Synthetic routes towards fluorine-containing amino sugars: Synthesis of fluorinated analogues of tomosamine and 4-amino-4-deoxyarabinose

Article abstract of DOI:10.1002/ejoc.201301614

Fluorinated analogues of bioactive amino sugars are of high interest in medicinal chemistry. We developed a straightforward synthetic route towards this class of carbohydrates by applying a titanium-mediated aldol addition. Thus, two-carbon chain elongations of serine- and threonine-derived aldehydes with a chiral fluoroacetyl-oxazolidinone could be achieved in good yields and excellent diastereoselectivities to generate a fluorohydrin-containing carbon skeleton. A short deprotection sequence subsequently furnished the pyranoid forms of various 4-amino-2-fluoropentoses and -hexoses, respectively. The versatility of this strategy was demonstrated by the stereoselective synthesis of naturally abundant 4-amino-4-deoxyarabinose and 4-amino-4,6-dideoxygalactose (tomosamine). 4-Amino-2-fluoropentoses and -hexoses were prepared through two-carbon chain elongations by Ti-mediated aldol additions of serine- and threonine-derived amino aldehydes to fluoroacetyl-ephedrine-oxazolidinone. Excellent stereoselectivities were attained for matched-case fluorohydrins, which were deprotected in a short sequence. Copyright

Full text of DOI:10.1002/ejoc.201301614

FULL PAPER
DOI: 10.1002/ejoc.201301614
Synthetic Routes towards Fluorine-Containing Amino Sugars: Synthesis of
Fluorinated Analogues of Tomosamine and 4-Amino-4-deoxyarabinose
Christopher Albler[a] and Walther Schmid*[a]
Dedicated to our colleague Professor Paul Kosma on the occasion of his 60th birthday
Keywords: Aldol reactions / Chiral auxiliaries / Carbohydrates / Fluorine
Fluorinated analogues of bioactive amino sugars are of high
interest in medicinal chemistry. We developed a straightfor-
ward synthetic route towards this class of carbohydrates by
applying a titanium-mediated aldol addition. Thus, two-car-
bon chain elongations of serine- and threonine-derived alde-
hydes with a chiral fluoroacetyl-oxazolidinone could be
achieved in good yields and excellent diastereoselectivities
to generate a fluorohydrin-containing carbon skeleton. A
short deprotection sequence subsequently furnished the
pyranoid forms of various 4-amino-2-fluoropentoses and
-hexoses, respectively. The versatility of this strategy was
demonstrated by the stereoselective synthesis of naturally
abundant 4-amino-4-deoxyarabinose and 4-amino-4,6-dide-
oxygalactose (tomosamine).
Introduction
these synthetic carbohydrate antigen fragments for the de-
velopment of conjugate vaccines owing to their beneficial
pharmacokinetic properties, such as enhanced metabolic
stability[8] and immunogenicity.[9] Fluorinated analogues of
sialic acids represent another promising application in me-
dicinal chemistry as they are potential sialidase inhibitors
and, therefore, may be used for the treatment of medical
conditions such as viral infections, cancer, or diabetes.[10]
Another advantage of fluorine is the possibility to perform
facile NMR-based investigations.[11] The naturally 100%
abundant isotope 19F is an excellent nucleus for NMR ex-
periments owing to its high sensitivity, large spectral disper-
sion, and the relative size of its coupling constants. Al-
though fluorine chemistry has experienced a quantum leap
within the past decade,[12] the most commonly used strategy
for the preparation of fluorinated amino sugars remains
F/OH substitution at a late stage with diethylaminosulfur
trifluoride (DAST).[13] To the best of our knowledge, these
classic carbohydrate chemistry approaches, which use nucle-
ophilic substitutions accompanied by multiple protection/
deprotection steps, suffer from considerable drawbacks such
as expensive starting materials, low overall yields owing to
lengthy linear synthetic routes, and/or limited scope. Hence,
we were interested in developing a short and efficient gene-
ral approach. Herein, we report our efforts towards the
preparation of fluorinated amino sugars through stereo-
selective titanium-mediated aldol additions.
Amino-functionalized carbohydrates play various impor-
tant roles in biological systems. To perform systematic stud-
ies for a better understanding of the biological function of
these compounds, short and high-yielding synthetic routes
for their preparation as well as sophisticated investigation
strategies are essential. In this respect, fluorine substitution
represents a valuable tool to probe the critical binding as-
pects of macromolecule complexes such as antigen–anti-
body adducts.[1] Various rare mono-, di-, and trideoxy (di)-
amino sugars can be found in the lipopolysaccharides
(LPSs) of the outer cell wall of Gram-negative bacteria.[2]
As these compounds are involved in immune response,
pathogenicity, and adaptation mechanisms (e.g., antibiotics
resistance),[3] it is highly desirable to understand their pre-
cise mode of interaction with biomolecules. Fluorinated an-
alogues of perosamine[4] (4-amino-4,6-dideoxymannose)
can be used to determine key hydrogen-bonding interac-
tions between the O-antigens of both Inaba and Ogawa
serotypes of Vibrio cholerae[5] and their respective anti-
bodies. As fluorine substitution results in major electronic,
but only minor steric changes,[6] the decrease or increase of
affinity constants of fluorinated antigen fragments depicts
the electronic environment of the binding interface. In the
example at hand, decreasing KD values were attributed to
loss of hydrogen-donor ability and/or unfavorable hydro-
phobic effects.[7] Additionally, there is an interest in using
[a] Department of Organic Chemistry, University of Vienna,
Währingerstrasse 38, 1090 Vienna, Austria
Results and Discussion
We started our reaction sequence by using the easily ac-
cessible serine- and threonine-derived amino aldehydes 1, 3,
E-mail: walther.schmid@univie.ac.at
https://bioorgchem.univie.ac.at/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301614.
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C. Albler, W. Schmid
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Scheme 1. Aldol additions of serine- and threonine-derived amino aldehydes to fluoroacetyl-ephedrine-oxazolidinone.
5, 7, and 9 (Scheme 1), which were prepared from the Table 1. Diastereoselectivities of aldol reactions.
matched, unnatural and mismatched, natural amino acids
according to the protocol of Garner et al.[14] These alde-
hydes were subjected to a two-carbon chain-elongation step
by applying a stereoselective Lewis acid mediated aldol ad-
dition.[15] As donor substrate, we used a chiral fluoroacetyl-
oxazolidinone, which was prepared from commercially
available ephedrine-oxazolidinone and fluoroacetyl chlor-
ide.[16] The best results for the chain-elongation reaction
were achieved when TiCl4 and N,N,NЈ,NЈ-tetramethylethyl-
enediamine (TMEDA) were used for enolization. This re-
sult is in agreement with observations made by Evans et
al.,[15a] who reported improvements to the selectivity of the
Entry
Compound
Yield (brsm)[a] [%]
dr[b]
1
2
3
4
5
2
4
6
8
66 (82)
68 (83)
55 (76)
44 (77)
47 (47)
17:1:1:1
8:2:1:1
32:2:1:0.5
15:3:1:1
20:1:0:0
10
[a] Yield based on recovered starting material. [b] Diastereomeric
ratios of four possible diastereomers: C-2/C-3 syn, C-4Ј/C-2 anti;
C-2/C-3 syn, C-4Ј/C-2 syn; C-2/C-3 anti, C-4Ј/C-2 anti; and C-2/C-
3 anti, C-4Ј/C-2 syn; determined by chromatographic separation of
the diastereomers, only the major diastereomer was characterized.
addition reaction for “nonchelate” syn-aldol products upon adducts also displayed acceptable selectivity. The yields ob-
the application of TMEDA to the reaction mixture. The tained were satisfactory in general, although a small
results of the diastereoselective aldol additions are summa- amount of product (3–5%) was lost owing to tert-butyloxy-
rized in Table 1. The stereoselectivities obtained were excel- carbonyl (Boc) deprotection under the harsh conditions em-
lent when matched (unnatural) d-amino acid derived alde- ployed. We also investigated various other Lewis acids in-
hydes were used (Table 1, Entries 1, 3, and 5). As titanium cluding different Li, B, SnII, and SnIV reagents, which all
is assumed to behave as a nonchelating metal in this reac- failed to furnish reasonable amounts of aldol adduct.
tion, the results may reflect the involvement of a nonchelat-
ing chairlike transition state as proposed by Pridgen et tional column chromatographic separation. For 2, 6, 8, and
al.[15b]
10, the major diastereomer could be obtained in pure form.
The diastereomeric ratios were determined by conven-
Although threonine derivatives generally furnished lower Compound 4 was obtained as a mixture of two dia-
yields, they exhibited higher diastereomeric ratios (dr) than stereomers, which were separated at a later stage of the syn-
the respective serine derivatives, and mismatched-case aldol thesis. The relative ratios of minor diastereomers, which in
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Synthetic Routes towards Fluorine-Containing Amino Sugars
most cases could not be separated, were estimated from in- sequently performed under standard conditions with tri-
tegrals of representative signals of NMR spectra of the re- fluoroacetic acid (TFA; Scheme 2).
spective product mixtures. Ultimately, extensive NMR in-
In the case of d-amino acid derived compounds 15 and
vestigations of the final products of the reaction sequence 16, immediate acetyl migration from C-3-OAc to C-4-NH2
(vide infra) made the exact assignment of the stereochemis- (within free amine intermediates), driven by the cis align-
try of all isolated compounds possible. The pyranose ring ments of the functional groups, occurred. However, we
system allows the assignment of the relative stereochemistry chose to prepare fully acetylated, l-amino acid derived
of the newly generated stereocenters in relation to that pres- compounds 17 and 18 as the migration did not occur in
ent in the chiral starting aldehyde by exhaustive analysis of these cases owing to the trans alignments of C-3-OAc and
the coupling constant pattern.
