Synthesis of new 2′,3′-dideoxy-6′,6′-difluoro- 3′-thionucleoside from gem-difluorohomoallyl alcohol

Article abstract of DOI:10.1021/ol048423j

(Chemical Equation Presented) 2′,3′-Dideoxy-6′,6′- difluoro-3′-thionucleoside 1b, an analogue of 3Tc that has high biological activities against HIV and HBV, has been synthesized from gem-difluorohomoallyl alcohol 3 in an efficient way. The key intermedia

Full text of DOI:10.1021/ol048423j

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3941-3944
Synthesis of New
,3 -Dideoxy-6′,6′-difluoro-3′-thionucleoside
2′
′
from gem-Difluorohomoallyl Alcohol
Yun-Yun Wu,† Xingang Zhang,† Wei-Dong Meng,‡ and Feng-Ling Qing*,†,‡
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and
College of Chemistry and Chemical Engineering, Donghua UniVersity,
1882 West Yanan Lu, Shanghai 200051, China
flq@mail.sioc.ac.cn
Received August 9, 2004
ABSTRACT
2′,3′-Dideoxy-6′,6′-difluoro-3′-thionucleoside 1b, an analogue of 3Tc that has high biological activities against HIV and HBV, has been synthesized
from gem-difluorohomoallyl alcohol 3 in an efficient way. The key intermediate 4-amino-3,3-difluorotetrahydrothiophen-2-ylmethyl benzoate 15
was prepared from 2,2-difluoro-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol 3 in 11 steps. The construction of pyrimidine ring with the
amino group of compound 15 gave the target compound 1.
Nucleoside analogues have drawn great attention due to their
high antitumor and antiviral activities. Among these classes
of modified nucleosides, the 2′,3′-dideoxynucleosides (ddNs)
have proved to be the most effective therapeutic agents
against human immunodeficiency virus (HIV) and hepatitis
B virus (HBV).1 However, the toxicities associated with
certain nucleoside analogues and the emergence of resistant
viral strains warrant the search for further novel and struc-
turally diversified compounds with minimum overlapped
resistance profiles and toxicities.2 Sulfur-containing dideoxy-
nucleosides, (-)-â-L-(2R,5S)-1,3-oxathiolanylcytosine (3TC)3
and its 5-fluorocytosine analogue, (-)-FTC,4 show higher
biological activities against HIV-1, HIV-2, and HBV with
lower toxicities than conventional ddNs. However, such
ddNs have shown limited stability: the glycoside linkage
of ddNs is susceptible to both acidic and enzymatic hydroly-
sis.5 One important phenomenon has been observed: the
replacement of the oxygen in the sugar portion of the
nucleoside with a methylene (CH2) unit results in carbocyclic
nucleoside analogues that are highly resistant to the phos-
phorylases, which cleave the glycosidic bond of natural
nucleosides.6
(3) (a) Chang, C. N.; Doong, S. L.; Zhou, J. H.; Beach, J. W.; Jeong, L.
S.; Chu, C. K.; Tasi, C. H.; Cheng, Y. C. J. Biol. Chem. 1992, 267, 13938.
(b) Doong, S. L.; Tasi, C. H.; Schinazi, R. F.; Liotta, D. C.; Cheng, Y. C.
Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8495.
(4) (a) Frick, L. W.; Lambe, C. U.; St. John, L.; Taylor, L. C.; Nelson,
D. J. Antimicrob. Agents Chemother. 1994, 38, 2722. (b) Frick, L. W.; St.
John, L.; Taylor, L. V.; Painter, G. R.; Furman, P. A.; Liotta, D. C.; Furfine,
E. S.; Nelson, D. J. Antimicrob. Agents Chemother. 1993, 37, 2285.
(5) (a) Desgranges, C.; Razaka, G.; Rabaud, M.; Bricaud, H.; Balzarini,
J.; Declercq, E. Biochem. Pharmacol. 1983, 3583. (b) Marquez, V. E.; Lim,
M.-I. Med. Res. ReV. 1986, 6, 1. (c) Kawaguchi, T.; Fukushima, S.; Ohmura,
M.; Mishima, M.; Nakano, M. Chem. Pharm. Bull. 1989, 37, 1944.
† Shanghai Institute of Organic Chemistry Chinese Academy of Sciences.
‡ Donghua University.
(1) (a) De Clercq, E. AdV. Drug Res. 1988, 17, 1. (b) Mitsuya, H.; Broder,
S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911. (c) Mansuri, M. M.; Starett,
J. E.; Ghazzouli, L.; Hitchcock, M. J. M.; Sommadossi, J. P.; Martin, J. C.
J. Med. Chem. 1989, 32, 4. (d) Yarchoan, R.; Mitsuya, H.; Thomas, R. V.;
Pluda, J. M.; Hartman, N. R.; Perno, C. F.; Marczyk, K. S.; Allain, J. P.;
Johns, D. G.; Broder, S. Science 1989, 245, 412.
(2) (a) Nair, V.; Jahnke, T. S. Antimicrob. Agents Chemother. 1995, 39,
1017. (b) Wang, P.; Hong, J. H.; Cooperwood, J. S.; Chu, C. K. AntiViral.
Res. 1998, 40, 19.
10.1021/ol048423j CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/30/2004

