Easy access to glycosyl phosphorothioates with microwaves technique

Article abstract of DOI:10.1080/07328300600732204

A simple, efficient, and general method for the synthesis of glycosyl phosphorothioate through a one-pot reaction of glycosyl bromide with diethyl phosphite, ammonium acetate, and sulphur in the presence of alumina under solvent-free conditions using microwave irradiation has been developed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328300600732204

Journal of Carbohydrate Chemistry, 25:163–171, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600732204
Easy Access to Glycosyl
Phosphorothioates with
Microwaves Technique
Laura Cipolla, Cristina Redaelli, Iris Faria,
and Francesco Nicotra
Department of Biotechnology and Biosciences, University of Milano-Bicocca,
Milano, Italy
A simple, efficient, and general method for the synthesis of glycosyl phosphorothioate
through a one-pot reaction of glycosyl bromide with diethyl phosphite, ammonium
acetate, and sulphur in the presence of alumina under solvent-free conditions using
microwave irradiation has been developed.
Keywords Glycosyl phosphorothioates, Green chemistry, Stereoselectivity, Micro-
wave, Solvent-free reaction
INTRODUCTION
Glycosyl phosphonate and thiophosphate analogs of naturally occurring
phosphates have found a wide range of applications as regulators, activators,
or inhibitors of carbohydrate-processing enzymes[1–3] since they are isosteric
and nonhydrolyzable analogs of phosphate esters. For example, mannopyrano-
syl thiophosphate analogs of dolichylphosphomannose (Dol-P-Man) have been
reported as potential inhibitors of mannosyl transferases operating in the
endoplasmic reticulum.[4]
In addition, many studies have shown the pharmacological value of the
thiophosphate group in oligonucleotide analogs with a phosphorothioate
group as internucleotide linkage that would confer stability to nucleases
while preserving the specificity and efficiency of complexation.[5–7] Further-
more, phosphorothioates and phosphorodithioates possess most favorable
Received October 3, 2004; accepted November 1, 2005.
Address correspondence to Laura Cipolla, Department of Biotechnology and
Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milano, Italy.
E-mail: laura.cipolla@unimib.it
163

L. Cipolla et al.
164
biological and pharmacological properties as potential antisense or antigen
agents,[8–10] and also as nucleic acid-based clinical diagnostics.[11–13]
Thiophosphate esters can be also useful as synthetic intermediates in the
preparation of many biologically active molecules such as nucleoside phosphor-
odithioates, phosphoramidothioates, or phosphoro fluorodithioates,[11,14] or
used as building blocks for solid-phase synthesis.[15] Moreover, phosphorothio-
ate leaving group at the anomeric position of monosaccharides have been
recently used for the preparation of C-glycosides.[16]
Many synthetic methods for the introduction of a phosphorothioate
moiety have been reported,[17–19] but drastic reaction conditions with some
severe side reactions, prolonged reaction times, and an elaborate purification
procedure are frequently required; other methods use toxic compounds, as thio-
cynates, as starting material, and harsh conditions due to the low nucleophili-
city of the NCS2 incompatible with the termally instable thiocyanate
moieties.[20,21]
In light of these considerations, an alternative and more efficient synthetic
method toward phosphorothioates is desirable.
Starting from the mid-1980s microwave activation as a nonconven-
tional energy source has become a very popular and useful technology in
organic chemistry.[22] Acceleration of organic reactions by microwave dielectric
heating has been widely exploited in organic syntheses under solvent-free con-
ditions.[23–25] The use of microwave dielectric heating may dramatically reduce
reaction times from days to minutes. In addition, there is an important increase
of the yields of the desired products reducing the decomposition of reactants as
well as the formation of side products due to local overheating observed under
conventional conditions. The use of microwave-assisted methods should satisfy
the rapidly increasing demand of speedy synthetic methods of new molecules
for organic and medicinal chemistry. The combination of the advantages of
the solvent-free reactions and microwave irradiations renders these reactions
particularly attractive in the field of green chemistry.
Despite the well-known advantages of microwave techniques, only a
limited number of microwave-assisted reactions have found application in
carbohydrate chemistry.[26,27] Carbohydrates play an important role in a vast
array of biological processes, and they are particularly interesting in the field
of drug discovery, thanks to their low toxicity and immunogenicity.[28–33]
In this context we describe a new methodology for the synthesis of glycosyl
phosphorothioates assisted by microwave dielectric heating.
