Synthesis of 2′,3′-dideoxy-6′,6′-difluoro-3′-azanucleosides

Article abstract of DOI:10.1016/j.jfluchem.2008.02.008

The straightforward synthesis of four novel 2′,3′-dideoxy-6′,6′-difluoro-3′-azanucleosides 1a-d is described. Efficient construction of the fluorine-containing pyrrolidine ring through two different ways and installation of pyrimidine rings using the amin

Full text of DOI:10.1016/j.jfluchem.2008.02.008

Journal of Fluorine Chemistry 129 (2008) 866–874
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of 20,30-dideoxy-60,60-difluoro-30-azanucleosides
Xuyi Yue a, Xiao-Long Qiu a, Feng-Ling Qing a,b,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
A R T I C L E I N F O
A B S T R A C T
The straightforward synthesis of four novel 20,30-dideoxy-60,60-difluoro-30-azanucleosides 1a–d is
described. Efficient construction of the fluorine-containing pyrrolidine ring through two different ways
and installation of pyrimidine rings using the amino groups in the intermediates 12, 26 were the key
steps of our synthesis.
Article history:
Received 14 January 2008
Received in revised form 20 February 2008
Accepted 20 February 2008
Available online 2 March 2008
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Fluorinated nucleosides
Azanucleosides
1. Introduction
cleosides [7]. Additionally, conformational studies have demon-
strated that the pyrrolidine rings in proline and 4-hydroxyproline
Over the past three decades, nucleosides and nucleoside
analogues have been the cornerstone of antiviral and anticancer
chemotherapy. Nucleoside analogues with good stability and high
bioactivity are popular targets of organic and medicinal chemists.
Accordingly a large number of nucleoside analogues have been
synthesized and evaluated [1]. Continuing endeavors of organic
and medicinal chemists have endowed human beings with great
benefits, and to date, several clinically useful nucleosides and
nucleotides have been approved by the FDA for the treatment of
HIV infection [2]. Perhaps the best known of the nucleosides
have substantial similarity to the furan and cyclopentyl structures
[8]. Taking all the above considerations together and as part of our
efforts to develop novel potential fluorinated sugar nucleosides, we
designed new types of 3TC analogues by replacing the oxygen atom
with a difluoromethylene group (CF2) based on bioisosteric
rationale, and by substitution of nitrogen atom for the sulfur
atom, which would provide the system with more conformational
flexibility (Fig. 1). Herein we would like to describe our synthesis of
the 20,30-dideoxy-60,60-difluoro-30-azanucleosides 1a–d starting
from our reported gem-difluoromethylenated intermediate.
against HIV are (ꢀ)-b-
L-(2R, 5S)-1,3-oxathiolanylcytosine (3TC) [3]
2. Results and discussion
and its 5-fluorocytosine analogue (ꢀ)-FTC [4] (Fig. 1), both of
which are approved as antiviral drugs that reduce the amount of
HIV in the body. However, clinical experiments demonstrated that
both 3TC and (ꢀ)-FTC can cause some common side effects
including headache, diarrhea, vomiting, rare cases of hair loss, etc.
Thus, there is an intense demand to develop new novel nucleoside
analogues effective against HIV. In view of the fact that the gem-
difluoromethylene (CF2) group has been suggested by Blackburn as
an isopolar and isosteric substituent for oxygen [5] and the fact
that the introduction of fluorine atoms to a nucleoside may
enhance its clinical efficacy by altering drug metabolism and
lipophilicity [6], recently we have designed and synthesized a
series of new 3TC analogues—60,60-difluoromethylenated thionu-
Our retrosynthetic analysis (Fig. 2) was based on the idea that
the target molecules 1a–d could be derived from a precursor of
type A by building a base moiety at the C1 position using the
procedure of Shaw and Warrener [9] and by converting
the isopropylidene ketal moiety to a hydroxyl-methyl group.
Transformation of the alcohol B into the amine A could be realized
by an SN2 substitution reaction. The pyrimidine ring in B should be
constructed via cyclization of the mesylate C, which was accessed
starting from our reported gem-difluoromethylenated azide D [7].
According to the retrosynthetic analysis, our synthesis
embarked from the gem-difluoromethylenated homoallylazide 2,
which was initially converted to the diol 3 in three steps [7b]
(Scheme 1). Selective mesylation of the primary hydroxyl group in
3 afforded the compound 4 in 92% yield, which was further
benzoylated to give compound 5 in almost quantitative yield.
Delightfully, the desired ring-closed product 6 was delivered in
* Corresponding author at: Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, China. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.02.008

X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
867
Fig. 1. Structures of 3TC, (S)-FTC and rationale for the design of the target
compounds 1a–d.
Fig. 3. ORTEP drawing of the X-ray crystallographic structure of compound 1a.
amine 12 with 3-ethoxy-2-propenoyl isocyanate in DMF at ꢀ45 8C
yielded compound 13, which was further treated with 2N H2SO4 in
dioxane to give the target nucleoside 1a. The structure of the target
compound 1a was unambiguously established by X-ray crystal-
lographic analysis (Fig. 3) [10]. Interestingly, we found that ring
closure of compound 13 could be achieved via treatment with
concentrated NH3ꢁH2O, affording compound 14 in 78% yield. The
uracil compound 14 was further converted to the cytosine
derivative 15 by isopropylbenzene-sulfonylation of the O-4
position followed by treatment with concentrated NH3ꢁH2O.
Finally, deprotection of the Boc and TBDPS protecting groups of
15 in one step with 2N H2SO4 afforded the cytosine nucleoside 1b.
At this stage, we noted that six steps were needed to build the
pyrrolidine ring derivative 6 starting from the azide 2. To improve
the synthesis efficiency, we decided to develop a novel and short-
step route to access the gem-difluoromethenated pyrrolidine ring
intermediate. Our new synthetic route was based on the idea
that the pyrrolidine ring skeletons 17 could be conveniently
constructed by hydrogenation of the mesylated azide derivatives
16 followed by spontaneous cyclization (Fig. 4).
Fig. 2. Retrosynthetic analysis of our target molecules.
high yield upon treatment of the mesylate 5 with t-BuOK in THF.
The conversion of isopropylidene ketal moiety in compound 6 to
the hydroxymethyl group of compound 7 was accomplished by
the following steps: (1) acid hydrolysis of the isopropylidene
group via exposure to 75% aqueous AcOH at 50 8C; (2) oxidative
scission of the resultant diol with NaIO4/acetone; (3) then, the
yielded aldehyde was directly reduced to the desired alcohol 7
with NaBH4/MeOH. Silylation of the alcohol 7 gave compound 8
in 95% yield, which was further subjected to treatment with
NH3/MeOH to deliver compound 9. Subsequent exposure of the
alcohol 9 to trifluoromethanesulfonic anhydride in dichloro-
methane at ꢀ55 8C generated the corresponding triflate 10 in
99% yield. Reaction of compound 10 with NaN3 in DMF at room
temperature smoothly provided the azide 11, which was reduced
by using Ph3P as the reducing agent to afford the desired amine 12
in 97% yield.
According to the new synthetic route, we first subjected the
azide derivative 18 [7a] to dihydroxylation to give the diol 19 in
83% yield (Scheme 3). Then, selective mesylation of the primary
hydroxyl group in 19 gave a mixture of the diastereoisomers 20a
and 20b in 82% yield. Fortunately, the diastereoisomers 20a and
20b could be separated by column chromatography. At this stage,
With the precursor amine 12 in hand, attention was turned to
construction of the nucleoside base, which is outlined in Scheme 2.
The construction of pyrimidine base utilized the procedure
reported by Shaw and Warrener [9]. Thus, condensation of the
Scheme 1. Reagents and conditions: (a) MsCl, 2,4,6-collidine, CH2Cl2, 0 8C, 24 h, 92%; (b) BzCl, Et3N, DMAP, CH2Cl2, 99%; (c) t-BuOK, THF, 89%; (d) (I) 75% AcOH, 50 8C, 3 h; (II)
NaIO4, acetone; (III) NaBH4, MeOH, 0 8C, 73%; (e) TBDPSCl, imidazole, DMF, 95%; (f) sat. NH3/MeOH, overnight, 67%; (g) Tf2O, pyridine, CH2Cl2, S35 8C, 99%; (h) NaN3, DMF,
overnight, 85%; (i) (I) Ph3P, THF, rt, 6 h; (II) H2O, reflux, 12 h, 97%.

