Facile total syntheses of idarubicinone-7-β-D-glucuronide: Convenient preparations of AB-ring synthon using some carboxylic acid derivatives

Article abstract of DOI:10.1081/SCC-120030758

Regiospecific syntheses of idarubicinone coupled with D-glucuronic acid are described. Cyclization of dimethoxybenzene with carboxylic acid derivatives in polyphosphoric acid (PPA) in one step afforded the naphthalenones 7, which were transformed to the (

Full text of DOI:10.1081/SCC-120030758

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Facile Total Syntheses of
Idarubicinone‐7‐β‐D‐glucuronide: Convenient
Preparations of AB‐Ring Synthon Using Some
Carboxylic Acid Derivatives
Young S. Rho a , Jihyung Park a , Gyuil Kim a , Hyesun Kim a , Hongsig Sin a , Pyoung Won
Suh a & Dong Jin Yoo b
a Department of Chemistry , Chonbuk National University , Chonju, Korea
b Department of Chemistry , Seonam University , Namwon, 590‐711, Korea
Published online: 16 Aug 2006.
To cite this article: Young S. Rho , Jihyung Park , Gyuil Kim , Hyesun Kim , Hongsig Sin , Pyoung Won Suh & Dong Jin Yoo
(2004) Facile Total Syntheses of Idarubicinone‐7‐β‐D‐glucuronide: Convenient Preparations of AB‐Ring Synthon Using Some
Carboxylic Acid Derivatives, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:9, 1703-1722, DOI: 10.1081/SCC-120030758
To link to this article: http://dx.doi.org/10.1081/SCC-120030758
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1703–1722, 2004
Facile Total Syntheses of Idarubicinone-7-
b-D-glucuronide: Convenient Preparations
of AB-Ring Synthon Using Some
Carboxylic Acid Derivatives
Young S. Rho,1 Jihyung Park,1 Gyuil Kim,1 Hyesun Kim,1
Hongsig Sin,1 Pyoung Won Suh,1 and Dong Jin Yoo2,
*
1Department of Chemistry, Chonbuk National University, Chonju, Korea
2Department of Chemistry, Seonam University, Namwon, Korea
ABSTRACT
Regiospecific syntheses of idarubicinone coupled with D-glucuronic acid
are described. Cyclization of dimethoxybenzene with carboxylic acid
derivatives in polyphosphoric acid (PPA) in one step afforded the
naphthalenones 7, which were transformed to the (+)-idarubicinone 3b
by general methods. Esterification of (+)-3b with (S)-(þ)-O-acetylman-
delic acid with subsequent separation and deprotection gave (þ)-3b
and (2)-3b. Reaction of separated two stereoisomers with acetobromo-
a-D-glucuronic acid methyl ester respective followed by hydrolysis
using lithium hydroxide and amberite cation exchange resin furnished
*
Correspondence: Dong Jin Yoo, Department of Chemistry, Seonam University,
Namwon 590-711, Korea; Fax: 82-63-620-0013; E-mail: djyoo@seonam.ac.kr.
1703
DOI: 10.1081/SCC-120030758
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Rho et al.
two kinds of idarubicinone-7-b-D-glucuronide (20 and 21) that are
coupled at C-7 position of idarubicinone.
Key Words: Anthracycline; Idarubicin analogs; Glucuronic acid;
Glycosylation.
INTRODUCTION
Anthracycline antibiotics are well-known antitumor agents. Daunomycin
(1a) and doxorubicin (2a) are a group of anthracyclines used widely in clinical
therapy as a major drug in the treatment of solid tumors since the early 1970s.
However, their utility is limited due to a number of side effects, the most series
being dose-dependant cardiotoxicity.[1] Idarubicin (3a) or 4-demethoxydoxo-
rubicin that belongs to one of the non-natural analogs was developed as arti-
ficial anthracyclines to improve the pharmacological profile (Fig. 1).[2] Its
pharmacodynamic and pharmacokinetic properties published by Hollingshead
and Faulds in 1991.[3] Because these compounds cannot be prepared from the
fermentation process, there have been also a number of reports on the syn-
thetic method of them. The antitumor activity of anthracyclines is mainly
dependent on the chirality of A-ring, and they are active only in their natural
absolute configuration.[4a] Therefore, much effort has been devoted to devel-
oping more efficient methods for the enantiomeric synthesis of aglycones.[4]
Recently, examples[5] are reports of coupling some drugs with glucuro-
nide that were found to have enhanced drug efficacy. The syntheses of anthra-
cycline analogs that are attached glucuronide at amino group of daunosamine
in doxorubicin and/or daunomycin have been also reported.[6a] Studies com-
paring antitumor activities of these derivatives and corresponding anthra-
cycline have been often reported.[6] However, the properties and preparation
of idarubicinone-7-D-glucuronides that are coupled idarubicinone [(+)-3b]
Figure 1. Some chemical structures of anthracyclines (1–3).

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Syntheses of Idarubicinone-7-b-D-glucuronide
1705
with D-glucuronic acid at C-7 have not been reported yet. In previous papers,
we reported the syntheses of novel fucosyl anthracycline[7a] having a fluorine
at C-9 position[7b] and idarubicinone (3b).[7c,d] Related to these reports, we
wished to prepare some idarubicin analogs containing glucuronic acid.
In this paper, we wish to report the synthesis of new idarubicinone-7-
b-D-glucuronide (20 and 21) attaching glucuronic acid moiety to (þ)-3b and
(2)-3b, respectively. Additionally, we wish to describe the facile synthetic
method on an AB-ring synthon 7a,b necessary for the synthesis of the aglycone.
RESULTS AND DISCUSSION
Many synthetic efforts have been devoted to prepare AB-synthon of ida-
rubicinone (3b).[4] In this paper, we envisaged that Friedel–Crafts reaction
using dimethoxybenzene would provide us with a naphthalenecarboxylic
acid that could be readily converted to the desired synthon, which can then
be built up to the tetracyclic ring system in gram scale. For this purpose com-
mercially available starting materials, e.g., itaconic anhydride (4), itaconic
acid (5), and 3-acetyl-3-butenoic acid (6) were considered as they can be
formed into a mixture of 7 and 8 in one step (Sch. 1). The reaction of
dimethoxybenzene with above carboxylic acid derivatives in the present of
polyphosphoric acid (PPA) or AlCl3 gave exciting results as follows: coupling
dimethoxybenzene with itaconic anhydride (4) using PPA (1008C, 10 min)[8]
gave the desired naphthalenecarboxylic acid 7a and the undesired acrylic acid
8a as 1 : 1 ratio in 82% yield (entry 1), whereas using AlCl3 (1.2 eq, r.t., 4 hr/
CH2Cl2) yielded as 1 to 4 ratio (7a/8a) in 83% yield (entry 2). However, the
reaction of dimethoxylbenzene with itaconic acid (5) using PPA afforded 7a
and 8a as 4 to 1 ratio in 82% yield because itaconic acid moiety strongly
favors the cyclization reaction in PPA condition (entry 3), whereas using
AlCl3 produced no any product (entry 4). Moreover, the same reaction with
3-acetyl-3-butenoic acid (6) obtained from the known procedure[9] using
PPA gave only 7b[10] in 72% without producing 8b (entry 5), whereas using
AlCl3 also furnished no any product (entry 6). Results of the coupling of
dimethoxybenzene with some carboxylic acid derivatives are summarized in
Table 1.
Tetralone 7a can be transformed to 11 by appropriate reactions and the
undesired 8 can be inverted to the desired 7 which can be recycled to 11.
Based on the prediction our attention has been directed to the preparation of
11. 7a for the synthesis of 11 was converted quantitatively into 9 with
NaBH4 (1.5 eq, 08C, 2 hr/MeOH). But, when using excess NaBH4, lactone
10[11] was obtained in 85%. Reaction of 9 with methyl lithium (4.2 eq, 08C,
2 hr/THF) for 9 transformed into 11 was not successful and only the lactone

