Synthesis and antitumor activity of the 7-O-(2,6dideoxy-2-fluoro-α-L- talopyranosyl)daunomycinone derivatives modified at C-3' or C-4'

Article abstract of DOI:10.1016/S0008-6215(98)00026-3

As a part of a study to exploit anthracycline glycosides effective against resistant tumor cells, the 3'-O-methyl (3), 4'-O-methyl (4), 3'- deoxy (6), 3'-deoxy-3'-fluoro (7), and 3'-deoxy-3'-iodo (8) derivatives of 7- O-(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)daunomycinone have been prepared by coupling suitably protected glycosyl bromides with daunomycinone. The doxorubicin-type analog (5) of 4 was also prepared. Among the compounds prepared, 5 showed the highest antitumor activity. Relationships between chemical structures of the synthetic products and antitumor activities, together with the degree of resistance were discussed.

Full text of DOI:10.1016/S0008-6215(98)00026-3

Carbohydrate Research 307 (1998) 217±232
Synthesis and antitumor activity of the 7-O-(2,6-
dideoxy-2-¯uoro-ꢀ-l-talopyranosyl)dauno-
mycinone derivatives modi®ed at C-30 or C-40
Yasushi Takagi, Naoki Kobayashi, Min Sun Chang, Geun-Jho Lim,
Tsutomu Tsuchiya *
Institute of Bioorganic Chemistry, 3-34-17 Ida, Nakahara-ku, Kawasaki 211, Japan
Received 26 August 1997; accepted with revisions 18 December 1997
Abstract
As a part of a study to exploit anthracycline glycosides e€ective against resistant tumor cells, the
30-O-methyl (3), 40-O-methyl (4), 30-deoxy (6), 30-deoxy-30-¯uoro (7), and 30-deoxy-30-iodo (8)
derivatives of 7-O-(2,6-dideoxy-2-¯uoro-ꢀ-l-talopyranosyl)daunomycinone have been prepared by
coupling suitably protected glycosyl bromides with daunomycinone. The doxorubicin-type analog
(5) of 4 was also prepared. Among the compounds prepared, 5 showed the highest antitumor
activity. Relationships between chemical structures of the synthetic products and antitumor
activities, together with the degree of resistance were discussed. # 1998 Elsevier Science Ltd. All
rights reserved
Keywords: Anthracycline glycoside; Antitumor activity; Multidrug resistance; 7-O-(2,6-Dideoxy-2-¯uoro-ꢀ-l-
talopyranosyl)daunomycinone
1. Introduction
reported the synthesis of 7-O-(2,6-dideoxy-2-
¯uoro-ꢀ-l-talopyranosyl)-daunomycinone (1) and
-adriamycinone (2), both of which showed higher
antitumor activities than DNR and DOX in mur-
ine leukemia L1210 in vivo; moreover they showed
stronger cytotoxicity against P388 and its DOX-
resistant cell lines (P388/DOX) than DNR and
DOX (this paper; Table 6). Another notable fact
was that they had lower toxicity than DNR and
DOX. From the standpoint of chemical structure,
1 and 2 have a ¯uorine atom at C-20 and a hydroxyl
group at C-30 instead of the 30-amino or 30-alkyl-
amino group present in conventional anthracycline
glycosides; this replacement by a hydroxyl group,
®rst reported by Horton and co-workers [5], is
Anthracycline antibiotics as exempli®ed by dauno-
rubicin (DNR) and doxorubicin (DOX) are anti-
tumor agents widely used in cancer chemotherapy.
Their clinical use is, however, limited by undesir-
able side-e€ects such as drug-cumulative cardio-
toxicity and myelosuppression, as well as the
appearance of multidrug resistance (MDR) in
tumor cells. To circumvent these drawbacks, many
chemical and biosynthetic modi®cations have
been undertaken [1,2]. In previous papers [3,4], we
* Corresponding author.
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00026-3

218
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
important in view of altering the resistance factor
[6]. We further synthesized the 14-hemipimelate [7]
of 2 to make 2 soluble in water, and found that this
compound exhibited stronger antitumor activity
than the parent compound 2 against sensitive P388,
but showed slightly lower activity against the P388/
DOX cell line ([8] and unpublished data). These
results stimulated us to exploit further derivatiza-
tion of 1 or 2 in the hope of obtaining compounds
more e€ective against MDR cells.
Studies on the mechanism of MDR have shown
considerable recent advances. A large proportion
of MDR cells has been shown to over-express
P-glycoprotein, an ATP-dependent drug-transport
protein [9,10], in the plasma membrane, which
causes such lipophilic drugs as doxorubicin to
remain outside the cells, resulting in low intracel-
lular drug-accumulation. Another interesting fea-
ture of MDR cells is their high Ca2+ content inside
the cells as compared to the normal cells [11]. It has
been reported that coadministration of verapamil,
a calcium channel blocker, or its analogs [12], or
calmodulin inhibitors, with DOX reversed the
MDR activity [13]. Other types of MDR and the
circumvention of resistance have been reviewed
[14].
of ®nding a clue to this MDR problem in anthra-
cycline glycosides [16].
2. Results and discussion
Synthesis.ÐAt ®rst, the 30-O- (3) and 40-O-
methyl derivatives (4) of 1 were prepared. Conven-
tional methylation (MeI, NaH in DMF) of methyl
4-O-benzyl-2,6-dideoxy-2-¯uoro-ꢀ-l-talopyrano-
side 9 [4] (to give 10) with subsequent catalytic
debenzylation gave the 4-ol 11 (Scheme 1). Its 19F
NMR spectrum showed a through-space coupling
(ꢀ5 Hz) between OH-4 and F-2, supporting the
1C4(l) conformation of 11 (the conformation is not
necessarily distinct if judged only from the JH,H
values) (Tables 1 and 2). Acetylation of 11 with
Ac2O in MeNO2 in the presence of a catalytic
amount of H2SO4 gave a mixture (ꢀ11:1) of 1,4-di-
O-acetyl-ꢀ-l (12) and -ꢁ-l anomers 13. Their
anomeric con®gurations were assigned based on
the small (JH-1,F-2 8.5 Hz for 12) and large (JH-1,F-2
20 Hz for 13) coupling constants. The mixture was
converted into the ꢀ-l-talopyranosyl bromide 14
by treatment with TiBr4, and 14 was used for the
next coupling. The corresponding 4-O-methyl-ꢀ-l-
talopyranosyl bromide 19 was prepared also from
9. A ®rst attempt at applying a sequence of reac-
tions involving 3-O-acetylation, catalytic debenzy-
lation, and methylation (MeI, Ag2O in DMF)
failed, giving a mixture of 3-O- and 4-O-methyl
derivatives, possibly by acetyl migration in the
®nal step. The hydroxyl group of 9 was there-
fore ®rst protected with 3,4-dihydro-2H-pyran and
the 3-O-tetrahydropyranyl derivative 15 was
hydrogenolyzed, and the resulting 4-ol 16 was
In spite of these ®ndings, however, the relation-
ship between drug structure and MDR is still
obscure, except for the lipophilicity of the drug
molecules [15]. For this reason, determination of
the direction required for improving the biological
properties of the drugs (in terms of antitumor
activity, MDR, and side e€ects) is not easy. In this
paper, we describe the activity-changes brought
about by altering the functional groups at C-30 or
40 in 1 and 2 with several other groups, in the hope
Scheme 1.

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
219
Table 1
1H and 19F chemical shifts (ꢂ (ppm)) and multiplicity of ¯uoro sugar derivatives in CDCl3
Multiplicity
H-1 dda
4.94
H-2 ddta
4.68
H-3 dta
3.46
H-4
H-5 dqa
3.83
H3C-5 da
1.24
CH3O s
3.37
Ac s
19F ddda
204.0
b
10
3.61
dt
3.81
br s
5.37
dt
5.33
dt
5.43
dt
3.57
dt
3.61
11
12
13
14
15
4.90
br d
6.33
4.68
br d
4.59
3.46
3.56
3.86
4.10
3.80
4.24
1.36
1.22
1.29
1.27
3.40
3.50
3.48
2.13
2.18
2.18
2.19
2.17
202.9
220.0
180.9
5.65
6.57
4.78
4.86
3.41
ddd
3.97
ddd
3.93
4.02
3.47
3.49
4.90
4.92
4.62
4.69
3.87
3.90
1.23
1.27
3.36
3.37
204.0
(0.44 F)
202.7
dt
(0.56 F)
201.8
ddt
200.4
ddt
204.1
(0.38 F)
202.9
16
17
4.89
4.90
4.63
4.69
br d
3.75±4.0!
1.35
1.32
3.40
4.90
4.87
6.29
4.57
(0.38H)
4.63
(0.62H)
4.56
3.97
3.92
5.12
5.44
5.06
4.58
ꢀ3.36
ꢀ3.91
3.37(3 H)
3.58
3.64
(0.62 F)
202.2
18
19
21
22
23
3.45
dt
ꢀ3.55
4.09
4.22
4.15
4.08
3.94
1.34
1.38
1.27
1.25
1.28
3.56
3.57
3.45
3.39
3.40
2.11
2.20
2.20
6.54
br d
4.73
4.84
180.2
4.41
ddd
4.46
br ddd
4.43
dddt
3.61
dd
3.52
m
3.29
m
194.7
dddq
185.1
4.83
4.79
br d
1.85
ddt
187.0
dddd
2.39
dddt
2.22
ddt
2.40
dddt
2.26
ddt
2.52
dddd
2.14
dddd
2.65
ddt
2.66
ddt
2.48
dddd
4.74
ddt
25
26
27
28
29
31
32
33
4.86
br d
4.49
dddt
5.06
m
4.15
4.26
4.08
4.37
1.26
1.27
1.34
1.32
3.46
186.5
ddt
6.29
br d
4.52
br d
5.12
br s
2.15
2.23
185.1
ddt
5.79
4.71
br dt
5.12
m
202.2
dddd
6.61
br d
4.81
br d
5.19
m
163.2
dddd
4.94
ddd
4.72
dddt
3.71
ddt
3.86
tq
1.26
dd
3.37
205.5(F-2)
dddd
2.02.9(F-3)
br ddq
204.6(F-2)
dddd
206.2(F-3)
br ddq
220.7(F-2)
dddd
202.6(F-3)
br dddd
182.8(F-2)
dddd
6.34
ddd
4.69
ddddd
4.84
br ddt
5.41
br ddt
4.14
tq
1.24
dd
2.13
2.19
5.67
br dd
4.87
dddt
4.68
dddd
5.38
ddt
3.83
tq
1.31
br d
2.19
2.20
6.53
br dd
4.97
dddt
5.21
dddd
5.49
ddt
4.28
br q
1.29
dd
2.18
(continued)