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X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
Scheme 2. Reagents and conditions: (a) 3-ethoxy-2-propenoyl isocyanate in benzene, DMF, overnight, 97%; (b) (I) 2N H2SO4, dioxane, reflux, 3.5 h; (II) 20% aq. NaOH, 66%; (c)
conc. NH3ꢁH2O, MeOH, 78%; (d) (I) TPSCl, Et3N, DMAP, MeCN; (II) conc. NH3ꢁH2O, 98%; (e) 2N H2SO4, dioxane, reflux, 3.5 h, 87%.
Scheme 3. Reagents and conditions: (a) OsO4, NMNO, acetone, H2O, 83%; (b) MsCl, 2,4,6-collidine, CH2Cl2, 0 8C, 29 h, 82%; (c) (I) Ph3P, THF, rt, 18 h; (I) Sat. NaHCO3, reflux,
30 h; (III) CbzCl, rt, 21 h, 43%; (d) (I) 75% AcOH, 50 8C, 3 h; (II) NaIO4, acetone; (III) NaBH4, MeOH, 0 8C, 80%; (e) BzCl, Py, S78 8C, 81%; (f) Tf2O, pyridine, CH2Cl2, S60 8C, 3 h, 89%;
(g) NaN3, DMF, rt, overnight, 81%; (h) (I) Ph3P, THF, rt, 24 h; (II) H2O, reflux, 24 h, 96%.
it was obvious that the isomer 20b was our desired compound
required to access the target nucleosides 1d–c. Thus, just as
expected in Fig. 4, the pyrrolidine ring intermediate 21 was
smoothly produced in 43% overall yield by hydrogenation of the
mesylated azide 20b using PPh3 as reducing reagent followed by in
situ protection of the resultant amine group with Cbz. The
conversion of the ispropylidene ketal moiety in the alcohol 21
to the hydroxymeythyl group was conveniently fulfilled using the
same procedures as described for the access of the alcohol 7 from
the compound 6, and our desired diol 22 was provided in 80% yield.
Selective protection of the primary hydroxyl group in 22 with BzCl
delivered compound 23 in 81% yield, which upon treatment with
Tf2O/pyridine provided the triflate 24 in excellent yield. Sub-
sequent reaction of compound 24 with NaN3 in DMF furnished the
azide 25. Finally, PPh3-mediated reduction of the azide 25 gave the
key amine 26 in 96% yield.
provided compound 27 in 92% yield (Scheme 4). 2N sulfuric acid-
mediated ring closure of the amide 27 followed by debenzoylation
with saturated NH3 in MeOH gave the desired uracil derivative 28 in
53% overall yield. Then, removal of the Cbz group via Pd-catalyzed
hydrogenation afforded the target nucleoside 1c in good yield. In
addition, conversion of the uracil derivative 28 to the cytosine
derivative 29 was accomplished in 50% yield via treatment with
Ac2O/pyridine/DMAP and TPSCl/Et3N/DMAP. Upon removal of the
Cbz group of 29 via hydrogenation, the desired nucleoside 1d was
provided in 70% yield. The structure of uracil nucleoside 1c was
further confirmed by X-ray crystal analysis (Fig. 5) [10].
In conclusion, based on a bioisosteric rationale, we successfully
synthesized four novel 3TC analogues 1a–d, which featured
replacement of the oxygen atom with a difluoromethylene group
(CF2) and substitution of a nitrogen atom for the sulfur atom.
Efficient construction of the fluorine-containing pyrrolidine ring
through two different ways and installation of pyrimidine rings
using the amino groups in the intermediates 12 and 26 were the
key steps of our synthesis. Antiviral and cytotoxicity evaluations of
the herein reported nucleosides 1a–d are currently in progress.
With the amine 26 in hand, the next goal was to install the
pyrimidine base using a traditional linear method. Thus, reaction of
the amine 26 with 3-ethoxy-2-propenoyl isocyanate in DMF
3. Experimental
3.1. General
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the
literature. Tetrahydrofuran was distilled from sodium and
Fig. 4. New route to construct the pyrrolidine ring skeleton 17.

X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
869
Scheme 4. Reagents and conditions: (a) 3-ethoxy-2-propenoyl isocyanate, DMF, benzene, overnight, 92%; (b) (I) 2N H2SO4, dioxane, reflux, 3.5 h; (II) 20% aq. NaOH; (III) sat.
NH3ꢁH2O 53%; (c) 10% Pd/C, 1 atm. H2, MeOH, 85%; (d) (I) Ac2O, Py, DMAP; (II) TPSCl, Et3N, DMAP, MeCN; (III) conc. NH3ꢁH2O, 50%; (e) 10% Pd/C, 1 atm. H2, MeOH, 70%.
3H), 3.70 (t, J = 7.5 Hz, 1H), 3.11 (s, 3H), 1.50 (s, 9H), 1.48 (s, 3H), 1.41
(s, 3H); 13C NMR (75.5 MHz, CDCl3) d 157.7 (d, J = 7.2 Hz), 121.6 (dd,
J = 192.0 Hz, 125.4 Hz), 110.4, 82.1 (d, J = 20.0 Hz), 70.6 (d,
J = 2.2 Hz), 68.4, 67.2 (d, J = 19.8 Hz), 63.6, 51.1 (t, J = 17.4 Hz),
37.6, 28.2, 26.1, 25.1; 19F NMR (282 MHz, CDCl3) d ꢀ121.3 (dd,
J = 255.8 Hz, 25.4 Hz, 1F), ꢀ123.5 (dd, J = 255.5 Hz, 25.1 Hz, 1F); IR
(KBr) ymax 3512, 3420, 1708, 1513, 1177 cmꢀ1; MS (ESI) m/z 442
(M+Na)+, 458 (M+K)+; Anal. Calcd. for C15H27NO8F2S: C, 42.95; H,
6.49; N, 3.34; found: C, 42.97; H, 6.51; N, 3.08.
3.3. (2R,4R)-4-(tert-Butoxycarbonylamino)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)-3,3-difluoro-1-(methylsulfonyloxy)butan-2-yl
benzoate (5)
Et3N (0.50 mL) and DMAP (12 mg, 0.10 mmol) were added to a
solution of the compound 4 (850 mg, 2.03 mmol) in dry CH2Cl2
(20 mL). After the reaction mixture was cooled to 0 8C, BzCl
(388 mg, 2.28 mmol) was added dropwise. Then, the mixture was
Fig. 5. ORTEP drawing of the X-ray crystallographic structure of compound 1c.
stirred at room temperature until the reaction was completed. The
benzophenone immediately before use. Dichloromethane was
distilled from CaH2. 1H NMR and 13C NMR spectra were recorded
reaction was quenched with water and the organic layer was
on a Bruker AM300 spectrometer. 19F NMR was recorded on a
separated. The aqueous layer was extracted with Et2O. The
combined organic layer was dried over Na2SO4 and concentrated
Bruker AM300 spectrometer (CFCl3 as outside standard and low
in vacuo. The residue was purified by column chromatography to
field is positive). Chemical shifts (d) are reported in ppm, and
give compound 5 (1.05 g, 99% yield): white solid, mp 55–57 8C;
[a]D22 = ꢀ13.18 (c 0.80, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.99–
7.96 (m, 2H), 7.53 (t, J = 6.9 Hz, 1H), 7.40 (t, J = 8.1 Hz, 2H), 5.79–
5.71 (m, 1H), 5.00 (d, J = 10.5 Hz, 1H), 4.64 (dd, J = 12.0 Hz, 3.6 Hz,
1H), 4.52–4.44 (m, 2H), 4.24–4.14 (m, 1H), 4.04–3.99 (m, 1H), 3.51
(t, J = 7.8 Hz, 1H), 2.93 (s, 3H), 1.32 (s, 9H), 1.29 (s, 3H), 1.26 (s, 3H);
13C NMR (75.5 MHz, CDCl3) d 164.3, 155.3, 133.4, 130.0, 129.9,
128.9, 128.6, 128.4, 128.9 (t, J = 190.0 Hz), 110.2, 80.8, 71.5, 68.3
(dd, J = 24.7 Hz, 20.1 Hz), 66.7, 65.1, 51.4 (t, J = 19.3 Hz), 37.8, 28.1,
25.8, 25.3; 19F NMR (282 MHz, CDCl3) d ꢀ115.3 to 115.5 (m, 2F); IR
(KBr) ymax 3375, 1720, 1603, 1368, 1178 cmꢀ1; MS (ESI) m/z 541
(M+NH4)+; Anal. Calcd. for C22H31NO9F2S: C, 50.47; H, 5.97; N,
2.68; found: C, 50.95; H, 5.91; N, 2.43.
coupling constants (J) are in Hz. The following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t = tri-
plet, q = quartet, m = multiplet, br = broad.
