Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose

Article abstract of DOI:10.1021/acs.joc.9b00310

There is an increasing interest in investigating how polyfluorination of carbohydrates modifies their physical and biological properties. An example that has caught much attention is 2,3,4-trideoxy-2,3,4-trifluoroglucose. Four syntheses of this compound have been reported, which are either low yielding or long (13 or more steps). We report a 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose starting from levoglucosan. The solution-phase structure of an intermediate, 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose, features a rare example of a bifurcated F···H(O)···F hydrogen bond and is compared to its crystal structure.

Full text of DOI:10.1021/acs.joc.9b00310

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Note
A synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose
Lucas Quiquempoix, Zhong Wang, Jerome Graton, Peter G
Latchem, Mark Light, Jean-Yves Le Questel, and Bruno Linclau
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00310 • Publication Date (Web): 14 Mar 2019
Downloaded from http://pubs.acs.org on March 18, 2019
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A synthesis of 2,3,4-trideoxy-2,3,4-
trifluoroglucose
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Lucas Quiquempoix,a Zhong Wang,a Jérôme Graton,b Peter G. Latchema, Mark Light,a Jean-
Yves Le Questel,b and Bruno Linclaua*
a School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ,
United Kingdom.
b CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes
2, rue de la Houssinière – BP 92208, 44322 Nantes Cedex 3, France.
bruno.linclau@soton.ac.uk
RECEIVED DATE
TOC Graphic:
X-ray
O
O
OH
OH
H
4 steps
2 steps
O
O
O
F
F
F
OH
O
HO
OH
F
F
2,3,4-trideoxy-
2,3,4-trifluoroglucose
H
levoglucosan
dt
3JOH-H 12.4 Hz
h1
J
2.2 Hz
OH-F
ABSTRACT
There is an increasing interest in investigating how polyfluorination of carbohydrates
modifies their physical and biological properties. An example that has caught much attention
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is 2,3,4-trideoxy-2,3,4-trifluoroglucose. Four syntheses of this compound have been reported,
which are either low yielding, or long (13 or more steps). We report a 6-step synthesis of
2,3,4-trideoxy-2,3,4-trifluoroglucose starting from levoglucosan. The solution-phase structure
of an intermediate, 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose, features a rare example of a
bifurcated F···HO···F hydrogen bond, and is compared to its crystal structure.
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The synthesis of compounds containing multiple stereogenic CHF centers has become a topic
of great interest. Seminal work has emanated from the O’Hagan group, first with acyclic
multivicinal fluorinated alkane chains,1-2 later with cyclic examples with 1,2,3,4,5,6-
hexafluorinated cyclohexane as highlight.3-5 Next to alkane fluorination, investigations have
also focused on replacing multiple heteroatoms with fluorines. A notable example is the
synthesis of a polyfluorinated analogue of the natural product danicalipin A by the Carreira
group, in which the organochlorine groups were replaced by organofluorines.6 Carbohydrate
deoxyfluorination, in which alcohol groups are replaced by fluorines, is well-investigated.7-9
Starting from levoglucosan (1,6-anhydroglucose), the group of Cerny already produced
dideoxy-difluorinated carbohydrates in the early seventies.10-11 The first systematic biological
activity and anomeric reactivity studies of dideoxy-difluorinated carbohydrates were reported
by Withers et al.12,13 The first syntheses of 2,3,4-trideoxy-2,3,4-trifluorinated carbohydrate
derivatives (glucose and galactose) were reported by Lukacs in 1989,14 but it is again the
O’Hagan group who first synthesized, using a different synthetic strategy, fully deprotected
2,3,4-trideoxy-2,3,4-trifluoroglucose 1 (Chart 1).15-16 Very recently, Giguère et al published
an impressive synthetic effort achieving the synthesis of many 2,3,4-trifluorinated
carbohydrates, as well as a 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluorinated glycoside.17
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Investigations of how such fluorination motifs modify physical and biological properties of
carbohydrates are of great interest. In addition, deoxyfluorination of carbohydrates has great
potential for NMR-based investigations of protein-carbohydrate interactions.18-20 O’Hagan
showed that the exchange of 1 through erythrocyte membranes was slightly slower than that
of glucose15 (and much slower than the corresponding hexafluorinated analogue).21-22 We
have shown that the lipophilicity of 1 is about three orders of magnitude higher than that of
glucose.23 This was confirmed by the Giguere group,17 who additionally demonstrated the
influence of sugar trifluorination stereochemistry on the lipophilicity.
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OH
O
F
F
F
OH
1
Chart 1. 2,3,4-Trideoxy-2,3,4-trifluoroglucose 1.
The synthesis of polyfluorinated substrates is a challenging undertaking, especially towards
upscaling to produce sufficient quantities. Hence, improving the pioneering syntheses of key
molecules has been a focus. The original synthesis of all-cis 1,2,3,4,5,6-
hexafluorocyclohexane has been superseded by Glorius’ stereoselective reduction of
hexafluorobenzene.24 Instead of the original de novo approaches to 2,3,4-trideoxy-2,3,4-
trifluoroglucose 1,15-16 and based on the Lukacs synthesis of 1,6-di-O-acetyl-2,3,4-trideoxy-
2,3,4-trifluoroglucose 6 (Scheme 1),14 Giguère’s team achieved a scaleable synthesis of 1
(Scheme 1).17 In both cases, the 4-OH group of 3 was inverted after conversion to the
corresponding triflate, using NaOBz (Lukacs), and by a Lattrell-Dax reaction (Giguère), to
arrive at the corresponding difluorinated galactosan 4. The subsequent deoxyfluorination
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reaction was achieved by DAST (Lukacs) or by a 2-step fluoride displacement (Giguère).
Finally, acetolysis to cleave the 1,6-anhydrobridge and deprotection gave 1 in 13 overall
steps.
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Ac2O, H2SO4
(90%)
or
O
O
O
O
OR
3 steps
(Lukacs)
DAST (90 %)
or
OH
F
F
F
7
O
F
O
O
O
O
HO
F
steps
2 steps
(Giguère)
1) Tf2O
2) TBAF•3H2O
Ac2O, H2SO4
then NaOAc
(63%, 3 st)
F
OR
HO
OH
HO
F
F
F
F
6 R = Ac
1 R = H
NaOMe
(98%)
2
3
4
5a
Scheme 1. The Lukacs14/Giguere17 Synthesis of 1 Starting from Levoglucosan.
As part of a research programme investigating GLUT-1 mediated erythrocyte membrane
exchange of fluorinated carbohydrates,25 we required 1 in >100 mg quantities. However, in
our hands the DAST-mediated deoxyfluorination according to Lukacs14 led to an inseparable
mixture of trifluorinated levoglucosan 5a and levogalactosan 7 (Scheme 2), in a 7:3 ratio.
