Synthesis of rebeccamycin and 11-dechlororebeccamycin

Article abstract of DOI:10.1021/jo982277b

Glycosylated 7-chloroindole-3-acetamide 9, prepared in four steps and 26% yield from 7-chloroindole (1), was condensed with methyl 7-chloroindole- 3-glyoxylate 11 and methyl indole-3-glyoxylate 12 to provide bisindolylmaleimides 7 and 8 in 86% and 84% yield, respectively. Oxidation of 7 and 8 followed by debenzylation provided a new approach to the synthesis of rebeccamycin and completed for the first time a synthesis of 11- dechlororebeccamycin.

Full text of DOI:10.1021/jo982277b

J . Org. Chem. 1999, 64, 2465-2470
2465
Syn th esis of Rebecca m ycin a n d 11-Dech lor or ebecca m ycin
Margaret M. Faul,* Leonard L. Winneroski, and Christine A. Krumrich
Lilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and
Development Division, Indianapolis, Indiana 46285-4813
Received November 16, 1998
Glycosylated 7-chloroindole-3-acetamide 9, prepared in four steps and 26% yield from 7-chloroindole
(1), was condensed with methyl 7-chloroindole-3-glyoxylate 11 and methyl indole-3-glyoxylate 12
to provide bisindolylmaleimides 7 and 8 in 86% and 84% yield, respectively. Oxidation of 7 and 8
followed by debenzylation provided a new approach to the synthesis of rebeccamycin and completed
for the first time a synthesis of 11-dechlororebeccamycin.
Sch em e 1
In tr od u ction
The indolocarbazoles are a well-known class of natural
products that have been reported to inhibit protein kinase
C and topoisomerase activity.1 Of this family of com-
pounds several members possess a single N-glycosidic
bond. The most well-known of this subgroup of com-
pounds is rebeccamycin, isolated in 1985 from an acti-
nomycete.2 The structure and absolute configuration of
rebeccamycin have been determined by X-ray crystal-
lography. Rebeccamcyin contains a symmetrical indolo-
carbazole chromophore and a 4-O-methylglucose residue
linked by a â-glycosidic bond. 11-Dechlororebeccamycin
has a similar structure but lacks the chlorine at C11.3
Both compounds are potent antitumor agents and, re-
cently, water soluble derivatives with increased potency
have been prepared and are being evaluated in clinical
trials.4
Two total syntheses of rebeccamycin have been re-
ported (Scheme 1). In 1985 Kaneko and Clardy reported
the first synthesis of rebeccamycin via the symmetrical
bisindolylmaleimide 3, prepared in two steps and 27%
yield, using the indole-Grignard chemistry developed by
Steglich.5 Treatment of 3 with Ag2O and 1-bromo-2,3,6-
tri-O-acetyl-4-O-methyl-D-glucose in refluxing benzene
accomplished the oxidation and glycosylation in one step
to afford 5 in 32% yield. Removal of the BOM and acetyl
protecting groups completed a six-step synthesis of
rebeccamycin.6 Using a similar strategy, Danishefsky
prepared the unsymmetrical bisindolylmaleimide 4 in
four steps and 60% yield.7 Selective preparation of the
â-glycoside in 48% yield by reaction of the sodium salt of
4 with the R-1,2-anhydrosugar 19, followed by SEM
deprotection and oxidation gave indolocarbazole 6 in 22%
yield. Although removal of the benzyl and BOM protect-
ing groups was complicated by competing hydrogenolysis
of the carbon-chlorine bonds, treatment of 6 with Pearl-
man’s catalyst followed by ammonolysis afforded rebec-
camycin in 13 steps.
We recently reported a new method for the synthesis
of symmetrical and unsymmetrical bisindolylmaleimides
by condensation of methyl indole-3-glyoxylates with
indole-3-acetamides using a 1.0 M solution of potassium
tert-butoxide in THF.8,9 To further illustrate the general-
ity of this reaction, we would like to report its application
(1) Gribble, G. W.; Berthel, S. J . Studies in Natural Product
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science Publishers: Am-
sterdam, 1993, Vol. 12.
(2) Nettleton, D. E.; Doyle, T. W.; Kirshnan, B.; Matsumoto, G. K.;
Clardy, J . Tetrahedron Lett. 1985, 25, 4011.
(3) Matson, J . Chem. Abstr. 1985, 103, 159104.
(4) (a) Kaneko, T.; Wong, H.; Utzig, J .; Doyle, T. W. J . Antiobiot.
1990, 43, 125. (b) A dibromo analogue of rebeccamycin has been
prepared: Sing Lam, K.; Schroeder, D. R.; Veitch, J . M.; Matson, J .
A.; Forenzea, S. J . Antiobiot. 1991, 44, 934.
(8) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J . Org. Chem.
1998, 63, 6053.
(5) Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W. Tetrahe-
dron 1988, 44, 2887.
(6) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J . Tetrahedron
Lett. 1985, 26, 4015.
(7) Gallant, M.; Link, J . T.; Danishefsky, S. J . J . Org. Chem. 1993,
58, 343.
(9) After the work reported herein had been completed and accepted
for publication,
a paper describing the application of a similar
condensation to the synthesis of the maleimide Didemnimide A was
published: 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.
10.1021/jo982277b CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

2466 J . Org. Chem., Vol. 64, No. 7, 1999
Faul et al.
Sch em e 2
Sch em e 3a
in a new synthesis of rebeccamcyin and to describe for
the first time a synthesis of 11-dechlororebeccamycin.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. Our retrosynthetic analy-
sis of rebeccamycin and 11-dechlororebeccamycin is
shown in Scheme 2. Bisindolylmaleimides 7 and 8,
containing an unprotected maleimide, were selected as
pivotal intermediates to be converted into the natural
products by oxidation followed by debenzylation. Using
our new methodology we envisioned that bisindolyl-
maleimides 7 and 8 could be prepared either (i) by
condensation of glycosylated 7-chloroindole-3-acetamide
9 with methyl indole-3-glyoxylates 11 and 12 (strategy
A); or (ii) by condensation of glycosylated methyl 7-
chloroindole-3-glyoxylate 10 with indole-3-acetamides 13
or 14 (strategy B). Both of these approaches have been
evaluated, and their success in the synthesis of rebecca-
mycin and 11-dechlororebeccamycin will be described.