C-4-NH2. Additionally, slow autocatalytic C-3-OAc cleav-
The deprotection of fluorohydrins 2, 4, 6, and 8 was per- age was observed within free amines.
formed under acidic conditions. Unfortunately, the use of
Finally, Zemplén saponification[17] of 15, 16, 17, and 18
HCl leads to the formation of γ-lactams, which prompted could be successfully achieved to yield the target com-
us to develop a sequential deprotection sequence. After dis- pounds 19, 20, 21, and 22 (Figure 1). As they adopt rigid,
placement of the chiral auxiliary with NaOMe, the aceton- chairlike conformations and their configurations at C-4
ide protecting group was cleaved with acidic ion-exchange (and C-5) are determined by the starting materials, the con-
resin to leave the Boc protecting group intact and, therefore, figurations at C-2 and C-3 can be deduced by the magni-
3
prevent the risk of lactam formation (Scheme 2). Unfortu- tude of the respective JH,H NMR coupling constants
nately, the d-allo-threonine derivative 10 resisted all (Table 2).
1
attempts at selective acetonide cleavage, possibly owing to
Interestingly, α-22 adopts a C4 chairlike conformation,
a shielding effect of the methyl group, which renders the whereas β-22 adopts the respective 4C1 conformation. How-
isopropylidene protecting group particularly stable.
ever, both anomers of acetylated compound 18 feature a
Subsequently, the reduction of 11, 12, 13, and 14 with 4C1 conformation in accordance with analogous ido-config-
diisobutylaluminium hydride (DIBAL) was performed, fol- ured substances.[18] Compounds 19 and 20, 4-amino-4-de-
lowed by acetylation to overcome the inherent problem of oxyarabinose and 4-amino-4,6-dideoxygalactose[19] (tomos-
imine formation during acidic Boc cleavage, which was sub- amine) derivatives, respectively, represent particularly inter-
Scheme 2. Deprotection sequence. Reagents and conditions: (i) (a) NaOMe/MeOH, –30 °C, 30 min; (b) DOWEX H+, MeOH, room temp.,
2–16 h, 35–59%, two steps. (ii) (a) DIBAL (1 m in toluene), THF, –78 °C, 1.5 h; (b) Ac2O/pyridine, DMAP, room temp., 16 h; (iii) TFA/
DCM, room temp., 1 h, 47–66%, two steps; (iv) TFA/DCM, room temp., 1 h, then Ac2O, room temp., 1 h, 53–56%, two steps; (v) NaOMe/
MeOH, room temp., 1 h, 89–100%.
Figure 1. Conformations of α/β-anomers of final products.
Eur. J. Org. Chem. 2014, 2451–2459
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C. Albler, W. Schmid
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3
dark-brown solution was stirred at –78 °C for 2 h, whereupon the
aldehyde dissolved in dry DCM was added. The reaction mixture
was warmed to –40 °C and was then allowed to slowly warm to
0 °C over 3 h. The reaction was quenched by the addition of satu-
rated ammonium chloride solution, and the yellow precipitate
formed was removed by filtration and rinsed with DCM. The
phases of the filtrate were separated, and the aqueous phase was
extracted three times with DCM. The combined organic extracts
were dried with anhydrous MgSO4 and filtered. After removal of
the solvent under reduced pressure, the crude product was purified
by flash column chromatography to yield fluorohydrins 2, 4, 6, 8,
and 10 as white crystalline solids.
Table 2. Characteristic JH,H coupling constants[Hz] of final prod-
ucts.
Compound
3J1-H,2-H
3J2-H,3-H
3J3-H,4-H
3J4-H,5-H
α-19
β-19
α-20
β-20
α-21
β-21
α-22
β-22
3.1
7.2
4.1
7.8
3.7
7.8
5.0
1.0
8.4
9.2
10.3
9.8
9.0
8.8
6.4
3.4
4.4
4.9
4.7
4.9
9.9
10.0
7.3
3.0
3.0, 4.5
2.2, 2.5
1.7
1.6
6.2, 10.1
5.2, 10.5
4.4
2.4
General Procedure for Oxazolidinone/Acetonide Cleavage
(Method B): A stirred solution of the fluorohydrin in dry methanol
under argon was cooled to the temperature stated, and sodium
methoxide was added. The resulting solution was stirred for
30 min, whereupon acidic ion-exchange resin was added. The reac-
tion mixture was warmed to room temperature, and stirred for the
time stated. Afterwards, the reaction mixture was filtered, and the
solvents were evaporated to dryness. The crude product was puri-
fied by flash column chromatography.
esting substances as their parent amino sugars are abundant
in the LPS of Gram-negative bacteria and, hence, are asso-
ciated with pathogenicity and survival of bacteria in hostile
environments.
Conclusions
We have developed a new approach for the synthesis of
fluorinated amino sugars by means of a stereoselective tita-
nium-mediated aldol addition of protected serine- and thre-
onine-derived aldehydes and fluoroacetyl-ephedrine-oxazol-
idinone to generate 4-amino-2-fluoropentoses and 6-deoxy-
hexoses within seven steps in overall yields of 16–23% (77–
81% per step). Although aldol[15c,15d] (and Reformatsky)[20]
type chain elongations of Garner’s aldehyde have been thor-
oughly investigated in the past, to the best of our knowl-
edge, there is no example of a (mono)fluoroacyl addition,
which effectively makes protected amino/fluoro sugars ac-
cessible in one step and, therefore, delivers the desired
mechanistic carbohydrate probes in a most simple way. The
configurations of 19, 20, 21, and 22 were proven by NMR
techniques and, therefore, the proposed stereochemical out-
come[15b] of the titanium-mediated aldol addition could be
verified. These compounds are of interest for binding stud-
ies as well as the development of conjugate vaccines and
antimicrobial agents. We are investigating the possibility of
anti-selective aldol additions with our system to broaden
the stereochemical scope of our approach.
General Procedure for DIBAL Reduction/Acetylation/Boc Cleavage
(Method C): A stirred solution of the methyl ester in dry tetra-
hydrofuran (THF) under argon was cooled to –78 °C, and DIBAL
(1 m in toluene) was added dropwise. The resulting solution was
stirred at –78 °C for 1.5 h, whereupon the reaction was quenched
by the addition of saturated potassium sodium tartrate solution
and warmed to room temperature. The resulting biphasic mixture
was diluted with ethyl acetate (EA) and stirred for 3 h. Afterwards
the phases were separated, and the aqueous phase was extracted
three times with EA. The combined organic extracts were dried
with anhydrous MgSO4 and filtered. After removal of the solvent
under reduced pressure, the crude product was dissolved in pyr-
idine/acetic anhydride (1:1) under argon, and a catalytic amount
of 4-(dimethylamino)pyridine (DMAP) was added. The resulting
solution was stirred at room temperature overnight and then con-
centrated under reduced pressure and co-evaporated with toluene.
The crude reaction product was redissolved in TFA/DCM (1:3) and
stirred at ambient temperature for 1.5 h. The reaction mixture was
then concentrated to dryness, and the crude product was redis-
solved in MeOH. The resulting solution was treated with basic ion-
exchange resin whilst being stirred until pH = 6. After filtration and
evaporation of the solvent, the crude product was further treated as
stated.
General Procedure for Zemplén Saponification (Method D): To a
solution of the acetylated fluoroamino sugar in dry MeOH under
argon, a catalytic amount of NaOMe was added, and the resulting
solution was stirred at room temperature for 1–2 h as judged by
TLC (DCM/MeOH, 9:1). Then a small amount of acidic ion-ex-
change resin was added, and the reaction mixture was stirred at
room temperature for an additional 10 min. After filtration, the
solvent was evaporated to dryness, and the residue was redissolved
in water and washed twice with ethyl acetate (EA), and the solvents
were evaporated to dryness. The obtained products needed no fur-
ther purification in general but can be purified by flash column
chromatography (DCM/MeOH, 9:1) if necessary.
Experimental Section
General Methods: NMR spectra were recorded with a Bruker Av-
ance DPX 400 or 600 spectrometer; CDCl3, D2O, or CD3OD were
used for calibration. MS experiments were measured in the ESI
mode with a Finnigan MAT 900 spectrometer. For chromatog-
raphy, Merck silica gel 60 (0.004–0.063 mm) was used. For TLC
monitoring, Merck plates (silica gel 60 F254) were used; the plates
were stained by treatment with a solution of ninhydrin (0.3 g) in
butanol (100 mL) and acetic acid (3 mL), followed by charring with
a heat gun. All solvents were distilled before use. Optical rotations
were measured with a Perkin–Elmer 341 polarimeter. Chemicals
were purchased in reagent grade.
Procedure for the Preparation of Flouroacetyl Chloride: Ethyl
fluoroacetate (13.6 mL, 141 mmol) was dissolved in EtOH/H2O
(9:1; 200 mL), and NaOH (6.72 g, 168 mmol) was added. A white
precipitate slowly started to form, and after the mixture had been
stirred at room temperature for 20 h, the solvent was removed un-
der reduced pressure. The sodium fluoroacetate obtained was redis-
General Procedure for Aldol Reactions (Method A): A stirred solu-
tion of (4S,5R)-3-(2-fluoroacetyl)-4-methyl-5-phenyloxazolidin-2-
one in dry dichloromethane (DCM) under argon was cooled to
–78 °C, and TiCl4 followed by TMEDA were added. The resulting
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Synthetic Routes towards Fluorine-Containing Amino Sugars
solved in HCl (3 m, 120 mL), and the aqueous solution was satu-
rated with NaCl and then extracted four times with Et2O (100 mL).