of carbonyl group with DAST is a common method for the
introduction of a gem-difluoromethylene group, very few
sterically hindered five-membered cyclic ketones have been
difluorinated by DAST.10 Recently, we have reported the
preparation of 3-deoxy-3,3-difluoro-D-arabinofuranose from
gem-difluorohomoallyl alcohol 3.11 We envisioned that the
gem-difluoromethylenated diol 13 could be a suitable precur-
sor for compound 15. Compound 13 can be derived from
the chiral gem-difluorohomoallyl alcohol 3 through dihy-
droxylation and followed by ring closure and opening. The
absolute configuration of the target compound could be
controlled by performing the synthesis in an enantioselective
fashion.
Figure 1. Rationale for the design of the target compound 1.
Therefore, what interests us most is to synthesize a new
type of 3TC analogue by replacing the oxygen with a
difluoromethylene group (CF2) on the basis of the bioisosteric
rationale (Figure 1). This is because the carbocyclic nucleo-
side analogues have more stable glycosidic bonds, which can
be of advantage to antiviral agents. Notably, the gem-di-
fluoromethylene has been considered as an isopolar-isosteric
substitute for oxygen.7 Additionally, the introduction of fluor-
ine atoms to a nucleoside may enhance its clinical efficacy
by altering drug metabolism and lipophilicity.8 However, as
far as we know, the synthesis of 6′,6′-difluoronucleoside is
extremely difficult, which has impeded the investigation of
structure-activity relationships (SARs) and their develop-
ment as clinical agents. Therefore, new and practical syn-
thetic methods are needed. Herein, a route to synthesize 2′,3′-
dideoxy-6′,6′-difluoro-3′-thionucleoside 1 is described.
Our retrosynthetic analysis (Scheme 1) was based on the
idea that the target molecule 1 could be derived from the
The gem-difluorohomoallyl alcohol 3 was obtained through
the coupling of gem-difluoroallylindium, generated from
3-bromo-3,3-difluoropropene and indium in DMF, with
1-(R)-glyceraldehyde acetonide 2 in 90% yield (Scheme 2).12
Scheme 2
Scheme 1. Retrosynthetic Analysis of 1
The ratio of anti/syn compound 3 is 7.7:1 determined by
19F NMR. The difluoromethylene group in anti-3 appeared
at a higher field than that in syn-3 in 19F NMR spectra.
Notably, the anti-3 isomer is our desired compound. Then,
compound 3 was treated with trifluoromethanesulfonic an-
hydride in dichloromethane at -25 °C to afford the corre-
sponding triflate 4. Subsequent treatment of compound 4 with
sodium azide in DMF at room temperature provided com-
pound 5. However, the reduction of the azide 5 was not easy
to accomplish. Initial attempts to obtain the amide 7 through
the reduction of compound 5 with LiAlH4 and then direct
protection of reduced product by tert-butoxycarbonyl group
failed. Fortunately, by using Ph3P as a reducing agent instead
of LiAlH4 in THF, our desired amine syn-6 was obtained in
62% overall yield from alcohol 3. The syn-6 could be easily
separated through column chromatography.
precursor of type 15 by building a base moiety at the C1
position through the procedure of Shaw and Warrener.9
However, construction of the special backbone of 15,
especially the introduction of a gem-difluoromethylene group
to the C4 position, is very difficult. Although the fluorination
However, to our surprise, the protection of amine syn-6
with di-tert-butyl dicarbonate (Boc2O) in a common way
afforded protected amide 7 in poor yield (16-29%, entries
1-3) together with byproduct 8 (Table 1). In addition, the
more equivalents of Et3N used, the lower the yield of product
(6) For reviews, see: (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(b) Ferrero, M.; Goto, V. Chem. ReV. 2000, 100, 4319.
(7) (a) Blackburn, G. M.; England, D. A.; Kolkmann, F. J. Chem. Soc.,
Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Brown, D.; Martin, S.
J. J. Chem. Res., Synop. 1985, 92. (c) Blackburn, G. M.; Eckstein, F.; Kent,
D. E.; Perree, T. D. Nucleosides Nucleotides 1985, 4, 165.
(8) For recent examples, see: (a) Zhou, W.; Gumina, G.; Chong, Y.;
Wang, J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2004, 47, 3399. (b)
Zhu, W.; Chong, Y.; Choo, H.; Mathews, J.; Schinazi, R.; Chu, C. K. J.
Med. Chem. 2004, 47, 1631. (c) Dai, Q.; Piccirilli, J. A. Org. Lett. 2003, 5,
807. (d) Gumina, G.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2003, 46,
3245. (e) Lee, K.; Choi, Y.; Gumina, G.; Zhou, W.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 2002, 45, 1313.
(10) Gumian, G.; Schinazi, R. F.; Chu, C. K. Org. Lett. 2001, 3, 4177
and references cited therein.
(11) Zhang, X.; Xia, H.; Dong, X.; Jin, J.; Meng, W.; Qing, F.-L. J.
Org. Chem. 2003, 68, 9026.
(12) Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T.; Nemoto, H.
Tetrahedron 2000, 56, 827.
(9) Shaw, G.; Warrener, R. N. J. Chem. Soc. 1958, 157.
3942
Org. Lett., Vol. 6, No. 22, 2004

