Synthesis of unstable 4-benzoyl-1,6-anhydro-3-keto-β-D-mannopyranose via stereoselective photobromination of 2,3-isopropylidene-4-benzoyl-1,6-anhydro-β-D-mannopyranose

Article abstract of DOI:10.1080/07328303.2019.1663204

Stereoselective photobromination of 1,6-anhydro-β-D-glucopyranose derivatives occurs at exo-H6. However, photobromination of 4-benzoyl-2,3-isopropylidene-1,6-anhydro-β-D-mannopyranose 6 produced unstable 4-benzoyl-1,6-anhydro-3-keto-β-D-mannopyranose 7. The mechanism of stereoselective oxidation at C-3 could be attributed to the facile radical proton abstraction at C-3, followed by the subsequent bromination of the isopropylidene group, which was subsequently eliminated during the aqueous workup. Thus, the aim of this article is to identify the molecular structure of the unstable compound 7.

Full text of DOI:10.1080/07328303.2019.1663204

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: https://www.tandfonline.com/loi/lcar20
Synthesis of unstable 4-benzoyl-1,6-anhydro-3-
keto-β-D-mannopyranose via stereoselective
photobromination of 2,3-isopropylidene-4-
benzoyl-1,6-anhydro-β-D-mannopyranose
Jassem G. Mahdi, Hanaa M. Dawoud, Abigail J. Manning, Harvey F.
Lieberman & David R. Kelly
To cite this article: Jassem G. Mahdi, Hanaa M. Dawoud, Abigail J. Manning, Harvey
F. Lieberman & David R. Kelly (2019): Synthesis of unstable 4-benzoyl-1,6-anhydro-3-
keto-β-D-mannopyranose via stereoselective photobromination of 2,3-isopropylidene-4-
benzoyl-1,6-anhydro-β-D-mannopyranose, Journal of Carbohydrate Chemistry, DOI:
10.1080/07328303.2019.1663204
To link to this article: https://doi.org/10.1080/07328303.2019.1663204
Published online: 11 Sep 2019.
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JOURNAL OF CARBOHYDRATE CHEMISTRY
https://doi.org/10.1080/07328303.2019.1663204
Synthesis of unstable 4-benzoyl-1,6-anhydro-3-keto-
b-D-mannopyranose via stereoselective
photobromination of 2,3-isopropylidene-4-benzoyl-1,
6-anhydro-b-D-mannopyranose
Jassem G. Mahdia, Hanaa M. Dawouda, Abigail J. Manningb,
Harvey F. Liebermana, and David R. Kellya†
b
aDepartment of Chemistry, Cardiff University, Cardiff, UK; University Hospital of Wales,
Cardiff, UK
ABSTRACT
ARTICLE HISTORY
Received 23 June 2019
Accepted 30 August 2019
Stereoselective photobromination of 1,6-anhydro-b-D-glucopyra-
nose derivatives occurs at exo-H6. However, photobromination
of 4-benzoyl-2,3-isopropylidene-1,6-anhydro-b-D-mannopyranose
6 produced unstable 4-benzoyl-1,6-anhydro-3-keto-b-D-man-
nopyranose 7. The mechanism of stereoselective oxidation at
C-3 could be attributed to the facile radical proton abstrac-
tion at C-3, followed by the subsequent bromination of the
isopropylidene group, which was subsequently eliminated
during the aqueous workup. Thus, the aim of this article is to
identify the molecular structure of the unstable compound 7.
