Aryl nucleoside h-phosphonates as a tool for investigation of stereospecificity during coupling

Article abstract of DOI:10.1081/NCN-200059239

It was found that in stereoselective condensations of ribonucleoside 3′-H-phosphonates with alcohols, the major diastereomer of the produced H-phosphonate diesters is formed from the minor diastereomer of the intermediate phosphonic-pivalic anhydride. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200059239

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ARYL NUCLEOSIDE H-PHOSPHONATES AS A TOOL
FOR INVESTIGATION OF STEREOSPECIFICITY DURING
COUPLING
Michal Sobkowski a , Jadwiga Jankowska a , Jacek Stawinski b & Adam Kraszewski a
a Institute of Bioorganic Chemistry, Polish Academy of Sciences , Poznan, Poland
b Department of Organic Chemistry, Arrhenius Laboratory , Stockholm University ,
Stockholm, Sweden
Published online: 15 Nov 2011.
To cite this article: Michal Sobkowski , Jadwiga Jankowska , Jacek Stawinski & Adam Kraszewski (2005) ARYL NUCLEOSIDE
H-PHOSPHONATES AS A TOOL FOR INVESTIGATION OF STEREOSPECIFICITY DURING COUPLING, Nucleosides, Nucleotides and
Nucleic Acids, 24:5-7, 887-890, DOI: 10.1081/NCN-200059239
To link to this article: http://dx.doi.org/10.1081/NCN-200059239
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):887–890, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059239
ARYL NUCLEOSIDE H-PHOSPHONATES AS A TOOL FOR
INVESTIGATION OF STEREOSPECIFICITY DURING COUPLING
5
Michal Sobkowski and Jadwiga Jankowska
Institute of Bioorganic Chemistry,
Polish Academy of Sciences, Poznan, Poland
5
Jacek Stawinski
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Stockholm, Sweden
5
Adam Kraszewski
Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Poznan, Poland
5
It was found that in stereoselective condensations of ribonucleoside 3’-H-phosphonates with alcohols,
the major diastereomer of the produced H-phosphonate diesters is formed from the minor diastereomer of
the intermediate phosphonic-pivalic anhydride.
Keywords H-phosphonates, Stereospecific Coupling, 31P NMR Spectroscopy
INTRODUCTION
During condensations of ribonucleoside H-phosphonate monoesters with
nucleosides the formation of SP diastereomers is favored, and thus the reaction is
noticeably stereoselective.[1,2] This stereoselectivity was found to be dependent
mainly on the nature of reacting H-phosphonate (e.g., kind of a nucleobase and
base and sugar protecting groups), and on the solvent composition.[1,2]
To find possible sources of the observed stereoselectivity, we investigated the
stereochemical aspects of the activation of H-phosphonate monoesters and
reactivity of the produced intermediates.
RESULTS AND DISCUSSION
The reaction of nucleoside H-phosphonates with pivaloyl chloride yields mixed
anhydrides,[3,4] which, due to chirality at the phosphorus center, exist as a mixture
The financial support from the state Committee for Scientific Research, Republic of Poland, and the Swedish
Research Council, is gratefully acknowledged.
Address correspondence to Michal Sobkowski, Institute of Bioorganic Chemistry, Polish Academy of
Sciences, Noskowskiego 12/14 61-704, Poznan, Poland; E-mail: msob@ibch.poznan.pl
887
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M. Sobkowski et al.
of two diastereoisomers. Since mixed anhydrides are extremely reactive species, it
is not possible to isolate them or to assign their configuration at the phosphorus
centre directly.
In the case of activation of 5’-O-dimethoxytrityl-2’-O-t-butyldimethylsilyl-uridin-
3’-yl H-phosphonate 1 (abbreviated as dmtUPH throughout the text) the ratio of
diastereomers of mixed anhydride 2 is usually ca. 2:1. Upon the reaction with
ethanol, these afforded two diastereomeric H-phosphonate diesters 3 in the 4:1
ratio. The configuration of the major diastereomer of 3 (resonating in 31P NMR at
lower field) was assigned as SP,[1,2] however, it was not known from which
diastereomer of the mixed anhydride 2, A (major) or B (minor), it was formed
(Figure 1).
Since the ratio of the formed H-phosphonate diesters 3 was different from that
of the mixed anhydride 2, one diastereomer of this compound, A or B, evidently
reacted faster than the other one. In addition, A and B diastereomers have to exist
in a rapid equilibrium to regenerate the more reactive species. For mixed
anhydride 2 this equilibrium was apparently significantly faster than the reaction
with ethanol, and thus it was difficult to find out from which diastereomer of 2, the
major diastereomer of 3 was formed and, in consequence, to assign the absolute
configuration to A and B. However, our earlier work on the less-reactive aryl
nucleoside H-phosphonates[5,6] suggested that these H-phosphonate derivatives
could be helpful in the present studies.
To this end, phenyl (4a), p-chlorophenyl (4b), and p-nitrophenyl (4c) uridine
H-phosphonates were reacted with ethanol and progress of these reactions was
followed by 31P NMR spectroscopy (Figure 2).
The reaction of phenyl derivative 4a (Figure 2, panel A) was very slow and
required a few days to reach completion. During this period the product 3a partly
FIGURE 1 31P NMR spectra of the reaction of mixed anhydride 2 with ethanol in methylene chloride
containing 3 equiv. of pyridine; (a) after addition of 0.1 equiv. of ethanol (b) after addition of another 2 equiv.
of ethanol.

