Synthesis of 3-Deoxy-d-threopentofuranose 5-phosphate, a substrate of arabinose 5-phosphate isomerase

Article abstract of DOI:10.1080/07328300903477812

3-Deoxy-d-threopentofuranose 5-phosphate, a substrate of arabinose 5-phosphate isomerase, has been synthesised starting from d-arabinose. Selective protection of the hydroxyl groups at C-1, C-2, and C-5 allowed deoxygenation of position 3 by conversion into a thiocarbamate and radical reduction. Deprotection and phosphorylation of the primary hydroxyl group and final deprotection of the other hydroxyl groups afforded the desired compound.

Full text of DOI:10.1080/07328300903477812

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Synthesis of 3-Deoxy-d-
threopentofuranose 5-Phosphate, a
Substrate of Arabinose 5-Phosphate
Isomerase
Cristina Airoldi a , Silvia Merlo a & Francesco Nicotra a
a Department of Biotechnology and Biosciences , University of
Milano-Bicocca , Piazza della Scienza 2, 1-20126, Milano, Italy
Published online: 04 Jan 2010.
To cite this article: Cristina Airoldi , Silvia Merlo & Francesco Nicotra (2010) Synthesis of 3-Deoxy-
d-threopentofuranose 5-Phosphate, a Substrate of Arabinose 5-Phosphate Isomerase, Journal of
Carbohydrate Chemistry, 29:1, 30-38, DOI: 10.1080/07328300903477812
To link to this article: http://dx.doi.org/10.1080/07328300903477812
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Journal of Carbohydrate Chemistry, 29:30–38, 2010
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300903477812
Synthesis of
3-Deoxy-D-threopentofuranose
5-Phosphate, a Substrate of
Arabinose 5-Phosphate
Isomerase
Cristina Airoldi, Silvia Merlo, and Francesco Nicotra
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza
della Scienza 2 1-20126, Milano, Italy
3-Deoxy-D-threopentofuranose 5-phosphate, a substrate of arabinose 5-phosphate iso-
merase, has been synthesised starting from D-arabinose. Selective protection of the hy-
droxyl groups at C-1, C-2, and C-5 allowed deoxygenation of position 3 by conversion
into a thiocarbamate and radical reduction. Deprotection and phosphorylation of the
primary hydroxyl group and final deprotection of the other hydroxyl groups afforded
the desired compound.
Keywords Deoxysugars; API; LPS biosynthesis
INTRODUCTION
Arabinose 5-phosphate isomerase (API) converts ribulose 5-phosphate into
arabinose 5-phosphate in bacteria. This reaction is the first step of the biosyn-
thesis of KDO (3-deoxy-D-manno-octulosonate), an essential component of LPS
(lipopolysaccharide) structure.[1] As a consequence, API activity is fundamen-
tal for Gram-negative bacteria survival,[2] which results in it being a relevant
pharmacological target for the development of new antibacterial agents.[3,4]
We therefore decided to investigate the structural requirements of the
active site of the enzyme in order to design inhibitors with potential an-
tibacterial activity. In particular, we studied several modifications on ara-
binose 5-phosphate to verify their effect on substrate recognition by the
Received September 8, 2009; accepted November 10, 2009.
Address correspondence to Francesco Nicotra Department of Biotechnology and Bio-
sciences, University of Milano-Bicocca, Piazza della Scienza 2, 1-20126 Milano, Italy.
E-mail: francesco.nicotra@unimib.it
30