Slower addition of DAST at 0 °C did lead to a much improved 97:3 ratio, but in a much
lower 50% yield (not shown). Combined with the unattractive length of this synthesis,
investigations were subsequently initiated towards a shorter route for 1.
OH
OH
F
O
O
O
BCl3, CH2Cl2; H2O
(91%)
O
O
O
F
F
F
F
+
F
F
F
DAST
O
O
O
+
F
OH
F
OH
F
HO
(separable after
repeated
preparative HPLC)
O
CH2Cl2
0 °C to rt
(83%)
1
8
F
F
F
F
F
7
5a
9
F
4
(7 : 3)
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Scheme 2. Unselective Deoxyfluorination of 4. Thermal ellipsoids drawn at the 50%
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probability level.
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The formation of the galactose isomer can be understood by a 2-step mechanism in which
expulsion of the leaving group is aided by neighboring group participation of the endocyclic
oxygen to form an intermediate akin to 9. Subsequent fluoride attack then leads to the
formation of the C-4 stereocenter with retention of configuration. The participation of 1,6-
anhydrosugar endocyclic oxygens in nucleophilic substitution reactions has been investigated
by the group of Karban.26 We have not observed fluoride attack at C-5 leading to a ring-
contracted product, which is not unprecedented for retentive 4-OH deoxyfluorinations.26 For
such cases, the involvement of an SNi mechanism has also been suggested as a possible
explanation.26
Interestingly, the equivalent DAST-mediated deoxyfluorination of 1,6-anhydro-2,3-
difluorolevotalosan 10 (Scheme 3) was reported to occur with a clean retention of
configuration,17 despite the presence of the antiperiplanar C2–F bond with the endocyclic
oxygen. In such a case, this could be expected to cause a reduction of the oxygen
polarizability and thus its capacity for anchimeric assistance to form an epoxonium-like
intermediate 12. However, this reaction was conducted at 100 °C in a microwave oven which
may have forced this process to dominate.
O
O
O
F
DAST
F
F
O
O
HO
F
F
F
O
F
(>77%)
F
10
12
11
Scheme 3. Deoxyfluorination of 1,6-Anhydro-2,3-dideoxy-2,3-difluorotalose 10.17
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To open the 1,6-anhydrobridge, the mixture of 5a and 7 was treated with BCl3. To our
delight, this conversion proceeds in excellent yield to give a mixture of the target compound
1 and 2,3,4-trideoxy-2,3,4-trifluorogalactose 8. These are separable albeit only via multiple
preparative HPLC runs. Recrystallisation of each pyranose followed by X-ray analysis
allowed unambiguous confirmation of their relative stereochemistry, and the structure of 1,
also reported by O’Hagan (CSD code: CUTVIX),15 is shown side-by-side to the novel
structure of 8.
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In designing a new, shorter synthesis which also would circumvent unselective
deoxyfluorination, we were attracted by a publication from Pacak et al, who reported that
treatment of 13 (Scheme 4a),27-28 with KHF2 in ethylene glycol leads to the difluorinated 14a
as the only isolable product in 5% yield (not shown).10-11 Pleasingly, optimization of this
reaction, which involved the addition of KF and working under more concentrated
conditions, improved this to a 54% yield of 14a on multigram scale. Lower yields were
obtained under rigorous exclusion of moisture.
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(a)
O
O
KHF2, KF,
ethylene glycol
OH
O
O
170 °C, 2 h
(4 g, 54%)
O
OTs
13
F
F
14a
KHF2,
O
O
(b) Barford (ref 29):
OH
OH
ethylene glycol
O
O
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200 °C
(47%)
TsO
OH
F
OH
16
15
O
O
(c)
KHF2, KF
ethylene glycol
OH
OH
(Giguère (ref 17):
KHF2, TBAF•3H2O
60% (multigram)
O
O
170 °C, 2 h
(>8 g, 55%)
TsO
OTs
F
F
17
14a
(d) Retentive deoxyfluorination examples:
X
Y
O
O
b
c
OBn N3 (78-88%)
(refs 30,31)
F
OH
DAST
O
O
OBn
F
(86%)
(refs 14,17, 32)
(86%)(ref 32)
X
Y
X
Y
d
e
f
OBn
H
5b-f
14b-f
14a
N3 OTs (72%) (ref 33)
OBn(67%) (ref 34)
F
(e)
DAST
no reaction
for X,Y = F
5a
Scheme 4. Synthesis of the 2,4-Dideoxy-2,4-difluorolevoglucosan 14a, and its Unsuccessful
Deoxyfluorination to 5a.
Then, inspired by a report by Barford et al,29 who achieved fluoride introduction starting
from tosylate 15 by in-situ epoxide formation under essentially the same conditions (Scheme
4b), this process was successfully repeated from known ditosylate 17 (Scheme 4c), which
was obtained from levoglucosan 2 in 82% yield (not shown),27-28 to give 14a in 55% yield.
While this manuscript was in preparation, this remarkable transformation was reported by
Giguère,17 who used 8 equiv of TBAF•3H2O as the extra fluoride source, in neat conditions
at 180 °C, to obtain a slightly higher yield of 60% (multigram scale).
Finally, the plan called for direct deoxyfluorination of 14a to give the desired 5a.
Deoxyfluorination of 3-OH groups of 1,6-anhydroglucose derivatives with retention of
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configuration is well-precedented (cf examples 14b-f, Scheme 4d),14, 17, 30-34 which has been
also been explained by neighboring group participation, now with a suitable group at the C-2
or C-4 position. This mechanism is not expected to take place with antiperiplanar fluorine
substituents; however, should an SNi mechanism take place, the retentive deoxyfluorination
of 14a may be successful. Unfortunately, we have not been able to find conditions to form 5a
in this way (Scheme 4e), with 19F NMR analysis indicating that the 3-OH group does not
react with DAST.
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Hence, it was decided to first effect 3-OH inversion (Scheme 5). Oxidation of 14a gave a
mixture of the ketone 18 and its hydrate 20, which was immediately followed by borohydride
reduction. While reduction of the corresponding (nonfluorinated) 2,4-dideoxy pyranulose 19
under similar conditions resulted in an 56:44 ratio of equatorial/axial attack,35 reduction of 18
gave predominantly the desired axial attack to give the levoallosan derivative 21. Axial attack
is sterically hindered by the anhydro bridge, but for 18, borohydride attack is also hindered
by the two axial fluorine groups. Unsurprisingly, reaction with the bulky L-selectride, which
selectively reduces cyclohexanones with an axial a-fluorine through axial attack,36 was
extremely sluggish. With NaBH4 in Et2O, the reaction was not fully selective, and 4-15% of
levoglucosan 14a was formed (not shown). This was separable from 21, but given 14a does
not react under deoxyfluorination conditions, separation is not necessary at this stage.