KEYWORDS
1,6-anhydro-3-keto-b-D-
mannopyranose; 6-bromo-
1,6-anhydroglycopyranose;
photobromination; synthesis
GRAPHICAL ABSTRACT
Introduction
1,6-Anhydro sugars with different orientations of stereocentres, allowing a
wide range of chiral organic synthesis, are useful synthetic building
blocks.[1] These natural product derivatives, including levoglucosan 1, man-
1
nosan 2, and galactosan 3 (Fig. 1), tend to have C4 conformations. From a
molecular structure point of view, both mannosan 2 and galactosan 3 pos-
sess two hydroxy groups cis to each other. Thus, isopropylidene and
CONTACT Jassem G. Mahdi
Cardiff, UK
mahdij2@cardiff.ac.uk
Department of Chemistry, Cardiff University,
†Deceased
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lcar
ß 2019 Taylor & Francis Group, LLC

2
J. G. MAHDI ET AL.
Figure 1. Structures of some common 1,6-anhydro sugars.
cyclohexylidene protecting groups can generate a second five-member ring
in 1,6-anhydro-pyranose derivatives (Fig. 1). Per se these anhydro sugars
1–3 have considerable synthetic potentials due to the bicyclic rings and dif-
ferent stereochemical arrangement of hydroxyl groups. These characteristics
contribute to enabling high regio- and stereo-controlled reactions in the
synthesis of various chiral biologically active molecules.[1–3] In this respect,
stereoselective bromination of monosaccharide derivatives provides an
opportunity for extending the sugar chain at C-1 and C-6 via alkylation,
for example. In addition, bromination of sugars is of potential interest, to
gain access for unsaturated sugar derivatives, stereospecific SN20 nucleo-
philic substitution, or as intermediates in radical carbon-carbon bond for-
mation.[4–8] When 1,6-anhydro sugars undergo bromination or other
reactions they often yield stable molecules. However, it has been reported
that photobromination of 1,6-anhydro-2-benzoyl-3,4-O-isopropylidene-b-D-
galactopyranose 4 and its cyclohexylidene derivative 5 gave decomposed
products.[9] An attempt to photobrominate 2,3-isopropylidene-4-benzoyl-
1,6-anhydro-b-D-mannopyranose
6
also gave unstable compounds.
Therefore, this research was focused on the preparation and identification
of the unstable 3-keto mannosan derivative 7.
Experiments
Reactions were carried out under nitrogen atmosphere in AnalaR grade or
freshly distilled solvents. They were monitored by thin-layer chromatog-
raphy (0.2 mm Merck aluminum pre-coated Silica gel plates, 60 F254) with
UV light and ethanolic phosphomolybdic acid and heat. Melting points
1
were determined on a Kofler hot stage. High-resolution H and 13C NMR
spectra were recorded on a Bruker WM 360 (360 MHz) pulsed Fourier

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
transform spectrometer. Chemical shifts are quoted in units relative to tet-
ramethylsilane (d). Mass spectra were recorded on Varian Mat CH5 05
Trio-1 spectrometer.
General procedure for photobromination of 1,6-anhydro-b-D-glycopyranose
derivatives
A mixture of the 1,6-anhydro-b-D-glycopyranose (1 equiv) and bromine or
NBS (1 equiv) in carbon tetrachloride (30 ml) was irradiated by a standard
150-W bulb wrapped with the flask by foil. After 2 h, the reaction mixture
was cooled to room temperature, washed with sodium thiosulfate solution
(2 ꢀ 10 ml), sodium bicarbonate (2 ꢀ 10 ml) and water (2 ꢀ 10 ml). The
organic layer was then dried over sodium sulfate.[7,8] Evaporation of the
solvent under reduced pressure gave:
1,6-Anhydro-2,3,4-tri-O-acetyl-6-bromo-b-D-glucopyranose 10 (0.57 g,
77% or 0.59 g, 80%, when Br2 or NBS was used respectively) as a yellowish
sirup, which was purified by flash silica, with 1,6-anhydro-2,3,4-tri-O-ace-
tyl-b-D-glucopyranose 8 (0.6 g, 1.79 mmole) as starting material. MP ¼
1
95–98 ꢁC. H NMR (CDCl3): d 6.44(1 H, s, H6endo, 5.84 (1 H, s, H3), 4.92
(1 H, br.s., H4), 4.85 (1 H, s, H1). 4.69 (1 H, br,s, H2), 4.57 (1 H, br. s, H5),
2.19, 2.18, 2.13 (9 H, s, Me-Ac). 13C NMR CDCl3): d 169.81, 169.55, 168.89
(C¼O Ac), 102.20 (C1), 84.29 (C6), 79.32 (C5), 69.43 (C3), 68.07 (C4),
67.84 (C2), 20.85 (CH3-Ac). FD-MS (C12H15O8Br): m/z 366.7
(C12H15O8Br-H), 286.1 (C12H15O8-H); EI-MS: m/z 367.0 [M]þ, 287.0
(C12H15O8), 227.0 (C10H11O6), 167.0 (C8H7O4), 139.0, 97.0, 71.0.