3.2. (2R,4R)-4-(tert-Butoxycarbonylamino)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)-3,3-difluoro-2-hydroxybutyl methanesulfonate
(4)
Collidine (4.8 mL, 35.2 mmol) was added to a solution of the diol
2 (1.20 g, 3.52 mmol) in CH2Cl2 (70 mL) at room temperature. The
mixture was cooled to 0 8C and MsCl (441 mg, 3.86 mmol) in CH2Cl2
(6 mL) was added dropwise. The reaction mixture was stirred for
24 h at 0 8C and quenched withaq. NaHCO3 (9 mL). The organic layer
was separated andthe aqueous layerwas extracted withCH2Cl2. The
combined organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography to give
compound 4 (1.36 g, 92% yield): white solid, mp 109–111 8C;
[a]D27 = +1.28 (c 0.76, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.32 (d,
J = 8.7 Hz, 1H), 4.61–4.51 (m, 2H), 4.43–4.36 (m, 1H), 4.21–4.04 (m,
3.4. (2R,4R)-tert-Butyl-4-(benzoyloxy)-2-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3,3-difluoropyrrolidine-1-carboxylate (6)
To a solution of the compound 5 (1.05 g, 2.01 mmol) in
anhydrous THF (18 mL) was added potassium tert-butoxide

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X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
(787 mg, 7.02 mmol) in several portions at 0 8C. Then, the reaction
mixture was stirred at 0 8C for 1 h. After that, saturated aq. NaCl
was added to quench the reaction and the resulting mixture was
extracted with EtOAc. The combined organic layer was dried over
anhydrous Na2SO4, filtered, and the solvent was removed in vacuo.
The residue was purified by silica gel column chromatography to
give compound 6 (763 mg, 89% yield): clear oil, [a]D25 = ꢀ15.08 (c
3.10, CHCl3); 1H NMR (300 MHz, CDCl3) d 8.05–8.02 (m, 2H), 7.56–
7.51 (m, 1H), 7.39 (t, J = 8.1 Hz, 2H), 5.50–5.43 (m, 1H), 4.41–4.38
(m, 1H), 4.25 (d, J = 18.0 Hz, 2H), 4.04 (t, J = 8.4 Hz, 1H), 3.95 (br,
NMR (300 MHz, CDCl3) d 7.82–7.79 (m, 2H), 7.59 (br, 4H), 7.48 (t,
J = 7.5 Hz, 1H), 7.33–7.24 (m, 6H), 7.21–7.16 (m, 2H), 5.45 (br, 1H),
4.30–4.16 (m, 1H), 4.01–3.87 (m, 3H), 3.46–3.40 (m, 1H), 1.38–1.27
(m, 9H), 0.96 (s, 9H); 13C NMR (75.5 MHz, CDCl3) d 165.0,
153.9,135.6, 135.5, 133.6, 133.2, 129.9, 129.7, 128.7, 128.5,
127.7, 124.5 (t, J = 219.9 Hz), 81.1, 71.5, 62.7, 61.2, 48.9, 28.3,
26.7, 19.2; 19F NMR (282 MHz, CDCl3) d ꢀ99.2 (dm, J = 250.1 Hz,
1F), ꢀ124.4 (dd, J = 249.3 Hz, 30.7 Hz, 1F); IR (thin film) ymax 3073,
1736, 1708, 1389, 1112 cmꢀ1; MS (ESI) m/z 618 (M+Na)+; Anal.
Calcd. for C33H39NO5F2Si: C, 66.53; H, 6.60; N, 2.35; found: C,
66.42; H, 6.62; N, 2.24.
1H), 3.50 (dd, J = 12.9 Hz, 3.9 Hz, 1H), 1.61 (s, 9H), 1.42 (s, 6H); 13
C
NMR (75.5 MHz, CDCl3) d 165.0, 154.2, 133.6, 129.9, 129.8, 128.9,
128.6, 128.4, 123.9 (dd, J = 201.4 Hz, 186.9 Hz), 109.7, 81.1, 73.4 (d,
J = 5.1 Hz), 71.3, 66.7 (d, J = 1.3 Hz), 62.3 (t, J = 20.4 Hz), 50.2, 30.7,
26.0, 25.6; 19F NMR (282 MHz, CDCl3) d ꢀ97.0 (dm, J = 205.9 Hz,
1F), ꢀ120.6 (dm, J = 229.8 Hz, 1F); IR (thin film) ymax 1733, 1705,
1454, 1270, 1117 cmꢀ1; MS (ESI) m/z 450 (M+Na)+; Anal. Calcd. for
3.7. (2R,4R)-tert-Butyl-2-((tert-butyldiphenylsilyloxy)methyl)-3,3-
difluoro-4-hydroxypyrrolidine-1-carboxylate (9)
Compound 8 (903 mg, 1.52 mmol) was dissolved in saturated
NH3 solution in MeOH and the resultant mixture was stirred at
room temperature for 24 h. After removal of the solvent in vacuo,
the residue was purified by silica gel column chromatography to
give compound 9 (492 mg, 66% yield): clear oil, [a]D19 = ꢀ44.08 (c
0.85, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.57 (s, 4H), 7.35 (d,
J = 7.5 Hz, 6H), 5.11 (br, 1H), 4.09 (t, J = 10.2 Hz, 2H), 3.94–3.83 (m,
1H), 3.76–3.63 (m, 1H), 3.56–3.52 (m, 2H), 1.21 (s, 9H), 0.99 (s, 9H);
19F NMR (282 MHz, CDCl3) d ꢀ101.0 (dm, J = 245.3 Hz, 1F), ꢀ125.2
(dd, J = 280.0, 244.8 Hz, 1F); IR (thin film) ymax 3387, 1706, 1367,
1113 cmꢀ1; MS (ESI) m/z 492 (M+H)+, 514 (M+Na)+; Anal. Calcd. for
C
21H27NO6F2: C, 59.01; H, 6.37; N, 3.28; found: C, 59.10; H, 6.44; N,
3.11.
3.5. (2R,4R)-tert-Butyl-4-(benzoyloxy)-3,3-difluoro-2-
(hydroxymethyl)pyrrolidine-1-carboxylate (7)
A mixture of compound 6 (867 mg, 2.03 mmol) and 75% of aq.
AcOH (9 mL) was stirred at 50 8C for 3 h. Then, the solvent was
removed in vacuo. The residue was dissolved in acetone (8 mL),
followed by treatment witha solution of NaIO4 (651 mg, 3.05 mmol)
in water (9 mL) at room temperature with stirring. After stirring for
3 h, the mixture was filtered and the filtrate was washed with
acetone. The solvent was removed in vacuo and the residue was
extracted with CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4. After filtration and removal of the solvent in
vacuo, the residue was dissolved in MeOH (22 mL). To the solution
was added NaBH4 (228 mg, 6.01 mmol) in several portions at 0 8C.
After stirring for 30 min, 75% of aq AcOH was added until no gas was
produced. The resulting mixture was extracted with ethyl acetate.
The combined organic layer was washed with saturated NaHCO3
solution, brine, dried over anhydrous Na2SO4 and filtered. After the
solvent was removed in vacuo, the residue was purified by silica gel
column chromatography to give 530 mg of compound 7 (73% yield,
three steps): clear oil, [a]D25 = ꢀ36.58 (c 8.60, CHCl3); 1H NMR
(300 MHz, CDCl3) d 8.05–8.02 (m, 2H), 7.61 (t, J = 6.9 Hz, 1H), 7.47 (t,
J = 8.1 Hz, 2H), 5.53 (br, 1H), 4.26 (d, J = 16.5 Hz, 1H), 4.07–3.94 (m,
3H), 3.62 (dt, J = 12.9 Hz, 2.7 Hz, 1H), 1.49 (s, 9H); 19F NMR
(282 MHz, CDCl3) (two rotamers) d ꢀ99.8 (d, J = 248.2 Hz, 0.24F),
ꢀ103.2 (dm, J = 248.7 Hz, 0.76F), ꢀ124.8 (d, J = 250.4 Hz, 0.24F),
ꢀ125.5 (d, J = 249.0 Hz, 0.76F); IR (thin film) ymax 3428, 1733, 1705,
1405, 1270 cmꢀ1; MS (ESI) m/z 380 (M+Na)+; Anal. Calcd. for
C26H35NO4F2Si: C, 63.52; H, 7.18; N, 2.85; found: C, 64.14; H, 7.39;
N, 2.82.
