Developing an asymmetric, stereodivergent route to selected 6-deoxy-6-fluoro-hexoses

Article abstract of DOI:10.1039/b815342f

Free radical bromination and nucleophilic fluorination allows the conversion of methyl sorbate into the 6-fluoro analogue which undergoes sequential asymmetric dihydroxylation reactions. A range of 6-deoxy-6- fluorosugars were prepared by using different

Full text of DOI:10.1039/b815342f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Developing an asymmetric, stereodivergent route to selected
6-deoxy-6-fluoro-hexoses†
Audrey Caravano,a Robert A. Field,b Jonathan M. Percy,*c Giuseppe Rinaudo,c Ricard Roiga and Kuldip Singha
Received 3rd September 2008, Accepted 11th December 2008
First published as an Advance Article on the web 23rd January 2009
DOI: 10.1039/b815342f
Free radical bromination and nucleophilic fluorination allows the conversion of methyl sorbate into the
6-fluoro analogue which undergoes sequential asymmetric dihydroxylation reactions. A range of
6-deoxy-6-fluorosugars were prepared by using different combinations of ligands. While the
enantiomeric excesses obtained were comparable to those from other 6-substituted sorbates, the
regioselectivity of dihydroxylation was moderate, with both 2,3- and 4,5-diols being obtained. A
successful temporary persilylation strategy was evolved to convert the products of dihydroxylation
rapidly to the fluorosugars 6-deoxy-6-fluoro-L-idose, 6-fluoro-L-fucose and 6-deoxy-6-fluoro-D-
galactose, which were obtained in overall yields of 4%, 6% and 8% from methyl
6-fluoro-hexa-2E,4E-dienoate 6.
Introduction
Fluorosugars are unknown in nature though fluoronucleoside
natural products have been reported;1,2 indeed, nature makes very
few fluorinated compounds,3 so selective fluorination represents
an extremely useful strategy for locating molecules within the
complex environments of cells or within the molecular diversity
of the secondary metabolites. 19F NMR can be used to locate
fluorinated molecules and follow their transformations in vitro and
potentially in vivo, and some valuable insights have been obtained
in this way.1,2 One of the most common biosynthetic modifications
of the hexoses involves deoxygenation at the 6-position; this (and
further deoxygenation at the 2- and 3-positions) is a characteristic
feature of the sugars with which many macrolide antibiotics are
embellished.
For example, rhamnose 1 is shown within the context of
antibiotics elloramycin 2,4 novclobiocin 122 3,5 and aranciamycin
4.6 In humans, fucose 5 is a common and critical sugar; many
key cellular events, for example the inflammatory response and
tumour metastasis, involve fucose-containing oligosaccharides,
synthesised via the action of fucosyltransferase enzymes. The
removal of fucosyl residues from the non-reducing end of gly-
coconjugates by fucosidases is also important; a clinical condition
levels are also associated with certain carcinomas.7 Fucose and
(fucosidosis) arises from the accumulation of fucosylated glycol-
ipids and glycoproteins in various tissues. Changes in fucosylation
other 6-deoxyhexoses are an interesting and important class of
monosaccharide which are attracting the attention of a wide range
aDepartment of Chemistry, University of Leicester, University Road, Leices-
of chemists.8
ter, LE1 7RH, UK
Significant differences between the ways in which the hexoses
and their 6-deoxy analogues are recognised would be anticipated
(Fig. 1).
bDepartment of Biological Chemistry, John Innes Centre, Colney Lane,
Norwich, NR4 7UH
cWestCHEM Department of Pure and Applied Chemistry, Thomas Graham
Building, 295 Cathedral Street, Glasgow, G1 1XL, UK. E-mail: jonathan.
percy@strath.ac.uk; Fax: +44 141 4822; Tel: +44 141 548 4398
Whereas in the former class of sugars C-6 bears an hydroxyl
group which is capable of forming hydrogen bonds as both
acceptor and donor, in the latter class C-6 is within a methyl group
which cannot participate in this type of interaction. Though our
ideas about sugar recognition are becoming more sophisticated as
new types of binding are characterised and studied quantitatively,9
recognition via the formation of networks of classical hydrogen
bonds is still the most accepted model.10 The most likely home
† Electronic supplementary information (ESI) available: Details of HPLC
procedures and chromatograms, Cartesian coordinates and energies from
electronic structure calculations for 6 and 7, details of T1 determination
for 37, identification of pyranose and furanose forms and their anomers by
13C and 1H NMR, comparison of AD enantiomeric excesses with related
systems from the literature, and characterisation spectra for 7, 13, 6, 15a
and 16a, 17a and 18a, 19 and 20, 15b and 16b, 23, 25, 26, 28, 30, 31, 33,
34, 37, 39 and 40; crystal structure data. See DOI: 10.1039/b815342f
996 | Org. Biomol. Chem., 2009, 7, 996–1008
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phosphate uridylyltransferase.20 We sought a divergent route to
6-deoxy-6-fluoro sugars to feed through these activation methods,
from readily-available and inexpensive starting materials.‡ We
proposed a de novo route: Kirschning21 has pointed out the
advantages of total synthesis for the preparation of unusual
sugars and has summarised developments in the area up to
2001.
The synthesis of deoxyfluorosugars from other carbohydrates
usually requires extensive use of protecting group chemistry to ex-
pose a single hydroxyl group for nucleophilic fluorination. Withers
et al.22 and Schengrund et al.13 inter alia synthesised 6-deoxy-
6-fluorosugars in this way using nucleophilic fluorinating agent
DAST.23,24 Nucleophilic displacement of a good leaving group at
C-6 by fluoride ion has also been used extremely successfully;
6-deoxy-6-fluoro-1,2-O-isopropylidene-a-D-glucofuranoses25 and
6-fluoro-D-olivose26 inter alia were prepared in this way. However,
because numerous protection and deprotection steps may be
required to isolate the C-6 hydroxyl group, fluorination can be
difficult, time consuming and inflexible, and is always subject
to stereoelectronic effects exerted by the C(5)–O bond in the
pyranose. A different synthesis may be required for each member
of series of related hexose analogues and some may use scarce or
expensive starting materials.27 A strategically different approach
would involve the introduction of fluorine early in the synthesis,
to prepare an achiral but highly functionalised building block,
which could be transformed into a range of different highly
enantiomerically-enriched 6-deoxy-6-fluorosugars.28 Scheme 1
shows a direct retrosynthetic analysis which raises two strategic
issues.
Fig. 1 Cartoon representations of features within the binding site of
a sugar processing enzyme. (a) The C-6 hydroxyl group makes classical
hydrogen bonding interations with the protein; (b) a weakly attractive
interaction and a potential repulsive interaction with proximal basic
broups on the enzyme arise when F replaces OH; (c) shows the likely
arrangement within the CH3 binding site for a 6-deoxysugar; (d) shows
how F for H replacement may be less deleterious within the CH3 binding
site.
for the C-6 methyl group is a hydrophobic pocket (Fig. 1c), a
favourable interaction making a modest additional contribution
to the overall binding energy. As CH3 and CH2OH also differ in
size, high selectivities for hexoses over 6-deoxyhexoses (or vice
versa) could be contrived (and would be expected) in higher
organisms, whereas species looking to maximise the diversity of
their molecular production (such as Streptomyces species) may
be more promiscuous11 and use less structured binding domains.
An enzyme which shows high affinity for galactosyl substrates,
for example a galactosyltransferase (GalT), may not accept a
6-deoxy-6-fluorogalactose as a substrate if hydrogen bonding
to the C-6 hydroxyl group is an important component of the
recognition motif. The independent studies of Kodama12 and
Schengrund13 would appear to support this idea. The former
study showed that a GalT could catalyse the transfer of UDP-6-
deoxy-6-fluoro-D-galactose and used the reaction in the synthesis
of antennary oligosaccharides (albeit with sacrificial loading of
enzyme), whereas the latter study showed the activated sugar
was bound by two GalTs, neither of which could use UDP-6-
fluoro-D-galactose as a substrate. While it is known that stabilising
C–F ◊ ◊ ◊ H–X interactions can be formed to allow other more
favourable non-covalent bonding events to take place (Fig. 1b),14,15
the interactions are relatively weak and unlikely to compensate for
the loss of a C–O ◊ ◊ ◊ H–X interaction. However, a fucosyltrans-
ferase (FucT) cannot use a hydrogen bond to recognise C-6, and
we might expect a CH2F group to fit reasonably well into the
hydrophobic binding site for a CH3, given that the monofluorina-
tion represents the minimal steric perturbation that we can make
(Fig. 1d).
Scheme 1 Retrosynthetic analysis.
The first issue concerns the practicality of regioselective and
sequential ADs of a fluorinated hexadienoate substrate. The
Sharpless group’s AD reactions of ethyl sorbate29 indicate that
multiple hydroxyl groups can be added to the hexadienoate
template; maintaining C-1 at the carboxylic acid oxidation level
could potentially save a number of oxidation/reduction steps.
Corey and Guzma´n-Pe´rez30 showed how the first issue could
be resolved (though no sugar syntheses were ever reported)
with highly enantioselective and diastereoselective sequential
dihydroxylations of protected sorbyl alcohols. The approach has
more recently been developed to great effect by Somfai31 and
O’Doherty32 in total syntheses of complex natural products.
In order to appreciate the fine detail of the structure and
mechanism of sugar nucleotide processing enzymes, including
epimerases,16 isomerases17 and glycosyltransferases,18,19 routine
access to sugar nucleotides is required. In the case of D-galactose
derivatives (and some other sugars), this is achieved practically
through the concerted action of galactokinase and galactose-1-
‡ Racemic 6-deoxy-6-fluoro-galactose prepared in this manner proved to
be an effective substrate for the enzymatic synthesis of UDP 6-deoxy-6-
fluoro-galactose; see accompanying publication (DOI: 10.1039/b815549f).
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product 14 was also identifiable in the product mixture;38
significant amount of bromide is diverted to this side product
(ratios of 6:14 of 2:1 to 3:1 were typical).
The second issue concerns the preparation of the 6-fluoro-
hexadienoate 6. Fluorides of this structural type are uncommon
in the literature; Purrington prepared 4-fluorobutenoate 9 by
direct fluorination of silylketene acetal 8 with elemental fluorine
(Scheme 2). Silver-mediated fluorinations of butenoyl bromide 10
are also known33 delivering 11 in moderate yield but via a slow
and expensive reaction. We decided to explore halogen exchange
reactions of known34 bromide 7 as an entry to 6.35
a
Hexadienoate 6 was then subject to sequential UpJohn dihy-
droxylations and the crude product was per-trialkylsilylated39 and
purified (Scheme 3). The products at this stage were insepara-
ble furanolactones 15 (major) and 16 (minor); in the HMBC
spectrum, a clear cross-peak connected the lactone carbonyl and
H-4. We were able to determine the ratio of diastereoisomers
1
19
by { H} F NMR, measuring ratios of 15:1 (R = SiMe3, 38%
over 2 steps) and 12:1 (R = SiMe2t-Bu, 42% over 2 steps).