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Rho et al.

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Syntheses of Idarubicinone-7-b-D-glucuronide
1707
Table 1. Coupling of dimethoxybenzene with carboxylic acid derivatives (4, 5,
and 6).
Products
Entry
Compound
Conditions
7/8 (%)a
7/8 ratio
1
2
3
4
5
6
4
4
5
5
6
6
PPA/1008C/10 min
AlCl3/r.t./4 hr
PPA/1008C/10 min
AlCl3/r.t./4 hr
PPA/1008C/10 min
AlCl3/r.t./4 hr
7a(41)/8a(41)
7a(17)/8a(66)
7a(66)/8a(16)
50/50
20/80
80/20
—
b
—
7b(72)/8b(0)
100/0
—
b
—
aIsolated yield after SiO2 column chromatography.
bNot obtained.
product 10 (94% overall yield) was mainly obtained because g-hydroxy acids
strongly favor the intramolecular lactonization rather than intermolecular
nucleophilic attack by methyl lithium. Synthetic attempt for the formation
of 11 from 10 using excess methyl lithium gave no reaction (Sch. 2).
Moreover, the reduction of benzylic carbonyl group of 7b using NaBH4 or
NaBH3CN to get 11 failed due to the non-selectivity of the reagents.
So, tetralin 13[12] was obtained from 7a by removing the carbonyl group
with Et3SiH/CF3CO2H followed by reacting with methyl lithium (3.5 eq, 08C,
2 hr/THF) (Sch. 3). To introduce two hydroxy groups at C-2 and C-4, 13 was
reacted under a basic oxygenation condition (O2, 2158C, 4.2 eq t-BuOK,
2.2 eq P(OEt)3/DMF).[13] However, monohydroxylated compound 14 was
only obtained in 85%.4c,8b After protecting of carbonyl group of 13 using
ethylene glycol or transformating two methoxy groups into hydroxy groups,
the efforts to introduce hydroxy group at C-4 position failed. Therefore,
Scheme 2. Attempted methods for synthesis of 11.

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1708
Rho et al.
Scheme 3. (a) MeLi/THF, 08C. (b) O2, t-BuOK, P(OEt)3/DMF, 2158C. (c) C6H4-1,2-
(COCl)2, AlCl3/PhNO2, 80–1008C. (d) 1. HOCH2CH2OH, p-TsOH/PhH, reflux.
2. NBS, AIBN/CCl4, reflux; SiO2/wet THF; HCl/dioxane. (e) (S)-(þ)-O-Acetylmandelic
˚
acid, DCC, DMAP/CH2Cl2. (f) Satd. NaOH solution (5 drops). (g) ZnBr2, 4 A molecu-
lar sieves/CH2Cl2. (h) LiOH, Amberite resin/MeOH, THF.
7-deoxyidarubicinone (16) was made from direct condensation of phthaloyl
dichloride with (+)-14 without further chiral resolution.[14] Additionally,
condensation of phthaloyl dichloride with 13 in the same manner yielding
15 (87%)[15] followed by treating 15 with the same basic oxygenation con-
dition gave 16 in 86%4c,8b,15a without formation of product 3b. Compound

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Syntheses of Idarubicinone-7-b-D-glucuronide
1709
14 and 16 were observed as 1 : 1 ratio at 13.69 and 17.96 min and the same
ratio at 43.32 and 53.47 min, respectively, by HPLC analysis (Daicel Chiralcel
OD-H, 20% IPA in hexane, 0.5 mL min21, 254 nm, 208C). And so, they should
be racemic mixture. The esterification of (+)-14 or (+)-16 with resolving
agents, (S)-(þ)-O-acetylmandelic acid or (þ)-tartaric acid for chiral resol-
ution were not successful, probably due to steric hindrance from acetyl
group and/or electron deficiency of hydroxy group resulting from electron
withdrawing of carbonyl group. Therefore, we wished to isolate the racemate
from diastereomer 3b as follows: selective hydroxylation at C-7 position was
achieved by converting carbonyl group at C-13 to acetal form using ethylene
glycol and p-TsOH in refluxing benzene and preventing the introduction of
OH group to C-14 and C-10 position. After bromination of the ketal with bro-
mine and AIBN as a catalyst in refluxing CCl4, cis form of 3b as a major pro-
duct was obtained in 78% by hydrolysis with silica gel in wet THF.[16]
Racemate (+)-3b looked like one spot on TLC.[15a,17a] From HPLC analysis
under the same manner above, however, it was confirmed that (+)-3b was
1 : 1 isomeric mixture at 85.64 and 103.12 min. After coupling OH group of
C-7 in (+)-3b with (S)-(þ)-O-acetylmandelic acid in the presence of DCC
and DMAP in dichloromethane to afford compound 17a and 17b followed
by isolation of two diastereomers by flash chromatography, cleavage the
ester linkage with saturated NaOH produced the same isomers, optically
active (þ)-3b and (2)-3b in total 86%. The physical and spectral properties
of obtained (þ)-3b were identical in all respects with the literature.[4c,17b]
However, the specific rotation of (þ)-3b and (2)-3b were þ1598 (lit.[17b]
[a]2D0 þ154, c 0.1, dioxane) and 21568 (c 0.1, dioxane), respectively. The
retention time of two isomers were also 85.64 min for (2)-3b and
103.12 min for (þ)-3b on HPLC spectra as described above. From NMR spec-
trum analysis, it was confirmed that two (+)-cis enantiomer 3b were formed
as axial forms from 16 as the results of Tamura and Kita.[16]
Glycosylation of acetobromo-a-D-glucuronic acid methyl ester prepared
from glucuronolactone[5c,18] with (þ)-3b or (2)-3b in the presence of HgBr2
and HgO gave small amounts of desired b-anomers (18 and 19, ꢀ6%) accom-
panied by lesser amount of a-anomer and unidentical material. However, the
attempt using ZnBr2 gave only b-anomers, 18 (56%) and 19 (53%) through
neighboring group participation of the Koenigs–Knorr reaction.[19] Their
configurations were easily determined by analyzing scalar coupling con-
stants[17,20,21] in NMR spectra of 18 and 19. The 10-H chemical shift of 18
0
0
0
0
and 19 were 5.16 ppm (J1 ,2 ¼ 7.8 Hz) and 5.05 ppm (J1 ,2 ¼ 8.3 Hz), respec-
tively. The 20-H of 18 and 19 was assigned to the double-doublet at 4.95 ppm
and the observed coupling constants of 8.3 and 8.8 Hz, indicating the axial–
axial interactions for both 10-H and 30-H protons on the sugar ring. Therefore,
all products were b-configuration. The optical rotations of b-anomer were