Syn t h esis of 7-Ch lor oin d ole-3-a cet a m id e (13).
Treatment of 7-chloroindole (1)10 with N,N-dimethyl-
methyleneammonium chloride in CH2Cl2 afforded gramine
17 in quantitative yield (Scheme 3).11 Treatment of 17
with NaCN in DMSO/EtOAc gave 7-chloroindole-3-ac-
etonitrile 18 in 82% yield. Hydrolysis of 18 using KOH
in tert-butyl alcohol completed the synthesis of 7-chlor-
oindole-3-acetamide 13 in three steps and 65% yield.
Glycosyla tion . Selective formation of the â-N-glyco-
sides of 7-chloroindole-3-acetamide (13) and 7-chloroin-
dole (1) was accomplished using the method of Danishef-
sky.7 The R-1,2-anhydrosugar 19 was prepared in four
steps, 80% yield, and 15:1 R:â-selectivity from com-
mercially available tri-O-acetyl-D-glucal 16. Deprotona-
tion of 13 and 1 (2.0 equiv) with NaH (2.1 equiv) in
MeCN, followed by treatment with 19 (1.0 equiv) at 50
°C overnight, afforded â-N-glucosides 9 and 20 in 40%
and 50% yield, respectively (eqs 1 and 2). Although the
selectivity of the reaction was >1:12 R:â, the minor
R-isomer was removed by chromatography to afford the
a
(a) CH2dNMe2Cl, CH2Cl2; (b) NaCN, DMSO, EtOAc, 80 °C;
(c) KOH, t-BuOH.
â-isomer in >98% diastereomeric purity prior to the
condensation reaction. Glycosylation of 13 was also
accomplished in 1 h using Cs2CO3 in DMF at 100 °C
affording 9 in 40% isolated yield, although the selectivity
of the reaction was lower [R:â ) 1:8].
(10) (a) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitigawa, A. J . Org.
Chem. 1979, 44, 578. (b) Bartoli, G.; Palmieri, G. Tetrahedron Lett.
1989, 30, 2129.
(11) (a) Brewster, J . H.; Eliel, E. L. Org. React. 1953, 7, 99. (b)
Kozikowski, A. P.; Ishida, H. Heterocycles 1980, 14, 55.
Glyoxyla t e E st er F or m a t ion . Treatment of 7-
chloroindole (1) with oxalyl chloride at room temperature

Synthesis of Rebeccamycin and 11-Dechlororebeccamycin
Sch em e 4
J . Org. Chem., Vol. 64, No. 7, 1999 2467
for 3 h followed by quench with NaOMe at -50 °C
afforded methyl 7-chloroindoleglyoxylate (11) in 89%
yield (eq 3). However, using analogous conditions, we
were unable to prepare the glyoxylate ester of 7-chloro-
F igu r e 1.
ide 7 in 86% yield. If the condensation reaction was
performed at lower temperatures, the unsubstituted
bisindolylmaleimide 30 was generated as a byproduct
(Figure 1). The reaction was also successful using 1.2
equiv of 11 to afford 7 in 80% yield. The lower yield was
due to the competing hydrolysis of 11 to glyoxylic acid
31. Glyoxylic acid 31 was easily removed from the
reaction by base extraction during workup.
Treatment of glycosylated 7-chloroindole-3-acetamide
(9) (1.0 equiv) and methyl indole-3-glyoxylate (12) (2.0
equiv) with a 1.0 M solution of potassium tert-butoxide
in THF (4.0 equiv) at room temperature for 20 h afforded
bisindolylmaleimide 8 in 84% yield. In this case dehydra-
tion of hydroxyimide 27 occurred under the basic reaction
conditions, and formation of the unsubstituted bisindoly-
maleimide 32 was not observed.
In our previous mechanistic work on this reaction we
indicated that if the indole-3-acetamide was N-substi-
tuted, dehydration of the intermediate hydroxyimides
occurred under the basic reaction conditions.8 Although
this result was true for formation of 8, in the synthesis
of bisindolylmaleimide 7, the first case we have examined
involving condensation of an N-alkylated indole-3-aceta-
mide and glyoxylate containing substitution on the
indole-aromatic ring, represents an example where this
is not the case. This result suggests that dehydration of
the hydroxyimides is dependent on the functionality
present in both reacting partners.
indole derivatives 21 or 22 (eq 4). In fact, treatment of
glycosylated indole 23 with excess oxalyl chloride (8
equiv) at room temperature overnight afforded only a
40% yield of methyl glyoxylate 25, much lower than the
93% yield of methyl indole-3-glyoxylate (12) obtained
when indole 15 was employed (eq 3). On the basis of these
data, we believe that the reduced reactivity of the indole-
C3 position is due to the presence of both the 7-chloro
substituent and the N-glucose moiety. Alternative ap-
proaches to 10 using either the C3-organometallic deriva-
tive of 21 or 22 or direct glycosylation of the sodium
indolate of 11 were also unsuccessful. Since the synthesis
of 10 and 24 was problematic, we directed our efforts to
the synthesis of rebeccamycin and 11-dechlororebecca-
mycin by condensation of glycosylated 7-chloroindole-3-
acetamide (9) and methyl indole-3-glyoxylates 11 and 12
(strategy A).
Bisin d olylm a leim id e F or m a t ion . Glycosylated 7-
chloroindole-3-acetamide 9 (1.0 equiv) and methyl 7-chlor-
oindole-3-glyoxylate 11 (2.0 equiv) were treated with a
1.0 M solution of potassium tert-butoxide in THF (4.5
equiv) at room temperature for 1 h to generate hydroxy-
imide 26 (Scheme 4). In-situ treatment of 26 with
concentrated HCl at reflux generated bisindolylmaleim-
Oxid a tion , Dep r otection , a n d Syn th esis of Rebec-
ca m ycin a n d 11-Dech lor or ebecca m ycin . Although a
number of methods have been reported to successfully
oxidize bisindolylmaleimides to indolocarbazoles [Pd-
(OAc)2, PdCl2, hv/O2 or I2, DDQ, CuCl2],12 they proved
(12) (a) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron
Lett. 1993, 34, 8361. (b) Ohkubo, M.; Nishimura, T.; J ona, H.; Honma,
T.; Morishima, H. Tetrahedron 1996, 52, 8099.