The combined organic extracts were dried with anhydrous MgSO4
and filtered, and the solvents were evaporated to dryness. The ob-
tained fluoroacetic acid (10.4 g, 133 mmol, 95%) was essentially
pure and was directly added to PCl5 (30.6 g, 147 mmol) in a flask
equipped with a reflux condenser under vigorous stirring and cool-
ing (Caution, strongly exothermic reaction!). After the initial reac-
tion subsided, the reaction mixture was heated at 80 °C for 1 h.
Afterwards, the fluoroacetyl chloride was directly distilled from the
reaction mixture by using a short distillation column (b.p. 70–
71 °C); yield: 12 g (80%). The obtained fluoroacetyl chloride con-
tained trace amounts of POCl3 and was used directly without fur-
ther purification.
tert-Butyl (4S)-4-{(1S,2R)-2-Fluoro-1-hydroxy-3-[(4S,5R)-4-methyl-
2-oxo-5-phenyloxazolidin-3-yl]-3-oxopropyl}-2,2-dimethyloxazol-
idine-3-carboxylate (4): (4S,5R)-3-(2-Fluoroacetyl)-4-methyl-5-
phenyloxazolidin-2-one (1.35 g, 5.67 mmol) in dry DCM (40 mL)
was treated according to Method A with TiCl4 (670 μL,
6.11 mmol), freshly distilled TMEDA (2.6 mL, 17.45 mmol), and
aldehyde 3 (1 g, 4.36 mmol). Purification by silica gel chromatog-
raphy was performed with HE/EA (3:1) as eluent. Yield: main dia-
stereomers (could not be separated at this stage) 1.24 g (61%, dr =
4:1); minor diastereomers 142 mg (7 %, dr = 1:1). 1H NMR
(CDCl3, 400 MHz, 25 °C, main diastereomer): δ = 0.98 (d,
3J4Ј-H,CH = 6.8 Hz, 3 H, CH3), 1.50, 1.52, 1.61 (3 s, 15 H, 5 CCH3),
4.03 (dd,33J4-H,5a-H = 6.0 Hz, 2J5a-H,5b-H = 9.4 Hz, 1 H, 5a-H), 4.09–
3
4.26 (m, 2 H, 3-H, 5b-H), 4.28–4.45 (m, 1 H, 4-H), 4.64 (d, J3-
3
= 7.1 Hz, 1 H, OH), 4.77 (dq, 3J4Ј-H,5Ј-H = 6.7 Hz, J
OH,3-H
4Ј-H,CH3
(4S,5R)-3-(2-Fluoroacetyl)-4-methyl-5-phenyloxazolidin-2-one:
A
3
= 6.8 Hz, 1 H, 4Ј-H), 5.78 (d, J4Ј-H,5Ј-H = 6.7 Hz, 1 H, 5Ј-H), 5.96
(d, J2-F,2-H = 48.8 Hz, 1 H, 2-H), 7.27–7.46 (m, 5 H, Ar H) ppm.
stirred solution of (4S,5R)-4-methyl-5-phenyloxazolidin-2-one
(14.52 g, 81.94 mmol) in dry THF (300 mL) under argon was co-
oled to –78 °C, and BuLi (1.6 m in hexanes; 53.8 mL, 86.08 mmol)
was added dropwise. The reaction mixture was stirred at –78 °C for
30 min, and then fluoroacetyl chloride (6.3 mL, 90.10 mmol) was
added dropwise. After additional stirring for 10 min, the reaction
mixture was warmed to 0 °C and quenched by the addition of
water. After separation of the phases, the aqueous layer was ex-
tracted three times with Et2O (100 mL). The combined organic ex-
tracts were washed with brine, dried with anhydrous MgSO4, and
filtered. After removal of the solvent under reduced pressure, the
crude product was purified by flash column chromatography eluted
with hexanes (HE)/EA (3:1). Yield: 11.08 g (57%). [α]2D0 = –23.5 (c
2
13C NMR (CDCl3, 100 MHz, 25 °C): δ = 14.2 (4Ј-CH3), 24.3, 27.3,
28.4 (5 CCH3), 55.5 (C-4Ј), 58.3 (C-4), 64.4 (C-5), 73.9 (d,
2J2-F,C-3 = 18.9 Hz, C-3), 80.3 (C-5Ј), 81.8 (Cq-Boc), 89.4 (d,
1J2-F,C-2 = 185.8 Hz, C-2), 94.7 (Cq-Isoprop), 125.6, 128.8, 129.0
2
(Ar), 132.6 (Ar Cq), 152.9 (C-2Ј), 166.5 (d, J2-F,C-1 = 24.1 Hz, C-
1) ppm. 19F NMR (CDCl3, 565 MHz, 25 °C): δ = –211.02 ppm.
HRMS (ESI): calcd. for C23H31FN2NaO7 [M + Na]+ 489.2013;
found 489.2012.
tert-Butyl (4S,5S)-4-{(1R,2S)-2-Fluoro-1-hydroxy-3-[(4S,5R)-4-
methyl-2-oxo-5-phenyloxazolidin-3-yl]-3-oxopropyl}-2,2,5-trimethyl-
oxazolidine-3-carboxylate (6): (4S,5R)-3-(2-Fluoroacetyl)-4-methyl-
= 6.9, CH2Cl2). M.p. 87–89 °C. 1H NMR (CDCl3, 400 MHz, 5-phenyloxazolidin-2-one (0.76 g, 3.20 mmol) in dry DCM (25 mL)
3
25 °C): δ = 0.96 (d, J4-H,CH = 6.7 Hz, 3 H, CH3), 4.80 (dq,
was treated according to Method A with TiCl4 (400 μL,
3.65 mmol), freshly distilled TMEDA (1.5 mL, 9.94 mmol), and al-
3
3J4-H,5-H = 7.1 Hz, J4-H,CH = 6.7 Hz, 1 H, 4-H), 5.43 (dd,
3
3
2J2aЈ-H,2bЈ-H = 16.6 Hz, 2J2Ј-H,2aЈ-F, = 47.5 Hz, 1 H, 2aЈ-H), 5.47 (dd, dehyde 5 (0.60 g, 2.47 mmol). Purification by silica gel chromatog-
2
2J2aЈ-H,2bЈ-H = 16.6 Hz, J2Ј-F,2bЈ-H = 47.5 Hz, 1 H, 2bЈ-H), 5.79 (d, raphy was performed with HE/EA (4:1) as eluent. Yield: main dia-
3J4-H,5-H = 7.1 Hz, 1 H, 5-H), 7.27–7.32 (m, 2 H, Ar H), 7.36–7.47
(m, 3 H, Ar H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ =
stereomers 624 mg (53%, dr = 16:1); minor diastereomers 27 mg
1
(2%, dr = 2:1). [α]2D0 = –4.8 (c = 9.3, CH2Cl2). M.p. 70–73 °C. H
1
14.7 (CH3), 54.5 (C-4), 80.2 (d, J2Ј-F,C-2Ј = 180.0 Hz, C-2Ј), 80.7
NMR (CDCl3, 400 MHz, 25 °C): δ = 0.97 (d, 3J
= 6.6 Hz,
4Ј-H,4Ј-CH3
3
(C-5), 125.6, 128.9, 129.1 (Ar H), 132.7 (Ar Cq), 153.0 (C-2), 167.1,
167.4 (C-1Ј) ppm. 19F NMR (CDCl3, 565 MHz, 25 °C): δ =
–229.89 ppm. HRMS (ESI): calcd. for C12H12FNNaO3 [M +
Na]+ 260.0699; found 260.0709.
3 H, 4Ј-CH3), 1.40 (d, J5-H,6-H = 6.3 Hz, 3 H, 6-CH3), 1.50, 1.51,
3
3
1.61 (3s, 9 H, 5 CCH3), 3.91 (dd, J3-H,4-H = 2.3 Hz, J4-H,5-H
=
6.8 Hz, 1 H, 4-H), 4.01–4.17 (m, 1 H, 3-H), 4.33–4.44 (m, 1 H, 5-
H), 4.79 (dq, 3J4Ј-H,4Ј-CH = 6.6 Hz, 3J4Ј-H,5Ј-H = 7.1 Hz, 1 H, 4Ј-H),
3
5.78 (d, 3J4Ј-H,5Ј-H = 7.1 Hz, 1 H, 5Ј-H), 6.08 (d, 2J2-F,2-H = 48.3 Hz,
1 H, 2-H), 6.15 (br. s, 1 H, OH), 7.27–7.31 (m, 2 H, Ar H), 7.36–
7.45 (m, 3 H, Ar H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ
= 14.2 (4Ј-CH3), 19.5 (C-6), 26.4, 28.5, 28.6 (5 CCH3), 55.7 (C-4Ј),
tert-Butyl (4R)-4-{(1R,2S)-2-Fluoro-1-hydroxy-3-[(4S,5R)-4-methyl-
2-oxo-5-phenyloxazolidin-3-yl]-3-oxopropyl}-2,2-dimethyloxazol-
idine-3-carboxylate (2): (4S,5R)-3-(2-Fluoroacetyl)-4-methyl-5-
phenyloxazolidin-2-one (1.35 g, 5.67 mmol) in dry DCM (40 mL)
was treated according to Method A with TiCl4 (670 μL,
6.11 mmol), freshly distilled TMEDA (2.6 mL, 17.45 mmol), and
aldehyde 1 (1 g, 4.36 mmol). Purification by silica gel chromatog-
raphy was performed with HE/EA (2:1) as eluent. Yield: main dia-
stereomers 1.18 g (58%, dr = 17:1); minor diastereomers 163 mg
2
67.9 (C-4), 70.7 (d, J2-F,C-3 = 18.5 Hz, C-3), 71.9 (C-5), 80.5 (C-
1
5Ј), 81.8 (Cq-Boc), 89.2 (d, J2-F,C-2 = 187.9 Hz, C-2), 94.7 (Cq-
Isoprop), 125.7, 128.9, 129.1 (Ar), 132.8 (Ar Cq), 153.2 (C-2Ј),
2
167.2 (d, J2-F,C-1 = 24.7 Hz, C-1) ppm. 19F NMR (CDCl3,
565 MHz, 25 °C): δ = –210.78 ppm. HRMS (ESI): calcd. for
C24H33FN2NaO7 [M + Na]+ 503.2170; found 503.2160.
