Enantioselective synthesis of tetrafluorinated ribose and fructose

Article abstract of DOI:10.1039/b817260a

A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.

Full text of DOI:10.1039/b817260a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective synthesis of tetrafluorinated ribose and fructose†
Bruno Linclau,*a A. James Boydell,‡a Roxana S. Timofte,§a Kylie J. Brown,a Victoria Vinaderb and
Alexander C. Weymouth-Wilsonc
Received 3rd October 2008, Accepted 4th November 2008
First published as an Advance Article on the web 12th January 2009
DOI: 10.1039/b817260a
A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a
tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in
the pyranose form, is described.
Introduction
Carbohydrates are central to a multitude of critical biological
functions.1 Glycosylation of proteins impacts on both stability
and folding, and can have a critical contribution to the activity
of the conjugate.2 In addition, glycosylation of natural prod-
ucts can significantly influence their biological activity.3 Hence,
Fig. 1 Perfluoroalkylidene containing monosaccharides.
the investigation of carbohydrate-based therapeutics is of great
interest.4 It is remarkable that typical experimental values for
erythrocyte membrane at a rate approximately 10 times higher
associated dissociation constants of monosaccharides for protein
than glucose itself, and it was demonstrated that this rate increase
receptors are usually only in the millimolar to micromolar range.
was due to enhanced affinity to the transporter protein (and not
The energetics of protein–carbohydrate interactions are complex,
because of simple membrane diffusion originated from increased
not least because of the highly participatory nature of the aqueous
lipophilicity).
solvent.5 In general, polar interactions are thought to be largely
The modulation of carbohydrate ligand affinities by polyflu-
responsible for the binding specificity and desolvation of non-
orination is very interesting and of great potential impact in
polar surface areas (the “hydrophobic effect”) for binding affinity.6
glycobiology and drug-development. Hence, further studies in
A strategy to enhance binding affinities consists of exploiting
this area require reliable and short synthetic approaches to a
this hydrophobic effect. By increasing the hydrophobic surface of
wide range of polyfluorinated carbohydrates and carbohydrate
a (non-sugar derived) carbonic anhydrase inhibitor, Whitesides
precursors.
et al. observed increased binding constants.7 It was noted that
In this respect, we have developed an efficient perfluoroalkyli-
compared to a hydrocarbon chain, a perfluorocarbon chain of
dene lithium mediated cyclisation process to obtain tetrafluo-
rinated carbohydrates. The synthesis of the ribose derivative 2
(Fig. 1), which upon deprotection leads to 6, starting from the
identical length exhibited a larger effect, which was attributed
to the larger hydrophobic surface to be desolvated. In pio-
neering work, DiMagno et al. introduced the concept of “po-
commercially available building block 8 (see below) has been
lar hydrophobicity”.8 By extensive replacement of carbohydrate
communicated,10a as has the synthesis of tetrafluorinated glucose
CHOH groups by CF2 groups, binding was expected to be
and galactose, which commenced from a different building block
enhanced due to the hydrophobic effect. Furthermore, favourable
(not shown).10b We now report in full the synthesis of the other
electrostatic interactions involving the polarised C–F bond with
prototypical cyclisation precursors that can be obtained from
cationic or dipolar sites in the receptor would be possible,9 with
building block 8. In a significant expansion in scope for the
cyclisation process, it was shown that the synthesis of ketosugars,
in both the furanose and pyranose forms, is also possible in high
such interactions being negligible in an aqueous medium. It was
shown that the hexafluorinated pyranose 1 (Fig. 1) crosses the
yield. Overall, starting from a single building block 8, a short,
aSchool of Chemistry, University of Southampton, Highfield, Southampton,
UK. E-mail: bruno.linclau@soton.ac.uk; Fax: 0044 (0)23 8059 6805;
Tel: 0044 (0)23 8059 3816
high-yielding access to a range of tetrafluorinated carbohydrates
2–7 is possible. In addition, a full account is provided of the
enantioselective dihydroxylation of 8, and of two complementary
selective protection methods of the resulting diol.
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, UK SG1 2NY
cDextra Laboratories Ltd. (Summit Corporation plc.), The Science and
Technology Centre, Whiteknights Road, Reading, UK RG6 6BZ
† Electronic supplementary information (ESI) available: Determination of
the ee of the SAD of8, confirmation of the ee of 11 and 20, crystal structures
of 2 and 22, HMBC spectra of 2, 5, 6, 7, 1H, 13C and 19F NMR spectra of
2–7, 9–11, 20, 22, 24, 25, 27, 30, 32–34. See DOI: 10.1039/b817260a
Results and discussion
Synthetic plan
‡ Current address: Dextra Laboratories Ltd. (Summit Corporation plc.),
The Science and Technology Centre, Whiteknights Road, Reading, UK
RG6 6BZ.
It was realised from the outset that versatile synthetic methodology
to access tetrafluorinated monosaccharides would have to fulfil
several conditions. First of all, selective and controlled access to the
§ Current address: KemoTech S.r.l., Via Mancinelli, 7, 20131 Milan, Italy.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 803
©

View Article Online
appropriately protected furanose and pyranose forms is required,
with the anomeric position available for further transformation.
Ideally, in a polysaccharide synthesis setting, choice over the
required protecting group(s) is necessary. The introduction of
the fluorine atoms would need to be convenient, and a crucial
requirement was that both enantiomeric forms would have to be
obtainable.
Though the conversion of a ketone to a CF2-group is well-
known, the transformation of an aliphatic 1,2-diketone to a
tetrafluoroethylene group was reported to be low-yielding.11 This
had led us to pursue a fluorinated building block approach,12 with
the introduction of chirality controlled by a catalytic enantiose-
lective reaction.
desired monosaccharides 2–5. To the best of our knowledge, such
an intramolecular CF2–C bond formation process was unknown
at the outset of this work.
Perfluoroalkyllithium species, known to be stable only at very
low temperatures, are prone to fluoride elimination to give the
corresponding trifluorovinyl derivative (see below). Hence, a
crucial issue in this plan was how the relative rate of this unwanted
elimination process compared to the rate of the desired cyclisation
reaction in the formation of both the 5- and the 6-membered ring
using different acceptor groups.
The Sharpless asymmetric dihydroxylation
Hence, it was envisioned (Scheme 1) that a Sharpless asymmetric
dihydroxylation (SAD) reaction13 of the commercially available 8,
followed by selective conversion to monoprotected derivatives 10
or 11, would give rise to the required chiral precursors to synthesise
aldopentoses and ketohexoses in both the furanose and pyranose
forms, with the perfluoroalkyl bromide group as a handle for a one-
or two-carbon chain extension. The required C–C bond formation
was planned via a Br–Li exchange reaction, followed by in situ
trapping with an appropriate ester electrophile (a formate and
acetate ester moiety, as a 1C and a 2C fragment respectively). In
order to minimise protecting group manipulations, it was decided
to investigate an intramolecular version, where the ester moiety
would be introduced prior to lithiation. Hence, this would lead to
12 or 13, with subsequent cyclitive C–C bond formation to give the
Literature precedents of SAD reactions on perfluoroalkyl-
substituted terminal alkenes showed only moderate enantio-
selectivities.14 For example, SAD of 3,3,3-trifluoropropene with
(DHQD)2PHAL 14 (Fig. 2) as ligand, only returns the corre-
sponding diol in 63% ee.15a With ligand 16, an ee of 81% was
obtained.15b SAD of CF3(CF2)5CH CH2 with 14 and 16 gave the
=
corresponding diols in 12% and 45% ee, but with 18, an ee of
68% was obtained.15c,d Hence, the standard PHAL-based ligands
appear not ideal for this type of substrate.
Our investigation of the SAD of 8 (Table 1) commenced by
evaluating the commercially available AD-mix. Using a typical
quantity (1.4 g mmol-1, equal to 0.4 mol% OsO4 and 1 mol%
15), the yield of 9 was low even after stirring for 1 week, which
reflects the unreactive nature of the electron poor double bond
Table 1 The Sharpless asymmetric dihydroxylation of 8
Entry
Ligand
Ligand (mol%)
OsO4 (mol%)
Time (d)
Yield (%)a
ee 9 (%)b
1c
2d
3d
4d
5d
6d
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2AQN
(DHQ)2PYR
(DHQ)2PYR
(DHQD)2PYR
2.0
2.0
2.0
2.0
10e
2.0
0.8
2.0
2.0
2.0
2.0
2.0
18
7
7
9
9
74
98
76
93
96
90f
50
54
56
78
81
83g
9
a Isolated yield. b Determined via chiral GC as the bis-acetate (see ESI†). c Commercial AD-mix, double amount. d In-house prepared AD-mix.
e Heterogeneous reaction mixture. f Ent-9. g Determined via chiral HPLC as the bis-benzoate (see ESI†).
Scheme 1 Synthetic plan.
804 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Fig. 2 Ligands used in the Sharpless asymmetric dihydroxylation reaction
based on the phthalazine (PHAL), anthraquinone (AQN) and pyrimidine
(PYR) spacer. DHQ = dihydroquinine, DHQD = dihydroquinidine.
towards dihydroxylation. For unreactive double bonds, an increase
in OsO4-loading is recommended. The reaction rate can also be
enhanced by maintaining a high pH of the reaction mixture, either
by external titration16 or by using NaClO2 as oxidant,17 but these
conditions have not been investigated by us. Hence, by doubling
the amount of AD-mix, a 74% yield was obtained after 18 days,
albeit the ee was low (50%, entry 1). A further improvement was
made, in terms of yield, with an in-house AD-mix formulation
consisting of 2 mol% of OsO4 and ligand, where 98% yield was
obtained after 7 days (entry 2). However, the ee remained low
(54%), and other ligands were screened, in otherwise identical
formulations and concentrations. With 17, only a 56% ee was
obtained (entry 3), but with 19, a much improved ee of 78%
was achieved (entry 4). In accord with empirical findings that the
pseudo-enantiomeric DHQD-based ligands typically afford higher
enantioselectivities, a slightly higher ee (83%, entry 6) was obtained
with (DHQD)2PYR under otherwise identical conditions. So far,
a 1 : 1 osmium : ligand molar ratio was applied, and next it was
investigated whether a higher ee could be obtained by increasing
the ligand concentration. While maintaining a 2 mol% of OsO4,
a 5 : 1 Os : ligand ratio was tried. This led to a heterogeneous
reaction mixture, from which the diol 9 was isolated in 81% ee
(entry 5). It was not attempted to dilute the reaction mixture as
this would increase the already long reaction time. Unfortunately,
attempts to improve the ee of the diol by recrystallisation of the
crystalline 1-benzyl and 1-(2-naphthylmethyl) derivatives 10 and
20 (Fig. 3) proved to be fruitless.
Scheme 2 Ester formation with (S)-Naproxen: confirmation of the
absolute configuration and resolution.
relative stereochemistry and confirmed that the stereoselection in
the Sharpless asymmetric dihydroxylation reaction occurred as
expected.
The crystallisation of the major diastereomer of the Naproxen
ester was possible on a large scale, and was exploited to obtain
enantiopure material by subsequent saponification. This resulted
in enantiopure 10 (Scheme 2).
The monofunctionalisation
Selective protection of the primary alcohol group of perfluoroalkyl
substituted terminal 1,2-diols as an ester19a–c or silyl ether19c–d
is known. Interestingly, under thermodynamically controlled
basic conditions, selective protection of the b-hydroxyl group is
observed, even with internal 1,2-diol moieties.19c,20 Hence, reaction
with TBDMSCl (Scheme 3) in DCM19c led to 24 in good yield.
