Synthesis and biological evaluation of a bicyclo[4.1.0]heptyl analogue of glucose-1-phosphate

Article abstract of DOI:10.1139/v04-109

The synthesis of a bicyclo[4.1.0]heptyl analogue of glucose-1-phophate, (1R,2R,3S,4S,5S,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)-bicyclo[4.1.0] heptan-2-yl dihydrogen phosphate (5) is reported. The synthetic route chosen started with methyl α-D-glucopyranos

Full text of DOI:10.1139/v04-109

1361
Synthesis and biological evaluation of a
bicyclo[4.1.0]heptyl analogue of glucose-1-
phosphate
Veedeeta Dookhun and Andrew J. Bennet
Abstract: The synthesis of a bicyclo[4.1.0]heptyl analogue of glucose-1-phophate, (1R,2R,3S,4S,5S,6S)-3,4,5-
trihydroxy-6-(hydroxymethyl)-bicyclo[4.1.0]heptan-2-yl dihydrogen phosphate (5) is reported. The synthetic route cho-
sen started with methyl α-D-glucopyranoside and was accomplished in 11 steps with an overall yield of 3%. Compound
5 was tested as a potential substrate of UTP:α-D-glucose-1-phosphate uridylyltransferase, the enzyme that converts
glucose-1-phosphate into UDP-glucose. However, the conformationally restricted glucose-1-phosphate analogue 5 was
found to be a weakly binding inhibitor, rather than a substrate, of the yeast transferase (12% inhibition at a concentra-
tion of 0.1 mmol L–1).
Key words: glucose 1-phosphate, inhibition, UTP:α-D-glucose-1-phosphate uridylyltransferase.
Résumé : On a réalisé la synthèse d’un analogue bicyclo[4.1.0]heptyle du 1-phosphate de glucose, le dihydrogène
phosphate de (1R,2R,3S,4S,5S,6S)-3,4,5-trihydroxy-6-(hydroxyméthyl)bicyclo[4.1.0]heptan-2-yle (5). La voie de synthèse
choisie utilise l’α-D-glucopyranoside de méthyle comme produit de départ et implique onze étapes avec un rendement
global de 3 %. Le composé 5 a été évalué comme substrat potentiel de l’uridylyltransférase UTP:1-phosphate d’α-D-
glucose, l’enzyme qui transforme le 1-phosphate de glucose en UDP-glucose. On a toutefois trouvé que, en raison de
ses restrictions conformationnelles, l’analogue 5 un faible inhibiteur de fixation plutôt qu’un substrat de la transférase
de la levure (12 % d’inhibition à une concentration de 0,1 mmol L–1).
Mots clés : 1-phosphate de glucose, inhibition, uridylyltransférase UTP:1-phosphate d’α-D-glucose.
[Traduit par la Rédaction] Dookhun and Bennet 1364
Introduction
Scheme 1. Reaction catalyzed by UTP:α-D-glucose-1-phosphate
Complex glycoconjugates are involved in numerous bio-
chemical recognition processes, examples include fertiliza-
tion, immune defense, viral and parasitic infections, cell
growth, cell adhesion, and inflammation (1, 2). The assem-
bly of oligosaccharides in living systems requires sugar nu-
cleotide donors, compounds that are biosynthesized from
glycosyl phosphates (3). For example, uridine 5′-(α-D-
glucopyranosyl diphosphate) (UDP-Glc), a key intermediate
in many biochemical pathways including that of glycogen
formation, is made enzymatically from α-D-glucopyranosyl
phosphate (Glc1P) and uridine 5′-triphosphate (UTP)
(Scheme 1) (3).
uridylyltransferase.
(5, 6); and (iii) 4 a mimic where O-5 has been substituted by
a phosphate group (7–9).
The biological importance of glycosyl phosphates has re-
sulted in many researchers investing considerable effort to
synthesize analogues of this important class of compounds.
In the specific case of α-D-glucopyranosyl phosphate (1), an-
alogues that have been reported include: (i) 2 a compound in
which the C-2 hydroxyl group has been replaced by a fluo-
rine atom (4); (ii) 3 an analogue that is hydrolytically stable
Received 13 April 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 23 October 2004.
