Stereoselective synthesis of amino-substituted apio dideoxynucleosides through a distant neighboring group effect

Article abstract of DOI:10.1016/S0040-4039(02)01295-9

Novel amino-substituted apio nucleoside (2R,4R)-LJ-45 as a potential anti-HBV agent was stereoselectively synthesized from the known oxazolidine 1 through a distant neighboring group effect. It is believed that this synthetic method using a chiral template, (-)-L-serine methyl ester can be generally applied to the synthesis of other chiral amino-substituted nucleosides.

Full text of DOI:10.1016/S0040-4039(02)01295-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6241–6243
Stereoselective synthesis of amino-substituted apio
dideoxynucleosides through a distant neighboring group effect
Won Jun Choi,a Hee Sung Ahn,a Hea Ok Kim,b Sanghee Kim,c Moon Woo Chunc and
Lak Shin Jeonga,*
aLaboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea
bDivision of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, Republic of Korea
cCollege of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
Received 29 March 2002; revised 26 June 2002; accepted 28 June 2002
Abstract—Novel amino-substituted apio nucleoside (2R,4R)-LJ-45 as a potential anti-HBV agent was stereoselectively synthesized
from the known oxazolidine 1 through a distant neighboring group effect. It is believed that this synthetic method using a chiral
template, (−)-L-serine methyl ester can be generally applied to the synthesis of other chiral amino-substituted nucleosides. © 2002
Elsevier Science Ltd. All rights reserved.
Hepatitis B is a viral disease which afflicts about 350
million people worldwide,1 but effective chemothera-
peutics are still not available for the treatment of
hepatitis B virus (HBV) infected individuals except
Since the discovery of lamivudine as an anti-HBV drug,
many nonclassical types of nucleosides such as 1,3-
dioxolanyl nucleosides,3 -nucleosides,4 isonucleosides,5
L
apio nucleosides6 and carbocyclic nucleosides7 have
been synthesized and found to be active against HBV.
L
-b-1,3-oxathiolanyl cytosine (3TC, lamivudine)2
approved by the Food and Drug Administration
(FDA).
Recently, we have reported the synthesis of racemic
amino and azido substituted apio nucleosides8 as poten-
tial antiviral agents, among which adenine derivative,
LJ-45 was found to be active (EC50=3.5 M in 2.2.15
cells)6 against hepatitis B virus (HBV) (Fig. 1).
NH2
N
N
N
N
NH2
O
Since biological activity of racemic mixture generally
resides in one enantiomer, it was of interest to synthe-
size each enantiomeric pure form of LJ-45 and to find
out which enantiomer is responsible for anti-HBV
activity. In this communication, we report the asym-
metric synthesis of one of the enantiomers, (2R,4R)-LJ-
45 and its anti-HBV activity. For the synthesis of
enantiomeric pure stereoisomer, (2R,4R)-LJ-45, we uti-
lized Seebach’s chemistry9 to fix the stereochemistry of
C3% position.
N
N
N
N
HO
NH2
O
(2R,4R)-LJ-45
HO
O
NH2
LJ-45
H2N
HO
N
N
N
N
NH2
(2S,4S)-LJ-45
Our initial attempt to synthesize the desired (2R,4R)-
LJ-45 started from the known oxazolidine 19 prepared
from (−)-L-serine methyl ester (Scheme 1).
Figure 1.
Reaction of 1 with LDA at −78°C followed by treat-
ment with allyl bromide gave 2 as a single stereoisomer
(55%). Treatment of allyl ester 2 with Super-hydride at
−78°C afforded the alcohol 3 which was subjected to
Keywords: apio nucleoside; oxazolidine intermediate; distant neigh-
boring group effect.
* Corresponding author. Tel: +82-2-3277-3466; fax: +82-2-3277-2851;
e-mail: lakjeong@ewha.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01295-9

