Synthesis of new anthracycline derivatives containing pyruvic, aspartic, or N-acetylaspartic acid molecule

Article abstract of DOI:10.1081/SCC-120004846

The new anthracycline analogues (2-10) as potential anti-cancer agents were synthesized from daunomycin (1a) and doxorubicin (1b). Compounds 2, 6, and 7 were prepared by the nucleophilic displacement type esterification of a 14-bromodaunomycin (1c) with a

Full text of DOI:10.1081/SCC-120004846

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SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
CONTAINING PYRUVIC, ASPARTIC, OR N-
ACETYLASPARTIC ACID MOLECULE
a
a
a
a
b
Young S. Rho , Siho Park , Wan-Joong Kim , Gyuil Kim , Dong Jin Yoo , Heun-Soo Kang
c
a
b
c
d
&
Soon-Ryang Chung
Department of Chemistry , Chonbuk National University , Chonju, 561-756, Korea
Department of Chemistry , Seonam University , Namwon, 590-711, Korea
Metabolic Engineering Laboratories Co., Ltd. , 28 Yongon-Dong, Chongno-Gu, Seoul,
10-799, Korea
1
d
Department of Chemistry , Woosuk University , Wanju, 565-701, Korea
Published online: 16 Aug 2006.
To cite this article: Young S. Rho , Siho Park , Wan-Joong Kim , Gyuil Kim , Dong Jin Yoo , Heun-Soo Kang & Soon-Ryang
Chung (2002) SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES CONTAINING PYRUVIC, ASPARTIC, OR N-ACETYLASPARTIC ACID
MOLECULE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
32:13, 1961-1975, DOI: 10.1081/SCC-120004846
To link to this article: http://dx.doi.org/10.1081/SCC-120004846
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SYNTHETIC COMMUNICATIONS, 32(13), 1961–1975 (2002)
SYNTHESIS OF NEW ANTHRACYCLINE
DERIVATIVES CONTAINING PYRUVIC,
ASPARTIC, OR N-ACETYLASPARTIC
ACID MOLECULE
1
,
1
1
Young S. Rho, * Siho Park, Wan-Joong Kim,
1
Gyuil Kim, Dong Jin Yoo, Heun-Soo Kang,
2
3
4
and Soon-Ryang Chung
1
Department of Chemistry, Chonbuk National
University, Chonju 561-756, Korea
Department of Chemistry, Seonam University,
Namwon 590-711, Korea
2
3
Metabolic Engineering Laboratories Co., Ltd., 28
Yongon-Dong, Chongno-Gu, Seoul 110-799, Korea
4
Department of Chemistry, Woosuk University,
Wanju 565-701, Korea
ABSTRACT
The new anthracycline analogues (2–10) as potential anti-
cancer agents were synthesized from daunomycin (1a) and
doxorubicin (1b). Compounds 2, 6, and 7 were prepared by
the nucleophilic displacement type esterification of a 14-bro-
modaunomycin (1c) with a sodium pyruvate, aspartate, and
*
Corresponding author. Fax: þ82-63-270-3408; E-mail: ysrho@moak.chonbuk.ac.kr
1
961
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
962
RHO ET AL.
N-acetylaspartic acid, respectively. Whereas compounds (3, 8)
and (4, 9) were prepared by the reaction of daunomycin (1a)
or doxorubicin (1b) with one equivalent of the corresponding
acids in the presence of EDCI/PP, compounds (5, 10) were
obtained from 1b by reaction with two equivalents of the
corresponding acids in the same manner.
The anticancer antibiotics daunomycin (1a) and doxorubicin (1b)
Figure 1) are the most representative examples of the anthracycline series
(
developed as antitumor agents and widely used intercalating drugs for the
treatment of several types of human cancers. Particularly, doxorubicin (1b) is
of growing current interest because of its powerful activity against major solid
[1]
tumors. Doxorubicin (1b) having broader activity spectrum and less toxi-
city than daunomycin (1a) is currently the most active and widely used agent
in anticancer drugs against breast, bladder, lung, thyroid, ovary, osteogenic,
sarcoma, wilm’s tumor, neuroblastoma, Hodgkin’s disease, lymphomas, leu-
[2]
kemia cancer, etc. In biological and clinical studies, 1a has been also known
to restrict the virus multiplication because of its strong activity against solid
and ascite tumors. However, their uses for cancer chemotherapy have
severely still lots of limitation by cytotoxicity and other undesirable side
[3]
effects. Moreover, the clinical utility of 1a is frequently restricted by the
appearance of the cardiotoxicity originated in the damage of normal cell by
[
4–7]
oxygen radical.
devoted to overcome these disadvantages culminating in the development
For this reason, numerous synthetic efforts have been
[
8–11]
of daunomycin (1a) or doxorubicin (1b) derivatives.
Anthracyclines containing a pyruvic or aspartic acid residue are
expected to be good potential delivery drugs as well as give a protection
[
12]
role of oxidative tissue damage depending on radical.
Recently, there
Figure 1. Structures of two clinically used daunomycin (1a) and doxorubicin (1b).

