Synthesis of bridged aza-rebeccamycin analogues

Article abstract of DOI:10.1016/j.tet.2005.04.043

The syntheses of rebeccamycin analogues possessing a 7-azaindole moiety instead of an indole unit, and with both indole and azaindole moieties linked to the carbohydrate are described. In these bridged aza compounds, the oxygen of the pyranose heterocycle is oriented towards either the indole, or the azaindole unit. In these series, compounds bearing a free imide nitrogen were synthesized by coupling the corresponding aglycones with a sugar pre-tosylated in 2-position via a Mitsunobu reaction. To obtain a precursor for bridged aza-rebeccamycin analogues substituted in 6-position on the sugar moiety, a 2,6-ditosylated sugar was used.

Full text of DOI:10.1016/j.tet.2005.04.043

Tetrahedron 61 (2005) 7304–7316
Synthesis of bridged aza-rebeccamycin analogues
Samir Messaoudi,a Fabrice Anizon,a Bruno Pfeifferb and Michelle Prudhommea,
*
a
´ ` `
Universite Blaise Pascal, Synthese et Etude de Systemes a Interet Biologique, UMR 6504 du CNRS, 63177 Aubiere, France
`
´
Institut de Recherches Servier, Division Recherche Cancerologie, 125 Chemin de ronde, 78290 Croissy sur Seine, France
´ ˆ
`
b
Received 2 February 2005; revised 29 March 2005; accepted 12 April 2005
Available online 15 June 2005
Abstract—The syntheses of rebeccamycin analogues possessing a 7-azaindole moiety instead of an indole unit, and with both indole and
azaindole moieties linked to the carbohydrate are described. In these bridged aza compounds, the oxygen of the pyranose heterocycle is
oriented towards either the indole, or the azaindole unit. In these series, compounds bearing a free imide nitrogen were synthesized by
coupling the corresponding aglycones with a sugar pre-tosylated in 2-position via a Mitsunobu reaction. To obtain a precursor for bridged
aza-rebeccamycin analogues substituted in 6-position on the sugar moiety, a 2,6-ditosylated sugar was used.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
analogues, we have synthesized 7-aza-rebeccamycin ana-
logues in which one or both indole moieties have been
replaced by a 7-azaindole unit.8,9 When only one azaindole
was introduced, the sugar part was linked either to the indole
or to the azaindole (Fig. 2). Important differences in DNA
binding properties and in topoisomerase I poisoning were
observed between the two series. Compounds with the sugar
moiety attached to the indole moiety exhibited strong DNA
binding and topoisomerase I inhibitory properties whereas
with compounds in which the sugar was attached to the
azaindole, DNA binding and topoisomerase I poisoning
were highly weakened or completely abolished. However,
compounds in both series could exhibit strong in vitro
cytotoxicities toward some tumor cell lines with IC50 values
in the nanomolar range, suggesting other biological targets
Rebeccamycin, isolated from cultures of Saccharothrix
aerocolonigenes, contains an indolocarbazole framework,
an imide upper heterocycle and a sugar part linked to one of
the indole nitrogens like other natural products such as some
tjipanazoles E, F1 and F2 and AT2433-A1 and B1 but
unlike staurosporine and UCN-01 in which the carbohydrate
moiety is linked to both indole nitrogens (Fig. 1).1–4
Rebeccamycin is a topoisomerase I inhibitor without
inhibitory properties toward kinases such as CDK1/cyclinB,
CDK5/p25 and PKC whereas staurosporine and UCN-01
are not topoisomerase I poisons but exhibit inhibitory
properties against a variety of kinases.5–7 In the course of
structure–activity relationship studies on rebeccamycin
Figure 1. Chemical structures of the bacterial metabolites rebeccamycin, staurosporine, UCN-01, AT2433 A1 and B1.
Keywords: Staurosporine; Rebeccamycin; 7-Azaindole; Antitumor compounds; Enzyme inhibitors.
*
Corresponding author. Tel.: C33 4 73 40 71 24; fax: C33 4 73 40 77 17; e-mail: Michelle.PRUDHOMME@univ-bpclermont.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.043

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7305
Figure 2. Aza-rebeccamycin analogues previously described.
than DNA and topoisomerase I for compounds in which the
sugar is linked to the azaindole. To get an insight into the
structural parameters inducing enzyme selectivity, we have
synthesized staurosporine analogues from rebeccamycin by
coupling the sugar moiety to the second indole nitrogen in
non aza series at first and recently, one N-methylated
compound has been prepared in 7-azaindole series.10–12 In a
previous brief communication, we described the synthesis
of the 7-aza staurosporine analogue 5 with the sugar
attached to both indole and azaindole nitrogens, with a
methyl group on the imide nitrogen and with the oxygen
heteroatom of the sugar ring oriented toward the indole unit
(Fig. 2).12 This compound was synthesized by coupling an
a-1-chloro-glucose on the N-methylated indolocarbazole
aglycone in the presence of a phase transfer catalyst. As
deduced from the crystal structures of staurosporine in
complex with various kinases, a free nitrogen in the upper
heterocycle seems to be necessary to establish a hydrogen
bond with the carbonyle of glutamate 81 in the ATP binding
pocket of the kinases.13,14 In this paper, the syntheses of new
7-aza bridged compounds, without the methyl group on the
imide nitrogen and with the oxygen of the sugar ring
oriented either toward the indole or toward the azaindole
moiety, are reported. The replacement of an indole moiety
Scheme 1. Synthetic scheme for compound 5.

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S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
by an azaindole in the bridged series could increase the
affinity for the binding site of the target enzyme(s) and
modify the electronic distribution on the aromatic frame-
work and the lipophilicity. Because, it has been shown that
substitutions in 6-position of the sugar unit can modify the
biological target15,16, we use a sugar unit ditosylated in 2-
and 6-positions allowing access to bridged aza compounds
substituted in 6-position of the sugar moiety with an azido
group, a precursor for amino and amido substituents.
chloro sugar 3 was prepared from acetylated compound 1
which could be obtained from the commercial triacetylated
glycal as described in literature.17–19 Tosylation of 1 yielded
tosylate 2 as a mixture of both a and b anomers, which was
further treated with HCl gas to give the a-chloro anomer
3.12 This chloro sugar was coupled to the aglycone A20
using potassium hydroxide and a phase transfer catalyst to
yield the required coupling product, which was further
treated with sodium azide to give the bridged compound 4
formed via a nucleophilic attack of the deprotonated
azaindolic nitrogen on the carbon bearing the tosyl group.
Elimination of the benzyl protecting groups of the sugar
moiety was carried out using boron tribromide. For the
synthesis of compound 12 (Scheme 3), the same procedure
as described for the synthesis of 5 was tried from aglycone
D, which was obtained from C9 by oxidative photocycliza-
tion (Scheme 2). However, the coupling reaction with the
chloro sugar 3 did not work. A Mitsunobu reaction was then
performed from aglycone B9 and sugar 6 prepared from 2
by reaction with MeONa/MeOH in THF (Scheme 3).
Compound 7 was obtained in 88% yield. After deprotection
of the azaindole nitrogen, oxidative photocyclization in the
presence of iodine gave 9 in 62% yield. Reaction of 9 with
sodium azide led to the bridged compound 10 in 72% yield.
Unlike for compound 4, debenzylation of 10 using boron
2. Results and discussion
2.1. Chemistry
The synthesis of compound 5 is outlined in Scheme 1. The
Scheme 2. Photocyclization of aglycone C.
Scheme 3. Synthesis of compound 12.

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7307
Scheme 4. Synthesis of di-tosylated sugar 17.
tribromide gave an inexploitable mixture. Removal of the
protective groups was achieved in two steps: hydrogenolysis
with Pd(OH)2/C as the catalyst leading to 11 in 52% yield,
followed by aminolysis giving the required compound 12 in
71% yield.
sugar moiety of 12, the Mitsunobu reaction was carried out
using 2,6-ditosyl-sugar 17, which was prepared from glycal
E as shown in Scheme 4.
Glycal E was prepared according to known procedures.21
Tosylation of E at 6-position led to compound 13.
Epoxidation performed using dimethyldioxirane provided
To introduce substituents selectively in 60 position on the
Scheme 5. Synthesis of 60-azido compound 23.

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S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
the anhydro sugar 14 as the major isomer. Reaction of 14
with glacial acetic acid gave compound 15 in 77% yield as a
mixture of both a and b anomers in 0.3:2 ratio, respectively.
Tosylation of 15 led to a mixture of both a and b anomers in
1:3.9 ratio, respectively, in only 24% yield. 31% of the
unreacted b anomer was recovered. The final step was
deacetylation with sodium methoxide/methanol affording
17 in 66% yield. The Mitsunobu reaction between 17 and
aglycone B led to compound 18 in 52% yield. Deprotection
of the azaindole nitrogen using tetrabutylammonium
fluoride gave 19 in 83% yield. Compound 19 was further
photocyclized to give 20. Reaction of 20 with sodium azide
in DMF induced the coupling of the sugar part with the
azaindole nitrogen and concomitant substitution at 60-
position to give 21 (Scheme 5). Contrary to compound 10,
debenzylation by hydrogenolysis could not be achieved
with compound 21. A mixture of compounds reduced on the
aromatic rings was obtained. Debenzylation carried out
using dimethyldioxirane22,23 afforded the required com-
pound 22 in 45% yield. Removal of the hydroxymethyl
substituent by aminolysis gave 23 in 77% yield.
rebeccamycin. Reaction of 26 with sodium azide led to 27 in
93% yield. Debenzylation carried out using trifluoroacetic
acid or dimethyldioxirane or by hydrogenolysis proved to be
unsuccessful. The required compound 28 was finally
obtained in 27% yield by debenzylation with boron
tribromide followed by aminolysis.
3. Conclusion
In conclusion, we have developed methods to synthesize
bridged aza-rebeccamycin analogues from 2-O-tosyl-gluco-
pyranose. Both analogues in which the anomeric carbon of
the sugar part is linked to either the azaindole or the indole
moiety have been synthesized. The use of 2,6-O-ditosyl-
glucopyranose, in the Mitsunobu 0 reaction, allowed the
introduction of an azido group in 6 -position. This method
can also be applied for introducing a wide range of
substituents in 6-position of the sugar moiety. The
cytotoxicities and the inhibitory activities of these new
compounds toward various kinases are now under
investigation.
Because in non-bridged aza rebeccamycins, important
differences in the biological activities were observed
between compounds in which the carbohydrate was linked
either to the indole nitrogen or to the azaindole unit, bridged
compounds with a nitrogen atom in 11-position instead of
1-position in the azaindolocarbazole were also synthesized
(Scheme 6). A similar sequence of reactions as for the
synthesis of 12 was performed from aglycone F9 until
elimination of the benzenesulfonyl protective group leading
to 25. Photocyclization of 25 in the presence of iodine did
not afford the required compound 26, only degradation was
observed. Cyclization was successfully achieved in 56%
yield using palladium triflate in DMF at 90 8C according to a
method described by Faul et al.24 for the synthesis of
4. Experimental
4.1. Chemistry
IR spectra were recorded on a Perkin Elmer 881
spectrometer. NMR spectra were performed on a Bruker
AVANCE 400 (1H: 400 MHz, 13C: 100 MHz) (chemical
shifts d in ppm, the following abbreviations are used: singlet
(s), doublet (d), triplet (t), pseudo-triplet (pt), doubled triplet
(dt), multiplet (m), br s (broad signal), tertiary carbons (C
tert), quaternary carbons (C quat). The signals were
assigned from 1H–1H COSY and 13C–1H correlations.
Scheme 6. Synthesis of the bridged compound 28.