1
(8%, dr = 1:1). [α]2D0 = +4.6 (c = 7.1, CH2Cl2). M.p. 87–90 °C. H
3
NMR (CDCl3, 400 MHz, 25 °C): δ = 0.97 (d, J
= 6.6 Hz, tert-Butyl (4R,5R)-4-{(1R,2S)-2-Fluoro-1-hydroxy-3-[(4S,5R)-4-
4Ј-H,CH3
3 H, CH3), 1.51, 1.64 (2s, 15 H, 5 CCH3), 3.97–4.23 (m, 2 H, 3-H, methyl-2-oxo-5-phenyloxazolidin-3-yl]-3-oxopropyl}-2,2,5-trimeth-
5a-H), 4.28–4.37 (m, 2 H, 4-H, 5b-H), 4.78 (dq, 3J4Ј-H,5Ј-H = 7.1 Hz,
yloxazolidine-3-carboxylate (8): (4S,5R)-3-(2-Fluoroacetyl)-4-
methyl-5-phenyloxazolidin-2-one (1.92 g, 8.09 mmol) in dry DCM
(60 mL) was treated according to Method A with TiCl4 (950 μL,
8.66 mmol), freshly distilled TMEDA (3.8 mL, 25.18 mmol), and
aldehyde 7 (1.516 g, 6.23 mmol). Purification by silica gel
3
3J4Ј-H,CH = 6.6 Hz, 1 H, 4Ј-H), 4.90 (d, J3-OH,3-H = 9.2 Hz, 1 H,
3
3
2
OH), 5.76 (d, J4Ј-H,5Ј-H = 7.1 Hz, 1 H, 5Ј-H), 6.16 (d, J2-F,2-H
=
47.8 Hz, 1 H, 2-H), 7.27–7.31 (m, 2 H, Ar H), 7.34–7.46 (m, 3 H,
Ar H) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 14.2 (4Ј-
CH3), 23.9, 26.5, 28.4 (5 CCH3), 55.5 (C-4Ј), 60.1 (C-4), 64.6 (C- chromatography was performed with HE/EA (4:1) as eluent. Yield:
2
5), 72.9 (d, J2-F,C-3 = 20.2 Hz, C-3), 80.3 (C-5Ј), 81.6 (Cq-Boc),
main diastereomers 1.20 g (40%, dr = 5:1); minor diastereomers
1
89.1 (d, J2-F,C-2 = 183.6 Hz, C-2), 94.7 (Cq-Isoprop), 125.6, 128.8,
120 mg (4%, dr = 1:1). [α]2D0 = –67.7 (c = 8.2, CH2Cl2). M.p. 164–
129.0 (Ar), 132.7 (Ar Cq), 152.9 (C-2Ј), 167.3 (C-1) ppm. 19F NMR 167 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 0.98 (d,
(CDCl3, 565 MHz, 25 °C): δ = –210.99 ppm. HRMS (ESI): calcd. 3J4Ј-H,4Ј-CH = 6.8 Hz, 3 H, 4Ј-CH3), 1.41 (d, J5-H,6-H = 6.3 Hz, 3
3
3
for C23H31FN2NaO7 [M + Na]+ 489.2013; found 489.2017.
H, 6-CH3), 1.49, 1.52, 1.64 (3s, 15 H, 5 CCH3), 4.12–4.27 (m, 2 H,
Eur. J. Org. Chem. 2014, 2451–2459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2455

C. Albler, W. Schmid
FULL PAPER
3
3
3-H, 4-H), 4.39 (dq, J4-H,5-H = 3.1 Hz, J5-H,6-H = 6.3 Hz, 1 H, 5- Methyl (2S,3R,4R,5S)-4-[(tert-Butoxycarbonyl)amino]-2-fluoro-3,5-
H), 4.78 (dq, 3J4Ј-H,4Ј-CH = 6.8 Hz, 3J4Ј-H,5Ј-H = 7.1 Hz, 1 H, 4Ј-H),
dihydroxyhexanoate (12): Fluorohydrin 6 (202 mg, 0.42 mmol) in
3
4.91 (br. s, 1 H, OH), 5.79 (d, 3J4Ј-H,5Ј-H = 7.1 Hz, 1 H, 5Ј-H), 5.92 dry MeOH (10 mL) was cooled to –30 °C and treated according to
3
2
(dd, J2-H,3-H = 1.3 Hz, J2-F,2-H = 48.5 Hz, 1 H, 2-H), 7.26–7.31
Method B with NaOMe (9 mg, 0.17 mmol) and then with acidic
ion-exchange resin for 2.5 h. Purification by silica gel chromatog-
(m, 2 H, Ar H), 7.35–7.46 (m, 3 H, Ar H) ppm. 13C NMR (CDCl3,
100 MHz, 25 °C): δ = 14.6 (4Ј-CH3), 21.8 (C-6), 28.1, 28.7, 29.4 (5 raphy was performed with toluene (T)/EA (2:1) as eluent. Yield:
CCH3), 55.9 (C-4Ј), 64.7 (C-4), 73.2 (C-5), 74.9 (C-3), 80.8 (C-5Ј),
82.2 (Cq-Boc), 89.3 (d, J2-F,C-2 = 184.3 Hz, C-2), 95.0 (Cq-Iso- NMR (MeOD, 600 MHz, 25 °C): δ = 1.15 [d, cf (conformers),
70 mg (56%). [α]2D0 = –10.8 (c = 7.1, CH2Cl2). M.p. 138–140 °C. 1H
1
prop), 126.0, 129.2 (Ar), 133.0 (Ar Cq), 153.4 (C-2Ј), 166.3 (d,
3J5-H,6-H = 6.5 Hz, 3 H, 6-CH3], 1.45 (s, 9 H, 3 CCH3), 3.62 (dd,
2J2-F,C-1 = 24.1 Hz, C-1) ppm. 19F NMR (CDCl3, 565 MHz, 25 °C): 3J4-H,5-H = 1.5 Hz, J3-H,4-H = 10.4 Hz, 1 H, 4-H), 3.80 (s, 3 H,
3
3
3
3
δ = –209.80 ppm. HRMS (ESI): calcd for C24H33FN2NaO7 [M +
OCH3), 4.04 (ddd, J2-H,3-H = 1.2 Hz, J3-H,4-H = 10.4 Hz, J2-F,3-H
Na]+ 503.2170; found 503.2176.
= 28.9 Hz, 1 H, 3-H), 4.20 (dq, J4-H,5-H = 1.5 Hz, J5-H,6-H
=
=
3
3
3
2
6.5 Hz, 1 H, 5-H), 5.06 (dd, cf, J2-H,3-H = 1.2 Hz, J2-F,2-H
tert-Butyl (4R,5R)-4-Formyl-2,2,5-trimethyloxazolidine-3-carboxyl-
ate (9):[21] Aldehyde 7[22] (1.5 g, 6.17 mmol) was dissolved in THF
(120 mL), and LiOH (15 mg, 0.62 mmol) was added. The resulting
solution was heated to reflux overnight and then concentrated to
dryness. The crude product was redissolved in Et2O (50 mL) and
washed with water and brine. The organic layer was dried with
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The diastereomers were separated by flash column
chromatography with HE/EA (19:1) as eluent. Yield: 495 mg
(33%), 990 mg (66%) starting material.
47.8 Hz, 1 H, 2-H) ppm. 13C NMR (MeOD, 150 MHz, 25 °C): δ =
3
20.4 (cf, 6-C), 28.7 (cf, 3 CCH3), 52.7 (OCH3), 56.4 (d, cf, J2-F,C-4
2
= 2.7 Hz, C-4), 65.7 (cf, C-5), 71.9 (d, J2-F,C-3 = 19.3 Hz, C-3),
80.4 (Cq-Boc), 90.3 (d, 1J2-F,C-2 = 188.5 Hz, C-2), 158.2 (C=O-Boc),
170.9 (d, cf, J2-F,C-1 = 25.2 Hz, C-1) ppm. 19F NMR (MeOD,
2
565 MHz, 25 °C): δ = –211.85 (cf) ppm. HRMS (ESI): calcd. for
C12H22FNNaO6 [M + Na]+ 318.1329; found 318.1327.
Methyl (2S,3R,4S)-4-[(tert-Butoxycarbonyl)amino]-2-fluoro-3,5-di-
hydroxypentanoate (13): Fluorohydrin 4 (788 mg, 1.69 mmol) in dry
MeOH (20 mL) was cooled to –40 °C and treated according to
Method B with NaOMe (18 mg, 0.34 mmol) and then with acidic
ion-exchange resin for 4 h. Purification by silica gel chromatog-
raphy was performed with HE/EA (1:1) as eluent. Yield: main dia-
tert-Butyl (4S,5R)-4-{(1R,2S)-2-Fluoro-1-hydroxy-3-[(4S,5R)-4-
methyl-2-oxo-5-phenyloxazolidin-3-yl]-3-oxopropyl}-2,2,5-trimethyl-
oxazolidine-3-carboxylate (10): (4S,5R)-3-(2-Fluoroacetyl)-4-
methyl-5-phenyloxazolidin-2-one (512 mg, 2.16 mmol) in dry DCM
(20 mL) was treated according to Method A with TiCl4 (260 μL,
2.37 mmol), freshly distilled TMEDA (1 mL, 6.63 mmol), and alde-
hyde 9 (404 mg, 1.66 mmol). Purification by silica gel chromatog-
raphy was performed with HE/EA (4:1) as eluent. Yield: main dia-
stereomers 374 mg (47%, dr = 20:1). [α]2D0 = –7.9 (c = 6.4, CH2Cl2).
