Convenient syntheses of daunomycinone-7-D-glucuronides and doxorubicinone-7-D-glucuronides

Article abstract of DOI:10.1081/SCC-200030978

The first synthesis of new doxorubicin and daunomycin analogs containing glucuronic acid moieties instead of daunosamine are described. The desired products, daunomycinone-7-D-glucuronide (DM7G, 10) and doxorubicinone-7-D- glucuronide (DX7G, 11) were conveniently prepared through the glycosylation at 7-hydroxyl group of daunomycinone (4) or 14-acetoxydoxorubicinone (6) with glucuronic acid derivative 7 by the Koenigs-Knorr procedure followed by alkaline deacetylatipn using aqueous LiOH solution and amberlite cation exchange material. The anomeric configuration and conformation of all products were fully characterized by assignment of ¹H NMR chemical shifts and H-H coupling constants based on reported literatures.

Full text of DOI:10.1081/SCC-200030978

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Convenient Syntheses of
Daunomycinone‐7‐D‐Glucuronides
and
Doxorubicinone‐7‐D‐Glucuronides
Young S. Rho a , Sun Y. Kim a , Wan‐Joong Kim a ,
Yeo Keun Yun a , Hong Sig Sin a & Dong Jin Yoo b
a Department of Chemistry, Chonbuk National
University, Chonju, 561‐756, Korea
b Department of Chemistry, Seonam University,
Namwon, 590‐711, Korea
Published online: 10 Jan 2011.
To cite this article: Young S. Rho , Sun Y. Kim , Wan‐Joong Kim , Yeo
Keun Yun , Hong Sig Sin & Dong Jin Yoo (2004): Convenient Syntheses of
Daunomycinone‐7‐D‐Glucuronides and Doxorubicinone‐7‐D‐Glucuronides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:19, 3497-3511
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3497–3511, 2004
Convenient Syntheses of
Daunomycinone-7-D-Glucuronides and
Doxorubicinone-7-D-Glucuronides
Young S. Rho,1 Sun Y. Kim,1 Wan-Joong Kim,1
Yeo Keun Yun,1 Hong Sig Sin,1 and Dong Jin Yoo2,
*
1Department of Chemistry, Chonbuk National University,
Chonju, 561-756, Korea
2Department of Chemistry, Seonam University, Namwon,
590-711, Korea
ABSTRACT
The first synthesis of new doxorubicin and daunomycin analogs contain-
ing glucuronic acid moieties instead of daunosamine are described. The
desired products, daunomycinone-7-D-glucuronide (DM7G, 10) and doxo-
rubicinone-7-D-glucuronide (DX7G, 11) were conveniently prepared
through the glycosylation at 7-hydroxyl group of daunomycinone (4) or
14-acetoxydoxorubicinone (6) with glucuronic acid derivative 7 by the
Koenigs-Knorr procedure followed by alkaline deacetylation using
aqueous LiOH solution and amberlite cation exchange material. The
anomeric configuration and conformation of all products were fully
*
Correspondence: Dong Jin Yoo, Department of Chemistry, Seonam University,
Namwon, 590-711, Korea; Fax: þ82-63-620-0013; E-mail: djyoo@seonam.ac.kr.
3497
DOI: 10.1081/SCC-200030978
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3498
Rho et al.
1
characterized by assignment of H NMR chemical shifts and H-H coup-
ling constants based on reported literatures.
Key Words: Anthracycline; Daunomycinone; Doxorubicinone;
Glucuronic acid; Glycosylation.
INTRODUCTION
Anthracyclines are among the most widely used anticancer agents. Notwith-
standing the large efforts to develop new drugs with a better pharmaceutical
profile, doxorubicin (DX, 1), daunorubicin (DM, 2), and idarubicin (IDA, 3)
are still the most used in clinical practice. Used as single agents or in combination
therapy, they are the components of adjuvant, curative, as well as palliative treat-
ments. Their clinical use is, however, limited by undesirable side effects such as
drug-cumulative cardiotoxicity and myelosuppression, as well as the appearance
of multidrug resistance (MDR) in tumor cells.[1] To circumvent these drawbacks,
many chemical and biosynthetic modifications have been undertaken.[2,3]
Many efforts have been made to modify the anthracyclines and to develop
analogs with high activity and low toxicity. Recently, the synthesis of anthra-
cycline analogs in which glucuronides are attached to the C-30 amino group of
doxorubicin (and/or daunomycin) have been reported.[4b] The studies
comparing antitumor activities of these derivatives and corresponding anthra-
cycline have been also reported.[4a,c] However, the synthesis of daunomyci-
none-7-D-glucuronide and doxorubicinone-7-D-glucuronide as potential
prodrugs has not been reported, and therefore the chemical and biological
properties remain unknown. In previous papers, we have been reported the
synthesis of novel fucosyl anthracycline analogs containing various amino
acids at the C-14 position and a fluorine at the C-9 or C-10 position as well
Figure 1. Chemical structures of anthracyclines.