However, reduction with NaBH4 in EtOH37 did lead to virtually complete selectivity, leading
to 21 in excellent yield. DAST mediated deoxyfluorination of 21 only led to trace amounts of
5a, while fluoride substitution of triflate 22a with Et3N•3HF also did not lead to appreciable
conversions. Pleasingly, successful conversion to give 5a was achieved with the use of
nonafluorobutyl sulfonyl fluoride (NfF)38 in the presence of Et3N•3HF as external fluoride
source, which proceeds via the corresponding nonaflate 22b. Given the volatility of 5a, for
which a crystal structure could be obtained, this reaction required execution in a sealed tube.
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Finally, BCl3-mediated opening of the 1,6-anhydro bridge gave the desired 1 in excellent
5
6
yield.
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O
O
OH
O
O
Tf2O
(65%)
O
O
Et3N•3HF
OH
F
F
O
OH
O
OH
F
OR
BCl3;
H2O
O
NaBH4
EtOH
OH
F
F
O
F
22a R = Tf
F
TCCA
20
+
O
OH
22b R = Nf
O
TEMPO
CH2Cl2
F
F
F
F
F
21 (>99% de)
(85%, 2 steps)
F
F
5a (69%)
O
1 (87%)
NfF, Et3N,
Et3N•3HF, THF
90 °C, 4d
14a
O
X
X
18 (X = F)
19 (X = H)
Nf = F9C4SO2
Scheme 5. Successful Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose 1. Thermal
Ellipsoids Drawn at the 50% Probability Level. One out of 4 Conformations Shown for 21.
The 1H NMR spectrum of 21 (CDCl3) displays a very defined doublets of triplets for the
alcohol group (Figure 1). Fluorine decoupling simplifies the signal to a 12.4 Hz doublet (3JH3-
OH), a magnitude consistent with an antiperiplanar alignment, and the triplet was assigned as
h1
J
couplings to F-2 and F-4, each measuring ±2.2 Hz. Hence, this indicates that in
OH∙∙∙F
solution, the O–H bond is positioned in between the two C–F bonds, with hydrogen bonding
to the fluorine atoms, possibly as a so-called “bifurcated hydrogen bond”. While it has been
calculated that there is no enthalpic advantage to form such a three-center interaction, it has
been suggested that this type of interaction ‘would become favorable if both acceptors
occurred in the same molecule, and were rigidly held in the proper arrangement’.39 Density
Functional Theory calculations (IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in
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chloroform, see Supporting Information) showed this conformation as the only one being
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6
populated (99%), with two OH!F distances (values around 2.45 Å) shorter than the sum of
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9
the H and F van der Waals radii (2.57 Å), and typical of hydrogen-bond interaction. The
interaction energies (E(2)n®s*) computed from NBO analysis40 indicated very weak charge
transfers (0.67 and 0.63 kJ mol-1) from the fluorine atoms lone pairs to the hydroxyl
antibonding orbital, in line with values previously encountered in such OH!F interactions.41
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In addition, calculation of coupling constants within this IMHB conformer lead to 3JH,OH
value of 13.5 Hz, and two h1JOH∙∙∙F values of -1.6 Hz and -1.4 Hz, close to the experimental
values (12.4 Hz and ±2.2 Hz), whereas the non-IMHB conformers exhibit couplings very far
from the experimental data. To the best of our knowledge, there are very few examples
involving an alcohol (phenol) donor and two C–F acceptors, either intermolecular (syn-2,4-
difluoroadamantane),42 or intramolecular (eg 2-(trifluoromethyl)phenol).43 We believe there
also is only one example of a 5-membered h1JOH∙∙∙F coupling in the literature (4.6 Hz),
reported by Bernet also on a 1,6-anhydrosugar derivative.44
Figure 1. Coupling Constants of the Alcohol Hydrogen Before and After Fluorine
Decoupling.
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The weak OH•••F hydrogen bond45-47does not play an important role in the overall
combination of interactions that determine crystal packings. The known crystal structure of
14a (CSD code ADFGLP) has attracted interest in that its crystal packing does not include
any intermolecular hydrogen bonding between the alcohol group and the fluorine atoms,
despite the availability of two C–F acceptors in a small molecule.48 In this context, we were
delighted to be able to obtain single crystals of 21 (Scheme 5). Its unit cell is quite complex,
containing 8 independent molecules, which differ in their OH orientation, including
structures with either an antiperiplanar (as shown in Scheme 5) or a synperiplanar orientation
between the O-H and alcohol C-H bonds. Like in 14a, the packing is clearly dominated by
intermolecular hydrogen bonding in which two different chains can be distinguished (see
Supporting Information for details), and not by intramolecular OH•••F hydrogen bonding.
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In conclusion, we have achieved a short, 6-step synthesis of 2,3,4-trideoxy-2,3,4-
trifluoroglucose 1 from levoglucosan in 24% overall yield. The key transformations involved
a selective difluorination of 2,4-di-O-tosyl levoglucosan 17, and the deoxyfluorination of 2,4-
dideoxy-2,4-difluorolevoallosan 21. A rare F•••OH•••F bifurcated hydrogen bond was
observed in solution for 21, but although this particular conformation was also present in the
crystalline state, the crystal packing of this compound is clearly dominated by intermolecular
O–H•••O hydrogen bonding.
EXPERIMENTAL SECTION
Computational details. To provide further evidence of the occurrence of a bifurcated
hydrogen-bond in 21, Density Functional Theory calculations have been performed by using
the A.03 version of the Gaussian 16 program.49 Following the methodology used in our
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previous work on the levoglucosan series,41 the geometries of the various structures have been
optimized at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in chloroform.
Frequency calculation of the various energetic minima were then carried out at the same level
of theory, allowing the calculations of the corresponding Gibbs free energies, and of the
Boltzmann distribution.
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IMHB interactions were analyzed through AIM topological analysis of the IEF-PCM/B97-
D3BJ/6-311++G(2d,p) wavefunctions with the AIM2000 program.50 The complementary
contribution of charge transfer between the acceptor lone pair(s) electrons and the s* donor
antibonding orbital was estimated through natural bond orbital (NBO) analyses.40 The NBO
method was applied at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level in CHCl3 to provide the
corresponding interaction energies (E(2)n®s*) evaluated from second-order perturbation theory,
using the NBO 6.0 program.51
The spin–spin coupling constants (J) were then estimated from the previous optimized
geometries by using the gauge-invariant atomic orbital (GIAO) method. The hybrid B97–2
functional and the pcJ-2 basis set, specifically designed for the calculation of these NMR
parameters,52 were used.