However, the use of imidazole in DMF as solvent only gave 24
in 42% yield, with 7% of the corresponding secondary silyl ether
isolated as well. Selective protection as pivaloate 25 also proceeded
in good yield.
Fig. 3 Crystalline derivatives of the diol 9.
For the up-scaling, a method to recycle the expensive
(DHQ)2PYR was desirable, which was achieved by a modified
Sharpless protocol18 by extraction with aq. HCl (2 M), neutralisa-
tion of the acidic aqueous phase with aq. NaOH (2 M), extraction
with EtOAc, followed by concentration and recrystallization
(EtOAc) to yield pure (DHQ)2PYR.
In order to confirm the absolute configuration of the diol,
derivatization of 10 and 20 with the enantiopure (S)-Naproxen was
carried out (Scheme 2). The reaction gave, as expected, a mixture
of both diastereoisomers in 92 and 97% yield respectively, from
which the major diastereomers 21 and 22 were obtained in 55%
and 63% yield after slow recrystallisation from hexane–acetone
(9 : 1). X-Ray crystallographic analysis (see ESI†) of 22 proved the
Scheme 3 Selective protection of the primary alcohol of 9. Reagents and
conditions: (a) TBDMSCl, DMAP, CH2Cl2, rt, 20 h. (b) PivCl, pyridine,
0 ◦C, 45 min. (c) Bu2SnO, toluene, reflux, 6 h. (d) add BnBr, TBAI, reflux,
16 h. (e) add NAPBr, TBAI, reflux, 24 h.
In order to achieve selective benzylation of the primary alcohol,
9 was converted to the stannylene acetal21 23, followed by direct
alkylation with BnBr–TBAI. This led to complete regioselective
formation of the primary benzyl ether 10 in excellent yield.
Equally, reaction of 23 with 2-naphthylmethyl bromide yielded
20. Confirmation of the regioselectivity was obtained by 1H NMR
via a D2O exchange experiment, which showed a simplification of
the CHOH multiplet. Efficient removal of the tin derivatives was
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 805
©

View Article Online
Table 2 Monobenzylation of 9 under basic conditions
Yield (%)a
Entry
Base (equiv.)
BnBr (equiv.)
Time (h)
11
36
9b
10
1d
NaH (1)
1.0
1.1
1.0
1.0
18
16.5
48
16
18
18
8g,h
3
—
44
11
16
62
—
15
—
—
0.8
—
4
—
2
2c
NaOH (7)
KOt-Bu (1)
BEMP (1)l
Na2CO3 (27)
3d,e
4f
51i,h
52
5d,j
56k,h
<1%
a Isolated yield. b Recovered starting material. c n-Bu4N(HSO4) (0.05 equiv. in H2O–DCM). d Ent-9 (85% ee) used as starting material. e Reaction at reflux
temperature. f n-Bu4NBr (0.1 equiv. in THF). g ee 62%. h Determined by chiral HPLC. i ee 79%. j 10 mol% of tetrabutyl ammonium bromide was present.
k ee 85%. l BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine.
achieved by an aqueous work-up with a KF (10% w/v) solution,22
followed by column chromatography on silica gel. The analysis of
the Mosher ester of 20 (19F NMR) confirmed that the stannylene
acetal procedure did not alter the ee of the product (see ESI†).
In addition to steric factors, the alcohol groups are also
differentiated by the electronic influence of the fluoroalkyl group,
resulting in the secondary alcohol group being less nucleophilic,
but more basic compared to the primary alcohol group. Hence,
selective benzylation of the secondary alcohol was expected under
basic conditions (Table 2).23
Scheme 4 The anionic cyclisation. Reagents and conditions: (a) HCOOH,
DCC, DMAP, CH2Cl2, rt, 16 h. (b) Me3SiCl, (Et2N)3P, PhCN.
However, low yields were obtained with NaH23a,24 and NaOH25
(entries 1,2). The use of KOt-Bu gave better results (entry 3),
though a substantial amount of the dibenzylated product 36
was isolated as well. An equally good yield was achieved with
BEMP (entry 4), with 16% of the dibenzylated 36 isolated as well.
Finally, the use of excess Na2CO3 under phase-transfer conditions
provided the best yield (56%, entry 5). Interestingly, virtually no
dibenzylated 36 was obtained, while a small amount of primary
benzyl ether 10 was isolated. It was confirmed that the benzylation
did not affect the ee of the product when Na2CO3 or KOt-Bu was
used. However, the ee of product formed when NaH was employed
appeared to be only 60% (see ESI†), despite that only 1 equiv. of
NaH was used. This erosion in ee was confirmed over duplicate
experiments, and could be the result of product epimerisation.24
b-fluoride elimination being a facile process.28,29 While generation
of perfluoroalkyl lithium via deprotonation is reported to lead
to b-fluoride elimination,30 in situ generation via a bromine–
lithium exchange reaction using BuLi or MeLi has proven to
be a suitable method for achieving subsequent intermolecular
attack to electrophiles including esters.29b,31 However, to the best
of our knowledge, such addition reactions were not yet reported
in an intramolecular fashion at the outset of this work, and we
investigated whether the cyclisation process would be faster than
the competing elimination process.
Hence, a number of organometal reagents were screened
(Table 3). We were pleased to observe that treatment of 27 with
n-BuLi and t-BuLi resulted in the formation of the desired
The anionic cyclisation
Table 3 Anionic cyclisation experiments to give 2 from 27
With both monobenzylated substrates 10 and 11 in hand, research
was directed to investigate the cyclisation reaction. The cyclisation
precursor 27 was synthesised by formylation of 10 (Scheme 4),
which was found to proceed best under DCC mediated coupling
conditions. It was initially envisaged to synthesise the correspond-
ing silane 28 as a “Rupperts-equivalent”, from which cyclisation
could be achieved via treatment with a fluoride source,26 but we
were unable to introduce the silyl group starting from 27 following
standard protocols.27
Yield (%)b
Entry
Reagent (equiv.)
2
30
10
27c
1
2
n-BuLi (1)
t-BuLi (2)
tBuLi (1)
PhMgBr (1)
i-PrMgCl (1)
MeLi (1)
43
11
43
—
59
78
11
29
22
—
18
<5
17
49
15
63
2
—
—
—
11
8
3
4d
5d
6
—
—
Explorations towards using perfluoroalkyl lithium inter-
mediates28 to achieve the cyclisation reaction proved to be very
fruitful. Perfluoroalkyl lithium species, however, are unstable with
a Reaction at -78 ◦C in THF for 1 h. b Isolated yield. c Recovered starting
material. d Reaction time 3 h.
806 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
pentafuranose 2 (entries 1–3), but a considerable amount of the
predicted elimination product was isolated as well. In addition,
alkyl lithium attack on the formate ester was observed as well, lead-
ing to 10 in rather high yields. As perfluoroalkyl magnesium species
have increased stability compared to their lithium counterparts,28
a Br–Mg exchange reaction was investigated as well. However,
phenyl magnesium bromide32 mainly reacted directly at the ester
group (entry 4), while the use of isopropylmagnesium chloride33
still gave significant amounts of elimination by-product 30
(entry 5). In the event, with methyl lithium as reagent, the desired
cyclisation product was obtained almost exclusively (entry 6). An
Alcohol deprotection
Using Pd/C in EtOAc as solvent, hydrogenolysis proceeded very
slowly, with 6 isolated in 85% yield after 14 days, together with
14% of starting material. However, by using Pearlman’s catalyst
(Scheme 6), the deprotection was completed in 4 h, giving 6 in
almost quantitative yield. The deprotected tetrafluoropentose was
isolated in the pyranose form as indicated by a HMBC experiment
(in d6-DMSO, see ESI†). Deprotection of 4 led to the same
monosaccharide 6 in equally good yield. Similarly, deprotection of
3 and 5 led to the ketohexapyranose 7 in excellent yield. Again, a
HMBC experiment proved that 7 existed in the pyranose form (see
ESI†). Both the protected and deprotected sugars were obtained
as a mixture of anomers.
X-ray structure of 2 was obtained (see ESI†). The alkene 30 was
-1 34a
=
easily identified by a characteristic CF CF2 band of 1790 cm ,
and by 19F NMR.34b
A solvent screen showed that tetrahydrofuran appeared to be
the best solvent for the reaction. Yields of 2 were lower when Et2O
(58%) or toluene (55%) were used, and the addition of HMPA also
resulted in a lower yield (34%). Employing MeLi·LiBr instead of
LiBr-free MeLi did not increase the yield (60%). A low temperature
is crucial for the reaction, but further lowering of the temperature
◦
◦
from -78 C to -100 C did not significantly increase the yield,
nor did the use of dried molecular sieves.
With a successful anionic cyclisation protocol developed, a
range of substrates 31–34 were synthesised in order to investigate
the scope of the reaction (Scheme 5). The acetate derivatives 31
and 32 were obtained from 10 by DMAP-catalysed ester formation
using acetic anhydride and a-benzyloxyacetyl chloride. From the
primary alcohol 11, the corresponding formate and benzyloxyac-
etate esters 33 and 34 were prepared by aforementioned methods.
Scheme 6 Deprotection leading to the pyranose form.
For the assignment of the pyranose-based anomers, the chemi-
cal shift of the anomeric proton, and the 2JF2–C1 couplings appeared
to be the most diagnostic data. An equatorial anomeric proton (a-
anomer) is downfield compared to an axial anomeric proton (b-
anomer). The magnitude of 2JF2–C1 is dependent on the orientation
of an electronegative substituent on the coupled carbon atom,
with an increase in magnitude going from a gauche to a trans
orientation with respect to the fluorine involved in the coupling.35
In this respect, the anomeric OH group outweighs the ring oxygen
in importance. For example, for the anomers of 4, the anomer with
the higher chemical shift for the anomeric proton is assigned as
Scheme 5 Scope of the anionic cyclisation. Reagents and conditions:
(a) Ac2O, Et3N, DMAP, CH2Cl2, rt, 2 h. (b) BnOCH2C(O)Cl, Et3N,
DMAP, CH2Cl2, rt, 6 h. (c) MeLi (1 equiv.), THF, -78 ◦C, 3 h. (d) HCOOH,
DCC, DMAP, CH2Cl2, rt, 16 h.
We were delighted to observe that all substrates 31–34 un-
derwent smooth cyclisation after MeLi-induced Br–Li exchange,
demonstrating the versatility of this methodology for both 5- and
6-membered rings, giving direct access to furanose and pyranose
sugars. In addition, cyclisation towards enolisable acetate-type
esters as electrophiles, gives access to ketose sugars. In all cases,
the corresponding elimination by-product was only present in very
small amounts and, pleasingly, no intramolecular deprotonation
was observed.
2
the a-anomer 4a. This is confirmed by the JF2–C1 values of 35.2
and 25.1 Hz with the large value being the coupling of Fax with
the anomeric carbon atom. For 4b, the 2JF2–C1 values are 28.9 and
2
21.6 Hz.21c,36 Interestingly, the JF3–C4 couplings (all between 19
and 20 Hz) confirmed that for both anomers the 4-OBn group is
4
in the equatorial position, suggesting a C1 chair conformation.