2468 J . Org. Chem., Vol. 64, No. 7, 1999
Faul et al.
(960 mg, 1.06 mL, 10.9 mmol) in dry DMSO (10 mL) was
heated at 80 °C under N2 for 6 h. The reaction mixture was
then cooled, diluted with EtOAc, and washed with water. The
organic layer was dried (MgSO4) and the solvent removed in
vacuo to give 410 mg of 18. Purification by column chroma-
tography (2:1 hexanes:EtOAc) afforded 340 mg (82%) of 18.
1H NMR (300 MHz, DMSO-d6) δ 11.48 (bs, 1H), 7.53 (d, 1H, J
) 7.9 Hz), 7.37 (bs, 1H), 7.18 (d, 1H, J ) 7.5 Hz), 7.03 (t, 1H,
J ) 7.7 Hz), 4.02 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 134.0,
127.8, 123.9, 122.7, 121.5, 118.3, 117.5, 117.2, 106.2, 14.8; IR
(KBr) 3324, 2257 cm-1. HRMS (EI) exact mass calcd for
C10H7N2Cl M+ 190.0298, found 190.0297. Anal. Calcd for
unsuccessful in oxidizing bisindolylmaleimides 7 and 8,
affording only trace amounts of the desired products.
However, using Pd(OTf)2 in DMF at 90 °C for 2.5 h,
indolocarbazoles 28 and 29 were prepared in 66% and
60% yield, respectively, from 7 and 8 (Scheme 4).13
Final deprotection of indolocarbazoles 28 and 29 was
achieved using Pearlman’s catalyst to afford rebeccamy-
cin and 11-dechlororebeccamycin in 83% and 86% yield,
respectively. In the absence of maleimide protection, the
hydrogenation conditions were sufficiently mild that
competition from hydrogenolysis of the aromatic carbon-
chlorine bonds was not observed. The synthetic material
thus obtained gave 1H NMR, 13C NMR, HRMS, and
optical rotation data identical to those reported for the
natural products rebeccamycin14 and 11-dechlororebec-
camycin.3
C
10H7N2Cl: C, 63.01, H, 3.70, N, 14.69, Cl, 18.60. Found: C,
62.85, H, 3.49, N, 14.59, Cl, 18.59.
7-Ch lor o-1H-in d ole-3-a ceta m id e (13). A solution of 18
(2.77 g, 14.5 mmol) and powdered 85% KOH (7.66 g, 116 mmol)
in tert-butyl alcohol (30 mL) was heated at reflux for 1.5 h.
The reaction mixture was then cooled to room temperature,
diluted with water (30 mL), and acidified with 1 N HCl (116
mL, 116 mmol) to give a slurry that was filtered and rinsed
with water and then Et2O (40 mL). The solid was dried in a
vacuum oven at 40 °C to give 2.39 g (79%) of 13. 1H NMR (300
MHz, DMSO-d6) δ 11.18 (bs, 1H), 7.47 (d, 1H, J ) 7.8 Hz),
7.30 (bs, 1H), 7.21 (bs, 1H), 7.10 (d, 1H, J ) 7.5 Hz), 6.94 (t,
1H, J ) 7.7 Hz), 6.81 (bs, 1H), 3.42 (s, 2H); 13C NMR (125
MHz, DMSO-d6) δ 173.5, 133.8, 130.2, 126.0, 121.3, 120.2,
Su m m a r y
In summary, we have reported a new method to
prepare functionalized bisindolylmaleimides in high yield
by condensation of indole-3-acetamides with methyl
indole-3-glyoxylates. The success of this methodology is
demonstrated by an improved synthesis of the antitumor
indolocarbazole glycoside rebeccamycin in 12 steps and
12% overall yield. The versatility of this method lies in
the fact that a number of different analogues can be
prepared from a single functionalized indole-3-acetamide,
as demonstrated by the first total synthesis of 11-
dechlororebeccamycin in 12 steps and 11% overall yield
from the same glycosylated indole-3-acetamide 9. Further
evaluation of the generality of this method to the
synthesis of other members of the bisindolymaleimide,
indolocarbazole, and staurosporine family of compounds
is being performed and will be reported in due course.
118.7, 116.6, 111.4, 33.3; IR (KBr) 3443, 3339, 3188, 1626 cm-1
.
HRMS (EI) exact mass calcd for C10H9N2OCl M+ 208.0403,
found 208.0411. Anal. Calcd for C10H9N2OCl: C, 57.57, H, 4.35,
N, 13.43. Found: C, 57.84, H, 4.19, N, 13.26.
Meth yl 7-Ch lor o-r-oxo-1H-in d ole-3-a ceta te (11). To a
solution of 7-chloroindole (1) (2.00 g, 13.2 mmol) in Et2O (24
mL) was added oxalyl chloride (2.33 g, 1.60 mL, 18.3 mmol),
and the resultant mixture was stirred at room temperature
for 3 h. The reaction mixture was cooled to -50 °C, treated
dropwise with a 25 wt % solution of NaOMe (7.94 g, 8.40 mL,
36.7 mmol), and then allowed to warm to room temperature
and stirred for 15 min. The reaction was diluted with EtOAc
and washed with 5% aqueous NaHCO3. The organic layer was
dried (MgSO4), and the solvent was removed in vacuo. The
resulting solid was triturated with Et2O (35 mL) and filtered
to give 2.80 g (89%) of 11. 1H NMR (300 MHz, DMSO-d6) δ
12.79 (bs, 1H), 8.43 (s, 1H), 8.08 (d, 1H, J ) 7.9 Hz), 7.35 (d,
1H, J ) 7.7 Hz), 7.24 (t, 1H, J ) 7.8 Hz), 3.85 (s, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 179.6, 164.3, 139.7, 134.5, 128.3,
124.9, 124.3, 121.0, 117.9, 114.1, 53.5; IR (KBr) 3139, 1732,
1634, 1625, 1614 cm-1. HRMS (EI) exact mass calcd for C11H8-
NO3Cl M+ 237.0193, found 237.0188. Anal. Calcd for C11H8-
NO3Cl: C, 55.60, H, 3.39, N, 5.89, Cl, 14.92. Found: C, 55.86,
H, 3.33, N, 5.92, Cl, 15.19.