General synthesis conditions. All air/ moisture sensitive reactions were carried out under an
inert atmosphere (Ar), in dried glassware. Dry CH2Cl2, THF, MeOH and hexane were bought
from commercial suppliers, and used as received. TLC was performed on aluminium-
precoated plates coated with silica gel 60 with an F254 indicator; visualised under UV light
(254 nm) and/or by staining with KMnO4 (10% aq.). Flash column chromatography was
performed with Sigma Aldrich 60 silica gel (40-63 micron). Preparative HPLC was carried
out using a Biorad Bio-Sil D 90-10 column (250 × 22 mm at 15 mL min-1). High-resolution
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MS samples were analysed using a MaXis (Bruker Daltonics, Bremen, Germany) mass
spectrometer equipped with a Time of Flight (TOF) analyser. Samples were introduced to the
mass spectrometer via a Dionex Ultimate 3000 autosampler and uHPLC pump, and eluted in
five minutes at 0.6 mL min using a gradient 20% acetonitrile (0.2% formic acid) to 100%
acetonitrile (0.2% formic acid) through an Acquity UPLC BEH C18 (Waters) 1.7 micron 50
´ 2.1mm column. High resolution mass spectra were recorded using positive ion electrospray
ionisation. 1H-, 19F- and 13C-NMR spectra were recorded at room temperature on a Bruker
Ultrashield 400 MHz or 500 MHz spectrometer. 1H and 13C chemical shifts (δ) are quoted in
ppm relative to residual solvent peaks as appropriate. 19F spectra were externally referenced
to CFCl3. The coupling constants (J) are given in Hertz (Hz). The NMR signals were
designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sxt
(sextet), spt (septet), m (multiplet), or a combination of the above. For all compounds,
detailed peak assignment was performed through the combined use of HSQC and COSY
NMR experiments.
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-1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose 5a and 1,6-anhydro-2,3,4-trideoxy-2,3,4-
trifluorogalactose 7 from 4 (Scheme 2).
To a solution of 1,6-anhydro-2,3-dideoxy-2,3-difluorogalactose 414, 17 (100 mg, 0.60 mmol)
in dry CH2Cl2 (2.3 mL) at 0 °C was added DAST (0.24 mL, 1.96 mmol) dropwise. The
resulting mixture was stirred at rt under argon for 24 h until TLC indicated full consumption
of the starting material. The reaction mixture was quenched by carefully adding sat. aq.
NaHCO3 (5 mL) at 0 °C, and the resulting aqueous layer was extracted with CH2Cl2 (3 ´ 10
mL). The combined organic layers were combined, dried over MgSO4, filtered, and the
solvent slowly evaporated under controlled reduced pressure (600 mbar). Purification by
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column chromatography (pentane/CH2Cl2 80:20 to 50:60) afforded 92 mg (0.50 mmol, 83%)
of an inseparable mixture of diastereoisomers trifluoro levoglucosan 5a and levogalactosan 7
(dr 69:31) as a white solid. Selected data: 1H NMR (400 MHz, CDCl3) δ 5.62 (1H, br. s,
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H
1(Glc)), 5.54 (1H, m, J = 5.1, 1.5 Hz is observed, H1(Gal)), 5.02 (1H, m, J 47.7 Hz is observed,
H3(Gal)), 4.93–4.59 (5H, m), 4.57 (1H, m, J 44.7, 14.9, 1.5 Hz is observed, H4(Glc)), 4.43 (1H,
m, J 45.5, 14.9, 1.5 Hz is observed, H2(Glc)), 4.34 (1H, br. d, J 8.1 Hz, H6endo(Gal)), 3.96 (1H,
br. dd, J 8.1, 1.0 Hz, H6endo(Glc)), 3.74–3.89 (2H, m, H6exo(Glc,Gal)) ppm; 19F NMR (376 MHz,
CDCl3) δ -188.0 (m, J 45.1, 15.6, 12.1, 3.5 Hz is observed, F4(Glc)), -191.1 (dquin, J 41.6, 13.8
Hz, F3(Glc)), -193.6 (m, J 45.1, 3.5 Hz is observed, F2(Glc)), -195.5 (ddd, J 44.6, 16.0, 8.7 Hz,
F4(Gal)), -208.8 (m, J 46.8, 24.3, 15.6 Hz is observed, F3(Gal)), -209.0 (br. d, J 43.4 Hz, F2(Gal)
)
ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -188.0 (d, J 12.1 Hz, F4(Glc)), -191.1 (t, J 12.1 Hz,
F3(Glc)), -193.6 (d, J 12.1 Hz, F2(Glc)), -195.5 (d, J 15.6 Hz, F4(Gal)), -208.8 (dd, J 15.6, 3.5 Hz,
F3(Gal)), -209.0 (d, J 5.2 Hz, F2(Gal)) ppm.
-2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 and 2,3,4-trideoxy-2,3,4-trifluoro-D-
galactopyranose 8 from the mixture of 5a and 7 (Scheme 2).
To a solution of the mixture of 5a/7 (89 mg, 0.53 mmol) in CH2Cl2 (3.6 mL) at 0 °C was
added BCl3 (1 M in CH2Cl2, 2.2 mL, 2.2 mmol) dropwise. The resulting mixture was stirred
at rt for 2 h before being quenched with water (5 mL). The organic solvent was then removed
under reduced pressure and the resulting aqueous phase was stirred for an additional 1 h at rt.
The remaining water was evaporated to give a brown dense oil, which was then purified by
column chromatography (pentane/acetone 90:10 to 60:40) to afford 90 mg (0.48 mmol, 91%)
of a “pure” mixture of 1 and 8. Complete separation of the two diastereoisomers could be
achieved via repeated HPLC separations (pentane/acetone 70:30).