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3499
as idarubicinone derivatives.[5] In more recent papers, we have also reported
the successful synthesis of idarubicinone-7-b-D-glucurnonide.[5c] Related to
these reports, we will report the synthesis of daunomycin or doxorubicin
analogs having glucuronic acid instead of daunosamine as a glycone at the
C-7 position. Additionally, we also wish to report the assignment of the
anomeric configuration of the glucuronic acid moiety.
RESULTS AND DISCUSSION
In this study we endeavored to prepare some DM7G (10) or DX7G (11)
from commercially available daunomycin (2). For the coupling reaction, we
used daunomycinone (4), 14-acetyldoxorubicinone (6), and methyl 2,3,4-
tri-O-acetyl-D-glucopyranosyuronate bromide (7) as starting materials as
shown in (Fig. 2). First, compound 4 was readily obtained in 98% from 2
by treating with 0.2 N HCl solution by the known procedure.[6] The synthesis
of 6 was accomplished by bromination of 4 with 30% bromine/chloroform in
methanol/dioxane followed by the nucleophilic displacement type esterifica-
tion of 14-bromodaunomycinone (5) with sodium acetate in acetone.[7]
Glucopyranosyl bromide 7 was prepared from available D-glucuronolactone
by the known procedure.[8] The target materials (10 and 11) were obtained
from coupling of 4 or 6 with a suitably protected glucopyranosyl bromide 7
by modified Koenigs-Knorr glycosylation using mercury (II) bromide[9e]
followed by alkaline deacetylation using aqueous LiOH solution.
The coupling reactions were attempted under several conditions in the
presence of various catalysts as shown in Table 1. The stereochemical
outcome of glycosidation was influenced by the kinds of catalysts and reaction
conditions: thus, coupling 4 with glycosyl bromide 7 using AgOTf[9a] or
[9b]
Ag2CO3
1 : 1 ratio, whereas using HgBr2
afforded a mixture of 8a (DM7aGa) and 8b (DM7bGa) with an
[9e]
[9d]
and CdCO3
of isomers of 3–7 (8a/8b). Interestingly, the reaction of idarubicinone (no
-OMe group at C4 position) with glycosyl bromide 7 using ZnBr2
led to a different ratio
[9c]
or
HgBr2 afforded the desired products in ꢀ 53% and ꢁ 6% yield,[5c] respect-
ively, whereas coupling 4 with ZnBr2 produced only b-anomer (30%) in
accordance with the neighboring group participation of Koenigs-Knorr reac-
tion,[10] and the reaction of 4 with HgBr2 gave the best yield of the a- and
b-anomers (a : b ¼ 3 : 7, 74%). Results of the coupling of 4 with glycosyl
bromide 7 in various reaction conditions are summarized in Table 1. The
thin-layer chromatography (TLC) spots were Rf ¼ 0.5 (b-anomer) and 0.7
(a-anomer) in 10% acetone/dichloromethane as an eluent. The tendency of
the coupling of 6 with glycosyl bromide 7 for synthesis of 9a (DX7aGa)/
9b(DX7bGa) was generally similar to that of the corresponding reaction for

3500
Rho et al.
Figure 2. (a) i) Trimethylorthoformate, MeOH/1,4-dioxane, rt, 20 min, ii)
Br2/CHCl3, 308C, 6 h. (b) NaOAc/acetone, reflux, 6 h. (c) HgBr2, yellow HgO,
˚
3 A molecular sieves/CH2Cl2, reflux, 36 h. (d) 0.1 N LiOH, MeOH/H2O/THF
(5/2/1, v/v), 08C, 2 h, amberite cation resin..
synthesis of 8a/8b. Therefore, we could isolate two stereochemical
compounds for each reaction through a careful flash column chromatography
using silica gel in the same eluent.
The assignment of anomeric configuration of DM7Ga (8) and DX7Ga (9)
1
was fully characterized based on H NMR data (chemical shifts and H-H
coupling constants) between the 10-H and 20-H protons on the glucuronic
acid moiety. The coupling constants for the 10-H and 20-H protons for
various types of drug-glucuronide conjugates have been reported.[11] For
0
0
a-anomers, coupling constants of J1 2 ¼ 2–5 Hz were observed, while
J1 2 ¼ 6–10 Hz were characteristic for the b-anomer.[9c,11] Additionally, the
axial anomeric proton (10-C) of the b-anomer always resonates at a higher
field than the equatorial proton of the corresponding a-anomer.[11a] Hence,
0
0

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3501
Table 1. Ratios and overall yields of 8a/8b in various reaction conditions.
Reagent
Equiv.
Solvent
Temp.
Ratioa
Yield (%)b
AgOTf
HgBr2
ZnBr2
1.1
1.1
1.1
1.1
1.1
CH2Cl2
CH2Cl2
CH2Cl2
Benzene
Benzene
rt
a/b ¼ 1 : 1
a/b ¼ 3 : 7
only b
46
74
30
49
58
reflux
rt
Ag2CO3
CdCO3
reflux
reflux
a/b ¼ 1 : 1
a/b ¼ 3 : 7
aRatio was determined by H NMR spectroscopy.
bTotal isolated yields.
1
the primary objective of this study was to identify unambiguously the anome-
ric 10-H proton and the neighboring 20-H proton, and to compare their chemi-
cal shifts and coupling constants (Table 2). The 4.5–5.3 ppm region of 1D
proton NMR spectra, which included the 40-H, 20-H, and 30-H signals, was
carefully analyzed. For a-anomer (DM7aGa, 8a) the 20-H was assigned to
the double-doublet at 4.52 ppm. The observed coupling constants of 3.4 and
6.8 Hz clearly suggest one axial-equatorial interaction (10-H, 20-H) and one
axial-axial interaction (20-H, 30-H). For comparison, in the b-anomer
(DM7bGa, 8b), the 20-H signal appears as a double-doublet (4.97 ppm,
J ¼ 7.3, 9.3 Hz), indicating the axial-axial interactions for both 10-H and
30-H protons on the sugar ring. The smaller coupling constant of the 20-H
signal in the a-anomer 8a was assigned to the 10-H and 20-H interaction cor-
responding to the 10-H doublet at 5.95 ppm, which has a measured coupling
constant of 4.9 Hz. It should be noted that the chemical shift of the 10-H
signal in the a-isomer 8a appears in a lower field than in b-isomer 8b
(5.15 ppm, J ¼ 7.8 Hz). In addition, the cross-peaks in the a-isomer of a
COSY experiment clearly connect the doublet at 5.95 ppm with the double-
doublet at 4.52 ppm. For the b-isomer, the cross-peaks clearly connect the
doublet at 5.15 ppm with the doublet-doublet at 4.97 ppm. For DX7Ga (9a
and 9b), the anomeric configurations of the glucuronic acid moiety have the
same tendency of the spectral data of DM7Ga (8a and 8b) as shown in Table 2.
Deprotection of the carbohydrate moieties of all compounds 8a,b and
9a,b was carried out using 0.1 N LiOH solution in MeOH/THF/H2O (5/2/
1, v/v). After the reaction was completed, the resulting solution was neutral-
ized with ion exchange resin and then the polar compound was purified with
reversed-phase C18 column chromatography.[4c] Deprotection of 8a gave
mainly hydrolyzed aglycone and glycone, and therefore the desired product,
DM7aG (10a), was obtained only in small amounts (,1%), whereas depro-
tection of 8b and 9a yielded DM7bG (10b) in 78% and DX7aG (11a) in
34%, respectively. Additionally, the deprotection of 9b was more reactive

