Synthesis and taste properties of 4,1', 6'-trihalodeoxy sucrose analogues

Article abstract of DOI:10.1081/CAR-100103958

Treatment of 3,4-di-O-acetyl-1,6-di-O-trityl-β-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-O-triflyl-α-D-galactopyranoside (3) with a halide source gave, via S_N2 displacement, the corresponding C-4 halogenated compounds which were subsequently trans

Full text of DOI:10.1081/CAR-100103958

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SYNTHESIS AND TASTE PROPERTIES OF 4,1′, 6′-
TRIHALODEOXY SUCROSE ANALOGUES
A. S. M. Sofian a & C. Kuan Lee b
a Department of Chemistry , National University of Singapore , Kent Ridge, 0511,
Singapore
b Department of Chemistry , National University of Singapore , Kent Ridge, 0511,
Singapore
Published online: 16 Aug 2006.
To cite this article: A. S. M. Sofian & C. Kuan Lee (2001) SYNTHESIS AND TASTE PROPERTIES OF 4,1′, 6′-TRIHALODEOXY
SUCROSE ANALOGUES , Journal of Carbohydrate Chemistry, 20:2, 191-205, DOI: 10.1081/CAR-100103958
To link to this article: http://dx.doi.org/10.1081/CAR-100103958
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J. CARBOHYDRATE CHEMISTRY, 20(2), 191–205 (2001)
SYNTHESIS AND TASTE PROPERTIES OF 4,1ꢀ,
6ꢀ-TRIHALODEOXY SUCROSE ANALOGUES1,2
A. S. M. Sofian and C. Kuan Lee*
Department of Chemistry, National University of Singapore,
Kent Ridge, Singapore 0511
ABSTRACT
Treatment of 3,4-di-O-acetyl-1,6-di-O-trityl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-
acetyl-4-O-triflyl-ꢂ-D-galactopyranoside (3) with a halide source gave, via SN2
displacement, the corresponding C-4 halogenated compounds which were sub-
sequently transformed into the monohalogenated 4-deoxy-4-halogenosucrose
derivatives, 10–12. Trihalogenated sucrose derivatives, 4-bromo-1ꢀ,6ꢀ-
dichloro 17, 1ꢀ,6ꢀ-dibromo 18, and 1ꢀ,6ꢀ-diiodosucrose 19, were synthesized
from 5. Exploiting the distinct reactivity at C-1ꢀ and C-6ꢀ trifluoromethanesul-
fonates enabled the introduction of different halogens at these positions. This
pathway led to the preparation of the 4-bromo-1ꢀ,6ꢀ-dihalodeoxysucrose
derivatives, 24–27. Preliminary taste properties of these mono- and tri-halo-
genated sucrose analogues were also investigated.
INTRODUCTION
The intense sweetness of halodeoxy analogues of sucrose, many of which are
several thousand times sweeter than sucrose, had puzzled researchers since the dis-
covery of the first of these in 1976.3 Currently, the Shallenberger-Kier AH, B, ꢃ
model4,5 is the most widely accepted model used to explain the initial mechanism
of sweet-taste response. However, the location of the AH,B,ꢃ glucophore for this
group of sucrose compounds is still uncertain and intensely debated. 6–12
*Corresponding author.
191
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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SOFIAN AND LEE
The high sweetness of these sucrose derivatives is clearly inexplicable in
terms of either the glucopyranosyl or fructofuranosyl residues alone since the
chlorodeoxy hexopyranoses or fructofuranoses are either very bitter or only mod-
erately sweet. The most likely location of the AH, B entity is located at hydroxyl
group of C-3ꢀ and the oxygen of the C-2 hydroxyl.12 The intense sweetness of the
halodeoxy sucrose derivatives clearly shows the importance of a halogen sub-
stituent(s) in enhancing sweetness, and it has been widely assumed that one or
more of these could be acting as the third ꢃ-site in these halodeoxy analogues. In
addition, the stereochemical disposition of the halogen substituent(s) is/are criti-
cal.13 1,6-Dichloro-1,6-dideoxy-ꢁ-D-fructofuranosyl 4-chloro-4-deoxy-ꢂ-D-
galactopyranoside (sucralose)14 and related 4-chloro-4-deoxy-galactosucrose
derivatives have been reported but, apart from 4,6,1ꢀ,6ꢀ-tetrachloro-4,6,1ꢀ,6ꢀ-
tetradeoxysucrose,14 we are not aware of any reports of the synthesis and taste of
the 4-chlorodeoxy sucrose derivatives. These derivatives are critical for determin-
ing the importance of a halogen substituent at C-4. We now report the synthesis as
well as the taste properties of these compounds.
RESULTS AND DISCUSSION
A convenient starting intermediate for the synthesis of the mono- and
tri-halogenated derivatives of sucrose is 3,4-di-O-acetyl-1,6-di-O-trityl-ꢁ-D-
Scheme 1. (a) Tf2O, pyridine/CH2Cl2; (b) NaNA2, DMF, rt, (c) 4: LiCl, acetone, rt, 5: LiBr, acetone,
rt; 6: KI, acetone, rt; (d) AcOH-CH2Cl2 (1:1), concd HCl, 0 ˚C; (e) NaOMe, MeOH, rt.

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Scheme 2. (f) Tf2O, pyridine/CH2Cl2; (g) 14: LiCl, acetone, rt, I5: LiBr, acetone, rt; 16: KI, acetone,
rt; (h) NaOMe, MeOH, rt; (i) 13a: KI, acetone, 0 ˚C; 13b: LiCl, acetone, 0 ˚C; 13c: LiBr, acetone, rt;
(j) 20: LiCl, acetone, rt, 21: LiBr, acetone, rt; 22 and 23: KI, acetone, rt; (k) NaOMe, MeOH, rt.
fructofuranosyl 2,3,6-tri-O-acetyl-ꢂ-D-glucopyranoside (1)15 (Scheme 1). This
was conveniently converted into the galacto isomer 2 via the C-4 triflate followed
by displacement with nitrite ion and in situ hydrolysis of the nitrite intermediate.16
The galacto configuration was evident from the small J3,4 coupling (2.7 Hz) in its
1H NMR spectrum.
The C-4 halodeoxy sucrose derivatives were synthesized by displacement of
the triflyl substituent of 3 using lithium chloride (→4), lithium bromide (→5) or
potassium iodide (→6). The 1H NMR spectra of compounds 4–6 all showed H-3
and H-4 as triplets with J2,3 ꢄ J3,4 ꢄ ꢀ10 Hz, characteristic of the gluco-configu-
ration. Further evidence was obtained from their 13C NMR spectra. The resonances
for C-4 in these compounds showed upfield shifts of between 13 to 43 ppm com-
pared to that of 1.
Detritylation of 4–6 in dichloromethane-acetic acid (1:1) in the presence of
concd HCl at 0°C (→7–9, respectively), followed by conventional deacetylation
gave the 4-halodeoxy derivatives 10–12, respectively, in good yields (Scheme 1).
Compounds 7 –9 served as key intermediates in the synthesis of a variety of
trihalogenated sucrose analogues. Thus, triflation of 8 gave the corresponding
1ꢀ,6ꢀ-disulfonate, which was easily converted to the 4-bromo-1ꢀ,6ꢀ-dichloro (14),
4,1ꢀ,6ꢀ-tribromo (15) and 4-bromo-1ꢀ,6ꢀ-diiodo (16) derivatives, respectively, on
treatment with lithium chloride, lithium bromide and potassium iodide. Zemplén
deacetylation of these compounds then gave the free trihalogenated derivatives 17
–19 (Scheme 2).