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1963
were many reported examples of coupling 1a or 1b with some amino acids as
[
8]
well as blending 1a or 1b with some acids. For example, DA-125 including
an ꢀ-alanine developed by Dong-A Pharmaceutical Co., Ltd. (KR) was
prepared by nucleophilic substitution with a N-Boc-ꢀ-alanine sodium salt
and a C-14 bromodaunomycin. The DA-125 prodrug was found to have
[
9]
higher anticancer activity and less cardiotoxicity than 1a and 1b. In this
report, we describe the synthesis of some new anthracycline analogues by
coupling 1a (or 1b) with pyruvic, aspartic acid, or N-acetylaspartic acid
expecting to obtain compounds with less toxicity than anything else
previously developed.
In the precedent publications, we frequently used Michael-type conden-
[17,18]
[13–16]
sation
or Friedel-Crafts acylation
for the total synthesis of
anthracyclinone derivatives. Here, we report the successful preparation of a
new aglycon containing an ester linkage at C-14 through a nucleophilic dis-
[
18]
placement esterification method. In connection with recent studies towards
the development of a new 7-deoxyidarubicinone derivative through function-
alization of the C-14 site in the aglycon, we wished to prepare some new
anthracycline analogues starting directly from commercially available anti-
cancer glycosides such as daunomycin (DM, 1a) or doxorubicin (DX, 1b).
Several new anthracycline derivatives were synthesized using two esterifica-
tion methods (Scheme 1). All compounds 2–10 were obtained through acyla-
0
tion of the C-14 hydroxyl group in the aglycon and/or the amine group at C-3
in the glycon moiety with aspartic, pyruvic, or N-acetylaspartic acid. Clearly
different reaction patterns were observed for the individual carboxylic acids.
DM-pyr (2) and DM-asp (6) were prepared by the nucleophilic dis-
placement type esterification of 14-bromo DM (1c) with the corresponding
acid sodium salts. The synthesis of 14-bromo DM (1c) was accomplished by
[19,20]
the known procedure:
1c was synthesized in best yield when a minimum
quantity of co-solvent (methanol/1,4-dioxane, v/v ¼ 1 : 2) was used which
diminished the formation of side product from dimethylketalization of
ketone at C-13. The rate of bromination depended on the reaction tempera-
ꢀ
ture and time. The optimal conditions are bromination at 30 C for 40 min.
After esterification of 14-bromo DM (1c) with 12equivalents of pyruvic acid
[18]
sodium salt, product separation by column chromatography on silica gel
(
etheral HCl afforded DM-pyr (2, 59%) as a red solid.
CH Cl /CH OH/HCO H/H O ¼ 88/15/2/1) followed by the treatment with
2
2
3
2
2
All our attempts to prepare DM-asp (6) through nucleophilic displace-
ment type esterification of 14-bromo DM (1c) with the sodium or potassium
salts of aspartic acid in various solvents were not successful. Only the
[21–23]
aglycon was obtained.
Protection of the amino group in sodium
aspartic acid with di-tert-butyldicarbonate and reaction of the N-BOC-
aspartic acid sodium salt with 1c gave daunomycin-14-(N-Boc)-aspartate

1
964
RHO ET AL.
Scheme 1. Synthesis of new anthracycline analogues 2–10.
in relatively low yield (< 50%). After removing the BOC group with
ꢀ
[24]
CF CO H at À20 C and treatment with methanolic HCl,
DM-asp (6)
total 34%) was obtained as a red solid. Prolonged reaction times in the
3
2
(
CF CO H deprotecting of the BOC group led to the cleavage of the glyco-
3
2
sidic bond. Therefore, evaporation of reaction solvent within 20 min is
necessary to avoid hydrolysis of the amino sugar moiety. The reaction
of 1a or 1b with aspartic acid or its acid sodium salt furnished only
compound 6.
Many attempts to prepare DM-Npyr (3) and DX-Npyr (4) through
direct coupling of the NH ÁHCl group in daunomycin (1a) or doxorubicin
2
[
25]
(1b) with pyruvic acid using DCC/DMAP
reduced DCU (dicyclohexylurea) were observed as main products.
failed. Reactants and
Eventually, DM-Npyr (3) and DX-Npyr (4) were synthesized by coupling
of the NH ÁHCl group in 1a and 1b with pyruvic acid using using
2
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)
and 4-pyrrolidinopyridine (PP) as catalysts.
[
26,27]
However, for the reaction

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1965
of 1b competition between the hydroxyl at C-14 and the amino group was
observed. Both products DX-Npyr 4 and DXpyr-Npyr 5 formed, the
product ratio depended on the amounts of pyruvic acid and EDCI used
in the reaction.
All coupling reactions of 1a or 1b with N-acetyl-L-aspartic acid were
very easily accomplished. DM-aas (7) was prepared from 1c by reaction with
N-acetyl-L-aspartic acid in triethylamine without using any coupling reagent.
However, DM-Naas (8), DX-Naas (9), and DXaas-Naas (10) were synthe-
sized using EDCI as coupling reagent. In all these cases, only one isomer was
[
28]
obtained pure as Kovach’s results. The reaction of N-acetyl-L-aspartic acid
with the corresponding aglycon furnished ꢀ-aspartic acid esters (7, 8, 9, and
10) rather than ꢁ-aspartic acid esters because the L-aspartic acid has
bulky N-acetyl group on the ꢁ-amine moiety. Synthesis of DX-Naas (9) and
DXaas-Naas (10) was carried out as follow: N-Acetyl-L-aspartic acid (1.2eq.)
and EDCI (2.0 eq.) was dissolved in dry DMF and the mixture was stirred at
ꢀ
0
C for 30 min; to the reaction mixture was added DX (1b) and catalytic
amounts of PP, and the resulting solution was stirred at room temperature
for 5 h to give DX-Naas (9). DXaas-Naas (10) was prepared using 2.2 equi-
valent of the corresponding acid and EDCI (2.5 eq.) in the same manner.
The cytotoxic activities of anthracycline derivatives 2–10 against two
kinds of human tumor cells (SNU-16 and MCF-7) and their adriamycin-
resistant cell lines are shown in Table 1. It showed that compounds 2 and 7
exhibited cytotoxicity activity equivalent to adriamycin against SNU-16 and
MCF7 cell lines, but compound 6 was much lower cytotoxic than free drug
against SNU-16 and MCF7 cell lines. In addition, the others (3–5 and 7–10)
exhibited very low antitumor activity compared with the reference. These
results indicate that acylation of C-14 OH (2, 7) maintains the activity
inherent in the parent anthracycline antibiotics, whereas amidation of
0
3
-NH (3–5 and 8–10) causes a decrease in the antibiotic activity.
2
In conclusion, we have synthesized the new anthracycline analogues
[
29]
expected to exhibit biologically activity and low cardiotoxicity as poten-
tial anticancer agents through the esterification reactions. Further detailed
biological tests of the title glycosides in vitro will be reported elsewhere
sooner or later.
EXPERIMENTAL SECTION
All reactions were carried out under argon atmosphere in dried glass-
[
30]
ware. Solvents were carefully dried and distilled as reported. Bulk grade
hexane was distilled prior to use. Merck pre-coated silica gel plates
(
Art.5554) with fluorescent indicator were used as analytical TLC. Flash