Synthesis of 3-deoxy-D-threopentofuranose 5-phosphate
31
enzyme. In this context, we synthesised a 3-deoxy derivative of the natural
substrate, namely 3-deoxy-D-threopentofuranose 5-phosphate, and we verified
API ability to recognize and convert it into the corresponding ketose. 3-Deoxy-
D-threopentofuranose 5-phosphate has been already reported as a weak API
inhibitor,[5] but the synthesis is not described; in this work we demonstrate
that this compound is in fact a substrate of this enzyme.
RESULTS AND DISCUSSION
The synthesis of 3-deoxy-D-threopentofuranose 5-phosphate was performed
starting from D-arabinose 1 (Sch. 1), which was treated first with t-butyldi-
phenylsilyl chloride (TBDPSC1) in order to protect selectively the primary
hydroxyl group affording compound 2,[6] and then with acetone dimethylac-
etal in dichloromethane, in the presence of camphorsulphonic acid (CSA),
to protect the hydroxyl groups in positions 1 and 2. Those two hydroxyl
groups are the only cis-related, in the β-anomer, that can generate the iso-
propylidene cycle. The obtained 5-O-t-butyldiphenylsilyl-1,2-O-isopropylidene-
β-D-arabinofuranose (3)[6,7] has the only hydroxyl group at C-3 deprotected,
Scheme 1: Reagents and conditions. (a) TBDPSCI, Py dry, 4◦C, 75% yield; (b) Me2C(OMe)2,
CSA, CH2Cl2, 4◦C, 63% yield; (c) thiocarbonyldiimidazole, CH3CH2Cl, rfx, 80◦C; (d)
(Me3Si)SiH, AIBN, toluene dry, rfx, 110◦C, 69% yield over two steps; (e) TBAF, THF, 91% yield; (f)
diphenyl chlorophosphate, Py dry, 80% yield; (g) H2, PtO2, MeOH, quantitative yield; (h) H2O,
quantitative yield.

C. Airoldi et al.
32
allowing its reduction to hydrogen, exploiting the radical displacement of
a thiocarbamate. To this purpose, compound 3 was treated with thiocar-
bonyldiimidazole in dry dichloroethane at 80◦C to afford the carbamate 4,
which was directly treated with (Me3Si)3SiH and AIBN in toluene under
reflux,[8] affording 5-O-t-butyldiphenylsilyl-3-deoxy-1,2-O-isopropylidene-β-D-
threopentofuranose 5[6] in 69% yield over two steps. The deoxygenated com-
pound 5 was then deprotected at the primary hydroxyl group by treatment
with tetrabutylammonium fluoride (TBAF) in THF affording 3-deoxy-1,2-O-
isopropylidene-β-D-threopentofuranose 6 in 91% yield. The primary hydroxyl
group of 6 was then converted into a diphenylphosphate by treatment with
diphenyl chlorophosphate in dry pyridine (80% yield), and the diphenylphos-
phate was quantitatively deprotected by treatment with PtO2 in degassed
methanol, affording 3-deoxy-1,2-O-isopropylidene-β-D-threopentofuranose 5-
phosphate 8. Finally, hydrolysis of the isopropylidene, the last protecting
group, afforded 3-deoxy-D-threopentofuranose 5-phosphate 9 in quantitative
yield.
STD NMR experiments[9] performed with Escherichia coli API[10] showed
that 3-deoxy-D-threopentofuranose 5-phosphate 9 is accepted in the active site
of the enzyme, and it is isomerized to the corresponding ketose sugar (Sch. 2,
Fig. 1). According to our data, positions 1 and 5 of both the deoxy-substrates
are fundamental for recognition and binding processes and their affinity for
API is lower with respect to the natural substrate. In addition, API-specific
activity for arabinose 5-phosphate and for compound 9 was determinated by
monitoring the enzymatic reaction by 1H-NMR. The calculated values are
2.306 0.467 × 10−4 and 3.295 0.165 × 10−5, respectively.
These results indicate that 3-OH deletion reduces the binding affinity, even
if it does not inhibit isomerisation. This observation can be exploited in or-
der to design and synthesize new API inhibitors as potential antibacterial
drugs.
Scheme 2: The reversible isomerization of 3-deoxy-D-threopentofuranose 5-phosphate to
3-deoxy-D-glyceropentulose 5-phosphate catalyzed by API. When the reaction is carried out
in D2O, the deuteration of 3-deoxy-D-glyceropentulose 5-phosphate at position 1 and of
3-deoxy-D-threopentofuranose 5-phosphate at position 2 occurs.

