V. S. Borodkin et al. / Tetrahedron Letters 45 (2004) 857–862
861
(d, JC;P 4.5, –OCH2CH2–), 68.1 (C-40), 69.1 (C-3), 70.7
(C-20), 70.8 (d, JC;P 9.0, C-2), 72.3 (C-30), 72.5 (C-5), 73.1
(C-1), 74.1 (d, JC;P 8.5, C-50), 77.7 (C-4), 103.2 (C-10),
114.0 (–CH@CH2), 140.2 (–CH@CH2); 31P NMR
(121 MHz, D2O): d 20.6 (P0), 22.3 (P); ES-MS ()) data:
Finally, sequential deprotection21 of 35 performed
without isolation of any intermediates followed by ion-
exchange chromatographic purification delivered the
phosphonodisaccharide–MBP–guanosine hybrid 122 as
the tris-ammonium salt in 80% yield.
m=z 692.28 (100%, [M)H]ꢀ) (expected m=z 692.29;
22
C27H53NO15P2 requires M, 693.29); ½aꢁ +15.2ꢁ (c 0.5,
D
In conclusion, we report here the synthesis of a potential
mechanism-based bisubstrate inhibitor of the elongating
a-mannosyl phosphate transferase in Leishmania
designed with the emphasis on the incorporation of a
guanosine moiety linked to the acceptor substrate
through the methylenebisphosphonate bridge mimicking
the important guanosine-pyrophosphate motif present
in the natural substrate donor GDP–mannose, as well as
its simplified analogues. The results of a biological
evaluation of these compounds will be disclosed else-
where in due course.
MeOH).
10. Compound 10 was prepared from tetramethyl methyl-
enebisphosphonate by saponification with neat t-BuNH2
at rt for 28 h, followed by evaporation of the amine,
treatment of the residue with Dowex-50 (Hþ) in MeOH
and concentration. The triester 10 (which contained up to
10% of the symmetric dimethyl ester) was used without
additional purification.
11. Malachowski, W. P.; Coward, J. K. J. Org. Chem. 1994,
59, 7616–7624.
12. Campbell, D. A.; Bermack, J. C. J. Org. Chem. 1994, 59,
658–660.
13. Compound 2: 1H NMR (300 MHz, D2O): d 1.20–1.35
(10H, m, 5 · CH2), 1.54 (2H, quintet, J 6.6, –OCH2CH2–),
1.89–2.02 (4H, m, H-1*a, -1*b and –CH2CH@CH2), 2.10
Acknowledgements
0
0
(2H, br t, JH;P 19.5, –PCH2P–), 3.46 (1H, dd, J2 ;3 10.0, H-
The Wellcome Trust International Grant supported this
work and V.S.B.
20), 3.50 (3H, d, JH;P 10.3, OMe), 3.62 (1H, dd, J3 ;4 3.5, H-
30), 3.65 (1H, m, H-5), 3.74–3.98 (11H, m, H-2, -3, -4, -40,
-50, -6a, -6b, -60a, -60b and –OCH2CH2–), 4.16 (1H, m,
0
0
H-1), 4.38 (1H, d, J1 ;2 7.8, H-10), 4.89 and 4.97 (2H, 2 · br
d, J 10.2, J 17.3, –CH2CH@CH2), 5.85 (1H, ddt, JH;CH2
6.7, –CH2CH@CH2); 13C NMR (75 MHz, D2O): d 25.2(t,
JC;P 125.9, –PCH2P–), 26.8 (d, JC;P 133.2, C-1*), 25.0, 28.2,
28.3, 28.4, 28.6 (5 · CH2), 30.2 (d, JC;P 6.0, –OCH2CH2–),
33.2 (–CH2CH@CH2), 51.6 (d, JC;P 3.5, –OMe), 60.4
(C-6), 62.6 (br, C-60), 64.9 (d, JC;P 5.6, –OCH2CH2–), 68.0
(C-40), 69.3 (C-3), 70.9 (d, JC;P 8.0, C-2), 71.0 (C-20), 72.4
(C-30), 72.9 (C-5), 73.5 (C-1), 73.8 (br, C-50), 77.6 (C-4),
103.3 (C-10), 114.0 (–CH@CH2), 140.6 (–CH@CH2);
31P NMR (121 MHz, D2O): d 18.8 (br, P0 + P00), 22.5 (P);
ES-MS ()) data: m=z 364.33 (100%, [M)2H]2ꢀ) (expected
0
0
References and notes
1. (a) Turco, S. J.; Spath, G. F.; Beverley, S. M. Trends
Parasitol. 2001, 17, 223–226; (b) Ilg, T. Parasitol. Today
2000, 16, 489–497.
2. (a) Carver, M. A.; Turco, S. J. J. Biol. Chem. 1991, 266,
10974–10981; (b) Carver, M. A.; Turco, S. J. Arch.
Biochem. Biophys. 1992, 295, 309–317.