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The triflate groups at C-1ꢀ and C-6ꢀ have been reported17 to show consider-
able difference in reactivity. This enables the introduction of different halogen sub-
stituents at these two positions. The reaction of 13 with potassium iodide at 0°C
gave the 4-bromo-6ꢀ-iodo-4,6ꢀ-dideoxy-1ꢀ-O-triflate (13a), which was then con-
verted to the corresponding chloro derivative 20 by reaction with lithium chloride
in acetone at room temperature. Compounds 21–23 were synthesized in a similar
manner. These were then deacetylated to give 24–27 (Scheme 2).
Preliminary taste properties of the above C-4 monohalodeoxy derivatives
showed all to possess little or no sweetness. The presence of only one halogen
substituent in the sucrose is clearly not sufficient to produce an optimum hy-
drophilic-lipophilic18,19 balance for interaction with the receptor. The trihalodeoxy
derivatives, on the other hand, were very much sweeter but all were lower than that
of sucralose. Thus, if the halo substituent at C-4 functions as a ꢃ-site,6,10 then it ap-
pears that the stereochemistry of the halogen substituent at this carbon is extremely
important for optimum binding to the receptor. The results of these taste tests will
be reported in detail elsewhere.
EXPERIMENTAL
General Methods. Melting points were measured with a Thermo Galen Hot
Stage Microscope. Optical rotations were taken with a Perkin Elmer 241 polarime-
ter at 26°C. NMR spectra were recorded at 298 K in CDCl3 (unless otherwise spec-
ified) on a Bruker DPX 300 spectrometer (300.13 MHz for 1H and 75.47 MHz for
13C). Mass spectra were recorded on either on a Finnigan MAT95XL-T instrument
using electronic ionisation (EI) (70 eV) mode with an accelerating voltage of 5 KV
and a resolution of 1000 (10% valley definition), or on a Finnigan TSQ 7000 (ion
trap) spectrometer using electron spray ionisation (ESI) with a spray voltage of 4.5
KV. The elemental composition of ions was determined with a resolution of 7,000
(10% valley definition). Microanalyses were carried out using a Perkin Elmer 2400
Elemental Analyser. Flash chromatography was performed on Silica Gel 60
(0.63–0.200 nm, Merck) at 5–10 p.s.i. Thin-layer chromatography was run on glass
plates precoated with silica gel 60F254 (Merck, Darmstadt, Germany); detection was
effected by observation under short wavelength UV light (254 nm), then spraying
with 10% sulphuric acid in ethanol and charring them on a hot plate.
3,4-Di-O-acetyl-1,6-di-O-trityl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-ꢂ-
D-galactopyranoside (2). To a solution of 1 (15.3 g, 14.8 mmol) in dry CH2Cl2-
pyridine (15:1, 64 mL) at ꢅ78°C, was added trifluoromethanesulfonic anhydride
(4.9 mL, 29.9 mmol). The mixture was stirred for 15 min at ꢅ78°C, then for about
2 h at 0°C. The mixture was diluted with dichloromethane and the organic solution
was washed successively with aq KHSO4 (10%), satd NaHCO3 and water, dried
(Na2SO4) and concentrated to give a syrupy product. This was dissolved in DMF
(60 mL) and sodium nitrite (5.6 g) was added. The solution was then stirred at room
temperature overnight, concentrated, and the residue diluted with

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195
dichloromethane. The filtered solution was again concentrated. Flash chromatog-
raphy (ethyl acetate/hexane, 1:2) gave 2, (10.6 g, 69%), mp 103–105°C; [ꢂ]D
ꢆ70.5° (c 1.21, CHCl3); 1H NMR (CDCl3) ꢇ 1.83–2.06 (s, 15H, 5 ꢈ CH3), 3.20
(s, 2H, H-1ꢀa, b), 3.33–3.52 (m, 2H, H-6ꢀa, b), 4.02 (d, 1H, J3,4 2.7 Hz, H-4), 4.10–
4.36 (m, 4H, H-5, 5ꢀ, 6ꢀa, b), 5.05 (dd, 1H, J2,3 10.8 J3,4 2.7 Hz, H-3), 5.14 (dd, 1H,
J1,2 3.7 J2,3 10.8 Hz, H-2), 5.37 (t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 7.3 Hz, H-4ꢀ), 5.56 (d, 1H, J1,2
3.7 Hz, H-1), 5.84 (d, 1H, J3ꢀ,4ꢀ 7.3 Hz, H-3ꢀ) and 7.21–7.51 (m, 30H, Ar-H). 13
C
NMR ꢇ 170.9, 170.0, 169.9, 169.8, 169.6 (COCH3), 143.6, 143.4 (CPh3),
129.0–127.0 (Ar-C), 104.1 (C-2ꢀ), 89.5 (C-1), 78.8 (C-5ꢀ), 75.7, 74.7 (C-3ꢀ, 4ꢀ),
69.9, 67.8, 67.2, 66.9 (C-2, 3, 4, 5), 63.8, 62.1 (C-1ꢀ,6, 6ꢀ) and 20.8, 20.7, 20.5, 20.4
(COCH3). EI-MS m/z (%): 1036 [Mꢆ] (ꢉ0.5), 731 [M - C12H17O9]ꢆ (ꢉ0.5), 289
[M - C48H43O8]ꢆ (6), 244 (32), 243 (100), 242 (26), 228 (9), 215 (6), 43 (100).
Anal. Calcd for C60H60O16: C, 69.49; H, 5.83. Found: C, 69.87; H, 5.46.
3,4-Di-O-acetyl-1,6-di-O-trityl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-
chloro-4-deoxy-ꢂ-D-glucopyranoside (4). A solution of 2 (1.66 g, 1.60 mmol)
in CH2Cl2- pyridine (15:1, 32 mL) at ꢅ78°C was triflated as described above to
give crude 3.
Without purification and characterization, the crude triflate 3 (1.70 g, 1.45
mmol) in dry acetone (20 mL), was stirred with lithium chloride (0.2 g) at room
temperature under argon for 4 h. When TLC (ether/hexane, 3:1) showed that all
starting material had reacted, the solution was concentrated and dichloromethane
added and filtered. The organic layer was washed with satd NaHCO3, brine, dried
(Na2SO4) and concentrated. Flash chromatography (ether/hexane, 1:1) gave 4 as
colourless crystals (1.25 g, 81%), mp 97–99°C; [ꢂ]D ꢆ44.0° (c 1.17, CHCl3); 1H
NMR ꢇ 1.83–2.06 (s, 15H, 5 ꢈ CH3), 3.20 (s, 2H, H-1ꢀa, b), 3.31–3.45 (2 ꢈ dd,
2H, J5ꢀ,6ꢀa 5.6 J5ꢀ,6ꢀb 4.8 J6ꢀa,6ꢀb 10.0 Hz, H-6ꢀa, b), 3.81 (t, 1H, J3,4 ꢄ J4,5 10.0 Hz,
H-4), 4.15 (m, 1H, H-5ꢀ), 4.23 (m, 3H, H-5, 6a,b), 4.66 (dd, 1H, J1,2 4.0 J2,3 10.0
Hz, H-2), 5.33 (t, 1H, J2,3 ꢄ J3,4 10.0 Hz, H-3), 5.42 (d, 1H, J1,2 4.0 Hz, H-1), 5.47
(d, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 6.0 Hz, H-4ꢀ), 5.80 (d, 1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ) and 7.20–7.47
(m, 30H, Ar-H). 13C NMR ꢇ 170.3, 169.8, 169.7, 169.5, 169.4 (COCH3), 143.6,
143.3 (CPh3), 128.7–127.1 (Ar-C), 104.7 (C-2ꢀ), 89.5 (C-1), 79.7 (C-5ꢀ), 76.0, 75.2
(C-3ꢀ, 4ꢀ), 71.4, 70.5, 70.2 (C-2, 3, 5), 63.7, 63.6, 62.4 (C-1ꢀ, 6, 6ꢀ), 55.1 (C-4) and
21.0, 20.8, 20.6, 20.5, 20.3 (COCH3). EI-MS m/z (%): 1054 [Mꢆ] (ꢉ0.5), 731 [M
- C12H16ClO8]ꢆ (1.5), 307, 309 [M - C48H43O8]ꢆ (3:1, 47), 244 (56), 243 (52), 242
(70), 241 (72), 215 (43), 43 (100).
Anal. Calcd for C60H59ClO15: C, 68.22; H, 5.63; Cl, 3.31. Found: C, 67.98;
H, 5.92; Cl, 3.67.
3,4-Di-O-acetyl-1,6-di-O-trityl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-
bromo-4-deoxy-ꢂ-D-glucopyranoside (5). A solution of crude 3 (11.3 g, 9.67
mmol) in dry acetone (60 mL) was treated with lithium bromide (2.5 g) as for 4 to
give after flash chromatography (ether/hexane, 1:1), 5 as colourless crystals (9.0 g,
85%), mp 97–99°C; [ꢂ]D ꢆ40.9° (c 1.12, CHCl3); 1H NMR ꢇ 1.79–2.05 (s, 15H,
5 ꢈ CH3), 3.21–3.43 (m, 4H, H-1ꢀa, b and H-6ꢀa, b), 3.85 (t, 1H, J3,4 ꢄ J4,5 10.8

