Synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones bearing a sugar moiety

Article abstract of DOI:10.1016/j.tet.2005.10.077

The synthesis of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6- tetraones, structurally related to the G2 checkpoint inhibitor granulatimide and bearing a sugar moiety, is described. Substitutions were carried out at the 6-position of the glycosyl u

Full text of DOI:10.1016/j.tet.2005.10.077

Tetrahedron 62 (2006) 1116–1123
Synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones
bearing a sugar moiety
a
Helene Henon, Fabrice Anizon, Bruno Pfeiffer and Michelle Prudhomme
a
b
a,
*
´ `
´
a
´ `
Laboratoire SEESIB, Universite Blaise Pascal, UMR 6504 du CNRS, 63177 Aubiere, France
b
´
Institut de Recherches SERVIER, Division Recherche Cancerologie, 125 Chemin de ronde, 78290 Croissy sur Seine, France
Received 3 October 2005; revised 27 October 2005; accepted 28 October 2005
Available online 23 November 2005
Abstract—The synthesis of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to the G2 checkpoint inhibitor
granulatimide and bearing a sugar moiety, is described. Substitutions were carried out at the 6-position of the glycosyl unit to lead to an
amino substituent as observed in many biologically active compounds such as anthracyclins or staurosporines.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
mitosis, due to an accumulation of DNA lesions. The G2
checkpoint is regulated by various kinases and mainly by
the Chk1 kinase. Granulatimide and isogranulatimide, as
well as staurosporine and UCN-01, are Chk1 inhibitors.
Compounds structurally related to granulatimide have
been recently synthesized.13–21
Many antitumor products from natural sources such as
anthracyclins, staurosporine and related compounds,
contain a heteroaromatic framework to which a sugar
moiety is attached (Fig. 1).1–6 In daunomycin, the
prototype anthracyclin antibiotic, the planar chromophore
intercalates into the DNA, whereas the amino-sugar lies
in the minor groove.7 In rebeccamycin, the sugar unit is
required for a tight interaction with DNA and for
topoisomerase I inhibition.8 In the case of staurosporine,
UCN-01 and K-252a, which are kinase inhibitors
interacting with the ATP binding site, the sugar unit
mimics the ATP ribose.9,10 An amino function on the
carbohydrate moiety is often present. Its amphiphilic
properties may facilitate the access to the different cell
compartments.
In this paper, we report the synthesis of bis-imide
granulatimide analogue 9 bearing a maleimide moiety
instead of the imidazole heterocycle, and a glucosyl unit
attached to the indole nitrogen. The sugar moiety was
introduced with the aim of improving the biological
activity but also to increase the solubility. Indeed,
the bis-imide granulatimide analogues previously syn-
thesized in our laboratory proved to be very insoluble
that could reduce cell penetration. Moreover, 60-chloro
then 60-azido substituents were introduced to finally
obtain the 60-amino derivative 13.
Granulatimide and isogranulatimide (Fig. 1) are natural
products, which inhibit the G2 checkpoint of the cell
cycle.11,12 In response to DNA damage, the cell cycle
checkpoints are activated. Their role consists in blocking
the cell cycle to allow time for DNA repair. G2
checkpoint inhibition has attracted a widespread interest
because, in more than 50% of tumors, the G1 checkpoint
2. Results and discussion
The first steps of the synthesis were perfected with a methyl
protective group on the imide nitrogen, which could be
removed via an anhydride according to a method described
by Brenner et al.,22 and, in parallel, with a benzyloxymethyl
protective group removable at the end of the synthesis23,24
to give the free imide nitrogen, necessary for kinase
inhibition.
is lacking. Therefore, the combination of
a G2
checkpoint inhibitor with a DNA damaging agent should
force selectively cancer cells into a premature and lethal
Keywords: Granulatimide; Antitumor agents; Dipyrrolo[3,4-a:3,4-c]-
carbazole-1,3,4,6-tetraone.
Several methods are described in the literature for the
glycosylation of indole derivatives. The Koenigs–Knorr
*
Corresponding author. Tel.: C33 473 40 7124; fax: C33 473 40 7717;
e-mail: Michelle.PRUDHOMME@univ-bpclermont.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.077

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1117
H
N
H
H
N
N
O
R
O
O
N
O
N
N
O
N
N
N
H
O
H
H3C
H3COOC
H3C
Cl
Cl
OH
O
OH
H3CO
HO
NHCH3
K-252a
OH
OCH3
rebeccamycin
H
staurosporine R = H
UCN-01 R = OH
H
N
O
C
O
O
N
O
OH
OH
O
O
CH3
OH
NH
N
N
N
H
N
O
N
H
OCH3
O
O
granulatimide
isogranulatimide
daunomycin
CH3
HO
NH2
Figure 1. Chemical structures of some natural antitumor compounds.
method was described by Kaneko et al.25 for the
synthesis of rebeccamycin. An anhydrosugar was coupled
to a bis-indolylmaleimide or to an indole-3-acetamide in
the syntheses of rebeccamycin described by
Danishefsky23 and Faul,24 respectively. Okhubo
et al.26,27 reported the glycosylation of indolocarbazoles
using an a-chlorosugar in a basic heterogeneous medium.
A Mitsunobu reaction was performed by Okhubo et al.28
and Zembower et al.29 for the glycosylation of bis-
indolylmaleimides and indolylbromomaleimides, respecti-
vely. For the synthesis of compound 9 (Scheme 1), we
chose the Mitsunobu reaction, which was performed on
indolylbromomaleimides A and B. The indolylbromo-
maleimides A and B, protected on the imide nitrogen
with either a methyl group or benzyloxymethyl sub-
stituent, were prepared from the corresponding
N-protected-dibromomaleimides and indolylmagnesium
bromide according to a known procedure.30
respectively. At this stage, the conversion of N-methyl-
maleimide22 of compound 5 to an anhydride failed.
Therefore, the synthesis was continued only from
compound 6. The Diels–Alder reaction with maleimide
gave the cycloadduct 7 from compound 6, as a mixture
of diastereoisomers 7a and 7b, which could be separated
by chromatography. In a previous work, we observed the
isomerization of the Diels–Alder cyclo-adduct from
indoline to indole.19 To get an insight into the structures
of compounds 7a and 7b, complementary NMR studies
were carried out. The indoline structure was proved from
1H–13C long range coupling (3J) between H1 and two
0
carbons of the indoline, one of them (C6b) bearing a
hydrogen (Fig. 2). The Diels–Alder reaction has been
performed using various amounts of maleimide and
various solvents. The best yield (94%) was obtained in
toluene with maleimide (5 equiv). The diastereoisomers
7a and 7b were further oxidized using either DDQ or
manganese dioxide in various solvents to give compound
8 (Table 1). The best yield (75%) was obtained from the
isomer 7b with MnO2 in chloroform.
