Synthesis of Protected 3-Deoxy-3-fluoro- and 4-Deoxy-4-fluoro-d-galactopyranosides from Levoglucosan

Article abstract of DOI:10.1021/acs.joc.7b00543

Fluorinated carbohydrates are invaluable tools to study various biochemical processes. Herein, we describe a new strategy to access orthogonally protected 3-deoxy-3-fluorogalactopyranose and acetylated 4-deoxy-4-fluorogalactopyranose. Starting from inexpensive levoglucosan, most reactions were performed on a gram scale and allowed excellent regio- and stereocontrol with a minimal use of protection/deprotection cycles. Hence, we developed practical alternatives to the decade-long reported method to access both 3-deoxy-3-fluoro- and 4-deoxy-4-fluorogalactopyranose.

Full text of DOI:10.1021/acs.joc.7b00543

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Note
Synthesis of protected 3-deoxy-3-fluoro and 4-deoxy-4-
fluoro-D-galactopyranosides from levoglucosan
Danny Lainé, Vincent Denavit, and Denis Giguère
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 Apr 2017
Downloaded from http://pubs.acs.org on April 19, 2017
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Synthesis of protected 3ꢀdeoxyꢀ3ꢀfluoro and 4ꢀdeoxyꢀ4ꢀfluoroꢀ
from levoglucosan
Dꢀgalactopyranosides
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Danny Lainé, Vincent Denavit and Denis Giguère*
PROTEO, RQRM, Département de Chimie, 1045 av. De la Médecine, Université Laval, Québec City, Qc,
Canada G1V 0A6
Abstract
Fluorinated carbohydrates are invaluable tools to study various biochemical processes.
Herein, we describe a new strategy to access orthogonally protected 3ꢀdeoxyꢀ3ꢀfluoroꢀ
galactopyranose and acetylated 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranose. Starting from
inexpensive levoglucosan, most reactions were performed on gram scale, allowed
excellent regioꢀ and stereocontrol with a minimal use of protection/deprotection cycles.
Hence, we developed practical alternatives to the decadeꢀlong reported method to access
both 3ꢀdeoxyꢀ3ꢀfluoroꢀ and 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranose.
Carbohydrates bearing a fluorine atom in replacement of a hydroxyl group have found
applications in biochemical investigations (lectinꢀcarbohydrate interactions, mechanistic
probes, etc.)1 and radiolabeling.2 More recently, fluorinated carbohydrates were used to
investigate the intramolecular hydrogen bonding properties of CHF and CF2 groups3 and
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an innovative logP determination method was developed to show the influence of deoxyꢀ
fluorination on carbohydrate lipophilicity.4
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The synthesis of fluorinated carbohydrates is hampered by the many hydroxyl groups'
protection/deprotection steps and the low nucleophilicity of fluoride ions. Additionally,
chemical processes are often tedious and time consuming due to fluorinating reagentsꢀ
driven side reactions (namely eliminations). Importantly, the deoxyfluorination reaction
is widely used in carbohydrate chemistry and usually occurs with inversion of
configuration. Diethylaminosulfur trifluoride (DAST) is a common reagent for the
preparation of fluorinated carbohydrates and its application on a wide range of substrates
is wellꢀdocumented.5 As part of our program related to the synthesis of fluorinated
galactosyl residues, our attention was turned towards the synthesis of 3ꢀdeoxyꢀ3ꢀfluoro
and 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranoses, as these motifs represent relevant
glycomimetics. Remarkably, 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranoses have been used as
molecular probes,6 involved in glycoside hydrolysis studies7 and complex
h
oligosaccharide syntheses.6c−e, Despite their importance, no methods are currently
available for the preparation of orthogonally protected 3ꢀdeoxyꢀ3ꢀfluoroꢀ
galactopyranoses. Hence, there is a major need to develop an efficient synthetic path to
access 3ꢀfluorinated galactopyranoside building blocks with orthogonal protecting groups
at the Oꢀ2, Oꢀ4, and Oꢀ6 positions. As for 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranoses, they are
invaluable probes used over the years to study various biochemical processes.8
Figure 1 shows the synthetic strategies used to access 3ꢀdeoxyꢀ3ꢀfluoro and 4ꢀdeoxyꢀ4ꢀ
fluoroꢀgalactopyranoses. The first synthesis of 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose was
reported in the late 60s and used 1,2:5,6ꢀdiꢀOꢀisopropylideneꢀαꢀDꢀgulofuranose 1 as an
expensive starting material (Figure 1a).9 Optimization of this process was proposed a
few years later,10 but a more convenient access to the gulofuranose framework was
described starting from glucose 2, requiring hydroxyl inversion at Cꢀ4 and fluorine
installation with retention of configuration at Cꢀ3.11 To the best of our knowledge, this is
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the only known synthetic route to access 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose derivatives;12
attempt to develop a new synthetic path proved to be unsuccessful (deoxyfluorination of
methyl 2,4,6ꢀtriꢀOꢀbenzylꢀαꢀD
ꢀgulopyranoside resulted in complex mixtures).13
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Two distinct approaches were reported regarding the preparation of 4ꢀdeoxyꢀ4ꢀfluoroꢀ
galactopyranoses (Figure 1b). The first one involved a selective trityl protection of the
Oꢀ6 hydroxyl group of methyl glucoside (3), followed by selective nucleophilic
deoxyfluorination using DAST.14 This approach was not reproducible on large scale in
our hands and generated numerous side products. The second approach involved a oneꢀ
pot selective 1,2,3,6ꢀprotection of glucopyranose (4), followed by the aforementioned
DASTꢀmediated deoxyfluorination.15 This transformation was also carried out through
activation of the free Oꢀ4 hydroxyl group of compound 4 as either a triflate,16 tosylate17
or mesylate,18 prior nucleophilic fluorination using TBAF (tetrabutylammonium
fluoride). It is worth mentioning that TASF (tris(dimethylamino)sulfonium
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difluorotrimethylsilicate) and Amberlyst Aꢀ26 resin (Fꢀ form)13, 20 have also been used
as fluorinating reagents in this context. The oneꢀpot selective 1,2,3,6ꢀprotection of
glucopyranose is quite difficult to achieve16, 21 thus, the most common approach to these
motifs are from i) an inversion of the Cꢀ4 hydroxyl group of a selectively protected
galactosyl derivative 522 or ii) a selective benzylidene opening from compound 6.11b, 23 In
a nutshell, the preparation of 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranoses is lengthy and affected
by many protection/deprotection steps. Also, the group of Liang recently reported that
transformation of intermediate 4 (with benzyl ether as protecting group (PG)) into 4ꢀ
deoxyꢀ4ꢀfluoroꢀgalactopyranoses was not possible using DAST since an unexpected
furanoside byꢀproduct was isolated instead.24 Consequently, the discovery of new
synthetic routes to access 3ꢀ and 4ꢀfluorinated galactosyl derivatives is thus deemed
necessary.
