Synthesis and antitumor activity of 7-O-[2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-α-L-talopyranosyl]-daunomycinone and -adriamycinone

Article abstract of DOI:10.1016/S0008-6215(99)00028-2

7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifluoromethyl)-α-L-talopyranosyl]-daunomycinone and -adriamycinone have been prepared by the coupling of 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-α-L-talopyranosyl iodide with daunomycinone. The key steps in this synthesis are the regioselective fluorination of methyl α-D-lyxopyranoside to give the 4-deoxy-4-fluoro-β-L-ribopyranoside and the C-trifluoromethylation of the aldehydo-L-ribose derivative to give the 1,1,1-trifluoro-5-monofluoro-L-altritol derivative. Antitumor activities of the synthetic products were compared with those for the 2'-deoxy-2'-fluoro and 2',6'-dideoxy-5'-C-trifluoromethyl analogs. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00028-2

Carbohydrate Research 316 (1999) 47–57
Synthesis and antitumor activity of
7-O-[2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-
-talopyranosyl]-daunomycinone and -adriamycinone
a-
L
Ken Nakai, Yasushi Takagi *, Tsutomu Tsuchiya
Institute of Bioorganic Chemistry, 3-34-17 Ida, Nakahara-ku, Kawasaki 211-0035, Japan
Received 13 November 1998; accepted 18 January 1999
Abstract
7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifluoromethyl)-a-
been prepared by the coupling of 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-a-
with daunomycinone. The key steps in this synthesis are the regioselective fluorination of methyl a-
to give the 4-deoxy-4-fluoro-b- -ribopyranoside and the C-trifluoromethylation of the aldehydo- -ribose derivative to
give the 1,1,1-trifluoro-5-monofluoro- -altritol derivative. Antitumor activities of the synthetic products were
L
-talopyranosyl]-daunomycinone and -adriamycinone have
-talopyranosyl iodide
-lyxopyranoside
L
D
L
L
L
compared with those for the 2%-deoxy-2%-fluoro and 2%,6%-dideoxy-5%-C-trifluoromethyl analogs. © 1999 Elsevier
Science Ltd. All rights reserved.
Keywords: Carbohydrates; Deoxyfluoro sugars; Anthracycline glycoside; Antitumor activity; 7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifl-
uoromethyl)-a-L-talopyranosyl]adriamycinone
leukemia L1210, with lower toxicity in vivo.
Chemically, compound 1 has the strongly elec-
tron-withdrawing fluorine atom at C-2%, stabi-
lizing the glycosidic bond against acidic
hydrolysis due to a decrease of the electron
density at the glycosidic oxygen, thus restrict-
ing protonation, and the 3%-amino group in
DOX is replaced by a hydroxyl group; this
replacement was first reported by Horton and
co-workers [10], suggesting that the 3%-amino
group in DOX is not necessarily essential.
Another example is 7-O-[2,6-dideoxy-5-C-
1. Introduction
Anthracycline glycosides, such as daunoru-
bicin and doxorubicin (DOX), are a group of
the most important antitumor agents used
during the past two decades. Their use is,
however, restricted by cardiotoxicity and
other undesirable side-effects, as well as the
occurrence of resistant tumor cells. In preced-
ing papers [1–9] we reported several fluorine-
containing analogs of daunorubicin and
doxorubicin, and some of them proved to
have strong antitumor activities. For example,
(trifluoromethyl) - a - - lyxo - hexopyranosyl]-
L
adriamycinone (2) [8]. This compound also
showed stronger antitumor activity than DOX
against murine leukemia L1210 in vivo in a
low dose range, as indicated by the survival of
seven out of 12 mice tested (ip injection) [8].
Compound 2 also has a strongly electron-
withdrawing trifluoromethyl group at C-5%; the
7-O-(2,6-dideoxy-2-fluoro-a- -talopyranosyl)-
L
adriamycinone (1) [1] showed stronger antitu-
mor activity than DOX against murine
* Corresponding author. Fax: +81-44-755-3099.
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00028-2

48
K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
Scheme 1.
CF3 group, as against a CH3 group, is also
expected to strengthen the glycosidic bond.
The higher lipophilicity of the CF3 group as
compared with the CH3 group would also be a
factor raising activity, enhancing the cellular
uptake and facilitating the transportation of
the compound into organs. Based on these
results, we have undertaken to introduce a
fluorine atom at C-2% and a CF3 group at C-5%,
hoping that the new compound would show
much stronger antitumor activity. We report
here the preparation and antitumor activity of
7 - O - [2,6 - dideoxy - 2 - fluoro - 5 - C - (trifluoro -
2. Results and discussion
Synthesis.—We prepared the fluorine-con-
taining sugar by introducing a CF3 group at
C-1 of a precursor sugar derivative. As this
approach necessarily requires head-to-tail in-
version, the fluorine atom at C-2 of the final
sugar, 2,6-dideoxy-2-fluoro-5-C-(trifluoro-
methyl)- -talopyranose, must be brought in
L
by attachment of a fluorine atom at C-4 of the
starting sugar. For this reason, we chose
methyl a- -lyxopyranoside (5) as the precur-
D
sor (see Scheme 1).
Treatment of 5 with diethylaminosulfur
trifluoride (DAST) in CH2Cl2 gave selectively
methyl) - a -
L
- talopyranosyl] - daunomycinone
(3) and -adriamycinone (4).
the 4-deoxy-4-fluoro-b- -ribopyranoside (6) in
L
high yield; the facile reaction may be at-
tributed to the formation of a 2,3,4-tris[diethy-
lamino(difluorosulfoxy)] intermediate; one of
the SF atoms of the 2-OSF2NEt2 group may
attack C-4 from the upper side, as reported in
the synthesis of methyl 4,6-dideoxy-4,6-difl-
uoro-a-
D
-talopyranoside from methyl a- -
D
mannopyranoside [11]. The large coupling
constants J4,F (49 Hz), J3,F (29.5 Hz) and J5ax,F
(38 Hz) in the H and 19F NMR spectra
1
indicate that the fluorine atom is introduced
axially at C-4 of 5. An interspace coupling
(7.5 Hz) between F and OH-2 also supports
the structure. The structure was further confi-

K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
49
amounts of Bu4NF (in oxolane) according to
the procedure of Prakash and co-workers [12],
followed by acid hydrolysis, gave the desired
1,5-dideoxy-1,1,1,5-tetrafluoro-
(29%), together with its epimer 1,5-dideoxy-
1,1,1,5-tetrafluoro- -allitol (2,6-dideoxy-2,6,-
6,6-tetrafluoro- -allitol) 14 (39%). The
L
-altritol
13
L
D
configurations of the newly introduced asym-
metric center at the C-2 of 13 and 14 were
determined by transforming the alditols into
the corresponding pyranoses (vide infra). The
undesired compound 14 could be converted
back into 13 by treatment of the triflate of 14
with NaNO2 in DMF [13] in 42% yield. After
Zemple´n deacetylation of 13, the primary hy-
droxyl group of 15 was oxidized selectively.