M.p. 80–83 °C. 1H NMR (CDCl3, 400 MHz, 25 °C): δ = 0.98 (d,
stereomer 165 mg (35%); minor diastereomer 33 mg (7%). [α]2D0
=
1
–6.1 (c = 15.0, CH2Cl2). H NMR (CDCl3, 400 MHz, 25 °C): δ =
1.43 (s, 9 H, 3 CH3), 3.24 (br. s, 1 H, 5-OH), 3.72–3.90 (m, 3 H, 4-
H, 5a-H, 5b-H), 3.82 (s, 3 H, OCH3), 4.30 (m, 1 H, 3-H), 5.06 (dd,
2
3J2-H,3-H = 3.0 Hz, J2-F,2-H = 48.0 Hz, 1 H, 2-H), 5.36 (d,
3J4-NH,4-H = 8.6 Hz, 1 H, NH) ppm. 13C NMR (CDCl3, 100 MHz,
25 °C): δ = 28.7, 28.7 (3 CH3), 53.1 (OCH3), 53.7 (C-4), 63.3 (C-
3
3J4Ј-H,4Ј-CH = 6.6 Hz, 3 H, 4Ј-CH3), 1.46 (d, J5-H,6-H = 6.6 Hz, 3
3
2
H, 6-CH3), 1.51, 1.56, 1.66 (3s, 9 H, 5 CCH3), 4.09–4.22 (m, 2 H,
3-H, 4-H), 4.31–4.40 (m, 1 H, 5-H), 4.62 (br. s, 1 H, OH), 4.77 (dq,
5), 70.7 (d, J2-F,C-3 = 19.1 Hz, C-3), 80.7 (Cq-Boc), 89.6 (d,
2
1J2-F,C-2 = 188.9 Hz, C-2), 157.0 (C=O-Boc), 168.6 (d, J2-F,C-1
=
3
3J4Ј-H,4Ј-CH = 6.6 Hz, J4Ј-H,5Ј-H = 6.8 Hz, 1 H, 4Ј-H), 5.76 (d,
24.6 Hz, C-1) ppm. 19F NMR (CDCl3, 565 MHz, 25 °C): δ =
–206.97 ppm. HRMS (ESI): calcd. for C11H20FNNaO6 [M +
Na]+ 304.1172; found 304.1177.
3
3J4Ј-H,5Ј-H = 6.8 Hz, 1 H, 5Ј-H), 6.10 (d, J2-F,2-H = 47.0 Hz, 1 H,
2
2-H), 7.27–7.31 (m, 2 H, Ar H), 7.35–7.45 (m, 3 H, Ar H) ppm.
13C NMR (CDCl3, 150 MHz, 25 °C): δ = 14.2 (4Ј-CH3), 15.0 (C-
6), 24.6, 26.7, 28.4 (5 CCH3), 55.7 (C-4Ј), 62.8 (C-4), 70.1 (d,
2J2-F,C-3=19.4 Hz,C-3),72.0(C-5),80.2(C-5Ј),81.4(Cq-Boc),89.9(d,
1J2-F,C-2 = 184.3 Hz, C-2), 93.4 (Cq-Isoprop), 125.6, 128.8, 129.0
(Ar H), 132.7 (Ar Cq), 152.59 (C-2Ј), 154.46 (C=O Boc), 167.3 (d,
2J2-F,C-1 = 24.5 Hz, C-1) ppm. 19F NMR (CDCl3, 565 MHz, 25 °C):
δ = –208.66 ppm. HRMS (ESI): calcd. for C24H33FN2NaO7 [M +
Na]+ 503.2170; found 503.2171.
Methyl (2S,3R,4S,5R)-4-[(tert-Butoxycarbonyl)amino]-2-fluoro-3,5-
dihydroxyhexanoate (14): Fluorohydrin 8 (200 mg, 0.42 mmol) in
dry MeOH (10 mL) was cooled to –30 °C and treated according to
Method B with NaOMe (11 mg, 0.20 mmol) and then with acidic
ion-exchange resin for 2 h. Purification by silica gel chromatog-
raphy was performed with T/EA (2:1) as eluent. Yield: 70 mg
(57%). [α]2D0 = –15.0 (c = 13.9, CH2Cl2). 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 1.23 (d, 3J5-H,6-H = 6.2 Hz, 3 H, 6-CH3), 1.44
(s, 9 H, 3 CCH3), 2.71 (br. s, 1 H, 5-OH), 3.42 (br. s, 1 H, 3-OH),
3.71 (m, 1 H, 4-H), 3.83 (s, 3 H, OCH3), 4.14 (m, 1 H, 5-H), 4.29
Methyl (2S,3R,4R)-4-[(tert-Butoxycarbonyl)amino]-2-fluoro-3,5-di-
hydroxypentanoate (11): Fluorohydrin 2 (486 mg, 1.04 mmol) in dry
MeOH (10 mL) was cooled to –25 °C and treated according to
Method B with NaOMe (23 mg, 0.42 mmol) and then with acidic
ion-exchange resin for 16 h. Purification by silica gel chromatog-
raphy was performed with HE/EA (1:2) as eluent. Yield: 121 mg
(41%). [α]2D0 = –17.2 (c = 4.7, CH2Cl2). M.p. 123–125 °C. 1H NMR
2
3
(m, 1 H, 3-H), 5.05 (dd, J2-F,2-H = 47.8 Hz, J2-H,3-H = 3.0 Hz, 1
H, 2-H), 5.24 (d, J4-NH,4-H = 9.60 Hz, 1 H, NH) ppm. 13C NMR
3
(CDCl3, 100 MHz, 25 °C): δ = 20.6 (C-6), 28.5 (3 CCH3), 52.9
2
(OCH3), 55.8 (C-4), 69.6 (C-5), 73.4 (d, J2-F,C-3 = 19.1 Hz, C-3),
80.1 (Cq-Boc), 89.3 (d, 1J2-F,C-2 = 188.9 Hz, C-2), 157.3 (C=O-Boc),
(CDCl3, 400 MHz, 25 °C): δ = 1.45 (s, 9 H, 3 CCH3), 3.78–3.88
2
168.3 (d, J2-F,C-1 = 23.8 Hz, C-1) ppm. 19F NMR (CDCl3,
3
(m, 2 H, 4-H, 5a-H), 3.85 (s, 3 H, OCH3), 4.06 (dd, J4-H,5b-H
=
565 MHz, 25 °C): δ = –207.49 ppm. HRMS (ESI): calcd. for
2
3.0 Hz, J5a-H,5b-H = 10.9 Hz, 1 H, 5b-H), 4.22 (m, 1 H, 3-H), 5.11
C12H22FNNaO6 [M + Na]+ 318.1329; found 318.1336.
3
2
(dd, J2-H,3-H = 1.8 Hz, J2-F,2-H = 47.5 Hz, 1 H, 2-H), 5.29 (br. s,
1 H, NH) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 28.3 (3 4-Acetamido-1-O-acetyl-2,4-dideoxy-2-fluoro-
D
-arabinose (15): Es-
2
CCH3), 52.5 (C-4), 52.7 (OCH3), 62.4 (C-5), 71.6 (d, J2-F,C-3
=
ter 11 (94 mg, 0.33 mmol) in dry THF (7 mL) was treated accord-
ing to Method C with DIBAL (2 mL, 2 mmol). Purification by sil-
ica gel chromatography was performed with EE/MeOH (99:1) as
1
19.8 Hz, C-3), 80.4 (Cq-Boc), 89.0 (d, J2-F,C-2 = 189.4 Hz, C-2),
156.0 (C=O Boc), 168.9 (d, J2-F,C-1 = 25.5 Hz, C-1) ppm. 19F
2
NMR (CDCl3, 565 MHz, 25 °C): δ = –208.49 ppm. HRMS (ESI): eluent. Yield: 52 mg (mixture of anomers: α/β = 1:1; 66%). 1H
calcd. for C11H20FNNaO6 [M + Na]+ 304.1172; found 304.1178.