3502
Rho et al.
d
b
a
b
a

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3503
than 8b, but DX7bG (11b) was less obtained than 10b. Although additional
attempts for deprotection of 8a with various bases (0.1 N NaOH, NaOMe,
Et3N, guanidine, etc.) in several reaction conditions were tried, small
amounts of product 11a was always produced in an impure state and the agly-
cone and glycone moieties were mainly recovered. Actually, 8a had a less
stable structure than 8b, 9a, and 9b; even if waiting for the deacetylation
process in room temperature, 8a was quickly destroyed to daunomycinone
(4) and glucuronic acid moiety. Moreover, unpurified 8a of the crude reaction
mixture state was converted for 24 h into about 50% of starting materials, 4,
and glycone moiety. Although completely purified, 8a was somewhat stable
in the freezing state, and in the course of the deprotecting process, 8a was
completely converted into starting material, independent of its purity or the
variety of reaction conditions. On the other hand, in the case of the other
a-anomer, (the tendency of 9a is not) in accordance with that of 8a, low
yields of a-anomers appeared indicating that a-anomers were less stable
than b-anomers. In contrast, b-anomers (8b and 9b) did not have the same
tendency; deacetylation of b-anomers progressed well, and therefore side
products from b-anomers were also not much more than those of a-anomer.
The b-Anomer of DM was clearly known to be more getting than DX due
to the base lability of DX.[4c] In addition, the product ratio of a/b-anomer
during coupling of DM or DX was almost similar, but the reaction time of
DM was much shorter than DX, and therefore the reactivity of the coupling
reaction for doxorubicinone seemed to decrease in comparison with
daunomycinone.
The solubility of 8, 9, 10, and 11 was significantly different between
a- and b-anomer: while a-isomers were soluble in ethylacetate and dichloro-
methane, b-anomers were found to be poorly soluble in ethylacetate and
slightly soluble in dichloromethane. Therefore, pure b-anomers crystallized
well using the solvents after charring out column chromatography of the
reaction mixture.
In conclusion, pharmaceutically important daunomycinone-7-D-glucuro-
nide (DM7G, 10) and doxorubicinone-7-D-glucuronide (DX7G, 11) were pre-
pared from glycosylation of 7 with 4 and 6, respectively. Detailed NMR
analyses unambiguously proved the anomeric configuration of the new
compounds.
EXPERIMENTAL SECTION
All reactions were carried out under argon atmosphere in dried glassware.
All solvents were carefully dried and distilled as reported.[12] Bulk grade
hexane was distilled prior to use. Merck precoated silica gel plates