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Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-glucopyranose 1 (white solid): Rf 0.12
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a
(pentane/EtOAc 60:40); Mp 98-100 °C (CHCl3/acetone), lit 103-105 °C (CHCl3); [ ]D
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+28.0 for α/β 0.30:1.00 (c 0.99, CD3OD, 21 °C), lit15 +40.1 for α/β 1:0.98 (c 1.15, THF-d8, 22
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°C); IR (neat) 3367 (m, br.), 3111 (m, br.), 2961 (m), 1032 (s), 995 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.49 (1H, br. q, J = 3.1 Hz, H1α), 5.09 (1H, ddddd, J = 55.0, 16.6, 14.0, 8.4,
7.9 Hz, H3α), 4.92 (1H, br. dd, J = 7.6, 3.0 Hz, H1β), 4.82 (1H, dddt, 53.1, 16.5, 15.9, 8.3 Hz,
H3β), 4.66 (1H, m, a doublet with J = 50.4 Hz can observed, H4β), 4.64 (1H, dddd J = 50.9,
15.1, 9.9, 8.3 Hz, H4α), 4.53 (1H, dddd, J = 49.8, 12.9, 8.9, 3.9 Hz, H2α), 4.35 (1H, dddd, J =
50.9, 14.5, 8.1, 7.6 Hz, H2β), 4.13 (1H, ddq, J = 9.8, 4.4, 2.5 Hz, H5α), 4.03–3.73 (4H, m,
H6,6’α + H6,6’β), 3.63–3.57 (1H, m, H5β), 3.34 (1H, br. s, OH1α), 1.84 (1H, br. s, OH6α) ppm;
1H{19F} NMR (500 MHz, CDCl3) δ 5.49 (1H, br. d, J = 3.6 Hz, H1α), 5.09 (1H, t, J = 8.5 Hz,
H3α), 4.92 (1H, d, J = 7.7 Hz, H1β), 4.82 (1H, t, J = 8.3 Hz, H3β), 4.67 (1H, dd, J = 9.8, 8.3
Hz, H4β), 4.64 (1H, dd, J = 9.3, 8.3 Hz, H4α), 4.53 (1H, dd, J = 8.8, 3.8 Hz, H2α), 4.35 (1H,
dd, J = 8.3, 7.7 Hz, H2β), 4.13 (1H, ddd, J = 9.9, 4.2, 2.4 Hz, H5α), 4.03–3.74 (4H, m, H6,6’α
+
H6,6’β), 3.60 (1H, ddd, J = 9.8, 4.7, 2.4 Hz, H5β), 3.34 (1H, br. s, OH1α), 1.84 (1H, br. s, OH6α)
ppm; 19F NMR (471 MHz, CDCl3) δ -195.1– -195.4 (m, a doublet of quintets with J = 53.2,
13.6 Hz is observed, F3β), -199.3– -199.6 (m, a doublet of triplets with J = 50.9, 14.4 Hz is
observed, F2α or F4α), -200.0 (dddt, J = 50.9, 15.9, 13.0, 2.9 Hz, F2β or F4β), -200.6– -200.9
(m, a doublet of triplets with J = 50.7, 14.5 Hz is observed, F2β or F4β), -201.0– -201.30 (m, a
doublet of quintets with J = 54.9, 13.5 Hz is observed, F3α), -201.5 (dtd, J = 49.9, 13.6, 2.0
Hz, F2α or F4α) ppm; 19F{1H} NMR (471 MHz, CDCl3) δ -195.3 (t, J = 12.9 Hz, F3β), -199.4
(dd, J = 12.9, 2.1 Hz, F2α or F4α), -200.0 (dd, J = 13.6, 2.9 Hz, F2β or F4β), -200.8 (dd, J =
12.5, 2.5 Hz, F2β or F4β), -201.1 (t, J = 12.9 Hz, F2α or F4α), -201.5 (dd, J = 12.9, 2.1 Hz, F2α
or F4α) ppm. The spectral dispersion in CD3OD is superior: 1H NMR (500 MHz, CD3OD) δ
5.33 (1H, q, J = 3.5 Hz, H1α), 4.97 (1H, dddt, J = 56.0, 17.0, 13.8, 8.6 Hz, H3α), 4.88 (1H,
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dddt, J = 54.3, 16.8, 15.9, 8.4 Hz, H3β), 4.82 (1H, dd, J = 7.7, 2.8 Hz, H1β), 4.68–4.49 (2H, m,
H4α + H4β), 4.49 (1H, ddddd, J = 50.4, 13.2, 8.9, 3.8, 0.4 Hz, H2α), 4.21 (1H, ddt, J = 51.5,
15.1, 8.3 Hz, H2β), 4.02–3.96 (1H, m, H5α), 3.84 (1H, dq, J = 12.4, 2.0 Hz, H6β), 3.78 (1H, dq,
J = 12.4, 2.0 Hz, H6α), 3.73 (1H, ddd, J = 12.4, 4.1, 1.8 Hz, H6’α), 3.70 (1H, ddd, J = 12.4,
4.7, 2.0 Hz, H6’β), 3.62–3.56 (1H, m, H5β) ppm; 1H{19F} NMR (500 MHz, CD3OD) δ 5.33
(1H, d, J = 3.8 Hz, H1α), 4.96 (1H, br. t, J = 8.4 Hz, H3α), 4.88 (1H, t, J = 8.4 Hz, H3β), 4.82
(1H, d, J = 7.7 Hz, H1β), 4.59 (1H, dd, J = 9.8, 8.3 Hz, H4β), 4.58 (1H, dd, J = 9.9, 8.2 Hz,
H4α), 4.49 (1H, dd, J = 9.0, 3.8 Hz, H2α), 4.21 (1H, t, J = 8.1 Hz, H2β), 3.99 (1H, br. ddd, J =
9.8, 4.1, 2.3 Hz, H5α), 3.84 (1H, dd, J = 12.4, 2.1 Hz, H6β), 3.79 (1H, dd, J = 12.4, 2.1 Hz,
H6α), 3.73 (1H, dd, J = 12.4, 4.1 Hz, H6’α), 3.70 (1H, dd, J = 12.4, 4.7 Hz, H6’β), 3.59 (1H,
ddd, J = 9.8, 4.7, 2.1 Hz, H5β) ppm; 19F NMR (471 MHz, CD3OD) δ -196.9– -197.2 (m, a
doublet of quintets with J = 54.4, 13.6 Hz is observed, F3β), -200.7– -201.0 (m, a doublet of
triplets with J = 51.5, 14.3 Hz is observed, F2α or F4α), -201.7 (dddt, J = 51.5, 15.7, 12.9, 2.9
Hz, F2β or F4β), -202.4– -202.8 (2F, m, F3α and F2β or F4β), -203.1 (dtd, J = 50.0, 13.6, 2.1 Hz,
F2α or F4α) ppm.; 19F{1H} NMR (471 MHz, CD3OD) δ -197.1 (t, J = 12.9 Hz, F3β), -200.9
(dd, J = 12.2, 2.1 Hz, F2α or F4α), -201.7 (dd, J = 12.9, 2.9 Hz, F2β or F4β), -202.6 (dd, J =
12.2, 2.9 Hz, F2β or F4β), -202.7 (t, J = 12.9 Hz, F3α), -203.1 (dd, J = 12.9, 2.1 Hz, F2α or F4α)
ppm. To obtain a 13C NMR spectrum with all carbon atoms clearly visible, acetone-d6 was
used as solvent (due to the low solubility of 1 in CDCl3, we did not obtain a high-quality
spectrum): 13C{1H} NMR (101 MHz, acetone-d6) δ 93.7 (ddd, J = 22.7, 10.3, 1.5 Hz, C1β),
92.7 (dt, J = 185.6, 19.8 Hz, C3β), 91.2 (ddd, J = 187.8, 17.6, 8.1 Hz, C2β), 91.1 (ddd, J =
185.6, 20.5, 19.8 Hz, C3α), 90.0 (dd, J = 21.3, 10.3 Hz, C1α), 88.0 (ddd, J = 189.3, 14.7, 8.1
Hz, C2α), 86.9 (ddd, J = 184.1, 17.6, 8.1 Hz, C4β), 86.9 (ddd, J = 182.7, 18.3, 7.3 Hz, C4α),
72.6 (dd, J = 23.5, 5.9 Hz, C5β), 68.6 (dd, J = 23.5, 5.9 Hz, C5α), 60.0 (s, C6β), 59.9 (s, C6α)
ppm; HRMS (ESI-) for C6H8F3O3 [M-H]- Calcd. 185.0426, Found. 185.0435. The literature