220
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
Table 1Ðcontd
Multiplicity
H-1 dda
H-2 ddta
H-3 dta
H-4
H-5 dqa
H3C-5 da
CH3O s
Ac s
2.10
19F ddda
207.4(F-3)
br ddq
191.9
dddd
185.6
35
40
41
42
4.78
br d
4.91
4.44
dddd
4.53
dddd
4.53
br d
4.81
5.07
ddt
4.74
ddd
4.75
ꢀ3.45
m
5.37
ddd
5.44
m
4.20
4.29
4.39
4.51
1.30
1.22
1.22
1.28
3.43
3.46
6.32
6.58
2.18
183.7
163.0
5.13
5.49
m
a
Unless otherwise stated.
See Experimental section.
b
Table 2
1H-1H and H-19F coupling constants (J, Hz) of ¯uoro sugar derivatives in CDCl3
1
J1,2
J2,3
J2,4
J3,4
J4,5
J
J1,F
J2,F
49.5
50
48.5
51
49.5
49.5
49.5
49.5
49
J3,F
5,CH3-5
10
11
12
13
14
15
16
17
18
19
21
22
23a,b
1.5
3
3
3
2.5
3
3
3
3
3
3
1.5
3
3
3.5
3.5
3.5
3
1.5
ꢀ1.5
1.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
9.5
9
8.5
33
32.5
31.5
30.5
30
2
ꢁ1
ꢀ1
1.5
1.5
1.5
2
1.5
4.5
1.5
2
ꢀ1
ꢀ1
1.5
1.5
1.5
1.5
ꢀ1.5
1.5
ꢀ0
1.5
ꢀ1.5
20
11.5
9
1.5
33
33
ꢀ7
9.5
8.5
11.5
9
3
3
3
6.5
3
33.5
31.5
30.5
12
37.5
45
ꢀ1.5
ꢀ1.5
4.5
50.5
48
46.5
47
6.5
3
ꢀ1.5
8.5
10
3.5
(J2,3ax
3
(J2,3eq
3.5
(J2,3ax
2.5
(J2,3eq
3.5
(J2,3ax
3.5
(J2,3eq
ꢀ1
3.5
(J3ax,4
3
(J3eq,4)
3.5
(J3ax,4
2.5
(J3eq,4)
3.5
(J3ax,4
2.5
(J3eq,4)
4
2
)
)
(J3ax,F
)
13
(J3eq,F
45.5
(J3ax,F
14.5
(J3eq,F
45
(J3ax,F
13.5
(J3eq,F
43.5
(J3ax,F
11.5
(J3eq,F
43.5
(J3ax,F
)
)
25a,c
26d
27d
28d
ꢀ1
ꢀ1
1.5
1.5
2
6.5
6.5
6.5
6.5
9.5
8.5
21
46.5
45.5
48.5
47
)
)
)
)
)
)
)
)
)
)
1
3
(J2,3ax
ꢀ3
)
(J3ax,4
ꢀ3
)
)
)
(J2,3eq
)
(J3eq,4
ꢀ3
)
ꢀ3
1.5
11
(J2,3ax
2.5
)
(J3ax,4
)
)
4.5
(J3eq,4)
14
(J3eq,F
(J2,3eq
3
)
)
29e,f,g,h
31i,f,j,k
32l,f,m
33e,n,h
1.5
2
1.5
1.5
1
3
1.5
1.5
1.5
1.5
6.5
6.5
6.5
6.5
9 (F-2)
49.5 (F-2)
7 (F-3)
49 (F-2)
6.5 (F-3)
52 (F-2)
7 (F-3)
50 (F-2)
5 (F-3)
45
31.5 (F-2)
44 (F-3)
30 (F-2)
43 (F-3)
28 (F-2)
42.5 (F-3)
28 (F-2)
42.5 (F-3)
11
7 (F-3)
8 (F-2)
6 (F-3)
19 (F-2)
2 (F-3)
11.5 (F-2)
6.5 (F-3)
13
3
3
3
4
4
4
1
1.5
1.5
35o
40
41
42
2
3.5
2.5
3
1
1
3.5
3.5
3
2
1.5
1.5
ꢀ1.5
6.5
6.5
6.5
6.5
1.5
1.5
1
7.5
7.5
46.5
46
46.5
36.5
35.5
3
1
3.5
10
34
a
b
c
d
e
f
g
h
J1,3eq 1.5 Hz. J3ax,3eq 15.5 Hz. J3ax,3eq 16 Hz. J3ax,3eq 16.5 Hz. J4,F-3 6 Hz. J5,F-3 1.5 Hz. J6,F-3 0.8 Hz. JF-2,F-3
n
14 Hz. i J4,F-3 5.5 Hz. j J6,F-3 1 Hz. k JF-2,F-3 13.5 Hz. l J4,F-3 5 Hz. m JF-2,F-3 13 Hz. J6,F-3 0.7 Hz. o J1,3 1 Hz.

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
221
methylated to give the 4-O-methyl derivative 17.
Compound 17 was then acetolyzed (Ac2O, AcOH,
cat. H2SO4) and the resulting 1,3-di-O-acetyl-ꢀ-l-
talopyranose (18) was brominated with TiBr4 to
give the ꢀ-1-bromide 19 in high yield.
Coupling of 12 with daunomycinone was ®rst
attempted according to the procedure reported [17]
(CF3SO3SiMe3 and molecular sieves 4A in
CH2Cl2±Et2O), but the desired product was not
obtained. Coupling of the bromide 14 with dauno-
mycinone under Koenigs±Knorr conditions, how-
ever, gave the ꢀ-l- (43) and ꢁ-l-glycosides 44 in 38
and 8% yields, respectively. The anomeric con®g-
urations of 43 and 44 were again determined by
poor yield of 43 (con®rmed by repeated experi-
ments), therefore, must be ascribed to the di€er-
ence in substituent at C-3 in 14. Alkaline treatment
of 43 gave the desired 7-O-(2,6-dideoxy-2-¯uoro-3-
O-methyl-ꢀ-l-talopyranosyl)daunomycinone (3).
1
The structure was con®rmed by the H (Table 3),
19F, and 13C NMR spectra (Table 4). In its 19F
0
NMR spectrum, through-space coupling JOH-4 ,F-2
(9 Hz) was observed.
0
Next, 4-O-methyl-ꢀ-l-talopyranosyl bromide 19
was coupled with daunomycinone as described for
43, giving the ꢀ-l-glycoside 45 in 50% yield. Alka-
line hydrolysis of 45 gave 7-O-(2,6-dideoxy-2-
¯uoro-4-O-methyl-ꢀ-l-talopyranosyl)daunomyc-
inone 4 in good yield. The daunomycin-type struc-
ture of 4 was then transformed into a doxorubicin-
type structure by applying, basically, a sequence of
reactions reported by Arcamone et al. [18]; bromi-
nation of 4 with Br2 in the presence of HC(OMe)3
gave the 14-bromo-13-dimethylacetal, the acetal
portion being then deblocked by treatment with
0
0
their JH-1 ,F-2 coupling constants (9.5 Hz for 43 and
19 Hz for 44). Previously, we reported [4] that the
coupling of 3,4-di-O-acetyl-2,6-dideoxy-2-¯uoro-ꢀ-
l-talopyranosyl bromide (an analog of 14) with
daunomycinone gave the 30,40-di-O-acetyl deriva-
tive of 1 in high yield (82%) without accompani-
ment of the undesirable ꢁ-l anomer; the present
Table 3
Selected H NMR chemical shifts (ꢂ (ppm)) and coupling constants (J, Hz) of 3±8 and 43±51 in CDCl3
1
Compound H-7 OMe-4 H-14 H-10 H-20 H-30ax H-40 OMe- J7,8ax J7,8eq J1 ,2 J2 ,3 ax J3 ax,4 J1 ,F-2 J2 ,F-2 J3 ax,F-2
0
0
0
0
0
0
0
0
0
0
0
0
30 or 40
0
(J3 eq,F-2
0
)
3
5.27 4.03 2.41 5.61 4.73
dd dd br d
5.26 4.07 2.40 5.58 4.50
dd
br d br d ddt a br d
5.34 4.09 4.74 5.62 4.47 3.65 3.34
dd
br s dd br d ddt a br d
5.35 4.08 2.41 5.50 4.56 1.92 3.55
dd
br d br d ddt b br d c
5.28 4.09 2.40 5.65 4.83 4.57 3.92
dd
ddd dddtd ddt
5.30 4.09 2.41 5.53 4.56
dd dd br d
5.30 4.09 2.41 5.63 4.62
dd dd br d
5.57 4.09 2.43 4.95 4.79
br t br dd ddd br dd
5.26 4.07 2.41 5.59 4.59 4.90 3.47
dd dd br d dt
5.39 4.09 2.43 5.60 4.52 2.08 5.10
dd
br d br d ddt b br s
5.63 4.09 2.45 5.11 4.68 2.05 4.96
dd
br d br d ddt b br s
5.28 4.09 2.40 5.66 4.73 4.67 5.39
dd ddd br d ddt
5.59 4.09 2.44 5.00 4.85 4.58 5.23
dd ddd dddd br dd
5.32 4.10 2.42 5.62 4.57 4.61 5.39
dd br d br d dt br s
5.62 4.09 2.46 5.21 4.73 4.48 5.23
dt br s
3.32 3.84
dt br d
3.69 3.33
3.44
s
3.60
s
3.61
s
4.5
4
1.5 ꢀ1
ꢀ2
3
3
4
10
10
10
10
ꢀ50
49.5
32.5
31.5
31
s
s
4
*
ꢀ4
s
s
5
4
2
2
2
1.5 ꢀ3
ꢀ4
3
49
s
6
4
*
3
3
3
47
49
(13)
31.5
s
s
7
4.5
4.5
4.5
2
3
9.5
50.5
46.5
49
s
s
m
8
4.42 3.59
1.5 1.5
3
8.5
9.5
38
s
s
dt
3.38 5.34
dt
3.31 5.18
br d e
43
44
45
46
47
48
49
50
51
3.39
s
3.45
s
3.55
s
2
1.5 ꢀ3
ꢀ3
4
32.5
30.5
32.5
s
s
m
3.5 ꢀ2.5 ꢀ0
2.5
19
51
s
s
d
4
ꢀ2
1.5
1.5
3
3
10
10
20
50
s
s
m
4
*
ꢀ3
ꢀ4
3.5
ꢀ3
ꢀ4
46
46
s
s
(13)
43.5
(12)
30
3.5
4.5
3
2
*
48.5
50
s
s
1.5
3.5
9.5
s
s
m
3.5 ꢀ3 ꢀ0
2.5
ꢀ3
4
ꢀ3
3
18
8
52
28.5
37
t
s
s
4
1.5
*
45.5
48
s
s
3.5 ꢀ2.5
*
3
19.5
34.5
br t
s
s
br d br dd
a
b
c
e
J3 ,OH-3 11.5 Hz. J3 ax,3 eq 16 Hz. J4 ,OH-4 11 Hz. d J2 ,4 2 Hz. J4 ,OH-4 10 Hz.
Not detected by broadening.
0
0
0
0
0
0
0
0
0
0
*

