Higher iodinated analogues of D-glucose: Syntheses of 3-C-iodomethyl, 6-C-iodomethyl and 6-C-iodophenyl derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00518-2

C-Substituted iodinated analogues of D-glucose have been prepared from diacetone-D-glucose or D-glucuronic acid derivatives; in these compounds, each hydroxyl group of glucose is present. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00518-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 629–638
Higher iodinated analogues of D-glucose: syntheses of 3-C-
iodomethyl, 6-C-iodomethyl and 6-C-iodophenyl derivatives
Christophe Morin ∗ and Lionel Ogier
LEDSS, UMR 5616, Bâtiment 52 Chimie Recherche, Université de Grenoble, B.P. 53X, 38041 Grenoble, France
Received 26 October 1999; accepted 16 November 1999
Abstract
C-Substituted iodinated analogues of D-glucose have been prepared from diacetone-D-glucose or D-glucuronic
acid derivatives; in these compounds, each hydroxyl group of glucose is present. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
The quest for iodinated analogues of carbohydrates which could be used in SPECT (single photon
emitted computed tomography) medical imaging1 has resulted in the preparation of derivatives in which
one of the oxygen atoms is substituted by an iodinated moiety (to get, for example, β-iodoethers)2 or
in compounds in which iodine has replaced a hydroxyl group. However, no higher homologues of the
general formula C7H15XO6 (X being any halogen), whether linear or branched, have been described to
date. In such compounds, the basic skeleton of the parent D-glucose together with each of its hydroxyl
group would be preserved; this work reports on the synthesis of two such analogues, namely 1 and 2, as
well as on the preparation of a C-iodophenyl derivative, 3.
∗
Corresponding author.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00518-2
tetasy 3153

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2. Preparation of a C-3 branched derivative
The rationale for linking an iodinated group to C-3 of glucose stems from the fact that although
substitution of O-3 by a methyl group is well tolerated,3 this is not the case when bulkier substituents are
introduced;4 the replacement of the OH-3 by iodine, as in 3-deoxy-3-iodoglucose,5 is also detrimental.
In 1, the 3-OH group is retained and the iodinated group has been introduced on carbon to give a C-3-
branched iodomethyl derivative of gluco configuration (Scheme 1).
Scheme 1.
6,7
Readily available ketone 4
appeared as a convenient starting material for the preparation of 1, by
direct iodomethylation to get 5 using SmI2/CH2I2.8,9 No such reaction occurred under these conditions,
however, presumably because of the difficulties in completely freeing 4 from its hydrate.7 Compound
4 was, therefore, converted by Peterson olefination10 to the known exo-methylene derivative 611 but no
electrophilic iodination (to get 5) using N-iodosuccinimide,12 hypoiodous acid13 or iodine14 could be
achieved. Epoxidation of 6 gave a 50:50 mixture of epimeric epoxides (83%) from which a small amount
of pure 7 could be obtained by crystallisation. Its configuration was identified as gluco by comparison of
its properties with those of the epoxide obtained15 by addition of diazomethane on ketone 4. However,
none of these methods is of preparative value to get pure epoxide 7.16 Compound 6 was then reacted17
with aqueous potassium permanganate to yield glycol 8 (70%) where configuration was assigned as
gluco because its C-3 allo epimer, 9, had been correlated with aldehyde 10. Aldehyde 10 was indeed
shown to exist in equilibrium with aminal 11, thus establishing the cis-relationship of their C-3 and C-4
substituents (Scheme 2).17

C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
631
Scheme 2.
To achieve the introduction of iodine on 8, displacement of its primary alcohol-derived sulfonate
proved to be the method of choice. As both tosylate and mesylate remained unreactive,18 it became
necessary to use triflate 12 (Tf2O, 2,4,6-collidine, −10°C, 15 min) which was reacted with sodium iodide
under protection from light to afford iodohydrin 5 (78% from 8). Trifluoracetic acid deprotection of both
of its acetals (62%) then gave the desired C-iodomethyl analogue 1 (δ CH2I=12.9 ppm).
3. Derivatives substituted at C-6
Position-6 was also selected for introduction of an iodinated moiety as structure/affinity relationships
of glucose derivatives have shown the possibility of modifications at C-6,19 which has been used in
particular for the development of 6-deoxy-6-iodo-D-glucose20,21 as a tracer of glucose transport.22
Glucuronamide derivatives, as probes for the study of glucose transport proteins,23 have also been
prepared by derivatisation of glucose at position-6. In all these analogues, however, the 6-OH of glucose
is ‘lost’ and since this hydroxyl can interact with hexokinases24–27 or phosphatases,25 the preparation of
C-6 substituted analogues 2 and 3 was undertaken; their synthesis is based on the methodology developed
by Fleet and co-workers24,25 starting with conformationally-locked glucuronolactone derivative 13.
