Synthesis of (±)-2′,3′-dideoxy-3′-fluoroapiosylpyrimidine nucleosides

Article abstract of DOI:10.1039/a800665b

Various (±)-2′,3′-dideoxy-3′-fluoroapiosylpyrimidine nucleoside analogs have been prepared.

Full text of DOI:10.1039/a800665b

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Synthesis of (±)-2A,3A-dideoxy-3A-fluoroapiosylpyrimidine nucleosides
Soon Kil Ahn,*a,b† Deukjoon Kim,a Hoe Joo Son,b Byeong Seon Jeong,b Ryung Kee Hong,b Bok Young Kim,b
Eung Nam Kim,b Ku Hun Chungb and Jung Woo Kimb
a College of Pharmacy, Seoul National University, San 56-1, Shinrim-dong, Kwanak-gu, Seoul, South Korea
a Chong Kun Dang Research Institute, 410 Shindorim-dong, Guro-gu, Seoul, South Korea
Various ( )-2A,3A-dideoxy-3A-fluoroapiosylpyrimidine nu-
reaction5 of bis-silyl protected dihydroxyacetone 16 with ethyl
bromoacetate in the presence of activated zinc gave a b-hydroxy
ester 2. This was then treated with a 12% methanolic HCl
solution at room temperature to afford hydroxy lactone 3 in 77%
yield over two steps. The primary hydroxy group of 3 was
selectively protected with a tert-butyldiphenylsilyl group to
give 4 in 93% yield.7 Fluorination of the tertiary alcohol of 4
with DAST in CH2Cl2 at room temperature gave fluoro lactone
5 in 32% yield. In this reaction the a,b-unsaturated lactone was
obtained by elimination reaction in 27% yield. Reduction of
fluoro lactone 5 to lactol with DIBAL-H at 278 °C followed by
acetylation with Ac2O gave the key intermediate, 2,3-dideoxy-
3-fluoroapiofuranosyl acetate 6, in 70% yield over two steps.
cleoside analogs have been prepared.
Since the discovery and synthesis of nucleocidin,1 which has a
unique 4A-fluorosugar, a number of 4A-substituted nucleosides2
and 4A-substituted carbocyclic nucleosides3 have been synthe-
sized and their biological activities evaluated. Among them,
4A-azidothymidine exhibited potent anti-HIV activity.
O
NH2
Me
N
N
HN
O
N
B
HO
2'
O
N
N
3'
F
1'
H2NSO3
HO
TBDPSO
OAc
O
O
4'
F
N3
HO
4'-Azidothymidine
F
O
2',3'-Dideoxy-3'-fluoroapiosyl
nucleoside
HO OH
Nucleocidin
6
i
Y
N
Y
N
In our effort to synthesize novel 4A-substituted nucleoside
derivatives with biological activity, we envisioned 2A,3A-
dideoxy-3A-substituted apiosyl nucleosides to be one of these
4A-substituted nucleosides. While the synthesis and biological
activities of a great many structurally modified nucleoside
analogs have been reported, relatively little work has been done
on the synthesis and biological activities of nucleoside analogs
which contain apiose as the sugar moiety.4 Here we report on
the synthesis of (±)-2A,3A-dideoxy-3A-fluoroapiosylpyrimidine
nucleosides.
X
X
N
N
O
O
+
TBDPSO
TBDPSO
F
F
O
O
7a X = Me, Y = OH, 24%
8a X = Me, Y = OH, 13%
b
c
d
e
f
X = F, Y = OH,
X = Cl, Y = OH, 12%
X = I, Y = OH, 35%
31%
b
c
d
e
f
X = F, Y = OH,
X = Cl, Y = OH, 56%
X = I, Y = OH, 46%
46%
The synthesis of the key intermediate, 2,3-dideoxy-3-fluor-
oapiofuranosyl acetate 6, is shown in Scheme 1. Reformatsky
X = H, Y = NHAc, 26%
X = F, Y = NHBz, 45%
X = H, Y = NHAc, 26%
X = F, Y = NHBz, 41%
TBDPSO
OH
TBDPSO
i
O
TBDPSO
CO2Et
TBDPSO
ii (for 9a–d)
iii (for 9g,h)
ii (for 10a–d)
1
2
3
iii (for 10g,h)
ii
Y
Y
X
X
TBDPSO
HO
HO
N
N
iii
O
O
HO
N
O
N
O
O
iv
O
4
HO
HO
F
F
O
O
9a X = Me, Y = OH, 94%
b X = F, Y = OH, 80%
c X = Cl, Y = OH, 78%
d X = I, Y = OH, 67%
10a X = Me, Y = OH, 92%
b X = F, Y = OH, 93%
c X = Cl, Y = OH, 62%
d X = I, Y = OH, 77%
TBDPSO
TBDPSO
v, vi
O
OAc
F
F
O
O
5
6
g X = H, Y = NH2, 72%
h X = F, Y = NH2, 77%
g X = H, Y = NH2, 90%
h X = F, Y = NH2, 95%
Scheme 1 Reagents and conditions: i, BrCH2CO2Et, activated Zn, benzene–
toluene (2:1), reflux, 4 h; ii, 12% HCl in MeOH, room temp., 20 h, 77% (2
steps); iii, TBDPSCl, DMAP, Et3N, CH2Cl2, room temp. overnight, 93%;
iv, DAST, CH2Cl2, room temp. 1 h, 32%; v, DIBAL-H, CH2Cl2, 278 °C,
0.5 h; vi, Ac2O, Et3N, DMAP, CH2Cl2, room temp. 0.5 h, 70% (2 steps)
Scheme 2 Reagents and conditions: i, bis-silylated base, TMSOTf,
ClCH2CH2Cl, 0 °C, 0.5 h; ii, TBAF, THF, room temp.; iii, methanolic NH3,
room temp. then TBAF, THF, room temp.
Chem. Commun., 1998
967

