Stereoselective synthesis of 1′-functionalized-4′- thionucleosides

Article abstract of DOI:10.1080/15257770701508588

Stereoselective functionalization of the 1′-position of 4′-thionucleosides was achieved using a stereoselective SN2 reaction controlled by 5-membered ring coordination. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701508588

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Stereoselective Synthesis of 1′-
Functionalized-4′-Thionucleosides
Lak Shin Jeong a , Prashantha Gunaga a , Hea Ok Kim a , Dilip K. Tosh
a , Hyuk Woo Lee a , Seung Ah Choe a , Hyung Ryong Moon b , Zhan-
Guo Gao c , Kenneth A. Jacobson c & Moon Woo Chun d
a College of Pharmacy , Ewha Womans University , Seoul, Korea
b College of Pharmacy , Pusan National University , Busan, Korea
c Laboratory of Bioorganic Chemistry, National Institute of Diabetes,
and Digestive and Kidney Disease, NIH , Bethesda, Maryland, USA
d College of Pharmacy , Seoul National University , Seoul, Korea
Published online: 10 Dec 2007.
To cite this article: Lak Shin Jeong , Prashantha Gunaga , Hea Ok Kim , Dilip K. Tosh , Hyuk Woo Lee ,
Seung Ah Choe , Hyung Ryong Moon , Zhan-Guo Gao , Kenneth A. Jacobson & Moon Woo Chun (2007)
Stereoselective Synthesis of 1′-Functionalized-4′-Thionucleosides, Nucleosides, Nucleotides and
Nucleic Acids, 26:8-9, 1011-1014, DOI: 10.1080/15257770701508588
To link to this article: http://dx.doi.org/10.1080/15257770701508588
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1011–1014, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508588
STEREOSELECTIVE SYNTHESIS OF
1ꢀ-FUNCTIONALIZED-4ꢀ-THIONUCLEOSIDES
Lak Shin Jeong, Prashantha Gunaga, Hea Ok Kim, Dilip K. Tosh,
Hyuk Woo Lee, and Seung Ah Choe
College of Pharmacy, Ewha Womans
2
University, Seoul, Korea
Hyung Ryong Moon
College of Pharmacy, Pusan National University,
2
Busan, Korea
Zhan-Guo Gao and Kenneth A. Jacobson
Laboratory of Bioorganic Chemistry,
2
National Institute of Diabetes, and Digestive and Kidney Disease, NIH, Bethesda,
Maryland, USA
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
2
Stereoselective functionalization of the 1ꢁ-position of 4ꢁ-thionucleosides was achieved using a
2
stereoselective SN 2 reaction controlled by 5-membered ring coordination.
Keywords 4ꢁ-Thionucleosides; SN2 reaction; 5-membered ring coordination, A3 adeno-
sine receptor antagonis
INTRODUCTION
It has been known to be difficult to discover A3AR antagonists with
a nucleoside skeleton due to the structural resemblance to a natural lig-
and, adenosine. Thus, nonnucleoside derivatives with a heterocyclic skele-
ton have been reported as potent and selective A3AR antagonists,[1,2] but
they had several drawbacks such as dependence of species and low water
solubility.[3] Therefore, it is very interesting to discover novel A3AR antago-
nists with a nucleoside skeleton to overcome the disadvantages of nonnucle-
oside A3AR antagonists. To achieve this goal, the potent and pure human
A3AR agonists[4] compounds 1a and 1b were first transformed to L-type nu-
cleosides 2 since D-type nucleosides were thought to possess the intrinsic
agonistic activity due to the structural resemblance with a natural ligand
This work was supported by the grant of the Seoul R&BD Program (10541).
Address correspondence to Lak Shin Jeong, College of Pharmacy, Ewha Womans University, Seoul
120-750, Korea. E-mail: lakjeong@ewha.ac.kr
1011

1012
L. S. Jeong et al.
FIGURE 1 Rationale for the design of the target nucleosides.
D-adenosine. In addition, the 5ꢁ-uronamide group of 1a and 1b, which is
essential for an A3AR agonistic activity through a hydrogen bonding[4] at
the binding site of the A3AR, was changed from β- to α-position to remove
a hydrogen bonding with the receptor, and to induce favorable interaction
for A3AR antagonism (Figure 1).
Herein, we report the synthesis of the target nucleoside 2 using the stere-
oselective functionalization of 4ꢁ-thionucleosides and their binding affinities
to adenosine receptors.
RESULTS AND DISCUSSION
In general, the stereoselective introduction of the functional groups at
the 1ꢁ-position of 4ꢁ-oxonucleosides was to utilize the enolization of the 2ꢁ-
ketouridine followed by treating with an electrophile like PhSeCl to give 1ꢁ-
α-branched derivative and 1ꢁ-β-branched derivative in low stereoselectivity
(1.2∼2.9:1).[5] Thus, we decided to functionalize directly the 1ꢁ-position of
the 4ꢁ-thionucleosides, utilizing the acidic character of the α-proton to the
sulfur atom, as shown in Scheme 1.
D-Gulonic γ -lactone (3) was converted to the diol 4 according to our
previously reported procedure.[4] Treatment of diol 4 with one equivalent
of lead tetraacetate at 0◦C produced the aldehyde, but use of excess lead
tetraacetate at room temperature gave the acetate 5 (68%) as a major prod-
uct. Condensation of the glycosyl donor 5 with 2,6-dichloropurine using
TMSOTf as a Lewis acid catalyst gave the β-anomer 6 as a single stereoisomer
1
in high yield, whose configuration was confirmed by H NOE experiment
between H-8 and 3ꢁ-H. During the condensation, the initially formed N3-
isomer was smoothly rearranged to the desired N9-isomer upon heating.[4]
Compound 6 was transformed to di-O-THP ether 7 easily removable under
very mild acidic conditions to prevent deglycosylation, which may happen
during the deprotection of the isopropylidene group due to the presence of
the electron-withdrawing 1ꢁ-methylamide group at the final step. Lithiation