V. Dookhun and A.J. Bennet.1 Department of Chemistry,
Simon Fraser University, 8888 University Drive, Burnaby,
BC V5A 1S6, Canada.
The synthesis and characterization of
a
novel,
conformationally rigid, carbocyclic analogue of Glc1P is de-
scribed. The target compound (5) was chosen on the basis of
the potent α-glucosidase inhibition reported by Tanaka et al.
1Corresponding author (e-mail: bennet@sfu.ca).
Can. J. Chem. 82: 1361–1364 (2004)
doi: 10.1139/V04-109
© 2004 NRC Canada

1362
Can. J. Chem. Vol. 82, 2004
Scheme 2. Synthesis of 5, a bicyclo[4.1.0]heptyl analogue of glucose-1-phosphate: (a) LiCl·H2O, Et3N, CH2Cl2; (b) L-selectride, THF,
0 °C; (c) (Me)2Zn, CH2I2, toluene, –10 °C; (d) dibenzyl diisopropylphosphoramidate, tetrazole, CH2Cl2; (e) bleach, THF at RT;
(f) 10% Pd-C, MeOH.
(10) of the compound 6, which is a rigid carbocyclic ana-
logue of α-D-glucopyranosylamine. In compound 6 the fused
cyclopropane ring forces the six-membered ring into a half-
chair conformation (10). In addition, 5 was examined with
the yeast UTP:α-D-glucose-1-phosphate uridylyltransferase
(Scheme 1) to test whether the UDP-analogue 7 could be
made by a chemoenzymatic approach.
Reaction of 11 with reagents such as diphenylphos-
phochloridate (13, 14) and tetraphenylpyrophosphate (15) in
the presence of various bases failed to yield any phosphoryl-
ated products. However, the use of the phosphitylation
method gave the expected phosphite product (16–18). The
phosphite was immediately oxidized using a solution of
bleach in THF–water. Standard work up procedures when
followed by column chromatography afforded analytically
pure 12 in a yield of 52%. Subsequent removal of the benzyl
protecting groups was realized, in a quantitative yield, by
hydrogenation in the presence of 10% Pd-C.
Enzymatic studies
Compound 5 was tested as a potential substrate for
Baker’s yeast UTP:α-D-glucose-1-phosphate uridylyltransfer-
ase (EC 2.7.7.9). Formation of the UDP-glucose analogue
(7) would be accompanied by the simultaneous production
of pyrophosphate (Scheme 1). The production of pyrophos-
phate was monitored by use of a commercial assay (19). Un-
fortunately, compound 5 was shown not to be a substrate for
the Baker’s yeast uridylyltransferase as no pyrophosphate
was detected. Moreover, addition of 5 (0.1 mmol L–1) to a
UTP:α-D-glucose-1-phosphate uridylyltransferase-catalyzed
reaction containing Glc1P (0.1 mmol L–1) and UTP
(0.1 mmol L–1) resulted in a 12% reduction in the rate of
pyrophosphate production. Therefore, it can be concluded
that 5, a conformationally rigid Glc1P analogue, is a weakly
binding inhibitor of the yeast uridylyltransferase enzyme.
Results and discussion
Enone 9 was synthesized from methyl α-D-glucopyranoside
in seven steps according to a literature procedure (11) except
that triethylamine and LiCl were used to cyclize compound
8 (see Experimental section for full details). This modifica-
tion was made because the cyclization of 8 proceeded faster
with these reagents than it did when the combination of 18-
crown-6 and K2CO3 (11) was used. As a consequence of this
modification, it was observed that the enone product was
less prone to aromatize. Attempted reduction of enone 9
with several reagents such as LiAlH4, LiAl(OBu-t)3H, and
ZnBH4 resulted in the formation of mixtures, of varying ra-
tio, of two diastereomeric alcohols. However, the use L-
selectride in THF at 0 °C gave a stereospecific reduction that
produced only the pseudo-axial allylic alcohol 10 in 78%
yield (Scheme 2). The stereochemistry of 10 was assigned
based on the smaller coupling constant observed between H-
Experimental
General
1
1 and H-6 in the H NMR spectrum in comparison to the re-
Toluene and dichloromethane were distilled from CaH2
prior to use. THF was dried over sodium in the presence of
benzophenone. NMR spectra were recorded on Varian
500 MHz spectrometer. Chemical shifts (δ in ppm) are given
relative to tetramethylsilane for (1H and 13C) and external
ported value for the pseudo-equatorial diastereomer (11).