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Hz, H-4), 4.08–4.35 (m, 4H, H-5, 5ꢀ, 6a, b), 4.63 (dd, 1H, J1,2 4.0 J2,3 10.0 Hz, H-
2), 5.38–5.49 (m, 3H, H-1, 3, 4ꢀ), 5.79 (d, 1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ) and 7.19–7.46
(m, 30H, Ar-H). 13C NMR ꢇ 170.2, 169.8, 169.7, 169.5, 169.3 (COCH3), 143.6,
143.3 (CPh3), 129.5–126.5 (Ar-C), 104.6 (C-2ꢀ), 89.5 (C-1), 79.7 (C-5ꢀ), 76.0, 75.2
(C-3ꢀ, 4ꢀ), 71.3, 70.4, 70.2 (C-2, 3, 5), 63.7, 63.5, 63.1 (C-1ꢀ, 6, 6ꢀ), 46.1 (C-4) and
20.8, 20.6, 20.3 (COCH3). EI-MS m/z (%): 351, 353 [M - C48H43O8]ꢆ (1:1, 8),
291, 293 (1:1, 12), 244 (83), 243 (88), 242 (79), 241 (80), 229 (26), 215 (19), 183
(54), 169 (21), 165, 167 (1:1, 79), 43 (100).
Anal. Calcd for C60H59BrO15: C, 65.50; H, 5.41; Br, 7.62. Found: C, 67.89;
H, 5.41; Br, 6.99.
3,4-Di-O-acetyl-1,6-di-O-trityl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-
deoxy-4-iodo-ꢂ-D-glucopyranoside (6). Treatment of crude 3 (1.51 g, 1.29
mmol) with potassium iodide (0.65 g) as described for 4 gave after flash chro-
matography (ether/hexane, 1:1), crystalline 6 (1.20g, 81%), mp 95–97°C; [ꢂ]D
ꢆ38.6° (c 1.01, CHCl3); 1H NMR ꢇ 1.79–2.07 (s, 15H, 5 ꢈ CH3), 3.21–3.44 (m,
4H, H-1ꢀa, b and H-6ꢀa, b), 3.92 (t, 1H, J3,4 ꢄ J4,5 11.0 Hz, H-4), 4.09–4.42 (m,
4H, H-5, 5ꢀ, 6a, b), 4.63 (dd, 1H, J1,2 4.0 J2,3 10.0 Hz, H-2), 5.41–5.50 (m, 3H, H-
1, 3, 4ꢀ), 5.79 (d, 1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ) and 7.19–7.46 (m, 30H, Ar-H). 13C NMR
ꢇ 170.1, 169.7, 169.6, 169.4, 169.0 (COCH3), 143.6, 143.3 (CPh3), 129.0–126.9
(Ar-C), 104.6 (C-2ꢀ), 89.6 (C-1), 79.6 (C-5ꢀ), 76.0, 75.2 (C-3ꢀ, 4ꢀ), 72.2, 71.0, 70.5
(C-2, 3, 5), 64.6, 63.8, 63.4 (C-1ꢀ, 6, 6ꢀ), 24.8 (C-4) and 20.7, 20.6, 20.5, 20.3
(COCH3). EI-MS m/z (%): 399 [M - C48H43O8]ꢆ (9), 279 (13), 244 (92), 243 (94),
242 (62), 241 (60), 165 (90), 43 (100); exact mass calcd for [C12H16IO7]ꢆ
398.9941, found 398.99285.
Anal. Calcd for C60H59IO15: C, 62.83; H, 5.18; I, 11.06. Found: C, 62.68; H,
5.61; I, 10.70.
3,4-Di-O-acetyl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-chloro-4-de-
oxy-ꢂ-D-glucopyranoside (7). To a solution of 4 (1.20 g, 1.14 mmol) in ice-cold
CH2Cl2-AcOH (1:1, 20 mL) was added dropwise, concentrated hydrochloric acid
(0.15 mL). After all starting material had reacted (ꢀ2 h), the solution was neutral-
ized with NaHCO3, filtered and concentrated under reduced pressure. The crude
product was subject to column chromatography (ethyl acetate/hexane, 1:1) to af-
ford 7 as colourless crystals (0.52 g, 80%), mp 99–101°C; [ꢂ]D ꢆ25.0° (c 1.12,
CHCl3); 1H NMR ꢇ 2.07–2.20 (s, 15H, 5 ꢈ CH3), 3.55–3.84 (m, 4H, H-1ꢀa, b and
H-6ꢀa, b), 3.91 (t, 1H, J3,4 ꢄ J4,5 10.4 Hz, H-4), 4.06 (m, 1H, H-5ꢀ), 4.33–4.55 (m,
3H, H-5, 6a, b), 4.84 (dd, 1H, J1,2 3.5 J2,3 10.4 Hz, H-2), 5.43–5.55 (m, 3H, H-3,
3ꢀ, 4ꢀ)and 5.68 (d, 1H, J1,2 3.5 Hz, H-1). 13C NMR ꢇ 170.6, 170.5, 170.2, 169.6
(COCH3), 104.8 (C-2ꢀ), 90.0 (C-1), 81.8 (C-5ꢀ), 76.7, 74.2 (C-3ꢀ, 4ꢀ), 71.0, 70.9,
70.7 (C-2, 3, 5), 64.1, 62.3, 61.5 (C-1ꢀ, 6, 6ꢀ), 54.9 (C-4) and 20.7, 20.6, 20.5
(COCH3). EI-MS m/z (%): 307, 309 [M - C10H15O8]ꢆ (3:1, 24), 247 [M -
C12H16ClO8]ꢆ (51), 225, 207 (3:1, 24), 187 (41), 43 (100).
Anal. Calcd for C22H31ClO15: C, 46.28; H, 5.47; Cl, 6.21. Found: C, 46.57;
H, 5.63; Cl, 6.33. HRMS-ESI (positive mode): calcd for [M ꢆ Na]ꢆ 593.1294,
595.1219. Found: 593.1263, 595.1247 (3:1).