3504
Rho et al.
(Art. 5554) with fluorescent indicator were used as analytical TLC. Gravity
column chromatography and flash column chromatography were carried out
1
on silica gel (230–400 mesh from Merck). H and 13C NMR spectra were
recorded on a JEOL JNM EX-400 spectrometer. Chemical shifts were intern-
1
ally referenced to TMS for H or to solvent signals for 13C. Infrared (IR)
spectra were recorded on a Nicolet 5-DXB series Fourier-transform infrared
(FT-IR) spectrophotometer. Mass spectra were obtained on a JEOL JMS
HX-110/110A Tandem mass spectrometer (FABþ, ESI). Ultraviolet-(UV-VIS)
absorption spectra were recorded on a Hitachi-556 spectrophotometer.
Optical rotations were determined using the Rudolph AUTOPOL IV apparatus
with a 0-100-1.5 polarimeter sample tube. Melting points were obtained on a
Bu¨chi 510 melting point apparatus and were uncorrected.
Daunomycinone (4). Daunomycin hydrochloride, 2 (1.00 g, 1.77 mmol)
was dissolved in 100 mL of 0.2 N HCl solution, and the resulting mixture was
heated for 3.5 h at 90–958C. After completion of the reaction, the mixture
cooled and the solid residue was filtered off and washed with water (pH 7).
The solid was recrystallized from acetone/ether, filtered off, washed with
ether, and dried under reduced pressure to give daunomycinone, 4 (0.69 g,
98%) as a red powder. Melting point (Mp) 213–2148C [a]2D0 þ 193.18 (c
0.1, dioxane); IR (KBr) 3443, 2361, 1710, 1617, 1579, 1421, 1286, 1211,
1123, 1085, 1036, 990, 796, 763 cm21 1H NMR (400 MHz, CDCl3) d
;
13.92 (s, 1 H, PhOH), 13.23 (s, 1 H, PhOH), 8.01 (d, 1 H, J ¼ 7.8 Hz, ArH),
7.78 (dd, 1 H, J ¼ 7.8, 8.3 Hz, ArH), 7.39 (d, 1 H, J ¼ 8.3 Hz, ArH), 5.32
(d, 1 H, J ¼ 3.4 Hz, C7eqH), 4.11 (s, 3 H, C4OCH3), 3.15 (d, 1 H,
J ¼ 18.5 Hz, C10eqH), 2.90 (d, 1 H, J ¼ 18.5 Hz, C10axH), 2.45 (s, 3 H,
C14CH3), 2.35 (d, 1 H, J ¼ 14.5 Hz, C8eqH), 2.15 (dd, 1 H, J ¼ 3.4, 14.5 Hz,
C
8axH); 13C NMR (100 MHz, CDCl3) d 211.91, 185.86, 185.73, 160.56,
155.69, 154.62, 137.04, 135.94, 134.22, 133; UV (CH3OH) lmax (log 1)
202 (0.34), 258 (0.11), 267 (0.11).
Daunomycinone-14-bromide (5). Trimethylorthoformate (0.20 mL,
1.83 mmol) was added to a solution of daunomycin hydrochloride, 2
(0.20 g, 0.35 mmol) dissolved in methanol/1,4-dioxane (v/v ¼ 1 : 2, 12 mL).
The reaction mixture was stirred at room temperature for 20 min. To the
mixture was added a Br2/CHCl3 (w/v ¼ 1 : 9, 2.24 mL, 1.42 mmol) solution,
and the mixture was then stirred for 6 h at 308C. The mixture was concentrate
in vacuo to give red residue 5 (0.15 g, 92%). Mp 198–2008C; [a]2D0 þ 158.28
(c 0.1, dioxane); IR (KBr) 3427, 2949, 1730, 1618, 1579, 1419, 1379, 1288,
1
1264, 1208, 1089, 1014, 991, 787 cm21; H NMR (400 MHz, DMSO-d6) d
13.87 (s, 1 H, PhOH), 13.13 (s, 1 H, PhOH), 7.83 (m, 1 H, ArH), 7.57
(m, 1 H, ArH), 5.46 (s, 1 H, C9OH), 5.07 (d, 1 H, J ¼ 17.7 Hz, C14H), 5.01
(d, 1 H, J ¼ 3.4 Hz, C7eqH), 4.96 (d, 1 H, J ¼ 17.7 Hz, C14H), 3.95 (s, 3 H,
C4OCH3), 3.04 (d, 1 H, J ¼ 18.9 Hz, C10eqH), 2.78 (d, 1 H, J ¼ 18.9 Hz,

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3505
C10axH), 2.26 (d, 1 H, J ¼ 14.0 Hz, C8eqH), 1.94 (dd, 1 H, J ¼ 3.4, 14.0 Hz,
8axH); 13C NMR (100 MHz, DMSO-d6) d 205.69, 186.19, 186.08, 160.68,
C
155.64, 154.62, 136.87, 136.06, 134.47, 132.88, 119.77, 119.55, 118.85,
110.62, 110.39, 76.81, 60.27, 56.48, 47.91, 36.09, 32.58; UV (CH2Cl2) lmax
(log 1) 234 (0.26), 253 (0.14), 288 (0.05); Mass (FABþ, Na) m/z 863
(M þ Na)þ.
Doxorubicinone-14-acetate (6). A solution of 14-bromodaunomyci-
none, 5 (0.05 g, 0.11 mmol) and sodium acetate (0.03 g, 0.21 mmol) in
acetone (50 mL) was refluxed for 6 h. Upon completion of the reaction the
solvent was evaporated. The residue was dissolved in CH2Cl2 (100 mL),
washed with water (2 ꢂ 100 mL) and brine (2 ꢂ 100 mL), dried over
MgSO4, and the solvent was removed under reduced pressure. The residue
was purified by column chromatography (CH2Cl2/Hexane/CH3OH,
10 : 4 : 1) to give doxorubicinone-14-acetate, 6 (46.0 mg, 96%) as a pale
red powder. Mp 242–2438C [a]D20 þ 192.98 (c 0.1, dioxane); IR (KBr)
3846, 3744, 3620, 2763, 2362, 1741, 1707, 1694, 1645, 1549, 1532, 1517,
1
1232, 677 cm21; H NMR (400 MHz, DMSO-d6) d 13.86 (s, 1 H, PhOH),
13.32 (s, 1 H, PhOH), 7.93 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.73 (dd, 1 H,
J ¼ 7.8, 8.3 Hz, ArH), 7.35 (d, 1 H, J ¼ 8.3 Hz, ArH), 5.60 (s, 1 H, C9OH),
5.26 (d, 1 H, J ¼ 17.1 Hz, C14H), 5.12 (d, 1 H, J ¼ 17.1 Hz, C14H),
4.84 (d, 1 H, J ¼ 3.4 Hz, C7eqH), 4.05 (s, 3 H, C4OCH3), 3.44 (s, 1 H,
C7OH), 3.21 (d, 1 H, J ¼ 18.5 Hz, C10eqH), 2.97 (d, 1 H, J ¼ 18.5 Hz,
C
10axH), 2.41 (d, 1 H, J ¼ 14.5 Hz, C8eqH), 2.91 (dd, 1 H, J ¼ 3.4, 14.5 Hz,
C
8axH), 2.15 (s, 3 H, C14OAc); 13C NMR (100 MHz, DMSO-d6) d 204.57,
186.60, 186.39, 170.15, 160.68, 156.43, 155.02, 136.07, 135.32, 119.31,
118.22, 111.04, 110.95, 75.34, 70.29, 64.57, 57.28, 56.45, 56.41, 37.02,
31.97, 29.05, 20.35; UV (CH2Cl2) lmax (log 1) 234 (0.15), 253 (0.09), 288
(0.04); Mass (FABþ, Na) m/z 863 (M þ Na)þ.
Daunomycinone-7-methyl(tri-O-acetyl
ester)-a-D-glucuronide
(DM7aGa, 8a) and daunomycinone-7-methyl(tri-O-acetyl ester)-b-D-
glucuronide (DM7bGa, 8b). A mixture of daunomycinone, 4 (0.30 g,
0.75 mmol), yellow HgO (0.90 g, 4.14 mmol), HgBr2 (0.43 g, 1.13 mmol),
˚
and powdered molecular sieves 3 A (1.0 g, activated at 3508C under a
stream of N2) in dry CH2Cl2 (50 mL) was stirred for 30 min at room temp-
erature. After glucopyranosyl bromide 7 (0.43 g, 1.13 mmol) in dry CH2Cl2
(5.0 mL) was added, the mixture was refluxed for 17 h in a dark place. In
TLC (CH2Cl2/acetone ¼ 10 : 1), the mixture showed spots at Rf 0.7 (8a,
minor), 0.6 (8b, major), and 0.3 (daunomycinone, slight) along with
several minor spots. The mixture was filtered through a celite bed, the bed
being washed repeatedly with CH2Cl2. The filtrate and washings combined
were washed with aqueous 30% KI, saturated aqueous NaHCO3, and
water, then dried (MgSO4) and concentrated. The residue was purified by

