Application of oxazolidinone α-fluoro amide chiral building blocks in the asymmetric synthesis of fluorinated carbohydrates: 2-Deoxy-2-fluoropentoses

Article abstract of DOI:10.1016/S0040-4020(00)00444-0

Deconjugative electrophilic fluorination of the lithium dienolate of Z-α,β-unsaturated imide (+)-9 with N-fluorobenzene-sulfonimide (NFSi) afforded the E-β,γ-unsaturated α-fluoro imide (+)-10 as a single diastereoisomer. Dihydroxylation resulted in the formation of 2-fluoro-2-deoxy-γ-xylonic and -lyxonic lactones, 12a and 12b, respectively. Reduction and deprotection of the lactones afforded 2-deoxy-2-fluoro-xylo-D-pyranose (15) and 2-deoxy-2-fluoro-lyxo-L-pyranose (17). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00444-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5303±5310
Application of Oxazolidinone a-Fluoro Amide Chiral Building
Blocks in the Asymmetric Synthesis of Fluorinated
Carbohydrates: 2-Deoxy-2-¯uoropentoses
*
Franklin A. Davis, Hongyan Qi and Gajendran Sundarababu
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA
Received 21 April 2000; revised 23 May 2000; accepted 24 May 2000
AbstractÐDeconjugative electrophilic ¯uorination of the lithium dienolate of Z-a,b-unsaturated imide (1)-9 with N-¯uorobenzene-
sulfonimide (NFSi) afforded the E-b,g-unsaturated a-¯uoro imide (1)-10 as a single diastereoisomer. Dihydroxylation resulted in the
formation of 2-¯uoro-2-deoxy-g-xylonic and -lyxonic lactones, 12a and 12b, respectively. Reduction and deprotection of the lactones
afforded 2-deoxy-2-¯uoro-xylo-d-pyranose (15) and 2-deoxy-2-¯uoro-lyxo-l-pyranose (17). q 2000 Elsevier Science Ltd. All rights
reserved.
The strategic placement of ¯uorine in bioactive molecules is
of considerable current interest because of the bene®cial
in¯uence this element often has on physical, chemical and
biological properties.1±3 This is particularly true of carbo-
hydrates where replacement of hydroxy by ¯uorine effects
the acidity, basicity and overall reactivity of neighboring
groups due to its extreme electronegativity. Since the van
means.13,14 A particularly attractive method is the use of
oxazolidone a-¯uoro amides ®rst introduced by us in
1992.15 These building blocks are prepared in a highly
stereode®ned manner because the commercially available
electrophilic ¯uorinating reagent, N-¯uorobenzenesulfoni-
mide (NFSi), approaches the N-aceyloxazolidinone enolate
from the least hindered direction.16,17 These building blocks
have been used in asymmetric syntheses of a-¯uoro alde-
hydes,18±20 a-¯uoro ketones,16 b-¯uoro hydrins,15 and a-
¯uoro esters.21 In this paper we report methodologies for
the stereoselective synthesis of ¯uorinated carbohydrates
from oxazolidone a-¯uoro amides and details of the asym-
metric synthesis of 2-deoxy-2-¯uorpentoses.22 This strategy
involves the use of an appropriately substituted enantiopure
b,g-unsaturated a-¯uoro carbonyl compound followed by
dihydroxylation and cyclization to the deoxy¯uorosugar.
Ê
der Waal's radius of ¯uorine (1.47 A) is not much different
Ê
than oxygen (1.57 A) only a minor steric perturbation on the
sugar's geometry is expected.4 However, replacement of
hydroxyl by ¯uorine removes a hydrogen bond donor site
while leaving intact a potential hydrogen bond acceptor
site.5,6 For these reasons ¯uorinated carbohydrates (deoxy-
¯uorosugars) have proven to be useful probes of biochem-
ical processes,7 as diagnostic agents8 and as potential
antiviral and antitumor drugs.7,9 Usually deoxy¯uorosugars
are prepared from carbohydrate substrates via multistep
procedures which require tedious protection/deprotection
chemistry as well as functionalization of the sugar prior to
¯uorination.10,11 Furthermore, controlling the stereochem-
istry at adjacent stereocenters is often problematic. In this
context the asymmetric synthesis of ¯uorinate carbo-
hydrates from non-carbohydrates precursors12 and, in par-
ticular, from a-¯uoro carbonyl compounds offers signi®cant
potential for avoiding the limitations associated with carbo-
hydrate precursors.
Nonracemic a-¯uoro carbonyl compounds are useful inter-
mediates for the asymmetric synthesis of ¯uoro organic
compounds and have been prepared by a variety of
Keywords: asymmetric synthesis; carbohydrates; ¯uorine compounds.
* Corresponding author. Tel.: 11-215-204-0477; fax: 11-215-204-0478;
e-mail: fdavis@astro.ocis.temple.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00444-0

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F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
Scheme 1.
Results and Discussion
reported that alkylations of Z-dienolate ions were highly
stereospeci®c, leading to E-3-alkenoate esters.
Our deoxy¯uorosugar synthesis begins with 3-benzyloxy-1-
propionaldehyde (2), prepared by Swern oxidation23 of
commercially available benzyloxy-1-propanol (1) in nearly
quantitative yield (Scheme 1). Treatment of 2 with the ylide
of triethyl phosphonoacetate in a Wadsworth±Horner±
Emmons reaction afforded the E-a,b-unsaturated ester 3
in 81% yield following chromatography. Hydrolysis of 3
with LiOH24 gave 4 (98% yield) which was converted to
the acid chloride and treated with the lithium salt of (4R,5S)-
(1)-4-methyl-5-phenyl-2-oxazolidinone. The E-a,b-conju-
gated chiral imide (1)-5 was obtained in 78% yield. Decon-
jugative electrophilic ¯uorination of the sodium dienolate
ion of (1)-5 with N-¯uorobenzenesulfonimide (NFOBS) at
2788C gave the a-¯uoro b,g-unsaturated amide 6 as an
inseparable 3:1 mixture of E/Z isomers in 78% yield.