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1710
Rho et al.
[a]2D0 þ45.58 for 18 and 279.88 for 19. Deprotection of the carbohydrate
moieties of protected compounds (18 and 19) was carried out using 0.1 M
lithium hydroxide and amberite cation exchange resin[5c,6a] to give idarubici-
none-7-b-D-glucuronides, 20 (84%) and 21 (82%) which will be studied on
biological activities.
In summary, we developed a synthetic method for the preparation of
AB-ring synthon 14 using carboxylic acid derivatives. We also prepared
(+)-idarubicinone (3b) from coupling phthaloyl dichloride with the AB-ring
synthon 14 and isolated two isomers of (þ)-3b and (2)-3b using (S)-(þ)-O-
acetylmandelic acid. Novel glycosides (20 and 21) containing glucuronic acid
moiety were readily also prepared via glycosylation of (þ)-idarubicinone 3b
and (2)-idarubicinone 3b with acetobromo-a-D-glucuronic acid methyl ester
using ZnBr2, followed by hydrolysis with lithium hydroxide and amberite
cation exchange resin. Detailed NMR analyses unambiguously proved the
anomeric configuration of the new compounds.
EXPERIMENTAL SECTION
All the reactions were carried out under dry argon and nitrogen atmo-
sphere with oven-dried glassware. Merck pre-coated silica gel plates
(Art.5554) with fluorescent indicator were used as analytical TLC. Gravity
column chromatography and flash column chromatography were carried out
on silica gel (230–400 mesh from Merck) and HPLC was carried out on a
Waters 4000 instrument having a Waters PDA UV spectrophotometer and a
Waters 410 differential refractometer. 1H and 13C NMR spectra were recorded
on a JEOL JNM EX-400 spectrometer. Chemical shifts were internally refer-
1
enced to TMS for H or to solvent signals for 13C. Infrared spectra were
recorded on a Nicolet 5-DXB series FT-IR spectrophotometer. Mass spectra
were obtained on a JEOL JNX-DX 300 spectrometer by the electron impact
or a Hewlett Packard 5972 series mass selective detector and a JEOL JMS
DX-110/110A Tandem mass spectrometer (FABþ). UV-VIS absorption spec-
tra were recorded on a Hitachi-556 spectrophotometer. The 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.
5,8-Dimethoxy-4-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid
(7a) and 2-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]acrylic acid (8a).
Method 1: Friedel–Crafts condensation. In a 100 mL three-necked, round-
bottomed flask fitted with a magnetic stirrer and reflux condenser was placed
itaconic anhydride (4) (0.61 g, 5.4 mmol) and dichloromethane (30 mL). After

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Syntheses of Idarubicinone-7-b-D-glucuronide
1711
brief stirring, aluminum chloride (0.86 g, 6.5 mmol) was added all at once.
The mixture was kept at room temperature for 10min and added with
1,4-dimethoxybenzene (0.5g, 3.6 mmol), and then stirred for 4 hr. The mixture
was acidified with 2 N hydrochloric acid and then extracted with dichloro-
methane. The combined organic layer was washed with saturated sodium
bicarbonate and brine. After drying over anhydrous magnesium sulfate, the
solvent was removed in vacuo and the crude material was purified by flash
column chromatography (ethyl acetate/hexane ¼ 1 : 1) to afford 7a (0.15 g,
17%) as a white solid and 8a (0.60 g, 66%) as a pale yellow solid. 7a: m.p.
180–1828C; 1H NMR (CDCl3) d 7.03 (d, 1H, J ¼ 8.8 Hz, ArH), 6.83
(d, 1H, J ¼ 8.8 Hz, ArH), 3.87 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.41 (dd,
1H, J ¼ 17.09, 3.42Hz, C1eqH), 3.16–3.09 (m, 1H, C2H), 2.96 (dd, 2H,
J ¼ 10.26 Hz, C3H), 2.85–2.78 (m, 1H, C1axH); 13C NMR (CDCl3) d 194.21,
174.66, 149.70, 132.00, 116.54, 110.98, 56.08, 55.92, 41.80, 38.13, 30.70,
1
25.54; MS (m/z) 250 (Mþ). 8a: m.p. 106–1188C; H NMR (CDCl3) d 7.36
(d, 1H, J ¼ 2.9 Hz, 1H, ArH), 7.05 (dd, 1H, J ¼ 2.9, 8.8 Hz, ArH), 6.45
(s, 1H, 55CH2), 5.73 (s, 1H, 55CH2), 4.01 (s, 2H, CH2), 3.88 (s, 3H, OCH3),
3.79 (s, 3H, OCH3); 13C NMR (CDCl3) d 197.78, 171.93, 153.43, 134.85,
129.92, 127.14, 120.88, 113.90, 113.07, 55.96, 55.77, 46.63; MS (m/z)
250 (Mþ).
Method 2: Tandem acylation-cycloaddition. Itaconic acid (5) (1.31 g,
10.1 mmol) and 1,4-dimethoxybenzene (2.78 g, 20.1 mmol) were added to
PPA (ca. 20 g), pre-heated to 1008C, and the mixture was stirred for 10 min
before being cooled to room temperature. Water and concentrated aqueous
NH3 solution was added to the residue and the aqueous mixture was extracted
several times with diethyl ether. The combined organic layer were dried over
anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude
material was purified by flash column chromatography (ethyl acetate/hexane
1 : 1) to afford 7a (3.32 g, 66%) as a white solid and 8a (0.81 g, 16%) as a
pale yellow solid. The physical and spectroscopic properties of the products
agreed well with those of method 1.
3-Acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenone (7b). Reac-
tion of dimethoxybenzene (3.24 g, 23.4 mmol) and 3-acetyl-3-butenoic acid (6)
(1.50 g, 11.7 mmol) in PPA (23.0 g) was carried out as described for the prep-
aration of 7a and 8a (upper method 2) to give 7b (4.19 g, 72%) as a white
1
solid: m.p. 121–1238C (lit.[10] 120–1228C); IR (KBr) 1721, 1683 cm21; H
NMR (CDCl3) d 7.02 (d, 1H, J ¼ 9.3 Hz, ArH), 6.83 (d, 1H, J ¼ 8.8 Hz, ArH),
3.86 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.36–3.31 (m, 1H, C1eqH), 3.16–3.08
(m, 1H, C2H), 2.84–2.80 (dd, J ¼ 11.7, 4.4 Hz, 2H, C3H), 2.77–2.71 (m, 1H,
C
1axH), 2.26 (s, 3H, CH3); 13C NMR (CDCl3) d 208.12, 195.90, 154.03,
150.17, 132.39, 122.32, 116.08, 110.51, 56.38, 56.08, 46.99, 41.81, 28.08,
25.41; MS (m/z) 248 (Mþ).