Mizutani and co-workers reported that the
hydroxyl group closest to a trifluoromethyl
group is unusually resistant to oxidation [14].
Thus, Swern oxidation of 15 gave a cyclic
sugar 17, which was isolated as its 1-acetate
Fig. 1. A stereoview of 12 in one of the lowest energy
,
conformations (the H-1ꢀF-4 distance is 2.98 A).
rmed by preparing the 2,3-diacetate 7. Benzyl-
ation of 6 (to give 8) with subsequent acid
hydrolysis gave the free sugar 9. This com-
1
pound showed a complicated H NMR spec-
trum, but its 19F NMR spectrum showed
distinct two-region signals, suggesting that 9 is
an anomeric mixture with a:b ratios of 1:2
(initially dissolved in CDCl3) and 4:1 (after
180 h). The a anomer was confirmed to have
1
the C4(
L
) structure by the large J4,5ax (10.5
Hz) coupling constant, an NOE between H-2
and H-4 (upon H-2 irradiation, a 4.1% signal
increase was observed), and a long-range cou-
pling (5Jꢀ4 Hz) between H-1 and F-4.
19. The a-
L
-talo structure of 19 with the
1C4(
L
) conformation was supported by a large
JF-2,3 (31 Hz) coupling constant, couplings of
1
J4,5 (1.5 Hz) and J1,F-2 (8.5 Hz) in its H NMR
Compound 9 was converted into the
dithioacetal 10 by treating it with 1,3-
propanedithiol in the presence of BF3·OEt2 in
CH2Cl2, and the product was acetylated to
give the 5-acetate 11. Removal of the dithioac-
etal group [Hg(ClO4)2·3H2O and CaCO3] gave
the aldehydo sugar 12. This compound
spectrum, and the presence of NOE between
H-3 and H-5. Similarly, 14 was converted into
the 1-acetate 20 through 16 and 18, whose
structure was determined to be b-
D-allo with
4
the C1(
D) conformation from the large cou-
pling constants J1,2 (8 Hz) and J4,5 (9.5 Hz)
and the existence of the NOE between H-2
and H-4.
1
showed in its H and 19F spectra a J1,F cou-
pling (3.5 Hz) (see Section 3). This coupling
was first considered to be derived from a
long-range coupling (5J) between the H-1 and
F-4, however, if the C-1, -2, -3, -4 and F-4
atoms adopt a periplanar zigzag conformation
(typical conditions to give a long-range cou-
Catalytic hydrogenolysis of 19 followed by
acetylation of the resulting 21 gave the tri-
acetate 22. Activation of the anomeric center of
22 was somewhat difficult, possibly because of
the electron-withdrawing F-2 and CF3-5. Con-
ventional bromination (30% HBr in AcOH or
TiBr4 in CH2Cl2–EtOAc) failed, giving rise
only to starting material. An attempt to pre-
pare the ethyl thioglycoside (using EtSH,
BF3·OEt2 in CH2Cl2) also gave only 22. How-
ever, phenyl thioglycosidation [PhSSiMe3,
Bu4NI, ZnI2 in Cl(CH2)2Cl] [15] gave a mix-
ture of the phenyl thioglycoside and the glyco-
syl iodide 23. Compound 22, therefore, was
treated with Me3SiI (in toluene at 80 °C),
whereupon 23 was produced successfully, al-
though the yield was not high (57%). The
5
pling; in 9, JH-1,F-4 coupling was observed due
to its periplanar conformation), the structure
does not satisfy the JH,H and JH,F coupling
values observed. Thus, a through-space cou-
pling between the slightly acidic CHO and the
basic F-4 atoms was considered instead. An
energy-minimal conformation (Fig. 1) ob-
tained by MOPAC calculation (in CHCl3) was
consistent with the data.
Trifluoromethylation of 12 by treatment
with Me3SiCF3 in the presence of catalytic

Table 1
1H and 19F NMR data (chemical shifts in ppm (l) and coupling constants (J) in Hz) for compounds 24, 3, and 4
Multiplicity H-1 d
(J1,2
H-2 t
(J2,3
H-3 d
H-7 dd
H-8ax dd
(J8ax,8eq
H-8eq br d H-10ax d
H-10eq dd
(J8eq,10eq
H-14 s OH-9 s OH-6, 11
(each s)
)
)
(J7,8ax
(J7,8eq
)
)
)
(J10ax,10eq
)
)
24a
3b
8.09 (7.5)
8.06 (7)
7.80 (8.5)
7.72 (8)
7.40
7.41
5.28 (4.5)
(ꢀ1.5)
5.50 (5.5)
(2.5)
2.22 (15.5)
2.49 (15)
2.47
2.92
2.96 (19)
3.41 (18)
3.15 (ꢀ1.5) 2.39
3.60
13.23, 14.02
13.55, 14.59
13.48, 14.55
c
3.50 (ꢀ1)
2.58
/
4b
8.05 (7.5)
7.72 (8.5)
7.42
5.48 (5) (2)
2.55 (15)
2.97
3.42 (18.5)
OAc s
3.56d
5.40e
c
Multiplicity OCH3 s
H-1% br d
H-2% br d
H-3% dt
H-4% br s
H-5% br q
F-2 ddd
F-6 d
(J1’,F-2’
)
(J2’,F-2’
)
(J2%,3%) (J3%,4%
)
(J5%,F-6%)
(J3%,F-2%
)
24a
3b
4.12
3.98
3.98
5.75 (9)
6.18 (9)
6.14 (9)
4.61 (49.5)
5.22 (49.5)
5.20 (49)
5.01 (3) (3)
(32)
4.31 (3) (3)
(34)
5.62
4.55
4.55
4.78 (6.5)
5.33 (7)
5.34 (7)
2.15, 2.03
−201.7
−200.3
−200.3
−74.1
−71.9
−71.9
316
9
4b
4.28 (ꢀ3)
(ꢀ3) (34)
4
a In CDCl3.
b In pyridine-d5.
c Not detected.
d br d.
e ABq, Jgem 20 Hz.

K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
51
anomeric structure of 23 could not be deter-
mined from the J1,F-2 value (13.5 Hz) be-
cause it is intermediate between the usual
and 5%-trifluoromethyl analogs (2) against
L1210 murine leukemia in vivo (Table 3).
The doxorubicin-type analog 4 showed a
slightly higher antitumor activity than 1, al-
though 4 did not attain the level exhibited
by 2. However, as the efficacy of antitumor
drugs is determined after a variety of biolog-
ical tests, a final evaluation of 4 remains to
be established. It is noteworthy, however,
that the daunorubicin-type analog 3 showed
only low activity, which suggests that the 14-
hydroxyl group is important in exhibiting
antitumor activity in these compounds.
a-
L
(ꢀ8 Hz) and b- (ꢀ20 Hz) values [16].
