Synthesis of a series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides

Article abstract of DOI:10.1016/j.tet.2006.12.014

A series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides 1a-d, analogues of 3TC that has high biological activities against HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis feat

Full text of DOI:10.1016/j.tet.2006.12.014

Tetrahedron 63 (2007) 1560–1567
Synthesis of a series of novel 20,30-dideoxy-
60,60-difluoro-30-thionucleosides
Xuyi Yue,a Yun-Yun Wua and Feng-Ling Qinga,b,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bInstitute of Biological Sciences and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
Received 5 September 2006; revised 7 December 2006; accepted 8 December 2006
Available online 26 December 2006
Abstract—A series of novel 20,30-dideoxy-60,60-difluoro-30-thionucleosides 1a–d, analogues of 3TC that has high biological activities against
HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis featured the
construction of thiofuranose skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group in
compounds 13a,b.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
X
H2N
NH2
20,30-Dideoxynucleosides (ddNs) have far proven to be the
most effective therapeutic agents against human immuno-
deficiency virus (HIV) and hepatitis B virus (HBV).1 Among
them, 30-azido-20,30-dideoxythymidine (AZT),2 20,30-dide-
oxyinosine (DDI),3 and 20,30-dideoxycytidine (DDC)4 have
been approved for the treatment of AIDS. In spite of the ini-
tial success obtained with these modified nucleosides, the
instability of the glycosidic bond of the 40-oxonucleosides
under physiological conditions5 as well as undesirable side
effects of certain nucleosides has prompted the search for
further novel nucleosides with improved biological and
chemical properties. Consequently, extensive modifications
have been made to both the heterocyclic base and the sugar
moiety of nucleosides.6 Sulfur-containing dideoxynucleo-
sides, (ꢀ)-b-L-(2R,5S)-1,3-oxathiolanylcytosine (3TC)7 and
its 5-fluorocytosine analogue (ꢀ)-FTC (Fig. 1),8 showed
higher biological activity than conventional ddNs and were
approved by the FDA for the treatment of HIV infection.
As the gem-difluoromethylene (CF2) group has been sug-
gested by Blackburn as an isopolar and isosteric substituent
for oxygen,9 recently we have designed and synthesized a
new difluoromethylenated thionucleoside A.10 To investigate
the structure–activity relationship of this novel analogue of
3TC, a series of 20,30-dideoxy-60,60-difluoro-30-thionucleo-
sides are needed. Herein, we wish to report the preparation
of stereoisomers 1c and 1d of compound A (Fig. 1).
N
O
N
F
S
F
N
OH
N
HO
O
S
O
X = H, 3TC
X = F, (-)-FTC
A
NH2
F
F
R6
R5
N
N
S
O
1c R5 = CH2OH, R6 = H
1d R5 = H, R6 = CH2OH
Figure 1.
2. Results and discussion
On the basis of our retrosynthetic analysis (Scheme 1), the
target molecules 1a–d can be reached from the gem-difluoro-
methylenated cyclic amine B by installing the pyrimidine
base moiety at C1 position through the reported method-
ology.11As thegem-difluoromethylenated thiofuranose could
be smoothly constructed via ring closure of the correspond-
ing dimesylate,12 we envisioned that the gem-difluoro-
methylenated diols C could be suitable precursors for B.
Compounds C could be afforded by removal of the isopropyl-
idene ketal of intermediate D followed by oxidation of the
dihydroxyl moiety and subsequent reduction. Conversion of
hydroxyl group of homoallyl alcohol E to amino group fol-
lowed bydihydroxylationwouldfurnishtheaminoalcoholD.
To obtain the desired base configuration of target nucleosides
Keywords: gem-Difluoromethylenated compounds; Thionucleoside.
* Corresponding author. Fax: +86 21 64166128; e-mail: flq@mail.sioc.
ac.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.014

X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
1561
construction of
pyrimidine ring
P2HN
HO
OH
*
F
F
F
F
NH2
base
P1O
HO
*
*
S
S
1a-d
F F
OP1
B
C
Br
O
OH
3
P2HN
OH
5
5
2
F
F
H
1
O
*
O
3
2
1
*
O
O
F
F
O
F F
O
OP1
2
E
D
Scheme 1. Retrosynthetic analysis of target molecules 1a–d.
1a–d, the configuration of amino group (C3 position) of com-
pound D must be R and thus the hydroxyl group of homoallyl
alcohol E should be formed with S configuration. We have
reported that the allylation of chiral aldehyde with 3-bromo-
3,3-difluoropropylene in the presence of indium provided the
anti-isomer of homoallyl alcohol as the major product.13
Therefore, (S)-glyceraldehyde acetonide 2 was chosen for
the preparation of the desired gem-difluoromethylenated
homoallyl alcohol E.
compound 4 with NaN3 in DMF provided azide 5. Reduction
of compound 5 with Ph3P in THF produced our desired
amine syn-6, which could be easily separated through col-
umn chromatography. Finally, protection of amine syn-6
with Boc2O gave amide 7 in 94% yield.
With the difluorohomoallyl amide 7 in hand, key inter-
mediates 13a and 13b were synthesized in a straightforward
fashion (Scheme 3). The Os-catalyzed dihydroxylation of
compound 7 gave a mixture of the diastereoisomers 8a and
8b in 83% yield (8a/8b¼1:1). Luckily, the diastereoisomers
8a and 8b were easily separated by column chromatography.
Benzoates 9a and 9b were obtained by selective benzoyl-
ation of the primary hydroxyl groups of diols 8a and 8b,
respectively. The conversions of benzoates 9a and 9b to their
respective difluoromethylenated furanoses 10a and 10b
were achieved by the following two steps: (1) the acidic
hydrolysis of the isopropylidene groups by treatment with
75% aqueous AcOH at 50 ꢁC and (2) the oxidative scission
of the resulting diols with NaIO4 and subsequent cyclization.
Difluorinated furanoses 10a and 10b were directly reduced
by NaBH4 in MeOH to give the diols 11a and 11b both in
77% yields from 9a and 9b, respectively. Mesylations at
C1 and C4 positions of diols 11a and 11b, followed by treat-
ment with Na2S in DMF, resulted in a ring closure to provide
thiofuranoses 12a and 12b as single stereoisomers, respec-
tively. Finally, removal of Boc group of thiofuranoses 12a
and 12b gave the key intermediates 13a and 13b in high
yields, respectively.