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Figure 1. Retrosynthetic approaches to a) 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranoses and b) 4ꢀ
deoxyꢀ4ꢀfluoroꢀgalactopyranoses
We aimed to develop a new synthetic route to 3ꢀdeoxyꢀ3ꢀfluoro and 4ꢀdeoxyꢀ4ꢀfluoroꢀ
galactopyranoses that could operate at a large scale, and comply with the following
criteria involving: i) inexpensive starting materials; ii) satisfactory regioꢀ and
stereocontrols; iii) a minimal use of protection/deprotection cycles; iv) no tedious
purifications. The intended synthetic purpose was centred around the development of a
practical alternative to the known decadeꢀlong reported method.9, 14 Furthermore, because
3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose has found multiple applications in oligosaccharide
synthesis, an orthogonally protected building block would be ideal. Figure 2 shows our
retrosynthetic analysis to orthogonally protected 3ꢀfluoro derivative 7 and 4ꢀfluoro
derivative 8 from commercially available 1,6ꢀanhydroꢀβꢀDꢀglucopyranose (levoglucosan)
12. Fully protected compound 7 could be accessible from a chemoselective protection of
3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose 9. The latter is readily available from intermediate 10
through acetolysis and inversion of the Oꢀ4 hydroxyl group. The fluorine atom will be
introduced stereoselectively through epoxide opening and functional group
manipulations. Correspondingly, 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranose 8 could be obtained
via acetolysis and nucleophilic fluorination from intermediate 11, readily accessible from
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levoglucosan 12 by means of selective pꢀtoluenesulfonylation. This strategy was
preferred since the use of 1,6ꢀanhydro core of levoglucosan avoided the preliminary
protection of the Oꢀ6 and anomeric positions and could easily afford scalable fluorinated
carbohydrates via simple experimental protocols.
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Figure 2. Retrosynthetic analysis of orthogonally protected 3ꢀfluoro derivative 7 and 4ꢀ
fluoro derivative 8 from levoglucosan 12
The synthesis of 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose 7 is summarized in Scheme 1.
Levoglucosan 12 was first converted to 1,6:2,3ꢀdianhydroꢀ4ꢀOꢀbenzylꢀβꢀDꢀallopyranose
13 on multiꢀgram scale through a known 5ꢀstep protocol requiring only one flash
chromatography purification (see experimental section).25 Fluorination of the latter was
achieved via exposure to potassium hydrogen fluoride in ethylene glycol affording the
desired 3ꢀdeoxyꢀ3ꢀfluoroꢀglucopyranose 10 in 65% yield. The rigid nature of the 1,6ꢀ
anhydro core allowed a regioselective epoxide opening with the formation of only one
fluorinated isomer as shown by the NMR of the crude reaction mixture.26 Benzoylation of
the free Oꢀ2 hydroxyl group generated compound 14 in high yield and was followed by
TiCl4 mediated benzyl deprotection of the 4ꢀOꢀbenzyl group.27 Intermediate 15 was the
perfect candidate for a LattrellꢀDax epimerization28 allowing the preparation on gram
scale of the desired 1,6ꢀanhydroꢀgalactopyranose derivative 17 via triflate 16. Finally, the
desired 1,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀ
D
ꢀgalactopyranose
9
was
generated from 17 through acetolysis (H2SO4, Ac2O) followed by treatment with sodium
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acetate (α/β = 3:1). Hence, with compound 9 in hand, the preparation of a useful
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orthogonally protected building block was the next task.
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Scheme 1. Synthesis of 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyrane 9: a) Reference 25; b) KHF2 (6.1
equiv), ethylene glycol, 200 °C, 5 h, 65%; c) BzCl (3.0 equiv), pyridine, CH2Cl2, rt, 1 h,
81%; d) TiCl4 (1.1 equiv), CH2Cl2, 0 °C, 1 h, 82%; e) (i) Tf2O (2.3 equiv), pyridine,
CH2Cl2, 0 °C to rt, 0.5 h; (ii) KNO2 (3.0 equiv), DMF, rt, 24 h, 72% over 2 steps; f) (i)
H2SO4 (10 equiv), Ac2O (30 equiv), rt, 18 h; (ii) NaOAc (20 equiv), rt, 0.3 h, 58% over 2
steps, α/β = 3:1. Ac2O = acetic anhydride, BzCl = benzoyl chloride, DMF = N,Nꢀ
dimethylformamide, NaOAc = sodium acetate, Tf2O = trifluoromethanesulfonic
anhydride.
The efficient synthesis of orthogonally protected fluorinated monosaccharide building
blocks could simplify the preparation of complex oligosaccharides. Consequently, the
preparation of the corresponding 3ꢀdeoxyꢀ3ꢀfluoro thiogalactoside could be of great
interest.6c−e, h With Oꢀ2 benzoate 9 in hand, functionalization of the anomeric position as
thiophenol and chemoselective protections of the Oꢀ4 and Oꢀ6 hydroxyl groups could be
straightforward (Scheme 2). Thus, treatment of compound 9 with 33% HBr in acetic acid
resulted in formation of the αꢀgalactosyl bromide 18. The crude bromide product was
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subjected to a phase transfer catalyzed nucleophilic displacements with thiophenol that
occurred with complete anomeric inversion to afford the corresponding phenyl 1ꢀthioꢀβꢀ
galactoside 19. After selective deꢀOꢀacetylations with methanolic sodium methoxide
(90% yield), diol 20 was submitted to sequential selective protections at Oꢀ4 and Oꢀ6.
Hence, silylation at Oꢀ6 was achieved with TBSCl in 84% yield and benzylether
formation at Oꢀ4 was then possible after treatment with NaH and benzyl bromide in 85%
yield. To the best of our knowledge, compound 7 represents the first orthogonally
protected phenyl 3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀthioꢀβꢀgalactoside donor and could be useful as a
versatile building block towards complex oligosaccharide synthesis.
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Scheme 2. Synthesis of orthogonally protected phenyl 3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀthioꢀβꢀ
galactoside 7: a) 33% HBr in AcOH, CH2Cl2, 0 °C to rt, 1.5 h; b) PhSH (3.0 equiv),
TBAHS (1.0 equiv), EtOAc, 1 M Na2CO3, rt, 18 h, 60% over 2 steps; c) 1M NaOMe,
MeOH, 0 °C to rt, 1.5 h, 90%; d) TBSCl (2.2 equiv), imidazole (1.5 equiv), DMF, 0 °C to
rt, 3.0 h, 84%; e) NaH (2.0 equiv), BnBr (4.0 equiv), DMF, rt, 0.5 h, 85%. AcOH = acetic
acid; BnBr = benzyl bromide; Bz = benzoate; PhSH = thiophenol; TBSCl = tertꢀ
butyldimethylsilyl chloride.
Levoglucosan is a useful synthetic starting material since 4ꢀsubstituted derivatives can be
selectively accessed in one synthetic step. The synthesis of 4ꢀdeoxyꢀ4ꢀfluoroꢀ
galactopyranose 8 was initiated with monoꢀOꢀpꢀtoluenesulfonylation as previously
described (Scheme 3).29 Nucleophilic fluorination on tosylate 22 resulted only in
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decomposition under various conditions. Thus, careful optimization led us to protect the
hydroxyl groups as MOM ethers in 97% yield. Upon extensive experimentation,
nucleophilic fluorination was achieved using excess TBAF in boiling THF for 3 days.