6242
W. J. Choi et al. / Tetrahedron Letters 43 (2002) 6241–6243
H
lowed by reductive work-up gave the lactol 12 as a
H
O
O
diastereomeric mixture in 82% yield. Lactol 12 was
converted to the corresponding acetate. However, the
Vorbru¨ggen coupling of this acetate did not yield the
glycosylated product. Hence, the lactol 12 was directly
condensed with 6-chloropurine under standard Mit-
sunobu conditions to give 13a (35%) and 13b (3.5%) in
10:1 ratio after flash silica gel column chromatography
with recovered lactol 12 (18%). High stereoselectivity
obtained during the condensation may be attributed to
the neighboring group effect by acetamido group
because the condensation using the corresponding free
amino sugar gave no stereoselectivity. It is very interest-
ing to note that neighboring group effect by distant
acetamido group, not by vicinal acetamido group can
exist although Mukaiyama et al.12 reported the elegant
LDA, HMPA, THF
CH2=CH-CH2Br
-78 oC to 0 oC
55%
N
N
CO2Me
CO2Me
O
O
2
1
Super-hydride
THF, -78 oC
75%
H
H
O
O
OH
N
N
i) O3
ii) CH3SCH3
48%
O
OH
O
O
3
4
6-chloropurine
PPh3, DEAD
THF
30%
H
H
O
H
O
NaH, n-Bu4NI
BnBr, THF
O
B
H+
N
N
decomposition
N
reflux
65%
O
OBn
O
OH
O
O
5 (B = 6-chloropurine)
8
3
p-TsOH
MeOH
reflux
57%
Super-
hydride
NH2
p-TsOH
NH2
2
OTBDPS
MeOH RO
HO
racemization
CO2Me
6a (R = H)
Ac2O
NH2
NHAc
OBn
7
TBDPSCl
80%
OBn
pyridine, 0 oC
67%
HO
AcO
6b (R = TBDPS)
9
10
guanidine, rt
Scheme 1.
91%
EtOH/CH2Cl2 = 9/1
ozonolysis to give spiro lactol 4. Spiro lactol 4 was
condensed with 6-chloropurine under the Mitsunobu
conditions10 to give the spiro nucleoside 5 in 30% yield
with high b-diastereoselectivity (b/a=20/1). This cou-
pling method turned out to be better than the acid-cat-
alyzed coupling method of the spiro lactol acetate
prepared from acetylation of 4 with silylated 6-chloro-
purine. Unfortunately, hydrolysis of 5 under the vari-
ous acidic conditions could not afford the desired
nucleoside, but resulted in deglycosylation.
O
OH
O3 then (CH3)2S
NHAc
OBn
BnO
HO
82%
NHAc
12
11
6-chloropurine
PPh3, DEAD, rt
Cl
NOE (0.63%)
N
N
N
No NOE
H
H
O
To circumvent the deglycosylation, we decided to
hydrolize oxazolidine ring before condensation with
6-chloropurine. Allyl ester 2 was treated with p-TsOH
in methanol to give 6a and the resulting alcohol was
protected as t-butyldiphenylsilyl ether to give 6b.
Reduction of 6b with Super-hydride at −78°C gave the
alcohol derivative, but racemization occurred under the
reaction conditions.
N
H
O
+
N
N
BnO
H
N
BnO
NHAc
N
NHAc
13a (35%)
Cl
13b (3.5%)
1) NH3, MeOH, 70 oC
2) Pd black,
1) NH3, MeOH, 70 oC
2) Pd black,
41%
44%
4.4% HCO2H/MeOH
3) NaOMe, MeOH, 70 oC
4.4% HCO2H/MeOH
3) NaOMe, MeOH, 70 oC
To avoid the racemization, the hydroxyl group of 3 was
protected as benzyl ether 8 which was hydrolyzed under
the same acidic conditions to give amino alcohol 9
without racemization (Scheme 2).
NH2
O
N
N
N
N
N
N
HO
O
N
NH2
N
Since ozonolysis of 9 under the presence of free amino
group did not give the satisfactory yield, 9 was treated
with acetic anhydride in pyridine to give 10, in which
acetate was selectively removed by treating with
guanidine11 to afford amide 11. Ozonolysis of 11 fol-
HO
NH2
NH2
14b
14a
Scheme 2.

