Anthracycline glycosides of 2,6-dideoxy-2-fluoro-α-l-talopyranose

Article abstract of DOI:10.1016/j.carres.2006.08.024

The methyl β-glycoside of the title sugar, obtained from 2-deoxy-2-fluoro-β-d-glucopyranose tetraacetate by a sequence with detailed characterization of all intermediates, was converted by acetolysis-bromination into 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-α

Full text of DOI:10.1016/j.carres.2006.08.024

Carbohydrate Research 341 (2006) 2631–2640
Anthracycline glycosides of 2,6-dideoxy-2-fluoro-a-L-talopyranose
Derek Hortona,* and Anakshi Khareb
aDepartment of Chemistry, American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, USA
bDepartment of Chemistry, Lucknow University, Lucknow 226 007, India
Received 3 July 2006; received in revised form 28 August 2006; accepted 29 August 2006
Available online 4 October 2006
Abstract—The methyl b-glycoside of the title sugar, obtained from 2-deoxy-2-fluoro-b-D-glucopyranose tetraacetate by a sequence
with detailed characterization of all intermediates, was converted by acetolysis–bromination into 3,4-di-O-acetyl-2,6-dideoxy-2-flu-
oro-a-L-talopyranosyl bromide, coupling of which with (7S,9S)-4-demethoxydaunomycinone afforded the 3,4-diacetate of 4-
demethoxy-9-O-(2,6-dideoxy-2-fluoro-a-L-talopyranosyl)daunomycinone (19). The antitumor-active 19 was converted by way of
its 14-bromo derivative into the 14-hydroxy analogue, the antitumor-active 4-demethoxyadriamycinone glycoside 21.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Fluoro sugars; Anthracycline glycosides; Glycosylation; Adriamycin analogues
1. Introduction
porating attributes favorable to high activity, a compo-
nent aglycon lacking the 4-methoxy group would be
easier to synthesize, as there would be no requirement
for a regiospecific step to correctly orient the methoxy
group. We have already demonstrated12,14 that a chiral
glycon can be used as a resolving agent in coupling to
synthetic, racemic 4-demethoxydaunomycinone16 to fur-
nish separable, enantiomerically pure diastereomers, one
of which has the stereochemistry of the natural aglycon.
Here we report the glycosidic attachment to the 9-
position of (+)-(7S,9S)-4-demethoxydaunomycinone
(idarubicinone)17 of a 2,6-dideoxy-2-fluoro-a-L-talo-
pyranosyl group, to afford a daunorubicin analogue
(19), and its subsequent conversion via hydroxylation
at the 14-position into the corresponding doxorubicin
analogue 21. Compounds 19 and 21 are 4-demethoxy-
30-hydroxy-30-deamino-20axial-fluoro analogues of the
parent natural antibiotics. Synthesis of the fluoro sugar
glycon follows essentially the steps of a concise synthesis
earlier reported,18 but gives detailed characterization of
all intermediates in both anomeric forms.
Analogues of the natural anthracycline antibiotics dau-
norubicin and doxorubicin having diminished toxicity
and/or enhanced antitumor activity have been targets
of synthesis in this laboratory1 and others.2–7 Replace-
ment of the 30-amino group by hydroxyl via semisynthe-
sis through appropriate glycosylation of dauno-
mycinone has yielded products of lower toxicity,8 and
hydroxylation of the aglycon at the 14-position has per-
mitted conversion into doxorubicin analogues of en-
hanced antitumor activity.9 Introduction of an axially
oriented halogen atom at the 2-position of the sugar
has afforded products demonstrating higher activity,10,11
the synthesis of which has been achieved via glycal inter-
mediates for the 20-chloro,11 20-bromo-,11 and 20-iodo10
structures; alternative strategy has been required to
obtain the 20-fluoro compounds.12,13
Although daunomycinone and adriamycinone, the
aglycons of the natural antibiotics, possess a methoxy
group at the 4-position of the aromatic ring, this group
does not appear to play any essential role in the biolog-
ical activity of their 7-glycosylated derivatives.12,14,15
Envisaging the target of a fully synthetic analogue incor-
2. Results and discussion
The previous report18 described the synthesis of methyl
2,6-dideoxy-2-fluoro-b-L-talopyranoside (15) in 27%
*
Corresponding author. Tel.: +1 202 885 1767; fax: +1 202 885
1095; e-mail: carbchm@american.edu
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.08.024

2632
D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
net yield by a nine-step sequence starting from 2-deoxy-
2-fluoro-b-D-glucopyranose tetraacetate (1), a com-
pound accessible19 in two steps from D-mannose. Com-
pound 15, the glycon precursor required for the target
anthracycline glycosides, was prepared essentially by
the route previously used,18 but in the present work
the anomeric mixtures obtained in the intermediate steps
were resolved and each of the products was character-
ized in detail (Scheme 1).
Acid-catalyzed methanolysis of 1, followed by benz-
ylidenation of the resultant methyl 2-deoxy-2-fluoro-
a,b-glucopyranoside (2), afforded 90% of a 2:3 mixture
of methyl 4,6-O-benzylidene-2-deoxy-a- and b-D-gluco-
pyranosides (3 and 4), which were separated chromato-
graphically and each obtained crystalline. The
levorotatory b anomer was characterized by detailed
1H, 13C, and 19F NMR spectroscopy; the dextrorotatory
a anomer had properties concordant with those already
reported.18
now obtained crystalline in 88% yield. Catalytic trans-
esterification of 14 then afforded methyl 2,6-dideoxy-2-
fluoro-b-L-talopyranoside18 (15), which was subjected
to acid-catalyzed acetolysis, yielding 89% of crystalline
1,3,4-tetra-O-acetyl-2,6-dideoxy-2-fluoro-a-L-talopyran-
ose (16), along with a minor proportion of its apparent
anomer. The a-anomeric configuration of 16, antici-
pated from consideration of the anomeric effect, was
supported by its strong levorotation and from NMR
data; in particular, the very small (ꢀ1 Hz) J1,2 coupling
constant, indicative of the diequatorial orientation of H-
1 and H-2.
Compound 16, the glycon precursor for the anthracy-
cline glycosides reported here, was earlier prepared by
Tsuchiya and co-workers13 by a sequence starting from
L-fucose, but the present approach, based on the general
strategy of our synthesis20 of daunosamine from D-man-
nose, has the advantage of a high net yield from the
inexpensive sugar precursor D-mannose.
Oxidation of the mixture of anomers 3 and 4 with
pyridinium dichromate gave 96% of the corresponding
glycos-3-ulosides 5 and 6, which were separated chro-
matographically to give the individual anomers, again
both crystalline and characterized by detailed NMR
studies; the a anomer was described in the earlier re-
port.18 Borohydride reduction of the mixed glycos-3-
ulosides 5 and 6 proceeded essentially stereospecifically
by predictable ‘topside’ attack to give 83% of the corre-
sponding mixed allosides 7 and 8, which on chromato-
graphic resolution furnished the less-polar, levo-
rotatory b anomer 8 and the earlier reported18 dextroro-
tatory a anomer 7, both crystalline. Conventional acet-
ylation of the individual anomers 7 and 8 gave the
corresponding 3-acetates 9 and 10.
Treatment of a alloside 9 with N-bromosuccinimide in
boiling carbon tetrachloride afforded 88% of the crystal-
line, dextrorotatory methyl 3-O-acetyl-4-O-benzoyl-
6-bromo-2,6-dideoxy-2-fluoro-a-D-allopyranoside (11)
identical with the product obtained12 by similar treat-
ment of the mixed anomers 9 and 10, while b alloside
10 underwent similar conversion into the corresponding
6-bromo 4-benzoate 12, obtained, however, in substan-
tially lower yield as an amorphous, levorotatory
product.