NMR (MeOD, 400 MHz, 25 °C): α-anomer: δ = 2.01 (s, 3 H,
2456
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2451–2459

Synthetic Routes towards Fluorine-Containing Amino Sugars
2
3
2
NHAc), 2.13 (s, 3 H, OAc), 3.66 (ddd, J5a-H,5b-H = 12.3 Hz,
3.91 (ddd, 4J = 1.5 Hz, J4-H,5b-H = 5.5 Hz, J5a-H,5b-H = 11.4 Hz, 1
3J4-H,5a-H = 3.9 Hz, J = 1.5 Hz, 1 H, 5a-H), 3.92 (dd, 2J5a-H,5b-H
12.3 Hz, J4-H,5b-H = 2.8 Hz, 1 H, 5b-H), 4.19 (ddd, J2-F,3-H
=
=
H, 5b-H), 4.18 (m, 1 H, 4-H), 4.63 (ddd, J1-H,2-H = 3.9 Hz,
4
3
3J2-H,3-H = 9.3 Hz, J2-F,2-H = 48.5 Hz, 1 H, 2-H), 5.28 (ddd,
3
3
2
3
3
3
3
10.7 Hz, J2-H,3-H = 8.7 Hz, J3-H,4-H = 4.6 Hz, 1 H, 3-H), 4.33–
3J2-H,3-H = 9.3 Hz, J3-H,4-H = 10.4 Hz, J2-F,3-H = 11.3 Hz, 1 H, 3-
4.38 (m, 1 H, 4-H), 4.67 (ddd, 3J1-H,2-H = 3.4 Hz, 3J2-H,3-H = 8.7 Hz,
H), 5.93 (d, J4-NH,4-H = 7.7 Hz, 1 H, NH), 6.32 (dd, J2-F,1-H =
3
3
2J2-F,2-H = 48.2 Hz, 1 H, 2-H), 6.21 (dd, J1-H,2-H = 3.4 Hz, 1.3 Hz, J1-H,2-H = 3.9 Hz, 1 H, 1-H) ppm; β-anomer: δ = 1.95 (s,
3
3
3J2-F,1-H = 5.1 Hz, 1 H, 1-H) ppm; β-anomer: δ = 2.00 (s, 3 H,
3 H, NHAc), 2.12, 2.14 (2s, 6 H, 2 OAc), 3.38 (dd, J4-H,5a-H
8.4 Hz, J5a-H,5b-H = 11.8 Hz, 1 H, 5a-H), 4.13 (dd, J4-H,5b-H
=
=
3
2
2
3
NHAc), 2.11 (s, 3 H, OAc), 3.62 (dd, J5a-H,5b-H = 11.6 Hz,
3J4-H,5a-H = 3.0 Hz, 1 H, 5a-H), 3.87 (ddd, J = 0.8 Hz, J4-H,5b-H 4.7 Hz, J5a-H,5b-H = 11.8 Hz, 1 H, 5b-H), 4.18 (m, 1 H, 4-H), 4.43
4
3
2
2
3
3
3
2
= 5.7 Hz, J5a-H,5b-H = 11.6 Hz, 1 H, 5b-H), 4.05 (ddd, J2-F,3-H
=
(ddd, J1-H,2-H = 6.2 Hz, J2-H,3-H = 7.3 Hz, J2-F,2-H = 48.7 Hz, 1
3
3
11.8 Hz, J2-H,3-H = 6.8 Hz, J3-H,4-H = 4.6 Hz, 1 H, 3-H), 4.25–
H, 2-H), 5.08 (ddd, 3J2-H,3-H = 7.3 Hz, 3J3-H,4-H = 8.2 Hz, 3J2-F,3-H
=
4.30 (m, 1 H, 4-H), 4.51 (ddd, 3J1-H,2-H = 5.3 Hz, 3J2-H,3-H = 6.8 Hz,
12.6 Hz, 1 H, 3-H), 5.78 (dd, 3J2-F,1-H = 5.9 Hz, 3J1-H,2-H = 6.2 Hz, 1
2J2-F,2-H = 48.1 Hz, 1 H, 2-H), 5.74 (dd, J1-H,2-H = 5.3 Hz, H, 1-H), 6.08 (d, J4-NH,4-H = 8.5 Hz, 1 H, NH) ppm. 13C NMR
3
3
3J2-F,1-H = 7.1 Hz, 1 H, 1-H) ppm. 13C NMR (MeOD, 100 MHz,
(CDCl3, 150 MHz, 25 °C): α-anomer: δ = 20.8, 20.9 (2 OAc), 23.1
3
3
25 °C): α-anomer: δ = 21.1 (OAc), 22.9 (NHAc), 51.3 (d, J2-F,C-4 (NHAc), 49.5 (d, J2-F,C-4 = 5.8 Hz, C-4), 62.0 (C-5), 70.3 (d,
= 6.6 Hz, C-4), 64.8 (C-5), 67.9 (d, J2-F,C-3 = 20.5 Hz, C-3), 89.2 2J2-F,C-3 = 18.9 Hz, C-3), 86.2 (d, J2-F,C-2 = 193.0 Hz, C-2), 89.0
2
2
1
2
2
(d, J2-F,C-2 = 186.8 Hz, C-2), 91.5 (d, J2-F,C-1 = 20.7 Hz, C-1),
(d, J2-F,C-1 = 22.7 Hz, C-1), 168.9, 172.0 (2 CO OAc), 170.3 (CO
171.3 (CO OAc), 174.1 (CO NHAc) ppm; β-anomer: δ = 21.1 NHAc) ppm; β-anomer: δ = 20.8, 20.8 (2 OAc), 23.1 (NHAc), 48.4
3
3
2
(OAc), 23.0 (NHAc), 50.0 (d, J2-F,C-4 = 4.5 Hz, C-4), 64.3 (C-5),
(d, J2-F,C-4 = 4.4 Hz, C-4), 63.6 (C-5), 70.8 (d, J2-F,C-3 = 21.1 Hz,
69.6 (d, J2-F,C-3 = 22.2 Hz, C-3), 90.5 (d, J2-F,C-2 = 179.4 Hz, C- C-3), 86.9 (d, 1J2-F,C-2 = 186.5 Hz, C-2), 91.4 (d, 2J2-F,C-1 = 26.0 Hz,
2
1
2
2), 93.4 (d, J2-F,C-1 = 29.0 Hz, C-1), 171.3 (CO OAc), 174.4 (CO
NHAc) ppm. 19F NMR (MeOD, 565 MHz, 25 °C): δ = –201.19,
–208.69 ppm. HRMS (ESI): calcd. for C9H14FNNaO5 [M + Na]+
258.0754; found 258.0751.
C-1), 169.0, 171.0 (2 CO OAc), 170.3 (CO NHAc) ppm. 19F NMR
(CDCl3, 565 MHz, 25 °C): δ = –201.08, –197.06 ppm. HRMS
(ESI): calcd. for C11H16FNNaO6 [M + Na]+ 300.0859; found
300.0845.
4-Acetamido-1-O-acetyl-2,4,6-trideoxy-2-fluoro-
L
-galactose (16):
4-Acetamido-1,3-di-O-acetyl-2,4,6-trideoxy-2-fluoro-D-idose (18):
Ester 12 (69 mg, 0.23 mmol) in dry THF (5 mL) was treated ac-
cording to Method C with DIBAL (1.6 mL, 1.6 mmol). After final
workup, the crude product was stirred in methanolic solution at
room temperature for 1 h. Purification by silica gel chromatography
was performed with EE/HE (4:1) as eluent. Yield: 27 mg (mixture
Ester 14 (66 mg, 0.22 mmol) in dry THF (6 mL) was treated ac-
cording to Method C with DIBAL (1.4 mL, 1.4 mmol). The crude
amino sugar was then dissolved in dry DCM (5 mL) and treated
with Ac2O (40 μL, 0.42 mmol) at room temperature for 1 h. After
evaporation of the solvent, purification by silica gel chromatog-
raphy was performed with HE/EA (1:2) as eluent. Yield: 33 mg
(mixture of anomers: α/β = 2:3; 53%). 1H NMR (CDCl3, 600 MHz,
1
of anomers: α/β = 2:3; 47%). H NMR (MeOD, 600 MHz, 25 °C):
3
α-anomer: δ = 1.08 (d, J5-H,6-H = 6.4 Hz, 3 H, 6-CH3), 2.05 (s, 3
3
H, NHAc), 2.13 (s, 3 H, OAc), 4.21 (ddd, J3-H,4-H = 4.8 Hz, 25 °C): α-anomer: δ = 1.19 (d, 3J5-H,6-H = 6.5 Hz, 3 H, 6-CH3), 2.04
3
3J2-H,3-H = 10.2 Hz, J2-F,3-H = 12.7 Hz, 1 H, 3-H), 4.22 (dq,
(s, 3 H, NHAc), 2.11, 2.12 (2s, 6 H, 2 OAc), 4.15 (m, 1 H, 4-H),
3
3
3
3J4-H,5-H = 2.0 Hz, J5-H,6-H = 6.4 Hz, 1 H, 5-H), 4.40 (m, 1 H, 4- 4.43 (dq, J4-H,5-H = 2.1 Hz, J5-H,6-H = 6.5 Hz, 1 H, 5-H), 4.45–
3
3
2
H), 4.66 (ddd, J1-H,2-H = 4.2 Hz, J2-H,3-H = 10.2 Hz, J2-F,2-H
=
4.47, 4.52–4.54 (m, 1 H, 2-H), 5.01–5.04 (m, 1 H, 3-H), 5.92 (d,
48.6 Hz, 1 H, 2-H), 6.28 (d, J1-H,2-H = 4.2 Hz, 1 H, 1-H) ppm; β- 3J4-NH,4-H = 10.5 Hz, 1 H, NH), 6.15 (d, J2-F,1-H = 11.8 Hz, 1 H,
anomer: δ = 1.13 (d, J5-H,6-H = 6.4 Hz, 3 H, 6-CH3), 2.05 (s, 3 H,
NHAc), 2.12 (s, 3 H, OAc), 3.92 (dq, J4-H,5-H = 1.7 Hz, J5-H,6-H 2.03 (s, 3 H, NHAc), 2.13, 2.19 (2s, 6 H, 2 OAc), 4.15 (m, 1 H, 4-
= 6.4 Hz, 1 H, 5-H), 4.03 (ddd, J3-H,4-H = 5.1 Hz, J2-H,3-H
9.7 Hz, J2-F,3-H = 14.9 Hz, 1 H, 3-H), 4.33 (m, 1 H, 4-H), 4.45
(ddd, J1-H,2-H = 8.0 Hz, J2-H,3-H = 9.7 Hz, J2-F,2-H = 51.6 Hz, 1
3
3
3
3
1-H) ppm; β-anomer: δ = 1.24 (d, J5-H,6-H = 6.3 Hz, 3 H, 6-CH3),
3
3
3
3
=
H), 4.23 (dq, 3J4-H,5-H = 2.3 Hz, 3J5-H,6-H = 6.3 Hz, 1 H, 5-H), 4.50–
3
4.52, 4.58–4.60 (m, 1 H, 2-H), 5.19 (m, 1 H, 3-H), 5.91 (d,
3
3
2
3
3J2-F,1-H = 22.8 Hz, 1 H, 1-H), 6.01 (d, J4-NH,4-H = 9.2 Hz, 1 H,
3
3
H, 2-H), 5.64 (dd, J2-F,1-H = 4.4 Hz, J1-H,2-H = 8.0 Hz, 1 H, 1-H)
NH) ppm. 13C NMR (CDCl3, 150 MHz, 25 °C): α-anomer: δ =
ppm. 13C NMR (MeOD, 150 MHz, 25 °C): α-anomer: δ = 16.7 (C-
16.5 (C-6), 20.8, 21.0 (2 OAc), 23.3 (NHAc), 47.8 (C-4), 64.5 (C-
3
2
1
6), 20.7 (OAc), 22.5 (NHAc), 55.3 (d, J2-F,C-4 = 8.4 Hz, C-4), 68.4
(d, J2-F,C-3 = 17.9 Hz, C-3), 69.1 (C-5), 88.8 (d, J2-F,C-2
5), 67.1 (d, J2-F,C-3 = 27.7 Hz, C-3), 83.2 (d, J2-F,C-2 = 171.6 Hz,
2
1
2
=
C-2), 90.5 (d, J2-F,C-1 = 35.3 Hz, C-1), 168.6, 169.2 (2 CO OAc),
186.7 Hz, C-2), 90.8 (C-1), 171.0 (CO OAc), 174.7 (CO NHAc) 170.2 (CO NHAc) ppm; β-anomer: δ = 16.5 (C-6), 20.9, 21.0 (2
2
ppm; β-anomer: δ = 16.6 (C-6), 20.7 (OAc), 22.4 (NHAc), 55.1 (d,
OAc), 23.3 (NHAc), 47.9 (C-4), 68.8 (d, J2-F,C-3 = 25.8 Hz, C-3),
2
1
2
3J2-F,C-4 = 8.7 Hz, C-4), 71.7 (d, J2-F,C-3 = 17.6 Hz, C-3), 72.3 (C-
71.4 (C-5), 84.4 (d, J2-F,C-2 = 184.9 Hz, C-2), 90.4 (d, J2-F,C-1 =
1
2
5), 91.4 (d, J2-F,C-2 = 159.9 Hz, C-2), 93.5 (d, J2-F,C-1 = 25.0 Hz, 15.2 Hz, C-1), 168.8, 168.9 (2 CO OAc), 170.0 (CO NHAc) ppm.