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(a)
NH2
N
conclusively on the basis of X-ray crystallography (Fig. 2).§
Compound 9g assumes the 4A-endo conformation, in which the
fluorine at C-4A is approximately in a gauche disposition relative
to the furan oxygen.
4.5%
3.3%
0%
H3''
H6
H3''
HO
H2'b
N
H2'a
0%
Evaluation of antiviral activities and asymmetric synthesis of
2A,3A-dideoxy-3A-fluoroapiosyl nucleosides are in progress.
We are grateful to Drs C. I. Hong and S. J. Lee for helpful
O
0%
F
H
O
4.3%
H4'b
1
H4'a
discussions. Special thanks are due to Mr W. K. Choi for H
NMR studies and Dr S. H. Kim for X-ray crystallography. One
of us (D. Kim) acknowledges financial support from the
KOSEF and Ministry of Health and Welfare (HMP-
96-D-1017).
(b)
0%
H3''
Notes and References
1.5%
H3''
HO
H2'b
† E-mail: hck@bora.dacom.co.kr
‡ All new compounds gave satisfactory analytical and spectral data.
Selected data for 9g: mp 179–181 °C; dH([2H6]DMSO)2.21 (ddd, J2A ,F 35.5
H
H2'a
0%
O
b
F
J2A ,2A 14.6, J2A ,1A 7.7, 1 H, Hb-2A), 2.44 (m, 1 H, Ha-2A), 3.66 (m, 2 H, H-3B),
O
N
3.94 (dd, J4A ,Fb21.5, J4A ,4A 10.8, 1 H, Ha-4A), 4.19 (dd, J4A ,F 35.1, J4A ,4A
b
a
4.1%
H4'b
H4'a
a
b
b
H6
N
1.9%
10.8, 1 H, Hb-4A), 6.10 a(dd, J1A,2A 7.7, J1A,2A 6.6, 1 H, H-b1A);dc(CD3ODa)
166.78, 157.14, 141.54, 105.40, 103.62, 95.1a4, 88.68, 75.33, 75.07, 63.00,
b
0%
NH2
62.73, 40.67, 40.44; lmax(H2O)/nm 269.4, 229.0 (sh) (pH 7), 278.0, 209.3
(sh) (pH 2), 268.0 (pH 11) (Calc. for C9H12N3O3F; C, 47.16; H, 5.28; N,
18.33. Found: C, 47.21; H, 5.36; N, 18.22%). For 10g: mp 219–220 °C;
dH([2H6]DMSO) 2.08 (dddd, J2A ,F 21.9, J2A ,2A 15.2, J2A ,1 2.5, J2A ,4A 1.5, 1
Fig. 1 NOE experiments of compounds (a) 9g and (b) 10g
H, Ha-2A), 2.56 (ddd, J2A ,F 35.7, J2A ,2A 15.2, J2bA ,1A 7.6,1 aH, Hb-2A), 3.59 (dd,
a
a
a
b
The coupling of acetate 6 with bis-silylated pyrimidine
derivatives under Vorbru¨ggen conditions is depicted in Scheme
2.8 Bis-silylated pyrimidine derivatives were condensed with
fluorosugar 6 in the presence of TMSOTf in 1,2-dichloroethane
to give an a:b mixture of 7 and 8 in moderate yield. The
mixtures were separated by silica gel column chromatography
to give the individual isomers 7 and 8. Deprotection of 7 and 8
afforded the pyrimidine nucleosides 9 and 10, respectively.‡