3.8. (2R,4R)-tert-Butyl-2-((tert-butyldiphenylsilyloxy)methyl)-3,3-
difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate
(10)
Compound 9 (440 mg, 0.90 mmol) was dissolved in dry CH2Cl2
(25 mL) and freshly distilled pyridine (1.2 mL, 14.9 mmol) was
added. The resulting mixture was cooled to ꢀ35 8C. Then,
trifluoromethanesulfonic anhydride (1.3 mL, 7.49 mmol) was
added dropwise with stirring. After that, the reaction mixture
was stirred for about 2 h at about ꢀ25 8C. Water was added to
quench the reaction. The mixture was warmed to room
temperature. The mixture was extracted with CH2Cl2 and the
combined organic phases were dried over anhydrous Na2SO4.
After filtration and removal of the solvent in vacuo, the residue
was purified by silica gel column chromatography to afford
compound 10 (550 mg, 99% yield): clear oil, [a]D20 = ꢀ20.88 (c
0.54, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.58–7.51 (m, 4H), 7.33–
7.30 (m, 6H), 5.13 (t, J = 3.0 Hz, 1H), 4.08–4.04 (m, 2H), 3.80 (br,
2H), 3.58–3.55 (m, 1H), 1.27–1.15 (br, 9H), 0.97 and 0.96 (two
singlets, 9H, amide isomers); 19F NMR (282 MHz, CDCl3) (two
rotamers) d ꢀ74.4 (s, 3F), ꢀ98.4 (d, J = 256.9 Hz, 0.39F), ꢀ99.0 (d,
J = 253.8 Hz, 0.61F), ꢀ120.7 (d, J = 254.6 Hz, 0.39F), ꢀ121.0 (d,
J = 251.5 Hz, 0.61F); IR (thin film) ymax 3074, 1711, 1428, 1221,
1144 cmꢀ1; MS (ESI) m/z 646 (M+Na)+, 662 (M+K)+; Anal. Calcd.
for C27H34NO6F5SSi: C, 51.99; H, 5.49; N, 2.25; found: C, 52.26; H,
5.60; N, 2.05.
C17H21NO5F2: C, 57.14; H, 5.92; N, 3.92; found: C, 57.18; H, 6.02; N,
3.94.
3.6. (2R,4R)-tert-Butyl-4-(benzoyloxy)-2-((tert-
butyldiphenylsilyloxy)methyl)-3,3-difluoropyrrolidine-1-carboxylate
(8)
To a solution of compound 7 (160 mg, 0.45 mmol) in DMF
(1 mL) was added imidazole (76 mg, 2.5 mmol) followed by
TBDPSCl (285 mg, 1.04 mmol). The reaction mixture was stirred
at room temperature for 24 h and water was added to quench the
reaction. The resulting mixture was extracted with EtOAc. The
combined organic layer was washed with 1N HCl, saturated
NaHCO3 and brine and dried over anhydrous Na2SO4, after
filtration and removal of the solvent in vacuo, the residue was
purified by silica gel column chromatography to give compound 8
(253 mg, 95% yield): clear oil, [a]D19 = ꢀ40.58 (c 4.85, CHCl3); 1H
3.9. (2R,4S)-tert-Butyl-4-azido-2-((tert-
butyldiphenylsilyloxy)methyl)-3,3-difluoropyrrolidine-1-carboxylate
(11)
A solution of compound 10 (540 mg, 0.87 mmol) in DMF
(20 mL) was cooled to 0 8C. Then, sodium azide (303 mg,
4.66 mmol) was added carefully with stirring. The reaction
mixture was stirred overnight at room temperature. Water was
added to quench the reaction. The combined organic layers were

X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
871
washed with brine and dried over anhydrous Na2SO4, and
3.12. 20,30-Dideoxy-60,60-difluoro-30-aza-a-
L-uridine (1a)
concentrated in vacuo. The residue was quickly purified by silica
gel column chromatography to afford compound 11 (382 mg, 85%
yield): clear oil, [a]D22 = ꢀ36.88 (c 3.70, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.65–7.58 (m, 4H), 7.48–7.35 (m, 6H), 4.54–4.37 (m, 1H),
4.10–4.03 (m, 1H), 3.98–3.78 (m, 3H), 3.45–3.30 (m, 1H), 1.52 (s,
4.5 H), 1.34 (s, 4.5H), 1.05 (s, 9H); 19F NMR (282 MHz, CDCl3) (two
rotamers) d ꢀ111.3 (dt, J = 232.1 Hz, 19.7 Hz, 0.51F), ꢀ111.5 (dt,
J = 231.8 Hz, 18.3 Hz, 0.49F), ꢀ118.0 (dd, J = 232.9 Hz, 7.9 Hz,
0.51F), ꢀ119.6 (dd, J = 232.7 Hz, 7.6 Hz, 0.49F); IR (thin film) ymax
2113, 1709, 1401, 1169, 1114 cmꢀ1; MS (ESI) m/z 539 (M+Na)+, 555
(M+K)+; Anal. Calcd. for C26H34N4O3F2Si: C, 60.44; H, 6.63; N,
10.84; found: C, 60.73; H, 6.68; N, 10.77.
A mixture of compound 13 (100 mg, 0.16 mmol) in dioxane
(2 mL) and 2N sulfuric acid (5 mL) was refluxed for 4 h. The
mixture was cooled to 0 8C and neutralized with diluted aq. NaOH.
After filtration and removal of the solvent in vacuo, the residue was
dissolved in methanol and the product was extracted into
methanol solution, then the methanol was removed in vacuo
and the residue was purified by silica gel column chromatography
to give compound 1a (26 mg, 66% yield): white solid, mp 197–
199 8C; [a]D24 = 0.858 (c 0.90, MeOH); 1H NMR (300 MHz, CD3OD) d
7.60 (dd, J = 7.8 Hz, 2.1 Hz, 1H), 5.63 (d, J = 8.1 Hz, 1H), 5.22–5.07
(m, 1H), 3.74–3.63 (m, 2H), 3.43–3.30 (m, 2H), 3.27–3.14 (m, 1H);
13C NMR (75.5 MHz, CD3OD) d 165.2, 151.9, 143.6 (d, J = 3.9 Hz),
126.7 (t, J = 260.9 Hz), 101.5, 64.0 (q, J = 25.8 Hz), 59.5 (q,
J = 18.3 Hz), 58.5 (q, J = 2.8 Hz), 45.6 (d, J = 6.2 Hz); 19F NMR
(282 MHz, CD3OD) d ꢀ108.8 (dm, J = 236.6 Hz, 1F), ꢀ114.9 (dm,
J = 236.3 Hz, 1F); IR (KBr) ymax 3432, 3300, 3095, 1703, 1673, 1448,
1389 cmꢀ1; MS (ESI) m/z 248 (M+H)+, 270 (M+Na)+; HRMS Calcd.
for C9H11N3O3F2Na: 270.0673; found: 270.0666.
