Synthesis of novel 2′-deoxy type trans-3′,4′-bridged nucleic acid

Article abstract of DOI:10.1080/15257770701516235

We newly designed and synthesized a 2 ′-deoxy type trans-3′,4′-bridged nucleic acid (trans-3′,4′-BNA) analogues bearing a 4,7-dioxabicyclo[4.3.0]nonane structure. The synthesis of the trans-3′,4′-BNA was carried out successfully from thymidine over 21 ste

Full text of DOI:10.1080/15257770701516235

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Synthesis of Novel 2′-Deoxy Type
Trans-3′,4′-Bridged Nucleic Acid
Tomohisa Osaki a , Satoshi Obika a b , Yasuki Harada a , Yasunori
Mitsuoka a , Kensaku Sugaya a , Mitsuaki Sekiguchi a , Somjing
Roongjang a & Takeshi Imanishi a
a Graduate School of Pharmaceutical Sciences, Osaka University ,
Osaka, Japan
b PRESTO, JST , Saitama, Japan
Published online: 10 Dec 2007.
To cite this article: Tomohisa Osaki , Satoshi Obika , Yasuki Harada , Yasunori Mitsuoka , Kensaku
Sugaya , Mitsuaki Sekiguchi , Somjing Roongjang & Takeshi Imanishi (2007) Synthesis of Novel 2′-Deoxy
Type Trans-3′,4′-Bridged Nucleic Acid, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 1079-1082,
DOI: 10.1080/15257770701516235
To link to this article: http://dx.doi.org/10.1080/15257770701516235
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1079–1082, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701516235
SYNTHESIS OF NOVEL 2’-DEOXY TYPE TRANS-3ꢀ,4ꢀ-BRIDGED
NUCLEIC ACID
Tomohisa Osaki
Graduate School of Pharmaceutical Sciences, Osaka University,
2
Osaka, Japan
Satoshi Obika
Graduate School of Pharmaceutical Sciences, Osaka University,
2
Osaka, Japan and PRESTO, JST, Saitama, Japan
Yasuki Harada, Yasunori Mitsuoka, Kensaku Sugaya, Mitsuaki Sekiguchi,
Somjing Roongjang, and Takeshi Imanishi
Graduate School of Pharmaceutical
2
Sciences, Osaka University, Osaka, Japan
We newly designed and synthesized a 2ꢁ-deoxy type trans-3ꢁ,4ꢁ-bridged nucleic acid (trans- 3ꢁ,4ꢁ-
2
BNA) analogues bearing a 4,7-dioxabicyclo[4.3.0]nonane structure. The synthesis of the trans-
3ꢁ,4ꢁ-BNA was carried out successfully from thymidine over 21 steps. The structure of trans-3ꢁ,4ꢁ-
BNA was confirmed by x-ray crystallographic analysis, indicating that the furanose ring has a
ꢁ
typical S-type conformation with C3 -exo puckering.
Keywords Trans-3ꢁ,4ꢁ-BNA; x-ray crystallographic analysis; conformation
INTRODUCTION
Recently, nucleoside analogues with a restricted S-type sugar conforma-
tion have been designed and synthesized actively.[1] Some of them were in-
troduced into oligonucleotides and the hybridizing properties were eval-
uated. However, in many cases, only moderate increase or considerable de-
crease of duplex stability was observed, probably due to improper restriction
of the sugar conformation and unexpected steric repulsion in the B-type
DNA duplex.
To overcome these problems, we designed novel nucleosides, trans-3ꢁ,4ꢁ-
Bridged Nucleic Acids (trans-3ꢁ,4ꢁ-BNAs) with S-type sugar conformation
(Figure 1). Preliminary molecular modeling experiments showed that an
additional six- or seven-membered ring between the C3ꢁ and C4ꢁ atoms
of trans-3ꢁ,4ꢁ-BNAs to restrict sugar conformation was located outside
Address correspondence to Takeshi Imanishi, Graduate School of Pharmaceutical Sciences, Osaka
University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: imanishi@phs.osaka-u.ac.jp
1079