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7309
Low-resolution mass spectra (ESIC and APCIC) were
determined on a MS Hewlett Packard engine. HRMS
spectra (FABC) were determined on a high resolution
Fisons Autospec-Q spectrometer at CESAMO (Talence,
France). Chromatographic purifications were performed by
flash silicagel Geduran SI 60 (Merck) 0.040–0.063 mm or
Kieselgel 60 (Merck) 0.063–0.200 mm column chromato-
graphy. For purity tests, TLC were performed on fluorescent
silica gel plates (60 F254 from Merck).
(C6), 73.6, 75.4, 75.6 (CH2), 73.4, 76.6, 78.6, 79.1, 91.8 (C1,
C2, C3, C4, C5), 127.7, 127.8–128.1, 128.3, 128.4, 128.5 (C
tert arom), 133.0, 137.5, 137.6, 137.7, 145.3 (C quat arom).
4.1.3. 6-Methyl-5,7-dihydro-12,13-(3,4,6-tri-O-benzyl-b-
D-mannopyranose-1,2-diyl)-pyrrolo[3,4-c]pyrido[20,30:
4,5] pyrrolo[2,3-a]carbazole-5,7-dione 4. To a solution of
aglycone A (73 mg, 0.214 mmol) in acetonitrile (8.5 mL)
were added powdered KOH (92 mg) and tris[2-(2-methoxy-
ethoxy) ethyl]amine (34 mL). After stirring at room
temperature for 15 min, a solution of 3 (290 mg,
0.466 mmol) in acetonitrile (4.5 mL) was added dropwise.
The mixture was stirred at room temperature for 48 h. After
acidification with 1 N HCl (10 mL), the mixture was
extracted with EtOAc. The organic phase was washed
with brine, dried over MgSO4 and the solvent was removed.
The residue was partly purified by flash chromatography
(eluent cyclohexane/EtOAc from 9:1 to 5:5 then EtOAc
100%) to give a mixture of glycosylated compounds
(24 mg). To the mixture of the glycosylated compounds in
DMF (1 mL) was added NaN3 (32 mg, 0.50 mmol). After
stirring at 70 8C for 48 h, water was added and the mixture
was extracted with EtOAc. The organic phase was dried
over MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc from 9:1 to 5:5 then EtOAc 100%) affording 4
(20 mg, 0.026 mmol, 12% yield from A) as a yellow solid.
4.1.1. 1-O-Acetyl-2-O-tosyl-3,4,6-tri-O-benzyl-a and b-D-
glucopyranose 2. To a solution of 1 (548 mg, 1.11 mmol,
a/b ratio 3:10) in pyridine (6 mL) and CH2Cl2 (15 mL) was
added tosyl chloride (766 mg, 5.55 mmol). After refluxing
for 72 h, 2 N HCl (15 mL) was added. After extraction with
EtOAc, the organic phase was washed with saturated
aqueous NaHCO3 and then with brine. The organic phase
was dried over MgSO4, the solvent was removed and the
residue was purified by flash chromatography (eluent
cyclohexane/EtOAc from 9:1 to 7:3) to give 2 as a colorless
oil (603 mg, 0.93 mmol, 84% yield) as a mixture of b and a
anomers in 8:5 ratio, respectively. Unreacted 1 (b anomer,
150 mg) was recovered.
Compound 2. IR (NaCl film), nC]O 1739, 1760 cmK1
.
HRMS (FABC) [MCNa]C, calcd for C36H38NaO9S1 669.
2134, found 669.2147. 1H NMR (400 MHz, CDCl3):
b
a
major anomer, minor anomer 1.92 (3Hb, s, CH3), 2.11
(3Ha, s, CH3), 2.35 (3Hb, s, CH3), 2.39 (3Ha, s, CH3), 3.54–
3.86 (5HbC5Ha, m), 4.43–4.82 (7HbC7Ha, m), 5.65 (1Hb,
d, JZ8.0 Hz, H1), 6.18 (1Ha, d, JZ3.5 Hz, H1), 7.04–7.10
(2HbC2Ha, m), 7.14–7.36 (15HbaromC15Haarom), 7.73–
7.79 (2HbC2Ha, m). 13C NMR (100 MHz, CDCl3): 20.7,
20.9, 21.6, 21.8 (CH3), 67.7, 67.8 (C6), 73.6, 73.7, 75.2,
75.4, 75.5, 75.7 (CH2), 72.6, 75.8, 77.0, 77.4, 78.1, 79.5,
79.7, 82.4, 89.6, 91.5 (C1, C2, C3, C4, C5), 127.6–128.6,
129.7, 130.0 (C tert arom), 133.2, 134.7, 137.6, 137.7,
137.8, 137.9, 144.7, 145.3 (C quat arom), 168.6, 169.3
(C]O).
Compound 4. Mp 67–69 8C. IR (KBr) nC]O 1700 cmK1
.
HRMS (FABC) [MCH]C, calcd for C47H39N4O6
755.2870, found 755.2871. The 1H NMR signals were
assigned from 1H–1H COSY correlations. 1H NMR
(400 MHz, CDCl3): 3.30 (3H, s, CH3), 3.79 (1H, d, JZ
0
11.0 Hz), 3.91 (1H, dd, J1Z10.5 Hz, J2Z5.5 Hz, H6 ),
0
0
0
3.96–4.03 (2H, m, H3 , H6 ), 4.09 (1H, t, JZ9.5 Hz, H4 ),
0
4.42 (1H, m, H5 ), 4.43 (1H, d, JZ11.0 Hz), 4.64 (1H, d,
JZ11.0 Hz), 4.66 (1H, d, JZ12.0 Hz), 4.75 (1H, d, JZ
0
11.5 Hz), 4.91 (1H, d, JZ11.0 Hz), 5.52 (1H, m, H2 ), 6.15
0
(1H, d, JZ3.5 Hz, H1 ), 6.45 (2H, d, JZ7.0 Hz), 6.89 (2H, t,
JZ7.5 Hz), 7.03 (1H, t, JZ7.5 Hz), 7.14–7.18 (2H, m),
7.24–7.30 (3H, m), 7.32–7.39 (2H, m), 7.40–7.47 (6H, m),
7.99 (1H, m), 8.52 (1H, dd, J1Z4.0 Hz, J2Z1.0 Hz), 8.82
(1H, m), 8.95 (1H, dd, J1Z8.0 Hz, J2Z1.0 Hz). 13C NMR
(100 MHz, CDCl3): 23.9 (NCH3), 58.3, 74.5, 78.3, 80.4,
4.1.2. 1-Chloro-1-deoxy-2-O-tosyl-3,4,6-tri-O-benzyl-a-
D-glucopyranose 3. HCl gas was bubbled for 20 min in a
solution of 2 (444 mg, 0.69 mmol) in diethylether. After
stirring for 48 h at room temperature, the solvent was
removed, the residue was dissolved in CH2Cl2 then the
solvent was removed. The residue was purified by flash
chromatography (eluent cyclohexane/EtOAc 7:3) to give 3
(a anomer) as a colorless oil (272 mg, 0.438 mmol, 66%
yield). Unreacted a anomer 2 (56 mg) was recovered. The
reaction performed with pure b anomer 2 afforded 3 in 86%
yield.
0
0
0
0
0
0
85.0 (C1 , C2 , C3 , C4 , C5 ), 68.9 (C6 ), 73.8, 75.1, 75.9
(CH2), 110.4, 113.3, 116.5, 117.7, 121.9, 125.3, 127.4,
130.2, 136.1, 137.6, 137.9, 143.3, 152.3 (C quat arom),
113.6, 117.3, 122.9, 125.6, 127.7–128.7, 134.1, 146.5 (C tert
arom), 170.0, 170.1 (C]O).
4.1.4. 6-Methyl-5,7-dihydro-12,13-(b-D-mannopyranose-
1,2-diyl)-pyrrolo[3,4-c]pyrido[20,30:4,5]pyrrolo[2,3-a]-
carbazole-5,7-dione 5. To a solution of 4 (10 mg,
0.013 mmol) in CH2Cl2 (5 mL) cooled to K78 8C was
added 1 M BBr3 in CH2Cl2 (87 mL, 0.08 mmol). After
stirring for 10 min at K78 8C, water was added, the mixture
was allowed to reach room temperature then it was extracted
with EtOAc. The organic phase was dried over MgSO4, the
solvent was removed and the residue was purified by flash
chromatography (eluent from EtOAc 100% to EtOAc/
MeOH 9:1) to give 5 (5.6 mg, 0.012 mmol, 90% yield) as a
yellow solid.
Compound 3. IR (NaCl film) nS]O 1739 cmK1. HRMS
(FABC) [MCNa]C, calcd for C34H35ClNaO7S 645.1690,
found 645.1699. 1H NMR (400 MHz, CDCl3): 2.39 (3H, s,
CH3), 3.66 (1H, dd, J1Z11.0 Hz, J2Z2.0 Hz), 3.76–3.83
(2H, m), 4.05 (1H, t, JZ9.5 Hz), 4.10 (1H, m), 4.48 (1H, d,
JZ10.5 Hz), 4.49 (1H, d, JZ12.0 Hz), 4.60 (1H, d, JZ
12.0 Hz), 4.61 (1H, dd, J1Z9.5 Hz, J2Z4.0 Hz), 4.69 (1H,
d, JZ11.0 Hz), 4.74 (1H, d, JZ11.0 Hz), 4.75 (1H, d, JZ
10.5 Hz), 6.21 (1H, d, JZ4.0 Hz, H1), 7.08–7.11 (2H, m),
7.16–7.23 (4H, m), 7.25–7.37 (11Harom), 7.80 (2H, d, JZ
8.5 Hz). 13C NMR (100 MHz, CDCl3): 21.7 (CH3), 67.4