L
However, the presence of NOEs between F-2
and H-1, and H-5 and H-3, and the absence
of NOE between H-5 and H-1 all indicate
that 23 should be mainly the a-
L
anomer.
The glycosyl iodide 23 was relatively stable
and could be stored for at least 3 days at
−30 °C without decomposition.
Coupling of 23 with daunomycinone under
Koenigs–Knorr conditions [yellow HgO and
HgI2, in Cl(CH2)2Cl at 80 °C] gave the a- -
L
glycoside 24 (J1%,F-2% 9 Hz) in 67% yield.
Judging from the fact that, in the prepara-
tion of 2 [8], the a-
L
- and b- -glycosides
L
were produced almost in equal amounts, the
-glycosidation might be at-
Table 2
selective a-
L
13C NMR chemical shifts (l, ppm) and coupling constants
tributable to the axial F-2 in 23. Alkaline
deacetylation of 24 gave the desired 7-O-
[2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-
(JC,F, Hz in parentheses) for compounds 3 and 4 in pyridine-
d5
C
3
4
a- -talopyranosyl]daunomycinone (3). Com-
L
pound 3 thus prepared was then transformed
into the doxorubicin-type compound 4 ac-
cording to the general procedure of Arca-
mone and co-workers [17], and the specific
procedure for the preparation of 1 [2].
Bromination of 3 with Br2 in the presence of
HC(OMe)3 gave the 14-bromo-13-dimethyl
acetal, which on treatment with acetone af-
forded the 14-bromo derivative together with
the small amount of the 14-bromo-3%,4%-iso-
propylidene acetal. Treatment of the mixture
with HCO2Na (aq acetone–oxolane) gave a
mixture of four products, namely 4, the 14-
formyloxy derivative of 4, the 14-hydroxy-
3%,4%-isopropylidene acetal, and the 14-
formyloxy-3%,4%-isopropylidene acetal. After
the formyloxy and isopropylidene groups
had been hydrolyzed off (aq NH3 in
MeOH–oxolane and aq 80% AcOH at
80 °C, respectively), the desired 7-O-[2,6-
1
2
3
4
4a
5
5a
6
6a
7
8
119.6
135.6
119.5
161.5
121.1
187.0a
111.6b
119.62
136.1
119.55
161.5
121.2
187.1a
111.7b
155.5c
155.5c
e
134.5d
73.2
73.4
36.9
76.1
37.3
76.0
9
10
10a
11
11a
12
12a
13
14
OMe
1%
32.8
33.3
e
134.8d
156.9c
157.0c
111.9b
112.0b
187.2a
135.6
187.2a
e
212.5
24.5
56.7
103.0 d (32.5)
90.0 d (180.7)
66.2 d (16.4)
67.4
70.9 q (30.4)
125.3 q (279.6)
215.2
65.6
56.7
103.0 d (31.7)
89.9 d (180.1)
66.2 d (16.6)
67.3
2%
3%
4%
5%
dideoxy-2-fluoro-5-C-(trifluoromethyl)-a- -
L
talopyranosyl]-adriamycinone (4) could be
obtained in 70% yield. The structures of 3
70.9 q (30.0)
6%
125.2f qg
1
and 4 were confirmed by the H, 19F (Table
a ,b,c,dFigures in the same column may be interconvertible.
e Not assigned due to overlapping of the signals with those
for pyridine-d5.
1) and 13C NMR spectra (Table 2).
Antitumor acti6ity.—Antitumor activities
of the synthetic products (3 and 4) were
compared with those for the 2%-fluoro (1)
f Judged from the F-6%-decoupled 13C NMR.
g Judged by the HMBC method.

52
K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
Table 3
Antitumor activitiesa (T/Cb (%) and 60-day survivor numbers/treated numbers of mice) of 3 and 4 in comparison with 1 and 2
against the murine L1210 cell line
Compound
Dose (mg kg−1 day−1
2.5
210c
)
5
1.25
0.6
0.3
0.15
3
158c
0/4
128c
0/4
\482c
2/4
135c
0/4
294
0/4
\348
1/4
\416
1/4
203
0/4
132
0/4
\459
1/4
\348
1/4
\406
1/4
119
0/4
\407
1/4
193
0/4
\606
3/4
106
0/4
144
0/4
164
0/4
\612
3/4
0/4
233c
0/4
\656
3/4
194c
0/4
4
1
2d
a Leukemia L1210 cells (105) were inoculated into CDF1 mice (2091 g) intraperitoneally. Drugs were administered daily,
starting 24 h after inoculation, from day 1 to 9 intraperitoneally.
b (Mean survival days of treated mice/mean survival days of control mice)×100.
c More than 10% weight decrease in the treated mice was observed.
d See ref. [8].
3. Experimental
added, and the mixture was filtered through a
Celite bed with successive washing with
CH2Cl2. The combined filtrate and washings
were concentrated to give a brown syrup,
which was chromatographed (7:1 CHCl3–ace-
tone) to give 6 as a syrup: 7.54 g (90%), TLC
(7:1 CHCl3–acetone): Rf 0.15 (cf 5: Rf 0.02),
[h]2D3 +146° (c 0.7, CHCl3); m/z 167.12
(M+ +1), calcd for C6H11FO4: m/z 166.11; 1H
NMR (CDCl3): l 4.79 (d, 1 H, J1,2 2 Hz, H-1),
4.74 (br d, 1 H, J4,F 49 Hz, H-4), 4.0–3.7 (m,
4 H, H-2,3,5ax, 5eq), 3.42 (s, 3 H, OMe), 3.08
(d, 1 H, J3,OH-3 10.5 Hz, OH-3), 2.34 (dd, 1 H,
J2,OH-2 11.5, JF,OH-2 7.5 Hz, OH-2). 19F NMR
(CDCl3): l −203.0 (ddddd, J3,F 29.5, J4,F 49,
J5ax,F 38, J5eq,F 15.5, JOH-2,F 7.5 Hz).
General methods.—Melting points were de-
termined on a Kofler block, and are uncor-
rected. Optical rotations were measured with a
Perkin–Elmer 241 polarimeter. NMR spectra
(1H at 250 and 500 MHz, 13C at 125.8 MHz,
and 19F at 235.3 MHz) were recorded with
Bruker AC-250P and AMX-500 spectrome-
ters, using Me4Si and CFCl3 (for 19F) as the
internal standards. Mass spectra were mea-
sured by the fast-atom bombardment method
with a Jeol SX-102 spectrometer. TLC was
performed on Kieselgel 60 F254 (E. Merck),
column chromatography on Wakogel C-200,
and flash column chromatography on
Wakogel C-300.