3.10. (2R,4S)-tert-Butyl-4-amino-2-((tert-
butyldiphenylsilyloxy)methyl)-3,3-difluoropyrrolidine-1-carboxylate
(12)
A solution of Ph3P (372 mg, 1.42 mmol) in THF (5 mL) was
slowly added at room temperature to a solution of compound 11
(360 mg, 0.70 mmol) in THF (30 mL). Then, the reaction mixture
was monitored by TLC. When the starting material was completely
consumed, water (5 mL) was added and the reaction mixture was
reflux for 12 h. The reaction mixture was cooled to room
temperature and brine was added. The resultant mixture was
extracted with CH2Cl2. The combined organic layers were washed
with water and dried over Na2SO4. After filtration and removal of
the solvent in vacuo, the residue was purified by silica gel column
chromatography to give compound 12 (330 mg, 97% yield): clear
oil, [a]D25 = ꢀ16.18 (c 0.95, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.58–7.55 (m, 4H), 7.34–7.32 (m, 6H), 4.04–3.69 (m, 5H), 3.03–2.92
(m, 1H), 1.43 (s, 5H), 1.19 (s, 4H), 0.97 and 0.96 (two singlets, 9H,
amide isomers); 19F NMR (282 MHz, CDCl3) (two rotamers) d
ꢀ114.3 (dt, J = 229.5 Hz, 19.2 Hz, 0.51F), ꢀ114.5 (dt, J = 229.8 Hz,
19.5 Hz, 0.49F), ꢀ122.4 (dd, J = 229.5 Hz, 7.1 Hz, 0.51F), ꢀ123.9
(dd, J = 229.8 Hz, 6.2 Hz, 0.49F); IR (thin film) ymax 3413, 1702,
1402, 1168, 1114 cmꢀ1; MS (ESI) m/z 491 (M+H)+; Anal. Calcd. for
3.13. 20,30-Dideoxy-60,60-difluoro-50-tert-butyldiphenylsilyl-30-aza-
tert-butoxycarbonyl-a-L-uridine (14)
A mixture of compound 13 (90 mg, 0.14 mmol) in MeOH (2 mL)
and concentrated NH3ꢁH2O (4 mL) in a sealable tube was heated to
75 8C for 12 h. Solvent was removed under reduced pressure. The
residue was subjected to silica gel column chromatography to give
65 mg (78%) of compound 14: white solid, mp 100–102 8C;
[a]D23 = ꢀ47.58 (c 0.86, CHCl3); 1H NMR (300 MHz, CD3OD) d 7.88–
7.81 (m, 1H), 7.74–7.67 (m, 4H), 7.50–7.39 (m, 6H), 6.27–6.13 (m,
1H), 5.75 (d, J = 7.8 Hz, 1H), 4.17–4.01 (m, 2H), 3.99–3.74 (m, 3H),
1.55 (s, 4H), 1.31 (s, 5H), 1.10 (d, J = 4.2 Hz, 9H); 19F NMR (282 MHz,
CD3OD) (two rotamers) d ꢀ109.2 (dt, J = 232.4 Hz, 22.8 Hz, 1F),
ꢀ119.1 (dd, J = 232.9 Hz, 7.1 Hz, 0.56F), ꢀ120.4 (dd, J = 232.7 Hz,
7.9 Hz, 0.44F); IR (KBr) ymax 3213, 1702, 1378, 1165, 1108 cmꢀ1
;
MS (ESI) m/z 586 (M+H)+, 608 (M+Na)+, 624 (M+K)+; Anal. Calcd. for
30H37N3O5F2Si: C, 61.52; H, 6.37; N, 7.17; found: C, 61.48; H, 6.46;
C
C26H36N2O3F2Si: C, 63.64; H, 7.40; N, 5.71; found: C, 63.65; H, 7.39;
N, 7.04.
N, 5.47.
3.14. 20,30-Dideoxy-60,60-difluoro-50-tert-butyldiphenylsilyl-30-aza-
3.11. (2R,4S,E)-tert-Butyl-2-((tert-butyldiphenylsilyloxy)methyl)-4-
(3-(3-ethoxyacryloyl)ureido)-3,3-difluoropyrrolidine-1-carboxylate
(13)
tert-butoxycarbonyl-a-L-cytidine (15)
To a 0 8C solution of compound 14 (60 mg, 0.10 mmol) in MeCN
(2 mL) under argon, TPSCl (63 mg, 0.21 mmol), Et3N (29 mL,
0.21 mmol) and DMAP (24 mg, 0.20 mmol) were added subse-
quently. Then, the reaction mixture was warmed to room
temperature and stirred for 12 h. After that, concentrated NH3ꢁH2O
H2O (28%, 1.3 mL) was added and the whole reaction mixture was
stirred overnight. The solvent was removed and the residue was
purified by silica gel column chromatography to give compound 15
(58 mg, 98% yield): white solid, mp 233–235 8C; [a]D25 = ꢀ43.58 (c
0.81, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.70–7.64 (m, 4H), 7.42–
7.40 (m, 7H), 6.44–6.30 (m, 1H), 6.22–6.13 (m, 1H), 4.14–3.75 (m,
4H), 3.60–3.45 (m, 1H), 1.52 (s, 4H), 1.34 (s, 5H), 1.25 (s, 2H), 1.08
(s, 9H); 19F NMR (282 MHz, CDCl3) (two rotamers) d ꢀ108.1 (dt,
J = 231.0 Hz, 22.6 Hz, 1F), ꢀ117.8 (d, J = 234.3 Hz, 0.57F), ꢀ119.0 (d,
J = 232.4 Hz, 0.43F); IR (KBr) ymax 3481, 3149, 1702, 1664, 1645,
1166 cmꢀ1; MS (ESI) m/z 585 (M+H)+, 607 (M+Na)+, 623 (M+K)+;
Anal. Calcd. for C30H33N4O4F2Si: C, 61.62; H, 6.55; N, 9.58; found: C,
61.73; H, 6.94; N, 9.20.
To a solution of compound 12 (210 mg, 0.43 mmol) in DMF
(4 mL) at ꢀ25 8C, a solution of 3-ethoxy-2-propenoyl isocyanate
(181 mg, 0.42 mmol) in benzene (4 mL) was added slowly enough
to cause no rise in temperature. After addition, the reaction
mixture was stirred overnight at room temperature. EtOH and
toluene were then added to form a low-boiling ternary azeotrope
that was evaporated under reduced pressure while the tempera-
ture was maintained below 40 8C. The solid residue was purified
by silica gel column chromatography to give compound 13
(248 mg, 97% yield): white solid, mp 78–80 8C; [a]D24 = ꢀ15.48 (c
1.90, CHCl3); 1H NMR (300 MHz, CDCl3) d 9.25 (d, J = 9.3 Hz, 1H),
9.11 (d, J = 15.3 Hz, 1H), 7.69–7.62 (m, 5H), 7.41–7.26 (m, 6H),
5.35–5.24 (m, 2H), 4.08–3.96 (m, 2H), 3.90–3.75 (m, 4H), 3.30–
3.22 (m, 1H), 1.51 (s, 4.5H), 1.33 (s, 4.5H), 1.24 (t, J = 7.5 Hz, 3H),
1.08 (s, 9H); 19F NMR (282 MHz, CDCl3) (two rotamers) d ꢀ110.7
(dm, J = 234.6 Hz, 1F), ꢀ119.7 (dd, J = 230.7 Hz, 5.9 Hz, 0.49F),
ꢀ121.1 (dd, J = 234.6 Hz, 6.2 Hz, 0.51F); IR (KBr) ymax 3236, 1707,
1681, 1552, 1401, 1115 cmꢀ1; MS (ESI) m/z 632 (M+H)+, 654
(M+Na)+, 670 (M+K)+; HRMS Calcd. for C32H43N3O6SiF2Na:
654.2781; found: 654.2763; Anal. Calcd. for C32H43N3O6F2Si: C,
60.83; H, 6.86; N, 6.65; found: C, 60.90; H, 6.94; N, 6.51.
