Preparation of 3′-C-branched uridine analogues, suitable for conversion into functionalised 3′-C-methylene derivatives

Article abstract of DOI:10.1081/NCN-100002562

A novel method for preparation of 1-[2- O-(tert-butyldimethylsilyl)-3-deoxy-3- C-hydroxymethyl-5-O-monomethoxytrityl-β-D-ribo-pentofuranosyl]uracil by hydroboration of corresponding 3′-deoxy-3′ -C-methyleneuridine derivative has been developed. Further conversion of the hydroxyl function into different leaving groups was carried out to afford derivatives suitable for conversion into various 3′-C-branched uridine analogues through substitution.

Full text of DOI:10.1081/NCN-100002562

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PREPARATION OF 3′-C-BRANCHED URIDINE
ANALOGUES, SUITABLE FOR CONVERSION INTO
FUNCTIONALISED 3′-C-METHYLENE DERIVATIVES
Anna Winqvist a & Roger Strömberg b
a Department of Organic Chemistry , Arrhenius Laboratory, Stockholm University ,
Stockholm, SE-106 91, Sweden
b Division of Organic and Bioorganic Chemistry, MBB , Scheele Laboratory, Karolinska
Institutet , Stockholm, SE-171 77, Sweden
Published online: 07 Feb 2007.
To cite this article: Anna Winqvist & Roger Strömberg (2001) PREPARATION OF 3′-C-BRANCHED URIDINE ANALOGUES,
SUITABLE FOR CONVERSION INTO FUNCTIONALISED 3′-C-METHYLENE DERIVATIVES, Nucleosides, Nucleotides and Nucleic
Acids, 20:4-7, 1389-1392, DOI: 10.1081/NCN-100002562
To link to this article: http://dx.doi.org/10.1081/NCN-100002562
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1389–1392 (2001)
PREPARATION OF 3ꢀ-C-BRANCHED URIDINE
ANALOGUES, SUITABLE FOR CONVERSION
INTO FUNCTIONALISED 3ꢀ-C-METHYLENE
DERIVATIVES
Anna Winqvist1,2 and Roger Stro¨mberg2,∗
1Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University, SE-106 91 Stockholm, Sweden
2Division of Organic and Bioorganic Chemistry, MBB, Scheele
Laboratory, Karolinska Institutet, SE-171 77 Stockholm, Sweden
ABSTRACT
A novel method for preparation of 1-[2-O-(tert-butyldimethylsilyl)-3-deoxy-3-
C-hydroxymethyl-5-O-monomethoxytrityl-β-D-ribo-pentofuranosyl]uracil by
hydroborationofcorresponding3ꢀ-deoxy-3ꢀ-C-methyleneuridinederivativehas
been developed. Further conversion of the hydroxyl function into different
leaving groups was carried out to afford derivatives suitable for conversion into
various 3ꢀ-C-branched uridine analogues through substitution.
INTRODUCTION
In the design of new potential antisense oligonucleotide analogues, resistance
to nucleases and enhanced hybridisation affinity to the complementary RNA has
to be considered. 3ꢀ-C-branched analogues containing internucleoside amide link-
ages (1,2,3,4,5) and methylene methylimino linkages (6,7) have shown promising
properties. Most investigations so far concern oligodeoxynucleotide analogues, and
to some extent 2ꢀ-O-alkyl derivatives (8,9,10), but only little has been done with
oligonucleotide analogues having 2ꢀ-hydroxyl functions and 3ꢀ-C-branched inter-
nucleoside linkages (11,12). Further investigations in this field would be aided by
∗Corresponding author.
1389
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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WINQVIST AND STROMBERG
1390
a concise method for synthesis of 3ꢀ-C-branched nucleoside analogues, which can
serve as precursors for the preparation of differently functionalised 3ꢀ-C-methylene
derivatives. Synthesis of a uridine analogue having the 3ꢀ-hydroxyl function re-
placed by a hydroxymethyl group, and further conversion into the corresponding
mesylate, iodo derivative and bromo derivative, is presented here.
RESULTS AND DISCUSSION
3ꢀ-C-branching of 2ꢀ-O-(tert-butyldimethylsilyl)-5ꢀ-O-monomethoxytritylu-
ridine (13) (1) was achieved by oxidation/Wittig reactions followed by hy-
droboration. Oxidation of 1 was carried out using a mixture of CrO3/acetic
anhydride/pyridine in CH2Cl2 to give 1-[2-O-(tert-butyldimethylsilyl)-5-O-
monomethoxytrityl-β-D-erythro-pentofuran-3-ulosyl]uracil (2). Wittig reaction
of 2 using methyltriphenylphosphonium bromide and n-butyl lithium in THF
afforded 1-[2-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-methylene-5-O-monome-
thoxytrityl-β-D-erythro-pentofuranosyl]uracil (3). Subsequent hydroboration using
•
9-BBN in hexane, followed by oxidative treatment with NaBO3 4H2O resulted in

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3ꢀ-C-BRANCHED URIDINE ANALOGUES
1391
twostereoisomers;1-[2-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-
5-O-monomethoxytrityl-β-D-ribo-pentofuranosyl]uracil (4) and 1-[2-O-(tert-but-
yldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-5-O-monomethoxytrityl-β-D-xylo-
pentofuranosyl]uracil. The ribo-isomer 4 was isolated from the mixture by silica
gel column chromatography to give isomerically pure 4 in a yield of 64%.
Conversion of the hydroxyl function of 3 into a leaving group gives a deriva-
tive, which allow for further functionalisation through substitution. Such derivatives
are valuable as intermediates in the synthesis of various 3ꢀ-C-branched uridine ana-
logues. To cover the requirement of different leaving groups for the nucleophiles
that might be used, mesylate 4a, iodo derivative 4b, and bromo derivative 4c, were
prepared.
CONCLUSIONS
We have developed a novel method for preparation of a 3ꢀ-deoxy-3ꢀ-C-hydro-
xymethyluridine derivative suitable for further conversion of the hydroxyl function
into a leaving group. Since different nucleophiles can be used for substitution, me-
sylate 4a, iodo derivative 4b and bromo derivative 4c are valuable intermediates in
the synthesis of various 3ꢀ-C-branched uridine analogues. A detailed description on
the synthesis of 1-[3-deoxy-3-C-hydroxymethyl-β-D-ribo-pentofuranosyl]uracil
derivatives, and investigation of the influence of reagents and solvents on the stere-
oselectivity, will be published elsewhere. The use of the above methodology in the
synthesis of some 3ꢀ-C-branched nucleoside analogues is now in progress.
ACKNOWLEDGMENTS
We thank the Swedish Natural Science Research Council and the Swedish
Research Council for Engineering Sciences for financial support.
REFERENCES
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