Compound 23 was isolated in modest yield as an inseparable mixture, but this process
was highly reproducible and could be done on large scale. The clear advantage of this
new methodology is the simultaneous acetolysis and MOM ether hydrolysis under acidic
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conditions allowing formation of the desired 1,2,3,6ꢀtetraꢀOꢀacetylꢀ4ꢀdeoxyꢀ4ꢀfluoroꢀ
galactopyranose 88a (α/β = 3:1).
Dꢀ
Scheme 3. Synthesis of 4ꢀdeoxyꢀ4ꢀfluoroꢀgalactopyranose 8: a) Reference 29; b)
MOMCl (10 equiv), DIPEA (11 equiv), CH2Cl2, 40 °C, 18 h, 97%; c) TBAF (10 equiv),
THF, 66 °C, 72 h, 31%, based on 76% purity; d) (i) H2SO4 (10 equiv), Ac2O (30 equiv),
rt, 18 h; (ii) NaOAc (20 equiv), rt, 0.3 h, 52% over 2 steps, α/β = 3:1. Ac2O = acetic
anhydride, DIPEA = N,Nꢀdiisopropylethylamine, MOMCl = chloromethyl methyl ether,
NaOAc = sodium acetate, TBAF = tetrabutylammonium fluoride.
New synthetic routes for the construction of 3ꢀdeoxyꢀ3ꢀfluoroꢀ and 4ꢀdeoxyꢀ4ꢀfluoroꢀ
galactopyranoses were developed. To the best of our knowledge, these strategies are the
only alternatives to the decadeꢀlong reported methods. Most reactions were performed on
gram scale, allowed excellent regioꢀ and stereocontrol and made minimal use of
protection/deprotection cycles. The described strategy allowed the preparation of an
orthogonally protected 3ꢀdeoxyꢀ3ꢀfluoroꢀgalactopyranose building block that could be
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useful in oligosaccharide synthesis. Finally, the development of new strategy to access
fluorinated carbohydrates of biological interest will address the needs of the glycobiology
field.
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Experimental section
General information. All reactions were carried out under an argon atmosphere with dry
solvents under anhydrous conditions, unless otherwise noted. Methylene chloride
(CH2Cl2) was distilled from CaH2 and N,N′ꢀdimethylformamide (DMF) from ninhydrin
and kept over molecular sieves. Tetrahydrofuran (THF) was distilled from
Na/benzophenone immediately before use. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reagents
were purchased at the highest commercial quality and used without further purification,
unless otherwise stated. Reactions were monitored by thinꢀlayer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60Fꢀ254) using UV light as visualizing
agent and charring with a solution of 3 g of PhOH and 5 ml of H2SO4 in EtOH, followed
by heating with a heatgun. SiliaFlash® P60 40ꢀ63 µm (230 ꢀ 400 mesh) was used for
flash column chromatography. NMR spectra were recorded with an Agilent DD2 500 MHz
spectrometer and calibrated using residual undeuterated solvent (CDCl3: 1H δ = 7.26 ppm,
13C δ = 77.16 ppm) as an internal reference. Coupling constants (J) are reported in Hertz
(Hz), and the following abbreviations were used to designate multiplicities: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet, br = broad. Assignments of NMR signals
were made by homonuclear (COSY) and heteronuclear (HSQC) twoꢀdimensional correlation
spectroscopy. Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FTꢀ
IR spectrometer. The absorptions are given in wavenumbers (cm−1). Highꢀresolution mass
spectra (HRMS) were measured with an Agilent 6210 LC Time of Flight mass spectrometer
in electrospray mode. Either protonated molecular ions [M + nH]n+, sodium adducts [M +
Na]+ or ammonium adducts [M + NH4]+ were used for empirical formula confirmation.
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Optical rotations were measured with a JASCO DIPꢀ360 digital polarimeter, and are reported
in units of 10−1 (deg cm2 g−1).
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1,6:2,3ꢀdianhydroꢀ4ꢀOꢀbenzylꢀβꢀ
D
ꢀallopyranose (13). To a stirred solution of 1,6ꢀ
ꢀglucopyranose
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anhydroꢀ4ꢀOꢀbenzylꢀ3ꢀOꢀmethanesulfonylꢀ2ꢀOꢀ(4ꢀtoluenesulfonyl)ꢀβꢀ
D
(6.80 g, 14.03 mmol, 1.0 equiv) in CH2Cl2 (30 ml) at −18 °C, was added a solution of
sodium methoxide (prepared from metalic sodium: 2.10 g, 91.20 mmol, 6.5 equiv) in
methanol (70 ml). The mixture was slowly warmed up to rt over 2 h, then stirred for 20 h.
The reaction was then neutralised with an aq. 10% HCl solution, and concentrated to
removed the MeOH. The residue was diluted with CH2Cl2 (100 ml) and water (100 ml),
then extracted with CH2Cl2 (2 × 100 ml). The combined organic phases were washed
with water (200 ml) and brine (200 ml), then dried over MgSO4, filtered and concentrated
under reduced pressure. The obtained crude was purified by flash column
chromatography (silica gel, acetone/toluene, 1:9) to give a white solid (2.65 g, 10.12
mmol, 58% yield over 2 steps). The spectroscopic data derived from compound 13 match
those reported in the literature.25
1,6ꢀAnhydroꢀ4ꢀOꢀbenzylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀβꢀDꢀglucopyranose (10). To a stirred
solution of compound 13 (2.65 g, 11.321 mmol, 1.0 equiv) in ethylene glycol (95 mL)
was added KHF2 (5.39g, 69.06 mmol, 6.1 equiv). The mixture was heated under reflux
(~200°C) for 5 h. After cooling, the reaction was quenched with an aqueous 5% solution
of K2CO3 (200ml) and stirred for 5 minutes. The mixture was then extracted with CH2Cl2
(5 × 25 ml) and the combined organic phases were washed with water (3 × 15 ml), dried
over MgSO4, filtered and concentrated under reduced pressure. The crude oil was
purified by flash column chromatography (silica gel, EtOAc:hexanes 1:2 → 2:3) to give
10 as a white amorphous solid (1.87 g, 7.36 mmol, 65% yield): Rf = 0.38 (silica,
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EtOAc:hexanes, 2:3); [α]D = –47.1° (c 0.5, MeOH); IR (ATR, ZnSe) ν : 3434, 2962,
2870, 1415, 1321, 1078, 720 cmꢀ1; 1H NMR: (500 MHz, CDCl3) δ = 7.41 – 7.31 (m, 5H,
Ar), 5.47 (t, J = 1.9 Hz, 1H, H1), 4.74 – 4.61 (m, 4H, CH2Ph, H3, H5), 4.01 (dt, J = 7.7,
1.2 Hz, 1H, H6a), 3.80 (ddd, J = 7.7, 5.7, 2.2 Hz, 1H, H6b), 3.67 (tqd, J = 12.3, 1.7, 0.7
Hz, 1H, H2), 3.53 (dqd, J = 12.9, 1.8, 0.7 Hz, 1H, H4), 2.50 (ddd, J = 12.4, 2.1, 1.2 Hz,
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1H, OH) ppm; C NMR: (126 MHz, CDCl3) δ = 136.9, 128.8, 128.5, 128.0 (6C, Ar),
101.4 (C1), 88.2 (d, J = 184.1 Hz, C3), 74.2 (d, J = 26.5 Hz, C4), 73.7 (C5), 71.8
(CH2Ph), 67.4 (d, J = 23.7 Hz, C2), 65.1 (d, J = 4.7 Hz, C6) ppm; 19F NMR: (470 MHz,
CDCl3) δ = –184.7 (dt, J = 44.2, 12.4 Hz, F3) ppm; HRMS calcd for C13H19O4NF+
[M+NH4]+ 272.1293 found 272.1300.