Alcohol 10 was then reacted using Furakawa et al.’s protocol
(12) to afford compound 11 as the only observable diaster-
eomer in a 62% yield. The stereochemistry of bicyclo-
[4.1.0]heptane 11 was confirmed by an nOe experiment to
be equivalent to that of D-glucose rather than L-idose. Spe-
cifically, a strong nOe contact was observed between H-7S
and H-4 (see numbering labels in Scheme 2).
1
85% H3PO4 (for 31P). Only definitive H and 13C assign-
1
ments, which were made using standard 1D, H–1H COSY,
and HMQC NMR experiments, are listed. All glassware was
flame-dried before use. Dibenzyl diisopropylphosphor-
© 2004 NRC Canada

Dookhun and Bennet
1363
amidite was stored as a 50 mg/mL solution in anhydrous di-
chloromethane under an atmosphere of nitrogen.
was allowed to warm up to room temperature. A saturated
solution of NH4Cl (50 mL) was added and the mixture was
stirred for another 30 min. The resulting solution was then
diluted with water (100 mL) and extracted with EtOAc (3 ×
100 mL). The combined organic extracts were washed with
10% H2SO4 (150 mL), NaHCO3 (150 mL), and brine
(150 mL), and then dried over Na2SO4. Removal of the
volatiles gave a yellow oil that was purified by column chro-
matography (hexanes–EtOAc, 2:1 v/v) to afford the
cyclopropanated allylic alcohol 11 as a colourless syrup
(317 mg, 62%). [α]D20 +24.5 (c 1.10, CH2Cl2). 1H NMR
(CDCl3) δ: 0.52 (dd, 1H, J7R,1 = 9.5 Hz, J7R,7S = 5.8 Hz, H-
7R), 1.14 (t, 1H, J7S,7R + J7S,1 = 11.4 Hz, H-7S), 1.34 (m,
1H, H-1), 2.55 (bs, 1H, OH), 2.67 (d, 1H, J8a,8b = 10.0 Hz,
H-8a), 3.42 (dd, 1H, J4,3 = 9.6 Hz, J2,3 = 4.6 Hz, H-3), 3.60
(dd, 1H, J4,5 = 7.8 Hz, 1H, H-4), 3.81 (d, 1H, H-8b), 4.18 (d,
1H, H-5), 4.31 (d, 1H, JA,B = 12.1 Hz, CHAHBC6H5), 4.38
(d, 1H, CHAHBC6H5), 4.43 (dd, 1H, J1,2 = 7.9 Hz, H-2), 4.61
(4R,5S,6R)-4,5,6-Tris(benzyloxy)-3-((benzyloxy)methyl)-
2-cyclohexen-1-one (9)
To a stirred solution of 3,4,5,7-tetra-O-benzyl-1-deoxy-1-
(dimethoxyphosphoryl)-D-xylo-2,6-heptodiulose
8
(11)
(9.4 g, 14 mmol) in dry CH2Cl2 (300 mL) was added
LiCl·H2O (0.30 g, 0.5 equiv.) and Et3N (2.18 mL, 1.1 equiv.).
The reaction mixture was stirred for about 6 h. The organic
phase was washed with aq. H2SO4 (100 mL, 5% v/v), satd.
aq. NaHCO3 (100 mL), brine (100 mL) and concentrated at
aspirator pressure to afford a yellow syrup. The crude prod-
uct material was purified by flash column chromatography
(hexanes–EtOAc, 2:1) to give the product (4.17 g, 60%) as a
1
colorless syrup. This material exhibited identical H and 13C
NMR data to those reported in the literature (11).