Dehydrobromination of the pure a 6-bromo com-
pound 11 by the action of 1,8-diaza-7-bicyclo-
[5.4.0]undecene (DBU) in boiling benzene led in 93%
yield to 5-enopyranoside 13, obtained as a low-melting,
dextrorotatory solid having physical constants concor-
dant with those earlier reported.18 Hydrogenation of
13 over palladium–barium sulfate proceeded stereospe-
cifically by ‘topside’ attack on the face of the ring oppo-
site to the other four ring substituents to effect net
conversion of the D-sugar precursor to the L-sugar prod-
uct, methyl 3-O-acetyl-4-O-benzoyl-2-fluoro-b-L-talo-
pyranoside (14), previously18 described as an oil and
Triacetate 16 was converted by the action of titanium
tetrabromide into the corresponding glycosyl bromide
17, obtained as an oil in 82% yield, and allowed to react
without
delay
with
(+)-(7S,9S)-4-demethoxy-
daunomycinone (idarubicinone)17,21 in dichloromethane
solution in the presence of mercuric bromide, yellow
mercuric oxide, and molecular sieves. Chromatographic
resolution of the product mixture afforded orange crys-
tals of the acetylated target glycoside, 4-demethoxy-7-O-
(3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-a-L-talopyrano-
syl)daunomycinone (18), in 47% yield, and whose
detailed 1H, 13C, and 19F NMR data supported the
assigned structure and a anomeric configuration (J1,2
1.2 Hz).
O-Deacetylation of 18 was effected with dilute aque-
ous sodium hydroxide at 0 ꢁC to give a 78% yield of
crystalline 4-demethoxy-(7-O-2,6-dideoxy-2-fluoro-a-L-
talopyranosyl)daunomycinone (19). Monobromination
of 19 at the 14-position was performed in methanol–
1,4-dioxane solution at 0 ꢁC by careful addition of a
small excess of bromine in chloroform solution and
TLC monitoring. The resultant 14-bromo derivative
20, obtained in 52% yield, was finally transformed
into the 14-hydroxy analogue, 4-demethoxy-(7-O-2,6-
dideoxy-2-fluoro-a-L-talopyranosyl)adriamycinone
(21), by reaction with warm aqueous dimethyl sulfox-
ide and TLC monitoring, followed by preparative
TLC. The anthracycline glycosides 18–21 were all
characterized by high-resolution mass spectrometry
together with 500-MHz 1H NMR, along with 13C
and 19F NMR data. The patent literature12,22 cites
the final target, compound 21; CAS Registry No.
125555-22-8.
The four anthracycline glycosides 18–21 were evalu-
ated in vitro, along with adriamycin, for antitumor
activity against five human-tumor cell-lines, including
lung, colon, and breast carcinoma, melanoma, and

D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
2633
O
Ph
CH2OH
CH2OAc
O
O
F
a
b
O
O
HO
HO
AcO
AcO
HO
OAc
OMe
OMe
F
F
α anomer
β anomer
3
1
2
4
c
Ph
O
O
Ph
O
O
Ph
O
O
O
O
O
d
e
OMe
OMe
OMe
F
F
F
O
HO
AcO
α anomer
β anomer
α anomer
α anomer
5
7
8
9
β anomer
β anomer
6
10
f
O
CH2Br
O
F
CH3
BzO
O
OMe
h
g
OMe
OMe
F
BzO
AcO
OAc
BzO
F
AcO
α anomer
β anomer
11
14
13
12
i
Br
OAc
CH3
CH3
HO
CH3
k
O
O
OMe
O
j
OAc
OAc
AcO
F
F
AcO
F
OH
15
16
17
l
O
O
OH
O
O
O
OH
O
OH
OH
OH
Br
CH3
OH
OH
OH
OH
OH
m
O
n
O
O
O
O
O
CH3
CH3
CH3
O
O
O
OH
OR
F
HO
F
OH
RO
F
HO
18 R = Ac
R = OH
20
21
19
Scheme 1. Reagents: (a) MeOH, H+; (b) PhCH(OMe)2, TsOH; (c) pyridinium dichromate; (d) NaBH4; (e) Ac2O, DMAP; (f) NBS; (g) DBU; (h) Pd,
H2; (i) NaOMe; (j) Ac2O, H2SO4; (k) TiBr4; (l) demethoxydaunomycinone, Hg salts; (m) Br2; (n) Me2SO, H2O.
Glioblastoma multiforme CNS tumor. All showed
activity, and details will be reported elsewhere. It is note-
worthy that computational studies on DNA binding23
suggest that removal of the 4-methoxy group from the
aglycon of anthracycline antibiotics correlates with
increase in antitumor potency and selectivity.
3. Experimental
3.1. General methods
Melting points were determined in open glass capillaries
with a Thomas–Hoover apparatus and are uncorrected.

2634
D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
Optical rotations were measured with a Perkin–Elmer
model 141 polarimeter. 1H NMR and 13C NMR spectra
were recorded with Bruker AM-250, AM-300, or
AM-500 spectrometers, and chemical shifts refer to an
internal standard of Me4Si (d = 0.00). 19F spectra were
recorded at 235 MHz with a Bruker AM-250 instru-
ment. Assignments were supported for all compounds
J2,3 8.5 Hz, H-2), 4.00 (dt, 1H, J3,F 15.4, J3,4 9.2 Hz,
H-3), 3.77 (t, 1H, J5,6a 9.4 Hz, H-6a), 3.59 (s, 3H,
OCH3), 3.53 (t, 1H, J4,5 9.4 Hz, H-4), 3.45 (dt, 1H,
J5,6e 4.9 Hz, H-5), 2.70 (d, 1H, J3,OH 2.7 Hz, OH, D2O
exchangeable); 13C NMR (62.89 MHz, CDCl3): d
136.71, 129.37, 128.36, 126.23 (Ar–C), 101.93 (benzyl-
idene-C), 101.89 (J1,F 23.71 Hz, C-1), 92.55 (J2,F
186.55 Hz, C-2), 79.93 (J4,F 8.99 Hz, C-4), 72.31 (J3,F
19.62 Hz, C-3), 68.48 (C-6), 66.03 (C-5), 57.40 (C–
OMe); 19F NMR d ꢁ201.459 (ddd). Anal. Calcd for
C14H17FO5 (284.30): C, 59.14; H, 6.04. Found: C,
58.30, H, 5.98.
1
by H–1H COSY experiments before and after D2O ex-
change as well as by 1H–13C HETCOR, and also by 19
F
decoupled spectra for compounds 18, 19, and 20. TLC
was performed on precoated glass plates (0.25 mm) of
Silica Gel 60 F-254 (E. Merck); components were de-
tected by spraying the plates with 10% H2SO4 and sub-
sequent heating. Column chromatography was
performed with Silica Gel 60 (230–400 mesh, E. Merck).
Solvents were dried and redistilled just prior to use.
Mass spectra (FAB) were recorded at The Ohio State
University Chemical Instrument Center with Kratos
MS-30 and VG-70 250S mass spectrometers; peak inten-
sities are recorded as percent of the base peak. IR spec-
tra were recorded on a Perkin–Elmer 1600 series FT-IR
spectrophotometer. Elemental analyses were determined
by Atlantic Microlab, Inc., Norcross Atlanta, Georgia.
3.4. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-a-D-
glucopyranoside (3)
This product was obtained by flash chromatography of
the anomeric mixture and was crystallized from ether;
20
yield 0.80 g, mp 156–157 ꢁC, ½aꢂD +105.3 (c 0.7, CHCl3);
20
(lit.24 mp 163–164 ꢁC, ½aꢂD +116.3 (CHCl3)).
