Highly convergent synthesis of a rebeccamycin analog with benzothioeno(2,3-a)pyrrolo(3,4-c)carbazole as the aglycone

Article abstract of DOI:10.1016/j.tetlet.2004.12.068

A highly convergent, scalable synthesis of the rebeccamycin analog 2 was demonstrated in seven steps and 31% overall yield based on the N-protected building block dibromomaleimide 7. The practical synthesis of other two building blocks, 5,6-difluoro-3-ben

Full text of DOI:10.1016/j.tetlet.2004.12.068

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 907–910
Highly convergent synthesis of a rebeccamycin analog with
benzothioeno(2,3-a)pyrrolo(3,4-c)carbazole as the aglycone
Jianji Wang,a,* Nachimuthu Soundarajan,a Nian Liu,a
Kurt Zimmermannb and B. Narasimhulu Naidub
aBristol-Myers Squibb Pharmaceutical Research Institute, Process Research & Development, 1 Squibb Drive, New Brunswick,
NJ 08903, USA
bBristol-Myers Squibb Pharmaceutical Research Institute, Drug Discovery, 5 Research Parkway, Wallingford, CT 06492, USA
Received 29November 2004; revised 15 December 2004; accepted 15 December 2004
Abstract—A highly convergent, scalable synthesis of the rebeccamycin analog 2 was demonstrated in seven steps and 31% overall
yield based on the N-protected building block dibromomaleimide 7. The practical synthesis of other two building blocks, 5,6-di-
fluoro-3-benzothiopheneboronic acid 6 and 5,6-difluoroindole 8, is described.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Our highly convergent synthetic strategy is shown in
Scheme 1. We envisioned that the b-glycosidic bond in
the target molecule 2 could be formed by Mitsunobu
coupling of the aglycone 3 with the benzyl protected
D-glucopyranose 4. The key intermediate, N-protected
benzothioeno(2,3-a)pyrrolo(3,4-c)carbazole 3, could be
assembled starting from the three building blocks 6, 7,
and 8. Consecutive displacement of two bromine atoms
in N-protected dibromomaleimide 7 by condensation
with the magnesium anion of 5,6-difluoroindole (8) fol-
lowed by Suzuki coupling with 5,6-difluoro-3-benzo-
thiopheneboronic acid (6) would afford intermediate 5.
Using our new methodology described previously,4 the
Rebeccamycin 1 and its family members are potent anti-
tumor agents which act by inhibition of protein kinase C
and have topoisomerase activity.1–3 As part of a pro-
gram for optimization of their biological activity by
modification of both the aglycone and the sugar por-
tions, we required a practical route to the rebeccamycin
analog 2 with benzothioeno(2,3-a)pyrrolo(3,4-c)carba-
zole as the aglycone. In particular, we were interested
in the practical synthesis of the N-protected aglycone
benzothioeno(2,3-a)pyrrolo(3,4-c)carbazole 3, which
we needed in large quantities.
H
N
H
N
O
O
O
O
F
F
F
F
N
N
H
N
S
N
O
O
Cl
Cl
F
F
F
O
O
OH
OH
S
N
F
H
HO
HO
OH
OMe
OH
OH
3
1
2
Keywords: Rebaccamycin analog; Carbazole.
*
Corresponding author. Tel.: +1 732 227 6876; fax: +1 732 227 3002; e-mail: jianji.wang@bms.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.068