RESULTS AND DISCUSSION
A general method for alkyl phosphorothioate synthesis was recently reported
using microwave irradiation under solvent-free conditions.[34] We envisaged
the possibility to extend this methodology to the preparation of glycosyl

Phosphorothioate Synthesis with Microwaves
165
phosphorothioates. Hence, per-O-acetylated glycosyl bromides were reacted
with a mixture of diethyl phosphite and an equimolar amount of ammonium
acetate and sulphur, in the presence of a slight excess of alumina (Fig. 1).
The reaction proceeded under solvent-free conditions using microwave
irradiation at 2.45 GHz. Both acidic (Al2O3 W-4)[34] and neutral alumina
were used as adsorbant; however, neutral alumina was preferred since yields
in most cases were higher (Table 1, entries 3, 5, 7, and 9).
The reaction involves in situ formation of the O,O-diethyl phosphorothioate
ammonium salt 1,[19] followed by reaction of 1 with the peracetylated glycosyl
bromides, affording the corresponding glycosyl phosphorothioates 2–6. The
products were isolated after filtration over a Celite pad and purification by
flash chromatography. In general, the reactions are very clean; the only bypro-
duct that can be observed in variable amounts depending on the substrate is
the aldose deriving from the hydrolysis of the corresponding glycosyl halide
to the free anomeric hydroxyl group. The phosphorothioate/hydrolyzed
aldose ratios (Table 1) were determined by 1H NMR spectroscopy of the
crude mixture.
Phosphorothioates 2, 4, and 6 were obtained in good yields (82–94%),
while compounds 3 and 5 were obtained in low yields. In particular, 2,3,4,6-
tetra-O-acetyl-b-D-mannosyl phosphorothioate 3 was obtained in 35% yield;
however, this result is in agreement with related phosphorothioate already
reported;[18] 2,3,4-tri-O-acetyl-L-rhamnosyl phosphorothioate 5 was obtained
in only 26% yield (as a mixture of anomers), but to the best of our knowledge
this is the first example of a rhamnosyl phosphorothioate. The reactivity of
the different peracetylated sugars was found to be in agreement with the
corresponding glycosyl halide used as glycoside donors in oligosaccharide
Figure 1: Diethyl phosphorothioate ammonium salt and the glycosyl phosphorothioates
synthesized.

L. Cipolla et al.
166
Table 1: Yields and product compositions in the preparation of glycosyl
phosphorothioate.
Phosphorothioate/
Entry
Compound
anomeric OHa
Yield %b
1
2
3
4
5
2 (Al2O3)
2 (Al2O3W-4)
3 (Al2O3)
3 (Al2O3 W-4)
4 (Al2O3)
9/1
9/1
4/6
3/7
82
82
35c
14c
94
.99%
Phosphorothioate
6
7
8
9
10
4 (Al2O3 W-4)
5 (Al2O3)
5 (Al2O3 W-4)
6 (Al2O3)
9/1
3/7
84
26c (a/b)
N.R.
.99% hydrolyzed
9/1
8/2
87c
6 (Al2O3 W-4)
73c
aPhosphorothioate/anomeric OH composition was established by 1H NMR of the
crude.
bAll yields refer to isolated products after purification.
cYields are calculated over two steps: formation of the glycosyl halide and its
subsequent thiophosphorylation.
synthesis,[35] with mannosyl derivatives being the less reactive; however,
higher yields have been reported in the synthesis of mannosyl
phosphorodithioates.[36]
1
The anomeric configuration of the products was determined by H NMR
and NOESY NMR experiments. All products were obtained with total
stereoselection at the anomeric position, with the exception of compound 5,
1
which was obtained as an inseparable 2 : 1 a/b mixture, as evidenced by H
NMR spectroscopy. Confirmatory evidence was obtained also from 31P NMR
data, which exhibited signals at d ¼ 23.71 ppm for stereoisomer a and at
d ¼ 24.03 ppm for the b one.