3.5. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-a,b-D-
ribo-hexopyranosid-3-ulose (5 and 6)
3.2. Methyl 2-deoxy-2-fluoro-a,b-D-glucopyranoside (2)
To a suspension of the mixture of 3 and 4 (3.32 g,
11.67 mmol) in dry CH2Cl2 (150 mL) was added pyridi-
nium dichromate (7.90 g, 20.19 mmol), pyridinium
Prepared as described earlier18 by acid-catalyzed meth-
anolysis of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-b-D-
glucopyranose and obtained as an oil in 95% yield.
´
˚
trifluoroacetate (0.90 g, 4.67 mmol), and crushed 3A
molecular sieves (11.68 g, dried overnight at 160 ꢁC in
vacuo). After 4 h, TLC (2:1 hexane–EtOAc) indicated
no starting material. The mixture was diluted with ether
(250 mL) and filtered through a sintered-glass funnel
containing a small pad of silica gel with 10% MgSO4.
Evaporation of the solvent gave the product as a white
solid; yield 3.30 g (96%), which by TLC and NMR
was an anomeric mixture. Analytical samples of the a
and b glycosiduloses were obtained by flash chromato-
graphy with 1:1 hexane–EtOAc.
3.3. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-a- and b-
D-glucopyranosides (3 and 4)
a,a-Dimethoxytoluene (2.78 mL, 18.5 mmol) and p-tol-
uenesulfonic acid (26 mg) were added to a suspension
of the anomeric mixture 2 (2.27 g, 11.6 mmol) in dry
MeCN (50 mL), and the mixture was stirred under
argon at room temperature, as previously described.18
After 3 h, TLC (1:1 hexane–EtOAc) showed the disap-
pearance of 2 and a double spot for the products. The
solvent was removed at 40 ꢁC to yield a light-yellow
oil, which was dissolved in boiling ether and the result-
ing solution cooled to ꢁ20 ꢁC. This gave a white solid,
which by TLC and NMR was an anomeric mixture
(40% a, 60% b), yield 2.96 g (90%). This was subjected
to flash chromatography with hexane–EtOAc with
increasing proportions of EtOAc. The first few fractions
gave methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-b-D-
glucopyranoside (4), which was crystallized from hex-
3.6. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-a-D-ribo-
hexopyranosid-3-ulose (5)
Compound 5 had a mp of 209–210 ꢁC (with decomposi-
20
tion), ½aꢂD +122.6 (c 0.47, CHCl3), [lit.18 mp 216–217 ꢁC,
20
½aꢂD +114 (c 1, CHCl3)]; mmax 1752 cmꢁ1 (CO); MS: m/z
283 (73, M+1), 251 (3, M+1ꢁMeOH), 205 (3,
1
M+ꢁC6H5); H NMR (300 MHz, CDCl3): d 7.52–7.48
(m, 2H, aryl), 7.38–7.34 (m, 3H, Ar), 5.55 (s, 1H, H-benz-
ylidene), 5.31 (d, 1H, J1,2 4.4 Hz, H-1), 5.02 (ddd, 1H, J2,F
47.0, J2,4 1.3 Hz, H-2), 4.42 (dd, 1H, J6e,6a 10.1, J5,6e
4.5 Hz, H-6e), 4.24 (dd, 1H, J4,5 9.7, J4,F 0.95 Hz, H-
4), 4.11 (dt, 1H, J5,6a 10.0 Hz, H-5), 3.92 (t, 1H, H-
6a), 3.50 (s, 3H, OCH3); 13C NMR (75.469 MHz,
CDCl3): d 192.42 (d, J3,F 16.1 Hz, C-3), 136.12,
129.44, 128.32, 126.39 (Ar–C), 102.1 (benzylidene-C),
101.03 (d, J1,F 19.59 Hz, C-1), 88.6 (d, J2,F 207.32 Hz,
20
ane–EtOAc; yield 1.20 g, mp 184–186 ꢁC, ½aꢂD ꢁ53.3
(c 1.1, CHCl3); MS: m/z 285 (100, M+1), 253 (2.7,
M+1ꢁMeOH), 207 (2.9, M+ꢁC6H5), 179 (4.4,
M+1ꢁC6H5CHO); 1H NMR (300 MHz, CDCl3): d
7.50–7.35 (m, 5H, aryl), 5.53 (s, 1H, H-benzylidene),
4.51 (dd, 1H, J1,2 7.5, J1,F 3.8 Hz, H-1), 4.37 (dd, 1H,
J6e,6a 10.3, J5,6e 4.9 Hz, H-6e), 4.25 (dt, 1H, J2,F 50.03,

D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
2635
C-2), 81.7 (C-4), 69.31 (C-6), 65.14 (C-5), 55.91 (C–
OMe); 19F NMR: d ꢁ208.069 (d). Anal. Calcd for
C14H15FO5 (282.28): C, 59.56; H, 5.37, Found: C,
59.34; H, 5.31.
(ddd, 1H, J2,F 46.3, J1,2 7.79, J2,3 2.7 Hz, H-2), 4.04
(dt, 1H, J4,5 9.6, J5,6a 10.3 Hz, H-5), 3.74 (t, 1H, H-
6a), 3.59 (s, 3H, OCH3), 3.55 (dd, 1H, H-4); 13C
NMR (62.896 MHz, CDCl3): d 136.79, 129.37, 128.39,
126.20 (Ar–C), 101.99 (benzylidene-C), 99.71 (d, J1,F
24.15 Hz, C-1), 89.06 (d, J2,F 190.63 Hz, C-2), 78.04
(d, J4,F 6.35 Hz, C-4), 69.0 (C-6), 68.11 (d, J3,4
17.36 Hz, C-3), 62.99 (C-5), 57.46 (C–OMe); 19F
NMR: d ꢁ204.37 (dd). Anal. Calcd for C14H17FO5
(284.30): C, 59.14; H, 6.04. Found: C, 59.17; H, 6.05.
The more-polar product 7 was eluted with 40%
EtOAc–hexane; yield 0.462 g (62%). It was crystallized
from EtOAc and hexane as needles; mp 116 ꢁC. 1H
NMR confirmed it to be methyl 4,6-O-benzylidene-2-
3.7. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-b-D-ribo-
hexopyranosid-3-ulose (6)
This compound had a mp of 225–230 ꢁC (with decom-
20
position), ½aꢂD ꢁ53.5 (c 0.6, CHCl3); mmax 1742 cmꢁ1
1
(CO); MS: 283 (34, M+1), 205 (5.1, M+ꢁC6H5); H
NMR (300 MHz, CDCl3): d 7.52–7.48 (m, 2H, Ar),
7.39–7.34 (m, 3H, Ar), 5.57 (s, 1H, Ph–CH), 4.79
(ddd, 1H, J2,F 47.05, J1,2 7.5, J2,4 1.56 Hz, H-2), 4.67
(dd, 1H, J1,F 5.1 Hz, H-1), 4.52 (dd, 1H, J6e,6a 10.45,
J5,6e 4.9 Hz, H-6e), 4.30 (dd, 1H, J4,5 9.9, J4,F 1.09 Hz,
H-4), 3.91 (t, 1H, J5,6a 9.9 Hz, H-6a), 3.63 (dt, 1H, H-
5), 3.65 (s, 3H, OCH3); 13C NMR (75.469 MHz,
CDCl3): d 192.71 (d, J3,F 16.3 Hz, C-3), 135.98,
129.51, 128.37, 126.34 (Ar–C), 104.16 (d, J1,F 24.1 Hz,
C-1), 101.97 (benzylidene-C), 91.75 (d, J2,F 201.7 Hz,
C-2), 81.56 (C-4), 69.04 (C-6), 66.68 (C-5), 57.88 (C–
OMe); 19F NMR: d ꢁ208.164 (dd). Anal. Calcd for
C14H15FO5 (282.28): C, 59.56; H, 5.37, Found: C,
59.50; H, 5.29.