Methyl 2,3-di-O-acetyl-4-deoxy-4-fluoro-i-
Computation.—Calculation for the stereo-
view of 12 (Fig. 1) was performed on a Macin-
tosh 9500 computer with CAChe Version 4.0
(Sony Tektronix) software using MM2,
refined by MOPAC6/PM3 by setting the
dielectric constant as 4.80 (CHCl3).
L-ribopyranoside (7).—A solution of 6 (50 mg,
0.30 mmol) and Ac2O (0.17 mL, 1.81 mmol)
in pyridine (1 mL) was kept for 2 h at rt. TLC
(12:1 CHCl3–acetone) of the solution showed
a single spot at Rf 0.55. Conventional work up
gave 7 as a syrup: 68 mg (91%), [h]2D4 +98° (c
1
Methyl 4-deoxy-4-fluoro-b-
L
-ribopyranoside
0.8, CHCl3); H NMR (CDCl3): l 5.24 (dt, 1
(6).—To a cold (−40 °C) suspension of 5 [18]
(8.27 g, 50.4 mmol) in dry CH2Cl2 (170 mL),
DAST (26.8 mL, 203 mmol) was added over 5
min and the mixture was stirred for 70 min at
room temperature (rt). After addition of
MeOH (170 mL) to the recooled solution
(−20 °C), the solution was kept for 15 h at rt.
Sodium hydrogencarbonate (105 g) was
H, J2,3 :J3,4 3.5, J3,F 29 Hz, H-3), 5.11 (ddd, 1
H, J1,2 2, J2,3 3.5, J2,4 ꢀ1 Hz, H-2), 4.75 (d, 1
H, H-1), 4.73 (br d, 1 H, J4,F 50 Hz, H-4),
4.04–3.83 (m, 2 H, H-5ax, 5eq), 3.43 (s, 3 H,
OMe), 2.15 and 2.11 (each 3 H s, Ac). 19F
NMR (CDCl3): l −202.9 (m). Anal. Calcd
for C10H15FO6: C, 48.00; H, 6.04. Found: C,
47.95; H, 6.07.

K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
53
and 4.58 (ABq, Jgem 12 Hz, PhCH2), 4.54
(dddd, J3,4 2.5, J4,5eq 5.5, J4,5ax 10.5, J4,F 46.5
Hz, H-4), 4.31 (br dd, J3,4 2.5, J3,F 10 Hz,
H-3), 4.11 (apparent dt, J4,5ax 10.5, J5ax,5eq 11,
J5ax,F 3 Hz, H-5ax), 3.72 (dddd, J4,5eq 5.5,
J5eq,5ax 11, J5eq,F 1.5, J5eq,3 ꢀ1 Hz, H-5eq),
3.40 (narrow-range m, H-2). 19F NMR
(CDCl3): l −199.2 (br dd, 0.8 F, J3,F 10, J4,F
47 Hz, a anomer), −202.5 (dddd, 0.2 F, J 48,
19, 15.5, 8.5 Hz, the minor product). Anal.
Calcd for C19H21FO4: C, 68.66; H, 6.37; F,
5.72. Found: C, 68.65; H, 6.50; F, 5.72.
Methyl 2,3-di-O-benzyl-4-deoxy-4-fluoro-i-
-ribopyranoside (8).—To a suspension of
L
NaH (9.36 g, 60% NaH in mineral oil, 234
mmol) in dry DMF (35 mL), a solution of 6
(7.44 g, 44.8 mmol) in DMF (35 mL) was
added over 10 min, and the mixture was
stirred until hydrogen evolution had ceased
(ꢀ1 h). PhCH2Br (16.0 mL, 135 mmol) was
added at 0 °C and the stirring was continued
for 2 h at rt. TLC (12:1 CHCl3–acetone) of
the solution showed a spot at Rf 0.65. The
mixture was poured into aq 2.6% AcOH (500
mL) and the whole mixture was extracted with
CHCl3. The extracts were washed with aq
NaHCO3 (saturated), dried (Na2SO4), and
concentrated together with xylene. Chro-
matography (30:1 toluene–EtOAc) of the
residue gave 8 as a syrup: 12.62 g (81%), [h]D23
2,3-Di-O-benzyl-4-deoxy-4-fluoro- -ribose
L
propane-1,3-diyl dithioacetal (10).—A mixture
of 9 (4.13 g, 12.4 mmol), 1,3-propanedithiol
(2.1 mL, 21 mmol), and BF3·OEt2 (0.53 mL,
4.3 mmol) in dry CH2Cl2 (75 mL) was stirred
for 2 h at rt. TLC (12:1 toluene–EtOAc) of
the mixture showed three spots at Rf 0.4,
(slight) 0.25 (10, major), and 0.15 (9, slight).
After dilution with CHCl3, the solution was
washed with aq 5% NaOH and water, dried
(Na2SO4), and concentrated. The residue was
chromatographed (12:1 toluene–EtOAc) to
give 10 as a colorless syrup: 3.92 g (75%) with
9 recovered 143 mg (3.5%). Compound 10,
1
+63° (c 1, CHCl3); H NMR (CDCl3; only
important signals): l 4.74 (d, 1 H, J1,2 4 Hz,
H-1), 4.66 (ddt, 1 H, J3,4=J4,5ax 3, J4,5eq 5, J4,F
48.5 Hz, H-4), 3.98 (ddd, 1 H, J5eq,4 5, J5eq,5ax
12, J5eq,F 9.5 Hz, H-5eq), 3.85 (dt, 1 H, J2,3=
J3,4 3, J3,F 23.5 Hz, H-3), 3.79 (ddd, 1 H,
J5ax,5eq 12, J5ax,4 3, J5ax,F 24 Hz, H-5ax), 3.52
19
(dd, 1 H, H-2), 3.40 (s, 3 H, OMe). F NMR
1
(CDCl3): l −202.3 (dddd, J3,F 23.5, J4,F 48.5,
J5ax,F 24, J5eq,F 9.5 Hz). Anal. Calcd for
C20H23FO4: C, 69.35; H, 6.69; F, 5.48. Found:
C, 69.20; H, 6.92; F, 5.63.
[h]2D4 −21° (c 1.3, CHCl3); H NMR (CDCl3):
l 7.45–7.20 (m, 10 H, Ph×2), 4.95 and 4.67
(ABq, Jgem 11 Hz, PhCH2), 4.87 (ddt, 1 H,
J3,4=J4,5a 3.5, J4,5b 5, J4,F 46.5 Hz, H-4), 4.78
and 4.67 (ABq, Jgem 11 Hz, PhCH2), 4.42 (d, 1
H, J1,2 4.5 Hz, H-1), 4.19 (ddd, 1 H, J2,3 6, J3,4
3.5, J3,F 14 Hz, H-3), 3.84 (dddd, 1 H, J4,5b 5,
J5a,5b 13, J5b,OH 6, J5b,F 24 Hz, H-5b), 3.78 (dd,
1 H, H-2), 3.74 (dddd, J4,5a 3.5, J5a,5b 13, J5a,OH
7, J5a,F 24.5 Hz, H-5a), 2.90–2.50 (m, 4 H,
SCH2×2), 2.09 (dd, 1 H, OH), 2.15–2.02 and
2.00–1.80 (each 1 H m, CH2CH2CH2). 19F
NMR (CDCl3): l −195.6 (ddt, J3,F 14, J4,F
46.5, J5a,F=J5b,F 24 Hz). Anal. Calcd for
C22H27FO3S2: C, 62.53; H, 6.44; S, 15.17.