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3,4-Di-O-acetyl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-bromo-4-de-
oxy-ꢂ-D-glucopyranoside (8). Treatment of 5 (5.97 g, 5.44 mmol) as for 7 gave
8 as colourless crystals (2.8 g, 84%), mp 77–80°C; [ꢂ]D ꢆ26.9° (c 1.01, CHCl3);
1H NMR ꢇ 2.06–2.21 (s, 15H, 5 ꢈ CH3), 3.56–3.86 (m, 4H, H-1ꢀa, b and H-6ꢀa,
b), 3.95 (t, 1H, J3,4 ꢄ J4,5 10.3 Hz, H-4), 4.05–4.57 (m, 4H, H-5, 5ꢀ, 6a, b), 4.82
(dd, 1H, J1,2 3.5 J2,3 10.3 Hz, H-2), 5.31–5.48 (m, 2H, H- 3ꢀ, 4ꢀ), 5.56 (t, 1H, J2,3
ꢄ J3,4 10.3 Hz, H-3) and 5.70 (d, 1H, J1,2 3.5 Hz, H-1). 13C NMR ꢇ 170.6, 170.4,
170.2, 170.1, 169.4 (COCH3), 104.8 (C-2ꢀ), 90.1 (C-1), 81.8 (C-5ꢀ), 76.7, 74.3 (C-
3ꢀ, 4ꢀ), 71.1, 70.7 (C-2, 3, 5), 64.1, 63.0, 61.5 (C-1ꢀ, 6, 6ꢀ), 45.8 (C-4) and 20.7,
20.6, 20.5, 19.6 (COCH3). EI-MS m/z (%): 351, 353 [M - C10H15O8]ꢆ (1:1, 7), 291,
293 (1:1, 12), 247 [M - C12H16BrO8]ꢆ (21), 231, 233 (1:1, 9), 189, 191 (1:1, 10),
187 (13), 169 (29), 43 (100); exact mass calcd for [C12H16BrO7]ꢆ 351.0079,
353.0059, found 351.0059, 353.0038 (1:1); calcd for [C10H15O7]ꢆ 247.0817,
found 247.0813.
Anal. Calcd for C22H31BrO15: C, 42.94; H, 5.08; Br, 12.98. Found: C, 42.67;
H, 5.19; Br, 13.32.
3,4-Di-O-acetyl-ꢁ-D-fructofuranosyl 2,3,6-tri-O-acetyl-4-deoxy-4-iodo-
ꢂ-D-glucopyranoside (9). Treatment of 6 (1.29 g, 1.12 mmol) as for 7 gave 9 as
colourless crystals (0.56 g, 75%), mp 93–95°C; [ꢂ]D ꢆ15.5° (c 1.08, CHCl3); 1H
NMR ꢇ 2.06–2.21 (s, 15H, 5 ꢈ CH3), 3.56–3.86 (m, 4H, H-1ꢀa, b and H-6ꢀa, b),
3.95 (t, 1H, J3,4 ꢄ J4,5 10.3 Hz, H-4), 4.05–4.57 (m, 4H, H-5, 5ꢀ, 6a, b), 4.82 (dd,
1H, J1,2 3.5 J2,3 10.3 Hz, H-2), 5.31–5.48 (m, 2H, H- 3ꢀ, 4ꢀ), 5.56 (t, 1H, J2,3 ꢄ J3,4
10.3 Hz, H-3) and 5.70 (d, 1H, J1,2 3.5 Hz, H-1). 13C NMR ꢇ 170.6, 170.4, 170.2,
170.1, 169.4 (COCH3), 104.8 (C-2ꢀ), 90.3 (C-1), 81.9 (C-5ꢀ), 76.8, 74.4 (C-3ꢀ, 4ꢀ),
72.0, 71.6, 71.0 (C-2, 3, 5), 64.5, 64.2, 61.5 (C-1ꢀ, 6, 6ꢀ), 24.3 (C-4) and 20.8, 20.7,
20.6 (COCH3). EI-MS m/z (%): 399 [M - C12H16IO8]ꢆ (21), 289 (16), 279 (27),
247 [M -C10H15O8]ꢆ (15), 211 (25), 187 (19), 169 (41), 45 (100); exact mass calcd
for [C12H16IO7]ꢆ 398.9941, found 398.9957; calcd for [C10H15O7]ꢆ 247.0817,
found 247.0812.
Anal. Calcd for C22H31IO15: C, 39.89; H, 4.72; I, 19.16. Found: C, 40.14; H,
5.11; I, 19.22.
ꢁ-D-Fructofuranosyl 4-chloro-4-deoxy-ꢂ-D-glucopyranoside (10).
A
solution of 7 (0.23 g, 0.40 mmol) in dry methanol (10 mL) was adjusted to pH ꢀ10
with methanolic sodium methoxide (0.5 M). It was stirred at room temperature for
4 h. It was then neutralized with Amberlite IR120 (Hꢆ) ion exchange resin and
concentrated. Flash chromatography (chloroform/methanol, 4:1) gave 10 as a
colourless syrup (0.12 g, 82%), [ꢂ]D ꢆ53.5° (c 0.52, H2O); 1H NMR (D2O) ꢇ 4.05
(dd, 1H, J1,2 3.8 J2,3 9.8 Hz, H-2), 4.66 (d, 1H, J3ꢀ,4ꢀ 8.7 Hz, H-3ꢀ) and 5.91 (d, 1H,
J1,2 3.8 Hz, H-1). 13C NMR (D2O) ꢇ 106.4 (C-2ꢀ), 94.8 (C-1), 84.0 (C-5ꢀ), 79.1,
76.7 (C-3ꢀ, 4ꢀ), 75.3, 75.2, 74.2 (C-2, 3, 5), 65.0, 64.0, 63.0 (C-1ꢀ, 6, 6ꢀ) and 60.5
(C-4).
Anal. Calcd for C12H21ClO10: C, 39.93; H, 5.87; Cl, 9.83. Found: C, 40.27;
H, 5.69; Cl, 10.02. HRMS-ESI (positive mode): calcd for [M ꢆ Na]ꢆ 383.0721,
385.0691. Found: 383.0733, 385.0720 (3:1).