Synthesis of 3-deoxy-D-threopentofuranose 5-phosphate
33
Figure 1: (a) 1H NMR spectrum of API: 3-deoxy-substrate mixture at equilibrium
(3-deoxy-D-threopentofuranose 5-phosphate: 3-deoxy-D-glyceropentulose 5-phosphate 4:6)
NS = 16; (b) STD spectrum of API-substrate mixture at equilibrium, at an API:
3-deoxy-D-threopentofuranose 5-phosphate 1:80 molar ratio and an API:
3-deoxy-D-glyceropentulose 5-phosphate 1:120 molar ratio, protein saturation time = 2 s,
NS = 2304, on-resonance frequency = 7.9 ppm, off-resonance frequency = 40 ppm. Spectra
were recorded on the same sample; the sample was dissolved in PBS, pH 7.3, 5◦C.
EXPERIMENTAL
Synthesis
General methods
˚
All solvents were dried with molecular sieves (4 A, Fluka) for at least 24 h
prior to use. When dry conditions were required, the reactions were performed
under argon. Thin layer chromatography (TLC) was performed on silica gel
60 F254 plates (Merck) with UV detection, or by using a developing solution
of concd. H2SO4/E1OH/H2O (10:45:45), followed by heating at 180◦C. Flash
column chromatography was performed on silica gel 230–400 mesh (Merck).
Mixtures of petroleum ether (boiling range 40–60◦C) and ethyl acetate were
1
1
1
used as eluents. H, 13C, H-1H COSY, and H-13C HSQC NMR spectra were
recorded with a Varian 400 MHz Mercury instrument at 25◦C unless otherwise
stated. Chemical shifts are reported in ppm downfield from TMS as internal
standard; mass spectra were recorded with a Q-TRAP 2000 instrument (Ap-
plied Biosystem). Optical rotations were measured at ambient temperature,
using the sodium-D line, with a POLAX-2L electronic polarimeter (ATAGO).
5-O-t-Butyldiphenylsilyl-D-arabinofuranose (2)
To a stirred suspension of D-arabinose (100 mg, 0.666 mmol) in dry Py
(2 mL), TBDPSC1 (188 µL, 0.733 mmol) was added dropwise at 0◦C under
argon atmosphere. Afer 10 min the reaction was stirred at 4◦C overnight. Wa-
ter was added to quench the reaction and the mixture was stirred for 15 min.