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1,6ꢀAnhydroꢀ2ꢀOꢀbenzoylꢀ4ꢀOꢀbenzylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀβꢀDꢀglucopyranose (14). To a
stirred solution of compound 10 (1.87 g, 7.359 mmol, 1.0 equiv) in CH2Cl2 (100 mL) at 0
°C was added pyridine (25 mL) and benzoyl chloride (2.56 mL, 22.08 mmol, 3.0 equiv).
The mixture was stirred at room temperature for 1 h and then quenched with a sat. aq.
NaHCO3 solution (100 mL). The mixture was extracted with CH2Cl2 (3 × 100 mL) and
the combined organic phases were washed with an aq. 10% H2SO4 solution (2 × 50 mL),
sat. aq. NaHCO3 solution (2 × 50 mL) and brine (100 ml). The organic solution was dried
over MgSO4, filtered and concentrated under reduced pressure. The obtained crude was
purified by flash column chromatography (silica gel, EtOAc:hexanes, 1:4) to give 14 as a
white amorphous solid (2.13 g, 5.94 mmol, 81% yield): Rf = 0.24 (silica, EtOAc:hexanes,
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1:4): [α]D = +27.6° (c 0.7, MeOH); IR (ATR, ZnSe) ν : 2903, 1717, 1269, 1098, 1011,
712, 698; 1H NMR: (500 MHz, CDCl3) δ = 8.10 – 8.06 (m, 2H, Ar), 7.63 – 7.55 (m, 1H,
Ar), 7.46 – 7.41 (m, 2H, Ar), 7.38 – 7.29 (m, 5H, Ar), 5.59 (s, 1H, H1), 5.01 (d, J = 16.7
Hz, 1H, H2), 4.82 – 4.67 (m, 4H, CH2Ph, H3, H5), 4.01 (d, J = 7.6 Hz, 1H, H6a), 3.82
(ddd, J = 7.6, 5.7, 1.8 Hz, 1H, H6b), 3.58 (d, J = 15.6 Hz, 1H, H4) ppm; 13C NMR: (126
MHz, CDCl3) δ = 165.5 (COPh), 137.3, 133.7, 130.2, 129.3, 128.7, 128.6, 128.2, 128.0
(12C, Ar), 99.3 (C1), 88.2 (d, J = 181.1 Hz, C3), 75.1 (d, J = 26.2 Hz, C4), 74.3 (d, J =
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1.4 Hz, C5), 71.9 (CH2Ph), 69.4 (d, J = 27.8 Hz, C2), 65.5 (d, J = 3.2 Hz, C6) ppm; F
NMR: (470 MHz, CDCl3) δ = –183.4 (dt, J = 43.8, 16.4 Hz, F3) ppm; HRMS calcd for
C20H20O5F+ [M+H]+ 359.1289 found 359.1307.
1,6ꢀAnhydroꢀ2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀβꢀDꢀglucopyranose (15). To a stirred
solution of compound 14 (2.11 g, 5.90 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 0 °C was
added TiCl4 (1 M in CH2Cl2, 6.5 ml, 1.1 equiv). The mixture was stirred at 0°C for 1 h
and then quenched at 0°C with water (50 mL). The mixture was extracted with CH2Cl2 (3
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× 30 mL) and the combined organic phases were washed with water (2 × 50 mL) and
brine (50 ml). The organic solution was dried over MgSO4, filtered and concentrated
under reduced pressure. The obtained crude was purified by flash column
chromatography (silica gel, EtOAc:hexanes, 1:1) to give 15 as a white amorphous solid
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(1.29 g, 4.81 mmol, 82% yield); Rf = 0.33 (silica, EtOAc:hexanes, 1:1): [α]D = +19.9°
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(c 0.6, MeOH); IR (ATR, ZnSe) ν : 3438, 2966, 2904, 1716, 1267, 1009, 713; H NMR:
(500 MHz, CDCl3) δ = 8.06 – 8.01 (m, 2H, Ar), 7.64 – 7.58 (m, 1H, Ar), 7.50 – 7.44 (m,
2H, Ar), 5.61 (t, J = 1.7 Hz, 1H, H1), 5.01 (dq, J = 14.7, 1.4 Hz, 1H, H2), 4.75 – 4.64 (m,
2H, H3, H5), 4.19 (dt, J = 7.8, 1.2 Hz, 1H, H6a), 3.89 (ddd, J = 8.0, 5.8, 2.5 Hz, 1H,
H6b), 3.85 (tq, J = 11.5, 1.9 Hz, 1H, H4), 2.72 (d, J = 11.4 Hz, 1H, OH) ppm; 13C NMR:
(126 MHz, CDCl3) δ = 165.0 (COPh), 133.9, 130.0, 129.0, 128.8 (6C, Ar), 99.3 (C1),
88.9 (d, J = 183.2 Hz, C3), 75.9 (C5), 68.5 (d, J = 28.5 Hz, C2), 67.9 (d, J = 27.2 Hz,
C4), 65.0 (d, J = 4.8 Hz, C6) ppm; 19F NMR: (470 MHz, CDCl3) δ = –183.5 (dt, J = 43.6,
