Synthesis of 2,4-disubstituted pyrimidin-5-yl C-2′- deoxyribonucleosides by sequential regioselective reactions of 2,4-dichloropyrimidine nucleosides

Article abstract of DOI:10.1002/ejoc.201000164

A new modular synthesis of diverse 2,4-disubstituted pyrimidin-5-yl C-2′-deoxyribonucleosides by sequential regioselective reactions of 2f6-dichloropyrimidm-5-yl C-nucleosides was developed. The intermediate was prepared by the Heck coupling of 2,6-dichloro-5-iodopyrimidine with glycal followed by desilylation and reduction. Its mild nucleophilic substitutions or Fe-catalyzed cross-coupling with MeMgCl proceeded regioselectively at position 4, whereas at elevated temperatures or with excess of MeMgCl, double substitution occurred. The 2-chloro-4-substituted intermediates undergo another substitution or coupling to afford 2,4-disubstituted derivatives.

Full text of DOI:10.1002/ejoc.201000164

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000164
Synthesis of 2,4-Disubstituted Pyrimidin-5-yl C-2Ј-Deoxyribonucleosides by
Sequential Regioselective Reactions of 2,4-Dichloropyrimidine Nucleosides
[a]
[a]
[a]
[a]
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Tomás Kubelka, Lenka Slavetínská, Blanka Klepetárová, and Michal Hocek*
Keywords: C-nucleosides / Nucleobases / Pyrimidines / Cross-coupling reactions / Nucleophilic substitution
A new modular synthesis of diverse 2,4-disubstituted pyrim-
idin-5-yl C-2Ј-deoxyribonucleosides by sequential regiose-
lective reactions of 2,6-dichloropyrimidin-5-yl C-nucleosides
was developed. The intermediate was prepared by the Heck
coupling of 2,6-dichloro-5-iodopyrimidine with glycal fol-
lowed by desilylation and reduction. Its mild nucleophilic
substitutions or Fe-catalyzed cross-coupling with MeMgCl
proceeded regioselectively at position 4, whereas at elevated
temperatures or with excess of MeMgCl, double substitution
occurred. The 2-chloro-4-substituted intermediates undergo
another substitution or coupling to afford 2,4-disubstituted
derivatives.
our approach to the synthesis of hetaryl C-nucleosides
bearing two different substituents (two-dimensional librar-
ies) by sequential double substitutions of dihalohetaryl in-
termediates. Here we report on the first example of this ap-
proach for the synthesis of 2,4-disubstituted-pyrimidin-5-yl
C-nucleosides.[10]
Introduction
C-Nucleosides are an important class of molecules which
display biological activities and find applications in chemi-
cal biology.[1] (Het)aryl C-2Ј-deoxyribonucleosides have at-
tracted prominent attention as candidates for novel base-
pairs in the quest for extension of the genetic alphabet.[2]
They form stable and selective (usually hydrophobic pairs)
in DNA duplexes due to increased packing and hydro-
phobic interactions.[3] Some artificial base-pairs were ef-
ficiently and selectively replicated by DNA polymerases.[4]
The most successful pairs based on 4-substituted 2-meth-
oxyphenyl C-nucleosides in combination with thioisocar-
bostyril base were not only replicated and extended[5] but
also used in the first successful PCR with a 6-letter genetic
alphabet.[6] Particularly important is the presence of a
methoxy group as an H-bond acceptor in the minor groove,
which stabilizes the active site of the polymerase and facili-
tates the extension of the growing DNA chain.
Results and Discussion
The synthesis of the key intermediate was based on the
Heck reaction[11] of 3Ј-TBDMS-protected glycal 1 with 2,4-
dichloro-5-iodopyrimidine 2 in the presence of Pd(OAc)2,
(PhF5)3P and Ag2CO3, which resulted in the formation of
the 2,4-dichloropyrimidin-5-yl nucleoside analogue 3 as a
pure β-anomer (no α-anomer formation was observed)
(Scheme 1). Since partial desilylation (10–20%) was ob-
served during the reaction and workup, the intermediate
3 was then (without purification) directly deprotected by
Et3N·3HF in THF to give ketone 4 in 42% overall yield
(from 1). Subsequent reduction of 4 by triacetoxyboro-
hydride in a mixture of acetonitrile/acetic acid gave the key
intermediate, 2,4-dichloropyrimidin-5-yl C-nucleoside 5 in
80% yield as a pure β-anomer. Its crystal structure was de-
termined by X-ray diffraction (Scheme 1) to show interest-
ing Cl····N bonds[12] of the chlorine atom at position 4 to
N3 of the neighbouring pyrimidine ring in the crystal (see
Supporting Information). Its silylation afforded TBDMS-
protected C-nucleoside 6 in 75% yield.
There are numerous approaches[1,7] to the synthesis of C-
nucleosides, but none of them is general, and some suffer
from low efficiency and stereoselectivity. In recent years we
have developed[8] a modular approach based on the synthe-
sis of halo(het)aryl C-nucleoside intermediates and their
follow-up functionalizations by cross-couplings, aminations
and other reactions to afford series (one-dimensional librar-
ies) of derivatives. Since it is known that many dihalohetero-
cycles undergo regioselective or chemoselective cross-cou-
plings[9] or nucleophilic substitutions, we decided to extend
The dichloropyrimidine intermediate 5 was then sub-
jected to a series of nucleophilic substitutions (Scheme 2,
Table 1). The reaction with methanolic ammonia at room
temp. gave regioselectively 4-amino-2-chloro derivative 7 in
74% yield. Similarly, the treatment with sodium methoxide
in methanol gave regioselectively 2-chloro-4-methoxy deriv-
ative 8 in 78% yield. The regioselectivity was verified by
[a] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Gilead Sciences & IOCB
Research Center,
Flemingovo nam. 2, 16610 Prague 6, Czech Republic
Fax: +420-220183559
E-mail: hocek@uochb.cas.cz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000164.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2666–2669