M. Sobkowski et al.
889
FIGURE 2 31P NMR spectra of the reactions of aryl nucleoside H-phosphonates 4a--4c with ethanol; (A)
reaction of 4a, (B) reaction of 4b, (C) reaction of 4c.
decomposed, making integration of the signals difficult. However, investigation of
this reaction at the earlier stages indicated that there was no significant changes in
the ratios of diastereomers of the starting material 4a and that of the produced
H-phosphonate 3. This was also true for the more reactive p-chlorophenyl H-
phosphonate 4b (Figure 2, panel B), and indicated that under the reaction

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conditions the equilibria between diastereomers of aryl H-phosphonates 4a and 4b
were faster than the reactions with ethanol, although the minor diastereomers of
these compounds seemed to react slightly faster.
Clear-cut results were obtained, however, for the most reactive p-nitrophenyl
H-phosphonate 4c. For this compound, the minor diastereomer disappeared
within a few minutes upon addition of ethanol, and the ratio of diastereomers of
the product 3 underwent gradual changes during the course of the reaction from
the initial value of ca. 2:1, to 1:1 at the end of the reaction (Figure 2, panel C).
On the basis of these experiments, we could conclude that in these reactions
the major diastereomer of product 3 was formed from the minor diastereomer of
the starting materials 4a--4c. Thus, assuming the SP configuration of the major
diastereomer of the product 3, one can assign SP configuration* to the minor, more
reactive diastereomer of 4 (high-field signal in the 31P NMR spectra) and RP
configuration to the main diastereomers of nucleoside aryl H-phosphonates 4 (low-
field signal in the 31P NMR spectra). Considering a similar type of reactivity and a
similar product distribution in condensations promoted by acyl chlorides, we
believe that this assignment can be extended to the mixed phosphonic-carboxylic
anhydrides. Thus, for phosphonic-pivalic mixed anhydride 2, we tentatively
assigned RP configuration to the diastereomer A (resonating at lower field in the 31P
NMR) and SP configuration to the isomer B7 (resonating at higher field in 31P
NMR) (Figure 1).
REFERENCES
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stereospecific sulfurization of H-phosphonate diesters. J. Org. Chem. 1992, 57(23), 6163–6169.
2. Almer, H.; Stawinski, J.; Stro¨mberg, R. Solid support synthesis of all-Rp-oligo(ribonucleoside phosphor-
othioate)s. Nucleic Acids Res. 1996, 24(19), 3811–3820.
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hydrogenophosphonate diester formation using acyl chlorides as coupling agents in oligonucleotide synthesis
by the hydrogenophosphonate approach. Nucleosides Nucleotides 1987, 6(3), 655–662.
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convert H-phosphonate mono- or diesters of nucleic acids into valuable phosphate di- or triesters. Recl. Trav.
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5. Cieslak, J.; Szymczak, M.; Wenska, M.; Stawinski, J.; Kraszewski, A. Aryl H-phosphonates. Part 11. Synthetic
and P-31 NMR studies on the formation of aryl nucleoside H-phosphonates. J. Chem. Soc., Perkin Trans. 1
1999 (22), 3327–3331.
6. Stawinski, J.; Kraszewski, A. How to get the most out of two phosphorus chemistries. Studies on H-
phosphonates. Acc. Chem. Res. 2002, 35(11), 952–960.
*This esterification reaction is assumed to proceed with inversion of configuration [SN2(P)], however
according to CIP rules, the priority of substituents simultaneously changes, so the substrate for the main product
diastereomer should also have the configuration noted SP.