13.3 Hz, F3) ppm; HRMS calcd for C13H14O5F+ [M+H]+ 269.0820 found 269.0824.
1,6ꢀAnhydroꢀ2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀβꢀDꢀgalactopyranose (17). To a stirred
solution of compound 15 (1.08 g, 4.03 mmol, 1.0 equiv) in CH2Cl2 (12 mL) at 0 °C was
added pyridine (3 mL) and Tf2O (1.55 mL, 9.23 mmol, 2.3 equiv). The mixture was
stirred at room temperature for 0.5 h and then quenched with water (10 mL). The mixture
was extracted with CH2Cl2 (4 × 10 mL) and the combined organic phases were washed
with sat. aq. NaHCO3 (1 × 20 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. Triflate 16 was used for the next step without further purification. To
the crude triflate in DMF (20 ml) at room temperature was added KNO2 (1.02 g, 12.03
mmol, 3.0 equiv). The mixture was stirred 24 h at room temperature, and then quenched
with water (20 mL). The mixture was extracted with CH2Cl2 (4 × 20 mL) and the
combined organic phases were washed with sat. aq. NaHCO3 (40 mL), water (2 × 40 ml)
and brine (40 ml). The organic solution was dried over MgSO4, filtered and concentrated
under reduced pressure to give 17 as a white amorphous solid (0.782 g, 2.92 mmol, 72%
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yield over two steps): Rf = 0.30 (silica, acetone:toluene, 5:95): [α]D = +40.8° (c 0.2,
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MeOH); IR (ATR, ZnSe) ν : 3411, 2920, 2851, 1716, 1269, 1101, 708; H NMR: (500
MHz, CDCl3) δ = 8.08 – 8.01 (m, 2H, Ar), 7.64 – 7.57 (m, 1H, Ar), 7.52 – 7.43 (m, 2H,
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Ar), 5.55 (t, J = 1.6 Hz, 1H, H1), 5.24 (dt, J = 13.4, 1.7 Hz, 1H, H2), 4.85 (ddq, J = 47.5,
4.6, 1.6 Hz, 1H, H3), 4.56 (t, J = 4.7 Hz, 1H, H5), 4.24 (d, J = 7.8 Hz, 1H, H6a), 4.17 (dt,
J = 26.6, 4.4 Hz, 1H, H4), 3.77 (dd, J = 7.8, 5.2 Hz, 1H, H6b) ppm; 13C NMR: (126
MHz, CDCl3) δ = 165.0 (COPh), 133.9, 130.1, 128.9, 128.7 (6C, Ar), 98.7 (C1), 88.5 (d,
J = 179.7 Hz, C3), 74.2 (C5), 70.4 (d, J = 27.7 Hz, C2), 65.4 (d, J = 18.0 Hz, C4), 63.9
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(d, J = 3.4 Hz, C6) ppm; F NMR: (470 MHz, CDCl3) δ = –204.2 (ddd, J = 47.6, 27.0,
13.6 Hz, F3) ppm; HRMS calcd for C13H13O5FNa+ [M+Na+] 291.0639 found 291.0644.
1,4,6ꢀTriꢀOꢀacetylꢀ2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀα/βꢀDꢀgalactopyranose (9). To a
stirred solution of compound 17 (0.782 g, 2.92 mmol, 1.0 equiv) in Ac2O (8.26 mL, 87.40
mmol, 30 equiv) at 0 °C was added H2SO4 (1.55 mL, 29.08 mmol, 10 equiv). The
mixture was stirred at room temperature for 18 h. After this time, the mixture was cooled
down to 0 °C and NaOAc (4.78 g, 58.27 mmol, 20 equiv) was added. The mixture was
stirred for an additional 20 min and then quenched with water (20 mL). The mixture was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic phases were washed with
water (1 × 50 mL) and brine (1 × 50 ml) and then dried over MgSO4, filtered and
concentrated under reduced pressure. The obtained crude was purified by flash column
chromatography (silica gel, acetone:toluene, 1:9) to give compound 9 (α/β, 1:3.4) as a
white amorphous solid (0.694 g, 1.691 mmol, 58% yield): Rf = 0.42 (silica,
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acetone:toluene, 1:9); [α]D = +82.2° (c 0.8, MeOH); IR (ATR, ZnSe) ν : 2960, 2878,
1
1736, 1208, 1010, 933, 710; H NMR: (500 MHz, CDCl3) δ = 8.05 – 7.97 (m, 4H, 2 ×
Arα, 2 × Arβ), 7.64 – 7.55 (m, 2H, 1 × Arα, 1 × Arβ), 7.49 – 7.42 (m, 4H, 2 × Arα, 2 ×
Arβ), 6.54 (t, J = 4.3 Hz, 1H, H1α), 5.83 (d, J = 8.3, 1H, H1β), 5.75 – 5.61 (m, 4H, H2α,
H2β, H4α, H4β), 5.12 (ddd, J = 48.4, 10.2, 3.7 Hz, 1H, H3α), 4.84 (ddd, J = 47.4, 9.6, 3.8
Hz, 1H, H3β), 4.34 (tt, J = 6.6, 1.5 Hz, 1H, H5α), 4.23 (dd, J = 11.4, 6.4 Hz, 1H, H6aβ),
4.21 – 4.15 (m, 2H, H6aα, H6bβ), 4.11 (ddd, J = 11.4, 6.7, 1.3 Hz, 1H, H6bα), 4.06 (tt, J
= 6.5, 1.6 Hz, 1H, H5β), 2.21 (s, 1H, COCH3β), 2.20 (s, 3H, COCH3α), 2.14 (s, 3H,
COCH3α), 2.08 (s, 1H, COCH3β), 2.07 (s, 3H, COCH3α), 2.06 (s, 1H, COCH3β) ppm;
13C NMR: (126 MHz, CDCl3) δ = 170.6, 170.6, 170.0, 170.0, 169.2, 168.7, 165.6, 165.1
(8C, 3 × COCH3α, 3 × COCH3β, COPhα, COPhβ), 133.8, 133.8, 130.0, 129.9, 129.0,
128.7, 128.7 (12C, 6 × Arα, 6 × Arβ), 91.6 (d, J = 11.3 Hz, C1β), 90.0 (d, J = 9.1 Hz,
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C1α), 89.0 (d, J = 195.7 Hz, C3β), 85.9 (d, J = 193.3 Hz, C3α), 71.3 (d, J = 5.8 Hz, C5β),
69.6 (d, J = 20.1 Hz, C2β), 68.8 (d, J = 5.3 Hz, C5α), 68.3 (d, J = 19.3 Hz, C2α), 67.5 (d,
J = 16.9 Hz, C4α), 66.9 (d, J = 16.8 Hz, C4β), 61.4 (d, J = 2.3 Hz, C6α), 61.3 (d, J = 2.6
Hz, C6β), 20.9, 20.8 (6C, 3 × COCH3α, 3 × COCH3β) ppm; 19F NMR: (470 MHz,
CDCl3) δ = –199.8 (ddd, J = 47.3, 11.6, 5.7 Hz, F3β), –203.5 (ddt, J = 48.5, 11.3, 5.7 Hz,
F3α) ppm; HRMS calcd for C19H21O9FNa+ [M+Na]+ 435.1062 found 435.1063.
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Phenyl 4,6ꢀdiꢀOꢀacetylꢀ2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside
(19). To a stirred solution of compound 9 (11.8 mg, 0.03 mmol, 1.0 equiv) in CH2Cl2 (0.2
mL) at 0 °C was added a 33% wt solution of HBr in AcOH (0.1 mL). The mixture was
stirred at room temperature for 90 min and then quenched with a sat. aq. NaHCO3 (2
mL). The mixture was extracted with CH2Cl2 (3 × 1 mL) and the combined organic
phases were washed with brine (1 × 2 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. The crude bromide 18 was used for the next step whitout further
purification. To a solution of the crude bromide in EtOAc (0.2 mL) at room temperature
was added tetrabutylammonium hydrogen sulfate (TBAHS) (9.7 mg, 0.03 mmol, 1
equiv), thiophenol (10 µL, 0.09 mmol, 3 equiv) and a 1 M aq. Na2CO3 solution (0.2 mL).