1,6-Anhydro-2,3,4-tri-O-benzoyl-6-bromo-b-D-glucopyranose 11 (4.96 g,
85% and 0.59 g, 80%, when Br2 or NBS was used respectively) as a yellow-
ish sirup, which was crystallised from diethyl ether solvent, with 1,6-anhy-
dro-2,3,4-tri-O-benzoyl-b-D-glucopyranose 9 (5.0 g, 10.5 mmole) as starting
1
material. MP ¼ 190–192 ꢁC. H NMR (CDCl3): d 8.147.25(15H, m, H-Ar),
6.69 (1 H, s, H6endo), 6.12 (1 H, br.s, H3), 5.48 (1 H, br, s, H4). 5.16 (1 H,
br,s, H1), 5.13 (1 H, br. s, H2), 5.5 (1 H, br. s, H5). 13C NMR CDCl3):
d 165.01, 164.86, 164.44 (C¼O Bz), 133.83, 133.74,133.72, 130.00–102.34
(C-Ar), 102.34 (C1), 84.28 (C6), 76.34 (C5), 69.41 (C3), 67.89 (C4), 67.67
(C2). FD-MS (C27H21O8Br-H): m/z 473.3.
1,6-Anhydro-3-keto 4-bezoyl-b-D-mannopyranose 7 (0.78 g, 46.0%) as a
yellow sirup, which was rapidly purified by column chromatography, with
1,6-anhydro-2,3-O-isopropylidene-4-benzoyl-b-D-mannopyranose
0.65 mmole) as starting material. 1H (CDCl3) d 8.07-8.04 (2 H, d,d,
1.12,1.34 Hz, H-OBz); 7.63–7.60 (1 H, d,d, J1.72,1.24 Hz, H-OBz); 7.50–7.46 (2 H,
d,d, J7.65,1.67 Hz, H-OBz); 5.72 (1 H, d, J2.3 Hz, 2.3 Hz, H1); 5.32(1 H, d,
2.00 Hz, H4); 5.10–5.08 (1 H, d,d, J1.2, 2.0 Hz, H5); 4.57 (1 H, d, J2.2 Hz, H2),
6
(2 g,
J
J

4
J. G. MAHDI ET AL.
3.10–3.92 (1 H, d,d, J1.1, 8.6 Hz, H6-exo), 3.83–3.80 (1 H, d,d, J5.7, 8.5 Hz, H6,
endo). 13C (CDC13) d 200.87 (C¼O, C3); 165.06 (C¼O, Bz); 134.09,
130.07, 128.74 (C-Ar); 103.93 (C1); 77.30, 76.94, 76.59 (C5, C2, C4), 65.69
(C6). EI-MS: m/z 142 (M-benzoic acid)þ, 121, 105, 77, 51; CI-MS: calcu-
lated for C13H13O6 [(M þ H)þ] 265.0712, found 265.0712; 162, 147, 137,
120, 105.