Exp er im en ta l Section
Unless otherwise noted, reagents and solvents were used
as received from commercial suppliers. TLC was performed
on Kieselgel 60 F254 plates (Merck) using reagent grade
solvents. Flash chromatography was performed using E. M.
Merck silica gel 60 (230-400 mesh). Mass spectral and
combustion analysis were performed by the Eli Lilly and Co.
Physical Chemistry Department.
7-Ch lor o-N,N-dim eth yl-1H-in d ole-3-m eth a n a m in e (17).
To a solution of 7-chloroindole (1) (4.00 g, 26.4 mmol) in CH2-
Cl2 (70 mL) was added N,N-dimethylmethyleneammonium
chloride (3.21 g, 34.3 mmol) in one portion, and the resultant
mixture was stirred at room temperature for 2 h under N2.
Water, followed by 1 M NaOH (34 mL, 34.0 mmol) were added,
and the reaction mixture was extracted with EtOAc. The
combined organic layers were then washed with saturated
NaCl and dried (MgSO4). The solvent was removed in vacuo
1-[4-O-Met h yl-2,3,6-t r is-O-(p h en ylm et h yl)-â-D-glu co-
p yr a n osyl]-1H-in d ole (23). To a solution of indole (329 mg,
2.81 mmol) in MeCN (10 mL) was added NaH (118 mg, 2.95
mmol), and the mixture was stirred at room temperature for
45 min. The R-anhydro sugar 19 (500 mg, 1.40 mmol) in MeCN
(2 mL) was added, and the reaction was heated at 50 °C for 2
h. The heat was removed, and the reaction mixture was
allowed to stir at room temperature overnight. The reaction
mixture was diluted with EtOAc and quenched with saturated
NH4Cl. The organic layer was washed with saturated NaCl
and dried (MgSO4), and the solvent was removed in vacuo to
give a brown oil that was purified by column chromatography
(4:1 hexanes:EtOAc) to afford 310 mg (47%) 1-[4-O-methyl-
3,6-bis-O-(phenylmethyl)-â-D-glucopyranosyl]-1H-indole as a
1
to give 5.51 g (100%) of 17. H NMR (300 MHz, DMSO-d6) δ
11.22 (bs, 1H), 7.52 (d, 1H, J ) 7.8 Hz), 7.23 (d, 1H, J ) 2.2
Hz), 7.09 (d, 1H, J ) 7.6 Hz), 6.93 (t, 1H, J ) 7.7 Hz), 3.47 (s,
2H), 2.08 (bs, 6H); 13C NMR (75 MHz, DMSO-d6) δ 133.1,
129.5, 125.6, 124.9, 120.4, 119.3, 118.2, 115.7, 113.1, 54.2; IR
(KBr) 2967, 2943 cm-1. LRMS (EI) m/z 209 (100%). Anal. Calcd
for C11H13N2Cl: C, 63.31, H, 6.28, N, 13.42. Found: C, 63.02,
H, 6.17, N, 13.23.
1
colorless oil. H NMR (300 MHz, DMSO-d6) δ 7.61-7.05 (m,
15H), 6.48 (d, 1H, J ) 3.3 Hz), 5.57 (d, 1H, J ) 8.8 Hz), 4.92
(d, 1H, J ) 11.7 Hz), 4.78 (d, 1H, J ) 11.7 Hz), 4.45 (d, 2H, J
) 9.1 Hz), 4.01 (t, 1H, J ) 7.7 Hz), 3.67-3.48 (m, 6H), 3.46 (s,
3H); 13C NMR (75 MHz, DMSO-d6) δ 138.3, 138.0, 135.8, 129.2,
128.4, 128.2, 127.8, 127.5, 125.1, 122.0, 121.0, 120.0, 116.4,
110.7, 103.2, 96.6, 86.0, 85.2, 79.3, 77.8, 75.3, 73.5, 72.9, 68.6,
7-Ch lor o-1H-in d ole-3-a ceton itr ile (18). A solution of 17
(450 mg, 2.18 mmol), NaCN (320 mg, 6.53 mmol), and EtOAc
(13) Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.; Morishima,
H. Tetrahedron 1997, 53, 585
(14) (a) Furusaki, A.; Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai,
Y.; Omura, S. Bull. Chem. Soc. J pn. 1982, 55, 3681. (b) Omura, S.;
Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J .; Tsuchiya, H.; Masuma,
R. J . Antibiot. 1977, 30, 275.
60.8; HRMS (FAB) calcd for
473.2208.