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Rho et al.
4-Hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic
acid (9). To a stirred solution of ketone 7a (2.0g, 7.99mmol) in methanol
(20mL) was added sodium borohydride (0.45 g, 12.0mmol). The mixture
was stirred for 2 hr at 08C and quenched with acetone (10 mL). The solvents
were removed in vacuo and then water and dichloromethane were added to
the residue. The organic layer was separated and the aqueous layer was
extracted with dichloromethane. The combined organic layers were washed
with water, dried over anhydrous magnesium sulfate, and evaporated giving
1
compound 9 (1.98 g, 98%) as a white crystal: m.p. 130–1348C; H NMR
(CDCl3) d 6.72 (s, 2H, ArH), 5.11–5.07 (m, 1H, C4H), 3.86 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 3.09–3.04 (m, 1H, C1H), 2.75–2.59 (d, 2H, C3H),
2.52–2.47 (m, 1H, C2H), 1.92–1.84 (m, 1H, C3H); 13C NMR (CDCl3)
d 176.52, 151.30, 150.75, 127.70, 125.59, 108.43, 107.50, 65.51, 55.25,
55.22, 37.24, 32.76, 25.83; MS (m/z) 235 (Mþ 2 OH), 207 (Mþ 2 COOH).
3,6-Dimethoxy-11-oxatricyclo[7.2.1.02,7]dodeca-2,4,6-trien-10-one
(10). Reaction of 7a (2.40 g, 9.59 mmol) and excessive sodium borohydride
(1.27 g, 33.6 mmol) in methanol (25 mL) was carried out as described for
the preparation of 9 to give 10 as pale yellow crystal (1.66 g, 85%): m.p.
106–1108C; 1H NMR (CDCl3) d 6.77 (d, 1H, J ¼ 8.8 Hz, ArH), 5.92 (d, 1H,
J ¼ 9.3 Hz, ArH), 5.92 (d, 1H, J ¼ 5.4 Hz, C8H), 3.79 (s, 3H, OCH3), 3.77
(s, 3H, OCH3), 3.07–2.90 (m, 3H), 2.68 (qt, 1H, J ¼ 5.9, 5.4 Hz); 13C
NMR (CDCl3) d 179.31, 151.66, 149.64, 126.01, 123.02, 110.93, 109.31,
71.77, 56.20, 55.52, 37.29, 33.93, 26.44; MS (m/z) 234 (Mþ), 219
(Mþ 2 CH3), 190 (Mþ 2 COO).
5,8-Dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid (12). A
solution of ketone 7a (0.39 g, 1.56 mmol) in trifluoroacetic acid (2.5 mL) was
treated with triethylsilane (0.62 mL, 3.90 mmol). Vigorous magnetic stirring
was necessary to obtain a homogeneous mixture for 30 min at 08C. Water was
added to the residue and the mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate and evaporated in
vacuo. The crude material was recrystallized by ethyl acetate/hexane to give
1
12 (0.32 g 88%): m.p. 180–1828C; H NMR (CDCl3) d 6.63 (s, 2H, ArH),
3.78 (s, 6H, OCH3), 3.13–3.10 (m, 1H), 2.95–2.92 (m, 1H), 2.77–2.64
(m, 1H) 1.82–1.70 (m, 1H); 13C NMR (CDCl3) d 181.90, 151.28, 151.16,
126.01, 125.05, 106.90, 106.85, 55.59, 55.57, 39.09, 25.68, 24.77, 22.79; MS
(m/z) 236 (Mþ).
1-(5,8-Dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1-ethanone
(13). A stirred solution of carboxylic acid 12 (0.26 g, 1.10 mmol) in THF
(10 mL) was cooled to 08C on ice-bath and treated rapidly with 1.4 M methyl
lithium in ether (3.1 mL, 4.4 mmol). After 2 hr at 08C, chlrorotrimethyl silane
(3 mL) was rapidly added while stirring continued. The ice bath was then
removed and the reaction mixture allowed to room temperature at which

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Syntheses of Idarubicinone-7-b-D-glucuronide
1713
point 30 mL of 1 N HCl was added, and the resulting two-phase system was
stirred at room temperature for 0.5 hr. The mixture was then transferred into
a separator funnel and extracted with dichloromethane. The organic layer
was dried over anhydrous magnesium sulfate, filtered and removal of solvent
from the filtrate in vacuo to give methyl ketone 13 (0.21 g, 81%): m.p. 83–
1
858C (lit.[12] 82–838C); H NMR (CDCl3) d 6.62 (s, 2H, ArH), 3.77 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.05–2.90 (m, 2H), 2.68–2.48 (m, 3H), 2.25
(s, 3H, COCH3), 2.18–2.13 (m, 1H), 1.67–1.57 (m, 1H); 13C NMR
(CDCl3) d 211.44, 151.22, 151.12, 126.14, 125.33, 106.81, 106.77, 55.48,
47.17, 28.04, 25.31, 24.31, 23.07; MS (m/z) 234 (Mþ), 219 (Mþ 2 CH3).
(+)-2-Acetyl-2-hydroxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene
(14). The mixture of 1 M t-BuOK (4.3mL, 4.3 mmol), triethyl phosphite
(0.38 mL, 2.2 mmol) in DMF (20 mL) was stirred at 2158C. Oxygen was
bubbled through the solution (approximately 3 bubbles sec21 from a disposable
pipette). Then ketone 13 (0.23 g, 1.0 mmol) was added in a minimum amount of
tetrahydrofuran. While the temperature was carefully maintained between 2158C
and 2108C, the color of the reaction mixture changed from yellow to orange
to red to dark red. By taking small aliquots and quenching these in water, one
can monitor the reaction by TLC. After 1 hr, the reaction was quenched by
addition of water (20 mL). The crude reaction mixture was stirred for 3 hr at
ambient temperature, the DMF was removed under vacuum, and the resulting
slurry was dissolved in dichloromethane. The organic phase was then
washed with water, dried over anhydrous magnesium sulfate, filtered and
concentrated, and the triethyl phosphate was removed at 508C (1024 torr). The
resulting oil was chromatographed on silica gel (ethyl acetate/hexane 1 : 3)
to afford C9-monohydroxylated b-tetralol (+)-14 (0.21 g, 85%) as a white
1
crystal: m.p. 100–1028C (lit.[4c,7b] 100–1018C); H NMR (CDCl3) d 6.67
(d, 1H, J ¼ 8.8 Hz, ArH), 6.64 (d, 1H, J ¼ 8.8 Hz, ArH), 3.79 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 3.62 (s, 1H, OH), 2.75–2.99 (m, 4H), 2.32
(s, 3H, CH3), 1.83–2.05 (m, 2H, CH); MS (m/z) 250 (Mþ), 232 (Mþ 2 H2O).
9-Acetyl-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacen-5,12-dione
(15). To a solution of 13 (0.75 g, 3.20 mmol) in nitrobenzene (30 mL) was
added a solution of aluminum chloride (0.85 g, 6.40 mmol) in nitrobenzene
(30 mL) at 08C and the mixture was slowly warmed to room temperature
for 30 min. Phthaloyl dichloride (0.51 mL, 3.52 mmol) was added to the result-
ing solution and the mixture was stirred at 1008C for 1 hr. A solution of 0.2 N
oxalic acid (40 mL) and dichloromethane (50 mL) were added to the resulting
solution and filtered. The water layer was extracted with dichloromethane and
the combined organic layer was washed with saturated sodium bicarbonate
and brine. After drying over anhydrous magnesium sulfate, the solvent was
removed in vacuo and the crude material was purified by recrystalization
(dichloromethane/diethyl ether/hexane) to afford 15 (0.94 g, 87%):