Unfortunately, unambiguous assignment of the fructose anomers
has not yet been achieved.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 807
©

View Article Online
(2 M, aq, 2 ¥ 50 mL) and brine (50 mL) then dried over MgSO4,
filtered and concentrated in vacuo to yield a colourless oil. The
acidic extracts were neutralised with NaOH (2 M, aq) and then
extracted with EtOAc (2 ¥ 100 mL). The EtOAc extracts were dried
over MgSO4, filtered then concentrated to give a white solid, which,
after recrystallisation from EtOAc gives pure (DHQ)2PYR. The
colourless oil obtained was purified by vacuum distillation (55 ◦C,
0.1 mm Hg) to give a colourless oil which crystallised on standing
to give a white deliquescent solid (12.0 g, 93%). nmax(film)/cm-1
3388 (br. s), 2956 (m), 2900 (w), 1414 (w), 1151 (s), 1087 (s),
919 (s); dH (400 MHz, CD3CN) 4.20 (1H, m, CHOH, simplifies
upon D2O exchange), 4.00 (1H, d, J 7.3 Hz, CHOH, disappears
upon D2O exchange), 3.78 (1H, m, CHHOH simplifies upon D2O
exchange), 3.66 (1H, dt, J 11.8 and 6.0 Hz, CHHOH, upon D2O
exchange simplifies to 1H, dd, J 11.8 and 7.0 Hz), 3.08 (1H, t,
J 6.2 Hz, CH2OH, disappears upon D2O exchange); dC(75 MHz,
CDCl3) 117.1 (tt, J 312.5 and 39.5 Hz, CF2Br), 114.4 (ddt, J 262.0,
257.8 and 31.0 Hz, CF2), 69.4 (dd, J 27.4 and 22.1 Hz, CHOH),
60.4 (CH2); dF (282 MHz, CDCl3) -64.12 (1F, dd, J 181.6 and
6.5 Hz, CFFBr), -64.93 (1F, dd, J 181.6 and 5.4 Hz, CFFBr),
-116.93 (1F, dt, J 271.9 and 5.4 Hz, CFFCF2Br), -123.29 (1F,
ddd, J 271.9, 17.2 and 6.5 Hz, CFFCF2Br); EIMS m/z 242 and
240 (M+, 12%, 1 : 1 ratio), 223 and 221 (16, 1 : 1 ratio), 192 and
190 (16, 1 : 1 ratio), 111 (100).
Conclusions
A short, enantioselective synthesis (81% ee) of tetrafluorinated
monosaccharide derivatives has been achieved, with a novel
perfluoroalkylidene lithium mediated cyclisation as the key step.
This cyclisation works well for the formation of both 5- and 6-
membered rings, and both formate and acetate groups are suitable
electrophiles. This methodology is suitable for the synthesis of a
range of tetrafluorinated aldo- and ketofuranoses and pyranoses,
in both enantiomeric forms, with a reasonable choice of protecting
groups. This process will also be useful for the synthesis of a
wider range of cyclic substrates. Research towards the synthesis of
other fluorinated saccharides, and towards efficient glycosylation
reactions for this class of sugars, is underway.
Experimental section
1H and 13C NMR spectra were recorded at room temperature on a
Bruker DPX400 or AV300 spectrometer as indicated. Chemical
shifts are quoted in ppm relative to residual solvent peaks as
appropriate. 19F NMR spectra were recorded on a Bruker AV300
spectrometer or a Bruker DPX400 spectrometer and are referenced
to C6F6 and CFCl3 respectively. Assignments were assisted by
COSY and HMQC experiments. EIMS were recorded on a Ther-
moquest Trace GCMS Quadrapole system. Infrared spectra were
recorded as neat films on a Nicolet Impact 380 ATR spectrometer.
Melting points were recorded on a Gallencamp Melting Point
Apparatus and are uncorrected. Column chromatography was
performed on 230–400 mesh Matrex silica gel. Preparative HPLC
was carried out using a Biorad Biosil D 90-10, 250 ¥ 22 mm
column eluting at 20 mL min-1, connected to a Kontron 475
refractive index detector. Reactions were monitored by TLC
(Merck) with detection by alkaline KMnO4 oxidation. Reaction
solvents were dried before use as follows: THF and Et2O were
distilled from sodium/benzophenone ketyl; CH2Cl2, m-xylene and
Et3N were distilled from CaH2; toluene and 1,2-dimethoxyethane
were distilled from Na; pyridine was double distilled from CaH2
and stored in a Schlenk flask; DMSO was distilled under reduced
pressure from CaH2 and was stored over molecular sieves; HMPA
(2R)-1-Benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol (10)
A solution of 9 (5.0 g, 20.75 mmol) and Bu2SnO (6.20 g,
24.89 mmol) in dry toluene (75 mL) was refluxed, using a Dean and
Stark condenser, for 6 h. BnBr (2.96 mL, 24.89 mmol) and TBAI
(1.92 g, 5.19 mmol) were added and the reaction was refluxed for
further 16 h. The mixture was allowed to cool, diluted with Et2O
(100 mL), washed with KF (10% w/v, aq, 2 ¥ 25 mL), dried over
MgSO4, filtered and then concentrated in vacuo. Purification by
column chromatography (petroleum ether–Et2O, 80 : 20) gave a
pale yellow oil (6.64 g, 97%) which solidified on standing to a
low melting solid. [a]D +9.43 (c 1.3, CHCl3, 26 ◦C, value after
Naproxen resolution); nmax(film)/cm-1 3432 (br. m), 2931 (m),
2875 (m), 1497 (w), 1455 (m), 1367 (m), 1154 (s), 1094 (s); dH
(400 MHz, CDCl3) 7.41–7.32 (5H, m, ArH), 4.62 (2H, s, CH2Ph),
4.37 (1H, m, CHOH, simplifies upon D2O exchange), 3.82–3.74
(2H, m, CHHOBn and CHHOBn), 2.98 (1H, br. s, CHOH,
disappears upon D2O exchange); dC (100 MHz, CDCl3) 137.0
(ArC), 128.6 (2 ¥ ArCH), 128.1 (ArCH), 127.8 (2 ¥ ArCH), 73.8
(CH2Ph), 68.5 (dd, J 28.2 and 22.3 Hz, CHOH), 67.5 (CH2CH).
The CF2CF2 carbons were not observed; dF (282 MHz, CDCl3)
-64.02 (1F, dd, J 178.5 and 6.5 Hz, CFFBr), -64.97 (1F, dd, J 178.5
and 4.3 Hz, CFFBr), -116.37 (1F, d, J = 269.9 Hz, CFFCF2Br),
-124.99 (1F, ddd, J 269.9, 19.6 and 6.5 Hz, CFFCF2Br); EIMS
m/z 332 and 330 (M+, 4%, 1 : 1 ratio), 249 (10), 91 (100); HRMS
(EI) for C11H1179BrF4O2 (M)+ calcd 329.9879, found 329.9785.
˚
was distilled from CaH2 and stored over 4 A sieves. Reaction
vessels were flame dried under vacuum and cooled under N2 prior
to use and all experiments were carried out under a N2 atmosphere.
All other reagents were purchased from commercial sources and
used without further purification.
(2R)-4-Bromo-3,3,4,4-tetrafluorobutane-1,2-diol (9)
A single necked flask was charged with K3Fe(CN)6 (52.7 g,
0.16 mol), K2CO3 (22.1 g, 0.16 mol), K2OsO4·2H2O (0.40 g,
1.08 mmol) and (DHQ)2PYR (0.85 g, 1.08 mmol). H2O (270 mL)
and t-BuOH (270 mL) were added, and the reaction stirred until
◦
complete dissolution occurred. The reaction was cooled to 4 C
whilst stirring and 4-bromo-3,3,4,4-tetrafluorobut-1-ene (11.2 g,
54.0 mmol) was added via syringe and the reaction stirred at 4 ◦C
for 9 days. Solid Na2SO3 (81.0 g) was added and the reaction
allowed to warm to rt with vigorous stirring over 2 h. The reaction
was diluted with H2O (50 mL) and Et2O (200 mL), the layers
were separated and the aqueous phase extracted with Et2O (2 ¥
200 mL). The combined organic phases were washed with HCl
(2R)-2-Benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-1-ol (11)
The diol 9 (0.3 g, 1.25 mmol, 1 equiv.) was added to a 1.9 M
aqueous solution (17.8 mL) of Na2CO3 (3.56 g, 33.61 mmol,
27 equiv.) and was stirred at rt for 15 min. Then BnBr (2.7 mL,
22.41 mmol, 18 equiv.) and TBAB (0.041 g, 0.125 mmol) were
added and the reaction was stirred at rt for 18 h. To the aqueous
808 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
phase was added CH2Cl2 (10 mL) and after separation of the
phases, the aqueous phase was extracted with CH2Cl2 (2 ¥ 10 mL).
The combined organic phase was washed with brine (2 ¥ 20 mL),
dried over MgSO4, filtered and concentrated in vacuo. Column
chromatography (petroleum ether–EtOAc: 70 : 30) gave product 11
as a transparent gel (0.23 g, 0.70 mmol, 56%), 10 as a transparent
gel (0.0083 g, 0.025 mmol, 2%) and 36 as a transparent gel
(<1%). nmax(film)/cm-1 3407 (br. w), 2947 (w), 2887 (w), 1456 (w),
1212 (m), 1126 (s), 1086 (s), 915 (m); dH (400 MHz, CDCl3) 7.42–
7.34 (5H, ArH), 4.89 (1H, d, J 11.0 Hz, CHHPh), 4.68 (1H, d,
J 11.3 Hz, CHHPh), 4.14 (1H, m, CHOBn), 3.89 (1H, dd, J
12.2 and 3.1 Hz, CHHOH), 3.83 (1H, dd, J 12.4 and 7.1 Hz,
CHHOH); dC (100 MHz, CDCl3) 136.6 (ArC), 128.7 (2 ¥ ArCH),
128.5 (ArCH), 128.2 (2 ¥ ArCH), 77.7 (dd, J 25.3 and 21.9 Hz,
CHCF2), 75.1 (CH2Ph), 60.3 (CH2OH). The CF2CF2 carbons
were not observed; dF (282 MHz, CDCl3) -63.47 (2F, s, CF2Br),
-114.20 (1F, m, CFFCF2Br), -117.87 (1F, ddt, J 275.6, 14.0 and
4.3 Hz, CFFCF2Br); EIMS m/z 332 and 330 (M+, 63%, 1 : 1 ratio),
249 (19), 181 (28), 127 (27), 107 (58), 91 (100); HRMS (ES+) for
C11H1179BrF4NaO2 (M + Na)+ calcd 352.9771, found 352.9766.
(ArCCH2), 133.19 (ArC), 133.14 (ArC), 128.49 (ArCH), 127.89
(ArCH), 127.73 (ArCH), 126.78 (ArCH), 126.32 (ArCH), 126.18
(ArCH), 125.52 (ArCH), 73.9 (CH2Ar), 68.49 (dd, J 28.7 and
22.4 Hz, CHCF2), 67.52 (CH2CH). The CF2CF2 carbons were
not observed; dF(282 MHz, CDCl3) -63.38 (1F, dd, J 179.5 and
7.5 Hz, CFFBr), -64.30 (1F, dd, J 179.5 and 4.3 Hz, CFFBr),
-115.85 (1F, d, J 269.3 Hz, CHCFF), -124.32 (1F, ddd, J 282,
18.2 and 7.5 Hz, CHCFF); EIMS: m/z 382 and 380 (M+, 8%, 1 :
1 ratio), 207 (8), 141 (100); HRMS (ES+) for C15H1379BrF4NaO2
(M + Na)+ calcd 402.9927, found 402.9929.
(2S)-[(2R)-4-Bromo-1-(2-benzyl)-3,3,4,4-tetrafluorobut-2-yl]-2-
(6-methoxy-2-naphthyl) propanoate (21)
To a stirred solution of 10 (4.606 g, 12.8 mmol) and DCC
(14.1 mmol, 2.91 g) in CH2Cl2 (65 mL) was added DMAP
(1.28 mmol, 157 mg). The suspension was stirred until complete
dissolution, upon which (S)-Naproxen (14.1 mmol, 3.25 g) was
added and the reaction stirred overnight. The mixture was filtered
to remove the precipitate formed and the residue washed with
CH2Cl2 (20 mL). The filtrate was concentrated in vacuo to give
a suspension which was loaded directly onto a silica gel column.