Preparation of 1,6-anhydro-2,3-isopropylidene-b-D-mannopyranose 14
p-Toluene sulfonyl chloride (13.7 g, 72.2 mmole) in 20 ml of pyridine was
added slowly to D-mannopyranose 12 (10 g, 44.6 mmole) in 100 ml of pyri-
dine. The reaction mixture was stirred for 1 h at 0 ꢁC-r.t. and then cooled
before aqueous NaOH (2.3 g, 55.5 mmole) solution (10 ml) was added
slowly. The reaction mixture was left stirring overnight then neutralized
with HCl. The solvent was evaporated under reduced pressure, azeotroped
with toluene (2 ꢀ 20 ml) and then extracted with ethanol. Evaporation of
ethanol gave a light syrup which was dissolved in acetone (100 ml), before
adding 2,2-dimethoxy propane (10 ml) and the reaction mixture was left
overnight, neutralized with triethyl amine (7 ml) and evaporated to give a
sirup which was crystallized with ethyl acetate to give 14 (4.2 g, 37%). MP
1
¼ 161-163 ꢁC. H NMR (CDC13) d 5.35 (1 H, d, J2.9 Hz, H1), 4.54 (1 H, d,d,
J1.4, 6.2 Hz, H2), 4.22 (1 H, d,d J1.0,5.1 Hz, H6 endo), 4.10–4.07 (1 H, d,d, J3.1,
6.2 Hz, H5), 4.05–4.03 (1 H, d,d, J1.1, 7.4 Hz, H3), 3.96 (1 H, d, J8.8 Hz, H6-exo),
3.78 (1 H, t, J6.8 Hz, H4), 2.32 (1 H, br. s, 4-OH), 1.35, 1.33 (6 H, s, 2Me).
13C NMR (CDCl3): d 110.22 (C-isopropy.), 99.53 (C1), 76.98 (C5), 75.80
(C4), 72.12 (C3), 69.48 (C2), 64.30 (C6), 25.95 (Me). EI-MS (C9H14O5):
M/Z 187.0 (M-CH3), 127.0 (C2H4O2), 100.0, 85.0. 59., 43.0.
Preparation of 1,6-anhydro-2,3-isopropylidene-4-benzoyl-b-D-
mannopyranose 6
Benzoyl chloride (13.91 g, 9.89 mmole) in dichloromethane (100 ml) was
added to 2,3-isopropylidene 1,6-anhydro-b-D-mannopyranose (20 g,
9.89 mmole) in pyridine (100 ml). The reaction mixture was refluxed over-
night then cooled to r.t. before a saturated NaCO3 (50 ml). The crude prod-
uct was extracted with dichloromethane (250 ml), washed with water
(3 ꢀ 50 ml) and dried over Na2SO4. Evaporation of dichloromethane under
reduced pressure gave brown sirup which was crystallised with chloroform
1
1
and methanol to give 6 (23.02 g, 76%). H NMR (CDC13) d H NMR
(CDC13) d 8.10, 7.60, 7.46 (5 H, Ar); 5.43 (1 H, d, J2.7 Hz, H1); 5.27 (1 H, s,
H2); 4.70 (1 H, d,d, J1.4, 1.2 Hz, H5); 4.30 (1 H, d, J5.4 Hz, H3); 4.17 (1 H, d,d,
J3.0,6.3 Hz, H4); 4.12(1 H, d,d, J6.6, 7.1 Hz, H6endo); 3.83 (1 H, d,d, J1.0,7.4 Hz
,

JOURNAL OF CARBOHYDRATE CHEMISTRY
5
H6-exo). 13C NMR (CDCl3) d 165.41 (C¼O, Bz); 133.74, 129.85 (C, Ar);
129.36 (C- isopropy); 99.33 (C1); 73.85 (C3); 73.31 (C5); 72.20 (C2); 71.43
(C4); 64.65 (C6); 25.95, 25.86 (2 C-CH3- isopropy).
X-Ray crystal structure analysis of 1,6-anhydro-2,3-isopropylidene-4-benzoyl-
b-D-mannopyranose 6
Data were obtained using a FAST TV area detector diffractometer with
graphite mononchromated Mo-Ka radiation (k ¼ 0.71069 Å), crystal system –
orthorhombic. Crystal data: C16H18O6, Mr¼306.30, Unit cell dimensions:
space group 21, a ¼ 6.3829(11) Å, b ¼ 10.689(3) Å, c ¼ 22.579(4) Å,
c ¼ 89.979(11)ꢁ, V ¼ 1540.4(6) Å3, Z ¼ 4, D ¼ 1.321 MgMꢂ3, T ¼ 239(2) K,
Absorption confinement ¼ 0.101 mmꢂ1, crystal size 0.02 ꢀ 0.03 ꢀ 0.02 mm.