3506
Rho et al.
column chromatography on silica gel (CH2Cl2/acetone ¼ 10 : 1) to give
DM7aGa, 8a (0.12 g, 22%) and DM7bGa, 8b (0.28 g, 52%) as a red
powder. DM7aGa (8a): Mp 115–1178C; [a]2D0 þ 72.018 (c 0.1, CH2Cl2);
IR (KBr) 3450, 2990, 2900, 1765, 1711, 1610, 1550, 1455, 1431, 1268,
1250, 1190, 1130, 1010, 850, 765 cm21 1H NMR (400 MHz, CDCl3) d
;
14.04 (s, 1 H, PhOH), 13.24 (s, 1 H, PhOH), 8.02 (d, 1 H, J ¼ 7.8 Hz,
ArH), 7.79 (dd, 1 H, J ¼ 7.8, 8.3 Hz, ArH), 7.40 (d, 1 H, J ¼ 8.3 Hz, ArH),
0
5.95 (d, 1 H, J ¼ 4.9 Hz, C1 H), 5.54 (s, 1 H, C7eqH), 5.23 (t, 1 H, J ¼ 7.3,
0
0
C3 H), 5.17 (d, 1 H, J ¼ 7.8, C4 H), 4.81 (s, 1 H, C9OH), 4.52 (dd, 1 H,
0
0
J ¼ 3.4, 6.8 Hz, C2 H), 4.31 (d, 1 H, J ¼ 7.8 Hz, C5 H), 4.08 (s, 3 H,
C4OCH3), 3.79 (s, 3 H, COOCH3), 3.17 (d, 1 H, J ¼ 18.6 Hz, C10eqH),
3.05 (d, 1 H, J ¼ 18.6 Hz, C10axH), 2.56 (d, 1 H, J ¼ 15.1 Hz, C8eqH), 2.40
(s, 3 H, C14CH3), 2.38 (s, 3 H, sugar OAc), 2.12 (s, 3 H, sugar OAc), 2.10
(s, 3 H, sugar OAc), 2.00 (dd, 1 H, J ¼ 4.4, 15.1 Hz, C8axH); 13C NMR
(400 MHz, CDCl3) d 211.52, 187.14, 186.88, 169.32, 168.77, 168.68,
161.02, 155.80, 155.47, 135.68, 135.45, 135.30, 133.24, 123.78, 122.95,
120.91, 119.77, 118.45, 111.54, 111.48, 96.38, 73.37, 71.87, 70.73, 70.29,
69.04, 68.05, 63.99, 56.66, 52.81, 34.14, 29.95, 24.71, 20.72; UV
(CH2Cl2) lmax (log 1) 235 (2.50), 250 (1.54), 482 (1.01); Mass (FABþ,
Na) m/z 736.8 (M þ Na)þ. DM7bGa (8b): Mp 215–2208C
[a]2D0 þ 162.298 (c 0.1, CH2Cl2); IR (KBr) 3500, 3010, 2980, 2950, 1791,
1749, 1651, 1590, 1475, 1405, 1363, 1265, 1190, 1110, 1050, 991,
780 cm21 1H NMR (400 MHz, CDCl3) d 14.03 (s, 1 H, PhOH), 13.22
;
(s, 1 H, PhOH), 8.26 (d, 1 H, J ¼ 7.3 Hz, ArH) 7.89 (dd, 1 H, J ¼ 7.3,
8.3 Hz, ArH), 7.63 (d, 1 H, J ¼ 8.3 Hz, ArH), 5.40 (s, 1 H, C7eqH), 5.31
0
0
(t, 1 H, J ¼ 9.3 Hz, C3 H), 5.24 (dd, 1 H, J ¼ 9.3, 9.8 Hz, C4 H), 5.15
0
0
(d, 1 H, J ¼ 7.8 Hz, C1 H), 4.97 (dd, 1 H, J ¼ 7.3, 9.3 Hz, C2 H), 4.19
0
(s, C9-OH), 4.16 (d, 1 H, J ¼ 9.8 Hz, C5 H), 4.10 (s, 3 H, C4OCH3), 3.79
(s, 3 H, CO2CH3), 3.22 (d, 1 H, J ¼ 19.1 Hz, C10eqH), 2.99 (d, 1 H,
J ¼ 19.1 Hz, C10axH), 2.61 (d, 1 H, J ¼ 14.7 Hz, C8eqH), 2.45 (s, 3 H,
C14CH3), 2.17 (s, 6 H, sugar OAc), 2.09 (dd, 1 H, J ¼ 4.9, 14.5 Hz,
C
8axH), 2.05 (s, 3 H, sugar OAc); 13C NMR (400 MHz, CDCl3) d 213.57,
187.56, 187.16, 170.30, 169.78, 167.46, 161.54, 156.54, 156.26, 136.40,
136.20, 136.00, 132.95, 121.35, 120.29, 118.88, 111.95, 111.75, 101.60,
72.83, 72.04, 71.44, 70.35, 69.90, 58.87, 57.12, 53.33, 35.57, 33.86, 25.44,
21.04, 20.95, 20.88, 18.83; UV (CH2Cl2) lmax (log 1) 233 (1.78), 252
(1.01), 483 (0.48); Mass (FABþ, Na) m/z 736.8 (M þ Na)þ.
14-Acetoxydoxorubicinone-7-methyl(tri-O-acetyl ester)-a-D-glucuronide
(DX7aGa, 9a) and 14-acetoxydoxorubicinone-7-methyl(tri-O-acetyl ester)-b-
D-glucuronide ((DX7bGa, 9b). A mixture of 14-acetoxydoxorubicinone,
6 (0.25 g, 0.55 mmol), yellow HgO (0.65 g, 3.01 mmol), HgBr2 (0.22 g,
˚
0.60 mmol), and powdered molecular sieves 3 A (1.5 g, activated at 3508C