The glycosylation was carried out using a commercial
anomeric mixture of 2,3,4,6-tetra-O-benzyl-D-glucopyra-
nose, leading to bromo-indolylmaleimides 1 and 2 in 94
and 92% yields, respectively. Removal of the bromine
atom was performed by hydrogenolysis in the presence
of pyridine to avoid the hydrogenolysis of the benzyl
groups.31,32 Succinimides 3 and 4 were obtained in 61
and 58% yields, respectively, as mixtures of diastereo-
isomers in 0.69:1 and 0.82:1 ratios. The diastereo-
Finally, the BOM and benzyl protective groups were removed
by hydrogenolysis using 20% palladium hydroxide on carbon
affording compound 9 in 71% yield. Compound 10, bearing
four acetyl groups on the sugar moiety, was also prepared to
serve as a possible prodrug, which could be hydrolyzed inside
the cells to release compound 9. This kind of prodrug has
been previously successfully used for glycosyl-indigo
derivatives.33,34
1
isomeric ratios were determined from H NMR spectra on
the signals at 3.47 and 3.50 ppm for compound 3 and at
2.85 and 2.92 ppm for compound 4. The oxydation step
to the corresponding maleimides was carried out using
DDQ to give compounds 5 and 6 in 62 and 91% yields,
Several substituents were introduced in 60-position on the
sugar moiety. In rebeccamycin series, we had observed that

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1118
R
N
R
N
R
N
OH
OBn
O
O
O
O
O
O
O
R
N
BnO
H2, Pd/C
pyridine,
1 bar
O
O
DDQ
dioxane
OBn
OBn
Br
Br
N
N
PPh3, DIAD
N
N
H
OBn
OBn
O
O
OBn
O
A R = CH3
5 R = CH3
6 R = BOM
3 R = CH3
4 R = BOM
OBn
OBn
B R = BOM
1 R = CH3
BnO
BnO
BnO
2 R = BOM
OBn
OBn
OBn
OBn
BOM
N
BOM
N
BOM
N
O
O
O
O
O
O
H
N
H
H
O
O
H
H
O
O
O
H
H
MnO2
CHCl3
H
H
+
6
NH
NH
NH
toluene
N
N
N
O
O
O
OBn
OBn
OBn
O
O
O
BnO
BnO
BnO
8
OBn
OBn
OBn
OBn
OBn
OBn
7a and 7b
Pd(OH)2/C
THF/MeOH
H2, 1 bar
H
N
H
N
O
O
O
O
Ac2O
pyridine
O
O
NH
NH
N
N
O
O
OAc
OH
O
O
AcO
6'
10
R
9 R = OH
OAc
OAc
OH
OH
9 R = OH
CCl4, PPh3
pyridine
11 R = Cl
NaN3, DMF
12 R = N3
H2, Pd/C, HCl
MeOH/THF
13 R = NH2,HCl
Scheme 1.
such substituents could modify the biological targets,
changing topoisomerase I inhibitors to kinases inhibitors.35
The chloro-derivative 11 was obtained in 76% yield by
treatment of compound 9 by CCl4 in the presence of
triphenylphosphine and pyridine. Nucleophilic substitution
using sodium azide led to the azido derivative 12 in 60%
yield. Compound 13 was obtained in a quantitative yield by
catalytic hydrogenation using 10% Pd/C in methanol/THF/
HCl. The hydrochloride was directly formed in the reaction
mixture.36

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1119
4.1.1. 3-(3-Bromo-2,5-dihydro-1-methyl-2,5-dioxo-
pyrrol-4-yl)-1-(1-deoxy-2,3,4,6-tetra-O-benzyl-b-D-
glucopyranos-1-y1)-indole (1). To a mixture of A (50 mg,
0.164 mmol), PPh3 (129 mg, 0.49 mmol) and an anomeric
mixture of 2,3,4,6-tetra-O-benzyl-D-glucopyranose
(266 mg, 0.49 mmol) in THF (3.2 mL) at K78 8C, DIAD
(95 mL) was added dropwise. The mixture was allowed to
reach room temperature and stirred for 5 h. 0.2 M HCl
(40 mL) was poured into the mixture. After extraction with
EtOAc, the organic phase was washed successively with a
saturated aqueous NaHCO3 solution and water. The organic
phase was dried over MgSO4. The solvent was removed and
the residue was purified by flash chromatography (eluent:
toluene/EtOAc 50:1) to give 1 as a red solid (128 mg,
0.155 mmol, 94% yield). Mp 55 8C. IR (KBr) nC]C
1615 cmK1, nC]O 1710, 1770 cmK1. HRMS (FABC)
calcd for C47H43N2O7Br [M]C826.2254, found 826.2265.
BOM
N
O
61.7 ppm, 7a
65.2 ppm, 7b
O
O
NH
6b
N
7a
155.7 ppm, 7a
154.5 ppm, 7b
O
H
1'
OBn
5.34 ppm, 7a
O
4.68-4.77 ppm, 7b
BnO
OBn
OBn
Figure 2.
Table 1. Experimental conditions and yields for the oxidation of 7a and 7b
to compound 8
1H NMR (400 MHz, CDCl3): 3.20 (3H, s), 3.67 (1H, d, JZ
10.5 Hz), 3.74–3.82 (2H, m), 3.85–3.92 (2H, m), 3.97 (1H,
t, JZ9.5 Hz), 4.06 (1H, t, JZ9.0 Hz), 4.28 (1H, d, JZ
10.5 Hz), 4.55 (1H, d, JZ12.0 Hz), 4.63 (1H, d, JZ
12.0 Hz), 4.71 (1H, d, JZ10.5 Hz), 4.93 (1H, d, JZ
10.5 Hz), 4.94 (1H, d, JZ11.0 Hz), 4.98 (1H, d, JZ
11.0 Hz), 5.45 (1H, d, JZ9.0 Hz), 6.71 (2H, d, JZ7.5 Hz),
7.07 (2H, t, JZ7.5 Hz), 7.13 (1H, m), 7.23–7.40 (17H, m),
7.67 (1H, m), 8.05–8.09 (2H, m).