1
966
RHO ET AL.
Table 1. The Cytotoxic Activity of the Novel Anthracycline Derivatives
2–10) was Tested ‘‘In Vitro’’ in Comparison with Adriamycin on Cultured
SNU-16 and MCF-7 Cells
(
c
IC50 (mM)
a
b
Agents
SNU-16
SNU-16/Adr MCF7
MCF7/Adr
d
0.35 (2.19 )
Adriamycin
0.16
0.14
0.29
0.26
17.63
21.78
30.26
1.33
0.43 (1.48)
0.49 (1.88)
19.29
20.47
20.58
3.56 (2.67)
0.52 (1.48)
22.24
20.33
30.15
2
3
4
5
6
7
8
9
0.38 (2.71)
20.55
24.28
28.21
25.12
32.87
21.20
0.23
34.84
30.98
37.29
37.96
28.35 (1.34)
0.78 (3.39)
38.15
40.63
42.54
0.35
18.96
16.25
22.36
1
0
a
Human stomach adenocarcinoma.
b
Human breast adenocarcinoma.
Concentration inhibiting colony growth by 50%.
c
d
Relative resistance (IC50 of resistant cell lines/IC50 of parental cell lines).
column chromatography was carried out on silica gel (230–400 mesh from
1
13
Merck). H and C NMR spectra were recorded on a JEOL JNM EX-400
1
spectrometer. Chemical shifts were internally referenced to TMS for H or
1
to solvent signals for C. Infrared spectra were recorded on a Nicolet
3
5
-DXB series FT-IR spectrophotometer. Mass spectra were obtained on a
þ
JEOL JMS HX-110/110A Tandem mass spectrometer (FAB , ESI).
UV–VIS absorption spectra were recorded on a Hitachi-556 spectrophot-
ometer. Optical rotatory dispersions (ORD) were determined using the
Rudolph AUTOPOL IV apparatus with a 0-100-1.5 polarimeter sample
¨
tube. Melting points were obtained on a Buchi 510 melting point apparatus
and are uncorrected.
1
4-Bromodaunomycin Hydrochloride (1c)
Trimethylorthoformate (0.20 mL, 1.83 mmol) was added to a solution
of daunomycin hydrochloride (1a, 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 Br /CHCl
2
3

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1967
(
for 40 min at 30 C. The resulting mixture was poured into dry ether
w/v ¼ 1 : 9, 0.68 mL, 0.43 mmol) solution, and the mixture was then stirred
ꢀ
(
(
1
200 mL), the solid residue was filtered with off and washed with ether
50 mL ꢁ 3). The solid was recrystallized from acetone/ether (v/v ¼ 1 : 1,
0 mL), filtered off, washed with ether, and dried over P O to give
2 5
ꢀ
1
4-bromo DM (1c, 0.19 g, 84%) as a red solid: m.p. 176–177 C; H NMR
1
(
2
400 MHz, DMSO-d ) d 14.00 (s, 1H, PhOH), 13.30 (s, 1H, PhOH), 7.99 (bs,
6
H, NH ), 7.91 (m, 2H, ArH), 7.89 (m, 1H, ArH), 5.55 (m, 1H, C H), 5.28
0
2
4
(
2
m, 1H, C7eqH), 4.49 (m, 1H, C1
0
H), 4.21 (q, 1H, J ¼ 6.68 Hz, C
0
H), 4.00 (s,
5
H, C H), 3.97 (s, 3H, C OCH ), 3.78 (bs, 1H, C
1
0
OH), 3.60 (m, 1H, C H),
3
0
4
4
3
4
3
.05 (d, 1H, J ¼ 18.10 Hz, C H), 2.92 (d, 1H, J ¼ 18.10 Hz, C10axH), 2.44
1
0eq
(
(
(
d, 1H, J ¼ 14.21 Hz, C H), 2.07 (dd, 1H, J ¼ 14.21, 5.43 Hz, C8axH), 1.88
0 0
2 eq 2 ax
8
eq
dd, 1H, J ¼ 12.70, 9.00 Hz, C
H), 1.85 (d, 1H, J ¼ 12.70 Hz, C
H), 1.65
1
3
d, 3H, J ¼ 6.68 Hz, C
0
CH ); C NMR (100 MHz, DMSO-d ) d 187.51,
5
3
6
1
1
5
86.11, 169.25, 161.20, 161.01, 160.12, 137.98, 135.80, 134.93, 132.21,
22.01, 120.10, 119.01, 109.90, 105.23, 98.54, 84.56, 73.47, 69.37, 68.01,
5.94, 54.11, 38.42, 37.04, 34.12, 21.20,16.72.
Daunomycin-14-pyruvate Hydrochloride (2)
1
4-Bromodaunomycin hydrochloride (1c, 0.50 g, 0.78 mmol) and pyru-
vic acid sodium salt (1.03 g, 9.33 mmol) in acetone (800 mL) were refluxed for
5 h. After completing the reaction by monitored on TLC, the solvent was
1
evaporated. To the residue dissolved in dry THF (250 mL) was added etheral
ꢀ
HCl, and the mixture was stirred at À20 C for 2h. The organic solvent was
concentrated by a rotary evaporator and purified by column chromatography
on silica gel (CH Cl /CH OH/HCO H/H O ¼ 88 : 15 : 2:1) to give dauno-
2
2
3
2
2
mycin-14-pyruvate hydrochloride (2, 0.30 g, 59%) as a red powder: m.p.
ꢀ
20
ꢀ
1
1
78–180 C;[ꢁ]D þ 224.94 (c0.004,CH OH);IR(KBr)3445,2939,1732,1615,
À1
6
3
1
584, 1406, 1289, 1215, 1116, 984 cm ; H NMR (400 MHz, DMSO-d )
d 13.99 (s, 1H, PhOH), 13.29 (s, 1H, PhOH), 8.26 (bs, 2H, NH ), 7.91 (m,
2
2
H, ArH), 7.66 (m, 1H, ArH), 5.86 (d, 1H, J ¼ 8.79 Hz, C
0
H), 5.46 (d, 1H,
4
J ¼ 3.91 Hz, C H), 5.31 (d, 1H, J ¼ 18.07 Hz, C H), 5.22 (m, 1H, C
0
H),
1
7
eq
14
5
C
.12(d, 1H, J ¼ 18.07 Hz, C H), 4.96 (s, 1H, C OH), 4.23 (q, 1H, J ¼ 6.84 Hz,
1
4
9
0
H), 3.99 (s, 3H, C OCH ), 3.58 (s, 1H, C
3
0
OH), 3.33 (m, 1H, C H), 3.05 (d,
3
0
5
4
4
1
1
3
H, J ¼ 19.53 Hz, C H), 2.80 (d, 1H, J ¼ 19.53 Hz, C10axH), 2.14 (d,
1
0eq
H, J ¼ 14.65 Hz, C H), 2.09 (s, 3H, C CH ), 2.02 (dd, 1H, J ¼ 14.65,
8eq 17 3
.91 Hz, C H), 1.88 (dd, 1H, J ¼ 12.70, 9.00 Hz, C
0
3
H), 1.67 (d, 1H,
2 eq
8
ax
1
J ¼ 12.70, C
0
H), 1.37 (d, 3H, J ¼ 6.84 Hz, C
0
CH ); C NMR (100 MHz,
5 3
2
ax
DMSO-d ) d 209.86, 187.53, 185.99, 160.96, 160.73, 160.06, 159.89, 138.38,
6
135.67, 134.93, 132.86, 122.11, 119.55, 118.45, 109.86, 105.07, 98.23, 79.08,