The mixtures were taken on and products arising from the
minor diastereoisomer were removed in the final purification.
Reduction with DIBAL-H was used to adjust the oxidation level at
C-1; the tris(trimethylsilyl) species 15b and 16b were reduced and
deprotected (3:6:1 HCOOH–THF–H2O) directly to afford the
racemic 6-deoxy-6-fluorogalactose as an 11:1 mixture of pyranose
19 and furanose 20 (58% over 2 steps). The data were identical
with those reported by Schengrund and Kovac13§ and co-workers,
so this represents a very direct preparation of a racemic 6-deoxy-
6-fluorosugar.
Scheme 2 Literature preparations of g-fluorobutenoates.
In this manuscript, we describe the two-step preparation of
6 from methyl sorbate, sequential AD reactions and the syn-
thetic endgame leading to the preparation of four 6-deoxy-6-
fluorohexoses and a 2,3,6-trideoxy-6-fluorohexose. The scope and
limitations of the route will be discussed.
Results and discussion
Hexadienoate synthesis and sequential (scalemic) dihydroxylation
Methyl sorbate was converted to bromide 7 using the method of
Green and co-workers.34 However, we were not able to reproduce
the high-yielding and selective reaction reported in the literature.
Crude reaction mixtures also contained two side-products believed
to be bromide 12 and dibromide 13 (characterised more fully
as a 1:1 mixture of syn- and anti-diastereoisomers);36 rigorous
separation of these compounds from 7 resulted in significant
yield loss. However, we note that Green and co-workers processed
several moles of dienoate (400 g scale); it may be that the procedure
is much more effective on the larger scale when fractional
distillation may allow purer bromide 7 to be obtained.
Nucleophilic fluorination was attempted using a range of
conditions; initially, we found that a fluorination using a mixture
of TBAF trihydrate and KHF2 mobilised with some hexane
afforded 6 in useful yield, after numerous attempts to employ
various forms (commercial “anhydrous” or the trihydrate) of
TBAF alone had resulted in decomposition. We were also able to
use the conditions described by Hou and co-workers (KF/TBAS
in MeCN),37 though the yield was lower using this method. The
hexadienoate was obtained as a crystalline volatile solid which
appeared to sublime close to 30 ◦C. The molecular structure in the
crystal was determined by X-ray crystallographic analysis.
The purity of the bromide used in the fluorination reaction
was critical; crude mixtures of products from the bromination
reaction could not be used and material which had been purified by
Kugelrohr failed to fluorinate cleanly, returning a complex mixture
of products. We were not able to scale the fluorination beyond
12 mmol without the yield decreasing still further. Hydrolysis
Scheme 3 Racemic dihydroxylation sequences. Reagents and conditions:
i, OsO4, NMO, t-BuOH, acetone, H2O, 20 ◦C; ii, TBSOTf, pyridine, dry
DMF, 24 h, rt for 15a, 16a; or iii, TMSCl, pyridine, 15 h, 0 ◦C for 15b,
16b, iv, DIBAL-H, dry PhMe, 0 ◦C; v, BF3·OEt2, CH3CN, 0 ◦C, 1 h (73%)
a
for 15a; or vi, THF–HCOOH–H2O (6:3:1), rt, 1 h (58%) for 15b. The
1
19
diastereoisomeric ratio was determined by { H} F NMR of the crude
reaction mixture.
We were able to isolate and purify a mixture of 17a and 18a (the
immediate products of DIBAL-H reduction) for characterisation.
These tris-O-TBDMS species required more forcing deprotection
§ The anomer assignment in this paper appears to be incorrect; the anomers
can be assigned with confidence from the HMBC spectrum using C1–H5
cross peaks, which are distinct for the two anomers.
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conditions after successful reduction. While treatment with TBAF
was destructive,40 ammonium fluoride (48 h in MeOH, rt) afforded
19 and 20 in moderate (49%) yi◦eld, exposure to boron trifluoride
etherate in acetonitrile (1 h, 0 C) was more effective,41 and the
free sugar was obtained in 80% yield. We were unable to detect
significant side products, such as those arising from fluoride ion
expulsion and epoxide formation, or dehydrofluorination and
alkene formation, during the formation of 19 or 20, or any of
the other intermediates or final sugars synthesised in this study.
Though the overall yields are slightly higher when TBS protec-
tion is used, the use of TMS allows a facile deprotection after which
no product purification is required. This is a distinct advantage
when valuable products are being isolated. The sequence of events
is likely to involve initial dihydroxylation across the C-4/C-5
alkenyl group on the basis of our asymmetric results (vide infra),
and those of O’Doherty. If this is the correct sequence of events, the
second UpJohn reaction is more stereoselective (and at a higher
temperature) than the outcome reported by O’Doherty and co-
workers for substrate-controlled UpJohn dihydroxylation of 21a
and 21b.
fully as possible. We did not find any products arising from
dihydroxylation of both alkenyl groups.
The ADs which delivered 21a and 21b were much more regios-
elective, with only these diols being formed. O’Doherty explained
these highly regioselective monodihydroxylation outcomes as
arising from the electronic deactivation of the a,b-alkenyl group by
the alkoxycarbonyl group. The potential second dihydroxylation
is disfavoured strongly by a conflict between the directing effect of
the g-hydroxyl group and the facial preference of the ligand.
In our case, the presence of even a single fluorine atom appears
to lower the reactivity of the g,d-alkenyl group of the diene as the
rates of the two dihydroxylations are now more alike. The fluorine
atom has a small effect on the diene HOMO energy, lowering it
from -8.92 eV for methyl sorbate to -9.19 eV for 6 (calculated in
Spartan06 at the MP2/6-311+G** level)43,44 (though the patterns
of Mulliken charges in the diene are very similar in fluorinated and
non-fluorinated cases). Even such small differences in HOMO
energy can affect dihydroxylation rates of alkenes significantly
according to quantitative studies of permanganate and chromyl
chloride-mediated dihydroxylations.45 The regiochemistry of the
dihydroxylation reaction of diene and polyene substrates has been
reviewed recently; though dienes like 6 were explicitly excluded
from consideration,46 it is clear that the factors determining
regioselectivity in diene dihydroxylation may be subtly balanced.
The ee values for our reactions were determined by chiral HPLC
(Chiralcel ODH, eluting with 1% i-PrOH in hexane) and compare
well with the values reported by O’Doherty for ethyl sorbate.47 The
second dihydroxylations revealed strong matched/mismatched
effects, summarised in Table 1. Diastereoselectivities as low as
2:1 (measured from the 19F NMR spectra of crude products) were
obtained in the mismatched cases.
The matched cases give much higher diastereoselectivities, as
expected from the results of O’Doherty inter alia. The protec-
tion strategy developed for the racemic syntheses was modi-
fied to deliver enantiomerically enriched 6-deoxy-6-fluorohexoses
(Scheme 7). After acetonide removal, per-trimethylsilylation
was achieved with N-methyl-N-trimethylsilyl trifluoroacetamide
before DIBAL-H reduction (Scheme 6); we used the more
reactive silylating reagent to shorten the reaction time with
the enantiomerically-enriched species and minimise the risk of
epimerisation. In the case of the major diastereoisomers 28 and
30 from the matched ADs, the per-trimethylsilylated furanolactols
were characterised fully, then deprotected (3:6:1 HCOOH–THF–
H2O) to afford the sugars. The major product 27 from the mis-
matched AD of 23 was taken through to sugar 31 directly; 29 was
converted to the bis-acetonide 34 and characterised at that stage.
The sugars were characterised by the usual NMR methods and
their rotations compared to those reported in the literature. The
Though the fluorine atom is remote, it appears to increase the
effectiveness of the g-hydroxyl group in exerting diastereofacial
control.
Sequential asymmetric dihydroxylation of 6
We exposed 6 to AD-mixes a and b at the osmate/ligand loadings
described by O’Doherty (Scheme 4),42 and converted the crude
products directly to their acetonides (Scheme 5). The AD reactions
were only moderately regioselective, affording 5:1 and 4:1 mixtures
of acetonides 23 (56% over two steps, 84% ee) and 24, and 25
(44% over two steps, 92% ee) and 26 respectively, but the products
were separable. The minor regioisomers were characterised as
Scheme 4 Substrate-controlled racemic dihydroxylation sequences re-
ported by O’Doherty. Reagents and conditions: i, OsO4, NMO, t-BuOH,
acetone, 0 ◦C; ii, Ac2O, pyridine.
Table 1 AD reactions of 23 and 25
From 23
From 25
Ratio
27:28b 29 (%)a 30 (%)a
Ratio
AD mix 27 (%)a 28 (%)a
29:30b
Scheme
5
Reagents and conditions: i, AD-mix-a: K2OsO4·2H2O,
a
b
31
(-)
30
2:1
(-)
52
52 (99% ee)c 1:22
25 2:1
(DHQ)2PHAL, CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH–H2O (1:1),
24 h, 4 ◦C; ii, 2-methoxypropene, p-TsOH(cat.), DMF, 3 h, rt (23, 56%
over 2 steps, ee = 84%); iii, AD-mix-b: K2OsO4·2H2O, (DHQD)2PHAL,
CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH–H2O (1:1), 24 h, 4 ◦C (25,
44% over 2 steps, ee = 92%).
64 (96% ee)c 1:14
a Yields are isolated purified yields. b Ratios were determined by 19F NMR
of crude product mixtures. c ee determined by chiral HPLC.
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33 and 8% for D-galactose analogue 37. The idose is a new
compound but 33 and 37 have been synthesised before. The
overall yields calculated using the methods of Kortynyk et al.49
for these compounds are 8% for 33 from L-galactono-1,4-lactone
and 32% for 37 from D-galactose respectively. As usual, the de novo
syntheses of a carbohydrate is less efficient and attractive than a
transformative method from a readily available precursor, but the
potential for fully asymmetric and divergent methodology from
an achiral precursor has been demonstrated.
Anomer ratios were assigned by comparison with literature
data; C-1, C-2 and C-4 13C NMR chemical shifts are often
diagnostic.50 The studies of Serianni and co-workers were par-
ticularly useful for deconvolution of the idose spectra.51
Scheme
6
Reagents and conditions: i, AD-mix-a: K2OsO4·2H2O,
(DHQ)2PHAL, CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH–H2O (1:1),
24 h, 4 ◦C; ii, AD-mix-b: K2OsO4·2H2O, (DHQD)2PHAL, CH3SO2NH2,
K3Fe(CN)6, K2CO3, t-BuOH–H2O (1:1), 24 h, 4 ◦C.