C. Airoldi et al.
34
The mixture was concentrated under reduced pressure. The product was pu-
rified by flash column chromatography (5:5, petroleum ether;EtOAc) affording
1
2 (194 g, 75% yield) as a yellow oil (mixture of α- and β- anomers). H NMR
(400 MHz, CDCl3) δ = 7.83–7.56 (m, 4H, Ar), 7.56–7.27 (m, 6H, Ar), 5.41 (s,
1H, H1), 5.29 (d, 1H, J = 3.8, H1), 4.39–3.57 (m, 5H), 1.21–0.97 (s, 9H, 3 ×
CH3). 13C NMR (101 MHz, CDCl3) δ 136.05, 135.87, 135.83, 132.25, 132.05,
130.43, 130.34, 130.26, 128.25, 128.20, 128.18, 128.01, 103.49, 96.72, 86.74,
82.92, 79.60, 78.03, 77.86, 76.28, 65.01, 64.39, 60.86, 27.10, 26.95, 19.29. MS:
m/z = 411.4 [M+Na]+; m/z = 427.4 [M+K]+ Anal. calcd. for C21H28O5Si: C,
64,92; H, 7.26; O, 20.59; Si, 7.23; found C, 64.95; H, 7.24; O, 20.58; Si, 7.24.
5-O-t-Butyldiphenylsilyl-1,2-O-isopropylidene-β-D-arabinofuranose (3)
To a stirred solution of 2 (50 mg, 0.129 mmol) in dry CH2Cl2 (2.5 mL), 2,2-
dimethoxypropane (24 µL, 0.194 mmol) and camphorsulphonic acid (catalytic
amount) were added at 4◦C under argon atmosphere. The reaction mixture was
stirred overnight at 4◦C. After 14 h, Et3N was added to neutralize the reaction
and the mixture was stirred for 15 min. The mixture was concentrated under
reduced pressure. The product was purified by flash column chromatography
(8:2, petroleum ether:EtOAc) giving 3 (35 mg, 63% yield) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ = 7.78–7.59 (m, 4H, Ar), 7.50–7.31 (m, 6H,
Ar), 5.89 (d1H, J = 4.0, H1), 4.55 (d, 1H, J = 4.0, H2), 4.43 (d, 1H, J = 1.9, H3),
4.19–3.98 (m, 1H, H4), 3.98–3.72 (m, 2H, 2 × H5), 1.34 (s, 3H, CH3), 1.29 (s, 3H,
3H, CH3), 1.10 (s, 9H, 3 × CH3). 13C NMR (101 MHz, CDCl3) δ 135.82, 133.35,
130.02, 128.01, 112.76, 105.81, 87.66, 87.29, 87.23, 76.49, 63.86, 27.09, 26.35,
19,45. [α]D = –12.1 (c = 1, CHCl3); MS: m/z = 451.4 [M+Na]+; m/z—467.4 [M
20
+ K]+ Anal. caled. for C24H32O5Si: C, 67.26; H, 7.53; O, 18.67; Si, 6.55; found:
C, 67.22; H, 7.54; O, 18.66; Si, 6.57.
5-O-t-Butyldiphenylsilyl-3-O-(imidazolylthiocarbonyl)-1,2–O-isopropylidene-
β-D-threopentofuranose (4)
To a stirred solution of 3 (65 mg, 0.151 mmol) in dry CH3CH2Cl2 (2 mL),
1,1ꢁ-thiocarbonyldiimidazole (35 mg, 0.197 mmol) was added under argon at-
mosphere. The reaction mixture was heated at reflux (80◦C). After 3 h, the
reaction mixture was cooled to r t and the mixture was concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 and the organic layer
was washed with water.
5-O-t-Butyldiphenylsilyl-3-deoxy-1,2-O-isopyropylidene-β-D-
threopentofuranose (5)
To a stirred solution of crude 4 in dry toluene (2 mL), tris(trimethyl-
silyl)silane (33 µL, 0.196 mmol) and α,αꢁ-azobisbutyronitrile (9 mg, 0.055
mmol) were added and the resulting solution was heated and stirred at 110◦C