Accordingly, the coupling of 1-(S)-glyceraldehyde aceto-
nide 2 with 3-bromo-3,3-difluoropropene in DMF in the
presence of indium provided gem-difluorohomoallyl alcohol
3 in 73% yield. The ratio of anti/syn is 8.1:1 determined by
19F NMR. Notably, anti-3 was our desired compound
(Scheme 2). Then, reaction of compound 3 with Tf2O in
CH2Cl2 at ꢀ25 ꢁC gave triflate 4. Subsequent treatment of
O
OTf
OH
a
b
H
O
O
O
O
F
F
F
F
O
O
3
2
4
anti : syn = 8.1 : 1
c
NH2
NHBoc
N3
d
e
O
O
O
F
F
O
F
F
F
F
O
O
syn-6
7
5
Scheme 2. Reagents and conditions: (a) In powder, CH2]CHCF2Br, DMF,
22 h, 73%; (b) Tf2O, pyridine, CH2Cl2, ꢀ25 ꢁC, 1 h, 92%; (c) NaN3, DMF,
12 h, rt, overnight, 75%; (d) (i) Ph3P, THF, rt, 6 h; (ii) H2O, 50 ꢁC, 40 h,
57%; (e) Boc2O, Et3N, THF, CH2Cl2, 94%.
The construction of pyrimidine was followed by the proce-
dure reported by Shaw and Warrener (Scheme 4).11 Conden-
sation of amines 13a and 13b with 3-ethoxy-2-propenoyl
R2 R1
F
R1
R2
F
BocHN
BocHN
NHBoc
c
a
b
OBz
OH
O
O
O
F
F
F
F
O
O
O
O
8a R1 = OH, R2 = H
8b R1 = H, R2 = OH
7
9a R1 = OH, R2 = H
9b R1 = H, R2 = OH
F
S
F
F
S
F
R2
N
BocH
HO
R1
R4
R3
R4
R4
R3
OH
d
e
f
NH2
NHBoc
R3
F
F
F
OBz
NHBoc
F
10a R3 = CH2OBz, R4 = H 11a R1 = OH, R2 = H 12a R3 = CH2OBz, R4 = H 13a R3 = CH2OBz, R4 = H
10b R3 = H, R4 = CH2OBz 11b R1 = H, R2 = OH 12b R3 = H, R4 = CH2OBz 13b R3 = H, R4 = CH2OBz
Scheme 3. Reagentsandconditions:(a)OsO4, NMNO, acetone, H2O, 48 h;(b)BzCl, pyridine, CH2Cl2, ꢀ78 ꢁC, 2 h;(c)(i)AcOH(aq75%), 50 ꢁC, 3 h;(ii) NaIO4,
H2O, rt, 3 h; (d) NaBH4, MeOH, 0 ꢁC, 20 min; (e) (i) MsCl, pyridine, 0 ꢁC–rt, overnight; (ii) Na2S$9H2O, DMF, 80 ꢁC, 10 min; (f) CF3CO2H, CH2Cl2, rt, 15 min.

1562
X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
EtO
O
O
F
S
F
F
S
F
F
S
F
H
N
R4
R3
R4
R3
R4
R3
a
b
c
NH2
NH
N
NH
O
O
13a R3 = CH2OBz, R4 = H
14a R3 = CH2OBz, R4 = H
15a R3 = CH2OBz, R4 = H
13b R3 = H, R4 = CH2OBz
14b R3 = H, R4 = CH2OBz
15b R3 = H, R4 = CH2OBz
NH2
O
F
S
F
F
S
F
R6
R5
R6
R5
d
N
N
N
NH
O
O
1a R5 = CH2OH, R6 = H
1c R5 = CH2OH, R6 = H
1b R5 = H, R6 = CH2OH
1d R5 = H, R6 = CH2OH
Scheme 4. Reagents and conditions: (a) 3-ethoxy-2-propenoyl isocyanate, DMF, benzene, ꢀ25 ꢁC, overnight; (b) 2 N H2SO4, reflux, 3 h; (c) satd NH3/MeOH,
rt, overnight; (d) (i) Ac2O, pyridine, DMAP, rt, 12 h; (ii) TPSCl, DMAP, Et3N, rt, 4 h; (iii) concd NH3$H2O, rt, overnight.
isocyanate in DMF at ꢀ25 ꢁC gave the compounds 14a and
14b followed by ring closure with 2 N H2SO4 in dioxane to
affordthe compounds15a and15b, respectively. Deprotection
of the compounds 15a and 15b was accomplished by ammo-
nolysis to give the corresponding 20,30-dideoxy-60,60-difluoro-
30-thiouridine 1a and 1b. Thiouridines 1a and 1b were further
converted intothe cytosine derivatives1c and 1d, respectively,
by isopropylbenzene-sulfonylation of the O-4 position fol-
lowed by treatment with concentrated NH3$H2O.
CaH2. 1H NMR spectra were recorded on a Bruker AM300
spectrometer. 19F NMR spectra were recorded on a Bruker
AM300 spectrometer (FCCl3 as external standard and low
field is positive). All the melting points and optical rotations
are uncorrected. The following abbreviations were used to
explain the multiplicities: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet.
3.1.1. 1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,2-di-
fluoro-but-3-en-1-ol (3). A suspension consisting of an alde-
hyde 2 (9.900 g, 76.15 mmol), 3-bromo-3,3-difluoropropene
(17.100 g, 108.92 mmol), powdered indium (9.700 g,
84.49 mmol), and DMF (500 mL) was stirred for 22 h at
room temperature. The reaction mixture was then quenched
with 1 N HCl and extracted with ether. The combined
organic extract was washed with brine, dried over anhydrous
Na2SO4, filtered, and the solvent was removed in vacuo. The
residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate¼3:1) to give 11.500 g
(72.6% yield) of compound 3 as a clear oil: 1H NMR
(300 MHz, CDCl3) d 6.12–5.94 (m, 1H), 5.74 (dt,
J¼17.4 Hz, 2.7 Hz, 1H), 5.60 (d, J¼11.1 Hz, 1H), 4.33–
4.27 (m, 1H), 4.06–3.99 (m, 3H), 2.38 (s, 1H), 1.44 (s,
3H), 1.37 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ106.36
(dm, J¼253.8 Hz, 0.11F), ꢀ108.01 (dm, J¼250.0 Hz,
0.89F), ꢀ110.23 (dm, J¼256.6 Hz, 0.89F), ꢀ111.29 (dm,
J¼248.2 Hz, 0.11F); IR (thin film) nmax 3444, 1652,
1219 cmꢀ1; MS m/z 209 (M++1, <1), 193 (14), 101 (77),
43 (100). Anal. Calcd for C9H14O3F2: C, 51.92; H, 6.78.
