Activation of methylphosphonates and their thio- and seleno congeners with 1,3,5-triazinyl morpholinium salts. selenono-selenolo isomerization

Article abstract of DOI:10.1080/10426500801901152

The stereospecific activation of nucleoside 3'-O-methylphosphonoselenoates (1) with N-methyl-N-4,6-dimethoxy-1,3,5-triazinyl-yl morpholinium chloride resulted in formation of both O-activated (5) and Se-activated (6) 1,3,5-triazin-yl esters.

Full text of DOI:10.1080/10426500801901152

This article was downloaded by: [New York University]
On: 04 November 2014, At: 23:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Activation of
Methylphosphonates and
Their Thio- and Seleno
Congeners with 1,3,5-Triazinyl
Morpholinium Salts. Selenono-
Selenolo Isomerization
Lucyna A. Wozniak a b , Marcin Góra a , Zbigniew
Kamiński a b & Wojciech J. Stec a
a Centre of Molecular and Macromolecular Studies,
Polish Academy of Sciences, Department of
Bioorganic Chemistry , Lodz, Poland
b Medical University of Lodz, Dept Structural
Biology , Lodz, Poland
c Institute of Organic Chemistry, Technical University
of Lodz , Lodz, Poland
Published online: 29 Oct 2008.
To cite this article: Lucyna A. Wozniak , Marcin Góra , Zbigniew Kamiński &
Wojciech J. Stec (2008) Activation of Methylphosphonates and Their Thio- and Seleno
Congeners with 1,3,5-Triazinyl Morpholinium Salts. Selenono-Selenolo Isomerization,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:4, 1076-1081, DOI:
10.1080/10426500801901152
To link to this article: http://dx.doi.org/10.1080/10426500801901152
PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 183:1076–1081, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801901152
Activation of Methylphosphonates and Their Thio- and
Seleno Congeners with 1,3,5-Triazinyl Morpholinium
Salts. Selenono-Selenolo Isomerization
1
Lucyna A. Wozniak,1,2 Marcin Gora,
´
Zbigniew Kaminski, and Wojciech J. Stec1
1,2
´
1Centre of Molecular and Macromolecular Studies, Polish Academy
of Sciences, Department of Bioorganic Chemistry, Lodz, Poland
2Medical University of Lodz, Dept Structural Biology, Lodz, Poland
3Institute of Organic Chemistry, Technical University of Lodz,
Lodz, Poland
The stereospecific activation of nucleoside 3ꢀ-O-methylphosphonoselenoates (1)
with N-methyl-N-4,6-dimethoxy-1,3,5-triazinyl-yl morpholinium chloride resulted
in formation of both O-activated (5) and Se-activated (6) 1,3,5-triazin-yl esters.
Keywords 1,3,5-triazines; 1,3,5-triazinyl salts; methylphosphonoselenoates; nucleotide
analogues; phosphoroselenoates
INTRODUCTION
The S(Se)- or O- activations of diastereomerically pure nucleoside 3ꢀ-
O-methanephosphonothio (seleno)ates (1, X=S, Se) provide monomers
for the synthesis of dinucleoside (3ꢀ,5ꢀ)-methyl phosphonates (2) or
methylphosphonothio(seleno)ates (3), respectively.1,2 The concept
of active esters and superactive esters as reactive intermediates in
Address correspondence to Lucyna A. Wozniak, Centre of Molecular and Macromolec-
ular Studies, Polish Academy of Sciences, Department of Bioorganic Chemistry, 112
Sienkiewicza Str., 90-363 Lodz, Poland.
1076