C29H31NO5 473.2202, found
To a solution of the above glycosylated indole (300 mg, 633
µmol) in THF (3 mL) was added NaH (30.4 mg, 760 µmol),

Synthesis of Rebeccamycin and 11-Dechlororebeccamycin
J . Org. Chem., Vol. 64, No. 7, 1999 2469
and the mixture was heated at reflux for 1 h. Benzyl bromide
(226 uL, 1.90 mmol) was added, and the reaction was heated
at reflux overnight, cooled to room temperature, diluted with
EtOAc, and quenched with saturated NH4Cl. The organic layer
was washed with saturated aqueous NaCl and dried (MgSO4),
and the solvent was removed in vacuo to give a brown oil which
was purified by column chromatography (4:1 hexanes:EtOAc)
saturated NH4Cl and saturated NaCl, and dried (MgSO4). The
solvent was removed in vacuo to afford an oil that was purified
by column chromatography (4:1 hexanes:EtOAc) to yield 600
mg (73%) of 22. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, 1H, J )
3.4 Hz), 7.59 (d, 1H, J ) 7.2 Hz), 7.37-7.21 (m, 14H), 7.13-
7.05 (m, 2H), 6.78 (d, 1H, J ) 7.2 Hz), 6.68 (d, 1H, J ) 3.4
Hz), 6.50 (d, 1H, J ) 9.0 Hz), 4.84 (d, 2H, J ) 3.8 Hz), 4.55 (d,
1H, J ) 12.1 Hz), 4.45 (d, 1H, J ) 12.1 Hz), 4.18 (t, 1H, J )
8.8 Hz), 4.07 (d, 1H, J ) 10.9 Hz), 3.88-3.65 (m, 6H), 3.50 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 128.2, 128.1, 127.9, 127.6,
127.5, 127.4, 127.3, 127.2, 124.0, 120.9, 119.9, 103.9, 85.0, 82.9,
80.2, 80.2, 79.4, 76.1, 75.0, 73.2, 72.1, 68.4, 59.9; IR (KBr) 2926,
20908, 2870, 1564 cm-1. LRMS (EI) m/z 598. Anal. Calcd for
1
to afford 140 mg of 23 (39%) as a colorless oil. H NMR (300
MHz, DMSO-d6) δ 7.67-7.04 (m, 18H), 6.68 (d, 2H, J ) 6.6
Hz), 6.57 (d, 1H, J ) 3.3 Hz), 5.73 (d, 1H, J ) 9.1 Hz), 4.80 (s,
2H), 4.55 (d, 1H, J ) 12.1 Hz), 4.47 (d, 1H, J ) 12.1 Hz), 4.20
(d, 1H, J ) 10.6 Hz), 4.02 (d, 1H, J ) 9.2 Hz), 3.83-3.52 (m,
6H), 3.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 138.3, 138.1,
136.9, 135.5, 129.2, 128.4, 128.3, 128.2, 128.0, 127.7, 127.6,
127.4, 125.8, 122.0, 121.0, 120.2, 111.4, 103.1, 86.4, 85.2, 80.9,
79.4, 77.9, 75.7, 74.5, 73.5, 68.7, 60.9; HRMS (FAB) calcd for
C
36H36NO5Cl: C, 72.29, H, 6.07, N, 2.34. Found: C, 72.54, H,
5.82, N, 2.48.
7-Ch lor o-1-[4-O-m et h yl-3,6-bis-O-(p h en ylm et h yl)-â-D-
glu cop yr a n osyl]-1H-in d ole-3-a ceta m id e (9). To a solution
of 13 (1.20 g, 5.75 mmol) in dry MeCN (10 mL) was added
NaH (240 mg, 6.04 mmol, 60% dispersion in mineral oil), and
the resultant mixture was stirred at room temperature under
N2 for 30 min. The R-anhydro sugar 19 (1.02 g, 2.88 mmol) in
dry MeCN (10 mL) was added and the reaction heated at 50
°C for 20 h. The reaction was cooled to room temperature,
diluted with EtOAc, and washed with saturated NH4Cl and
saturated NaCl. The organic layer was dried (MgSO4) and the
solvent removed in vacuo to give a dark oil. HPLC analysis
indicated an R:â ratio of 1:16.16 The oil was purified by column
chromatography (1:1:1 hexanes:EtOAc:acetone) to afford 660
C
36H37NO5 563.2672, found 563.2677 (100%).
Meth yl r-Oxo-[4-O-m eth yl-2,3,6-tr is-O-(p h en ylm eth yl)-
â-D-glu cop yr a n osyl]-1H-in d ole-3-a ceta te (25). To a solu-
tion of 23 (50.0 mg, 88.7 µmol) in Et2O (10 mL) was added
oxalyl chloride (46.5 µL, 531 µmol), and the resultant mixture
was stirred at room temperature for 6 h. The reaction was
cooled to -60 °C and treated dropwise with a 25 wt % solution
of NaOMe in MeOH (304 uL, 1.33 mmol). The reaction was
then allowed to warm to room temperature and stirred for 15
min. The reaction was diluted with EtOAc and washed with
saturated NH4Cl. The organic layer was washed with satu-
rated NaCl and dried (MgSO4), and the solvent was removed
in vacuo to give a crude oil which was purified by column
chromatography (4:1 hexanes:EtOAc) to afford 23.0 mg of 25
(40%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.43-
8.40 (m, 2H), 7.65 (d, 1H, J ) 7.3 Hz), 7.40-6.94 (m, 17H),
6.63 (d, 2H, J ) 6.6 Hz), 5.73 (d, 1H, J ) 8.9 Hz), 4.80 (s, 2H),
4.61 (d, 1H, J ) 11.0 Hz), 4.53 (d, 1H, J ) 11.0 Hz), 4.25 (d,
1H, J ) 11.9 Hz), 3.94 (s, 3H), 3.95-3.50 (m, 5H), 3.48 (s, 3H);
HRMS (FAB) calcd for C39H40NO8 650.2754, found 650.2741
(100%).
1
mg (40%) 9 (HPLC analysis indicated 100% â). H NMR (500
MHz, CDCl3) δ 7.43-7.36 (m, 5H), 7.33-7.26 (m, 7H), 7.23
(d, 1H, J ) 7.6 Hz), 7.06 (t, 1H, J ) 7.8 Hz), 6.34 (d, 1H, J )
8.6 Hz), 5.62 (bs, 1H), 5.43 (bs, 1H), 5.00 (d, 1H, J ) 11.4 Hz),
4.87 (d, 1H, J ) 11.4 Hz), 4.59 (d, 1H, J ) 11.9 Hz), 4.49 (d,
1H, J ) 11.9 Hz), 4.03 (t, 1H, J ) 8.7 Hz), 3.77 (d, 2H, J ) 2.3
Hz), 3.67 (t, 2H, J ) 9.0 Hz), 3.58 (s, 4H), 3.54 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 174.0, 138.8, 138.4, 133.0, 131.4,
129.0, 128.7, 128.4, 128.4, 128.2, 128.0, 125.5, 125.4, 121.6,
118.1, 117.4, 110.8, 86.1, 84.4, 80.0, 75.7, 73.9, 72.7, 69.1, 60.9,
33.1; IR (KBr) 3466, 3336, 1630 cm-1. HRMS (EI) exact mass
calcd for C31H33N2O6Cl M+ 564.2027, found 564.2021. Anal.