Reaction of 1324,25 with benzyloxymethyllithium, prepared in situ from (benzyloxymethyl)tributyl-
stannane and n-butyllithium at −100°C,28,29 gave lactol 14, the best yields (45%) being obtained with
a 1:2:1.8 (13:Sn:Li) ratio. As observed previously in related cases,24,25 sodium borohydride reduction
(98%) of lactol 14 was accompanied by migration of the silyl group (O-5 to O-6) and the stereochemistry
at C-6 of the single 7-deoxy-heptose derivative thus obtained was assigned as S in accordance with
previous work.25 Since selective replacement by iodine of the 7-OH of 16 obtained after debenzylation
of 15 could not be effected satisfactorily, 15 was converted (CF3COOH then Ac2O) to a mixture of
acetylated anomers from which pure α-pyranose 17 could be crystallised. Completion of the synthesis
involved debenzylation (to get 18, 95%), iodination with the iodine/chlorodiphenylphosphine/imidazole
system30 (19, 56%) and Zemplén deacylation to give 2 (95%) (Scheme 3).
Preparation of 3 was straightforward: reaction of lactone 13 with tributylstannylphenyl lithium (pre-
pared in situ by monolithiation of 1,4-bis(tributylstannyl)benzene at −100°C)31 gave a lactol which was
not isolated but which could be reduced (NaBH4, 77% from 13) to give a single epimer at C-6;32 its
stereochemistry at C-6 was assigned as R33 after comparison of its 1H NMR data with those of a similar
compound (20, R=H) whose structure could be established unambiguously.24 Electrophilic iodination34
(iodine chloride, 95%) gave 21 whose acetal was cleaved (CF3COOH, 65%) to afford 3.

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C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
Scheme 3.
In all three derivatives 1, 2 and 3, the iodinated moiety has been found to be stable, which should
enable radiolabelling (123I or 131I) of these glucose analogues for their biological evaluation towards
SPECT medical imaging.
4. Experimental
4.1. General methods
Anhydrous solvents were obtained as follows: methanol was distilled over magnesium methoxide,
tetrahydrofuran and toluene over sodium, dichloromethane was dried on 4 Å molecular sieves before
use. After work-up, the volatiles were evaporated under reduced pressure without heating and the iodo
derivatives were protected from light. Column chromatography was performed on Silica Gel SI 60

C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
633
(70–230 mesh) Geduran. Standard abbreviations are used for NMR description of spectra which were
recorded on Bruker AC 200, WM 250 and AM 300 apparatus, using built-in software, at the field and
in the solvent indicated for each compound. The residual absorption of the NMR solvent was taken as
the internal reference, except for 13C NMR spectra in water. A Perkin–Elmer 241 polarimeter was used
for the determination of optical rotations. Elemental analyses were performed by the Service Central
d’Analyses du CNRS, Vernaison (France).
4.2. 1,2:5,6-Di-O-isopropylidene-3-C-trifluoromethanesulfonyloxymethyl-α-D-glucofuranose 12
To a stirred solution of 817 (100 mg, 0.34 mmol) in dichloromethane (3 mL) at −10°C were added
successively 2,4,6-collidine (72 µL, 1.6 equiv.) and a solution of trifluoromethanesulfonic anhydride (72
µL, 1.3 equiv.) in dichloromethane (3 mL). After 15 min stirring at −10°C, ice was added followed by
dichloromethane (20 mL). The layers were separated and the aqueous layer extracted three times with
dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated
under reduced pressure to give 12 (115 mg, 79%) as a colourless oil which was used without delay in the
next step. 1H NMR (200 MHz, CDCl3) δ 5.85 (d, J1–2=4 Hz, 1H, H-1), 4.75 (AB system, J=12 Hz, 2H,
SO2CH2), 4.4 (d, J1–2=4 Hz, 1H, H-2), 4.4–3.9 (m, 3H, H-5, H-6, H-60), 3.7 (d, J4–5=11 Hz, 1H, H-4),
1.5 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.3 (s, 6H, 2*CH3). 13C NMR (62.5 MHz, CDCl3) δ 113.2, 109.9
(2*C(Me)2), 104.8 (C-1), 84.6, 80.6, 72.0 (C-2, C-4 and C-5), 81.1 (C-3), 76.1 (SO2CH2), 67.6 (C-6),
26.9, 26.6, 26.3, 24.8 (4*C(Me)2).
