supplied as a decane solution,11 it is very expensive. Bis-
(trimethylsilyl) peroxide11 and CSO11 are commercially
available but also expensive. Further, the silylated peroxide
is rather explosive. Dimethyldioxirane is rather explosive and
not commercially supplied. Moreover, this reagent causes
undesired oxidative modification of thymine,12 uracil,12 and
adenine bases.13 Therefore, development of an oxidizing
agent without any of these disadvantages has been strongly
demanded. We present here ethyl(methyl)dioxirane (2-
butanone peroxide) as such a reagent. This peroxide is
commercially available as a dimethyl phthalate solution at a
lower price than MCPBA, bis(trimethylsilyl) peroxide, or
TBHP/decane solution. Oxidation with this reagent can be
efficiently applied to the nucleotide synthesis both in a
solution phase and in a solid phase.
building blocks. Actually, the dinucleoside phosphates, 17-
29, were prepared by the use of suitable building blocks
among 1-15. HPLC and 31P NMR analyses showed that, in
A 55% (7.3 M) solution of ethyl(methyl)dioxirane in
dimethyl phthalate14 was diluted with dichloromethane to
obtain a desired concentration of the solution. The use of a
0.1 or 0.01 M solution is suitable for the reaction in a solution
phase or on solid supports, respectively. These low-
concentration solutions are quite stable under ordinary
conditions and can be kept for a long period without any
decomposition. For example, solution stored at ambient
temperature for 1 month was effectively used in the following
reactions. First, the utility of this peroxide was demonstrated
in the solution-phase synthesis of a dinucleoside phosphate,
which was conducted via the condensation of a nucleoside
3′-phosphoramidite (1 equiv) and a 5′-O-free nucleoside (1
equiv) by the aid of benzimidazolium triflate15 (1 equiv) in
the presence of 3Å molecular sieves and the subsequent
oxidation with ethyl(methyl)dioxirane (1 equiv). In this
process, the condensation and the oxidation were generally
completed at 25 °C for 1 and 5 min, respectively, to give
the target product as a mixture of two diastereomers in almost
quantitative (>98%) yield.16 Noteworthy here is that the
oxidation was rapidly and quantitatively achieved by the use
of 1 equiv of the oxidizing agent. This method is useful for
the synthesis with both N-unprotected and N-protected
(11) A TBHP/decane solution was supplied by Aldrich. Bis(trimethylsilyl)
peroxide was supplied by United Chemical Technologies, Gelest, etc. CSO
was supplied by Aldrich or another company.
(12) (a) Luppattelli, P.; Saladino, R.; Mincione, E. Tetrahedron Lett.
1993, 34, 6313-6316. (b) Saladino, R.; Bernini, R.; Crestini, C.; Mincione,
E.; Bergamini, A.; Marini, S.; Palamara, A. T. Tetrahedron 1995, 51, 7561-
7578.
(13) Saladino, R.; Crestini, C.; Bernini, R.; Mincione, E.; Ciafrino, R.
Tetrahedron Lett. 1995, 36, 2665-2668.
(14) The ethyl(methyl)dioxirane (2-butanone peroxide)/dimethyl phthalate
solution is available from Aldrich or Kishida (Japan).
(15) Hayakawa, Y.; Kataoka, M.; Noyori, R. J. Org. Chem. 1996, 61,
7996-7997.
(16) General procedure for the preparation of a dinucleoside phosphate
via the phosphoramidite approach with ethyl(methyl)dioxirane oxidation.
A mixture of a nucleoside phosphoramidite (0.1 mmol), a nucleoside (0.1
mmol), and benzimidazolium triflate (0.1 mmol) in acetonitrile (0.2 mL)
containing powdery molecular sieves 3Å (30 mg) was stirred at 25 °C for
1 min. To this mixture was added a 0.1 M ethyl(methyl)dioxirane solution
in dichloromethane (1.0 mL), and stirring was continued at 25 °C for an
additional 5 min. The reaction mixture was diluted with dichloromethane
(10 mL). The molecular sieves were removed by filtration. The filtrate was
diluted with petroleum ether (300 mL) to give the target product as
precipitates. The 31P NMR analysis using H3PO4 as the standard indicated
that the yield of the desired product was generally >98%, and in some
cases a small amount (<2%) of a nucleoside H-phosphonate, which results
from hydrolysis of the starting nucleoside phosphoramidite, was formed as
a byproduct. HPLC analysis also gave a similar result.
some cases, the crude product is contaminated by a small
amount (<2%) of the nucleoside H-phosphonate, which is
resulting from hydrolysis of the starting nucleoside phos-
phoramidite.16 However, other undesired products were not
816
Org. Lett., Vol. 3, No. 6, 2001
Kataoka