(d, 1H, JC,D = 11.4 Hz, CHCHDC6H5), 4.63 (d, 1H, JE,F
=
(1S,4R,5S,6S)-4,5,6-Tris(benzyloxy)-3-
11.5 Hz, CHEHFC6H5), 4.70 (d, 1H, JG,H = 10.8 Hz,
CHGHHC6H5), 4.78 (d, 1H, CHCHDC6H5), 4.82 (d, 1H,
CHGHHC6H5), 4.84 (d, 1H, CHEHFC6H5), 7.18–7.42 (m,
20H, H-Ar). 13C NMR (CDCl3) δ: 8.8 (C-7), 22.3 (C-1), 28.3
(C-6), 64.6 (C-2), 72.7 (CHAHBC6H5), 73.1 (CHCHDC6H5),
74.5 (CHEHFC6H5), 74.9 (2 C, C-8, CHGHHC6H5), 78.6 (C-
4), 79.2 (C-5), 80.9 (C-3), 127.4, 127.6 (2 C), 127.7, 127.8,
128.2, 128.3, 128.4 (2 C), 138.0, 138.2, 138.6, 139.0. Anal.
calcd. for C36H39O5: C 78.52, H 6.95; found: C 78.40, H
6.95.
((benzyloxy)methyl)-2-cyclohexen-1-ol (10)
A 1 mol L–1 solution of L-selectride in THF (11.7 mL,
1.5 equiv.) was added in a dropwise manner to a stirred and
cooled (0 °C) solution of enone 9 (4.17 g, 7.8 mmol) in THF
(200 mL) under a nitrogen atmosphere. The mixture was
stirred for 18 h as it warmed to room temperature gradually.
A saturated solution of NH4Cl (50 mL) was added and the
resulting mixture was stirred for 15 min after which water
(100 mL) was added. Then the aqueous solution was ex-
tracted with EtOAc (2 × 150 mL), the organic extracts were
washed with brine and dried over Na2SO4. A pale yellow
syrup was obtained upon removal of the volatiles under re-
duced pressure. The resultant crude product was purified by
column chromatography (hexanes–EtOAc, 2:1 v/v) to afford
allylic alcohol 12 as a colourless syrup (3.22 g, 77%). [α]D20
(1S,2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-
((benzyloxy)methyl)-bicyclo[4.1.0]heptan-2-yl dibenzyl
phosphate (12)
Dibenzyl
diisopropylphosphoramidite
(358
mg,
1
–39.0 (c 1.00, CH2Cl2). H NMR (CDCl3) δ: 2.57 (bs, 1H,
1.03 mmol) and tetrazole (105 mg, 1.50 mmol) were mixed
vigorously in dry CH2Cl2 (30 mL) under nitrogen for about
30 min after which time the tetrazole had partially dissolved.
A solution of alcohol 11 (275 mg, 0.5 mmol), which had
previously been co-evaporated with dry toluene (3 × 50 mL),
in dry CH2Cl2 (20 mL) was added to the above reaction mix-
ture via a syringe. The resulting reaction mixture was stirred
until the starting material had disappeared (monitored by
TLC, hexanes – ethyl acetate, 2:1 v/v). Then the solution
was concentrated under reduced pressure and the resulting
residue was purified by column chromatography (hexanes–
EtOAc, 2:1 v/v) to give the expected phosphite. After this
material had been dissolved in THF (75 mL), a 5% v/v
bleach solution (2 mL) was added and this mixture was
stirred for about 1 h. The solvent was removed under re-
duced pressure, and then water (100 mL) was added and the
aqueous solution was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts was washed with water
(100 mL) and dried over MgSO4. After removal of the sol-
vent under reduced pressure, the residue was purified by col-
umn chromatography (toluene–acetone, 8:1 v/v) to afford a
colorless oil (213 mg, 52%). [α]2D0 +58.0 (c 1.00, CH2Cl2).
