Participation of sulfur occurred during the Mitsunobu reaction: Synthesis of novel isodideoxythionucleosides

Article abstract of DOI:10.1039/a806562d

Novel isodideoxythionucleosides have been synthesized from our versatile intermediate, L-4-thioarabitol derivative 5 using the Mitsunobu reaction as a key step. It is found that the sulfur atom of the 4-thiofuranose derivative takes part in the Mitsunobu

Full text of DOI:10.1039/a806562d

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Participation of sulfur occurred during the Mitsunobu reaction:
synthesis of novel isodideoxythionucleosides
Lak Shin Jeong,*a Su Jeong Yoo,a Hyung Ryong Moon,a Yun Ha Kima and Moon Woo Chunb
a Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea
b College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Received (in Cambridge) 20th August 1998, Accepted 9th September 1998
Novel isodideoxythionucleosides have been synthesized
HO
S
O
S
ref. 6
a
from our versatile intermediate, L-4-thioarabitol derivative
5 using the Mitsunobu reaction as a key step. It is found
that the sulfur atom of the 4-thiofuranose derivative takes
part in the Mitsunobu reaction.
OH
OH
OBn
86%
HO
O
BnO
O
OBz
6
OBz
4
5
Ph
93%
b
R = Si C(CH3)3
Introduction
Ph
S
S
S
1,3-Oxathiolanyl pyrimidine and purine nucleosides (1) belong
to an unusual class of nucleosides in that the C3 methylene is
substituted by an oxygen atom.1 Many of them have been found
to show potent antiviral activities against the human immuno-
deficiency virus (HIV) and hepatitis B virus (HBV).1 In partic-
ular, -1,3-oxathiolanyl cytosine (3TC, lamivudine) is being
clinically used for the treatment of AIDS patients2 and -1,3-
oxathiolanyl 5-fluorocytosine (FTC) is now undergoing clinical
trials as an anti-HBV agent.3
Isodideoxynucleosides in which the ring oxygen and 3Ј-
carbon of 2Ј,3Ј-dideoxyribose unit are interchanged are also an
unusual class of nucleosides developed since the discovery of
3TC.4 Among these compounds, iso-ddA (2a) and iso-ddG (2b)
have been reported to exhibit potent anti-HIV activity without
apparent cytotoxicity.4,5 These compounds possess enhanced
chemical and enzymatic stability of the labile glycosidic bond
when compared to 2Ј,3Ј-dideoxynucleosides.
c
d
OH
F
F
54%
100%
RO
RO
RO
OBz
OBz
OH
9
8
7
Scheme 1 Reagents and conditions: (a) BCl3, CH2Cl2, Ϫ78 ЊC, 0.5 h;
(b) RCl, imidazole, DMF, 0 ЊC, 1 h; (c) DAST, CH2Cl2, Ϫ4 ЊC, 10 min;
(d) NaOMe, MeOH, CH2Cl2, 0 ЊC, 2 h.
efficient procedure developed by our laboratory.6 The benzyl
protecting groups of 5 were removed by boron trichloride at
Ϫ78 ЊC to give the diols 6. Treatment of diols 6 with tert-
butyldiphenylsilyl chloride at 0 ЊC gave silyl ether 7 in 93%
yield. Treatment of 7 with DAST (diethylaminosulfur trifluo-
ride) at Ϫ4 ЊC yielded the fluoro compound 8 with complete
retention of stereochemistry.7–9 The benzoyl group of 8 was
removed with NaOMe to give 9 in quantitative yield.
Since the stereochemistry of the hydroxy group at C2 had to
be inverted to synthesize the desired β nucleosides, we employed
the Mitsunobu reaction as shown in Scheme 2. Mitsunobu reac-
tion of compound 9 under standard conditions (Ph3P, DEAD,
C6H5CO2H, THF, RT or 60 ЊC) always afforded the desired 11a
as the major product, but these conditions also gave 11b as
a minor product (3–10% isolated yield) which was formed by
the participation of the sulfur atom of the 4-thiofuranose.10
In order to confirm the participation of sulfur, we tried other
Mitsunobu reactions using benzoic acid or diphenylphosphoryl
azide (DPPA) as incoming nucleophiles. Thus, Mitsunobu reac-
tions of 10 (benzoic acid, 60 ЊC, 48 h; DPPA, RT, 2 h)7 afforded
12b and 13b (3–15% isolated yield) as minor products,
respectively.
Therefore, it is concluded that sulfur takes some participation
in the Mitsunobu reaction, leading to the formation of
products with retention of stereochemistry, whose yields were
increased by the use of more Mitsunobu reagents at higher
temperatures.
Compound 11a was treated with methanolic ammonia to
give 14 which serves as a versatile intermediate for the synthesis
of the desired nucleosides (Scheme 3). Condensation of 14 with
N3-benzoyluracil under the Mitsunobu conditions gave the pro-
tected nucleoside 15 in 56% yield.11 Deprotection of the benzoyl
group (NH3, MeOH) and tert-butyldiphenylsilyl group (n-
Bu4NF, THF) afforded the final uracil derivative 3a. The inter-
mediate 14 was also condensed with 6-chloropurine under the
same conditions used in the preparation of 15 to give com-
pound 1611 which was treated with tetra-n-butylammonium
fluoride to yield 6-chloropurine derivative 17. Treatment of 17
with methanolic ammonia at 100 ЊC afforded the final adenine
B
B
B
HO
HO
HO
O
F
O
S
S
1
3a (B = uracil)
3b (B = adenine)
2a (B = Adenine)
2b (B = Guanine)
(B = pyrimidines and purines)
Chart 1
As a part of our ongoing efforts to develop new antiviral
agents, it was interesting to design compound 3 because C–F
can act as a bioisostere of oxygen and sulfur is also a bioisostere
of oxygen. Thus, we synthesized the target nucleosides 3 utiliz-
ing a Mitsunobu reaction as a key step from the versatile inter-
mediate, an -4-thioarabitol derivative6 developed by our
laboratory. While preparing compound 3, we discovered the
sulfur participation of the 4-thiofuranose derivative in the
Mitsunobu reaction. This contrasts with the results which
Yoshimura and his co-workers had reported, that the sulfur
atom of 4-thiofuranoses does not take part in the Mitsunobu
reaction.7 Here, we wish to report the sulfur chemistry related
to the Mitsunobu reaction and the synthesis of novel fluoro
substituted isodideoxythionucleosides.
Results and discussion
Synthesis of the precursor 9 for the Mitsunobu reaction is
shown in Scheme 1. 1,2-O-Isopropylidene--xylose was con-
verted to -thioarabitol derivative 5 according to the short and
J. Chem. Soc., Perkin Trans. 1, 1998, 3325–3326
3325

