Oxidative transformations of nucleoside fluorenemethyl H-phosphonoselenoate diesters

Article abstract of DOI:10.1081/NCN-200060173

9-Fluorenemethyl H-phosphonoselenoate monoester has been used to produce thymidine 3′-O-phosphoroselenoate monoester from which various P(V) derivatives containing multiple modifications at phosphorus were obtained; e.g., thymidine 3′-O-phosphoroselenoflu

Full text of DOI:10.1081/NCN-200060173

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OXIDATIVE TRANSFORMATIONS OF NUCLEOSIDE
FLUORENEMETHYL H-PHOSPHONOSELENOATE DIESTERS
Martin Kullberg a & Jacek Stawinski a b
a Department of Organic Chemistry, Arrhenius Laboratory , Stockholm University ,
Stockholm, Sweden
b Institute of Bioorganic Chemistry, Polish Academy of Sciences , Poznan, Poland
Published online: 15 Nov 2011.
To cite this article: Martin Kullberg & Jacek Stawinski (2005) OXIDATIVE TRANSFORMATIONS OF NUCLEOSIDE
FLUORENEMETHYL H-PHOSPHONOSELENOATE DIESTERS, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 659-661, DOI:
10.1081/NCN-200060173
To link to this article: http://dx.doi.org/10.1081/NCN-200060173
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):659–661, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060173
OXIDATIVE TRANSFORMATIONS OF NUCLEOSIDE FLUORENEMETHYL
H-PHOSPHONOSELENOATE DIESTERS
5
Martin Kullberg
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Stockholm, Sweden
5
Jacek Stawinski
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Stockholm, Sweden and Institute of Bioorganic Chemistry, Polish Academy of
Sciences, Poznan, Poland
5
9-Fluorenemethyl H-phosphonoselenoate monoester has been used to produce thymidine 3’-O-
phosphoroselenoate monoester from which various P(V) derivatives containing multiple modifications at
phosphorus were obtained; e.g., thymidine 3’-O-phosphoroselenofluoridate, 3’-O-phosphoroselenothioate,
or 3’-O-phosphorodiselenoate monoesters.
INTRODUCTION
We have previously reported on the use of 9-fluorenemethyl H-phosphono-
selenoate monoester as a useful reagent for transferring of an H-phosphonosele-
noate moiety[1] to nucleosides. In this article, we expand the uses of
9-fluorenemethyl H-phosphonoselenoate monoester by performing several oxida-
tive transformations on the intermediate nucleoside fluorenemethyl H-phosphono-
selenoate diester 1 prior to the removal of the fluorenemethyl protecting group.
This gives access to several novel phosphoroselenoate monoesters.
RESULTS AND DISCUSSION
The nucleoside fluorenemethyl H-phosphonoselenoate diester 1 is easily
available through previously published procedures.[1] The most basic oxidative
transformation is oxidation of 1 into the corresponding phosphoroselenoate diester
3. By performing this reaction using standard protocol developed for H-
phosphonate diesters[2] a significant deselenization occurred, even with equimolar
Financial support from the Swedish Research Council is gratefully acknowledged.
Address correspondence to Jacek Stawinski, Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Noskowskiego 12/14, Poznan 61-704, Poland.
659
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660
M. Kullberg and J. Stawinski
amounts of iodine used. However, when the reaction was run in MeCN with iodine
(1 eq), pyridine (20 eq), and water (60 eq), the deselenization of the product could
be almost completely suppressed. Changing from iodine to carbon tetrachloride as
an oxidizing agent simplified further the synthetic protocol. The reaction with CCl4
(10 eq), pyridine (20 eq), and water (60 eq) in MeCN resulted in clean and fast
(15 min) formation of the desired phosphoroselenochloridate 2, which upon
hydrolysis afforded product 3 in isolated yield of 80%.
Deprotection of diester 3 to produce monoester 4 using the protocol
developed for the sulfur analogue[3] that involved treatment with aqueous ammonia
was accompanied by severe side products formation. It was found that the cleanest
deprotection of 3 could be achieved by using TMS-Cl (10 eq) and TEA (20 eq) in
pyridine (10 min). Under such conditions, 4 was the only observable product and it
was isolated in 96% yield by precipitation from diethyl ether. The obtained
phosphoroselenoate monoester 4 was, however, unstable in aqueous solution and
loses selenium within hours, in contrast to the corresponding diesters of type 3,
which were much more stable (Scheme 1).
The intermediate phosphoroselenochloridate 2 can also be treated with 1 eq
triethylammonium trishydrofluoride (TAF) to produce fast (5 min) and quan-
titatively (31P NMR) the corresponding phosphoroselenofluoridate 5. Crude 5
could easily be deprotected using TEA (10 eq) in pyridine and the monoester 6 was
isolated in 93% yield.
The diastereoisomers of 1 could easily be separated by flash column
chromatography and their sulfurization gave rise to novel phosphate monoester
analogues, phosphoroselenothioates, with a chiral phosphorus center. Sulfurization
of 1 with elemental sulfur (3 eq) and pyridine (20 eq) in MeCN was uneventful and
SCHEME 1 Oxidative transformations of nucleoside fluorenemethyl H-phosphonoselenoate diesters.

M. Kullberg and J. Stawinski
661
yielded within 20 min the diesters 7a and 7b essentially quantitatively (31P NMR;
isolated yields ca 90%).
The deprotection of diesters 7a and 7b using aqueous conditions turned out to
be a difficult task. Changing to anhydrous conditions with thiophenol and triethyl
amine gave the desired monoesters 8a and 8b, but the reaction was slow (2 h) and
side products were formed over time. However, using piperidine (20 eq) in
pyridine furnished clean formation of the desired products. The produced am-
monium salts of 8a and 8b were somewhat unstable, but titration of the salts with
DBU stabilized the products sufficiently to permit their isolation and characteri-
zation. These monoesters were, however, even more prone to degradation than
phosphoroselenoate 4 and in the presence of air or moisture, compound 8
decomposed within hours.
Selenization of 1 turned out to be less straightforward than sulfurization
because using elemental selenium and pyridine in MeCN gave slow conversion
and some by-products formation. Changing to KSeCN as a selenizing agent gave a
somewhat faster reaction, but formation of side products was not completely
suppressed. Attempts to use triphenyl phosphine selenide or triphenyl phosphor-
oselenoates gave no formation of the desired product. The best results were
obtained with selenization of 1 with 1.1 eq of 3H-1,2-benzothiaselenol-3-one[4]
(BTSe) and 20 eq of pyridine in MeCN. This gave clean and fast (5 min) formation
of diselenoate 9, which upon treatment with piperidine (20 eq) afforded monoester
10 (31P NMR). Unfortunately, phosphorodiselenoate 10 was too unstable to allow
its isolation and more detailed characterization.
CONCLUSION
Nucleoside 9-fluorenemethyl H-phosphonoselenoate monoester 1 was found to
be a convenient starting material for the preparation of various P(V) derivatives with
multiple modifications at the phosphorus center. By oxidative transformations of 1,
several novel selenium-containing nucleotide analogues have been synthesized.
REFERENCES
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H-phosphonoselenoate group. Nucleosides Nucleotides Nucleic Acids 2003, 22, 1463–1465.
2. Garegg, P.J.; Regberg, T.; Stawinski, J.; Str¨omberg, R. Studies on the oxidation of nucleoside
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reagent for the preparation of H-phosphonothioate, phosphorothioate, and phosphorodithioate monoesters.
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phosphorothioselenoates via stereospecific selenization of the corresponding H-phosphonate and H-phospho-
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