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S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
Compound 5. Mp 245–250 8C (decomposition). IR (KBr)
nC]O 1700 cmK1, nOH 3040–3680 cmK1. HRMS (FABC)
[MCH]C, calcd for C26H21N4O6 485.1461, found
485.1465. H NMR (400 MHz, DMSO-d6): 3.19 (3H, s,
NCH3), 3.59–3.66 (2H, m), 3.79 (1H, m), 3.97 (1H, m), 4.06
4.1.7. 1-Benzyloxymethyl-2,5-dihydro-3-[1-(2-O-tosyl-
3,4,6-tri-O-benzyl-b-D-glucopyranos-1-yl)-indol-3-yl]-4-
[1-phenylsulfonyl-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-
2,5-dione 7. To a solution of B (89 mg, 0.152 mmol) in THF
(8 mL) were added 6 (205 mg, 0.338 mmol) and triphenyl-
phosphine (89 mg, 0.338 mmol). The mixture was cooled to
K78 8C then diisopropyl azodicarboxylate (DIAD)
(65.5 mM, 0.338 mmol) was added dropwise. The mixture
was allowed to reach room temperature then was stirred for
18 h. Water was added. After extraction with EtOAc, the
organic phase was dried over MgSO4, the solvent was
removed and the residue was purified by flash chromato-
graphy (eluent cyclohexane/EtOAc 8:2) to give 7 (156 mg,
0.133 mmol, 88% yield) as a red solid.
1
0
(1H, m), 5.18–5.28 (3H, m, 2OH, H2 ), 5.40 (1H, d, JZ
0
5.5 Hz, OH), 6.42 (1H, d, JZ4.0 Hz, H1 ), 7.49 (1H, dd,
J1Z8.0 Hz, J2Z5.0 Hz), 7.51 (1H, t, JZ7.5 Hz), 7.64 (1H,
dt, J1Z7.5 Hz, J2Z1.0 Hz), 8.24 (1H, d, JZ8.0 Hz), 8.63
(1H, dd, J1Z5.0 Hz, J2Z1.5 Hz), 8.72 (1H, d, JZ7.5 Hz),
8.89 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz). 13C NMR
0
0
(100 MHz, DMSO-d6): 23.6 (CH3), 61.1 (C6 ), 59.2 (C2 ),
0
0
0
0
70.1, 73.6, 76.8 (C3 , C4 , C5 ), 84.6 (C1 ), 109.2, 114.6,
116.1, 120.1, 120.9, 124.4, 127.6, 130.2, 143.0, 152.8 (C
quat arom), 114.1, 116.9, 122.1, 124.2, 127.7, 132.1, 146.9
(C tert arom), 169.5, 169.6 (C]O).
Compound 7. Mp 47–50 8C. IR (KBr) nC]O 1710,
1770 cmK1. Mass (ESIC) [MCH]C 1175. 1H NMR
(400 MHz, CDCl3): 1.93 (3H, s, CH3), 3.53–3.59 (2H, m),
3.63 (1H, dd, J1Z9.0 Hz, J2Z3.5 Hz), 3.70 (1H, t, JZ
9.0 Hz), 3.84 (1H, t, JZ9.5 Hz), 4.34 (1H, d, JZ12.0 Hz),
4.42 (1H, d, JZ12.0 Hz), 4.43–4.47 (2H, m), 4.57 (2H, s),
4.58 (1H, d, JZ8.5 Hz), 4.62 (1H, d, JZ10.5 Hz), 5.03 (1H,
4.1.5. 2-Benzyloxymethyl-5,7-dihydro-12H,13H-pyr-
rolo[3,4-c]pyrido[20,30:4,5]pyrrolo[2,3-a]carbazole-5,7-
dione D. To a solution of aglycone C (218 mg, 0.486 mmol)
in benzene (300 mL) was added iodine (1.32 g, 5.32 mmol).
The mixture was irradiated for 7 h with a medium pressure
mercury lamp (400 W). The solvent was removed, and the
residue dissolved in EtOAc (250 mL) and washed with
saturated aqueous sodium thiosulfate (100 mL) and then
with brine. The organic phase was dried over MgSO4, the
solvent was removed and the residue was purified by flash
chromatography (eluent EtOAc/cyclohexane 5:5) to give D
(120 mg, 0.267 mmol, 55% yield) as a yellow solid.
0
d, JZ9.0 Hz), 5.07 (2H, s), 5.34 (1H, d, JZ9.0 Hz, H1 ),
6.19–6.28 (2H, m), 6.56 (2H, d, JZ8.0 Hz), 6.62 (1H, dd,
J1Z8.0 Hz, J2Z3.5 Hz), 6.82 (1H, t, JZ8.0 Hz), 6.91–6.97
(2H, m), 7.02–7.19 (20Harom), 7.23 (2H, d, JZ8.0 Hz), 7.31
(2H, t, JZ7.5 Hz), 7.43 (1H, dt, J1Z8.0 Hz, J2Z1.0 Hz),
7.90 (1H, s), 7.96 (2H, d, JZ8.0 Hz), 7.98 (1H, s), 8.07 (1H,
d, JZ5.0 Hz). 13C NMR (100 MHz, CDCl3): 22.0 (CH3),
0
67.4, 68.0 (CH2), 71.8, 73.5, 75.2, 75.4 (C6 CCH2), 70.1,
0
0
0
0
0
77.5, 78.2, 79.9, 83.0 (C1 , C2 , C3 , C4 , C5 ), 119.3, 121.4,
121.5, 123.0, 127.2, 127.5–128.5, 129.1, 129.3, 131.4,
134.1, 145.4 (C tert arom), 106.5, 109.5, 123.6, 126.0,
131.1, 133.3, 135.6, 137.5, 137.6, 137.7, 137.8, 138.0,
144.3, 146.6 (C quat arom), 170.7 (2 C]O).
Compound D. Mp O290 8C (degradation). IR (KBr) nC]O
1700, 1750 cmK1, nNH 3000–3600 cmK1. Mass (ESIC)
1
[MCH]C 447. H NMR (400 MHz, DMSO-d6): 4.67 (2H,
s, CH2), 5.08 (2H, s, CH2), 7.24–7.43 (7H, m), 7.57 (1H, t,
JZ7.5 Hz), 7.78 (1H, d, JZ8.0 Hz), 8.55 (1H, d, JZ
3.5 Hz), 8.90 (1H, d, JZ8.0 Hz), 9.05 (1H, d, JZ7.5 Hz),
11.45 (1H, s, NH), 12.08 (1H, s, NH). 13C NMR (100 MHz,
CDCl3): 66.4, 70.3 (CH2), 112.1, 116.6, 120.4, 124.1, 127.1,
127.4, 127.5 (2C), 128.2 (2C), 132.1, 147.3 (C tert arom),
113.0, 114.1, 116.1, 118.5, 118.8, 121.1, 127.8, 128.8,
137.8, 140.2, 151.8 (C quat arom), 168.9, 169.0 (C]O).
4.1.8. 1-Benzyloxymethyl-2,5-dihydro-3-[1-(2-O-tosyl-
3,4,6-O-benzyl-b-D-glucopyranos-1-yl)-indol-3-yl]-4-
[1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione 8. To
a solution of 7 (160 mg, 0.136 mmol) in THF (5 mL) was
added a 1.1 M solution of tetrabutylammonium fluoride in
THF (409 mL, 0.448 mmol). The mixture was stirred for
2.5 h at room temperature. Water was added. After
extraction with EtOAc, the organic phase was dried over
MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc 3:2) to give 8 (114 mg, 0.110 mmol, 81% yield) as
a red solid.
4.1.6. 2-O-Tosyl-3,4,6-tri-O-benzyl-a-D-glucopyranose 6.
To a solution of 2 (300 mg, 0.462 mmol, anomeric ratio a/b
5:8) in THF/MeOH (5 mL, 1:1 v/v) at 0 8C was added
dropwise 1 M NaOMe/MeOH (60 mL). The mixture was
stirred at 0 8C for 1 h, the solvent was removed and the
residue purified by flash chromatography (eluent cyclo-
hexane/EtOAc 7:3) affording 6 (204 mg, 0.038 mmol, 73%
yield) as a white solid.
Compound 8. Mp 75–80 8C. IR (KBr) nC]O 1765,
1710 cmK1, nNH 3240–3600 cmK1. Mass (ESIC) [MC
H]C 1035. 1H NMR (400 MHz, CDCl3): 2.12 (3H, s, CH3),
3.72–3.86 (3H, m), 3.94 (1H, t, JZ9.0 Hz), 4.04 (1H, t, JZ
9.0 Hz), 4.53 (1H, d, JZ12.0 Hz), 4.60 (1H, d, JZ12.0 Hz),
4.67 (1H, d, JZ11.0 Hz), 4.80 (4H, sCm), 4.85 (1H, d, JZ
Compound 6. Mp 118–120 8C. IR (KBr) nOH 3240–
3600 cmK1. Mass (ESIC) [MCH]C 604, [MCNa]C 627.
1H NMR (400 MHz, CDCl3): 2.17 (3H, s, CH3), 3.35–3.50
(4H, m), 3.80–3.90 (2H, m), 4.23 (1H, d, JZ10.0 Hz), 4.24
(1H, d, JZ11.5 Hz), 4.30 (1H, d, JZ12.0 Hz), 4.39 (1H, d,
JZ11.5 Hz), 4.48 (2H, s), 4.53 (1H, d, JZ11.0 Hz), 5.24
(1H, br s, H1), 6.85–6.89 (2H, m), 6.94–6.98 (4H, m), 7.04–
7.16 (11Harom), 7.58 (2H, d, JZ8.0 Hz). 13C NMR
(100 MHz, CDCl3): 21.7 (CH3), 68.3 (C6), 73.5, 75.1,
75.2 (CH2), 70.0, 77.9, 79.0, 80.0, 90.9 (C1, C2, C3, C4, C5),
127.5–128.5, 129.6, 129.8 (C tert arom), 133.3, 137.6,
137.8, 138.0, 144.9 (C quat arom).
0
10.5 Hz), 5.30 (3H, sCm), 5.56 (1H, d, JZ9.0 Hz, H1 ),
6.69–6.78 (5H, m), 7.02 (1H, m), 7.15–7.21 (2H, m), 7.26–
7.40 (19H), 7.47 (2H, d, JZ7.5 Hz), 7.55 (1H, t, JZ
8.0 Hz), 8.00 (2H, d, JZ9.5 Hz), 8.14 (1H, d, JZ4.5 Hz),
12.4 (1H, s, NH). 13C NMR (100 MHz, CDCl3): 21.5 (CH3),
0
67.2, 68.2 (CH2), 71.7, 73.5, 75.3, 75.4 (C6 CCH2), 77.6,
78.2, 80.1, 83.1 (C1 , C2 , C3 , C4 , C5 ), 116.7, 120.9, 122.1,
122.8, 127.0, 127.5–128.5, 129.1, 129.8, 131.4, 142.8 (C tert
0
0
0
0
0