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ꢁ-D-Fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-glucopyranoside (11).
Treatment of 8 (0.24 g, 0.39 mmol) as for 10 gave 11 as a colourless syrup (0.14 g,
89%), [ꢂ]D ꢆ34.7° (c 0.49, H2O); 1H NMR (D2O) ꢇ 4.11 (dd, 1H, J1,2 3.8 J2,3 9.7
Hz, H-2), 4.73 (d, 1H, J3ꢀ,4ꢀ 8.7 Hz, H-3ꢀ) and 6.01 (d, 1H, J1,2 3.8 Hz, H-1). 13
C
NMR (D2O) ꢇ 106.4 (C-2ꢀ), 94.8 (C-1), 84.0 (C-5ꢀ), 79.0, 76.6 (C-3ꢀ, 4ꢀ), 75.3,
75.2, 74.4 (C-2, 3, 5), 64.9, 63.9, 63.7 (C-1ꢀ, 6, 6ꢀ) and 52.9 (C-4).
Anal. Calcd for C12H21BrO10: C, 35.57; H, 5.22; Br, 19.72. Found: C, 35.42;
H, 5.69; Br, 19.52. HRMS-ESI (positive mode): calcd for [M ꢆ Na]ꢆ 427.0215,
429.0195. Found: 427.0232, 429.0219 (1:1).
ꢁ-D-Fructofuranoside
4-deoxy-4-iodo-ꢂ-D-glucopyranosyl
(12).
Deacetylation of 9 (0.23 g, 0.35 mmol) as for 10 gave 12 as a colourless syrup (0.13
g, 83%): [ꢂ]D ꢆ39.1° (c 1.62, H2O); 1H NMR (D2O) ꢇ 4.06 (dd, 1H, J1,2 3.8 J2,3
9.1 Hz, H-2), 4.71 (d, 1H, J3ꢀ,4ꢀ 8.7 Hz, H-3ꢀ) and 5.98 (d, 1H, J1,2 3.8 Hz, H-1).
13C NMR (D2O) ꢇ 106.4 (C-2ꢀ), 95.0 (C-1), 84.0 (C-5ꢀ), 79.1, 76.6 (C-3ꢀ, 4ꢀ), 76.2,
75.9, 74.3 (C-2, 3, 5), 65.4, 65.0, 63.9 (C-1ꢀ, 6, 6ꢀ) and 33.5 (C-4).
Anal. Calcd for C12H21IO10: C, 31.87; H, 4.68; I, 28.06. Found: C, 31.49; H,
4.69; I, 27.92. HRMS-ESI (positive mode): calcd for [M ꢆ Na]ꢆ 475.0077. Found:
475.0077.
3,4-Di-O-acetyl-1,6-dideoxy-1,6-dichloro-ꢁ-D-fructofuranosyl 2,3,6-tri-
O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (14). To a solution of 8 (0.79
g, 1.29 mmol) in dry CH2Cl2-pyridine (15:1, 32 mL) at ꢅ78°C, was added trifluo-
romethanesulfonic anhydride (0.86 mL, 5.24 mmol). The mixture was stirred at
ꢅ78°C for 15 min and then at 0°C for 2 h. It was diluted with dichloromethane and
the organic solution was washed successively with aq KHSO4 (10%), satd NaHCO3,
and water. After drying (Na2SO4) and concentration, the crude product 13 (0.47 g,
0.53 mmol) was dissolved in dry acetone (20 mL) and lithium chloride (0.10 g) was
added to the solution. The mixture was then allowed to stir overnight at room tem-
perature, and concentrated. The residue was taken up in dichloromethane, filtered,
and the organic layer was washed with satd NaHCO3, water, dried and concentrated.
Flash chromatography (ether/hexane, 3:1) gave 14 as colourless crystals (0.30 g,
86%): 50–52°C; [ꢂ]D ꢆ22.9° (c 1.11, CHCl3); 1H NMR ꢇ 2.07–2.19 (s, 15H, 5 ꢈ
CH3), 3.56–3.79 (m, 4H, H-1ꢀa, b and H-6ꢀa, b), 3.92 (t, 1H, J3,4 ꢄ J4,5 10.4 Hz, H-
4), 4.22–4.60 (m, 4H, H-5, 5ꢀ, 6a, b), 4.83 (dd, 1H, J1,2 3.5 J2,3 10.1 Hz, H-2), 5.38
(t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 5.9 Hz, H-4ꢀ), 5.54 (t, 1H, J2,3 ꢄ J3,4 10.1 Hz, H-3), 5.65 (d, 1H,
J1,2 3.5 Hz, H-1) and 5.67 (d, 1H, J3ꢀ,4ꢀ 5.9 Hz, H-3ꢀ). 13C NMR ꢇ 170.4, 170.0,
169.7, 169.5, 169.4 (COCH3), 104.4 (C-2ꢀ), 90.3 (C-1), 81.4 (C-5ꢀ), 77.0, 75.9 (C-
3ꢀ, 4ꢀ), 70.9, 70.8 (C-2, 3, 5), 63.3 (C-6), 45.8 (C-4), 44.8 (C-1ꢀ), 43.8 (C-6ꢀ) and
20.7, 20.6, 20.5, 20.4 (COCH3). EI-MS m/z (%): 351, 353 [M - C10H13Cl2O6]ꢆ (1:1,
39), 347 (43), 292, 294 (1:1, 52), 285 (46), 284, 286, 288 [M - C12H16BrO8]ꢆ (9:6:1,
14), 283 (61), 249, 251 (15), 231, 233 (1:1, 59), 225 (55), 224, 226, 228 (16), 223
(69), 189, 191 (1:1, 50), 43 (100), exact mass calcd for (C12H16BrO7) 351.0079,
353.0058, found 351.0076, 353.0054 (1:1); calcd for (C10H13Cl2O5) 283.0141,
285.0114, 287.0081, found 283.0136, 285.0114, 287.0077 (8:5:1)

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Anal. Calcd for C22H29BrCl2O13: C, 40.51; H, 4.48; Br, 12.25; Cl, 10.87.
Found: C, 40.32; H, 4.58; Br, 11.19.
3,4-Di-O-acetyl-1,6-dibromo-1,6-dideoxy-ꢁ-D-fructofuranosyl 2,3,6-tri-
O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (15). Treatment of a solution
of 13 (6.54 g, 7.45 mmol) in acetone (60 mL) with lithium bromide (3.0 g) as for
14 gave, after column chromatography, crystalline 15 (4.5 g, 82%), mp 72–73°C;
[ꢂ]D ꢆ24.6° (c 2.79, CHCl3); 1H NMR ꢇ 2.07–2.21 (s, 15H, 5 ꢈ CH3), 3.47–3.64
(m, 4H, H-1ꢀa, b and H-6ꢀa, b), 3.92 (t, 1H, J3,4 ꢄ J4,5 10.4 Hz, H-4), 4.26–4.60
(m, 4H, H-5, 5ꢀ, 6a, b), 4.84 (dd, 1H, J1,2 3.5 J2,3 10.4 Hz, H-2), 5.35 (t, 1H, J3ꢀ,4ꢀ
ꢄ J4ꢀ,5ꢀ 6.0 Hz, H-4ꢀ), 5.56 (t, 1H, J2,3 ꢄ J3,4 10.4 Hz, H-3), 5.66 (d, 1H, J1,2 3.5
Hz, H-1) and 5.71 (d, 1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ). 13C NMR ꢇ 170.3, 170.0, 169.7,
169.4, 169.3 (COCH3), 103.9 (C-2ꢀ), 90.4 (C-1), 81.2 (C-5ꢀ), 77.2 (C-3ꢀ, 4ꢀ), 71.0,
70.8, 70.7, (C-2, 3, 5), 63.3 (C-6), 45.8 (C-4), 32.6 (C-1ꢀ), 31.2 (C-6ꢀ) and 20.7,
20.6, 20.4 (COCH3). EI-MS m/z (%): 371, 373, 375 [M - C12H16O8]ꢆ (1:2:1, 39),
351, 353 [M - C10H13Br2O6]ꢆ (1:1, 44), 291, 293 (1:1, 50), 269, 271, 273 (1:2:1,
15), 249, 252 (1:1, 10), 231, 233 (1:1, 55), 189, 191 (1:1, 56), 169 (46), 43 (100);
exact mass calcd for [C10H13Br2O5]ꢆ 370.9129, 372.9109, 374.9089, found
370.9128, 372.9111, 374.9090 (1:2:1); calcd for [C12H16BrO7]ꢆ 351.0079,
353.0058, found 351.0076, 353.0061 (1:1).
Anal. Calcd for C22H29Br3O13: C, 35.65; H, 3.94; Br, 32.34. Found: C, 35.42;
H, 3.51; Br, 32.32.
3,4-Di-O-acetyl-1,6-dideoxy-1,6-diiodo-ꢁ-D-fructofuranosyl 2,3,6-tri-O-
acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (16). A solution of 13 (0.49 g,
0.56 mmol) in acetone (20 mL) was stirred with potassium iodide (0.40 g) for
ꢀ15 h at room temperature. The solvent was removed and the residue taken up
in dichloromethane. The suspension was filtered and the organic solution was
washed with aq Na2S2O3 (10%), satd NaHCO3, water, dried (Na2SO4) and con-
centrated. Flash chromatography (ether/hexane, 3:1) gave 16 as colourless crys-
1
tals (0.38 g, 82%), mp 75–77°C; [ꢂ]D ꢆ21.9° (c 1.81, CHCl3); H NMR ꢇ
2.10–2.20 (s, 15H, 5 ꢈ CH3), 3.41–3.43 (m, 4H, H-1ꢀa, b and H-6ꢀa, b), 3.93 (t,
1H, J3,4 ꢄ J4,5 10.4 Hz, H-4), 4.21–4.59 (m, 4H, H-5, 5ꢀ, 6a, b), 4.84 (dd, 1H,
J1,2 3.6 J2,3 10.4 Hz, H-2), 5.30 (t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 6.0 Hz, H-4ꢀ), 5.58 (t, 1H,
J2,3 ꢄ J3,4 10.4 Hz, H-3), 5.64 (d, 1H, J1,2 3.6 Hz, H-1) and 5.70 (d, 1H, J3ꢀ,4ꢀ 6.0
Hz, H-3ꢀ). 13C NMR ꢇ 170.4, 169.6, 169.4 (COCH3), 103.3 (C-2ꢀ), 90.7 (C-1),
80.9 (C-5ꢀ), 77.8, 77.6 (C-3ꢀ, 4ꢀ), 70.8, 70.6 (C-2, 3, 5), 63.3 (C-6), 45.8 (C-4),
20.9, 20.8, 20.6, 20.5 (COCH3), 6.3 (C-1ꢀ), and 3.4 (C-6ꢀ). EI-MS m/z(%): 467
[M - C12H16BrO8]ꢆ (43), 351, 353 [M - C10H13I2O6]ꢆ (1:1, 44), 291, 293 (1:1,
65), 249, 251 (1:1, 14), 237 (51%), 231, 233 (1:1, 65), 189, 191 (1:1, 48), 169
(72), 43 (100); exact mass calcd for [C10H13I2O5]ꢆ 466.8853, found 466.8858;
exact mass calcd for [C12H16BrO7]ꢆ 351.0079, 353.0058, found 351.0073,
353.0055 (1:1).
Anal. Calcd for C22H29BrI2O13: C, 31.64; H, 3.50; Br, 9.57, I, 30.39. Found:
C, 31.54; H, 3.57; Br, 9.32, I, 29.99.