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NMR data are reported in CDCl3 (1H NMR without J values); otherwise the data above are
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Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-galactopyranose 8 (while solid): Rf 0.12
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(pentane/EtOAc 60:40); Mp 114-116 °C (CHCl3/acetone); [ ]D +62.4 for (c 0.21, CD3OD,
21 °C; sample equilibrated for 48h, α/β 1.00:0.64 at time of measurement), lit17 +58.9 for (c
0.6, MeOH, 25 °C); IR (neat) 3362 (w, br.), 3134 (w, br.), 2961 (w), 1159 (m), 1059 (s) cm-1;
1H NMR (500 MHz, acetone-d6) δ 6.46 (1H, br. d, J = 7.2 Hz, OH1β), 6.28 (1H, br. d, J = 4.5
Hz, OH1α), 5.47 (1H, q, J = 4.4 Hz, H1α), 5.18 (1H, ddddd, J = 51.4, 7.6, 3.7, 3.0, 0.7 Hz,
H4α), 5.19–5.04 (1H, m, H4β), 5.13–4.87 (3H, m, H3α + H3β + H1β), 4.86–4.70 (1H, m, a
doublet with J = 51.2 Hz is observed, H2α), 4.47 (1H, ddddd, J = 52.6, 13.2, 9.1, 7.7, 1.2 Hz,
H2β), 4.22–4.11 (2H, m, OH6β + H5α), 4.11 (1H, dd, J = 6.5, 5.1 Hz, OH6α), 3.78 (1H, dddd, J
= 27.0, 7.5, 5.4, 1.8 Hz, H5β), 3.73–3.61 (4H, m, H6,6’α + H6,6’β) ppm; 1H{19F} NMR (500
MHz, acetone-d6) δ 6.46 (1H, d, J = 7.1 Hz, OH1β), 6.28 (1H, br. dd, J = 4.5, 0.6 Hz, OH1α),
5.47 (1H, t, J = 4.2 Hz, H1α), 5.18 (1H, br. d, J = 3.0 Hz, H4α), 5.11 (1H, br. d, J = 3.4 Hz,
H4β), 5.08 (1H, dd, J = 9.5, 2.9 Hz, H3α), 4.97 (1H, dd, J = 9.2, 3.2 Hz, H3β), 4.88 (1H, t, J =
7.4 Hz, H1β), 4.78 (1H, br. dd, J = 9.6, 3.8 Hz, H2α), 4.47 (1H, dd, J = 9.2, 7.7 Hz, H2β), 4.19
(1H, br. dd, J = 6.1, 5.4 Hz, OH6β), 4.16 (1H, br. t, J = 6.9 Hz, H5α), 4.10 (1H, dd, J = 6.4, 5.1
Hz, OH6α), 3.78 (1H, dd, J = 7.7, 6.0 Hz, H5β), 3.75–3.61 (4H, m, H6,6’α + H6,6’β) ppm;
13C{1H} NMR (101 MHz, acetone-d6) δ 94.1 (dd, J = 22.7, 10.3 Hz, C1β), 90.9 (dd, J =
184.9, 18.3 Hz, C2β), 90.5 (dd, J = 20.5, 9.5 Hz, C1α), 89.8 (ddd, J = 188.5, 19.1, 17.6 Hz,
C3β), 87.9 (ddd, J = 181.2, 16.1, 8.8 Hz, C4α), 87.4 (ddd, J = 187.8, 19.1, 17.6 Hz, C3α), 87.1
(ddd, J = 181.9, 16.1, 8.8 Hz, C4β), 87.0 (ddd, J = 187.8, 17.6, 2.2 Hz, C2α), 72.6 (dd, J =
17.6, 5.1 Hz, C5β), 68.7 (ddd, J = 19.1, 3.7, 1.5 Hz, C5α), 59.3 – 59.0 (m, C6α + C6β) ppm; 19F
NMR (471 MHz, acetone-d6) δ -202.7 (dqd, J = 47.7, 14.1, 6.4 Hz, F3β), -207.7 (dtt, J = 52.2,
13.8, 3.6 Hz, F2β or F4β), -207.9 – -208.1 (m, a doublet with J = 48.6 Hz is observed, F3α), -
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208.7 (dddd, J = 51.5, 13.6, 12.2, 3.6 Hz, F2α or F4α), -219.5– -219.8 (m, a doublet of triplets
of doublets with J = 51.0, 26.5, 15.7 Hz is observed, F2β or F4β), -222.3– -222.6 (m, a doublet
of triplets of doublets with J = 52.2, 28.6, 15.1 Hz is observed, F2α or F4α) ppm; 19F{1H}
NMR (471 MHz, acetone-d6) δ -202.7 (dd, J = 15.0, 13.6 Hz, F3β), -207.7 (d, J = 14.3 Hz, F2β
or F4β), -208.0 (dd, J = 15.0, 13.6 Hz, F3α), -208.7 (d, J = 13.6 Hz, F2α or F4α), -219.7 (d, J =
15.0 Hz, F2β or F4β), -222.5 (d, J = 15.0 Hz, F2α or F4α) ppm. NMR data match those
previously reported.17
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-1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 13 (Scheme 4).
To a solution of 1327-28 (4.04 g, 13.5 mmol) in ethylene glycol (34 mL) were added KHF2
(6.34 g, 81.2 mmol) and KF (4.72 g, 81.4 mmol). The resulting mixture was stirred for 2 h in
a setup let open to the air at 170 °C before being allowed to cool down and loaded onto a
silica gel column (CHCl3/acetone 70:30), which afforded pure 2,4-difluoro levoglucosan 14a
(1.21 g, 7.29 mmol, 54%) as slightly orange crystals. Rf 0.38 (petroleum ether/acetone
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70:30). Mp 96-98 °C (chloroform/acetone), lit 99-100 °C (no solvent given); [ ]D -63.0 (c
0.82, water, 21 °C), lit11 -62 (c 0.82, water, 20 °C); IR (neat) 3454 (w, br.), 2961 (w), 1038
(s), 1016 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.61 (1H, br. dt, J = 3.8, 1.4 Hz, H1), 4.78
(1H, br. ddq, J = 12.9, 5.7, 1.3 Hz, H5), 4.45 (1H, m, J = 46.4 Hz is observed, H4), 4.30 (1H,
br. dquin, J = 46.4, 1.3 Hz, H2), 4.11 (1H, m, J = 18.0 Hz can be extracted, H3), 4.04 (1H, dt,
J = 7.8, 0.9 Hz, H6endo), 3.80 (1H, m, H6exo), 2.30 (1H, br. d, J = 6.1 Hz, OH3) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 99.3 (d, J = 28.6 Hz, C1), 89.9 (dd, J = 181.9, 5.1 Hz, C4), 88.0
(dd, J = 184.1, 4.4 Hz, C2), 74.3 (d, J = 22.7 Hz, C5), 69.5 (dd, J = 29.3, 27.9 Hz, C3), 64.7
(d, J = 9.5 Hz, C6) ppm; 19F NMR (471 MHz, CDCl3) δ -183.3 (m, J = 46.3, 17.3, 12.8, 4.1,
0.9 Hz, F4), -188.4 (ddd, J = 46.5, 18.4, 3.9 Hz, F2) ppm; 19F{1H} NMR (471 MHz, CDCl3) δ
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-183.3 (s, F4), -188.4 (s, F2) ppm; HRMS (CI) for C6H9F2O3 [M+H]+ Calcd. 167.05143,
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Found 167.05391. NMR data match those previously reported.17
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-1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 17 (Scheme 4).