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7311
0
arom), 105.3, 107.4, 119.0, 126.4, 126.9, 133.2, 135.6,
137.5–137.9, 144.2, 148.6 (C quat arom), 171.3, 171.7
(C]O).
8.0 Hz), 6.20 (1H, d, JZ6.0 Hz, H1 ), 6.71 (2H, t, JZ
7.5 Hz), 6.86 (1H, t, JZ7.5 Hz), 7.10–7.38 (17H, m), 7.42
(1H, dt, J1Z7.5 Hz, J2Z1.0 Hz), 7.85 (1H, d, JZ8.0 Hz),
8.36 (1H, dd, J1Z5.0 Hz, J2Z1.5 Hz), 8.71 (1H, d, JZ
7.5 Hz), 8.84 (1H, dd, J1Z7.5 Hz, J2Z1.5 Hz). 13C NMR
4.1.9. 6-Benzyloxymethyl-12-(3,4,6-tri-O-benzyl-2-O-
tosyl-b-D-glucopyranos-1-yl)-5,7-dihydro-13H-pyrido-
[30,20:4,5]pyrrolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-
dione 9. To a solution of 8 (50 mg, 0.048 mmol) in benzene
(150 mL) was added iodine (18 mg, 0.071 mmol). The
mixture was irradiated for 1.5 h with a medium pressure
mercury lamp (400 W). The solvent was removed, and the
residue was dissolved in EtOAc (250 mL) and washed with
saturated aqueous sodium thiosulfate (50 mL) and then with
brine. The organic phase was dried over MgSO4, the solvent
was removed and the residue was purified by flash
chromatography (eluent EtOAc/cyclohexane 3:7) to give 9
(31 mg, 0.030 mmol, 62% yield) as a yellow solid.
0
0
(100 MHz, CDCl3): 52.6, 72.8, 72.9, 75.4, 80.7 (C1 , C2 ,
0
0
0
0
C3 , C4 , C5 ), 66.7 (C6 ), 70.2, 71.5, 71.8, 72.3, 73.2 (CH2),
109.3, 114.2, 117.5, 120.2, 120.4, 124.6, 128.8, 129.0,
136.1, 137.4, 137.8, 138.0, 142.5, 151.7 (C quat arom),
113.4, 117.3, 122.3, 125.3, 127.4, 127.6–128.7, 133.4, 146.6
(C tert arom), 169.6 (2 C]O).
4.1.11. 6-Hydroxymethyl-5,7-dihydro-12,13-(b-D-man-
nopyranose-1,2-diyl)-pyrrolo[3,4-c]pyrido[20,30:4,5]-
pyrrolo[2,3-a]carbazole-5,7-dione 11. To a suspension of
10 (50 mg, 0.058 mmol) in EtOH/EtOAc (5 mL, 4:1 v/v)
was added Pd(OH)2/C (20%) (50 mg). The mixture was
hydrogenated under pressure (40 psi) at room temperature
for 3 days. After filtration over Celite, the filtrate was
evaporated. The residue was purified by flash chromato-
graphy (eluent CH2Cl2/MeOH 95:5) to give 11 (15 mg,
0.030 mmol, 52% yield) as a yellow solid. 16 mg of a
mixture of partially debenzylated compounds could be
recovered and recycled.
Compound 9. Mp 37–40 8C. IR (KBr) nC]O 1710,
1755 cmK1, nNH 3200–3600 cmK1. Mass (ESIC) [MC
H]C 1033. 1H NMR (400 MHz, CDCl3): 2.10 (3H, s, CH3),
3.65 (1H, dd, J1Z10.0 Hz, J2Z2.5 Hz), 3.81 (1H, d, JZ
10.0 Hz), 3.93 (1H, d, JZ10.0 Hz), 3.99 (1H, t, JZ9.0 Hz),
4.17 (1H, d, JZ10.5 Hz), 4.44 (1H, d, JZ10.0 Hz), 4.47
(1H, d, JZ9.0 Hz), 4.70 (1H, d, JZ10.5 Hz), 4.74 (2H, s),
4.76 (1H, d, JZ11.5 Hz), 5.00 (1H, d, JZ10.5 Hz), 5.03
(1H, d, JZ13.5 Hz), 5.15 (1H, t, JZ9.0 Hz), 5.30 (2H, s),
Compound 11. Mp O200 8C (decomposition). IR (KBr)
nC]O 1700, 1750 cmK1; nOH 3100–3600 cmK1. HRMS
(FABC) [MCH]C, calcd for C26H20N4O7 501.1410, found
501.1416. H NMR (400 MHz, DMSO-d6): 3.33 (1H, m,
0
H6 ), 3.47–3.61 (2H, m, H4 CH6 ), 3.70 (1H, m, H5 ), 4.30
(1H, m, H3 ), 4.35 (1H, t, JZ5.5 Hz, OH6 ), 5.10 (2H, d, JZ
6.5 Hz, CH2OH), 5.35 (1H, d, JZ2.5 Hz, H2 ), 5.48 (1H, d,
JZ5.0 Hz, OH4 ), 6.46 (1H, t, JZ7.0 Hz, CH2OH), 6.97
(1H, s, H1 ), 7.55 (1H, t, JZ8.0 Hz), 7.66 (1H, dd, J1Z
0
5.99 (1H, d, JZ9.0 Hz, H1 ), 6.37 (2H, d, JZ8.0 Hz), 6.46
1
(2H, d, JZ8.0 Hz), 6.74 (2H, d, JZ7.5 Hz), 6.76–6.83 (2H,
m), 6.90 (1H, m), 6.95–7.00 (3H, m), 7.10–7.45 (14H), 7.50
(2H, dd, J1Z7.5 Hz, J2Z0.5 Hz), 8.56 (1H, dd, J1Z5.0 Hz,
J2Z1.5 Hz), 9.02 (1H, d, JZ8.0 Hz), 9.43 (1H, dd, J1Z
8.0 Hz, J2Z1.5 Hz), 11.10 (1H, s, NH). 13C NMR
(100 MHz, CDCl3): 21.5 (CH3), 65.2, 66.9 (CH2), 71.6,
0
0
0
0
0
0
0
0
0
73.2, 75.3, 76.2 (C6 CCH2), 76.3, 78.4, 79.7, 82.3, 83.4
8.0 Hz, J2Z5.0 Hz), 7.74 (1H, dt, J1Z8.0 Hz, J2Z1.0 Hz),
8.04 (1H, d, JZ8.0 Hz), 8.20 (1H, d, JZ12.5 Hz, OH3 ),
0
0
0
0
0
0
(C1 , C2 , C3 , C4 , C5 ), 109.4, 115.3, 115.7, 115.8, 117.5,
120.5, 120.8, 121.5, 125.9, 126.0, 126.6, 126.7, 127.2,
127.3, 127.6, 127.8–129.3, 129.7, 130.3, 133.8, 148.3 (C tert
arom), 119.3, 120.5, 120.8, 121.9, 132.2, 137.2, 137.3,
137.6 (2C), 140.7, 144.3, 153.5 (C quat arom), 169.4 (2C,
C]O).
8.68 (1H, dd, J1Z5.0 Hz, J2Z1.5 Hz), 8.71 (1H, d, JZ
7.5 Hz), 9.06 (1H, dd, J1Z7.5 Hz, J2Z1.5 Hz). 13C NMR
0
(100 MHz, DMSO-d6): 59.8, 59.9 (C6 , CH2), 64.5 (C2 ),
0
0
0
0
0
66.6 (C4 ), 73.0 (C3 ), 79.8 (C1 ), 80.6 (C5 ), 109.6, 113.4,
117.2, 120.2, 120.3, 123.3, 129.7, 130.2, 140.8, 151.7 (C
quat arom), 111.8, 117.5, 122.1, 124.4, 127.7, 133.7, 144.9
(C tert arom), 168.5, 168.6 (C]O).
4.1.10. 6-Benzyloxymethyl-5,7-dihydro-12,13-(3,4,6-tri-
O-benzyl-b-D-mannopyranose-1,2-diyl)-pyrrolo[3,4-c]-
pyrido[20,30:4,5]pyrrolo[2,3-a]carbazole-5,7-dione 10.
To a solution of 9 (60 mg, 0.06 mmol) in DMF (2 mL)
was added NaN3 (37 mg, 0.60 mmol). The mixture was
stirred for 48 h at 70 8C, then water was added. After
extraction with EtOAc, the organic phase was dried over
MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc 4:1) to give 10 (37 mg, 0.043 mmol, 72% yield) as
a yellow solid.
4.1.12. 5,7-Dihydro-12,13-(b-D-mannopyranose-1,2-
diyl)-6H-pyrrolo[3,4-c]pyrido[20,30:4,5]pyrrolo[2,3-a]-
carbazole-5,7-dione 12. To a solution of 11 (30 mg,
0.060 mmol) in THF (6 mL) was added 28% aqueous
NH4OH (12 mL). The mixture was stirred overnight at room
temperature. The solvent was removed and the residue was
purified by flash chromatography (eluent CH2Cl2/MeOH
95:5) to give 12 (20 mg, 0.0425 mmol, 71% yield) as a
yellow solid.
Compound 10. Mp 38–40 8C. IR (KBr) nC]O 1700,
1750 cmK1. Mass (ESIC) [MCH]C 861. 1H NMR
(400 MHz, CDCl3): 3.60 (1H, dd, J1Z10.0 Hz, J2Z
4.5 Hz), 3.63 (1H, d, JZ11.5 Hz), 3.70 (1H, d, JZ
12.0 Hz), 3.71 (1H, m), 3.76 (1H, m), 4.23 (1H, d, JZ
12.0 Hz), 4.31 (1H, d, JZ11.5 Hz), 4.32 (1H, m), 4.49 (1H,
d, JZ12.0 Hz), 4.57 (1H, m), 4.58 (1H, d, JZ12.0 Hz), 4.68
(2H, s), 5.16 (2H, AB system, JZ11.0 Hz, DnZ13.0 Hz),
Compound 12. Mp O300 8C. IR (KBr) nC]O 1620,
1670 cmK1, nNH,OH 3200–3500 cmK1. Mass (APCIC)
[MCH]CZ471. HRMS (FABC) [MCH]C, calcd for
C25H18N4O6 471.1304, found 471.1300. 1H NMR
0
(400 MHz, DMSO-d6): 3.30 (1H, m, H6 ), 3.46–3.59 (2H,
0
0
0
m, H4 C H6 ), 3.70 (1H, m, H5 ), 4.29 (1H, dt, J1Z12.5 Hz,
0
0
J2Z3.0 Hz, H3 ), 4.35 (1H, t, JZ5.5 Hz, OH6 ), 5.28 (1H, d,
JZ2.0 Hz, H2 ), 5.47 (1H, d, JZ5.0 Hz, OH4 ), 6.93 (1H, s,
H1 ), 7.48 (1H, t, JZ7.5 Hz), 7.60 (1H, dd, J1Z7.5 Hz,
0
0
0
0
5.56 (1H, dd, J1Z5.5 Hz, J2Z3.5 Hz, H2 ), 6.18 (2H, t, JZ