Elution with petroleum ether–acetone (85 : 15) gave a yellow solid
as a mixture of diastereomers. The desired major diastereomer
was then obtained by recrystallisation from hexane as an off-white
solid (3.843 g, 55%). The remaining supernatant was reduced in
vacuo to give 2.588 g (37%) as a mixture of diastereomers. Data
for 21: mp 69–71 ◦C (hexane); [a]D +33.2 (c 0.87, CHCl3, 26 ◦C);
Data for (2R)-1,2-bisbenzyloxy-4-bromo-3,3,4,4-tetrafluorobutane
(36)
n
max(film)/cm-1 3090 (w), 3065 (w), 3032 (w), 2922 (w), 2873 (w),
1497 (w), 1454 (m), 1127 (s); dH (CDCl3, 400 MHz) 7.30–7.39
(10 H, m, ArH), 4.82 (1H, d, J 11.0 Hz, CHHPh), 4.77 (1H, d, J
11.0 Hz, CHHPh), 4.58 (2H, s, CH2Ph), 4.27 (1H, dtd, J 15.8, 7.3
and 2.8 Hz, CHOBn), 3.89 (1H, app d, J 10.6 Hz, CHHOBn),
3.79 (1H, dd, J 10.6 and 7.4 Hz, CHHOBn); dC (d6-acetone,
100 MHz): 139.38 (ArC), 138.69 (ArC), 129.36 (ArCH), 129.29
(ArCH), 129.07 (ArCH), 128.89 (ArCH), 128.68 (ArCH), 128.65
(ArCH), 76.77 (dd, J 27.5 and 22.5 Hz, CHCF2), 75.21 (CH2Ph),
74.18 (CH2Ph), 69.46 (CHCH2). The CF2CF2 carbons were not
observed; dF (CDCl3) -62.43 (1F, dd, J 178.1 and 6.5 Hz, CFFBr),
-63.15 (1F, dd, J 178.1 and 4.3 Hz, CFFBr), 112.42 (1F, app d, J
273.1 Hz, CFFCH), -120.43 (1F, ddd, J 273.1, 16.1 and 6.4 Hz,
CFFCH); ES+MS m/z 443 and 445 (M + Na+, 100%, 1 : 1 ratio);
HRMS (ES+): for C18H1779BrF4NaO2 (M + Na)+: calcd: 443.0240,
found 443.0238.
n
max(film)/cm-1 2938 (br), 1754 (s), 1633 (w), 1606 (m), 1506 (w),
1485 (w), 1454 (w), 1140 (s); dH (400 MHz, CDCl3) 7.68–7.64 (3 H,
m, ArH), 7.40 (1H, dd, J 8.5 and 1.7 Hz, ArH), 7.24–7.10 (5H,
m, ArH), 7.01 (2H, d, J 6.7 Hz, ArH), 5.86 (1H, dtd, J 16.4, 7.5
and 3.2 Hz, CHCF2), 4.31 (1H, d, J 11.9 Hz, CHHPh), 4.22 (1H,
d, J 11.9 Hz, CHHPh), 4.00–3.92 (4H, m, CHCH3 + OCH3),
3.76 (1H, ddd, J 11.2, 3.2 and 2.0 Hz, CHHOBn), 3.60 (1H, dd,
J 11.0 and 7.8 Hz, CHHOBn), 1.62 (1H, d, J 7.2 Hz, CHCH3);
=
dC (100 MHz, CDCl3) 172.7 (C O), 157.7 (CAr), 137.1 (CAr),
134.6 (CAr), 133.8 (CAr), 129.3 (CAr), 128.9 (CAr), 128.2 (2 ¥
CAr), 127.3 (2 ¥ CAr), 127.2 (CAr), 126.2 (CAr), 126.1 (CAr),
119.0 (CAr), 105.6 (CAr), 73.2 (CH2Ph), 67.8 (dd, J 29.7 and
21.9 Hz, CHCF2), 66.5 (CHOBn), 55.3 (CHCH3), 45.1 (CCH3),
18.4 (OCH3). CF2CF2 carbons were not visible; dF (282 MHz,
CDCl3) -119.5 (1 F, dd, J 275.1 and 17.2 Hz, CHCFF), -114.0
(1 F, d, J 275.1 Hz, CHCFF), -64.2 (2 F, s, CF2Br); LRMS (ESI+)
m/z 565.3 and 567.2 ((M + Na)+, 100%, 1 : 1 ratio); HRMS (ESI+)
for C25H2381BrF4O4 (M + Na)+ calcd 565.0614, found 565.0605.
(2R)-4-Bromo-1-(naphth-2-ylmethyloxy)-3,3,4,4-tetrafluorobutan-
2-ol (20)
Diol 9 (9.5 g, 39.42 mmol) and Bu2SnO (11.8 g, 47.31 mmol)
were dissolved in dry toluene (145 mL). The reaction was brought
to reflux and stirred under Dean and Stark conditions for 16 h.
2-(Bromomethyl)naphthalene (10.5 g, 47.31 mmol) and TBAI
(3.64 g, 9.86 mmol) were added and the reaction refluxed for a
further 24 h. The reaction was allowed to cool, diluted with Et2O
(200 mL), washed with KF (10% w/v, aq, 2 ¥ 100 mL), dried over
MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (petroleum ether–Et2O, 85 : 15) gave a pale yellow
(2S)-[(2R)-4-Bromo-1-(2-naphthylmethyl)-3,3,4,4-tetrafluorobut-
2-yl]-2-(6-methoxy-2-naphthyl) propanoate (22)
To a stirred solution of 20 (0.5 g, 1.31 mmol) and DCC (0.3 g,
1.44 mmol) in CH2Cl2 (7 mL) was added DMAP (0.016 g,
0.131 mmol). The suspension was stirred until complete disso-
lution, upon which (S)-Naproxen (0.33 g, 1.44 mmol) was added
and the reaction stirred overnight. The mixture was filtered to
remove the white precipitate formed and the residue washed with
CH2Cl2 (2 ¥ 10 mL). The filtrate was concentrated in vacuo to
give a white suspension which was loaded directly onto a silica
gel column. Elution with petroleum ether–acetone (90 : 10) gave a
◦
solid (14.4 g, 96%). Mp 80–82 C; nmax(film)/cm-1 3386 (br. m),
3061 (w), 2946 (w), 1146 (m), 1113 (s), 1091 (s), 1055 (s), 1031 (m);
d
H (400 MHz, CDCl3) 7.88–7.84 (3H, m, 3 ¥ ArH), 7.79 (1H, br s,
ArH), 7.54–7.49 (2H, m, ArH), 7.47 (1H, dd, J 8.4 and 1.6 Hz,
ArH), 4.78 (2H, s, CH2Ar), 4.40 (1H, m, CHOH), 3.86–3.78 (2H,
m, CH2ONap), 3.03 (1H, br s, OH); dC (100 MHz, CDCl3) 134.41
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 809
©

View Article Online
white solid (1.27 g, 97%). HPLC (hexane–acetone, 90 : 10) followed
by slow evaporation of the desired fractions gave 22 as white
needles of a single diastereomer (0.489 g, 63%). Mp 86–88 ◦C;
white solid (0.478 g, 81%). Mp 49–52 ◦C; nmax(film)/cm-1 3045 (m),
2984 (m), 1735 (m), 1266 (s), 1156 (m), 740 (s); dH (300 MHz,
CDCl3) 4.50–4.38 (3H, m, CH2O and CHOH), 3.04 (1H, d, J
7.2 Hz, CHOH), 1.24 (9H, s, C(CH3)3); dC (100 MHz, CDCl3)
179.2 (CO), 68.5 (dd, J 28.0 and 23.0 Hz, CHOH), 62.8 (CH2O),
38.9 (C), 27.0 (3 ¥ CH3). The CF2CF2 carbons were not observed;
dF (282 MHz, CDCl3) -64.10 (1F, dd, J 178.5 and 6.5 Hz, CFFBr),
-65.03 (1F, dd, J 180.7 and 4.3 Hz, CFFBr), -116.33 (1F, d, J
272.1 Hz, CFFCF2Br), -124.90 (1F, ddd, J 269.9, 19.6 and 6.5 Hz,
CFFCF2Br); EIMS: m/z 327 and 325 (M + H+, 10%, 1 : 1 ratio),
281 (5), 225 (8), 129 (10), 103 (52), 85 (90), 69 (50); HRMS (EI)
for C9H1479BrF4O3 (M + H)+ calcd 325.0062, found 325.0067.
n
max(film)/cm-1 2975 (w), 2936 (w), 1758 (m), 1135 (s), 1072 (s),
1027 (m), 861 (m); dH (400 MHz, CDCl3) 7.78 (1H, m, ArH),
7.69–7.67 (2H, m, 2 ¥ ArH), 7.60 (3H, m, 3 ¥ ArH), 7.47–7.44
(2H, m, 2 ¥ ArH), 7.39 (1H, dd, J 8.4 and 1.6 Hz, ArH), 7.09
(1H, dd, J 8.7 and 1.9 Hz, ArH), 7.04 (1H, d, J 2.3 Hz, ArH),
5.89 (1H, dtd, 15.7, 7.8 and 3.0 Hz, CHO), 4.45 (1H, d, J 12.1 Hz,
CHHNap), 4.36 (1H, d, J 12.1 Hz, CHHNap), 3.96 (1H, q, J
7.3 Hz, CH3CH), 3.90 (3H, s, OCH3), 3.81 (1H, m, CHCHHO),
3.65 (1H, dd, J 11.3 and 7.8 Hz, CHCHHO), 1.62 (3H, d, J 7.3 Hz,
CHCH3); dC (100 MHz, CDCl3): 172.7 (CO), 157.7 (COCH3),
134.7 (ArC), 134.6 (ArC), 133.8 (ArC), 133.1 (ArC), 132.9 (ArC),
129.3 (ArCH), 128.9 (ArC), 128.1 (ArCH), 127.9 (ArCH), 127.6
(ArCH), 127.2 (ArCH), 126.2 (ArCH), 126.1 (ArCH), 126.0
(ArCH), 125.9 (ArCH), 125.2 (ArCH), 119.0 (ArCH), 105.6
(ArCH), 73.4 (CH2Nap), 67.9 (dd, J 28.7 and 21.9 Hz, CHCF2),
66.6 (CHCH2), 55.3 (CHCH3), 45.1 (OCH3), 18.4 (CHCH3). The
CF2CF2 carbons were not observed; dF (282 MHz, CDCl3) -64.42
(2F, m, CF2Br), -114.33 (1F, app. d, J 274.0 Hz, CHCFF), 119.69
(1F, ddt, J 274.0, 16.1 and 4.8 Hz, CHCFF); ESMS (ES-) m/z 591
and 593 ((M - H)+, 55%, 1 : 1 ratio), 212 (100).