Following the same procedure as described just above, 2,4-di-O-tosyl levoglucosan 1727-28
(8.36 g, 17.8 mmol) was converted into 2,4-difluoro levoglucosan 14a (1.51 g, 9.09 mmol,
55%), obtained pure as a white solid after column chromatography (CH2Cl2/EtOAc 60:40).
-1,6-Anhydro-2,4-dideoxy-2,4-difluoroallose 21 (Scheme 5).
To a round-bottom flask were added 2,4-difluoro levoglucosan 14a (790 mg, 4.76 mmol) and
anhydrous CH2Cl2 (78.3 mL). The resulting solution was cooled to 0 °C, followed by the
addition of TCCA (2.19 g, 9.42 mmol) and TEMPO (40 mg, 0.256 mmol). The reaction
mixture was stirred at room temperature for 2 h, and monitored by TLC analysis. Upon
completion, the mixture was filtered over Celite, dried over Na2SO4 and concentrated under
reduced pressure. The crude mixture was eluted over a pad of silica gel (acetone/CH2Cl2
10/90-20/80) to afford a mixture of the 3-uloside 18 and its hydrate form 20. Following a
modified literature procedure,37 this mixture (~4.76 mmol) was dissolved in EtOH (reagent
grade, 25 mL), followed by slow addition of a solution of NaBH4 (540 mg, 14.27 mmol) in
EtOH (25 mL). The reaction mixture was stirred at room temperature for 2 h, and then
monitored by 19F{1H} NMR analysis. Upon completion, acetic acid (1 mL) was slowly added
to the reaction mixture, and the solvent was then removed by evaporation under reduced
pressure. The residue was diluted with water (100 mL), and extracted with EtOAc (100 mL ×
7). The combined organic layer was dried over Na2SO4, filtered and concentrated. 19F{1H}
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NMR analysis of the crude mixture indicated that reduction of the ketone was highly
diastereoselective (de »99%, see Supporting Information). The crude mixture was purified by
flash chromatography (acetone/CH2Cl2 10/90) to afford the desired product 21 (670 mg, 4.03
mmol, 85%) as a white solid. An analytical sample of pure 21 was obtained by HPLC
(CH2Cl2/EtOAc 70:30), as a white solid. Rf 0.70 (CH2Cl2/acetone 70:30); Mp 108-110 °C
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(hexane/CH2Cl2), lit 113-115 °C (EtOAc); [ ]D -69.0 (c 1.06, MeOH, 24 °C), lit -85 (c
0.6, CHCl3, 23-25 °C); IR (neat) 3265 (m, br.), 2989 (w), 2915 (w), 1339 (m), 1033 (s) cm-1;
1H NMR (500 MHz, CDCl3) δ 5.67 (1H, br. t, J =2.1 Hz, H1), 4.90–4.83 (1H, m, H5), 4.68
(1H, m, J =48.5 Hz is observed, H4), 4.57 (1H, m, J =49.8 Hz is observed, H2), 3.92–3.75
(1H, m, H6exo), 3.84 (1H, m, J = 12.4, 4.2 Hz is observed, H3), 3.72 (1H, br. dt, J =8.4, 1.1
Hz, H6endo), 2.73 (1H, dt, J = 12.4, 2.3 Hz, OH3) ppm; 1H{19F} NMR (500 MHz, CDCl3) δ
5.67 (1H, d, J = 2.6 Hz, H1), 4.87 (1H, m, H5), 4.68 (1H, br. t, J = 3.4 Hz, H4), 4.57 (1H, ddd,
J = 4.1, 2.8, 1.1 Hz, H2), 3.84 (1H, dt, J = 12.1, 4.1 Hz, H3), 3.83 (1H, dd, J = 8.6, 5.6 Hz,
H6exo), 3.72 (1H, dd, J = 8.4, 1.0 Hz, H6endo), 2.73 (1H, d, J = 12.4 Hz, OH3) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 98.5 (d, J = 24.2 Hz, C1), 88.0 (d, J = 184.9 Hz, C2), 86.5 (d, J =
184.9 Hz, C4), 73.6 (d, J = 19.1 Hz, C5), 63.7 (d, J = 6.6 Hz, C6), 62.8 (t, J = 18.3 Hz, C3)
ppm; 19F NMR (471 MHz, CDCl3) δ -204.8 (m, F4), -207.0 (br. dddt, J = 49.9, 25.6, 8.9, 2.3
Hz, F2) ppm; 19F{1H} NMR (471 MHz, CDCl3) δ -204.8 (d, J = 9.3 Hz, F4), -207.0 (d, J = 9.3
Hz, F2) ppm; HRMS (CI) for C6H9F2O3 [M+H]+ Calcd. 167.05143, Found 167.05425.
- 1,6-Anhydro-3-O-trifluoromethanesulfonyl-2,4-dideoxy-2,4-difluoroallose 22a (Scheme 5).