7312
S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
0
C2 , C3 , C4 , C5 ), 127.6–128.6, 129.9 (C tert arom), 132.6,
137.5, 138.2, 145.0 (C quat arom), 169.4; 169.5 (C]O).
0
0
0
J2Z5.0 Hz), 7.68 (1H, t, J1Z8.0 Hz), 8.00 (1H, d, JZ
0
8.0 Hz), 8.22 (1H, d, JZ12.0 Hz, OH3 ), 8.60–8.67 (2H, m),
9.00 (1H, d, JZ7.5 Hz), 11.17 (1H, s, NH). 13C NMR
0
(100 MHz, DMSO-d6): 59.9 (C6 ), 64.4, 66.6, 73.0, 79.8,
4.1.15. 1-O-Acetyl-3,4-di-O-benzyl-2,6-di-O-tosyl-a- and
b-D-glucopyranose 16. To a solution of 15 (558 mg,
1.00 mmol) in pyridine (2 mL) and CH2Cl2 (4 mL) was
added tosyl chloride (315 mg, 1.65 mmol). The mixture was
refluxed for 72 h, then 2 N HCl (15 mL) was added. After
extraction with EtOAc, the organic phase was washed with
saturated aqueous NaHCO3 then with brine, dried over
MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc from 8:2 to 7:3) to give 16 (171 mg, 0.241 mmol,
0
0
0
0
0
80.6 (C1 , C2 , C3 , C4 , C5 ), 109.5, 113.4, 117.4, 121.5,
121.6, 123.5, 129.6, 130.1, 140.8, 151.7 (C quat arom),
111.8, 117.3, 122.0, 124.5, 127.5, 133.9, 144.7 (C tert
arom), 170.6 (2 C]O).
4.1.13. 3,4-Di-O-benzyl-6-O-tosyl-D-glucal 13. To a solu-
tion of glucal E (700 mg, 2.14 mmol) in pyridine (3 mL)
and CH2Cl2 (7.5 mL) was added tosyl chloride (1.45 g,
7.6 mmol). The mixture was refluxed overnight, then 2 N
HCl (15 mL) was added. After extraction with EtOAc, the
organic phase was washed with saturated aqueous NaHCO3
then with brine, dried over MgSO4, the solvent was removed
and the residue was purified by flash chromatography
(eluent cyclohexane/EtOAc 9:1) to give 13 (503 mg,
1.048 mmol, 49% yield) as a colorless oil.
24% yield) as a colorless oil. The anomeric ratio calculated
0
1
from H NMR spectrum on H1 at 6.15 ppm, (a anomer) and
5.62 ppm (b anomer) was 1:3.9, respectively. 171 mg of
unreacted 15 (b anomer) was recovered.
b
a
Compound 16. Major anomer, minor anomer. IR (NaCl
film) nC]O 1737, 1767 cmK1. Mass (ESIC) [MCNa]C
733. 1H NMR (400 MHz, CDCl3): 2.06 (3Hb, s, CH3), 2.09
(3Ha, s, CH3), 2.35 (3Hb, s, CH3), 2.39 (3Ha, s, CH3), 2.42
(3Hb, s, CH3), 2.43 (3Ha, s, CH3), 3.58–4.01 (m, 3HbC
3Ha), 4.19–4.32 (2HbC2Ha, m), 4.43–4.52 (1HaC1Hb, m),
4.64–4.73 (3HbC3Ha, m), 4.74–4.80 (1HbC1Ha, m), 5.62
(1Hb, d, JZ8.0 Hz, H1), 6.15 (1Ha, d, JZ3.5 Hz, H1), 7.10–
7.40 (10HbC10Ha), 7.77 (2HbC2Ha, pt, JZ8.5 Hz). 13C
NMR (100 MHz, CDCl3): 20.5, 20.7 (CH3), 21.5, 21.6
Compound 13. IR (NaCl film) nC]O 1647, 1733 cmK1
.
Mass (ESIC) [MCNa]C 503. 1H NMR (400 MHz,
CDCl3): 2.45 (3H, s, CH3), 3.84 (1H, dd, J1Z8.0 Hz, J2Z
6.0 Hz, H4), 4.16 (1H, m, H5), 4.22 (1H, m, H3), 4.34 (1H,
dd, J1Z11.0 Hz, J2Z2.5 Hz, H6), 4.45 (1H, dd, J1Z
11.0 Hz, J2Z5.5 Hz, H6), 4.57 (1H, d, JZ12.0 Hz), 4.68
(1H, d, JZ11.0 Hz), 4.69 (1H, d, JZ11.0 Hz), 4.89 (1H, d,
JZ11.0 Hz), 4.96 (1H, dd, J1Z6.5 Hz, J2Z3.0 Hz, H2),
6.35 (1H, d, JZ6.0 Hz, H1), 7.30–7.45 (12H, m), 7.85 (2H,
d, JZ8.0 Hz). 13C NMR (100 MHz, CDCl3): 21.7 (CH3),
68.2, 70.4, 73.5 (C6C2CH2), 73.4, 74.5, 74.7 (C3, C4, C5),
100.1 (C2), 127.6–128.9, 129.9 (C tert arom), 144 (C1),
132.8, 137.9, 138.2, 145.0 (C quat arom).
0
(CH3), 67.3, 67.5 (C6 ), 75.2, 75.5 (CH2), 70.7, 73.5, 76.2,
0
0
0
0
0
76.3, 77.6, 79.2, 82.1, 89.1, 91.1 (C1 , C2 , C3 , C4 , C5 ),
127.4–128.5, 129.7, 129.9 (C tert arom), 132.4, 132.5,
132.8, 134.0, 137.1, 137.4, 137.6, 144.8, 145.1, 145.4 (C
quat arom), 168.3 (C]O).
4.1.16. 3,4-O-Benzyl-2,6-di-O-tosyl-a-D-glucopyranose
17. To a solution of 16 (170 mg, 0.24 mmol) in THF/
MeOH (2 mL, 1:1) at 0 8C was added dropwise 1 M
MeONa/MeOH (31 mL). The mixture was stirred at 0 8C
for 2 h, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc 7:3) affording 17 (106 mg, 0.158 mmol, 66%
yield) as a colorless oil.
4.1.14. 1-O-Acetyl-3,4-di-O-benzyl-6-O-tosyl-a- and b-D-
glucopyranose 15. To a solution of 13 (291 mg,
0.606 mmol) in CH2Cl2 (6 mL) at 0 8C was added a solution
of dimethyldioxirane in acetone (0.07–0.09 M, 20 mL). The
mixture was stirred at 0 8C for 1 h, the solvent was removed
at room temperature and compound 14 was dried under
vacuum for 2 h. Glacial acetic acid (6 mL) was added to 14
under nitrogen atmosphere. The mixture was stirred at room
temperature overnight. After evaporation of acetic acid, the
residue was dissolved in CH2Cl2 then saturated aqueous
NaHCO3 was added. After extraction with EtOAc, the
organic phase was dried over MgSO4, the solvent was
removed and the residue was purified by flash chroma-
tography (eluent cyclohexane/EtOAc from 8:2 to 7:3) to
give 15 (258 mg, 0.465 mmol, 77% yield from E) as a
Compound 17. IR (NaCl film), nC]O 1589, 1735 cmK1, nOH
3500 cmK1. Mass (ESIC) [MCNa]C 691. 1H NMR
(400 MHz, CDCl3): 2.26 (3H, s, CH3), 2.31 (3H, s, CH3),
3.40 (1H, t, JZ9.5 Hz), 3.55 (1H, m), 3.89 (1H, t, JZ
9.5 Hz), 3.94 (1H, d, JZ10.0 Hz), 4.06 (1H, dd, J1Z
10.5 Hz, J2Z1.5 Hz), 4.13 (1H, dd, J1Z11.0 Hz, J2Z
3.5 Hz), 4.21 (1H, dd, J1Z10.0 Hz, J2Z3.5 Hz), 4.32 (1H,
d, JZ10.5 Hz), 4.54 (2H, s), 4.61 (1H, d, JZ10.5 Hz), 5.24
(1H, d, JZ3.0 Hz, H1), 6.97–7.23 (14H), 7.66 (4H, pt, JZ
10.0 Hz). 13C NMR (100 MHz, CDCl3): 21.6 (CH3), 68.3
1
colorless oil. The anomeric ratio calculated from H NMR
0
spectrum on H1 at 5.98 ppm (a anomer) and 5.34 ppm
(b anomer) was 0.3:2, respectively.
Compound 15. IR (NaCl film) nC]O 1710, 1757 cmK1, nOH
3517 cmK1. Mass (ESIC) [MCNa]C 579. 1H NMR
(400 MHz, CDCl3) of the major anomer: 2.00 (3H, s,
CH3), 2.30 (3H, s, CH3), 2.54 (1H, br s, OH), 3.49 (4H, br s),
4.11 (1H, d, JZ10.5 Hz), 4.17 (1H, d, JZ10.0 Hz), 4.43
(1H, d, JZ10.5 Hz), 4.73 (1H, d, JZ10.5 Hz), 4.77 (1H, s),
4.78 (1H, d, JZ8.5 Hz), 5.34 (1H, d, JZ7.0 Hz, H1), 7.08–
7.29 (12H, m), 7.67 (2H, d, JZ8.5 Hz). 13C NMR
(100 MHz, CDCl3) of the major anomer: 20.9, 21.6 (CH3),
0
(C6 ), 75.1, 75.3 (CH2), 68.4, 77.0, 78.8, 79.6, 90.8 (C1 , C2 ,
0
0
0
0
0
C3 , C4 , C5 ), 127.4–128.5, 129.9 (C tert arom), 132.6,
133.0, 137.4, 137.8, 145.1 (2C) (C quat arom).
4.1.17. 1-Benzyloxymethyl-2,5-dihydro-3-[1-(3,4-di-O-
benzyl-2,6-di-O-tosyl-b-D-glucopyranos-1-yl)-indol-3-
yl]-4-[1-phenylsulfonyl-pyrrolo[2,3-b]pyridin-3-yl]-pyr-
role-2,5-dione 18. To a solution of B (41 mg, 0.070 mmol)
in THF (4 mL) were added 17 (104 mg, 0.155 mmol) and
triphenylphosphine (41 mg, 0.155 mmol). The mixture was
0
67.8 (C6 ), 74.9, 75.3 (CH2), 72.8, 73.5, 76.1, 84.3, 93.7 (C1 ,
0

