An efficient synthesis of 7-functionalized 7-deazapurine β-D- or β-L-ribonucleosides: Glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-o-benzoyl-D-or L-ribofuranose

Article abstract of DOI:10.1080/15257770701490332

The glycosylation reaction performed with 7-halogenated 7-deazapurines employing commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-D- or L-ribofuranoses is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701490332

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An Efficient Synthesis Of 7-
Functionalized 7-Deazapurine β-D-
Or β-L-Ribonucleosides: Glycosylation
Of Pyrrolo[2,3-D]Pyrimidines With 1-
O-Acetyl-2,3,5-Tri-O-Benzoyl-D-Or L-
Ribofuranose
Xiaohua Peng a b & Frank Seela a b
a Laboratorium für Organische und Bioorganische Chemie ,
Universität Osnabrück , Osnabrück, Germany
b Laboratory of Bioorganic Chemistry and Chemical Biology, Center
for Nanotechnology , Münster, Germany
Published online: 10 Dec 2007.
To cite this article: Xiaohua Peng & Frank Seela (2007) An Efficient Synthesis Of 7-Functionalized
7-Deazapurine β-D- Or β-L-Ribonucleosides: Glycosylation Of Pyrrolo[2,3-D]Pyrimidines With 1-O-
Acetyl-2,3,5-Tri-O-Benzoyl-D-Or L-Ribofuranose, Nucleosides, Nucleotides and Nucleic Acids, 26:6-7,
603-606, DOI: 10.1080/15257770701490332
To link to this article: http://dx.doi.org/10.1080/15257770701490332
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Nucleosides, Nucleotides, and Nucleic Acids, 26:603–606, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701490332
AN EFFICIENT SYNTHESIS OF 7-FUNCTIONALIZED 7-DEAZAPURINE
β-D- OR β-L-RIBONUCLEOSIDES: GLYCOSYLATION
OF PYRROLO[2,3-d]PYRIMIDINES WITH
1-O-ACETYL-2,3,5-TRI-O-BENZOYL-D- OR L-RIBOFURANOSE
Xiaohua Peng and Frank Seela
Laboratorium fu¨r Organische und Bioorganische
2
Chemie, Universita¨t Osnabru¨ck, Osnabru¨ck, Germany, and Laboratory of Bioorganic
Chemistry and Chemical Biology, Center for Nanotechnology, Mu¨nster, Germany
The glycosylation reaction performed with 7-halogenated 7-deazapurines employing commer-
2
cially available 1-O-acetyl-2,3,5-tri-O-benzoyl-D- or L-ribofuranoses is described.
Keywords 7-deazapurines; pyrrolo[2,3-d]pyrimidines; glycosylation; functionalization;
ribonucleosides; Silyl Hilbert-Johnson reaction
INTRODUCTION
The frequent occurrence and unusual biological properties of 7-
deazapurine nucleosides have promoted studies towards the synthesis,
biological activity, and incorporation into oligonucleotides of their chem-
ically designed analogs.[1] The 7-position of 7-deazapurine is an ideal site
for modifications that can lead to compounds with increased antiviral
activity, oligonucleotides labelled with dyes, or a more stable DNA or RNA
duplex through the introduction of substituents of moderate size (e.g.,
alkynyl residues or halogens).[1−3] Earlier, 7-deazapurine ribonucleosides
(e.g., 1a, 2a, or 3a; Scheme 1) were prepared by nucleobase anion glyco-
sylation using reactive sugar halides.[4] However, until now no efficient
procedure has been reported to synthesize 7-functionalized derivatives
related to compounds 1a, 2a, or 3a due to the low nucleophilicity of the
pyrrol nitrogen in the pyrrolo[2,3-d]pyrimidine system. Here, a conve-
nient method is described for the synthesis of 7-substituted 7-deazapurine
Address correspondence to Frank Seela, Laboratorium fu¨r Organische und Bioorganische Chemie,
Universita¨t Osnabru¨ck, Barbarastraße 7, 49069 Osnabru¨ck, Germany and Laboratory of Bioorganic
Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstraße 11, 48149 Mu¨nster,
Germany. E-mail: frank.seela@uni-osnabrueck.de
603