ORDER
REPRINTS
1714
Rho et al.
m.p. 198–2018C (lit.[15a] 199–2018C); 1H NMR (CDCl3) d 13.52 (s, 1H, OH),
13.49 (s, 1H, OH), 8.30 (m, 2H, ArH), 7.80 (m, 2H, ArH), 3.10 (m, 2H, C10H),
2.75 (m, 2H, C7H), 2.31 (s, 3H, COCH3), 1.95 (m, 1H, CH), 1.90 (m, 2H,
CH2); MS (m/z) 336 (Mþ), 293 (Mþ 2 COCH3).
(+)-9-Acetyl-6,9,11-trihydroxy-7,8,9,10-tetrahydronaphthacen-5,12-
dione (16). Reaction of 14 (0.45 g, 1.80 mmol), phthaloyl dichloride
(0.28 mL, 1.98 mmol) and aluminum chloride (0.49 g, 3.65 mmol) in nitroben-
zene (40 mL) at 08C was carried out as described for the preparation of 15 to
yield 16 (0.54 g, 86%) as a red crystal: m.p. 216–2188C (lit.[4c] 214–2168C);
1H NMR (CDCl3) d 13.48 (s, 2H, ArOH), 8.48–8.19 (m, 2H, ArH), 7.95–7.74
(m, 2H, ArH), 3.79 (bs, 1H, OH), 3.48–2.79 (m, 4H, CH2), 2.39 (s, 3H,
OCH3), 2.19–1.68 (m, 2H, CH2); MS (m/z) 352 (Mþ), 309 (Mþ 2 COCH3).
(+)-9-Acetyl-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydronaphthacen-
5,12-dione [(+)-3b]. A mixture ketone 16 (0.53 g, 1.50 mmol), ethylene
glycol (0.84 g, 15.0 mmol), p-TsOH (0.04 g), in benzene (150 mL) was
refluxed for 3–5 hr with azeotropic removal of water formed using a
Dean–Stark apparatus. After cooling down, the mixture was partitioned
between dichloromethane and saturated aqueous sodium bicarbonate and
the organic layer was separated. The aqueous layer was extracted with
dichloromethane and the combined organic layer was washed with brine,
dried with magnesium sulfate, concentrated in vacuo. The residue was
recrystallized with dichlormethane/diethyl ether/hexane to afford the pure
acetal (0.57 g, 95%) as a red powder.
A mixture of acetal (0.15 g, 0.38 mmol), N-bromosuccinimide (72.0 mg,
0.40 mmol), and catalytic amounts of AIBN (0.03 g, 0.18 mmol) in carbon
tetrachloride was heated at reflux for 30 min with stirring under irradiation
with a 500 W halogen lamp. After being cooled, silica gel (5 g, for column
chromatography) and ice-cooled wet tetrahydrofuran (30 mL, containing
about 3% water) were successively added to the mixture and stirred at r.t.
for 1.5 hr. Silica gel was separated by filter and washed several times with
methanol/dichloromethane (1 : 10). The combined organic layer was concen-
trated in vacuo. After the residue was dissolved in a mixture of 1 N hydro-
chloric acid (10 mL) and dioxane (20 mL), the acidic solution was stirred at
808C for 1 hr to hydrolyze the acetal group. The residue obtained by concen-
tration of the mixture in vacuo was dissolved in chloroform. The organic
solution was washed with brine, and distilled waster, then dried on anhydrous
magnesium sulfate, filtered, and evaporated. The residue was chromato-
graphed on silica gel (acetone/methanol/dichloromethane 2 : 1 : 20) to give
enantiomeric mixture (+)-Idarubicinone (3b) (0.11 g, 78% overall yield).
The enantiomeric ratio (1 : 1) was determined by HPLC analysis with a chiral
column (Daicel Chiralcel OD-H; eluent, 20% isopropyl alcohol in hexane;
flow rate, 0.5 mL min21; Rt ¼ 85 min and 105 min): m.p. 175–1778C