Oxidizing agent
Solvent
Temperature (time
of reaction)
Yields
DDQ (2.05 equiv)
DDQ (2.05 equiv)
DDQ (2.5 equiv)
Dioxane
Toluene
Toluene
Reflux (20 h)
35% from 7a,
0% from 7b
47% from 7a
Room temperature
(30 h)
Room temperature
(24 h) then reflux
(1 h)
Room temperature
(6 h) then 4 days
(40 8C)
0% from 7b
53% from 7a
MnO2 (20 equiv)
MnO2 (20 equiv)
CH2Cl2
CHCl3
13C NMR (100 MHz, CDCl3): 24.9 (CH3), 68.5, 73.6, 75.1,
75.4, 75.9 (CH2), 77.5, 78.1, 80.8, 85.5, 86.9 (CH), 112.3,
121.9, 123.4, 123.6, 127.5–128.6, 131.4 (C tert arom),
105.6, 115.8, 126.1, 136.1, 136.7, 137.3, 137.9, 138.1, 138.3
(C quat), 166.8, 169.3 (C]O).
Reflux (65 h)
73% from 7a,
75% from 7b
3. Conclusion
4.1.2. 3-(1-Benzyloxymethyl-3-bromo-2,5-dihydro-2,5-
dioxo-pyrrol-4-yl)-1-(1-deoxy-2,3,4,6-tetra-O-benzyl-b-
D-glucopyranos-1-y1)-indole (2). Identical procedure as
described for 1 was used from B (302 mg, 0.73 mmol), PPh3
(578 mg, 2.20 mmol), 2,3,4,6-tetra-O-benzyl-D-glucopyra-
nose (1.19 g, 2.20 mmol) and DIAD (427 mL) in THF
(13.5 mL) to give after purification by flash chromatography
(eluent: toluene/EtOAc 50:1 then 50:2) compound 2 as an
orange solid (632 mg, 0.68 mmol, 92% yield). Mp 40 8C. IR
(film, NaCl) nC]O 1725, 1780 cmK1. Mass (ESIC) 955,
957 [MCNa]C.
In conclusion, we have synthesized new bis-imide granu-
latimide analogues bearing a sugar moiety on the indole
nitrogen with the aim of increasing the solubility and the
interaction with the target enzyme(s). Moreover, various
substituents have been introduced on the sugar unit. The
biological activities of these novel granulatimide analogues
are under investigation.
4. Experimental
4.1. General
1H NMR (400 MHz, CDCl3): 3.64 (1H, d, JZ10.5 Hz), 3.72–
3.80 (2H, m), 3.83–3.90 (2H, m), 3.96 (1H, t, JZ9.5 Hz), 4.03
(1H, t, JZ9.0 Hz), 4.26 (1H, d, JZ10.5 Hz), 4.54 (1H, d, JZ
12.0 Hz), 4.61 (1H, d, JZ12.0 Hz), 4.69 (2H, s), 4.69 (1H, d,
JZ10.5 Hz), 4.89–4.97 (3H, m), 5.19 (2H, s), 5.43 (1H, d, JZ
9.0 Hz), 6.67–6.71 (2H, m), 7.02–7.13 (3H, m), 7.22–7.40
(22H, m), 7.65 (1H, m), 8.03 (1H, m), 8.04 (1H, s).
IR spectra were recorded on Perkin-Elmer 881 or Perkin-
Elmer Paragon 500 spectrometers (n in cmK1). NMR
spectra were performed on a Bruker AVANCE 400 and
AVANCE 500 (chemical shifts d in ppm, the following
abbreviations are used: singlet (s), broad signal (br s),
doublet (d), doubled doublet (dd), doubled doubled doublet
(ddd), doubled triplet (dt), triplet (t), multiplet (m), tertiary
carbons (C tert), quaternary carbons (C quat). The signals
were assigned from 1H–1H COSY and 13C–1H correlations.
Low-resolution mass spectra (ESIC, CI) and HRMS were
determined on a Hewlett Packard MS engine. Chromato-
graphic purifications were performed by flash silicagel
Geduran SI 60 (Merck) 0.040–0.063 mm column
chromatography.
13C NMR (100 MHz, CDCl3): 67.7, 68.5, 71.9, 73.6, 75.1,
75.4, 75.9 (CH2), 77.5, 78.1, 80.8, 85.4, 86.8 (CH), 112.4,
122.0, 123.5, 123.7, 127.6–128.7, 131.7 (C tert arom),
105.3, 116.1, 126.0, 136.1, 136.6, 137.4, 137.5, 137.9,
138.1, 138.3 (C quat), 166.3, 168.8 (C]O).
4.1.3. 1-(1-Deoxy-2,3,4,6-tetra-O-benzyl-b-D-gluco-
pyranos-1-y1)-3-(1-methyl-2,5-dioxo-pyrrolidin-3-yl)-
indole (3). A solution of compound 1 (344 mg, 0.416 mmol)

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1120
in methanol (11.5 mL) and THF (4 mL) was hydrogenated
(1 atm) for 3 h in the presence of 10% Pd/C (34 mg) and
pyridine (39 mL, 0.48 mmol). After filtration over Celite, the
filtrate was evaporated, and the residue was purified by flash
chromatography (eluent: cyclohexane/EtOAc 8:2) to give 3
as a pale orange solid (191 mg, 0.254 mmol, 61% yield).
Compound 3 was isolated as a mixture of diastereoisomers.
IR (KBr) nC]O 1705, 1775 cmK1. Mass (ESIC) 751 [MCH]C,
773 [MCNa]C.
13C NMR (100 MHz, CDCl3): 36.2, 36.4, 68.0, 68.6, 72.3,
73.5, 74.6, 74.7, 75.3, 75.8 (CH2), 38.0, 38.1, 77.5, 77.9,
81.0, 81.1, 85.4, 86.4 (CH), 112.1, 118.9, 119.0, 120.8,
123.0, 123.9, 124.0, 127.6–128.7 (C tert arom), 111.6,
111.7, 127.1, 127.2, 136.3, 136.4, 136.9, 137.6, 138.0,
138.1, 138.4 (C quat arom), 175.9, 176.0, 177.2, 177.3
(C]O).
4.1.5. 1-(1-Deoxy-2,3,4,6-tetra-O-benzyl-b-D-gluco-
pyranos-1-y1)-3-(2,5-dihydro-1-methyl-2,5-dioxo–
pyrrol-3-yl)-indole (5). A solution of DDQ (21.7 mg,
0.096 mmol) in dioxane (1 mL) was slowly added to a
solution of 3 (65.2 mg, 0.087 mmol) in dioxane (1 mL). The
mixture was stirred at room temperature overnight, then it
was filtered off. After evaporation of the filtrate, the residue
was purified by flash chromatography (eluent: cyclohexane/
EtOAc 9:1) to give 5 as a yellow solid (40.4 mg,
0.054 mmol, 62% yield). Mp 97–103 8C. IR (KBr) nC]C
1617 cmK1, nC]O 1703, 1765 cmK1. Mass (ESIC) 749
[MCH]C.