20
deoxy-2-fluoro-a-D-allopyranoside (7), ½aꢂD +129.3
(c 1.29, CHCl3) (lit.18 mp 109–110 ꢁC, [a]D +126
(CHCl3)); MS: m/z: 285 (100, M+1), 253 (31,
M+1ꢁMeOH), 207 (5.2, M+ꢁC6H5), 179 (5.9,
M+1ꢁC6H5CHO); 1H NMR (250 MHz, CDCl3): d
7.53–7.34 (m, 5H, Ar), 5.56 (s, 1H, H-benzylidene),
4.95 (d, 1H, J1,2 3.6 Hz, H-1), 4.51 (dt, J2,F 45.28, J2,3
3.4 Hz, H-2), 4.51 (br m, 1H, H-3), 4.39 (dd, 1H, J6e,6a
10.3, J5,6e 5.0 Hz, H-6e), 4.15 (dt, 1H, J5,6a 10.0, J4,5
9.9 Hz, H-5), 3.74 (t, 1H, H-6a), 3.5 (s, 3H, OCH3),
3.48 (br d, 1H, H-4), 3.12 (d, 1H, J 7.14 Hz, OH, D2O
exchangeable); 13C NMR (62.896 MHz, CDCl3): d
136.98, 129.21, 128.28, 126.30 (Ar–C), 102.09 (benzyl-
idene-C), 98.40 (d, J1,F 22.32 Hz, C-1), 85.49 (d, J2,F
195.48 Hz, C-2), 78.07 (d, J4,F 7.17 Hz, C-4), 69.00
(C-6), 68.38 (d, J3,F 18.11 Hz, C-3), 57.69 (C-5), 56.28
(C–OMe); 19F NMR: d ꢁ202.98 (dd). Anal. Calcd for
C14H17FO5 (284.30): C, 59.14; H, 6.04. Found: C,
59.24; H, 6.08.
3.8. Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-a- and
b-D-allopyranoside (7 and 8)
A solution of 5 and 6 (0.90 g, 3.17 mmol) in EtOH
(50 mL) was cooled to ꢁ20 ꢁC and NaBH4 (0.362 g,
9.57 mmol) was added. It was stirred at this temperature
for 1 h and then allowed to warm slowly to room tem-
perature, at which point it became homogeneous. The
excess of NaBH4 was decomposed by dropwise addition
of 1.0 M HOAc until effervescence ceased. The solvent
was removed in vacuo, and the residue was dissolved
in CH2Cl2 (50 mL). The resulting solution was washed
with satd aq NaHCO3 followed by brine. The organic
layer was dried (MgSO4), and the solvent removed to
give an oily foam; yield 0.750 g (83.3%), which by
TLC (1:1 hexane–EtOAc) was a mixture of two prod-
ucts. The product was chromatographed over silica gel
(80 g, using 10% EtOAc in hexane initially and gradu-
ally increasing the percentage of EtOAc to 20%, 25%,
30%, and 35%). The less-polar product 8 came at 35%
EtOAc–hexane; yield 0.280 g (37%). It was crystallized
from EtOAc and hexane as granules, mp 192–194 ꢁC.
NMR confirmed it to be methyl 4,6-O-benzylidene-2-
3.9. Methyl 3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-
fluoro-a-D-allopyranoside (9)
To a solution of 7 (0.46 g, 1.61 mmol) in dry pyridine
(15 mL) at 0 ꢁC were added Ac2O (5 mL) and a catalytic
amount of 4-dimethylaminopyridine, and the solution
was kept overnight under stirring and warming to room
temperature. Removal of the solvent using toluene
(4 · 20 mL) for azeotropic distillation of pyridine gave
a yellow oil, which was purified by column chromato-
graphy over silica gel using 3:2 hexane–EtOAc. It was
crystallized from isopropyl ether; yield 0.50 g (98%),
20
mp 79–80 ꢁC, ½aꢂD +93.9 (c 0.59, CHCl3) (lit.12 mp 79–
80 ꢁC, [a]D +91); MS: m/z 327 (82, M+1), 295 (77,
M+1ꢁMeOH), 267 (2.6, M+1ꢁAcOH), 221 (23,
M+1ꢁC6H5CHO); 1H NMR (300 MHz, CDCl3): d
7.37–7.43 (m, 5H, Ar), 5.91 (m, 1H, H-3), 5.53 (s, 1H,
H-benzylidene), 4.91 (d, 1H, J1,2 4.3 Hz, H-1), 4.62
(dt, 1H, J2,F 43.4, J2,3 4.1 Hz, H-2), 4.35 (dd, 1H,
J6e,6a 10.4, J5,6e 5.14 Hz, H-6e), 4.19 (dt, 1H, J5,6a 10.1,
J4,5 9.9 Hz, H-5), 3.71 (t, 1H, H-6a), 3.62 (ddd, 1H,
J3,4 2.74, J4,F 1.53 Hz, H-4), 3.49 (s, 3H, OCH3); 13C
20
deoxy-2-fluoro-b-D-allopyranoside (8); ½aꢂD ꢁ43.4 (c
1.4, CHCl3); MS: m/z 285 (60, M+1), 253 (7.5,
M+1ꢁMeOH), 207 (4, M+ꢁC6H5); 1H NMR
(250 MHz, CDCl3): d 7.51–7.35 (m, 5H, Ar), 5.55 (s,
1H, H-benzylidene), 4.88 (dd, 1H, J1,2 7.79, J1,F
2.27 Hz, H-1), 4.53 (dt, J3,F 7.48, J2,3 2.7, J3,4 2.5 Hz,
H-3), 4.42 (dd, 1H, J6e,6a 10.3, J5,6e 5.0 Hz, H-6e), 4.26

2636
D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
NMR (75.469 Hz, CDCl3): d 170.30 (OCOCH3), 136.80,
128.98, 128.12, 125.93 (Ar–C), 101.37 (benzylidene-C),
97.35 (d, J1,F 21.50 Hz, C-1), 84.26 (d, J2,F 198.78 Hz,
C-2), 75.74 (d, J4,F 5.81 Hz, C-4), 68.94 (C-6), 66.56
(d, J3,F 17.35 Hz, C-3), 57.94 (C–OMe), 55.99 (C-5),
20.86 (OCOCH3); 19F NMR: d ꢁ202.66 (dd). Anal.
Calcd for C16H19FO6 (326.34): C, 58.88; H, 5.88.