3.15. 20,30-Dideoxy-60,60-difluoro-30-aza-a-
L-cytidine (1b)
A mixture of compound 15 (60 mg, 0.10 mmol) in dioxane
(1.2 mL) and 2N sulfuric acid (3 mL) was refluxed for 4 h. After

872
X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
that, the mixture was cooled to 0 8C and neutralized with dilute
aq. NaOH. After filtration and removal of the solvent in vacuo,
the residue was dissolved in methanol and the product was
extracted into methanol solution. Then, the methanol was
removed and the residue was purified by silica gel column
chromatography to give compound 1b (22 mg, 87% yield):
white solid, mp 148–150 8C; [a]D24 = ꢀ5.18 (c 0.44, MeOH); 1H
NMR (300 MHz, CD3OD) d 6.37 (d, J = 6.3 Hz, 1H), 4.62 (d,
J = 7.2 Hz, 1H), 4.09–4.01 (m, 1H), 2.48–2.42 (m, 2H), 2.21–2.14
(m, 2H), 2.02–1.92 (m, 1H); 13C NMR (75.5 MHz, CD3OD) d 166.0,
157.3, 144.0 (d, J = 4.4 Hz), 126.8 (t, J = 258.4 Hz), 94.9, 64.3 (t,
J = 23.6 Hz), 60.1 (q, J = 18.6 Hz), 58.5 (d, J = 6.9 Hz), 46.0 (d,
3.18. (2S,4S)-Benzyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,3-
difluoro-4-hydroxypyrrolidine-1-carboxylate (21)
To a solution of compound 20b (2.47 g, 7.16 mmol) in THF
(150 mL) was added a solution of PPh3 (3.75 mg, 14.3 mmol) in THF
(33 mL) dropwise at room temperature. After the starting material
was completely consumed, saturated aq. NaHCO3 (33 mL) was
added and the reaction mixture was heated to reflux for 30 h. The
reaction mixture was cooled to the room temperature and CbzCl
(1.34 g, 7.88 mmol) was added. The reaction mixture was stirred for
further 21 h, the phases were separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were washed
with brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography to afford
compound 21 (1.10 g, 43% yield): clear oil, [a]D23 = 61.68 (c 1.41,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.36–7.26 (m, 5H), 5.23–5.13
(m, 2H), 4.45–4.37 (m, 1H), 4.34–4.15 (m, 3H), 4.05–3.91 (m, 1H),
3.48–3.41 (m, 1H), 1.38 and 1.25 (two singlets, 6H, amide isomers);
13C NMR (75.5 MHz, CDCl3) (two rotamers) d 156.28, 136.00, 128.61
and 128.54, 128.46 and 128.31, 127.83 and 126.96, 127.61 (t,
J = 211.4 Hz), 110.55, 74.02 and 73.51, 71.29 and 71.01, 68.13 and
67.82, 66.32 and 65.33, 61.51 (t, J = 15.2 Hz), 54.35, 29.67 and 29.33,
25.70 and25.59;19FNMR(282 MHz, CDCl3)(tworotamers)dꢀ100.7
(dt, J = 243.4 Hz, 16.6 Hz, 0.34F), ꢀ101.0 (dm, J = 244.5 Hz, 0.66F),
ꢀ124.6 (d, J = 249.9 Hz, 0.34F), ꢀ125.3 (d, J = 245.6 Hz, 0.66F); IR
(thin film) ymax 3417, 1709, 1412, 1345, 1115 cmꢀ1; MS (ESI) m/z
358 (M+H)+, 380 (M+Na)+; Anal. Calcd. for C17H21NO5F2: C, 57.14; H,
5.92; N, 3.92; found: C, 57.18; H, 6.14; N, 4.00.
J = 4.9 Hz); 19F NMR (282 MHz, CD3OD)
d
ꢀ109.0 (dt,
J = 237.4 Hz, 11.6 Hz, 1F), ꢀ114.6 (dt, J = 236.3 Hz, 16.9 Hz,
1F); IR (KBr) ymax 3357, 1655, 1497, 1397, 787 cmꢀ1; MS (ESI)
m/z 247 (M+H)+; HRMS Calcd. for C9H12N4O2F2Na: 269.0821;
found: 269.0824.
3.16. (4S)-4-Azido-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,3-
difluorobutane-1,2-diol (19)
To a solution of compound 18 (7.50 g, 32.2 mmol) in acetone
(160 mL) was added NMNOꢁH2O (8.26 g, 61.2 mmol), followed by
water (30 mL) at room temperature with stirring. Then, a catalytic
amount of OsO4 solution (4%) in water was added. After the reaction
mixture was stirred at room temperature for 48 h, the reaction was
quenched with saturated aq. NaHSO3 and extracted with ethyl
acetate. The combined organic layers were washed with 1N HCl and
brine, and dried over anhydrous Na2SO4. After filtration and removal
of the solvent in vacuo, the residue was purified by silica gel column
chromatography to give compound 19 (7.20 g, 83% yield): clear oil,
1H NMR (300 MHz, CDCl3) d 4.55–4.49 (m, 1H), 4.19–4.07 (m, 2H),
3.95–3.80 (m, 3H), 3.73 (td, J = 11.1 Hz, 5.1 Hz, 1H), 3.52 (br, 2H),
1.49 (s, 3H), 1.40 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ109.1 (dm,
J = 263.4 Hz, 0.82F), ꢀ117.1 (dm, J = 291.3 Hz, 0.82F), ꢀ118.0 (dm,
J = 259.2 Hz, 0.18F), ꢀ119.1 (dm, J = 261.7 Hz, 0.18F); IR (thin film)
ymax 3412, 2122, 1376, 1261, 1215, 1064 cmꢀ1; MS (ESI) m/z 285
(M+NH4)+, 290 (M+Na)+; Anal. Calcd. for C9H15N3O4F2: C, 40.45; H,
5.66; N, 15.72; found: C, 40.57; H, 5.73; N, 15.42.
3.19. (2S,4S)-Benzyl 3,3-difluoro-4-hydroxy-2-
(hydroxymethyl)pyrrolidine-1-carboxylate (22)
The compound 22 was prepared from the compound 21 using
the same procedure as described for the compound 7. Colorless
oil: [a]D23 = 47.88 (c 1.50, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.37–7.32 (m, 5H), 5.18–5.08 (m, 2H), 4.17–4.13 (m, 3H), 4.05–
3.98 (m, 1H), 3.87–3.71 (m, 2H), 3.58 (d, J = 12.6 Hz); 19F NMR
(282 MHz, CDCl3) (two rotamers) d ꢀ101.7 (dm, J = 246.2 Hz,
0.39F), ꢀ102.3 (dm, J = 246.5 Hz, 0.61F), ꢀ125.1 (d, J = 246.2 Hz,
0.39F), ꢀ126.7 (d, J = 247.0 Hz, 0.61F); IR (thin film) ymax 3342,
1689, 1425, 1353, 1110 cmꢀ1; MS (ESI) m/z 288 (M+H)+, 310
(M+Na)+; Anal. Calcd. for C13H15NO4F2: C, 54.35; H, 5.26; N, 4.88;
found: C, 54.52; H, 5.55; N, 4.74.
3.17. (2S,4S)-4-Azido-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,3-
difluoro-2-hydroxybutyl methanesulfonate (20b) and (2R,4S)-4-
Azido-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,3-difluoro-2-
hydroxybutyl methanesulfonate (20a)
3.20. (2S,4S)-Benzyl 2-(benzoyloxymethyl)-3,3-difluoro-4-
hydroxypyrrolidine-1-carboxylate (23)
Compounds 20a and 20b were prepared using the same
condition as described for the compound 4. 20b: white solid, mp
95–98 8C; [a]D25 = ꢀ12.88 (c 0.25, CHCl3); 1H NMR (300 MHz,
CDCl3) d 4.55–4.36 (m, 4H), 4.21–4.16 (m, 1H), 3.95–3.84 (m, 2H),
3.13 (s, 3H), 1.51 (s, 3H), 1.43 (s, 3H); 19F NMR (282 MHz, CDCl3) d
ꢀ115.7 (dd, J = 263.7 Hz, 19.5 Hz, 1F), ꢀ118.2 (dd, J = 262.0 Hz,
22.3 Hz, 1F); IR (KBr) ymax 3406, 2126, 1355, 1174 cmꢀ1; MS (ESI)
m/z 363 (M+NH4)+, 368 (M+Na)+; Anal. Calcd. for C10H17N3O6F2S:
C, 34.78; H, 4.96; N, 12.17; found: C, 34.90; H, 4.97; N, 11.97. 20a:
White solid, mp 87–91 8C; [a]D22 = ꢀ7.58 (c 1.01, CHCl3); 1H NMR
(300 MHz, CDCl3) d 4.49–4.26 (m, 3H), 4.11(t, J = 8.4 Hz, 1H), 3.87
(t, J = 7.8 Hz, 1H), 3.73 (td, J = 11.1 Hz, 5.1 Hz, 1H), 3.04 (d,
J = 1.2 Hz, 3H), 3.04 (d, J = 1.2 Hz, 3H), 1.42 (s, 3H), 1.32 (s, 3H);
13C NMR (75.5 MHz, CDCl3) d 120.4 (dd, J = 188.0 Hz, 191.9 Hz),
110.2, 73.2, 68.4, 66.5, 63.3 (t, J = 19.5 Hz), 37.2, 30.6, 25.8, 25.0;
19F NMR (282 MHz, CDCl3) d ꢀ107.0 (dm, J = 265.9 Hz, 1F),
ꢀ116.9 (dm, J = 264.2 Hz, 1F); IR (KBr) ymax 3375, 2122, 1635,
To
a solution of compound 22 (382 mg, 1.33 mmol) in
anhydrous CH2Cl2 (10 mL) was added pyridine (3.7 mL) followed
by BzCl (0.20 mL, 1.65 mmol) in CH2Cl2 (1.2 mL) at ꢀ78 8C. After
the mixture was stirred at the same temperature for 2 h, MeOH
(2 mL) was added and the mixture was stirred for 30 min. Then
water was added to quench the reaction. The aqueous layer was
extracted with ether. The combined organic layers were washed
with 1N HCl, saturated aq. NaHCO3, and brine and further dried
over anhydrous Na2SO4. After filtration and removal of the solvent
in vacuo, the residue was purified by silica gel column
chromatography to give compound 23 (420 mg, 81% yield): clear
oil, [a]D23 = 0.928 (c 4.10, CHCl3); 1H NMR (300 MHz, CDCl3) d 8.02
(br, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.45–7.40 (m, 2H), 7.33–7.26 (m,
4H), 5.20–5.00 (m, 2H), 4.75–4.33 (m, 4H), 3.91–3.85 (m, 1H), 3.59
(d, J = 12.3 Hz, 1H), 2.84 (br, 1H); 19F NMR (282 MHz, CDCl3) (two
rotamers) d ꢀ103.2 (dm, J = 246.5 Hz, 1F), ꢀ127.0 (d, J = 245.1 Hz,
0.48F), ꢀ128.4 (d, J = 247.3 Hz, 0.52F); IR (thin film) ymax 3433,
1719, 1419, 1276, 1113 cmꢀ1; MS (ESI) m/z 392 (M+H)+, 409
1351 cmꢀ1
10H17N3O6F2S: C, 34.78; H, 4.96; N, 12.17; found: C, 33.95; H,
5.08; N, 11.88.