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SOFIAN AND LEE
1,6-Dichloro-1,6-dideoxy-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-
glucopyranoside (17). Compound 14 (0.33 g, 0.51 mmol) was treated with
sodium methoxide (0.566 M) as described for 10 to afford 17 as a colourless syrup
(0.18 g, 80%): [ꢂ]D ꢆ54.5° (c 1.44, H2O); 1H NMR (D2O) ꢇ 4.12 (dd, 1H, J1,2 3.8
J2,3 9.4 Hz, H-2), 4.91 (d, 1H, J3ꢀ,4ꢀ 8.7 Hz, H-3ꢀ) and 6.01 (d, 1H, J1,2 3.8 Hz, H-
1). 13C NMR (D2O) ꢇ 106.1 (C-2ꢀ), 95.5 (C-1), 83.7 (C-5ꢀ), 79.0, 77.9 (C-3ꢀ, 4ꢀ),
75.6, 75.2, 74.4 (C-2, 3, 5), 63.9 (C-6), 53.0 (C-4), 47.5 (C-6ꢀ) and 46.0 (C-1ꢀ).
Anal. Calcd for C12H19BrCl2O8: C, 32.60; H, 4.32; Br, 18.07, Cl, 16.04.
Found: C, 32.45; H, 4.73; Br, 18.29, Cl, 16.09. HRMS-ESI (positive mode): calcd
for [M ꢆ Na]ꢆ 462.9539, 464.9519, 466.9489, 468.9459. Found: 462.9540,
464.9514, 466.9491, 468.9433 (10:16:7:1).
1,6-Dibromo-1,6-dideoxy-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-
glucopyranoside (18). Compound 15 (0.16 g, 0.22 mmol) was deacetylated as
for 10 to afford 18 as a colourless syrup (0.10 g, 87%), [ꢂ]D ꢆ47.4° (c 1.90, H2O);
1H NMR (D2O) ꢇ 4.12 (dd, 1H, J1,2 3.8 J2,3 9.8 Hz, H-2), 4.17–4.31 (m, 4H),
4.35–4.77 (m, 7H), 4.97 (d, 1H, J3ꢀ,4ꢀ 8.0 Hz, H-3ꢀ) and 6.01 (d, 1H, J1,2 3.8 Hz, H-
1). 13C NMR (D2O) ꢇ 103.6 (C-2ꢀ), 93.5 (C-1), 81.5 (C-5ꢀ), 77.8, 77.0 (C-3ꢀ,4ꢀ),
73.6, 73.2, 72.4 (C-2, 3, 5), 61.9 (C-6), 51.0 (C-4), 33.5, 32.4 (C-1ꢀ, 6ꢀ).
Anal. Calcd for C12H19Br3O8: C, 27.14; H, 3.61; Br, 45.14. Found: C, 26.84;
H, 3.77; Br, 44.89. HRMS-ESI (positive mode): calcd for [M ꢆ Na]ꢆ 550.8519,
552.8507, 554.8487, 556.8467. Found: 550.8519, 552.8526, 554.8486, 556.8468
(1:3:3:1).
1,6-Dideoxy-1,6-diiodo-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-glu-
copyranoside (19). Compound 16 (0.43 g, 0.51 mmol) was deacetylated as for
10 to afford 19 as a colourless syrup (0.26 g, 81%), [ꢂ]D ꢆ43.5° (c 0.83, H2O); 1H
NMR (D2O) ꢇ 3.86–4.74 (m, 11H), 4.97 (d, 1H, J3ꢀ,4ꢀ 8.4 Hz, H-3ꢀ) and 5.99 (d,
1H, J1,2 3.8 Hz, H-1) 13C NMR (D2O) ꢇ 102.9 (C-2ꢀ), 93.4 (C-1), 81.4 (C-5ꢀ), 79.1,
78.3 (C-3ꢀ,4ꢀ), 73.4, 73.0, 72.2 (C-2, 3, 5), 61.8 (C-6), 50.8 (C-4), 6.2, 5.6 (C-1ꢀ,
6ꢀ).
Anal. Calcd for C12H19BrI2O8: C, 23.06; H, 3.06; Br, 12.79, I, 40.61. Found:
C, 23.34; H, 3.27; Br, 12.92, I, 40.99. HRMS-ESI (positive mode): calcd for [M ꢆ
Na]ꢆ 646.8251, 648.8231. Found 646.8250, 648.8229 (1:1).
3,4-Di-O-acetyl-1-chloro-1,6-dideoxy-6-iodo-ꢁ-D-fructofuranosyl 2,3,6-
tri-O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (20). A solution of 13
(0.93 g, 1.06 mmol) in acetone (25 mL) was stirred with potassium iodide (0.35 g)
for 30 min at 0°C. The mixture was concentrated and the residue was taken up in
dichloromethane. Work-up in the usual manner gave a syrupy residue, which was
dissolved (0.49 g, 0.57 mmol) in acetone (15 mL) and treated with lithium chloride
(0.10 g) at room temperature overnight and worked up in the usual way. Flash chro-
matography (ethyl acetate/hexane, 1:2) gave 20 as colourless crystals (0.35 g,
63%), mp 49–51°C; [ꢂ]D ꢆ24.8° (c 1.08, CHCl3); 1H NMR ꢇ 2.08–2.18 (s, 15H,
5 ꢈ CH3), 3.39–3.77 (m, 4H, H-1ꢀa, b and H-6ꢀa, b), 3.93 (t, 1H, J3,4 ꢄ J4,5 10.3

