Facile synthesis of core intermediates toward sialyl nucleoside mimetics

Article abstract of DOI:10.1016/j.tetlet.2009.03.050

6-Deoxyphosphonated intermediates, 8 and 12, were efficiently synthesized from d-fructose and sucrose, respectively. These novel intermediates will be useful to synthesize various d-tagato- and fructofuranoside derivatives as inhibitors of sialyl transfer

Full text of DOI:10.1016/j.tetlet.2009.03.050

Tetrahedron Letters 50 (2009) 2543–2544
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Tetrahedron Letters
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Facile synthesis of core intermediates toward sialyl nucleoside mimetics
Hyeok Beom Kwon a, Mark von Itzstein b, Kang-Yeoun Jung a,
*
a Department of Environmental & Applied Chemistry, College of Engineering, Kangnung National University, 210-702, Republic of Korea
b Institute for Glycomics, Griffith University, PMB 50 Gold Coast Mail Centre, Gold Coast, 9726 QLD, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Deoxyphosphonated intermediates, 8 and 12, were efficiently synthesized from
D
-fructose and sucrose,
Received 23 February 2009
Accepted 10 March 2009
Available online 13 March 2009
respectively. These novel intermediates will be useful to synthesize various
side derivatives as inhibitors of sialyl transferase or sialidase.
D-tagato- and fructofurano-
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
D-Tagatofuranoside
Sucrose
Epoxy phosphonate
Phosphonated sugar
Sialic acids, which are abundant on human cell surfaces, are
crucial receptors at the non-reducing end of oligosaccharide chains
in cell wall glycoconjugates.1–3 They are, therefore, ideally located
for a wide variety of functions such as cell–cell communication,
blood coagulation, fertilization, and other biological events.4,5 In
addition, sialic acids involvement in the pathogenesis of a variety
of diseases including inflammatory disease, cancer metastasis,
and virus infection has led to a wide interest in the synthesis of
modified sialic acids including sialyl nucleoside mimetics as probes
for the study of sialic acid-recognizing proteins.6,7 Our interest lies
in investigating mimetics of CMP-Neu5Ac or CMP-KDN (Fig. 1)
through the synthesis of compounds of the general structure 1.
These sialylmimetics are designed to retain the structural features
essential for the interaction with a particular protein, but are struc-
turally simpler compounds with potentially improved pharmaco-
logical profiles.
An earlier investigation into the importance of the sialyl moiety
of transition-state analogues of CMP-Neu5Ac revealed that the
complete Neu5Ac residue may not be required for high enzyme
affinity.8 Thus, our design for sialylmimetics contained a phospho-
nate group that has replaced the entire sialic acid portion (Fig. 2,
structure 1).9 This approach would allow attachment of an accep-
tor as a monoester while at the same time retaining a negative
charge under physiological conditions. In addition, we are inter-
ested in investigating the role of the C-4 position of the nucleoside
and the pyrimidine base in the binding affinity. Herein, we report
the synthesis of two key intermediates of phosphonate monoester
Figure 1.
tose and sucrose. These intermediates,
-tagatofuranoside derivatives, would allow us to explore the
D-fructofuranoside and
D
hydrophobicity, hydrophilicity, and steric bulk and also the effect
of epimerization at C-4 position on sialic acid recognizing proteins.
In a previous report, a route was developed for the preparation
of sialyl nucleoside mimetic of the general structure 2 (Fig. 2) start-
ing from the carbohydrate D
-fructose.10 However, in the first step,
the methyl glycoside was prepared via a Fischer type methodology
sialylmimetics based on very inexpensive carbohydrates, D-fruc-
* Corresponding author. Tel.: +82 33 640 2403; fax: +82 33 641 2410.
E-mail address: kyjung@kangnung.ac.kr (K.-Y. Jung).
Figure 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.050