1
968
RHO ET AL.
7
2
3.46, 69.41, 67.46, 66.04, 56.54, 53.57, 41.08, 37.28, 37.05, 34.81, 23.11,
0.67; UV (CH OH) l (log e) 204 (0.59), 234 (0.77), 251 (0.55); Mass
3
þ
þ
(
FAB , Na) m/z 637 (M-HCl þ Na) .
0
Daunomycin-3 -N-pyruviccarboamide (3)
The mixture of pyruvic acid (0.10 mL, 1.49 mmol) and EDCI (0.48 g,
.48 mmol) in dry DMF (500 mL) was stirred on an ice bath for 30 min and
2
allowed to reach room temperature. To the stirred solution was added
daunomycin hydrochloride (1a, 0.70 g, 1.24 mmol) and catalytic amounts
of 4-pyrrolidinopyridine, and the mixture was then stirred for 12h. The
resulting mixture was dissolved with CH Cl (300 mL), washed with water
2
2
(
was removed under reduced pressure. The residue was purified by column
200 mL ꢁ 2) and brine (200 mL ꢁ 2), dried over MgSO , and the solvent
4
chromatography on silica gel (CH Cl /hexane/CH OH ¼ 12: 6 : 1) to give
2
2
3
0
daunomycin-3 -N-pyruviccarboamide (3, 0.45 g, 61%) as a red powder:
ꢀ
20
ꢀ
m.p. 167-169 C; [ꢁ]D þ 74.98 (c 0.004, CH OH); IR (KBr) 3445, 2939,
3
À1
1
713, 1627, 1578, 1418, 1289, 1209, 1123, 990 cm ; H NMR (400 MHz,
1
CDCl ) d 13.93 (s, 1H, PhOH), 13.19 (s, 1H, PhOH), 7.89 (d, 1H, J ¼ 7.81 Hz,
3
ArH), 7.75 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.34 (d, 1H, J ¼ 8.30 Hz, ArH),
6
1
.04 (d, 1H, J ¼ 8.30 Hz, C H), 5.45 (d, 1H, J ¼ 3.91 Hz, C H), 5.17 (m,
0
5
0
4
7eq
H, C
0
H), 4.46 (s, 1H, C OH), 4.20 (q, 1H, J ¼ 6.84 Hz, C
H), 4.02(s, 3H,
1
9
C OCH ), 3.64 (s, 1H, C
4
0
OH), 3.39 (m, 1H, C H), 3.16 (d, 1H,
3
0
3
4
J ¼ 19.04 Hz, C H), 2.83 (d, 1H, J ¼ 19.04 Hz, C10axH), 2.41 (s, 3H,
1
0eq
C CH ), 2.27 (d, 1H, J ¼ 14.65 Hz, C H), 2.06 (dd, 1H, J ¼ 14.65,
1
4
3
8eq
3
4
.91 Hz, C H), 1.93 (s, 3H, sugar-NPyCH ), 1.83 (dd, 1H, J ¼ 13.18,
8
ax
3
.46 Hz, C2
0
H), 1.74 (dd, 1H, J ¼ 13.18, 4.39 Hz, C
0
H), 1.28 (d, 3H,
2 ax
eq
1
3
J ¼ 6.84 Hz, C
0
CH ); C NMR (100 MHz, CDCl ) d 211.92, 186.66,
5
3
3
1
1
6
86.26, 172.38, 169.33, 160.75, 156.22, 155.59, 135.52, 135.31, 134.33,
33.88, 120.68, 119.66, 118.25, 111.27, 111.08, 100.58, 76.60, 69.94, 69.53,
7.09, 56.61, 45.44, 35.10, 33.42, 29.94, 24.98, 23.41, 16.84; UV (CH OH)
3
þ
l (log e) 204 (0.41), 233 (0.59), 251 (0.42); Mass (FAB , Na) m/z 621
þ
(
M þ Na) .
0
Doxorubicin-3 -N-pyruviccarboamide (4)
The mixture of pyruvic acid (0.09 mL, 1.29 mmol) and EDCI (0.48 g,
.07 mmol) in dry DMF (500 mL) was stirred on an ice bath for 30 min and
allowed to reach room temperature. To the stirred solution was added
2
doxorubicin hydrochloride (1b, 0.60 g, 1.04 mmol) and catalytic amounts