(2R)-(1-Benzyloxy-4-bromo-3,3,4,4-tetrafluoro)but-2-yl
formate (27)
To a stirred solution of 10 (8.85 g, 26.73 mmol) and DCC (6.07 g,
29.4 mmol) in CH2Cl2 (140 mL) was added DMAP (0.33 g,
2.67 mmol). The reaction was stirred until complete dissolution
upon which formic acid (98%, 1.1 mL, 29.4 mmol) was added
and the reaction stirred overnight. The reaction was diluted with
hexane (100 mL), filtered to remove the white precipitate formed
and the residue was washed with hexane (2 ¥ 20 mL). The filtrate
was concentrated in vacuo to give a colourless oil. Purification by
column chromatography (petroleum ether–Et2O, 90 : 10) gave a
colourless oil (8.89 g, 93%); nmax(film)/cm-1 3033 (m), 2949 (m),
2874 (m), 1744 (s), 1369 (m), 1152 (s); dH (400 MHz, CDCl3) 8.13
(1H, s, CHO), 7.39–7.31 (5H, m, ArH), 5.91 (1H, dtd, J 15.4, 7.8
and 3.3 Hz, CHCF2), 4.62 (1H, d, J 12.1 Hz, CHHPh), 4.55 (1H,
d, J 11.8 Hz, CHHPh), 3.89 (1H, dt, J 11.3 and 2.4 Hz, CHHCH),
3.80 (1H, dd, J 11.2 and 7.9 Hz, CHHCH); dC (100 MHz, CDCl3)
158.5 (CHO), 137.0 (ArC), 128.5 (2 ¥ ArCH), 128.0 (ArCH),
127.7 (2 ¥ ArCH), 73.4 (PhCH2O), 66.9 (dd, J 29.2 and 22.4,
CHCF2), 66.2 (CH2CH). The CF2CF2 carbons were not observed;
dF (282 MHz, CDCl3) -67.18 (2F, s, CF2Br), -117.24 (1F, d, J
272.5 Hz, CFFCF2Br), -122.52 (1H, dd, J 274.7 and 15.5 Hz,
CFFCF2Br); EIMS m/z 360 and 358 (M+, 10%, 1 : 1 ratio),
253 and 251 (26, 1 : 1 ratio), 181 (12), 91 (100); HRMS (EI)
for C12H1179BrF4O3 (M)+ calcd 357.9828, found 357.9831.
(2R)-4-Bromo-1-(t-butyldimethylsilyloxy)-3,3,4,4-
tetrafluorobutan-2-ol (24)
To a stirred solution of 9 (0.250 g, 1.04 mmol) and TBDMSCl
(0.170 g, 1.15 mmol) in DCM (1.2 mL) was added DMAP (0.270 g,
2.25 mmol) and the mixture was stirred for 20 h. DCM (10 mL)
was added, and the mixture was extracted with water (5 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. Purification by column chromatography (hexane–acetone
95 : 5) gave a colourless oil (0.264 g, 71%). A small amount of the
secondary alcohol protected product was also isolated (0.033 g,
9%). nmax(film)/cm-1 3550 (w, br), 2932 (m), 1472 (m), 1255 (m),
1082 (s), 834 (s), 777 (s); dH (300 MHz, CDCl3) 4.20 (m, 1H,
CHOH), 3.94 (1H, ddd, J 10.5, 4.5 and 1.5 Hz, CHHOSi), 3.89
(1H, ddd, J 10.5, 4.0 and 2.3 Hz, CHHOSi), 3.07 (1H, d, J 7.3 Hz,
CHOH), 0.93 (9H, s, t-Bu), 0.12 (6H, s, 2 ¥ CH3); dC (100 MHz,
CDCl3) 69.18 (dd, J 29.2 and 21.9 Hz, CHOH), 60.39 (CH2OSi),
25.70 (3 ¥ CH3), 18.19 (C(CH3)3), -5.60 (2 ¥ CH3). The CF2CF2
carbons were not observed; dF (282 MHz, CDCl3) -63.01 (1F, dd,
J 179.2 and 8.6 Hz, CFFBr), -64.06 (1F, d, J 178.1 and 4.3 Hz,
CFFBr), -115.44 (1F, d, J 270.4 Hz, CFFCF2Br), -124.72 (1F,
ddd, J 269.4, 19.3 and 8.6 Hz, CFFCF2Br); EIMS m/z 297 and
299 ((M – t-Bu)+, 4%, 1 : 1 ratio), 210 and 203 (5, 1 : 1 ratio),
107 (100); HRMS (ES+) for C10H1979BrF4NaO2 (M + Na)+ calcd
377.0166, found 377.0168.
(2R)-[(1-Benzyloxy-4-bromo-3,3,4,4-tetrafluoro)but-2-yl]
benzyloxyethanoate (32)
To a stirred solution of 10 (0.5 g, 1.5 mmol) in CH2Cl2 (5 mL)
was added Et3N (0.23 mL, 1.65 mmol) and DMAP (0.018 g,
0.15 mmol). The solution was stirred at rt for 5 min and
then benzyloxyacetyl chloride (0.36 mL, 2.25 mmol) was added
dropwise. The reaction was stirred at rt for 4 h. The reaction was
diluted with CH2Cl2 (10 mL) then washed with HCl (1 M, aq.,
10 mL), dried over MgSO4, filtered and concentrated in vacuo. The
resultant oil was purified by column chromatography (petroleum
ether–acetone, 90 : 10) to give a colourless oil (0.703 g, 98%).
(2R)-[(4-Bromo-2-hydroxy-3,3,4,4-tetrafluorobut-1-yl)]-
2,2-dimethyl propanoate (25)
n
max(film)/cm-1 2881 (w), 1777 (m), 1122 (s), 1079.8 (m), 908
To a stirred solution of 9 (0.444 g, 1.84 mmol) in dry pyridine
(3.45 mL) at 0 ◦C was added pivaloyl chloride (0.4◦5 mL,
3.68 mmol) and the reaction was stirred for 45 min at 0 C. Ice
(5 g) was added and the reaction was stirred for 5 min. The mixture
was concentrated in vacuo to give a colourless oil. Purification by
column chromatography (petroleum ether–Et2O, 80 : 20) gave a
(m); dH (400 MHz, CDCl3) 7.37–7.29 (10H, m, ArH), 5.92 (1H,
dtd, J 15.6, 7.8 and 3.2 Hz, CHO), 4.66–4.60 (3H, m, CH2Ph +
CHHCO2), 4.52 (1H, d, J 11.9 Hz, CHHCO2), 4.21 (1H, d, J
16.9 Hz, CHHPh), 4.16 (1H, d, J 16.9 Hz, CHHPh), 3.88 (1H,
dt, J 11.1 and 2.5 Hz, CHCHH), 3.78 (1H, dd, J 11.0 and 8.0 Hz,
CHCHH); dC (100 MHz, CDCl3) 168.6 (CO), 137.1 (ArC), 136.8
810 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
(ArC), 128.5 (4 ¥ ArCH), 128.1 (2 ¥ ArCH), 128.0 (2 ¥ ArCH),
127.7 (2 ¥ ArCH), 73.3 (2 ¥ PhCH2), 67.6 (dd, J 29.2 and 22.4 Hz,
CHCF2), 66.5 (CH2CO2), 66.2 (CH2CH). The CF2CF2 carbons
were not observed; dF (282 MHz, CDCl3) -67.3 (2F, s, CF2Br),
-117.2 (1F, app. d, J 269.2 Hz, CFFCF2Br), -122.4 (1F, ddt, J
273.6, 16.6 and 4.8 Hz, CFFCF2Br); EIMS: m/z 389 and 387
((M - CH2Ph)+, 8%, 1 : 1 ratio), 283 and 281 (1 : 1 ratio, 21), 107
(32), 91 (100); HRMS (ES+) for C20H1979BrF4O4 (M + Na)+ calcd
501.0295, found 501.0305.
(CH2Ph), 66.8 (CH2CO2), 61.6 (CHCH2). The CF2CF2 carbons
were not observed; dF (282 MHz, CDCl3) -63.51 (2F, m, CF2Br),
-113.21 (1F, app. d, J 274.7 Hz, CHCFF), -120.05 (1F, ddd, J
274.7, 12.9 and 6.4 Hz, CHCFF); EIMS m/z 389 and 387 ((M -
PhCH2)+, 29%, 1 : 1 ratio), 331 and 329 (18, 1 : 1 ratio), 283 and 281
(13, 1 : 1 ratio), 181 (24), 132 (28), 107 (72), 91 (100); HRMS (EI)
for C20H1979BrF4NaO4 (M + Na)+ calcd 501.0295, found 501.0298.
General procedure for the cyclisation reaction
(2R)-(2-Benzyloxy-4-bromo-3,3,4,4-tetrafluoro)but-1-yl
formate (33)
A solution of the substrate (1 equiv.) in dry CH2Cl2 (0.17 M)
was filtered through a plug of MgSO4 into a round-bottomed
flask. The CH2Cl2 was removed under a stream of dry nitrogen,
followed by drying under high vacuum for 16 h. The resulting
oil was dissolved in THF (10 mL mmol-1 substrate) and cooled
to -100 to -78 ◦C. MeLi (1.6 M in Et2O, 1 equiv) was slowly
added dropwise. The reaction was stirred for 3–4 h at -100 to
-78 ◦C. A saturated aqueous solution of NH4Cl (around 3 mL
mmol-1 substrate) was added at that temperature, after which the
resulting suspension was allowed to warm to room temperature.
The mixture was then diluted with H2O and Et2O or EtOAc.
The layers were separated and the aqueous phase extracted with
Et2O or EtOAc. The organic phases where combined, dried over
MgSO4, filtered and concentrated in vacuo to give a colourless
oil. The mixture was purified by column chromatography and
preparative HPLC (hexane or petroleum ether–acetone 80–85 :
20–15).
To a stirred solution of 11 (0.60 g, 1.8 mmol) and DCC (0.41 g,
1.99 mmol) in CH2Cl2 (9.6 mL) was added DMAP (0.022 g,
0.18 mmol). The reaction was stirred until complete dissolution
upon which formic acid (98%, 0.075 mL, 1.99 mmol) was added
and the reaction stirred overnight. The reaction was diluted with
hexane (10 mL), then filtered to remove the white precipitate
formed and the residue washed with hexane (2 ¥ 5 mL). The filtrate
was concentrated in vacuo to give a colourless oil. Purification by
column chromatography (petroleum ether–Et2O, 90 : 10) gave a
colourless oil (0.633 g, 98%). nmax(film)/cm-1 3035 (w), 2944 (w),
1728 (s), 1134 (s), 1079 (s), 1027 (m), 907 (m); dH (300 MHz,
CDCl3) 8.01 (1H, s, OCHO), 7.42–7.31 (5H, m, ArH), 4.80 (1H,
d, J 11.2 Hz, PhCHH), 4.72 (1H, d, J 11.2 Hz, PhCHH), 4.57
(1H, dd, J 12.0 and 3.4 Hz, OCHHCH), 4.39 (1H, dd, J 12.2
and 6.7 Hz, OCHHCH), 4.29 (1H, dtd, J 14.2, 7.1 and 3.4 Hz,
CHCF2); dC (75 MHz, CDCl3) 160.1 (CO), 136.1 (ArC), 128.5
(2 ¥ ArCH), 128.4 (ArCH), 128.3 (2 ¥ ArCH), 74.7 (dd, J 27.1
and 22.3 Hz, CHCF2), 74.6 (CH2Ph), 60.9 (CH2CH). The CF2CF2
carbons were not observed; dF (282 MHz, CDCl3) -63.22 (2F, m,
CF2Br), -112.91 (1F, d, J 272.9 Hz, CHCFF), -119.64 (1F, app
ddd, J 277.2 can be observed, CHCFF); EIMS: m/z 360 and 358
(M+, 26%, 1 : 1 ratio), 253 and 251 (6, 1 : 1 ratio), 91 (100); HRMS
(ES+) for C12H1179BrF4NaO3 (M + Na)+ calcd 380.9720, found
380.9719.