For compounds 2 and 4 coupling constants between J1,2 ¼ 9.2 and
J1,2 ¼ 10.0 Hz, respectively, typical for a trans-diaxial arrangement of the
substituents, indicated a b-orientation of the phosphorothioate group in a
4C1 chair conformation. Similar considerations can be drawn for compound 6
1
(J1,2 ¼ 10.0 Hz, in a C4 chair conformation). For compound 3, a small value
of the coupling constant J1,2 ¼ 1.3 Hz, together with a NOE effect between
H-1 and H-5, indicated a b-configuration of the anomeric group in a 4C1
chair conformation.
Finally, 31P NMR of derivatives 2–6 confirmed the presence of the S–P55O
group in which the phosphorous atom resonates at approximately 20 ppm,
while no resonance was observed at around 60 ppm, as expected for the
isomers possessing an O–P55S group.[18]
In conclusion, a new and mild procedure for the synthesis of glycosyl
phosphorothioates has been developed through the application of microwave

Phosphorothioate Synthesis with Microwaves
167
dielectric heating under solvent-free conditions and without any acidic, basic,
or even aqueous work-up.
The proposed methodology gave variable yields ranging from 94% for
galactose to 26% for rhamnose, shortened reaction times, and limited bypro-
duct formation compared to other procedures reported for the synthesis of
glycosyl phosphorothioates.
EXPERIMENTAL
Thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates
(Merck) charring with a solution containing conc. H2SO4/EtOH/H2O in a
ratio of 5/45/45. Flash column chromatography was performed on silica gel
1
230–400 mesh (Merck). H, 13C, 31P NMR spectra were recorded at 400 MHz
on a Varian Mercury instrument using CDCl3 as solvent unless otherwise
stated. Chemical shifts are reported in ppm downfield from TMS as an
internal standard. Coupling constants (J) are given in Hz. For all compounds
the assignments of the 1H NMR spectra were based on 2D proton–proton shift-
correlation spectra. The assignments of 13C NMR spectra were based on
carbon–proton shift-correlation spectra. Optical rotations were measured at
rt with a Kru¨ss-Optronic P3002 polarimeter.
General Procedure
A mixture of ammonium acetate (2.0 equiv.) and sulphur (2.0 equiv.) was
finely grounged with alumina (2.7 equiv.) in a crucible until a homogeneous
powder was obtained. Diethyl phosphite (2.0 equiv.) was added, and the
mixture was irradiated by microwaves for 3 to 15 min at 720 W. The glycosyl
bromide (1.0 equiv.) was then added and the mixture irradiated by microwaves
for a further 6 to 15 min at 720 W. The alumina was filtered over a Celite pad
and washed with dichloromethane, and the crude purified by flash chromato-
graphy with petroleum ether/EtOAc (1:1).
All reactions were performed with a domestic microwave oven. The multi-
mode domestic ovens is well suited for many classical organic reactions,
provided that adequate safety precaution was undertaken.
The required protected glycosyl bromides were prepared from the per-O-
acetylated monosaccharide by reaction with HBr/AcOH (33% w/w), according
to literature procedures.[37]
2,3,4,6-Tetra-O-acetyl-b-D-glucosyl phosphorothioate 2. [a]2D0 þ 11.58 (c 1,
CHCl3). 1H NMR (400 MHz, CDCl3): d ¼ 5.16 (t, 1 H, J ¼ 9.2 Hz, H3), 5.02 (2t, 2
H, J ¼ 9.2 Hz, H2, H4), 4.96 (dd, 1 H, JH-P ¼ 10.0, J ¼ 9.2 Hz, H1), 4.18–4.07
(m, 6 H, H6a, H6b, CH3CH2P), 3.75–3.70 (ddd, 1 H, J ¼ 10.1, 4.5, 2.6 Hz,
H5), 2.01, 2.00, 1.97, 1.94 (4s, 12 H, CH3CO), 1.32–1.28 (m, 6 H, CH3CH2P).

L. Cipolla et al.
168
31P NMR (162.01 MHz, CDCl3):d ¼ 23.65. 13C NMR (100.57 MHz, CDCl3):
d ¼ 170.53, 170.04, 169.44, 169.27 (4 CH3CO), 83.41 (d, JC-P ¼ 3.8 Hz, C-1),
76.50 (C-5), 73.92 (C-3), 70.80 (C-2), 68.14 (C-4), 64.49, 64.24 (2d,
JC-P ¼ 5.3 Hz, 2 PCH2CH3), 62.11 (C-6), 21.11, 21.11, 21.09, 20.97 (4 CH3CO),
16.46, 16.28 (2 d, JC-P ¼ 7.7 Hz, CH3CH2P). Anal. Calcd for C18H29O12PS: C,
43.20; H, 5.84. Found: C, 43.22; H, 5.81.