Found: C, 51.45; H, 6.72.
The absolute configuration of the target molecules 1a–d
was assigned on the basis of the X-ray crystal structures of
compounds 1a,b (Fig. 2).14
In summary, based on the bioisosteric rationale, we have
synthesized a series of 20,30-dideoxy-60,60-difluoro-30-thio-
nucleosides. Our synthesis featured the construction of thio-
furanose skeleton through ring closure of key intermediates
and construction of pyrimidine ring with amino group in
compounds 13a,b. Antiviral and cytotoxicity evaluations
of herein synthesized 20,30-dideoxy-60,60-difluoro-30-thio-
nucleosides 1a–d are currently in progress.
3. Experimental section
3.1. General
Tetrahydrofuran (THF) was distilled from sodium metal.
Dichloromethane (CH2Cl2) and pyridine were distilled from
1a
1b
Figure 2. ORTEP drawing of the X-ray crystallographic structures of compounds 1a and 1b.

X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
1563
3.1.2. Trifluoromethanesulfonic acid 1-(2,2-dimethyl-
[1,3]dioxolan-4-yl)-2,2-difluorobut-3-enyl ester (4).
Compound 3 (10.000 g, 48.08 mmol) was dissolved in dry
CH2Cl2 (144 mL), after that freshly distilled pyridine
(7.8 mL, 96.21 mmol) was added. The resulting mixture was
cooled to ꢀ35 ꢁC. Then, trifluoromethanesulfonic anhydride
(12.1 mL, 72.12 mmol) was added dropwise to the solution
with stirring. After that, the reaction mixture was stirred for
about 1 h at about ꢀ25 ꢁC. Water and NaHCO3 solution
were added successively after the mixture was warmed to
the room temperature. Then the mixture was extracted
with CH2Cl2, dried over anhydrous Na2SO4, and purified
by silica gel column chromatography (petroleum ether/ethyl
acetate¼8:1) to afford compound 4 (15.000 g, 91.8% yield)
(m, 1H), 5.74–5.67 (m, 1H), 5.55 (d, J¼10.8 Hz, 1H),
4.26–4.20 (m, 1H), 4.10–4.05 (m, 1H), 3.87 (t, J¼7.5 Hz,
1H), 3.04 (td, J¼10.2 Hz, 4.5 Hz, 1H), 1.42 (s, 3H), 1.37
(s, 3H); 13C NMR (75.5 MHz, CDCl3) d 130.38 (t, JC–F
25.8 Hz), 121.00 (t, JC–F¼9.5 Hz), 120.99 (t, JC–F
¼
¼
227.93 Hz), 109.35, 73.94, 67.19, 57.72 (t, JC–F¼27.6 Hz),
26.34, 25.49; 19F NMR (282 MHz, CDCl3) d ꢀ106.00
(dm, J¼249.3 Hz), ꢀ106.82 (dm, J¼247.3 Hz); IR (thin
film) nmax 3408, 1608, 1065 cmꢀ1; MS (ESI) m/z 208
(M++H). Anal. Calcd for C9H15NO2F2: C, 52.17; H, 7.29;
N, 6.76. Found: C, 52.30; H, 7.34; N, 6.31.
3.1.5. [1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2,2-difluoro-
but-3-enyl]-carbamic acid tert-butyl ester (7). A solu-
tion of compound 6 (3.870 g, 18.70 mmol) in CH2Cl2
(152 mL) was added to di-tert-butyl dicarbonate (20.500 g,
94.04 mmol) dropwise at room temperature with vigorous
stirring. After the starting material completely disappeared,
water was added to quench the reaction and the mixture was
stirred for another 10 min. The organic layer was washed
with brine and dried over Na2SO4. After filtration and
removal of the solvent in vacuo, the residue was purified
by silica gel column chromatography (petroleum ether/ethyl
acetate¼8:1) to give compound 7 (5.410 g, 94.3% yield) as a
yellow oil: [a]2D0 ꢀ32.7 (c 1.2, CHCl3); 1H NMR (300 MHz,
CDCl3) d 6.05–5.91 (m, 1H), 5.72 (dd, J¼17.4 Hz, 1.2 Hz,
1H), 5.57 (d, J¼10.8 Hz, 1H), 4.99 (d, J¼10.8 Hz, 1H),
4.49 (t, J¼6.6 Hz, 1H), 4.13–4.07 (m, 2H), 3.69–3.63 (m,
1H), 1.45 (s, 9H), 1.44 (s, 3H), 1.37 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) d 155.74, 130.58 (t, JC–F¼17.7 Hz),
121.09 (t, JC–F¼6.2 Hz), 119.46 (t, JC–F¼184.1 Hz),
110.00, 80.28, 72.03, 66.86, 54.39 (t, JC–F¼21.7 Hz),
28.23, 26.07, 25.33; 19F NMR (282 MHz, CDCl3)
d ꢀ105.30 (dm, J¼248.7 Hz), ꢀ107.81 (dm, J¼248.7 Hz);
IR (thin film) nmax 3458, 3352, 1721, 1503 cmꢀ1; MS m/z
330 (M++Na). Anal. Calcd for C14H23NO4F2: C, 54.71; H,
7.54; N, 4.56. Found: C, 55.10; H, 7.65; N, 4.13.
1
as a clear oil: H NMR (300 MHz, CDCl3) d 6.02–5.82
(m, 2H), 5.73–5.70 (m, 1H), 5.20–5.12 (m, 1H), 4.41
(td, J¼6.9 Hz, 2.7 Hz, 1H), 4.08–3.93 (m, 2H), 1.45 (s,
3H), 1.37 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ74.1
(s, 3F), ꢀ102.19 (dm, J¼269.9 Hz, 0.06F), ꢀ106.38
(dm, J¼254.1 Hz, 0.94F), ꢀ107.29 (dm, J¼219.7 Hz,
0.94F), ꢀ108.41 (dm, J¼265.1 Hz, 0.06F); IR (thin film)
nmax 1421, 1214, 1143 cmꢀ1; MS m/z 325 (M+ꢀCH3, 24),
101 (12), 77 (14), 43 (100). Anal. Calcd for C10H13O5F5S:
C, 35.30; H, 3.85. Found: C, 35.23; H, 3.83.
