Synthesis of a dual-purpose 2-deoxy-2-fluoro-glucopyranosyl building block

Article abstract of DOI:10.1080/00397911.2011.648001

We demonstrate a straightforward route to 1,3,6-tri-O-acetyl-4-O-benzyl-2- deoxy-2-fluoro-D-glucopyranose through potassium hydrogen fluoride opening of a Cerny epoxide under microwave irradiation followed by acetolysis. The fluoroglucose building block was used as a key intermediate in the synthesis of 2,20-dideoxy-2,20-difluoromaltose. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.648001

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Synthesis of a Dual-Purpose 2-Deoxy-2-
fluoro-glucopyranosyl Building Block
Agnete H. Viuff a , Jacob C. Hansen a , Anja B. Christiansen a
Henrik H. Jensen a
&
a Department of Chemistry, Aarhus University, Aarhus, Denmark
Accepted author version posted online: 10 May 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Agnete H. Viuff , Jacob C. Hansen , Anja B. Christiansen & Henrik H. Jensen
(2013): Synthesis of a Dual-Purpose 2-Deoxy-2-fluoro-glucopyranosyl Building Block, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:11, 1557-1562
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Synthetic Communications1, 43: 1557–1562, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.648001
SYNTHESIS OF A DUAL-PURPOSE 2-DEOXY-2-
FLUORO-GLUCOPYRANOSYL BUILDING BLOCK
Agnete H. Viuff, Jacob C. Hansen, Anja B. Christiansen, and
Henrik H. Jensen
Department of Chemistry, Aarhus University, Aarhus, Denmark
GRAPHICAL ABSTRACT
Abstract We demonstrate a straightforward route to 1,3,6-tri-O-acetyl-4-O-benzyl-2-
ˇ
´
deoxy-2-fluoro-D-glucopyranose through potassium hydrogen fluoride opening of a Cerny
epoxide under microwave irradiation followed by acetolysis. The fluoroglucose building
block was used as a key intermediate in the synthesis of 2,20-dideoxy-2,20-difluoromaltose.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Epoxide opening; glycosylation; maltose; microwave
INTRODUCTION
The introduction of fluorine into bioactive compounds can be a demanding syn-
thetic task but is a widely used and often valuable maneuver to obtain compounds
with increased bioactivity and=or stability.[1] In practice, both a nucleophilic (fluoride
or diethylaminosulfurtrifluoride, DAST) and an electrophilic (SelectFluor)[2]
approach can be used for placing a fluorine atom at a sp3 center in an organic
molecule.
Conducting nucleophilic substitution reactions at C-2 of aldohexoses is known to
be notoriously difficult. For the synthesis of the 2-deoxy-2-fluoroglucose building block,
a good leaving group (triflate or Et2NS(O)F from DAST)[3] and a favorable dipole
orientation[4] (b-mannose) is required to obtain a successful reaction. This nucleophilic
approach is used for the preparation of 18F labelled 2-deoxy-2-fluoroglucose (FDG) for
Received November 23, 2011.
Address correspondence to Henrik H. Jensen, Department of Chemistry, Aarhus University,
Langelandsgade 140, 8000 Aarhus C, Denmark. E-mail: hhj@chem.au.dk
1557

1558
A. H. VIUFF ET AL.
Scheme 1. Often used approaches for preparing 2-deoxy-2-fluoroglucopyranoses.
use in tumor localization by positron emission tomography[5] but is additionally
widely used for the synthesis of the unlabelled FDG (Scheme 1A).[6] Another often
employed preparation of this building block (FDG) is electrophilic fluorination of
D-glucal with SelectFluor.[7] A significant drawback with this protocol, however, is that
the reaction outcome is often an inseparable mixture of D-manno=D-gluco isomers
(Scheme 1B).[8]
The presence of fluorine in place of O-2 in synthetic glycosides leads to dramati-
cally increased hydrolytic stability of the glycosidic linkage[9] and in some cases
interesting biological results have been obtained.[10] Both approaches for attaining
2-deoxy-2-fluoro-D-glucose building blocks for disaccharide synthesis, for example,
are not ideal because still a number of steps will be required for installation of the
appropriate protecting groups and donor function. As a supplement to the existing
methods we here present a straightforward strategy for the synthesis of a dual-
purpose 2-deoxy-2-fluoroglucose building block, which can be converted to both
a glucosyl donor and 4-OH glucosyl acceptor.
RESULTS AND DISCUSSION
Our synthesis started from commercially available levoglucosan, which in four
ˇ
steps was converted into Cerny´ epoxide 6 without the need for chromatographic
purification (Scheme 2).[11] trans-Diaxial opening of this epoxide with KHF2 has
previously been demonstrated, albeit with moderate success, giving a yield of 40%
of the 1,6-anhydro-4-O-benzyl-2-deoxy-2-fluoro-glucopyranose sugar (7) along with
Scheme 2. Synthesis of fluorinated acceptor (9) and donor (11) from levoglucosan.

