hydrogen balloon and stirred for 2 h
at room temperature. The mixture was filtered through a pad
of Celite to remove catalyst and then concentrated in vacuo.
The residue was purified using a Dowex 50-8x column to give
425.1639, obsd 425.1641; [R]23 +0.62 (c 1.0, MeOH). Anal.
D
Calcd for C24H25ClFNO5: C, 62.41; H, 5.46; N, 3.03. Found:
C, 62.28; H, 5.46; N, 3.03. HPLC: ee g98% (Chiralpak AD;
1:1 n-hexane/EtOH + 0.2% diethylamine; flow rate 1 mL/min;
retention time (2S,3R)-enantiomer ) 14.68 min, (2R,3S)-
enantiomer ) 11.22 min).
1
30.5 mg (94%) of the desired 1b: gray solid, mp >250 °C; H
NMR (CD3OD) δ 6.90 (t, J ) 8.4 Hz, 1H), 6.67 (d, J ) 8.7 Hz,
1H), 5.46 (d, J ) 3.9 Hz, 1H), 4.09 (d, J ) 3.9 Hz, 1H); 13C
NMR (CD3OD) δ 169.9, 150.7 (d, J ) 236.8 Hz), 149.1 (d, J )
4.0 Hz), 134.8 (d, J ) 16.0 Hz), 119.2 (d, J ) 11.9 Hz), 117.9
(d, J ) 4.6 Hz), 112.1 (d, J ) 2.3 Hz), 66.8 (d, J ) 2.3 Hz),
59.3; MS (FAB+) m/z (M+ + H) calcd 232.0621, obsd 232.0620;
(2S,3R)-2-Am in o-3-[3,4-bis(ben zyloxy)-2-flu or op h en yl]-
3-h yd r oxyp r op ion ic Acid (10b). To a solution of compound
9b (40 mg, 0.87 mmol) in MeOH (2.5 mL) immersed in a room-
temperature water bath was added dropwise 2 N NaOH (2.5
mL). The heterogeneous milky reaction mixture was stirred
for 1 d at room temperature and then concentrated in vacuo
to remove MeOH. The aqueous solution was then cooled to 0
°C and neutralized to pH 6-7 by slow addition of concentrated
HCl followed by final adjustment with 1 N HCl. The resulting
white precipitate was filtered and washed with cold water and
ether to give 34.4 mg (96%) of compound 10b: white solid;
[R]23 -13.1 (c 1.0, 1 M HCl), -15.1 (c 0.65, MeOH).
D
(2S ,3R )-3-(4,5-D ih y d r o x y p h e n y l-2-flu o r o p h e n y l)-
ser in e (6-F -L-th r eo-DOP S) (1c). To a solution of compound
10c (60 mg, 0.146 mmol) in MeOH (24 mL) was added 120
mg of 10% Pd/C. The flask was connected to a hydrogen-filled
balloon and stirred for 2 h at room temperature. After removal
of catalyst by filtration and concentration, the resulting solid
was purified by recrystallization from MeOH and ether to give
27 mg (80%) of the desired 1c: dark brown solid; mp >250
1
mp 170-172 °C; H NMR (DMSO-d6) δ 7.48-7.32 (m, 10H),
7.17 (d, J ) 8.4 Hz, 1H), 6.98 (d, J ) 8.7 Hz, 1H), 5.28 (d,
J ) 3.3 Hz, 1H), 5.18 (d, J ) 12.6 Hz, 1H), 5.14 (d, J ) 12.6
Hz, 1H), 5.02 (s, 2H), 3.31 (d, J ) 3.6 Hz, 1 H); 13C NMR
(DMSO-d6) δ 167.9, 153.0 (d, J ) 242.5 Hz), 151.8 (d, J ) 4.6
Hz), 137.2, 136.8, 135.3 (d, J ) 13.7 Hz), 128.5 (2C), 128.2 (2C),
128.1 (2C), 128.04, 127.98, 127.7 (2C), 122.7 (d, J ) 12.5 Hz),
122.1, 109.1, 75.0, 70.3, 64.9, 58.3; MS (FAB-) m/z (M+-H) calcd
1
°C; H NMR (CD3OD) δ 7.00 (d, J ) 7.5 Hz, 1H), 6.54 (d, J )
11.4 Hz, 1H), 5.45 (d, J ) 3.3 Hz, 1H), 3.71 (d, J ) 3.6 Hz,
1H); 13C NMR (CD3OD) δ 172.3, 154.5 (d, J ) 234.5 Hz), 147.2
(d, J ) 11.4 Hz), 143.0 (d, J ) 2.3 Hz), 119.3 (d, J ) 14.8 Hz),
114.9 (d, J ) 5.1 Hz), 104.1 (d, J ) 26.2 Hz), 66.9, 61.1; MS
410.1404, obsd 410.1390; [R]23 -6.2 (c 0.52, DMSO).
(FAB+) m/z (M+ + H) calcd 232.0621, obsd 232.0618; [R]23
-22.6 (c 0.073, MeOH).
D
D
(2S,3R)-2-Am in o-3-[4,5-bis(ben zyloxy)-2-flu or op h en yl]-
3-h yd r oxyp r op ion ic Acid (10c). Saponification of 9c (40 mg,
0.87 mmol) in MeOH (2 mL) by the same procedure gave
34 mg (94%) of 10c: white solid; mp 147-148 °C; 1H NMR
(CD3OD) δ 7.47-7.30 (m, 11H), 6.88 (d, J ) 11.7 Hz, 1H), 5.51
(d, J ) 3.0 Hz, 1H), 5.13 (br s, 4H), 3.74 (d, J ) 3.6 Hz, 1H);
13C NMR (CD3OD) δ 172.0, 155.7 (d, J ) 237.9 Hz), 151.2 (d,
Su p p or tin g In for m a tion Ava ila ble: The IR spectra of
compounds 1b,c-10b,c are provided. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J O010327Y