222
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
Table 4
13C NMR chemical shifts (ꢂ (ppm)) and coupling constants (JC,F, Hz, in parentheses) for compounds 3±8 in CDCl3
C
3
4
5
6
7 a
8
1
2
3
4
4a
5
5a
6
6a
119.9
135.8
118.6
161.2
120.9
187.0 b
111.6 c
156.3 d
133.2 e
71.4
119.7
135.7
118.5
161.1
120.8
186.8 b
111.54 c
155.7 d
133.1 e
71.0
119.9
135.8
118.6
161.2
120.9
187.0 b
111.7
156.0 c
132.7 d
70.8
119.8
135.4
118.5
161.1
120.8
186.9 b
111.4
156.6 c
133.4 d
70.9
119.9
135.9
118.6
161.2
120.9
187.1
111.7
156.2
132.9
71.4
119.9
135.9
118.6
161.2
120.9
187.1 b
111.7 c
156.2 d
133.0 e
71.4
7
8
9
10
35.2
76.5
33.1
35.0
76.4
33.1
35.6
76.6
33.9
35.1
76.6
33.2
35.3
76.3
33.1
35.4
76.3
33.1
10a
11
11a
12
12a
13
14
134.3 e
155.6 d
111.5 c
186.7 b
135.5 e
211.1
24.6
134.0 e
155.1 d
111.48 c
186.6 b
135.4 e
211.3
24.6
133.4 d
155.4 c
111.7
186.8 b
135.5 d
213.4
65.4
134.4 d
155.3 c
111.4
186.7 b
135.8 d
211.5
24.7
134.1
155.5
111.6
186.9
135.5
211.0
24.5
134.1 e
155.6 d
111.6 c
186.8 b
135.5 e
211.0
24.5
OMe-4
OMe-30
OMe-40
10
56.7
55.9
56.6
56.7
56.7
56.7
56.7
62.9
63.0
101.4 d (31.5)
86.3 d (176.9)
74.5 d (14.8)
68.7
68.0
16.5
101.3 d (32.2)
87.3 d (177.0)
66.0 d (17.1)
81.0
67.5
16.7
101.1 d (32.2)
87.1 d (177.6)
66.0 d (16.9)
80.9
67.8
16.8
100.3 d (34.0)
86.5 d (166.7)
30.8 d (17.6)
66.5
67.9
16.9
101.3 dd (30.5, 6.8)
87.0 dd (178.2, 17.1)
85.7 dd (192.3, 14.7)
70.4 d (17.4)
67.8 d (5.9)
16.1 d (2.1)
100.5 d (34.4)
89.9 d (176.9)
25.8 d (16.9)
72.3
68.2
17.4
20
30
40
50
60
a
Measured at 125.8 MHz and con®rmed by the HMQC followed by HMBC method.
b, c, d, e
Figures in the same column may be interconvertible.
acetone. The resulting 14-bromo-13-oxo derivative
was hydrolyzed with sodium formate in aq acetone
giving a mixture of 5 and its 14-O-formyl deriva-
tive; thorough deblocking of the mixture with
NH4OH in CHCl3±MeOH gave the doxorubicin-
type derivative 5.
structure, the JH-3,F-2 value should be small, irre-
spective of the conformations. Its 13C NMR spec-
trum showed a doublet (JC-3,F-2 15.7 Hz) at high
®eld (ꢂ 24.2), indicating the presence of I-3. Radical
deiodination of 22 with Bu3SnH gave the 3-deoxy
derivative 23 quantitatively. Hydrogenolysis of 23
(to give 24) followed by p-nitrobenzoylation a€or-
ded the 4-p-nitrobenzoate 25. Acetylation of 25 in
the manner described for 12 gave a mixture of 1-O-
acetyl-ꢀ-l (26) and -ꢁ-l anomers 27, the ratio being
6:1. Compound 26 was then converted into the ꢀ-l-
lyxo-hexopyranosyl bromide 28 by treatment with
HBr in AcOH.
Preparation of 3-deoxy-3-¯uoro-ꢀ-l-talopyr-
anosyl bromide 33 was attempted initially by
treatment of 20 with Et2NSF3 (DAST), but it
failed, giving only a complex mixture. Then the 3-
tri¯ate 21 was treated with (Me2N)3S+ (Me3SiF2)
(TASF) [19] and the resulting 2,3,6-trideoxy-2,3-
Next, the 30-deoxy (6), 30-deoxy-30-¯uoro (7),
and 30-deoxy-30-iodo derivatives (8) of 1 were pre-
pared. The synthetic routes for the glycosyl bro-
mides are shown in Scheme 2. Treatment of methyl
4-O-benzyl-2,6-dideoxy-2-¯uoro-ꢀ-l-idopyranoside
20 [4] with (CF3SO2)2O gave the unstable 3-tri¯ate
21, whose 19F NMR spectrum showed interspace
coupling (6 Hz) between F-2 and CF3. It is worth
mentioning that 21 showed somewhat di€erent
JH,H values from those for similar ꢀ-l-ido deriva-
tives (20 [4], 34 [4], 35), suggesting the presence of
some in¯uence of the CF3SO2-3 group on its con-
formation. Iodination (NaI in DMF, 90 ꢂC) of 21
gave the 3-deoxy-3-iodo derivative 22. The l-talo
structure was con®rmed by the large coupling
constant (JH-3,F-2 37.5 Hz); if l-ido had been the
di¯uoro-ꢀ-l-talopyranoside
29
was
hydro-
genolysed (to give 30) and acetolyzed as described
for 18 to give a mixture of 1,3-di-O-acetyl-ꢀ-l (31)

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
223
Scheme 2.
and -ꢁ-l anomers 32, the ratio being 2.5:1. Bromi-
nation of 31 as described for 28 gave the crystalline
ꢀ-l-talopyranosyl bromide 33.
The 3-deoxy-3-iodo-ꢀ-l-talopyranosyl bromide
42 was prepared from methyl 3-O-acetyl-4-O-ben-
zyl-2,6-dideoxy-2-¯uoro-ꢀ-l-idopyranoside 34 [4].
Successive debenzylation of 34 (to give 35), pro-
tection of the OH-4 group with
a
tetra-
hydropyranyl group (to give 36), deacetylation of
36 (to give 37), and tri¯ation gave the unstable 3-
tri¯ate 38. Iodination of 38 with NaI in DMF gave
the 3-deoxy-3-iodo-ꢀ-l-talopyranoside 39, the tet-
rahydropyranyl group in 38 being removed during
the reaction. After p-nitrobenzoylation, the result-
ing ester 40 was acetolyzed (to give the 1-acetate
41), and brominated to give the ꢀ-l-talopyranosyl
bromide 42.
Characteristic features of the 1-bromides pre-
pared in the 19F NMR spectra are that the shift-
values for F-2 always appear down®eld by
ꢀ20 ppm compared to those for the parent methyl
ꢀ-l-glycosides or ꢀ-l-glycosyl acetates (compare
11 (or 12) and 14; 17 (or 18) and 19; 25 (or 26) and
28; 29 (or 31) and 33; and 40 (or 41) and 42;
Table 1).
Coupling of the respective glycosyl bromides 28,
33, and 42 with daunomycinone was performed in
the manner described for 43 to give the corre-
sponding coupling products: ꢀ-l (46, 43%) and ꢁ-l
anomers (47, 41%) from 28; ꢀ-l (48, 28%) and ꢁ-l
anomers (49, 16%) from 33; ꢀ-l (50, 22%) and ꢁ-l
anomers (51, 62%) from 42, the ratios of ꢀ-l: ꢁ-l
anomers being ꢀ1:1, 1.8:1, and 1:2.8, in the fore-
going order. In these coupling reactions, the ꢀ-
selectivity observed [4] in 1 was completely lost and
the undesirable ꢁ-l anomers were sometimes major
products. The anomeric con®gurations of the pro-
0
0
ducts were determined by their JH-1 ,F-2 values in
1
the H and 19F NMR spectra. Alkaline treatment