1H NMR (400 MHz, CDCl3): (a: major diastereoisomer; b:
minor diastereoisomer) 2.86 (1Ha, dd, J1Z18.5 Hz, J2Z
5.0 Hz), 2.92 (1Hb, dd, J1Z18.5 Hz, J2Z5.0 Hz), 3.10
(3Hb, s), 3.11 (3Ha, s), 3.27 (1Hb, dd, J1Z18.5 Hz, J2Z
9.5 Hz), 3.29 (1Ha, dd, J1Z18.5 Hz, J2Z9.5 Hz), 3.47
(1Ha, d, JZ10.0 Hz), 3.50 (1Hb, d, JZ10.0 Hz), 3.69–3.74
(1HaCb, m), 3.75–3.87 (3HaCb, m), 3.92 (1HaCb, t, JZ
9.5 Hz), 3.97 (1Hb, t, JZ9.0 Hz), 3.98 (1Ha, t, JZ9.0 Hz),
4.16 (1Hb, d, JZ10.5 Hz), 4.19 (1Ha, d, JZ10.0 Hz), 4.29–
4.35 (1HaCb, m), 4.54 (1HaCb, d, JZ12.0 Hz), 4.62 (1Ha, d,
JZ12.0 Hz), 4.62 (1Hb, d, JZ12.0 Hz), 4.68 (1HaCb, d, JZ
10.5 Hz), 4.88–4.98 (3HaCb, m), 5.35 (1HaCb, d, JZ
9.0 Hz), 6.69–6.75 (2HaCb, m), 7.07–7.38 (21HaCb, m),
7.45–7.50 (1HaCb, m), 7.59–7.63 (1HaCb, m).
1H NMR (400 MHz, CDCl3): 3.11 (3H, s), 3.65 (1H, d, JZ
10.5 Hz), 3.72–3.80 (2H, m), 3.83 (1H, dd, J1Z11.0 Hz,
J2Z4.0 Hz), 3.86 (1H, t, JZ9.0 Hz), 3.93 (1H, t, JZ
9.0 Hz), 4.00 (1H, t, JZ9.0 Hz), 4.25 (1H, d, JZ10.5 Hz),
4.54 (1H, d, JZ12.0 Hz), 4.60 (1H, d, JZ12.0 Hz), 4.68
(1H, d, JZ10.5 Hz), 4.89–4.96 (3H, m), 5.42 (1H, d, JZ
9.0 Hz), 6.66–6.70 (3H, m), 7.03 (2H, t, JZ7.5 Hz), 7.08–
7.13 (1H, m), 7.21–7.36 (17H, m), 7.66 (1H, d, JZ8.0 Hz),
7.80 (1H, d, JZ8.0 Hz), 8.51 (1H, s).
13C NMR (100 MHz, CDCl3): 25.2 (CH3), 36.3, 36.6, 68.6,
73.5, 74.6, 74.7, 75.3, 75.8 (CH2), 38.0, 38.1, 77.5, 77.9,
81.0, 81.1, 85.4, 86.5 (CH), 112.1, 119.0, 119.1, 120.8,
123.0, 123.8, 123.9, 127.7–128.5 (CH arom), 112.0, 112.1,
127.2, 127.3, 136.3, 136.4, 137.0, 138.0, 138.1, 138.4 (C
quat arom), 176.3, 176.4, 177.7, 177.8 (C]O).
13C NMR (100 MHz, CDCl3): 23.8 (CH3), 68.6, 73.6, 75.0,
75.4, 75.8, (CH2), 77.5, 78.1, 80.8, 85.5, 86.8 (CH sugar),
112.8, 116.0, 120.6, 122.7, 123.8, 127.7–128.6, 131.8 (CH),
106.8, 127.2, 136.3, 136.7, 137.9, 138.1, 138.3, 139.0 (C
quat), 171.8, 172.3 (C]O).
4.1.4. 3-(1-Benzyloxymethyl-2,5-dioxo-pyrrolidin-3-yl)-
1-(1-deoxy-2,3,4,6-tetra-O-benzyl-b-D-glucopyranos-1-
y1)-indole (4). Identical procedure as for the preparation of
3 was carried out from a mixture of 2 (559 mg, 0.60 mmol)
in methanol (16.6 mL) and THF (6 mL) in the presence of
Pd/C (56 mg) and pyridine (56 mL, 0.69 mmol), which was
hydrogenated for 8 h. Compound 4 was isolated after
purification by flash chromatography (eluent: cyclohexane/
EtOAc 8:2) as an orange solid (296 mg, 0.345 mmol, 58%
yield). Compound 6 was also obtained in mixture with
the starting product 2 (117 mg containing 15% of 2
as determined on 1H NMR spectrum). Compound 4
was isolated as a mixture of diastereoisomers. IR (KBr)
nC]O 1715, 1780 cmK1. Mass (ESIC) 879 [MCNa]C, 895
[MCK]C.
4.1.6. 3-(1-Benzyloxymethyl-2,5-dihydro-2,5-dioxo-
pyrrol-3-yl)-1-(1-deoxy-2,3,4,6-tetra-O-benzyl-b-D-
glucopyranos-1-y1)-1H-indole (6). A solution of DDQ
(78.2 mg, 0.344 mmol) in dioxane (3.4 mL) was slowly
added to a solution of 4 (281 mg, 0.328 mmol) in dioxane
(3.4 mL). The mixture was stirred at room temperature for
3 h then it was filtered off. The filtrate was evaporated and
the residue was purified by flash chromatography (eluent:
cyclohexane/EtOAc 8:2) to give 6 as a yellow solid
(254 mg, 0.297 mmol, 91% yield). Mp 47 8C. IR (KBr)
nC]C 1615 cmK1, nC]O 1710, 1770 cmK1. Mass (ESIC)
877 [MCNa]C, 893 [MCK]C.
