Bi- and tricyclic nucleoside derivatives restricted in S-type conformations and obtained by RCM-reactions

Article abstract of DOI:10.1081/NCN-120022619

Ring-closing metathesis (RCM) is applied as a new and powerful technology in the construction of nucleoside analogues that are conformationally restricted in S-type conformations due to additional 3′,4′- and/or 3′,5′-linkages.

Full text of DOI:10.1081/NCN-120022619

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Bi- and Tricyclic Nucleoside Derivatives Restricted in S-
Type Conformations and Obtained by RCM-Reactions
Nanna Albæk a , Jacob Ravn a , Morten Freitag a , Helena Thomasen a , Nanna K. Christensen
a , Michael Petersen a & Poul Nielsen a b
a Nucleic Acid Center , Department of Chemistry , University of Southern Denmark , Odense
M, Denmark
b The Panum Institute, University of Copenhagen , Blegdamsvej 3, Copenhagen, DK-2200,
Denmark
Published online: 31 Aug 2006.
To cite this article: Nanna Albæk , Jacob Ravn , Morten Freitag , Helena Thomasen , Nanna K. Christensen , Michael Petersen
& Poul Nielsen (2003) Bi- and Tricyclic Nucleoside Derivatives Restricted in S-Type Conformations and Obtained by RCM-
Reactions, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 723-725, DOI: 10.1081/NCN-120022619
To link to this article: http://dx.doi.org/10.1081/NCN-120022619
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 723–725, 2003
Bi- and Tricyclic Nucleoside Derivatives Restricted
in S-Type Conformations and Obtained
by RCM-Reactions
Nanna Albæk, Jacob Ravn, Morten Freitag, Helena Thomasen,
*
Nanna K. Christensen, Michael Petersen, and Poul Nielsen
Nucleic Acid Center, Department of Chemistry, University of
Southern Denmark, Odense M, Denmark
ABSTRACT
Ring-closing metathesis (RCM) is applied as a new and powerful technology in
the construction of nucleoside analogues that are conformationally restricted in
S-type conformations due to additional 30,40- and=or 30,50-linkages.
Key Words: Conformational restriction; Nucleosides; Ring-closing metathesis.
Nucleic acid analogues that are strongly conformationally restricted due to bi-
or tricyclic nucleoside monomers have been introduced as potentially therapeutic
and diagnostic agents.[1,2] LNA (Locked Nucleic Acid) is a nucleic acid analogue
that displays unprecedented recognition of both DNA and RNA due to the bicyclic
nucleoside monomers being perfect N-type conformational mimics.[3,4] Among
several examples of S-type mimics,[1,2,5] however, the perfect one has not been
obtained. We have recently applied the RCM-reaction (and the catalyst 1, Sch. 1)[6]
*Correspondence: Poul Nielsen, The Panum Institute, University of Copenhagen, Blegdams-
vej 3, DK-2200 Copenhagen, Denmark; Fax: +45 35 39 60 42; E-mail: pen@imbg.ku.dk.
723
DOI: 10.1081/NCN-120022619
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

724
Albæk et al.
Scheme 1. a) n ¼ 0: ref. 7.; n¼1: five similar steps, 70%; b) n ¼ 0: ref. 7; n ¼ 1: six similar steps,
43%; c) i. (Im)2CS, CH3CN, toluene; ii. Bu3SnH, AIBN, CH3CN, 61%; d) H2, Pd(OH)2-C,
EtOH, 75%; e) OsO4, NMO, THF, H2O, 52%; f) i. NaOMe, MeOH; ii. H2, Pd(OH)2-C,
MeOH, 71%. T ¼ thymin-1-yl.
as an efficient tool in the construction of new bi- and tricyclic nucleosides.[7–9] Here,
we present the recent synthetic results towards nucleosides that are restricted in S-
type conformations.
As a very convenient general starting material, diacetone-a-D-glucose has been
used as a skeleton for the incorporation of terminal double bonds as demonstrated in
the construction of 2,[7] 3 and 4[9] via stereoselective Grignard reactions. After RCM-
reactions and subsequent Vorbruggen nucleobase couplings, 5[7] and 6 have been
¨
obtained in high yields. The former has been used in an improved preparation of
the well known bicycloDNA monomer 7[5] as well as in the construction of a tricyclic
nucleoside derivative 8.[8] Also 4 has been transformed through standard steps to a
nucleoside 9 and subsequently used in a very efficient RCM-reaction to afford the
bicyclic nucleoside 10.[9] This nucleoside has been used as a substrate for a dihydroxy-
lation reaction giving, after deprotection, only one major product 11 as an example
of a strongly conformationally restricted poly-hydroxylated bicyclic nucleoside. The
1
configuration of 11 has been determined using Karplus equations and H NMR in
connection to ab initio calculations.
ACKNOWLEDGMENT
The Nucleic Acid Center is funded by the Danish National Research Founda-
tion for the studies on nucleic acid chemical biology.

Restricted Bi- and Tricyclic Nucleoside Derivatives
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725
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