4.3. 1,2:5,6-Di-O-isopropylidene-3-C-iodomethyl-α-D-glucofuranose 7
To a solution of 12 (115 mg, 0.72 mmol) in acetone (3 mL) was added sodium iodide (410 mg, 2.735
mmol, 10 equiv.) and the solution was stirred overnight at 60°C under protection from light. After cooling
and evaporation of the solvent, the residue was partitioned between dichloromethane and water, the latter
being extracted with dichloromethane. The combined organic layers were washed with brine, dried and
concentrated to dryness. Silica gel column chromatography (dichloromethane:methanol, 98:2) afforded 7
20
as a yellowish oil (108 mg, 0.27 mmol, 99%). [α] =+48 (c 0.44, CHCl3). 1H NMR (200 MHz, CDCl3)
D
δ 5.8 (d, J1–2=3.8 Hz, 1H, H-1), 4.2 (d, J1–2=3.8 Hz, 1H, H-2), 4.35–3.9 (m, 3H, H-5, H-6, H-60), 3.85 (d,
J4–5=8.2 Hz, 1H, H-4), 3.6 (AB system, J=10 Hz, 2H, CH2I), 1.5 (s, 3H, CH3), 1.4 (s, 3H, CH3), 1.3 (s,
6H, 2*CH3). 13C NMR (62.5 MHz, CDCl3) δ 112.8, 109.6 (2*C(CH3)2), 103.8 (C-1), 87.5, 79.7, 72.7
(C-2, C-4, C-5), 80.7 (C-3), 67.8 (C-6), 27.1, 26.8, 26.4, 25.1 (4*C(CH3)2), 11.5 (CH2I). Anal. calcd for
C13H21IO6: C, 39.02; H, 5.29. Found: C, 39.11; H, 5.32.
4.4. 3-C-Iodomethyl-α,β-D-glucopyranose 1
To a stirred solution of 7 (160 mg, 0.4 mmol) in 9:1 dichloromethane:water (5 mL) at 4°C was added
dropwise trifluoracetic acid (1.6 mL, 20 mmol, 50 equiv.). The mixture was stirred at rt for 2 h and
the volatiles were evaporated. The residue obtained after co-evaporation with toluene was taken up in
water and extracted with dichloromethane. After drying and evaporation, the residue was recrystallised
21
from ethanol to afford 1 as white crystals (80 mg, 62%). M.p.=132.5°C. [α] =+33 (c 0.23, H2O) 5
D
1
min→+42°C (24 h). H NMR (200 MHz, D2O) δ 5.4 (d, J1–2=3.2 Hz, H-1α), 4.85 (detected in DOH,
H-1β), 3.95–3.4 (m, other Hs). 13C NMR (62.5 MHz, D2O+(CD3)2C_O) δ 102.2 (C-1β), 96.3 (C-
1α), 82.1, 80.6, 78.7, 78.4, 70.9, 70.1 (C-2, C-4, C-5α+β), 82.0, 81.1 (C-3α+β), 64.1 (C-6α+β), 12.9
(CH2Iα+β). Anal. calcd for C7H13IO6: C, 26.27; H, 4.09; I, 39.65. Found: C, 26.32; H, 4.11; I, 39.44.

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C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
4.5. 7-O-Benzyl-5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-D,L-glycero-α-D-gluco-hepto-keto-
6,3-aldo-1,5-difuranose 14
To a stirred solution of benzyloxymethyltributylstannane29 (13.9 g, 33.8 mmol, 2 equiv.) in dry THF
(50 mL) under argon at −100°C was added n-butyllithium (21 mL of a 1.45 M soln in hexane, 30.4
mmol, 1.8 equiv). Then 1324,25 (5.6 g, 16.95 mmol, 1 equiv.), dissolved in the minimum amount of dry
THF, was added at once and the mixture was warmed to −50°C before quenching with water (50 mL).
The mixture was then brought to room temperature, diluted with diethyl ether (100 mL) and washed
with brine. After drying and evaporation of the volatiles, column chromatography on silica gel (99:1,
22
D
dichloromethane:methanol) afforded 14 (3.56 g,45%) as a colourless oil. [α] =+31 (c 0.25, CHCl3).
1H NMR (250 MHz, CDCl3) δ 7.4–7.2 (m, 5H, Ar-CH2O), 5.95 ( d, J1–2=4 Hz, 1H, H-1), 4.7–4.45
(m, 5H, H-2, H-3, H-4, H-6a, H-6b), 4.25 (d, J4–5=4.8 Hz, 1H, H-5), 4.0 (s, 1H, OH), 3.45–3.3 (AB
system, J=11 Hz, 2H, Ar-CH2O), 1.4 (s, 3H, CH3), 1.3 (s, 3H, CH3), 0.85 (s, 9H, Si-C(CH3)3), 0.1,
0.0 (2*s, 2*3H, Si-(CH3)2). 13C NMR (50 MHz, CDCl3) δ 137.9 (Phipso), 128.3, 127.8, 127.7 (Phortho,
meta and para), 112.4 (C(CH3)2), 107.1 (C-1), 104.6 (C-6), 85.5, 83.8, 82.2, 72.5 (C-2 to C-5), 73.6, 70.5
(CH2OCH2Ar), 27.3, 26.8 (C(CH3)2), 25.7 (Si-C(CH3)3), 18.1 (Si-C(CH3)3), −4.7, −5.1 (Si-(CH3)2).
Anal. calcd for C23H36O7Si: C, 61.04; H, 8.02. Found: C: 61.24; H, 7.89.