The mixture was vigorously stirred at room temperature for 18 h. After this time, water (2
mL) was added, and the mixture was extracted with EtOAc (3 × 1 mL). The combined
organic phases were washed with brine (1 × 2 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The resulting crude was purified by flash column
chromatography (silica gel, EtOAc/hexanes, 3:7) to give 19 as a white amorphous solid
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(7.9 mg, 0.0171 mmol, 60% yield); Rf = 0.27 (silica, EtOAc/hexanes, 3:7): [α]D
=
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+15.8° (c 0.3, MeOH); IR (ATR, ZnSe) ν : 2920, 2850, 1733, 1451, 1215, 1028, 707; H
NMR: (500 MHz, CDCl3) δ = 8.09 – 8.06 (m, 2H, Ar), 7.64 – 7.59 (m, 1H, Ar), 7.51 –
7.46 (m, 4H, Ar), 7.32 – 7.27 (m, 3H, Ar), 5.64 (ddd, J = 5.9, 3.7, 1.1 Hz, 1H, H4), 5.57
(ddd, J = 11.2, 10.1, 9.3 Hz, 1H, H2), 4.81 (dd, J = 10.0, 0.9 Hz, 1H, H1), 4.81 (ddd, J =
47.5, 9.3, 3.7 Hz, 1H, H3), 4.24 – 4.17 (m, 2H, H6a, H6b), 3.95 (tdd, J = 7.0, 1.8, 1.1 Hz,
1H, H5), 2.16 (s, 3H, COCH3), 2.08 (s, 3H, COCH3) ppm; 13C NMR: (126 MHz, CDCl3)
δ = 170.6, 170.1 (2C, COCH3), 165.3 (1C, COPh), 133.6, 133.0, 132.4, 130.1, 129.5,
129.0, 128.6, 128.5 (12C, Ar), 89.9 (d, J = 196.9 Hz, 1C, C3), 86.2 (d, J = 7.6 Hz, 1C,
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C1), 74.3 (d, J = 5.4 Hz, 1C, C5), 68.9 (d, J = 19.6 Hz, 1C, C2), 67.4 (d, J = 16.7 Hz, 1C,
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C4), 61.9 (d, J = 2.6 Hz, 1C, C6), 20.9, 20.8 (2C, COCH3) ppm; F NMR: (470 MHz,
CDCl3) δ = –195.2 (ddd, J = 47.1, 11.1, 5.6 Hz, F3) ppm; HRMS calcd for C23H24O7SF+
[M+H]+ 463.1221 found 463.1240.
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Phenyl 2ꢀOꢀbenzoylꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (20). To a stirred
solution of compound 19 (25.7 mg, 0.06 mmol, 1.0 equiv) in MeOH (1.4 mL) at 0 °C was
added a solution of sodium methoxide (1 M in MeOH) until pH = 8–9. The mixture was
slowly warmed up to room temperature over 90 min. After this time, the mixture was
neutralized to pH = 7 with acid resin (Amberlite IRꢀ120), filtered and concentrated under
reduced pressure. Compound 20 was isolated as a white amorphous solid (19.0 mg, 0.05
mmol, 90% yield) and used for the next step whitout further purification: Rf = 0.20
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(silica, EtOAc:hexanes, 7:3): [α]D = +32.3° (c 0.2, MeOH); IR (NaCl film) ν : 2962,
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2921, 2854, 1724, 1262, 1069, 803; H NMR: (500 MHz, (CD3)2CO) δ = 8.10 – 8.05 (m,
2H, Ar), 7.70 – 7.65 (m, 1H, Ar), 7.57 – 7.52 (m, 2H, Ar), 7.49 – 7.46 (m, 2H, Ar), 7.31
– 7.24 (m, 3H, Ar), 5.70 (ddd, J = 11.0, 10.0, 9.3 Hz, 1H, H2), 5.07 (dd, J = 10.0, 1.0 Hz,
1H, H1), 4.95 (ddd, J = 49.1, 9.3, 3.3 Hz, 1H, H3), 4.70 (d, J = 4.8 Hz, 1H, C4OH), 4.41
– 4.37 (m, 1H, H4), 4.08 (t, J = 5.9 Hz, 1H, C6OH), 3.89 – 3.79 (m, 3H, H5, H6a, H6b)
ppm; 13C NMR: (126 MHz, (CD3)2CO) δ = 165.8 (1C, COPh), 135.0, 134.3, 131.8,
130.9, 130.4, 129.8, 129.5, 128.1 (12C, Ar), 93.4 (d, J = 189.0 Hz, 1C, C3), 86.3 (d, J =
7.9 Hz, 1C, C1), 79.4 (d, J = 6.3 Hz, 1C, C5), 70.1 (d, J = 19.1 Hz, 1C, C2), 68.1 (d, J =
16.6 Hz, 1C, C4), 61.8 (d, J = 2.9 Hz, 1C, C6) ppm; 19F NMR: (470 MHz, (CD3)2CO) δ =
–195.5 (ddd, J = 49.6, 11.3, 7.5 Hz, F3); HRMS calcd for C19H20O5SF+ [M+H]+ 379.1010
found 379.1002.
Phenyl
2ꢀOꢀbenzoylꢀ6ꢀOꢀ(tertꢀbutyldimethylsilyloxy)ꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀthioꢀβꢀDꢀ
galactopyranoside (21). To a stirred solution of compound 20 (11.1 mg, 0.03 mmol, 1.0
equiv) in DMF (1 mL) at 0 °C was added imidazole (3.0 mg, 0.04 mmol, 1.5 equiv) and
tertꢀbutyldimethylsilyl chloride (9.6 mg, 0.06 mmol, 2.2 equiv). The mixture was stirred
at room temperature for 4.5 h and then quenched with sat. aq. NH4Cl solution (2 mL).