2,3,4,6-Tetra-O-acetyl-b-D-mannosyl phophorothioate 3. [a]2D0 þ 58.88
(c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): d ¼ 5.75 (dd, 1 H, J ¼ 1.6 Hz,
JH-P ¼ 12.4 Hz, H1), 5.40 (dd, 1 H, J ¼ 2.9, 1.6 Hz, H2), 5.34 (t, 1 H,
J ¼ 9.9 Hz, H4), 5.24 (dd, 1 H, J ¼ 9.9, 2.9 Hz, H3), 4.22–4.14 (m, 5 H, H-6a,
H5, PCH2CH3), 4.10 (dd, 1 H, J ¼ 12.3, 2.2 Hz, H6b), 2.17, 2.09, 2.07, 2.01
(4s, 12 H, CH3CO), 1.38 (t, 6 H, J ¼ 7.1 Hz, CH3CH2P). 31P NMR
(162.01 MHz, CDCl3): d ¼ 23.34. 13C NMR (100.57 MHz, CDCl3): d ¼ 170.62,
169.95, 169.85, 169.66 (4 CH3CO), 83.51 (d, JC-P ¼ 3.1 Hz, C-1), 71.90
(d, JC-P ¼ 9.2 Hz, C-2), 71.51 (C-5), 69.16 (C-3), 66.01 (C-4), 64.74, 64.47 (2d,
JC-P ¼ 5.3 Hz, PCH2CH3), 62.54 (C-6), 21.31, 21.17, 21.14, 21.07 (4 CH3CO),
16.52, 16.44 (CH3CH2P). Anal. Calcd for C18H29O12PS: C, 43.20; H, 5.84.
Found: C, 43.24; H, 5.85.
2,3,4,6-Tetra-O-acetyl-b-D-galactosyl phosphorothioate 4. [a]2D0 þ 26.48 (c
1
1, CHCl3). H NMR (400 MHz, CDCl3): d ¼ 5.42 (dd, 1 H, J ¼ 3.4, 1.0 Hz, H4),
5.27 (t, 1 H, J ¼ 10.0 Hz, H2), 5.03 (dd, 1 H, J ¼ 10.0, 1.0 Hz, H3), 5.02 (t, 1 H,
J ¼ 10.0 Hz, JH-P ¼ 16.3 Hz, H1), 4.22–4.00 (m, 7 H, H5, H6a, H6b,
PCH2CH3), 2.09, 2.01, 1.97, 1.91 (4s, 12 H, CH3CO), 1.32–1.28 (m, 6 H,
CH3CH2P). 31P NMR (162.01 MHz, CDCl3): d ¼ 24.03. 13C NMR (100.57 MHz,
CDCl3): d ¼ 170.40, 170.22, 169.94, 169.51 (4 CH3CO), 84.04 (d, JC-
¼ 3.8 Hz, C-1), 75.30 (C-5), 71.96 (C-3), 68.10 (d, JC-P ¼ 10.0 Hz, C-2), 67.47
P
(C-4), 64.49, 64.22 (2d, JC-P ¼ 5.4 Hz, PCH2CH3), 61.77 (C-6), 21.16, 21.11,
21.09, 20.99 (4 CH3CO), 16.51, 16.37 (CH3CH2P). Anal. Calcd for
C18H29O12PS: C, 43.20; H, 5.84. Found: C, 43.18; H, 5.82.
