Synthesis study of 2′-O-(2-methoxyethyl)-purine derivatives

Article abstract of DOI:10.1080/15257770701528180

Alkylation of adenosine and 2-aminoadenosine was studied in dimethylsulfoxide with application of 1-methanesulfonyloxy-2-methoxyethane as an alkylating agent and t-BuOK, KOH and NaH as bases under mild heating. Using new reaction conditions, the improved synthesis of 2′-O-MOE-purine derivatives is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701528180

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Synthesis Study of 2′-O-(2-
Methoxyethyl)-Purine Derivatives
Grigorii G. Sivets a
a Institute of Bioorganic Chemistry , National Academy of Sciences ,
Minsk, Belarus
Published online: 05 Dec 2007.
To cite this article: Grigorii G. Sivets (2007) Synthesis Study of 2′-O-(2-Methoxyethyl)-
Purine Derivatives, Nucleosides, Nucleotides and Nucleic Acids, 26:10-12, 1237-1240, DOI:
10.1080/15257770701528180
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1237–1240, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701528180
SYNTHESIS STUDY OF 2ꢀ-O-(2-METHOXYETHYL)-PURINE
DERIVATIVES
Grigorii G. Sivets
Institute of Bioorganic Chemistry, National Academy of Sciences,
2
Minsk, Belarus
Alkylation of adenosine and 2-aminoadenosine was studied in dimethylsulfoxide with appli-
2
cation of 1-methanesulfonyloxy-2-methoxyethane as an alkylating agent and t-BuOK, KOH and
NaH as bases under mild heating. Using new reaction conditions, the improved synthesis of 2ꢁ-O-
MOE-purine derivatives is described.
Keywords Nucleosides; purine; methanesulfonyloxy-2-methoxyethane; 2ꢁ-O-MOE der-
ivatives
INTRODUCTION
Among different 2ꢁ-O-alkyl nucleosides, 2ꢁ-O-(2-methoxyethyl)(2ꢁ-O-
MOE) ribonucleosides are of special interest because antisense oligonu-
cleotides containing them possess improved hybridization properties,
favorable nuclease resistance and, therefore, belong to a promising class
of potential chemotheraupetic agents. A number of synthetic routes to
2ꢁ-O-MOE-nucleosides have been investigated,[1−3] but the development of
approaches which are best suited for preparing 2ꢁ-O-MOE-purine ribonucle-
osides is of importance. Previously, we have reported the synthesis of 2ꢁ-O-(2-
methoxyethyl) purine derivatives by selective 2ꢁ-O-alkylation of adenosine
and 2-aminoadenosine in moderate yields, using readily accessible 1-
methanesulfonyloxy-2-methoxyethane (MOE-OMs) as alkylating agent and
NaH in N,N -dimethylformamide followed by column chromatography on
silica gel as a method for effective separation of alkylation products.[4] This
article presents the synthetic study of direct 2ꢁ-O-alkylation of purine ribonu-
cleosides by MOE-OMs in dimethylsulfoxide in presence of different bases.
This work was supported from Belarus State Program of FOI “Physiological Active Compounds”
(Grant 2.04).
Address correspondence to G.G. Sivets, Laboratory of Nucleotides and Polynucleotides, Institute
of Bioorganic Chemistry, Minsk, Acad. Kuprevicha 5/2, Belarus. E-mail: gsivets@yahoo.com
1237

