Improvement of the synthesis of sugar phosphonates using microwave irradiations

Article abstract of DOI:10.1080/15257770701543049

Sugar and nucleoside phosphonates have been prepared using a microwave-assisted reaction. Results concerning optimization of the reaction for various substrates as well as comparison of thermal and microwave experimental conditions of the Michaelis-Arbuzov reaction is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701543049

Nucleosides, Nucleotides, and Nucleic Acids, 26:1513–1515, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701543049
IMPROVEMENT OF THE SYNTHESIS OF SUGAR PHOSPHONATES
USING MICROWAVE IRRADIATIONS
Suzanne Peyrottes, Franck Gallier, Alain Papillaud, Je´roˆ me Be´jaud,
and Christian Pe´rigaud
UMR 5625 CNRS–UMII, Universite´ Montpellier II,
2
Montpellier, France
Sugar and nucleoside phosphonates have been prepared using a microwave-assisted reaction.
2
Results concerning optimization of the reaction for various substrates as well as comparison of
thermal and microwave experimental conditions of the Michaelis-Arbuzov reaction is reported.
Keywords Arbuzov reaction; microwave-assisted reaction; nucleoside; sugar
phosphonates
INTRODUCTION
Sugar phosphonate derivatives are valuable intermediates for the synthe-
sis of potential therapeutic compounds such as nucleotide analogues.[1,2]
Although several synthetic methods are described for the preparation
of such compounds, one of the most versatile is the Michaelis-Arbuzov
reaction. Unfortunately, it presents some drawbacks when using classical
conditions such as length of reaction time, high temperature and removal of
the trivalent phosphorus ester used in large excess. These drastic conditions
may be responsible for side reactions, low yields and limits the application
of such reactions to sensitive substrates. Thus, we decided to explore the
use of microwave (MW) irradiation for the synthesis of sugar phosphonic
esters as key intermediates. Indeed, despite the considerable and still
growing interest on MW irradiation applications in organic synthesis[3,4]
only few reports have been made in the field of organophosphorus
chemistry.[5−8]
This work was supported by Association pour la Recherche contre le Cancer (ARC). F. G and J. B.
are grateful to the CNRS & Re´gion Languedoc-Roussillon, and La Ligue contre le Cancer, respectively,
for doctoral fellowships.
Address correspondence to Suzanne Peyrottes, UMR 5625 CNRS–UMII, Universite´ Montpellier II,
cc 08, place E. Bataillon, 34095 Montpellier cedex 05, France. E-mail: peyrottes@univ-montp2.fr
1513

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RESULTS
S. Peyrottes et al.
Optimization of the Michaelis-Arbuzov reaction conditions under
MW irradiation was investigated using compound 1 as model substrate
(Scheme 1). Reaction progress was monitored using TLC and 31P NMR, and
various experimental conditions were studied such as temperature (range
of 160 to 220◦C), reaction time, power of the irradiation (range of 150 to
300W), quantity of triethylphosphite engaged. This last factor is of particu-
lar importance because the removal of this reagent excess usually required
fastidious and long high-vacuum evaporation. 31P NMR experiments enable
us to follow the disappearance of the triethylphosphite and the formation
of the desired phosphonate 5 as well as the expected side-product, (diethyl)
ethylphosphonate (Scheme 1). The best conditions were treating 1 for 90
minutes at 220◦C, irradiation power of 300W, with 5 equivalents of P(OEt)3.
This experiment was reproducible and the scale of the reaction was ex-
tended to grams.
SCHEME 1 Reaction carried out for the optimization study.
Thus, similar protocol was applied to various sugar or nucleosidic sub-
strates, results are summarized in Table 1 and compared to thermal con-
ditions. Concerning the sugar derivatives (1–3), the use of MW irradiation
led to a small decrease of the yield of the corresponding phosphonates af-
ter chromatographic separation. However, the amount of trialkylphosphite
engaged was significantly reduced as illustrated for substrate 2, from 25 to 5
equivalents, and the reaction time was shortened to 1 hour, or less, instead
of few days. Furthermore, we have shown that MW conditions were compat-
ible with various sugar protections such as isopropylidene (1), benzoyl (2),
and benzyl (3) groups. Applied to a nucleosidic derivative such as 4 both
thermal and MW conditions led to disappointing results, the correspond-
ing phosphonate was indeed isolated in less than 25% yield. Formation of
a dark-coloured reaction mixture and side-products were observed, suggest-
ing a degradation of the substrate.
In conclusion, microwave heating is an effective technique to promote
the Michaelis-Arbuzov reaction with short reaction times and reduces the
amount of chemical wastes, but the high temperatures required to perform
the reaction under both thermal and MW conditions are still limiting its
application to sensitive substrates.

Sugar Phosphonates
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TABLE 1 Comparison of thermal and microwave experimental conditions and isolated
yields.
Thermal experiments
MW experiments
Substrate
P(OEt)3
(eq.)
Temp.
(◦C)
Time
(days)
Yield P(OEt)3
Temp.
(◦C)
Time
(min.)
Yield
(%)
(%)
(eq.)
15
25
10
110
110
100
3
2
2
60
70
77
5
5
5
220
180
200
90
30
90
50
63
70
10
110
3
25
5
200
60
14
REFERENCES
1. Leblond, L.; Attardo, G.; Hamelin, B.; Bouffard, D.Y.; Nguyen-Ba, N.; Gourdeau, H. BCH-1868 [(-)-2-
R-dihydroxyphosphinoyl-5-(S)-(guanin-9ꢁ-yl-methyl) tetrahydrofuran]: A cyclic nucleoside phospho-
nate with antitumoral activity. Molecular Cancer Therapeutics 2002, 1, 737–746.
2. Nair, V.; Sharma, P.K.; Synthesis of the 5ꢁ-phosphonate of 4(S)-(6-amino-9H-purin-9-yl) tetrahydro-
2(S)-furanmethanol [s,s-IsoddA]. Arkivoc 2003, XV, 10–14.
3. Hayes, B.L.; Recent advances in microwave-assisted synthesis. Aldrichimica Acta 2004, 37, 66–77.
4. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted organic synthesis—A review.
Tetrahedron 2001, 57, 9225–9283.
5. Wu, J.; Wu, H.; Wei, S.; Dai, W.M. Highly regioselective Wittig reactions of cyclic ketones with stabi-
lized phosphorus ylide under controlled microwave heating. Tetrahedron Lett. 2004, 45, 4401–4404.
6. Kiddle, J.J.; Gurley, A.F. Microwave irradiation in organaphosphorus chemistry 1: the Michaelis-
Arbuzov reaction. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 160, 195–205.
7. Kiddle, J.J. Microwave irradiation in organophosphorus chemistry. Part 2: Synthesis of phosphonium
salts. Tetrahedron Lett. 2000, 41, 1339–1341.
8. Sabitha, G.; Reddy, M.M.; Srinavas, D.; Yadov, J.S. Microwave irradiation: Wittig olefination of lactones
and amides. Tetrahedron Lett. 1999, 40, 165–166.