Found: C, 58.77; H, 5.83.
the solvent removed to yield a light-yellow solid. This
solid was recrystallized from 95% EtOH to yield 11
20
(1.70 g, 88%), mp 149 ꢁC, ½aꢂD +104 (c 1, CHCl3)
(lit.18 mp 149–150 ꢁC, [a]D +105); MS: m/z 405 (22,
1
M+), 373 (52, MꢁMeOH), 325 (3, MꢁHBr); H NMR
(250 MHz, CDCl3): d 7.96–7.41 (m, 5H, Ar), 5.95 (m,
1H, H-3), 5.09 (ddd, 1H, J4,5 9.6, J3,4 3.1, J4,F 1.45 Hz,
H-4), 5.00 (d, 1H, J1,2 4.04 Hz, H-1), 4.70 (dt, 1H, J2,F
40.0, J2,3 4.02 Hz, H-2), 4.45 (ddd, 1H, J5,6a 7.0, J5,6b
2.4 Hz, H-5), 3.60 (dd, 1H, J6a,6b 11.2, H-6b), 3.47 (dd,
1H, H-6a), 2.12 (s, 3H, OAc); 13C NMR (62.896 MHz,
CDCl3): d 170.08, 164.64 (–OCOPh, –OCOCH3),
133.66, 129.64, 128.86, 128.57 (Ar–C), 97.06 (d, J1,F
21.69 Hz, C-1), 83.72 (d, J2,F 198.94 Hz, C-2), 68.59
(d, J4,F 5.15 Hz, C-4), 66.78 (d, J3,F 17.61 Hz, C-3),
64.97 (C-5), 56.30 (C–OMe), 31.67 (C-6), 20.75
(OCOCH3); 19F NMR d ꢁ203.57 (dd). Anal. Calcd
for C16H18BrFO6 (405.23): C, 47.42; H, 4.49. Found:
C, 47.35, H, 4.48.
3.10. Methyl 3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-
fluoro-b-D-allopyranoside (10)
To a solution of 8 (63 mg, 0.22 mmol) in dry pyridine
(2 mL) at 0 ꢁC were added Ac2O (1 mL) and a catalytic
amount of 4-dimethylaminopyridine, and the solution
was left overnight under stirring to warm to room tem-
perature. Removal of the solvent using toluene
(3 · 5 mL) for azeotropic distillation of pyridine gave a
yellow oil, which was purified by column chromatogra-
phy over silica gel using 3:2 hexane–EtOAc and crystal-
lized from hexane–EtOAc; yield 70 mg (98%). mp
3.12. Methyl-3-O-acetyl-4-O-benzoyl-6-bromo-2,6-dide-
oxy-2-fluoro-b-D-allopyranoside (12)
20
169–170 ꢁC; ½aꢂD ꢁ59 (c 0.6, CHCl3); MS: m/z 327
(91.5, M+1), 295 (47, M+1ꢁMeOH), 267 (4.3,
M+1ꢁCH3CO2H), 221 (19, M+1ꢁC6H5CHO); 1H
NMR (300 MHz, CDCl3): d 7.36–7.26 (m, 5H, Ar),
5.85 (m, 1H, H-3), 5.45 (s, 1H, H-benzylidene), 4.72
(dd, 1H, J1,2 7.84, J1,F 2.04 Hz, H-1), 4.30 (ddd, 1H,
J2,F 45.80, J2,3 3.36, J2,4 0.9 Hz, H-2), 4.32 (dd, 1H,
J6e,6a 10.2, J5,6e 4.9 Hz, H-6e). 3,85 (dt, 1H, J5,6a 9.5,
J4,5 9.4 Hz, H-5), 3.67 (t, 1H, H-6a), 3.57 (dd, 1H, J3,4
1.1 Hz, H-4), 3.53 (s, 3H, OCH3); 13C NMR
(76.469 MHz, CDCl3):d 169.36 (–OCOCH3), 136.66,
129.00, 128.13, 125.89 (Ar–C), 101.38 (benzylidene-C),
100.10 (d, J1,F 24.22 Hz, C-1), 87.02 (d, J2,F 194.12 Hz,
C-2), 76.25 (d, J4,F 5.66 Hz, C-4), 68.85 (C-6), 67.82
(d, J3,F 17.74 Hz, C-3), 63.99 (s, C–OMe), 57.22 (C-5),
20.67 (OCOCH3); 19F NMR: d ꢁ203.94 (br dd). Anal.
Calcd for C16H19FO6 (326.34): C, 58.88; H, 5.88.
Found: C, 58.79; H, 5.83.
Dry CCl4 (5 mL) was filtered over alumina into a round-
bottomed flask containing a mixture of 10 (39 mg,
0.12 mmol), N-bromosuccinimide (0.031 g, 0.17 mmol),
and BaCO3 (35 mg, 0.17 mmol). The NBS and BaCO3
had been dried in vacuo for 3 h at 80 ꢁC. The resulting
mixture was stirred vigorously at 75–80 ꢁC under reflux
until the usual color changes were complete (2 h). TLC
(3:2 hexane–EtOAc) indicated no significant change in
the polarity of the product and the starting material.
Addition of more NBS and BaCO3 did not bring any
further color changes. The mixture was filtered through
Celite and the filter cake was washed with hot CCl4. The
solvent was removed and the residue dissolved in
CH2Cl2 (50 mL). The resulting solution was washed
with satd aq NaHCO3 and brine, dried (Na2SO4) and
the solvent removed. It was then subjected to column
chromatography. Product 12 was obtained as an amor-
20
3.11. Methyl 3-O-acetyl-4-O-benzoyl-6-bromo-2,6-dide-
oxy-2-fluoro-a-D-allopyranoside (11)
phous residue; yield 15 mg (31%), ½aꢂD ꢁ84.0 (c 0.1,
CHCl3); MS: m/z 405 (17, M+), 373 (17, MꢁMeOH),
1
325 (2, MꢁHBr); H NMR (250MHz, CDCl3): d 7.96–
Dry CCl4 (100 mL) was filtered over alumina into a
7.42 (m, 5H, Ar), 5.96 (dt, 1H, J3,F 8.4, J3,4 3.1, J2,3
3.2 Hz, H-3), 5.08 (ddd, 1H, J4,5 9.7, J4,F 1.3 Hz, H-4),
4.88 (dd, 1H, J1,2 7.6, J1,F 1.8 Hz, H-1), 4.46 (ddd, 1H,
J2,F 46.4 Hz, H-2), 4,20 (ddd, 1H, J5,6a 7.0, J5,6b
2.6 Hz, H-5), 3.64 (s, 3H, OCH3), 3.59 (dd, 1H, J6a,6b
11.2 Hz, H-6b), 3.46 (dd, 1H, H-6a), 2.14 (s, 3H,
OAc); 13C NMR (62.896 MHz, CDCl3): d 169.29,
164.78 (–OCOPh, –OCOCH3), 133.72, 129.68, 128.80,
128.60 (Ar–C), 99.53 (d, J1,F 24.09 Hz, C-1), 86.25 (d,
J2,F 195.29 Hz, C-2), 71.85 (C-5), 69.31 (d, J4,F
4.46 Hz, C-4), 67.87 (d, J3,F 17.29 Hz, C-3), 57.07 (C–
OMe), 31.26 (C-6), 20.59 (OCOCH3); 19F NMR: d
ꢁ203.93 (br dd).
round-bottomed flask containing a mixture of
9
(1.57 g, 4.8 mmol) and N-bromosuccinimide (NBS,
0.96 g, 5.38 mmol). The NBS and BaCO3 had been dried
in vacuo for 3 h at 80 ꢁC. The resulting mixture was stir-
red vigorously at 75–80 ꢁC under reflux. The color chan-
ged to yellow, yellow red, yellow, and then colorless.
TLC (3:2 hexane–EtOAc) showed the reaction to be
complete after 2 h. The mixture was filtered through
Celite and the filter cake was washed with hot CCl4.
The solvent was removed and the residue was dissolved
in CH2Cl2 (150 mL). The resulting solution was washed
with satd aq NaHCO3 and brine, dried (Na2SO4) and

D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
2637
3.13. Methyl 3-O-acetyl-4-O-benzoyl-2,6-dideoxy-2-
fluoro-a-D-ribo-hex-5-enopyranoside (13)
Anal. Calcd for C16H19FO6 (326.34): C, 58.88; H,
5.88, Found: C, 58.81; H, 5.87.