Similar results were described by Kende and Toder for the
alkylation of E-dienolate ions.25 However these workers
The Z-a,b-conjugated imide (1)-9 was prepared as outlined
in Scheme 2 and makes use of the Still modi®cation of the
Wittig reaction.26 This procedure involves the reaction of
bis(2,2,2-tri¯uoroethyl)(methoxycarbonylmethyl)phospho-
nate with KHMDS/18-crown-6 to generate the ylide which
on treatment with aldehyde 1 gave Z-7 in 94% yield. A
small amount of the E-alkene (,5%) was removed in the
puri®cation step. Attempts to convert acid 8 into the corre-
sponding acid chloride with SOCl2 resulted in complex
mixtures and it was, therefore, converted into the pivaloyl
anhydride with pivaloyl chloride.11 The pivaloyl anhydride,
without isolation, was transformed into (1)-9 in 78% yield
as described above. Deprotonation of (1)-9 by NaHMDS
followed by ¯uorination of the resulting dienolate with
NFOBS afforded the E-a-¯uoro imide 10 as the only
product in 82% de and 78% yield. When LiHMDS was
Scheme 2.

F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
5305
Scheme 3.
used as the base the de improved to 88%. Signi®cantly,
¯uorination of the lithium enolate of (1)-9 with NFSi
gave (2R)-10 as a single diastereoisomer in 76% yield.
The improved diastereoselectivity of NSFi compared to
NFOBS is attributed to the greater steric bulk of the former
reagent.
philic reactions at acyclic double bond where Z-ole®ns
exhibit greater selectivity than E-ole®ns. According to the
analyses of Kishi30,31 and Vedejs32 conformer A, where F
adopts an `inside' position, is expected to be less favorable
than conformer B where A1,3 strain is presumable lower.
This is consistent with dihydroxylation of B taking place
from the least hindered bottom face, syn to the hydrogen,
resulting in 12b as the major product. Although this model
explains our results, electronic and secondary orbital effects
of F on the selectivity cannot be excluded.
Dihydroxylation of (1)-10 using a catalytic amount of
osmium tetroxide with triethyl amine N-oxide (TMNO)27
directly furnished diastereomeric g-lactones 12a and 12b
in a 1:2.3 ratio in 96% yield (Scheme 3). The intermediate
b,g-dihydroxy a-¯uoro amides were not detected as they
underwent rapid cyclization to the corresponding lactones
12 with recovery of the Evan's auxiliary in .90% yield
(Scheme 3). The two lactones were readily separated by
¯ash chromatography affording 12a as a glassy oil and
12b as a white solid in 86 and 94% yield, respectively,
based on the theoretical yield. Structures were assigned
from their NMR spectra as follows. Since the dihedral
angle between H(3) and F(2) and H(3) and H(2) in lyxo-
g-lactone28,29 approaches 908, isomer 12b with the smaller
coupling constants, JH(2)±H(3)ˆ4.4 Hz and (JH(3)±F(2)ˆ0), was
assigned the lyxo geometry where F(2) and H(3) are syn to
each other. Conversely, the other isomer 12a, with larger
coupling constants (JH(3)±H(2)ˆ7.7 Hz and JH(3)±Fˆ22.0 Hz),
was assigned the xylo geometry where F(2) and H(3) are
anti to each other. These assignments were later con®rmed
by their transformation into the corresponding known
2-¯uoropentoses 15 and 17 (see below).
We next attempted to improve the diastereoselectivity of the
dihydroxylation by treatment of (R)-10 with Sharpless AD-
mix-b. Unfortunately this led to recovery in .80% of the
chiral auxiliary in the organic phase, and lactones 12 were
not detected. This apparently resulted from faster saponi®-
cation of the amide bond in 10, as a consequence of the
electron withdrawing a-¯uoro group, under the basic AD-
mix conditions.
Fluoro lactone 12a was converted into 2-deoxy-2-¯uoro-
xylo-d-pyranose (15) by reduction with DIBAL in CH2Cl2
at 2788C to give lactal 14 in 68% yield (Scheme 5). Reduc-
tive removal of the benzyl group (H2/Pd) afforded 15 in
85%.7b,11h,29 The same reduction/deprotection sequence
afforded 2-deoxy-2-¯uoro-lyxo-l-pyranose (17)11b,g in
80%. The overall yields of 15 and 17 from 1 were 29 and
27%, respectively. Although the 2-¯uorolyxose 17 is a
known compound, reliable spectral data was lacking for
comparison, and it was further transformed to 1,3,4-tri-O-
acetyl-2-deoxy-2-¯uoro-l-lyxo-pyranose (18a and 18b) by
acetylation with acetic anhydride in 95% yield to give a 2.5/
1 mixture of anomers. The reported 1H NMR and 13C NMR
spectra of the b-d isomer of 18 matches that of the minor
product 18b which is the enantiomer of the b-d isomer.11g
Consequently, the major product of 18a is assigned as the
a-l anomer.
