Synthesis of P-fluorodithioacids of phosphorus and their synthetic application

Article abstract of DOI:10.1080/10426500212294

Oligonucleotides containing 3′-S-P(S) and 5′-S-P(S) fragments in the deoxy-series are available only by tedious multistep procedures. We have developed a novel and efficient methodology based on ring opening of anhydronucleosides by phosphorus dithioacids

Full text of DOI:10.1080/10426500212294

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of P-Fluorodithioacids of Phosphorus and
Their Synthetic Application
Izabela Tworowska a , Wojciech Dabkowski a & Jan Michalski a
a Centre of Molecular and Macromolecular Studies , Polish Academy of Sciences , 90-363
Łódź, Sienkiewicza 112, Poland
Published online: 27 Oct 2010.
To cite this article: Izabela Tworowska , Wojciech Dabkowski & Jan Michalski (2002) Synthesis of P-Fluorodithioacids of
Phosphorus and Their Synthetic Application, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:6-7, 1855-1858,
DOI: 10.1080/10426500212294
To link to this article: http://dx.doi.org/10.1080/10426500212294
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1855–1858
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DOI: 10.1080/10426500290093298
SYNTHESIS OF P-FLUORODITHIOACIDS OF
PHOSPHORUS AND THEIR SYNTHETIC
APPLICATION
Izabela Tworowska, Wojciech Dabkowski, and Jan Michalski
Centre of Molecular and Macromolecular Studies, Polish
Academy of Sciences, 90-363Lo´dz´, Sienkiewicza 112, Poland
(Received July 29, 2001; accepted December 25, 2001)
Oligonucleotides containing 30-S-P(S) and 50-S-P(S) fragments in the
deoxy-series are available only by tedious multistep procedures. We have
developed a novel and efficient methodology based on ring opening of
anhydronucleosides by phosphorus dithioacids. This approach allows
efficient synthesis of modified dinucleotides of the ribo-series.
Keywords: 1,3,2-Dithiaphospholane method; anhydronucleosides;
phosphorodithioic acids; thionucleotides
INTRODUCTION
The rapid development of antisense chemotherapy1 and studies to elu-
cidate the mechanism of rybozyme action2 have encouraged organic
chemists to undertake the synthesis of oligonucleotide analogues in
which the sugar residues and internucleotide linkages are modified.
Interest in oligonucleotides containing 30-S- or 50-S-phosphorothioate
linkages has recently increased. These compounds have been prepared
1) via nucleophilic displacement of 30-iodo-, 50-tosyl-, or 50-bromo-50-
deoxynucleosides by nucleoside 30-phosphorothioates,3 2) via phospho-
roamidide chemistry,4 3) via Michaelisa-Arbusov reaction between a
nucleosid-50-yl phosphite and a nucleosid-30-yl-S-disulfide.5 Methods
presented to date, though elegant, are laborious and difficult to carry
out.3 6 For this reason we have sought an alternative strategy avoiding
30-S- or 50-S-thionucleosides. Our long-standing interest in the chem-
istry of modified nucleotides containing P F bond also stimulated this
Address correspondence to J. Michalski, Center of Molecular and Macromolecular
Studies, Polish Academy of Sciences, 90-363 Lo´dz´, Sienkiewicza 112, Poland. E-mail:
jmich@bilbo.cbmm.lodz.pl
1855

1856
I. Tworowska et al.
work.7 It is known that readily available 2,30-anhydrothymidine reacts
with a variety of nucleophiles, usually under harsh conditions.8 Our
laboratory has been involved in the design and synthesis of modified
nucleotides, with the fluorine ligand attached to a tetracoordinate or
tricoordinate phosphorus center. Continuing our efforts to explore this
field, we report a new synthesis of nucleosidyl phosphorodithioates in
both DNA and RNA series. Our approach is based on the reaction of
anhydronucleosides with a variety of phosphorofluoridodithioic acids.9
Efficient synthesis of the latter is based on 1,3,2-dithiaphospholane
derivatives, which are known to undergo facile ring opening by nucle-
ophilic reagents.10
RESULTS AND DISCUSSION
Compound 1 was prepared from 1,2-ethanediol and diisopropylphos-
phoramidous dichloride and allowed to react with a nucleoside in the
presence of trimethylchlorosilane (TMCS),11 yielding the nucleosidyl-
O-(1,3,2-dithiaphospholane) 2. The latter was sulfurized by elemental
sulfur to give compound 3. The crucial step leading to the derived phos-
phorofluoridodithioates 4 is the reaction with tetra-butylammonium flu-
oride (TBAF). All reactions presented in Scheme 1 proceed in very high
yield. Yields of the final products exceeded 95%. This strategy allowed
us to prepare a number of novel organic structures and can also be
extended to analogues of 4 containing a P Se group.
SCHEME 1
The reaction proceeds in THF solution at room temperature. While
methods used previously are less suitable, ours gives easy access to this
class of compounds and opens a door to the study of their interesting
chemistry.

Synthesis of P-Fluorodithioacids of Phosphorus
1857
Having such excellent access to phosphorofluoridodithioic acids, we
used them in reactions with anhydronucleosides in both DNA and RNA
series. Scheme 2 illustrates opportunities connected with our strategy.
SCHEME 2
Ring opening reactions proceed at ambient temperature in over 95%
yield. The expected inversion of configuration at 30- or 20-carbon atoms
was observed in all our experiments. The dinucleotides 5, 7, obtained
from 4a or 6, are formed as a 1:1 mixture of diastereoisomers and can
be purified by silica gel chromatography. As expected, they are rela-
tively stable towards nucleophilic reactions. The special feature of this
ring opening is the high rate of the reaction with free dithioic acid and
the sluggish reaction rate with their salts. This means that protona-
tion is vital to form a good leaving group. The dithioic acids were pre-
pared in situ by treating their salts with excess of p-toluenesulfonic acid
monohydrate. The low nucleophilicity of sulfonic acids is well known.
Water introduced in this way does not interfere with the ring open-
ing reaction but effects the removal of acid sensitive protective groups.
We are currently exploring the use of anhydronucleoside to construct

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I. Tworowska et al.
FIGURE 1
analogues of oligonucleotides containing phosphorothiolate linkages by
this methodology in the RNA series. The representative example (see
Figure 1) is the synthesis of dithymidine-20-S-phosphorodithioate per-
formed in very high yield and purity.
In conclusion, our approach proves to be generally applicable to var-
ious classes phosphorus dithioacids and anhydronucleosides.
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