One feature of the NMR behaviour requires comment. We were
unable to obtain satisfactory integration of one of the H-2 protons
in 33 and 37 despite repeated re-purification of the sample, so we
measured the T1 values for as many protons as possible, and found
that the errant proton had a longer T1 than expected (6.3 s). All
the other T1 values measured lay between 1.5 and 4 s, similar to
the behaviour reported for galactose.52 Recording the spectra with
D1 = 30 s allowed correct integration of this signal.
We also hydrogenated 25 to prepare 6-fluoro-D-rhodinose53 via
lactone 38 (Scheme 8), which could be reduced directly under the
usual conditions to afford the 6-fluoro-2,3,6-trideoxysugar54 as a
complex mixture of furanoses 39 and pyranoses 40 (both anomers
of each).
Conclusions
The route is most effective at delivering syn,anti,syn combinations
of stereogenic centres with the all-syn diastereoisomers being more
difficult to make because of the mismatch between the ligand and
substrate-controlled selectivity.
The initial fluorination is difficult but our melt conditions and
the phase-transfer protocol of Hou and co-workers allows gram
quantities to be prepared. This study provides a valuable proof-of-
concept that simple fluorinated building blocks can be deployed
in effective stereodivergent syntheses of fluorinated sugars.
Scheme 7 Reagents and conditions: i, 3 M HCl, MeOH, 24 h, rt; ii,
CF3CON(Me)SiMe3, neat, 60 min, 60 ◦C; iii, DIBAL-H, dry PhMe,
-78 ◦C, 30 min; iv, THF–HCOOH–H2O (6:3:1) rt; v, 2-methoxypropene,
p-TsOH (cat.), DMF, 3 h, rt.
Experimental
NMR spectra were recorded on Bruker DPX-300, DRX-400,
AV400, DPX-500 or AV-600 spectrometers. 1H NMR spectra
were recorded at 300, 400, 500 and 600 MHz, 13C NMR spectra
at 75 and 100 MHz, and 19F spectra at 282 and 376 MHz.
1H and 13C NMR spectra were recorded using the deuterated
solvent as the internal reference. 19F NMR spectra were recorded
relative to an external standard of fluorotrichloromethane. Unless
Scheme 8 Reagents and conditions: i, H2, 10% w/w Pd/C, EtOH; ii, HCl,
MeOH, 18 h, rt; iii, DIBAL-H, dry PhMe, -78 ◦C.
3
otherwise stated, couplings, J, refer to JH-H couplings and are
given in Hertz. Thin layer chromatography (TLC) was performed
on precoated aluminium silica gel plated supplised by E. Merck,
A. G. Darmstadt, Germany (silica gel 60 F254, thickness 0.2 mm,
art. 1.05554) and compounds were visualised with UV light or a
potassium permanganate stain. Solvents were dried using a Pure-
Solv apparatus (Innovate Technology Inc). All other chemicals
were used as received without any further purification.
rotations of the D-6-deoxy-6-fluorogalactose48 and L-6-deoxy-6-
fluorogalactose49 were reported as [a]D = +76.5 (c 1.0, H2O)
22
22
and [a]D = -76.5 (c 0.23, H2O) respectively; the rotations for
18
our synthetic compounds were [a]D = +64.0 (c 0.5, H2O) and
18
[a]D = -65.9 (c 0.5, H2O) respectively, confirming the authenticity
of the final products and the sense of stereochemical assignment
throughout the sequences.
GC analyses were carried out using a Perkin Elmer Autosystem
◦
The overall yields of sugars from our sequences all calculated
from 6 are 4% for L-idose analogue 31, 6% for L-fucose analogue
XL instrument, using a standard PE-5◦column (injector 250 C,
◦
start temperature 40 C, ramp rate 10 C/min, end temperature
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280 ◦C) or a Finnegan Pro GC-MS system, using the same
temperature ramping programme, up to 320 ◦C Low resolution
mass spectral data were collected either on a Finnegan Pro GC-
MS system, using electron impact ionisation or on a Finnegan
Pro electrospray system (by manual injection), using methanol
or acetonitrile as solvents. High resolution mass spectra were
recorded by the EPSRC Mass Spectrometry service by either
electrospray or chemical ionisation, where polyethyleneimine was
used as a reference compound. Infra-red analyses were carried out
on a Perkin Elmer IR spectrometer, using KBr discs.
Crystals for X-ray analysis were grown by vapour diffusion.
Flash column chromatography was carried out on Biotage
Horizon (with pre-packed cartridges) or Buchi Sepacore (with self-
packed or Biotage SnapTM cartridges) instruments. Determination
of enantiomeric excess by HPLC was carried out using a CHI-
RALCEL OD-H (25 ¥ 0.46 cm ID) column with UV detection at
236 or 254 nm. Preparative HPLC was carried out on a Kromosil
6.8, H-5), 1.86 (d, 3H, J 6.8, CH3); dC (100 MHz, CDCl3) 143.9
(C-3), 123.4 (C-2), 54.7 (C-4), 49.4 (C-5), 24.5 (CH3).
In the 1H NMR the following signals were not assigned to one
diastereoisomer: 3.74 (s, 3H, OCH3), 3.73 (s, 3H, OCH3) In the
13C NMR, the following signals were not assigned to a single
=
=
diastereoisomer: 165.5 (C O), 165.4 (C O) 51.7 (OCH3),
Methyl 6-fluoro-hexa-2E,4E-dienoate, 6: method A
A mixture of tetrabutylammonium fluoride trihydrate (3.91 g,
12.39 mmol) and potassium◦ hydrogen fluoride (3.87 g,
49.56 mmol) was melted at 100 C with stirring. Hexane (5 mL)
was added followed by bromide 7 (2.54 g, 12.39 mmol) and the
viscous suspension was stirred vigorously for 30 minutes at 100 ◦C,
then cooled to room temperature. The reaction mixture was diluted
with Et2O (25 mL) and H2O (10 mL) was added to solubilise all
the salts. The organic layer was separated and the aqueous layer
was neutralized with solid NaHCO3 (2 g) and extracted with Et2O
(3 ¥ 50 mL). The combined original organic layer and extracts
were dried (MgSO4), filtered and concentrated. The crude product
was purified by flash chromatography on silica gel (0–10% diethyl
ether in hexane) to afford fluoride 6 (0.75 g, 42%, 98% by GC/MS)
as a colourless solid (CAUTION: pure 6 is volatile, P >700 mmHg
˚
(10 m ¥ 100 A, 250 ¥ 10 mm ID) column with UV detection at
254 nm.
Methyl 6-bromohexa-2E,4E-dienoate, 7 and
methyl-4,5-dibromohex-2E-enoate 13
◦
◦
at 40 C for evaporation of column fractions); mp 27–29 C; Rf
(10% ethyl acetate in hexane) 0.42; umax (neat)/cm-1 3000–2952 w,
1716 s, 1647 m, 1622 m, 1435 m, 1267 s, 1235 s, 1141 s, 999 m,
A mixture of methyl sorbate (20.2 g, 160.1 mmol) and N-
bromosuccinimide (29.93 g, 168.1 mmol) in dry chlorobenzene
(140 mL) was heated to 100 ◦C over 1 hour; dibenzoylperoxide
(1.75 g, 7.2 mmol) was then cautiously added in portions (0.10 g).
CAUTION: the radical reaction can initiate violently; for effective
containment, the reaction volume should be no more than one
third of the volume of the reaction vessel). After the addition was
4
977m; dH (400 MHz, CDCl3) 7.28 (ddd, 1H, J 15.4, 11.0, J 1.5,
H-3), 6.43-6.37 (m, 1H, H-4), 6.17 (app. tt, 1H, J 16.8, JH-F 16.8,
J 5.0, H-5), 5.94 (d, 1H, J 15.4, H-2), 4.97 (ddd, 2H, 2JH-F 46.2, J
5.0, 4J 1.6, H-6), 3.74 (s, 3H, OCH3); dC (75 MHz, CDCl3) 167.1),
2
3
143.0, 135.5 (d, JC-F 15.7), 129.8 (d, JC-F 12.0), 122.5, 82.0 (d,
◦
complete, the reaction mixture was heated under reflux (130 C)
1JC-F 165.7), 51.7; dF (376 MHz, CDCl3) -217.5 (app. tddt, JF-H
2
for 3 h, then cooled and the chlorobenzene was removed by
evaporation under reduced pressure (15 mmHg). The residual
paste was triturated with Et2O (300 mL) and the ethereal extract
was washed with sodium hydroxide (50 mL of a 5% aqueous
solution) until the washings were colourless. The organic layer
was then dried (MgSO4), filtered and concentrated. The crude
residue was purified first by distillation (Kugelrohr, bp 80–
90 ◦C/0.06 mmHg) and then by chromatography on silica gel (0 to
10% ethyl acetate in hexane) to afford bromide 7 as a colourless oil
(8.18 g, 25%, 97% by GC/MS); Rf (10% ethyl acetate in hexane)
0.48; umax (neat)/cm-1 3000–2952 w, 1716 s, 1662w, 1645w, 1615w,
1435 m, 1250 m, 997 m, 977m; dH (300 MHz, CDCl3) 7.24 (dd, 1H,
J 15.4, 10.6, H-3), 6.34 (ddq, 1H, J 15.0, 10.6, 4J 0.7, H-4), 6.24
(dt, 1H, J 15.0, 7.6, H-5), 5.92 (d, 1H, J 15.4, H-2), 4.01 (dd, 2H,
J 7.6, 4J 0.6, H-6), 3.73 (3H, OCH3); dC (75 MHz, CDCl3) 166.9,
142.8, 136.7, 131.8, 122.7, 51.7, 31.2. HRMS (EI) m/z: 203.97850
[M+]; calc. for C7H979BrO2:203.97859; m/z (EI) 204 (44%, M+),
173 (29), 125 (100), 93 (71).
A small fraction of dibromides 13 (289 mg, 1%) was also
isolated as an inseparable mixture of racemic syn- and anti-
diastereoisomers: Rf (10% ethyl acetate in hexane) 0.42; umax
(film)/cm-1 3000–2952 w, 1728 s, 1659w, 1436 m; the diastereoiso-
mers have the following distinct assignable signals:dH (400 MHz,
CDCl3) 6.99 (dd, 1H, J 15.4, J 9.1, H-3), 6.06 (dd, 1H, J 15.4, 0.8,
H-2), 4.86 (ddd, 1H, J 9.1, 3.8, 0.8 H-4), 4.37 (qd, 1H, J 6.8, 3.8,
H-5), 1.78 (d, 3H, J 6.8, CH3); dC (100 MHz, CDCl3) 141.0, 125.2,
53.8, 49.0, 20.9; and, 6.91 (dd, 1H, J 15.4, J 9.8, H-3), 5.97 (dd,
1H, J 15.4, 0.5, H-2), 4.64–4.58 (m, 1H, H-4), 4.20 (dq, 1H, J 8.8,
4
5
46.2, JF-H 16.8, JF-H 3.2, JF-H 1.5). HRMS (EI): m/z 144.05861
[M+]; calc. for C7H9FO2 144.05866; m/z (EI) 144 (28%, M+), 113
(53), 111 (100), 85 (70). Satisfactory microanalysis could not be
obtained for this volatile solid, though the molecular structure in
the crystal could be elucidated.¶
Methyl 6-fluoro-hexa-2E,4E-dienoate, 6: method B
Potassium fluoride dihydrate (32.3 mmol, 3.04 g), then tetrabuty-
lammonium hydrogen sulfate (9.78 mmol, 3.32 g) were added to a
solution of bromide 7 (8.08 mmol, 1.66 g) in acetonitrile (32 mL).