The modest de observed for the dihydroxylation of (1)-10
suggests that ¯uorine has little if any in¯uence on the
diastereoselectivity. Similar results were observed for
`HCN' addition to a-¯uoro N-sul®nyl imines in the sul®ni-
mine mediated asymmetric Strecker synthesis of b-¯uoro
a-amino acids.19 The chiral auxiliary is also expected not to
effect the diastereoselectivity because of its distance from
the reactive site. Indeed dihydroxylation of racemic ester
13, under similar conditions, afforded a 1:2 ratio of racemic
lactones 12a and 12b (Scheme 4). These modest de's are in
line with studies on the stereochemical outcome of electro-
In summary, the asymmetric synthesis of 2-deoxy-2-¯uoro-
xylo-d-pyranose (15) and 2-deoxy-2-¯uoro-lyxo-l-pyranose
(18) was accomplished in 27±29% overall yields from a
Scheme 4.

5306
F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
Scheme 5.
noncarbohydrate precursor. The key step in this synthesis is
the highly diastereoselective ¯uorination of a chiral enolate
using the electrophilic ¯uorinating reagent N-¯uoroben-
zenesulfonimide (NFSi).
dropwise in CH2Cl2 (5 mL). After 15 min, triethylamine
(7.0 mL, 50 mmol) was added, the solution was stirred for
5 min at which time the reaction mixture was warmed to
room temperature. After stirring for 30 min the reaction was
quenched with saturated NH4Cl (10 mL), and the aqueous
phase was washed with CH2Cl2 (2£20 mL). The combined
organic phase was washed with saturated NaHCO3
(2£10 mL), brine (10 mL), dried (Na2SO4) and concen-
trated. Puri®cation by ¯ash chromatography (EtOAc/hexane
1:4) gave aldehyde 3 as a clear oil (1.63 g, 99%); 1H NMR
(CDCl3) d 7.2±7.4 (m, 5H), 4.5 (s, 2H), 3.8±3.9 (t, 2H,
Jˆ6.1 Hz), 2.6±2.7 (m, 2H); 13C NMR (CDCl3) d 201.2,
134.4, 129.7, 128.9, 128.4, 127.7, 127.6, 73.2, 63.2, 43.8; IR
(neat) 1724 (CvO) cm21; Anal. calcd for C10H12O2: C,
73.17; H, 7.32. Found: C, 72.77; H, 7.25.
Experimental
General procedure
Infrared spectra were recorded on a Mattson 4020 FTIR
spectrometer using sodium chloride plates for liquids and
potassium bromide disks for solids. 1H and 13C NMR
spectra were referenced to CDCl3 (7.26 and 77.0 ppm)
using GE 300 and QE 500 MHz NMR spectrometers. 19F
NMR spectra were referenced to CFCl3 (0.00) using QE
500 MHz NMR spectrometer. High resolution mass spectra
were obtained on a Fissions ZAB HF double-focusing mass
spectrometer. Column chromatography was performed on
silica gel, Merck grade 60 (230±400 mesh) purchased from
Aldrich Chemical Co. Analytical and preparative thin layer
chromatography were performed on pre-coated silica gel
plates (250 and 1000 mm) purchased from Analtech Inc.
TLC plates were visualized with UV light, KMnO4 solution
or an iodine chamber. Melting points were recorded on Mel-
Temp apparatus and are uncorrected. Optical rotations were
measured on a Perkin±Elmer 341 polarimeter. THF was
freshly distilled under nitrogen from sodium and benzo-
phenone and CH2Cl2 from CaH2. Elemental analyses were
performed by the Department of Chemistry, University of
Pennsylvania. N-Fluorobenzenesulfonimide (NFOBS)17
was prepared as previously described and N-¯uorobenzene-
sulfonimide (NFSi) was provided by AlliedSignal Inc. and
is commercially available from Aldrich.
Ethyl 5-benzyloxy-2-(E)-pentenoate (3). Triethyl phospho-
noacetate (9.81 mL, 49.5 mmol) was added to a suspension
of NaH (60%, 2.28 g, 57 mmol) in benzene at 08C. The
mixture was stirred at room temperature for 1 h, cooled to
08C and 3 (5.41 g, 33 mmol) was added. The reaction
mixture was stirred at 08C for 1 h, quenched with saturated
NH4Cl (20 mL), and the aqueous phase was washed with
Et2O (2£30 mL). The combined organic phases were
washed with satd. NaHCO3 (20 mL), brine (20 mL), dried
(MgSO4) and concentrated. Puri®cation by ¯ash chroma-
tography (EtOAc/hexane 1:9) gave 4.37 g (81%) of 3 as a
clear oil: IR (neat) 1656 cm21; 1H NMR (CDCl3) d 7.4±7.2
(m, 5H), 6.98 (dt, 1H, Jˆ15.7, 6.9 Hz), 5.89 (dt, 1H, Jˆ
15.7, 1.5 Hz), 4.52 (s, 2H), 4.19 (q, 2H, Jˆ7.1 Hz), 3.58 (t,
2H, Jˆ6.5 Hz), 2.51 (dq, 2H, Jˆ13.2, 6.6, 1.4 Hz), 1.29 (t,
3H, Jˆ7.1 Hz); 13C NMR (CDCl3) d 166.3, 145.5, 138.0,
128.3, 128.1, 127.8, 127.6, 122.8, 72.9, 68.2, 60.1, 32.5,
14.2; Anal. Calcd for C14H18O2: C, 71.79; H, 7.69. Found:
C, 71.08; H, 7.74.