224
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
Table 5
Antitumor activitiesa (T/Cb (%)) of 1±8 against the murine L1210 cell line
1
c
Compound
Dose (mg kg 1 day
2.5
)
C150
Ec
10
5
1.25
0.6
0.3
0.15
1
2
3
4
5
6
7
8
184
>740
109
217
>352
112
171
275
100
146
>501
113
114
125
185
91
124
279
96
105
182
94
117
152
110
108
97
105
127
Ð
111
Ð
107
105
97
0.9
0.2
8.2
1.25
0.3
>5
5
>5
5.7
6.0
12.3
5.1
174
>314d
124d
121
260
102d
>761d
113
135
6.0
>12.5
18
>16
148
116
117
103
97
106
a
Leukemia L1210 cells (105) were inoculated into CDF1 mice (20‹1 g) intraperitoneally. Drugs were administered daily, starting
24 h after inoculation, from day 1 to 9 intraperitoneally. Survival studies were continued up to 60 days; a part of the data were
reported [3,16].
b
Mean survival days of treated mice/mean survival days of control mice Â100.
c
See text portion.
More than 10% weight decrease in the treated mice was observed.
d
of 46, 48, and 50 gave the respective desired pro-
ducts 6, 7, and 8 in good yields.
well as 1 and 2) are estimated as being almost
equal, and superior to those of the other deriva-
tives. Since the Ca2+ ion is considered to play an
important role in MDR, the pursuit of the rela-
tionship between Ca-chelating ability of our syn-
thetic products and RF (or E) value will be an
interesting problem in future.
Antitumor activity.ÐAntitumor activities of 3±8
against L1210 murine leukemia in vivo (Table 5)
showed that only 4 and 5 exhibited strong anti-
tumor activity (5 was much stronger). This result
suggests, together with the activities [3] of the par-
ent compounds 1 and 2, that those modi®cations
that remove the exchangeable hydrogen from the
HO-3 group (as in 3, 6±8) cause total loss or great
decreases in the activity inherent in the parent
anthracycline antibiotics. However, in view of drug
resistance against P388/DOX (Table 6), there was a
considerable di€erence between 4 and 5 (4 showed
partial drug-resistance against P388/DOX). Jud-
ging from the resistant factor (RF)-values (Table 6),
it appears that HO-14 (in 2, 5, and DOX) induced
resistance (possibly by MDR), and absence of the
HO-30 (or H2N-30) group reversed the resistance.
However, these hydroxyl groups, especially HO-30,
seem to be the groups essential for manifesting
antitumor activity in these anthracycline glyco-
sides. It appears, therefore, that the more active
compounds su€er the stronger resistance. In this
context, a 30,40-di-O-methyl analog of DNR, SO-
075R1 [20] was expected to show only weak anti-
tumor activity. However, we set a parameter (E) as
a measure for estimating the antitumor activity and
resistance (to P388/DOX) concurrently, by multi-
3. Experimental
General methods.ÐMelting points were deter-
mined on a Ko¯er block, and are uncorrected.
Optical rotations were measured with a Perkin±
1
Elmer 241 polarimeter. H NMR (at 250 MHz)
and 19F NMR (at 235.7 MHz) spectra were recor-
ded with a Bruker WM 250 spectrometer. 13C
NMR (at 62.9 or 125.8 MHz) spectra were recor-
ded with a Bruker WM 250 or Bruker AMX 500
1
spectrometer. Chemical shifts (ꢂ) for H, 13C, and
19F spectra were measured, down®eld from internal
Me4Si, down®eld from Me4Si with aid of internal
1,4-dioxane (ꢂ ˆ ꢂ1;4
‡67:4), and down®eld
-dioxane
from internal Freon 11 (CFCl3), respectively. TLC
was performed on Kieselgel 60 F254 (Merck), and
column chromatography on Wakogel C-200.
Methyl 4-O-benzyl-2,6-dideoxy-2-¯uoro-3-O-
methyl-a-l-talopyranoside (10).ÐA mixture of
NaH (170 mg, 60% NaH in mineral oil, 4.3 mmol)
and 9 [4] (460 mg, 1.7 mmol) in dry DMF (4.6 ml)
was stirred under an atmosphere of N2. After
hydrogen evolution had ceased, MeI (1 mL,
10.8 mmol) was added, and the stirring was con-
tinued for 1 h at room temperature. After addition
plying the RF-value in Table 6 and the dose (C150
)
needed to attain the value of T/C 150% in Table 5
(for example, in 4: 4.1Â1.25=5.1; the values are
shown in the last column in Table 5). Based on this
parameter, the antitumor activities of 4 and 5 (as

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
225
Table 6
Growth inhibitory e€ect of 1±8, DNR, and DOX against P388 and P388/DOX cell lines in vitro a
1
Compound
Substituent
IC50 (ꢃg mL
)
RFb
R1
R2
R3
R4
P388
P388/DOX
1
2
3
4
5
6
7
8
H
OH
H
H
OH
H
H
H
H
OH
F
F
F
F
F
F
F
F
H
H
OH
OH
OMe
OH
OH
H
F
I
NH2
NH2
OH
OH
OH
OMe
OMe
OH
OH
OH
OH
OH
0.008
0.003
0.066
0.032
0.004
0.150
0.073
0.130
0.020
0.014
0.05
0.09
0.10
0.13
0.08
0.37
0.26
0.42
6.3
30
1.5
4.1
20
2.5
3.6
3.2
DNR
DOX
0.34
>0.50
17
>36
a
IC50 values (50% inhibition concentration) were determined on day-3 culture.
Resistant factor (RF): IC50 for resistant subline/IC50 for sensitive subline.
b
of AcOH (0.2 mL) followed by CHCl3, the solution
TLC (30:1 CHCl3±acetone) showed two spots at Rf
0.3 (12, major) and 0.2 (13, minor). After pouring
into NaHCO3 (4.7 g) suspended in water (13.7 mL),
and stirring for 1 h, the mixture was extracted with
CHCl3. The solution was washed with aq 10%
NaCl, dried (Na2SO4), and concentrated. Chro-
matography (30:1 CHCl3±acetone) of the residue
gave 12 as crystals, 236 mg (67%), and a mixture of
12 and 13 (74 mg). Rechromatography of the latter
with the same solvent system gave an additional
crop of 12, 38 mg (11%), and 13 as a syrup, 25 mg
was washed with aq NaCl (saturated), dried
(Na2SO4), and concentrated with occasional addi-
tion of xylene. The residue was chromatographed
(9:1 toluene±EtOAc) to give 10 as a syrup, 409 mg
(84%), TLC (10:1 toluene±EtOAc): Rf 0.27 (cf 9:
38ꢂ (c 1, CHCl3). Anal. Calcd for
24
Rf 0.17), [ꢀ]d
C15H21FO4: C, 63.36; H, 7.44; F, 6.68. Found: C,
63.37; H, 7.41; F, 6.73.
1,4-Di-O-acetyl-2,6-dideoxy-2-¯uoro-3-O-methyl-
a- (12) and -b-l-talopyranose (13).ÐTo a solution of
10 (379 mg, 1.3 mmol) and AcOH (1.9 mL) in 1,4-
dioxaneÐH2O (8:1, 21mL) was gently introduced
H2 in the presence of palladium black for 1 h at
room temperature. Filtration followed by con-
centration with aid of toluene gave 11 as a syrup,
which was chromatographically homogeneous,
260 mg (quant), Rf 0.2 (TLC, 30:1 CHCl3±acet-
one); 19F NMR (CDCl3) ꢂ 201.6 (br dddd, which
(7.2%). Compound 12, mp 139±140 ꢂC (prisms
21
from CHCl3±diisopropyl ether); [ꢀ]d
159ꢂ (c 1,
CHCl3). Anal. Calcd for C11H17FO6: C, 50.00; H,
6.48; F, 7.19. Found: C, 49.90; H, 6.72; F, 6.93.
28ꢂ (c 1, CHCl3). Anal.
23
Compound 13 had [ꢀ]d
Calcd for C11H17FO6: C, 50.00; H, 6.48. Found: C,
50.20; H, 6.51.
4-O-Acetyl-2,6-dideoxy-2-¯uoro-3-O-methyl-a-l-
talopyranosyl bromide (14).ÐA mixture of 12
(329 mg, 1.2 mmol) and TiBr4 (1.14 g, 3.8 mmol) in
dry CH2Cl2±EtOAc (9:1, 7.3 mL) was stirred for
16 h at room temperature. TLC (3:1 hexane±acet-
one) of the deep-brown mixture showed a single
collapsed to sharp ddd in addition of D2O; JOH
4,F
ꢀ5 Hz; Table 2). To an ice-cold solution of the
syrup in dry MeNO2 (8 mL) were added Ac2O
(1.3 mL, 13.8 mmol) and H2SO4 (8 ꢃL), and the
solution was kept for 2.5 h at room temperature.