Calcd for C31H33N2O6Cl: C, 65.89, H, 5.89, N, 4.96, Cl, 6.27.
Found: C, 66.03, H, 5.70, N, 4.95, Cl, 6.39.
7-Ch lor o-1-[4-O-m et h yl-3,6-b is-O-(p h en ylm et h yl)-â-D-
glu cop yr a n osyl]-1H-in d ole (21). To a solution of 7-chlor-
oindole (1) (88 mg, 5.78 mmol) in dry MeCN (10 mL) was
added NaH (240 mg, 6.07 mmol, 60% dispersion in mineral
oil), and the reaction mixture was stirred at room temperature
under N2 for 30 min. The R-anhydro sugar 19 (1.03 g, 2.89
mmol) in dry MeCN (10 mL) was then added and the reaction
mixture heated at 50 °C for 20 h. The reaction was cooled to
room temperature, diluted with EtOAc, and washed with
saturated NH4Cl and saturated NaCl. The organic layer was
dried (MgSO4), and the solvent was removed in vacuo to give
21 as a dark oil. HPLC analysis indicated an R:â ratio of 1:12.15
The oil was purified by column chromatography (4:1 hexanes:
EtOAc) to afford 710 mg (50%) of 21 (HPLC analysis indicated
98:2 â:R). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, 1H, J ) 3.4
Hz), 7.55 (d, 1H, J ) 7.9 Hz), 7.46-7.19 (m, 11H), 7.07 (t, 1H,
J ) 7.7 Hz), 6.60 (d, 1H, J ) 3.4 Hz), 6.22 (d, 1H, J ) 9.0 Hz),
5.66 (d, 1H, J ) 7.1 Hz), 4.96 (d, 1H, J ) 11.3 Hz), 4.80 (d,
1H, J ) 11.3 Hz), 4.47 (d, 1H, J ) 11.8 Hz), 4.40 (d, 1H, J )
12.0 Hz), 4.17-4.08 (m, 1H), 3.71-3.63 (m, 2H), 3.46 (s, 3H),
3.35-3.31 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 128.1, 128.0,
127.7, 127.5, 127.4, 127.3, 127.2, 127.1, 124.9, 123.7, 120.8,
119.7, 103.0, 85.9, 83.9, 78.9, 75.7, 74.0, 72.1, 71.3, 66.8, 59.8;
IR (KBr) 1731 cm-1. LRMS (EI) m/z 508. Anal. Calcd for
3-[(7-Ch lor o-1H-in d ol-3-yl)-4-[7-ch lor o-1-[4-O-m eth yl-
3,6-bis-O-(p h en ylm eth yl)-â-D-glu cop yr a n osyl]-1H-in d ol-
3-yl]-1H-p yr r ole-2,5-d ion e (7). To a solution of 9 (100 mg,
0.18 mmol) and 11 (80.0 mg, 0.35 mmol) in dry THF (3 mL)
was rapidly added 1.0 M potassium tert-butoxide in THF (710
µL, 710 mmol) at room temperature. The reaction was stirred
under N2 for 1 h and then quenched with concentrated HCl
(0.50 mL) and heated at reflux for 1 h. The reaction mixture
was cooled to room temperature, diluted with EtOAc, and
washed with water. The organic layer was dried (MgSO4) and
the solvent removed in vacuo to give a red foam that was
purified by column chromatography (2:1 hexanes:EtOAc) to
give 130 mg (86%) of 7. [R]20D +69.3 ° (c, 1.04, CHCl3); 1H NMR
(500 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.01 (s, 1H), 8.02 (s,
1H), 7.78 (d, 1H, J ) 2.9 HZ), 7.42 (d, 2H, J ) 7.1 Hz), 7.35 (t,
2H, J ) 7.3 Hz, J ) 7.8 Hz), 7.29-7.22 (m, 7H), 7.06 (d, 1H,
J ) 7.5 Hz), 6.98 (d, 1H, J ) 7.5 Hz), 6.76 (d, 1H, J ) 8.2 Hz),
6.72 (d, 1H, J ) 6.8 Hz), 6.66 (t, 1H, J ) 7.8 Hz, J ) 7.8 Hz),
6.60 (t, 1H, J ) 8.0 Hz, J ) 7.8 Hz), 6.24 (d, 1H, J ) 9.6 Hz),
5.82 (d, 1H, J ) 6.6 Hz), 4.93 (d, 1H, J ) 11.7 Hz), 4.79 (d,
1H, J ) 11.2 Hz), 4.56 (d, 1H, J ) 11.9 Hz), 4.42 (d, 1H, J )
11.7 Hz), 4.0 (m, 1H), 3.74-3.61 (m, 4H), 3.44 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 173.0, 172.3, 138.9, 138.3, 133.8, 133.1,
130.8, 130.0, 129.3, 129.1, 129.0, 128.7, 128.4, 127.4, 126.0,
122.8, 122.1, 122.0, 121.7, 121.4, 117.7, 117.2, 108.1, 107.8,
86.1, 84.6, 80.4, 76.5, 76.2, 73.8, 72.3, 69.2, 62.7, 61.3, 45.6,
30.6, 29.7; IR (KBr) 3402, 3273, 1757, 1706 cm-1. HRMS (EI)
C
29H30N1O5Cl: C, 68.57, H, 5.95, N, 2.76. Found: C, 68.78, H,
5.88, N, 2.60.