C-1), 170.9 (CO OAc), 174.7 (CO NHAc) ppm. 19F NMR (CDCl3, 19F NMR (CDCl3, 565 MHz, 25 °C): δ = –190.05, –208.98 ppm.
565 MHz, 25 °C): δ = –208.92, –210.42 ppm. HRMS (ESI): calcd. HRMS (ESI): calcd. for C12H18FNNaO6 [M + Na]+ 314.1016;
for C10H16FNNaO5 [M + Na]+ 72.0912; found 272.0908.
found 314.0998.
4-Acetamido-1,3-di-O-acetyl-2,4-dideoxy-2-fluoro-D-xylose (17): Es- 4-Acetamido-2,4-dideoxy-2-fluoro-D-arabinose (19): Acetylated
ter 13 (88 mg, 0.31 mmol) in dry THF (7 mL) was treated accord-
ing to Method C with DIBAL (1.9 mL, 1.9 mmol). The crude
amino sugar was then dissolved in dry DCM (5 mL) and treated
with Ac2O (60 μL, 0.63 mmol) at room temperature for 1 h. After
evaporation of the solvent, purification by silica gel chromatog-
raphy was performed with HE/EA (1:4) as eluent. Yield: 49 mg
(mixture of anomers: α/β = 1:7; 56%). 1H NMR (CDCl3, 600 MHz,
25 °C): α-anomer: δ = 1.93 (s, 3 H, NHAc), 2.13, 2.15 (2s, 6 H, 2
OAc), 3.50 (dd, 2J5a-H,5b-H = 11.4, 3J4-H,5a-H = 11.3 Hz, 1 H, 5a-H),
sugar 15 (52 mg, 0.22 mmol) in dry MeOH (5 mL) was treated ac-
cording to Method D. Purification by silica gel chromatography
was performed with DCM/MeOH (9:1) as eluent. Yield: 38 mg
(mixture of anomers: α/β = 1:2; 89%). [α]2D8 = –66.8 (c = 14.0, H2O).
1H NMR (D2O, 600 MHz, 25 °C): α-anomer: δ = 2.06 (s, 3 H,
3
2
NHAc), 3.42 (ddd, 4J = 1.8 Hz, J4-H,5a-H = 4.5 Hz, J5a-H,5b-H
=
=
=
3
2
12.2 Hz, 1 H, 5a-H), 4.06 (dd, J4-H,5b-H = 3.0 Hz, J5a-H,5b-H
3
3
12.2 Hz, 1 H, 5b-H), 4.29 (ddd, J3-H,4-H = 4.4 Hz, J2-H,3-H
3
8.4 Hz, J2-F,3-H = 10.4 Hz, 1 H, 3-H), 4.35 (m, 1 H, 4-H), 4.62
Eur. J. Org. Chem. 2014, 2451–2459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2457

C. Albler, W. Schmid
FULL PAPER
3
3
2
2
(ddd, J1-H,2-H = 3.1 Hz, J2-H,3-H = 8.4 Hz, J2-F,2-H = 48.2 Hz, 1
2J2-F,C-3 = 18.7 Hz, C-3), 90.0 (d, J2-F,C-1 = 21.1 Hz, C-1), 90.6 (d,
3
3
H, 2-H), 5.39 (dd, J1-H,2-H = 3.1 Hz, J2-F,1-H = 6.3 Hz, 1 H, 1-H)
1J2-F,C-2 = 184.9 Hz, C-2), 174.6 (CO NHAc) ppm; β-anomer: δ =
3
3
ppm; β-anomer: δ = 2.08 (s, 3 H, NHAc), 3.75 (dd, J4-H,5a-H
=
21.9 (NHAc), 50.7 (d, J2-F,C-4 = 7.9 Hz, C-4), 63.3 (C-5), 71.5 (d,
2
4
1
2.2 Hz, J5a-H,5b-H = 12.7 Hz, 1 H, 5a-H), 3.87 (ddd, J = 1.5 Hz,
2J2-F,C-3 = 18.4 Hz, C-3), 93.3 (d, J2-F,C-2 = 182.6 Hz, C-2), 94.2
3J4-H,5b-H = 2.5 Hz, J5a-H,5b-H = 12.7 Hz, 1 H, 5b-H), 4.15 (ddd,
(d, J2-F,C-1 = 23.3 Hz, C-1), 174.7 (CO NHAc) ppm. 19F NMR
2
2
3J3-H,4-H = 4.9 Hz, J2-H,3-H = 9.2 Hz, J2-F,3-H = 14.0 Hz, 1 H, 3- (CDCl3, 565 MHz, 25 °C): δ = –199.71, –199.04 ppm. HRMS
3
3
3
3
2
H), 4.32 (ddd, J1-H,2-H = 7.2 Hz, J2-H,3-H = 9.2 Hz, J2-F,2-H
=
(ESI): calcd. for C7H12FNNaO4 [M + Na]+ 216.0648; found
50.5 Hz, 1 H, 2-H), 4.34 (m, 1 H, 4-H), 4.84 (dd, 3J2-F,1-H = 3.9 Hz, 216.0636.
3J1-H,2-H = 7.2 Hz, 1 H, 1-H) ppm. 13C NMR (D2O, 150 MHz,
4-Acetamido-2,4,6-trideoxy-2-fluoro-D-idose (22): Acetylated sugar
3
25 °C): α-anomer: δ = 21.9 (CH3), 49.1 (d, J2-F,C-4 = 4.8 Hz, C-4),
18 (19 mg, 0.07 mmol) in dry MeOH (2 mL) was treated according
to Method D. Yield: 13 mg (mixture of anomers: α/β = 1:2; 97%).
2
1
60.9 (C-5), 65.9 (d, J2-F,C-3 = 21.8 Hz, C-3), 88.7 (d, J2-F,C-2
=
2
185.1 Hz, C-2), 90.3 (d, J2-F,C-1 = 20.1 Hz, C-1), 174.6 (CO) ppm;
β-anomer: δ = 21.9 (CH3), 50.1 (d, 3J2-F,C-4 = 8.2 Hz, C-4), 64.5 (C-
5), 69.4 (d, 2J2-F,C-3 = 17.2 Hz, C-3), 91.9 (d, 1J2-F,C-2 = 177.1 Hz, C-
[α]2D0 = +18.3 (c = 5.9, H2O). H NMR (D2O, 600 MHz, 25 °C): α-
1
3
anomer: δ = 1.19 (d, J5-H,6-H = 6.9 Hz, 3 H, 6-CH3), 2.02 (s, 3 H,
NHAc), 3.95 (dd, 3J4-H,5-H = 4.4 Hz, 3J3-H,4-H = 7.3 Hz, 1 H, 4-H),
2
2), 94.2 (d, J2-F,C-1 = 24.1 Hz, C-1), 174.7 (CO) ppm. 19F NMR
4.02 (ddd, 3J2-H,3-H = 6.4 Hz, 3J3-H,4-H = 7.3 Hz, 3J2-F,3-H = 12.1 Hz,
(CDCl3, 565 MHz, 25 °C): δ = –207.10, –203.18 ppm. HRMS
(ESI): calcd. for C7H12FNNaO4 [M + Na]+ 216.0648; found
216.0644.