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201
Hz, H-4), 4.22–4.59 (m, 4H, H-5, 5ꢀ, 6a, b), 4.84 (dd, 1H, J1,2 3.5 J2,3 10.3 Hz, H-
2), 5.31 (t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 6.0 Hz, H-4ꢀ), 5.56 (t, 1H, J2,3 ꢄ J3,4 10.3 Hz, H-3)
and 5.65–5.69 (m, 2H, H-1, 3ꢀ) 13C NMR ꢇ 170.4, 170.0, 169.4 (COCH3), 104.3
(C-2ꢀ), 90.4 (C-1), 81.5 (C-5ꢀ), 77.3, 76.3 (C-3ꢀ, 4ꢀ), 71.0, 70.9, 70.8 (C-2, 3, 5),
63.3 (C-6), 45.8 (C-4), 44.7 (C-1ꢀ), 20.8, 20.7, 20.6, 20.5 (COCH3) and 3.3 (C-6ꢀ).
EI-MS m/z(%): 375, 377 [M - C12H16BrO8]ꢆ (3:1, 63), 351, 353 [(C10H13ClIO6]ꢆ
(1:1, 64), 317 (75), 315 (63), 291, 293 (1:1, 71), 275 (45), 249, 251 (1:1, 24), 231,
233 (1:1, 74), 189, 191 (1:1, 78), 169 (74), 43 (100), exact mass calcd for
[C10H13ClIO6]ꢆ 374.9497, 376.9467, found 374.9489, 376.9471; calcd for
[C12H16BrO7]ꢆ 351.0079, 353.0058, found 351.0078, 353.0061 (1:1).
Anal. Calcd for C22H29BrClIO13: C, 35.53; H, 3.93; Br, 10.74, Cl, 4.77; I,
17.02. Found: C, 35.41; H, 3.73; Br, 11.12; Cl, 4.78; I, 16.87.
3,4-Di-O-acetyl-1-bromo-1,6-dideoxy-6-iodo-ꢁ-D-fructofuranosyl 2,3,6-
tri-O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (21). Treatment of 13
(0.46 g, 0.52 mmol) with potassium iodide (0.18 g) and then lithium bromide (0.12
g) as for 20 gave crystalline 21 (0.30 g, 67%), mp 58–61°C; [ꢂ]D ꢆ22.3° (c 1.27,
CHCl3); 1H NMR ꢇ 2.08–2.20 (s, 15H, 5 ꢈ CH3), 3.37–3.63 (m, 4H, H-1ꢀa, b and
H-6ꢀa, b), 3.93 (t, 1H, J3,4 ꢄ J4,5 10.3 Hz, H-4), 4.23–4.59 (m, 4H, H-5, 5ꢀ, 6a, b),
4.85 (dd, 1H, J1,2 3.5 J2,3 10.3 Hz, H-2), 5.30 (t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 6.0 Hz, H-4ꢀ),
5.56 (t, 1H, J2,3 ꢄ J3,4 10.3 Hz, H-3), 5.65 (d, 1H, J1,2 3.5 Hz, H-1) and 5.72 (d,
1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ). 13C NMR ꢇ 170.4, 170.1, 169.8, 169.5, 169.4 (COCH3),
103.8 (C-2ꢀ), 90.5 (C-1), 81.4 (C-5ꢀ), 77.6, 77.1 (C-3ꢀ, 4ꢀ), 71.0, 70.9, 70.8 (C-2,
3, 5), 63.3 (C-6), 45.8 (C-4), 32.6 (C-1ꢀ), 20.8, 20.7, 20.6, 20.5 (COCH3) and 3.3
(C-6ꢀ). EI-MS m/z(%): 419, 421 [M -C10H13BrIO6]ꢆ (1:1, 68), 359, 361 (1:1, 75),
351, 353 [M - C12H16BrO8]ꢆ (1:1, 55), 317, 319 (1:1, 40), 291, 293 (1:1, 63), 249,
251 (1:1, 21), 231, 233 (1:1, 71), 189, 191 (1:1, 58), 169 (60), 43 (100); exact mass
calcd for [C10H13BrIO5]ꢆ 418.8991, 420.8971, found 418.8987, 420.8968 (1:1);
exact mass calcd for [C12H16BrO7]ꢆ 351.0079, 353.0058, found 351.0079,
353.0056 (1:1).
Anal. Calcd for C22H29Br2IO13: C, 33.53; H, 3.71; Br, 20.28; I, 16.10. Found:
C, 33.44; H, 3.37; Br, 20.12, I, 16.37.
3,4-di-O-acetyl-6-chloro-1,6-dideoxy-1-iodo-ꢁ-D-fructofuranosyl 2,3,6-
tri-O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (22). Compound 13
(0.33 g, 0.37 mmol) in acetone (10 mL) was stirred with lithium chloride (0.05 g)
at 0°C for 30 minutes. The mixture was concentrated, then taken up in
dichloromethane, filtered, and the organic solution was washed with satd NaHCO3,
water, dried (Na2SO4) and concentrated. The residue (0.24 g, 0.31 mmol) was
dissolved in acetone (10 mL) and stirred with potassium iodide (0.15 g) at room
temperature overnight, and then worked-up in the usual method. Flash chromatog-
raphy (ethyl acetate/hexane, 1:2) on the crude product gave 22 as colourless crys-
tals (0.19 g, 60%), 50–52°C; [ꢂ]D ꢆ36.3° (c 0.52, CHCl3); 1H NMR ꢇ 2.03–2.11
(s, 15H, 5 ꢈ CH3), 3.40 (s, 2H, H-1ꢀa, b), 3.70 (d, 2H, J5ꢀ,6ꢀa,b 6.3 Hz, H-6ꢀa, b),
3.86 (t, 1H, J3,4 ꢄ J4,5 10.4 Hz, H-4), 4.17 (q, 1H, J4ꢀ,5ꢀ 5.9 J5ꢀ,6ꢀa,b 6.3 Hz, H-5ꢀ),

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SOFIAN AND LEE
4.29 (dd, 1H, J5,6a 4.5 J6a,6b 12.2 Hz, H-6a), 4.40 (m, 1H, H-5), 4.49 (dd, 1H, J5,6b
1.7 J6a,6b 12.2 Hz, H-6b), 4.77 (dd, 1H, J1,2 3.5 J2,3 10.4 Hz, H-2), 5.29 (t, 1H, J3ꢀ,4ꢀ
ꢄ J4ꢀ,5ꢀ 5.9 Hz, H-4ꢀ), 5.50 (t, 1H, J2,3 ꢄ J3,4 10.4 Hz, H-3), 5.57 (d, 1H, J1,2 3.5
Hz, H-1) and 5.63 (d, 1H, J3ꢀ,4ꢀ 5.9 Hz, H-3ꢀ). 13C NMR ꢇ 170.3, 170.0, 169.6,
169.5, 169.2 (COCH3), 103.3 (C-2ꢀ), 90.4 (C-1), 80.9 (C-5ꢀ), 77.3, 76.1 (C-3ꢀ, 4ꢀ),
70.7, 70.6, 70.5 (C-2, 3, 5), 63.2 (C-6), 45.7 (C-4), 43.8 (C-6ꢀ), 20.6, 20.5, 20.4
(COCH3) and 6.4 (C-1ꢀ). EI-MS m/z (%): 375, 377 [M - C12H16BrO8]ꢆ (3:1, 64),
351, 353 [M - C10H13ClIO6]ꢆ (1:1, 65), 291, 293 (1:1, 66), 249, 251 (1:1, 24) 231,
233 (1:1, 74), 189, 191 (1:1, 78), 169 (100), 43 (90); exact mass calcd for
[C10H13ClIO5]ꢆ 374.9497, 376.9470, found 374.9489, 376.9471 (3:1); exact mass
calcd for [C12H16BrO7]ꢆ 351.0079, 353.0058, found 351.0078, 353.0061 (1:1).
Anal. Calcd for C22H29BrClIO13: C, 35.53; H, 3.93; Br, 10.74, Cl, 4.77; I,
17.02. Found: C, 34.41; H, 3.73; Br, 11.12, I, 16.87.
3,4-Di-O-acetyl-6-bromo-1,6-dideoxy-1-iodo-ꢁ-D-fructofuranosyl 2,3,6-
tri-O-acetyl-4-bromo-4-deoxy-ꢂ-D-glucopyranoside (23). Treatment of 13
(0.45 g, 0.51 mmol) in acetone (15 mL) with lithium bromide (0.08 g) and then
potassium iodide (0.22 g) gave 23 as colourless crystals (0.29 g, 67%), mp
50–52°C; [ꢂ]D ꢆ30.9° (c 1.07, CHCl3); 1H NMR ꢇ 2.03–2.10 (s, 15H, 5 ꢈ CH3),
3.40 (s, 2H, H-1ꢀa, b), 3.55 (d, 2H, J5ꢀ,6ꢀa,b 6.4 Hz, H-6ꢀa, b), 3.87 (t, 1H, J3,4 ꢄ J4,5
10.4 Hz, H-4), 4.21 (q, 1H, J4ꢀ,5ꢀ 6.0 J5ꢀ,6ꢀa,b 6.4 Hz, H-5ꢀ), 4.29 (dd, 1H, J5,6a 4.5
J6a,6b 12.2 Hz, H-6a), 4.42 (m, 1H, H-5), 4.49 (dd, 1H, J5,6b 1.7 J6a,6b 12.2 Hz, H-
6b), 4.77 (dd, 1H, J1,2 3.5 J2,3 10.4 Hz, H-2), 5.28 (t, 1H, J3ꢀ,4ꢀ ꢄ J4ꢀ,5ꢀ 5.9 Hz, H-
4ꢀ), 5.50 (t, 1H, J2,3 ꢄ J3,4 10.4 Hz, H-3), 5.57 (d, 1H, J1,2 3.5 Hz, H-1) and 5.63
(d, 1H, J3ꢀ,4ꢀ 6.0 Hz, H-3ꢀ). 13C NMR ꢇ 170.3, 170.1, 169.7, 169.5, 169.3 (COCH3),
103.4 (C-2ꢀ), 90.5 (C-1), 80.7 (C-5ꢀ), 77.7, 77.0 (C-3ꢀ, 4ꢀ), 70.9, 70.8, 70.7 (C-2,
3, 5), 63.3 (C-6), 45.8 (C-4), 31.3 (C-6ꢀ), 20.7, 20.6, 20.5 (COCH3) and 6.5 (C-1ꢀ).
EI-MS m/z (%): 419, 421 [M - C12H16BrO8]ꢆ (1:1, 55), 359, 361 (1:1, 67), 351,
353 [M - C10H13BrIO6]ꢆ (1:1, 56), 317, 319 (1:1, 28), 291, 293 (1:1, 53), 249, 251
(1:1, 12), 231, 233 (1:1, 56), 189, 191 (1:1, 78), 169 (66), 43 (100); exact mass
calcd for [C10H13BrIO6]ꢆ 418.8991, 420.8971, found 418.9000, 420.8980 (1:1);
exact mass calcd for [C12H16BrO7]ꢆ 351.0079, 353.0058, found 351.0080,
353.0060 (1:1).
Anal. Calcd for C22H29Br2IO13: C, 33.53; H, 3.71; Br, 20.28; I, 16.10. Found:
C, 33.86; H, 3.97; Br, 20.54; I, 15.92.
1-Chloro-1,6-dideoxy-6-iodo-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-
D-glucopyranoside (24). Deacetylation of 20 (0.20 g, 0.27 mmol) as described
for 10 afforded 24 as a colourless syrup (0.12 g, 84%), [ꢂ]D ꢆ55.6° (c 1.34, H2O);
1H NMR (D2O) ꢇ 4.12 (dd, 1H, J1,2 3.8 J2,3 9.4 Hz, H-2), 4.91 (d, 1H, J3ꢀ,4ꢀ 8.7 Hz,
H-3ꢀ) and 6.02 (d, 1H, J1,2 3.8 Hz, H-1). 13C NMR (D2O) ꢇ 106.0 (C-2ꢀ), 95.5 (C-
1), 83.8 (C-5ꢀ), 80.3, 79.5 (C-3ꢀ, 4ꢀ), 75.6, 75.2, 74.4 (C-2, 3, 5), 64.0 (C-6), 53.0
(C-4), 45.9 (C-1ꢀ) and 8.1 (C-6ꢀ).
Anal. Calcd for C12H19BrClIO8: C, 27.01; H, 3.59; Br, 14.98; Cl, 6.64; I,
23.79. Found: C, 36.97; H, 3.72; Br, 14.61; Cl, 6.33; I, 24.09. HRMS-ESI (positive