3-Benzyloxy-1-propionaldehyde (2). DMSO (1.6 mL,
22 mmol) was added to a solution of (COCl)2 (1.0 mL,
11 mmol) in CH2Cl2 (100 mL) at 2788C. The reaction
mixture was stirred for 10 min at which time 3-benzyl-1-
propyl alcohol (1, Aldrich, 1.66 g, 10.0 mmol) was added
5-Benzyloxy-2-(E)-pentenecarboxylic acid (4). Ester 3
(3.70 g, 17.0 mmol) was dissolved in acetone (85 mL) and
LiOH (1 M in H2O, 85 mL) was added. After warming to
room temperature and stirring for 1 h, the reaction mixture

F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
5307
was diluted with H2O (85 mL), concentrated and washed
with Et2O (50 mL). The aqueous phase was acidi®ed to
pH 1 by addition of concentrated HCl and washed with
Et2O (3£50 mL). The combined organic phases were
washed with brine (50 mL), dried (MgSO4), concentrated
and placed under high vacuum for 8 h to give 3.40 g
(97%) of acid 4 as a clear oil; IR (neat) 1654 (CvC),
2 mmol) in THF (20 mL) was cooled to 2788C and
KHMDS (0.5 M in toluene, 2 mL, 1 mmol) was added.
After 5 min, aldehyde 2 (0.164 g, 1 mmol) in THF (3 mL)
was added and the solution was stirred for 30 min. At this
time the reaction mixture was quenched at 2788C by addi-
tion of satd. NH4Cl (5 mL) and washed with Et2O
(3£30 mL). The combined organic phases were washed
with satd. NaHCO3 (10 mL), brine (10 mL), dried
(MgSO4) and concentrated. Puri®cation by ¯ash chroma-
tography (EtOAc/hexane 1:9) gave 0.276 g (96%) of 7 as
1
1696 (CvO); H NMR (CDCl3) d 7.47±7.30 (m, 5H),
7.11 (dt, 1H, Jˆ16.6, 7.7 Hz), 6.91 (d, 1H, Jˆ16.7 Hz),
4.53 (s, 2H), 3.61 (t, 2H, Jˆ7.5 Hz), 2.56 (q, 2H, Jˆ
7.7 Hz); 13C NMR (CDCl3) d 171.6, 148.6, 138.0, 128.4,
127.9, 127.78, 127.7, 122.2, 73.1, 68.0, 32.7; Anal. Calcd
for C12H14O3 C, 69.90; H, 6.80. Found: C, 69.72; H, 6.72.
1
a yellow oil: IR (neat) 1727 cm21; H NMR (CDCl3) d
7.40±7.27, (m, 5H), 6.36 (dt, 1H, Jˆ11.5, 7.1 Hz), 5.86
(dt, 1H, Jˆ11.5, 1.6 Hz), 4.53 (s, 2H), 3.71 (s, 3H), 3.59
(t, 2H, Jˆ6.3 Hz), 3.00 (dq, 2H, Jˆ6.6, 1.6 Hz); 13C NMR
(CDCl3) d 166.6, 147.1, 138.2, 128.2 (2 C), 127.5 (2 C),
127.4, 120.5, 72.7, 68.9, 50.9, 28.4.
(4R,5S)-(1)-(5-Benzyloxy-2-(E)-pentenoyl)-4-methyl-5-
phenyl-2-oxazolidinone (5). Acid 4 (2.67 g, 13 mmol) was
dissolved in SOCl2 (5 mL) at 08C, stirred for 1 h and
concentrated. The residue was dissolved in benzene
(10 mL), concentrated and repeated to remove all traces of
SOCl2. The residue was placed under high vacuum for 1 h
and the crude acid chloride (2.80 g) was used without
additional puri®cation. In a separate ¯ask, n-BuLi (2.5 M
in hexane, 5.72 mL, 14.3 mmol) was added to a solution of
(4R,5S)-(1)-4-methyl-5-phenyl-2-oxazolidinone (2.30 g,
13 mmol) in THF (60 mL) at 2788C. After 45 min, the
resulting red solution was cannulated to a solution of the
acid chloride in THF (10 mL) at 2788C. The reaction
mixture was stirred for 2 h, quenched with satd. NH4Cl
solution (10 mL), warmed to rt and washed with Et2O
(3£30 mL). The combined organic phases were washed
with satd. NaHCO3 (30 mL), brine (30 mL), dried
(MgSO4) and concentrated. Puri®cation by ¯ash chroma-
tography (EtOAc/hexane 1:4) gave 3.72 g (78%) of (1)-5
5-Benzyloxy 2-(Z)-pentenoic acid (8). Ester 7 (3.09 g,
15 mmol) was hydrolyzed as described above affording
2.79 g (99%) of 8 as an oil: IR (neat) 1697, 1640 cm21
;
1H NMR (CDCl3) d 7.36±7.27 (m, 5H), 6.44 (dt, 1H,
Jˆ11.6, 7.2 Hz), 5.86 (dt, 1H, Jˆ11.6, 1.7 Hz), 4.52 (s,
2H), 3.58 (t, 2H, Jˆ6.3 Hz), 2.97 (dq, 2H, Jˆ6.4, 1.7 Hz),
2.15 (s, 2H); 13C NMR (CDCl3) d 170.9, 148.9, 137.9, 130.5
(2C), 127.5 (3C), 120.5, 72.6, 68.6, 53.6; HRMS calcd for
C12H15O3 (M1H) 207.1021, found 207.1022.
(4R,5S)-(1)-(5-Benzyloxy-2-(Z)-pentenoyl)-4-methyl-5-
phenyl-2-oxazolidinone (9). To a solution of acid 8
(0.194 g, 1.0 mmol) in THF (5 mL) at 2788C was added
triethylamine (0.18 mL, 1.3 mmol) and pivaloyl chloride
(0.13 mL, 1.1 mmol). The reaction mixture was stirred at
2788C for 1 h and the resulting pivaloyl anhydride was used
without puri®cation. In a separate ¯ask, n-BuLi (2.5 M in
hexane, 0.4 mL, 1.3 mmol) was added to a solution of
(4R,5S)-(1)-4-methyl-5-phenyl-2-oxazolidinone (0.212 g,
1.2 mmol) in THF (5 mL) at 2788C. After 30 min, the
resulting red solution was cannulated to a solution of the
pivaloyl chloride at 2788C. The reaction mixture was
stirred at this temperatue for 1 h, quenched with satd.