ORDER
REPRINTS
Syntheses of Idarubicinone-7-b-D-glucuronide
1715
(lit.[15a] 173–175, lit.[17a] 176–1788C); 1H NMR (DMSO-d6) d 13.25 (s, 1H,
OH), 13.10 (s, 1H, OH), 8.13–8.09 (m, 2H, ArH), 7.90–7.88 (m, 2H, ArH),
6.06 (s, 1H, C7eqH), 5.26 (s, 1H, C7OH), 4.91 (s, 1H, C9OH), 2.93 (d, 1H,
J ¼ 18.6 Hz, C10H), 2.77 (d, 1H, J ¼ 18.0 Hz, C10H), 2.31 (s, 3H, COCH3),
2.16 (d, 1H, J ¼ 13.7 Hz, C8H), 1.90 (dd, 1H, J ¼ 14.2, 4.39 Hz, C8H); 13C
NMR (DMSO-d6) d 211.85, 186.06, 185.83, 156.16, 155.38, 136.85,
135.15, 134.96, 134.86, 132.70, 132.52, 126.47, 126.44, 110.36, 109.82,
76.24, 60.43, 35.71, 32.11, 24.45; MS (FABþ, Na) m/z 391.0 (M þ Na)þ.
3-Acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naph-
thacenyl (2R)-2-(acetyloxy)-2-phenylethanoate (17). (+)-Idarubicinone
3b (0.15 g, 0.41 mmol) and (S)-(þ)-O-acetylmandelic acid (0.30 g,
1.54 mmol) in the presence of dicyclohexylcarbodiimide (DCC, 0.30 g,
1.45 mmol) and 4-(dimethylamino) pyridine (DMAP) (0.03 g, 0.24 mmol)
in anhydrous dichloromethane were stirred at r.t. for 15 hr. After filtration
of the precipitated urea, solvent was removed under reduced pressure and
the residue was purified by column chromatography with acetone/dichloro-
methane (1 : 20) as eluent. Two products are obtained 17a (0.11 g, 47%) and
17b (0.09 g, 40%) as red crystals: 17a; m.p. 98–1008C; [a]2D0 þ77.78 (c 0.1,
dichloromethane); IR (KBr) 2942, 2840, 1745, 1631, 1591, 1427, 1381,
1
1176, 1046, 983, 792, 741, 695 cm21; H NMR (CDCl3) d 13.31 (s, 1H,
ArOH), 12.99 (s, 1H, ArOH), 8.35–8.31 (m, 2H, ArH), 7.83–7.86 (m,
2H, ArH), 7.48–7.51 (m, 2H, ArH), 7.39–7.36 (m, 3H, ArH), 6.36 (d, 1H,
J ¼ 3.9 Hz, OCOCH), 5.72 (s, 1H, C7eqH), 3.32 (dd, 1H, J ¼ 2.0, 18.6 Hz,
C10H), 2.95 (d, 1H, J ¼ 19.0 Hz, C10H), 2.46 (s, 3H, OCH3), 2.27 (d, 1H,
J ¼ 5.9 Hz, C8H), 2.24 (s, 3H, OCH3), 2.2–2.17 (m, 2H); 13C NMR
(CDCl3) d 212.29, 187.04, 186.40, 171.56, 168.09, 156.37, 155.98, 137.23,
134.61, 134.48, 133.47, 133.33, 132.36, 130.39, 129.39, 128.67, 127.34,
127.11, 126.97, 111.97, 110.62, 75.75, 75.59, 64.29, 33.74, 32.19, 30.92,
24.76, 20.73; UV lmax (log 1) 252 (0.94), 258 (0.90), 283 (0.27), 487
(0.23). 17b; m.p. 82–848C; [a]2D0 þ40.18 (c 0.1, CH2Cl2); IR (KBr) 2933,
1748, 1630, 1594, 1428, 1374, 1238, 1053, 982, 926, 789, 738, 685 cm21
;
1H NMR (CDCl3) d 13.28 (s, 1H, ArOH), 13.27 (s, 1H, ArOH), 8.35–8.33
(m, 2H, ArH), 7.87–7.82 (m, 2H, ArH), 7.50–7.47 (m, 2H, ArH), 7.44–
7.37 (m, 3H, ArH), 6.51 (d, 1H, J ¼ 4.4 Hz, OCOCH), 5.96 (s, 1H,
C
7eqH), 3.20 (dd, 1H, J ¼ 2.0, 18.8 Hz, C10H), 2.85 (d, 1H, J ¼ 19.0 Hz,
C10H), 2.61 (s, 1H, C9OH), 2.27 (s, 3H, OCH3), 2.24–2.22 (m, 2H, CH2),
2.20 (s, 3H, COCH3), 2.18–2.17 (m, 2H, CH2), 2.06–2.02 (m, 1H, CH2);
13C NMR (CDCl3) d 211.43, 187.07. 186.46, 170.98, 167.22, 156.38,
155.82, 136.90, 134.68, 134.50, 133.47, 133.44, 133.26, 130.33, 129.59,
128.98, 127.89, 127.08, 127.06, 112.03, 110.74, 75.37, 74.83, 63.63,
34.38, 32.25, 30.92, 24.46, 20.80; UV lmax (log 1) 253 (1.09), 258 (1.09),
487 (0.26).

ORDER
REPRINTS
1716
Rho et al.
(7S,9S)-9-Acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydro-5,12-
naphthacenedione, (7S,9S)-(1)-idarubicinone [(1)-3b]. A solution of 17a
(0.55 g, 1.01 mmol) in dichloromethane (50 mL) and saturated aqueous NaOH
solution (5 drops) was stirred at room temperature. After 2 hr, 1 N HCl
(50 mL) was added and the resulting mixture was stirred for 0.5 hr. The mix-
ture was then transferred into a separator funnel and extracted with dichloro-
methane. The organic layer was dried over anhydrous magnesium sulfate and
removal of solvent from the residue in vacuo gave enantiomerically pure ida-
rubicinone (þ)-3b (0.32 g, 86%) as reddish brown crystals: m.p. 184–1858C;
[a]D20 þ1598 (c 0.1, dioxane), (lit.[17b] m.p. 184–1858C; [a]2D0 þ1548, c 0.1,
dioxane, lit.[4c] m.p. 183.5–184.58C, [a]2D0 þ1538, c 0.09, dioxane); IR
(KBr) 3442, 2943, 1710, 1629, 1594, 1425, 1384, 1238, 1133, 985, 921,
1
784, 734 cm21; H NMR (CDCl3) d 13.24 (s, 1H, OH), 12.96 (s, 1H, OH),
8.12–8.25 (m, 2H, ArH), 7.68–7.85 (m, 2H, ArH), 5.22 (m, 1H, C7H,
n1/2 ¼ 12.0 Hz), 4.61 (s, 1H, C9OH), 3.90 (d, 1H, J ¼ 6.0 Hz, C7OH), 3.12
(dd, 1H, J ¼ 18.0, 1.0 Hz, C10Heq), 2.88 (d, 1H, J ¼ 18.0 Hz, C10Hax), 2.44
(s, 3H, COCH3), 2.32 (br d, 1H, J ¼ 16.0 Hz, C8Heq), 2.12 (dd, 1H,
J ¼ 16.0, 4.0 Hz, C8Hax); 13C NMR (DMSO-d6) d 211.85, 186.06, 185.83,
156.16, 155.38, 136.85, 135.15, 134.96, 134.86, 132.70, 132.52, 126.47,
126.44, 110.36, 109.82, 76.24, 60.43, 35.71, 32.11, 24.45; UV lmax (log 1)
252 (1.50), 485 (0.38), 288 (0.40); MS (FABþ, Na) m/z 391.0 (M þ Na)þ.
(7R,9R)-9-Acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydro-5,12-
naphthacenedione, (7R,9R)-(2)-idarubicinone [(2)-3b]. Reaction of 17b
(0.51g, 0.94 mmol), and saturated aqueous NaOH in dichloromethane was car-
ried out as described for the preparation of (þ)-3b to yield enantiomerically
pure (2)-idarubicinone (2)-3b (0.29 g, 85%) as reddish brown crystals: m.p.
183.5–184.58C; [a]2D0 21568 (c 0.1, dioxane); IR (KBr) 3432, 2952, 2584,
1
1714, 1614, 1590, 1443, 1375, 1240, 1129, 1036, 990, 790, 738 cm21; H
NMR (CDCl3) d 13.24 (s, 1H, OH), 12.96 (s, 1H, OH), 8.12–8.25 (m, 2H,
ArH), 7.68–7.85 (m, 2H, ArH), 5.22 (m, 1H, C7H, n1/2 ¼ 12.0 Hz), 4.61
(s, 1H, C9OH), 3.90 (d, 1H, J ¼ 6.0Hz, C7OH), 3.12 (dd, 1H, J ¼ 18.0,
1.0 Hz, C10Heq), 2.88 (d, 1H, J ¼ 18.0 Hz, C10Hax), 2.44 (s, 3H, COCH3),
2.32 (br d, 1H, J ¼ 16.0 Hz, C8Heq), 2.12 (dd, 1H, J ¼ 16.0, 4.0 Hz, C8Hax);
13C NMR (DMSO-d6) d 211.85, 186.06, 185.83, 156.16, 155.38, 136.85,
135.15, 134.96, 134.86, 132.70, 132.52, 126.47, 126.44, 110.36, 109.82,
76.24, 60.43, 35.71, 32.11, 24.45; UV lmax 252 (1.42), 485 (0.36), 288
(0.34); Mass (FABþ, Na) m/z 391.0 (M þ Na)þ.
Methyl-3,4,5-tri(acetyloxy)-6-f[(1S,3S)-3-acetyl-3,5,12-trihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxygtetrahydro-2H-
2-pyrancarboxylate, (7S,9S)-(1)-idarubicinone-7-methyl(tri-O-acetyl-
ester)-b-D-glucuronide (18). A suspension of (þ)-idarubicinone (þ)-3b
(0.20 g, 0.54 mmol), acetobromo-a-D-glucuronic acid methyl ester (0.32 g,

