Unusual stereochemistry of esterification of uridine 3'-H-phosphonothioate

Article abstract of DOI:10.1080/10426507.2010.503212

According to ³¹P-NMR correlation analysis, reactive derivatives of uridine 3'-Hphosphonothioate react with O-nucleophiles, probably with retention of configuration. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.503212

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Phosphorus, Sulfur, and Silicon and the
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Unusual Stereochemistry of
Esterification of Uridine 3′-H-
Phosphonothioate
Michał Sobkowski a , Jadwiga Jankowska a , Jacek Stawiński a b
&
Adam Kraszewski a
a Institute of Bioorganic Chemistry , Polish Academy of Sciences ,
Poznań , Poland
b Department of Organic Chemistry, Arrhenius Laboratory ,
Stockholm University , Sweden
Published online: 25 Apr 2011.
To cite this article: Michał Sobkowski , Jadwiga Jankowska , Jacek Stawiński & Adam Kraszewski
(2011) Unusual Stereochemistry of Esterification of Uridine 3′-H-Phosphonothioate, Phosphorus,
Sulfur, and Silicon and the Related Elements, 186:4, 952-955, DOI: 10.1080/10426507.2010.503212
To link to this article: http://dx.doi.org/10.1080/10426507.2010.503212
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Phosphorus, Sulfur, and Silicon, 186:952–955, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.503212
UNUSUAL STEREOCHEMISTRY OF ESTERIFICATION
OF URIDINE 3ꢀ-H-PHOSPHONOTHIOATE
Michał Sobkowski,1 Jadwiga Jankowska,1 Jacek Stawin´ski,1,2
and Adam Kraszewski1
1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan´, Poland
2Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
Sweden
Abstract According to 31P-NMR correlation analysis, reactive derivatives of uridine 3ꢁ-H-
phosphonothioate react with O-nucleophiles, probably with retention of configuration.
Keywords Nucleoside H-phosphonothioates; retention of configuration; stereochemistry
Condensation of ribonucleoside 3ꢁ-H-phosphonate monoesters 1 with nucleosides or
alcohols owes its stereoselectivity to dynamic kinetic asymmetric transformation (DYKAT).
The main DP (SP) diastereomer of the product of type 3 is formed from the minor LP
(SP) diastereomer of a pivalic-H-phosphonic mixed anhydride 2 (Figure 1A). This was
found, for example, in transesterifications of aryl nucleoside H-phosphonates, for which
a correlation between the diastereomers of the reactant and the product implied that the
minor diastereomer was more reactive and had an LP (SP) configuration (Figure 1B).1
Ribonucleoside 3ꢁ-H-phosphonothioates 4 react with alcohols with high stereose-
lectivity with dominant formation of the expected DP (SP) diastereomers of the products
6 (Figure 2A). However, transesterification of aryl nucleoside H-phosphonothioates with
MeOH revealed a completely different stereochemical course of the reaction in comparison
to the oxo series (Figure 2B). This indicated that in the thio series the major diastereomer
of an intermediate involved is the more reactive one.
The results can be explained assuming that the major and more reactive DP (RP)
diastereomer of the mixed anhydride 5 (or of the aryl nucleoside H-phosphonothiate diester)
reacts with O-nucleophiles with unusual retention of configuration (Figure 3), probably due
to the apical-equatorial geometry of the transition state or pseudorotation of an intermediate
phosphorane.
Received 14 June 2010; accepted 15 June 2010.
Address correspondence to Michał Sobkowski, Institute of Bioorganic Chemistry, Polish Academy of
Sciences, Noskowskiego 12/14, Poznan´ 61-704, Poland. E-mail: msob@ibch.poznan.pl
952

URIDINE 3ꢀ-H-PHOSPHONOTHIOATE
953
Figure 1 Stereochemistry of reactions of ribonucleoside 3ꢁ-H-phosphonates (OXO series). A. The dynamic
kinetic asymmetric transformation scheme for asymmetric induction during condensation. B. Time course of
transesterification of p-chlorophenyl uridine H-phosphonate with methanol.

954
M. SOBKOWSKI ET AL.
Figure 2 Stereochemistry of reactions of ribonucleoside 3ꢁ-H-phosphonothioates (THIO series). A. 31P NMR
spectra recorded during condensation of uridine H-phosphonothioate with EtOH. B. Time course of transesterifi-
cation of p-chlorophenyl uridine H-phosphonothioate with methanol.

URIDINE 3ꢀ-H-PHOSPHONOTHIOATE
955
Figure 3 Putative mechanism for asymmetric induction during condensations of ribonucleoside 3ꢁ-H-
phosphonothioates (solid arrows—main paths, dashed arrows—minor paths).
REFERENCE
1. Sobkowski, M. New. J. Chem. 2010, 34, 854–869.