View Article Online
S
F
S
F
OBz
TBDPSO
RO
RO
11a
OH
9
a
80%
DEAD, PPh3
THF
BzOH
S
RT or heating
F
OH
d
S
S
F
14
F
OBz
b
TBDPSO
TBDPSO
54%
56%
OBz
11b (minor)
11a (major)
S
S
F
F
RO
RO
O
N
N
N
N
DEAD, PPh3
N
S
S
S
N
Bz
THF
OBn
OBn
OBn
16
OBz
Cl
BnO
BnO
BnO
O
BzOH, 60 °C
15
95%
e
OH
OBz
12b (minor)
50%
c
S
10
12a (major)
F
DEAD, PPh3
S
THF
DPPA, RT
HO
F
N
N
X
N
N
HO
O
N
S
S
NH
OBn
OBn
N3
17 (X = Cl)
BnO
BnO
78%
f
O
N3
3a
3b (X = NH2)
13a (major)
13b (minor)
Scheme 3 Reagents and conditions: (a) NH3, RT, 2 h; (b) N3-
benzoyluracil, DEAD, PPh3, THF, 0 ЊC to RT, 15 h; (c) NH3, MeOH,
RT, 2 h, then n-Bu4NF, THF, RT, 1 h; (d) 6-chloropurine, DEAD,
PPh3, THF, 0 ЊC to RT, 15 h; (e) n-Bu4NF, THF, RT, 1 h; (f) NH3,
MeOH, 100 ЊC, 48 h.
Scheme 2
derivative 3b. The structure of compound 3b was confirmed by
NOESY and HMQC NMR experiments.
In summary, we have completed the synthesis of novel iso-
dideoxythionucleosides from the versatile intermediate, -4-
thioarabitol derivative in which we discovered the participation
of the sulfur during the Mitsunobu reaction as in the DAST
fluorination. It is a new finding in sulfur chemistry since it had
been reported that sulfur did not participate in the Mitsunobu
reaction.
5 D. M. Huryn, B. C. Sluboski, S. Y. Tam, M. Weigele, I. Sim, B. D.
Anderson, H. Mitsuya and S. Broder, J. Med. Chem., 1992, 35, 2347.
6 L. S. Jeong, H. R. Moon, Y. J. Choi, M. W. Chun and H. O. Kim,
J. Org. Chem., 1998, 63, 4821.
7 (a) Y. Yoshimura, K. Kitano, H. Satoh, M. Watanabe, S. Miura,
S. Sakata, T. Sasaki and A. Matsuda, J. Org. Chem., 1996, 61, 822;
(b) Y. Yoshimura, K. Kitano, K. Yamada, H. Satoh, M. Watanabe,
S. Miura, S. Sakata, T. Sasaki and A. Matsuda, J. Org. Chem., 1997,
62, 3140.
8 L. S. Jeong, M. C. Nicklaus, C. George and V. E. Marquez,
Tetrahedron Lett., 1994, 35, 7569.
9 L. S. Jeong, H. R. Moon, S. J. Yoo, S. N. Lee, M. W. Chun and
Y.-H. Lim, Tetrahedron Lett., 1998, 39, 5201.
Acknowledgements
This research was supported by a grant from the Korea Science
and Engineering Foundation (96-0403-01-01-3).
10 To a solution of triphenylphosphine (1.5 mol) in dry THF was
added dropwise diethyl azodicarboxylate (DEAD, 1.5 mol) at 0 ЊC
and the reaction mixture was stirred at room temperature for 2 h. To
this mixture was added a solution of benzoic acid (1.5 mol) in THF
followed by a solution of 9 (1.0 mol) in dry THF and the reaction
mixture was stirred at 60 ЊC for 8 h. More triphenylphosphine (1.5
mol), DEAD (1.5 mol) and benzoic acid (1.5 mol) were added to the
mixture at room temperature and the mixture was stirred at 60 ЊC
for 15 h. Since starting material 9 still remained on TLC, more
triphenylphosphine (1.5 mol), DEAD (1.5 mol) and benzoic acid
(1.5 mol) were again added to the mixture at room temperature and
the mixture was further stirred at 60 ЊC for 6 h. The mixture was
evaporated and the residue was purified by silica gel column
chromatography (hexanes–ethyl acetate 15:1) to give 11a (85%) and
11b (15%).
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Communication 8/06562D
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J. Chem. Soc., Perkin Trans. 1, 1998, 3325–3326