Selenono-Selenolo Isomerization
1077
SCHEME 1 Reagents and reaction conditions: (i) 5ꢀ-O-DMT- thymidine and 2
(2 equiv) in THF, 30 min at RT. (ii) H2O (20 equiv) and DBU (5 equiv), 30 min,
(iii) 3 (1 equiv), overnight at RT, column chromatography.
acylation reactions has been widely used in synthesis of peptides,3
amides,4 or carboxylic acids5 with very promising results obtained with
triazine based coupling reagents.6,7 Previously, this approach has been
also used successfully in organophosphorus chemistry, where both
PIII and PIVcompounds have been activated by several 1,2,4-triazoles8
and hydroxybenzotriazoles.9 In our search for methods of synthesis of
chimeric oligonucleotides modified with P-methylphosphono- or phos-
phorothioates, we investigated bis(1,2,4-triazoyl) methylphosphonite10
and bis(hydroxybenzotriazoyl) phosphorothioate11 as phosphorylating
agents, accordingly.
It seemed therefore attractive to confront the “superactive es-
ter” approach for the synthesis of P-stereodefined chimeric oligonu-
cleotides with methods evaluated previously. We found that
chemoselective and stereospecific O-activation of nucleoside 3ꢀ-O-
methylphosphonothioates (1) with N-methyl-N-4,6-dimethoxy-1,3,5-
triazinyl-yl morpholinium chlorides (2) resulted in formation of active
esters 3 which were used as monomers for stereoselective synthesis
of dinucleoside (3ꢀ,5ꢀ)-methylphosphonothioates and have been conve-
nient intermediates for interconversion of RP-1 into S -1 (the stere-
P
ochemical Walden cycle) monomers for stereoselective synthesis of 4
(Figure 1)12 (Scheme 1).
The same strategy appeared to be promising for synthesis of
chimeric oligonucleotides, modified with stereoregular dinucleo-
side (3ꢀ,5ꢀ)-methylphosphonoselenoates, useful tools for structural
studies, because of the MAD effect, connected with the presence of
selenium in the X-ray analyzed molecules,13 and a diagnostic value
of the P-Se coupling constants. However, in contrast to nucleoside
3ꢀ-O-methylphosphonothioates (1), exclusivelyO-activated with 1,3,5-
triazin-yl-morpholinium chloride (2), the corresponding activation of
nucleoside 3ꢀ-O-methylphosphonoselenoates14 (1) was not selective,

1078
L. A. Wozniak et al.
FIGURE 1

Selenono-Selenolo Isomerization
1079
SCHEME 2
and we observed a formation of both O-activated (5) and Se-activated
(6) 1,3,5-triazin-yl esters.
In the reported experiments (Scheme 2), followed by 31P NMR (Fig-
ure 1), we found that O-activation was faster, and the protected 3ꢀ-O-
(O-1,3,5-triazinyl) methylphosphonoselenoate 5 (δ: 97.64, 90.76 ppm,
J
= 911 Hz) was a dominant isomer at the beginning of the reaction,
P−Se
when diastereomerically enriched methylphosphonoselenoate 1 (RP:S
P
(2:1) δ: 71.08, 70.62 ppm; J
= 701 Hz for both diast.) was activated
P−Se
with 3 equivalents of the corresponding the in situ generated 1,3,5-
triazin-yl chloride 2. The amount of thymidine 3ꢀ-O-(Se-1,3,5-triazinyl)
methylphosphonoselenolate 6 increased in due course of the activation
(δ: 49.67 ppm, JP-Se = 425 Hz; 49.59 ppm, JP-Se = 423 Hz). After four
h, there was a mixture of 1:1 ratio of the esters 5 and 6, and after
72 h, only the ester 6 was observed.15 The performed ab initio stud-
ies of the relative stabilities of esters 5 and 6 (Hyperchem 7.5, Am-
ber 99; conjugate gradient ꢀ =0.01) confirmed that there existed only
small differences in esters stabilities, decreasing in the following order
S -6 > RP-6 > S -5 > RP-5. Therefore, the selenono-selenolo isomer-
P
P
ization, observed during activation of 1 with 2 is a consequence of a