1H NMR (400 MHz, CDCl3): (a: major diastereoisomer; b:
minor diastereoisomer) 2.85 (1Ha, dd, J1Z18.5 Hz, J2Z
5.5 Hz), 2.92 (1Hb, dd, J1Z18.5 Hz, J2Z5.5 Hz), 3.19
(1Hb, dd, J1Z18.5 Hz, J2Z9.5 Hz), 3.21 (1Ha, dd, J1Z
18.5 Hz, J2Z9.5 Hz), 3.51 (1Ha, d, JZ10.0 Hz), 3.52 (1Hb,
1H NMR (400 MHz, CDCl3): 3.65 (1H, d, JZ10.5 Hz),
3.72–3.80 (2H, m), 3.83 (1H, dd, J1Z11.0 Hz, J2Z4.0 Hz),
3.86 (1H, t, JZ9.0 Hz), 3.93 (1H, t, JZ9.0 Hz), 3.99 (1H, t,
JZ9.0 Hz), 4.26 (1H, d, JZ10.5 Hz), 4.53 (1H, d, JZ
12.0 Hz), 4.60 (1H, d, JZ12.0 Hz), 4.66–4.70 (3H, m),
4.89–4.96 (3H, m), 5.13 (2H, s), 5.43 (1H, d, JZ9.0 Hz),
6.65–6.69 (2H, m), 6.71 (1H, s), 6.98–7.04 (2H, m), 7.07
(1H, m), 7.21–7.41 (22H, m), 7.66 (1H, d, JZ8.0 Hz), 7.79
(1H, d, JZ7.5 Hz), 8.52 (1H, s).
d, JZ10.5 Hz), 3.72–3.77 (1HaCb, m), 3.78–3.83 (1HaCb
,
m), 3.84–3.91 (2HaCb, m), 3.95 (1HaCb, t, JZ9.0 Hz), 4.00
(1Hb, t, JZ9.0 Hz), 4.01 (1Ha, t, JZ9.0 Hz), 4.16–4.25
(2HaCb, m), 4.56 (1Ha, d, JZ12.0 Hz), 4.57 (1Hb, d, JZ
12.0 Hz), 4.64 (1Ha, d, JZ12.0 Hz), 4.65 (1Hb, d, JZ
12.0 Hz), 4.68–4.75 (3HaCb, m), 4.92–5.02 (3HaCb, m),
5.15 (2Hb, s), 5.16 (2Ha, s), 5.37 (1HaCb, d, JZ9.0 Hz),
6.72–6.76 (2HaCb, m), 7.10–7.43 (26HaCb, m), 7.48–7.52
(1HaCb, m), 7.62–7.66 (1HaCb, m).
13C NMR (100 MHz, CDCl3): 66.6, 68.5, 71.5, 73.5, 75.0,
75.4, 75.8 (CH2), 77.5, 78.1, 80.8, 85.4, 86.7 (CH), 106.7,
127.1, 136.3, 136.6, 137.6, 137.9, 138.0, 138.3, 139.2

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1121
(C quat), 112.8, 116.0, 120.5, 122.8, 124.0, 127.7–128.6,
132.1 (CH), 171.3, 171.6 (C]O).
solvent was removed and the residue was purified by flash
chromatography (eluent: cyclohexane/EtOAc 7:3) to give 8
as an orange solid (62.7 mg, 0.066 mmol, 75% yield). Mp
78–80 8C. IR (KBr) nC]O 1722, 1781 cmK1, nNH 3130–
3530 cmK1. Mass (ESIC) 970 [MCNa]C.
4.1.7. 2-Benzyloxymethyl-7-(1-deoxy-2,3,4,6-tetra-O-ben-
zyl-b-D-glucopyranos-1-y1)-1,3,3a,3b,4,6,6a,6b-octahydro-
dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7a) and
(7b). A mixture of 6 (171 mg, 0.20 mmol) and maleimide
(97 mg, 1.0 mmol) in toluene (5 mL) was refluxed for 19 h.
The solvent was removed and the residue was purified by
flash chromatography (eluent: cyclohexane/EtOAc from 7:3
to 4:6) to give 7 (94% yield) as two diasteroisomers 7a
(117 mg, 0.123 mmol) and 7b (61.4 mg, 0.064 mmol).
1H NMR (400 MHz, CDCl3): 3.20 (1H, d, JZ11.5 Hz),
3.90–4.03 (5H, m), 4.09–4.14 (1H, m), 4.21 (1H, d, JZ
11.5 Hz), 4.68 (1H, d, JZ12.0 Hz), 4.71–4.78 (2H, m), 4.79
(2H, s), 4.85 (1H, d, JZ11.0 Hz), 4.92 (1H, d, JZ11.0 Hz),
4.98 (1H, d, JZ11.0 Hz), 5.26 (1H, d, JZ11.0 Hz), 5.31
(1H, d, JZ11.0 Hz), 6.15 (2H, d, JZ7.5 Hz), 6.68 (2H, t,
JZ7.5 Hz), 6.85 (1H, t, JZ7.5 Hz), 7.23–7.48 (21H, m),
7.53 (1H, t, JZ7.5 Hz), 7.61 (1H, d, JZ8.5 Hz), 8,02 (1H,
d, JZ8.5 Hz), 8.67 (1H, br s, NH), 9.13 (1H, d, JZ8.0 Hz).
Compound 7a. Mp 95 8C. IR (KBr) nC]C 1605 cmK1, nC]O
1650, 1710, 1725, 1765 cmK1, nNH 3150–3550 cmK1. Mass
(ESIC) 974 [MCNa]C.
13C NMR (100 MHz, CDCl3): 67.3, 69.0, 72.0, 73.3, 74.5,
75.3, 75.9 (CH2), 77.5, 77.9, 79.8, 85.7, 87.0 (CH), 115.2,
123.5, 126.7–128.6, 130.7 (C tert arom), 118.3, 119.3,
121.7, 126.4, 127.2, 130.0, 136.7, 137.5, 137.9 (2C), 138.1,
140.1, 142.1 (C quat arom), 163.9 (2C), 166.6, 166.9
(C]O).
1H NMR (400 MHz, CDCl3): 2.81 (1H, d, JZ6.5 Hz), 3.31
(1H, dd, J1Z8.5 Hz, J2Z6.5 Hz), 3.59–3.66 (2H, m), 3.72–
3.89 (6H, m), 4.17 (1H, d, JZ10.5 Hz), 4.38 (1H, d, JZ
12.0 Hz), 4.45 (1H, d, JZ10.5 Hz), 4.46 (1H, d, JZ
12.0 Hz), 4.65 (1H, d, JZ12.0 Hz), 4.66 (1H, d, JZ
10.5 Hz), 4.70 (1H, d, JZ12.0 Hz), 4.86 (1H, d, JZ
11.0 Hz), 4.87 (1H, d, JZ11.0 Hz), 4.94 (1H, d, JZ
11.0 Hz), 5.09 (1H, d, JZ10.5 Hz), 5;15 (1H, d, JZ
10.5 Hz), 5.33 (1H, d, JZ8.5 Hz), 6.55–6.60 (2H, m), 6.82
(1H, t, JZ7.5 Hz), 6.93 (1H, d, JZ8.5 Hz), 7.01–7.09 (3H,
m), 7.18–7.35 (19H, m), 7.39 (2H, d, JZ7.5 Hz), 7.90 (1H,
br s, NH), 8.60 (1H, d, JZ7.5 Hz).