The resulting suspension was stirred under reflux overnight. The
reaction mixture was then diluted with Et2O (300 mL) and the
organic phase washed with water (3 ¥ 100 mL), brine (100 mL)
and dried (MgSO4). After filtration and careful evaporation of the
solvent (P >700 mmHg at 40 ◦C), the crude product was purified
by flash chromatography on silica gel (0 to 10% gradient of diethyl
ether in hexane) to afford 6 (0.41 g, 35%) as a colourless solid. The
data were as reported previously.
¶ The identity of this product was confirmed by XRD analysis; C7H9FO2,
crystal size 0.23 ¥ 0.16 ¥ 0.15 mm3, M = 144.14, crystal system
monoclinic, unit cell dimensions a = 8.4625(16), b = 8.0276(16), c =
◦
◦
◦
3
˚
˚
21.142(4) A, a = 90 , b = 90.378(5) , g = 90 , U = 1436.2(5) A ,
T = 150(2) K, space group C2/c, absorption coefficient m (Mo-Ka) =
0.113 mm-1, 4948 reflections collected 1256 unique [R(int) = 0.0410],
which were used in all calculations. Final R indices [I > 2s(I)] R1 =
0.0455, wR2 = 0.1063; R indices (all data) R1 = 0.0535, wR2 = 0.1101.
CCDC number 700908.
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 996–1008 | 1001
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(3S*,4R*,5S*)-3,4-Bis(tert-butyldimethylsilyloxy)-5-((R*)-1-
(tert-butyldimethylsilyloxy)-2-fluoroethyl)dihydrofuran-2(3H)-one
( )-15a and (3R*,4S*,5S*)-3,4-bis(tert-butyldimethylsilyloxy)-5-
((R*)-1-(tert-butyldimethyl-silyloxy)-2-fluoroethyl)dihydrofuran-
2(3H)-one ( )-16a; preparation via racemic UpJohn
dihydroxylation and protection
allowed to warm to about -20 ◦C (internal temperature), and then
poured into a vigorously stirred solution of Rochelle salt (aqueous
potassium sodium tartrate, 20 mL of a 1.2M solution). The viscous
solution was stirred vigorously for 2 h, after which time it settled
into two clear phases. The organic layer was separated and the
aqueous layer was extracted three times with Et2O (50 mL). The
combined organic layers were dried (MgSO4), evaporated in vacuo
and purified by flash column chromatography on silica gel (0 to
3% gradient of ethyl acetate in hexane) to afford a mixture of
protected lactols 17a and 18a (724 mg, 91%, 97% by GC/MS)
as a colourless oil (17a:18a 8.9:1; a/b anomeric ratio for major
diastereoisomer 17a: 1:2.1 by 19F NMR): dF (376 MHz, CDCl3)
-223.8 (td, 2JF-H 47.5, 3JF-H 14.1, 17a, a anomer), -225.4 (td, 2JF-H
47.5, 3JF-H 17.2, 17a, b anomer), -230.8 (td, 2JF-H 46.7, 3JF-H 20.6,
18a), -231.8 (td, 2JF-H 46.7, 3JF-H 20.6, 18a). A small pure fraction
of major diastereoisomer 17a was isolated and characterised: Rf
(5% ethyl acetate in hexane) 0.30; umax (neat)/cm-1 2954–2859 w,
1473 w, 1464 w, 1253 m, 1114 m, 1072 m, 834 s, 776 s; dH (400 MHz,
CDCl3)* 5.16 (dd, 1H, J 12.2, J 4.1, H-1a), 5.08 (d, 1H, J 11.8,
H-1b), 4.56-4.23 (m, 4H, H-6a, H-6b), 4.22 (t, 1H, J 3.2, H-3a),
4.15-3.94 (m, 5H, H-2b, H-3b, H-4b, H-5a, H-5b), 3.93 (m, 1H,
H-2a), 3.83 (dd, 1H, J 4.0, J 3.2, H-4a), 3.64 (d, 1H, J 12.2,
OHa), 3.63 (d, 1H, J 11.8, OHb), 0.93, 0.92, 0.90, 0.89, 0.88 (s,
27H, SiC(CH3)3), 0.17, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.08 (s,
Racemic UpJohn dihydroxylation, cyclisation and protection.
A
solution of NMO (463 mg, 3.95 mmol) in water (1 mL) was
added to a stirred solution of dienoate 6 (285 mg, 1.98 mmol) in
acetone (2.3 mL) and t-BuOH (2.3 mL) at room temperature. The
mixture was stirred for 15 minutes then cooled to 0 ◦C, and OsO4
(0.039 mmol, 2 mol%, 402 mL of a 2.5% solution in t-BuOH) was
added dropwise. The mixture was warmed to room temperature
slowly and stirred vigorously overnight, then quenched by the
addition of solid sodium sulfite (2 g). After stirring for a further
30 min, the entire mixture was filtered through a pad of Celite and
the filter pad washed with a mixture of EtOAc and MeOH (1:1 v/v,
50 mL). The filtrate was concentrated under reduced pressure and
the crude product was dried under high vacuum and taken on
without purification.
The crude tetrols were taken up in dry DMF (13 mL) and treated
with pyridine (83 mmol, 6.7 mL) and tert-butyldimethylsilyl
trifluoromethanesulfonate (8.9 mmol, 2 mL) at 0 ◦C under an
atmosphere of argon. The solution was then allowed to warm
to room temperature and stirred for 24 h. The reaction mixture
was evaporated to dryness in vacuo and the residue was taken
up in CH2Cl2 (100 mL). The solution was washed with water
(2 ¥ 20 mL), dried (MgSO4) and concentrated to afford a
mixture of 15a and 16a (12:1 by 19F NMR). The residue was
purified by flash chromatography on silica gel (0–2% gradient of
diethylether in hexane) to afford a mixture of inseparable protected
furanolactones 15a and 16a (432 mg, 42% yield over two steps, 91%
by GC/MS) as a colourless oil. Rf (5% ethyl acetate in hexane)
0.51; umax (neat)/cm-1 2955–2858 w, 1801 s, 1472 w, 1464 w, 1252 m,
834 s, 777 s; dH (400 MHz, CDCl3) 4.46 (dd, 2H, 2JH-F 46.4, J 6.0,
H-6), 4.42 (t, 1H, J 6.0, H-3), 4.30 (d, 1H, J 5.6, H-2), 4.15 (ddd,
1H, J 5.6, J 2.8, 4JH-F 0.4, H-4), 4.09 (dtd, 1H, 3JH-F 12.4, J 6.0, J
2.8, H-5), 0.92 (s, 9H, SiC(CH3)3), 0.89 (s, 9H, SiC(CH3)3), 0.88 (s,
9H, SiC(CH3)3), 0.20, 0.15, 0.13, 0.12, 0.10 (s, 18H, Si(CH3)2); dC
(100 MHz, CDCl3) 173.2, 83.7 (d, 1JC-F 172.1), 82.6 (d, 3JC-F 6.0),
3
18H, Si(CH3)2). dC (100 MHz, CDCl3) 103.4, 97.5, 89.7 (d, JC-F
6.4), 85.5 (d, 3JC-F 6.4), 85.0 (d, 1JC-F 171.0), 84.9 (d, 1JC-F 171.0),
4
2
81.2, 80.0, 77.2, 77.1 (d, JC-F 3.0), 71.6 (d, JC-F 19.2), 71.5 (d,
2JC-F 20.8), 25.9, 25.8, 25.7, 25.6, 18.3, 18.1, 18.0, 17.7, -4.3, -4.4,
-4.5, -4.6, -4.7, -4.8, -5.0; HRMS (FAB-); 523.31019 [M - H+];
calc. for C24H52FO5Si3 523.31067; m/z (FAB-) 523 (6%, M - H+),
467 (4), 260 (100).
*The a and b suffixes refer to the pyranose anomer to which the
signal belongs.
Racemic 6-deoxy-6-fluoro galactose ( )-19 and ( )-20
Deprotection with boron trifluoride. BF3 etherate (102 mL,
0.80 mmol) was added to a solution of protected lactols 17a and
18b (140 mg, 0.268 mmol) in dry acetonitrile (4 mL) at 0 ◦C
under an argon atmosphere. The mixture was stirred for 1 h
at 0 ◦C, then neutralised with a saturated solution of NaHCO3
and concentrated in vacuo. The crude residue was purified by
chromatography on silica gel (0 to 20% gradient of MeOH in
CH2Cl2) to afford ( )-6-deoxy-6-fluoro-galactose as a mixture of
pyranose 19 and furanose 20 (39 mg, 80%) as a hygroscopic solid;
2
76.7, 75.1, 69.6 (d, JC-F 22.1), 25.7, 25.6, 18.2, 17.8, -4.0, -4.2,
2
-4.4, -4.8, -4.9; dF (376 MHz, CDCl3) -223.86 (td, JF-H 46.4,
2
3
3JF-H 12.4, 15a), -227.83 (td, JF-H 46.4, JF-H 16.0, 16a). HRMS
(FAB+) 523.31051 [M + H+]; calc. for C24H52FO5Si3 523.31067;
m/z (FAB+) 523 (11%, M + H+), 465 (35), 407 (6), 231 (100).
1
by H NMR, the product is a 10.9:1 mixture of pyranoses and
furanoses; the anomeric ratio of pyranoses is a:b = 1:1.8 and the
anomeric ratio of furanoses is a:b = 1:1.5.
