Synthesis of a base-protected α-L-LNA guanine nucleoside

Article abstract of DOI:10.1081/NCN-120022824

Synthesis of (1R,3R,4S,7R)-7-hydroxy-1-hydroxymethyl-3-(2-N-isobutyroylguanin-9-yl)-2, 5-dioxabicyclo[2.2.1]heptane (12), a protected α-L-LNA guanine nucleoside, has been accomplished using a convergent synthetic strategy starting from 1,2-di-O-acetylfura

Full text of DOI:10.1081/NCN-120022824

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Synthesis of a Base-Protected α-L-LNA Guanine
Nucleoside
Gilles Gaubert a & Jesper Wengel a b
a Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Odense M,
Denmark
b Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej
55, DK-5230, Odense M, Denmark
Version of record first published: 31 Aug 2006.
To cite this article: Gilles Gaubert & Jesper Wengel (2003): Synthesis of a Base-Protected α-L-LNA Guanine Nucleoside,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1155-1157
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1155–1157, 2003
Synthesis of a Base-Protected a-L-LNA Guanine Nucleoside
*
Gilles Gaubert and Jesper Wengel
Nucleic Acid Center, Department of Chemistry, University of Southern
Denmark, Odense M, Denmark
ABSTRACT
Synthesis of (1R,3R,4S,7R)-7-hydroxy-1-hydroxymethyl-3-(2-N-isobutyroylgua-
nin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane (12), a protected a-L-LNA guanine
nucleoside, has been accomplished using a convergent synthetic strategy starting
from 1,2-di-O-acetylfuranose 4.
Key Words: LNA (locked nucleic acids); a-L-LNA; Guanine nucleoside.
The unprecedented thermal stability of duplexes involving LNA[1] (Locked
Nucleic Acid) and a-L-LNA[2] (a-l-ribo configured LNA; adenin-9-yl, 5-methyl-
cytosin-1-yl and thymin-1-yl monomers) has stimulated us to synthesize the guanine
a-L-LNA derivative 12 (Sch. 1).
Coupling between di-O-acetyl-di-O-mesyl furanose 4[2] and per(trimethylsilyl)-
2-N-acetyl-6-O-(diphenylcarbamoyl) guanine[3] afforded stereoselectively the desired
N-9 regioisomer 5 in 59% yield. Treatment of nucleoside 5 with half-saturated
methanolic ammonia gave chemoselectively the O-deacylated derivative 6 in 95%
yield. To accomplish epimerisation at C20, nucleoside 6 was reacted with trifluoro-
methanesulfonic anhydride in a mixture of pyridine and dichloromethane and
*Correspondence: Jesper Wengel, Nucleic Acid Center, Department of Chemistry, University
of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark; Fax: þ45 66 15 87 80;
E-mail: jwe@chem.sdu.dk.
1155
DOI: 10.1081/NCN-120022824
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1156
Gaubert and Wengel
Scheme 1. Reagents and conditions: a) GAc,DPC(SiMe3)2, TMSOTf, toluene, 59%; b) half sat.
NH3, MeOH, 95%; c) 1) Tf2O, pyridine, CH2Cl2, 2) AcOK, 18-crown-6, toluene, 63%; d) half
sat. NH3, MeOH, 96%; e) 1) NaH, THF; 2) AcOK, 18-crown-6, dioxane; f) NH3, MeOH,
i
35%; g) 1) TMSCl, pyridine; 2) Bu2O; 3) NH4OH, 72%; h) HCO2NH4, Pd=C, MeOH, 46%.
subsequently with potassium acetate and 18-crown-6 in toluene to afford the desired
derivative 7 in 46% yield. Selective O-deacylation of 7 using half-saturated methano-
lic ammonia gave in 96% yield nucleoside 8, the C20-epimer of nucleoside 6. Nucleo-
side 8 was treated with sodium hydride in THF to induce cyclization, which was
followed by substitution of the remaining mesyloxy group with an acetate group
by reaction with potassium acetate and 18-crown-6 in dioxane at reflux, affording
the bicyclic nucleoside derivative 9. Complete deacetylation of 9 in saturated metha-
nolic ammonia gave nucleoside 10 in 35% yield (from compound 8). 2-N-Isobutyroyl
protection of 10 was accomplished in 72% yield using transient protection[4] of
the free hydroxy groups followed by acylation of the amine function giving nucleo-
side 11. Debenzylation of this intermediate (ammonium formate, Pd=C, 46% yield)
eventually afforded the desired 2-N-isobutyroyl a-L-LNA guanine nucleoside 12
(Sch. 1).
In spite of many synthetic steps leading to a relatively low overall yield, a via-
ble strategy for the preparation of a a-L-LNA nucleoside of guanine has been
developed.
ACKNOWLEDGMENTS
Exiqon A=S is thanked for financial support.
REFERENCES
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of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclo-
nucleoside monomers, oligomerisation, and unprecedented nucleic acid recogni-
tion. Tetrahedron 1998, 54, 3607 pp.

Base-Protected a-L-LNA Guanine Nucleoside
1157
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