3
3
1 H, 3-H), 4.29 (ddd, J1-H,2-H = 5.0 Hz, J2-H,3-H = 6.4 Hz,
3
2J2-F,2-H = 48.7 Hz, 1 H, 2-H), 4.40 (dq, J4-H,5-H = 4.4 Hz,
3
3
3J5-H,6-H = 6.9 Hz, 1 H, 5-H), 5.17 (dd, J1-H,2-H = 5.0 Hz, J2-F,1-H
= 8.1 Hz, 1 H, 1-H) ppm; β-anomer: δ = 1.17 (d, 3J5-H,6-H = 6.6 Hz,
3 H, 6-CH3), 2.04 (s, 3 H, NHAc), 3.82 (dddd, 4J = 0.6 Hz,
4J2-F,4-H = 0.9 Hz, 3J4-H,5-H = 2.4 Hz, 3J3-H,4-H = 3.0 Hz, 1 H, 4-H),
4-Acetamido-2,4,6-trideoxy-2-fluoro-D-galactose (20): Acetylated
sugar 16 (20 mg, 0.08 mmol) in dry MeOH (mL) was treated ac-
cording to Method D. Yield: 16 mg (mixture of anomers: α/β = 1:2;
96%). [α]2D0 = –66.7 (c = 4.7, H2O). 1H NMR (D2O, 600 MHz,
25 °C): α-anomer: δ = 1.11 (d, 3J5-H,6-H = 6.5 Hz, 3 H, 6-CH3), 2.11
3
3
4.14 (ddd, 3J3-H,4-H = 3.0 Hz, J2-H,3-H = 3.4 Hz, J2-F,3-H = 6.7 Hz,
3
3
1 H, 3-H), 4.24 (dq, J4-H,5-H = 2.4 Hz, J5-H,6-H = 6.6 Hz, 1 H, 5-
3
3
3
4
3
(s, 3 H, NHAc), 4.30 (ddd, J3-H,4-H = 4.7 Hz, J2-H,3-H = 10.3 Hz,
H), 4.45 (dddd, J1-H,2-H = 1.0 Hz, J = 1.0 Hz, J2-H,3-H = 3.4 Hz,
3J2-F,3-H = 13.2 Hz, 1 H, 3-H), 4.35 (m, 1 H, 4-H), 4.42 (dq,
4
3
2J2-F,2-H = 46.0 Hz, 1 H, 2-H), 5.09 (ddd, J = 0.5 Hz, J1-H,2-H
=
3
3J4-H,5-H = 1.7 Hz, J5-H,6-H = 6.5 Hz, 1 H, 5-H), 4.58 (ddd,
1.0 Hz, J2-F,1-H = 23.2 Hz, 1 H, 1-H) ppm. 13C NMR (D2O,
3
3
2
3J1-H,2-H = 4.1 Hz, J2-H,3-H = 10.3 Hz, J2-F,2-H = 49.0 Hz, 1 H, 2-
150 MHz, 25 °C): α-anomer: δ = 13.9 (C-6), 21.7 (NHAc), 52.0 (d,
3
3J2-F,C-4 = 3.9 Hz, C-4), 65.5 (C-5), 67.2 (d, J2-F,C-3 = 21.5 Hz, C-
2
H), 5.44 (d, J1-H,2-H = 4.1 Hz, 1 H, 1-H) ppm; β-anomer: δ = 1.16
3
2
1
(d, J5-H,6-H = 6.4 Hz, 3 H, 6-CH3), 2.12 (s, 3 H, NHAc), 3.99 (dq,
3), 90.3 (d, J2-F,C-1 = 28.6 Hz, C-1), 90.9 (d, J2-F,C-2 = 177.1 Hz,
C-2), 174.4 (CO NHAc) ppm; β-anomer: δ = 15.8 (C-6), 21.7
3
3J4-H,5-H = 1.6 Hz, J5-H,6-H = 6.4 Hz, 1 H, 5-H), 4.14 (ddd,
3
3
3J3-H,4-H = 4.9 Hz, J2-H,3-H = 9.8 Hz, J2-F,3-H = 14.8 Hz, 1 H, 3-
2
(NHAc), 50.4 (C-4), 67.3 (d, J2-F,C-3 = 24.0 Hz, C-3), 68.9 (C-5),
3
3
2
1
2
H), 4.24 (ddd, J1-H,2-H = 7.8 Hz, J2-H,3-H = 9.8 Hz, J2-F,2-H
=
87.8 (d, J2-F,C-2 = 179.9 Hz, C-2), 91.2 (d, J2-F,C-1 = 15.9 Hz, C-
1), 174.3 (CO NHAc) ppm. 19F NMR (D2O, 565 MHz, 25 °C): δ
= –194.82, –211.86 ppm. HRMS (ESI): calcd. for C8H14FNNaO4
[M + Na]+ 230.0805; found 230.0796.
51.0 Hz, 1 H, 2-H), 4.31 (m, 1 H, 4-H), 4.86 (dd, 3J2-F,1-H = 3.6 Hz,
3J1-H,2-H = 7.8 Hz, 1 H, 1-H) ppm. 13C NMR (D2O, 150 MHz,
3
25 °C): α-anomer: δ = 15.4 (C-6), 21.8 (NHAc), 54.3 (d, J2-F,C-4
=
2
8.3 Hz, C-4), 65.0 (C-5), 66.7 (d, J2-F,C-3 = 17.9 Hz, C-3), 88.8 (d,
Supporting Information (see footnote on the first page of this arti-
1J2-F,C-2 = 183.3 Hz, C-2), 89.8 (d, J2-F,C-1 = 21.1 Hz, C-1), 175.5
2
cle): Copies of the H and 13C NMR spectra of all key intermedi-
1
(CO NHAc) ppm; β-anomer: δ = 15.4 (C-6), 21.8 (NHAc), 54.0 (d,
ates and final products.
3J2-F,C-4 = 8.8 Hz, C-4), 70.1 (d, J2-F,C-3 = 17.5 Hz, C-3), 70.1 (C-
2
1
2
5), 92.2 (d, J2-F,C-2 = 180.6 Hz, C-2), 93.9 (d, J2-F,C-1 = 23.6 Hz,
C-1), 175.5 (CO NHAc) ppm. 19F NMR (D2O, 565 MHz, 25 °C):
δ = –206.13, –206.34 ppm. HRMS (ESI): calcd. for C8H14FNNaO4
[M + Na]+ 230.0805; found 230.0804.
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4-Acetamido-2,4-dideoxy-2-fluoro-D-xylose (21): Acetylated sugar
17 (32 mg, 0.12 mmol) in dry MeOH (3 mL) was treated according
to Method D. Yield: 22 mg (mixture of anomers: α/β = 2:3; 100%).
[α]2D0 = –45.9 (c = 8.5, H2O). H NMR (D2O, 600 MHz, 25 °C): α-
1
anomer: δ = 1.94 (s, 3 H, NHAc), 3.59 (ddd, 4J = 1.8 Hz,
2
3J4-H,5a-H = 6.2 Hz, J5a-H,5b-H = 11.4 Hz, 1 H, 5a-H), 3.62 (dd,
2
3J4-H,5b-H = 10.1 Hz, J5a-H,5b-H = 11.4 Hz, 1 H, 5b-H), 3.86 (ddd,
3
3
3J4-H,5a-H = 6.2 Hz, J3-H,4-H = 9.9 Hz, J4-H,5b-H = 10.1 Hz, 1 H,
3
3
3
4-H), 3.94 (ddd, J2-H,3-H = 9.0 Hz, J3-H,4-H = 9.9 Hz, J2-F,3-H
=
12.4 Hz, 1 H, 3-H), 4.41 (ddd, 3J1-H,2-H = 3.7 Hz, 3J2-H,3-H = 9.0 Hz,
2J2-F,2-H = 48.9 Hz, 1 H, 2-H), 5.35 (d, J1-H,2-H = 3.7 Hz, 1 H, 1-
3
3
H) ppm; β-anomer: δ = 1.94 (s, 3 H, NHAc), 3.26 (dd, J4-H,5a-H
=
=
2
3
10.5 Hz, J5a-H,5b-H = 11.4 Hz, 1 H, 5a-H), 3.78 (ddd, J2-H,3-H
8.8 Hz, 3J3-H,4-H = 10.0 Hz, 3J2-F,3-H = 14.3 Hz, 1 H, 3-H), 3.83 (dd,
2
3J4-H,5b-H = 5.2 Hz, J5a-H,5b-H = 11.4 Hz, 1 H, 5b-H), 3.87 (ddd,
3
3
3J4-H,5b-H = 5.2 Hz, J3-H,4-H = 10.0 Hz, J4-H,5a-H = 10.5 Hz, 1 H,
3
3
2
4-H), 4.08 (ddd, J1-H,2-H = 7.8 Hz, J2-H,3-H = 8.8 Hz, J2-F,2-H
=
3
3
51.0 Hz, 1 H, 2-H), 4.75 (dd, J2-F,1-H = 2.8 Hz, J1-H,2-H = 7.8 Hz,
1 H, 1-H) ppm. 13C NMR (D2O, 150 MHz, 25 °C): α-anomer: δ =
3
21.9 (NHAc), 50.5 (d, J2-F,C-4 = 7.3 Hz, C-4), 59.1 (C-5), 68.4 (d,
2458
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