4.1.9. 7-(1-Deoxy-b-D-glucopyranos-1-y1)-1,3,4,6-tetra-
hydro-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone
(9). A solution of 8 (567 mg, 0.60 mmol) in a mixture THF/
MeOH 4:1 (44 mL) was hydrogenated (1 atm) for 24 h in
the presence of Pearlman catalyst (20% Pd(OH)2/C,
283 mg). THF and MeOH were added, the reaction mixture
was stirred at room temperature for 2 h before filtration over
Celite. The filtrate was evaporated and the residue was
purified by flash chromatography (eluent: THF/cyclohexane
8:2) leading to 9 as an orange solid, which was further
washed with CH2Cl2 (199 mg, 0.43 mmol, 71% yield). Mp
O300 8C. IR (KBr) nC]O 1720, 1755, 1770 cmK1, nNH,OH
3100–3600 cmK1. HRMS (ESIC) calcd for C22H17N3O9Na
[MCNa]C490.0862, found 490.0877.
13C NMR (100 MHz, CDCl3): 38.9, 42.1, 43.7, 61.7, 76.7,
77.4, 77.8, 85.7, 86.2 (CH), 67.5, 68.3, 71.8, 73.4, 74.5,
75.2, 75.7 (CH2), 110.6, 119.3, 127.6–128.8, 134.9 (CH),
110.3, 120.9, 136.7, 137.7, 137.9 (2C), 138.3, 147.7, 155.7
(C quat), 165.9, 172.1, 173.0, 174.4 (C]O).
Compound 7b. Mp 94 8C. IR (KBr) nC]O 1650, 1705, 1720,
1760 cmK1, nNH 3200–3550 cmK1. Mass (ESIC) 974 [MC
Na]C.
1H NMR (400 MHz, DMSO-d6): 3.40–3.52 (2H, m), 3.59–
3.73 (2H, m), 3.84–3.94 (2H, m), 4.74 (1H, t, JZ5.5 Hz,
OH), 5.02 (1H, d, JZ5.5 Hz), 5.19 (1H, d, JZ5.0 Hz, OH),
5.23 (1H, d, JZ5.0 Hz, OH), 7.53 (1H, d, JZ9.0 Hz),
7.54 (1H, t, JZ7.5 Hz), 7.74 (1H, t, JZ7.5 Hz), 8.09 (1H, d,
JZ7.5 Hz), 9.28 (1H, d, JZ8.0 Hz), 11.62–11.91 (2H, br s,
NH).
1H NMR (400 MHz, CDCl3): 2.62 (1H, m), 3.58–3.70 (3H,
m), 3.80 (1H, t, JZ9.0 Hz), 3.86–3.89 (2H, m), 3.91 (1H, t,
JZ9.5 Hz), 4.03 (1H, d, JZ11.0 Hz), 4.15 (1H, t, JZ
9.0 Hz), 4.52–4.57 (2H, m), 4.65 (1H, d, JZ10.5 Hz), 4.68–
4.77 (5H, m), 4.88 (1H, d, JZ10.5 Hz), 4.90 (1H, d, JZ
11.0 Hz), 4.98 (1H, d, JZ11.0 Hz), 5.15 (1H, d, JZ
10.5 Hz), 5.20 (1H, d, JZ10.5 Hz), 6.87–6.96 (3H, m),
7.08–7.14 (3H, m), 7.22–7.39 (20H, m), 7.44 (2H, d, JZ
7.5 Hz), 7.98 (1H, br s, NH), 8.72 (1H, d, JZ8.0 Hz).
13C NMR (100 MHz, DMSO-d6): 61.0 (CH2), 69.9, 70.4,
77.4, 80.3, 87.7 (CH), 115.4, 122.5, 126.0, 129.8 (C tert
arom), 118.5, 120.5, 121.5, 125.2, 127.8, 131.8, 140.2,
141.8 (C quat arom), 165.6, 165.8, 168.3, 169.0 (C]O).
13C NMR (100 MHz, CDCl3): 67.5, 68.5, 71.8, 73.3, 75.2,
75.6, 75.7 (CH2), 39.9, 41.3, 42.1, 65.2, 77.8, 77.9, 79.2,
86.2, 86.8 (CH), 113.3, 120.4, 127.5–128.7; 129.0, 134.7
(CH), 110.8, 122.6, 137.3, 137.7, 138.0, 138.2, 138.4, 147.5,
154.5 (C quat), 165.9, 172.0, 173.4, 174.5 (C]O).
4.1.10. 7-(1-Deoxy-2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranos-1-y1)-1,3,4,6-tetrahydro-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (10). Acetic anhydride
(101 mL, 1.07 mmol) was added to a mixture of 9 (50 mg,
0.107 mmol) in pyridine (221 mL, 2.73 mmol) at 0 8C. The
mixture was stirred at room temperature for 20 h. Water was
added. After extraction with EtOAc, the organic phase was
dried over MgSO4, and the solvent was removed. The
residue was purified by flash chromatography (eluent:
cyclohexane/EtOAc from 5:5 to 4:6) to give 10 as a yellow
solid (32.6 mg, 0.051 mmol, 48% yield). Mp 176 8C. IR
4.1.8. 2-Benzyloxymethyl-7-(1-deoxy-2,3,4,6-tetra-O-
benzyl-b-D-glucopyranos-1-y1)-1,3,4,6-tetrahydro-
dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (8). This
procedure is also applicable to stereoisomer 7a.
A mixture of 7b (84 mg, 0.088 mmol) and MnO2 (153 mg,
1.76 mmol) in chloroform (4 mL) was refluxed for 60 h. The
(KBr) nC]O 1685–1800 cmK1, nNH 3100–3550 cmK1
.

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1122
HRMS (ESIC) calcd for C30H26N3O13 [MCH]C636.1466,
found 636.1495.
(ESIC) calcd forC22H16N6O8Na [MCNa]C515.0927,
found 515.0934.