ORDER
REPRINTS
Syntheses of Idarubicinone-7-b-D-glucuronide
1717
˚
0.81 mmol) and 4 A molecular sieves (0.60 g) in dry dichloromethane (50 mL)
was stirred for 30 min at room temperature. Then, anhydrous ZnBr2 (0.31 g,
1.35 mmol) was added and the resulting suspension was refluxed for 48 hr
with stirring. More dichloromethane (50 mL) was added, the suspension
was filtered through celite and stirred for 20 min with a saturated aqueous
solution of NaHCO3 (50 mL). The aqueous phase was separated, washed
with dichloromethane, the organics were combined, washed with water,
dried over anhydrous sodium sulfate, filtered, and evaporated. The residue
was passed through a silica gel column (dichloromethane/MeOH/acetone ¼
20 : 1 : 2 ! dichloromethane/acetone ¼ 15 : 1) to give stereochemically pure
b-anomer 18 (0.21 g, 56%) as a orange powder: m.p. 274–2788C; [a]D20
þ45.58 (c 1.0, dichloromethane); IR (KBr) 3839, 3742, 3618, 3100, 1751,
1
1723, 1626, 1540, 1418, 1405, 1230, 1063, 1043, 794, 668 cm21; H NMR
(CDCl3) d 13.67 (s, 1H, ArOH), 13.28 (s, 1H, ArOH), 8.36–8.34 (m, 2H,
0
ArH), 7.86–7.27 (m, 2H, ArH), 5.38 (t, 1H, J ¼ 9.3 Hz, C3 H), 5.35 (s, 1H,
0
0
C
7eqH), 5.25 (t, 1H, J ¼ 9.8 Hz, C4 H), 5.16 (d, 1H, J ¼ 7.8 Hz, C1 H), 4.98
0
0
(t, 1H, J ¼ 8.3, 8.8 Hz, C2 H), 4.18 (d, 1H, J ¼ 9.8 Hz, C5 H), 4.17 (s, 1H,
C9–OH), 3.80 (s, 3H, COOCH3), 3.24 (d, 1H, J ¼ 19.5 Hz, C10eqH), 3.00
(d, 1H, J ¼ 19.0 Hz, C10axH), 2.63 (d, 1H, J ¼ 15.1 Hz, C8eqH), 2.46 (s, 3H,
COCH3), 2.08 (dd, 1H, C8axH), 2.05 (s, 3H, OAc), 2.01 (s, 3H, OAc), 1.85
(s, 3H, OAc); 13C NMR (CDCl3) d 213.29, 186.86, 186.79, 170.01, 169.46,
169.36, 167.05, 156.41, 156.40, 137.43, 134.66, 134.62, 133.40, 133.38,
132.06, 127.19, 127.05, 111.66, 110.59, 101.48, 76.24, 72.36, 71.54, 71.06,
70.27, 69.37, 53.03, 35.07, 33.49, 25.14, 20.61, 20.52, 20.48; UV lmax
(log 1) 253(0.86), 258 (0.83); MS (FABþ, Na) m/z 706.8 (M þ Na)þ.
Methyl-3,4,5-tri(acetyloxy)-6-f[(1R,3R)-3-acetyl-3,5,12-trihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxygtetrahydro-2H-
2-pyrancarboxylate, (7R,9R)-(2)-idarubicinone-7-methyl (tri-O-acetyl-
ester)-b-D-glucuronide (19). Reaction of (2)-idarubicinone (2)-3b, (0.27g,
0.73 mmol), acetobromo-a-D-glucuronic acid methyl ester (0.44 g, 1.10 mmol),
˚
4 A molecular sieves (0.60g) and ZnBr2 (0.41 g, 1.83 mmol) in dichloromethane
was carried out as described for the preparation of 18 to yield stereochemically
pure b-anomer 19 (0.26 g, 53%) as a orange powder: m.p. 214–2188C; [a]D20
279.88 (c 0.01, dichloromethane); IR (KBr) 3838, 3739, 3674, 3651, 3526,
2955, 1757, 1718, 1624, 1588, 1417, 1375, 1230, 1041, 985, 791, 735,
1
672 cm21; H NMR (CDCl3) d 13.71 (s, 1H, ArOH), 13.27 (s, 1H, ArOH),
8.35–8.32 (m, 2H, ArH), 7.85–7.27 (s, 2H, ArH), 5.51 (s, 1H, C7eqH), 5.32
0
0
(t, 1H, J ¼ 9.3 Hz, C3 H), 5.15 (t, 1H, J ¼ 9.8 Hz, C4 H), 5.05 (d, 1H,
0
0
J ¼ 8.3 Hz, C1 H), 4.96 (t, 1H, J ¼ 9.3, 8.3 Hz, C2 H), 4.16 (s, 1H, C9–OH),
0
4.03 (d, 1H, J ¼ 9.8 Hz, C5 H), 3.47 (s, 3H, COOCH3), 3.26 (d, 1H,
J ¼ 19.5 Hz, C10eqH), 3.06 (d, 1H, J ¼ 19.5Hz, C10axH), 2.42 (s, 3H, OAc),
2.30 (d, 1H, J ¼ 14.6 Hz, C8eqH), 2.13 (dd, 1H, C8axH), 2.11 (s, 3H, OAc),