The structural assignment of the uracil and cytosine analogs
was made on the basis of 1H NMR studies. For example, upon
irradiation of the H-3B protons in compound 9g, nuclear
Overhauser effects (NOEs) were observed for the H-2Ab (4.5%)
and H-4Ab (4.3%) protons, while no NOEs were detected for the
H-2Aa and H-4Aa protons. Irradiation of the H-6 proton resulted in
an NOE for the H-2Ab (3.3%) proton, while no NOE was
observed for the H-2Aa proton. In compound 10g, upon
irradiation of the H-3B proton, NOEs were detected for the H-2Ab
(1.5%) and H-4Ab (4.1%) protons, while no NOEs were observed
for the H-2Aa and H-4Aa protons. Irradiation of the H-6 proton
resulted in an NOE for the H-4Aa (1.9%) proton, while no NOE
was detected for the H-4Ab proton (Fig. 1). The above results
showed 9g was the b-isomer and 10g was the a-isomer. The
relative configuration of the rest of the compounds in this report
was assigned using the results of the same NOE experiments.
The b-configuration of cytosine analog 9g was determined
b
a
b
J3B,F 20.7, J3B,3B 12.1, 1 H, H-3B), 3b.65(dd, J3B,F 16.7, J3B,3B 12.1, 1 H, H-3B),
3.96 (dd, J4A ,F 34.5, J4A ,4A 10.9, 1 H, Hb-4A), 4.26 (ddd, J4A ,F 20.5, J4A 4A
10.9, J4A ,2A 1.5, 1 H, Hab-4A), 6.02 (dd, J1A,2A 7.6, J1A,2Aa 2.5, 1aH, H-1A), 7a.54
b
a
b
(d, J6,5 7.4,a1 H, H-6); dC(CD3OD) 166.81,b157.20, 141.15, 141.10, 104.64,
a
102.87, 94.45, 87.87, 76.15, 75.91, 62.81, 62.53, 40.93, 40.71; lmax(H2O)/
nm 269.8, 229.2 (sh) (pH 7), 278.6, 219.6 (sh) (pH 2), 270.2 (pH 11) (Calc.
for C9H12N3O3F; C, 47.16; H, 5.28; N, 18.33. Found: C, 47.09; H, 5.18; N,
18.48%).
§ Crystal data for 9g: C9H12FN3O3, M = 229.22, monoclinic, space group
P21/c (No. 14), unit cell dimensions a = 5.1519 (10), b = 10.7326 (13), c
= 17.756 (2) Å, b = 92.39 (2)°, V 981.0 (3) Å3, T = 293 (2) K, Z = 4, m
= 0.130 mm21, F(000) = 480, 1580 reflections were measured and 1409
independent reflections were used for the structure solution. Final R values
are as follows: wR2
182/821.
= 0.0970 {R1 = 0.0373 [I = 2s(I)]}. CCDC
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¨
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O(2)
F
Fig.
2
ORTEP drawing of (±)-1-(2,3-dideoxy-3-fluoroapio-
b-furanosyl)cytosine 9g
Received in Cambridge, UK, 26th January 1998; 8/00665B
968
Chem. Commun., 1998