2,3,4-Tri-O-acetyl-a,b-L-rhamnosyl phosphorothioate 5. 5a 1H NMR
(400 MHz, CDCl3): d ¼ 5.60 (dd, 1 H, J ¼ 1.7 Hz, JH-P ¼ 12.2 Hz, H1), 5.32
(dd, 1 H, J ¼ 3.2, 1.7, Hz, H2), 5.15 (ddd, 1 H, J ¼ 9.8, 3.2 Hz, JH-P ¼ 1.3 Hz,
H3), 5.04 (t, 1 H, J ¼ 9.8 Hz, H4), 4.20–4.04 (m, 4 H PCH2CH3), 4.02–3.98
(m, 1 H, H5), 2.13, 2.09, 2.00 (3s, 9 H, CH3CO), 1.32–1.27 (m, 6 H,
CH3CH2P), 1.20–1.17 (m, 6 H, H-6). 31P NMR (162.01 MHz, CDCl3):
1
d ¼ 23.71. 5b H NMR (400 MHz, CDCl3): d ¼ 5.44 (d, 1 H, J ¼ 1.7 Hz, H2),
5.18 (dd, 1 H, J ¼ 1.7 Hz JH-P ¼ 12.4 Hz H1), 5.01–5.00 (m, 2 H, H3, H4)
4.20–4.04 (m, 4 H, PCH2CH3), 3.59–3.55 (m, 1H, H5), 1.98, 1.93, 1.91 (3s,
9 H, CH3CO), 1.32–1.27 (m, 6 H, CH3CH2P), 1.20–1.17 (m, 3 H, H6).
31P NMR (162.01 MHz, CDCl3 d ¼ 24.03. 13C NMR 5a 1 5b (100.57 MHz,

Phosphorothioate Synthesis with Microwaves
169
CDCl3): d ¼ 170.18, 170.03, 170.00, 169.98, 169.95, 169.77 (6s, CH3CO), 83.24
(d, JC-P ¼ 3.5 Hz, C-1a), 81.82 (d, JC-P ¼ 2.6 Hz, C-1b), 75.61 (C-5b), 72.14
(d, JC-P ¼ 9.2 Hz, C-2a), 71.94 (C-4b), 71.57 (d, JC-P ¼ 8.2 Hz, C-2b), 70.89 (C-
4a), 70.14 (C-3b), 69.73 (C-5a), 69.19 (C-3a), 64.62, 64.30 (2d, JC-P ¼ 6.0 Hz,
PCH2CH3), 21.27, 21.20, 21.20, 21.07, 21.07, 21.03, (6 CH3CO), 17.82, 17.81
(2 C-6) 16.50, 16.48, 16.47, 16.40 (4 CH3CH2P).
2,3,4-Tri-O-acetyl-b-D-fucosyl phosphorothioate 6. [a]2D0 223,48 (c 1,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 5.20 (dd, 1 H, J ¼ 0.8, 3.3 Hz, H4),
5.19 (t, 1 H, J ¼ 10.0 Hz, H2), 4.97 (dd, 1 H, J ¼ 3.3, 10.0 Hz, H3), 4.92 (dd,
1 H, J ¼ 10.0 Hz, JH-P ¼ 12.0 Hz, H1), 4.19–4.04 (m, 4 H, PCH2CH3), 3.86–
3.81 (bd, 1 H, H 5), 2.11, 1.99, 1.91 (3s, 9 H, CH3CO), 1.31–1.27 (m, 6 H,
CH3CH2P), 1.14 (t, 3 H, J ¼ 2.2 Hz, H6). 31P NMR (162.01 MHz, CDCl3):
d ¼ 24.63. 13C NMR (100.57 MHz, CDCl3): d ¼ 170.61, 170.02, 169.59 (3
CH3CO), 83.70 (d, JC-P ¼ 3.2 Hz, C-1), 73.99 (C-5), 72.42 (C-3), 70.49 (C-4),
68.29 (d, JC-P ¼ 10.7 Hz, C-2), 64.39, 64.20 (2d, JC-P ¼ 5.4 Hz, PCH2CH3),
21.17, 21.12, 21.01 (3 CH3CO), 16.73 (C-6) 16.46, 16.36 (2 CH3CH2P). Anal.
Calcd for C16H27O10PS: C, 43.44; H, 6.15. Found: C, 43.40; H, 6.16.
ACKNOWLEDGEMENTS
The authors aknowledge financial support from the European Comm-
unity’s Human Potential Programme under contract HPRN-CT-2002-00173,
[GLYCIDIC SCAFFOLDS], and from the FIRB (design, preparation and
biological evaluation of new organic molecules as potential innovative drugs).
REFERENCES
[1] Engel, R. Phosphonate as analogues of natural phosphates. Chem. Rev. 1977, 77,
349–367.