ORDER
REPRINTS
1718
Rho et al.
2.02 (s, 3H, OAc), 2.00 (s, 3H, OAc); 13C NMR (CDCl3) d 212.12, 186.80,
186.50, 170.08, 169.55, 169.30, 166.56, 156.60, 156.04, 136.95, 134.60,
134.53, 133.42, 133.32, 132.47, 127.18, 126.78, 111.72, 110.59, 100.95,
75.93, 72.43, 71.94, 71.12, 70.05, 69.22, 52.67, 34.27, 34.23, 24.84, 20.73,
20.59, 20.48; UV lmax (log 1) 252 (0.74), 258 (0.71); MS (FABþ, Na) m/z
706.8 (M þ Na)þ.
6-f[1S,3S]-3-Acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexa-
hydro-1-naphthacetylgoxyg-3,4,5-trihydoxytetrahydo-2H-2-pyrancarboxy-
lic acid, (7S,9S)-(1)-idarubicinone-7-b-D-glucuronide (20). To a solution
of 18 (30.0 mg, 0.044 mmol) in MeOH/THF (5 : 1, v/v) was added 2.6 mL
(6.0 eq) of a 0.1 N LiOH solution, the resulting deep blue solution was stirred
at 08C under an argon atmosphere. Progress of the deprotection was monitored
on reversed-phase TLC (SiO2-C18 MeCN/H2O, 1/2). After 2 hr of deprotec-
tion, the reaction mixture was diluted with 10 mL of water and neutralized by
adding ca. 200 mg of amberlite cation exchange resin (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 the red aqueous product solution was transferred to a reversed
phase column packed with RP-C18 material. The column was successively
washed with MeCN/H2O (1 : 3, v/v) to elute the product and the MeCN
was removed by evaporation and removal of water from the residue in
vacuo to give 20.0 mg (84%) of compound 20 as a reddish orange powder:
m.p. 1308C (decomp); [a]2D0 þ60.08 (c 0.1, MeOH/H2O); IR(KBr) 3482.38,
2949.93, 2889.94, 1699.07, 1620.56, 1586.92, 1418.69, 1347.66, 1250.47,
1
1198.13, 1063.55, 861.25, 835.00, 735.63, 690.63, 658.75 cm21; H NMR
(CD3OD) d 8.27 (m, 2H, ArH), 7.87 (m, 2H, ArH), 5.21 (d, 1H,
0
J ¼ 2.93 Hz, C1 H), 4.82 (s, 1H, C7eqH), 4.80 (s, 1H, OH), 3.71 (d, 1H,
0
0
0
J ¼ 9.3 Hz, C5 H), 3.50–3.42 (m, 2H, C3 H, C2 H), 3,33 (s, 1H, OH), 3.23
0
(t, 1H, J ¼ 8.3, 8.8 Hz, C4 H), 3.08 (d, 1H, J ¼ 2.5 Hz, C10eqH), 2.78
(m, 2H, C8eq, C10ax), 2.41 (s, 3H, CH3), 2.10 (dd, 1H, J ¼ 15.1, 4.88 Hz,
C
8axH); 13C NMR (CD3OD) d 215.45, 188.23, 187.84, 176.85, 157.87,
157.01, 137.60, 135.77, 135.08, 134.79, 134.60, 127.90, 112.53, 111.82,
106.00, 77.48, 77.35, 76.58, 75.15, 73.75, 71.71, 36.29, 33.33, 25.13; UV
lmax (log 1) 251 (2.85), 287 (1.35), 484 (1.42); MS (FABþ, Na) m/z 567.2
(M þ Na)þ.
6-f[1R,3R]-3-Acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexa-
hydro-1-naphthacetylgoxyg-3,4,5-trihydoxytetrahydo-2H-2-pyrancarboxylic
acid, (7R,9R)-(2)-idarubicinone-7-b-D-glucuronide (21). To a solution of
19 (20.0 mg, 0.029 mmol) in MeOH/THF (5 : 1, v/v) was added 1.8 mL
(6.0 eq) of a 0.1 N LiOH solution and the resulting deep blue solution was
stirred at 08C under an argon atmosphere. Progress of the deprotection was
monitored on reversed-phase TLC (SiO2-C18 MeCN/H2O, 1/2). After 2 hr

ORDER
REPRINTS
Syntheses of Idarubicinone-7-b-D-glucuronide
1719
of deprotection, the reaction mixture was diluted with 8 mL of water and
neutralized by adding ca. 150 mg 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 the red aqueous product solution was
transferred to a reversed phase column packed with RP-C18 material. The
column was successively washed with MeCN/H2O (1/3, v/v) to elute the pro-
duct and the MeCN was removed by evaporation and removal of water from
the residue in vacuo to give 13.0 mg (82%) of compound 21 as a reddish
orange powder: m.p. 2248C (decomp); [a]2D0 274.08 (c 0.1, MeOH/H2O);
IR (KBr) 3482.38, 2957.43, 2837.44, 1703.43, 1646.73, 1459.81, 1414.95,
1201.87, 1056.07, 1029.91, 1018.69, 833.13, 752.50, 641.88 cm21
;
1H
NMR (CD3OD) d 8.35 (m, 2H, ArH), 7.89 (m, 2H, ArH), 5.35 (m, 1H,
0
0
0
0
C1 H), 4.93 (s, 1H, C7eqH), 3.54–3.45 (m, 3H, C5 H, C3 H, C2 H), 3.11
0
(m, 2H, C4 H, C10eq,), 2.78 (m, 1H, C10ax), 2.60 (d, 1H, J ¼ 16.6 Hz, C8eq),
2.36 (s, 3H, CH3), 2.14 (m, 1H, C8axH); UV lmax (log 1) 251 (2.75), 286
(1.29), 485 (1.45); MS (FABþ, Na) m/z 567.2 (M þ Na)þ.
ACKNOWLEDGMENTS
This study was supported by a grant of the Korea Health 21 R&D Project,
Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG3-21500-0031).
Also we are grateful to KBSI (Korean Basic Science Institute) for NMR and
Mass analysis.
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Received in Japan September 30, 2003

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