(3S*,4R*,5S*)-3,4-Bis(tert-butyldimethylsilyloxy)-5-((R*)-1-
(tert-butyldimethylsilyloxy)-2-fluoroethyl)dihydrofuran-2(3H)-ol
( )-17a and (3R*,4S*,5S*)-3,4-bis(tert-butyldimethylsilyloxy)-5-
((R*)-1-(tert-butyldimethylsilyloxy)-2-fluoroethyl)dihydrofuran-
2(3H)-ol ( )-18a via DIBAL-H reduction
Rf (20% MeOH in CH2Cl2) 0.29; umax (neat)/cm-1 3342br, 2498
m, 1408 m, 1360 m, 1253 m, 1147 m, 1070 s, 1024 s, 997 s, 782m;
dH (400 MHz, D2O)* 5.34 (d, 1H, J 3.7, H-1a), 4.82–4.50 (m, 4H,
H-6a, H-6b), 4.66 (d, 1H, J 7.8, H-1b), 4.41 (ddd, 1H, 3JH-F 16.6,
J 7.2, J 3.8, H-5a), 4.09 (dd, 1H, J 3.2, J 0.9, H-4a), 4.08-3.98
(m, 1H, H-5b), 4.02 (d, 1H, J 3.7, H-4b), 3.92 (dd, 1H, J 10.3,
J 3.2, H-3a), 3.86 (dd, 1H, J 10.3, J 3.7, H-2a), 3.71 (dd, 1H, J
9.9, J 3.5, H-3b), 3.55 (dd, 1H, J 9.9, J 7.9, H-2b); dC (100 MHz,
A solution of DIBAL in toluene (2 mL of a 1.5M solution,
3.04 mmol) was added very slowly to a solution of protected
furanolactones 15a and 16a (794 mg, 1.52 mmol) in dry toluene
◦
1
1
(75 mL) under an atmosphere of ◦argon at -78 C. The reaction
D2O) 96.4, 92.4, 83.5 (d, JC-F 164.6), 83.2 (d, JC-F 166.2), 73.4
2
3
2
was stirred for 15 minutes at -78 C, before being quenching by
(d, JC-F 20.8), 72.5, 71.7, 69.0 (d, JC-F 7.9), 69.0 (d, JC-F 22.4),
the dropwise addition of dry methanol (3 mL). The reaction was
68.9, 68.4 (d, 3JC-F 8.0), 68.2; dF (376 MHz, D2O) -229.2 (td, 2JF-H
1002 | Org. Biomol. Chem., 2009, 7, 996–1008
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47.3, 3JF-H 19.1, 20), -229.6 (ddd, 2JF-H 48.1, 2JF-H 45.6, 3JF-H 15.5,
of 15b and 16b (268 mg, 0.68 mmol) in dry toluene (10 mL) under
an atmosphere of argon at -78 C. The reaction was stirred for
◦
2
2
3
19, b anomer), -229.7 (ddd, JF-H 48.1, JF-H 45.6, JF-H 16.6, 19,
a anomer), -230.7 (td, JF-H 47.0, JF-H 20.7, 20); HRMS (ES+):
20 minutes at -78 ◦C, then quenched by the dropwise addition of
dry methanol (300 mL). The reaction was allowed to warm to about
-20 ◦C (internal temperature), then poured into water (5 mL). The
viscous solution was stirred vigorously for 10 minutes, after which
time it formed two clear phases. The organic layer was separated
and the aqueous layer was extracted with Et2O (3 ¥ 20 mL). The
original organic layer and combined extracts were dried (MgSO4),
evaporated and the mixture of 17b and 18b was taken on without
purification.
2
3
200.0930 [M + NH4 ]; calc. for C6H15FNO5 200.0929; m/z (ES-)
+
181 (29%, M - H+), 59 (100). The data were in agreement with
those reported by Schengrund and Kovac.13
* The a and b suffixes refer to the pyranose anomer to which
the signal belongs. Signals from the furanose are too weak to be
reported and assigned.
Deprotection with ammonium fluoride. A mixture of 17a and
18a (85.8 mg, 0.16 mmol) was suspended in a NH4F (14.7 mL
of 0.5M solution in methanol, 7.35 mmol) under an argon
atmosphere and stirred for 2 days at room temperature. Silica gel
(2.8 g) was then added and the resulting suspension was evaporated
to dryness (until the silica was free flowing). The dry silica gel
was then washed at the pump with a solution of CH2Cl2/MeOH
(4:12, 50 mL) and the filtrate was concentrated to give the racemic
galactose as a mixture of pyranose 19 and furanose 20 (14.3 mg,
49%) as a hygroscopic solid. The data were in agreement with those
reported previously.
Deprotection. The crude residue from the previous step was
taken up in a mixture of THF, HCOOH and H2O (5:0.5:1, 3 mL)
and the solution was stirred 1 hour at room temperature. The mix-
ture was evaporated to dryness in vacuo. For full characterisation,
the residue was purified by chromatography on silica gel (0 to 20%
gradient of MeOH in CH2Cl2) to afford an 11:1 mixture of ( )-19
(anomer ratio a/b: 1:1.8) and ( )-20 (71 mg, 58% over 2 steps) as a
hygroscopic solid. The data were in agreement with those reported
previously.
Methyl 4S,5R-dihydroxy-6-fluoro-4,5-O-isopropylidene-hex-
2E-enoate 23 and methyl 2S,3R-dihydroxy-6-fluoro-2,3-O-iso-
propylidene-hex-4E-enoate 24: representative asymmetric
dihydroxylation procedure
Racemic 6-deoxy-6-fluoro galactose ( )-19 and ( )-20 via
temporary protection
Dihydroxylation/temporary protection. A solution of NMO
(811 mg, 6.92 mmol) in water (1 mL) was added to a stirred
solution of 6 (499 mg, 3.46 mmol) in acetone (4 mL) and tBuOH
(4 mL) at room temperature. After stirring for 15 min, the mixture
was cooled to 0 ◦C, and OsO4 (1.05 mL, 0.01 mmol, 3 mol%
of 2.5% solution in t-BuOH) was added dropwise over 5 minutes.
The mixture was allowed to warm to room temperature and stirred
vigorously overnight. The reaction mixture was quenched by the
addition of solid sodium sulfite (5 g) and stirred for 30 min. The
mixture was filtered through a pad of Celite and washed at the
pump with a mixture of EtOAc–MeOH (1:1, 50 mL). The filtrate
was concentrated in vacuo and the residue was dried in vacuo and
taken up in dry pyridine (15 mL).
(DHQ)2PHAL (120 mg, 0.15 mmol, 2.1 mol%) and K2OsO4·2H2O
(54 mg, 0.15 mmol, 2 mol%) were added to a mixture of,
K3Fe(CN)6 (7.24 g, 21.98 mmol), K2CO3 (3.04 g, 21.98 mmol),
and MeSO2NH2 (697 mg, 7.33 mmol) in t-BuOH (26 mL) and
water (26 mL), and the mixture was stirred at room temperature
for about 15 minutes and then cooled to 0 ◦C. Dienoate 6 (1.06 g,
7.35 mmol) was added to this solution and the reaction was stirred
vigorously at 0 ◦C for 24 h. The reaction was then quenched with
solid sodium sulfite (11 g) at room temperature. Ethyl acetate
(200 mL) was added to the reaction mixture, and (after separation
of the layers) the aqueous phase was further extracted with ethyl
acetate (2 ¥ 100 mL). The combined original organic layer and
extracts were dried (MgSO4) and evaporated to dryness in vacuo.
The residue was taken up in DMF (73 mL) and 2-
methoxypropene (2.8 mL, 29.3 mmol) and a few crystals of p-
TsOH monohydrate (139 mg, 0.73 mmol) were added. The mixture
was stirred 3 h at room temperature, then poured into Et2O
(300 mL) and washed with water (2 ¥ 50 mL), then brine (50 mL).
The organic phase was dried (MgSO4), filtered, concentrated in
vacuo, then purified by flash chromatography (silica gel, 2 to 10%
gradient of ethyl acetate in hexane) to afford acetonide 23 (884 mg,
56% over 2 steps, 99% by GC/MS, 84% ee) as a colourless oil;
Chlorotrimethylsilane (2 mL, 15.57 mmol, 1.5 eq per OH group)
was added to the stirred solution at 0 ◦C. After 15 h, pentane
(200 mL) was added and the mixture was washed with cold water
(6 ¥ 30 mL). The organic layer was dried (MgSO4), filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (0 to 10% gradient of ethyl acetate in hexane) to afford
an inseparable mixture of lactones 15b and 16b (15:1 by 19F NMR)
(524 mg, 38% yield over two steps, 98% by GC/MS) as a colourless
oil; Rf (4% ethyl acetate in hexane) 0.26; umax (neat)/cm-1 2958–
2850 w, 1800 m, 1251 s, 1138 s, 1066 ws, 837 s; dH (400 MHz,
2
CDCl3) 4.47 (part of an ABMX system, 1H, JH-F 46.4, J 9.4, J
21
[a]D = +8.4 (c 1.0, CHCl3); Rf (10% ethyl acetate in hexane)
2
5.0, H-6), 4.45 (part of an ABMX system, 1H, JH-F 46.4, J 9.4,
0.28; umax (neat)/cm-1 2989–2850 w, 1725 s, 1664 w, 1457 w, 1438
m, 1374 m, 1306 m, 1258 m, 1165 s, 1026 s; dH (300 MHz, CDCl3)
6.90 (dd, 1H, J 15.5, J 5.8, H-3), 6.15 (dd, 1H, J 15.5, J 1.5,
H-2), 4.58 (part of an ABMX system, 1H, 2JH-F 46.8, J 10.5, 3.5,
H-6), 4.51 (m, 1H, H-4), 4.44 (part of an ABMX system, 1H, 2JH-F
J 6.6, H-6), 4.36-4.30 (m, 2H, H-2, H-3), 4.13-4.05 (m, 2H, H-4,
H-5), 0.23, 0.18, 0.16 (s, 27H); dC (100 MHz, CDCl3) 172.8, 83.8
(d, 1JC-F 172.6), 80.1 (d, 3JC-F 8.0), 76.1, 74.5, 68.8 (d, 2JC-F 22.4),
0.4; dF (376 MHz, CDCl3) -224.1 (td, 2JF-H 46.4, 3JF-H 12.2, 15b),
2
3
-225.7 (td, JF-H 46.4, JF-H 15.5, 16b); HRMS (EI): 396.16190
[M+] calc. for C15H33FO5Si3 396.16199; m/z (EI) 396 (53%, M+),
381 (25), 73 (100).
3
46.8, J 10.5, 4.0, H-6), 3.96 (app. ddt, 1H, JH-F 20.7, J 8.4, 3.7,
H-5), 3.75 (s, 3H, OCH3), 1.45 (s, 3H, CH3), 1.44 (s, 3H, CH3); dC
(75 MHz, CDCl3) 166.2, 143.4, 122.8, 110.7, 81.1 (d, 1JC-F 174.7),
79.0 (d, 2JC-F 20.3), 75.8 (d, 3JC-F 7.2), 51.8, 26.7, 26.6; dF (282 MHz,
CDCl3) -231.1 (td, 2JF-H 46.4, 3JF-H 20.6); HRMS (EI): 217.08757
Reduction. A solution of DIBAL in toluene (0.81 mL of a
1.5M solution, 1.22 mmol) was added over 10 minutes to a solution
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[M - H+]: calc. for C10H14FO4 217.08761; m/z (EI) 217 (2%, M -
H+), 203 (14); 187 (2), 145 (11), 113 (79), 99 (91), 84 (100). HPLC:
Chiralcel ODH column, 1% i-PrOH in hexane eluant, 1 mL/min
flow rate, 254 nm detection; tR (major) = 12.5 min; tR (minor) =
8.4 min.
extracts were dried (MgSO4) and evaporated to dryness in vacuo.