3.1.3. 4-(1-Azido-2,2-difluoro-but-3-enyl)-2,2-dimethyl-
[1,3]dioxolane (5). A solution of compound 4 (15.000 g,
44.12 mmol) in DMF (120 mL) was cooled to 0 ꢁC in an
ice bath. Then, sodium azide (13.192 g, 202.95 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 layer was
washed with brine and dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was quickly purified by
silica gel column chromatography (petroleum ether/ethyl
acetate¼8:1) to afford compound 5 (7.700 g, 74.9% yield):
clear oil, 1H NMR (300 MHz, CDCl3) d 6.06–5.92 (m,
1H), 5.81–5.73 (m, 1H), 5.60 (d, J¼11.1 Hz, 1H), 4.32–
4.26 (m, 1H), 4.13–4.08 (m, 1H), 3.91–3.85 (m, 1H), 3.57–
3.51 (m, 1H), 1.47 (s, 3H), 1.40 (s, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ99.84 (dm, J¼253.5 Hz, 0.95F), ꢀ103.70 (dm,
J¼252.7 Hz, 0.05F), ꢀ106.07 (dm, J¼249.6 Hz, 0.05F),
ꢀ106.62 (dm, J¼253.8 Hz, 0.95F); IR (thin film)
3.1.6. [1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2,2-difluoro-
3,4-dihydroxy-butyl]-carbamic acid tert-butyl esters 8a
and 8b. To a solution of compound 7 (5.410 g, 17.62 mmol)
in acetone (107 mL) was added NMNO (4.502 g,
33.34 mmol), followed by addition of water (24 mL) at
room temperature with stirring. Then, a catalytic amount of
OsO4 (5–10 mol %) solution in water (4% solution) was
added. After the reaction mixture was stirred at room temper-
ature for 48 h, the reaction was quenched with saturated aq
NaHSO3 and extracted with ethyl acetate. The combined
organic layers were washed with 1 N 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 (petroleum ether/ethyl acetate¼2:1) to give
compound 8a (2.700 g, 46.7% yield) as a white solid and
compound 8b (2.101 g, 36.3% yield).
nmax 2120, 1263, 1216, 1065 cmꢀ1
; MS m/z 218
(M+ꢀCH3, 41), 101 (49), 77 (16), 43 (100). Anal. Calcd
for C9H13O2F2N3: C, 46.35; H, 5.62; N, 18.02. Found: C,
46.69; H, 5.79; N, 17.72.
3.1.4. 1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2,2-difluoro-
but-3-enylamine (6). A solution of Ph3P (14.701 g,
56.05 mmol) in THF (20 mL) was slowly added at room tem-
perature to a solution of compound 5 (7.700 g, 33.05 mmol)
in THF (93 mL), and then, the reaction mixture was moni-
tored by TLC. When the starting material was completely
consumed, water (70 mL) was added and the reaction mix-
ture was stirred for 40 h at 50 ꢁC. The reaction mixture
was cooled to room temperature and brine was added. 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 chroma-
tography (petroleum ether/ethyl acetate¼4:1) to give com-
pound 6 (3.870 g, 56.6% yield) as a yellow oil: [a]2D6 +4.7
Compound 8a: white solid, mp 91–93 ꢁC; [a]D23 ꢀ4.6 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3) d 5.32 (d, J¼9.0 Hz,
1H), 4.58 (td, J¼6.9 Hz, 1.8 Hz, 1H), 4.18–4.08 (m, 2H),
3.88–3.84 (m, 3H), 3.68 (t, J¼8.1 Hz, 1H), 1.46 (s, 9H),
1.39 (s, 3H), 1.25 (s, 3H); 13C NMR (75.5 MHz, CDCl3)
d 157.53, 121.57 (t, JC–F¼190.9 Hz), 110.25, 81.84,
70.80, 70.18 (dd, JC–F¼23.6, 18.0 Hz), 67.33, 60.10 (d,
JC–F¼3.4 Hz), 51.32 (dd, JC–F¼22.9 Hz, 18.0 Hz), 28.20,
1
(c 2.0, CHCl3); H NMR (300 MHz, CDCl3) d 6.08–5.94

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X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
26.12, 25.19; 19F NMR (282 MHz, CDCl3) d ꢀ122.61 (dm,
J¼254.9 Hz), ꢀ123.26 (dm, J¼255.5 Hz); IR (KBr) nmax
3332, 1710, 1533, 1017 cmꢀ1; MS (ESI) m/z 364
(M++Na). Anal. Calcd for C14H25O6NF2: C, 49.26; H,
7.38; N, 4.10. Found: C, 49.06; H, 7.17; N, 3.72.
and 75% of aq AcOH (13 mL) was stirred at 50 ꢁC for 3 h.
The solvent was then removed in vacuo. The residue was dis-
solved in acetone (11 mL), followed by treatment with a
solution of NaIO4 (0.810 g, 3.78 mmol) in water (13 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 aqueous
layer 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 dis-
solved in MeOH (20 mL). To the solution of compound
10a was added NaBH4 (0.187 g, 5.00 mmol) in portions at
0 ꢁC. After stirring for 20 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, filtered, and the solvent was removed
in vacuo. The residue was purified by silica gel column chro-
matography (petroleum ether/ethyl acetate¼2:1) to give
0.730 g of compound 11a (77.3% yield, three steps).
Compound 8b: white solid, mp 88–91 ꢁC; [a]D24 ꢀ25.0 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3) d 5.11 (d, J¼12.6 Hz,
1H), 4.54 (t, J¼6.3 Hz, 1H), 4.26–4.11 (m, 2H), 4.10–3.85
(m, 3H), 3.68 (t, J¼7.5 Hz, 3H), 1.46 (s, 12H), 1.38 (s,
3H); 19F NMR (282 MHz, CDCl3) d ꢀ113.3 (dm,
J¼253.8 Hz), ꢀ119.64 (dm, J¼260.0 Hz); IR (KBr) nmax
3234, 1698, 1513, 1163 cmꢀ1; MS (ESI) m/z 364
(M++Na). Anal. Calcd for C14H25O6NF2: C, 49.26; H,
7.38; N, 4.10. Found: C, 48.95; H, 7.34; N, 3.83.