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7313
cooled to K78 8C then diisopropyl azodicarboxylate
(DIAD) (30 mM, 0.155 mmol) was added dropwise. The
mixture was allowed to reach room temperature then was
stirred for 18 h. Water was added. After extraction with
EtOAc, the organic phase was dried over MgSO4, the
solvent was removed and the residue was purified by flash
chromatography (eluent cyclohexane/EtOAc 8:2 then
CH2Cl2/EtOAc 9:1) to give 18 (45 mg, 0.036 mmol, 52%
yield) as a red solid.
4.1.19. 12-(3,4-Di-O-benzyl-2,6-di-O-tosyl-b-D-gluco-
pyranos-1-yl)-13H-2,5-dihydro-pyrido[30,20:4,5]pyr-
rolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7-dione 20. To a
solution of 19 (381 mg, 0.346 mmol) in benzene (300 mL)
was added iodine (137 mg, 0.52 mmol). The mixture was
irradiated for 1 h with a medium pressure mercury lamp
(400 W). The solvent was removed, and the residue
dissolved in EtOAc (250 mL) and washed with saturated
aqueous sodium thiosulfate (50 mL) and then with brine.
The organic phase was dried over MgSO4, the solvent was
removed and the residue was purified by flash chromato-
graphy (eluent CH2Cl2/EtOAc 9:1) to give 20 (228 mg,
0.208 mmol, 60% yield) as a yellow solid.
Compound 18. Mp 65–68 8C. IR (KBr) nC]O 1708,
1760 cmK1. Mass (ESIC) [MCNa]C 1261. 1H NMR
(400 MHz, CDCl3): 2.02 (3H, s, CH3), 2.19 (3H, s, CH3),
3.68 (1H, m), 3.75–3.84 (2H, m), 4.05 (1H, dd, J1Z11.0 Hz,
J2Z2.0 Hz), 4.17 (1H, dd, J1Z11.0 Hz, J2Z4.0 Hz), 4.53
(2H, t, JZ10.5 Hz), 4.64 (1H, d, JZ11.0 Hz), 4.67 (2H, s),
4.73 (1H, d, JZ10.5 Hz), 5.10 (1H, m), 5.17 (2H, AB
system, JZ11.0 Hz, DnZ5 Hz), 5.37 (1H, d, JZ9.0 Hz,
Compound 20. Mp 82–85 8C. IR (KBr) nC]O 1710,
1760 cmK1, nNH 3300–3500 cmK1. Mass (APCIC) [M]C
1097. 1H NMR (400 MHz, CDCl3): 1.99 (6H, s, CH3), 3.84
0
0
(1H, t, JZ6.0 Hz, H4 ), 4.19 (1H, t, JZ5.5 Hz, H3 ), 4.28
0
0
H1 ), 6.34–6.42 (2H, m), 6.66 (2H, d, JZ8.0 Hz), 6.71 (1H,
(1H, m, H5 ), 4.34 (2H, d, JZ11.0 Hz), 4.42 (1H, dd, J1Z
dd, J1Z8.0 Hz, J2Z5.0 Hz), 6.94 (1H, dt, J1Z7.0 Hz, J2Z
1.5 Hz), 7.03 (2H, d, JZ8.0 Hz), 7.05–7.10 (2H, m), 7.11–
7.29 (14H), 7.30–7.35 (3H, m), 7.42 (2H, t, JZ8.5 Hz), 7.53
(1H, t, JZ7.5 Hz), 7.63 (2H, d, JZ8.0 Hz), 7.90 (1H, s),
8.07 (2H, dd, J1Z8.5 Hz, J2Z1.5 Hz), 8.10 (1H, s), 8.16
(1H, dd, J1Z5.0 Hz, J2Z1.5 Hz). 13C NMR (100 MHz,
CDCl3): 21.5 (CH3), 21.6 (CH3), 67.4, 67.5 (CH2), 71.8
11.0 Hz, J2Z5.5 Hz), 4.61 (1H, d, JZ11.5 Hz), 4.70 (1H, d,
JZ9.0 Hz), 4.72 (2H, s), 5.06 (1H, dd, J1Z9.0 Hz, J2Z
4.5 Hz), 5.15 (1H, d, JZ11.0 Hz), 5.27 (2H, s), 6.04 (1H, d,
0
JZ9.0 Hz, H1 ), 6.19 (2H, d, JZ8.0 Hz), 6.47 (2H, d, JZ
7.5 Hz), 6.69 (2H, d, JZ8.0 Hz), 7.10–7.30 (19H, m), 7.50
(2H, d, JZ7.5 Hz), 8.50 (1H, d, JZ4.5 Hz), 8.99 (1H, d,
JZ8.0 Hz), 9.33 (1H, d, JZ8.0 Hz), 10.07 (1H, s). 13C
NMR (100 MHz, CDCl3): 21.1 (CH3), 21.4 (CH3), 66.9,
68.4, 71.7, 73.7, 74.0 (CH2), 74.6, 78.6, 79.0, 79.6, 81.3
0
(C6 ), 75.3, 75.5 (CH2), 75.9, 76.6, 79.4, 82.9 (C1 , C2 , C3 ,
0
0
0
0
0
C4 , C5 ), 119.4, 121.5, 123.2, 127.0–130.0, 131.4, 134.2,
145.5 (C tert arom), 106.9, 109.4, 121.2, 124.1, 126.0,
130.8, 132.1, 133.1, 135.6, 136.8, 137.4, 137.6, 138.0,
144.5, 145.1, 146.6 (C quat arom), 170.6 (C]O).
0
0
0
0
0
(C1 , C2 , C3 , C4 , C5 ), 109.3, 117.6, 121.9, 125.7, 126.1,
127.0–129.0, 129.4, 133.7, 148.3 (C tert arom), 114.7,
116.4, 119.1, 119.9, 120.8, 121.7, 126.9, 131.1, 132.4,
136.4, 136.7, 137.6, 140.6, 144.5, 144.8, 152.7 (C quat
arom), 169.2 (2 C]O).
4.1.18. 1-Benzyloxymethyl-2,5-dihydro-3-[1-(3,4-di-O-
benzyl-2,6-di-O-tosyl-b-D-glucopyranos-1-yl)-indol-3-
yl]-4-[pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione 19.
To a solution of 18 (45 mg, 0.036 mmol) in THF (2 mL)
was added a 1.1 M solution of tetrabutylammonium fluoride
in THF (109 mL, 0.120 mmol). The mixture was stirred
for 2.5 h at room temperature. Water was added. After
extraction with EtOAc, the organic phase was dried over
MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent CH2Cl2/EtOAc
4:1) to give 19 (33 mg, 0.030 mmol, 83% yield) as a red
solid.
4.1.20. 6-Benzyloxymethyl-5,7-dihydro-12,13-(6-azido-
3,4-diO-benzyl-6-deoxy-b-D-mannopyranose-1,2-diyl)-
pyrido[30,20:4,5]pyrrolo[2,3-a]pyrrolo[3,4-c]carbazole-
5,7-dione 21. To a solution of 20 (12.5 mg, 0.011 mmol) in
DMF (1 mL) was added NaN3 (7.3 mg, 0.112 mmol). The
mixture was stirred overnight at 70 8C. Water was added.
After extraction with EtOAc, the organic phase was dried
over MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent CH2Cl2 100% to
CH2Cl2/EtOAc 9:1) to give 21 (7.5 mg, 0.0094 mmol, 82%
yield) as a yellow solid.
Compound 19. Mp 105–107 8C. IR (KBr) nC]O 1708,
1764 cmK1, nNH 3402 cmK1. Mass (ESIC) [MCH]C
Compound 21. Mp 45–47 8C. IR (KBr) nC]O 1704,
1754 cmK1, nN3 2100 cmK1. Mass (ESIC) [MCH]C 796.
1H NMR (400 MHz, CDCl3): 3.62 (1H, dd, J1Z13.0 Hz,
1
1099, [MCNa]C 1121. H NMR (400 MHz, CDCl3): 2.01
(3H, s, CH3), 2.18 (3H, s, CH3), 3.68 (1H, m), 3.72–3.85
(2H, m), 4.11 (2H, br s), 4.50 (1H, d, JZ10.5 Hz), 4.64 (2H,
s), 4.68 (2H, s), 4.74 (1H, d, JZ10.5 Hz), 5.13 (1H, t, JZ
0
J2Z6.0 Hz, H6 ), 3.66 (1H, dd, J1Z13.0 Hz, J2Z7.0 Hz,
0
0
H6 ), 3.79 (1H, m, H4 ), 3.76 (1H, m), 3.81 (1H, d, JZ
13.0 Hz), 3.87 (1H, d, JZ12.0 Hz), 4.22 (1H, dd, J1Z
0
8.5 Hz), 5.18 (2H, s), 5.37 (1H, d, JZ9.0 Hz, H1 ), 6.60–
0
6.70 (5H, m), 6.93 (1H, m), 7.02 (2H, d, JZ8.0 Hz), 7.06–
7.11 (2H, m), 7.13–7.28 (14H), 7.34 (2H, d, JZ7.5 Hz),
7.43 (1H, d, JZ8.0 Hz), 7.62 (2H, d, JZ8.0 Hz), 7.78 (1H,
s), 7.89 (1H, s), 8.03 (1H, br s), 11.57 (1H, br s, NH). 13C
NMR (100 MHz, CDCl3): 21.5 (CH3), 21.6 (CH3), 67.3,
11.0 Hz, J2Z6.5 Hz, H5 ), 4.53 (1H, d, JZ12.0 Hz), 4.69
(1H, m, H3 ), 4.70 (1H, d, JZ11.5 Hz), 4.78 (2H, s), 5.32
(2H, s), 5.69 (1H, dd, J1Z5.5 Hz, J2Z3.5 Hz, H2 ), 6.34
(1H, d, JZ6.0 Hz, H1 ), 6.37 (2H, d, JZ7.5 Hz), 6.87 (2H, t,
0
0
0
JZ7.5 Hz), 6.99 (1H, t, JZ7.5 Hz), 7.20–7.50 (11H, m),
7.60 (1H, t, JZ7.5 Hz), 7.94 (1H, d, JZ8.0 Hz), 8.48 (1H,
dd, J1Z5.0 Hz, J2Z1.0 Hz), 8.85 (1H, d, JZ8.0 Hz), 8.99
(1H, dd, J1Z7.5 Hz, J2Z0.5 Hz). 13C NMR (100 MHz,
0
67.5 (CH2), 71.7 (C6 ), 75.4 (2C) (CH2), 75.8, 75.9, 76.7,
0
0
0
0
0
79.6, 83.0 (C1 , C2 , C3 , C4 , C5 ), 116.9, 121.1, 122.1,
123.0, 127.0–130.0, 131.5, 143.0 (C tert arom), 105.5,
107.6, 119.0, 126.4, 127.0, 132.2, 133.1, 135.6, 136.9,
137.5, 137.7, 144.4, 144.5, 145.1, 148.3 (C quat arom),
171.3, 171.6 (C]O).
0
0
0
0
CDCl3): 52.5 (C6 ), 52.6, 73.0, 73.4, 75.0, 80.8 (C1 , C2 , C3 ,
0
0
C4 , C5 ), 66.8, 71.5, 72.1, 72.5 (CH2), 109.5, 114.4, 117.6,
120.3, 120.7, 124.7, 128.6, 135.9, 137.0, 137.8, 142.3, 151.7