A solution of 11 (1.01 g, 2.49 mmol) in dry benzene
(50 mL) was heated to reflux and DBU (1.13 mL,
7.55 mmol) was added to the solution under argon.
TLC (3:1 hexane–EtOAc) after 3 h indicated the disap-
pearance of starting material. The mixture was diluted
with benzene, washed with 5% HCl (2 · 50 mL), satd
aq NaHCO3 (2 · 50 mL), and brine, dried (Na2SO4),
and the solvent removed in vacuo to yield 13 (0.75 g,
93%), as a chromatographically homogeneous, very
3.15. Methyl 2,6-dideoxy-2-fluoro-b-L-talopyranoside
(15)
Prepared from 14 essentially as described,18 compound
20
15 was obtained as a white solid, mp136–137 ꢁC; ½aꢂD
+63.7 (c 1.45, CHCl3); MS: m/z 181 (15.4, M+1), 149
1
(66.4, M+1ꢁMeOH); H NMR (250 MHz, CDCl3): d
4.71 (d, 1H, J2,F 51.05 Hz, H-2), 4.31 (d, J1,F
20.12 Hz, H-1), 3.54–3.59 (m, 6H, OCH3, H-3, H-4,
H-5), 3.0 (br, 1H, OH), 1.93 (br, 1H, OH), 1.40 (d,
1H, J5,6 6.46 Hz, H-6); 13C NMR (62.896 Hz, CDCl3);
d 100.52 (d, J1,F 20.12 Hz, C-1), 90.28 (d, J2,F
182.90 Hz, C-2), 71.575, 71.278 (C-4, C-5), 69.28 (d,
J3,F 16.10 Hz, C-3), 57.32 (C–OMe), 16.163 (C-6); 19F
NMR: d ꢁ220.7. Anal. Calcd for C7H13FO4 (180.19):
C, 46.66; H, 7.29, Found: C, 46.77; H, 7.29.
20
low-melting solid; ½aꢂD +91 (c 1, CHCl3) (lit.18 [a]D
+91); MS: m/z 325 (M+1), 293 (M+1ꢁMeOH), 265
1
(M+1ꢁHOAc); H NMR (250 MHz, CDCl3): d 8.08–
7.40 (m, 5H, Ar), 5.76 (d, 1H, J3,4 3.7 Hz, H-4), 5.47
(dt, 1H, J3,F 19.83, J2,3 3.4 Hz, H-3), 4.97 (br s, 1H,
H-6a), 4.88 (br s, 1H, H-6b), 4.83 (dt, 1H, J2,F
47.99 Hz, H-2), 4.81 (dd, 1H, J1,F 9.70, J1,2 2.3 Hz,
H-1), 3.65 (s, 3H, OCH3), 2.09 (s, 3H, OAc); 13C
NMR (62.896 MHz, CDCl3):
d
170.09, 169.18
3.16. 1,3,4-Tri-O-acetyl-2,6-dideoxy-2-fluoro-a-L-talo-
pyranose (16)
(–OCOPh, –OCOCH3), 149.49 (C-5), 133.37, 129.31,
128.42 (Ar–C), 101.82 (C-6), 99.72 (d, J1,F 18.23 Hz,
C-1), 84.51 (d, J2,F 197.3 Hz, C-2), 67.59 (d, J3,F
16.47 Hz, C-3), 66.78 (d, J4,F 2.74 Hz, C-4), 57.18 (C–
OMe), 20.67 (OCOCH3); 19F NMR: d ꢁ212.9 (ddd).
Anal. Calcd for C16H17FO6 (324.32): C, 59.25; H,
5.29. Found: C, 59.18; H, 5.33.
To a solution of methyl 2,6-dideoxy-2-fluoro-b-L-talo-
pyranoside (15, 0.190 g,1.05 mmol) in dry MeNO2
(6 mL) were added Ac2O (1.10 mL) and H2SO4
(30 lL), and the solution was stirred at room tempera-
ture. After 4 h, TLC (3:1 hexane–acetone) showed the
consumption of all of the starting material and the pres-
ence of two less-polar spots. Addition of more H2SO4
did not change the composition of the products. The
solution was made neutral with satd aq NaHCO3 and
the mixture was extracted with CHCl3. The organic
layer was washed with water, dried (MgSO4), and the
solvent evaporated to a syrup that was purified by flash
chromatography with hexane–acetone, using gradient
elution. The less-polar product (16) crystallized from
ether–hexane; yield 0.272 g (89%), mp 102–103 ꢁC,
3.14. Methyl 3-O-acetyl-4-O-benzoyl-2,6-dideoxy-2-
fluoro-b-L-talopyranoside (14)
To a solution of 13 (0.643 g, 1.98 mmol) in dry EtOAc
(10 mL) was added 10% Pd/BaSO4 (0.090 g), and hydro-
gen was gently bubbled into the stirred mixture. TLC
(2:1 hexane–EtOAc) after 30 min showed the consump-
tion of starting material. The mixture was filtered
through Celite, the filter cake washed with EtOAc and
the filtrate evaporated. The residue was purified by col-
umn chromatography over silica gel using 10% EtOAc
in hexane initially and gradually increasing the percent-
age of EtOAc. Product 14 (0.57 g, 88%) was obtained as
20
20
½aꢂD ꢁ109 (c 1, CHCl3), (lit.13 mp 102–103 ꢁC, ½aꢂD
1
ꢁ111). The H NMR spectral data were identical with
those reported.7 MS: m/z 293 (5.2, M+1), 233 (100,
M+1ꢁCH3CO2H), 173 (5.6, M+1ꢁ2CH3CO2H), 113
(3, M+1ꢁ3CH3CO2H). Anal. Calcd for C12H17FO7
(292.28): C, 49.32; H, 5.86. Found C 49.24; H, 5.82.
20
very low-melting flakes, mp 49 ꢁC, ½aꢂD ꢁ128 (c 1.9,
CHCl3) (the previously reported value18 may have been
in error); MS: m/z 327 (69, M+1), 307 (7.8, M+1ꢁHF),
295 (79, M+1ꢁMeOH); 1H NMR (250 MHz, CDCl3): d
8.16–7.40 (m, 5H, Ar), 5.42 (dd, 1H, J3,4 3.6, J4,5 1.0 Hz,
H-4), 5.04 (dt, 1H, J3,F 31.7, J2,3 2.7 Hz, H-3), 4.74 (dd,
1H, J2,F 51.4 Hz, H-2), 4.47 (d, 1H, J1,F 18.4 Hz, H-1),
3.87 (dq, 1H, J5,6 6.4 Hz, H-5), 3.64 (s, 3H, OCH3),
2.02 (s, 3H, OAc), 1.32 (d, 3H, H-6); 13C NMR
3.17. 3,4-Di-O-acetyl-2,6-dideoxy-2-fluoro-a-L-talo-
pyranosyl bromide (17)
To a solution of 16 (0.200 g, 0.684 mmol) in dry EtOAc–
CH2Cl2 (12 mL) was added TiBr4 (0.81 g, 2.2 mmol),
and the resulting mixture was stirred at room tempera-
ture. After 48 h, the mixture was diluted with MeCN
(8 mL), and anhydrous NaOAc (1.05 g) was added.
The resulting mixture was stirred until the color faded
to pale yellow. After filtration, the solvent was removed
to yield a pale-yellow oil, which was purified by column
(62.896 Hz, CDCl3):
d
169.98, 166.38 (OCOPh,
OCOCH3), 133.20, 130.15, 129.39, 128.34 (Ar–C),
99.97 (d, J1,F 15.61 Hz, C-1), 85.63 (d, J2,F 195.31 Hz,
C-2), 70.16 (C-4), 69.15 (d, J3,F 15.80 Hz, C-3), 68.32
(C-5), 57.43 (C–OMe), 20.55 (OCOCH3), 16.04 (C-6).