4.6. 7-O-Benzyl-6-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-L-glycero-α-D-gluco-heptofuranose
15
To a solution of 14 (2.76 g, 6 mmol) in ethanol (30 mL) at 4°C was added sodium borohydride (346
mg, 9.15 mmol, 1.5 equiv.). The cooling bath was removed and when the room temperature was reached
aqueous saturated ammonium chloride solution was added. Extraction was performed with ethyl acetate
(100 mL) and the organic layer was washed with brine. After drying and evaporation of the volatiles, the
residue was purified by column chromatography on silica gel. Elution with dichloromethane:methanol
22
(95:5) gave 15 as a colourless oil (2.72 g, 98%). [α] =+1.6 (c 0.8, CHCl3). 1H NMR (250 MHz, CDCl3)
D
δ 7.4–7.2 (m, 5H, Ar), 5.85 (d, J1–2=4 Hz, 1H, H-1), 4.55–4.45 (m, 3H, Ar-CH2O, H-2), 4.5–4.3 (m, 1H,
H-3), 4.1–4.05 (m, 2H, H-4, H-6), 3.95 (t, J=8 Hz, 1H, H-5), 3.6–3.4 (m, 2H, BnO-CH2), 3.0 (d, J=4 Hz,
1H, OH), 2.8 (d, J=9 Hz, 1H, OH), 1.4 (s, 3H, CH3), 1.3 (s, 3H, CH3), 0.85 (s, 9H, Si-C(CH3)3), 0.1,
0.05 (2*s, 2*3H, Si-(CH3)2). 13C NMR (62.5 MHz, CDCl3) δ 137.9 (Phipso), 128.3, 127.8 (Phortho, meta
and para), 111.0 (C(CH3)2), 105.1 (C-1), 85.1, 79.6, 75.4, 70.1, 69.7 (C-2 to C-6), 71.6, 70.1 (Ar-CH2-O-
CH2), 26.6, 25.9 (C(CH3)2), (Si-C(CH3)3), 18.1 (Si-C(CH3)3), −4.4, −5.0 (Si-(CH3)2). Anal. calcd for
C23H38O7Si: C, 60.76; H, 8.42. Found: C, 60.84; H, 8.39.
4.7. 7-O-Benzyl-1,2,3,4,6-penta-O-acetyl-L-glycero-β-D-gluco-heptopyranose 17
Dichloromethane (4.5 mL) and water (0.5 mL) were added to 15 (200 mg, 0.44 mmol) and the biphasic
mixture was stirred efficiently. Trifluoracetic acid was added and when deprotection was complete (tlc),
the volatiles were removed. Co-evaporation with toluene was performed twice and the residue was then
taken up in pyridine (2 mL) before the addition of acetic anhydride (1 mL, 10.6 mmol, 24 equiv.). After
stirring overnight, ice was added and the mixture extracted with dichloromethane (3×10 mL). After
washing the organic layer with brine and water, crystallisation of the residue — which consisted mainly
22
D
of a 1:1 mixture of anomers — from ethanol gave 17 (52 mg, 23%). M.p.=160–162°C. [α] =−15 (c
0.1, CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.4–7.2 (m, 5H, Ar), 5.7 (d, J1–2=8 Hz, 1H, H-1), 5.3–5.0
(m, 4H, H-2, H-3, H-4, H-6), 4.6–4.4 (AB system, J=12 Hz, 2H, Ar-CH2O), 3.95 (dd, J=1.5 Hz, J=8.5

C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
635
Hz, 1H, H-5), 3.55 (m, 2H, BnO-CH2), 2.1 (s, 3H, CH3CO), 2.05 (s, 3H, CH3CO), 2.0 (s, 3H, CH3CO),
1.95 (s, 6H, 2*CH3CO). 13C NMR (75 MHz, CDCl3) δ 170. 1, 170.0, 169.4, 169.1, 168.7 (CH3CO),
137.8 (Phipso), 128.3, 127.8, 127.7 (Phortho, meta and para), 92.2 (C-1), 73.5 (Ar-CH2O), 73.1, 72.3, 70.4,
67.1, 66.9 (C-2 to C-6), 66.8 (BnO-CH2), 20.7 (CH3CO), 20.6 (CH3CO), 20.5 (CH3CO). Anal. calcd for
C23H38O12: C, 56.47; H, 5.92. Found: C, 56.16; H, 5.84.