1
19
The residue (a 2.1:1 mixture of diastereoisomers by { H} F
NMR) was purified by chromatography on silica gel (12 to 50%
gradient of ethyl acetate in hexane) to afford diol 27 (213 mg,
18
31%) [a]D = -21.6 (c 1.0, CHCl3); Rf (50% ethyl acetate in
From a mixed column fraction, 24 was isolated and purified by
preparative HPLC, eluting with 10% ethyl acetate in hexane; dH
hexane) 0.28; umax (neat)/cm-1 3461br, 2989–2957 w, 1740 s, 1440,
1374, 1214 s, 1167 m, 1102 s, 1048 s; dH (400 MHz, CDCl3) 4.60
(part of an ABMX system, 1H, 2JH-F 47.2, J 10.2, 3.5, H-6), 4.52
(part of an ABMX system, 1H,2JH-F 47.2, J 10.2, 4.1, H-6), 4.31
(d, 1H, J 2.6, H-2), 4.28 (app. ddt, 1H, J 20.6, 8.0, 3.8 H-5), 4.16
(dd, 1H, J 8.0, 3.5, H-4), 3.95 (app. t, 1H, J 3.0, H-3), 3.84 (s,
3H, OCH3), 1.45 (s, 3H, CH3), 1.44 (s, 3H, CH3); dC (100 MHz,
CDCl3) 172.7, 110.5, 82.0 (d, 1JC-F 172.6), 77.1 (d, 3JC-F 4.8), 76.1
(d, 2JC-F 19.2), 71.7, 70.8, 52.9, 26.8; dF (376 MHz, CDCl3) -229.7
(td, 2JF-H 47.2, 3JF-H 20.6); HRMS (EI): 253.10869 [M + H+]; calc.
for C10H18FO6 253.10874; m/z (EI) 253 (1%, M + H+), 237 (75),
221 (17), 193 (24), 177 (64), 163 (72), 133 (81), 59 (100). and 28
(206 mg, 30%); the data for diastereoisomer 28 are reported in the
next experiment.
3
(400 MHz, CDCl3) 6.05 (ttd, 1H, JH-F 15.3, J 15.3, J 5.0, 1.0,
2
H-5), 5.95-5.88 (m, 1H, H-4), 4.91 (dddd, 2H, JH-F 46.5, J 5.0,
J 1.4, J 0.8, H-6), 4.65-4.58 (m, 1H, H-3), 4.23 (d, 1H, J 7.7,
H-2), 3.80 (s, 3H, OCH3), 1.49 s, (3H, CH3), 1.48 (s, 3 H, CH3);
3
2
dC (100 MHz, CDCl3) 170.3, 129.5 (d, JC-F 11.7), 128.9 (d, JC-F
2
5
16.9), 111.5, 82.1 (d, JC-F 165.6), 79.0 (d, JC-F 1.9), 78.6, 52.6,
25.9, 26.9; dF (376 MHz, CDCl3) -216.5 (tdt, 2JF-H 46.5, 3JF-H 15.3,
4JF-H 3.0, JF-H 3.0); HRMS (ES+): 236.1290 [M + NH4 ]; calcd
for C10H19FNO4: 236.1293; m/z (EI) 203 (16); 161 (24), 141 (70),
81 (58), 73 (100). This minor regioisomer was not characterised
further and the enantiomeric purity was not determined.
5
+
Methyl 4R,5S-dihydroxy-6-fluoro-4,5-O-isopropylidene-hex-
2E-enoate 25 and methyl 2R,3S-dihydroxy-6-fluoro-2,3-O-
isopropylidene-hex-4E-enoate 26
Matched asymmetric dihydroxylation affording 28. From
(DHQD)2PHAL (39 mg, 0.05 mmol, 2.1 mol%), K2OsO4·2H2O
(17.5 mg, 0.047 mmol, 2 mol%), K3Fe(CN)6 (2.36 g, 7.15 mmol),
K2CO3 (989 mg, 7.15 mmol), MeSO2NH2 (227 mg, 2.38 mmol),
and acetonide 23 (520 mg, 2.38 mmol) in t-BuOH (8.5 mL) and
water (8.5 mL), according to the previous procedure, work up and
isolation. The residue was purified by chromatography on silica
gel (12 to 50% gradient of ethyl acetate in hexane) to afford diols
27 and 28 (385 mg, 64%, 1:14.5 by 19F NMR, 99% by GC/MS):
From (DHQD)2PHAL (130 mg, 0.17 mmol, 2.1 mol%),
K2OsO4·2H2O (59 mg, 0.16 mmol, 2 mol%), K3Fe(CN)6 (7.88 g,
23.93 mmol), K2CO3 (3.31 g, 23.93 mmol), MeSO2NH2 (0.76 g,
7.97 mmol) and 6 (1.15 g, 7.97 mmol) in t-BuOH (30 mL) and
water (30 mL), according to the previous procedure, work up and
isolation.
for 28; [a]D = +13.3 (c 1.0, CHCl3); mp 56–57 ◦C; found: C,
18
The residue was protected in DMF (80 mL) containing 2-
methoxypropene (3.0 mL, 31.88 mmol) and a few crystals of
p-TsOH monohydrate (152 mg, 0.80 mmol) according to the
previous procedure, work up and isolation. Flash chromatography
(silica gel, 2 to 10% gradient of ethyl acetate in hexane) afforded
acetonide 25 (783 mg, 44% over two steps, 94% by GC/MS,
47.69; H, 6.89; C10H17FO6 requires: C, 47.62; H, 6.79%; Rf (50%
ethyl acetate in hexane) 0.34; umax (neat)/cm-1 3286br, 2986–2949
w, 1748 s, 1458 w, 1379 m, 1371 m, 1252 m, 1207 m, 1136 m,
1105 s, 1048 s; dH (400 MHz, CDCl3) 4.66 (ABMX system, 1H,
2JH-F 47.2, J 9.9, 2.6, H-6), 4.52 (part of an ABMX system, 1H,
2JH-F 47.2, J 9.9, 4.7, H-6), 4.48 (d, 1H, J 1.2, H-2), 4.33-4.17 (m,
1H, H-5), 4.04-3.95 (m, 2H, H-3, H-4), 3.85 (s, 3H, OCH3), 1.44 (s,
3H, CH3), 1.43 (s, 3H, CH3); dC (100 MHz, CDCl3) 173.6, 110.2,
24
92% ee) as a colourless oil; [a]D = -8.7 (c 1.0, CHCl3); HPLC:
Chiralcel ODH, 1% i-PrOH in hexane, 1 mL/min, 254 nm; tR
(major) = 8.4 min; tR (minor) = 12.5 min. The rest of the data
were in agreement with those reported for 23.
1
2
3
83.1 (d, JC-F 172.6), 79.1 (d, JC-F 17.6), 74.8 (d, JC-F 6.4), 73.8,
70.7, 53.0, 27.1, 26.8; dF (376 MHz, CDCl3) -228.9 (td, 2JF-H 47.2,
3JF-H 22.1); HRMS (EI): 253.10878 [M + H+]; calc. for C10H18FO6
253.10874; m/z (EI) 253 (2%, M + H+), 237 (71), 219 (64), 195
(47), 177 (63), 163 (65), 133 (79), 59 (100). The data for minor
diastereoisomer 27 were reported in the previous experiment.
The presence of 26 was also detected in the 19F NMR spectrum
but the second regioisomer was not isolated in this case.
Methyl 6-fluoro-2R,3R,4S,5R-tetrahydroxy-4,5-O-isopropylidene-
hexanoate 27 and methyl 6-fluoro-2S,3S,4S,5R-tetrahydroxy-
4,5-O-isopropylidene-hexanoate 28
Methyl 6-fluoro-2S,3S,4R,5S-tetrahydroxy-4,5-O-isopropylidene-
hexanoate 29 and methyl 6-fluoro-2R,3R,4R,5S-tetrahydroxy-
4,5-O-isopropylidene-hexanoate 30
Mismatched asymmetric dihydroxylation affording 27.
(DHQ)2PHAL (44 mg, 0.057 mmol, 2.1 mol%) and K2OsO4·2H2O
(20 mg, 0.054 mmol, 2 mol%) were added to a solution of
K3Fe(CN)6 (2.69 g, 8.16 mmol), K2CO3 (1.13 g, 8.16 mmol),
MeSO2NH2 (259 mg, 2.72 mmol) in t-BuOH (10 mL) and water
(10 mL) and the mixture was stirred at room temperature for
about 15 minutes and then cooled to 0 ◦C. Acetonide 23 (593 mg,
2.72 mmol) was added to this solution and the reaction was stirred
vigorously at 0 ◦C for 24 h. The reaction was then quenched with
solid sodium sulfite (5.5 g) at room temperature. Ethyl acetate
(150 mL) was added to the reaction mixture, and (after separation
of the layers) the aqueous phase was further extracted with ethyl
acetate (2 ¥ 50 mL). The original organic layer and the combined
Mismatched asymmetric dihydroxylation affording 29. From
(DHQ)2PHAL (34.2 mg, 0.044 mmol, 2.1 mol%), K2OsO4·2H2O
(15.4 mg, 0.042 mmol, 2 mol%), K3Fe(CN)6 (2.07 g, 6.28 mmol),
K2CO3 (868 mg, 6.28 mmol), MeSO2NH2 (199 mg, 2.09 mmol)
and acetonide 25 (456 mg, 2.09 mmol) in t-BuOH (11.5 mL) and
water (11.5 mL), according to the previous procedure, work up
and isolation. The residue (a 2.1:1 mixture of diastereoisomers by
1
19
{ H} F NMR) was purified by flash column chromatography on
silica gel (12 to 50% gradient of ethyl acetate in hexane) afforded
18
diol 29 (275 mg, 52%, 90% by GC/MS), [a]D = +21.8 (c 1.0,
CHCl3) as a colourless oil and diol 30 (131 mg, 25%, 99% by
1004 | Org. Biomol. Chem., 2009, 7, 996–1008
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18
GC/MS) as a colourless solid. The rest of the data for 29 and 30
were in agreement with those reported for 27 and 28 respectively.