226
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
as a syrup, 338 mg (74%), TLC (10:1 CHCl3±
spot at Rf 0.35. After dilution with dry MeCN
(13 mL), anhydrous NaOAc (2.88 g) was added at
0 ꢂC and the mixture was stirred until the color
faded to pale yellow. The mixture was ®ltered
through Celite with aid of toluene, and the organic
solution was concentrated. Extraction of the resi-
due with toluene followed by concentration gave
14 as a pale-yellow syrup (314 mg, 88%), which
was used without further puri®cation.
Methyl 4-O-benzyl-2,6-dideoxy-2-¯uoro-3-O-
tetrahydropyran-2-yl-a-l-talopyranoside (15).ÐA
mixture of 9 (536 mg, 2.0 mmol), 3,4-dihydro-
2H-pyran (0.53 mL, 6 mmol), and pyridinium
p-toluenesulfonate (57 mg, 0.23 mmol) in dry
CH2Cl2 (8 mL) was kept for 5 h at room tempera-
ture. The solution, after pouring into aq NaHCO3
(saturated), was extracted with CHCl3 and the
extract was concentrated. Chromatography (20:1
toluene±acetone) of the residue gave a diaster-
eoisomeric mixture (1:0.8 by 19F NMR) of 15 as a
103ꢂ (c 1, CHCl3); H
25
1
EtOAc): Rf 0.3, [ꢀ]d
NMR (CDCl3) (signals not listed in Table 1): ꢂ
4.78±4.90 (1 H, H-20), 3.86±3.96 (2 H, H-5, 60b),
3.3±3.6 (2 H, H-4, 60a), 1.5±2.0 (6 H, H-30a,b, 40a,b,
50a,b). Anal. Calcd for C13H23FO5: C, 56.10; H,
8.33; F, 6.83. Found: C, 55.94; H, 8.27; F, 6.96.
1,3-Di-O-acetyl-2,6-dideoxy-2-¯uoro-4-O-methyl-
a-l-talopyranose (18).ÐA mixture of 17 (425 mg,
1.5 mmol), Ac2O (4.2 mL), AcOH (4.2 mL), and
H2SO4 (85 ꢃL, 1.6 ꢃmol) was kept for 1 h at 0 ꢂC,
then for 1.5 h at room temperature. The dark-
brown solution resulted was poured into ice-cold
aq NaHCO3 (saturated, 40 mL) and the mixture
was stirred for 1.5 h. Extraction of the product
with CHCl3 and concentration gave a residue,
which was chromatographed (30:1 CHCl3±EtOAc)
to give 18 as crystals, 260 mg (64%), mp 92±93 ꢂC
22
(prisms from EtOAc±hexane), [ꢀ]d
97ꢂ (c 1,
CHCl3). Anal. Calcd for C11H17FO6: C, 50.00; H,
6.48; F, 7.19. Found: C, 50.12; H, 6.48; F, 7.20.
3-O-Acetyl-2,6-dideoxy-2-¯uoro-4-O-methyl-a-l-
talopyranosyl bromide (19).ÐA mixture of 18
(230 mg, 0.87 mmol) and TiBr4 (800 mg, 2.2 mmol)
in dry CH2Cl2±EtOAc (10:1, 5 mL) was stirred for
16 h at room temperature. The deep-brown mixture
was treated as described for 14 to give 19 as a pale-
yellow syrup, 246 mg (quant), which was used
without further puri®cation.
syrup, 571 mg (81%), TLC (20:1 toluene±acetone):
47ꢂ (c 1, CHCl3); 1H NMR
22
Rf 0.25, [ꢀ]d
(CDCl3) (signals not listed in Table 1): ꢂ 7.2±7.5 (5
H, m, Ph), 4.81±4.87 (1 H, H-20), 4.71, 4.75, 4.91,
5.01 (each d, 2 H in total, J 12 Hz, PhCH2), ꢀ3.9
(1 H, H-60b), 3.48-3.55 (1 H, H-60a), 1.5±2.0 (6 H,
H-30a,b, 40a,b, 50a,b of THP), Anal. Calcd for
C19H27FO5: C, 64.39; H, 7.68; F, 5.36. Found: C,
64.31; H, 7.66; F, 5.11.
Methyl 2,6-dideoxy-2-¯uoro-3-O-tetrahydro-
pyran-2-yl-a-l-talopyranoside (16).ÐCompound 15
(666 mg, 1.9 mmol) was hydrogenolyzed in 1,4-
dioxane±H2O (16:1, 34 mL) for 2 h as described for
11, and the products were chromatographed (10:1
CHCl3±EtOAc) to give 16 as a diastereoisomeric
mixture of semi-crystalline syrup, 411 mg (83%).
1H NMR (CDCl3) (signals not listed in Table 1): ꢂ
4.85±4.94 (1 H, H-20), 3.75±4.0 (4 H, H-3, 4, 5, 60b),
3.54 (m, 1 H, H-60a), 2.39 (t, 0.86 H, J4,OH-4=JOH-
Methyl 4-O-benzyl-2,6-dideoxy-2-¯uoro-3-O-tri-
¯uoromethylsulfonyl-a-l-idopyranoside (21).ÐTo a
cold ( 20 ꢂC) solution of 20 [4] (2.00 g, 7.4 mmol)
in pyridine (3.6 mL)±CH2Cl2 (20 mL) was added
(CF3SO2)2O (1.9 mL, 11 mmol) and the solution
was kept for 1 h at 0 ꢂC. After addition of MeOH
(10 mL) followed by dilution with CHCl3, the
solution was washed successively with aq 20%
KHSO4, aq NaHCO3 (saturated), and water, dried
(Na2SO4), and concentrated to give 21 as a pale-
yellow syrup, 2.83 g (95%) which was used without
further puri®cation; 19F NMR (CDCl3): ꢂ 194.7
(dddq, 1 F, F-2; collapsed to ddd by irradiation at
7 Hz, OH-4 of the major isomer), 2.28 (t, 0.14
4,F
H, J4,OH-4=JOH-4,F 8.5 Hz, OH-4 of the minor
isomer), 1.5±2.0 (6 H, H-30a,b, 40a,b, 50a,b). Anal.
Calcd for C12H21FO5: C, 54.53; H, 8.01; F, 7.19.
Found: C, 54.62; H, 8.01; F, 6.88.
ꢂ
75.1), 75.1 (d, 3 F, JCF ,F-2 6 Hz, CF3).
Methyl 4-O-benzyl-2,3,6-trideoxy-2-¯uoro-3-iodo-
3
Methyl 2,6-dideoxy-2-¯uoro-4-O-methyl-3-O-
tetrahydropyran-2-yl-a-l-talopyranoside (17).Ð
Compound 16 (434 mg, 1.6 mmol) in DMF
(4.3 mL) was treated with NaH (188 mg, 60% in
mineral oil, 4.7 mmol) and MeI (0.4 mL, 6.4 mmol;
2 h) as described for 10. Column chromatography
(10:1 CHCl3±EtOAc) of the products gave a dia-
stereoisomeric mixture (1:0.6 by 19F NMR) of 17
a-l-talopyranoside (22).ÐA mixture of 21 (2.83 g,
7.0 mmol) and NaI (5.28 g, 32 mmol) in DMF
(29 mL) was stirred the dark place for 3 h at 90 ꢂC.
Dilution of the solution with CHCl3 gave a pre-
cipitate, which was ®ltered and washed with
CHCl3. The ®ltrates combined were washed with
aq 20% Na2S2O3 and water, dried (Na2SO4), and
concentrated with aid of xylene. Chromatography

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
227
(50:1 toluene±EtOAc) of the residue gave 22 as an
74ꢂ (c 1,
for 1 h, and the products were extracted with
CHCl3. The solution was washed with water, dried
(Na2SO4), and concentrated. Chromatography
(50:1 CHCl3±EtOAc) of the residue gave 26 as
crystals, 356 mg (78%), TLC: Rf 0.35 (3:1 hexane±
23
amorphous solid, 2.01 g (75%), [ꢀ]d
CHCl3); 13C NMR (CDCl3): ꢂ 127.7, 128.1, 128.3,
137.4 (Ph), 98.3 (d, JC-1,F 31.3 Hz, C-1), 87.9 (d, JC-
188.4 Hz, C-2), 78.9 (C-4), 76.3 (PhCH2), 67.3
2,F
(C-5), 55.2 (OCH3), 24.2 (d, JC-3,F 15.7 Hz, C-3).
Anal. Calcd for C14H18FIO3; C, 44.23; H, 4.77; F,
5.00; I, 33.38. Found: C, 44.56; H, 4.93; F, 4.84; I,
33.56.
acetone) and 27 as crystals, 58 mg (13%), Rf 0.25.
Compound 26, mp 126±127.5 ꢂC, [ꢀ]d
62ꢂ (c,
23
1.5, CHCl3). Anal. Calcd for C15H16FNO7: C,
52.79; H, 4.73; F, 5.57; N, 4.10. Found: C, 52.96;
H, 4.65; F, 5.30; N, 4.04. Compound 27, mp 189.5±
Methyl 4-O-benzyl-2,3,6-trideoxy-2-¯uoro-a-l-
lyxo-hexopyranoside (23).ÐA mixture of 22
(1.99 g, 5.2 mmol), Bu3SnH (8.4 mL, 31.3 mmol),
and 2,20-azobisisobutyronitrile (43 mg, 0.26 mmol)
in dry 1,4-dioxane was stirred for 1 h at 80 ꢂC
under the atmosphere of N2. After concentration,
the residue was chromatographed (1:1 toluene±
hexane!CHCl3) to give 23 as a syrup, 1.32 g
190.5 ꢂC, [ꢀ]d
5ꢂ (c 1, CHCl3). Anal. Calcd for
23
C15H16FNO7: C, 52.79; H, 4.73; F, 5.57; N, 4.10.
Found: C, 52.59; H, 4.63; F, 5.40; N,3.83.
2,3,6-Trideoxy-2-¯uoro-4-O-p-nitrobenzoyl-a-l-
lyxo-hexopyranosyl bromide (28).ÐA solution of
26 (329 mg, 0.97 mmol) in 30% HBr in AcOH
(3.3 mL) was kept for 1.5 h at room temperature.
CHCl3 (60 mL) was added, and the solution was
washed with cold aq NaHCO3 (saturated) and
water, dried (MgSO4), and concentrated to give 28
as a pale-yellow syrup, 349 mg (quant), which was
used without puri®cation; TLC (3:1 hexane±acet-
one) Rf 0.45.
(quant), TLC (50:1 toluene±EtOAc) Rf 0.25 (cf 22 :
23
Rf 0.35), [ꢀ]d
31ꢂ (c 2, CHCl3). Anal. Calcd for
C14H19FO3: C, 66.12; H, 7.53; F, 7.47. Found: C,
65.85; H, 7.64; F, 7.61.
Methyl 2,3,6-trideoxy-2-¯uoro-4-O-p-nitrobenzoyl-
a-l-lyxo-hexopyranoside (25).ÐA solution of 23
(50 mg, 0.20 mmol) in 1,4-dioxane±H2O±AcOH
(10:1:1, 1 mL) was hydrogenated in the presence of
Pd black under gentle bubbling of H2 for 2 h at
room temperature. In TLC (3:1 hexane±acetone),
the solution showed a single spot at Rf 0.4 of 24 (cf
23: Rf 0.5). After ®ltration followed by dilution
with CH2Cl2, the organic solution was washed with
aq NaHCO3 (saturated), dried (MgSO4), and con-
centrated. To the residue in CH2Cl2 (1.5 mL) p-
nitrobenzoyl chloride (110 mg, 0.59 mmol) and
pyridine (0.7 mL) were added, and the mixture was
stirred for 11 h at room temperature. Water
(0.05 mL) was added, and stirring was continued
for 1 h. After addition of large amount of CHCl3,
the organic solution was washed successively with
aq 20% KHSO4, aq NaHCO3 (saturated), and
water, dried (Na2SO4), and concentrated to give 25
Methyl 4-O-benzyl-2,3,6-trideoxy-2,3-di¯uoro-a-
l-talopyranoside (29).ÐA mixture of 21 (2.70 g,
6.7 mmol)
and
tris(dimethylamino)sulfonium
di¯uorotrimethylsilicate [19] (6.67 g, 24.2 mmol) in
dry CH2Cl2 (54 mL) was stirred for 15 h under an
atmosphere of N2 at room temperature. After
dilution with CHCl3, the solution was washed with
aq NaHCO3 (saturated) and water, dried (Na2SO4),
and concentrated. The residue was chromato-
graphed (30:1 toluene±EtOAc) to give 29 as a solid,
1.20 g (66%). Recrystallization from CHCl3±hex-
41ꢂ (c 1,
ane gave prisms, mp 51.5±52.5 ꢂC, [ꢀ]d
25
CHCl3). Anal. Calcd for C14H18F2O3: C, 61.75; H,
6.66; F, 13.95. Found: C, 61.84; H, 6.85; F, 13.75.
1,4-Di-O-acetyl-2,3,6-trideoxy-2,3-di¯uoro-a- (31)
and -b-l-talopyranose (32).ÐA solution of 29
(1.09 g, 4.0 mmol) in 1,4-dioxane±H2O±AcOH
(10:1:1, 22 mL) was hydrogenated in the presence of
Pd black under gentle bubbling of H2 for 3.5 h at
room temperature. After ®ltration, the ®ltrate dilu-
ted with CH2Cl2 was washed with aq NaHCO3
(saturated) and water, dried (MgSO4), and con-
centrated to give 30 as a syrup, 0.63 g (86%), TLC
(30:1 CHCl3±EtOAc) Rf 0.3 (cf 29: Rf 0.6). To an
ice-cold solution of 30 (0.62 g, 3.4 mmol) in AcOH
(6.2 mL) were added Ac2O (9.3 mL) and H2SO4
(0.06 mL), and the solution was kept for 4 h at room
temperature. Processing as described for 12 followed
by chromatography (30:1 CHCl3±EtOAc) gave the
as needles (58 mg, 94% based on 23), mp 107±
108 ꢂC, [ꢀ]d
(C=O), 1530 cm
56ꢂ (c 1, CHCl3), IR (KBr): 1720
23
1
(NO2). Anal. Calcd for
C14H16FNO6: C, 53.68; H, 5.15; F, 6.06; N, 4.47.
Found: C, 53.97; H, 5.12; F, 6.09; N, 4.44.
1-O-Acetyl-2,3,6-trideoxy-2-¯uoro-4-O-p-nitro-
benzoyl-a- (26) and -b-l-lyxo-hexopyranose (27).Ð
A solution of 25 (420 mg, 1.3 mmol), Ac2O
(1.0 mL, 10.8 mmol), and H2SO4 (7.2 ꢃL) in dry
MeNO2 (9 mL) was kept for 1 h at room tempera-
ture. After pouring into cold water (13 mL) con-
taining NaHCO3 (3.6 g), the mixture was stirred