Data were recorded within ꢂ4 ꢃ h ꢃ 7ꢁ, ꢂ4 ꢃ k ꢃ 11ꢁ, ꢂ26 ꢃ 1ꢃ25ꢁ, giving
6502 measurements and 2386 unique (Rint¼0.0603),. Refinement with 271
parameter gave R1¼0.0339, wR2¼0.0643 for 2386 data with I > 2r (0.0492,
0.0668 respectively for all data) Goodness-Of-Fit on F2¼0.812. Carbon and
oxygen atoms were refined anisotropically. Hydrogens were inserted in
idealized positions with Uiso-values.
Preparation of 1,6-anhydro-2,4-dibenzoly-b-D-glucopyranose 18 and 1,6-
anhydro-2,3,4-tribenzoly-b-D-glucopyranose 19
Benzoyl chloride (2.674 g, 19.02 mmole) in dichloromethane (20 ml) was
added to 1,6-anhydro-b-D-glucoyranose 1 (1.5 g, 19.02 mmole) in pyridine
(10 ml). The reaction mixture was refluxed overnight then cooled to r.t.
before saturated NaCO3 (2 ꢀ 5 ml) was added. The crude product was
extracted with dichloromethane (20 ml), washed with water (3 ꢀ 15 ml) and
dried over Na2SO4. Evaporation of dichloromethane under reduced pres-
sure gave a brown sirup which was subjected to crystallization with chloro-
form and methanol to give 18 (2.15 g, 7.36%) and 19 (0.38 g, 12.5%) after
1
purified by column chromatography. 18: H NMR (CDCl3) d 8.05–8.10
(4 H, m, H-Bz), 7.66–7.58 (3 H, m, H-Bz), 7.45–7.38 (4 H, m, H-Bz), 5.72
(1 H, s, H1), 5.06 (1 H, s, H3). 4.93 (1 H, s, H5), 4.86–4.80 (1 H, d, J5.2 Hz,
H2), 4.38–4.00 (1 H, d, J7.02, H4), 4.10 (1 H, s, H6endo), 3.90–3.85 (1 H,
d,d, J2.10, 5.20 Hz, H6-exo). 13C NMR (CDCl3) d 166.09 (C¼O, Bz); 129.7,
128.3, 133.81 (C-Ar); 101.33 (C1); 73.17, 73.50, 72.11 (C5, C2, C4), 65.10
(C3), 68.02 (C6). 19: 1H NMR (CDCl3) d 8.18-8.07 (4 H, m, H-Bz),
7.66–7.58 (3 H, m, H-Bz), 7.51–7.40 (4 H, m, H-Bz), 5.73 (1 H, s, H1), 5.45
(1 H, s, H2). 5.44 (1 H, s, H2), 4.43 (1 H, s, H4), 5.10 (1 H, d, J0.56 Hz, H5),
4.40–4.38 (1 H, d, J7.7 Hz, H6endo), 3.99–3.98 (1 H, d,d, J6.79, 5.71 Hz,
H6-exo). 13C NMR (CDCl3) d 165.32, 165.08, 164.68 (C¼O-Bz), 133.67,

6
J. G. MAHDI ET AL.
133.56, 133.54 (C-Ar), 130.02–128.44 (CH-Ar), 99.47 (C1), 73.83 (C5),
70.19 (C4), 69.81 (C2), 69.11 (C3), 65.53 (C6).