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3507
under a stream N2) in dry CH2Cl2 (60 mL) was stirred for 30 min at room
temperature. After glucopyranosyl bromide 7 (0.33 g, 0.82 mmol) in dry
CH2Cl2 (5.5 mL) was added, the mixture was refluxed for 36 h in a dark
place. In TLC (CH2Cl2/acetone ¼ 10 : 1), the mixture showed spots at Rf
0.6 (9a, minor), 0.5 (9b, major), and 0.2 (14-acetoxydoxorubicinone, slight)
along with several minor spots. The mixture was filtered through a celite
bed, the bed being washed repeatedly with CH2Cl2. The filtrate and washings
combined were washed with aqueous 30% KI, saturated aqueous NaHCO3,
and water, then dried (MgSO4) and concentrated. The residue was purified
by column chromatography on silica gel (CH2Cl2/acetone ¼ 10 : 1) to give
DX7aGa, 9a (0.09 g, 21%) and DX7bGa, 9b (0.20 g, 48%) as a red
powder. DX7aGa (9a): Mp 118–1208C; [a]2D0 þ98.128 (c 0.1, CH2Cl2); IR
(KBr) 3054, 2986, 2685, 2305, 1754, 1606, 1550, 1422, 1259, 896,
768 cm21 1H NMR (400 MHz, CDCl3) d 13.95 (s, 1 H, PhOH), 13.20
;
(s, 1 H, PhOH), 8.03 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.79 (dd, 1 H, J ¼ 7.8,
8.3 Hz, ArH), 7.40 (d, 1 H, J ¼ 8.3 Hz, ArH), 6.31 (d, 1 H, J ¼ 3.4 Hz,
0
C1 H), 5.56 (s, 1 H, C9OH), 5.36 (d, 1 H, J ¼ 18.6 Hz, C14H), 5.34 (m, 1 H,
0
0
C3 H), 5.21 (m, 1 H, C4 H), 5.15 (d, 1 H, J ¼ 18.6 Hz, C14H), 4.92 (dd, 1 H,
0
0
J ¼ 2.9, 9.8 Hz, C2 H), 4.71 (s, 1 H, C7eqH), 4.33 (d, 1 H, J ¼ 9.7 Hz, C5 H),
4.09 (s, 3 H, C4OCH3), 3.75 (s, 3 H, COOCH3), 3.28 (d, 1 H, J ¼ 18.6 Hz,
C
10eqH), 2.97 (d, 1 H, J ¼ 18.6 Hz, C10axH), 2.49 (d, 1 H, J ¼ 15.1 Hz,
8eqH), 2.23 (dd, 1 H, J ¼ 15.1, 4.4 Hz, C8axH), 2.21 (s, 3 H, C14OAc), 2.09
C
(s, 3 H, sugar OAc), 2.06 (s, 3 H, sugar OAc), 2.03 (s, 3 H, sugar OAc); 13C
NMR (400 MHz, CDCl3) d 207.62, 187.60, 187.04, 170.80, 169.94, 169.70,
169.67, 167.17, 161.50, 156.54, 155.88, 136.29, 135.97, 135.50, 134.10,
122.12, 120.29, 118.86, 112.04, 111.96, 111.69, 73.34, 73.08, 71.35, 71.08,
69.89, 69.52, 68.93, 68.71, 66.53, 62.74, 35.89, 33.99, 22.16, 21.04, 20.86;
UV (CH2Cl2) lmax (log 1) 237 (2.20), 255 (1.61), 481 (0.75); Mass (FABþ,
Na) m/z 794.8 (M þ Na)þ. DX7bGa (9b): Mp 210–2138C [a]2D0 þ158.988
(c 0.1, CH2Cl2); IR (KBr) 3536, 2957, 1755, 1618, 1581, 1440, 1375, 1225,
1043, 809 cm21; H NMR (400 MHz, CDCl3) d 14.04 (s, 1 H, PhOH), 13.16
1
(s, 1 H, PhOH), 8.02 (d, 1 H, J ¼ 7.8 Hz, ArH), 7.79 (dd, 1 H, J ¼ 7.8,
8.3 Hz, ArH), 7.40 (d, 1 H, J ¼ 8.3 Hz, ArH), 5.39 (s, 1 H, C9OH),
0
5.37 (d, 1 H, J ¼ 18.6 Hz, C14H), 5.30 (t, 1 H, J ¼ 9.3 Hz, C3 H), 5.23 (dd,
0
1 H, J ¼ 9.8, 9.3 Hz, C4 H), 5.20 (d, 1 H, J ¼ 18.6 Hz, C14H), 5.14 (d, 1 H,
0
0
J ¼ 7.8 Hz, C1 H), 4.95 (dd, 1 H, J ¼ 9.3, 7.8 Hz, C2 H), 4.72 (s, 1 H,
0
C
7eqH), 4.17 (d, 1 H, J ¼ 9.8 Hz, C5 H), 4.09 (s, 3 H, C4OCH3), 3.80 (s, 3 H,
COOCH3), 3.24 (d, 1 H, J ¼ 19.0 Hz, C10eqH), 2.98 (d, 1 H, J ¼ 19.0 Hz,
C
10axH), 2.26 (d, 1 H, J ¼ 14.0 Hz, C8eqH), 2.20 (s, 3 H, C14OAc), 2.09 (dd,
1 H, J ¼ 14.0, 3.4 Hz, C8axH), 2.05 (s, 3 H, sugar OAc), 2.00 (s, 3 H, sugar
OAc), 1.84 (s, 3 H, sugar OAc); 13C NMR (100 MHz, CDCl3) d 207.57,
187.09, 186.64, 170.35, 169.92, 169.52, 169.46, 167.04, 161.08, 155.97,

