Methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside: A useful intermediate for the synthesis of conformationally restrained nucleosides

Article abstract of DOI:10.1081/NCN-100002473

The synthesis of methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside, a tetrahydrofuro [3,4-d]oxazole is described. The key step involves the reaction of methyl 3-amino-3-deoxy-5-O-benzoyl-D-ribofuranoside with N,N-dimethylformamide dimethyl acetal with cyclisation to the 2,3-oxazole via a prototropic rearrangement-elimination reaction.

Full text of DOI:10.1081/NCN-100002473

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METHYL 5-O-BENZOYL-2,3-OXAZOLE-D-
RIBOFURANOSIDE: A USEFUL INTERMEDIATE FOR THE
SYNTHESIS OF CONFORMATIONALLY RESTRAINED
NUCLEOSIDES
José Molina a , Hannah L. Maslen a & Claire Simons b
a Medicinal Chemistry Division , Welsh School of Pharmacy, Cardiff University , King
Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom
b Medicinal Chemistry Division , Welsh School of Pharmacy, Cardiff University , King
Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom
Published online: 07 Feb 2007.
To cite this article: José Molina , Hannah L. Maslen & Claire Simons (2001) METHYL 5-O-BENZOYL-2,3-OXAZOLE-D-
RIBOFURANOSIDE: A USEFUL INTERMEDIATE FOR THE SYNTHESIS OF CONFORMATIONALLY RESTRAINED NUCLEOSIDES,
Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 981-983, DOI: 10.1081/NCN-100002473
To link to this article: http://dx.doi.org/10.1081/NCN-100002473
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 981–983 (2001)
METHYL 5-O-BENZOYL-2,3-OXAZOLE-D-
RIBOFURANOSIDE: A USEFUL INTERMEDIATE
FOR THE SYNTHESIS OF CONFORMATIONALLY
RESTRAINED NUCLEOSIDES
Jose´ Molina, Hannah L. Maslen, and Claire Simons∗
Medicinal Chemistry Division, Welsh School of Pharmacy,
Cardiff University, King Edward VII Avenue,
Cardiff CF10 3XF, United Kingdom
ABSTRACT
The synthesis of methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside, a tetrahy-
drofuro[3,4-d]oxazoleisdescribed. Thekeystepinvolvesthereactionofmethyl
3-amino-3-deoxy-5-O-benzoyl-D-ribofuranosidewithN,N-dimethylformamide
dimethyl acetal with cyclisation to the 2,3-oxazole via a prototropic rearrange-
ment-elimination reaction.
The conformation of nucleosides is important for optimal binding at a speci-
fied enzyme active site and can therefore have a profound impact on the biological
activity. For example, conformational analysis of HIV-1 reverse transcriptase in-
hibitors has shown that the 3ꢀ-exo (and to a lesser extent 2ꢀ-endo) character of
the sugar moiety with a trans (ap) C4ꢀ–C5ꢀ conformation is the most favourable
conformation with regards to biological activity (1). The introduction of either
fused rings, e.g. benzofuran (2), in place of the sugar moiety or the introduc-
tion of cyclic moieties, e.g. cyclopropyl (3), in the sugar component, can result
in the nucleoside being ‘locked’ in a specific conformation. The objective was
to develop methodology for the synthesis of novel tetrahydrofuro[3,4-d]oxazoles
(2,3-oxazole-D-ribofuranosides), which could be used for the synthesis of confor-
mationally restrained nucleosides.
∗Corresponding author.
981
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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MOLINA, MASLEN, AND SIMONS
Initialstudiesinvolvedthesynthesisofmethyl2,3-oxazole-D-glucofuranoside,
which was achieved in five steps from diacetone-D-glucose (4). The methodology
established in this synthesis was then applied to the preparation of the required
methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside 1, using 1,2-O-isopropylidene-
D-xylofuranose 2 as the starting material.
After selective 5-O-benzoylation to give 3, the 3-hydroxy was then converted
to the triflate 4 in quantitative yield on reaction with triflic anhydride. Displacement
of the triflate with azide anion gave the 3-azido-sugar 6 in only 26% yield owing to
a competing base-induced elimination of TfOH from 4, resulting in the formation
of the 3,4-ene-sugar 5 in 44% yield (Scheme 1).
Removal of the 1,2-O-isopropylidene group of 6 with concommittant methy-
lation at C-1 was achieved in a 1-pot reaction to give the methyl furanoside 7,
using methodology previously described by us (5), and reduction of the azido
function with Ph3P/H2O gave the precursor methyl 3-amino-3-deoxy-5-O-benzoyl-
D-ribofuranoside 8. The resulting amino-sugar 8 was reacted with N,N-dimethylfor-
mamide dimethylacetal to give the cyclised product, methyl 5-O-benzoyl-2,3-
oxazole-D-ribofuranoside 1, via a prototropic rearrangement followed by ring
closure with consecutive elimination of dimethylamine (5).
Scheme 1. Reagents and conditions: (i) BzCl, pyridine, CH2Cl2, −20 to −30◦C, 10 min, 84% (ii)
Tf2O, pyridine, CH2Cl2, −20◦C, 1.5 h, 97% (iii) NaN3, DMF, 50◦C, 2 h, 44% for 5 and 26% for 6
(iv) 0.5% wt/vol I2 in MeOH, 80◦C, 7 h then r.t. o/n, 80% (v) Ph3P, THF, r.t. 1 h then H2O, 60◦C,
30 min, 86% (vi) N,N-dimethylformamide dimethylacetal, DMF, 20 h, 85%.

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METHYL 5-O-BENZOYL-2,3-OXAZOLE-D-RIBOFURANOSIDE
983
The methodology for the synthesis of novel tetrahydrofuro[3,4-d]oxazoles has
been applied to the synthesis of a 2,3-oxazole-fused-ribose intermediate, which can
be employed in the preparation of conformationally restrained nucleosides. Further
work involving the preparation of conformationally restrained nucleosides using
the tetrahydrofuro[3,4-d]oxazoles, as well as extension of the described method-
ology for the preparation of intermediates with modification in both the oxazole
component and position of fusion, is currently underway.
REFERENCES
1. Van Roey, P.; Taylor, E.W.; Chu, C.K.; Schinazi, R.F. Ann. N.Y. Acad. Sci., 1990, 616,
29–39.
2. Ewing, D.F.; Fahmi, N-E.; Len, C.; Mackenzie, G.; Ronco, G.; Villa, P.; Shaw, G.
Nucleosides & Nucleotides, 1999, 18, 2613–2630.
3. Marquez, V.E.; Siddiqui, M.A.; Ezzitouni, A.; Russ, P.; Wang, J.; Wagner, R.W.;
Matteucci, M.D. J. Med. Chem., 1996, 39, 3739–3747.
4. Molina, J.; Simons, C. J. Carbohydr. Res., 1999, 18, 535–544.
5. Molina, J.; Simons, C. J. Carbohydr. Res., 2000, 19, 991–996.

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