W. J. Choi et al. / Tetrahedron Letters 43 (2002) 6241–6243
6243
and highly stereoselective synthesis of b-deoxyribonu-
cleosides using similar distant neighboring group parti-
cipation. However, they obtained high b-stereoselectiv-
ity by using thiocarbamate group, but low b-selectivity
by using the benzoyl group, while we obtained the very
high b-selectivity by using acetamido group. To our
best knowledge, it is the first example of neighboring
group participation by the distant acetamido group.
Anomeric configurations of 13a and 13b were easily
assigned by 1H NOE experiments. Treatment of 13a
and 13b with methanolic ammonia at 70°C gave the
adenine derivatives which were reacted with palladium
black in 4.4% formic acid/methanol followed by sodium
methoxide solution to afford the final adenine deriva-
tives 14a13 and 14b, respectively.
(b) Jeong, L. S.; Schinazi, R. F.; Beach; Kim, H. O.;
Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMil-
lan, A.; Chu, C. K. J. Med. Chem. 1993, 36, 181.
3. Kim, H. O.; Shanmuganathan, K.; Alves, A. J.; Jeong, L.
S.; Beach, J. W.; Schinazi, R. F.; Chang, C.-N.; Cheng,
Y.-C.; Chu, C. K. Tetrahedron Lett. 1992, 33, 6899.
4. (a) Chu, C. K.; Ma, T.; Shanmuganathan, K.; Wang, C.;
Xiang, Y.; Pai, S. B.; Tao, G.-Q.; Sommadossi, J.-P.;
Cheng, Y.-C. Antimicrob. Agents Chemother. 1995, 39,
979; (b) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Zhu, Y.-L.;
Gullen, E.; Dutschman, G. E.; Cheng, Y.-C. J. Med.
Chem. 1996, 39, 1757.
5. Yoo, S. J.; Kim, H. O.; Lim, Y.; Kim, J.; Jeong, L. S.
Bioorg. Med. Chem. 2002, 10, 215.
6. Jeong, L. S.; Moon, H. R.; Hong, J. H.; Yoo, S. J.; Choi,
W. J.; Kim, H. O.; Ahn, H. S.; Baek, H. W.; Chun, M.
W.; Kim, H.-D.; Kim, J.; Choi, J.-R. Nucleosides, Nucle-
otides Nucleic Acids 2001, 20, 657.
7. (a) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J. P.;
Innaimo, S.; Jacobs, G. A.; Kocy, O.; Lapointe, P.;
Martel, A.; Merchant, Z.; Slusarchyk, W. A.; Sundeen, J.
E.; Young, M. G.; Colonno, R.; Zahler, R. Bioorg. Med.
Chem. Lett. 1997, 7, 127; (b) Innaimo, S. F.; Seifer, M.;
Bisacchi, G. S.; Standring, D. N.; Zahler, R.; Colonno,
R. J. Antimicrob. Agents Chemother. 1997, 41, 1444; (c)
Genovesi, E. V.; Lamb, L.; Medina, I.; Tayler, D.; Seifer,
M.; Innaimo, S.; Colonno, R. J.; Standring, D. N.; Clark,
J. M. Antimicrob. Agents Chemother. 1998, 42, 3209.
8. Jeong, L. S.; Lee, Y. A.; Moon, H. R.; Chun, M. W.
Nucleosides Nucleotides 1998, 17, 1473.
Anti-HBV activity and cytotoxicity of the final
nucleosides 14a and 14b were determined in 2.2.15 cells,
but both compounds exhibited neither significant anti-
HBV activity nor cytotoxicity up to 100 mM, indicating
that anti-HBV activity of LJ-45 may reside in (2S,4S)-
LJ-45. Further biological evaluation and asymmetric
synthesis of the other enantiomer, (2S,4S)-LJ-45 are in
progress in our laboratory.
In summary, we have accomplished the stereoselective
synthesis of amino-substituted apio nucleoside (2R,4R)-
LJ-45 from oxazolidine 1, through a distant neighbor-
ing group effect. It is believed that this synthetic
method using a chiral template, (−)-L-serine methyl
ester can be generally applied to the synthesis of other
chiral amino-substituted nucleosides.
9. Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R.
Helv. Chim. Acta 1987, 70, 1194.
10. Mitsunobu, O. Synthesis 1981, 1.
11. Kunesch, N.; Miet, C.; Poisson, J. Tetrahedron Lett.
1987, 28, 3569.
Acknowledgements
12. Mukaiyama, T.; Hirano, N.; Uchiro, H. Chem. Lett.
1996, 99.
This work was supported by the grant from the Korea
Health R&D Project, Ministry of Health and Welfare,
Korea (HMP-01-PJ1-PG1-01CH13-0002).
13. Compound 14a: mp 165.1–165.7°C; MS (FAB) m/z 251
(M+H+); UV (MeOH) umax 260 nm (m=13 040); [h]2D5
−42.7 (c 0.1, MeOH); 1H NMR (CD3OD, 400 MHz) l
2.39 (dd, 1H, J=6.8, 14.0 Hz, 2%-Ha), 2.74 (dd, 1H,
J=6.8, 14.0 Hz, 2%-Hb), 3.69 (dd, 2H, J=10.8, 19.6 Hz,
CH2OH), 4.03 (dd, 2H, J=8.8, 20.8 Hz, 4%-H), 6.49 (t,
1H, J=7.2 Hz, anomeric H), 8.20 (s, 1H, H-8), 8.30 (s,
1H, H-2); 13C NMR (CD3OD, 100 MHz) l 41.692,
62.803, 66.369, 77.097, 85.655, 139.825, 149.173, 152.570,
156.098. Anal. calcd for C10H14N6O2: C, 47.99; H, 5.64;
N, 33.58. Found: C, 47.86; H, 5.28, N, 33.20%.
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