Synthesis of 3-deoxy-D-threopentofuranose 5-phosphate
35
under argon atmosphere and refluxed. After 20 min, the mixture was cooled
to r t and the mixture was concentrated under reduced pressure. The product
was purified by flash column chromatography (9.5:0.5, petroleum ether:EtOAc)
affording 5 (42 mg, 69% yield over 2 steps) as a yellow oil. 1H NMR (400 MHz,
CDCl3) δ–7.72–7.63 (m, 4H, Ar), 7.46–7.32 (m, 6H, Ar), 5.79 (d, 1H, J = 3.9,
H1), 4.79–4.69 (m, 1H, H2), 4.37–4.23 (m, 1H, H4), 3.91–3.73 (m, 2H, 2 × H5),
2.27 (dd, 1H, J = 14.2, 2.4, H3a), 2.15 (ddd, 1H, J = 14.3, 8.1, 6.2, H3b), 1.33
(s, 3H, CH3), 1.28 (s, 4H, CH3), 1.06 (s, 9H, 3 × CH3). 13C NMR (101 MHz,
CDCl3) δ 135.86, 133.74, 129.86, 127.90, 112.33, 106.87, 81.49, 80.96, 66.06,
20
33.78, 27.20, 27.06, 26.14, 19.46, [α]D = –10 (c = 1, CHCl3); MS: m/z = 413.7
[M+H]+, m/z = 435.7 [M+Na]+. Anal. calcd. for C24H32O4Si: C, 69,86; H,7.82;
O, 15.51; Si, 6,81; found: C, 69.87; H, 7.84; O, 15.49; Si, 6.80.
3-Deoxy 1,2-O-isopropylidene-β-D-threopentofuranose (6)
To a stirred solution of 5 in dry THF (2 mL), tetrabutylammonium fluoride
1M in THF (121 µL, 0.121 mmol) was added at r t under argon atmosphere,
After 1 h, silica was added and the mixture was conecentrated under reduced
pressure. The product was purified by flash column chromatography (9.5:0.5,
1
petroleum ether: (CH3)2CO) giving 6 (19.3 mg 91% yield) as a yellow oil. H
NMR (400 MHz, CDCl3) δ = 5.81 (d, 1H, J = 3.8, H1), 4.75 (m, 1H, H2), 4.31
(m, 1H, H4), 3.81 (dd, 1H J–11.5, 8.0, IH, H5a), 3.60 (dd, 1H, J = 11.5, 3.9,
H5b), 2.19 (ddd, 1H J = 14.7, 8.6, 6.3, H3a), 1.98 (dd, 1H J = 14.2, 3.3, H3b),
1.54 (s, 3H, CH3), 1.31 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 112.35,
20
106.67, 81.95, 80.91, 65.23, 33.39, 27.21, 26.13. [α]D = +4.9 (c = 1, CHCl3);
MS: m/z = 197.2 [M+Na]1. Anal. calcd. for C8H14O4; C, 55.16; H, 8.10; O, 36.74;
found: C, 55.14; H, 8.11; O, 36.70.
3-Deoxy-1,2-O-isopropylidene-β-D-threopentofuranose 5-diphenylphosphate (7)
To a stirred solution of 6 (220 mg, 1.26 mmol) in dry Py (13 mL),
diphenylphosphochloridate (24 µL, 0.194 mmol) was added at 0◦C under ar-
gon atmosphere. After 1 h, MeOH was added to quench the reaction and
the mixture was stirred for 15 min. The mixture was concentrated under re-
duced pressure. The product was purified by flash column chromatography
(6:4, petroleum ether:EtOAc) affording 7 (35 mg, 80% yield) as a white solid. 1H
NMR (400 MHz, CDCl3) δ = 7.41–6.93 (m, 10H, Ar), 5.75 (d, 1H, J = 3.7, H1),
4.64 (bt, 1H, J = 4.1, H2), 4.52–4.38 (m, 1H, J = 9.5, 7.1, H5a), 4.39–4.30
(m, 1H, J = 8.6, 2.4, H4), 4.30–4.21 (m, 1H, J = 9.6, 6.6, H5b), 2.13–1.97
(m, 2H, 2 × H3), 1.46 (s, 3H, CH3), 1.22 (s, 3H, CH3). 13C NMR (101 MHz,
CDCl3) δ 150.31, 130.00, 125.58, 120.32, 112.66, 107.07, 80.57, 79.04, 70.38,
33.63, 27.17, 25.95. 31P NMR (162 MHz, CDCl3) δ –10.96, [α]D = +5.9 (c = 1,
20
CHCl3); MS: m/z = 407.3 [M+H]+; m/z = 429.3 [M+Na]+; m/z = 445.3 [M+K]+.