4.8. 1,2,3,4,6-Penta-O-acetyl-L-glycero-β-D-gluco-heptopyranose 18
Methanol (3 mL) was added to 17 (100 mg, 0.196 mmol) followed by the minimum amount of
dichloromethane to ensure dissolution. Palladium (10% on carbon, 40 mg) was then added and the
mixture was stirred overnight under an atmosphere of hydrogen. After filtration on Celite, evaporation of
21
D
the volatiles afforded pure 18 (78 mg, 95%) as a colourless solid. M.p.=149–150°C. [α] =−12 (c 0.1,
CHCl3). 1H NMR (250 MHz, CDCl3) δ 5.5 (d, J1–2=8 Hz, 1H, H-1), 5.3–5.0 (m, 4H, H-2, H-3, H-4, H-
6), 3.9 (dd, J=2.4 Hz, J=9.5 Hz, 1H, H-5), 3.7 (m, 2H, CH2OH), 3.4 (s, 1H, OH), 2.15 (s, 3H, CH3CO),
2.1 (s, 3H, CH3CO), 2.0 (s, 3H, CH3CO), 1.95 (s, 6H, 2*CH3CO). 13C NMR (62.5 MHz, CDCl3) δ
170.4, 169.9, 169.4, 169.3, 169.1 (CH3CO), 92.2 (C-1), 72.7, 72.3, 69.9, 68.7, 66.7 (C-2 to C-6), 59.9
(CH2OH), 20.5, 20. 3 (CH3CO). Anal. calcd for C17H24O12: C, 48.57; H, 5.75. Found: C, 48.61; H, 5.73.
4.9. 7-Deoxy-7-iodo-1,2,3,4,6-penta-O-acetyl-L-glycero-β-D-gluco-heptopyranose 19
To a stirred solution of 18 (510 mg, 1.21 mmol) protected from light in dry toluene (40 mL) were added
successively imidazole (186 mg, 2.73 mmol, 2.25 equiv.), freshly distilled chlorodiphenylphosphine (287
µL, 1.6 mmol, 1.32 equiv.) and, after having stirred the turbid mixture for 10 min at 40°C, iodine (399 mg,
1.57 mmol, 1. 3 equiv.). After 30 min stirring, the same quantities of imidazole, chlorodiphenylphosphine
and iodine were added in that order and the mixture was stirred overnight at room temperature. After
addition of a saturated aqueous sodium hydrogenocarbonate, iodine was added portionwise under stirring
until a persistent brown colouration of the organic layer was observed. Ethyl acetate (100 mL) was added
and the organic layer was washed with a saturated aqueous solution of sodium thiosulfate, then brine.
After drying and evaporation of the volatiles, the orange oil was purified by column chromatography on
silica gel. Elution with dichloromethane:methanol (99:1) gave 19 after crystallisation from diethyl ether
22
(361 mg, 56%). M.p.=187–190°C. [α] =−21 (c 0.31, CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.7 (d,
D
J1–2=8 Hz, 1H, H-1), 5.25–5.0 (m, 4H, H-2, H-3, H-4, H-6), 4.1 (dd, J=2 Hz, J=10 Hz, 1H, H-5), 3.3–3.1
(AB of ABMX, J=9 Hz, 2H, CH2I), 2.1 (s, 3H, CH3CO), 2.05 (s, 3H, CH3CO), 2.0 (s, 3H, CH3CO),
1.95 (s, 3H, CH3CO), 1.9 (s, 3H, CH3CO). 13C NMR (62.5 MHz, CDCl3) δ 169. 9, 169.8, 169.3, 169.1,
168.6 (CH3CO), 92.2 (C-1), 72.9, 72.8, 70.2, 68.9, 67.5 (C-2 to C-6), 20.6, 20.5, 20.4 (CH3CO), −0.7
(CH2I). Anal. calcd for C17H23IO11: C, 38.50; H, 4.37; I, 29.93. Found: C, 38.75; H, 4.42; I, 23.73.
4.10. 7-Deoxy-7-iodo-L-glycero-α,β-D-gluco-heptopyranose 2
To a solution of 19 (300 mg, 0.57 mmol) in dry 1:1 dichloromethane:methanol (20 mL) was added
sodium methoxide (10 drops of a 1 M solution in dry methanol). The solution was set at 4°C overnight
and water (20 mL) was added. Concentration to half-volume was performed under reduced pressure and
the pH was adjusted to 7.0 (Dowex 50 (H+)). After filtration, evaporation of the volatiles afforded 2 (172
22
mg, 95%) as an amorphous solid. [α] =+40 (c 0.1, CH3OH) 5 min→+47°C (24 h). 1H NMR (250 MHz,
D
D2O+CD3OD) (α/β=1) δ 5.25 (d, J1–2=3 Hz, 1H, H-1α), 4.7 (d, J1–2=8 Hz, 1H, H-1β), 4.3–3.25 (m,
other Hs). 13C NMR (62.5 MHz, D2O+CD3OD) δ 96.6 (C-1β), 92.1 (C-1α), 75.9, 75.2, 74.2, 73.1, 71.5,

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C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
70.6, 69.9, 68.9 (C-2α+β to C-6α+β), 7.2 (CH2Iα+β). Anal. calcd for C7H13IO6: C, 26.27; H, 4.09; I,