To a solution of a 8:92 mixture of 14a/21 (205 mg, 1.23 mmol, 1.13 mmol of 21) in dry
CH2Cl2 (3.2 mL) at 0 °C was added pyridine (0.12 mL, 1.48 mmol). Stirring was continued at
0 °C for 10 min before Tf2O (0.21 mL, 1.26 mmol) was added. The resulting mixture was
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allowed to warm to rt and stirred for an additional hour before being filtered through a pad of
silica. Solvent was removed under vacuum and the resulting orange oil purified by column
chromatography (hexane/CH2Cl2 80:20 to 60:40) which afforded 218 mg (0.73 mmol, 65%)
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of compound 22a as a white solid. Rf 0.24 (pentane/ CH2Cl2 50:50). Mp 108-110 °C
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(pentane/CH2Cl2); [ ]D -50.2 (c 0.52, CHCl3, 22 °C); H NMR (500 MHz, CDCl3) δ 5.71
(1H, br. t, J 2.2 Hz, H1), 4.95–4.91 (1H, m, H5), 4.90 (1H, m, J 24.3, 3.9 Hz is observed, H3),
4.87 (1H, m, J 50.9 Hz is observed, H4), 4.75 (1H, m, J 50.3 Hz is observed, H2), 3.88 (1H,
m, J 8.6, 5.1, 2.2 Hz is observed, H6exo), 3.80 (1H, br. dt, J 8.9, 1.0 Hz, H6endo) ppm; 1H{19F}
NMR (500 MHz, CDCl3) δ 5.71 (1H, d, J 2.8 Hz, H1), 4.94 (1H, br. dd, J 4.8, 2.7 Hz, H5),
4.90 (1H, t, J 3.8 Hz, H3), 4.88–4.84 (1H, m, H4), 4.76 (1H, m, J 3.9, 2.6, 1.4 Hz is observed,
H2), 3.88 (1H, dd, J 8.8, 5.6 Hz, H6exo), 3.80 (1H, dd, J 8.8, 0.9 Hz, H6endo) ppm; 13C{1H)
NMR (101 MHz, CDCl3) δ 118.3 (q, J 319.1 Hz, CF3), 98.4 (d, J 23.5 Hz, C1), 85.6 (d, J
195.1 Hz, C4), 84.3 (d, J 197.3 Hz, C2), 75.7 (t, J 16.9 Hz, C3), 73.9 (d, J 19.1 Hz, C5), 63.7
(d, J 5.9 Hz, C6) ppm. 19F NMR (376 MHz, CDCl3) δ -75.04 (s, CF3), -202.1– -202.5 (m), -
204.2 (ddd, J 50.3, 24.3, 10.4 Hz) ppm; 19F{1H} NMR (376 MHz, CDCl3) δ -75.0 (s, CF3), -
202.3 (d, J 10.4 Hz), -204.2 (d, J 10.4 Hz) ppm; HRMS (CI) for C7H8F5O5S [M+H]+ Calcd.
299.00071, Found 299.00012.
-1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose 5a from 21 (Scheme 5).
To a solution of 21 containing 4% of 14a (335 mg, 2.02 mmol, 1.94 mmol of 21) in
anhydrous THF (5.7 mL) in a sealed tube reactor was added triethylamine (1.62 mL, 11.6
mmol, 5.8 equiv), Et3N•3HF (0.63 mL, 3.86 mmol), and NfF (0.65 mL, 3.92 mmol). The
resulting mixture was stirred at 90 °C for 4 days before being quenched with sat. aq. NaHCO3
(17 mL). The layers were separated and the aqueous phase was diluted with water (20 mL) to
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dissolve the large amount of salts formed during quenching, and extracted with CH2Cl2 (3 ´
50 mL). The organic phases were combined, dried over MgSO4, and concentrated under
vacuum. Purification by column chromatography (pentane/DCM 90:10 to 50:50) afforded 5a
(222 mg, 1.34 mmol, 69%) as a white solid, as well as unreacted 14a (10 mg). Rf 0.64
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(pentane/EtOAc 80:20); Mp 66-68 °C (hexane/CH2Cl2); [ ]D -53.8 (c 1.30, CHCl3, 24 °C),
lit14 -56.0 (c 1.32, CHCl3, 22 °C); 1H NMR (400 MHz, CDCl3) δ 5.62 (1H, br. s, H1), 4.85–
4.78 (1H, m, H5), 4.83 (1H, dtquin, J = 42.5, 15.2, 1.7 Hz, H3), 4.57 (1H, ddd, J = 44.7, 14.9,
1.2 Hz, H4), 4.43 (1H, ddd, J = 45.5, 15.2, 1.2 Hz, H2), 3.97 (1H, dd, J = 8.1, 1.0 Hz, H6endo),
3.90–3.78 (1H, m, H6exo) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 98.6 (dd, J = 28.6, 2.2
Hz, C1), 87.2 (dt, J = 178.3, 33.7 Hz, C3), 86.4 (ddd, J = 182.7, 31.5, 4.4 Hz, C4), 84.5 (ddd, J
= 182.7, 27.9, 3.7 Hz, C2), 73.5 (dd, J = 21.6, 1.8 Hz, C5), 64.1 (dd, J = 9.2, 2.6 Hz, C6) ppm;
19F NMR (376 MHz, CDCl3) δ -188.0 (ddtd, J = 44.8, 15.7, 10.9, 4.3 Hz, F4), -191.1 (dquin,
J = 42.4, 14.1 Hz, F3), -193.6 (m, J = 45.1 Hz is observed, F2) ppm; 19F{1H} NMR (376
MHz, CDCl3) δ -188.0 (d, J = 12.1 Hz, F4), -191.1 (t, J = 12.1 Hz, F3), -193.6 (1F, d, J = 12.1
Hz, F2) ppm. 13C NMR matches the literature data (pyridine d5).14
-2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 from pure 5a (Scheme 5).
To a solution of trifluoro levoglucosan 5a (124 mg, 0.74 mmol) in CH2Cl2 (5.1 mL) at 0 °C
was added BCl3 (1 M in CH2Cl2, 3.1 mL, 3.1 mmol) dropwise. The resulting mixture was
stirred at rt for 2 h before being quenched with water (7 mL). DCM was then removed under
reduced pressure and the resulting aqueous phase was stirred for an additional 1 h at rt. The
remaining water was evaporated to give a brown dense oil, which was then purified by
column chromatography (pentane/acetone 90:10 to 60:40) to afford 119 mg of
trifluoroglucose 1 (0.64 mmol, 87%) as a dense clear oil which solidified upon standing.
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Supporting Information: Copies of NMR spectra, ratio determination for the DAST
reaction of 4 and reduction of 18, tables with the relative Gibbs energy and populations of the
energetic minima of 21 and discussion about the coupling constant analysis, CIF files and X-
ray data of compounds 1, 5a, 8, and 21, and crystal packing discussion for 14a and 21. This
material is available free of charge via the Internet at http://pubs.acs.org/. The raw NMR data
files are available free of charge at http://dx.doi.org/xxxxxxxxxxxxxxx
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Corresponding Author: *E-mail: bruno.linclau@soton.ac.uk
Acknowledgements: We thank the University of Southampton, the Leverhulme Trust (grant
RPG-2015-211), and the European Community (INTERREG IVa Channel Programme,
IS:CE-Chem, project 4061) for funding, and the EPSRC for a core capability grant
(EP/K039466/1). The CCIPL (Centre de Calcul Intensif des Pays de Loire) also is
acknowledged for provision of computer time. Prof Philip Kuchel and Dr Dmitry Shishmarev
are acknowledged for stimulating discussions.
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