For 31: [a]D = -6.0 (c 0.5, H2O); Rf (20% MeOH in CH2Cl2)
0.34; umax (neat)/cm-1 3337br, 2494br, 1408 m, 1355 m, 1254 m,
1147 m, 1072 s, 1025 s, 998 s, 784m; dH (300 MHz, D2O) 5.48 (d,
1H, J 4.3, H-1b furanose), 5.27 (d, 1H, J 1.2, H-1a furanose),
5.15 (d, 1H, J 1.6, H-1b pyranose), 5.07 (dd, 1H, J 6.6, 1.6, H-1a
pyranose), 4.99-4.46 (m, 8H, H-6), 4.38-4.09 (m, 11H,H-2, H-3,
H-4, H-5 a and b furanose, H-5a, H-3b, H-5b pyranoses), 3.91
(dd, 1H, J 8.3, 5.8, H-4a pyranose), 3.79 (td, 1H, J 8.3, 1.7, H-3a
pyranose), 3.76-3.73 (m, 2H, H-2b, H-4b, pyranoses), 3.40 (m, 1H,
Matched asymmetric dihydroxylation affording 30. From
(DHQD)2PHAL (24 mg, 0.030 mmol, 2.1 mol%; 130 mg,
0.17 mmol, 2.1 mol%), K2OsO4·2H2O (11 mg, 0.029 mmol,
2 mol%; 59 mg, 0.16 mmol, 2 mol%), K3Fe(CN)6 (1.42 g,
4.32 mmol; 7.88 g, 23.93 mmol), K2CO3 (597 mg, 4.32 mmol;
3.31 g, 23.93 mmol), MeSO2NH2 (137 mg, 1.44 mmol; 0.76 g,
7.97 mmol) and acetonide 25 (476 mg, 2.18 mmol) in t-BuOH
(5 mL; 30 mL) and water (5 mL; 30 mL), according to the previous
procedure, work up and isolation.
4
H-2a, pyranoses); dC (100 MHz, D2O) 101.8, 95.6 93.9 (d, JC-F
3.4), 92.4, 84.8 (d, 1JC-F 165.7), 84.7 (d, 1JC-F 166.0), 83.7 (d, 1JC-F
164.5), 83.2 (d, 1JC-F 167.0), 80.7, 80.6 (d, 3JC-F 8.1), 77.2 (d, 3JC-F
7.6), 76.0, 74.9, 74.7, 73.3, 73.2 (d, 2JC-F 19.8), 72.5 (d, 4JC-F 3.4),
72.1 (d, 2JC-F 18.0) 69.9 (d, 2JC-F 4.0), 69.8, 69.6, 69.5 (d, 2JC-F 18.3),
68.5 (d, 2JC-F 18.8), 67.7 (d, 3JC-F 7.5); dF (282 MHz, D2O) -225.4
(td, 2JF-H 47.3, 3JF-H 31.6), (-228.3)-(-229.0) (m), -230.34 (td, 2JF-H
47.2, 3JF-H 20.8), -231.9 (td, 2JF-H 47.2, 3JF-H 24.8); HRMS (FAB-):
181.05116 [M - H+]; calc. for C6H10FO5 181.05123; m/z (FAB-)
181 (73%, M - H+), 168 (100), 122 (94).
1
19
The residue (a 48:1 mixture of diastereoisomers by { H} F
NMR) was purified by flash column chromatography on silica gel
(12 to 50% gradient of ethyl acetate in hexane) to afford diol 30
18
(285 mg, 52%) as a colourless solid; [a]D = -13.3 (c 1.0, CHCl3).
The rest of the data were in agreement with those reported for 28.
6-Deoxy-6-fluoro-L-idose 31
*The a and b suffixes refer to the anomer to which the signal
belongs.
Four-step deprotection/reduction procedure. Hydrochloric
acid (675 mL of a 3M aqueous solution, 2.02 mmol) was added
to a stirred solution of diol 27 (170 mg, 0.67 mmol) in MeOH
(2.5 mL) at room temperature and the mixture was stirred for
1 day at that temperature. The MeOH was removed in vacuo and
the residue was washed through a pad of Celite mixed with silica
gel, with a mixture of ethyl acetate and MeOH (7:3, 15 mL).
The solvent was removed in vacuo and the residue was dried
under vacuum overnight. the residue was taken up in N-methyl-
N-(trimethylsilyl)-trifluoroacetamide (525 mL, 2.83 mmol, 1.4 eq.
6-Fluoro-2,3,5-tri-O-trimethylsilyl-L-fucofuranose 32
Three-step preparation from 28. From diol 28 (220 mg,
0.87 mmol), hydrochloric acid (873 mL of a 3M aqueous solution,
2.62 mmol) and MeOH (4 mL) according to the previous proce-
dure, work up and isolation. The residue was taken up in N-methyl-
N-(trimethylsilyl)-trifluoroacetamide (558 mL, 3.0 mmol, 1.15 eq.
per OH group) and treated according to the previous procedure,
work up and isolation. The residue was reduced in dry toluene
(8.7 mL) with DIBAl-H (1.16 mL of a 1.5M solution in toluene,
1.76 mmol) quenched with methanol (400 mL) according to the
previous procedure, work up and isolation. Flash chromatography
of the residue on silica gel (3 to 10% gradient of ethyl acetate in
hexane) afforded protected lactol 32 as a 1:1 mixture of anomers
(by 19F NMR) (133 mg, 38% over 3 steps, 92% by GC/MS,)
as a colourless oil, Rf (10% ethyl acetate in hexane) 0.30; umax
(neat)/cm-1 3498w, 2959–2906 w, 1400 w, 1250 s, 1115 m, 964 s,
876 s, 837 s; dH (300 MHz, CDCl3) 5.10 (dd, 1H, J 11.1, 4.1, H-1a),
5.06 (d, 1H, J 9.6, H-1b), 4.57-4.17 (m, 4H, H-6, a and b anomers),
4.13-3.78 (m, 8H, H-2, H-3, H-4, H-5, a and b anomers), 3.62 (d,
1H, J 11.1, OH a), 3.59 (d, 1H, J 9.6, OHb), 0.22-0.12 (m, 54H,
OTMS); dC (75 MHz, CDCl3) 102.9, 96.7, 87.0 (d, 3JC-F 7.5), 84.9
(d, 1JC-F 168.7), 84.5 (d, 1JC-F 169.8), 83.6 (d, 3JC-F 7.2), 80.9, 79.3,
◦
per OH group) was added and the mixture was heated to 60 C
and stirred vigorously for 1 hour, then dried for 24 h in vacuo.
A solution of the residue in dry toluene (6.7 mL) was cooled
under an atmosphere of argon to -78 ◦C. DIBAL-H (0.9 mL of a
1.5M solution in toluene, 1.76 mmol) was added very slowly and
the reaction was stirred for 30 minutes at -78 ◦C, then quenched
by the dropwise addition of methanol (250 mL). The reaction
was allowed to warm to about -20 ◦C (internal temperature)
and then water (4.5 mL) was added. The viscous solution was
stirred vigorously for 30 minutes, after which two clear phases
formed. The organic layer was separated and the aqueous layer was
extracted with Et2O (3 ¥ 15 mL). The original organic layer and
combined extracts were dried (MgSO4), evaporated in vacuo and
purified by flash chromatography on silica gel (2 to 10% gradient of
ethyl acetate in hexane) to afford a colourless oil (89 mg, 33% over
3 steps, 90% by GC/MS); Rf (10% ethyl acetate in hexane) 0.4; the
two anomers are separable in GC-MS: m/z (EI): 217 (15%), 173
(19%), 147 (12%), 145 (12%), 145 (22%), 129 (15%), 77 (30%), 75
(80%), 73 (100%) and 217 (13%), 147 (15%), 129 (13%), 77 (20%),
75 (38%), 73 (100%).
4
4
2
76.9 (d, JC-F 1.1), 76.8 (d, JC-F 1.7), 70.8 (d, JC-F 19.6), 70.6 (d,
2JC-F 19.4), 0.2, 0.0 (2 signals), -0.1, -0.2, -0.3; dF (282 MHz,
2
3
2
CDCl3) -224.9 (td, JF-H 47.4, JF-H 14.9), -225.7 (td, JF-H 47.8,
3JF-H 19.2); HRMS (EI): 398.17766 [M+]; calc. for C15H35FO5Si3
398.17764; m/z (EI) 398 (1%, M+), 383 (1), 233 (4), 217 (44), 145
(75), 73 (100).
The oil (89 mg, 0.226 mmol) was taken up in a mixture of THF,
HCOOH and H2O (3:0.2:1, 2.5 mL) and the solution was stirred
1 hour at room temperature. The solvents were removed in vacuo
and the residue was purified by chromatography on silica gel (0
to 15% of MeOH in CH2Cl2) to give 6-deoxy-6-fluoro-L-idose 31
6-Fluoro-L-fucose 33
From 32 (100 mg, 0.25 mmol) in THF, HCOOH and H2O (3:0.2:1,
3 mL) according to the previous procedure, work up and isolation;
6-fluoro-a,b-L-fucose 33 (46 mg, 38% over 4 steps) was obtained
as a white hygroscopic solid. By 1H NMR, the product is a
10.9:1 mixture of pyranoses and furanoses; the anomeric ratio
1
(30 mg, 25% over 4 steps) as a white hydroscopic solid. By H
NMR, the product is a 2.6:1 mixture of pyranoses and furanoses;
the anomeric ratio of pyranoses is a:b = 1.6:1 and the anomeric
ratio of furanoses is a:b = 1:1.5.
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of pyranoses is a:b = 1:1.8 and the anomeric ratio of furanoses is
a:b = 1:1.5.
solution in toluene, 1.76 mmol) and quenched with methanol
(300 mL 400 mL) according to the previous procedure, work up and
isolation. Flash chromatography on silica gel (3 to 10% gradient of
ethyl acetate in hexane) afforded 36 (117 mg, 37%) as a colourless
oil (ratio a/b = 1/1.3 by 1H NMR) (93% by GC/MS). The rest
of the data were in agreement with those reported for 32.
18
For 33: [a]D = -65.9 (c 0.5, H2O); Rf (20% MeOH in CH2Cl2)
0.29; umax (neat)/cm-1 3333br, 2494br, 1408 m, 1353 m, 1254 m,
1147 m, 1071 s, 1025 s, 999 s, 783m; dH (400 MHz, D2O) 5.34 (d,
1H, J 3.7, H-1a), 4.82-4.50 (m, 4H, H-6a, H-6b), 4.66 (d, 1H,
3
J 7.8, H-1b), 4.41 (ddd, 1H, JH-F 16.6, J 7.2, J 3.8, H-5a), 4.09
(dd, 1H, J 3.2, J 0.9, H-4a), 4.08-3.98 (m, 1H, H-5b), 4.02 (d,
1H, J 3.7, H-4b), 3.92 (dd, 1H, J 10.3, J 3.2, H-3a), 3.86 (dd,
1H, J 10.3, J 3.7, H-2a), 3.71 (dd, 1H, J 9.9, J 3.5, H-3b), 3.55
(dd, 1H, J 9.9, J 7.9, H-2b); dC (100 MHz, D2O) 96.4, 92.4, 83.5
6-Deoxy-6-fluoro-D-galactopyranose 37
A solution of lactol 36 (100 mg, 0.25 mmol) in a mixture
of THF, HCOOH and H2O (3:0.2:1, 2 mL) was stirred for
1 hour at room temperature. The solvents were removed under
reduced pressure and 6-deoxy-6-fluoro-D-galactose 37 (45 mg, ca.