2544
H. B. Kwon et al. / Tetrahedron Letters 50 (2009) 2543–2544
tive 10, which was converted into the 6-iodo fructofuranose 11
in good yield. Michaelis-Arbuzov reaction15 of iodo compound 11
with P(OMe)3 afforded 6-deoxy-6-dimethoxyphosphinyl deriva-
tive 12.16 The acetyl group at C-4 position of compound 12 can
be easily converted to a leaving group which can then undergo
SN2-type reaction resulting in tagatofuranoside derivatives.
In summary, we have synthesized two 6-deoxy-6-dimethoxy
phosphonates, 8 and 12, which can be manipulated to prepare no-
vel sialyl nucleoside mimetics for the inhibition of sialic acid recog-
nizing proteins. Both compounds 8 and 12 provide flexibility in
terms of introduction of functionality in the unit but while inter-
mediate 8 gives access to fructofuranoside derivatives, intermedi-
ate 12 results in tagatofuranoside derivatives allowing us to
explore the importance of C-4 position of the nucleoside.
Acknowledgments
Scheme 1. Reagents and conditions: (a) AcCl, CH3OH, 38%; (b) PPH3, DIAD, N,N-
DMF, 0 °C, 65%; (c) TsCl, pyridine, 0 °C, 66%; (d) Ac2O, pyridine, 0 °C, 86%; (e) NaI,
acetone, 95 °C, 72%; (f) P(OMe)3, reflux, 72%.
Financial support from the Australian Research Council (Inter-
national Fellowship Grant) is gratefully acknowledged. We also
thank the Regional Technology Innovation Program of the Ministry
of Knowledge Economy (MKE), Korea, for financial support (Grant
No. RTI05-01-02).
Supplementary data
Representative experimental details for the synthesis and the
characterization data for key intermediates are provided. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.03.050.
References and notes
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Scheme 2. Reagents and conditions: (g) (i) 2,2-DMP, p-TsOH, 1,4-dioxane, 80 °C;
(ii) TsCl, pyridine, 0 °C, overall 53%; (h) Ac2O, pyridine, 0 °C, 83%; (i) NaI, acetone,
95 °C, 79%; (j) P(OMe)3, reflux, 80%.
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which resulted in a mixture of a/b fructofuranoside and fructopyr-
anoside, respectively (Scheme 1). The tetrahydroxyl compound 3
obtained was then purified by passing through an ion-exchange
resin column with water as eluent which proved to be an exceed-
ingly time-consuming step. In our current synthesis of compound
3, we modified the purification method by performing an efficient
column chromatography using 40% methanol in ethyl acetate to
obtain the pure compound. Following modified Mitsunobu condi-
tion,11,12 epoxide 4 was obtained as a mixture of stereoisomers in
9:1 ratio as determined from 1H NMR data.
Regioselective tosylation of the 6-hydroxy group in compound 4
gave the tosylate 5. Subsequent acetylation afforded fully pro-
tected compound 6. It should be noted that we only report analyt-
ical data for the major isomer of compounds 4, 5, and 6 in this note.
Interestingly, iodination of the mixture of isomers 6 resulted in
a single compound 7 in 72% yield after purification. This iodo com-
pound 7 was treated with freshly distilled P(OMe)3 to obtain the
corresponding 6-deoxy-6-dimethoxy phosphonate 8.13 A series of
nucleophiles can then be introduced at the C-4 position of phos-
phonate 8 to build a library of fructofuranoside derivatives.
In our effort to access tagatofuranoside derivatives we at-
tempted a different route using an inexpensive starting material,
sucrose, as shown in Scheme 2.
12. Guthrie, R. D.; Jenkins, I. D. Aust. J. Chem. 1982, 35, 767–774.
13. Selected data for 8: Rf = 0.53 (9:1 EtOAc–acetone); 1H NMR (CDCl3, 300 MHz) d
0
2.11 (s, 3H, MeCO), 2.15 (dd, 1H, J6,P = 1.8, J6,6 = 18.6 Hz, H-6), 2.17 (dd, 1H,
J6 ,P = 1.8, J6 ,6 = 18.6 Hz, H-60), 3.29 (s, 3H, OMe), 3.68 (d, 1H, J3,4 = 2.7 Hz, H-3),
3.70 (d, 3H, JMe,P = 10.9 Hz, POMe), 3.71 (d, 3H, JMe,P = 10.9 Hz, POMe), 3.85 (d,
0
0
0
1H, J4,3 = 2.7 Hz, H-4), 3.95 (d, 1H, J1,1 = 12.1 Hz, H-1), 4.38 (q, 1H, J = 6.2 Hz, H-
5), 4.44 (d, 1H, J1 ,1 = 12.1 Hz, H-10); 13C NMR (CDCl3, 75 MHz) d 20.8, 26.3
0
(d, JC-P = 139.5 Hz), 49.5, 52.3 (d, JC-P = 6.5 Hz), 52.7 (d, JC-P = 6.2 Hz), 56.8
(d, JC-P = 6.4 Hz), 58.2, 59.7, 72.6, 103.6, 170.3; 31P NMR (85% H3PO4) d 29.59;
HRESI-MS m/z: [M + Na]+ calcd for 333.0709. Found 333.0710.
14. (a) Hanaya, T.; Sato, N.; Yamamoto, H. Carbohydr. Res. 2005, 340, 2494–2501;
(b) Hanaya, T.; Okamoto, R.; Prikhod’ko, Y. J.; Armour, M-A.; Hogg, A. M.;
Yamamoto, H. J. Chem. Soc. Perkin Trans. 1 1993, 1663–1671.
15. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430.
16. Selected data for 12: Rf = 0.43 (E); 1H NMR (CDCl3) d 1.34 (s, 3H, Me2C), 1.38 (s,
3H, Me2C), 2.05 (s, 3H, MeCO), 2.32 (m, 2H, H-6, H-60), 3.25 (s, 3H, OMe), 3.69
(d, 3H, JMe,P = 9.0 Hz, POMe), 3.75 (d, 3H, JMe,P = 9.0 Hz, POMe), 3.81 (d, 1H,
J1,1 = 12.3 Hz, H-1), 3.87 (d, 1H, J1 ,1 = 12.3 Hz, H0-1), 4.01 (br s, 1H, H-3), 4.23
(m, 1H, H-5), 4.78 (bd, 1H, J4,5 = 4.2 Hz, H-4); 13C NMR (CDCl3) d 20.2, 20.9, 27.1,
29.8 (d, Jc,p = 140.6 Hz), 48.5, 52.1 (d, Jc,p = 6.4 Hz), 52.8 (d, Jc,p = 6.3 Hz), 62.2,
78.0 (d, Jc,p = 6.2 Hz), 79.3, 82.4 (d, Jc,p = 14.6 Hz), 99.2, 102.1, 170.3; 31P NMR
(85% H3PO4) d 29.14; HRESI-MS m/z: [M+Na]+ calcd for C14H25O9P391.1128.
Found 391.1119.
0
0
6-Tosylated 1,3-isopropylidene 9 was synthesized directly from
sucrose using a previously reported method.14 Compound 9 was
treated with acetic anhydride-pyridine to give 4-O-acetyl deriva-