3. Routier, F. H.; Higson, A. P.; Ivanova, I. A.; Ross, A. J.;
Tsvetkov, Y. E.; Yashunsky, D. V.; Bates, P. A.; Niko-
laev, A. V.; Ferguson, M. A. J. Biochemistry 2000, 39,
8017–8025.
4. For the definition of the bisubstrate inhibition concept:
Palcic, M.; Heerze, L.; Srivastava, O. P.; Hindsgaul, O. J.
Biol. Chem. 1989, 264, 17174–17181; For recent advances
in this area: Hinou, H.; Sun, X.-L.; Ito, Y. Tetrahedron
Lett. 2002, 43, 9147–9150, and references cited therein.
5. Borodkin, V. S.; Ferguson, M. A. J.; Nikolaev, A. V.
Tetrahedron Lett. 2001, 42, 5305–5308.
m=z 364.10), 729.05 (40%, [M)H]ꢀ) (expected m=z 729.21;
22
C25H49O18P3 requires M, 730.21); ½aꢁ +11.2ꢁ (c 0.52,
D
MeOH–H2O, 1:1).
14. (a) Turner, J. J.; Filipov, D. V.; Overhand, M.; van der
Marel, G. A.; van Boom, J. A. Tetrahedron Lett. 2001, 42,
5763–5767; (b) Vincent, S. P.; Mioskowski, C.; Lebeau, L.
Nucleos. Nucleot. 1999, 18, 2127–2139.
15. Routier, F. H.; Nikolaev, A. V.; Ferguson, M. A. J.
Glycoconjugate J. 2000, 16, 773–780.
6. Borodkin, V. S.; Milne, F. C.; Ferguson, M. A. J.;
Nikolaev, A. V. Tetrahedron Lett. 2002, 43, 7821–7825.
7. Van der Klein, P. M. A.; Dreef, C. E.; van der Marel, G.
A.; van Boom, J. H. Tetrahedron Lett. 1989, 30, 5473–
5476.
16. For the regioselective monodeprotection of the nucleoside-
methylenebisphosphonate tribenzyl ester derivative: Ik-
eda, H.; Abushanab, E.; Marquez, V. E. Bioorg. Med.
Chem. Lett. 1999, 9, 3069–3074.
17. Daub, G. W.; Van Tamelen, E. E. J. Am. Chem. Soc. 1977,
99, 3526–3528.
18. (a) Creary, X. Org. Synth. 1985, 64, 207–216; (b) Liotta, L.
J.; Ganem, B. Tetrahedron Lett. 1989, 30, 4759–4762.
19. Saady, M.; Lebeau, L.; Mioskowski, C. Helv. Chim. Acta
1995, 78, 670–678.
20. Compound 24 was synthesised following the preparation
of 23 (Ref. 14a), by treatment of the common 60-O-TBDPS
precursor with Ph2NCOCl–DIPEA in pyridine (rt, 16 h,
50%) prior to desilylation with TBAF–AcOH in THF (rt,
1 h, 90%).
21. Simultaneous de-O-acylation and cleavage of the N,N-
dimethylformamidine N-protecting group was performed
with t-BuOK in t-BuOH–THF–H2O as recommended in
Ref. 14b.
22. Compound 1: 1H NMR (300 MHz, D2O): d 1.15–1.31
(10H, m, 5 · CH2), 1.51 (2H, quintet, J 6.8, –OCH2CH2–),
1.87–1.98 (4H, m, H-1*a, -1*b and –CH2CH@CH2),
8. All new compounds showed satisfactory analytical and
spectral data.
9. Compound 3: 1H NMR (300 MHz, D2O): d 1.16–1.31
(10H, m, 5 · CH2), 1.51 (2H, quintet, J 6.5, –OCH2CH2–),
1.85–2.07 (6H, m, H-1*a, -1*b, –CH2CH2NMe2 and
–CH2CH@CH2), 2.76 and 2.77 (6H, 2 · s, –NMe2), 3.23
(2H, m, –CH2NMe2), 3.44 (1H, dd, J2 ;3 9.8, H-20), 3.58
0
0
(1H, dd, J3 ;4 3.5, H-30), 3.60 (1H, m, H-5), 3.70–4.00
0
0
(11H, m, H-2, -3, -4, -40, -50, -6a, -6b, -60a, -60b and
0
0
–OCH2CH2–), 4.13 (1H, m, H-1), 4.35 (1H, d, J1 ;2 7.8,
H-10), 4.86 and 4.94 (2H, 2 · br d, J 10.4, J 17.2,
–CH2CH@CH2),
5.81
(1H,
ddt,
JH;CH2
6.5,
–CH2CH@CH2); 13C NMR (75 MHz, D2O): d 22.0 (d,
JC;P 133.7, –CH2CH2NMe2), 26.6 (d, JC;P 133.7, C-1*),
25.0, 28.1, 28.3, 28.4, 28.5 (5 · CH2), 30.1 (d, JC;P 5.8,
–OCH2CH2–), 33.1 (–CH2CH@CH2), 42.3 (–NMe2), 53.1
(–CH2NMe2), 60.3 (C-6), 63.1 (d, JC;P 4.5, C-60), 64.7