Found: C, 62.68; H, 6.31; S, 15.33.
2,3-Di-O-benzyl-4-deoxy-4-fluoro- -ribopy-
L
ranose (9).—A solution of 8 (3.06 g, 8.83
mmol) in 0.4 M HCl in aq 80% AcOH (30
mL) was kept for 3.5 h at 80 °C. TLC (5:2
hexane–EtOAc) of the solution showed spots
at Rf 0.15 (9) and 0.4 (slight, 8). After cooling
to rt, the solution was poured into an aq
suspension (200 mL) containing NaHCO3 (38
g), and the whole mixture was extracted with
CHCl3. The extracts were washed with brine,
dried (Na2SO4), and concentrated to give a
dark brown syrup, which was chro-
matographed (5:2 hexane–EtOAc) to give a
pale-yellow syrup of 9 (an anomeric mixture):
2.58 g (88%) with 8 recovered, 0.29 g (9.4%).
Compound 9, [h]D22 +45° (c 0.75, CHCl3, after
5-O-Acetyl-2,3-di-O-benzyl-4-deoxy-4-
fluoro- -ribose propane-1,3-diyl dithioacetal
L
(11).—A solution of 10 (2.40 g, 5.67 mmol)
and Ac2O (2.7 mL, 28.4 mmol) in pyridine (24
mL) was kept for 4 h at rt. TLC (12:1
toluene–EtOAc) of the solution showed a sin-
gle spot at Rf 0.5. Conventional work up gave
11, 2.64 g (quant), as a colorless syrup, [h]D24
1
180 h); H NMR (CDCl3) (only signals for the
major a anomer were described): l 7.45–7.20
(m, Ph), 5.25 (d, J1,OH 10.5 Hz, OH), 5.11 (br
dt, J1,2 3.5, J1,F ꢀ4, J1,OH 10.5 Hz, H-1), 4.83
and 4.77 (ABq, Jgem 11.5 Hz, PhCH2), 4.67
1
−26° (c 1.1, CHCl3); H NMR (CDCl3; only

54
K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
dried (Na2SO4), and concentrated to give a
brown syrup; the TLC (30:1 toluene–EtOAc)
of the syrup showed three spots at Rf 0.45
(trimethylsilyl ethers of 13 and 14), 0.25 (13)
and 0.15 (14). The syrup dissolved in aq 80%
AcOH (20 mL) was kept for 3 h at 50 °C,
whereupon the spot at Rf 0.45 disappeared.
Concentration of the solution together with
toluene gave a residue, which was chro-
matographed (30:1 toluene–EtOAc) to give
13, 649 mg (29%) and 14, 873 mg (39%) as
colorless syrups, respectively. Compound 13,
important signals): l 5.01 (ddt, 1 H, H-4),
4.44 (d, 1 H, J1,2 3.5 Hz, H-1), 4.40–4.17 (m,
2 H, H-5a, 5b), 4.14 (ddd, 1 H, H-3), 3.74 (dd,
1 H, H-2), 2.05 (s, 3 H, OAc). 19F NMR
(CDCl3): l −193.0 (dddd, J3,F 15, J4,F 48,
J5a,F 32, J5b,F 21 Hz). Anal. Calcd for
C24H29FO4S2: C, 62.04; H, 6.29. Found: C,
62.00; H, 6.15.
5-O-Acetyl-2,3-di-O-benzyl-4-deoxy-4-
fluoro-aldehydo- -ribose (12).—To a solution
L
of 11 (2.58 g, 5.55 mmol) in 10:3 oxolane–wa-
ter (35 mL), CaCO3 (10.24 g, 102 mmol) and
Hg(ClO4)2·3H2O [6.01 g (12.5 mmol) in 20 mL
oxolane] were added, and the mixture was
stirred for 2 h at rt. More Hg(ClO4)2·3H2O
(0.57 g in 6 mL oxolane) was added, and the
stirring was continued for a further 30 min.
The mixture was filtered through a Celite bed
with successive washing with CH2Cl2. The
combined filtrate and washings were washed
with aq NaHCO3 (saturated) and the resultant
precipitate was filtered off. The organic solu-
tion was washed with aq 10% KI and water,
dried (Na2SO4), and concentrated to give 12
as a syrup: 1.92 g (92%). An analytical sample
was prepared by flash column chromatogra-
phy (30:1 toluene–EtOAc). TLC: Rf 0.4 (12:1
1
[h]1D9 −20° (c 1.4, CHCl3); H NMR (CDCl3):
l 7.40–7.20 (m, 10 H, Ph×2), 4.92 (ddt, 1 H,
J4,5=J5,6b 3, J5,6a 7, J5,F-5 48 Hz, H-5), 4.74
and 4.64 (ABq, Jgem 11 Hz, PhCH2), 4.67 (s, 2
H, PhCH2), 4.38 (ddd, 1 H, J5,6b 3, J6a,6b 13,
J6b,F-5 30 Hz, H-6b), 4.30 (ddd, 1 H, J5,6a 7,
J6a,6b 13, J6a,F-5 21.5 Hz, H-6a), 4.17 (br dq, 1
H, J2,OH 10, J2,F-1(1%,1%%) 7.5 Hz, H-2), 3.99–3.87
(m, 2 H, H-3,4), 3.11 (d, 1 H, OH), 2.08 (s, 3
H, OAc). 19F NMR (CDCl3): l −77.0 (d, 3
F, J2,F-1 7.5 Hz, CF3), −193.3 (m, 1 F, F-5).