FLUOROSUGARS
1559
Scheme 3. Synthesis of 2,20-dideoxy-2,20-difluoro maltose.
its anti-Furst–Plattner opened 1,6-anhydro-4-O-benzyl-3-deoxy-3-fluoro-altropyra-
¨
nose (3%, structure not shown).[12] We decided to investigate whether carrying out
the reaction in a sealed tube under microwave irradiation had a beneficial effect
on the reaction outcome. To our delight, full conversion of the epoxide starting
material (6) was observed after only 20 min at 220 ꢀC, affording the desired gluco-
configured fluorosugar 7 in an isolated yield of 69% without any traces of the
trans-diequatorial product.
Next, the 2-fluoro-1,6-anhydrosugar (7) was smoothly opened by an acetolysis
reaction under scandium triflate catalysis[13] to give an anomeric mixture of tri-
acetate 8. To obtain a 4-OH acceptor (9), the benzyl ether was uneventfully cleaved
by hydrogenolysis without any sign of acetyl migration.
To translate the key tri-acetate (8) into a useful glucosyl donor, the anomeric
acetate was successfully removed by benzylamine in tetrahydrofuran (THF) to
give reducing sugar 10 before this was treated with trichloroacetonitrile in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give trichloroacetimidate
glucosyl donor 11.
To demonstrate the usefulness of the acceptor (9) and donor (11), the synthesis
of a disaccharide from the two prepared building blocks was attempted. The reaction
was carried out in the nonparticipating solvent dichloromethane and a majority of
maltose rather than cellubiose was expected.[14] Because of the strongly electron-
withdrawing nature of fluorine, no activation was found to take place below 0 ꢀC
by using TMSOTf as the promoter.
Only the a-linked product could be isolated from the reaction mixture in the
moderate yield of 50%. Yields in this range are not uncommon for glycosylations
with 2-fluoro-donors.[10]
CONCLUSION
ˇ
We have shown that Cerny´ epoxide 6 can be efficiently opened by KHF2 under
microwave irradiation and produce a 2-deoxy-2-fluoro sugar, which in a straightfor-
ward manner can be converted into both a glucosyl donor and a 4-OH glucosyl
acceptor. The present approach is well suited for the synthesis of larger oligosacchar-
ide fragments containing 1,4-linkages to and from a 2-deoxy-2-fluoro-glucosyl build-
ing block. This was demonstrated by the synthesis of 2,20-deoxy-2,20-fluoro-maltose.
EXPERIMENTAL
General experimental details about the synthesis of compounds 8–11 can be
found in the Supporting Information, available online.