1
1
2
(d, JC-F 164.6), 83.2 (d, JC-F 166.2), 73.4 (d, JC-F 20.8), 72.5,
3
2
3
71.7, 69.0 (d, JC-F 7.9), 69.0 (d, JC-F 22.4), 68.9, 68.4 (d, JC-F
18
100%) was obtained as a white hygroscopic solid. [a]D = +64.0
2
3
8.0), 68.2; dF (376 MHz, D2O) -229.2 (td, JF-H 47.3, JF-H 19.1,
furanose), -229.6 (ddd, 2JF-H 48.1, 2JF-H 45.6, 3JF-H 15.5, pyranose
b anomer), -229.7 (ddd, 2JF-H 48.1, 2JF-H 45.6, 3JF-H 16.6, pyranose
(c 0.5, H2O). The rest of the data (including the furanose:pyranose
and anomer ratios) were in agreement with those reported for 33.
2
3
a anomer), -230.7 (td, JF-H 47.0, JF-H 20.7, furanose); HRMS
2,3,6-Trideoxy-6-fluoro-D-galactono-1,4-lactone 38
(ES+): 200.0929 [M + NH4 ]; calc. for C6H15FNO5 200.0929.
+
*The a and b suffixes refer to the anomer to which the signal
belongs. Signals from the furanose are too weak to be reported
and assigned.
A solution of 25 (178 mg, 0.82 mmol) in absolute EtOH (15 mL)
containing palladium-on-carbon (10% w/w, 72 mg) was stirred
vigorously overnight at room temperature under an atmosphere
of hydrogen (1 bar). The suspension was then filtered through a
pad of CeliteTM and the filtrate was concentrated to a colourless
oil. The residue was taken up in MeOH (2.4 mL) and HCl (0.8 mL
of a 3 M aqueous solution, 2.45 mmol) was added. The resulting
solution was stirred overnight, then concentrated in vacuo. The
residue was purified by chromatography on silica gel (60% ethyl
acetate in hexane) to afford lactone 38 (94 mg, 77% over two
steps, 99% by GC/MS) (CAUTION: the lactone is volatile) as a
Methyl 6-fluoro-2S,3R,4R,5S-2,3:4,5-bis(isopropylidene)
hexanoate 34
From diol 29 (256 mg, 1.01 mmol), 2-methoxypropene (390 mL,
4.06 mmol), p-TsOH monohydrate (19 mg, 0.1 mmol) in DMF
(10 mL) according to the previous procedure, work up and
isolation.
Flash chromatography (silica gel, 0 to 10% gradient of ethyl
acetate in hexane) to afford bis-acetonide 34 (213 mg, 72%, 99%
23
colourless oil; [a]D = -48.5 (c 1.0, CHCl3); Rf (60% ethyl acetate
in hexane) 0.27; umax (neat)/cm-1 3421br, 2961–2920 w, 1755 s,
1462 w, 1419 w, 1189 s; dH (400 MHz, CDCl3) 4.63 (ddd, 1H, J
7.5, 6.9, 3.3, H-4), 4.52 (part of an ABMX system, 1H, 2JH-F 47.0,
18
by GC/MS) as a colourless oil; [a]D = +21.4 (c 1.0, CHCl3); Rf
(10% ethyl acetate in hexane) 0.17; umax (neat)/cm-1 2990–2840 w,
1762 s, 1456 w, 1439w, 1382 m, 1372 m, 1249 m, 1209 s, 1165 s;
dH (400 MHz, CDCl3) 4.61 (d, 1H, J 7.6, H-2), 4.59 (part of an
ABMX system, 1H, 2JH-F 47.2, J 10.2, 4.0, H-6), 4.54 (part of an
2
J 9.7, 5.6, H-6), 4.51 (part of an ABMX system, 1H, JH-F 47.0,
3
J 9.7, 5.6, H-6), 3.90 (dtd, 1H, JH-F 15.1, J 5.6, 3.3, H-5), 3.16
(br, 1H, OH), 2.62 (part of an ABMN system, 1H, J 17.8, 9.8,
6.0, H-2), 2.53 (part of an ABMN system, 1H, J 17.8, 9.6, 8.2,
H-2), 2.37-2.20 (2H, m, H-3); dC (100 MHz, CDCl3) 177.8, 83.4
(d, 1JC-F 169.5), 79.3 (d, 3JC-F 5.8), 71.6 (d, 2JC-F 21.0), 28.3, 23.5;
2
ABMX system, 1H, JH-F 47.2, J 10.2, 4.0, H-6), 4.34 (ddt, 1H,
3JH-F 20.4, J 8.2, 4.0, H-5), 4.23 (dd, 1H, J 7.6, 3.2, H-3), 4.15
(dd, 1H, J 8.2, 3.2, H-4), 3.82 (s, 3H, OCH3), 1.49 (s, 3H, CH3),
1.46 (s, 3H, CH3), 1.45 (s, 6H, CH3); dC (100 MHz, CDCl3) 170.8,
2
3
dF (376 MHz, CDCl3) -223.0 (td, JF-H 47.0, JF-H 15.1); HRMS
(EI): 147.04578 [M - H+]; calc. for C6H8FO3 147.04575; m/z (EI)
147 (1%, M - H+), 128 (7), 115 (73), 97 (12), 85 (100).
1
3
111.7, 110.4, 82.1 (d, JC-F 172.6), 77.5, 75.8 (d, JC-F 6.4), 75.6
2
(d, JC-F 20.8), 75.4, 52.6, 27.0, 26.7, 26.5, 26.0; dF (282 MHz,
CDCl3) -230.2 (td, 2JF-H 47.4, 3JF-H 20.0); HRMS (EI): 293.14010
[M + H+]; calc. for C13H22FO6 293.14004; m/z (EI) 293 (1%, M +
H+), 277 (62), 159 (57), 133 (52), 59 (100). This product was not
progressed to sugar 35.
6-Fluoro-D-rhodinose (2,3,6-trideoxy-6-fluoro-D-galactose)
39 and 40
From lactone 38 (31 mg, 0.21 mmol) in dry toluene (2 mL), and
DIBAL-H (276 mL of a 1.5M solution in toluene, 0.42 mmol)
according to the previous procedure, work up and isolation. Flash
chromatography on silica gel (60 to 90% gradient of ethyl acetate
6-Deoxy-6-fluoro-2,3,5-tri-O-trimethylsilyl-D-galactofuranose 36
From hydrochloric acid (790 mL of a 3M aqueous solution,
2.36 mmol), diol 30 (198 mg, 0.79 mmol 220 mg, 0.87 mmol)
in MeOH (2.6 mL 4 mL) according to the previous procedure,
work up and isolation.
The residue was silylated with N-methyl-N-(trimethylsilyl)-
trifluoroacetamide (502 mL, 2.7 mmol, 558 mL, 3.0 mmol, 1.15 eq.
per OH group) according to the previous procedure, work up and
isolation.
1
in hexane) afforded 6-fluoro-D-rhodinose (16 mg, 51%). By H
NMR, the product is a 1:1:1 mixture of furanoses 39 and pyranoses
40; the anomeric ratio of pyranoses is a:b = 1:1.4 and the anomeric
ratio of furanoses is a:b = 1:1.1.
Rf (90% ethyl acetate in hexane) 0.36; umax (neat)/cm-1 3362br,
2956w, 1443w, 1256w, 1199 m, 1111 m, 1000s; dH (500 MHz, D2O)
5.59 (dd, 1H, J 2.1, 4.2, H-1), 5.53 (d, 1H, J 4.3, H-1), 5.37 (br s,
1H, H-1a), 4.91 (dd, 1H, J 2.6, 9.5, H-1b, pyranose), 4.74-4.42 (m,
12H, H-6), 4.36-4.26 (m, 2H, H-5a pyranose, H-4), 4.15 (m, 1H,
The reduction was effected in dry toluene (8.7 mL) with DIBAL-
H (1.05 mL of a 1.5M solution, 1.57 mmol 1.16 mL of a 1.5M
1006 | Org. Biomol. Chem., 2009, 7, 996–1008
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H-4), 3.99 (dddd, 1H, 3JH-F 16.4, J 7.4, 3.7, 1.3, H-5b), 3.97-3.94
(m, 1H, H-4a), 3.94-3.82 (m, 3H, H-4b, H-5, H-5), 2.29-1.51 (m,
12H, H-2 and H-3); dC (100 MHz, D2O) 98.6, 97.8, 95.8, 90.9,
10 (a) N. K. Vyas, M. N. Vyas, M. C. Chervenak, D. R. Bundle, B. M.
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Salas and C. Mendez, Chem. Commun., 2005, 1604–1606; (c) B. Ostash,
U. Rix, L. L. R. Rix, T. Liu, F. Lombo, A. Luzhetskyy, O. Gromyko,
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1
1
1
85.0 (d, JC-F 164.6), 84.9 (d, JC-F 166.2), 84.5 (d, JC-F 164.6),
83.9 (d, 1JC-F 164.6), 79.9 (d, 3JC-F 8.0), 77.7 (d, 3JC-F 8.0), 76.6 (d,
2
2
2
2JC-F 19.2), 72.8 (d, JC-F 17.6), 71.7 (d, JC-F 19.2), 69.3 (d, JC-F
19.2), 63.8 (d, 3JC-F 8.0), 62.9 (d, 3JC-F 8.0), 33.3, 32.5, 28.6, 26.3,
2
25.2, 24.6, 23.8, 23.4; dF (376 MHz, D2O) -229.8 (td, JF-H 47.8,
3JF-H 20.2), -229.9 (td, JF-H 46.0, JF-H 16.5), -230.48 (td, JF-H
2
3
2
47.8, 3JF-H 18.4), -231.5 (td, 2JF-H 46.0, 3JF-H 22.1); HRMS (ES+):
168.1031 [M + NH4 ]; calc. for C6H15FNO3 168.1030; m/z (ES-)
+
12 H. Kodama, Y. Kajihara, T. Endo and H. Hashimoto, Tetrahedron
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149 (100%, M - H+), 129 (21).
Acknowledgements
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This work was supported by the Engineering and Physical Sciences
Research Council (EPSRC, GR/S82053/02, fellowships to AC,
GR), the University of Leicester (studentship to RR), and the
University of Strathclyde Principal’s Fund (fellowship to GR).
We also thank the EPSRC’s National Mass Spectrometry Service
Centre, University of Wales Swansea for mass spectrometric
measurements and Dr Martin Rejzek for assistance with chro-
matography.
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