3.1.7. Benzoic acid 4-tert-butoxycarbonylamino-4-(2,2-
dimethyl-[1,3]dioxolan-4-yl)-3,3-difluoro-2-hydroxy-bu-
tyl ester (9a). To a solution of compound 8a (1.390 g,
4.08 mmol) in anhydrous CH2Cl2 (23 mL) and pyridine
(9.9 mL) was added BzCl (0.50 mL, 4.08 mmol) in
CH2Cl2 (3 mL) slowly at ꢀ78 ꢁC. After the mixture was
stirred at the same temperature for 2 h, MeOH (5 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 1 N HCl, saturated aq NaHCO3, and brine,
dried over anhydrous Na2SO4. After filtration and removal
of the solvent in vacuo, the residue was purified by silica
gel column chromatography (petroleum ether/ethyl
acetate¼4:1) to give compound 9a (1.696 g, 93.5% yield).
Compound 11a: white solid, mp 106–110 ꢁC; [a]D26 +8.7
(c 0.8, CHCl3); H NMR (300 MHz, CDCl3) d 8.08–8.05
1
(m, 2H), 7.59–7.54 (m, 1H), 7.47–7.41 (m, 2H), 5.52 (d,
J¼8.1 Hz, 1H), 5.01 (br, 1H), 4.71–4.67 (m, 1H), 4.52–
4.46 (m, 1H), 4.22–4.11 (m, 3H), 3.87–3.85 (m, 1H), 1.75
(br, 1H), 1.47 (s, 9H); 19F NMR (282 MHz, CDCl3)
d ꢀ121.29 (dd, J¼253.8 Hz, 25.1 Hz), ꢀ122.76 (dd,
J¼253.2 Hz, 23.1 Hz); IR (KBr) nmax 3286, 1728, 1680,
1557, 713 cmꢀ1; MS (ESI) m/z 398 (M++Na). Anal. Calcd
for C17H23O6NF2: C, 54.39; H, 6.18; N, 3.73. Found: C,
54.45; H, 6.17; N, 3.18.
Compound 9a: white solid, mp 90–91 ꢁC; [a]D23 ꢀ6.0 (c 0.9,
1
CHCl3); H NMR (300 MHz, CDCl3) d 8.07 (d, J¼8.4 Hz,
Compound 11b: it was prepared using the same condition as
described for compound 11a; white solid, mp 84–86 ꢁC;
2H), 7.56 (t, J¼7.2 Hz, 1H), 7.44 (t, J¼7.8 Hz, 2H), 5.32
(d, J¼9.3 Hz, 1H), 4.69–4.48 (m, 4H), 4.25–4.14 (m, 3H),
3.70 (t, J¼7.8 Hz, 1H), 1.47 (s, 12H), 1.40 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) d 166.53, 157.48, 133.09,
129.93, 129.78, 128.36, 121.49 (t, JC–F¼192.1 Hz),
110.30, 81.85, 70.86, 68.30 (dd, JC–F¼23.3 Hz, 17.5 Hz),
67.34, 62.81 (d, JC–F¼4.5 Hz), 51.27 (dd, JC–F¼23.3 Hz,
17.4 Hz), 28.20, 26.13, 25.20; 19F NMR (282 MHz,
CDCl3) d ꢀ121.12 (dd, J¼256.1 Hz, 25.4 Hz), ꢀ123.57
(dd, J¼255.2 Hz, 24.8 Hz); IR (KBr) nmax 3313, 1733,
1674, 1550, 1450 cmꢀ1; MS (ESI) m/z 468 (M++Na).
Anal. Calcd for C21H29O7NF2: C, 56.62; H, 6.56; N, 3.14.
Found: C, 56.98; H, 6.64; N, 2.97.
1
[a]2D6 ꢀ7.2 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3)
d 8.06–8.03 (m, 2H), 7.58–7.54 (m, 1H), 7.45–7.40 (m,
2H), 5.35 (d, J¼9.3 Hz, 1H), 4.68–4.52 (m, 2H), 4.35–
4.29 (m, 2H), 3.94–3.76 (m, 2H), 1.44 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) d 166.84, 156.18, 133.18, 129.66,
129.42, 128.28, 121.52 (t, JC–F¼191.8 Hz), 80.70, 69.51
(t, JC–F¼21.2 Hz), 63.70, 60.03, 53.65 (t, JC–F¼16.2 Hz),
28.10; 19F NMR (282 MHz, CDCl3) d ꢀ113.16 (dm,
J¼260.0 Hz), ꢀ118.90 (dm, J¼234.1 Hz); IR (KBr) nmax
3367, 1704, 1278, 713 cmꢀ1; MS (ESI) m/z 398 (M++Na),
414 (M++K). Anal. Calcd for C17H23O6NF2: C, 54.39; H,
6.18; N, 3.73. Found: C, 54.52; H, 6.13; N, 3.42.
Compound 9b: it was prepared using the same condition as
described for compound 9a; white solid, mp 100–103 ꢁC;
3.1.9. Benzoic acid 4-tert-butoxycarbonylamino-3,3-di-
fluoro-tetrahydro-thiophen-2-ylmethyl ester (12a). To
a solution of compound 11a (0.730 g, 1.95 mmol) in anhy-
drous CH2Cl2 (6 mL) and pyridine (5.7 mL) was added MsCl
(0.62 mL, 7.79 mmol) slowly at 0 ꢁC. The reaction mixture
was then warmed to room temperature and stirred overnight.
The reaction was quenched with water. The resulting mix-
ture was extracted with ethyl acetate. The combined organic
layers were washed with 1 N HCl, saturated aq NaHCO3,
water, and brine, dried over anhydrous Na2SO4. After filtra-
tion and removal of the solvent in vacuo, the residue was
dissolved in DMF (24 mL) and Na2S$9H2O (0.700 g,
2.93 mmol) was added. Then, the reaction mixture was
heated to 80 ꢁC. After stirring for 20 min, the reaction mix-
ture was cooled to room temperature and water was added.
