A concise route to tiazofurin

Article abstract of DOI:10.1016/S0040-4039(02)01470-3

Successful oxidation of a key thiazoline intermediate allows an efficient synthesis of tiazofurin in four steps from commercially available 1′-acetoxy-2′,3′,5′-tri-O-benzoyl-β-D- ribofuranose.

Full text of DOI:10.1016/S0040-4039(02)01470-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6561–6562
A concise route to tiazofurin
Richard S. Brown, James Dowden,* Christelle Moreau and Barry V. L. Potter
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down,
Bath BA2 7AY, UK
Received 14 May 2002; accepted 16 July 2002
Abstract—Successful oxidation of a key thiazoline intermediate allows an efficient synthesis of tiazofurin in four steps from
commercially available 1%-acetoxy-2%,3%,5%-tri-O-benzoyl-b-
D
-ribofuranose. © 2002 Elsevier Science Ltd. All rights reserved.
Tiazofurin 41 is converted in vivo into the active
metabolite thiazole-4-carboxamide adenine dinucleotide
(TAD), an analogue of NAD that prevents de novo
guanine nucleotide synthesis via inhibition of inosine
2%,3%-benzoate esters to afford thiazole-furan 2 in each
case (Scheme 1).
Instead, isopropylidene 3 was converted into the target
monophosphate
dehydrogenase
(IMPDH,
EC
compound 4 with good reported yields, but the intro-
duction and removal of the isopropylidene protecting
group introduced an extra three steps from 1%-acetoxy-
1.1.1.205).2 The consequent decrease in cellular GTP
and deoxyGTP concentrations interrupts DNA and
RNA synthesis in rapidly-dividing tumour cells. Tiazo-
furin proved effective in reducing the leukaemic cell
burden in acute myelogenous leukaemia patients, but
was found to be too toxic for general clinical applica-
tion.3–5 Subsequent discovery of two IMPDH isoforms,
of which type II is up-regulated in human leukaemia
cell lines,6,7 has prompted studies to inform the design
of isoform selective inhibitors8 and has renewed interest
in tiazofurin and its analogues.9,10
2%,3%,5%-tri-O-benzoyl-b- -ribofuranose 5 (Scheme 2).
D
We now report the successful oxidation of thiazoline 1
that removes the need for this detour and reduces the
synthesis of tiazofurin to a simple four-step procedure.
Thiazoline 1 was prepared by reaction of 1%-cyano-
2%,3%,5%-tri-O-benzoyl-b-D L-cysteine
-ribofuranose12 with
methyl ester in the presence of triethylamine according
to an established protocol.11 Complete epimerisation of
1
the cysteine a-proton was observed by H NMR, but
Several routes have been published toward this com-
pound; of these the preparation reported by Ramasamy
and co-workers11 provides tiazofurin, while avoiding
the use of hydrogen sulfide gas. These authors reported
unsuccessful oxidation of thiazoline 1 with MnO2, or a
range of other conditions, observing elimination of the
this centre will become part of the aromatic thiazole. A
number of oxidation conditions, including DDQ in
toluene,13 did not proceed to our satisfaction, but we
were pleased to observe clean conversion of the thiazo-
line 1 in the presence of bromotrichloromethane and
DBU.14 Thiazole 6 was thus prepared from commer-
H2N
O
N
OBz
OBz
O
HO
OAc
CN
a) - d)
O
O
O
S
OH
BzO
OBz
HO
O
Scheme 1. Reagents and conditions:11 (a) MnO2/benzene/
5
3
4
reflux.
Scheme 2. Reagents and conditions:11 (a) cysteine ethyl
ester·HCl/Et3N; (b) MnO2/benzene/reflux; (c) 90% TFA; (d)
NH3/MeOH.
* Corresponding author. E-mail: j.dowden@bath.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01470-3