1H NMR (400 MHz, CDCl3): 1.53 (3H, s), 2.03 (3H, s), 2.17
(3H, s), 2.20 (3H, s), 4.32–4.44 (2H, m), 4.54 (1H, d, JZ
11.5 Hz), 5.50 (1H, t, JZ9.5 Hz), 5.67 (1H, t, JZ9.5 Hz),
5.89 (1H, t, JZ9.5 Hz), 7.38 (1H, t, JZ7.5 Hz), 7.71 (1H, t,
JZ8.0 Hz), 7.99 (1H, d, JZ8.5 Hz), 8.07 (1H, d, JZ
9.0 Hz), 8.82 (1H, br s, NH), 8.96 (1H, d, JZ8.0 Hz), 9.06
(1H, br s, NH).
1H NMR (400 MHz, DMSO-d6): 3.40–3.48 (1H, m), 3.50–
3.58 (1H, m), 3.65 (1H, dd, J1Z13.0 Hz, J2Z6.0 Hz), 3.76–
3.84 (2H, m), 3.93–4.01 (1H, m), 5.13 (1H, d, JZ6.0 Hz),
5.33 (1H, d, JZ5.5 Hz), 5.52 (1H, d, JZ5.5 Hz), 7.52–7.58
(2H, m, H1 CHarom), 7.76 (1H, t, JZ8.0 Hz), 8.06 (1H, d,
JZ8.5 Hz), 9.27 (1H, d, JZ8.0 Hz), 11.73 (1H, br s, NH),
11.83 (1H, br s, NH).
0
13C NMR (100 MHz, CDCl3): 20.1, 20.6, 20.7, 20.9 (CH3),
61.8 (CH2), 68.2, 69.2, 73.5, 74.8, 85.5 (CH), 114.3, 123.7,
127.0, 131.0 (C tert arom), 117.7, 121.2, 121.6, 126.9,
127.4, 131.5, 139.8, 141.5 (C quat arom), 164.5, 165.1,
166.9, 167.4, 169.5, 169.8, 170.3, 171.0 (C]O).
13C NMR (100 MHz, DMSO-d6): 51.2 (CH2), 70.1, 70.3,
77.1, 77.9, 87.7 (CH sucre), 114.9, 122.5, 126.0, 128.9 (CH
arom), 118.5, 120.7, 121.5, 125.2, 127.7, 131.8, 140.2,
141.5 (C quat arom), 165.4, 165.7, 168.2, 168.8 (C]O).
4.1.13. 7-(6-Amino-1,6-dideoxy-b-D-glucopyranos-1-y1)-
1,3,4,6-tetrahydro-dipyrrolo[3,4-a:3,4-c]carbazole-
1,3,4,6-tetraone hydrochloride (13). A solution of 12
(20 mg, 0.041 mmol) in MeOH/THF 2:1 (1.5 mL) was
hydrogenated for 5 h in the presence of 10% Pd/C (2 mg)
concentrated HCl (4 mL). 10% Pd/C (3 mg) was added and
the reaction mixture was hydrogenated for 18 h before
filtration over Celite. After evaporation on reduced pressure,
compound 13 (20 mg, 0.040 mmol, 98% yield) was
obtained as a yellow solid. Mp O235 8C (decomposition).
4.1.11. 7-(6-Chloro-1,6-dideoxy-b-D-glucopyranos-1-y1)-
1,3,4,6-tetrahydro-dipyrrolo[3,4-a:3,4-c]carbazole-
1,3,4,6-tetraone (11). PPh3 (337 mg, 1.28 mmol) then CCl4
(62 mL, 0.64 mmol) were successively added to a solution of
9 (150 mg; 0.321 mmol) in pyridine (1.6 mL). The mixture
was stirred at room temperature for 8 h. The solvent was
removed and the residue was dried under vaccum. CH2Cl2
was added to the residue and the mixture was filtered off.
The solid was purified by flash chromatography (eluent:
cyclohexane/THF from 8:2 to 100% THF then THF/
methanol 95:5) to give 11 (118 mg, 0.243 mmol, 76%
yield) as an orange solid. Mp O300 8C. IR (KBr) nC]O
1725, 1780 cmK1, nNH 3150–3650 cmK1. HRMS (ESIC)
calcd for C22H16N3O8NaCl [MCNa]C508.0524, found
508.0544.
IR (KBr) nC]O 1725, 1770 cmK1, nNH 3100–3650 cmK1
.
HRMS (ESIC) calcd for C22H19N4O8 [MCH]C467.1203,
found 467.1216.
1H NMR (400 MHz, DMSO-d6): 3.12–3.21 (1H, m), 3.34–
3.41 (1H, m), 3.44–3.58 (2H, m), 3.82–3.89 (1H, m), 3.98–
4.05 (1H, m), 5.21 (1H, d, JZ5.5 Hz, OH), 5.48 (1H, br s,
OH), 5.75 (1H, d, JZ4.5 Hz, OH), 7.56 (1H, t, JZ7.5 Hz),
1H NMR (400 MHz, DMSO-d6): 3.46 (1H, dt, J1Z9.0 Hz,
J2Z5.5 Hz), 3.59 (1H, dt, J1Z9.0 Hz, J2Z6.0 Hz), 3.84–
3.90 (1H, m), 3.92 (1H, dt, J1Z9.0 Hz, J2Z6.0 Hz), 4.02
(1H, dd, J1Z12.0 Hz, J2Z5.0 Hz), 4.08 (1H, dd, J1Z
12.0 Hz, J2Z2.5 Hz), 5.13 (1H, d, JZ6.0 Hz), 5.33 (1H, d,
JZ5.5 Hz), 5.58 (1H, d, JZ6.0 Hz), 7.55 (1H, ddd, J1Z
8.0 Hz, J2Z7.0 Hz, J3Z1.0 Hz), 7.58 (1H, d, JZ9.0 Hz),
7.75 (1H, ddd, J1Z8.5 Hz, J2Z7.0 Hz, J3Z1.5 Hz), 8.08
(1H, d, JZ8.5 Hz), 9.28 (1H, ddd, J1Z8.0 Hz, J2Z1.0 Hz,
J3Z0.5 Hz), 11.62–11.97 (2H, br s, NH).
0
7.61 (1H, d, JZ9.0 Hz, H1 ), 7.75 (1H, t, JZ7.5 Hz), 8.07
(3H, br s, NH2, HCl), 8.15 (1H, d, JZ8.5 Hz), 9.27 (1H, d,
JZ8.0 Hz), 11.74 (1H, s, NH), 11.88 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 40.5 (CH2), 70.0, 71.0,
75.6, 76.8, 87.5 (CH), 115.4, 122.6, 126.0, 129.9 (CH
arom), 118.3, 120.8, 121.5, 125.1, 127.7, 131.9, 140.2,
141.5 (C quat arom); 165.5, 165.7, 168.2, 168.8 (C]O).