7-Ch lor o-1-[4-O-m eth yl-2,3,6-tr is-O-(p h en ylm eth yl)-â-
D-glu cop yr a n osyl]-1H-in d ole (22). To a solution of 21 (700
mg) in THF (10 mL) was added NaH (70.0 mg, 1.65 mmol,
60% dispersion in mineral oil), and the reaction was heated
at reflux for 1 h. The reaction mixture was cooled to room
temperature and benzyl bromide (305 mg, 246 µL, 2.07 mmol)
added. The reaction mixture was heated at reflux overnight,
cooled to room temperature, diluted with EtOAc, washed with
exact mass calcd for
751.1860.
C
41H35N3O7Cl2 M+ 751.1852, found
(15) HPLC conditions: Column Zorbax SB-CN, flow rate 1 mL/min,
233 nm, 50:50 MeCN: 0.1% TFA. tR 21 R-isomer ) 7.9 min, tR 21
â-isomer ) 8.9 min, tR 1 ) 5.0 min.
(16) HPLC conditions: Column Zorbax SB-CN, flow rate 1 mL/min,
233 nm, 50: 50 MeCN: 0.1% TFA. tR 9R-isomer ) 9.0 min, tR 9â-isomer
) 10.5 min, tR 13 ) 4.0 min.

2470 J . Org. Chem., Vol. 64, No. 7, 1999
Faul et al.
3-[(1H-In d ol-3-yl)-4-[7-ch lor o-1-[4-O-m eth yl-3,6-bis-O-
(p h en ylm eth yl)-â-D-glu cop yr a n osyl]-1H-in d ol-3-yl]-1-H-
p yr r ole-2,5-d ion e (8). To a solution of 9 (350 mg, 0.61 mmol)
and methyl indole-3-glyoxylate (12) (250 mg, 1.22 mmol) in
dry THF (10 mL) was rapidly added 1.0 M potassium tert-
butoxide in THF (3.66 mL, 3.66 mmol) at room temperature.
The reaction was stirred under N2 for 20 h and then quenched
with saturated NH4Cl. The reaction mixture was diluted with
EtOAc and washed with water. The organic layer was dried
(MgSO4) and the solvent removed in vacuo to give a red foam
that was purified by column chromatography (2:1 hexanes:
washed with 0.5 N HCl (50 mL). The organic layer was dried
(MgSO4) and filtered through Hyflo, and the solvent was
removed in vacuo to give the crude carbazole that was purified
by column chromatography (2:1 hexanes:EtOAc) to give 120
mg (60%) of 29. [R]20 +123.1° (c, 1.04, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 10.82 (s, 1H), 8.95 (d, 1H, J ) 7.8 Hz), 8.31 (d,
1H, J ) 8.0 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J ) 7.5 Hz), 7.41-
7.13 (m, 13H), 6.91 (t, 1H, J ) 7.8 Hz, 7.1 Hz), 4.92 (s, 2H),
4.88 (d, 1H, J ) 12.6 Hz), 4.75 (d, 1H, J ) 12.1 Hz), 4.28 (bs,
2H), 4.12-3.97 (m, 4H), 3,85 (t, 1H, J ) 8.9 Hz, J ) 8.9 Hz),
3.77 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.4, 169.7, 141.4,
138.9, 138.4, 137.6, 131.5, 130.6, 129.5, 129.4, 129.1, 128.8,
128.6, 128.4, 126.6, 125.9, 125.2, 123.6, 122.9, 121.6, 120.8,
119.7, 119.3, 117.4, 111.8, 86.5, 85.0, 78.9, 78.1, 76.8, 74.9, 73.0,
68.2, 61.9; IR (KBr) 3331, 1753, 1706 cm-1. HRMS (FAB) exact
mass calcd for C41H34N3O7Cl M+ 716.1870, found 716.1678.
EtOAc) to afford 370 mg (84%) of 8. [R]20 -110.9° (c 1.01,
D
MeOH); 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.02
(s, 1H), 7.99 (s, 1H), 7.79 (d, 1H, J ) 3.0 Hz), 7.43 (d, 2H, J )
7.1 Hz), 7.36-7.21 (m, 10 H), 7.05 (d, 1H, J ) 7.5 Hz), 6.90 (t,
1H, J ) 7.3 Hz, J ) J .8 Hz), 6.79 (d, 1H, J ) 8.2 Hz), 6.75 (d,
1H, J ) 7.1 Hz), 6.63 (d, 1H, J ) 8.0 Hz, J ) 7.8 Hz), 6.59 (t,
1H, J ) 7.5 Hz, J ) 7.3 Hz), 6.23 (d, 1H, J ) 8.9 Hz), 5.83 (d,
1H, J ) 7.55 Hz), 4.94 (d, 1H, J ) 11.4 Hz), 4.79 (d, 1H, J )
11.2 Hz), 4.50 (d, 1H, J ) 11.9 Hz), 4.43 (d, 1H, J ) 11.9 Hz),
3.99 (m, 1H), 3.73-3.66 (m, 4H), 3.44 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 173.3, 172.7, 138.9, 138.4, 136.7, 133.1, 131.3,
130.9, 130.5, 129.2, 129.1, 129.0, 128.7, 128.6, 128.4, 126.4,
125.8, 125.7, 123.2, 122.8, 122.0, 121.2, 117.6, 112.1, 108.1,
107.0, 86.0, 84.6, 80.4, 76.6, 76.1, 73.8, 72.3, 69.5, 61.3; IR
(CHCl3) 3465, 1758, 1714 cm-1. Anal. Calcd for C41H36N3O7-
Cl: C, 69.02, H, 5.66, N, 5.62. Found. C, 68.71, H, 5.53, N, 5.95.
1, 11-Dich lor o-12,13-d ih yd r o-12-[4-O-m eth yl-3,6-bis-O-
(p h en ylm et h yl)-â-D-glu cop yr a n osyl]-5-H -in d olo[2,3-a ]-
p yr r olo[3,4-c]ca r ba zole-5,7(6H)-d ion e (28). A mixture of
7 (400 mg, 0.53 mmol) and Pd(OTf)2 (530 mg, 1.59 mmol) in
DMF (20 mL) were heated at 90 °C for 2 h under N2. The
reaction was then cooled, diluted with EtOAc (50 mL), and
washed with 0.5 N HCl (100 mL). The organic layer was dried
(MgSO4) and filtered through Hyflo, and the solvent was
removed in vacuo to give the crude carbazole that was purified
by column chromatography (2:1 hexanes:EtOAc) to give 262
Rebecca m ycin . To a solution of indolocarbazole 28 (0.18
g, 240 µmol) in THF (10 mL) was added Pd(OH)2 (90.0 mg).