3508
Rho et al.
155.67, 135.90, 135.44, 135.30, 132.14, 120.73, 119.89, 118.53, 111.55,
111.36, 101.21, 77.24, 76.62, 72.38, 71.51, 70.96, 69.96, 69.42, 66.43,
56.73, 53.06, 35.27, 33.61, 20.59, 20.53, 20.52; UV (CH2Cl2) lmax (log 1)
236 (3.15), 251 (2.52), 483 (1.38); Mass (FABþ, Na) m/z 794.8 (M þ Na)þ.
Daunomycinone-7-a-D-glucuronide (DM7aG, 10a). DM7aGa, 8a
(0.18 g, 0.25 mmol) was dissolved in 18 mL of MeOH/H2O/THF (5/2/1,
v/v) and 15.1 mL (6.0 equiv) of 0.1 N LiOH/H2O solution was added at
08C. The resulting deep blue solution was stirred at 08C under argon atmos-
phere. Progress of the deprotection was monitored on reversed-phase TLC
(SiO2-C18, MeCN/H2O, 1/2). After 2 h of deprotection, the reaction
mixture was diluted with 15 mL of H2O and neutralized by adding ca.
0.50 g of amberlite cation exchange material (Hþ form); 2 mL of THF was
added to homogenize the suspension. The amberlite resin was removed by
filtration. The MeOH and THF suspended in the water layer were removed
by evaporation, and red aqueous product solution was transferred to a reversed
phase column packed with RP-C18 material and eluted with MeCN/H2O
(1 : 3) to purification. The solvents were removed under reduced pressure to
give DM7aG, 10a (1.4 mg, 0.98%) as a red solid. Mp 156–1578C; IR
(KBr) 3286, 2922, 2890, 1726, 1614, 1396, 1263, 1217, 1053, 905,
1
748 cm21; H NMR (400 MHz, D2O) d 7.78 (bs, 1 H, ArH), 7.51 (m, 2 H,
0
ArH), 5.46 (d, 1 H, J ¼ 4.2 Hz, C1 H), 5.39 (s, 1 H, C7eqH), 4.05 (d, 1 H,
0
0
0
J ¼ 10.2 Hz, C5 H), 3.97 (s, 3 H, C4OMe), 3.75 (m, 2 H, C3 H, C4 H), 3.52
0
(m, 1 H, C2 H), 2.95 (d, 1 H, J ¼ 18.1 Hz, C10eqH), 2.71 (d, 1 H, J ¼ 14.2,
C
8eqH), 2.60 (d, 1 H, J ¼ 18.1 Hz, C10axH), 2.43 (s, 1 H, C14CH3), 2.04
(d, 1 H, J ¼ 14.2 Hz, C8axH); Mass (FABþ, Na) m/z 596.7 (M þ Na)þ.
Daunomycinone-7-b-D-glucuronide (DM7bG, 10b). Following the
above procedure described for 10a, reaction of DM7bGa, 8b (0.09 g,
0.13 mmol) with 0.1 N LiOH (7.6 mL, 0.76 mmol) in 12 mL of MeOH/
H2O/THF (5/2/1, v/v) yielded 56.4 mg (78%) of solid 10b. Mp
166–1688C; [a]2D0 þ79.878 (c 0.1, H2O þ MeOH); IR (KBr) 3480, 3210,
2910, 2880, 1715, 1698, 1392, 1248, 1229, 1190, 1045, 1011, 991, 898,
798, 772 cm21; H NMR (400 MHz, Methanol-d4) d 7.38 (bs, 1 H, ArH),
1
0
7.09 (m, 2 H, ArH), 5.21(s, 1 H, C7eqH), 4.80 (d, 1 H, J ¼ 7.2 Hz, C1 H),
0
3.67 (d, 1 H, J ¼ 9.3 Hz, C5 H), 3.64 (s, 3 H, C4OMe), 3.41 (m, 2 H,
0
0
0
C3 H, C4 H), 3.20 (dd, 1 H, J ¼ 7.8, 8.3 Hz, C2 H), 2.64 (d, 1 H,
J ¼ 17.6 Hz, C10eqH), 2.47 (d, 1 H, J ¼ 14.7, C8eqH), 2.27 (bs, 4 H,
C
10axH, C14CH3), 1.77 (d, 1 H, J ¼ 15.1 Hz, C8axH); 13C NMR (400 MHz,
Methanol-d4) d 212.98, 186.63, 186.34, 173.03, 160.94, 155.94, 155.62,
135.75, 135.57, 135.08, 132.21, 120.35, 119.61, 118.43, 111.36, 111.26,
104.27, 77.61, 76.18, 75.29, 74.31, 73.38, 60.41, 56.62, 34.00, 32.53,
24.80; UV (H2O) lmax (log 1) 230 (2.40), 251 (1.53), 479 (0.79); Mass
(FABþ, Na) m/z 596.7 (M þ Na)þ.