Scheme 3
Table 1. Protection of Amine syn-6 with Boc2O
Boc2O
T
time yield of 7 yield of 8
entry (equiv) (°C)
base
(h)
(%)
(%)
1a
2a
3a
4a
5b
6b
7b
8b
1.5
1.5
1.5
3.0
1.5
1.5
2.0
5.0
rt
24
29
20
16
16
25
37
54
90
52
58
62
rt Et3N (2 equiv) 24
rt Et3N (4 equiv) 24
-35
rt
rt
rt
rt
20
12
20
24
10
a Common method: adding the solution of Boc2O in CH2Cl2 to amine
6. b Adding the solution of amine 6 in CH2Cl2 to Boc2O.
7 obtained and, at the same time, the more byproduct 8
(52-62%) produced (entries 1-3). On the basis of the
thought that the formation of byproduct 8 was possibly due
to the coupling between the protected amide 7 and amine 6,
the reaction was cooled to -35 °C in order to lower the
reactivity of amine 6 (entry 4). As expected, no byproduct 8
was produced; however, the yield of our desired compound
7 was not satisfactory (16%). When the addition sequence
of reactants was changed by adding the amine 6 to Boc2O,
only product 7 was obtained with no trace of byproduct 8
(entries 5-7). What excited us most was that, when 5.0 equiv
of Boc2O was used, product 7 was obtained in 90% yield
(entry 8).
With the difluorohomoallyl amide 7 in hand, we turned
our attention to the synthesis of key intermediate 15. The
Os-catalyzed dihydroxylation of compound 7 gave a mixture
of compound 9 and 10 in 90% yield (9/10 ≈ 1:1, Scheme
3). Meanwhile, the catalytic asymmetric dihydroxylation
(AD) of compound 7 by the procedure of Sharpless also gave
a mixture of compound 9 and 10 in a ratio of 1:1. Luckily,
compounds 9 and 10 were easily separated by column
chromatography and the absolute configurations of these two
compounds were determined by the X-ray crystal structure
of compound 9 (Figure 2). Selective benzoylation at the
primary hydroxyl group of the resulting diol 9 at -78 °C
gave benzoate 11 in 84% yield. The conversion of benzoate
11 to the difluoromethylenated furanose 12 was achieved
by the following two steps: (1) the acidic hydrolysis of the
isopropylidene group by treatment with 75% acetic acid at
50 °C and (2) the oxidative scission of the resulting diol
with sodium periodate and subsequent cyclization to com-
pound 12. Without further purification, the difluorinated
furanose 12 was directly reduced by sodium borohydride in
methanol to give the diol 13 in 80% overall yield from 11
(three steps). Mesylation at C1 and C4 positions of 13,
followed by treatment with sodium sulfide in DMF, resulted
in a ring closure to give thiofuranose 14 as a single stereo-
isomer in 45% yield. The absolute configuration of com-
Figure 2. ORTEP drawing of the X-ray crystallographic structure
of compound 9.
pound 14 was determined by X-ray crystal structure (Figure
3). Deprotection of compound 14 with trifluoroacetic acid
in CH2Cl2 gave the key intermediate 15 in 85% yield. At
this stage, a novel and efficient method to prepare the di-
fluoromethylenated compound 15 was successfully developed
in our laboratory. The construction of pyrimidine was
followed by the procedure reported by Shaw and Warrener.9
Condensation of amine 15 with 3-ethoxy-2-propenoyl iso-
cyanate in DMF at -25 °C gave compound 16 followed by
ring closure with 2 M sulfuric acid in dioxane successfully
to afford compound 17. Deprotection of compound 17 was
Org. Lett., Vol. 6, No. 22, 2004
3943

The absolute configuration of the target molecule 1b was
made on the basis of the X-ray crystal structure of compound
14 (Figure 3).
In summary, on the basis of bioisosteric rationale, we have
synthesized 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleoside 1,
an analogue of 3TC, in 16 steps and developed a novel
method to synthesize 6′,6′-difluoronucleosides. Now, the
enantioselective synthesis of D/L-2′,3′-dideoxy-6′,6′-difluoro-
3′-thionucleosides and the evaluation of these nucleoside
analogues are in progress.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, Ministry of Education of China,
and Shanghai Municipal Scientific Committee for funding
this work.
Figure 3. ORTEP drawing of the X-ray crystallographic structure
of 14.
accomplished by ammonolysis to give the target molecule
2′,3′-dideoxy-6′,6′-difluoro-3′-thiouridine 1a (55% yield,
three steps). Compound 1a was also converted into the
cytosine derivative 1b by triisopropylbenzene-sulfonylation
of the O4-position of 1a, followed by treatment with
concentrated NH3‚H2O.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
crystallographic data for compounds 9 and 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048423J
3944
Org. Lett., Vol. 6, No. 22, 2004