1
[a]2D6 ꢀ22.9 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3)
d 8.08–8.05 (m, 2H), 7.58–7.56 (m, 1H), 7.48–7.42 (m, 2H),
5.13 (d, J¼10.2 Hz, 1H), 4.68–4.56 (m, 3H), 4.34–4.29 (m,
2H), 4.14 (t, J¼8.4 Hz, 1H), 3.70 (t, J¼7.5 Hz, 1H), 1.47 (s,
12H), 1.38 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ110.73
(dm, J¼260.9 Hz), ꢀ119.19 (dm, J¼267.1 Hz); IR (KBr)
nmax 3494, 3382, 1707, 1506, 717 cmꢀ1; MS (ESI) m/z 468
(M++Na). Anal. Calcd for C21H29O7NF2: C, 56.62; H, 6.56;
N, 3.14. Found: C, 56.13; H, 6.72; N, 2.78.
3.1.8. Benzoic acid 4-tert-butoxycarbonylamino-3,3-di-
fluoro-5-hydroxy-tetrahydrofuran-2-ylmethyl ester
(11a). A mixture of compound 9a (1.120 g, 2.52 mmol)

X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
1565
The resulting mixture was extracted with ethyl acetate. The
combined organic layers were washed with water and
brine, dried over anhydrous Na2SO4. After filtration and re-
moval of the solvent in vacuo, the residue was purified by
silica gel column chromatography (petroleum ether/ethyl
acetate¼6:1) to give compound 12a (0.468 g, 64.5% yield,
two steps).
JC–F¼2.3 Hz); 19F NMR (282 MHz, CDCl3) d ꢀ114.08
(dm, J¼233.8 Hz), ꢀ116.77 (dm, J¼233.5 Hz); IR (KBr)
nmax 3394, 1720, 1273, 713 cmꢀ1; MS (ESI) m/z 274
(M++H), 291 (M++NH4).
Compound 13b: it was prepared using the same condition as
described for compound 13a; clear oil, [a]2D4 +14.7 (c 0.5,
CHCl3); 1H NMR (300 MHz, CDCl3) d 8.05–8.02 (m,
2H), 7.59–7.54 (m, 1H), 7.46–7.41 (m, 2H), 4.70–4.63 (m,
1H), 4.52–4.46 (m, 1H), 3.99–3.90 (m, 1H), 3.62 (br, 1H),
2.99 (t, J¼9.9 Hz, 1H), 2.72 (t, J¼10.5 Hz, 1H), 1.55
(s, 2H); 13C NMR (75.5 MHz, CDCl3) d 165.88, 133.12,
129.64, 129.58, 128.34, 125.13 (t, JC–F¼188.0 Hz), 62.80
Compound 12a: white solid, mp 94–95 ꢁC; [a]D25 ꢀ72.2 (c
0.7, CHCl3); 1H NMR (300 MHz, CDCl3) d 8.06 (d,
J¼8.1 Hz, 2H), 7.61–7.55 (m, 1H), 7.48–7.43 (m, 2H),
4.99 (d, J¼7.8 Hz, 1H), 4.63–4.57 (m, 2H), 4.44 (dd,
J¼11.7 Hz, 6.0 Hz, 1H), 3.88–3.80 (m, 1H), 3.17–3.11 (m,
1H), 2.67 (t, J¼9.6 Hz, 1H), 1.46 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) d 165.97, 154.84, 133.28, 129.79,
129.53, 128.48, 126.21 (dd, JC–F¼175.5 Hz, 152.3 Hz),
(d, JC–F¼7.4 Hz), 58.96 (t, JC–F¼18.8 Hz), 44.77 (t, JC–F
¼
18.0 Hz), 30.99 (t, JC–F¼4.5 Hz); 19F NMR (282 MHz,
CDCl3) d ꢀ110.09 (dm, J¼222.5 Hz), ꢀ129.67 (dm, J¼
219.1 Hz); IR (thin film) nmax 3394, 1720, 1452, 1278,
1115 cmꢀ1; MS (ESI) m/z 274 (M++H).
80.71, 63.19, 55.78 (t, JC–F¼13.7 Hz), 45.13 (t, JC–F
¼
16.5 Hz, 12.8 Hz), 29.10, 28.25; 19F NMR (282 MHz,
CDCl3) d ꢀ109.54 (dm, J¼234.9 Hz), ꢀ115.87 (dm,
J¼234.6 Hz); IR (KBr) nmax 3368, 1729, 1696, 1523,
1283, 709 cmꢀ1; MS (ESI) m/z 391 (M++NH4). Anal. Calcd
for C17H21O4NSF2: C, 54.68; H, 5.67; N, 3.75. Found:
C, 54.85; H, 5.81; N, 3.63.
3.1.11. Benzoic acid 4-[3-(3-ethoxy-acryloyl)-ureido]-3,3-
difluoro-tetrahydro-thiophen-2-ylmethyl ester (14a). To
a solution of compound 13a (0.060 g, 0.22 mmol) in DMF
(3 mL) at ꢀ25 ꢁC, a solution of 3-ethoxy-2-propenoyl isocy-
anate (0.059 g, 0.42 mmol) in benzene (1.6 mL) was added
slowly enough to cause no rise in temperature. After addi-
tion, 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 temperature was maintained
below 40 ꢁC. The solid residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate¼
3:1) to give compound 14a (0.125 g, 82.4% yield).
Compound 12b: it was prepared using the same condition as
described for compound 12a; white solid, mp 116–118 ꢁC;
1
[a]2D6 +41.9 (c 0.7, CHCl3); H NMR (300 MHz, CDCl3)
d 8.05–8.02 (m, 2H), 7.60–7.55 (m, 1H), 7.47–7.41 (m,
2H), 4.97 (d, J¼8.7 Hz, 1H), 4.67–4.60 (m, 2H), 4.51–
4.45 (m, 2H), 4.06–3.92 (m, 1H), 3.08 (t, J¼10.2 Hz, 1H),
2.77 (t, J¼10.2 Hz, 1H), 1.46 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) d 165.92, 154.81, 133.26, 129.76,
129.55, 128.44, 124.65 (dd, JC–F¼196.5 Hz, 189.3 Hz),
80.76, 62.42 (d, JC–F¼8.0 Hz), 56.65 (t, JC–F¼16.4 Hz),
44.10 (t, JC–F¼17.1 Hz), 29.14 (d, JC–F¼4.8 Hz), 28.24;
19F NMR (282 MHz, CDCl3) d ꢀ109.21 (dm, J¼
231.2 Hz), ꢀ125.85 (dm, J¼231.0 Hz); IR (KBr) nmax
3369, 1730, 1695, 1529, 708 cmꢀ1; MS (ESI) m/z 396
(M++Na), 391 (M++NH4). Anal. Calcd for C17H21O4NSF2:
C, 54.68; H, 5.67; N, 3.75. Found: C, 54.66; H, 5.56; N, 3.59.