Preparation of 1,6-anhydro-2,4-dibenzoly 3-keto-b-D-glucopyranose 20
Pyridinium chlorochromate (PCC) (0.582 g, 2.7 mmol) was added to 1,6-
anhydro-2.3-dibenzoyl-b-D-glucopyranose 18 (0.5 g, 1.35 mmol) in dry
dichloromethane (20 ml). The reaction mixture was stirred overnight at r.t.,
before being filtered off and washed with 3 ꢀ 15 ml CH2Cl2. The solvent
was then removed under reduced pressure. The crude product was then
1
purified by column chromatography to give 20 (0.368 g, 72%). H NMR
(CDCl3) d 8.09–8.1 (4 H, d, J8.02 H-Bz), 7.61–7.57 (2 H, t, J7.67, 7.21, H-
Bz), 7.45–7.41 (4 H, d,d, J1.41, 7.51 Hz, H-Bz), 5.85 (1 H,s, H1), 5.48 (1 H,
s, H2). 5.43 (1 H, s, H2), 4.98 (1 H, d, J5.11 Hz, H5). 4.31 (1 H, d, J8.05 Hz,
H6endo), 4.28–3.99 (1 H, d,d, J2.41, 5.17 Hz, H6-exo). 13C NMR (CDCl3) d
201.65 (C¼O, C3); 166.09 (C¼O, Bz); 133.1, 130.2, 128.7 (3 C, C-Ar);
102.21 (C1); 78.17, 75.58, 76.21 (C5, C2, C4), 66.03 (C6).
Results and discussion
Synthesis of 3-keto mannosan derivative 7
The irradiation of a stoichiometric mixture of 2,3,4-triacetyl (8)/tribenzoyl
(9)-1,6-anhydro-b-D-glucopyranose and bromine or N-bromo succinimide
in carbon tetrachloride gave the corresponding bromo-compounds 10 and
11, respectively (Sch. 1). The stereospecific photobromination at C6-exo
proton of 1,6-anhydro-b-D-hexo glycopyranoses is due to the fact that the
axial proton is more reactive than the equatorial proton. Ring protons in
1,6-Anhydro-b-D-glucopyranose 1 (H2, H3 and H4) are equatorial and
thus are less reactive than the axial counterparts. Furthermore, the bridge-
head protons (H1 and H5) are not reactive. In addition, H2, H3 and H4
protons in 1,6-anhydro sugars are deactivated by the geminal acetyl and
benzoyl groups. In the case of 1,6-anhydro-b-D-mannopyranose 2 and 1,6-
anhydro-b-D-galactopyranose 3, each has an axial proton at C2 and C4,
Scheme 1. (i) Br2 (or NBS), CCl4, k, 200 W, 30 min.

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
respectively. These protons are still deactivated by the acetyl or benzoyl
protecting group, leaving the H6-exo proton only to undergo stereospecific
photobromination.
However, photobromination of 2,3-isopropylidene-4-benzoyl-1,6-anhy-
dro-b-D-mannopyranose 6 gave 1,6-anhydro-3-keto-4-benzoyl-b-D-manno-
pyranose 7, as an unstable compound (Sch. 2). The synthesis of compound
7 started with the preparation of 2,3-isopropylidene-1,6-anhydro-b-D-man-
nopyranose 6 by a two-step, one-pot reaction (Sch. 2). The first step
included the formation of 6-tosyl mannose, 13, which gave 1,6-anhydro-
2,3-isopropylidene-b-D-mannopyranose, 14, after treatment with sodium
hydroxide and then trimethyl orthoformate. Benzoylation of isopropylidene
mannosan 14 with benzoyl chloride in dichloromethane gave 4-benzoyl-2-
3-isopropylidene-1,6-anhydromannosan 6 in 78% yield.
Scheme 2. (i) TsCl, Pyr, 0 ꢁC-r.t.; (ii) aq. NaOH, 0 ꢁC-r.t. overnight; (iii) aq. HCl; (iv) 2,2-dimethoxy
propane, acetone (yield ¼ 37%), (v) BzCl, K-tButoxide, CH2Cl2 (yield ¼ 78%), (vi) Br2, CCl4, k,
200 W, 30 min (yield ¼ 46.0%).
The photobromination reaction of compound 6 was repeated three times.