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203
mode): calcd for [M ꢆ Na]ꢆ 554.8895, 556.8875, 558.8845. Found: 554.8906,
556.8868, 556.8856 (3.7:4.7:1).
1-Bromo-1,6-dideoxy-6-iodo-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-
glucopyranoside (25). Deacetylation of 22 (0.29 g, 0.37 mmol) as above gave
25 as a colourless syrup (0.18 g, 85%), [ꢂ]D ꢆ49.7° (c 1.53, H2O); 1H NMR (D2O)
ꢇ 4.10 (dd, 1H, J1,2 3.8 J2,3 9.7 Hz, H-2), 4.96 (d, 1H, J3ꢀ,4ꢀ 8.4 Hz, H-3ꢀ) and 6.00
(d, 1H, J1,2 3.8 Hz, H-1). 13C NMR (D2O) ꢇ 103.3 (C-2ꢀ), 93.3 (C-1), 81.5 (C-5ꢀ),
78.1, 77.9 (C-3ꢀ, 4ꢀ), 73.4, 73.0, 72.2 (C-2, 3, 5), 61.8 (C-6), 50.7 (C-4), 32.1 (C-
1ꢀ) and 5.6 (C-6ꢀ).
Anal. Calcd for C12H19Br2IO8: C, 24.94; H, 3.62; Br, 27.65; I, 21.96. Found:
C, 27.39; H, 3.72; Br, 14.61; I, 24.09. HRMS-ESI (positive mode): calcd for [M
ꢆ Na]ꢆ 598.8389, 600.8369, 602.8349. Found: 598.8391, 600.8372, 602.8354
(1:2:1).
6-Chloro-1,6-dideoxy-1-iodo-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-
D-glucopyranoside (26). Deacetylation of 21 (0.21 g, 0.28 mmol) as above gave
26 as a colourless syrup (0.12 g, 80%), [ꢂ]D ꢆ45.1° (c 0.92, H2O); 1H NMR (D2O)
ꢇ 4.12 (dd, 1H, J1,2 3.8 J2,3 9.8 Hz, H-2), 4.99 (d, 1H, J3ꢀ,4ꢀ 8.4 Hz, H-3ꢀ) and 6.00
(d, 1H, J1,2 3.8 Hz, H-1). 13C NMR (D2O) ꢇ 105.3 (C-2ꢀ), 95.6 (C-1), 83.6 (C-5ꢀ),
80.9, 78.0 (C-3ꢀ, 4ꢀ), 75.6, 75.2, 74.5 (C-2, 3, 5), 63.9 (C-6), 53.0 (C-4), 47.4 (C-
6ꢀ) and 8.5 (C-1ꢀ).
Anal. Calcd for C12H19BrClIO8: C, 27.01; H, 3.59; Br, 14.98; Cl, 6.64; I,
23.79. Found: C, 26.87; H, 3.27; Br, 14.57; Cl, 7.01; I, 23.60. HRMS-ESI (positive
mode): calcd for [M ꢆ Na]ꢆ 554.8895, 556.8875, 558.8845. Found: 554.8901,
556.8879, 558.8841 (3.8:4.9:1)
6-Bromo-1,6-dideoxy-1-iodo-ꢁ-D-fructofuranosyl 4-bromo-4-deoxy-ꢂ-D-
glucopyranoside (27). Deacetylation of 23 (0.29 g, 0.37 mmol) as above gave
27 as a colourless syrup (0.17 g, 80%), [ꢂ]D ꢆ41.7° (c 1.53, H2O); 1H NMR (D2O)
ꢇ 4.13 (dd, 1H, J1,2 3.8 J2,3 9.6 Hz, H-2), 5.01 (d, 1H, J3ꢀ,4ꢀ 8.4 Hz, H-3ꢀ) and 6.02
(d, 1H, J1,2 3.8 Hz, H-1). 13C NMR (D2O) ꢇ 105.4 (C-2ꢀ), 95.7 (C-1), 83.5 (C-5ꢀ),
81.2, 79.2 (C-3ꢀ, 4ꢀ), 75.6, 75.2, 74.4 (C-2, 3, 5), 64.0 (C-6), 53.1 (C-4), 35.6 (C-
6ꢀ) and 8.6 (C-1ꢀ).
Anal. Calcd for C12H19Br2IO8: C, 24.94; H, 3.31; Br, 27.65; I, 21.96. Found:
C, 25.35; H, 3.23; Br, 26.61; I, 21.70. HRMS-ESI (positive mode): calcd for [M ꢆ
Na]ꢆ 598.8389, 600.8369, 602.8349. Found: 598.8386, 600.8389, 602.8352
(1:2:1).
ACKNOWLEDGMENTS
We thank the National University of Singapore for financial support under a
grant (RP960671) awarded to C.K.L. We also thank L.K. Wong, L. Chen, K.F.
Choo and F.Y. Soong and for their assistance in the mass spectra determination and
microanalyses.

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Received September 13, 2000
Accepted November 30, 2000

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