Anal. Calcd for C22H24F4O5: C, 59.46; F,
17.10; H, 5.44. Found: C, 59.62; H, 5.57; F,
17.16. Compound 14, [h]2D1 −33° (c 0.9,
CHCl3); 1H NMR (CDCl3): l 7.41–7.22 (m 10
H, Ph×2), 5.02 (dddd, 1 H, J4,5 7, J5,6a 6, J5,6b
2, J5,F-5 47 Hz, H-5), 4.73 and 4.64 (ABq, Jgem
11 Hz, PhCH2), 4.71 and 4.63 (ABq, Jgem 11.5
Hz, PhCH2), 4.44 (ddd, 1 H, J5,6b 2, J6a,6b 13,
J6b,F-5 28 Hz, H-6b), 4.35–4.21 (m, 1 H, H-2),
4.27 (ddd, 1 H, J5,6a 6, J6a,6b 13, J6a,F-5 27.5 Hz,
H-6a), 4.08 (ddd, 1 H, J3,4 2.5, J4,5 7, J4,F-5 9.5
Hz, H-4), 4.01 (dd, J2,3 7.5, J3,4 2.5 Hz, H-3),
2.83 (d, 1 H, J2,OH 5 Hz, OH), 2.04 (s, 3 H,
OAc). 19F NMR (CDCl3): l −76.2 (d, 3 F,
J2,F-1 7 Hz, CF3), −194.9 (apparent ddt, 1 F,
J4,F-5 9.5, J5,F-5 47, J6a,F-5:J6b,F-5 28 Hz, F-5).
Anal. Calcd for C22H24F4O5: C, 59.46; H,
5.44; F, 17.10. Found: C, 59.15; H, 5.34; F,
17.35.
1
toluene–EtOAc), [h]2D3 −62° (c 1, CHCl3), H
NMR (CDCl3): l 9.65 (dd, 1 H, J1,2 1.5, J1,F
3.5 Hz, H-1), 7.50–7.20 (m, 10 H, Ph×2),
4.93 (dddd, J3,4 7.5, J4,5a 5, J4,5b 2, J4,F 46 Hz,
H-4), 4.77 and 4.70 (ABq, Jgem 12 Hz,
PhCH2), 4.62 and 4.52 (ABq, Jgem 11.5 Hz,
PhCH2), 4.41 (ddd, 1 H, J4,5b 2, J5a,5b 13, J5b,F
26 Hz, H-5b), 4.23 (ddd, 1 H, H-5a), 4.09 (dd,
1 H, J1,2 1.5, J2,3 3 Hz, H-2), 4.00 (ddd, 1 H,
H-3), 2.01 (s, 3 H, OAc). 19F NMR (CDCl3):
l −194.7 (ddddd, J1,F 3.5, J3,F 5.5, J4,F 46,
J5a,F 29, J5b,F 26 Hz). Anal. Calcd for
C21H23FO5: C, 67.37; H, 6.19. Found: C,
67.02; H, 6.04.
6-O-Acetyl-3,4-di-O-benzyl-1,5-dideoxy-
1,1,1,5-tetrafluoro-
L
-altritol (13) and 6-O-
Preparation of 13 from 14.—A solution of
14 (768 mg, 1.73 mmol), (CF3SO2)2O (0.52
mL, 3.1 mmol) and pyridine (0.85 mL, 10.5
mmol) in dry CH2Cl2 (8 mL) was kept for 1.5
h at 0 °C. MeOH (0.63 mL) was added, and
the solution, after dilution with CH2Cl2, was
washed with aq NaHCO3 (saturated), aq 20%
KHSO4, and water, dried (Na2SO4) and con-
centrated to give the 2-triflate of 14 as a
acetyl-3,4-di-O-benzyl-1,5-dideoxy-1,1,1,5-tetra-
fluoro- -allitol (14).—To an ice-cold solution
L
of 12 (1.87 g, 5.0 mmol) and Me3SiCF3 (1.18
mL, 8.0 mmol) in oxolane (15 mL),
Bu4NF·3H2O [158 mg (0.5 mmol) in 3.6 mL
oxolane] was added and the solution was kept
for 1 h at rt. After concentration, the residue
dissolved in CHCl3 was washed with water,

K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
55
give a pale-yellow syrup of crude 17: 1.07 g.
19F NMR (CDCl3): l −73.5 (d, ꢀ3 F, J5,F-6
6.5 Hz, CF3), −203.5 (m, ꢀ1 F; sharp ddd
on deuteration, J1,F-2 9, J2,F 49.5, J3,F-2 32 Hz,
F-2). A solution of the syrup and Ac2O (0.38
mL, 4.0 mmol) in pyridine (9 mL) was kept
for 15 h at rt, water (0.2 mL) was added, and
the mixture was concentrated to a small vol-
ume. After dilution with CHCl3, the solution
was washed with aq 20% KHSO4, aq
NaHCO3 (saturated), and water, dried
(Na2SO4), and concentrated. Flash chro-
matography (30:1 toluene–EtOAc) of the
residue gave a syrup of 19, which was crystal-
lized (EtOAc–hexane) to give needles: 878 mg
(78%), mp 80.5–81 °C, [h]2D2 −57° (c 0.85,
chromatographically homogeneous syrup:
1.00 g (quant); 19F NMR (CDCl3): l −72.4
(br dq, 3 F, J2,F-1 ꢀ6, JF-1,SO CF(F%,F%%) 3.5 Hz,
2
CF3-2), −74.2 (q, 3 F, CF3SO2), −194.9
(ddt, 1 F, J4,F-5 13, J5,F-5 47, J6a,F-5=J6b,F-5 26
Hz, F-5). A mixture of the syrup and NaNO2
(964 mg, 14 mmol) in DMF (6 mL) was
stirred for 1.5 h at 80 °C. After concentration
together with xylene, water was added, and
the mixture was extracted with toluene. The
organic solution was washed with water, dried
(Na2SO4), and concentrated. Duplicate chro-
matographies (30:1 toluene–EtOAc) of the
residue gave 13, 324 mg (42% based on 14),
which was identical to the specimen obtained
from 12.
1
3,4-Di-O-benzyl-1,5-dideoxy-1,1,1,5-tetra-
CHCl3). H NMR (C6D6; benzyl signals are
fluoro-
L
-altritol (15).—A solution of 13 (618
not described): l 6.49 (dd, 1 H, J1,2 1.5, J1,F-2
8.5 Hz, H-1), 4.28 (ddt, 1 H, J1,2 =J2,4 1.5, J2,3
3, J2,F-2 48.5 Hz, H-2), 3.83 (br, 1 H, H-4),
3.76 (dq, 1 H, J4,5 1.5, J5,F-6(6%,6%%) 6.5 Hz, H-5),
3.17 (dt, 1 H, J2,3=J3,4 3, J3,F-2 31 Hz, H-3),
1.43 (s, 3 H, OAc); irradiation of H-3 showed
a 8.3% signal increase of H-5. 19F NMR
(C6D6): l −72.9 (d, 3 F, J5,F-6 6.5 Hz, CF3),
−202.1 (ddd, 1 F, J1,F-2 8.5, J2,F-2 48.5, J3,F-2
31 Hz, F-2). Anal. Calcd for C22H22F4O5: C,
59.73; H, 5.01. Found: C, 59.87; H, 4.98.
1-O-Acetyl-3,4-di-O-benzyl-2,6-dideoxy-2-
mg, 1.39 mmol) in methanolic 0.023 M
NaOMe (17 mL) was kept for 20 min at rt.