Compound 14a: white solid, mp 146–148 ꢁC; [a]D26 ꢀ76.4 (c
0.9, CHCl3); 1H NMR (300 MHz, CDCl3) d 9.37 (d,
J¼8.7 Hz, 1H), 9.13 (s, 1H), 8.06 (d, J¼8.1 Hz, 2H), 7.68
(d, J¼11.7 Hz, 1H), 7.58 (t, J¼7.8 Hz, 1H), 7.45 (t,
J¼7.2 Hz, 2H), 5.28 (d, J¼12.0 Hz, 1H), 4.93–4.88 (m,
1H), 4.64 (dd, J¼11.7 Hz, 6.3 Hz, 1H), 4.45 (dd, J¼
11.7 Hz, 6.0 Hz, 1H), 3.95–3.87 (m, 3H), 3.20 (dd,
J¼10.5 Hz, 6.9 Hz, 1H), 2.80 (t, J¼8.4 Hz, 1H), 1.33 (t,
J¼6.9 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d 168.29,
165.93, 163.64, 155.08, 133.32, 129.78, 129.49, 128.50,
126.39 (dd, JC–F¼195.7 Hz, 192.4 Hz), 97.55, 67.75, 62.92
(d, JC–F¼8.0 Hz), 55.09 (dd, JC–F¼22.3 Hz, 16.1 Hz),
3.1.10. Benzoic acid 4-amino-3,3-difluoro-tetrahydro-
thiophen-2-ylmethyl ester (13a). Trifluoroacetic acid
(4 mL) was added in one portion to a solution of compound
12a (0.373 g, 1.23 mmol) in CH2Cl2 (8 mL). The reaction
mixture was stirred at room temperature for 15 min. Vola-
tiles were evaporated and the residue was dissolved in ether
and washed with NaHCO3. The aqueous layer was extracted
with ether. The combined organic layers were dried over
Na2SO4. After filtration and removal of the solvent in vacuo,
the residue was purified by silica gel column chromato-
graphy (petroleum ether/ethyl acetate¼2:1) to give com-
pound 13a (0.322 g, 95.6% yield).
45.28 (dd, JC–F¼20.5 Hz, 16.1 Hz), 29.35 (t, JC–F
¼
2.6 Hz), 14.43; 19F NMR (282 MHz, CDCl3) d ꢀ109.34
(dm, J¼234.9 Hz), ꢀ115.17 (dm, J¼234.6 Hz); IR (KBr)
nmax 3242, 1738, 1706, 1677, 1541 cmꢀ1; MS (ESI)
m/z 415 (M++H), 437 (M++Na).
Compound 14b: it was prepared using the same condition as
described for compound 14a; white solid, mp 150–153 ꢁC;
1
[a]2D7 ꢀ13.1 (c 0.1, CHCl3); H NMR (300 MHz, CDCl3)
Compound 13a: clear oil, [a]2D0 ꢀ102.5 (c 0.5, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.05–8.02 (m, 2H), 7.60–
7.55 (m, 1H), 7.45 (t, J¼7.8 Hz, 2H), 4.64–4.58 (m, 1H),
4.48–4.42 (m, 1H), 4.00–3.88 (m, 1H), 3.67–3.65 (m, 1H),
3.12 (dd, J¼11.4 Hz, 6.3 Hz, 1H), 2.67–2.61 (m, 1H), 1.55
(s, 2H); 13C NMR (75.5 MHz, CDCl3) d 165.97, 133.24,
129.71, 129.65, 128.46, 127.34 (t, JC–F¼193.7 Hz), 63.10
(dd, JC–F¼5.7 Hz, 2.4 Hz), 57.89 (dd, JC–F¼21.3 Hz,
17.9 Hz), 45.11 (dd, JC–F¼20.3 Hz, 16.5 Hz), 31.27 (t,
d 9.32 (d, J¼8.7 Hz, 1H), 9.23 (s, 1H), 8.05–8.02 (m, 2H),
7.67 (d, J¼12.3 Hz, 1H), 7.60–7.54 (m, 1H), 7.47–7.41
(m, 2H), 5.30 (d, J¼12.3 Hz, 1H), 4.93–4.81 (m, 1H), 4.65
(dd, J¼11.4 Hz, 7.8 Hz, 1H), 4.55–4.49 (m, 1H), 4.08–
3.95 (m, 3H), 3.11 (dd, J¼10.2 Hz, 6.9 Hz, 1H), 2.91 (t,
J¼10.8 Hz, 1H), 1.35 (t, J¼6.9 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3) d 168.18, 165.90, 163.64, 154.94,
133.23, 129.73, 129.51, 128.39, 124.75 (t, JC–F
195.5 Hz), 97.63, 67.97, 62.44 (d, JC–F¼7.9 Hz), 55.61 (t,
¼

1566
X. Yue et al. / Tetrahedron 63 (2007) 1560–1567
JC–F¼15.6 Hz), 44.35 (t, JC–F¼17.6 Hz), 29.14 (d, JC–F
¼
and stirred for 4 h. After that concd NH3$H2O (28%, 1 mL)
was added and the whole reaction mixture kept stirring over-
night. Then, the solvent was removed and the residue was
purified by silica gel column chromatography (dichloro-
methane/methanol¼10:1) to give compound 1d (0.010 g,
50.2% yield, three steps).
4.8 Hz), 14.47; 19F NMR (282 MHz, CDCl3) d ꢀ107.82
(dm, J¼231.5 Hz), ꢀ124.50 (dm, J¼231.5 Hz); IR (KBr)
nmax 3248, 1697, 1683, 1620, 1270, 715 cmꢀ1; MS (ESI)
m/z 415 (M++H), 437 (M++Na). Anal. Calcd for
C18H20O5N2SF2: C, 52.17; H, 4.86; N, 6.76. Found: C,
52.73; H, 4.79; N, 6.40.