The reaction was stirred for 2 h under a H2 atmosphere and
then filtered through Hyflo using THF to rinse. The solvent
was partially removed in vacuo to give a concentrated THF
solution of product that was absorbed onto silica and purified
by column chromatography (15 g silica gel, 100% EtOAc) to
give 110 mg (83%) of rebeccamycin. [R]20 +143.0° (c, 1.02,
D
THF); 1H NMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.70 (s,
1H), 9.27 (d, 1H, J ) 7.7 Hz), 9.08 (d, 1H, J ) 7.8 Hz), 7.72 (d,
1H, J ) 7.6 Hz), 7.68 (d, 1H, J ) 7.6 Hz), 7.44 (t, 2H, J ) 7.6
Hz), 6.97 (d, 1H, J ) 9.1 Hz), 5.40 (d, 1H, J ) 5.5 Hz), 5.31 (br
t, 1H), 5.01 (d, 1H, J ) 5.4 Hz), 4.01 (bs, 2H), 3.87 (d, 1H, J )
9.3 Hz), 3.73-3.58 (m, 3H), 3.62 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 171.3, 171.2, 138.6, 138.1, 130.8, 130.6, 127.9,
126.0, 124.9, 124.4, 124.2, 123.4, 123.0, 121.5, 120.3, 118.6,
117.1, 117.1, 85.3, 81.1, 80.1, 78.3, 73.1, 61.0, 60.8; IR (CHCl3)
3350, 1753, 1703 cm-1. HRMS (EI) exact mass calcd for
C
27H21N3O7Cl2 M+ 570.0834, found 570.0839.
11-Dech lor or ebecca m ycin . To a solution of indolocarba-
zole 29 (200 mg, 280 µmol) in THF (20 mL) was added Pd-
(OH)2 (100 mg). The reaction was stirred for 4 h under a H2
atmosphere and then filtered through Hyflo using THF to
rinse. The solvent was partially removed in vacuo and a
concentrated THF solution of product absorbed onto silica and
purified by column chromatography to afford 128 mg (86%) of
mg (66%) of 28. [R]20 +141.7° (c, 1.03, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 10.5 (s, 1H), 8.73 (d, 1H, J ) 7.72 Hz), 7.84 (d,
1H, J ) 7.74 Hz), 7.80 (s, 1H), 7.44-7.38 (m, 3H), 7.32-7.19
(m, 9H), 7.10 (t, 1H, J ) 7.69 Hz), 7.06 (d, 1H, J ) 7.54 Hz),
6.70 (t, 1H, J ) 7.69 Hz), 5.03 (d, 1H, J ) 11.55 Hz), 4.97 (d,
1H J ) 11.55 Hz), 4.66 (d, 1H, J ) 12.60 Hz), 4.57 (d, 1H, J )
12.60 Hz), 4.43 (t, 1H, J ) 8.94 Hz), 4.16-3.96 (m, 4H), 3.89
(t, 1H, J ) 8.40 Hz), 3.70 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 169.2, 169.1, 138.6, 137.7, 137.4, 130.7, 129.9, 129.8, 128.7,
128.6, 128.4, 128.2, 128.1, 127.1, 124.7, 123.3, 123.2, 122.1,
121.7, 120.1, 118.8, 116.9, 116.5, 86.3, 85.0, 80.1, 79.3, 76.2,
11-dechlororebeccamycin as a yellow solid. [R]20 +128.1° (c,
D
1.01, THF); 1H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H),
11.24 (s, 1H), 9.26 (d, 1H, J ) 8.0 Hz), 9.11 (d, 1H, J ) 8.0
Hz), 7.76 (d, 1H, J ) 8.0 Hz), 7.63 (m, 2H), 7.41 (t, 2H, J )
6.9 Hz, J ) 8.0 Hz), 6.91 (d, 1H, J ) 8.8 Hz), 6.29 (bs, 1H),
5.24 (d, 1H, J ) 6.2 Hz), 4.90 (d, 1H, J ) 5.4 Hz), 4.01 (bs,
2H), 3.91 (d, 1H, J ) 9.9 Hz), 3.68 (t, 1H, J ) 9.1 Hz, J ) 9.5
Hz), 3.62 (s, 3H), 3.53 (m, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 170.7, 170.6, 140.6, 138.1, 130.4, 129.9, 129.4, 127.3,
125.5, 124.6, 123.8, 122.7, 122.3, 121.1, 120.6, 119.4, 119.1,
117.3, 116.4, 112.1, 83.8, 77.5, 77.0, 76.5, 72.0, 60.0, 58.6; IR
(CHCl3) 3317, 1747, 1703 cm-1. HRMS (EI) exact mass calcd
for C27H22N3O7Cl M+ 536.1225, found 536.1230.
73.7, 73.3, 68.4, 61.47; IR (CHCl3) 3439, 3339, 1755, 1707 cm-1
.
HRMS (EI) exact mass calcd for C41H33N3O7Cl2 M+ 750.1774,
found 750.1765.
1-C h lo r o -12,13-d ih y d r o -12-[4-O -m e t h y l-3,6-b is -O -
(p h en ylm et h yl)-â-D-glu cop yr a n osyl]-5-H-in d olo-[2,3-a ]-
p yr r olo[3,4-c]ca r ba zole-5,7(6H)-d ion e (29). A mixture of
8 (200 mg, 0.28 mmol) and Pd(OTf)2 (280 mg, 0.83 mmol) in
DMF (10 mL) was heated at 90 °C for 2 h under N2. The
reaction was then cooled, diluted with EtOAc (25 mL), and
J O982277B