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1969
of 4-pyrrolidinopyridine, and the mixture was then stirred for 13 h. The
resulting mixture was dissolved with CH Cl (300 mL), washed with water
2
2
(
was removed under reduced pressure. The residue was purified by column
200 mL ꢁ 2) and brine (200 mL ꢁ 2), dried over MgSO , and the solvent
4
chromatography on silica gel (CH Cl /hexane/CH OH ¼ 8 : 8 : 1) to give
2
2
3
0
ꢀ
doxorubicin-3 -N-pyruviccarboamide (4, 0.38 g, 60%) as a red powder:
20
ꢀ
m.p. 175–176 C; [ꢁ]D þ 49.99 (c 0.004, CH OH); IR (KBr) 3445, 2939,
3
À1
1
1
732, 1627, 1578, 1418, 1289, 1215, 1116, 1018, 990 cm
;
H NMR
(
400 MHz, CDCl ) d 13.98 (s, 1H, PhOH), 13.26 (s, 1H, PhOH), 8.05 (d,
3
1
H, J ¼ 7.81 Hz, ArH), 7.79 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.39 (d, 1H,
J ¼ 8.30 Hz, ArH), 5.82(d, 1H, J ¼ 8.30 Hz, C H), 5.49 (d, 1H, J ¼ 3.91 Hz,
0
4
C
H), 5.29 (m, 1H, C H), 4.75 (s, 2H, C H), 4.53 (s, 1H, C OH), 4.17 (q,
1 14 9
0
7
eq
1
1
C
H, J ¼ 6.84 Hz, C
0
H), 4.09 (s, 3H, C OCH ), 3.64 (s, 1H, C OH), 3.33 (d,
4
0
5
4
3
H, J ¼ 18.55 Hz, C H), 3.04 (d, 1H, J ¼ 18.55 Hz, C10axH), 2.92 (m, 1H,
1
0eq
0
H), 2.34 (d, 1H, J ¼ 14.65 Hz, C H), 2.17 (dd, 1H, J ¼ 14.65, 3.91 Hz,
8eq
3
C8 H), 1.95 (s, 3H, sugar-NPyCH ), 1.77 (dd, 1H, J ¼ 13.67, 4.88 Hz,
ax
3
C2
0
H), 1.72(dd, 1H,
0
J ¼ 13.67, 4.40 Hz,
C
0
H), 1.29 (s, 3H,
2 ax
eq
13
J ¼ 6.84 Hz, C
CH3); C NMR (100 MHz, CDCl ) d 204.76, 190.82,
5
3
1
1
7
86.94, 186.52, 160.91, 159.70, 156.07, 155.56, 154.96, 135.68, 135.41,
33.47, 133.44, 120.78, 119.79, 118.36, 111.53, 111.34, 100.83, 79.67,
7.20, 69.79, 67.53, 67.36, 56.69, 47.49, 35.45, 30.25, 26.91, 16.83; UV
þ
(
CH OH) l (log e) 204 (0.45), 234 (0.56), 251 (0.41); Mass (FAB , Na)
3
þ
m/z 637 (M þ Na) .
0
Doxorubicin-14,3 -N-dipyruvate (5)
The mixture of pyruvic acid (0.16 mL, 2.30 mmol) and EDCI (0.50 g,
.59 mmol) in dry DMF (500 mL) was stirred on an ice bath for 30 min and
2
allowed to reach room temperature. To the stirred solution was added
doxorubicin hydrochloride (1b, 0.60 g, 1.03 mmol) and catalytic amounts
of 4-pyrrolidinopyridine, and the mixture was then stirred for 12h. The
resulting mixture was extracted with CH Cl (300 mL), washed with water
2
2
(
was removed under reduced pressure. The residue was purified by column
200 mL ꢁ 2) and brine (200 mL ꢁ 2), dried over MgSO , and the solvent
4
chromatography on silica gel (CH Cl /hexane/CH OH ¼ 8 : 2: 1) to give
2
2
3
0
doxorubicin-14,3 -N-dipyruvate (5, 0.40 g, 57%) as a red powder: m.p.
ꢀ
20
ꢀ
1
1
36–138 C; [ꢁ]D þ 166.63 (c 0.004, CH Cl ); IR (KBr) 3432, 2927, 2953,
À1
3
2
2
1
738, 1621, 1375, 1246, 1129, 1018 cm
; H NMR (400 MHz, CDCl )
d 13.99 (s, 1H, PhOH), 13.27 (s, 1H, PhOH), 8.03 (d, 1H, J ¼ 7.81 Hz,
ArH), 7.79 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.40 (d, 1H, J ¼ 8.30 Hz,

1
970
RHO ET AL.
ArH), 5.80 (d, 1H, J ¼ 8.30 Hz, C
0
H), 5.51 (d, 1H, J ¼ 3.40 Hz, C7eqH), 5.48
4
(
(
(
d, 1H, J ¼ 18.07 Hz, C H), 5.33 (d, 1H, J ¼ 18.07 Hz, C H), 5.29
0 0
1 9 5
1
4
14
m, 1H, C
H), 4.82(s, 1H, C OH), 4.30 (q, 1H, J ¼ 6.34 Hz, C
H), 4.09
s, 3H, C OCH ), 3.65 (s, 1H, C
4
0
OH), 3.49 (m, 1H, C H), 3.34 (d, 1H,
3
0
3
4
J ¼ 19.53 Hz, C H), 2.93 (d, 1H, J ¼ 19.53 Hz, C10axH), 2.56 (s, 3H,
1
0eq
C CH ), 2.45 (d, 1H, J ¼ 14.65 Hz, C H), 2.02 (dd, 1H, J ¼ 14.65,
1
7
3
8eq
3
1
1
1
9
1
.40 Hz, C H), 1.95 (s, 3H, sugar-NPyCH ), 1.43–1.74 (m, 2H, C H),
0
8
ax
3
2
1
3
.32(d, 3H, J ¼ 6.34 Hz, C5
0
CH3); C NMR (100 MHz, CDCl ) d 210.23,
3
96.52, 191.80, 187.12, 187.11, 163.44, 160.29, 159.95, 150.85, 150.84,
40.32, 132.97, 131.25, 131.23, 125.33, 125.31, 125.25, 122.10, 117.50,
2.11, 83.83, 78.37, 68.65, 63.54, 57.20, 49.62, 45.29, 41.10, 35.67, 26.55,
7.68, 16.02, 14.91; UV (CH Cl ) l (log e) 235 (2.31), 251 (1.42), 482
2
2
þ
þ
(
0.69); Mass (FAB , Na) m/z 707 (M þ Na) .
Daunomycin-14-aspartate Dihydrochloride (6)
Di-tert-butyldicarbonate (0.84 g, 3.85 mmol) and dioxane (10 mL) was
added to aspartic acid sodium salt (0.50 g, 3.22 mmol) in H O (2 0 mL), and
2
the mixture was stirred for 10 min. Et N (0.90 mL, 6.45 mmol) and dioxane
3
(10 mL) was slowly added to the reaction mixture, and the resulting mixture
was then stirred overnight. The organic solvent was removed, and the result-
ing mixture was recrystallized from acetone to yield N-BOC-aspartic acid
ꢀ
sodium salt (54%, m.p. 240 C) as a white powder. 14-Bromodaunomycin
hydrochloride (1c, 0.10 g, 0.16 mmol) and N-BOC-aspartic acid sodium salt
(
6
0.24 g, 0.92 mmol) in acetone (350 mL) was vigorously stirred at reflux for
0 h. After the reaction mixture was cooled to room temperature, the pre-
cipitate was filtered and the organic solvent was evaporated. After the com-
ꢀ
bined products was dissolved in CF CO H (10 mL) at À20 C, the resulting
3
2
mixture was stirred for 20 min, and then the solvent was evaporated under
reduce pressure. After the residue was purified by column chromatography
on silica gel (CH Cl /CH OH/HCO H/H O ¼ 88 : 20 : 2 : 1), the isolated
2
2
3
2
2
ꢀ
product was dissolved in HCl/CH OH (10 mL) at 0 C and allowed to
3
reach room temperature for 1 h. The organic solvent was concentrated by
ꢀ
a rotary evaporator to give 6 (0.04 g, 34%) as a red solid: m.p. 209–211 C;
ꢀ
2
0
[
ꢁ] À 125.01 (c 0.004, 0.2 N HCl solution); IR (KBr) 3432, 2939, 1732,
D
À1
1
1
615, 1387, 1283, 1215, 1116, 990 cm ; H NMR (400 MHz, DMSO-d ) d
6
1
4.01 (s, 1H, PhOH), 13.95 (s, 1H, PhOH), 8.01 (bs, 2H, NH ), 7.90
2
(
(
(
(
m, 2H, ArH), 7.64 (t, 1H, J ¼ 7.89 Hz, ArH), 5.63 (m, 1H, C
0
H), 5.05
4
m, 1H, C H), 4.82(m, 1H, C
7
0
H), 4.60 (t, 1H, J ¼ 5.41 Hz, C H), 4.05
14 4 3
eq
1
16
q, 1H, J ¼ 6.80 Hz, C
0
H), 4.02(s, 2H , C H), 3.98 (s, 3H, C OCH ), 3.80
0
5
d, 2H, J ¼ 5.92Hz, C 17H), 3.68 (bs, 1H, C4
OH), 3.28 (m, 1H, C3 H),
0