;
MS (ESI) m/z 363 (M+NH4)+; Anal. Calcd. for
C

X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
873
(M+NH4)+, 414 (M+Na)+; Anal. Calcd. for C20H19NO5F2: C, 61.38; H,
4.89; N, 3.58; found: C, 61.43; H, 4.95; N, 3.34.
3.25. 20,30-Dideoxy-60,60-difluoro-30-aza-benzyloxycarbonyl-a-
uridine (28)
D-
3.21. (2S,4S)-Benzyl 2-(benzoyloxymethyl)-3,3-difluoro-4-
(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate (24)
A mixture of compound 27a (180 mg, 0.34 mmol) in dioxane
(2.2 mL) and 2N sulfuric acid (5.1 mL) was heated at reflux for 4 h.
After that, the mixture was cooled to 0 8C and neutralized with
diluted aq. NaOH. Then, the resulting mixture was extracted with
EtOAc. The combined organic layer was washed with brine, dried
over anhydrous Na2SO4. After filtration and removal of all the
solvent, the residue was dissolved in saturated NH3 in MeOH (5 mL).
The resultant mixture was stirred at room temperature for 24 h. The
solvent was removed in vacuo and the residue was purified by silica
gel column chromatography to give compound 28 (68 mg, 53%
yield): white solid, mp 97–100 8C; [a]D23 = 35.48 (c 0.46, MeOH); 1H
NMR (300 MHz, CD3OD) d 7.77 (dd, J = 8.1 Hz, 2.7 Hz, 1H), 7.41–7.33
(m, 5H), 6.06–5.90 (m, 1H), 5.72 (d, J = 7.8 Hz,1H), 5.27–5.16(m, 2H),
The compound 24 was prepared from compound 23 using the
same procedure as described for 10: clear oil, [a]D23 = 15.28 (c 0.65,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.94 (d, J = 6.9 Hz, 2H), 7.52–
7.47 (m, 1H), 7.35 (t, J = 8.1 Hz, 2H), 7.26 (s, 5H), 5.21–5.16 (m, 1H),
5.13–5.03 (m, 2H), 4.56–4.45 (m, 3H), 4.12–4.07 (m, 1H), 3.77–3.72
(m, 1H); 19F NMR (282 MHz, CDCl3) (two rotamers) d ꢀ74.3 (s, 3F),
ꢀ100.5 (dm, J = 253.2 Hz, 1F), ꢀ120.8 (d, J = 256.1 Hz, 0.50F),
ꢀ122.4 (d, J = 254.9 Hz, 0.50F); IR (thin film) ymax 1719, 1604,
1425, 1274, 1220, 1141 cmꢀ1; MS (ESI) m/z 524 (M+H)+, 541
(M+NH4)+, 546 (M+Na)+; Anal. Calcd. for C21H18NO7F5S: C, 48.19;
H, 3.47; N, 2.68; found: C, 48.31; H, 3.74; N, 2.70.
4.18 (d, J = 19.8 Hz, 1H), 4.03–3.89 (m, 2H), 3.83–3.76 (m, 2H); 13
C
NMR (75.5 MHz, CD3OD) d 164.2, 154.6, 151.4, 142.8 (d, J = 6.0 Hz),
136.2, 128.2, 127.9, 127.8, 123.9 (t, J = 259.0 Hz), 101.6, 67.3, 63.3 (q,
J = 26.5 Hz), 57.5 (d, J = 66.4 Hz), 54.2 (t, J = 17.4 Hz), 44.8; 19F NMR
(282 MHz, CD3OD) (two rotamers) d ꢀ109.3 (dt, J = 233.5 Hz,
20.0 Hz, 1F), ꢀ119.7 (dd, J = 232.4 Hz, 7.9 Hz, 0.45F), ꢀ121.2 (dd,
J = 233.2 Hz, 5.4 Hz, 0.55F); IR (KBr) ymax 3439, 3066, 1697, 1458,
1422, 1345 cmꢀ1; MS (ESI) m/z 382 (M+H)+, 404 (M+Na)+; HRMS
Calcd. for C17H17N3O5F2Na: 404.1029; found: 404.1033.
3.22. (2S,4R)-Benzyl 4-azido-2-(benzoyloxymethyl)-3,3-
difluoropyrrolidine-1-carboxylate (25)
Compound 25 was prepared from compound 24 using the same
procedureasdescribedfor 11: clearoil, [a]D23 = 32.28 (c3.32, CHCl3);
1H NMR (300 MHz, CDCl3) d 7.97 (d, J = 7.5 Hz, 2H), 7.62–7.57 (m,
1H), 7.49–7.44 (m, 2H), 7.35–7.32 (m, 5H), 5.22–5.13 (m, 2H), 4.76–
4.67 (m, 1H), 4.59–4.36 (m, 2H), 4.21–4.12 (m, 1H), 3.87–3.81 (m,
1H), 3.56–3.54 (m, 1H); 19F NMR (282 MHz, CDCl3) (two rotamers) d
ꢀ111.8 (dt, J = 237.7 Hz, 13.8 Hz, 0.49F), ꢀ112.2 (dt, J = 237.2 Hz,
14.7 Hz, 0.51F), ꢀ115.1 (d, J = 236.3 Hz, 0.49F), ꢀ116.6 (d,
J = 236.9 Hz, 0.51F); IR (thin film) ymax 3067, 2115, 1724, 1415,
1272, 1113 cmꢀ1; MS (ESI) m/z 417 (M+H)+, 434 (M+NH4)+, 439
(M+Na)+, 455 (M+K)+; Anal. Calcd. for C20H18N4O4F2: C, 57.69; H,
4.36; N, 13.46; found: C, 57.88; H, 4.40; N, 13.42.
3.26. 20,30-Dideoxy-60,60-difluoro-30-aza-a-
D-uridine (1c)
A mixture of 28 (20 mg, 0.053 mmoL) and 10% Pd/C (13 mg) in
MeOH (5 mL) was vigorously stirred under H2 atmosphere (1atm).