13C NMR (100 MHz, DMSO-d6): 45.1 (CH2), 70.2 (2C),
76.8, 77.8, 87.6 (CH), 115.0, 122.6, 126.1, 129.8 (C tert
arom), 118.5, 120.7, 121.6, 125.2, 127.7, 131.8, 140.2,
141.6 (C quat arom), 165.5, 165.7, 168.3, 168.8 (C]O).
Acknowledgements
´
The authors are grateful to Bertrand Legeret, University
Blaise Pascal, Clermont-Ferrand, for recording the mass
spectra.
4.1.12. 7-(6-Azido-1,6-dideoxy-b-D-glucopyranos-1-y1)-
1,3,4,6-tetrahydro-dipyrrolo[3,4-a:3,4-c]carbazole-
1,3,4,6-tetraone (12). NaN3 (95 mg, 1.46 mmol) was added
to a solution of compound 11 (71 mg, 0.146 mmol) in
anhydrous DMF (3.8 mL). The mixture was heated at 90 8C
for 3 days. After evaporation, water was added to the
residue. The mixture was filtered off and the solid residue
was washed with water. The residue was purified by flash
chromatography (eluent: cyclohexane/THF from 8:2). The
solid obtained after chromatography was washed with
CH2Cl2 to give 12 (43.0 mg, 0.087 mmol, 60% yield) as
an orange solid. Mp O300 8C. IR (KBr) nC]O 1722,
1775 cmK1, nN3 2104 cmK1, nNH 3110–3620 cmK1. HRMS
References and notes
1. Prudhomme, M. Curr. Pharm. Des. 1997, 3, 265–290.
2. Capranico, G.; Zunino, F.; Kohn, K. W.; Pommier, Y.
Biochemistry 1990, 29, 562–569.
3. Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.;
Morimoto, M.; Tomita, F. Biochem. Biophys. Res. Commun.
1986, 135, 397–402.
4. Takahashi, I.; Saitoh, Y.; Yoshida, M.; Sano, H.; Nakano, H.;
Morimoto, M.; Tamaoki, T. J. Antibiot. 1989, 42, 571–576.

´
H. Henon et al. / Tetrahedron 62 (2006) 1116–1123
1123
´
20. Henon, H.; Messaoudi, S.; Hugon, B.; Anizon, F.; Pfeiffer, B.;
5. Nakanishi, S.; Matsuda, Y.; Iwahashi, K.; Kase, H. J. Antibiot.
1986, 39, 1066–1071.
Prudhomme, M. Tetrahedron 2005, 61, 5599–5614.
´
21. Henon, H.; Anizon, F.; Kucharczyk, N.; Loynel, A.; Casara, P.;
6. Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.; Tomita, K.
J. Antibiot. 1987, 40, 668–678.
Pfeiffer, B.; Prudhomme, M. Synthesis, in press.
22. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W.
Tetrahedron 1998, 44, 2887–2892.
7. Chaires, J. B. Biopolymers 1998, 44, 201–215.
8. Anizon, F.; Belin, L.; Moreau, P.; Sancelme, M.; Voldoire, A.;
`
Prudhomme, M.; Ollier, M.; Severe, D.; Riou, J. F.; Bailly, C.;
23. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. Chem.
1999, 64, 2465–2470.
Fabbro, D.; Meyer, T. J. Med. Chem. 1997, 40, 3456–3465.
9. Zhao, B.; Bower, M. J.; McDevitt, P. J.; Zhao, H.; Davis, S. T.;
Johanson, K. O.; Green, S. M.; Concha, N. O.; Zhou, B. B. S.
J. Biol. Chem. 2002, 277, 46609–46615.
´
10. Gray, N.; Detivaud, L.; Doerig, C.; Meijer, L. Curr. Med.
Chem. 1999, 6, 859–875.
24. Gallant, M.; Link, J. T.; Danishefsky, S. J. J. Org. Chem. 1993,
58, 343–349.
25. Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J. Tetrahedron
Lett. 1985, 26, 4015–4018.
26. Okhubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Morishima, H.
Tetrahedron 1996, 52, 8099–8112.
11. Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.;
Moreira da Rocha, R.; Andersen, R. J. J. Org. Chem. 1998, 63,
9850–9856.
27. Okhubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.;
Morishima, H. Tetrahedron 1997, 53, 585–592.
28. Okhubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Ito, S.;
Morishima, H. Tetrahedron 1997, 53, 5937–5950.
29. Zembower, D. E.; Zhang, H.; Lineswala, J. P.; Kuffel, M. J.;
Aytes, S. A.; Ames, M. M. Bioorg. Med. Chem. 1999, 9,
145–150.
12. Roberge, M.; Berlinck, R. G. S.; Xu, L.; Anderson, H. J.;
Lim, L. Y.; Curman, D.; Stringer, C. M.; Friend, S. H.;
Davies, P.; Vincent, I.; Haggarty, S. J.; Kelly, M. T.;
Britton, R.; Piers, E.; Andersen, R. J. Cancer Res. 1998, 58,
5701–5706.
13. Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.;
Sanghera, J. S.; Zhou, B.-B.S.; Piers, E.; Andersen, R. J.;
Roberge, M. Mol. Cancer Ther. 2004, 3, 1221–1227.
14. Piers, E.; Britton, R.; Andersen, R. J. J. Org. Chem. 2000, 65,
530–535.
´
´
´
30. Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce, S.;
Joubert, A.; Bailly, C.; Renard, P.; Hickman, J.; Prudhomme, M.
J. Med. Chem. 2003, 46, 609–622.
31. Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1998, 39,
7127–7130.
15. Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.;
Kotani, E. Chem. Pharm. Bull. 2002, 50, 872–876.
16. Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.;
Kotani, E. Chem. Pharm. Bull. 2003, 51, 209–214.
17. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
Tetrahedron Lett. 2003, 44, 3927–3930.
32. Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981–13996.
33. Wang, L.; Liu, X.; Chen, R. U.S. Patent US 6566341, 2003;
Chem. Abstr. 138, 379213.
34. Wang, L.; Liu, X.; Chen, R. WO Patent WO 03051900, 2003;
Chem. Abstr. 139, 47135.
35. Prudhomme, M. Curr. Med. Chem. Anti-Canc. Agents 2004, 4,
509–521.
18. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
Tetrahedron Lett. 2003, 44, 4607–4611.
36. Hong, F.; Zaidi, J.; Cusack, B.; Richelson, E. Bioorg. Med.
Chem. 2002, 10, 3849–3858.
19. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
Tetrahedron Lett. 2003, 44, 3935–3937.