NH4Cl (2 mL), and washed with Et2O (2£10 mL). The
combined organic phases were washed with satd. NaHCO3
(5 mL), brine (5 mL), dried (MgSO4) and concentrated.
Puri®cation by ¯ash chromatography (EtOAc/hexane 1:4)
gave 0.276 g (78%) of 9 as a yellow oil; [a]2D0ˆ6.1 (c 0.01,
1
as a clear oil; IR (neat) 1780, 1684, 1637 cm21; H NMR
(CDCl3) d 7.5±7.2 (m, 10H), 7.2±7.0 (m, 2H), 5.68 (d, 1H,
Jˆ7.2 Hz), 4.9±4.7 (m, 1H), 4.55 (s, 2H), 3.64 (t, 2H,
Jˆ6.5 Hz), 2.62 (q, 2H, Jˆ7.5 Hz), 0.93 (d, 3H, Jˆ
7.5 Hz); 13C NMR (CDCl3) d 164.1, 152.7, 148.0, 133.9,
128.7, 128.4, 127.7, 127.6, 125.6, 121.9, 79.0, 73.1, 68.3,
54.9, 33.1, 14.6; Anal. Calcd for C22H23NO4 C, 72.32; H,
6.30. Found: C, 71.93; 6.24.
Attempted preparation of (4R,5S)-(1)-(5-benzyloxy-2-
¯uoro-3-(E)-pentenoyl)-4-methyl-5-phenyl-2-oxazolidi-
none (6). LiHMDS (1 M in hexane, 3.1 mL, 3.1 mmol) was
added to a solution of (1)-5 (0.92 g, 2.6 mmol) in THF
(15 mL) at 2788C. After 1 h, NFOBS (1.23 g, 5.2 mmol)
in THF (5 mL) was added dropwise, the solution was stirred
for 2 h at 2788C and the reaction mixture was quenched
with satd. NH4Cl (10 mL). The solution was washed with
Et2O (2£30 mL) and the combined organic phases were
washed with satd. KI (10 mL), Na2S2O3 (10 mL) [to remove
excess NFOBS], brine (10 mL), dried (MgSO4) and concen-
trated. Puri®cation by ¯ash chromatography (EtOAc/hexane
1:9) gave 0.732 g (76%) of a 3:1 mixture of 6E and 6Z as a
yellow oil; 19F NMR (CDCl3) d 2185.7 (d, Jˆ48.8 Hz) and
2187.0 Jˆ47.0 Hz). HRMS calcd for C22H23FNO4 (M1H),
384.1603 found 384.1611. Attempts to separate the E,Z-6
isomers were unsuccessful.
1
CHCl3); IR (neat) 1782, 1684 cm21; H NMR (CDCl3) d
7.45±7.27 (m, 10H), 7.13 (br d, 1H, Jˆ11.6 Hz), 6.50 (dt,
1H, Jˆ11.7, 7.1 Hz), 5.64 (d, 1H, Jˆ7.3 Hz), 4.85±4.64 (m,
1H), 4.54 (s, 2H), 3.62 (t, 2H, Jˆ6.3 Hz), 3.01±2.94 (m,
2H), 0.92 (d, 3H, Jˆ6.6 Hz); 13C NMR (CDCl3) d 164.3,
152.7, 148.1, 138.2, 133.0, 128.5, 128.2, 127.5, 127.4, 125.5
(10 C, 128.5±125.5), 120.3, 78.7, 72.7, 68.8, 54.5, 30.3,
14.4; HRMS calcd for C22H24NO4 (M1H), 366.1707,
found 366.1705.
(4R,5S)-(1)-(5-Benzyloxy-(2R)-¯uoro-3-(E)-pentenoyl)-
4-methyl-5-phenyl-2-oxazolidinone
(10).
LiHMDS
(3.1 mL, 3.1 mmol, 1 M in hexane) was added to a solution
of the imide (1)-9 (0.92 g, 2.6 mmol) in THF (15 mL) at
2788C. After 1 h, NFSi (1.99 g, 5.2 mmol) in THF (5 mL)
was added, the reaction mixture was stirred for 2 h and
quenched at 2788C with satd. NH4Cl (2 mL). The solution
was washed with Et2O (2£20 mL) and the combined
Methyl 5-benzyloxy-2-(Z)-pentenoate (7). A solution of
bis(2,2,2-tri¯uoroethyl)(methoxy)carbonylmethylphospho-
nate (0.318 g, 1 mmol, Aldrich) and 18-crown-6 (0.528 g,

5308
F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
organic phases were washed with satd. KI (10 mL), Na2S2O3
(10 mL) [to remove excess NFSi], brine (10 mL), dried
(MgSO4) and concentrated. Puri®cation by ¯ash chroma-
tography (EtOAc/hexane 1:9) gave 0.732 g (76%) of 10 as
was quenched with a few drops of H2O, diluted with ether
(20 mL) and stirred for 1 h at room temperature. The
mixture was dried (MgSO4), and concentrated to give
0.034 g (68%) of 14 as a colorless glassy oil as a 5:1 mixture
of anomers by 19F NMR; 19F NMR (CDCl3) d 2206.9 (d,
Jˆ61.0 Hz, major), 2193.9 (d, Jˆ48.8 Hz, minor); 1H
NMR (500 MHz, CDCl3) major anomer: d 7.45±7.27 (m,
5H), 5.36 (d, H1, Jˆ12.1 Hz), 4.85 (dd, H2, Jˆ49.7, 1.2 Hz),
4.65±4.55 (m, 2H); minor anomer: 5.56 (dd, H1, Jˆ10.3,
3.3 Hz), 4.78 (dt, H2, Jˆ51.7, 3.1 Hz); 13C NMR (CDCl3)
major anomer: d 136.8, 127.9 (2C), 128.2, 128.6 (2C), 100.4
(d, C1, Jˆ31 5 Hz), 98.0 (d, C2, Jˆ183.7 Hz), 80.22, 74.5
(d, C3, Jˆ26.4 Hz), 74.0, 68.8.