604
X. Peng and F. Seela
SCHEME 1 Structures of β-D-ribonucleosides 1–3 or β-L-ribonucleosides 4–6.
β-D- or β-L-ribonucleosides (1–3 or 4–6) using commercially available
1-O-acetyl-2,3,5-tri-O-benzoyl-D- or L-ribofuranose (7 or 8).
RESULTS AND DISCUSSION
The Silyl Hilbert-Johnson glycosylation was employed for the gly-
cosylation of 7-halogenated 2-amino-7-deazapurines with the ribosugar
7.[5,6] The reaction conditions were changed systematically: (i) different
nucleobases and silylation reagents (e.g., HMDS and BSA) were employed;
(ii) various solvents (CH2Cl2, ClCH2CH2Cl, MeNO2, and MeCN) were
used; (iii) different catalysts (SnCl4 and TMSOTf) were applied; (iv)
different reaction temperatures were tested. When all parameters were
carefully chosen, a reliable and convenient procedure was developed which,
for the first time, makes 7-functionalized 7-deazapurine ribonucleosides
easily accessible. The glycosylation of 2-pivaloylamino-6,7-dihalogenated
7-deazapurines 9b–d with the sugar 7 performed in the one-pot reac-
tion condition (BSA/MeCN/TMSOTf) afforded the β-D-ribonucleosides
10b–d in 73–75% yield (Scheme 2). The intermediates 10b–d are useful
for further manipulations using nucleophilic displacement reactions or
the palladium-catalyzed cross-coupling reaction leading to a series of
SCHEME 2 One-pot glycosylation of the nucleobases 9b–d with sugar derivative 7.

Glycosylation of Pyrrolo[2,3-d]Pyrimidines
605
SCHEME 3 Transformation of intermediates 10b–d to the nucleosides 1b–d, 2b–d, and 3b–d.
7-functionalized 7-deazapurine ribonucleosides. This method was also
applied to the synthesis of corresponding β-L-ribonucleosides.[5]
The 2,6-diamino ribonucleosides 2b–d were prepared from 10b–d when
treated with aq. NH3 (120◦C, 24 h) in an autoclave (Scheme 3). The
precursors 10b-d were also converted to the 4-methoxy derivatives 11b–d
(0.5M NaOMe, reflux). The latter were heated in 2M NaOH giving the
guanosine analogs 1b–d. The deamination of the intermediates11b–d with
NaNO2/AcOH furnished the nucleosides 12b–d, which after demethylation
with 2N NaOH gave the 7-deazaxanthosine derivatives 3b-d (74–78% yield).
The iodinated 7-deazapurine ribonucleosides are valuable starting ma-
terials for the introduction of alkynyl or aminoalkynyl chains by the Pd-
catalyzed cross-coupling reaction.[8] Thus, the 7-iodo compounds 1d, 2d,
and 3d were employed in the Sonogashira reaction, yielding a number of
SCHEME 4 Palladium-catalyzed Sonogashira cross-coupling reaction.

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X. Peng and F. Seela
SCHEME 5 Glycosylation of 9b–d with L-ribofuranose 8.
novel 7-alkynyl- or aminoalkynyl 7-deazapurine ribonucleosides in 50–92%
yields (1e–i, 2e–i or 3e; Scheme 4).
a
Conditions: (a) HC≡CR, anhydrous DMF, Pd(0)(PPh3)4, CuI, Et3N;
(b) MeOH, K2CO3.
Considering the identical chemical properties of L- and D-nucleosides
and their precursors in a nonchiral environment, the protocols devel-
oped for the 7-deazapurine D-ribonucleoside synthesis (as described above)
can be employed for the preparation of the L-enantiomers. Instead of
D-ribofuranose derivative 7, its L-enantiomer 8 was used as sugar compo-
nent. The glycosylation of the 2-pivaloylamino-7-deazapurine derivatives
9b–d with 8 was performed in MeCN/BSA/TMSOTf, affording the β-L-
ribonucleosides 13b–d in 66–73% yield (Scheme 5).[9] Similar to the trans-
formation of 10b–d into 1–3, compounds 13b–d were converted to the 7-
functionalized 7-deazapurine β-L-ribonucleosides 4b–d,5b–d, and6b–d by
nucleophilic displacement reactions (Scheme 1).
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1. Suhadolnik, R.J. Pyrrolopyrimidine nucleosides. In Nucleoside Antibiotics. Wiley-Interscience,
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2. Uhlmann, E.; Peyman, A. Antisense oligonucleotides: A new therapeutic principle. Chem. Rev. 1990,
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3. Seela, F.; Peng, X. Base-modified oligodeoxyribonucleotides: Using pyrrolo[2,3-d] pyrimidines to
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Hoboken, NJ, 2005, Vol. 1, 4.25.1–4.25.24.
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and β-D-ribofuranosides related to 7-deazaguanosine. Helv. Chim. Acta 1990, 73, 1879–1887.
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guanosine, and xanthosine: Glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-
benzoyl-D-ribofuranose. J. Org. Chem. 2006, 71, 81–90.
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2-amino-7-deaza-2ꢁ-deoxyadenosine and 7-deaza-2ꢁ-deoxyisoguanosine. Synthesis 2004, 1203–1210.
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