In the first, ketomannose compound 7 was obtained after flash silica purifi-
cation in a solid-state; however, it decomposed within approximately
30 minutes. In the second run, close monitoring of the purified white pow-
der compound 7 indicated that the decomposition started within approxi-
mately 10 minutes and became dark brown-syrup-like and dark solid
substance(s) within two hours. In the third run, the ketomannose com-
pound 7 was kept in the organic solvents (diethyl ether and petroleum
ether) used for chromatography or chloroform-d to run spectroscopies. In
addition, several organic solvents, including carbon tetrachloride, ethylace-
tate, and diethyl ether were used to test the stability of ketomannose

8
J. G. MAHDI ET AL.
compound 7. The results indicated that it was stable to certain extent, for
no longer than three weeks in the above organic solvents.
The triacetyl and tribenzoyl 1,6-anhydropyrinosides are often selectively
photobrominated at the C-6 exo proton, but the presence of an isopropyli-
dene group in 1,6-anhydromannosan 6 showed equatorial H3 is preferen-
tially abstracted and not the axial H2 or H6-exo. The reaction for the
formation of 4-benzoyl-1,6-anhydro-3-keto-b-D-mannopyranose 7 may
suggest a mechanism that the radical abstraction took place at H3, forming
the intermediate radical, 15 which rapidly cleaved off the O-C bond of iso-
propylidene group, forming the tertiary radical intermediate 16. Then,
compound 16 reacted with bromine radicals to give compound 17.
Hydrolysis of the ketobromo compound 17 during the aqueous work-up
leads to the cleavage of the isopropylidene group (Sch. 3) giving the keto-
mannosan 4-benzoylate compound 7. It may be possible that compound 7
underwent b-elimination and subsequent decomposition.
Scheme 3. The reaction mechanism for the formation of keto mannosan 7.
In addition, the benzoylation of 1,6-anhydro-b-D-glucopyranose 1 with 2
equivalents of benzoyl chloride gave 2,4-dibenzoly-1,6-anhydro-glucopyra-
nose 18 as a major product. The benzoylation occurred at the C-2 and C-4
positions, as the hydroxyl groups at these positions are more reactive than
the counterpart at C-3. 2,4-Dibenzoyl-1,6-anhydro-b-D-glucopyranose 18
was then oxidized with pyridinium chlorochromate (PCC) or potassium
permanganate[10] to yield 2,4-dibenzoyl-3-keto-1,6-anhydro b-D-glucopyra-
nose 19 in 72% or 29% yield (Sch. 4).

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
Scheme 4. (i) BzCl (1.6equ), K-tButoxide, CH2Cl2 (yield of 18 ¼ 70.36% and 19 ¼ 12.48%); (ii)
PCC, CH2Cl2, r.t. (yield ¼ 72%)
Molecular structure analysis of keto mannopyranose 7
1
The H-NMR spectrum of 3-keto-4-benzoyl-b-D-mannopyranose 7 showed
three doublets at the resonances of 5.72, 5.31 and 4.57 ppm with coupling
constants of 2.3, 2.0 and 2.2 Hz, which were respectively assigned as H1,
H4 and H2. These three doublets exist only if the carbonyl is at C3, as
each has one vicinal neighbor proton only. It is unlikely that these splitting
results are from long-range coupling. The magnitude of the long-range
coupling for H2 and H4 in 1,6-anhydro-levoglucosan is 1.1 Hz.[11]
Furthermore, Table 1 shows close chemical shift values between the two 3-
keto-1,6-anhydro-b-D-glycopyranose derivatives 7 and 20 for H1, H4, H5
and H6 endo. In addition, 13C-NMR spectrum of 3-keto-4-benzoyl-1,6-
anhydro-b-D-mannopyranose 7 showed two off resonance singlets at d
200.87 and d 165.06 for C¼O (C3) and C¼O (Bz), respectively, which are
both similar to the shift value of the corresponding single carbon [C¼O of
C3: d 201.65 and C¼O of Bz: d 166.09)] of 1,6-anhydro-2,4-dibenzoly-3-
keto-b-D-glucopyranose 20. Furthermore, the accurate mass spectrum of
the mannosan derivative 7 gave a value of 265.0712, corresponding
to (C13H12O6þH)þ}.