Compound 1d: white solid, mp 234–238 ꢁC; [a]D27 +90.1 (c
0.6, CH3OH); H NMR (300 MHz, CD3OD) d 7.66 (dd,
1
3.1.12. 1-(4,4-Difluoro-5-hydroxymethyl-tetrahydro-
thiophen-3-yl)-1H-pyrimidine-2,4-dione (1a). A solution
of compound 14a (0.125 g, 0.30 mmol) in dioxane (2 mL)
and 2 N sulfuric acid (5 mL) was refluxed for 3 h. The
mixture was cooled to room temperature and neutralized
by diluted aq NaOH. The mixture was extracted by ethyl
acetate. The organic layers were dried over Na2SO4. After
filtration and removal of the solvent in vacuo, the residue
was dissolved in saturated solution of ammonia in methanol
(8 mL) and stirred overnight at room temperature. The
solvent was removed and the residue was purified by silica
gel column chromatography (dichloromethane/methanol¼
35:1) to give compound 1a (0.063 g, 79.0% yield, two steps).
J¼7.8 Hz, 2.4 Hz, 1H), 5.82 (d, J¼7.5 Hz, 1H), 5.79–5.62
(m, 1H), 3.91 (dd, J¼11.4 Hz, 6.3 Hz, 1H), 3.80–3.75 (m,
1H), 3.72–3.69 (m, 1H), 3.62–3.50 (m, 1H), 3.00–2.94 (m,
1H); 13C NMR (75.5 MHz, CD3OD) d 167.64, 158.81,
144.50 (d, JC–F¼4.9 Hz), 126.77 (dd, JC–F¼195.4 Hz,
190.8 Hz), 96.74, 64.62, 61.95 (d, JC–F¼7.9 Hz), 60.02
(dd, JC–F¼20.1 Hz, 14.6 Hz), 27.24 (d, JC–F¼5.4 Hz);
19F NMR (282 MHz, CD3OD)
d
ꢀ109.49 (dm,
J¼229.3 Hz), ꢀ124.91 (dm, J¼229.3 Hz); IR (KBr) nmax
3398, 1663, 1181, 1016 cmꢀ1; MS (ESI) m/z 264 (M++H).
Compound 1c: it was prepared using the same condition as
described for compound 1d; white solid, mp 210–214 ꢁC;
[a]2D9 ꢀ27.6 (c 0.2, CH3OH); 1H NMR (300 MHz,
CD3OD) d 7.69 (dd, J¼7.5 Hz, 2.1 Hz, 1H), 5.85 (d, J¼
7.5 Hz, 1H), 5.79–5.64 (m, 1H), 3.75–3.66 (m, 2H), 3.61–
3.50 (m, 1H), 3.14–3.02 (m, 2H); 13C NMR (75.5 MHz,
CD3OD) d 167.66, 158.85, 144.67 (d, JC–F¼4.2 Hz),
128.04 (dd, JC–F¼195.9 Hz, 190.6 Hz), 96.83, 62.55 (t,
JC–F¼4.0 Hz), 59.78 (dd, JC–F¼21.7 Hz, 14.6 Hz), 50.90
(dd, JC–F¼18.6 Hz, 15.5 Hz), 26.89 (d, JC–F¼5.3 Hz); 19F
NMR (282 MHz, CD3OD) d ꢀ106.29 (dm, J¼231.8 Hz),
ꢀ116.35 (dm, J¼230.1 Hz); IR (KBr) nmax 3419, 1659,
1499, 1395 cmꢀ1; MS (ESI) m/z 264 (M++H).
Compound 1a: white solid, mp 86–88 ꢁC; [a]D26 ꢀ48.3 (c 0.4,
CH3OH); 1H NMR (300 MHz, CD3OD) d 7.69 (d,
J¼8.1 Hz, 1H), 5.63 (d, J¼8.1 Hz, 1H), 5.59–5.49 (m,
1H), 3.70–3.68 (m, 2H), 3.58–3.48 (m, 1H), 3.21–3.02 (m,
3H); 13C NMR (75.5 MHz, CD3OD) d 165.92, 152.99,
144.18 (d, JC–F¼3.4 Hz), 127.96 (dd, JC–F¼157.0 Hz,
152.4 Hz), 103.39, 62.28 (t, JC–F¼3.2 Hz), 59.27 (dd, JC–F
¼
17.4 Hz, 11.6 Hz), 50.71 (dd, JC–F¼14.9 Hz, 12.6 Hz),
26.37 (d, JC–F¼4.1 Hz); 19F NMR (282 MHz, CD3OD)
d ꢀ106.14 (dm, J¼232.9 Hz), ꢀ116.41 (dm, J¼230.7 Hz);
IR (KBr) nmax 3384, 1730, 1386, 1095 cmꢀ1; MS (ESI)
m/z 265 (M++H), 282 (M++NH4), 287 (M++Na).
Compound 1b: it was prepared using the same condition as
described for compound 1a; white solid, mp 206–214 ꢁC;
[a]2D8 +88.4 (c 0.2, CH3OH); 1H NMR (300 MHz, CD3OD)
d 7.80 (dd, J¼8.1 Hz, 2.7 Hz, 1H), 5.74 (d, J¼8.4 Hz, 1H),
5.70–5.58 (m, 1H), 4.05–3.99 (m, 1H), 3.92–3.87 (m,
1H), 3.84–3.68 (m, 1H), 3.43–3.36 (m, 1H), 3.14–3.08 (m,
1H); 13C NMR (75.5 MHz, CD3OD) d 165.87, 152.97,
144.04 (d, JC–F¼4.4 Hz), 126.79 (dd, JC–F¼195.3 Hz,
191.1 Hz), 103.29, 61.88 (d, JC–F¼7.6 Hz), 59.56 (dd,
JC–F¼20.3 Hz, 14.7 Hz), 49.23 (t, JC–F¼17.2 Hz), 26.78 (t,
JC–F¼5.4 Hz); 19F NMR (282 MHz, CD3OD) d ꢀ109.63
(dm, J¼230.4 Hz), ꢀ125.00 (dm, J¼229.0 Hz); IR (KBr)
nmax 3386, 3172, 1718, 1667, 1383 cmꢀ1; MS (ESI) m/z
265 (M++H), 287 (M++Na).
Acknowledgements
National Natural Science Foundation of China, Ministry of
Education of China, and Shanghai Municipal Scientific
Committee are greatly acknowledged for funding this work.
References and notes
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