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1971
2
.85 (d, 1H, J ¼ 18.36 Hz, C H), 2.58 (d, 1H, J ¼ 18.36 Hz, C10axH), 2.47
1
0eq
(
(
(
1
1
6
d, 1H, J ¼ 14.56 Hz, C H), 2.27 (dd, 1H, J ¼ 14.56, 4.40 Hz, C8axH), 2.06
0 0
2 eq 2 ax
8
eq
dd, 1H, J ¼ 12.05, 7.98 Hz, C
H), 1.95 (d, 1H, J ¼ 12.05 Hz, C
H), 1.26
1
3
d, 3H, J ¼ 6.80 Hz, C
0
CH ); C NMR (100 MHz, DMSO-d ) d 210.01,
5
3
6
88.12, 186.12, 178.96, 167.78, 160.89, 160.12, 139.05, 135.98, 135.00,
32.92, 122.32, 120.01, 118.56, 110.10, 105.45, 98.52, 79.09, 73.51, 69.49,
7.86, 56.52, 53.69, 37.52, 37.15, 34.98, 20.78; UV (0.2 N HCl solution) l
þ
(
(
log e) 233 (0.67), 253 (0.44), 481 (0.20); Mass (FAB , Na) m/z 682
M-2HCl þ Na) .
þ
Daunomycin-14-(N-acetyl)aspartate Hydrochloride (7)
1
4-bromodaunomycin hydrochloride (1c, 0.30 g, 0.47 mmol) and
N-acetyl-L-aspartic acid (0.10 g, 0.57 mmol) was dissolved in acetone
300 mL). To the mixture was added triethyl amine (0.08 mL, 0.57 mmol),
(
and the mixture was then stirred at room temperature for 8 h. After remov-
ing the solvent by a rotary evaporator, an etheral HCl in dry THF (200 mL)
was added to the reaction mixture. The resulting mixture was stirred at
ꢀ
À20 C for 2h, and the solvent was then removed under reduced pressure.
Purification of the residue by column chromatography (CH Cl /CH OH/
2
2
3
HCO H/H O ¼88 : 15 : 2: 1) gave pure daunomycin-14-( N-acetyl)aspartate
2
2
ꢀ
hydrochloride (7, 0.21 g, 61%) as a red powder: m.p. 155–157 C;
2
0
ꢀ
[
ꢁ] À 41.66 (c 0.004, CH OH); IR (KBr) 3420, 2939, 1738, 1621, 1578,
D
3
À1
1
1
1
1
412, 1289, 1215, 1116, 1012, 984 cm ; H NMR (400 MHz, DMSO-d ) d
6
3.98 (s, 1H, PhOH), 13.22 (s, 1H, PhOH), 8.34 (s, 1H, C NHAc), 8.25 (d,
1
7
H, J ¼ 7.81 Hz, ArH), 7.87 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.67 (d, 1H,
NH), 5.73 (m, 1H, C H), 5.71 (s, 1H,
J ¼ 8.30 Hz, ArH), 7.60 (m, 1H, C
0
0
4
3
C OH), 5.28 (d, 1H, J ¼ 18.06 Hz, C H), 5.17 (m, 1H, C7eqH), 5.10 (d, 1H,
9
14
J ¼ 18.07 Hz, C H), 4.91 (m, 1H, C
0
1
H), 4.32(dd, 1H, J ¼ 6.84, 7.81 Hz,
1
4
C H), 4.20 (q, 1H, J ¼ 6.34 Hz, C
0
H), 3.96 (s, 3H, C OCH ), 3.70 (m, 1H,
5 4 3
1
7
C
0
OH), 3.34 (m, 1H, C
0
H), 3.02(d, 1H, J ¼ 17.58 Hz, C10eqH), 2.80 (d, 1H,
16
4
3
J ¼ 17.58 Hz, C
H), 2.75 (dd, 1H, J ¼ 16.40, 6.84 Hz, C H), 2.60 (dd, 1H,
16 8eq
1
0ax
J ¼ 16.40, 7.81 Hz, C H), 2.24 (d, 1H, J ¼ 12.70 Hz, C H), 2.04 (dd, 1H,
J ¼ 12.70, 4.34 Hz, C H), 1.80 (s, 3H, C NHAc), 1.63–1.87 (m, 2H, C
0
H),
2
8
ax
17
1
3
1
2
1
1
2
.12(d, 3H, J ¼ 6.34 Hz, C
0
CH3); C NMR (100 MHz, DMSO-d ) d
5
6
11.56, 189.93, 189.08, 178.27, 173.21, 171.60, 163.23, 154.01, 149.93,
41.30, 135.74, 132.20, 128.46, 123.52, 120.70, 120.38, 119.66, 110.64,
10.11, 96.68, 70.74, 65.36, 55.45, 54.10, 52.16, 49.19, 46.49, 32.01, 30.03,
8.42, 22.74, 16.86, 12.12; UV (CH OH) l (log e) 233 (0.76), 253 (0.58), 482
0.28); Mass (FAB , Na) m/z 724 (M-HCl þ Na) .
3
þ
þ
(