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R. S. Brown et al. / Tetrahedron Letters 43 (2002) 6561–6562
4. Tricot, G. J.; Jayaram, H. N.; Lapis, E.; Natsumeda, Y.;
Nichols, C. R.; Kneebone, P.; Heerema, N.; Weber, G.;
Hoffman, R. Cancer Res. 1989, 49, 3696–3701.
5. Wright, D. G.; Boosalis, M. S.; Waraska, K.; Oshry, L.
J.; Weintraub, L. R.; Vosburgh, E. Anticancer Res. 1996,
16, 3349–3354.
6. Konno, Y.; Natsumeda, Y.; Nagai, M.; Yamaji, Y.;
Ohno, S.; Suzuki, K.; Weber, G. J. Biol. Chem. 1991,
266, 506–509.
7. Natsumeda, Y.; Ohno, S.; Kawasaki, H.; Konno, Y.;
Weber, G.; Suzuki, K. J. Biol. Chem. 1990, 265, 5292–
5295.
8. Colby, T. D.; Vanderveen, K.; Strickler, M. D.;
Markham, G. D.; Goldstein, B. M. Proc. Natl. Acad. Sci.
USA 1999, 96, 3531–3536.
9. Franchetti, P.; Marchetti, S.; Cappellacci, L.; Jayaram,
H. N.; Yalowitz, J. A.; Goldstein, B. M.; Barascut, J. L.;
Dukhan, D.; Imbach, J. L.; Grifantini, M. J. Med. Chem.
2000, 43, 1264–1270.
10. Franchetti, P.; Grifantini, M. Curr. Med. Chem. 1999, 6,
599–614.
Scheme 3. Reagents and conditions: (a) TMSCN, SnCl4,
CH2Cl2, rt, 2 min; (b) L-cysteine methyl ester hydrochloride,
Et3N, CH2Cl2; (c) BrCCl3, DBU, CH2Cl2, 0°C, 61% over
three steps; (d) NH3/MeOH, rt, 20 h, 86%.
11. Ramasamy, K. S.; Bandaru, R.; Averett, D. J. Org.
Chem. 2000, 65, 5849–5851.
12. Dudfield, P. J.; Le, V. D.; Lindell, S. D.; Rees, C. W. J.
Chem. Soc., Perkin Trans. 1 1999, 2937–2942.
13. Yoshino, K.; Kohno, T.; Morita, T.; Tsukamoto, G. J.
Med. Chem. 1989, 32, 1528–1532.
cially available 1%-acetoxy-2%,3%,5%-tri-O-benzoyl-b-D-
ribofuranose 5 in an unoptimised isolated yield of 61%
over the three steps with just one chromatographic
separation (Scheme 3).15
14. Williams, D. R.; Lowder, P. D.; Gu, Y. G.; Brooks, D.
A. Tetrahedron Lett. 1997, 38, 331–334.
15. Preparation of methyl 2-(2%,3%,5%-tri-O-benzoyl-b-D-ribo-
Ester aminolysis and global deprotection were effected
by stirring 6 in methanolic ammonia.16 Dissolution of
the concentrated crude reaction mixture into water and
extraction of all contaminants into ethyl acetate proved
sufficient to afford pure tiazofurin 4 in 86% yield.
furanosyl)thiazole-4-carboxylate 6. 1,8-Diazabicyclo[5.4.0]-
undec-7-ene (2.4 mL, 16 mmol, 2 equiv.) was added to a
stirred solution of methyl 1%-(2%,3%,5%-tri-O-benzoyl-b-D-
ribofuranosyl)thiazoline-4%-carboxylate 1 (4.7 g, 8 mmol)
in CH2Cl2 (250 mL). The solution was cooled to 0°C and
BrCCl3 (1.9 g, 9 mmol, 1.0 mL) was added dropwise and
the resulting mixture stirred overnight. The reaction mix-
ture was then concentrated, dissolved into ethyl acetate
and the solution washed 3× with satd aq. NH4Cl. The
organic layer was dried (Na2SO4), filtered, concentrated
and subject to column chromatography on silica gel using
a gradient of hexane:ethyl acetate from 9:1 to 7:3 as
eluent to afford 6 as a light yellow foam. Yield 3.6 g, 6.1
mmol, 61% over three steps. [h]2D5 −43.3 (c 1, CHCl3); IR
In summary, selective dehydrogenation of a thiazoline 1
in the presence of sensitive ribose 2%,3%,5%-tribenzoate
ester protecting groups is described. The immediate
benefit of this discovery is to improve the efficiency of
tiazofurin synthesis in the absence of hydrogen sulfide
affording a productive four-step protocol.
Acknowledgements
1
(KBr) 1726, 1269, 1095, 710 cm−1; H NMR (400 MHz
CDCl3): l 8.15 (1H, s, SCH) 8.09–8.07 (2H, m, Ar-H)
8.00–7.97 (2H, m, Ar-H) 7.92–7.87 (2H, m, Ar-H) 7.58–
7.51 (3H, m, Ar-H) 7.45–7.33 (6H, m, Ar-H) 5.91–5.88
(2H, m, H-2%,3%) 5.75 (1H, d, J=4.7, H-1%) 4.89 (1H, dd,
J=12.1, 3.1, H-5%a) 4.75–4.78 (1H, m, H-4%) 4.61 (1H, dd,
J=12.1, 3.9, H-5%b) 3.91 (3H, s, COOCH3); 13C NMR
(100 MHz (DEPT) CDCl3): l 169.6(0), 166.2(0), 165.3(0),
165.2(0), 161.6(0), 147.3(0), 133.8(1), 133.7(1), 133.5(1),
130.1(1), 129.92(1), 129.91(1), 129.6(0), 128.98(0),
128.92(0), 128.76(1), 128.7(1), 128.6(1), 80.9(1), 80.8(1),
76.9(1), 72.5(1), 64.0(2), 52.8(3). MS (FAB+) m/z (M+H)+
588 (100). MS (FAB+/HR) m/z (M+H)+ calcd for
C31H25NO9S: 588.1329. Found: 588.1341.
We thank the EPSRC for a studentship (to R.S.B.) and
the BBSRC for a project grant, and we acknowledge
the use of the EPSRC Chemical Database Service at
Daresbury.
References
1. Tiazofurin is the generic name approved by the United
States Adopted Name Council.
2. Lui, M. S.; Faderan, M. A.; Liepnieks, J. J.; Natsumeda,
Y.; Olah, E.; Jayaram, H. N.; Weber, G. J. Biol. Chem.
1984, 259, 5078–5082.
16. Srivastava, P. C.; Pickering, M. V.; Allen, L. B.; Streeter,
D. G.; Campbell, M. T.; Whitowski, J. T.; Sidwell, R.
W.; Robins, R. K. J. Med. Chem. 1977, 20, 256–262.
3. Tricot, G.; Weber, G. Anticancer Res. 1996, 16, 3341–
3347.