Synthesis of a base-protected xylo-LNA adenine nucleoside

Article abstract of DOI:10.1081/NCN-120022826

Synthesis of (1S,3R,4R,7R)-7-hydroxy-1-hydroxymethyl-3-(6-N-benzoyl-adenin-9-yl)-2, 5-dioxabicyclo[2.2.1]heptane (2), a base-protected xylo-LNA adenine nucleoside, has been accomplished using a convergent synthetic strategy starting from 1,2-di-O-acetylfu

Full text of DOI:10.1081/NCN-120022826

This article was downloaded by: [Florida Atlantic University]
On: 19 November 2014, At: 23:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of a Base-Protected xylo-LNA Adenine
Nucleoside
Torsten Bryld 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, Odense M, DK-5230, Denmark
Published online: 31 Aug 2006.
To cite this article: Torsten Bryld & Jesper Wengel (2003) Synthesis of a Base-Protected xylo-LNA Adenine Nucleoside,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1163-1165, DOI: 10.1081/NCN-120022826
To link to this article: http://dx.doi.org/10.1081/NCN-120022826
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1163–1165, 2003
Synthesis of a Base-Protected xylo-LNA Adenine Nucleoside
*
Torsten Bryld and Jesper Wengel
Nucleic Acid Center, Department of Chemistry, University of Southern
Denmark, Odense M, Denmark
ABSTRACT
Synthesis of (1S,3R,4R,7R)-7-hydroxy-1-hydroxymethyl-3-(6-N-benzoyl-adenin-
9-yl)-2,5-dioxabicyclo[2.2.1]heptane (2), a base-protected xylo-LNA adenine
nucleoside, has been accomplished using a convergent synthetic strategy starting
from 1,2-di-O-acetylfuranose 3.
Key Words: LNA (locked nucleic acid); xylo-LNA; Xylonucleoside.
Synthesis of the xylo-LNA thymine nucleoside 1 has been previously reported.[1–3]
Incorporation of nucleoside 1 into oligodeoxynucleotides induced lowered affinity for
a partly modified xylo-LNA=DNA oligonucleotide, but enhanced affinity for a fully
modified xylo-LNA oligonucleotide. Herein we present our efforts towards synthesis
of the xylo-LNA adenine nucleoside 2.
*Correspondence: Jesper Wengel, Nucleic Acid Center, Department of Chemistry, University
of Southern Denmark, Campusvej 55, Odense M DK-5230, Denmark; Fax: þ45 66 15 87 80;
E-mail: jwe@chem.sdu.dk.
1163
DOI: 10.1081/NCN-120022826
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1164
Bryld and Wengel
Scheme 1. i) ABz, SnCl4, CH3CN (52%) or ABz, TMS-triflate, BSA, CH3CN (43%); ii) 50%
sat. NH3 in MeOH (85%); iii) TBDMSCl, imidazole, DMF (72%); iv) sat. NH3 in MeOH
(94%); v) a) TMSCl, pyridine, b) BzCl, pyridine, c) 10% sat. aq. NH3 in MeOH; vi) MsCl,
pyridine (79% from 7); vii) TBAF, THF (87%); viii) NaH, DMF (83%); ix) KOH, EtOH
(90%); x) H2, 10% Pd=C, EtOH (76%); xi) a) TMSCl, pyridine, b) BzCl, pyridine, c) 16%
sat. NH3 in H2O (81%).
The known furanose 3[3] was subjected to base coupling with 6-N-benzoylated
adenine under various conditions. Standard Vorbruggen conditions (TMS-triflate,
¨
BSA) required heating for several hours and yielded both the N7- and the N9-iso-
mers of nucleoside 4. A better 52% yield, shorter reaction time, and regioselective
formation of the N9-isomer were the results when using SnCl4 instead of BSA and
TMS-triflate.
A series of protection group manipulations (see Sch. 1) was performed in order
to obtain selective introduction of mesyl groups at the two primary hydroxy groups
and a free hydroxy group at the 20-position (nucleoside 10). Base-induced ring
closure yielded the bicyclic nucleoside 11, which was deprotected to give the unpro-
tected nucleoside 13. Eventually, the benzoyl group was reintroduced at the N6-
position of the adenine moiety.
In spite of many synthetic steps leading to a relatively low overall yield, a viable
strategy for the preparation of the 6-N-benzoyl-protected xylo-LNA nucleoside of
adenine has been developed. We are currently studying the synthesis and properties
of adenine-containing xylo-configured oligonucleotides.
ACKNOWLEDGMENTS
The Danish National Research Foundation and The Danish Research Agency
are thanked for financial support.
REFERENCES
˚
1. Rajwanshi, V.K.; Hakansson, A.E.; Dahl, B.M.; Wengel, J. LNA stereoisomers:
xylo-LNA (b-d-xylo configured locked nucleic acid) and a-l-LNA (a-l-ribo con-
figured locked nucleic acid). Chem. Commun. 1999, 1395 pp.

Base-Protected xylo-LNA Adenine Nucleoside
1165
˚
2. Rajwanshi, V.K.; Hakansson, A.E.; Kumar, R.; Wengel, J. High-affinity nucleic
acid recognition using ‘LNA’ (locked nucleic acid, b-d-ribo configured LNA),
‘xylo-LNA’ (b-d-xylo configured LNA) or ‘a-l-LNA’ (a-l-ribo configured
LNA). Chem. Commun. 1999, 2073 pp.
3. Rajwanshi, V.K.; Kumar, R.; Kofoed-Hansen, M.; Wengel, J. Synthesis and
restricted furanose conformations of three novel bicyclic thymine nucleosides:
a xylo-LNA nucleoside, a 30-O,50-C-methylene-linked nucleoside, and a 20-O,50-
C-methylene-linked nucleoside. J. Chem. Soc., Perkin-Trans. 1 1999, 1407 pp.