(5R)-5-Benzyloxymethyl-3,3,4,4-tetrafluoro-tetrahydro-
furan-2-ol (2)
A colourless oil (0.734 g, 85%) as an inseparable mixture of
anomers (approximately 1.4 : 1 ratio). nmax(film)/cm-1 3388 (br.
m), 3034 (w), 2928 (w), 1621 (br. w), 1497 (w), 1455 (m), 1239 (m),
1146 (s), 1023 (s); dH (400 MHz, CDCl3) 7.42–7.31 (10H, m,
ArH), 5.37 (1H, br s, CHOH, minor isomer, simplifies upon
D2O exchange), 5.28 (1H, t, J 8.9 Hz, CHOH, major isomer,
simplifies upon D2O exchange), 4.74 (1H, d, J 11.04 Hz, CHOH,
major isomer, disappears upon D2O exchange), 4.67–4.52 (5H,
m, CH2Ph, major and minor isomer, CHCH2, minor isomer),
4.39 (1H, m, CHCH2, major isomer), 3.88 (1H, m, CHOH,
minor isomer, disappears upon D2O exchange), 3.88–3.67, (4H,
m, CH2OBn, major and minor isomer); dC (100 MHz, CDCl3)
136.87 (ArC), 135.87 (ArC), 128.72 (ArCH), 128.55 (ArCH),
128.51 (ArCH), 128.13 (ArCH), 128.08 (ArCH), 127.94 (ArCH),
96.12 (dddd, J 40.1, 22.2, 2.4 and 1.4 Hz, CHOH), 94.72 (dddd,
J 38.6, 21.3, 2.4 and 1.4 Hz, CHOH, major isomer), 79.34 (dddd,
J 29.5, 22.7, 2.4 and 1.4 Hz, CHCH2, minor or major isomer),
77.20 (m, CHCH2, minor or major isomer), 74.22 (PhCH2), 73.87
(PhCH2), 66.36–66.24 (m, 2 ¥ CH2OBn); dF (376 MHz, CDCl3)
-116.84 (1F, dd, J 245.0 and 6.5 Hz, HOCHCFF), -119.24 (1F,
dd, J 248.0 and 13.0 Hz, HOCHCFF), -124.83 (1F, d, J 247.0 Hz,
CH2CHCFF), -125.65 (1F, dd, J 250.0 and 8.0 Hz, HOCHCFF),
-127.67 (1F, dd, J 247.0 and 7.0 Hz, HOCHCFF), -128.11 (1F, m,
CH2CHCFF), -130.82 (1F, d, J 249.0 Hz, CH2CHCFF), -134.06
(1F, dd, J 246.0, 15.0 Hz, CH2CHCFF); EIMS: m/z 280 (M+,
5%), 91 (100). HRMS (EI) for C12H12F4O3 (M)+: calcd 280.07226,
found 280.07206.
(2R)-[(2-Benzyloxy-4-bromo-3,3,4,4-tetrafluoro)but-1-yl]
benzyloxyethanoate (34)
To a stirred solution of 11 (0.5 g, 1.5 mmol) in CH2Cl2 (10 mL)
was added Et3N (0.25 mL, 1.81 mmol) and DMAP (0.018 g,
0.15 mmol). The solution was stirred at rt for 5 min and
then benzyloxyacetyl chloride (0.29 mL, 1.81 mmol) was added
dropwise. The reaction was stirred at rt for 4 h. The reaction was
diluted with CH2Cl2 (10 mL) then washed with HCl (1 M, aq.,
10 mL), dried over MgSO4, filtered and concentrated in vacuo. The
resultant oil was purified by column chromatography (petroleum
ether–acetone, 90 : 10) to give a colourless oil (0.683 g, 95%).
n
max(film)/cm-1 2877 (w), 1760 (m), 1455 (m), 1120 (s), 736 (m);
dH (400 MHz, CDCl3) 7.37–7.33 (10H, m, ArH), 4.78 (1H, d, J
11.3 Hz, OCHHPh), 4.69 (1H, d, J 11.3 Hz, OCHHPh), 4.62
(2H, s, CH2Ph), 4.58 (1H, dd, J 12.1 and 3.5 Hz, CHCHH), 4.38
(1H, dd, J 12.1 and 6.8 Hz, CHCHH), 4.27 (1H, dtd, J 14.2,
7.3 and 3.6 Hz, CHOBn), 4.07 (2H, s, CH2CO2); dC (100 MHz,
CDCl3) 169.8 (CO), 136.9 (ArC), 136.2 (ArC), 128.5 (4 ¥ ArCH),
128.4 (ArCH), 128.3 (ArCH), 128.1 (2 ¥ ArCH), 128.0 (2 ¥ ArCH),
74.8 (dd, J 27.0 and 22.7 Hz, CHOBn), 74.5 (CH2Ph), 73.4
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 811
©

View Article Online
(2R)-1-Benzyloxy-3,4,4-trifluorobut-3-en-2-ol (30)
(100); HRMS (ES+) for C12H12F4NaO3 (M + Na)+ calcd 303.0615,
found 303.0614.
Colourless oil. nmax(film)/cm-1 3396 (m, br), 2870 (m), 1790 (s),
1455 (m), 1309 (s), 1257 (s), 1104 (s); dH (300 MHz, CDCl3) 7.42–
7.31 (5H, m, ArH), 4.67–4.54 (3H, m, CH2Ph and CHOH), 3.70
(1H, dd, J 9.6 and 7.5 Hz, CHCHH), 3.65 (1H, dd, J 9.6 and
5.2 Hz, CHCHH), 2.82 (1H, br s, OH); dC (100 MHz, CDCl3)
137.2 (ArC), 128.5 (2 ¥ ArCH), 128.0 (ArCH), 127.8 (2 ¥ ArCH),
73.5 (CH2Ph), 69.7 (CH2CH), 64.7 (CH, d, J 20.9 Hz, CHOH).
The CF2CF2 carbons were not observed; dF (282 MHz, CDCl3
referenced to CFCl3) -100.94 (1F, dd, J 76.2 and 33.2 Hz, CFF),
-119.18 (1F, ddd, J 114.8, 76.2 and 2.1 Hz, CFF), -188.88 (1F,
ddd, J 114.8, 32.2 and 24.7 Hz, CF); ES+MS m/z 255.2 ((M +
Na)+, 100%); HRMS (ES+) for C11H11F3NaO2 (M + Na)+ calcd
255.0603, found 255.0603.
Data for 4b: mp 86–88 ◦C; nmax(film)/cm-1 3356 (br m), 2893 (w),
1346 (w), 1231 (m), 1136 (m), 1117 (m), 1066 (s), 975 (s), 949 (m);
dH (400 MHz, CDCl3) 7.41–7.35 (5H, m, ArH), 4.94 (1H, br s,
CHOH), 4.89 (1H, d, J 12.0 Hz, CHHPh), 4.67 (1H, d, J 12.0 Hz,
CHHPh), 3.99 (1H, dt, J 12.1 and 4.7 Hz, CHCHH), 3.90 (1H,
m, CHOBn), 3.57 (1H, m, CHCHH), 3.36 (1H, br s, OH); dC
(100 MHz, CDCl3) 136.5 (ArC), 128.7 (2 ¥ ArCH), 128.5 (ArCH),
128.1 (2 ¥ ArCH), 92.1 (ddd, J 28.9, 21.6 and 2.2 Hz, CHOH), 74.2
(CH2Ph), 73.0 (t, J 19.2 Hz, CHOBn), 61.7 (dd, J 6.1 and 1.7 Hz,
CHCH2); dF (282 MHz, CDCl3 referenced to CFCl3) -127.99
(1F, d, J 263.3 Hz, CFFCHOH), -133.1 (1F, dt, J 261.1 and
16.1 Hz, CFFCHOBn), -134.18 (1F, d, J 263.3 Hz, CFFCHOH),
-139.27 (1F, m, J 262.2 Hz can be observed, CFFCHOBn); EIMS
m/z 280 (M+, 19%), 262 (3), 107 (22), 91 (100); HRMS (ES+) for
C12H12F4NaO3 (M + Na)+ calcd 303.0615, found 303.0615.
(5R)-2,5-Bisbenzyloxymethyl-3,3,4,4-tetrafluoro
tetrahydrofuran-2-ol (3)
(5R)-2,5-Bisbenzyloxymethyl-3,3,4,4-tetrafluoro
tetrahydropyran-2-ol (5)
A colourless oil (0.084 g, 75%), as an inseparable mixture of
anomers. nmax(film)/cm-1 3398 (w), 3032 (w), 2876 (w), 1497 (w),
1454 (m), 1366 (w), 1148 (s), 1101 (s); dH (400 MHz, CDCl3)
7.21–7.10 (20H, m, ArH), 4.51–4.21 (10H, m), 4.07 (1H, br s),
3.66–3.45 (8H, m); dC (100 MHz, CDCl3) 137.3 (C), 136.9 (C),
136.8 (C), 136.6 (C), 128.59 (2 ¥ CH), 128.52 (2 ¥ CH), 128.51
(2 ¥ CH), 128.4 (2 ¥ CH), 128.25 (CH), 128.11 (CH), 128.04 (CH),
127.94 (2 ¥ CH), 127.88 (3 ¥ CH), 127.85 (2 ¥ CH), 127.72 (2 ¥
CH), 99.3 (m, C), 98.7 (dd, J 31.1 and 21.4 Hz, C), 78.2 (dd, J
29.1 and 24.3 Hz, CH), 77.2 (dd, J 28.0 and 23.2 Hz, CH), 74.10
(CH2), 74.03 (CH2), 73.79 (CH2), 73.64 (CH2), 68.6 (m, CH2),
68.1 (d, J 4.9 Hz, CH2), 67.3 (dd, J 6.3 and 3.4 Hz, CH2), 66.12
(d, J 7.8 Hz, CH2); dF (282 MHz, CDCl3) -111.1 (1F, dddd, J
243.0, 11.7, 4.2 and 2.7 Hz, CFFC), -122.35 (1F, ddt, J 245.5,
13.8 and 5.4 Hz, CFFC), -123.49 (1F, m, CFFC), -129.4 (1F,
dt, J 239.4 and 5.0 Hz, CHCFF), -130.81 (1F, d, J 185.7 Hz,
CHCFF), -131.45 (1F, d, J 184.5, CHCFF), -131.90 (1F, dt, J
241.0 and 6.3 Hz, CHCFF), -134.10 (1F, dd, J 243.5, 13.9 and
5.4 Hz, CFFC); CIMS: m/z 418 ((M + NH4)+, 8%), 309 (2), 106
(100), 91 (65); HRMS (ES+) for C20H20F4O4 (M)+ calcd 423.1190,
found 423.1186.