OH), 3.59 (dd, 1H, J6,5 = 9.3 Hz, J6,1 = 4.1 Hz, H-6), 3.94
(d, 1H, J7a,7b = 12.3 Hz, CH7aH7bOBn), 4.05 (dd, 1H, J5,4
6.8 Hz, H-5), 4.16 (dd, 1H, J4,2 = 1.0 Hz, H-4), 4.23 (dd,
1H, J7b,2 = 1.0 Hz, CH7aH7bOBn), 4.30 (t, 1H, J1,2 + J1,6
=
=
8.9 Hz, H-1), 4.46 (d, 1H, JA,B = 11.9 Hz, CHACHBC6H5),
4.48 (d, 1H, CHACHBC6H5), 4.66 (d, 1H, JC,D = 10.3 Hz,
CHCHDC6H5), 4.68 (d, 1H, JE,F = 11.5 Hz, CHEHFC6H5),
4.74 (d, 1H, JG,H = 11.2 Hz, CHGHHC6H5), 4.78 (d, 1H,
CHCHDC6H5), 4.79 (d, 1H, CHEHFC6H5), 4.87 (d, 1H,
CHGHHC6H5), 5.91 (dd, 1H, J2,1 = 4.9 Hz, J2,6 = 1.4 Hz, H-
2) 7.10–7.52 (m, 20H, H-Ar). 13C NMR (CDCl3) δ: 65.1 (C-
1), 70.2 (C-7), 72.6 (CHAHBC6H5), 72.9 (CHEHFC6H5), 74.0
(CHCHDC6H5), 74.7 (CHGHHC6H5), 78.7 (C-4), 78.8 (C-6),
79.1 (C-5), 124.6 (C-2), 127.5, 127.6, 127.7, 127.9 (2 C),
128.0, 128.3 (2 C), 128.4, 128.5, 137.9, 138.1, 138.5, 138.6.
Anal. calcd. for C35H37O5: C 78.33, H 6.76; found: C 78.17,
H 6.65.
(1S,2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-
((benzyloxy)methyl)-bicyclo[4.1.0]heptan-2-ol (11)
To rigorously dried allylic alcohol 12 (500 mg, 0.9 mmol)
in dry toluene (100 mL) under nitrogen at –10 °C was added
a 2 mol L–1 solution of Me2Zn in toluene (4.00 mL, 8 mmol)
dropwise. The mixture was stirred for 15 min, following
which CH2I2 (1.4 mL, 18 mmol) was added dropwise and
the resulting mixture was stirred overnight as the solution
1H NMR (CDCl3) δ: 0.53 (dd, 1H, J7R,1 = 9.5 Hz, J7R,7S
=
5.8 Hz, H-7R), 1.12 (t, 1H, J7S,7R + J7S,1 = 11.4 Hz, H-7S),
1.41 (m, 1H, H-1), 2.60 (d, 1H, J8a,8b = 10.0 Hz, H-8a), 3.44
(m, 1H, H-3), 3.56 (dd, 1H, J4,5 = 8.1 Hz, J3,4 = 10.1 Hz, H-
4), 3.72 (d, 1H, H-8b), 4.16 (d, 1H, H-5), 4.30 (d, 1H, JA,B
=
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1364
Can. J. Chem. Vol. 82, 2004
12.3 Hz, CHACHBC6H5), 4.31 (d, 1H, CHACHBC6H5), 4.57–
4.64 (m, 3H, CHCHDC6H5, CHEHFC6H5, CHGHHC6H5)
4.75–4.88 (m, 3H, CHCHDC6H5, CEHFC6H5, CHGHHC6H5),
methylpurine was monitored using a Cary 3E spectro-
photometer at a wavelength of 360 nm. Similar assays were
performed in the absence of either glucose-1-phosphate or
compound 5.
4.94–5.08 (m, 4H, 2P(O)OCH2OPh), 5.33 (td, 1H, J2,3
=
4.5 Hz, J1,2 + J2,P = 15.4 Hz, H-2) 7.18–7.40 (m, 30H, H-
Ar). 13C NMR (CDCl3) δ: 10.0 (C-7), 22.1 (C-1), 29.1 (C-6),
69.3 (2 C, P(O)OCH2OPh), 72.7 (C-2), 72.6 (CHAHBC6H5),
72.64 (CHCHDC6H5), 74.2 (C-8), 74.7 (CHEHFC6H5),
74.9(CHGHHC6H5), 78.2 (C-4), 78.4 (C-3) 127.4, 127.5,
127.6, 127.7, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5,
128.7, 135.5, 135.6, 136.1, 138.1, 138.5, 138.9. 31P NMR
(CDCl3) δ: –0.53. Anal. calcd. for C50H52O8P: C 74.06, H
6.34; found: C 73.76, H 6.49.
Acknowledgements
The authors wish to thank the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) for funding
this research.
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© 2004 NRC Canada