2638
D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
chromatography (hexane–acetone) using gradient elu-
tion to give the product as a colorless oil, yield 0.175 g
(82%). The1H NMR spectral data of the product were
identical with those reported.13
9.64, 32.71, 42.36 Hz). HREIMS: 600.1644 for
C30H29FO12, Calcd 600.1643. Anal. Calcd for
C30H29FO12Æ0.5H2O (609.58): C, 59.11; H, 4.97. Found:
C, 59.22; H, 5.04.
3.18. 4-Demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-
fluoro-a-L-talopyranosyl)daunomycinone (18)
3.19. 4-Demethoxy-7-O-(2,6-dideoxy-2-fluoro-a-L-talo-
pyranosyl)daunomycinone (19)
A
mixture of (+)-(7S,9S)-4-demethoxydaunomycin-
Compound 18 (60 mg, 0.09 mmol) was taken up in
0.2 M aq NaOH (5 mL) and stirred at 0 ꢁC. The solu-
tion turned deep purple. The progress of the reaction
was monitored by TLC (4:1 benzene–acetone). After
5 h the reaction was complete, showing the formation
of a very polar product, Rf 0.1. The mixture was care-
fully neutralized with cold aqueous M HCl, whereupon
the color changed to orange. The solution was ex-
tracted with CHCl3 and washed with satd aq NaCl.
The organic layer was dried (MgSO4), evaporated,
and the residue crystallized from CHCl3 and hexane;
one17 (0.206 g, 0.56 mmol), freshly dried yellow HgO
(0.61 g, 2.8 mmol), HgBr2 (0.183 g, 0.5 mmol), and
˚
freshly activated 3 A crushed molecular sieves (2.0 g)
in dry CH2Cl2 (10 mL) was stirred for 30 min under ar-
gon at room temperature. A solution of 17 (0.160 g,
0.5 mmol) in dry CH2Cl2 (3 mL) was added slowly and
the mixture was stirred in the dark for 24 h. TLC in
4:1 benzene–acetone indicated the disappearance of
starting materials and the formation of a product
slightly less polar than 4-demethoxydaunomycinone,
but more polar than 17. The mixture was diluted with
CHCl3, filtered, and the organic solution washed succes-
sively with 30% aq KI, satd aq NaHCO3, and then dried
(MgSO4), and evaporated. The orange residue was puri-
fied by column chromatography over silica gel with benz-
ene–acetone. The amorphous product crystallized from
CHCl3–hexane as orange crystals, mp 168–169 ꢁC, yield
20
mp 185–187 ꢁC, yield 40 mg (78%); ½aꢂD +47.1 (c
0.14, CHCl3); mmax: 1716, 1626, 1588 cmꢁ1 (KBr);
MS: m/z 517.35 (3, M+1), 516.34 (4.8, M+), 368 (7.2,
aglycon), 351 (16, M+1ꢁglycon), 333 (17, M+1ꢁgly-
conꢁH2O), 307 (29, MꢁglyconꢁCH3CO), 291 (44,
M+1ꢁglyconꢁH2OꢁCH2@C@O), 149 (82, M+1ꢁ
aglycon); 1H NMR (500 MHz, CDCl3): d 13.60 (s,
1H, enolic OH), 13.28 (s, 1H, enolic OH), 8.36 (m,
1H, Ar–H), 7.86 (m, 1H, Ar–H), 7.70 (m, 1H, Ar–H),
20
KBr
0.076 g (47%), ½aꢂD +104 (c 0.2, CHCl3); m : 1744,
max
1721, 1626, 1588 cmꢁ1; MS: m/z 601.15 (4, M+1),
600.14 (6, M+), 583.22 (1.3, MꢁOH), 557.22 (0.45,
MꢁCH3CO), 522.57 (0.6, MꢁOHꢁCH3CO2H), 367.97
(7.8, aglycon), 350.92 (18, M+1ꢁglycon), 333.01 (36,
M+1ꢁglyconꢁH2O), 306.99 (52, MꢁglyconꢁCOCH3),
0
0
0
7.53 (m, 1H, Ar–H), 5.59 (dd, 1H, J1 ;F 9:35, J1 ;2
<1 Hz, H-10), 5.27 (dd, 1H, J7,8a 4.4, J7,8e <1 Hz,
H-7), 4.63 (br d, 1H, J2 ;F 49:0, J2 ;3 2:8 Hz, H-20),
0
0
0
4.21 (br q, 1H, J5 ;6 6:5, J4 ;5 1:4 Hz, H-50), 3.96 (s,
0
0
0
0
291.00
(100.0,
M+1ꢁglyconꢁH2OꢁCH2@C@O),
1H, D2O exchangeable, 9-OH), 3.66 (br m, 1H, H-40),
233.06 (28.8, M+1ꢁaglycon); 1H NMR (500 MHz,
CDCl3): d 13.59 (s, 1H, enolic OH), 13.29 (s, 1H, enolic
OH), 8.35 (m, 2H, Ar–H), 7.86 (m, 2H, Ar–H), 5.63 (dd,
3.65 (dt, 1H, J3 ;F 32:43, J3 ;4 2:8 Hz, H-30), 3.25 (dd,
1H, J10a,10e 19.1, J8e,10e 1.75 Hz, H-10e), 2.97 (d, 1H,
H-10a), 2.96 (s, 1H, D2O exchangeable, 30 or 40 OH),
2.41 (s, 3H, H-14), 2.37 (br d, J8e,8a 14.9 Hz, H-8e),
2.19 (dd, 1H, H-8a), 1.94 (dd, 1H, D2O exchangeable,
J 11.3, 8.1 Hz, 30 or 40 OH), 1.38 (d, 3H, H-60); 13C
NMR (125.759 Hz, CDCl3): d 211.10 (C-13), 186.91
(C-5 or C-12), 186.65 (C-5 or C-12), 156.41 (C-6 or
C-11), 156.09 (C-6 or C-11), 135.70, 133.38, 133.28,
132.60 (C-4a, C-6a, C-10a, C-12a), 134.66, 130.85,
128.79, 127.10 (C-1, C-2, C-3, C-4), 111.73, 110.93
0
0
0
1H, J1 ;F 8:31, J1 ;2 1:2 Hz, H-10), 5.30 (dd, 1H, J7,8a 4.5,
0
0
0
0
0
0
0
J7,8e <1 Hz, H-7), 5.24 (dd, 1H, J3 ;4 3:4, J4 ;5 <1 Hz, H-
40), 5.017 (dt, 1H, J3 ;F 32:70, J2 ;3 3:1 Hz, H-30), 4.60
0
0
0
(br d, 1H, J2 ;F 49:32 Hz, H-20), 4.37 (dq, 1H,
0
J5 ;6 6:6 Hz, H-50), 3.85 (s, 1H, D2O exchangeable, 9-
OH), 3.25 (dd, 1H, J10e,10a 18.9, J8e,10e 1.7 Hz, H-10e),
2.98 (d, 1H, H-10a), 2.41 (s, 3H, H-14), 2.36 (br d,
1H, J8e,8a 15.5 Hz, H-8e), 2.20 (dd, 1H, H-8a), 2.17 (s,
3H, OAc), 2.03 (s, 3H, OAc), 1.27 (d, 3H, H-60); 13C
NMR (125.759 Hz, CDCl3): d 211.19 (C-13), 186.96
(C-5 or C-12), 186.74 (C-5 or C-12), 170.89 (OCOCH3),
169.70 (OCOCH3), 156.46 (C-6 or C-11), 156.14 (C-6 or
C-11), 135.79 (C-12a), 134.67, 134.63 (C-6a, C-10a),
133.44, 133.35 (C-2, C-4), 132.53 (C-4a), 127.17,
127.08 (C-1, C-3), 111.78, 110.99 (C-5a, C-11a), 101.28
0
0
(C-5a, C-11a), 101.03 (d, J1 ;F 31:87 Hz, C-10), 89.3
0
(d, J2 ;F 172:30 Hz, C-20), 76.34 (C-9), 71.05 (C-7),
0
68.17 (C-40),67.71 (C-50), 66.13 (d, J3 ;F 15:61 Hz,
0
C-30), 35.20 (C-8), 33.34 (C-10), 24.57 (C-14), 16.33
(C-60); 19F NMR: (235.36 MHz), d ꢁ201.688 (m).