39.65. Found: C, 26.38; H, 4.18; I, 39.41.
4.11. 6-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-6-C-(4-(tri-n-butylstannyl)phenyl)-L-glycero-
α-D-gluco-hexofuranose 20
To a stirred solution of 1,4-bis-(tri-n-butylstannyl)benzene31 (3 g, 4.74 mmol, 1.28 equiv.) in dry
THF (15 mL) under argon at −100°C, was added n-butyllithium (2.31 mL of 1.6 M soln in hex-
ane, 3.7 mmol, 0.8 equiv.). The cooling bath was removed and when the temperature had reached
−20°C the solution was cooled again at −100°C and 1324,25 (1.51 g, 4.4 mmol, 1.1 equiv.) in dry
THF (2 mL) was rapidly added. The mixture was then stirred at −78°C for 1 h and the cooling
bath was removed. A saturated aqueous ammonium chloride solution was added, followed by diethyl
ether (100 mL). The organic layer was washed with brine, dried and the volatiles were evaporated
under reduced pressure. The residue was purified by column chromatography. Elution with dichlo-
romethane:methanol (99:1) gave crude 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-6-C-(40-(tri-n-
butylstannyl)phenyl)-D,L-glycero-α-D-gluco-hepto-keto-6,3-aldo-1,5-difuranose (2.8 g) which was used
without further purification. 13C NMR (75 MHz, CDCl3) δ 141.9, 140.7 (Phipso and para), 136.2, 125.3
(Phortho, meta), 112.4 (C(CH3)2), 107.3 (C-1), 103.7 (C-6), 85.9, 84.3, 82.4, 80.0 (C-2 to C-5), 29.1
(SnCH2CH2CH2CH3), 27.3, 26.8 (C(CH3)2), 27.2 (SnCH2CH2CH2CH3), 25.5 (Si-C(CH3)3), 18.0 (Si-
C(CH3)3), 13.5 (SnCH2CH2CH2CH3), 9.5 (SnCH2CH2CH2CH3), −5.0, −5.4 (Si-(CH3)2).
To a solution of this lactol (2.6 g) in ethanol (20 mL) at 4°C was added sodium borohydride (210
mg, 5.55 mmol). The cooling bath was removed and, after stirring for 2 h, aqueous ammonium chloride
solution was added followed by ethyl acetate (100 mL). The organic layer was washed with water, brine
and dried. After evaporation of the volatiles the residue was purified by column chromatography on silica
21
D
gel. Elution with 95:5 dichloromethane:methanol gave 20 (2.0 g, 77%) as a colourless oil. [α] =+9 (c
2.8, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.45 and 7.25 (AA0XX0, Japp.=8 Hz, 4H, Ar), 5.9 (d, J1–2=3
Hz, 1H, H-1), 4.85 (d, J5–6=2.4 Hz, 1H, H-6), 4.5 (d, J1–2=3 Hz, 1H, H-2), 4.3 (m, 1H, H-3), 4.05 (dd,
J=8, 2.4 Hz, 1H, H-4), 3.85 (m, 1H, H-5), 3.3 (d, J=3 Hz, 1H, OH), 2.95 (d, J=7 Hz, 1H, OH), 1.5 (m,
J=8 Hz, 2H, SnCH2CH2CH2CH3), 1.4 (s, 3H, C(CH3)2), 1.35 (m, J=8 Hz, 2H, SnCH2CH2), 1.3 (s, 3H,
C(CH3)2), 1.05 (m, 2H, SnCH2), 0.95 (s, 9H, Si-C(CH3)3), 0.9 (t, J=7.1 Hz, 3H, SnCH2CH2CH2CH3),
0.1, −0.15 (2*s, 2*3H, Si-(CH3)2). 13C NMR (75 MHz, CDCl3) δ 141.2, 141.1 (Phipso and para), 136.2
(Phmeta), 125.9 (Phortho), 111.2 (C(CH3)2), 104.9 (C-1), 85.2, 79.3, 75.4, 74.6, 74.1 (C-2 to C-6), 29.1
(SnCH2CH2CH2CH3), 27.2 (SnCH2CH2), 26.5, 26.1 (C(CH3)2), 25.8 (Si-C(CH3)3), 18.1 (Si-C(CH3)3),
13.6 (SnCH2CH2CH2CH3), 9.5 (SnCH2), −4.6, −5.1 (Si-(CH3)2). Anal. calcd for C33H60O6SiSn: C,
56.65; H, 8.64. Found: C, 56.72; H, 8.66.
4.12. 6-O-tert-Butyldimethylsilyl-6-C-(4-iodophenyl)-1,2-O-isopropylidene-L-glycero-α-D-gluco-
hexofuranose 21
To a solution of 20 (500 mg, 0.15 mmol) in dichloromethane (10 mL) was added dropwise a 0.2 M
solution of iodine chloride in dichloromethane until a persistent orange–brown colouration was observed.
After evaporation of dichloromethane, the residue was purified by column chromatography on silica
gel. Elution with 98:2 dichloromethane:methanol afforded 21 as a colourless syrup (365 mg, 95%).