Preparative HPLC (hexane–acetone, 85 : 15) gave 5 as a single
anomer (0.11 g, 65%) and mixed fractions containing both 5a
and 5b (0.017 g, 10%). The data given are for the major isomer
5a. nmax(film)/cm-1 3489 (br w), 3033 (w), 2879 (w), 1455 (m),
1303 (m), 1214 (m), 1104 (s), 1062 (s), 926 (m); dH (400 MHz,
CDCl3) 7.41–7.31 (10H, m, ArH), 4.90 (1H, d, J 12.1 Hz,
CHOCHHPh), 4.70 (1H, d, J 12.0 Hz, CH2OCHHPh), 4.68–4.62
(2H, m, CH2OCHHPh + CHOCHHPh), 4.20 (1H, t, J 2.8 Hz,
OH), 4.04 (1H, t, J 11.2 Hz, CHCHH), 3.90 (1H, m, CHOBn),
3.75 (1H, d, J 10.7 Hz, CHHOBn), 3.72 (1H, m, CHCHH), 3.62
(1H, app d, J 10.6 Hz, CHHOBn); dC (100 MHz, CDCl3) 136.8
(ArC), 136.6 (ArC), 128.63 (2 ¥ ArCH), 128.61 (2 ¥ ArCH), 128.33
(ArCH), 128.30 (ArCH), 127.98 (2 ¥ ArCH), 127.92 (2 ¥ ArCH),
95.5 (dd, J 28.2 and 25.3 Hz, CCF2), 74.4 (CH2Ph), 74.2 (CH2Ph),
72.7 (t, J 18.5 Hz, CHCF2), 68.4 (d, J 3.9 Hz, CH2OBn), 59.3 (d,
J 7.8 Hz, CHCH2); dF (282 MHz, CDCl3 referenced to CFCl3)
-127.41 (1F, dddd, J 254.7, 19.9, 9.7 and 5.4 Hz, CFFCOH),
-127.92 (1F, m, J 264.0 Hz can be observed, CFFCOH), -130.39
(1F, dtd, J 255.8, 17.2 and 7.5 Hz, CHCFF), -135.71 (1F, ddd,
J 266.5, 17.3 and 9.9 Hz, CHCFF); EIMS m/z 309 ((M - Bn)+,
10%), 91 (100); HRMS (ES+) for C20H20F4NaO4 (M + Na)+ calcd
423.1190, found 423.1192.
(2S,5R)-5-Benzyloxy-3,3,4,4-tetrafluoro tetrahydropyran-2-ol
(4a) and (2R,5R)-5-benzyloxy-3,3,4,4-tetrafluoro tetrahydro-
pyran-2-ol (4b)
(5R)-3,3,4,4-Tetrafluoro tetrahydropyran-2,5-diol
(2,3-dideoxy-2,2,3,3-tetrafluororibopyranose) (6)
White solids: 4a (0.028 g, 18%) and 4b (0.08 g, 51%).
Data for 4a: mp 85–88 ◦C; nmax(film)/cm-1 3380 (m), 1216 (m),
1134 (s), 1115 (m), 1067 (s), 1053 (s), 1028 (m), 988 (m); dH
(400 MHz, CDCl3) 7.41–7.33 (5H, m, ArH), 5.09 (1H, br s,
CHOH), 4.89 (1H, d, J 11.8 Hz, CHHPh), 4.68 (1H, d, J 12.1 Hz,
CHHPh), 4.05 (1H, m, CHCHH), 3.89 (1H, m, CHOBn), 3.72
(1H, dt, J 11.9 and 4.1 Hz, CHCHH), 3.56 (1H, m, OH); dC
(100 MHz, CDCl3) 136.5 (ArC), 128.7 (2 ¥ ArCH), 128.4 (ArCH),
128.1 (2 ¥ ArCH), 92.0 (dd, J 35.2 and 25.1 Hz, CHOH), 74.1
(CH2Ph), 73.1 (dd, J 20.4 and 19.0 Hz, CHOBn), 60.5 (CHCH2);
dF (282 MHz, CDCl3 referenced to CFCl3) -124.51 (1F, br d, J
268.6 Hz, CFF), -124.98 (1F, br d, J 262.2 Hz, CFF), -130.76
(1F, dt, J 264.3 and 15.0 Hz, CFF), -136.24 (1F, dd, J 269.7 and
15.0 Hz, CFF); EIMS m/z 280 (M+, 50%), 262 (8), 107 (49), 91
To a stirred solution of 2 (0.1 g, 0.36 mmol) in EtOAc (2.9 mL) was
added Pd(OH)2/C (10% Pd/C, 0.12 g). The flask was evacuated
and purged with H2. This sequence was repeated twice more
and then the reaction allowed to stir for 4 h. The reaction was
diluted with EtOAc (10 mL) and then filtered through celite. The
residue was washed with EtOAc (2 ¥ 10 mL) and the combined
filtrates concentrated in vacuo. The resulting oil was purified by
column chromatography (petroleum ether–acetone, 70 : 30) to
give a colourless oil (0.067 g, 98%) which solidified on standing,
which was found to be 6 as an inseparable 2.8 : 1 mixture of
anomers. Mp 87–89 ◦C; nmax(film)/cm-1 3313 (br m), 2968 (w),
1635 (br w), 1264 (m), 1206 (m), 1111 (s), 1065 (s), 1040 (s),
812 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
997 (s); dH (400 MHz, d6-DMSO) 7.87 (1H, d, J 6.52 Hz, OCHOH,
major isomer, disappears upon D2O exchange), 7.69 (1H, d, J
4.02 Hz, OCHOH, minor isomer, disappears upon D2O exchange),
6.18 (1H, d, J 5.77 Hz, CH2CHOH, major isomer, disappears
upon D2O exchange), 6.13 (1H, d, J 6.53 Hz CH2CHOH, minor
isomer, disappears upon D2O exchange), 5.14 (1H, m, OCHOH,
minor isomer, simplifies to ddd, J 7.0, 5.2 and 1.7 Hz upon D2O
exchange), 4.90 (1H, m, OCHOH, major isomer, simplifies to
app. dd, J 14.7 and 3.9 Hz), 3.40–3.89 (3H, m, 2 ¥ CF2CH +
CHH), 3.81 (1H, t, J 10.4 Hz, CHH, minor isomer), 3.66 (1H,
m, CHH, minor isomer), 3.42 (1H, t, J 10.3 Hz, CHH, major
isomer); dC (100 MHz, d6-DMSO) 91.4 (m, OCHOH, major
isomer), 90.9 (dd, J 35.1 and 24.3 Hz, OCHOH, minor isomer),
66.6–66.1 (m, 2 ¥ CH2CH), 62.7 (d, J 6.8 Hz, CH2, major isomer),
60.0 (CH2, minor isomer); dF (376 MHz, d6-DMSO, recorded
at 50 ◦C) -121.25 (1F, br d, J 261.0 Hz, CF2CFFCH), -127.15
(1F, br d, J 250.7 Hz, CF2CFFCH), -128.87 (1F, bdd, J 253.3
and 13.4 Hz, CF2CFFCH), -130.95 (1F, ddd, J 252.6, 16.7 and
5.8 Hz, CHCFFCF2), -132.66 (1F, br d, J 254.5 Hz, CF2CFFCH),
-132.86 (1F, ddd, J 214.3, 16.1 and 4.9 Hz Hz, CHCFFCF2),
-133.54 (1F, ddd, J 223.2, 16.1 and 6.5 Hz, CHCFFCF2), -136.80
(1F, ddd, J 257.9, 16.8 and 5.4 Hz, CHCFFCF2); ESMS (ES-)
m/z 189 (M - H+, 100%), 161 (12), 149 (8), 129 (22); HRMS (ES+)
for C5H6F4NaO3 (M + Na)+ calcd 213.0145, found 213.0148.
minor isomer), -129.39 (1F, dddd, J 247.8, 18.2, 16.1 and 6.4 Hz,
CFFCHOH, major isomer), -132.32 (1F, dddd, J 261.8, 15.0,
9.7 and 5.4 Hz, CFFCHOH, minor isomer), -133.88 (1F, m,
CFFCHOH, major isomer); ESMS (ES+) m/z 243 ((M + Na)+,
55), 139 (100); HRMS (ES+) for C6H8F4NaO4 (M + Na)+ calcd
243.0257, found 243.0251.
Acknowledgements
AJB thanks GlaxoSmithKline and EPSRC for a CASE stu-
dentship. RST thanks ORS for a stipend. KJB thanks Dextra
Laboratories and EPSRC for a CASE studentship. We thank Luke
W. Judd for starting with the monobenzylation experiments. We
are grateful to Prof. R. J. Whitby and Dr Martin Swarbrick for
support. We also wish to acknowledge the use of the EPSRC’s
Chemical Database service at Daresbury.37
References and notes
1 (a) A. Varki, Glycobiology, 1993, 3, 97–130; (b) L. A. Lasky, Annu.
Rev. Biochem., 1995, 64, 113–139; (c) R. A. Dwek, Chem. Rev., 1996,
96, 683–720; (d) H. Lis and N. Sharon, Chem. Rev., 1998, 98, 637–674;
(e) P. M. Rudd, T. Elliott, P. Cresswell, I. A. Wilson and R. A. Dwek,
Science, 2001, 291, 2370–2376; (f) G. E. Ritchie, B. E. Moffatt, R. B.
Sim, B. P. Morgan, R. A. Dwek and P. M. Rudd, Chem. Rev., 2002, 102,
305–319; (g) R. S. Haltiwanger and J. B. Lowe, Annu. Rev. Biochem.,
2004, 73, 491–537.
2 (a) A. Helenius, Mol. Biol. Cell, 1994, 5, 253–265; (b) E. S. Trombetta
and A. Helenius, Curr. Opin. Struct. Biol., 1998, 8, 587–592; (c) A.
Helenius and M. Aebi, Science, 2001, 291, 2364–2369.
(5R)-2-Hydroxymethyl-3,3,4,4-tetrafluoro tetrahydropy-ran-
2,5-diol (3,4-dideoxy-3,3,4,4-tetrafluorofructopyranose) (7)
3 (a) A. C. Weymouth-Wilson, Nat. Prod. Rep., 1997, 14, 99–110; (b) J. M.
Langenhan, B. R. Griffith and J. S. Thorson, J. Nat. Prod., 2005, 68,
1696–1711; (c) J. S. Thorson, T. J. Hosted, Jr., J. Jiang, J. B. Biggins and
J. Ahlert, Curr. Org. Chem., 2001, 5, 139–167.
4 (a) K. J. Doores, D. P. Gamblin and B. G. Davis, Chem.–Eur. J., 2006, 12,
656–665; (b) B. G. Davis, Science, 2004, 303, 480–482; (c) B. G. Davis,
Chem. Rev., 2002, 102, 579–601; (d) S. A. W. Gruner, E. Locardi, E.
Lohof and H. Kessler, Chem. Rev., 2002, 102, 491–514; (e) T. K. Ritter
and C.-H. Wong, Angew. Chem., Int. Ed., 2001, 40, 3508–3533; (f) K. M.
Koeller and C.-H. Wong, Nat. Biotechnol., 2000, 18, 835–841; (g) G. D.
Armstrong, Curr. Opin. Drug Discovery Dev., 2000, 3, 191–202; (h) P.
Sears and C.-H. Wong, Angew. Chem., Int. Ed., 1999, 38, 2300–2324;
(i) L. A. Marcaurelle and C. R. Bertozzi, Chem.–Eur. J., 1999, 5, 1384–
1390.
5 (a) M. Ambrosi, N. R. Cameron and B. G. Davis, Org. Biomol. Chem.,
2005, 3, 1593–1608; (b) R. U. Lemieux, Acc. Chem. Res., 1996, 29,
373–380; (c) E. J. Toone, Curr. Opin. Struct. Biol., 1994, 4, 719–728.
6 (a) N. F. Burkhalter, S. M. Dimick, E. J. Toone, in Carbohydrates in
Chemistry and Biology, ed. B. Ernst, G. W. Hart, P. Sinay, Wiley-VCH,
Weinheim, 2000, ch. 31; (b) R. U. Lemieux, Chem. Soc. Rev., 1989, 18,
347–374.