908
J. Wang et al. / Tetrahedron Letters 46 (2005) 907–910
OH
PG
N
O
O
O
OBn
PG =
2
3
+
F
F
F
F
BnO
OBn
OBn
S
N
H
4
5
PG
N
B(OH)2
+
F
F
F
F
O
O
+
N
S
H
Br
Br
6
7
8
Scheme 1. Retrosynthesis of 2.
oxidative cyclization of the above assembled intermedi-
ate 5 should afford the desired aglycone 3.
brominating reagent, significantly less of the dibromide
impurity was formed. Bromination of 5,6-difluorobenzo-
thiophene (10) with 1.2 equiv of NBS in a mixture of sol-
vents (acetic acid, 10% by v/v in a,a,a-trifluorotoluene)
at 80 °C for 4 h afforded 11 in 71% yield. A solvent effect
was observed during the preparation of boronic acid 6;
tert-butyl methyl ether in place of THF gave much better
quality and yield of the product. Lithium–bromine ex-
change of bromide 11 with n-BuLi at À80 °C in tert-butyl
methyl ether followed by quenching the resulting anion
with trimethyl borate, then hydrolysis of the crude
borate with 3 N HCl, completed the synthesis of 5,6-di-
fluoro-3-benzothiopheneboronic acid 6, obtained as a
white solid in five steps and 25% overall yield from 9.
As for the three building blocks, the synthesis of N-pro-
tected dibromomaleimide 7 has been disclosed in our
previous publication.4 Herein, we disclose a practical
synthesis of other two building blocks, 5,6-difluoro-3-
benzothiopheneboronic acid (6) and 5,6-difluoroindole
(8). The ultimate assembly of these building blocks into
the aglycone, benzothioeno(2,3-a)pyrrolo(3,4-c)carba-
zole (3) followed by conversion to the final product 2
is described below.
2. Synthesis of 5,6-difluoro-3-benzothiopheneboronic acid
6 (Scheme 2)
3. Synthesis of 5,6-difluoroindole 8 (Scheme 3)
The Grignard reagent, derived from reaction of bromide
9 with magnesium, on quenching with sulfur gave a 76%
yield of the thiophenol.5,6 Treatment with 1-chloro-2,2-
diethoxyethane afforded the acetal in 95% yield. Cycliza-
tion of the crude acetal with PPA in chlorobenzene gave
5,6-difluorobenzothiophene (10) in 67% yield. Bromina-
tion (Br2)7–9 of 10 gave the expected 11 in low yield
(38%). The major impurity was identified as 2,3-di-
bromo-5,6-difluorobenzothiophene. With NBS as the
Iodination of 3,4-difluoroaniline (12) with ICl in acetic
acid gave 2-iodo-4,5-difluoroaniline in 96% yield.10,11
Without further purification, protection of the amino
group by reaction with chloromethylformate afforded
carbamate 13 in 89% yield. Heck coupling of carbamate
13 with trimethylsilylacetylene mediated by Pd(OAc)2
(1.5% mol) and tris-o-tolylphosphine (2.0% mol) in
Et3N afforded acetylenide 14 in 94% yield. Treatment
B(OH)2
Br
F
F
F
F
a-c
e
d
F
S
S
S
F
F
Br
F
9
10
11
6
Scheme 2. Reagents and conditions: (a) 1. Mg, 2. Sulphur, 76%; (b) ClCH2CH(OEt)2, EtONa, reflux 36 h, 95%; (c) PPA, PhCl, reflux, 3 h, 67%; (d)
NBS, 1.2 equiv, AcOH, 80 °C, 4 h, 71%; (e) 1. n-BuLi, 1.08 equiv, À80 °C, 30 min, 2. B(OMe)3, 2.4 equiv, À80 °C, 1 h, 3. HCl, 3 N, rt, 1.5 h, 72%.
TMS
F
F
F
F
F
F
F
I
a-b
c
d
F
N
H
NHCOOMe
NHCOOMe
NH2
12
13
14
8
Scheme 3. Reagents and conditions: (a) ICl, HOAc, rt, 0.5 h, 96%; (b) ClCOOMe, pyridine, 0 °C, 2 h, 89%; (c) Pd(OAc)2, 1.5 mol%, (o-tolyl)3P,
2.0 mol%, EtN3, TMSacetylene, rt, 16 h, 94%; (d) EtONa, EtOH, 70 °C, 14 h, 82%.