21
1
[α] =+8.5 (c 0.2, CHCl3). H NMR (200 MHz, CDCl3) δ 7.6–7.05 (AA0XX0 syst., Japp.=8 Hz, 4H,
D
Ar), 5.85 (d, J1–2=4 Hz, 1H, H-1), 4.85 (d, J5–6=1.5 Hz, 1H, H-6), 4.45 (d, J1–2=4 Hz, 1H, H-2), 4.25 (m,
1H, H-3), 4.00 (dd, J=8, 3 Hz, 1H, H-4), 3.7 (m, 1H, H-5), 3.1 (M, 1H, OH), 2.75 (d, J=9 Hz, 1H, OH),

C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
637
1.4 (s, 3H, C(CH3)2), 1.25 (s, 3H, C(CH3)2), 0.9 (s, 9H, Si-C(CH3)3), 0.1, −0.15 (2*s, 2*3H, Si-(CH3)2).
13C NMR (50 MHz, CDCl3) δ 141.6 (Phipso), 137.2 (Phmeta), 128.2 (Phortho), 111.3 (C(CH3)2), 105.0 (C-
1), 93.0 (C-I), 85.0, 79.5, 75.0, 73.9, 73.0 (C-2 to C-6), 26.6, 26.0 (C(CH3)2), 25.8 (Si-C(CH3)3), 18.1
(Si-C(CH3)3), −4.6, −5.1 (Si-(CH3)2). Anal. calcd for C21H33IO6Si: C, 47.02; H, 6.20; I, 23.65. Found:
C, 46.83; H, 6.08.; I, 23.83.
4.13. 6-C-(4-Iodophenyl)-L-glycero-α,β-D-gluco-hexopyranose 3
Dichloromethane (4.5 mL) and water ( 0.5 mL) were added to 21 (210 mg, 0.39 mmol) and the biphasic
mixture was stirred efficiently. Trifluoroacetic acid was added and when deprotection was complete (tlc),
the volatiles were removed. Co-evaporation with toluene was performed and the residue dissolved in
water (20 mL). The aqueous layer was washed with dichloromethane and evaporated. The residue was
21
D
recrystallised from ethanol to afford 3 (97 mg, 65%) as white crystals. M.p.=158–159°C. [α] =+29.5 (c
0.38, CH3OH) 5 min→+32°C (24 h). 1H NMR (250 MHz, D2O) δ 7.55–7.05 (AA0XX0 system, Japp.=8
Hz, 4 H, Ar), 5.0 (d, J1–2=3.2 Hz, H-1α), 4.9–4.75 (M, H-6α, H-6β), 4.25 (d, J1–2=8 Hz, 1H, H-1β),
3.85–3.1 (m, other Hs). 13C NMR (62.5 MHz, D2O+(CD3)2C_O) δ 140.7, 140.4 (Phipso α+β), 136.8
(Phmeta α+β), 128.0, 127.7 (Phortho α+β), 95.7 (C-1β), 92.8, 92.4 (Phpara α+β), 91.6 (C-1α), 77.5, 75.3,
73.7, 73.2, 72.5, 71.0, 69.4, 69.2, 69.1, 68.9 (C-2α+β to C-6α+β). Anal. calcd for C12H15IO6: C, 37.72;
H, 3.96; I, 33.21. Found: C, 37.89; H, 3.93; I, 33.12.
References
1. For a review, see: Morin, C. Synthèse de sucres iodés; vers l’imagerie SPECT du transport du D-glucose. In
Radiopharmaceutiques, Chimie des traceurs et applications biologiques. Comet, M.; Vidal, M., Eds. Presse Universitaire de
Grenoble: France, 1998; pp. 295–305.
2. Hamant, S.; Mathieu, J.-P.; Morin, C.; Trimcev, I.; Vidal, M. Bioorg. Med. Chem. Lett. 1994, 4, 1687–1690; see also: Morin,
C.; Ogier, L. J. Carbohydr. Chem. 2000, 19, in press, and references cited therein.
3. 3-O-Methyl-D-glucose (3-OMG) is the reference tracer of glucose transport, see: Vyska, K.; Magloire, J. R.; Freundlieb,
C.; Höck, A.; Becker, A.; Schmid, A.; Feinendegen, L. E.; Kloster, G.; Stöcklin, G.; Schuier, F. J.; Thal, H. U. Eur. J. Nucl.
Med. 1985, 11, 97–106.
4. For 3-(3-iodoprop-2-en)-yl-D-glucose, see: Goodman, M. M.; Kabalka, G. W.; Waterhouse, R. N.; Daniel, G. B. J. Labelled
Compds Radiopharm. 1991, 30, 278–279. For 3-(2-iodoethyl)-D-glucose, see: Bignan, G. Morin, C.; Vidal, M. Carbohydr.
Res. 1993, 248, 371–375.
5. For 3-deoxy-3-iodo-D-glucose, see: Tsuya, A.; Shigematsu, A. Ger. Off. 2817336; see also: Kloster, G.; Laufer, P.; Wutz,
W.; Stöcklin, G. J. Labelled Compds Radiopharm. 1982, 19, 1626–1628.