Table 1. The Chemical shift (ppm) of the related 1,6-anhydrosugars.
1,6-Anhydrosugar
HI
H2
H3
H4
H5
H6-Exo
H6-Endo
2,3-Isopropylidene-4-
benzoyl-mannosan 6
4-Benzoyl-3-
ketomannosan 7
2,4-Dibenzoyl-3-
5.43, d
J2.7Hz
5.72, d,
J2.3HZ
4.17, d,d
J6.3.3.0HZ
4.57, d,
J2.2Hz
5.43, s
4.30, d
J5.4Hz
–
5.27, s
4.70, d,
4.12, d,d,
J1.0,7.4Hz
3.82, d,d,
J1.1,8.6Hz
4.30, d,
J8.1Hz
3.83, d,d,
J7.1,6.6Hz
3.93, d,d,
J5.7, 8.5Hz
4.00, d,d,
J5.1. 8.1Hz
J1.4.1.2Hz
5.32, d,d, 5.09, d,d,
J2.2Hz J1.2,5.6Hz
5.48, s 4.99, d,
J5.1Hz
5.85, s
–
ketolevoglucosan 20
Molecular modeling of five-member rings in compound 6
Molecular modeling studies were based on the X-ray diffraction structure
of compound 6 (Fig. 2) at which the molecular geometry was optimized
under GAMESS using A 3-21 G basis set and the resultant low energy
structure was studied with CHEM-X.[12,13] In this respect, the molecular
geometry of the five-member rings was also based on the X-ray diffraction

10
J. G. MAHDI ET AL.
Figure 2. X-ray crystal structure of 4-benzoyl-2,3-isopropylidene-1,6-anhydromannosan 6.
Figure 3. Envelope conformations of optimized five rings of 4-benzoyl-2.3-isopropylidene-1,6-
anhydromannosan 6.
data of compound 6. The results showed conformational differences
between the two five-member rings (Fig. 3).
Both the isopropylidene and 1,6-anhydro ring adopt an envelope con-
formation,[14] although not with the same atom out of the plane (isopropy-
lidene ring q2¼0.327 Å, ɸ2¼103ꢁ; 1,6-anhydro ring q2¼0.384 Å, ɸ2¼356ꢁ;
Fig. 3). According to the crystallographic structure of 6, the isopropylidene
ring adopts a different conformation, namely a twist (isopropylidene ring

JOURNAL OF CARBOHYDRATE CHEMISTRY
11
q2 ¼ 0.304, Å, ɸ2¼86ꢁ; 1,6-anhydro ring q2¼0.405 Å, ɸ2¼357ꢁ). The twist
conformation is most likely due to crystal packing forces. This is, however,
unlikely to have a great effect on the H2, H6-exo and H3 protons, as all
are freely available for reaction and the oxygen atoms in the ring are
unlikely to undergo any stereoelectronic effect. The equatorial H3 proton is
most likely abstracted, due to the proximity of the benzoyl group, which is
three bonds away from H3 and four bonds away from H2 and H6-exo.
Conclusion
This article was focused on the identification of the chemical structure of
the
unstable
1,6-anhydro-3-keto-4-benzoyl-b-D-mannopyranose
7.
Although molecular geometry results showed conformational differences
between the five-member rings, further study is required to find the transi-
tion states using quantum software, such as Gaussian or Jaguar.
Acknowledgment
We thank Dr Dai Hibbs, Department of Chemistry, Cardiff University, Cardiff, UK, for
running the X-ray diffraction. Also, we thank the EPSRC for time allocations at the Mass
Spectrometry Center in Swansea, Wales, UK.
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