228
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
23
ꢀ-l anomer 31 as prisms, 0.44 g (52%) and the ꢁ-l
anomer 32 as plates, 0.17 g (20%). Compound 31,
TLC (30:1 CHCl3±EtOAc) Rf 0.3, mp 143.5-
37 as a pale-yellow syrup, 103 mg (98%), [ꢀ]d
89ꢂ (c 3, CHCl3); H NMR (CDCl3) (only selec-
ted signals): ꢂ 3.47 and 3.46 (each s, 3 H in total,
OMe), 1.37 and 1.28 (each d, 1:2 in strength, 3 H in
total, J5,6 6.5 Hz, Me-5). 19F NMR (CDCl3): ꢂ
196.2 (br dt, 0.33 F, J1,F=J3,F ꢀ10, J2,F 47 Hz),
197.9 (ddd, 0.67 F, J1,F 9.5, J2,F 49.5, J3,F 13 Hz).
Anal. Calcd for C12H21FO5: C, 54.53; H, 8.01; F,
7.19. Found: C, 54.36; H, 7.96; F, 7.47.
Methyl 2,3,6-trideoxy-2-¯uoro-3-iodo-4-O-p-nitro-
benzoyl-a-l-talopyranoside (40).ÐTo an ice-cold
solution of 37 (315 mg, 1.2 mmol) in pyridine
(0.6 mL, 7.3 mmol)±CH2Cl2 (4.4 mL) was added
(CF3SO2)2O (0.3 mL, 2.1 mmol) and the solution
was kept for 1 h in the cold. MeOH (0.4 mL) was
added, and after dilution with CHCl3, the solution
was washed successively with cold aq 20%
KHSO4, aq NaHCO3 (saturated), and water, dried
(Na2SO4), and concentrated to give 38 (442 mg,
94%) as an unstable syrup, TLC (4:1 toluene±
EtOAc) Rf 0.65. A mixture of the syrup (430 mg,
1.1 mmol) and NaI (820 mg, 5.5 mmol) in dry
DMF (4.5 mL) was stirred for 3 h at 90 ꢂC. In TLC
(4:1 toluene±EtOAc), the mixture showed a main
spot at Rf 0.5 (39). After cooling to room tem-
1
144.5 ꢂC, [ꢀ]d
120ꢂ (c 1, CHCl3). Anal. Calcd for
25
C10H14F2O5: C, 47.62; H, 5.60; F, 15.07. Found: C,
47.76; H,5.80; F, 14.79. Compound 32, TLC (30:1
CHCl3±EtOAc) Rf 0.2, mp 108±109 ꢂC, [ꢀ]d
20ꢂ
23
(c 1, CHCl3). Anal. Calcd for C10H14F2O5: C, 47.62;
H, 5.60; F, 15.07. Found: C, 47.43; H, 5.73; F, 14.83.
4-O-Acetyl-2,3,6-trideoxy-2,3-di¯uoro-a-l-talo-
pyranosyl bromide (33).ÐA solution of 31 (320 mg,
1.3 mmol) in 30% HBr in AcOH (3.2 mL) was kept
for 2 h at room temperature. Working up as
described for 28 gave 33 as crystals, 346 mg
(quant). Analytical samples were prepared by
recrystallization (CHCl3±hexane) as prisms, mp
57.5±59 ꢂC, [ꢀ]d
260ꢂ (c 1, CHCl3). Anal. Calcd
19
for C8H11BrF2O3: C, 35.19; H, 4.06; Br, 29.26; F,
13.91. Found: C, 35.46; H, 4.30; Br, 28.99; F,
13.99.
Methyl 3-O-acetyl-2,6-dideoxy-2-¯uoro-a-l-
idopyranoside (35).ÐA solution of 34 [4] (108 mg,
0.35 mmol) in 1,4-dioxane±H2O±AcOH (10:1:1,
2.5 mL) was hydrogenated as described for 11 to
23
give 35 as a pale yellow syrup, 77 mg (quant), [ꢀ]d
104ꢂ (c 1.8, CHCl3). Anal. Calcd for C9H15FO5:
C, 48.65; H, 6.80; F, 8.55. Found: C, 48.69; H,
6.86; F, 8.85.
perature,
p-nitrobenzoyl
chloride
(610 mg,
3.3 mmol) and 4-dimethylaminopyridine (400 mg,
3.3 mmol) were added, and the mixture was stirred
for 2.5 h at room temperature. Water (0.2 mL) was
added, and after dilution with CHCl3, the organic
solution was washed successively with aq 20%
Na2S2O3, aq 20% KHSO4, aq NaHCO3 (satu-
rated), and water, dried (Na2SO4), and con-
centrated. Chromatography (toluene) of the
residue gave 40 as an amorphous solid, 276 mg
Methyl 3-O-acetyl-2,6-dideoxy-2-¯uoro-4-O-tetra-
hydropyran-2-yl-a-l-idopyranoside (36).ÐA solu-
tion of 35 (71 mg, 0.32 mmol), 3,4-dihydro-2H-
pyran (88 ꢃL, 0.96 mmol), and pyridinium p-tolue-
nesulfonate (8 mg, 0.03 mmol) in dry CH2Cl2
(1.5 mL) was kept overnight at room temperature.
After working up as described for 15, the products
were chromatographed (10:1 toluene±EtOAc) to
(58% based on 38), TLC (4:1 toluene±EtOAc) Rf
117ꢂ (c 1.8, CHCl3). 13C NMR
give a diastereoisomeric mixture (1:2 by 19F NMR)
0.7, [ꢀ]d
22
23
of 36 as a syrup, 95 mg (97%), [ꢀ]d
92ꢂ (c 3,
(CDCl3): ꢂ 164.2 (C=O), 150.9, 134.8, 131.5, 123.7
(Ph), 98.1 (d, JC-1,F 32.8 Hz, C-1), 87.7 (d, JC-2,F
183.2 Hz, C-2), 72.8 (C-4), 65.8 (C-5), 55.5 (OCH3),
21.1 (d, JC-3,F 18.6 Hz, C-3), 17.3 (Me-5). Anal.
Calcd for C14H15FINO6: C, 38.29; H, 3.44; F, 4.33;
I, 28.89; N, 3.19. Found: C, 38.44; H, 3.54; F, 4.40;
I, 28.95; N, 3.16.
1-O-Acetyl-2,3,6-trideoxy-2-¯uoro-3-iodo-4-O-p-
nitrobenzoyl-a-l-talopyranose (41).ÐA solution of
40 (170 mg, 0.39 mmol), Ac2O (0.29 mL, 3.1 mmol),
and H2SO4 (7 ꢃL) in dry MeNO2 (3.8 mL) was
kept for 2 h at room temperature. Working up as
described for 26 gave a solid, which was chroma-
CHCl3); 1H NMR (CDCl3) (only selected signals): ꢂ
5.33 and 5.24 (each dt, 2:1 in strength, 1 H in total,
H-3), 4.35 (ddd, 0.67 H, H-2), 3.444 and 3.436 (each
s, 3 H in total, OMe), 2.10 (s, 3 H, Ac), 1.38 and
1.28 (each d, 1:2 in strength, 3 H in total, Me-5); J1,2
3.5, J2,3=J3,4 5.5 Hz. 19F NMR (CDCl3): ꢂ 194.8
(ddd, 0.33 F, J1,F 10.5, J2,F 46.5, J3,F 12.5 Hz),
195.9 (dt, 0.67 F, J1,F=J3,F 11.5, J2,F 47 Hz).
Anal. Calcd for C14H23FO6: C, 54.89; H, 7.57; F,
6.20. Found: C, 55.25; H, 7.69; F, 6.19.
Methyl 2,6-dideoxy-2-¯uoro-4-O-tetrahydro-
pyran-2-yl-a-l-idopyranoside (37).ÐZemplen dea-
cetylation of 36 (122 mg, 0.40 mmol) in MeOH
(0.1 mL) gave, after conventional post-treatment,
tographed (20:1 toluene±EtOAc) to give 41 as an
147ꢂ (c
22
amorphous solid, 130 mg (72%), [ꢀ]d