1238
G.G. Sivets
RESULTS AND DISCUSSION
The use of KOH/DMSO and MOE-Br or Cl was described for
the efficient preparation of 2-O-MOE derivatives of D-ribose and 2-
aminoadenosine.[5−6] MOE-OMs as a moderate electrophile displays
lower reactivity in comparison with MOE-Br.[4] Taking into account this
fact, selective 2ꢁ-O-alkylation of adenosine (1) by mesylate 2 was stud-
ied in dimethylsulfoxide in the presence of a strong base such as
potassium tert-butoxide under mild heating (Scheme 1a). As a result
of rapid alkylation of 1, 2ꢁ-O-MOE-adenosine (3), N6, 2ꢁ-di-O- MOE-
derivative 4, 2ꢁ,3ꢁ-di-O-MOE-derivative (5), 3ꢁ-O-MOE-derivative (6) were
isolated by column chromatography on silica gel in 35, 30, 1, and
9% yields, respectively. From the previous study of 2ꢁ-O-alkylation of
SCHEME 1 Reagents and conditions: (a) 1/ DMSO, t-BuOK (1.3 equiv.), rt, 7 minutes, mesylate 2 (2.1
equiv.), 48–49◦C, 15 minutes, 2 (1.6 equiv.), 48–49◦C, 35 minutes, SiO2 column chromatography ( 3,
35%; 4, 30%; 5, 1%; 6, 9%); (b) 1/ DMSO, LiBr (3 equiv.), t-BuOK (1.5 equiv.), 8 minutes, mesylate
2 (2×2.3 equiv.), 50–52◦C, 180 minutes, SiO2 column chromatography ( 3, 38%; 4, 3%; 5, 10%; 6,
10%); (c) 1/ DMSO, LiBr (3 equiv.), KOH (ꢀ2.6 equiv.), mesylate 2 (ꢀ3.6 equiv.), 50–52◦C, 18 hours,
SiO2 column chromatography ( 3, 33%); (d) [i] 1/ DMF /LiBr (2 equiv.), NaH (1.2 equiv.), removal of
solvent in vacuo; DMSO, mesylate 2 (1.7 equiv.), 50–52◦C, 180 minutes; [ii] KOH (ꢀ1.7 equiv.), mesylate
2 (ꢀ2.2 equiv.), 18 hours, ( 3, 47%; 5, 21%; 6, 9%); (d) [i] 7/ DMF, LiBr (2 equiv.)/DMF, NaH (1.3
equiv.), removal of solvent in vacuo; DMSO, mesylate 2 (1.7 equiv.), 50–52◦C, 180 minutes; [ii] KOH
(1.34 equiv.), mesylate 2 (1.27 equiv.), 18 hours, ( 8, 47%; 9, 5%; 10, 25%).

2ꢁ-O-MOE-Purin
1239
adenosine and 2-aminoadenosine by MOE-OMs in DMF under heating
(70–72◦C), it was noted that the simpler reaction mixture (TLC) was ob-
served with the formation of O-alkylated derivatives 1 and 7 in the pres-
ence of anhydrous lithium bromide. The interesting influence of LiBr on
selective alkylation of carbohydrates by alkyl bromides has been reported
earlier.[7] Therefore, the alkylation of 1 in the presence of LiBr/t-BuOK
was investigated under conditions (b) presented on Scheme 1. The deriva-
tives of adenosine 3, 4, 5, 6 were isolated by chromatography on silica gel
in 38, 3, 10, and 10% yields, respectively, after alkylation. Comparing results
of alkylation of 1 under conditions (a) and (b) it may be concluded that
alkylation of adenosine in DMSO in the presence of LiBr resulted in reduc-
ing yield of undesirable 2ꢁ-O-MOE derivative 4 alkylated at the amino group
of the heterocyclic base and increasing yield of 2ꢁ-O-MOE (3), 2ꢁ, 3ꢁ-di-O-
MOE derivative (5), but reaction time rised in this case. Starting from this
observation, alkylation of adenosine (1) by MOE-OMs in the presence of
KOH and LiBr (Scheme 1c) was studied. It proceeded practically with the
formation of derivatives 5, 6, and 2ꢁ-O-MOE derivative 3, isolated in 33%
yield after chromatography and crystallization. 2-Aminoadenosine is alky-
lated under above described conditions (c) to afford a similar distribution
of alkylation products. The best results of selective alkylation of adenosine
and 2-aminoadenosine were those utilizing sodium hydride in tandem with
potassium hydroxide as bases (Scheme 1d). Thus, consecutive treatment of
2ꢁ-O-Na salts of purine ribonucleosides, generated from 1 or 7 in DMF in
the presence of NaH/LiBr, by MOE-OMs in DMSO under mild heating fol-
lowed by additional alkylation of unreacted starting nucleosides in the pres-
ence of KOH gave rise to 2ꢁ-O-MOE derivatives 3 and 8 in 47% yields after
chromatography and crystallization.
It should be noted from the data above that alkylation of adenosine
and 2-aminoadenosine by MOE-OMs in DMSO resulted in a more efficient
[4]
preparation of 2ꢁ-O-MOE purine derivatives than the one in DMF.
An
interesting effect of lithium salt on the alkylation in DMSO was noticed.
Making use of sodium hydride and potassium hydroxide, sequentially, as
bases for direct alkylation of 1 and 7 by mesylate 2 in DMSO permits us to
prepare pure 2ꢁ-O-MOE-purine derivatives in high yields. But such an ap-
proach has the essential limitation that is due to the application of column
chromatography for the isolation of target compounds.
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1240
G.G. Sivets
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