a yellow oil; [a]2D0ˆ4.3 (cˆ0.01, CHCl3); IR (neat) 1781,
1
1721 cm21
;
19F NMR (CDCl3) d 2185.7 (d, Jˆ48.8); H
NMR (CDCl3) d 7.45±7.27 (m, 10H), 6.46 (ddd, 1H,
Jˆ48.4, 6.4, 0.9 Hz), 6.31±6.21 (m, 1H), 6.08±5.96 (m, 1H),
5.72 (d, 1H, Jˆ7.2 Hz), 4.73 (m, 1H), 4.55 (s, 2H), 4.12±4.09
(m, 2H), 0.97 (d, 3H, Jˆ6.61 Hz); 13C NMR (CDCl3) d 167.9,
167.6, 152.3, 137.8, 134.6, 134.5, 132.5, 128.9, 128.7,
128.4, 127.7 (6 C, 128.9±127.7), 125.6, 123.1, 122.8, 87.5
(d, Jˆ296.2 Hz), 79.9, 72.6, 69.1, 55.2, 14.3; HRMS calcd
for C22H23FNO4 (M1H), 384.1603 found 384.1611.
5-O-Benzyl-2-deoxy-2-¯uoro-l-lyxofuranose (16). Accor-
ding to the procedure for the preparation of 14, g-lyxonic
lactone 12b (0.024 mg, 0.1 mmol) was reduced by DIBAL
(0.3 mL, 0.3 mmol) to give 0.018 g (75%) of 16 as a color-
5-O-Benzyl-2-deoxy-2-¯uoro-d-g-xylonic lactone (12a)
and 5-O-benzyl-2-deoxy-2-¯uoro-l-g-lyxonic lactone
(12b). To a solution of (1)-10 (0.957 g, 2.5 mmol) in
acetone and H2O (20/1, 12.5 mL), were added trimethyla-
mine N-oxide dihydrate (0.659 g, 6.25 mmol) and OsO4
(2.5 mL of 2.5% w/w in t-BuOH). After 2 h at room
temperature, solid NaHSO3 (excess) was added, the solution
was stirred for 10 min, diluted with EtOAc (20 mL), dried
(MgSO4) and concentrated. Puri®cation by ¯ash chroma-
tography (EtOAc/hexane 1:1) afforded 12a (0.115 g), 12b
(0.322 g) and a mixture of 12a and 12b (0.137 g) which was
further puri®ed. The total yield of 12a (86%) and 12b (94%)
was 96%. Eluting after 12a±b was (4R,5S)-(1)-4-methyl-5-
phenyl-2-oxazolidinone, 0.40 g (90%). Both lactones were
initially obtained as slightly glassy yellow solids, but on
standing 12b solidi®ed.
1
less glassy oil that was a 2.7:1 mixture of anomers (by H
NMR) which equilibrated to a 1:1 mixture of anomers (by
19F NMR and 13C NMR); 19F NMR (CDCl3) d 2215.3 (d,
1
Jˆ48.8 Hz,), 2209.2 (d, Jˆ48.8 Hz); H NMR (500 MHz,
CDCl3) major anomer: d 5.55 (d, H1, Jˆ9.9 Hz), 4.77 (dd,
H2, Jˆ53.0, 4.6 Hz), 4.64±4.53 (m, 3H), 4.35±4.32 (m,
1H), 4.02 (bs, OH), 3.81±3.68 (m, 2H), 3.11 (br d, OH,
Jˆ7.5 Hz); minor, 5.21 (dd, H1, Jˆ13.6, 4.4 Hz); 13C
NMR (CDCl3) two anomers d 137.4 and 137.1, 128.5 and
128.4, 128.0, 127.8 and 127.7, 98.6 (d, C2, Jˆ184.0 Hz) and
88.6 (d, C2, Jˆ199.9 Hz), 77.8, 73.8, 71.4 (d, C3,
Jˆ16.0 Hz) and 70.2 (d, C3, Jˆ16.0 Hz), 68.9.
2-Deoxy-2-¯uoro-d-xylopyranose (15). Pd/C (0.028 g,
10%) was added to a solution of the 14 (0.028 g,
0.1 mmol) in MeOH (10 mL) and was subjected to H2 at
1 atm provided by a balloon. After 2 h, the reaction mixture
was ®ltered through ®lter paper and washed with MeOH and
H2O. The ®ltrate was concentrated to give 0.015 g (85%)
of 15 as a colorless glassy oil with an anomeric ratio of
b/aˆ1.3:1 (by 19F NMR); minor: 19F NMR (CDCl3) d
Properties of 12a: [a]D20ˆ37.4 (cˆ0.01, CHCl3); IR (neat)
1793, 1732 cm21
;
19F NMR (CDCl3) d 2198.7 (dd, Jˆ61.1,
1
24.4 Hz); H NMR (500 MHz, CDCl3) d 7.40±7.25 (m,
5H), 5.32 (dd, H2, JH2±Fˆ52.8 Hz, JH2±H3ˆ7.4 Hz), 4.73
(dt, H3, JH3±Fˆ22.0 Hz, JH3±H2ˆ7.7 Hz), 4.64 (dt, H4,
0
JH4±H3ˆ8.1 Hz, JH4±H5,H5 ˆ1.8 Hz), 4.57 (AB, 2H
0
(benzylic), Jˆ11.7), 3.89 (dd, H5, JH5±H5 ˆ11.4 Hz,
1
0
0
0
JH5±H4ˆ1.8 Hz), 3.89 (dt, H5 , JH5 ±H5ˆ11.0 Hz, JH5 ±H4
ˆ
2201.1 (d Jˆ48 Hz), H NMR (500 MHz, CDCl3) d 5.38
1.8 Hz, JH5 ±Fˆ2.2 Hz); 13C NMR (CDCl3) d 169.7 (C1),
136.6, 128.7, 128.3, 127.8 (2C), 95.4 (d, C2, Jˆ192.8 Hz),
77.6 (benzylic), 73.9 (C4), 73.0 (d, C3, Jˆ21.7 Hz), 66.8
(C5); HRMS calcd for C12H13FNaO4 (M1Na1) 263.0691,
found 263.0695.