C. Airoldi et al.
36
Anal. calcd. for C20H23O7P: C, 59,11; H, 5.70; O, 27.56; P, 7.62; found: C, 59.09;
H, 5.71; O, 27.54; P, 7.61.
3-Deoxy-1,2-O-isopropylidene-β-D-threopentofuranose 5-phosphate (8)
Compound 7 (30 mg, 0.074 mmol) was dissolved in degassed MeOH (3 ml)
and PtO2 was added (16.8 mg). The reaction mixture was stirred under H2 at r
t for 2 h. The catalyst was removed by filtration through Celite and the filtrate
was concentrated under reduced pressure, obtaining 8 (19 mg, quantitative
1
yield) as a white solid. H NMR (400 MHz, CD3OD) δ = 5.77 (d, 1H, J = 3.0,
H1), 4.84–4.67 (m, 1H, H2), 4.44–4.23 (m, IH, H4), 4.23–3.86 (m, 2H, J = 40.3,
2 × H5), 2.34–1.94 (m, 2H, J = 33.4, 17.6, 2 × H3), 1.51 (s, 3H, CH3), 1.28 (s,
3H, CH3). 13C NMR (101 MHz, CD3OD) δ 112.38, 106.99, 80.75, 79.73, 68.07,
33.10, 26.26, 24.98. 31P NMR (162 MHz, D2O) δ 1.07. [α]D = +5.9 (c = 1, H2O);
20
MS: m/z = 255.3 [M+H]+; m/z = 277.3 [M+Na]+; m/z = 293.3 [M+K]+. Anal.
calcd. for C8H15O7P: C, 37.80; H, 5.95; O, 44.06; P, 12.19; found: C, 37.78; H,
5.97; O, 44.02; P, 12.20.
3-Deoxy-D-threopentofuranose 5-phosphate (9)
Compound 8 was dissolved in H2O and the solution was transferred into an
NMR-tube. The reaction was monitored by 1H NMR. After 1 h pH was neutral-
ized by adding NaOH 1.0 M and the solution was lyophilized to give 9 in quan-
titative yield (mixture of α- and β- anomers). 1H NMR (400 MHz, D2O) δ = 5.10
(s, 1H, H1), 5.02 (d, 1H, J = 4.3, H1), 4.26 (m, 1H, H2), 4.18–3.93 (m, 1H, H4),
3.93–3.58 (m, 2H, 2 × H5), 2.38–2.06 (m, 1H, H3a), 1.66–1.35 (m, 1H, H3b).
13C NMR (101 MHz, D2O) δ 102.23, 95.63, 77.48, 77.24, 75.21, 74.35, 70.83,
67.84, 32.84, 30.94. MS: m/z = 259.1 [M(disodium salt)+H]+. Anal. calcd. for
C5H11O7P: C, 28.05; H, 5.18; O, 52.31; P, 14.47; found: C, 28.07; H, 5.19; O,
52.28; P, 14.49.
NMR experiments
Binding studies
The ligand resonances were assigned using 1H-1H COSY and 1H-13C HSQC
NMR spectroscopy. A basic 1D-STD sequence was used with the on-resonance
frequency of 7.9 ppm and the off-resonance frequency of 40 ppm. A train of
Gaussian-shaped pulses of 50 ms each was employed, with a total saturation
time of the protein envelope of 2 s. A T1p filter of 2 ms was employed to elim-
inate the background signals from protein. All the samples were dissolved in
deuterated PBS at pH 7.3, containing NaCl (300 mM), at 5◦C. Total sample
volumes were 550 µL. The on-resonance and the off-resonance spectra were ac-
quired simultaneously with the same number of scans. The STD spectrum was

Synthesis of 3-deoxy-D-threopentofuranose 5-phosphate
37
obtained by subtraction of the on-resonance spectrum from the off-resonance
spectrum. Subtraction was performed by phase cycling to minimize artifacts
arising from magnet and temperature instabilities.[11] Reference experiments
of samples containing only the free tested compound itself were performed un-
der the same experimental conditions to verify true ligand binding. The effects
observed in the presence of the protein were due to true saturation transfer,
as no signal was present in the STD spectra obtained in the reference experi-
ments, except residues from HDO, indicating artifacts from the subtraction of
compound signals to be negligible.
Enzymatic assays
API-specific activity was determined as increase of ribulose 5-phosphate
H3 or of 3-deoxy-D-glyceropentulose 5-phosphate H3 integral value vs. time
per µg of API. Spectra were collected in 33 s time intervals over 673 s. Mea-
surement is the mean of five independent determinations.
ACKNOWLEDGEMENTS
This work was supported by the Italian Cystic Fibrosis Research Foundation
(Grant FFC#10/2008) and the Italian Consortium CINMPIS.
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