1080
L. A. Wozniak et al.
formation of the thermodynamically more stable products 6, and pre-
liminary formation of the kinetically favored esters 5,16 most probably
catalyzed by amine chlorides present in the reaction mixture.17
In the presence of strong bases, e.g., DBU, both esters reacted in
stereospecific way, affording the corresponding 5ꢀ-O-DMT-thymidine
3ꢀ-O-(O-methyl methanephosphono selenoates) (7), and 5ꢀ-O-DMT-
thymidine 3ꢀ-O-methanephosphonates (8), respectively. Since we used
diastereomerically enriched (1:2 RP/S ) methanephosphonoselenoates
P
1 in these experiments, this permitted us to assign the absolute con-
figuration of the active esters 7 (Scheme 2) and stereoretention of the
activations. The formation of O-methyl methylphosphonoselenoate 7
(δ: 100.1, 99.86 ppm; J
= 876 Hz) (and O-methyl methylphospho-
P−Se
nate 8 (δ: 31.25, 31.18 ppm) in reactions of the corresponding esters
5 and 6 with methanol activated by DBU occurred with inversion of
configuration.18
REFERENCES
[1] L. A. Wozniak, M. Janicka, and M. Bukowiecka-Matusiak, J. Organomet. Chem.,
690, 2658–2663 (2005).
[2] L. A. Wozniak and W. J. Stec, In Frontiers in Nucleosides and Nucleic Acids, R. F.
Schinazi and D. C. Liotta, Eds. (IHL Press, Tucker, GA, 2004), pp. 457–477.
[3] (a) Z. J. Kaminski, Synthesis, 917–920 (1987); (b) C. E. Garrett, X. Jiang, K. Prasad,
and O. Repic, Tetrahedron Lett., 43, 4161–4165 (2002).
[4] B. P. Bandgar and S. S. Pandit, Tetrahedron Lett., 44, 3855–3858 (2003).
[5] C. Barnett, T. M. Wilson, S. R. Wendel, M. J. Winningham, and J. B. Deeter, J. Org.
Chem., 59, 7038–7045 (1994).
[6] Z. J. Kaminski, B. Kolesinska, J. Kolesinska, G. Sabatino, M. Chelli, P. Rovero, M.
Blaszczyk, M. L. Glowka, and A. M. Papini, J. Am. Chem. Soc., 127, 16,912–16,920
(2005).
[7] Z. J. KamiÒski, B. KolesiÒska, J. E. KamiÒska, and J.Go´ra, J. Org. Chem., 66,
6276–6281 (2001).
[8] J. L.Fourrey and J. Varrenne, Tetrahedron Lett., 26, 2663–2666 (1985).
[9] J. E. Marugg, E. de Vroom, C. E. Dreef, M. Tromp, G. A. van der Marel, and J. H.
van Boom Nucleic Acids Res., 11, 2171–2185 (1986).
[10] L. A. Wozniak, M. Bukowiecka-Matusiak, M. Gora, and W.J. Stec, Synlett, 1324–
1331 (2006).
[11] L. A. Wozniak, M. Bukowiecka-Matusiak, M. Go´ra, K. Misiura, S. Mourgues, and
W. J. Stec, Europ. J. Org. Chem., 2924–2930 (2005).
[12] L. A. Wozniak, M. Gora, and W. J. Stec, J. Org. Chem., 72, 8584–8587 (2007).
[13] (a) N. Carrasco and Z. Huang, J. Am. Chem. Soc., 126, 448–449 (2004); (b) N. Car-
rasco, J. Caton-Williams, G. Brandt, S. Wang, and Z. Huang, Angew. Chem. Int. Ed,
45, 94–97 ( 2006).
[14] Into a solution of 1,2,4-triazole (5 mmol, 2.5 equiv) and Et3N (6 mmol, 3 equiv)
in THF (10 mL), cooled to 0◦C, MePCl2 (2.2 mmol, 1.1 equiv) was added, and a
reaction mixture was stirred for 20 min. 5ꢀ-O-DMT-thymidine (2 mmol) dissolved
in THF (10 mL) was added to this mixture dropwise, with stirring continued for

Selenono-Selenolo Isomerization
1081
30 min. After this time, elemental Se was added, and the reaction mixture was left
overnight. Hydrolysis (30 min) was performed with a mixture H2O/Et3N, followed
by extraction of products with chloroform, and purification/separation of 1 via silica
gel column chromatography with a mixture of CHCl3 and EtOH (19:1, v/v) cont. 1%
Et3N as an eluent. Yield 80%.
[15] Diastereomerically enriched substrate 1 (RP:SP (2:1) δ: 71.08, 70.62 ppm; JP-Se
=
701) and 2 (3 equiv.) were stirred at room temp. in dry MeCN. The reaction progress
was followed by 31P NMR. After the reaction was complete, and only the ester 6
(δ: 49.7 ppm, JP-Se = 425 Hz; 49.6 ppm, JP-Se = 423 Hz) was present, the reaction
mixture was concentrated, washed with water, and purified by a silica gel column
chromatography. Product 6 was eluted with 4% methanol in CHCl3. Yield 67%.
[16] Similar results were observed in case of O,O-dimethyl phosphoroselenoates, when
both O-triazinyl phosphoroselenoates (δ: 52.34. ppm, JP−Se = 780 Hz) and Se-
triazinyl selenolates (δ: 24.79 ppm, JP-Se = 488 Hz) were formed under similar
conditions. Moreover, a mixture of both O-triazinyl and S-triazynyl isomers was
also formed in a reaction of O,O-dimethyl phosphorothioate with 2 (δ: 53.8 ppm,
and 32.97 ppm, respectively).
[17] (a) W. J. Stec, B. Uznanski, and J. Michalski, Phosphorus, 2, 235 (1973);
(b) M. Michalska, J. Borowiecka, P. Lipka, and T. Rokita-Trygubowicz, J. Chem.
Soc., Perkin Trans., 1, 1619–1622 (1989).
[18] L. A. Wozniak, A. Chworos, J. Pyzowski, and W.J. Stec, J. Org. Chem., 63, 9109–9112
(1998).