(d, H1, Jˆ3.7), 4.38 (ddd, H2, Jˆ49.0, 9.2, 3.7 Hz), 3.95±
0
3.60 (m, H3, H4, H5, H5 ); major: 19F NMR (CDCl3) d
0
1
2200.3 (d, Jˆ36.6 Hz); H NMR (500 MHz, CDCl3) 4.80
(dd, H1, Jˆ7.7, 3.0 Hz), 4.05 (ddd, H2, Jˆ51.2, 8.4, 7.7 Hz),
3.31 (ddd, H5, Jˆ11.7, 10.3 Hz); 13C NMR (CDCl3) (both
anomers) d 94.2 (d, C1, Jˆ24.0 Hz) and 89.8 (d, C1 Jˆ
20.1 Hz), 92.8 (d, C2, Jˆ184.4 Hz) and 90.2 (d, C2, Jˆ
195.9 Hz), 24.1 (d, C3, Jˆ16.9 Hz) and 71.2 (d, C3, Jˆ
17.8 Hz), 68.9, 68.8, 65.2 and 60.8 (C4 and C5).
Recrystallization from ether afforded 12b as a white solid;
mp 75±778C; 10b: [a]2D0ˆ24.38 (cˆ0.01, CHCl3); IR (neat)
1793 cm21
;
19F NMR (CDCl3) d 2216.8 (d, Jˆ48.4 Hz); 1H
NMR (500 MHz, CDCl3) d 7.40±7.25 (m, 5H), 5.14 (dd,
H2, JH2±Fˆ48.4 Hz, JH2±H3ˆ4.4 Hz), 4.55 (AB, 2H
(benzylic) Jˆ12.0 Hz), 4.60±4.52 (m, 3H, 2H (benzylic)
2-Deoxy-2-¯uoro-l-lyxopyranose (17). Hydrogenaton of
16 (0.040 g, 0.15 mmol) in a similar manner afforded
0.018 (80%) of 17 as a colorless glassy oil with an anomeric
ratio of a/bˆ2.6:1 (by 19F NMR): 19F NMR (CDCl3) d
0
and H3), 4.51±4.48 (m, H4), 3.88±3.81 (m, H5, H5 ), 3.15
(bs, OH); 13C NMR (CDCl3) d 170.2 (C1), 137.1, 128.5,
128.4, 128.2, 128.0, 127.9, 86.5 (d, C2 Jˆ202.8 Hz), 78.1
(benzylic), 73.8 (C4), 68.3 (d, C3, Jˆ18.8 Hz), 67.5 (C5);
HRMS calcd for C12H13FNaO4 (M1Na1) 263.0691, found
263.0695.
1
2223.1 (br s), 2206.6 (dd, Jˆ48.8, 24.4 Hz); H NMR
(500 MHz, D2O) major d 5.23 (t, H1, Jˆ2.9 Hz), 4.65 (dd,
H2, Jˆ48.8, 2.9 Hz), 3.97±3.64 (m, 4H); 13C NMR (D2O)
major: 91.9 (d, C1, Jˆ28.9 Hz), 91.2 (d, C2, Jˆ175.0 Hz), 69.8
(d, C3, Jˆ16.6 Hz), 67.6, 62.8; minor: 93.4 (d, C1, Jˆ15.7 Hz),
91.1 (d, C2, Jˆ180 Hz), 72.1 (d, C3, Jˆ16.7 Hz), 66.7, 65.2.
5-O-Benzyl-2-deoxy-2-¯uoro-d-xylofuranose (14). DIBAL
(1 M in toluene, 0.51 mL, 0.51 mmol) was added to a solu-
tion of g-xylonic lactone 12a (0.047 g, 0.19 mmol) in
CH2Cl2 (2 mL) at 2788C. After 1 h, the reaction mixture
1,3,4-Triacetyl-2-deoxy-2-¯uoro-l-lyxopyranose (18). 2-
Fluorolyxose 17 (0.022 g, 0.145 mmol) was stirred with

F. A. Davis et al. / Tetrahedron 56 (2000) 5303±5310
5309
7. For reviews on ¯uorinated carbohydrates see: (a) Tsuchiya, T.
Adv. Carbohydr. Chem. Biochem. 1990, 48, 91. (b) Penglis, A. A. E.
Adv. Carbohydr. Chem. Biochem. 1981, 38, 195. (c) Welch, J. T.
Tetrahedron 1987, 43, 3123. (d) Mann, J. Chem. Soc. Rev. 1987,
16, 381. (e) Curd, P. J. J. Carbohydr. Chem. 1985, 4, 451.