The mixture was extracted with EtOAc (3 × 1 mL) and the combined organic phases
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were washed with brine (1 × 2 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The obtained crude was purified by flash column chromatography
(silica gel, EtOAc:hexanes, 1:4) to give 21 as a white amorphous solid (12 mg, 0.02
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mmol, 84% yield); Rf = 0.35 (silica, EtOAc:hexanes, 1:4): [α]D = +20.4° (c 0.6,
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MeOH); IR (NaCl film) ν : 2979, 2928, 2869, 1731, 1261, 1142, 708; H NMR: (500
MHz, CDCl3) δ = 8.11 – 8.03 (m, 2H, Ar), 7.67 – 7.55 (m, 1H, Ar), 7.53 – 7.42 (m, 4H,
Ar), 7.30 – 7.26 (m, 3H, Ar), 5.64 (ddd, J = 11.3, 10.0, 9.1 Hz, 1H, H2), 4.79 (dd, J =
10.0, 1.0 Hz, 1H, H1), 4.70 (ddd, J = 48.7, 9.2, 3.2 Hz, 1H, H3), 4.37 (dt, J = 6.5, 3.0 Hz,
1H, H4), 4.00 (dd, J = 10.4, 6.1 Hz, 1H, H6a), 3.93 (ddd, J = 10.4, 5.0, 1.3 Hz, 1H, H6b),
3.60 (dd, J = 6.1, 5.1 Hz, 1H, H5), 2.73 (d, J = 3.4 Hz, 1H, C4OH), 0.92 (s, 9H,
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SiC(CH3)3), 0.12 (s, 3H, Si(CH3)2), 0.11 (s, 3H, Si(CH3)2) ppm; C NMR: (126 MHz,
CDCl3) δ = 165.3 (1C, COPh), 133.4, 132.8, 132.7, 130.1, 129.8, 129.0, 128.6, 128.1
(12C, Ar), 92.8 (d, J = 190.8 Hz, 1C, C3), 86.2 (d, J = 7.7 Hz, 1C, C1), 77.5 (d, J = 6.0
Hz, 1C, C5), 69.0 (d, J = 19.5 Hz, 1C, C2), 67.9 (d, J = 16.7 Hz, 1C, C4), 62.4 (d, J = 2.8
Hz, 1C, C6), 26.0 (3C, SiC(CH3)3), 18.4 (1C, SiC(CH3)3), –5.3, (2C, Si(CH3)2) ppm; 19F
NMR: (470 MHz, CDCl3) δ –194.5 (ddd, J = 48.8, 11.4, 7.0 Hz, F3); HRMS calcd for
C25H34O5SFSi+ [M+H]+ 493.1875 found 493.1867.
Phenyl 2ꢀOꢀbenzoylꢀ4ꢀOꢀbenzylꢀ6ꢀOꢀ(tertꢀbutyldimethylsilyloxy)ꢀ3ꢀdeoxyꢀ3ꢀfluoroꢀ1ꢀ
thioꢀβꢀDꢀgalactopyranoside (7). To a stirred solution of compound 21 (11 mg, 0.02
mmol, 1.0 equiv) in DMF (1 mL) at room temperature was added NaH (1.8 mg, 0.04, 2
equiv) and benzyl bromide (11 µL, 0.09 mmol, 4 equiv). The mixture was stirred at room
temperature for 45 min. The reaction was then quenched with sat. aq. NH4Cl solution (2
mL), and extracted with EtOAc (3 × 1 mL). The combined organic phases were washed
with brine (2 mL), dried over MgSO4, filtered and concentrated under reduced pressure.
The obtained crude was purified by flash column chromatography (silica gel,
EtOAc:hexanes, 1:9) to give 7 as a white amorphous solid (11 mg, 0.02 mmol, 85%
25
yield): Rf = 0.34 (silica, EtOAc/hexanes, 1:9); [α]D = +3.34° (c 0.5, CHCl3); IR (ATR,
1
ZnSe) ν : 2925, 2852, 1719, 1258, 1115, 854, 706; H NMR: (500 MHz, CDCl3) δ = 8.13
– 7.98 (m, 2H, Ar), 7.65 – 7.55 (m, 1H, Ar), 7.51 – 7.42 (m, 4H, Ar), 7.34 (d, J = 5.1 Hz,
4H, Ar), 7.31 – 7.27 (m, 1H, Ar), 7.25 – 7.19 (m, 3H, Ar), 5.71 (q, J = 9.9 Hz, 1H, H2),
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4.79 (d, J = 9.9 Hz, 1H, H1), 4.78 (ddd, J = 48.7, 9.3, 3.0 Hz, 1H, H3), 4.78 (ABq, J =
166.0, 11.5 Hz, 2H, OCH2Ph), 4.15 (dd, J = 7.1, 3.0 Hz, 1H, H4), 3.88 – 3.77 (m, 2H,
H6a, H6b), 3.59 (dd, J = 7.1, 5.9 Hz, 1H, H5), 0.91 (s, 9H, SiC(CH3)3), 0.07 (s, 3H,
Si(CH3)2), 0.07 (s, 3H, Si(CH3)2) ppm; 13C NMR: (126 MHz, CDCl3) δ = 165.3 (1C,
COPh), 138.5, 133.2, 133.1, 132.7, 130.4, 130.1, 128.9, 128.5, 128.4, 128.0, 127.9, 127.8
(18C, Ar), 94.2 (d, J = 194.2 Hz, 1C, C3), 86.2 (d, J = 7.5 Hz, 1C, C1), 78.8 (d, J = 6.7
Hz, 1C, C5), 75.0 (d, J = 3.8 Hz, 1C, OCH2Ph), 74.3 (d, J = 15.2 Hz, 1C, C4), 69.9 (d, J
= 19.0 Hz, 1C, C2), 61.6 (d, J = 2.4 Hz, 1C, C6), 26.1 (3C, SiC(CH3)3), 18.4 (1C,
SiC(CH3)3), –5.2, –5.3 (2C, Si(CH3)2) ppm; 19F NMR: (470 MHz, CDCl3) δ –192.6 (dt, J
= 48.8, 8.8 Hz, F3); HRMS calcd for C32H39O5SFSiNa+ [M+Na]+ 605.2164 found
605.2164.
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1,6ꢀAnhydroꢀ2,3ꢀdiꢀOꢀmethoxymethylꢀ4ꢀOꢀ(4ꢀtoluenesulfonyl)ꢀβꢀDꢀglucopyranose
(11). To a stirred solution of compound 2229 (2.09 g, 6.61 mmol, 1.0 equiv) in CH2Cl2
(70.0 ml) was added N,Nꢀdiisopropylethylamine (12.7 ml, 72.57 mmol, 11 equiv) and
chloromethyl methyl ether (5.0 ml, 65.83 mmol, 10 equiv). The mixture was stirred at 40
°C for 18 h and then quenched with water (50 mL). The mixture was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic phases were washed with sat. aq.
NaHCO3 solution (100 mL), water (100 ml) and brine (100 ml), then dried over MgSO4,
filtered and concentrated under reduced pressure. The obtained crude was purified by
flash column chromatography (silica gel, EtOAc:hexanes, 1:1) to give 11 as a colorless
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oil (2.59 g, 6.40 mmol, 97% yield); Rf = 0.35 (silica, EtOAc:hexanes, 1:1): [α]D = –
1
43.1° (c 1.0, CHCl3); IR (ATR, ZnSe) ν : 2951, 2897, 1359, 1175, 1035, 956, 814; H
NMR: (500 MHz, CDCl3) δ = 7.83 (d, J = 8.1 Hz, 2H, Ar), 7.34 (d, J = 8.4 Hz, 2H, Ar),
5.44 (s, 1H, H1), 4.63 (s, 2H, OCH2OCH3), 4.57 (s, 2H, OCH2OCH3), 4.54 (d, J = 5.6
Hz, 1H, H5), 4.42 (s, 1H, H4), 4.03 (d, J = 7.6 Hz, 1H, H6), 3.85 – 3.82 (m, 1H, H3),
3.72 – 3.68 (m, 1H, H6), 3.49 (s, 1H, H2), 3.36 (s, 3H, OCH2OCH3), 3.31 (s, 3H,
OCH2OCH3), 2.44 (s, 3H, ArCH3) ppm; 13C NMR: (126 MHz, CDCl3) δ = 145.3, 133.7,
130.0, 128.0 (6C, Ar), 100.8 (1C, C1), 96.2, 96.1 (2C, OCH2OCH3), 77.0 (1C, C4), 74.0
(1C, C5), 73.42 (1C, C3), 73.35 (1C, C2), 64.9 (1C, C6), 56.0, 55.8 (2C, OCH2OCH3),
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+
21.8 (1C, ArCH3) ppm; HRMS calcd for C34H52O18NS2 [2M+NH4]+ 826.2620 found
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826.2600.