TLC (6:1 toluene–EtOAc) of the solution
showed a single spot at Rf 0.25. Neutralization
with Dowex 50WX2 (H+ form) followed by
concentration gave a pale-yellow syrup, which
was crystallized from CHCl3–hexane to give
15 as needles, 521 mg, (97%); mp 64.5–65 °C,
[h]2D3 −3° (c 0.9, CHCl3). Anal. Calcd for
C20H22F4O4: C, 59.70; H, 5.51. Found: C,
59.79; H, 5.63.
3,4-Di-O-benzyl-1,5-dideoxy-1,1,1,5-tetra-
fluoro-5-C-(trifluoromethyl)-b- -allopyranose
D
fluoro-
L
-allitol (16).—Compound 14 (175 mg,
(20).—Compound 16 (100 mg, 0.25 mmol)
was treated with (COCl)2 (28 mL, 0.33 mmol)
and (CH3)2SO [35 mL (0.49 mmol) in 2.2 ml
0.39 mmol) was deacetylated as described for
15 to give 16 as a pale-yellow syrup, 158 mg
(quant), [h]2D2 −25° (c 0.7, CHCl3). Anal.
Calcd for C20H22F4O4: C, 59.70; H, 5.51.
Found: C, 59.30; H, 5.50.
i
CH2Cl2] and subsequently with Pr2NEt (0.23
mL, 1.3 mmol) as described for 17 to give a
pale-yellow syrup of 18 (104 mg). Acetylation
of the syrup in a usual manner followed by
flash chromatography (toluene) gave a syrup,
which was recrystallized from EtOAc–hexane
to give 20 as needles: 77 mg (74%), mp 79.5–
1-O-Acetyl-3,4-di-O-benzyl-2,6-dideoxy-2-
fluoro-5-C-(trifluoromethyl)-a- -talopyranose
L
(19).—To a cold (−78 °C) solution of
(COCl)2 (0.27 mL, 3.15 mmol) in dry CH2Cl2
(8 mL), (CH3)2SO [0.36 mL (5.0 mmol) in
CH2Cl2 (3.5 mL)] and 15 [1.02 g (2.54 mmol)
in CH2Cl2 (8.6 mL)] were added, and the
mixture was stirred for 40 min at the same
temperature. Ethyldiisopropylamine (2.15 mL,
12.3 mmol) was added, and the mixture was
stirred for 30 min, then for 1 h at 0 °C. After
addition of ice-cooled aq NH4Cl (saturated,
50 mL), the mixture was extracted with
CH2Cl2 and the extracts were washed with
water, dried (MgSO4), and concentrated to
1
80 °C, [h]2D3 +48° (c 0.7, CHCl3). H NMR
(CDCl3; benzyl signals are not described): l
6.16 (dd, 1 H, J1,2 8, J1,F-2 ꢀ2 Hz, H-1), 4.44
(dq, 1 H, J4,5 9.5, J5,F-6(6%,6%%) 6 Hz, H-5), 4.32
(ddd, 1 H, J1,2 8, J2,3 2.5, J2,F-2 48 Hz, H-2),
4.25 (dt, 1 H, J2,3 2.5, J3,4 ꢀ2, J3,F-2 ꢀ9 Hz,
H-3), 3.65 (dt, 1 H, H-4; J4,F-2 ꢀ2 Hz), 2.15
(s, 3 H, OAc); irradiation of H-4 showed a
5.2% signal increase of H-2. 19F NMR
(CDCl3): l −74.5 (d, 3 F, J5,F-6 6 Hz, CF3),
−202.1 (br dd, 1 F, J2,F-2 ꢀ48, J3,F-2 ꢀ9 Hz,

56
K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
further purification; TLC (6:1 hexane–
EtOAc): Rf 0.2, positive Beilstein test. H
F-2). Anal. Calcd for C22H22F4O5: C, 59.73;
H, 5.01. Found: C, 59.84; H, 4.98.
1
1-O-Acetyl-2,6-dideoxy-2-fluoro-5-C-(trifl-
NMR (CDCl3): l 7.01 (br d, 1 H, J1,F-2 13.5
Hz, H-1), 5.75 (slightly deformed dd, 1 H, J3,4
ꢀ3, J4,5 1.5 Hz, H-4), 5.60 (dt, 1 H, J2,3 =J3,4
ꢀ3, J3,F-2 28.5 Hz, H-3), 4.92 (br d, 1 H, J2,F-2
49.5 Hz, H-2), 4.36 (br q, 1 H, J5,F-6(6%,6%%) 6 Hz,
H-5), 2.14 and 2.11 (each 3 H s, OAc); irradi-
ation of F-2 showed a 32% signal increase of
H-1 based on a 100% signal increase of H-2.
uoromethyl)-a- -talopyranose (21).—A solu-
L
tion of 19 (598 mg, 1.35 mmol) in 1,4-
dioxane–H2O–AcOH (10:1:1, 18 mL) was hy-
drogenolyzed in the presence of Pd black un-
der gentle bubbling of H2 for 7 h at rt. After
filtration, the filtrate was concentrated with
toluene to give a residue that was recrystal-
lized from EtOAc–hexane to give 21 as
needles: 332 mg (94%). TLC (1:1 CHCl3–
EtOAc): Rf 0.2, mp 117–119.5 °C, [h]2D7 −90°
19F NMR (CDCl3): l −73.8 (d, 3 F, J5,F-6
6
Hz, CF3), −173.6 (ddd, 1 F, J1,F-2 13.5, J2,F-2
49.5, J3,F-2 28.5 Hz, F-2).
1
(c 1, MeOH). H NMR (CD3OD): l 6.21 (dd,
7-O-(3,4-Di-O-acetyl-2,6-dideoxy-2-fluoro-
1 H, J1,2 1.5, J1,F-2 8.5 Hz, H-1), 4.50 (dddd, 1
H, J1,2 1.5, J2,3 3, J2,4 ꢀ1, J2,F-2 48.5 Hz, H-2),
4.32 (dq, 1 H, J4,5 ꢀ1, J5,F-6(6%,6%%) 7 Hz, H-5),
4.04 (br d, 1 H, J3,4 3.5 Hz, H-4), 3.79 (appar-
ent dt, 1 H, J2,3 3, J3,4 3.5, J3,F-2 32.5 Hz, H-3),
2.03 (s, 3 H, OAc). 19F NMR (CD3OD): l
−73.6 (d, 3 F, J5,F-6 7 Hz, CF3), −202.8
(dddd, 1 F, J1,F-2 8.5, J2,F-2 48.5, J3,F-2 32.5,
J4(?),F-2 ꢀ1 Hz, F-2). Anal. Calcd for
C8H10F4O5: C, 36.65; H, 3.85. Found: C,
36.75; H, 4.07.