2,4-Disubstituted Pyrimidin-5-yl C-2Ј-Deoxyribonucleosides
Scheme 2. Regioselective nucleophilic substitutions.
Table 1. Regioselective nucleophilic substitutions.
Scheme 1. Synthesis of 2,4-dichloropyrimidin-5-yl C-nucleoside in-
termediates.
Entry Starting compound Conditions
X
Y
Product (yield)
1
2
3
4
5
6
5
5
7
8
5
5
i
ii
iii
iv
iv
iii
NH2
OMe
NH2 OMe
OMe NH2
NH2 NH2
OMe OMe
–
–
7 (74%)
8 (78%)
X-ray diffraction of compound 8 (Scheme 2). The second
chlorine atom can be still replaced by another substitution.
Thus, 4-amino-2-chloro derivative 7 was converted to 4-
amino-2-methoxypyrimidine 9 by heating with sodium
methoxide in methanol in 71% yield. However, when we
attempted the amination of 2-chloro-4-methoxy derivative
8 with methanolic ammonia at 120 °C, a mixture of three
9 (71%)
10 (25%)[a]
11 (83%)
12 (87%)
[a] Accompanied by 7 (52%) and 9 (15%).
Scheme 3. Cross couplings and follow-up substitutions of TBDMS-protected nucleoside 6.
Eur. J. Org. Chem. 2010, 2666–2669
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T. Kubelka, L. Slaveˇtínská, B. Klepetárˇová, M. Hocek
SHORT COMMUNICATION
products was obtained. The desired 2-amino-4-methoxy- tive reaction was the amination of 2-chloro-4-methoxypyr-
pyrimidine 10 was isolated in 25% yield, accompanied by imidine 8 at high temperature when the OMe group was
4-amino-2-chloro derivative 7 (52%) and 4-amino-2-meth- also partially replaced.
oxypyrimidine 9 (15%). Apparently, under these harsh con-
This methodology is a general approach to the synthesis
ditions, the 4-OMe substituent acts as a leaving group, of diverse 2,4-disubstituted pyrimidine C-nucleosides by the
which can be replaced by an amino group, and methanol sequential reactions with two different nucleophiles (the
may serve as a nucleophile to methoxylate the C-2 position first one at position 4 and the second one at position 2). It
by replacing the chlorine atom. On the other hand, the reac- can be used in the synthesis of important pyrimidine nu-
tion of 5 with methanolic ammonia at 120 °C gave cleanly cleosides with different substituents pointing to the minor
the 2,4-diamino derivative 11 as product of disubstitution and major groove of DNA. In this respect, the 4-methoxy-
in 83% yield. Also, the reaction with excess of sodium pyrimidine nucleosides 8, 10 and 12 seem to be promising
methoxide under heating gave disubstituted 2,4-dimethoxy candidates for new efficiently replicable base-pairs.[6] More-
derivative 12 in 87% yield.
over, this approach is applicable in the synthesis of a 2D
Silylated C-nucleoside 6 was subjected to Fe-catalyzed library of derivatives. Studies along these lines are now in
cross-coupling[13,14] with MeMgCl in the presence of Fe- progress in our laboratory.
(acac)3 (Scheme 3). When using 1.5 equiv. of MeMgCl,
monosubstituted 2-chloro-4-methyl derivative 13 was re-
Supporting Information (see footnote on the first page of this arti-
cle): Complete Experimental Section and additional figures of crys-
gioselectively prepared in 46% yield, whereas the use of
4 equiv. of MeMgCl gave 2,4-dimethyl derivative 14 in 68%
yield. The silylated derivatives 13 and 14 were readily de-
protected by treatment with Et3N·3HF to give the free nu-
cleosides 15 and 16. The free 2-chloro-4-methylpyrimidine
nucleoside 16 was then subjected to nucleophilic substitu-
tions with NaOMe or methanolic ammonia at 120 °C giv-
ing rise to 2-methoxy- or 2-amino-4-methylpyrimidines 17
and 18 in 65 and 68%, respectively. The Suzuki cross-cou-
pling of silylated intermediate 13 with PhB(OH)2 in the
presence of Pd(PPh3)4 gave 2-phenyl-4-methylpyrimidine
nucleoside 19 in 59% yield, which was further desilylated
by using Et3N·3HF to give the free C-nucleosides 20 in 73%
tal structures and packings.
Acknowledgments
This work was supported by the Academy of Sciences of the Czech
Republic (Z4 055 905), by the Ministry of Education (LC 512), by
the Grant Agency of the ASCR (IAA400550902), and by Gilead
Sciences, Inc..
ˇ
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Received: February 4, 2010
Published Online: March 30, 2010
Eur. J. Org. Chem. 2010, 2666–2669
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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