[2] Swierczek, K.; Pandey, A.S.; Peters, J.W.; Hengge, A.C. A comparison of phospho-
nothioic acids as phosphatase inhibitors. J. Med. Chem. 2003, 46, 3703–3708.
[3] Knight, W.B.; Sem, D.S.; Smith, K.; Miziorko, H.M.; Rendina, A.R.; Cleland, W.W.
Phosphorylated thiosugars: synthesis, properties, and reactivity in enzymatic reac-
tions. Biochemistry 1991, 30, 4970–4977.
[4] Kulesza, A.; Frank, C.G.; Aebi, M.; Vasella, A. Synthesis of stable dolichylphospho-
mannose analogues. Helv. Chim. Acta 2004, 87, 3106–3118.
[5] Zon, G. Oligonucleotide analogues as potential chemotherapeutic agents. Pharm.
Res. 1988, 5, 539–349.
´
´
[6] Cieslak, J.; Jankowska, J.; Stawinski, J.; Kraszewski, A. Aryl H-phosphonates 12.
Synthetic and 31P NMR studies on the preparation of nucleoside H-phosphonothio-
ate and nucleoside H-phosphonodithioate monoesters. J. Org. Chem. 2000, 65,
7049–7054.

L. Cipolla et al.
170
[7] Deshpande, M.C.; Garnett, M.C.; Vamvakaki, M.; Bailey, L.; Armes, S.P.;
Stolnik, S. Influence of polymer architecture on the structure of complexes
formed by PEG–tertiary amine methacrylate copolymers and phosphorothioate
oligonucleotide. J. Controlled Release 2002, 81, 185–199.
[8] Cummins, L.; Graff, D.; Beaton, G.; Marshall, W.S.; Caruthers, M.H. Biochemical
and physicochemical properties of phosphorodithioate DNA. Biochemistry 1996,
35, 8734–8741.
[9] Furrer, P.; Billeci, T.M.; Donati, A.; Kojima, C.; Karwowski, B.; Sierzchala, A.;
Stec, W.; James, T.L. Structural effect of complete [Rp]-phosphorothioate and phos-
phorodithioate substitutions in the DNA strand of a model antisense inhibitor-
target RNA complex. J. Mol. Biol. 1999, 285, 1609–1622.
[10] Mukherjee, S.; Bhattacharyya, D. Effect of phosphorothioate chirality on the
grooves of DNA double helices: a molecular dynamics study. Biopolymers 2004,
73, 269–282.
[11] Seeberger, P.H.; Yau, E.; Caruthers, M.H. 20-Deoxynucleoside dithiophosphates:
synthesis and biological studies. J. Am. Chem. Soc. 1995, 117, 1472–1478.
[12] Brummer, O.; Wentworth, P.; Weiner, D.P.; Janda, K.D. Phosphorodithioates: syn-
thesis and evaluation of new haptens for the generation of antibody acyl trans-
ferases. Tetrahedron Lett. 1999, 40, 7307–7310.
[13] Uhlmann, E.; Peyman, A. Antisense oligonucleotides: a new therapeutic principle.
Chem. Rev. 1990, 90, 544–579.
[14] Kudelska, W. The cyanation reaction of O-acetylated S-glycosyl phosphorothioates.
Carbohydr. Res. 2000, 329, 687–691.
[15] Seeberger, P.H.; Caruthers, M.H.; Bankaitis-Davis, D.; Beaton, G. Synthesis of
phosphorodithioate DNA by the H-phosphonothioate method. Tetrahedron 1999,
55, 5759–5772.
[16] Kudelska, W. Synthesis of C-glycosides from S-glycosyl phosphorothioates. Zeits-
chrift fuer Naturfoschung, B: Chem. Sci. 2002, 57, 243–247.
[17] Michalska, M. Glycosylation of organic thio-and selenoacids of phosphorus. Tetra-
hedron 1978, 34, 617–622.
[18] Chmielewski, M.; BeMiller, J.N. Derivatives of S-alfa- and -beta-D-hexopyranosyl
thiophosphates. Carbohydr. Res. 1981, 96, 73–78.