1560
A. H. VIUFF ET AL.
1,6-Anhydro-4-O-benzyl-2-deoxy-2-fluoro-b-D-glucopyranose (7)
The 2,3-epoxy-1,6-anhydrosugar (489 mg, 2.1 mmol) and potassium hydrogen
fluoride (1.19 g, 15.2 mmol, 7 eq) was added to ethylene glycol (6 mL) in a 10 to
20-mL microwave vial. The mixture was subjected to microwave irradiation for
20 min at 220 ꢀC. The reaction was then cooled to rt and diluted with water (50 mL)
before the aqueous layer was extracted with ethyl acetate (7 ꢁ 30 mL), and the com-
bined organic phases were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash column chromatography
(pentane=EtOAc 1:2) to give the product (7) as a colorless oil (351 mg, 69%). Rf
(pentane=EtOAc 2:3) 0.44. 1H NMR (400 MHz, CDCl3) dH 7.40–7.27 (m, 5H,
ArH), 5.52 (d, 1H, J1,F 5.2 Hz, H1), 4.70 (d, 1H, Jgem 12.2 Hz, PhCHH), 4.65 (d,
1H, PhCHH), 4.59 (d, 1H, J5,6a 5.4 Hz, H5), 4.24 (dd, 1H, J2,3 2.8 Hz, J2,F 47.2 Hz,
H2), 3.97 (dt, 1H, J2,3;3,4 2.8 Hz, J3,F 20.0 Hz, H3), 3.87 (d, 1H, J6a,6b 7.6 Hz, H6a),
3.66 (dd, 1H, J5,6b 5.4 Hz, H6b), 3.32 (d, 1H, H4), 2.60 (b s, 1H, OH). 13C NMR
2
(100 MHz, CDCl3) dC 137.5, 128.6, 128.1, 127.9 (Ar), 99.5 (d, J 30 Hz, C1), 89.7
(d, J 181.5 Hz, C2), 78.2 (d, J 6.2 Hz, C4), 74.9 (C5), 71.7 (CH2Ph), 69.8 (d, J
26.2, C3), 66.1 (C6). LRMS (ES): calcd. for C13H15FO4Na: 277.1, found 277.0.
1
3
2
4-(3,6-Di-O-acetyl-4-O-benzyl-2-deoxy-2-fluoro-a-D-glucopyranosyl)-
1,3,6-tri-O-acetyl-2-deoxy-2-fluoro-a=b-D-glucopyranose (12)
Donor 11 (220 mg, 0.44 mmol, 2.1 eq) and acceptor 9 (64 mg, 0.21 mmol) were
mixed in CH2Cl2 and concentrated under reduced pressure. The mixture was then
redissolved in dry CH2Cl2 (4 mL) and cooled to 0 ꢀC before TMSOTf (0.09 mL,
0.50 mmol, 2.4 eq) was added under an N2 atmosphere. The reaction was left to react
overnight at 5 ꢀC, after which additional TMSOTf (0.03 mL) was added. After stir-
ring for additional 3 h at 0 ꢀC, the reaction was quenched with Et3N, concentrated
under reduced pressure, and purified by flash column chromatography (pentane=
EtOAc 20:1!5:1!CH2Cl2=EtOAc 20:1) to give disaccharide (67 mg, 50%). Rf
1
(pentane=EtOAc 2:1) 0.14. [a]295K 10.6 (c 1, CHCl3). Major isomer: H NMR
D
(400 MHz, CDCl3) dH 7.33–7.17 (m, 5H, ArH), 6.31 (d, 1H, J1,2 3.8 Hz, H1), 5.59
(q, 1H, J 9.6 Hz, H3=H30), 5.50 (q, 1H, J 9.8 Hz, H30=H3), 5.15 (d, 1H, J1 ,2
0
0
3.9 Hz, H10), 4.55 (d, 1H, Jgem11.1 Hz, PhCHH), 4.49 (d, 1H, PhCHH), 4.44 (dd,
1H, J2,F 48.6 Hz, J2,3 9.7 Hz, H2), 4.30 (dd, 1H, J2 ,3 9.8 Hz, J2 ,F 48.6 Hz, H20),
4.35 (dd, 1H, J 1.9 Hz, J 12.3 Hz, H6a=H60a), 4.28–4.12 (m, 3H, H60a=H6a, H6b,
H60b), 3.97 (ddd, 1H, J 1.8 Hz, J 4.2 Hz, J 10.1 Hz, H5=H50), 3.92 (ddd, 1H, J
2.2 Hz, J 4.2 Hz, J 10.0 Hz, H50=H5), 3.77 (t, 1H, J 9.6 Hz, H4=H40), 3.48 (t, 1H,
J 9.6, H40=H4), 2.19 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.01 (s,
3H, CH3), 1.99 (s, 3H, CH3). Major isomer: 13C NMR (100 MHz, CDCl3) dC
170.5, 170.5, 169.5, 169.3, 169.0 (CO), 137.1, 128.7, 128.3, 128.1 (ArC), 98.8 (d,
0
0
0
J2 ,F 21.1, C20), 88.4 (d, J1,F 22.2, C1), 87.6 (d, J2 ,F 195.4, C20), 86.8 (d, J2,F 195.8,
C2), 75.4 (C40=C4), 75.4 (C4=C40), 74.8 (PhCH2), 71.8 (d, J 17.6 Hz, C3=C30), 71.3
(d, J 18.9 Hz, C30=C3), 70.5 (C5=C50), 70.1 (C50=C5), 62.5 (C6=C60), 62.3 (C60=
C6), 21.1, 21.0, 20.9, 20.8, 20.7 (CH3). Major isomer: 19F NMR (377 MHz, CDCl3)
dF ꢂ200.8 (dd, J 12.4 Hz, J 52.4 Hz), ꢂ202.5, (dd, J 12.0 Hz, J 52.0 Hz). Minor iso-
mer 19F NMR (377 MHz, CDCl3) dF ꢂ201.4 (dd, J 12.4 Hz, J 52.4 Hz), ꢂ202.35 (dd,
0
0

FLUOROSUGARS
1561
J 12.8 Hz, J 51.2 Hz). HRMS (ES): calcd. for C36H38O6Na 669.1971; found
669.1974.
ACKNOWLEDGMENTS
We are grateful for support from the Carlsberg Foundation and the OChem
Graduate School, Aarhus University.
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