1ꢁ-Functionalized-4ꢁ-Thionucleosides
1013
SCHEME 1 Regents and cnditions: a) Pb(OA)4, EtOAC, rt; b) silylated 2.6-dichloropurine, TMSOTf,
DCE, 70◦C; c) 2 M HCl, THF; d) 3,4-dihydro-2H-pryan, PPTS, CH2Cl2; e) LiHMDS, THF, ClCOOMe,
−78◦C ; f) R1NH2, THF-EtOH, rt, 2 hours; g) MeNH2 , THF, rt, 2 hours; h) p- TsOH, MeOH, CH2CL2.
of 7 with LiHMDS at the most acidic 1ꢁ-position followed by treatment of
methyl chloroformate gave the 1ꢁ-α carbonate 8 as a single stereoisomer.
Stereoselective formation of 8 might be explained with stable 5-membered
ring coordination between N3 atom and 1ꢁ-lithium, which allowed an elec-
trophile (alkyl chloroformate) to approach only from the α-side. Selective
N 6-amination of 8 with various amines at room temperature followed by con-
version of methyl ester into methyl amide afforded the corresponding N 6-
substituted derivatives, whose THP groups were deprotected with p -TsOH
in MeOH to give 9a–f. Binding affinity of the final 4ꢁ-thionucleosides 9a–f
were measured using radioligand binding assays.[2] All final nucleosides did
not show any significant binding affinity to human A3AR.
In summary, we have achieved stereoselective synthesis of 1ꢁα-
substituted-4ꢁ-thionucleosides using stereoselective nucleophilic substitu-
tion with 100% retention of stereochemistry. To our best knowledge, it is
the first example to functionalize 1ꢁ-position of 4ꢁ-thionucleosides in stere-
oselective manner.
REFERENCES
1. Baraldi, P.G.; Cacciari, B.; Romagnoli, R.; Merighi, S.; Varani, K.; Borea, P.A.; Spalluto, G. A3 adeno-
sine receptor ligands: History and perspectives. Med. Res. Rev. 2000, 10, 103–128.
2. Gao, Z.-G.; Jeong, L.S.; Moon, H.R.; Kim, H.O.; Choi, W.J.; Shin, D.H.; Elhalem, E.; Comin, M.J.;
Melaman, N.; Mamedova, L.; Gross, A.S.; Rodriguez, J.B.; Jacobson, K.A. Structural determinants of

1014
L. S. Jeong et al.
efficacy at A3 adenosine receptors: Modification of the ribose moiety. Biochem. Pharmacol. 2004, 67,
893–901.
3. Gao, Z.-G.; Joshi, B.V.; Klutz, A.M.; Kim, S.-K.; Lee, H.W.; Kim, H.O.; Jeong, L.S.; Jacobson, K.A.
Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5ꢁ-
ribofuran-uronamide moiety. Bioorg. Med. Chem. Lett. 2006, 16, 596–601.
4. Jeong, L.S.; Lee, H.W.; Jacobson, K.A.; Kim, H.O.; Shin, D.H.; Lee, J.A.; Gao, Z.-G.; Lu, C.; Duong,
H.T.; Gunaga, P.; Lee, S.K.; Jin, D.Z.; Chun, M.W.; Moon, H.R. Structure-activity relationships of 2-
Chloro-N 6-substituted-4ꢁ-thioadenosine-5ꢁ-uronamides as highly potent and selective agonists at the
human A3 adenosine receptor. J. Med. Chem. 2006, 49, 273–281.
5. Kodama, T.; Shuto, S.; Nomura, M.; Matsuda, A. Synthesis of a 1ꢁ-α-phenylselenouridine derivative as
a synthetic precursor for various 1ꢁ-modified nucleosides, via enolization at the 1ꢁ-position of 3ꢁ,5ꢁ-O-
TIPDS-2ꢁ-ketouridine. Tetrahedron Lett. 2000, 41, 3643–3646.