6. Onodera, K.; Hirano, S.; Kashimura, N. Carbohydr. Res. 1968, 6, 276–285.
7. Shing, T. K. M.; Wong, C.-H.; Yip, T. Tetrahedron: Asymmetry 1996, 7, 1323–1340.
8. Imamoto, T.; Takeyama, T.; Koto, H. Tetrahedron Lett. 1986, 27, 3243–3246.
9. Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 3891–3894.
10. Peterson, D. J. J. Org. Chem. 1968, 33, 780–784.
11. Lankin, D. C.; David, C.; Nugent, S. T.; Rao, S. N. Carbohydr. Res. 1993, 244, 49–68.
12. Belluci, G.; Chiappe, C.; LoMoro, G. J. Org. Chem. 1995, 60, 6214–6217.
13. Ohta, H.; Sakata, Y.; Takeuchi, T.; Ishii, Y. Chem. Lett. 1990, 733–736.
14. Cambie, R. C.; Noall, W. I.; Potter, G. J.; Rutledge, P. S.; Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1977, 226–230.
15. Izquierdo Cubero, I. Carbohydr. Res. 1983, 114, 311–316.
16. After completion of this work (Ogier, L. Thèse de Doctorat, Grenoble, 1998), an efficient preparation of epoxide 7 has been
disclosed: Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1998, 9, 3939–3943.
17. Yoshimura, J.; Kobayashi, K.; Sato, K.-I.; Funabashi, M. Bull. Chem. Soc. Jpn. 1972, 45, 1806–1812.
18. The adverse beta effect of oxygen in such displacements has been discussed; see: Fleet, G. W. J. Chem. Brit. 1989, 25,
287–292. For advantages of betaiodoethers in radiolabelling see Ref. 2.

638
C. Morin, L. Ogier / Tetrahedron: Asymmetry 11 (2000) 629–638
19. Barnett, J. E. G.; Holman, G. D.; Munday, K. A. Biochem. J. 1973, 131, 211–221.
20. Schering-Kalbaum, A. G. Brit. Pat. 361437.
21. Charronneau, E.; Mathieu, J.-P.; Morin, C. Appl. Radiat. Isot. 1998, 49, 1605–1607.
22. Bignan, G.; Ghezzi, C.; Henry, C.; Koumanov, F.; Mauclaire, L.; Morin, C.; Ogier, L. Fr. Pat. 95214. Henry, C.; Tanti, J.-F.;
Grémeaux, T.; Morin, C.; Van Obberghen, E.; Comet, M.; Le Marchand-Brustel, Y. Nucl. Med. Biol. 1997, 24, 99–104.
23. Abbadi, M.; Holman, G. D.; Morin, C.; Rees, W. D.; Yang, J. Tetrahedron Lett. 1999, 40, 5861–5864.
24. Blériot, Y.; Veighey, C. R.; Smelt, K. H.; Cadefau, J.; Stalmans, W.; Biggadike, K.; Lane, A. L.; Müller, M.; Watkin, D. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 1996, 9, 2761–2772. Masaguer, C. F.; Blériot, Y.; Charlwood, J.; Winchester, B. G.;
Fleet, G. W. J. Tetrahedron 1997, 53, 15147–15156.
25. Blériot, Y.; Smelt, K. H.; Cadefau, J.; Bollen, M.; Stalmans, W.; Biggadike, K.; Johnson, L. N.; Oikonomakos, N. G.;
Lane, A. L.; Crook, S.; Watkin, D. J.; Fleet, G. W. J. Tetrahedron Lett. 1996, 39, 7155–7158. Blériot, Y.; Masaguer, C. F.;
Charlwood, J.; Winchester, B. G.; Lane, A. L.; Crook, S.; Watkin, D. J.; Fleet, G. W. J. Tetrahedron 1997, 53, 15 135–15 146.
26. Chenault, H. K.; Mandes, R. F.; Hornberger, K. R. J. Org. Chem. 1997, 62, 331–336.
27. Schmidt, U.; Stiller, R.; Brade, H.; Thiem, J. Synlett. 1998, 125–126.
28. Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762–763.
29. Kaufmann, T. S. Synlett 1997, 1377–1378.
30. Classon, B.; Liu, Z. J. Org. Chem. 1988, 53, 6126–6130.
31. Koo, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1995, 117, 3389–3404.
32. For a recent approach to C-phenyl terminally substituted carbohydrates, see: Bruns, R.; Wernicke, A.; Köll, P. Tetrahedron
1999, 55, 9793–9800.
33. Although the absolute configurations at C-6 of C-iodomethyl and C-iodophenyl derivatives are the same, priority rules using
Cahn–Ingold–Prelog descriptors result in 6S and 6R naming, respectively.
34. The use of stannylated precursors may allow radiolabelling with high specific activity; for a review of tin intermediates to
get radiopharmaceuticals, see: Ali, H.; Van Lier, J. E. Synthesis 1996, 423–445.