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
229
2.7, CHCl3). Anal. Calcd for C15H15FINO7: C,
38.56; H, 3.24; F, 4.07; I, 27.16; N, 2.30. Found: C,
38.64; H, 3.49; F, 3.67; I, 27.33; N, 2.52.
2,3,6-Trideoxy-2-¯uoro-3-iodo-4-O-p-nitrobenzoyl-
a-l-talopyranosyl bromide (42).ÐA solution of 41
(200 mg, 0.43 mmol) in 30% HBr in AcOH (2 mL)
was kept for 2 h at room temperature. Working up
as described for 28 gave 42 as an amorphous solid,
(Na2SO4), and concentrated. Chromatography of
the residue (6:1 CHCl3±acetone) gave 3 as a red-
dish-orange solid, 34 mg (69%), TLC (6:1 CHCl3±
acetone) Rf 0.3, [ꢀ]d +176ꢂ (c 0.02, CHCl3); 19F
24
0
NMR (CDCl3): ꢂ 199.6 (ddt; JOH-4 ,F ꢀ9 Hz; the
signals collapsed to ddd on addition of D2O).
.
Anal. Calcd for C28H29FO11 0.5 H2O: C, 59.05; H,
5.31; F,3.34. Found: C, 59.29; H, 5.23; F, 3.39.
7-O-(3-O-Acetyl-2,6-dideoxy-2-¯uoro-4-O-methyl-
a-l-talopyranosyl)daunomycinone (45).ÐA mixture
of daunomycinone (292 mg, 0.73 mmol), yellow
HgO (713 mg, 3.3 mmol), HgBr2 (212 mg,
0.59 mmol), and powdered molecular sieves 3A
(2.84 g) in dry CH2Cl2 (48 mL) was stirred for
30 min at room temperature. A solution of 19
(254 mg, 0.89 mmol) in dry CH2Cl2 (1.9 mL) was
added, and the mixture was re¯uxed for 19 h in the
dark place. In TLC (15:1 CHCl3±acetone), the
mixture showed spots at Rf 0.26 (45, major), 0.18
(trace), 0.13 (slight), and 0.09 (slight). Working up
as described for 43 gave a solid, which was doubly
chromatographed (15:1 CHCl3±acetone) to give 45
as a reddish-orange solid, 220 mg (50%). An ana-
lytical sample was prepared by reprecipitation
209 mg (99%), TLC (20:1 toluene±EtOAc) Rf 0.7
223ꢂ (c 1.5, CHCl3). Anal.
Calcd for C13H12BrFINO5: C, 31.99; H, 2.48; F,
3.89; N, 2.87. Found: C, 31.77; H, 2.64; F, 3.59; N,
2.58.
22
(cf 41: Rf 0.3), [ꢀ]d
7-O-(4-O-Acetyl-2,6-dideoxy-2-¯uoro-3-O-methyl-
a- (43) and -b-l-talopyranosyl)daunomycinone (44).Ð
A mixture of daunomycinone (349 mg, 0.88 mmol),
yellow HgO (1.26 g, 5.8 mmol), HgBr2 (360 mg,
1.0 mmol), and powdered molecular sieves 3A
(3.34 g, activated at 350 ꢂC under a stream of N2)
in dry CH2Cl2 (58 mL) was stirred for 30 min at
room temperature. After 14 (304 mg, 1.1 mmol) in
dry CH2Cl2 (2.4 mL) was added, the mixture was
re¯uxed for 17 h in a dark place. In TLC (10:1
CHCl3±acetone), the mixture showed spots at Rf
0.33 (43, major), 0.22 (daunomycinone, slight), and
0.14 (44, minor) along with several minor spots.
The mixture was ®ltered through a Celite bed, the
bed being washed repeatedly with CHCl3. The ®l-
trate and washings combined were washed with aq
30% KI, aq NaHCO3 (saturated), and water, dried
(Na2SO4), and concentrated. Triplicate chromato-
graphies (10:1 CHCl3±acetone !1:1 CHCl3±EtOAc
!1:1 toluene±EtOAc) of the residue gave 43,
206 mg (38%) and 44, 42 mg (8%) as reddish-
orange solids. Analytical samples were prepared by
reprecipitation from CHCl3±hexane. Compound
from CHCl3±Et2O±hexane, [ꢀ]d +251ꢂ (c, 0.02,
22
CHCl3); 19F NMR (CDCl3): ꢂ 201.3 (ddd). Anal.
Calcd for C30H31FO12: C, 59.80; H, 5.19; F, 3.15.
Found: C, 59.89; H, 5.13; F, 2.98.
7-O-(2,6-Dideoxy-2-¯uoro-4-O-methyl-a-l-talo-
pyranosyl)daunomycinone (4).ÐTo an ice-cold
solution of 45 (115 mg, 0.19 mmol) in oxolane
(7.3 mL) was added aq 1 M NaOH (1.7 mL), and
the mixture was stirred for 1 h in the cold. The
resultant deep-purple solution was neutralized with
aq 1 M HCl, concentrated to a small volume, and
after addition of CHCl3, the solution was washed
with aq 20% NaCl, dried (Na2SO4), and con-
centrated. The residue was passed through a short
column of silica gel with 5:1 CHCl3±acetone giving
4 as a reddish-orange solid, 103 mg (96%). An
analytical sample was prepared by reprecipitation
from CHCl3±Et2O±hexane, TLC (5:1 CHCl3±acet-
43, [ꢀ]d +175ꢂ (c 0.02, CHCl3); 19F NMR
24
(CDCl3): ꢂ 202.2 (ddd). Anal. Calcd for C30H31
.
FO12 0.5 H2O: C, 58.92; H, 5.27; F, 3.11. Found: C,
59.19; H, 5.07; F, 2.70. Compound 44, [ꢀ]d26 +426ꢂ
(c 0.02, CHCl3); 19F NMR (CDCl3): ꢂ 220.9 (ddd).
.
Anal. Calcd for C30H31FO12 0.5 H2O: C, 58.92; H,
22
5.27; F, 3.11. Found: C, 58.62; H, 5.10; F, 2.98.
7-O-(2,6-Dideoxy-2-¯uoro-3-O-methyl-a-l-talo-
pyranosyl)daunomycinone (3).ÐTo an ice-cold
solution of 43 (53 mg, 0.09 mmol) in 2:1 CHCl3±
MeOH (6.3 mL) was added 0.3 M methanolic
NaOH (2.1 mL), and the mixture was stirred for
4 h at 0 ꢂC under the atmosphere of N2. After neu-
tralization of the deep-purple mixture with aq
0.5 M HCl, the mixture was extracted with CHCl3.
The extract was washed with water, dried
one): Rf 0.6, [ꢀ]d +159ꢂ (c, 0.02, CHCl3); 19F
NMR (CDCl3): ꢂ 204.2 (slightly br ddd, which
sharpened on addition of D2O). Anal. Calcd for
.
C28H29FO11 0.5 H2O: C, 59.05; H, 5.31; F, 3.34.
Found: C, 58.96; H, 5.19; F, 3.35.
7-O-(2,6-Dideoxy-2-¯uoro-4-O-methyl-a-l-talo-
pyranosyl)adriamycinone (5).ÐTo a solution of 4
(83 mg, 0.15 mmol) and HC(OMe)3 (0.11 mL,
1.0 mmol) in dry 2:3 MeOH±1,4-dioxane (5 mL)
was added Br2 (35 mg, 0.22 mmol) in CH2Cl2