5-C-(trifluoromethyl)-a- -talopyranosyl)dauno-
L
mycinone (24).—A mixture of 23 (130 mg,
0.32 mmol), daunomycinone (178 mg, 0.45
mmol), yellow HgO (617 mg, 2.85 mmol),
,
HgI2 (298 mg, 0.66 mmol), and powdered 3 A
molecular sieves (694 mg, activated at 350 °C
under a stream of N2) in dry Cl(CH2)2Cl (8.5
mL) was stirred for 9.5 h at 80 °C in a dark
place. The mixture was filtered through a
Celite bed, which was repeatedly washed with
CHCl3. The filtrate and washings combined
were washed with aq 30% KI, aq NaHCO3
(saturated), and water, dried (Na2SO4), and
concentrated. The residue was chro-
matographed (7:1 CHCl3 –EtOAc) to give 24
as a red solid: 145 mg (67%). An analytical
sample was prepared by reprecipitation from
CHCl3–hexane, [h]2D4 +202° (c 0.7, CHCl3).
Anal. Calcd for C31H28F4O13: C, 54.39; H,
4.12. Found: C, 54.14; H, 4.10.
1,3,4-Tri-O-acetyl-2,6-dideoxy-2-fluoro-5-C-
(trifluoromethyl)-a-
L
-talopyranose
(22).—A
solution of 21 (271 mg, 1.0 mmol) and Ac2O
(0.98 mL, 10.3 mmol) in pyridine (5.5 mL)
was kept for 21 h at rt. Working up as de-
scribed for 19 gave 22 as a colorless syrup: 318
mg (89%), which crystallized on standing for a
day. Recrystallization from EtOAc–hexane
gave needles, mp 86–87 °C, [h]2D3 −72° (c 1,
19
CHCl3). F NMR (CDCl3): l −74.5 (d, 3 F,
7-O-(2,6-Dideoxy-2-fluoro-5-C-(trifluoro-
J5,F-6 6 Hz, CF3), −202.3 (ddd, 1 F, J1,F-2 8,
J2,F-2 48, J3,F-2 30.5 Hz, F-2). Anal. Calcd for
C12H14F4O7: C, 41.63; H, 4.08. Found: C,
41.65; H, 4.05.
methyl)-a- -talopyranosyl)daunomycinone (3).
L
—A suspension of 24 (28 mg, 0.041 mmol) in
aq 0.2 M NaOH (2.8 mL) was stirred for 3.5
h at 0 °C under the atmosphere of N2. After
neutralization of the resulting deep purple so-
lution with aq 1 M HCl (0.56 mL), followed
by addition of NaCl (1.1 g), the mixture was
extracted with CHCl3. The extracts were
washed with brine, dried (Na2SO4), and con-
centrated to give 3 as a red solid: 23 mg
(94%). An analytical sample was prepared by
reprecipitation from oxolane–hexane. TLC
(2:1 toluene–acetone): Rf 0.3, [h]2D4 +138° (c
0.56, oxolane). Anal. Calcd for C27H24F4O11:
C, 54.01; H, 4.03. Found: C, 54.24; H, 4.10.
3,4-Di-O-acetyl-2,6-dideoxy-2-fluoro-5-C-
(trifluoromethyl)-a- -talopyranosyl iodide (23).
L
—A solution of 22 (195 mg, 0.56 mmol) and
Me3SiI (0.53 mL, 3.7 mmol) in dry toluene
(3.8 mL) was kept for 15 h at 80 °C in the
dark. After dilution with toluene, the solution
was washed successively with aq 10%
Na2S2O3, aq NaHCO3 (saturated), and water,
dried (Na2SO4) and concentrated. The residue
was subjected to flash chromatography (6:1
hexane–EtOAc) to give 23 as a pale-brown
syrup: 132 mg (57%), which was used without

K. Nakai et al. / Carbohydrate Research 316 (1999) 47–57
57
7-O-(2,6-Dideoxy-2-fluoro-5-C-(trifluoro-
methyl)-a- -talopyranosyl)adriamycinone (4).
Acknowledgements
L
—A solution of 3 (42 mg, 0.07 mmol) and
HC(OMe)3 (59 mL, 0.54 mmol) in 3:5 dry
MeOH–1,4-dioxane (2.5 mL) was kept for 30
min at rt, then Br2 [16 mg (0.1 mmol) in 0.2 mL
dry CH2Cl2] was added at 0 °C, and the solution
was kept for 20 min at that temperature, and
2.5 h at rt. TLC (20:3.8:0.45 CHCl3–MeOH–
aq 17% NH4OH) of the solution showed a main
spot at Rf 0.52 (the 14-bromo-13-dimethyl ac-
etal; cf 3: Rf 0.48). After concentration to a half
volume, the solution was poured into hexane
(20 mL), and the resulting precipitate was
collected by centrifugation and washed with
hexane. The solid was suspended in acetone (4.5
mL) and the mixture was stirred for 3 h at rt.
TLC (2:1 toluene–acetone) showed two spots
at Rf 0.3 (major; the 14-bromo-13-oxo deriva-
tive) and 0.75 (minor, the 14-bromo-3%,4%-O-iso-
propylidene derivative). After concentration, a
mixture of the residue and HCO2Na [83 mg in
2:1 acetone–oxolane (4 mL)] was stirred vigor-
ously for 15 h at rt; the mixture showed, in TLC
(2:1 toluene–acetone), four spots at Rf 0.15 (4),
0.25 (the 14-O-formyl derivative of 4), 0.6
(minor, the 14-hydroxy-3%,4%-O-isopropylidene
derivative), and 0.7 (minor, the 14-O-formyl-
3%,4%-O-isopropylidene derivative). After evapo-
ration of the solvent, cold water was added, and
the insoluble matter was collected by centrifu-
gation (to give a red solid, 43 mg). A suspension
of the solid in 18:6:1 oxolane–MeOH–aq 1 M
NH4OH (3.5 mL) was stirred for 45 min at 0 °C,
whereupon the spots at Rf 0.25 and 0.7 had
disappeared. Concentration of the solution
gave a residue, which was dissolved in aq 80%
AcOH (2 mL) and the solution was kept for 3
h at 80 °C. Concentration with aid of toluene
gave a residue, which was suspended in water
and collected by centrifugation. The solid ob-
tained was reprecipitated from oxolane–diiso-
propyl ether to give 4 as a dark red solid, 30
mg (70%). An analytical sample was prepared
by reprecipitation from oxolane–toluene, [h]D24
+154° (c 0.07, oxolane). Anal. Calcd for
C27H24F4O12: C, 52.60; H, 3.92. Found: C,
52.55; H, 3.61.
The authors express deep thanks to Dr
Tomio Takeuchi (the director) and Ms Chisato
Nosaka of the Institute of Microbial Chemistry
for the antitumor assay. They are also grateful
to Dr Yoshihiko Kobayashi of their institute
for carrying out computation work.
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