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1,6ꢀAnhydroꢀ4ꢀdeoxyꢀ4ꢀfluoroꢀ2,3ꢀdiꢀOꢀmethoxymethylꢀβꢀDꢀgalactopyranose (23).
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Compound 11 (2.21 g, 5.46 mmol, 1.0 equiv) was stirred in tetrabutylammonium fluoride
(1 M in THF, 55 ml, 10 equiv) under reflux for 72 h. After this time, water (50 ml) was
added and the mixture was extracted with CH2Cl2 (3 × 50 ml). The combined organic
phases were washed with sat. aq. NaHCO3 solution (1 × 100 mL) and brine (1 × 100 ml),
then dried over MgSO4, filtered and concentrated under reduced pressure. The obtained
crude was purified by flash column chromatography (silica gel, EtOAc:hexanes, 2:3) to
give 23 as a white amorphous solid (0.433 g, 31% yield, 76% purity). The inseparable
mixture containing the desired fluoro product 23 was used for the next step without
further purification. Rf = 0.51 (silica, EtOAc:hexanes, 2:3); 19F NMR: (470 MHz, CDCl3)
δ –205.78 (dt, J = 44.8, 5.3 Hz, F4); HRMS calcd for C10H17O6FNa+ [M+Na]+ 275.0901
found 275.0897.
1,2,3,6ꢀTetraꢀOꢀacetylꢀ4ꢀdeoxyꢀ4ꢀfluoroꢀα/βꢀDꢀgalactopyranose (8). To a stirred
solution of the mixture containing compound 23 (0.433 g, 1.0 equiv) in Ac2O (4.9 mL,
51.84 mmol, 30 equiv) at 0 °C was added H2SO4 (0.92 mL, 17.26 mmol, 10 equiv). The
mixture was stirred at room temperature for 18 h. After this time, the mixture was cooled
down to 0 °C and NaOAc (2.81 g, 34.26 mmol, 20 equiv) was added. The mixture was
stirred for an additional 20 min and then quenched with water (20 mL). The mixture was
extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were washed with
water (1 × 30 mL) and brine (1 × 30 ml) and then dried over MgSO4, filtered and
concentrated under reduced pressure. The obtained crude was purified by flash column
chromatography (silica gel, AcOEt:hexanes 1:1) to give compound 8 (α/β, 1:3.7) as a
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yellow oil, (0.313 g, 0.89 mmol, 52% yield): Rf = 0.43 (silica, AcOEt:hexanes 1:1); [α]D
= +66.7° (c 0.2, CHCl3); IR (ATR, ZnSe) ν : 2921, 2850, 1741, 1371, 1208, 1070, 938;
1H NMR: (500 MHz, CDCl3) δ = 6.39 (d, J = 3.6 Hz, 1H, H1α), 5.70 (dd, J = 8.3, 0.9 Hz,
1H, H1β), 5.42 – 5.38 (m, 2H, H2α, H2β), 5.28 (ddd, J = 26.6, 10.9, 2.5 Hz, 1H, H3α),
5.00 (ddd, J = 27.4, 10.5, 2.7 Hz, 1H, H3β), 4.97 (dd, J = 50.2, 2.5 Hz, 1H, H4α), 4.89
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(dd, J = 50.0, 2.7 Hz, 1H, H4β), 4.34 – 4.14 (m, 6H, 1 × H5α, 1 × H6aα, 1 × H6bα, 1 ×
H6aβ, 1 × H6bβ), 3.95 (dt, J = 26.1, 6.5 Hz, 1H, H5β), 2.15 (s, 3H, COCH3α), 2.14 (s,
3H, COCH3α), 2.12 (s, 3H, COCH3β), 2.12 (s, 3H, COCH3β), 2.09 (s, 3H, COCH3α),
7
8
9
13
2.08 (s, 3H, COCH3β), 2.05 (s, 3H, COCH3β), 2.03 (s, 3H, COCH3α) ppm; C NMR:
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(126 MHz, CDCl3) δ = 170.6, 170.54, 170.52, 170.4, 169.8, 169.3, 169.2, 168.9 (8C, 4 ×
COCH3α, 4 × COCH3β), 92.0 (1C, C1β), 89.7 (1C, C1α), 86.5 (d, J = 185.9 Hz, 1C,
C4α), 85.7 (d, J = 187.2 Hz, 1C, C4β), 72.0 (d, J = 18.0 Hz, 1C, C5β), 71.5 (d, J = 18.0
Hz, 1C, C3β), 69.2 (d, J = 18.2 Hz, 1C, C5α), 68.0 (d, J = 17.6 Hz, 1C, C3α), 67.8 (d, J =
1.1 Hz, 1C, C2β), 66.3 (d, J = 2.4 Hz, C2α), 61.5 (d, J = 6.3 Hz, 1C, C6α), 61.4 (d, J =
6.0 Hz, 1C, C6β), 21.02, 20.96, 20.94, 20.89, 20.87, 20.84, 20.76, 20.66 (8C, 4 ×
COCH3α, 4 × COCH3β) ppm; 19F NMR: (470 MHz, CDCl3) δ –217.07 (dt, J = 50.1, 27.2
Hz, F4β), –219.23 (ddd, J = 50.4, 30.3, 26.5 Hz, F4α) ppm; HRMS calcd for
C14H23O9NF+ [M+NH4]+ 368.1351 found 368.1369.
Associated content
Supporting information
Copies of 1H, 13C 19F, COSY and HSQC NMR spectra for new compounds.
Author information
Corresponding Author
Eꢀmail: denis.giguere@chm.ulaval.ca
Notes
The authors declare no competing financial interest.
Acknowledgements
This work was supported by the Natural Sciences and Engineering Research Council of
Canada (NSERC), the Fonds de Recherche du Québec – Nature et Technologies and the
Université Laval. D.L. thanks the Bourse de la Fondation GeorgesꢀÉlieꢀAmyot and
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PROTEO for a postgraduate fellowship. Finally, the authors would like to thank Dr.
Yoann M. Chabre for proof reading of this article and Dr. JeanꢀFrançois Paquin for useful
discussion.
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