230
Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
23
(0.35 mL), and the solution was kept for 0.5 h at
0 ꢂC, and then for 3 h at room temperature. TLC
(2:1 benzene±acetone) of the solution showed a
main spot at Rf 0.35. Addition of diisopropyl ether
followed by hexane gave a precipitate, which was
collected and washed with hexane to give a red
solid (mainly the 14-bromo-13-dimethylacetal
derivative). A suspension of the solid in acetone
(15 mL) was shaken for 1.5 h at room temperature,
and concentrated to give a dark-red solid (mainly
the deacetalated 14-bromo derivative). A mixture
of the solid and HCO2Na (169 mg, 2.5 mmol) in 4:1
acetone±H2O (10 mL) was stirred vigorously for
15 h at room temperature, whereupon, in TLC (2:1
benzene±acetone), two spots of Rf 0.28 (the 14-O-
formyl derivative of 5) and 0.15 (5) appeared. After
concentration to a small volume followed by addi-
tion of water, the products were extracted with
CHCl3. The organic solution was washed with
water, dried (Na2SO4), and concentrated. A sus-
pension of the dark-red solid (83 mg) in 4:4:1
CHCl3±MeOH±aq 1 M NH3 (9 mL) was shaken for
45 min at 0 ꢂC, when a substance with Rf 0.28 dis-
appeared and 5 became the major one. After dilu-
tion with water, products were extracted with
CHCl3, and the solution was washed with aq
0.05 M HCl and aq 20% NaCl, dried (Na2SO4),
and concentrated. The residue was chromato-
graphed on a short column with 3:2 CHCl3±acetone
to give 5 as a red solid, 64 mg (75%). An analytical
sample was prepared by reprecipitation from
CHCl3±MeOH±Et2O±hexane, [ꢀ]d23 +155ꢂ (c 0.02,
CHCl3); 19F NMR (CDCl3): ꢂ 204.0 (ddd). Anal.
Compound 47, [ꢀ]d +601ꢂ (c 0.1, CHCl3). 19F
NMR (CDCl3): ꢂ 205.4 (dddd). Anal. Calcd for
.
C34H30FNO13 H2O: C, 58.54; H, 4.62; F, 2.72; N,
2.01. Found: C, 58.84; H, 4.49; F, 2.92; N, 1.87.
7-O-(2,3,6-Trideoxy-2-¯uoro-a-l-lyxo-hexopyrano-
syl)daunomycinone (6).ÐA mixture of 46 (15 mg,
0.022 mmol) in 0.2 M NaOH in oxolane±H2O (4:1,
1.9 mL) was stirred for 15 h at 0 ꢂC. Conventional
work-up as described for 3 gave a solid, which was
chromatographed (15:1 CHCl3±acetone) and pur-
i®ed by reprecipitation from CHCl3±Et2O±hexane
gave 6 as a red solid, 10.1 mg (76%), [ꢀ]d +72ꢂ
(c 0.06, CHCl3). 19F NMR (CDCl3): ꢂ 180.8
0
(ddddd; JOH-4 ,F 11 Hz). Anal. Calcd for
.
C27H27FO10 0.5 H2O: C, 60.11; H, 5.23; F, 3.52.
Found: C, 60.23; H, 5.18; F, 3.21.
23
7-O-(4-O-Acetyl-2,3,6-trideoxy-2,3-di¯uoro-a- (48)
and -b-l-talopyranosyl)daunomycinone (49).ÐA
mixture of 33 (296 mg, 1.1 mmol), daunomycinone
(424 mg, 1.1 mmol), yellow HgO (693 mg,
3.2 mmol), HgBr2 (194 mg, 0.54 mmol), and pow-
dered molecular sieves 3A (2.31 g) in dry CH2Cl2
(71 mL) was re¯uxed under stirring for 19 h in a
dark place. Additional yellow HgO (700 mg,
3.2 mmol), HgBr2 (145 mg, 0.40 mmol), and pow-
dered molecular sieves 3A (567 mg) were added
and the re¯uxing was continued for further 21 h.
Post-treatment as described for 43 gave a red solid,
which showed, in TLC (6:1 toluene±acetone), three
spots at Rf 0.15 (daunomycinone), 0.25 (49), and
0.4 (48). Chromatography (6:1 toluene±acetone) of
the solid gave 48, 175 mg (28%) and 49, 99 mg
(16%). An analytical sample of 48 was prepared by
recrystallization from CHCl3±acetone±Et2O as red
needles, and the sample of 49 by reprecipitation
from CHCl3±Et2O as a red solid. Compound 48,
.
Calcd for C28H29FO12 0.25 H2O: C, 57.88; H, 5.12;
F, 3.27. Found: C, 57.91; H, 5.19; F, 2.93.
7-O-(2,3,6-Trideoxy-2-¯uoro-4-O-p-nitrobenzoyl-
a- (46) and -b-l-lyxo-hexopyranosyl)daunomycinone
(47). A mixture of 28 (349 mg, 0.97 mmol), dauno-
mycinone (298 mg, 0.73 mmol), yellow HgO
(729 mg, 3.37 mmol), HgBr2 (216 mg, 0.60 mmol),
and powdered molecular sieves 3A (1.2 g) in dry
CH2Cl2 (65 mL) was re¯uxed under stirring for
17 h in a dark place. Post-treatment as described
for 43 gave a residue, which showed, in TLC (30:1
CHCl3±acetone), three spots at Rf 0.03 (daunomy-
cinone), 0.15 (47), and 0.2 (46). Chromatography
(10:1 CHCl3±EtOAc) of the residue gave 46,
mp 222.5±225 ꢂC, [ꢀ]d +85ꢂ (c 0.02, CHCl3). 19F
NMR (CDCl3): ꢂ 206.1 (br ddq, 1 F, J1 ,F-3 =J2 ,F-
24
0
0
0
0
0
0
0
0
0
0
0
3 =J4 ,F-3 ꢀ6, J3 ,F-3 43, JF-2 ,F-3 14 Hz F-3 ), 203.9
(dddd, 1 F, F-20). Anal. Calcd for C29H28F2O11 0.5
.
H2O: C, 58.10; H, 4.88; F, 6.34. Found: C, 58.16; H,
4.71; F, 6.24. Compound 49, [ꢀ]d +431ꢂ (c 0.02,
22
CHCl3), 19F NMR (CDCl3): ꢂ 221.4 (br dddd, 1 F;
JF-2 ,F-3 13Hz, F-20), 202.4 (br dddd, 1 F, J2 ,F-3
0
0
0
0
7.5, J3 ,F-3 43, J4 ,F-3 5, JF-2 ,F-3 13Hz, F-30). Anal.
0
0
0
0
0
0
.
Calcd for C29H28F2O11 0.5 H2O: C, 58.10; H, 4.88; F,
6.34. Found: C, 58.28; H, 5.03; F, 6.42.
217 mg (43%) and 47, 207 mg (41%) as red solids.
119ꢂ (c 0.1, CHCl3). 19F
NMR (CDCl3): ꢂ 184.3 (ddt). Anal. Calcd for
.
C34H30FNO13 H2O: C, 58.54; H, 4.62; F, 2.72; N,
2.01. Found: C, 58.33; H, 4.43; F, 3.05; N, 1.76.
7-O-(2,3,6-Trideoxy-2,3-di¯uoro-a-l-talopyrano-
syl)daunomycinone (7).ÐTo a cold solution of 48
(30 mg, 0.05 mmol) in 3:2 CHCl3±MeOH (1.2 mL)
was added 0.3 M NaOH in MeOH (1.5 mL) and
the mixture was stirred for 3 h at 5 ꢂC under an
23
Compound 46, [ꢀ]d

Y. Takagi et al./Carbohydrate Research 307 (1998) 217±232
231
atmosphere of N2. Working up as described for 3
gave a red solid, which was chromatographed (7:1
CHCl3±acetone) to give 7, 22 mg (78%), [ꢀ]d
+111ꢂ (c 0.02, CHCl3). 19F NMR (CDCl3): ꢂ
Ms. Chisato Nosaka, and Keiko Komuro of Insti-
tute of Microbial Chemistry (IMC) for antitumor
assay for Table 5, and to Ms. Hiroko Hino of IMC
for elemental analysis.
24
0
0
0
0
0
0
205.2 (br ddq, 1 F, J1 ,F-3 =J2 ,F-3 =J4 ,F-3 6,
J3 ,F-3 43.5, JF-2 ,F-3 16 Hz, F-30), 200.8 (br dddt,
1 F, JOH-4 ,F-2 9.5, JF-2 ,F-3 16 Hz, F-20). Anal.
0
0
0
0
References
0
0
0
0
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Calcd for C27H26F2O10 0.25 H2O: C, 58.64; H,
4.83; F, 6.87. Found: C, 58.72; H, 4.82; F, 7.16.
7-O-(2,3,6-Trideoxy-2-¯uoro-3-iodo-4-O-p-nitro-
benzoyl-a- (50) and -b-l-talopyranosyl)dauno-
mycinone (51).ÐA mixture of 42 (209 mg,
0.43 mmol), daunomycinone (142 mg, 0.36 mmol),
yellow HgO (348 mg, 1.6 mmol), HgBr2 (103 mg,
0.29 mmol), and powdered molecular sieves 3A
(568 mg) in dry CH2Cl2 (29 mL) was re¯uxed for
14 h in the dark place. Additional yellow HgO
(348 mg, 1.6 mmol) and HgBr2 (103 mg, 0.29 mmol)
were added and the re¯uxing was continued for
further 24 h. Working up as described for 43 gave a
red solid, which was chromatographed (30:1
CHCl3±acetone) to give 50, 63 mg (22%), Rf 0.35
in TLC (30:1 CHCl3±acetone), and 51, 178 mg
(62%), Rf 0.25. Compound 50, [ꢀ]d +20ꢂ (c 0.1,
22
CHCl3). 19F NMR (CDCl3): ꢂ 183.4 (ddd). Anal.
.
Calcd for C34H29FINO13 H2O: C, 49.59; H, 3.79;
F, 2.31; I, 15.41; N, 1.70. Found: C, 49.75; H, 3.73;
22
F, 2.66; I, 15.63; N, 1.78. Compound 51, [ꢀ]d
+427ꢂ (c 0.1, CHCl3). 19F NMR (CDCl3): ꢂ
.
203.7 (ddd). Anal. Calcd for C34H29FINO13 1.5
H2O: C, 49.05; H, 3.87; F, 2.28; I, 15.24; N, 1.68.
Found: C, 48.96; H, 3.62; F, 2.54; I, 15.18; N, 1.82.
7-O-(2,3,6-Trideoxy-2-¯uoro-3-iodo-a-l-talopyr-
anosyl)daunomycinone (8).ÐA mixture of 50
(33 mg, 0.04 mmol) in 0.1 M NaOH in oxolane±
H2O (1:1, 3.3 mL) was stirred for 19 h at 0 ꢂC.
Working up as described for 3 gave a red solid,
which was chromatographed (20:1 CHCl3±acetone)
and reprecipitated from CHCl3±Et2O±hexane to
give 8, 18 mg (68%), [ꢀ]d +203ꢂ (c 0.1, CHCl3).
23
19F NMR (CDCl3): ꢂ 180.6 (apparently ddt; JOH-
.
9 Hz). Anal. Calcd for C27H26FIO10 H2O: C,
40,F
48.09; H, 4.18; F, 2.82; I, 18.82. Found: C, 48.05;
H, 4.21; F. 3.18; I, 18.49.
Acknowledgements
The authors are grateful to the Pharmaceutical
Research Center of Meiji Seika Co., Ltd. for car-
rying out the bioassay for Table 6. We also express
deep thanks to Dr. Tomio Takeuchi (the director),
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