1080
T. Osaki et al.
FIGURE 1 Structures of trans-3ꢁ,4ꢁ-BNAs.
the B-type DNA duplex, indicating that the bridged structure has no
adverse repulsion against neighboring residues. We successfully synthesized
two trans-3ꢁ,4ꢁ-BNAs (1 and 2) having the 4,7-dioxabicyclo[4.3.0]nonane
skeleton from D-glucose.[2a−2c] The thermodynamic stability of oligonu-
cleotide duplexes containing 2 was evaluated. The results suggested that the
C2ꢁ-substituent of the trans-3ꢁ,4ꢁ-BNA affected duplex stability. Therefore, we
newly designed and synthesized two 2ꢁ-deoxy type trans-3ꢁ,4ꢁ-BNA analogues.
One has a 4,7-dioxabicyclo[4.3.0]nonane structure and the other has a
3,5,8-trioxabicyclo[5.3.0]decane structure (3 and 4[2d], respectively). In
this article, we would like to report the synthesis of the novel 2ꢁ-deoxy type
trans-3ꢁ,4ꢁ-BNA 3.
RESULTS AND DISCUSSION
To prepare the nucleoside 3 having no substituent at the C2ꢁ-position,
we chose thymidine as the starting material. The synthetic route for an
SCHEME 1 Reagents and conditions: i) DMTrCl, Et3N, CH2Cl2, room temp.; ii) NaH, BnBr, n-Bu4NI,
DMF, room temp.; iii) (+)-10-camphorsulfonic acid, CH2Cl2–MeOH, room temp. (83% over 3 steps).

2ꢁ-Deoxy Type Trans-3ꢁ,4ꢁ-Bridged Nucleic Acids
1081
important intermediate 9 is shown in Scheme 1. Thymidine was transformed
into known 3ꢁ-deoxy-3ꢁ-C-methylenethymidine derivative 5.[3] The diol 6 was
prepared from 5 in a seven-step sequence according to our methodology.[2d]
After selective protection of the pro-S hydroxymethyl group in 6 by the
dimethoxytrityl group, benzylation of another hydroxyl group in 7 provided
8, followed by deprotection of the dimethoxytrityl group gave the interme-
diate 9 in good yield (83% over three steps).[4] The nucleoside 9 was a com-
mon intermediate for the synthesis of not only trans-3ꢁ,4ꢁ-BNA 3 but also
trans-3ꢁ,4ꢁ-BNA 4.[2d]
Next, we successfully synthesized 3 through the intermediate 9 as shown
in Scheme 2. The tosyl group as leaving group was introduced into the hy-
droxyl group in 9 and the MOM group was removed by TMSBr to give alco-
hol 11. The aldehyde 12 obtained by an oxidation of 11 was subjected to the
Wittig reaction to give the enol ether 13 in 66% yield over 2 steps. Treatment
of 13 with mercury acetate afforded the corresponding aldehyde 14, which
was reduced with NaBH4 to afford the alcohol 15. A base-mediated cycliza-
tion of 15 using NaHMDS[2a] proceeded smoothly to give compound 16.
SCHEME 2 Reagents and conditions: i) p-TsCl, Et3N, DMAP, CH2Cl2, room temp. (quant); ii) TMSBr,
CH2Cl2, −30◦C (97%); iii) Dess–Martin periodinane, CH2Cl2, room temp.; iv) Ph3PCH2OMeCl, LiH-
MDS, THF, −78◦C (66% over 2 steps); v) Hg(OAc)2, TBAI, THF–H2O, room temp.; vi) NaBH4, THF–
H2O, 0◦C (63% over 2 steps); vii) NaHMDS, THF, reflux (92%); viii) HCOONH4, 20%Pd(OH)2/C,
EtOH containing a little amount of AcOH, reflux (50%).

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T. Osaki et al.
Finally, full deprotection of 16 was accomplished by a catalytic hydrogenoly-
sis over Pd(OH)2-C with HCOONH4 under subtle acidic conditions, afford-
ing the target molecule 3 in 50% yield. All spectral data were in agreement
with the structure of 3 and it was confirmed by x-ray crystallographic analy-
sis. The data showed that the sugar conformation of 3 was restricted to S-type
ꢁ
puckering (C3 -exo).
In conclusion, we have succeeded in preparation of a novel 2ꢁ-deoxy type
trans-3ꢁ,4ꢁ-BNA 3 having a 4,7-dioxabicyclo[4.3.0]nonane structure from
thymidine. The oligonucleotides containing 3 are expected to form stable B-
type DNA duplex. Further investigation on 3 and its oligonucleotide deriva-
tive is in progress.
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4. The direct benzylation of 6 under various conditions did not give 9 effectively.