8. Dwek, R. A. CIBA Foundation Symposium: Carabon Fluorine
Compounds; Elsevier: Amsterdam, 1977, p 239.
acetic anhydride (0.136 mL, 1.45 mmol) and pyridine
(0.234 mL, 2.9 mmol) at rt for 8 h. The reaction mixture
was diluted with EtOAc (10 mL) and washed with satd.
NH4Cl (3£5 mL), satd. NaHCO3 (5 mL), brine (5 mL),
dried (MgSO4), ®ltered and concentrated. Puri®cation by
¯ash chromatography (EtOAc/hexane 1:2) gave 1,3,4-tri-
acetyl-2-deoxy-2-¯uoro-a-l-lyxo-pyranose 18a (0.0263 g)
and 1,3,4-triacetyl-2-deoxy-2-¯uoro-b-l-lyxopyranose 18b
(0.0224 g). The total yield of the two anomers was 95%;
18a: 19F NMR (CDCl3) d 2205.9 (dd Jˆ48.8, 24.4 Hz); 1H
NMR (500 MHz, CDCl3) d 6.15 (dd, H1, Jˆ5.9, 3.4 Hz),
5.30 (ddd, H3, Jˆ48.4, 5.0, 2.5 Hz), 5.25±5.20 (m, H4), 4.79
(ddd, H2, Jˆ48.4, 5.0, 2.5 Hz), 4.00 (dd, H5, Jˆ11.8,
4.7 Hz), 3.70 (dd, H5, 11.4, 8.8 Hz); 13C NMR (CDCl3) d
169.9, 169.6, 168.4, 90.2 (d, C1, Jˆ30.3 Hz), 85.8 (d, C2,
Jˆ182.5 Hz), 68.7 (d, C3, Jˆ17.0 Hz), 66.4, 61.9, 20.8,
20.7, 20.6. 18b: 19F NMR (CDCl3) d 2215.3 (br d,
9. Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
10. For a recent review on the asymmetric synthesis of ¯uorinated
carbohydrates see: Novo, B.; Resnati, G. In Enantiocontrolled
Synthesis of Fluoro-Organic Compounds; Soloshonok, V. A.,
Ed.; Wiley: Chichester, 1999; Chapter 11, p 349.
11. (a) Albano, E. L.; Tolman, R. L.; Robins, R. K. Carbo-
hydr. Res. 1971, 19, 63. (b) Butchard, C. G.; Kent, P. W.
Tetrahedron 1971, 27, 3457. (c) Wright, J. A.; Fox, J. J.
Carbohydr. Res. 1970, 13, 297. (d) Reichman, U.; Watanabe, K.
A.; Fox, J. J. Carbohydr. Res. 1975, 42, 233. (e) Su, T.-S.; Klein, R.
S.; Fox, J. J. J. Org. Chem. 1981, 46, 1790. (f) Lundt, K.; Pedersen,
1
Jˆ24.4 Hz); H NMR (500 MHz, CDCl3) d 6.01 (dd, H1,
Jˆ10.7, 2.5 Hz), 5.23 (ddd, H3, Jˆ17.6, 6.8, 2.9 Hz), 5.18±
5.10 (m, H4), 4.90 (dt, H2, Jˆ47.5, 2.8 Hz), 4.19 (dd, H5,
Jˆ12.5, 4.3 Hz), 3.58 (ddd, H5, Jˆ12.5, 6.0, 1.6 Hz), 2.17,
2.15, 2.10; 13C NMR (CDCl3) d 169.7, 169.5, 169.0, 89.4 (d,
C1, Jˆ22.0 Hz), 84.5 (d, C2, Jˆ191.0 Hz), 68.5 (d, C3,
Jˆ16.0 Hz), 67.5, 61.7, 20.7 (3C). The spectra properties
of 18b are in agreement with literature values.11g
È
C. Mikrochem. Acta S. 1966, 126. (g) Dax, K.; Glanzer, B. I.
Carbohydr. Res. 1987, 162, 13. (h) Bols, M.; Lundt, I. Acta
Chem. Scand. 1990, 44, 252.
12. For examples, and leading references to the synthesis of
¯uorinated carbohydrates from non-carbohydrate sources see: (a)
Yan, F.; Nguyen, B. V.; York. C.; Hudlicky, T. Tetrahedron, 1997,
53, 11541. (b) Welch, J. T.; Eswarakrishna, S. J. Chem. Soc.,
Chem. Commun. 1985, 186. (c) Ref. 10.
13. For reviews on a-¯uoro carbonyl compounds see: (a) Davis,
F. A.; Kasu, P. V. N. Org. Procd. Int. 1999, 31, 127. (b) Rozen, S.;
Filler, R. Tetrahedron 1985, 41, 1111.
Acknowledgements
We thank Christopher K. Murphy for preliminary studies
and Mr George Kemmerer of the Temple NMR facilities for
assistance in obtaining the 19F NMR spectra. This work was
supported by a grant from the National Science Foundation.
We thank Prof. John T. Welch, SUNY Albany, for helpful
discussions and Dr George A. Shia, AlliedSignal, for a
generous gift of NFSi.
14. For reviews on the asymmetric synthesis of ¯uoro organic
compounds which includes sections on a-¯uoro carbonyl
compounds see: (a) Resnati, G. Tetrahedron 1989, 45, 5703. (b)
Iseki, K.; Kobayashi, Y. Rev. Heteroatom Chem. 1995, 12, 211.
Davis, F. A.; Qi, H.; Sundarababu, G. In Enantiocontrolled
Synthesis of Fluoro-Organic Compounds: Stereochemical
Challenges and Biomedical Targets; Soloshonok, V. A., Ed.;
Wiley: Chichester, 1999; Chapter 1.
15. Davis, F. A.; Han, W. Tetrahedron Lett. 1992, 33, 1153.
16. Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.
17. Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60,
4730.
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