HREIMS: m/z 516.145 for C26H25FO10. Calcd 516.143.
(d, J1 ;F 31:73 Hz, C-10), 85.01 (d, J2 ;F 184:2 Hz, C-20),
3.20. 14-Bromo-4-demethoxy-7-O-(2,6-dideoxy-2-fluoro-
a-L-talopyranosyl)-daunomycinone (20)
0
0
76.26 (C-9), 71.22 (C-7), 68.78 (C-40), 66.58 (d,
J3 ;F 15:4 Hz, C-30), 66.082 (C-50), 35.28 (C-8), 33.36
0
(C-10), 24.63 (C-14), 20.73, 20.611 (OCOCH3), 16.15
To a solution of 19 (20 mg, 0.036 mmol) in a mixture of
dry MeOH (0.5 mL) and 1,4-dioxane (1.6 mL) was
(C-60); 19F NMR (235.36 MHz), d ꢁ201.593 (ddd, J

D. Horton, A. Khare / Carbohydrate Research 341 (2006) 2631–2640
2639
added a solution of Br2 in CHCl3 (0.4 mL, prepared
from 10.0 g of bromine in 100 mL of CHCl3). The solu-
tion was stirred at 0–5 ꢁC for 4 h and then kept at room
temperature. The progress of the reaction was moni-
tored by TLC, which indicated complete consumption
of starting material after 6 days and the formation of a
slightly less-polar product. The reaction was terminated
by first removing the excess of Br2 by bubbling air
through the mixture followed by precipitating the prod-
uct (20) with ether (10 mL). It was collected by centrifu-
gation and washed twice with ether (2 mL); yield 12 mg
aglyconꢁH2O), 353.10 (0.2, aglyconꢁCH2OH), 348.07
(0.25, aglyconꢁ2H2O), 335.12 (0.1, aglyconꢁ
H2OꢁCH2OH), 166.11 (0.8, glycon). HREIMS: m/z
531.967 (M+) for C26H25FO11. Calcd 532.138;
366.0730 for C20H14O7 (aglyconꢁH2O), calcd
366.0739; 348.0636 for C20H12O6 (aglyconꢁ2H2O),
1
calcd 348.0634; H NMR (500 MHz, CDCl3): d 13.64
(s, 1H, enolic OH), 13.28 (s, 1H, enolic OH), 8.37 (m,
2H, Ar–H), 7.87 (m, 2H, Ar–H), 5.63 (br d, 1H,
J1 ;F 9:21, J1 ;2 <1 Hz, H-10), 5.36 (br m, 1H, H-7),
0
0
0
0
4.75 (br s, 2H, H-14), 4.62 (br d, 1H, J2 ;F 49:0 <1 Hz,
20
(50%), mp 202 ꢁC, ½aꢂD +171 (c 0.14, 1:1 CHCl3–
H-20), 4.12 (br q, 1H, H-50), 3.98 (s, 1H, D2O exchange-
MeOH); MS: m/z 596.27 (1.3, M+1), 595.30 (0.7,
M+), 447.15 (0.3, aglycon), 430.13 (1.3, M+1ꢁglycon),
429.12 (1.7, aglyconꢁH2O), 149.05 (69, M+1ꢁaglycon);
1H NMR (500 MHz, CDCl3): d 13.62 (s, 1H, enolic
OH), 13.26 (s, 1H, enolic OH), 8.36 (m, 2H, Ar–H),
able, 9-OH), 3.67 (br m, 1H, H-40), 3.61 (dt, 1H,
J3 ;F 31:80 Hz, H-30), 3.33 (dd, 1H, J10e,10a 19.0, J8e,10e
0
1.8 Hz, H-10e), 3.07 (d, 1H, H-10a), 2.96-2.40 (br m,
2H, D2O exchangeable, 14-OH, 30-OH), 2.42 (br d,
1H, J8e,8a 14.9 Hz, H-8e), 2.25 (dd, 1H, J7,8a 4.24 Hz,
H-8a), 1.88 (br m, 1H, D2O exchangeable, 40-OH),
0
0
0
7.85 (m, 2H, Ar–H), 5.64 (dd, 1H, J1 ;F 9:61, J1 ;2
<1 Hz, H-10), 5.33 (br m, 1H, H-7), 4.62 (br d, 1H,
J2 ;F 48:12 Hz, H-20), 4.57 (d, 1H, J14a,14b 13.1 Hz, H-
1.40 (d, 3H, J5 ;6 6:5 Hz, H-60); 19F NMR
(235.36 MHz), d ꢁ201.561 (m). Insufficient sample was
0
0
0
1
14 a or b), 4.32 (d, 1H, H-14 a or b), 4.17 (q, 1H,
available for H–13C HETCOR.
J5 ;6 6:6, J4 ;5 <1 Hz, H-50), 4.10 (s, 1H, D2O exchange-
0
0
0
0
able, 9-OH), 3.68 (br m, 1H, H-40), 3.63 (br dt, 1H,
J3 ;F 33, J2 ;3 3:2, J3 ;4 3:7 Hz, H-30), 3.34 (dd, 1H,
J10e,10a 19.0, J8e,10e 1.5 Hz, H-10e), 3.04 (d, 1H, H-
10a), 2.89 (d, 1H, D2O exchangeable, J 10.9 Hz, 30-
OH), 2.52 (br d, 1H, J8e,8a 15.0 Hz, H-8e), 2.32 (dd,
1H, J7,8a 4.15 Hz, H-8a), 1.88 (dd, 1H, D2O exchange-
able, J 11.6, 8.1 Hz, 40-OH), 1.39 (d, 1H, H-60); 13C
NMR (125.759 Hz, CDCl3): d 204.87 (C-13), 187.05
(C-5 or C-12), 186.85 (C-5 or C-12), 155.75 (C-6 or C-
11), 155.59 (C-6 or C-11), 134.89, 133.43, 133.34,
131.89 (C-4a, C-6a, C-10a, C-12a), 134.80, 134.75,
127.21, 127.17 (C-1, C-2, C-3, C-4), 112.03, 111.21 (C-
0
0
0
0
0
Acknowledgements
This work was supported, in part, by NIH grant GM-
11976. A.K. thanks the Fulbright Foundation (CIES)
for support. The authors thank Dr. Ralph Stephens of
Ohio State University for the cell culture data, and
Dr. S. Todd Deal for performing initial preparations,
including compound 18.
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5a, C-11a), 100.98 (d, J1 ;F 32:15 Hz, C-10), 89.13 (d,
0
J2 ;F 172:05 Hz, C-20), 76.77 (C-9), 71.72 (C-40), 70.96
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192 ꢁC, ½aꢂD +259 (c 0.1, 1:1 CHCl3–MeOH); FABMS:
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