1
972
RHO ET AL.
0
Daunomycin-3 -N-(N-acetyl)asparticcarboamide (8)
The mixture of N-acetyl-L-aspartic acid (0.15 g, 0.86 mmol) and EDCI
(
0.27 g, 1.41 mmol) in dry DMF (250 mL) was stirred on an ice bath for
0 min and allowed to room temperature. To the stirred solution was added
daunomycin hydrochloride (1a, 0.40 g, 0.71 mmol) and catalytic amounts of
-pyrrolidinopyridine, and the mixture was then stirred for 4 h. The result-
ing mixture was extracted with 5% CH OH in CHCl (200 mL), washed
3
4
3
3
with water (100 mL ꢁ 2) and brine (100 mL ꢁ 2), dried over MgSO , and
4
the solvent was then removed under reduced pressure. The residue was
purified by column chromatography (CH Cl /CH OH/HCO H/H O ¼
2
2
3
2
2
0
8
7
8 : 15 : 2: 1) to give daunomycin-3 -(N-acetyl)asparticcarboamide (8, 0.36 g,
ꢀ
20
ꢀ
4%) as a red powder: m.p. 149–151 C; [ꢁ]D þ 149.97 (c 0.004, CH OH);
3
À1
IR (KBr) 3420, 2927, 1713, 1652, 1578, 1418, 1289, 1209, 1129, 987 cm
1
;
H NMR (400 MHz, DMSO-d ) d 13.93 (s, 1H, PhOH), 13.18 (s, 1H,
6
PhOH), 8.10 (d, 1H, J ¼ 7.81 Hz, ArH), 7.80 (dd, 1H, J ¼ 8.30, 7.81 Hz,
ArH), 7.55 (bs, 1H, sugar-NHAc), 7.32(d, 1H, J ¼ 8.30 Hz, ArH), 5.47
(
(
C
m, 1H, C4
0
H), 5.19 (d, 1H, J ¼ 3.42Hz, C H), 4.85 (m, 1H, C
7eq
0
H), 4.47
1
dd, 1H, J ¼ 5.86, 7.81 Hz, sugar-aspCHCO H), 4.17 (q, 1H, J ¼ 6.84 Hz,
2
0
H), 3.93 (s, 3H, C OCH ), 3.59 (m, 1H, C
4
0
OH), 3.37 (m, 1H, C H), 3.03
3
0
5
3
4
(
2
1
1
d, 1H, J ¼ 18.06 Hz, C H), 2.85 (d, 1H, J ¼ 18.06 Hz, C10axH), 2.57 (d,
1
0eq
H, J ¼ 5.86 Hz, sugar-aspCH ), 2.39 (d, 1H, J ¼ 12.14 Hz, C8eqH), 2.28 (dd,
0
8ax 2 eq
2
H, J ¼ 12.14, 3.42 Hz, C H), 2.17 (d, 1H, J ¼ 14.16 Hz, C
H), 2.06 (dd,
H), 1.79 (s, 3H, sugar-aspNHAc), 1.12(d, 3H,
ax
H, J ¼ 14.16, 5.86 Hz, C
0
2
1
3
J ¼ 6.84 Hz, C
0
CH ); C NMR (100 MHz, DMSO-d ) d 211.44, 186.05,
5
3
6
1
1
7
1
85.97, 175.86, 175.55, 171.56, 169.10, 160.44, 151.30, 150.39, 148.88,
41.25, 135.35, 119.42, 118.57, 110.50, 110.37, 100.18, 89.59, 80.06, 77.78,
5.09, 74.37, 71.17, 67.85, 66.62, 56.47, 49.44, 47.19, 36.12, 24.09, 22.48,
6.98; UV (CH OH) l (log e) 203 (0.70), 234 (0.91), 251 (0.66); Mass
3
þ
þ
(
FAB , Na) m/z 708 (M þ Na) .
0
Doxorubicin-3 -N-(N-acetyl)asparticcarboamide (9)
The mixture of N-acetyl-L-aspartic acid (0.11 g, 0.63 mmol) and EDCI
0.20 g, 1.05 mmol) in dry DMF (200 mL) was stirred on an ice bath for
(
30 min and allowed to reach room temperature. To the stirred solution was
added doxorubicin hydrochloride (1b, 0.30 g, 0.52mmol) and catalytic
amounts of 4-pyrrolidinopyridine, and the mixture was then stirred for
5
h. The resulting mixture was extracted with 5% CH OH in CHCl
3 3
(
over MgSO , and the solvent was then removed under reduced pressure.
200 mL), washed with water (100 mL ꢁ 2) and brine (100 mL ꢁ 2), dried
4