[19] Lipka, P.; Michalska, M. Efficient synthesis of S- and Se-(2,3,4,6-tetra-O-acetyl-b-
D-glucosyl) thiophosphates and selenophosphates. Carbohydr. Res. 1983, 113,
317–320.
[20] Renard, P.-Y.; Schwebel, H.; Vayron, P.; Josien, L.; Valleix, A.; Mioskowski, C. Easy
access to phosphonothioates. Chem. Eur. J. 2002, 8, 2910–2916.
[21] Bulman Page, P.C.; Wilkes, R.D.; Reynolds, D. Comprehensive Organic Functional
Group Transformation; Katrizky, A.R., Meth-Cohn, O., Rees, C.W., Eds.; Elsevier:
Oxford, 1995; Vol. 2, 252–259.
[22] Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J.
The use of microwave ovens for rapid synthesis. Tetrahedron Lett. 1986, 27,
279–282.
[23] Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted organic
synthesis a review. Tetrahedron 2001, 57, 9225–9283.

Phosphorothioate Synthesis with Microwaves
171
[24] Perreux, L.; Loupy, A. A tentative rationalization of microwave effects in organic
synthesis according to the reaction medium, and mechanistic considerations.
Tetrahedron 2001, 57, 9199–9223.
[25] Larhed, M.; Hallberg, A. Microwave-assisted high-speed chemistry: a new tech-
nique in drug discovery. Drug Discov. Today 2001, 6, 406–416.
[26] Das, S.K. Application of microwave irradiation in the synthesis of carbohydrates.
Synlett. 2004, 6, 915–932.
`
[27] Corsaro, A.; Chiacchio, U.; Pistara, V.; Romeo, G. Microwave-assisted chemistry of
carbohydrates. Curr. Org. Chem. 2004, 8, 511–538.
[28] Wong, C.-H. Ed.; Carbohydrate-Based Drug Discovery; Wiley-VCH Verlag GmbH:
Weinheim, 2003; Vol. 1.
[29] Hanessian, S. Total Synthesis of Natural Products: The “Chiron” Approach;
Baldwin, J.E., Ed.; Pergamon: Oxford, 1983.
[30] Peri, F.; Cipolla, L.; Forni, E.; Nicotra, F. Carbohydrate-based scaffolds for the gen-
eration of bioactive compounds. Monatshefte fu¨r Chemie 2002, 133, 369–382.
[31] Hirschmann, R.; Nicolau, K.C.; Pietranico, S.; Leahy, E.M.; Salvino, J.; Arison, B.;
Cichy, M.A.; Spoors, P.G.; Shakespeare, W.C.; Sprengler, P.A.; Hamley, P.;
Smith, A.B.; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.;
Freidinger, R.M.; Cascieri, M.R.; Strader, C.D. De novo design and synthesis of
somatostatin non-peptide peptidomimetics utilizing beta-D-glucose as a novel scaf-
folding. J. Am. Chem. Soc. 1993, 115, 12550–12568.
[32] Lohof, E.; Planker, E.; Mang, C.; Burkhart, F.; Dechantstreiter, M.A.; Haubner, R.;
¨
Wester, H.J.; Schwaiger, M.; Holzemann, G.; Goodman, S.L.; Kessler, H.;
Kessler, H. Carbohydrate derivatives for use in drug design: cyclic alpha(v)-selec-
tive RGD peptides. Angew. Chem. Int. Ed. Engl. 2000, 39, 2761–2764.
[33] Cipolla, L.; Peri, F.; La Ferla, B.; Redaelli, C.; Nicotra, F. Carbohydrate scaffolds for
the production of bioactive compounds. Curr. Org. Synth. 2005, 2, 153–173.
[34] Kaboudin, B. A simple and new method for the synthesis of thiophosphates. Tetra-
hedron Lett. 2002, 43, 8713–8714.
[35] Zhang, Z.; Ollmann, I.R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. Program-
mable one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 1999, 121, 734–753.
[36] Kudelska, W.; Michalska, M. A novel stereoselective synthesis of S-glycosyl phos-
phorodithioates from peracetylated sugars. Synthesis 1995, 1539–1544.
[37] Tropper, F.D.; Andersson, F.O.; Braun, S.; Roy, R. Phase transfer catalysis as a
general and stereoselective entry into glycosyl azides from glycosyl halides.
Synthesis 1992, 618–620.