To a stirred solution of 3 (0.50 g, 1.25 mmol) in EtOAc (10 mL) was
added Pd(OH)2/C (10% Pd/C, 0.40 g). The flask was evacuated
and purged with H2. This sequence was repeated twice more
and then the reaction allowed to stir for 16 h. The reaction was
diluted with EtOAc (30 mL) and then filtered through celite. The
residue was washed with EtOAc (2 ¥ 30 mL) and the combined
filtrates concentrated in vacuo. The resulting oil was purified by
column chromatography (petroleum ether–acetone, 60 : 40) to
give a colourless oil (0.26 g, 96%), which was found to be 7 as
an inseparable mixture of anomers (ratio approximately 14 : 1).
n
max(film)/cm-1 3354 (br m), 1698 (m), 1150 (s), 1094 (s), 1046 (s),
870 (s); dH (400 MHz, d6-DMSO) 6.83 (1H, br s, OH, major
isomer), 6.70 (1H, br s, OH, minor isomer), 6.10 (1H, br s, OH,
major isomer), 5.96 (1H, br s, OH, minor isomer), 5.13 (2H, m,
2 ¥ CH2OH, major and minor isomer), 4.09 (1H, d, J 12.8 Hz,
CHHOH, minor isomer), 3.90 (2H, m, 2 ¥ CHOH), 3.77 (1H,
t, J 10.39 Hz, CHCHH, major isomer), 3.65 (1H, m, CHCHH,
major + minor isomer), 3.58 (1H, d, J 12.1 Hz, CHHOH, major
isomer), 3.53 (1H, app. s, CHHOH, minor isomer), 3.48 (1H,
d, J 11.8, CHHOH, major isomer); dC (100 MHz, d6-DMSO)
95.6 (dd, J 29.2 and 21.9 Hz, CCF2, major isomer, signal minor
isomer is obscured), 67.9 (dd, J 30.8 and 18.7 Hz, CHCF2, minor
isomer), 66.0 (t, J 18.95 Hz, CHCF2, major isomer), 61.7 (CH2OH,
major isomer), 61.6 (CH2OH, minor isomer), 59.4 (d, J 7.3 Hz,
2 ¥ CH2OC, major isomer, signal minor isomer is obscured); dF
(282 MHz, d6-DMSO referenced to CFCl3) -115.83 (1F, ddt, J
260.0, 15.0 and 7.5 Hz, CFFCOH, minor isomer), -123.80 (1F,
ddd, J 261.8, 17.2 and 7.5 Hz, CFFCOH, minor isomer), -124.51
(1F, m, J 262.2 can be observed, CFFCOH, major isomer),
-128.06 (1F, m, J 248.2 Hz can be seen, CFFCHOH, major
isomer), -128.27 (1F, m, J 260.5 Hz can be seen, CFFCOH,
7 J. Gao, S. Qiao and G. M. Whitesides, J. Med. Chem., 1995, 38, 2292–
2301.
8 (a) H. W. Kim, P. Rossi, R. K. Schoemaker and S. G. DiMagno, J. Am.
Chem. Soc., 1998, 120, 9082–9083; (b) J. C. Biffinger, H. W. Kim and
S. G. DiMagno, ChemBioChem, 2004, 5, 622–627.
9 K. Mu¨ller, C. Faeh and F. Diederich, Science, 2007, 317, 1881–1886.
10 (a) A. J. Boydell, V. Vinader and B. Linclau, Angew. Chem., Int. Ed.,
2004, 43, 5677–5679; (b) R. S. Timofte and B. Linclau, Org. Lett., 2008,
10, 3673–3676.
11 R. P. Singh, U. Majumder and J. Schreeve, J. Org. Chem., 2001, 66,
6263–6267.
12 J. M. Percy, Top. Curr. Chem., 1997, 193, 131–195.
13 (a) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483–3547; (b) A. B. Zaitsev and H. Adolfsson, Synthesis,
2006, 1725–1756.
14 B. Linclau, Chim. Oggi, 2007, 25, 51–54.
15 (a) K. P. M. Vanhessche and K. B. Sharpless, Chem.–Eur. J., 1997,
3, 517–522; (b) H. Becker and K. B. Sharpless, Angew. Chem., Int.
Ed. Engl., 1996, 35, 448–451; (c) C. Do¨bler, G. M. Mehltretter,
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 803–814 | 813
©

View Article Online
U. Sundermeier and M. Beller, J. Am. Chem. Soc., 2000, 122, 10289–
10297; (d) C. Do¨bler, G. M. Mehltretter, U. Sundermeier and M. Beller,
J. Organomet. Chem., 2001, 621, 70–76.
28 (a) Reviews: D. J. Burton and Z.-Y. Yang, Tetrahedron, 1992, 48,
189–275; (b) H. Uno and H. Suzuki, Synlett, 1993, 91–96; (c) D. J.
Burton and L. Lu, Top. Curr. Chem., 1997, 193, 45–89; (d) H. Gilman,
J. Organomet. Chem., 1975, 100, 83–95.
29 (a) Examples: J. Hine and P. B. Langford, J. Org. Chem., 1962, 27,
4149–4151; (b) P. Johncock, J. Organomet. Chem., 1969, 19, 257–265;
(c) R. D. Chambers, W. K. R. Musgrave and J. Savory, J. Chem. Soc.,
1962, 1993–1999; (d) K. Tanaka, T. Nakai and N. Ishikawa, Tetrahedron
Lett., 1978, 48, 4809–4810; (e) L. S. Chen, G. J. Chen and C. Tamborski,
J. Fluorine Chem., 1984, 26, 341–358; (f) S. T. Patel, J. M. Percy and
R. D. Wilkes, Tetrahedron, 1995, 51, 9201–9216; (g) G.-Q. Shi and
W. - L . C a i , Synlett, 1996, 371–372; (h) G. Magueur, B. Crousse, M.
Oure´vitch, D. Bonnet-Delpon and J.-P. Be´gue´, J. Fluorine Chem., 2006,
127, 637–642.
16 G. M. Mehltretter, C. Do¨bler, U. Sundermeier and M. Beller, Tetrahe-
dron Lett., 2000, 41, 8083–8087.
17 M. H. Junttila and O. E. O. Hormi, J. Org. Chem., 2004, 69, 4816–4820.
18 Y. L. Bennani, K. P. M. Vanhessche and K. B. Sharpless, Tetrahedron:
Asymmetry, 1994, 5, 1473–1476.
19 (a) A. Ayari, S. Szonyi, E. Rouvier and A. Cambon, Bull. Soc. Chim.
Fr., 1992, 129, 315–318; (b) J. Kv´ıcala, B. Dolensky and O. Paleta,
J. Fluorine Chem., 1997, 85, 117–125; (c) A. M. Kornilov, I. B. Kulik,
A. E. Sorochinsky and V. P. Kukhar, Tetrahedron: Asymmetry, 1995,
6, 199–206; (d) K. Li, C. Leriche and H.-W. Liu, Bioorg. Med. Chem.
Lett., 1998, 8, 1097–1100.
20 (a) T. Yamazaki, K. Mizutani and T. Kitazume, J. Org. Chem., 1993, 58,
4346–4359; (b) T. Yamazaki, T. Oniki and T. Kitazume, Tetrahedron,
1996, 52, 11753–11762.
30 (a) C. Wakselman and T. Nguyen, J. Org. Chem., 1977, 42, 565–566;
(b) T. Nguyen and C. Wakselman, J. Org. Chem., 1989, 54, 5640–5642.
31 (a) O. R. Pierce, E. T. McBee and G. F. Judd, J. Am. Chem. Soc., 1954,
76, 474–478; (b) P. G. Gassman and N. J. O’Reilly, Tetrahedron Lett.,
1985, 26, 5243–5246; (c) P. G. Gassman and N. J. O’Reilly, J. Org.
Chem., 1987, 52, 2481–2490; (d) H. Uno, Y. Shiraishi and H. Suzuki,
Bull. Chem. Soc. Jpn., 1989, 62, 2636–2642.
32 (a) O. R. Pierce, A. F. Meiners and E. T. McBee, J. Am. Chem. Soc.,
1953, 75, 2516; (b) C. F. Smith, E. J. Soloski and C. Tamborski,
J. Fluorine Chem., 1974, 4, 35–45; (c) See also: K. Uneyama and H.
Amii, J. Fluorine Chem., 2002, 114, 127–131.
33 M. Rottla¨nder, L. Boymond, L. Be´rillon, A. Lepreˆtre, G. Varchi, S.
Avolio, W. Laaziri, G. Que´guiner, A. Ricci, G. Cahiez and P. Knochel,
Chem.–Eur. J., 2000, 6, 767–770.
34 (a) Examples: R. Sauveˆtre, D. Masure, C. Chuit and J. F. Normant,
Synthesis, 1978, 128–130; (b) J. Burdon, P. L. Coe, I. B. Haslock and
R. L. Powell, J. Fluorine Chem., 1999, 99, 127–131.
21 (a) S. David and S. Hanessian, Tetrahedron, 1985, 41, 643–663;
(b) For a stannylene acetal mediated regioselective acetylation (internal
allylic difluoroalkene): C. Audouard, J. Fawcett, G. A. Griffith, E.
Ke´roure´dan, A. Miah, J. M. Percy and H. Yang, Org. Lett., 2004,
6, 4269–4272; (c) The opposite regioselectivity was reported for a
stannylene acetal mediated methylation reaction: M. I. Barrena, M. I.
Matheu and S. Castillo´n, J. Org. Chem., 1998, 63, 2184–2188.
22 J. E. Leibner and J. Jacobus, J. Org. Chem., 1979, 44, 449–450.
23 (a) T. Katagiri, in Enantiocontrolled Synthesis of Fluoro-Organic
Compounds, ed. V. A. Soloshonok, Wiley, Chichester, 1999, p. 165;
(b) C. F. Morelli, A. Fornili, M. Sironi, L. Dur`ı, G. Speranza and P.
Manittoa, Tetrahedron: Asymmetry, 2002, 13, 2609–2618.
24 X. Zhang, H. Xia, X. Dong, J. Jin, W.-D. Meng and F.-L. Qing, J. Org.
Chem., 2003, 68, 9026–9033.
25 C. Audouard, J. Fawcett, G. A. Griffiths, J. M. Percy, S. Pintat and C. A.
Smith, Org. Biomol. Chem., 2004, 2, 528–541.
26 (a) G. K. Surya Prakash, R. Krishnamurti and G. A. Olah, J. Am. Chem.
Soc., 1989, 111, 393–395; (b) G. K. Surya Prakash and A. K. Yudin,
Chem. Rev., 1997, 97, 757–786; (c) R. P. Singh and J. M. Schreeve,
Tetrahedron, 2000, 56, 7613–7632; (d) G. K. Surya Prakash and M.
Mandal, J. Fluorine Chem., 2001, 112, 123–131.
35 V. Wray, J. Chem. Soc., Perkin Trans. 2, 1976, 1598–1605.
36 (a) These sets of coupling constants correspond with literature examples
of a and b-anomers of 2-deoxy-2,2-difluoro pyranosides: A. El-
Laghdach, R. Echarri, M. I. Matheu, M. I. Barrena, S. Castillo´n and J.
Garcia, J. Org. Chem., 1991, 56, 4556–4559; (b) A. El-Laghdach, M. I.
Matheu, S. Castillo´n, C. Bliard, A. Olesker and G. Lukacs, Carbohydr.
Res., 1992, 233, C1–C3.
27 I. Ruppert, K. Schlich and W. Volbach, Tetrahedron Lett., 1984, 25,
2195–2198.
37 The United Kingdom Database Service. D. A. Fletcher, R. F. McMeek-
ing and D. Parkin, J. Chem. Inf. Comput. Sci., 1996, 36, 746–749.
814 | Org. Biomol. Chem., 2009, 7, 803–814
This journal is
The Royal Society of Chemistry 2009
©