SYNTHESIS OF NEW ANTHRACYCLINE DERIVATIVES
1973
The residue was purified by column chromatography (CH Cl /CH OH/
2
2
3
HCO H/H O ¼ 88 : 15 : 2: 1) to give 9 (0.26 g, 71%) as a red powder: m.p.
2
2
ꢀ
20
ꢀ
1
1
1
1
(
(
63–165 C; [ꢁ] þ83.32 (c 0.004, H O); IR (KBr) 3445, 2939, 1726, 1627,
À1
6
D
2
1
560, 1412, 1283, 1215, 1123, 984 cm ; H NMR (400 MHz, DMSO-d ) d
3.96 (s, 1H, PhOH), 13.95 (s, 1H, PhOH), 8.42(bs, 1H, C 3 NH), 8.16 (d,
H, J ¼ 7.81 Hz, ArH), 7.83 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.59
0
d, 1H, J ¼ 7.81 Hz, sugar-aspNH), 7.38 (d, 1H, J ¼ 8.30 Hz, ArH), 5.76
m, 1H, C
0
H), 5.71 (s, 1H, C OH), 5.33 (d, 1H, J ¼ 18.07 Hz, C H),
0
7eq 14
4
9
14
5
C1
.26 (m, 1H, C
H), 5.18 (d, 1H, J ¼ 18.07 Hz, C H), 4.89 (m, 1H,
2
0
H), 4.49 (dd, 1H, J ¼ 5.86, 7.81 Hz, sugar-aspCHCO H), 4.21 (q,
0 0
5 4 3 4
J ¼ 6.84 Hz, 1H, C
H), 3.95 (s, 3H, C OCH ), 3.37 (s, 1H, C OH), 3.03
(
d, 1H, J ¼ 18.06 Hz, C10eqH), 2.73–2.87 (m, 2H, C3
0
&C10axH), 2.67 (dd, 1H,
J ¼ 16.40, 5.86 Hz, sugar-aspCH ), 2.59 (dd, 1H, J ¼ 16.40, 7.81 Hz, sugar-
2
aspCH ), 2.39 (d, 1H, J ¼ 12.14 Hz, C H), 2.31 (dd, 1H, J ¼ 12.14, 3.91 Hz,
2
8eq
C
H), 2.02 (m, 2H, C H), 1.80 (s, 3H, sugar-aspNHAc), 1.13 (d, 3H,
0
2
8
ax
1
3
J ¼ 6.84 Hz, C
0
CH3); H NMR (100 MHz, DMSO-d ) d 207.27, 186.09,
5
6
1
1
1
2
86.02, 172.69, 171.89, 171.53, 171.02, 170.60, 170.54, 169.61, 169.13,
69.05, 168.55, 160.48, 155.83, 154.27, 135.15, 134.33, 119.69, 110.56,
10.41, 75.10, 75.08, 56.52, 54.91, 48.67, 48.55, 36.11, 22.57, 22.46, 22.39,
2.29, 16.97; UV (H O) l (log e) 202 (1.93), 251 (1.05), 480 (0.45); Mass
2
þ
þ
(
FAB , Na) m/z 724 (M þ Na) .
0
Doxorubicin-14,3 -N-di(N-acetyl)aspartate (10)
The mixture of N-acetyl-L-aspartic acid (0.20 g, 1.14 mmol) and EDCI
0.25 g, 1.30 mmol) in dry DMF (200 mL) was stirred on an ice bath for
(
30 min and allowed to reach room temperature. To the stirred solution was
added doxorubicin hydrochloride (1b, 0.30 g, 0.52mmol) and catalytic
amounts of 4-pyrrolidinopyridine, and the mixture was then stirred for
10 h. The resulting mixture was extracted with 5% CH OH in CHCl
3 3
(
over MgSO , and the solvent was then removed under reduced pressure.
200 mL), washed with water (100 mL ꢁ 2) and brine (100 mL ꢁ 2), dried
4
The residue was purified by column chromatography on silica gel
(
CH Cl /CH OH/HCO H/H O ¼ 88 : 15 : 2: 1) to give 10 (0.30 g, 67%) as
ꢀ ꢀ
D 2
2
2
3
2
2
20
a red solid: m.p. 110–112 C; [ꢁ] þ249.95 (c 0.004, H O); IR (KBr)
À1
3
383, 3087, 2939, 1732, 1627, 1547, 1412, 1283, 1215, 1024, 984 cm ;
1
H NMR (400 MHz, DMSO-d ) d 14.00 (s, 1H, PhOH), 13.20 (s, 1H, PhOH),
6
8
7
.36 (s, 1H, C3
.88 (dd, 1H, J ¼ 8.30, 7.81 Hz, ArH), 7.62(d, 1H, J ¼ 7.32Hz, sugar-
H), 5.30 (d, 1H,
0
NH), 8.24 (s, 1H, C NHAc), 8.13 (d, 1H, J ¼ 7.81 Hz, ArH),
17
aspNH), 7.37 (d, 1H, J ¼ 8.30 Hz, ArH), 5.63 (m, 1H, C
0
4
J ¼ 18.07 Hz, C H), 5.19 (d, 1H, J ¼ 3.91 Hz, C7eqH), 5.16 (d, 1H,
1
4

1
974
RHO ET AL.
J ¼ 18.07 Hz, C H), 4.91 (m, 1H, C
0
1
H), 4.69 (dd, 1H, J ¼ 6.84, 7.81 Hz,
1
4
C H), 4.45 (dd, 1H, J ¼ 5.86, 7.81 Hz, sugar-aspCHCO H), 4.17 (q, 1H,
1
7
2
J ¼ 6.35 Hz, C
0
H), 3.96 (s, 3H, C OCH ), 3.49 (s, 1H, C OH), 3.31 (m, 1H,
0
4
5
4
3
C
0
H), 3.04 (d, 1H, J ¼ 18.55 Hz, C H), 2.85 (d, 1H, J ¼ 18.55 Hz,
10eq
3
C1 H), 2.78 (dd, 1H, J ¼ 16.38, 6.84 Hz, C CH ), 2.70 (dd, 1H,
0ax 16 2
J ¼ 16.40, 5.86 Hz, sugar-aspCH ), 2.63 (dd, 1H, J ¼ 16.38, 7.81 Hz,
2
C CH ), 2.55 (dd, 1H, J ¼ 16.40, 7.81 Hz, sugar-aspCH ), 2.36 (d, 1H,
1
6
2
2
J ¼ 12.14 Hz, C H), 2.29 (dd, 1H, J ¼ 12.14, 3.91 Hz, C H), 1.96 (m,
8
eq
8ax
2
H, C H), 1.82(s, 3H, C NHAc), 1.78 (s, 3H, aspNHAc), 1.11 (d, 3H,
0
2 17
1
3
J ¼ 6.35 Hz, C
0
CH3); C NMR (100 MHz, DMSO-d ) d 212.27, 187.23,
5
6
1
1
9
3
73.08, 172.35, 171.71, 169.72, 169.05, 168.98, 168.09, 163.79, 145.32,
44.56, 134.52, 131.34, 124.99, 118.83, 109.54, 106.63, 101.85, 100.30,
9.65, 83.82, 78.21, 67.83, 66.62, 57.62, 56.54, 53.67, 49.57, 45.09, 40.51,
6.61, 36.44, 28.66, 22.49, 22.34, 19.03, 16.95; UV (H O) l (log e) 2 33
0.59), 253 (0.42), 480 (0.19); Mass (FAB , Na) m/z 881 (M þ Na) .
2
þ
þ
(
ACKNOWLEDGMENT
This work was supported by a grant of the Korea Health 21 R&D
project (HMP-98-D-4-0026), Ministry of Health & Welfare, Republic
of Korea.
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Received in the USA June 23, 2001