Syntheses of Daunomycinone- and Doxorubicinone-7-D-Glucuronide
3509
Doxorubicinone-7-a-D-glucuronide (DX7aG, 11a). Following the
above procedure described for 10a, reaction of DM7bGa, 9a (0.11 g,
0.14 mmol) with 0.1 N LiOH (10.0 mL, 0.10 mmol) in 16 mL of MeOH/
H2O/THF (5/2/1, v/v) yielded 28.6 mg (34%) of solid 11a. Mp
184–1878C; [a]2D0 þ 53.298 (c 0.1, H2O þ MeOH); IR (KBr) 3427, 2922,
2861, 1957, 1741, 1625, 1516, 1430, 1376, 1249, 11044, 897, 767, 720,
602 cm21
;
1H NMR (400 MHz, D2O) d 7.55 (t, 1 H, J ¼ 8.0 Hz, ArH),
7.37 (bs, 1 H, ArH), 7.27 (d, 1 H, J ¼ 7.7, ArH), 5.79 (d, 1 H,
0
J ¼ 4.8 Hz, C1 H), 5.09 (s, 1 H, C7eqH), 4.91 (m, 2 H, C14H), 3.78 (s, 3 H,
0
0
0
C4OMe), 3.69 (d, 1 H, J ¼ 9.6 Hz, C5 H), 3.43 (m, 2 H, C3 H, C2 H), 3.18
0
(dd, 1 H, J ¼ 9.6, 8.8 Hz C4 H), 2.77 (d, 1 H, J ¼ 18.0 Hz, C10eqH), 2.52
(d, 1 H, J ¼ 15.2, C8eqH), 2.40 (d, 1 H, J ¼ 18.0 Hz, C10axH), 2.01 (d, 1 H,
J ¼ 15.2 Hz, C8axH; 13C NMR (400 MHz, D2O) d 210.06, 187.90,
186.81, 172.10, 166.51, 163.48, 161.20, 160.30, 139.90, 138.78, 131.20,
130.86, 126.56, 121.79, 120.87, 120.65, 118.95, 101.10, 77.16, 73.98,
72.87, 72.68, 71.23, 65.43, 63.18, 56.81, 31.29, 30.26; UV (H2O) lmax
(log 1) 238 (1.97), 249 (1.13), 477 (0.45); Mass (FABþ, Na) m/z 612.9
(M þ Na)þ.
Doxorubicinone-7-b-D-glucuronide (DX7bG, 11b). Following the
above procedure described for 10a, reaction of DM7bGa, 9b (0.12 g,
0.16 mmol) with 0.1 N LiOH (10.9 mL, 1.09 mmol) in 18 mL of MeOH/
H2O/THF (5/2/1,v/v) yielded 51.4 mg (56%) of solid 11b. Mp
170–1728C (decomp); [a]D20 þ96.568 (c 0.1, H2O þ MeOH); IR (KBr)
3400, 2919, 2843, 1960, 1733, 1617, 1584, 1413, 1281, 1235, 1061,
797 cm21; H NMR (400 MHz, D2O) d 7.45 (bs, 1 H, ArH), 7.18 (bs, 2 H,
1
0
ArH), 4.77 (d, 1 H, J ¼ 7.6 Hz, C1 H), 4.67 (m, 3 H, C7eqH, C14H), 3.69
0
0
0
(s, 3 H, C4OMe), 3.66 (d, 1 H, J ¼ 8.8 Hz, C5 H), 3.41 (m, 2 H, C3 H, C2 H),
0
3.19 (dd, 1 H, J ¼ 8.4, 8.0 Hz C4 H), 2.75 (d, 1 H, J ¼ 18.4 Hz, C10eqH),
2.54 (d, 1 H, J ¼ 15.6, C8eqH), 2.31 (d, 1 H, J ¼ 18.4 Hz, C10axH), 1.82 (dd,
1 H, J ¼ 14.0, 4.0 Hz, C8axH; 13C NMR (400 MHz, D2O) d 210.21, 188.24,
187.16, 173.24, 162.36, 159.12, 159.07, 136.18, 134.87, 133.68, 133.17,
123.36, 121.68, 120.99, 120.87, 119.16, 103.36, 78.13, 76.87, 75.96, 73.98,
70.30, 64.17, 63.90, 61.76, 56.17, 32.98, 32.76; UV (H2O) lmax (log 1) 241
(2.21), 251 (1.40), 479 (0.56); Mass (FABþ, Na) m/z 612.9 (M þ Na)þ.
ACKNOWLEDGMENTS
This work was supported by a grant of the Korea Health 21 R & D
project (01-PJ-PG3-21500-0031), Ministry of Health and Welfare. We
gratefully acknowledge Korea Basic Science Institute (KBSI) for the NMR
and mass analyses.

3510
Rho et al.
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Received in Japan February 18, 2004