7314
S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
(C quat arom), 113.0, 117.4, 122.5, 125.5, 127.7–128.9,
133.6, 146.7 (C tert arom), 169.6 (2 C]O).
0.341 mmol) in THF (18 mL) were added 6 (459 mg,
0.76 mmol) and triphenylphosphine (199 mg, 0.76 mmol).
The mixture was cooled to K78 8C then diisopropyl
azodicarboxylate (DIAD) (147 mM, 0.76 mmol) was added
dropwise. The mixture was allowed to reach room
temperature then was stirred for 18 h. Water was added.
After extraction with EtOAc, the organic phase was dried
over MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent CH2Cl2/EtOAc
9:1) to give 24 as the major product of the reaction (190 mg,
0.161 mmol, 47% yield) as a red solid.
4.1.21. 6-Hydroxymethyl-5,7-dihydro-12,13-(6-azido-6-
deoxy-b-D-mannopyranos-1,2-diyl)-pyrido[30,20:4,5]-
pyrrolo[2,3-a] pyrrolo[3,4-c]carbazole-5,7-dione 22. To a
solution of 21 (96 mg, 0.120 mmol) in CH2Cl2 (6 mL) was
added a solution of dimethyldioxirane in acetone (0.07–
0.09 M, 60 mL) during 7 days. After removal of the solvent,
the residue was purified by flash chromatography (eluent
from cyclohexane/EtOAc 2:8 to EtOAc 100%) to give 22
(28.3 mg, 0.054 mmol, 45% yield).
Compound 24. Mp 80–82 8C. IR (KBr), nC]O 1711 cmK1
.
Mass (ESIC) [MCH]C 1175. 1H NMR (400 MHz,
CDCl3): 2.13 (3H, s, CH3), 3.69–3.80 (2H, m), 3.77 (1H,
d, JZ9.5 Hz), 3.91–3.99 (2H, m), 4.55 (1H, d, JZ12.0 Hz),
4.62 (1H, d, JZ10.5 Hz), 4.63 (1H, d, JZ12.5 Hz), 4.65
(1H, d, JZ12.5 Hz), 4.75 (1H, d, JZ13.5 Hz), 4.76 (2H, s),
Compound 22. Mp 145–148 8C. IR (KBr) nC]O 1702,
1753 cmK1, nN3 2100 cmK1, nOH 3038–3653 cmK1 1H
.
NMR (400 MHz, DMSO-d6): 3.15 (1H, dd, J1Z13.5 Hz,
0
0
0
J2Z6.0 Hz, H6 ), 3.37 (1H, m, H6 ), 3.50 (1H, m, H4 ), 3.97
0
0
(1H, m, H5 ), 4.34 (1H, dt, J1Z12.5 Hz, J2Z3.0 Hz, H3 ),
4.90 (2H, m, CH2OH), 5.32 (1H, d, JZ2.5 Hz, H2 ), 5.76
(1H, d, JZ5.0 Hz, OH4 ), 6.37 (1H, t, JZ7.0 Hz, CH2OH),
7.03 (1H, s, H1 ), 7.47 (1H, t, JZ8.0 Hz), 7.57 (1H, dd, J1Z
0
0
4.80 (1H, d, JZ10.5 Hz), 5.20 (1H, m, H2 ), 5.27 (2H, s),
0
0
6.19 (1H, d, JZ9.0 Hz, H1 ), 6.34 (1H, dd, J1Z8.0 Hz, J2Z
0
4.5 Hz), 6.65 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 6.75 (2H, d,
JZ8.0 Hz), 6.84 (1H, t, JZ7.5 Hz), 7.02 (1H, d, JZ
8.0 Hz), 7.07–7.13 (2H, m), 7.16 (1H, t, JZ8.0 Hz), 7.21–
7.40 (18H), 7.42 (2H, d, JZ7.5 Hz), 7.51 (2H, t, JZ
8.0 Hz), 7.63 (1H, t, JZ7.5 Hz), 7.95–8.01 (3H, m), 8.06
(1H, d, JZ1.5 Hz), 8.08 (1H, s), 8.34 (1H, s). 13C NMR
(100 MHz, CDCl3): 21.5 (CH3), 67.5, 68.2, 71.9, 73.5, 75.3,
8.0 Hz, J2Z5.0 Hz), 7.70 (1H, dt, J1Z8.5 Hz, J2Z1.0 Hz),
0
7.98 (1H, d, JZ8.5 Hz), 8.26 (1H, d, JZ12.0 Hz, OH3 ),
8.57 (1H, d, JZ8.0 Hz), 8.60 (1H, dd, J1Z4.5 Hz, J2Z
1.5 Hz), 8.90 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz). 13C NMR
0
(100 MHz, DMSO-d6): 50.1 (C6 ), 59.6 (CH2OH), 64.2,
0
0
0
0
0
67.4, 72.6, 78.8, 79.6 (C1 , C2 , C3 , C4 , C5 ), 109.6, 113.6,
117.1, 120.2, 123.4, 129.5, 130.0, 139.1, 140.8, 151.5 (C
quat arom), 111.7, 117.5, 122.2, 124.4, 127.7, 133.7, 144.9
(C tert arom), 168.3, 168.4 (2 C]O).
0
75.4 (C6 C5CH2), 77.7, 78.2, 80.5, 83.0 (C1 , C2 , C3 , C4 ,
0
0
0
0
0
C5 ), 113.5, 117.2, 122.5, 124.0, 125.3, 127.0–128.6, 128.7,
129.5, 129.7, 130.5, 134.2, 143.7 (C tert arom), 105.8,
112.4, 118.6, 124.7, 130.8, 133.5, 134.4, 137.5, 137.7,
137.9, 144.2, 147.8 (C quat arom), 170.5 (2C, C]O).
4.1.22. 12,13-(6-Azido-6-deoxy-b-D-mannopyranos-1,2-
diyl)-6H-pyrido[30,20:4,5]pyrrolo[2,3-a]pyrrolo[3,4-c]-
carbazole-5,7-dione 23. To a solution of 22 (28 mg,
0.053 mmol) in THF (6 mL) was added 28% aqueous
NH4OH (11 mL). The mixture was stirred for 5 h at room
temperature. The solvent was removed and the residue was
purified by flash chromatography (eluent EtOAc 100%) to
give 23 (20 mg, 0.041 mmol, 77% yield) as a yellow solid.
4.1.24. 1-Benzyloxymethyl-3-(1H-indol-3-yl)-4-[1-(2-O-
tosyl-3,4,6-tri-O-benzyl-b-D-glucopyranos-1-yl)-pyr-
rolo[2,3-b]pyridin-3-yl]-2,5-dihydro-pyrrole-2,5-dione
25. To a solution of 24 (160 mg, 0.136 mmol) in THF
(5 mL) was added a 1.1 M solution of tetrabutylammonium
fluoride in THF (409 mL, 0.448 mmol). The mixture was
stirred for 2.5 h at room temperature. Water was added.
After extraction with EtOAc, the organic phase was dried
over MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent from CH2Cl2
100% to CH2Cl2/EtOAc 9:1) to give 25 (90 mg,
0.087 mmol, 64% yield) as a red solid.
Compound 23. Mp O200 8C (decomposition). IR (KBr)
nC]O 1719, 1746 cmK1, nN3 2100 cmK1, nNH,OH 3138–
3618 cmK1
.
HRMS (ESIC) [MCH]C, calcd for
C25H18N7O5 496.1369, found 496.1372. 1H NMR
(400 MHz, DMSO-d6): 3.20 (1H, dd, J1Z13.5 Hz, J2Z
0
0
6.0 Hz, H6 ), 3.40 (1H, dd, J1Z13.5 Hz, J2Z2.0 Hz, H6 ),
0
3.54 (1H, m, H4 ), 3.99 (1H, dt, J1Z9.0 Hz, J2Z2.0 Hz,
H5 ), 4.31 (1H, dt, J1Z13.0 Hz, J2Z3.0 Hz, H3 ), 5.40 (1H,
d, JZ2.5 Hz, H2 ), 5.76 (1H, d, JZ5.0 Hz, OH4 ), 7.05 (1H,
s, H1 ), 7.53 (1H, dt, J1Z8.0 Hz, J2Z1.0 Hz), 7.67 (1H, dd,
Compound 25. Mp 38–40 8C. IR (KBr) nC]O 1706,
1743 cmK1, nNH 3163–3608 cmK1. Mass (ESIC) [MC
H]C 1035. 1H NMR (400 MHz, CDCl3): 2.13 (3H, s, CH3),
3.67 (1H, d, JZ10.0 Hz), 3.72–3.80 (2H, m), 3.92 (1H,
t, JZ9.0 Hz), 3.97 (1H, t, JZ9.0 Hz), 4.47 (1H, d, JZ
12.0 Hz), 4.55 (1H, d, JZ12.0 Hz), 4.62 (1H, d, JZ
11.0 Hz), 4.80 (3H, sCm), 4.82 (1H, d, JZ10.5 Hz), 5.00
0
0
0
0
0
J1Z8.0 Hz, J2Z5.0 Hz), 7.73 (1H, dt, J1Z7.5 Hz, J2Z
1.0 Hz), 8.03 (1H, d, JZ8.0 Hz), 8.33 (1H, d, JZ12.0 Hz,
0
OH3 ), 8.66–8.72 (2H, m), 9.08 (1H, dd, J1Z8.0 Hz, J2Z
1.5 Hz), 11.25 (1H, s, NH). 13C NMR (100 MHz, DMSO-
0
0
d6): 50.2 (C6 ), 64.2, 67.5, 72.7, 78.8, 79.6 (C1 , C2 , C3 , C4 ,
0
0
0
0
(1H, m), 5.27 (3H, sCm), 6.17 (1H, d, JZ9.0 Hz, H1 ), 6.45
0
C5 ), 109.6, 113.6, 117.3, 121.1, 121.6, 123.5, 129.5, 130.0,
140.7, 151.6 (C quat arom), 111.7, 117.4, 122.1, 124.5,
127.5, 133.9, 144.7 (C tert arom), 170.5 (2 C]O).
(1H, br s), 6.67 (1H, dd, J1Z7.5 Hz, J2Z4.5 Hz), 6.72 (2H,
d, JZ8.0 Hz), 6.82 (1H, t, JZ8.0 Hz), 7.00–7.40 (23H),
7.44 (2H, d, JZ7.5 Hz), 7.71 (1H, d, JZ2.0 Hz), 8.08 (2H,
s), 8.88 (1H, s, NH). 13C NMR (100 MHz, CDCl3): 22.0
0
(CH3), 67.3, 68.3, 71.7, 73.5, 75.3, 75.5 (C6 C5CH2), 70.1,
4.1.23. 1-Benzyloxymethyl-3-(1-phenylsulfonyl-1H-
indol-3-yl)-4-[1-(2-O-tosyl-3,4,6-tri-O-benzyl-b-D-gluco-
pyranos-1-yl)-pyrrolo[2,3-b]pyridin-3-yl]-2,5-dihydro-
pyrrole-2,5-dione 24. To a solution of F (200 mg,
0
0
0
0
0
77.7, 78.1, 80.7, 83.1 (C1 , C2 , C3 , C4 , C5 ), 111.4, 116.9,
121.1, 122.1, 122.8, 126.8–129.1, 129.7, 130.5, 143.4 (C tert
arom), 106.5, 106.6, 118.9, 125.3, 126.2, 133.5, 135.9,