After 40 min, the solution was filtered over celite and evaporated,
the residue was purified by silica gel column chromatography to
give the nucleoside 1c (11 mg, 85% yield) as a white solid: mp 192–
194 8C; [a]D23 = ꢀ2.78 (c 0.27, MeOH); 1H NMR (300 MHz, CD3OD) d
7.70 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 5.70 (d, J = 7.8 Hz, 1H), 5.28–5.14
(m, 1H), 3.81–3.70 (m, 2H), 3.51–3.42 (m, 2H), 3.26–3.22 (m, 1H);
13C NMR (75.5 MHz, CD3OD) d 164.5, 151.4, 143.6 (d, J = 2.6 Hz),
126.7 (t, J = 258.5 Hz), 101.4, 64.1 (t, J = 27.1 Hz), 59.5 (q,
J = 18.0 Hz), 58.4 (q, J = 2.9 Hz), 45.5 (d, J = 7.3 Hz); 19F NMR
(282 MHz, CD3OD) d ꢀ107.9 (dm, J = 237.2 Hz, 1F), ꢀ114.1 (dm,
J = 237.7 Hz, 1F); IR (KBr) ymax 3431, 3300, 3095, 1702, 1673, 1448,
1389 cmꢀ1; MS (ESI) m/z 248 (M+H)+, 270 (M+Na)+; HRMS Calcd.
for C9H11N3O3F2Na: 270.0661; found: 270.0664.
3.23. (2S,4R)-Benzyl 4-amino-2-(benzoyloxymethyl)-3,3-
difluoropyrrolidine-1-carboxylate (26)
Compound 26 was prepared from compound 25 using the same
procedure as described for compound 12: clear oil, [a]D25 = 42.08 (c
0.76, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.98 (d, J = 7.2 Hz, 2H),
7.61–7.56 (m, 1H), 7.48–7.43 (m, 2H), 7.36–7.31 (m, 5H), 5.17–5.16
(m, 2H), 4.80–4.70 (m, 1H), 4.46–4.40 (m, 2H), 3.92–3.89 (m, 2H),
3.18–3.15 (m, 1H), 1.55 (br, 2H); 13C NMR (75.5 MHz, CDCl3) d
165.7, 154.6, 136.0, 135.9, 133.3, 129.5, 128.6, 128.3, 127.9, 122.4
(t, J = 103.7 Hz), 67.8, 67.5, 60.7 (d, J = 21.8 Hz), 54.6, 49.7; 19F NMR
(282 MHz, CDCl3) (two rotamers) d ꢀ115.3 (dm, J = 233.8 Hz, 1F),
ꢀ121.9 (d, J = 234.3 Hz, 0.47F), ꢀ123.7 (d, J = 232.9 Hz, 0.53F); IR
(thin film) ymax 3399, 1719, 1417, 1274, 1112 cmꢀ1; MS (ESI) m/z
391 (M+H)+, 408 (M+NH4)+; Anal. Calcd. for C20H20N2O4F2: C,
61.53; H, 5.16; N, 7.18; found: C, 61.50; H, 5.06; N, 7.22.
3.27. 20,30-Dideoxy-60,60-difluoro-30-aza-benzyloxycarbonyl-a-
cytidine (29)
D-
To a solution of compound 28 (10 mg, 0.026 mmol) in pyridine
(0.60 mL), DMAP (2 mg, 0.016 mmol) and Ac2O (0.10 mL,
1.06 mmol) were added subsequently. After being stirred for 12 h,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The organic layers were combined and washed with
1N HCl, saturated aq NaHCO3, and brine. The organic phase was
dried over anhydrous Na2SO4. After filtration and removal of the
solvent invacuo, theresiduewasdissolvedinCH3CN(1.5 mL)at0 8C.
Then, TPSCl (15 mg, 0.050 mmol), DMAP (6 mg, 0.048 mmol), and
Et3N (7 mL, 0.048 mmol) were added subsequently. The reaction
mixturewas warmed toroomtemperatureand stirred for12 h. After
that, concentratedNH3ꢁH2O(28%, 0.40 mL)wasaddedandthewhole
reaction mixture was stirred overnight. The resulting mixture was
extracted with Et2O. The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and filtered. The solvent was
removed in vacuo. The residue was dissolved in the saturated NH3 in
MeOH (3 mL) and the reaction mixture was stirred at room
temperature for 36 h. After that, the solvent was removed in vacuo
3.24. (2S,4R,E)-Benzyl 2-(benzoyloxymethyl)-4-(3-(3-
ethoxyacryloyl)ureido)-3,3-difluoropyrrolidine-1-carboxylate (27)
Compound 27 was prepared from compound 26 using the same
procedure as described for compound 13: white solid, mp 62–64 8C;
[a]D24 = 19.98 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3) d 9.50 (d,
J = 19.5 Hz, 1H), 9.28 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 7.5 Hz, 2H), 7.65–
7.55 (m, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.34 (s, 5H), 5.28–5.16 (m, 4H),
4.90 (t, J = 12.0 Hz, 1H), 4.50–4.29 (m, 2H), 4.01 (t, J = 10.2 Hz, 1H),
3.78–3.66 (m, 2H), 3.35–3.31 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H); 19F
NMR (282 MHz, CDCl3) (two rotamers) d ꢀ110.9 (dt, J = 235.2 Hz,
19.7 Hz, 1F), ꢀ119.1 (d, J = 234.9 Hz, 0.45F), ꢀ120.9 (d, J = 235.2 Hz,
0.55F); IR (KBr) ymax 3248, 1716, 1680, 1550, 1272, 1108 cmꢀ1; MS
(ESI) m/z 532 (M+H)+, 549 (M+NH4)+; Anal. Calcd. for C26H27N3O7F2:
C, 58.75; H, 5.12; N, 7.91; found: C, 58.40; H, 5.12; N, 7.63.

874
X. Yue et al. / Journal of Fluorine Chemistry 129 (2008) 866–874
References
andthe residue was purified by silica gel column chromatography to
give compound 29 (5 mg, 50% yield): white solid, mp 145–147 8C;
[a]D25 = 26.48 (c 1.70, MeOH); 1H NMR (300 MHz, CD3OD) d 7.74 (dd,
J = 7.2 Hz, 2.4 Hz, 1H), 7.44–7.33 (m, 5H), 6.23–6.06 (m, 1H), 5.92 (d,
J = 8.4 Hz, 1H), 5.20–5.16 (m, 2H), 4.16 (d, J = 20.4 Hz, 1H), 4.02–3.90
(m, 2H), 3.80–3.73 (m, 2H); 19F NMR (282 MHz, CD3OD) (two
rotamers) d ꢀ109.3 (dm, J = 232.4 Hz, 1F), ꢀ119.7 (dd, J = 231.0 Hz,
5.4 Hz, 0.46F), ꢀ121.2 (dd, J = 232.7 Hz, 7.3 Hz, 0.54F); IR (KBr) ymax
3327, 1655,1496, 1342, 1106 cmꢀ1; MS(ESI)m/z381(M+H)+; HRMS
Calcd. for C17H19N4O4F2: 381.1369; found: 381.1372.
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D-cytidine (1d)
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The nucleoside 1d was prepared from compound 29 using the
same procedure as described for 1c: white solid, mp 138–140 8C;
[a]D25 = 11.98 (c 0.08, MeOH); 1H NMR (300 MHz, CD3OD) d 7.68 (dd,
J = 7.8 Hz, 2.1Hz, 1H), 5.92 (d, J = 7.2 Hz, 1H), 5.42–5.28 (m, 1H),
3.84–3.73 (m, 2H), 3.52–3.36 (m, 2H), 3.29–3.22 (m, 1H); 13C NMR
(75.5 MHz, CD3OD) d 166.0, 157.3, 144.0 (d, J = 2.0 Hz), 126.8 (t,
J = 242.9 Hz), 94.8, 64.3 (t, J = 21.8 Hz), 60.1 (q, J = 19.9 Hz), 58.5 (t,
J = 6.9 Hz), 46.0 (d, J = 5.4 Hz); 19F NMR (282 MHz, CD3OD) d ꢀ107.7
(dm, J = 236.0 Hz, 1F), ꢀ113.3 (dm, J = 236.9 Hz, 1F); IR (KBr) ymax
3355, 3195, 1655, 1488, 1399, 1198 cmꢀ1; MS (ESI) m/z 247 (M+H)+;
HRMS Calcd. for C9H12N4O2F2Na: 269.0821; found: 269.0824.
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[10] Crystal data have been deposited at the Cambridge Crystallographic Data Center
with reference numbers: compound 1a, CCDC 666126; compound 1c, CCDC
666127.
Acknowledgements
The National Natural Science Foundation of China, Ministry of
Education of China, and Shanghai Municipal Scientific Committee
are greatly acknowledged for funding this work.