J. Wang et al. / Tetrahedron Letters 46 (2005) 907–910
909
N
N
a
b
c
O
O
O
O
8
3
F
F
F
F
F
Br
S
N
N
F
H
H
15
5
Scheme 4. Reagents and conditions: (a) 1. EtMgBr, 2. 7, rt, 3 h, then 50 °C, 2 h, 91%; (b) 6, PdCl2(PPh3)2, 20 mol%, Na2CO3, DME/EtOH, 5:1,
reflux 2 h, 82%; (c) air, Pd(OAc)2, 5 mol%, CuCl2, 100 mol%, 90 °C, 6 h, 70%.
O
O
O
N
OH
F
F
F
F
O
O
S
N
F
F
F
a
d
b,c
O
OBn
2
+
3
S
N
O
F
OH
BnO
OBn
OBn
O
OBn
HO
OH
OH
4
BnO
OBn
OBn
17
18
Scheme 5. Reagents and conditions: (a) PPh3, 1.5 equiv, DIAD, 1.5 equiv, THF, rt, 20 h, 95%; (b) Pd(OH)2/C, cyclohexene, EtOH, reflux 7 h; (c)
KOH, 4.45 equiv, EtOH, 30 °C 16 h; then conc. HCl, pH < 1.5, 80%; (d) HN(TMS)2, 10 equiv, MeOH, rt, 6 h, 78%.
of 14 with EtONa (70 °C, 14 h) in EtOH12,13 completed
the synthesis of another building block, 5,6-difluoro-
indole (7) in four steps and 66% yield.
Without further purification, treatment with 4.45 equiv
of KOH in EtOH for 16 h at 30 °C followed by HCl
acidification (pH < 1.5) afforded anhydride 18 in 80%
yield. Reaction of 18 with 10 equiv of HN(TMS)2 in
MeOH at rt for 6 h accomplished our synthesis of target
molecule 218 in four steps and 59% yield from the key
intermediate 3.
4. Assembly of 6, 7, and 8 into the key intermediate 3
(Scheme 4)
With the three building blocks 6, 7, 8 in hand, we
embarked on their assembly and conversion to the key
intermediate 3. Reaction of 5,6-difluoroindole 8 with N-
protected dibromomaleimide 7 mediated by EtMgBr at
40 °C for 8 h afforded the bromide 15 in 91% yield. Pro-
tection of the indole nitrogen was not necessary for the
subsequent Suzuki coupling reaction. The cross-coupling
of 15 with boronic acid 6 catalyzed by PdCl2(PPh3)2 and
Na2CO3 as the base gave the coupled product 5 in 82%
yield. Oxidative cyclization of 5 using DDQ14,15 gave
the expected product 3, but in low isolated yield (<50%)
due to the poor solubility of 3 and the resultant difficulties
in removing reduced DDQ. As an alternative, using
atmospheric O2 as the stoichiometric oxidant and
Pd(OAc)2 (5 mol%)/CuCl2 (100 mol%) as the catalysts,4
afforded the key intermediate 3 in three steps and 52%
overall yield from the building block 8.
In summary, we have developed a convergent, scalable
synthesis of 2 in seven steps and 31% overall yield based
on the N-protected building block dibromomaleimide 7.
We also demonstrated the practical synthesis of the two
building blocks 5,6-difluoro-3-benzothiophenebronic
acid (6) and 5,6-difluoroindole (8).
Acknowledgements
The authors would like to thank Drs. James Sherbine,
David Kronenthal, and Richard Mueller for helpful
discussions.
References and notes
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with 2,3,4,6-tetra-O-benzyl-D-glucopyranose 4 gave al-
most exclusively the b-anomer 17 in 95% yield. The four
benzyl protecting groups in 17 were removed by hydro-
genation on Pd(OH)2/C in the presence of cyclohexene.

910
J. Wang et al. / Tetrahedron Letters 46 (2005) 907–910
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1
1
acid 6: MS: (M+H)+ 215; H NMR (500 MHz, DMSO-
d6): d 9.3 (s, 2H), 8.35 (dd, J = 8.2, 12.9, 1H), 8.33 (s, 1H),
8.21 (dd, J = 8.5, 11.4, 1H) ppm. Building block 5,6-
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1
difluoroindole 8: MS: (M+H)+ 154; H NMR (500 MHz,
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CDCl3): d 8.12 (s, 1H, N–H), 7.49(dd, J = 7.7, 10.3, 1H),
7.25 (d, J = 2.9, 1H), 7.40 (dd, J = 7.0, 11.3, 1H), 6.51 (d,
1
J = 2.9, 1H) ppm. Compound 3: (M+H)+ 561; H NMR
(500 MHz, THF-d8) d 11.63 (s, 1H), 9.74 (dd, J = 12.4,
8.1 Hz, 1H), 8.92 (dd, J = 10.8, 8.4 Hz, 1H), 7.88–7.85 (m,
1H), 7.45 (d, J = 8.1 Hz, 2H), 7.40–7.35 (m, 3H), 4.88 (s,
2H), 1.3 (s, 9H) ppm. Final product 2: MS: yellow solid;
(M+H)+ 577; 1H NMR (500 MHz, DMSO-d6) d 11.52,
11.48 (s, 1H), 9.74, 9.48 (dd, J = 12.7, 8.1 Hz, 1H), 8.95,
8.91 (dd, J = 11.2, 8.5 Hz, 1H), 8.31, 8.00 (dd, J = 10.3,
7.7 Hz, 1H), 8.22, 7.90 (dd, J = 12.2, 6.9Hz, 1H), 6.14,
6.05 (d, J = 8.9Hz, 1H), 5.30–4.78 (br s, 2H), 4.08–3.28
(m, 8H) ppm.