S. Messaoudi et al. / Tetrahedron 61 (2005) 7304–7316
7315
137.6, 137.7, 137.8, 138.0, 143.9, 147.7 (C quat arom),
171.2, 171.5 (C]O).
118.2, 122.0, 125.8, 127.4–129.4, 133.7, 146.8 (C tert
arom), 111.0, 115.2, 120.3, 120.9, 124.5, 129.2, 131.3,
136.6, 137.7, 142.9, 151.8 (C quat arom), 169.3, 169.4
(C]O).
4.1.25. 6-Benzyloxymethyl-13-(2-O-tosyl-3,4,6-tri-O-
benzyl-b-D-glucopyranos-1-yl)-5,7-dihydro-12H-pyri-
do[30,20:4,5]pyrrolo[3,2-a]-pyrrolo[3,4-c]carbazole-5,7-
dione 26. To a solution of 25 (54 mg, 0.052 mmol) in DMF
(2 mL) was added Pd(OTf)2 (52 mg, 0.158 mmol). The
mixture was stirred at 90 8C for 5 h. EtOAc was added, then
0.5 N HCl (10 mL). After extraction with EtOAc, the
organic phase was dried over MgSO4, the solvent was
removed and the residue was purified by flash chromato-
graphy (eluent from cyclohexane/CH2Cl2 3:7 to CH2Cl2
100%) to give 26 (30 mg, 0.029 mmol, 56% yield) as a
yellow solid.
4.1.27. 5,7-Dihydro-13,12-(b-D-mannopyranose-1,2-
diyl)-6H-pyrido[30,20:4,5]pyrrolo[2,3-a]pyrrolo[3,4-c]-
carbazole-5,7-dione 28. To a suspension of 27 (135 mg,
0.157 mmol) in CH2Cl2 (18 mL) at K78 8C was added a
1 M solution of BBr3 in CH2Cl2 (3.16 mL). The mixture was
stirred at K78 8C for 30 min, then it was allowed to reach
room temperature. After extraction with EtOAc, the organic
phase was dried over MgSO4 and the solvent was removed.
The residue was dried under vacuum for 1 h. To a solution
of the residue (56 mg) in THF (6 mL) was added 28%
aqueous NH4OH (12 mL). The mixture was stirred over-
night at room temperature. The solvent was removed and the
residue was purified by flash chromatography (eluent from
EtOAc 100% to EtOAc/MeOH 95:5) to give 28 (20 mg,
0.0425 mmol, 27% yield) as a yellow solid.
Compound 26. Mp 147–149 8C. IR (KBr) nC]O 1710,
1760 cmK1, nNH 3200–3600 cmK1. Mass (ESIC) [MC
Na]C 1055. 1H NMR (400 MHz, CDCl3): 2.02 (3H, s, CH3),
3.55 (1H, d, JZ10.0 Hz), 3.75 (1H, d, JZ10.5 Hz), 3.84
(1H, d, JZ10.0 Hz), 3.96 (1H, t, JZ8.5 Hz), 4.26 (1H, d,
JZ9.5 Hz), 4.31 (1H, d, JZ11.0 Hz), 4.46 (2H, t, JZ
12.0 Hz), 4.58 (1H, d, JZ10.0 Hz), 4.62 (2H, s), 4.81 (1H,
d, JZ10.0 Hz), 4.83 (1H, d, JZ10.5 Hz), 5.05 (1H, dt, J1Z
9.0 Hz, J2Z1.0 Hz), 5.18 (2H, s), 6.35 (2H, d, JZ8.0 Hz),
6.41 (2H, d, JZ7.5 Hz), 6.67 (1H, dd, J1Z9.5 Hz, J2Z
1.0 Hz), 6.95–7.30 (25H), 8.28 (1H, d, JZ5.0 Hz), 9.03
(1H, d, JZ8.0 Hz), 9.06 (1H, d, JZ8.0 Hz), 10.31 (1H, s,
NH). 13C NMR (100 MHz, CDCl3): 21.5 (CH3), 66.6, 67.0,
71.7, 74.2, 75.6, 76.5 (CH2), 76.4, 77.9, 79.7, 80.4, 83.7
Compound 28. Mp O300 8C. IR (KBr) nC]O 1703,
1747 cmK1, nNH,OH 3038–3619 cmK1. Mass (ESIC)
[MCH]C 471. HRMS (FABC) [MCH]C, calcd for
C25H18N4O6 471.1304, found 471.1291. 1H NMR
(400 MHz, DMSO-d6): 3.30 (1H, dd, J1Z12.5 Hz, J2Z
0
0
5.5 Hz, H6 ), 3.55 (1H, dd, J1Z12.5 Hz, J2Z1.5 Hz, H6 ),
0
0
3.70 (1H, d, JZ9.5 Hz, H5 ), 3.76 (1H, m, H4 ), 4.43 (1H, t,
JZ5.5 Hz, OH6 ), 4.58 (1H, m, H3 ), 5.16 (1H, d, JZ2.0 Hz,
H2 ), 5.60 (1H, br s, OH4 ), 6.74 (1H, d, JZ4.0 Hz, OH3 ),
6.90 (1H, s, H1 ), 7.47 (1H, t, JZ7.5 Hz), 7.60 (1H, dd, J1Z
0
0
0
0
0
0
0
0
0
0
(C1 , C2 , C3 , C4 , C5 ), 112.0, 117.7, 121.6, 125.7, 126.1
(2C), 127.5–129.0, 134.0, 146.8 (C tert arom), 115.2, 116.3,
119.3, 120.3, 121.0, 122.6, 127.0, 130.1, 133.0, 136.6,
137.3, 137.6, 137.8, 141.8, 144.3, 151.4 (C quat arom),
169.3, 169.4 (C]O).
0
8.0 Hz, J2Z5.0 Hz), 7.64 (1H, dt, J1Z7.0 Hz, J2Z1.5 Hz),
8.68 (1H, dd, J1Z4.5 Hz, J2Z1.5 Hz), 8.84 (1H, d, JZ
8.0 Hz), 8.94 (1H, dd, J1Z7.5 Hz, J2Z1.5 Hz), 9.08 (1H, d,
JZ8.5 Hz), 11.17 (1H, s, NH). 13C NMR (100 MHz,
0
0
DMSO-d6): 60.2 (C6 ), 64.3, 65.8, 72.3, 79.5, 80.9 (C1 ,
4.1.26. 6-Benzyloxymethyl-5,7-dihydro-13,12-(3,4,6-tri-
O-benzyl-b-D-mannopyranose-1,2-diyl)-pyrido[30,20:
4,5]pyrrolo[2,3-a] pyrrolo[3,4-c]carbazole-5,7-dione 27.
To a solution of 26 (15 mg, 0.0145 mmol) in DMF (1 mL)
was added NaN3 (10 mg, 0.154 mmol). The mixture was
stirred overnight at 70 8C. Water was added. After
extraction with EtOAc, the organic phase was dried over
MgSO4, the solvent was removed and the residue was
purified by flash chromatography (eluent cyclohexane/
EtOAc 4:1 then CH2Cl2/EtOAc 9:1) to give 27 (11.6 mg,
0.0137 mmol, 93% yield) as a yellow solid.
0
0
0
0
C2 , C3 , C4 , C5 ), 109.3, 113.6, 117.0, 120.9, 121.4, 123.4,
129.1, 131.1, 143.0, 151.0 (C quat arom), 116.4, 118.0,
121.0, 124.2, 127.0, 132.6, 146.7 (C tert arom), 170.7, 171.0
(2 C]O).
References and notes
1. Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.; Tomita,
K. J. Antibiot. 1987, 40, 668–678.
Compound 27. Mp 59–61 8C. IR (KBr) nC]O 1700,
1750 cmK1. Mass (ESIC) [MCNa]C 883. 1H NMR
(400 MHz, CDCl3): 3.34 (1H, dd, J1Z10.0 Hz, J2Z
2. Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto,
M.; Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135,
397–402.
0
4.0 Hz), 3.47 (1H, dd, J1Z11.0 Hz, J2Z2.5 Hz, H6 ), 3.58
3. Matson, J. A.; Claridge, C.; Bush, J. A.; Titus, J.; Bradner,
W. T.; Doyle, T. W.; Horan, A. C.; Patel, M. J. Antibiot. 1989,
42, 1547–1555.
0
0
(1H, dd, J1Z11.5 Hz, J2Z4.0 Hz, H6 ), 3.95 (1H, m, H5 ),
0
3.97 (2H, s), 4.11 (1H, t, JZ8.5 Hz, H4 ), 4.30 (1H, dd, J1Z
9.0 Hz, J2Z3.0 Hz, H3 ), 4.56 (1H, d, JZ11.0 Hz), 4.65
0
4. Takahashi, I.; Kobayashi, E.; Asano, K.; Yoshida, M.; Nakano,
H. J. Antibiot. 1987, 40, 1782–1784.
5. Rodrigues Pereira, E.; Belin, L.; Sancelme, M.; Prudhomme,
(2H, s), 4.74 (2H, s), 4.84 (1H, d, JZ11.0 Hz), 5.08 (1H, s,
0
0
H2 ), 5.11 (1H, d, JZ3.5 Hz), 6.41 (1H, s, H1 ), 6.64 (2H, d,
JZ8.0 Hz), 6.91 (2H, t, JZ7.5 Hz), 7.02 (1H, t, JZ7.5 Hz),
7.12 (1H, t, JZ7.5 Hz), 7.15–7.35 (15H, m), 7.40 (1H, t,
JZ8.0 Hz), 7.47 (1H, t, JZ8.0 Hz), 8.43–8.48 (2H, m),
8.88 (1H, d, JZ7.5 Hz), 8.91 (1H, d, JZ6.5 Hz). 13C NMR
`
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´
Baldeyrou, B.; Bailly, C.; Pierre, A.; Hickman, J.; Pfeiffer, B.;
0
0
(100 MHz, CDCl3): 60.5, 73.1, 78.6, 80.0, 80.5 (C1 , C2 ,
Renard, P.; Prudhomme, M. Bioorg. Med. Chem. 2003, 11,
4871.
0
C3 , C4 , C5 ), 66.7, 68.2, 71.5, 73.1, 73.3, 75.0 (CH2), 114.5,
0
0

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¨
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